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Superpage Topics
Abemaciclib (pending)
Acinic cell carcinoma
Acute mastitis / abscess
Adenoid cystic
Adenoid cystic-solid
Adenomyoepithelial adenosis
Adenomyoepithelioma & malignant adenomyoepithelioma
Adenosis
Amastia / aplasia / hypoplasia / athelia
Amastia / aplasia / hypoplasia / athelia
Amyloid
Anatomy
Angiosarcoma
Antibody drug conjugate therapy (pending)
Apocrine
Apocrine adenoma
Apocrine adenosis / atypical apocrine adenosis
Apocrine metaplasia
Atezolizumab
Atypical ductal hyperplasia
Atypical lobular hyperplasia
Atypical vascular proliferation
Axillary lymph nodes
Benign breast implant related changes
Biopsy marking devices
BRCA associated carcinoma
Breast implant associated anaplastic large cell lymphoma
Classic
Collagenous spherulosis
Columnar cell change / hyperplasia
Core biopsy
Cribriform
Cystic hypersecretory carcinoma
Cystic hypersecretory hyperplasia
Cystic neutrophilic granulomatous mastitis
Cytology
DCIS
Duct ectasia
Ductal adenoma
Encapsulated papillary carcinoma
Fat necrosis
Fibroadenoma
Fibroadenomatoid change
Fibroadenomatoid change
Fibromatosis
Fibromatosis-like
Flat epithelial atypia
Foreign body reaction
Frozen section procedure
Frozen sections
Galactocele
Granular cell tumor
Grossing & features to report
Gynecomastia
Hamartoma
Hemangioma
HER2 low breast cancer
Histologic grading
Histology
Hormonal therapy
Hormone receptors
Idiopathic granulomatous mastitis
Inflammatory
Intraductal papilloma
Invasive breast cancer of no special type (NST)
Juvenile papillomatosis
Ki67 breast
Lactating adenoma
LCIS florid
LCIS pleomorphic
Leiomyoma
Lobular carcinoma in situ (LCIS) classic
Low grade adenosquamous
Lymphocytic / diabetic mastitis
Lymphoma
Male invasive
Medullary
Metaplastic
Metastases
Microcalcifications
Microcalcifications
Microcysts
Microglandular adenosis
Microinvasive
Micropapillary
Mixed NST
Molecular subtypes
Mucinous
Mucinous cystadenocarcinoma
Mucocele-like lesion
Mucoepidermoid
Multigene products
Myoepithelioma and myoepithelial carcinoma
Myofibroblastoma
Neoadjuvant chemotherapy
Neuroendocrine carcinoma (NEC)
Neuroendocrine tumor
Nipple adenoma
Nonproliferative fibrocystic changes
NST, rare variants
Other sarcomas
Paget disease
Papillary
Pertuzumab
Phyllodes tumor
Pleomorphic adenoma
Pleomorphic lobular carcinoma
Polymorphous
Pseudoangiomatous stromal hyperplasia
Pubertal macromastia
Radial scar / complex sclerosing lesion
Radiation therapy & cryoprobe
Sclerosing adenosis
Secretory
Secretory change
Sentinel lymph nodes
Silicone leak / lymphadenopathy
SMOLD
Solid papillary carcinoma
Sparganosis
Spread and metastases
Squamous cell carcinoma
Staging
Subareolar sclerosing duct hyperplasia
Supernumerary / accessory tissue
Syringomatous tumor
Tall cell carcinoma with reverse polarity
Transgender breast pathology
Trastuzumab
Triple negative breast cancer
Tuberculosis
Tubular
Tubular adenoma
Tubulolobular carcinoma
Usual ductal hyperplasia
WHO classification
Yokohama system, malignantAbemaciclib (pending)
[Pending]
Acinic cell carcinoma
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Negative stains | Electron microscopy description | Electron microscopy images | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2 | Board review style question #3 | Board review style answer #3Definition / general
- Acinic cell carcinoma is a malignant epithelial neoplasm characterized by clear and granular cells that may contain zymogen granules in the cytoplasm and shows microglandular and solid growth patterns
Essential features
- Granular eosinophilic and basophilic cytoplasm with intracytoplasmic granules that are positive for periodic acid-Schiff with diastase (PASD)
- Infiltrative microglandular and solid growth patterns
- Positive immunohistochemical staining for EMA and markers of serous acinar differentiation
Terminology
- Acinar cell carcinoma
ICD coding
Epidemiology
- Rare carcinoma of the breast affecting females (20 - 80 years old); 1 case has been reported in a male, 68 cases reported in the literature (2022) (Breast Cancer 1998;5:77, Breast 2022;66:208)
Sites
- Breast, with no site predilection (Pathology 2017;49:215)
Pathophysiology
- Breast glands may show acinic differentiation that could possibly give rise to acinic cell carcinoma (Histopathology 2009;54:262)
- Acinic cell carcinoma shows similar mutations and DNA copy numbers to conventional triple negative breast carcinomas or those associated with microglandular adenosis (J Pathol 2015;237:166, Mod Pathol 2017;30:69)
- Morphologic and genetic relationship with microglandular adenosis has been reported and discussed (Mod Pathol 2017;30:1504, Mod Pathol 2017;30:1505)
- Breast acinic cell carcinomas have different mutation profiles from salivary gland acinic cell carcinomas, suggesting the entities are unrelated (Histopathology 2015;67:529)
Etiology
- Unknown
Clinical features
- Presentation is similar to invasive breast carcinoma of no special type, palpable mass (Pathology 2017;49:215)
Diagnosis
- Histologic and immunohistochemical examination of lesional tissue (Pathology 2017;49:215)
Radiology description
- Poorly defined lump / mass with microcalcifications, although may vary in clinical and radiological appearance (Breast 2022;66:208)
Radiology images
Contributed by Miralem Mrkonjic, M.D., Ph.D.
Left breast mass with nonmass enhancement
Images hosted on other servers:
Doppler ultrasound, molybdenum target
MRI and PET / CT
Prognostic factors
- Knowledge about prognosis is limited, thought to be a triple negative tumor with intermediate aggressive potential
- Molecular evidence suggests that it could be the precursor of more aggressive forms of triple negative breast carcinoma (J Pathol 2015;237:166)
- Axillary lymph node metastases are rare, reported in 11 of 68 reports (Breast 2022;66:208)
- Potential for distant metastases to liver, bone and lung (Histopathology 2004;45:645, J Clin Pathol 2002;55:545, Ann Diagn Pathol 2011;15:84)
- Peritoneal metastases have also been reported (Mol Clin Oncol 2022;16:43)
Case reports
- 26 year old woman diagnosed with acinic cell carcinoma of the breast within a fibroadenoma (Int J Surg 2014;12:S232)
- 41 year old woman with palpable right breast lump (Ann Med Surg (Lond) 2018;35:137)
- 44 year old woman diagnosed with acinic cell carcinoma of the breast and carrying a BRCA1 mutation (BMC Cancer 2013;13:46)
- 52 year old woman with palpable lump in the outer quadrant of her right breast (Medicine (Baltimore) 2017;96:e8866)
- 59 year old woman with a lump in her right breast (Mol Clin Oncol 2022;16:43)
Treatment
- Breast conserving surgery or mastectomy, generally with sentinel lymph node excision or axillary lymph node dissection; with or without neoadjuvant or adjuvant chemotherapy and radiotherapy, hormonal therapy (if ER positive) (Breast 2022;66:208)
Gross description
- Poorly defined, gray-brown, rubbery, slightly lobulated appearance (J Breast Cancer 2011;14:160)
Gross images
Images hosted on other servers:
Ill defined, slightly lobulated mass
Gray-brown rubbery tumor
Microscopic (histologic) description
- Cells with serous differentiation containing zymogen granules in the cytoplasm that stain with PASD
- Predominantly solid or microglandular growth but may be cystic, trabecular or show other growth patterns (Breast 2022;66:208)
Microscopic (histologic) images
Contributed by Miralem Mrkonjic, M.D., Ph.D.
Infiltrative growth pattern
Microglandular architecture
Microglandular architecture and eosinophilic cytoplasm
Areas resembling
invasive ductal
carcinoma of no
special type
Prominent cytoplasmic eosinophilic granules
Background of extensive MGA and AMGA
MGA in the adipose tissue
Nuclear atypia in MGA
Absence of staining around invasive carcinoma
Invasive carcinoma is negative for ER
Invasive carcinoma is negative for HER2
Invasive carcinoma is positive for S100
Invasive carcinoma is positive for lysozyme
PASD cytoplasmic staining
Cytology description
- Fine needle aspiration: hypercellular, atypical cells in sheets, round to oval nuclei, single nucleoli, mild pleomorphism in size, moderately increased N:C ratio, intercellular cystic spaces, acinic pattern, cytoplasmic vacuoles and granules visible on Papanicolaou and Giemsa stains (Cytopathology 2013;24:403)
Positive stains
- PASD
- EMA (100% positive, 29/29 cases)
- S100 (93% positive, 50/54 cases)
- Lysozyme (95% positive, 39/41 cases)
- Alpha-1-antichymotrypsin / trypsin (96% positive, 25/26 cases)
- Amylase (94% positive, 17/18 cases)
- E-cadherin (100% positive, 7/7 cases)
- CK7 (100% positive, 9/9 cases)
- Ki67 (range 5 - 30% most commonly reported)
- GCDFP-15 (56% positive, 14/25 cases)
- Reference: Breast 2022;66:208
Negative stains
Electron microscopy description
- Cells with vacuolated cytoplasm containing many electron dense granules of varying size and a prominent rough endoplasmic reticulum (RER) (J Breast Cancer 2011;14:160)
Electron microscopy images
Images hosted on other servers:
Cytoplasmic electron dense granules
Dilation of RER
Acinar cell granules, prominent RER
Molecular / cytogenetics description
- No pathognomonic genomic alterations have been described
- Has a similar molecular profile to triple negative breast carcinoma and does not share the genomic rearrangement seen in salivary gland acinic cell carcinoma
- TP53 mutations are the most consistent molecular event (Breast 2022;66:208)
- PIK3CA and other mutations have been described in a subset of cases (Mod Pathol 2017;30:69)
- BRCA1 gene alterations have also been described (BMC Cancer 2013;13:46, Histol Histopathol 2023;38:91)
Sample pathology report
- Breast (right), lumpectomy:
- Acinic cell carcinoma (see comment)
- Comment: Sections show breast tissue involved by acinic cell carcinoma in solid nests and acini of polygonal cells with granular eosinophilic cytoplasm. These tumor cells display round, uniform nuclei with prominent nucleoli. Periodic acid-Schiff with diastase (PASD) staining demonstrates the presence of zymogen-like granules in the cytoplasm, confirming the acinar differentiation characteristic of this tumor.
Differential diagnosis
- Lactational changes:
- Cytoplasmic vacuolization and secretory material
- Microglandular adenosis:
- Intact basal lamina
- Adenoid cystic carcinoma:
- Dual cell population showing positivity for myoepithelial markers like SMA
- Mucoepidermoid carcinoma:
- Presence of intracellular and extracellular mucin
- Mucicarmine positive
Board review style question #1
A premenopausal woman presents with a painless, palpable, slow growing mass in her left breast. Histological examination reveals cells with abundant eosinophilic and basophilic cytoplasm with large coarse PASD+ intracytoplasmic granules and centrally located nuclei with prominent nucleoli, showing an infiltrative microglandular growth pattern. What is the most likely diagnosis?
- Acinic cell carcinoma
- Angiolipoma
- Burkitt lymphoma
- Fibroadenoma
- Invasive lobular carcinoma
Board review style answer #1
A. Acinic cell carcinoma. These are the features of acinic cell carcinoma (see microscopic image).
Answer D is incorrect because fibroadenoma is a fibroepithelial lesion, which is not infiltrative and the epithelial component does not have diffuse acinar morphology.
Answer B is incorrect because angiolipoma is a mesenchymal neoplasm comprised of mature adipocytes and blood vessels.
Answer E is incorrect because invasive lobular carcinoma lacks cytoplasmic granules and microglandular growth pattern.
Answer C is incorrect because Burkitt lymphoma is a non-Hodgkin lymphoma growing in solid sheets with starry sky appearance.
Comment Here
Reference: Acinic cell carcinoma
Comment Here
Reference: Acinic cell carcinoma
Board review style question #2
Which immunostain expression would be the most helpful to support the suspected diagnosis?
- E-cadherin+
- HER2+ (3+)
- Lysozyme+
- Ki67 > 90%
- S100+
Board review style answer #2
C. Lysozyme+. Acinic cell carcinoma is positive for EMA and lysozyme.
Answer E is incorrect because S100 is positive in acinic cell carcinoma and angiolipoma, so it would not help in differentiating between these entities.
Answer D is incorrect because Burkitt lymphomas and not acinic cell carcinomas have a Ki67 index close to 100%.
Answer A is incorrect because E-cadherin positivity is not specific to acinic cell carcinoma.
Answer B is incorrect because acinic cell carcinomas are not HER2 amplified.
Comment Here
Reference: Acinic cell carcinoma
Comment Here
Reference: Acinic cell carcinoma
Board review style question #3
Which biomarker profile is typical of acinic cell carcinoma?
- ER+, PR+, HER2+
- ER+, PR+, HER2-
- ER+, PR-, HER2-
- ER-, PR-, HER2+
- ER-, PR-, HER2-
Board review style answer #3
E. ER-, PR-, HER2-. Acinic cell carcinomas are predominantly triple negative with rare cases showing weak ER positivity.
Answer C is incorrect because only rare cases of acinic cell carcinoma have been reported to have weak ER positivity. Answers A, B and D are incorrect because acinic cell carcinoma does not share luminal, HER2 amplified or triple positive biomarker profile.
Comment Here
Reference: Acinic cell carcinoma
Comment Here
Reference: Acinic cell carcinoma
Acute mastitis / abscess
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Positive stains | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2 | Board review style question #3 | Board review style answer #3Definition / general
- Infection or inflammation of breast tissue, usually bacterial, often seen in association with lactation
- If untreated, may form abscess and fistulous tracts
Essential features
- Infection or inflammation of breast tissue, usually bacterial, often seen in association with lactation
- If untreated, may form abscess and fistulous tracts
- Staphylococcus aureus most common organism
- Microscopic examination reveals a mixed dense inflammatory infiltrate, predominantly neutrophils, in breast tissue
Terminology
- Puerperal mastitis
ICD coding
- ICD-10:
- ICD-11:
Epidemiology
- Incidence in 2 - 33% of lactating women (Am J Epidemiol 2002;155:103, Med Microbiol Immunol 2018;207:83)
- 3% with mastitis have an abscess (BJOG 2004;111:1378)
- Risk factors: age (21 - 35 years old), mastitis with previous child, cracked or sore nipples, use of ointments, incorrect breastfeeding practices, peripartum antibiotic therapy (Med Microbiol Immunol 2018;207:83)
Sites
- Subareolar (nonpuerperal)
Pathophysiology
- Infection via the mammary duct system; typically occurs within 2 - 3 weeks after the start of lactation (Breastfeed Med 2014;9:239)
- Staphylococcus aureus is most common organism transmitted from skin or infant (Breastfeed Med 2014;9:239)
- Accumulation of inadequately drained milk in ducts and lobules creates a microenvironment that fosters bacterial growth (Hoda: Rosen’s Breast Pathology, 4th Edition, 2014)
- Infrequent complication is abscess formation (localized collection of purulent material)
- Milk samples show loss of bacterial diversity (J Hum Lact 2015;31:406)
- Subareolar or nonpuerperal abscesses most often a consequence of squamous metaplasia of lactiferous ducts (SMOLD) (J Pathol Transl Med 2015;49:279)
Etiology
- Associated with lactation and cracks in nipple
- Common scenarios: infrequent feeding, oversupply of milk, rapid weaning, illness in mother or child, clogged duct (J Hum Lact 1998;14:101)
- Also associated with eczema, nipple dermatoses and postreduction mammoplasty
- Bacteria often not isolated from culture
- Pregnancy related infections are usually due to Staphylococcus
- Usually unilateral, often methicillin resistant Staphylococcus aureus (MRSA) (Arch Surg 2007;142:881, Asian J Surg 2009;32:55)
- Also Staphylococcus epidermidis (BMC Microbiol 2009;9:82, J Hum Lact 2015;31:406)
- Streptococcus usually causes diffuse infections leading to scarring but is uncommon today (J Hum Lact 2020;890334420965147)
- Tuberculosis may occur in endemic areas (Med Princ Pract 2009;18:245, Int J Infect Dis 2019;87:135)
- Nonpregnancy related infections may be polymicrobial or associated with diabetes (Am J Med Sci 2009;338:123)
Clinical features
- Erythema, swelling, firmness, breast pain, fever, malaise, decreased milk outflow
- Abscess: well circumscribed fluctuant mass in addition to above features
- African Americans may have higher risk of abscess formation (World J Surg 2009;33:2582)
- Obesity (BMI > 30) and smoking risk factors for abscess (World J Surg 2009;33:2582)
- Zuska disease (periductal mastitis): clinical scenario of recurring subareolar abscesses and sinus formation (Am J Surg 1951;81:312)
- Fungal mastitis: rare
- Actinomycosis may develop in nipple and form a sinus tract
- Candida infection may interfere with breast feeding but Candida albicans is not present in milk ducts in women with clinical symptoms of ductal candidiasis (Breastfeed Med 2009;4:57)
Diagnosis
- Based on history and clinical findings
- Ultrasound preferred imagining modality (Radiol Bras 2020;53:405)
- Biopsy may be warranted for suspected abscess, atypical presentation, recurrent infection or treatment failure; Gram stain and culture (aerobic and anaerobic) with sensitivities to guide antibiotic selection (rarely needed)
- FNA can be used to drain (Am Fam Physician 2008;78:727)
Radiology description
- Ultrasound (preferred modality): abscess shows hypoechoic lesion of purulent material, well circumscribed, macrolobulated, irregular or ill defined with septa and thick echogenic rim (Radiographics 2011;31:1683, Radiographics 2007;27 Suppl 1:S101)
- Mammography of limited value due to nonspecific findings
Radiology images
Contributed by Kristen E. Muller, D.O.
Ultrasound hypoechoic process
Ultrasound irregular fluid collection
Prognostic factors
- Recurrent breast abscesses are more likely to be smokers and have mixed bacterial and anaerobic infections (World J Surg 2009;33:2582)
Case reports
- 16 year old girl with MRSA abscess and toxic shock syndrome (Oxf Med Case Reports 2019;2019:omz054)
- 21 year old lactating woman with Listeria breast abscess (Cureus 2017;9:e1006)
- 22 year old woman with endogenous endophthalmitis secondary to mastitis (Indian J Ophthalmol 2020;68:2595)
- 30 year old woman with Mycobacterium fortuitum abscess following breast nipple piercing (IDCases 2020;21:e00847)
- 31 year old woman with tubercular mastitis mimicking malignancy (Prague Med Rep 2020;121:267)
- 32 year old nonlactating woman with Neisseria gonorrhoeae mastitis and abscess (IDCases 2019;18:e00620)
- 36 year old woman with Histoplasma capsulatum causing granulomatous mastitis (Arch Pathol Lab Med 2006;130:e1)
- 39 year old woman with nonpuerperal breast abscess due to Prevotella bivia (Clin Case Rep 2020;8:1399)
- 48 year old woman with Salmonella enteritidis breast abscess (BMJ Case Rep 2018;2018:bcr2018226075)
- 52 year old man with Trichophyton rubrum causing bilateral male breast enlargement (Breast 2006;15:263)
- 55 year old diabetic woman with Fusarium (Indian J Med Microbiol 2005;23:198)
- Report of saline filled breast implants contaminated with Curvularia in 5 patients (J Infect Dis 2005;192:170)
- Immunosuppressed patient with breast nodule due to coccidiomycosis (Arch Pathol Lab Med 1991;115:1064)
- Cryptococcus in HIV+ patient (J Infect 2008;57:82)
- 2 cases of Histoplasma capsulatum causing granulomatous mastitis (Hum Pathol 1989;20:47)
- Young woman who had nipples pierced, presented with right breast pain, erythema and drainage (Case of the Month #515)
Treatment
- Symptomatic treatment: effective milk removal via breastfeeding, pumping or hand expressing to fully empty breasts, analgesia, warm compress (Am Fam Physician 2008;78:727)
- Kneading and dispersing manipulation for early stage disease (Zhong Xi Yi Jie He Xue Bao 2009;7:1130)
- Antibiotics targeting Staphylococcus species are mainstay of treatment, although effectiveness is debated (J Hum Lact 2008;24:311, Cochrane Database Syst Rev 2013:CD005458)
- Aspiration or incision and drainage; now considered last resort for abscess management (Radiographics 2011;31:1683, Expert Rev Anti Infect Ther 2014;12:753)
- Urokinase irrigation may be useful for large abscesses (J Ultrasound Med 2009;28:449)
- Ultrasound guided drainage (Radiology 2004;232:904, Br J Radiol 2005;78:186)
- Probiotics (Benef Microbes 2014;5:169, Appl Environ Microbiol 2008;74:4650, Clin Infect Dis 2010;50:1551)
Clinical images
Contributed by Ayesha Farooq, M.B.B.S. and Julie Jorns, M.D. (Case #515)
Nipple piercing related infection
Images hosted on other servers:
Mastitis and breast abscess
Lactational abscess
Gross description
- Excisions rare; specimens usually from incision and drainage procedures and typically received in fragments
Microscopic (histologic) description
- Mixed dense inflammatory infiltrate, predominantly neutrophils, in breast tissue
- May obscure underlying normal breast tissue
- Tissue necrosis may be present
- Gram stain for microorganisms may reveal bacterial forms (gram positive cocci) associated with neutrophilic infiltrate
- Granulation tissue and chronic inflammation with resolution
- Lymphocytes, giant cells and granulomas are not typical (J Pathol Transl Med 2015;49:279)
Microscopic (histologic) images
Contributed by Kristen E. Muller, D.O.
Acute mastitis and abscess
Lobular inflammation
Dense inflammatory infiltrate
Dense neutrophilic infiltrate
Contributed by Ayesha Farooq, M.B.B.S. and Julie Jorns, M.D. (Case #515)
Nipple piercing related infection
Virtual slides
Images hosted on other servers:
Breast abscess and necrosis
Cytology description
- Background of acute inflammation and necrotic debris (Cytopathology 1992;3:281)
Positive stains
- Gram stain may highlight Gram positive bacterial forms
Sample pathology report
- Right breast, core needle biopsy:
- Breast tissue with abundant acute inflammation and bacterial forms identified on Gram stain (see comment)
- Comment: The histologic findings are compatible with acute mastitis and abscess formation in the appropriate clinical context. Clinical correlation and correlation with microbiology studies (if performed) is recommended.
Differential diagnosis
- Squamous metaplasia of lactiferous ducts (SMOLD):
- Subareolar location
- Lactiferous ducts with squamous metaplasia
- Multinucleated giant cells associated with keratin debris
- Strong association with smoking
- Fat necrosis:
- Infarcted adipocytes, lipid laden macrophages, foreign body giant cell reaction
- Initially acute inflammatory infiltrate may be present, chronic inflammation predominates in older lesions
- History of surgery, prior biopsy, radiation, trauma
- Idiopathic granulomatous mastitis:
- Granulomatous inflammation (lymphocytes, plasma cells, histiocytes, multinucleated giant cells)
- Lobulocentric pattern, may obliterate lobules
- May have neutrophils forming microabscesses surrounding empty microcysts; features overlap with cystic neutrophilic granulomatous mastitis, which may have gram positive bacilli within microcysts (Corynebacterium)
- Duct ectasia:
- Foamy histiocytes within lumen and within wall and epithelium of ducts, periductal fibrosis
- Inflammatory cells typically chronic; acute inflammatory infiltrate rarely present
Additional references
Board review style question #1
What is the most appropriate diagnosis for this breast biopsy from a 32 year old postpartum woman?
- Acute mastitis
- Duct ectasia
- Fat necrosis
- Idiopathic granulomatous mastitis
- Invasive lobular carcinoma
Board review style answer #1
Board review style question #2
Which of the follow is true regarding acute mastitis?
- Abscess may form as a complication if left untreated
- Acute mastitis typically occurs in postmenopausal women
- Granulomas are common
- Most common organism isolated is Streptococcus species
Board review style answer #2
A. Abscess may form as a complication if left untreated
Comment Here
Reference: Acute mastitis / abscess
Comment Here
Reference: Acute mastitis / abscess
Board review style question #3
What is a common causative microorganism associated with nipple piercing related infection?
- Salmonella
- Shigella
- Staphylococcus
- Stenotrophomonas
Board review style answer #3
Adenoid cystic
Table of Contents
Definition / general | Essential features | ICD coding | Epidemiology | Diagnosis | Radiology images | Prognostic factors | Case reports | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Positive stains | Negative stains | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Histologically similar to salivary gland counterpart
- Triple negative and basal-like subtype of mammary carcinoma with excellent long term survival
Essential features
- Rare subtype of breast cancer, histomorphologically identical to salivary gland counterpart
- Comprised of epithelial and myoepithelial cells arranged in solid, cribriform or tubular arrangements and associated basement membrane material
- Associated with MYB::NFIB fusion
ICD coding
- ICD-10: C50.91 - malignant neoplasm of breast of unspecified site, female
Epidemiology
- Rare, 0.1% of breast carcinomas (Am J Surg 2002;183:646)
- Mean age: 64 years; range: 25 - 80 years (Breast Cancer Res 2010;12:R54)
- May be associated with microglandular adenosis (Am J Surg Pathol 2003;27:1052)
Diagnosis
- Mammogram or other imaging detects a mass
- Diagnosis made by tissue biopsy or resection, often utilizing immunohistochemistry
Radiology images
Contributed by Mark R. Wick, M.D.
Mammogram
Images hosted on other servers:
MRI
Prognostic factors
- Low rates of recurrence and better long term outcome compared with ductal NOS type (Breast 2012;21:124, Breast Cancer Res Treat 2004;87:225, Breast Cancer Res 2010;12:R54, J Clin Pathol 2010;63:220)
- High rates of margin positivity (Am J Clin Oncol 2010;33:28)
- Axillary nodal metastases are rare, more frequently seen in the solid variant (Am J Surg Pathol 2002;26:413)
- Treatment is excision with clear margins and possibly radiation; axillary dissection may not be necessary (J Surg Oncol 2010;102:342, Breast 2017;31:214)
Case reports
- 21 year old man with left nipple swelling (Breast J 2020;26:502)
- 56 year old woman with a breast mass (Case Rep Oncol 2019;12:698)
- 63 year old woman with a breast mass (J Surg Case Rep 2019;2019:rjy355)
- 65 year old woman with a breast mass, metastases to lung, kidney and brain (J Med Case Rep 2017;11:303)
- 69 year old woman with a breast mass (Ann Med Surg (Lond) 2019;43:1)
- 71 year old woman with a breast mass (Int J Surg Case Rep 2018;42:196)
- 85 year old woman with a breast mass (J Med Invest 2018;65:289)
Gross description
- 1 - 3 cm, well circumscribed, firm
- May have cystic cut surface
- Reference: Pathology 2017;49:215
Microscopic (histologic) description
- Dual population of cells (Arch Pathol Lab Med 1986;110:1045):
- Luminal / ductal epithelial cells with variable glandular / squamous / sebaceous differentiation
- Myoepithelial / basaloid cells
- Cribriform, solid, tubular or trabecular architectural patterns
- 2 types of lumens that are lined by 2 cell types
- True glandular lumina lined by luminal / ductal epithelial cells (low molecular weight cytokeratin+, CK7+)
- Pseudolumens containing eosinophilic cylinders comprised of basement membrane material (laminin and collagen IV positive) lined by myoepithelial / basal type cells (p63 / p40+, smooth muscle myosin+, calponin+, high molecular weight cytokeratin+, S100+)
- Histologic variants
- Classic variant: most frequent variant, low to intermediate nuclear grade, composed of mixture of 3 different architectural patterns (tubular, cribriform and solid) (Diagn Histopathol 2022;28:142)
- Solid - basaloid variant: solid nests, increased mitotic rate, presence of necrosis, Ki67 > 30%, prominent basaloid features with more aggressive clinical course (Am J Surg Pathol 2002;26:413, APMIS 1999;107:762, BMJ Case Rep 2011;2011:bcr0820114692, Int J Surg Pathol 2016;24:97)
- Adenoid cystic carcinoma with high grade transformation: associated with different higher grade component subtypes such as invasive breast cancer of NST type (Int J Surg Pathol 2011;19:230)
Microscopic (histologic) images
Contributed by Gary Tozbikian, M.D.
Extensive cribriform architecture, infiltrative growth pattern
Dual population of basaloid and epithelioid cells
Estrogen receptor
p40
CD117 / KIT
Cytology description
- Clusters of epithelial cells oriented around solid spheres of basement membrane material
Cytology images
Contributed by Mark R. Wick, M.D.
FNAB
Images hosted on other servers:
Papanicolaou
Monomorphic tumor cells around mucoid material
Positive stains
- Luminal / ductal epithelial cells
- Basaloid / myoepithelial type cells
- Secretions in true lumina
- PAS+ diastase resistant
- Cribriform spaces
- Pseudolumen secretions
- Laminin
- Collagen IV
Negative stains
Molecular / cytogenetics description
- MYB::NFIB fusion gene (t(6;9)(q22-23;p23-24)) identified in the majority adenoid cystic carcinomas of breast, as well as in solid variant (J Pathol 2012;226:84, Proc Natl Acad Sci U S A 2009;106:18740, Hum Pathol 2014;45:2270)
- Molecular profiling of adenoid cystic carcinomas assign them to the basal-like subtype but have lower genetic instability and copy number aberrations compared with metaplastic, medullary and basal-like no special type (NST) tumors (Breast Cancer Res Treat 2013;142:257, Histopathology 2013;62:543, J Pathol 2008;216:141)
- Solid - basaloid variant: NOTCH and CREBB mutations (Mod Pathol 2020;33:1041)
Sample pathology report
- Left breast, mass 10:00, ultrasound guided core needle biopsy:
- Adenoid cystic carcinoma, 1.2 cm in greatest length (see comment)
- Estrogen receptor: negative (0%, no intensity)
- Progesterone receptor: negative (0%, no intensity)
- HER2: negative (score 0)
- Comment: Additional immunohistochemical stains show that the tumor is positive for CD117, MYB and p40 (in basaloid cells), supporting the diagnosis.
Differential diagnosis
- Collagenous spherulosis:
- Noninfiltrative proliferation of myoepithelial cells enclosing basement membrane material confined within preexisting ducts / lobules and lacking epithelial cell component
- Lacks dual cell population
- Calponin+, smooth muscle myosin heavy chain / SMMHC+, CD117 / KIT- (Mod Pathol 2006;19:1351)
- Invasive cribriform carcinoma:
- Infiltrative glands lack circumscription by myoepithelial cells (myoepithelial cells limited to periphery of ducts involved by ductal carcinoma in situ component)
- Lacks dual cell population
- Estrogen receptor+, progesterone receptor+, CD117 / KIT-
Additional references
Board review style question #1
A 55 year old woman undergoes an excision for a 3 cm breast mass (histologic image of the tumor is shown above). Which statement is true regarding this tumor?
- CD117 / KIT expression is present in the luminal / ductal epithelial cell component
- Frequently shows regional lymph node metastases
- Recurrent t(12;15)(p13;q25) translocation resulting in ETV6::NTRK3 gene fusion is commonly seen
- Represents ~5% of all mammary cancers
- Triple negative for ER / PR / HER2 and has an aggressive clinical course
Board review style answer #1
A. CD117 / KIT expression is present in the luminal / ductal epithelial cell component. The excision shows an adenoid cystic carcinoma, which is a rare subtype of mammary carcinoma representing < 1% of breast cancers. Despite triple negative status, these tumors generally show excellent long term survival. Similar to the salivary gland counterparts, adenoid cystic carcinomas of the breast are characterized by t(6;9)(q22-23;p23-24) translocation resulting in a MYB::NFIB fusion gene. The t(12;15)(p13;q25) translocation resulting in ETV6::NTRK3 gene fusion (answer C) is seen in secretory carcinoma of the breast. Consistent CD117 / KIT protein expression is observed in most adenoid cystic carcinomas of the breast; however, underlying KIT gene alterations have not been identified (Histopathology 2013;62:543).
Comment Here
Reference: Adenoid cystic carcinoma
Comment Here
Reference: Adenoid cystic carcinoma
Board review style question #2
Which immunohistochemical stain finding is typically observed in adenoid cystic carcinoma of the breast?
- CD117 / KIT negative, estrogen receptor negative
- CD117 / KIT positive, estrogen receptor positive
- CD117 / KIT positive, HER2 positive
- MYB positive, estrogen receptor negative
- MYB positive, HER2 positive
Board review style answer #2
D. MYB positive, estrogen receptor negative. Adenoid cystic carcinoma of the breast is a biphasic tumor comprised of a ductal / epithelial cell and myoepithelial / basaloid cell components. The ductal / epithelial cells are immunoreactive for low molecular weight keratins such as CK7 and CK8/18. The myoepithelial / basaloid cell component is positive for high molecular weight keratins (CK5/6, CK14, CK17) and myoepithelial markers (p40 / p63, SMMS, calponin). Additionally, mammary adenoid cystic carcinomas generally express CD117 / KIT and MYB, and are triple negative for estrogen receptor, progesterone receptor and HER2.
Comment Here
Reference: Adenoid cystic carcinoma
Comment Here
Reference: Adenoid cystic carcinoma
Adenoid cystic-solid
Table of Contents
Terminology | Clinical features | Case reports | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Negative stains | Differential diagnosisTerminology
- Also called basaloid type
Clinical features
- Axillary nodal metastases in 2 of 6 cases (Am J Surg Pathol 2002;26:413)
- May have poorer prognosis than classic type (APMIS 1999;107:762)
Case reports
- Solid variant of mammary "adenoid cystic carcinoma with basaloid features" merging with "small cell carcinoma" (Pathol Res Pract 2005;201:705)
Gross description
- Solitary mass, mean 4 cm
Gross images
Contributed by Dr. Semir Vranic
Microscopic (histologic) description
- Basaloid cells with moderate to marked nuclear atypia, often with 5+ mitotic figures / 10 HPF
Microscopic (histologic) images
Scroll to see all images.
AFIP images
Contributed by Dr. Hind Nassar, Johns Hopkins Medical Center, Maryland (USA):
Contributed by Dr. Semir Vranic, University of Sarajevo, Bosnia and Herzegovina:
AFIP images
Solid pattern with
inconspicuous
cylindromatous
elements at arrows
Contributed by Dr. Hind Nassar, Johns Hopkins Medical Center, Maryland (USA):
Various images
p63
Actin
Contributed by Dr. Semir Vranic, University of Sarajevo, Bosnia and Herzegovina:
Core biopsy
Low power
Low power
Medium power
High power
High power
Differential diagnosis
- Cylindroma: no atypia, no mitotic figures, no infiltration, no mucin (Am J Clin Pathol 2005;123:866)
Adenomyoepithelial adenosis
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1Definition / general
- Uncommon variant of adenosis with proliferation of epithelial and myoepithelial cells
Essential features
- Lobulocentric proliferation of both epithelial and myoepithelial components
- Prominent myoepithelial cells, 1 - 3 layers
Terminology
- Tubular variant of adenomyoepithelioma (Schnitt: Biopsy Interpretation of the Breast, 3rd Edition, 2017)
ICD coding
Epidemiology
- No known associations
- Wide age range but most frequent in third to fourth decades (WHO Classification of Tumours Editorial Board: Breast Tumours, 5th Edition, 2019)
Sites
- Lobulocentric but otherwise no specific location within the breast
Pathophysiology
- Unknown
Etiology
- Unknown
Clinical features
- May present with a palpable mass
- May be a precursor to benign adenomyoepithelioma, malignant adenomyoepithelioma or invasive duct carcinoma (Am J Clin Pathol 1988;89:308, Virchows Arch A Pathol Anat Histopathol 1984;405:55, Springerplus 2013;2:50)
Diagnosis
- Histologic examination of tissue with or without immunohistochemistry
Radiology description
- No specific features
- May show asymmetry, architectural distortion or mass with irregular margins, with or without microcalcifications
Radiology images
Images hosted on other servers:
Left breast
Hypoechoic mass
Irregular spiculated dense mass
Spiculated hypoechoic mass
Prognostic factors
- Unknown but progression to malignancy may be associated with older age (> 50 years) and mass on imaging (Springerplus 2013;2:50)
Case reports
- 17 year old girl with a palpable lump (Turk Patoloji Derg 2017;33:240)
- 35 year old woman with adenomyoepithelial adenosis associated with breast cancer (Springerplus 2013;2:50)
- 46 year old woman with a palpable mass (Breast Care (Basel) 2008;3:427)
- Malignant progression of adenomyoepithelial adenosis of breast (Pathol Int 1994;44:475)
Treatment
- Excision recommended due to possibility of recurrence and association with malignancy
- Best predictors of recurrence are initial incomplete excision and close margins
Gross description
- May form a firm mass with circumscribed or ill defined borders or may be grossly indistinguishable from surrounding fibrotic breast tissue
Microscopic (histologic) description
- Multiple foci of haphazardly arranged ducts with eosinophilic granular secretions
- Lined by cuboidal to columnar cells surrounded by hyperplastic myoepithelial cells
- Resembles microglandular adenosis but with larger and more irregularly shaped glands, taller lining epithelial cells with eosinophilic granular cytoplasm and bland basal nuclei
- May show apocrine or squamous metaplasia (Breast Care (Basel) 2008;3:427)
- May have mild nuclear atypia
- Rare to no mitotic activity
Microscopic (histologic) images
Contributed by Julie M. Jorns, M.D. and Kristen E. Muller, D.O.
Adenomyoepithelial adenosis
Adenomyoepithelial adenosis
p63
Calponin
Positive stains
- Myoepithelial cells are positive for p63, CK5/6, S100, alpha smooth muscle actin
Sample pathology report
- Right breast, core biopsy:
- Benign breast tissue with adenomyoepithelial adenosis
Differential diagnosis
- Cannot be distinguished from a microscopic adenomyoepithelioma
Board review style question #1
- The breast lesion pictured (H&E and p63 IHC, 20x) is most difficult to distinguish from which of the following lesions on core biopsy?
- Adenomyoepithelioma
- Invasive ductal carcinoma
- Microglandular adenosis
- Phyllodes tumor
Board review style answer #1
A. Adenomyoepithelioma.
The pictured lesion is adenomyoepithelial adenosis, an uncommon variant of adenosis with a prominent myoepithelial component. This benign lesion may be difficult to distinguish from adenomyoepithelioma, which forms a circumscribed tumor but has similar microscopic features. Adenomyoepithelial adenosis, like other adenosis variants, may have similar features to microglandular adenosis or low grade invasive ductal carcinoma; however, these lesions lack myoepithelium, which is readily evident in adenomyoepithelial adenosis. Phyllodes tumor is a fibroepithelial neoplasm with dissimilar features, namely stromal proliferation with a resulting leaf-like growth pattern.
Comment Here
Reference: Adenomyoepithelial adenosis
Comment Here
Reference: Adenomyoepithelial adenosis
Adenomyoepithelioma & malignant adenomyoepithelioma
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Positive stains | Negative stains | Electron microscopy description | Molecular / cytogenetics description | Molecular / cytogenetics images | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1Definition / general
- Biphasic tumor composed of variable number of myoepithelial cells surrounding epithelial lined spaces
- Usually expanded and prominent myoepithelial component
- First recognized in the breast by Hamperl (Curr Top Pathol 1970;53:161)
Essential features
- Biphasic tumor with epithelial and myoepithelial components
- Benign to low grade malignant behavior and a propensity for recurrence
- Either epithelial or myoepithelial component can show malignant transformation so thorough evaluation recommended
- Wide surgical excision with appropriate margins recommended to prevent recurrence
- Microscopy shows tubular or lobulated structures with epithelial and myoepithelial components
- Epithelial component: cytokeratin+, EMA+, CEA+; myoepithelial component: S100+, SMA+, SMMHC+, p63+
Terminology
- WHO (2019) divides adenomyoepithelioma into benign and malignant tumors
- Malignant adenomyoepithelioma = adenomyoepithelioma with carcinoma, which can arise in epithelial or myoepithelial component or in both components (J Clin Pathol 2013;66:465)
ICD coding
- Adenomyoepithelioma
- ICD-O: 8983/0 adenomyoepithelioma
- ICD-11: 2F30.Y & XH2V57 - other specified benign neoplasm of breast and adenomyoepithelioma, benign
- Malignant adenomyoepitheliomas
- ICD-O: 8562/3 epithelial-myoepithelial carcinoma
- ICD-11: 2C6Y & XH7TL5 - malignant neoplasms of breast and adenomyoepithelioma with carcinoma
Epidemiology
- Uncommon, median age 67 years (Breast J 2020;26:653)
- F > M
Sites
- Usually occurs in the peripheral portion of the breast but can be central or areolar region (Hum Pathol 1987;18:1232)
- No predilection for either breast
- Malignant adenomyoepitheliomas can be seen in any location (Histopathology 2020;77:181)
Clinical features
- Usually presents as a solitary palpable mass or screen detected on breast imaging
- Most are benign, although may recur locally; malignant transformation can occur (Hum Pathol 1987;18:1232, Am J Surg Pathol 1992;16:868, Arch Pathol Lab Med 2006;130:1349)
- Associated carcinomas may be low or high grade and may metastasize to lung, brain or liver (Virchows Arch 1995;427:243, Vestn Ross Akad Med Nauk 1992:46, Virchows Arch 2003;442:504, J Cardiothorac Surg 2016;11:121, Arch Pathol Lab Med 2000;124:632)
Diagnosis
- Well circumscribed mass, infrequently associated with tenderness and nipple discharge
- Diagnosis on core biopsy specimen can be challenging
- Presence of tightly aggregated glands arranged in compact nodules and prominent clear cell or spindle cell myoepithelium are clues to the diagnosis (Breast J 2004;10:522)
- Immunohistochemical stains for myoepithelial markers are useful to highlight the myoepithelial component (Breast J 2004;10:522)
- Excision is necessary for thorough evaluation of atypia or carcinoma arising in an adenomyoepithelioma
Radiology description
- Ultrasound: irregular / angulated or oval / circumscribed, hypoechoic mass (Korean J Radiol 2010;11:522, J Clin Ultrasound 2013;41:218)
- Mammography: oval, equal density mass (J Clin Ultrasound 2013;41:218, Breast 2016;29:132)
- Appears dense, mostly circumscribed, can have focally indistinct margins
- Calcifications and cystic change are not typical
- MRI: round, lobulate or oval masses with clear or shaded borders (Clin Radiol 2016;71:235)
- Malignant: irregular shapes with spiculate margins
Radiology images
Contributed by Melissa Krystel-Whittemore, M.D. and Mark R. Wick, M.D.
Mammogram, irregular mass
Ultrasound, hypoechoic mass
Mammogram
Prognostic factors
- Tubular type of adenomyoepithelioma, intraductal extension along periphery of lesion, incomplete excision and cytologic atypia are associated with local recurrence (Am J Surg Pathol 1991;15:554)
- High mitotic rate, atypia, necrosis, cellular pleomorphism and infiltrative borders favor malignancy (Am J Surg Pathol 1992;16:868)
- Malignant adenomyoepithelioma has prognosis dependent on histological subtype and grade of the malignant component
Case reports
- 28 year old woman and 42 year old woman with tubular variant of adenomyoepithelioma (Cytojournal 2017;14:29)
- 47 year old man with adenomyoepithelioma (Hum Pathol 1993;24:678)
- 47 year old woman with malignant adenomyoepithelioma (J Breast Cancer 2019;23:93)
- 53 year old woman with adenomyoepithelioma with associated lobular neoplasia (Ann Diagn Pathol 2015;19:20)
- 56 year old woman with adenomyoepithelioma and late pulmonary metastases (J Cardiothorac Surg 2016;11:121)
- 56 year old woman with intracystic adenomyoepithelioma (Breast Cancer 2007;14:429)
- 58 year old woman with adenomyoepithelioma with myoepithelial carcinoma (Clin Case Rep 2019;7:930)
Treatment
- Complete wide excision with negative margins is standard treatment to prevent local recurrence
- Mastectomy with or without axillary node dissection - only needed if malignant transformation
- Reference: AJR Am J Roentgenol 2003;180:799
Gross description
- Usually solitary nodule, median size: 2 cm, can be up to 8 cm (Breast J 2020;26:653)
- Recurrent tumors usually larger
- Sectioning reveals well circumscribed, firm, pink-white to gray-tan lesion
- Can have focal cystic changes or necrosis
- Malignant adenomyoepithelioma can show infiltrative borders (J Clin Pathol 2011;64:477)
Gross images
Contributed by Melissa Krystel-Whittemore, M.D., Case #418
Tan-gray mass
Malignant adenomyoepithelioma
Microscopic (histologic) description
- Well circumscribed, may be encapsulated or multinodular and lobulated
- Biphasic proliferation of epithelial and myoepithelial cells
- Epithelial cells usually form glandular spaces; can show apocrine, sebaceous or squamous metaplasia
- Can have papillary epithelial proliferation
- Myoepithelial cells usually dominant and may be polygonal shaped with clear cytoplasm or spindled
- Variants:
- Spindle cell: spindle myoepithelial cells proliferation, epithelial lined spaces may be sparse
- Tubular: proliferation of rounded tubules, ill defined margins
- Lobulated: nests of myoepithelial cells surround compressed epithelial lined spaces
- Malignant cases have infiltrative growth pattern, high mitotic rate or severe atypia which can be seen in the epithelial or myoepithelial component or in both components (Arch Pathol Lab Med 2000;124:632, Am J Surg Pathol 1992;16:868, Virchows Arch 1998;432:123)
- Malignant transformation of epithelial component can have features of invasive carcinoma no special type, invasive lobular carcinoma, metaplastic carcinoma, including squamous cell carcinoma, spindle cell carcinoma or matrix producing carcinoma, low grade adenosquamous carcinoma or adenoid cystic carcinoma (Breast 2016;29:132, Pathol Int 2009;59:179, Virchows Arch 1995;427:243, Pathol Res Pract 2007;203:599, Virchows Arch 1998;432:123, Am J Surg Pathol 1998;22:631, Breast J 2019;25:731, Diagn Pathol 2014;9:148)
- Malignant transformation of myoepithelial component shows features of myoepithelial carcinoma including overgrowth of myoepithelial cells, nuclear atypia and mitotic activity (Pathol Int 2006;56:211, Breast J 2007;13:203, J Clin Pathol 2011;64:477)
- Biphasic malignant tumors (of epithelial and myoepithelial components) can be seen, with myoepithelial cells being the predominant component (Breast J 2019;25:1273)
- Usually multilobulated or multinodular and can show a distinct transition from benign to malignant components
- Malignant changes must be seen in both epithelial and myoepithelial cell types, specifically including increased mitotic activity
- Malignant adenomyoepithelioma can be ER positive or negative but the carcinoma component is most commonly ER / PR / HER2 negative (Nat Commun 2018;9:1816)
Microscopic (histologic) images
Contributed by Hannah Y. Wen, M.D., Ph.D.
Circumscribed lobulated tumor
Myoepithelial cells surrounding glands
Compressed tubules
Hyaline-like basement membrane
Calponin
p63
Contributed by Fresia Pareja, M.D., Ph.D.
Malignant adenomyo-
epithelioma
Biphasic epithelial and myoepithelial proliferation
Nuclear atypia and mitoses
Fat invasion
Virtual slides
Images hosted on other servers:
Adenomyoepithelioma
Cytology description
- Moderate to highly cellular with large clusters of epithelium and myoepithelium
- Tubular structures occasionally found
- Myoepithelium appears as small clusters or dispersed cells with epithelioid morphology, intranuclear or intracytoplasmic vacuoles, often naked bipolar nuclei
- Mild to moderate nuclear atypia present
- Metachromatic fibrillary stroma occasionally found
- No mitotic figures, no necrosis
- Often classified incorrectly as fibroadenoma, suspicious for malignancy or malignant (Cancer 2006;108:250)
- Malignant adenomyoepithelioma is highly cellular with neoplastic appearing cells
- Metachromatic matrix material can be seen around nests of neoplastic cells (J Clin Pathol 2011;64:477)
Positive stains
- Epithelial component:
- Keratin (AE1 / AE3), CAM 5.2, CK7, EMA; variable ER
- Myoepithelial component:
Electron microscopy description
- Myoepithelial features (classic) include myofibrils with dense bodies, pinocytotic vesicles, desmosomes or tight junctions, patchy basement membrane
Molecular / cytogenetics description
- ER positive adenomyoepitheliomas: PIK3CA or AKT1 activating mutations (Nat Commun 2018;9:1816, Mod Pathol 2020;33:1764)
- ER negative adenomyoepitheliomas: Q61R HRAS hotspot mutations with concurrent PIK3CA or PIK3R1 mutations (Nat Commun 2018;9:1816)
- IHC analysis of RAS Q61R for detection of HRAS Q61R mutations has been shown to be a useful marker in ER negative adenomyoepitheliomas (Histopathology 2020;76:865)
- Case report with t(8;16)(p23;q21) (Cancer Genet Cytogenet 2005;156:14)
- Malignant adenomyoepithelioma displays similar mutational profile as that of benign (Nat Commun 2018;9:1816, Mod Pathol 2020;33:1764)
- Homozygous CDKN2A homozygous deletions, TERT promoter mutations or MYC amplifications may be associated with tumor progression (Nat Commun 2018;9:1816, J Breast Cancer 2019;23:93)
Molecular / cytogenetics images
Images hosted on other servers:
MYC amplification
Sample pathology report
- Breast, left, excision:
- Adenomyoepithelioma, 3.2 cm
- Surgical margins negative for tumor
Differential diagnosis
- Sclerosing adenosis:
- Proliferation of epithelial glands with stromal sclerosis, which can cause architectural distortion of the glands
- Less commonly mass forming
- No prominent myoepithelial component
- Intraductal papilloma:
- Papillary lesion comprised of epithelial proliferation with fibrovascular cores
- No prominent myoepithelial component
- Invasive carcinoma (on core biopsy):
- Nipple adenoma:
- Epithelial proliferation arising in the collecting ducts of the nipple
- No prominent myoepithelial component
- Tubular adenoma:
- Very well circumscribed
- Proliferation of tubules with only single layer of myoepithelial cells surrounding the epithelial component without expansion of myoepithelial component
Additional references
Board review style question #1
A 58 year old woman presents with a 2 cm nontender, firm nodule in the upper outer quadrant of her left breast. A core biopsy and subsequent resection of the lesion is performed. Representative microscopic images from the excision specimen are shown, which revealed an adenomyoepithelioma. Which of the following is true?
- Chemotherapy is the standard treatment of this lesion
- This lesion is usually HER2 positive and treated with anti-HER2 therapy
- This is a malignant lesion
- Without negative surgical margins, there is a risk of local recurrence of the lesion
Board review style answer #1
D. Without negative surgical margins, there is a risk of local recurrence of the lesion
Comment Here
Reference: Adenomyoepithelioma
Comment Here
Reference: Adenomyoepithelioma
Adenosis
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Clinical features | Diagnosis | Radiology description | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Positive stains | Videos | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Any hyperplastic process (see subtypes below) displaying increase in glands, typically within terminal duct lobular units
- Common, often accompanied by fibrocystic changes
Essential features
- Proliferation of glands, typically lobulocentric (expanding terminal duct lobular unit)
Terminology
- Simple adenosis
- Special subtypes:
- Adenomyoepithelial adenosis
- Apocrine adenosis
- Sclerosing adenosis
- Tubular adenosis (tubular adenoma)
- Nodular adenosis / adenosis tumor
- Blunt duct adenosis (now classified as columnar cell change)
ICD coding
Epidemiology
- Wide age range, highest in third and fourth decades, paralleling fibrocystic changes
- Premenopausal: lesions with predominant epithelial component (proliferation of acini and ducts); nodular adenosis
- Postmenopausal: lesions with more sclerosis (sclerosing adenosis)
Sites
- Terminal duct lobular unit; otherwise, no specific location within the breast
Clinical features
- Considered a part of the spectrum of fibrocystic changes
- Can present as a palpable mass if nodular adenosis / adenosis tumor
Diagnosis
- Histologic examination of tissue with or without immunohistochemistry
Radiology description
- Not visualized on imaging if focal (incidental finding when there is another indication for tissue evaluation)
- Increased mammographic breast density (Breast Cancer Res 2017;19:134)
- Architectural distortion, calcifications and asymmetry may prompt biopsy (Medicine (Baltimore) 2019;98:e17061)
- Mass can be seen with nodular adenosis / adenosis tumor; may mimic invasive carcinoma (Breast Cancer Res Treat 2020;181:127)
Prognostic factors
- With some subtypes (e.g. sclerosing adenosis), the risk of subsequent breast cancer is 1.5 - 2 times higher, as seen with proliferative fibrocystic changes
- 2 times higher risk of breast cancer with increased Ki67 proliferation index in sclerosing adenosis or associated normal background breast tissue (Breast Cancer Res Treat 2015;151:89)
Case reports
- 35 year old woman with heterogeneous echogenicity who underwent excisional biopsy revealing adenomyoepithelial adenosis (Int J Clin Exp Med 2014;7:1166)
- 51 year old woman with nodular adenosis detected an enhancing mass (Radiol Case Rep 2020;15:1211)
- 63 year old woman with adenosis tumor evaluated on cytology with surgical pathology correlation (Diagn Cytopathol 2008;36:496)
Treatment
- Does not require treatment unless there is cytologic atypia (rare)
Gross description
- Variable - may be indistinguishable from surrounding benign breast tissue, ill defined fibrosis or fibrotic mass with relatively well defined borders
- See separate adenosis topics for specific subtypes
Microscopic (histologic) description
- Simple adenosis: proliferation of acini, with 2 layers (inner epithelial and outer myoepithelial), surrounded by basement membrane, without distortion of lobular architecture
- Adenomyoepithelial adenosis: adenosis, with proliferation of glands (2 layers) with prominent myoepithelial cells
- Apocrine adenosis: adenosis, with proliferation of glands (2 layers) with predominant apocrine cytology
- Sclerosing adenosis: adenosis, with proliferation of glands (2 layers) with glandular compression and (mild to marked) distortion due to stromal fibrosis / sclerosis; entrapped secretions frequently become calcified
- Tubular adenosis: adenosis with haphazard proliferation of branching tubules (2 layers)
- Nodular adenosis / adenosis tumor: adenosis that is mass forming
- Cytologic atypia is uncommon
- See also separate topics for specific subtypes
Microscopic (histologic) images
Contributed by Julie M. Jorns, M.D.
Simple adenosis
Tubular adenosis
Nodular adenosis
Virtual slides
Images hosted on other servers:
Breast, adenosis
Breast, adenosis (myosin / smooth muscle stain)
Cytology description
- Cellular with small groups of benign epithelial cells with variable architecture, including sheets and individual cells and dense hyalinized stroma (Acta Cytol 2001;45:353)
Positive stains
Videos
What is adenosis?
Sample pathology report
- Left breast, core biopsy:
- Nodular adenosis with microcalcifications
Differential diagnosis
Additional references
Board review style question #1
A 48 year old woman had calcifications detected on a screening mammogram, which showed the pictured lesion. What should be done next?
- Biopsy adjacent breast tissue
- Excision of the lesion
- Mammography per routine screening
- Neoadjuvant chemotherapy
- Perform breast MRI
Board review style answer #1
C. Mammography per routine screening. The pictured lesion is sclerosing adenosis, which is a benign lobular proliferation with distortion of glands by fibrosis. Microcalcifications (as seen above as dark purple intraluminal material) are frequently seen in sclerosing adenosis and are a result of calcification of entrapped secretions, making this biopsy benign and concordant with imaging findings. Therefore, no treatment or additional imaging is needed outside of routine screening.
Comment Here
Reference: Breast adenosis
Comment Here
Reference: Breast adenosis
Board review style question #2
Which of the following is usually true regarding simple adenosis of the breast?
- Clinically palpable
- Displays cytologic atypia
- Involves terminal duct lobular units
- Lacks myoepithelium
- Requires immunohistochemistry for diagnosis
Board review style answer #2
C. Involves terminal duct lobular units. Simple adenosis of the breast is a proliferation of glands with normal 2 cell layer (inner epithelial and outer myoepithelial) configuration involving terminal duct lobular units. It rarely harbors atypia and does not show distortion by fibrosis as seen in other forms of adenosis (e.g. sclerosing, tubular), making diagnosis relatively easy via H&E staining alone. It is often incidental or may less frequently show distortion or calcifications on imaging. This contrasts with nodular adenosis / adenosis tumor, which is mass forming and may be clinically palpable.
Comment Here
Reference: Breast adenosis
Comment Here
Reference: Breast adenosis
Amastia / aplasia / hypoplasia / athelia
Table of Contents
Definition / general | Epidemiology | Sites | Etiology | Case reports | Treatment | Clinical imagesDefinition / general
- Amastia: no glandular tissue (no breast bud), no nipple and no areola
- Aplasia: nipple and areola present but no glandular tissue
- Athelia: very rare; breast glandular tissue but no nipple or areola (Wikipedia: Athelia (Disease)); also a genus of fungi
- Hypoplasia: small rudimentary breasts (i.e. breast underdevelopment); also called micromastia
Epidemiology
- Uncommon
- Occurs more often in females than males
Sites
- Unilateral or bilateral
Etiology
- Can be acquired or congenital
- Amastia occurs when breast anlage is destroyed in the embryo
- Amastia and hypoplasia are both associated with Poland syndrome (musculoskeletal deformities of chest wall and ipsilateral upper extremity, eMedicine: Poland Syndrome [Accessed 17 August 2018], OMIM: Poland Syndrome [Accessed 17 August 2018]); also damage to breast bud by surgery (Postgrad Med J 2003;79:235) or radiation (Acta Oncol 1989;28:519)
- Athelia:
- Associated with Poland syndrome (musculoskeletal deformities of chest wall and ipsilateral upper extremity, eMedicine: Poland Syndrome, OMIM: Poland Syndrome)
- Part of scalp ear nipple (Finlay-Marks) syndrome (Br J Dermatol 1978;99:423)
- Associated with carbimazole use for thyrotoxicosis during pregnancy (Am J Med Genet 1998;75:220)
- Associated with focal dermal hypoplasia (Clin Genet 2008;73:373)
- Ipsilateral breast hypoplasia is associated with Becker nevus (Indian J Dermatol Venereol Leprol 2009;75:202)
- Coexistence of skin and breast lesions (see case reports below) may be due to their common embryologic origin
Case reports
- Newborn girl with choanal atresia, renal tubulopathy and family history of neck cysts, who died shortly after birth (Am J Med Genet A 2007;143A:1231)
- 3 year old girl with bilateral athelia, congenital jejunal atresia and choanal atresia (Clin Dysmorphol 2006;15:37)
- 9 year old girl with multiple lentigines over nevus depigmentosus and hypoplasia of underlying breast (Dermatol Online J 2004;10:12)
- 26 year old woman with bilateral amastia and ectodermal dysplasia (Case Rep Med 2009;2009:927354)
Treatment
- Breast augmentation surgery (Semin Pediatr Surg 2008;17:161, Acta Chir Plast 2001;43:39)
Clinical images
Images hosted on other servers:
Amastia in 11 year old girl
Hypoplasia in 9 year old girl
(fig 1)
Becker nevus with hypoplasia
Hypoplasia of right breast
26 year old woman:
Preoperative of bilateral amastia
Amastia / aplasia / hypoplasia / athelia
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Diagrams / tables | Clinical features | Diagnosis | Laboratory | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Gross images | Frozen section description | Frozen section images | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Cytology images | Immunofluorescence description | Immunofluorescence images | Positive stains | Negative stains | Electron microscopy description | Electron microscopy images | Molecular / cytogenetics description | Molecular / cytogenetics images | Videos | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1Definition / general
- Amastia: complete absence of breast and nipple areola complex (NAC) (J Pediatr Endocrinol Metab 2003;16:471)
- Aplasia / hypoplasia: failure of breast growth despite presence of mammary gland (J Pediatr Endocrinol Metab 2003;16:471)
- Athelia: congenital absence of nipple areola complex (J Pediatr Endocrinol Metab 2003;16:471)
Essential features
- Congenital breast anomalies are rare; unilateral or bilateral
- Athelia and amastia are associated with Poland syndrome
- Amastia can be part of other syndromes, such as AREDYLD (acral renal ectodermal dysplasia lipoatrophic diabetes) syndrome
- Athelia can be congenital or acquired
- Breast reconstruction using transverse rectus abdominis muscle (TRAM) flap and nipple areola reconstruction is the treatment of choice
Terminology
- Polymastia: presence of > 2 breasts (J Pediatr Endocrinol Metab 2003;16:471)
- Polythelia: many nipples (J Pediatr Endocrinol Metab 2003;16:471)
ICD coding
Not applicable
Epidemiology
- All congenital breast anomalies are rare, athelia being the rarest (J Pediatr Endocrinol Metab 2003;16:471)
- Amastia: F > M (F:M = 5:1) (J Pediatr Endocrinol Metab 2003;16:471)
- Amastia can occur in young males (Neurol India 2019;67:1167)
- Polythelia: M:F = 1.7:1 (J Pediatr Endocrinol Metab 2003;16:471)
Sites
- Congenital anomalies can be unilateral or bilateral (unilateral amastia is associated with Poland syndrome) (J Pediatr Endocrinol Metab 2003;16:471)
Pathophysiology
Not applicable
Etiology
- Amastia occurs due to complete failure of mammary line development at 6 weeks in utero (J Pediatr Endocrinol Metab 2003;16:471)
- Unilateral amastia is frequently associated with the absence of the pectoralis major muscle (Poland sequence) (J Pediatr Endocrinol Metab 2003;16:471)
- Amastia can be part of other syndromes, such as AREDYLD syndrome (Indian J Pediatr 2013;80:870)
- Polymastia presents with 2 general patterns: supernumerary breast (SNB) and aberrant (accessory) mammary tissue (AMT) (J Pediatr Endocrinol Metab 2003;16:471)
- Unilateral mammary hypoplasia / aplasia has been reported in conjunction with Becker nevus and Poland sequence (J Pediatr Endocrinol Metab 2003;16:471)
- Unilateral hypoplasia can be associated with nevus depigmentosus (Dermatol Online J 2004;10:12)
- Breast hypoplasia is one of the reasons for insufficient milk supply (J Hum Lact 2021;37:242)
- Breast hypoplasia can occur after infantile hemangioma (J Eur Acad Dermatol Venereol 2017;31:e355)
- Athelia can be congenital or acquired; acquired due to trauma or ablation (Br J Plast Surg 2005;58:833)
- Athelia can occur due to failure in parathyroid hormone related protein production (Br J Plast Surg 2005;58:833)
- Athelia may be isolated or associated with other anomalies, such as dermoid cysts, pectus excavatum, choanal atresia posterior or renal tubular dysgenesis (J Pediatr Endocrinol Metab 2003;16:471)
- Unilateral athelia has been described in Poland sequence and bilateral athelia in ectodermal dysplasia (tricho-odonto-onychial type) and scalp ear nipple syndrome (J Pediatr Endocrinol Metab 2003;16:471)
Diagrams / tables
N/A
Clinical features
- Patients usually present with no breast development with or without nipple areola complex in pediatric or surgery outpatient department (OPD)
Diagnosis
- Ultrasound is the preferred method for diagnosis as compared to mammography (Korean J Radiol 2018;19:978)
Laboratory
Not applicable
Radiology description
Not applicable
Radiology images
Not applicable
Prognostic factors
Not applicable
Case reports
- 3 year old girl with a case of congenital jejunal atresia associated with bilateral athelia and choanal atresia (Clin Dysmorphol 2006;15:37)
- 3 year old girl presented with bilateral congenital amastia (Indian J Pediatr 2013;80:870)
- 14 year old boy with Poland syndrome with amastia and athelia (Neurol India 2019;67:1167)
- 17 year old girl with bilateral athelia (Br J Plast Surg 2005;58:833)
- 17 year old girl with congenital unilateral amastia underwent a 3 step reconstruction of breast (Cureus 2021;13:e18540)
- 19 year old woman presented with breast hypoplasia after infantile hemangioma (J Eur Acad Dermatol Venereol 2017;31:e355)
Treatment
- 3 step breast reconstruction surgery in amastia (Cureus 2021;13:e18540)
- Nipple areola reconstruction in bilateral athelia (Br J Plast Surg 2005;58:833)
- Breast reconstruction for aplasia using free TRAM flap (Acta Chir Plast 2001;43:39)
Clinical images
Images hosted on other servers:
Bilateral athelia
Amastia (before reconstruction)
Amastia (after implant)
Amastia (after NAC reconstruction)
Polythelia
Gross description
Not applicable
Gross images
Not applicable
Frozen section description
Not applicable
Frozen section images
Not applicable
Microscopic (histologic) description
- Histopathology of hypoplasia is mostly normal; sometimes shows decreased gland to stroma ratio with predominance of fibrocollagenous stroma and mature adipose tissue
- Histologically, both unilateral and bilateral hypoplastic breast tissue consists of fibrous stroma and ductal structures without acinar differentiation
- Ducts typically resemble those in the prepubertal breast and lack lobular development (Semin Plast Surg 2013;27:42)
Microscopic (histologic) images
Contributed by Reena Tomar, M.B.B.S., M.D.
Hypoplasia
Hypoplasia
Virtual slides
Not applicable
Cytology description
Not applicable
Cytology images
Not applicable
Immunofluorescence description
Not applicable
Immunofluorescence images
Not applicable
Positive stains
Not applicable
Negative stains
Not applicable
Electron microscopy description
Not applicable
Electron microscopy images
Not applicable
Molecular / cytogenetics description
Not applicable
Molecular / cytogenetics images
Not applicable
Videos
Not applicable
Sample pathology report
- Left breast, trucut biopsy:
- Rare benign breast ductules with fibrocollagenous stroma (clinically breast hypoplasia) (see comment)
- Comment: A 16 year old girl presented with left side hypoplasia in surgery OPD. Trucut biopsy was done from left breast.
- Gross: 4 trucut cores of breast swelling measuring 1 x 0.2 cm, 0.8 x 0.2 cm, 0.7 x 0.1 cm and 1.1 x 0.2 cm
- Microscopy: Section shows few benign breast ductules with fibrocollagenous stroma. Predominance of mature adipose tissue seen. No features of atypia are seen.
Differential diagnosis
- Turner syndrome:
- Can present with hypoplasia
- Presents as amenorrhea, short stature and webbed neck, which is not present in breast congenital anomalies
- Karyotyping is 45X, whereas breast congenital anomalies karyotyping is normal 46XX
Additional references
N/A
Board review style question #1
A 16 year old normal statured girl presents to the general surgery outpatient department with no development of breast on both sides. On ultrasonography (USG) of the abdomen, uterus and bilateral ovaries are normal. Menstrual cycles are regular. Karyotyping shows 46XX. Which of the following syndromes can be associated with this condition?
- Androgen insensitivity syndrome
- Klinefelter syndrome
- Poland syndrome
- Turner syndrome
Board review style answer #1
C. Poland syndrome. Bilateral amastia is very commonly associated with Poland syndrome.
Answer D is incorrect because Turner syndrome presents as short stature and amenorrhea.
Answer B is incorrect because Klinefelter syndrome is 46XXY on karyotyping.
Answer A is incorrect because androgen insensitivity syndrome patients have no uterus or ovaries but can have normal breast development.
Comment Here
Reference: Amastia / aplasia / hypoplasia / athelia
Comment Here
Reference: Amastia / aplasia / hypoplasia / athelia
Amyloid
Table of Contents
Definition / general | Essential features | Terminology | Epidemiology | Sites | Pathophysiology | Etiology | Diagrams / tables | Clinical features | Laboratory | Radiology description | Radiology images | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Positive stains | Negative stains | Electron microscopy description | Differential diagnosisDefinition / general
- Extracellular mass-like deposition of amorphous and insoluble proteins in an abnormal fibrillary configuration
Essential features
- Extracellular deposition of acellular eosinophilic material in fat, stoma or blood vessels creating a mass effect
- Stains positively for Congo red; metachromatic on Wright stain
- May be localized or part of systemic amyloidosis
- Treatment by complete excision
Terminology
- Amyloidosis in the breast first reported by Fernandez and Hernandez in 1973 (J Clin Pathol 2002;55:634)
- Also called amyloidoma
Epidemiology
- Very rare
- Usually women ages 45 - 79 years
Sites
- 80% occur in right breast
- Bilateral or unilateral but only rarely is confined to breast
Pathophysiology
- Abnormal deposition of insoluble protein in an abnormal fibrillary configuration
- Most common types are amyloid light chain (AL) and amyloid A (AA)
- AL is caused by immunoglobin light chains and is secondary to plasma cell dyscrasia
- AA is reactive amyloidosis and is secondary to chronic inflammatory disease
- In vast majority of patients, breast amyloidosis is part of a systemic AL type disease (usually kappa light chain proteins)
- It can be associated with malignancies of the breast
Etiology
- Depends on the type of amyloidosis:
- AL type amyloidosis - plasma cell dyscrasia (myeloma, Waldenström macroglobulinemia)
- AA type amyloidosis - chronic inflammatory disease (rheumatoid arthritis, reactive arthritis)
Diagrams / tables
Images hosted on other servers:
Figure 7: Flow chart for diagnosis of amyloidosis
Clinical features
- Painless mass
- May occur late in systemic disease
- Complete physical examination needed to differentiate primary and secondary amyloid tumors
Laboratory
- See diagram above
Radiology description
- Visualized as mass on ultrasound and MRI
Radiology images
Images hosted on other servers:
Figures 1 and 2
Case reports
- 58 year old woman with amyloid tumor mimicking breast carcinoma (South Med J 2008;101:199)
- 59 year old woman with sclerosing lymphocytic lobulitis and amyloid of the breast (Breast 2006;15:281)
- 60 year old woman with amyloid tumor in silicone implanted breast (Plast Aesthet Res 2016;3:240)
- 76 year old woman with amyloid deposition of breast (AJR Am J Roentgenol 2000;175:1590)
- 77 year old woman with bilateral breast masses (Arch Pathol Lab Med 2004;128:e67)
- Amyloid deposition of the breast in primary Sjögren syndrome (JBR-BTR 2006;89:313)
Treatment
- Excisional biopsy is successful if amyloid tumor is limited to the breast
Gross description
- 5 cm or less, firm, gray white, opalescent
Microscopic (histologic) description
- Amorphous eosinophilic extracellular deposits in fat, stroma or vessels
- May cause ductal atrophy, form rings around individual fat cells, have associated multinucleated giant cell reaction or osseous metaplasia (J Clin Path 2002;55:634)
Microscopic (histologic) images
Contributed by Dr. Mark R. Wick
Amyloid tumor
Thioflavin T stain
Parenchyma - Congo red
AFIP images
Thick wavy bands of
amyloid around lobular
glands and a nodular deposit
that is virtually acellular
Amyloid occurs in
lobule (lower left) and
as separate stromal
nodule (upper right)
Images hosted on other servers:
Various images
Amyloid with osseous metaplasia
Cytology description
- Amorphous acellular material with scattered plasma cells, lymphocytes, stromal cells and epithelial cells
- Rare multinucleated giant cells
- Metachromatic by modified Wright stain (Diagn Cytopathol 2003;28:325)
Cytology images
Images hosted on other servers:
Dense hyaline material and giant cells
Positive stains
- Congo red (red orange with apple green birefringence under polarized light)
- Metachromatic with crystal violet
Negative stains
Electron microscopy description
- Straight, nonbranching, haphazard amyloid fibrils, 5 - 10 nm, mixed with collagen fibers (Am J Surg Pathol 1986;10:539)
Differential diagnosis
- Plasmacytoma: immature plasma cells, no amyloid
- Stromal fibrosis: may have hyaline material but it has different histologic features from amyloid; also Congo red negative
Anatomy
Table of Contents
Definition / general | Thelarche | Gross anatomy | Breast proper | Stroma | Nipple areolar complex | Diagrams / tables | Gross images | Microscopic (histologic) imagesDefinition / general
- Specialized modified skin appendage and defining features of class Mammalia (Wikipedia: Mammal)
- Demonstrates morphologic alteration throughout the reproductive life cycle (menarche, pregnancy, lactation and menopause, in addition to maternal hormonal effects in utero)
- Reference: Mills: Histology for Pathologists, Fourth Edition, 2012
Thelarche
- Rapid growth of breasts at onset of puberty, usually age 10 - 11 in females (Wikipedia: Thelarche, Arch Dis Child 1976;51:170)
- Onset prior to age 8 in girls with normal BMI in general population
- Breast tissue resembles gynecomastia with epithelial hyperplasia in ductal system in a solid or micropapillary configuration (BMC Pediatr 2008;8:27)
- Excision of initial subareolar disc will lead to amastia after puberty
- Associated with increased BMI and non-Hispanic black and Mexican American ethnicity (Pediatrics 2009;123:84)
- May be isolated or part of precocious (central) puberty if other signs of puberty are present
- No tests currently predict risk of progression to precocious puberty in premature thelarche (J Pediatr 2010;156:466)
- Earlier onset of thelarche and longer interval between thelarche and menarche may be associated with increased breast cancer risk (Breast Cancer Res 2014;16:R18)
Tanner staging:
Stage I: preadolescent
Stage II: breast budding (thelarche)
Stage III: enlargement of areolar diameter
Stage IV: areola / papilla
form secondary mound
with separation of contours
Stage V: mature female breasts
Gross anatomy
- Breast Proper:
- Suspended from anterior chest by ligaments of Cooper (Wikipedia: Cooper's Ligaments) attached to skin and fascia of major and minor pectoral muscles
- Covered by skin and subcutaneous tissue anteriorly
- Spans 2nd rib to 6th rib sacroiliac (SI), midaxillary line to medial border at edge of sternum midline, in addition to axillary tail of Spence (Wikipedia: Tail of Spence), which extends into axilla
- Posterior / deep margin is fascia of pectoralis major muscle
- Breast tissue may extend beyond these limits into adjacent subcutaneous tissue
- In some patients, mastectomy removes most but not all breast epithelial elements, raising possibility of breast disease at these sites
- Accessory breast tissue may be present along the milk line (axilla → anterior chest wall → pubis → upper thighs)
- Accessory / supernumerary nipples but also breast parenchyma
- Both malignant and benign breast disease may arise in these ectopic sites
- Glandular tissue is most abundant in upper outer quadrant of breast; as a result, half of all breast cancers occur here
- Nipple areolar complex:
- Located slightly medial and inferior on breast, level of 4th intercostal on nonpendulous breast
- Cone shaped protuberance, 10 - 12 mm in average height, mean nipple diameter 11 - 13 mm, mean areolar diameter 4 cm
- Montgomery tubercles - areolar protuberances (10 - 20), more prominent during pregnancy; composed of ducts and sebaceous apparatus
- Lymphatic drainage:
- Four major routes => cutaneous, axillary, internal thoracic, posterior intercostal
- Cutaneous
- Superficial plexus within dermis
- Most if not all lymphatics connect to areolar lymphatic plexus (plexus of Sappey)
- Significant for sentinel lymph node procedure, injection in area of nipple will likely identify sentinel nodes, as would injection in region of tumor
- Cutaneous lymphatic anastomoses account for rare cases of metastases to contralateral breast in absence of distant metastases
- Cutaneous lymphatics of inferior breast may drain to epigastric plexus → lymphatic channels of liver and intra-abdominal lymph nodes
- Axilla
- Majority (75%) of drainage
- Initially through 1 - 2 sentinel nodes, first to be involved in 90% of patients with lymph node metastases
- Three levels
- Level I - low axilla
- Level II - mid axilla
- Includes Rotter nodes (interpectoral)
- Level III
- Apical or infraclavicular nodes
- Metastases here portend a worse prognosis
- Intramammary nodes
- May be found anywhere in breast parenchyma
- Considered as axillary lymph nodes for staging purposes
- Only very rarely the sentinel node
- Internal thoracic
- < 10% of lymphatic flow from breast, may be more prominent if lymphatic drainage is obstructed / disrupted due to disease in axilla or previous treatment
- Terminates in internal mammary nodes
- Involvement does not alter treatment in most cases; as a result, rarely sampled when systemic therapy is planned
- Posterior intercostal
- Least important route of drainage
- Supraclavicular nodes
- Are deemed regional nodes for staging purposes
- Metastases to all other lymph nodes, including cervical and contralateral axillary nodes, are classified as distant metastases
- Cutaneous
- References (lymphatics): Ann Surg Oncol 2008;15:863, Hum Pathol 2001;32:178
- Four major routes => cutaneous, axillary, internal thoracic, posterior intercostal
Breast proper
- Epithelial and stromal components; specific lesions arise in each component or may have a dual morphology
- Epithelium
- Large ducts
- Three dimensional arborizing fan shaped system with apex towards the nipple
- Large ducts → segmental ducts → subsegmental ducts → lobules
- Lactiferous sinuses are likely artifactual (J Anat 2005;206:525); this study changed commonly held views of anatomy (Wikipedia: Breast)
- Duct systems are only rarely confined to a single quadrant and may overlap
- Anastomoses may exist between large duct regions
- Involvement of multiple duct systems by DCIS (a clonal proliferation) may be explained as follows
- DICS arising in single large duct system may be present in overlapping quadrants
- DCIS arising in single large duct system may involve adjacent systems through anastomotic connections
- Separate foci of DCIS may arise in different duct systems
- Terminal duct lobular units (TDLU)
- "Functional unit" of breast (lacation)
- Postulated as origin of most epithelial neoplasms (breast or myoepithelial)
- Two types of epithelia: luminal cells and myoeptihelium
Luminal cells ("epithelial cells"):- Innermost layer of bilayered ductolobular system
- Usually express luminal keratins LMWCK, CK7, CK8, CK18, CK19
- May express "basal keratins" HMWCK, CK5 / 6, CK14, CK17 (J Histochem Cytochem 1986;34:869)
- Most express ER-α and or PgR in a heterogeneous pattern at any given time
- Also expresses E-cadherin, mammaglobin and GCDFP-15
- Outer layer resting on basement membrane
- Contractile meshwork partially covering basement membrane, i.e. incomplete on cross section
- Usually expresses "basal" keratins HMWCK, CK5 / 6, CK14, CK17
- Also smooth muscle actin, calponin, smooth muscle myosin heavy chain, in addition to p63, S100, CD10, P-cadherin and mapsin
- Does NOT express ER or PgR
- Loss of myoepithelium usually considered hallmark of invasive process, with the exception of microglandular adenosis, encapsulated papillary carcinoma and solid papillary carcinoma
- Large ducts
Stroma
- Interlobular
- Surrounds large ducts and TDLUs
- Mature adipose tissue (majority of breast volume), fibroconnective tissue (fibroblasts, myofibroblasts), blood vessels and lymphatics, nerves
- Stromal fat varies throughout reproductive life
- Stromal myofibroblasts
- May express ER and PgR
- Usually also CD34
- Stromal lesions not specific to breast may arise in interlobular stroma, including angiolipoma, angiosarcoma, desmoid fibromatosis, lipoma, myofibroblastoma
- PASH (pseudoangiomatous stromal hyperplasia) is specific to breast
- Intralobular
- Surrounds acini in TDLUs
- Compared to interlobular stroma, looser in appearance or even myxoid
- Often small numbers of inflammatory cells
- Lesions arising here are biphasic involving epithelial and stromal components, including fibroadenoma, phyllodes tumor
Nipple areolar complex
- Ramifying duct system terminating in 15 - 20 major ducts, which open onto areola
- Covered in pigmented skin
- Toker cells
- Cytologically benign cells with clear / pale cytoplasm
- Immunoprofile similar to luminal epithelial cells
- Are most abundant adjacent to duct orifices
- Must distinguish from mammary Paget disease (DCIS involving nipple)
- Keratin producing squamous cells extend into proximal 1 - 2 mm of large ducts
- Squamous metaplasia of lactiferous ducts (SMOLD) is extension of squamous epithelium beyond proximal 1 - 2 mm; associated with smoking
- Keratin entrapment may cause epidermal inclusions and abscess formation with marked inflammatory response
- Basement membrane of ducts and duct lobular system is contiguous with that of skin
- Tumor cells may extend onto skin from DCIS without crossing basement membrane (Paget disease)
- External shape / size of the breast is not predictive of internal anatomy or its lactation potential
- References (nipple): Breast Cancer Res Treat 2007;106:171, Eur Surg Res 2006;38:545, Cancer 2004;101:1947, Aesthetic Plast Surg 2009;33:295, Am J Surg 2007;194:433, Arch Pathol Lab Med 1982;106:60
Diagrams / tables
Images hosted on other servers:
Milk lines
Breast anatomy
Regional lymph nodes - schematic
Radical mastectomy
Supraclavicular fossa
Radiograph of lymphatics
Tracing of lymphatics
Gross images
Images hosted on other servers:
Nipple orifices, some cannulated with guide wires
Microscopic (histologic) images
AFIP images
Premature thelarche (9 year old girl)
Proliferation of ducts without lobules
Images hosted on other servers:
Perforating lymphatic
Instillation of
water insoluble and
differently colored
dyes in orifices
Angiosarcoma
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Gross images | Frozen section description | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Cytology images | Positive stains | Negative stains | Electron microscopy description | Molecular / cytogenetics description | Videos | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Malignant vascular neoplasm, which may arise in previously irradiated skin or breast tissue (secondary postradiation angiosarcoma) or in nonirradiated tissue (primary angiosarcoma)
Essential features
- Irregular, infiltrative anastomosing vascular channels with endothelial atypia
- Postradiation angiosarcoma demonstrates amplification of MYC
Terminology
- Alternate terminology: hemangiosarcoma, lymphangiosarcoma
ICD coding
- ICD-O: 9120/3 - angiosarcoma, postradiation angiosarcoma
- ICD-10: C50 - malignant neoplasm of breast
- ICD-11: 2B56.2 & XH6264 - angiosarcoma of breast & angiosarcoma
Epidemiology
- Rare (0.05% of malignant breast tumors) but is the most common type of mammary sarcoma
- Most often arises after radiation treatment for breast cancer
- Postradiation angiosarcoma
- Incidence of 0.03 - 0.14% after breast irradiation (BMC Cancer 2018;18:463, J Am Acad Dermatol 2006;54:499)
- Median age of 70 years (Cancer 2005;104:2682)
- Arises within the radiation field with a median latency of 6 - 7 years (Br J Surg 2021;108:388, Ann Surg Oncol 2013;20:1267)
- Rare cases may develop within a shorter latency period of 1 - 2 years
- Primary angiosarcoma
- Median age of 40 years (Am J Surg Pathol 2008;32:1896)
Sites
- Postradiation angiosarcoma
- Typically arises in irradiated skin and may secondarily extend into the breast parenchyma (Breast J 2020;26:458)
- Less commonly arises in breast parenchyma
- Primary angiosarcoma
- Usually arises in breast parenchyma
- Stewart-Treves syndrome
- Cutaneous angiosarcoma of the upper limb arising in the setting of chronic lymphedema, typically occurring after mastectomy and axillary dissection (J Am Acad Dermatol 2012;67:1342)
- May secondarily extend to the breast / chest wall
Pathophysiology
- Malignancy of vascular or lymphatic endothelial cells
- Exact lineage remains unclear since endothelial cells may undergo transdifferentiation
Etiology
- Ionizing radiation (postradiation angiosarcoma)
- Longstanding lymphedema (Stewart-Treves syndrome)
- Unknown (primary angiosarcoma)
Clinical features
- Solitary or multiple erythematous to violaceous plaques, papules, nodules or areas of discoloration on the skin (postradiation angiosarcoma) (Am J Clin Pathol 1994;102:757)
- Rapidly growing poorly defined mass, swelling or asymmetry of the breast parenchyma (primary angiosarcoma) (Am J Surg Pathol 2008;32:1896)
Diagnosis
- Histologic examination of tissue obtained by biopsy or surgical excision
Radiology description
- Mammography
- Cutaneous tumors: skin thickening (may be masked by postradiation changes)
- Parenchymal tumors: focal or diffuse asymmetry or an ill defined mass, sometimes with a lobulated or oval shape; a minority are mammographically occult (AJR Am J Roentgenol 2008;190:533, BMC Womens Health 2019;19:73)
- Ultrasonography
- Hyperechoic mass or areas of mixed hyper and hypoechogenicity with architectural distortion (Radiology 2007;242:725)
- Doppler sonography shows hypervascularity
- Magnetic resonance imaging
- High signal intensity in T2 weighted images
- Low grade tumors show progressive enhancement
- High grade tumors show rapid enhancement and washout
Radiology images
Contributed by Melinda J. Lerwill, M.D.
Postradiation angiosarcoma arising in the skin
Postradiation angiosarcoma of the breast parenchyma
Prognostic factors
- Poor prognostic features include older age, large tumor size, high histological grade, tumor spread and incomplete initial resection, although results differ among studies (Ann Surg Oncol 2013;20:1267, BMC Cancer 2017;17:295, BMC Cancer 2018;18:463, Breast Cancer Res Treat 2019;178:523)
- Correlation between histologic grade and outcome is debated (Am J Surg Pathol 2008;32:1896)
- Primary and postradiation angiosarcomas appear to have a similar prognosis after adjustment for clinicopathological variables (BMC Cancer 2017;17:295)
Case reports
- 32 year old woman with Li-Fraumeni syndrome and postradiation angiosarcoma (Sao Paulo Med J 2015;133:151)
- 39 year old woman with primary angiosarcoma (Int J Clin Exp Pathol 2019;12:664)
- 62 year old woman with bilateral postradiation angiosarcoma (Case Rep Oncol Med 2020;2020:5768438)
Treatment
- Complete surgical excision is the primary treatment modality
- Radical resection of all previously irradiated skin may improve recurrence rate and disease specific survival in cases of postradiation angiosarcoma (Ann Surg 2017;265:814)
- Role of chemotherapy is poorly defined but it may improve survival in patients with tumors > 5 cm (Breast Cancer Res Treat 2019;175:409)
- Radiation therapy remains controversial, particularly in cases of postradiation sarcoma
Clinical images
Contributed by Mark R. Wick, M.D.
Postradiation angiosarcoma
Gross description
- Average size of 4 - 6 cm (Breast Cancer Res Treat 2019;178:523)
- Multifocality is more common in postradiation than in primary angiosarcoma
- Firm to spongy hemorrhagic mass
- Cystic necrosis can occur in higher grade tumors
- Tumors are often larger than is grossly evident
Gross images
Contributed by Melinda Lerwill, M.D. and Mark R. Wick, M.D.
Postradiation angiosarcoma
Postradiation angiosarcoma
Frozen section description
- See Microscopic (histologic) description section
Microscopic (histologic) description
- Morphologic heterogeneity is typically present within individual tumors
- Irregular anastomosing vascular channels dissect through the stroma
- Infiltrative growth through normal structures (e.g., terminal duct lobular units)
- Poorly differentiated tumors often show solid growth of spindle or epithelioid cells with limited vasoformative features
- Necrosis and blood lakes can be seen in poorly differentiated tumors
- Endothelial cell atypia can range from minimal to marked
- Endothelial tufting and papillary formations are common
- Mitotic activity increases in proportion to grade
- Grading is based on a combination of histologic features (Table 1) (Am J Surg Pathol 1981;5:629)
- Low grade features are more common as a dominant finding in primary angiosarcomas
- Majority of postradiation angiosarcomas are high grade (Ann Surg Oncol 2013;20:1267, Ann Surg Oncol 2020;27:1002)
- All histologic grades of angiosarcoma may contain low grade areas, especially at the periphery of the tumor
Table 1. Histologic characteristics of different grades of mammary angiosarcoma
| Histologic features | Low grade | Intermediate grade | High grade |
| Endothelial cell atypia | Minimal | Moderate | Marked |
| Endothelial tufting | Minimal | Present | Prominent |
| Papillary formations | Absent | Focally present | Present |
| Solid and spindle cell foci | Absent | Absent or minimal | Present |
| Mitotic figures | Absent or rare | Present | Numerous and present in structurally low grade areas |
| Blood lakes (pools of extravasated erythrocytes) | Absent | Absent | Present |
| Necrosis | Absent | Absent | Present |
Microscopic (histologic) images
Contributed by Melinda Lerwill, M.D.
Low grade primary angiosarcoma
Irregular vessels
Infiltrative growth
Postradiation angiosarcoma
High grade cytologic atypia
Solid growth
Epithelioid cells
Blood lake
ERG
MYC
Virtual slides
Images hosted on other servers:
High grade mammary angiosarcoma
Cytology description
- Variable cellularity: specimens from well differentiated tumors tend to be hypocellular and bloody, while those from poorly differentiated tumors are usually more cellular
- Dispersed cells, cells in loose or cohesive groups or focal papillae with fibrovascular cores (Cancer Cytopathol 2016;124:659)
- Variable cellular morphology (spindle, epithelioid or mixed)
- Prominent epithelioid cells can mimic carcinoma
- Oval to spindled nuclei with variable pleomorphism
- Multiple nucleoli and bar or bullet shaped nucleoli are common; chromatin stranding may be seen (delicate radiating chromatin strands connecting the nucleolus to the nuclear membrane)
- Vasoformative features (hemophagocytosis, cytoplasmic lumina / vacuoles with red blood cells or neutrophils, endothelial wrapping) are often present but their prominence and extent vary
Cytology images
Contributed by Sofia Lérias, M.D.
Atypical spindle cells
Positive stains
- CD31, ERG: strong and diffuse
- CD34, D2-40, Factor VIII, FLI1: variable, often strong and diffuse
- Cytokeratins and EMA: focal expression in epithelioid variants
- MYC: strong and diffuse nuclear positivity in postradiation angiosarcoma (Hum Pathol 2014;45:709)
Negative stains
- H3K27me3: loss or reduced expression in a subset of postradiation angiosarcomas (Histopathology 2021;79:836, Virchows Arch 2018;472:361)
- ER / PR / HER2
Electron microscopy description
- Groups of cells surrounded by basal lamina and closely associated with pericytes, with intercellular and intracellular lumina with or without red blood cells (Am J Surg Pathol 1998;22:683)
- Weibel-Palade bodies may be present (Hum Pathol 1985;16;144)
Molecular / cytogenetics description
- Postradiation angiosarcoma
- High level amplification of MYC at 8q24 in > 90% of cases (Genes Chromosomes Cancer 2011;50:25)
- Coamplification of FLT4 in 25% (Genes Chromosomes Cancer 2011;50:25)
- Angiosarcoma secondary to chronic lymphedema
- Can also show high level amplification of MYC (Am J Pathol 2010;176:34)
- Primary angiosarcoma
- Only rare cases show MYC amplification (Am J Surg Pathol 2016;40:645)
Videos
Postradiation angiosarcoma
Sample pathology report
- Breast, mastectomy:
- Post-radiation angiosarcoma (see comment)
- Comment: The angiosarcoma measures 7.5 x 5 cm and involves the skin and underlying breast parenchyma. The tumor is high grade with pleomorphic spindle and epithelioid cells, a high mitotic rate (up to 30 MF / 10 HPF) and focal areas of necrosis. By immunohistochemistry, the tumor cells are positive for CD31, CD34, D2-40, ERG and MYC and negative for pancytokeratin and S100, supporting the diagnosis. Angiosarcoma extends to 0.5 cm of the superior skin margin, 1 cm from the inferior skin margin and is greater than 2 cm from the remaining margins.
Differential diagnosis
- Atypical vascular lesion:
- Small vascular proliferation occurring in the dermis of irradiated skin
- Most lesions are < 1 cm in size (and often < 0.5 cm)
- Relatively circumscribed, often wedge shaped proliferation of thin walled vessels within the superficial to mid dermis
- Lacks evidence of infiltration
- No significant endothelial atypia or proliferation
- Lacks amplification of MYC and negative or only weakly reactive for MYC by immunohistochemistry
- Clinicopathological correlation is needed to ensure that the biopsy does not represent sampling at the edge of an angiosarcoma
- Hemangioma:
- Well defined
- No destructive invasion of terminal duct lobular units
- Flattened endothelial cells without atypia or significant mitotic activity
- Angiomatosis:
- Very rare benign vascular proliferation involving large areas of breast parenchyma
- Large dilated vascular channels permeate the breast but show exquisite sparing of the terminal duct lobular units, unlike angiosarcoma
- No endothelial atypia, stratification or notable mitotic activity
- Carcinoma:
- Evidence of epithelial differentiation or in situ carcinoma
- Negative for vascular markers
Additional references
Board review style question #1
Which of the following is true regarding postradiation angiosarcoma of the breast?
- Greater than 90% are low grade
- Incidence of 10% among patients receiving breast irradiation for breast cancer treatment
- Most often arises in the breast parenchyma and then secondarily involves the skin
- Patients have a median age of 40 years
- Shows strong positivity for MYC by immunohistochemistry
Board review style answer #1
E. Shows strong positivity for MYC by immunohistochemistry. Greater than 90% of postradiation angiosarcomas of the breast show high level amplification of MYC and corresponding strong overexpression of MYC by immunohistochemistry. Postradiation angiosarcoma develops in 0.03 - 0.14% of patients after radiation therapy for the treatment of breast cancer. Reflective of that cohort, the mean age is 70 years. Most postradiation angiosarcomas arise in the skin (from which they may secondarily involve the breast parenchyma) and the majority are of high histologic grade.
Comment Here
Reference: Angiosarcoma
Comment Here
Reference: Angiosarcoma
Board review style question #2
A 27 year old woman with no significant prior medical history presents with an 8 cm poorly defined left breast mass. A representative histological image is shown above. What is the most likely diagnosis?
- Atypical vascular lesion of the skin
- Capillary hemangioma
- Low grade angiosarcoma
- Pseudoangiomatous stromal hyperplasia
- Spindle cell carcinoma with acantholytic pattern
Board review style answer #2
C. Low grade angiosarcoma. The illustrated lesion is a primary, low grade angiosarcoma of the breast parenchyma. It demonstrates irregularly shaped, anastomosing vascular channels that dissect through the fat and collagen and around normal glandular structures. This pattern of destructive invasion distinguishes it from benign vascular proliferations.
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Reference: Angiosarcoma
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Reference: Angiosarcoma
Antibody drug conjugate therapy (pending)
[Pending]
Apocrine
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Negative stains | Electron microscopy description | Electron microscopy images | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1Definition / general
- Invasive breast carcinoma comprised of large cells with abundant eosinophilic and granular cytoplasm, enlarged nuclei and prominent nucleoli
- Apocrine morphology in > 90% of tumor cells
Essential features
- Apocrine morphology in > 90% of tumor cells
- Estrogen receptor (ER) negative, progesterone receptor (PR) negative and androgen receptor (AR) positive
Terminology
- Carcinoma with apocrine differentiation
- Invasive apocrine carcinoma
- Apocrine carcinoma
ICD coding
- ICD-O: 8401/3 - apocrine adenocarcinoma
- ICD-11: 2C61 & XH4GA3 - invasive carcinoma of breast & adenocarcinoma with apocrine metaplasia
Epidemiology
- Rare subtype of invasive breast carcinoma, representing ~1% of invasive carcinomas
- Mean age of diagnosis is typically older than invasive breast carcinoma, NST
Sites
- Breast
- Can occur in axilla
Etiology
- Most carcinomas with apocrine differentiation are sporadic
- Some carcinomas in patients with germline PTEN mutation (Cowden syndrome) display apocrine morphology (Breast Cancer Res 2010;12:R63)
Clinical features
- Similar to those of invasive breast cancer of no special type (NST)
- Typically a firm, poorly circumscribed mass
Diagnosis
- Histologic examination of involved tissue
Radiology description
- Imaging findings are similar to invasive breast cancer of no special type (NST)
Radiology images
Contributed by Jonathan Marotti, M.D.
Mammogram
Ultrasound
Prognostic factors
- Prognosis is based on conventional factors such as grade, tumor size and nodal status
- Studies evaluating clinical outcomes have contradictory results (Clin Breast Cancer 2022;22:e576)
Case reports
- 61 year old woman with abnormal screening mammography (Iran J Radiol 2016;13:e35298)
- 70 year old woman with right breast mass (J Cytol 2014;31:96)
- 75 year old woman with axillary lymphadenopathy (Cureus 2021;13:e18523)
Treatment
- Surgical excision
- Chemotherapy and radiation are dependent on stage
- Neoadjuvant therapy may be considered
- Anti-HER2 therapy for HER2+ tumors
- Single agent anti-AR therapy has shown limited therapeutic benefit; clinical trials are ongoing (Clin Breast Cancer 2022;22:e576)
Gross description
Microscopic (histologic) description
- Infiltrating tumor cells with apocrine morphology: abundant eosinophilic and granular cytoplasm, well defined cell borders, enlarged round nuclei and prominent nucleoli
- Apocrine morphology in > 90% of tumor cells
- Typically high grade / poorly differentiated
- Often associated with ductal carcinoma in situ (DCIS) with apocrine features
Microscopic (histologic) images
Contributed by Jonathan Marotti, M.D.
Large atypical epithelial cells
AR positive
ER negative
PR negative
Large atypical epithelial cells
AR positive
Cytology description
- Highly cellular
- Sheets, clusters and single cells with abundant eosinophilic cytoplasm, large nuclei with variable pleomorphism and prominent nucleoli (Acta Cytol 1996;40:247)
- Binucleate and multinucleate forms; often many bare nuclei
- Difficult to differentiate from benign apocrine metaplastic lesions on cytologic preparations (Diagn Cytopathol 2017;45:1156)
Positive stains
Electron microscopy description
- Extensive rough endoplasmic reticulum and numerous osmophilic membrane bound granules (Am J Pathol 1986;123:532)
- Large mitochondria with incomplete cristae (Histol Histopathol 2013;28:13935)
Electron microscopy images
Images hosted on other servers:
Cytoplasm rich in organelles
Electron dense granules
Molecular / cytogenetics description
- Most genetic alterations found in carcinoma with apocrine differentiation are also found in invasive breast carcinoma, NST
- Frequent mutations of TP53 and PIK3CA / PTEN / AKT genes (Mod Pathol 2020;33:2473)
- Gene expression profiling has defined a molecular apocrine / luminal AR signature (with or without HER2 activation)
- Molecular apocrine / luminal AR signature does not always correlate with apocrine morphology
Sample pathology report
- Left breast, partial mastectomy:
- Carcinoma with apocrine differentiation (see synoptic report and comment)
- Comment: Sections show an infiltrating tumor comprised entirely of large epithelial cells with abundant eosinophilic and granular cytoplasm, well defined cell borders, enlarged nuclei and prominent nucleoli. The tumor cells are diffusely and strongly positive for AR and AMACR; they are negative for ER, PR and HER2. The combined cytomorphologic and immunohistochemical findings are consistent with a carcinoma with apocrine differentiation.
Differential diagnosis
- Invasive breast carcinoma, NST with focal apocrine differentiation:
- Focal apocrine differentiation may be present in up to 60% of invasive ductal carcinoma, NST (J Clin Pathol 2007;60:1313)
- Carcinoma with apocrine differentiation must have > 90% apocrine morphology
- Invasive breast carcinoma, NST with oncocytic carcinoma pattern:
- Tumor cells with abundant eosinophilic and granular cytoplasm with well defined cell borders and round, centrally located nuclei with prominent nucleoli
- Positive for mitochondrial immunostains
- Mostly positive for ER
- Often display chromosomal gains of 11q13.1-q13.2 and 19p13
- Granular cell tumor:
- Apocrine DCIS:
- DCIS with apocrine cytology
- Myoepithelial cell layer present
- Apocrine adenosis / atypical apocrine adenosis:
- Lobulocentric proliferation with apocrine cytology and distortion by stromal fibrosis / sclerosis
- Myoepithelial cell layer present
- Histiocytic proliferations:
- Pale to foamy cytoplasm without nuclear atypia
- CD68 positive
Additional references
Board review style question #1
A 3.3 cm irregular mass was detected within the right breast of a 78 year old woman. Lumpectomy showed a tumor with histology as represented in the image throughout the tumor. What biomarker profile is concordant with this subtype of breast cancer?
- AR+, ER+, PR-, HER2-
- AR+, ER+, PR+, HER2-
- AR+, ER-, PR-, HER2-
- AR-, ER-, PR-, HER2-
Board review style answer #1
C. AR+, ER-, PR-, HER2-. Carcinomas with apocrine differentiation are comprised of tumor cells with apocrine cytology: large atypical epithelial cells with abundant eosinophilic and granular cytoplasm, enlarged nuclei and prominent nucleoli. Apocrine morphology must be present in > 90% of the tumor. Carcinomas with apocrine differentiation are usually triple negative (ER-, PR- and HER2-); however, HER2 amplification / overexpression has been reported in 30 to 60% of tumors. Carcinomas with apocrine differentiation demonstrate diffuse and strong AR immunoreactivity. It should be noted that focal apocrine morphology and AR immunoreactivity may be seen in up to 60% of invasive breast carcinomas, NST. Additionally, AMACR, a marker of apocrine differentiation, is positive in the majority of carcinomas with apocrine differentiation.
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Reference: Apocrine carcinoma
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Reference: Apocrine carcinoma
Apocrine adenoma
Table of Contents
Definition / general | Essential features | Terminology | Etiology | Clinical features | Prognostic factors | Case reports | Treatment | Microscopic (histologic) description | Cytology description | Positive stains | Negative stains | Differential diagnosis | Additional referencesDefinition / general
- Adenoma with apocrine cytology throughout
- Rare adenoma that is:
- Composed exclusively of benign apocrine cells (homogeneous)
- Sharply demarcated from surrounding breast tissue
- Contains only epithelial proliferative elements
- Has minimal supportive stroma
Essential features
- Nodular mass composed exclusively of apocrine cells without cytological atypia
- Sharply demarcated from adjacent breast tissue and has minimal stromal component if any
- Considered benign, excision is curative
- Cytological atypia, necrosis and invasive features suggest atypical hyperplasia / apocrine malignancy (DCIS / invasive), recommend careful evaluation of the entire lesion
Terminology
- Pure breast adenomas with apocrine differentiation were first described by Hertel et al. in 1976 (Cancer 1976;37:2891)
Etiology
- May represent nodular sclerosing adenosis with apocrine differentiation
Clinical features
- Can present as a mass
Prognostic factors
- Generally accepted to be benign, however, the number of cases reported is not sufficient to determine the level of risk associated (J Clin Pathol 2007;60:1313)
Case reports
- 45 year old man with 3 mm tumor (Arch Pathol Lab Med 2003;127:1498)
- 47 year old woman with mammographically detected tumor (WV Med J 2008;104:16)
- 53 year old woman with coexisting invasive ductal carcinoma (Pathol Res Pract 2007;203:809)
Treatment
- Complete excision is curative
Microscopic (histologic) description
- By definition, composed exclusively of benign apocrine cells (homogeneous), sharply demarcated from surrounding breast tissue, containing only epithelial proliferative elements, with minimal supportive stroma
- Localized nodular focus of tubular, papillary and cystic apocrine metaplasia; benign glands have abundant granular eosinophilic cytoplasm, apical luminal blebs and decapitation secretion
- May contain calcifications (Pathology 2001;33:149)
Cytology description
- Can be cuboidal or flattened, two distinct types seen:
- Cytoplasm granular and strongly eosinophilic, supranuclear vacuole containing yellow brown pigment (rich in iron / hemosiderin)
- Globoid and pale nuclei with 1 - 2 prominent nucleoli (nuclei may become hyperchromatic in flattened epithelium as in tension apocrine cysts)
- Cytoplasm distinctly foamy with small vacuoles that may coalesce and show lipofuscin pigment in cytoplasm
- Central nuclei with 1 - 2 prominent nucleoli
- Cytoplasm granular and strongly eosinophilic, supranuclear vacuole containing yellow brown pigment (rich in iron / hemosiderin)
- Recommend caution to exclude apocrine DCIS or invasive apocrine carcinoma if necrosis / atypia / mitosis present
Positive stains
Differential diagnosis
- Apocrine DCIS: extensive proliferation, marked nuclear pleomorphism, multiple prominent nucleoli and comedo-type necrosis
- Atypical apocrine hyperplasia: architectural atypia such as Roman bridges, cribriform patterns and multiple papillary fronds; no connective cores or cytological atypia such as three fold variation in nuclear size and marked pleomorphism
- Fibroadenoma: prominent proliferating stromal component, compressed epithelium in intracanalicular variant
- Prominent apocrine changes as a part of fibrocystic changes: not nodular, no distinct mass
- Well differentiated apocrine carcinoma: has obvious malignant changes
Additional references
Apocrine adenosis / atypical apocrine adenosis
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Clinical features | Diagnosis | Radiology description | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Positive stains | Negative stains | Electron microscopy description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Defined as the presence of apocrine cytology in a recognizable terminal duct lobular unit (TDLU) associated with sclerosing adenosis (J Clin Pathol 2007;60:1313)
- Preserved 2 cell layer (inner epithelial and outer myoepithelial cells) in which the epithelial layer has prominent apocrine features
Essential features
- Lobulocentric proliferation with distortion by stromal fibrosis / sclerosis and apocrine cytology
Terminology
- Recommended by WHO:
- Apocrine adenosis
- Not recommended by WHO:
- Sclerosing adenosis with apocrine metaplasia
- Nodular adenosis with apocrine metaplasia
- Terminology apocrine adenosis has also been used to refer to adenomyoepithelial adenosis, a different lesion
- Atypical apocrine adenosis (AAA): rare, defined as ≥ threefold variation in nuclear size
- Previous (historical) names for AAA:
- Atypical apocrine hyperplasia
- Atypical apocrine metaplasia
ICD coding
Epidemiology
- Most frequent in third to fourth decades but occurs over a wide age range
- Atypical apocrine adenosis: rare - 0.4% of 9,340 cases in the Mayo Benign Breast Disease Cohort; average age is 58 years (Arch Pathol Lab Med 2012;136:179, Mod Pathol 1991;4:1)
Sites
- Terminal duct lobular unit; otherwise, no specific location within the breast
Pathophysiology
- Loss of heterozygosity in several loci (1p, 3, 11q, 16 and 17q)
- Accumulation of losses and gains if progression through apocrine DCIS and apocrine carcinoma
Clinical features
- Considered a part of the spectrum of fibrocystic changes
- Often an incidental finding or detected by screening
- Can present as a palpable mass if nodular adenosis / adenosis tumor
Diagnosis
- Histologic examination of tissue with or without immunohistochemistry
Radiology description
- Variable depending on the size / extent of breast involvement
- If focal, may not be visualized (i.e. incidental finding on histologic examination)
- Amorphous or pleomorphic clustered microcalcifications; architectural distortion or circumscribed to spiculated mass on mammogram
- Irregular, noncircumscribed mass on ultrasound is associated with upgrade to malignancy on resection (J Ultrasound Med 2020;39:1517, Breast J 2017;23:569)
Prognostic factors
- Increased risk of cancer of 1.5 - 2 times, as seen with proliferative fibrocystic changes
- Atypical apocrine adenosis (AAA): conflicting evidence of increased cancer risk
- Study of 37 patients showed no increased risk for carcinoma (Arch Pathol Lab Med 2012;136:179)
- Study of 37 patients showed the relative risk of developing carcinoma was 5.5 (95% CI 1.9 - 16), with age association - all patients developing cancer were > 60 years at diagnosis of AAA (Cancer 1996;77:2529)
- Upgrade risk: surgical resection showed carcinoma only in patients with coexisting carcinoma present on core biopsy (N = 10) in a study of 41 patients with apocrine adenosis (N = 29) and atypical apocrine adenosis (N = 12) (Ann Diagn Pathol 2016;24:4)
Case reports
- 37 year old woman with atypical apocrine adenosis diagnosed via fine needle aspiration (Acta Cytol 2002;46:369)
- 54 year old woman with atypical apocrine adenosis diagnosed via incidental discovery on coronary angiogram CT (Cureus 2020;15:e8624)
- 66 year old woman with nodular atypical apocrine adenosis with monoclonality via restriction fragment length polymorphism (RFLP) (Histopathology 2001;38:221)
Treatment
- Presence of apocrine adenosis alone in a core biopsy does not require surgical excision
- Coexisting atypia typically prompts surgical consultation, although excision is controversial based on limited prognostic data
Gross description
- Variable depending on extent of involvement and calcifications
- May be indistinguishable from surrounding breast tissue
- Multinodular, ill defined cuts with increased resistance due to fibrosis
- Gritty due to frequent calcifications but no chalky yellow white foci or streaks as seen in fat necrosis
- Circumscribed to ill defined white, fibrotic mass if nodular adenosis / adenosis tumor
Microscopic (histologic) description
- Cells with apocrine metaplasia have abundant eosinophilic cytoplasm with bright eosinophilic granules that are PAS positive
- Apocrine cells have round nuclei and may show nuclear pleomorphism (≥ threefold in atypical apocrine adenosis); a central, round, eosinophilic nucleolus is generally seen
- Rare multinucleation may be observed and is not considered atypical
- Rare to no mitosis
- No necrosis
Microscopic (histologic) images
Contributed by Julie M. Jorns, M.D.
Distortion, apocrine features
Apocrine features
Distortion, cytologic atypia
Cytologic atypia
Cytology description
- Often highly cellular
- Cells have apocrine metaplasia with prominent nucleoli and pleomorphism, possibly resembling carcinoma but minimal hyperchromasia
- Naked nuclei are present (Diagn Cytopathol 2007;35:296)
Cytology images
Contributed by Volodymyr Shponka, M.D.
Fine needle aspiration
Positive stains
- EMA, GCDFP-15 (Am J Surg Pathol 1993;17:99)
- Androgen receptor
- PAS for basement membrane (J Clin Pathol 1999;52:838, Mod Pathol 1993;6:318)
Electron microscopy description
- Distinct basal lamina present
Sample pathology report
- Left breast, core biopsy:
- Fibrocystic changes, including apocrine adenosis with microcalcifications
Differential diagnosis
- Apocrine carcinoma:
- Infiltrative growth
- Associated desmoplasia
- Lack of myoepithelium
- Cancerization of lobule by apocrine DCIS:
- Architectural atypia: expansile glandular involvement by atypical, monotonous cells
- Other architectural patterns of DCIS are typically also present (e.g. comedo, cribriform, etc.)
- Mitosis and necrosis frequently identified
- Microglandular adenosis:
- Glands are smaller, more regular
- Lacks myoepithelial cells
- Tubular adenosis:
- Haphazard proliferation of elongated tubules
Additional references
Board review style question #1
The above pictured lesion was from a breast biopsy for mammographically detected calcifications. The area of concern was successfully biopsied. What are the next steps in patient care?
- Excision
- Magnetic resonance imaging (MRI)
- Neoadjuvant chemotherapy
- Observation
- Rebiopsy
Board review style answer #1
D. Observation. The pictured lesion is apocrine adenosis with microcalcifications. There is no significant atypia present; thus, this biopsy is benign and concordant with imaging findings and the patient can be observed with routine screening. There is no need to rebiopsy, excise, do additional imaging or initiate any therapies.
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Reference: Apocrine adenosis
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Reference: Apocrine adenosis
Board review style question #2
What feature is present in apocrine ductal carcinoma in situ (DCIS) but is lacking in atypical apocrine adenosis (AAA)?
- Calcifications
- Cytologic atypia
- Epithelial expansion
- Myoepithelium
- Prominent nucleoli
Board review style answer #2
C. Epithelial expansion. Atypical apocrine adenosis (AAA) and apocrine ductal carcinoma in situ (DCIS) share features of apocrine cytology, including enlarged nuclei with prominent nucleoli and eosinophilic cytoplasm, as well as significant cytologic atypia and an intact myoepithelial cell layer. Both may also have calcifications; however, apocrine DCIS is differentiated from AAA by architectural atypia or epithelial expansion by clonal, monotonous cells.
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Reference: Apocrine adenosis
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Reference: Apocrine adenosis
Apocrine metaplasia
Table of Contents
Definition / general | Essential features | Epidemiology | Sites | Etiology | Clinical features | Diagnosis | Radiology description | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Negative stains | Electron microscopy description | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Is considered one of the most common metaplastic changes of the breast, characterized by enlarged epithelial cells with abundant granular eosinophilic cytoplasm that can show apical snouting (Schnitt: Biopsy Interpretation of the Breast, 2nd Edition, 2012)
Essential features
- Cells with abundant eosinophilic cytoplasm and apical snouts
- Nuclei are round with variable size, vesicular chromatin with prominent nucleoli
- Supranuclear vacuoles or eosinophilic granules may be present
Epidemiology
- Common in women > 25 years of age (J Clin Pathol 2007;60:1313)
- Occasionally can be found in younger woman
Sites
- Breast parenchyma ducts and lobules
Etiology
- Unknown; the relation to hormonal imbalances is not well established
- Appears to be part of the fibrocystic complex manifested in cysts or part of ordinary duct hyperplasia (Hoda: Rosen's Breast Pathology, 4th Edition, 2014)
Clinical features
- Grossly palpable cysts can be lined by apocrine epithelium but there are no specific clinical features per se due to the apocrine metaplasia itself
- Can be concurrent with both benign and malignant lesions (J Clin Pathol 2007;60:1313)
- Apocrine cysts and hyperplasia with apocrine metaplasia were more common in the breasts of American women in New York than in Japanese women in Tokyo (Hoda: Rosen's Breast Pathology, 4th Edition, 2014)
Diagnosis
- Histologic examination of tissue removed
Radiology description
- Mammographic features are nonspecific, although an enlarging lobular or micro lobulated mass may be noted
- Heterogeneous microcalcification clusters may sometimes represent apocrine metaplasia
- These findings can lead to needle core biopsy for definitive diagnosis (AJR Am J Roentgenol 2003;180:795)
Prognostic factors
- No relationship or minimal impact on the development of mammary carcinoma (Hoda: Rosen's Breast Pathology, 4th Edition, 2014)
- Florida apocrine metaplasia with atypia may coexist with apocrine carcinoma, although most patients with short term follow up remained well
Case reports
- 48 year old woman presented with a growing palpable mass in her right breast of 3 months' duration (J Korean Soc Radiol 2018;78:103)
Treatment
- Specific treatment is not indicated for proliferative lesions with apocrine metaplasia
- Surgical excision of apocrine cysts is not indicated unless there is bloody fluid, the cysts reform or there is atypia in the cytologic specimen
- Atypical apocrine metaplasia warrants a clinical evaluation comparable to that of women with other atypical proliferative lesions, yet the precancerous significance of this abnormality remains uncertain
Gross description
- No specific gross findings are noted
- Apocrine areas may show a brown color when unfixed (Hoda: Rosen's Breast Pathology, 4th Edition, 2014)
Microscopic (histologic) description
- Cells are enlarged with abundant eosinophilic cytoplasm and apical snouts
- Supranuclear vacuoles or eosinophilic granules may be present
- Nuclei are round with variable size, vesicular chromatin with prominent nucleoli
- Can be a single or multiple layer epithelium; even papillary configurations can be seen (papillary apocrine change)
- Apocrine cells can show a degree of nuclear variability, even in simple epithelium; this is partly a product of cross cutting of a large nucleus and partly an intrinsic property of apocrine epithelium
- Moderate degrees of nuclear variation and atypia are ignored unless there is necrosis or significant mitotic activity (J Clin Pathol 2007;60:1313)
- Cytologic atypia tends to be more severe in sclerosing adenosis
- Highly complex architecture with cytologic atypia should be categorized as atypical ductal hyperplasia or ductal carcinoma in situ
Microscopic (histologic) images
Contributed by Carlos C. Diez Freire, M.D.
Dilated eosinophilic glands
Papillary projections
Abundant cytoplasm
Early apocrine metaplasia and p63
Cytology description
- Nuclei of benign apocrine cells are eccentrically located with slight variation in size; the nuclear membrane is smooth with fine granular dispersed chromatin and a single prominent nucleolus
- Cytoplasm is abundant and dense with distinct cell borders with diffuse finely granular cytoplasm that stains pink / blue in PAP stains and purple / gray in Romanowsky stains
- Atypical apocrine cells can include nuclear enlargement, pleomorphism, prominent nucleoli and cellular dyshesion
- Features more concerning for carcinoma include crowded cell clusters, more pleomorphism, irregular nuclear borders, dark clumpy chromatin and increased nuclear to cytoplasmic ratio and necrosis
- Be cautious in a diagnosis of malignancy when atypical apocrine cells occur together with benign cells or if the lesion is clinically or mammographically benign (Demay: The Art & Science of Cytopathology, 2nd Edition, 2011)
Positive stains
- PAS (coarse glycolipid granules), GCDFP-15, androgen receptor (J Clin Pathol 2007;60:1313)
- EMA
- MYC nuclear staining but no amplification by FISH (Breast 2002;11:466)
Negative stains
- ER, PR
- BCL2 and rare staining for p53
- Low Ki67 but can be slightly higher in complex papillary cases with higher values associated with atypical apocrine cells (Mod Pathol 2000;13:13, Breast J 2009;15:475)
- p63 may show reduction or complete loss of myoepithelial cell layer (Am J Surg Pathol 2011;35:202)
Electron microscopy description
- Abundant endoplasmic reticulum, numerous mitochondria, intermediate filaments and secretory vesicles in the cytoplasm
Molecular / cytogenetics description
- Loss of heterozygosity in 53% (Am J Pathol 2000;157:323)
- Most common losses were at 1p, 17q and 22q and gains at 2q and 13q (Am J Pathol 2001;158:207)
Sample pathology report
- Left breast, 2 o’clock, 5 cm from nipple, ultrasound guided core biopsy:
- Papillary apocrine metaplasia and duct dilation
Differential diagnosis
- Atypical apocrine adenosis:
- Cytologic atypia with more than threefold variation in nuclear size with prominent multiple nucleoli (J Clin Pathol 2007;60:1313)
- Apocrine DCIS:
- Extensive proliferation, marked nuclear pleomorphism (J Clin Pathol 2007;60:1313)
- Architectural complexity such as well formed Roman bridges or rigid cribriform structures
Additional references
Board review style question #1
Apocrine metaplasia of the breast is characterized by
- Dilation of terminal ducts with periductal fibrosis and chronic inflammation
- Epithelial cells with abundant granular eosinophilic cytoplasm and prominent nucleoli
- Monotonous population of histiocytes with foamy cytoplasm distending the ducts
- Severely atypical and pleomorphic cells of mesenchymal origin
Board review style answer #1
B. Apocrine metaplasia of the breast is characterized by enlarged epithelial cells with abundant granular eosinophilic cytoplasm that can show apical snouting, eccentric nuclei and prominent nucleoli.
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Reference: Apocrine metaplasia of breast
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Reference: Apocrine metaplasia of breast
Board review style question #2
The histologic findings in the above breast images are an example of
- Apocrine metaplasia
- Intraductal papilloma
- Mammary duct ectasia
- Papillary ductal carcinoma in situ
Board review style answer #2
A. Apocrine metaplasia. Cells are enlarged with abundant eosinophilic cytoplasm and apical snouts. Supranuclear vacuoles or eosinophilic granules may be present. Nuclei are round with variable size, vesicular chromatin with prominent nucleoli. Can be a single or multiple layer epithelium, even papillary configurations can be seen (papillary apocrine change).
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Reference: Apocrine metaplasia of breast
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Reference: Apocrine metaplasia of breast
Atezolizumab
Table of Contents
Definition / general | Trade name | Indications | Pathophysiology | Diagrams / tables | Clinical information | Uses by pathologists | Side effects | Drug administration | Molecular theory | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- A humanized IgG1 monoclonal antibody blocking programmed death ligand 1 (PDL1)
- Developed by Genentech, Inc.
- Synonyms: MPDL3280A, RG7446
Trade name
- Tecentriq®
Indications
- Urothelial carcinoma locally advanced or metastatic disease fulfilling 1 of the following criteria
- Not eligible for cisplatin based chemotherapy and tumor expresses PDL1 (PDL1 stained tumor infiltrating immune cells covering ≥ 5% of the tumor area) - FDA approved 2017
- Not eligible for platinum based chemotherapy with any PDL1 staining status - FDA approved 2017 (Oncologist 2019;24:563)
- Disease progression with platinum based chemotherapy - FDA approved 2016
- Non small cell lung cancer (NSCLC) fulfilling one of the following criteria
- First line treatment for metastatic NSCLC with high PDL1 expression (PDL1 staining ≥ 50% tumor cells or immune cells ≥ 10%) and no EGFR or ALK gene alterations - FDA approved 2020
- In combination with chemotherapy (paclitaxel protein bound; nab-paclitaxel and carboplatin) for metastatic nonsquamous NSCLC with no EGFR or ALK gene alterations - FDA approved 2019
- In combination with bevacizumab, paclitaxel and carboplatin for metastatic nonsquamous NSCLC with no EGFR or ALK gene alterations - FDA approved 2018
- Metastatic NSCLC with EGFR or ALK gene alterations and disease progression when treated with platinum based chemotherapy - FDA approved 2016 (Lancet 2017;389:255)
- Triple negative breast cancer locally advanced or metastatic with PDL1 expression of immune cells ≥ 1% of tumor area - FDA approved 2019 (N Engl J Med 2018;379:2108)
- Small cell lung cancer advanced stage in combination with carboplatin and etoposide - FDA approved 2019 (N Engl J Med 2018;379:2220)
- Hepatocellular carcinoma in combination with bevacizumab - FDA approved 2020 (N Engl J Med 2020;382:1894)
- Melanoma unresectable or metastatic with BRAF V600 mutation in combination with cobimetinib and vemurafenib - FDA approved 2020 (Nat Med 2019;25:929)
- Reference: Drugs.com: Tecentriq FDA Approval History [Accessed 18 December 2020]
Pathophysiology
- PD1 receptor expressed on activated T cells, B cells, macrophages and NK cells (Nat Rev Immunol 2018;18:153)
- PDL1 expressed on antigen presenting cells and many types of cancer cells (Nature 2016;534:402)
- Binding of PD1 to PDL1 or B7H1 can suppress T cell proliferation, cytokine production and cytolytic activity
- Aberrant expression of PDL1 on cancer cells through interaction with PD1 receptor blocks antitumor immunity and escape immune surveillance (Nature 2016;534:402)
- Atezolizumab, a PDL1 inhibitor, blocks the binding of PD1 with PDL1, resulting in prevention of inhibition of T cell immune response and reactivation of T cell mediated antitumor cytolytic activity (Clin Cancer Res 2017;23:1886)
Diagrams / tables
Images hosted on other servers:
Atezolizumab blocks PDL1 on tumor cells
Inhibition of PDL1 through STAT3 / caspase 7 signaling
(a,c) Crystals of PDL1 with atezolizumab
Clinical information
- Immune mediated diseases associated with treatment with atezolizumab
- Pneumonitis: withhold or discontinue based on severity (Chest 2017;152:271)
- Hepatitis: monitor liver function, withhold or discontinue
- Colitis: withhold or discontinue based on severity (JAMA Oncol 2018;4:1721)
- Endocrinopathies (JAMA Oncol 2018;4:173):
- Hypophysitis: withhold based on severity of hypophysitis
- Hyperthyroidism: monitor thyroid function
- Adrenal insufficiency: withhold based on severity
- Type 1 diabetes mellitus: withhold based on severity
- Infections: withhold for severe infection (Respir Med 2020;161:105853)
- Infusion related reactions: slow the rate of infusion or discontinue
- Embryo fetal toxicity: advise females of reproductive potential
- Pharmacokinetics (Clin Pharmacol Ther 2017;102:305):
- Dose range: 1 - 20 mg/kg, including a dose of 1,200 mg every 3 weeks
- Clearance: 0.20 L/day
- Volume of distribution: 6.91 L
- Terminal half life: 27 days
- Steady state: achieved after 6 - 9 weeks (2 - 3 cycles)
- Tecentriq treatment costs approximately $13,860 per month (Drugs.com: What Is the Cost of Tecentriq? [Accessed 17 December 2020])
Uses by pathologists
- VENTANA PDL1 SP142 Assay (Roche Diagnostics): FDA approved companion diagnostic to atezolizumab; not substitutable with other PDL1 assays (22C3, SP263) (Appl Immunohistochem Mol Morphol 2019;27:92)
- Tumor cell (TC) staining: membranous, linear, partial to complete circumferential staining pattern at any intensity (Mod Pathol 2019;32:929, Arch Pathol Lab Med 2018;142:982)
- Immune cell (IC), including lymphocyte, neutrophil and macrophage staining: punctate, incomplete, membranous staining pattern at any intensity; exclude intravascular immune cells and cells in necrotic area (Mod Pathol 2019;32:929, Arch Pathol Lab Med 2018;142:982)
- Total tumor area: the area covered by tumor cells with intratumoral and peritumoral stroma
- Urothelial carcinoma: evaluate immune cells only and disregard tumor cells
- Positive: presence of staining at any intensity in immune cells ≥ 5% of tumor area
- Negative: absence of any staining in immune cells < 5% of tumor area (see PDL1 SP142) (Am J Surg Pathol 2018;42:1059)
- NSCLC: evaluate tumor cells and then evaluate immune cells (if tumor cells negative)
- Positive: presence of staining at any intensity in tumor cells ≥ 50%
- Negative: staining at any intensity in tumor cells < 50% (proceed to immune cell count)
- Positive: presence of staining at any intensity in immune cells ≥ 10% of tumor area
- Negative: staining at any intensity in immune cells < 10% of tumor area (Histopathology 2018;72:449)
- Triple negative breast carcinoma: evaluate immune cells only and disregard tumor cells
- Positive: presence of staining at any intensity in immune cells ≥ 1% of tumor area
- Negative: staining at any intensity in immune cells < 1% of tumor area (see PDL1 SP142)
Side effects
- Tecentriq as a single agent (reported in > 20% of patients)
- Constipation, cough, decreased appetite, dyspnea, fatigue, nausea (N Engl J Med 2020;383:1328)
- Tecentriq in combination with bevacizumab, paclitaxel and carboplatin (reported in > 20% of patients)
- Arthralgia, asthenia, alopecia, constipation, decreased appetite, diarrhea, hypertension, nausea, peripheral neuropathy (N Engl J Med 2018;378:2288)
- Tecentriq in combination with paclitaxel protein bound (reported in > 20% of patients)
- Alopecia, anemia, constipation, cough, decreased appetite, diarrhea, fatigue, headache, nausea, neutropenia, peripheral neuropathies, vomiting (N Engl J Med 2018;379:2108)
- Others: hyponatremia, pneumonia, hyperkalemia, thrombocytopenia, death
- Reference: FDA: Tecentriq (atezolizumab) [Accessed 18 December 2020]
Drug administration
- For metastatic urothelial carcinoma:
- Tecentriq 1,200 mg IV over 60 min for 3 weeks
- For treatment of nonsquamous non small cell lung cancer:
- Tecentriq 1,200 mg IV over 60 minutes, followed by bevacizumab, paclitaxel and carboplatin every 3 weeks for a maximum of 4 - 6 cycles
- Following completion of chemotherapy, Tecentriq 1,200 mg IV, followed by bevacizumab every 3 weeks
- For metastatic triple negative breast cancer:
- Tecentriq 840 mg IV over 60 minutes, followed by 100 mg/m² paclitaxel
- Every 28 days, Tecentriq is administered on days 1 and 15 and paclitaxel is administered on days 1, 8 and 15
- Reference: PDR: Atezolizumab - Drug Summary [Accessed 17 December 2020]
Molecular theory
- PDL1 expressed on tumor cells, through binding to PD1, inhibits T cell immune response
- PDL1 may suppress IFN mediated cytotoxicity through a STAT3 / caspase 7 dependent signaling pathway (Sci Adv 2020;6:2712)
- The RMLDVEKC motif of PDL1 is essential to hinder interferon toxicity, while the DTSSK motif blocks this function (Sci Adv 2020;6:2712)
- PDL1 protects tumor cells from T cell dependent cytotoxicity
- Crystal structures of interaction of PDL1 with atezolizumab antigen binding fragment through the immunoglobulin superfamily V set domain of PDL1 (Sci Rep 2017;7:5532)
Additional references
Board review style question #1
Which of the following proteins is blocked by atezolizumab?
- PD1
- PDE1
- PDGF
- PDL1
Board review style answer #1
D. PDL1. Atezolizumab is a humanized IgG1 monoclonal antibody that blocks programmed death ligand 1 (PDL1). Answers A - C are incorrect because PD1, PDGF and PDE1 are not blocked by atezolizumab.
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Reference: Atezolizumab
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Reference: Atezolizumab
Board review style question #2
Which of the following is true about the PDL1 SP142 assay?
- Evaluates percentage of tumor cells stained positive for PDL1 and disregards tumor infiltrating immune cells in non-small cell lung cancer
- Evaluates percentage of tumor cells stained positive for PDL1 and evaluates tumor infiltrating immune cells if tumor cells are negative in non-small cell lung cancer
- Evaluates percentage of tumor cells stained positive for PDL1 in triple negative breast carcinoma
- Evaluates percentage of tumor cells stained positive for PDL1 in urothelial carcinoma
Board review style answer #2
B. Evaluates percentage of tumor cells stained positive for PDL1 and evaluates tumor infiltrating immune cells if tumor cells are negative in non-small cell lung cancer. Answers C and D are incorrect because PDL1 SP142 evaluates immune cells only and disregards tumor cells in both urothelial carcinoma and triple negative breast carcinoma. Answer A is incorrect because in non-small cell lung cancer, PDL1 SP142 evaluates tumor cells and then evaluates immune cells if tumor cells are negative.
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Reference: Atezolizumab
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Reference: Atezolizumab
Atypical ductal hyperplasia
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Radiology description | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Positive stains | Negative stains | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Intraductal clonal epithelial cell proliferation with similar histologic features to (but insufficient involvement or volume for the diagnosis of) low grade ductal carcinoma in situ (DCIS)
Essential features
- Intraductal clonal epithelial cell proliferation with cytologic and morphologic features similar to low grade ductal carcinoma in situ
- Differentiated from low grade ductal carcinoma in situ by size (≤ 2 mm) or space occupied by clonal cells (≤ 2 spaces or only portion of involved space)
- Rigid bridges, polarization around lumen and estrogen receptor (ER) (diffuse, strong) positivity
Terminology
- B3 lesion (uncertain malignant potential)
- Atypical intraductal hyperplasia (AIDH)
- Ductal intraepithelial neoplasia (DIN) 1B
- Mammary intraepithelial neoplasia (MIN)
- Atypical hyperplasia is not recommended by WHO unless ductal versus lobular differentiation cannot be discerned
ICD coding
Epidemiology
- F > M (rare incidental finding in gynecomastia)
- Commonly presents in fourth decade
- 5 - 20% of breast biopsies (StatPearls: Atypical Breast Hyperplasia [Accessed 19 November 2019])
- Reduction of postmenopausal hormonal therapy linked to decreased rates (Cancer Epidemiol Biomarkers Prev 2009;18:2822)
- 4 - 5x risk of developing ductal carcinoma in situ within 5 years (Cancer Prev Res (Phila) 2014;7:211)
- Absolute risk of breast cancer is approximately 1% per year for at least 25 years, with a mean latency period of 8 - 12 years after initial diagnosis
- Recent radiological pathological concordance series have shown that biopsy diagnosed atypical ductal hyperplasia (ADH) has an upgrade rate of 10 - 20% to DCIS or invasive carcinoma
Sites
- 2:1 ratio of ipsilateral to contralateral breast (Cancer Prev Res (Phila) 2014;7:211)
Pathophysiology
- Low grade model of progression from normal breast / benign proliferative breast disease to atypical ductal hyperplasia (Histopathology 2010;57:171)
Etiology
- EZH2 (enhancer of zeste homolog 2) overexpression has an important role in oncogenesis (Arch Pathol Lab Med 2018;142:1182)
- Lifelong exposure to estrogen causes a continued accumulation of genomic changes that leads to defective growth control (Cancer Prev Res (Phila) 2014;7:211)
- Shared alterations with low grade ductal carcinoma in situ: gains 1q and loss 16q-17p (Histopathology 2010;57:171)
Radiology description
- No specific diagnostic features differentiate atypia from malignant lesions (AJR Am J Roentgenol 2014;202:1389)
- Incidentally discovered on routine screening mammograms (3.3 per 10,000)
- Often identified in breast biopsies performed as a result of calcifications on imaging (Acad Radiol 2019;26:893)
- May be seen as nonmass enhancement on breast MRI
Prognostic factors
- Higher risk with
- Younger age
- BRCA1 / BRCA2 mutations
- Family history
- Higher number of separate foci (overall volume)
- Extent of lobular involution (complete / partial) correlated with age (J Natl Cancer Inst 2017;109:djx035, Cancer Prev Res (Phila) 2014;7:211)
Case reports
- 15 year old girl with atypical ductal hyperplasia and juvenile fibroadenoma (Clin Breast Cancer 2018;18:e751)
- 21 year old man with atypical ductal hyperplasia in gynecomastia (Adv Plast Reconstr Surg 2017;1:1)
- 42 year old man with gynecomastia, atypical ductal hyperplasia and ductal carcinoma in situ associated with invasive breast carcinoma, undergoing antiretroviral therapy (Int J Surg Pathol 2016;24:139)
Treatment
- Most biopsy proven lesions undergo excision with some variation, as directed by
- Imaging findings (e.g., small versus larger extent of calcifications)
- Biopsy type / size: excision rate 60% if diagnosed by vacuum assisted biopsy
- Patient / surgeon preference
- Tamoxifen reduced the risk of subsequent cancer from 21 to 7.5% (Breast Cancer Res 2018;20:39)
Gross description
- Usually difficult to detect grossly
- Associated calcifications may feel gritty
Microscopic (histologic) description
- Histologic sections show well defined, monomorphic cells with evenly spaced, small rounded nuclei
- Variable patterns:
- Solid
- Cribriform (polarization around lumina)
- Micropapillary (club shaped)
- Unicentric or multicentric
- Uniform thickness of rigid bridges or arcades (differential feature from usual ductal hyperplasia)
- Intraluminal microcalcifications are often seen
- Rarely can be mixed with usual ductal hyperplasia or other proliferations within the same lobule
- Differentiation from low grade ductal carcinoma in situ is controversial and shows interobserver variability with low agreement rate on biopsy (40 - 60%), especially because the majority of the distinction is based on the following (generally accepted) quantitative features:
- Size: ≤ 2 mm (Cancer 1990;65:518)
- Space involvement: ≤ 2 spaces or only portion of involved space (Cancer 1985;55:2698)
- Conservative approach is suggested on biopsy; definitive diagnosis should be upon surgical excision if the lesion is borderline between atypical ductal hyperplasia and low grade ductal carcinoma in situ
- If nuclear atypia warrants a diagnosis of intermediate or high grade ductal carcinoma in situ, atypical ductal hyperplasia should not be diagnosed based on size
- Intermediate or high grade ductal carcinoma in situ should be diagnosed regardless of size or extent
Microscopic (histologic) images
Contributed by Julie M. Jorns, M.D.
Cribriform
Small foci with cribriforming and monotony
Polarization
Bridges with uniform thickness
Cribriform and solid
Solid growth
Micropapillary
Short papillae
Partial gland involvement
Virtual slides
Images hosted on other servers:
Atypical ductal
hyperplasia with
microcalcifications
Positive stains
- Low molecular weight cytokeratins: CK8, CK18, CK19 (Schnitt: Biopsy Interpretation of the Breast, 3rd Edition, 2018)
- Strong and uniform estrogen receptor / ER expression
Negative stains
Sample pathology report
- Left breast, 1 o'clock, stereotactic core biopsy:
- Focal (0.1 cm) atypical ductal hyperplasia (ADH) with microcalcifications
Differential diagnosis
- Usual ductal hyperplasia:
- Nonclonal cell proliferation
- Cells are not uniform; they show different sizes and shapes with overlapping / streaming architecture
- Cells not oriented around lumen
- Bridges stretch with central attenuation and lumina are flattened / slit-like
- Positive mosaic or patchwork pattern of CK5/6 staining
- Low grade ductal carcinoma in situ:
- Same cytologic and morphologic characteristics of atypical ductal hyperplasia but ≥ 2 mm in size, involving the entire lobular space and extending to > 2 lobules
Board review style question #1
A breast biopsy was performed for calcifications. The above image is most characteristic of which pattern of atypical ductal hyperplasia?
- Cribriform
- Flat
- Micropapillary
- Solid
Board review style answer #1
C. Micropapillary
While specifying the pattern of atypical ductal hyperplasia is not clinically important or necessary in the pathology report, recognizing key features and patterns is important in making the diagnosis. Atypical ductal hyperplasia is defined by having some but not all features of low grade ductal carcinoma in situ, with low volume or size (≤ 2 spaces or including only a portion of the involved space or ≤ 2 mm in overall size). Common patterns of atypical ductal hyperplasia include cribriform, micropapillary and solid. Flat patterns are more in keeping with the diagnosis of flat epithelial atypia. The example above has short, club shaped micropapillae, characteristic of the micropapillary pattern of atypical ductal hyperplasia.
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Reference: Atypical ductal hyperplasia
While specifying the pattern of atypical ductal hyperplasia is not clinically important or necessary in the pathology report, recognizing key features and patterns is important in making the diagnosis. Atypical ductal hyperplasia is defined by having some but not all features of low grade ductal carcinoma in situ, with low volume or size (≤ 2 spaces or including only a portion of the involved space or ≤ 2 mm in overall size). Common patterns of atypical ductal hyperplasia include cribriform, micropapillary and solid. Flat patterns are more in keeping with the diagnosis of flat epithelial atypia. The example above has short, club shaped micropapillae, characteristic of the micropapillary pattern of atypical ductal hyperplasia.
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Reference: Atypical ductal hyperplasia
Board review style question #2
What is the most useful immunohistochemical stain in the differential diagnosis of usual ductal hyperplasia and atypical ductal hyperplasia?
- Calponin
- CK5/6
- CK7
- CK20
- p63
Board review style answer #2
B. CK5/6
Usual ductal hyperplasia and atypical ductal hyperplasia of the breast may sometimes be difficult to distinguish morphologically. Thus, use of CK5/6 immunohistochemical staining may be helpful in the differential diagnosis, as usual ductal hyperplasia is positive (in a mosaic or patchwork pattern) and atypical ductal hyperplasia is negative for CK5/6. Both usual ductal hyperplasia and atypical ductal hyperplasia are typically positive for CK7 and negative for CK20 (breast ductal epithelium immunophenotype). Myoepithelial markers p63 and calponin show positive myoepithelial staining in both usual ductal hyperplasia and atypical ductal hyperplasia.
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Reference: Atypical ductal hyperplasia
Usual ductal hyperplasia and atypical ductal hyperplasia of the breast may sometimes be difficult to distinguish morphologically. Thus, use of CK5/6 immunohistochemical staining may be helpful in the differential diagnosis, as usual ductal hyperplasia is positive (in a mosaic or patchwork pattern) and atypical ductal hyperplasia is negative for CK5/6. Both usual ductal hyperplasia and atypical ductal hyperplasia are typically positive for CK7 and negative for CK20 (breast ductal epithelium immunophenotype). Myoepithelial markers p63 and calponin show positive myoepithelial staining in both usual ductal hyperplasia and atypical ductal hyperplasia.
