Breast-malignant, males, children - Printer Friendly Version

Breast-malignant, males, children

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Last revised 30 April 2009

Last major update August 2008

Reviewed by Daniel Visscher, M.D. in February 2009 (see Reviewers page)

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Diagnosis: Juvenile papillomatosis

Table of Contents-Breast-malignant, males, children

Primary references

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, mucin-producing, mucinous cystadenocarcinoma, mucoepidermoid, myoepithelial, neuroendocrine, oncocytic, papillary, sebaceous, secretory, signet ring cell, 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

Primary references

AJCC Cancer Staging Manual (6th Ed)

American Journal of Clinical Pathology (AJCP) [random articles are 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)

Websites (images): Digital Atlas of Breast Pathology, Geneva Foundation for Medical Education and Research, Johns Hopkins Breast Center, National Institutes of Health, Online Management of Breast Diseases, PathoPic

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 (intraductal carcinoma) - general - Breast malignant chapter

Definition: neoplastic proliferation having malignant features and ductal phenotype confined to epithelial compartment (i.e. within spaces bordered by myoepithelium and basal lamina); may involve ducts and/or lobules; variable (nuclear grade based) tendency to progress to invasive carcinoma

Accounts for 15-30% of all breast carcinoma

Mean age 50-59 years

Most clinically occult/mammogram detected, but some present with nipple discharge or palpable lesion

Rare lesions have nodal metastases for unclear reasons

Often multifocal, particularly low grade DCIS (Hum Path 2007;38:1736); 10-20% develop contralateral in suit or invasive carcinoma (synchronous or metachronous)

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

Increased incidence in 1990s due to mass screening (Breast Cancer Res Treat 2008 May 31 [Epub ahead of print])

May arise in adenosis, radial scar, fibroadenoma or papilloma; rarely perineural invasion occurs (Hum Path 2001;32:785)

Gross: usually no gross lesion, but high grade DCIS may present as firm gritty mass with multiple areas of round, pale comedonecrosis; must carefully examine specimens to exclude small foci of invasive carcinoma

Xray: MRI may be a useful adjunct to mammography and ultrasound (Hong Kong Med J 2008;14:229)

Case reports: with osteoclast-like giant cells (Hum Path 2006;37:369)

Treatment: surgery and radiation therapy (if lumpectomy), some studies have deferred radiation for small (<1 cm) or low grade lesions (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); 30-50% of disease recurrences represent invasive disease (at or near tumor site)

Risk factors for recurrence: ipsilateral - comedonecrosis, micropapillary histology, multifocality; contralateral - micropapillary histology, gross size of 1 cm or more (AJCP 2007;128:86)

Grading: based on cytologic features of neoplastic cells; interobserver agreement is poor if no standardized criteria are used

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

Grade heterogeneity is common; place cases into higher category if 30% or more ducts are involved by higher grade cells

Lobular cancerization: variation in growth pattern of DCIS in which cells fill a lobule with preservation of normal acinar pattern

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)

Positive stains: E-cadherin (AJSP 2001;25:229); ER+ in low grade cases/variable in high grade (Mod Path 2005;18:615), HER2 often + in high grade DCIS but there is no clinical indication for HER2 testing in DCIS

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 (may resemble low grade DCIS but is 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

Definition: DCIS with cells containing abundant eosinophilic cytoplasm, vesicular nuclei and prominent nucleoli

Uncommon variant; clinical behavior similar to classic DCIS

Micro:

Tumor grade is based on nuclear features and presence of comedo-type necrosis (Hum Path 2001;32:487)

Low grade lesions have micropapillary architecture

Due to partial overlap with apocrine atypia, lesion size/extent are important in differential diagnosis

Nuclear grade (compared to benign apocrine cells) is 1-3 based on nuclear size, pleomorphism and nucleoli
Nuclear size (compared to benign apocrine cells) is 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; may 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

Positive stains: androgen receptor, ER-beta (73%, Histopathology 2007;50:425), p53 (62%), HER2 (47%), Ki-67 (5% of cells) (Mod Path 2000;13:13); also B72.3 (92%, 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

Definition: classified based on immunohistochemistry or gene expression profiling (Breast Cancer Res 2006;8:R61), not morphology

8% of DCIS

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 have basal-like phenotype (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

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

Molecular: loss of heterozygosity identified in 77% (Cancer 2000;88:2072)

Comedo DCIS / comedocarcinoma - Breast malignant chapter

Definition: high nuclear grade lesion with wide spread comedo necrosis (central necrosis within involved ducts); necrosis is due to apoptosis and oncosis (passive cell death) (Ultrastruct Pathol 2000;24:135)

1/3 appear multicentric (but many are actually continuous in 3 dimensions, as demonstrated by serial section mapping studies), 10% bilateral

1-3% patients have axillary nodal metastases even without evidence of invasive carcinoma

Lesions may be extensive (>5 cm); should look carefully for invasive carcinoma

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)

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)

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: multiple secondary lumens having round, regular spaces with sharp borders that appear to be made from “cookie-cutters”, usually low grade (image); nuclei are small and uniform, equidistant from each other; usually no 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)

DD: atypical ductal hyperplasia; 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

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

Involves multiple quadrants of breast (multicentricity) in 25%

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)

Neuroendocrine DCIS - Breast malignant chapter

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, either mucinous (colloid) or with neuroendocrine features (AJSP 1996;20:921)

Presents as breast mass, occasionally nipple discharge (AJSP 1996;20:921)

67% of solid intraductal papillary carcinomas exhibit 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)

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

Also called noninvasive papillary carcinoma

Definition: proliferation of tumor cells in association with fibrovascular stalks; unlike papilloma, a myoepithelial cell layer is not present

90% of lesions low grade/outcome thus favorable

Mean age older than DCIS overall (65 years)

Thought to arise from large ducts; patients often have multiple papillomas

Involves multiple ducts, unlike intracystic papillary carcinoma (see below) but there is partial overlap between these lesions

Gross: well circumscribed mass within a distended duct or may extend throughout ducts to involve a large area; mean 2 cm

Micro: delicate fibrovascular or avascular connective tissue cores covered by monotomous epithelial cells; often cribriform DCIS present; detached “secondary papilla” are common

Features favoring papillary DCIS vs. papilloma are uniformity in size and shape of epithelial cells, columnar cells are arranged perpendicular to duct axis, no/scattered myoepithelial cells (J Clin Pathol 2007;60:315), nuclear hyperchromasia, high nuclear/cytoplasmic ratio, loss of nuclear polarity, cell layering, frequent mitotic activity with atypical mitotic figures; may resemble urothelial carcinoma (Mod Path 1999;12:287), minimal stroma, no apocrine metaplasia, no cribriform or trabecular patterns, usually no benign proliferative disease in adjacent breast

Note: scattered, large pale eosinophilic cells (clear / globoid bodies) may be mistaken for myoepithelial cells, but are GCDFP15 positive and actin negative

Cytology: compared to intraductal papilloma, is more cellular with more complex papillae containing thin disorganized fronds, mild to moderate nuclear atypia, and prominent dissociation with many single papillae (Cancer 2002;96:92)

Negative stains: myoepithelial markers, including smooth muscle actin, smooth muscle myosin heavy chain, calponin, p63, CD10 or CK 5/6 (may be variable staining for myoepithelial cells-Histopathology 2007;51:657, AJCP 2005;123:36)

DD: papilloma, invasive papillary carcinoma (neoplastic epithelial structures infiltrate breast beyond the fibrous wall and have a recognized pattern of invasive carcinoma)

Intracystic (encysted) papillary carcinoma

Also called encapsulated papillary carcinoma

Note: considered non or minimally invasive, despite frequent lack of myoepithelial layer, due to lack of infiltrating growth pattern and rate metastases

Rare, usually seen in elderly women

May be associated with conventional DCIS or invasive carcinoma

Favorable prognosis (AJSP 2006;30:1002), but see Hum Path 1998;29:1097 (prognosis is related to that of coexisting DCIS or invasive carcinoma)

Positive predictive value of stromal invasion is 92% if either high nuclear grade, frequent mitotic activity, or positive immunostains for cyclin D1 or p53 (Breast J 2005;11:2)

Gross: mural nodule within a large cystic space; may be encapsulated

Signet ring cell DCIS - Breast malignant chapter

Not a distinct subtype of DCIS

Signet ring cells are seen in neuroendocrine DCIS, LCIS and secretory carcinoma

Solid DCIS - Breast malignant chapter

Micro: glandular lumen filled by small to medium, uniform cells without necrosis; may produce a microacinar or rosette-like pattern; cells are larger than LCIS but smaller and more uniform than comedocarcinoma; often pale cytoplasm with sharply outlined cell borders; may contain secretions but no necrosis; usually but not always low grade (Anal Quant Cytol Histol 2001;23:418)

DD: lobular carcinoma in situ (Semin Diagn Pathol 2004;21:25)

Solid papillary DCIS - Breast malignant chapter

Also called neuroendocrine DCIS

Uncommon

Age 60+ years

Associated with invasive colloid/mucinous or neuroendocrine carcinomas (AJSP 1995;19:1237, Pathol Int 2007;57:421)

Indolent behavior if no invasion; with invasion, patients often die of disease (AJSP 2006;30:501)

Case reports: solid and cystic papillary carcinoma (Ann Diagn Pathol 2004;8:126)

Micro: circumscribed, large cellular nodules separated by bands of dense fibrosis; resembles usual duct hyperplasia involving a papilloma; papillary architecture with solid growth, cellular streaming and low grade nuclear features; cytoplasm is often eosinophilic and granular; may have pseudorosettes with palisading around small vascular spaces; often mitotic figures; may have intracytoplasmic mucin with signet ring cells

Positive stains: chromogranin or synaptophysin in 50%, ER, p63 or smooth muscle actin at epithelial-stromal interface in 27% (Histopathology 2007;51:657)

Negative stains: CK 5/6 (entrapped benign and myoepithelial cells may be positive, Hum Path 2006;37:787) and 34betaE12 (Virchows Arch 2007;450:539)

DD: ductal hyperplasia involving a papilloma (strong CK 5/6+), LCIS (no fibrovascular septa), solid variant of adenoid cystic carcinoma (biphasic with small inconspicuous intercalated ducts mixed with myoepithelium and small collagenous spherules), metastatic carcinoid (ER negative)

Spindle cell ductal carcinoma in situ - Breast malignant chapter

Very rare (0.1% of breast carcinomas)

May be a variant of neuroendocrine DCIS (Zhonghua Bing Li Xue Za Zhi 2006;35:13)

Mean age 59 years

Invasive tumors are considered a subset of metaplastic carcinoma

Symptoms: nipple discharge, breast lump or mammographic abnormality

Gross: 3 to 41 mm

Micro: 10-80% of DCIS cells are spindled; fascicular, streaming or papillary patterns; usually low nuclear grade, variable necrosis and microinvasion (Histopathology 2004;45:343)

Cytology: predominantly clusters and a small population of single cells in a necrotic background; cells are mostly spindled, with minor population of epithelioid cells; cells have high N/C ratio with hyperchromatic and pleomorphic nuclei, prominent nucleoli; resembles metaplastic carcinoma (Acta Cytol 2005;49:323)

Positive stains: usually synaptophysin or chromogranin, ER and PR

Negative stains: HER2, HMW keratin, smooth muscle actin

DD: florid hyperplasia (HMW keratin+), metaplastic spindle cell tumors associated with fibrosclerotic lesions (keratin+, Mod Path 2003;16:893)

References: Virchows Arch 2001;439:70

Squamous cell carcinoma in situ - Breast malignant chapter

May be extensive

Micro: obvious squamous features

References: AJSP 2007;31:1414

Bowen’s disease (intraepidermal squamous cell carcinoma) of nipple

Case reports: Hum Path 1994;25:1371

Treatment: wide local excision, possibly phototherapy (Breast 2005;14:65)

Positive stains: high molecular weight keratin

Negative stains: mucin, melanin

Lobular carcinoma in situ (LCIS) - Breast malignant chapter

Definition: lobulocentric proliferation of small, monotonous, loosely cohesive cells; must fill/distend lobular unit (in contrast to ALH)

