Breast-nonmalignant
Last revised 21 July 2008
Last major update November 2007
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Reviewed by Hind Nassar, M.D. in January 2008 (see Reviewers page)
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Table of Contents - Breast-nonmalignant
General: primary references, WHO classification, embryology, neonatal, thelarche, normal anatomy, normal histology, pregnancy/lactation, pubertal macromastia
Congenital anomalies: amastia/hypoplasia, accessory glandular tissue, aplasia, athelia, nipple inversion, supernumerary
Procedures: biopsy marking devices, cautery artifact, core biopsy, cytology, open biopsy/frozen section, MRI directed, reduction mammoplasty
Inflammatory / infectious / parasitic: acute mastitis/abscess, duct ectasia, fat necrosis, foreign body reaction, fungi, giant cell arteritis, granulomatous mastitis, hemorrhagic necrosis, infarct, lymphocytic mastitis, Mondor's disease, nephrogenic systemic fibrosis, ossification, parasites, plasma cell mastitis, polyarteritis nodosa, reactive spindle cell nodule, sarcoidosis, silicone implants, tuberculosis
Fibrocystic disease: general, apocrine metaplasia, chronic inflammation, collagenous spherulosis, columnar cell lesion, cystic hypersecretory hyperplasia, cysts, epithelial ductal hyperplasia, fibroadenomatoid change, fibrosis, microcalcifications, pseudolactational hyperplasia, radial scar, sclerosing lobular hyperplasia
Adenosis: general, adenomyoepithelial, blunt duct, microglandular, sclerosing, tubular
Benign (usually) tumors/changes: adenomyoepithelioma, amyloid tumor, angiolipoma, apocrine adenoma, atypical or benign vascular proliferations post-radiation, Carney’s syndrome, chondrolipoma, clear cell “sugar” tumor, cylindroma, ductal adenoma, eccrine spiradenoma, fibroadenoma, fibromatosis, galactocele, granular cell tumor, gynecomastia-like, hamartoma, hemangioma, hemangiopericytoma, inflammatory pseudotumor, juvenile xanthogranuloma, lactating adenoma, leiomyoma, lipoma, lymphangioma, mucocele, myoepithelioma, myofibroblastoma, nipple adenoma/florid papillomatosis, nodular mucinosis, papilloma, phyllodes, pleomorphic adenoma, pseudoangiomatous stromal hyperplasia (PASH), subareolar sclerosing duct hyperplasia, syringomatous adenoma of nipple, tubular adenoma
Atypical hyperplasia: flat epithelial atypia, atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH)
Go to Breast-malignant chapter (DCIS, invasive carcinoma, other malignancies, miscellaneous, children, males)
Primary references for Breast chapter
American Journal of Clinical Pathology (AJCP) [free full text, no registration after 1 year]; January 2000 to November 2007
American Journal of Surgical Pathology (AJSP), March 1977 to October 2007
Archives of Pathology and Laboratory Medicine (Archives) [free full text, no registration always]; January 1976 to October 2007
BMC Clinical Pathology [free full text, no registration always]; December 2003 to 19 September 2007
Cytojournal [free full text, no registration always]; July 2004 to 31 October 2007
Human Pathology (Hum Path), March 1970 to October 2007
Modern Pathology (Mod Path) [free full text, no registration after 1 year]; January 1988 to September 2007
Rosen: Tumors of the Mammary Gland (AFIP Fascicle, 3rd series, volume 7); 1994
Rosai, J: Ackerman’s Surgical Pathology (9th Ed), Mosby, 2004
Sternberg, S: Diagnostic Surgical Pathology (4th Ed); Lippincott Williams & Wilkins, 2004
Websites (images): Digital Atlas of Breast Pathology, Johns Hopkins Breast Center, National Institutes of Health, Online Management of Breast Diseases, PathologyResources.com (online version of AFIP fascicle 3rd Series)
Virtual slides: University of Iowa, USCAP
Journal search terms: “breast” and each topic below
Please refer to these primary references for more detailed discussions and photographs
WHO classification of breast tumors
2003 classification: Table, listing
References: Tavassoli: Tumours of the Breast and Female Genital Organs (WHO, 2003, Volume 4)
Breast is considered an epidermal gland because it develops as diverticula of epidermis into dermis
Breast is also considered a modified and highly specialized apocrine gland
Mammary gland development begins at week 4, when ectoderm and underlying mesoderm proliferate and differentiate into skin