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Reference: Atypical ductal hyperplasia
Atypical lobular hyperplasia
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology and etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Negative stains | Electron microscopy description | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Clonal proliferation of discohesive epithelial cells arising in terminal duct lobular units
- Similar histologic features to lobular carcinoma in situ (LCIS) but of insufficient quantity
Essential features
- Clonal proliferation of discohesive cells identical to lobular carcinoma in situ but in smaller quantity
- Typical dysfunction / loss of E-cadherin
- Generally considered incidental finding (clinically / radiologically occult)
- 4 - 5 times increased risk of (bilateral risk but higher risk ipsilateral) invasive breast carcinoma compared with general population
- Does not necessarily require excision if isolated finding
Terminology
- Lobular intraepithelial neoplasia 1 (LIN1)
ICD coding
Epidemiology
- F > M (Ann Plast Surg 2015;74:163)
- Typically adults with wide age range, most commonly diagnosed in 50s (Arch Pathol Lab Med 2018;142:391)
- Found in less than 1% of core needle biopsies performed for BI-RADS 4 assessment (Am J Surg 2014;207:24)
Sites
- Bilateral breasts with no specific location
Pathophysiology and etiology
- 16q loss / CDH1 deletion and loss of function of E-cadherin, a transmembrane cell adhesion molecule (Breast Cancer Res 2019;21:76)
- Change in function of E-cadherin rather than loss in some cases and rarely other adhesion proteins implicated with E-cadherin stable
- Low grade neoplasia pathway / family (Breast Cancer Res 2019;21:76)
- Increased expression ESR1, decreased expression SFRP1 (Breast Cancer Res 2019;21:76)
Clinical features
- Frequently associated with columnar cell lesions and flat epithelial atypia; less commonly associated with low grade invasive carcinomas which may have mammographically detectable calcifications, density or mass targeted on biopsy (Am J Surg Pathol 1998;22:1521, Am J Surg Pathol 2007;31:417)
- Does not form a palpable mass
- 19% develop invasive cancer at mean 15 years after diagnosis (4 - 5 times usual risk), 42% are special subtypes with good prognosis (Cancer 2006;107:1227)
Diagnosis
- Core biopsy
- Incidental after mammography, ultrasound or MRI
Radiology description
- Classically considered to be an incidental finding with no radiologic correlates
- Calcifications, if associated with atypical lobular hyperplasia in biopsy or non-mass enhancement on MRI, may be considered concordant after biopsy is read (Breast Dis 2016;36:5)
Radiology images
Prognostic factors
- Lower risk of upgrade than lobular carcinoma in situ
- 4 - 5 times usual risk of carcinoma, higher in ipsilateral breast, higher if age < 50 years; risk increased further if ductal involvement (Am J Surg Pathol 2002;26:421, Cancer 2007;109:180, Hum Pathol 1988;19:201)
- If present at core biopsy, is surgical excision appropriate (controversial)?
- Many studies support excision due to risk of subsequent in situ or invasive carcinoma
- Yes: subsequent DCIS / invasive carcinoma occurs in 6 - 8%, invasive ductal / lobular carcinoma occurs in 25% (Arch Pathol Lab Med 2008;132:979, Am J Surg Pathol 2007;31:717, Am J Surg Pathol 2005;29:534, AJR Am J Roentgenol 2008;190:637)
- No, unless:
- Radiologic pathologic discordance suggests that the targeted lesion was not excised
- Other high risk lesions such as atypical ductal hyperplasia are present that would warrant further surgery
- Atypical lobular hyperplasia has features resembling ductal carcinoma in situ (Am J Surg Pathol 2002;26:1095)
- Atypical lobular hyperplasia has pleomorphic features (Mod Pathol 2008;21:1208, Cancer 2008;112:2152)
- There is diffuse lobular neoplasia at core biopsy (Breast J 2007;13:55)
- No: because there is no significantly increased risk and any subsequent cancer is diffuse, in either breast and not at location of biopsy (Am J Surg 2009;198:792)
Case reports
- 42 year old woman with microcalfications on routine screening mammogram (Arch Pathol Lab Med 2000;124:463)
- 44 year old woman with 1.5 cm palpable smooth lump in the right breast with popcorn-like calcifications (BMC Res Notes 2013;6:267)
- 50 year old woman with abnormal calcifications on screening (Arch Pathol Lab Med 2014;138:1344)
- 53 year old woman with asymmetry on annual screening mammogram (Ann Diagn Pathol 2015;19:20)
- 59 year old woman with 5 cm opacity in upper inner quadrant of left breast detected by mammogram (J Clin Pathol 1992;45:936)
- Premenopausal woman with family history of breast cancer was found to have a subcentimeter mass with calcifications on mammogram (Case of the month #533)
Treatment
- Controversial; some surgeons excise, others get lifelong screening / follow up screening intervals
- Growing evidence to avoid excision for well sampled lesions (Ann Surg Oncol 2017;24:2848)
- Selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) can lower risk of subsequent invasive carcinoma in patients with atypical hyperplasias (atypical lobular hyperplasia or atypical ductal hyperplasia not separated) (J Natl Compr Canc Netw 2018;16:1391)
Gross description
- No specific gross findings
- May be associated with calcifications but typically due to other coexisting lesions
Microscopic (histologic) description
- Solid, discohesive proliferation of cells that are monomorphic, small, have pale pink cytoplasm, uniform oval nuclei and indistinct nuclei
- Some cells have plasmacytoid or signet ring appearance (intracytoplasmic vacuoles)
- Do not form arcades, lumens or papillary projections
- Criteria of Page et al. (Schnitt: Biopsy Interpretation of the Breast, 3rd Edition, 2017):
- Distends 50% or more acini within a lobule (so resembles lobular carcinoma in situ) but not uniformly present throughout entire lobule OR
- Involves all acini in a terminal duct lobular unit (TDLU) and so resembles lobular carcinoma in situ but does not distend the acini (i.e. caliber of the involved acini is similar to that of uninvolved acini)
- Can involve ducts; alteration occurs around the duct as outpouchings producing a cloverleaf pattern
- Lacks intracytoplasmic mucin
- May be no / minimal inflammatory response
Microscopic (histologic) images
Contributed by Eric Statz, M.D., Julie M. Jorns, M.D. and Azadeh Khayyat, M.D. (Case #533)
ALH in fibroadenoma
ALH in fat
Plasmacytoid ALH
Duct with ALH
Lobule expanded by ALH
ALH full lobule
Loss of E-cadherin
Loss of E-cadherin ALH / LCIS
Ductal carcinoma in situ (DCIS), solid type, with microcalcifications, confined to a fibroadenoma; lobular neoplasia (atypical lobular hyperplasia / lobular carcinoma in situ), with involvement of a fibroadenoma
Cytology description
- Loosely cohesive cell clusters composed of uniform cells with occasional intracytoplasmic lumina, minimal nuclear atypia but frequent eccentric nuclei
Positive stains
- ER: ER alpha stronger than ER beta (Virchows Arch 2007;451:893)
- PR
- 34betaE12: polarized
- p120 catenin: cytoplasmic, not membranous (Am J Surg Pathol 2007;31:427)
Negative stains
- E-cadherin (Mod Pathol 2005;18:741): reduced or absent
- HER2
- CK5/6 (Histopathology 2000;37:232)
- Alpha and beta catenin
Electron microscopy description
- Intracytoplasmic lumina, microvilli with secretory droplets; basement membrane and myoepithelial cells are present
Molecular / cytogenetics description
- Diploid
- LOH 16q (Mod Pathol 2005;18:741)
- CDH1 methylation in subset (Breast Cancer Res Treat 2018;167:9)
- Multiple others seen including 22q loss, 2p11.2 gain, 5q32-33.1 (CSF1R) gain, 6q gain, 11q13 gain, 14q32.33 gain, 16p loss (Breast Cancer Res Treat 2018;167:9)
Sample pathology report
- Left breast, 12 o'clock, core biopsy:
- Atypical lobular neoplasia (ALH) (see comment)
- Comment: An immunohistochemical stain for E-cadherin is negative in the atypical focus, supporting the diagnosis of ALH. Controls are appropriate.
Differential diagnosis
- Atypical ductal hyperplasia (ADH):
- Cells should be cohesive with rigid architecture
- E-cadherin positive
- p120 catenin membranous positive
- Lobular carcinoma in situ (LCIS):
- Greater than 50% distension
- Greater than 50% involvement of a lobule
- Benign lobule with clear cell change
Additional references
Board review style question #1
- A lesion was biopsied with immunohistochemistry pictured above. It is best diagnosed as
- Atypical apocrine adenosis (AAA)
- Atypical ductal hyperplasia (ADH)
- Atypical lobular hyperplasia (ALH)
- Flat epithelial atypia (FEA)
Board review style answer #1
C. Atypical lobular hyperplasia (ALH)
Explanation: The above images show an in situ proliferation of small to moderate sized, monotonous epithelial cells with mild expansion of involved glands. There are a few cells with intracytoplasmic vacuoles as well as variably prominent cell borders. Thus, the differential diagnosis includes atypical ductal hyperplasia (ADH) with a solid growth pattern and atypical lobular hyperplasia (ALH). Atypical apocrine adenosis (AAA) has larger cells with apocrine cytology including large, round nuclei with prominent nucleoli and abundant eosinophilic cytoplasmic. Flat epithelial atypia (FEA) has dilated glands with atypical low columnar to cuboidal epithelium with high nuclear cytoplasmic ratio and lack of orientation toward lumina. Characteristic features of AAA and FEA are lacking in the pictured lesion. In the differential of ALH and solid ADH immunohistochemistry can be very helpful, with ALH showing lack or attenuation of E-cadherin and cytoplasmic staining via p120 as shown above. ADH in contrast has strong, diffuse E-cadherin staining and membranous staining via p120.
Comment Here
Reference: Atypical lobular hyperplasia (ALH)
Explanation: The above images show an in situ proliferation of small to moderate sized, monotonous epithelial cells with mild expansion of involved glands. There are a few cells with intracytoplasmic vacuoles as well as variably prominent cell borders. Thus, the differential diagnosis includes atypical ductal hyperplasia (ADH) with a solid growth pattern and atypical lobular hyperplasia (ALH). Atypical apocrine adenosis (AAA) has larger cells with apocrine cytology including large, round nuclei with prominent nucleoli and abundant eosinophilic cytoplasmic. Flat epithelial atypia (FEA) has dilated glands with atypical low columnar to cuboidal epithelium with high nuclear cytoplasmic ratio and lack of orientation toward lumina. Characteristic features of AAA and FEA are lacking in the pictured lesion. In the differential of ALH and solid ADH immunohistochemistry can be very helpful, with ALH showing lack or attenuation of E-cadherin and cytoplasmic staining via p120 as shown above. ADH in contrast has strong, diffuse E-cadherin staining and membranous staining via p120.
Comment Here
Reference: Atypical lobular hyperplasia (ALH)
Board review style question #2
- Atypical lobular hyperplasia (ALH) seen on core biopsy most frequently correlates to the following feature via breast imaging
- Asymmetry
- Calcifications
- Mass
- No specific finding
Board review style answer #2
D. No specific finding
Explanation: Atypical lobular hyperplasia (ALH) is typically not identified via standard imaging modalities. Occasionally ALH has calcifications, although if a core biopsy that has ALH has an indication of calcifications, these are more frequently identified in other lesions in the biopsy such as fibrocystic change or other atypias (e.g. flat epithelial atypia or atypical ductal hyperplasia). ALH is not typically identified as a mass or asymmetry on breast imaging.
Comment Here
Reference: Atypical lobular hyperplasia (ALH)
Explanation: Atypical lobular hyperplasia (ALH) is typically not identified via standard imaging modalities. Occasionally ALH has calcifications, although if a core biopsy that has ALH has an indication of calcifications, these are more frequently identified in other lesions in the biopsy such as fibrocystic change or other atypias (e.g. flat epithelial atypia or atypical ductal hyperplasia). ALH is not typically identified as a mass or asymmetry on breast imaging.
Comment Here
Reference: Atypical lobular hyperplasia (ALH)
Atypical vascular proliferation
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Negative stains | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1Definition / general
- Atypical vascular proliferations on irradiated skin, often small and multiple
Essential features
- Superficial dermal based growth of narrow vascular spaces
- Develops after external radiation for breast carcinoma
- Typically involves the skin overlying breast
- 2 subtypes: lymphatic type and vascular type
- Differentiated from angiosarcoma by lack of multilayering, mitosis, marked cytologic atypia, blood lakes and absence of extension into subcutaneous tissue
Terminology
- Atypical vascular lesion term coined by Fineberg and Rosen in 1994 (Am J Clin Pathol 1994;102:757)
- Acceptable terminology: atypical vascular proliferation
Epidemiology
- Wide age range has been reported but is most common in late sixth to early seventh decade (Breast Cancer Res Treat 2014;146:347, Am J Surg Pathol 2005;29:983)
- Develops 3 to 6 years after radiation treatment (Semin Diagn Pathol 2017;34:410)
Sites
- Skin of breast or anterior chest wall exposed to previous radiation
Pathophysiology
- Secondary to irradiation but precise pathogenesis is unknown
Etiology
- Directly associated with radiation treatment
- Median total administered dose: 50 Gy (Am J Surg Pathol 2005;29:983)
Clinical features
- Multiple, small papules or vesicles and erythematous plaques (Am J Surg Pathol 2002;26:328)
Diagnosis
- Requires correlation of clinical history and physical examination with microscopic features
- Complete excision of the lesion is required for definitive diagnosis
Prognostic factors
- Mostly follows a benign course (Am J Surg Pathol 2005;29:983)
- Local recurrences and development of further similar lesions may occur in the radiation field
- Progression to angiosarcoma is rare but reported (Am J Surg Pathol 2005;29:983)
Case reports
- 41 and 61 year old women with small vascular lesions of the breast diagnosed by MRI guided vacuum assisted biopsy (Radiol Case Rep 2022;17:2492)
- 43 year old woman presented with 29 atypical vascular lesions following breast conserving surgery and radiation (Cutis 2019;103:E22)
- 49 year old woman presented with postradiation atypical vascular proliferation mimicking angiosarcoma 8 months following breast conserving therapy for breast carcinoma (J Clin Aesthet Dermatol 2011;4:47)
Treatment
- Complete excision with uninvolved surgical margins and follow up (Am J Surg Pathol 2005;29:983)
Clinical images
Contributed by Anna Purdy, M.S.N.
Upper outer quadrant erythema
Axillary papules
Images hosted on other servers:
Postmastectomy
Left breast is erythematous with sclerotic tissue changes
Papules and nodules around the mastectomy scar
Gross description
- ≥ 1 circumscribed papules, bluish purple nodules, small vesicles or erythematous plaques, median of 0.5 cm
- Tends to be well demarcated, symmetric and wedge shaped (Semin Diagn Pathol 2017;34:410)
Microscopic (histologic) description
- Relatively well circumscribed lesion with a somewhat wedge shaped outline, limited to the dermis and not extending into subcutis
- 2 histologic subtypes with overlapping histologic features (Am J Surg Pathol 2008;32:943):
- Lymphatic subtype:
- More common subtype
- Irregularly shaped, thin walled vascular channels with a branching and anastomosing growth
- Lymphatic valve-like structures may be evident
- Vessels lined by single layer of endothelial cells without atypia
- Hobnailing and nuclear hyperchromasia may be seen
- Vascular subtype:
- Thin capillary channels lined by flattened to hobnail endothelium, lacking lobular growth pattern
- Lymphatic subtype:
- Individual lesions may show composite features of both subtypes
Microscopic (histologic) images
Contributed by Indu Agarwal, M.D., Sharlene See, M.D. and Julie M. Jorns, M.D.
Wedge shaped outline
Flat to plump endothelial cells
Vascular channels
Excision specimen
Papule
Skin punch biopsy
Skin punch biopsy (CD31)
Skin punch biopsy (c-MYC)
Positive stains
- CD31, D2-40 (lymphatic type) (Breast Cancer Res Treat 2014;146:347)
- Variable CD34
Negative stains
Molecular / cytogenetics description
- Unknown
Sample pathology report
- Left breast skin, punch biopsy:
- Atypical vascular lesion (see comment)
- Comment: The lesion is comprised of a vascular proliferation dissecting the collagen in the superficial dermis. There is no significant nuclear pleomorphism or mitotic activity. An immunostain performed for c-MYC is negative in the lesion. Morphologic and immunohistochemical findings support the diagnosis.
Differential diagnosis
- Angiosarcoma, well differentiated:
- Features of angiosarcoma which are lacking in atypical vascular lesions:
- Large (median size is 7.5 cm) infiltrative lesion with destruction of adnexa and extension into subcutaneous tissues, multilayering of endothelial cells, prominent nucleoli, mitoses, blood lakes and solid areas
- Unlike secondary angiosarcomas, atypical vascular lesions lack MYC amplification (by FISH) and MYC overexpression by immunohistochemistry
- However, angiosarcoma may be part of morphologic continuum with atypical vascular lesions and may need additional biopsies to distinguish these entities (J Am Acad Dermatol 2007;57:126)
- Features of angiosarcoma which are lacking in atypical vascular lesions:
- Hemangioma of skin:
- No history of radiation
- Lesions consist of dilated blood vessels in skin, filled with blood
- Vessels have rounded contours and are nonanastomosing
- Benign lymphangioendothelioma (Am J Surg Pathol 2000;24:1047):
- Rare lesion with no history of radiation
- Head and neck are more common sites, followed by limbs and trunk
- Skin lesions may be macular or papular and pigmented
- Anastomosing dilated vessels lined by flattened endothelium are present in superficial dermis; spaces may be empty or contain blood
- Cytologic atypia and mitoses are absent
Additional references
Board review style question #1
A brownish papular lesion of skin on the breast is excised. Histopathologic examination shows that it is comprised of a wedge shaped, relatively well circumscribed vascular proliferation, dissecting the collagen in the superficial dermis. No significant nuclear pleomorphism or mitotic activity is noted. What is the most important information you need to make the diagnosis?
- Family history of cancer
- History of cancers of other sites
- History of chemotherapy
- History of radiation to the site
Board review style answer #1
D. History of radiation to the site. Atypical vascular lesions only occur in previously irradiated areas of the breast. The histologic description matches that of an atypical vascular lesion but to make a confident diagnosis, prior history of irradiation and histologic examination of the entire lesion is essential.
Comment Here
Reference: Atypical vascular proliferation
Comment Here
Reference: Atypical vascular proliferation
Axillary lymph nodes
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Clinical features | Diagnosis | Radiology description | Prognostic factors | Case reports | Treatment | Frozen section description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Negative stains | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Extent of axillary lymph node involvement is important for breast cancer stage, clinical management and prognosis
Essential features
- Evaluation of axillary lymph nodes for pathologic staging of invasive breast cancer requires sentinel lymph node biopsy with or without axillary lymph node dissection
- Axillary lymph node dissection should contain 10 or more lymph nodes
- Primary goal when histologically evaluating axillary lymph nodes is to identify all macrometastases
Terminology
- Macrometastases: > 2.0 mm
- Micrometastases: > 0.2 mm to 2.0 mm, or > 200 cells in a single histologic cross section
- Isolated tumor cells (ITCs): ≤ 0.2 mm or ≤ 200 cells in a single histologic cross section
ICD coding
Clinical features
- Axillary lymph node dissection typically removes level I and level II lymph nodes
- Lymph node dissection of level I and level II of the axilla should contain 10 or more lymph nodes
- If level III lymph nodes are surgically removed, the surgeon should separately identify them for staging purposes
- Regional lymph nodes:
- Axillary (ipsilateral), subdivided as follows:
- Level I (low axilla): lateral to the lateral border of pectoralis minor muscle
- Level II (mid axilla): between medial and lateral borders of pectoralis minor muscle, plus the interpectoral (Rotter) lymph nodes
- Level III (apical axilla or infraclavicular nodes): medial to the medial margin of the pectoralis minor muscle and inferior to the clavicle
- Internal mammary (ipsilateral): lymph nodes in the intercostal spaces along the edge of the sternum in the endothoracic fascia
- Supraclavicular (ipsilateral)
- Axillary (ipsilateral), subdivided as follows:
- Intramammary nodes are present within breast tissue and are most commonly found in the upper outer quadrant and may rarely be sentinel lymph nodes; these nodes are included with axillary nodes for AJCC N classification
- Side effects of axillary nodal dissection include lymphedema, shoulder restriction, numbness, weakness and pain syndromes (Cancer J 2008;14:216)
Diagnosis
- Lymph nodes are thinly sliced at 2 mm intervals (to detect all macrometastasis)
- All lymph node tissue is submitted for histologic evaluation
- If grossly positive then a representative section (including any possible areas of extranodal extension) is adequate
- Additional evaluation of SLNs to detect occult metastasis, including multiple levels and cytokeratin immunohistochemistry, offers no clinical benefit (N Engl J Med 2011;364:412)
- Intraoperative evaluation of sentinel lymph nodes can be avoided in most patients who are clinically node negative and are undergoing breast conserving surgery (Arch Pathol Lab Med 2016;140:830)
Radiology description
- Axillary ultrasound (US) is the primary modality for evaluating axillary lymph node status prior to surgery
- Cortical thickening, hilar effacement and nonhilar cortical blood flow are more important than size criteria in the identification of metastases (Radiographics 2013;33:1589)
- Preoperative axillary US and fine needle aspiration (FNA) cytology are routine at many breast units, with a sensitivity of 56% (confidence interval: 47 - 64%) and specificity of 90% (84 - 93%) for US alone, and 76% (61 - 87%) and 100% (65 - 100%) when combined with FNA cytology (J BUON 2011;16:454)
- Standard breast MRI is comparable to dedicated axillary US in breast cancer patients; subsequent axillary US can be done on those with suspicious nodal findings (Eur J Radiol 2016;85:2288)
- CT and radionuclide imaging play a lesser role in imaging the axilla (Radiographics 2013;33:1589)
Prognostic factors
- Presence of axillary lymph node metastases is the most important prognostic factor for disease free and overall survival in the absence of distant metastasis and is important for determining treatment for breast cancer
- Macroscopic extranodal extension presents clinically as palpable matted lymph nodes and is a risk factor for local regional recurrence
- Microscopic extranodal extension measuring > 2 mm is associated with greater axillary nodal burden (Ann Surg Oncol 2014;21:2897)
- Tumor deposits and intravascular tumor emboli in extranodal axillary fat are associated with greater axillary nodal burden (Ann Surg Oncol 2020;27:3585)
- Presence of treatment effect (fibrosis with or without macrophages or hemosiderin) after neoadjuvant chemotherapy is an important prognostic factor
Case reports
- 49 year old man with axillary lymph node metastasis as first manifestation of occult breast cancer (Medicine (Baltimore) 2018;97:e13706)
- 55 year old woman with DCIS arising in intraductal papilloma in axillary lymph node (Arch Pathol Lab Med 2008;132:1940)
- 63 year old woman with nevus cell aggregate in axillary lymph node mimicking metastatic breast carcinoma (Breast J 2019;25:726)
- 70 year old woman with sentinel lymph node involvement by epithelial inclusions mimicking metastatic carcinoma (Am J Case Rep 2020;21:e926094)
- 81 year old woman with contralateral axillary lymph node metastasis in second primary breast cancer (Int J Surg Case Rep 2017;40:47)
Treatment
- Sentinel lymph node biopsy (SLNB) at time of breast surgery for early stage breast cancer with clinically negative axillary nodes (J Clin Oncol 2017;35:561):
- If no sentinel lymph node (SLN) metastasis, then no axillary lymph node dissection (ALND)
- If 1 or 2 SLNs with metastases are present and patient is undergoing breast conserving surgery with whole breast radiotherapy, then no ALND
- If SLN metastases are present and patient is undergoing mastectomy, then ALND should be offered
- ALND can be omitted in patients who undergo mastectomy for early stage clinically node negative breast cancer with 1 or 2 SLN metastases, if treated with axillary radiotherapy (Pract Radiat Oncol 2016;6:e219)
- ALND can be avoided in patients with early stage breast cancer and only micrometastasis in the SLNs (Lancet Oncol 2013;14:297)
- SLNB may be considered optional for elderly patients, particularly if axillary staging will not affect selection of adjuvant systemic or radiotherapy
- ALND at time of breast surgery, if clinically palpable lymph nodes or ≥ 3 suspicious nodes by imaging with axillary nodal metastasis confirmed on core biopsy or FNA; SLNB may be considered if clinically node negative after neoadjuvant therapy
Frozen section description
- Axillary SLN are identified by the surgeon by determining uptake of radioisotope technetium 99 sulfur colloid, methylene blue dye or both
- Intraoperative frozen section or imprint cytology may be performed on the SLN to determine need for axillary lymph node dissection (World J Surg Oncol 2008;6:69, Eur J Surg Oncol 2009;35:16)
- Frozen section (FS) had an overall mean sensitivity of 73% (macrometastasis: 94%; micrometastasis 40%) and mean specificity of 100% (meta-analysis of 47 studies, Cancer 2011;117:250)
- SLN FS may be safely omitted in patients who meet ACOSOG Z11 criteria (Clin Breast Cancer 2018;18:276, J Clin Pathol 2016;146:57)
- False negative rate of intraoperative frozen section, post neoadjuvant chemotherapy, was 5.4% in a single institution study of 711 cases (Am J Surg Pathol 2019;43:1377)
- Atypical cases on FS are usually negative on permanent sections (Mod Pathol 2005;18:58)
- In most cases, if metastases are present, the SLN will be involved; in rare cases, only nonsentinel nodes contain metastases
- Metastasis to nonsentinel lymph nodes can occur if the true SLN is completely replaced by tumor (and therefore is not detected by radioactive tracer or dye), if there is unusual lymphatic drainage or if there is failure of the technique to identify the node
Microscopic (histologic) description
- Size of a metastatic deposit consists of a contiguous focus of tumor cells, including any intervening desmoplasia (for post neoadjuvant treatment, do not include intervening fibrous tumor bed for deposit size)
- Tumor cells of metastatic lobular carcinoma are often dispersed and not contiguous
- 200 cell cutoff helps to determine if dispersed cells in a lymph node should be classified as isolated tumor cells
- Extranodal extension (ENE) is included in the size of the metastatic deposit
- ENE is defined as carcinoma invading into fat outside of a lymph node, either via invasion through the capsule of the node or invasion into fat outside the node at the hilum
- Invasion into fat located within the contours of the lymph node is not ENE
- Carcinoma located within lymphatics or blood vessels in axillary fat is not ENE
- ENE is reported as present or not present; If present, the amount of ENE can be reported as ≤ 2 mm or > 2 mm or the measurement of the largest dimension
- Nodular tumor deposits in axillary fat without evidence of residual lymph node are counted as positive axillary lymph nodes
- pN: see staging topic
- (sn) modifier for pN stage is used when 5 or fewer lymph nodes are sampled / evaluated
- Intramammary lymph nodes are included in the axillary lymph node count
- Metastasis to an ipsilateral level III axillary lymph node is staged as pN3a
- Metastasis to a contralateral axillary lymph node is staged as pM1
Microscopic (histologic) images
Contributed by Mary Ann G. Sanders, M.D., Ph.D.
Benign squamous epithelial inclusion
Benign glandular epithelial inclusion
PAX8
Treatment effect
Pankeratin
Matted lymph nodes
Extranodal extension
Cytology description
- FNA smears of positive axillary lymph node are characterized by crowded, disorganized groups of cells with enlarged nuclei, nuclear pleomorphism, irregular nuclear membranes and intracytoplasmic vacuoles with or without mucin
- Necrosis or mucin in the background and single intact malignant cells may be present
- Imprint cytology had an overall sensitivity of 63% (macrometastasis: 81%, micrometastasis: 22%) and specificity of 99% (meta analysis of 31 studies) (Br J Surg 2005;92:1068)
- Factors that can affect the outcome of FNA are the size of the metastasis in the lymph node, experience of the person performing image guided FNA and evaluation of the sample for adequacy by a pathologist (at the time of FNA)
Positive stains
- Note: "enhanced methods" of SLN metastasis detection, including routine immunohistochemistry, are not recommended (i.e., should be used on a case by case basis / when necessary for diagnosis) (J Clin Oncol 2014;32:1365)
- AE1 / AE3, CK7, GATA3
- Estrogen receptor / ER (depends on biomarker status)
- Reference: Semin Diagn Pathol 2018;35:143
Negative stains
Molecular / cytogenetics description
- Some studies have reported usefulness of molecular assays, usually reverse transcriptase polymerase chain reaction (RT-PCR) (J Clin Oncol 2008;26:3338)
- False positive and false negative results can occur with RT-PCR
- Significance of a positive RT-PCR result for a histologically negative lymph node is unknown (J Clin Oncol 2008;26:3338)
- Current AJCC cancer staging manual (8th edition) includes positive molecular findings by RT-PCR; no isolated tumor cell clusters detected as pN0 (mol+)
Sample pathology report
- Right axillary lymph nodes, dissection:
- Metastatic carcinoma is present in 3 of 10 lymph nodes, two macrometastases and one micrometastasis, (3/10)
- The largest metastatic deposit measures 8 mm
- Extranodal extension is present (measuring 3 mm)
Differential diagnosis
- Benign epithelial inclusions (Am J Surg Pathol 2011;35:1123):
- Glandular type:
- Breast-like:
- Have myoepithelial cells which are p63+ and smooth muscle myosin+
- Müllerian-like:
- Breast-like:
- Mixed glandular and squamous type
- Squamous type
- Glandular type:
- Benign transport after prior breast biopsy (Am J Clin Pathol 2000;113:259):
- Additional features such as giant cells and hemosiderin are indicative of benign transport rather than true metastases
- Ectopic breast tissue (Breast Cancer 2007;14:425)
- Muciphages:
- Resemble signet ring cell carcinoma
- Associated with prior surgery
- Alcian blue+, CD68+, MAC387+, keratin- (Am J Surg Pathol 1998;22:545)
- Nevus cells (Am J Clin Pathol 1994;102:102, Am J Surg Pathol 2003;27:673, Arch Pathol Lab Med 1985;109:1044)
- Occult breast cancer:
- Axillary nodal metastasis consistent with breast cancer and no evidence of primary breast cancer by physical exam and imaging (Ann Surg Oncol 2017;24:3141)
- Lymphoma:
- Melanoma:
- Keratin-, SOX10+, HMB45+, MelanA / MART1+
- Metastatic carcinoma other than breast:
Additional references
Board review style question #1
The gross image provided is a right axillary sentinel lymph node received from the OR of a patient with stage 1 breast cancer undergoing lumpectomy and sentinel lymph node biopsy. Recommendations provided by the College of American Pathologists (CAP) for evaluating axillary lymph nodes in breast cancer include which of the following?
- Evaluate 3 H&E levels for sentinel lymph nodes
- Submit all lymph node tissue if grossly positive
- Thinly slice each lymph node at 2 mm intervals
- Tumor deposits in axillary tissue are counted as extranodal extension
- Use cytokeratin immunohistochemistry on all negative lymph nodes
Board review style answer #1
C. Thinly slice each lymph node at 2 mm intervals. Per the CAP guidelines, sampling of lymph nodes must be adequate to detect all macrometastasis (> 2 mm deposit). Therefore, all lymph nodes must be thinly sliced at 2 mm intervals. All tissue from grossly negative lymph nodes must be submitted for histologic evaluation. For grossly positive lymph nodes, a representative section including areas suspicious for extranodal extension is adequate. Additional evaluation, including multiple H&E levels and cytokeratin immunohistochemistry, increases detection of isolated tumor cells and micrometastasis (occult metastasis), however this provides minimal clinical benefit. Therefore, the CAP recommends evaluating 1 H&E level from the surface of the tissue block when lymph node tissue has been sliced at 2 mm intervals. Tumor deposits in axillary tissue are counted as positive axillary lymph nodes (lymph node replaced by tumor).
Comment Here
Reference: Axillary lymph nodes
Comment Here
Reference: Axillary lymph nodes
Board review style question #2
A 50 year old woman underwent core needle biopsy of a 10 mm right breast mass detected on ultrasound and diagnosed as invasive ductal carcinoma, grade 2, that was estrogen receptor positive, progesterone receptor positive and HER2 negative. Right axillary ultrasound showed normal appearing lymph nodes. Breast MRI showed no additional lesions. There was no evidence of distant metastasis. What is the appropriate surgical management for this patient?
- Double mastectomy
- Lumpectomy
- Lumpectomy with axillary lymph node dissection
- Lumpectomy with sentinel lymph node biopsy
- No surgery
Board review style answer #2
D. Lumpectomy with sentinel lymph node biopsy. This patient has early stage breast cancer with clinically negative axillary lymph nodes; therefore, she will need sentinel lymph node biopsy to stage the axilla and to determine further axillary management and adjuvant systemic therapy and radiotherapy.
Comment Here
Reference: Axillary lymph nodes
Comment Here
Reference: Axillary lymph nodes
Benign breast implant related changes
Table of Contents
Definition / general | Essential features | Terminology | Epidemiology | Sites | Pathophysiology | Clinical features | Diagnosis | Radiology description | Radiology images | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Positive stains | Negative stains | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Saline and silicone breast implants are suitable for use in augmentation mammaplasty and breast reconstruction following mastectomy
- Soft tissue surrounding breast implants can display various benign histological findings over time, including dense fibrosis (capsule), chronic inflammation, granulomatous reaction, calcification and synovial metaplasia (Aesthetic Plast Surg 2010;34:481)
- Implant associated reactions vary based on the implant composition, duration and mechanical forces along the capsule and if violated / ruptured (Biomaterials 2003;24:1101)
Essential features
- Capsules can form around breast implants over time, especially silicone type implants
- Chronic movement and gliding of the implant in its cavity produces benign changes along the implant capsule interface with associated clinical and histological findings (Acta Cytol 2014;58:511)
- Implant related changes include dense fibrosis, chronic inflammation / granulomatous reaction, calcification and synovial metaplasia
- Leaking or rupture of silicone implant leads to silicone granuloma, which consists of amorphous / crystalline material with a foreign body giant cell reaction
- Synovial metaplasia can be noted, which consists of epithelioid cells lining the inner capsular surface with a well developed reticulin network histologically indistinguishable from normal joint synovium
Terminology
- Synovial metaplasia is also referred to as synovial-like reaction or synovial-like metaplasia
Epidemiology
- Occurs in smooth and textured silicone surfaced breast implants as well as in saline filled and polyurethane coated implants (Plast Reconstr Surg 1997;100:1558, Biomaterials 2003;24:1101)
- Risk of implant related changes increases with prolonged implant duration
- Textured surface breast implants with a duration of 0 - 5 years exhibit the highest incidence of synovial metaplasia (Biomaterials 2003;24:1101)
- Risk of rupture increases with duration, with a minimum of 15% estimated to rupture between the third and tenth year after implantation in a cohort followed by MRI (Arch Surg 2003;138:801)
Sites
- Breast implant capsule interface
Pathophysiology
- Inflammatory changes
- Immune recognition of breast implants as foreign results in inflammatory response, leading to the formation of scar (capsule) around the implant, which may contract and cause the implant to feel hard or change shape
- Thick, fibrous capsule is formed as a host reaction to foreign material (implant) or possibly as a form of repair
- Breast implant related changes can lead to other complications, such as implant rupture or displacement and breast implant associated anaplastic large cell lymphoma (BIA-ALCL) in the context of textured implants (Plast Reconstr Surg 2017;140:645)
- Synovial metaplasia
- Persistent movement of the implant induces a local cellular response along the inner capsular surface that evolves into an organized synovial-like structure resembling normal joint synovium (Plast Reconstr Surg 1995;96:1747)
Clinical features
- Usually delayed onset of symptoms
- Pain with or without swelling
- Distortion / capsular contracture
- Excessive firmness of breast
- Infection
- Reference: Plast Reconstr Surg 1997;100:1558
Diagnosis
- History of breast implant
- Clinically presents in the setting of suspected silicone leak or implant rupture
- Nonspecific imaging findings, including fibrous capsule thickening
- Can mistakenly raise suspicion for breast implant associated anaplastic large cell lymphoma (BIA-ALCL) or infection (Clin Imaging 2020;59:144)
- Capsulectomy, with histopathologic evaluation
Radiology description
- Capsular thickening with or without peri-implant fluid on breast ultrasound / MRI (Clin Imaging 2020;59:144)
- MRI has high accuracy in diagnosing silicone implant rupture (Eur Radiol 2014;24:1167)
- Ruptured implant: asymmetric circumferential increased density can be seen on mammography
Radiology images
Contributed by Di Ai, M.D., Ph.D., Kristen E. Muller, D.O. and Samantha A. Stephen, D.O. (Case #530)
Chest Xray
Case reports
- 25 year old woman with peri-implant fluid collection mimicking implant rupture / silicone leak, 1 year after bilateral breast augmentation (J Med Case Rep 2008;2:277)
- 53 year old woman undergoing surgery for capsular contracture of textured, silicone breast implants (Diagn Cytopathol 2018;46:769)
- 55 year old HIV+ transgender woman with sudden onset breast skin thickening and swelling, 9 years after bilateral saline breast implant mammoplasty (Clin Imaging 2020;59:144)
- 66 year old woman with a history of invasive lobular carcinoma and bilateral mastectomy with breast implant reconstruction developed rib pain (Case of the month #530)
Treatment
- Surgical excision is the choice of treatment for capture contracture (Breast J 2003;9:428)
- Implant replacement is the choice of treatment for silicone implant leakage (Hoda: Rosen's Breast Pathology, 5th Edition, 2020)
Gross description
- Silicon implant rupture
- Implant ruptures may be intracapsular or extracapsular
- An intracapsular rupture occurs when the shell of the implant ruptures but the formed fibrous capsule remains intact; silicone does not extravasate freely
- An extracapsular rupture occurs when the formed capsule ruptures, which can lead to a change in the implant contour
- Implant ruptures may be intracapsular or extracapsular
Gross images
Contributed by Di Ai, M.D., Ph.D.
Ruptured silicone breast implants
Microscopic (histologic) description
- Thickened fibrosis (capsule) with varying degrees of chronic inflammation, fat necrosis, foreign body giant cell reaction, hemosiderin laden macrophages, calcifications
- Synovial metaplasia
- Consists of a layer that is 1 - 7 cells thick, lined by epithelioid cells arranged in a palisading pattern and embedded in a well developed reticulin network
- Cells are perpendicularly oriented with round to oval fibroblast-like nuclei, inconspicuous nucleoli and abundant eosinophilic cytoplasm
- No atypia
- Silicone granuloma
- Multiple cystic spaces and vacuoles partially filled with silicone granules and surrounded by fibrosis with accompanying local foreign body giant cell reaction, foamy histiocytes and lymphocytes (J Clin Pathol 1998;51:493)
- Usually secondary to extracapsular implant rupture
- Silicone gel leakage may be seen even in the absence of implant rupture
- References: Biomaterials 2003;24:1101, Aesthetic Plast Surg 2010;34:481
Microscopic (histologic) images
Contributed by Di Ai, M.D., Ph.D., Julie M. Jorns, M.D., Kristen E. Muller, D.O. and Samantha A. Stephen, D.O. (Case #530)
Synovial metaplasia
Synovial metaplasia
Synovial metaplasia CD68
Synovial metaplasia vimentin
Synovial metaplasia AE1 / AE3
Silicone leakage
Silicone granuloma
Silicone leakage
Virtual slides
Images hosted on other servers:
Breast, silicone granuloma
Positive stains
- Vimentin
- CD68
- Reference: Ultrastruct Pathol 1995;19:83
Negative stains
Sample pathology report
- Right breast tissue, capsulectomy:
- Dense fibroconnective tissue with chronic inflammation, fat necrosis, foreign body giant cells and amorphous foreign materials (see comment)
- Comment: Foreign materials are amorphous, transparent and nonpolarized, consistent with silicone leakage.
- Right breast capsule, excision:
- Benign fibrous capsule with chronic (lymphohistiocytic) inflammation and giant cell reaction to silicone
Differential diagnosis
- Breast implant associated fibromatosis (J Surg Case Rep 2018;2018:rjy249):
- Can be locally aggressive, with high rates of recurrence despite adequate excision, while lacking metastatic potential
- Develop from fibroblasts or myofibroblasts, in association with the capsule surrounding a silicone breast implant
- Long fascicles of spindle cells with no / minimal cytologic atypia and no mitotic figures
- Focal prominent stromal collagen
- Nuclear staining for beta catenin, while negative for CD34 and p63
- Squamous cell carcinoma (Ann Plast Surg 1992;29:425):
- Poorly differentiated squamous cell carcinoma is rarely seen
- The histologic features of lining of squamous epithelium around a breast implant include: pleomorphic and hyperchromatic nuclei, single cell dyskeratosis, atypical mitotic figures and infiltration into the stroma around the capsule
- Immunostaining positive for cytokeratin
- Squamous metaplasia is bland and lacks the histologic features mentioned above
- Implant associated anaplastic large cell lymphoma (Clin Imaging 2020;59:144):
- Tumor lymphocytes have significant atypia (anaplastic) with horseshoe shaped nuclei, CD30 positive
- High grade sarcoma:
- High grade sarcoma, such as liposarcoma and angiosarcoma, has been reported to be associated with breast implant; also, breast implant associated fibrosarcoma was reported in 35% in a rat model (Plast Reconstr Surg Glob Open 2013;1:e11)
- Histologic features include high grade nuclear atypia, atypical mitotic figures and necrosis
Additional references
Board review style question #1
A 44 year old woman with history of breast implants underwent capsulectomy. Which of the following markers is positive in the lining epithelium of the inner capsular surface (denoted by blue arrows in the image shown above)?
- AE1 / AE3
- CD3
- CD68
- EMA
- Factor VIII
Board review style answer #1
C. CD68. The lining cells exhibit an immunohistochemical profile similar to synovial cells, including positive staining for CD68 and vimentin. Answers A, B, D and E are incorrect because staining for cytokeratins, CD3, EMA and factor VIII are negative.
Comment Here
Reference: Benign breast implant related changes
Comment Here
Reference: Benign breast implant related changes
Board review style question #2
Which of the following statements is true about acellular dermal matrix?
- Comprised of avascular and acellular collagen fibers after implantation
- Never clinically palpable
- Not commonly used in breast reconstructive surgery
- Shows hypercellular stroma with intermixed breast ducts and lobules
Board review style answer #2
A. Comprised of avascular and acellular collagen fibers after implantation. The histologic features of acellular matrix vary based on the stage of tissue remodeling. After implantation, the tissue is comprised of acellular and avascular disorganized collagen fibers. Eventually, the acellular matrix undergoes neovascularization with the production of small capillaries and proliferation of fibroblasts around the collagen fibers. Once acellular dermal matrix undergoes tissue remodeling and incorporation, the tissue may resemble mature dense fibrous tissue (see Case #530 for more information).
Comment Here
Reference: Benign breast implant related changes
Comment Here
Reference: Benign breast implant related changes
Biopsy marking devices
Table of Contents
Definition / general | Essential features | Clinical features | Radiology images | Case reports | Clinical images | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Differential diagnosis | Board review style question #1 | Board review style answer #1Definition / general
- Clip placement, indicating the location of a percutaneous breast core biopsy, is utilized in many settings:
- Correlate lesion location across different imaging modalities (i.e. ultrasound, mammogram, tomosynthesis, MRI)
- Follow up progression of benign lesions over time
- Indicate tumor location in patients receiving neoadjuvant chemotherapy
- Assist surgeons in localizing lesions or extent of disease in nonpalpable lesions, confirming excision of the appropriate region
- Guide the pathologist to identify the area of interest on gross specimen examination
- Different clips help distinguish separate lesions
- Markers are most commonly metallic, in various shapes, generally 2 - 3 mm in size, placed with or without accompanying packing / embedding material such as collagen, hydrogel or starch
Essential features
- Biopsy marker placement is an important step in any breast biopsy procedure
- Clips of varying material and shapes are placed to help distinguish different biopsied sites / lesions
- Clips may migrate away from the biopsy site or be incorrectly positioned; microscopic features of biopsy site changes must therefore still be identified in excision specimens
- Accompanying packing material placed with marker clips may make biopsy sites more readily detectable radiographically and often increase homeostasis immediately following the biopsy procedure
Clinical features
- Routine biopsy clip placement is associated with a higher rate of negative margins for wire localization excisions (Am J Surg 2005;190:618)
- Advantages to packing material with marker placement include decreased clip displacement, increased homeostasis, better identification of clip site soon after biopsy procedure
- Depending on clip design, some markers are delivered into the biopsy cavity through the biopsy probe while others are delivered manually by image guidance
- Clip migration away from the biopsied site is a well recognized complication and occurs for various reasons (Radiographics 2004;24:147), including breast decompression (aka the accordion effect, J Radiol 2009;90:31) or displacement due to hematoma formation following the biopsy procedure; migration may be reduced in clips placed with an embedding material (Eur Radiol 2016;26:866)
- FDA reports of allergic reactions to metallic biopsy markers have been reported (FDA: Johnson and Johnson, Ethicon Division Titanium Breast Clip [Accessed 14 December 2017]) but are rare
- Although markers with collagen embedding material are not placed in people with allergies to beef products, collagen or collagen products, there are no reports of allergic reactions in the current literature
Radiology images
Contributed by Emily S. Reisenbichler, M.D.
Biopsied area with marker placement
Biopsy clips with localization wires
M shaped and top hat clips
Images hosted on other servers:
Lost biopsy marking clips (arrows)
Case reports
- 37 year old woman with complete disappearance of biopsy marking clip following MRI guided breast biopsy (BMJ Case Rep 2014 Aug 19;2014)
- 39 year old woman undergoing excision for a biopsy marker and associated collagen plug mistaken for a mass lesion (Breast J 2005;11:504)
- Report of atopic dermatitis in relation with a surgical titanium clip in the breast (J Gynecol Obstet Biol Reprod (Paris) 2011;40:174)
Clinical images
Images hosted on other servers:
Devices and radiographs (various images)
Gross images
Images hosted on other servers:
Biopsy clips may be much smaller than standard surgical clips
Microscopic (histologic) description
- Gel / polymer pellets:
- Initially hypocellular fibrotic reaction around empty spaces (processing dissolves the polymer), then multinucleated giant cell reaction with eosinophilic material in marker core (Am J Surg Pathol 2005;29:814)
- May also retain blue / grey material, resembling suture with multinucleated giant cell reaction to material (see microscopic images)
- Collagen plugs:
- Eosinophilic, hyalinized and acellular material with lymphocytic and eosinophilic infiltrate that gradually penetrates into the core
- No prominent multinucleated giant cell reaction
- May resemble amyloidosis (see microscopic images)
Microscopic (histologic) images
Contributed by Emily S. Reisenbichler, M.D.
Acellular hyalinized collagen plug
Gel material and central hemorrhage
Gel material resembling suture material
Prominent multinucleated giant cell reaction
Differential diagnosis
- Calcifications may be mistaken for clips radiographically
Board review style question #1
Which of the following is not a use for biopsy marker placement?
- Assist the pathologist in gross identification of the targeted lesion in the surgical excision specimen
- Identification of a nonpalpable breast lesion (such as calcifications, asymmetry or distortion) for excision
- Identification of a palpable lesion in a patient with a metal allergy
- To follow the appearance and possible progression of a benign biopsied lesion over time
- Tumor localization in a patient undergoing neoadjuvant chemotherapy prior to surgery
Board review style answer #1
C.
Although there are almost no contraindications for placing a biopsy marker, there are rare reports of allergic reaction to metallic clips. Forgoing clip placement in this situation may be considered, particularly if the lesion is palpable and has not been entirely removed by the biopsy procedure. For most cases, a marker clip is necessary and helpful to surgeons, oncologist and pathologists.
Comment Here
Reference: Breast biopsy marking devices
Comment Here
Reference: Breast biopsy marking devices
BRCA associated carcinoma
Table of Contents
Definition / general | Essential features | Terminology | Epidemiology | Sites | Pathophysiology | Etiology | Diagrams / tables | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Negative stains | Molecular / cytogenetics description | Molecular / cytogenetics images | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Group of inherited breast cancers attributed to mutations in the breast cancer associated genes: BRCA1 and BRCA2
- Associated with increased risk of breast and ovarian cancers in women with BRCA germline mutations
Essential features
- Presence of BRCA1 / 2 genes germline mutation
- Responsible for 25 - 30% of familial breast cancers and ~2% of all breast cancers
- Differs from sporadic breast carcinoma genotypically and phenotypically
- Occurs at a younger age (< 50 years) with high predilection for contralateral breast involvement
- Often well demarcated with pushing margins and medullary-like features
- Usually high grade (poorly differentiated) and triple negative
Terminology
- BRCA1 related breast cancer or BRCA1 germline mutation related breast cancer
- BRCA1 / 2 associated hereditary breast and ovarian cancer syndrome
Epidemiology
- Familial breast cancer was first described by Paul Broca in 1866 (Broca: Traite Des Tumeurs, 2018)
- Constitutes 5 - 10% of all breast cancers (Breast Cancer 2021;28:1167)
- BRCA1 / 2 genes germline mutation is responsible for 25 - 30% of familial breast cancers and ~2% of all breast cancers (Crit Rev Oncol Hematol 2006;59:27, Sci Rep 2020;10:7073)
- Prevalence varies among ethnic groups and countries (Clin Epidemiol 2019;11:543)
- Majority of studies are from White populations in Europe and North America (Clin Epidemiol 2019;11:543)
- Founder mutations have been documented in Ashkenazi Jewish, Icelandic, Polish, Slovenian and other populations (Am J Hum Genet 1997;60:1059, Am J Hum Genet 1997;60:1079, Int J Cancer 2004;110:683, BMC Med Genet 2008;9:83)
- Prevalence of pathogenic BRCA1 and BRCA2 variants is estimated to be between 1 in 300 and 1 in 800 in the general population (Sci Rep 2020;10:7669)
- ~1 in 40 Ashkenazi Jewish women are known to have a BRCA gene mutation (Sci Rep 2020;10:7669)
Sites
- Breast, ovarian, pancreatic, prostate and possibly other cancers can be associated with BRCA1 / 2 associated hereditary breast and ovarian cancer syndrome
Pathophysiology
- BRCA stands for BReast CAncer gene (Ann Lab Med 2020;40:114)
- BRCA1 and BRCA2 are 2 distinct tumor suppressor genes located on chromosome 17p2.1 and chromosome 13q12.3, respectively (Ann Lab Med 2020;40:114)
- BRCA1 / BRCA2 play crucial roles in chromatin remodeling, transcription control, cell cycle regulation and DNA repair processes (Mol Pathol 2003;56:191, Ann Lab Med 2020;40:114)
- Cell cycle checkpoints and DNA repair management have been attributed to tumor suppressive effects (Ann Lab Med 2020;40:114)
- > 1,600 and 1,800 known variants in BRCA1 and BRCA2, respectively (Genet Med 2010;12:245)
- Majority induce frameshifts, leading to missense or nonfunctional proteins (Genet Med 2010;12:245)
- Pathogenic variant of BRCA1 increases the risk of breast cancer by 65% (44 - 78%) and ovarian cancer by 39% (18 - 54%) by the age of 70; corresponding risks are 45% (31- 56%) and 11% (2.4 - 19%) for BRCA2 (Am J Hum Genet 2003;72:1117, Ann Lab Med 2020;40:114)
- There is an increased risk of ovarian cancer, endometrial cancer, Hodgkin disease and prostate cancer associated with BRCA1 pathogenic variants (JAMA 2017;317:2402, Prostate 2019;79:880, Hered Cancer Clin Pract 2015;13:16, Medicina (Kaunas) 2021;57:905)
- Additionally, BRCA2 pathogenic variants increase the risk of cholangiocarcinoma, esophageal cancer, gastric cancer, uveal melanoma and bone cancer (Ann Lab Med 2020;40:114, Hered Cancer Clin Pract 2015;13:16, Cancers (Basel) 2022;14:5953, Medicina (Kaunas) 2021;57:905)
Etiology
- Associated with underlying BRCA1 / BRCA2 germline mutation (Am J Hum Genet 2003;72:1117, Ann Lab Med 2020;40:114)
- High penetrance mutations, inherited in an autosomal dominant fashion (Am J Hum Genet 1998;62:676)
Diagrams / tables
Images hosted on other servers:
Breast cancer predisposition genes
Clinical features
- Younger age at onset (usually < 50 years) (Breast Cancer 2021;28:1167)
- Higher prevalence of bilateral breast cancer (GeneReviews: BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer [Accessed 1 November 2023])
- Risk factors for contralateral breast involvement are initial cancer at a young age, family history and BRCA1 pathogenic variant (Cancers (Basel) 2020;12:378)
- Higher tumor grade at the time of presentation (Cell Oncol (Dordr) 2011;34:71, Crit Rev Oncol Hematol 2006;59:27)
Diagnosis
- Genetic testing to detect BRCA1 and BRCA2 sequence variants is recommended (Eur J Hum Genet 2016;24:S10)
- Selection of candidates for high risk assessments is based on guidelines set by international societies such as National Comprehensive Cancer Network (NCCN) and European Society of Medical Oncology (ESMO) (J Natl Compr Canc Netw 2020;18:380, Ann Oncol 2023;34:33)
- Typically, blood is used; other samples such as buccal scrapes and saliva can also be used (Eur J Hum Genet 2016;24:S10, J Natl Compr Canc Netw 2020;18:380)
- Direct (Sanger) DNA sequencing is considered the gold standard (Eur J Hum Genet 2016;24:S10)
- Next generation sequencing (NGS) is better due to its ability to detect large genomic rearrangements (LGRs) in a single workflow (Eur J Hum Genet 2016;24:S10)
- Other methods include quantitative PCR and multiplex ligation dependent probe amplification (MLPA) but are more labor intensive (Eur J Hum Genet 2016;24:S10)
Radiology description
- Generally presents as round to oval, hypoechoic mass with a circumscribed margin (Radiology 2019;291:554)
- Not typically associated with architectural distortion and calcification (Radiology 2019;291:554)
- Mammography and ultrasound have decreased sensitivity due to (Radiology 2019;291:554, AJR Am J Roentgenol 2017;209:920)
- Masking effect of dense breast tissue in young women
- Benign appearance
- Lower incidence of ductal carcinoma in situ (especially in BRCA1 carriers)
- Dynamic contrast enhanced breast MRI is the most sensitive screening modality (sensitivity of 71 - 94%) (Radiology 2019;291:554, AJR Am J Roentgenol 2017;209:920)
- Most guidelines recommend an annual MRI screening as an adjunct to mammography (N Engl J Med 2004;351:427, AJR Am J Roentgenol 2017;209:920)
- Calcification, ductal carcinoma in situ (DCIS), irregular / spiculated margins and architectural distortion are more commonly seen in BRCA2 associated cases (AJR Am J Roentgenol 2017;209:920)
Radiology images
Images hosted on other servers:
Mammogram and USG findings
Circumscribed hypoechoic mass with BRCA1 mutation
Irregular obscured isodense mass
Hypoechoic, irregular shape, calcifications in BRCA2
Prognostic factors
- Prognostic significance of BRCA1 / 2 mutational status on breast cancer survival is still debatable (Breast Cancer Res Treat 2010;119:13)
- Majority of studies have failed to demonstrate a significant overall survival difference between BRCA associated breast cancer and sporadic breast cancer (Breast Cancer Res Treat 2010;119:13)
- High risk of contralateral breast cancers (10 year risk ranging from 20 to 40%) (Breast Cancer Res Treat 2010;119:13)
- Metastases to the CNS occur frequently in women with BRCA1 / BRCA2 germline mutations, especially with BRCA2 mutation (Cancer 2020;126:271)
- Negative factors for overall survival may be infiltration of axillary lymph nodes, negative steroid receptor status and increased size of the primary tumor (Oncol Lett 2019;17:1986)
Case reports
- 14 year old girl with early onset breast cancer with germline pathogenic variants in both BRCA1 and TP53 genes (Front Oncol 2022;12:970641)
- 15 year old girl with BRCA positive breast cancer (Int J Surg Case Rep 2022;98:107513)
- 33 year old BRCA1 positive African American woman with locoregional recurrence (Clin Case Rep 2018;6:2457)
- 50 year old BRCA1 positive woman with brainstem metastasis under PARP inhibitors (Arch Clin Cases 2021;6:69)
- 64 year old man with a BRCA1 gene mutation associated with HER2 expression on receptor analysis (Ochsner J 2015;15:448)
Treatment
- BRCA mutation carriers
- Genetic counseling
- Regular screening as recommended by NCCN guidelines (J Natl Compr Canc Netw 2021;19:77)
- As early as 18 years of age in women and 35 years of age in men, a clinical breast examination and radiological evaluation (breast MRI and mammogram) are recommended
- Ovarian cancer screening: transvaginal ultrasound and serum CA125
- Screening for prostate cancer starting 40 years of age
- Risk reduction surgeries: prophylactic bilateral salpingo-oophorectomy and bilateral mastectomy (nipple sparing, skin sparing) (Onco Targets Ther 2022;15:815, J Natl Cancer Inst 2009;101:80, J Natl Compr Canc Netw 2021;19:77)
- Chemoprevention: estrogen receptor modulators (i.e., tamoxifen, raloxifene) and aromatase inhibitors in postmenopausal women (J Natl Compr Canc Netw 2021;19:77)
- Counseling for reproductive options: prenatal diagnosis and assisted reproduction using preimplantation genetic testing (PGT) (J Natl Compr Canc Netw 2021;19:77)
- BRCA mutation associated breast cancer (Onco Targets Ther 2022;15:815)
- Total mastectomy is preferred over breast conserving surgery
- Responsive to platinum based therapy
- PARP inhibitors are effective in adjuvant, neoadjuvant and metastatic settings
Clinical images
Images hosted on other servers:
Mass in BRCA positive man
Gross description
- Usually presents as well circumscribed / well demarcated fleshy mass
Microscopic (histologic) description
- Majority of BRCA1 and BRCA2 breast cancers are invasive ductal adenocarcinoma (~74%) (Crit Rev Oncol Hematol 2006;59:27)
- Specific features of BRCA1 associated breast cancer
- Higher frequency of invasive breast carcinoma, NST with medullary pattern and basal-like features than sporadic breast cancer (13% versus 2%) (Lancet 1997;349:1505, Mod Pathol 2010;23:S46)
- Mostly (66 - 100%) poorly differentiated grade 3 carcinoma with syncytial appearance, large pleomorphic cells and indistinct cell membranes (Crit Rev Oncol Hematol 2006;59:27, Cell Oncol (Dordr) 2011;34:71)
- Usually well demarcated with pushing borders, solid growth and prominent lymphoplasmacytic infiltrate (Crit Rev Oncol Hematol 2006;59:27, Histopathology 2023;82:70)
- A high proportion (~48%) show extensive areas of necrosis (Crit Rev Oncol Hematol 2006;59:27)
- Low grade subtypes such as tubular carcinoma are rare (J Clin Oncol 2010;28:5265)
- Specific features of BRCA2 associated breast cancer
- More heterogeneous in grade and spectrum of histological type (Mod Pathol 2010;23:S46)
- Generally low to intermediate grade compared to BRCA1 associated breast cancer (Crit Rev Oncol Hematol 2006;59:27, Histopathology 2023;82:70)
- Studies have documented a higher incidence of tubular, lobular and cribriform carcinomas (Mod Pathol 2010;23:S46, Histopathology 2023;82:70)
Microscopic (histologic) images
Contributed by Kristen E. Muller, D.O. and Chanchal Rana, M.D.
Well demarcated pushing borders
High grade nuclear features
Lymphoplasmacytic
infiltration
Syncytial growth with necrosis
ER negative
PR negative
HER2 neu negative
Ki67
p53 expression
Cytology description
- No specific cytology findings
- Corresponds to the histological type
Positive stains
- Basal / myoepithelial cell markers: CK5/6, CK14, EGFR (Crit Rev Oncol Hematol 2006;59:27, Rev Bras Ginecol Obstet 2022;44:761)
- High Ki67 expression (Cell Oncol (Dordr) 2011;34:71, Am J Cancer Res 2015;5:2330)
- p53 overexpression (37 - 77%) (Crit Rev Oncol Hematol 2006;59:27, Med Sci Monit 2016;22:1939)
- Hypoxia related proteins: HIF1a, GLUT1, CAIX (Cell Oncol (Dordr) 2011;34:71, Asian Pac J Cancer Prev 2020;21:629)
- Cell cycle related proteins: cyclin A, cyclin B1, cyclin E (Nucleic Acids Res 2006;34:1416)
Negative stains
- Hormone receptor, usually triple negative: ER (63 - 90%), PR (60 - 80%) and HER2 neu (97 - 100%) (Crit Rev Oncol Hematol 2006;59:27, Rev Bras Ginecol Obstet 2022;44:761)
- Cell cycle and apoptosis markers: cyclin D1, p27 (kip1), p21, p16, BCL1, BAX (Nucleic Acids Res 2006;34:1416, Cell Oncol (Dordr) 2011;34:71)
- BRCA (variable) (J Clin Pathol 2001;54:476)
Molecular / cytogenetics description
- Presence of heterozygous germline pathogenic variants in BRCA1 and BRCA2 gene (GeneReviews: BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer [Accessed 1 November 2023])
- > 1,600 and 1,800 known variants in BRCA1 and BRCA2, respectively, the majority of which lead to missense or nonfunctional proteins (Genet Med 2010;12:245)
- Sequence variant can include a single nucleotide change, a small insertion or deletion or a large genomic rearrangement (LGRs) (Eur J Hum Genet 2016;24:S10)
- Founder mutations BRCA1.185delAG, BRCA1.5382insC and BRCA2.6174delT account for 99% of the pathogenic variants in the Ashkenazi Jewish population (BJOG 2020;127:364)
- Other associated high penetrance mutations are TP53, PTEN, CDH1 and STK11 (GeneReviews: BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer [Accessed 1 November 2023])
- MYC amplification (18 - 23%), chromosome 8 polysomy, MYB amplification (~30%) are more frequently encountered in BRCA1 breast cancer as compared to sporadic (Eur J Hum Genet 2016;24:S10, Clin Cancer Res 2004;10:499, Cancer Res 2000;60:5323)
Molecular / cytogenetics images
Images hosted on other servers:
BRCA pedigree
LGRs BRCA1
LGRs BRCA2
MYC amplification
Sample pathology report
- Right breast mass, mastectomy:
- Invasive breast carcinoma of no special type with medullary pattern (see synoptic report)
- Grade III
- Triple negative (ER / PR / HER2 neu negative)
- Comment: In view of the presence of young age, medullary pattern and triple negativity, there is a possibility of BRCA associated breast carcinoma; genetic analysis may be advised if clinically indicated.
Differential diagnosis
- Sporadic high grade invasive breast carcinoma of no special type (invasive ductal carcinoma) with tumor infiltrating lymphocytes:
- Usually elderly age group with an absence of family history
- Generally lacks circumscription and pushing margins
- Lacks BRCA mutation
- Variable hormone receptor expression
- Sporadic invasive breast carcinoma of no special type with medullary features:
- Median age is 53 years
- Lacks family history
- Genetic analysis is often needed to differentiate
- Metastatic high grade carcinoma to the breast from another site:
- Mammaglobin negative
- Radiological evidence of a primary site
- Lymphoma:
- Tumor cells will stain with lymphoid markers, cytokeratin negative, mammaglobin negative
Board review style question #1
Which statement about BRCA1 positive breast cancer, with histological features shown in the image above, is true?
- Expression of ER, PR and HER2 neu on immunohistochemistry
- High probability of the development of contralateral breast cancer in the future
- Low chance of association with ovarian cancer
- Patient is likely to be > 60 years of age
Board review style answer #1
B. High probability of the development of contralateral breast cancer in the future. BRCA associated breast cancer has high rates of contralateral breast cancer. Answer D is incorrect because BRCA associated breast cancer develops at a younger age, usually < 50 years. Answer A is incorrect because BRCA associated breast cancer is mostly triple negative. Answer C is incorrect because patients with BRCA associated breast cancers have a high chance of developing other cancers, especially ovarian cancer in women.
Comment here
Reference: BRCA1 associated breast carcinoma
Comment here
Reference: BRCA1 associated breast carcinoma
Board review style question #2
Which of the following is the most sensitive radiological investigation to diagnose as well as follow up a patient with BRCA1 associated breast cancer?
- Dynamic contrast enhanced MRI
- Mammography
- Next generation sequencing
- Ultrasound
Board review style answer #2
A. Dynamic contrast enhanced MRI. Dynamic contrast enhanced MRI is the most sensitive screening modality, with a sensitivity of 71 - 94%. Answers B and D are incorrect because ultrasound and mammography are limited by the masking effect of dense breast tissue in young women, demarcated nature and lower incidence of ductal carcinoma in situ BRCA associated breast cancer. Answer C is incorrect because next generation sequencing is a molecular technique.
Comment here
Reference: BRCA1 associated breast carcinoma
Comment here
Reference: BRCA1 associated breast carcinoma
Breast implant associated anaplastic large cell lymphoma
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Diagrams / tables | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Positive stains | Negative stains | Flow cytometry description | Molecular / cytogenetics description | Molecular / cytogenetics images | Videos | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- A new provisional entity recognized in the 2017 revision of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (Mod Pathol 2019;32:166)
- Arising primarily in association with breast implants
- Rare type of non-Hodgkin lymphoma characterized by abnormal growth of strongly positive CD30 lymphocytes within the breast capsule
- Features are not different from ALK- anaplastic large cell lymphoma
Essential features
- Strongly positive CD30 pleomorphic lymphocytes in the peri-implant seroma or capsular tissue
Terminology
- Breast implant associated anaplastic large cell lymphoma is recognized as BIA-ALCL
- Synonymous to seroma associated anaplastic large cell lymphoma
ICD coding
- ICD-O: 9715/3 - mucosal associated lymphoid tissue lymphoma (MALT)
Epidemiology
- 1:3,817 - 1:30,000 women with textured implants (Plast Reconstr Surg 2017;140:645)
Sites
- Peri-implant seroma or capsular tissue (Ann Oncol 2016;27:306)
- Locoregional lymph nodes may be involved
Pathophysiology
- Although breast implants are associated with an increased risk of developing BIA-ALCL, the pathogenesis is still unknown
- Almost all documented BIA-ALCL cases have been associated with a textured device
- Genetic susceptibility may play a role
- BIA-ALCL is characterized by a triple negative genetic subtype and activation of the JAK-STAT3 pathway (Aesthet Surg J 2019;39:S14)
- Other contributing factors may include:
- Particle erosion of the implants (Breast Cancer Res Treat 2016;156:65)
- A subclinical biofilm
- Chronic T cell stimulation (Dtsch Arztebl Int 2018;115:628)
Etiology
- Theoretically can be caused by active components in manufactured silicone, such as residual vinyl groups
- Possibly a result of chronic antigenic stimulation (Aesthet Surg J 2016;36:773)
- It is hypothesized that manufactured silicone contains several components that are potentially biologically active, such as residual vinyl groups, which can access the circulation via lymphatics leading to a foreign body carcinogenesis (Plast Reconstr Surg 2007;120:94S)
- Another hypothesis is that breast implant associated anaplastic large cell lymphoma results from chronic bacterial antigen stimulation, sustained T cell proliferation and subsequent genetic events in the capsular tissues and the surrounding seromas (Aesthet Surg J 2016;36:773)
Diagrams / tables
Images hosted on other servers:
Anaplastic large cell
lymphoma cells in
seroma and within
fibrous capsule
Clinical features
- On average, develops 10.9 years after the initial implants have been placed
- Unilateral effusion confined to the capsule, pain, rash, mass or ulceration of affected breast
- Can form a mass that invades locally through the capsule into breast parenchyma or soft tissue or spreads to regional lymph nodes (Mod Pathol 2019;32:166)
- Axillary lymphadenopathy may be present in up to 29% but not always positive for tumor (Swerdlow: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th Edition, 2017)
Diagnosis
- Pleomorphic, neoplastic, strongly positive CD30 lymphocytes present on cytology, lining the breast capsule may show capsular invasion
Radiology description
- Ultrasonography can show a fluid collection between the breast implant and the capsule
- MRI can show effusions, masses or capsular enhancement with ruptured implants
- T2 weighted axial MRI can show a peri-implant collection around the subpectoral saline implant (Breast J 2019;25:69)
- PET / CT: fluorodeoxyglucose (18F) avidity on positron emission tomography
Radiology images
Prognostic factors
- 2 pathological subtypes, associated with 2 clinical pictures:
- Effusion around the implant corresponding to a localized disease confined to the capsule
- Palpable mass massively invading the capsule and adjacent tissues corresponding to an invasive disease
- Generally considered an indolent T cell lymphoma but the mass forming variant requires more intensive therapeutic approaches (Ann Oncol 2016;27:306)
- Median survival rate is 12 years
- Those associated with tumor cells forming solid masses have adverse prognosis
Case reports
- 32 year old woman presented with several weeks of pain and firmness in right breast (Cureus 2016;8:e546)
- 33 year old transgender woman with 5 cm tumorous mass (Aesthetic Plast Surg 2018;42:451)
- 53 year old woman with Li-Fraumeni syndrome and a history of breast cancer (Case Rep Genet 2019;2019:5647940)
- 54 year old transgender African American woman was treated with radiotherapy (J Investig Med High Impact Case Rep 2019;7:2324709619842192)
- 61 year old woman with right breast fullness and fluid collection around right breast silicone implant (Case #512)
- 65 year old Caucasian woman with prior bilateral fibrocystic breast disease (Case Rep Oncol Med 2017;2017:6478467)
Treatment
- In localized disease, complete capsulectomy without chemotherapy is curative
- Adjuvant chemotherapy may be required for more invasive disease
- Brentuximab may be used as second line treatment (Eur J Surg Oncol 2017;43:1393)
Clinical images
Images hosted on other servers:
Clinical presentation / intraoperative appearance
Gross description
- Arises in the fibrous capsule rather than the breast parenchyma or skin (JPRAS O 2015;6:1)
- Usually has fluid around the implant
Gross images
Images hosted on other servers:
Breast capsule
Microscopic (histologic) description
- Neoplastic cells line the fibrous capsule
- Neoplastic lymphoid cells have large malignant anaplastic nuclei, coarse and occasionally fine granular to pale chromatin with prominent nucleoli (Arch Pathol Lab Med 2014;138:842)
- Tumor cells show eccentric, horseshoe or kidney shaped nuclei referred to as hallmark cells
- Mitotic figures are conspicuous
- Cells have abundant cytoplasm
- Rarely, the malignant cells form a distinct tumor mass (Breast J 2019;25:69)
- Malignant cells are seen in a background containing fibrinoid material and inflammatory cells
- When forming a solid mass,
- Can show multinodular appearance
- Neoplastic cells are arranged in sheets
- Can show extensive sclerosis and fibrosis
- Can show areas of extensive coagulative necrosis
Microscopic (histologic) images
Contributed by Dia Kamel, M.D., Ph.D.
Breast capsule
Pleomorphic cells
CD30
EMA
ALK1
CD4
Contributed by Andrii Puzyrenko, M.D., Ph.D. and Julie Jorns, M.D. (Case #512)
Capsule
Aspirated fluid
Cytology description
- CD30+ tumor cells can be recognized in samples aspirated from breast implants (Cytopathology 2018;29:294)
Cytology images
Contributed by Dia Kamel, M.D., Ph.D.
Cell block
Positive stains
- CD2, CD3, CD4, CD43 and CD30 (strong and uniform)
- Majority express cytotoxic markers
- Minority of cases express epithelial membrane antigen (EMA) (Breast J 2019;25:69)
- Overall similar immunophenotype to ALK- anaplastic large cell lymphoma
Negative stains
- Negative for anaplastic lymphoma kinase 1 (ALK1)
- Frequent loss of T cell markers
Flow cytometry description
- Identification of CD30+ atypical, large cells in peri-implant effusions with relatively increased CD40 expression may help in confirming histological diagnosis (Cytometry B Clin Cytom 2015;88:58)
Molecular / cytogenetics description
- Molecular abnormalities are similar to those seen in ALK- systemic anaplastic large cell lymphoma
- Genomic characterization shows JAK / STAT activation and MYC / TP53 dysregulation
- Majority of cases show clonal rearrangement of the TR genes
- Despite molecular similarities, the clinical behavior is different as systemic anaplastic large cell lymphoma has aggressive behavior in comparison to breast implant associated anaplastic large cell lymphoma (Plast Reconstr Surg 2019;143:59S, Aesthet Surg J 2019;39:S14)
Molecular / cytogenetics images
Images hosted on other servers:
2D: PCR studies
Cytogenetic studies
Videos
Update on plastic surgery of anaplastic large cell lymphoma
Sample pathology report
- Clinical details: Suspected breast implant associated anaplastic large cell lymphoma
- Specimen: Right and left breast capsules
- Macroscopy:
- Right breast capsule: Capsule weighs 38 g and measures 120 x 39 x 5
- Left breast capsule: Capsule weighs 35 g and measures 110 x 40 x 5
- Microscopy:
- Right breast capsule:
- Sections of the capsule show hyalinized tissue with focal chronic inflammatory cell infiltrate and foreign body giant cell reaction to the implant material. There are occasional atypical cells of hallmark type, seen within the inner capsule surface and in one focus; the atypical lymphoid cells appear to superficially infiltrate the fibrous capsule. Immunohistochemical stains highlight the atypical lymphoid cells which show positive immunoreactivity to CD3, CD43 and CD30. On the other hand, ALK1 is negative. CD20 decorates the reactive B lymphocytes and CD68 stains macrophages.
- The features together with the immunohistochemical staining profile are in keeping with anaplastic large cell lymphoma that is breast implant associated and involving the right breast capsule. As the atypical lymphoid cells are seen in the inner surface of the capsule, this is compatible with the effusion variant which carries a better prognosis. However, clinical and pathological correlation and followup are recommended.
- Left breast capsule:
- Sections show hyalinized fibrous tissue with focal chronic inflammation and foreign body giant reaction to implant material. There is no evidence of infiltration by atypical lymphoid cells in the examined sections. This is confirmed by negative immunohistochemical staining for CD30.
- Right breast capsule:
- Diagnosis:
- Right breast capsule: Breast implant associated anaplastic large cell lymphoma
- Left breast capsule: Chronic inflammation
- Comment: On verbal communication with the consultant radiologist, it was stated that the implant capsule is not significantly thickened and therefore this is most likely of effusion variant type.
Differential diagnosis
- Inflammation: reactive T lymphocytes are seen and absence of large and anaplastic CD30+ cells (reactive infiltrate may have scattered nonanaplastic CD30+ immunoblasts)
- Other types of non-Hodgkin lymphoma: absence of CD30 strongly positive tumor cells
- Primary or recurrent carcinoma: cohesive architectural pattern that mimics carcinoma, which is positive for cytokeratin and negative for CD30 and T cell antigens (Arch Pathol Lab Med 2014;138:842)
- Anaplastic large cell lymphoma with EMA positivity should be differentiated from high grade triple negative breast carcinoma
- Systemic anaplastic large cell lymphoma
- CD30+ lymphomas such as classical Hodgkin lymphoma, especially when anaplastic large cell lymphoma loses T cell markers
Additional references
Board review style question #1
The hallmark cell of breast implant associated anaplastic large cell lymphoma stains strongly positive for which of the following?
- CD20
- CD23
- CD30
- CD68
- S100
Board review style answer #1
C. CD30. Breast implant associated anaplastic large cell lymphoma is characterized by abnormal growth of pleomorphic lymphocytes within the peri-implant seroma or capsular tissue. Answers A and D are incorrect because CD20 stains the reactive B lymphocytes and CD68 highlights histiocytic and monocytic cells / macrophages, which aren't the hallmark cells for this condition. Answers B and E are incorrect because CD23 and S100 are not useful for characterizing this condition.
Comment Here
Reference: Breast implant associated anaplastic large cell lymphoma
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Reference: Breast implant associated anaplastic large cell lymphoma
Board review style question #2
Which of the following is best for management of patients with early / localized breast implant associated anaplastic large cell lymphoma?
- Capsulectomy only
- Capsulectomy with radiotherapy and chemotherapy
- Chemotherapy only
- Radiotherapy and chemotherapy
- Radiotherapy only
Board review style answer #2
A. Capsulectomy only. In early, localized disease, complete casulectomy without chemotherapy is curative. Answers B - E are incorrect because in early disease, radiotherapy and chemotherapy are not needed. Adjuvant chemotherapy may be required for more invasive disease.
Comment Here
Reference: Breast implant associated anaplastic large cell lymphoma
Comment Here
Reference: Breast implant associated anaplastic large cell lymphoma
Classic
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Gross images | Frozen section description | Frozen section images | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Cytology images | Positive stains | Negative stains | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Invasive breast carcinoma with loss of cellular adhesion, characteristically arranged in discohesive or single file patterns
Essential features
- Special subtype of invasive breast carcinoma characterized by discohesive tumor cells arranged in single files or as individual single cells
- Shows 16q loss (CDH1 gene located at 16q22.1 encodes E-cadherin, integral in formation of adherens junction responsible for cell adhesion)
- Loss of E-cadherin expression on immunohistochemistry helpful but not required for diagnosis
Terminology
- Invasive lobular carcinoma, classic type
ICD coding
- ICD-O: 8520/3 - lobular carcinoma, NOS
- ICD-11: 2C61.1&XH2XR3 - invasive lobular carcinoma of breast & lobular carcinoma, NOS
Epidemiology
- Comprises about 10% of invasive breast carcinomas (Breast Cancer Res 2015;17:37)
- Most common special subtype of invasive breast carcinoma (Br J Cancer 2005;93:1046)
- Only comprises 1% of male breast carcinomas (Breast Cancer (Dove Med Press) 2017;9:337)
- Mean age of diagnosis is 63.4 years, higher than that for invasive breast carcinoma of no special type (Br J Cancer 2005;93:1046)
- Endogenous (lower parity, younger age at menarche and later menopause) and exogenous (hormone replacement therapy and oral contraceptives) estrogen exposure increases risk (Breast Cancer Res 2015;17:37)
- Alcohol consumption and obesity are risk factors, which may be mediated by increased levels of circulating estrogen
- 60% lifetime risk in women with hereditary diffuse gastric cancer syndrome (germline CDH1 mutation) (J Med Genet 2010;47:436)
- Under represented in breast carcinomas of BRCA1 carriers (2.2%) and similar proportion BRCA2 carriers (8.4%) (Cancer Epidemiol Biomarkers Prev 2012;21:134)
Sites
- Breast
- Can occur in axilla accessory breast tissue
Etiology
- Invasiveness and loss of cellular cohesion due to abnormalities of the adherens complex, formed by cadherins and catenins (Biochim Biophys Acta 2008;1778:660)
- Majority of lobular carcinomas show loss of E-cadherin expression (Am J Surg Pathol 2010;34:1472)
- α, β and γ catenins and p120 expression can be aberrant in E-cadherin positive lobular carcinomas (Am J Surg Pathol 2010;34:1472)
- Lobular carcinoma in situ is a risk factor and nonobligate precursor of invasive lobular carcinoma
Clinical features
- Presents as vague findings including thickening, induration or poorly defined breast mass (Breast Dis 2008-2009;30:31)
- Overall, diagnosed at a more advanced stage than invasive breast carcinoma of no special type (Br J Cancer 2005;93:1046)
- More frequently bilateral and multifocal / multicentric (Breast 2018;38:101, Ann Surg Oncol 2020;27:4711)
- Leptomeningeal spread, cerebrospinal fluid, gastrointestinal tract, uterus and ovary and peritoneal metastasis more common in lobular carcinoma compared with other subtypes (AJR Am J Roentgenol 2000;175:795)
Diagnosis
- Mainly histological or radiological
Radiology description
- Ultrasound (Radiographics 2009;29:165)
- Hypoechoic mass with spiculated or ill defined margins and posterior acoustic shadowing
- Mammography (Radiographics 2009;29:165)
- Does not consistently present as a mass (44% - 65%)
- Less commonly manifests as architectural distortion
- Microcalcification infrequent
- Magnetic resonance imaging findings similar (Radiographics 2009;29:165)
- Can aid in identifying multifocal or residual disease
- Preoperative breast MRI may improve surgical planning (Breast J 2016;22:143)
Radiology images
Contributed by Dr. Mark R. Wick
Mammogram
Images hosted on other servers:
Irregular mass (mammography), hypoechoic area (ultrasound)
Prognostic factors
- Older age, larger tumor size and metastatic axillary lymph node involvement are independent risk factors for survival and recurrence (Cancer 2008;113:1511)
- Higher histological grade is associated with poorer outcome (Breast Cancer Res Treat 2008;111:121, Histopathology 2015;66:409)
- Independently predicts shorter disease specific survival and disease free interval
- Associated with higher stage and hormone receptor negativity
- Classic type more favorable than solid, pleomorphic and other types (Cancer 2008;113:1511)
- Lower number of lymph node metastases and risk of recurrence
- E-cadherin negative lobular carcinomas have a higher disease specific mortality than E-cadherin positive counterparts (Histopathology 2015;66:409)
- High Ki67 index associated with risk of distant metastasis (Cancer 2008;113:1511)
- Better initial outcome but worse long term (> 10 years after diagnosis) survival compared with invasive ductal carcinoma (Eur J Cancer 2008;44:73)
Case reports
- 55 year old woman with vague thickening and negative mammography and ultrasound (Clin Case Rep 2019;7:442)
- 73 year old man with invasive lobular carcinoma (Radiol Case Rep 2020;15:727)
- 73 year old woman with diffuse gastrointestinal metastasis 15 years after mastectomy for lobular carcinoma (Oxf Med Case Reports 2019;2019:omy133)
- 76 year old woman presenting with carcinoma en cuirasse (BMJ Case Rep 2017;2017:bcr2017222121)
Treatment
- Mastectomy may be preferred over breast conservation due to risk of local recurrence (Breast 2003;12:23)
- Lobular carcinomas likely to have positive margins on initial excision but risk of recurrence not increased if final margins are clear (Breast Cancer Res Treat 2015;149:555)
- Efficacy of chemotherapy may be limited
- Low rates of successful breast conservation after neoadjuvant chemotherapy (Ann Surg Oncol 2009;16:1606)
- Pathological complete response rate low (14%) (Am J Surg 2018;215:509)
- Adjuvant chemotherapy less effective for lobular carcinoma (Oncol Ther 2020;8:1)
- Response to hormone therapy superior to invasive breast carcinoma of no special type (Eur J Cancer 2008;44:73)
- Benefit from radiotherapy similar to invasive breast carcinoma of no special type (Clin Breast Cancer 2016;16:319)
Clinical images
Images hosted on other servers:
Carcinoma en cuirasse
Gross description
- Can form a discrete irregular mass (BMJ Case Rep 2016;2016:bcr2016215665)
- Frequently ill defined borders, due to lack of sclerotic stromal response
- Not uncommonly grossly unidentifiable or is grossly underestimated, only slightly firm on palpation
Gross images
Images hosted on other servers:
Anal metastasis
Multiple foci with irregular margins
Frozen section description
- Discohesive tumor cells may be difficult to identify on frozen sections, particularly when cellularity is low
- Single tumor cells can be mistaken as inflammatory cells (histiocytes and lymphocytes) and vice versa
- Ill defined nature of lesion increases chance of margins sent for frozen section being involved by tumor microscopically
Frozen section images
Contributed by Emily S. Reisenbichler, M.D.
Invasive lobular carcinoma
Microscopic (histologic) description
- Tumor cells arranged in single files, cords and single cells (Breast Cancer Res 2015;17:12)
- Can be arranged concentrically around normal ducts, giving a targetoid appearance
- Tumor cells discohesive, small, monomorphic and lacking marked atypia
- Round or notched ovoid nuclei, usually grade 1 or 2 nuclear score
- Scant cytoplasm, occasional with intracytoplasmic lumen
- Mitosis infrequent
- Desmoplastic reaction and necrosis uncommon
- Requires high index of suspicion for metastasis
- Single and scattered tumor cells with mild atypia requires examination on high power magnification with caution (Int J Surg Case Rep 2021;80:105612)
- Other (nonclassic) patterns of lobular carcinoma
- Solid:
- Sheets or large nests of tumor cells
- Alveolar:
- Clusters and aggregates of ≥ 20 cells
- Tubulolobular carcinoma:
- Tumor cells arranged in small round tubules mixed with classical lobular carcinoma
- Pleomorphic:
- Markedly pleomorphic (nuclear size > 4 times lymphocyte or nuclear pleomorphism equivalent to high grade ductal carcinoma in situ)
- Higher rate of hormone receptor negativity, HER2 and p53 immunohistochemistry positivity
- Histiocytoid:
- Foamy cytoplasm resembling histiocytes
- Apocrine:
- Abundant eosinophilic granular cytoplasm
- Signet ring
- Solid:
Microscopic (histologic) images
Contributed by Joshua J.X. Li, M.B.Ch.B., Gary M. Tse, M.B.B.S and Kristen E. Muller, D.O.
Tumor cells in single file
Low grade nuclei
Adjacent in situ component
E-cadherin loss
Intracytoplasmic vacuoles
Luminal A subtype
Alveolar pattern
Signet ring pattern
Solid pattern
Virtual slides
Images hosted on other servers:
Core biopsy
In situ and invasive tumor
Gastrointestinal metastasis
Cytology description
- Cellularity can be low
- Tumor cells arranged in chains, single files or as single cells
- Tumor cells arranged in small chains are helpful clues
- Nuclear atypia mostly mild
- Nuclei round to oval and eccentric
- Cytoplasm scanty with a high nuclear / cytoplasmic ratio
- Occasional intracytoplasmic vacuolations may be seen
- Cytologic features can resemble mesothelial cells in effusion fluid (Diagn Cytopathol 2012;40:311)
Cytology images
Contributed by Joshua J.X. Li, M.B.Ch.B. and Gary M. Tse, M.B.B.S
Discohesive tumor cells
Mild atypia
Loose chains of cells
Intracytoplasmic vacuolation
Positive stains
- Estrogen receptor (97%) and progesterone receptor (80%) (Breast Cancer Res Treat 2012;133:713)
- Androgen receptor (87%) (Virchows Arch 2005;447:695)
- Abnormal expression of catenins
- p120 (88%) (cytoplasmic) (Oncogene 2004;23:3272)
- Beta catenin (42% nuclear and cytoplasmic; 23% retained membranous staining) (Eur J Surg Oncol 2001;27:31)
- GATA3 (97 - 100%) (Am J Surg Pathol 2013;37:1756, Ann Diagn Pathol 2015;19:6)
- Mammaglobin (69%) (Ann Diagn Pathol 2015;19:6)
- GCDFP-15 (52%) (BMC Cancer 2014;14:546)
- Mucicarmine (highlights intracellular mucin)
Negative stains
- Abnormal expression of catenins
- E-cadherin (16%) (Am J Surg Pathol 2010;34:1472, Hum Pathol 2020;102:44)
- E-cadherin absence or reduction of membranous staining, useful but not necessary for diagnosis of lobular carcinoma
- Beta catenin (35% lost) (Eur J Surg Oncol 2001;27:31)
- E-cadherin (16%) (Am J Surg Pathol 2010;34:1472, Hum Pathol 2020;102:44)
- HER2 (1 - 11%) (Annals of Oncology 2018;29: ix1)
Molecular / cytogenetics description
- Mostly luminal A subtype by gene expression profiling (Cell 2015;163:506)
- Followed by luminal B but rarely HER2 enriched or basal-like
- 1q gain, 16p gain and 16q loss frequent (J Pathol 2008;215:231)
- CDH1 gene located at 16q22.1 (Br J Cancer. 1997;76(9):1131-1133)
- CDH1 (65%) and PIK3CA (48%) mutations common (Cell 2015;163:506)
- CDH1 loss of function through truncating mutation or promoter hypermethylation combined with loss of heterozygosity at chromosome 16, resulting in loss of protein (Int J Cancer 2001;92:404, Int J Cancer. 2003;106(2):208-215, Breast Cancer Res 2015;17:12)
Sample pathology report
- Left breast, mastectomy:
- Invasive lobular carcinoma (see comment)
- Comment: Sections show breast tissue with malignant cells in a diffuse and discohesive pattern, with some forming single files and small clusters. Targetoid pattern is noted. The tumor cells show mild nuclear pleomorphism with rare mitoses, corresponding to a Nottingham histological grade of I. No lymphovascular permeation is seen. The tumor measures ___cm in maximal dimension. The remaining breast tissue and nipple are unremarkable. All the resection margins are clear, with a minimal clearance of ___cm at the ___ margin. Immunohistochemical staining shows tumor cells are E-cadherin negative. The features are those of an infiltrating lobular carcinoma, classic type.
Differential diagnosis
- Primary disease
- Mixed invasive breast carcinoma and invasive lobular carcinoma:
- Presence of ductal component
- Lobular component more commonly E-cadherin positive (92%) (Breast Cancer Res Treat 2013;138:719)
- Lobular carcinoma in situ involving sclerosing adenosis:
- Retained lobular architecture
- Myoepithelial cells present and can be demonstrated by immunohistochemistry
- Inflammatory infiltrates and lymphoma:
- Lacks background lobular carcinoma in situ
- Lymphoid cells may be more hyperchromatic and have less cytoplasm
- No intracellular cytoplasmic vacuolation
- Cytokeratin negative and lymphocyte markers positive
- Melanoma:
- Lacks background lobular carcinoma in situ
- Can display marked nuclear atypia
- Cytokeratin negative and melanocytic markers positive
- Myofibroblastoma, epithelioid variant:
- Well circumscribed borders
- Lacks background lobular carcinoma in situ
- Presence of spindle cell component
- Cytokeratin negative
- Mixed invasive breast carcinoma and invasive lobular carcinoma:
- Metastatic disease
- Histiocytes and lymphocytes
- Signet ring cell carcinoma of gastrointestinal origin:
Board review style question #1
Which of the following germline mutations is associated with an increased risk of developing lobular carcinoma of the breast?
- APC
- BRCA1
- BRCA2
- CDH1
- TP53
Board review style answer #1
D. CDH1. CDH1 encodes E-cadherin and germline mutation results in hereditary diffuse gastric cancer syndrome. No increased risk of developing lobular carcinoma of the breast is reported for germline BRCA1 and BRCA2 mutations. Germline TP53 and APC mutations result in Li-Fraumeni syndrome and familial adenomatous polyposis, which are not associated with lobular carcinoma of the breast. (Cancer Epidemiol Biomarkers Prev 2012;21:134, Breast J 2019;25:16)
Comment Here
Reference: Classic lobular carcinoma
Comment Here
Reference: Classic lobular carcinoma
Board review style question #2
Which of the following features is more commonly seen in classic lobular carcinoma compared with pleomorphic lobular carcinoma?
- Formation of invasive tubular structures
- Grade 3 (markedly pleomorphic) nuclear features
- HER2 positivity
- Hormone receptor positivity
- TP53 mutation
Board review style answer #2
D. Hormone receptor positivity. Compared with classic lobular carcinoma, pleomorphic lobular carcinoma is more likely to be HER2 positive, hormone negative and TP53 mutated. Marked nuclear pleomorphism is a required feature of pleomorphic lobular carcinoma. Neither classic nor pleomorphic lobular carcinoma feature glandular formation. (Cell Oncol (Dordr) 2012;35:111)
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Reference: Classic lobular carcinoma
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Reference: Classic lobular carcinoma
Collagenous spherulosis
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Positive stains | Negative stains | Electron microscopy description | Videos | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Nonneoplastic alteration characterized by spherules of basement membrane material surrounded by myoepithelial cells (Hoda: Rosen's Diagnosis of Breast Pathology by Needle Core Biopsy, 4th Edition, 2017)
- Almost always an incidental finding in association with proliferative lesions (papilloma, sclerosing adenosis and rarely carcinoma in situ) (Pathology 2017;49:181)
Essential features
- Benign proliferation with intraluminal pink basement membrane material (spherule) surrounded by myoepithelial cells
Terminology
- Collagenous spherulosis
- Simple spherulosis
- Mucinous spherulosis
- Adenoid cystic hyperplasia (not recommended due to confusion with adenoid cystic carcinoma)
ICD coding
Epidemiology
- Adult women
- Frequency < 1% of excision specimens (Hoda: Rosen's Diagnosis of Breast Pathology by Needle Core Biopsy, 4th Edition, 2017); likely underreported
Sites
- No specific site in the breast
Pathophysiology
- Unclear
- Accumulation of basement membrane material in spaces
Etiology
- Unknown
Clinical features
- Usually incidental
- Very rarely presents as mass (Pathology 2017;49:181)
Diagnosis
- Based on histologic examination of removed tissue
Radiology description
- May present as radiologic or rarely as architectural distortion, density or mass (Pathology 2017;49:181)
Prognostic factors
- No evidence of association with precancerous state (Hoda: Rosen's Diagnosis of Breast Pathology by Needle Core Biopsy, 4th Edition, 2017)
- May be seen in association with neoplastic proliferations, particularly lobular carcinoma in situ (LCIS) (Am J Surg Pathol 2006;30:20)
Case reports
- 48 year old woman with collagenous spherulosis in an adenomyoepithelioma (J Clin Pathol 2004;57:83)
- 50 year old woman with cystic mass with solid component (Breast J 2008;14:301)
- 51 year old woman with slow growing mass (Acta Cytol 2010;54:314)
- 47 year old and 51 year old women with cases of collagenous spherulosis associated with lobular carcinoma in situ (J Pathol Transl Med 2018;52:420)
- 53 year old woman with a 3.5 cm breast mass (Breast J 2000;6:199)
Treatment
- No treatment required
Gross description
- No specific gross features (usually not discernable from background breast tissue)
Microscopic (histologic) description
- Round spaces filled with acellular pink basement membrane material (spherules) (Pathology 2017;49:181)
- Spherules measure 20 - 100 μm in diameter (Hoda: Rosen's Diagnosis of Breast Pathology by Needle Core Biopsy, 4th Edition, 2017)
- Center of the spherules may be transparent but thin rim of basement membrane material always present
- Radiating stellate fibrils or microcalcifications may be seen in the spherules
- Spherules surrounded by small oval / spindle myoepithelial cells with interspersed cuboidal luminal cells
- Myoepithelial cells are uniformly present at the periphery of involved glands
- Majority associated with benign proliferative lesions, mostly intraductal papilloma
Microscopic (histologic) images
Contributed by Iskender Sinan Genco, M.D. and Sabina Hajiyeva, M.D.
Cribriform architecture
Multiple ducts
2 different sized ducts
Cribriform architecture
Partial involvement
Adjacent apocrine metaplasia
Columnar cell changes
Smooth muscle myosin heavy chain
CD10
KIT / CD117
In situ carcinoma
ER
CK5/6
Adjacent invasive carcinoma
Smooth muscle actin
Smooth muscle myosin heavy chain
Calponin
p63
PAS
Cytology description
- Hyalinized green (Papanicolaou stain) or dark purple (Giemsa stain) spherules (Cytopathology 2010;21:157)
- 20 - 60 μm in diameter
- Present in the center of epithelial clusters (Cytopathology 2002;13:116)
- Surrounded by 1 - 2 layers of small uniform oval / spindle cells (Cytopathology 2002;13:116, Acta Cytol 2010;54:314)
Cytology images
Contributed by Mark R. Wick, M.D.
FNA
Positive stains
- Myoepithelial cells:
- Cytoplasmic: alpha smooth muscle actin, smooth muscle myosin heavy chain, calponin, CK5/6 (Mod Pathol 2006;19:1351)
- Membranous: CD10 (Pathol Res Pract 2012;208:405)
- Nuclear: p63, S100 (Mod Pathol 2006;19:1351)
- Basement membrane material:
- PAS, mucicarmine, type IV collagen, laminin (Pathology 2017;49:181)
Negative stains
- Myoepithelial cells: KIT / CD117, ER and CK7 (Mod Pathol 2006;19:1351)
Electron microscopy description
- Myoepithelial cells with intracytoplasmic myofilaments (Breast J 2000;6:199)
- Spherules composed of collagen fibers and external laminar material (Ultrastruct Pathol 1998;22:239)
Videos
Breast calcifications
Sample pathology report
- Breast, left, 3 o'clock, stereotactic core biopsy:
- Lobular carcinoma in situ (LCIS) involving collagenous spherulosis, with microcalcifications (see comment)
- Comment: Immunohistochemical stain for E-cadherin is negative in LCIS, supporting the diagnosis. Controls are appropriate.
Differential diagnosis
- Adenoid cystic carcinoma:
- Invasive pattern
- Intraluminal material is denser
- Myoepithelial cells are negative for CD10
- Luminal cells are positive for KIT / CD117, negative for ER and PR
- Ductal carcinoma in situ, cribriform type:
- Cribriform spaces are rounder and more regular (cookie cutter appearance)
- No pink material present in cribriform spaces
- Cribriform spaces surrounded by luminal cells, not myoepithelial cells
- Negative for CK5/6
- Lobular carcinoma in situ, signet ring cell type:
- Intracytoplasmic vacuoles
- Negative for E-cadherin
- Some, but not all, features of low grade ductal carcinoma in situ (see above)
- Negative for CK5/6
Additional references
Board review style question #1
A premenopausal woman had a stereotactic breast core biopsy for calcifications. Microscopic examination revealed fibrocystic changes with microcalcifications as well as the microscopic finding shown above (H&E). Regarding this entity, which of the following statements is true?
- Comprised of a clonal (neoplastic) proliferation
- Epithelial cells interspersed between spaces are negative for ER
- Flattened (myoepithelial) cells around spaces are positive for CD10
- Luminal epithelial cells are positive for KIT / CD117
- Surgical excision should be performed
Board review style answer #1
C. The flattened (myoepithelial) cells around spaces are positive for CD10. The picture shows slightly expanded ducts with spaces filled with eosinophilic material. The spaces are surrounded by small oval / spindle myoepithelial cells with interspersed cuboidal luminal cells, features consistent with collagenous spherulosis. Collagenous spherulosis is a benign finding and does not require treatment. Adenoid cystic carcinoma is the main differential diagnosis which shows MYB-NFIB fusion gene, is negative for ER and PR, positive for KIT / CD117 and should be surgically excised.
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Reference: Collagenous spherulosis
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Reference: Collagenous spherulosis
Board review style question #2
A 34 year old woman was diagnosed with invasive ductal carcinoma on core biopsy and subsequently underwent surgical excision. One of the surgical specimen sections showed the microscopic lesion with cribriform architecture (middle) adjacent to invasive carcinoma. Based on the provided H&N, SMMH, and PAS stains, what is the correct diagnosis?
- Atypical ductal hyperplasia
- Collagenous spherulosis
- Ductal carcinoma in situ
- Lobular carcinoma in situ involving ductal carcinoma in situ
- Usual ductal hyperplasia
Board review style answer #2
B. Collagenous spherulosis
The H&E slide shows invasive carcinoma (upper), benign breast tissue (right lower), and a duct with cribriform architecture (middle). SMMH highlights the myoepithelial cells around the cribriform spaces and the periphery of the involved duct, whereas invasive carcinoma is negative for SMMH. This lesion with cribriform architecture represents collagenous spherulosis. PAS stain highlights the basement membrane material within the cribriform spaces produced by the surrounding myoepithelial cells. The other options may also show cribriform architecture but do not have myoepithelial cells surrounding the cribriform spaces. PAS stain helps confirm the diagnosis of collagenous spherulosis, but does not entirely rule out the other options.
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Reference: Collagenous spherulosis
The H&E slide shows invasive carcinoma (upper), benign breast tissue (right lower), and a duct with cribriform architecture (middle). SMMH highlights the myoepithelial cells around the cribriform spaces and the periphery of the involved duct, whereas invasive carcinoma is negative for SMMH. This lesion with cribriform architecture represents collagenous spherulosis. PAS stain highlights the basement membrane material within the cribriform spaces produced by the surrounding myoepithelial cells. The other options may also show cribriform architecture but do not have myoepithelial cells surrounding the cribriform spaces. PAS stain helps confirm the diagnosis of collagenous spherulosis, but does not entirely rule out the other options.
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Reference: Collagenous spherulosis
Columnar cell change / hyperplasia
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Negative stains | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Enlarged terminal duct lobular units (TDLUs) with irregularly dilated acini lined by columnar epithelial cells
- Intraluminal secretions and calcifications common
Essential features
- Terminal duct lobular units are lined by columnar epithelial cells
- Lacks low grade cytologic atypia of flat epithelial atypia and architectural atypia of atypical ductal hyperplasia or ductal carcinoma in situ
Terminology
- WHO acceptable:
- Columnar cell change
- Columnar cell hyperplasia
- Not recommended by WHO:
- Blunt duct adenosis
- Columnar alteration of lobules
- Columnar metaplasia
- Hyperplastic unfolded lobules
- Hyperplastic enlarged lobular units
- Enlarged lobular units with columnar alteration
- Lesions with cytologic atypia are flat epithelial atypia (FEA)
ICD coding
Epidemiology
- Columnar cell lesions (columnar cell change / hyperplasia and flat epithelial atypia) seen in as high as 42% of biopsies for calcifications (Am J Surg Pathol 1998;22:1521)
Sites
- Breast terminal duct lobular units
Pathophysiology
- Might represent the earliest nonobligate precursor in low grade breast neoplasia pathway and a marker for potential presence of atypia
Etiology
- Unknown
Clinical features
- No specific clinical features
- Most often detected on screening mammography when associated with microcalcifications
Diagnosis
- Image guided needle core or surgical excisional biopsy with tissue histologic examination
- Diagnosis is reproducible with available histologic diagnostic criteria (Mod Pathol 2006;19:172)
Radiology description
- Heterogeneously dense tissue with clustered, amorphous or fine pleomorphic calcifications on mammography (Radiographics 2007;27:S79)
- Branching microcalcifications are not common (Am J Surg Pathol 1998;22:1521)
Radiology images
Contributed by Jonathan Marotti, M.D.
Calcifications associated with columnar cell change / hyperplasia
Prognostic factors
- Slight increased risk for breast cancer development (relative risk ~1.5) but risk with columnar cell change / hyperplasia not independent of risk associated with concurrent proliferative lesions (Breast Cancer Res 2010;12:R61, Cancer 2008;113:2415)
- Can be associated with other lesions on the low grade breast neoplasia pathway (flat epithelial atypia, atypical ductal hyperplasia, low grade ductal carcinoma in situ, lobular neoplasia) (Surg Pathol Clin 2018;11:177)
Case reports
- 43 year old woman with columnar cell hyperplasia and mucocele-like lesion (J Med Case Rep 2008;2:138)
- 2 cases (41 and 49 year old Japanese women) in which epithelial detachment artifact of columnar cell lesions was thought to result in pseudomicropapillae mimicking atypia (Virchows Arch 2013;463:93)
Treatment
- Excision not required when columnar cell change / hyperplasia without atypia is the most significant pathology in core biopsy specimens
- No further management required when columnar cell lesions are the most significant pathology in excision specimens
- Reference: Ann Surg 2012;255:259
Gross description
- No specific gross features
Microscopic (histologic) description
- Columnar cell change:
- Terminal duct lobular units with irregular, variably dilated acini
- Acini lined by 1 - 2 cell layers
- Lining cells have uniform, ovoid to elongated nuclei oriented perpendicular to basement membrane
- Apical snouts are frequently present
- Luminal secretions and calcifications may be present
- Columnar cell hyperplasia:
- Terminal duct lobular units with irregular, variably dilated acini
- Acini lined by stratified cells (more than 2 cell layers); may form tufts or mounds
- Lining cells have uniform, ovoid to elongated nuclei that may appear crowded and overlap
- Apical snouts often present
- Luminal secretions and calcifications may be present
- Columnar cell change / hyperplasia with cytologic atypia (high nuclear cytoplasmic ratio, irregular nuclear chromatin, variably prominent nucleoli) can be classified as flat epithelial atypia
- Round nuclei with variably prominent nucleoli and loss of orientation perpendicular to basement membrane is flat epithelial atypia
- Rigid bars, arcades and true micropapillations is atypical ductal hyperplasia or low grade ductal carcinoma in situ
- Reference: Adv Anat Pathol 2003;10:113
Microscopic (histologic) images
Contributed by Jonathan Marotti, M.D.
Columnar cell change
Dilated TDLU
Flocculent secretions
Columnar cells
Columnar cell hyperplasia
Irregular TDLU
Calcifications
Tufts / mounds
Cytology description
- Range of atypia; cannot reliably differentiate from papillary neoplasms or well differentiated adenocarcinoma
- Flat sheets of cells with distinct cell borders, finely granular cytoplasm, enlarged nuclei and few myoepithelial cells (Diagn Cytopathol 2007;35:73)
- 3 dimensional clusters of polygonal epithelial cells mixed with myoepithelial cells; palisading columnar cells peripherally (Diagn Cytopathol 2004;31:370)
Positive stains
Molecular / cytogenetics description
- Loss of 16q (Mod Pathol 2018;31:1816, Am J Surg Pathol 2005;29:734)
- Low prevalence of molecular alterations in columnar cell change; progressive accumulation of allelic damage through columnar cell hyperplasia, atypia and invasive carcinoma (Mod Pathol 2006;19:344)
Sample pathology report
- Right breast, needle core biopsy:
- Columnar cell change and columnar cell hyperplasia with associated microcalcifications
Differential diagnosis
- Cysts:
- Attenuated, cuboidal or apocrine epithelium (noncolumnar)
- Apocrine metaplasia:
- Abundant, granular eosinophilic cytoplasm
- Round nuclei with prominent nucleoli
- Prominent apical snouting not typically seen
- Cystic hypersecretory hyperplasia:
- Cystic structures containing dense eosinophilic colloid-like material
- Epithelium can demonstrate spectrum of alterations
- Flat epithelial atypia:
- Dilated terminal duct lobular units with round contours
- Low grade, monomorphic, round to ovoid nuclei with variably prominent nucleoli and increased nuclear cytoplasmic ratio
- Nuclei lose perpendicular orientation to basement membrane
- Atypical ductal hyperplasia (ADH) and low grade ductal carcinoma in situ:
- Architectural features of atypical ductal hyperplasia and low grade ductal carcinoma in situ (arcades, bridges, papillations, round fenestrations) are present
- Ductal carcinoma in situ, clinging type:
- Marked cytologic atypia (typically high grade)
Additional references
Board review style question #1
What is the appropriate clinical management for the above lesion when identified on core biopsy?
- Follow up breast MRI
- No additional action required
- Surgical excision with negative margins
- Tamoxifen
Board review style answer #1
B. No additional action required. The image demonstrates the histologic features of columnar cell hyperplasia: stratified columnar epithelial cells forming tufts, exaggerated apical snouts and luminal calcifications. If columnar cell hyperplasia is the most significant alteration in the core biopsy sample and assuming adequate radiology and pathology correlation, no further clinical management is required. Surgical excision with negative margins is typically appropriate for ductal carcinoma in situ and invasive carcinomas. Tamoxifen is reserved for patients with higher risk lesions. Breast MRI is not indicated for columnar cell change / hyperplasia.
Comment Here
Reference: Columnar cell change / hyperplasia
Comment Here
Reference: Columnar cell change / hyperplasia
Board review style question #2
Columnar cell change / hyperplasia is often diagnosed because of
- Calcifications seen on mammography
- Large irregular mass seen on ultrasound
- New palpable breast mass
- Nipple discharge
Board review style answer #2
A. Calcifications seen on mammography. Columnar cell change / hyperplasia is often biopsied following identification of calcifications on mammography. Columnar cell change / hyperplasia can also be an incidental finding in core biopsies or surgical excisions.
Comment Here
Reference: Columnar cell change / hyperplasia
Comment Here
Reference: Columnar cell change / hyperplasia
Core biopsy
Table of Contents
Definition / general | Core biopsy versus fine needle aspiration biopsy | Guidance modalities | Technical details | False negatives | Complications | Reporting system of UK National Health Service Screening Programme | Diagrams / tables | Microscopic (histologic) imagesDefinition / general
- See also discussion of core biopsies under specific diagnoses and core biopsy imprint cytology as part of cytology topic
- Percutaneous large core needle biopsy using stereotactic mammography or ultrasound guidance is routinely used to evaluate clinically occult breast lesions and is an alternative to open biopsy for many patients
- Recommended as the initial diagnostic procedure in patients with suspicious mammograms, due to association with improved pathologic margins and fewer surgical procedures (Breast J 2008;14:471)
- May be an alternative to surgery for some lesions (Breast 2008;17:546, Radiology 2008;248:406)
- Has led to reduction in surgical interventions after benign or negative diagnoses (Eur J Cancer 2008;44:2580)
- Overall high level of interpathologist agreement (Am J Surg Pathol 2004;28:126)
- Diagnostic performance is comparable to excisional specimens (Int J Cancer 2008;122:468) but tumor grade in invasive carcinoma may differ (Am J Surg Pathol 2003;27:11, Am J Surg 2009;197:266)
- Performing imprint cytology on core may be useful for rapid diagnosis (Cytopathology 2008;19:311)
- eMedicine: Breast Stereotactic Core Biopsy / Fine Needle Aspiration, National Breast Cancer Centre: Breast Fine Needle Aspiration Cytology and Core Biopsy: A Guide for Practice, First Edition, 2004
Core biopsy versus fine needle aspiration biopsy
Core biopsy is favored over fine needle aspiration because core biopsy:
- Is useful for evaluating cytologic and architectural characteristics and diagnosing invasive carcinoma (Diagn Cytopathol 2007;35:681)
- Is more reliable (Acta Radiol 2008;49:863)
- Reduces need for additional biopsies (Acta Oncol 2008;47:1037)
Guidance modalities
MRI directed breast excision:
Definition / general:
Indications:
Clinical features:
- Widely used in U.S. (AJR Am J Roentgenol 2008;191:332)
- MRI cannot verify that suspicious lesion is in specimen (unlike traditional radiography) because MRI requires IV injection of gadolinium and uptake into suspicious area, which cannot be done after specimen has been excised
- References: eMedicine: Breast Biopsy With Needle Localization
Indications:
- Screening of high risk women for breast cancer (AJR Am J Roentgenol 2003;181:619, Cancer 2005;103:1898)
- Monitoring response to neoadjuvant chemotherapy (Radiology 2007;244:672)
- If uncertain diagnosis on mammography, ultrasound or clinically (AJR Am J Roentgenol 1999;173:1323)
- If lymph node metastases from unknown primary (Radiology 1999;212:543)
Clinical features:
- Low (87%) sensitivity for diagnosing mammographically detected microcalcifications (AJR Am J Roentgenol 2006;186:1723)
- Recommended to submit entire specimen for microscopic examination because usually no gross findings (Hum Pathol 2007;38:1754)
- Complete removal of MRI target does not ensure complete histologic excision of the cancer (AJR Am J Roentgenol 2008;191:1198)
- MRI guided vacuum assisted biopsy may provide an alternative to surgery and MRI guided needle biopsy (AJR Am J Roentgenol 2003;181:1283)
- May overestimate gross tumor size (AJR Am J Roentgenol 2003;181:1283)
Technical details
- First generation: computer assisted stereotactic mammography or ultrasound used to localize target lesion, then automated spring loaded biopsy gun was used, usually with 14 gauge cutting needle
- Second generation: includes Mammotome (Breast Cancer 2007;14:292, World J Surg Oncol 2007;5:83); uses vacuum assistance to draw tissue into the needle and permits use of larger caliber needles (8 to 11 gauge) and more thorough sampling of lesions (thicker, longer, multiple specimens with single needle insertion)
- Processing: should routinely obtain 3 - 5 deeper levels; 5 levels recommended to detect ADH and atypical proliferations (Arch Pathol Lab Med 2001;125:1055) or minimally invasive carcinoma (Arch Pathol Lab Med 2004;128:996); but see Mod Pathol 2001;14:350
- May need only one level routinely for MRI detected lesions (Arch Pathol Lab Med 2009;133:1961)
- Underestimation of findings compared to excision is comparable with 9 or 12 gauge needles (Breast Cancer 2011;18:42)
- Some recommend routine radiologic examination of cores for microcalcifications and deeper levels if microcalcifications are not in slide
- Minimal invasion in core biopsies (1 mm or less) is usually associated with invasive tumors of 1 cm or more at excision (Arch Pathol Lab Med 2004;128:996)
- Rarely mastectomy (or excisional biopsy) after malignant core biopsy will show no cancer (Mod Pathol 1997;10:1209)
- Immunostains for ER, PR and HER2 show 85 - 95% concordance with excision specimens (Acta Oncol 2008;47:38, Pathology 2007;39:391); substantial discordance for PR in some studies (Ann Oncol 2009;20:1948)
- Not associated with significant bleeding in patients on anticoagulant therapy (AJR Am J Roentgenol 2008;191:1194)
- Cytopathologists may be able to perform ultrasound guided FNAs and core biopsies (Diagn Cytopathol 2008;36:317)
False negatives
- Radiologic - histologic correlation: must determine if histologic results provide a sufficient explanation for the imaging features - if not, lesion may not have been adequately sampled
- Most false negatives are due to radiologic - histologic discordance and are discovered immediately (Eur Radiol 2010;20:782, Eur J Cancer 2010;46:1835)
- Follow up imaging is recommended, even in patients with concordant benign findings (Radiographics 2007;27:79)
Complications
- Seeding / displacement of normal epithelium along needle tract, particularly with papillary lesions, which may simulate malignancy (Arch Pathol Lab Med 2005;129:1465)
- Seeding of tumor cells along needle tract (Breast Cancer Res Treat 2008;110:51), particularly intracystic papillary carcinoma (J Clin Pathol 2002;55:780)
- Seeding of tumor cells into lymphovascular spaces (Am J Clin Pathol 2010;133:781)
- Reactive spindle cell proliferation
- Epidermal inclusion cyst
- Pseudoaneurysms are rare (Breast Cancer 2010;17:75)
Reporting system of UK National Health Service Screening Programme
- B1: normal tissue / inadequate sample (comment on microcalcifications and specimen adequacy)
- B2: benign lesion (specify)
- B3: uncertain malignant potential (includes radial scar, some papillary lesions, ADH, lobular neoplasia)
- B4: suspicious of malignancy (suggestive but not diagnostic due to scanty material or artifacts)
- B5: malignant; specify if invasive or not, if possible; indicate grade of DCIS
- References: J Clin Pathol 2004;57:897
Diagrams / tables
Images hosted on other servers:
Mammotome
Microscopic (histologic) images
Images hosted on other servers:
Displaced epithelial cells; #2 - intracystic papillary carcinoma
Detached clusters
of ductal carcinoma
in situ from
pre-existing ducts
Cribriform
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Cytology images | Positive stains | Negative stains | Electron microscopy description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Low grade invasive breast carcinoma microscopically characterized by a predominant cribriform pattern
- By WHO classification, a specific subtype of invasive breast carcinoma
- Variants:
- Pure: cribriform architecture is > 90% of the tumor
- Mixed: tumor composed of 10 - 90% of another morphological type (other than tubular carcinoma)
Essential features
- Invasive breast carcinoma with > 90% of tumor composed of cribriform islands of malignant epithelial cells
- Low grade nuclei and sparse mitosis (grade 1)
- ER+ and HER2-
Terminology
- Invasive cribriform carcinoma (ICC)
ICD coding
- ICD-O: 8201/3 - cribriform carcinoma, NOS
- ICD-10: C50.9 - malignant neoplasm of breast of unspecified site
- ICD-11: 2C60 & XH1YZ3 - carcinoma of breast, specialized type & cribriform carcinoma, NOS
Epidemiology
- Rare (0.3 - 3.5% of breast carcinomas) (Ann Oncol 2009;20:1763)
- Mean age: 63 years, postmenopausal, rare in < 50 years
- Elderly males: 1.7% (BMC Cancer 2021;21:168)
Sites
- Breast
- Axilla - accessory breast tissue
Pathophysiology
- Luminal A molecular pathway / subtype of breast cancer (Cell Genom 2021:1;100067)
- Expresses hormone receptors and lacks HER2 overexpression
Etiology
- Unclear
Clinical features
- May present as a small lump / asymptomatic
- May be clinically occult
- Multifocal: 10 - 20% (Breast Care (Basel) 2013;8:149)
- Nodal metastases in 14% of pure ICC and 25% in mixed ICC (World J Surg Oncol 2012;10:251)
Diagnosis
- Breast imaging including mammogram and ultrasound of breast
- Cytologic or histologic examination of involved tissue
Radiology description
- Mammogram: density, asymmetry, spiculated mass, microcalcifications
- Ultrasound: mass
- MRI: enhancing focus or mass
Radiology images
Images hosted on other servers:
Mammogram: 2.5 cm tumor, fuzzy border
Prognostic factors
- Pure ICC: excellent; usually less lymph node metastasis and lower stage
- Mixed ICC: prognosis poorer than pure but better than invasive ductal carcinoma of no special type (IDC, NST)
- Lymph node / distant metastasis is rare (BMC Cancer 2021;21:168)
- ICC: more favorable prognosis than invasive breast carcinoma with less cribriform pattern and low grade IDC (J Clin Exp Pathol 2013;6:445)
Case reports
- 59 year old woman, postmenopausal, presented with a large left breast mass of 13 years (World J Surg Oncol 2012;10:251)
- 64 year old man with tumor microcalcifications (Breast Cancer 2005;12:145)
- 68 year old woman with incidentally detected invasive cribriform carcinoma on CT (Clin Case Rep 2021;9:e05214)
- 12 cases of invasive cribriform carcinoma of the breast (Int J Clin Exp Pathol 2017;10:9917)
Treatment
- Primary surgical excision
- Postsurgical local radiation therapy (typically in the setting breast conserving therapy only for this special subtype of breast carcinoma)
- Endocrine therapy
Gross description
- Similar to IDC
- Usually small size, < 2 cm; some 2 - 5 cm; firm / hard spiculated mass, gritty if calcifications are present (Int J Clin Exp Pathol 2017;10:9917)
Microscopic (histologic) description
- Irregular cribriform growth pattern > 90% of cells
- Nuclear grade I pure ICC: > 90% cribriform pattern
- Mixed: 10 - 90% other morphological type, other than tubular carcinoma
- Low grade: Nottingham grade 1 tumors
- Invasive islands or nests of malignant cells with round or angulated contours and well defined cribriform spaces formed by arches of epithelial cells; this gives a sieve-like appearance
- Tumor cells: small, mild / moderate pleomorphism, no nuclear atypia
- No / sparse mitotic activity
- Desmoplastic stroma
- Mucin positive secretion, microcalcifications in lumen
- Osteoclastic giant cells may be seen
- Myoepithelial cells absent
- Associated with cribriform ductal carcinoma in situ (DCIS)
Microscopic (histologic) images
Contributed by Sunitha Shankaralingappa, M.B.B.S, M.D., D.M.
Epithelial cells in cribriform pattern
Pure ICC
Low grade, cribriform pattern, mucin
Low grade nuclei
Cribriform carcinoma with cribriform DCIS
Cribriform DCIS with invasive component
Cribriform DCIS
IHC: ER strongly positive
IHC: PR strongly positive
IHC: HER2 negative
Virtual slides
Images hosted on other servers:
Cribriform (> 90%), grade I, desmoplastic stroma
Cytology description
- Cytologic features and limitations
- 3D clusters and cohesive sheets of bland ductal cells, cribriform pattern (Acta Cytol 2001;45:593)
- Naked bipolar nuclei and myoepithelial cells are absent
- Definitive diagnosis on cytology is rare; core needle biopsy is preferred
Cytology images
Images hosted on other servers:
Large sheets, cribriform architecture
Negative stains
- HER2
- Myoepithelial markers: distinguish ICC from cribriform DCIS
Electron microscopy description
- Numerous mitochondria
- Luminal surfaces have abundant microvilli (Ultrastruct Pathol 1994;18:519)
Sample pathology report
- Breast, right, modified radical mastectomy
- Invasive cribriform carcinoma, grade 1, measuring 1.5 cm
- Immunohistochemical biomarker results: estrogen receptor positive (90%, strong intensity), progesterone receptor positive (50%, moderate intensity), HER2 negative (score 0).
Differential diagnosis
- Adenoid cystic carcinoma:
- Cribriform DCIS:
- Noninfiltrating
- Regularly distributed clusters
- Myoepithelial cells are present
- Collagenous spherulosis:
- Circumscribed, intraductal or intralobular proliferation
- Fibrillar / laminated spherules
- Myoepithelial cells are present
- Lacks cytologic atypia
- Well differentiated neuroendocrine tumor:
- Intracytoplasmic argyrophilic granules
- Salt and pepper chromatin
- Neuroendocrine markers are positive
- Well differentiated invasive breast cancer of no special type (NST):
- May share similar nuclear features but lacks prominent cribriform architecture
Additional references
Board review style question #1
A 62 year old woman underwent a core needle biopsy for a lump, 1.2 cm in diameter, detected on mammogram. The histopathology pattern is shown above. Which statement is true regarding this tumor?
- Has an increased chance of distant metastasis
- Lesion is high grade
- Strong and diffuse positivity for ER
- Strongly positive (3+) for HER2 by IHC
Board review style answer #1
C. Strong and diffuse positivity for ER. This biopsy shows cribriform carcinoma. This type of breast carcinoma is seen in elderly, postmenopausal women and is most often detected on mammogram. It is strongly positive for ER, usually positive for PR and negative for HER2. It is a low grade tumor (Nottingham grade I) with a good prognosis and lower frequency of lymph node and distant metastasis.
Comment Here
Reference: Cribriform carcinoma
Comment Here
Reference: Cribriform carcinoma
Board review style question #2
Which of the following is one of the diagnostic criteria for invasive cribriform carcinoma of the breast?
- < 50% component of tubular carcinoma
- ER, PR, HER2 negative
- At least 90% of tumor composed of cribriform islands with low grade nuclei
- Presence of myoepithelial cells on IHC
Board review style answer #2
C. Nuclear grade I in at least 90% of cells. Invasive cribriform carcinoma (ICC) is an infiltrating breast carcinoma with predominantly cribriform pattern. It is pure when > 90% of tumor is of cribriform pattern. It is termed mixed ICC when the other invasive component constitutes 10 - 90%. It is a low grade tumor with grade I nuclei and sparse mitotic activity. It is differentiated from cribriform DCIS by absence of myoepithelium. ICC is a luminal A molecular subtype of breast carcinoma and expresses hormone receptors and lacks HER2 overexpression.
Comment Here
Reference: Cribriform carcinoma
Comment Here
Reference: Cribriform carcinoma
Cystic hypersecretory carcinoma
Table of Contents
Definition / general | Clinical features | Case reports | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Differential diagnosisDefinition / general
- Not part of WHO breast classification
- First described in 1984 (Am J Surg Pathol 1984;8:31)
- Very rare (< 100 cases reported)
- DCIS or hyperplasia is more common
Clinical features
- Usually low grade for several years but may metastasize
Case reports
- 40 year old woman with painful breast mass (Arch Pathol Lab Med 2005;129:e79)
- 43 year old woman (Jpn J Radiol 2011;29:660)
- 45 year old woman (J Korean Med Sci 2004;19:149)
- 48 year old woman with Paget’s disease of nipple (Int J Surg Pathol 2008;16:208)
- 49 year old woman with invasive lobular carcinoma in opposite breast 10 years after diagnosis (Arch Pathol Lab Med 1999;123:1108, free full text)
Gross description
- Numerous cysts with mucoid or gelatinous secretions
Gross images
Contributed by Dr. Okechukwu C. Okafor
Mastectomy with 12 cm multicystic tumor
Images hosted on other servers:
Numerous cysts with a gelatinous secretion
Microscopic (histologic) description
- Cystic dilation of ducts containing colloid-like eosinophilic material that often retracts from epithelium
- Epithelium focally has micropapillary DCIS
- Also invasion of surrounding stroma by nests of carcinoma, which may be high grade, usually without hypersecretory characteristics
- Extravasation of cyst material into stroma is not invasion
Microscopic (histologic) images
AFIP images
ated carcinoma
invades stroma
next to cyst
prominent cysts with
no apparent ducts
containing carcinoma
Associated micropapillary DCIS, invasion elsewhere
Associated micropapillary DCIS with no
evident secretion in tumor cells, which have
a hobnail appearance, nuclei are relatively
clear with small, discrete nucleoli
Associated micropap-
illary DCIS with sparse
secretion that is re-
tracted from epithelium
Cysts lined by flat cuboidal epithelium contain
homogeneous secretions, these cysts are
nonspecific - they can be found in cystic
hypersecretory hyperplasia or carcinoma
Axillary nodal
metastases, with
some cells exhib-
iting clear nuclei
Note transition in cyst epithelium with plaque of tumor cells
in bottom half, micropapillary pattern is obscured where carcinoma
nearly fills ducts, but traces of retracted secretion remain
(arrows), clear nuclei are also evident, even at this magnification
Contributed by Dr. Okechukwu C. Okafor
12 cm tumor
Images hosted on other servers:
Various images
Cytology description
- Orange to grayish green colloid-like background with cracking artifact (Pap stain), clusters of malignant cells
- Also histiocytes and apocrine cells (Acta Cytol 1999;43:273, Acta Cytol 1997;41:892)
Positive stains
- Androgen receptors, HER2 (Ceska Gynekol 2005;70:73)
- Variable p53, ER and PR (Histopathology 2005;46:43)
Differential diagnosis
- Secretory carcinoma: predominantly microcysts, t(12;15)(p13;q25) in most cases
- Mucinous / colloid carcinoma: extracellular mucin, not intracystic secretions
- Cystic hypersecretory hyperplasia: no invasion present (Cancer 1988;61:1611)
Cystic hypersecretory hyperplasia
Table of Contents
Definition / general | Terminology | Epidemiology | Etiology | Clinical features | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Negative stains | Differential diagnosisDefinition / general
- Cystically dilated ducts of various sizes with colloid-like material
- Ducts are lined by flat, orderly, bland columnar epithelial cells
- Not included in WHO classification of breast lesions
Terminology
- Cystic hypersecretory carcinoma: lesions that resemble cystic hypersecretory hyperplasia but with proliferative atypical epithelium
Epidemiology
- Rare
Etiology
- Unknown
Clinical features
- Palpable mass or occasionally asymptomatic with mammographic abnormality
- Benign lesion with good prognosis when not associated with atypia or carcinoma
Case reports
- 48 year old woman with mass exhibiting atypia (Arch Pathol Lab Med 2003;127:e389)
Treatment
- Wide excision (Cancer 1988;61:1611)
- If atypia present at core biopsy, excise entire lesion because DCIS can be present (Am J Surg Pathol 2004;28:789)
Gross description
- Resembles juvenile papillomatosis
- Large, ill defined, firm to rubbery, spongy mass of fibrous tissue containing multiple small cysts
- Also abundant thick, sticky mucin within the cysts; resembles thyroid colloid
- May coexist with atypia or DCIS of cystic hypersecretory type, so sample generously
Microscopic (histologic) description
- Cystically dilated ducts of various sizes with colloid-like material, often with parallel fracture lines, retraction halo and overlapping due to processing
- Ducts are lined by flat, orderly, columnar epithelial cells with eosinophilic cytoplasm; nuclei are round / oval, vesicular, bland
- Atypical features are epithelial crowding, enlarged nuclei lacking normal polarization, hyperchromasia and rare mitotic figures
- Can be associated with pregnancy-like (pseudolactational) hyperplasia (Am J Surg Pathol 2000;24:1670)
Microscopic (histologic) images
AFIP images
Cysts lined by flat
cuboidal epithelium
contain eosinophilic
material
Atypia - focal atypical epithelium between cysts
Case #35
Cysts lined by flat cuboidal epithelium contain eosinophilic material
Intraluminal secretions show
fine, parallel cracks and
shrinkage of the cyst content
with peripheral scalloping
Cytology description
- Secretory material (same as histology) with isolated or clusters of epithelial cells
Positive stains
- PR in a small subset
Negative stains
Differential diagnosis
- Cystic hypersecretory DCIS
Cystic neutrophilic granulomatous mastitis
Table of Contents
Definition / general | Essential features | Terminology | Epidemiology | Sites | Etiology | Clinical features | Diagnosis | Laboratory | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Negative stains | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2 | Board review style question #3 | Board review style answer #3Definition / general
- Inflammatory process of the breast usually due to Corynebacterium species
Essential features
- Most patients are women, parous or currently pregnant
- Characteristic morphologic features include granulomas comprised of epithelioid histiocytes and giant cells with central lipid vacuoles containing gram positive bacteria and rimmed by neutrophils
- Association with Corynebacterium species, especially Corynebacterium kroppenstedtii, although microbiologic evidence can be difficult to obtain
- Prolonged antibiotic therapy required for complete resolution
Terminology
- Not recommended: granulomatous mastitis, idiopathic granulomatous mastitis, granulomatous lobular mastitis, idiopathic lobular granulomatous mastitis
Epidemiology
- Rare, with at least 141 cases reported since 2002 (J Clin Pathol 2020;73:445)
- Female patients, parous or currently pregnant
- Mean age 35 years (range 19 - 57)
Sites
- Usually unilateral (J Clin Pathol 2020;73:445)
- Approximately 8.5% present with bilateral disease
Etiology
- Strong association with Corynebacterium infection (Am J Clin Pathol 2016;145:635)
Clinical features
- Most commonly painful breast mass, nipple inversion or sinus formation (J Clin Pathol 2020;73:445)
- Nipple discharge, skin erythema and abscess
- Fever and leukocytosis
- Axillary lymphadenopathy
Diagnosis
- Microscopic examination and Gram stain with or without microbiologic culture
Laboratory
- Corynebacteria may be difficult to detect and culture
- Corynebacterium species require culture medium containing 1% polysorbate (Tween) 80 and longer incubation periods (Lett Appl Microbiol 2018;66:472)
- Alternative methods include matrix assisted laser desorption / ionization time of flight mass spectrometry (MALDI-TOF MS) or 16S rRNA and rpoB gene sequencing (J Thorac Dis 2017;9:3239, J Clin Microbiol 2005;43:1934, Int J Surg Pathol 2020;28:371)
Radiology description
- Seldom reported (Am J Surg Pathol 2015;39:1440, Breast J 2019;25:80, Clin Case Rep 2018;6:2208)
- Mammography: mass or asymmetry, most commonly BI-RADS 4 (suspicious of malignancy)
- Ultrasound: mass, dilated ducts, abscesses, edema or fluid collection
Radiology images
Images hosted on other servers:
Palpable breast mass
Prognostic factors
- Prolonged (weeks to months) antibiotic therapy required for complete resolution
- May recur with inadequate therapy
Case reports
- 30 year old woman with a fluctuant mass-like lesion (Case #462)
- 33 year old woman with recurrent breast abscess (Clin Infect Dis 2014;59:410)
- 37 year old woman with abscess and skin ulceration (Clin Microbiol Infect 2020 Jul 9 [Epub ahead of print])
- 52 year old woman with a tender left breast mass (Clin Case Rep 2018;6:2208)
Treatment
- Observation
- Antibiotics:
- Empirical antimicrobial therapy may be started prior to histologic diagnosis
- Lipophilic antibiotics such as doxycycline, trimethoprim sulfamethoxazole, clarithromycin and rifampicin may be more effective (J Clin Microbiol 2015;53:2895)
- Antibiotic susceptibility test should be performed
- Steroids
- Surgery including incision and drainage, excision and even mastectomy
- Combination of the above therapies
Gross description
- Definitive gross lesions may not be identified
- Solid lesions or masses with abscess cavities (Int J Surg Pathol 2020;28:371)
Microscopic (histologic) description
- Presence of 2 - 3 of the following features (J Clin Pathol 2020;73:445):
- Lobulocentric mixed inflammatory infiltrate composed of lymphocytes, neutrophils and scattered multinucleated giant cells
- Round to oval cystic spaces (lipid vacuoles) rimmed by neutrophils (microabscesses)
- Nonnecrotizing granulomas
- Combined with either:
- Presence of coryneform gram positive bacilli (rod shaped bacteria arranged in V shaped forms or palisades like Chinese characters) within lipid vacuoles or
- Positive Corynebacteria culture or molecular testing
Microscopic (histologic) images
Contributed by Jessie M. Wu, M.B.Ch.B. and Gulisa Turashvili, M.D., Ph.D.
Mixed inflammation
Lipid vacuoles
Gram stain
Contributed by Ankur Sangoi, M.D. (Case #462)
Mixed inflammation
Lipid vacuoles
Gram stain
Cytology description
- Cytologic diagnosis may be difficult
- Limited by significant cytomorphologic overlap with granulomatous mastitis and other inflammatory breast lesions
- Features suggestive of cystic neutrophilic granulomatous mastitis on ThinPrep include cystic spaces, inflammatory cells such as neutrophils with aggregates of epithelioid histiocytes, multinucleated giant cells, lymphocytes and plasma cells and lack of necrosis (Diagn Cytopathol 2018;46:966)
Positive stains
- CD68: positive in histiocytes
- Gram positive coryneform bacteria within lipid vacuoles:
- Rod shaped bacteria arranged in V shaped forms or palisades like Chinese characters
- Bacteria may not be identified in all lipid vacuoles
- Thick section Gram stain performed at 6 µm (vs 4 µm) improves both detection rate and ease of identification of gram positive bacilli (Am J Clin Pathol 2020;153:593)
Negative stains
- Pancytokeratin: negative in histiocytes
Molecular / cytogenetics description
- Matrix assisted laser desorption / ionization time of flight mass spectrometry (MALDI-TOF MS)
- 16S rRNA and rpoB gene sequencing (J Thorac Dis 2017;9:3239, J Clin Microbiol 2005;43:1934, Int J Surg Pathol 2020;28:371)
Sample pathology report
- Right breast, core biopsy:
- Cystic neutrophilic granulomatous mastitis (see comment)
- Comment: A tissue gram stain highlights gram positive bacilli, supporting the diagnosis. Controls are appropriate.
- Microscopic description (optional): Sections show a perilobular mixed inflammatory infiltrate composed of central lipid vacuoles rimmed by neutrophils and an outer cuff of epithelioid histiocytes. Some of the lipid vacuoles contain sparse, rod shaped, gram positive bacilli. The surrounding inflammatory infiltrate contains multinucleated giant cells, lymphocytes and neutrophils. The morphology combined with the presence of gram positive bacilli on Gram stain is consistent with cystic neutrophilic granulomatous mastitis.
Differential diagnosis
- Granulomatous mastitis due to other causes:
- Infection (bacterial, fungal, parasitic):
- Tuberculosis mastitis:
- Necrotizing or nonnecrotizing granulomas composed of epithelioid histiocytes, Langerhans type multinucleated giant cells, eosinophils, lymphocytes and plasma cells commonly affecting ducts rather than lobules
- Ziehl-Neelsen staining, culture or polymerase chain reaction can be used for establishing the diagnosis
- Tuberculosis mastitis:
- Foreign body reaction:
- Presence of foreign material
- Fat necrosis:
- Clinical history, vacuoles lacking gram positive bacilli
- Autoimmune diseases:
- Granulomatosis with polyangiitis:
- Positive pANCA and cANCA, prominent vasculitis
- Rheumatoid arthritis:
- Joint symptoms, elevated rheumatoid factor, fibrinoid necrosis surrounded by lymphocytes and plasma cells
- Granulomatosis with polyangiitis:
- Sarcoidosis:
- Non-necrotizing epithelioid granulomas, asteroid bodies, Schaumann bodies
- Granulomatous lobular mastitis:
- Diagnosis of exclusion, negative microbiologic examination, without known etiology
- Infection (bacterial, fungal, parasitic):
- Subareolar breast abscesses / squamous metaplasia of lactiferous ducts (SMOLD):
- Strongly associated with smoking
- Predominantly anaerobic organisms
Additional references
Board review style question #1
A 35 year old woman presents with a right breast mass. Core biopsy shows empty appearing cystic spaces rimmed by neutrophils and an outer cuff of epithelioid histiocytes. Some vacuoles contain sparse, rod shaped bacilli. Which organism is most commonly associated with this type of granulomatous mastitis?
- Corynebacterium diphtheriae
- Corynebacterium kroppenstedtii
- Mycobacterium tuberculosis
- Staphylococcus aureus
- Staphylococcus epidermidis
Board review style answer #1
B. Corynebacterium kroppenstedtii. Cystic neutrophilic granulomatous mastitis is most commonly associated with Corynebacterium kroppenstedtii.
Comment Here
Reference: Cystic neutrophilic granulomatous mastitis
Comment Here
Reference: Cystic neutrophilic granulomatous mastitis
Board review style question #2
Cystic neutrophilic granulomatous mastitis most commonly affects which of the following patient population?
- Female smokers
- Parous women
- Postmenopausal women
- Women living in endemic areas of tuberculosis
- Women with a history of Corynebacterium diphtheriae infection
Board review style answer #2
B. Parous women. Cystic neutrophilic granulomatous mastitis most commonly affects women who are currently pregnant or have been pregnant.
Comment Here
Reference: Cystic neutrophilic granulomatous mastitis
Comment Here
Reference: Cystic neutrophilic granulomatous mastitis
Board review style question #3
Which of the following statements is true regarding cystic neutrophilic granulomatous mastitis?
- Diagnosis may require matrix assisted laser desorption / ionization time of flight mass spectrometry
- Gram positive bacilli are identified in nearly all cases
- Resolution typically takes days
- Usually presents as a painless palpable mass in postmenopausal women
Board review style answer #3
A. Diagnosis may require matrix assisted laser desorption / ionization time of flight mass spectrometry. Diagnosis of cystic neutrophilic granulomatous mastitis may require culture, 16S rRNA gene sequencing or matrix assisted laser desorption / ionization time of flight mass spectrometry.