“Lobular neoplasia” is a term which donotes histologic overlap/frequent co-existance of ALH and LCIS (Cancer 1978;42:737)

Diagnosed as an incidental microscopic finding since no distinguishing features on gross examination and usually not associated with microcalcifications

Estimated incidence of 2.8 per 100K; present in 0.5 to 8% of benign breast biopsies

Mean age 53 years

30-70% are bilateral (vs. 20% for invasive lobular carcinoma and 10% for DCIS); 75% are multicentric; 5% have coexisting invasive carcinoma (i.e. contralateral or other quadrant)

20-30% risk of subsequent breast cancer, which may occur in either breast (relative risk versus population of 8-10x), often develops after long f/u (>10 year) (J Clin Oncol 2005;23:5534), risk is slightly greater in ipsilateral breast; invasive disease may be ductal or lobular but 5x risk of invasive lobular carcinoma for LCIS versus DCIS (Cancer 2006;106:2104)

LCIS is considered to be a precursor of some invasive lobular carcinoma (Verh Dtsch Ges Pathol 2007;91:208, Breast Cancer Res Treat 2008;107:331)

May be present in fibroadenomas, sclerosing adenosis (AJSP 1981;5:233); not in nipple and only rarely in large lactiferous ducts

Minimal risk of dying from breast cancer since most subsequent tumors are treatable/low stage

“Pleomorphic LCIS”: large cells, ductal pattern with necrosis; these are commonly associated with invasive carcinoma, usually lobular (AJSP 2006;30:1445)

Case reports: occurring within a fibroadenoma (Postgrad Med J 1999;75:293)

Treatment: watchful waiting (Cancer 2004;100:238), possibly with tamoxifen; alternative is ipsilateral or bilateral mastectomy (if strong family history of carcinoma); presence of LCIS at margin is not a risk factor for recurrence of DCIS or invasive carcinoma (Ann Surg Oncol 2008;15:2263, Cancer 2006;106:28) but see Int J Radiat Oncol Biol Phys 2006;66:365)

If LCIS in core biopsy, recommend excision due to subsequent invasive ductal or lobular carcinoma in 10-31% (Archives 2008;132:979, AJSP 2005;29:534 but see AJCP 2006;126:310-low risk of DCIS or invasive disease at excision); higher risk if neoplastic epithelial microcalcifications present (AJSP 2007;31:717) or if associated with a mass lesion (Mod Path 2003;16:120); note-residual LCIS is usually present at excision

Micro: affects terminal duct lobular unit (TDLU) with expansion/effacement of acini; proliferation of monomorphic evenly spaced cells that are loosely cohesive and slightly larger than normal with uniform nuclei, evenly distributed chromatin, small/no nucleoli

Classic type lacks pleomorphism/necrosis; resembles “marbles in a bag”; intracytoplasmic lumina (not specific for LCIS); signet ring cells with mucin are common

“Pagetoid growth” refers to continous row beneath adjacent terminal duct epithelium, causing cloverleaf or necklace patterns; myoepithelial cells may be replaced or unchanged; minimal mitotic figures

May involve/arise in sclerosing adenosis, radial scar, fibroadenoma, collagenous spherulosis, papillary lesions

Type A pattern: small, round, bland cells; diploid

Type B pattern: larger cells with more cytoplasm, less uniform nuclei and distinct nucleoli

By definition, E-cadherin negative (DCIS is positive)

Page criteria for LCIS: cells must fill ALL acini, expand or distort 50%+ acini in lobule, otherwise call atypical lobular hyperplasia

Cytology: commonly either benign appearing / nondiagnostic or cell groups diagnostic or consistent with LCIS due to loosely cohesive cell groups of uniform cells with occasional intracytoplasmic lumina, slightly irregular and eccentric nuclei; may have hypercellular, dissociated, pleomorphic tumor cells (Diagn Cytopathol 2002;27:22)

Thin-Prep - tight or loosely cohesive clusters of crowded mildly enlarged nuclei with at least moderate cellularity; occasional single epithelial cells, small but prominent nucleoli, intracytoplasmic lumina (Diagn Cytopathol 2005;32:276)

Positive stains: ER (60-90%, both alpha and beta forms, Histopathology 2007;50:875), usually PR, 75% mucin positive (Alcian blue, mucicarmine), high molecular weight cytokeratin (34betaE12/CK903-perinuclear); also S100 (60%), p120 catenin (AJSP 2007;31:427), EMA, milk fat globule membrane antigen

Negative stains: E-cadherin (Hum Path 2002;33:620, AJSP 2001;25:229), CK 5/6, p53, HER2

Molecular: 16q- (88%, Hum Path 2001;32:292, Breast Cancer Res Treat 2008 Jan 23 [Epub ahead of print]), 17p- (18%), 8p- (12%), 12q24- (12%)

DD: cancerization of lobules by DCIS (has high grade cytology, necrosis, different architecture), atypical lobular hyperplasia (normal sized lobules, central lumina still present), pregnancy-like or pseudolactational hyperplasia (premenopausal women who aren’t pregnant), myoepithelial hyperplasia (normal glandular cells remain with clear cytoplasm, small, round, hyperchromatic nuclei, image), clear cell change (premenopausal women), poor tissue preservation (loosely cohesive cells but no lobular distension)

Pleomorphic lobular carcinoma in situ - Breast malignant chapter

Also called ductal-lobular carcinoma in situ

Morphologic features of pleomorphic LCIS and invasive disease are similar

Case reports: almost pure signet ring cell morphology (Pathol Int 2006;56:683)

Treatment: similar to DCIS (excision with negative margins, variable radiation)

Micro: one or more lobular units with distended terminal ducts and acini; medium/large cells with eosinophilic, granular and occasionally vacuolated cytoplasm; eccentrically placed nuclei 4x size of lymphocytes; moderate/marked pleomorphism, distinct nucleoli; cells usually non-cohesive; central necrosis in 60%, microcalcifications in 40%; “classic” LCIS often seen

Cytology: ductal lavage - epithelial cells in small clusters, single file arrangement or solitary, cytoplasmic vacuoles and nuclear atypia

Positive stains: ER (100%), GCDFP-15 (74%), Ki-67 > 20% (47%)

Negative stains: E-cadherin (100%), HER2 (96%), p53 (75%)

Molecular/cytogenetics: similar changes as classic LCIS and distinct from DCIS (J Pathol 2008;215:231)

DD: DCIS (no lobular involvement, nuclei not eccentric, cells are cohesive, E-cadherin+, pleomorphic cells are ER-, HER2+)

References: Mod Path 2002;15:1044

Ductal intraepithelial neoplasia (DIN) - Breast malignant chapter

This terminology avoids use of “carcinoma”, but is not widely used

Proponents claim it reduces the “artificial separation” between ADH and low grade DCIS (Virchows Arch 2006;449:609)

If DIN terminology is used in a report, recommended to also reference traditional terminology

UDH: usual ductal hyperplasia

DIN 1A: flat epithelial atypia

DIN 1B: atypical ductal hyperplasia

DIN 1C: DCIS grade 1 (low grade)

DIN2: DCIS grade 2 (intermediate grade)

DIN3: DCIS grade 3 (high grade)

Source: Tavassoli: Tumours of the Breast and Female Genital Organs (WHO, 2003)

Initial version as proposed by Tavassoli (Mod Path 1998;11:140), but subsequently modified as above

DIN 1a: usual ductal hyperplasia

Din 1b: flat epithelial atypia

Din 1c: ADH and small Grade I DCIS

DIN 2 - large Grade I and Grade II DCIS

DIN 3 - Grade III DCIS

Mammary intraepithelial neoplasia (MIN) - Breast malignant chapter

Lesions with intermediate or overlapping ductal and lobular features may be called mammary intraepithelial neoplasia, NOS (Hum Path 2002;33:620)

Some can be classified based on immunostains as ductal (E-cadherin+, high MW keratin-) or lobular (E-cadherin-, HMW keratin+), but others cannot

May have classic histological changes of DCIS and LCIS merging in single lobular-duct systems (AJSP 1980;4:241)

This terminology is also used to describe mouse tumors

Paget’s disease - Breast malignant chapter

Definition: malignant epithelial cells randomly disposed within epidermis of nipple areola; a type of in situ carcinoma that arises in/involves main excretory (lactiferous) ducts

Present in 1-2% of all patients with breast carcinoma, median age 54 years

Associated with underlying DCIS or invasive disease in almost all cases (Breast Cancer Res Treat 2008 Feb 1 [Epub ahead of print], Ann Surg Oncol 2005;12:391)

Described by Sir James Paget in 1874 (crusted lesion of nipple caused by breast carcinoma)

Differs from Paget’s disease of vulva (usually not associated with underlying carcinoma) and Paget’s disease of bone

May derive from Toker cells (clear cells in nipple), or from epidermotropism of existing carcinoma (Hum Path 2003;34:1321)

Prognosis depends on underlying DCIS or invasive carcinoma

Case reports: 64 year old woman with nipple discharge and inverted nipple; bilateral Paget’s disease derived from LCIS (Archives 2002;126:90), acinar pattern (Breast J 2007;13:520)

Treatment: mastectomy or possibly breast conserving surgery

Gross: skin is fissured, oozing, ulcerated; resembles eczema

Micro: single cells, groups or rarely tubules; cells are large, atypical and spread throughout epidermis; have abundant clear or light staining cytoplasm, abundant mucin and occasionally intracytoplasmic melanin (Melanoma Res 2004;14:S13); have large vesicular nuclei with prominent nucleolus; DCIS is usually present and may also have invasive component; underlying breast carcinoma is usually adjacent to Paget’s disease if take enough sections

Positive stains: CK7 (also stains Toker and Merkel cells, AJSP 1999;23:212), EMA, CEA, low molecular weight keratin (CAM 5.2, AE1, AJSP 1992;16:58), HER2 and androgen receptor (Mod Path 2005;18:1283), MUC1 (AJSP 2001;25:1469), GCDFP-15 (50%); variable p53 and ER

Negative stains: MUC2, MUC5AC (mucin expressed in extramammary Paget’s disease), S100, HMB45

EM: intracytoplasmic lumina with microvilli, evidence of glandular differentiation

DD: carcinoma in situ of skin (Bowen’s disease, has individual cell keratinization and multinucleated giant cells), superficial spreading melanoma (tumor cells invade dermis, Dermatology Online Journal 13(2):18), benign proliferative nipple duct lesions or Toker cells (APMIS 2008;116:139), pemphigus vulgaris (clinically different, Breast J 2003;9:319); clear cell keratinocytes (image)

References: AJSP 2002;26:617 (mucins), eMedicine

Anaplastic Paget’s disease - Breast malignant chapter

Only one published report (AJSP 1992;16:1085)

Gross: scaling erythematous lesions confined to nipple, but no breast mass

Micro: full thickness epidermal atypia, loss of nuclear polarity, anaplastic cells, intraepidermal acantholysis; variable single cells; invasive ductal carcinoma in 50% of cases

Positive stains: EMA, CEA (50%), AE1-AE3 (50%)

Negative stains: mucicarmine

DD: Bowen’s disease (dyskeratotic cells, no cleft like acantholysis, no basal cell layer)

Breast cancer

Breast cancer-general - Breast malignant chapter

Most common malignant tumor in women after skin cancer (annually 1 million cases worldwide, 100K in US)

Occurs in 1 of 8 to 9 women in US (1 of 232 at age 30-39 years, 1 of 29 at age 70-79); much lower incidence in Japan

Sharp decrease in incidence in US in women 50-69 years old may reflect reduced use of hormone replacement therapy (Breast Cancer Res 2007;9:R28)

Death rate is 27 per 100,000 women (~40,000 deaths per year in US), unchanged for 60 years, slowly falling for 10 years in North America, Western Europe and Australia

Clinical: 50% occur in upper outer quadrant, 17% central (subareolar), 5-15% other quadrants, 13% involve more than one quadrant (3% diffuse)

Tumors in outer quadrant are more likely to have axillary nodes than those in inner quadrant

Common symptoms are breast lumps and nipple abnormalities, sometimes discomfort

Tumors presenting between mammographic screenings (interval tumors) are more aggressive