Week 4: paired ectodermal thickenings called mammary ridges or milk lines develop along ventral embryo and extend in curvilinear convex pattern from axilla to medial thigh; ridges will eventually disappear except at 4th intercostal space on anterior thorax, where mammary gland develops
Week 5: remnant of mammary ridge ectoderm proliferates and is termed primary mammary bud
Week 7: primary mammary bud grows downward into underlying dermis
Week 10: primary mammary bud branches into secondary buds
Week 12: secondary mammary buds start lobule development
Week 20: small lumina develop with mammary buds that coalesce and elongate to form lactiferous ducts
Month 5: areola is formed by ectoderm
Drawings: milk lines #1; #2; lifetime mammary gland development
Micro images: various images
References: eMedicine
Identical in males and females
Nipple is small pit in center of areola, becomes everted shortly after birth due to proliferation of mesenchyme underlying the areola
Breast enlargement (uni- or bilateral) is present in up to 70% of neonates due to neonatal prolactin production, caused by falling levels of maternal estrogens; associated with production of “witch’s milk” in males and females
Continued breast stimulation (squeezing or massaging breasts) may cause hypersecretory state to persist
Milk secretion: resembles colostrum; contains water, fat, cellular debris
Clinical images: 12 day old boy
Micro: duct dilation without acini
Micro images: neonatal breast ectasia with dilation of mammary ducts
Rapid growth of breasts at onset of puberty, usually age 10-11 in females
Signifies entry into Tanner stage II of development (Arch Dis Child 1976;51:170)
Growth is due to fat deposition, periductal connective tissue and elongation and thickening of ductal system; growth may be sporadic
Influenced by estrogens, growth hormone and prolactin, but not progesterone
Excision of initial subareolar disc will lead to amastia after puberty
Premature: if prior to 9 years; may be isolated, or part of precocious puberty if other signs of puberty are present; no lobules present
Tanner staging: Stage I; Stage II; Stage III; Stage IV; Stage V
Gross: initially rubbery subareolar discoid mass; may be asymmetric
Micro: prior to puberty, breasts of both sexes have ducts with variable branching lined by cuboidal epithelium, no lobules, no necrosis (AFIP, p11); at puberty in females, lobules develop
Micro images: premature thelarche (9 year old girl with premature breast enlargement): proliferation of ducts without lobules; intraductal epithelial hyperplasia with uniform cells and prominent nuclei
References: Wikipedia
Also called mammary gland
Covered by skin and subcutaneous tissue
Separated from pectoralis muscle by fascia
Composed of terminal duct lobular units (TDLU, terminal duct and lobule, has secretory function) plus 6-10 (AFIP: 15-25) large ducts which drain into lactiferous sinus and collecting duct (below nipple); large ducts subdivide into segmental ducts, subsegmental ducts and then lobules
Montgomery's tubercles: areolar protuberances (10-20), more prominent during pregnancy; composed of collecting lactiferous duct and sebaceous apparatus (Archives 1982;106:60)
TDLU: site of origin of fibrocystic changes, hyperplasia, carcinoma (including most ductal carcinomas)
Ducts: site of origin of solitary papillomas, duct ectasia, rarely ductal carcinoma
Regional lymph nodes: (a) axillary - interpectoral [Rotter’s] nodes and lymph nodes along axillary vein and its tributaries, (b) internal mammary - in the intercostal spaces along the edge of the sternum in the endothoracic fascia; supraclavicular lymph nodes are not considered regional
Lymph nodes: occur normally in any quadrant; but should biopsy in cancer patients (Hum Path 2001;32:178)
Drawings: breast anatomy #1; #2; #3; #4; #5; Netter drawing #1 (anatomy); #2 (blood supply); #3 (lymphatics); regional lymph nodes #1; #2; supraclavicular fossa
Major ducts: lined by pseudostratified columnar epithelium (extralobular) or double layer of cuboidal epithelium (intralobular); extralobular ducts are surrounded by well developed layer of elastic tissue
Terminal duct lobular unit (TDLU): ductules (acini) with lobular architecture and intralobular connective tissue
Ductules (lobular ducts): lined by inner layer of columnar or cuboidal epithelium (secretory and absorptive) and outer basal layer of myoepithelium (myofilaments oriented parallel to long axis of duct)
