BREAST TUMORS-RARE SUBTYPES

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DISCUSSION ON WHO HISTOLOGICAL CLASSIFICATION OF BREAST TUMORS WITH EMPHASIS ON RARE SUBTYPES

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UPDATE ON WHO CLASSIFICATION OF malignant BREAST TUMORS WITH EMPHASIS ON RARE SUBTYPES:

UPDATE ON WHO CLASSIFICATION OF malignant BREAST TUMORS WITH EMPHASIS ON RARE SUBTYPES

WHO CLASSIFICATION:

WHO CLASSIFICATION 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

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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

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● 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

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Myoepithelial lesions ========================================================================= ● Myoepitheliosis ● Adenomyoepithelial adenosis ● Adenomyoepithelioma - 8983/0 ● Malignant myoepithelioma - 8982/3 Mesenchymal Tumors ========================================================================= ● 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

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Fibroepithelial Tumors ========================================================================= ● 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 Tumors of the nipple ========================================================================= ● 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 tumors - Tumors of the male breast ========================================================================= ● Gynaecomastia ● Carcinoma ● Invasive - 8500/3 ● In situ - 8500/2

Rare subtypes:

Rare subtypes

INVASIVE CRIBRIFORM CARCINOMA:

INVASIVE CRIBRIFORM CARCINOMA Definition Low grade infiltrating carcinoma with a cribriform pattern Diagnostic Criteria Irregular cribriform growth pattern Round and angular masses of cells embedded in desmoplastic stroma Sharply punched out round spaces Tubular carcinoma has same behavior so may constitute more than 10% Nuclear grade I in at least 90% of cells Slightly enlarged cells Uniform nuclei, inconspicuous nucleoli, uniform chromatin Pleomorphism minimal or absent Mitotic figures unusual

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Pure Mucinous Carcinoma of the Breast Definition A breast carcinoma of which at least one third of the volume of the tumor is extracellular mucin throughout Invasion is in the form of pools of stromal mucin containing neoplastic cells Diagnostic Criteria: Pools of extracellular mucin make up at least one third of volume throughout If focal areas are not at least 33% mucinous , designate as mixed mucinous / ductal i.e. if only some areas are 33% mucinous , call it mixed If mucin does not attain 33% threshhold in any area, designate as infiltrating ductal carcinoma with mucinous differentiation i.e. if no area makes it to 33% mucinuos , call it carcinoma with mucinous differentiation Detached epithelial elements present floating in the mucin May be trabecular , cribriform , micropapillary , sheet like or clumps No areas of the usual type of invasion of stroma in the absence of mucin If present, designate as mixed mucinous / ductal Usually low grade cytology In situ component may be present May be seen in association with neuroendocrine differentiation

APOCRINE CARCINOMA:

APOCRINE CARCINOMA Definition Breast carcinoma with abundant eosinophilic cytoplasm, large round nuclei and sharp cell borders Alternate / Historical Names Carcinoma with apocrine metaplasia Sweat gland carcinoma of the breast Diagnostic Criteria Clinically significant criteria have not generally been agreed upon Most describe some degree of abundant eosinophilic cytoplasm, sharp cell borders, round nuclei and prominent nucleoli Some simply refer to GCDFP15 positive carcinomas as apocrine Japaze 2005 has proposed the following criteria: At least 75% of microscopic fields must demonstrate the following features : Large cells with abundant eosinophilic cytoplasm Usually granular Nucleus to cytoplasm ratio of 1:2 or more Nuclei round, large and vesicular May be pleomorphic Sharply defined cell borders Minor (non-mandatory) criteria Prominent nucleoli in >50% of fields Apical cytoplasmic snouts into lumenal spaces

solid neuroendocrine carcinoma:

solid neuroendocrine carcinoma Diagnostic Criteria Diagnosis requires all of the following four criteria At least 50% of cells are neuroendocrine marker positive Most cases positive for chromogranin and/or synaptophysin Neuron specific enolase is not sufficiently specific for this diagnosis Lesser numbers of positive cells are seen in usual type breast carcinomas Growth in solid sheets or insular pattern Peripheral palisading common Stippled chromatin Low grade cytologic features Round, regular to mildly irregular nuclei up to 2-3x the size of a RBC No comedo necrosis Extracellular mucin is common May merge with mucinous carcinoma Frequently associated with endocrine DCIS Spindle cell variant Above criteria required Predominantly composed of spindle cells Subset of cells may be cuboidal and form glands Reported cases all low grade

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Medullary Carcinoma of the Breast Definition A rare breast carcinoma with a syncitial growth pattern and high grade cytology reported to have a good prognosis Diagnostic Criteria: Syncitial growth pattern in at least 75% of tumor Cell margins not distinct Heavy mononuclear inflammatory infiltrate Microscopically circumscribed No infiltration Absence of neoplastic ducts or glands High grade pleomorphic nuclei with prominent nucleoli

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Definition A rare (<1%) low grade breast carcinoma composed of cells with abundant granular or clear vacuolated cytoplasm Alternate / historical names Juvenile breast carcinoma Juvenile secretory carcinoma Diagnostic Criteria Abundant granular cytoplasm or clear vacuolated cytoplasm Tubule formation common, may have secretion in lumens Follicular pattern (thyroid-like) may be seen Secretory material in cells, lumens and stroma Mucicarmine , alcian blue and PAS positive, diastase resistant May have extracellular secretion Fibrous bands often prominent Low grade nuclear cytology Bland, uniform nuclei Mitotic figures rare Sheet-like growth with mainly circumscribed margins Occasional foci of infiltration are common Most common under age 30 Most common type of breast carcinoma in children May occur at any age In situ component is common SECRETORY CARCINOMA