Synchronous: second tumor discovered within 2 months of initial primary tumor; molecular studies can determine if synchronous tumors are two primaries or one primary with metastases (Mod Path 2008 May 9 [Epub ahead of print])

Clinical examination: for breast, palpation is less sensitive/specific than mammography; for axillary nodes, 40% of clinically negative nodes have tumor and 15% of clinically positive nodes lack tumor

Mammography: can detect tumors as small as 1-2 mm via microcalcifications; microcalcifications are present in 50% of carcinomas vs. 20% of benign breast disease

Suspicious mammographic features are opacity with irregular, spiculated margins +/- calcifications; also clusters of fine calcifications, asymmetry, but only 20% of “suspicious” microcalcifications are actually malignant

Up to 30% of tumors are not detectable by mammography due to poor resolution from surrounding fibrous breast (generally younger women)

MRI: detects increased tumor vascularity and increased tumor uptake of contrast agents; usually no gross findings so must examine entire specimen (Hum Path 2007;38:1754)

Ultrasound: increasingly utilized clinically, can distinguish solid versus cystic lesions (latter are generally benign)

Needle biopsy: radiologist marks microcalcifications with needle, surgeon removes area around needle, specimen is Xrayed to verify specimen includes microcalcifications; pathologist should verify presence of microcalcifications (note: calcium oxalate crystals are easily missed by pathologists – must look for birefringence under polarized light)

Case reports: recurrence in myocutaneous flaps (Archives 2004;128:1157), massive thyroid tumoral emboli (Archives 2004;128:804)

Treatment: surgery (usually lumpectomy or modified radical mastectomy, lumpectomy cavity margins may be helpful, AJSP 2005;29:1625), radiation therapy if positive margins or to control locally recurrent disease (44% recur without radiation if close/non-involved margins for DCIS versus 94% recurrence if margins extensively positive, Mod Path 2004;17:81), anti-estrogen drugs (tamoxifen and others to reduce risk of recurrence in same or opposite breast, particularly for ER+ tumors), combination chemotherapy (for metastatic disease, to reduce the risk of contralateral breast carcinoma); preoperative chemotherapy shrinks large tumors to allow surgery for large tumors or more conservative surgery

Micro: invasive if stromal invasion present; most tumors are adenocarcinomas arising from terminal duct lobular unit; in situ carcinoma present to variable extent (“extensive” if >25% of tumor volume seen inside and outside of invasive tumor field)

References: Wikipedia, eMedicine, National Cancer Comprehensive Network guidelines

Risk factors for breast cancer - Breast malignant chapter

Primarily genetic, hormonal or environmental

After menopause, about 40% of risk is modifiable (Am J Epidemiol 2008 Jun 13 [Epub ahead of print])

Genetic risk factors for breast cancer - breast malignant chapter

(a) first degree relatives with breast cancer; with one first degree relative (mother, sister, daughter), relative risk is 2-3x, higher if relative is affected before age 50 or had bilateral disease (Int J Cancer 1997;71:800); relative risk with two relatives is 4-6x

(b) Li-Fraumeni syndrome (germline p53 mutations) - 25% of patients develop breast cancer

(c) mutations of BRCA1 (see below) and BRCA2 (see below) genes are associated with familial breast cancer at an early age, account for 20-60% of familial breast cancer, only 5% of all cases

(d) Cowden's disease (multiple hamartoma syndrome) - autosomal dominant, due to 10q mutation: 30-50% risk of breast cancer (DCIS or invasive ductal carcinoma) by age 50; also benign skin tumors (Hum Path 1998;29:47)

(e) heterozygous carriers for ataxia-telangiectasia have an 11% risk of breast cancer by age 50

(f) women have 100x risk of breast cancer compared to men

Hormone related risk factors for breast cancer - breast malignant chapter

(a) early menarche

(b) late menopause

(d) having first child after age 30

(d) post-menopausal women with hyperandrogenic plasma hormone profile

(e) postmenopausal women with obesity (BJOG 2006;113:1160) or estrogen producing ovarian tumors

(f) women using combined hormone replacement therapy with progestins, also estrogens alone

(g) risk with oral contraceptives is controversial, but see Mayo Clin Proc 2006;81:1290

Proposed mechanism is strong or prolonged estrogen stimulation, which may allow secretion of growth promoters

Associated with reduced risk of breast cancer:

(a) oophorectomy before age 35 or first child before age 18

(b) obesity prior to age 40 - due to anovulatory cycles and lower progesterone levels in late cycle

Environmental risk factors for breast cancer - breast malignant chapter

Rates in US > Japan or Taiwan (5:1), also high in Northern Europe, low in Asia/Africa; may be due to known risks of obesity/high fat diet (Nutr Cancer 2008;60:492) and heavy alcohol use (Am J Epidemiol 2000;152:950); differences diminish with immigration

Breast cancer is not associated with smoking

Blacks (compared to whites) present with higher stage tumors with higher nuclear grade and more likely ER/PR negative, have higher mortality rate, more frequent breast cancers in women < age 40

In Nigeria, breast cancers are high-grade, high-stage and high-proliferating, and occur at a younger age than in Western countries (Mod Path 2002;15:783)

Physical activity has a protective effect (J Natl Cancer Inst 2008;100:728)

Other risk factors for breast cancer - breast malignant chapter

(a) older age

(b) proliferative breast disease (see individual topics in Breast-nonmalignant chapter), particularly in situ carcinoma, and possibly concurrent multiple nonproliferative or proliferative benign breast lesions at biopsy (Clin Cancer Res 2007;13:5474)

(d) radiation exposure (including women < age 30 with supradiaphragmatic radiation for Hodgkin's lymphoma, Int J Radiat Oncol Biol Phys 2008 Jun 4 [Epub ahead of print])

(e) mammographic density (J Br Menopause Soc 2006;12:186)

Breast cancer - spread and metastases - Breast malignant chapter

Local spread: to skin or chest wall; nipple invasion more common if tumors are within 2.5 cm of nipple; local recurrence after surgery appears as nodules, often near old scar, but can be simulated by post-surgical granulomas

Nodal metastases: axilla is most common site of nodal metastases; also supraclavicular and internal mammary region

Distant metastases: common sites are adrenal gland, bone (desmoplasia may cause dry taps in bone marrow), central nervous system (more often basal-like phenotype - high grade, CK 5/6+, EGFR+, ER negative, AJSP 2006;30:1097), liver, lung/pleura (often mammaglobin+, Mod Path 2007;20:208), ovary (60-80% bilateral, are GCDFP-15+), adrenal gland

Lobular carcinoma tends to metastasize to abdominal/pelvic cavities including GI tract, ovaries and serosal surfaces

Occult primary: if enlarged axillary node contains carcinoma and no breast mass or other tumor is detected clinically or radiologically, usually a primary breast carcinoma will eventually be found in adjacent breast, although may be very small (usually < 2 cm); radiation therapy may be adequate therapy (Oncology 2006;71:456); melanomas may also present in this manner

Metastatic breast carcinomas to GI tract are usually positive for GCDFP-15 (78%), ER (72%), CK5/6 (61%); also PR (33%), androgen receptors and HER2; negative for CDX2 and CK20 (Archives 2005;129:338)

Androgen receptor nuclear staining suggests breast or ovarian primary (Diagn Pathol 2006;1:34)

Case reports of metastatic sites: colonic polyp (Archives 1984;108:318), liver (Archives 2004;128:1418), lung causing cor pulmonale (Archives 1986;110:1197), ovarian granulosa cell tumor (Hum Path 2002;33:445), stomach #1 (Archives 2001;125:567), #2 (World J Surg Oncol 2007;5:75), thyroid follicular adenoma (Archives 1994;118:551)

Positive stains in unknown primary: GCDFP-15, lactalbumin, ER and PR are relatively specific for breast primary; breast carcinoma is usually CK7+/CK20- (also carcinomas of lung and ovary, but GI, pancreaticobiliary and some ovarian tumors are CK20+); mammaglobulin in more sensitive but less specific than GCDFP-15 (AJCP 2007;127:103)

Markers to distinguish specific primaries: Breast vs. lung: GCDFP-15 (breast) and TTF-1 (lung); breast vs. ovary: GCDFP-15 (breast) and WT1 (ovary) (AJSP 2004;28:1076), although breast mucinous carcinomas may also be WT1+ (Mod Path 2008 May 9 [Epub ahead of print])

WHO histological classification of tumours of the breast - Breast malignant chapter

Also listed is ICD-O (morphology code) and behavior code: /0 for benign, /1 for borderline or uncertain, /2 for in situ and grade 3 intraepithelial neoplasia, /3 for malignant

Epithelial tumors - Breast malignant chapter

Invasive ductal carcinoma, not otherwise specified (NOS) - 8500/3

Mixed type carcinoma

Pleomorphic carcinoma - 8022/3

Carcinoma with osteoclastic giant cells - 8035/3

Carcinoma with choriocarcinomatous features

Carcinoma with melanotic features

Invasive lobular carcinoma - 8520/3

Tubular carcinoma - 8211/3

Invasive cribriform carcinoma - 8201/3

Medullary carcinoma - 8510/3

Mucinous carcinoma and other tumours with abundant mucin

Mucinous carcinoma - 8480/3

Cystadenocarcinoma and columnar cell mucinous carcinoma - 8480/3

Signet ring cell carcinoma - 8490/3

Neuroendocrine tumours

Solid neuroendocrine carcinoma

Atypical carcinoid tumour - 8249/3

Small cell / oat cell carcinoma - 8041/3

Large cell neuroendocrine carcinoma - 8013/3

Invasive papillary carcinoma - 8503/3

Invasive micropapillary carcinoma - 8507/3

Apocrine carcinoma - 8401/3

Metaplastic carcinomas - 8575/3

Pure epithelial metaplastic carcinomas - 8575/3

Squamous cell carcinoma - 8070/3

Adenocarcinoma with spindle cell metaplasia - 8572/3

Adenosquamous carcinoma - 8560/3

Mucoepidermoid carcinoma - 8430/3

Mixed epithelial/mesenchymal metaplastic carcinomas - 8575/3

Lipid-rich carcinoma - 8314/3

Secretory carcinoma - 8502/3

Oncocytic carcinoma - 8290/3

Adenoid cystic carcinoma - 8200/3

Acinic cell carcinoma - 8550/3

Glycogen-rich clear cell carcinoma - 8315/3

Sebaceous carcinoma - 8410/3

Inflammatory carcinoma - 8530/3

Lobular neoplasia

Lobular carcinoma in situ - 8520/2

Intraductal proliferative lesions

Usual ductal hyperplasia

Flat epithelial atypia

Atypical ductal hyperplasia

Ductal carcinoma in situ - 8500/2

Microinvasive carcinoma

Intraductal papillary neoplasms

Central papilloma - 8503/0

Peripheral papilloma - 8503/0

Atypical papilloma

Intraductal papillary carcinoma - 8503/2

Intracystic papillary carcinoma - 8504/2

Benign epithelial proliferations

Adenosis including variants: sclerosing adenosis, apocrine adenosis, blunt duct adenosis,

microglandular adenosis, adenomyoepithelial adenosis

Radial scar / complex sclerosing lesion

Adenomas

Tubular adenoma - 8211/0

Lactating adenoma - 8204/0

Apocrine adenoma - 8401/0

Pleomorphic adenoma - 8940/0

Ductal adenoma - 8503/0

Myoepithelial lesions - Breast malignant chapter

Myoepitheliosis

Adenomyoepithelial adenosis

Adenomyoepithelioma - 8983/0

Malignant myoepithelioma - 8982/3

Mesenchymal tumours - Breast malignant chapter

Hemangioma - 9120/0

Angiomatosis

Haemangiopericytoma - 9150/1

Pseudoangiomatous stromal hyperplasia

Myofibroblastoma - 8825/0

Fibromatosis (aggressive) - 8821/1

Inflammatory myofibroblastic tumour - 8825/1

Lipoma - 8850/0

Angiolipoma - 8861/0

Granular cell tumour - 9580/0

Neurofibroma - 9540/0

Schwannoma - 9560/0

Angiosarcoma - 9120/3

Liposarcoma - 8850/3

Rhabdomyosarcoma - 8900/3

Osteosarcoma - 9180/3

Leiomyoma - 8890/0

Leiomyosarcoma - 8890/3

Fibroepithelial tumours - Breast malignant chapter

Fibroadenoma - 9010/0

Phyllodes tumour - 9020/1

Benign - 9020/0

Borderline - 9020/1

Malignant - 9020/3

Periductal stromal sarcoma, low grade - 9020/3

Mammary hamartoma

Tumours of the nipple - Breast malignant chapter

Nipple adenoma - 8506/0

Syringomatous adenoma - 8407/0

Paget disease of the nipple - 8540/3

Malignant lymphoma

Diffuse large B cell lymphoma - 9680/3

Burkitt lymphoma - 9687/3

Extranodal marginal-zone B-cell lymphoma of MALT type - 9699/3

Follicular lymphoma - 9690/3

Metastatic tumours

Tumours of the male breast - Breast malignant chapter

Gynaecomastia

Carcinoma

Invasive - 8500/3

In situ - 8500/2

Breast cancer - Histologic grading - Breast malignant chapter

Histologic grade is a strong predictor of survival (J Clin Oncol 2008;19:3153)