A continuous basement membrane follows contour of duct and ductules
Occasional neuroendocrine cells are present
Ochrocytes (histiocytes containing lipofuscin pigment) occur in 15-20% (J Pathol 1975;117:39)
Intralobular connective tissue: loose myxomatous stroma with fibroblasts, lymphocytes, macrophages, vessels; hormonally responsive; no elastic fibers
Interlobular connective tissue: denser, more collagenous than intralobular connective tissue; becomes more fatty after age 18 years
Nipple: contains numerous sebaceous glands independent of hair follicles, dense fibrous stroma containing erectile smooth muscle tissue, stratified squamous epithelium resembling skin but with increased melanin pigment, Toker cells (clear cells basally located in the epidermis); lactiferous sinuses often appear irregularly corrugated; stratified squamous epithelium extends into duct lumens for short distance
Areola: contains sebaceous glands
Menstrual cycle: proliferative phase breast has small lobules with few terminal duct structures, rare mitotic figures, condensed intralobular stroma; secretory phase breast has larger lobules, more terminal duct structures, basal epithelial cell proliferation and vacuolization, stromal edema (breast fullness), increased mitotic figures; stromal lymphocytes increase at end of secretory phase; followed by desquamation, apoptosis, atrophy, shrinkage (AJSP 1986;10:382)
Pregnancy related changes and lactation: see below
Clear cell change: clear cytoplasm contains glycogen, may represent metaplastic change towards eccrine sweat glands
Post-menopausal: largely adipose tissue with few residual ducts, acini or vessels; atrophy of glandular component is normal with age, may be microcystic (but not considered fibrocystic disease); in elderly women, residual estrogenic stimulation maintains vestigial remnants of lobules; elastosis (excess elastic fibers) found in 50% of women age 50+ years without breast disease, either diffusely in stroma, around vessels or around ducts; marked perivascular elastosis is suggestive of malignancy (Archives 1991;115:1241)
Males: testosterone causes involution of male mammary gland, except in testicular feminization syndrome (no testosterone receptors)
Normal histology of breast (continued)
Micro images: normal lobules #1; #2; #3; #4; two layers #1; #2; various images; epithelial cells have ER+ nuclei #1; #2; epithelial cells have PR+ nuclei; E-cadherin #1; #2; atrophy; clear cell change #1; #2; myoepithelial hyperplasia with clear round myoepithelial cells displacing glandular epithelial cells
myoepithelial cell stains - smooth muscle actin; calponin #1; #2; p63+ #1; #2; CD10, smooth muscle actin, S100; type IV collagenase (upper left)
metaplasia: myoid metaplasia derived from myoepithelial cells highlighted by HHF; squamous metaplasia arising in duct
post-treatment: normal acini (see also Breast malignant chapter-treatment effect)
menstrual cycle stages: stage 1 (days 0-5, eosinophilic luminal secretions), stage 2 (days 6-15, vacuoles, can distinguish ductal and myoepithelial cells), stage 3 (days 16-24, prominent myoepithelial vacuoles), stage 4 (days 25-28, extensive stromal edema)
Cytology images: normal breast
Virtual slides: infant breast; normal breast #1; #2; #3
Videos: normal breast
Positive stains (epithelium): CK 8/18, CK 19, EMA (apical region of active secretory cells), milk fat globule membrane antigen, lactalbumin, E-cadherin
Positive stains (myoepithelial cells): smooth muscle actin, CK5/6, CK14, CK17, S100, p63 (nuclear staining, AJSP 2001;25:1054),
CD10 (Mod Path 2002;15:397), E-cadherin and P-cadherin (J Pathol 1993;169:245), calponin, smooth muscle myosin heavy chain, maspin, type IV collagenase
Positive stains (basement membrane): laminin, type IV collagen, reticulin
Negative stains (myoepithelial cells): EMA, ER, PR, p53, HER2 (AJCP 2003;120:161)
EM images: acini; glandular and myoepithelial cells
Pregnancy / lactation - breast
See also lactating adenoma, pseudolactational hyperplasia
Changes usually begin at time of first missed menstrual period (gestational week 4)
Due to progesterone, estrogens, prolactin, placental lactogen secretion in third trimester
