Breast-malignant, males, children
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Diagnosis: Juvenile papillomatosis
Table of Contents-Breast-malignant, males, children
In situ carcinoma: DCIS-general, DCIS variants: apocrine, basal-like, clinging, comedocarcinoma, cribriform, cystic hypersecretory, micropapillary, neuroendocrine, papillary, signet ring cell, solid, solid papillary, spindle cell, squamous cell; LCIS, ductal intraepithelial neoplasia; mammary intraepithelial neoplasia, Paget’s disease
Breast cancer: general, risk factors, spread/metastases, WHO classification, histologic grading, EGFR, HER2, hormone receptors, prognostic factors, axillary nodes, sentinel nodes, microinvasive/suspicious, pregnancy-related
Carcinoma subtypes: general, acinic cell, adenoid cystic, adenosquamous, apocrine, basal cell-nipple, basal-like, BRCA1, BRCA2, central necrotizing, colloid/mucinous, cribriform, cystic hypersecretory, ductal NOS, glycogen rich, inflammatory, lipid rich, lobular, luminal, lymphoepithelioma-like, medullary, metaplastic, metastases to breast, micropapillary, mixed, mucinous cystadenocarcinoma, mucoepidermoid, myoepithelial, neuroendocrine, oncocytic, papillary, sebaceous, secretory, small cell, squamous cell, tall-cell like, tubular, tubulolobular
Sarcoma: general, angiosarcoma, leiomyosarcoma, liposarcoma, MFH, MPNST, myofibrosarcoma, osteosarcoma, rhabdomyosarcoma, sarcoma NOS, stromal sarcoma
Other malignancies: lymphoma, myeloid sarcoma, plasmacytoma, Rosai-Dorfman
Childhood tumors: general, juvenile fibroadenoma, juvenile papillomatosis, carcinoma
Male tumors: general, gynecomastia, papilloma, myofibroblastoma, carcinoma, metastases
Miscellaneous: treatment effect - chemotherapy, cryoprobe, hormone therapy, radiation therapy, frozen sections, grossing, features to report, staging
Go to Breast-nonmalignant chapter
AJCC Cancer Staging Manual (6th Ed)
American Journal of Clinical Pathology (AJCP) [random articles free full text-no registration], January 2000 to June 2008
American Journal of Surgical Pathology (AJSP), March 1977 to June 2008
Archives of Pathology and Laboratory Medicine (Archives) [always free full text and no registration], January 1976 to June 2008
Biomed Central [always free full text and no registration], January 2000 to 2 June 2008
BMC Clinical Pathology [always free full text and no registration], December 2003 to 30 May 2008
Cytojournal [always free full text and no registration], July 2004 to 25 April 2008
Human Pathology (Hum Path), March 1970 to May 2008
Modern Pathology (Mod Path) [free full text and no registration after 1 year], January 1988 to June 2008
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
Tavassoli: Tumours of the Breast and Female Genital Organs (WHO, 2003), not pages 13-59, 94-98, 105-112, 335-351
Websites (images): Digital Atlas of Breast Pathology, Geneva Foundation for Medical Education and Research (did A), Johns Hopkins Breast Center, National Institutes of Health, Online Management of Breast Diseases, PathoPic, (did 1-1)
Virtual slides - ASCP, USCAP, vSlides
Journal search terms: each disease entity listed - last searched June08
Please refer to these primary references for more detailed discussions and photographs
In situ carcinoma
DCIS - general - Breast malignant chapter
Definition: neoplastic intraductal lesion with increased epithelial proliferation, variable cellular atypia and variable tendency to progress to invasive carcinoma; by definition, tumor is confined to glandular component of breast and has not invaded through basement membrane or into stroma, although tumor may spread along ducts
Also called intraductal carcinoma
Tumor cells cannot spread through lymphatics or blood vessels, as they are not present in the epithelial layer
Often multifocal when use large histologic sections, particularly low grade DCIS (Hum Path 2007;38:1736)
4x more common than LCIS
Mean age 50-59 years
Relative risk of 8-10x for invasive carcinoma compared to general population