Comment Here
Reference: Cystic neutrophilic granulomatous mastitis
Comment Here
Reference: Cystic neutrophilic granulomatous mastitis
Cytology
Table of Contents
Definition / general | Essential features | CPT coding | Sites | Ancillary testing | Procedure (FNA) | Limitations / disadvantages of FNA | Breast cytologic studies other than FNA | Case reports | Breast FNA C1 - C5 classification | Breast FNA Masood and Modified Masood classification | Cytology description of benign lesions | Cytology description of malignant lesions | Grading of malignant smears | Cytology images | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Refers mainly to fine needle aspiration cytology (FNA) and also includes cytologic examination of imprint, nipple discharge and ductal lavage
- Although largely replaced by core needle biopsy, FNA can increase the accuracy rate if both tests are combined, minimizing false negative results of core needle biopsy related to sampling issues, as more needle passes are performed in FNA (Diagn Cytopathol 2016;44:578)
- Nowadays, it is used as part of the triple approach (along with clinical and radiologic findings) to confirm a benign diagnosis, as a conjugate to core needle biopsy to enhance the accuracy rate, solo for palpable breast lesions in one step clinic, for lymph node assessment and for lesions difficult to access by core needle biopsy, like those near the chest wall
- Breast FNA is a safe, reliable, accurate, fast, cost saving, almost complication free method that can be performed without anesthesia
- Along with core needle biopsy, these tests replaced frozen sections and surgical biopsies for diagnosing breast lesions
- Breast FNA cytology doesn't give a definite diagnosis name to the lesion most of the time and also can't differentiate atypical ductal hyperplasia from low grade cancer or high grade in situ carcinoma from invasive cancer
Essential features
- Breast FNA can't differentiate atypical duct hyperplasia from low grade ductal carcinoma in situ or high grade ductal carcinoma in situ from invasive carcinoma
- It is a screening test; it doesn't usually provide a specific diagnosis name to the lesion but enhances the sensitivity of cancer detection if combined with core needle biopsy
- Biomarkers and other ancillary studies can be performed on cell block
- False negative result is frequent in special types of carcinoma, like lobular and tubular, and false positive diagnoses are seen with changes associated with lactation and therapy
CPT coding
- 10004: FNA without imaging guidance, each additional lesion
- 10005: FNA including ultrasound guidance, first lesion
- 10006: FNA including ultrasound guidance, each additional lesion
- 10007: FNA including fluoroscopic guidance, first lesion
- 10008: FNA including fluoroscopic guidance, each additional lesion
- 10009: FNA including CT guidance, first lesion
- 10010: FNA including CT guidance, each additional lesion
- 10011: FNA including MRI guidance, first lesion
- 10012: FNA including MRI guidance, each additional lesion
- 10021: FNA without imaging guidance, first lesion only
- 19000: Puncture aspiration of breast cyst
- 19001: Puncture aspiration of breast cyst, each additional cyst (used with 19000)
Sites
- Breast, lymph node
Ancillary testing
- Ancillary studies include biomarker testing in carcinoma cases, flow cytometry in lymphoma cases and molecular studies
- Biomarker testing on breast FNA
- Useful for patients who will undergo neoadjuvant therapy if core needle biopsy is not available
- Also, the American Society of Clinical Oncology / College of American Pathologists (ASCO / CAP) recommends evaluating the biomarkers on FNA obtained from foci of metastasis and local recurrence after treatment
- Same ASCO / CAP criteria that is used for tissue can be applied to cytology specimens, including the cold ischemia time (ideally less than an hour), as well as fixation time (6 - 72 hours) (College of American Pathologists: CAP QCDR Measure Formalin Fixation Time [Accessed 19 August 2021])
- Recommendation of CAP is to report the percentage of positive nuclei for ER and PR; minimum of 100 cells should be counted (Arch Pathol Lab Med 2010;134:907)
- FISH is more reliable than IHC for HER2 / neu
- HER2 gene amplification can be reliably detected in cytology specimen when air fixed or fixed with FISH fixative
- More interobserver discordance rate than the corresponding biomarker testing in histologic samples is attributed to the admixed inflammatory cells and mesothelial cells in body cavities; adding GATA3 or GCDFP-15 is recommended to enhance the accurate detection of tumor cells (Acta Cytol 2018;62:288)
- It is impossible to distinguish the positivity of markers in the invasive component from the in situ component
Procedure (FNA)
- Ideally performed by a trained radiologist under ultrasound or stereotactic guidance
- Direct smearing is the most common preparation method in FNA
- Both alcohol fixed and air dried are used
- Alternatives include cytospin preparation, thin layer preparation, cell block
Limitations / disadvantages of FNA
- Requires training, subjective in interpretation; the accuracy is influenced by both the quality of smear and the expertise of the reader
- Can't differentiate atypical duct hyperplasia from low grade ductal carcinoma in situ
- Can't differentiate high grade ductal carcinoma in situ from invasive carcinoma
- Doesn’t give a definite diagnosis name to the lesion most of the time
- Equivocal, false positive, false negative results
Breast cytologic studies other than FNA
- Cell block:
- Enhances the utility of FNA
- Ancillary studies including biomarkers can be done
- Diagnostic architectural features can be displayed
- Returned cell block from a Papanicolaou stained smear is also useful in difficult cases to interpret, e.g. if the morphology is obscured by blood (Diagn Cytopathol 2016;44:505)
- Nipple discharge cytology:
- Nipple discharge fluid commonly reflects hormonopathy, like dysthyroidism and hyperprolactinemia
- Papilloma is the most common breast lesion that presents with nipple discharge
- It has a weak association with cancer; increased if the discharge is bloody or associated with a mass
- Nipple discharge cytology has a low sensitivity (Ann Surg Oncol 2020 Nov 9 [Epub ahead of print], Diagnosis (Berl) 2020 Jun 26 [Epub ahead of print])
- Negative discharge: acellular or hypocellular, composed mainly of proteinaceous fluid and foamy cells; benign ductal epithelial or apocrine cells can be seen with no atypical features
- Ductal lavage cytology:
- Has a questionable utility in risk stratification of getting breast cancer in women with contralateral breast cancer or BRCA1 or BRCA2 mutation
- Imprints:
- Intraoperative imprint cytology of sentinel lymph node: limited sensitivity for micrometastasis
- Intraoperative imprint cytology for diagnosing breast carcinoma and evaluating margins: useful in combination with frozen section or alone
- Intraoperative imprint cytology to predict occult nipple involvement before performing nipple sparing mastectomy (Breast Cancer Res Treat 2015;153:557)
- Touch imprint cytology of core needle biopsy: to complement core needle biopsy, providing immediate cytologic diagnosis to the lesion (Geburtshilfe Frauenheilkd 2016;76:59)
Case reports
- 44 year old woman with positive FNA and negative excision (Int J Surg Case Rep 2016;25:132)
- 45 year old woman with silicone nipple discharge (Int J Surg Case Rep 2020;74:73)
- 47 year old woman with primary cystic type squamous cell carcinoma of the breast (Asian J Surg 2017;40:243)
- 48 year old woman with nodular faciitis of the breast diagnosed by FNA (BMJ Case Rep 2015;2015:bcr2015213076)
- 54 year old woman with metaplastic breast carcinoma (In Vivo 2017;31:737)
- 57 year old woman with Hodgkin lymphoma of the breast diagnosed by FNA (Case Rep Hematol 2019;2019:9256807
- 62 and 70 year old men with cytologic examination of nipple discharges revealed atypia and positive results (Diagn Cytopathol 2019;47:121)
- 74 year old man with ductal carcinoma in situ, diagnosed as atypia in nipple discharge cytology (Breast J 2002;8:112)
- 77 year old woman diagnosed with adenoid cystic carcinoma of the breast based on immunohistochemistry done on FNA (Diagn Cytopathol 2015;43:722)
- 86 year old woman with solid papillary carcinoma; cytologic findings of nipple discharge and FNA are described (Diagn Cytopathol 2020;48:53)
Breast FNA C1 - C5 classification
- In U.K. and Europe, numerical system of 5 points classification is used (C1 to C5)
- In U.S. and Canada, same system but without the numerical designation
- 5 categories: inadequate, benign, atypia favor benign, suspicious probably malignant and malignant
- Inadequate / C1:
- Smear is not interpretable or is undiagnostic
- Common causes include: low cellularity, obscured morphology due to blood, crushing artifact, poor fixation and degenerated cells
- No definite criteria for adequacy in breast FNA cytology
- MD Anderson Cancer Center Group proposed that 4 - 6 well visualized cell groups with 10 or more cells / flat sheets as an adequacy criteria (Cancer 1997;81:3)
- Samples that lack epithelial cells are considered inadequate in general
- If the lesion is suspected to be lipoma or fat necrosis, the absence of epithelial clusters doesn't indicate inadequacy
- Benign / C2:
- Benign epithelial clusters are seen with no atypia or malignant features
- Cellularity is usually not high; cells are seen in flat sheets, depicting fine chromatin, smooth nuclear membrane, low nuclear cytoplasmic (N/C) ratio, no pleomorphism
- Fatty fragments are commonly seen
- Bare nuclei of myoepithelial cells are easily seen
- Histiocytes and apocrine cells can be found
- In duct ectasia: inspissated material within macrophages and multinucleated giant cells
- Atypia / C3:
- Similar to the findings of benign category but with higher cellularity, slight crowdedness, 3 dimensional groups, nuclear enlargement and pleomorphism
- Common lesions encountered in this category: proliferative fibrocystic change with or without atypia, papillary lesions, lobular lesions including atypical lobular hyperplasia / lobular carcinoma in situ and some special types of breast carcinoma commonly missed in FNA, like lobular, tubular and cribriform
- Suspicious / C4:
- Highly atypical findings but insufficient to be called malignant
- Commonly encountered reasons: hypocellular or poorly preserved smear, the findings are focally seen in a benign background or the degree of atypia is more than the previously described in C3 category but not sufficient for C5 category
- Common lesions encountered in this category: atypical duct hyperplasia, low grade ductal carcinoma in situ, invasive carcinoma that wasn't adequately sampled and special types of carcinoma like lobular, tubular and cribriform
- Malignant / C5:
- Cellularity is usually high and the cytologic features are malignant (high N/C ratio, irregular nuclear contour, hyperchromasia, conspicuous nucleoli)
- Malignant cells are seen singly or in loose clusters
- Necrotic debris might be seen in background
- Some special types of carcinoma can be specifically recognized or suspected, like mucinous, medullary-like, papillary
Breast FNA Masood and Modified Masood classification
- Suggested scoring systems: Masood followed by the more reproducible Modified Masood Scoring System (Acta Cytol 2019;63:233)
- It is based on 6 morphologic features:
| Cell arrangement | Cell pleomorphism | Myoepithelial cells | Anisonucleosis | Nucleoli | Chromatin clumping | Score |
| Monolayer | No | Many | No | No | No | 1 |
| Nuclear overlapping | Mild | Moderate | Mild | Micronucleoli | Rare | 2 |
| Clustering | Moderate | Few | Moderate | Rare macronucleoli | Occasional | 3 |
| Discohesion | Marked | No | Marked | Mainly macronucleoli | Marked | 4 |
- Breast lesions are classified into 4 categories according to the given score:
| Breast lesion | Total score in Masood system | Total score in Modified Masood system |
| Nonproliferative breast disease | 6 - 10 | 6 - 8 |
| Proliferative breast disease with no atypia | 11 - 14 | 9 - 14 |
| Proliferative breast disease with atypia | 15 - 18 | 15 - 18 |
| Malignancy | 19 - 24 | 19 - 24 |
Cytology description of benign lesions
- Fibrocystic change:
- Cellularity is variable, commonly moderately cellular but can be paucicellular if fibrotic
- Epithelial cells are arranged in cohesive flat sheets, polarized to give honeycomb pattern
- Myoepithelial cells naked nuclei are seen in background and overlying the epithelial sheets
- With or without apocrine and foam cells, fat and stroma
- Fibroadenoma:
- Moderately to highly cellular smear
- Sheets of cohesive epithelial cells that branch, giving the antler horn pattern
- Myoepithelial cells naked nuclei are numerous
- Stromal fragments can be seen
- Apocrine and foam cells: less likely than fibrocystic change
- If hypercellular stromal fragment is seen with atypia, the lesion is likely to be phyllodes tumor
- Adenomyoepithelioma:
- Moderately to highly cellular smear
- More chance to show crowded groups or 3 dimensional clusters than fibroadenoma
- Epithelial cells and myoepithelial cells are seen in variable proportions
- Myoepithelial cells can be seen as naked nuclei as in other lesions or take the form of comma shaped dark nuclei, spindle, epithelioid or plasmacytoid
- Epithelioid cells with intranuclear inclusion and intracytoplasmic vacuoles gives the characteristic soap bubble appearance (Cancer 2006;108:250)
- Papillary lesions (intraductal papilloma, etc):
- Difficult to segregate benign papilloma from well differentiated carcinoma in FNA
- Cellular smear, branching epithelial sheets like fibroadenoma or 3 dimensional clusters with or without stromal cores
- Columnar cells favor papilloma over fibroadenoma (Cancer 2003;99:156)
- Uniformity of cells favor malignancy and polymorphism favor benign papilloma
- Gynecomastia:
- Spectrum of pictures from overtly benign to fibroadenoma-like changes to worrisome morphology like nuclear molding, atypia, conspicuous nucleoli and inconspicuous myoepithelial cell component
Cytology description of malignant lesions
- Invasive breast carcinoma of no special type:
- Cellular smear
- Less cohesiveness with or without single epithelial cells scattered in background
- Epithelial sheets are crowded with 3 dimensional or syncytial pattern; might form acini
- No or minimal myoepithelial cells
- With or without tumor diathesis
- Lobular carcinoma:
- Can be missed as false negative due to the low cellularity and limited atypia
- Some cases resemble invasive carcinoma of no special type
- Cellularity is frequently low to moderate
- Cells are uniform, mildly atypical, dispersed in singles, linear cords or loose clusters
- Myoepithelial cells are absent
- Signet ring cells can be seen
Grading of malignant smears
- Not routinely done
- Mainly depends on nuclear grading due to the difficulty of assessing mitoses and tubular formation
- Robinson and McKee proposed a grading system that correlates well with the histologic grading, depending on 6 parameters: dissociation, nuclear size and margin, nucleoli, chromatin and uniformity of cells (Acta Cytol 1995;39:1257)
- Another proposed prognostic system is based on 3 characteristics: nuclear grade, architecture (discohesion) and background features (bare atypical epithelial cell nuclei); it is claimed to correlate well with histologic grading, lymph node status, positivity for HER2 / neu, p53 and Ki67 (Diagn Cytopathol 2006;34:542)
Cytology images
Contributed by Areej M. Al Nemer, M.D.
Benign epithelial clusters (C2)
Granulomatous inflammation (C2)
Fibrocystic change (C2)
Lactational changes (C2, false positive diagnosis is a possible pitfall)
Lactational changes (C2)
Fibroadenoma (C2, 5 images)
Phyllodes tumor (C2 / C3)
Phyllodes tumor (C2 / C3)
Suspicious nipple
discharge (C4):
invasive & in situ
apocrine carcinoma
Suspicious nipple discharge (C4): juvenile papillomatosis
Malignant (C5): invasive carcinoma of no special type
Malignant (C5): invasive lobular carcinoma
Malignant DCIS (C5)
Sample pathology report
- Should state the category, followed by detailed explanation of the findings that justify the specified category
- If positive for malignancy, it is recommended to comment on the nuclear grade
- Examples:
- Left breast, FNA:
- Inadequate (C1)
- The smear shows only blood and rare degenerated cells.
- Right breast, FNA:
- Malignant (C5)
- Markedly hypercellular smear with single epithelial cells admixed with cohesive and discohesive clusters of malignant cells, depicting enlarged, highly pleomorphic nuclei, coarse chromatin, some prominent nucleoli, nuclear molding and occasional mitoses. Nuclear grade 3/3.
- Left breast, FNA:
Differential diagnosis
- False positive diagnosis:
- Poor fixation:
- Cellular enlargement and irregular chromatin
- Crush artifacts: hyperchromatic dissociated cells
- Ultrasound gel: contaminating the aspirate resembling necrotic debris
- Fibroadenoma:
- Cellular smear, mild pleomorphism, some discohesion, irregular clusters
- Hint: myoepithelial cells are easily seen
- Apocrine lesions:
- Might show atypia and discohesion
- Hint: no necrosis, admixture with benign ductal cells and macrophages, low N/C ratio
- Lactational changes / adenoma:
- Cellular smear, mild pleomorphism, enlarged hyperchromatic nuclei, prominent nucleoli, discohesion with fragile granular / vacuolated cytoplasm
- Myoepithelial cells are there but less conspicuous
- Background is dirty, with secretions that can be confused with necrosis by the nonexpert
- Clinical history of pregnancy, lactation or hormonal intake is helpful
- Proliferative fibrocystic change:
- Cellular smear with mild atypia
- Myoepithelial cells are plentiful
- Seroma:
- Cystic lesion that might follow breast conserving surgery
- Smear is usually hypocellular with a few degenerated cells
- Might show atypia with high N/C ratio and squamous metaplasia
- Treatment induced cellular change:
- Commonly hypocellular smear with scattered atypical, maybe enlarged epithelial cells
- Might show nuclear enlargement with prominent nucleolus, chromatin clearing, nuclear and cytoplasmic vacuolation
- Clinical data of prior therapy is crucial for accurate diagnosis
- Intramammary lymph node:
- Some activated lymphocytes might resemble lobular carcinoma
- Smear will show nodal polymorphic population of lymphocytes admixed with tangible body macrophages
- CD45+ and cytokeratin-
- Axillary lymph node:
- Sampling through apocrine glands, presence of benign intranodal epithelial inclusions, activated lymphocytes mimicking lobular carcinoma, granulomas, metastatic melanoma or carcinoma from other sites can cause false positive diagnosis
- Immunohistochemistry is helpful to resolve any ambiguity
- Poor fixation:
- False negative diagnosis:
- Sampling issues:
- In unguided biopsies and in small, fibrous, vascular or necrotic lesions
- Lobular carcinoma:
- Hypocellular to normocellular smear, minimal atypia
- Look for intracytoplasmic vacuoles (not diagnostic; seen in myoepithelial cells)
- Tubular carcinoma:
- Can be confused with radial scar, microglandular adenosis, tubular adenoma and fibroadenoma
- Clues: angulated clusters with one cell type with some nuclear atypia
- Sampling issues:
Additional references
Board review style question #1
Nipple discharge cytologic examination of a 45 year old woman revealed the picture shown above. What is your diagnosis?
- Atypia
- Inadequate
- Malignant
- Negative
- Suspicious
Board review style answer #1
D. Negative. In nipple fluid cytology, the presence of epithelial cells is not mandatory to call it adequate.
Comment Here
Reference: Cytology
Comment Here
Reference: Cytology
Board review style question #2
Which of the following is correct regarding breast biomarker testing on cytologic specimen?
- Any positivity for hormonal receptors is counted as positive results
- Exact percentage of positivity is less accurate than the corresponding tissue assessment
- For HER2 / neu assessment, only immunohistochemistry can be performed on cytologic specimens
- It has similar interobserver discordance rate as in the tissue testing
Board review style answer #2
B. Exact percentage of positivity is less accurate than the corresponding tissue assessment. It is impossible to differentiate the malignant cells of the in situ component from the invasive component. For hormonal receptor positivity, the same cutoff point of 1% is used as in tissue.
Comment Here
Reference: Cytology
Comment Here
Reference: Cytology
DCIS
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Cytology images | Positive stains | Negative stains | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Ductal carcinoma in situ (DCIS) is a neoplastic proliferation of mammary ductal epithelial cells confined to the ductal-lobular system without evidence of invasion through the basement membrane into the surrounding stroma (Arch Pathol Lab Med 2009;133:15)
- Is a nonobligate precursor lesion of invasive breast cancer (Breast Cancer Res Treat 2010;123:757, Cancer 2005;103:2481)
- Encompasses a heterogeneous group of lesions in terms of histomorphology, underlying genetic alterations, biomarker expression profile and biologic potential for progression to invasive carcinoma
Essential features
- Neoplastic proliferation of mammary ductal epithelial cells that is confined within ducts and lobules
- Nonobligate precursor of invasive breast disease
- Heterogenous entity with wide range of histologic appearances, growth patterns, genetic abnormalities and clinical behavior
Terminology
- Ductal carcinoma in situ (DCIS)
- Intraductal carcinoma
- Ductal intraepithelial neoplasia: terminology never widely adopted and removed from the 4th Edition WHO classification of mammary neoplasms (International Agency for Research on Cancer: WHO Classification of Tumours of the Breast, 4th Edition, 2012)
- Mammary intraepithelial neoplasia: a general term to include both ductal and lobular intraepithelial neoplasia but never adopted, terminology should not be used (Am J Surg Pathol 1991;15:209, Hum Pathol 2002;33:620, Am J Surg Pathol 1980;4:241)
- Extensive DCIS / extensive intraductal component: terminology should only be used to describe DCIS that is associated with invasive carcinoma in which the DCIS component constitutes > 25% of the entire area of invasive carcinoma and DCIS extends beyond the invasive carcinoma into the surrounding breast tissue (Pathol Annu 1988;23:1)
- Multicentric DCIS: no uniform definition, generally refers to DCIS that involves multiple breast quadrants and different distinct regions of the breast
ICD coding
Epidemiology
- Similar epidemiologic risk factors to invasive breast cancer, including older age, family history of breast cancer, nulliparity, late age at first birth, late menopause, elevated body mass index, high mammographic breast density, postmenopausal hormonal therapy use and genetic risk factors (e.g. BRCA1/2) (Mol Oncol 2010;4:357, Clinics (Sao Paulo) 2013;68:674, J Transl Med 2015;13:335)
- Incidence of DCIS increased significantly from 1983 - 1992 due to greater mammographic screening, particularly in patients younger than 50 years old (JAMA 1996;275:913, J Natl Cancer Inst Monogr 1997:151)
- Represents 20 - 25% of newly diagnosed breast cancers in the United States (CA Cancer J Clin 2017;67:7, Am Surg 2018;84:1)
- 3.3 - 5.9% of women with DCIS carry a germline mutation in BRCA1 or BRCA2 and prevalence of BRCA mutation is significantly greater in women diagnosed with DCIS before the age 50 and personal or family history of breast cancer (JAMA 2005;293:964, Cancer Prev Res (Phila) 2010;3:1579, J Clin Oncol 2002;20:1480)
Sites
- Breast
- Can occur in axillary breast tissue
Clinical features
- Majority are non-palpable and detected mammographically as microcalcifications (70 - 80%) (Am Surg 2018;84:1, Curr Treat Options Oncol 2013;14:75)
- Less frequently presents as palpable mass, nipple discharge, Paget disease of the nipple
- 2 - 8.6 times higher risk for subsequent development of invasive breast carcinoma of compared general population (N Engl J Med 1985;312:146, Ann Surg 1997;225:69, Lancet 2000;355:724, Int J Cancer 1998;77:392)
- Uncommon in women younger than 30 years, mean age 50 - 59 years (Arch Surg 1992;127:1392, Eur J Surg Oncol 1990;16:220)
- Rate of DCIS increases with age (0.6 per 1000 screening examinations in women aged 40 - 49 years versus 1.3 per 1,000 in women aged 70 - 84 years) (J Natl Cancer Inst Monogr 2010;2010:139)
Diagnosis
- Calcifications or distortion on imaging raises concern and need for obtaining tissue
- Diagnosis is made by histologic examination of tissue obtained via needle core biopsy, lumpectomy or mastectomy
Radiology description
- Mammography is highly sensitive, microcalcifications found in 72 - 98% of DCIS (Radiology 1989;170:411, Curr Treat Options Oncol 2013;14:75)
- Microcalcifications are usually the only radiologic finding; less frequently DCIS presents as mass or architectural distortion without calcifications (Eur J Radiol 2005;54:55)
- Pleomorphic calcifications are often associated with high grade DCIS; while fine or granular calcifications are more common in low grade DCIS, the distribution is generally clustered or linear (J Natl Cancer Inst Monogr 2010;2010:214)
- Ultrasound generally has limited utility in detecting DCIS
- MRI may be a useful adjunct to detect DCIS that lacks calcifications, multifocal DCIS, contralateral disease and measure extent of disease (Breast J 2005;11:382, Radiology 2007;243:670)
Radiology images
Contributed by Azadeh Khayyat, M.D. and Julie M. Jorns, M.D. (Case #533)
Mammogram
Images hosted on other servers:
Microcalcifications detected by mammography and tomosynthesis
Microcalcifications detected by mammography
Irregular mass via ultrasound
MRI of an irregular mass
MRI of a linear enhancement
Prognostic factors
- Women diagnosed with DCIS have 10 times higher risk of developing ipsilateral invasive breast if untreated (N Engl J Med 2004;350:1430, Cancer 1982;49:751)
- 36 - 53% of low grade DCIS lesions progress to invasive lesions if untreated (Mod Pathol 2015;28:662, Cancer 1980;46:919)
- Risk of progression of untreated high grade DCIS to invasive carcinoma is not well characterized as most clinically detected high grade DCIS is excised surgically (N Engl J Med 2004;350:1430)
- Time interval to the development of recurrence varies, low grade DCIS has longer interval (> 15 years), shorter interval observed in high grade DCIS (< 5 years) (Cancer 2005;103:1778)
- Long term outcome meta analysis study of DCIS showed a 15 year total local recurrence rate of 40% with 28% recurring as invasive disease (BMC Cancer 2015;15:890)
- Positive surgical margins, high nuclear grade, large lesion size, comedo necrosis and young age (< 45 years) reported as the most important clinical pathologic predictors associated with local recurrence and prognosis (J Clin Oncol 1996;14:754, Int J Radiat Oncol Biol Phys 2001;50:991, Cancer 1999;85:616, J Clin Oncol 2006;24:3381, Cancer 2005;103:2481, Breast Cancer Res Treat 2008;109:405, Eur J Cancer 2007;43:291, Breast J 2005;11:242)
- A nomogram for predicting recurrence risk after breast conserving surgery based on clinical, pathologic and treatment variables has shown utility in providing individualized estimates of recurrence risk (J Clin Oncol 2010;28:3762)
- Predictive and prognostic biomarkers and ancillary testing in DCIS:
- Estrogen receptor
- Currently the only immunohistochemical biomarker recommended for routine clinical use; progesterone receptor is considered optional (J Clin Oncol 2020:JCO1902309)
- Determines potential benefit of endocrine therapies (J Clin Oncol 2020:JCO1902309, Lancet 1999;353:1993)
- ER negative status correlates with ipsilateral recurrence risk (Breast Cancer Res Treat 2018;167:751)
- Oncotype DX for DCIS® assay is a genomic test that predicts radiation therapy benefit and the likelihood of 10 year breast cancer local recurrence risk in patients with DCIS treated with breast conserving surgery (J Natl Cancer Inst 2013;105:701, Breast Cancer Res Treat 2015;152:389, J Natl Cancer Inst 2017;109)
- Estrogen receptor
- Novel biomarkers not used in routine clinical practice
- Recent studies correlated presence of associated tumor infiltrating lymphocytes (TIL) in periductal stroma and TIL immune phenotype to high risk features and Oncotype DX® Breast DCIS Score (Ann Oncol 2017;28:321, Breast Cancer Res Treat 2017;161:17, Mod Pathol 2015;28:1167)
- High Ki67 proliferation index has reported to correlate with increased recurrence risk (Appl Immunohistochem Mol Morphol 2016;24:20, Clin Breast Cancer 2018;18:157, J Breast Cancer 2016;19:185)
- HER2 (epidermal growth factor receptor family member 2) more frequently expressed (~ 40%) in DCIS than invasive carcinoma and reported to correlate with increased recurrence risk (J Cancer 2011;2:232, Breast Cancer Res Treat 2016;158:179)
- Several novel biomarkers such as COX-2, FOXA1, SIAH2 and p16 have been evaluated in DCIS with regard to radiotherapy benefit and recurrence risk (Breast Cancer Res Treat 2016;157:351)
Case reports
- 19 year old woman with DCIS arising in phyllodes tumor (Ann R Coll Surg Engl 2018;100:e97)
- 30 year old woman with BRCA2 mutation undergoes prophylactic mastectomy (Cureus 2019;11:e5311)
- 43 year old woman with metastases after mastectomy for DCIS (BMC Cancer 2019;19:844)
- 58 year old man with left breast mass (Eur J Breast Health 2019;16:77)
- 73 year old woman with palpable breast mass (Int J Surg Case Rep 2018;45:9)
- Premenopausal woman with family history of breast cancer was found to have a subcentimeter mass with calcifications on mammogram (Case #533)
Treatment
- Breast conserving surgery alone, breast conserving surgery with radiotherapy or mastectomy
- Excision to negative margins (≥ 2 mm) for patients treated with breast conserving surgery (Pract Radiat Oncol 2016;6:287)
- Possible sentinel lymph node sampling if patients are planned for mastectomy or who have DCIS size > 5 cm or at high risk of microinvasive carcinoma (Ann Surg Oncol 2016;23:2229, Am J Surg 2008;196:81, Breast J 2008;14:135)
- Radiation reduces the risk of local recurrence by 50% in patients undergoing breast conserving therapy (J Clin Oncol 2008;26:1247)
- Tamoxifen therapy further decreases the risk of ipsilateral and contralateral recurrence by 30% in patients with estrogen receptor positive DCIS (Semin Oncol 2006;33:647, Breast Cancer Res Treat 2002;75:S7)
- Aromatase inhibitors with similar overall effectiveness to tamoxifen, with different safety profile (Lancet 2016;387:866, Lancet 2016;387:857)
- Omission of radiotherapy may be considered if DCIS is small, low grade and has clear margins (J Clin Oncol 2009;27:3211)
- Mastectomy may be recommended for multicentric DCIS, inability to attain clear surgical margins, large span or diffuse microcalcifications on imaging studies
Gross description
- Usually no gross lesion, but high grade DCIS may present as firm gritty mass with multiple yellow punctate flecks on the cut surface representing comedonecrosis
- Serial sequential sampling with mammographic correlation is useful to estimate DCIS size (Arch Pathol Lab Med 2009;133:31, Arch Pathol Lab Med 2009;133:26)
Microscopic (histologic) description
- DCIS traditionally classified based on architectural growth pattern (no clinical relevance other than comedo pattern):
- Cribriform:
- Fenestrated proliferation with multiple, round, rigid extracellular lumens with punched out appearance
- Neoplastic cells are frequently evenly distributed equidistant and polarized with long axis of cell perpendicular to the central lumen
- Trabecular bars comprised of rigid rows of cells with long axes perpendicular or at least not parallel to the long axis of the bar
- Roman bridges comprised of curvilinear trabecular bars connecting two portions of the epithelial lining
- Micropapillary:
- Papillary fronds and tufts lacking fibrovascular cores projecting into duct lumen
- Papillae often have club shaped cells comprising the micropapillae are uniform in appearance
- Tips of fronds may fuse, forming bridges and arcades
- Papillary:
- Papillary fronds containing prominent fibrovascular septa projecting into duct lumen, papillary cores generally lack myoepithelial cell layer
- Solid:
- Lumen of ducts or lobules filled with sheets of cohesive cells
- Cells are evenly spaced especially in low or intermediate grade DCIS
- Flat or clinging:
- 1 - 2 layers of generally high grade malignant cells lining a gland with a large empty lumen
- Comedo:
- Central expansile necrosis containing cellular debris, generally associated with high grade DCIS, frequently associated with coarse microcalcifications
- Cribriform:
- No universally accepted grading system for DCIS but more recently endorsed classification systems stratify DCIS by nuclear grade (low, intermediate, high) and presence or absence of necrosis (Lancet 1995;345:1154, Hum Pathol 1998;29:1056, Cancer 1997;80:1798, Surg Clin North Am 1990;70:853)
- Nuclear grade:
- Low grade:
- Monotonous, round nuclei with smooth contours, small size nuclei (size of normal ductal epithelial cell or 1 - 1.5 diameter of normal red blood cell)
- Diffuse fine chromatin, absent or indistinct nucleoli, no or rare mitotic figures, necrosis is uncommon but does not preclude the diagnosis of low grade DCIS
- Intermediate grade:
- Moderate pleomorphism, mild to moderate variability in nuclear size
- Variably coarse chromatin, occasional nucleoli, infrequent mitoses, features in between low and high grade DCIS
- Loss of monotony can mimic usual ductal hyperplasia
- High grade:
- Prominent pleomorphism, large size nuclei (> 2.5 size of normal ductal epithelial cell)
- Vesicular chromatin with irregular distribution, prominent nucleoli, frequent mitoses, comedo necrosis frequent but not required
- Low grade:
- Necrosis:
- College of American Pathologists DCIS protocol recommends reporting necrosis as not present or present and if present must be differentiated as focal or comedo
- Protocol for the examination of specimens from patients with ductal carcinoma in situ (DCIS) of the breast (College of American Pathologists: Protocol for the Examination of Specimens from Patients with Ductal Carcinoma In Situ (DCIS) of the Breast [Accessed 6 March 2020])
- Myoepithelial cell layer surrounding ducts spaces containing DCIS is intact, but may be attenuated especially in high grade DCIS
- Associated stromal reaction (chronic inflammatory infiltrate, fibrosis / sclerosis) may be prominent in areas surrounding DCIS, especially in high grade DCIS and does not indicate invasion
- Cancerization of lobules, extension of DCIS into acini of terminal duct lobular unit
- Variants include apocrine, cystic hypersecretory, squamous, spindle cell, clear cell, signet ring cell, mucinous, small cell, others
Microscopic (histologic) images
Contributed by Gary Tozbikian, M.D., Azadeh Khayyat, M.D. and Julie M. Jorns, M.D. (Case #533)
Low grade, cribriform
Intermediate grade, cribriform
Intermediate grade, papillary and cribriform
Intermediate grade, papillary
Intermediate grade, solid
Intermediate grade, micropapillary
High grade, flat
High grade, solid
High grade, solid and cribriform
High grade, solid and cribriform
Ductal carcinoma in situ (DCIS), solid type, with microcalcifications, confined to a fibroadenoma; lobular neoplasia (atypical lobular hyperplasia / lobular carcinoma in situ), with involvement of a fibroadenoma
Virtual slides
Images hosted on other servers:
Intermediate grade, solid, comedo necrosis
Cytology description
- Non high grade DCIS: cohesive sheets and aggregates, balls or papillary fragments, mild to variable atypia, some debris, often microcalcifications (Lancet 1995;345:1154, Cancer 2005;105:21)
- High grade DCIS: large pleomorphic cells, irregular aggregates and single cells, necrotic debris, individual cell necrosis, microcalcifications (Lancet 1995;345:1154, Cancer 2005;105:21)
- Core needle biopsy is preferred to fine needle aspiration cytology (FNAC) due to the uncertainty in differentiating between in situ and invasive carcinoma by aspiration (Cancer 1998;84:186, Diagn Cytopathol 1993;9:713, Am J Clin Pathol 1989;92:736)
Cytology images
Images hosted on other servers:
Low grade
High grade
Positive stains
- Myoepithelial cells:
- p40, p63, SMMS, calponin, CK5/6 and CK5 highlight surrounding intact myoepithelial cell layer (but may be attenuated compared to normal mammary ductal-lobular structures, especially in high grade DCIS) (Am J Surg Pathol 2009;33:227)
- Acinar cells:
- E-cadherin (strong membranous) (Am J Surg Pathol 2001;25:229)
- p120 (strong membranous)
- Estrogen receptor and progesterone receptor, overall ER positive rate ~69%, expression is correlated with nuclear grade (strongly positive in low grade DCIS, frequently negative in high grade DCIS) (J Cancer 2011;2:232, Br J Cancer 2008;98:137)
Negative stains
- Acinar cells:
- CK5/6 and CK5, CK14, 34betaE12 usually negative, however may be positive if high grade with basal-like phenotype or squamous differentiation and should not be mistaken for heterogenous pattern of expression that is seen in usual type ductal hyperplasia (Hum Pathol 2002;33:620, Am J Surg Pathol 1999;23:1048, Mod Pathol 2010;23:S8)
Molecular / cytogenetics description
- Low grade DCIS and high grade DCIS are genetically distinct
- Low grade has frequent chromosomal losses at 16q and 17p and gains at 1q
- High grade has frequent losses at 8p, 11q, 13q and 14q, and gains at 5p, 8q and 17q (J Pathol 2005;205:248)
- High grade DCIS has similar molecular profile as invasive breast cancer (Cancer Res 2015;75:3980)
Sample pathology report
- Right breast, 10:00 calcifications with ribbon clip, stereotactic core needle biopsy:
- Ductal carcinoma in situ (DCIS), intermediate nuclear grade, solid and cribriform patterns with comedo necrosis and microcalcifications
- Immunohistochemical biomarker results: Estrogen receptor positive (90%, strong intensity), Progesterone receptor positive (40%, moderate intensity)
- Ductal carcinoma in situ (DCIS), intermediate nuclear grade, solid and cribriform patterns with comedo necrosis and microcalcifications
Differential diagnosis
- Usual type ductal hyperplasia:
- Heterogenous proliferation of cells with variable size/shape, that are irregularly distributed with cohesive or syncytial growth, haphazard orientation of nuclei, nuclear overlap, nonrigid peripheral slit-like fenestrations with nuclei parallel to the lumina
- Heterogeneity can mimic intermediate grade DCIS
- Variable or mosaic pattern of expression of CK5/6 and CK5 and estrogen receptor
- Atypical ductal hyperplasia:
- Architectural and cytologic features suggestive of but not diagnostic for a diagnosis of low grade DCIS, partial involvement of ducts, limited quantitative extent
- Lobular carcinoma in situ:
- Low grade discohesive cells, often feathery clear space between cells, with solid growth pattern, intracytoplasmic vacuoles, lack of polarization around luminal spaces
- Reduced or absent membranous expression of E-cadherin, cytoplasmic reactivity for p120
- Invasive cribriform carcinoma:
- Infiltrative growth pattern, stromal reaction
- Lack circumscription by myoepithelial markers (p40 / p63 / SMMS / calponin / CK5/6 and CK5)
- Adenoid cystic carcinoma:
- Infiltrative growth pattern, dual cell population comprised of ductal epithelial cells and basal or myoepithelial cells, pseudolumens containing basement membrane material
- Myoepithelial markers (p40 / p63 / SMMS / calponin / CK5/6 and CK5) highlight myoepithelial cell component
- Negative for estrogen receptor and progesterone receptor
- Positive for CD117/KIT and MYB
- Collagenous spherulosis:
- Pseudolumens containing nodules of flocculent blue-grey basement membrane enclosed by cuticle of basement membrane and surrounded by stellate myoepithelial cells
- Lacks true cribriform spaces with ductal epithelial cells polarized around true lumens
- Can be involved by atypical lobular hyperplasia or lobular carcinoma in situ
- Myoepithelial markers (p40 / p63 / SMMS / calponin / CK5/6 and CK5) highlight myoepithelial cell component
- Lymphovascular invasion:
- Gynecomastia:
- Micropapillae have tapered (nonclubbed) configuration, features of usual type ductal hyperplasia (cellular heterogeneity, haphazard, nonuniform distribution)
- Solid papillary carcinoma:
- Solid growth pattern punctuated by delicate fibrovascular cores, perivascular pseudorosettes, neuroendocrine features, extracellular mucin
- Lack circumscription by myoepithelial markers (p40 / p63 / SMMS / calponin / CK5/6 and CK5) at periphery of nodules
Board review style question #1
- Which of the following statements regarding DCIS is correct?
- Adjuvant anti endocrine therapy reduces the risk of local recurrence in patients with DCIS who have undergone breast conserving surgery with radiation therapy
- DCIS is generally a clinically and mammographically occult lesion
- Low grade DCIS is a nonobligate precursor lesion to high grade DCIS
- Recommended standard biomarkers to evaluate and report in patients with DCIS include estrogen receptor, progesterone receptor, and HER2
- Sentinel lymph node sampling is not indicated in patients with DCIS only, as the disease is noninvasive and there is no risk of metastatic involvement of axillary lymph nodes
Board review style answer #1
A. DCIS is a nonobligate precursor lesion to invasive breast cancer. Molecular studies have demonstrated that low and high grade DCIS are genetically distinct biologic entities. DCIS most often presents mammographically as microcalcifications. Per ASCO/CAP guidelines, currently the only recommended biomarker for DCIS is estrogen receptor, while testing for progesterone receptor is optional. Unlike for invasive breast carcinoma, HER2 is not assessed in patients with DCIS only as anti HER2 therapy is not indicated. Sentinel lymph node sampling has a role in subset of DCIS only patients, the reported positive rate is 0.4 - 13.7% (mostly isolated tumor cell deposits and micrometastases) presumably due to missed or undersampled invasive disease. In the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-24 trial, tamoxifen reduced the likelihood of ipsilateral recurrence at five years from 9 - 6%, and also reduced the risk of a tumor in the contralateral breast. (J Clin Oncol 2014;32:1365, Lancet 1999;353:1993)
Comment Here
Reference: DCIS - general
Comment Here
Reference: DCIS - general
Board review style question #2
- A 55 year old woman undergoes a stereotactic core needle biopsy for mammographically detected microcalcifications. Which statement is true regarding the grade and expected immunohistochemical staining pattern of this lesion?
- Negative for circumferential calponin and p63
- Positive (Score 3+) for HER2 by immunohistochemistry
- Reduced or absent membranous reactivity for E-cadherin
- Strongly, diffusely positive for estrogen receptor
- The lesion is high grade
Board review style answer #2
D. The biopsy shows low grade DCIS with a cribriform pattern and associated microcalcifications. Loss of E-cadherin expression is seen lobular neoplasia. Myoepithelial markers such as calponin and p63 will show retained myoepithelial cell layer surrounding foci of DCIS. Assessment of HER2 status in DCIS is not indicated per current guidelines, however HER2 overexpression is more often observed in high grade DCIS. Low grade DCIS typically shows strong estrogen receptor expression.
Comment Here
Reference: DCIS - general
Comment Here
Reference: DCIS - general
Duct ectasia
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Etiology | Clinical features | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Mammary duct ectasia is a disorder of the extralobular ducts
- Is characterized by different degrees of periductal inflammation, periductal fibrosis and duct dilatation
- Foamy histiocytes are typically present within the luminal secretions and infiltrate the wall of the involved ducts
Essential features
- Foamy histiocytes within luminal secretions and within wall and epithelium of involved ducts
- Periductal inflammation, can be plasma cell heavy
- Periductal fibrosis in late stages
Terminology
- Also called mastitis obliterans and comedo mastitis, although these terms have not been as widely used as duct ectasia
ICD coding
- ICD-10: N60.49 - mammary duct ectasia of unspecified breast
Epidemiology
- Usually women in perimenopausal and postmenopausal age
- It can occur in neonates
Sites
- Extralobular ducts; retro areolar, can be bilateral
Etiology
- Not well known
- Some authors believe that involution seen in postmenopausal women is the primary pathologic process (gland atrophy → stasis of secretions → leakage of lipid rich material through duct wall → periductal inflammation)
- Other authors believe that periductal inflammation is the inciting process that is followed by duct sclerosis, obliteration and finally ectasia
- Stasis caused by duct obstruction is considered by some to be the inciting cause of duct inflammation with further obstruction, stasis and dilatation as observed in cases of squamous metaplasia of lactiferous ducts (SMOLD)
- Smoking, phenothiazine treatment and hyperprolactinemia have been postulated as possible causes (Hoda: Rosen's Breast Pathology, 4th Edition, 2014)
Clinical features
- Typically, the age of presentation can range from 40 - 70 years old although it has been described in children and is rarely seen in men (Hoda: Rosen's Breast Pathology, 4th Edition, 2014)
- Pain, nipple discharge (can be clear, cloudy or bloody), nipple retraction or a mass (worm-like doughy palpable mass beneath the nipple) can be the clinical presentation (Hoda: Rosen's Breast Pathology, 4th Edition, 2014)
- By mammography can resemble DCIS due to the ductal pattern of calcifications that can be present (Schnitt: Biopsy Interpretation of the Breast, 3rd Edition, 2017, O'Malley: Breast Pathology, A Volume in the Series, Foundations in Diagnostic Pathology, 2nd Edition, 2011)
Case reports
- 14 month old boy with nipple discharge (Ann Surg Treat Res 2014;86:165)
- 42 year old woman with galactorrhea (Endocrine Abstracts 2017;49:EP1053)
Treatment
- Circumareolar incision and removal of the affected duct and fistula tract, if present, is the treatment of choice
Gross description
- Firm fibrotic breast tissue with prominent dilated and thick walled ducts filled with a tan-white, creamy to brown colored pasty or granular secretions (Schnitt: Biopsy Interpretation of the Breast, 3rd Edition, 2017, O'Malley: Breast Pathology, A Volume in the Series, Foundations in Diagnostic Pathology, 2nd Edition, 2011)
- Calcifications with abscess formation can also be seen (Hoda: Rosen's Breast Pathology, 4th Edition, 2014)
Microscopic (histologic) description
- Dilation of ducts with foamy histiocytes within the luminal secretions and infiltrating the wall of the involved ducts
- Periductal inflammation with lymphocytes, plasma cells, neutrophils and histiocytes; these can become multinucleated in cases of duct rupture due to reaction to spilled secretions in the stroma
- Periductal fibrosis with obliteration of the duct’s lumen can also be seen (garland sign)
Microscopic (histologic) images
Contributed by Carlos C. Diez Freire, M.D.
Dilated ducts with foamy macrophages
Dilated ducts with foamy macrophages
Garland sign
Cytology description
- Thick cheesy secretion composed of amorphous material and cellular debris that resembles necrosis
- Amorphous material may have a crack artifact as seen in watery thyroid colloid
- Small crowded groups or sheets of ductal cells with reactive atypia may be present
- The inflammatory component has plasma cells (can be abundant), neutrophils and foamy macrophages that can have pigment
- Giant cells, calcifications and cholesterol clefts can also be present (DeMay: Art and Science of Cytopathology, Volume 2, Superficial Aspiration Cytology, 2nd Edition, 2012)
Positive stains
- CD68 highlights luminal and subepithelial histiocytes
Sample pathology report
- Left breast, 2 o’clock, 5 cm from nipple, ultrasound guided core biopsy:
- Duct ectasia
Differential diagnosis
- Breast abscess:
- Presence of severe acute inflammatory infiltrate
- Often associated with lactation
- Ductal carcinoma in situ:
- Neoplastic epithelial cells confined to the mammary ductal lobular unit
- Can have expansive comedo type necrosis
Board review style question #1
Which of the following is true about the breast entity depicted above?
- Increases the risk of invasive ductal carcinoma
- Is always a unilateral process
- Most commonly affects the extralobular ducts in the retroareolar region
- Most frequently affects men and children
Board review style answer #1
C. Most commonly affects the extralobular ducts in the retroareolar region. The photo depicts duct ectasia. Answer A is incorrect because a history of duct ecstasia does not increase risk for breast carcinoma. Answer B is incorrect because duct ecstasia can be bilateral. Answer D is incorrect because duct ecstasia is most common in perimenopausal and postmenopausal women.
Comment Here
Reference: Duct ectasia of breast
Comment Here
Reference: Duct ectasia of breast
Board review style question #2
Mammary duct ectasia is characterized by which of the following microscopic findings?
- Epithelial proliferation that fills and distends the terminal duct lobular units
- Infiltrating ductal proliferation with desmoplastic stromal response
- Periductal inflammation and dilation of ducts, with foamy histiocytes within the luminal secretions and infiltrating the wall of ducts
- Proliferation of both stromal and glandular elements
Board review style answer #2
C. Periductal inflammation and dilation of ducts, with foamy histiocytes within the luminal secretions and infiltrating the wall of ducts with periductal inflammation. Duct estasia is characterized by different degrees of periductal inflammation, periductal fibrosis and duct dilation, as well as the presence of foamy histiocytes within luminal secretions and the periductal epithelium. Answers A, B and D are incorrect because duct ectasia is a benign nonproliferative disease.
Comment Here
Reference: Duct ectasia of breast
Comment Here
Reference: Duct ectasia of breast
Ductal adenoma
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Negative stains | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1Definition / general
- Benign tumor composed of distorted glands in a sclerotic stroma surrounded by a fibrous capsule
- First described by Azzopardi and Salm in 1984 (J Pathol 1984;144:15)
Essential features
- Rare, benign adenomatous lesion of medium and small sized ducts in the peripheral breast
- Well circumscribed, single (occasionally multinodular), solid proliferation of tubules set within a fibrous stroma and surrounded by a thickened fibroelastotic wall
- Considered a highly sclerotic variant of intraductal papilloma with obliterated papillary growth
- May show calcifications, hemorrhage, infarction, squamous or apocrine metaplasia, epithelial hyperplasia, myxoid or chondroid change, central scar or pseudoinfiltrative pattern (exclude invasion by showing intact myoepithelial cells; e.g., p63, SMMHC)
- Excision is curative
Terminology
- Not recommended: sclerosing papilloma
ICD coding
Epidemiology
- Uncommon
- Patient age > 60 years
- No family or personal history of breast cancer (Hum Pathol 1989;20:903)
- Ductal adenomas with tubular features occur as part of Carney complex (Am J Surg Pathol 1991;15:722, Am J Surg Pathol 1996;20:1154)
Sites
- Usually arises in small and medium sized ducts of the peripheral breast, rarely in larger or major subareolar ducts (J Pathol 1984;144:15, Hum Pathol 1989;20:903)
- This is in contrast to intraductal papilloma, which arises from both small to medium sized peripheral ducts and predominantly larger subareolar ducts
- Unilateral (bilateral breast involvement seen in Carney syndrome) (Am J Surg Pathol 1991;15:722, Am J Surg Pathol 1996;20:1154)
Pathophysiology
- Most likely, it originates from intraductal papilloma in small and medium sized ducts (J Pathol 1984;144:15, Hum Pathol 1989;20:903)
- Due to the stromal repair process, papilloma undergoes sclerosis, resulting in loss of the arborizing papillary architecture
- Another theory implicates a direct expansion of hyperplastic processes such as sclerosing adenosis into small and medium sized ducts or coexistent intraductal papilloma (Hum Pathol 1989;20:903)
- Stromal degenerative changes may occur in the center, similar to radial scar
Etiology
- Breast proliferative lesion genetically related to papilloma (Genes Chromosomes Cancer 2017;56:11)
- Similar to papilloma, AKT1 E17K mutations activate the PIK3CA pathway involved in cell proliferation, survival, angiogenesis and motility (Mod Pathol 2010;23:27)
Clinical features
- Presents as palpable lump or nipple discharge (less common) or mammographic abnormality (J Pathol 1984;144:15, Hum Pathol 1989;20:903)
Diagnosis
- May resemble carcinoma on clinical examination, imaging, needle aspiration cytology and core biopsy (J Pathol 1984;144:15, Breast Cancer 2006;13:354)
- Excision is often recommended due to histological and radiological mimicry of carcinoma
Radiology description
- Imaging features may suggest papilloma, fibroadenoma or mimic carcinoma (Breast Cancer 2006;13:354)
- Mammography shows well to ill defined mass with or without calcification
- Ultrasonography shows a well defined, round hypoechoic nodule with shadowing and posterior enhancement
- On contrast enhanced MRI, margins are smooth despite histologic pseudoinvasion (Breast Cancer 2016;23:597)
Radiology images
Contributed by Thomas Lienhoop, M.D.
Screening mammogram
Diagnostic ultrasound
Prognostic factors
- Benign, with no increased risk for recurrence or malignant transformation after complete excision (Hum Pathol 1989;20:903)
- 1 case reported in the literature associated with malignant transformation to apocrine and epithelial myoepithelial carcinoma (Malays J Pathol 2015;37:281)
Case reports
- 32 and 64 year old women with ductal adenoma of the breast (Breast Cancer 2006;13:354)
- 57 year old woman with malignant transformation of breast ductal adenoma (Malays J Pathol 2015;37:281)
- 58 and 78 year old women with ductal adenoma of the breast (with immunohistochemistry) (Pathol Int 2008;58:801)
- 63, 71 and 82 year old women with ductal adenoma of the breast (with imaging characteristics and radiologic - pathologic correlation) (Breast Cancer 2016;23:597)
- 66 year old woman with ductal adenoma of the breast with chondromyxoid change (Pathol Int 2002;52:239)
Treatment
- Complete excision is curative (Hum Pathol 1989;20:903)
Gross description
- Ranges in size from 0.5 to 5.0 cm (average: 0.85 cm) (J Pathol 1984;144:15)
- Solid white nodule with lobulated and granular cut surface and central gray softening
- Gritty texture and elastic streaks mimic carcinoma
- Solitary or occasionally multiple nodules in close proximity
- Multinodular tumors due to the involvement of different parts of the same ductal system (Hum Pathol 1989;20:903)
Microscopic (histologic) description
- Well circumscribed, intraductal, solitary or multinodular (rare) lesion, surrounded by a thickened concentric fibroelastotic wall (J Pathol 1984;144:15)
- Adenomatous portion has solid architecture and consists of proliferating tubules set in a fibrous stroma
- No arborizing papillary fronds (as seen in intraductal papilloma) or myoepithelial hyperplasia (as seen in adenomyoepithelioma)
- Glands range from round to oval, elongated to branched
- Epithelial and myoepithelial cell types are present (the latter may be inconspicuous)
- Ductal cells are cuboidal, columnar or spindled, with no atypia and only rare mitoses
- Cystic gland dilatation, epithelial hyperplasia, apocrine or squamous metaplasia, eosinophilic secretions or laminated calcifications may be present (Hum Pathol 1989;20:903)
- Stroma is usually fibrous, modest in amount and may show myxoid change, prominent hyalinization and rarely cartilaginous metaplasia (Pathol Int 2002;52:239)
- Compression of glands similar to sclerosing adenosis is frequently seen (Hum Pathol 1989;20:903)
- Distortion and entrapment of glands in the sclerotic wall may result in a pseudoinfiltrative pattern
- Glandular proliferation may protrude into surrounding tissue, pushing beyond ductal confines (pushing borders) (J Pathol 1984;144:15)
- Duct wall may contain dystrophic calcifications; periductal chronic inflammation may be seen (Hum Pathol 1989;20:903)
- In stellate form, central fibroelastosis with entrapped epithelial tubules and peripheral dilated glandular elements resembles radial scar (J Pathol 1984;144:15)
- Secondary changes such as hemorrhage or infarction may occur (Breast Cancer 2006;13:354)
Microscopic (histologic) images
Contributed by Susanne M. Crespo-Ramos, M.D., Anna Biernacka, M.D., Ph.D. and AFIP
Epithelial cell nests and glands
Compressed glands
Well circumscribed adenomatous nodule
Duct wall / capsule
Duct distention and pseudoinvasion
Pseudoinfiltrative and pushing borders
Glands and stroma
Epithelial and myoepithelial cells
Eosinophilic secretions
Usual ductal hyperplasia
Central fibrosis, peripheral bland ducts
Nodular lesion, primarily spindle cells
Spindle cells with residual ducts
Spindled myoepithelial cells around peripheral duct
Ducts lined by apocrine cells
Smooth muscle myosin
p63
Cytokeratin 5/6
Cytology description
- Highly cellular aspirates (Diagn Cytopathol 1994;10:143, Diagn Cytopathol 1995;13:252)
- Numerous branching flat sheets of regularly spaced cohesive ductal cells
- Large fragments of purple stroma in tight association with epithelial cells, forming finger-like hyaline structures or globules between cells
- Background of single cells, naked nuclei, histiocytes and apocrine cells
- Nuclei are round / oval with bland chromatin
- Cytoplasm with small punched out vacuoles
Positive stains
- Luminal cells: keratin
- Myoepithelial cells: S100, actin, p63
- Basement membrane: laminin, type IV collagen
- Stromal spindle cells (myofibroblasts): actin and vimentin (Pathol Res Pract 1993;189:515)
- Heterogenous staining pattern for CK5/6 and ER
Negative stains
- Low Ki67 and p53 (Pathol Int 2008;58:801)
Molecular / cytogenetics description
- 9 cases of ductal adenoma that have been studied using next generation sequencing showed recurrent missense mutations affecting AKT1, GNAS and PIK3CA genes (Genes Chromosomes Cancer 2017;56:11)
- Given the high frequency of AKT1 mutations in breast papillomas, these data support the notion that ductal adenomas are closely related to or are, in fact, intraductal papillomas that have undergone sclerosis (Mod Pathol 2010;23:27)
Sample pathology report
- Right breast, excisional biopsy:
- Benign intraductal glandular proliferation with sclerotic stroma consistent with ductal adenoma (see comment)
- Comment: The specimen shows a solid nodule with a prominent component of glands and stromal sclerosis, surrounded by a thickened hyalinized wall. Immunohistochemical studies show a heterogenous staining pattern for cytokeratin 5/6 and estrogen receptor and focally attenuated yet retained myoepithelial cells highlighted by smooth myosin heavy chain and p63. The overall findings are consistent with ductal adenoma, which is a benign tumor with features similar to sclerosing intraductal papilloma.
Differential diagnosis
- Intraductal papilloma:
- Proliferative epithelial cells with fibrovascular cores (papillary architecture)
- Can arise from small to medium sized peripheral ducts but also from larger subareolar ducts
- Tubular adenoma:
- Closely packed round and oval tubules with sparse intervening stroma
- Histogenetically related to the pericanalicular subset of fibroadenomas
- Fibroadenoma:
- Biphasic tumor; proliferation of both glandular epithelial and stromal components
Additional references
Board review style question #1
A 65 year old woman had a right breast lumpectomy showing a well circumscribed firm nodule with a lobulated and granular cut surface. Histologic features are shown in the image. Which of the following is the correct diagnosis?
- Ductal adenoma
- Fibroadenoma
- Intraductal papilloma
- Invasive ductal carcinoma
- Tubular adenoma
Board review style answer #1
A. Ductal adenoma. Ductal adenoma is a benign, well circumscribed adenomatous lesion in a duct surrounded by a densely thickened fibroelastotic wall. It has a solid architecture with an intermixture of tubules and sclerotic stroma and lacks arborizing papillary fronds. Answer C is incorrect because intraductal papillomas display arborizing papillary fronds. Answer D is incorrect because although gland distortion by sclerosis may mimic an infiltrative pattern, the myoepithelium is retained in this specimen. Answers B and E are incorrect because fibroadenomas and tubular adenomas arise from terminal duct lobular units rather than duct lumens and lack a prominent capsule. They are histogenetically related biphasic lesions, with the stromal component dominating fibroadenoma and florid adenosis-like epithelial proliferation dominating tubular adenoma.
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Reference: Ductal adenoma
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Reference: Ductal adenoma
Encapsulated papillary carcinoma
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Diagrams / tables | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Positive stains | Negative stains | Molecular / cytogenetics description | Videos | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2 | Board review style question #3 | Board review style answer #3Definition / general
- Expansile papillary tumor, occurring in postmenopausal women, with low or intermediate grade nuclei surrounded by a fibrous capsule that lacks myoepithelial cells along the papillae and at the periphery or shows focal peripheral myoepithelial staining
Essential features
- Papillary tumor comprised of delicate papillary fronds with fibrovascular cores lined by cuboidal to columnar epithelial cells with low to intermediate grade atypia, often within a cystically dilated duct surrounded by a thick fibrous capsule
- Lacks myoepithelial cells along the papillae and around the periphery of the tumor or only focal peripheral myoepithelial staining
- Staged as ductal carcinoma in situ (DCIS) (i.e., Tis) in the absence of invasive carcinoma, due to indolent behavior and excellent prognosis
- Encapsulated papillary carcinoma (EPC) with high grade cytologic atypia and increased mitotic activity are rare; they are best classified as high grade invasive breast carcinoma with features of EPC and staged as an invasive carcinoma
Terminology
- Intracystic papillary carcinoma (not recommended)
- Encysted papillary carcinoma
ICD coding
- ICD-O:
- ICD-11:
- 2E65.Y & XH9XV2 - other specified carcinoma in situ of breast & noninfiltrating intracystic carcinoma
- 2C6Y & XH0GT6 - other specified malignant neoplasms of breast & encapsulated papillary carcinoma with invasion
Epidemiology
- Postmenopausal women, seventh decade (Am J Surg Pathol 2011;35:1093, Pathol Res Pract 2018;214:579, Breast J 2019;25:539)
- Rare in males (Breast Cancer Res Treat 2020;182:317, Cancer 2008;113:916)
Sites
- Breast, possible central predilection (Pathol Res Pract 2018;214:579)
Pathophysiology
- Classification and pathogenesis are debated:
- Variant of ductal carcinoma in situ (DCIS)
- Progression from in situ disease to invasive carcinoma
- Low grade indolent invasive tumor with pushing border
- References: Am J Surg Pathol 2011;35:1093, Curr Probl Cancer 2018;42:291, Breast Cancer Res Treat 2020;182:317
Etiology
- Unknown
Diagrams / tables
Images hosted on other servers:
Myoepithelium and hormone receptors in EPC
Clinical features
- Presentation may include palpable mass or nipple discharge (Cancer 2008;113:916, Curr Probl Cancer 2018;42:291, Pathol Res Pract 2018;214:579)
Diagnosis
- Histologic examination of tissue removed by biopsy or surgical excision
Radiology description
- No distinct imaging findings can distinguish between subtypes of papillary carcinomas (AJR Am J Roentgenol 2012;198:264, Front Surg 2022;8:743881)
- Imaging does not distinguish encapsulated papillary carcinoma (EPC) with and without invasion beyond the capsule (Breast J 2019;25:539, Breast J 2021;27:209)
- Mammography:
- Circumscribed to lobulated, round to oval mass
- May have irregular, angulated or multilobulated borders
- Calcifications uncommon
- Ultrasound:
- Hypoechoic solid mass, sometimes with cystic component
- Color Doppler often highlights prominent vascular supply
- Magnetic resonance imaging (MRI):
- Well defined, round to oval, heterogeneous mass with varying signal intensity depending on cystic fluid content
Radiology images
Contributed by Mariel Molina Nunez, M.D. and Julie Jorns, M.D. (Case #518)
Mammogram of the left breast mass
Ultrasound view of the complex mass
Images hosted on other servers:
Mammographic, sonographic and MRI findings
Mammographic findings
Mammographic findings
Prognostic factors
- Low and intermediate grade EPC without conventional invasive carcinoma (Am J Surg Pathol 2011;35:1093, Curr Probl Cancer 2018;42:291, Am J Clin Pathol 2009;131:228)
- Similar clinical behavior to ductal carcinoma in situ (DCIS), staged as DCIS in the absence of invasive carcinoma
- > 95% 10 year survival in the absence of associated invasive carcinoma
- Local recurrence possible (7%) (Histopathology 2016;68:45)
- Lymph node metastases rare (3%) (Int J Surg Pathol 2007;15:143, Histopathology 2016;68:45)
- If invasion beyond the capsule is present, it is staged based on the size of the invasive component, not the size of the EPC
- Patients with invasive carcinomas arising from EPCs may have a better prognosis compared to age and stage matched conventional invasive carcinomas (Breast Cancer Res Treat 2010;122:637)
- Similar clinical behavior to ductal carcinoma in situ (DCIS), staged as DCIS in the absence of invasive carcinoma
- High grade carcinoma with EPC features (Histopathology 2015;66:740, Histol Histopathol 2019;34:137, Am J Surg Pathol 2011;35:1093)
- Low incidence (3% of EPC)
- Similar clinical behavior to invasive carcinoma with greater propensity of lymphovascular invasion and lymph node metastases when compared to low and intermediate grade EPC
- Best classified as high grade invasive breast carcinoma with features of EPC and staged as an invasive carcinoma
Case reports
- 62 year old woman with nipple discharge and encapsulated papillary carcinoma (Radiol Case Rep 2021;16:748)
- 62 year old woman with sudden hemorrhage in encapsulated papillary carcinoma resulting in anemia and emergency surgery (Int J Surg Case Rep 2019;65:201)
- 63 year old man with encapsulated papillary carcinoma (Asian J Surg 2022;45:1511)
- 63 year old man with gynecomastia and encapsulated papillary carcinoma (Eur J Breast Health 2018;14:127)
- 67 year old woman with distant metastasis following encapsulated papillary carcinoma (Case Rep Oncol 2020;13:1196)
- A postmenopausal woman with a 15 mm mass in the lower inner quadrant of the left breast (Case of the Month #518)
Treatment
- May be treated adequately with surgical excision alone, similar to in situ carcinoma (Am J Surg Pathol 2011;35:1093, Mod Pathol 2021;34:1044)
- The need for axillary sentinel lymph node sampling is debated (Breast J 2021;27:209, Clin Breast Cancer 2017;17:127)
- Hormonal therapy may be indicated in certain cases (Am J Surg Pathol 2011;35:1093)
- Chemotherapy not indicated (Am J Surg Pathol 2011;35:1093)
Gross description
- Well circumscribed solid to papillary mass expanding a cystic space lined by a fibrotic capsule (Virchows Arch 2022;480:65)
- Typically between 1 - 2 cm (Curr Probl Cancer 2018;42:291)
Gross images
Images hosted on other servers:
Papillary tumor within cystic space
Solid tumor within cystic duct
High grade EPC with hemorrhage
Microscopic (histologic) description
- Papillary tumor with pushing borders, may be within a cystically dilated duct, surrounded by a thick fibrous capsule (Histopathology 2008;52:20, Mod Pathol 2021;34:1044, Virchows Arch 2022;480:5)
- Delicate papillary fronds with fibrovascular cores lined by cuboidal to columnar epithelial cells with low to intermediate grade atypia
- Cribriform and solid architecture may be present
- Low mitotic activity (average 3 mitoses per 10 high power fields [HPFs]) (Am J Surg Pathol 2011;35:1)
- Most show complete lack of myoepithelial cells along the papillae and around the periphery of the tumor (Am J Surg Pathol 2006;30:1002, Am J Surg Pathol 2011;35:1)
- Basement membrane markers (collagen IV, laminin) may be expressed around the periphery (Pathobiology 2021;88:359, Am J Clin Pathol 2009;131:228)
- Invasive carcinoma is defined as the presence of neoplastic cells infiltrating beyond fibrous capsule (Mod Pathol 2021;34:1044)
- Most commonly invasive carcinoma of no special type (IDC NST), small (pT1), ER+, HER2- and low grade (Am J Surg Pathol 2011;35:1093, Breast J 2021;27:209, Breast J 2019;25:539, Curr Probl Cancer 2018;42:291)
- Staging is based on the size of the conventional invasive component if present
- Epithelial displacement / entrapment of neoplastic cells within capsule can occur and must be distinguished from true invasion beyond the fibrous capsule
- High grade invasive carcinoma with EPC features (Histopathology 2015;66:740, Histol Histopathol 2019;34:137)
- High grade cytologic atypia with nuclear pleomorphism, frequent mitotic figures (mean mitotic activity 22 per 10 HPFs) and occasional necrosis
- More likely to be ER- or triple negative
Microscopic (histologic) images
Contributed by Kristen E. Muller, D.O. , Mariel Molina Nunez, M.D. and Julie Jorns, M.D. (Case #518)
Encapsulated papillary carcinoma with invasion
Synaptophysin
EPC, circumscribed with fibrous capsule
Low grade nuclear atypia
EPC with invasion
EPC with DCIS and invasion
High grade EPC
Estrogen receptor (ER)
Absent myoepithelium
Progesterone receptor (PR)
Thick fibrous capsule encircles mass
Surrounding encapsulation and cystic space
Fibrovascular cores within epithelial proliferation
Loss of E-cadherin in the lesion
Virtual slides
Images hosted on other servers:
Encapsulated papillary carcinoma
Cytology description
- No formal cytologic criteria exist to distinguish EPC from other benign papillary lesions (J Clin Pathol 2008;61:945)
- Sensitivity and specificity for specific diagnoses is low
- If papillary lesion is suspected on FNA, surgical biopsy is necessary for further classification
- General findings in fine needle aspirates of EPC (Breast J 2006;12:237, J Clin Pathol 2008;61:945)
- High cellularity, presence of cell balls, presence of slender papillae, mild cytologic atypia
Positive stains
- ER and PR (strong, diffuse) (Curr Probl Cancer 2018;42:291, Mod Pathol 2021;34:1044)
Negative stains
- Myoepithelial markers (i.e., p63, calponin, actin, smooth muscle myosin heavy chain, CD10) negative within papillae and around the tumor or focally present at the periphery of the lesion (Am J Surg Pathol 2006;30:1002, Am J Surg Pathol 2011;35:1, Curr Probl Cancer 2018;42:291)
- HER2
- Chromogranin, synaptophysin (J Pathol 2012;226:427)
Molecular / cytogenetics description
- Similar to ER+, low grade invasive breast carcinomas (J Pathol 2012;226:427, Mol Oncol 2014;8:1588)
- Luminal A
- Frequent PIK3CA mutations
- 16q losses, 16p gains and 1q gains
- Similar copy number alterations to solid papillary carcinoma and invasive papillary carcinoma (Mol Oncol 2014;8:1588)
Videos
Papillary lesions of the breast
Sample pathology report
- Breast, right, partial mastectomy:
- Encapsulated papillary carcinoma (see comment)
- Comment: Histologic sections show a circumscribed papillary tumor surrounded by a thick fibrous capsule. Cytologically, the tumor cells are columnar and cuboidal with low grade nuclear atypia. The lesion lacks myoepithelium throughout the fibrovascular cores and around the periphery. Conventional invasive carcinoma is not seen infiltrating into or beyond the fibrous capsule. In the absence of an invasive carcinomatous component, encapsulated papillary carcinomas are staged as in situ (Tis); however, some believe that they may actually be a very good prognosis subtype of invasive carcinoma due to the lack of myoepithelium.
- Breast, right, core needle biopsy (when entire lesion is not removed or cannot be visualized):
- Low grade papillary carcinoma (see comment)
- Comment: The biopsy contains fragments of an atypical lesion with papillary architecture and low grade monomorphic nuclear atypia. p63 and calponin immunostains are negative for myoepithelium throughout the lesion and around the periphery; however, the periphery of the lesion is not completely visualized in the biopsy. The findings raise the possibility of a low grade encapsulated papillary carcinoma. Papillary ductal carcinoma in situ is also in the differential. A conventional invasive carcinoma is not present in this biopsy. Definitive classification is deferred to the surgical specimen.
Differential diagnosis
- Papilloma with atypical ductal hyperplasia (ADH) or ductal carcinoma in situ (DCIS):
- Residual underlying papilloma may be present with areas of usual ductal hyperplasia (UDH), apocrine metaplasia and columnar cell change which lack atypia
- Myoepithelial cells present in residual fibrovascular cores in nonatypical areas and at the periphery
- Papillary ductal carcinoma in situ (DCIS):
- Involvement of multiple ducts in DCIS pattern
- May coexist with other patterns of DCIS
- Myoepithelium present at the periphery
- Intraductal papilloma:
- Lacks cytological atypia
- Areas of benign proliferative changes (UDH, apocrine metaplasia, columnar cell changes)
- Myoepithelium present throughout papillae and at the periphery
- Solid papillary carcinoma:
- Single or multiple nodules with solid architecture and rudimentary, delicate fibrovascular cores
- Lacks encircling dense fibrous capsule
- Cells may be spindled, produce mucin and have neuroendocrine features
- Similar to encapsulated papillary carcinoma, lacks myoepithelium within tumor nests and around the periphery
- Invasive papillary carcinoma:
- Cystically dilated small glands with papillae with frankly infiltrative pattern without surrounding fibrous capsule
- Negative for myoepithelium
- Invasive lobular carcinoma with papillary growth pattern (Breast J 2020;26:1231, Breast Cancer 2021;28:1383, Pathobiology 2016;83:221):
- Rare growth pattern of invasive lobular carcinoma that mimics encapsulated or solid papillary carcinoma
- Classic invasive lobular carcinoma, atypical lobular neoplasia (ALH), LCIS present beyond the capsule
- Discohesive tumor cells
- Negative for E-cadherin
Additional references
Board review style question #1
What is the expected pattern of myoepithelial cell distribution in encapsulated papillary carcinoma of the breast?
- Absent both centrally within the lesion and along the periphery
- Absent centrally within the lesion but diffusely present along the periphery
- Present both centrally within the lesion and along the periphery
- Present only focally within the center of the lesion but diffusely present along the periphery
Board review style answer #1
A. Absent both centrally within the lesion and along the periphery. Encapsulated papillary carcinomas characteristically lack myoepithelial cells both within and along the edge of the lesion. The remaining answer choices apply to other papillary lesions of the breast; a benign intraductal papilloma has myoepithelial cells lining the entirety of the proliferation both centrally and peripherally, whereas a papilloma involved by DCIS and papillary DCIS will show focal to complete absence of myoepithelium centrally (corresponding to the regions of atypia) with retention peripherally.
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Reference: Encapsulated papillary carcinoma
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Reference: Encapsulated papillary carcinoma
Board review style question #2
A 72 year old woman undergoes partial mastectomy for a 1.8 cm papillary lesion in the retroareolar tissue of her left breast. A diagnosis of encapsulated papillary carcinoma is made upon finding absent myoepithelium within the papillae and around the periphery. How should this lesion be staged, according to the AJCC TNM classification system?
- T0
- Tis
- T1
- T2
Board review style answer #2
B. Tis. Encapsulated papillary carcinoma is staged as an in situ lesion given its similar clinical behavior to ductal carcinoma in situ. If conventional invasive carcinoma is found, infiltrating beyond the fibrous capsule, the lesion should be staged according to the size of the invasive component only; the size of the EPC should not be included for staging.
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Reference: Encapsulated papillary carcinoma
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Reference: Encapsulated papillary carcinoma
Board review style question #3
In which group is encapsulated papillary carcinoma of the breast most commonly seen?
- Childhood (≤ 18 years)
- Lactating / pregnant
- Men
- Postmenopausal women
Board review style answer #3
D. Postmenopausal women. Encapsulated papillary carcinoma (EPC) of the breast is an uncommon breast cancer that is classified as in situ, is typically low to intermediate grade and most frequently occurs in elderly, postmenopausal women rather than in younger women. EPCs constitute a slightly higher proportion of breast cancers in male patients as compared to female patients. However, male breast cancer is uncommon and is most frequently invasive ductal carcinoma (comprising about 85% of male breast cancers).
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Reference: Encapsulated papillary carcinoma
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Reference: Encapsulated papillary carcinoma
Fat necrosis
Table of Contents
Definition / general | Essential features | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Gross images | Frozen section description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Positive stains | Negative stains | Videos | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Nonneoplastic inflammatory breast lesion characterized by necrotic adipose tissue with foamy histiocytes, chronic inflammatory cells and multinucleated giant cells
Essential features
- Nonneoplastic inflammatory reaction that is commonly secondary to adipose tissue injury
- May simulate carcinoma both clinically and radiologically
- There are different radiographical and histological stages which vary based on time from inciting event
Epidemiology
- 0.6% of breast excisions
- Age range: 37 - 68 years (mean age: ~50 years) (Breast 2006;15:313)
- Most described in perimenopausal women after trauma, surgery or biopsy
Sites
- Any part of the breast may be affected
- After trauma, typically occurs at site of injury and is commonly detected in periareolar and subareolar region; it is often superficial in location since these sites are most vulnerable to trauma (Lipids Health Dis 2019;18:158)
- In patients with no history of trauma, lesion is most often seen in upper outer quadrant of breast
Pathophysiology
- Many cases are due to previous biopsy procedures (such as fine needle aspiration or needle core biopsy), surgical procedure or radiation therapy (Plast Reconstr Surg 2014;134:1202)
- May result from incidental trauma
Etiology
- Trauma:
- Blunt trauma to breast (e.g., seat belt injury after motor vehicle accident) (J Plast Reconstr Aesthet Surg 2015;68:382)
- Iatrogenic injury:
- Fine needle aspiration, core needle biopsy, mastectomy or lumpectomy of breast, autologous fat injection, reduction mammoplasty, breast implants (Breast Cancer 2019;26:125)
- Radiation therapy:
- Due to postradiation vascular damage with subsequent ischemia, including external beam, MammoSite, iridium implantation, intraoperative radiation
- Other rare causes:
- Anticoagulant treatment (warfarin [Coumadin]), polyarteritis nodosa, Weber-Christian disease, granulomatous angiopanniculitis, lupus mastitis, injection of methylene blue dye
- Unknown cause in ~50% of patients
Clinical features
- Typically present with a painless superficial solitary mass which may mimic cancer, especially in patients who have undergone breast conserving surgery and radiation therapy (Lipids Health Dis 2019;18:139)
- Firm and relatively circumscribed on palpation, may span 2 cm in diameter (average)
- Occasionally can be associated with skin changes: bruising and tenderness, tethering or dimpling of the overlying skin if the lesion is superficially located, nipple retraction
Diagnosis
- Palpation of breast mass, radiographical findings and correlation with clinical history of trauma or breast procedures (Lipids Health Dis 2019;18:139)
- Core needle biopsy is frequently performed if there are masses or calcifications
- Tissue diagnosis needs to correlate with imaging findings and must be used to distinguish from fat necrosis next to another lesion
Radiology description
- Many cases can be identified by radiographic appearance (e.g., forming mammographic masses or mammographic calcifications)
- Manifestations on mammography, ultrasonography and MRI depend upon its stage of evolution; features can be variable and may be indistinguishable from carcinoma (Radiol Res Pract 2015:613139)
- Time from inciting event may be useful in correlating radiographic findings (Br J Radiol 2018;91:20180213)
- Mammography usually reveals ill defined irregular mass with or without calcifications or focal asymmetries around central area of necrotic adipose tissue
- May contain punctate, irregular or coarse pleomorphic calcifications
- Sonography demonstrates a discrete mass which may be well circumscribed or ill defined
- Sonographic appearance is variable and is usually associated with distortion of the parenchymal architecture
- Less frequently, the lesion may appear as a lipid (oil) cyst which consists of a circumscribed, round or oval radiolucent oil filled cyst that is partly calcified
- Oil cysts typically show posterior acoustic shadowing by sonography
- Eggshell calcifications are late findings with characteristic appearance around central area of necrotic adipose tissue
- MRI demonstrates a wide spectrum of findings
- Necrotic fat usually shows low signal intensity on T1 weighted MRI
- Fibrosis may be seen as architectural distortion
Radiology images
Images hosted on other servers:
Contraction
and
microcalcification
Fat necrosis within surgical site
Prognostic factors
- Should resolve or regress over time (Br J Radiol 2018;91:20180213)
- Degenerated fat may persist for years within a fibrotic scar
Case reports
- 40 year old woman with breast pain for 3 months (Pan Afr Med J 2016;25:235)
- 63 year old woman was found to have a left breast mass after quadrantectomy and radiation (Magn Reson Imaging 2004;22:285)
- 66 year old woman with palpable breast masses one month after a car accident (Eur J Ultrasound 2000;11:213)
- 71 year old woman with painful bilateral breast masses and overlying skin changes (Dermatol Online J 2018;24:13030)
- Case series of fat necrosis after breast conserving oncoplastic surgery (Breast Cancer 2019;26:125)
Treatment
- Biopsy the lesion to confirm the diagnosis if clinical / radiological features can not distinguish from cancer
- Follow up with imaging and clinical examination to detect occult carcinoma that might be masked by coexisting fat necrosis
- Surgical excision is usually not necessary after the diagnosis has been established, only for painful or aesthetically undesirable lesions (StatPearls: Breast Fat Necrosis [Accessed 1 May 2020])
Clinical images
Images hosted on other servers:
Skin and fat necrosis due to methylene blue
Gross description
- Varies based on time from injury
- Early lesion has the appearance of hemorrhage in indurated fat (Radiol Res Pract 2015:613139)
- Cut surface of the lesion has a variegated, yellow-gray appearance with focally reddish color
- After several weeks, it appears as a firm yellow-gray nodule / mass with a demarcated border
- Mass may retract surrounding parenchyma, cystic degeneration may develop in the center, showing a cavity containing oily fluid secondary to necrotic fat with calcification in the cystic walls
- At a later stage, the lesion may show a dense scar that may appear like a mass
- Early lesion has the appearance of hemorrhage in indurated fat (Radiol Res Pract 2015:613139)
Gross images
Contributed by Elizabeth Abels, M.D.
Fat necrosis within biopsy site
Frozen section description
- Frozen sections are difficult to obtain due to high fat content of specimen
Microscopic (histologic) description
- Histiocytes are relatively uniform in size with round nuclei, fine intracytoplasmic vacuoles and no indentation of the nucleus
- Varies based on time from injury
- Early stage:
- Necrosis of adipocytes (fine vacuolization, diminished size and dropout)
- Focal hemorrhage in fat (AJR Am J Roentgenol 2009;192:815)
- Cystic degeneration may result in cavity with or without calcifications in cyst walls
- Formation of demarcated distinct yellow-gray and focally reddish mass over several weeks
- Intermediate stage:
- Mixed inflammatory cell infiltrate of histiocytes, lymphocytes, plasma cells, sometimes with eosinophils
- Lipid laden foamy histiocytes and multinucleated foreign body type giant cells are due to phagocytosis of necrotic adipocytes
- Hemosiderin deposition
- Early fibrosis with hypercellular areas of fibroblastic proliferation
- Late stage:
- Varying degrees of fibrosis and calcifications may remain for years
- Fibrosis contract into a scar and may result in irregular mass
- Loculated necrotic fat within a cyst surrounded by dense fibrous tissue (oil cyst) with dense calcification in the walls of cysts (eggshell calcifications)
- Reactive squamous metaplasia may develop in the epithelium of ducts and lobules in the area of lesion
- Early stage:
Microscopic (histologic) images
Contributed by Jing He, M.D.
Disruption of adipocytes
Mixed inflammation
Mixed inflammatory cells
Hemorrhage and hemosiderin
Hemosiderin and giant cells
Multinucleated giant cells
Lipid laden histiocytes and hemorrhage
Lipid laden histiocytes
Mass formation
Necrotic adipocytes
Cystic degeneration
Early fibrosis
Oil cyst
Late stage fibrosis
Eggshell calcifications
CD68
AE1 / AE3
Cytology description
- Characterized by lipid laden histiocytes (lipophages), multinucleated giant cells and degenerating adipocytes (AJR Am J Roentgenol 2009;192:815)
- Lipid laden macrophages demonstrate abundant foamy cytoplasm with variably sized clear lipid vacuoles and small, bland nuclei
- Histiocytes are relatively uniform in size with round nuclei, fine intracytoplasmic vacuoles and no indentation of the nucleus
- Degenerating adipocytes are characterized by aggregates of adipocytes that have lost their nuclei and have finely granular cytoplasm instead of the clear cytoplasm that is characteristic of lipid
- Reactive and reparative changes involving fibroblasts and histiocytes can result in cells with large pleomorphic nuclei and prominent nucleoli
- Background may show scattered inflammatory cells, hemosiderin laden macrophages, globules and acellular lipid
- Scant clusters of ductal epithelial cells are usually cytologically bland but may exhibit cytologic atypia with pleomorphic nuclei and prominent nucleoli
Cytology images
Images hosted on other servers:
Stages of fat necrosis
Positive stains
Videos
Breast traumatic fat necrosis
Breast inflammatory conditions
Sample pathology report
- Breast, right, retroareolar, core biopsy:
- Fat necrosis
Differential diagnosis
- Breast carcinoma:
- May have abundant foamy cytoplasm and small bland nuclei that can mimic histiocytes
- Usually demonstrates more nuclear atypia
- Cytokeratin+, CD68-
- Lipomatous neoplasm:
- Granular cell tumor:
- Amyloidosis (Pathol Res Pract 2019;215:152699):
- Can present as mass or calcifications with amyloid surrounding adipocytes
- Usually associated with systemic amyloidosis and hematologic disorder such as plasmacytoma
- No chronic inflammatory cell infiltrate
- Amyloid deposits within blood vessel walls and causes thickening of basement membranes and vascular walls
- Congo red apple green birefringence under polarized microscopy
- Erdheim-Chester disease:
- Infrequent xanthomatous form of non Langerhans cell histiocytosis
- Usually synchronous nonmammary subcutaneous nodules, osseous and orbital lesions
- Infiltration of foamy histiocytes, Touton type giant cells, plasma cells and epithelioid granuloma
- CD68+, factor XIIIa (strong)+, S100 variable, CD1a-
Board review style question #1
- A 65 year old woman has a clinical history of right breast carcinoma treated with local resection and radiation therapy. Her mammogram showed an ill defined irregular mass with calcifications within the right breast. A stereotactic core biopsy shows microcalcifications within the lesion. Which of the following is true about this lesion?
- Continue routine surveillance for this patient
- Negative CD68 and positive AE1 / AE3 are characteristic of this lesion
- The patient has recurrent breast carcinoma
- The patient requires surgical excision of this lesion followed by chemotherapy
Board review style answer #1
A. Continue routine surveillance for this patient. Fat necrosis of the breast is a possible sequela of breast tissue trauma or surgical procedure. This patient likely developed fat necrosis after her initial resection and radiation therapy. When the diagnosis is unclear from radiology, biopsy is necessary to rule out cancer. The biopsy section shows foamy lipid laden histiocytes, mixed inflammatory cells infiltrate and disruption of adipocytes, associated with microcalcification. Positive CD68 and negative AE1 / AE3 can help to distinguish fat necrosis from recurrent carcinoma of breast. Fat necrosis is a nonneoplastic inflammatory process and usually surgical treatment is not required.
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Reference: Fat necrosis of breast
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Reference: Fat necrosis of breast
Board review style question #2
- A 45 year old woman developed a palpable mass in the subareolar area of the left breast. Mammogram shows a cystic lesion with eggshell calcifications in the cyst wall. She reports a recent history of a car accident in which she had minor injuries and was wearing her seatbelt. Which of the following is the most likely sequela of the lesion?
- The cyst will often become infected and require surgical drainage
- The lesion will be replaced by varying degrees of fibrosis
- The lesion will eventually progress to invasive carcinoma if left untreated
- The lesion will grow and compress surrounding tissue
Board review style answer #2
B. The lesion will be replaced by varying degrees of fibrosis. Fat necrosis has three stages of evolution. The first stage is characterized by disruption of adipocytes following an inciting event. This can lead to local cyst formation with or without calcifications. In the intermediate stage, inflammatory cells phagocytose the necrotic adipocytes and fibroblasts proliferate. Eventually the fibroblasts replace the necrotic areas with varying degrees of fibrosis. Fat necrosis is a nonneoplastic inflammatory lesion that usually resolve or regress over time.
Comment Here
Reference: Fat necrosis of breast
Comment Here
Reference: Fat necrosis of breast
Fibroadenoma
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Cytology images | Positive stains | Negative stains | Molecular / cytogenetics description | Videos | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2 | Board review style question #3 | Board review style answer #3 | Board review style question #4 | Board review style answer #4Definition / general
- Benign biphasic tumor composed of a proliferation of both glandular epithelial and stromal components of the terminal duct lobular unit
Essential features
- Most common breast tumor in adolescent and young women
- Benign biphasic tumor comprised of glandular epithelium and specialized interlobular stroma of the terminal ductal lobular unit (Pathol Annu 1994;29:1)
- Can show a spectrum of histologic appearances; generally uniform in stromal cellularity and distribution of glandular and stromal elements within a given lesion (an important distinction from phyllodes tumor)
- Fibroadenomas with hypercellular stroma and prominent intracanalicular pattern can show morphologic overlap with benign phyllodes tumors, especially in needle biopsy specimens
Terminology
- Fibroadenoma, usual type fibroadenoma, adult type fibroadenoma
- Myxoid fibroadenoma
- Juvenile fibroadenoma
- Complex fibroadenoma
ICD coding
- ICD-10: D24 - benign neoplasm of breast
Epidemiology
- Most common benign tumor of the female breast
- Most common breast tumor in adolescent and young women
- Can occur at any age, median age of 25 years (J R Coll Surg Edinb 1988;33:16)
- Juvenile fibroadenoma generally occurs in younger and adolescent patients < 20 years; reported in children at a very young age (Am J Surg Pathol 1985;9:730, Jpn J Clin Oncol 2011;41:260)
- Complex fibroadenoma reported in older patients with median age between 35 - 47 years (Am J Clin Pathol 2001;115:736, AJR Am J Roentgenol 2008;190:214)
- Myxoid fibroadenoma is associated with Carney complex (Am J Surg Pathol 1991;15:713)
- Increased relative risk (1.5 - 2.0) of subsequent breast cancer; relative risk is higher (3.1) in complex fibroadenomas; no increased risk for juvenile fibroadenoma (N Engl J Med 1994;331:10, Int J Cancer 1994;57:681, Breast J 2017;23:182)
Sites
- Breast
- Can occur in axilla accessory breast tissue
Etiology
- Increased risk associated with cyclosporine immunosuppression (Clin Nephrol 2004;61:151)
Clinical features
- Often presents as painless, firm, mobile, slow growing mass
- Usually solitary, can be multiple and bilateral
- Usually less than 3 cm in diameter but may grow to large size (AJR Am J Roentgenol 2008;190:214)
Diagnosis
- Histologic examination of involved tissue
Radiology description
- Sonographically seen usually as a round or oval mass, smooth margins with hypo or isoechoic features (Radiology 1989;172:671, Invest Radiol 1986;21:34, AJR Am J Roentgenol 1983;140:369)
- Can be associated with calcifications, especially in postmenopausal patients
Radiology images
Contributed by Mark R. Wick, M.D., Azadeh Khayyat, M.D. and Julie M. Jorns, M.D. (Case #533)
Mammogram
Images hosted on other servers:
Juvenile fibroadenoma
Case reports
- 12 year old girl with breast mass (Int J Surg Case Rep 2017;41:427)
- 16 year old girl with 28 cm left breast mass (BMJ Case Rep 2019;12:e227277)
- 17 year old girl with recurrent juvenile fibroadenoma (Medicine (Baltimore) 2018;97:e10765)
- 18 year old woman with mass in axilla accessory breast tissue (BMJ Case Rep 2015;2015:bcr2015209535)
- 35 year old woman with left breast mass (Breast Dis 2015;35:49)
- 37 year old woman with increased uptake of breast mass on PET scan (Clin Nucl Med 2017;42:145)
- 44 year old woman with bilateral breast masses (Oncol Lett 2015;10:1397)
- Premenopausal woman with family history of breast cancer was found to have a subcentimeter mass with calcifications on mammogram (Case of the month #533)
Treatment
- Management depends on patient risk factors and patient preference
- Conservative management with close clinical followup, especially if concordant radiology findings (Br J Surg 1987;74:857)
- Local surgical excision, especially if symptomatic (Am J Surg Pathol 1985;9:730)
- If atypia / neoplasia is found within a fibroadenoma, the surgical and systemic therapeutic management is specific and appropriate to the primary atypical / neoplastic lesion
Gross description
- Firm, well circumscribed, ovoid mass with bosselated surface, lobulations bulge above the cut surface, slit-like spaces
- May have mucoid or fibrotic appearance; can be calcified
Gross images
Contributed by Gary Tozbikian, M.D.
Well circumscribed tumor with bulging cut surface
Microscopic (histologic) description
- Well circumscribed, unencapsulated
- Biphasic tumor, proliferation of both glandular and stromal elements
- Glandular component
- 2 recognized growth patterns (of no clinical significance, both patterns may occur within a single lesion)
- Intracanalicular: glands are compressed into linear branching structures by proliferating stroma
- Pericanalicular: glands retain open lumens but are separated by expanded stroma
- Glandular elements have intact myoepithelial cell layer
- Often associated with usual type ductal hyperplasia, apocrine metaplasia, cyst formation or squamous metaplasia
- Rare mitotic activity can be observed in the glandular component, has no clinical significance
- 2 recognized growth patterns (of no clinical significance, both patterns may occur within a single lesion)
- Stromal component
- Generally uniform cellularity within a given lesion
- Collagen and bland spindle shaped stromal cells with ovoid or elongated nuclei
- Usually no mitotic activity; rare mitotic activity may be present in young or pregnant patients (Breast J 2017;23:182)
- No stromal atypia
- Stroma may show myxoid change or hyalinization
- May show multinucleated giants cells (Am J Surg Pathol 1986;10:823, Arch Pathol Lab Med 1994;118:912)
- Rarely benign heterologous stromal elements (adipose, smooth muscle, osteochondroid metaplasia)
- Fibroadenomas may be involved by mammary neoplasia (e.g. invasive breast carcinoma, ductal carcinoma in situ, lobular carcinoma in situ) and atypical epithelial proliferations (e.g. atypical ductal hyperplasia, atypical lobular hyperplasia) often as a result of spread from an adjacent lesion
- Variants
- Myxoid fibroadenoma
- Similar structure but with prominent myxoid stromal change composed of abundant pale, blue-gray extracellular matrix material
- Complex fibroadenoma
- Cysts > 3 mm, sclerosing adenosis, epithelial microcalcifications or papillary apocrine metaplasia (N Engl J Med 1994;331:10)
- Cellular fibroadenoma
- Diffuse stromal hypercellularity
- Juvenile fibroadenoma
- Increased stromal cellularity
- Increased epithelial hyperplasia with gynecomastoid-like micropapillary projections
- Fascicular stromal arrangement
- Pericanalicular growth pattern
- May show rapid growth and large size (Am J Surg Pathol 1985;9:730)
- Myxoid fibroadenoma
Microscopic (histologic) images
Contributed by Gary Tozbikian, M.D., Debra Zynger, M.D., Azadeh Khayyat, M.D. and Julie M. Jorns, M.D. (Case #533)
Fibroadenoma
Fibroadenoma
Complex fibroadenoma
Myxoid fibroadenoma
Juvenile fibroadenoma
Cellular fibroadenoma
Fibroadenoma with ALH
Fibroadenoma with atypical ductal hyperplasia
Fibroadenoma with atypical ductal hyperplasia
Multinucleated stromal cells
Ductal carcinoma in situ (DCIS), solid type, with microcalcifications, confined to a fibroadenoma; lobular neoplasia (atypical lobular hyperplasia / lobular carcinoma in situ), with involvement of a fibroadenoma
Virtual slides
Contributed by Andrey Bychkov, M.D., Ph.D.
Fibroadenoma
Cytology description
- Usual (adult type) fibroadenoma: biphasic population composed of abundant spindle stromal cells and naked nuclei, epithelium arranged in antler horn clusters or fenestrated honeycomb sheets (Am J Clin Pathol 1988;89:707, Acta Cytol 1991;35:695)
- Myxoid fibroadenoma: high cellularity with stroma and epithelium embedded in myxoid background (Diagn Cytopathol 2001;25:278, Am J Clin Pathol 2003;120:194)
Cytology images
Contributed by Areej M. Al Nemer, M.D.
Branching sheets
Bare nuclei
Bland stromal fragments
Images hosted on other servers:
Diff-Quik
Pap
Positive stains
- Stromal cells
- Epithelial cells
Negative stains
- Stromal cells
- Cytokeratins
- Ki67 proliferation index is lower compared with phyllodes tumors but some overlap with benign phyllodes tumor (Am J Clin Pathol 2005;124:342, Histopathology 2010;57:220, Int J Surg Pathol 2008;16:137, Pathol Res Pract 1998;194:97)
Molecular / cytogenetics description
- MED12 exon 2 mutations in usual (adult type) fibroadenoma; likely a driver genetic event (NPJ Breast Cancer 2016;2:16035, Nat Genet 2014;46:877, Histopathology 2015;67:719)
- Myxoid fibroadenomas lack MED12 mutations (Histopathology 2017;71:626)
- RARA mutations (Nat Genet 2015;47:1341, J Pathol 2016;238:508)
- Cellular variant of fibroadenoma shows higher rates of mutation in PIK3CA and MAP3KI (Mod Pathol 2021;34:1320)
- Fewer mutations (e.g. MED12, TERT promoter, RB1, EGFR) compared with benign phyllodes tumor (Mod Pathol 2021;34:1320)
Videos
Fibroadenoma
Sample pathology report
- Breast, right, 2:00 zone 2, ultrasound guided core biopsy:
- Fibroadenoma
Differential diagnosis
- Phyllodes tumor:
- Well developed leaf-like architecture, with accompanied increased stromal cellularity
- Prominent mitotic activity ≥ 3/10 high power fields or the finding of 3 or more characteristic histologic features (stromal overgrowth, fat infiltration, stromal fragmentation, subepithelial stromal condensation, stromal nuclear pleomorphism) is predictive of phyllodes tumor (versus fibroadenoma) in core biopsy specimens (Am J Clin Pathol 2014;142:362)
- Hamartoma of breast:
- Integral adipose component
- Disordered but morphologically normal appearing ducts and lobules
- Tubular adenoma:
- Prominent pericanalicular adenosis-like epithelial proliferation with little intervening stroma
- Fibroadenomatoid changes (sclerosing lobular hyperplasia, fibroadenomatoid mastopathy):
- Generally does not form a clinically dominant mass
- Individual lobule or few groups of lobules with collagenized interlobular stroma and loss of interlobular stromal mucopolysaccharides (Hum Pathol 1984;15:336, Pathology 1987;19:393, Malays J Pathol 1991;13:101)
- Myxoma:
- Lacks glandular elements (versus myxoid fibroadenoma)
Board review style question #1
A 13 year old girl presents with a firm, palpable 3.5 cm breast mass. She undergoes an ultrasound guided biopsy and subsequent local excision showing a fibroepithelial lesion with circumscribed borders, uniformly increased stromal cellularity, glandular proliferation with pericanalicular growth pattern and prominent gynecomastoid-like usual type ductal hyperplasia. Rare mitotic activity (< 1/10 high power fields) is identified. Stromal cytologic atypia is not present. What is the correct diagnosis?
- Fibroadenoma
- Juvenile fibroadenoma
- Myxoid fibroadenoma
- Phyllodes tumor (benign)
- Phyllodes tumor (borderline)
Board review style answer #1
B. Juvenile fibroadenoma. The clinical presentation and histologic features are characteristic of a juvenile fibroadenoma.
Comment Here
Reference: Fibroadenoma
Comment Here
Reference: Fibroadenoma
Board review style question #2
A 25 year old woman presents with a 3 cm breast mass. An ultrasound guided biopsy shows a fibroepithelial lesion. Which histologic feature is consistent with a diagnosis of fibroadenoma?
- Circumscribed borders
- Marked stromal cytologic atypia
- Stromal condensation around glandular structures
- Stromal mitotic activity (7 - 8/10 high power fields)
- Stromal overgrowth
Board review style answer #2
A. Circumscribed borders. Fibroadenomas generally show noninfiltrative, circumscribed borders. The histologic features in answer choices B, C, D and E are observed in phyllodes tumors.
Comment Here
Reference: Fibroadenoma
Comment Here
Reference: Fibroadenoma
Board review style question #3
Which of the following is true about the breast lesion shown above?
- Displays infiltrative margins
- Most common benign tumor arising in the breast
- Occurs primarily in postmenopausal women
- Often has a brisk mitotic rate
- Stromal overgrowth is a key finding
Board review style answer #3
B. Most common benign tumor arising in the breast. This is a fibroadenoma.
Comment Here
Reference: Fibroadenoma
Comment Here
Reference: Fibroadenoma
Board review style question #4
Fibroadenomas harbor epithelial atypia or malignancy at approximately what rate?
- 0.2%
- 2%
- 20%
- 50%
Board review style answer #4
B. 2%. The classification and behavior of fibroepithelial tumors of the breast including fibroadenoma and phyllodes tumor is driven by the stroma. However, epithelial changes may be seen and are thought to occur by chance or are driven by unrelated risk factor(s). Thus, epithelial atypia and malignancy is uncommon, with a recent large study by Krishnamurthy et al. showing a rate of ~2% (Breast Dis 2019;38:97). See Case #533 for more information.
Comment Here
Reference: Fibroadenoma
Comment Here
Reference: Fibroadenoma
Fibroadenomatoid change
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Diagrams / tables | Clinical features | Diagnosis | Laboratory | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Gross images | Frozen section description | Frozen section images | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Cytology images | Immunofluorescence description | Immunofluorescence images | Positive stains | Negative stains | Electron microscopy description | Electron microscopy images | Molecular / cytogenetics description | Molecular / cytogenetics images | Videos | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Benign, often incidental finding in a background of fibrocystic changes
- Lesion with features resembling a fibroadenoma but lacking sharp circumscription
Essential features
- Proliferation of intralobular stroma with the formation of stromal nodularity that often appears to blend in with the surrounding breast tissue
- Morphologically reminiscent of a fibroadenoma but not forming a well circumscribed mass
- May represent an incipient fibroadenoma
- Often multifocal and surrounded by fibrocystic changes
Terminology
- Also known as fibroadenomatous change, fibroadenomatoid hyperplasia, fibroadenomatoid mastopathy, fibroadenomatosis, sclerosing lobular hyperplasia
- Less frequently referred to as mixed lesion, reflecting the common association of fibroadenomatoid change and fibrocystic changes
ICD coding
- ICD-10: N60.2 - fibroadenosis of breast
Epidemiology
- F > M
- Mean age: 28 - 34 years
- Represents 5 - 7% of nonneoplastic surgical biopsies in one study; 8% of nonneoplastic breast diagnoses in another
- References: AJR Am J Roentgenol 1998;171:1331, Am J Epidemiol 1978;108:112, Hum Pathol 1984;15:336
Sites
- Most common site is the upper outer quadrant of the breast (Hum Pathol 1984;15:336)
Pathophysiology
- Proliferation of intralobular stroma
- May represent a stage in the evolution of a fibroadenoma, produced by the coalescence of fibroadenomatoid nodules
- Reference: Hum Pathol 1984;15:336
Etiology
- Unknown; possibly due to or influenced by reproductive hormones, similar to fibroadenoma
Diagrams / tables
No information provided
Clinical features
- May be detected by imaging modalities (see Radiology description below) as a palpable mass or incidentally in breast tissue sampled for a different lesion
Diagnosis
- Breast imaging modalities with core biopsy (stereotactic, ultrasound or MRI guided) or surgery followed by histologic examination of resected tissue
- References: AJR Am J Roentgenol 1995;165:291, AJR Am J Roentgenol 1998;171:1331
Laboratory
No information provided
Radiology description
- Hypoechoic mass
- Asymmetric increased density
- Suspicious granular clustered microcalcifications (more frequent in women > 50 years old)
- No suspicious radiographic findings in patient with palpable mass
- Complex cystic lesion
- Imaging findings in one study of fibroadenomatoid hyperplasia showed that 53% were well defined masses
- 33% had normal mammographic findings
- 13% had an asymmetric density
- 1% with mammographic calcifications
- References: AJR Am J Roentgenol 1995;165:291, AJR Am J Roentgenol 1998;171:1331, Hum Pathol 1984;15:336, J Ultrasound Med 2022;41:2071
Radiology images
Images hosted on other servers:
Well circumscribed nodule
Suspicious granular microcalcifications
Prognostic factors
- Widely considered to have no increased risk of malignancy
- Single study reported co-occurrence of fibroadenomatoid change and HER2 negative invasive breast carcinoma (PLoS One 2015;10:e0129500)
Case reports
- Boy with disorder of sexual development and breast development (Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2022;39:868)
- 12 year old girl with a 3 month history of enlarging right breast mass (Cytojournal 2006;3:8)
- 14 year old girl with a 3 month history of painless enlarging right breast lump (Acta Cytol 2001;45:765)
- 24 year old woman with a 7 cm mass (Gynecol Obstet Invest 2014;77:134)
- 69 year old man with heart failure treated with digoxin and spironolactone presents with bilateral gynecomastia (Am J Surg Pathol 1990;14:774)
Treatment
- No treatment required
Clinical images
No information provided
Gross description
- Lesion appears dense and poorly circumscribed on cut section
- Difficult to distinguish from fibrocystic changes by gross examination
- Reference: Malays J Pathol 1991;13:101
Gross images
No information provided
Frozen section description
No information provided
Frozen section images
No information provided
Microscopic (histologic) description
- Proliferation of intralobular stroma containing epithelial elements, sometimes closely resembling a microfibroadenoma or microfibroadenomata
- Stroma may appear loose and cellular or dense and hyalinized
- Often multifocal in a background of fibrocystic changes, including cysts and adenosis
- Periphery may appear to blend into the surrounding breast tissue
- References: Hum Pathol 1984;15:336, Pathology 1987;19:393, Malays J Pathol 1991;13:101, AJR Am J Roentgenol 1998;171:1331, Schnitt: Biopsy Interpretation of the Breast, 3rd Edition, 2017
Microscopic (histologic) images
Contributed by Melissa Alexander, M.D., Ph.D.
Edges blending with surrounding
Vague stromal nodularity
Poorly circumscribed
Background fibrocystic change
Multiple nodules
Multiple nodules
Loose stroma versus dense hyalinized
Dense stroma
Loose versus dense nodules
Loose stroma, compressed glands
Fibroadenomatoid nodule, compressed glands
Virtual slides
No information provided
Cytology description
- Elements similar to fibroadenoma, including stromal fragments; however, lacking other elements of fibroadenoma, including branching antler horn epithelial clusters (Cytojournal 2006;3:8, Acta Cytol 2001;45:765)
Cytology images
No information provided
Immunofluorescence description
No information provided
Immunofluorescence images
No information provided
Positive stains
No information provided
Negative stains
No information provided
Electron microscopy description
No information provided
Electron microscopy images
No information provided
Molecular / cytogenetics description
No information provided
Molecular / cytogenetics images
No information provided
Videos
No information provided
Sample pathology report
- Breast, right, core biopsy:
- Fibroadenomatoid change associated with calcifications (see comment)
- Comment: Correlation with specimen radiograph was performed.
Differential diagnosis
- Fibroadenoma:
- Well circumscribed mass comprised of stromal and epithelial components sharply demarcated from the surrounding breast parenchyma
Additional references
Board review style question #1
A poorly circumscribed nodular focus was identified in a breast needle core biopsy, shown in the image above. Which of the following is the best diagnosis for this histologic finding?
- Apocrine metaplasia
- Duct ectasia
- Columnar cell change
- Fibroadenomatoid change
- Microcalcifications
Board review style answer #1
Board review style question #2
Which of the following is true regarding fibroadenomatoid change?
- Arises from interlobular stroma
- It is considered a precursor lesion to invasive carcinoma
- Often presents in a background of fibrocystic changes
- Sharply circumscribed lesion on cut section
- Treatment is surgical excision
Board review style answer #2
C. Often presents in a background of fibrocystic changes
Comment Here
Reference: Fibroadenomatoid change
Comment Here
Reference: Fibroadenomatoid change
Fibroadenomatoid change
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1Definition / general
- Benign, often incidental finding in a background of fibrocystic changes
- Lesion with features resembling a fibroadenoma but lacking sharp circumscription
Essential features
- Proliferation of intralobular stroma with the formation of stromal nodularity that often appears to blend in with the surrounding breast tissue
- Morphologically reminiscent of a fibroadenoma but not forming a well circumscribed mass
- May represent an incipient fibroadenoma
- Often multifocal and surrounded by fibrocystic changes
Terminology
- Also known as fibroadenomatous change, fibroadenomatoid hyperplasia, fibroadenomatoid mastopathy, fibroadenomatosis, sclerosing lobular hyperplasia
- Less frequently referred to as mixed lesion, reflecting the common association of fibroadenomatoid change and fibrocystic changes
ICD coding
- ICD-10: N60.2 - fibroadenosis of breast
Epidemiology
- F > M
- Mean age 28 - 34 years
- Represents 5 - 7% of nonneoplastic surgical biopsies in one study; 8% of nonneoplastic breast diagnoses in another
- References: AJR Am J Roentgenol 1998;171:1331, Am J Epidemiol 1978;108:112, Hum Pathol 1984;15:336
Sites
- Most common site is the upper outer quadrant of the breast (Hum Pathol 1984;15:336)
Pathophysiology
- Proliferation of intralobular stroma
- May represent a stage in the evolution of a fibroadenoma, produced by the coalescence of fibroadenomatoid nodules
- Reference: Hum Pathol 1984;15:336
Etiology
- Unknown; possibly due to or influenced by reproductive hormones, similar to fibroadenoma
Clinical features
- May be detected by imaging modalities (see Radiology below), as a palpable mass or incidentally in breast tissue sampled for a different lesion
Diagnosis
- Breast imaging modalities with core biopsy (stereotactic, ultrasound or MRI guided) or surgery followed by histologic examination of resected tissue
- References: AJR Am J Roentgenol 1995;165:291, AJR Am J Roentgenol 1998;171:1331
Radiology description
- Hypoechoic mass
- Asymmetric increased density
- Suspicious granular clustered microcalcifications (more frequent in women > 50 years old)
- No suspicious findings in patient with palpable mass
- Imaging findings in one study of fibroadenomatoid hyperplasia showed 53% were well defined mass
- 33% had normal mammographic findings
- 13% had an asymmetric density
- 1% with mammographic calcifications
- References: AJR Am J Roentgenol 1995;165:291, AJR Am J Roentgenol 1998;171:1331, Hum Pathol 1984;15:336
Radiology images
Images hosted on other servers:
Well circumscribed nodule
Suspicious granular microcalcifications
Prognostic factors
- No increased risk of malignancy
Case reports
- 12 year old girl with 3 month history of enlarging right breast mass (Cytojournal 2006;3:8)
- 14 year old girl with a 3 month history of painless enlarging right breast lump (Acta Cytol 2001;45:765)
- 24 year old woman with 7 cm mass (Gynecol Obstet Invest 2014;77:134)
- 69 year old man with heart failure treated with digoxin and spironolactone presents with bilateral gynecomastia (Am J Surg Pathol 1990;14:774)
Treatment
- No treatment required
Gross description
- Lesion appears dense and poorly circumscribed on cut section
- Difficult to distinguish from fibrocystic changes by gross examination
- Reference: Malays J Pathol 1991;13:101
Microscopic (histologic) description
- Proliferation of intralobular stroma containing epithelial elements, sometimes closely resembling a microfibroadenoma or microfibroadenomata
- Stroma may appear loose and cellular or dense and hyalinized
- Often multifocal in a background of fibrocystic changes, including cysts and adenosis
- Periphery may appear to blend into the surrounding breast tissue
- References: Hum Pathol 1984;15:336, Pathology 1987;19:393, Malays J Pathol 1991;13:101, AJR Am J Roentgenol 1998;171:1331, Schnitt: Biopsy Interpretation of the Breast, 3rd Edition, 2017
Microscopic (histologic) images
Contributed by Melissa Alexander, M.D., Ph.D.
Edges blending with surrounding
Vague stromal nodularity
Poorly circumscribed
Background fibrocystic change
Multiple nodules
Multiple nodules
Loose stroma versus dense hyalinized
Dense stroma
Loose versus dense nodules
Loose stroma, compressed glands
Fibroadenomatoid nodule, compressed glands
Cytology description
- Elements similar to fibroadenoma, including stromal fragments; however, lacking other elements of fibroadenoma including branching antler horn epithelial clusters (Cytojournal 2006;3:8, Acta Cytol 2001;45:765)
Sample pathology report
- Breast, right, core biopsy:
- Fibroadenomatoid change associated with calcifications (see comment)
- Comment: Correlation with specimen radiograph was performed.
Differential diagnosis
- Fibroadenoma:
- Well circumscribed mass comprised of stromal and epithelial components sharply demarcated from the surrounding breast parenchyma
Additional references
Board review style question #1
A poorly circumscribed nodular focus was identified in a breast needle core biopsy, shown in the image. The best diagnosis for this histologic finding is which of the following?
- Apocrine metaplasia
- Duct ectasia
- Columnar cell change
- Fibroadenomatoid change
- Microcalcifications
Board review style answer #1
Fibromatosis
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Frozen section description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Positive stains | Negative stains | Molecular / cytogenetics description | Videos | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Low grade infiltrative spindle cell neoplasm composed of fibroblasts and myofibroblasts
Essential features
- Rare low grade neoplasm with infiltrative pattern
- Bland spindle cells arranged in long intersecting fascicles within a collagenous stroma
- Characterized by alterations in WNT / beta catenin pathway
- Does not metastasize but can locally recur after surgical excision
Terminology
- Desmoid tumor, aggressive fibromatosis, desmoid type fibromatosis, extra-abdominal desmoid
ICD coding
- ICD-O: 8821/1 - desmoid type fibromatosis
- ICD-11: 2F75 & XH13Z3 - neoplasms of uncertain behavior of breast & aggressive fibromatosis
Epidemiology
- < 0.2% of tumors of the breast
- F > M, third through fifth decades
- Reference: Breast Care (Basel) 2021;16:77
Sites
- May be primary to the breast or be secondary extension into the breast from the chest wall
Pathophysiology
- Up to 95% harbor CTNNB1 activating mutation (sporadic); APC gene inactivating mutation responsible for remainder of cases (hereditary) (Cancers (Basel) 2020;12:1851)
- Through the WNT / beta catenin pathway, these mutations motivate cells to proliferate while destabilizing beta catenin that then accumulates within the nucleus (J Clin Oncol 2018;36:202)
Etiology
- Can consequently occur after surgery, trauma or rarely, after breast implants (Breast Care (Basel) 2021;16:77, Cancers (Basel) 2020;12:1851)
- Estrogen thought to influence growth (Breast Care (Basel) 2021;16:77, Indian J Surg Oncol 2020;11:71)
- Can be associated with Gardner syndrome or familial adenomatous polyposis
Clinical features
- Slow growing, often self detected firm mass
Diagnosis
- May arise as palpable mass that appears as abnormality on mammography
- Rarely presents with breast pain, nipple discharge and skin retraction (Breast Care (Basel) 2021;16:77)
Radiology description
- Imaging may show well circumscribed mass or poorly defined / spiculated mass that can be mistaken for malignant process (Breast Care (Basel) 2021;16:77)
Radiology images
Contributed by Carissa LaBoy, M.D.
Mammogram of right breast
Ultrasound of right breast
Mammogram of breast mass
Ultrasound of left breast
Prognostic factors
- Does not metastasize (Pathologica 2019;111:344)
- Locally aggressive, local recurrence rates reported in 29% to as high as 40 - 50% of cases after excision (Ann Surg Oncol 2008;15:274, J Clin Oncol 2018;36:202)
- Margin status not reliable risk factor for recurrence (J Clin Oncol 2018;36:202, Cancers (Basel) 2020;12:1851)
Case reports
- 25 year old woman with indentation and pain in left inframammary fold (Radiol Case Rep 2018;13:1174)
- 31 year old woman with dimpling in the left breast (Int J Surg Case Rep 2017;41:392)
- 36 year old woman with rapidly growing lump in right breast (Oncol Lett 2017;14:1433)
- 42 year old woman with breast implants and palpable lump in left breast (Radiol Case Rep 2017;12:431)
- 60 year old man with 2 year history of right breast mass (Chirurgia (Bucur) 2019;114:664)
Treatment
- Surgical local excision
- Other options include active surveillance for asymptomatic patients and systemic therapy, such as adjuvant radiation for patients with multiple recurrences (Breast Care (Basel) 2021;16:77, Cancers (Basel) 2020;12:1851)
Gross description
- Well to poorly circumscribed mass of variable size (from < 1 cm to > 10 cm), with white-gray whorled or trabeculated cut surface
Gross images
Images hosted on other servers:
White trabeculated cut surface
Chest wall mass
Frozen section description
- Bland spindle cells seen on intraoperative frozen section would prompt benign diagnosis
Microscopic (histologic) description
- Long intersecting fascicles composed of bland spindle cells with indistinct borders, hyperchromatic nuclei with occasional nucleoli and eosinophilic cytoplasm
- Cells infiltrate normal ducts and lobules, adipose tissue and skeletal muscle, thus mimicking invasive process
- Mitosis is rare
- Background stroma has thickened collagen resembling keloid
- Older lesions may calcify
- Lymphoid aggregates may be seen at the periphery of the lesion
- Reference: Pathologica 2019;111:344
Microscopic (histologic) images
Contributed by Carissa LaBoy, M.D.
Infiltrative breast mass
Cells entrapping normal ducts
Cells in collagenous stroma
Bland spindle cells
Positive margin on excision
Beta catenin positivity
Beta catenin nuclear positivity
CD34 negative spindle cells
Pancytokeratin negative spindle cells
Cytology description
- Fine needle aspiration is difficult and often yields fibrous nondiagnostic material
- When successful, fine needle aspiration shows bland spindle cells with hyperchromatic nuclei and wispy cytoplasm within abundant stroma (Cancer 2007;111:166)
Cytology images
Images hosted on other servers:
Fine needle aspiration of fibromatosis
Fine needle aspiration of fibromatosis
Positive stains
- Beta catenin (80% of cases) (Pathologica 2019;111:344)
- Not specific, can also be positive in spindle cell carcinomas, metaplastic breast carcinomas and benign phyllodes tumors (Breast Care (Basel) 2021;16:77)
- SMA
- Calponin
Negative stains
- Pancytokeratin
- p63
- CD34
- ER
- PR
- HER2
- Reference: Breast Care (Basel) 2021;16:77
Molecular / cytogenetics description
- Sequencing can identify activating CTNNB1 mutation or inactivating APC mutation in 79% of cases (Hum Pathol 2002;33:39, Curr Opin Oncol 2017;29:268)
- Trisomies in chromosome 8 or 20 occur, significance is unknown (J Clin Oncol 2018;36:202)
Videos
Review of fibromatosis
Sample pathology report
- Left breast, needle localized lumpectomy:
- Fibromatosis, measuring 2.8 cm in greatest dimension
- Margins negative with tumor > 0.5 cm from all margins
Differential diagnosis
- Scar:
- Focally infiltrative lesion composed of bland spindle cells with associated histiocytes, foreign body giant cell reaction and lymphocytes
- History of prior procedure
- Nodular fasciitis:
- Focally infiltrative lesion composed of spindle cells forming short fascicles or storiform pattern with increased mitotic activity
- Does not display nuclear beta catenin staining
- Dermatofibrosarcoma protuberans:
- Focally infiltrative lesion with spindle cells in storiform growth pattern and low mitotic activity
- Low grade fibromatosis-like metaplastic carcinoma:
- Infiltrative lesion composed of spindle to epithelioid cells arranged in small clusters with low mitotic activity
- Cytokeratin and p63 positive
- Low grade myofibroblastic sarcoma:
- Focally infiltrative lesion composed of spindle cells arranged in fascicles
- Mild to moderate nuclear pleomorphism and brisk mitosis
- Myofibroblastoma:
- Spindle cells arranged in short, disorganized fascicles with intersecting thick collagen bands resembling keloid; do not typically entrap normal ducts or lobules
- Benign phyllodes tumor:
- Well circumscribed mass with hyperplastic epithelium within a hypercellular stroma composed of spindle cells with mild atypia and low mitotic activity
Board review style question #1
What is the pattern of beta catenin immunohistochemical staining for fibromatosis pictured above?
- Cytoplasmic
- Cytoplasmic and membranous
- Membranous
- Nuclear
Board review style answer #1
D. Nuclear. The pathophysiology of fibromatosis involves an activating CTNNB1 mutation in sporadic cases and an APC gene inactivating mutation in hereditary cases. Both types of mutations activate the WNT / beta catenin pathway, motivating cells to proliferate while degrading beta catenin, which then accumulates within the nucleus. This in turn yields a nuclear pattern of staining by immunohistochemistry.
Comment Here
Reference: Fibromatosis
Comment Here
Reference: Fibromatosis
Board review style question #2
Which of the following is correct regarding the histologic features and clinical behavior of breast fibromatosis?
- Chemotherapy is the preferred treatment due to high mitotic activity
- Metastasis is a common feature of this tumor
- Necrosis and pleomorphism make this a high grade tumor
- Tumor has a high frequency of local recurrence
Board review style answer #2
D. Tumor has a high frequency of local recurrence. Breast fibromatosis is a low grade tumor consisting of bland spindle cells with rare or no mitotic activity and no metastatic potential. However, due to its infiltrative nature, this tumor has a tendency to locally recur after surgical excision.
Comment Here
Reference: Fibromatosis
Comment Here
Reference: Fibromatosis
Fibromatosis-like
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Positive stains | Negative stains | Electron microscopy description | Electron microscopy images | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Variant of metaplastic carcinoma with low grade, bland spindle cells histologically resembling fibromatosis
- May arise de novo or in association with papillary or sclerosing lesions
- High propensity for local recurrence but lymph node and distant metastases are rare
- May represent a distinct subtype as these tumors do not share similar genomic alterations with other types of metaplastic carcinomas
Essential features
- Variant of metaplastic carcinoma composed of cytologically bland spindle cells resembling fibromatosis within abundant stromal collagen
- Immunohistochemical stains needed to establish epithelial differentiation (cytokeratins, p63) since in situ and conventional type invasive breast carcinoma are typically absent
Terminology
- Low grade fibromatosis-like metaplastic carcinoma
- Fibromatosis-like spindle cell metaplastic carcinoma
ICD coding
- ICD-O: 8575/3 - metaplastic carcinoma, NOS
- ICD-11: 2C6Y & XH0RD4 - metaplastic carcinoma of breast & metaplastic carcinoma, NOS
Epidemiology
- Rare; 70 reported cases in the literature (Virchows Arch 2021 Jul 22 [Epub ahead of print])
- Women > 50 years old (Virchows Arch 2021 Jul 22 [Epub ahead of print])
Sites
- Breast, unilateral
Pathophysiology
- Unknown; may arise in association with papillary or sclerosing lesions
Etiology
- Unknown
Clinical features
- Detected as solitary palpable mass; increasingly detected by imaging (Virchows Arch 2021 Jul 22 [Epub ahead of print])
Diagnosis
- Core needle biopsy or surgical excision
Radiology description
- Variable appearance: round, oval, lobular or irregularly shaped; densely solid, heterogeneous or cystic parenchyma; well circumscribed or irregular / spiculated shaped (Arch Pathol Lab Med 2015;139:552)
- Calcifications uncommon
Radiology images
Images hosted on other servers:
Mammogram, microlobulated high density mass
Ultrasound, hypoechoic mass
MRI, irregular mass with heterogeneous enhancement
Prognostic factors
- Low grade variant of spindle cell carcinoma of the breast, with a favorable prognosis compared to other metaplastic carcinoma variants (Arch Pathol Lab Med 2015;139:552)
- High risk of local recurrence (Cancer 1999;85:2170, Am J Surg Pathol 2001;25:1009)
- Lymph node and distant metastases are rare (Cancer 1999;85:2170, Am J Surg Pathol 2001;25:1009)
Case reports
- 56 year old woman with fibromatosis-like metaplastic carcinoma (Surg Case Rep 2021;7:16)
- 65 year old woman with self palpated lump (Diagn Pathol 2020;15:20)
- 77 year old woman with fibromatosis-like metaplastic carcinoma and adjacent papilloma (World J Surg Oncol 2007;5:24)
Treatment
- Surgical excision with adequately excised margins
- Axillary dissection, chemotherapy and radiation therapy likely not necessary (Cancer 1999;85:2170, Am J Surg Pathol 2001;25:1009)
Gross description
- White, firm, 2 - 3 cm in size (range 1 - 7 cm), well circumscribed or irregular borders, rarely cystic, never encapsulated (Arch Pathol Lab Med 2015;139:552, Virchows Arch 2021 Jul 22 [Epub ahead of print])
- Necrosis, hemorrhage and calcifications not typical (Arch Pathol Lab Med 2015;139:552)
Microscopic (histologic) description
- Bland spindle cell tumor resembling desmoid type fibromatosis
- Characterized by proliferation of spindle shaped, fibroblast-like and myofibroblast-like cells arranged in interlacing fascicles with irregular infiltrative margins into surrounding breast parenchyma (Virchows Arch 2021 Jul 22 [Epub ahead of print])
- Minimal nuclear pleomorphism: nuclei may vary from thin, spindled with tapered ends to more plump, round to oval with discrete nucleoli (Virchows Arch 2021 Jul 22 [Epub ahead of print])
- Mitotic activity absent or rare (Virchows Arch 2021 Jul 29 [Epub ahead of print])
- Usually lacks in situ and conventional invasive breast carcinoma components
- Background stroma can be fibrotic, sclerotic, collagenized
- Associated stromal lymphocytic infiltrates common, often present at the periphery (Am J Surg Pathol 2001;25:1009)
- Squamous or glandular elements may be seen but should be a minor component (< 5% tumor area) (Arch Pathol Lab Med 2015;139:552)
- May be associated / arising from sclerosing lesions such as radial scars / complex sclerosing lesions and papillary lesions (Mod Pathol 2003;16:893)
Microscopic (histologic) images
Contributed by Kristen E. Muller, D.O. and Julie M. Jorns, M.D.
Fibromatosis-like metaplastic carcinoma
Squamous and glandular elements
Fascicular arrangement
Bland spindle cells
Round cells with nucleoli
Focal squamous and glandular elements
Infiltrative border
p63
CK MNF 116
Virtual slides
Images hosted on other servers:
Breast fibromatosis-like metaplastic carcinoma
Cytology description
- Low cellularity smear with clusters of round to oval and spindle shape cells with low grade, bland nuclear features (Acta Cytol 2010;54:712)
Positive stains
- Expression of epithelial markers; panel of cytokeratin antibodies (broad spectrum and high molecular weight keratins) suggested since tumor cells can show focal to diffuse cytokeratin expression
- p63
- Myoepithelial markers may show scattered expression (CD10, calponin, SMA)
- References: Arch Pathol Lab Med 2015;139:552, Virchows Arch 2021 Jul 22 [Epub ahead of print]
Negative stains
- ER, PR, HER2
- Beta catenin (nuclear) expression
- References: Arch Pathol Lab Med 2015;139:552, Virchows Arch 2021 Jul 22 [Epub ahead of print]
Electron microscopy description
- Tumor cells show fibroblastic, myoepithelial and epithelial features with peripheral villous processes with a focal basal lamina and intercellular junctions (World J Surg Oncol 2007;5:24)
Electron microscopy images
Images hosted on other servers:
Fibroblastic, myoepithelial and epithelial features
Molecular / cytogenetics description
- PIK3CA and TERT promoter mutations common (J Clin Pathol 2021 May 5 [Epub ahead of print])
- Low genomic instability, common 9p21.3 loss in one study (2 of 3 tumors tested), do not share copy number alterations with other metaplastic carcinoma types (J Clin Pathol 2015;68:362)
- Claudin low phenotype (Virchows Arch 2014;465:185)
Sample pathology report
- Breast, right, partial mastectomy:
- Fibromatosis-like spindle cell metaplastic carcinoma (see comment and synoptic report for additional details and staging)
- Comment: H&E sections show an infiltrative spindle cell tumor arranged in long sweeping fascicles. The lesional cells lack significant nuclear atypia and mitotic activity is scarce. Conventional in situ (DCIS) and invasive carcinoma are not identified. Immunohistochemical staining shows that the tumor cells are positive for multiple cytokeratins (CK5, CK MNF 116, CK AE1 / AE3) and p63. The morphology and immunoprofile are consistent with fibromatosis-like metaplastic carcinoma.
Differential diagnosis
- Bland spindle cell lesions:
- Fibromatosis:
- Beta catenin nuclear staining, CTNNB1 mutations
- Lacks focal overt epithelial (glandular or squamous) components
- Negative for keratins and p63
- Myofibroblastoma:
- Pseudoangiomatous stromal hyperplasia (PASH):
- Scar:
- Fibromatosis:
Board review style question #1
The lesion depicted in the image was taken from a 67 year old woman with a 2 cm mass. Which immunohistochemical panel supports a diagnosis of fibromatosis-like metaplastic carcinoma?
- ER positive, CD34 negative, beta catenin cytoplasmic expression
- ER positive, CD34 negative, beta catenin nuclear expression
- ER negative, CK AE1 / AE3 negative, beta catenin cytoplasmic expression
- ER negative, CK AE1 / AE3 positive, beta catenin cytoplasmic expression
Board review style answer #1
D. ER negative, CK AE1 / AE3 positive, beta catenin cytoplasmic expression. Fibromatosis-like metaplastic carcinoma shows the following immunoprofile: cytokeratin positive (typically high molecular weight and broad spectrum keratins), p63 positive, ER, PR and HER2 negative and are CD34 negative. A distinguishing factor in differentiating this lesion with desmoid type fibromatosis is the lack of nuclear beta catenin expression that is characteristic of fibromatosis.
Comment Here
Reference: Fibromatosis-like metaplastic carcinoma
Comment Here
Reference: Fibromatosis-like metaplastic carcinoma
Board review style question #2
The lesion depicted in the image was taken from a 72 year old woman with a 3 cm mass. The lesional cells showed scattered expression of CK5/6 and p63. Focal squamous differentiation was seen, which comprised approximately 2% of the tumor. Which statement is true regarding this lesion?
- These tumors typically lack cytologic atypia and conspicuous mitoses
- This variant is an unfavorable pattern of metaplastic breast carcinoma with frequent lymph node metastases
- This variant is commonly associated with conventional invasive ductal carcinoma or ductal carcinoma in situ
- This variant shares similar molecular alterations with other variants of metaplastic breast carcinoma
Board review style answer #2
A. These tumors typically lack cytologic atypia and conspicuous mitoses. The photo and vignette describe a fibromatosis-like metaplastic breast carcinoma. These tumors can histologically mimic desmoid type fibromatosis and are composed of bland spindle cells arranged in long sweeping fascicles with infrequent mitotic activity. Focal glandular and squamous elements can be present; however, conventional invasive carcinoma and ductal carcinoma in situ are rarely present. Compared to other variants of metaplastic breast carcinomas, fibromatosis-like metaplastic carcinoma portends a more favorable prognosis with infrequent lymph node and distant metastases. These tumors show low genomic instability and do not share copy number alterations with other metaplastic carcinoma types.
Comment Here
Reference: Fibromatosis-like metaplastic carcinoma
Comment Here
Reference: Fibromatosis-like metaplastic carcinoma
Flat epithelial atypia
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Negative stains | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Introduced by World Health Organization (WHO) Working Group on Pathology and Genetics of Tumours of the Breast to encompass columnar cell lesions with low grade / monomorphic cytologic atypia that lack architectural features of atypical ductal hyperplasia (ADH) or low grade ductal carcinoma in situ (LG DCIS)
Essential features
- Atypical epithelial proliferation with one to several layers of disorganized, monotonous, low columnar to cuboidal cells without architectural atypia
Terminology
- WHO acceptable:
- Flat epithelial atypia
- Also columnar alteration with atypia (columnar cell change with atypia or columnar cell hyperplasia with atypia)
- Not recommended by WHO:
- Low grade clinging carcinoma (monomorphous type)
- Atypical cystic lobules
- Atypical lobules type A
- Other (historical):
- Flat ductal intraepithelial neoplasia grade 1A (DIN1A)
- Atypical columnar alternation with prominent apical spouts and secretions
ICD coding
Epidemiology
- Seen in 3.8 - 10% of core needle biopsy samples (Am J Clin Pathol 2009;131:802)
- Radiologically classified as B3 - uncertain malignant potential (Hum Pathol 2010;41:522)
Sites
- Breast terminal duct lobular units (TDLUs)
Etiology
- Biology still being investigated - may be an early neoplastic breast lesion (Semin Diagn Pathol 2010;27:37)
- Mitochondrial DNA sequencing and phylogenetic tree clustering revealed direct transitions between flat epithelial atypia and low grade ductal carcinoma in situ in 10 of 10 cases, supporting the interpretation of flat epithelial atypia as part of the low grade pathway in the development of breast cancer (Am J Surg Pathol 2012;36:1247)
- Shares features with other nonobligate precursor lesions (atypical ductal hyperplasia, atypical lobular hyperplasia, classic lobular carcinoma in situ and low grade ductal carcinoma in situ), supporting the low grade breast neoplasia pathway (Surg Pathol Clin 2018;11:177)
Clinical features
- Diagnosis is reproducible with available histologic diagnostic criteria (Mod Pathol 2006;19:172)
- Underdiagnosed; often coexists with lobular neoplasia (Histopathology 2007;50:859)
- Associated with tubular carcinoma (Am J Surg Pathol 2007;31:417)
Diagnosis
- Imaging guided (frequently stereotactic due to mammographically detected calcifications) needle core or surgical excisional biopsy with tissue histologic examination
Radiology description
- Grouped amorphous calcifications on mammography (frequent) (AJR Am J Roentgenol 2011;197:740)
- No radiologic correlate / incidental (occasional)
Radiology images
Contributed by Julie M. Jorns, M.D. and Shadie Majidi, M.D.
Calcifications corresponding to FEA
Calcifications, craniocaudal view
Calcifications, mediolateral view
Prognostic factors
- Subsequent excision after core biopsy shows atypical ductal hyperplasia, atypical lobular hyperplasia, ductal carcinoma in situ or invasive carcinoma in 5 - 15%
- Risk for ductal carcinoma in situ / invasive carcinoma after core biopsy varies:
- Slightly increased warranting follow up (Virchows Arch 2007;451:883, Breast 2014;23:352)
- Similar to traditional atypical ductal hyperplasia warranting excision (Hum Pathol 2007;38:35, J Clin Pathol 2011;64:1001, Virchows Arch 2012;461:419)
- Warranting excision if > 1 cm (J Radiol 2006;87:1671)
- Clonally related to invasive tubular carcinoma and thought to be a nonobligate precursor (Am J Surg Pathol 2009;33:1646)
Case reports
- 47 year old woman with sonographic features of flat epithelial atypia manifesting as a nonmass-like lesion (Am J Case Rep 2019;20:340)
Treatment
- No consensus on whether to excise after biopsy diagnosis of pure flat epithelial atypia
- Recommended:
- See Breast J 2010;16:55, Am J Clin Pathol 2009;131:802, Breast Cancer Res Treat 2011;125:121, Ann Surg Oncol 2013;20:133
- Or consider since upgrade risk is not negligible (Ann Clin Lab Sci 2009;39:270)
- If residual microcalcification / lesion present due to possibility of atypical ductal hyperplasia / atypical lobular hyperplasia (17.2%) or ductal carcinoma in situ (5.4%) or if size > 1 cm (Breast J 2014;20:606, Breast Cancer 2015;22:634, J Radiol 2006;87:1671)
- See Breast J 2010;16:55, Am J Clin Pathol 2009;131:802, Breast Cancer Res Treat 2011;125:121, Ann Surg Oncol 2013;20:133
- Not recommended:
- If pure flat epithelial atypia and 9 or 11 gauge biopsy has removed most of small radiologic target (Am J Surg Pathol 2009;33:1078, Clin Breast Cancer 2013;13:450)
- If only low radiologic risk calcifications are present (Mod Pathol 2009;22:762)
- If concordant pathology and imaging results and patient has serial breast imaging and no prior / concurrent carcinoma (Mayo Clin Proc 2014;89:536, Eur J Surg Oncol 2020;46:235, Am J Surg Pathol 2020;44:182)
- In general, according to some authors, due to insufficient data for evidence based guidelines (Cancer 2015;121:1548)
- Recommended:
Gross description
- No discernible lesion (typically a microscopic finding only)
Microscopic (histologic) description
- Atypia that does not fulfill criteria of atypical ductal hyperplasia or low grade ductal carcinoma in situ due to flat growth pattern (i.e. cytologic atypia and lack of architectural atypia)
- Distention of terminal duct lobular unit with dilated glands
- Glands usually more blue than normal terminal duct lobular units at low power
- Frequent secretions and calcifications within cystically dilated glands
- Atypical epithelial proliferation with lack of regular orientation perpendicular to basement membrane
- One to several layers of low columnar or cuboidal cells with low grade cytologic atypia resembling low grade ductal carcinoma in situ
- Increased nuclear:cytoplasmic ratio (imparts blue low power appearance)
- Prominent apical tufting (snouts)
- Nuclei are usually round with variably prominent nucleoli
- Apocrine features such as eosinophilic cytoplasm may be present
Microscopic (histologic) images
Contributed by Julie M. Jorns, M.D.
Bluer appearance
Luminal secretions
Lack of polarity
Microcalcifications
Apocrine features
Apocrine
features and
luminal secretions
Prominent nucleoli
Cytology description
- Flat sheets of atypical cells with enlarged nuclei, distinct cell borders; indistinguishable from well differentiated in situ and invasive carcinoma (Diagn Cytopathol 2007;35:73)
Positive stains
Negative stains
Molecular / cytogenetics description
- Phosphatidylinositol 3 kinase catalytic subunit (P13KCA) mutations frequently observed similar to other breast epithelial proliferations (Mod Pathol 2014;27:740)
Sample pathology report
- Right breast, core biopsy:
- Flat epithelial atypia (FEA) with microcalcifications
Differential diagnosis
- Atypical ductal hyperplasia:
- Architectural features of atypical ductal hyperplasia (arcades / bridges / papillations / fenestrations) are present
- Lacks prominent apical snouts
- Columnar cell change:
- Lacks atypia (no prominent nucleoli, less basophilic)
- Ovoid nuclei perpendicular to basement membrane (no loss of polarity)
- Lacks prominent apical snouts
- Ductal carcinoma in situ, clinging type:
- Increased cytologic atypia
Additional references
Board review style question #1
Acceptable WHO (5th edition) terminology for the pictured lesion (H&E, 10x) includes
- Atypical cystic lobules
- Atypical lobules type A
- Flat epithelial atypia
- Low grade clinging carcinoma (monomorphous type)
Board review style answer #1
C. Flat epithelial atypia
The pictured lesion has classic features of flat epithelial atypia (FEA), at low power showing a terminal duct lobular unit (TDLU) with dilated, blue glands owing to increased nuclear:cytoplasmic ratios, which at high power show loss of orientation toward lumina and prominent apical tufting or snouts. Other current WHO accepted names include columnar cell alteration (change / hyperplasia) with atypia. Atypical cystic lobules, atypical lobules type A and low grade clinging carcinoma (monomorphous type) are terms that are not recommended for use by the WHO.
Comment Here
Reference: Flat epithelial atypia of breast
The pictured lesion has classic features of flat epithelial atypia (FEA), at low power showing a terminal duct lobular unit (TDLU) with dilated, blue glands owing to increased nuclear:cytoplasmic ratios, which at high power show loss of orientation toward lumina and prominent apical tufting or snouts. Other current WHO accepted names include columnar cell alteration (change / hyperplasia) with atypia. Atypical cystic lobules, atypical lobules type A and low grade clinging carcinoma (monomorphous type) are terms that are not recommended for use by the WHO.
Comment Here
Reference: Flat epithelial atypia of breast
Board review style question #2
Flat epithelial atypia most commonly has the corresponding imaging feature of
- Calcifications on mammography
- Enhancing mass on magnetic resonance imaging (MRI)
- Filling defect on ductogram (galactogram)
- Mass on ultrasound
Board review style answer #2
A. Calcifications on mammography
Flat epithelial atypia (FEA) is typically diagnosed by stereotactic biopsy of mammographically detected intraluminal calcifications. Less frequently, it constitutes an incidental finding on biopsy or excision. It does not typically present as mass on imaging nor a filling defect on ductogram or galactogram.
Comment Here
Reference: Flat epithelial atypia of breast
Flat epithelial atypia (FEA) is typically diagnosed by stereotactic biopsy of mammographically detected intraluminal calcifications. Less frequently, it constitutes an incidental finding on biopsy or excision. It does not typically present as mass on imaging nor a filling defect on ductogram or galactogram.