In US, blacks overall have higher grade tumors than whites (Cancer 2003;98:908)

Most commonly used system is Elston/Nottingham modification of Bloom-Richardson system:

Tumor tubule formation:

1 point: > 75% of tumor

2 points: 10-75% of tumor

3 points: < 10% of tumor

Note: the overall appearance of the tumor must be taken into consideration in scoring tubule formation

Note: tubules must have clear central lumina to be counted

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

Notes:

(a) count mitotic figures at periphery of 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; ignore cells with hyperchromatic and pyknotic nuclei, which may be undergoing apoptosis

(b) quick scan mitotic impression is less accurate (Hum Path 2008;39:584)

(d) the concept of a moderately differentiated category has been criticized (Pathobiology 2008;75:104, J Natl Cancer Inst 2006;98:262); tumors with 3+3+1 pattern (i.e. <10% tubules, marked nuclear pleomorphism but few mitotic figures) may be 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; Ki-67 may serve as surrogate for mitotic figure counting in these cases (Oncologist 2008;13:477)

Nuclear pleomorphism:

1 point: minimal nuclear variation in size and shape; small regular uniform cells

2 points: moderate nuclear variation in size and shape

3 points: marked nuclear variation in size and shape

Note: evaluate areas with greatest atypia

Total: well differentiated (grade I) if 3-5 points; moderately differentiated (grade II) if 6-7 points; poorly differentiated (grade III) if 8-9 points

References: Br J Cancer 1957;11:359, Histopathology 1991;19:403, Archives 1983;107:411 (grade based on representative portion of tumor, not least differentiated part), California Cancer Registry

Epidermal Growth Factor Receptor (EGFR) - Breast malignant chapter

Also called HER1; related to HER2

Associated with these breast cancers - basal-like (BMC Genomics 2007;8:258), metaplastic (76%, Breast Cancer Res 2005;7:R1028), sarcoma NOS (5 of 7, AJSP 2006;30:450), squamous cell carcinoma (87%, Int J Surg Pathol 2005;13:319); also ER negative tumors (Pathol Res Pract 1988;183:25 , Breast Cancer Res 2008;10:R49), phyllodes tumors (all types-19%, malignant-75%, Lab Invest 2006;86:54)

Associated with poor survival (J Clin Oncol 2007;25:4405)

6% of breast carcinomas show moderate to low level EGFR amplification associated with protein overexpression, and may be responsive to anti-EGFR-therapy (Mod Path 2005;18:1027); EGFR inhibitors have been used for lung cancer patients

HER2 (c-erbB2) and malignant breast tumors - Breast malignant chapter

Also called Human Epidermal growth factor Receptor 2, c-erbB2, neu, ERBB2, CD340

HER2 gene encodes transmembrane growth factor receptor (p185); cytoplasmic tyrosine kinase is constituitively active when overexpressed due to homo/heterodimerization (diagram)

“3+” protein stain is associated with HER2 gene amplification (at 17q21); not due to (a) chromosome 17 polysomy without HER2 gene amplification (AJSP 2005;29:1221) or (b) chromosome 17 aneusomy [aneusomy means other than 2 copies of chromosome] (Mod Path 2002;15:137)

HER2 gene amplification: present in 18-25% of breast tumors; associated with comedocarcinoma and aggressive invasive tumors; detectable by FISH; defined as increased ratio of HER2 gene to chromosome 17 (count >2.2)

Immunohistochemistry/IHC (HER2 protein overexpression); weak/moderate staining is common without amplification; usually appears first in ADH or DCIS (Mod Path 2002;15:116); also seen in nonbreast cancers (Mod Path 2007;20:192)

Anti-HER2 therapy (trastuzumab/Herceptin) plus chemotherapy reduces recurrence, metastases and mortality in HER2 gene amplified breast cancer patients (Int Semin Surg Oncol 2008;5:9, Acta Oncol 2008 Apr 30:1 [Epub ahead of print]); may improve survival in metastatic disease (Am J Clin Oncol 2008;31:250, N Engl J Med 2007;357:1496), but is associated with cardiac toxicity (BMC Cancer 2007 Aug 8;7:153)

Detection of HER2 gene amplification: predominantly determined using immunohistochemistry/IHC as screening test; 3+ staining (see below) is highly correlated with gene amplification (FISH, more sensitive but more expensive and difficult to distinguish in situ from invasive lesions, Mod Path 2000;13:1239, Hum Path 2005;36:250 (quality assurance) and chromogenic in situ hybridization (CISH, Mod Path 2002;15:657, Mod Path 2005;18:1015, Mod Path 2006;19:481, Breast Cancer Res 2007;9:R68); can also use quantitative reverse transcription-polymerase chain reaction (AJCP 2008;129:563)

FISH may be an appropriate screening test (instead of immunohistochemistry) under some conditions (Oncol Rep 2008;19:1271); use of cutpoint of 1.5 instead of 2.2 (signifies intermediate outcome between amplification negative and positive) is suggested (Breast Cancer Res Treat 2008 Jan 9 [Epub ahead of print])

For IHC, should compare intensity of patient sample to 3+ control slide with negative normal epithelium

For node negative patients, FISH and IHC results are generally similar with some discrepant cases (Archives 2001;125:746); equivocal IHC and borderline FISH cases are difficult to interpret, even for highly experienced and validated laboratories (Mod Path 2007;20:584)

HER2 overexpression by IHC is associated with high Ki-67 index and negative ER/PR

ASCO/CAP recommendations: (a) determine HER2 by IHC for all invasive breast cancer cases, (b) specific procedures are recommended to reduce assay variation, (c) define HER2 amplification as either 3+ IHC staining (uniform, intense stain of >30% of tumor cells), FISH of > 6 HER2 gene copies/nucleus or FISH ration > 2.2, (d) define negative tests as 0 or 1+ IHC, FISH <4.0 or FISH ratio < 1.8, (d) classify other results as equivocal and require additional testing, (e) labs should show 95% concordance with another validated test (Archives 2007;131:18-full text, Mod Path 2008;21 Suppl 2:S8); similar recommendations in UK (J Clin Pathol 2008;61:818)

FDA and ASCO/CAP schemes for HER2 evaluation select patients differently, with major discordances for low-grade, borderline HER2 amplification (AJCP 2008;129:907); high concordance between FISH and ISH requires modification of FDA scoring system (Mod Path 2008 May 16 [Epub ahead of print])

FDA approved assays for HercepTest and Pathway give comparable results when strictly handled (Archives 2004;128:627)

Staining pattern:

0 (negative) - no staining or membrane staining in <30% of tumor cells

1+ (negative) - faint membrane staining in > 30% of tumor cells; only part of membrane is stained

2+ (weak positive) - weak/moderate complete membrane staining in >30% of tumor cells

3+ (strong positive) - strong complete membrane staining in >30% of tumor cells

Note: 30% threshold is from ASCO/CAP scheme in 2008, prior threshold was 10%

Testing algorithm #1; #2

IHC stain scores of 0/1+ (negative/weak) or 3+ (strong) are predictive of FISH results (negative and positive amplification respectively); 2+ is not predictive and has significant interobserver variability (Mod Path 2001;14:1079); suggested to perform FISH or PCR for 2+ tests (AJCP 2005;123:766); for equivocal HER2 results by FISH or PCR on breast core biopsies, recommended to evaluate on larger tumor sample (AJCP 2008;129:383)

Serum HER2 levels may predict histopathologic response to chemotherapy (AJCP 2007;128:630)

HER2 gene status remains highly conserved as breast cancers metastasize; the discrepancies present are often due to interpretational difficulties and heterogeneity of HER2 amplification (Breast Cancer Res 2007;9:R31)

Case reports: overgrowth of HER2 negative cells after anti-HER2 antibody therapy (Hum Path 2004;35:379)

Sources for testing (advertisements): Genzyme

References: Wikipedia

Hormone receptors - Breast malignant chapter

Estrogen receptors have alpha and beta subtypes

ER-alpha: “classic” functions of ER; may render breast epithelium susceptible to proliferative stimulation of estrogen; expressed in breast and endometrium; immunostains not specifically classified as ER-alpha or ER-beta are usually ER-alpha

ER-beta: “housekeeping” functions; expressed in normal ovary and granulosa cells, carcinoma of breast, colon, prostate; values differ from ER-alpha in BRCA1 associated breast carcinoma (BMC Cancer 2008;8:100); expression in ER-alpha negative breast cancer patients is an independent marker for favorable prognosis after adjuvant tamoxifen treatment (Clin Cancer Res 2007;13:1987)

Presence of estrogen (type alpha) and progesterone receptors correlates best with response to anti-estrogen treatment (tamoxifen or others) or chemotherapy (but ER-alpha is associated with resistance to paclitaxel-Cancer Res 2007;67:5337), correlates only weakly with prognosis; presence is associated with older age

Endocrine therapy responsiveness is observed even with low expression of ER (1-5%)

ER gene profiling (BMC Genomics 2008;9:239) or ER-beta mRNA (BMC Cancer 2007;7:131) may predict the 30-40% of ER+ tumors that will NOT respond to tamoxifen

Report % of tumor nuclei stained and intensity of staining (none, weak, moderate, strong)

Immunostaining is done on paraffin fixed tissue (previously required fresh tissue)

Metastases to skin are often positive for androgen receptor, even if ER- and PR- (Mod Path 2000;13:119)

Antigen retrieval techniques are required for ER if glyoxal fixative is used (Hum Path 2004;35:1058)

Compared to ER, PR staining adds only a limited amount of additional predictive information for response to hormonal therapy (Mod Path 2004;17:1545)

6F11 antibody (Novocastra) may produce better results than 1D5 (Dako, AJCP 2005;123:276)

ER/PR positive tumors: most colloid carcinomas, most well differentiated tumors, bcl2+ tumors; ER+ tumors have lower microvessel density (Int Semin Surg Oncol 2007;4:22)

Tutorial: US National Cancer Institute

Micro: nuclear, not cytoplasmic, staining; may be heterogeneous within tumors

References: Hum Path 2001;32:113 (ER beta), Cancer Res 2002;62:4849 (ER beta cx, a splice variant), Wikipedia (ER), Wikipedia (PR)

ER/PR negative tumors

Tumors are usually moderate/poorly differentiated with axillary nodal metastases and poor prognosis (Archives 2002;126:325)

Includes metaplastic, adenoid cystic, apocrine and acinic cell carcinomas; also comedocarcinoma and medullary carcinoma

Often occurs in premenopausal women

ER negative tumors: 30% of primary operable breast cancers, 94% are high grade, 85% are invasive ductal NOS (Mod Path 2005;18:26)

Micro: usually lymphoid stroma, pushing margin, central fibrosis/necrosis, poorly differentiated

Positive stains: more likely p53+, HER2+, EGFR+ than ER+ tumors (Mod Path 2005;18:26); express one or more myoepithelial markers (CD10, S100, smooth muscle actin) more frequently than ER- tumors (47% vs. 8%, Mod Path 2004;17:646)