Causes intralobular ducts to form buds that become secretory alveoli with grape-like clusters and scant stroma; epithelial cells accumulate cytoplasmic organelles to sustain postpartum lactation; glands have dilated lumina, contain lipid secretory vacuoles with large, apical nuclei resembling Arias Stella reaction; may have clear cell change in ductal or lobular epithelium; these changes may also occur without pregnancy or hormonal manipulation (see pseudolactational hyperplasia)
Prolactin stimulates alveolar epithelium to produce and secrete casein, alpha-lactalbumin and lipids
Lactation: increase in number of lobules and number of acini within each lobule; reduction in interlobular and intralobular stroma; myoepithelial cells are present but difficult to identify; luminal epithelial cells are secretory and have cytoplasmic vacuoles; after lactation ends, lobules involute over several months and are infiltrated by lymphocytes and plasma cells
Crying or suckling causes hypothalamus to produce oxytocin, causing contraction of myoepithelial cells, which expels milk
When nursing stops, prolactin level drops, causing milk production to stop
May cause macromastia - erythematous, edematous, painful breasts with variable ulceration of overlying skin; usually recurs with subsequent pregnancies
Drawings: breast during lactation; breast lobules during lactation
Micro: acinar proliferation with minimal intra- and interlobular connective tissue
Micro images: pregnancy related change; lactational change #1; #2; #3 (8 month pregnant patient); #4-ectatic acinar lumens are lined by vacuolated epithelium and contain secretion, typical of late third trimester; pregnancy related change
Virtual slides: hyperplasia of pregnancy; lactating breast #1; #2
Videos: hyperplasia of pregnancy #1; #2
Pubertal (virginal) macromastia
Occasionally breasts undergo rapid and massive enlargement at puberty, instead of development over several years
If unilateral, usually due to multiple fibroadenomas
Treatment: reduction mammoplasty usually needed
Clinical: diffusely enlarged breasts with flattening of nipples
Micro: abundant connective tissue separating ducts, usually poorly developed or no lobules; may resemble gynecomastia
Micro images: 15 year old girl with massive bilateral enlargement of breasts, dense connective tissue, only minimal lobular development
Congenital anomalies of breast
Amastia / hypoplasia of breast tissue
Uncommon
Unilateral or bilateral
Amastia: no glandular tissue (breast bud), nipple or areola
Hypoplasia: small rudimentary breasts
Both are associated with Poland syndrome (musculoskeletal deformities of chest wall and ipsilateral upper extremity, OMIM 173800), also surgery or radiation that affects breast bud (Acta Oncol 1989;28:519)
Clinical images: amastia in 11 year old girl; hypoplasia (left image)
References: eMedicine
Accessory glandular tissue of breast
See supernumerary nipples / breasts below
Nipple and areola present, but no glandular tissue
Associated with Poland syndrome (musculoskeletal deformities of chest wall and ipsilateral upper extremity, OMIM 173800)
Breast glandular tissue, but no nipple or areola
Very rare
Associated with Poland syndrome (musculoskeletal deformities of chest wall and ipsilateral upper extremity, OMIM 173800)
Case reports: female infant who died shortly after birth (Am J Med Genet A 2007;143:1231), bilateral athelia and congenital jejunal atresia (Clin Dysmorphol 2006;15:37)
Affects males and females
Occurs in 3% of women, 87% are bilateral (Aesthetic Plast Surg 1999;23:144)
Familial in 50%
Usually caused by fibrous bands and hypoplastic ductal system tethering nipple in inverted position
Also associated with large, pendulous breasts
Interferes with nursing, may be confused with cancer
Grade I, II or III (Plast Reconstr Surg 1999;104:389)
Treatment: surgery (Plast Reconstr Surg 2007;119:1178), continuous elastic outside distraction (Ann Plast Surg 2005;54:120)
Clinical images: inverted nipple; grade I; grade II; man with inverted nipples
Supernumerary nipples / breasts
Also called pseudomamma
Persistent epidermal thickenings along milk line from axilla to perineum/vulva due to clusters of primordial breast cells that fail to involute
Ectopic tissue may be combinations of breast glandular tissue and nipple
Often not noticed until pregnancy
Polythelia (3+ nipples) is more common than polymastia (ectopic breast tissue)