Evolution to invasive disease may take decades (particularly for low grade lesions, Cancer 2005;103:2481), or be very short
Associated with invasive disease at or near tumor site, but 22% develop in situ or invasive carcinoma in contralateral breast
Increased incidence (now 15-30% of all carcinoma) is due to mass screening (Breast Cancer Res Treat 2008 May 31 [Epub ahead of print]), but deaths due to DCIS are decreasing
Must carefully examine specimens to exclude small foci of invasive carcinoma
Risk factors for recurrence: ipsilateral - comedonecrosis, micropapillary histology, multifocality; contralateral - micropapillary histology, gross size of 1 cm or more (AJCP 2007;128:86)
Xray: MRI may be a useful adjunct to mammography and ultrasound (Hong Kong Med J 2008;14:229)
Xray images: clusters of microcalcifications #1; #2
Case reports: with osteoclast-like giant cells (Hum Path 2006;37:369)
Treatment: surgery; radiation therapy for comedo type lesions, positive or close margins and probably for extensive intraductal component, but perhaps not for small (<1 cm) or low grade lesions; some recommend radiation in all cases (Pathol Oncol Res 2008 Apr 26 [Epub ahead of print]); radiation may eradicate precursor lesions in addition to residual disease (AJSP 2003;27:828, AJCP 2007;128:1023); possibly sentinel lymph node dissection if patients are planned for mastectomy (Ann Surg Oncol 2008;15:268) or size >5 cm (Am J Surg 2008 Apr 22 [Epub ahead of print]), or at high risk of microinvasive carcinoma (Breast J 2008;14:135); possibly tamoxifen if ER+ (Semin Oncol 2006;33:647);
Gross: usually no gross lesion, but high grade DCIS may present as firm gritty mass with multiple areas of round, pale comedonecrosis; may be sharp demarcation between comedo DCIS and adjacent fibrous stroma
DCIS - general - Breast malignant chapter
Micro: subtypes are discussed separately below, grading is based on cytologic features of neoplastic cells; interobserver agreement is poor if no standardized criteria are used; presence of nuclear debris, ghosts of dead cell outlines, granular and fragmented products or densely staining inspissated material is suggestive of DCIS
Low grade: monotonous round cell population with subtle increase in N/C ratio, small (1.5-2.0x normal size) monotonous round nuclei with smooth contours, diffuse fine chromatin, no/indistinct nucleoli; cells resembles LCIS; usually no/rare comedo-type necrosis, no/rare mitotic figures; usually cribriform, micropapillary, papillary or solid subtypes
High grade: nuclei are large (2.5x normal size), markedly pleomorphic and angular with irregular contours, coarse chromatin, prominent nucleoli; frequent mitoses; comedo-type necrosis (central zone of necrosis within a duct) nearly always present and often extensive; often amorphous microcalcifications
Intermediate grade: between high grade and low grade; either (a) cells resemble low grade, but some ducts contain intraluminal necrosis, or (b) nuclei have coarse chromatin and occasional nucleoli and variable necrosis
Put lesions with grading heterogeneity into higher category if 30% or more ducts are involved by higher grade cells; some suggest reporting percentage of various grades
Rarely perineural invasion, which is usually associated with sclerosing adenosis or radial scar (Hum Path 2001;32:785)
Lobular cancerization: DCIS tumor cells are within a lobule with preservation of normal lobular pattern; probably represents a variation in growth pattern of DCIS, not secondary extension of DCIS into a lobule
Specific grading systems (AJSP 2000;24:651), are independent of morphologic type:
Van Nuys: 1, 2 or 3: based on nuclear grade (low, intermediate, high grade) and necrosis (not applicable, absent, present) (Lancet 1995;345:1154), table; may guide treatment (Cancer 1996;77:2267), but validity has been questioned (Cancer 2007;110:2648, Br J Surg 2003;90:426)
Modified Lagios: low, intermediate, high grade: based on nuclear grade and necrosis (absent, focal, extensive) (Hum Path 1997;28:967)