Comment Here
Reference: Flat epithelial atypia of breast
Foreign body reaction
Table of Contents
Definition / general | Terminology | Clinical features | Case reports | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | VideosDefinition / general
- Foreign body giant cell inflammation that usually is localized and occurs 1 - 2 weeks after trauma, surgery or radiation
Terminology
- See also fat necrosis, silicone breast implants
- Also called biopsy site changes
Clinical features
- Clinically resembles carcinoma due to skin retraction
Case reports
Due to injections:
- Carbon for biopsy tracking (Clin Radiol 1998;53:845)
- Gear oil (Indian J Pathol Microbiol 2007;50:373)
- Hydrophilic polyacrylamide gel (Hong Kong Med J 2007;13:137)
- Paraffin (Breast 2006;15:540)
- Petroleum jelly (South Med J 2008;101:422)
Gross description
- Localized to subcutaneous tissue
- May be nodular, fibrotic, orange brown (due to hemosiderin)
- Up to 1 cm
Microscopic (histologic) description
- Not encapsulated
- Fibrosis, foreign body giant cells, chronic inflammatory cells, fat necrosis, calcification, cholesterol clefts (needle-like empty spaces, due to substances dissolved during processing), hemosiderin
- May see a foreign body
Microscopic (histologic) images
Contributed by Dr. Saroona Haroon, The Aga Khan University Hospital (Pakistan)
Cholesterol granuloma in 56 year old woman with 4 month history of hard immobile mass of left breast; no history of pus or blood discharge
Images hosted on other servers:
Asteroid body
Granulation tissue
Videos
Foreign body reaction
Frozen section procedure
Table of Contents
Definition / general | Indications | Tissue type | Freezing tissue | Cryosectioning | Staining slides | Troubleshooting | Microscopic (histologic) images | Videos | Additional referencesDefinition / general
- A frozen section (cryosection) is a pathological laboratory technique used for rapid microscopic analysis / diagnosis of a specimen / disease
- Usually used with oncologic surgery
- Rapid diagnosis can guide intra-operative patient management
Indications
- Use frozen section to
- Provide rapid gross or microscopic diagnosis to identify an unknown pathologic process, identify extent of disease / evaluate margins, identify metastases or simply identify a tissue
- Process tissue to provide appropriate and accurate diagnosis, prognosis and to adhere to research and special study protocols
- Confirm that pathological tissue is present for diagnosis on permanent sections
- Do not use if
- Frozen section diagnosis has no immediate implications for decision making
- Tissue is needed for permanent processing (is unique or small or requires extensive study for diagnosis)
- Consider not freezing tissue if
- Frozen section is known to produce severe artifacts that hinder proper interpretation
- Tissue is heavily ossified / calcified
- Risk of serious infection (HIV, TB, hepatitis B or C)
- Tissue is fatty
Tissue type
- Tissue should be received fresh, otherwise it will not stay on slide
- At time of receipt of tissue, decide whether to obtain smears or touch preps and whether to freeze all or part of it
- Touch preps and smears are often performed on lymph nodes suspicious for lymphoma
- Some primary small lesions should not be entirely submitted for frozen section
- There is debate on whether sentinel nodes should be entirely or representatively submitted for frozen section
- Fixed tissue:
- There are special slides to keep tissue affixed to slide
- To freeze fixed tissue, make sure it has been preserved in formalin and not alcoholic fixatives like Carnoy's, because tissue fixed in alcohol is harder to freeze
- Avoid freezing tissue fixed with heavy metal salts such as B5 and Helly's (Zenker’s formal solution), which can denature proteins and shrink the tissue
- Avoid hard tissues like bone and cartilage that require decalcification
- Avoid tissues with a lot of fat
- Avoid tissues from patients with known TB or other infection (if absolutely necessary, wear appropriate protection)
- Avoid freezing tissue that will be needed to make a permanent diagnosis
Freezing tissue
- OCT (optimal cutting temperature) or similar embedding media like TBS or Cryogel should be placed on an appropriate sized chuck that has been precooled in a cryostat
- The chuck should be clean
- A toothbrush is useful to remove tissue and OCT
- Dipping the chuck in methanol removes ice crystals
- Place the chuck into a -20 to -15 degree (optimal) cryostat; note that the OCT media should not be frozen completely
- It is better to have a semisolid consistency; this will alleviate tissue artifact
- Tissue size should be no greater than 3mm - 5mm in greatest dimension (thinner specimens have shorter freezing time and minimal ice crystal artifact formation)
- The smaller the tissue, the more even and thorough the freeze
- Place the tissue on the semisolid chuck and add more media rapidly over the tissue, covering it entirely but avoiding overflow
- Place chuck quickly back into the cryostat
- Apply heat sink or CO2 aerosol (optional) to rapidly freeze or use "quick freeze" option on cryostat
- Histobath: being phased out
- Cryowells: useful in keeping all tissue on an even plane; also helpful in eliminating loss of smaller tissues that are frozen with larger ones, although recommended to not freeze different sizes together
- Aerosol sprays: often canned CO2 (but may aerosolize infectious diseases)
- Liquid nitrogen
- Isopentane based workflow (Virchows Arch 2008;452:305)
Cryosectioning
- Once the chuck is in position, there should be a manual or an automatic advance option to move the block close to the cutting blade
Tissue embedded within OCT
- Fully face the tissue by using a trim setting on your cryostat; if you do not have this setting, then an advance button should be available, which should be pressed each time before one full revolution of the instrument's wheel
- If wells are used to freeze the blocks, then the tissue should be on an even plane and the tissue will be faced faster
- To polish the tissue, avoid advancing the cryostat or deselect the trim setting on the cryostat and turn 10 - 15 times
- As you cut the tissue, anchor the tissue to prevent folding or curling; this can be done with an anti roll bar (a plastic plate attached to cryostat) or by using a precooled paintbrush with stiff bristles and a wide gripping surface
- The brush should be held like a pen with your left hand at an angle
- You can rest your fifth finger on the stage for stabilization
- Cutting the brushes' bristles at an angle can aid in the brush meeting the tissue flat over its length because you will hold it at an angle
- Turn the wheel with your right hand in a continuous motion without stopping; avoid speeding up or slowing down
- Avoid stopping the wheel at the beginning of the section, slowly grabbing the tissue and then resuming wheel revolutions; this can cause artifacts such as variation in section thickness and tissue folding
- Move the brush as the chuck moves
towards the blade; your brush should move down in
pace with the chuck
Riding the block: as the block descends
toward the brush, the brush keeps pace
with the block by gently resting on the
bottom 2 - 3 mm of the block - You can rest your brush softly on the very bottom of your chuck avoiding tissue contact
- Pull the brush away easily as the chuck meets the blade
Catching the curl: as the block meets the blade and
the section begins its curl, the brush leaves the block
while catching the curling edge of the section;
then the brush jumps off the block with the curl - The downward motion of the brush allows you to keep a continuous motion as you take your section
Pull over the blanket: the brush holding the curl
pulls the section horizontally over the stage,
like pulling the blanket over yourself,
without pressing the tissue to the stage - A glass slide is gently laid upon the tissue section
Gently touch the section to the slide; avoid stretching or folding the section by keeping a steady hand, and keep the transverse axis of the slide parallel to the section
- The tissue section should melt onto the slide
- Prepared slides should immediately go into formal alcohol, 95% alcohol (methanol/ethanol) or formalin while awaiting the stain line; if you delay this step, drying artifact will occur
- You can take a deeper level after approximately 20 turns (multiple levels may be needed for breast or prostate biopsies)
- Optimal cutting thickness is 4 - 7 microns for sectioning and 20 - 40 microns for trimming
Staining slides
- Keep all stains and solutions fresh and well maintained
- Dip slide in reagents in this order for H&E staining:
- After obtaining frozen section, IMMEDIATELY fix in 95% ethanol (even 15 seconds of delay can cause significant artifact)
- Formal alcohol, formalin or 95% alcohol: 45 - 60 seconds
- Water: 5 - 7 seconds
- Hematoxylin: 60 seconds
- Lithium carbonate or 0.2 % aqueous ammonia (Bluing): 15 - 20 seconds
- Eosin: 20 - 60 seconds
- 95% alcohol: 10 seconds
- 100% alcohol: 10 seconds
- Xylene, toluene, limonene derivatives and Clearite: 10 seconds
- Then add mounting media for cover slipping
Troubleshooting
- Ice crystal artifacts
- Due to slow freezing of tissue
- Solution: Freeze fast (flash / snap); the faster the freeze, the smaller the ice crystals, the less tissue damage (best freezing method is arguably liquid nitrogen)
- Smaller tissues yield less artifact - optimally tissue should be 0.5 x 0.5 x 0.3 cm or less
- Never freeze fragments larger than the diameter of the chuck
- Avoid freezing fat around tissue
- Blot the outer surface of the tissue dry with gauze before making your block
- Knife artifact
- A nicked cutting blade will produce a split / tear in your section
- Solution: change your blade every few cases; some institutions use a new blade for each case
- Overfreezing
- Can cause section to have holes
- Solution: polish block with a couple extra turns of the blade to create friction and warm up block by pressing on it with your finger (5 - 10 seconds)
- Underfreezing
- Underfreezing can be troublesome for fatty tissue
- Solution: add heat sink to block or select rapid freeze setting on your cryostat (if available)
- Staining issues
- Dirty "stain line" can cause floaters (extraneous foreign tissue) to adhere to slides; overly diluted stains and alcohols can diminish slide quality
- Poor staining hinders frozen section diagnoses, as nuclear detail is compromised
- Solutions: (a) maintain a clean stain line by frequent solution changes; (b) follow recommended staining times; (c) don't rush
- Note: brain tissue may stain best in eosin for 60+ seconds
- Water: should be changed after each frozen section
- Alcohols and stains: change at least weekly, alcohols may need to be changed more frequently depending on work load
- Fatty tissue
- Includes lymph nodes, breast, skin; may be too soft to cut
- Solution: maintain an extremely cold cutting temperature (-20C)
- Firm lymph nodes, spleen, brain and liver cut better at -10C; tissue may shatter if sectioning is performed at lower temps
- Air bubbles
- May be trapped under cover slips, which can cause the underlying tissue to dry out
- Solution: make sure an appropriate amount of resin (2 drops) is applied; gently move air bubbles off the slide with finger or tweezers; do not press on the slide too hard or it will break
- Overly thick sections
- May cause tissue to fall off slide
- Solution: reduce the cryostat's sectioning thickness
Microscopic (histologic) images
Images hosted on other servers:
Left: ice crystals in edematous stroma by frozen section, right: H&E
Nuclear ice crystals (particularly a problem with thinner sections): left - lung adenocarcinoma, right - uterine sarcoma
Glioma
Videos
Brush technique
Embedding small specimens
Speed embedding
Additional references
Frozen sections
Table of Contents
Definition / general | Essential features | Clinical features | Microscopic (histologic) description | Microscopic (histologic) images | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1Definition / general
- Click here for the frozen section procedure topic
- Historically used for incisional biopsies for primary diagnosis in the breast (Pathologica 2011;103:325); now core biopsy is utilized
- Currently used most frequently for axillary sentinel lymph node evaluation to determine need for further axillary dissection (Breast 2017;34:S64) and to evaluate nipple margins in nipple sparing mastectomies (Breast J 2016;22:18)
- Select institutions utilize intraoperative margin assessment by frozen section for breast conserving surgery (Ann Surg Oncol 2017 Jan 5 [Epub ahead of print])
Essential features
- Frozen section introduces histologic artifacts: (a) alteration of architectural features makes benign lesions such as sclerosing adenosis more closely mimic invasive carcinoma; (b) artifactual clefting / spaces around tumor cells simulates lymphovascular invasion (Arch Pathol Lab Med 2005;129:1565)
- Use of frozen section for sentinel lymph node assessment has declined following American College of Surgeons Oncology Group Z0011 trial findings (Arch Pathol Lab Med 2016;140:830, Am J Clin Pathol 2016;146:57)
- Frozen section has been shown to be highly sensitive (86%) and specific (96%) in a meta-analysis of intraoperative breast margin assessment (Ann Surg 2017;265:300)
- Frozen section use should be considered for margin assessment if reoperation rates at an institution are > 15% (Ann Surg Oncol 2017 Jan 5 [Epub ahead of print])
Clinical features
- Use of frozen section to intraoperatively assess breast margins has reduced reoperative rates at selected institutions by 12.3% (Eur J Surg Oncol 2017;43:1273)
- Frozen section use on margins for invasive lobular carcinomas or for those with extensively close margins may not significantly lower subsequent breast operations (Eur J Surg Oncol 2017;43:1273)
- Frozen assessment of margins for DCIS has shown mixed results in the effect on reoperative rates (Breast Cancer (Auckl) 2016;10:205, Ann Surg Oncol 2016;23:2788)
- Frozen section of lumpectomy margins offers potential cost saving to patients and payers (Oncol Pract 2016;12:e413)
- Frozen section assessment of nipple margins for nipple sparing mastectomy is highly specific but only moderately sensitive for the detection of carcinoma in subareolar tissue, allowing nipple resection at the time of mastectomy (Breast J 2016;22:18)
Microscopic (histologic) description
- Diagnostic errors in frozen section of breast tissue include sampling errors or proliferative lesions mimicking in situ (usual ductal hyperplasia, papilloma) and invasive carcinoma (sclerosing adenosis) (Tumori 1999;85:15)
Microscopic (histologic) images
Contributed by Emily S. Reisenbichler, M.D.
Dermal lymphovascular invasion
Invasive lobular carcinoma
Invasive mammary carcinoma
Nipple with chronic inflammation
Sclerosing adenosis
Ductal carcinoma in situ
Images hosted on other servers:
Infiltrating ductal carcinoma
Differential diagnosis
- Cautery and frozen artifact may cause sclerosing lesions to more closely mimic invasive carcinoma, and usual ductal hyperplasia (UDH) to mimic atypical proliferations such as atypical ductal hyperplasia (ADH), ductal carcinoma in situ/DCIS or lobular carcinoma in situ (LCIS)
- Histiocytes in frozen section of sentinel lymph nodes may mimic metastatic carcinoma (Int J Surg Pathol 2009;17:262)
- Lymphocytic infiltration can mimic invasive lobular carcinoma; a linear growth pattern or a touch preparation of the area to more closely evaluate cytologic features such as intracytoplasmic mucin droplets supports a diagnosis of lobular carcinoma
- Papillomas may mimic ductal carcinoma in situ (DCIS)
Additional references
Board review style question #1
- Which of the following is not currently a typical use of intraoperative frozen section in breast cancer surgical management?
- Axillary sentinel lymph node evaluation.
- Breast margin evaluation in breast conserving surgery.
- Nipple margin evaluation in nipple sparing mastectomy.
- Primary diagnosis of a breast mass for same day surgical management.
Board review style answer #1
D. Primary diagnosis of a breast mass for same day surgical management.
In the past, breast carcinoma could be diagnosed intraoperatively, allowing surgical management to take place at the time of the primary biopsy. In the current age of neoadjuvant therapy, testing breast carcinomas for estrogen / progesterone receptor and HER2 status prior to definitive surgical management is the standard of care.
Comment Here
Reference: Frozen sections
In the past, breast carcinoma could be diagnosed intraoperatively, allowing surgical management to take place at the time of the primary biopsy. In the current age of neoadjuvant therapy, testing breast carcinomas for estrogen / progesterone receptor and HER2 status prior to definitive surgical management is the standard of care.
Comment Here
Reference: Frozen sections
Galactocele
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Laboratory | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Galactoceles are benign, milk filled cysts that occur almost exclusively in lactating and pregnant women (StatPearls: Galactocele [Accessed 21 September 2022], J Cytol 2020;37:149, Case Rep Obstet Gynecol 2017;2017:4807013, Ultrasonography 2020;39:298, Plast Reconstr Surg Glob Open 2021;9:e3943, J Comput Assist Tomogr 2022;46:282)
- ~4% of cases are among benign breast conditions (StatPearls: Galactocele [Accessed 21 September 2022])
Essential features
- Benign, milk filled cysts that occur almost exclusively in lactating and pregnant women, occurring anywhere along the milk line (StatPearls: Galactocele [Accessed 21 September 2022], J Cytol 2020;37:149, Case Rep Obstet Gynecol 2017;2017:4807013, J Comput Assist Tomogr 2022;46:282, J Pediatr Adolesc Gynecol 2017;30:499)
- Triad of secretory breast epithelium, prolactin stimulus and ductal obstruction results in cyst formation (StatPearls: Galactocele [Accessed 21 September 2022])
- Triple assessment (clinical examination, radiological and histologic correlation) is essential (StatPearls: Galactocele [Accessed 21 September 2022], J Cytol 2020;37:149, Ultrasonography 2020;39:298)
Terminology
- Lactocele / lacteal cyst (StatPearls: Galactocele [Accessed 21 September 2022])
ICD coding
- ICD-10: N64.89 - other specified disorders of breast
Epidemiology
- Age: occurs in second to fifth decade of life with a peak incidence in fourth to fifth decade; rare cases reported in male and female infants (StatPearls: Galactocele [Accessed 21 September 2022], Eur J Pediatr Surg 2012;22:246)
- Common in third trimester of pregnancy (StatPearls: Galactocele [Accessed 21 September 2022], Case Rep Obstet Gynecol 2017;2017:4807013, J Comput Assist Tomogr 2022;46:282)
- Gender: women are almost exclusively affected, with few reported cases in men (StatPearls: Galactocele [Accessed 21 September 2022], J Cytol 2020;37:149, Case Rep Obstet Gynecol 2017;2017:4807013, Eur J Breast Health 2021;18:102, Plast Reconstr Surg Glob Open 2021;9:e3943)
- No genetic risk factors have been identified to date (StatPearls: Galactocele [Accessed 21 September 2022])
Sites
- Most common in breast, unilateral / bilateral
- May occur anywhere along the milk line, with a predilection for retroareolar region (StatPearls: Galactocele [Accessed 21 September 2022])
Pathophysiology
- In women, mammary duct obstruction following trauma, nipple abnormalities or tumor (StatPearls: Galactocele [Accessed 21 September 2022])
- In men, small silent retention cysts in neonatal period (StatPearls: Galactocele [Accessed 21 September 2022])
- Drugs such as metoclopramide / domperidone can increase the risk of galactocele formation (StatPearls: Galactocele [Accessed 21 September 2022])
Etiology
- Triad of secretory breast epithelium, prolactin stimulus and ductal obstruction results in cyst formation
- Secretory breast epithelium: estrogen and progesterone contribute to mammogenesis
- Prolactin stimulus: transplacental passage of prolactin, pituitary adenoma, hyperprolactinemia due to prolactinomas
- Ductal obstruction: postaugmentation following periareolar incisions (Ann Plast Surg 2021;86:115, StatPearls: Galactocele [Accessed 21 September 2022], J Cytol 2020;37:149, Case Rep Obstet Gynecol 2017;2017:4807013)
- Difficulty in breastfeeding: infants with cleft palate
- Breastfeeding contraindications, such as in congenital disease-like phenylketonuria, congenital diaphragmatic hernia, mothers with HIV, human T lymphotropic virus (HTLV) and taking radioactive agents
- Oral contraceptive pills (StatPearls: Galactocele [Accessed 21 September 2022], Ann Plast Surg 2021;86:115)
Clinical features
- Solitary / multiple, palpable, nontender, firm, discrete, movable, often associated with a milky discharge (StatPearls: Galactocele [Accessed 21 September 2022], Case Rep Obstet Gynecol 2017;2017:4807013, Ultrasonography 2020;39:298, J Comput Assist Tomogr 2022;46:282)
- Does not demonstrate inflammation unless secondarily infected (StatPearls: Galactocele [Accessed 21 September 2022])
Diagnosis
- Triple assessment (clinical examination, radiological and histologic correlation) (StatPearls: Galactocele [Accessed 21 September 2022], J Cytol 2020;37:149, Ultrasonography 2020;39:298)
Laboratory
- Presence of milk is confirmed chemically by a positive mucic acid test (StatPearls: Galactocele [Accessed 21 September 2022])
Radiology description
- Ultrasound:
- Solitary, well defined, anechoic lesion with thin, echogenic walls and some distal acoustic enhancement
- Simple cyst if centrally located or thinly septated, multilocular cyst in peripheral location (StatPearls: Galactocele [Accessed 21 September 2022], Radiographics 2013;33:2003)
- Mammogram:
- Indeterminate mass or a circumscribed mass with high radiolucency due to high fat content and water fat level (StatPearls: Galactocele [Accessed 21 September 2022])
Radiology images
Images hosted on other servers:
Cyst with circumscribed rounded margins
Oval shaped mass with hypoechoic rim
Prognostic factors
- Benign condition; carries excellent prognosis (StatPearls: Galactocele [Accessed 21 September 2022])
Case reports
- 3 year old prepubertal girl presented with galactocele in right breast (J Pediatr Adolesc Gynecol 2017;30:499)
- 22 year old woman presented with fine needle aspiration cytology (FNAC) diagnosis of crystallizing galactocele (J Cytol 2020;37:149)
- 32 year old woman presented with axillary accessory breast mimicking suspicious solid mass on ultrasound (Case Rep Obstet Gynecol 2017;2017:4807013)
- 48 year old woman presented with nipple eczema causing galactorrhea by reactive hyperprolactinemia complicated by a galactocele (Eur J Breast Health 2021;18:102)
Treatment
- Conservative; resolves spontaneously on cessation of lactation (StatPearls: Galactocele [Accessed 21 September 2022])
- Aspiration and surgical excision can be performed in complicated cases (StatPearls: Galactocele [Accessed 21 September 2022])
- Dopamine agonists help in postaugmentation galactocele (StatPearls: Galactocele [Accessed 21 September 2022])
- Treat underlying condition such as prolactinoma (StatPearls: Galactocele [Accessed 21 September 2022])
Gross description
- Circumscribed to oval lesions usually ranging in size from 1 - 6 cm; cut section showing cyst filled with thin yellow fluid
Gross images
Contributed by Nasir Ud Din, M.B.B.S.
Oval multicystic lesion with well circumscribed borders
Microscopic (histologic) description
- Multiple variable sized anastomosing cysts that are lined by cuboidal or flat epithelial cells
- Lining epithelium exhibits regular nuclei with cytoplasmic vacuolations due to lipid accumulation
- Apocrine metaplasia may be seen
- Intact cysts are surrounded by fibrous wall of varying thickness
- Little to no inflammatory reaction, unless leakage of cyst contents occurs
- Fat necrosis can be present (Hoda: Rosen's Breast Pathology, 5th Edition, 2020)
Microscopic (histologic) images
Contributed by Saba Anjum, M.B.B.S.
Multiple variable sized anastomosing cysts
Cystic lesion lined by cuboidal epithelium
Proteinaceous material
Cyst lined by cuboidal epithelium
Galactocele with lactational change and mild fibrosis
Cytology description
- Thick, chalky white material with a gritty sensation during aspiration; well defined purple crystals, which show positive birefringence
- Granular, amorphous, proteinaceous material in the background admixed with frothy appearing lipid micelles
- Absence of distinct epithelial fragments, bipolar nuclei and fibrous stroma (J Cytol 2020;37:149, StatPearls: Galactocele [Accessed 21 September 2022])
Cytology images
Contributed by Dhiraj B. Nikumbh, M.D.
27 year old woman with 1.5 cm nontender breast nodule and fine needle aspiration cytology
Images hosted on other servers:
Dark purple crystals in a proteinaceous background
Sample pathology report
- Breast, excision:
- Galactocele (see comment)
- Comment: It is a benign condition with no recurrence.
- Microscopic description: Breast tissue exhibiting dilated anastomosing channels lined by cuboidal epithelium with secretory activity. Adjacent tissue shows secretory change and fibroinflammatory reaction with foamy macrophages. No evidence of granulomatous or neoplastic processes are seen.
Differential diagnosis
- Lactating adenoma:
- Composed of collections of lobules exhibiting lactational changes
- Fibroadenoma:
- Biphasic lesion exhibiting epithelial and stromal proliferations with intracanacular or pericanacular pattern
- Hamartoma:
- Circumscribed lesion showing lobulated architecture composed of ducts, lobules, fibrous tissue and adipose tissue in varying proportions
- Duct ectasia:
- Presents in premenopausal women and women 45 - 55 years of age (StatPearls: Mammary Duct Ectasia [Accessed 9 November 2022])
- May present with nipple discharge, soft to firm swelling with mild erythema or asymptomatic (StatPearls: Mammary Duct Ectasia [Accessed 9 November 2022])
- Radiology may show microcalcifications, lobulated partially smooth masses, nipple retraction, retroareolar duct dilatation and rarely speculated looking mass (StatPearls: Mammary Duct Ectasia [Accessed 9 November 2022])
- Histologically shows dilation of large ducts, lipid rich detritus accumulation in lumen, fibrous thickening of walls, florid inflammatory reaction on leakage of luminal contents (StatPearls: Mammary Duct Ectasia [Accessed 9 November 2022])
- Mucocele-like lesion:
- Rare, usual age of presentation is between 25 - 61 years (Am J Surg Pathol 1986;10:464)
- Radiology may show multiple aggregated cystic lesions, calcifications can be present (Am J Case Rep 2019;20:926)
- Histologically shows multiple cysts lined by cytologically uniform flat or cuboidal to columnar epithelium with extravasated mucin (Ultrasonography 2015;34:133)
Additional references
Board review style question #1
34 year old lactating mother presented with the history of a palpable lump in the left breast. Breast ultrasound examination showed a circumscribed cystic lesion. Histology is shown in the picture above. What is the diagnosis?
- Fibroadenoma
- Galactocele
- Hamartoma
- Invasive breast carcinoma of no special type
- Lactating adenoma
Board review style answer #1
Board review style question #2
Galactocele formation is related to which of the following conditions?
- Age of the mother
- Duct obstruction
- Estrogen effect
- Family history
- Number of pregnancies
Board review style answer #2
Granular cell tumor
Table of Contents
Definition / general | Essential features | Terminology | Epidemiology | Sites | Etiology | Clinical features | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Positive stains | Negative stains | Electron microscopy description | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1Definition / general
- Tumor whose cells have granular eosinophilic cytoplasm and bland small nuclei
Essential features
- Uncommon benign breast tumor that may present as a mass lesion
- Imaging shows ill defined spiculated lesion mimicking malignancy
- Microscopy shows sheets / cords of polygonal cells with abundant eosinophilic cytoplasm, round nuclei and prominent nucleoli; no mitosis or atypia seen
- Treated by complete excision
Terminology
- First described by A.I. Abrikosoff in 1926 as "myoblastic myoma" (Virchows Arch A Pathol Anat 1926;260:215)
Epidemiology
- Uncommon, < 1 per 1000 malignancies (J Ultrasound Med 2008;27:467)
- More common in women in 40s; may be more common in African American women
- Can occur anywhere, breast accounts for 5 - 8% of all granular cell tumors (Br J Radiol 2007;80:970)
Sites
- Usually inner quadrant of breast
Etiology
- Appears to derive from Schwann cells of peripheral nerves (at all sites)
Clinical features
- Resembles invasive carcinoma clinically but almost always benign
- Xray: suggestive of malignancy due to apparent infiltration
- Painless lump most commonly in upper middle and medial quadrants
Radiology description
- On mammography appears as an ill defined spiculated lesion mimicking malignancy
- On ultrasound appears as solid, hypoechoic mass with posterior shadow
Radiology images
Contributed by Mark R. Wick, M.D.
Mammogram spot film
Images hosted on other servers:
Fig 2, case 1:
ultrasonography
revealed a tumor
7 x 8 mm in size
Mammograph of the breast
Prognostic factors
- Most are benign and reportedly malignant cases are rare, occurring in only 1% or 2% of cases
- Metastasis to liver, lung, bone and axillary lymph nodes are reported with malignant granular cell tumor (J Ultrasound Med 2011;30:1295)
Case reports
- 22 year old woman with granular cell tumor of the breast (Cases J 2009;2:8551)
- 32 year old woman with granular cell tumor of the breast (J Med Case Rep 2014;8:465)
- 36 year old woman with metachronous GCT of breast, skin and scalp (Case Rep Pathol 2016;2016:8043183 )
- 47 year old woman with outer quadrant breast mass (Arch Pathol Lab Med 2003;127:1525)
- 52 year old woman with granular cell tumor of the breast (Breast Cancer (Dove Med Press) 2017;9:245)
- 55 year old woman with granular cell tumour of the pectoral muscle mimicking breast cancer (Cases J 2008;1:142)
- 55 and 67 year old women with granular cell traumatic neuroma (Arch Pathol Lab Med 2000;124:709)
- 57 year old woman with colocalized granular cell tumor and infiltrating ductal carcinoma of the breast (Arch Pathol Lab Med 2002;126:731)
- 57 year old woman with benign granular cell tumor of the breast (Radiol Case Rep 2016;10:1116)
- 64 year old woman with small irregular mass on her left breast (Case of the Week #252)
- Malignant granular cell tumor in the right breast (Arch Pathol Lab Med 1992;116:206)
- Two patients with granular cell tumors in breast (World J Surg Oncol 2012;10: 204)
Treatment
- Local excision, local recurrence reported with incomplete excision
Gross description
- Firm, homogenous, gray white and yellow, usually 3 cm or less and ill defined
Gross images
Contributed by Mark R. Wick, M.D. and AFIP
Dense
homogenous
tumor with
infiltrating margins
Various images
Images hosted on other servers:
Firm tumor with irregular borders
Granular cell tumor in right breast
52 year old woman with 1 cm nodule
Microscopic (histologic) description
- Infiltrating sheets / cords of polygonal bland cells with well defined cell borders, abundant eosinophilic granular cytoplasm and round / oval nuclei with prominent nucleoli
- Collagenous stroma
- May be close to small nerve bundles and have infiltrative margins; occasional multinucleation
- Overlying epithelium may show pseudoepitheliomatous hyperplasia
- Rare mitotic figures, no / mild atypia
- Histologic criteria for malignancy (proposed by Fanburg-Smith et al., Am J Surg Pathol 1998;22:779):
- Spindling
- Necrosis
- Vesicular nuclei with large nucleoli
- High N/C ratio
- Nuclear pleomorphism
- Increased mitotic activity
- 1 or 2 of 6 criteria are considered atypical and 3 or more are considered to be associated with malignant behavior (Breast J 2004;10:528, Arch Pathol Lab Med 2004;128:771), but metastasis remains the only unequivocal sign of malignancy (Virchows Arch 2016;468:527)
Microscopic (histologic) images
Contributed by Emily S. Reisenbichler, M.D., Mark R. Wick, M.D., Dr. Oleksandr Grygoruk, AFIP and @ThatGlassTho on Twitter
Infiltration into fat
S100+ tumor cells and myoepithelial cells
Granular cell tumor
Various images
Various images
S100
Granular cell tumor
9 year girl with a 2 cm granular cell tumor near the left nipple, unchanged in size over past 3 years
9 year girl with a 2 cm granular cell tumor near the left nipple, unchanged in size over past 3 years
Images hosted on other servers:
Core biopsy
Abundant eosinophilic, granular cytoplasm
Beneath squamous epithelium (not necessarily breast): H&E and S100
Compact nests of polygonal cells
Cells contained granular eosinophilic cytoplasm
IHC study showed reactivity for S100 protein
H&E staining of granular cells
Cytology description
- Highly cellular, large cohesive groups and single cells mixed with connective tissue
- Cells have ill defined, abundant granular cytoplasm and bland small nuclei with prominent nucleoli
- No mitotic figures, no necrosis (Diagn Cytopathol 2007;35:725)
Cytology images
Contributed by Mark R. Wick, M.D.
FNAB
Positive stains
Negative stains
Electron microscopy description
- Myelin figures, lysosomes
Differential diagnosis
- Alveolar soft part sarcoma: cells are divided into packets by thin walled vessels
- Apocrine carcinoma: usually ductal carcinoma also present, keratin+, mucin+, S100-
- Granulomatous mastitis (idiopathic)
- Histiocytic tumors
- Melanoma
- Myoblastomatoid: keratin+
- Renal cell carcinoma
Additional references
Board review style question #1
- A 45 year old woman presents with a breast mass. Excisional biopsy shows a granular cell tumor. Which one of the following is not in the differential diagnosis based on morphologic findings?
- Apocrine carcinoma
- Melanoma
- Metastatic renal cell carcinoma
- Tubular carcinoma
Board review style answer #1
D. Tubular carcinomas form angulated tubular structures composed of mildly atypical ductal cells whereas granular cell tumors have sheets of large cells with abundant eosinophilic granular cytoplasm.
Comment here
Reference: Granular cell tumor
Comment here
Reference: Granular cell tumor
Grossing & features to report
Table of Contents
Definition / general | Essential features | Excisions with palpable masses | Excisions for lesions localized with imaging studies | Cavity / shave margins performed simultaneously with primary excisions | Re-excision specimens | Mastectomy specimens | Postneoadjuvant specimens | Sentinel lymph node excisions | Axillary dissection specimens | Microdochectomy specimens | Microdochectomy images | Nipple resections | Specimens from oncoplastic procedures | Grossing implant specimens with suspicion of implant associated lymphoma | Reduction mammoplasty specimens | Specimens removed for gynecomastia | Gender reassignment specimens (top surgery) | Features to report | Gross images | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- This summary describes how to sample breast resection specimens with documented, suspected or potential malignancy
- Essential clinical history:
- Indication
- Prior biopsy findings
- Imaging findings
- Presence of prior biopsy clips / localization devices
- Treatment history
- Multicolor inks recommended for oriented specimens; sample inked margins with perpendicular, not tangential / en face, sections to provide optimal clinical information (Cancer 1997;79:1568, Arch Pathol Lab Med 2018;142:496)
- Inking may be performed by pathologists or surgeons; the latter may be more accurate (Ann Surg Oncol 2009;16:285, World J Surg Oncol 2010;8:4)
- Orange / yellow inks may be difficult to distinguish microscopically; apply to opposite ends
- Blot specimen dry, apply ink(s) and blot dry again prior to sectioning to prevent ink artifact; consider mordant (i.e., acetic acid) to optimize ink adherence
- Slice specimens as thinly as possible; palpate each section for lesions that may not be visible
- Change gloves if soiled to prevent ink artifact
- Diagrams or photographs that provide orientation / section keys facilitate accurate reporting
- Maintain specimen orientation following sampling in case additional sections required
- Ensure cold ischemic time < 1 hour and total fixation time 6 - 72 hours
Essential features
- Know indication for procedure, results of prior procedures, presence of biopsy clips
- Carefully ink specimens and blot dry to avoid inking artifact
- Sample all lesions and all margins (perpendicular, not tangential / en face, margins)
- For pure ductal carcinoma in situ lesions, submit all or as much fibrous tissue as practical to assess for invasion
- Consider utilizing specimen diagrams or photographs to illustrate orientation / section key
Excisions with palpable masses
- Gross exam:
- Measure, weigh specimen and describe orienting sutures
- Ink specimen as above; if fragmented, ink each fragment
- Describe / measure all lesions, including color / consistency / tumor border (i.e., well circumscribed, irregular, stellate); note presence of necrosis / hemorrhage
- If multiple lesions, measure the distance between each
- Measure distance between lesions and closest inked margins
- Note biopsy site changes / fat necrosis
- See below for discussion of postneoadjuvant specimens
- Sections:
- Suspected benign lesions: 1 section per cm (2 sections per cassette)
- Suspected malignant lesions: submit entire lesion up to 4 cassettes
- Provide a full face section(s) of the tumor across the longest axis of the tumor where possible, using adjoining ink to indicate contiguous sections (Ann Diagn Pathol 2011;15:291)
- If the longest axis of the tumor is perpendicular to the plane of sectioning, tumor size can be calculated by multiplying the average slice thickness by the number of consecutive slices involved (Int J Surg Pathol 2021;29:39, Arch Pathol Lab Med 2009;133:15)
- Sample all grossly heterogeneous areas, including areas of necrosis
- If no discrete lesion, submit up to 12 cassettes of fibrous tissue as a screening step
- Sample intervening tissue between lesions
- Margins: document / sample closest margins; include lesion in section if possible
- Sample remaining margins with at least 2 sections (1 cassette) each
- Submit section of skin if present
- If specimen or lesion not entirely submitted, estimate proportion sampled
- For pure ductal carcinoma in situ, the College of American Pathologists recommends "when practical, the entire specimen should be submitted in a sequential fashion for histologic examination" (CAP: Protocol for the Examination of Resection Specimens from Patients With Ductal Carcinoma In Situ (DCIS) of the Breast [Accessed 18 March 2021])
- Nevertheless, there is significant variability in sampling between labs (Arch Pathol Lab Med 2018;142:496)
Excisions for lesions localized with imaging studies
- Gross exam:
- Specimen imaging typically performed
- Findings regarding targeted lesions, calcifications, biopsy clips and localization devices should be reconciled with gross exam
- Clips may be present and not grossly identified
- Lesions may or may not be grossly identified
- Same instructions for grossing specimens with palpable lesions should be followed
- Various localization devices are utilized; be familiar with devices at your institution:
- Localizing wires
- Radioactive seeds
- Tags using radiofrequency, infrared or electromagnetic waves
- Radiation safety officers should approve radioactive seed processing protocols
- See below for discussion of postneoadjuvant specimens
- Specimen imaging typically performed
- Sections:
- Visible lesions should be sampled in the same manner as palpable masses
- If no lesions grossly identified, use imaging studies, clips and localizing devices to guide sampling so that the targeted lesions are entirely submitted
- Submit up to 12 cassettes of fibrous tissue as a screening step
- Sample margins and skin in the same manner as palpable masses
Cavity / shave margins performed simultaneously with primary excisions
- To decrease need for subsequent re-excisions, surgeons often perform multiple cavity / shave margins simultaneously with primary excisions
- Gross exam:
- Primary excision may or may not be oriented
- If oriented, primary excision should be processed similarly to oriented primary excisions without cavity / shave margins
- If unoriented, primary excision can be inked black and processed similarly to unoriented primary excisions without cavity / shave margins; some labs do not ink unoriented primary excisions and report margins only on separate cavity / shave margins
- Cavity / shave margins should be measured in 3 dimensions
- True margin surface of cavity / shave margins should be inked with care to avoid artifactual ink seeping onto the nonmargin surface; some labs ink the nonmargin surface a different color to assist orientation microscopically
- Sections:
- Entire specimen can typically be submitted in < 10 cassettes
Re-excision specimens
- Subsequent procedures performed to obtain negative margins; may be global, surrounding the entire excision site or targeted, excising 1 or more specific margins
- Gross exam:
- True margins should be inked similarly to cavity / shave margins, avoiding artifactual ink seeping onto nonmargin surface
- Describe grossly evident or palpable lesions and biopsy cavity contents
- Measure range of thickness of cavity walls
- Sections:
- Global re-excisions:
- If re-excision is for invasive carcinoma, representative sections generally suffice
- If re-excision is for pure ductal carcinoma in situ, it is important to exclude invasive carcinoma; all parenchymal / fibrous tissue should be submitted if practical
- Submit all gross lesions and at least 4 sections from the biopsy cavity with closest margins
- Submit at least 2 sections from remaining margins (2 sections per cassette)
- If not completely submitted, include an estimate of proportion submitted
- Sample attached skin, if present
- Targeted re-excisions:
- Entire specimen can usually be submitted in < 10 cassettes
- For larger re-excisions, at least 1 section per 1 cm should be submitted
- For pure ductal carcinoma in situ lesions, all parenchymal / fibrous tissue should be submitted if practical
- Global re-excisions:
Mastectomy specimens
- Removal of most breast tissue to treat malignancy or to reduce risk of cancer (prophylactic)
- Mastectomy types:
- Simple: remove breast, skin and nipple / areola, typically without axillary nodes
- Modified radical: simple mastectomy and axillary dissection
- Radical: includes pectoralis muscle (rarely performed)
- Skin sparing: remove breast and nipple / areola leaving skin intact
- Subcutaneous: remove breast leaving skin and nipple intact; typically for benign indications
- Nipple sparing: remove breast leaving skin and nipple intact; typically for patients with cancer or at high risk; often includes biopsy of nipple duct margin
- Indications:
- Gross exam:
- Know indication, prior procedures, presence of biopsy clips and other clinical questions (i.e., residual calcifications)
- Intraoperative imaging often not performed; may need to obtain imaging to facilitate gross exam and document lesion / clip removal, particularly if no prior excision
- Weigh / measure specimen; describe orienting sutures
- Note presence / absence of skin, nipple / areola, skeletal muscle, axillary nodes; measure / describe each
- Describe skin, nipple / areolar lesions (retraction, ulceration, scars, etc.); palpate skin, as skin tumor satellites may not be visible
- Describe surgical defects (i.e., exposed biopsy cavity, etc.)
- Ink posterior / fascial aspect; the significance of soft tissue margins other than deep / fascial margin is unknown
- Examine lateral aspect for nodes; may occasionally be found in simple mastectomies
- Serially section fresh specimen from posterior anterior, without cutting through skin
- Estimate proportion of fatty to parenchymal / fibrous tissue
- Describe all lesions present similarly to excision protocol, including quadrants, distance between lesions and distance between lesions and margins
- Discrepancies between clinical and gross findings should be reconciled with surgeon
- See below for discussion of postneoadjuvant specimens
- Sections:
- Follow protocol for excision specimens regarding sampling lesion(s) and biopsy site(s)
- Section perpendicular deep / fascial margin closest to lesion(s)
- Sample uninvolved quadrants (2 sections / 1 cassette each)
- Sample skeletal muscle (1 perpendicular section closest to tumor or biopsy site)
- Sample nipple / areola; if no lesions, 1 central perpendicular section; if lesion or suspected Paget disease, more extensive sampling is recommended
- Sample skin lesions, including scars (1 section)
- For nipple sparing mastectomies, nipple / areolar margin insertion site on anterior surface should be inked / sampled (2 perpendicular sections, 1 cassette)
- Sample all lymph nodes, as detailed below
- For prophylactic mastectomies, sample all gross lesions as above; if no lesions, submit 2 sections per quadrant and sample nipple / areola and deep / fascial margins, as above
Postneoadjuvant specimens
- Neoadjuvant chemo or endocrine therapy may be used to shrink tumors prior to definitive excision or mastectomy
- Assessment of treatment response in the breast / nodes provides useful prognostic information
- Review imaging reports describing tumor location, local extent, pre / posttherapy characteristics and presence of biopsy clip(s)
- Gross exam:
- If significant treatment response, may be difficult to identify tumor bed
- Coordinated gross / microscopic evaluation required to define tumor bed in at least 2 dimensions (Surg Pathol 2018;11:213)
- For multiple discrete primary tumors, tumor bed estimates should be provided for each
- Sections:
- In addition to standard sections for excision / mastectomy specimens, submit sections spanning largest span of tumor bed to assess overall tumor cellularity
- Amount of sampling is dictated by pretreatment tumor size and presence of visible tumor bed / gross residual tumor
- Recommended minimum of 1 block per cm of pretreatment tumor size (Int J Surg Pathol 2021;29:39)
Sentinel lymph node excisions
- Gross exam:
- Quantitate discrete nodes / node candidates
- Comment on blue dye, if present
- If previously biopsied, document clips (specimen imaging may be required)
- Slice each node as thinly as possible, 2 mm or thinner; comment on size, color, consistency and presence / absence of grossly evident tumor or scarring
- If tumor evident, comment on tumor border / evidence of extranodal extension
- Sections:
- Entirely submit each node
- Provide detailed slide key regarding number of nodes in each cassette
Axillary dissection specimens
- Gross exam:
- Quantitate discrete nodes / node candidates
- If nodes previously biopsied, document clips (specimen imaging may be required)
- Section / describe each node as described above
- Multiple positive nodes may be fused / matted; estimate number of fused nodes, if possible
- Full axillary dissections should yield 10 or more nodes; if < 10 nodes, consider utilizing clearing solutions (i.e., Carnoy fixative) or sample surrounding adipose tissue
- Sections:
- Entirely submit each node
- Large grossly positive nodes may be representatively sampled; include any irregular tumor borders to assess for extranodal extension
Microdochectomy specimens
- Usually small excisions performed to evaluate patients with nipple discharge (with or without abnormal ductogram)
- Gross exam:
- If oriented, maintain orientation; ink using the protocol above
- If dilated duct grossly evident, serially section perpendicular to the duct, as thinly as possible; examine for intraductal lesions
- Sections:
- Entirely submit
Microdochectomy images
Images hosted on other servers:
Insertion of ductoscope
Selective lactiferous duct sample
Nipple resections
- Usually performed for Paget disease of the nipple
- Gross exam:
- Measure in 3 dimensions; describe orienting sutures
- If oriented, apply multiple inks to maintain orientation, similarly to skin excisions
- Describe color and consistency of skin surface; measure and describe lesions and distance to inked margins
- Sections:
- Serially section perpendicular to skin surface
- Entirely submit in a manner allowing assessment of all perpendicular lateral and deep margins
Specimens from oncoplastic procedures
- Procedures involve removal of tumor simultaneously with plastic surgery techniques designed to obtain cosmetically optimal results
- Typically results in large, irregular and difficult to orient specimens
- Gross exam:
- Communicate with the surgeon to identify appropriate margins to sample
- Surgeon may submit multiple separate shave margins to ensure optimal margin evaluation; process similarly to targeted re-excision specimens, as above
- Due to specimen complexity, utilize diagrams / photographs with orientation / section key
- Sections:
- Sample all lesions using excision protocol, above
- Sample all relevant perpendicular inked margins indicated by surgeon
Grossing implant specimens with suspicion of implant associated lymphoma
- Implants (intact or ruptured) are typically sent to pathology for gross exam, often with attached or separate peri-implant capsular tissue that should be sampled for histologic evaluation
- Implant associated anaplastic large cell lymphoma is a rare entity most commonly associated with textured implants (silicone or saline), usually associated with a peri-implant effusion and rarely associated with a grossly evident mass (Plast Reconstr Surg 2019;143:65S)
- Lymphoma may arise many decades following implant placement
- If lymphoma is clinically suspected, determine if there is associated effusion; if so, fluid should be aspirated / sent for cytologic evaluation and flow cytometry; could be performed by surgeon intraoperatively or by pathologist if effusion is resected intact
- Gross exam:
- All specimens should be photographed, including implant manufacturer information
- Weigh specimen and measure in 3 dimensions
- Describe the surface of the implant (adherent tissue / capsule, smooth or textured surface, intact or disrupted, color of effusion) and implant contents
- Sections:
- If effusion received intact, aspirate and send for fluid for cytology and flow cytometry
- Extensively sample tissue surrounding the effusion; may require sampling material scraped from implant surface
- Sample adherent tissue and peri-implant capsule (multiple sections for each of 6 margins if possible)
Reduction mammoplasty specimens
- Typically includes unoriented breast tissue and skin
- Tissue weights often important for billing purposes
- Unsuspected atypical and malignant lesions more commonly discovered in older patients (Arch Pathol Lab Med 2017;141:1523)
- Gross exam:
- Report weights provided by surgeon as these may differ from lab weights due to blood / fluid loss and fixation
- Measure specimens in aggregate
- Describe skin surfaces (lesions, etc.)
- If oriented, ink specimen / maintain orientation when sectioning
- Serially section as thinly as possible; inspect and palpate slices for lesions
- Sections:
- Sample all grossly evident breast and skin lesions
- In no lesions, submit sections of fibrous parenchyma:
- Women < 40: 4 sections in 2 cassettes
- Women ≥ 40 or known risk factors: 8 sections in 4 cassettes
Specimens removed for gynecomastia
- Subcutaneous mastectomies, often bilateral and unoriented
- Gross exam:
- Weigh, measure and ink each specimen
- Serially section as thinly as possible, examining for visible and palpable lesions
- Sections:
- Submit all lesions, with nearest inked margins
- If no lesions, submit 4 sections (2 cassettes) of each specimen focusing on fibrous parenchyma
Gender reassignment specimens (top surgery)
- There is lack of evidence for specific guidelines at this time
Features to report
- Click here for recommendations from the College of American Pathologists based on the specimen type
Gross images
Contributed by Anthony J. Guidi, M.D.
Uninked specimen
Inked specimen
Sectioned perpendicular to margins
Board review style question #1
Regarding breast excision specimens for ductal carcinoma in situ, the College of American Pathologists recommends which of the following?
- Measuring the specimen and sampling 1 section per cm, focusing on fibrous / parenchymal tissue
- Sampling up to 10 sections as a screening step
- Serially sectioning the specimen and submitting every other slice
- Serially sectioning the specimen and submitting 1 section per slice
- Submitting the entire specimen in a sequential fashion, when practical
Board review style answer #1
E. Submitting the entire specimen in a sequential fashion, when practical. If this is not possible, at least the entire region of the targeted lesion should be examined microscopically (CAP: Protocol for the Examination of Resection Specimens from Patients With Ductal Carcinoma In Situ (DCIS) of the Breast [Accessed 14 February 2022]).
Comment Here
Reference: Breast - Grossing & features to report
Comment Here
Reference: Breast - Grossing & features to report
Board review style question #2
Which statement pertaining to breast specimen processing is true?
- Biopsy clips may be present in excision or mastectomy specimens by specimen imaging but not grossly evident
- For breast cancer specimens, tangential / en face margins provide similar clinically relevant information as margins taken perpendicular to inked surfaces
- It is rarely necessary to correlate the gross examination of breast specimens with specimen imaging studies for specimens excised for image detected lesions
- Knowledge of the indications for mastectomy is rarely required to optimally process these specimens
Board review style answer #2
A. Biopsy clips may be present in excision or mastectomy specimens by specimen imaging but not grossly evident
Comment Here
Reference: Breast - Grossing & features to report
Comment Here
Reference: Breast - Grossing & features to report
Gynecomastia
Table of Contents
Definition / general | Essential features | ICD coding | Epidemiology | Sites | Etiology | Clinical features | Diagnosis | Laboratory | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Cytology images | Positive stains | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Benign enlargement of the male breast, typically presenting as a palpable subareolar mass
- Histologically identical gynecomastoid hyperplasia can be seen in female breast
Essential features
- Benign ductal and stromal proliferation with characteristic stromal cuffing, typically with 3 layered ductal lining and pseudoangiomatous stromal hyperplasia
Epidemiology
- Trimodal age distribution:
- Infancy and neonatal period
- Puberty (peak incidence age 13 - 14)
- Older males age 50 - 80 (likely due to increased adiposity, decreased testosterone, medications)
- Estimated lifetime prevalence of 32 - 65% of men, depending on method of assessment (Indian J Endocrinol Metab 2014;18:150)
Sites
- Most cases retroareolar and bilateral
- Rare cases of unilateral gynecomastia related to trauma or of unknown pathophysiology (Andrologia 2006;38:31, J Plast Reconstr Aesthet Surg 2011;64:1684, GMS Interdiscip Plast Reconstr Surg DGPW 2012;1:Doc01)
- Can be localized or generalized
Etiology
- Imbalance of estrogens and androgens by various mechanisms
- Idiopathic in > 40% of cases (Biomed Res Int 2018;2018:8364824)
- Physiologic: in newborns and infants, due to in utero estrogen exposure and tends to resolve spontaneously; hormonal changes in puberty (Pediatr Endocrinol Rev 2017;14:371)
- Drugs: finasteride, anabolic steroids, digitalis, spironolactone, metronidazole (Eur J Clin Pharmacol 2015;71:569, Biomed Res Int 2018;2018:8364824)
- Systemic disorders: obesity, hyperthyroidism, hypogonadism, cirrhosis, chronic renal failure, chronic pulmonary disease
- Syndromes: androgen insensitivity, Klinefelter, Carney complex, Peutz-Jeghers, spinobulbar muscular atrophy (Andrology 2016;4:1178, Case Rep Pediatr 2015;2015:439239, Am J Transl Res 2017;9:2639, J Neurol 2018;265:1026)
- Paraneoplastic hormone production by various testicular germ cells, pulmonary and adrenocortical neoplasms
- Mechanical: repeated impact against the body as seen in male rifle shooters with unilateral gynecomastia (GMS Interdiscip Plast Reconstr Surg DGPW 2012;1:Doc01)
Clinical features
- Most common male breast lesion
- Mastalgia in 88% (J Family Med Prim Care 2021;10:648)
Diagnosis
- Histologic changes are necessary for the diagnosis; important to exclude malignancy
Laboratory
- Usually not needed, except to identify underlying causes
- Estrogen to testosterone ratio (E2/TTE), follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin, thyroid stimulating hormone (TSH), hCG, AFP, dehydroepiandrosterone (DHEA), cortisol, karyotyping
Radiology description
- 3 patterns of mammographic findings (Radiographics 1999;19:559, Andrology 2021 May 25 [Epub ahead of print])
- Nodular: 72%, corresponds to florid histologic phase; fan shape radiating from nipple into surrounding fat
- Dendritic: 18%, corresponds to fibrous histologic phase; flame shaped opacity with radiating projections penetrate surrounding fat / upper outer quadrant
- Diffuse: ~10%, typically in transgender females undergoing gender affirming hormonal therapy; resembles dense female breast but heterogeneous and without Cooper ligaments
- Imaging useful to exclude pseudogynecomastia and carcinoma
Radiology images
Contributed by Elaine Zhong, M.D.
Mammogram
Prognostic factors
- May recur if underlying cause is not addressed
- No strong evidence of increased risk of breast carcinoma
- Present in 3 - 46% of male breast carcinoma (Cancer 2004;101:51, Cancer 1996;77:490)
Case reports
- 4 year old boy with adrenocortical carcinoma, with gynecomastia as presenting symptom (Clin Pediatr Endocrinol 2018;27:9)
- 13 year old boy with gynecomastia secondary to imatinib related hypogonadism (Indian J Hematol Blood Transfus 2017;33:448)
- 38 year old male to female transgender individual with concern for breast malignancy following hormonal replacement therapy (Case Rep Oncol Med 2017;2017:5172072)
Treatment
- Some regress spontaneously within 2 years and do not require treatment
- Sudden or symptomatic gynecomastia may be treated medically
- Aromatase inhibitor, anti-estrogen, androgen therapy (tamoxifen, danazol) (Breast 2006;15:276, J Pediatr Endocrinol Metab 2013;26:803)
- Identify and treat any underlying causes
- Excision in adult patients to rule out malignancy and for cosmesis; however, recurrence is common if the underlying cause is not identified and treated
Clinical images
Images hosted on other servers:
Physiologic gynecomastia in puberty
Spironolactone induced
Gross description
- Soft, rubbery to firm gray-white subareolar mass
- Can be ill defined subareolar induration
Microscopic (histologic) description
- Increased number of ducts with characteristic 3 layer epithelium (Am J Surg Pathol 2012;36:762):
- Luminal epithelium expressing CK5/6, CK14
- Intermediate cuboidal to columnar epithelium expressing ER, PR, AR
- Outer myoepithelium expressing CK5/6 and CK14
- 3 patterns of proliferative changes, without correlation to age or duration of lesion (Am J Clin Pathol 1972;57:431, J Plast Surg Hand Surg 2018;52:166)
- Florid: irregular branching ducts, mild to moderate epithelial hyperplasia, cellular / myxoid / edematous stroma cuffing around ducts; can have papillary or cribriform architecture, myoepithelial hyperplasia
- Intermediate: mixture of florid and fibrous patterns
- Fibrous: quiescent epithelium, hyalinized hypocellular stroma
- Other findings can include pseudoangiomatous stromal hyperplasia (PASH), apocrine or squamous metaplasia
- Atypical ductal hyperplasia (ADH) in 0.4 - 5.4% (Ann Plast Surg 2015;74:163, Histopathology 2015;66:398)
- Not clearly precancerous (Breast Cancer Res Treat 2019;175:1)
Microscopic (histologic) images
Contributed by Elaine Zhong, M.D.
Florid pattern
3 layer epithelium
Fibrous pattern
ADH in gynecomastia
DCIS in gynecomastia
Virtual slides
Images hosted on other servers:
Excision from 33 year old man
Biopsy from 81 year old man
Cytology description
- Biphasic epithelial and stromal fragments in a background of scattered single bipolar nuclei, similar to fibroadenoma
- Spindle cells, apocrine cells, foamy macrophages can be present
Cytology images
Images hosted on other servers:
Clusters of bland, cohesive epithelial cells
Positive stains
Sample pathology report
- Breast, retroareolar; core biopsy:
- Gynecomastia, (florid, intermediate or fibrotic) stage.
Differential diagnosis
- Male breast cancer:
- Histology identical to carcinoma of the female breast
- Atypical ductal hyperplasia:
- Monomorphic intraductal cells in rigid cribriform, micropapillary or solid formations
- Myofibroblastoma:
- Mass forming spindle cell proliferation that may entrap normal glandular elements
- Variable morphology and cellularity
- Mammary hamartoma:
- Circumscribed mass
- Additional mesenchymal elements (smooth muscle, adipose tissue, cartilage, etc.) may be present
- Fibroadenoma:
- Circumscribed mass
- Uniform stroma without significant periductal cuffing
- Intracanalicular or pericanalicular pattern of glandular elements
Additional references
Board review style question #1
Which of the following is the most common etiology in the development of gynecomastia?
- Cirrhosis
- Estrogen exposure in utero
- Hyperthyroidism
- Idiopathic
- Klinefelter syndrome
Board review style answer #1
Board review style question #2
What is the immunohistochemical profile of the intermediate epithelial cells of gynecomastia?
- ER/PR/AR+, CK5/6+
- ER/PR/AR+, CK5/6-
- ER/PR/AR-, CK5/6+
- ER/PR/AR-, CK5/6-
Board review style answer #2
Hamartoma
Table of Contents
Definition / general | Essential features | Terminology | Epidemiology | Sites | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1Definition / general
- Well circumscribed, often encapsulated mass composed of normal but disorganized components of breast tissue
Essential features
- Uncommon breast mass lesion that contains normal breast elements in varying proportions
- Clinically presents as painless lump or detected via breast imaging
- Microscopy shows well circumscribed mass with normal breast components (e.g., mammary glands, adipose tissue and fibrous stroma)
- Definitive diagnosis on core needle biopsy requires correlation with imaging
Terminology
- First described by Hogeman and Ostberg in 1968; term first used by Arrigoni in 1971 (Sem Hop 1976;52:1405)
- Acceptable by WHO: adenolipoma, chondrolipoma, myoid hamartoma
- Not recommended by WHO: fibroadenolipoma, adenolipofibroma
Epidemiology
- Uncommon; < 5% of all benign breast masses (Histopathology 2022;80:304)
- Predominantly women in fifth decade but can be seen at any age
Sites
- No specific location in the breast
Etiology
- Largely unknown; unclear whether a malformation or neoplasm
- Mostly sporadic; rarely associated with Cowden syndrome (multiple hamartomas)
Clinical features
- Presents as painless breast mass or detected by screening mammography or other breast imaging modalities
Diagnosis
- Mammographic or sonographic abnormality
- Often cannot be definitively diagnosed on core needle biopsy; excisional biopsy is more definitive
Radiology description
- Mammography: well circumscribed mass, described as "breast within breast" (Eur J Breast Health 2021;17:328, Med J Armed Forces India 2015;71:377)
- Ultrasound: mass with heterogeneous internal echogenicity
Radiology images
Images hosted on other servers:
Mammographic findings
Prognostic factors
- Rarely recurs; reported recurrences represent incomplete excisions (Aust J Gen Pract 2019;48:275)
- No increase in malignancy (same malignant potential as normal breast tissue)
Case reports
- 30 year old man with a 1 month history of a painless mass in his right breast (Medicine (Baltimore) 2019;98:e18372)
- 40 year old woman with huge myoid hamartoma of the breast treated with reduction mammaplasty (Surg Today 2014;44:2369)
- 41 year old woman with giant breast hamartoma (Oncol Lett 2015;10:3719)
Treatment
- Surgical excision is curative but not necessary
Gross description
- Well circumscribed, round to oval, range 1 - 14 cm; may resemble normal breast tissue, lipoma or fibroadenoma
Gross images
Images hosted on other servers:
Cut section of mammary hamartoma
Microscopic (histologic) description
- Circumscribed mass comprised of ducts, lobules, fibrous stroma, adipose tissue in varying proportions with disorganized architecture
- May have smooth muscle, cartilage or pseudoangiomatous stromal hyperplasia (PASH) (Histopathology 2022;80:304)
- Lesions with prominent myoid changes called myoid hamartomas (Geburtshilfe Frauenheilkd 2012;72:412)
- 2 variants:
- Adenolipoma: mature fat and mammary parenchyma in varying proportions, glands appear structurally normal with little proliferation
- Chondrolipoma: contains hyaline cartilage / cartilaginous metaplasia and fat, glandular elements are often scanty (Virchows Arch 2017;471:531)
Microscopic (histologic) images
Contributed by Indu Agarwal, M.D.
Mammary hamartoma
Components of mammary hamartoma
Myoid hamartoma
Myoid hamartoma, immunostain desmin
Myoid hamartoma, immunostain SMA
Cytology description
- Moderately cellular, bland epithelial and stromal components
- Diagnosis limited as findings are not specific (J Clin Pathol 2002;55:951)
Positive stains
- ER and PR expression similar to normal breast epithelium
- ER, PR and HMGA expression in stromal cells (Histopathology 2022;80:304)
- CD34 in intralobular, perilobular and interlobular distribution (Histopathology 2022;80:304)
- p63, CK5/6, calponin, smooth muscle myosin positive in myoepithelial cells
- Smooth muscle actin, desmin positive if smooth muscle elements present (Clinics (Sao Paulo) 2014;69:515)
Molecular / cytogenetics description
- Translocation in HMGA2 and germline mutations in tumor suppressor gene PTEN have been described (Cancer Genomics Proteomics 2019;16:563)
- Data is limited
Sample pathology report
- Left breast, mass at 11 o'clock, ultrasound guided core needle biopsy:
- Consistent with mammary hamartoma (see comment)
- Comment: A well circumscribed lesion is seen comprised of benign breast elements arranged in a disorganized manner. In light of the known breast mass seen on imaging, findings are consistent with a mammary hamartoma.
Differential diagnosis
- Fibroadenomas:
- In fibroadenoma, the epithelial elements often show more proliferative changes (e.g., usual type ductal hyperplasia, apocrine metaplasia)
- Fibroadenomas only rarely include adipose tissue
- Phyllodes tumor:
- Hypercellular stromal component, stromal atypia, frond formation, may show infiltrative borders
Additional references
Board review style question #1
A 45 year old woman presents for screening mammogram and a multilobulated 1.5 cm mass is detected. Ultrasound confirms the findings and a guided core needle biopsy is performed, which shows normal breast ducts, lobules, fibrous stroma and adipose tissue. The radiologist confirms that the lesion was biopsied. What is the most likely possibility?
- Angiolipoma
- Breast hamartoma
- Myofibroblastoma
- Radiologist missed the lesion
Board review style answer #1
B. Breast hamartoma. The mass lesion by imaging and the histologic finding of normal breast components with somewhat disorganized architecture support this diagnosis. Also, since the radiologist was confident that the lesion was biopsied, the possibility that the lesion was missed is excluded.
Comment here
Reference: Hamartoma
Comment here
Reference: Hamartoma
Hemangioma
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Diagrams / tables | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Negative stains | Videos | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Hemangioma:
- Benign vascular lesions, microscopically well circumscribed and lacking endothelial cell atypia (Semin Diagn Pathol 2017;34:410)
- Origination from large nonneoplastic "feeding" vessels, may be seen at the periphery of the lesion
- The following categories are recognized:
- Capillary (composed of compact, lobular, collections of small blood vessels)
- Cavernous (dilated vessels filled with erythrocytes)
- Venous (featuring vascular structures containing muscular walls of varying thickness) (Am J Surg Pathol 1985;9:659)
- Perilobular (≤ 2 mm, capillary hemangiomas, intra or interlobular location)
- Angiomatosis:
- Often clinically present as large mass (9 - 22 cm)
- Histologically benign vascular proliferation affecting a large segment of the breast
- Lacks circumscription of hemangioma and can involve the subcutaneous tissue and skin (Am J Surg Pathol 1985;9:652, Cancer 1988;62:2392)
Essential features
- Proliferation of well differentiated vessels of varying sizes
- Angiomatosis shows diffuse growth of blood vessels of varying sizes that surrounds ducts / lobules but without invasion of the intralobular stroma
- No complex anastomotic channels, cytologic atypia, cellular multilayering, solid areas, mitotic activity, necrosis or hemorrhage (blood lakes), features differentiating from angiosarcoma
Terminology
- Acceptable: angioma
ICD coding
- ICD-O: 9120/0 - hemangioma, NOS
- ICD-11: 2F30.Y & XH5AW4 - other specified benign neoplasm of breast and hemangioma, NOS
Epidemiology
- Small incidental hemangiomas of the breast are not uncommon (Eur J Surg 1992;158:503, J Clin Ultrasound 2012;40:512)
- Angiomatosis of the breast is very rare, most in younger women (< 40) years old
- In general, benign vascular tumors of breast are uncommon
- Reported in all ages, range 18 months to 82 years (J Clin Ultrasound 2012;40:512)
- Most common type: perilobular hemangioma, typically incidental and present in 1.2 - 11% of breast specimens (Arch Pathol Lab Med 1983;107:308)
Sites
- Mammary parenchyma, subcutaneous tissue or dermis
Pathophysiology
- Unknown
Etiology
- Nonneoplastic vascular malformations
Diagrams / tables
Images hosted on other servers:
Normal arterial and venous anatomy of the breast
Clinical features
- All age groups, mostly nonpalpable, found on imaging
- Occasionally a palpable lesion (Br J Radiol 2006;79:e177)
Diagnosis
- Biopsy or excision
Radiology description
- Mostly nonpalpable, found on imaging (MRI or mammography)
- No pathognomonic features, may show mammographic density or mass on mammogram or ultrasound, with oval or lobular shape and well circumscribed or microlobulated margins (AJR Am J Roentgenol 2008;191:W17)
Radiology images
Contributed by Indu Agarwal, M.D.
Cavernous hemangioma, ultrasound
Cavernous hemangioma, mammography
Capillary hemangioma, ultrasound
Prognostic factors
- Can recur; no metastasis reported
Case reports
- 18 year old woman with breast angiomatosis (J Clin Diagn Res 2012;6:709)
- 33 year old woman with breast hemangioma (J Clin Imaging Sci 2012;2:53)
- 43 year old woman, gravida 4, para 2, with cavernous breast hemangioma mimicking an invasive lesion on contrast enhanced MRI (Case Rep Surg 2019;2019:2327892)
- 60 year old woman with breast hemangioma mimicking carcinoma (Breast 2002;11:357)
- 64 year old man with hemangioma after thorn injury (BJR Case Rep 2021;7:20200187)
Treatment
- Excision has been done in the past; excision may not be mandatory if radiological / pathologic correlation is available (Histopathology 2017;71:795)
- Complete surgical excision necessary for angiomatosis (Radiol Case Rep 2017;12:219)
Clinical images
Contributed by Mark R. Wick, M.D.
Capillary hemangioma, breast skin
Images hosted on other servers:
Diffuse dermal angiomatosis
Gross description
- Larger lesions: circumscribed red or dark-brown spongy lesion
- Small lesions may not be appreciated grossly
- Angiomatosis presents as a large, red, hemorrhagic, cystic, spongy mass lesion
Gross images
AFIP images
Angiomatosis composed of vessels / breast parenchyma
Images hosted on other servers:
Soft tissue mass with smooth external surface
Cut surface shows congestion and slit-like areas
Microscopic (histologic) description
- Hemangioma:
- Proliferation of well differentiated blood vessels of varying sizes, generally small (< 2 cm), usually nonanastomosing
- Largely well circumscribed
- Cytologic atypia, hemorrhage, mitotic activity and necrosis are absent
- Within interlobular stroma, except in perilobular hemangioma which involves intralobular stroma
- Perilobular hemangioma: usually incidental microscopic lesions, ≤ 2 mm, conglomerate of small, thin walled capillary vessels in and around a lobule (Am J Surg Pathol 1985;9:491)
- Angiomatosis:
- Proliferation of vascular channels with wide variation in caliber, diffusely growing throughout the breast with some anastomosis
- Unencapsulated with infiltrative borders
- No invasion of intralobular stroma
- May extend to overlying skin (Clin Breast Cancer 2016;16:e7)
- Absence of destructive invasion, solid areas, hemorrhage and necrosis, differentiating it from angiosarcoma
- Low mitotic rate, Ki67 proliferation index < 2%
Microscopic (histologic) images
Contributed by Indu Agarwal, M.D. and AFIP images
Cavernous hemangioma of breast
Capillary hemangioma
Perilobular hemangioma
Complex hemangioma
Angiomatosis
Negative stains
Videos
Histopathology breast, soft tissue - hemangioma
Sample pathology report
- Left breast, MRI guided core needle biopsy:
- Breast tissue with perilobular hemangioma
Differential diagnosis
- Angiolipoma:
- Has intermixed adipose tissue, clusters of capillary sized vessels, some with microthrombi
- Angiosarcoma:
- Has solid areas, mitotic activity, infiltrative pattern of growth and complex anastomosing vascular channels
- Atypical vascular lesion:
- Often past history of radiation
- Anastomosing thin walled vessels, unlike well formed vessels of hemangioma
Additional references
Board review style question #1
A 58 year old woman had a 4.0 cm breast mass with overlying erythematous skin patch. A stereotactic biopsy showed the histology above. What is the best treatment recommendation for this patient?
- Excision with wide margins
- Lumpectomy with hormone therapy
- Lumpectomy with radiation
- No further treatment needed
Board review style answer #1
A. Excision with wide margins. This is an angiosarcoma with a predominantly solid appearance and the cells demonstrate nuclear atypia, unlike a hemangioma, which lacks these features. Wide excision, preferably mastectomy, should be performed.
Comment here
Reference: Hemangioma
Comment here
Reference: Hemangioma
Board review style question #2
A 35 year old woman presents with a 10 cm palpable breast mass. Core needle biopsy shows the lesion occupying the entire biopsy tissue and consisting of large, thin walled vessels lined by bland endothelial cells. The lesion surrounds but does not invade the normal breast lobular units. No cytologic atypia, necrosis, solid areas or mitotic activity is seen. The Ki67 proliferation index is 1%. What is the most likely diagnosis?
- Angiomatosis
- Angiosarcoma
- Cavernous hemangioma
- Lymphangioma
Board review style answer #2
A. Angiomatosis. This is a case of angiomatosis of breast. The lesion is large and consists of large, thin walled vessels, which lack atypia, mitosis and other malignant cytologic features, and do not invade the normal breast lobular stroma.
Comment here
Reference: Hemangioma
Comment here
Reference: Hemangioma
HER2 low breast cancer
Table of Contents
Definition / general | Essential features | Terminology | Clinical features | Interpretation | Uses by pathologists | Prognostic factors | Treatment | Microscopic (histologic) images | Molecular / cytogenetics images | Sample pathology report | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- HER2 low breast cancer is defined as either HER2 IHC score of 1+ or 2+ / ISH not amplified
Essential features
- HER2 low breast cancer is defined as either HER2 IHC score of 1+ or 2+ / ISH not amplified
- Heterogenous group that includes hormone receptor positive and triple negative breast cancers
- Per 2023 American Society of Clinical Oncology (ASCO) / College of American Pathologists (CAP) guidelines, interpretation for HER2 low is not recommended in the final pathology report at this time
Terminology
- HER2 negative by IHC (score 1+)
- HER2 equivocal by IHC (score 2+) and HER2 ISH not amplified
Clinical features
- Nearly half (~55 - 60%) of breast cancer patients will fit in HER2 low category
- Heterogenous group that includes hormone receptor positive and triple negative breast cancers
- Reference: Nat Med 2022 Jun 16 [Epub ahead of print]
Interpretation
- 2023 ASCO / CAP update on HER2 IHC and FISH interpretation still follows the 2018 ASCO / CAP guidelines (J Clin Oncol 2023;41:3867)
- HER2 IHC with a score of 0 or 1+ is still interpreted as negative, while score of 2+ is reported as equivocal with a reflex FISH test (please see also HER2 stain topic)
- However, the 2023 ASCO / CAP update recommends addition of a footnote to HER2 IHC interpretation report to address HER2 low results and the potential eligibility / benefit for these patients with the new class of ADC drugs (see Sample pathology report below for ASCO / CAP recommended footnote)
- See 2023 ASCO / CAP update on HER2 testing in breast cancer (Arch Pathol Lab Med 2023;147:993)
- See 2018 ASCO / CAP update on HER2 testing in breast cancer (J Clin Oncol 2018;36:2105)
Uses by pathologists
- HER2 IHC positive (score 3+)
- HER2 IHC equivocal (score 2+) with reflex to HER2 ISH
- HER2 IHC negative (score 0 or 1+)
- Per 2023 ASCO / CAP guidelines, interpretation for HER2 low is not recommended at this time
- Reference: Nat Med 2022 Jun 16 [Epub ahead of print]
Prognostic factors
- Prognosis is impacted by poor interrater reliability in interpretation of HER2 0 versus 1+ IHC (Mod Pathol 2023;36:100032, Hum Pathol 2022;127:50, J Clin Oncol 2022;40:1087)
- Conflicting data in literature with regards to prognostic implications
- Some studies have shown HER2 low patient subgroup have poorer prognosis compared to HER2 negative (score 0) subgroup (Oncologist 2012;17:1418, Endocr Relat Cancer 2015;22:725, Ann Oncol 2008;19:1706, Am J Surg Pathol 2009;33:759)
- Other studies have indicated that HER2 low results do not have distinct prognostic or predictive implications in breast cancer (JAMA Oncol 2022;8:1, JAMA Oncol 2022;8:1177, Eur J Cancer 2021;155:1)
- Currently no definite evidence of prognostic or predictive implications for HER2 low breast cancer patients
Treatment
- HER2 targeted monoclonal antibodies have not shown benefit in HER2 low breast cancer
- New class of HER2 monoclonal antibodies conjugated with a chemotherapy drug has been developed recently (antibody drug complex, ADC)
- Bystander effect / killing of ADC: HER2 antibodies target the covalently linked cytotoxic drugs to HER2 expressing cancer cells and kills them; these cytotoxic drugs are then released into extracellular space that are then uptaken by surrounding non-HER2 expressing cancer cells
- ADCs have shown benefit in HER2 low breast cancer in phase I / II clinical trials (Nat Med 2023;29:2110, J Clin Oncol 2020;38:1887)
- Phase 3 DESTINY-Breast04 trial shows increased median progression free survival (PFS) in patients receiving trastuzumab deruxtecan with advanced breast cancer (either unresectable or in a metastatic disease setting) (N Engl J Med 2022;387:9)
- DESTINY-Breast04 trial also shows the risk of disease progression / death is 50% lower in treatment group compared to control arm
Microscopic (histologic) images
Contributed by Anand C. Annan, M.D., Ph.D., Doaa Atwi, M.D. and Lewis A. Hassell, M.D.
Invasive ductal carcinoma, Nottingham grade 2
HER2 score 2+
Invasive ductal carcinoma, grade 2
HER2 score 2+
HER2 IHC score 1+
Invasive ductal carcinoma with cord and tubule formation
HER2 IHC score 1+
Molecular / cytogenetics images
Contributed by Terry Dunn, Ph.D.
Nonamplified HER2 FISH
Sample pathology report
- Breast, left, ultrasound guided core needle biopsy:
- Invasive breast carcinoma of no special type (ductal), grade 2
- Estrogen receptor: positive (90%, strong intensity)
- Progesterone receptor: positive (70%, intermediate intensity)
- HER2 by IHC: negative (score 1+) (see comment)
- Comment: Patients with breast cancers that are HER2 IHC 3+ or IHC 2+ / ISH amplified may be eligible for several therapies that disrupt HER2 signaling pathways. Invasive breast cancers that test HER2 negative (IHC 0, 1+ or 2+ / ISH not amplified) are more specifically considered HER2 negative for protein overexpression / gene amplification despite having some level of protein expression. Patients with breast cancers that are HER2 IHC 1+ or IHC 2+ / ISH not amplified may be eligible for treatment with a cytotoxic drug regimen that targets nonamplified / nonoverexpressed levels of HER2 (IHC 0 results do not currently result in eligibility).
- Invasive breast carcinoma of no special type (ductal), grade 2
Board review style question #1
According to the current 2023 update of American Society of Clinical Oncology (ASCO) / College of American Pathologists (CAP) guidelines for HER2 interpretation in breast cancer, how should the IHC result (see image above) be interpreted in a pathology report?
- HER2 negative (score 0)
- HER2 negative (score 1+)
- HER2 low positive (score 1+)
- HER2 positive (score 3+)
Board review style answer #1
B. HER2 negative (score 1+). The above IHC for HER2 shows faint / incomplete staining for HER2 in > 10% of tumor cells and is therefore interpreted with a score of 1+. Answer D is incorrect because as per the 2023 ASCO / CAP update, this IHC result should still be HER2 negative. Answer A is incorrect because tumors demonstrating HER2 IHC score 0 expression show no staining or ≤ 10% incomplete, faint / barely perceptible staining. Answer C is incorrect because although this is considered HER2 low positive, ASCO / CAP guidelines do not recommend using this terminology in the pathology report at this time. See 2023 ASCO / CAP update on HER2 interpretation (J Clin Oncol 2023;41:3867).
Comment Here
Reference: HER2 low breast cancer
Comment Here
Reference: HER2 low breast cancer
Board review style question #2
What is the current understanding of the prognostic implication of HER2 low positive breast cancer patients?
- HER2 low breast cancer patients with an IHC score of 2+ have a better prognosis that those with an IHC score of 1+
- There is no definite evidence of distinct prognostic implications
- They have a better prognosis than HER2 negative (score 0) patients
- They have a poorer prognosis than HER2 negative (score 0) patients
Board review style answer #2
B. There is no definite evidence of distinct prognostic implications. Answers A, C and D are incorrect because although there is some evidence in the literature that shows poorer prognoses for HER2 low patients compared to HER2 negative (score 0) patients, there is no distinct prognostic or predictive implications for HER2 low status.
Comment Here
Reference: HER2 low breast cancer
Comment Here
Reference: HER2 low breast cancer
Histologic grading
Table of Contents
Definition / general | Essential features | Epidemiology | Diagrams / tables | Prognostic factors | Microscopic (histologic) images | Videos | Sample pathology report | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Most commonly used system is the Nottingham combined histologic grade (Elston-Ellis modification of Scarff-Bloom-Richardson grading system) based on (a) tubule and gland formation, (b) nuclear pleomorphism, (c) number of mitotic figures in most active areas (Histopathology 1991;19:403, Br J Cancer 1957;11:359)
- Tumor should be graded based on representative portion of tumor (Arch Pathol Lab Med 1983;107:411)
Essential features
- Nottingham modification of Bloom-Richardson system, based on (a) tumor tubule formation, (b) nuclear pleomorphism and (c) number of mitotic figures in most active areas, with each given a score of 1, 2 or 3
- Scoring is done as follows
- 3 - 5 points: well differentiated (grade I)
- 6 - 7 points: moderately differentiated (grade II)
- 8 - 9 points: poorly differentiated (grade III)
- Histologic grade is a strong predictor of survival
Tumor tubule or gland formation
- 1 point: > 75% of tumor
- 2 points: 10 - 75% of tumor
- 3 points: < 10% of tumor
- Notes
- Overall appearance of the tumor must be taken into consideration in scoring tubule formation
- Tubules must have clear central lumina to be counted
Nuclear pleomorphism
- 1 point: minimal nuclear variation in size and shape (< 1.5 times the size of benign epithelial cell nuclei), even chromatin, inapparent to inconspicuous nucleoli
- 2 points: moderate nuclear variation in size and shape (1.5 - 2 times the size of benign epithelial cell nuclei), typically visible but small nucleoli
- 3 points: marked nuclear variation in size and shape (> 2 times the size of benign epithelial cell nuclei), often prominent nucleoli
- Notes
- Evaluate areas with greatest atypia
- For infiltrating lobular carcinoma, more emphasis has been placed on nuclear pleomorphism since tubule formation and mitotic activity show little variation, with proposal of a 2 tiered (nuclear grade 1 versus 2 / 3) system by some (Ann Diagn Pathol 2009;13:223)
Number of mitotic figures in most active area, counting 10 high power fields
| (a) | (b) | (c) | |
| 1 point | 0 - 5 | 0 - 9 | 0 - 11 |
| 2 points | 6 - 11 | 10 - 19 | 12 - 22 |
| 3 points | 11+ | 20+ | 23+ |
- (a) Nikon or Labophot 40x objective or comparable with field diameter of 0.44 mm
- (b) Leitz or Ortholux 25x objective or comparable with field diameter of 0.59 mm
- (c) Leitz or Diaplan 40x objective or comparable with field diameter of 0.63 mm
- Notes
- Count mitotic figures at peripheral leading edge of the tumor in most mitotically active area; count 10 high power fields in the same area but not necessarily contiguous; select fields with as much tumor as possible; avoid poorly preserved areas
- Hyperchromatic, karyorrhectic or apoptotic nuclei should be excluded; only clearly identifiable mitotic figures should be counted
- Quick scan mitotic impression is less accurate (Hum Pathol 2008;39:584)
Scoring
- 3 - 5 points: well differentiated (grade I)
- 6 - 7 points: moderately differentiated (grade II)
- 8 - 9 points: poorly differentiated (grade III)
| Feature | Subcategory | Score | |
| 1 | Tumor tubule or gland formation | > 75% of tumor | 1 |
| 10 - 75% of tumor | 2 | ||
| < 10% of tumor | 3 | ||
| 2 | Nuclear pleomorphism | Minimal variation in nuclear size and shape | 1 |
| Moderate variation in nuclear size and shape | 2 | ||
| Marked variation in nuclear size and shape | 3 | ||
| 3 | Mitotic count (per 10 high power fields) | See table above (dependent on microscope field area) | 1 |
| 2 | |||
| 3 | |||
| Total score | Grade I (well differentiated) | 3 - 5 | |
| Grade II (moderately differentiated) | 6 or 7 | ||
| Grade III (poorly differentiated) | 8 or 9 |
Epidemiology
- In the U.S., Black people overall have higher grade tumors than White people (Cancer 2003;98:908)
Diagrams / tables
Images hosted on other servers:
Breast cancer grade
Prognostic factors
- Histologic grade is an independent predictor of both breast cancer specific survival (BCSS) and disease free survival (DFS) in operable breast cancer (Mod Pathol 2005;18:1067)
Criticisms of Nottingham-Bloom-Richardson grading system
- Grading has been criticized for low reproducibility (Mod Pathol 2005;18:1067, Virchows Arch 2007;450:627)
- Reproducibility is highest at the ends of the spectrum of grade, with highest interobserver agreement for tubule formation versus other components (Mod Pathol 2021;34:701, Am J Clin Pathol 1995;103:195, Mod Pathol 2005;18:1067)
- Concept of a moderately differentiated category has been criticized (Pathobiology 2008;75:104, J Natl Cancer Inst 2006;98:262)
- Grade components are given equal weight but have different predictive value, with tubule formation being least predictive and nuclear pleomorphism and mitotic index having higher predictive value (Cancer 1989;64:1914)
Challenges of Nottingham-Bloom-Richardson grading system
- Small foci of carcinoma and crush or other artifacts on core biopsy may not allow adequate assessment of mitotic activity
- Spot count (number of mitoses in a single high power field) has been suggested as a surrogate and may be the only way to estimate mitotic activity in cases with limited tumor (Cancer 1989;64:1914)
- Tumors with 3 + 3 + 1 pattern (i.e., < 10% tubules, marked nuclear pleomorphism but few mitotic figures) may have low mitotic count due to failure to fix tumor immediately after excision, which allows tumor cells to complete cell division and leads to reduction in observed mitotic figures; Ki67 may serve as surrogate for mitotic figure counting in these cases (Oncologist 2008;13:477)
Possible steps to overcome limitations
- Interobserver reproducibility of histologic grade can be improved by better distinction between various categories for nuclear pleomorphism (Am J Clin Pathol 1995;103:195)
- Correlation with a proliferation marker such as Ki67 can help facilitate reproducibility and add complementary information to the modified Bloom-Richardson grading system; it can be used to further categorize grade II tumors into 2 prognostic subgroups with prognosis equivalent to grades I and III, respectively (J Cancer Res Ther 2018;14:537, Mod Pathol 2005;18:1067)
- Counting 20 - 30 rather than 10 high power fields to generate the mitotic score has been suggested to allow for lowering the cutoffs for mitotic index (Mod Pathol 2005;18:1067)
Microscopic (histologic) images
Contributed by Julie M. Jorns, M.D.
Grade 1 invasive lobular carcinoma
Grade 1 invasive ductal carcinoma
Grade 2 invasive ductal carcinoma
Grade 3 invasive ductal carcinoma
Videos
Breast ductal carcinoma (breast cancer)
Breast cancer grading and staging
Sample pathology report
- Right breast, core biopsy:
- Invasive ductal carcinoma, preliminary Nottingham (modified Bloom-Richardson) grade 1 (tubules - 1, nuclear pleomorphism - 2, mitotic activity - 1)
Additional references
Board review style question #1
A 52 year old woman has a breast biopsy showing the histology pictured above (H&E, 20x). A subsequent resection shows similar histology throughout the tumor. What is the Nottingham grade of this invasive breast carcinoma?
- Grade 1 (tubules - 1, nuclear pleomorphism - 1, mitotic activity - 1)
- Grade 1 (tubules - 1, nuclear pleomorphism - 2, mitotic activity - 1)
- Grade 1 (tubules - 3, nuclear pleomorphism - 1, mitotic activity - 1)
- Grade 2 (tubules - 3, nuclear pleomorphism - 2, mitotic activity - 1)
- Grade 2 (tubules - 3, nuclear pleomorphism - 2, mitotic activity - 2)
Board review style answer #1
C. Grade 1 (tubules - 3, nuclear pleomorphism - 1, mitotic activity - 1). The tumor is an invasive lobular carcinoma, which consists of infiltrative small cells (score 1 - similar in size to adjacent benign glandular epithelial cells) with minimal pleomorphism (score 1) arranged in linear files with no tubule formation (score 3), resulting in a Nottingham combined score of 5, for overall grade of 1 or a well differentiated carcinoma. Invasive lobular carcinomas have little variation in tubule formation (there is typically none but tubules may occasionally be seen) and mitotic activity, which is usually low. Thus, the Nottingham grade is often reliant on the degree of nuclear pleomorphism, which is typically minimal (score 1), resulting in an overall grade of 1 or moderate (score 2), resulting in an overall grade of 2. The other answers are incorrect as the tumor does not show any significant tubule formation (indicated in answers A and B), pleomorphism (answers B, D and E) or mitotic activity (answer E).
Comment Here
Reference: Breast - Histologic grading
Comment Here
Reference: Breast - Histologic grading
Board review style question #2
When evaluating Nottingham grade of invasive breast carcinoma, what is typically the best area of the tumor to assess mitotic score?
- Central portion
- Entire tumor
- Peripheral leading edge
- Region with greatest tubules
Board review style answer #2
C. Peripheral leading edge.
Answer B is incorrect because while the entire tumor should be examined for histologic features, the peripheral leading edge is typically most mitotically active and this area should be focused on while generating the mitotic score component in Nottingham grading. Answer A is incorrect because the central portion of a breast cancer may have central fibrosis or necrosis and may be less well preserved in resection specimens, potentially resulting in falsely lower mitotic activity than indicative of the tumor biology. Answer D is incorrect because areas with higher tubule formation are more likely to be well differentiated areas of a heterogeneous tumor with lower mitotic activity and not representative of the most aggressive portion of the tumor.
Comment Here
Reference: Breast - Histologic grading
Comment Here
Reference: Breast - Histologic grading
Histology
Table of Contents
Definition / general | Essential features | Embryology | Histology | Menstrual cycle related changes | Pregnancy / lactation | Menopause | Neonatal breast | Male breast | Transsexual breast | Clinical features | Gross description | Gross images | Microscopic (histologic) images | Positive stains | Negative stains | Electron microscopy images | Videos | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Mammary glands located on the upper anterior thorax that produce and secrete milk in females
Essential features
- Adult female breast consists of branching ducts and acini; the acini group together to form lobules
- Ductal - lobular system: composed of ducts and acini lined by a dual inner (luminal) epithelial cell layer and outer (basal) myoepithelial cell layer, resting on a basement membrane, enveloped by stroma
- Exhibits physiologic histomorphologic changes during menstrual cycle, pregnancy / lactation, menopause, exogenous hormone therapy
Embryology
- Considered an epidermal gland, as it develops as diverticula of epidermis into dermis
- Mammary gland development begins at week 5
- Week 5:
- Ectodermal thickenings called mammary ridges develop along ventral embryo, extending from axilla to medial thigh
- Ridges eventually disappear, except at fourth intercostal space where mammary gland develops
- Week 15 - 20:
- Mesenchyme condenses around epithelial stalk under testosterone influence
- Solid epithelial columns develop within mesenchyme
- Week 20 - 32:
- Differentiation of mesenchyme into fat within collagenous stroma
- Stroma of reticular dermis forms suspensory ligaments of Cooper, attaching breast to skin and subdividing breast into lobes
- Areola formed by ectoderm
- Week 32 - 40:
- Epithelial cords canalize and branch, forming lobuloalveolar structures
- Depression in epidermis forms at the convergence of lactiferous ducts: mammary pit
- Near term birth: nipple formed by evagination of mammary pit
- Reference: Mills: Histology for Pathologists, 4th Edition, 2012
Histology
- Ductal - lobular system:
- Consists of large lactiferous ducts that open to the surface of the nipple via lactiferous sinuses, which branch into ducts and terminal ductules which terminate in acini
- Acini are grouped together in clusters to form lobules (terminal duct lobular unit)
- Ductal - lobular system is arranged in series of segments (5 - 10)
- Cellular lining of the ductal - lobular system is bilayered and consists of:
- Inner (luminal) epithelial cells: cuboidal to columnar epithelium with pale eosinophilic cytoplasm
- Outer (basal) myoepithelium: variably distinctive, varies in appearance from flattened cells with compressed nuclei to prominent epithelioid cells with abundant clear cytoplasm, can sometimes have myoid appearance
- Both epithelial and myoepithelial cells thought to arise from a bipotent progenitor cell (Oncotarget 2017;8:10675)
- Basement membrane surrounds mammary ducts, ductules and acini (Virchows Arch A Pathol Anat Histopathol 1992;421:323)
- Basement membrane contains type IV collagen and laminin, demarcates ductal - lobular system from the surrounding stroma
- Transgression of the myoepithelial layer and basement membrane by tumor cells defines invasion
- Stroma:
- Consists of varying amounts of fibrous tissue and adipose tissue and can be divided into:
- Interlobular stroma:
- Surrounds large ducts and terminal duct lobular units (TDLUs), denser, more collagenous than intralobular connective tissue
- Multinucleated giant cells of unknown significance are sometimes present (Virchows Arch 2001;439:768)
- Intralobular stroma: surrounds acini within TDLUs, loose, contains fibroblasts, scattered inflammatory cells and histiocytes
- Interlobular stroma:
- Consists of varying amounts of fibrous tissue and adipose tissue and can be divided into:
- Nipple - areolar complex: skin variably pigmented, contains numerous sebaceous glands
- Independent of hair follicles, except at periphery of areola; contains dense fibrous stroma with bundles of smooth muscle
- Montgomery tubercles: sebaceous glands sharing ostium with a lactiferous duct, more prominent during pregnancy and lactation
- Epidermis may contain occasional clear cells, either clear keratinocytes or Toker cells (epidermally located mammary duct epithelium)
- Toker cells found in 10% of normal nipple (Histol Histopathol 2009;24:367)
- Stratified squamous epithelium extends into duct lumens for 1 - 2 mm (Clin Radiol 2012;67:e42)
Pregnancy / lactation
- Dramatic increase in the number of lobules, as well as acinar units
- Increased epithelial cell proliferation and lobuloalveolar differentiation
- Decrease in intralobular and interlobular stroma
- Second and third trimester:
- Increase in size of epithelial cells and cytoplasmic vacuolization, myoepithelial cells difficult to discern
- Lactation:
- Abundant secretory material and prominent cytoplasmic vacuoles, epithelial cells may have bulbous or hobnail appearance
- Myoepithelial cells remain inconspicuous
- Rarely areas of infarction (Exp Ther Med 2015;10:1888)
Menopause
- Reduction of estrogen and progesterone causes involution and atrophy of TDLUs
- Reduction in size and complexity of acini, loss of specialized intralobular stroma
- Hyalinized stroma with relative increase in fat
- Reference: Mills: Histology for Pathologists, 4th Edition, 2012
Neonatal breast
- Identical in males and females at birth
- Breast enlargement due to neonatal prolactin production, caused by falling maternal estrogen
- Associated with production of colostrum
- Extramedullary hematopoiesis may be seen (J Pediatr Hematol Oncol 2012;34:229)
Male breast
- Composed of ductal structures only within collagenized stroma, with no / rare acini
Transsexual breast
- Female to male conversion results from prolonged androgen administration, starting prior to mastectomy
- Reduction in glandular tissue and prominence of stroma (J Histochem Cytochem 2006;54:905)
- Calcifications more frequent (J Pathol 1993;170:37)
- Male to female conversion involves prolonged estrogen therapy and chemical castration with progestational agents
- Changes include well developed lobular structures and pregnancy related changes
Clinical features
- Gross anatomy:
- Lies on the anterior chest wall over the pectoralis major muscle, extends from second to sixth rib vertically and from sternal edge to midaxillary line horizontally
- Also projects into the axilla as the tail of Spence
- Microscopic foci of glandular tissue may extend through the pectoral fascia
- Clinical relevance: total mastectomy does not remove all glandular breast tissue
- Arterial supply, lymphatic flow:
- Principal arterial supply by the internal mammary and lateral thoracic arteries
- Lymphatic drainage: > 90% to axillary lymph nodes, remaining to internal mammary and posterior intercostal nodes
- Relevance to staging, as metastasis to internal mammary node is higher nodal stage
- Breast tissue is typically less nodular, late follicular phase is the optimal time for mammography (Radiol Phys Technol 2018;11:20)
- Loss of myoepithelium is usually considered evidence of invasion, with the exception of microglandular adenosis, encapsulated papillary carcinoma and solid papillary carcinoma
- Transsexual breast may develop any benign or malignant process seen in nontranssexual breast (Hoda: Rosen's Breast Pathology, 4th Edition, 2014)
Gross description
- Mastectomy attempts to remove all breast tissue
- Different types of mastectomies: simple, modified radical, prophylactic, skin sparing, nipple sparing and radical
- Axillary dissections performed for the staging of invasive carcinoma
- Number of lymph nodes with metastases is the most important prognostic factor for breast carcinoma
- Reference: Lester: Manual of Surgical Pathology, 3rd Edition, 2010
Gross images
Images hosted on other servers:
Mastectomy specimen, anterior view
Microscopic (histologic) images
Contributed by Indu Agarwal, M.D.
Terminal duct lobular unit (TDLU)
Extralobular and TDLU
Myoepithelial cells
Myoid appearance
Clear cell change
Cross section of nipple
Lactiferous duct
Lactational changes
Immunostain ER
Immunostain p63
Positive stains
- Basement membrane: laminin, type IV collagen and reticulin
- Epithelium / luminal cells:
- Usually express luminal cytokeratins: LMWCK, CK7, CK8, CK18, CK19 (J Pathol 2004;203:661)
- Also express mammaglobin, gross cystic disease fluid protein (GCDFP)
- Most express ER alpha or PR in a heterogeneous pattern
- E-cadherin, p120, beta catenin in membranous pattern
- Myoepithelial cells:
- Basal cytokeratins: HMWCK, CK5/6, CK14 (Front Biosci (Landmark Ed) 2010;15:226)
- P-cadherin, calponin, smooth muscle myosin heavy chain (SMMHC), smooth muscle actin, CD10, S100 (Arch Pathol Lab Med 2008;132:349)
- At least 2 markers, 1 with a nuclear staining pattern (e.g. p63) and 1 with cytoplasmic staining (e.g. SMMHC) recommended
- Toker cells: CK7, EMA and usually positive for ER and PR
Negative stains
- HER2 / neu overexpression or amplification not seen in normal breast, restricted to carcinomas (J Clin Oncol 2000;18:267)
Electron microscopy images
Images hosted on other servers:
Acini
Glandular and myoepithelial cells
Videos
Shotgun histology inactive breast
Additional references
Board review style question #1
From the image above, what is the most likely diagnosis?
- Atypical apocrine adenosis
- Lactational changes
- Microglandular adenosis
- Secretory carcinoma
Board review style answer #1
B. Lactational changes. During lactation, epithelial cells are enlarged and have a bulbous or hobnail appearance with attenuated myoepithelial cells. These florid changes seen can be alarming and can be mistaken for atypia or malignancy.
Comment Here
Reference: Breast - Histology
Comment Here
Reference: Breast - Histology
Board review style question #2
Myoepithelial cells are always retained in which of the following?
- Atypical ductal hyperplasia
- Encapsulated papillary carcinoma
- Invasive tubular carcinoma
- Microglandular adenosis
Board review style answer #2
A. Atypical ductal hyperplasia. Myoepithelium is retained in atypical ductal hyperplasia and most benign and in situ lesions, with the exception of microglandular adenosis and a few in situ lesions, e.g. encapsulated papillary carcinoma.
Comment Here
Reference: Breast - Histology
Comment Here
Reference: Breast - Histology
Hormonal therapy
Table of Contents
Definition / general | Essential features | Prognostic factors | Microscopic (histologic) description | Microscopic (histologic) images | Molecular / cytogenetics description | Board review style question #1 | Board review style answer #1Definition / general
- Endocrine / hormonal therapy may be utilized in the treatment of hormone receptor positive breast carcinoma in the adjuvant (postoperative) or neoadjuvant (preoperative) setting
- Most commonly used endocrine therapies are the antiestrogen / inhibiting agent tamoxifen or aromatase inhibitors (e.g. letrozole, anastrozole)
Essential features
- Hormone receptor positive breast carcinomas may be treated with neoadjuvant endocrine therapy with lower toxicity and cost than the alternative of neoadjuvant chemotherapy
- Neoadjuvant endocrine therapy with aromatase inhibitors shows response rates similar to those seen with neoadjuvant chemotherapy (JAMA Oncol 2016;2:1477)
- Change in proliferative rate (as measured by Ki67), in the pre- vs posttreatment tumor, is related to long term prognosis and is a validated endpoint for neoadjuvant endocrine therapy (Eur J Surg Oncol 2016;42:333, Oncotarget 2017;8:26122)
Prognostic factors
- The PEPI (preoperative endocrine proliferative index) score, calculated from a sum of risk points derived from the pT stage, pN stage, Ki67 level and ER status of the posttreatment surgical specimen, is predictive of recurrence free survival (J Clin Oncol 2005;23:5108)
Microscopic (histologic) description
- Microscopic effects in invasive breast carcinomas (Eur J Cancer 2003;39:462)
- Treatment with the aromatase inhibitor, letrozole, results in decreased mitoses and decreased progesterone receptor expression
- Treatment with the antiestrogen / inhibiting agent, tamoxifen, results in increased tubule formation, decreased estrogen receptor expression and increased progesterone receptor
- Microscopic effects in ductal carcinoma in situ (DCIS) (BMC Cancer 2009;9:285)
- Treatment with antiestrogen therapy results in increased multinucleated histiocytes and degenerated cells, decrease duct extension and prominent periductal fibrosis
Microscopic (histologic) images
Images hosted on other servers:
Various images
Molecular / cytogenetics description
- Invasive lobular and invasive ductal carcinomas demonstrate similar molecular changes in gene expression in response to endocrine therapy, such as downregulation of proliferation genes and upregulation of immune function and extracellular matrix remodeling genes (Cancer Res 2014;74:5371)
Board review style question #1
What tumor change, in response to preoperative endocrine therapy, would be considered predictive of a favorable outcome?
- Decreased histiocytes
- Decreased tubule formation
- Increased estrogen receptor expression
- Increased tumor cellularity
- Lower proliferative index
Board review style answer #1
E.
The effects of preoperative endocrine therapy seen microscopically in the posttreatment surgical specimen may vary but most commonly include reduced tumor cellularity with decreased estrogen receptor expression in tumor cells. Response to therapy also typically includes increased histiocytic infiltration and tubule formation. A reduction in tumor proliferative index following endocrine therapy is associated with improved recurrence free survival.
Comment Here
Reference: Hormonal therapy
Comment Here
Reference: Hormonal therapy
Hormone receptors
Table of Contents
Definition / general | Essential features | Terminology | Pathophysiology | Clinical features | Interpretation | Uses by pathologists | Prognostic factors | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Positive staining - normal | Positive staining - disease | Negative staining | Sample pathology report | Board review style question #1 | Board review style answer #1Definition / general
- The most clinically important hormone receptors in breast cancer are estrogen, progesterone, and to a lesser extent, androgen receptors
- Hormone receptor status is strongly associated with histology, prognosis and treatment response
Essential features
- Clinically used hormone receptor markers for breast cancers include estrogen, progesterone and androgen receptors
- Expression of hormone markers is associated with favorable prognostic features and less aggressive histologic features
- Estrogen and progesterone expression select breast cancer patients for hormone therapy
Terminology
- Estrogen receptor alpha
- ERα is the routinely used marker in a clinical setting
- Predictive value in prognostication and treatment response is better established in ERα compared to ERβ (Biomark Res 2020;8:39)
- ER immunostain usually refers to ERα unless otherwise specified
Pathophysiology
- General
- The hormone receptors most commonly expressed in breast cancers are for sex steroid hormones (estrogen, progesterone and androgen), which are involved in breast cancer behavior and treatment (Breast 2013;22:S38)
- These hormones activate nuclear receptors involved in gene transcription and directly control cellular functions (Cold Spring Harb Perspect Biol 2013;5:a016709)
- Glucocorticoid receptor also expressed in breast cancers but is not commonly used in clinical settings (Int J Mol Sci 2021;22:4446)
- Estrogen receptor (ER)
- 2 subtypes: ERα and ERβ
- ERα
- ER subtype that is assessed in breast cancer typing, prognostication and treatment decision
- ER immunostain usually refers to ERα unless specified
- Expressed in breast epithelium and > 70% of breast cancers (Clin Cancer Res 2019;25:1970)
- Promotes carcinogenesis through oxidative damage and induces proliferation and inhibits apoptosis in breast cancer (N Engl J Med 2006;354:270)
- ERβ
- Discovered after ERα, as the second estrogen receptor (Proc Natl Acad Sci U S A 1996;93:5925)
- Expressed in breast epithelium, myoepithelium and 20 - 30% of breast cancers (Breast Cancer Res Treat 2020;179:241)
- Isoforms ERβ1, ERβ2 and ERβ5 are important in breast cancer with prognostic associations (Clin Cancer Res 2008;14:5228)
- ERβ inhibits epithelial to mesenchymal transition and exerts antiproliferative effects in breast cancers (Mol Cell Endocrinol 2014;382:665)
- Progesterone receptor (PR)
- PR is dependent on estrogen for its expression, upregulated by ER and modulates the behavior of ER (Nature 2015;523:313)
- > 80% of ER positive breast cancers are PR positive; > 95% of PR positive breast cancers are ER positive (Breast Cancer Res 2007;9:R6)
- PR activity is implicated in tumor differentiation and chemotherapy resistance (Womens Health (Lond) 2008;4:151)
- Androgen receptor (AR)
- AR is positive in 73 - 88% of breast cancers and 41 - 55% of triple negative breast cancers (Ann Oncol 2011;22:1288, Am J Cancer Res 2014;4:353, PLoS One 2018;13:e0197827)
- AR exhibits tumor suppressive effects in ER positive breast cancers but may assert protumor effects in triple negative breast cancers (Nat Med 2021;27:310, Breast Cancer Res Treat 2010;123:139)
- Not currently used in routine breast marker assessment since an independent prognostic value has not been established and lacks approved androgen related therapy for breast cancers (Molecules 2020;25:358)
Clinical features
- Estrogen receptor
- Older average age of presentation in ER positive breast cancers (Breast Cancer Res Treat 2002;74:199)
- ER positivity is associated with smaller tumor size and lower risk of lymph node metastasis (Breast Cancer Res 2007;9:R6)
- Expression of AR and PR are correlated with ER and demonstrate similar associations with demographic and disease parameters (Asian Pac J Cancer Prev 2012;13:5047, Appl Immunohistochem Mol Morphol 2016;24:550)
Interpretation
- Estrogen, progesterone and androgen receptors are nuclear stains
- Interpretation of ER and PR outlined by ASCO / CAP guideline on estrogen and progesterone receptor testing in breast cancer (J Clin Oncol 2020;38:1346)
- Staining is considered positive regardless of intensity
- Reported as percentage of tumor nuclei positive (0 - 100%)
- 1 - 100% staining considered as positive, < 1% staining considered as negative
- ER low positive category (1 - 10% staining) introduced in the latest ASCO / CAP Guideline
- Other scoring methods (Ann Oncol 2013;24:47)
- Allred score
- Summation of proportion (0 - 5) and intensity (0 - 3) of ER positive tumor cells into a score of 0 to 8 out of 8
- Proportion
- 0: 0%
- 1: < 1%
- 2: 1 - 10%
- 3: 11 - 33%
- 4: 34 - 66%
- 5: > 66%
- Intensity
- 0: negative
- 1: weak
- 2: moderate
- 3: strong
- Scores 0 and 2 interpreted as negative; scores 3 to 8 interpreted as positive
- H score
- Score of 0 to 300 from multiplying proportion as percentage (0 - 100) and intensity (0 - 3) of ER positive tumor cells
- % of tumor cells with weak staining x 1 + % of tumor cells with moderate staining x 2 + % of tumor cells with strong staining x 3
- Allred score
- Pitfalls in ER and PR assessment are not uncommon and should be avoided (Pathobiology 2022 Mar 4 [Epub ahead of print])
- Positive staining in nonneoplastic or entrapped breast tissue, proliferative and in situ lesions should be excluded
- Prolonged cold ischemia time can decrease ER and PR expression
- ER and PR antigenicity are also sensitive to tissue processing, fixation protocol and decalcification
Uses by pathologists
- Routine assessment of breast cancer
- For prognostication of breast cancers
- Selecting ER positive breast cancers for hormonal therapy
- ER and PR are components of the surrogate classification for breast cancer subtyping (Breast 2016;29:181)
- ER / PR positivity indicates luminal-like breast cancers
- Differentiating hyperplastic and neoplastic breast lesions
- Homogenous uniform ER staining indicates clonality and favors a neoplastic process (Mod Pathol 2010;23:S1)
- Homogenous uniform ER staining: columnar cell change, columnar cell hyperplasia, flat epithelial atypia, atypical ductal hyperplasia and carcinoma in situ
- Heterogenous ER staining: normal breast epithelium, usual ductal hyperplasia and florid epithelial hyperplasia
- AR can be used to demonstrate apocrine differentiation, usually with coexpression of GCDFP15 (Pathol Res Pract 1997;193:753, BMC Cancer 2014;14:546)
- Homogenous uniform ER staining indicates clonality and favors a neoplastic process (Mod Pathol 2010;23:S1)
- There are many other uses to ER and PR, including assessment of metastatic carcinomas and gynecological lesions
- These uses are not in the scope of this topic; please refer to estrogen receptor
Prognostic factors
- ERα
- ER is the primary marker used in selection of patients for hormone therapy and its expression is correlated with response to endocrine therapy (Tumori 2008;94:370)
- ER expression is an independent favorable prognostic factor for overall and disease specific survival (Cancer 2005;103:2241)
- Late recurrences, although uncommon, are more frequent in ER positive breast cancers (J Natl Cancer Inst 2022;114:391)
- ER low positive breast cancers behave more similarly to ER negative breast cancers, with worse outcomes and inferior response to hormonal therapy
- ERβ
- ERβ1 and ERβ2 associated with improved disease free and overall survival but no independent prognostic value over ERα (Oncotarget 2016;7:10373)
- Potential for selecting ERα negative breast cancers for ERβ selective agonists (Clin Breast Cancer 2016;16:256)
- Progesterone receptor
- PR expression is associated with improved clinical outcomes, independent from ER (Br J Cancer 2014;110:565)
- Androgen receptor
- Conflicting results on prognostic value of AR in breast cancers but unlikely to have independent predictive value over ER (Breast Cancer Res 2019;21:30, J Clin Med 2020;9:1083, Appl Immunohistochem Mol Morphol 2016;24:550)
Microscopic (histologic) description
- The most common type of ER positive (and PR, AR positive breast cancers which are correlated with ER expression) breast cancer is low grade invasive breast carcinoma of no special type (IBC, NST) (Breast Care (Basel) 2020;15:327)
- Features include prominent tubule formation, mild nuclear pleomorphism and a low mitotic count
- Other histological features include fewer tumor infiltrating lymphocytes, less lymphovascular invasion and more fibrotic foci (Br J Cancer 2020;123:1223, Ann Surg Oncol 2013;20:2842)
- Special types of breast cancer which are commonly ER positive include lobular, micropapillary, mucinous, papillary and tubular carcinomas (Breast Care (Basel) 2020;15:327)
Microscopic (histologic) images
Contributed by Joshua J.X. Li, M.B.Ch.B. and Gary M. Tse, M.B.B.S.
Low grade IBC, NST
Invasive lobular carcinoma
Papillary carcinoma
Estrogen receptor
Progesterone receptor
Androgen receptor
Apocrine carcinoma
Androgen receptor
Atypical ductal hyperplasia
Estrogen receptor
Columnar cell change
Estrogen receptor
Florid epithelial hyperplasia
Estrogen receptor
Estrogen receptor low positive
Estrogen receptor low positive
Virtual slides
Images hosted on other servers:
Invasive lobular carcinoma
Low grade IBC, NST
ER immunostaining
Positive staining - normal
- Estrogen receptor:
- Breast epithelium and stromal fibroblasts (Int J Cancer 2002;102:334, Breast Cancer Res Treat 2013;142:211)
- Breast myoepithelium expresses ERβ but not ERα (J Mammary Gland Biol Neoplasia 2005;10:231)
- Progesterone receptor:
- Breast epithelium (J Mammary Gland Biol Neoplasia 2004;9:3)
- Androgen receptor:
- Breast epithelium, stromal fibroblasts and adipocytes (Mol Endocrinol 2012;26:1252)
- Apocrine and sebaceous glands (J Endocrinol 1992;133:467)
- For staining in tissue other than the breast, please refer to estrogen receptor, progesterone receptor, androgen receptor
Positive staining - disease
- Estrogen receptor (ERα):
- Clonal proliferative lesions: columnar cell change, columnar cell hyperplasia and flat epithelial atypia (Breast J 2005;11:326)
- Malignant and premalignant lesions: ductal carcinoma in situ (low grade is diffusely positive, intermediate and high grade lesions can be positive or negative), lobular carcinoma in situ, low grade invasive breast carcinoma of no special type; special types of breast cancer - cribriform, lobular, micropapillary, mucinous, neuroendocrine, papillary and tubular carcinomas (Arch Pathol Lab Med 2016;140:686, Histopathology 2007;50:875, Breast Care (Basel) 2020;15:327)
- Cancer associated fibroblasts (Breast Cancer Res Treat 2013;142:211)
- Progesterone receptor:
- Expression of PR is highly associated with and similar to ER in most breast lesions (J Clin Pathol 2007;60:1307, Br J Cancer 2020;123:1223)
- Androgen receptor:
- Apocrine lesions: apocrine metaplasia, apocrine ductal carcinoma in situ and apocrine carcinoma (Pathol Res Pract 1997;193:753)
- Expression of AR in ductal carcinoma in situ and invasive carcinomas is associated with ER expression (J Clin Pathol 2002;55:14, Mod Pathol 2010;23:205)
- Skin adnexal lesions: Paget disease (mammary and extramammary), sebaceous lesions (sebaceous hyperplasia, sebaceous adenoma, sebaceoma and sebaceous carcinoma) (Mod Pathol 2005;18:1283, Mod Pathol 2010;23:205)
- For staining in tissue other than the breast, please refer to estrogen receptor, progesterone receptor, androgen receptor
Negative staining
- Estrogen receptor:
- Microglandular adenosis
- Invasive breast carcinoma of no special type of high grade or with medullary features (Mod Pathol 2005;18:26)
- Special types of breast cancer: acinic cell carcinoma, adenoid cystic carcinoma, apocrine carcinoma, metaplastic carcinomas (fibromatosis-like, monophasic and biphasic) (Diag Histopathol 2020;26:76, Cancer Biol Med 2020;17:293)
- Progesterone receptor and androgen receptor expression is closely related to estrogen receptor expression in most breast lesions, with the exception of apocrine lesions (see Positive staining - disease)
Sample pathology report
- Left breast, biopsy:
- Invasive breast carcinoma of no special type (see comment)
- Comment: Immunostaining shows that the invasive tumor cells are ER positive (strong [3+] intensity, 70%) and PR positive (strong [3+] intensity, 70%).
Board review style question #1
Which of the following is a histological feature associated with estrogen receptor positivity in breast cancers?
- Abundant intratumoral and stromal lymphocytes
- Frequent mitotic figures
- Highly pleomorphic nuclei
- Lymphovascular invasion
- Prominent tubule formation
Board review style answer #1
E. Prominent tubule formation. ER positivity is associated with low grade features (Breast Care (Basel) 2020;15:327). Lymphovascular invasion, medullary features and tumor infiltrating lymphocytes are associated with ER negativity (Br J Cancer 2020;123:1223, Cancer Biol Med 2020;17:293).
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Reference: Hormone receptors
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Reference: Hormone receptors
Idiopathic granulomatous mastitis
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Laboratory | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Negative stains | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1Definition / general
- Lobulocentric granulomatous inflammation
- Diagnosis of exclusion (excluding other causes of granulomatous inflammation)
Essential features
- Rare, benign inflammatory process affecting women of childbearing age
- Clinical symptoms and radiologic findings concerning for breast cancer
- Reported association with pregnancy, lactation, oral contraceptive pill use, hyperprolactinemia, autoimmunity
- Lobulocentric granulomatous inflammation
- Diagnosis of exclusion
Terminology
- Idiopathic granulomatous mastitis
- Lobular granulomatous mastitis
Epidemiology
- Rare
- Most common in parous women, childbearing age
- Frequent in postpartum and breastfeeding women
- Median age in the 30s
Sites
- Breast, most often unilateral, rarely bilateral
Pathophysiology
- Unknown
Etiology
- Unknown
- Proposed causes or associations: pregnancy, lactation, oral contraceptive pill use, hyperprolactinemia, autoimmunity, infection
Clinical features
- Mimics breast cancer, including inflammatory breast cancer (Breast J 2019;25:1245)
- Palpable breast mass
- Breast pain
- Abscess formation with fistula tract formation
- Nipple retraction
- Peau d'orange
- Rare lymphadenopathy
Diagnosis
- Breast core biopsy or surgical excision with histologic examination
Laboratory
- Microbiology studies to exclude infection
- Serologic markers to exclude autoimmune processes
- Endocrine studies
Radiology description
- Nonspecific imaging findings (Radiographics 2018;38:330)
- Mammography: focal asymmetric density (Clin Imaging 2021;69:126)
- Ultrasound: irregular hypoechoic mass with tubular projections (Clin Imaging 2021;69:126)
- MRI: nonmass-like enhancement; ring enhancing lesions (Acta Radiol 2016;57:796, Clin Imaging 2021;69:126)
Radiology images
Images hosted on other servers:
Mammogram; focal asymmetry
Ultrasound; hypoechoic tubular extensions
MRI; enhancing retroareolar mass
Prognostic factors
- Self limiting in approximately 50% of patients (Am J Surg 2015;210:258)
- Can persist or recur, prompting treatment
Case reports
- 33 year old woman with chronic breast wound (Breast J 2020;26:281)
- 36 year old woman with tender breast mass (Int Semin Surg Oncol 2007;4:21)
- 37 year old woman with painless breast mass (J Clin Diagn Res 2017;11:PD14)
- 43 year old woman with tender breast mass and erythema nodosum (JAAD Case Rep 2016;2:125)
Treatment
- No standard treatment guidelines
- Observation (Am J Surg 2015;210:258)
- Corticosteroids after infection excluded
- Antibiotics might not be effective
- Immunosuppressants (methotrexate, azathioprine) in persistent or recurrent disease (Surgeon 2021 Apr 6 [Epub ahead of print])
- Surgery
Clinical images
Contributed by Nicolas Ajkay, M.D.
IGLM with multiple
sinus tracts
opening onto skin
IGLM with response
to corticosteroids
Images hosted on other servers:
Appearance of second lump postbiopsy
Firm mass with multiple sinuses
Gross description
- Gray-tan firm mass
- Size variable; average 5 - 6 cm
- Ill defined margins
- Subtle nodularity
Microscopic (histologic) description
- Lobulocentric granulomatous inflammation (Pathology 2004;36:254)
- Granulomas often contain neutrophils
- Neutrophils can create microabscesses; overlapping features with cystic neutrophilic granulomatous mastitis
- Multinucleated giant cells, lymphocytes, plasma cells and eosinophils within and around lobules
- Extensive inflammation might obliterate lobulocentric distribution
- Caseous necrosis not present
- Schauman and asteroid bodies not common
Microscopic (histologic) images
Contributed by Jonathan Marotti, M.D. and Mary Ann Gimenez Sanders, M.D., Ph.D.
Lobulocentric inflammation
Multinucleated giant cells
Nonnecrotizing granulomas
Lobulocentric inflammation
Granulomas and multinucleated giant cells
Cytology description
- Nonspecific cytologic findings (J Clin Pathol 2003;56:519, Acta Cytol 2009;53:667)
- Epithelioid histiocytes, multinucleated giant cells, granulomas
- Necrosis usually absent
Positive stains
- CD68: positive in histiocytes
Negative stains
- Gram stain for gram positive bacilli (Corynebacterium)
- Acid fast stain for mycobacteria
- GMS or PAS stains for fungi
- IgG4 in plasma cells for IgG4 related sclerosing mastitis
Sample pathology report
- Left breast, needle core biopsy:
- Breast tissue with lobulocentric granulomatous inflammation (see comment)
- Comment: Sections show a lobulocentric mastitis with histiocytes, granulomas, neutrophils and lymphocytes. The histologic findings are nonspecific but the main differential diagnosis includes idiopathic granulomatous mastitis, cystic neutrophilic granulomatous mastitis (typically caused by Corynebacterium), other infection, sarcoidosis and reaction to foreign material, among others. Given the lobulocentric nature of the granulomatous inflammation and lack of currently identifiable microorganisms, idiopathic granulomatous mastitis is favored. However, clinical and microbiologic correlation is required. Special stains for bacteria, acid fast bacilli and fungi are negative. Foreign material is not identified. There is no evidence of malignancy in this sample.
Differential diagnosis
- Cystic neutrophilic granulomatous mastitis (CNGM) (J Clin Pathol 2020;73:445):
- Small cystic spaces lined by neutrophils with cuff of epithelioid histiocytes
- Cysts contain rare gram positive bacilli (Corynebacterium)
- Granulomatous mastitis due to infection:
- Tuberculosis mastitis:
- Necrotizing granulomas
- Inflammation affects ducts and lobules
- Acid fast stain, culture or polymerase chain reaction to identify Mycobacterium
- Fungal mastitis:
- Tuberculosis mastitis:
- Foreign body reaction:
- Foreign body type granulomas and giant cells
- Presence of foreign material
- Granulomatosis with polyangiitis:
- Necrotizing vasculitis
- c-ANCA positive
- Sarcoidosis:
- Well formed granulomas not confined to the lobules
- Squamous metaplasia of lactiferous ducts (SMOLD):
- Associated with smoking
- Keratinizing squamous metaplasia of nipple ducts with foreign body inflammatory response
- IgG4 related sclerosing mastitis (J Clin Pathol 2020 Dec 16 [Epub ahead of print]):
- Storiform fibrotic process with eosinophils and increased IgG4 positive plasma cells
- Obliterative phlebitis
- Granulomas typically absent
Additional references
Board review style question #1
A 33 year old woman presents with a painful breast lump concerning for breast cancer. A core biopsy is performed. Which histologic finding is most characteristic of idiopathic granulomatous mastitis?
- Keratin debris with associated foreign body inflammatory response
- Large necrotizing granulomas
- Lobulocentric granulomatous inflammation
- Microcysts with gram positive bacilli
- Well formed granulomas within interlobular stroma
Board review style answer #1
C. Lobulocentric granulomatous inflammation. Although not specific, the most characteristic histologic finding of idiopathic granulomatous mastitis is granulomatous inflammation centered on lobules (lobulocentric inflammation). Idiopathic granulomatous mastitis can have overlapping histologic features with cystic neutrophilic granulomatous mastitis (CNGM); however, microcysts with gram positive bacilli (Corynebacterium) are identified in CNGM. Keratin debris with an associated foreign body inflammatory response is usually seen in squamous metaplasia of lactiferous ducts (SMOLD). Large necrotizing granulomas are more typical of an infectious processes, such as mycobacterial infection. The presence of well formed granulomas within the interlobular stroma suggests sarcoidosis.
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Reference: Idiopathic granulomatous mastitis
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Reference: Idiopathic granulomatous mastitis
Inflammatory
Table of Contents
Definition / general | Essential features | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Positive stains | Negative stains | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Clinicopathologic entity characterized by rapid onset (≤ 6 months) and enlarged, erythematous and edematous (peau d’orange) breast due to dermal plugging of lymphatic vessels by tumor (Breast Cancer Res 2005;7:52)
- Involvement of dermal lymphatics alone without the classic clinical presentation is not considered inflammatory carcinoma
Essential features
- Clinical presentation of breast cancer with dermal lymphatic involvement
- Breast skin with erythema and edema occupying at least 33% of the breast is required to make the diagnosis
- Must be of rapid onset; duration of symptoms of ≤ 6 months
ICD coding
Epidemiology
- Accounts for 2 - 5% of all newly diagnosed breast cancer cases (J Natl Cancer Inst 2005;97:966)
- Contributes to 7% of breast cancer related mortality (J Natl Cancer Inst 2005;97:966)
- Incidence is higher in black women, intermediate in white women and lowest in Asian women (Ann Surg Oncol 2014;21:1267)
- Mean age is 56 years (but wide age range) (BMC Cancer 2021;21:138)
Sites
- Breast, breast skin (dermal lymphatics)
Pathophysiology
- Tumor microemboli in the lymphatic spaces causes obstruction that leads to the clinical presentation of peau d’orange appearance
- RhoC overexpression induces angiogenesis and facilitates rapid metastasis (Breast Cancer Res Treat 2004;84:3)
- E-cadherin accumulation / overexpression within tumor emboli (Anticancer Res 2010;30:3903)
Etiology
- No association with inherited genetic mutation
- No association with family history
Clinical features
- Rapid onset of erythema, edema, induration, warmth and tenderness of the breast skin (Ann Oncol 2011;22:515)
- Patients may have a history of being diagnosed with mastitis that does not respond to at least 1 week of antibiotics (Ann Oncol 2011;22:515)
- Erythema occupying at least 33% of the breast (Ann Oncol 2011;22:515)
- Duration of history < 6 months (Ann Oncol 2011;22:515)
- May or may not have a breast mass, typically not palpable due to rapid spread to lymphatics and distant sites but low volume of invasive carcinoma in breast
Diagnosis
- At least 2 skin punch biopsies between 2 - 8 mm of the most prominent area of skin discoloration (Ann Oncol 2011;22:515)
Radiology description
- Mammogram (Breast Cancer Res Treat 2008;109:417)
- Low sensitivity compared with other modalities (ultrasound, MRI) in identifying a breast tumor
- Skin thickening due to edema and dermal collagen deposition
- Ultrasound, MRI, PET / CT (J Med Imaging Radiat Oncol 2016;60:83, Radiol Med 2010;115:70, Acad Radiol 2022;29:637, Clin Imaging 1992;16:183, Breast Cancer Res Treat 2008;109:417)
- Breast skin thickening and edema are the most common findings
- Used to further evaluate for the presence of breast lesion(s), nodal disease and distant metastatic disease
Radiology images
Contributed by Kiran Manjee, M.D. and Julie M. Jorns, M.D.
Skin thickening and mass
Prognostic factors
- Previous studies have reported poor survival rates; however, this may be due to advanced stage at presentation and delayed diagnosis
- 2010 - 2015 Surveillance, Epidemiology and End Results (SEER) database showed similar breast cancer specific survival in patients with inflammatory breast cancer and stage T4 noninflammatory breast cancer (BMC Cancer 2021;21:138)
- 2010 - 2011 SEER data showed worse outcomes in hormone receptor positive / HER2 negative and triple negative breast cancer compared with triple positive and hormone receptor negative / HER2 positive subtypes (J Cancer Res Clin Oncol 2017;143:161)
- Use of neoadjuvant therapy has improved survival rates
- Histologic subtype does not impact survival (PLoS One 2016;11:e0145534)
- 50% of patients with complete pathological response will subsequently recur
- Overall 5 year survival rate is 41% (Cancer.Net: Breast Cancer - Inflammatory: Statistics [Accessed 27 December 2022])
- 5 year survival with regional lymph node involvement is 56%
- 5 year survival with distant metastasis is 19%
- p53 status is not evaluated routinely but positive staining (≥ 10%) was associated with decreased response to chemotherapy (n = 59) (Clin Cancer Res 2004;10:6215)
Case reports
- 31 year old woman with inflammatory breast cancer that was misdiagnosed as plasma cell mastitis on first biopsy (Asian J Surg 2023;46:1153)
- 75 year old woman with invasive lobular carcinoma that presented clinically as inflammatory breast cancer (Cureus 2022;14:e27358)
- 78 year old man with inflammatory breast carcinoma (Int J Surg Case Rep 2021;80:105696)
Treatment
- Multidisciplinary team approach is critical
- Neoadjuvant chemotherapy, mastectomy with lymph node dissection, radiation therapy and adjuvant endocrine therapy if indicated (Ann Oncol 2011;22:515)
- If there is a good clinical response to neoadjuvant chemotherapy, some may be able to safely undergo breast conserving therapy instead of a mastectomy (Gland Surg 2018;7:520)
Clinical images
Contributed by Amanda L. Kong, M.D., M.S. and Mark R. Wick, M.D.
Erythema and edema
Discoloration
Gross description
- Skin findings and mass lesions are usually not present after neoadjuvant therapy
Microscopic (histologic) description
- Presence of tumor cells in dermal lymphovascular spaces
- Tumor cells or lymphatic spaces may be scant and therefore assessment at multiple levels is recommended
- It is not a specific histological subtype
- Most associated invasive carcinoma is high grade invasive ductal carcinoma, no special type; however, other types of breast cancers can present as inflammatory carcinoma (PLoS One 2016;11:e0145534)
- Ductal carcinoma in situ is often absent
- Classified as T4d in AJCC cancer staging
- T stage does not change following neoadjuvant therapy (ypT4d)
Microscopic (histologic) images
Contributed by Kiran Manjee, M.D., Julie M. Jorns, M.D., Weijie Li, M.D. and AFIP
Dilated lymphatics
Dermal lymphovascular invasion
Dermal lymphovascular invasion
Dermal lymphovascular invasion
HER2 / neu
Locally advanced breast cancer
Skin punch biopsy
Infiltrative nests
Tumor emboli
Tumor in dermal lymphatics
Virtual slides
Images hosted on other servers:
Inflammatory breast carcinoma
Positive stains
- E-cadherin positive tumor emboli (Mod Pathol 2001;14:458, Anticancer Res 2010;30:3903)
- HER2 (52%) (Breast 2004;13:97)
- ER (41 - 52%) (Breast 2004;13:97, Mod Pathol 2001;14:458)
- CD31, ERG highlight endothelial cells surrounding foci of lymphovascular invasion
Negative stains
- PR (35%) (Mod Pathol 2001;14:458)
Sample pathology report
- Skin, left breast, punch biopsy:
- Positive for high grade mammary (ductal) carcinoma within dermal lymphovascular spaces
- Comment: Immunohistochemistry shows carcinoma to be:
- GATA3 (subset, moderate) positive, supporting breast origin
- Estrogen receptor (< 1%) negative
- Progesterone receptor (< 1%) negative
- HER2 / neu (0) negative for overexpression
Differential diagnosis
- Invasive carcinoma involving dermis:
- Ductal carcinoma in situ (DCIS):
- Tumor clusters within myoepithelial lined spaces
- Infection (mastitis, cellulitis, abscess):
- More common in lactating women or in those with history of recent trauma or surgery
- Responds to antibiotic treatment
- Radiation dermatitis:
- Clinical history of radiation
- Benign biopsies
- Other causes of edema (lymphatic obstruction or surgical removal, congestive heart failure):
- Clinical history of medical condition, surgery, travel (parasitic infections)
- Benign biopsies
- Locally advanced carcinoma with skin involvement:
- Skin changes may be present due to dermal lymphatic involvement but clinical history is of longer duration (> 6 months), often with palpable mass
- Histologically bulky invasive carcinoma is present alongside lymphovascular space involvement
- Metastatic neoplasms from other sites:
- Unusual histology for breast
- Immunohistochemistry can help differentiate
Additional references
Board review style question #1
A middle aged woman presents with rapid onset (< 6 months) of breast skin thickening and discoloration. A punch biopsy is done and the patient is diagnosed with inflammatory breast cancer. She undergoes neoadjuvant chemotherapy and subsequent mastectomy reveals focal ductal carcinoma in situ (DCIS) but no residual invasive or metastatic carcinoma. How would she be staged?
- ypTX
- ypT0
- ypTis
- ypT4d
Board review style answer #1
D. ypT4d. In inflammatory breast cancer, the T stage is classified as T4d and does not change after neoadjuvant chemotherapy.
Comment Here
Reference: Inflammatory
Comment Here
Reference: Inflammatory
Board review style question #2
What feature best distinguishes inflammatory breast carcinoma from locally advanced breast cancer?
- Mammographic mass
- Peau d’orange
- Skin thickening and discoloration < 6 months
- Tumor emboli within lymphatic spaces
Board review style answer #2
C. Skin thickening and discoloration < 6 months. Inflammatory breast cancer is defined as breast cancer with rapid onset of clinical symptoms of skin thickening and discoloration / erythema involving at least 33% of the breast. There is frequent peau d’orange and tumor emboli within lymphatic spaces on skin punch biopsy; however, these findings are not necessary to make the diagnosis of inflammatory breast cancer nor are they unique to inflammatory breast cancer as they can also be seen in locally advanced breast cancer. A mass may or may not be seen on mammogram as in inflammatory breast cancer tumor quickly spreads to lymphatics (and beyond) and mammography has lower sensitivity in this setting.
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Reference: Inflammatory
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Reference: Inflammatory
Intraductal papilloma
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Gross images | Frozen section description | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Positive stains | Molecular / cytogenetics description | Videos | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2 | Board review style question #3 | Board review style answer #3Definition / general
- Benign intraductal proliferation of epithelial cells with fibrovascular cores and underlying myoepithelial cells
Essential features
- Common benign breast lesion
- Distinction with malignant papillary lesions may be difficult on biopsy and immunohistochemistry may be necessary
- No consensus regarding management of papilloma without atypia
- Surgical excision of intraductal papilloma with atypical epithelial proliferation is recommended
Terminology
- Duct papilloma of the breast
- Intracystic papilloma of the breast (old terminology)
ICD coding
- ICD-10: D24 - benign neoplasm of the breast
Epidemiology
- 5% of benign breast lesions (Am J Surg Pathol 2006;30:665)
- Involves women of all ages (Arch Pathol Lab Med 2016;140:628)
- Uncommon in men
Sites
- Central intraductal papilloma: arises from large lactiferous ducts, usually solitary (Arch Pathol Lab Med 2016;140:628)
- Peripheral intraductal papilloma: involves terminal duct lobular unit, usually multiple (papillomatosis) (Arch Pathol Lab Med 2016;140:628)
Pathophysiology
- Poorly understood
- Intraductal papilloma might originate from bipotent progenitor cells that differentiate as luminal and myoepithelial cells (Am J Pathol 2018;188:1106)
Clinical features
- Solitary central intraductal papilloma may present as a retroareolar mass with serous or serosanguineous nipple discharge
- Peripheral intraductal papilloma is often discovered incidentally
Diagnosis
- Screening mammography
- Core needle biopsy, vacuum assisted biopsy, excisional biopsy (Surg Pathol Clin 2018;11:1)
Radiology description
- Nonspecific findings
- Mammography (Diagn Interv Radiol 2013;19:471, AJR Am J Roentgenol 2012;198:264)
- Can be large (usually central papilloma), rounded or ovoid well circumscribed mass
- Calcifications may be seen
- Small lesions (usually peripheral papilloma) may not be visible
- Ultrasonography (Diagn Interv Radiol 2013;19:471, AJR Am J Roentgenol 2012;198:264)
- Classic pattern is solid mural nodule within a dilated duct
- Vascular pedicle may be seen on color Doppler
- MRI (Diagn Interv Radiol 2013;19:471, AJR Am J Roentgenol 2012;198:264)
- Well circumscribed round or ovoid intraductal mass with variable enhancement
- May be associated with ductal dilation
Radiology images
Contributed by Mark R. Wick, M.D.
Mammogram
Images hosted on other servers:
Round or ovoid mass on mammogram and ultrasound
Well circumscribed
mass with
calcifications
Ductal dilatation on mammogram
Prognostic factors
- Long term risk of developing breast carcinoma (Mod Pathol 2021;34:78)
- Papilloma without atypia: ~X2 if single; ~X3 if multiple
- Papilloma with atypia: ~X5 if single; ~X7 if multiple
- Risk of upgrade to malignancy (DCIS or invasive breast carcinoma)
- Upgrade rate of papilloma without atypia and with pathology / radiology concordance is low (Mod Pathol 2021;34:78, Am J Surg 2020;220:677, Cancer 2016;122:2819, Clin Imaging 2020;60:67, Breast Cancer Res Treat 2020;183:577, Ann Surg Oncol 2021;28:2573)
- Upgrade rate of intraductal papilloma with atypia is high (Hum Pathol 2021;110:43, Breast Cancer Res Treat 2020;183:577, Ann Surg Oncol 2021;28:2573)
Case reports
- 52 year old man with intraductal papilloma that progressed to ductal carcinoma in situ (Radiol Case Rep 2018;13:602)
- 53 year old woman with a large intraductal papilloma (Int J Surg Case Rep 2019;55:1)
- 55 year old man with unilateral bloody discharge and intraductal papilloma (J Surg Case Rep 2019;2019:rjz023)
Treatment
- No consensus for intraductal papilloma without atypia
- Complete surgical excision often performed (Am J Surg 2020;220:677)
- Different management among institutions (Clin Imaging 2020;60:67)
- Complete surgical excision should be performed for intraductal papilloma with atypia
Clinical images
Images hosted on other servers:
Male with nipple discharge
Gross description
- Central intraductal papilloma: well circumscribed polypoid nodule in a cystically dilated duct (Arch Pathol Lab Med 2016;140:628)
- Peripheral intraductal papilloma: not grossly visible (Arch Pathol Lab Med 2016;140:628)
Gross images
Contributed by Mark R. Wick, M.D.
Intracystic mass
Images hosted on other servers
Intraductal polypoid mass
Frozen section description
- Frozen section not performed on lesions suspected to be intraductal papilloma
Microscopic (histologic) description
- Circumscribed intraductal proliferation comprised of arborizing fibrovascular cores lined by outer layer of luminal cells and an inner layer of myoepithelial cells (Histopathology 2016;68:22)
- Myoepithelial cells might be inconspicuous in sclerotic areas
- Myoepithelial cells also present at the periphery of the involved duct
- Frequently associated with usual type ductal hyperplasia and apocrine metaplasia, less frequently squamous, osseous or chondroid metaplasia may be seen
- May undergo ischemic or hemorrhagic changes, either spontaneously or secondary to biopsy / trauma
- May show prominent fibrosis / sclerosis which may contained entrapped glands (sclerosing papilloma)
- May be involved by:
Microscopic (histologic) images
Contributed by Xiaoxian (Bill) Li, M.D., Ph.D.
Minute intraductal papillomas
Papillary cores
Involved by usual ductal hyperplasia
Involved by apocrine metaplasia
Involved by ductal carcinoma in situ
Contributed by Jijgee Munkhdelger, M.D., Ph.D. and Andrey Bychkov, M.D., Ph.D.
Intraductal papilloma with DCIS immunoprofile
Intraductal papilloma with DCIS, CK5/6
Intraductal papilloma with DCIS, p63
Virtual slides
Images hosted on other servers:
Sclerosing intraductal papilloma
Cytology description
- Large stellate tissue fragments of benign ductal cells in a proteinaceous background (Diagn Cytopathol 2007;35:386)
Positive stains
- Myoepithelial cell markers (CK5, p63, p40, calponin, alpha smooth muscle actin, smooth muscle myosin heavy chain / SMMHC) show myoepithelial cells in fibrovascular cores and at the periphery of the involved duct (Arch Pathol Lab Med 2016;140:628)
- In intraductal papilloma involved by usual ductal hyperplasia
- ER is patchy positive (Pathol Int 2012;62:381)
- CK5 is patchy positive in a mosaic pattern (Pathol Int 2012;62:381)
Molecular / cytogenetics description
- PIK3CA / AKT1 pathway mutations commonly involved (Mod Pathol 2010;23:27, Mod Pathol 2021;34:1044):
- AKT1 mutations are commonly seen in papilloma without (54%) or with mild hyperplasia (15%)
- PIK3CA mutations can be seen in 21 - 42% in papilloma with or without atypia
Videos
Intraductal papilloma
Sample pathology report
- Right breast, 9 o'clock, 1 cm from the nipple, ultrasound guided core biopsy:
- Intraductal papilloma with apocrine metaplasia
- Comment: Patchy positivity for CK5 and ER supports the above diagnosis.
Differential diagnosis
- Atypical ductal hyperplasia involving an intraductal papilloma (atypical papilloma) (Histopathology 2016;68:22):
- Monotonous low grade cellular proliferation
- Atypical proliferation is small (≤ 3 mm) (Cancer 1996;78:258, Am J Surg Pathol 2006;30:665)
- Decreased myoepithelial cells
- CK5/6 negative, ER diffusely positive
- Monotonous low grade cellular proliferation
- Intraductal papillary carcinoma (papillary DCIS) (Histopathology 2016;68:22):
- Encapsulated papillary carcinoma (Histopathology 2016;68:22):
- Adenomyoepithelioma (Mod Pathol 2021;34:1044, Mod Pathol 2020;33:1764, Am J Surg Pathol 1991;15:554):
- Rare, usually benign, well circumscribed nonencapsulated biphasic tumor with myoepithelial and epithelial components
- Multiple patterns (spindle cell, tubular, lobulated, papillary)
- Papillary pattern might be difficult to differentiate from intraductal papilloma
- In adenomyoepithelioma, myoepithelial cells are more conspicuous
- Invasive papillary carcinoma (Mod Pathol 2021;34:1044):
- Uncommon subtype of breast carcinoma
- Invasive carcinoma with > 90% papillary architecture
- Negative for myoepithelial cells
- Tall cell carcinoma with reverse polarity (Mod Pathol 2021;34:1044):
- Rare papillary lesion with uncertain malignant potential
- Distinctive morphology:
- Columnar epithelial cells with apically located nucleus with papillary, solid and follicular architecture
- Nuclei with clearing, groove and pseudoinclusion (reminiscent of tall cell variant of papillary thyroid carcinoma)
- Recurrent IDH2 R172 hotspot mutation
- Solid papillary carcinoma (Mod Pathol 2021;34:1044):
- Uncommon subtype of breast carcinoma
- Expansile solid nodules with interspersed fibrovascular cores composed of monotonous atypical cells (low or intermediate grade)
- Considered as an in situ disease
- Myoepithelial cells may be attenuated at the periphery
Board review style question #1
Regarding this breast specimen, what is the correct diagnosis?
- Intraductal papillary carcinoma
- Intraductal papilloma with apocrine metaplasia
- Intraductal papilloma with DCIS
- Intraductal papilloma with LCIS
- Invasive papillary carcinoma
Board review style answer #1
B. This intraductal papilloma shows typical features of apocrine metaplasia.
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Reference: Intraductal papilloma
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Reference: Intraductal papilloma
Board review style question #2
What is the staining pattern of p63 for intraductal papilloma of the breast without atypia?
- At the periphery of involved duct only
- In the fibrovascular cores only
- Intraductal papillomas do not stain for p63
- At the periphery and in the fibrovascular cores
Board review style answer #2
D. p63 stain for myoepithelial cells is positive throughout the lesion, including in the fibrovascular cores and at the periphery of the involved duct.