Breast cancer - Prognostic factors - Breast malignant chapter

Prognostic factors: assess future outcome, such as survival

See also prognostic factors for particular subtypes

Negative prognostic factors: classic factors include high stage (defined by tumor size, nodal and distant metastases, including possibly nodal micrometastases, Ann Surg Oncol 2007;14:3378), high histologic grade (J Clin Oncol 2008;26:3153), younger age, skin invasion, nipple invasion, angiolymphatic invasion (see below), fibrotic focus (see below); negative prognostic factors that are based on fewer studies than classic factors include retraction artifact mimicking angiolymphatic invasion (AJSP 2007;31:129), infiltrative margins versus pushing margins, local recurrence, bcl2 negativity (Clin Cancer Res 2006;12:2468, BMC Cancer 2008;8:153), p53 mutation or HER2+ (Acta Oncol 2008;47:618), phosphohistone H3 >=13 (Mod Path 2007;20:1307), disseminated tumor cells to bone marrow (Clin Cancer Res 2008;14:3306), tumor detection by symptoms versus screening (Cancer Epidemiol Biomarkers Prev 2008;17:1096)

Favorable histologic types: tubular, cribriform, medullary, colloid, papillary, adenoid cystic and secretory/juvenile; unfavorable types are signet ring, basal-like and inflammatory

S phase fraction may have prognostic value for fine needle aspirates (Cytopathology 2007 Dec 7 [Epub ahead of print]); otherwise ploidy and S phase fraction appear to NOT have prognostic value (Archives 2001;125:364)

Value of traditional prognostic factors persists for assessing survival 10+ years (Breast Cancer Res Treat 2008;107:309)

Nottingham Prognostic Index: based on tumor size, stage and grade (details, Breast Cancer Res Treat 1992;22:207, Pathol Oncol Res 2008;14:113)

For local recurrence, margin status is more important in node negative than node positive patients (Int Semin Surg Oncol 2008;5:13)

Women with metastatic disease: age at initial diagnosis, hormonal receptor status and site of metastasis (Ann Oncol 2008 Jul 17 [Epub ahead of print])

Predictive factors: assess response to treatment, such as ER and PR (response to anti-estrogens) or HER2 (response to anti-HER2 treatment)

Angiolymphatic invasion - prognostic factors - Breast malignant chapter

Prognostic significance particularly for lymphatic invasion (AJSP 2007;31:1825) and D2-40 microvessel density (AJCP 2008;129:578); note that D2-40 is not specific for lymphatic endothelium because it also stains breast myoepithelium (Hum Path 2008;39:175)

Lymphatic invasion occurs primarily at invasive front of tumor

Related variables - presence of 6+ apoptotic figures in tumor emboli in patients without nodal metastases and 4+ mitotic figures in tumor emboli of patients with nodal metastases (Mod Path 2002;15:904, Hum Path 2008;39:427)

Lymph vessel tumor emboli in stroma invasive tumor area (by H&E or D2-40) predicts high risk of tumor recurrence or death (Hum Path 2007;38:247, Mod Path 2007;20:183)

Lymphatic invasion may be particularly important in node negative patients (Ann Oncol 2007;18:1632)

References: AJSP 1977;1:25

Fibrotic focus - prognostic factors - Breast malignant chapter

Definition: mixture of fibroblasts and collagen fibers that may occupy almost the entire center of an invasive ductal carcinoma, replacing the necrotic central area (see also centrally necrotic carcinoma subtype)

May be due to intratumoral hypoxia (Histopathology 2007;51:440), leading to clonal heterogeneity of tumor cells (Mod Path 2001;14:325)

Invasive ductal carcinomas with fibrotic focus have poorer survival than those without (Mod Path 2002;15:502, Jpn J Cancer Res 1997;88:590); also predicts bone metastases (Hum Path 2008;39:681)

Associated with basal-like subtype, activated wound-healing signature and a poor prognosis 76-gene signature (Clin Cancer Res 2008;14:2944)

Multigene prognostic products - prognostic factors - Breast malignant chapter

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^TMand MammaPrint®, although validity of tests may not be relevant to all patient subsets (Oncologist 2008;13:477)

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)

Sources for testing (advertisements): Genzyme

Axillary lymph node examination - Breast malignant chapter

Presence of axillary lymph node metastases is the most important prognostic factor for disease-free and overall survival, and important for determining treatment regimens

Presurgical staging of axillary nodes (ultrasound with FNA) is increasingly popular (Cancer 2008;114:89)

Micrometastases: 2 mm or less

Isolated tumor cells: 0.2 mm or less

Occult metastases (identified retrospectively by step-sectioning and immunohistochemical staining) are an independent predictor of disease-free survival, but not overall survival, in node-negative patients, particularly if > 0.5 mm (AJSP 2002;26:1286)

Clearing solutions, such as ethanol, diethyl ether, Carnoy’s solution (Chin Med J (Engl) 2007;120:1762), glacial acetic acid and formalin may identify additional lymph nodes (AJSP 1997;21:1387, Archives 2001;125:642)

Neoadjuvant chemotherapy is associated with identification of fewer lymph nodes (J Am Coll Surg 2008;206:704)

Regional lymph nodes are:

1. 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’s) lymph nodes

Level III (apical axilla): medial to the medial margin of the pectoralis minor muscle, including those designated as apical, excluding those designated as subclavicular or infraclavicular

2. Infraclavicular (subclavicular) (ipsilateral)

3. Internal mammary (ipsilateral): lymph nodes in the intercostal spaces along the edge of the sternum in the endothoracic fascia

4. Supraclavicular (ipsilateral)

Side effects of axillary nodal dissection include lymphedema, shoulder restriction, numbness, weakness and pain syndromes (Cancer J 2008;14:216)

Case reports: melanoma and breast ductal carcinoma metastasizing to same node (Int Semin Surg Oncol 2006;3:32)

DD: ectopic breast tissue (Breast Cancer 2007;14:425), mullerian-type epithelial inclusions (Archives 2004;128:361, Archives 1995;119:841), muciphages (resemble signet-ring carcinoma, associated with prior surgery or lactation, Alcian blue+, CD68+, Mac387+, keratin-, AJSP 1998;22:545), nevus cells (AJCP 1994;102:102, AJSP 2003;27:673, Archives 1985;109:1044), after prior breast biopsy (AJCP 2000;114:190)

Sentinel lymph nodes - Breast malignant chapter

Definition: first node to which lymphatic drainage and metastasis from breast cancer occurs; usually an axillary node in central group of level I, but may be at level II (behind the pectoralis minor muscle), level III (infraclavicular) or be intramammary, interpectoral (Rotter's) or internal mammary node (Eur J Surg Oncol 2008 Aug 4 [Epub ahead of print]); tumor is more likely at inflow junction of afferent lymphatic vessel (AJSP 2003;27:385)

Sentinel node may have characteristics that prevent further tumor spread up the lymphatic chain (Int Semin Surg Oncol 2006;3:39)

Surgeon injects blue dye or radioactive colloid around tumor, which travels to and identifies the first draining sentinel lymph node

Considered a suitable replacement for axillary dissection for staging/diagnosis in T1 and T2 tumors, with reduced patient morbidity

Intraoperative frozen section (World J Surg Oncol 2008;6:69), intraoperative imprint cytology (Eur J Surg Oncol 2008 Jun 11 [Epub ahead of print]) or molecular assays may be useful (J Clin Oncol 2008;26:3338)

Frozen section has 60% sensitivity and 100% specificity in one study, with “atypical” cases usually negative on permanent sections (Mod Path 2005;18:58); concentrated smear technique is more sensitive than direct smears (AJCP 2004;122:944)

Extensive examination is performed of sentinel node (see below) to look for micrometastases

If sentinel node(s) negative, other nodes are negative in >95% of cases

High risk (60%) of tumor in nonsentinel nodes if sentinel node has macroscopic tumor (2 mm or more) versus low risk (3%) if microscopic tumor (0.2 to 2 mm, Mod Path 2005;18:762); micrometastases may not affect survival (Ann Oncol 2008 Jul 24 [Epub ahead of print]), but cohesive cluster of malignant cells, 0.2 mm to 2.0 mm, may indicate significant axillary disease; smaller clusters are highly unlikely to be associated with significant residual metastasis or poor prognosis

Isolated tumor cells: single cells interpreted as malignant; clinical significance not yet demonstrated

False positives with cytokeratin: wrong antibody (Archives 2001;125:1497), nevus cells (Eur J Dermatol 2008;18:586), reticulum cells that are AE3+ (Archives 2002;126:248, image; less of a problem with AE1-AE3), mesothelial cell inclusions, ectopic breast tissue (AJSP 2003;27:513), benign epithelial cells associated with pre-sentinel biopsy breast massage (AJSP 2004;28:1641) or megakaryocytes (Archives 2002;126:618, image)

Consensus recommendations (Hum Path 2002;33:579):

Submit entire node unless gross tumor

Slice large nodes into 3-4 mm thick sections and submit all

Other recommendations [non-consensus]:

If examination of the initial H & E stained section does not reveal metastases, then obtain:

(a) 2 additional hematoxylin and eosin-stained sections and one pancytokeratin (AE1-AE3) stained section (AJSP 2002;26:377)

(b) 3 additional H & E stained sections (no immunohistochemistry since occult metastases have minimal predictive value, Mod Path 2002;15:641)

(d) AE1-AE3 better than CAM 5.2 since less staining of reticulum cells (Archives 2000;124:1310)

Recommendations for handling radioactive specimens: AJSP 2000;24:1549

Case reports: 45 year old woman with distinct populations of infiltrating ductal carcinoma and lobular carcinoma in both breast and sentinel lymph node (Archives 2004;128:365), level III sentinel node (World J Surg Oncol 2006;4:31)

References: AJSP 2002;26:383 (other recommendations), AJSP 2003;27:842 (which micrometastases are significant), Wikipedia

Microinvasive / suspicious for microinvasion - Breast malignant chapter

Microinvasive carcinoma

Definition of microinvasion: dominant lesion is not invasive, but there are 1+ separate small, microscopic foci of infiltration, each 1 mm or less in size

“Minimal breast carcinoma” includes microinvasive carcinoma and DCIS

Less than 1% of all breast cancers

Usually detected by mammography due to abnormal calcifications in associated DCIS

Mean age 61 years

72% associated with comedo DCIS; 89% with high nuclear grade, 89% with necrosis

Sentinel lymph node dissection may be appropriate, as axillary nodal metastases occur in less than 10% (Breast J 2008 Jun 5 [Epub ahead of print]); controversial whether to perform complete axillary dissection if positive sentinel node (yes-Breast 2007;16:146, no-Am J Surg 2007;194:845); frozen section analysis of sentinel nodes not recommended routinely

Cure rate is close to 100% with surgical excision (Ann Oncol 2004;15:1633)

Prognosis may be dependent on features of DCIS (AJSP 2000;24:422)

Commonly misdiagnosed (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, often with large invasive foci at excision, rarely with no other significant findings (Archives 2004;128:996)

Report number of foci of invasion, size of largest focus

False positives: lobular cancerization, radial scar, sclerosing adenosis (Archives 2001;125:1259)

False negatives: masking of invasion by inflammatory cells or histiocytes; use cytokeratin to highlight

Micro: usually ductal, rarely tubular or lobular morphology; nodules of invading neoplastic cells in periductal or perilobular stroma, none exceeding 1.0 mm; usually arising in background of high grade DCIS; stromal microinvasion typically associated with fibroblast proliferation, collagenization and focal inflammatory cell infiltrates

Can confirm using myoepithelial stains (to observe absence) and keratin (to observe infiltrative growth) Diagnosis requires certainty of invasion; if doubt remains after recuts and immunostains, call DCIS or suspicious

Negative stains: no myoepithelial markers in invasive component (smooth muscle myosin heavy chain, smooth muscle actin, calponin)

References: Hum Path 1998;29:1412

Suspicious for invasion - Breast malignant chapter

In one study, 90% with core biopsies that were suspicious for invasion had definitive invasive disease at excision (Ann Surg Oncol 2007;14:704)

Micro: periductal or perilobular stroma contains either isolated individual neoplastic cells or rare clusters of cells thought to be neoplastic, but review of multiple levels fails to demonstrate continuity of cells/groups with adjacent in situ neoplasm or underlying residual epithelial structures