Holland: well, intermediate or poorly differentiated; based on nuclear grade and cell polarization (absent, present/not prominent, prominent) (Semin Diagn Pathol 1994;11:167)
DCIS - general - Breast malignant chapter
Micro images: grades 1-3 (Van Nuys scoring), p53 staining; low, intermediate and high grade; DCIS grade 1
cancerization of lobules - image; extension of DCIS into intralobular ducts (source: AFIP) #1; #2 (note marked pleomorphism more typical of DCIS than LCIS)
other - perineural invasion; tumor in dermal lymphatics, attributed to benign mechanical transport; CD10 and smooth muscle actin; no invasion identified based on myoepithelial markers present; ER and HER2 staining #1; #2
Not DCIS: infiltrative carcinoma with central necrosis #1; #2; #3-axillary nodal metastasis; #4-negative staining for myoepithelial markers
Cytology images: DCIS #1; #2; #3; #4; #5; #6
Virtual slides: DCIS; DCIS and LCIS
Positive stains: E-cadherin (AJSP 2001;25:229); 12% of ER+ cases are also HER2+ (Mod Path 2005;18:615), HER2+ in high grade but not low grade cases; p53 more common in high grade cases
Negative stains: high molecular weight cytokeratin / 34betaE12 (Hum Path 2002;33:620, AJSP 1999;23:1048)
Molecular: low grade DCIS and high grade DCIS appear to be genetically distinct disorders; high grade DCIS has increase in chromosome gains by FISH compared to low grade (Hum Path 2000;31:201); multicentric low grade tumors likely represent different clones than multicentric high grade tumors (Hum Path 2003;34:1163); DCIS shares genomic alterations with invasive ductal carcinoma (Clin Cancer Res 2008;14:1956)
DD: lobular neoplasia (resembles low grade DCIS but is 34betaE12+, E cadherin negative), atypical ductal hyperplasia, microinvasion, infiltrative ductal carcinoma with comedonecrosis (J Med Case Reports 2007;1:83)
References: Mod Path 2002;15:95
Morphologic variants of DCIS
Apocrine DCIS - Breast malignant chapter
Rare variant; save behavior as classic DCIS
Micro:
Tumor grade is based on nuclear grade and presence of comedo-type necrosis (Hum Path 2001;32:487)
Nuclear
grade is 1-3 based on nuclear size, pleomorphism and nucleoli compared to
nuclei of benign apocrine cells
Nuclear size (compared to benign apocrine cells) is either small (1-2x),
intermediate (3-4x) or large (5x or larger)
Grade 1 nuclei: low pleomorphism, small/intermediate size, usually single prominent nucleolus
Grade 2 nuclei: moderate pleomorphism, small/intermediate size, multiple nucleoli; might have occasional large nuclei or multinucleated cells
Grade
3 nuclei: intermediate/large size,
marked pleomorphism, coarse chromatin, irregular nuclear contour, frequently
multiple nucleoli
Necrosis: focal or extensive comedo-type necrosis, must be centrally
localized in at least 1 duct or acinus; isolated necrotic or apoptotic cells
are ignored
Low-grade: nuclear grade 1 or 2 without necrosis
High-grade: tumors with grade 3 nuclei and necrosis; similar to high
grade nonapocrine DCIS, but with cytoplasmic apocrine features and 10%+ nuclei
with single large nucleolus and vesicular chromatin
Intermediate-grade: cases not classified as low or high histologic grade
Micro images: AFIP - cells have abundant cytoplasm, vesicular nuclei and prominent nucleoli #1; #2; #3; micropapillary pattern; cribriform pattern
other sources - comedonecrosis; in adenosis; image #1; #2; #3; #4; #5; secretory features #1; #2; #3; #4; #5; #6; androgen receptor staining; apocrine adenosis with atypia (not DCIS)
Virtual slides: high grade apocrine DCIS
Positive stains: androgen receptor, ER-beta (Histopathology 2007;50:425), p53 (62%), HER2 (47%), Ki-67 (5% of cells) (Mod Path 2000;13:13); also B72.3 (APMIS 2006;114:712)
Negative stains: ER-alpha, PR, bcl2
References: Hum Path 1994;25:164, Mod Path 1994;7:813, Stanford University
Basal like DCIS - Breast malignant chapter
8% of DCIS