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Reference: Intraductal papilloma
Comment Here
Reference: Intraductal papilloma
Board review style question #3
What is the typical staining pattern of atypical epithelial proliferation involving an intraductal papilloma of the breast?
- Diffusely positive for ER and patchy positive for CK5/6, negative for p63
- Diffusely positive for ER, negative for p63 and CK5/6
- Diffusely positive for ER, p63 and CK5/6
- Negative for ER, p63 and CK5/6
- Patchy positive for ER, negative for p63 and CK5/6
Board review style answer #3
B. The atypical low grade epithelial proliferation is diffusely positive for ER, negative for CK5/6 and negative for p63.
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Reference: Intraductal papilloma
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Reference: Intraductal papilloma
Invasive breast cancer of no special type (NST)
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Positive stains | Negative stains | Electron microscopy description | Molecular / cytogenetics description | Molecular / cytogenetics images | Videos | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2 | Board review style question #3 | Board review style answer #3Definition / general
- Most common type of invasive breast carcinoma (75 - 80%)
- Invasive carcinoma with evidence of mammary epithelial origin either by morphology or immunohistochemistry
- Diagnosis of exclusion, lacks the histologic features to classify morphologically as a special subtype of breast cancer
- Arises from epithelial (progenitor / stem) cells at the terminal duct lobular unit (as do lobular and other types of breast carcinoma)
- Although the ductal and lobular nomenclature does not reflect the histogenesis of these tumor types, this terminology remains in common use
- Patient age, tumor stage, lymph node status, histologic grade, clinical biomarker profile and gene expression signature are important prognostic factors
- Treated with surgical excision, with or without radiotherapy, systemic chemotherapy or targeted therapies
- ASCO / CAP guidelines require assessment by standard breast biomarkers (estrogen and progesterone receptors and HER2)
Essential features
- Large and heterogenous group of tumors that lack features diagnostic of special types
- Range in morphology, grade, biomarker profile, molecular subtype and clinical behavior
Terminology
- Invasive breast carcinoma, not otherwise specified (NOS)
- Invasive ductal carcinoma
- Not recommended: scirrhous carcinoma
ICD coding
Epidemiology
- Breast cancer is the commonly diagnosed cancer in females (24%) (CA Cancer J Clin 2018;68:394)
- Leading cause of female cancer death worldwide (CA Cancer J Clin 2018;68:394)
- 8 - 9% of women diagnosed with invasive breast cancer before age 75 in North America and West Europe (NIH: SEER Cancer Statistics Review (CSR) 1975-2018 [Accessed 23 June 2022])
- Majority are sporadic; 5 - 10% of all breast cancers are associated with hereditary cancer susceptibility genes (Am J Hum Genet 1991;48:232, Semin Oncol 2016;43:528, Eur J Hum Genet 2009;17:722)
Sites
- Breast
- Can occur in axilla accessory breast tissue
Etiology
- Origin of breast cancer is multifactorial and complex but most studies point to hormones, reproductive factors, diet, environment and genetics as general factors
- After menopause, about 40% of risk is modifiable (Am J Epidemiol 2008;168:404)
- Hormone related risk factors:
- Prolonged exposure to estrogen: early menarche, late menopause, nulliparity, having first child after age 30 and lack of breast feeding (Br J Cancer 2009;100:538)
- Postmenopausal women with obesity and estrogen producing ovarian tumors (BJOG 2006;113:1160)
- Women using combined hormone replacement therapy with progestins or estrogens alone (Int J Cancer 2007;121:645)
- Risk with oral contraceptives is controversial (Mayo Clin Proc 2006;81:1290)
- Associated with increased risk of hormone receptor positive breast cancer (Breast Cancer Res Treat 2014;144:1)
- Parity may be associated with an increased risk of triple negative breast cancers
- Hormone factors associated with reduced risk of breast cancer:
- Oophorectomy before age 35 or first child before age 18
- Obesity prior to age 40 - due to anovulatory cycles and lower progesterone levels in late cycle (J Natl Cancer Inst 2011;103:250)
- Genetic risk factors:
- Breast cancer shows familial clustering
- First degree relatives with breast cancer; having 1 first degree relative (mother, sister, daughter) creates a relative risk of 2 - 3x, higher if relative is affected before age 50 or had bilateral disease; relative risk with 2 first degree relatives is 4 - 6x (Int J Cancer 1997;71:800)
- Li-Fraumeni syndrome (germline p53 mutations) - 25% of patients develop breast cancer
- Mutations of BRCA1 and BRCA2 genes are associated with familial breast cancer at an early age, account for 20 - 60% of familial breast cancer but only 5% of all cases
- Germline BRCA1 mutations are associated with risk for triple negative breast cancers, whereas germline BRCA2 mutations are associated with hormone receptor positive breast cancers (J Clin Oncol 2015;33:304)
- Cowden disease (multiple hamartoma syndrome): autosomal dominant, due to 10q mutation: 30 - 50% risk of breast cancer (ductal carcinoma in situ or invasive ductal carcinoma) by age 50; also benign skin tumors (Hum Pathol 1998;29:47)
- Heterozygous carriers for ataxia telangiectasia have an 11% risk of breast cancer by age 50
- Black women (compared to white women) have more frequent breast cancers in women < age 40; present with higher stage tumors with higher nuclear grade that are more likely ER / PR negative, have higher mortality rate (J Natl Cancer Inst 200;100:1804, Cancer 1998;83:2509)
- Women have 100x risk of breast cancer compared to men (J Clin Oncol 2011;29:4381)
- Environmental risk factors:
- Rates in U.S. > Japan / Taiwan (5:1), also high in Northern Europe, low in Asia / Africa; may be due to known risks of obesity / high fat diet and heavy alcohol use; however, differences diminish with immigration (Nutr Cancer 2008;60:492, Am J Epidemiol 2000;152:950)
- Alcohol consumption has been consistently associated with a moderate increase in risk, particularly hormone receptor positive breast cancers (JAMA 1998;279:535)
- Adult dietary soy foods and carotenoids have protective effect (Am J Clin Nutr 2009;89:1920, Int J Cancer 2009;124:2929)
- Physical activity has a protective effect (J Natl Cancer Inst 2008;100:728, Breast Cancer Res Treat 2010;120:235)
- Other risk factors:
- Female sex and older age are probably the most common risk factors of breast cancer
- Proliferative breast disease (see individual topics in Breast chapter), particularly in situ carcinoma (Clin Cancer Res 2007;13:5474)
- Carcinoma of opposite breast or endometrium
- Radiation exposure in young women, including women < age 30 with supradiaphragmatic radiation for Hodgkin lymphoma; reduced risk if also have irradiation of ovaries > 5 Gy (Int J Radiat Oncol Biol Phys 2009;73:69, J Clin Oncol 2009;27:3901)
- Mammographic density is a highly heritable risk (J Br Menopause Soc 2006;12:186, Breast Cancer Res 2011;13:R132)
Clinical features
- In patients > 65 years, 87% of patients with invasive breast carcinoma have NST (Crit Rev Oncol Hematol 2008;67:263)
- Most (~90%) are unifocal and with higher frequency in the upper outer quadrant (Cancer Epidemiol 2016;44:186)
- In nonscreened populations, NST carcinoma commonly presents as a palpable mass
- Less commonly, it presents with skin retraction, nipple discharge, nipple inversion, a change in the size or shape of the breast or a change in the color or texture of the skin
- In screened populations, it commonly presents as a spiculated mass with or without calcifications but may present as well circumscribed masses, architectural distortion or calcifications alone
- Clinically, IBC NST is further divided into the following biomarker defined subtypes for treatment purposes:
- ER positive, HER2 negative
- ER positive, HER2 positive cancers
- ER negative, HER2 positive cancers
- ER negative, HER2 negative cancers
- Frequency of these biomarker / clinical subtypes varies by population characteristics but the ER positive subtype is the most common
- HER2 positive subtype comprises 10 - 15%, whereas ER negative / HER2 negative subtype comprises approximately 15 - 30% (Crit Rev Oncol Hematol 2010;76:44, JAMA 2006;295:2492)
Diagnosis
- Histologic examination of involved tissue
Radiology description
- Mammographically often presents as a spiculated mass with or without calcifications but may present as an architectural distortion or calcifications alone
- Targeted ultrasonography often used to enhance visualization
- MRI often shows enhancing mass lesion with variable washout kinetic patterns (Breast J 2010;16:394)
- MRI is sensitive but nonspecific technique is reserved for screening patients at high risk (e.g., BRCA mutation carriers), patients with dense breast tissue, estimating extent of disease in patients with lobular carcinoma, evaluating response to neoadjuvant chemotherapy or evaluating indeterminate abnormalities on mammography / ultrasound (Breast 2013;22:S77)
Radiology images
Contributed by Mark R. Wick, M.D.
Invasive
Mammogram
Spot film
Spot film
Prognostic factors
- Patient age (Cancer Epidemiol Biomarkers Prev 2019;28:303)
- Stage as determined by pT size and lymph node status (Cancer 2003;98:2133)
- Histologic grade is an independent prognostic factor (Arch Pathol Lab Med 2014;138:1048)
- Lymphovascular invasion associated with higher risk of local recurrence and distant recurrence (Cancer 2012;118:3670)
- Biomarker profile:
- Hormone receptor expression associated with better short term survival
- HER2 expression associated with improved survival when anti-HER2 therapy is received
- Gene expression signature, observed survival is highest in luminal A, lowest in basal-like (Cancer Treat Rev 2012;38:698)
Case reports
- 47 year old woman with a subareolar breast mass (Int J Clin Exp Pathol 2014;7:7020)
- 53 year old woman with a breast mass (Medicine (Baltimore) 2022;101:e28433)
- 56 year old woman with cystic breast lesion (Medicine (Baltimore) 2018;97:e13740)
- 70 year old woman with a benign appearing breast mass (Am J Case Rep 2017;18:813)
Treatment
- Surgical excision by breast conserving surgery (lumpectomy) or mastectomy, with or without axillary lymph node dissection
- May be offered local radiotherapy to the breast after lumpectomy or to the chest wall after mastectomy to reduce local recurrence risk
- May be offered systemic chemotherapy either neoadjuvantly or adjuvantly
- May be offered targeted therapies (e.g., antiendocrine or anti-HER2 directed)
- Selection of treatment (type of surgery, inclusion of radiotherapy and selection of systemic therapies) is based on multifactorial consideration of several factors including but not limited to tumor size, histologic grade, stage, biomarker status, results of genomic risk assessment (e.g., Oncotype DX Recurrence Score ®), anatomic location, patient age and comorbidities, heritable breast cancer risk (e.g., BRCA status), prior exposure to chemotherapy or radiation therapy, cosmetic outcome and patient's preference
Clinical images
Contributed by Mark R. Wick, M.D.
Fungating, breast skin
Gross description
- Grossly evident mass, with an irregular, stellate outline or nodular configuration
- Mass is usually poorly circumscribed and contracts from surrounding tissue
- Firm or even hard on palpation and may have a gritty feel when cut with a knife, grating sound when scraped
- May show streaks of chalky white elastotic stroma penetrating surrounding stroma (crab-like), calcification
- Large tumors have hemorrhage, necrosis and cystic degeneration
- May be fixed to chest wall and cause skin dimpling or nipple retraction
- Some tumors, including neoadjuvant treated cancers, may be grossly inapparent and require careful correlation with the imaging at the time of gross examination and tissue sampling
Gross images
Contributed by Mark R. Wick, M.D. and @Andrew_Fltv on Twitter
Irregular stellate mass
Irregular stellate mass
Invasive breast cancer of no special type (NST)
Microscopic (histologic) description
- Histologic grading is based on the Nottingham / modified Bloom & Richardson Score (Histopathology 1991;19:403):
- Tubule formation (1 - 3 points):
- > 75% (1 point)
- 10 - 75% (2 points)
- < 10% (3 points)
- Nuclear pleomorphism (1 - 3 points):
- Small, regular, uniform, similar to normal ductal epithelial cells, 2 - 3x RBC (1 point)
- Moderate increase in size / variability (2 points)
- Large nuclei, marked variation, often vesicular chromatin with prominent nucleoli (3 points)
- Mitotic count (1 - 3 points), dependent on microscopic field area
- Total score (add points for tubule formation, nuclear pleomorphism and mitotic count):
- 3 - 5 points: grade 1
- 6 - 7 points: grade 2
- 8 - 9 points: grade 3
- Histological features of IBC NST vary considerably from case to case and even within the same case
- Margins vary from highly infiltrative, permeating the surrounding tissue, to continuous pushing margins
- Architecture varies from sheets, nests, clusters, cords or individual cells (but lacks the cytomorphological characteristics of invasive lobular carcinoma)
- Tubular formations are prominent in well differentiated tumors but absent in poorly differentiated tumors
- Variable cytological features:
- Cytoplasm may be abundant and eosinophilic but it can show other features in some tumors, including as clear, foamy or granular
- Nuclei may be regular and uniform or highly pleomorphic with prominent or multiple nucleoli
- Mitotic figures are variable from virtually absent to extensive
- 2 distinct growth patterns exist:
- Large and solid nests or syncytial infiltrative growth pattern with little associated stroma and an expansive growth that compresses the surrounding stroma (e.g., most basal-like breast cancers)
- Tumors characterized by small cancer nests accompanied by marked fibrosis (desmoplastic / scirrhous); this type diffusely infiltrates the surrounding tissue as an irregular shaped spiculated mass
- Calcification in 60% of cases, variable necrosis
- Elastosis involves stroma, wall of vessels and ducts and causes grossly noted chalky streaks
- Often ductal carcinoma in situ (DCIS) (up to 80%)
- In some cases, DCIS is extensive
- Associated DCIS is usually of same nuclear grade as the invasive carcinoma
- Perineural invasion (28%)
- Mast cells are associated with low grade tumors
- Uncommon features: eosinophils intraluminal crystalloids (BMC Cancer 2007;7:165, Arch Pathol Lab Med 1997;121:593)
- No myoepithelial cell lining (as seen in DCIS or benign lesions)
- Angiolymphatic invasion in 35%; differs from tissue retraction because:
- Occurs outside margin of carcinoma
- Does not conform precisely to space it is in
- Endothelial lining is present and is CD31+, ERG, D2-40+, CD34+ and factor VIII+
- Mixed IBC NST and special subtype pattern:
- IBC NST with < 10% special type should be classified as IBC NST with an option to describe the focal specialized pattern in the report comment
- Invasive breast carcinoma with > 90% specialized type patterns should be classified as the special type
- When IBC NST contains a component of specialized tumor type that comprises > 10% but < 90%, the tumor is classified as mixed tumor
- It is recommended to report both the specific special type present and the overall percentage of the cancer with the special pattern (e.g., mixed IBC NST and mucinous carcinoma [40% mucinous])
- Biomarker status of both areas should be reported since they can be distinct
- Grade of the overall tumor should be considered
- Special morphologic patterns of NST:
- IBC NST shows a wide spectrum of differentiation with variable extent of these differentiation lineages
- Some tumors comprises the end of the differentiation spectrum but the prognostic value and the morphological features are not sufficient to classify them as special types, even if such differentiation features comprise > 90%
- Current opinion is to consider such tumors as special morphologic patterns of IBC NST to improve the diagnostic concordance of the classification system and to highlight the lack of prognostic and management implications
- These patterns include:
- Basal-like or medullary-like patterns:
- These include breast carcinomas previous described as medullary-like carcinoma or carcinoma with medullary features, as well as basal-like carcinoma
- These tumors typically show high histological grade, a prominent tumor associated lymphocytic (TIL) infiltrate, a triple negative phenotype and often have basal-like molecular profiles
- Oncocytic, sebaceous, melanocytic, glycogen rich, lipid rich, carcinomas with osteoclast-like stromal giant cells, pleomorphic and choriocarcinomatous carcinoma patterns
- Invasive carcinoma with neuroendocrine differentiation:
- A proportion of IBC NST shows neuroendocrine differentiation of variable extent as determined by histological, histochemical and immunohistochemical analysis occurs but lack histologic features to classify as large cell or small cell neuroendocrine carcinoma or neuroendocrine tumor of the breast
- These tumors do not carry prognostic or clinical significance and they can be considered as variant (morphological pattern) of IBC NST (Hum Pathol 2003;34:1001)
- Basal-like or medullary-like patterns:
- Tubule formation (1 - 3 points):
Microscopic (histologic) images
Contributed by Julie M. Jorns, M.D., Kristen E. Muller, D.O., Gary Tozbikian, M.D. and Emad Rakha, M.D.
Invasive ductal carcinoma, grade 1
Invasive ductal carcinoma, grade 2
Invasive ductal carcinoma with necrosis, grade 3
Invasive ductal carcinoma with scattered apoptotic cells
CK5/6
Central necrosis
Central fibrosis
Adjacent normal breast
CK7
GATA3
Lobular and apocrine features, E-cadherin
Lobular and apocrine features
Lobular features
Lobular features, E-cadherin
GCDFP-15 positive invasive ductal carcinoma
GCDFP-15
Angiolymphatic invasion
Involvement of a fibroadenoma
Involvement of a fibroadenoma, p63
Microinvasion, p63
Microinvasion
Actin - muscle specific
Pseudo DCIS pattern
Calponin, pseudo DCIS pattern
Mammaglobin positive invasive ductal carcinoma
Mammaglobin
SOX10+ invasive ductal carcinoma
SOX10
p120+ invasive ductal carcinoma
p120
Invasive ductal carcinoma, grade 3
Invasive ductal carcinoma, grade 2
Invasive ductal carcinoma, grade 1
Cytology description
- Can use cellular pleomorphism, nuclear size, nuclear margin, nucleoli, lack of naked nuclei, cellular dyscohesion and mitoses in addition to necrosis to assess cytologic tumor grade, which correlates with histologic grade (Diagn Cytopathol 2003;29:185)
Cytology images
Contributed by Mark R. Wick, M.D. and Abdulaziz Mohamed, M.D.
FNAB
Diff-Quik
47 year old woman with 3 x 2 cm painless retroareolar mass and ipsilateral axillary lymphadenopathy
Positive stains
- Luminal low molecular weight cytokeratins (CK8 / 18, CK19 and CK7 and pancytokeratins such as AE1 / AE3, CAM 5.2, MNF-116), EMA, E-cadherin, p120, ER (60 - 80%), PR (50 - 70%), HER2 (15 - 20%) (Am J Clin Pathol 2006;125:377)
- GCDFP-15 (30 - 40%)
- GATA3 (~91 - 100% of hormone receptor positive breast cancers, ~43 - 66% in triple negative breast cancer) (Hum Pathol 2014;45:2225, Hum Pathol 2015;46:1829)
- Also mammaglobin, milk fat globule, lactalbumin, CEA, B72.3, BCA225
- High molecular weight cytokeratins (CK5/6, CK14 and CK17) (10 - 30%)
- Glycogen (60%), mucin (moderate / marked in 20%)
- S100 (10 - 45%), RCC Ma (renal cell carcinoma marker)
- CD5 clone 4C7 (Arch Pathol Lab Med 2001;125:781)
- TRPS1 (Mod Pathol 2021;34:710)
- SOX10 (57 - 58% of triple negative breast cancers) (Hum Pathol 2019;85:221, Hum Pathol 2017;67:205)
Negative stains
- CK20, CD34
- Myoepithelial markers: p63 (positive in benign lesions), CD10, calponin (Am J Surg Pathol 2001;25:1054, Mod Pathol 2002;15:397)
- Other tissue specific transcription factors: TTF1, CDX2, PAX8 and WT1 (nonspecific weak to moderate or strong focal staining can be in up to 10% of cases but typically weaker than its expression in the relevant tumors)
Electron microscopy description
- Glandular differentiation (microvilli and terminal bars on luminal side)
Molecular / cytogenetics description
- ER+ pathway: characterized by gains of 1q, loss of 16q, sometimes amplification of 17q12
- ER- pathway: characterized by loss of 13q, gain of 11q13, amplification of 17q12, p53 mutations common, increased expression of genes associated with cell proliferation
- PI3KCA mutations associated with endocrine therapy resistance (Virchows Arch 2016;469:35, Int J Breast Cancer 2020;2020:3759179)
- p53 mutations in many basal-like tumors (Nature 2012;490:61)
- HER2 gene amplification in approximately 15% (Cancer Res 1993;53:4960, J Clin Oncol 1989;7:1120)
- Gene expression profiling stratifies breast cancers into several intrinsic molecular subtypes (e.g., luminal A, luminal B, HER2 enriched, basal-like, etc.) (Nature 2012;490:61)
- 5 - 10% of breast cancers are hereditary as result of mutations in various genes, such as BRCA1, BRCA2, TP53, STK11, CD1, PTEN, MDM2, RB, CHEK2 (Acta Oncol 2019;58:135)
- ESR1 mutations associated with resistance to endocrine therapy (JAMA Oncol 2016;2:1310)
Molecular / cytogenetics images
Contributed by Mark R. Wick, M.D. and Semir Vranic, M.D.
HER2 amp FISH
TOP2A CEP17 FISH - no gene amplification
Videos
Ductal carcinoma - breast
Breast ductal carcinoma (breast cancer)
Breast carcinoma: invasive - pathology mini tutorial
Sample pathology report
- Left breast, mass, ultrasound guided core needle biopsy:
- Invasive breast carcinoma, NST (invasive ductal carcinoma), grade 2, measuring 1.5 cm
- Estrogen receptor: positive (95%, strong intensity)
- Progesterone receptor: negative (0%)
- HER2: negative (score 1+)
Differential diagnosis
- IBC NST should be differentiated from special types of breast carcinoma:
- > 90% special tumor characteristics
- IBC NST admixed with 10 - 90% of other special subtype(s) is designated as mixed IBC NST and special subtype with description of the percentage of special subtype components provided
- Metastatic adenocarcinoma with overlapping features, including lung adenocarcinoma, endometrioid carcinoma, serous carcinoma and renal cell carcinoma:
- Correlation with clinical and radiologic history
- Appropriate use of immunohistochemical panel of stains (e.g., estrogen receptor, GATA3, TRPS1, etc.)
- Rarely, examples of skin adnexal (sweat gland) carcinoma of the breast skin:
- Morphology and immunohistochemical profile may be indistinguishable from breast cancer, superficial location centered in the skin versus within the breast (adjacent ducts / lobules)
- Melanoma:
- Can mimic high grade breast cancer
- Melanin pigment, lack of cytokeratin expression, positive for melanoma melanocytic markers
- Ductal carcinoma in situ involving sclerosing lesions (e.g., sclerosing adenosis):
- IHC using myoepithelial markers shows retained myoepithelial cell layer
Additional references
Board review style question #1
Which of the following immunohistochemical stains would be most helpful for distinguishing DCIS from an invasive beast carcinoma with a cribriform growth pattern?
- Calponin and p63
- CD31 and CK7
- CK5/6 and estrogen receptor
- Estrogen receptor and progesterone receptor
- HER2 and cytokeratin AE1 / AE3
Board review style answer #1
A. Calponin and p63. The use of myoepithelial markers is most useful for distinguishing in situ from invasive carcinoma. Utilization of 2 myoepithelial markers, including both a cytoplasmic marker (e.g., calponin or smooth muscle myosin) and a nuclear marker (p63 or p40) is recommended, as myoepithelial expression can be patchy or attenuated (p63 / p40) and show nonspecific expression in endothelial cells (SMMS); the combination of 2 markers provides increased sensitivity and specificity. Both DCIS and invasive breast carcinoma (NST) may show expression of hormone receptors, HER2 and cytokeratins.
Comment Here
Reference: Invasive breast cancer of no special type (NST)
Comment Here
Reference: Invasive breast cancer of no special type (NST)
Board review style question #2
Which of the following is true regarding the diagnosis of invasive breast carcinoma of no special type (NST)?
- Always shows extensive (> 90%) tubular / acinar formation
- Generally negative for E-cadherin and p120 (cytoplasmic)
- Low grade tumors are generally positive for HER2 overexpression by immunohistochemistry
- Majority of cases are hereditary due to mutations in either BRCA1 or BRCA2
- Requires assessment of standard biomarkers estrogen and progesterone receptors and HER2
Board review style answer #2
E. Per ASCO / CAP guideline recommendations, all new primary invasive breast cancers require assessment of standard breast biomarkers: estrogen receptor, progesterone receptor and HER2. IBC NST show positive membranous reactivity of E-cadherin and p120. Degree of tubular formation can range between tumors and within tumors. Generally, low grade tumors show greater tubule formation, are positive for hormone receptor expression and are negative for HER2. The majority of breast cancer is sporadic; only 5 - 10% of breast cancer is considered familial.
Comment Here
Reference: Invasive breast cancer of no special type (NST)
Comment Here
Reference: Invasive breast cancer of no special type (NST)
Board review style question #3
Which of the following findings would you expect from a low grade invasive breast carcinoma of no special type?
- Basal-like intrinsic molecular subtype
- Lack of desmoplastic stromal response, positive for S100, positive for laminin and collagen IV around glands, estrogen receptor negative
- Positive for HER2 overexpression
- Positive for hormone receptors (estrogen and progesterone receptors)
- Positive for p63 and calponin
Board review style answer #3
D. The majority of low grade invasive breast carcinomas of no special type belong to the luminal A intrinsic molecular subtype, are positive for hormone receptors (estrogen and progesterone receptors) and are negative for HER2. The invasive component will lack expression of myoepithelial markers (e.g., p63 and calponin). Lack of desmoplasia, expression of S100, negativity for estrogen receptor and expression of laminin and collagen IV around infiltrative glands would be consistent with microglandular adenosis.
Comment Here
Reference: Invasive breast cancer of no special type (NST)
Comment Here
Reference: Invasive breast cancer of no special type (NST)
Juvenile papillomatosis
Table of Contents
Definition / general | Terminology | Epidemiology | Clinical features | Case reports | Clinical images | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Additional referencesDefinition / general
- Grossly distinct multinodular mass with clustering of cystic formations resembling swiss cheese, composed of epithelial proliferation and clustered cysts
- First described by Rosen in 1980 (Am J Surg Pathol 1980;4:3)
Terminology
- Not part of WHO breast classification
Epidemiology
- Mean age 19 years
- 2 / 3 are less than age 20 years
Clinical features
- Resembles fibroadenoma clinically
- 10% develop breast carcinoma, higher risk if recurrent, bilateral disease and family history of breast cancer (Am J Clin Pathol 1990;93:599)
- 26 - 58% have positive family history of breast cancer (Cancer 1982;49:2591, Am J Clin Pathol 1986;86:745), 15% have bilateral disease
- May be associated with secretory carcinoma (Jpn J Clin Oncol 1985;15:457)
Case reports
- Juvenile papillomatosis of the breast in a male infant with Noonan syndrome (Pediatr Blood Cancer 2005;45:991)
- 6 year old girl with juvenile secretory carcinoma and juvenile papillomatosis (J Pediatr Surg 1987;22:637)
- 16 year old girl with multiple juvenile papillomatosis of the breast (Breast Cancer 1998;5:187)
- 17 year old boy with juvenile papillomatosis of the breast (G Chir 2011;32:374)
Clinical images
Contributed by Mark R. Wick, M.D.
Mammogram
Gross description
- Localized multinodular mass with clustering of cystic formations resembling swiss cheese
Gross images
Contributed by Mark R. Wick, M.D.
Juvenile papillomatosis
Microscopic (histologic) description
- Florid epithelial hyperplasia and papillomatosis, cysts with foamy histiocytes and sclerosing adenosis
- Variable apocrine metaplasia, atypia and necrosis
Microscopic (histologic) images
Contributed by Mark R. Wick, M.D.
Juvenile papillomatosis
AFIP images
Multiple cystically dilated ducts
Hyperplastic epithelium in dilated duct
Intraductal epithelial proliferation with necrosis
Apocrine metaplasia
of hyperplastic
intraductal
epithelium
Hyperplastic epithelium and foam cells
With sclerosing adenosis
and apocrine metaplasia
adjacent to cystically
dilated ducts
Multiple small intraductal papillomas in 15 year old girl
High power shows hyperplastic
intraductal epithelium, myoepithelial
cells are associated with the
delicate fibrovascular stalks
Cytology description
- Difficult to diagnose
- Cystic fluid, but mass persists after aspiration
- Sheets of hyperplastic breast epithelium with areas resembling fibroadenoma, macrophages and apocrine cells (Diagn Cytopathol 1993;9:457)
Cytology images
Contributed by Areej M. Al Nemer, M.D.
Suspicious nipple discharge
Additional references
Ki67 breast
Table of Contents
Definition / general | Essential features | Terminology | Pathophysiology | Clinical features | Interpretation | Uses by pathologists | Prognostic factors | Microscopic (histologic) images | Positive staining - normal | Positive staining - disease | Sample pathology report | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Nuclear protein that is expressed during all active phases of the cell cycle (G1, S, G2 and M) but is absent in resting cells (G0) (Pathology 2017;49:166)
- Encoded by MKI67 gene on chromosome 10q25 (Pathology 2017;49:166)
- Ki67 expression level varies throughout the cell cycle (Pathology 2017;49:166)
Essential features
- Cellular proliferation marker that is reported as percentage of tumor cells with nuclear staining
- Low in benign tumors, luminal A carcinomas and low grade carcinomas (Breast Cancer Res 2016;18:104, Mod Pathol 2014;27:554, BMC Res Notes 2019;12:605)
- High in high grade carcinomas, triple negative breast carcinomas, HER2 positive carcinomas and luminal B carcinomas (Breast Cancer Res 2016;18:104, Mod Pathol 2014;27:554, BMC Res Notes 2019;12:605)
- Independent prognostic marker to predict disease free survival, overall survival and complete pathologic response to neoadjuvant chemotherapy (Pathology 2017;49:166, J Natl Cancer Inst 2021;113:808)
- Associated with low interlaboratory reproducibility and high interobserver variability (Breast Cancer Res 2016;18:104, J Natl Cancer Inst 2013;105:1897, Histopathology 2019;75:225)
Terminology
- MIB1 is not equivalent to Ki67; rather, it is a widely used monoclonal antibody against the Ki67 antigen (Breast Cancer 2020;27:1058)
Pathophysiology
- Anti-Ki67 antibody binds Ki67 protein in formalin fixed paraffin embedded tissue block and highlights nuclei of all cells in nonresting cell cycle phases (Pathology 2017;49:166)
- Increased expression in tumor cells is a marker of cell cycle activation and proliferative activity
- Ki67 often is heterogeneously expressed in breast carcinomas, with hot spots and inactive areas (J Natl Cancer Inst 2013;105:1897)
Clinical features
- Can be used to predict and monitor response to neoadjuvant endocrine or chemotherapy (Pathology 2017;49:166, J Natl Cancer Inst 2021;113:808)
- Used in distinguishing luminal A and luminal B breast carcinomas (Breast Cancer Res 2016;18:104, Mod Pathol 2014;27:554, BMC Res Notes 2019;12:605)
- Used by oncologists to guide adjuvant chemotherapy (Pathology 2017;49:166, J Natl Cancer Inst 2021;113:808)
- High Ki67 expression correlated with decreased survival (Pathology 2017;49:166, J Natl Cancer Inst 2021;113:808)
Interpretation
- Nuclear staining (any intensity)
- Number of tumor cells with positive staining divided by total number of tumor cells (hot spots [less reproducible] or average across tumor section [recommended]) (Pathology 2017;49:166)
- No consensus on number of tumor cells to be scored (J Natl Cancer Inst 2013;105:1897)
- Marked variability in published thresholds separating high and low scores (Pathology 2017;49:166)
- Due to significant interlaboratory and interobserver variability, thresholds ideally should be established in each laboratory (J Natl Cancer Inst 2021;113:808)
- In ER+ / HER2- T1-2, N0-1 patients Ki67 is prognostic, with Ki67 ≤ 5% considered low and Ki67 ≥ 30% considered high (J Natl Cancer Inst 2021;113:808)
- Several automated scoring algorithms for Ki67 quantitation have been developed which reduce interobserver variability (Mod Pathol 2019;32:59, Lab Invest 2019;99:107)
Uses by pathologists
- As an independent prognostic marker to predict disease free survival, overall survival and complete pathologic response to neoadjuvant chemotherapy
- Subtyping ER positive breast carcinomas into 2 prognostically distinct subtypes:
- Luminal A (low Ki67 index; better prognosis)
- Luminal B (high Ki67 index; worse prognosis) (Mod Pathol 2014;27:554)
- Ki67 IHC MIB1 pharmDx has been approved by the FDA as a companion diagnostic for detecting Ki67 expression in patients with high risk breast cancer who may be eligible for treatment with abemaciclib combined with endocrine therapy
- FDA approval of abemaciclib was restricted to patients at high risk of recurrence and with a Ki67 score ≥ 20%, as determined by an FDA approved test; however, restricting the approval to patients with a high Ki67 and the 20% cutoff is debated (Ann Oncol 2022;33:234)
Prognostic factors
- Prognostic factor in early stage, ER positive breast cancer (Breast Cancer Res 2016;18:104, Pathology 2017;49:166)
- High Ki67 expression in a breast carcinoma is associated with higher pathologic stage, higher grade, estrogen and progesterone receptor negativity, HER2 overexpression, extracapsular extension and lymphovascular invasion (Eur J Breast Health 2019;15:256)
- High Ki67 index is associated with shortened disease free survival and overall survival (Breast Cancer Res Treat 2013;139:539)
- High Ki67 proliferative index is a predictive marker for pathological complete response to neoadjuvant chemotherapy (Medicine (Baltimore) 2017;96:e9384)
Microscopic (histologic) images
Contributed by Anas Mohamed, M.D. and Joseph Geradts, M.D.
Lobular carcinoma, low proliferation
Lobular carcinoma, low Ki67
Ductal carcinoma, low proliferation
Ductal carcinoma, low Ki67
Ductal carcinoma, intermediate proliferation
Ductal carcinoma, intermediate Ki67
Ductal carcinoma, high proliferation
Ductal carcinoma, high Ki67
Positive staining - normal
- Normal breast tissue demonstrates very low levels of Ki67 index (< 3%) (Front Endocrinol (Lausanne) 2021;12:687244)
Positive staining - disease
- Low Ki67 index is observed in benign breast tumors, luminal A carcinomas, low grade ductal carcinomas, lobular carcinomas and tubular carcinomas
- High Ki67 index is observed in triple negative breast carcinomas, including metaplastic and medullary carcinomas, HER2 positive carcinomas, luminal B carcinomas, high grade carcinomas and pleomorphic lobular carcinomas (BMC Res Notes 2019;12:605)
Sample pathology report
- Right breast, core needle biopsy:
- Invasive ductal carcinoma, grade 2
- Ki67 index: 5% (low)
- Left breast, total mastectomy:
- Invasive mammary carcinoma with medullary pattern
- Ki67 index: 40% (high)
Additional references
Board review style question #1
Which of the following breast neoplasms is most likely to be associated with an elevated Ki67 labeling index?
- Invasive ductal carcinoma, grade 1
- Invasive lobular carcinoma, classic type
- Metaplastic carcinoma
- Tubular carcinoma
Board review style answer #1
C. Metaplastic carcinoma. High Ki67 index is observed in triple negative breast carcinomas, including metaplastic and medullary carcinomas, as well as HER2 positive carcinomas, luminal B carcinomas, high grade carcinomas and pleomorphic lobular carcinomas (BMC Res Notes 2019;12:605).
Comment Here
Reference: Ki67 breast
Comment Here
Reference: Ki67 breast
Board review style question #2
Which of the following breast tumors is likely to demonstrate a Ki67 labeling index similar to the one shown in the picture?
- Invasive cribriform carcinoma
- Invasive ductal carcinoma, grade 3
- Medullary carcinoma
- Pleomorphic lobular carcinoma
Board review style answer #2
A. Invasive cribriform carcinoma. Low Ki67 index is observed in benign breast tumors, luminal A carcinomas, low grade ductal carcinomas, lobular carcinomas and tubular carcinomas and lower grade breast cancer subtypes, such as invasive cribriform carcinoma (BMC Res Notes 2019;12:605).
Comment Here
Reference: Ki67 breast
Comment Here
Reference: Ki67 breast
Lactating adenoma
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Cytology images | Positive stains | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Well circumscribed mass, arising during or shortly after pregnancy, composed of cuboidal cells with actively secreting, closely packed glands
Essential features
- Most prevalent breast lesion in pregnant women and during postpartum period
- Must be distinguished from carcinoma, as breast cancer is the second most common malignancy during pregnancy
- Age range (19 - 34 years), female
- Benign, slow growing
- Unknown capability of malignant transformation
Terminology
- Adenomatous lactational hyperplasia, nodular lactational hyperplasia (not recommended by WHO)
ICD coding
Epidemiology
- 19 - 34 years, female, predominantly in third decade of life
- Most prevalent breast lesion in pregnant women (mostly third trimester) and during postpartum period (puerperium)
Sites
- Predominantly in breast, may develop in ectopic breast tissue along milk line extending from axilla to vulva (Radiol Case Rep 2017;12:215, Pan Afr Med J 2012;13:47)
Pathophysiology
- Unknown if de novo neoplasm or hyperplastic condition
- Some postulate may arise in a pre-existing adenoma (tubular adenoma, fibroadenoma) with superimposed lactational changes; however, lack of MED12 exon 2 mutations, frequently found in fibroadenomas, does not support this theory (Genes Chromosomes Cancer 2017;56:11)
- Increase in serum estrogen, progesterone and prolactin
Clinical features
- Painless, soft, palpable, solid, mobile discrete mass
- May be bilateral and multifocal
- Infarction may lead to pain, tenderness and rapid enlargement
Diagnosis
- Imaging: ultrasound (first line modality given increased density of pregnant / lactating breast tissue), mammogram, MRI (J Am Coll Radiol 2018;15:S263, AJR Am J Roentgenol 2013;200:3213)
- Invasive procedure: biopsy, fine needle aspiration
Radiology description
- Homogeneous, circumscribed, hypoechoic mass, with posterior acoustic enhancement and gentle lobulations (J Hum Lact 2016;32:559)
- May show hypervascularization (Breast Care (Basel) 2019;14:30)
- May appear hyperechoic or radiolucent due to milk fat
- Rarely shows irregular margins mimicking malignancy (Radiology 1998;206:271)
Radiology images
Contributed by Kristen E. Muller, D.O.
Well circumscribed hypoechoic mass
Hypoechoic mass with hypervascularity
Prognostic factors
- Slow growing, spontaneous regression
- No progression to cancer on follow up studies
- Unknown if capable of carcinogenesis or risk factor
- Coexistence of lactating adenoma with breast malignancy reported (Indian J Cancer 2015;52:585, J Clin Pathol 2005;58:87)
Case reports
- 21 year old woman with rapidly enlarging giant lactating adenoma (J Surg Case Rep 2010;2010:8)
- 22 year old woman with continuously enlarging lactating adenoma misdiagnosed as malignancy on imaging (Breast J 2019;25:1278)
- 25 year old lactating woman with co-occurrence of lactating adenoma and infiltrating ductal carcinoma (J Clin Diagn Res 2015;9:ED14)
- 33 year old woman with aggressively enlarging lactating adenoma prompting multiple biopsies (Radiol Case Rep 2017;12:215)
- 35 year old woman with lactating adenoma 6 months postpartum and continued breast feeding within 24 hours post operation (J Hum Lact 2016;32:559)
Treatment
- Observation for slow growing
- Many spontaneously regress after termination of breastfeeding
- Enucleation in cases that warrant excision (enlarging, worrisome clinical or histologic features)
Clinical images
Images hosted on other servers:
Large mass
Gross description
- Lacks true capsule, well circumscribed, lobulated, solitary or multiple, firm / rubbery mass, gray-tan cut surface, may have necrosis / infarction (Radiol Case Rep 2017;12:215)
- Size: usually < 5 cm, rare reported cases of giant lactating adenomas up to 25 cm (J Surg Case Rep 2010;2010:8, AJR Am J Roentgenol 1999;173:933)
Gross images
Contributed by Dr. Mark R. Wick
Lactating adenoma
Images hosted on other servers:
Well circumscribed mass
Microscopic (histologic) description
- Well circumscribed proliferation of hyperplastic closely packed lobules with both epithelial and myoepithelial cell layers separated by thin, delicate connective tissue
- Glands lined by actively secreting cuboidal or hobnail shaped cells with small round nuclei and granular to clear vacuolated cytoplasm
- Variably prominent small, pinpoint nucleoli may be seen but cells lack cytologic atypia
- Occasional mitoses may be seen
- Resembles pregnancy-like (pseudolactational) changes
- May resemble fibroadenoma or tubular adenoma with lactational change microscopically
Microscopic (histologic) images
Contributed by Kristen E. Muller, D.O.
Lactating adenoma biopsy
Vacuolated cytoplasm
Hypersecretory features
Delicate stroma
Prominent hobnailing
Psammomatous calcification
Virtual slides
Images hosted on other servers:
Lactating adenoma
Cytology description
- Loose cohesive clusters of monomorphic cells or single cells
- Cells contain foamy to finely vacuolated cytoplasm, round uniform nuclei with fine chromatin and small nucleoli (J Clin Diagn Res 2013;7:2417)
- Background of foamy material
Cytology images
Contributed by Dr. Mark R. Wick
FNAB
Images hosted on other servers:
Increased lobular size
Cytoplasmic vacuoles and background foamy material
Molecular / cytogenetics description
- 50 gene NGS panel showed no mutations in three lactating adenomas in one series, including MED12 exon 2 mutations (frequently seen in fibroadenomas) (Genes Chromosomes Cancer 2017;56:11)
Sample pathology report
- Right breast mass, needle biopsy:
- Breast tissue with lactational change / lactating adenoma
- Microcalcifications associated with lactational change / lactating adenoma
Differential diagnosis
- Lobular hyperplasia (normal physiologic event in pregnancy):
- Not a well defined mass
- Delayed involution of lactation:
- Not a well defined mass
- Hyperplastic and involuting lobules
- Neutrophils, macrophages and lymphocytes in background
- More frequently associated with calcifications
- Fibroadenoma with secretory activity:
- Fibroepithelial architecture
- Prominent stroma
- Focal, not diffuse, proliferation of cells with secretory activity
Additional references
Board review style question #1
Which of the following is correct for the entity pictured from this breast biopsy from a 27 year old pregnant woman?
- Frequently shows a prominent stromal component similar to fibroepithelial lesions
- Histologically composed of closely packed glands lined by actively secreting cuboidal or hobnail shaped cells
- Never develops in ectopic breast tissue along milk line
- The glands lack a myoepithelial cell layer
- Third most prevalent breast lesion in pregnant women
Board review style answer #1
B. Histologically composed of closely packed glands lined by actively secreting cuboidal or hobnail shaped cells
Comment Here
Reference: Lactating adenoma
Comment Here
Reference: Lactating adenoma
Board review style question #2
What is the most common breast lesion in pregnant and lactating women?
- Adenomyoepithelioma
- Atypical ductal hyperplasia
- Fibroadenoma
- Invasive ductal carcinoma
- Lactating adenoma
Board review style answer #2
LCIS florid
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Diagnosis | Radiology description | Radiology images | Prognostic factors | Treatment | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Negative stains | Molecular / cytogenetics description | Videos | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Nonclassical or variant form of lobular carcinoma in situ (LCIS) where acini and ducts are markedly distended with little to no intervening stroma, sometimes imparting a mass-like architecture and comprising cells with cytologic features of classical LCIS (type A or type B cells) with or without comedonecrosis and calcifications
Essential features
- Nonclassical or variant form of lobular carcinoma in situ (LCIS) defined by markedly distended acini / ducts of involved terminal duct lobular units (TDLUs) with scanty to no intervening stroma or an expanded acinus / duct filling at least 1 high power field (~40 - 50 cells in diameter)
- Cells share cytologic features of classic LCIS (type A or type B cells) and lack significant cytologic atypia and pleomorphism
- Commonly unifocal and shows a continuous distribution compared to classic LCIS
- Shows features of a high risk precursor lesion of invasive carcinoma with a higher upgrade rate, increased association with invasive carcinoma and more genetic complexity compared to classic LCIS
Terminology
- Florid LCIS or LCIS, florid type (F-LCIS)
- LCIS with necrosis / comedonecrosis
- Lobular neoplasia (can include atypical lobular hyperplasia and LCIS)
- LCIS, variant type (not recommended)
- The term florid is not synonymous with extensive or diffuse
ICD coding
Epidemiology
- F > M
- Florid LCIS tends to significantly affect older, postmenopausal women (mean ages reported: 56 - 61 years) compared to classic LCIS (mean age: 50 years) (Hum Pathol 2013;44:1998, Am J Surg Pathol 2006;30:1445, Eur J Surg Oncol 2019;45:2279)
- Rare; comprises < 5% of LCIS
- Majority arise in association with classic LCIS or atypical lobular hyperplasia (ALH) (Ann Diagn Pathol 2020;45:151481)
- Strong association with invasive lobular carcinoma, potentially as a direct precursor (Am J Surg Pathol 2019;43:399, Arch Med Res 2010;41:436, Ann Diagn Pathol 2020;45:151481, Ann Surg Oncol 2011;18:1845)
Sites
- Florid and pleomorphic LCIS tend to be unifocal and shows a continuous distribution compared to classic LCIS, which has a tendency to be multicentric and bilateral (Virchows Arch 2000;436:421, Virchows Arch 2022;481:823, Am J Surg Pathol 2019;43:399)
Pathophysiology
- First described in 2006 as a form of LCIS with central necrosis (Am J Surg Pathol 2006;30:1445)
- Early tumorigenesis of LCIS is marked by loss of heterozygosity of the wild type allele and inactivating mutations of E-cadherin (Br J Cancer 1997;76:1131)
- E-cadherin, encoded by the CDH1 gene on chromosome 16q22.1, is a cell - cell adhesion molecule that helps maintains lobular architecture
- Clonal relationship to classic LCIS: harbors characteristic signature of LCIS showing 16q loss and 1q gain (Hum Pathol 2013;44:1998)
- Florid LCIS is proposed to progress from classic LCIS by acquiring additional genetic (i.e., frequent ERBB2 or ERBB3 alterations, CCND1 amplifications) and chromosomal alterations (Mod Pathol 2020;33:1287, Mod Pathol 2020;33:1078, Hum Pathol 2013;44:1998)
- Significantly more genome alterations and amplifications compared to classic LCIS (Hum Pathol 2013;44:1998)
- Similar genetic complexity as apocrine pleomorphic LCIS (Hum Pathol 2013;44:1998)
Etiology
- No specific risk factors reported for florid LCIS
- In patients with nonclassic LCIS variants, including florid LCIS, 10/24 patients (41.7%) are reported to have a first degree family history of breast cancer (Surg Oncol 2019;28:190)
- Overall, there is increased risk of LCIS with the following
- High mammographic breast density (Cancer 2015;121:1369)
- History of breast biopsy (J Natl Cancer Inst 2001;93:1811)
- Older age at menopause (J Natl Cancer Inst 2001;93:1811)
- Family history of breast cancer (Breast Cancer Res Treat 2003;78:7)
- Hormone replacement therapy in postmenopausal women (Am J Epidemiol 2017;186:1329)
Diagnosis
- Diagnostic core or excisional biopsy, surgical excision
Radiology description
- Florid and pleomorphic LCIS tend to have a radiographic (95%) or palpable target (5%) (Am J Surg Pathol 2019;43:399)
- Among nonclassic LCIS, including florid LCIS, calcifications were the most common biopsy indication (80%) and all categorized as BI-RADS 4 (Ann Surg Oncol 2019;26:55, Eur J Surg Oncol 2019;45:2279)
- Florid LCIS with necrosis typically presents with calcifications and rarely can present with a mass or density (Mod Pathol 2021;34:1495, Am J Surg Pathol 2019;43:399)
- Florid LCIS without necrosis typically presents as nonmass enhancement on magnetic resonance imaging (MRI) and architectural distortion (Mod Pathol 2021;34:1495, Am J Surg Pathol 2019;43:399)
Radiology images
Contributed by Kristen E. Muller, D.O. and Victoria M. Jones, M.D.
Mammographic calcifications
Prognostic factors
- Outcome data on pure florid LCIS is limited, many studies combine nonclassical LCIS (florid and pleomorphic LCIS) when reporting outcomes
- Florid LCIS shows features of a high risk precursor lesion of invasive carcinoma, which is frequently grade 2 or 3 invasive lobular carcinoma (Mod Pathol 2021;34:1495, Breast J 2020;26:2350, Am J Surg Pathol 2019;43:399, Eur J Surg Oncol 2019;45:2279)
- Pathologic excisional upgrade rate to invasive carcinoma or ductal carcinoma in situ (DCIS) on excision ranges from 17 to 39% (Mod Pathol 2021;34:1495, Am J Surg Pathol 2019;43:399, Eur J Surg Oncol 2019;45:2279)
- 57 - 87% of florid LCIS with necrosis and calcification shows an associated invasive carcinoma, frequently invasive lobular phenotype (Hum Pathol 2013;44:1998)
- Upgrade rate may be associated with the extent of radiographic microcalcifications, extensive florid LCIS (mean: 3.2 cm) and possibly the presence of necrosis (Eur J Surg Oncol 2019;45:2279, Mod Pathol 2021;34:1495)
- ER and HER2 biomarker expression, compared to classic LCIS, suggests a more unfavorable phenotype (Hum Pathol 2013;44:1998)
- Frequent ERBB2 / ERBB3 alterations are associated with more aggressive potential and invasive lobular carcinoma (Mod Pathol 2020;33:1078)
- There is significant variability in recurrence rates but one study found that 25 patients with nonclassic LCIS (including florid LCIS) treated solely with excision had a 4% incidence of future ipsilateral malignancy (Ann Surg Oncol 2019;26:55)
- Recurrences tend to be ipsilateral lobular tumors (Breast J 2020;26:2350)
- Natural history is unknown; out of 3 cases of florid LCIS without necrosis on core biopsy not excised due to patient preference or clinical recommendation, none recurred within a follow up range of 56 - 73 months (Am J Surg Pathol 2019;43:399)
Treatment
- Complete surgical excision of florid LCIS is recommended (WHO) (Virchows Arch 2022;481:823, Hum Pathol 2013;44:1998, Eur J Surg Oncol 2019;45:2279, Mod Pathol 2021;34:1495, Arch Pathol Lab Med 2017;141:1668)
- In one study, 58% of pure LCIS variants (including 5 florid LCIS) were excised to negative margins and treated with endocrine but not radiation therapy (Am J Surg Pathol 2019;43:399)
- No recurrences in a mean follow up interval of 50 months
- Consensus and optimal treatment regimens remain unclear, including the benefits of hormone chemoprevention in women without associated invasive carcinoma (WHO) (Virchows Arch 2022;481:823)
- There are no data supporting the use of adjuvant radiation therapy (Ann Diagn Pathol 2020;45:151481, Virchows Arch 2022;481:823)
Microscopic (histologic) description
- Diagnosis requires the presence of at least 1 of 2 architectural features (Mod Pathol 2020;33:1287, Am J Surg Pathol 2019;43:399, Ann Diagn Pathol 2020;45:151481)
- Markedly distended acini / ducts of involved TDLUs with little to no intervening stroma or
- Expanded acinus / duct filling at least 1 high power field (~40 - 50 cells in diameter)
- Marked distention of acini and ducts with little intervening stroma may impart a confluent, mass-like architecture
- Solid, dyshesive, monomorphic proliferation of classic LCIS type A cells (scant cytoplasm, small uniform nuclei, inconspicuous nucleoli) or type B cells (increased cytoplasm, larger nuclei, more prominent nucleoli) (Am J Surg Pathol 2019;43:399, Ann Diagn Pathol 2020;45:151481)
- Absence of marked nuclear pleomorphism and atypia, distinguishes from pleomorphic LCIS
- Comedo or single cell necrosis is common, up to 71% of cases (Mod Pathol 2020;33:1287, Mod Pathol 2021;34:1495)
- Comedo type necrosis, mitosis and apoptosis are more frequent in florid LCIS than in pleomorphic LCIS (Hum Pathol 2018;78:163)
- May observe apocrine features (rounded, enlarged nuclei with prominent nucleoli and abundant eosinophilic and granular cytoplasm), more commonly in ER negative cases (Mod Pathol 2021;34:1495)
- Rarely composed entirely of signet ring cells, which has a high frequency of associated invasive lobular carcinoma (80% of 10 cases in small series) (Arch Med Res 2010;41:436)
- Often coexists with classic or pleomorphic LCIS
Microscopic (histologic) images
Contributed by Kristen E. Muller, D.O. and Victoria M. Jones, M.D.
Florid LCIS with mass-like architecture
Single acinus
Little intervening stroma
Necrosis
Calcifications
Type B cells
Type A cells
Mitoses
Apocrine features
Invasive lobular carcinoma
E-cadherin
Positive stains
- ER, strong and diffuse (77 - 100%) (Hum Pathol 2013;44:1998, Am J Surg Pathol 2019;43:399, Mod Pathol 2021;34:1495)
- ER positive in 33% in florid LCIS with apocrine features, 94% in florid LCIS without apocrine features (Mod Pathol 2021;34:1495)
- Ki67 (median of 7.5% and range of 1 - 23% in LCIS variants of no significant difference between florid and pleomorphic LCIS) (Am J Surg Pathol 2019;43:399)
- p120, abnormal cytoplasmic accumulation (Surg Pathol Clin 2018;11:123)
- Androgen receptor expression, positive in all LCIS variants, independent of apocrine features (Virchows Arch 2022;481:823, Mod Pathol 2021;34:1495)
Negative stains
- PR (35% in LCIS variants including florid LCIS) (Am J Surg Pathol 2019;43:399)
- HER2 (13 - 18%, florid LCIS) (Hum Pathol 2013;44:1998), Mod Pathol 2021;34:1495)
- Classic LCIS is typically ER positive, PR positive, HER2 negative (Breast Cancer Res Treat 2005;90:249, Surg Pathol Clin 2018;11:123)
- ER and HER2 are consistently concordant between florid LCIS variants and upgraded invasive lobular carcinoma (Am J Surg Pathol 2019;43:399)
- Cyclin D1 protein expression (40%, florid LCIS) (Hum Pathol 2013;44:1998)
- E-cadherin, negative or aberrant membranous expression in florid LCIS (Mod Pathol 2021;34:1495)
- Loss of beta catenin membranous expression in LCIS variants, including florid LCIS (Mod Pathol 2020;33:1287)
Molecular / cytogenetics description
- Florid LCIS shares the LCIS molecular hallmarks of 16q loss and 1q gain (Mod Pathol 2020;33:1287, Mod Pathol 2020;33:1078)
- CDH1 gene encoding for E-cadherin on chromosome 16
- Pathogenic alterations in CDH1, ERRB2, PIK3CA, ERRB3, RUNX1, FOXA1, CCND1 and CBFB (Mod Pathol 2020;33:1287, Mod Pathol 2020;33:1078)
- Frequent ERBB2 / ERBB3 alterations (HER2 / HER3) are associated with more aggressive potential and invasive lobular carcinoma (Mod Pathol 2020;33:1078)
- Additional, complex genomic alterations including (Mod Pathol 2020;33:1078)
- Gain of interstitial or whole arm 17q, loss of distal or whole arm 8p, 11q and 17p, loss of distal or whole arm 18q or whole chromosome 18, loss of 13q or whole chromosome 13, gain of distal or whole arm 16p, gain of 8q or whole chromosome 8
- Significantly more fraction genome alteration and loss, number of breakpoints and chromosomes with breakpoints and amplifications than classic LCIS (Hum Pathol 2013;44:1998)
- Similar genetic complexity to apocrine pleomorphic LCIS (Hum Pathol 2013;44:1998)
Videos
Lobular carcinoma in situ and high risk breast lesions
Sample pathology report
- Breast, right, core needle biopsy:
- Lobular carcinoma in situ (LCIS), florid type (see comment)
- Comment: The biopsy shows ducts and lobules that are markedly distended by a proliferation of classic LCIS cells (small, round, discohesive, uniform cells) with comedo type necrosis and calcifications. An E-cadherin immunostain is negative in lesional cells supporting interpretation as florid LCIS.
Differential diagnosis
- Classic LCIS:
- Similar cytologic features as florid LCIS (type A or type B cells)
- Lacks marked distention of acini and ducts
- If borderline distension is between florid and classic, it should be categorized as classic (Ann Diagn Pathol 2020;45:151481)
- Florid is not synonymous with extensive or diffuse LCIS (implies extensive involvement of multiple terminal duct lobular units [TDLUs] but without marked distension) (Mod Pathol 2021;34:8)
- Pleomorphic LCIS:
- Similar expanded architecture, large ducts, comedonecrosis and calcifications as florid LCIS
- Distinguishing high grade, pleomorphic nuclei
- Large (> 4x lymphocyte nuclei), occasional multinucleation (Ann Diagn Pathol 2020;45:151481)
- Solid pattern DCIS, low and intermediate grade:
- May have necrosis, degeneration and a discohesive appearance
- Sharply defined cell membranes
- Retained E-cadherin (Ann Diagn Pathol 2020;45:151481)
- Usual ductal hyperplasia, florid type:
- Heterogeneous cohesive cells that may be spindled and overlapping
- May also have central necrosis
- E-cadherin positive
- Atypical lobular hyperplasia:
- Similar cytologic features as florid LCIS (type A or type B cells)
- Lacks uniform, marked distention of acini and ducts
- Criteria of Page et al. (Schnitt: Biopsy Interpretation of the Breast, 3rd Edition, 2017)
- Distends 50% or more acini within a lobule (so resembles lobular carcinoma in situ) but not uniformly present throughout entire lobule or
- Involves all acini in a TDLU and so resembles lobular carcinoma in situ but does not distend the acini (i.e., caliber of the involved acini is similar to that of uninvolved acini)
Additional references
Board review style question #1
The photomicrographs above are from a 63 year old woman who underwent core needle biopsy for screen detected calcifications. An E-cadherin immunostain is negative in lesional cells. What is the most appropriate diagnosis?
- Atypical lobular hyperplasia
- Ductal carcinoma in situ
- Lobular carcinoma in situ, classic type
- Lobular carcinoma in situ, florid type
- Lobular carcinoma in situ, pleomorphic type
Board review style answer #1
D. Lobular carcinoma in situ, florid type. The images show markedly expanded acini with central necrosis and calcification and little intervening stroma. The cells are uniform, small and round without marked pleomorphism. The differential usually includes ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS). A negative E-cadherin immunostain supports interpretation as LCIS and given the marked distention with scanty stroma, florid LCIS is the best diagnosis. Answer B is incorrect because this lesion is negative for E-cadherin and DCIS would have it retained. Answer C is incorrect because this meets diagnostic criteria for florid LCIS given the marked acinar distention. Answer E is incorrect because the lesional cells lack cytologic features of pleomorphic LCIS. Answer A is incorrect because atypical lobular hyperplasia (ALH) shows similar cytologic features to florid LCIS; however, criteria for ALH include either type A or type B cells that distend 50% or more acini within a lobule but not uniformly present throughout the entire terminal duct lobular unit (TDLU) or involves all acini in a TDLU but does not distend the acini. In contrast, florid LCIS shows markedly distended acini in a TDLU.
Comment Here
Reference: LCIS florid
Comment Here
Reference: LCIS florid
Board review style question #2
Which of the following is a true statement regarding florid lobular carcinoma in situ (LCIS)?
- Florid LCIS is always HER2 negative
- Florid LCIS is not typically detected by mammography
- Florid LCIS is rarely upgraded to invasive carcinoma; thus, surgical excision is not recommended
- Florid LCIS shares the classic LCIS molecular hallmarks of 16q loss and 1q gain
Board review style answer #2
D. Florid LCIS shares the classic LCIS molecular hallmarks of 16q loss and 1q gain. In addition, florid LCIS has significantly more genomic alterations and amplifications compared to classic LCIS and in some studies, shows a similar genetic complexity to apocrine pleomorphic LCIS. Answer B is incorrect because florid LCIS is frequently detected by imaging and presents with calcifications (most commonly) or a mass / density. Answer C is incorrect because the upgrade rate to invasive carcinoma or DCIS is between 17 and 39%. Although consensus guidelines are not yet available, most experts agree that surgical excision should be recommended. Answer A is incorrect because florid LCIS is reported to be HER2 positive 13 - 18% of the time and shows frequent ERBB2 / ERBB3 alterations in molecular studies.
Comment Here
Reference: LCIS florid
Comment Here
Reference: LCIS florid
LCIS pleomorphic
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Cytology images | Positive stains | Negative stains | Molecular / cytogenetics description | Videos | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- A morphologic subtype of lobular carcinoma in situ (LCIS) composed of a noninvasive neoplastic proliferation of large dyscohesive cells with marked nuclear pleomorphism (nuclei are > 4 times the size of a lymphocyte, equivalent to the cells of high grade DCIS)
- With or without apocrine features (Histopathology 2020;77:181)
Essential features
- Lobulocentric proliferation of cells which are significantly more pleomorphic and larger when compared to cells of classic LCIS
- Lobular acini involved by pleomorphic LCIS and often substantially expanded
- Cytologic features more closely resemble high grade DCIS rather than classic LCIS
- Large nuclei (≥ 4x larger than a lymphocyte)
- Pleomorphism: 2 - 3x variation in nuclear size and shape
- May be associated with necrosis, including comedonecrosis
- Other features overlap with classic LCIS
- Loss / dysfunction of E-cadherin
- Cellular dyscohesion
- Lack of cell polarity
- Intracytoplasmic lumina, may have signet ring cells
- Pagetoid spread
- Regarded as a genetically and biologically more advanced lesion than classic LCIS and is a direct precursor to invasive carcinoma
Terminology
- First described by Frost et al. in 1996 (AJSP Rev Rep 1996;1:27)
- Pleomorphic LCIS (may be denoted as PLCIS, PL LCIS or P LCIS) is considered a morphologic variant of classic LCIS (CLCIS)
- Although it falls under the category of lobular neoplasia, the terms nonclassic lobular carcinoma in situ and variant lobular carcinoma in situ are not preferred because they do not distinguish between PCLIS and another morphologic subgroup called florid LCIS (FLCIS)
- In the past, some have referred to what is now PLCIS as pleomorphic ductal lobular carcinoma in situ (PL / DLCIS), which is no longer used
- The terms lobular carcinoma in situ with pleomorphic morphology or lobular carcinoma in situ with pleomorphic features are not preferred as they are more vague than using pleomorphic lobular carcinoma in situ
- While there is no established cutoff, some have suggested that lobular lesions be considered pleomorphic when at least 10% of the tumor cells show high grade nuclei (Histopathology 2014;64:981)
- Lobular acini involved by pleomorphic lobular cells are often substantially expanded but they may be only mildly distended or show no distension; the latter still qualify as pleomorphic LCIS since there is no recognized category of pleomorphic atypical lobular hyperplasia (ALH) (analogous to not having a high grade atypical ductal hyperplasia)
- Currently there is no term for a lesion with both the nuclear morphology of pleomorphic LCIS and architectural features of florid LCIS
ICD coding
- ICD-O:
- ICD-11:
- 2E65.0 & XH6EH0 - lobular carcinoma in situ of breast & lobular carcinoma in situ, NOS
Epidemiology
- PLCIS is relatively rare, with an estimated incidence of < 5% of all LCIS (Histopathology 2014;64:981)
- Prevalence may be underestimated given the similarities of PLCIS to DCIS, especially high grade DCIS and probable misdiagnoses as such in the past
- Most patients with PLCIS are White females (Ann Surg Oncol 2015;22:4263)
- Compared to CLCIS, patients with PLCIS are typically older and postmenopausal
- Multiple studies have found PLCIS patients have a mean age of ~55 years (range: 36 - 86 years) (Am J Surg Pathol 2009;33:1683, Mod Pathol 2002;15:1044)
- One study found this age difference was mostly attributed to apocrine PLCIS, which was diagnosed primarily in postmenopausal women with a mean age of 60 years, whereas the mean age for nonapocrine PLCIS was 51 years (Am J Surg Pathol 2009;33:1683)
Sites
- Occurs in the breast with no specific laterality predilection
- PLCIS has been noted to be more unifocal and continuous in distribution than CLCIS, which is typically multicentric and bilateral (Am J Surg Pathol 2019;43:399)
Pathophysiology
- CDH1 inactivation, which leads to loss or impaired function of E-cadherin, is an early event and hallmark of lobular lesions, including PLCIS (Histopathology 2020;77:181)
- E-cadherin plays a major role in intercellular adhesion and cell polarity
- 1q gain and 16q loss combined with the lack of E-cadherin expression observed in PLCIS support a lobular lineage
- PLCIS accumulates additional alterations and generally exhibits greater genomic instability than classic LCIS (J Pathol 2005;207:1, Mod Pathol 2020;33:1287)
- Whether PLCIS arises from CLCIS and represents a genetically more advanced lesion or if PLCIS originates from a separate disease process is not entirely clear; however
- PLCIS and pleomorphic invasive lobular carcinoma (ILC) are frequently associated with foci of classic ILC and areas showing a morphological continuum between PLCIS and CLCIS have also been described (J Pathol 2005;207:1)
- Synchronous CLCIS and apocrine PLCIS share similar chromosomal changes with additional changes present in the apocrine PLCIS, suggesting evolution from the same precursor or through the same genetic pathway (Am J Surg Pathol 2009;33:1683)
Etiology
- No well known causative factors specific to PLCIS
- Etiologic factors associated with the development of CLCIS currently have insufficient data for being considered etiologic factors for PLCIS
- A study found that in their cohort of patients with nonclassic LCIS, which also included florid LCIS and LCIS with pleomorphic features, none had a personal history of breast cancer nor were known BRCA1 / 2 carriers but 41.7% (10/24) had a first degree family history of breast cancer (Surg Oncol 2019;28:190)
Clinical features
- Patients are usually asymptomatic
- The majority of patients (up to 87%) present with abnormal screening detected mammographic findings, such as calcifications (Am J Surg Pathol 2009;33:1683)
- Some cases of PLCIS lack specific radiologic features and may be an incidental microscopic finding in breast biopsies
- Less commonly, patients can present with a palpable mass or nipple discharge (Histopathology 2014;64:981, Surg Oncol 2019;28:190)
- Patients who present with a palpable mass usually have PLCIS involving other lesions (e.g., a fibroadenoma) or have associated invasive carcinoma (AJR Am J Roentgenol 2018;211:462)
- Only 15 - 52.2% of patients have pure PLCIS alone on final surgical pathology on core biopsy or excision (Ann Surg Oncol 2015;22:4263, Am J Surg Pathol 2019;43:399)
- In the majority of cases (up to 77%), there is an associated invasive carcinoma, usually consisting of pleomorphic ILC but classic ILC or other histologic types may occur (Am J Surg Pathol 2019;43:399)
Diagnosis
- Most patients have imaging abnormalities detected on mammogram or ultrasound, leading to image directed core needle biopsies
- In a subset of patients, PLCIS may be detected at the time of excisional biopsy or operations for other lesions (Ann Surg Oncol 2018;25:3064)
Radiology description
- Most patients present with suspicious mammographic calcifications similar to those associated with DCIS (AJR Am J Roentgenol 2012;199:929, AJR Am J Roentgenol 2001;176:1255)
- Rarely a patient may have a circumscribed mass identified on a diagnostic mammogram or ultrasound (AJR Am J Roentgenol 2018;211:462)
- The following imaging findings (from most to least common) were described in one study: fine pleomorphic grouped calcifications on mammograms, mammographic distortion, amorphous calcifications or regional clumped nonmass enhancement at screening MRI (AJR Am J Roentgenol 2018;211:462)
- Other studies using advanced breast imaging with MRI found nonmass-like enhancement (37.5 %), no MRI abnormality (31.3 %), mass / space occupying lesion (25.0%) or focal < 5 mm area of enhancement (6.3%) (Ann Surg Oncol 2015;22:4263)
Radiology images
Images hosted on other servers:
50 year old woman screening mammogram
54 year old woman screening mammogram
Prognostic factors
- Pure PLCIS is relatively rare and the natural history of PLCIS not associated with invasive carcinoma remains largely unknown
- PLCIS is considered both a genetically advanced risk factor for and direct precursor to ILC / pleomorphic ILC
- PLCIS is associated with a high incidence of associated invasive carcinoma either on core needle biopsy or excision
- Reported numbers vary; one study cohort found 46 of 93 (49%) PLCIS patients had concurrent invasive disease on excision specimen analysis (World J Clin Oncol 2014;5:546)
- Given the increased genomic instability of PLCIS, the risk of subsequent breast cancer is suspected to be higher than CLCIS but further studies with more patients and longer follow up are necessary
- PLCIS is more likely to be ER or PR negative and HER2 positive when compared with CLCIS and FLCIS (Breast 2013;22:194)
- Up to 18% of patients may be triple negative (Mod Pathol 2020;33:1287)
- PLCIS also frequently has a high Ki67 labeling index and accumulation of p53 protein by immunohistochemistry, both features indicative of aggressive behavior (Breast 2013;22:194)
- Overall, due to its unfavorable immunoprofile and a higher likelihood of being associated with invasive disease, it is regarded as having a worse prognosis than CLCIS
Case reports
- 44 year old woman with PLCIS of the breast composed almost entirely of signet ring cells (Pathol Int 2006;56:683)
- 52 year old woman with metastatic invasive pleomorphic lobular carcinoma with PLCIS / high grade DCIS-like morphology in affected lymph nodes (Int J Surg Pathol 2020;28:436)
- 68 year old woman with apocrine differentiation in invasive pleomorphic lobular carcinoma arising in a background of multiple in situ lesions, including apocrine PLCIS, classic LCIS and DCIS (Pathol Oncol Res 2002;8:151)
- 79 year old woman with apocrine PLCIS associated with microglandular adenosis and metaplastic matrix producing carcinoma (Diagnostics (Basel) 2022;12:1458)
Treatment
- There are no well defined guidelines for the treatment of PLCIS
- It is currently debated whether it is necessary to achieve negative margins and if there is any potential benefit of adjuvant radiation
- WHO Classification of Tumors Editorial Board recommends excision for PLCIS diagnosed on core needle biopsy (Histopathology 2020;77:181)
- In a resection specimen, the margin status of CLCIS is not reported but many recommend it should be reported for PLCIS to help inform subsequent management decisions (Arch Pathol Lab Med 2011;135:737)
- For management guidelines, many organizations suggest considering excision of PLCIS with negative margins (World J Clin Oncol 2014;5:546)
- Others recommend PLCIS should be treated similarly to DCIS; surgical excision with negative margins with or without other adjuvant treatments (World J Clin Oncol 2014;5:546)
- As with high grade DCIS, some suggest that a sentinel lymph node biopsy may be considered at the time of PLCIS excision (World J Clin Oncol 2014;5:546)
- Reported recurrence rates of PLCIS treated with conservative surgery with or without antiestrogen therapy vary widely from 0% to as high as 57% (Histopathology 2020;77:181)
- It is unclear whether positive margin status affects the likelihood of recurrence
- One study evaluating only PLCIS at or near an excision margin found an overall recurrence rate of 3.8% regardless of treatment (Arch Pathol Lab Med 2011;135:737)
- Chemoprevention can be considered in ER positive PLCIS patients
Gross description
- Not associated with any specific grossly recognizable abnormalities
- Cut surface of breast tissue harboring PLCIS may have a faintly granular appearance when viewed with tangential light because affected lobules may be sufficiently enlarged to be visible and microcalcifications are almost always present
Microscopic (histologic) description
- Pleomorphic LCIS has architectural features similar to CLCIS, characterized by solid proliferation of dyscohesive neoplastic cells within terminal duct lobular units (TDLUs)
- Pagetoid spread to adjacent ducts may be seen, similar to CLCIS
- Differs from classic LCIS with regard to the degree of nuclear atypia or lobular acinar expansion
- Unlike CLCIS, PLCIS has more nuclear enlargement and variability
- Lobular acini involved by pleomorphic lobular cells are often substantially expanded but they may be only mildly distended or show no distension
- Individual cells are medium to large with high N:C ratios, PLCIS nuclei are larger (≥ 4x the size of a lymphocyte), often exhibit moderate to marked nuclear pleomorphism (> 2 - 3x variation in nuclear size) and have distinct small to prominent nucleoli (Mod Pathol 2002;15:1044)
- Nuclei are often eccentrically placed and binucleated / multinucleated cells are frequently seen (Am J Clin Pathol 2015;144:722)
- Chromatin is coarse and mitotic figures can be seen
- Cytoplasm of PLCIS cells is moderate to abundant, dense eosinophilic or granular
- Intracytoplasmic vacuoles are often present with or without mucin; may be large enough to produce signet ring cell forms
- Apocrine differentiation is observed in a subset of pleomorphic LCIS, referred to as apocrine PLCIS
- This subset is characterized by abundant eosinophilic cytoplasm, cytoplasmic granules and prominent nucleoli
- Central, comedo type necrosis is often present but not required for diagnosis
- Microcalcifications are a common associated finding
- PLCIS coexists with classic LCIS in > 40% of cases (Mod Pathol 2002;15:1044)
- Associated with invasive carcinoma, most commonly pleomorphic ILC but may be of any histologic type, careful assessment of surrounding tissue is essential
Comparison of cytomorphologic features
| Type of carcinoma | Nuclear sizea | Nuclear pleomorphism | Nucleoli | Cytoplasm | Dyshesion | Central necrosis and calcifications |
| PLCIS | ≥ 4x | Moderate / marked | Small (occasionally prominent) | Moderate / abundant | Yes (often) | Yes (common) |
| Classic LCIS type A | 1.5x | Absent | Indistinct | Scant | Absent | Absent |
| Classic LCIS type B | 2x | Mild / moderate | Indistinct | Moderate | Yes (common) | Absent |
| FLCIS | 1.5 - 2x | Absent to moderate | Indistinct | Scant to moderate | Occasional | Yes (common) |
- Adapted and modified from Mod Pathol 2002;15:1044
- aSize in comparison with a mature lymphocyte
- Florid LCIS (FLCIS) cells show the cytological features of classic LCIS
- FLCIS can be composed of type A or type B LCIS cells and is defined based on architectural not cytologic features (Mod Pathol 2002;15:1044)
- Pleomorphic LCIS and florid LCIS often demonstrate comedonecrosis and calcifications
Microscopic (histologic) images
Contributed by Anna Biernacka, M.D., Ph.D.
PLCIS with central necrosis and calcifications
Marked nuclear pleomorphism
Cellular dyscohesion and pleomorphism
Apocrine PLCIS
PLICS, solid proliferation of discohesive cells
PLICS, absent E-cadherin
PLCIS, attenuated E-cadherin
CLCIS and PLCIS
PLCIS with associated invasive carcinoma
PLCIS within the lobule
Virtual slides
Images hosted on other servers:
Distending lobules with necrosis and calcifications
Cytology description
- Samples are typically highly cellular
- Cells are dyscohesive, predominately single but may form small, loosely cohesive aggregates
- Cells have abundant dense cytoplasm and may have signet ring morphology
- Nuclei are large, pleomorphic and frequently have nucleoli
- Cells may be bi or multinucleated, lobulated, indented or eccentrically placed
- Cells can resemble those of DCIS
- Intracytoplasmic mucin or signet ring cells can be present, which can help to distinguish from DCIS
- Microcalcifications or necrosis may be seen in the background
- In ductal lavage (DL), the degree of cytologic atypia is lower than that seen in fine needle aspiration (FNA) (Acta Cytol 2008;52:207)
- There are no reliable cytologic criteria for distinguishing between PLCIS and ILC
- Reference: Cancer 2008;114:111
Cytology images
Images hosted on other servers:
Cytoplasm
Nuclei
E-cadherin
Positive stains
- ER and PR are frequently positive
- In PLCIS
- ER is positive in 72 - 100% of cases
- PR is positive in 50 - 100% of cases
- HER2 is overexpressed in 1 - 41% of cases (Surg Pathol Clin 2018;11:123)
- Notably, PLCIS is more likely to be ER negative than CLCIS
- CLCIS are typically diffusely and strongly positive for ER and PR (> 90% of cases) and very rarely show ERBB2 (HER2) overexpression or gene amplification (0 - 4%) (Histopathology 2020;77:181)
- In a study comparing PLCIS and classic lobular with pleomorphic features (borderline CLCIS lesions with focal atypia), expression of ER was identified in 81% of PLCIS cases and 100% of CLCIS with pleomorphic features (Breast Cancer Res Treat 2017;165:411)
- Apocrine PLCIS appears to be a biologically and immunohistochemically distinct subtype
- It is mostly (~80%) negative for ER and PR, has HER2 gene amplification in 33% of cases and has elevated Ki67 (> 10%) (Am J Surg Pathol 2009;33:1683)
- Although AR expression in a study (see table below) was identified in all LCIS lesions, nonapocrine PLCIS had significantly lower AR levels than both CLCIS and apocrine PLCIS (Am J Surg Pathol 2009;33:1683)
| Comparison of biomarkers among lobular carcinoma in situ (LCIS) subtypes | ||||||||
| ER | PR | AR | AR intensity | Mean Ki67 | HER2 | GCDFP-15 | CK5/6 | |
| CLCIS | 100% | 100% | 100% | Moderate | 4.20% | 0% | Not done | 19% |
| All PLCIS | 66% | 62% | 100% | Variable | 11.5% | 13% | 74% | 23% |
| Nonapocrine PLCIS | 100% | 94% | 100% | Weak | 9.9% | 0% | 50% | 28% |
| Apocrine PLCIS | 23% | 17% | 100% | Strong | 13.9% | 31% | 100% | 17% |
- Adapted from Am J Surg Pathol 2009;33:1683
Negative stains
- Loss of membranous expression of E-cadherin is the defining immunohistochemical feature of lobular differentiation including PLCIS
- Inactivation of E-cadherin usually leads to loss of p120 and beta catenin expression on cell membranes and aberrant accumulation of p120 in the cytoplasm (Arch Pathol Lab Med 2017;141:1668)
- Rarely attenuated E-cadherin expression (scattered cells showing dot-like discontinuous and weak membranous staining or patchy cytoplasmic staining) is seen but this does not preclude the diagnosis of PLCIS if typical morphology is present
Molecular / cytogenetics description
- The molecular hallmark of LCIS, including PLCIS, is the loss of expression or function of membranous E-cadherin, a transmembrane glycoprotein encoded by the CDH1 gene on the long arm of chromosome 16 (16q)
- Overall, PLCIS and CLCIS share similar genomic alterations: both groups are characterized by 1q gain (75% in PLCIS versus 69% in CLCIS) and 16q loss (85% versus 76%, for PLCIS and CLCIS, respectively) (Am J Surg Pathol 2009;33:1683)
- PLCIS is thought to evolve through a molecular genetic pathway similar to that of CLCIS but then undergoes additional genetic events
- PLCIS exhibits greater genomic instability than CLCIS, with increased copy number changes, gene amplifications and additional mutations
- Mutations (and amplification) of ERBB2 (HER2) are frequent molecular alterations in PLCIS
- Amplification of HER2 is found in ~15 - 40% of cases
- HER2 mutations in ~20% of cases (more frequent in apocrine PLCIS)
- Mutations and amplifications are mutually exclusive
- HER2 alterations are more common in ER- lesions
- At least some PLCIS are nonobligate precursors of pleomorphic ILC, analogous to high grade DCIS and invasive ductal carcinoma
- These lesions show additional molecular genetic changes, including gains of c-myc (8q24) and HER2 (17q12), gains on 8p, 8q and 13q and losses on 1p, 8p, 12p, 14q, 18q, 19p and 19q (J Pathol 2005;207:1)
- When separating apocrine and nonapocrine PLCIS, one study found that the overall extent of genomic alterations was similar between CLCIS and nonapocrine PLCIS; additional genomic changes were observed only in the apocrine PLCIS (Am J Surg Pathol 2009;33:1683)
Videos
Lobular carcinoma in situ and invasive lobular carcinoma including variants
Sample pathology report
- Breast, left, seed localized partial mastectomy:
- Pleomorphic lobular carcinoma in situ, largest focus measuring 1.5 cm in greatest dimension, surgical margins negative (see comment)
- Comment: Immunohistochemical stains are performed and show the tumor cells to be negative for E-cadherin and beta catenin consistent with a lobular phenotype supporting the diagnosis above.
Differential diagnosis
- Florid LCIS:
- Has nuclear features of CLCIS and lacks the nuclear pleomorphism of PLCIS
- FLCIS shows marked distention of ducts and lobules with little residual stroma between the expanded spaces
- It may or may not have necrosis or calcifications (Am J Surg Pathol 2019;43:399)
- Classic LCIS with a predominance of type B cells:
- Type B cells of CLCIS have slightly larger vesicular nuclei with mild variability in size and shape and with small nucleoli when compared to type A cells
- They lack the marked nuclear pleomorphism of PLCIS
- The distinction may be difficult in some cases
- Many authors and the current WHO recommend LCIS lesions that are borderline between CLCIS composed of type B cells and PLCIS should be categorized as CLCIS composed of type B cells (Histopathology 2020;77:181, Ann Diagn Pathol 2020;45:151481)
- High grade ductal carcinoma in situ:
- No intracytoplasmic vacuoles, mucin or signet ring cells
- E-cadherin positive
- Apocrine intraductal carcinoma:
- Predilection for lobular involvement
- E-cadherin positive
Board review style question #1
The depicted image is of a breast lesion from a postmenopausal woman. The first image is stained with H&E. The second image is the same area as the first image, stained immunohistochemically with E-cadherin. Other areas (not depicted) had associated microcalcifications. What is the most likely diagnosis?
- Apocrine intraductal carcinoma
- Classic lobular carcinoma in situ
- High grade ductal carcinoma in situ
- Invasive ductal carcinoma
- Pleomorphic lobular carcinoma in situ
Board review style answer #1
E. Pleomorphic lobular carcinoma in situ, PLCIS. Answer B is incorrect because although the lesion has some similar characteristics to classic lobular carcinoma in situ (CLCIS), such as distension of an affected lobule and loss of membranous E-cadherin staining, the cells have enlarged markedly pleomorphic nuclei, which would not be seen in CLCIS. Also, the patient being postmenopausal and the lesion being associated with microcalcifications favors PLCIS rather than CLCIS. Answers A, C and D are incorrect because apocrine intraductal carcinoma, high grade ductal carcinoma in situ and invasive ductal carcinoma would not demonstrate loss of E-cadherin staining. Also, regarding answer D, PLCIS is an in situ lesion and not an invasive carcinoma.
Comment here
Reference: LCIS pleomorphic
Comment here
Reference: LCIS pleomorphic
Board review style question #2
Which of the following is true about pleomorphic lobular carcinoma in situ (PLCIS)?
- Displays positive beta catenin membranous staining by IHC
- Infrequently associated with central, comedo type necrosis
- Is a precursor of invasive carcinoma
- Most patients present with bloody nipple discharge
- The majority of patients are triple negative (estrogen receptor, progesterone receptor and HER2 negative)
Board review style answer #2
C. Is a precursor of invasive carcinoma. Although pleomorphic lobular carcinoma in situ (PLCIS) is an in situ lesion, it is considered a precursor of invasive carcinoma. Answer A is incorrect because beta catenin is part of the cadherin - catenin complex and PLCIS would lose membranous staining by immunohistochemistry. Answer B is incorrect because this lesion is frequently associated with central comedonecrosis. Answer D is incorrect because most patients present with a screening detected abnormality on imaging. Answer E is incorrect because ~10% of patients with PLCIS are triple negative.
Comment here
Reference: LCIS pleomorphic
Comment here
Reference: LCIS pleomorphic
Leiomyoma
Table of Contents
Definition / general | Essential features | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Case reports | Treatment | Clinical images | Gross description | Gross images | Frozen section description | Frozen section images | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Negative stains | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Benign mesenchymal tumor of smooth muscle, rare in breast (BMC Womens Health 2022;22:119, J Cutan Pathol 2019;46:343)
Essential features
- Benign smooth muscle tumor
- Spindle shaped cells with cigar shaped nuclei arranged in whorls and fascicles
- SMA, desmin, caldesmon positive
Epidemiology
- Middle aged women (BMC Womens Health 2022;22:119)
- F:M = 3:1 (Case Rep Surg 2013;2013:475215)
Sites
- Rare in breast (1% of breast neoplasms) (Eur J Breast Health 2017;13:156)
- Superficial (nipple areola complex) or deep (breast parenchyma)
- Subareolar area (Eur J Breast Health 2017;13:156)
- Nipple (Case Rep Surg 2013;2013:475215)
- More common in other sites such as uterus, gastrointestinal tract, skin and lower extremities (J Oral Maxillofac Pathol 2013;17:281)
Pathophysiology
- Arises from smooth muscles (J Cutan Pathol 2019;46:343)
- Hormonal association (J Oral Maxillofac Pathol 2013;17:281)
Etiology
- Trauma (J Med Case Rep 2013;7:49)
- Tamoxifen and antiobesity drug use associated with enlargement of breast leiomyoma (AJR Am J Roentgenol 2005;185:1595)
Clinical features
- Typically a firm, mobile lump but can be nonmobile (Breast J 2020;26:529)
- Intermittent pain (Case Rep Surg 2013;2013:475215, Breast J 2020;26:529)
- No nipple discharge (Case Rep Surg 2013;2013:475215)
Diagnosis
- Can be detected on mammography or ultrasound (AJR Am J Roentgenol 2005;185:1595, Korean J Radiol 2020;21:955)
- Excisional biopsy is diagnostic as well as therapeutic due to risk of local recurrence (Int J Sci Stud 2015;3:210, J Med Case Rep 2013;7:49)
Radiology description
- Ultrasound shows an oval, circumscribed hypoechoic mass with internal vascularity (Korean J Radiol 2020;21:955)
- MRI scan reveals an intense, homogeneous enhancement (Korean J Radiol 2020;21:955)
- Well defined lesion, hypoechoic on mammography (AJR Am J Roentgenol 2005;185:1595)
- No calcifications (Eur J Breast Health 2017;13:156)
Radiology images
Images hosted on other servers:
Well defined, circumscribed, hypoechoic mass
Case reports
- 31 year old woman with enlarging hard lesion in bilateral nipple (Case Rep Surg 2013;2013:475215)
- 40 year old woman with mass in right nipple (Breast J 2020;26:529)
- 43 year old woman with bilateral breast lump with atypical features and 46 year old woman with a 3 cm lesion in left breast (BMC Womens Health 2022;22:119)
- 44 year old woman with painless lump in right breast (Eur J Breast Health 2017;13:156)
- 47 year old woman with a 2 cm mass in sonography of left breast (AJR Am J Roentgenol 2005;185:1595)
- 59 year old woman for routine mammography (Radiol Bras 2016;49:343)
Treatment
- Excisional biopsy is therapeutic (J Med Case Rep 2013;7:49)
- Calcium channel blocker, alpha adrenergic blocker may be used to reduce pain (Case Rep Surg 2013;2013:475215)
Clinical images
Images hosted on other servers:
1 cm nodule (black arrow) on left areola
Left nipple (white arrow), nodule (black arrow)
Swollen left nipple compared with the right nipple
Gross description
- Circumscribed (Breast J 2020;26:529)
- 0.8 - 2.7 cm in size (Breast J 2020;26:529)
- Fleshy, pale, whitish (Eur J Breast Health 2017;13:156)
- Homogenous white cut surface (Breast J 2020;26:529)
Gross images
Images hosted on other servers:
Well circumscribed skin covered mass
Frozen section description
- Frozen section has been described to evaluate margins (Case Rep Surg 2013;2013:475215)
Frozen section images
Contributed by Reena Tomar, M.B.B.S., M.D.
Scrapes
Scrapes (toluidine blue)
Microscopic (histologic) description
- Proliferation of monotonous spindle cells (BMC Womens Health 2022;22:119)
- Spindle cells are relatively uniform in size and shape with cigar shaped nuclei (Breast J 2020;26:529)
- Interlacing bundles of smooth muscle cells separated by a small amount of well vascularized connective tissue (J Med Case Rep 2013;7:49)
- Circumscribed, overlying epidermis is unremarkable (Breast J 2020;26:529)
- Nipple leiomyoma shows dermal lesion, glandular components are absent
- No mitosis, no necrosis, no atypia (BMC Womens Health 2022;22:119)
- Atypical leiomyoma has features of nuclear atypia and up to 3 mitosis/10 high power fields (BMC Womens Health 2022;22:119)
Microscopic (histologic) images
Contributed by Reena Tomar, M.B.B.S., M.D., Mark R. Wick, M.D. and Julie M. Jorns, M.D.
Dermal circumscribed leiomyoma
Spindle shaped cells
Fascicles
Whorls and fascicles
SMA
Caldesmon
Desmin
PR
S100
Fascicles
Breast core biopsy
Breast core biopsy
Positive stains
- SMA (Breast J 2020;26:529)
- Desmin (Breast J 2020;26:529)
- HHF35 (Breast J 2020;26:529)
- Caldesmon (Breast J 2020;26:529)
- Ki67 5% in atypical leiomyoma (BMC Womens Health 2022;22:119)
- ER, PR (EJMED 2023;5:26)
- Vimentin (Radiol Bras 2016;49:343)
Negative stains
Sample pathology report
- Right breast (nipple), punch biopsy:
- Nipple leiomyoma (see comment)
- Comment: There is a circumscribed dermal proliferation of monotonous spindle cells. On immunohistochemistry, spindle cells are positive for SMA and desmin and negative for S100 and CK, supporting the diagnosis.
Differential diagnosis
- Leiomyosarcoma (EJMED 2023;5:26, BMC Womens Health 2022;22:119):
- Atypical features, pleomorphism, mitosis and necrosis are seen
- Phyllodes tumor (Eur J Breast Health 2017;13:156):
- Biphasic epithelial and stromal neoplasm
- Stromal cellularity and stromal overgrowth with atypia, necrosis and mitosis in borderline and malignant phyllodes
- Nipple adenoma:
- Florid benign epithelial (glandular or squamous) proliferation with intact myoepithelium throughout
- May have papillary architecture
- Connected to the epidermis
- Adenomyoepithelioma (Eur J Breast Health 2017;13:156):
- Biphasic with glandular and myoepithelial components
- Myoepithelial prominence
- Nodular fasciitis (BMC Womens Health 2022;22:119):
- Fibrous proliferation, variably loose, tissue culture-like to more collagenized stroma
- Negative for desmin
- Myoid hamartoma (J Med Case Rep 2013;7:49):
- Biphasic benign proliferation with glandular and stromal components with prominent smooth muscle
- Within stromal component, glandular components are also seen; this is absent in leiomyoma
Board review style question #1
A 35 year old woman presents with a freely mobile lump in the nipple areolar area of the left breast. Microscopy shows features in image above with no mitosis or atypia. Which of the following immunohistochemical markers is best to confirm and highlight the diagnosis?
- CK72
- Ki67
- S100
- SMA
Board review style answer #1
D. SMA highlights smooth muscle origin. Answer A is incorrect because CK72 is an epithelial marker. Answer C is incorrect because S100 is a neural marker. Answer B is incorrect because Ki67 is a proliferation marker that will be low in benign leiomyoma but will not help in diagnosis.
Comment Here
Reference: Leiomyoma
Comment Here
Reference: Leiomyoma
Board review style question #2
Which of the following is typically true about breast leiomyoma?
- Has nipple discharge
- Has no hormonal association
- Is imaging occult
- May be painful
Board review style answer #2
D. May be painful. Nipple adenomas may be painful, which may be alleviated by calcium channel or alpha adrenergic blockers that cause smooth muscle relaxation. Answer C is incorrect because breast leiomyoma may be seen as a mass on breast imaging modalities such as mammogram and ultrasound. Answer B is incorrect because breast leiomyomas are associated with hormonal agents. Answer A is incorrect because breast leiomyoma has not been associated with nipple discharge.
Comment Here
Reference: Leiomyoma
Comment Here
Reference: Leiomyoma
Lobular carcinoma in situ (LCIS) classic
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Diagrams / tables | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Frozen section description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Positive stains | Negative stains | Molecular / cytogenetics description | Videos | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2 | Board review style question #3 | Board review style answer #3Definition / general
- Noninvasive, neoplastic proliferation of small, uniform, dyscohesive cells, which originates in the terminal duct lobular unit (TDLU) and fills and distends most of the acini of the involved lobule (Histopathology 2020;77:181)
Essential features
- Lobulocentric proliferation of monomorphic cells, which expands lobular units; with or without pagetoid involvement of terminal ducts
- Hallmark feature is loss of cellular cohesion due to dysfunctional E-cadherin catenin axis
- Loss of E-cadherin protein is the most common etiology (> 95%) and can be caused by mutations, deletions or methylation
- Aberrant E-cadherin expression can be observed in some cases
- Characterized by uniform, loosely cohesive and evenly spaced cells (marbles in a bag); cells are slightly larger than normal, with indistinct cell borders and pale cytoplasm, small uniform nuclei, evenly distributed chromatin and inconspicuous nucleoli
- Constitutes both a risk factor and nonobligate precursor of invasive breast cancer
- No longer classified as a tumor in situ (Tis) because it is considered a risk factor, not a malignancy (Amin: AJCC Cancer Staging Manual, 8th Edition, 2016)
Terminology
- Lobular neoplasia (LN) of the breast includes atypical lobular neoplasia (ALH) and lobular carcinoma in situ (LCIS)
- Distinction between ALH and LCIS is the percentage of the TDLU involved (> 50% in LCIS and < 50% in ALH) with acini that are filled and expanded to qualify as LCIS
- Some authors use LN terminology to denote the histologic overlap and frequent coexistence of ALH and LCIS (Cancer 1978;42:737)
- This approach is not recommended as it combines into one category lesions, which (although parts of a spectrum) differ in the magnitude of the associated breast cancer risk (Tokai J Exp Clin Med 1989;14:361)
- Classic LCIS (CLCIS) consists of type A or B epithelial cells, which have different morphologic characteristics
- Other morphologic subtypes of LCIS that are nonclassical include pleomorphic and florid
ICD coding
Epidemiology
- Identified in 0.5 - 3.6% of benign breast biopsies and in 1.8 - 2.5% of all breast biopsies (Surg Pathol Clin 2018;11:123, Histopathology 2020;77:181)
- Incidentally found in 0.04 - 1.5% of reduction mammoplasty specimens (Breast Cancer Res Treat 2019;173:201, Hum Pathol 2013;44:1877)
- Incidence has varied over time (Ann Surg Oncol 2013;20:3240, Breast Cancer Res Treat 2002;75:259)
- Rapid increase after the introduction of mammography (1978 - 1998)
- Sharp decline associated with decreased use of hormone replacement therapy (2001 and 2004)
- In 2009, the estimated rate was 2.75 per 100,000
- Full age range of affected women is broad (27 - 83 years) but it is most often diagnosed in premenopausal women (J Clin Oncol 2015;33:3945)
- Mean age at diagnosis is 49 - 53.7 years (Ann Surg Oncol 2017;24:2509, AJR Am J Roentgenol 1991;157:257)
Sites
- Frequently found as multiple foci within the same or both breasts
- Multicentric in the same breast in up to 70% of patients (AJR Am J Roentgenol 1991;157:257)
- Bilateral in 20 - 60% of patients (Ann Surg 1972;176:178, Cancer 1984;53:798)
- May arise in ectopic breast tissue but this is incredibly rare (Gynecol Oncol 1999;73:155)
Pathophysiology
- E-cadherin gene mutations and loss of the wild type allele by loss of heterozygosity (LOH) is an early genetic event that plays a critical role in pathogenesis (Br J Cancer 1997;76:1131)
- E-cadherin mediates intracellular adhesion and cell polarity and plays a key role in the maintenance of lobular architecture; it can also inhibit the growth and invasion of breast cancer cells (Breast Cancer Res 2001;3:289)
- Defective E-cadherin results in loss of cell to cell cohesion, increased cell proliferation and altered organization of the lobules, giving rise to the characteristic appearance of lobular neoplasia
Etiology
- Many risk factors for LCIS are similar to those established for DCIS and invasive breast carcinoma
- Exposure to hormones likely plays a role in etiology; the majority of LCIS shows a strong diffuse expression of ER
- Increased risk of LCIS is associated with a family history of breast cancer, a previous benign breast biopsy, nulliparity, older age at first full term birth, older age at menopause and high mammographic density (J Natl Cancer Inst 2001;93:1811, Cancer 2015;121:1369)
- In postmenopausal women, the risk of LCIS increases with the use of unopposed estrogen replacement therapy (Am J Epidemiol 2017;186:1329)
Clinical features
- No specific reproducible clinical or imaging findings
- Usually identified in biopsy or surgical excision specimen performed for other indications (Am J Pathol 1941;17:491)
- Rare cases (< 2%) of classic LCIS can be targeted for biopsy due to associated imaging abnormalities; this includes grouped amorphous or granular calcifications on mammography, a shadowing, avascular, irregular, hypoechoic mass on the ultrasound or heterogeneous nonmass-like enhancement with persistent enhancement kinetics on MRI (Breast 2016;27:109, Acad Radiol 2013;20:463)
- Uncommonly, after biopsy for a palpable mass or nipple discharge, patients may be found to have LCIS (J Clin Oncol 2015;33:3945)
Diagnosis
- Diagnosis of classic LCIS is usually an incidental finding in a breast biopsy performed for other indications, including screen detected calcifications or mass producing lesions (Breast Cancer Res 2003;5:258)
- Columnar cell lesions (frequently associated with LCIS) often have calcifications; these are the targets on mammography leading to the discovery of LCIS (Am J Surg Pathol 2007;31:417)
- Cases of LCIS or DCIS are distinguished based on histomorphology or by using E-cadherin and p120 catenin immunostains (Int J Clin Exp Pathol 2014;7:2551)
Radiology description
- There are no radiologic features specific to classic LCIS
- In a retrospective radiologic review of patients that were diagnosed pathologically with only classic LCIS, the majority had no abnormalities on mammography; few patients had masses or calcifications (J Clin Ultrasound 2011;39:59)
- Generally, the sensitivity of ultrasound is low; however, when present, associated sonographic findings include an avascular, irregularly shaped, ill defined, hypoechoic mass with posterior shadowing (Acad Radiol 2013;20:463)
- When detected via MRI, the most common finding was heterogeneous nonmass-like enhancement with delayed persistent enhancement kinetics (Acad Radiol 2013;20:463)
- Microcalcifications are not commonly seen in LCIS but can be present (AJR Am J Roentgenol 2001;176:1255)
- In one study, small focal calcifications were associated with LCIS on biopsy in up to 20% of patients (Cancer 2013;119:1073)
- Calcifications are more common in lesions that may coexist with LCIS, such as sclerosing adenosis, columnar cell change / hyperplasia, atrophic lobules and ducts and collagenous spherulosis
Radiology images
Images hosted on other servers:
Classic LCIS ultrasound
Classic LCIS mammogram
LCIS MRI
Prognostic factors
- LCIS is both a risk factor for and a nonobligate precursor of invasive breast carcinoma
- Compared with the general population, women with LCIS have a 7 - 10 fold increase in breast cancer risk (N Engl J Med 1985;312:146)
- Absolute risk is ~1 - 2% per year for lifetime risk of 30 - 40%
- Slightly greater risk to ipsilateral than contralateral breast
- Time to cancer from LCIS diagnosis ranges 15 - 30 years
- Subsequent invasive carcinomas are 3x more likely to be lobular (than in the general population) but most commonly are of no special type
- Clinical and histologic features that may identify patients with LCIS that are likely to develop invasive breast cancer have not been consistently identified
- Presence of LCIS at (or close to) the margin of resection is not associated with increased local recurrence (Ann Surg Oncol 2008;15:2263)
- Concurrent lobular neoplasia increases the risk of ipsilateral breast cancer recurrence in patients with ductal carcinoma in situ treated with breast conserving therapy (Cancer 2009;115:1203)
Case reports
- 45 year old woman with LCIS within a fibroadenoma of the breast (Postgrad Med J 1999;75:293)
- 47 year old woman with axillary lymph node metastasis of breast cancer after risk reducing mastectomy, in which only LCIS was present on histopathology (J Surg Case Rep 2012;2012:2)
- 64 year old woman with LCIS presenting as a solid mass (Br J Radiol 2011;84:e48)
Treatment
- Excision is not recommended after incidental diagnosis of classic LCIS by percutaneous image guided core needle biopsy, as the risk of finding invasive carcinoma on excision is very low (< 5%) (Radiology 2013;269:340, Mod Pathol 2008;21:1208, Cancer 2013;119:1073, Cancer 2008;112:2152, Ann Surg Oncol 2016;23:722, Ann Surg Oncol 2012;19:3131)
- Surgical biopsy is recommended when core needle biopsy contains classic LCIS in addition to other high risk proliferative lesions (e.g., radial scar or ADH or there is discordance between histology and imaging) (AJR Am J Roentgenol 1999;173:291, Clin Breast Cancer 2016;16:507)
- Management options for classic LCIS include active surveillance and chemoprevention with anti estrogens (J Clin Oncol 2013;31:2942)
- Clinical trials with anti estrogens have shown a 56% reduction in risk of developing subsequent carcinoma in patients with LCIS and other risk factors (e.g., positive family history) (Recent Results Cancer Res 2009;181:113)
- Identification of nonclassical LCIS in a needle core biopsy specimen mandates surgical excision (Ann Surg Oncol 2019;26:55, Am J Surg Pathol 2019;43:399, Arch Pathol Lab Med 2010;134:1024)
- Mirror biopsy of the contralateral breast, once advocated for treatment of LCIS, is no longer routinely performed
- Obtaining negative surgical margins in excision specimens for classic LCIS is not necessary or recommended
- In patients who are BRCA1 or BRCA2 gene mutation carriers, prophylactic mastectomy is the most effective single intervention for overall survival (Avicenna J Med 2018;8:67)
Gross description
- Classic LCIS by itself does not cause any grossly visible / palpable alteration in breast tissue
- May have abnormal findings secondary to the coexisting lesions / proliferative changes (e.g., cysts, firm / hard tissue or nodularity, which are not attributable to LCIS)
Frozen section description
- Due to the relatively bland cytological features of classic LCIS frozen section, diagnosis is generally not performed
Microscopic (histologic) description
- LCIS involves the terminal duct lobular unit (TDLU), filling and distending acini
- > 50% of the acini in a TDLU must be filled and expanded to qualify as LCIS; otherwise, called atypical lobular neoplasia
- Lobular distention is defined as the presence of ≥ 8 cells in the cross sectional diameter of an acinus
- Involved lobules may be compared with uninvolved lobules to estimate the degree of distension
- ALH only partially involves the lobule by filling up the acini without significant distention
- LCIS most often involves lobules but may also grow along the basement membrane of ducts (i.e., pagetoid spread)
- Pagetoid spread in ducts is the characteristic growth of cells between luminal and myoepithelial layers of a duct without destroying ductal epithelium or filling up ductal lumina
- Often makes the ducts appear convoluted; this is called a cloverleaf pattern
- LCIS may secondarily involve (or arise in) sclerosing adenosis, radial scar, fibroadenoma, collagenous spherulosis or papilloma
- Rosen triad: the presence of tubular carcinoma, columnar cell lesions and LCIS / ALH
- Initial morphologic observation of lesions that are genetically linked
- Classic LCIS cells are monomorphic, evenly spaced, loosely cohesive and do not show polarization or gland formation
- 2 types of cells are described:
- Type A: nuclei are small to slightly enlarged (1 - 1.5x size of lymphocyte) with uniform round nuclei and inconspicuous nucleoli
- Type B: nuclei larger (2x size of lymphocyte), more abundant cytoplasm and more prominent nucleoli
- Type A and B cells can coexist in the same lesion
- Cytoplasm of LCIS cells is typically pale to lightly eosinophilic with indistinct cell borders
- In almost all cases of LCIS, at least some cells contain intracytoplasmic vacuoles or lumina, which may contain an eosinophilic globule; this feature is not specific to LCIS
- Vacuoles may be subtle such that special histochemical stains for mucin are required in order to demonstrate; alternatively, they may be large enough to push the nucleus against the cell membrane and produce signet ring cell forms
- Outer layer of myoepithelial cells is retained in the acini and ducts involved but it may be attenuated
- In some cases, scattered myoepithelial cells can be admixed with the neoplastic epithelial cells within the involved spaces
- Myoepithelial cells show weak positivity for E-cadherin due to the cross reactivity of P-cadherin
- Cytologic or architectural features of LCIS may deviate from the classical appearances and exhibit distinct cell membranes, clear cell change or apocrine change, or have a myoid appearance with dark, eccentric nuclei and dense eosinophilic cytoplasm similar to rhabdomyoblasts
- Classic LCIS does not show significant nuclear pleomorphism or mitosis
- Classic LCIS may rarely display single cell apoptosis or minute foci of necrosis but typically does not show comedo type necrosis
- Rarely, comedo necrosis can be present in classic LCIS that has typical cytological and architectural features; this (by itself) should not be diagnosed as pleomorphic LCIS (Am J Surg Pathol 2006;30:1445)
- Pleomorphic LCIS is defined as having large cells with enlarged pleomorphic nuclei; additionally, central necrosis and apocrine features can be present
- Florid LCIS, with or without central necrosis, refers to lesions with cytologic features of classic LCIS but with marked duct distension in a solid architectural pattern
- LCIS lesions, which are borderline between classic LCIS composed of type B cells and pleomorphic LCIS, should be categorized as classic LCIS composed of type B cells
- Lesions with cytological features of classic LCIS, which show distension of the acini borderline between classic LCIS and florid LCIS, should be designated as classic LCIS, even when LCIS is extensive
Microscopic (histologic) images
Contributed by Anna Biernacka, M.D., Ph.D.
Classic LCIS involving terminal duct lobular units
Classic LCIS, terminal duct lobular unit expansion
Classic LCIS, cell morphology
Lobular distension
Pagetoid spread, cloverleaf pattern
Pagetoid spread in ADH
Preserved lobular architecture
Type A cells
Type B cells
Type A and B cells
LCIS, mixed cell population
Signet ring cells, breast type
Signet ring cells, gastric type
Histiocytoid appearance
Clear cell change
LCIS involving an intraductal papilloma
LCIS in intraductal papilloma
Rosen triad
LCIS in collagenous spherulosis
LCIS in sclerosing adenosis
LCIS, sclerosing adenosis, calcifications
LCIS, E-cadherin
LCIS and ILC,
E-cadherin
LCIS and ILC, p63
LCIS, ER
LCIS and DCIS, low grade
LCIS versus DCIS, nucleoli
Cytology description
- Fine needle aspiration (FNA) of classic LCIS shows loosely cohesive groups of small, uniform and cytologically bland neoplastic cells (Am J Clin Pathol 1989;92:22, Diagn Cytopathol 1993;9:713, Diagn Cytopathol 2002;27:22)
- Nuclei are mildly enlarged and eccentrically placed and may show small but prominent nucleoli (Diagn Cytopathol 2005;32:276)
- Cytoplasm may have occasional intracytoplasmic lumina
- Nonatypical spindled myoepithelial cells may be present in association with classic LCIS cells
- Classic LCIS may be suspected in an FNA sample if signet ring cells are identified and associated with detached fragments of the lobular epithelium; however, definitive diagnosis in these sparely cellular samples is rarely possible
- There are no reliable cytological criteria for distinguishing between classic LCIS and invasive lobular carcinoma (ILC) (Diagn Cytopathol 1993;9:713, Diagn Cytopathol 2002;27:22)
- FNA samples of classic LCIS are usually cellular, whereas samples of ILC are often scant due to prominent desmoplasia that surrounds the infiltrative tumor cells (Diagn Cytopathol 2002;27:22)
- ILC samples generally have a higher proportion of noncohesive cells with more nuclear atypia and pleomorphism (Am J Clin Pathol 1989;92:22)
- > 50% of aspirates from classic LCIS are determined to be benign or nondiagnostic (Diagn Cytopathol 2002;27:22)
Cytology images
Images hosted on other servers:
Cytology classic LCIS
Positive stains
- Strong and diffuse nuclear ER and PR, low Ki67 proliferation index (Cancer 1996;78:1403)
- Mucin, Alcian blue, mucicarmine in cells with cytoplasmic vacuoles
- p120 catenin in a cytoplasmic pattern (Arch Pathol Lab Med 2017;141:1668, Int J Clin Exp Pathol 2014;7:2551)
Negative stains
- E-cadherin: most cases of classic LCIS demonstrate complete loss of E-cadherin staining
- In some cases of classic LCIS, attenuated or aberrant E-cadherin expression is observed, with scattered cells that show dot-like discontinuous / weak membranous staining or patchy cytoplasmic staining
- Atypical E-cadherin patterns or membranous positivity do not preclude the diagnosis of classic LCIS (Surg Pathol Clin 2018;11:123)
- Most cases show loss of expression of membrane beta catenin
- HER2 / neu
- See Diagrams / tables
Molecular / cytogenetics description
- Molecular data has shown that LCIS is a clonal neoplastic proliferation and an early lesion in the low grade neoplasia pathway
- Studies comparing LCIS and synchronous ILC highlight the shared copy number aberrations and somatic genetic mutations, indicating that LCIS is a nonobligate precursor to ILC (Genes Chromosomes Cancer 2010;49:463, Cancer 2004;100:2562, J Pathol 2005;207:1)
- LCIS associated with ILC has more genetic alterations than pure LCIS
- Most frequent copy number changes include loss of 16q and gain of 1q (Breast Cancer Res Treat 2005;90:249, Hum Pathol 2001;32:292, Cancer Res 1998;58:4721, Mol Pathol 2000;53:118)
- Loss of 16q and gain of 1q are also seen in other ER positive proliferations, including columnar cell lesions and well differentiated invasive ductal carcinoma, including tubular carcinoma and low grade DCIS
- This has led to an understanding that LCIS belongs to a group of lesions in a low grade, ER positive pathway of breast carcinogenesis (Histopathology 2011;59:549, Arch Pathol Lab Med 2017;141:1668)
- Although the target gene of 16q deletion in DCIS and IDC remains to be identified in lobular lesions, it involves the CDH1 tumor suppressor gene encoding for cell adhesion molecule E-cadherin (mapping at 16q22.1)
- Loss of 16q is often accompanied by CDH1 inactivating mutations, CDH1 homozygous deletions or CDH1 gene promoter methylation, which results in biallelic silencing of the gene
- Different combinations of alterations can result in different patterns of immunoreactivity
- Completely absent, weak and beaded, or aberrantly present in the cytoplasm in a dot-like pattern
- Rare cases (< 10%) may show membrane staining even though the protein is nonfunctional
- Other tumor suppressor genes located on chromosome 16 have been shown to be lost in LCIS:
- CCCTC binding factor (CTCF) gene, a transcriptional regulator of several genes linked to tumorigenesis
- Dipeptidase 1 (DPEP1) gene, which is involved in the metabolism of important glutathione and may have a role in the degradation of the surrounding extracellular matrix
- Somatic genetic mutations: CDH1 is the most frequently mutated gene in LCIS (in as many as 81% of cases), followed by PIK3CA (41%) and CBFB (12%); p53 and PTEN mutations are remarkably rare (Clin Cancer Res 2019;25:674, Mol Oncol 2016;10:360, Breast Cancer Res 2017;19:7)
- Germline mutations in CDH1, which are highly penetrant, are associated with an increased risk of hereditary diffuse gastric cancer and an increased risk of lobular carcinoma, including bilateral LCIS, with or without ILC (J Med Genet 2018;55:431, Br J Cancer 2014;110:1053)
- Variants of LCIS: pleomorphic and florid variants exhibit greater genomic instability than classic LCIS, with increased copy number alterations and gene amplification (Am J Surg Pathol 2009;33:1683)
Videos
Histopathology breast: lobular carcinoma in situ
Lobular carcinoma in situ and invasive lobular carcinoma
Sample pathology report
- Right breast, core needle biopsy:
- Lobular carcinoma in situ, classic type
- No longer classified as Tis because it is considered a risk factor, not a malignancy (Amin: AJCC Cancer Staging Manual, 8th Edition, 2016)
- Reporting on size or margin status is not necessary
Differential diagnosis
- Atypical lobular hyperplasia:
- Identical to classic LCIS morphologically but defined by limited extent
- < 50% of acini in a lobule are involved or all the acini are involved but are not distended
- Artifactual dyshesion:
- Poor tissue fixation may result in artifactual dyshesion of the epithelial cells lining normal ductal lobular structures or comprising benign lesions
- Appearance can mimic LCIS; however, diagnostic cytologic features of LCIS are not present
- Intraepithelial histiocytes:
- May be mistaken for pagetoid, classic LCIS cells
- Small nuclei, abundant foamy to granular cytoplasm and the lack of intracytoplasmic vacuoles distinguish these cells from classic LCIS
- IHC specific for histiocytes, such as CD68, can be used in these cases
- Myoepithelial hyperplasia:
- Myoepithelial cells surrounding normal lobular acini or ducts may assume an epithelioid appearance, with abundant pale to clear cytoplasm and prominent round nuclei
- Myoepithelial cell markers (calponin, smooth muscle myosin heavy chain and p63) are positive
- Clear cell change:
- Variant of apocrine metaplasia
- Pseudolactational hyperplasia:
- Vacuolated cytoplasm, apical apocrine tufts, hyperchromatic or atypical nuclei, psammoma-like calcifications, usually in postmenopausal women
- Invasive carcinoma:
- LCIS involving a pre-existing sclerosing lesion (e.g., sclerosing adenosis, radial scar or complex sclerosing lesion) may produce a pattern mimicking stromal invasion
- Solid or alveolar patterns of invasive lobular carcinoma (ILC) can be difficult to distinguish from LCIS
- Myoepithelial cell markers are retained in LCIS and absent in invasive carcinoma
- Pleomorphic LCIS:
- May be difficult to distinguish from LCIS composed of type B cells
- Nuclei of type B LCIS are larger and more variable than in type A LCIS
- Still, the nuclear size and shape variability is relatively subtle compared with pleomorphic LCIS
- In cases of uncertainty, the lesion should be categorized as classic LCIS with type B cells rather than as pleomorphic LCIS
- Ductal carcinoma in situ:
- Solid low grade DCIS:
- Cohesive cells, microacini with cells polarized around microlumen, no intracytoplasmic vacuoles, no pagetoid ductal involvement
- E-cadherin positive
- Cancerization of lobules by DCIS:
- Cellular cohesion, moderate to high grade cytology, necrosis or calcifications
- E-cadherin positive
- Cribriform DCIS and collagenous spherulosis involved by LCIS:
- Lumens of DCIS are formed by polarized epithelial cells and are empty or contain necrosis or calcifications
- Myoepithelial cells in DCIS surround the periphery of the involved lobule
- Lumens in collagenous spherulosis contain eosinophilic basement membrane material or myxoid material and are lined by myoepithelial cells
- Pagetoid LCIS versus pagetoid DCIS:
- Pagetoid ductal involvement is a common feature of LCIS, less commonly seen in DCIS
- Cellular dyshesion and the presence of intracytoplasmic vacuoles favor LCIS, cellular cohesion and moderate to high grade nuclear atypia favor DCIS
- LCIS with comedo necrosis versus DCIS with comedo necrosis:
- Some examples of LCIS composed of classical type A or type B cells may show comedo necrosis in the involved spaces and may simulate DCIS
- Recognition of characteristic cytologic features of LCIS (particularly dyshesion and intracytoplasmic vacuoles) and, in problematic cases, an immunostain for E-cadherin leads to the correct diagnosis
- In situ carcinoma with mixed ductal and lobular phenotype:
- Mixed architectural and cytological features; heterogeneous expression of E-cadherin
- Solid low grade DCIS:
Additional references
Board review style question #1
What is the Rosen triad?
- DCIS, LCIS, tubular carcinoma
- LCIS, flat epithelial atypia, columnar cell hyperplasia
- Tubular carcinoma, DCIS, apocrine metaplasia
- Tubular carcinoma, LCIS, columnar cell hyperplasia
- Tubular carcinoma, LCIS, flat epithelial atypia
Board review style answer #1
D. Tubular carcinoma, LCIS, columnar cell hyperplasia
Comment here
Reference: Lobular carcinoma in situ (LCIS) classic
Comment here
Reference: Lobular carcinoma in situ (LCIS) classic
Board review style question #2
Which of the following is true of classical lobular carcinoma in situ (classic LCIS)?
- Classic LCIS belongs to group lesions in a low grade, ER positive pathway of breast carcinogenesis
- Classic LCIS increases the patients' risk only for subsequent unilateral breast cancer
- Classic LCIS is staged as Tis using the AJCC 8th edition cancer staging
- If present at a surgical margin, it should be noted in the final pathology report
- Loss of nuclear expression of E-cadherin is the defining immunohistochemical feature of classic LCIS
Board review style answer #2
A. Classic LCIS belongs to group lesions in a low grade, ER positive pathway of breast carcinogenesis
The presence of classic LCIS at or close to the margin of resection is not associated with increased local recurrence and does not need to be reported. Classic LCIS increases the patients' risk for breast cancer in either breast. E-cadherin typically displays a membranous staining pattern. Classic LCIS is no longer classified as Tis because it is considered a risk factor, not a malignancy.
Comment here
Reference: Lobular carcinoma in situ (LCIS) classic
The presence of classic LCIS at or close to the margin of resection is not associated with increased local recurrence and does not need to be reported. Classic LCIS increases the patients' risk for breast cancer in either breast. E-cadherin typically displays a membranous staining pattern. Classic LCIS is no longer classified as Tis because it is considered a risk factor, not a malignancy.
Comment here
Reference: Lobular carcinoma in situ (LCIS) classic
Board review style question #3
Which of the following morphologic features would be most consistent with the entity depicted above?
- Comedo type necrosis
- Intracytoplasmic lumens / vacuoles
- Intranuclear inclusions
- Microcalcifications
- Single prominent nucleoli
Board review style answer #3
B. Intracytoplasmic lumens / vacuoles
Intracytoplasmic lumens, vacuoles and even signet ring morphology are associated with the diagnosis of classic LCIS. Prominent nucleoli, microcalcifications and comedo type necrosis are morphologic features more commonly seen in DCIS or the pleomorphic variant of LCIS. Although type B LCIS cells may have nucleoli, they are typically multiple and scattered, with the lesional cells having uniform and smooth nuclear contours. Intranuclear inclusions are typically secondary to viral cytopathic effect and are not associated with breast lobular neoplasia.
Comment here
Reference: Lobular carcinoma in situ (LCIS) classic
Intracytoplasmic lumens, vacuoles and even signet ring morphology are associated with the diagnosis of classic LCIS. Prominent nucleoli, microcalcifications and comedo type necrosis are morphologic features more commonly seen in DCIS or the pleomorphic variant of LCIS. Although type B LCIS cells may have nucleoli, they are typically multiple and scattered, with the lesional cells having uniform and smooth nuclear contours. Intranuclear inclusions are typically secondary to viral cytopathic effect and are not associated with breast lobular neoplasia.
Comment here
Reference: Lobular carcinoma in situ (LCIS) classic
Low grade adenosquamous
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Positive stains | Negative stains | Electron microscopy description | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1Definition / general
- Rare variant of metaplastic carcinoma comprised of an intimately admixed combination of bland, well developed glands and solid squamous cell nests within a fibrotic or cellular spindle stroma
- First reported in 1917 (Br J Surg 1917;5:417)
- Formally recognized in 1987 (Am J Surg Pathol 1987;11:351)
Essential features
- Rare variant of metaplastic carcinoma with low grade cytomorphology
- Largely clinically indolent but may be locally aggressive
- Diagnosis is based primarily on morphologic features, which can be challenging in small samples
- Immunostaining patterns can be variable and unreliable
- May arise in association with other breast lesions
Terminology
- Syringomatous squamous tumor or infiltrative syringomatous adenoma
ICD coding
- ICD-10: C50.919 - malignant neoplasm of unspecified site of unspecified female breast
Epidemiology
- 0.2 to 1%
- Median age: fifth decade; range: 20 - 85 years
- Females; only one case report in male
Sites
- Breast parenchyma
Pathophysiology
- Unknown at this time
- Association with other proliferative and sclerosing breast lesions has led some to suggest they represent precursors (Pathology 2014;46:402)
Etiology
- Multifactorial
Clinical features
- Frequently presents as a palpable mass, typically < 5 cm (Am J Surg Pathol 2012;36:1009, Am J Surg Pathol 1993;17:248)
- May be associated with benign lesions, including
- Papilloma
- Adenomyoepithelioma
- Radial scar / complex sclerosing lesions
- Collagenous spherulosis
- Fibroadenoma or phyllodes tumor
- Indolent course with a favorable prognosis (Am J Surg Pathol 1993;17:248)
- May be locally aggressive and recurrences occur with incomplete excision (Am J Surg Pathol 1993;17:248)
Diagnosis
- Most frequently diagnosed via surgical resection
- Difficult to diagnose by fine needle aspiration, core biopsy or frozen section (Histopathology 2006;49:603)
Radiology description
- Nonspecific radiologic appearance
- Mammography:
- Round or irregular solid mass or density (Can Assoc Radiol J 2013;64:339, Histopathology 2006;49:603)
- Calcifications may be present (Can Assoc Radiol J 2013;64:339)
- Ultrasound:
- Solid, irregular hypoechoic mass with irregular borders on (Can Assoc Radiol J 2013;64:339, Histopathology 2006;49:603)
Radiology images
Images hosted on other servers:
Mammogram: asymmetry
Mammogram: calcifications
Mammogram: mass
Ultrasound: mass
Prognostic factors
- Indolent course with a favorable prognosis (Am J Surg Pathol 1993;17:248)
- Local recurrence is common, particularly if incompletely excised (Am J Surg Pathol 1993;17:248)
- Lymph node metastases and distant metastases are rare (Am J Surg Pathol 1993;17:248)
Case reports
- 42 year old woman presented with a palpable mass (Medicine (Baltimore) 2017;96:e8785)
- 49 year old woman with a palpable mass (Ultrasound Q 2018;34:88)
- 52 year old man with axillary low grade adenosquamous carcinoma (Front Oncol 2020;10:1714)
- 67 year old woman with mass around a residual localization wire fragment (Lab Med 2015;46:241)
- 69 year old woman with a palpable mass (Korean J Pathol 2014;48:229)
Treatment
- Surgical excision with negative margins (Am J Surg Pathol 1987;11:351)
- Radiotherapy is standard for patients with breast conserving surgery
- Role of chemotherapy is indeterminate
Gross description
- Firm to hard, white or pale yellow tumor with ill defined borders (Am J Surg Pathol 1993;17:248)
- Typically measures < 5 cm (Am J Surg Pathol 2012;36:1009, Am J Surg Pathol 1993;17:248)
Gross images
Contributed by Paula S. Ginter, M.D.
Excisional biopsy of mass
Microscopic (histologic) description
- Infiltrative glandular elements with a variable degree of squamous differentiation (Am J Surg Pathol 1987;11:351, Am J Surg Pathol 2012;36:1009)
- Glands are lined by cytologically bland epithelial cells and may be angulated, compressed or ovoid (Am J Surg Pathol 1993;17:248, Am J Surg Pathol 2012;36:1009)
- Luminal keratin debris may be present (Am J Surg Pathol 1993;17:248)
- Associated stroma may be fibrotic or cellular (Am J Surg Pathol 2012;36:1009)
- In cases with cellular stroma, the bland spindled cells frequently demonstrate a circumferential distribution around the neoplastic glands (Am J Surg Pathol 1993;17:248, Am J Surg Pathol 1987;11:351)
- Infrequent epithelial and stromal mitoses
- Frequent peripheral lymphoid aggregates and intratumor lymphocytic infiltrates (Am J Surg Pathol 2012;36:1009)
- May be associated with benign lesions, such as intraductal papilloma, adenomyoepithelioma, radial / complex sclerosing lesions, collagenous spherulosis and fibroepithelial tumors (Mod Pathol 2003;16:893, Virchows Arch 1995;427:243, Am J Surg Pathol 2012;36:1009)
Microscopic (histologic) images
Contributed by Paula S. Ginter, M.D.
Glands and squamous nests
Bland cytology
Spindle stroma
Lymphoid aggregates
Luminal keratin debris
Associated papilloma
Myosin: variable myoepithelial staining
p63: variable myoepithelial staining
CK7: core staining
ER negative
Virtual slides
Images hosted on other servers:
Low grade adenosquamous carcinoma and DCIS
p63: variable myoepithelial and luminal staining
ER negative
(< 1%)
Cytology description
- Variable cellular yield; not reliable as a surrogate for considering malignancy
- Irregularly clustered cells, angulated sheets and tubular structures with monomorphic cytology (Acta Cytol 2014;58:427, Diagn Cytopathol 2012;40:713, Diagn Cytopathol 1999;20:13)
- Whorl-like arrangements of epithelial cells may hint of squamous differentiation
- Individually dispersed, atypical cells may be seen
- Background may show mildly atypical naked nuclei and spindle cells (representing the stromal component)
- Combination of epithelial and spindle elements is distinctive and should raise the possibility of low grade adenosquamous carcinoma
- Accurate cytological identification is challenging
Positive stains
- Luminal cells show varying immunoreactivity for p63 (highlighting squamous differentiation) (74%) (Am J Surg Pathol 2012;36:1009)
- Glandular component often shows core staining, where luminal cells demonstrate greater intensity of cytokeratin staining compared with the basal cells (Am J Surg Pathol 2012;36:1009)
- CK AE1 / AE3 (57%)
- CK5/6 (58%)
- CK7 (50%)
- Distinctive stromal lamellar staining pattern, frequently seen with SMMHC (53%) and calponin (57%) (Am J Surg Pathol 2012;36:1009)
- Inconsistent staining patterns
- Commonly utilized diagnostic markers of limited use
Negative stains
- Often triple negative: ER, PR, HER2 (Mod Pathol 2010;23:951)
- Variable degrees of circumferential complete, discontinuous and absent myoepithelial cell markers (Am J Surg Pathol 2012;36:1009)
Electron microscopy description
- Glandular and squamous differentiation (Am J Surg Pathol 1993;17:248)
- Squamous cells resemble acrosyringium of eccrine sweat gland (Am J Surg Pathol 1993;17:248)
Molecular / cytogenetics description
- Harbor recurrent PIK3CA mutations (Mod Pathol 2010;23:951, Histopathology 2018;73:273)
- Mutations in PTEN, GNAS, KIT and CDKN2A have also been described (Mod Pathol 2010;23:951, Histopathology 2018;73:273)
- TP53 mutations are absent (Mod Pathol 2010;23:951, Histopathology 2018;73:273)
- Gains in 6p, 7pq and 8q; losses of 1p, 6p, 6q, 8p and 9p; no amplifications by microarray comparative genomic hybridization (Mod Pathol 2010;23:951)
Sample pathology report
- Left breast, 3 o'clock, lumpectomy:
- Low grade adenosquamous carcinoma (see comment and synoptic report)
- Ductal carcinoma in situ
- Comment: Low grade adenosquamous carcinoma is grade 1 (2, 2, 1), measures 1.7 cm in greatest dimension, is associated with a sclerotic papilloma, is present less than 1 mm from the inked surgical margin and is ER negative (< 1%), PR negative (< 1%) and HER2 negative (0). No lymphovascular invasion identified. Ductal carcinoma in situ is solid type with intermediate nuclear grade and is present as a single 0.2 cm focus associated with the low grade adenosquamous carcinoma. Ductal carcinoma in situ is present > 2 mm from the inked surgical margin.
Differential diagnosis
- Tubular carcinoma:
- Radial scar with squamous metaplasia:
- Heterogeneous, positive staining for ER
- Syringomatous adenoma:
- Morphologically similar to low grade adenosquamous carcinoma
- Composed of tubules and solid nests with comma-like or tail-like extensions and squamous cysts embedded in desmoplastic stroma
- More superficial, involving the nipple areolar complex
- Lacks lymphoid aggregates
- Multinucleated giant cell reactions to ruptured cysts may be seen
- Some authors suggest these are identical entities (Histopathology 2014;65:9)
- High grade adenosquamous carcinoma:
- Shows both squamous and glandular components with moderate to high cellularity and nuclear atypia
- Mitotic activity is moderate to high
- Areas of necrosis may be present
Additional references
Board review style question #1
Which of the following is true about low grade adenosquamous carcinoma of the breast?
- Associated with a poor prognosis
- Commonly estrogen receptor (ER) positive
- Consistent loss of myoepithelial cells by immunohistochemistry
- May be associated with other breast lesions
Board review style answer #1
D. May be associated with other breast lesions. Multiple reports have demonstrated an association of low grade adenosquamous carcinoma with other breast entities (i.e. papilloma, adenomyoepithelioma, radial scar / radial sclerosing lesions and fibroepithelial tumors). Low grade adenosquamous carcinoma is frequently ER negative. Low grade adenosquamous carcinoma demonstrates variable degrees of circumferential myoepithelial cell markers and immunohistochemistry is consistently inconsistent in this entity, limiting use. Low grade adenosquamous carcinoma is associated with a good prognosis.
Comment Here
Reference: Low grade adenosquamous
Comment Here
Reference: Low grade adenosquamous
Lymphocytic / diabetic mastitis
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Laboratory | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Positive stains | Negative stains | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Histologic triad of keloidal type fibrosis, lymphocytic inflammation and epithelioid myofibroblasts
- Associated with type I (insulin dependent) diabetes or other autoimmune diseases
Essential features
- Young to middle aged women presenting with breast mass(es)
- Histologic triad of keloidal type fibrosis, lymphocytic infiltrates and epithelioid stromal myofibroblasts
- Associated with type I (insulin dependent) diabetes or other autoimmune diseases
Terminology
- Lymphocytic mastopathy / diabetic mastopathy
- Sclerosing lymphocytic mastitis / lobulitis
- Diabetic fibrous breast disease
ICD coding
Epidemiology
- Uncommon, < 1% benign breast disease (Arch Surg 2000;135:1190)
- Usually women, may occur in men, premenopausal, average age 45 years (Ann Plast Surg 2017;78:471, Am J Clin Pathol 2000;113:541, Arch Surg 2000;135:1190)
- Often associated with longstanding type I diabetes (insulin dependent) or other autoimmune disease (Hashimoto thyroiditis, Graves disease, pernicious anemia, rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus) but may occur in type II diabetes or nondiabetic patients (Diabetes Care 2002;25:121, Hum Pathol 1994;25:819, Hum Pathol 1992;23:780, Ann Plast Surg 2017;78:471)
Sites
- Breast
Pathophysiology
- Unknown
- Theories include:
- Hyperglycemia leads to stromal matrix expansion and accumulation of glycosylation end products and a B cell inflammatory response (Hum Pathol 1992;23:780)
- Immunologic response to exogenous insulin (Hum Pathol 1994;25:819)
Etiology
- Unknown
Clinical features
- Associated with insulin dependent diabetes (type I > II), autoimmune disorders and endocrine disorders
- Firm, palpable, nontender, mobile masses or diffuse nodularity at presentation common (Am J Clin Pathol 2000;113:541, Ann Plast Surg 2017;78:471)
Diagnosis
- Needle core biopsy or surgical excision with histologic examination
Laboratory
- Correlate with serologic markers for diabetes and other autoimmune diseases
Radiology description
- Mammography: frequently negative; may show asymmetric density or dense breast tissue, discrete mass not seen (Breast J 2007;13:607)
- Ultrasound: irregular shaped mass(es), indistinct margins, parallel orientation to chest wall, hypoechogenicity, posterior shadowing (Clin Imaging 2019;53:204, Breast J 2000;6:183)
Radiology images
Contributed by Kristen E. Muller, D.O.
Acoustic shadowing
Prognostic factors
- Recurrence rates vary; 10 - 30% (Am J Clin Pathol 2000;113:541, Ann Plast Surg 2017;78:471)
- No associated increased risk of lymphoma (Mod Pathol 2003;16:223)
Case reports
- 29 year old woman with diabetic mastopathy (Cureus 2020;12:e7003)
- 32 year old woman with bilateral diabetic mastopathy (Ann Plast Surg 2017;78:471)
- 37 year old woman with lymphocytic mastitis mimicking breast carcinoma (Malays J Med Sci 2013;20:83)
- 47 year old woman with lymphocytic mastitis and invasive carcinoma (BJR Case Rep 2016;2:20150234)
- 50 year old woman with metabolic syndrome and lymphocytic mastitis (Breast Care (Basel) 2012;7:493)
Treatment
- Conservative management
- Surgical excision (partial mastectomy, mastectomy) an option if symptomatic, especially if multiple and bilateral masses present (Breast J 2006;12:559, Ann Plast Surg 2017;78:471)
Gross description
- Firm, ill defined, homogenous, tan-white or white-gray cut surface
- Size variable, up to 6.0 cm
Gross images
Images hosted on other servers:
Dense white fibrous stroma
Firm white cut surface
Microscopic (histologic) description
- Triad of dense, keloidal type fibrosis, periductal, perilobular and perivascular lymphocytic infiltrates and epithelioid stromal myofibroblasts
- Epithelioid characteristics of myofibroblasts include enlarged cells with round to polygonal nuclei, prominent nucleoli and abundant cytoplasm
- Epithelioid features of myofibroblasts may be subtle or absent
- Stromal mitoses absent
- Mature lymphocytic infiltrates are nonclonal, predominantly B lymphocytes and lack germinal centers (Mod Pathol 2003;16:223)
Microscopic (histologic) images
Contributed by Kristen E. Muller, D.O.
Dense fibrous stroma
Perivascular lymphocytic inflammation
Enlarged myofibroblasts
Fibrous stroma, periductal and perivascular inflammation
Periductal lymphocytes
Epithelioid myofibroblasts
CD20
CD3
Virtual slides
Images hosted on other servers:
Lymphocytic mastopathy
Cytology description
- Clusters of ductal cells, lymphocytes and epithelioid fibroblasts in fragments of dense connective tissue (Acta Cytol 1997;41:1349)
- Cytology usually insufficient for diagnosis (Arch Surg 2000;135:1190)
Positive stains
Negative stains
- Cytokeratins, p63 (useful in differential of invasive carcinoma)
- Nuclear beta catenin (useful in differential of fibromatosis)
Molecular / cytogenetics description
- Lymphocytes are not clonal (Mod Pathol 2003;16:223)
Sample pathology report
- Left breast, needle core biopsy:
- Breast tissue with dense stromal keloidal type fibrosis, epithelioid myofibroblasts and perilobular lymphocytic inflammation (see comment)
- Comment: The histologic findings are compatible with lymphocytic / diabetic mastopathy in the appropriate clinical context.
Differential diagnosis
- Invasive carcinoma:
- Epithelioid myofibroblasts may be mistaken for carcinoma tumor cells
- Supportive of invasive carcinoma: cytokeratin positive, gland formation if invasive ductal carcinoma, mitoses, background of in situ carcinoma, lacks keloid-like fibrosis
- Low grade fibromatosis-like metaplastic carcinoma:
- Cytokeratin and p63 positive, infiltrative, background of in situ carcinoma, rare mitoses
- Fibromatosis:
- Beta catenin nuclear expression
- Lacks keloid-like fibrosis
- Amyloid:
- Stromal amyloid is amorphous and acellular, lacks epithelioid myofibroblasts
- Congo red positive
- MALT Lymphoma:
- Clonal B cells
- Lacks keloid-like fibrosis and epithelioid myofibroblasts
Additional references
Board review style question #1
For the breast stroma shown, which of the following is true?
- Lesion is associated with increased risk of developing lymphoma
- Lymphocytes are predominantly T cells and are clonal
- Patient may have insulin dependent diabetes or an autoimmune disorder
- Spindle cells in the stroma show beta catenin nuclear expression
Board review style answer #1
C. Patient may have insulin dependent diabetes or an autoimmune disorder
Comment Here
Reference: Lymphocytic / diabetic mastitis
Comment Here
Reference: Lymphocytic / diabetic mastitis
Board review style question #2
Which of the following is true regarding diabetic / lymphocytic mastopathy?
- All patients have a history of diabetes
- Characteristic histologic triad includes dense keloid-like fibrosis, epithelioid myofibroblasts and periductal, perilobular and perivascular lymphocytic inflammation
- If surgically excised, these lesions never recur
- Typical mammographic finding is an infiltrative mass lesion
Board review style answer #2
B. Characteristic histologic triad includes dense keloid-like fibrosis, epithelioid myofibroblasts and periductal, perilobular and perivascular lymphocytic inflammation
Comment Here
Reference: Lymphocytic / diabetic mastitis
Comment Here
Reference: Lymphocytic / diabetic mastitis
Lymphoma
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Etiology | Clinical features | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Positive stains | Negative stains | Molecular / cytogenetics description | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Lymphomas of the breast may be primary or secondary
- Primary breast lymphoma is generally defined as lymphoma limited to the breast, with or without axillary lymph node involvement, in a patient without evidence of distant disease at presentation and without prior history of lymphoma (Histopathology 1985;9:297, Cancer 1972;29:1705)
- Some accept lymphoma as primary if the initial presentation and the dominant mass or symptoms occur in the breast, even if other involved sites are identified (Am J Surg Pathol 2008;32:1299, Ann Surg 1987;205:144, Cancer 1990;66:2602)
- Most common types include diffuse large B cell lymphoma, extranodal marginal B cell lymphoma arising from mucosal associated lymphoid tissue (MALT lymphoma), follicular lymphoma and Burkitt lymphoma
- Implant associated anaplastic large cell lymphoma is discussed in a separate section
Essential features
- Lymphoma seen in close proximity to breast parenchyma, not limited to lymph nodes
- Primary breast lymphoma is uncommon and must be distinguished from secondary breast involvement from another primary site in the setting of widespread disease / relapse (more common)
- Must distinguish from mammary carcinoma, as therapeutic / surgical management is different; use of immunohistochemical panel (cytokeratins and lymphoid lineage markers) will confirm the diagnosis
Terminology
- Diffuse large B cell lymphoma (DLBCL) / DLBCL not otherwise specified (NOS)
- Extranodal marginal B cell lymphoma arising from mucosal associated lymphoid tissue (MALT lymphoma) / marginal zone lymphoma MALT type / MALT lymphoma
- Follicular lymphoma / follicular center cell lymphoma
- Burkitt lymphoma
ICD coding
- ICD-O:
- ICD-10:
Epidemiology
- Uncommon, accounts for 0.1 - 0.15% of primary breast malignancies (Cancer 1972;29:1705, Cancer 1990;66:2602, Cancer 2002;94:6)
- Most patients are older or postmenopausal; however, younger patients have been reported (especially with Burkitt lymphoma)
- Usually presents with painless lump; regional lymph nodes are involved in 50% of cases (Am J Surg Pathol 1993;17:574)
Etiology
- Diffuse large B cell lymphoma (DLBCL):
- Activated B cell type (IRF4+, FLIP+, BCL2+), germinal center type (BCL6+, CD10+, CD38+) or neither
- Commonly arises de novo or can occur through progression / transformation of a less aggressive non-Hodgkin lymphoma
- Extranodal marginal B cell lymphoma arising from mucosal associated lymphoid tissue (MALT lymphoma):
- Less association with underlying autoimmune disease compared to MALT lymphomas of other sites
- Follicular lymphoma:
- Originates from germinal / follicular center B cells
- Burkitt lymphoma:
- 3 variants: endemic (> 95% Epstein-Barr virus [EBV]+), immunodeficiency associated (often HIV+) and sporadic (less frequently EBV+)
- c-Myc translocation
Clinical features
- Middle age to elderly, median in sixth to seventh decade (Am J Surg Pathol 2008;32:1299, Leuk Lymphoma 2005;46:1321)
- Reports of younger patients in pregnant or lactating women (Burkitt lymphoma)
- Most present with painless palpable mass, with or without ipsilateral lymphadenopathy (11 - 50%) (Am J Surg Pathol 1993;17:574)
- Bilateral in 10%
- Treatment and prognosis are related to specific type of lymphoma:
- Diffuse large B cell lymphoma (DLBCL):
- Most common primary breast lymphoma (50 - 65%) (Cancer 2007;110:25, Am J Hematol 2009;84:133)
- Wide age range, median in sixth decade
- Median size 4 - 5 cm, may present as rapidly enlarging mass, few present with diffuse breast enlargement
- Aggressive clinical behavior, most common sites of relapse include ipsilateral or contralateral breast and central nervous system
- Must be distinguished from poorly differentiated carcinomas
- Extranodal marginal B cell lymphoma arising from mucosal associated lymphoid tissue (MALT lymphoma):
- Sixth to seventh decade
- Typically unilateral
- Indolent, > 90% 5 year survival (Ann Oncol 2009;20:1993)
- Large cell transformation reported
- Follicular lymphoma:
- Middle aged and older women
- Usually unilateral
- Similar prognosis compared to nodal follicular lymphoma, some have reported worse prognosis (Ann Oncol 2009;20:1993)
- Burkitt lymphoma:
- Uncommon, younger to middle aged females, some pregnant or postpartum at presentation
- Endemic variant is the most common presentation in the breast
- May present with massive bilateral breast enlargement
- Aggressive B cell lymphoma has more favorable prognosis with aggressive therapy
- Diffuse large B cell lymphoma (DLBCL):
Radiology description
- On mammography, primary breast lymphomas have been reported to present as unilateral diffuse involvement (25%), bilateral diffuse involvement (8%), solitary masses (58%) or as multiple masses (8%) (Breast J 2002;8:294)
- Masses may have either irregular, partially defined or well defined borders (Clin Imaging 2007;31:234)
- Useful MRI features may include strong enhancement with penetrating vessels on early images of dynamic MR imaging, strong high signal intensity on diffusion weighted imaging, a cerebroid appearance and septal enhancement on delayed contrast enhanced images (Jpn J Radiol 2013;31:668)
- Often mimic primary breast cancer
Radiology images
Contributed by Mark R. Wick, M.D. and Julia Braza, M.D.