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Adenoid Cystic Carcinoma of the Breast Definition Very rare type of breast carcinoma resembling adenoid cystic carcinoma of other sites Diagnostic Criteria: Biphasic cell population One population with phenotype of duct lining cells Surrounds small lumens CK5/6, CK7, CK8/18, C-KIT positive Small cells with sparse cytoplasm and indistinct nucleoli One population with phenotype of myoepithelial cells Surrounds many nests and basement membrane cores p63, actin positive Various growth patterns, usually at least focally cribriform Biphasic, cylindromatous Cribriform growth surrounding cores of basement membrane material PASd positive Continuous with surrounding basement membrane Indistinct true lumens, frequently discernable only on immunohistologic stains Trabecular Tubular Solid (predominantly myoepithelial cells) Basaloid (predominantly lumenal cells) Rarely exhibits sebaceous or squamous differentiation

SMALL CELL CARCINOMA (HIGH GRADE NEUROENDOCRINE CARCINOMA):

SMALL CELL CARCINOMA (HIGH GRADE NEUROENDOCRINE CARCINOMA) EXTRAMAMMARY ORIGIN NEEDS TO BE RULED OUT Diagnostic Criteria: Scant cytoplasm Fine granular chromatin Inconspicuous nucleoli High mitotic rate Necrosis common In situ small cell component may be present May be associated with other conventional breast carcinoma patterns

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SMALL CELL NEUROENDOCRINE CARCINOMA

Large cell neuroendocrine carcinoma:

Large cell neuroendocrine carcinoma Small nests of large tumor cells with faintly granular cytoplasm separated by dense collagen bundles Cytologic features : large cell size, polygonal shape, low nuclear- cytoplasmic ratio, finely granular eosinophilic cytoplasm, occasionally prominent nucleoli, peripheral palisading , mitosis, and necrosis

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LARGE CELL NEUROENDOCRINE CARCINOMA

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Invasive Micropapillary Carcinoma of the Breast Definition Breast carcinoma with a prominent (pseudo) micropapillary pattern Diagnostic Criteria Numerous small pseudo-papillary clusters of cells No fibrovascular cores Frequent central lumen formation in clusters Peripherally located nuclei frequently bulge out with knobby appearance, "the hedgehog" tumor Clusters surrounded by clear spaces One or only a few clusters per space Scant mucin rarely detectable in spaces Spaces surrounded by loose fibrocollagenous stroma Frequent high nuclear grade reported in some series Frequently has abundant eosinophilic cytoplasm Frequent lymphatic involvement Occasional psammoma bodies Pattern may be predominant or focal Frequently mixed with infiltrating ductal carcinoma Rarely mixed with other type

Metaplastic carcinoma:

Metaplastic carcinoma Diagnostic Criteria Must have a neoplastic component that is either squamous or non-epithelial Carcinoma mixed with a mesenchymal or other non-epithelial component May exhibit obviously malignant stroma May resemble pleomorphic MFH or fibrosarcoma May exhibit heterologous differentiation Usually osteosarcoma or chondrosarcoma Less commonly glioma , melanoma, rhabdomyosarcoma , angiosarcoma or liposarcoma Stroma may be composed of bland spindle cells (spindle cell carcinoma) p63 positive, often high molecular weight keratin positive May contain fibroblasts and or myofibroblasts May resemble nodular fasciitis or fibromatosis Mesenchymal component may be keratin positive in about half of cases High molecular weight keratin is most often positive Epithelial component may be sparse May be identified only by presence of keratin reactivity Broad spectrum and high molecular weight keratins are useful Squamous component may be cystic

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Carcinomas with metaplastic squamous components May be pure squamous or mixed with ductal carcinoma Low grade adenosquamous carcinoma May be considered as metaplastic carcinoma or as a distinct entity Most have a component of ductal carcinoma There are rare reports of metaplastic carcinoma associated with lobular, medullary , mucinous and tubular carcinoma DIFFERENTIALS TO BE CONSIDERED: Metaplastic carcinomas with bland spindle cells need to be distinguished from exuberant scars, fibromatosis and nodular fascitis and, more infrequently, from myofibroblastomas , PASH, and acute and chronic abscess with fat necrosis Metaplastic carcinomas with evident atypia must be distinguished from malignant phyllodes tumor and primary or metastatic sarcoma

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SPINDLE CELL METAPLASTIC CARCINOMA

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MIXED EPITHELIAL AND MESENCHYMAL METAPLASTIC CARCINOMA

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Lipid Rich Carcinoma of the Breast Definition Breast carcinoma exhibiting clear cytoplasm due to lipid Alternate / Historical Names Lipid secreting carcinoma Diagnostic Criteria Clear, multivacuolated or foamy cytoplasm May have areas of oxyphilic cytoplasm Abundant intracytoplasmic lipid Oil red O or Sudan III stain positive Requires unprocessed tissue May have any grade cytology Wide variety of patterns Nests, cords, sheets, alveoli

“UNCLASSIFIED” DUE TO LACK OF SUFFICIENT INFORMATION:

“UNCLASSIFIED” DUE TO LACK OF SUFFICIENT INFORMATION Glycogen-rich clear cell carcinoma Oncocytic carcinoma Sebaceous carcinoma

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