Classified based on immunohistochemistry or gene expression profiling (Breast Cancer Res 2006;8:R61), not morphology
Of academic interest only, not currently used clinically
Associated with high grade nuclei, p53 overexpression, increased Ki-67 index (Hum Path 2007;38:197), but only a small percentage of high grade DCIS (Mod Path 2006;19:617)
Commonly found with invasive basal-like carcinomas (Mod Path 2006;19:1506)
Micro: solid, flat or micropapillary; high nuclear grade, comedonecrosis, intense lymphocytic infiltrate
Micro images: H&E and stains #1; #2; H&E and variable CK5/6 staining
Positive stains: CK 5/6, CK14 or CK17; usually EGFR or c-kit/CD117; vimentin; also alphaB-crystallin (Ann Diagn Pathol 2008;12:33) and P-cadherin (Virchows Arch 2007;450:73)
Negative stains: usually defined as ER-, PR- and HER2-
Clinging DCIS - Breast malignant chapter
Terminology no longer widely used, now usually described as flat epithelial atypia (mild atypia, not considered DCIS, Breast Cancer Res 2003;5:263), atypical columnar alteration or comedo-DCIS (marked atypia and central necrosis)
Micro: 1-2 layers of malignant cells lining a gland with a large empty lumen; tumor cells often are highly atypical and associated with apoptosis; lumina may contain granular intraluminal material with ghosts of tumor cells, resembling comedocarcinoma
Micro images: clinging/flat DCIS #1; #2
Molecular: loss of heterozygosity identified in 77% (Cancer 2000;88:2072)
Comedo DCIS / comedocarcinoma - Breast malignant chapter
50% are central, 1/3 appear multicentric (but many are actually continuous in 3 dimension), 10% bilateral
40% progress to invasive disease
Some patients have axillary nodal metastases even without evidence of invasive carcinoma
Should look carefully for invasive carcinoma and report estimated % of DCIS and invasive carcinoma (extensive intraductal component if DCIS is 25% or more of area of infiltrating tumor)
Necrosis is due to apoptosis and oncosis (passive cell death, Ultrastruct Pathol 2000;24:135)
Xray: mammography usually shows linear and branching microcalcifications due to calcification of necrotic material, more often central than other tumors; occasionally lacks calcifications
Gross: cheesy appearance (resembling comedones) due to plugging of thick walled ducts with necrotic material
Micro: solid growth of large, pleomorphic, high grade cells with central necrosis (either central focus or individual cells) and frequent mitotic figures; usually minimal stroma within the duct and minimal/no myoepithelial cells; coarse microcalcifications common; periductal fibrosis and inflammation common; often cancerization of lobules; may have pseudocribriform architecture (but with high grade cells)
Micro images: AFIP - central necrosis with dystrophic calcifications
other - #1; #2; #3; central necrosis #1; #2; large pleomorphic tumor cells with prominent nucleoli and mitotic activity #1; #2; with periductal fibrosis; involving lobules; cancerization of lobules; HER2+ (#1); #2; androgen receptor+
Cytology images: low power; high power; atypical cells with large nuclei #1; #2; #3
Virtual slides: DCIS and LCIS #1; #2-calponin
Positive stains: HER2 amplification (Cancer 2000;89:2153), p53, P-cadherin
Negative stains: ER, PR (Br J Surg 2005;92:429)
Molecular: aneuploid; multicentric tumors were monoclonal in one study (Hum Path 2003;34:1163)
Molecular images: tetraploid DNA; aneuploid DNA
DD: invasive ductal carcinoma with central necrosis (J Med Case Reports 2007;1:83), intraductal papilloma with comedo-like necrosis (Ann Diagn Pathol 2004;8:276)
References: Archives 1996;120:81
Cribriform DCIS - Breast malignant chapter
Micro: glands have round, regular spaces with sharp borders that appear to be made from “cookie-cutters” (image); cells are usually small and uniform; nuclei are equidistant from each other; usually low grade; usually no central necrosis; associated with flat epithelial atypia (Mod Path 2007;20:1149)