Positive stains: myoepithelial cells (favor noninvasive process) – p63 (sensitive and specific), smooth muscle actin (also stains myofibroblasts), calponin, smooth muscle myosin heavy chain; basement membrane - type IV collagen, laminin

References: Mod Path 2002;15:95 (core biopsies), AJSP 2004;28:1076 (immunostains), AJSP 2003;27:82 (immunostains)

Pregnancy related carcinoma - Breast malignant chapter

Associated with higher stage, larger primary tumors than non-pregnancy associated tumors (Obstet Gynecol 2008;112:71)

Findings are similar to features of breast carcinoma in other young women, and clinical course may not be as aggressive as initially reported (Cancer 2003;98:1055)

Tumors usually contain rare fetal cells (Breast Cancer Res 2008;10:R14)

Treatment: sentinel lymph node mapping can be performed (Breast J 2008;14:250, Ann Surg Oncol 2007;14:218); recommended to wait until after first trimester to use chemotherapy (Cancer 2006;106:237, Eur J Surg Oncol 2008 Jun 10 [Epub ahead of print]); recommended to delay until after delivery the use of radiotherapy, also Herceptin / trastuzumab (associated with anhydramnios, Ann Oncol 2008;19:607)

Micro: 80% high grade; cancerization of lobules in 79%

Positive stains: MUC2 (if during lactation); variable HER2 (Virchows Arch 2003;443:44)

Negative stains: usually ER, PR

Reference: Archives 2000;124:1053, National Cancer Institute (US), US Guidelines

Carcinoma subtypes

Carcinoma subtypes-general - Breast malignant chapter

Subtypes other than ductal NOS or lobular are uncommon; they have distinctive clinical features only if “pure”; i.e. if histologic features are present in >90% of tumor

Subtypes often differ greatly in age of onset (Cancer Epidemiol Biomarkers Prev 2006;15:1899), clinical presentation and hormone receptor profiles (Br J Cancer 2005;93:1046) and prognosis (Int J Cancer 2007;121:127, Br J Cancer 2004;91:1263)

Special types can often be suspected / diagnosed by fine needle aspiration (Diagn Cytopathol 2007;35:408)

DNA microarray profiling studies have divided invasive breast carcinoma into molecular subtypes: luminal A (ER+, HER2-), luminal B (ER+, HER2+), HER2 positive (ER-, HER2+), normal breast-like and basal-like (ER-, HER2-, EGFR+, and/or cytokeratin 5/6+)

All breast carcinomas are usually CK7+, CK20-, except mucinous/colloid (often CK20+) and <5% of special types (Ann Diagn Pathol 1999;3:350)

Special types should be assigned a histologic grade

References: AJSP 2003;27:832

Acinic cell carcinoma - Breast malignant chapter

Definition: identical to salivary gland counterpart, has serous differentiation

Uncommon in breast, <20 cases reported

DD: metastatic carcinoma (Breast Cancer 2008 Mar 1 [Epub ahead of print], Int J Dermatol 2007;46:303), nephrogenic systemic fibrosis (Archives 2007;131:145), post-surgical changes (Mayo Clin Proc 1996;71:552); mastitis (clinical)

Lipid rich carcinoma - Breast malignant chapter

Definition: 90%+ cells have prominent intracytoplasmic neutral lipid

Rare; 1-2% of breast carcinomas

Poor prognosis due to frequent (70%) nodal metastases at presentation

Axillary metastases may resemble histiocytes

Case reports: 53 year old woman (Acta Chir Belg 2008;108:115), 56 year old woman with focal chondroid metaplasia in tumor (Pathol Int 1998;48:912), 62 year old woman (Archives 2003;127:e396), 78 year old woman with solid alveolar pattern in tumor (Breast Cancer 1998;5:171); 55 year old man (Pathology 1995;27:280)

Gross: lobulated, variable circumscription, firm, 1 to 15 cm

Micro: 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

Cytology: cells with fine, variably sized cytoplasmic vacuoles (Acta Cytol 1997;41:561)

Positive stains: lipid stains (Sudan black, Oil red O on fresh tissue); PR, variable ER

Negative stains: glycogen, mucin

EM: 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)

DD: secretory carcinoma, glycogen-rich carcinoma, apocrine carcinoma, oncocytic carcinoma, myoepithelial carcinoma, epithelioid liposarcoma

References: Stanford University

Lobular carcinoma - Breast malignant chapter

Definition: invasive tumor associated with LCIS, composed of noncohesive cells that are individually dispersed or arranged in a single file pattern; minimal desmoplastic response

10% of all breast carcinomas; appears to be increasing over past 20 years

10-20% are bilateral; multicentric within same breast is more common; often not well seen on mammograms (may also be more extensive than clinically suspected)

Metastasizes to cerebrospinal fluid and leptomeninges (Archives 1991;115:507), bone marrow, GI tract, serosal surfaces, ovary, uterus (resembles low grade stromal sarcoma) more than other subtypes

Pan-keratin staining of negative bone marrow biopsies is recommended to detect metastases (AJSP 2000;24:1593, Hum Path 1994;25:781)

Lack of cohesion likely due to lack of expression of E-cadherin function, an adhesion molecule that is deleted or mutated in lobular carcinoma

Variants usually coexist with classic pattern

May have similar long term prognosis as infiltrating ductal carcinoma (Breast Cancer Res Treat 2008 Jul 16 [Epub ahead of print]), but see J Clin Oncol 2008;26:3006 (lobular has better survival at 6 years but worse at 10 years)

Recommended to report histologic (Nottingham) grade for these tumors (Breast Cancer Res Treat 2008;111:121)

Classic infiltrating lobular carcinoma - Breast malignant chapter

Case reports: with coexisting DCIS and LCIS, examined by comparative genomic hybridization (Hum Path 2004;35:759), metastases to tamoxifen associated endometrial polyps (Mod Path 2003;16:395)

Gross: may have mass with ill-defined margins but often no mass because of diffuse growth pattern

Micro: cells grow in single file (linear, Indian file) or targetoid pattern of noncohesive cells encircling ducts, loosely dispersed throughout fibrous matrix; tumor cells are small, uniform, round with minimal pleomorphism, evenly disbursed chromatin and no nucleoli (i.e. nuclear grade 1, like LCIS cells); commonly signet ring cells, intracellular lumina, intracellular mucin, +/- dense fibrous stroma with periductal and perivenous elastosis, LCIS (90%); may have dense lymphoid infiltrate; no glandular formation in classic cases, but may have preservation of normal glandular structures and “skip areas” uninvolved by tumor; < 10 mitoses/10 HPF, no necrosis

Bone marrow biopsies: highly suspicious features for metastatic disease are fibrosis, signet ring cells, cells with intracytoplasmic lumina, cells resembling histiocytes; architecture is often NOT disrupted

Cytology: moderate/highly cellular, pattern is predominantly or partly dissociated; usually small/intermediate cells with eccentric nuclei, intracytoplasmic lumina with or without signet ring cells in 57% (Acta Cytol 2000;44:169)

Positive stains: ER, PR, HMW keratin (helpful in bone marrow biopsy), mucicarmine (intracellular mucin), GCDFP-15 (30%)

Negative stains: p53, E-cadherin (complete absence suggests lobular carcinoma, but rarely is positive and may vary by antibody, AJSP 2008;32:773, Mod Path 2008 Jun 27 [Epub ahead of print]), HER2, Ki-67

Molecular: usually diploid; truncation mutations in E-cadherin gene (16q) or inactivation of wild-type allele

DD: lymphoma (resembles lobular metastases to axillary nodes or eyelid), carcinoma with neuroendocrine features, invasive ductal adenocarcinoma

References: AJSP 1990;14:12 (prognosis differs from variants), Mod Path 2005;18:621 (grading), Stanford University

Alveolar variant of lobular carcinoma- Breast malignant chapter

Micro: sharply outlined groups or nests of cells separated by fibrovascular tissue; may have osteoclast giant cells

Cytology: rosette like pattern

EM: similar to classic lobular tumors (Ultrastruct Pathol 1986;10:311)

DD: lobular carcinoma in situ

Basal like variant (subset) of invasive lobular carcinoma - Breast malignant chapter

Present in 17% of cases based on CK5/6 positivity (Hum Path 2008;39:331)

Associated with higher rate of grade 3 tumors (50%), ER negativity, but similar morphology otherwise

Negative stains: E-cadherin (by definition in above study)

Histiocytoid variant of lobular carcinoma - Breast malignant chapter

Also called myoblastomatoid variant of lobular carcinoma

Metastases may appear before diagnosis of primary tumor; may metastasize to eyelid

May be a variant of apocrine carcinoma (AJSP 1995;19:553)

Case reports: 93 year old woman with erythematous breast (Archives 2003;127:1626), histiocytoid metastases at autopsy (Archives 1986;110:759)

Micro: diffuse growth of tumor cells with abundant granular, foamy (vacuolated) cytoplasm and small bland nuclei; resembles histiocytes or granular cell tumor

Cytology: loosely cohesive tumor cells with abundant foamy to granular cytoplasm and bland nuclei (Pathol Int 2005;55:353)

Positive stains: GCDFP-15, mucicarmine, keratin, EMA, PAS, ER, PR

Negative stains: E-cadherin, Oil red O, CD68, lysozyme, S100, HER2

DD: lipid rich carcinoma (infiltrating ductal carcinoma with lipid in tumor cytoplasm, no mucin; very rare), granular cell tumor, xanthoma, xanthelasma, histiocytoma

References: Pathol Int 1998;48:549, Histopathology 1989;14:515

Pleomorphic variant of lobular carcinoma - Breast malignant chapter

Aggressive variant, associated with postmenopausal women (mean age 57 years, range 24-92)

Usually presents with stage 2-3 (locally advanced) disease

Micro: multifocal nodular aggregates of discohesive pleomorphic, high-grade tumor cells in dense fibrotic breast parenchyma; also single file and targetoid pattern of classic lobular carcinoma; often signet ring cells (29%), globoid plasmacytoid cells with eosinophilic or foamy or vacuolated cytoplasm, high nuclear grade and often multiple nucleoli; pleomorphic LCIS (45%) and classic LCIS (21%) often present; 3-10 mitoses per 10 HPF; usually no microcalcifications, no duct formation present

Cytology: more cellular than classic lobular, large tumor cells with single filing, tumor cells have cytoplasmic vacuoles and pleomorphic nuclei (Cancer 1997;81:29)

Positive stains: GCDFP-15 (71%, due to apocrine nature), HER2 (2+ to 3+ in 81%), p53 (48%), variable ER and PR

Negative stains: E-cadherin (Mod Path 2003;16:674)

Molecular: resembles infiltrating lobular carcinoma more than infiltrative ductal carcinoma (J Pathol 2008;215:231)

DD: chemotherapy or radiation treatment effect

Reference: AJSP 2000;24:1650, Hum Path 1992;23:1167, Hum Path 1992;23:655, Mod Path 1998;11:814

Signet ring variant of lobular carcinoma - Breast malignant chapter

Different entity than colloid carcinoma

Signet ring appearance may be due to blockage in secretion due to deletion of necessary enzyme

Associated with poor prognosis, metastases to GI tract and female genital tract (metastases may not have signet ring features)

Case reports: 68 year old woman (Pathol Int 2000;50:67)

Micro: “significant” number of cells with signet rings (20% in one study); cells not as bizarre as pleomorphic lobular carcinoma

Positive stains: mucin+ intracytoplasmic vacuoles (MUC1, 100%), CK7 (95%), ER (81%), PR, GCDFP-15, E-cadherin (29%) (AJCP 2004;121:884)

Negative stains: CDX2, HEPPAR1

EM: large membrane bound vacuole

References: Archives 1994;118:245, Mod Path 1993;6:516

Solid variant of lobular carcinoma - Breast malignant chapter

Cells grow in sheets that engulf normal structures and infiltrate fat

Little intervening stroma present

Resembles lymphoma

Case reports: Acta Cytol 1994;38:767

Trabecular variant of lobular carcinoma - Breast malignant chapter

Tumor cells arranged in 2-3 cell wide branching sheets

Tubulolobular variant of lobular carcinoma - Breast malignant chapter

See tubulolobular carcinoma

Luminal phenotype - Breast malignant chapter

Not in WHO breast classification

Based on gene expression profile studies; subtype reflects clustering of genes activated by ER signaling pathways