Mammogram, large cell lymphoma
Mammogram, lymphoblastic lymphoma
Mammogram, CLL / SLL
Images hosted on other servers:
Mammogram and ultrasound, DLBCL, 47 yo
Mammogram and ultrasound, DLBCL, 56 yo
T1w MRI, DLBCL, fat suppressed
MRI, MALT lymphoma, 56 yo
Prognostic factors
- Prognosis is dependent on stage and type of lymphoma
Case reports
- 23 year old postpartum woman with bilateral breast swelling and Burkitt lymphoma (J Res Med Sci 2012;17:1188)
- 38 year old HIV+ woman and 55 year old woman diagnosed with primary breast non-Hodgkin lymphoma (Diagn Cytopathol 2016;44:235)
- 46 year old man with follicular lymphoma of the breast (Cancer Res Treat 2014;46:104)
- 59 year old woman with extranodal marginal zone lymphoma (MALT) of the breast (Case Rep Hematol 2016;2016:1831792)
- 59 year old woman with 2 breast nodules diagnosed as diffuse large B cell lymphoma (DLBCL) (Int J Surg Case Rep 2017;40:1)
Treatment
- Depends on diagnosis; is the same as lymphoma at any other site
Clinical images
Contributed by Mark R. Wick, M.D.
Large cell lymphoma
Images hosted on other servers:
Burkitt lymphoma
DLBCL
Large cell lymphoma
Gross description
- Grossly circumscribed mass, tan-white, fleshy cut surface
- Focal hemorrhage or necrosis may be present
Gross images
Contributed by Mark R. Wick, M.D. and AFIP images
Large cell lymphoma
Follicular lymphoma
Images hosted on other servers:
DLBCL
Microscopic (histologic) description
- Despite gross circumscription, microscopically these are diffusely infiltrative with invasion into surrounding breast parenchyma
- Infiltrates around and occasionally obliterates mammary gland structures
- Diffuse large B cell lymphoma (DLBCL):
- Diffuse infiltration by large lymphoid cells, centroblastic > immunoblastic, activated B cell type > germinal center type
- Extranodal marginal B cell lymphoma arising from mucosal associated lymphoid tissue (MALT lymphoma):
- Median size 3 cm
- Vaguely nodular growth pattern, neoplastic cells occupy the marginal zone surrounding the B cell follicle mantle zone but can have diffuse growth pattern if follicles infiltrated / replaced
- Marginal zone B cells, variable plasma cells, reactive follicles (±), lymphoepithelial lesions not conspicuous
- Monocytoid-like cells: medium sized lymphocytes with slightly irregular nuclei, dispersed chromatin, inconspicuous nucleoli, variable amounts of pale cytoplasm
- Variable scattered large transformed immunoblasts can be present
- Reactive follicles with infiltration by neoplastic marginal zones in some cases
- Plasmacytic differentiation in up to 75% (Arch Pathol Lab Med 2007;131:1673)
- Low mitotic rate
- Lymphoepithelial lesions may be seen if glands / ducts present but are usually not prominent, less conspicuous than MALT lymphoma in other sites
- Transformation into large B cell lymphoma described (Arch Pathol Lab Med 2007;131:1673)
- Follicular lymphoma:
- Median size 2 - 3 cm
- Morphology similar to nodal follicular lymphomas; follicular and diffuse architectural patterns, grade 1 or 2 > grade 3
- Monotonous population of small cleaved cells (centrocytes) and variable numbers of centroblasts (large noncleaved cells)
- Associated sclerosis can cause single file infiltration pattern
- Burkitt lymphoma:
- Sheets of uniform medium sized lymphocytes with round nuclei, multiple basophilic nucleoli, course chromatin, scant to moderate basophilic cytoplasm, minimal intervening stroma
- High mitotic rate
- Tingible body macrophages containing apoptotic debris produce a "starry sky" appearance
Microscopic (histologic) images
Contributed by Gary Tozbikian, M.D. and Julia Braza, M.D.
Marginal zone lymphoma
Invasion of adipose
Follicular colonization
Monocytoid-like B cells
DLBCL, activated B cell type
DLBCL, germinal center type
Sheet-like growth
Lymphoid cells surround glands
Marked atypia and frequent mitoses
Large lymphoid cells
CLL / SLL
CLL / SLL, CD5
CLL / SLL, CD20
Images hosted on other servers:
Follicular lymphoma
Follicular lymphoma, BCL2
Mantle cell lymphoma
Cytology description
- Primary cytomorphologic features include the presence of dissociated monomorphic cells with high nuclear cytoplasmic ratio, finely granular lymphoid chromatin and the presence of lymphoglandular bodies in the background of the cytologic smear (Diagn Cytopathol 2013;41:53)
- Differential diagnosis includes lobular carcinoma, small cell carcinoma, lesions with prominent lymphoid population including medullary carcinoma, chronic mastitis and intramammary lymph node (Diagn Cytopathol 2016;44:235)
- Lobular carcinoma: intracytoplasmic lumina, signet ring cells, intracytoplasmic mucin secretions
- Small cell carcinoma: cell clustering, cell molding, lacks lymphoglandular bodies, positive keratin and neuroendocrine immunohistochemistry staining
- High grade carcinomas with medullary features: admixture of pleomorphic epithelial cells as well as reactive lymphoid and plasma cells
- Intramammary lymph nodes and mastitis can show reactive lymphoid infiltrate and pose a diagnostic problem (Diagn Cytopathol 2013;41:53)
- Final categorization generally requires flow cytometric immunophenotyping / immunohistochemistry on cell blocks to allow morphologic and immunohistochemical evaluation (Diagn Cytopathol 2016;44:235)
Cytology images
Contributed by Mark R. Wick, M.D.
Large cell lymphoma
Positive stains
- Diffuse large B cell lymphoma (DLBCL):
- Extranodal marginal B cell lymphoma arising from mucosal associated lymphoid tissue (MALT lymphoma):
- Follicular lymphoma:
- Burkitt lymphoma:
Negative stains
Molecular / cytogenetics description
- Diffuse large B cell lymphoma (DLBCL):
- Rare MALT1 rearrangements, trisomy 18 in some, possible NFκB activation in minority (Mod Pathol 2006;19:1402, Mod Pathol 2013;26:421)
- Extranodal marginal B cell lymphoma arising from mucosal associated lymphoid tissue (MALT lymphoma):
- Clonal rearrangements of immunoglobulin genes
- Often trisomy of 3, 12, 18
- Usually negative for characteristic MALT1 rearrangements t(11;18)(q21;q21) and t(14;18)(q32;q21) (Mod Pathol 2006;19:1402, Mod Pathol 2013;26:421, Oncol Rep 2012;28:1211)
- Follicular lymphoma:
- Presence of t(14;18)(q32;q21) translocation has not been systematically assessed in primary breast follicular lymphoma
- Burkitt lymphoma:
- t(8;14)(q24;q32) c-Myc and IgH translocation is most frequent
- t(2;8)(p12;q24) IgΚ and c-Myc
- t(8;22)(q24;q11) c-Myc and Igλ
Differential diagnosis
- Invasive ductal carcinoma:
- Poorly differentiated carcinoma mimics high grade lymphoma
- Presence of cohesive growth, identification of gland / tubule formation and presence of in situ component favor a diagnosis of ductal carcinoma
- Cytokeratin+, CD45-, CD20-, CD3-
- Invasive lobular carcinoma:
- Mimics low grade lymphoma
- Cytokeratin+, CD45-, CD20-, CD3-; usually ER+
- Chronic inflammatory infiltrates (e.g. diabetic mastopathy):
- Mimics low grade lymphoma
- Immunohistochemistry and flow cytometry will not identify a clonal B cell population
- Diabetic mastopathy shows perilobular / periductal / perivascular infiltrate with reactive lymphoid follicles, keloidal fibrosis and lobular atrophy
- Nodal lymphoma:
- Differentiation of lymphoma within a lymph node from a primary breast lymphoma may be difficult in small biopsy specimens if breast parenchyma is not identifiable
Additional references
Board review style question #1
A 22 year old woman presents with bilateral breast swelling. Breast biopsy shows diffuse sheets of uniform medium sized cells with round nuclei, multiple nucleoli, coarse chromatin, a thin rim of basophilic cytoplasm and interspersed tingible body macrophages. The tumor cells are positive for CD45, CD20, CD10 and BCL6. The Ki67 proliferation index is nearly 100%. The tumor cells are negative for CD5, CD23 and BCL2.
What molecular / cytogenetic abnormality may be associated with this lymphoma?
What molecular / cytogenetic abnormality may be associated with this lymphoma?
- Deletion of 13q14
- t(8;14)(q24;q32)
- t(11;14)(q13;q32)
- t(14;18)(q32;q21)
- Trisomy of 3, 12, 18
Board review style answer #1
Board review style question #2
What is the most common type of primary breast lymphoma?
- Burkitt lymphoma
- Diffuse large B cell lymphoma
- Follicular lymphoma
- Hodgkin lymphoma
- MALT lymphoma
Board review style answer #2
Male invasive
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Negative stains | Molecular / cytogenetics description | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1Definition / general
- Male breast cancer is uncommon, accounting for < 1% of all male cancers and 0.1% of male cancer deaths
- Tends to occur at an older age group (60 - 70s) when compared to women (50 - 60s) and has a larger tumor size (J Clin Oncol 2010;28:232)
- Surveillance, Epidemiology and End Results (SEER) program shows a rise in the incidence across the U.S. (Cancer 2004;101:51)
Essential features
- Most are ductal carcinoma in situ or invasive ductal carcinoma
- Most are ER+ (Ann Oncol 2013;24:viii75)
- BRCA2 is the strongest familial risk factor in men (associated with 17% of male breast cancers) (Histopathology 2016;68:110)
Terminology
- Invasive ductal carcinoma, ductal carcinoma in situ
ICD coding
- ICD-10: C50 - malignant neoplasm of breast
Epidemiology
- Average age of onset of DCIS is sixth decade; for invasive carcinoma is seventh decade, although highest incidence occurs in the eighth decade of life (Breast Cancer Res Treat 2004;83:77)
- Incidence is lower in Japanese and higher in African Americans from West Africa and United States when compared to Caucasians from United States
- Death rate is higher among nonwhite men in the United States and lower among Japanese men in Japan (J Natl Cancer Inst 1978;60:1223, Am J Public Health Nations Health 1963;53:890)
- Despite the differences in the hormone receptor and HER2 status expression among the different races and ethnicities, no difference in the overall survival (Cancer 2013;119:1611)
- 2x increased risk among first degree relatives of male breast cancer patients
Sites
- Tend to be located centrally in retroareolar position and also in upper outer quadrants
Etiology
- Associated with increased serum estrogen: liver disease, obesity, exogenous therapy, antiandrogen therapy
- Associated with decreased serum androgen: Klinefelter syndrome, testicular injury / atrophy, occupational exposure to high temperatures
- Drugs, exogenous agents: digitalis, tricyclic antidepressants, marijuana, lavender oil, tea tree oil
- Radiation
- Pituitary gland dysfunction: hyperprolactinemia
- Hereditary: BRCA2 mutation carriers, PTEN mutation (Cowden syndrome), CHEK2 mutation carriers
Clinical features
- Invasive carcinoma:
- Average age of presentation is 60 to 70 years, although can present in younger men and children
- ~75% present with a palpable mass
- Can also present with nipple retraction, ulceration or nipple discharge (serous); may be nodular and cystic
- Time lapse between symptoms and clinical consultation varies from 6 months to 1 year
- Tends to present with larger size and at a higher stage in men than in women
- Lymph node metastases are more common in men than women
- Axillary nodal staging is done by sentinel lymph node biopsy
- History of breast cancer does not significantly affect the age or stage at time of diagnosis or the prognosis (Cancer 1999;86:821)
- Annual clinical screening exam recommended in men with BRCA mutations
Diagnosis
- Clinical presentation, imaging findings and ultimately image guided biopsies of the lesion provide tissue for an accurate pathologic diagnosis
Radiology description
- No guidelines recommending mammographic screening for men have been established, even with documented genetic predisposition
- Mammographic findings in men with breast cancer reveal distinct lesions with invasive margins that contrast sharply with the surrounding fatty tissue
- Microcalcifications found in 9 - 30%
- Ultrasound: round mass with calcifications and papillary components like those seen in cystic or encapsulated papillary carcinoma
- Can be used to differentiate gynecomastia from carcinoma
- Inflammatory carcinoma of the male breast produces diffuse enlargement and thickening of the skin that can be detected by MRI
Radiology images
Images hosted on other servers:
Ultrasound of lymph node metastasis
Prognostic factors
- Poor prognostic factors: lymphatic tumor emboli, tumor size over 2 cm, poor histologic differentiation, HER2 overexpression, p53 expression, amplification of CCND1 (11q13)
- Men with a prior diagnosis of breast carcinoma have a 30x increased risk of invasive carcinoma in the contralateral breast, increasing to 110x if the original diagnosis was before age 50
- Death rate is higher among nonwhite U.S. men and lower among Japanese men
- Most investigators believe men and women with the same stage disease have similar prognosis, but some believe men have poorer prognosis
- AR+ luminal type A male breast cancer (ER+ HER2-, tumor grade 1/2) has better overall survival at 5 years but not 10 years compared to female breast cancer (Breast Cancer Res Treat 2012;133:949)
Case reports
- 40 year old man with occult breast cancer first manifesting as axillary lymph node metastasis (Medicine (Baltimore) 2015;94:e1038)
- 72 year old man with acromegaly and breast cancer (BMC Cancer 2015;15:397)
- 75 year old man with bilateral synchronous breast cancer (Saudi Med J 2015;36:359)
Treatment
- Treatment recommendations for male breast cancer are based on guidelines established for female breast cancer
- Most men are treated with mastectomy and axillary lymph node dissection
- Radiation, hormonal therapy and chemotherapy are also used
- Breast conservation therapy may be possible, especially in older patients
- Tamoxifen has less mortality when compared to aromatase inhibitors in men with stage I - III ER+ carcinoma (Breast Cancer Res Treat 2013; 137:465)
Clinical images
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Bilateral tumors
Gross description
- Male breast cancers are grossly identical to female breast cancers; cystic papillary carcinomas can be striking
Gross images
Images hosted on other servers:
Intracystic papillary carcinoma
Microscopic (histologic) description
- In situ carcinoma with papillary architecture is the most common pattern; also cribriform, micropapillary and solid patterns
- Most (~85%) male breast carcinoma is poorly differentiated infiltrating ductal carcinoma, followed by papillary carcinoma and other types similar to female breast cancer
- Lobular carcinoma represents 2% of cases
Microscopic (histologic) images
Contributed by Carlos C. Diez Freire, M.D.
Male invasive ductal carcinoma
ER
PR
Male mucinous carcinoma
Lymph node metastasis, mucinous
Male mucinous carcinoma, ER
Male mucinous carcinoma, PR
Contributed by Semir Vranić, M.D., Ph.D.
Man with adenoid cystic carcinoma
c-kit
CK14
Cytology description
- Reliable but underused
- Dispersed epithelial cells with atypical features and high N/C ratio
- Cell clusters can be present in papillary tumors
- Gynecomastia present with sparsely cellular aspirate with loosely cohesive sheets of cells
Positive stains
Negative stains
- HER2 (usually)
Molecular / cytogenetics description
- p53 mutations in exon 6 found in over 90% of male cases compared to 33% of females with p53 mutations in exon 5 and 6 (Neoplasma 1996;43:305)
- Gene expression performed in 66 male breast cancer tumors revealed 2 unique subgroups (luminal M1 and M2) that were different in biologic features and outcome when compared to female breast cancers (Breast Cancer Res 2012;14:R31)
- EGFR and CCND1 genes are amplified more in male than female breast cancers
- High methylation status of MSH6, WT1, PAX5, PAX6, GATA5 and CDH13 correlates with more aggressive phenotype and poor survival
- Male and female breast cancers share many of these methylated genes but many genes are less frequently methylated in males
- Methylation of RASSF1A (downregulation of ER alpha and micro RNAs) is more common in male than female breast carcinomas
Differential diagnosis
- Gynecomastia: especially with radiation induced changes
Additional references
Board review style question #1
What is the most common type of male breast carcinoma?
- Invasive lobular carcinoma
- Invasive papillary carcinoma
- Mucinous carcinoma
- Poorly differentiated invasive ductal carcinoma
- Well differentiated invasive ductal carcinoma
Board review style answer #1
D. Poorly differentiated invasive ductal carcinoma. Approximately 85% of male breast carcinomas are poorly differentiated infiltrating ductal carcinomas, followed by papillary carcinomas and other forms similar to those found in female breast cancer. Lobular carcinomas represent 2% of cases.
Comment Here
Reference: Male invasive breast carcinoma
Comment Here
Reference: Male invasive breast carcinoma
Medullary
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Positive stains | Negative stains | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2 | Board review style question #3 | Board review style answer #3Definition / general
- Medullary pattern is a histological pattern that can be applied to an invasive breast carcinoma of no special type that contains pushing borders, syncytial growth, high grade nuclei and prominent lymphoid infiltrate
- Represents one end of the spectrum of tumor infiltrating lymphocyte (TIL) rich invasive breast carcinomas of no special type rather than a distinct morphological subtype
Essential features
- Medullary pattern of invasive breast carcinoma no special type has 4 characteristic histological features (ideally, all 4 should be present for the diagnosis):
- Pushing border
- Syncytial growth pattern
- High grade nuclei
- Prominent lymphoid infiltrate
Terminology
- Preferred term according to WHO: invasive breast carcinoma of no special type with medullary pattern
- Historically described as medullary carcinoma, atypical medullary carcinoma, medullary features
ICD coding
- ICD-O: 8500/3 - infiltrating duct carcinoma, NOS
- ICD-11: 2C61.0 & XH7KH3 - invasive carcinoma of breast, NOS & infiltrating duct carcinoma, NOS
Epidemiology
- Often present earlier in life, median age of 53 (45 - 62) years (JAMA Netw Open 2021;4:e214123)
- Rare: less than 5% of all invasive breast cancers
Sites
- Breast
Pathophysiology
- Basal-like molecular subtype
- Same as molecular subtype matched invasive breast carcinoma of no special type (Breast Cancer Res Treat 2013;142:257)
Etiology
Clinical features
- Younger age
- Soft, palpable, circumscribed mass
- May have lymphadenopathy (due to hyperplasia rather than metastasis, which is uncommon)
Diagnosis
- Diagnostic steps are identical to invasive breast carcinoma (screening mammogram, diagnostic mammogram, ultrasound, core biopsy, etc.)
Radiology description
- Round, oval or lobulated mass on mammography
- Hypoechoic mass on ultrasound with thick echogenic halo
Radiology images
Contributed by Julie M. Jorns, M.D. and Mark R. Wick, M.D.
Mammogram
Mammogram
Prognostic factors
- Prognostic factors identical to invasive breast carcinoma of no special type: patient age, tumor histological grade, tumor stage, lymphovascular invasion, ER, PR and HER2 status, molecular subtype
- Additional prognostic factors:
- Triple negative breast cancers have more unfavorable prognosis then nontriple negative breast cancer (JAMA Netw Open 2021;4:e214123)
- Similar prognosis to stage matched grade 3 ductal carcinoma with prominent inflammation
- Better prognosis than grade 3 ductal carcinoma without prominent inflammation (Eur J Cancer 2009;45:1780)
- Tumor infiltrating lymphocytes have been shown to be of prognostic value (Ann Oncol 2015;26:259)
Case reports
- 38 year old woman who presented with a lump in both breasts for 3 months (J Cancer Res Ther 2012;8:129)
- 72 year old woman with invasive breast carcinoma with medullary pattern that had spontaneous pathological complete regression (Pol J Pathol 2019;70:139)
Treatment
- Identical to treatment options for invasive breast carcinoma of no special type with considerations for targeted therapy based on ER, PR, HER2 status
- Tumor infiltrating lymphocytes do not alter therapy currently
Gross description
- Well circumscribed, 2 - 3 cm in size, soft and fleshy (may resemble fibroadenoma)
- Homogenous with white to gray appearance
Gross images
Contributed by Mark R. Wick, M.D.
White mass
Microscopic (histologic) description
- Well circumscribed pushing border
- Cells in syncytial growth pattern with no glandular structures
- High histologic grade, high grade nuclei with prominent nucleoli
- Prominent tumor infiltrating lymphocyte infiltrate
Microscopic (histologic) images
Contributed by Shannon M. Welter, M.D., Julie M. Jorns, M.D. and @SeoparjooAzmel on Twitter
Circumscribed tumor
Prominent lymphoid infiltrate
Syncytial growth pattern
Stromal lymphocytes
High grade nuclei
High grade nuclei
Numerous mitotic figures
Biopsy site and circumscription
Syncytial growth and lymphoplasmacytic infiltrate
Lymphoplasmacytic
infiltrate
Invasive breast carcinoma of no special type with medullary pattern
Virtual slides
Images hosted on other servers:
Breast cancer with medullary pattern
Cytology description
- Hypercellular specimen
- Numerous isolated cells and loose clusters
- Markedly enlarged, vesicular nuclei
- Prominent, often irregular macronucleolus
- Many lymphocytes and some plasma cells
Positive stains
- Variably expresses basal markers such as CK5/6, CK14, EGFR (HER1) and p53
- Higher rate of PDL1 expression (83.1%) as compared to other triple negative breast cancers (Eur J Breast Health 2019;15:235)
Negative stains
- Most often negative for hormone receptors (ER and PR) and HER2 (triple negative breast cancer)
Molecular / cytogenetics description
- Genomic instability is common
- Majority of these tumors fall within the basal-like molecular profile
- Approximately 15% of tumors in BRCA1 mutation carriers are classified as invasive breast carcinoma with medullary pattern (J Natl Cancer Inst 1998;90:1138)
Sample pathology report
- Breast, right, segmental mastectomy:
- Invasive breast carcinoma of no special type with medullary pattern (see synoptic report)
- Carcinoma contains 90% stromal tumor infiltrating lymphocytes
Differential diagnosis
- Metastatic high grade carcinoma to the breast from another site:
- Lacks a coexistent in situ component
- May be within a lymph node or have abundant associated angiolymphatic invasion
- Immunohistochemistry is often needed for distinction
- Lymph node:
- Contains capsule or subcapsular sinus; both may have germinal centers
- Lymphoma:
- Tumor cells will stain with lymphoid markers, cytokeratin negative
Additional references
Board review style question #1
The tumor in the above image is found in the breast of a 45 year old woman. The tumor was round and soft on palpation and had pushing borders on microscopy. What is the most likely diagnosis?
- Ductal carcinoma in situ
- Invasive breast carcinoma with medullary pattern
- Invasive lobular carcinoma
- Secretory carcinoma
Board review style answer #1
B. Invasive breast carcinoma with medullary pattern
Comment Here
Reference: Invasive breast carcinoma of no special type with medullary pattern
Comment Here
Reference: Invasive breast carcinoma of no special type with medullary pattern
Board review style question #2
Which of the following is a feature of invasive breast carcinoma with medullary pattern?
- Extensive surrounding ductal carcinoma in situ
- Low histologic grade
- Present as calcifications on mammography
- Prominent lymphocytic infiltrate
Board review style answer #2
D. Prominent lymphocytic infiltrate
Comment Here
Reference: Invasive breast carcinoma of no special type with medullary pattern
Comment Here
Reference: Invasive breast carcinoma of no special type with medullary pattern
Board review style question #3
This breast tumor most often falls into which molecular profile?
- Basal-like
- HER2 enriched
- Luminal A
- Luminal B
Board review style answer #3
A. Basal-like
Comment Here
Reference: Invasive breast carcinoma of no special type with medullary pattern
Comment Here
Reference: Invasive breast carcinoma of no special type with medullary pattern
Metaplastic
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Positive stains | Negative stains | Molecular / cytogenetics description | Videos | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1Definition / general
- Heterogeneous group of invasive breast carcinomas characterized by differentiation of the neoplastic epithelium towards squamous cells or mesenchymal looking elements, including but not restricted to spindle, chondroid and osseous cells
Essential features
- Invasive breast carcinoma with atypical squamous, spindle cell or mesenchymal / matrix producing differentiation
- When lacking a ductal carcinoma in situ or conventual mammary carcinoma component, a panel of immunohistochemical stains (cytokeratins, including high molecular weight and p63) is needed to confirm the presence of epithelial differentiation
Terminology
- Acceptable: metaplastic carcinoma, NOS
- Not recommended: carcinosarcoma, sarcomatoid carcinoma, carcinoma with pseudosarcomatous metaplasia, carcinoma with pseudosarcomatous stroma
ICD coding
- ICD-O: 8575/3 - metaplastic carcinoma, NOS
- ICD-11: 2C6Y & XH0RD4 - metaplastic carcinoma of breast and metaplastic carcinoma, NOS
Epidemiology
- Uncommon (0.2 - 1% of breast carcinomas)
- Average 55 years
Sites
- Any anatomical part of breast
Pathophysiology
- Unclear
- Some studies indicate a monoclonal origin of the heterogeneous components (J Pathol 2010;220:562, J Pathol 2004;204:131, Clin Cancer Res 2017;23:4875)
Etiology
- Multifactorial
- Same as invasive breast carcinoma of no special type, especially triple negative breast carcinomas
Clinical features
- Presents like invasive breast carcinoma of no special type
- Biological behavior variable from low to high grade
- Tends to have large tumor size, less nodal involvement and higher American Joint Committee on Cancer (AJCC) stage (Ann Surg Oncol 2014;21:3497, Ann Surg Oncol 2018;25:2249)
- Poor response to neoadjuvant systemic therapy with pathology complete response (pCR) rate of ~ 10% - 17% (Breast Cancer Res Treat 2019;176:709, Mod Pathol 2019;32:807, Ann Oncol 2006;17:605)
Diagnosis
- By histopathological examination
Radiology description
- Similar to invasive breast carcinoma of no special type
- Most appear as a mass on mammography with a mean size of 32 mm
- Microcalcification is uncommon but may be present, especially in a carcinoma in situ component
- Reference: Br J Radiol 2016;89:20140644
Radiology images
Images hosted on other servers:
Spiculated mass
Prognostic factors
- Fibromatosis-like carcinomas and low grade adenosquamous carcinomas are associated with more indolent behavior (Histopathology 2016;68:45, Tumori 2009;95:264, Am J Surg Pathol 1993;17:248)
- Matrix producing metaplastic carcinomas have relatively better prognosis (Br J Cancer 2015;112:283)
- High grade spindle cell carcinomas, squamous cell carcinomas, high grade adenosquamous carcinomas and higher numbers of morphologies within mixed metaplastic carcinomas are associated with a worse prognosis (Br J Cancer 2015;112:283)
Case reports
- 39 year old woman with a recurred, 3.5 cm breast mass (Case Rep Pathol 2020;2020:4806342)
- 41 year old woman with neurofibromatosis type 1 and breast mass (Cold Spring Harb Mol Case Stud 2018;4:a002352)
- 47 year old man with a 2.4 cm spiculated nodule and associated nipple retraction (BMJ Case Rep 2018;2018:bcr2017222033)
- 47 year old woman with pleomorphic liposarcoma diagnosis on core biopsy (Pathobiology 2018;85:261)
- 48 year old woman with painless calcified breast mass (Int J Surg Case Rep 2017;34:100)
- 60 year old woman with metaplastic carcinoma arising in microglandular adenosis (J Pathol Transl Med 2017;51:418)
- 88 year old woman with huge bleeding tumor (J Med Invest 2020;67:365)
Treatment
- Mastectomy or local excision, with or without radiation and chemotherapy
- Lower response rates to conventional chemotherapy (Breast J 2019;25:418)
Clinical images
Images hosted on other servers:
Right breast mass
Gross description
- Often firm, well circumscribed and solid
- Pearly, white to grayish and glistening cut surface in areas of squamous and chondroid differentiation
- Mean 3.9 cm, ranging from 2 cm to > 10 cm
Gross images
AFIP images
Bisected squamous tumor
Carcinoma with osteoclast-like giant cells
Images hosted on other servers:
Well circumscribed
mass with
central bleeding
Causing skin ulceration
Sharply circumscribed tumor
Microscopic (histologic) description
- Morphologically heterogenous
- Can be epithelial only carcinomas, pure (monophasic) sarcomatoid carcinomas and biphasic epithelial and sarcomatoid carcinomas
- Epithelial only carcinomas include low grade adenosquamous carcinoma, high grade adenosquamous carcinoma and squamous cell carcinoma
- Pure (monophasic) sarcomatoid carcinomas include fibromatosis-like metaplastic carcinoma and spindle cell carcinoma
- Heterologous mesenchymal components include chondroid, osseous, rhabdomyosarcomatous, angiosarcomatous, liposarcomatous and neuroglial differentiation or in combination
- Mesenchymal component can show a wide spectrum of atypia, ranging from minimal atypia to frankly malignant
- May need to look carefully, extensive sampling or performing immunohistochemistry (a combination of several stains) for identification of epithelial component
Microscopic (histologic) images
Contributed by Huina Zhang, M.D., Ph.D. and Julie M. Jorns, M.D.
Spindle cell carcinoma
Metaplastic carcinoma with squamous differentiation
Matrix producing metaplastic carcinoma
Squamous type
Spindle cell type
Osseous differentiation
Spindle cell type
Chondromyxoid matrix producing
Contributed by Indu Agarwal M.D. and Semir Vranić, M.D., Ph.D.
Chondroid differentiation
Squamous component
EGFR expression
Virtual slides
Images hosted on other servers:
Fibromatosis-like metaplastic carcinoma
Cytology description
- Moderate to marked cytologic atypia
- Large, pleomorphic and spindle shaped cells or malignant squamous cells
- Isolated or clusters of malignant cells
- Rarely, malignant cartilage or bone or osteoclastic-like giant cells
- Dual components usually not identified
- Reference: Cibas: Cytology - Diagnostic Principles and Clinical Correlates, 5th Edition, 2020
Positive stains
- Broad spectrum keratin AE1 / AE3, CAM5.2, OSCAR, 34 beta E12, MNF116: 75 - 90% (Appl Immunohistochem Mol Morphol 2020 Aug 28 [Epub ahead of print])
- High molecular weight keratin CK5/6, CK14: 70 - 77%
- p63: 77%
- Low molecular weight keratin CK8/18, CK7, CK19: 36 - 61%
- Myoepithelial cell markers SMA, CD10: 60 - 70%
Negative stains
Molecular / cytogenetics description
- Basal-like or claudin low molecular subtype
- No uniform molecular profile
- May affect TP53, RB1, TERT promoter genes, chromatin remodeling genes (i.e. ARID1A, KMT2C), genes related to PI3K pathway (i.e. PIK3CA, PIK3R1, PTEN), MAPK pathway (NF1, KRAS, NRAS) or WNT pathway (FAT1, APC, CCN6) (Clin Breast Cancer 2020;20:326, Cancers (Basel) 2020;12:1832, Mod Pathol 2018;31:1661, Clin Cancer Res 2017;23:3859)
Videos
Metaplastic carcinoma by
Dr. Alexander Damron
Sample pathology report
- Breast, left, 3:00 (mass), ultrasound guided core needle biopsy:
- Malignant spindle cell lesion, consistent with spindle cell carcinoma (see comment)
- Comment: H&E sections show a high grade spindle cell lesion with pleomorphic nuclei, irregular nuclear borders and occasional mitotic figures, including atypical mitosis. There is no leaf-like growth pattern. Immunohistochemical staining shows that the neoplastic cells are positive for pancytokeratin, p63, CK5 and AE1 / AE3 and are negative for CD34. The morphology and immunoprofile of this malignant spindle cell lesion are consistent with a spindle cell (metaplastic) carcinoma.
Differential diagnosis
- Phyllodes tumor:
- Primary breast sarcoma:
- Metastatic sarcoma:
- Adenomyoepithelioma:
- Bland epithelial and stromal component
- Stromal only with myoepithelial differentiation
- Lack of squamous differentiation
- Myoepithelial carcinoma:
- Entirely or almost entirely malignant spindle cells with myoepithelial differentiation
- No squamous component or other mesenchymal differentiation
- Pleomorphic adenoma:
- Usually retroareolar region
- Well organized biphasic pattern with inner layer of regular epithelial cells
- Thin, continuous outer layer of myoepithelial cells
- No cytologic atypia, atypical mitosis or necrosis
- See others in variants sections
Additional references
Board review style question #1
A 55 year old woman without significant medical history was found to have a 2.5 cm mass on mammogram and a biopsy was performed. Histology and immunohistochemical stain for p63 were shown (see images above). What is the likely diagnosis?
- Malignant phyllodes tumor
- Metaplastic carcinoma
- Metastatic sarcoma
- Primary breast sarcoma
Board review style answer #1
B. Metaplastic carcinoma
H&E section shows a high grade spindle cell lesion with pleomorphic nuclei, irregular nuclear borders and occasional mitotic figures, including atypical mitosis. Based on the morphology, all the listed choices should be considered. Performing a panel of immunohistochemical stains including high molecular weight cytokeratin and p63 is very important and helpful. In this case, the positivity for p63 (as well as other cytokeratins, not shown here) supports the diagnosis of spindle cell carcinoma and makes other choices less likely. It needs to be noted that cytokeratins and p63 are often focal and patchy, therefore a panel of immunostains is usually needed.
Comment Here
Reference: Metaplastic carcinoma
H&E section shows a high grade spindle cell lesion with pleomorphic nuclei, irregular nuclear borders and occasional mitotic figures, including atypical mitosis. Based on the morphology, all the listed choices should be considered. Performing a panel of immunohistochemical stains including high molecular weight cytokeratin and p63 is very important and helpful. In this case, the positivity for p63 (as well as other cytokeratins, not shown here) supports the diagnosis of spindle cell carcinoma and makes other choices less likely. It needs to be noted that cytokeratins and p63 are often focal and patchy, therefore a panel of immunostains is usually needed.
Comment Here
Reference: Metaplastic carcinoma
Metastases
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Positive stains | Negative stains | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Metastasis to the breast from a malignancy arising outside the breast
Essential features
- Rare, < 1% of breast malignancies (Eur J Surg Oncol 2003;29:854, Cancer 2007;110:731, J Clin Pathol 2007;60:1333)
- Can be initially misdiagnosed due to nonspecific / overlapping clinical, radiologic, morphologic and immunophenotypic features with primary breast carcinoma, especially if inadequate clinical history is provided
- Accurate identification of extramammary metastases is critical to avoid unnecessary surgery and inappropriate treatment
Terminology
- Nonmammary metastases to the breast, extramammary metastases to the breast
ICD coding
- ICD-10: C80.0 - disseminated malignant neoplasm, unspecified
Epidemiology
- Metastases to the breast represents 0.2 - 1.3% of breast malignancies (Eur J Surg Oncol 2003;29:854, Cancer 2007;110:731, J Clin Pathol 2007;60:1333)
- More common in women (Cancer 2001;92:2259, Mod Pathol 2013;26:343)
- Median age in fifth decade but can occur in pediatric patients (Mod Pathol 2013;26:343)
Etiology
- A wide range of extramammary malignancies can metastasize to the breast, including lymphoma, melanoma, sarcoma (uterine leiomyosarcoma, rhabdomyosarcoma, liposarcoma) and carcinoma (common primary sites include gynecologic, lung, gastrointestinal, genitourinary, head and neck) (Cancer 2007;110:731, Mod Pathol 2013;26:343)
- Most common primary sites include cutaneous malignant melanoma, lung and ovary (Cancer 2007;110:731, Mod Pathol 2013;26:343)
- In pediatric patients, most common primaries include rhabdomyosarcoma and lymphoma (Pathol Annu 1989;24:296, J Pediatr Surg 1994;29:48)
- Lymphoma involving the breast can be either primary or due to secondary systemic involvement
Clinical features
- Majority of patients have a history of malignancy, often with prior or coincident metastases to other nonmammary sites (Cancer 2007;110:731, J Surg Oncol 2006;94:101, Mod Pathol 2013;26:343)
- In 11 - 30% of cases, breast metastasis is the initial presentation of an occult extramammary malignancy (Cancer 2001;92:2259, J Clin Pathol 2007;60:1333, Mod Pathol 2013;26:343)
- Long interval between primary malignancy and the breast metastasis can be observed in melanoma and ovarian carcinoma (J Clin Pathol 2007;60:1333, Clin Oncol 1976;2:393)
- Frequently presents as a solitary, rapidly growing, palpable mass (Acta Pathol Microbiol Scand A 1981;89:251, AJR Am J Roentgenol 1977;129:673, Mod Pathol 2013;26:343)
- Can present with axillary lymphadenopathy (J Ultrasound Med 2000;19:257, Am J Surg Pathol 2004;28:1646)
- Presentation can mimic inflammatory breast cancer (Eur J Nucl Med Mol Imaging 2016;43:389, Breast Cancer 2008;15:315)
Diagnosis
- Possibility of a nonmammary metastasis should be considered when encountering a breast lesion with unusual clinical, radiologic or histomorphologic features
- Clinical history is critical to establish the correct diagnosis; there is often history of advanced stage, nonbreast malignancy
- Biopsy is performed if clinical evaluation and imaging are inconclusive for primary versus metastasis
- Identification of a definitive in situ component can be useful to rule out metastasis and confirm a breast primary
- Absence of an in situ component does not conclusively exclude a nonmammary metastasis, as an in situ component is not present in all primary mammary carcinomas
- Immunohistochemical work up is generally required for confirmation of the diagnosis
Radiology description
- Can show variable imaging features depending on the origin and location of the primary tumor (Case Rep Radiol 2019;2019:9454201)
- Generally well defined, discrete, rounded mass, with less spiculation compared with primary breast malignancies (J Ultrasound Med 2000;19:257, Eur J Surg Oncol 2003;29:854)
- Usually presents initially as a unilateral, solitary mass but with progression may present as multiple or bilateral masses (Int J Surg Case Rep 2014;5:34, Am J Surg Pathol 2004;28:1646, Mod Pathol 2013;26:343)
- Calcifications are rare, except in serous carcinoma of the ovary (Am J Surg Pathol 2004;28:1646, Surgery 1991;110:552)
Radiology images
Images hosted on other servers:
Gastric signet ring cell carcinoma
Malignant melanoma
Ovarian serous carcinoma
Prognostic factors
- Poor prognosis; most patients present with advanced stage, widely disseminated disease (Cancer 2007;110:731)
- Median survival of 8 - 10 months (Cancer 2007;110:731, J Am Coll Surg 1994;179:49)
- Individual prognosis is dependent on the specific clinical characteristics of the metastatic neoplasm
Case reports
- 40 year old woman with history of ovarian serous cystadenocarcinoma presented with a left breast mass (Cancer Manag Res 2020;12:13015)
- 47 year old woman with pulmonary adenocarcinoma presented with left breast nodule (BMC Cancer 2014;14:736)
- 56 year old woman with colonic adenocarcinoma presented with palpable right breast mass (Case Rep Oncol Med 2015;2015:458423)
- 58 year old woman with melanoma presented with a right breast mass (J Med Case Rep 2016;10:363)
- 63 year old woman with renal cell carcinoma presented with breast mass detected by mammography (BMJ Case Rep 2017;2017:bcr2016219124)
- 67 year old woman with a solitary, rapidly enlarging, 2.2 cm right breast mass (Case #504)
- 76 year old woman with ovarian serous carcinoma presented with left breast mass and axillary lymphadenopathy (J Cutan Pathol 2018;45:234)
- 85 year old woman presented with right breast mass (World J Gastrointest Oncol 2020;12:1073)
Treatment
- Primary therapeutic approach is systematic treatment that is specific and appropriate to the primary lesion
- Generally, surgical excision is not indicated for metastatic tumors to the breast, unless performed to palliate symptoms (e.g., bulky, ulcerated lesions)
- It is critically important for the pathologist to recognize the metastatic nature of the lesion, as the treatment and prognosis differ significantly from primary breast cancer and misdiagnosis can result in unnecessary surgery and inappropriate treatment (Mod Pathol 2013;26:343)
Gross description
- Generally well circumscribed
Gross images
Images hosted on other servers:
Malignant melanoma
Pulmonary adenocarcinoma
Microscopic (histologic) description
- General
- Often morphologic features are unusual for a primary mammary tumor (J Clin Pathol 2007;60:1333)
- Lack of an in situ component (J Clin Pathol 2007;60:1333)
- Metastatic tumors with certain morphologies (e.g., spindle cell, mucinous, squamous, clear cell, neuroendocrine) may show significant morphologic overlap with primary breast malignancies
- Malignant melanoma
- Wide range of histologic appearances, may be amelanotic
- Generally high grade cytology
- Pigment, spindle cell morphology, intranuclear inclusions can suggest melanoma (Histopathology 2000;36:387)
- Pulmonary carcinoma
- Wide range of histologic appearances, including cystic papillary and glandular architecture
- Small cell features can suggest pulmonary site of origin
- Ovarian carcinoma
- Usually serous type, less commonly mucinous or clear cell types
- Wide range of histologic appearances, including papillary, glandular and solid architecture
- May show necrosis and high grade cytology
- Papillary morphology, psammomatous calcifications can suggest ovarian serous carcinoma (Am J Surg Pathol 2004;28:1646)
- Often morphologic overlap with breast primary
- Gastrointestinal carcinoma
- If mucinous morphology, can show histologic overlap with mucinous subtype of breast carcinoma
- If signet ring cell morphology, can show histologic overlap with lobular subtype of breast carcinoma
- If neuroendocrine / carcinoid, can show histologic overlap with neuroendocrine carcinoma of the breast
- Renal cell carcinoma
- Clear cell features can suggest renal site of origin
- If spindle cell and sarcomatoid morphology, can show histologic overlap with metaplastic breast carcinoma
- Prostatic adenocarcinoma
- Can show morphologic overlap with breast primary
Microscopic (histologic) images
Contributed by Gary Tozbikian, M.D., Julie M. Jorns, M.D. and Case #504
Metastatic ovarian serous carcinoma
Metastatic leiomyosarcoma
Metastatic malignant melanoma
Metastatic melanoma
Metastatic clear cell renal cell carcinoma
Metastatic melanoma, SOX10
Metastatic melanoma,
AE1 / AE3
Metastatic melanoma, HMB45
Cytology description
- Malignant melanoma
- Dispersed polygonal and plasmacytoid cells with a moderate amount of granular and vacuolated cytoplasm, can show spindle cell morphology (Diagn Cytopathol 2017;45:446)
- Pulmonary adenocarcinoma
- Groups of medium sized cells showing complex papillary arrangement (Ann Oncol 2008;19:682)
- Ovarian carcinoma
- Medium sized cells arranged in papillary clusters with round nuclei with evident nucleoli and a moderate quantity of grayish cytoplasm, psammomatous microcalcifications (Ann Oncol 2008;19:682)
Cytology images
Images hosted on other servers:
Metastatic ovarian serous carcinoma
Metastatic lung adenocarcinoma
Positive stains
- Malignant melanoma
- S100, HMB45, MelanA (versus negative in breast)
- SOX10 (also positive in triple negative breast cancer) (Hum Pathol 2019;85:221, Hum Pathol 2013;44:959)
- Pulmonary carcinoma
- Ovarian carcinoma
- PAX8, WT1 (serous and clear cell carcinoma) (versus negative in breast) (WT1 can be seen mucinous and micropapillary subtypes of breast cancer) (Am J Surg Pathol 2008;32:1566, Am J Surg Pathol 2011;35:816, Int J Gynecol Pathol 2004;23:110, Mod Pathol 2008;21:1217, Histopathology 2007;51:824)
- CK7, estrogen receptor, progesterone receptor (also positive in breast carcinoma)
- Gastrointestinal carcinoma
- Renal cell carcinoma
- PAX8, PAX2, RCC (versus negative in breast) (Am J Surg Pathol 2011;35:816)
- Prostatic adenocarcinoma
- PSA, PSAP, NKX3.1 (versus negative in breast)
- Androgen receptor (also positive in breast carcinoma)
Negative stains
- Estrogen receptor and progesterone receptor (except metastasis from gynecologic primary sites)
- GATA3 (except metastasis from urothelial, salivary gland, pancreatic adenocarcinoma and squamous primary sites) (Am J Surg Pathol 2014;38:13)
- TRPS1 (can be positive in ovarian serous carcinoma, salivary duct carcinoma)
- p63 / p40, calponin / SMMS (myoepithelial markers to confirm lack of in situ component)
- Malignant melanoma
- Cytokeratin (versus positive in breast)
- Prostatic adenocarcinoma
- CK7 (versus positive in breast)
Sample pathology report
- Breast, left, 2:00 zone 2, ultrasound guided core biopsy:
- Metastatic carcinoma, consistent with metastasis of Müllerian origin (see comment)
- Comment: Per the electronic medical record, the patient's history of ovarian cancer is noted. Immunohistochemical stains show that the tumor cells are positive for CK7, estrogen receptor, PAX8 and WT1 and are negative for GATA3, BRST2 and mammaglobin. The findings are consistent with metastasis of Müllerian origin (ovarian serous carcinoma).
Differential diagnosis
- Invasive ductal carcinoma:
- Invasive lobular carcinoma:
- Metaplastic carcinoma:
- Can mimic renal cell carcinoma
- Negative: PAX8
- Mucinous carcinoma of the breast:
- Papillary carcinomas of the breast (solid, encapsulated, invasive):
Board review style question #1
A 55 year old woman with history of cutaneous malignant melanoma presents with a solitary, palpable, rapidly enlarging breast mass. Ultrasound guided core biopsy shows a high grade malignant neoplasm. What panel of immunohistochemical stains would be most useful in distinguishing metastatic melanoma versus a primary breast malignancy?
- Cytokeratin and estrogen receptor
- Cytokeratin, HMB45 and MelanA
- Estrogen receptor and S100
- SOX10 and estrogen receptor
- SOX10 and S100
Board review style answer #1
B. Cytokeratin, HMB45 and MelanA. A panel of cytokeratins and melanoma markers (e.g., S100, HMB45, MelanA) would be most useful. 20% of breast cancers will be negative for estrogen receptor. A negative result for estrogen receptor would not rule out a breast primary. SOX10 can be expressed in both melanoma as well as triple negative breast cancer.
Comment Here
Reference: Metastases
Comment Here
Reference: Metastases
Board review style question #2
A 45 year old BRCA+ woman with a history of ER+ primary ductal carcinoma of the breast 5 years ago now presents with ascites and omental caking. Peritoneal biopsy shows a high grade malignant neoplasm with glandular and papillary features. Given the history, an initial panel of breast biomarkers is performed. The tumor is strongly positive for ER and PR and negative for HER2. What panel of additional immunohistochemical stains would be most useful in the diagnosis?
- CK20 and CDX2
- GATA3 and androgen receptor
- MelanA and HMB45
- PAX8 and WT1
- TTF1 and Napsin A
Board review style answer #2
D. PAX8 and WT1. Given the clinical presentation, hormone receptor positivity and history of BRCA mutation, a metastasis from a gynecological primary (e.g., ovarian carcinoma) is the main concern. The most appropriate immunohistochemical stain panel would include PAX8 and WT1.
Comment Here
Reference: Metastases
Comment Here
Reference: Metastases
Microcalcifications
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Diagrams / tables | Clinical features | Diagnosis | Laboratory | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Gross images | Frozen section description | Frozen section images | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Cytology images | Immunofluorescence description | Immunofluorescence images | Positive stains | Negative stains | Electron microscopy description | Electron microscopy images | Molecular / cytogenetics description | Molecular / cytogenetics images | Videos | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2 | Board review style question #3 | Board review style answer #3Definition / general
- Small deposits of calcium in breast tissue that measure < 0.5 mm and are visible on mammographic imaging (Mol Clin Oncol 2022;16:81)
Essential features
- Common finding on mammograms and can represent both benign and malignant conditions
- Microcalcifications are the most common mammographic presentation (~42%) of nonpalpable cancer (AJR Am J Roentgenol 1986;146:661)
- 2 main types based on biochemical composition
- Type I: calcium oxalate
- Type II: calcium phosphate (hydroxyapatite)
Terminology
- Mammary microcalcifications
- 2 main types based on biochemical composition
- Type I: calcium oxalate (CO)
- Type II: calcium phosphate / hydroxyapatite (HA)
ICD coding
- Considered a radiologic finding rather than a diagnosis; related ICD codes include
- ICD-O
- ICD-10
- ICD-11
Epidemiology
- Can occur at any age but is more common in older women
- Women with a history of breast cancer may have a higher likelihood of developing microcalcifications (Breast Cancer Res 2022;24:96)
- Women with microcalcifications have a higher risk of developing breast cancer (Breast Cancer Res 2022;24:96)
- Strong association between the presence of calcifications and HER2 overexpression (Mol Oncol 2015;9:967)
Sites
- Found throughout the breast tissue, most commonly within the mammary ducts and the surrounding fibroglandular tissue (stroma, vessels, skin)
Pathophysiology
- Thought to arise from mineral deposition which results from various physiologic processes
- Secretory
- Inflammatory
- Senescence
- Traumatic injury
- Necrosis
Etiology
- Dystrophic calcification in breast tissue is traditionally perceived as a passive phenomenon but type II microcalcifications (MCs) are often associated with abnormal epithelial cells; suggesting an active process
- Bone hydroxyapatite (HA) deposition is recognized as an active and physiological process; however, in breast tissue, HA deposition is considered pathological
- Breast MCs may undergo regulation similar to that of physiologic bone mineralization, despite being considered a pathologic process
- Formation of mammary MCs likely involves active secretion and may include epithelial to mesenchymal transition (EMT) of breast cells
- Upregulation of osteogenic proteins such as osteopontin and BMP2 in breast cancer suggests a connection between breast cancer and osteogenic characteristics (Mol Clin Oncol 2022;16:81)
Diagrams / tables
Not relevant
Clinical features
- Asymptomatic and too small to be palpated
- Identified during a mammogram and classified based on number, size, morphology and distribution using the BI-RADS (breast imaging reporting and data system) scoring system
- Presence of microcalcifications on mammography has led to the detection of breast tumors as small as 1 - 2 mm (Mol Clin Oncol 2022;16:81)
- Microcalcifications are present in 50% of carcinomas, compared to 20% in benign breast disease (Mol Clin Oncol 2022;16:81)
- Only 20% of suspicious microcalcifications are actually part of a malignant process (Br J Cancer 2021;125:759)
Diagnosis
- Breast microcalcifications are typically first identified during mammography (Mol Clin Oncol 2022;16:81)
- Radiographical findings and correlation with clinical history is necessary
- Core biopsy is frequently performed if there are microcalcifications (Korean J Radiol 2015;16:996)
- Pathological diagnosis needs to correlate with imaging findings
Laboratory
Not relevant
Radiology description
- Microcalcifications are detected during mammography
- Based on their number, size, morphology and distribution, a BI-RADS category indicative of the likelihood of malignancy is assigned (see Table 1 and 2)
- Suspicious microcalcifications are irregular and fine; nonsuspicious are coarse and chunky
- Pathologists must detect microcalcifications in glass slides that correspond to those observed in radiographs; if microcalcifications are not initially identified, they should consider submitting additional tissue, obtaining additional levels or employing polarized microscopy to identify calcium oxalate (Pathologica 2007;99:5)
- Note: microcalcifications may be absent from biopsy specimen due to retrieval failure (Radiology 2006;239:61)
- Note: it is recommended to histologically examine all vacuum assisted breast biopsy specimens, regardless of the presence or absence of microcalcifications (Eur Radiol 2008;18:925)
- Detection of calcium phosphate microcalcifications is diminished with glyoxal fixative (Eur Radiol 2008;18:925)
Table 1: BI-RADS assessment categories and likelihood of cancer (adapted from Biochim Biophys Acta Rev Cancer 2018;1869:310)
| Category | Assessment | Management | Likelihood of cancer |
| 0 | Incomplete; needs additional imaging evaluation or prior mammograms for comparison | Additional imaging or comparison with prior examination(s) | N/A |
| 1 | Negative | Routine mammography screening | 0% |
| 2 | Benign | Routine mammography screening | 0% |
| 3 | Probably benign | Short interval (6 month) follow up or continued surveillance mammography | > 0% but ≤ 2% |
| 4 | Suspicious for malignancy
| Tissue diagnosis | > 2% but < 95%
|
| 5 | Highly suggestive of malignancy | Tissue diagnosis | ≥ 95% |
| 6 | Known biopsy proven malignancy | Surgical excision when clinically appropriate | N/A |
Table 2: Mammographic characteristic features of benign versus suspicious breast calcifications (Biochim Biophys Acta Rev Cancer 2018;1869:310, Mol Clin Oncol 2022;16:81, YouTube: Breast Imaging Calcifications - module 2 | Health4TheWorld Academy [Accessed 8 April 2024], Nov Approaches Cancer Study 2021;6:582)
| Features | Typically Benign | Suspicious for Malignancy |
| Quantity | Few | Many |
| Size (diameter) | Large and chunky, 1.0 - 4.0 mm | < 0.5 mm |
| Shape | Coarse, round, oval, uniform | Fine, linear |
| Borders | Well defined, regular | Irregular, less defined |
| Groups | 5 calcifications within 1 cm | > 5 calcification within 2 cm |
| Distribution | Diffuse / scattered, regional | Linear, segmental |
| Morphology | Eggshell like, pop-corn-like, rod-like | Amorphous, coarse heterogenous, fine pleomorphic, fine linear branching |
| Other associations | Skin, vascular, dystrophic, milk of calcium, suture, breast infarcts |
Radiology images
Contributed by Agnes Ikpoto Udoh, M.D., M.B.A.
Microcalcifications in grouped distribution
Round microcalcifications (BI-RADS 4A)
Linear microcalcifications (BI-RADS 4B)
Linear microcalcifications (BI-RADS 4C)
Images hosted on other servers:
Involuting fibroadenoma with popcorn microcalcifications
Breast calcification BI-RADS 2
Linear microcalcifications in DCIS
Prognostic factors
- Microcalcifications are associated with both favorable prognostic factors (i.e., small size and hormone receptor positivity) and unfavorable factors (i.e., high grade), depending on the associated diagnosis (Cancer 2017;123:219)
- Casting (duct centric) calcification subtype is an independent unfavorable prognostic factor in breast cancer patients, affecting ~10 - 12% of cases; it is associated with specific genetic and molecular characteristics and is linked to decreased overall survival rates (Semin Cancer Biol 2021;72:165)
Case reports
- 27 year old woman with pleomorphic calcifications and segmental distribution on mammography, highly suggestive of breast cancer; however, the pathological findings were fibrocystic disease (Radiol Case Rep 2023;18:3828)
- 42 year old breastfeeding woman with multiple groups of microcalcifications in bilateral breasts (Breast J 2004;10:247)
- 54 year old woman with a history of gastric cancer and pleomorphic microcalcifications in the breast (J Breast Cancer 2012;15:356)
- 73 year old woman diagnosed with primary breast amyloidosis and persistent microcalcifications (Int J Surg Pathol 2013;21:177)
Treatment
- Most causes of breast calcification are benign and do not require treatment (Cleveland Clinic: Breast Calcifications [Accessed 8 April 2024])
- Biopsy is indicated for BI-RADS 4 lesions or more (Diagn Interv Radiol 2015;21:189, Radiopaedia: Breast Imaging-Reporting and Data System (BI-RADS) Assessment Category 4 [Accessed 8 April 2024])
- Based on the final diagnosis, the next course of management could involve monitoring for benign lesions, excisional biopsy, lumpectomy or mastectomy
- Further treatment also depends on the diagnosis and may include chemotherapy, radiotherapy, targeted drug therapy or a combination thereof
Clinical images
Not available
Gross description
- Typically, specimens come as core biopsies
Gross images
Not relevant to this topic
Frozen section description
Not relevant to this topic
Frozen section images
Not relevant to this topic
Microscopic (histologic) description
- There are 2 primary types of microcalcifications based on biochemical composition: calcium oxalate and calcium phosphate
- Calcium oxalate (type I)
- Less common
- These crystals do not bind with the hematoxylin stain and appear as clear refractile structures; they are best visualized under polarized light, with the condenser flipped down for optimal observation (Am J Surg Pathol 1990;14:961, Mod Pathol 1992;5:146)
- Predominantly found within benign cysts or terminal ductules, often demonstrating histological features of apocrine cells
- Can be associated with lobular carcinoma in situ and are rarely seen in association with invasive carcinoma (Am J Surg Pathol 1991;15:586)
- Calcium phosphate (type II)
- More common
- Manifest as purple / blue psammoma-like aggregates, either solitary or clustered, when stained with H&E
- May be observed in both benign and malignant lesions; they are commonly associated with premalignant and malignant lesions (Mol Clin Oncol 2022;16:81)
- If a mammogram reveals the presence of microcalcifications, diligent efforts should be undertaken to locate them; furthermore, the presence of microcalcifications must be documented in the histology report, along with any associated lesions
- Location of the microcalcifications may suggest the following possible differentials
- Lobular calcifications
- Cystic breast disease
- Milk of calcium
- Sclerosing adenosis
- Atypical lobular hyperplasia (ALH)
- Lobular carcinoma in situ (LCIS)
- Invasive lobular carcinoma (ILC)
- Ductal calcifications
- Columnar cell change
- Flat epithelial atypia (FEA)
- Atypical ductal hyperplasia (ADH)
- Ductal carcinoma in situ (DCIS)
- Invasive ductal carcinoma (IDC)
- Lobular calcifications
- The following steps are recommended to locate the microcalcifications
- Step 1: examine the H&E stained slides meticulously for microcalcifications
- Step 2: if not apparent on H&E, utilize polarized light microscopy, especially for detecting calcium oxalate crystals
- Step 3: consider cutting deeper levels of the H&E slides to further evaluate for microcalcifications
- Step 4: utilize Xray imaging of the tissue block for enhanced detection
- Step 5: consult with the radiologist to confirm that the lesion has been biopsied
Microscopic (histologic) images
Contributed by Jing He, M.D.
DCIS
Collagenous spherulosis
Fibroadenoma
Columnar cell lesion
Apocrine metaplasia
Radial scar
Papillary lesion
Fibrocystic changes
Invasive tubular carcinoma
IDC after neoadjuvant chemotherapy
Sclerosing adenosis
LCIS
Fat necrosis
Flat epithelial atypia
Usual ductal hyperplasia
Fibrocystic changes with calcium oxalate calcifications
Calcium oxalate calcifications with polarized light
Virtual slides
Not available.
Cytology description
Not relevant to this topic
Cytology images
Not relevant to this topic
Immunofluorescence description
Not relevant to this topic
Immunofluorescence images
Not relevant to this topic
Positive stains
Not relevant to this topic
Negative stains
Not relevant to this topic
Electron microscopy description
Not relevant to this topic
Electron microscopy images
Not relevant to this topic
Molecular / cytogenetics description
Not relevant to this topic
Molecular / cytogenetics images
Not relevant to this topic
Videos
Breast imaging: calcifications (basic radiology)
Breast imaging calcifications (module 1)
Breast imaging calcifications (module 2)
Sample pathology report
- Breast, right, 3 o'clock, 5 cm from nipple, microcalcifications, stereotactic core biopsy:
- Sclerosing adenosis with associated microcalcifications
Differential diagnosis
- Dystrophic calcification:
- These can develop in areas of old scarring and may warrant biopsy during follow up after conservation surgery for malignant disease
- Typically, they appear coarse and may exhibit an eggshell-like appearance
- They can pose a diagnostic challenge if they are arranged in clusters
- Vascular calcification:
- Typically conspicuous but can resemble casting calcifications
- They are arranged in parallel streaks and distributed along a vessel
Additional references
Not available
Board review style question #1
Which of the following characteristics is most suggestive of benign microcalcifications on mammography?
- Fine pleomorphic calcifications
- Linear or branching distribution
- Round or oval shape with smooth borders
- Segmental distribution
Board review style answer #1
C. Round or oval shape with smooth borders. Benign microcalcifications commonly exhibit a round or oval shape with smooth margins, which typically suggest benign conditions like fibrocystic changes or benign breast calcifications. Answer B is incorrect because linear or branching distribution is more commonly associated with malignant lesions, particularly ductal carcinoma in situ (DCIS). Answer A is incorrect because fine pleomorphic calcifications are irregular in shape and size and have a higher likelihood of being associated with malignant lesions than the classifications that are round with smooth borders. Answer D is incorrect because segmental distribution is usually suggestive of malignancy; however, there are few reports of its association with fibrocystic change (Radiol Case Rep 2023;18:3828).
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Reference: Microcalcifications
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Reference: Microcalcifications
Board review style question #2
What is the recommended next step if microcalcifications are not initially identified in histological examination?
- Consult with a radiologist for further imaging
- Submit additional tissue for analysis
- Disregard the findings as insignificant
- Perform electron microscopy for better resolution
Board review style answer #2
B. Submit additional tissue for analysis. Of the provided options, the best option would be to submit additional tissue for analysis. It would be most appropriate to first obtain additional levels before doing so, after which you should employ polarized microscopy to identify calcium oxalate crystals if still not seen on H&E. Answer A is incorrect because while consulting with a radiologist for further imaging might be a further step taken in the diagnostic process, it is not the recommended next step if microcalcifications are not initially identified in histological examination. Answer C is incorrect because disregarding the findings as insignificant without further investigation would be inappropriate and potentially harmful. Microcalcifications can be indicative of various benign and malignant conditions, so their presence or absence could have implications for diagnosis and treatment planning. Dismissing them without proper evaluation could lead to missed diagnoses or incorrect management decisions. Answer D is incorrect because electron microscopy is a highly specialized technique used for examining ultrastructural details of tissues at a very high resolution. While electron microscopy can provide detailed information, it is not routinely used for identifying microcalcifications in breast tissue.
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Reference: Microcalcifications
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Reference: Microcalcifications
Board review style question #3
A 49 year old woman is seen for bilateral breast tenderness. She is not pregnant or on hormone therapy. Mammography of the left breast revealed grouped punctate and indistinct calcifications measuring 6 mm at 12 o'clock position and 5 cm from the nipple, BIRADS 4A. No lesions are seen in the right breast. A follow up biopsy is shown above. IHC showed heterogenous ER staining and positive CK5/6. What is the most likely diagnosis?
- DCIS with microcalcifications
- Fat necrosis with microcalcificatons
- Invasive ductal carcinoma with microcalcificatons
- Usual ductal hyperplasia with microcalcifications
Board review style answer #3
D. Usual ductal hyperplasia with microcalcifications. The histology shows benign appearing hyperplastic ductal cells admixed with myoepithelial cells with associated microcalcifications. Answer A is incorrect because of the presence of myoepithelial cells and heterogenous ER staining. In DCIS, ER is diffuse strong positive. Answer C is incorrect because the cells appear benign with myoepithelial cells admixed with the ductal cells. Myoepithelial cells are absent in invasive breast cancer. Also, radiology had a low suspicion for malignancy. Answer D is incorrect because fat necrosis usually follows trauma and consists of cystic spaces surrounded by lipid laden (foamy) macrophages. Though histiocytes can be seen in this picture the more appropriate diagnosis is usual ductal hyperplasia.
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Reference: Microcalcifications
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Reference: Microcalcifications
Microcalcifications
Table of Contents
Definition / general | Terminology | Epidemiology | Etiology | Clinical features | Radiology description | Radiology images | Case reports | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Differential diagnosis | Additional referencesDefinition / general
- Deposits of calcium in breast tissue visible on mammographic imaging
Terminology
- Microcalcifications are either calcium phosphate (basophilic, nonbirefringent) or calcium oxalate (seen with polarized microscopy, not H&E, Am J Surg Pathol 1990;14:961, Arch Pathol Lab Med 1989;113:1367, Mod Pathol 1992;5:146)
Epidemiology
- Can occur at any age but more common after menopause
Etiology
- Can be associated with both benign and malignant lesions
Clinical features
- Presence of microcalcifications on mammography has led to detection of breast tumors as small as 1 - 2 mm
- Microcalcifications are present in 50% of carcinomas versus 20% of benign breast disease but only 20% of "suspicious" microcalcifications are actually part of a malignant process
Radiology description
- Suspicious microcalcifications are irregular and fine; nonsuspicious are coarse and chunky
- Pathologists must detect microcalcifications in glass slides that correspond to those in radiographs - if not present, submit additional tissue, obtain additional levels or use polarized microscopy to look for calcium oxalate (Pathologica 2007;99:5)
- Exhaustive searching for microcalcifications yields a small increase in specific diagnostic information but with a high technical cost (Mod Pathol 2001;14:350)
- Note: microcalcifications may be missing from biopsy due to retrieval failure (Radiology 2006;239:61)
- Note: recommended to examine all vacuum assisted breast biopsy specimens histologically, even those without microcalcifications (Eur Radiol 2008;18:925)
- Detection of calcium phosphate microcalcifications is reduced with glyoxal fixative (Hum Pathol 2004;35:1058)
Radiologic BI-RADS (Breast Imaging Reporting and Data System of American College of Radiology) classification:
- Category 0 - need additional imaging evaluation
- Category 1 - negative
- Category 2 - benign finding
- Category 3 - probably benign finding - short term interval follow up suggested
- Category 4 - suspicious abnormality - biopsy should be considered
- Category 5 - highly suggestive of malignancy - appropriate action should be taken
- References: American College of Radiology: ACR BI-RADS® Atlas, Fifth Edition, 2013
- Suggested that radiologists subcategorize BI-RADS 4 as 4A (low suspicion for malignancy), 4B (intermediate suspicion of malignancy) and 4C (moderate concern but not classic for malignancy, Breast J 2010;16:28)
LeGal classification of microcalcifications
- Type 1 - annular
- Type 2 - regularly punctiform
- Type 3 - too fine for precizing the shape
- Type 4 - irregularly punctiform
- Type 5 - vermicular (Bull Cancer 1984;71:57)
Radiology images
Images hosted on other servers:
DCIS
Case reports
- 61 year old woman with suspicious mammographic calcifications (Case of the Week #25)
- Gold salts within intramammary nodes may simulate microcalcifications (Hum Pathol 1988;19:992)
Microscopic (histologic) description
- Calcium phosphate microcalcifications are associated with benign and malignant disease; are blue / purple psammoma like chunks
- Calcium oxalate crystals are typically within benign cysts or terminal ductules that are histologically apocrine or GCDFP-15 positive; are associated with LCIS but only rarely with invasive carcinoma (Am J Surg Pathol 1991;15:586)
- Calcium oxalate crystals may be present in centrifuged fixative (Am J Surg Pathol 1997;21:255)
Microscopic (histologic) images
AFIP images
Calcium oxalate calcifications
With polarized light
Without polarized light
Benign lesions with microcalcifications
ADH
Sclerosing adenosis
Images hosted on other servers:
Benign lesions with microcalcifications:
Mucocele-like lesion
Positive stains
- von Kossa for calcium phosphate
Differential diagnosis
- FloSeal hemostatic sealant (AJR Am J Roentgenol 2008;191:1371): mimics malignant calcifications
Additional references
Microcysts
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Round to ovoid fluid filled structures of variable size lined by bland epithelium, part of nonproliferative fibrocystic changes
Essential features
- Very common nonproliferative fibrocystic change
- Round to ovoid fluid filled cysts lined by flat, cuboidal or columnar cells that may be attenuated and denuded
- Cysts alone do not increase risk of breast cancer
Terminology
- Blue dome cysts: based on gross appearance
- Type 1 cysts:
- Na/K ratio of 3 or less: increased breast cancer risk; associated with higher levels of estrogen, melatonin, epidermal growth factor and DHEA-S and lower levels of TGF-B2 than type 2 cysts (Breast Cancer Res Treat 2007;103:331)
- Type 2 cysts:
- Na/K above 3: reduced breast cancer risk, although patients may have both types of cysts and type 2 cysts can be associated with cancer (Breast 2005;14:37)
- Microcysts: seen during imaging or microscopic exam; not palpable
- Macro or gross cysts: large enough to be palpated
Note:
- Type 1 and type 2 terminology is not commonly used
ICD coding
Epidemiology
- Most common nonproliferative change in breast along with metaplastic changes
- Any age
- 20 - 25% of palpable breast abnormalities that underwent fine needle aspiration were simple cysts (Cancer 2001;93:263)
- Prevalence estimated between 50 - 90% (Breast Cancer Res Treat 2006;97:115)
Sites
- Usually multifocal and bilateral
Pathophysiology
- Arises in the terminal ductal lobular unit (TDLU) → dilation and coalescence of lobular acini
- Gross cysts defined by Haagensen are palpable (Cancer 1989;63:2156)
Etiology
- Unknown
Clinical features
- Large cysts may present as a palpable mass
Diagnosis
- Fine needle aspiration:
- Mass disappears after aspiration and the fluid is nonbloody, yellow or green and serous, no further workup necessary (Can Fam Physician 2012;58:1240)
- Further workup starting with imaging required after aspiration if no fluid, bloody or tenacious fluid or mass persists (Am Fam Physician 2003;68:1983)
- Bloody or cloudy or turbid fluid should be sent for cytopathology review
Radiology description
- Mammography: low density, circumscribed, round, oval or occasionally lobulated masses
- Amorphous, round microcalcifications may be present (Radiol Clin North Am 2010;48:931)
- Ultrasound: avascular, anechoic, oval or round mass with posterior enhancement, cyst flattens with compression, thin septations may be present (Radiol Clin North Am 2010;48:931)
- MRI: no contrast enhancement, hypointense on T1 and hyperintense on T2 (Radiol Clin North Am 2010;48:931)
Radiology images
Contributed by Kristen E. Muller, D.O.
Hypoechoic mass, ultrasound
Circumscribed mass, mammogram
Prognostic factors
- Cysts alone: no increased risk of breast cancer (J Natl Cancer Inst 1978;61:1055, Arch Pathol Lab Med 1998;122:1053, N Engl J Med 1985;312:146)
- Cysts and family history of breast cancer, relative risk = 2.7 times higher (N Engl J Med 1985;312:146)
- Gross cysts: may be associated with slight (relative risk = 1.6) increased risk of breast cancer (N Engl J Med 1985;312:146, J Natl Cancer Inst 2004;96:616)
Case reports
- 37 year old man with breast cyst (Cureus 2019;11:e4814)
- 58 year old man with breast cyst (J Radiol Case Rep 2011;5:35)
- 3 family members with autosomal dominant polycystic kidney disease and breast cysts (Iran J Kidney Dis 2009;3:246)
Treatment
- Aspiration / decompression if symptomatic or for diagnostic purposes (See Diagnosis section)
Gross description
- Variable size, usually visible grossly, contains clear, straw colored or brown fluid
- Larger intact cysts may appear blue (blue domed cyst) (Breast Cancer Res Treat 2006;97:115)
Gross images
Contributed by Kristen E. Muller, D.O. and AFIP images
Numerous grossly visible cysts
Large hemorrhagic cysts
Images hosted on other servers:
Unopened cyst
Extensive cystic disease
Microscopic (histologic) description
- Dilated glands lined by flat cuboidal or columnar cells
- Epithelium layer may be attenuated or absent
- Cyst wall may show dense fibrosis and scattered inflammatory cells
- May rupture and elicit inflammatory response with foamy macrophages, cholesterol clefts and fibrosis (Breast Cancer Res Treat 2002;75:213, Breast Cancer Res Treat 2006;97:115)
Microscopic (histologic) images
Contributed by Kristen E. Muller, D.O.
Simple epithelial lining
Flattened epithelial lining
Denuded epithelial lining
Cysts, columnar cell change
Surrounding fibrosis and inflammation
Ruptured cyst
Cluster of microcysts
Cytology description
- Hypocellular aspirate, macrophages with other inflammatory cells, with or without few clusters of benign ductal epithelial and myoepithelial cells (Patholog Res Int 2011;2011:547580)
- Prior rupture of the cyst may result in turbid or milky fluid, degenerated cells and debris in an abundant background of inflammatory cells (Patholog Res Int 2011;2011:547580)
Cytology images
Contributed by Kristen E. Muller, D.O.
Predominantly debris, cell block
Hypocellular specimen, LBP
Sample pathology report
- Left breast, 2 o’clock, 1 cm from nipple, core needle biopsy:
- Benign breast tissue with fragments of cyst wall with surrounding fibrosis and chronic inflammation
Differential diagnosis
- Flat epithelial atypia:
- Low grade monomorphic cytologic atypia, cells lack polarity, apical tufting, increased N/C ratios, round nuclei with variably prominent nucleoli
- Cystic hypersecretory hyperplasia:
- Colloid-like secretions
- Duct ectasia:
- Elastic tissue in wall, macrophages in lumen and epithelium
- Ductal carcinoma in situ, clinging type:
- Typically high grade cytologic atypia, central necrosis
- Mucocele-like lesion:
- Cysts and dilated ducts are filled with mucin frequently with extravasated acellular mucin in periductal stroma
- May be associated with ADH
- Juvenile papillomatosis:
- Microcysts may be present, however, in addition, there is florid epithelial hyperplasia and papillomatosis
Board review style question #1
The findings pictured are from a 38 year old woman with a cystic breast mass. What is the diagnosis?
- Atypical ductal hyperplasia
- Cysts
- Duct ectasia
- Flat epithelial atypia
- Lymphocytic mastitis
Board review style answer #1
Board review style question #2
The findings pictured are from a 67 year old woman with a palpable breast mass. Ultrasound showed a complex cystic and solid mass. What is the diagnosis?
- Duct ectasia
- Ductal carcinoma in situ
- Granulomatous mastitis
- Ruptured cyst wall
Board review style answer #2
Microglandular adenosis
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Negative stains | Electron microscopy description | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Rare benign lesion composed of haphazard, irregularly distributed, small, uniform, rounded, open glands with eosinophilic secretions
- Mimics invasive carcinoma due to infiltrative stromal growth and single epithelial layer devoid of myoepithelium
Essential features
- Disordered proliferation of small open glands comprised of bland epithelial cells
- Retains basement membrane but lacks myoepithelium
- Infiltrates adipose and fibrous stroma without a stromal response
- S100+, ER-, PR-
- Potential precursor to triple negative invasive breast cancer
Terminology
- Microglandular adenosis (MGA)
- Less frequently referred to as:
- Microglandular hyperplasia
- Microglandular adenoma
ICD coding
Epidemiology
- Rare, represented in case reports and series and small studies
- No specific known epidemiologic associations (reported in women over a wide age range)
Sites
- No specific location in breast
Pathophysiology
- Gain of somatic mutations including TP53, PIK3CA pathway related and tyrosine kinase receptor signaling elated genes have been identified in MGA and MGA associated triple negative breast cancers, supporting a role as a nonobligate cancer precursor (J Pathol 2016;238:677)
Etiology
- Unknown
Clinical features
- Can present as a thickening, palpable mass or no clinical abnormality (seen on imaging only or incidental finding)
Diagnosis
- Histologic examination of tissue often with immunostains performed
Radiology description
- Mammographic density or calcifications
Radiology images
Contributed by Julie M. Jorns, M.D.
Mammographic density: MGA / atypical MGA
Prognostic factors
- Benign although has been associated with carcinoma in 27% of cases (Am J Surg Pathol 1986;10:237)
- Transition to invasive carcinoma (with immunohistochemical profile similar to microglandular adenosis)
- Associated carcinomas include adenoid cystic, secretory and squamous, matrix producing and triple negative, basal-like carcinomas (Int J Surg Pathol 2000;8:303, Am J Surg Pathol 2009;33:496, Am J Surg Pathol 2003;27:1052, Hoda: Rosen's Breast Pathology, 4th Edition, 2014, Hum Pathol 2019;85:65, Histopathology 2009;55:732, J Pathol 2016;238:677)
- Higher risk of progression to carcinoma if atypical features are present
Case reports
- 57 year old woman with atypical microglandular adenosis postneoadjuvant chemotherapy (Pathology 2016;48:S75)
- 73 year old woman with mammary carcinoma arising in microglandular adenosis (Arch Pathol Lab Med 2003;127:77)
- Microglandular adenosis of the breast: fine needle aspiration biopsy of 2 cases (Diagn Cytopathol 1993;9:72)
Treatment
- Complete excision to rule out invasion and close followup, particularly if atypical features (Am J Surg Pathol 2008;32:544, Am J Surg Pathol 1983;7:137)
- May recur if incompletely excised
- Wide excision with documented negative margins is advised in atypical microglandular adenosis (Arch Pathol Lab Med 2007;131:1397)
Gross description
- Indiscernible from surrounding tissue
- Mass / nodule: more frequently identified with coexisting carcinoma
- Ill defined margins
Microscopic (histologic) description
- Haphazardly infiltrating collection of small, uniform, rounded, open glands with eosinophilic secretions, irregularly distributed in fibrous or adipose tissue
- Glands lined by single layer of cuboidal / flat cells with vacuolated / granular cytoplasm and bland nuclei
- No apocrine snouts, no nucleoli, no myoepithelial layer but thick basement membrane
- Atypical microglandular adenosis:
- Increased complexity including multilayered epithelium, fused glandular units, luminal bridging, cribriform architecture
- Mild cytologic atypia, hyperchromatic nuclei, prominent nucleoli, occasional mitotic figures (WHO Classification of Tumours Editorial Board: Breast Tumours (Medicine), 5th Edition, 2019)
Microscopic (histologic) images
Contributed by Julie M. Jorns, M.D.
Scattered round glands
Eosinophilic secretions
PAS
S100
p63
With atypia, cribriforming
With atypia, complex architecture
With atypia, S100
With atypia, collagen IV
Cytology description
- Sparse cellularity, monotonous population of medium sized cells with vacuolated clear cytoplasm, round and uniform nuclei, small nucleoli
- Also clear cells that are solitary or clustered with spindly fibroblasts (Diagn Cytopathol 1993;9:72)
Positive stains
- CAM 5.2, AE1, S100, p63 (secretory epithelium) (Arch Pathol Lab Med 2007;131:1397, Histopathology 2005;47:611)
- CK8 / CK18 and EGFR (Am J Surg Pathol 2008;32:544)
- PAS+ diastase resistant secretions
- Variable smooth muscle actin, vimentin, type IV collagen and laminin (around glands)
Negative stains
Electron microscopy description
- Thick basement membrane around epithelium; electron lucent cytoplasm, sparse organelles (Am J Surg Pathol 1983;7:731)
Molecular / cytogenetics description
- Clonal in some cases, array CGH and sequencing studies demonstrate molecular progression to matched invasive carcinoma, supports the role of MGA as a nonobligate precursor to triple negative breast cancer (Hum Pathol 2019;85:65, Histopathology 2012;60:E115)
- Mutations in PI3K pathway (PIK3CA, PTEN, INPP4B and BRCA1) in MGA and atypical MGA (Mod Pathol 2017;30:69)
Sample pathology report
- Right breast, core biopsy:
- Microglandular adenosis (MGA) (see comment)
- Comment: Immunohistochemistry shows the lesion to be S100 positive (diffusely, strongly), estrogen receptor negative and to lack myopithelium via p63 and calponin, supporting the diagnosis. Controls are appropriate.
Differential diagnosis
- Well differentiated invasive ductal carcinoma:
- Tubular carcinoma:
- Stellate growth pattern, desmoplastic stroma, glands vary in size and shape with angulated tear drop appearance
- Lined by cells with prominent apical snouts
- Also lacks a surrounding basement membrane
- EMA+, S100- (Arch Pathol Lab Med 2007;131:1397)
- ER+, PR+
- MGA associated invasive carcinoma:
- Infiltrative, irregular glands with moderate severe atypia and desmoplastic response
- S100 variable, ER-, PR-, HER2- (Arch Pathol Lab Med 2020;144:42)
- Apocrine adenosis:
- Larger glands lined by luminal tall columnar cells with apocrine features and surrounded by flat myoepithelial cells
- Sclerosing adenosis:
- Benign lobules with glands distorted by fibrosis but surrounded by a myoepithelial layer
- In situ carcinoma:
- Proliferation of atypical epithelial cells with preserved basement membrane and myoepithelial
Additional references
Board review style question #1
- The pictured lesion shows 3 regions in a breast core biopsy. What is the expected biomarker profile of the invasive carcinoma?
- ER-, PR-, HER2-
- ER+, PR-, HER2-
- ER+, PR+, HER2-
- ER+, PR+, HER2+
Board review style answer #1
A. ER-, PR-, HER2-. The pictured lesion is microglandular adenosis (MGA) with associated invasive carcinoma, which is supported by S100 positivity in the MGA. Both MGA and associated carcinomas are most frequently ER-, PR- and HER2- (triple negative).
Comment Here
Reference: Microglandular adenosis of breast
Comment Here
Reference: Microglandular adenosis of breast
Board review style question #2
- What is a feature that is characteristic of atypical microglandular adenosis (versus typical microglandular adenosis)?
- Bland cytology
- Fused / cribriform glands
- Intraluminal secretions
- S100 positivity
Board review style answer #2
B. Fused / cribriform glands. Typical microglandular adenosis (MGA) is characterized by haphazardly infiltrative tubules with characteristic luminal secretions and lined by a single layer of bland epithelial cells. Atypical forms have atypical cytology and architecture, including multilayered epithelium, gland fusion and cribriform architecture. Atypical MGA may not have as prominent secretions as in more typical forms. Both typical and atypical MGA are S100 (diffusely, strongly) positive.
Comment Here
Reference: Microglandular adenosis of breast
Comment Here
Reference: Microglandular adenosis of breast
Microinvasive
Table of Contents
Definition / general | Terminology | Epidemiology | Clinical features | Treatment | Microscopic (histologic) description | Microscopic (histologic) images | Negative stains | Additional referencesDefinition / general
- Dominant lesion is not invasive, but there are 1+ separate small, microscopic foci of infiltration, each 1 mm or less in size
Terminology
- “Minimal breast carcinoma” includes microinvasive carcinoma and DCIS
- Can confirm using myoepithelial stains (myoepithelial layer is not intact) and keratin (to observe infiltrative growth)
- Diagnosis requires certainty of invasion; if doubt remains after recuts and immunostains, call DCIS or suspicious
Epidemiology
- Mean age 61 years
Clinical features
- Less than 1% of all breast cancers
- Usually detected by mammography due to abnormal calcifications in associated DCIS
- 72% associated with comedo DCIS, 89% with high nuclear grade and 89% with necrosis
- Sentinel lymph node dissection may be appropriate, although axillary nodal metastases occur in less than 10% (Breast J 2008;14:335, Breast 2008;17:395); controversial whether to perform complete axillary dissection if positive sentinel node (yes - Breast 2007;16:146, no - Am J Surg 2007;194:845)
- Commonly misdiagnosed, as true diagnosis is usually DCIS or T1a carcinoma (Cancer 2000;88:1403)
- In breast core needle biopsies, invasive carcinomas 1 mm or less are rare, are associated with DCIS and ADH, and often with large invasive foci at excision (Arch Pathol Lab Med 2004;128:996)
- Report number of foci of invasion, size of largest focus
Treatment
- Cure rate is close to 100% with surgical excision (Ann Oncol 2004;15:1633)
- Prognosis may depend on features of DCIS (Am J Surg Pathol 2000;24:422)
- Natural history closely resembles that of DCIS; thus, microinvasion alone should not be the sole criterion for more aggressive treatment (Int J Radiat Oncol Biol Phys 2012;82:7)
Microscopic (histologic) description
- Usually ductal, rarely tubular or lobular morphology
- Nodules of invading neoplastic cells in periductal or perilobular stroma, none exceeding 1.0 mm
- Usually arises in background of high grade DCIS; stromal microinvasion typically associated with fibroblast proliferation, collagenization and focal inflammation
- False positives: lobular cancerization, radial scar, sclerosing adenosis (Arch Pathol Lab Med 2001;125:1259)
- False negatives: masking of invasion by inflammatory cells or histiocytes; use cytokeratin to highlight tumor cells
Microscopic (histologic) images
Images hosted on other servers:
Invasive carcinoma (arrow) < 1 mm, surrounded by DCIS
Figures 1, 2 and 3
Figure 1
Negative stains
- Myoepithelial layer is not intact in invasive component (detected with smooth muscle myosin heavy chain, smooth muscle actin, calponin, p63)
Additional references
Micropapillary
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Negative stains | Electron microscopy description | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Micropapillary carcinoma is characterized by pseudopapillary, tubular and morular epithelial structures with inside out growth pattern (WHO Classification of Tumours Editorial Board: Breast Tumours, 5th Edition, 2019)
- Micropapillae are composed of cell clusters with inverted polarity floating in empty spaces and often separated by delicate strands of fibrous stroma (Am J Clin Pathol 2004;121:857)
- First described by Fisher et al. as exfoliative appearance (Am J Clin Pathol 1980;73:313)
- Micropapillary carcinoma terminology first used by Tavassoli (Mod Pathol 1993;6:660)
Essential features
- Pseudopapillae, morulae or tubules with inside out growth pattern characterized by reverse polarity of cells
Terminology
- Invasive micropapillary carcinoma: > 90% of invasive component consists of micropapillary carcinoma
- Also acceptable: micropapillary carcinoma (WHO Classification of Tumours Editorial Board: Breast Tumours, 5th Edition, 2019)
- Invasive breast carcinoma with micropapillary component: micropapillary pattern is present in association with other histologic types (more common)
ICD coding
Epidemiology
- < 2 - 8% of all breast cancers (Mod Pathol 2018;31:956)
- Pure micropapillary carcinoma is rare, 0.9 - 2% of all breast cancers; often admixed with other histologic subtypes
- Reported median age: 50 - 62 years
- Mean age: 59 years; range: 25 - 92 years
- Also described in male breast (Breast Care 2018;13:192)
Sites
- Breast parenchyma
Pathophysiology
- Upregulation of several nutrient transporters, such as glucose transporter 1 (GLUT1) via the activation of a transcription factor, hypoxia-inducible factor (Histol Histopathol 2019;34:1009)
- Frequent overexpression of MUC4 (cytoplasmic) (BMC Cancer 2017;17:895)
- Plakoglobin, a key component in cell adhesion, promotes metastasis and downregulates apoptosis in the cell clusters through activation of PI3K / Akt / BCL2 signaling (J Cancer 2019;10:2800)
- Tumor infiltrating lymphocytes usually lack cytotoxic phenotype (Mod Pathol 2008;21:1101)
- Low expression of Fas and FasL in lymphocytes (Mod Pathol 2008;21:1101)
- Increased expression of CD146 and microvessel density (Pathol Res Pract 2011;207:739)
- Overexpression of beta1 integrin and the resultant upregulation of Rac1 contribute to polarity reversal and metastasis (Mod Pathol 2004;17:1045, Oncotarget 2017;9:4338)
- Increase in CD44+ / CD24-/low tumor cells (Pathol Res Pract 2010;206:828, Arch Pathol Lab Med 2016;140:799)
- Sialyl Lewis X / CD15s, the ligand of E-selectin, also exhibits reversed cell polarity in these tumors (Int J Surg Pathol 2010;18:193)
Etiology
- Unknown
Clinical features
- Almost 90% present as a palpable mass
- Radiologic findings, locations and gross features similar to conventional invasive breast carcinoma (BMC Cancer 2017;17:839)
- Aggressive clinical presentation with large tumor size (often T2), frequent positive lymph nodes at initial presentation and advanced stage when compared with invasive ductal carcinoma (Cancer Med 2017;6:2775)
- Mean size: 1.5 - 3.9 cm
- Frequent and higher number of axillary nodal metastasis (44 - 85%) at initial diagnosis
Diagnosis
- Tissue biopsy or surgical resection
Radiology description
- Multiple lesions, accompanying nonmass enhancement and axillary lymph node enlargement
- Irregular spiculated mass on mammogram
- Irregular hypoechoic mass with spiculated margins and posterior acoustic shadowing on ultrasound
- Irregular mass with washout kinetics and diffuse heterogeneous mass-like enhancement in MRI
- Radiologists to consider axillary sonography if this entity is found in a core needle biopsy specimen (AJR Am J Roentgenol 2013;200:689)
Prognostic factors
- Traditionally, presence of micropapillary carcinoma component has been considered a poor prognostic factor; however, the data has been controversial
- Meta analysis of 14 published studies showed that presence of micropapillary carcinoma histology is an unfavorable prognostic factor for recurrence free survival and locoregional recurrence free survival (BMC Cancer 2017;17:839)
- Micropapillary carcinoma component did not significantly impact overall survival, disease specific survival and distant metastasis free survival (BMC Cancer 2017;17:839)
- Similar overall survival and better disease specific survival has been described when compared with invasive ductal carcinoma (PLoS One 2014;9:e106564)
- Other studies have reported poorer relapse free survival and overall survival with micropapillary carcinoma when compared with invasive ductal carcinoma (Int J Surg Pathol 2008;16:155, Clin Breast Cancer 2015;15:353, BMC Cancer 2017;17:839)
- Similar prognosis as other breast carcinoma subtypes if node status, tumor size and other classic prognostic markers are considered (Hum Pathol 1999;30:1459)
- Focal component found in 6% of all breast carcinomas - these cases have same poor prognosis regardless of amount of micropapillary component (Mod Pathol 2001;14:836, Am J Clin Pathol 2006;126:740)
- Exception is that presence of micropapillary pattern in mucinous / colloid carcinoma of breast may have no clinical significance (Int J Surg Pathol 2008;16:251)
- Presence of micropapillary features and retraction artifact in core biopsies predicts nodal metastases (Am J Surg Pathol 2009;33:202)
Case reports
- 35 year old woman with multifocal grade 3 invasive micropapillary carcinoma associated with metaplastic breast carcinoma (Int J Surg Pathol 2012;20:488)
- 51 year old woman with myoepithelial carcinoma and contralateral invasive micropapillary carcinoma of the breast (J Korean Surg Soc 2011;81:211)
- 60 year old man with triple positive micropapillary carcinoma with axillary lymph node involvement (Breast Care 2018;13:192)
- 66 year old man with pure invasive micropapillary carcinoma (Can J Surg 2005;48:156)
- 69 year old woman with micropapillary carcinoma associated with osteoclast giant cells (Int J Surg Pathol 2015;23:654)
Treatment
- Tumors are typically ER positive and are eligible for antiestrogen treatment
- Treatment varies depending on clinical stage (tumor size and lymph node metastasis)
Gross description
- No specific gross features; tumors with > 50% of micropapillary growth tend to be larger (mean: 6 cm) than those with lesser amount of this pattern (mean: 3.5 cm)
- Mean tumor size: 2 cm; range: 0.1 - 10 cm
- Lobulated outline
Microscopic (histologic) description
- Tufts of cells arranged in pseudopapillae, hollow tubules and morula that are surrounded by empty clear spaces formed by fibrocollagenous stroma (Arch Pathol Lab Med 2016;140:799)
- Cells show characteristic reverse polarity, also called inside out pattern, with apical surface abutting the epithelial stromal interface
- Densely cellular, with minimal stroma
- Abundant eosinophilic cytoplasm
- Nuclei around the periphery bulge with knobby / serrated appearance
- Extensive true angiolymphatic invasion (78%)
- Foci of necrosis may be present
- May have intracytoplasmic mucin
- Uncommon variant feature: psammoma bodies, microcystic dilation of lumens with cell clusters, apocrine differentiation, multinucleated giant cells (e.g. osteoclast)
- Variable histologic grade, usually grade 2 or 3
- Mucinous carcinoma can contain micropapillary component, also called mucinous micropapillary carcinoma
Microscopic (histologic) images
Contributed by Kamaljeet Singh, M.D.
Micropapillary carcinoma
Lymphovascular invasion
EMA
E-cadherin
p120
HER2 2+
HER2 3+
Mucinous micropapillary carcinoma
Mucinous hypercellular tumor
HER2+ mucinous micropapillary carcinoma
Cytology description
- Increased cellularity, angulated clusters, abortive papillae and isolated malignant cells
- Staghorn epithelial structures in 35%, giving serrated border (Pathology 2007;39:401)
- May have few malignant appearing multinucleated giant cells or focal mucin (Acta Cytol 2009;53:463)
- No fibrovascular cores (Cancer 2002;96:280)
Positive stains
- EMA, CD15s, E-cadherin and p120 catenin: inside out pattern (Arch Pathol Lab Med 2016;140:799)
- EMA and CD15s: membranous staining of tumor cells abutting stroma
- E-cadherin and p120 catenin: cup shaped basolateral membranous staining with sparing of the apical surface
- ER (70 - 94%)
- PR (50 - 84%)
- HER2:
- Reported positivity varies in different studies ranging from 10 - 30% to up to 50 - 80%
- Incomplete basolateral (cup shaped) staining (similar to E-cadherin and p120 catenin)
- GATA3
Negative stains
Electron microscopy description
- Microvilli on their cell membranes lining the outer surfaces of the cell clusters
- Secretory activity in stroma facing surface of tumor cells
Molecular / cytogenetics description
- BC-1514 (C21orf118) is commonly upregulated in the micropapillary area (BMC Cancer 2019;19:76)
- CAMK2N1, CD1d, PJA2, RPL5, SAMD13, TCF4 and TXNIP are commonly downregulated in the micropapillary area (BMC Cancer 2019;19:76)
- Gains of 1q, 8q, 17q, 20q and losses of 1p, 8p, 13q, 16q and 20q (J Pathol 2008;215:398, J Pathol 2014;232:553)
- Mixed tumors have genetic profiles more similar to pure tumors than to ductal carcinoma (J Pathol 2009;218:301)
- High cyclin D1 expression, high proliferation rates and MYC (8q24) amplification (J Pathol 2008;215:398)
Sample pathology report
- Breast, right, 12:00 mass, core needle biopsy:
- Invasive breast carcinoma with micropapillary component, preliminary Nottingham (or modified Bloom-Richardson) grade 2
- Lymphovascular invasion is present
- Comment: The tumor is ER positive (90%; 3+), PR positive (50%; 3+) and HER2 (score 2+) equivocal for overexpression.
- Microscopic (optional): The sample shows a moderately differentiated carcinoma comprised of invasive ductal carcinoma and micropapillary carcinoma components.
- ±% of subtype components: This may be of particular importance if micropapillary pattern makes up the majority (> 90%) of the biopsy sample and the diagnosis of pure micropapillary carcinoma is of consideration, pending full histologic evaluation at resection.
Differential diagnosis
- Metastatic ovarian papillary serous carcinoma:
- Clinical history of ovarian tumor
- PAX8+, WT1+, GATA3-, GCDFP-15- (Hum Pathol 2008;39:666)
- Metastatic micropapillary carcinoma of nonmammary / nonovarian origin (lung, bladder):
- Breast primaries are GATA3+ and ER+, mammaglobin+, PAX8 / WT1-
- Other primaries have different patterns (Am J Surg Pathol 2009;33:1037)
- Extensive lymphovascular invasion by a primary or metastatic breast carcinoma:
- Tumor clusters do not demonstrate reverse polarity
- Mucinous carcinoma with micropapillary pattern:
- Micropapillary epithelium floating in mucin pools
Additional references
Board review style question #1
Which of the following is true regarding the pictured special subtype of breast carcinoma?
- Low stage disease is typical presentation
- Pure micropapillary carcinoma is common
- Tumor cells show circumferential HER2 staining
- Tumor cells show inside out pattern with EMA staining
- Tumor is frequently ER negative
Board review style answer #1
D. Tumor cells show inside out pattern with EMA immunostaining. The pictured lesion shows characteristic features of the micropapillary subtype of invasive breast carcinoma, which is frequently ER positive, with cup shaped basolateral HER2 immunostaining. Tumors often present at high stage with lymph node involvement. Tumor cells show reverse polarity, also known as inside out pattern with apical surface placed towards the stroma. Inside out pattern can be demonstrated by EMA staining of the apical surface.
Comment Here
Reference: Micropapillary carcinoma
Comment Here
Reference: Micropapillary carcinoma
Board review style question #2
The HER2 immunohistochemical staining pattern of tumor cells in micropapillary carcinoma of the breast is
- Apical
- Basal
- Basolateral
- Circumferential
- Cytoplasmic
Board review style answer #2
C. Basolateral. The basal and lateral surfaces of tumor cells in the micropapillary variant of invasive breast carcinoma frequently show membranous staining (cup shaped pattern). No staining is noted on the apical surface that stains with EMA.
Comment Here
Reference: Micropapillary carcinoma
Comment Here
Reference: Micropapillary carcinoma
Mixed NST
Table of Contents
Definition / general | Terminology | Clinical features | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Differential diagnosisDefinition / general
- Mixture of ductal carcinoma NOS and lobular carcinoma
Terminology
- Not part of WHO breast classification
Clinical features
- Age of onset similar to infiltrating ductal carcinoma
- Survival similar to pure ductal or lobular types
- Compared to pure ductal carcinomas, have higher rate of second primary breast cancers (World J Surg Oncol 2010;8:51, Breast Cancer Res Treat 2009;114:243)
- Compared to pure lobular carcinomas, have lower rate of synchronous contralateral breast cancer
- 4% of breast carcinomas
- 89% have DCIS, 31% have LCIS
- 41% have positive lymph nodes at diagnosis
- May have higher plasma levels of Soluble human leukocyte antigen s(HLA)-G (Anticancer Res 2012;32:1021)
Microscopic (histologic) description
- Definite features of invasive ductal carcinoma and invasive lobular carcinoma in same tumor
Microscopic (histologic) images
Images hosted on other servers:
Mixed ductal / lobular tumor
E-cadherin immunostaining of ductal components of tumor
Positive stains
- E-cadherin patterns include no staining (similar to lobular), full staining (similar to ductal) or staining of ductal areas only (Am J Clin Pathol 2001;115:85)
Differential diagnosis
- Tubulolobular carcinoma: typical areas of invasive lobular carcinoma with cords of single file cells, which merge with small round to angulated tubules with minute or undetectable lumina
- Collision of two separate neoplasms
Molecular subtypes
Table of Contents
Definition / general | Essential features | Terminology | Epidemiology | Pathophysiology | Etiology | Diagnosis | Radiology description | Prognostic factors | Treatment | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Negative stains | Molecular / cytogenetics description | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Gene expression profiling and hierarchical cluster analyses have categorized breast cancer into 4 major intrinsic subtypes with distinct molecular characteristics, risk factors, treatment effectiveness and prognosis (Nature 2000;406:747, Proc Natl Acad Sci USA 2001;98:10869, J Pathol 2010;220:263, Cancer Res 2018;78:6011)
- Traditional immunohistochemical biomarkers (ER, PR, HER2, Ki67 proliferative index) and pathologic features such as histological type and tumor grade serve as surrogates to classify tumors into molecular subtypes in clinical practice
Essential features
- Luminal subtype (subdivided into luminal A and luminal B)
- Luminal A (ER positive, PR positive, HER2 negative, Ki67 proliferative index low)
- Luminal B
- HER2 negative (ER positive, PR negative / low, HER2 negative, Ki67 proliferative index high)
- HER2 positive (ER positive, PR positive or negative, HER2 positive, Ki67 proliferative index varies)
- Triple negative subtype (ER negative, PR negative, HER2 negative)
- Umbrella term that includes basal-like (1 and 2), luminal androgen receptor positive, mesenchymal, mesenchymal stem-like and immunomodulatory
- HER2 enriched (HER2 positive; ERBB2 positive)
- ER negative, PR negative, HER2 / neu amplified or overexpressed
- Other rare subtypes: claudin low, normal breast-like
Terminology
- Intrinsic subtypes, molecular classification of breast cancer
Epidemiology
- Frequency and lifetime risk by molecular subtype and age (Cancers (Basel) 2015;7:908, Surg Oncol Clin N Am 2018;27:95)
- Lifetime risk
- Luminal A and B: 6.79%
- HER2 positive: 1.78%
- Triple negative: 1.2%
- Overall frequency
- Luminal A: 30 - 40%
- Luminal B: 20 - 30%
- HER2 positive: 12 - 20%
- Triple negative: 15 - 20%
- Molecular subtype by age
- < 40: triple negative > luminal B > HER2 > luminal A
- 40 - 59: triple negative > luminal B > HER2 > luminal A
- 60 - 69: luminal A > HER2 > luminal B > triple negative
- > 70: luminal A > luminal B and HER2 > triple negative
- Lifetime risk
- Triple negative
- Younger age, African ancestry, BRCA1 mutations (Breast Cancer Res Treat 2009;113:357)
- BRCA1, BRCA2, TP53 mutation carriers: triple negative
- 20 - 30% of triple negative patients have either BRCA1 or BRCA2 gene mutations (Ann Surg Oncol 2013;20:3254)
- BRCA1, BRCA2, TP53 mutation carriers: triple negative
- Younger age, African ancestry, BRCA1 mutations (Breast Cancer Res Treat 2009;113:357)
Pathophysiology
- Luminal
- Transformed from luminal progenitor cells (Cold Spring Harb Perspect Biol 2010;2:a003160)
- Nonobligate precursors: FEA, ADH, ER positive ductal carcinoma in situ (DCIS)
- Triple negative (Annu Rev Pathol 2022;17:181, Cell Stem Cell 2010;7:403)
- Originally thought to arise from basal stem cells
- Most likely cell of origin for nonmetaplastic triple negative breast cancer (TNBC) is an ER negative luminal progenitor cell
- TNBC with metaplastic features likely arises from the myoepithelial progenitor cells
- Defects in homologous recombination (i.e., double stranded DNA repair)
- ~15% of all TNBCs harbor deleterious germline mutations in a homologous recombination deficiency (HRD) related gene (BRCA1, BRCA2, ATM, CHK2, RAD51, PALB2, BRIP1)
- Nonobligate precursors
- Low grade: microglandular adenosis (MGA) and atypical microglandular adenosis, which contain nearly identical copy number variants and TP53 somatic variants to those seen in high grade TNBC
- High grade: ER negative ductal carcinoma in situ with basal-like phenotypes (~7% of all ductal carcinoma in situ)
- HER2 enriched (Oncologist 2002;7:2)
- HER2 is part of the epidermal growth factor (EGF) family, along with 3 other receptors: epidermal growth factor receptor HER1, HER2, HER3 and HER4
- HER2 gene is located on the long arm of chromosome 17 and encodes a 185 kDa transmembrane protein and an activator of several downstream signaling cascades, including the MAPK and PI3K pathways
Etiology
- Risk factors by subtype (Cancer Res 2018;78:6011, Int J Epidemiol 2017;46:373, Breast Cancer Res 2019;21:40)
- Luminal A and B
- Nulliparity, alcohol consumption, early menarche, use of menopausal hormones, increased BMI / weight, older age at first birth, late menopause
- For parous women, greater number of years between menarche and first birth
- Nulliparity, alcohol consumption, early menarche, use of menopausal hormones, increased BMI / weight, older age at first birth, late menopause
- Triple negative
- Ever parous (23% higher risk than nulliparous women), high BMI
- Breastfeeding might ameliorate the higher risk of triple negative breast cancer associated with parity (Ann Oncol 2015;26:2398)
- Disproportionally affects African American women and germline BRCA1 and PALB2
- HER2 enriched
- Risk factors are less well defined than luminal and triple negative subtypes
- HER2 positive / enriched tumors overexpress HER2 and genes associated with the HER2 pathway or the HER2 amplicon on 17q12
- All subtypes: family history of breast cancer, personal history of benign breast disease, smoking (women who initiate smoking before first childbirth)
- Luminal A and B
Diagnosis
- Luminal (subdivided into luminal A and B)
- Luminal A (ER positive, PR positive, HER2 negative, Ki67 proliferative index low)
- Luminal B, HER2 negative (ER positive, PR negative / low, HER2 negative, Ki67 proliferative index high)
- Luminal B, HER2 positive (ER positive, PR positive or negative, HER2 positive, Ki67 proliferative index varies)
- Triple negative (ER negative, PR negative, HER2 negative)
- Umbrella term that includes basal-like (1 and 2), luminal androgen receptor positive, mesenchymal, mesenchymal stem-like and immunomodulatory
- HER2 enriched (ERBB2 positive)
- ER negative, PR negative, HER2 amplified or overexpressed
- Invasive breast tumors that are HER2 positive (amplification via FISH testing or overexpression via IHC)
- ER negative, PR negative, HER2 amplified or overexpressed
- Reference: J Pathol 2010;220:263
Radiology description
- Imaging findings do not distinguish between molecular subtypes; however
- Luminal subtype is associated with architectural distortion
- HER2 positive subtype is more likely to be associated with mammographic calcifications
- Triple negative subtype is most likely to be associated with a mammographic mass (Ann Surg Oncol 2013;20:3247, Radiology 2008;246:367)
Prognostic factors
- Survival rate at 4 years from diagnosis (Cancer Epidemiol Biomarkers Prev 2018;27:619)
- Luminal (92.5%) > luminal HER2 positive (90.3%) > HER2 enriched (82.7%) > triple negative (77.0%)
- Local regional recurrence and distant metastasis rates by molecular subtype (Cureus 2016;8:e924)
- Local regional
- Luminal A: 2%
- Luminal B: 4%
- HER2 positive: 8%
- Triple negative: 12%
- Distant
- Luminal A: 6.4%
- Luminal B: 12.1%
- HER2 positive: 19.2%
- Triple negative: 27.4%
- Local regional
- Luminal A
- Generally low grade, indolent and slow growing, favorable prognosis
- Less frequent and less extensive lymph node involvement
- Risk of late recurrence and mortality after 10+ years from diagnosis
- ~30% of ER positive patients will eventually develop anti-estrogen resistant metastatic or locally advanced breast cancer
- Luminal B
- More aggressive clinical behavior and worse prognosis compared to luminal A
- Higher histologic grade than luminal A
- Loss of PR expression adverse prognostic factor (J Clin Oncol 2013;31:203)
- Triple negative
- Aggressive phenotype with shorter time to relapse and metastasis compared to stage matched HR positive / HER2 positive tumors, despite more aggressive therapy (Breast J 2009;15:454)
- African American women are twice as likely to die from triple negative breast cancer even when controlling for treatment, stage and socioeconomic factors (Cancer J 2021;27:8)
- Of note, a subset of TNBC with distinct histomorphology is associated with significantly better prognosis (Am J Pathol 2017;187:2133)
- Adenoid cystic carcinoma, secretory carcinoma, medullary carcinoma, low grade metaplastic carcinomas (adenosquamous carcinoma, fibromatosis-like metaplastic carcinoma)
- HER2 enriched
- Associated with aggressive biology and poor prognosis with high risk of recurrence and metastasis in the absence of targeted therapies (Science 1987;235:177)
- HER2 positivity is a predictive factor for response to anti-HER2 agents
- Anti-HER2 agents drastically improve outcomes in HER2 positive breast cancer (PLoS One 2011;6:e21030, J Clin Oncol 2023;41:1638, Lancet Oncol 2011;12:236)
Treatment
- Luminal
- Standard of care surgery and adjuvant endocrine therapy with or without irradiation (depending on surgical, pathological and clinical factors)
- Endocrine therapy for 5 - 10 years (tamoxifen, aromatase inhibitor) with or without ovarian suppression
- Duration and choice of endocrine therapy is dependent upon menopausal status at time of diagnosis
- Luminal tumors are less sensitive to chemotherapy compared to triple negative and HER2 enriched (pathologic complete response rates for neoadjuvant chemotherapy is 10 - 20% compared to 50 - 60%, respectively) (Lancet 2014;384:164)
- Neoadjuvant endocrine therapy is not widely used (Ann Surg Oncol 2017;24:418)
- Trials such as neoadjuvant aromatase inhibitor (NAOMI) therapy for ER positive breast cancer evaluate the effects of neoadjuvant aromatase inhibitor (letrozole) in postmenopausal women with stage I - III ER positive, HER2 negative breast cancer
- The NCCN Guidelines allow for the use of breast conserving surgery (pathologically negative margin required) with 5 years of tamoxifen or an aromatase inhibitor, without breast irradiation, for patients over 70 years of age with clinically negative lymph nodes and ER positive T1 breast cancers
- Triple negative
- Surgery and chemotherapy with or without irradiation (depending on surgical, pathological and clinical factors)
- Endocrine therapy and anti-HER2 therapies are ineffective due to absent expression of ER, PR and HER2
- While surgery and postoperative radiation remains standard of care, chemotherapy, either in the neoadjuvant or adjuvant setting, is also recommended
- Neoadjuvant therapy is preferred in individuals with ≥ cT2 or ≥ cN1 TNBC and can be considered in those with cT1c, cN0 TNBC as well
- Pathologic complete response (pCR) is associated with extremely favorable disease free and overall survival (J Clin Oncol 2012;30:1796, Lancet 2014;384:164)
- Preferred therapeutics include anthracyclines, taxanes, antimetabolites, microtubule inhibitors, platinum based therapy, cyclophosphamide
- If recurrent / unresectable or metastatic, additional testing for
- PDL1 expression (first line) variable
- Germline BRCA1 / BRCA2 testing (second line) variable
- Directed biomarkers (i.e., MSI high, TRK, mTOR inhibitors, RET, etc.) are warranted (Oncol Lett 2021;22:512, Int J Mol Sci 2022;23:1665)
- If any are positive, the relevant targeted agents can be utilized in concert with the standard chemotherapy regimen
- In PDL1 positive TNBC, pembrolizumab and chemotherapy significantly increased event free survival in high risk early stage TNBC patients (N Engl J Med 2020;382:810)
- HER2 enriched
- Surgery, anti-HER2 agents and chemotherapy with or without irradiation (depending on surgical, pathological and clinical factors)
- Neoadjuvant therapy may be employed; pathologic complete response (pCR) in HER2 positive (nonluminal) tumors is associated with excellent prognosis (J Clin Oncol 2012;30:1796, Cancer Treat Rev 2020;84:101965)
- Chemotherapy and anti-HER2 agents (i.e., trastuzumab / Herceptin®, pertuzumab / Perjeta®) show marked clinical benefit for HER2 positive patients (N Engl J Med 2005;353:1659, Lancet Oncol 2011;12:236, Lancet 2017;389:1195)
- Patients may develop de novo and acquired resistance to anti-HER2 agents (Front Oncol 2012;2:62)
- Additional agents for advanced HER2 positive breast cancer include neratinib, lapatinib and T-DM1 (Am J Cancer Res 2020;10:1045, Cancer 2020;126:4278)
Microscopic (histologic) description
- Luminal
- Invasive ductal carcinoma, no special type (IDC, NST)
- Also tubular, mucinous, invasive lobular carcinoma (classic and variants), cribriform, invasive carcinoma with neuroendocrine differentiation, micropapillary, some apocrine / oncocytic carcinomas
- Luminal A: IDC, NST, grade 1 or 2
- ER positive, PR positive, HER2 negative, Ki67 low
- Luminal B: IDC, NST, grade 2 or 3
- ER positive, HER2 positive (Ki67 and PR can show any degree of expression)
- ER positive, PR negative or low, HER2 negative, Ki67 high
- Luminal A: IDC, NST, grade 1 or 2
- Triple negative (J Pathol 2008;216:141, Breast Care (Basel) 2020;15:327, Semin Cancer Biol 2021;72:136)
- ER negative, PR negative, HER2 negative, includes high and low grade tumors
- High grade TNBC: IDC, NST grade 3, spindle cell metaplastic breast carcinoma, medullary carcinoma, apocrine carcinoma
- Low grade TNBC: salivary gland-like tumors (secretory carcinoma, adenoid cystic carcinoma, acinic cell carcinoma, mucoepidermoid carcinoma), tall cell carcinoma with reverse polarity, low grade metaplastic carcinomas (adenosquamous carcinoma, low grade fibromatosis-like metaplastic carcinoma)
- Broken down into basal-like type 1, basal-like type 2, mesenchymal and luminal androgen receptor
- Debated distinct subtypes include immunomodulatory (IM) (high rates of tumor infiltrating lymphocytes [TILs]) and mesenchymal stem-like (MSL) (high levels of tumor associated mesenchymal tissue)
- Immunomodulatory and mesenchymal stem-like characteristics that may be present in different degrees of all TNBC subtypes
- Basal-like: high grade IDC, NST, solid tumor growth with pushing borders, geographic necrosis, nuclear pleomorphism, brisk inflammatory infiltrate, high mitotic index, high Ki67
- Most express basal cytokeratins (keratin 5/6, 14, 17) and EGFR
- Medullary (immunomodulatory), metaplastic (mesenchymal and mesenchymal stem-like), adenoid cystic, acinic cell, secretory carcinoma
- Molecular apocrine: invasive lobular carcinoma (ILC) (pleomorphic), apocrine
- Breast carcinomas with apocrine differentiation may cluster into several intrinsic subtypes, including luminal (ER positive), HER2 enriched and molecular apocrine (also known as luminal AR)
- ER negative, PR negative, HER2 negative, includes high and low grade tumors
- HER2 enriched
- Predominantly IDC, NST of high histological grade
- Tumor cells frequently have pleomorphic nuclei and more abundant eosinophilic cytoplasm than triple negative cancers
- Ki67 proliferative rate is high (20 - 60%)
- Frequently associated with high grade comedo ductal carcinoma in situ
- Some pleomorphic invasive lobular carcinoma are HER2 positive
Microscopic (histologic) images
Contributed by Kristen E. Muller, D.O. and Evan R.J. Goyette, M.D.
Luminal A
ER positive
Luminal B
HER2 positive
TNBC basal-like
TNBC basal-like
CK5
EGFR
Positive stains
- Luminal
- Triple negative
- High molecular weight basal cytokeratins: CK5/6, CK14, CK17 (Clin Cancer Res 2007;13:4429)
- EGFR (J Lab Physicians 2015;7:79)
- TRPS1 (positive in 86% of triple negative and metaplastic carcinomas)
- GATA3 (nonmetaplastic: 51%, metaplastic: 21%)
- HER2 enriched
- Reference: Mod Pathol 2021;34:710
Negative stains
Molecular / cytogenetics description
- Luminal A (Nature 2012;490:61)
- PIK3CA (45%) > GATA3 (14%) > TP53 (12%)
- Gains 1q and 16p, loss 16q
- Luminal B (Nature 2012;490:61)
- PIK3CA (29%) and TP53 (29%) > GATA3 (15%)
- Gains 1q, 8q, 17q, 20q; losses 1p, 3q, 8p, 13q, 16q, 17p, 22q
- Triple negative (J Clin Invest 2011;121:2750, Nature 2012;490:61, PLoS One 2016;11:e0157368, Semin Cancer Biol 2021;72:136, Annu Rev Pathol 2022;17:181)
- TP53 (80%) > PIK3CA (9%) > GATA3 (2%)
- Many gains and losses across the entire genome
- Distinct gene profiles are associated with each TNBC subtype
- Basal-like 1
- Cell cycle and cell division pathways, BRCA1 / BRCA2 in minority
- Basal-like 2
- Growth factor signaling (EGFR, NGF, MET, Wnt / beta catenin)
- Luminal androgen receptor positive
- Steroid synthesis, androgen metabolism
- Mesenchymal-like
- Cell motility, cell differentiation
- Mesenchymal stem-like
- Cell motility, cell differentiation, genes associated with stem cells
- Growth factor signaling pathways (EGFR / PDGF)
- Low levels of claudin expression
- Epithelial mesenchymal transition
- Immunomodulatory
- Immune cell processes (TH1 / TH2, NK cell, B, T cell, antigen processing and presenting cytokine signaling)
- Basal-like 1
- HER2 enriched (Nature 2012;490:61)
- TP53 (72%) > PIK3CA (39%) > GATA3 (2%)
- Many gains and losses across entire genome
- HER2 / neu gene is a member of a family of genes encoding transmembrane receptors for growth factors, including epidermal growth factor receptor (EGFR), HER2, HER3 and HER4 (N Engl J Med 2005;353:1652)
- Amplification of the HER2 gene (ERBB2 gene) at the DNA level results in protein overexpression (Science 1989;244:707)
Additional references
Board review style question #1
Board review style answer #1
C. Luminal A. Invasive breast tumors classified as luminal A by gene expression profiling are typically low grade invasive ductal carcinomas. By definition, the luminal A intrinsic subtype shows strong expression of hormone receptors (ER and PR) and is negative for HER2 / neu overexpression and amplification. Special histologic subtypes that cluster with the luminal A subtype include tubular, mucinous and cribriform carcinomas. Answers A, B and D are incorrect because basal-like, HER2 enriched and luminal B tumors are characteristically high grade.
Comment Here
Reference: Molecular subtypes
Comment Here
Reference: Molecular subtypes
Board review style question #2
A 67 year old woman underwent a partial mastectomy for a breast tumor shown in the image. Microscopic sections revealed a high grade invasive ductal carcinoma growing as a solid mass with pushing borders, areas of necrosis, brisk mitoses and abundant tumor infiltrating lymphocytes. The tumor was negative for ER, PR and HER2 and was classified as basal-like by gene expression profiling. What other immunostain(s) might be positive?
- Androgen receptor (AR)
- EGFR
- KIT
- Synaptophysin
Board review style answer #2
B. EGFR. Basal-like breast cancers are typically high grade invasive ductal carcinoma of no special type that show solid tumor growth with pushing borders, geographic necrosis, nuclear pleomorphism, a brisk inflammatory infiltrate, a high mitotic index and a high proliferative index with Ki67. Most basal-like breast cancers express basal cytokeratins (keratin 5/6, 14, 17) and EGFR. Answer A is incorrect because while a minor proportion of triple negative breast cancers can express androgen receptor, the prototypical AR positive breast tumor has apocrine features (apocrine carcinoma). Answer C is incorrect because KIT is not characteristically expressed in breast carcinomas. Answer D is incorrect because synaptophysin may be expressed in breast tumors with neuroendocrine differentiation, which typically cluster within the luminal category.
Comment Here
Reference: Molecular subtypes
Comment Here
Reference: Molecular subtypes
Mucinous
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Cytology images | Positive stains | Negative stains | Electron microscopy images | Molecular / cytogenetics description | Videos | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Breast neoplasm with mucinous component that comprises > 90% of tumor, usually with favorable prognosis
Essential features
- Rare tumor occurring in older women
- Epithelial clusters that lie within secreted mucin (type A) or large sheets of tumor cells with neuroendocrine features and mucin production (type B)
- Mucinous component must be > 90% of tumor to be pure and have favorable prognosis
- ER and PR hormone receptor positive and HER2 negative (luminal A subtype)
Terminology
- Colloid carcinoma
- Mucinoid carcinoma
- Gelatinous carcinoma
- Mucoid carcinoma
- Mucinous adenocarcinoma
ICD coding
Epidemiology
- < 5% of breast carcinomas have mucinous component; of these, only 2% are pure mucinous carcinoma
- F > M, sixth through eighth decades
Sites
- Most are unifocal and can occur in any quadrant
Pathophysiology
- Occurs through ER positive pathway, though lack gains of 1q, loss of 16q and PIK3CA mutations, which are typical of low grade neoplasms (Breast 2020;49:87)
- Lesions express hormone receptors while lacking HER2 and basal markers
Etiology
- Multifactorial, with factors including hormones (early menarche, nulliparity or exogenous hormone use), genetics and diet
Clinical features
- Imaging can vary from a well circumscribed mass (more likely to be pure) to an irregular, spiculated mass (more likely to have mixed mucinous component) (Breast 2020;49:87)
- Due to potential circumscription seen on imaging, may be mistaken for benign process
Diagnosis
- More often palpable mass that appears as abnormality on mammography (StatPearls: Mucinous Breast Carcinoma [Accessed 8 January 2021])
Radiology images
Contributed by Carissa LaBoy, M.D.
Mammogram of right breast
Ultrasound of left breast
Mammogram of breast mass
Mammogram of left breast
Prognostic factors
- Prognosis dependent on extent of mucinous involvement; pure mucinous carcinoma has favorable prognosis with 10 year survival rate of 90.4% (Breast 2020;49:87)
- No prognostic significance between type A and type B
- Patients tend to have localized disease with low recurrence rate and rare involvement of axillary lymph nodes (Breast 2020;49:87)
- Component of micropapillary pattern is associated with worse prognosis, with increased rate of lymph node metastasis (Breast J 2018;24:339)
- Acellular mucin seen in postneoadjuvant chemotherapy specimens does not correlate with residual disease
- Only when residual neoplastic epithelium is identified is the patient classified as partial response and staged with residual disease by measuring the extent of extracellular mucin (Histopathology 2018;72:965)
Case reports
- 25 year old woman with slow growing mass radiologically diagnosed as fibroadenoma (Int J Surg Case Rep 2018;53:58)
- 48 year old woman with lump in right breast (Int J Surg Case Rep 2018;42:242)
- 55 year old woman with large left breast mass (Cureus 2018;10:e3606)
- 67 year old woman with swelling of the left breast (Iran J Pathol 2015;10:231)
- 75 year old woman with multiple masses in the left breast (J Med Radiat Sci 2020;67:155)
Treatment
- Surgical excision and adjuvant hormone therapy
- Cases associated with worse prognosis, such as micropapillary variant, may warrant neoadjuvant chemotherapy (Breast J 2018;24:339, Histopathology 2018;72:965)
- HER2 positivity is associated with tamoxifen resistance and should be treated with chemotherapy, anti-HER2 therapy and endocrine therapy via an aromatase inhibitor (Medicine (Baltimore) 2020;99:e20996)
Gross description
- Well circumscribed mass of variable size (from < 1 cm to > 20 cm) with gelatinous cut surface
Gross images
Contributed by Mark R. Wick, M.D.
Pure mucinous carcinoma
Images hosted on other servers:
Gross mass in the breast
Microscopic (histologic) description
- Clusters / nests of tumor cells with low or intermediate nuclear grade floating in pools of extracellular mucin
- Mucin pools separated by fibrous septa with capillaries
- Considered pure when mucinous component comprises > 90% of the tumor, which is associated with favorable prognosis
- Otherwise, tumor is mixed (mucinous component comprises 50 - 90% of tumor) or has mucinous features (mucinous component comprises < 50% of tumor), both of which have less favorable prognosis
- Capella type A: abundant extracellular mucin production with scattered small epithelial clusters, strips or cribriform structures floating in pools of mucin
- Capella type B: large sheets of tumor cells with mucin production and neuroendocrine features
- Micropapillary pattern
- Clusters of tumor cells with intermediate to high grade nuclei, occasional hobnailing and reverse polarity; more likely to be HER2 positive, which in turn has a worse prognosis (more likely to have lymph vascular space invasion and metastasis to lymph nodes) (Breast J 2018;24:339)
- PIK3CA and TP53 mutations more frequent with recurrent gains of 8q (Histopathology 2019;75:139)
Microscopic (histologic) images
Contributed by Carissa LaBoy, M.D., Mark R. Wick, M.D. and AFIP images
Type A mucinous carcinoma
Type A ER positive
Type A PR positive
Type A HER2 negative
Clusters in mucin pools
Bland epithelial cell clusters
Strips of epithelium
Type B mucinous carcinoma
Neuroendocrine
features
Grimelius stain
Grimelius stain
Virtual slides
Images hosted on other servers:
Type A, tumor clusters
Type B, neuroendocrine features
Cytology description
- Small to intermediate sized cohesive groups of epithelial cells with low grade nuclei floating within pools of extracellular mucin
- Mucinous carcinoma type B displays neuroendocrine differentiation in discohesive clusters with plasmacytoid cells with low grade nuclei (Cytopathology 2016;27:193)
- Low cellularity coupled with bland nuclear features and potentially scant background mucin can make the FNA diagnostically challenging (Arch Pathol Lab Med 2011;135:1533)
Cytology images
Images hosted on other servers:
FNA of mucinous carcinoma
Cytology smear of mucinous carcinoma
Cytospin preparation
Colloid carcinoma
Positive stains
- ER (94%), PR (80%) (Int J Surg Case Rep 2018;42:242)
- MUC2
- Type B: chromogranin, synaptophysin, neuron specific enolase (NSE) (Maedica (Bucur) 2015;10:14)
- WT1
- GATA3
Negative stains
- HER2 (up to 7% are positive) (Medicine (Baltimore) 2020;99:e20996, Int J Surg Case Rep 2018;42:242)
- AR (Breast 2020;49:87)
- MUC1 (membrane bound mucin)
Electron microscopy images
AFIP images
Cytoplasmic mucigen granules
Molecular / cytogenetics description
- Categorized as luminal A with favorable prognosis
- Lacks 1p gains and 16q losses and somatic mutations of PIK3CA and AKT1, which are common in other ER+, HER2- invasive breast carcinomas (J Natl Cancer Inst 2019;111:737)
- More often diploid (J Natl Cancer Inst 2019;111:737)
Videos
Review of mucinous carcinoma
Sample pathology report
- Left breast, needle localized lumpectomy:
- Invasive mucinous carcinoma, grade 1 (1+2+1), measuring 1.4 cm in greatest dimension (see synoptic report)
- Margins negative with invasive carcinoma > 0.5 cm from all margins
Differential diagnosis
- Mucocele-like lesion:
- Ruptured cyst with detached strips of bland epithelium lined by myoepithelial cells floating within extravasated mucin
- Mucinous cystadenocarcinoma:
- Cribriform, papillary or micropapillary carcinoma lining the cysts with mucin production
- ER and PR-
- Invasive micropapillary carcinoma:
- Nests of tumor cells floating in spaces, mucin production absent
- Metastasis:
- Correlate with clinical and radiologic history, such as colorectal, lung and gynecologic
- Expression profile dependent on origin
- Solid papillary carcinoma:
- Nests of cells with neuroendocrine features, fibrovascular cores and possible mucin production; may potentially be precursor to mucinous carcinoma
- Invasive ductal carcinoma, no special type, with mucinous features:
- Histologic features are those of pure mucinous carcinoma but mucinous component does not fulfill > 90% criteria
- May be initial diagnosis on core needle biopsy for pure mucinous carcinoma
- Due to limited material sampled on core needle biopsy, amount of mucinous component is more reliably assessed on excision specimen
Board review style question #1
What is the most likely hormone receptor profile of the above breast lesion?
- ER+, PR+, HER2-
- ER-, PR-, HER2-
- ER+, PR+, HER2+
- ER-, PR+, HER2+
Board review style answer #1
A. ER+, PR+, HER2-
Mucinous carcinomas are ER+, PR+ and largely HER2-, making them a luminal A lesion, which is associated with a favorable prognosis.
Comment Here
Reference: Breast - Mucinous
Mucinous carcinomas are ER+, PR+ and largely HER2-, making them a luminal A lesion, which is associated with a favorable prognosis.
Comment Here
Reference: Breast - Mucinous
Board review style question #2
What percentage of a breast carcinoma must have a mucinous component to be considered pure mucinous carcinoma?
- 75%
- 50 - 90%
- > 90%
- 30%
Board review style answer #2
C. > 90%
To be considered a pure mucinous carcinoma with a favorable prognosis, the mucinous component must comprise > 90% of a breast carcinoma. If it comprises 50 - 90% of the tumor, it is termed mixed. If the mucinous component is < 50%, the tumor is termed invasive ductal carcinoma with mucinous features. The latter two diagnoses do not have as favorable a diagnosis.
Comment Here
Reference: Mucinous carcinoma
To be considered a pure mucinous carcinoma with a favorable prognosis, the mucinous component must comprise > 90% of a breast carcinoma. If it comprises 50 - 90% of the tumor, it is termed mixed. If the mucinous component is < 50%, the tumor is termed invasive ductal carcinoma with mucinous features. The latter two diagnoses do not have as favorable a diagnosis.
Comment Here
Reference: Mucinous carcinoma
Mucinous cystadenocarcinoma
Table of Contents
Definition / general | Epidemiology | Case reports | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Negative stains | Differential diagnosisDefinition / general
- Very rare as primary breast tumor (< 50 cases reported)
- Carcinoma composed of tall columnar cells with basal, bland nuclei and abundant intracytoplasmic and extracytoplasmic mucin (as opposed to mucinous / colloid carcinoma with only extracellular mucin, and signet ring cell carcinoma with only intracellular mucin)
- Either grossly cystic (mucinous cystadenocarcinoma) or solid (columnar cell mucinous carcinoma)
- Resembles similar tumors of ovary, pancreas and appendix (Am J Surg Pathol 1998;22:698)
Epidemiology
- Mean age 58 - 68 years, range 49 - 96 years
Case reports
- 41 year old woman with a basal-like immunophenotype (Pathol Int 2012;62:429)
- 52 year old woman (Case Rep Oncol 2009;2:210)
- 65 year old woman whose tumor coexisted with infiltrating ductal carcinoma (Pathol Int 2004;54:781)
- 65 year old woman with primary mammary mucinous cystadenocarcinoma (Diagn Cytopathol 2012;40:624)
- 96 year old woman with mucinous cystadenocarcinoma of breast (Arch Pathol Lab Med 2003;127:1031)
- Mucinous cystadenocarcinoma of the breast with Her2 amplification (Hum Pathol 2010;41:910)
Gross description
- Multicystic, up to 19 cm
- Resembles ovarian and pancreatic cystadenocarcinoma, cystic hypersecretory carcinoma of breast
Gross images
Images hosted on other servers:
Ovary - multicystic tumor
Microscopic (histologic) description
- Cystic spaces lined by bland, tall columnar cells with abundant intracytoplasmic mucin
- Tumor cells exhibit stratification, tufting and papillary formation
- Variable cytologic atypia
- Gradual loss of intracytoplasmic mucin and transformation to eosinophilic squamoid cells that are focally invasive
- Columnar cell variant has round and convoluted glands in loose aggregates, lined by tall columnar mucinous epithelium with basal bland nuclei
- Demonstrates both intracellular and extracellular mucin
Microscopic (histologic) images
Images hosted on other servers:
Mucinous cystadenocarcinoma of breast with estrogen receptor expression
Retroperitoneal tumor
Positive stains
- CK7, Ki67 (high % of cells) and ER (rarely positive, Case Rep Oncol 2009;2:210)
Differential diagnosis
- Colloid / mucinous carcinoma: clusters of tumor cells floating in lakes of extracellular mucin
- Cystic hypersecretory carcinoma: prominent epithelial hyperplasia and eosinophilic secretions
- Metastatic tumor
Mucocele-like lesion
Table of Contents
Definition / general | Essential features | Terminology | Epidemiology | Sites | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Rare lesion characterized by dilated epithelium lined ducts filled with mucin; associated with extravasation of acellular mucin into the stroma
- Cysts lined by flat or low cuboidal epithelium
Essential features
- Characterized by extravasated acellular mucin in periductal stroma
- Although there is variable associated hyperplasia of the cyst lining in mucocele-like lesions, there are no epithelial cells floating within the luminal or extravasated mucin, which is a critical finding in distinguishing mucocele-like lesions from mucinous carcinoma of the breast
- Although originally described as a benign lesion, associations with atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS) and invasive carcinoma have been reported in several studies
- Searching for atypia when a mucocele-like lesion is present is important to exclude possibility of ADH, DCIS or invasive carcinoma
- Pure mucocele-like lesions without atypia typically have benign behavior
Terminology
- Mucocele-like lesion (MLL), mucocele-like tumor
Epidemiology
- Mean age 40 years, range 25 - 61 years (Am J Surg Pathol 1986;10:464)
Sites
- Anywhere in the breast
Etiology
- Pathogenesis is unclear but excessive mucinous secretions or ductal obstruction may be responsible
Clinical features
- Many reports have described an association between mucocele-like lesions and the simultaneous presence of ADH, DCIS or mucinous carcinoma (Hum Pathol 2016;49:33, Mod Pathol 2011;24:683, Diagn Pathol 2011;6:29, Histopathology 2013;62:894, Arch Pathol Lab Med 1991;115;137, Am J Clin Pathol 2012;138:783, N Eng J Med 2005;353:229)
- Mucin extravasation or mucocele-like lesions at core biopsy warrant radiological pathological correlation and close followup is recommended to rule out any atypical lesion (Histopathology 2009;55:609)
Diagnosis
- Diagnosis can be made on core biopsy or surgical specimen but careful evaluation of excised tissue, multiple H&E levels and clinicopathologic correlation may be helpful to rule out in situ lesions and invasive mucinous carcinoma
Radiology description
- There is no definitive test or imaging for differentiating mucocele-like lesions from other suspicious lesions
- Mammographic findings: heterogeneously dense breast tissue with mostly clustered round or pleomorphic calcifications (AJR Am J Roentgenol 2006;186:1356, AJR Am J Roentgenol 2005;185:1310)
- Ultrasonographic findings: usually multiple, oval shaped cysts with calcified or noncalcified solid areas; clustered cysts with thick septations and complex masses are associated with atypical proliferations or malignancy (Ultrasonography 2015;34:133, AJR Am J Roentgenol 2011;196:1424)
Radiology images
Images hosted on other servers:
Microcalcifications
Mucocele-like lesion with focal atypical proliferation
Pleomorphic calcifications
Palpable mass with tubular cystic structures
Prognostic factors
- Pure mucocele-like lesions without atypia are usually associated with a benign outcome (Histopathology 2013;62:894, Ultrasonography 2015;34:133, Breast J 2016;22:173)
- Risk of associated malignancy is much higher if atypia is present
Case reports
- 34 year old woman with associated ductal carcinoma in situ and mucinous carcinoma (J Korean Med Sci 2001;16:516)
- 47 year old woman with mucocele-like lesion on core biopsy (Bezmialem Science 2018;6:147-9)
- 71 year old woman with associated ductal carcinoma in situ and ductal carcinoma (J Clin Diagn Res 2016;10:ED16)
- 2 cases of mucocele-like lesions with cytologic findings that illustrate the difficulty of separating those lesions from colloid carcinoma (Am J Clin Pathol 1991; 95:875)
- Mucocele-like tumor associated with ductal carcinoma in situ diagnosed as mucinous carcinoma by fine needle aspiration cytology (Surg Today 2012;42:280)
Treatment
- Several studies have recommended close clinical followup as an alternative to surgical excision in women with a core biopsy of a mucocele-like lesion without atypia and no associated mass (Am J Clin Path 2012;138:783, Ultrasonography 2015;34:133, Ann Surg Oncol 2019;26:3478)
- Complete surgical excision recommended in certain situations where core needle biopsy reveals the presence of associated ADH / DCIS or where a mass with indistinct and irregular margins is shown by mammography or sonography (Clin Imaging 2011;35:94, Diagnostic Pathol 2011;6:29)
Microscopic (histologic) description
- Cysts and dilated ducts filled with mucin
- Mucin containing cysts that often rupture with extravasation of mucin into surrounding stroma
- Myoepithelial cells adhere to strips of cells floating in lakes of mucin
- Calcifications are often present
- Epithelium lining the cysts may show typical and atypical proliferative changes including benign / flat, hyperplasia, ADH, DCIS or mucinous carcinoma
- Microscopic examination of the entire specimen is important to rule out any atypia / malignancy
Microscopic (histologic) images
Contributed by Cansu Karakas, M.D.
Mucin filled cyst
Multiple cysts
Coarse calcifications
Extravasation of mucin
Cytology description
- Poorly cellular with cohesive clusters of bland cells in 2 dimensional sheets with abundant mucoid background, no / rare intact single tumor cells, no atypia if mucocele only (Am J Surg Pathol 1999;23:552, Am J Clin Pathol 1991; 95:875)
- Excisional biopsy is necessary to confirm diagnosis (Breast Cancer 2009;16:77)
- Most important features favoring a benign mucocele-like lesion over mucinous carcinoma on FNA are:
- Younger patient
- Cells arranged in cohesive monolayers
- No significant nuclear atypia
- Scant cellularity
- No or rare single, intact tumor cells
- Mucinous carcinomas are usually more cellular with more single tumor cells, 3 dimensional clusters, mild / moderate nuclear atypia and a solid mass by imaging (Cytopathology 2004;15:104, Acta Cytologica 2000;44:765)
Positive stains
- Mucicarmine
- PAS diastase
- Alcian blue
- At pH 2.7: positive
- At pH 0.9: equivocal
- Myoepithelial markers: smooth muscle myosin heavy chain (SMMHC), p63, calponin
Sample pathology report
- Left breast, upper outer quadrant, core needle biopsy:
- Mucocele-like lesion
Differential diagnosis
- Cystic mastopathy:
- Associated with prominent apocrine differentiation
- Florid duct ectasia with luminal mucin:
- Generally contains lipid rich material within ducts with prominent foamy histiocytes
- Mucinous carcinoma:
- Prominent luminal cell proliferation and variable number of tumor cells floating within the mucin
- Luminal cells in mucin are not associated with myoepithelial cells
- Nodular mucinosis:
- Rare lesion with accumulation of stromal mucin, typically located under or adjacent to nipple
- Can be distinguished from mucocele-like lesions by location and staining feature of mucous substance
Additional references
Board review style question #1
Which of the following statements is true about mucocele-like lesions of the breast?