Trabecular bars: rigid rows of cells with long axes perpendicular or at least not parallel to long axis of the bar (not just partial detachments of duct lining)
Roman bridges: curvilinear trabecular bars connecting two portions of the epithelial lining (image-Roman Bridge)
Cytology: three dimensional structures, occasionally with tumor cells bordering central lumina; few single tumor cells; clear or slightly hemorrhagic background without necrosis; tumor cells are uniform and oval, with round/oval nuclei, finely granular chromatin, indistinct nucleoli, slight nuclear membrane condensation (Acta Cytol 1992;36:48)
Micro images: AFIP - cribriform growth due to merging of intraductal epithelial bridges; uniform cells either haphazard or at right angles to long axis of intraductal columns #1; #2; prominent Roman bridge
other - glandular spaces and monotonous epithelial cells #1; #2; #3; #4; #5; #6; #7; #8; #9; #10; #11; prominent roman bridges #1; #2; classic area (fig c) and areas resembling low grade clinging carcinoma (fig a) and ADH (fig b); low grade cytology but with comedonecrosis #1; #2; with microcalcifications; post-chemotherapy; Factor VIII staining shows only rare vascular proliferation (fig 2a); low MIB1 staining (fig 2b)
Virtual slides: cribriform and solid DCIS #1; #2
Cytology images: complex tissue fragment superficially resembles branching papillae, but has intercepting arches and lacks fibrovascular cores
DD: adenoid cystic carcinoma
Cystic hypersecretory DCIS - Breast malignant chapter
First described in 1984 by Rosen and Scott (AJSP 1984;8:31)
Rare (<100 cases described); usually large palpable mass with pain
Mean age 55 years, range 32-79 years
20% are associated with an invasive component, usually poorly differentiated ductal carcinoma with solid growth pattern and no secretory features
Xray: single, irregular, spiculated mass with occasional calcifications
Case reports: Case of the week #35, 40 year old woman with cystic, ill-defined breast mass and invasive carcinoma (Archives 2005;129:e79)
Treatment: excision with careful search for invasive component; may recur as in situ or invasive disease (Ceska Gynekol 2005;70:73, Cancer 1988;61:1611)
Gross: numerous cysts with sticky, mucoid or gelatinous secretions
Micro: dilated ducts and cysts mixed with micropapillary carcinoma in epithelium lining cystic spaces; cysts contain eosinophilic secretions resembling colloid; secretions may retract from epithelium, causing smooth or scalloped margin; associated with cystic hypersecretory hyperplasia with or without atypia; DCIS is usually low grade
Cytology: distinct granular, colloid-like material in background; often reported as negative or suggestive of malignancy
Micro images: AFIP - micropapillary intraductal carcinoma and sparse secretion retracted from epithelium; micropapillary type pattern with prominent secretion; hobnail type cells
case of week - variably sized cysts; cysts lined by flattened epithelium; intraluminal secretions show cracks and shrinkage of cyst content with peripheral scalloping; cysts lined by micropapillary projections with atypical cells containing plemorphic nuclei;
other - cysts contain colloid type material, and epithelium has changes of DCIS #1; #2; #3; fig 1: color Doppler is suggestive of cancer; fig 2: FNA shows sparsely cellular smears with groups of cells in 3 dimensional clusters, papillary formation and granular background (inset: hyperchromatic cell with increased N/C ratio); fig 3: core biopsy shows dilated ducts with papillary proliferation; fig 4: excision shows dilated ducts with micropapillary architecture and eosinophilic colloid-like material
Virtual slides: biopsy
Cystic hypersecretory DCIS - Breast malignant chapter (continued)
Positive stains: epithelial cells - EMA, androgen receptor (Histopathology 2005;46:43), variable ER and PR; myoepithelial cells - S100, smooth muscle actin, p63, CD10; secretions - EMA, PAS, Alcian blue (focal)
Negative stains: secretions - thyroglobulin