Polythelia occurs in 2-6% of females and 1-3% of males; may be more common on left side and in males (Eur J Pediatr 1998;157:821)
Sites (nipples): thorax or abdomen (65%), axilla (20%); back, buttock, face, neck are less common
Sites (glandular tissue): axilla most common
May undergo same disease or physiologic processes as other breast tissue, including lactation (J Reprod Med 1994;39:657)
Associated with renal disease in some studies (7% vs. 0.7% in controls, Int J Dermatol 1996;35:349, but not all, Pediatr Dermatol 2001;18:291); also associated with hematologic disorders (Pediatr Hematol Oncol 2004;21:461), mitral valve prolapse (Am J Cardiol 2000;86:695)
Case reports (disease in supernumerary nipples or breast): carcinoma in vulva (Cancer 1976;38:2570), fibroadenoma (J BUON 2007;12:285), hamartoma (Breast 2006;15:135), metaplastic carcinoma (South Med J 2002;95:462), mucinous adenocarcinoma of vulva (Archives 2002;126:1216), Paget’s disease (Virchows Arch 1998;432:289), secretory carcinoma (Archives 2001;125:1372)
unusual sites - face (J Pediatr Surg 1997;32:1377), foot (Dermatol Online J 2006;12:7), male perineum (Urology 1997;50:122)
occurrence in three generations (Eur J Pediatr 2001;160:375)
Drawing: usual sites
Clinical images: nipple on foot #1; #2; accessory breast tissue of lower abdomen; post-partum axillary mass; accessory nipple and bilateral accessory breasts in axilla
Micro: supernumerary nipple has same features as regular nipple, including hyperpigmentation, slight hyperkeratosis, pilosebaceous structure of Montgomery tubercles, smooth muscle, Toker cells (J Cutan Pathol 2003;30:256), possibly breast lobules and ducts
Micro images: normal breast tissue in axilla of 12 year old girl; normal breast tissue and breast carcinoma in vulva; fibroadenoma in axillary supernumerary breast; mucinous adenocarcinoma in vulva; secretory carcinoma in axilla
References: eMedicine
Procedures involving breast
Devices mark the site of radiographic biopsies for future localization and resection
Either pellets of resorbable polylactic acid/polyglycolic acid copolymers or plugs of bovine collagen; both contain metallic clips for long-term radiographic marking; pellets are placed within biopsy cavity to fix clip in place and reduce clip migration away from biopsy site; collagen plugs may also promote hemostasis
Gross: pellets resemble soft grains of rice; collagen plugs are spongiform with variable hemorrhagic changes
Micro:
pellets - initially hypocellular fibrotic reaction around empty spaces (processing dissolves the polymer), then multinucleated giant cell reaction with eosinophilic material in marker core
collagen plugs - eosinophilic, hyalinized, acellular material with lymphocytic and eosinophilic infiltrate that gradually penetrates into the core; no prominent multinucleated giant cell reaction; may resemble amyloidosis
References: AJSP 2005;29:814, AJR Am J Roentgenol 2003;181:1295
Electrocautery instruments reduce bleeding and risk of hematoma
Thermal distortion may make it difficult to distinguish hyperplasia and DCIS, assess histologic grade or interpret immunostaining
Micro images: parallel linear cracks typify cautery artifact; blurred cell outlines, hyperchromatic nuclei and parallel linear cracks; epithelial distortion (fig 9A, 9B); artifact may make specimen uninterpretable
References: Am J Surg 2001;182:384 (laser treatment), Ann Surg 1986; 204: 612
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
Overall high level of inter-pathologist agreement, but less consensus for ADH, DCIS and lobular neoplasia (AJSP 2004;28:126)
Core biopsy results are comparable to excisional specimens (Int J Cancer 2008;122:468) but tumor grade in invasive carcinoma may differ (AJSP 2003;27:11)
Core biopsy is favored over fine needle aspiration due to ability to evaluate cytologic and architectural characteristics and definitely diagnose invasive carcinoma (Diagn Cytopathol 2007;35:681); imprint cytology may be useful for rapid diagnosis (Cytopathology 2007 Oct 22; [Epub ahead of print])
Not associated with significant bleeding in patients on anticoagulant therapy (AJR Am J Roentgenol 2000;174:245)
First generation: computer-assisted stereotactic mammography or ultrasound used to localize target lesion, then automated spring-loaded biopsy gun, usually with 14-gauge cutting needle
Second-generation: includes Mammotome (Breast Cancer 2007;14:292