Luminal cytokeratins are CK 7/8, 18 and 19

Subtypes include luminal A (ER+, PR+, HER2-) and luminal B (ER+, PR-, HER2+)

Subtype A usually low grade, with slow growth

Positive stains: CK7, CK8/18, ER

Lymphoepithelioma-like carcinoma - Breast malignant chapter

Not in WHO breast classification

Rare in breast, more common in pharynx

Usually older patients

Case reports: 47 year old woman (Virchows Arch 2005;447:653), 50 year old woman with coexisting lymphocytic mastitis (Archives 2001;125:669), 65 year old woman (Mod Path 1994;7:129), HPV33+ tumor (Hum Path 2008;39:298)

Gross: multiple nodules, without circumscription

Micro: dense inflammatory infiltrate of mature round lymphocytes and lymphoid follicles with occasional plasma cells, histiocytes, eosinophils; also single large cells with abundant pale cytoplasm, large vesicular nuclei, prominent nucleolus and infiltrative pattern at margin of tumor; occasional mitotic figures; lymphoid cells “cuff” large cells in rosette-like manner; tumor cells are occasionally pleomorphic and multinucleated with lymphophagocytosis; also lobulocentric lymphoid infiltrate in hyalinized, sclerotic stroma

Positive stains: keratin (AE1/AE3, CAM5.2), EMA

Negative stains: EBV (Breast 2004;13:522), usually ER, PR, HER2 and E-cadherin (Ann Diagn Pathol 2004;8:309)

DD: medullary carcinoma (circumscribed, syncytial growth pattern)

Medullary carcinoma - Breast malignant chapter

Definition: well circumscribed, composed of poorly differentiated cells in syncytia or large sheets, with prominent lymphoplasmacytic infiltrate, scant fibrous stroma, no glandular structures, minimal DCIS

Uncommon, <1% of invasive breast carcinomas

Usually < 50 years old, often < 35 years old, common in Japanese, associated with BRCA1 mutations

“Medulla” refers to soft structure of marrow (tumors are often soft)

Slightly better prognosis than invasive ductal carcinoma NOS, even though high grade, aneuploid, ER/PR negative, p53 positive, high proliferation rates (Int J Radiat Oncol Biol Phys 2005;62:1040)

More activated cytotoxic lymphocytes than poorly differentiated ductal carcinomas (Mod Path 1999;12:1050, Mod Path 2008 May 9 [Epub ahead of print])

Considered a type of basal-like carcinoma (Breast Cancer Res. 2007;9:R24)

Gross: well circumscribed, often large, resembles fibroadenoma but without whorls; soft, fleshy, tan-gray; no desmoplasia, easy to cut, large areas of necrosis and hemorrhage

Micro: (1) indistinct cell borders (syncytial growth) making up 75% of tumor with large pleomorphic tumor cells containing large nuclei, prominent nucleoli, numerous mitotic figures; peripheral cells are more eosinophilic; (2) prominent lymphoplasmacytic infiltrate at periphery composed of T cells and IgA plasma cells; (3) pushing borders / well circumscribed

Also sparse stroma; variable spindle cell or squamous metaplasia, occasional bizarre tumor giant cells and extensive necrosis; no/minimal glandular differentiation, no intraductal growth or DCIS, no mucin, no calcification

Classify as medullary carcinoma if tumor has above three features; classify as atypical medullary carcinoma (or infiltrating ductal carcinoma) if tumor has 2 of 3 features listed above (atypical medullary carcinoma has similar prognosis as ductal carcinoma NOS)

Cytology: mononuclear inflammation, moderate/marked nuclear pleomorphism, nuclear irregularities (Diagn Cytopathol 2007;35:408)

Positive stains: CK 5/6 (94%), p53 (77%); also high Ki-67 index, HLA-DR, S100

Negative stains: ER, PR, HER2 amplification (Archives 2003;127:1458), EBV

Molecular: microsatellite instability is uncommon, in contrast to medullary colonic tumors (AJCP 2001;115:823); has similar genetic alterations as basal-like carcinomas; usually aneuploid; associated with BRCA1 mutations

DD: undifferentiated ductal carcinoma, lymphoepithelioma-like carcinoma, lymph node in axillary tail, collision tumor of invasive ductal NOS and MALT lymphoma (Archives 2004;128:99)

References: Hum Path 1988;19:1340, Stanford University

Metaplastic carcinoma - Breast malignant chapter

Definition: heterogeneous group of neoplasms with predominant component other than epithelial / glandular

Also called sarcomatoid carcinoma, carcinosarcoma (if mesenchymal component is malignant), spindle cell carcinoma, carcinoma with osteoclastic giant cells, carcinoma with osseous metaplasia, matrix producing carcinoma

Uncommon (<5% of breast carcinomas)

“Metaplastic” due to the transformation of epithelial component into a nonglandular component, such as spindle cells, squamous cells or heterologous elements.

More aggressive than invasive ductal NOS with larger tumor size, higher grade, poor prognosis; metastases tend to be hematogenous and not nodal (Ann Surg Oncol 2007;14:166, Breast Cancer Res Treat 2007;101:349)

Represents a type of basal-like carcinoma lacking EGFR and KIT activating mutations but exhibiting high EGFR copy number, primarily via aneusomy (Mol Cancer Ther 2008;7:944)

Tumors with no/minimal carcinoma-like component (but keratin+ sarcomatoid areas) behave more like sarcomas (AJSP 2005;29:1456)

Case reports: Case of the Week #6, 42 year old woman with breast mass, 80 year old woman with spindle cell type tumor, presenting as abscess (Int Semin Surg Oncol 2006;3:23), matrix producing tumor #1 (World J Surg Oncol 2008;6:60), #2 (Archives 2003;127:1385), #3 (Univ Pittsburgh), bilateral tumors, each clonal but different clones (Hum Path 2002;33:677), tumor with ductal, squamous and cartilaginous components (Mod Path 2001;14:1183), with melanocytic differentiation (Mod Path 1997;10:592), giant cystic tumor (Acta Cytol 2006;50:327)

Treatment: mastectomy or local excision

Gross: well circumscribed, median 3-4 cm, range 1-21 cm; usually firm, nodular; squamous or chondroid areas are pearly white to firm glistening areas on cut surface

Micro: sarcomatous component resembles fibromatosis (see separate section below), fibrosarcoma, MFH, chondrosarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma or combination; may need to look carefully for epithelial component (may be DCIS or invasive ductal carcinoma), may have osteoclast-like giant cells (Hum Path 1990;21:1142)

Some split into 3 categories: carcinoma with abundant matrix but without spindle cell component; spindle cell carcinoma with lesser amount of carcinoma or carcinosarcoma with biphasic pattern of malignant elements

Some classify as “with squamous metaplasia” or “with heterologous metaplasia”

Matrix producing carcinoma: rare; characterized by myxochondroid matrix formation; nest-like, sheet-like or cord-like growth of tumor cells with atypia, plus scattered tumor cells in myxoid or myxohyaline stroma; often hypocellular matrix-rich zone in tumor center (Mod Path 2008 Jul 11 [Epub ahead of print])

Recommended to test any keratin negative stromal tumor of the breast with myoepithelial markers before calling it a primary sarcoma (AJSP 2005;29:347)

Cytology: moderate/high cellularity (68%), necrosis (47%), cells are sarcomatoid, poorly differentiated carcinoma or squamous carcinoma; dual components usually not identified (J Clin Pathol 2007;60:529); matrix producing carcinomas have markedly atypical spindle cells with mitotic figures, also atypical chondrocytes; background is necrotic debris and myxoid substance displaying metachromasia; also clusters of carcinoma cells (Diagn Cytopathol 2006;34:772)

Positive stains: vimentin in mesenchymal elements, keratin (broad spectrum or 34betaE12) in spindle or epithelial cells, EGFR (76%, Breast Cancer Res 2005;7:R1028); squamous components are p63+; nonsquamous tumors express myoepithelial markers smooth muscle actin and p63 (nuclear staining, AJSP 2004;28:1506); also laminin 5 (AJSP 2008;32:345), CD10, CD29, 14-3-3-sigma (AJSP 2005;29:347); variably positive for CK5 and CK14 (Hum Path 2003;34:1009); chondroid cells are S100+

Negative stains: mucin, ER, PR, HER2, often S100

Molecular: epithelial and sarcoma components originate from same clone; EGFR overexpression in 2/3, 1/3 of these have EGFR gene amplification, but no activating EGFR mutations (J Pathol 2006;209:445)

DD: phyllodes tumor, primary breast sarcoma, nodular fasciitis, fibromatosis (negative for epithelial markers), myofibroblastic tumors, myoepithelial carcinoma (may have ducts with prominent myoepithelial cells at periphery, diffusely S100+)

References: AJSP 1998;22:188 (with osteocartilaginous heterologous elements), AJSP 1987;11:918 (early study), Stanford University

Adenocarcinoma with spindle cell metaplasia - Breast malignant chapter

Definition: adenocarcinoma with marked spindle cell transformation, but spindle cells are not squamous or mesenchymal

Usually post-menopausal women

Gross: well circumscribed

Micro: adenocarcinoma glands plus malignant tumor cells

Positive stains: CK7

Negative stains: CK5/6

Fibromatosis-like variant of metaplastic carcinoma - Breast malignant chapter

Definition: variant of metaplastic carcinoma resembling fibromatosis with propensity for local recurrence

Mean age 65 years (range, 40-85 years)

May recur locally or have distant metastases (AJSP 2001;25:1009), usually no nodal metastases

Case reports: 59 year old woman (Archives 2006;130:e81), 77 year old woman (World J Surg Oncol 2007;5:24)

Gross: mean 3 cm (1-7 cm), well defined borders

Micro: fibromatosis-like or myofibroblastic-like growth pattern of bland spindle cells in prominent collagenous stroma, infiltrative borders, usually inflammatory infiltrate; <5% of tumor is composed of carcinoma or epithelial elements; low mitotic activity

Positive stains: cytokeratin for epithelial elements (high molecular weight subtypes), p63, smooth muscle actin (usually only in keratin negative cells)

Negative stains: ER, PR, HER2

DD: benign or malignant spindle cell lesions (keratin negative) including pseudoangiomatous stromal hyperplasia, myofibroblastoma, solitary fibrous tumor, nodular fasciitis, primary mammary fibromatosis, myoepithelial carcinoma, melanoma, fibrosarcoma

Spindle cell subtype of metaplastic carcinoma - Breast malignant chapter

Aggressive, high rate of extranodal metastases but low rate of nodal metastases (AJSP 2006;30:300)

High rate of local relapse (AJSP 2005;29:1456)

Metastases to breast - Breast malignant chapter

Rare (1-2% of breast tumors), usually from contralateral breast (Archives 2008;132:931); also lung, melanoma, ovary, kidney, stomach, thyroid (World J Surg Oncol 2007;5:74)

Metastatic tumors are often superficial (in soft tissue), well-circumscribed firm nodules, without skin retraction or peau d’orange

Metastatic ovarian or peritoneal serous carcinoma to breast or axilla is rare but may resemble poorly differentiated ductal carcinoma or micropapillary carcinoma; usually occurs in patients with advanced disease; tumors have papillary architecture, often WT1+ and GCDFP-15 negative (AJSP 2004;28:1646, AJSP 1993;17:193), although breast mucinous carcinomas may also be WT1+ (Mod Path 2008 May 9 [Epub ahead of print])

In children, rhabdomyosarcoma (alveolar variant) is most common metastasis to breast

Usually reflects disseminated disease

Case reports: colonic carcinoid (Archives 2003;127:1373), lung small cell carcinoma (Diagn Cytopathol 2009;37:208), melanoma-amelanotic spindle cell (Diagn Cytopathol 2000;22:246), pancreatic islet cell tumor in child (AJSP 2006;30:912), renal carcinoid tumor (Am J Surg 2006;191:799, Diagn Cytopathol 2007;35:306), renal cell carcinoma (World J Surg Oncol 2007;5:25), small intestinal carcinoid #1 (Archives 2004;128:292), #2 (World J Surg Oncol 2006;4:15)