DD: fibrocystic disease with microcyst formation (apocrine metaplasia, benign epithelial lining, no micropapillary formation or colloid-like secretions within cysts), juvenile papillomatosis (teenagers with "Swiss cheese" pattern of ductal papillomatosis, papillary hyperplasia, sclerosing adenosis, variable atypia), cystic hypersecretory hyperplasia (no atypia), secretory/juvenile carcinoma (invasive), mucocele-like lesions, mucinous cystadenocarcinoma, metastatic thyroid carcinoma (history, thyroglobulin+)
Micropapillary DCIS - Breast malignant chapter
Often involves multiple quadrants of breast
Micro: elongated epithelial papillary formations projecting into glandular lumen, usually without fibrovascular cores, may have bulbous expansion at tip resembling a club; composed of small, uniform cells without necrosis; usually low grade; associated with flat epithelial atypia (Mod Path 2007;20:1149)
Micro images: AFIP - discontinuous fragments related to plane of sectioning; micropapillae lack fibrovascular cores, cells are homogeneous
other - other images #1; #2; #3; #4; #5; #6; #7; #8; #9; within a papilloma #1; #2; #3; #4; #5; with apocrine features #1; #2; #3; with cribriform DCIS; with hypersecretory features; with columnar cell change #1; #2
Cytology images: micropapillary DCIS
Virtual slides: micropapillary DCIS
Neuroendocrine DCIS - Breast malignant chapter
Rare, also called endocrine DCIS, intraductal or solid papillary carcinoma (AJSP 1995;19:1237)
First described in 1985 (Histopathology 1985;9:21)
Mean age 70 years, usually > age 60 years (Zhonghua Bing Li Xue Za Zhi 2006;35:594)
May have associated invasive component, also with neuroendocrine features (AJSP 1996;20:921)
Presents as breast mass, occasionally nipple discharge (AJSP 1996;20:921)
May recur
67% of solid intraductal papillary carcinomas have positive neuroendocrine markers (Virchows Arch 2007;450:539); almost all DCIS with spindle cells have neuroendocrine differentiation (Histopathology 2004;45:343)
Neuroendocrine DCIS is associated with intraductal papilloma and pagetoid involvement by tumor cells
Case reports: Case of the Week #45, 68 year old woman with 1.5 cm breast nodule (Am Surg 2000;66:1163)
Micro: solid lobular growth, neuroendocrine-like festoons and rosettes and prominent fibrovascular septa; cells are polygonal, oval or spindled with abundant granular eosinophilic cytoplasm and bland ovoid nuclei; accumulation of basophilic intracellular mucin; often pagetoid spread; variable stromal sclerosis or signet ring cells; usually no necrosis
Cytology: plasmacytoid tumor cells and arborizing papillary fronds (Cancer 2000;90:286)
Micro images: AFIP - small cells with dense, deeply stained amphophilic cytoplasm and uniform round nuclei; focal Grimelius+ cells
case of week - image #1; #2; #3; #4; #5; #6; #7; #8; synaptophysin #1; #2
other - solid proliferation #1; #2; cribriform pattern; tumor cells in cords and festoons with well defined fibrovascular septa and vascular cores
Cytology images: highly cellular with cell clusters with papillary architecture; multiple single detached cells with plasmacytoid appearance due to eccentric nuclei and granular cytoplasm; single plasmacytoid tumor cells with cytoplasmic granularity; papillary fronds in moderately cellular background
Virtual slides: two cases
Positive stains: chromogranin, synaptophysin, neuron-specific enolase, ER, PR (Histopathology 2004;45:343); low Ki-67
Negative stains: p53, HER2
EM: dense core neurosecretory granules, larger mucigen granules
DD: florid epithelial hyperplasia and papilloma (lack the monomorphic cell population associated with DCIS, negative for neuroendocrine markers)
Papillary DCIS - Breast malignant chapter
Definition: proliferation of fibrovascular stalks, 90% without a myoepithelial cell layer present, within a distended duct or its branches
Note: literature often does NOT differentiate between in situ and invasive disease
90% of lesion must be low grade DCIS
Also called noninvasive papillary carcinoma
<2% of DCIS, mean age 65 years