- Frequently found in a retroareolar location
- Mammographically they usually form a palpable mass
- Most of the patients are elderly
- Usually benign, although they can be associated with atypia or malignancy
Board review style answer #1
D. Mucocele-like lesions are typically benign, although they can be associated with atypia or malignancy. Mucocele-lesions without atypia or carcinoma are benign lesions. The other statements are false. They can arise anywhere in the breast. They commonly present with calcifications with variable circumscribed mass on mammography. There is a wide range at presentation with mean age of 40.
Comment Here
Reference: Mucocele-like lesion (MLL) of breast
Comment Here
Reference: Mucocele-like lesion (MLL) of breast
Board review style question #2
A 35 year old woman had a mammogram showing polymorphous, grouped microcalcifications. The histologic details of the core needle biopsy are shown in the image above. Which of the following statements are true about this entity?
- CK5/6 and p63 are negative
- Likelihood of carcinoma is very high
- Mucicarmine staining is negative
- When there is a rupture to stroma, the possibility of mucinous carcinoma must always be considered
Board review style answer #2
D. When there is a rupture to stroma, the possibility of mucinous carcinoma must always be considered. A mucocele-like lesion may show CK5/6 and p63 expression and highlight the myoepithelial cells surrounding the benign cystic lining of mucocele-like lesion. Mucin in the cyst and stroma usually show strong and diffuse mucicarmine staining in mucocele-like lesion. Mucocele-like lesion without associated carcinoma is a benign lesion.
Comment Here
Reference: Mucocele-like lesion (MLL) of breast
Comment Here
Reference: Mucocele-like lesion (MLL) of breast
Mucoepidermoid
Table of Contents
Terminology | Clinical features | Case reports | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Negative stains | Electron microscopy description | Differential diagnosisTerminology
- See also adenosquamous carcinoma; also called adenoacanthoma
Clinical features
- Very rare
- Grading system used for salivary gland tumors is recommended (Virchows Arch 2004;444:13)
Case reports
- 46 year old woman with high grade tumor and axillary metastases (Arch Pathol Lab Med 1981;105:612)
- 54 year old woman with mucoepidermoid carcinoma of breast (Pathol Int 2006;56:549)
- Two low grade tumors (Arch Pathol Lab Med 1979;103:196)
- High grade and low grade tumors (Neoplasma 2007;54:168)
Microscopic (histologic) description
- Resembles salivary gland counterpart (Virchows Arch 2004;444:13)
- Mixture of neoplastic mucus secreting, squamous and intermediate cells
Microscopic (histologic) images
Images hosted on other servers:
In breast affected by burn scars
Salivary gland tumors: H&E and Alcian blue - PAS
Cytology description
High grade tumors:
- Clusters of epithelial ductal cells with mixed glandular, squamous and intermediate cells
- May be scant intra- and extracellular mucin (Acta Cytol 2006;50:344)
Positive stains
- Keratin, EMA and CEA
- Mucin is PAS+
- Have basal-like phenotype: strong and diffuse expression of CK5 / 6, p-cadherin, p63, EGFR (Appl Immunohistochem Mol Morphol 2013;21:283)
Negative stains
- ER, PR and HER2 (Mod Pathol 2010;23:951)
Electron microscopy description
- Intermediate cells are modified myoepithelial cells (Hum Pathol 1985;16:941)
Differential diagnosis
- Metastatic salivary gland tumor (Acta Cytol 2002;46:377)
Multigene products
Table of Contents
Definition / general | Essential features | Oncotype Dx® | Breast Cancer Index | EndoPredict® | MammaPrint® | PAM 50 (Prosigna)® | Mammostrat | IHC4 | Prognostic factors | Additional references | Board review style question #1 | Board review style answer #1Definition / general
- Gene expression profiles are associated with overall survival for several tumor types, including breast (N Engl J Med 2007;356:217)
- Several multigene prognostic products are commercially successful, including Oncotype DX® and MammaPrint® (Oncologist 2008;13:477, Adv Anat Pathol 2009;16:204)
- US Food and Drug Administration (FDA) has in vitro diagnostic multivariate index assay (IVDMIA) classification for these tests (US FDA: In Vitro Diagnostic Multivariate Index Assays [Accessed 10 September 2018])
- For all tests, the relationship of predicted to observed risk in different populations and their incremental contribution over conventional predictors, optimal implementation and relevance to patients receiving current therapies need further study (Ann Intern Med 2008;148:358, Ann Oncol 2007;18 Suppl 6:vi58, Genet Med 2009;11:66)
- Testing most valuable for ER+ HER2- patients (Breast 2011;20:S87)
Essential features
- New AJCC (8th edition) incorporates multigene panel results into staging, placing T1 and T2 hormone receptor positive, HER2- and lymph node negative tumors with low risk scores into the T1a-T1bN0M0 prognostic category
- Multigene panels are not currently incorporated into staging for triple negative or HER2+ tumors
- Use of these assays is not required for staging
- Oncotype DX, with Level 1 evidence, is the only assay incorporated into the Pathological Prognostic Stage Table
- No one multigene assay is preferred by the AJCC over another assay for treatment decisions
Oncotype Dx®
- ER+, HER2 - tumors, can have up to 3 involved lymph nodes
- Most widely accepted and used multigene expression assay; offered by Genomic Health
- First available in January 2004
- Measures changes in 21 genes on paraffin fixed tissue to predict likelihood of disease recurrence and which patients are most likely to respond to chemotherapy (Breast Cancer Res 2006;8:R25)
- Results in recurrence score (RS) of 0 - 100, categorized into low (< 11), intermediate (11 - 25) or high (> 25) recurrence risk
- TAILORx trial found that endocrine therapy was "noninferior" (comparable) to chemotherapy plus endocrine therapy for disease free survival in up to 85% of women with hormone receptor positive, early invasive breast cancer
- Particularly relevant for women > 50 years old with a recurrence score ≤ 25 as they may be spared adjuvant chemotherapy (N Engl J Med 2018;379:111)
Breast Cancer Index
- 11 gene assay including 4 normalization genes; offered by BioTheranostics
- Results are predictive for benefit of extended endocrine therapy and prognostic for the risk of late (> 5 years) and overall (0 - 10 years) distant recurrence following 5 years of endocrine therapy
- ER+ tumors can have up to 3 involved lymph nodes
- Breast Cancer Index prognostic score reported as continuous percentage risk of late distant recurrence (> 5 years) and Breast Cancer Index predictive score reported as categorical (low versus high) likelihood of benefit from extended endocrine therapy
- Breast Cancer Index scores resulted in a 26% net decrease in the recommendation of extended endocrine therapy (Breast Cancer Res Treat 2015;154:533)
EndoPredict®
- 12 gene expression assay, including 3 proliferation related genes, 5 hormone related, 3 normalization genes and 1 control gene for DNA contamination (Br J Cancer 2015;112:1405)
- ER+, HER2- tumors, can have up to 3 involved lymph nodes
- EPclin Risk Score integrates the 12 gene molecular score with tumor size and nodal status to categorize patients into low or high risk of distant recurrence within 10 years if treated with 5 years of endocrine therapy alone
MammaPrint®
- 70 gene assay, originally developed in 2002 to determine risk of distant metastases (Nature 2002;415:530); offered by Agendia
- Originally FDA approved in 2007, requiring fresh tissue but later FDA approved in 2015 for formalin fixed paraffin embedded tissue
- No estrogen or HER2 status restriction
- Results in binary stratification into low risk or high risk of cancer recurrence within 10 years without any adjuvant treatment (either hormonal therapy or chemotherapy)
- MINDACT trial found that 46% of women with early stage breast cancer at high clinical risk (defined as 10 year probability of breast cancer specific survival without systemic therapy of more than 88% for ER+ and more than 92% for ER- tumors as calculated by Adjuvant! Online version 8.0 [website currently under construction]) and low genomic risk for recurrence (as determined by MammaPrint low versus high risk result) may be spared adjuvant chemotherapy (N Engl J Med 2016;375:717)
PAM 50 (Prosigna)®
- Developed by NanoString, the assay measures expression profiles of 50 genes by PCR and classifies them into intrinsic subtypes (luminal A, luminal B, HER2 enriched, basal-like)
- Results in risk of recurrence score (ROR) of 0 - 100 that correlates with probability of distant recurrence within 10 years (BMC Med Genomics 2012;5:44, J Clin Oncol 2013;31:2783)
- Can be used on stage 1 or stage 2 and lymph node negative for stage 2 with 1 to 3 positive nodes
- Node negative cancers are classified as low (0 - 40), intermediate (41 - 60) or high (61 - 100) risk
- Node positive cancers are classified as low (0 - 40) or high (41 - 100) risk
- Is incorporated into the Prosigna Breast Cancer Prognostic Gene Signature Assay (BMC Med Genomics 2015;8:54)
Mammostrat
- Developed by Clarient Diagnostic Services
- IHC evaluation of the expression of five genes (p53, NDRG1, CEACAM5, SLC7A5 and HTF9C) in early stage, hormone receptor positive breast cancers to predict outcomes (J Clin Oncol 2006;24:3039)
- Subdivides patients into low, moderate and high risk, age specific groups
IHC4
- Combines semiquantitative ER, PR, HER2 and Ki67 results by immunohistochemistry in a public mathematical formula to assign a risk score (J Clin Oncol 2011;29:4273, Lancet Oncol 2013;14:1067, J Clin Oncol 2013;31:2783)
Prognostic factors
- T1 and T2, hormone receptor-positive, HER2- and lymph node negative tumors with any of the following multigene panel results:
- Oncotype Dx® recurrence score less than 11 (Level 1 Evidence)
- Breast Cancer Index in the low risk range (Level 2 Evidence)
- EndoPredict® low risk score (Level 2 Evidence)
- Mammaprint® low risk score (Level 2 Evidence)
- PAM 50® risk of recurrence score in the low range (Level 2 Evidence)
- Are placed into the same prognostic category as T1a-T1bN0M0 tumors
Additional references
Board review style question #1
- Which multigene test has been integrated into the 8th edition of AJCC staging system for breast cancer with Level 1 evidence?
- Oncotype Dx
- Breast Cancer Index
- Endopredict
- Mammaprint
- PAM 50
Board review style answer #1
A. The 21 - gene recurrence score from Oncotype Dx is incorporated into the 8th edition of AJCC staging for breast cancer based on Level 1 Evidence (large scale prospective clinical trial published data) indicating that for patients with ER positive, lymph node negative, tumors with a recurrence score < 11, prognosis is excellent.
Comment Here
Reference: Multigene products
Comment Here
Reference: Multigene products
Myoepithelioma and myoepithelial carcinoma
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Positive stains | Negative stains | Electron microscopy description | Molecular / cytogenetics description | Molecular / cytogenetics images | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1Definition / general
- Myoepithelioma: bland spindle cell lesion with myoepithelial phenotype
- Myoepithelial carcinoma: very rare malignant lesion, mostly arising in association with adenomyoepitheliomas, composed of purely malignant myoepithelial cells, primarily spindle shaped to polygonal
- Associated with myoepithelioma or adenomyoepithelioma (most frequent)
- Currently classified as metaplastic carcinoma with myoepithelial differentiation
- WHO classification of breast tumors (4th edition) has included myoepithelial carcinoma under the category of metaplastic carcinoma of no special type
Essential features
- Myoepithelioma: benign lesion comprised of cells of myoepithelial derivation
- Myoepithelial carcinoma: rare, malignant tumor of the breast comprised of cells of myoepithelial derivation
Terminology
- Myoepithelioma
- Myoepitheliosis: multifocal, often microscopic proliferation of myoepithelial cells in or around small ducts; usually an incidental finding and not palpable (Am J Surg Pathol 1991;15:554)
- Myoepithelial carcinoma (not recognized by WHO):
- Malignant myoepithelioma (not recognized by WHO) (Mol Clin Oncol 2016;4:723)
- Myoepithelial rich carcinoma (not recognized by WHO) (Histopathology 1997;30:542)
- Metaplastic carcinoma with myoepithelial differentiation
- Metaplastic carcinoma of no special type
ICD coding
- ICD-O: 8982/3 - malignant myoepithelioma
- ICD-11:
- Myoepithelioma:
- Myoepithelial carcinoma:
- 2C6Z - malignant neoplasms of breast, unspecified
- 2C6Y & XH43E6 - other specified malignant neoplasms of breast & myoepithelial carcinoma
- XH43E6 - myoepithelial carcinoma
Epidemiology
- Myoepithelioma: premenopausal and postmenopausal women; wide age range
- Myoepithelial carcinoma:
- Incidence is 15 per 100,000 population
- Mean age for myoepithelial carcinoma in breast: 50 years; range 45 - 86 years (Transl Cancer Res 2017;6:441)
Sites
- Breast, without specific site predilection
Pathophysiology
- Tumors that arise from the peripheral myoepithelial cell layer
Etiology
- Unknown
Clinical features
- Myoepithelioma is benign but may recur locally
- Myoepithelial carcinoma may recur or metastasize to regional lymph nodes or distant sites (Eur J Surg Oncol 2004;30:357)
Diagnosis
- Histologic evaluation of tissue, typically with assistance of immunohistochemistry
Radiology description
- Mammography: circumscribed or irregular, noncalcified mass
- Ultrasound: hypoechoic, irregular or oval mass with microlobulated or indistinct margins
- MRI: enhancing mass with an irregular or spiculated margin and delayed washout or plateau kinetics
- References: Breast J 2007;13:203, Taehan Yongsang Uihakhoe Chi 2020;81:207
Prognostic factors
- Myoepithelioma: can recur locally
- Myoepithelial carcinoma (Eur J Surg Oncol 2004;30:357):
- Associated with aggressive course, including recurrence and metastasis
- 2 and 5 year survival is 88% and 55%
- Increased tumor size is associated with worse outcome
Case reports
- 56 year old postmenopausal woman with a palpable mass (Breast Care (Basel) 2010;5:246)
- 57 year old woman with lump in her left breast for 4 months (South Asian J Cancer 2017;6:185)
- 58 year old postmenopausal woman with a palpable lump in the left breast with calcifications on mammogram (Clin Case Rep 2019;7:930)
- 61 year old woman with an elastic hard mass measuring 2 cm in the upper central area of the left breast (Case Rep Oncol Med 2013;2013:164761)
- 67 year old woman with myoepithelial carcinoma of the breast with focal rhabdoid features (Breast J 2013;19:100)
- 71 year old woman with local recurrence (Tunis Med 2004;82:324)
- 73 year old postmenopausal woman with a palpable and a nontender lump in the left breast (J Clin Diagn Res 2013;7:1191)
- Renal dialysis patient with benign appearing tumor with metastatic behavior (ANZ J Surg 2004;74:1135)
Treatment
- Myoepithelioma: complete surgical excision (J Cytol 2013;30:62)
- Myoepithelial carcinoma:
- Wide local excision, segmental mastectomy or total mastectomy with regional lymph node excision and radiotherapy (Mol Clin Oncol 2016;4:723)
- Role of chemotherapy is not well defined
- Platinum analogs and paclitaxel combination has shown some efficacy in few cases reported (Oncologist 2016;21:1492)
Gross description
- Well circumscribed, firm mass; irregular borders more frequent with myoepithelial carcinoma (Diagn Pathol 2008;3:7)
- Cut surface is grayish white and solid (Virchows Arch 2010;457:337)
- Larger tumors may show variable areas of cystic degeneration, hemorrhage and necrosis (myoepithelial carcinoma) (Mol Clin Oncol 2016;4:723)
Microscopic (histologic) description
- Myoepithelioma:
- Dense spindle cell neoplasm; may be arranged in storiform pattern (J Cytol 2013;30:62)
- Tumor cells have eosinophilic cytoplasm, oval and regular nuclei (J Cytol 2013;30:62)
- May have polygonal cells with clear cytoplasm and hyperchromatic nuclei (J Cytol 2013;30:62)
- May infiltrate fat or surround normal ducts (J Cytol 2013;30:62)
- Few mitotic figures, no necrosis, no atypia (J Cytol 2013;30:62, Tunis Med 2004;82:324)
- Myoepithelial carcinoma:
- Plump, atypical spindle cells with readily identifiable mitotic figures (Breast Care (Basel) 2010;5:246)
- Mitotic activity ranges from 0 to 9 mitoses per 10 high power fields (Virchows Arch 2010;457:337)
- Variable amount of necrosis and cystic degeneration (Case Rep Oncol Med 2013;2013:164761)
- Clear cell and plasmacytoid variants (very rare) (Breast 2004;13:506)
Microscopic (histologic) images
Contributed by Julie M. Jorns, M.D. and Koteeswaran Govindaswamy, M.D. (Case #407)
Myoepithelioma with adjacent benign glands
Myoepithelioma
Myoepithelial carcinoma
Myoepithelioma - p63
Myoepithelial carcinoma - p63
Myoepithelial carcinoma - CK 5/6
Myoepithelial carcinoma - pan CK
Myoepithelial carcinoma - Ki67 IHC with high Ki67 index
Myoepithelial carcinoma - tumor cells are negative for ER, positive for PR and negative for Her2Neu
Cytology description
- Cellular smears showing single spindle or polymorphic, polygonal cells with dense blue cytoplasm and admixed groups of benign ductal epithelial cells and lymphocytes (Virchows Arch 2010;457:337, Cytojournal 2007;4:3)
- Granular metachromatic stromal component in the background (Cytojournal 2007;4:3)
Cytology images
Images hosted on other servers:
Myoepithelioma FNA
Positive stains
- Myoepithelioma: broad spectrum keratin AE1 / AE3, EMA, alpha smooth muscle actin, calponin, caldesmon, vimentin, CD10, p63, S100
- Myoepithelial carcinoma:
- Strong and diffusely positive for p63, CD10, CK903 and CK5/6 (Virchows Arch 2010;457:337)
- Focal weak to diffuse positivity for calponin, S100 and SMA (Virchows Arch 2010;457:337)
- Strong positivity for EGFR (Virchows Arch 2010;457:337)
Negative stains
Electron microscopy description
- Curvilinear bundles of tonofilaments (about 8 - 10 nm in diameter) usually located in perinuclear areas or centrally located in cytoplasmic extensions (Ultrastruct Pathol 1985;8:1)
- Subplasmalemmal bundles of microfilaments (about 5 - 7 nm in diameter) in cytoplasm of many spindle cells (Ultrastruct Pathol 1985;8:1)
- Tumor cells also show pinocytic vesicles, intermediate junctions, dense plaques (hemidesmosomes) and are poorly connected by desmosomes (Ultrastruct Pathol 1985;8:1)
- Dense bodies in the microfilament bundles (Ultrastruct Pathol 1985;8:1)
- Spindle cells show fragmented external lamina (Ultrastruct Pathol 1985;8:1)
Molecular / cytogenetics description
- Loss of 16q (3/10 cases), 17p (3/10), 11q (2/10) and 16p (2/10) (Lab Invest 2000;80:831)
- Basal specific microRNAs such as miR-126, miR-127-3p, miR-143, miR-145 and miR-199a-3p are upregulated (Breast Cancer Res Treat 2011;130:735)
- Luminal specific miR-200c and miR-429 are significantly lower expressed compared to luminal A, luminal B and basal-like breast cancer (Breast Cancer Res Treat 2011;130:735)
Molecular / cytogenetics images
Images hosted on other servers:
Summary karyogram 10 cases
Sample pathology report
- Left breast, core biopsy:
- Spindle cell neoplasm (see comment)
- Comment: Histologic sections show a spindle cell neoplasm arranged in storiform pattern. The tumor cells have vesicular nuclei, prominent nucleoli, variable nuclear atypia and eosinophilic cytoplasm. Mitoses are readily identifiable (with up to 4 mitoses/10 high power fields). Focal areas of cystic degeneration and necrosis are seen. Immunohistochemistry shows tumor cells to be positive for p63 and cytokeratins 5/6 and 903 and negative for cytokeratin 7, desmin, ER, PR and HER2 / neu. Overall, findings are suggestive of metaplastic carcinoma, spindle cell type or myoepithelial carcinoma.
Differential diagnosis
- Metaplastic carcinoma:
- Variable group of breast carcinomas with mesenchymal differentiation
- Myoepithelial carcinoma is considered a subtype by WHO
- Spindle cell sarcoma:
- Negative for myoepithelial markers
- Leiomyosarcoma:
- Blunt ended nuclei with abundant cytoplasm
- Positive for desmin
- Fibromatosis:
- Infiltrative fibroblastic and myofibroblastic proliferation
- Minimal pleomorphism with no mitosis
- Positive for actin, desmin and S100
- Negative for cytokeratins
- Adenomyoepithelioma:
- Biphasic, circumscribed tumor composed of variable number of myoepithelial cells surrounding epithelial lined spaces
- Myofibroblastoma:
Additional references
Board review style question #1
Biopsy of a breast nodule showed the histology in the image above. All tumor cells are strongly and diffusely positive for p63. What is the most likely diagnosis?
- Adenoid cystic carcinoma
- Adenomyoepithelioma
- Myoepithelial carcinoma
- Myoepithelioma
Board review style answer #1
C. Myoepithelial carcinoma. The biopsy shows an atypical proliferation with plump spindle cells and readily identifiable mitoses. p63 positivity supports myoepithelial differentiation. The morphology is malignant, arguing against adenomyoepithelioma and myoepithelioma. Adenomyoepithelioma and adenoid cystic carcinoma additionally have a biphasic composition, making these answers incorrect. In this case, tumor cells are of uniform myoepithelial differentiation, making the best diagnosis myoepithelial carcinoma, which is considered a metaplastic carcinoma of no special type by the WHO.
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Reference: Myoepithelioma and myoepithelial carcinoma
Myofibroblastoma
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Cytology images | Positive stains | Negative stains | Electron microscopy description | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2 | Board review style question #3 | Board review style answer #3Definition / general
- Benign spindle cell tumor of mammary stroma composed of fibroblasts and myofibroblasts with recurrent monoallelic loss of 13q14 region including RB1
- First recognized in 1981 and described by Wagotz in 1987 (Am J Surg Pathol 1987;11:493)
- When present in mesenchymal soft tissue, termed mammary type myofibroblastoma
- Rarely involves the lower genital tract, predominantly vagina (less commonly vulva and cervix)
Essential features
- Well circumscribed spindle cell tumor comprised of short fascicles of bland spindled cells and dense hyalinized collagen bundles
- Variants include collagenized / fibrous, cellular, infiltrative, myxoid, deciduoid, epithelioid, lipomatous and atypical
- Part of 13q / Rb family of tumors, as majority show deletion or rearrangement of 13q (13q14), which may result in loss of Rb expression by immunohistochemistry
- Benign and adequately treated by excision alone
Terminology
- Mammary type myofibroblastoma
- Benign stromal spindle cell tumor with predominant myofibroblastic differentiation
ICD coding
- ICD-O: 8825/0 - myofibroblastoma
- ICD-10: D24.9 - benign neoplasm of unspecified breast
- ICD-11: 2F30 & XH3NQ0 - benign neoplasm of breast & myofibroblastoma
Epidemiology
- Breast: 25 - 87 years, F = M, predominantly seen in postmenopausal women and older men (Arch Pathol Lab Med 2008;132:1813)
- Soft tissue: median age 55 years, 80% men
- No race predilection (Arch Pathol Lab Med 2008;132:1813)
- Limited cases reported in the setting of gynecomastia (Int J Surg Pathol 2001;9:331, Oncol Rep 1998;5:731)
Sites
- Breast, can also occur in extramammary sites including vagina, vulva, inguinal / groin, abdominal wall, perineum and paratesticular region (Oncol Rep 1998;5:731, Am J Surg Pathol 2016;40:361, Am J Surg Pathol 2001;25:1022, Ann Diagn Pathol 2010;14:358)
- Soft tissue: usually subcutis but may be deeper
Pathophysiology
- Arises from CD34+ mammary stromal fibroblasts and myofibroblasts capable of multidirectional mesenchymal differentiation (Ultrastruct Pathol 1999;23:249)
- Some debate exists over cells of origin and differentiation, myofibroblastic versus smooth muscle (Histopathology 2003;42:233, Ultrastruct Pathol 1999;23:249)
- Part of the so called 13q / Rb family of tumors, which have deletion or rearrangement of 13q14 resulting in loss of Rb expression by immunohistochemistry (J Pathol 2000;191:282, Hum Pathol 2012;43:1887, Mod Pathol 2011;24:82)
Etiology
- Pathogenetic role of hormones has been suggested due to ER, PR and AR expression (Histopathology 2000;36:515, Hum Pathol 1998;29:347)
Clinical features
- Painless, nontender, slow growing, mobile mass
- Clinically mistaken for fibroadenoma
Diagnosis
- Imaging: ultrasound, mammogram, MRI
- Invasive procedure: biopsy, fine needle aspiration (FNA)
Radiology description
- Well circumscribed, homogenous, hyperdense or isodense, solid mass (Clin Imaging 2018;51:300)
- Typically devoid of calcifications
- Hypoechoic on ultrasound, may have posterior enhancement
- May be multilobulated
- Bilateral and multicentric tumors rare (Mod Pathol 1996;9:786, Int J Surg Pathol 2018;26:242)
Radiology images
Contributed by Kristen E. Muller, D.O.
Ultrasound, well circumscribed mass
Ultrasound, multilobulated mass
Mammogram
Mammogram, multiple masses
Prognostic factors
- Clinically benign behavior, local excision is curative
- No tendency for recurrence or distant metastasis (Virchows Arch 2002;440:249)
Case reports
- 37 year old woman with superficial myofibroblastoma in the vulva (Case Rep Pathol 2019;2019:1582714)
- 53 year old woman with epithelioid myofibroblastoma mimicking invasive lobular carcinoma (Int J Surg Pathol 2015;23:284)
- 55 year old postmenopausal woman with 2 cm mass (J Midlife Health 2018;9:47)
- 55 year old woman underwent a breast needle core biopsy after routine mammography that showed a slight interval size increase of a subcentimeter nodule (Case of the month #536)
- 61 year old man with 8 cm mass who presented first with shoulder pain (J Breast Health 2017;13:100)
- 62 year old man with giant myofibroblastoma arising in the background of gynecomastia (Malays J Med Sci 2012;19:74)
- 63 year old woman with vaginal superficial myofibroblastoma (Rom J Morphol Embryol 2007;48:165)
- 73 year old man with retroareolar mass on CT (Clin Imaging 2017;42:109)
- 74 year old man with bilateral multiple mammary myofibroblastomas (Int J Surg Pathol 2018;26:242)
- Myofibroblastoma with extensive myxoedematous stroma (Pathol Res Pract 2014;210:1106)
Treatment
- Surgical excision alone
Clinical images
Images hosted on other servers:
Myofibroblastoma in gynecomastia
15 cm tumor
Gross description
- 2 mm to 15 cm, most cases not exceeding 3 cm (Arch Pathol Lab Med 2008;132:1813, Am J Surg Pathol 1994;18:1170)
- Well circumscribed, unencapsulated solid mass
- Firm, rubbery to gelatinous, whitish gray to pink nodular or whorled cut surface
Gross images
Images hosted on other servers:
13 cm, lobulated
white cut surface
Microscopic (histologic) description
- Well circumscribed, lacks true capsule, rarely infiltrative
- Bland, uniform, short to elongated spindle cells arranged as short haphazard intersecting fascicles admixed with bands of hyalinized, brightly eosinophilic collagen and variable amounts of fat
- No more than mild nuclear atypia
- Mitoses usually absent, atypical mitoses and necrosis absent
- Mast cells common, perivascular lymphocytic infiltrates on occasion
- Focal myxoid stromal changes common
- May show smooth muscle leiomyomatous differentiation (elongated spindle cells with cigar shaped nuclei and pink cytoplasm)
- Rarely cartilaginous or osseous components
- Variants:
- Collagenized / fibrous: collagenous stroma predominates, may have hypocellular myofibroblastic spindle cell component
- Cellular: dense proliferation of myofibroblasts, ratio of spindle cells to collagen increased compared with classical variant, may have infiltrative borders, storiform or herringbone arrangement
- Infiltrative: irregular margins, grows into surrounding mammary parenchyma entrapping glandular tissue
- Myxoid: stellate and spindle cells in abundant myxoid stroma (Histol Histopathol 2016;31:1)
- Deciduoid: large round, polygonal cells with abundant eosinophilic glassy cytoplasm, single or multiple prominent nucleoli which may be eccentrically placed, binucleation, sharp cell borders, eosinophilic intracytoplasmic inclusions (Histopathology 2008;52:652)
- Lipomatous: abundant adipocytic component
- Epithelioid: oval to polygonal cells arranged in clusters, cords, alveolar groups, linear strands, mono, bi or multinucleated, may have eccentrically placed nuclei with small nucleoli, well defined cell borders, single file arrangement may mimic invasive lobular carcinoma (Am J Surg Pathol 2009;33:1085)
- Atypical: single or scattered atypical mono or multinucleated cells with mild to severe nuclear pleomorphism, regarded as degenerative (Arch Pathol Lab Med 2008;132:1813)
Microscopic (histologic) images
Contributed by Kristen E. Muller, D.O. and Victoria Jones, M.D., M.S. (Case #536)
Well circumscribed mass
Classical type
Hypocellular, collagenized / fibrous variant
Collagenized / fibrous variant
Admixed adipocytes
Lipomatous variant
Myxoid stroma
Myxoid stroma and fat
Mast cells
Cellular variant
Epithelioid variant
Epithelioid / deciduoid variant
Epithelioid with single file growth
Smooth muscle differentiation
Chondroid metaplasia
Focal cytological atypia
Lipomatous variant
Lipomatous variant
Keratin
CD34
CD34
Desmin
ER
PR
Loss Rb1
Virtual slides
Images hosted on other servers:
Breast, myofibroblastoma
Cytology description
- Bland spindle to ovoid cells with scant cytoplasm dispersed as clusters and single cells (Acta Cytol 2012;56:501, Diagn Cytopathol 2016;44:1064)
- Intranuclear inclusions and mast cells may be present
Cytology images
Images hosted on other servers:
Loosely cohesive myoepithelial cell groups
Positive stains
- Desmin (91%), vimentin, ER, PR, AR, BCL2, CD10, CD99 (Histopathology 2000;36:515, Virchows Arch 2007;450:727)
- CD34 (89%) diffuse and strong characteristic but may uncommonly show absent / focal expression (Am J Surg Pathol 2016;40:361, Breast J 2018;24:55)
- H-caldesmon if smooth muscle differentiation / leiomyomatous variant (Hum Pathol 2016;58:54, Histopathology 2003;42:233)
Negative stains
- Rb (negative in 89 - 92%) (Am J Surg Pathol 2016;40:361, Am J Surg Pathol 2012;36:1119)
- Actin (negative in 63%)
- Cytokeratins, S100, p63
Electron microscopy description
- Features of smooth muscle and myofibroblasts: rough endoplasmic reticulum, bundles of myofilaments with focal densities, intermediate filaments and attachment plaques (Pathol Res Pract 1999;195:1, Ultrastruct Pathol 1999;23:249)
Molecular / cytogenetics description
- Recurrent monoallelic loss of 13q14 region, including RB1 and FOXO1 loci (J Pathol 2000;191:282, Hum Pathol 2012;43:1887)
- Related to multiple CD34 positive neoplasms with similar morphology and deletion of 13q14: spindle cell lipoma, extramammary myofibroblastoma, cellular angiofibroma and superficial acral fibromyxoma (J Pathol 2000;191:282, Hum Pathol 2017;60:192)
Sample pathology report
- Left breast, mass, needle core biopsy:
- Bland spindle cell lesion consistent with myofibroblastoma (see comment)
- Comment: Sections show bland spindle cells arranged in short fascicles admixed with hyalinized collagen bundles and adipose tissue. The lesional cells express CD34, desmin, smooth muscle actin, BCL2 and PR, are negative for cytokeratins and show a loss of Rb1 by immunohistochemistry. Overall, the morphologic and immunohistochemical findings are compatible with mammary type myofibroblastoma.
Differential diagnosis
- Invasive lobular carcinoma:
- Cytologic atypia, mitoses
- Presence of in situ carcinoma supports malignant process
- Cytokeratin positive, CD34 negative, desmin negative
- Both may be ER and PR positive
- Metaplastic spindle cell carcinoma:
- More cytologic atypia, mitoses, infiltrative borders
- May have areas with glandular morphology or squamous metaplasia
- Presence of in situ carcinoma supports malignant process
- Cytokeratin and p63 positive, CD34 negative
- Fibromatosis:
- Long, sweeping fascicles
- Stellate or infiltrative appearing
- CD34 negative, nuclear expression of beta catenin
- CTNNB1 mutations
- Nodular fasciitis:
- Loose storiform proliferation of bland spindle cells; mitoses may be present and conspicuous
- Extravasated erythrocytes often present
- Scattered inflammatory cells (lymphocytes, histiocytes) present
- CD34 and desmin negative
- MYH9-USP6 fusion or other USP6 rearrangement by FISH, PCR or RNA sequencing
- May spontaneously regress
- Pseudoangiomatous stromal hyperplasia (PASH):
- Solitary fibrous tumor:
- STAT6 positive (Pathol Res Pract 2018;214:1544)
- No loss of RB1 (13q14) by FISH (Am J Clin Pathol 2012;137:963)
- Spindle cell lipoma:
- Fat component usually predominates
- Focal or absent myogenic marker expression
- In the lower female genital tract:
- Cellular angiofibroma:
- Morphologic overlap with similar genetics
- Thicker, hyalinized vessels, focal to absent myogenic marker expression
- Lacks thick hyalinized collagen bundles
- Angiomyofibroblastoma:
- Alternating zones of hypo and hypercellularity
- More prominent vascular component (delicate capillary sized vessels)
- Usually CD34 negative
- Aggressive angiomyxoma:
- Infiltrative, not circumscribed, involves deep soft tissues
- Hypocellular with abundant myxoid matrix
- Medium to large sized hyalinized vessels
- Cellular angiofibroma:
Additional references
Board review style question #1
Which of the following immunohistochemical stains is positive in the lesion depicted above?
- AE1 / AE3
- Calponin
- CD34
- p63
- S100
Board review style answer #1
Board review style question #2
Which of the following is true regarding mammary type myofibroblastomas?
- The cellular and epithelioid variants are positive for cytokeratins
- They are always CD34 positive
- They are genetically related to spindle cell lipoma and cellular angiofibroma and cytogenetically show monoallelic loss of 13q14 region
- They are related to solitary fibrous tumors and are STAT6 positive by immunohistochemistry
- They may have aggressive behavior if cytologic atypia is present
Board review style answer #2
C. They are genetically related to spindle cell lipoma and cellular angiofibroma and cytogenetically show monoallelic loss of 13q14 region
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Board review style question #3
Which immunoprofile is most suggestive of mammary type myofibroblastoma?
- CD34 negative, desmin positive, smooth muscle actin positive, Rb1 positive
- CD34 negative, desmin negative, cytokeratin positive, Rb1 negative
- CD34 positive, desmin positive, CD10 negative, Rb1 positive
- CD34 positive, desmin positive, STAT6 negative, Rb1 negative
- CD34 positive, STAT6 positive, Rb1 positive
Board review style answer #3
D. CD34 positive, desmin positive, STAT6 negative, Rb1 negative
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Reference: Myofibroblastoma
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Reference: Myofibroblastoma
Neoadjuvant chemotherapy
Table of Contents
Definition / general | Essential features | Clinical features | Radiology description | Radiology images | Prognostic factors | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Positive stains | Sample pathology report | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Chemotherapy preceding surgical resection to downstage disease
- Associated with characteristic histological features on the resection specimen, with prognostic implications
Essential features
- The treatment effects associated with neoadjuvant chemotherapy can be seen in the primary tumor (tumor bed), axillary nodal metastases and normal breast tissue
- Neoadjuvant chemotherapy improves survival and functional outcome by allowing resection in initially nonresectable disease or by reducing the extent of surgical resection
- Degree of response (extent of residual disease) is predictive of outcome, in particular, a complete pathologic response without residual tumor detected is indicative of good prognosis (Mod Pathol 2015;28:1185)
Clinical features
- Indications for neoadjuvant chemotherapy include
- Locally advanced disease, to allow resection of unresectable disease
- Disease where breast conservation is not possible but potentially feasible if downstaging is achieved
- Temporary / treatable conditions that contraindicate surgery and thus require bridging therapy (Curr Oncol 2021;28:1338)
- Clinically, node positive disease with response to neoadjuvant chemotherapy and negative sentinel lymph nodes may be spared from axillary dissection (Br J Surg 2021;108:748)
- Grade, stage and biomarker status are additional considerations for neoadjuvant chemotherapy (J Clin Oncol 2021;39:1485)
- Clinical response to neoadjuvant chemotherapy is classified as
- Clinical complete response: complete disappearance of tumor
- Clinical partial response: ≥ 50% reduction greatest dimension of tumor
- Clinically positive nodes may also respond (reduce in size) after neoadjuvant chemotherapy
- Clinical assessment may overestimate tumor size due to posttreatment fibrosis (Radiology 2017;285:358)
- Clinical response is predictive of outcome and correlates with pathological response (J Surg Oncol 2002;80:4, Zhonghua Bing Li Xue Za Zhi 2010;39:734)
Radiology description
- Conventional imaging modalities for assessment of radiological response includes mammography, ultrasound, MRI
- Radiological response is defined by resolution of original imaging finding (complete response) or by change in lesion size
- Radiological response is predictive of outcome and correlates with pathological response (Eur J Surg Oncol 2021;47:232)
- MRI is more sensitive and is preferred over other imaging modalities (Anticancer Res 2014;34:1219, Insights Imaging 2013;4:163)
- Functional imaging is also used for assessment of radiological response
- Response is defined by normalization of tracer uptake (complete response) or by change in tracer uptake (Radiology 2017;285:358)
- MRI is more accurate in predicting complete pathological response than PET / CT (Oncologist 2016;21:931)
Radiology images
Contributed by Joshua J.X. Li, M.B.Ch.B. and Gary M. Tse, M.B.B.S.
Pretreatment MRI
Posttreatment MRI
Prognostic factors
- Complete pathologic response demonstrates good prognostic prediction in certain types of breast cancers but not all (J Clin Oncol 2012;30:1796)
- Strong positive correlation with survival in HER2 positive, triple negative and luminal B / HER2 negative (ER / PR positive, HER2 negative, grade 3) breast cancers
- Poor correlation with survival in luminal A (ER / PR positive, HER2 negative) and luminal B / HER2 positive (ER / PR positive, HER2 positive) breast cancers
- Multiple systems for reporting and evaluating response to neoadjuvant chemotherapy have been described (Drug Des Devel Ther 2020;14:2423)
- American Joint Committee on Cancer (classification after preoperative therapy, i.e., prefix "y")
- ypT0 denotes no residual cancer (including in situ carcinoma)
- ypTis denotes residual in situ carcinoma only
- ypT1-4 denotes presence of residual disease
- Residual cancer burden (Mod Pathol 2015;28:1185)
- In situ carcinoma is not considered residual disease but is recommended for reporting
- Miller-Payne (Breast 2003;12:320)
- Residual in situ carcinoma allowed for grade 5 (complete) response
- Chevallier (Am J Clin Oncol 1993;16:223)
- Fisher (J Clin Oncol 1998;16:2672)
- Japanese Breast Cancer Society (Breast Cancer 2008;15:5)
- Pinder (Histopathology 2007;50:409)
- Sataloff (J Am Coll Surg 1995;180:297)
- Sinn (Geburtshilfe Frauenheilkd 1994;54:552)
- American Joint Committee on Cancer (classification after preoperative therapy, i.e., prefix "y")
Gross description
- Gross appearance of tumor may indicate degree of pathological response
- Tumors with poor response demonstrate a firm, gritty and spiculated appearance (i.e., no difference from typical untreated tumors)
- Response can be indicated by fibrosis or softening of the tumor bed (Mod Pathol 2015;28:1185)
- Tumors with partial response can be nodular, multifocal with and less well defined borders (Breast 2022;62:S25)
- In cases of complete response, the tumor bed may be soft and indistinguishable from normal breast tissue
- Tumor mapping with radiographs, photographs or drawings of the sectioned gross specimen is recommended (Mod Pathol 2015;28:1185)
- Considerations in tumor sampling
- Sampling should include all grossly residual disease, visible tumor bed, marker clips and adjacent tissue
- Recommendations on sampling extent are based on pretreatment size and whether residual tumor is grossly identifiable
- Residual carcinoma grossly present
- Usually 1 full face section of largest area and similar full face sections 1 cm apart to investigate the extent of the lesion (Surg Pathol Clin 2018;11:213)
- For very large tumors, 5 representative sections per full face are sufficient (Surg Pathol Clin 2018;11:213)
- No invasive carcinoma grossly identified
- Minimum of 1 block per cm of the pretreatment tumor size or at least 10 blocks in total, whichever is greater (Food and Drug Administration) (Surg Pathol Clin 2018;11:213)
- 5 blocks of a cross section per 1 - 2 cm, up to 25 blocks for very large tumors (Breast International Group and the North American Breast Cancer Group)
- Residual carcinoma grossly present
- In cases where the tumor bed cannot be identified, correlation with preoperative clinical and radiological findings is recommended for determining the location of sampling
Gross images
Contributed by Emily S. Reisenbichler, M.D.
Complete response to neoadjuvant chemotherapy
No significant response to neoadjuvant chemotherapy
Microscopic (histologic) description
- Breast
- Multiple reporting systems are described but generally response is classified into
- Pathological complete response (pCR)
- Most widely agreed upon definition of pCR is no residual invasive carcinoma in both the breast and axillary lymph nodes, regardless of the presence of residual DCIS ypT0 ypN0 or ypTis ypN0 (Lancet 2014;384:164, Mod Pathol 2021;34:1271)
- Residual tumor within lymphovascular spaces (lymphovascular invasion) is not allowed for pCR (Mod Pathol 2015;28:1185)
- Currently, presence of in situ cancer after treatment in the absence of residual invasive cancer in the breast and lymph nodes constitutes pCR
- However, there is debate on whether ductal carcinoma in situ should be considered as residual disease due to its association with shorter disease free survival but not overall survival (Mod Pathol 2015;28:1185, J Clin Oncol 2012;30:1796)
- Incomplete response / residual disease: evidence of tumor response but residual tumor cells are present
- Cutoffs for categories vary for different systems
- No response: treatment associated changes are not seen histologically
- Pathological complete response (pCR)
- Histologic evidence of tumor response includes fibrosis, hyalinization, lymphohistiocytic infiltration, hemosiderin laden macrophages, giant cell formation and vascular proliferation
- These histologic features are indicative of the tumor bed
- Patterns observed in partial response includes concentric tumor shrinkage, reduction in tumor cellularity and scattered multifocal tumor deposits (Mod Pathol 2015;28:1185)
- Tumor cells show degenerative changes including nuclear and cytoplasmic vacuolation, karyorrhexis, karyolysis and pyknosis (Int J Appl Basic Med Res 2012;2:111)
- There may be a change in histologic grading after neoadjuvant therapy
- Normal breast tissue shows ductal and lobular atrophy, atypia and hyalinization of vessel wall
- Multiple reporting systems are described but generally response is classified into
- Lymph node
- Possible scenarios include
- Presence of tumor cells, with no evidence of histologic treatment response
- Presence of tumor cells, histologic evidence of treatment response seen
- Absence of tumor cells, histological evidence of treatment response seen
- Absence of tumor cells and histologic evidence of treatment (true negative nodes)
- Histological evidence of tumor response in the lymph node includes fibrosis, mucin pools, histiocytic infiltrates and lymphoid depletion
- Presence of tumor response indicates possible previous nodal involvement and is associated with prognosis intermediate between node negative and node positive patients (Ann Surg Oncol 2003;10:734)
- Residual nodal disease is associated with shorter disease free and overall survival (J Clin Oncol 2012;30:1796)
- Possible scenarios include
Microscopic (histologic) images
Contributed by Joshua J.X. Li, M.B.Ch.B., Gary M. Tse, M.B.B.S. and Emily S. Reisenbichler, M.D.
Tumor with treatment effect
Fibrotic tumor bed
Minimal residual disease
Complete pathologic response
Posttreatment lymph node
No residual invasive or in situ tumor
Small clusters of residual invasive tumor cells
Virtual slides
Images hosted on other servers:
Tumor with incomplete response
Near complete response with isolated residual tumor focus
Positive stains
- Cytokeratins are also used in assessment of sentinel lymph nodes in a postneoadjuvant chemotherapy setting (Breast 2022;62:S25)
- Entrapped normal breast epithelium in the tumor bed is positive to cytokeratins and should not be confused for residual tumor cells
- Myoepithelial markers may help in distinguishing normal breast epithelium and residual in situ carcinoma from residual invasive carcinoma (Arch Pathol Lab Med 2011;135:422)
- Histiocytic markers (CD68, CD163) may help distinguish residual invasive carcinoma from infiltrating histiocytes in the tumor bed (Histopathology 2015;67:279)
- Endothelial markers (CD31, ERG) may help distinguish residual invasive carcinoma from lymphovascular invasion
- Entrapped normal breast epithelium in the tumor bed is positive to cytokeratins and should not be confused for residual tumor cells
- Biomarker status may change after neoadjuvant chemotherapy (Pathobiology 2022;89:297)
Sample pathology report
- Left breast, local excision:
- No residual tumor (complete pathologic response) (see comment)
- Comment: Sections of the tumor bed shows fibrosis and atrophic changes, with lymphohistiocytic infiltrates and hemosiderin deposition. No viable tumor cells are seen, indicating a pathologic complete response to neoadjuvant chemotherapy. The remaining breast tissue is unremarkable.
- Left breast, local excision:
- Residual invasive breast carcinoma, NST type, with therapy effect status postneoadjuvant chemotherapy, indicating partial / incomplete response (see comment)
- Comment: Sections show residual invasive carcinoma of ______ (histotype) and _______ (grade). Fibrosis, lymphohistiocytic infiltrates and hemosiderin deposition in keeping with treatment effects are / are not noted. The residual tumor cellularity is ______%. In situ carcinoma is / is not noted and comprises ______% of the residual tumor cellularity. Lymphovascular invasion is / is not identified. The tumor measures ______ mm and is clear from (specify if < 1 cm ____) / involves the resection margins.
- Left axillary dissection:
- __ out of ___ lymph nodes involved by metastatic carcinoma (see comment)
- Comment: Sections show a total of ____ lymph nodes. ____ lymph nodes show metastatic carcinoma with ____ showing fibrosis, mucin pools and histiocytic infiltrates, suggestive of treatment response. Extracapsular spread is / is not seen. Similar features are seen / not seen in ___ of the remaining benign lymph nodes.
Board review style question #1
Which of the following cases is considered a complete pathologic response to neoadjuvant chemotherapy?
- Absence of invasive carcinoma in the tumor bed but isolated tumor cells present in an axillary lymph node
- Absence of invasive carcinoma in the tumor bed but with viable tumor cells present in lymphovascular spaces of quadrant samplings
- Fibrous tumor bed with adjacent lobules showing atypical epithelial lining cells
- Significant tumor necrosis in the tumor bed with rare viable invasive carcinoma
- Small clusters of invasive carcinoma constituting < 5% of cellularity among a fibrous tumor bed
Board review style answer #1
C. Fibrous tumor bed with adjacent lobules showing atypical epithelial lining cells. Complete pathologic response is defined as the absence of residual tumor cells. Presence of any viable tumor cells, regardless of cellularity, in the tumor bed, lymph nodes or lymphovascular spaces should not be considered as complete pathologic response. Chemotherapy can result in atypia in normal breast epithelium and should not be confused with residual disease.
Comment Here
Reference: Neoadjuvant chemotherapy
Comment Here
Reference: Neoadjuvant chemotherapy
Board review style question #2
In which of the following scenarios is neoadjuvant chemotherapy generally considered?
- Early stage, low grade, hormone positive / HER2 negative invasive breast cancer
- Patient with ductal carcinoma in situ of the breast
- Patient with local invasive breast cancer and active hepatitis B infection
- Patient with radiological evidence of bone metastasis with biopsy proven stage IV breast cancer
- Patient with suspected muscle invasive breast cancer
Board review style answer #2
E. Patient with suspected muscle invasive breast cancer. General contraindications to chemotherapy apply to neoadjuvant chemotherapy, including active hepatitis. Patients with unresectable disease or bulky nodal disease are also not indicated for neoadjuvant chemotherapy. The current role of adjuvant therapy in phyllodes tumor is unclear and is generally not offered (Histopathology 2016;68:5). T4 disease (muscle invasion) is not a contraindication to neoadjuvant therapy.
Comment Here
Reference: Neoadjuvant chemotherapy
Comment Here
Reference: Neoadjuvant chemotherapy
Neuroendocrine carcinoma (NEC)
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Pathophysiology | Etiology | Clinical features | Diagnosis | Laboratory | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Cytology images | Positive stains | Negative stains | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Invasive carcinoma with characteristic high grade neuroendocrine features and supported by immunoreactivity to neuroendocrine markers
Essential features
- Neuroendocrine markers helpful for diagnosis
- Not to be confused with distinct breast neoplasms that exhibit neuroendocrine differentiation (e.g., solid papillary carcinoma, mucinous carcinoma of the breast)
- Morphologically indistinguishable from neuroendocrine carcinomas (small cell carcinoma and large cell carcinoma) of other organ primaries
Terminology
- Small cell neuroendocrine carcinoma
- Large cell neuroendocrine carcinoma
- Oat cell carcinoma (for small cell carcinoma, not recommended by the WHO)
ICD coding
- ICD-O:
- ICD-10: C50.9 - malignant neoplasm of breast of unspecified site
- ICD-11:
Epidemiology
- Small cell carcinoma of the breast:
- 0.1% of primary breast cancers (Springerplus 2015;4:138)
- 4% of extrapulmonary small cell carcinomas (J Surg Oncol 2011;104:604)
- More commonly presents in postmenopausal age (Springerplus 2015;4:138)
- Large cell carcinoma of the breast:
- < 0.1% of primary breast cancers; rarer than small cell carcinoma of the breast (Breast Care (Basel) 2015;10:281)
Pathophysiology
- Unconfirmed at this time but proposed theories include:
- Neoplastic transformation from native neuroendocrine cells in the breast (J Clin Pathol 2012;65:699)
- Divergent neuroendocrine differentiation of neoplastic stem cells (Arch Pathol Lab Med 2017;141:1577)
- Invasive and in situ ductal carcinomas occasionally identified in small cell carcinomas of the breast (Am J Surg Pathol 2000;24:1231)
- May suggest acquisition of neuroendocrine features and transformation from invasive or in situ breast carcinomas
Etiology
- Unknown at this time
Clinical features
- Presents as a mass lesion (J Clin Pathol 2005;58:775):
- Tumor size ranges from 1 - 11 cm (AJR Am J Roentgenol 2014;203:W221)
- Higher risk of presenting with distant disease than primary breast cancers overall (31% versus 5%) (BMC Cancer 2015;15:185, JAMA 2015;313:165)
Diagnosis
- Largely dependent on histologic evidence of neuroendocrine differentiation and small cell / large cell features (see Microscopic description)
- Supplemented by positivity to neuroendocrine markers
- Clinical exclusion of metastasis to breast from a nonmammary primary site is essential
- Identification of in situ component is the most helpful feature for confirmation of the breast as the primary site of origin (e.g. gastrointestinal tract, pulmonary) (Am J Case Rep 2021;22:e932274)
Laboratory
- Serum chromogranin A not demonstrated to be useful in detection and disease monitoring in a large case control cohort (Int J Biol Markers 2001;16:268)
Radiology description
- Mammogram (AJR Am J Roentgenol 2014;203:W221):
- High density
- Round, oval or lobular mass
- Nonspiculated margins
- Ultrasound:
- Hypoechoic
- Irregular with indistinct margins
- With or without posterior acoustic enhancement (Appl Radiol 2016;45:27)
- MRI:
- Irregular mass
Radiology images
Contributed by Mark R. Wick, M.D.
Large cell carcinoma
Left lateral MRI
Images hosted on other servers:
Small cell carcinoma
Hyperdense mass on mammography
Hypoechoic mass on ultrasound
Prognostic factors
- Histological grade:
- Small cell carcinomas show worse survival than other neuroendocrine neoplasms of the breast (Breast Cancer Res Treat 2014;148:637)
- Neuroendocrine carcinomas are most commonly Nottingham grade 3, whereas neuroendocrine tumors of the breast are usually grades 1 and 2 (Case Rep Pathol 2016;2016:6762085)
- Tumor stage:
- Small cell and large cell carcinomas of the breast demonstrate unfavorable prognosis (Breast Cancer Res Treat 2014;148:637)
- Neuroendocrine marker expression:
- Low synaptophysin and chromogranin expression correlates with poor disease free survival (Oncologist 2020;25:e1318)
- INSM1 expression associated with better survival (Pathology 2021;53:170)
Case reports
- 38 year old woman with self detected breast mass (Proc (Bayl Univ Med Cent) 2017;30:200)
- 39 year old woman presenting with left breast refusal (Am J Case Rep 2021;22:e932274)
- 42 year old woman with mixed neuroendocrine tumor and large cell carcinoma of the breast (Korean J Radiol 2013;14:395)
- 50 year old woman with small cell carcinoma of breast showing TTF1 positivity (Front Endocrinol (Lausanne) 2020;11:228)
- 64 year old woman with rapidly progressive fungating breast mass (Case Rep Oncol 2021;14:761)
Treatment
- Mainstay of treatment is surgical resection, usually with lymphadenectomy (Am J Surg Pathol 2000;24:1231)
- Adjuvant radiotherapy not associated with improved prognosis (Springerplus 2015;4:138)
- Hormonal therapy given for chemoprevention and palliation with reports of good outcome (Am J Surg Pathol 2000;24:1231, Clin Breast Cancer 2012;12:226)
Clinical images
Images hosted on other servers:
Before and after chemotherapy
Gross description
- Ill defined firm mass (Am J Surg Pathol 2000;24:1231)
- Tan or fleshy cut surface
- Calcification, hemorrhage and necrosis uncommon
Gross images
Contributed by Mark R. Wick, M.D.
Small cell carcinoma
Microscopic (histologic) description
- Small cell carcinoma:
- Infiltrative growth pattern
- Crush artifact frequent
- Necrosis and lymphovascular invasion common
- Tumor cells densely packed with ill defined cell borders
- High N/C ratio with scanty cytoplasm
- Small dark hyperchromatic nuclei and inconspicuous nucleoli
- Mitotic count high
- Associated with proliferative changes, in situ carcinomas and invasive carcinomas (Am J Surg Pathol 2000;24:1231)
- In situ small cell carcinoma present in 5 out of 9 cases in a case series
- In situ / invasive ductal, lobular and squamous neoplastic components occasionally identified
- Infiltrative growth pattern
- Large cell carcinoma:
- High grade features (frequent necrosis, lymphovascular invasion and mitosis) similar to small cell carcinoma
- Tumor cells have a larger amount of cytoplasm
- Chromatin pattern coarse with occasional distinct nucleoli
- Neuroendocrine carcinomas of the breast histologically indistinguishable from their counterparts of other primaries
Microscopic (histologic) images
Contributed by Joshua J.X. Li, M.B.Ch.B., Gary M. Tse, M.B.B.S. and Kristen E. Muller D.O.
Small cell carcinoma
Tumor cell in cords
Fine chromatin pattern
Uniform tumor cells
Cords and necrosis
Crush artifact
Abundant mitoses
Synaptophysin
Large cell carcinoma
Infiltrative tumor edge
Frequent mitotic figures
Coarse chromatin pattern
Marked nuclear pleomorphism
CD56
Chromogranin
Virtual slides
Images hosted on other servers:
Small cell carcinoma
Large cell carcinoma
Cytology description
- Neuroendocrine features, including nuclear molding and fine salt and pepper chromatin, may be identified in small cell carcinoma
- Necrosis can be present in the background (J Cytol 2011;28:91)
- Smear preparation can accentuate crush artifact
Cytology images
Contributed by Joshua J.X. Li, M.B.Ch.B. and Gary M. Tse, M.B.B.S.
Crush artifact
Neuroendocrine nuclear features
Metastatic small cell carcinoma
Positive stains
- Cytokeratins:
- Neuroendocrine markers:
- Hormonal markers:
- Estrogen receptor (30 - 67%), progesterone receptor (13 - 56%) (Am J Surg Pathol 2000;24:1231, Breast Cancer Res Treat 2016;158:195)
- Of note, pulmonary neuroendocrine carcinomas also not uncommonly express estrogen and progesterone receptor (Arch Pathol Lab Med 2008;132:1889)
- Other markers:
Negative stains
Molecular / cytogenetics description
- TP53 (75%) and PIK3CA (33%) mutations common in small cell carcinoma of the breast (Breast Cancer Res Treat 2016;158:195):
- PIK3CA mutation not present in small cell carcinoma of lung
- RB1 mutation present in small cell carcinoma of lung but not of breast primary
- Mutations in AKT1, ARID1A, CDH1, FOXA1, GATA3 and TBX3 also detected (J Pathol 2017;241:405)
- Compared to luminal breast cancers, PIK3CA mutations are less frequent, whereas FOXA1 and TBX3 mutations are more common
Sample pathology report
- Left breast, local excision:
- Small cell carcinoma (see comment)
- Comment: Sections show breast tissue infiltrated by cords, nests and sheets of tumor cells. The tumor cells possess small dark hyperchromatic nuclei and inconspicuous nucleoli with scanty cytoplasm. The mitotic count is at __ per 10 high power fields. The tumor measures __ in maximal dimension and is clear from (specify if < 1 cm __) / involves the resection margins.
- The tumor cells are diffusely positive for synaptophysin and focally positive for chromogranin.
- Right breast, local excision:
- Large cell carcinoma (see comment)
- Comment: Sections show breast tissue infiltrated by nests and sheets of tumor cells. The tumor cells possess enlarged nuclei with coarse chromatin pattern, distinct nucleoli and a moderate amount of cytoplasm. The mitotic count is at __ per 10 high power fields. The tumor measures __ in maximal dimension and is clear from (specify if < 1 cm __) / involves the resection margins.
- The tumor cells are diffusely positive for synaptophysin and focally positive for chromogranin.
Differential diagnosis
- Neuroendocrine carcinomas of other, nonmammary origin:
- Neuroendocrine carcinomas of the breast histologically indistinguishable from their counterparts of other primaries
- Background ductal in situ or invasive, when present, highly suggestive of breast primary (Am J Surg Pathol 2000;24:1231)
- Hormonal markers, GATA3 and TTF1 stains can be helpful but not entirely sensitive or specific (Mod Pathol 2016;29:788, Front Endocrinol (Lausanne) 2020;11:228)
- Correlation with clinical history and radiological findings often required
- Neuroendocrine tumors:
- Majority of neuroendocrine tumors are Nottingham grade 1 or 2 (low nuclear grade and infrequent mitosis)
- Necrosis and lymphovascular invasion not features of neuroendocrine tumors
- Ki67 index is lower in neuroendocrine tumors than neuroendocrine carcinomas
- Invasive carcinoma with neuroendocrine differentiation:
- Invasive carcinomas with neuroendocrine differentiation show neuroendocrine features in terms of nuclear morphology or positivity to neuroendocrine markers in 10 - 90% of the tumor
- Complete small cell or large cell nuclear features usually absent
- Negativity to neuroendocrine markers, in particular synaptophysin, may help identify nonneuroendocrine areas
- Adenoid cystic carcinoma (solid):
- Solid pattern of adenoid cystic carcinoma can resemble small cell carcinoma
- Focal cribriform pattern, tubular pattern and luminal secretion, if identified, aids in diagnosing adenoid cystic carcinoma
- Markedly hyperchromatic nuclei with crush artifact not a feature of adenoid cystic tumor
- Positivity to KIT, MYB and SOX10 with negativity to hormonal markers confirms a diagnosis of adenoid cystic carcinoma
- Lymphoma:
- Markedly hyperchromatic nuclei with crush artifact in small cell carcinoma can resemble lymphoma
- Lymphoma does not show cellular cohesion
- Cytokeratins, hormonal, neuroendocrine and lymphoid markers differentiate lymphomas from carcinomas
- Melanoma:
- Degree of nuclear atypia and nuclear features of melanoma can overlap with large cell carcinoma
- Melanin pigment, when identified, indicates melanoma
- Definitive confirmation may require melanocytic markers
Board review style question #1
Which of the following features distinguishes large cell carcinoma from small cell carcinoma of breast primary?
- Coarse chromatin pattern and distinct nucleoli
- Positive axillary lymph nodes
- Positivity to estrogen and progesterone receptors
- Positivity to synaptophysin but not chromogranin
- Presence of extensive tumor necrosis
Board review style answer #1
A. Coarse chromatin pattern and distinct nucleoli. Large cell carcinoma is distinguished from small cell carcinoma based on cellular morphologic features, including a coarse chromatin pattern, distinct nucleoli and a greater amount of cytoplasm. The immunoprofile of large cell and small cell carcinomas are similar (Breast Care (Basel) 2015;10:281). Other histological and clinical features are also not useful in distinguishing large cell carcinoma from small cell carcinoma.
Comment Here
Reference: Neuroendocrine carcinoma (NEC)
Comment Here
Reference: Neuroendocrine carcinoma (NEC)
Board review style question #2
Which of the following findings most favors small cell carcinoma of breast primary over metastatic small cell carcinoma from the lung?
- Positivity to estrogen and progesterone receptors
- Positivity to TTF1 stain
- Presence of adjacent ductal carcinoma in situ
- Presence of RB1 mutation
- Presence of TP53 mutation
Board review style answer #2
C. Presence of adjacent ductal carcinoma in situ. The majority of small cell carcinomas of the breast are associated with proliferative changes, in situ and invasive carcinomas (Am J Surg Pathol 2000;24:1231). TP53 mutation is detected in small cell carcinomas of both lung and breast primaries, whereas RB1 mutation was only present in small cell carcinomas of lung primary from a cohort described by McCullar et al. (Breast Cancer Res Treat 2016;158:195). TTF1, estrogen receptor and progesterone receptor expression do not accurately distinguish small cell carcinomas of breast and lung (Front Endocrinol (Lausanne) 2020;11:228, Am J Surg Pathol 2000;24:1231).
Comment Here
Reference: Neuroendocrine carcinoma (NEC)
Comment Here
Reference: Neuroendocrine carcinoma (NEC)
Neuroendocrine tumor
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Pathophysiology | Etiology | Clinical features | Diagnosis | Laboratory | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Positive stains | Negative stains | Electron microscopy description | Electron microscopy images | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Primary, low to intermediate grade neoplasm of the breast with histological features of neuroendocrine differentiation and supported by immunoreactivity to neuroendocrine markers
Essential features
- Uncommon, primary neuroendocrine neoplasm of the breast of low to intermediate grade
- Morphology is the primary feature for classification, requires > 90% neuroendocrine tumor (NET) pattern
- Neuroendocrine markers helpful for diagnosis
- Not to be confused with distinct breast neoplasms that exhibit neuroendocrine differentiation (e.g., solid papillary carcinoma, mucinous carcinoma of the breast, invasive ductal carcinoma, no special / specific type [IDC-NST] with neuroendocrine differentiation)
Terminology
- Carcinoid tumor, atypical carcinoid, not recommended
- Prior to WHO 5th edition, often referred to as the category of tumors with neuroendocrine differentiation; the current WHO 5th terminology is neuroendocrine neoplasms, which includes neuroendocrine tumors (NET), neuroendocrine carcinomas (small cell and large cell NEC)
ICD coding
- ICD-O:
- ICD-10:
- C50.9 - malignant neoplasm of breast of unspecified site
- ICD-11:
Epidemiology
- Accounts for < 1% of primary breast cancers (Am J Surg 2006;191:799)
- Age of presentation commonly > 65 years (Eur J Surg Oncol 1995;21:609)
Pathophysiology
- Unconfirmed at this time but proposed theories include:
- Neoplastic transformation from native neuroendocrine cells in the breast (J Clin Pathol 2012;65:699)
- Divergent neuroendocrine differentiation of neoplastic stem cells (Arch Pathol Lab Med 2017;141:1577)
Etiology
- Unknown at this time
Clinical features
- Typically presents as a mass lesion
- ~10% are bilateral (Am J Surg 2006;191:799)
- Tumor size ranges from 1 - 5 cm (Eur J Surg Oncol 1995;21:609)
- Nodal and systemic metastasis not uncommon on presentation (Eur J Surg Oncol 1995;21:609)
- Carcinoid syndrome not reported in neuroendocrine tumors of the breast (Am J Surg 2006;191:799)
- Published data suggests worse prognosis compared to IDC-NST (Breast Cancer Res Treat 2021;186:403)
Diagnosis
- Requires histomorphologic evidence of neuroendocrine differentiation
- Supplemented by positivity to neuroendocrine immunohistochemical markers
- Radiology and serology not sensitive nor specific in diagnosis
Laboratory
- Serum chromogranin (neuroendocrine secretory protein) can be elevated (Cureus 2021;13:e16860)
Radiology description
- Mammography (Eur J Surg Oncol 1995;21:609)
- Lobular, well defined dense mass
- Not associated with microcalcification
- Ultrasound (Radiat Med 2008;26:28)
- Mixed hypo and hyperechogenicity
- Increased vascularity
Radiology images
Contributed by Joshua J.X. Li, M.B.Ch.B. and Gary M. Tse, M.B.B.S.
Mammogram
Doppler ultrasound
Prognostic factors
- Tumor stage (Histopathology 2014;64:647)
- Histological grade
- Most neuroendocrine tumors of the breast are Nottingham grades 1 and 2
- Ki67 proliferation index
- High Ki67 proliferative index may indicate tumor aggressiveness
- No formal grading system defined
Case reports
- 42 year old woman with mixed neuroendocrine tumor and large cell carcinoma of the breast (Korean J Radiol 2013;14:395)
- 58 year old woman with liver metastasis (Cureus 2021;13:e16860)
Treatment
- Mainstay of treatment is surgical resection, with or without lymphadenopathy (Eur J Surg Oncol 1995;21:609)
- Report of good response in metastatic disease with combination of traditional chemotherapy and somatostatin analog (Cureus 2021;13:e16860)
Gross description
- Well circumscribed, nonencapsulated tumors (Eur J Surg Oncol 1995;21:609)
Microscopic (histologic) description
- Requires morphologic threshold of > 90% of NET pattern, consistent with the criteria defining other special subtypes of the breast
- Densely cellular, insular, organoid nests and trabeculae with delicate intervening fibrovascular stroma (Arch Pathol Lab Med 2017;141:1577, Korean J Radiol 2013;14:395)
- Papillary and insular patterns and alveolar-like structures may be seen
- Tumor cells display classical neuroendocrine morphology:
- Spindle, plasmacytoid or polygonal cells
- Eosinophilic granular cytoplasm
- Eccentric nuclear placement
- Salt and pepper stippled chromatin may be present, often not obvious
- Intranuclear inclusions
- Mammary NET often lacks classic carcinoid-like features (ribbons, cords and rosettes) (Histopathology 2015;66:761)
- Majority Nottingham grade 1 or 2
Microscopic (histologic) images
Contributed by Joshua J.X. Li, M.B.Ch.B. and Gary M. Tse, M.B.B.S.
Nests of tumor cells
Neuroendocrine morphology
Neuroendocrine nuclear features
Synaptophysin
Ki67
Chromogranin
CD56
Virtual slides
Images hosted on other servers:
Neuroendocrine tumor, grade 1
Positive stains
- Neuroendocrine markers:
- Hormonal markers:
- ER, PR and AR (Mod Pathol 2001;14:768)
- Other markers:
Negative stains
Electron microscopy description
- Dense core vesicles and presynaptic vesicles
Electron microscopy images
AFIP images
Dense core granules
Molecular / cytogenetics description
- ARID1A, ATRX, FOXA1, GATA3 and PIK3CA mutations reported (J Pathol 2017;241:405, Mod Pathol 2018;31:68)
- TP53 mutation more common in (high grade) neuroendocrine carcinomas (Mod Pathol 2018;31:68)
Sample pathology report
- Left breast, local excision:
- Neuroendocrine tumor, grade __, measuring ___ cm (see comment and synoptic report)
- Comment: Sections show breast tissue infiltrated by groups and rounded nests of tumor cells. The tumor cells possess low grade nuclei that are rounded to ovoid, scanty to moderate amount of cytoplasm and some of them show plasmacytoid features with stippled chromatin. The mitotic count is at __ per 10 high power fields. The features are those of neuroendocrine tumor, grade __. The tumor measures __ in maximal dimension and is clear from (specify if < 1 cm __) / involves the resection margins.
- The tumor cells are diffusely positive for synaptophysin and focally positive for chromogranin. Ki67 proliferative index is approximated at __%.
Differential diagnosis
- Metastatic neuroendocrine tumors of other primaries:
- Cannot be reliably distinguished by morphology
- Dependent on history of neuroendocrine tumors in other sites, correlation with clinical history and imaging is required
- Positivity to hormonal markers and breast markers; negativity to markers associated with other primaries (e.g., TTF1, glypican 3) may be helpful
- Identification of an in situ component can help distinguish primary breast from metastatic nonmammary tumors
- Breast neoplasms with neuroendocrine differentiation:
- Neuroendocrine carcinomas:
- Small cell carcinoma:
- Small hyperchromatic nuclei, nuclear molding, often crushed
- Very high nuclear / cytoplasmic ratio
- Mitotic count and Ki67 proliferative index high
- Necrosis
- Large cell carcinoma:
- Grade 3, large pleomorphic nuclei with coarse chromatin
- Mitotic count and Ki67 proliferative index high
- Often necrosis
- Small cell carcinoma:
- Invasive carcinoma with neuroendocrine differentiation:
- If an NEN pattern is present in 10 - 90% of a malignancy, the terminology for mixed invasive (NST or other special type) and NET may be used, with an estimation of the percent of each component reported
- Negativity to neuroendocrine markers, in particular synaptophysin, may help identify nonneuroendocrine areas
- IBC-NSTs can be immunoreactive for neuroendocrine markers, expression of neuroendocrine markers alone is not sufficient for a diagnosis of mammary NET
- Solid papillary carcinoma:
- Nuclear and cytologic features can be similar
- Fibrovascular cores with palisading, when identified, are helpful for diagnosing solid papillary carcinoma
- Majority of solid papillary carcinomas are positive for neuroendocrine markers (Am J Surg Pathol 2016;40:1334)
- Mucinous carcinoma:
- Nuclear and cytologic features can be similar
- > 90% mucinous morphology (e.g. extracellular mucin pools)
- Mucinous carcinomas can be positive to neuroendocrine markers (Mod Pathol 2004;17:568)
- Positivity to neuroendocrine markers more common in type B than type A mucinous carcinoma (Front Oncol 2021;10:558760)
- Neuroendocrine carcinomas:
- Apocrine carcinoma:
- Abundant eosinophilic cytoplasm may resemble neuroendocrine differentiation
- Prominent nucleoli and vesicular chromatin distinguish apocrine from neuroendocrine differentiation
- Apocrine carcinomas are negative to neuroendocrine markers
- Lobular neoplasia:
- Monomorphic low grade nuclei in lobular neoplasia can be confused with neuroendocrine differentiation
- In situ lesions may appear similar to the nested pattern in neuroendocrine tumors
- Genuine neuroendocrine nuclear features are not observed in lobular neoplasia
- Lobular neoplasia is noninvasive with preserved myoepithelial cells
- Loss of E-cadherin staining confirmatory of lobular neoplasia
Additional references
Board review style question #1
Which of the following clinicopathological features best supports the diagnosis of a neuroendocrine tumor of breast primary (as compared to neuroendocrine tumors metastasizing to the breast)?
- Absence of carcinoid syndrome
- Negative imaging and endoscopy findings
- Negativity to TTF1
- Positivity to CK7
- Positivity to ER and PR
Board review style answer #1
B. Negative imaging and endoscopy findings. CK7 is also positive in neuroendocrine tumors of the lung. ER and PR positivity are not uncommon in neuroendocrine tumors of other primaries such as the lung and pancreas. TTF1 negative tumors are less likely of lung origin but do not exclude other primaries. Carcinoid symptoms are not reported in neuroendocrine tumors of the breast but do not exclude metastasis. Negative imaging and endoscopy findings best support the diagnosis of a primary neuroendocrine tumor of the breast by excluding metastasis from other sites (Hum Pathol 2001;32:1087, Arch Pathol Lab Med 2008;132:1889, Neuroendocrinology 2011;93:249, Am J Surg 2006;191:799).
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Reference: Neuroendocrine tumor of breast
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Reference: Neuroendocrine tumor of breast
Board review style question #2
In which of the following breast tumors are neuroendocrine markers most likely to be negative?
- Grade 1 neuroendocrine tumor
- Grade 2 neuroendocrine tumor
- Mucinous carcinoma, type A
- Mucinous carcinoma, type B
- Small cell carcinoma
Board review style answer #2
C. Mucinous carcinoma, type A. Neuroendocrine tumors and small cell carcinomas are neuroendocrine neoplasms of the breast. Solid papillary carcinomas and mucinous carcinomas are specific breast cancer subtypes with frequent neuroendocrine differentiation and positivity to neuroendocrine markers. Positivity to neuroendocrine markers is more common in type B than type A mucinous carcinoma (Front Oncol 2021;10:558760).
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Reference: Neuroendocrine tumor of breast
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Reference: Neuroendocrine tumor of breast
Nipple adenoma
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Gross images | Frozen section description | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Positive stains | Negative stains | Molecular / cytogenetics description | Videos | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2 | Board review style question #3 | Board review style answer #3Definition / general
- Nipple adenoma is a benign epithelial proliferation with a variety of morphological patterns that arise near the collecting ducts of the nipple and may be continuous with the overlying epidermis
Essential features
- Benign, often florid, epithelial proliferation with retained myoepithelial cell layer involving superficial ducts of the nipple; the proliferation may extend and replace the overlying squamous epithelium resulting in erosion, hemorrhage and inflammation
- Histologic patterns include a mix of sclerosing adenosis, papillary hyperplasia and usual ductal hyperplasia
Terminology
- Synonym: nipple duct adenoma
- Not recommended: florid papillomatosis of the nipple, erosive adenomatosis of the nipple, papillomatosis of the nipple, superficial papillary adenomatosis, papillary adenoma of the nipple
ICD coding
Epidemiology
- Rare; occurs in males and females
- Most common in women in the fifth decade of life but has a wide age range (5 months to 89 years)
Sites
- Breast; superficial duct orifices of the nipple, the associated stroma and often the adjacent overlying epidermis
Etiology
- Unknown
Clinical features
- Detected when small due to skin changes
- Clinically, epidermal involvement mimics the appearance of Paget disease
- On physical examination, small, palpable dermal nodule
- Nipple may appear eroded and erythematous as glandular epithelium replaces squamous epithelium
- Bleeding and exudative crust may be interpreted as nipple discharge
- If left untreated for years, may develop into large pedunculated mass (World J Surg Oncol 2014;12:91)
Diagnosis
- Diagnosis can be made on biopsy (often of the skin due to clinical presentation) or cytology specimen and confirmed on excision
- Imaging findings are generally nonspecific (see Radiology description)
Radiology description
- Mammography: undetected in 33% of cases due to superficial location and small size (World J Surg Oncol 2014;12:91)
- Ultrasound: nonspecific; may detect a circumscribed mass for larger lesions, with or without cystic components, hypervascular on Doppler (Chin Med J (Engl) 2016;129:2386)
- MRI: nipple may show enhancement (J Comput Assist Tomogr 2006;30:148)
Radiology images
Images hosted on other servers:
Mammography, ultrasound and MRI of palpable left nipple mass with clear nipple discharge
Mammography, sonography and MRI images of nipple adenoma
Prognostic factors
- Can recur if not completely excised
- Risk of developing a subsequent breast cancer is comparable to other proliferative lesions of the breast (Am J Surg Pathol 1986;10:87)
Case reports
- 22 year old woman with a papillomatous nodule on the left nipple from childhood (Clin Case Rep 2020;8:3254)
- 46 year old woman with pedunculated papillomatous mass on top of the nipple of the right breast (BMJ Case Rep 2019;12:e231516)
- 49 year old woman with a reddish nodule with surface crust on the nipple of the right breast (Dermatol Online J 2021;27)
- 82 year old woman with small painful mass in the right axilla (Diagn Pathol 2012;7:162)
Treatment
- Surgical excision depending on the size and extent of lesion (ANZ J Surg 2015;85:444)
- Alternative treatments:
- Mohs micrographic surgery (Dermatol Surg 2016;42:684)
- Cryotherapy (Breast J 2016;22:584, Ann Dermatol 2021;33:182)
Clinical images
Images hosted on other servers:
Nipple erythema and induration
Eroded crusted nipple adenoma
Nipple nodule with erosion
Pedunculated papillomatous nipple adenoma
Accessory breast nipple adenoma
Erosion and bloody discharge
Nipple adenoma, preoperative and postconservative excision
Gross description
- Rubbery; white to gray; 0.5 cm to > 4 cm
Gross images
Images hosted on other servers:
Complete nipple resection
Frozen section description
- Glandular nests of various sizes with diffuse growth within ducts lined by myoepithelial cells; complex and irregular structure may falsely mimic invasion (Chin Med J (Engl) 2007;120:630)
Microscopic (histologic) description
- Nodular florid epithelial proliferation of the lactiferous ducts of the nipple with papillary hyperplasia / adenosis / sclerosis / mixed pattern
- Epithelium is cytologically bland
- Myoepithelial cell layer is preserved uniformly (Mod Pathol 1990;3:288)
- 4 major morphologic patterns:
- Sclerosing papillary hyperplasia pattern:
- Intraductal papillary growth with prominent stromal proliferation (collagenous bands, myxoid change or elastosis)
- Focal central necrosis may be present
- Squamous cysts can be present in duct orifices
- Papillary hyperplasia pattern:
- Papillary growth in large ducts with less prominent stromal proliferation and focal necrosis
- Replacement of epidermis with glandular epithelium
- Adenosis pattern:
- Small duct proliferation with a pattern resembling sclerosing adenosis and may be pseudoinfiltrative
- Necrosis is uncommon
- Mixed pattern:
- Any combination of the above described patterns (Am J Surg Pathol 1986;10:87)
- Sclerosing papillary hyperplasia pattern:
- May be in continuity with the skin surface, which may appear eroded or ulcerated
- Fairly well circumscribed but unencapsulated (Br Med J 1963;1:563)
- Other features often seen:
- Squamous metaplasia and superficial keratin cysts
- Acanthosis
- Toker cell hyperplasia in the epidermis
- Multinucleated giant cells
- Apocrine metaplasia (Oncol Lett 2014;7:1839)
- In rare cases, ductal carcinoma in situ involving an adenoma or a contiguous invasive carcinoma have been reported (Mod Pathol 1995;8:633)
Microscopic (histologic) images
Contributed by Hal Berman, M.D., Ph.D., Miralem Mrkonjic, M.D., Ph.D. and Mary Ann Gimenez Sanders, M.D., Ph.D.
Epidermal involvement
Focal ulceration
Shave biopsy of nipple
Nipple duct involved by benign papillary proliferation
Well circumscribed epithelial proliferation
Epithelial hyperplasia and epidermal ulceration
Usual ductal hyperplasia with focal squamous metaplasia
Prominent squamous hyperplasia
Ductal carcinoma in situ
Prominent epithelial
proliferation with
papillary architecture
and tufting
Nipple section
Mixed pattern on mastectomy
Sclerosing adenosis
Papillary growth within ducts
Mixed pattern on punch biopsy
Florid usual ductal hyperplasia
Small tubules
Prominent epithelial proliferation
Virtual slides
Images hosted on other servers:
Nipple adenoma sclerosing
Nipple adenoma adenosis pattern
Nipple adenoma papillomatous pattern
Nipple adenoma florid usual ductal hyperplasia
Cytology description
- Obtained by fine needle aspiration (FNA), brush cytology or tumor imprint cytology
- Reported features vary; benign when myoepithelial cells are detected
- FNA:
- Large cell clusters with a papillary or sheet structure, as well as small clusters and solitary epithelial cells in a necrotic background
- Duct epithelial and myoepithelial 2 cell pattern in the clusters
- Round to oval or spindle nuclei, fine and bland chromatin
- Brush cytology (Diagn Cytopathol 2015;43:664):
- Small papillary clusters with attached myoepithelial cells and solitary epithelial cells in a hemorrhagic or neutrophilic background
- Round to oval nuclei, with smooth contour, bland and granular chromatin
- Squamous metaplasia-like cells present
- Cytology often classified as atypical or suspicious, especially in the presence of coagulative necrosis (ANZ J Surg 2015;85:444)
Positive stains
- AE1 / AE3, CK7: positive in epithelium (Mod Pathol 2003;16:893, Oncol Lett 2014;7:1839)
- p63, smooth muscle myosin, calponin: positive in myoepithelium (Oncol Lett 2014;7:1839, Am J Surg 2010;200:e39)
- ER and CK5/6: heterogeneous, mosaic type staining of the epithelium with florid usual ductal hyperplasia (Am J Surg Pathol 2010;34:896, Oncol Lett 2014;7:1839)
Negative stains
Molecular / cytogenetics description
- Activating PIK3CA mutations reported in 12/24 cases
- KRAS (1/24 cases) and BRAF mutations (2/24 cases) (Histopathology 2017;70:195)
Videos
Dr. Jerad Gardner presents normal nipple histology and 2 cases of nipple adenoma
3 minute overview of the presentation and histology of nipple adenomas
Sample pathology report
- Right breast (nipple), punch biopsy:
- Nipple adenoma (see comment)
- Comment: Sections show ductal proliferation involving a large nipple duct with areas of papillary growth and usual ductal hyperplasia in continuity with the epidermis. Ductal epithelial cells are cuboidal to columnar with eosinophilic cytoplasm and bland nuclei. Focal areas of stromal sclerosis are identified. Immunohistochemistry for smooth muscle myosin and p63 highlights the myoepithelial cell layer while ER and CK5/6 show heterogeneous staining patterns of epithelial cells. Taken together, the histomorphology and immunohistochemistry are consistent with a nipple adenoma.
Differential diagnosis
- Syringomatous tumor:
- Ducts with teardrop, comma and branching shapes
- Infiltrative growth with desmoplastic stroma, may see perineural invasion
- Does not involve the epidermis
- Invasive ductal carcinoma, no special type (low grade):
- Negative for myoepithelial cell markers (p63, smooth muscle myosin, calponin)
- Infiltrative growth pattern
- DCIS:
- Intraductal papilloma:
- Similar to nipple adenoma
- Papillary projections with fibrovascular cores
- Arises below the skin surface, involves lactiferous ducts within deeper breast parenchyma and is unlikely to be a palpable subdermal mass
- Tubular adenoma:
- Well circumscribed
- Uniform glands with scant stroma
- Encapsulated papillary carcinoma:
- Circumscribed mass found deeper in the breast compared with nipple adenomas
- Cytologic atypia
- Myoepithelial cells absent in papillae and along the periphery
Board review style question #1
A punch biopsy of the nipple was performed to sample a nodular lesion associated with skin changes in a 48 year old woman. What is the diagnosis?
- Ductal adenoma
- Intraductal papilloma
- Nipple adenoma
- Paget disease of the breast
- Tubular adenoma
Board review style answer #1
C. Nipple adenoma. Nipple adenoma is a benign epithelial proliferation in the breast, often in continuity with the epidermis of the nipple. It forms a nodular mass that can have a number of different morphologic patterns including sclerosing adenosis, papillary hyperplasia and epithelial hyperplasia. Myoepithelial cells are retained in nipple adenoma. Focal necrosis can be seen and squamous cysts can be seen superficially.
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Reference: Nipple adenoma
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Reference: Nipple adenoma
Board review style question #2
A fairly well circumscribed lesion associated with the nipple of a 55 year old woman and consisting of papillary growth within ducts with areas of focal central necrosis in areas of florid epithelial hyperplasia is suspected to be a nipple adenoma on needle core biopsy. What stain can be used to confirm this diagnosis?
- CK7
- ER
- HER2
- p53
- p63
Board review style answer #2
E. p63. Nipple adenoma is a benign epithelial proliferation of the breast that retains a myoepithelial cell layer. p63, a marker of myoepithelial cells, can be used to rule out invasive carcinoma and support the diagnosis of nipple adenoma.
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Reference: Nipple adenoma
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Reference: Nipple adenoma
Board review style question #3
A 54 year old woman presents with erythema, erosion and crusting of the nipple. A punch biopsy is performed showing nipple adenoma. Which of the following statements is true regarding nipple adenomas?
- HER2 positivity is an essential characteristic of nipple adenomas
- Myoepithelial cells are absent in nipple adenoma
- Sclerosing adenosis, papillary hyperplasia and epithelial hyperplasia can be seen in mixed patterns in a nipple adenoma
- The presence of necrosis excludes nipple adenoma in the differential diagnosis
- The skin changes that can be seen in nipple adenoma are clinically distinct from Paget disease
Board review style answer #3
C. Sclerosing adenosis, papillary hyperplasia and epithelial hyperplasia can be seen in mixed patterns in a nipple adenoma. Nipple adenoma is a benign breast lesion and can consist of sclerosing adenosis, papillary hyperplasia and epithelial hyperplasia, which can be seen in mixed patterns. Necrosis can sometimes be seen in areas of florid epithelial hyperplasia. The myoepithelial cell layer is retained and HER2 IHC is negative. Nipple adenoma can present clinically with skin changes that are very similar to Paget disease.
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Reference: Nipple adenoma
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Reference: Nipple adenoma
Nonproliferative fibrocystic changes
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Diagrams / tables | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Nonspecific, general term to describe a range of common and benign breast conditions, which may occur together or in isolation
- Cause clinical, radiographic (e.g. calcifications, mass or architectural distortion) or histologic changes of the breast tissue that may result in concern for malignancy
- Nonproliferative and nonatypical fibrocystic changes are not associated with increased risk of subsequent breast carcinoma
- Some proliferative fibrocystic changes are associated with a slightly increased risk of subsequent breast carcinoma
Essential features
- Histologically benign structural alterations in epithelial and stromal elements
Terminology
- Fibrocystic disease
- Use in surgical pathology reports is discouraged (N Engl J Med 1982;307:1010, N Engl J Med 1985;312:179)
- Diffuse cystic mastopathy
ICD coding
- ICD-10: N60.19 - diffuse cystic mastopathy of unspecified breast
Epidemiology
- Common, affecting 50% of women (Dtsch Arztebl Int 2019;116:565)
- Occurs during reproductive years, usually presenting between the ages of 25 - 45 years
- Reduced incidence in postmenopausal women (Am J Obstet Gynecol 1986;154:161)
Sites
- Breast
- Can occur in axilla from the accessory breast tissue
Pathophysiology
- Excess estrogen leads to proliferation of epithelium in terminal duct lobular units and induces stromal fibrosis
- Fibrosis and epithelial proliferation may lead to obstruction of ducts and acini, leading to involution or cyst formation
- Some cysts may rupture, inducing adjacent fibroinflammatory stromal reactions
- Reference: J Adv Sci Res 2020;11:30
Etiology
- Associated with hormonal imbalance (increased estrogen to progesterone ratio) (Am J Obstet Gynecol 1986;154:161)
Diagrams / tables
Images hosted on other servers:
Breast tissue with cysts
Clinical features
- Breast pain, tenderness, lumpiness, cysts or mass
- Manifestations may be cyclic, reflecting menstrual cycle
- Associated with polycystic ovary syndrome (Arch Gynecol Obstet 2009;280:249)
- Usually bilateral, although one breast may be affected more than the other
- Symptoms tend to abate after menopause
- Nonproliferative lesions are the most common finding in breast cancer screening biopsies, accounting for about 70% of all cases (N Engl J Med 2005;353:275)
Diagnosis
- Needle biopsy, needle aspiration or excisional biopsy
Radiology description
- Ultrasound: may be a solid mass, cyst, heterogeneous echogenic tissue or no visible abnormality (Invest Radiol 2005;40:436)
- MRI: mass or a nonmass-like regional enhancing lesion with benign enhancement kinetics (Invest Radiol 2005;40:436)
- Can also present as densities with associated calcifications, areolar skin thickening alone or normal dense fibroglandular tissue with no abnormality on mammogram (Invest Radiol 2005;40:436)
Radiology images
Images hosted on other servers:
Increased fibroglandular density
Prognostic factors
- Risk of breast cancer (Am J Surg Pathol 2003;27:836)
- Nonproliferative lesions: no increased risk
- Proliferative lesions without atypia: 1.5 - 2 fold risk
Case reports
- 2 year old girl with an ill defined lump (Fetal Pediatr Pathol 2021;40:535)
- 35 year old woman with left breast lump that was diagnosed as cystic fibroadenoma (Breast Dis 2015;35:49)
- 38 year old woman with left breast enlargement (Am J Case Rep 2018;19:1550)
- 43 year old woman with right breast lump that was diagnosed as cystic fibroadenoma (Turk Patoloji Derg 2011;27:254)
Treatment
- Close clinical follow up of patients with high risk for breast cancer, including physical examination (every 4 - 6 months) and mammography (every 1 - 2 years) in most patients (Am J Obstet Gynecol 1986;154:161, N Engl J Med 2005;353:275)
- Nonsteroidal anti-inflammatory drugs, aspirin or hormonal manipulation with low estrogen oral contraceptive, cyclic progestogen or danazol therapy is used less commonly in women with cyclical breast pain (Am J Obstet Gynecol 1986;154:161, N Engl J Med 2005;353:275)
Gross description
- Breast tissue is heterogeneously fibrous and indurated
- Cysts ranging from 1 - 20 mm, clear or blue domed, may be seen
Gross images
Images hosted on other servers:
Cysts surrounded by fibrous tissue
Irregular fibrosis and small cysts
Fibrosis and dilated ducts
Microscopic (histologic) description
- Nonproliferative fibrocystic changes; characterized by 3 features: adenosis, fibrosis and cyst formation
- Adenosis:
- Increased number of acini per lobule
- Acini are lined by columnar cells, which may be benign or have atypia
- Adenosis is frequently seen in pregnancy and may be focal in nonpregnant women
- Fibrosis:
- Stromal fibrosis
- Cyst rupture may result in chronic inflammation, prominent histiocytic reaction and fibrosis
- Causes increased density observed on imaging and nodularity observed on palpation
- Cyst formation:
- Cystically dilated ducts or lobules
- May contain eosinophilic secretions, foamy macrophages and calcifications
- Lined by cuboidal epithelium or may have apocrine metaplasia
- Outer myoepithelial layer present but may be attenuated
- Apocrine metaplasia: single or multilayered ductal epithelium with abundant granular eosinophilic cytoplasm, apical snouts, enlarged nuclei and prominent nucleoli
- Columnar cell changes / columnar cell hyperplasia: enlargement of terminal duct lobule with variably dilated lumens and irregular contours, lined by cuboidal to columnar cells, lacking cytologic atypia, frequently with apical snouts
- Adenosis:
Microscopic (histologic) images
Contributed by Apeksha N. Agarwal, M.B.B.S., M.D.
Fibrocystic change
Apocrine metaplasia
Fibrosis, cysts and microcalcifications
Cysts
Cytology description
- Nonproliferative breast lesions
- Apocrine cells, foam cells and small, uniform, evenly spaced ductal epithelial cells
- Proliferative breast lesions
- Sheets and tight clusters of cells without significant nuclear overlap
- Reference: Clin Lab Med 2005;25:713
Cytology images
Contributed by Areej M. Al Nemer, M.D.
Fibrocystic change
Apocrine metaplasia
Sample pathology report
- Breast, 12:00, microcalcifications, stereotactic core needle biopsy:
- Benign breast parenchyma with fibrocystic changes, including florid usual type ductal hyperplasia and apocrine metaplasia
- Microcalcifications associated with apocrine metaplasia
Differential diagnosis
- Proliferative lesions without atypia:
- Mild usual ductal hyperplasia:
- Proliferation of ductal epithelium no more than 3 or 4 cell layers in thickness
- Moderate to severe (florid):
- Proliferation of ductal epithelium more than 4 cell layers in thickness that may fill and extend the luminal space
- Arrangement of nuclei is haphazard, with cellular heterogeneity, oval nuclei with grooves and small indistinct nucleoli
- Sclerosing adenosis:
- Lobulocentric proliferation of acini within dense hyaline sclerotic stroma
- Intraluminal calcifications may be present
- Mild usual ductal hyperplasia:
- Cystic fibroadenoma:
- Fibroadenoma with extensive cystic changes and cysts that are more than 3 mm (Breast Dis 2015;35:49, Turk Patoloji Derg 2011;27:254)
- Pseudoangiomatous stromal hyperplasia:
- Stroma with prominent slit-like spaces lined by bland spindle cells; the slit-like spaces are empty and have an anastomosing appearance
Additional references
Board review style question #1
Which of the following is true about proliferative fibrocystic changes in the breast?
- Apocrine metaplasia is considered a proliferative fibrocystic change
- Duct ectasia is considered a proliferative fibrocystic change
- Proliferative fibrocystic change has no associated increased lifetime risk of breast cancer
- Proliferative fibrocystic change without atypia has an associated 1.5 - 2 fold increased lifetime risk of breast cancer
Board review style answer #1
D. Proliferative fibrocystic change without atypia has an associated 1.5 - 2 fold increased lifetime risk of breast cancer
Comment Here
Reference: Fibrocystic changes
Comment Here
Reference: Fibrocystic changes
Board review style question #2
A 40 year old woman presents with heterogeneous echogenic tissue in the breast on ultrasound. Which of the following is shown in the biopsy above?
- Atypical ductal hyperplasia
- Columnar cell change
- Duct ectasia
- Flat epithelial atypia
Board review style answer #2
B. Columnar cell change. The biopsy shows classic findings of fibrosis, cystic changes and microcalcifications along with the lining epithelium in a couple of cysts lined by columnar epithelium.
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Reference: Fibrocystic changes
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Reference: Fibrocystic changes
NST, rare variants
Table of Contents
Choriocarcinomatous / pleomorphic patterns (pending) | Clear cell (pending) | Glycogen rich | Lipid rich | Oncocytic (pending) | Osteoclast | Sebaceous | Signet ring cellChoriocarcinomatous / pleomorphic patterns (pending)
Clear cell (pending)
Glycogen rich
Definition / general
Radiology images
Images hosted on other servers:
Prognostic factors
Case reports
Gross images
Images hosted on other servers:
Microscopic (histologic) description
Microscopic (histologic) images
AFIP images
Images hosted on other servers:
Cytology description
Positive stains
Negative stains
Electron microscopy description
Differential diagnosis
Additional references
- Breast carcinoma in which at least 90% of the neoplastic cells have abundant clear cytoplasm due to glycogen
- First described in 1981 (Cancer 1981;48:2003)
- Rare, 1% - 3% of breast carcinomas
- May be a variant of apocrine carcinoma
Radiology images
Images hosted on other servers:
Mammogram shows circumscribed mass
Prognostic factors
- Prognosis similar to invasive ductal carcinoma (Am J Surg Pathol 1995;19:904)
Case reports
- 33 year old woman whose tumor had neuroendocrine features (Pathologica 2001;93:676)
- 45 year old woman with solid papillary tumor (J Clin Pathol 2003;56:552)
- 55 year old woman (Case Rep Oncol 2011;4:452)
- 59 year old woman (World J Surg Oncol 2008;6:44)
- 61 year old woman (Arch Med Lab Pathol 2003;127:1629)
- Intraductal lipid rich carcinoma with component of glycogen rich carcinoma (J Breast Cancer 2012;15:135)
Gross images
Images hosted on other servers:
Solid papillary pattern within cystically dilated duct
Microscopic (histologic) description
- Solid or solid / papillary patterns of large clear cells with distinct cell borders containing glycogen in 90% or more cells
- Often associated with intraductal component of varied type
- Often has apocrine features
- Cells have clear to granular cytoplasm
- May have scant intracellular mucin (Histopathology 1987;11:857)
- No cytoplasmic vacuoles
Microscopic (histologic) images
AFIP images
PAS+ dark granules
Clear cells
Sheets of polygonal cells
Images hosted on other servers:
Ample clear cytoplasm
PAS positive
Abundant calcifications
Resembles renal clear cell carcinoma
Intraductal lipid rich carcinoma with component of glycogen rich carcinoma
CK8 / 18+
Polygonal cells
Cytology description
- Hypercellular with tumor cells in loosely cohesive syncytial groups and some single cells
- Most tumor cells have abundant, finely granular eosinophilic cytoplasm or foamy to clear cytoplasm with well defined cytoplasmic membranes and moderate / marked nuclear pleomorphism with central round/oval nuclei containing prominent nucleoli (Acta Cytol 2008;52:65)
- PAS staining may be helpful (J Med Invest 2002;49:193)
Positive stains
- PAS diastase sensitive (glycogen)
Negative stains
- CK20, lipid stains (done on fresh / frozen tissue)
Electron microscopy description
- Non membrane bound glycogen and empty glycogen lakes
- Tight junctions between tumor cells, immature desmosomes, occasional short microvilli (Am J Surg Pathol 1986;10:553)
Differential diagnosis
- Apocrine carcinoma
- Clear cell sugar tumor:
- Positive for melanocytic markers (Am J Surg Pathol 2002;26:670)
- Lipid rich carcinoma:
- Positive for lipid stains, negative for glycogen
- Myoepithelial lesions
- Secretory carcinoma:
- Younger patients, low grade histology
Additional references
Lipid rich
Definition / general
Clinical features
Prognostic factors
Case reports
Gross description
Microscopic (histologic) description
Microscopic (histologic) images
AFIP images
Positive stains
Negative stains
Electron microscopy description
Electron microscopy images
AFIP images
Differential diagnosis
- 90%+ cells have prominent intracytoplasmic neutral lipid
Clinical features
- 1% - 2% of breast carcinomas
- Axillary metastases may resemble histiocytes
Prognostic factors
- Poor prognosis due to frequent (70%) nodal metastases at presentation
Case reports
- 53 year old woman (Acta Chir Belg 2008;108:115)
- 55 year old man (Pathology 1995;27:280)
- 56 year old woman with focal chondroid metaplasia in tumor (Pathol Int 1998;48:912)
- 62 year old woman (Arch Pathol Lab Med 2003;127:e396)
- 78 year old woman with solid alveolar pattern in tumor (Breast Cancer 1998;5:171)
Gross description
- Lobulated, variable circumscription, firm
- 1 to 15 cm
Microscopic (histologic) description
- Nests, cords and sheets of large polygonal cells with foamy or vacuolated cytoplasm containing lipid
- May resemble clear cells or lipoblasts
- Irregular nuclei with coarse chromatin, moderate atypia, prominent nucleoli
- Other patterns are large pleomorphic cells in alveolar pattern with hobnail appearance, oncocytic or apocrine type change
Microscopic (histologic) images
AFIP images
Polygonal tumor cells
Positive stains
- Lipid stains (Sudan black, Oil red O on fresh tissue)
- HER2 (71%+) (Tumori 2008;94:342, Ann Diagn Pathol 2011;15:225)
Negative stains
Electron microscopy description
- Numerous intracytoplasmic non membrane bound lipid droplets, often within autophagocytic vacuoles
- No evidence of lipid synthesis by rough ER or Golgi complexes (Virchows Arch A Pathol Anat Histopathol 1988;413:381)
Electron microscopy images
AFIP images
Luminal microvilli, lipid droplets and mitochondria
Differential diagnosis
- Apocrine carcinoma:
- Uniformly granular and eosinophilic cytoplasm, GCDFP-15+, no lipid
- Glycogen rich carcinoma:
- Clear cytoplasm, secretions are glycogen (PAS+), not lipid
- Oncocytic carcinoma:
- Granular and markedly eosinophilic cytoplasm, no lipid
- Secretory carcinoma:
- Low grade, PASd+ secretions, no lipid
- Xanthogranulomatous mastitis (on core biopsy):
- Not invasive, cells are CD68+, alpha-1-antitrypsin+ histiocytes (Pathol Int 2009;59:234)
Oncocytic (pending)
Osteoclast
Definition / general
Case reports
Gross description
Microscopic (histologic) description
Microscopic (histologic) images
Images hosted on other servers:
Cytology description
Positive stains
Negative stains
Electron microscopy description
Additional references
- Part of WHO classification
- Osteoclastic giant cells are present in stroma
- Presence of giant cells does not alter prognosis
Case reports
- 44 year old and 83 year old women (Diagn Pathol 2010;23:55)
- 46 year old woman (Radiographics 2002;22:691)
- 51 year old woman with pleomorphic carcinoma and prominent osteoclastic giant cells (Pathol Int 2009;59:91)
- Cases with neuroendocrine carcinoma (Pathologica 2008;100:176)
Gross description
- Often brown due to vascular stroma with hemosiderin
Microscopic (histologic) description
- Giant cells are associated with vascular stroma with extravasated red blood cells and hemosiderin, also chronic inflammatory cells and fibroblasts
- Giant cells have variable size and variable numbers of nuclei
- Similar histologic features in nodal metastases and recurrences (Arch Pathol Lab Med 1986;110:636)
- Carcinoma component may be any type
Microscopic (histologic) images
Images hosted on other servers:
Invasive ductal carcinoma of the breast with osteoclast-like giant cells
Various images
Differentiated well cribriform carcinoma
Osteoclast-like giant cells in close contact to tumor cells
Cytology description
- Abundant giant cells and mononucleated stromal cells associated with carcinoma cells (Diagn Cytopathol 2005;33:246)
Positive stains
- Osteoclastic giant cells: CD68; also acid phosphatase, lysosome, nonspecific esterase; also MMP9, TRAP, cathepsin K
Negative stains
Electron microscopy description
- Osteoclasts are histiocytes
Additional references
Sebaceous
Definition / general
Clinical features
Case reports
Microscopic (histologic) description
Microscopic (histologic) images
Images hosted on other servers:
Positive stains
Negative stains
Electron microscopy description
Differential diagnosis
- Very rare primary breast carcinoma resembling skin adnexal tumor with sebaceous differentiation, but no evidence of cutaneous derivation (see J Med Case Rep 2008;2:276 for cutaneous tumor of breast)
Clinical features
- Associated with Muir-Torre syndrome (Cancer 2005;103:1018)
Case reports
- 45 year old woman with extensive metastatic disease (Pathol Int 2000;50:63)
- 46 year old woman with Muir-Torre syndrome (AJR Am J Roentgenol 2000;174:541)
- 50 year old woman (Pathol Int 2009;59:188)
- 63 year old woman (Virchows Arch 2006;449:484)
- 83 year old woman with tumor of nipple (J Cutan Pathol 2008;35:608)
Microscopic (histologic) description
- Well defined solid sheets or lobules of atypical epithelial cells, including large, pale or clear cells with coarsely vacuolated cytoplasm, containing Oil red O staining lipid and often scalloped nuclei
- Often focal squamous morules
Microscopic (histologic) images
Images hosted on other servers:
Skin
Positive stains
- Cytokeratin, including 35betaH11, EMA (Pathol Res Pract 1993;189:888)
- ER, PR, Oil Red O
- Mismatch repair genes: MLH1, PMS2, MSH2, MSH6 (Ceska Gynekol 2010;75:50)
- Some cells may express neuroendocrine markers
Negative stains
- GCDFP-15, CEA, S100 and vimentin
- Alpha smooth muscle actin, p63, androgen receptor (usually), mucins, HER2 and CK15
Electron microscopy description
- Empty appearing, non membrane bound vacuoles
Differential diagnosis
- Apocrine carcinoma:
- > 90% of tumor cells have cytologic or immunohistochemical features of apocrine cells
- Lipid rich carcinoma:
Signet ring cell
Definition / general
Case reports
Microscopic (histologic) description
Microscopic (histologic) images
Images hosted on other servers:
Cytology description
Differential diagnosis
- Ductal carcinoma with cells resembling gastric carcinoma due to acidic mucin that fills cytoplasm and displaces nucleus
- Excludes cases with lobular features (signet ring cell variant of lobular carcinoma)
Case reports
- 40 year old woman with signet ring cell carcinoma of the breast as a source of pelvic floor metastatic mass (Acta Chir Belg 2005;105:224)
- 52 year old woman with signet ring cell carcinoma associated with invasive ductal carcinoma (Breast Cancer 1999;6:223)
- 54 year old woman with signet ring cell carcinoma of the breast with uterine metastasis (J Obstet Gynaecol Res 2012;38:948)
- 68 year old woman with signet ring cell carcinoma of the breast (Pathol Int 2000;50:67)
- 73 year old woman with invasive ductal carcinoma of the breast with signet ring cell and mucinous carcinoma components (Diagn Cytopathol 2007;35:171)
- 74 year old woman with metastatic breast cancer to the stomach (Case Rep Oncol 2010;3:142)
- Ductal type signet ring cell carcinoma of breast (Pathology 2011;43:282)
Microscopic (histologic) description
- Mucin fills cytoplasm and displaces nucleus
- Usually coexists with invasive ductal NOS
- High nuclear grade; DCIS may be present, but no lobular features (by definition)
Microscopic (histologic) images
Images hosted on other servers:
Breast metastasis to stomach
Cytology description
- Look for signet ring cells if plasmacytoid cells are identified
- Favor ductal carcinoma if hypercellular, single signet ring cells, high nuclear grade and tubule formation
- Favor lobular carcinoma if hypocellular, single signet ring cells and mild / moderate nuclear grade (Cytopathology 2009;20:321)
Differential diagnosis
- Metastatic GI signet ring cell carcinoma:
- History, no DCIS, CDX2+ and ER- (Am J Clin Pathol 2004;121:884, ISRN Obstet Gynecol 2011;2011:426150)
- Signet ring cell variant of lobular carcinoma:
- Usually classic lobular component present, no DCIS, ER+ and E-cadherin negative
Other sarcomas
Table of Contents
Leiomyosarcoma | Low grade myofibroblastic sarcoma | Osteosarcoma | Rhabdomyosarcoma | Stromal sarcoma | Undifferentiated pleomorphic sarcomaLeiomyosarcoma
Definition / general
Essential features
Etiology
Clinical features
Radiology description
Prognostic factors
Case reports
Treatment
Gross images
Images hosted on other servers:
Microscopic (histologic) description
Microscopic (histologic) images
Contributed by Emily S. Reisenbichler, M.D., Mark R. Wick, M.D. and AFIP
Cytology description
Cytology images
Images hosted on other servers:
Positive stains
Negative stains
Molecular / cytogenetics description
Differential diagnosis
- Malignant smooth muscle neoplasm of the breast
Essential features
- Rare, < 1% of all breast malignancies
- < 50 primary leiomyosarcomas of the breast reported in the literature
- Should be distinguished from metastatic tumor
Etiology
- Primary tumors likely arise from smooth muscle of the nipple or vascular wall
- Have been reported to occur secondary to radiation (Surg Case Rep 2015;1:76)
Clinical features
- Occur most frequently in the fourth and seventh decades of life, typically in postmenopausal women (Case Rep Pathol 2012;2012:491984)
- Average size of 5 cm
Radiology description
- Mammographically presents as a mass or architectural distortion
- By ultrasound, lesions are homogenously hypoechoic, lobular or oval with microlobulated or indistinct margins (Acta Radiol 2011;52:597)
Prognostic factors
- Type of surgery does not affect prognosis as long as the tumor is excised with an adequate (2 - 3 cm) margin (Breast 2011;20:389)
- Due to the rare nature of this tumor, no specific prognostic features are established in primary leiomyosarcoma arising in the breast
- If the tumor is cutaneous and limited to the dermis of the breast skin (i.e., atypical intradermal smooth muscle neoplasm), rather than arising in the mammary parenchyma, prognosis is excellent without metastases
Case reports
- 18 year old woman with leiomyosarcoma invading the breast skin (Breast 2011;20:389)
- 19 year old woman with primary leiomyosarcoma clicinally suspected to be fibroadenoma (Case Rep Pathol 2012;2012:491984)
- 51 year old woman with primary breast leiomyosarcoma located in the premammary zone / subcutaneous fat (Clin Imaging 2015;39:1105)
- 59 year old woman with leiomyosarcoma arising in irradiated region after breast conserving surgery (Surg Case Rep 2015;1:76)
Treatment
- As no axillary lymph node metastases have been reported with primary breast leiomyosarcoma, sentinel lymph node excision is not indicated (Breast 2011;20:389)
- Wide excision with at least 2 cm margin but 3 cm margin is recommended (Breast 2011;20:389)
- In tumors > 3 cm or with inadequate excision, radiotherapy may be indicated
- Adjuvant chemotherapy may result in greater clinical response in radiation induced sarcomas (Surg Case Rep 2015;1:76)
Gross images
Images hosted on other servers:
Lobulated elastic tumor
Microscopic (histologic) description
- Intersecting fascicle of spindled cells with abundant eosinophilic cytoplasm and cigar shaped nuclei demonstrating variable pleomorphism, mitotic activity and necrosis
- Tumor borders are typically infiltrative
Microscopic (histologic) images
Contributed by Emily S. Reisenbichler, M.D., Mark R. Wick, M.D. and AFIP
Interesecting fascicles, pleomorphic nuclei and mitotic activity
Nuclear pleomorphism and mitotic activity
Dense cellularity and intersecting fascicles
Dermis involvement
Parenchyma
Desmin
Cytology description
- Large, dissociated round to spindle cells, medium to large, with abundant vacuolated cytoplasm with occasional intranuclear cytoplasmic invaginations
- Mitotic activity, including abnormal forms, nuclear atypia and a necrotic background favor a malignant process
- Immunohistochemistry is typically required to distinguish leiomyosarcoma from other malignant spindle cell tumors of the breast (Diagn Pathol 2006;1:13)
Cytology images
Images hosted on other servers:
Spindle cell lipoma
Positive stains
Negative stains
Molecular / cytogenetics description
- Loses of 16q and 1p (Oncogene 2010;29:845)
Differential diagnosis
- Leiomyosarcomatous differentiation in a malignant phyllodes tumor
- Metaplastic (spindle cell) carcinoma
- Myofibroblastoma
Low grade myofibroblastic sarcoma
Definition / general
Essential features
Prognostic factors
Case reports
Treatment
Gross description
Microscopic (histologic) description
Microscopic (histologic) images
Contributed by Mark R. Wick, M.D.
Positive stains
Negative stains
Electron microscopy description
Molecular / cytogenetics description
Differential diagnosis
- Spindle cell sarcoma with myofibroblastic differentiation
- Also called myofibrosarcoma
Essential features
- Uncommon tumor overall, occurring predominantly in the head and neck or extremities with only rare reports within the breast
- At least moderate cytologic atypia must be seen focally
- Not part of WHO breast classification
Prognostic factors
- Frequently recurs, particularly when incompletely excised
- Low rates of metastasis but lung is most common site when it occurs (Am J Surg Pathol 2001;25:219)
Case reports
- 46 year old woman with palpable low grade myofibroblastic sarcoma (J Clin Oncol 2005;23:6249)
- 55 year old woman with diffuse pleuropulmonary metastases (Am J Surg Pathol 1997;21:489)
- 61 year old woman with low grade myofibroblastic sarcoma arising in a fibroadenoma (Diagn Pathol 2016;11:33)
- 81 year old woman with myofibrosarcoma (Breast J 2011;17:300)
Treatment
- Complete local excision with negative margins
- Radiation has been used but its effectiveness is unclear (Laryngoscope 2016 Jul 5 [Epub ahead of print])
Gross description
- Well circumscribed tumor with firm, pale cut surface, despite infiltrative microscopic growth
Microscopic (histologic) description
- Spindle cells in a fascicular or storiform growth pattern
- Variable stromal collagen
- Cells demonstrate pale eosinophilic cytoplasm and the nuclei must show at least moderate atypia focally and hyperchromasia
- Diffusely infiltrative borders
Microscopic (histologic) images
Contributed by Mark R. Wick, M.D.
Low grade myofibroblastic sarcoma
Positive stains
Negative stains
- S100, keratins, EMA, CD34 (focal staining has been reported), h-caldesmon, nuclear beta-catenin
Electron microscopy description
- Prominent rough endoplasmic reticulum, peripheral myofilaments and the fibronectin fibrils of the fibronexus junctions (J Clin Pathol 2009;62:236)
Molecular / cytogenetics description
- Gains at 1p11 → p36.3 (66%), 12p12.2 → p13.2 (45%), 5p13.2 → p15.3 (31%), +22 (28%), loss at 15q25 → q26.2 (24%) (Am J Clin Pathol 2009;131:701)
- Complex DNA copy number changes
- Higher average number of chromosomal aberrations than seen in nodular fasciitis
Differential diagnosis
- Desmoid fibromatosis:
- Long sweeping fascicles with stromal collagen deposition
- Lacks cytologic atypia
- Inflammatory myofibroblastic tumor:
- Variably cellular fascicles
- Background lymphoplasmacytic infiltrate
- Lacks cytologic atypia
- ALK positive in ~50%
- Leiomyosarcoma:
- Shorter fascicles, lacks stromal collagen, h-caldesmon positive
- Myofibroblastoma:
- Myofibromatosis:
- Lacks cytologic atypia
- Biphasic fascicular and pericytoma-like areas
- Nodular growth, protruding into vascular spaces
- Lacks cytologic atypia
- Nodular fasciitis:
- Lacks fascicular growth pattern and cytologic atypia
- Border is typically not infiltrative
- Usually small (< 3 cm)
- Solitary fibrous tumor:
- Spindle cells lacking a fascicular architecture (i.e., patternless pattern)
- Hemangiopericytoma-like vessels
- Spindle cell (metaplastic) carcinoma:
- At least focal keratin positivity
- Spindle cell rhabdomyosarcoma:
Osteosarcoma
Definition / general
Essential features
Etiology
Clinical features
Radiology description
Prognostic factors
Case reports
Treatment
Gross description
Gross images
Contributed by Nitin Marwaha, M.D.
Microscopic (histologic) description
Microscopic (histologic) images
Contributed by Emily S. Reisenbichler, M.D. and Nitin Marwaha, M.D.
Positive stains
Negative stains
Differential diagnosis
- Malignant osteoid producing neoplasm
Essential features
- Exceedingly rare tumor in the breast with < 150 reported cases in the literature
- Comprised of cytologically malignant cells with osteoid production, lacking morphologic or immunohistochemical evidence of an epithelial / carcinomatous component
- Must extensively sample tumors to exclude diagnoses of malignant phyllodes with osteosarcomatous differentiation and metaplastic carcinoma with osteogenic matrix production
- Some experts believe that most, if not all, reported osteosarcomas of the breast actually represent matrix producing carcinomas (Breast 2013;22:13)
Etiology
- Has been reported to occur following radiation therapy (Case Rep Oncol 2013;6:367)
Clinical features
- Typically presents in the fifth or sixth decade of life
- Large, palpable mass
Radiology description
- Irregular hyperdense mass by mammography
- Hypoechoic mass by ultrasound
Prognostic factors
- Tumor size is the single most reliable prognostic factor in primary breast sarcomas (Br J Cancer 2004;91:237)
Case reports
- 63 year old woman with primary osteosarcoma of the breast 3 years following surgical excision of metaplastic ossification (J Med Case Rep 2016;10:231)
- 65 year old woman with osteosarcoma of the breast developing 1 year following the identification of a calcified fibroadenoma (Clin Case Rep 2015;4:62)
- 69 year old woman with a 10 cm primary osteosarcoma of the breast (Rev Assoc Med Bras (1992) 2015 ;61:497)
- 87 year old with breast osteosarcoma 29 years after radiation therapy for breast carcinoma (Case Rep Oncol 2013;6:367)
Treatment
- Complete resection with negative margins
- Routine axillary lymph node dissection not necessary due to tendency to metastasize to lungs rather than regional lymph nodes
- Utility of adjuvant radiation or chemotherapy is unclear due to rarity of this tumor type in this location
Gross description
- Well circumscribed large tumor with firm to gritty cut surface
- Difficulty in sectioning possible if abundant osteoid production present
Gross images
Contributed by Nitin Marwaha, M.D.
Well circumscribed, bony hard mass
Microscopic (histologic) description
- Spindle to epithelioid cells with nuclear atypia, hyperchromasia and mitotic activity, including atypical forms
- Lace-like osteoid production
- Absence of an in situ carcinoma component
Microscopic (histologic) images
Contributed by Emily S. Reisenbichler, M.D. and Nitin Marwaha, M.D.
Osteosarcoma, 40x magnification
Osteosarcoma, 60x magnification
45 year old woman with right breast mass
Positive stains
- SATB2: may also be focally positive in a subset of breast carcinomas (Adv Anat Pathol 2015;22:149)
Negative stains
- Cytokeratins (typically high molecular weight keratins such as CK5 / 6) and myoepithelial markers (such as p63): to rule out a metaplastic carcinoma
Differential diagnosis
- Metaplastic carcinoma:
- Presence of an epithelial / carcinomatous component, associated DCIS or demonstration of epithelial differentiation with immunohistochemistry (i.e., cytokeratins, myoepithelial markers, EMA)
- Malignant phyllodes with osteosarcomatous differentiation:
- Thorough sampling of the tumor reveals an epithelial component
- Benign heterotopic ossification / fasciitis ossificans:
- Mature lamellar bone formation lacking the zonation seen in myositis ossificans
- Intervening cells lack significant pleomorphism, hyperchromasia and mitotic activity
- Metastatic osteosarcoma:
- Clinical history of primary osteosarcoma elsewhere
Rhabdomyosarcoma
Definition / general
Essential features
Clinical features
Radiology description
Prognostic factors
Case reports
Treatment
Clinical images
Contributed by Mark R. Wick, M.D.
Gross description
Gross images
Images hosted on other servers:
Microscopic (histologic) description
Microscopic (histologic) images
Contributed by Mark R. Wick, M.D.
Cytology images
Contributed by Mark R. Wick, M.D.
Positive stains
Negative stains
Electron microscopy description
Molecular / cytogenetics description
Differential diagnosis
- Malignant neoplasm with skeletal muscle differentiation
Essential features
- Comprises < 3% of all adult primary soft tissue sarcomas and exceedingly rare as a primary breast tumor
- Primary rhabdomyosarcoma of the breast is most commonly alveolar subtype and is seen more frequently in the pediatric / adolescent population (Med Pediatr Oncol 1997;29:181)
- Typically composed of small, round to spindled cells, with eosinophilic cytoplasm, some of which show cytoplasmic cross striations (embryonal and alveolar subtypes); larger cells with greater degree of atypia seen in pleomorphic subtype
- Must exclude other tumor types with heterologous rhabdomyosarcomatous differentiation (such as malignant phyllodes)
Clinical features
- Primary rhabdomyosarcoma of the breast is seen most frequently in the pediatric / adolescent population and therefore is not typically identified by routine screening mammography
- Presents as a palpable, circumscribed, rapidly growing mass
- Presentation as a metastasis from a primary rhabdomyosarcoma elsewhere in the body occurs in 3 - 6% cases and portends a very poor prognosis (J Pediatr Hematol Oncol 2017;39:62)
Radiology description
- Due to the breast density of the pediatric and adolescent population, ultrasound is the imaging modality of choice for radiographic characterization of this tumor type (Eur J Radiol 2003;48:282)
- Hypoechoic, round or lobulated nodule / mass by ultrasound
Prognostic factors
- Patients with primary breast alveolar rhabdomyosarcoma have a poor prognosis, frequently dying of disease with disseminated metastases (J Pediatr Hematol Oncol 2017;39:62)
- Embryonal subtype portends much better prognosis than alveolar or pleomorphic subtypes
Case reports
- 13 year old girl with primary alveolar rhabdomyosarcoma of the breast (Surg Today 2007;37:38)
- 19 year old woman with primary mammary rhabdomyosarcoma (Indian J Cancer 2015;52:295)
- 49 year old woman with primary pleomorphic rhabdomyosarcoma of the breast (J Res Med Sci 2014;19:1200)
Treatment
- As with all primary breast sarcomas, wide excision without axillary dissection is the mainstay of treatment
- Adjuvant or neoadjuvant radiation often used in large or incompletely resected tumors
- Utility of chemotherapy is unclear due to the rarity of this tumor type
Clinical images
Contributed by Mark R. Wick, M.D.
Alveolar
Gross description
- Circumscribed, nonencapusulated mass
Gross images
Images hosted on other servers:
Large fungating mass involving right breast
Large firm lobulated tumor
Microscopic (histologic) description
- 3 microscopic subtypes:
- Alveolar: sheets of small, round cells clustered with variable amounts of fibrous septa; may contain scattered giant cells
- Embryonal: cytologically round to spindle cells with scant cytoplasm in a myxoid background; elongated cells with more abundant eosinophic cytoplasm referred to as strap cells or tadpole cells
- Pleomorphic: sheets of large cells demonstrating marked nuclear atypia or "anaplasia" with eosinophilic cytoplasm
Microscopic (histologic) images
Contributed by Mark R. Wick, M.D.
Alveolar
Alveolar with differentiation
Embryonal
Cytology images
Contributed by Mark R. Wick, M.D.
Embryonal, FNAB
Positive stains
- MyoD1 (nuclear)
- Myogenin (nuclear); stronger, diffuse staining seen in alveolar than in embryonal subtype
- Desmin
- Muscle specific actin
Negative stains
Electron microscopy description
- Skeletal differentiation, as evidenced by ultrastructural specific myofilament arrays, focal density, Z band material and pinocytotic vesicle, is suggestive of rhabdomyosarcomatous differentiation but is not specific for the diagnosis of rhabdomyosarcoma (J Pathol Transl Med 2015;49:93)
- Features may not be evident in solid variants of the alveolar subtype
Molecular / cytogenetics description
- Alveolar: t(2;13)(q35;q4), PAX3::FOXO1 fusion more frequent than t(1;13)(p36;q14), PAX7::POXO1 fusion
- Embryonal: chromosome loss, deletion or uniparental disomy resulting in loss of chromosome 11 loci
- Pleomorphic: complex karyotype
Differential diagnosis
- Ewing sarcoma:
- Heterologous rhabdomyosarcomatous differentiation in a malignant phyllodes tumor or in malignant peripheral nerve sheath tumor:
- Extensive sampling to find diagnostic features of these tumor types
- Invasive lobular carcinoma:
- Metastatic rhabdomyosarcoma:
- Clinical history of primary rhabdomyosarcoma elsewhere
Stromal sarcoma
Definition / general
Essential features
Clinical features
Prognostic factors
Case reports
Treatment
Clinical images
Contributed by Mark R. Wick, M.D.
Gross description
Microscopic (histologic) description
Microscopic (histologic) images
Contributed by Emily S. Reisenbichler, M.D. and Mark R. Wick, M.D.
Positive stains
Negative stains
Electron microscopy description
Differential diagnosis
- The 4th WHO edition (2012) reclassified this periductal stromal tumor as the preferred neutral term in the family of fibroepithelial tumor
- Stromal proliferation around open, benign tubules
Essential features
- Considered a type of fibroepithelial tumor lesion with stromal proliferation around benign tubules
- Lacks the defined tumor borders and compressed tubules of fibroadenoma and leaf-like architecture of phyllodes tumor
- Must demonstrate stromal atypia and mitotic activity to be considered a sarcoma
Clinical features
- Occurs in peri and postmenopausal women (median 55.3 years), ~10 years older than the median phyllodes presentation (Am J Surg Pathol 2003;27:343)
- Variable clinical presentation
Prognostic factors
- Good overall prognosis
- Low recurrence risk, ~10% (Am J Surg Pathol 2003;27:343)
Case reports
- 14 year old boy with periductal stromal sarcoma (J Med Case Rep 2011;5:249)
- 35 year old woman with periductal stromal sarcoma of the breast with liposarcomatous differentiation (Int J Surg Pathol 2015;23:221)
- 43 year old woman with periductal stroma sarcoma 5 months following excision of a phyllodes tumor (Oncol Lett 2014;8:1181)
- 45 year old woman with periductal stromal tumor and synchronous bilateral breast cancer (Anticancer Res 2014;34:3635)
- 52 year old woman with low grade periductal stromal sarcoma of the breast with myxoid features (Pathol Int 2009;59:588)
Treatment
- Given the likely relationship to fibroepithelial lesions, treatment is similar to that of phyllodes tumor
- Wide excision with negative margins
- As with primary breast sarcoma, assessment of axillary sentinel lymph nodes is not necessary
- Adjuvant chemotherapy and radiation are not typically warranted unless presenting with a higher grade sarcomatous component
Clinical images
Contributed by Mark R. Wick, M.D.
Mammogram
Gross description
- Ill defined nodular mass (mean 3 cm)
Microscopic (histologic) description
- Increased stromal cellularity of spindled stroma surrounding or cuffing benign ducts in a pericanalicular pattern
- Involved tubules and ducts are not malignant
- Stromal cells demonstrate at least moderate cytologic atypia and mitotic activity
- Infiltrative and often multinodular microscopic border
- May be seen with areas of angiosarcomatous or liposarcomatous components (Am J Surg Pathol 2003;27:343, Int J Surg Pathol 2015;23:221)
Microscopic (histologic) images
Contributed by Emily S. Reisenbichler, M.D. and Mark R. Wick, M.D.
Cytologically atypical spindled cells cuffing benign ducts
Numerous mitoses present in
cytologically atypical stromal
cells adjacent to ducts
Various images
Positive stains
Negative stains
Electron microscopy description
- Undifferentiated mesenchymal cell features such as free ribosomes and irregular profiles of rough endoplasmic reticulum
- Fibroblastic differentiation such as well organized dilated rough endoplasmic reticulum, Golgi complexes, cytoplasmic filaments and pericellular collagen (Cancer 1979;43:209)
Differential diagnosis
- Periductal stromal hyperplasia:
- Nodular growth, lacks the cytologic atypia and mitoses typical of a stromal sarcoma (0 - 2 mitoses per 10 high power fields)
- Phyllodes tumor:
- Has a more defined tumor border with compression and distortion of ductal elements causing a leaf-like architecture
- Abundant stromal overgrowth of intralobular stroma, not limited only to periductal areas
Undifferentiated pleomorphic sarcoma
Definition / general
Essential features
Etiology
Clinical features
Diagnosis
Radiology description
Prognostic factors
Case reports
Treatment
Clinical images
Images hosted on other servers:
Gross images
Images hosted on other servers:
Microscopic (histologic) description
Microscopic (histologic) images
Contributed by Emily S. Reisenbichler, M.D. and Mark R. Wick M.D.
Cytology description
Positive stains
Negative stains
Molecular / cytogenetics description
Differential diagnosis
- See also Soft tissue topic
- A malignant tumor showing no line of differentiation
- Not part of the WHO classification of breast tumors
- Previously known as malignant fibrous histiocytoma (MFH)
Essential features
- High grade sarcoma with no distinctive microscopic, immunohistochemical or molecular features fitting any specific line of differentiation
- Diagnosis of exclusion
- Undifferentiated sarcomas account for ~20% of soft tissue sarcomas in other parts of the body but are exceedingly rare in the breast
Etiology
- May occur as a primary / de novo tumor or in the postradiation setting
Clinical features
- Most occur in fifth to sixth decade of life
- Majority present as rapidly enlarging palpable mass but can be incidental finding at screening
Diagnosis
- A limited core biopsy may underestimate tumor grade as grading systems such as the 3 tier French (FNCLCC) system are dependent on percentage necrosis and mitotic rate
Radiology description
- On mammography, appears as a noncalcified hyperdense mass (Expert Rev Anticancer Ther 2014;14:705)
- By MRI, shows irregular borders and marked inhomogeneous contrast enhancement (AJR Am J Roentgenol 2012;198:W386)
Prognostic factors
- Close / involved margins, large tumor size (> 5 cm) and high grade histology typically indicate a worse prognosis
Case reports
- 29 year old woman with UPS of the breast (World J Surg Oncol 2016;14:186)
- 50 year old man with giant cell variant of MFH of the breast (J Cancer Res Ther 2015;11:657)
- 50 year old woman with breast UPS containing osteoclast-like giant cells (World J Surg Oncol 2013;11:21)
- 72 year old woman with inflammatory MFH of the breast (Pathol Res Pract 2013;209:534)
Treatment
- Surgical resection with a negative margin (R0) is standard treatment
- Sentinel lymph node biopsy is not warranted
- Adjuvant radiation is often utilized in large tumors or following incomplete (R1 / R2) surgical resections
- Response to adjuvant chemotherapy is typically low but may be used in patients with large, unresectable or metastatic tumors
Clinical images
Images hosted on other servers:
Cystic tumor with skin tethering
Gross images
Images hosted on other servers:
Tumor invades skin
Specimen includes ribs posteriorly
Microscopic (histologic) description
- Cell morphology may be spindle, round / epithelioid or pleomorphic, demonstrating marked cytologic atypia
- Often high mitotic activity
- May be associated with multinucleated giant cells or an inflammatory background
Microscopic (histologic) images
Contributed by Emily S. Reisenbichler, M.D. and Mark R. Wick M.D.
Spindle and epithelioid cells
Pleomorphic cells
Various images
Cytology description
- Single or clustered spindled cells with nuclear pleomorphism
- Absence of an epithelial component
Positive stains
- By definition, no staining to fit a specific line of differentiation
- May show focal staining with keratin, actin, desmin, EMA, CD99, CD34
Negative stains
- Typically negative for most markers
Molecular / cytogenetics description
- Complex karyotypes without specific recurrent aberrations
Differential diagnosis
- Dedifferentiated liposarcoma:
- MDM2 amplified
- Metaplastic (spindle cell) carcinoma:
- Should show at least some keratin or myoepithelial marker expression
- Metastatic sarcoma:
- Must be excluded clinically
- Sarcomatous differentiation in a malignant phyllodes tumor:
- Extensive sampling needed to identify an epithelial component
Paget disease
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Diagrams / tables | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Gross images | Frozen section description | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Cytology images | Positive stains | Negative stains | Electron microscopy description | Electron microscopy images | Molecular / cytogenetics description | Videos | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Mammary Paget disease (MPD) is a proliferation of malignant glandular epithelial cells (in situ carcinoma) in the nipple areolar epidermis (Histopathology 2020;77:181)
- Disease is named after the pathologist and surgeon Sir James Paget, who published his findings of a relationship between a nipple rash and mammary gland tumors in 1874 (JAMA Dermatol 2018;154:335)
Essential features
- Uncommon clinical presentation of breast cancer
- Most often presents as an eczematous / erythematous change of the nipple areolar skin
- Cutaneous manifestation is due to tumor cells involving the epidermis and disrupting intercellular junctions
- Underlying high grade ductal carcinoma in situ (DCIS) or invasive carcinoma is present in > 95% of patients
- Majority of Paget cells and associated underlying carcinoma are HER2+
Terminology
- Mammary Paget disease
- Paget disease of the breast
- Paget disease of the nipple
- DCIS involving nipple skin
- Paget disease with dermal invasion occurs when Paget cells cross the basement membrane of the epidermis; the invasive component is usually small in size (Arch Pathol Lab Med 2013;137:72)
- Secondary Paget disease occurs when invasive carcinoma arising deep in the breast invades the skin; the invasive carcinoma is usually large in size
ICD coding
- ICD-O: 8540/3 - Paget disease of breast
- ICD-10: C50.019 - malignant neoplasm of nipple and areola, unspecified female breast
- ICD-11: 2E65.5 & XH3E21 - Paget disease of nipple and Paget disease, mammary
Epidemiology
- Relatively uncommon; occurs in 1 - 4% of women and 1 - 2% of men with breast cancer (Breast Cancer Res Treat 2008;111:313)
- Wide age range of 20 - 90 years, with a peak incidence between sixth and seventh decade (mean: 64 years) (Breast Dis 2020;39:119)
- Between 20 - 30% of patients are premenopausal
- Histologic (subclinical) evidence of MPD may be more frequent
Sites
- Affects the nipple or areola region and may extend into the adjacent breast skin
- Lesions are almost always unilateral and rarely bilateral (Breast J 2005;11:355)
- May occur in supernumerary nipples (J Cutan Pathol 1994;21:283)
Pathophysiology
- 2 theories on the pathogenesis:
- Epidermotropic theory (most widely accepted): Paget cells are DCIS cells that migrate along the basement membrane of the nipple, supported by the presence of DCIS deeper in the breast identical to Paget cells in almost all cases; migration may be mediated through a motility factor heregulin α, produced by keratinocytes and exerting its effect via the HER2 receptor (J Natl Cancer Inst 2000;92:622)
- Transformation theory: Paget cells originate from malignant transformation of keratinocytes or Toker cells; it would explain rare cases (< 5%) in which cancer is not present in underlying breast (Intractable Rare Dis Res 2019;8:203)
- When no parenchymal cancer is identified, there is a possibility that the underlying tumor has gone undetected / unsampled
Etiology
- Specific risk factors beyond those recognized for breast cancer have not been identified
Diagrams / tables
Images hosted on other servers:
Development of Paget disease
Clinical features
- Majority of patients present clinically with slow onset nipple changes (Breast Cancer Res Treat 2008;111:313)
- Most common: nipple erythema, scaling crust, ulceration, eczematoid type rash, pruritus or bleeding
- Less common: bloody nipple discharge, pain, retraction or no clinically identifiable changes of the nipple
- May present as a pigmented macule and can be mistaken for melanoma (Am J Dermatopathol 2009;31:223, Br J Dermatol 2018;178:e143)
- Changes begin at the nipple / areola and may spontaneously regress or continue to progress with extension into the skin of the breast
- Approximately 50% of patients present with an associated palpable mass, usually indicating an underlying invasive carcinoma
- Affected men have similar clinical presentations as women (Am J Dermatopathol 2020;42:981)
- Clinical presentation may be mistaken for skin inflammatory disease or infection, leading to delayed diagnosis
Diagnosis
- In symptomatic cases, the diagnosis is primarily clinical and confirmed by histologic examination
- Most commonly used techniques include skin punch or shave biopsy and less often, core needle biopsy; samples are usually small due to concern about the cosmetic appearance of the nipple (Breast J 2019;25:1328, Radiol Med 2021;126:936)
- Nipple scrape cytology can detect tumor cells on the surface of the epidermis or in the scale crust but it may be painful for the patients and is rarely used (Diagn Cytopathol 2019;47:249)
- In addition to nipple biopsy, any underlying masses or mammographic abnormalities must be biopsied, usually by core needle; in patients with a palpable lump, alternatively by fine needle aspiration cytology
- If these methodologies are not definitive for a preoperative diagnosis, an open surgical biopsy / wedge excision may be needed
- In asymptomatic / unsuspected cases, MPD may be an incidental finding in a mastectomy specimen; detecting Paget cells depends on the extent of sampling of the nipple and the use of IHC (Am J Surg 1979;138:135)
Radiology description
- Imaging is mainly used to detect and evaluate the extent of an underlying malignancy and enable appropriate treatment planning (Eur J Radiol 2006;60:256, Radiographics 2011;31:1973)
- Mammography is most useful in detecting masses, distortions or calcifications; however, approximately half of the patients with MPD have normal mammograms
- Ultrasound may show ductal ectasia or changes of the nipple areolar complex, such as flattening, asymmetry and thickening
- Magnetic resonance imaging (MRI) is sensitive, particularly for mammographically occult underlying disease; it may show abnormal nipple enhancement, thickened nipple areolar complex, associated enhancing DCIS or invasive tumor or a combination of these findings (J Am Coll Surg 2008;206:316)
Radiology images
Images hosted on other servers:
Abnormal mammogram
Normal mammogram
Ultrasound
MRI
Prognostic factors
- Prognosis largely depends on the presence, extent and characteristics of the underlying tumor
- Patients with MPD and DCIS only have excellent outcomes (> 95% survival at 20 years) (Cancer 2006;107:1448)
- Patients with isolated MPD (no parenchymal tumor detected) have even better outcomes; 5 and 10 year survival rates of 100%, compared with those with underlying DCIS of 94.7% and 75.8%, in 1 study (Am Surg 2013;79:1009)
- If invasive carcinoma is present in the underlying breast, prognosis depends on tumor size and lymph node status, with the 5 year relative survival rate declining with increasing tumor stage (stage I, 95.8%; II, 77.7%; III, 46.3%; IV, 14.3%) (Breast Dis 2020;39:119)
- In general, women presenting with MPD and a palpable mass (indicating more advanced disease) have worse survival than women without a palpable mass
- Dermal invasion arising directly from MPD in the epidermis and localized to the nipple (invasive Paget disease) is typically detected early and has a favorable outcome (Arch Pathol Lab Med 2013;137:72, Hum Pathol 2014;45:2480)
- MPD must be distinguished from inflammatory carcinoma and locally advanced invasive carcinoma ulcerating skin, as they have poorer prognoses
Case reports
- 52 year old woman with Paget disease associated with invasive papillary carcinoma (BMJ Case Rep 2018;2018:bcr2017222817)
- 53 year old woman with bilateral Paget disease derived from lobular carcinoma in situ (LCIS) (Arch Pathol Lab Med 2002;126:90)
- 54 year old woman with recurrence of breast carcinoma as Paget disease of the skin along core biopsy tract (Histopathology 2004;45:416)
- 55 year old man with bilateral metachronous Paget disease of the accessory breasts (J Breast Cancer 2020;23:665)
- 63 year old woman with Paget disease involving breast skin without the involvement of nipple / areola (Pathol Res Pract 2017;213:1454)
- 68 year old woman with invasive Paget disease and axillary lymph node metastases (Int J Surg Pathol 2014;22:566)
- 73 year old woman with bilateral synchronous Paget disease associated with bilateral breast carcinoma (Breast J 2005;11:355)
- 91 year old man with mammary Paget disease (Surg Case Rep 2015;1:103)
Treatment
- Extent of surgery is determined by the extent of underlying breast carcinoma (Am J Surg 2010;200:241)
- Patients with limited disease are candidates for breast conserving therapy with central lumpectomy and whole breast irradiation (J Surg Res 2019;241:178)
- Those with larger extent of disease (multicentric cancer, diffuse calcifications) undergo simple mastectomy
- Entire nipple areolar complex is removed in all cases; a variety of techniques can be used to reconstruct the nipple
- Evaluation and treatment of the axilla in MPD are the same as for any breast cancer (Am J Surg 2006;192:481)
- Recommendations regarding systemic therapy in neoadjuvant or adjuvant settings are based solely upon any associated invasive carcinoma or DCIS characteristics (Breast Cancer Res Treat 2008;112:513)
Clinical images
Contributed by Jennifer Tseng, M.D. and Mark R. Wick, M.D.
Nipple, crusted lesion
Nipple erosion and erythema
Images hosted on other servers:
Well demarcated, eczematous scaly lesion
Gross description
- Nipple areolar complex with red-pink crusting lesion, discoloration, thickening, ulceration, exudate, nipple retraction, etc.
- Typically well demarcated; epidermal involvement usually does not extend beyond the grossly evident lesion (Cancer Treat Rev 2001;27:9)
- Scaling crust may be removed by skin preparation prior to surgery
Gross images
Contributed by Alexis Synder, M.H.S. and Emily S. Reisenbichler, M.D.