Gross: nodular, solitary, well circumscribed

Micro: most important feature is that it does not resemble a primary breast carcinoma; usually no DCIS, although infiltrative pattern may resemble DCIS (Ann Diagn Pathol 2001;5:15)

Negative stains: GCDFP-15, ER, PR (usually)

Micropapillary carcinoma - Breast malignant chapter

Definition: tumor composed of small clusters of cells within clear stromal spaces resembling dilated vascular channels

Rare, <2% of invasive breast cancers have substantial micropapillary pattern

First described by Tavassoli (Mod Path 1993;6:660)

Mean age 59 years, range 25-92 years

Morphologically similar to micropapillary tumors of bladder, lung and major salivary glands

Very aggressive with poor prognosis (Adv Anat Path 2004;11:297), 95% have lymph node metastases at presentation; 70% recur, 50% die of disease

Similar prognosis as other breast carcinoma subtypes if node status, tumor size and other classic prognostic markers are considered (Hum Path 1999;30:1459)

Note: focal component found in 6% of all breast carcinomas; these cases have same poor prognosis regardless of amount of micropapillary component (Mod Path 2001;14:836, AJCP 2006;126:740); exception is that presence of micropapillary pattern in mucinous/colloid carcinoma of breast has no clinical significance (Int J Surg Pathol 2008;16:251)

May be caused by reversal of cell polarity and MUC1 expression, causing detachment of tumor cells from stroma, promoting their spread and leading to early nodal metastases (Mod Path 2004;17:1045); Sialyl Lewis X/CD15s, the ligand of E-selectin, also exhibits reversed cell polarity (Int J Surg Pathol 2008 Jul 8 [Epub ahead of print])

Tumor infiltrating lymphocytes usually lack cytotoxic phenotype (Mod Path 2008 May 9 [Epub ahead of print])

Case reports: Case of the week #4, 66 year old man (Can J Surg 2005;48:156)

Gross: mean tumor size 2 cm, range 0.1 to 10 cm, lobulated outline

Micro: well formed angular avascular papillary clusters or morula-like epithelial groups of cells without a fibrovascular core, floating in aqueous or mucinous material in lymphatic-like spaces (but without a definite lining); cells have abundant eosinophilic cytoplasm, round vesicular nuclei and prominent nucleoli; also fibrocollagenous stroma; extensive true angiolymphatic invasion; often psammoma bodies; variable histologic grade; minimal mitotic activity, no necrosis, no lymphocytic inflammation

Cytology: angulated clusters, abortive papillae and isolated malignant cells; staghorn epithelial structures (35%) (Pathology 2007;39:401); no fibrovascular cores (Cancer 2002;96:280)

Positive stains: MUC1 (on stroma-facing surface of cell clusters [basal], which accentuates outlines of micropapillary units to form a distinct band on this surface), HER2 (95%), p53 (70%), bcl-2 (70%), ER and PR (20-35%), GCDFP-15 (30%)

Negative stains: MUC2, CK5, CK20, c-kit/CD117, EGFR (Archives 2005;129:1277), WT1 (usually)

Molecular: high cyclin D1 expression, high proliferation rates, MYC (8q24) amplification (J Pathol 2008;215:398)

EM: secretory activity in stroma-facing surface of tumor cells

DD: metastatic ovarian papillary serous carcinoma (WT1+, GCDFP15-, Hum Path 2008;39:666), extensive lymphovascular invasion by a primary or metastatic breast carcinoma

References: Mod Path 1999;12:499, AJCP 2004;121:857, AJR 2002;179:927-931, Stanford University

Mixed ductal and lobular carcinoma - Breast malignant chapter

Not in WHO breast classification

4% of breast carcinomas

89% have DCIS, 31% have LCIS

41% have positive lymph nodes at diagnosis

No distinct clinical features (Breast Cancer Res Treat 2008 Apr 11 [Epub ahead of print])

Micro: definite features of invasive ductal carcinoma and invasive lobular carcinoma in same tumor

DD: tubulolobular carcinoma, collision of two separate neoplasms

Mucin producing carcinomas - Breast malignant chapter

Colloid/mucinous carcinoma

Mucinous cystadenocarcinoma

Columnar cell mucinous carcinoma

Signet ring carcinoma

Ductal carcinoma NOS with focal mucin production

Mucinous cystadenocarcinoma and columnar cell mucinous carcinoma - Breast malignant chapter

Definition: carcinoma composed of tall columnar cells with basal, bland nuclei and abundant intracytoplasmic mucin; either grossly cystic (mucinous cystadenocarcinoma) or solid (columnar cell mucinous carcinoma)

Very rare as primary breast tumor (<25 cases reported)

Resembles similar tumors of ovary and pancreas

Mean age 58-68 years, range 49-96 years (AJSP 1998;22:698)

May have more favorable prognosis than common breast carcinomas

Case reports: 96 year old woman (Archives 2003;127:1031), coexisting with infiltrating ductal carcinoma (Pathol Int 2004;54:781)

Gross: multicystic, up to 19 cm, resembles ovarian and pancreatic cystadenocarcinoma, cystic hypersecretory carcinoma of breast

Micro: 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

Positive stains: CK7, Ki-67 (high % of cells)

Negative stains: CK20, ER, PR

DD: colloid/mucinous carcinoma, cystic hypersecretory carcinoma, metastatic tumor

Mucoepidermoid carcinoma - Breast malignant chapter

Rare; high grade or low grade (Neoplasma 2007;54:168)

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 (Archives 1981;105:612), 54 year old woman (Pathol Int 2006;56:549), low grade tumors (Archives 1979;103:196)

Micro: mixture of neoplastic mucus-secreting, squamous and intermediate cells

Cytology: 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, CEA; mucin is PAS+

EM: intermediate cells are modified myoepithelial cells (Hum Path 1985;16:941)

Myoepithelial carcinoma - Breast malignant chapter

Definition: rare tumor composed solely of cytologically malignant myoepithelial cells with mitotic activity

Also called malignant myoepithelioma

Mean age 60 years; 2 and 5 year survival is 88% and 55% (Eur J Surg Oncol 2004;30:357)

Case reports: 52 year old woman with infiltrating tumor (Diagn Pathol 2008;3:7), 70 year old woman (Br J Radiol 2005;78:444), tumor arising in adenomyoepithelioma (Pathol Int 2006;56:211)

Treatment: complete excision with negative margins

Gross: up to 21 cm, well defined with focal marginal irregularity, may be stellate; large tumors may have hemorrhage and necrosis

Micro: infiltrating spindle cells with fibrillar eosinophilic cytoplasm; tumor appears to arise from myoepithelial cells of ductules at periphery of lesion; cells have variable atypia; mitotic figures common, but may be less than 4/10 HPF; may have clear cells (Tohoku J Exp Med 2003;200:103); may have necrosis

Cytology: cohesive cell groups composed of spindle cells with atypical cigar-shaped nuclei; also epithelioid cells, mitotic figures

Positive stains: myoepithelial markers - smooth muscle actin, S100, p63, and CD10; also cytokeratin (pankeratin and CK14), vimentin

Negative stains: ER, PR

EM: perinuclear tonofilaments, subplasmalemmal bundles of microfilaments with dense bodies, intermediate junctions, poorly developed desmosomes, pinocytic vesicles, fragmented external lamina (Int J Surg Pathol 2002;10:281)

DD: spindle cell carcinoma (negative for myoepithelial markers), fibromatosis (no dominant nodule), myofibroblastic lesions (usually no dominant nodule, keratin negative)

References: J Clin Pathol 2003;56:497

Neuroendocrine carcinoma - Breast malignant chapter

Definition: carcinoma with neuroendocrine features in at least 50% of cells; often (although not consistently) used to refer to cases lacking another specific histologic type, such as solid papillary, mucinous/colloid or micropapillary; usually restricted to low grade tumors (high grade tumors are usually considered small cell carcinoma)

Also called endocrine carcinoma or solid cohesive neuroendocrine carcinoma; some cases formerly called carcinoid tumor (Eur J Surg Oncol 1995;21:609)

See also small cell carcinoma (also called small cell neuroendocrine carcinoma, but a different entity)

Up to 5% of all breast carcinomas, depending on how defined

Frequency increases with age

Similar clinical presentation as ductal NOS; i.e. no carcinoid syndrome is present

Similar prognosis as ductal NOS

Apocrine phenotype (androgen receptor positive in 50% of cells) is present in elderly women (Mod Path 2001;14:768)

Case reports: presenting as perianal mass (Clin Breast Cancer 2007;7:892), presenting as kidney and adrenal metastases (Pathol Res Pract 2008 Jun 5 [Epub ahead of print]); metastases to skin (Am J Clin Dermatol 2007;8:379)

Treatment: similar to ductal carcinoma NOS, but possibly add somatostatin for nuclear scanning and treatment of metastatic disease (G Chir 2008;29:203, Breast 2008;17:111)

Gross: no distinctive gross features

Micro: small, low grade tumor cells in nests separated by fibrous tissue; rarely ribbons, rosettes or mitotic figures; usually no mucin, no DCIS; no specific histologic patterns (solid papillary, small cell or mucinous/colloid)

By definition, at least 50% of tumor cells express neuroendocrine markers; exclude tumors with neuroendocrine expression in <50% of cells

Cytology: markedly cellular with mostly dispersed tumor cells, also some loose clusters, acinus-like formations, small sheets, rosette like formations, ribbons; cells are small and regular with moderate cytoplasm, fairly uniform and round/oval nuclei, often plasmacytoid

with eccentric nuclei (Acta Cytol 1994;38:73, Indian J Pathol Microbiol 2007;50:65)

Positive stains: chromogranin, synaptophysin, neuron-specific enolase, ER, GCDFP-15 (50%), TTF1 (20%)

EM: dense core secretory granules

DD: lobular carcinoma, metastatic carcinoid tumor (Am J Surg 2006;191:799, Diagn Cytopathol 2007;35:306), other breast tumors with neuroendocrine features (small cell carcinoma, colloid carcinoma, invasive ductal carcinoma NOS with <50% neuroendocrine tumor cells), neuroendocrine DCIS

References: Stanford University

Large cell neuroendocrine carcinoma - Breast malignant chapter

WHO diagnostic category

Definition: poorly differentiated tumor composed of crowded large clusters of cells with moderate/abundant cytoplasm, nuclei with vesicular or finely granular chromatin, frequent mitotic figures (18+/10 HPF)

Micro: neuroendocrine differentiation morphologically and by immunohistochemistry; frequent necrosis

DD: metastatic carcinoid tumor or small cell carcinoma

Solid neuroendocrine carcinoma - Breast malignant chapter

WHO diagnostic category

Minimal publications directly on this topic

Micro: densely cellular, solid nests and trabeculae or spindled, plasmacytoid or large cell cells, separated by a delicate fibrovascular stroma; rarely rosettes or resembling carcinoid tumor; may originate from solid papillary DCIS, or resemble alveolar subtype of lobular carcinoma

Oncocytic carcinoma - Breast malignant chapter

Definition: composed of >70% oncocytic cells

Very rare (<10 cases reported), usually age 60+ years

Case reports: 46 year old woman (Zentralbl Allg Pathol 1987;133:279), 70 year old woman (Zentralbl Allg Pathol 1989;135:357), 76 year old man (Archives 1989;113:1396)

Micro: well circumscribed, abundant granular eosinophilic cytoplasm, low grade nuclei with conspicuous nucleolus; no/rare mitotic figures

Positive stains: anti-mitochondrial antibody

Negative stains: GCDFP-15

EM: numerous mitochondria dispersed throughout cell, occupying 60%+ of cytoplasm

DD: apocrine differentiation (GCDFP-15+, negative for antimitochondrial antibody)

References: AJSP 1998;22:221, Stanford University

Papillary carcinoma - invasive - Breast malignant chapter

Rare; invasive and in-situ tumors together are 1-2% of breast carcinomas in women

Note: literature often does NOT clearly differentiate between in situ and invasive disease