Nipple ulceration
Nipple ulceration, enlarged
MPD, cut section with underlying mass
Frozen section description
- Frozen section for intraoperative management of Paget disease has been studied more extensively in extramammary sites but not in MPD
Microscopic (histologic) description
- Single cells or clusters of cells spread throughout the epidermis
- Cells have abundant pale cytoplasm, large irregular nuclei with prominent nucleoli
- Underlying dermis may have chronic inflammation
- Epidermis with hyperkeratosis and possibly ulceration
- Florid cases can show gland formation
- Paget cells may phagocytose melanin, mimicking melanocytes
- Underlying carcinoma is most commonly high grade invasive carcinoma of no special type (NST; 53 - 64%) or DCIS (24 - 43%) (Histopathology 2020;77:181)
Microscopic (histologic) images
Contributed by Anna Biernacka, M.D., Ph.D. and Mary Ann Gimenez Sanders, M.D, Ph.D.
Paget disease with dermal reaction
Paget cells in basal location
Superficial extension and inflammation
Cytologic features
Spread to skin adnexa
Paget cells, shrinkage artifact
Paget cells, melanin uptake
Melanocyte hyperplasia
Full thickness with erosion
Invasive Paget disease
Mammary Paget disease CK7
Mammary Paget disease CK5/6
Mammary Paget disease HER2
Secondary Paget disease
Florid Paget disease
Virtual slides
Images hosted on other servers:
Paget cells involving nipple ducts
Cytology description
- Tumor cells are often present on the surface of the epidermis and in the scale crust
- Nipple scrape preparation can be performed by using a scalpel to scrape the nipple, smearing it on 2 slides and performing either a Papanicolaou or May-Grunwald-Giemsa (MGG) stain
- 1 study, by comparing scrape smears and histological specimens, found that nipple scraping correctly detected MPD in 91.4% of cases (Diagn Cytopathol 2019;47:249)
- Cytomorphologic features include isolated and loosely clustered malignant glandular cells with enlarged nuclei, prominent nucleoli and pale cytoplasm, detected among squamous cells
- Cytologic differential diagnoses include nipple adenoma and squamous cell carcinoma detected
- In cases of clinical doubt, a punch biopsy may be indicated in parallel to scrape smears
Cytology images
Images hosted on other servers:
Dyscohesive cell groups
Positive stains
- CK7 (> 90%)
- HER2 (80 - 100%)
- CAM5.2 (70 - 100%)
- ER (10 - 40%)
- PR (0 - 30%) (Breast Cancer Res Treat 2013;141:1)
- CK7 negative Paget disease is rare and can be a diagnostic pitfall (Pathol Res Pract 2016;212:279)
Negative stains
- HMB45 (<1%)
- MelanA (<1%)
- CK5/6 (0 - 2%)
- CK20 (0 - 1%)
- S100 (0 - 25%)
- References: Breast Cancer Res Treat 2013;141:1, Am J Dermatopathol 2011;33:e54, J Am Acad Dermatol 2011;65:247, Am J Dermatopathol 2011;33:e54
Electron microscopy description
- Desmosomal attachments have been identified between Paget cells and adjacent epidermal keratinocytes (Am J Pathol 1969;57:49)
- Same authors described a pre-Paget cell with an electron microscopy appearance intermediate between that of a keratinocyte and a Paget cell, suggesting that epidermal cells can acquire the characteristics of ductal cells as they undergo malignant transformation (transformation theory)
Electron microscopy images
Images hosted on other servers:
Large, pale intraepidermal Paget cells
Single Paget cell
Molecular / cytogenetics description
- No association with a specific gene mutation has been reported
- Paget cells are genetically similar to the underlying carcinoma cells in 80% of cases (Histopathology 2020;77:181)
Videos
Brief overview of Paget disease with pathologic images by Pathology mini tutorials
Sample pathology report
- Right nipple areolar complex, biopsy:
- Ductal carcinoma in situ involving the nipple epidermis (Paget disease) (see comment)
- Comment: The tumor cells are positive for CK7 and HER2 (3+) by immunohistochemistry, supporting the above diagnosis of Paget disease. ER and PR show no staining of in situ nuclei.
- For synoptic reporting, the appropriate AJCC T category is Tis (Paget) if no underlying DCIS is present or Tis (DCIS) if underlying DCIS is present
- If there is associated invasive carcinoma in the underlying breast parenchyma, the T category is based on the size of the invasive tumor
- If there is invasion from MPD into the dermis, only the size of the invasion should be used as size for T classification
Differential diagnosis
- Differential diagnosis for MPD includes squamous cell carcinoma in situ (Bowen disease) and melanoma, although these diseases very rarely involve the nipple (Am J Dermatopathol 2017;39:419)
- Carcinoma in situ of skin / Bowen disease (Am J Dermatopathol 2017;39:419):
- Melanoma in situ:
- Toker cells and pagetoid dyskeratosis (Histol Histopathol 2009;24:367):
Board review style question #1
Which immunohistochemical stain is most likely to be positive in Paget disease?
- CK5/6
- CK20
- ER
- HER2
- PR
Board review style answer #1
D. HER2. The majority of Paget disease cases are HER2 positive and therefore HER2 can be used to confirm the diagnosis. In the absence of invasive carcinoma, HER2 positivity does not influence treatment, since Paget disease is an in situ carcinoma. Paget disease is negative for CK5/6 and CK20. ER and PR show variable expression.
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Reference: Paget disease
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Reference: Paget disease
Board review style question #2
Which of the following is true regarding the lesion identified in the nipple in the image shown above?
- Invasion into the dermis is associated with a poor prognosis
- Lesional cells can contain melanin pigment
- Lesional cells have a specific recurring genetic alteration
- Most disease is an extension of lobular carcinoma in situ (LCIS) from the underlying ducts
- Nipple always has eczematoid change
Board review style answer #2
B. Paget cells may contain melanin, which is a diagnostic pitfall. Invasion into the dermis is not associated with a poor prognosis. The nipple in Paget disease may appear grossly normal. Most mammary Paget disease (MPD) is an extension of ductal carcinoma in situ (DCIS) from the underlying ducts, not LCIS. Paget cells have no known specific recurring genetic alterations and are genetically similar to the underlying breast carcinoma cells in most cases.
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Reference: Paget disease
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Reference: Paget disease
Papillary
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Etiology | Clinical features | Diagnosis | Radiology description | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Negative stains | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1Definition / general
- A rare subtype of invasive ductal carcinoma (IDC) (J Surg Res 2021;261:105)
- Comprises about 0.5 - 0.7% of all invasive breast cancers (J Surg Res 2021;261:105, J Cancer Res Clin Oncol 2013;139:77)
Essential features
- A rare subtype of invasive ductal carcinoma with infiltrative papillary growth
- Imperative to distinguish it from other invasive and noninvasive mammary lesions, as well as extramammary tumors metastasizing to the breast
Terminology
- Invasive papillary carcinoma (IPC)
ICD coding
Epidemiology
- Most commonly seen in non-Caucasian postmenopausal women in their sixth to eighth decade of life (J Cancer Res Clin Oncol 2013;139:77, J Surg Res 2021;261:105)
- More common in lower economic status and lower household income (J Surg Res 2021;261:105)
Sites
- No specific location in the breast
Etiology
- Insufficient clinicopathological data on this tumor (Mod Pathol 2021 Jan 18 [Epub ahead of print])
- Much of the published literature about IPC in fact describes variants of encapsulated or solid papillary carcinoma with invasion (Mod Pathol 2021 Jan 18 [Epub ahead of print])
Clinical features
- Due to the rarity of this tumor, specific clinical features have not been described
- Typically presents with bloody nipple discharge, an abnormal mass or radiographic abnormalities
- However, it is not clear if these features refer to true IPC or other types of papillary carcinomas misdiagnosed as IPC (J Surg Res 2021;261:105)
Diagnosis
- Mammogram
- Breast ultrasound (US)
- Breast MRI
Radiology description
- Solitary mass, solid, solid and cystic, round, oval, lobulated or irregular (Clin Radiol 1997;52:865, Curr Probl Diagn Radiol 2019;48:348)
- Hypoechoic solid, smooth walled abnormalities, with good sound transmission on ultrasound (Cureus 2020;12:e11026)
Prognostic factors
- Tumors should be graded according to the Nottingham grading system (Histopathology 1991;19:403)
- Tumors should be staged according to their pathological size and axillary lymph node status
- Poor prognostic factors include old age, advanced pathologic stage and patients without radiation (J Surg Res 2021;261:105)
- Conflicting data; some report favorable prognosis when compared with invasive ductal carcinoma (J Cancer Res Clin Oncol 2013;139:77)
- Others report similar prognosis (J Surg Res 2021;261:105)
Case reports
- 45 year old woman with a right breast lump (J Cancer Res Ther 2015;11:1029)
- 52 year old woman with a right nipple lump (BMJ Case Rep 2018;2018:bcr2017222817)
- 61 year old woman with a painless breast mass (Indian J Pathol Microbiol 2012;55:543)
- 79 year old woman with an irregular 9 mm right breast mass (Pathol Int 2019;69:183)
Treatment
- Surgical excision followed by adjuvant radiation and systemic therapy based on the predictive and prognostic factors (J Cancer Res Clin Oncol 2013;139:77)
Gross description
- Size ranging from less than 2 cm to more than 5 cm (Cureus 2020;12:e11026)
Microscopic (histologic) description
- Invasive carcinoma with > 90% papillary architecture (Mod Pathol 2021 Jan 18 [Epub ahead of print])
- Frankly invasive growth pattern without surrounding fibrous capsule (Mod Pathol 2021;34:78)
- Growth pattern is characterized by arborizing fibrovascular stalks lined by epithelial cells (J Cancer Res Clin Oncol 2013;139:77)
- Mitotic figures and necrosis are not common (Sci Rep 2016;6:24037)
- Carcinoma cells show cytologic atypia and stratification (J Cancer Res Clin Oncol 2013;139:77)
- Nuclear grade ranges from low to high (Sci Rep 2016;6:24037)
Microscopic (histologic) images
Contributed by Marilin Rosa, M.D.
Invasive mixed papillary and micropapillary carcinoma
No surrounding fibrous capsule
Desmoplasia
Invasive papillary carcinoma
No surrounding fibrous capsule
Invasive papillary fronds
Invasive papillary carcinoma
Papillae lack myoepithelial cells
Necrosis and calcifications
Mitotic figures
Positive stains
Negative stains
- Myoepithelial cell stains, such as p63, calponin and smooth muscle myosin heavy chain (Mod Pathol 2021 Jan 18 [Epub ahead of print])
- HER2 (J Cancer Res Clin Oncol 2013;139:77)
- PAX8, WT1, TTF1, Napsin A and thyroglobulin (Mod Pathol 2021 Jan 18 [Epub ahead of print])
Sample pathology report
- Right / left breast, mastectomy:
- Invasive papillary carcinoma, Nottingham histologic grade (X), measuring (X) cm (please see detailed synoptic report)
- Associated ductal carcinoma in situ (DCIS), (X) nuclear grade, (X) patterns, comprising X% of tumor (if present).
- Lymphovascular invasion (is / is not) identified.
- Biopsy site changes are identified.
- Margins are (involved / uninvolved).
Differential diagnosis
- Encapsulated papillary carcinoma:
- Rounded pushing border
- Typically surrounded by a fibrous capsule
- Frank invasion may be present when tumor cells infiltrate beyond the fibrous capsule
- Solid papillary carcinoma, invasive and noninvasive:
- Expansile nodules with solid pattern and delicate fibrovascular cores
- Extracellular mucin may be present
- Invasive micropapillary carcinoma (an aggressive form of mammary carcinoma):
- More than 90% of tumor consists of morula-like epithelial clusters
- Tumor clusters are surrounded by empty spaces, devoid of fibrovascular cores and show reverse polarity
- Extramammary carcinoma metastatic to the breast, such as ovarian carcinoma, lung carcinoma with papillary features or thyroid papillary carcinoma (J Cancer Res Clin Oncol 2013;139:77, J Surg Res 2021;261:105):
- Tall cell carcinoma with reversed polarity (Am J Surg Pathol 2003;27:1114):
- Carcinoma cells arranged in solid, papillary and glandular structures, resembling thyroid follicles
- Carcinoma glands contain colloid-like material
- Tumor cells are columnar or cuboidal
- Many of the nuclei sit near the luminal membranes, hence the term reversed polarity
- Most tumors are negative for ER and PR
Additional references
Board review style question #1
Which of the following is a relevant feature of invasive papillary carcinoma of the breast?
- Commonly encountered breast tumor
- Graded according to nuclear size
- May mimic metastases from other organs
- Myoepithelial cells at the periphery
- Positive for Napsin A and PAX8
Board review style answer #1
C. It may mimic metastases from other organs (metastases to the breast from other organs such as ovary, lung and thyroid must be excluded)
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Reference: Invasive papillary carcinoma
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Reference: Invasive papillary carcinoma
Pertuzumab
Table of Contents
Definition / general | Trade name | Pathophysiology | Diagrams / tables | Clinical information | Uses by pathologists | Side effects | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Humanized IgG1 kappa monoclonal antibody targets extracellular domain of HER2 tyrosine kinase receptor
- Discovered and developed by Genentech, Inc., South San Francisco, CA
- Synonym: 2C4 (monoclonal antibody)
- rhuMAb-2C4
Trade name
- Perjeta®
Pathophysiology
- HER2, a member of HER family, does not have a receptor specific ligand binding site
- HER2/neu signaling in cancer cells (N Engl J Med 2007;357:39)
- HER2 heterodimerizes with HER1, HER3 or HER4, phosphorylates and activates intracellular tyrosine kinase domain
- The activated tyrosine kinase on HER2 activates PI3K-Akt pathway and induces cellular survival
- The activated tyrosine kinase activates SOS, induces a cascade of activation of RAS-RAF-MAPK-MEK and MAPK, eventually promotes cellular proliferation
- Cleavage of HER2 extracellular domain produces phosphorylated P95 that could activate downstream signal transduction
- Mechanism of action of pertuzumab (Oncology (Williston Park) 2014;28:186)
- Upon binding the extracellular dimerization subdomain II of HER2, pertuzumab reduces activation of HER2 by disrupting dimerization of HER2 with HER1, HER3 or HER4
- See Diagrams / tables, figure 7
Diagrams / tables
Clinical information
- Approved by United States Food and Drug Administration (FDA) on June 8, 2012 (Clin Cancer Res 2019;25:2949)
- Used in combination with trastuzumab and docetaxel or other drugs to treat HER2 positive breast cancer (National Cancer Institute: Pertuzumab [Accessed 17 February 2020]):
- Metastatic breast cancer that has not been treated with either hormone or chemotherapy
- Locally advanced, inflammatory or early stage breast cancer
- Early breast cancer with high risk of tumor recurrence
- Clinical pharmacokinetics: (Ann Oncol 2013;24:273)
- Route of administration: intravenous infusion
- Elimination: metabolized through proteolytic catabolism
- Half life: 10 days
- Mechanism of drug resistance:
- HER2 positive cancer cells with S310F mutation might disrupt the interaction between pertuzumab and HER2 (Onco Targets Ther 2019;12:11597)
- Pertuzumab costs about $5,900 a month, about $71,000 a year or about $180,000 for a course of treatment (Drugs.com: Perjeta Prices, Coupons and Patient Assistance Programs [Accessed 18 February 2020])
- Comparisons between pertuzumab and trastuzumab (Ann Oncol 2013;24:273)
- See Diagrams / tables, figure 8
Uses by pathologists
- Identify HER2 positive breast adenocarcinomas
- HER2 testing needed on all newly diagnosed breast adenocarcinomas
- Metastatic diseases (test performed in a metastatic site)
- HER2 immunohistochemistry in breast adenocarcinoma (see Diagrams / tables, figure 1)
- ASCO-CAP HER2 Test 2013 and 2018 Guideline Recommendation (Arch Pathol Lab Med 2014;138:241, Arch Pathol Lab Med 2018;142:1364)
- Negative (score 0):
- No staining
- Incomplete faint membrane staining ≤ 10% invasive tumor cells
- Negative (score 1+):
- Incomplete faint membrane staining > 10% invasive tumor cells
- Equivocal (score 2+): perform HER2 ISH (see Diagrams / tables, figure 2)
- Incomplete, weak / moderate membrane staining > 10% invasive tumor cells
- Complete, intense membrane staining ≤ 10% invasive tumor cells
- Positive (score 3+):
- Complete, intense circumferential membrane staining > 10% invasive tumor cells
- Negative (score 0):
- ASCO-CAP HER2 Test 2013 and 2018 Guideline Recommendation (Arch Pathol Lab Med 2014;138:241, Arch Pathol Lab Med 2018;142:1364)
- HER2 single probe in situ hybridization (ISH) in breast adenocarcinoma (see Diagrams / tables, figure 2)
- ISH negative (not amplified)
- Single probe HER2 copy number < 4.0
- ISH positive (amplified)
- Single probe HER2 copy number ≥ 6.0 signals/cell
- ISH equivocal: perform HER2/CEP17 dual probe ISH (see Diagrams / tables, figure 3)
- Single probe HER2 copy number ≥ 4.0 and < 6.0 signals/cell
- ISH negative (not amplified)
- HER2 dual probe ISH in breast adenocarcinoma (see Diagrams / tables, figure 3)
- Negative:
- Dual probe HER2/CEP17 < 2.0, HER2 copy number < 4.0 signals/cell
- Positive:
- Dual probe HER2/CEP17 ≥ 2.0, HER2 copy number ≥ 4.0 signals/cell
- Equivocal (see Diagrams / tables, figures 4, 5 and 6):
- HER2/CEP17 ≥ 2.0, with HER2 copy number < 4.0 signals/cell (see Diagrams / tables, figure 4)
- HER2/CEP17 < 2.0, HER2 copy number ≥ 6.0 signals/cell (see Diagrams / tables, figure 5)
- HER2/CEP17 < 2.0, HER2 copy number ≥ 4.0 and < 6.0 signals/cell (see Diagrams / tables, figure 6)
- Negative:
Side effects
- Common side effects (> 30% of patients) when given in combination with trastuzumab and docetaxel (MedWatch: The FDA Safety Information and Adverse Event Reporting Program [Accessed 17 February 2020]):
- Diarrhea
- Hair loss
- Leukopenia
- Nausea
- Fatigue
- Rash
- Peripheral neuropathy
Additional references
Board review style question #1
- Which of the following drugs target HER2 / neu on cancer cells?
- Dabrafenib
- Larotrectinib
- Pertuzumab
- Trametinib
Board review style answer #1
Board review style question #2
- Which of the following results is interpreted as positive staining (score 3+) for HER2 in
breast adenocarcinoma?
- Complete, intense basolateral membranous staining > 10% of tumor cells
- Complete, intense circumferential membranous staining > 10% of tumor cells
- Complete, intense luminal membranous staining > 10% of tumor cells
- Complete, intense nuclear and cytoplasmic staining > 10% of tumor cells
Board review style answer #2
B. Complete, intense circumferential membranous staining > 10% of tumor cells
Comment Here
Reference: Pertuzumab
Comment Here
Reference: Pertuzumab
Phyllodes tumor
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Cytology images | Positive stains | Negative stains | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2 | Board review style question #3 | Board review style answer #3Definition / general
- Biphasic fibroepithelial neoplasm with leaf-like epithelial (phyllodal) pattern and stromal proliferation
Essential features
- Biphasic fibroepithelial lesion characterized by leaf-like phyllodal epithelial pattern
- Graded and prognosticated by histologic changes of the stromal proliferation
- Epithelial component is benign in phyllodes tumor
Terminology
- Phyllodes tumor
- Cystosarcoma phyllodes (the use of this term is discouraged)
ICD coding
- Phyllodes tumor
- ICD-O: 9020/1 - Phyllodes tumor, NOS
- Benign phyllodes tumor
- Borderline phyllodes tumor
- Malignant phyllodes tumor
Epidemiology
- Incidence rate of 2.1 per 1 million women (Cancer 1993;71:3020)
- Constitutes 1% of breast tumors
- Benign phyllodes tumor most common (60 - 75%), followed by borderline (15 - 26%) and malignant (8 - 20%) tumors (WHO Classification of Tumours Editorial Board: Breast Tumours, 5th Edition, 2019)
- Average age 40 - 50 years (Cancer Med 2018;7:1030)
- Benign phyllodes tumor occurs at a younger age compared with borderline and malignant phyllodes tumors (J Clin Pathol 2012;65:69)
- Can occur rarely in pediatric age group and male
Sites
- Most commonly breast
- Reported to develop in ectopic breast tissue, including vulva (Am J Surg Pathol 1993;17:946)
Pathophysiology
- Biphasic lesion with epithelial stromal interaction involved in tumorigenesis (Cancer 1992;70:2115)
- Loss of epithelial interaction in stromal component believed to lead to malignant progression (Histopathology 2012;61:667)
- Areas resembling well differentiated liposarcoma in phyllodes tumor lack CDK4 and MDM2 expression / gene amplification as seen in primary well differentiated liposarcoma (Histopathology 2016;68:1040, Breast J 2016;22:282)
Etiology
- Currently unclear
- Increased incidence reported in Li-Fraumeni syndrome (Oncogene 2001;20:4621)
Clinical features
- Commonly presents with firm, asymptomatic, mobile breast mass
- Large tumor (up to 20 cm) can cause skin ulceration and pain (J Surg Case Rep 2015;2015:rjv162)
- Bloody nipple discharge uncommon and attributed to infarction and intraductal involvement (Histopathology 2007;50:666)
- Rare cases of hypoglycemia due to insulin-like growth factor II production (Breast J 2007;13:189)
Diagnosis
- Largely dependent on histologic diagnosis
- Imaging not accurate in diagnosis
- Ultrasound and mammography do not accurately differentiate phyllodes tumor from fibroadenoma (Br J Radiol 2014;87:20140239)
- Ultrasound unreliable in grading of phyllodes tumor (AJR Am J Roentgenol 2018;210:W173)
Radiology description
- Oval and lobulated lesions
- Hypoechoic on ultrasound
- Microcalcifications rare
Radiology images
Contributed by Mark R. Wick, M.D.
Mammogram, benign
Prognostic factors
- Prognosis correlates with histologic grade
- Benign phyllodes tumor
- Very low rate of local recurrence regardless of margin status (Breast Cancer Res Treat 2013;141:353)
- Does not metastasize or cause mortality (Breast Cancer Res Treat 2013;141:353)
- Recurrences may be benign but may also progress to borderline or malignant phylldoes tumors (Ann Surg Oncol 2019;26:2747)
- Borderline phyllodes tumor
- Behavior intermediate between benign and malignant phyllodes tumors (Histopathology 2016;68:5)
- Higher risk of local recurrence than benign phyllodes tumor
- Risk of metastasis present but very low
- Malignant phyllodes tumor
- 23 - 30% risk of local recurrence (Histopathology 2016;68:5)
- 9% risk of distant metastasis
- Sites include lung, pleura, bone, central nervous system, visceral organs and soft tissue
- Occurs within 10 years of diagnosis (Am Surg 2007;73:967)
- Presence of malignant heterologous elements, necrosis and tumor size correlated with metastasis (Virchows Arch 2018;472:615, Ann Surg Oncol 2019;26:2747)
- Axillary nodal involvement by metastatic disease uncommon
- Benign phyllodes tumor
- Positive margin status associated with local recurrence
- Tumor size is an independent risk factor for local recurrence (Ann Surg Oncol 2015;22:2912)
Case reports
- 30 year old woman with painless breast mass (Case #255)
- 37 year old woman with multiple metastases including adrenal gland (Ann Med Surg (Lond) 2018;36:113)
- 44 year old woman with repeated local recurrence (Onco Targets Ther 2018;11:7787)
- 47 year old woman with malignant phyllodes tumor showing liposarcomatous differentiation (Radiol Case Rep 2019;14:531)
- 70 year old woman with benign phyllodes tumor and concomitant ductal carcinoma in situ (Am J Case Rep 2017;18:813)
Treatment
- Local excision with clear margins
- Narrow margins may be adequate for benign phyllodes tumor
- Exact extent of clearance under debate, currently no consensus as to adequate margin width, while 10 mm is generally considered acceptable (NCCN Guidelines: Breast Cancer - Phyllodes Tumor [Accessed 2 July 2020], Ann Surg Oncol 2019;26:2747)
- Axillary dissection not indicated
- Efficacy of radiotherapy unclear, may improve local control but not overall survival in borderline and malignant phyllodes tumor (Int J Radiat Oncol Biol Phys 2008;70:492)
- Efficacy of chemotherapy unclear
Clinical images
Images hosted on other servers:
Large tumor
Malignant tumor
Swollen breast
Gross description
- Rounded, shelled out borders
- Infiltrative in malignant and less commonly borderline phyllodes tumor
- Whorled, bosselated cut surface in a leaf-like pattern
- Skin ulceration, hemorrhage and cystic changes in large lesions (Int J Surg Case Rep 2020;67:114)
- Ulceration and hemorrhage do not indicate malignant behavior per se
- Infarcted or very large benign phyllodes tumor can also show necrosis
Gross images
Contributed by Mark R. Wick, M.D.
Benign phyllodes tumor
Images hosted on other servers:
Large, well circumscribed tumor, benign
Malignant
Microscopic (histologic) description
- Leaf-like (phyllodal) epithelial pattern formed by an exaggerated intracanalicular pattern
- Subepithelial condensation with increased stromal cellularity adjacent to epithelium
- Some regard tumors with predominant periductal stromal expansion (i.e., periductal stromal tumor) as a distinct subtype of phyllodes tumor
- Graded into benign, borderline and malignant histologic grades
Benign Borderline Malignant Stromal atypia Mild Moderate Marked Stromal cellularity Mildly increased, can be focal Moderately increased, can be focal Markedly and diffusely increased Stromal overgrowth* Absent Absent or very focal Present Mitotic count < 5/10 HPF or < 2.5/mm² 5 - 9/10 HPF or 2.5 - < 5/mm² ≥ 10/10 HPF or ≥ 5/mm² Tumor border Well defined Well defined or focally permeative Diffusely permeative Malignant heterologous elements Absent Absent Presence directly upgrades to malignant category** -
*Defined as absence of epithelial elements containing stroma only in 1 low power field
**Includes chondrosarcoma, liposarcoma (except well differentiated liposarcoma), osteosarcoma, rhabdomyosarcoma, angiosarcoma and leiomyosarcoma
- Cystic degeneration, hemorrhage, stromal hyalinization and myxoid change reported
- Does not indicate malignancy (J Clin Diagn Res 2016;10:EC14)
- Multinucleated stromal giant cells occasionally seen (Pathology 2001;33:153)
- Can be found in phyllodes tumor of all histologic grades
- Epithelial elements usually bland
- Epithelium can be scarce in malignant phyllodes tumor with extensive stromal overgrowth
- Can show squamous metaplasia (Am J Clin Pathol 2005;123:529)
- Incidental involvement by in situ and invasive carcinomas (Clin Breast Cancer 2018;18:e421)
- Myoepithelial layer is preserved but can be attenuated
Microscopic (histologic) images
Contributed by Joshua J.X. Li, M.B.Ch.B. and Gary M. Tse, M.B.B.S.
Benign phyllodes tumor
Leaf-like epithelial pattern
Low stroma to epithelium ratio
Rounded borders
Shelled out tumor
Benign stromal cells
Borderline phyllodes tumor
Phyllodal pattern
Stromal overgrowth
Distorted epithelium
Stromal mitosis
Stromal atypia
Malignant phyllodes tumor
Infiltrative borders
Marked stromal overgrowth
High stromal cellularity
Stromal atypia
Stromal giant cells
Atypical mitosis
Virtual slides
Images hosted on other servers:
Benign phyllodes tumor
Benign phyllodes tumor
Intraductal growth pattern
Borderline phyllodes tumor
Borderline phyllodes tumor
Malignant phyllodes tumor
Malignant lipomatous element
Malignant osteosarcomatous element
Extensive stromal overgrowth
Cytology description
- Fibromyxoid stromal clumps
- Reduced epithelial stromal ratio compared with fibroadenomas
- Higher nuclear atypia and cellularity in phyllodes tumor of higher grades
- Large wavy and folded epithelial clusters
- Usually exhibits benign cytomorphology
- Occasionally, hyperplastic changes with enlarged and vesicular nuclei and small visible nucleoli may be seen
- Fibroblastic pavements
- Increased atypia in dispersed cells in phyllodes tumor of higher grades (Cancer Cytopathol 2010;118:33)
- Multinucleated tumor cells and marked stromal anaplasia reported in malignant phyllodes tumor (Cancer Cytopathol 2010;118:33)
Cytology images
Contributed by Joshua J.X. Li, M.B.Ch.B. and Gary M. Tse, M.B.B.S.
Benign phyllodes tumor
Biphasic pattern
Fibromyxoid stromal clumps
Benign stromal cells
Borderline phyllodes tumor
Increased stroma to epithelium ratio
Stromal cellularity
Stromal atypia
Malignant phyllodes tumor
Atypical stromal cells
Positive stains
- Epithelial cells
- Cytokeratins, ER, PR, GCDFP-15
- Stromal cells
- Vimentin, CD34, BCL2, ER beta
- Increased KIT, p53 and Ki67 in phyllodes tumor of higher grade
- Cytokeratins, p63 (focal, can be confused with metaplastic carcinoma) (J Clin Pathol 2012;65:339, Am J Surg Pathol 2014;38:1689)
Negative stains
- Stromal cells
- Cytokeratins, p40, p63 (except malignant phyllodes tumor)
Molecular / cytogenetics description
- Recurrent MED12 and RARA mutations in phyllodes tumors of all grades and fibroadenoma (Nat Genet 2015;47:1341)
- More frequent in benign phyllodes tumor
- Mutations in cancer driver genes (NF1, RB1, PIK3CA, EGFR, TP53 and ERBB4) exclusively seen in borderline and malignant phyllodes tumors (Nat Genet 2015;47:1341)
- TERT promoter mutation more common in borderline phyllodes tumor (Sci Rep 2018;8:3881)
- Chromosome abnormalities increase with grade (Mod Pathol 2007;20:435)
- Notably 1q gain and 13q loss
Sample pathology report
- Left breast, local excision:
- Benign phyllodes tumor
- Microscopic (optional): Sections show a stromal proliferation in a leaf-like pattern capped by benign ductal epithelium and intact intervening myoepithelial cell layer. The stromal proliferation is of low cellularity and the stromal cells show mild atypia. Stromal mitosis and stromal overgrowth are not prominent. The tumor is circumscribed. The tumor measures ____ in maximal dimension and is clear from (specify if < 1 cm ____) / involves the resection margins.
- Left breast, wide local excision:
- Borderline phyllodes tumor
- Microscopic (optional): Sections show a stromal proliferation featuring areas of leaf-like pattern and stromal expansion with moderate cellularity and stromal atypia. Scattered stromal mitotic figures are noted. The tumor is largely circumscribed with focally infiltrative borders. The tumor measures ____ in maximal dimension and is clear from (specify if < 1 cm ____) / involves the resection margins.
- Left breast, local excision:
- Malignant phyllodes tumor
- Microscopic (optional): Sections show a malignant spindle cell proliferation with diffusely increased cellularity, stromal overgrowth and marked stromal atypia. Stromal mitotic figures are frequent. The tumor shows infiltrative borders. The tumor measures ____ in maximal dimension and is clear from (specify if < 1 cm ____) / involves the resection margins.
Differential diagnosis
- Benign phyllodes tumor
- Fibroadenoma:
- Shows a combination of pericanalicular and intracanalicular epithelial patterns
- No phyllodal epithelial pattern
- Relatively uniform stromal cellularity, no subepithelial condensation
- Overlap in stromal cellularity and mitosis in cellular and juvenile fibroadenomas
- No significant stromal expansion
- Fibromatosis:
- Lacks epithelial component
- Spindle cells arranged in long sweeping fascicles
- CD34 negative (Histopathology 1994;25:469)
- Nuclear localization of beta catenin
- Fibroadenoma:
- Borderline / malignant phyllodes tumor
- Biphasic metaplastic carcinoma:
- Epithelial component often harbors in situ or invasive carcinomatous components
- Malignant heterologous element can be present
- Well differentiated liposarcoma (MDM2+) may histologically resemble heterologous liposarcomatous elements (MDM2-) in malignant phyllodes tumors but MDM2 staining is distinguishing
- Monophasic metaplastic carcinoma:
- Lacks epithelial components
- Malignant heterologous element can be present
- Cytokeratins, p63 positive
- Fibromatosis-like metaplastic carcinoma:
- Lacks marked atypia and stromal giant cells
- Cytokeratins, p63 positive
- Lacks nuclear beta catenin expression
- Primary or metastatic sarcomas:
- Very low incidence relative to malignant heterologous differentiation in phyllodes tumor and metaplastic carcinoma; correlate with clinical history
- Lacks epithelial component
- Immunohistochemistry not helpful in differentiation
- Biphasic metaplastic carcinoma:
Additional references
Board review style question #1
A 36 year old woman presents with a self palpated breast mass. Imaging shows a rounded nodule; excision with narrow negative margins was performed. Stromal atypia and mitosis are absent. What is the most suitable follow up management for the patient?
- Adjuvant chemotherapy
- Hormonal therapy
- Local radiotherapy
- Lymph node dissection
- Observation
Board review style answer #1
E. Observation. Benign phyllodes tumor is not associated with mortality or metastasis; additional therapy is not indicated.
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Reference: Phyllodes tumor
Board review style question #2
Which of the following features is diagnostic of malignant phyllodes tumor?
- Focus of infiltrative tumor border
- Involvement by low grade ductal carcinoma in situ
- Multinucleated stromal giant cells
- Small focus of osteosarcomatous differentiation
- Stromal overgrowth
Board review style answer #2
D. Small focus of osteosarcomatous differentiation. Borderline phyllodes tumor allows for, albeit a lesser degree compared to malignant phyllodes tumor, stromal overgrowth and an infiltrative tumor border. Multinucleated stromal giant cells can be seen in all grades of phyllodes tumor and does not impact histologic grading. The epithelial component of phyllodes tumor can show metaplasia, hyperplasia, in situ or invasive malignant changes, which may impact prognosis but does not affect histologic grading. Presence of malignant heterologous differentiation directly upgrades a phyllodes tumor into the malignant category.
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Reference: Phyllodes tumor
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Reference: Phyllodes tumor
Board review style question #3
Which of the following features can be seen in malignant phyllodes tumors but not metaplastic carcinomas?
- Bizarre anaplastic tumor cells
- Cytokeratin expression
- MED12 mutation
- p53 expression
- Rhabdomyosarcomatous differentiation
Board review style answer #3
C. MED12 mutation. MED12 and RARA are frequent mutations in fibroepithelial lesions of the breast and are believed to be involved in the tumorigenesis of fibroepithelial lesions. MED12 and RARA mutations are absent in metaplastic carcinomas (Clin Cancer Res 2017;23:3859). p53 expression and TP53 mutation are detected in both malignant phyllodes tumor and metaplastic carcinomas. Aberrant cytokeratin expression, albeit patchy, can be seen in malignant phyllodes tumor. Bizarre tumor cells and malignant heterologous elements can be seen in both entities.
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Reference: Phyllodes tumor
Pleomorphic adenoma
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Positive stains | Negative stains | Electron microscopy description | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional referencesDefinition / general
- Biphasic benign breast tumor with varying epithelial and stromal components
Essential features
- Similar to pleomorphic adenoma of the salivary gland in morphology, immunohistochemistry, prognosis and treatment, except rarer in breast
- Hypothesized to be a variant of intraductal papilloma
- Biphasic benign tumor easily misdiagnosed as mucinous or matrix producing metaplastic carcinoma
Terminology
- Also called benign mixed tumor, chondroid syringoma (in skin)
ICD coding
Epidemiology
- 1906 - current: < 100 case reports (Histopathology 2016;68:45)
Sites
- Periareolar, upper outer quadrant
Pathophysiology
- Breast and salivary glands are embryologically similar exocrine glands that originate from the same ectodermal layer and can differentiate towards dual epithelial myoepithelial cell differentiation
Etiology
- May derive from divergent differentiation of a single pluripotent stem cell resulting in epithelial myoepithelial cell differentiation and stroma (Hum Pathol 1991;22:1206)
- Periareolar location:
- Large ducts with numerous myoepithelial cells (Clin Oncol 1982;8:361)
- Arise in association with intraductal papilloma and therefore may be the same entity (Am J Surg Pathol 1990;14:913)
Clinical features
- Age range: 19 - 85 years
- F > M, only 3 case reports in men (J Clin Pathol 2003;56:497)
Diagnosis
- Diagnosis may be made on core biopsy or FNA with radiologic correlation but definitive with excision
Radiology description
- Mammogram: circumscribed round lesion simulating fibroadenoma, variable calcifications (Case Rep Pathol 2015;2015:172750)
- Ultrasound: homogeneously smooth lobulated internal mass or complex cystic mass, resembling intraductal papilloma
- Tomography: isointense mass with internal septations
Radiology images
Contributed by Shabnam Jaffer, M.D., Mark R. Wick, M.D.
Periareolar nodule
Mammogram
Prognostic factors
- Low grade indolent tumor
- Recurrences (3 case reports) due to inadequate margins or multifocal tumors (Hum Pathol 1991;22:1206, Cancer 1988;61:997, Breast J 2007;13:418)
Case reports
- 55 year old woman with subareolar breast mass (Pathol Res Pract 2005;201:333)
- 57 and 78 year old women with breast masses (BMJ Case Rep 2015;2015:bcr2015210906)
- 59 year old woman with pleomorphic adenoma of the breast (Arch Pathol Lab Med 2003;127:474)
- 70 year old woman with 2 cm mass, electron microscopy study (Am J Clin Pathol 1990;93:795)
- 71 year old woman with fine needle aspiration of 23 mm breast mass (Diagn Cytopathol 2018;46:56)
Treatment
- Wide excision with clear margins (2 - 5 mm) (Breast J 2007;13:418)
Gross description
- Circumscribed yellow white gritty solid nodules > polypoid, multinodular or satellite lesions
- Size: typically 0.8 - 4.5 cm (mean = 2.0 cm) (South Med J 1975;68:97)
- Intraductal nodule with cystification
Gross images
Contributed by Shabnam Jaffer, M.D.
Circumscribed tumor
Microscopic (histologic) description
- Admixture of epithelial and myoepithelial cells embedded in a chondromyxoid stroma, may show chondroid or osseous metaplasia
- Architecture includes tubules, islands, cords, trabeculae, sheets or pseudoglandular structures lined by 2 cell types
- Inner epithelial cells: cuboidal or columnar epithelial cells, with or without apocrine or squamous metaplasia
- Outer myoepithelial cells: polygonal, plasmacytoid, fusiform or stellate with clear to eosinophilic cytoplasm
- No atypia, mitoses, necrosis or infiltrative growth
- Rare malignant transformation
- Carcinoma ex pleomorphic adenoma = 3 cases (Virchows Arch 2005;446:142)
- Epithelial myoepithelial carcinoma ex pleomorphic adenoma = 1 case (Med J Armed Forces India 2011;67:74)
Microscopic (histologic) images
Contributed by Shabnam Jaffer, M.D.
Encapsulated tumor
Biphasic benign tumor
LMWCK
SMA
Virtual slides
Images hosted on other servers:
Myxoid stromal breast tumor
Cytology description
- Cellular smears consisting of epithelial and myoepithelial cell clusters and sheets arranged in branched glandular structures
- Epithelial cells: round cells with abundant cytoplasm
- Myoepithelial cells: stellate, plasmacytoid
- Stroma: myxochondroid, light green on Pap, metachromatic (red-purple) on Giemsa
- No atypia, mitoses or necrosis
- Pitfall for misdiagnosis as mucinous or matrix producing metaplastic carcinoma (Breast Dis 2017;37:105)
Positive stains
Electron microscopy description
- Biphasic tumor (Am J Clin Pathol 1990;93:795)
- Epithelial: microvilli and lumina
- Myoepithelial: spindled stromal cells with intermediate filaments, dense bodies and intercellular junctions
Molecular / cytogenetics description
- Diploid
- Deletion of PLAG1 by FISH
- HMGIC and HGMIY not rearranged by FISH (Pathol Res Pract 2005;201:333)
- Similar to ear, nose and throat sites, HMGA2-WIFI and CTNNB1-PLAG1 have been identified in case reports (NPJ Breast Cancer 2020;6:20)
Sample pathology report
- Left breast, mass, lumpectomy:
- Pleomorphic adenoma, 3.2 cm (see comment)
- Surgical margins, negative for tumor
- Comment: The lesion is a circumscribed benign biphasic tumor by morphology and immunohistochemistry. AE1/3 and p63 are expressed. There is associated myxoid stroma. These findings are consistent with pleomorphic adenoma.
Differential diagnosis
- Intraductal papilloma with chondromyxoid stroma:
- Chondromyxoid stroma is focal, has uniform composition and is a minor component
- Metaplastic carcinoma, matrix producing:
- May be difficult to differentiate on a core needle biopsy
- Infiltrative tumor, has atypia, mitoses, necrosis
- Ductal adenoma:
- Lacks myxoid stroma
- Intraductal / within duct lumen
- May be a variant of intraductal papilloma
- Mucinous carcinoma:
- Infiltrative tumor, has atypia, mitoses, mucin
- With or without ductal carcinoma in situ
- Alcian blue hyaluronidase resistant (Arch Pathol Lab Med 2003;127:474)
- Adenomyoepithelioma:
- Lacks chondromyxoid stroma
- Phyllodes tumor with chondromyxoid differentiation:
- Leafy architecture with cellular stroma
- Stroma with mitotic figures
- Chondromyxoid areas with atypia
Additional references
Pleomorphic lobular carcinoma
Table of Contents
Definition / general | Essential features | Terminology | Epidemiology | Etiology | Clinical features | Diagnosis | Radiology description | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Positive stains | Negative stains | Molecular / cytogenetics description | Molecular / cytogenetics images | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1Definition / general
- Cytologic variant of invasive lobular carcinoma (ILC)
Essential features
- Aggressive variant which accounts for approximately 10% of ILC
- May show focal areas of classical ILC
Terminology
- Predominant cytologic features determine the histologic type of ILC
Epidemiology
- ILC are more common in older women (mean age 57, range 24 - 92) and very rare in men
- When they do occur in men, it is often in BRCA2 carriers
Etiology
- CDH1 germline mutation is seen in many ILC tumors, resulting in the loss of E-cadherin gene expression in approximately 85% of ILC
Clinical features
- Most tumors form mass-like lesions or result in architectural distortion
- Presents at more advanced stage than classic lobular carcinoma (J Surg Oncol 2008;98:314)
- Traditionally considered to have aggressive clinical course (Am J Surg Pathol 2000;24:1650) but see Ann Diagn Pathol 2012;16:185
- Poorer clinical outcome: older patients, negative hormonal receptor status
Diagnosis
- Diagnosis is often made on core needle biopsy
- Histologic tumor grade is assigned following the Nottingham grading system
- Reporting according to College of American Pathologists (CAP) invasive breast cancer protocol
Radiology description
- Tumors are most commonly detected as spiculated mass lesions on mammography
- Use of magnetic resonance imaging can aid in the detection of multicentric and contralateral lesions
Prognostic factors
- Factors which result in worse prognosis include high histologic grade (particularly high mitotic scores) and negative hormone receptor status
- Although the prognosis is typically worse for this variant versus the classic type ILC, it is thought to be more related to tumor grade versus variant type
Case reports
- 48 year old with pancreatic metastasis (Diagn Pathol 2017;12:52)
- 49 year old woman with vertebral metastasis (Spine J 2016;16:e303)
- 89 year old woman (Int J Surg Pathol 2018;26:434)
- Periocular breast carcinoma metastasis (Ophthal Plast Reconstr Surg 2017;33:361)
Treatment
- Similar to that of invasive ductal carcinoma and depends on the tumor pathologic stage and hormone receptor status
Gross description
- Spiculated mass with ill defined margins; often no mass because of diffuse growth pattern
Gross images
Images hosted on other servers:
Circumscribed tumor
Microscopic (histologic) description
- Moderately to poorly differentiated carcinomas
- Multifocal nodular aggregates of pleomorphic, high grade tumor cells with grade 2 - 3 nuclei which may contain prominent nucleoli
- Typical single file pattern or targetoid growth in a background of dense fibrotic breast parenchyma
- Distinctive cytologic cellular features with abundant eosinophilic cytoplasm (may look apocrine), signet ring and plasmacytoid cells
- Commonly positive for apocrine marker GCDFP-15
- Prognosis is related to the high tumor grade
Microscopic (histologic) images
Contributed by Mirna B. Podoll, M.D.
Desmoplastic stroma
Pleomorphic invasive lobular carcinoma
E-cadherin
ER
PR
Contributed by Mark R. Wick, M.D.
Pagetoid spread
Cadherin neg
Images hosted on other servers:
Pleomorphic tumor cells
E-cadherin negative
p53
Cytology description
- More cellular than classic lobular, large tumor cells with single filing, tumor cells have cytoplasmic vacuoles and pleomorphic nuclei (Cancer 1997;81:29)
- May have apocrine features and resemble atypical mesothelial cells (Diagn Cytopathol 2008;36:657)
- Ductal lavage: similar features, although less striking, including epithelial cells in small clusters, single-file or isolated; also nuclear atypia, cytoplasmic vacuoles and signet ring features (Acta Cytol 2008;52:207)
Cytology images
Images hosted on other servers:
Various images
Positive stains
Negative stains
- E-cadherin (Mod Pathol 2003;16:674), beta-catenin (membrane staining is absent, Appl Immunohistochem Mol Morphol 2007;15:260)
- 13% are triple negative (Histopathology 2012;61:365)
Molecular / cytogenetics description
- Resembles infiltrating lobular carcinoma more than infiltrative ductal carcinoma (J Pathol 2008;215:231)
- Frequent gains on 1q and 16p, losses on 11q and 16q and genomic amplifications of 8q24, 11q13, 12q13, 17q12 and 20q13 (Future Oncol 2009;5:233)
- More frequent p53 mutations than classic lobular (Cell Oncol (Dordr) 2012;35:111)
Molecular / cytogenetics images
Contributed by Mark R. Wick, M.D.
HER2 amp
Differential diagnosis
- Invasive ductal carcinoma single cell pattern of infiltration in ILC; can be difficult to recognize particularly at metastatic sites
- Lymphoma: may involve breast as primary site but is not seen associated with LCIS Immunohistochemical studies for cytokeratin and lymphoid markers can aid in the diagnosis
- Metastatic melanoma: one of the most common metastasis to the breast; immunohistochemical studies for cytokeratin and melanoma markers can aid in the diagnosis
- Chemotherapy or radiation treatment effect
Additional references
Board review style question #1
- Which of the following is true of pleomorphic variant of invasive lobular carcinoma?
- Are usually hormone receptor negative
- Do not show HER2 overexpression
- Frequency of p53 expression is similar to that of classic ILC
- The aggressive nature of these tumors is reflected by the pleomorphic variant designation
- The high histologic grade contributes to the poor patient outcomes
Board review style answer #1
E. The aggressive nature of the pleomorphic variant of invasive lobular carcinoma (ILC) and poorer outcomes are related to the high histologic grade of this variant, rather than the pleomorphic designation itself. While these tumors may be ER and PR negative in approximately 5 - 10% of cases, the majority are hormone receptor positive. HER2 expression can be seen in approximately 20% of cases. In addition, the pleomorphic variant of ILC more commonly shows p53 expression when compared to the classic type ILC.
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Reference: Pleomorphic lobular carcinoma
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Reference: Pleomorphic lobular carcinoma
Polymorphous
Table of Contents
Definition / general | Essential features | Clinical features | Treatment | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Negative stains | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1Definition / general
- Primary breast tumor with morphology similar to that of polymorphous low grade adenocarcinoma of the salivary glands
- "Low grade" terminology not used in these tumors due to reported case with widespread metastases
Essential features
- Very rare tumor; only 3 reported cases, first described in 2006 (Virchows Arch 2006;448:29)
- Similar to tumors of the salivary glands; they are composed of monotonous cells arranged in nests and cords
- Difficult to know prognosis of such a rare tumor but shows slow, aggressive growth with metastatic potential
Clinical features
- The rare reported cases all presented as:
- Palpable masses
- 1.5 - 4 cm in greatest dimension (mean 3 cm) with infiltrative borders
- Patient mean age 55 (range 37 - 74)
- No axillary metastases reported but one patient developed distant metastases within 3 years
Treatment
- All reported cases were treated with surgical resection (plus radiotherapy if breast conserving surgery) and axillary dissection
Microscopic (histologic) description
- Monotonous proliferation of neoplastic cells arranged in varying architectural patterns including tubules, trabeculae, alveolar, cribriform and solid nests
- Nuclei are round to ovoid with vesicular chromatin, moderate mitotic activity without necrosis
- Central and peripheral areas of the tumor may demonstrate differing architectural and immunohistochemical features
Microscopic (histologic) images
Contributed by Emily S. Reisenbichler, M.D.
Salivary gland equivalent polymorphous low grade adenocarcinoma
Differential diagnosis
- Adenoid cystic carcinoma: both have cribriform and alveolar growth with possible basal lamina-like material and are triple negative (ER / PR / HER2)
- Adenoid cystic carcinoma has two cell types with a population of actin positive cells that are absent in polymorphous adenocarcinoma
- Invasive lobular carcinoma: both can have single file pattern of growth but polymorphous adenocarcinoma has membranous E-cadherin and is negative for ER / PR and AR
- Salivary tumor metastatic to the breast: clinical history of a salivary neoplasm
Additional references
Board review style question #1
- What receptor profile is expected in a primary polymorphous adenocarcinoma of the breast?
- ER+, PR+, HER2- (Luminal A)
- ER-, PR-, HER2- (Basal-like)
- ER-, PR-, HER2+ (HER2 positive)
- ER+, PR+, HER2+
Board review style answer #1
B. Like many of the salivary gland-like tumors of the breast, polymorphous adenocarcinoma is a triple negative, basal-like tumor. Unlike the poor prognosis seen in many triple negative breast tumors, salivary gland-like tumors, including polymorphous adenocarcinoma, may have a more favorable prognosis. (Appl Immunohistochem Mol Morphol 2013;21:283)
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Reference: Polymorphous carcinoma
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Reference: Polymorphous carcinoma
Pseudoangiomatous stromal hyperplasia
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Negative stains | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Benign stromal myofibroblastic proliferation forming clefts, simulating a vascular lesion
- First described in 1986 (Hum Pathol 1986;17:185)
Essential features
- Benign stromal myofibroblastic proliferation
- Usually an incidental finding but may produce palpable or mammographic mass
- Complex interanastomosing spaces in dense collagenous, keloid-like stroma resembling blood vessels
- Some of these spaces have spindle shaped myofibroblasts at their margins, simulating endothelial cells
- Spindle cells usually positive for ER, PR and CD34 but negative for other vascular markers (e.g., CD31) (Breast J 2012;18:242)
- Pseudoangiomatous stromal hyperplasia (PASH) is an incidental microscopic finding in up to 23% of breast surgical resections (Int J Surg 2011;9:20)
Terminology
- Also called pseudoangiomatous hyperplasia of mammary stroma
ICD coding
- ICD-11: GB20.Y - other specified benign breast disease
Epidemiology
- Mostly occurs in pre and perimenopausal women but can occur in males too (Radiol Case Rep 2022;17:2919)
- Also occurs in children (Pediatr Dev Pathol 2009;12:450)
Sites
- Breast stroma
Etiology
- Myofibroblastic origin, postulated role of hormonal factors (Breast J 2012;18:242)
Clinical features
- Incidental finding, can occur in both females and males
- Can be associated with other benign and malignant lesions
Diagnosis
- Histologic examination of resected or biopsied tissue
Radiology description
- Incidental but may present as a mass, well defined or irregular (SA J Radiol 2018;22:1366)
- Nonspecific findings on magnetic resonance imaging (MRI), ranging from an enhancing mass to clumped, nonmass-like enhancement (Clin Radiol 2010;65:145)
Radiology images
Images hosted on other servers:
Round mass
Prognostic factors
- Nonneoplastic but mass forming lesion may rarely recur, especially in younger patients
Case reports
- 13 year old girl with a giant mass in the left breast for 3 months (J Pediatr Adolesc Gynecol 2021;34:209)
- 14 year old premenarchial girl with PASH presenting as bilateral gigantomastia (J Breast Cancer 2023;26:391)
- 46 year old woman with bilateral marked breast enlargement (BMJ Case Rep 2015;2015:bcr2014204343)
Treatment
- Local excision needed only in symptomatic mass forming lesions
- If diagnosed on core needle biopsy, no surgical excision is required, provided the diagnosis is concordant with radiologic findings
Gross description
- Usually unilateral, well circumscribed, firm rubbery mass (Am J Surg Pathol 1995;19:270)
- Cut surface is firm, gray-white
Gross images
Images hosted on other servers:
Well demarcated lesion
Microscopic (histologic) description
- Complex interanastomosing spaces in dense collagenous, keloid-like stroma
- Some of these spaces have spindle shaped myofibroblasts at their margins that simulate endothelial cells
- Spaces are usually empty but may contain rare erythrocytes
- Cellular areas or plump spindle cells may obscure pseudoangiomatous structure
- Often gynecomastia-like changes (Mod Pathol 2008;21:201)
- Rarely multinucleated giant cells (Breast J 2007;13:568)
- No mitotic figures, no necrosis, no atypia
- Fascicular PASH: cellular variant in which myofibroblasts aggregate into fascicles with reduced or absent clefting, resembles myofibroblastoma (Am J Surg Pathol 1995;19:270)
Microscopic (histologic) images
Contributed by Indu Agarwal, M.D.
Interlobular PASH
Slit-like spaces
Spindle cells lining the spaces
PASH within areas of fibroadenoma
CD31
CD34
Positive stains
- Spindle cells
- PR (intense), ER beta, androgen receptor, vimentin, CD34 (Am J Surg Pathol 1991;15:145, Am J Surg Pathol 1995;19:270)
- Variable desmin and actin
Negative stains
- Spindle cells
- Factor VIII, Ulex, CD31, keratin
Sample pathology report
- Left breast, at 5 o'clock and 4 cm from the nipple, ultrasound core needle biopsy:
- Breast tissue with pseudoangiomatous stromal hyperplasia (PASH)
Differential diagnosis
- Low grade angiosarcoma:
- Hemorrhagic, soft, interanastomosing vascular channels containing red blood cells with invasion into breast parenchyma
- Papillary endothelial growth and hyperchromatic endothelial cells
- CD31+, factor VIII+ (Breast J 2012;18:242)
- Myofibroblastoma:
- Absence of typical breast epithelial elements within myofibroblastoma
- Neoplastic clonal tumors with characteristic genetic change (del 13q14) (this can be demonstrated by loss of Rb protein immunohistochemistry in myofibroblastoma)
- Other spindle cell tumors (e.g., fibromatosis):
- Tumor cells arranged in long fascicles without significant clefting, nuclear beta catenin staining and CD34-
Additional references
Board review style question #1
The finding shown in the image above was obtained on the core needle biopsy of the breast in a 35 year old woman. What is the most likely mammographic finding?
- Architectural distortion
- Calcifications
- Irregular mass
- Mass with smooth borders
- No abnormality; incidental finding
Board review style answer #1
E. No abnormality; incidental finding. Pseudoangiomatous hyperplasia is usually an incidental finding but may less commonly produce palpable or mammographic mass. Answers A, B, C and D are incorrect because the most common presentation is an incidental finding only.
Comment Here
Reference: Pseudoangiomatous stromal hyperplasia
Comment Here
Reference: Pseudoangiomatous stromal hyperplasia
Board review style question #2
Which of the following sets of immunohistochemical stains would be most suitable for the diagnosis of pseudoangiomatous hyperplasia (PASH)?
- CD34-, CD31-, ER-, nuclear beta catenin+
- CD34-, CD31-, nuclear beta catenin+, AE1 / AE3+
- CD34+, CD31-, ER+, factor VIII-
- CD34+, CD31+, ER-, factor VIII+
Board review style answer #2
C. CD34+, CD31-, ER+, factor VIII-. This immunoprofile is indicative of PASH.
Answer D is incorrect because the immunoprofile is most consistent with angiosarcoma or other vascular lesions, with positive vascular markers. Answer A is incorrect because it is the immunoprofile for fibromatosis with positive nuclear beta catenin. It is important to note that fibromatosis is negative for CD34 as it does not arise from myofibroblasts. Answer B is incorrect because it is the classic staining pattern for a spindle cell carcinoma with positive AE1 / AE3.
Comment Here
Reference: Pseudoangiomatous stromal hyperplasia
Comment Here
Reference: Pseudoangiomatous stromal hyperplasia
Pubertal macromastia
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Laboratory | Radiology description | Radiology images | Case reports | Treatment | Clinical images | Gross description | Frozen section description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Rare form of breast hypertrophy that is characterized by an atypical, alarmingly rapid and continual breast growth during puberty or in the peripubertal age group (J Breast Health 2014;10:122)
Essential features
- Rare form of breast hypertrophy characterized by rapid and continual breast enlargement
- Pathogenesis is not clear
- Surgery with or without medical therapy is the treatment of choice
- Breast hypertrophy is defined as a medical condition of the breast connective tissues in which the breasts become excessively large
- There is no universal classification or definition
- Based on the severity, it can be of 2 types (Hoda: Rosen's Breast Pathology, 5th Edition, 2020)
- Gigantomastia: refers to cases with extreme breast enlargement, where excessive tissue is > 2.5 kg
- Macromastia: refers to sustained, steady breast enlargement that develops throughout puberty, where excessive tissue is < 2.5 kg
Terminology
- Also known as
- Juvenile macromastia or juvenile gigantomastia (Case Rep Surg 2017;2017:3491012)
- Virginal breast hypertrophy or virginal mammary hypertrophy (J Breast Health 2014;10:122)
- Adolescent breast hypertrophy, gigantomastia or macromastia (Clin Plast Surg 2016;43:383)
ICD coding
- ICD-10: N62 - hypertrophy of breast
- Applicable to
- Hypertrophy of breast, NOS
- Gynecomastia
- Massive pubertal hypertrophy of breast
- Applicable to
Epidemiology
- Affects girls in pubertal and peripubertal age group (10 - 17 years old) (Semin Plast Surg 2013;27:49)
- Incidence is increasing in general population; however, true incidence is not known (Semin Plast Surg 2013;27:49)
Sites
- Can affect unilateral or bilateral breasts (Semin Plast Surg 2013;27:49)
Pathophysiology
- Underlying mechanism not yet elucidated (Case Rep Surg 2017;2017:3491012)
- Most accepted hypothesis is end organ sensitivity to normal levels of hormones (estrogen, progesterone and prolactin) or growth factor (hepatocyte growth factor, insulin-like growth factor 1 and epidermal growth factor) (Arch Med Sci 2019;18:1016, Case Rep Surg 2017;2017:3491012)
Etiology
- Some suggest association with unhealthy lifestyle and hormone laden diet
- ~66% of women with macromastia are obese (Plast Reconstr Surg 2002;109:64)
- Macromastia is also known to be associated with hypercalcemia, systemic lupus erythematosus and pseudoangiomatous stromal hyperplasia (Plast Reconstr Surg Glob Open 2015;3:e501, Scuderi: International Textbook of Aesthetic Surgery, 1st Edition, 2016)
- Familial virginal breast hypertrophy is seen in association with Cowden syndrome (Ann Intern Med 1963;58:136)
- PTEN gene abnormalities can be a possible factor for precocious puberty and has been postulated as genetic basis of this disease (Development 2002;129:4159)
Clinical features
- Characterized by 6 months of extreme breast enlargement followed by longer period of slower and sustained breast growth
- Breast weight exceeds ~3% of the total body weight (J Plast Reconstr Aesthet Surg 2011;64:160)
- May be associated with neck, shoulder and back pain (J Breast Health 2014;10:122)
- Shoulder grooving, skin irritation or intertrigo may be present due to brassiere straps
- Often accompanied with skin hyperemia, dilated subcutaneous veins and skin ulceration (J Breast Health 2014;10:122)
- Emotional distress due to dissatisfaction with body image and poor self esteem (J Adolesc Health 2004;35:151)
Diagnosis
- Physical examination typically reveals normal sexual development
- Breasts are generally enlarged, pedunculated, ptotic with widened areolas
- Often firm on palpation and diffusely tender
- Discrete nodules may be present
- Breast growth, velocity and stability should be evaluated along with pubertal development and onset of thelarche (Semin Plast Surg 2013;27:49)
- Family history regarding breast disorders particularly related to breast hypertrophy should be noted (Semin Plast Surg 2013;27:49)
Laboratory
- Endocrinology profile, specifically estradiol, progesterone, luteinizing hormone (LH), follicle stimulating hormone (FSH) and prolactin, does not reveal any abnormalities and is not routinely indicated (Semin Plast Surg 2013;27:62)
Radiology description
- Breast imaging is of limited value owing to the dense breast tissue
- May be required if mass lesion is present
Radiology images
Images hosted on other servers:
Breast mammogram
Case reports
- 11 year old girl with virginal breast hypertrophy associated with Beckwith-Wiedmann syndrome (Clin Case Rep 2018;6:484)
- 12 year old girl with complaint of rapid growth in bilateral breast with symptomatic treatment (J Pediatr Surg 1988;23:1014)
- 12 year old girl with gigantomastia and giant fibroadenomas (BJR Case Rep 2021;8:20210181)
- 14 year old girl with rapid growth of bilateral breast (Clin Case Rep 2020;9:198)
- 22 year old woman with gigantomastia as a cause of pulmonary hypertension (Arch Plast Surg 2022;49:369)
Treatment
- No standard treatment; treated on a case by case basis
- Usually treated with surgical procedures, like reduction mammoplasty or subcutaneous mastectomy with implant application, with or without medical therapy (Case Rep Surg 2017;2017:3491012)
- Higher recurrence rates after reduction mammoplasty but better cosmetic results (J Pediatr Surg 1988;23:1014, Plast Reconstr Surg 2011;127:2224)
- Subcutaneous mastectomy has fewer cosmetic satisfaction rates, no reserve for lactation and lifetime risk of implant but has the lowest risk of recurrence (Plast Reconstr Surg 2011;127:2224, J Pediatr Surg 1988;23:1014)
- Medical therapy includes use of tamoxifen, bromocriptine, medroxyprogesterone, danazole, chorionic gonadotropin hormone and thyroid extracts (Plast Reconstr Surg 2011;127:2224)
Clinical images
Contributed by Pooja Ramakant, M.S., M.Ch.
Bilateral pubertal macromastia
Images hosted on other servers:
Adolescent macromastia
Virginal (juvenile) breast hypertrophy
Autoimmune related cases
Gross description
- No specific gross findings; only fibrofatty tissue seen
Frozen section description
- No role of frozen in these cases
- May be used whenever there is preoperative suspicion of cancer
Microscopic (histologic) description
- Clinical diagnosis
- Histomorphological findings resemble gynecomastia
- Increased stromal collagenization and fibrosis
- Poorly developed or reduced lobules
- Sometimes usual ductal hyperplasia is also seen
- Reference: Case Rep Surg 2017;2017:3491012
Microscopic (histologic) images
Contributed by Chanchal Rana, M.D. and AFIP
Increased stromal collagenization
Increase in interlobular stroma
Juvenile / pubertal breast hypertrophy
Marked stroma collagenization
Cytology description
- It is a clinical diagnosis, which does not require use of fine needle aspiration cytology
- Findings are nonspecific
- Smears may be paucicellular
- Resembles benign breast disease characterized by sheets of benign ductal and myoepithelial cells with bare nuclei in the background
Sample pathology report
- Bilateral breast, reduction mammoplasty:
- Consistent with clinical diagnosis of bilateral breast hypertrophy
- No evidence of malignancy
- Bilateral breast, subcutaneous mastectomy:
- Consistent with clinical diagnosis of bilateral breast hypertrophy
- No evidence of malignancy
Differential diagnosis
- Clinical diagnosis
- Need to exclude other causes of breast hypertrophy
- Breast hypertrophy associated with endocrine disorder:
- Histology is similar but also associated with laboratory abnormalities like aromatase excess, hyperprolactinemia and excessive production of parathyroid hormone
- Drugs:
- Penicillamine, ciclosporin, prednisolone, indinavir, etc.
- There is a history of drug intake followed by development of hypertrophy
- Obesity
Board review style question #1
Which of the following statements relating to pubertal macromastia is true?
- Characterized by increased sensitivity to normal levels of hormone
- Characterized by presence of increased levels of hormone
- Does not recur after reduction mammoplasty
- Medical management is the treatment of choice
Board review style answer #1
A. Characterized by increased sensitivity to normal levels of hormone. There is heightened end organ sensitivity with normal hormonal as well as growth factor levels. Answer B is incorrect because cases of pubertal macromastia have normal hormonal levels, only the sensitivity to their levels is increased. Answer D is incorrect because pubertal / virginal / juvenile macromastia is generally treated surgically with or without medical therapy. Answer C is incorrect because recurrence rates are high with reduction mammoplasty.
Comment Here
Reference: Pubertal macromastia
Comment Here
Reference: Pubertal macromastia
Board review style question #2
Which of the following statements about breast hypertrophy is true?
- Drugs such as bromocriptine and tamoxifen are used as a part of medical management
- Medical therapy is never indicated
- Obesity is not one of the major causes
- Subcutaneous mastectomy is never done
Board review style answer #2
A. Drugs such as bromocriptine and tamoxifen are used as a part of medical management. Bromocriptine and tamoxifen are used as medical therapy to reduce breast proliferation. Answer C is incorrect because pubertal / virginal / juvenile macromastia can be associated with obesity. Answer D is incorrect because subcutaneous mastectomy is also one of the surgical management options. Answer B is incorrect because medical management may be given before or after the surgical procedures for breast reduction to prevent further growth.
Comment Here
Reference: Pubertal macromastia
Comment Here
Reference: Pubertal macromastia
Radial scar / complex sclerosing lesion
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Positive stains | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Benign breast lesion comprised of a central fibroelastotic stromal core with radiating ducts and lobules with varying degrees of proliferative and cystic changes arranged in a stellate configuration
Essential features
- Benign breast lesion comprised of a central fibroelastotic stromal core with radiating ducts and lobules with varying degrees of proliferative and cystic changes arranged in a stellate configuration
- May simulate invasive carcinoma mammographically, clinically, grossly and microscopically
- Atypia or malignancy may arise within or in association with radial scars / complex sclerosing lesions
- Treatment ranges from observation with clinical and radiologic follow up to surgical excision
Terminology
- Radial sclerosing lesion, complex sclerosing lesion (> 1.0 cm)
ICD coding
Epidemiology
- 40 - 70 years
- Common; incidence 0.03 - 0.09% in screening populations (J Clin Pathol 2003;56:721)
- Similar frequency in benign (28%) and cancer (26%) specimens (Histopathology 1985;9:287, Hum Pathol 1984;15:475)
- Frequently multicentric and bilateral (J Pathol 1985;147:23, Ann Diagn Pathol 2015;19:24, Semin Diagn Pathol 2010;27:5, Histopathology 1985;9:287)
Sites
- Breast parenchyma
Pathophysiology
- Pathogenesis uncertain
- Stromal-epithelial interactions and increased expression for several factors involved in formation of vascular stroma may play a role (Hum Pathol 2002;33:29)
Etiology
- Unknown
- Scar is a misnomer; not related to prior trauma or surgery
Clinical features
- Most often incidental microscopic findings in breast tissue removed for other targets / abnormalities; however, some palpable (Clin Radiol 1993;48:319)
Diagnosis
- Imaging: ultrasound, mammogram, MRI
- Invasive procedure: core needle biopsy, fine needle aspiration (not recommended)
Radiology description
- Spiculated mass, architectural distortion, may be indistinguishable from invasive carcinoma (J Med Imaging Radiat Oncol 2010;54:415, Ochsner J 2015;15:219)
- Radiolucent or dense center
- Microcalcifications may be present
- Irregular hypoechoic mass with ill defined borders and posterior acoustic shadowing on ultrasound (Ultrasonography 2014;33:58)
- MRI enhancement characteristics variable (Breast J 2005;11:23, Breast J 2019;25:393, Can Assoc Radiol J 2020 Jun 10 [Epub ahead of print])
Radiology images
Contributed by Kristen E. Muller, D.O.
Mammogram, spiculated mass
Ultrasound, hypoechoic mass
Prognostic factors
- Associated risk with invasive breast cancer debated:
- Not found to be independently associated with increased risk of breast cancer (Cancer 2006;106:1453, Breast Cancer Res Treat 2008;108:167, Cancer Causes Control 2010;21:821, Eur J Surg Oncol 2011;37:709)
- Independently associated with a twofold increased risk of breast cancer, which may increase with larger and multiple radial scars (N Engl J Med 1999;340:430)
- Rare association with adenosquamous carcinoma (Histopathology 2000;36:203, Mod Pathol 2003;16:893)
- Size greater than or less than 10 mm does not influence prognosis (comparing radial scar and complex sclerosing lesion) (Eur J Surg Oncol 2011;37:709)
Case reports
- 32 year old woman with radial sclerosing lesion mimicking invasive carcinoma (Case Rep Oncol 2012;5:99)
- 40 year old woman with secretory carcinoma arising in a radial scar (Indian J Pathol Microbiol 2009;52:83)
- 45 year old with bilateral, multicentric adenosquamous carcinomas arising within radial scars / complex sclerosing lesions (Pathology 2014;46:85)
- 57 year old woman with DCIS arising in a radial scar (Breast Cancer 2006;13:107)
Treatment
- Ranges from excision to clinical observation due to variation in reported upgrade rates to malignancy at excision
- Upgrade rates for radial scar without atypia: 0 - 16%; mean: 7% (Mod Pathol 2016;29:1471)
- May not warrant routine surgical excision given low upgrade rates if multidisciplinary approach taken including radiologic-pathologic correlation, clinical and imaging follow up (Breast Cancer Res Treat 2018;170:313, Breast J 2018;24:133, Breast 2016;30:201, Am J Surg Pathol 2015;39:779, Surg Pathol Clin 2018;11:1, Springerplus 2016;5:398)
- Incidental and small (< 5 mm) radial scars less likely to be upgraded on excision (Arch Pathol Lab Med 2015;139:1137)
- If atypia is present, manage according to standards for the concurrent high risk lesion (J Clin Pathol 2019;72:800)
- Vacuum assisted large core biopsy may be reliable for excluding malignancy without surgery (Histopathology 2019;75:900, Breast Cancer Res Treat 2019;174:165)
Gross description
- Stellate, rubbery to firm mass with retracted center; resembles invasive ductal carcinoma
- Usually 1 cm or less; complex sclerosing lesions > 1 cm
- May be firm, irregular, with yellow streaks and flecks (due to elastotic stroma)
Gross images
AFIP images
Central sclerosis and elastosis resembling carcinoma
Microscopic (histologic) description
- Low power stellate configuration
- Central sclerotic zone composed of fibrosis and elastosis with ducts and lobules radiating outward between bands of sclerotic tissue
- Central core frequently contains small entrapped obliterated ductules that may mimic invasive carcinoma; squamous metaplasia may occur in central nidus
- Variable amounts of usual ductal hyperplasia (may be florid with necrosis), sclerosing adenosis, apocrine metaplasia and cysts
- Stroma tends to be more cellular in early lesions and more collagenized and sclerotic with abundant elastin in older lesions
- Atypical hyperplasia (ADH, ALH) observed in 21 - 51% (Breast Cancer Res Treat 2008;107:371, Cancer 2003;97:345)
- In situ or invasive carcinoma may arise within or in association with radial scar / complex sclerosing lesions
- Complex sclerosing lesions are larger (typically > 1 cm) and show features of radial scar that combine and converge with intermingling areas of sclerosis, entrapped and distorted glands and fibrocystic changes; however, may not have the well defined configuration of radial scar
Microscopic (histologic) images
Contributed by Kristen E. Muller, D.O.
Stellate architecture
Central fibroelastotic core
Central fibroelastotic core
Squamous metaplasia
Usual ductal hyperplasia and cysts
Complex sclerosing lesion
With atypical ductal hyperplasia
With atypical lobular hyperplasia
With invasive ductal carcinoma
Tubular carcinoma for comparison
Contributed by Emily S. Reisenbichler, M.D.
Central sclerosis with fibroelastotic stroma and entrapped glands radiating outward
Virtual slides
Images hosted on other servers:
Complex sclerosing lesion
Cytology description
- FNA not reliable for diagnosis; may show usual ductal hyperplasia, apocrine metaplasia and spindle shaped stromal cells (Diagn Cytopathol 1997;16:537)
Positive stains
- Myoepithelial stains: p63, calponin, CD10, smooth muscle myosin heavy chain, smooth muscle actin, CK5
- Central part of the lesion may show attenuated or absent myoepithelium
- Suggested panel: smooth muscle myosin heavy chain, calponin and p63 (Am J Surg Pathol 2010;34:896)
- Elastic stains
Molecular / cytogenetics description
- Focally increased numbers of blood vessels and expression of mRNA for collagen type 1, total fibronectin, ED-A+ fibronectin, thrombospondin 1, VPF / VEGF and KDR (Hum Pathol 2002;33:29)
- Allelic imbalance chromosome 16q and 8p; some areas may be clonal (Hum Pathol 2002;33:715)
Sample pathology report
- Right breast, needle core biopsy:
- Radial scar (see comment)
- Microcalcifications: associated with radial scar
- Comment: The radial scar measures 4 mm and appears adequately sampled and completely excised in this biopsy. No atypia or malignancy is identified. Clinical and radiologic correlation is recommended.
- Right breast, needle core biopsy:
- Complex sclerosing lesion (see comment)
- Microcalcifications: not identified
- Comment: The biopsy shows several tissue cores containing a complex sclerosing lesion comprised of benign glands with varying degrees of fibrocystic changes (usual ductal hyperplasia, cysts and apocrine metaplasia) radiating around a central fibroelastotic core. No atypia or malignancy is identified. The largest contiguous microscopic measurement in a single tissue core is 7 mm. Clinical and radiologic correlation is recommended to ensure adequate sampling of the targeted lesion.
Differential diagnosis
- Invasive ductal carcinoma:
- Lacks myoepithelial cells
- Infiltration into surrounding fat / breast parenchyma may be a clue
- Tumor cells show cytologic atypia
- Tubular carcinoma:
- Glands show distinctive angulated shapes
- Lacks myoepithelial cells
- Infiltration into surrounding fat / breast parenchyma may be a clue
- Surrounding usual ductal hyperplasia, apocrine metaplasia and cysts commonly seen at the periphery of radial scars typically absent
- Low grade adenosquamous carcinoma:
- Irregular glands with varying degrees of squamous differentiation
- Infiltrative pattern; if arising within a radial scar / complex sclerosing lesion, the malignant cells infiltrate beyond the sclerosing lesion
- Lymphoid aggregates within and at periphery of the lesion may be a clue
- Variable expression of myoepithelial and cytokeratin markers
- Negative for ER, PR, HER2
Additional references
Board review style question #1
Which of the following is true regarding the lesion pictured?
- It is frequently associated with concurrent invasive cancer
- All the glands lack myoepithelial cells and invade into adipose tissue
- Imaging features include irregular spiculated mass with dense center frequently mimicking invasive carcinoma
- There is a known association with malignant phyllodes tumors
Board review style answer #1
C. This is a radial scar. Imaging features include irregular spiculated mass with dense center frequently mimicking invasive carcinoma
Comment Here
Reference: Radial scar
Comment Here
Reference: Radial scar
Board review style question #2
Which statement is true regarding the treatment and prognosis of radial scars and complex sclerosing lesions?
- They require excision since malignancy is found in 50 - 65% of excision specimens
- Management options include surgical excision and observation without surgery
- They confer a fourfold increased risk for developing breast cancer
- Small (< 5 mm) radial scars are more likely to be upgraded on excision
Board review style answer #2
B. Management options include surgical excision and observation without surgery
Comment Here
Reference: Radial scar
Comment Here
Reference: Radial scar
Radiation therapy & cryoprobe
Table of Contents
Definition / general | Essential features | Clinical features | Cryoprobe | Radiology description | Case reports | Microscopic (histologic) description | Microscopic (histologic) images | Differential diagnosis | Board review style question #1 | Board review style answer #1Definition / general
- Whole breast irradiation primarily occurs following breast conserving surgery for breast carcinoma
- Also patients with Hodgkin lymphoma receiving mediastinal radiation with secondary breast exposure to radiation
- Radiation can also be delivered intraoperatively to the surgical cavity after removing the tumor but prior to closing the wound
Essential features
- Effects of radiation on skin, such as changes in vascularity, pigmentation and fibrosis, may be induced acutely or as a latent reaction years after radiation (Clin Cosmet Investig Dermatol 2016;9:473)
- Increased risk of secondary radiation induced sarcomas, most commonly angiosarcoma, with an incidence of 0.03 - 0.2% and average latency period of 10 years (Cases J 2008;1:313) (see also Breast angiosarcoma)
- Radiation may induce cytologic changes in normal breast tissue that can mimic atrophy, recurrent carcinoma or sarcoma
Clinical features
- In acute stages, breast skin may become pink or red and peel, as with a sunburn, followed by thickening of the skin in later stages
- Firmness of the breast may result from fibrosis
- Lactation may still occur after pregnancy in at least 50% of women who have undergone prior radiation therapy, but production is reduced
- Lactation is unaffected in the contralateral, untreated breast (Expert Rev Anticancer Ther 2013;13:159)
- Radiation may induce bullous pemphigoid in the skin (Dermatol Online J 2016;22:13030)
- In patients undergoing immediate reconstructive surgery, volume loss and fat necrosis may occur due to postmastectomy radiation; however it has not resulted in higher rates of revision surgery in the radiated breast (Ann Plast Surg 2013;71:149)
Cryoprobe
- Cryoprobe: uses cryotherapy to makes nonpalpable carcinomas well defined and palpable by creating an ice ball, leading to removal of less tissue (Am J Surg 2006;192:462)
- Alters tumor morphology making it difficult to grade tumor, distinguish DCIS and invasive tumor, and identify angiolymphatic invasion or mitotic figures (Am J Clin Pathol 2007;128:239)
- Alternative to excision of fibroadenomas (Radiology 2005;234:63)
- Normal breast parenchyma in cryozone shows dense fibrosis, fat necrosis, xanthogranulomatous reaction, endovascular fibrosis and hemorrhage (Cryobiology 2007;55:44)
- Causes reduction in ER / PR receptors, but does not affect Ki67 staining or margin evaluation
Radiology description
- Mammographic changes following radiation therapy include increased breast density and skin thickening, both of which are more common following whole breast radiotherapy than with intraoperative radiotherapy (Eur J Surg Oncol 2014;40:163)
Case reports
- 57 year old woman with radiation induced morphea (J Med Case Rep 2008;2:136)
- 62 year old woman with radiation fibrosis imitating breast cancer recurrence (J Breast Health (2013) 2017;13:40)
- Two cases of papillary endothelial hyperplasia mimicking angiosarcoma after breast irradiation (Pathol Res Pract 2016;212:604)
- Series of 10 cases of postradiation angiosarcoma of the breast mimicking radiation dermatitis (J Cutan Pathol 2017;44:456)
Microscopic (histologic) description
- Giant tumor cells with bizarre nuclear changes (J Clin Pathol 1990;43:152), naked nuclei and abnormal mitotic figures
- Extensive tumor necrosis demarcated by thick fibrous walls (when radiating tumor prior to surgery)
- Changes in nonneoplastic breast take place primarily in the terminal duct lobular unit and include atypia, lobular sclerosis and atrophy (may distort lobular architecture and obscure myoepithelial cells, Hum Pathol 1984;15:545)
- Intimal thickening in small muscular arteries (Radiother Oncol 2009;92:477) and fat necrosis, but usually no mitotic activity or loss of polarity
- Epithelial atypia in larger ducts ranges from mild to severe but proliferation of the epithelium is generally seen only with mild cytologic atypia (Am J Surg Pathol 2004;28:47)
- Atypical stromal fibroblasts
- Changes do not regress over time (Am J Surg Pathol 2004;28:47)
Microscopic (histologic) images
Contributed by
Emily S. Reisenbichler, M.D.
Radiation atypia
AFIP images
Thickened basement membranes
Atypical stromal fibroblasts
LCIS unchanged
by radiation
compared to
atrophic normal glands
Collagenization
of intralobular
stroma and glandular
atrophy
Images hosted on other servers:
Large stromal
fibroblasts may
also occur in
nonirradiated tissue
Atypia in normal duct
Atypia within normal lobule
Fat necrosis postiridium implant
Vessel shows
reduplicated elastic
lamina and intimal
thickening (elastin stain)
Edematous
lobules with atypia
of some epithelial
cells
Edematous
lobules with atypia
of some epithelial
cells
Atrophic lobules
with atypia of some
epithelial cells
Atypical stromal
cells, lymphocytic
infiltrate and
increased collagen bundles
Differential diagnosis
- Recurrent carcinoma (invasive or in situ): cells should be keratin positive and demonstrate similar histologic grade and receptor profile as the previous carcinoma
- Atypical stromal fibroblasts will be keratin negative
- Cytologic atypia in a lobule secondary to radiation will typically not fill and distend lumina or demonstrate necrosis and mitotic activity (features suggestive of recurrent high grade DCIS)
- Sarcoma (radiation induced or primary): radiation induced sarcomas typically present as mass forming lesions rather than microscopic atypical stromal cells seen postradiation
- Primary sarcoma of the breast would likely be a component of a malignant phyllodes and therefore demonstrate other features of a fibroepithelial lesion
- Primary sarcoma of the breast would likely be a component of a malignant phyllodes and therefore demonstrate other features of a fibroepithelial lesion
Board review style question #1
- Which statement about distinguishing radiation induced changes in benign breast tissue from recurrent carcinoma is true?
- Cytologically atypical cells scattered in the stroma that are estrogen receptor and keratin positive likely represent fibroblasts with radiation induced atypia.
- If the radiation took place more than 10 years previously, any atypia must represent recurrent malignancy.
- Low grade cytologic atypia is not seen in benign lobules secondary to radiation effect.
- Necrosis in proliferative ductal epithelium with high grade cytologic atypia is indicative of carcinoma in situ.
- Proliferative epithelium with high grade cytologic atypia is commonly seen secondary to radiation effect.
Board review style answer #1
D. Radiation may induce cytologic atypia of any degree from low to high, but proliferation of epithelium takes place secondary to radiation generally with only low grade atypia. Necrosis, mitoses and proliferative epithelium with high grade atypia together are suggestive of carcinoma rather than radiation atypia. Changes secondary to radiation do not regress over time and can be seen for more than 10 years following radiation therapy. Atypical, postradiation stromal fibroblasts should not be keratin or estrogen receptor positive. This staining pattern is more in keeping with recurrent invasive carcinoma.
Comment Here
Reference: Radiation therapy & cryoprobe
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Reference: Radiation therapy & cryoprobe
Sclerosing adenosis
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Videos | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Adenosis or lobulocentric processes with increase in glandular elements of terminal duct lobular unit (TDLU) with stromal fibrosis / sclerosis that distorts and compresses glands
- Preserved 2 cell layer (inner epithelial and outer myoepithelial cells)
Essential features
- Enlarged terminal duct lobular unit with distortion by stromal fibrosis / sclerosis
Terminology
- Nodular adenosis / adenosis tumor:
- Palpable mass (AJR Am J Roentgenol 2000;175:31)
- Coalescent foci of typical sclerosing adenosis
- Myoepitheliosis:
- Rare; sclerosing adenosis with predominance of myoepithelial cells, presents as multifocal microscopic lesions (Am J Surg Pathol 1991;15:554)
ICD coding
Epidemiology
- Most frequent in third to fourth decades but occurs over a wide age range
- Found in 12 - 28% of all benign and 5 - 7% of malignant biopsies (J Ultrasound Med 2013;32:2029)
Sites
- Terminal duct lobular unit; otherwise, no specific location within the breast
Pathophysiology
- Unknown
Etiology
- Unknown
Clinical features
- Considered a part of the spectrum of fibrocystic changes
- Often an incidental finding or detected by screening
- Can present as a palpable mass if nodular adenosis / adenosis tumor
- Reference: Schnitt: Biopsy Interpretation of the Breast, 3rd Edition, 2017
Diagnosis
- Histologic examination of tissue with or without immunohistochemistry
Radiology description
- Variable depending on the size / extent of breast involvement
- If focal, may not be visualized (i.e. incidental finding on histologic examination)
- Amorphous or pleomorphic clustered microcalcifications; architectural distortion or circumscribed to spiculated mass on mammogram (Diagn Interv Radiol 2011;17:311, Mol Clin Oncol 2017;6:157)
- Associated with increased mammographic breast density (Breast Cancer Res 2017;19:134)
- Heterogeneous echogenicity, irregular and ill defined mass, focal acoustic shadowing may be seen on ultrasound (Mol Clin Oncol 2017;6:157)
- Small (< 1 cm) mass with benign kinetics on MRI (Breast J 2019;25:143)
Radiology images
Contributed by Julie M. Jorns, M.D.
Calcifications, craniocaudal view
Calcifications, mediolateral oblique view
Prognostic factors
- As a single feature, increased risk of cancer of 1.5 - 2x, as seen with proliferative fibrocystic changes (Cancer 1989;64:1977)
- 2x higher risk of breast cancer with increased Ki67 proliferation index in sclerosing adenosis or associated normal background breast tissue (Breast Cancer Res Treat 2015;151:89)
- Does not provide further risk stratification in the presence of other proliferative disease / atypical hyperplasias (Breast Cancer Res Treat 2014;144:205)
- Rarely involved by lobular carcinoma in situ and mistaken for invasive carcinoma (Mod Pathol 1991;4:1)
- Ductal carcinoma in situ arising in sclerosing adenosis has a higher frequency of bilaterality (Clin Breast Cancer 2012;12:398, Breast Cancer 2014;21:732)
- Can mimic malignancy clinically and radiologically
Case reports
- 46 year old woman with sclerosing adenosis with mammogram and cytology mimicking malignancy (J Cytol 2013;30:49)
- 73 year old woman with sclerosing adenosis and coexisting ductal carcinoma in situ (Int J Surg Case Rep 2018;45:9)
- 82 year old woman with sclerosing adenosis in sentinel axillary lymph nodes (Arch Pathol Lab Med 2008;132:1439)
Treatment
- Presence of sclerosing adenosis alone in a core biopsy does not require surgical excision
- Coexisting atypia will typically prompt surgical consultation
Gross description
- Variable depending on extent of involvement and calcifications
- May be indistinguishable from surrounding breast tissue
- Multinodular, ill defined, cuts with increased resistance due to fibrosis
- Gritty due to frequent calcifications but no chalky yellow white foci or streaks as seen in fat necrosis
- Circumscribed to ill defined white, fibrotic mass if nodular adenosis / adenosis tumor
- Reference: Schnitt: Biopsy Interpretation of the Breast, 3rd Edition, 2017
Microscopic (histologic) description
- Low power: increase in glandular elements plus stromal fibrosis / sclerosis that distorts and compresses glands
- Maintains lobular architecture at low power with rounded and well defined nodules
- Centrally is more cellular with distorted and compressed ductules; peripherally has more open or dilated ductules
- Often has microcalcifications, due to calcification of entrapped secretions
- Often has associated fibrocystic changes of other types, such as apocrine metaplasia
- Preservation of luminal epithelium and peripheral myoepithelium (2 cell layer) with surrounding basement membrane
- Myoepithelial cells may vary from being prominent to indistinct on routine H&E staining
- Myoepithelial cells are readily apparent via immunohistochemistry, even if difficult to identify on H&E
- Rarely penetrates walls of blood vessels or perineural spaces
- No necrosis, no pleomorphism
- Apocrine adenosis: variant of sclerosing adenosis with prominent apocrine features
- Epithelium may be involved by proliferative, atypical lesions or in situ carcinoma
- Can mimic malignancy:
- If involved by atypia or in situ carcinoma
- If florid and overtly non-lobulocentric / (pseudo) infiltrative into fat or stroma
- Conspicuous myoepithelial cells with attenuated epithelial cells can appear like stands of single cells and mimic invasive lobular carcinoma
- Atypical apocrine metaplasia: nuclear atypia / rare mitosis (Mod Pathol 1991;4:1)
- (Pseudo) perineural invasion
Microscopic (histologic) images
Contributed by Julie M. Jorns, M.D.
Lobule with distortion
Calcifications and drag
Drag mark
Calponin
p63
Sclerosing adenosis with DCIS
Sclerosing adenosis with DCIS
Cytology description
- Moderate to markedly cellular, with small to large groups of benign epithelial cells in acinar sheets / cohesive groups / tubules and scattered individual epithelial cells
- Also small foci of dense hyalinized stroma (Acta Cytol 2001;45:353, Diagn Cytopathol 2008;36:496)
- Tubules may have an angular configuration (Am J Clin Pathol 2012;138:96)
Positive stains
- Epithelial cells: CK7
- Myoepithelial cells: p63, CK5/6, calponin, alpha smooth muscle actin
- Basement membrane (surrounds tubules): laminin, type IV collagen
- Reference: Schnitt: Biopsy Interpretation of the Breast, 3rd Edition, 2017
Videos
Pathology mini tutorial
Sample pathology report
- Left breast, core biopsy:
- Fibrocystic changes including sclerosing adenosis with microcalcifications
Differential diagnosis
- Microglandular adenosis:
- Haphazardly distributed glands (lacks lobulocentric pattern)
- Lacks myoepithelium but has intact basement membrane
- Tubular adenoma:
- Well circumscribed
- Nodular growth may mimic nodular adenosis / adenosis tumor
- Uniform, closely packed tubules (lacks significant distortion by fibrosis)
- Invasive carcinoma:
- May be difficult to morphologically distinguish from florid sclerosing adenosis with marked distortion and/or involvement by atypia or DCIS
- Displays desmoplastic stromal response
- Lacks myoepithelium
- Invasive tubular carcinoma:
- More widely spaced tubules with single epithelial layer
- Displays desmoplastic stromal response
Additional references
Board review style question #1
A premenopausal woman underwent breast biopsy for screening detected microcalcifications showing the pictured lesion. This lesion typically is associated with
- Abundant cytologic atypia
- Clinically palpable mass
- Lack of myoepithelium
- Variable imaging features
Board review style answer #1
D. Variable imaging features. The pictured lesion is sclerosing adenosis, a benign breast lesion characterized by expansion of glands (with preserved 2 cell layers: inner epithelial and outer myoepithelial cells) within the terminal duct lobular unit with distortion by fibrosis / sclerosis. Most of the time, sclerosing adenosis lacks cytologic atypia. Sclerosing adenosis frequently has calcifications due to entrapped secretions. However, when abundant, sclerosing adenosis may present as a distortion or mass on imaging. Sometimes sclerosing adenosis clinically presents as a palpable mass, as with nodular adenosis / adenosis tumor. However, sclerosing adenosis can often be an incidental finding when there is another indication for biopsy. Thus, imaging findings are variable, depending on size and extent of the lesion.
Comment Here
Reference: Sclerosing adenosis
Comment Here
Reference: Sclerosing adenosis
Board review style question #2
Sclerosing adenosis of the breast (without atypia) imparts what risk for future breast cancer?
- No increased risk
- 1.5 - 2x increased risk
- 4 - 5x increased risk
- 8 - 10x increased risk bilaterally
- 8 - 10x increased risk ipsilaterally
Board review style answer #2
B. 1.5 - 2x increased risk. Sclerosing adenosis is considered part of the spectrum of proliferative fibrocystic changes, which imparts a 1.5 - 2x increased risk for future breast cancer. This is opposed to nonproliferative fibrocystic change which has no increased risk and atypical ductal hyperplasia (ADH) with 4 - 5x, ductal carcinoma in situ (DCIS) with 8 - 10x (unilateral: ipsilateral side) and lobular carcinoma in situ (LCIS) with 8 - 10x (bilateral) increased risk for breast cancer.
Comment Here
Reference: Sclerosing adenosis
Comment Here
Reference: Sclerosing adenosis
Secretory
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Clinical features | Diagnosis | Radiology description | Radiology images | Case reports | Treatment | Clinical images | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Negative stains | Molecular / cytogenetics description | Molecular / cytogenetics images | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Rare subtype of low grade, translocation associated invasive breast carcinoma
- Tumor with microcystic, solid and tubular architecture, composed of vacuolated tumor cells producing intracellular and extracellular secretions
- Generally triple negative with basal-like phenotype (Mod Pathol 2012;25:567)
- First described by McDivitt and Stewart in 1966 (JAMA 1966;195:388)
Essential features
- Rare, < 1% of breast cancers
- Most common primary pediatric breast cancer but can occur at any age
- Circumscribed margins, solid nests, cysts and gland formation with PAS+ intraluminal secretions
- Tumor cells with abundant vacuolated or granular cytoplasm, low nuclear grade
- Generally triple negative for estrogen receptor, progesterone receptor and HER2
- Most tumors have translocation yielding ETV6-NTRK3 fusion gene
- Associated with a favorable prognosis in younger patients
Terminology
- Originally named juvenile breast carcinoma, the terminology was changed to secretory carcinoma after reports of the tumor occurring in adults
ICD coding
- ICD-O: 8502/3 - secretory carcinoma of breast
Epidemiology
- Rare, < 0.02% of all breast cancers (Breast 2012;21:350, J Surg Oncol 2016;113:721)
- Initially described in children; most common childhood breast cancer (JAMA 1966;195:388)
- Wide age range, bimodal age distribution with peaks in second and seventh decades (Breast 2012;21:350, Diagn Histopathol 2020;26:51)
- M:F = 1:6 to 1:31 (World J Surg Oncol 2005;3:35, Mod Pathol 2012;25:567, J Surg Oncol 2016;113:721, Ann Oncol 2000;11:1343)
Clinical features
- Tumor size, rates of axillary lymph node involvement, AJCC stage at presentation and surgical treatment are similar to invasive ductal carcinoma (J Surg Oncol 2016;113:721)
- Generally associated with indolent clinical behavior, excellent prognosis (Cancer 1980;45:2404, Clin Cancer Res 2004;10:5367)
- 5 year overall survival: 87%
- 5 year disease specific survival: 94% (Breast 2012;21:350)
- Subsets with aggressive clinical course and distant metastases have been reported (World J Surg Oncol 2005;3:35, Histopathology 2019;75:213)
- Outcome may be better in patients < 20 years old (Hum Pathol 1999;30:1435)
- Limited data regarding patterns of use and analysis of effectiveness of adjuvant radiation and chemotherapy
Diagnosis
- Histologic examination of tissue with immunohistochemistry, demonstration of ETV6-NTRK3 gene fusion by fluorescent in situ hybridization
Radiology description
- Variable, nonspecific, with reports ranging from presentation as a small, round, well circumscribed mass / nodular density to suspicious lesions with spiculated margins and microcalcifications on ultrasound and mammography (J Clin Ultrasound 2003;31:425, Breast J 2003;4:2000, Ann Surg Oncol 2002;9:663)
Radiology images
Images hosted on other servers:
Hypoechoic lesion on ultrasound
Case reports
- 6 year old girl treated with mastectomy and sentinel lymph node dissection (Pediatr Surg Int 2015;31:677)
- 13 year old boy with secretory breast carcinoma (Breast Cancer Res Treat 2012;133:813)
- 24 year old man with axillary lymph node metastasis (Int J Clin Exp Pathol 2015;8:3322)
- 41 year old man with long term follow up of secretory breast carcinoma (Future Oncol 2015;11:1767)
- 53 year old woman with papillary predominant pattern (Histopathology 2017;71:488)
- 79 year old woman with a palpable breast mass (Rare Tumors 2016;8:6650)
Treatment
- Surgical treatment, use of antihormonal targeted therapy similar to invasive ductal carcinoma (J Surg Oncol 2016;113:721)
Clinical images
Images hosted on other servers:
Breast mass involving skin
Gross description
- Small, well circumscribed, mobile mass
- Median size 1.9 - 2.4 cm (J Surg Oncol 2016;113:721, Breast 2012;21:350)
- Often central, located near the areola
Microscopic (histologic) description
- Well circumscribed with pushing borders but may be infiltrative at periphery
- Central sclerosis may be observed
- Architecture is usually microcystic, solid or tubular or admixture of all 3 patterns
- Can display peripheral papillary architecture
- Low grade cytologic atypia, bland uniform nuclei, low mitotic rate
- Histologic hallmark is the presence of tumor cells with vacuolated, foamy cytoplasm and abundant intracellular and extracellular pale blue to dense pink secretions, which are periodic acid Schiff (PAS) positive and diastase resistant (JAMA 1966;195:388, Mod Pathol 2012;25:567)
- Often an in situ component (Mod Pathol 2009;22:291)
Microscopic (histologic) images
Contributed by Gary Tozbikian, M.D. and Case #8
Glands and solid nests
Tumor cells with vacuolated cytoplasm
Low nuclear grade, no mitoses
Microcystic pattern
Extracellular secretory material
Solid pattern
PASD
S100
Positive stains
- S100, although expressed frequently in acinic cell carcinoma and in 30% of invasive ductal carcinoma, NOS, so not useful for these differentials (Mod Pathol 2012;25:567, Mod Pathol 2009;22:291)
- CK5/6, EGFR (Mod Pathol 2012;25:567, Mod Pathol 2017;30:1086)
- CK14 in 33% (Mod Pathol 2009;22:291)
- CD117 (focal) (Mod Pathol 2009;22:291)
- MUC4, SOX10 (Mod Pathol 2017;30:1086)
- GATA3 (Mod Pathol 2017;30:1086)
- PAS (periodic acid Schiff) positive and diastase resistant
Negative stains
- Triple negative or focal / weak (44 - 64%) for ER, PR and HER2 (Mod Pathol 2012;25:567, Mod Pathol 2017;30:1086, J Surg Oncol 2016;113:721, Am J Surg Pathol 2015;39:1458, Hum Pathol 2003;34:1299)
- p63 (Mod Pathol 2009;22:291)
Molecular / cytogenetics description
- Associated with chromosomal translocation t(12;15)(p13;q25), resulting in ETV6-NTRK3 fusion gene in 95% of cases (J Pediatr Surg 2000;35:765, Cancer Cell 2002;2:367, Genes Chromosomes Cancer 2004;40:152, World J Surg Oncol 2005;3:35, Mod Pathol 2017;30:1086, Histopathology 2019;75:213)
- Lacks the complex genomic alterations such as high mutational burden, frequent copy number alterations or TP53 mutations seen in conventional basal-like triple negative breast cancers (Mod Pathol 2017;30:1086, Am J Surg Pathol 2015;39:1458)
- Lacks chromosomal alterations 1q gains and 16q losses seen in low grade neoplasia pathway (Mod Pathol 2017;30:1086)
- Amplification of 16p13.3, TERT promoter mutation, loss of 9p21.3 locus, reported in cases with aggressive clinical course (Histopathology 2019;75:213)
Molecular / cytogenetics images
Images hosted on other servers:
Karyogram with t(12;15)(p13;q25)
FISH with disrupted ETV6 gene
Sample pathology report
- Breast, right, 3:00, ultrasound guided core biopsy:
- Secretory carcinoma, 0.7 cm in greatest length
- Estrogen receptor: negative (0%)
- Progesterone receptor: negative (0%)
- HER2: negative (score 0)
Differential diagnosis
- Acinic cell carcinoma:
- Cells with clear cytoplasm (hypernephroid pattern)
- Expresses proteins of the salivary gland counterpart of acinic cell carcinoma (e.g. alpha-1-chymotrypsin, salivary gland amylase, lysozyme)
- Lacks the t(12;15) translocation
- Invasive ductal carcinoma, NOS:
- Lacks vacuolated cytoplasm and secretions
- Typically conventional triple negative breast cancer (TNBC) is high grade, not cytologically bland as in secretory carcinoma
- Cystic hypersecretory hyperplasia:
- Cysts containing abundant, homogenous intraluminal secretions resembling thyroid colloid
- Cells lining cysts are bland, flat or cuboidal / columnar cells lacking vacuolated / granular cytoplasm
- Presence of intact myoepithelial cell layer
- Glycogen rich carcinoma:
- PAS positive, diastase sensitive secretions
- Can demonstrate any grade of nuclear atypia
- Lipid rich carcinoma:
Additional references
Board review style question #1
Secretory carcinoma is associated with which cytogenetic abnormality?
- 1q chromosomal gains and 16q chromosomal losses
- HER2 gene amplification
- t(12;15)(p13;q25), resulting in ETV6-NTRK3 fusion gene
- t(6;9)(q22-23;p23-24), resulting in fusion of MYB and NFIB
- TP53 mutation
Board review style answer #1
C. Secretory carcinoma of breast is associated with t(12;15)(p13;q25), resulting in ETV6-NTRK3 fusion gene
Comment Here
Reference: Secretory carcinoma of breast
Comment Here
Reference: Secretory carcinoma of breast
Board review style question #2
What histological and immunophenotypic features are most likely to be observed in a breast secretory carcinoma?
- Abundant PAS+, diastase sensitive secretions
- High grade cytologic atypia with brisk mitotic activity
- Irregular clusters of epithelial cells floating in pools of extracellular mucin
- Low grade cytologic atypia, triple negative for ER, PR and HER2
- Negative for basal-like markers CK5/6 or CK14
Board review style answer #2
D. Secretory carcinoma of breast is most likely to show low grade cytologic atypia, triple negative for ER, PR and HER2
Comment Here
Reference: Secretory carcinoma of breast
Comment Here
Reference: Secretory carcinoma of breast
Secretory change
Table of Contents
Definition / general | Terminology | Epidemiology | Etiology | Clinical features | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Differential diagnosis | Additional referencesDefinition / general
- Pregnancy-like changes in a nonpregnant, nonlactating patient
Terminology
- See also pregnancy / lactation, lactating adenoma
Epidemiology
- Present in 2 - 3% of breast biopsies
- Identified in needle localization and core biopsies due to calcifications or presence of a mass
- Women, mean age 44 years, range 38 - 52 years
- Not lactating, not pregnant (by definition)
Etiology
- May be associated with phenothiazine or other medications (Am J Clin Pathol 1987;87:23)
Clinical features
- Often multifocal
- Associated with / may merge with cystic hypersecretory hyperplasia
- May have associated ADH or DCIS (Am J Clin Pathol 2004;122:714) but invasive carcinoma is rare (Am J Surg Pathol 2004;28:789)
Treatment
- Recommend excision if atypia found in core biopsy (Am J Surg Pathol 2000;24:1670)
Gross description
- No gross lesion
Microscopic (histologic) description
- Glands and terminal ducts with little or no secretion
- Glandular cells are swollen with abundant pale or clear, finely granular or vacuolated cytoplasm
- Luminal cytoplasmic borders of glandular cells are frayed with small cytoplasmic blebs extending into lumen that may contain nuclei
- Small, uniform, round and darkly stained nuclei
Microscopic (histologic) images
AFIP images
Expanded acinar glands
Cells have abundant pale cytoplasm but no secretion
Micropapillary pattern
of columnar cells with
luminal cytoplasmic buds
Images hosted on other servers:
Cells have finely vacuolated cytoplasm
Differential diagnosis
- Apocrine adenosis or apocrine metaplasia: cytoplasm more eosinophilic, vacuoles are usually only focal
- Apocrine DCIS: abundant eosinophilic cytoplasm, architectural or cytologic atypia
- Columnar cell lesion: tightly packed columnar epithelial cells
Additional references
Sentinel lymph nodes
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Diagrams / tables | Clinical features | Diagnosis | Radiology description | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Frozen section / intraoperative description | Frozen section images | Microscopic (histologic) description / diagnostic criteria | Microscopic (histologic) images | Virtual slides | Cytology description | Cytology images | Positive stains | Negative stains | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2 | Board review style question #3 | Board review style answer #3Definition / general
- Sentinel lymph nodes (SLN) are the first lymph nodes to receive lymphatic drainage and metastasis from a tumor
Essential features
- Blue dye (isosulphan blue or methylene blue) or radioactive isotope labeled colloid (technetium sulfur colloid) is injected to identify the draining SLN
- Entire breast largely drains to the same few SLN (Arch Surg 2004;139:614)
- SLN are usually axillary nodes (level I) but may be at level II or III; rarely intramammary, interpectoral (Rotter) or internal mammary node (Eur J Surg Oncol 2009;35:252)
- Intraoperative frozen section or intraoperative imprint cytology can be performed on the SLN (even after neoadjuvant chemotherapy) to determine need for axillary lymph node dissection (ALND) (Acad Radiol 2009;16:551)
Terminology
- At least 1 node with presence or absence of cancer as documented by pathologic examination is required for pathologic N classification in breast cancer staging
- Axillary lymph node metastases are classified into 3 groups: isolated tumor cell clusters, micrometastasis and macrometastasis
- AJCC sn modifier: when the number of sentinel and nonsentinel nodes removed is < 6
- AJCC f modifier: when nodal metastasis is confirmed by FNA or core biopsy only
ICD coding
Epidemiology
- 15 - 20% of clinically node negative patients will have a positive SLN (Breast Care (Basel) 2018;13:331)
- If SLN are negative, other axillary nodes are negative in > 95% of cases and axillary recurrence rate is only 0.3% at median 34 months (Eur J Surg Oncol 2008;34:1277)
Sites
- Breast lymphatic drainage (Am J Clin Pathol 2018;150:4):
- Superficial system: superficial breast and skin to axilla, independent
- Deep system: breast to axilla, anastomoses with perforating system
- Perforating system: traverses pectoralis muscles and drains into internal mammary node
- Axillary lymph nodes are divided into 3 levels:
- Low axilla: lateral to the lateral border of the pectoralis minor muscle
- Mid axilla: between the medial and lateral borders of the pectoralis minor muscle, plus the interpectoral (Rotter) lymph nodes
- Apical axilla or infraclavicular nodes: medial to the medial margin of the pectoralis minor muscle and inferior to the clavicle
- Intramammary nodes are most commonly present in the upper outer quadrant and are included with axillary nodes in AJCC N classification
- Internal mammary nodes, supraclavicular nodes and infraclavicular nodes are rarely removed for breast cancer staging
- If metastases are present in these nodes, there are specific AJCC N categories
- Medially located tumors are more likely to drain to internal mammary nodes (medial 28%; lateral 15%) (Am J Clin Pathol 2018;150:4)
- Tumor is more likely at the inflow junction of afferent lymphatic vessels (Am J Surg Pathol 2003;27:385)
Diagrams / tables
Images hosted on other servers:
Sentinel lymph node biopsy
Clinical features
- SLN biopsy is successful in > 90% of eligible breast cancer patients
- False negative rate (FNR) in surgical practice (i.e. inability of the procedure to identify a positive draining lymph node): 5.5 - 16.7% (J Clin Oncol 2014;32:1365)
- Lowest FNR: if both blue dye and radioactive tracer are used, 6.7% (J Natl Cancer Inst 2006;98:599)
- Increased FNR when only a single SLN is removed (Lancet Oncol 2010;11:927)
- FNR in large multifocal / multicentric tumors appears to be similar to small unifocal tumors (systematic review of 26 studies, Eur J Surg Oncol 2011;37:371)
Diagnosis
- Gross sectioning of SLN at 2 mm intervals and histological examination of submitted tissue
Radiology description
- Axillary ultrasound (US) is the primary modality for evaluating axillary lymph node status prior to surgery
- Cortical thickening, hilar effacement and non-hilar cortical blood flow, are more important than size criteria (Radiographics 2013;33:1589)
- Preoperative axillary US and FNA cytology are routine at many breast units, with a sensitivity of 56% (confidence interval: 47 - 64%) and specificity of 90% (84 - 93%) for US alone and 76% (61 - 87%) and 100% (65 - 100%) when combined with FNA cytology (J BUON 2011;16:454)
- Standard breast MRI is comparable to dedicated axillary US in breast cancer patients; subsequent axillary US can be done on those with suspicious nodal findings (Eur J Radiol 2016;85:2288)
- CT and radionuclide imaging play a lesser role in imaging the axilla (Radiographics 2013;33:1589)
Prognostic factors
- High risk (60%) of tumor in nonsentinel nodes if sentinel node has macrometastatic tumor (≥ 2 mm) versus low risk (3%) if micrometastatic tumor (0.2 - 2 mm) (Mod Pathol 2005;18:762)
- Extranodal extension was a predictor of nonsentinel node involvement in a single institution study of 266 cases (Sci Rep 2020;10:14684)
Case reports
- Middle aged woman with subcapsular deposit of metastatic carcinoma and benign mammary inclusion (Breast J 2020;26:274)
- 63 year old woman with intravascular nevus cell aggregate in axillary lymph node mimicking metastatic carcinoma (Breast J 2019;25:726)
- 86 year old woman with isolated tumor cells and benign Müllerian inclusions in axillary sentinel lymph node (Appl Immunohistochem Mol Morphol 2016;24:144)
Treatment
- SLN biopsy (versus ALND) is standard of care in staging clinically node negative T1 / T2 tumors
- Notable exception per Choosing Wisely Society of Surgical Oncology recommendations: don't routinely use SLNB in clinically node negative women ≥ 70 years of age with early stage hormone receptor positive, HER2 negative invasive breast cancer
- Number of involved lymph nodes and size of deposit (micro / macrometastasis) are important for clinical decision making (Ann Oncol 2018;29:2153)
- Per current NCCN guidelines, clinically node negative patients with only micrometastasis or with macrometastasis meeting ACOSOG Z11 criteria (T1 / T2 tumor, ≤ 2 positive nodes, breast conserving surgery, whole breast RT planned, no preoperative chemotherapy) may be spared ALND
- ER+ / HER2- patients with limited involvement of axillary lymph nodes might be spared adjuvant chemotherapy if the tumor biology is favorable (Ann Oncol 2018;29:2153)
- Role of nodal radiation therapy in patients with 1 - 3 positive lymph nodes is unclear, though there is modest increase in disease free survival (JAMA Oncol 2016;2:991)
- Current NCCN guidelines recommend strongly considering radiation therapy
Clinical images
Images hosted on other servers:
.jpg)
Blue stained axillary node
Gross description
- Axillary SLN may be blue dyed, with or without surrounding adipose tissue
Frozen section / intraoperative description
- Axillary SLN are identified by the surgeon by determining uptake of radioisotope technetium 99 sulfur colloid, methylene blue dye or both
- Intraoperative frozen section or imprint cytology may be performed on the SLN to determine need for axillary lymph node dissection (World J Surg Oncol 2008;6:69, Eur J Surg Oncol 2009;35:16)
- Frozen section (FS) had an overall mean sensitivity of 73% (macrometastasis: 94%; micrometastasis 40%) and mean specificity of 100% (metaanalysis of 47 studies, Cancer 2011;117:250)
- SLN FS may be safely omitted in patients who meet ACOSOG Z11 criteria (Clin Breast Cancer 2018;18:276, J Clin Pathol 2016;146:57)
- FNR of intraoperative frozen section post neoadjuvant chemotherapy was 5.4% in a single institution study of 711 cases (Am J Surg Pathol 2019;43:1377)
- Atypical cases on FS are usually negative on permanent sections (Mod Pathol 2005;18:58)
- In most cases, if metastases are present, the SLN will be involved; in rare cases, only nonsentinel nodes contain metastases
- Metastasis to nonsentinel lymph nodes can occur if the true SLN is completely replaced by tumor (and therefore is not detected by radioactive tracer or dye), if there is unusual lymphatic drainage or if there is failure of the technique to identify the node
Frozen section images
Contributed by Sucheta Srivastava, M.D.
Macrometastasis
Micrometastasis
Microscopic (histologic) description / diagnostic criteria
- See Staging of breast carcinoma
- Size of the metastatic focus is measured from the largest contiguous cluster of tumor cells
- Direct extension of primary tumor into a regional node is classified as node positive
- Tumor nodule with a smooth contour in a regional node area is classified as a positive node
- Size of the metastasis, not the size of the node, is used for the criterion for the N category
- Cases with isolated tumor cells only in lymph nodes are classified as pN0(i+)
- Dispersed pattern of lymph node metastasis can be difficult to categorize
- Particularly lobular carcinomas metastasize as single cells and do not form cohesive clusters
- If > 200 tumor cells are present in 1 cross section of the node, then the category isolated tumor cells should not be used
- If there is difficulty in assigning the N classification, it is recommended that the reason be provided in a note
- The area of extracapsular extension is included in the overall size of the lymph node metastasis if contiguous
- Size of the metastasis includes the tumor cells and the desmoplastic response in treatment naïve patients (i.e. the cells do not need to be contiguous but the cells plus fibrosis should be contiguous)
- Finding of extranodal invasion is also reported
- Areas of carcinoma invading into the stroma in axillary adipose tissue, without residual nodal tissue, are considered to be positive lymph nodes
- However, if there is surrounding breast tissue or ductal carcinoma in situ, then the focus should be classified as an invasive carcinoma and not as a lymph node metastasis (CAP: Protocol for the Examination of Specimens from Patients with Invasive Carcinoma of the Breast [Accessed 20 August 2021])
Microscopic (histologic) images
Contributed by Sucheta Srivastava, M.D. and Jaya Ruth Asirvatham, M.B.B.S.
Macrometastasis
Macrometastasis with extranodal extension
Micrometastasis
Status post neoadjuvant chemotherapy
Isolated tumor cells
Isolated tumor cells, cytokeratin
Isolated tumor cells, pancytokeratin
Virtual slides
Images hosted on other servers:
Metastatic breast ductal adenocarcinoma, lymph node
Cytology description
- Fine needle aspiration smears of positive axillary lymph node are characterized by crowded, disorganized groups of cells with enlarged nuclei, nuclear pleomorphism, irregular nuclear membranes and intracytoplasmic vacuoles with or without mucin
- Necrosis or mucin in the background and single intact malignant cells may be present
- Imprint cytology had an overall sensitivity of 63% (macrometastasis: 81%, micrometastasis: 22%) and specificity of 99% (meta analysis of 31 studies, Br J Surg 2005;92:1068)
- Factors that can affect the outcome of fine needle aspiration are size of the metastasis in the lymph node, experience of the person performing image guided fine needle aspiration and pathologist evaluation of the sample for adequacy (at the time of fine needle aspiration)
Cytology images
Contributed by Sucheta Srivastava, M.D.
Touch prep
Diff-Quik
Papanicolaou
Cell block
Positive stains
- Note: "enhanced methods" of SLN metastasis detection, including routine immunohistochemistry, are not recommended (i.e. should be used on a case by case basis / when necessary for diagnosis) (J Clin Oncol 2014;32:1365)
- AE1 / AE3, CK7, GATA3
- Estrogen receptor / ER (depends on biomarker status)
- Reference: Semin Diagn Pathol 2018;35:143
Negative stains
Molecular / cytogenetics description
- Some studies have reported usefulness of molecular assays, usually reverse transcriptase polymerase chain reaction (RT-PCR) (J Clin Oncol 2008;26:3338)
- False positive and false negative results can occur with RT-PCR
- Significance of a positive RT-PCR result for a histologically negative lymph node is unknown (J Clin Oncol 2008;26:3338)
- Current AJCC cancer staging manual (8th edition) includes positive molecular findings by RT-PCR; no isolated tumor cell clusters detected as pN0 (mol+)
Sample pathology report
- Right axilla, sentinel lymph node #1, excision:
- One lymph node negative for metastatic carcinoma (0/1)
- Right axilla, sentinel lymph node #1, excision:
- One lymph node with macrometastatic carcinoma (12 mm deposit) with extranodal extension (measuring 2 mm) (1/1)
Differential diagnosis
- Benign epithelial inclusions in axillary lymph node (Int J Surg Pathol 2018;26:564, Breast J 2020;26:274):
- These inclusions can be glandular (most common) or squamous epithelium lining cystic lumina
- Glandular inclusions often have a luminal and myoepithelial cell layer
- In some cases, the glandular epithelium shows proliferative changes like usual ductal hyperplasia in the breast
- Immunoreactivity for myoepithelial cell markers (p63, calponin, SMMHC / smooth muscle myosin heavy chain, actin - alpha smooth muscle) is often demonstrable but it may be variable or absent in morphologically benign inclusions
- Endosalpingiosis of axillary lymph nodes (Case Rep Pathol 2016;2016:2856358, Am J Surg Pathol 2010;34:1211, Breast J 2020;26:274):
- Müllerian type glandular inclusions lined by cytologically bland cuboid to columnar epithelial cells that are reminiscent of fallopian tube type lining or coelomic type lining
- Cilia, when present, is a reassuring feature to confirm a benign diagnosis
- Positive for PAX8 and WT1 (good markers of Müllerian origin) and negative for GATA3
- Nevus cell clusters:
- Positive for MelanA and HMB45
- Negative for estrogen receptor / ER, GATA3
- Nevus cells may rarely be intravascular (Breast J 2019;25:726)
Additional references
Board review style question #1
The finding in the image above of a pancytokeratin immunostain of an axillary sentinel lymph node from a breast cancer patient is best described as
- pN0(i+)
- pN1a
- pN1mi
- pNX
Board review style answer #1
A. pN0(i+): isolated tumor cell clusters (malignant cell clusters ≤ 0.2 mm)
Comment Here
Reference: Sentinel lymph nodes
Comment Here
Reference: Sentinel lymph nodes
Board review style question #2
Which of the following is true for axillary sentinel lymph nodes?
- Evaluation requires grossing at 2 mm intervals and routine use of immunohistochemistry
- Isolated tumor cell clusters are clusters of cells ≤ 0.2 mm and ≤ 200 cells in a single cross section
- Most commonly, sentinel lymph node is in level II
- Only the first excised lymph node is a sentinel lymph node
Board review style answer #2
B. Isolated tumor cell clusters are clusters of cells ≤ 0.2 mm and ≤ 200 cells in a single cross section
Comment Here
Reference: Sentinel lymph nodes
Comment Here
Reference: Sentinel lymph nodes
Board review style question #3
Which of the following supports a diagnosis of metastatic carcinoma in sentinel lymph nodes?
- Bland nests located within lymph node capsule that are positive for MelanA
- Cell clusters within lymph node parenchyma with significant nuclear atypia
- Glands with ciliated cells that are positive for PAX8
- Glandular structures with peripheral myoepithelial cells
Board review style answer #3
B. Cell clusters within lymph node parenchyma with significant nuclear atypia
Comment Here
Reference: Sentinel lymph nodes
Comment Here
Reference: Sentinel lymph nodes
Silicone leak / lymphadenopathy
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Positive stains | Negative stains | Electron microscopy description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Foreign body inflammatory reaction induced by silicone
- Diffuse in the breast → silicone mastitis
- Nodular in the breast → silicone granulomas
- Leakage to regional lymph nodes → silicone lymphadenitis
Essential features
- Complication of leakage or rupture of silicone containing breast prosthesis or as a reaction to silicone injection
- Foreign body inflammatory reaction induced by silicone
- Most common sites: breast, regional lymph nodes
Terminology
- Silicone granuloma
- Silicone mastitis
- Silicone lymphadenopathy
ICD coding
Epidemiology
- Incidence rates vary between manufactures and radiological detection methods (Gland Surg 2017;6:163):
- 10 year incidence for Allergan round: 9.3% (primary augmentation) and 35.4% (primary / revision reconstruction) (Plast Reconstr Surg 2014;133:1354)
- 10 year incidence for Allergan shaped: 17.7% (primary augmentation) and 12.4% (primary reconstruction) (Aesthet Surg J 2015;35:145)
- 6 year incidence for Mentor round: 1.1% (primary augmentation) and 3.8% (primary reconstruction) (Aesthetic Plast Surg 2009;33:440)
- 6 year incidence for Mentor shaped: 2.1% (primary augmentation) and 1.5% (primary reconstruction) (Plast Reconstr Surg 2012;129:1381)
- 8 year incidence for Sientra: 6.4% (primary augmentation) and 2.8% (primary reconstruction) (Aesthet Surg J 2016;36:404)
Sites
- Breast and regional lymph nodes
Pathophysiology
- See etiology
Clinical features
- In breast:
- Breast implant rupture is often clinically silent (Ann Plast Surg 2005;54:583)
- Palpable masses
- Change in breast size, shape or firmness
- Breast pain
- Induration of skin, draining sinuses, deformity
- In lymph nodes:
- Incidental finding
- Painful or enlarged lymph nodes:
- Axillary (Breast J 2020;26:1821)
- Internal mammary (J Med Imaging Radiat Oncol 2021;65:216)
- Cervical (Ann R Coll Surg Engl 2016;98:e118)
Diagnosis
- Can be suspected clinically and radiologically
- Histopathology is the gold standard for a definitive diagnosis
Radiology description
- Mammography: radiopaque silicone outside the implant shell in the breast or lymph nodes with or without irregular and coarse calcifications
- Ultrasound: extracapsular silicone in the breast or lymph nodes (snowstorm sign) (Indian J Radiol Imaging 2016;26:216)
- Magnetic resonance imaging: high signal intensity deposits in the breast or lymph nodes
Radiology images
Images hosted on other servers:
Rupture of silicone implant (mammography)
Snowstorm sign (ultrasound)
Extracapsular free silicone conglomerates (MRI)
Case reports
- 34 year old woman with silicone breast implant associated fibromatosis (J Surg Case Rep 2018;2018:rjy249)
- 35 year old woman with extensive silicone lymphadenopathy mimicking lymphoma (Ann Surg Treat Res 2017;93:331)
- 39 year old woman with pericarditis after breast implant rupture (Cardiol Res 2018;9:381)
- 45 year old woman with silicone nipple discharge (Int J Surg Case Rep 2020;74:73)
- 57 year old woman with silicone implant incompatibility syndrome (BMJ Case Rep 2017;2017:bcr2016218709)
- 58 year old woman with breast implant associated anaplastic large cell lymphoma (Case Rep Hematol 2018;2018:2414278)
- 72 year old woman with silicone granuloma associated with pectoral muscle involvement (Eur J Breast Health 2018;14:54)
Treatment
- Replacement of the prosthesis with removal of the surrounding contracture (Clin Plast Surg 2021;48:1)
- Excision of enlarged masses or lymph nodes caused by migration of silicone (Am J Med 2018;131:1383)
- Total mastectomy to control significant inflammatory or cosmetic complications (Indian J Plast Surg 2015;48:317)
Gross description
- Firm to hard nodular surface, gritty if there is calcification (Insights Imaging 2018;9:59)
- Cystic spaces containing thick pale yellow or white material
Gross images
Contributed by Debra L. Zynger, M.D.
Breast mass
Images hosted on other servers:
Fibrous capsule
Silicone lymphadenopathy
Microscopic (histologic) description
- Features are not specific:
- Chronic inflammatory cells, foreign body giant cell reaction and fibrosis
- Fat necrosis → histiocytes containing clear, refractile, nonpolarizable material within cytoplasmic vacuoles
- Extracellular silicone can also be seen as nonbirefringent crystals or particles within empty spaces
- Later features include:
- Fibrous capsule or bursa: well defined band of collagenized fibrous tissue and mixed chronic inflammatory cells
- Calcifications in the capsule or around: globular aggregates, may have bone formation
Microscopic (histologic) images
Contributed by Syed Hoda, M.B.B.S. and Julie M. Jorns, M.D.
Capsule with silicone
Silicone and synovial metaplasia
Foamy histiocytes
Clinically ruptured silicone implant
Silicone lymphadenitis
Implant with associated seroma
Silicone lymphadenitis
Virtual slides
Images hosted on other servers:
Breast, silicone granuloma
Lymph node, silicone lymphadenopathy
Cytology description
- Papillary synovial spherules consisting of an extracellular matrix and bland looking cells (Diagn Cytopathol 2018;46:769)
- Vacuolated histiocytes containing refractile particles (Acta Cytol 1990;34:10)
Positive stains
- Macrophages and foreign body giant cells: CD11b, CD44, CD68, CD163 (J Histochem Cytochem 2006;54:763, Cell Rep 2015;13:1937)
Negative stains
Electron microscopy description
- Calcifications are composed of hydroxyapatite crystals
Sample pathology report
- Left breast, core needle biopsy:
- Benign breast tissue with fibrous capsule with associated foreign body giant cell reaction to silicone, chronic inflammation and fat necrosis
Differential diagnosis
- Sinus histiocytosis with massive lymphadenopathy:
- Fever, leukocytosis, anemia
- Usually no history of breast implant
- Large histiocytes with emperipolesis, plasma cells
- No foreign body giant cell reaction
- No foreign material
- Fat necrosis:
- Usually secondary to injury or previous procedures
- No history of breast implant
- May have foreign material from prior procedure(s) but is morphologically different from silicone
- Abscess / acute mastitis:
- Associated with lactation in most cases
- Neutrophils are predominant
- Bacteria are usually present (gram positive)
- No foreign material
- Cystic neutrophic granulomatous mastitis:
- Fever, leukocytosis, anemia
- Granulomatous inflammation with cystic spaces rimmed by neutrophils
- Coryneform bacteria is present in cystic spaces (gram positive, culture or molecular testing)
- No foreign material
Additional references
Board review style question #1
A 34 year old nulliparous female presented with a unilateral breast mass 8 years after bilateral breast augmentation with silicone implants. On examination, the patient was afebrile but her breast was tender with a focal deformity. Which of the following histomorphological features is associated with her condition?
- Caseating granulomas
- Cystically dilated ducts with inspissated material
- Gram positive bacteria
- Histiocytes with refractile material
Board review style answer #1
Board review style question #2
Which of the following features is seen in silicone lymphadenitis?
- Crystals
- Emperipolesis
- Fungal hyphae
- Langhans giant cells
Board review style answer #2
SMOLD
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Case reports | Treatment | Clinical images | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Negative stains | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Keratinizing squamous metaplasia of lactiferous ducts (SMOLD) in association with acute and chronic inflammation including foreign body giant cells
Essential features
- Retroareolar inflammatory lesion due to lactiferous duct blockage and rupture secondary to keratinizing squamous metaplasia
- Strong association with smoking
- Characteristic microscopic findings include a mixed inflammatory infiltrate including keratinaceous debris within giant cells and lactiferous ducts with squamous metaplasia or intraluminal keratin
- Recurrence is common without definitive treatment, including excision of the affected duct and smoking cessation
Terminology
- Zuska disease, recurrent subareolar abscess, periductal mastitis, subareolar fistula
ICD coding
- ICD-10: N61 - inflammatory disorders of breast
Epidemiology
- Uncommon, found in women and men
- Often fourth to fifth decade of life; range: 14 - 79 years old (Surg Clin North Am 2022;102:1103)
Sites
- Subareolar, breast (bilateral)
Pathophysiology
- Accumulation of keratin secondary to squamous metaplasia in deeper lactiferous ducts with subsequent blockage and rupture
- Rupture of duct with extrusion of keratinaceous debris incites a mixed inflammatory response
- Secondary infection or abscess may occur
- Repeat recurrences may lead to fistula formation
- Fistula tract forms beneath smooth muscle of areola, which is a path of least resistance
- Reference: Schnitt: Biopsy Interpretation of the Breast, 3rd Edition, 2017
Etiology
- Strong correlation with smoking
- Relative vitamin A deficiency related to smoking may be a causative factor in squamous metaplasia
- Less common associations
- Congenital nipple cleft and nipple piercings (Surg Clin North Am 2022;102:1103)
Clinical features
- Painful, warm, erythematous swelling or mass near nipple
- Often misinterpreted as an abscess
- Less common features include purulent nipple discharge, skin thickening or ipsilateral axillary lymphadenopathy
- Inverted nipple can be seen
- Fistula tract opening at the edge of the areola is characteristic
- Reference: Schnitt: Biopsy Interpretation of the Breast, 3rd Edition, 2017
Diagnosis
- Integrative diagnosis utilizing clinical findings, radiology and pathology
Radiology description
- Mammogram: retroareolar localized increased stroma / asymmetric density; less common findings include stromal distortion, solitary mass or normal imaging (Clin Radiol 2012;67:e42)
- Ultrasound: medial periareolar hypoechoic lesion, possibly with discreet sinus or abscess with adjacent dilated ducts (Clin Radiol 2012;67:e42)
Case reports
- 29 year old woman with 8 month history of nipple cellulitis and inversion (BMJ Case Rep 2020;13:e237568)
- 56 year old woman with recurrent left subareolar breast abscesses and fistula associated with Prevotella bivia infection (Cureus 2022;14:e28904)
- 82 year old woman with diagnosis of SMOLD in association with primary squamous cell carcinoma (Breast Cancer 2018;25:365)
Treatment
- Excision of affected duct is most effective
- Antibiotics or incision and drainage procedures result in recurrence
- Ultrasound guided percutaneous needle electrolysis (PNE) was effective treatment in a small series (J Clin Med 2020;9:649)
- Smoking cessation is recommended
- Reference: BMJ Case Rep 2020;13:e237568
Clinical images
Contributed by Nicolas Ajkay, M.D.
Acute abscess
Single fistula
Gross description
- Portion (or entire) nipple - areola complex and underlying breast tissue containing possible fistula tract or abscess
Microscopic (histologic) description
- Squamous metaplasia past the normal transition point to ductal epithelium, which is 1 - 2 mm beneath the skin surface
- Ducts filled or expanded by keratin debris
- Duct rupture with keratin debris inciting acute and chronic inflammatory reaction
- Keratin debris within giant cells is characteristic
- Reference: Schnitt: Biopsy Interpretation of the Breast, 3rd Edition, 2017
Microscopic (histologic) images
Contributed by Katie C. Hall, M.D., Anna Biernacka, M.D., Ph.D. and Mary Ann Gimenez Sanders, M.D., Ph.D.
Extension of squamous epithelium
Squamous metaplasia of lactiferous duct
Squamous metaplasia
Keratin accumulation, duct distension
Squamous and glandular lining
Duct rupture
Inflammatory response
Keratin and acute inflammation
Foreign body giant cells
Giant cells engulfing keratin
Inflammation, giant cells, keratin
Keratin, slit-like spaces
Periductal inflammation
Metaplastic squamous epithelium
Plasma cell rich infiltrate
Surface epithelium
Involved duct
Keratin debris
Lactiferous ducts of the nipple
Deep in nipple
Normal transition
Normal transition, CK7
Normal transition, p63
Cytology description
- Metaplastic squamous cells, anucleated squamous cells and mixed inflammation including macrophages and giant cells (Clin Radiol 2012;67:e42)
Cytology images
Contributed by Mary Ann Gimenez Sanders, M.D., Ph.D.
Pap smear
Sample pathology report
- Breast, left, retroareolar, ultrasound guided biopsy:
- Skin and breast parenchyma with chronic active inflammation including foreign body giant cells (see comment)
- Comment: There are rare keratin flakes associated with the inflammatory infiltrate. Given the patient's history of recurrent painful subareolar abscesses and chronic tobacco use, these findings could be compatible with squamous metaplasia of lactiferous ducts (SMOLD). Clinical correlation is recommended.
Differential diagnosis
- Mammary duct ectasia:
- Major and minor ducts affected with lymphocyte predominant inflammatory reaction
- Histiocytes within and surrounding duct wall in response to lipid or secretory material, not keratin
- Periductal fibrosis may be present
- Retroareolar abscess secondary to infection:
- Specific microorganism(s) identified via special stains or culture
- Squamous metaplasia or keratin debris not present in stroma
- Epidermal inclusion cyst:
- Present within superficial dermis and not continuous with lactiferous duct
- Cystic neutrophilic granulomatous mastitis or idiopathic granulomatous mastitis:
- Lobulocentric granulomatous inflammation
- Peripheral location
- Sinus tracts may open to skin surface without associated squamous metaplasia or central location
Board review style question #1
A 39 year old woman presents with a retroareolar mass. She has a history of recurrent retroareolar abscesses previously treated with antibiotics and incision / drainage. An ultrasound guided biopsy of the mass shows similar findings to those in the photo. What is the definitive treatment?
- Central excision to include entire nipple
- Excision of affected duct
- Incision / draining and antibiotics
- Smoking cessation
Board review style answer #1
B. Excision of affected duct. This is the correct answer and definitive treatment; squamous metaplasia of lactiferous ducts (SMOLD) is likely to recur without excision of the affected duct. Answer D is incorrect because while smoking cessation is suggested, it is not the definitive treatment.
Answer A is incorrect because excision is the definitive treatment; however, the entire nipple does not necessarily need to be included.
Answer C is incorrect because antibiotics and incision / drainage is the treatment for an abscess.
Comment Here
Reference: SMOLD
Comment Here
Reference: SMOLD
Board review style question #2
What finding differentiates squamous metaplasia of lactiferous ducts (SMOLD) from other inflammatory breast conditions?
- Duct rupture with associated acute and chronic inflammation
- Lack of microorganisms on special stains and culture
- Lobulocentric granulomatous inflammation with neutrophils
- Squamous metaplasia with keratinaceous debris, possibly with foreign body giant cells
Board review style answer #2
D. Squamous metaplasia with keratinaceous debris, possibly with foreign body giant cells. These findings in the appropriate clinical context and location are diagnostic for SMOLD.
Answer B is incorrect because this is not the only inflammatory breast disease that can lack microorganisms on special stains or culture.
Answer C is incorrect because a lobulocentric pattern of inflammation would not be expected in SMOLD. This is pattern of inflammation can be seen in cystic neutrophilic granulomatous mastitis and idiopathic granulomatous mastitis.
Answer A is incorrect because duct rupture can be seen in SMOLD as well as mammary duct ectasia.
Comment Here
Reference: SMOLD
Comment Here
Reference: SMOLD
Solid papillary carcinoma
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Frozen section description | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Cytology images | Positive stains | Negative stains | Electron microscopy description | Molecular / cytogenetics description | Videos | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Definition / general
- Subtype of ductal carcinoma characterized by solid cellular nodules punctuated by thin fibrovascular cores
- Frequently demonstrates neuroendocrine differentiation
- May be either in situ or invasive
Essential features
- Circumscribed solid growth pattern with interspersed delicate fibrovascular cores
- Low or intermediate grade nuclear atypia
- Neuroendocrine differentiation is common
- In situ carcinoma is diagnosed when the tumor is composed of well circumscribed solid nests in a distribution pattern consistent with an intraductal process; myoepithelial cells may or may not be demonstrable at the periphery
- Invasive carcinoma is diagnosed when there is a lack of myoepithelium and a convincing pattern of infiltrative growth
- ER+ / PR variable / HER2-
- Associated with an excellent prognosis (Breast 2016;26:67)
Terminology
- In situ or invasive nature of the tumor should be specified
- Also called neuroendocrine breast carcinoma in situ, spindle cell ductal carcinoma in situ, neuroendocrine ductal carcinoma in situ, endocrine ductal carcinoma in situ
ICD coding
- ICD-O: 8509/2 - solid papillary carcinoma in situ
- ICD-O: 8509/3 - solid papillary carcinoma with invasion
- ICD-10: C50 - malignant neoplasm of breast
- ICD-11: 2E65.Y & XH0134 - other specified carcinoma in situ of breast & solid papillary carcinoma in situ
- ICD-11: 2C64 - solid papillary carcinoma of breast with evidence of invasion
Epidemiology
- Postmenopausal women (median age = 73 years) (Am J Surg Pathol 1995;19:1237)
Sites
- Any part of the breast but the central / subareolar region is most common
Pathophysiology
- Unknown
Etiology
- No specific etiologic factors
Clinical features
- May present as a mammographic abnormality, palpable mass or bloody nipple discharge (Am J Surg Pathol 1995;19:1237)
Diagnosis
- Diagnosed by histologic examination of tissue removed by biopsy or surgical excision
Radiology description
- On mammography, solid papillary carcinoma can appear as a lobulated, circumscribed mass, with or without calcifications
- Margins may be indistinct in invasive cases (AJR Am J Roentgenol 2012:198;264)
- Ultrasonography may demonstrate a hypoechoic or heterogeneous solid mass (AJR Am J Roentgenol 2012:198;264)
- Magnetic resonance imaging findings include mass enhancement with circumscribed margins, oval or irregular shapes, heterogeneous signal intensity and rapid enhancement in initial contrast phases (BMC Cancer 2017;17:525)
Radiology images
Contributed by Melinda Lerwill, M.D.
Invasive solid papillary carcinoma
Prognostic factors
- Excellent prognosis
- Axillary lymph node metastasis (6%) and distant metastasis are rare and appear limited to cases with an overt invasive component (Breast 2016;26:67)
Case reports
- 46 year old woman with a left breast mass (Surg Case Rep 2020;6:143)
- 73 year old woman with synchronous bilateral solid papillary carcinomas (Case Rep Surg 2013;2013:812129)
- 86 year old woman with a solid papillary carcinoma diagnosed by fine needle aspiration (Diagn Cytopathol 2020;48:53)
Treatment
- Solid papillary carcinoma in situ is a form of ductal carcinoma in situ and is managed as such
- Surgical excision
- Radiation therapy in the setting of breast conserving surgery
- Consideration of endocrine therapy for risk reduction
- Invasive solid papillary carcinoma is managed as an invasive breast carcinoma
- Surgical excision and sentinel node evaluation
- Radiation therapy in the setting of breast conserving surgery
- Endocrine therapy is typically recommended due to the strong ER positivity of these tumors
- Systemic therapy decisions should factor in the favorable prognosis of this histologic subtype
Gross description
- Mass forming examples demonstrate a well circumscribed, firm to soft tumor with tan-white to tan-pink cut surfaces (Am J Surg Pathol 1995;19:1237)
- In situ examples with less confluent growth may demonstrate scattered firm nodularity
Gross images
Contributed by Melinda Lerwill, M.D.
Invasive solid papillary carcinoma
Frozen section description
Microscopic (histologic) description
- Expansile nodules composed of a solid epithelial proliferation punctuated by delicate fibrovascular cores
- Cytologic features (Am J Surg Pathol 1995;19:1237)
- Monomorphic cytologic appearance
- Round, oval, plasmacytoid or spindle shaped cells
- Low to intermediate grade nuclear atypia
- Mildly enlarged, round to oval nuclei with fine chromatin and indistinct nucleoli
- Some examples have slightly more open, granular chromatin and small nucleoli
- Nuclear grooves are occasionally conspicuous
- Variable mitotic activity
- Cytoplasm ranges from pale and amphophilic to eosinophilic and granular
- Intracellular and extracellular mucin are common and signet ring cells are occasionally observed
- Architectural features (Am J Surg Pathol 1995;19:1237)
- Solid epithelial growth pattern with interspersed thin fibrovascular cores
- Cellular palisading around fibrovascular cores
- Streaming growth pattern is common in cases with spindle cells
- Microcystic spaces are occasionally present
- Fibrovascular cores can demonstrate hyalinization
- Solid papillary carcinoma in situ
- In situ carcinoma is diagnosed when the nodules have smooth rounded contours and a distribution pattern consistent with involvement of the underlying glandular tree
- Myoepithelial cells may be retained, attenuated or absent around the perimeter of the nodules
- If the morphology is consistent with an intraductal process, in situ carcinoma (pTis) is diagnosed even if no myoepithelial cell layer is seen
- Careful histologic assessment of tumor distribution and borders is required in cases without an identifiable myoepithelial cell layer
- Myoepithelial cells are often attenuated or absent along the internal fibrovascular cores
- Graded according to nuclear features
- Solid papillary carcinoma with invasion
- Invasive carcinoma arising in association with solid papillary carcinoma in situ may take one of several forms:
- Invasive solid papillary carcinoma
- Mucinous carcinoma
- Type B / cellular mucinous carcinoma is the most common pattern in this setting (
- Invasive carcinoma arising in association with solid papillary carcinoma in situ may take one of several forms: