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Breast malignant, males, children

Superpage - Carcinoma subtypes

Revised: 12 December 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Ductal carcinoma, NOS - general


Reviewers: Nat Pernick,, M.D., Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 15 November 2012, last major update September 2009
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Most common type of invasive breast carcinoma (75-80%)
● Lacks features of any other subtypes (i.e. is a diagnosis of exclusion)
● Arises from terminal duct lobular unit (as does lobular carcinoma), not ductal epithelium, so nomenclature is not actually accurate

Terminology
=========================================================================

● Also called invasive ductal carcinoma, no special / specific type (NST)

Clinical description
=========================================================================

● In patients >65 years, 87% of patients have “no special type” (Crit Rev Oncol Hematol 2008;67:263)
● Presence of focal neuroendocrine features has no prognostic significance (Hum Pathol 2003;34:1001)

Case reports
=========================================================================

● 50 year old woman with neuroendocrine carcinoma in morphologically composite tumor (Arch Pathol Lab Med 2003;127:e131)
● 71 year old woman with poorly differentiated tumor containing central necrosis, and resembling comedo DCIS (Case of the Week #236)

Gross description
=========================================================================

● Firm, poorly circumscribed, contracts from surrounding tissue, hard cartilaginous consistency, grating sound when scraped, streaks of chalky white elastotic stroma penetrating surrounding stroma (“crab like”), calcification
● Large tumors have hemorrhage, necrosis and cystic degeneration
● May be fixed to chest wall and cause skin dimpling or nipple retraction

Gross images
=========================================================================


       
Irregular borders, infiltrating into adjacent tissue


Central necrosis and hemorrhage


AFIP image


Large irregular mass

   
Possible central necrosis

Micro description
=========================================================================

● Sheets, nests, cords or individual cells
● Tubular formations are prominent in well differentiated tumors but absent in poorly differentiated tumors
● Tumor cells are more pleomorphic than lobular carcinoma
● Stroma usually desmoplastic and may obscure tumor cells
● Calcification in 60% of cases, variable necrosis
● Elastosis involves wall of vessels and ducts and causes grossly noted chalky streaks
● Often DCIS (up to 80%), perineural invasion (28%)
● Mitotic figures are often prominent
● Mast cells are associated with low grade tumors
● Uncommon features: eosinophils (BMC Cancer 2007;7:165), intraluminal crystalloids (Arch Pathol Lab Med 1997;121:593)
● No myoepithelial cell lining (as seen in DCIS or benign lesions)

Angiolymphatic invasion:
● In 35% - differs from tissue retraction because:
      (a) occurs outside margin of carcinoma
      (b) does not conform precisely to space it is in
      (c) endothelial lining is present and is CD31+, Factor VIII+
      (d) blood vessels are in vicinity
      (e) see also Prognostic Factors-Angiolymphatic invasion

Micro images
=========================================================================


See other subtypes and topics for more images


Common histologic features:


Infiltration of fibroadipose


With cribriform DCIS


Occult invasive carcinoma and DCIS (arrows) - AFIP


Primary tumor with lymphocytic infiltration and fibrous stromal reaction that contains invasive carcinoma around a duct with DCIS

           
Resembling comedo DCIS but negative for myoepithelial markers (cocktail)


Desmoplastic stroma


Focal lobular features


Multinucleated giant cells (arrows)


Minimal tumor in core biopsy (fig 3a and 3b)


Perineural invasion (AFIP)



Angiolymphatic invasion:


Various image


Arrow points to possible blood vessel invaded by carcinoma #1 (AFIP)


#2-elastic stain accentuates the venous elastica involved by carcinoma and an artery below


Not angiolymphatic invasion, but shrinkage artifact with partly necrotic tumor in space created by shrinkage,
no endothelial cells are present, elastic stain highlights elastic tissue in walls of vessels; marked
lymphoplasmacytic infiltrate



Not angiolymphatic invasion


Grading:

               
Low grade

   
Intermediate grade

           
High grade



Stains:


ER+


E-cadherin+


Mast cells (stained with tryptase) are associated with low grade ER+ tumors



Other images:


PR+

Calponin negative (normal ducts are positive)


Cytology description
=========================================================================

● Can use cellular pleomorphism, nuclear size, nuclear margin, nucleoli, naked tumor nuclei and mitoses to assess cytologic tumor grade, which correlates with histologic grade (Diagn Cytopathol 2003;29:185)

Cytology images
=========================================================================


   
Ductal carcinoma, Figure A

   
Poorly differentiated ductal carcinoma

Virtual slides
=========================================================================



Core biopsy


Invasive ductal carcinoma

Other: With cancerization of lobules

Positive stains
=========================================================================

● CK8/18, CK19, CK7, EMA, E-cadherin (Am J Clin Pathol 2006;125:377), ER (70%)
● Also milk fat globule, lactalbumin, CEA, B72.3, BCA-225
● Glycogen (60%), mucin (moderate/marked in 20%), cytokeratin 5/6 (30%)
● S100 (10-45%), HER2 (15-30%), RCC Ma (renal cell carcinoma marker)
● CD5 clone 4C7 (Arch Pathol Lab Med 2001;125:781)
Note: laminin, collagen IV and myoepithelial markers often show no or discontinuous staining

Negative stains
=========================================================================

● CK20
Myoepithelial markers - p63 (positive in benign lesions, Am J Surg Pathol 2001;25:1054), CD10 (Mod Pathol 2002;15:397), calponin

Electron microscopy
=========================================================================

● Glandular differentiation (microvilli and terminal bars on luminal side)

Differential diagnosis
=========================================================================

● Cases with necrosis may resemble DCIS (J Med Case Reports 2007;8:83)

Videos
=========================================================================




Additional references
=========================================================================

Stanford University



With choriocarcinomatous features


Reviewer: Monika Roychowdhury, M.D., (see Reviewers page)
Revised: 4 October 2012, last major update October 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.
PubMed Search: breast choriocarcinomatous
Broken links/comments: click here or email CopyrightPathOut@gmail.com, subject=breastmalignantductalNOSchoriocarcinomatous

General
=========================================================================

● Rare tumor (< 50 cases reported) with choriocarcinomatous differentiation, first described in 1981 (Am J Surg Pathol 1981;5:773, Arch Pathol Lab Med 2011;135:1097)
● Histologic origin of syncytiotrophoblastic cells is unclear - most plausible theory is metaplastic process
● Part of WHO classification
● Often elevated serum beta-hCG (although nonspecific)

Case reports
=========================================================================

● Two cases (Ann Diagn Pathol 2004;8:74)
● Choriocarcinomatous and neuroendocrine features (Sao Paulo Med J 2001;119:154)

Clinical features
=========================================================================

● Rapidly growing palpable mass indistinguishable from conventional breast carcinoma
● Usually characterized by locally advanced disease and poor prognosis

Treatment
=========================================================================

● Usually surgical resection; chemotherapeutic regimen unclear since tumor is rare

Gross description
=========================================================================

● Tumor size ranges from 1-10 cm
● Cut surface may be hemorrhagic
● Skin ulceration may be present and correlates with size and advanced stage

Micro description
=========================================================================

● Markedly pleomorphic multinucleated choriocarcinomatous cells with abundant eosinophilic cytoplasm and occasional cytoplasmic vacuoles
● Associated with ductal carcinoma in situ, invasive ductal carcinoma, and frank metaplastic carcinoma with distinctive heterologous components or sarcomatoid areas

Micro images
=========================================================================


   
Multinucleated giant cells with atypical nuclei that are hCG+

   
Metaplastic carcinoma with areas of choriocarcinomatous differentiation


Metastatic choriocarcinoma to breast, for comparison

Cytology description
=========================================================================

● Abundant multinucleated giant cells with highly pleomorphic tumor cells in a hemorrhagic necrotic background (Acta Cytol 2008;52:99)

Positive stains
=========================================================================

● Giant cells: human placental lactogen, beta-hCG (Breast J 2002;8:244)

Negative stains
=========================================================================

● Giant cells: ER/PR (usually)

Differential diagnosis
=========================================================================

Metastatic choriocarcinoma to breast: clinically history; no usual type breast carcinoma, no DCIS (AJR Am J Roentgenol 2005;184:S53)



Carcinoma with melanotic features


Reviewer: Monika Roychowdhury, M.D., Daniel Visscher, M.D., (see Reviewers page)
Revised: 2 October 2012, last major update October 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Part of WHO classification
● Combination of ductal carcinoma and melanoma
● Rare

Case reports
=========================================================================

● 38 year old woman (Pathol Int 2009;59:676)
● Ductal carcinoma with differentiation to melanoma (Am J Surg Pathol 1999;23:1280)

Differential diagnosis
=========================================================================

● Lipofuscin (Histopathology 2000;37:456) or melanin pigment (Ultrastruct Pathol 2000;24:109, Br J Dermatol 1998;139:287) in otherwise typical ductal carcinoma
● Metastatic melanoma



Ductal NOS mixed type carcinoma


Reviewer: Monika Roychowdhury, M.D., (see Reviewers page)
Revised: 10 October 2012, last major update October 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Part of WHO classification
● Ductal NOS: >50% must have non-specialized pattern
● Mixed type carcinoma: 10-49% of tumor has ductal NOS pattern and remainder has a special pattern
● Mixed types are either mixed ductal and special type or mixed ductal and lobular carcinoma

Clinical description
=========================================================================

● For special types with good prognosis when pure, mixed tumors often have intermediate prognosis between special type and ductal NOS



Ductal NOS - Carcinoma with osteoclastic giant cells


Reviewer: Monika Roychowdhury, M.D., (see Reviewers page)
Revised: 10 October 2012, last major update October 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Part of WHO classification
● Osteoclastic giant cells are present in stroma
● Presence of giant cells does not alter prognosis

Case reports
=========================================================================

● 44 year old and 83 year old women (Diagn Pathol 2010;23:55)
● 46 year old woman (Radiographics 2002;22:691)
● 51 year old woman with pleomorphic carcinoma and prominent osteoclastic giant cells (Pathol Int 2009;59:91)
● Cases with neuroendocrine carcinoma (Pathologica 2008;100:176)

Gross description
=========================================================================

● Often brown due to vascular stroma with hemosiderin

Micro description
=========================================================================

● Giant cells are associated with vascular stroma with extravasated red blood cells and hemosiderin, also chronic inflammatory cells and fibroblasts
● Giant cells have variable size and variable numbers of nuclei
● Similar histologic features in nodal metastases and recurrences (Arch Pathol Lab Med 1986;110:636)
● Carcinoma component may be any type

Micro images
=========================================================================



Whole mount


Tubular growth, vascular stroma and hemorrhage

   
Giant cells in stroma and intraductal spaces

       
Various images, contributed by Semir Vranic

   
Various images

Various images: differentiated well cribriform carcinoma #1, #2, #3, osteoclast like giant cells in close contact to tumor cells

Cytology description
=========================================================================

● Abundant giant cells and mononucleated stromal cells associated with carcinoma cells (Diagn Cytopathol 2005;33:246)

Positive stains
=========================================================================

Osteoclastic giant cells: CD68; also acid phosphatase, lysosome, nonspecific esterase; also MMP9, TRAP, cathepsin K

Negative stains
=========================================================================

Osteoclastic giant cells: S100, actin, keratin, EMA, ER, PR, alkaline phosphatase

Electron microscopic description
=========================================================================

● Osteoclasts are histiocytes

Additional References
=========================================================================

Ann Pathol 1989;9:189, Hum Pathol 1990;21:1142
Stanford University



Pleomorphic carcinoma variant of ductal NOS


Reviewer: Monika Roychowdhury, M.D., (see Reviewers page)
Revised: 10 October 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Part of WHO classification
● Variant of high grade ductal NOS with pleomorphic and bizarre tumor cells comprising 50% or more of tumor cells

Clinical description
=========================================================================

● Aggressive behavior

Case reports
=========================================================================

● 83 year old woman with pleomorphic tumor with predominantly micropapillary features (Pathol Int 2007;57:694)

Micro description
=========================================================================

● 50%+ of tumor has pleomorphic cell population (> 6X variation in nuclear size) (Histopathology 2000;36:505)
● Excludes tumors of lobular origin
● Adjacent DCIS or classic ductal carcinoma in 73%
● Usually brisk mitotic activity

Positive stains
=========================================================================

● CAM 5.2, pan-keratin, EMA
● p53 (2/3), S100 (1/3)

Negative stains
=========================================================================

● ER, PR, bcl2

Differential diagnosis
=========================================================================

● Sarcoma

Additional references
=========================================================================

Pathologica 2011;103:68



Classic infiltrating lobular carcinoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 29 October 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

See variants: alveolar, basal-like, histiocytoid, pleomorphic, signet-ring, solid, trabecular

General
=========================================================================

● Invasive tumor associated with LCIS, composed of noncohesive cells that are individually dispersed or arranged in a single file pattern (Stanford University)
● Minimal desmoplastic response

Clinical features
=========================================================================

● 10% of all breast carcinomas
● Incidence decreasing in US (Cancer Epidemiol Biomarkers Prev 2009;18:1763)
● 10-20% are bilateral; multicentricity within same breast is more common than invasive ductal carcinoma
● Often not well seen on mammograms, and may be more extensive than clinically suspected
● Metastasizes to bone marrow, cerebrospinal fluid and leptomeninges (Arch Pathol Lab Med 1991;115:507), GI tract, ovary, serosal surfaces, uterus (resembles low grade stromal sarcoma) more than other subtypes
● Pan-keratin staining of negative bone marrow biopsies is recommended to detect metastases (Am J Surg Pathol 2000;24:1593, Hum Pathol 1994;25:781), but has minimal value for nodal metastases (Hum Pathol 2008;39:1011)
● Lack of cohesion due to alterations in E-cadherin, an adhesion molecule that is deleted or mutated
● Variants usually coexist with classic pattern

Case reports
=========================================================================

● 58 year old man with carcinomatosis (Am J Surg Pathol 2009;33:470)
● 60 year old woman whose tumor had pools of extracellular mucin (Pathol Int 2009;59:405)
● 61 year old woman with c-kit+ gastric metastasis resembling GIST tumor (Breast Cancer 2010;17:303)
● 70 year old woman presenting with orbital mass (Intern Med 2012;51:1635)
● 88 year old woman with anal metastasis (World J Gastroenterol 2009;15:1388)
● With coexisting DCIS and LCIS, examined by comparative genomic hybridization (Hum Pathol 2004;35:759)
● Metastases to tamoxifen associated endometrial polyps (Mod Pathol 2003;16:395)
● Metastasis to uterus associated with anastrozole (anti-estrogen) therapy (Onkologie 2009;32:424)

Treatment
=========================================================================

● Classic variant has better prognosis than non-classic variants overall (Cancer 2008;113:1511, Am J Surg Pathol 1990;14:12)
● May have similar long term prognosis as infiltrating ductal carcinoma (Breast Cancer Res Treat 2009;117:211), but see J Clin Oncol 2008;26:3006 (lobular has better survival at 6 years but worse survival at 10 years)
● In one study, 12 year local relapse free survival was 89%; predictors of relapse were positive margins, age >50 years and contralateral breast cancer (Eur J Surg Oncol 2010;36:176)

Gross description
=========================================================================

● Mass with ill-defined margins; often no mass because of diffuse growth pattern

Gross images
=========================================================================



Solid firm mass

   
Infiltration into adipose tissue


Anal metastasis

Other images: Multiple foci with irregular margins #1, #2

Micro description
=========================================================================

● Cells grow in single file (linear, Indian file) or targetoid pattern of noncohesive cells encircling ducts, loosely dispersed throughout fibrous matrix
● Tumor cells are usually 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, LCIS (90%)
● Variable dense fibrous stroma with periductal and perivenous elastosis
● 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
● Histologic grading is recommended (Mod Pathol 2005;18:621)
● Most tumors are histologic grade 2 (Breast Cancer Res Treat 2008;111:121)
● 2 tiered nuclear grading system may reduce interobserver variability (Ann Diagn Pathol 2009;13:223), as may nuclear and proliferation grading system (Ann Clin Lab Sci 2009;39:25)

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

Micro images
=========================================================================



Single file pattern

           
Classic features

       
Single dyscohesive cells


Minute focus (arrow) of tumor around a small duct (AFIP)


Classic targetoid (bulls eye) pattern of tumor cells around duct (AFIP)


With LCIS


Minimal tumor in core biopsy (Fig 1A/1B)

   
Grade I of III-minimal nuclear pleomorphism

   
Grade II of III-moderate nuclear pleomorphism


Grade III of III-severe nuclear pleomorphism


Tumor of male breast

Invasive lobular carcinoma within fibroadenoma:

Left to right: H&E (2), ER, CK5/6, E-cadherin

Metastases:
           
Endometrial polyp: H&E and AE1/AE3


Lymph node


Soft tissue

   
Stomach

Other images: single file pattern, prominent intracytoplasmic mucin, targetoid pattern #1, #2, with LCIS #1, #2

Virtual slides
=========================================================================


   
Lobular carcinoma


With LCIS

Cytology description
=========================================================================

● Moderate / highly cellular, pattern is predominantly or partly dissociated
● Usually small / intermediate cells with intracytoplasmic lumina in 57%, light cytoplasm
● Small, eccentric nuclei with finely granular chromatin (Acta Cytol 2000;44:169, Med Mol Morphol 2008;41:121, Cancer 2008;114:111)

Cytology images
=========================================================================



FNA shows small cells arranged in linear pattern (figure B)

Various images

Positive stains
=========================================================================

● ER, PR
● HMW keratin (helpful in bone marrow biopsy)
● Mucicarmine (intracellular mucin)
● GCDFP-15 (30%)
● PLEKHA7 (Hum Pathol 2012 Apr 25 [Epub ahead of print])

Negative stains
=========================================================================

● E-cadherin (complete absence suggests lobular carcinoma, but rarely is positive and may vary by antibody, Am J Surg Pathol 2008;32:773, Mod Pathol 2008;21:1224)
● p53, HER2, Ki-67

Molecular description
=========================================================================

● Usually diploid
● Truncation mutations in E-cadherin gene (16q) or inactivation of wild-type allele

Electron microscopic images
=========================================================================



Line of tumor cells surrounded by collagen, with cytokeratin bundles (arrows), but no basement membrane


Intracytoplasmic lumina lined by microvilli, elastic tissue (arrows) and collagen in stroma


Intracytoplasmic lumen with numerous microvilli and perinuclear mucin granules

Videos
=========================================================================




Differential diagnosis
=========================================================================

Lymphoma: resembles lobular metastases to axillary nodes or eyelid
Invasive ductal adenocarcinoma: may have focal lobular features, immunostains may be helpful (Appl Immunohistochem Mol Morphol 2012 May 16 [Epub ahead of print])
Invasive ductal carcinoma with neuroendocrine features



Alveolar variant of lobular carcinoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 29 October 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Clinical features
=========================================================================

● 4-15% of infiltrating lobular carcinoma cases (Br J Cancer 1989;60:605, Breast Cancer Res Treat 2012;133:713)
● Often postmenopausal women (Am J Clin Pathol 1986;85:1)
● May have poorer prognosis than classic lobular carcinoma (Cancer 2008;113:1511)

Case reports
=========================================================================

● 74 year old woman with synchronous classic and alveolar lobular carcinomas (Am J Surg Pathol 2011;35:1743)

Micro description
=========================================================================

● Sharply outlined (rounded) groups or nests of 20 or more cells, resembling alveoli, separated by delicate fibrovascular tissue
● May have osteoclast giant cells (Pathologica 1993;85:525)

Micro images
=========================================================================


       
Uniform alveolar growth pattern


Tumor cells in discrete rounded aggregates separated by fibrous stroma (AFIP)


E-cadherin negative


May have retained E-cadherin staining (fig d/e)

Cytology description
=========================================================================

● Rosette like pattern (Acta Cytol 2000;44:169)

Electron microscopy
=========================================================================

● Tumor cells are similar to classic lobular tumors, but nests of cells are surrounded by elongated fibroblasts or myofibroblasts (Ultrastruct Pathol 1986;10:311)

Differential diagnosis
=========================================================================

● Lobular carcinoma in situ - groups of cells have distinct myoepithelial layer and basement membrane
● Lymphoma - negative for epithelial markers, positive for lymphocytic markers



Basal-like variant (subset) of invasive lobular carcinoma


Reviewer: Monika Roychowdhury, M.D., (see Reviewers page)
Revised: 29 October 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Clinical description
=========================================================================

● Invasive lobular carcinoma cases include all molecular subtypes, include basal-like, and basal-like carcinomas include a variety of histologic subtypes (J Pathol 2008;216:141)
● CK5/6 positivity, part of definition of basal-like tumors, is present in 17% of lobular tumors (Hum Pathol 2008;39:331)
● Associated with grade 3 tumors (50%) and ER negativity, but similar morphology otherwise

Negative stains
=========================================================================

● E-cadherin



Histiocytoid variant of lobular carcinoma


Reviewer: Monika Roychowdhury, M.D., (see Reviewers page)
Revised: 15 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Diffuse growth of tumor cells with abundant granular, foamy (vacuolated) cytoplasm and small bland nuclei
● First described by Hood et al (Cancer 1973;31:793)

Terminology
=========================================================================

● Also called myoblastomatoid variant of lobular carcinoma

Clinical features
=========================================================================

● Metastases may appear before diagnosis of primary tumor
● May metastasize to eyelid
● May be a variant of apocrine carcinoma (Am J Surg Pathol 1995;19:553)

Case reports
=========================================================================

● 68 year old man with 2.5 cm mass (Ann Diagn Pathol 2011;15:190)
● 93 year old woman with erythematous breast (Arch Pathol Lab Med 2003;127:1626)
● Histiocytoid metastases at autopsy (Arch Pathol Lab Med 1986;110:759)
● Triple negative case (Breast J 2010;16:84)

Micro description
=========================================================================

● Diffuse growth of tumor cells with abundant granular, foamy (vacuolated) cytoplasm and small bland nuclei
● Resembles histiocytes or granular cell tumor

Micro images
=========================================================================


       
Tumor cells have abundant cytoplasm and vesicular nuclei, resembling histiocytes


Fig A: LCIS (arrows) and large cells in single file with focal targetoid growth, inset and
Fig B: finely granular pale pink cytoplasm; inset: intracytoplasmic lumina
Fig C: tumor infiltration of fat mimics fat necrosis, inset: GCDFP-15+
Fig D: E-Cadherin in LCIS and invasive tumor



Figures 1-2: H&E and stains

Cytology description
=========================================================================

● 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
● Also PAS, ER, PR

Negative stains
=========================================================================

● E-cadherin, Oil red O (fresh tissue), CD68
● Lysozyme, S100, HER2

Differential diagnosis
=========================================================================

Granular cell tumor: PAS+ cytoplasmic granules
Histiocytoma: no atypia, histiocytes are CD68+, keratin-
Lipid rich carcinoma: infiltrating ductal carcinoma with lipid in tumor cytoplasm, no mucin, very rare
Xanthelasma: lipid filled cells, often in eyelid
Xanthoma: no atypia

Additional references
=========================================================================

Pathol Int 1998;48:549, Histopathology 1989;14:515, J Clin Pathol 2011;64:654, Stanford University



Pleomorphic variant of lobular carcinoma


Reviewer: Monika Roychowdhury, M.D., (see Reviewers page)
Revised: 14 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Aggressive variant with high grade tumor cells

Epidemiology
=========================================================================

● Mean age 57 years, range 24-92 years

Clinical features
=========================================================================

● Presents at more advanced stage than classic lobular carcinoma (J Surg Oncol 2008;98:314)
● Traditionally considered to have aggressive clinical course (Am J Surg Pathol 2000;24:1650) but see Ann Diagn Pathol 2012;16:185
● Poorer clinical outcome: older patients, negative hormonal receptor status

Gross images
=========================================================================


Circumscribed tumor

Micro description
=========================================================================

● Multifocal nodular aggregates of dyscohesive, 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

Micro images
=========================================================================


           

           
Pleomorphic tumor cells

   
Signet ring type cells

   
With pleomorphic LCIS

               
Contributed by Dr. Semir Vranic

   
E-cadherin negative (staining of residual normal ducts), by Dr. Semir Vranic


p53

Other images: pleomorphic tumor cells,   E-cadherin negative

Cytology description
=========================================================================

● More cellular than classic lobular, large tumor cells with single filing, tumor cells have cytoplasmic vacuoles and pleomorphic nuclei (Cancer 1997;81:29)
● May have apocrine features and resemble atypical mesothelial cells (Diagn Cytopathol 2008;36:657)
Ductal lavage: similar features, although less striking, including epithelial cells in small clusters, single-file or isolated; also nuclear atypia, cytoplasmic vacuoles and signet ring features (Acta Cytol 2008;52:207)

Cytology images
=========================================================================


Various images

Virtual slides
=========================================================================



With ductal NOS

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 Pathol 2003;16:674), beta-catenin (membrane staining is absent, Appl Immunohistochem Mol Morphol 2007;15:260)
● 13% are triple negative (Histopathology 2012;61:365)

Molecular / cytogenetic description
=========================================================================

● Resembles infiltrating lobular carcinoma more than infiltrative ductal carcinoma (J Pathol 2008;215:231)
● Frequent gains on 1q and 16p, losses on 11q and 16q, and genomic amplifications of 8q24, 11q13, 12q13, 17q12 and 20q13 (Future Oncol 2009;5:233)
● More frequent p53 mutations than classic lobular (Cell Oncol (Dordr) 2012;35:111)

Differential diagnosis
=========================================================================

Chemotherapy or radiation treatment effect

Additional references
=========================================================================

Hum Pathol 1992;23:1167, Hum Pathol 1992;23:655, Mod Pathol 1998;11:814



Signet ring variant of lobular carcinoma


Reviewer: Monika Roychowdhury, M.D., (see Reviewers page)
Revised: 15 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● “Significant” number of cells with signet rings (20% in one study)
● First described in 1976 (Cancer 1976;37:828)
● Signet ring: a ring that can create a wax impression or seal to close an envelope or sign a document, in a secure, not easily copied way (image)

Clinical features
=========================================================================

● Rare
● Signet ring appearance may be due to blockage in secretion because of deletion of necessary enzyme, or to disruption of E-cadherin/beta-catenin complex (J Pathol 2007;212:278)
● Associated with poor prognosis, metastases to GI tract and female genital tract (metastases may not have signet ring features)

Case reports
=========================================================================

● 50 year old woman presenting with abnormal cervicovaginal pap smear (Acta Cytol 2000;44:824)
● 57 year old woman with tumor associated with papilloma (Cases J 2009;2:130)

Micro description
=========================================================================

● “Significant” number of cells with signet rings (20% in one study)
● Cells not as bizarre as pleomorphic lobular carcinoma
● Some lobular features

Micro images
=========================================================================



Mixed classic and signet ring morphology


Prominent signet ring cells


Vacuolated cytoplasm with crescentic nuclei


(AFIP)


Associated with papilloma


CK8

Other images: vacuolated cytoplasm with crescentic nuclei

Positive stains
=========================================================================

● Mucin+ intracytoplasmic vacuoles (MUC1, 100%), CK7 (95%)
● ER (91%), PR (91%)
● GCDFP-15
● E-cadherin (29%) (Am J Clin Pathol 2004;121:884)

Negative stains
=========================================================================

● CDX2, HepPar1

Electron microscopy
=========================================================================

● Large membrane bound vacuoles

Differential diagnosis
=========================================================================

● Signet ring cells can also be a component of ductal or mucinous/colloid carcinomas (Am J Clin Pathol 1980;73:31)
● GI metastasis (World J Gastroenterol 2006;12:2958)

Additional references
=========================================================================

Arch Pathol Lab Med 1994;118:245, Mod Pathol 1993;6:516



Solid variant of lobular carcinoma


Reviewer: Monika Roychowdhury, M.D., (see Reviewers page)
Revised: 15 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● First described in 1975 (Hum Pathol 1975;6:373)
● Cells grow in sheets that engulf normal structures and infiltrate fat, but have cytologic features of classic lobular carcinoma
● Little intervening stroma present
● Resembles lymphoma

Clinical features
=========================================================================

● In 1989, represented 6% of all lobular carcinomas, and had poorest survival of all subtypes (Br J Cancer 1989;60:605)

Case reports
=========================================================================

● Resembling non-Hodgkin's lymphoma (Acta Cytol 1994;38:767)

Micro images
=========================================================================



Diffuse tumor cell infiltration

   
Solid pattern, but cells are still separate and distinct


Pan-keratin


E-cadherin

Differential diagnosis
=========================================================================

Histiocytoid variant of lobular carcinoma: solid growth pattern, but with foamy to granular cytoplasmic change (Pathol Int 2005;55:353)



Trabecular variant of lobular carcinoma


Reviewer: Monika Roychowdhury, M.D., (see Reviewers page)
Revised: 15 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Classic lobular carcinoma infiltrating in trabeculae (linear bands) two to four cells thick
● Trabecula - supporting beam of bar, plural is trabeculae
● Trabeculae variant is usually not considered a distinct variant because it overlaps the classic and mixed patterns (Schnitt, Stuart J. (2009). Biopsy interpretation of the breast. Philadelphia, PA: Lippincott Williams & Wilkins.)

Electron microscopy description
=========================================================================

● Tumor cells are similar to classic lobular carcinoma (J Pathol 1985;145:39)
● Compared to LCIS, tumor cells are more irregular, with more organelles and filaments



Metaplastic carcinoma - general


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 25 September 2012, last major update September 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

See also subtypes / variants: fibromatosis-like,, matrix producing, spindle cell

Definition
=========================================================================

● Heterogeneous group of neoplasms with predominant component other than epithelial / glandular

Terminology
=========================================================================

● Also called carcinosarcoma (if mesenchymal component is malignant), carcinoma with osteoclastic giant cells and carcinoma with osseous metaplasia
● “Metaplastic” due to the transformation of epithelial component into a non-glandular component, such as spindle cells, squamous cells or heterologous elements

Clinical features
=========================================================================

● Uncommon (< 5% of breast carcinomas)
● More aggressive than invasive ductal NOS due to larger tumor size, higher grade
● 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 epidermal growth factor receptor and KIT activating mutations, but exhibiting high epidermal growth factor receptor copy number, primarily via aneusomy (Mol Cancer Ther 2008;7:944)

Case reports
=========================================================================

● 35 year old woman BRCA1 carrier (Breast Cancer 2011;18:137)
● 37 year old woman with giant cystic tumor (Acta Cytol 2006;50:327)
● 49 year old woman with metaplastic carcinoma of abdominal wall muscle (Breast Cancer 2012 Mar 2 [Epub ahead of print])
● 52 year old woman with CD117+ tumor (The Internet Journal of Pathology 2009;8:2)
● 52 year old woman with ductal, squamous and cartilaginous components in tumor (Mod Pathol 2001;14:1183)
● 57 year old woman with abscess (Int Semin Surg Oncol 2006;3:23)
● 66 year old woman with circumscribed mass (Case of the Week #6)
● 77 year old woman with extensive osseous differentiation (Breast 2008;17:314)
● Bilateral tumors, each clonal but different clones (Hum Pathol 2002;33:677)
● With melanocytic differentiation (Mod Pathol 1997;10:592)

Treatment
=========================================================================

● Mastectomy or local excision

Gross description
=========================================================================

● Well-circumscribed
● Median 3-4 cm, range 1-21 cm
● Usually firm, nodular
● Squamous or chondroid areas are pearly white to gray glistening areas on cut surface

Gross images
=========================================================================



Bisected squamous tumor (arrows at tumor margin)


Carcinoma with osteoclast-like giant cells

Causing skin ulceration

Sharply circumscribed tumor


Micro description
=========================================================================

● Sarcomatous component resembles fibromatosis (see variant), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma or osteosarcoma (see variant), rhabdomyosarcoma, spindle cells (see variant), angiosarcoma or combination
● May need to look carefully for epithelial component (may be ductal carcinoma in situ or invasive ductal carcinoma), may have osteoclast-like giant cells (Hum Pathol 1990;21:142)
● Some classify as “with squamous metaplasia” or “with heterologous metaplasia”
● Recommended to test any keratin negative stromal tumor of the breast with myoepithelial markers before calling it a primary sarcoma (Am J Surg Pathol 2005;29:347)

Micro images
=========================================================================


   
Epithelioid and spindled areas

               
Various images

                
With osteoclast-like giant cells                        Various images

                    
Case of the Week #6                                            CK7                             S100

   
Left: glandular component; right: glandular and squamous components

   
Left: squamous differentiation; right: ductal, squamous and cartilaginous components

   
Invasion patterns: left-irregular; right-DFSP like

               
Fibrosarcoma-like pattern

           
Angiomatoid pattern                                                                         Keratin+

          
Osteosarcoma-like         Low-grade spindle cell metaplastic carcinoma arising within papilloma

   
Nodal metastases

       
Keratin+ cells                                            Epithelium is keratin+, stroma is keratin-

       
H&E, EGFR and         EGFR                          EGFR and HER2 overexpression
EGFR-CISH                                                   in spindle cell carcinoma

           
Malignant squamous component                                             Storiform squamous type


Various images

AFIP images:
                                                         
Well differentiated epidermoid carcinoma                 Adenocarcinoma with a tubular pattern
and poorly differentiated adenocarcinoma                in the metaplastic spindle cell component
merge with the spindle cell component

                                                         
Carcinomatous glands are surrounded by an           Transition from adenocarcinoma
undifferentiated round cell proliferation                     to spindle cell pattern
that merges with the spindle cells

                                                         
Poorly differentiated carcinoma with traces              Invasive adenocarcinoma at upper right, but most
of squamous metaplasia giving rise to the                tumor is solid pseudosarcomatous metaplastic
spindle cell component                                                elements with pale, serpiginous areas of necrosis

                                                         
Adenocarcinoma with transition to                             Recurrent metaplastic carcinoma 4 years
undifferentiated carcinoma, an intermediate             after mastectomy, tumor was initially
step in conversion to spindle cell metaplasia            interpreted as a radiation induced sarcoma

                                                             
Osteoclast-like giant cells in stroma                           Resembles giant cell tumor of bone
associated with the carcinoma component                due to osteoclast-like giant cells

Cytology description
=========================================================================

● 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)
● Also clusters of carcinoma cells (Diagn Cytopathol 2006;34:772)

Virtual slides
=========================================================================


   
Left: two tumors; right: with myoepithelial and myxoid components

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+
● Non-squamous tumors express smooth muscle actin and p63 (nuclear staining, Am J Surg Pathol 2004;28:1506)
● Chondroid cells are S100+
● Also laminin 5 (Am J Surg Pathol 2008;32:345), CD10, CD29 and 14-3-3-sigma (Am J Surg Pathol 2005;29:347)
● Variably positive for CK5 and CK14 (Hum Pathol 2003;34:1009)

Negative stains
=========================================================================

● ER, PR, HER2 (Turk Patoloji Derg 2012;28:134) and mucin
● Often S100
● Mammaglobin (Am J Clin Pathol 2012;137:747)

Molecular description
=========================================================================

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

Differential diagnosis
=========================================================================

Myoepithelial carcinoma: may have ducts with prominent myoepithelial cells at periphery, diffusely S100+
Myofibroblastic tumors
Phyllodes tumor
Primary breast sarcoma: no epithelial elements or keratin+ elements

Additional references
=========================================================================

Am J Surg Pathol 1998;22:188, Am J Surg Pathol 1987;11:918, Stanford University
J Clin Imaging Sci 2012;2:21, J BUON 2011;16:652, Tumori 2011;97:e1



Metaplastic carcinoma - fibromatosis-like variant


Reviewer: Monika Roychowdhury, M.D. (see Reviewerspage)
Revised: 25 September 2012, last major update September 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● Variant of metaplastic carcinoma resembling fibromatosis with propensity for local recurrence
● First described in 1999 (Cancer 1999;85:2170)
● A basal-like tumor with a favorable clinical outcome (Tumori 2009;95:264)

Clinical features
=========================================================================

● Mean age 65 years (range, 40-85 years)
● May recur locally or have distant metastases (Am J Surg Pathol 2001;25:1009), usually no nodal metastases

Case reports
=========================================================================

● 59 year old woman (Arch Pathol Lab Med 2006;130:e81)
● 74 year old woman (Acta Cytol 2010;54:712)
● 77 year old woman (World J Surg Oncol 2007;5:24)

Gross description
=========================================================================

● Mean 3 cm (1-7 cm), well-defined borders

Micro description
=========================================================================

● 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 (Cesk Patol 2002;38:164)

Micro images
=========================================================================


           
Various images


Fig 1: rare nests of bland epithelial cells with focal squamous metaplasia (inset); fig 2: rare mitotic figures; fig 3: keratin+ and smooth muscle actin+ spindle cells; fig 4: p63+ spindle cells

Positive stains
=========================================================================

● Cytokeratin for epithelial elements (high molecular weight subtypes)
● p63
● Smooth muscle actin (usually only in keratin negative cells)

Negative stains
=========================================================================

● Estrogen receptor (ER), progesterone receptor (PR), HER2

Electron microscopy images
=========================================================================



Single cell with peripheral villous processes in collagenous stroma
Inset shows tumor cell cluster with microvilli and cell junctions (arrow)


Differential diagnosis
=========================================================================

Benign or malignant spindle cell lesions (keratin negative) including:
Fibrosarcoma
Melanoma
Myoepithelial carcinoma
Myofibroblastoma
Nodular fasciitis
Primary mammary fibromatosis
Pseudoangiomatous stromal hyperplasia
Solitary fibrous tumor

Additional references
=========================================================================

Breast Cancer Res Treat 2008;109:199



Metaplastic carcinoma - matrix producing subtype


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 25 September 2012, last major update September 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● Invasive breast carcinoma with direct transition of carcinoma to cartilaginous or osseous matrix, without an intervening spindle cell component (Hum Pathol 1989;20:628)

Epidemiology
=========================================================================

● Rare
● 44% are age 50 years or less

Clinical features
=========================================================================

● Poorer prognosis than invasive ductal carcinoma (Am J Surg Pathol 2009;33:534), but may have comparable outcomes with aggressive treatment (Am J Surg 2006;191:657)
● A type of basal-like carcinoma

Case reports
=========================================================================

● 42 year old woman (World J Surg Oncol 2008;6:60), #2 (Univ Pittsburgh Case #116)
● 49 year old woman (Arch Pathol Lab Med 2003;127:1385)

Gross description
=========================================================================

● 31% are 2 cm or smaller, 50% are between 2-5 cm and 19% are 5 cm or larger

Gross images
=========================================================================


                    
Metaplastic carcinoma with chondroid differentiation

                    
Cartilaginous tumor with       Circumscribed tumor with
arrows at tumor margin         bulging mucoid surfaces

Micro description
=========================================================================

● Invasive breast carcinoma with direct transition of carcinoma to cartilaginous or osseous matrix, without an intervening spindle cell component
● Nests, sheets and cords of tumor cells with cellular atypia, plus scattered cancer cells within myxoid or myxohyalinous stroma
● Almost always chondroid matrix, rarely osseous matrix
● Matrix volume varies from 10% of less (44% of cases) to 40% or higher (28%)
● Usually (94%) high grade matrix tumor cells with peripheral lymphocytic infiltration
● Expansile growth with well-circumscribed margins, accompanied by basophilic and myxoid intercellular matrix
● Gradual transition from cellular to acellular areas, with gradual loss of tumor cell adhesion
● Central necrosis (59%), angiolymphatic invasion (25%) and axillary nodal metastases (22%)

Micro images
=========================================================================


                                                 
Malignant chondrocytes with     Various images                            Central myxoedematous
chondroid matrix                                                                                area with necrosis

       
Chondroid matrix and necrosis

           
Chondroid areas

           
Left to right: vimentin+; AE1/AE3+; various markers; cartilaginous markers

AFIP images:
                                          
Junction between poorly differentiated      Matrix producing carcinoma
carcinoma and lobulated areas of
chondromyxoid metaplasia

                                          
Chondroid appearance of                             Chondroid metaplasia in anaplastic
matrix metaplasia                                          portion of a carcinoma


Zone of osteoid separates two areas of poorly differentiated carcinoma

Cytology description
=========================================================================

● Markedly atypical spindle cells with mitotic figures, also atypical chondrocytes (Diagn Cytopathol 2005;33:205)
● Background is necrotic debris and myxoid substance displaying metachromasia

Cytology images
=========================================================================



Fig 1: FNA shows metachromatic chondromyxoid extracellular material with chondrocyte-like cells
Fig 2: poorly differentiated tumor with sheets of small undifferentiated cells, mitotic figures and necrosis
Fig 3: chondromyxoid matrix with pleomorphic cells within lacunae
Fig 4: cells in chondromyxoid matrix are S100+


Various images

Positive stains
=========================================================================

● Keratin, EMA and S-100
● Also EGFR (J Clin Pathol 2005;58:700), myoepithelial differentiation (Am J Clin Pathol 2003;120:161, Ceska Gynekol 2004;69:229)
● Also aggrecan and type II collagen (cartilage-specific matrix molecules, Mod Pathol 2008;21:1282)

Negative stains
=========================================================================

● ER, PR and HER2 (triple negative, Pathol Int 2011;61:415)

Electron microscopy images
=========================================================================



Actin filaments and desmosome-like junctions

Differential diagnosis
=========================================================================

Central acellular carcinoma: margins are relatively sharp with infiltrative growth accompanied by eosinophilic intercellular matrix; abrupt transition from peripheral cellular to central acellular zones without alteration of tumor cell adhesion (Pathol Int 2009;59:390)



Metaplastic carcinoma - spindle cell subtype


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 2 October 2012, last major update October 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● Sarcomatoid morphology, plus either limited (< 5%) invasive carcinoma component or keratin positive sarcoma component (Am J Surg Pathol 2005;29:1456)
● Excludes low grade fibromatosis-like metaplastic tumors
Note: some cases called spindle cell carcinoma in the literature have > 5% invasive carcinoma component

Terminology
=========================================================================

● Also called sarcomatoid carcinoma or spindle cell carcinoma

Clinical features
=========================================================================

● Sarcoma-like behavior (Am J Surg Pathol 2005;29:1456)
● Aggressive, high rate of local relapse and extranodal metastases
● Rate of nodal metastases varies from minimal (Am J Surg Pathol 2006;30:300) to 40% (Eur J Surg Oncol 2003;29:600)

Case reports
=========================================================================

● 80 year old woman with a single, palpable irregular breast mass (Univ Pittsburgh Case #294)
● 84 year old woman with triple negative mixed metaplastic breast carcinoma with squamous and spindle cells (BMJ Case Rep 2012 Feb 25)
● Woman with spindle cell carcinoma of the breast (Breast Dis 2012 Mar 29 [Epub ahead of print])

Micro images
=========================================================================


   
Spindle cell stroma

       
Various images

Positive stains
=========================================================================

● 34betaE12 (60%), SMA (56%, Hum Pathol 2003;34:1009) and p53
● Wide-spectrum keratin screening recommended since variable staining for CK5, CK14, Cam5.2 and AE1/AE3 (Histopathology 2002;40:556)
● Variable S100

Negative stains
=========================================================================

● Usually ER, PR and HER2 (J Clin Pathol 2006;59:1079)
● CD34, bcl2



Neuroendocrine carcinoma - general


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 3 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● Carcinoma with neuroendocrine features in at least 50% of cells
● Terminology usually restricted to low grade tumors (high grade tumors are often called small cell carcinoma)
● May arise from neuroendocrine cell hyperplasia (Pathol Int 2012;62:331, J Clin Pathol 2012;65:699)

Terminology
=========================================================================

● Often (although not consistently) refers to cases lacking another specific histologic type, such as solid papillary, mucinous / colloid or micropapillary
● Also called endocrine carcinoma or solid cohesive neuroendocrine carcinoma
● Some cases were formerly called carcinoid tumor (Eur J Surg Oncol 1995;21:609)

Clinical features
=========================================================================

● 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 Pathol 2001;14:768)

Case reports
=========================================================================

● 60 year woman presenting with kidney and adrenal metastases (Pathol Res Pract 2008;204:851)
● 63 year old woman presenting with perianal mass (Clin Breast Cancer 2007;7:892)
● 63 year old woman with local recurrence and metastatic progression one month after surgery (Ann Ital Chir 2012 May 31 [Epub ahead of print])
● 76 year old woman with metastases to skin (Am J Clin Dermatol 2007;8:379)
● 77 year old woman with HER2+ tumor (Breast Cancer 2012 Jun 19 [Epub ahead of print])

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)

Clinical images
=========================================================================



10 cm mass

Gross description
=========================================================================

● No distinctive gross features

Micro description
=========================================================================

● 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, such as solid papillary, small cell or mucinous / colloid

Micro images
=========================================================================


AFIP images:
           
Ribbon type growth pattern with  Tumor cells often have argyrophilic Grimelius+
some spindled cells        granules, tumor is immunoreactive for chromogranin

Contributed by Dr. Semir Vranic, Sarajevo:
           
Focal mucin production

           
Chromogranin expression     Synaptophysin expression

           
Estrogen receptor         HER2 protein


Distinct nests of cells with salt and pepper chromatin


Fig 2: H&E, chromogranin and synaptophysin

           
Various markers (Fig G, H, I)    (Fig A-D, H-I)

Well differentiated tumor with alveolar growth pattern: #1;   #2;   #3-with carcinomatous lymphangitis;  #4-synaptophysin+

Cytology description
=========================================================================

● Markedly cellular with mostly dispersed tumor cells, also some loose clusters, acinus-like formations, small sheets, rosette like formations and 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
=========================================================================

● ER, PR (usually, Med Oncol 2012;29:2613)
● Also chromogranin, synaptophysin, neuron-specific enolase, GCDFP-15 (50%), TTF1 (20%)

Electron microscopy description
=========================================================================

● Dense core secretory granules

Electron microscopy images
=========================================================================



Dense core granules throughout the cytoplasm, but increased at cell membrane


Dense core granules measure 270-430 nm cluster near cell membrane

Differential diagnosis
=========================================================================

Lobular carcinoma: linear and targetoid patterns, nuclear features not neuroendocrine
● Metastatic carcinoid tumor (Am J Surg 2006;199:799, Diagn Cytopathol 2007;35:306)
Neuroendocrine DCIS: not invasive
● Other breast tumors with neuroendocrine features include small cell carcinoma, colloid carcinoma and invasive ductal carcinoma NOS with < 50% neuroendocrine tumor cells

Additional references
=========================================================================

Stanford University, Zhonghua Bing Li Xue Za Zhi 2011;40:604



Neuroendocrine carcinoma - solid type


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 29 October 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● Neuroendocrine carcinomas with 50%+ neuroendocrine differentiation (based on chromogranin or synaptophysin staining), and densely cellular solid nests or trabeculae separated by a delicate fibrovascular stroma

Terminology
=========================================================================

● This is a distinct WHO diagnostic category

Clinical features
=========================================================================

● May have similar clinical features to breast carcinoma in general (Oncol Rep 2008;20:1369)

Case reports
=========================================================================

● 40 year old woman with solid neuroendocrine carcinoma of the breast (Breast Cancer 2007;14:250)
● 60 year old woman with breast tumor metastatic to renal cell carcinoma (Pathol Res Pract 2008;204:851)
● 63 year old woman with inflammatory carcinoma features (Ann Ital Chir 2012 May 31 [Epub ahead of print])
● Elderly man with argyrophilic neuroendocrine carcinoma of the breast (Ultrastruct Pathol 1993;17:115)
● Two cases with osteoclastic giant cells (Pathologica 2008;100:176)

Micro description
=========================================================================

● Densely cellular solid nests and trabeculae, or spindled, plasmacytoid or large cells, separated by a delicate fibrovascular stroma
● Rarely rosettes or other features resembling carcinoid tumor
● May originate from solid papillary DCIS or resemble alveolar subtype of lobular carcinoma

Micro images
=========================================================================



Various images


Various stains (fig a, b, g, h, i)

Other images: #1, #2, #3, #4

Cytology description
=========================================================================

● Dyscohesive polygonal cells with abundant cytoplasm, many containing eosinophilic granules located at one pole (Malays J Pathol 2008;30:57)



Neuroendocrine carcinoma - large cell


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 3 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

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

Terminology
=========================================================================

● Part of WHO classification

Case reports
=========================================================================

● 27 year old woman (J Korean Med Sci 2008;23:1118)
● 63 year old woman with CK20+ tumor (Breast Cancer 2012;19:360)

Treatment
=========================================================================

● Aggressive tumor requiring multimodal treatment

Micro description
=========================================================================

● Neuroendocrine differentiation morphologically and by immunohistochemistry; larger cell size than small cell carcinoma; frequent necrosis

Micro images
=========================================================================


      
Nests of large tumor cells   Chromogranin+

Differential diagnosis
=========================================================================

● Metastatic carcinoid tumor
Small cell carcinoma: scant cytoplasm, small (diameter of three lymphocytes) nuclei with finely granular, evenly distributed chromatin and absent or inconspicuous nucleoli



General


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 24 February 2012, last major update February 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Histological subtypes (also called special types) other than ductal NOS account for up to 25% of invasive breast carcinomas, although lobular constitutes about 10% of invasive breast carcinoma
● Have distinctive clinical features only if “pure”; i.e. if histologic features are present in >90% of tumor
● Histological 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), prognosis (Int J Cancer 2007;121:127, Br J Cancer 2004;91:1263), and response to therapy (Breast Cancer 2009;16:168)
● Subtypes can often be suspected / diagnosed by fine needle aspiration (Diagn Cytopathol 2007;35:408)
● Subtypes should be assigned a histologic grade

Molecular
=========================================================================

● 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 (ER+, PR+, HER2-) and basal-like (ER-, HER2-, EGFR+ or cytokeratin 5/6+)
● Most histologic subtypes other than lobular and apocrine belong to only one molecular subtype (J Pathol 2008;216:141)
● By hierarchical clustering analysis, some histological subtypes types appear to be discrete entities (micropapillary carcinoma), but others appear similar to each other (tubular and lobular)

Stains
=========================================================================

● Breast carcinomas are usually CK7+, CK20-, except mucinous/colloid (often CK20+) and < 5% of special types (Ann Diagn Pathol 1999;3:350)
Sources for Unknown primary testing (advertisements): bioTheranostics

Additional references
=========================================================================

Am J Surg Pathol 2003;27:832



Acinic cell carcinoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 13 November 2012, last major update March 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Identical to salivary gland counterpart, has serous differentiation
● These carcinomas show diffuse infiltrative growth patterns of small glandular structures and are composed of cells with a coarse granular or clear cytoplasm resembling acinar cells of the salivary glands or Paneth cells
● See also Salivary Glands chapter
● Although similar in some respects to secretory carcinoma (Histopathology 2002;40:223),it lacks its characteristic ETV6 gene rearrangement (Histopathology 2008;52:840)

Epidemiology
=========================================================================

● Uncommon in breast, < 20 cases reported

Case reports
=========================================================================

● 39 year old woman (J Breast Cancer 2011;14:160)
● 42 year old woman (Virchows Arch 1996;429:69)
● 49 year old woman with death due to disease (J Clin Pathol 2002;55:545)
● Japanese woman (Pathol Int 2007;57:43)

Clinical description
=========================================================================

● In salivary glands, may undergo high grade transformation (Am J Surg Pathol 2009;33:1137)
● In parotid gland, poorer prognosis if high mitotic activity and necrosis (Cancer 2009;115:2128)
● Clinically low-grade malignant tumor even if unfavorable prognostic parameters such as high mitotic activity and steroid hormone receptor negativity (Histopathology 2004;45:645)

Gross description
=========================================================================

● Often well circumscribed but may be infiltrative
● Gray-pink and hemorrhagic cut surface
● 2-5 cm

Gross images
=========================================================================



5.5 cm ill defined mass

Micro description
=========================================================================

● Monotonous proliferation of cells with abundant finely granular, weakly eosinophilic or clear vacuolated cytoplasm, central round nuclei and prominent nucleoli, resembling acinic cells of salivary gland (J Clin Pathol 2003;56:497)
● Cytoplasmic dark eosinophilic coarse granules (resembling Paneth cells) can be seen
● Often clear cells
● May have microglandular pattern (Virchows Arch 2000;437:74)
● Up to 15 mitotic figures/10 HPF
● May be mixed with ductal carcinoma-like cells (Am Surg 2002;68:993)

Micro images
=========================================================================


               
Various images


Tumor cells have prominent cytoplasmic granularity


Post-chemotherapy tumor has cells with clear vacuolated cytoplasm


Fig A/B

Salivary gland tumors:

Papillary fronds with hobnail cells and vacuolated cells


Microcystic and solid patterns in tumors from father and daughter


Tumor with clear cells


Dedifferentiated tumor

       
Various micro images


Fig 1: Dedifferentiated parotid tumor with some classic areas
Fig 2: Mitotic figures and necrosis
Fig 3: Differentiated areas with basophilic cytoplasm and vesicular nuclei
Fig 4: PAS+ diastase resistant granules



Various images

Cytology images
=========================================================================


       
Salivary gland: acinar-like cells with larger nuclei, no ducts, no fibrofatty stroma, no “bunch of grapes” architecture

Positive stains
=========================================================================

● CK7 (may be focal or weak), amylase
● Granules are PAS+ diastase resistant
● E-cadherin
● Also lysozyme, EMA, myoepithelial markers (including S100), alpha-1-antitrypsin

Negative stains
=========================================================================

● ER, PR, HER2, CK20; also GCDFP-15, CD68, NSE, MUC2, SMA

EM description
=========================================================================

● Multiple round, electron dense, cytoplasmic secretory granules

EM images
=========================================================================



Electron dense granules


Clear cells in post-chemotherapy patient have dilated endoplasmic reticulum


Variably sized electron dense granules in the cytoplasm

Differential diagnosis
=========================================================================

Lactating lobule: lysozyme+, benign morphology
Microglandular adenosis: intact basal lamina



Adenoid cystic carcinoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewerspage)
Revised: 11 December 2012, last major update March 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Identical to salivary gland counterpart
● May be associated with microglandular adenosis(Am J Surg Pathol 2003;27:1052)

Epidemiology
=========================================================================

● Rare, 0.1% of breast carcinomas (Am J Surg 2002;183:646)
● Mean age 50-63 years, range 25-80 years
● 50% are sub-periareolar

Treatment and prognosis
=========================================================================

● Good to excellent prognosis (Breast Cancer Res Treat 2004;87:225)
● Recurs or metastasizes less than usual ductal carcinoma
● High rates of positive margins(Am J Clin Oncol 2010;33)
● Axillary nodal metastases are rare
● Treatment is excision with clear margins, possibly radiation, axillary dissection may not be necessary
● Prognosis better than that of adenoid cystic carcinoma of other localizations (Breast 2011 Dec 9 [Epub ahead of print])
● Existence of a dedifferentiated component of higher malignancy grade worsens the prognosis (Mod Pathol 2003;16:1265)

Case reports
=========================================================================

● 54 year old woman (UPMC Case #140)
● 55 year old woman (The Internet Journal of Pathology 2008;7(2))
● 67 year old woman with mixed adenoid cystic and infiltrating ductal carcinoma of the breast (J Med Case Reports 2011;5:437)
● 71 year old woman (Int Semin Surg Oncol 2006;3:17)
● 75 year old woman (Arch Pathol Lab Med 2003;127:e436)
● 82 year old man (Int Surg 2006;91:234)
● Metastatic to kidney (Hum Pathol 2007;38:1425)

Gross description
=========================================================================

● 1-3 cm, well circumscribed, firm
● May have cystic cut surface

Micro description/grading
=========================================================================

● Identical to salivary gland counterpart; has cribriform, solid, trabecular or basaloid patterns
● Two types of cavities and two types of cells: (1) true glandular lumina lined by ductal epithelium (EMA+, keratin+) and (2) eosinophilic “cylinders” with basement membrane material lined by basal / myoepithelial-type cells (vimentin+)
● Microscopic infiltration and perineural invasion are common
● May have sebaceous differentiation (Arch Pathol Lab Med 1986;110:1045)

Micro images
=========================================================================


      
Low power


Cribriform pattern

   
Trabecular pattern


Solid, cribriform, tubular and trabecular patterns of small dark tumor cells
with scant cytoplasm and vesicular nuclei



Cribriform architecture in fibrous background


Lumina contain blue material or eosinophilic cylinders


High power


H&E and stains

   
Various images


CK5/6, CK 8/18 and p63


c-kit/CD117+


H&E and stains - comparison with collagenous spherulosis


c-kit comparison with collagenous spherulosis


Mucicarmine

AFIP Third Series:


Tumor nodule with central cysts and invasive elements above


13 year old boy with classic invasive growth pattern


Area with primarily cylindromatous component and rare glands (arrow)

Other images: Smooth muscle actin+

Cytology description
=========================================================================

● Clusters of epithelial cells oriented around solid spheres of basement membrane material

Cytology images
=========================================================================



Various images

Other images:Monomorphic tumor cells around mucoid material #1;#2;#3;#4

Positive stains
=========================================================================

Ductal epithelial cells:
● EMA
● Keratin
● c-kit/CD117 (Mod Pathol 2005;18:1623)

Basaloid/myoepithelial-type cells:
● p63
● S100
● Smooth muscle actin

Secretions in true lumina:
● PAS+ diastase resistant

Cribriform spaces:
● Alcian blue (Am J Clin Pathol 2005;124:733)

Negative stains
=========================================================================

● ER, PR (usually), HER2 (Mod Pathol 2005;18:1277)
● Calponin
● Smooth muscle myosin heavy chain

Cytogenetics description
=========================================================================

● MYB-NFIB fusion gene (t(6;9)(q22-23;p23-24)) has been found in adenoid cystic carcinomas of breast (J Pathol. 2012 Jan;226(1):84-96),making them a genomically distinct subgroup of triple-negative breast cancer

Differential diagnosis
=========================================================================

Collagenous spherulosis: has one cell type, calponin+, smooth muscle myosin heavy chain+, c-kit/CD117-(Mod Pathol 2006;19:1351)
Cribriform carcinoma: in situ or invasive, has only one cell type, ER+, PR+, p63-, c-kit/CD117-

Additional references
=========================================================================

Am J Surg Pathol 1998;22:569, Hum Pathol 1987;18:1276 (grading), Mod Pathol 1996;9:215, Stanford University


Solid variant of adenoid cystic carcinoma

Terminology
=========================================================================

● Also called basaloid type

Features
=========================================================================

● Axillary nodal metastases in 2 of 6 cases (Am J Surg Pathol 2002;26:413)
● May have poorer prognosis than classic type(APMIS 1999;107:762)

Case reports
=========================================================================

● Merging with small cell carcinoma (Pathol Res Pract 2005;201:705)

Gross description
=========================================================================

● Solitary mass, mean 4 cm

Gross images
=========================================================================



Contributed by Dr. Semir Vranic, University of Sarajevo, Bosnia and Herzegovina

Micro description
=========================================================================

● Basaloid cells with moderate to marked nuclear atypia, often with 5+ mitotic figures/10 HPF

Micro images
=========================================================================



Solid pattern with inconspicuous cylindromatous elements at arrows (AFIP)

Contributed by Dr. Hind Nassar, Johns Hopkins Medical Center, Maryland (USA):
      

   
p63                          Actin

Contributed by Dr. Semir Vranic, University of Sarajevo, Bosnia and Herzegovina:
   
Core biopsy

         

      
Low power

   
Medium power

         

      
High power

Virtual slides
=========================================================================



Adenoid cystic carcinoma - solid/basaloid type

Positive stains
=========================================================================

● Keratin, basement membrane, vimentin

Negative stains
=========================================================================

● ER, PR

Differential diagnosis
=========================================================================

Cylindroma: no atypia, no mitotic figures, no infiltration, no mucin (Am J Clin Pathol 2005;123:866)



Adenosquamous carcinoma - low grade


Reviewer: Monika Roychowdhury, M.D. (see Reviewerspage)
Revised: 11 December 2012, last major update March 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Carcinoma with well developed tubule/gland formation mixed with widely dispersed solid nests of squamous cells

Terminology
=========================================================================

● Also called syringomatous carcinoma, adenocarcinoma with squamous differentiation
● See also mucoepidermoid carcinoma

Clinical description
=========================================================================

● Uncommon; considered a rare variant of metaplastic breast carcinoma (Am J Surg Pathol 1987;11:351)
● May originate from an intraductal papillary tumor, or be associated with sclerosing adenosis, radial scar or ductal adenoma
● Recurs locally with conservative therapy, metastases unusual
● Difficult to diagnose by fine needle aspiration, core biopsy or frozen section (Histopathology 2006;49:603)

Case reports
=========================================================================

● 19 year old woman(World J Surg Oncol 2010 May 27;8:44)

Gross description
=========================================================================

● Mean 2-3 cm, range 1-9 cm
● Hard, tan-yellow, infiltrative

Gross images
=========================================================================



Well circumscribed mass (AFIP)

Micro description
=========================================================================

● Resembles syringomatous adenoma of nipple; often originates from intraductal papillary tumor
● Has tadpole or comma shaped epithelial structures with inner epithelial cells and outer myoepithelial cells
● Also other areas of obvious squamous differentiation, desmoplastic stroma
● Often keratinizing squamous component

Micro images
=========================================================================


         
Various images

AFIP Third Series

DCIS in large duct below and at arrows giving rise to adenosquamous carcinoma


Invasive ductal elements with syringomatous features in dense collagenous stroma


Neoplastic ductules around a lobule


Neoplastic ductules with secretion and squamous area

Other images: Figure 1, Figure 3

Cytology description
=========================================================================

● Proliferating ductal cells and atypical squamous cells in the same cell clusters (Pathol Int 1997;47:264)

Positive stains
=========================================================================

● Variable myoepithelial marker expression (HHF35, calponin, S100, CK14, CK5/6, p63)
● Positive for CK5, CK17 and CK14(Mod Pathol 2010;23:951)

Negative stains
=========================================================================

● ER, PR (Pathol Annu 1994;29:181)
● Often triple negative tumors (ER-, PR-, HER2-, Mod Pathol 2010;23:951)

EM description
=========================================================================

● Glandular and squamous differentiation
● Squamous cells resemble acrosyringium of eccrine sweat gland

Differential diagnosis
=========================================================================

Syringomatous adenoma of nipple: similar histology, but more superficial, involving nipple areolar complex; benign

Additional references
=========================================================================

Am J Surg Pathol 1993;17:248, Am J Surg Pathol 1987;11:351
Stanford University, Diagn Cytopathol 2011 Apr 28 [Epub ahead of print]



Apocrine carcinoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 18 March 2012, last major update March 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● >90% of tumor cells have cytologic or immunohistochemical features of apocrine cells
● Rare, 1-4% of all breast carcinomas

Case reports
=========================================================================

● 46 year old woman (Univ Pittsburgh Case #209)
● 71 year old woman with nipple (skin) tumor (Cases J 2008 Aug 12;1(1):88)
● 84 year old woman (Case of the Week #68)

Treatment and prognosis
=========================================================================

● Similar (Breast J 2008;14:164), or slightly better (Breast 2005;14:3) prognosis as invasive ductal carcinoma

Gross description
=========================================================================

● Indistinguishable from infiltrating ductal carcinoma (J Clin Pathol 2007;60:1313)
● May be mural nodule within cyst
● Often multicentric (Breast Cancer Res Treat 2004;88:49)

Micro description
=========================================================================

● Tumor cells have distinct cell margins, abundant acidophilic cytoplasm with eosinophilic granules, central to eccentric vesicular nuclei with prominent nucleoli
● May have glandular differentiation with apocrine snouts and prominent nucloeoli
● Limit diagnosis to tumors with widespread apocrine change and obvious malignancy
Type A cells: abundant granular and intensely eosinophilic cytoplasm, granules are PAS+ diastase resistant, nuclei vary from globoid with prominent nucleoli to hyperchromatic
Type B cells: abundant cytoplasm with fine empty vacuoles, creating a foamy appearance resembling histiocytes, nuclei are similar to type A cells
● Exclude: cases with clear cells of any type in any amount; other subtypes including tubular, lobular, mucinous, invasive micropapillary or medullary

Micro images
=========================================================================


           
Various images

   
Contributed by Dr. Semir Vranic, Sarajevo

       
Case of the week images


Cells have abundant cytoplasm with distinct cell margins


Cytoplasm is granular, nuclei are round with prominent nucleoli

       
GCDFP-15


bcl2 negative


AR expression, 20x


Estrogen receptor, 20x


Her2 protein, 20x

   
HER2 gene, CISH 2

AFIP Fascicle Third Series

Tumor with solid growth pattern


Histiocytoid variant with isolated cells resembling
histiocytes in desmoplastic stroma, may be confused with granular cell tumor


Other images: cells have abundant cytoplasm with distinct cell margins #1; #2; #3; cytoplasm is granular, nuclei are round with prominent nucleoli #1; #2; #3; #4; #5; with apocrine DCIS

Positive stains
=========================================================================

● Keratin, GCDFP-15 (76-100%), B72.3 (92%, APMIS 2006;114:712), PAS (granules)
● ER-beta (73%, Histopathology 2007;50:425), particularly ER-beta1 (APMIS 2008;116:923)
● Androgen receptor (54%)
● HER2 (33%), p53 (29-39%), Ki-67
● Note that GCDFP-15 and AR expression decrease in larger or node-positive tumors (Histopathology 2005;47:195)

Negative stains
=========================================================================

● ER-alpha (usually), PR (usually), bcl-2

EM description
=========================================================================

● Prominent mitochondria, some with abnormal cristae
● Large membrane bound vesicles with dense homogenous osmophilic cores

EM images
=========================================================================



Cytoplasm is rich in organelles


Electron dense granules, condensed, at secretory pole of cell

AFIP Fascicle Third Series

Smooth and rough endoplasmic reticulum, dense nucleoli


Cytokeratin filaments (arrow), lipid droplets, mitochondria, lysosomes


Cytoplasm contains numerous lysosomes, lipid droplets, dilated mitochondria and vesicular endoplasmic reticulum

Molecular/cytogenetics description
=========================================================================

● Form a distinct, even if heterogeneous, molecular subgroup of breast carcinomas that recapitulate the phenotype of apocrine sweat glands (Mol Oncol 2009;3:220)
● Abnormalities at 7q (codes for GCDFP-15 and prolactin-inducible protein)
● Also loss of heterozygosity for p53 gene, VHL (3p25) gene, NB gene (1p35-36), PKD1/TSC2 gene at 16p13 (Mod Pathol 1999;12:1083)

Differential diagnosis
=========================================================================

Apocrine metaplasia: not infiltrative, no atypia
Granular cell tumor
Lipid rich carcinoma: may overlap, although in lipid tumors, 90%+ cells have prominent intracytoplasmic neutral lipid (Am J Surg Pathol 2011;35:861)
● Histiocytic proliferation
● Inflammation
Granular cell tumors

Additional references
=========================================================================

Pathol Res Pract 2008;204:367, Breast Cancer 2002;9:43, Stanford University



Basal cell carcinoma of nipple


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 15 November 2012, last major update March 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Terminology
=========================================================================

● Not in WHO breast classification
● See also Skin-Nonmelanocytic tumors chapter

Epidemiology
=========================================================================

● Very rare (< 50 cases reported), usually age 60+ years, equal distribution between men and women

Clinical
=========================================================================

● May behave aggressively with axillary nodal metastases

Treatment and prognosis
=========================================================================

● No consensus - wide local excision, mastectomy, radiation therapy
● Patients should be followed up for primary site recurrence and axillary metastasis as there is greater incidence than with BCC at other anatomical sites (Dermatol Surg 2009;35:1771)
● Photodynamic therapy proposed as an alternative in superficial tumors (Onkologie 2010;33:613)

Case reports
=========================================================================

● 47 year old woman (Onkologie 2010;33:613)
● 59 year old man with metastatic tumor to axillary nodes (Arch Pathol Lab Med 1986;110:761)
● 67 year old man (Arch Pathol Lab Med 2004;128:792)
● 74 year old woman (Ann Saudi Med 2007;27:296)

Clinical images
=========================================================================



Fungating, ulcerated, bleeding mass


Pigmented lesion

Micro description
=========================================================================

● Proliferating nests of basaloid cells arising from epidermis and extending into superficial dermis and nipple stroma
● May involve underlying lactiferous ducts

Micro images
=========================================================================



Various images


Nodules of basal cell carcinoma


Pigmented lesion


Skin-not nipple: superficial tumor

Differential diagnosis
=========================================================================

Paget’s disease: tumor cells are large with clear cytoplasm, not basaloid
Bowen’s disease: in situ disease without invasion; cells typically are not basaloid



Basal-like invasive ductal carcinoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 3 November 2012, last major update March 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● Not rigidly defined, usually positive for CK5/6, CK14 or CK17, and triple negative (ER-, PR-, HER2-), often positive for EGFR
● Original definition based on gene expression profile (Nature 2000;406:747, Proc Natl Acad Sci USA 2001;98:10869)
● Generally considered to not be comparable to triple negative tumors by immunostains (Clin Cancer Res 2008;14:1368, Med Mol Morphol 2009;42:128) but see Breast Cancer Res 2007;9:R65
● Classification of particular tumors may vary based on which classification system is used (Hum Pathol 2008;39:506)
● Tumors are clinically heterogeneous

Terminology
=========================================================================

● Not in WHO breast classification
● “Basal like” because tumors have high expression of genes characteristic of basal epithelial cells of normal mammary gland, including CK 5/6, CK14, CK15 and CK17

Epidemiology
=========================================================================

● 15% of all invasive ductal carcinoma NOS (Breast Cancer 2010;17:118), higher percentage (26-30%) of CNS metastases or primaries that metastasize to CNS (Mod Pathol 2007;20:864); higher percentage (34%) in Africa (APMIS 2007;115:1391)
● Basal-like expression also present in 17% of infiltrating lobular carcinoma based on CK5/6 expression, these cases are more likely to be ER- (Hum Pathol 2008;39:331)
● Associated with younger age, African-American women, high grade tumors, metaplastic subtype (Mol Cancer Ther 2008;7:944), medullary subtype (Breast Cancer Res 2007;9:R24), high stage, angiolymphatic invasion, BRCA1 (Oncogene 2006;25:5846)
● Not a common subtype in men (Breast Cancer Res 2009;11:R28)

Clinical description
=========================================================================

● Of academic interest, not currently used clinically (Arch Pathol Lab Med 2009;133:860); may not be a distinct clinical entity (Pathobiology 2008;75:119, J Biophotonics 2012 Jan 9 [Epub ahead of print])
● Associated with epithelial-mesenchymal transition, defined by the loss of epithelial characteristics and the acquisition of a mesenchymal phenotype (Cancer Res 2008;68:989)
● Poorer survival if express CK 17 or CK 5/6 (Am J Pathol 2002;161:1991), CK 5/6 or EGFR (BMC Cancer 2007;7:134), HER2+ (not common, Hum Pathol 2008;39:167)

Micro description
=========================================================================

● High grade or metaplastic morphology, may have medullary features (Am J Surg Pathol 2007;31:501)
● Also geographic necrosis, pushing borders, stromal lymphocytic response, increased mitotic count
● Subtypes include pure (negative for S100 and actin) or myoepithelial (S100+ or actin+, Mod Pathol 2007;20:1200)
● Includes secretory breast carcinomas with ETV6-NTRK3 fusion gene (Mod Pathol 2009;22:291)
Core biopsy: solid growth pattern, high nuclear grade, marked lymphocytic infiltrate and geographic necrosis are helpful features, also immunostains (Appl Immunohistochem Mol Morphol 2008;16:411)

Micro images
=========================================================================


   
Various images


H&E and CK14


p16+

           
Various immunostains


Sheet-like growth and high Ki-67 index


Tumor without sheet-like growth but with high Ki-67 index

Contributed by Dr. Semir Vranic, Sarajevo:

H&E


Central necrosis


40x


Inflammatory response, periphery


ER negative


CK 5/6


CK7


CK14


S100

Basoluminal variant:

CK 5/14 (Fig B/C)


CK 5/14 and K1-67

Normal breast:

CAM 5.2 (CK 8/18) stains luminal
epithelium, CK17 stains basal cells



CK5 and CK14

Virtual slides
=========================================================================



Tumor

Positive stains
=========================================================================

● Usually CK5 or CK5/6 (CK5 more sensitive, Am J Clin Pathol 2008;130:724), CK14 or CK17
● Ki-67 (high labeling index)
● Often EGFR, IGF-IR or c-kit/CD117
● CD109 (60%, Pathol Int 2008;58:288), laminin 5 (96%, Am J Surg Pathol 2008;32:345), vimentin (55-90%), p16 (Am J Surg Pathol 2009;33:163)
● Note: basoluminal variant may be HER2+ and only partially positive for CK5/14 (Clin Cancer Res 2006;12:4185)

Negative stains
=========================================================================

● ER, PR and HER2 (triple negative)

Molecular description
=========================================================================

● p53 mutations (Cancer Res 2009;69:663)



BRCA1 associated breast carcinoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 15 November 2012, last major update March 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● BRCA1 is a tumor suppressor gene at 17q21 (OMIM 113705); may interact with p53 (Cancer Lett 2008;268:137)
● Germline mutations occur in 0.1% of Caucasians but in 2% of Ashkenazi Jews

Terminology
=========================================================================

● BRCA1 associated breast carcinoma is not part of WHO breast classification

Epidemiology
=========================================================================

● 12% of women referred for genetic testing have BRCA1/BRCA2 deleterious mutations, rate is similar among different enthnicities (Cancer 2009;115:2222), but higher in Ashkenazi Jewish women
● Inherited in autosomal dominant manner
● BRCA1 mutations are present in 10% of women with (a) no family history, (b) breast cancer onset by age 40 years, and (c) high grade, triple negative tumors (BMC Cancer 2009;9:86)
● 56-68% of BRCA1 carriers with germline mutations get breast cancer by age 70 years, 80% by age 80, but usually at ages 40-59 (BMC Cancer;2008:8;155)
● Most effective predictor of BRCA1 mutations in breast cancer is age of onset < 50 years, HER2 status (negative), and either ER or PR status (negative), as compared with sporadic or non-BRCA1/BRCA2 cancers (Breast Cancer Res 2008;10:R17)
● The Manchester scoring system is a risk assessment model which may be applied to evaluate an individual’s risk of having a BRCA1 or BRCA2 mutation (J Med Genet 2009;46:811)
● 60% chance of mutation if 4+ family members had breast cancer prior to age 60 years (Eur J Cancer 1999;35:1954)
● Not cost effective to screen if only 10% risk of having a BRCA1/2 mutation (Value Health 2009;12:207)

Treatment and prognosis
=========================================================================

● Carriers: close follow up or prophylactic mastectomy (reduces risk of cancer by 85-90%, Ann Surg Oncol 2007;14:3335)
● Tumors: tamoxifen may prevent bilateral breast cancers in ER alpha negative tumors that are ER beta+ (BMC Cancer 2008;8:100)
● Tumors: increased risk of recurrence after breast conserving surgery (Ann Surg Oncol 2009;16:3380)
● Tumors: BRCA1 status does not appear to affect death rates (N Engl J Med 2007;357:115), but is associated with resistance to docetaxel based chemotherapy (Med Sci Monit 2008;14:SC7)

Case reports
=========================================================================

● BRCA1 carrier with primary ovarian carcinoma and metastases 3 and 6 years later, due to occult breast carcinoma (Hum Pathol 2004;35:629)

Micro description
=========================================================================

● Usually high grade (basal-like phenotype) with abundant intra- and peritumoral lymphocytes, but no syncytial growth pattern, no fibrous capsule (Mod Pathol 2005;18:1321)
● Greater incidence of medullary tumors
● High incidence of DCIS (Cancer Prev Res (Phila Pa) 2009;2:122)

Micro images
=========================================================================


       
Various images and immunostains

   
ER alpha (left) and beta (right)

Positive stains
=========================================================================

● p53 and P-cadherin (Hum Pathol 2008;39:857), also Ki-67 (Cancer Genet Cytogenet 2009;189:105)
● ER beta positive in 44% (BMC Cancer 2008;8:100), although usually ER alpha negative
● CK14 in 39% (Breast Cancer Res 2008;10:R17), although expression of basal cytokeratins and EGFR does not predict BRCA1 status in women with triple negative tumors (Am J Surg Pathol 2009;33:1093)

Negative stains
=========================================================================

● Usually triple negative (ER alpha negative in 85%, PR-, HER2-), but often ER beta positive
● Androgen receptor negative

Additional references
=========================================================================

Arch Pathol Lab Med 1999;123:1023, Wikipedia, National Cancer Institute



BRCA2 associated breast carcinoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 15 November 2012, last major update April 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● BRCA2 associated breast cancer is not part of WHO breast classification
● BRCA2 is a tumor suppressor gene at 13q12-13 (OMIM 600185)
● See also Stains chapter

Epidemiology
=========================================================================

● 12% of women referred for genetic testing have BRCA1/BRCA2 deleterious mutations, rate is similar among different ancestries (Cancer 2009;115:2222), but higher in Ashkenazi Jewish women
● Manchester scoring system assesses individual risk of BRCA1/2 mutations (J Med Genet 2009;46:811)
● 60-75% with germline mutations get breast cancer by age 70, 88% at age 80 (BMC Cancer 2008;8:155), but usually by age 50
● Patients also have higher risk of cancers of ovary (39-63%), bone, pharynx, prostate, pancreas (J Med Genet 2005;42:711); also other organs
● Slightly more frequent in black (2.6%) versus white (2.1%) American patients (Cancer Res 2006;66:8297)
● For patients with 10% or lower risk of BRCA1/2 mutation, genetic screening is not cost effective (Value Health 2009;12:207)

Case reports
=========================================================================

● Invasive cancer 33 years after prophylactic bilateral subcutaneous mastectomies (World J Surg Oncol 2005;3:52)

Micro description
=========================================================================

● Usually invasive ductal carcinoma, no special type
● High grade features and pushing tumor margin (Am J Surg Pathol 2007;31:121)
● High incidence of DCIS (Cancer Prev Res (Phila Pa) 2009;2:122)

Micro images
=========================================================================



Typical histological patterns


Various immunostains

Positive stains
=========================================================================

● ER; usually luminal phenotype (ER+, HER2-)
● bcl1/cyclinD1 (Mod Pathol 2008;21:1262)

Negative stains
=========================================================================

● CK5 (usually), HER2 (usually)

Additional references
=========================================================================

Arch Pathol Lab Med 1999;123:1023, Wikipedia, National Cancer Institute



Central acellular carcinoma


Reviewer: Monika Roychowdhury, M.D., (see Reviewers page)
Revised: 1 October 2012, last major update October 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Not in WHO breast classification
● Aggressive behavior despite small size and minimal nodal involvement

Terminology
=========================================================================

● Also called invasive ductal carcinoma with large central acellular zone, ring carcinoma, central necrotizing carcinoma

Clinical description
=========================================================================

● Mean age 58 years, mean tumor size only 2.5 cm, but 28% had positive axillary nodes (central necrotizing carcinoma)
● 62% developed recurrence at median 16 months, 60% died at median 22 months from diagnosis (Am J Surg Pathol 2001;25:331)
● Lacks malignant features by mammography and ultrasound (Breast 2005;14:419)
● Metastases to lung and brain more common than usual (Am J Surg Pathol 2000;24:197)
● Considered a type of basal-like carcinoma (Histopathology 2010;57:193, Breast Cancer 2009;16:254)
● May be related to metaplastic carcinoma (Med Mol Morphol 2012;45:14)

Treatment and prognosis
=========================================================================

● Poorer prognosis than matched patients with poorly differentiated tumors containing less extensive necrosis

Microscopic description / grading
=========================================================================

● Well-circumscribed, solitary nodule with extensive central necrosis or collagen / hyaline deposition, constituting a majority of tumor volume, surrounded by a narrow rim of viable high-grade tumor cells (ring like hypercellular zone) with pushing border and minimal tubule formation
● Relatively sharp margin but infiltrative growth accompanied by eosinophilic intercellular matrix
● Abrupt transition between peripheral cellular and central acellular zones without alteration of cancer cell adhesion (Pathol Int 2009;59:390)

Micro images
=========================================================================



Tumor with well circumscribed borders and central necrosis

Positive stains
=========================================================================

● S100, CK14, smooth muscle actin, p63 (myoepithelial phenotype likely due to aberrant differentiation, not a reflection of tumor histogenesis, Hum Pathol 1999;30:1134)
● Ki-67, p53 (Pathol Int 2008;58:26)
● CK5/6 in surrounding ring of viable cells

Negative stains
=========================================================================

● ER/PR (94%), HER2

Differential diagnosis
=========================================================================

Matrix producing carcinoma: expansive growth with basophilic and myxoid matrix, gradual transition from cellular to acellular areas with gradual loss of tumor cell adhesion (Pathol Int 2009;59:390)



Cribriform carcinoma - invasive


Reviewer: Monika Roychowdhury, M.D., (see Reviewers page)
Revised: 1 October 2012, last major update October 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Invasive tumor with cribriform pattern similar to cribriform DCIS
● May have minor (<50%) component of tubular carcinoma

Clinical description
=========================================================================

● Rare (1-3% of breast carcinomas), related to tubular carcinoma (Histopathology 1983;7:525)
● Nodal metastases in 14%
● Mixed patterns have intermediate prognosis between invasive cribriform and invasive ductal carcinomas

Case reports
=========================================================================

● 64 year old man with tumor microcalcifications (Breast Cancer 2005;12:145)
● Perineural invasion (Hum Pathol 1992;23:202)
● Internal mammary node metastasis (Tumori 2006;92:241)

Treatment and prognosis
=========================================================================

● Excellent prognosis, even with nodal metastases, if restrict diagnosis to pure pattern (Histopathology 1983;7:525, Eur J Gynaecol Oncol 1996;17:228)

Micro description
=========================================================================

● Low grade, cribriform appearance (well defined spaces formed by arches of cells) similar to cribriform DCIS but with larger cells, more cytoplasm and more vesicular nuclei
● Tumor cells are small, often have apical snouts, mild/moderate nuclear pleomorphism
● Also stromal invasion by islands of cells, often angulated
● May have predominantly solid appearance
● Associated with cribriform DCIS
● Often mixed with tubular carcinoma
● No/rare mitotic figures, no mucin production
Note: pure pattern is defined as 90%+ cribriform; also considered “classic” even if minor component of tubular carcinoma

Micro images
=========================================================================


           
Various images

   
Perineural invasion


Luminal microcalcifications


Low grade nuclei


Extensive secondary lumen formation with angular clusters of tumor cells


ER+

Cytology description
=========================================================================

● Cohesive sheets and three dimensional cribriform clusters of bland ductal cells in a blood-stained background
● Variable osteoclast-like giant cells (Acta Cytol 2001;45:593, Acta Cytol 1992;36:48)

Positive stains
=========================================================================

● ER, PR (usually)

Electron microscopy description
=========================================================================

● Numerous mitochondria
● Luminal surfaces have abundant microvilli (Ultrastruct Pathol 1994;18:519)

Differential diagnosis
=========================================================================

Adenoid cystic carcinoma: second cell population, intracystic basement membrane material and secretory material
Carcinoid tumor: intracytoplasmic granules, positive for neuroendocrine markers
Collagenous spherulosis: intense eosinophilic secretions, circumscribed, not invasive (Am J Surg Pathol 1995;19:1366)
Cribriform DCIS: non infiltrative, clusters are more regularly distributed, myoepithelial layer is present

Additional references
=========================================================================

Hum Pathol 1990;21:333
Cribriform Carcinoma of the Breast, Stanford University



Cystic hypersecretory carcinoma - invasive


Reviewer: Monika Roychowdhury, M.D., (see Reviewers page)
Revised: 1 October 2012, last major update October 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Not part of WHO breast classification
● First described in 1984 (Am J Surg Pathol 1984;8:31)
● Very rare (<100 cases reported)
● DCIS or hyperplasia is more common

Clinical description
=========================================================================

● Usually low grade for several years but may metastasize

Case reports
=========================================================================

● 40 year old woman with painful breast mass (Arch Pathol Lab Med 2005;129:e79)
● 43 year old woman (Jpn J Radiol 2011;29:660)
● 45 year old woman (J Korean Med Sci 2004;19:149)
● 48 year old woman with Paget’s disease of nipple (Int J Surg Pathol 2008;16:208)
● 49 year old woman with invasive lobular carcinoma in opposite breast 10 years after diagnosis (Arch Pathol Lab Med 1999;123:1108, free full text)

Gross description
=========================================================================

● Numerous cysts with mucoid or gelatinous secretions

Gross images
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Numerous cysts with a gelatinous secretion

Micro description
=========================================================================

● Cystic dilation of ducts containing colloid-like eosinophilic material that often retracts from epithelium
● Epithelium focally has micropapillary DCIS
● Also invasion of surrounding stroma by nests of carcinoma, which may be high grade, usually without hypersecretory characteristics
● Extravasation of cyst material into stroma is not invasion

Micro images
=========================================================================




Poorly differentiated carcinoma invades stroma next to cyst


Low power shows prominent cysts with no apparent ducts containing carcinoma


Associated micropapillary DCIS, invasion elsewhere


Associated micropapillary DCIS with no evident secretion in tumor cells, which have a hobnail appearance,
nuclei are relatively clear with small, discrete nucleoli



Associated micropapillary DCIS with sparse secretion that is retracted from epithelium


Cysts lined by flat cuboidal epithelium contain homogeneous secretions,
these cysts are nonspecific - they can be found in cystic hypersecretory hyperplasia or carcinoma



Note transition in cyst epithelium with plaque of tumor cells in bottom half, micropapillary pattern
is obscured where carcinoma nearly fills ducts, but traces of retracted secretion remain (arrows),
clear nuclei are also evident, even at this magnification



Axillary nodal metastases, with some cells exhibiting clear nuclei


Other images:

Fig 1: increased vascularity on power color Doppler imaging
Fig 2: sparse cellular smears with finely granular background and cells in 3D clusters and papillary formation with rare single hyperchromatic degenerating cell with increased N/C ratio (inset)
Fig 3: core needle biopsy
Fig 4: dilated ducts with eosinophilic colloid-like material with occasional scalloping at luminal borders and micropapillary proliferations



Various images

Cytology description
=========================================================================

● Orange to gray-green colloid-like background with cracking artifact (Pap stain), clusters of malignant cells
● Also histiocytes and apocrine cells (Acta Cytol 1999;43:273, Acta Cytol 1997;41:892)

Positive stains
=========================================================================

● Androgen receptors, HER2 (Ceska Gynekol 2005;70:73)
● Variable p53, ER and PR (Histopathology 2005;46:43)

Differential diagnosis
=========================================================================

Secretory carcinoma: predominantly microcysts, t(12;15)(p13;q25) in most cases
Mucinous/colloid carcinoma: extracellular mucin, not intracystic secretions
Cystic hypersecretory hyperplasia: no invasion present (Cancer 1988;61:1611)



Glycogen rich (clear cell) carcinoma


Reviewer: Monika Roychowdhury, M.D., (see Reviewers page)
Revised: 10 October 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Breast carcinoma in which at least 90% of the neoplastic cells have abundant clear cytoplasm due to glycogen
● First described in 1981 (Cancer 1981;48:2003)
● Rare, 1-3% of breast carcinomas
● May be a variant of apocrine carcinoma

Treatment
=========================================================================

● Prognosis similar to invasive ductal carcinoma (Am J Surg Pathol 1995;19:904)

Radiology images
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Mammogram shows circumscribed mass

Case reports
=========================================================================

● 33 year old woman whose tumor had neuroendocrine features (Pathologica 2001;93:676)
● 45 year old woman with solid papillary tumor (J Clin Pathol 2003;56:552)
● 55 year old woman (Case Rep Oncol 2011;4:452)
● 59 year old woman (World J Surg Oncol 2008;6:44)
● 61 year old woman (Arch Med Lab Pathol 2003;127:1629)
● Intraductal lipid rich carcinoma with component of glycogen rich carcinoma (J Breast Cancer 2012;15:135)

Gross images
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Solid papillary pattern within cystically dilated duct (Fig 1A)

Micro description
=========================================================================

● Solid or solid / papillary patterns of large clear cells with distinct cell borders containing glycogen in 90% or more cells
● Often associated with intraductal component of varied type
● Often has apocrine features
● Cells have clear to granular cytoplasm
● May have scant intracellular mucin (Histopathology 1987;11:857)
● No cytoplasmic vacuoles

Micro images
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Various images

       
Intraductal lipid-rich carcinoma with component of glycogen-rich carcinoma


Tumor cells with distinct borders and clear cytoplasm


Resembles renal clear cell carcinoma

   
Tumor cells contain abundant cytoplasmic glycogen


Fig 1/2: Infiltrating nests of atypical cells with abundant clear cytoplasm
Fig 3: PAS+ granules
Fig 4: PAS staining is removed by diastase



Polygonal cells with distinct cell borders,
clear cytoplasm and prominent nucleoli (Fig 1B/1C)



CK8/18+


AFIP images:


Sheets of polygonal cells with distinct borders, clear cytoplasm and
small nuclei, also lymphocytes and plasma cells (arrows)



Clear cells surround a small group of tumor cells with amphophilic cytoplasm


PAS+ dark granules are due to glycogen, and are abolished by diastase

Cytology description
=========================================================================

● Hypercellular with tumor cells in loosely cohesive syncytial groups and some single cells
● Most tumor cells have abundant, finely granular eosinophilic cytoplasm or foamy to clear cytoplasm with well defined cytoplasmic membranes and moderate/marked nuclear pleomorphism with central round/oval nuclei containing prominent nucleoli (Acta Cytol 2008;52:65)
● PAS staining may be helpful (J Med Invest 2002;49:193)

Positive stains
=========================================================================

● PAS-diastase sensitive (glycogen)

Negative stains
=========================================================================

● CK20, lipid stains (done on fresh/frozen tissue)

Electron microscopic description
=========================================================================

● Non-membrane bound glycogen and empty glycogen lakes
● Tight junctions between tumor cells, immature desmosomes, occasional short microvilli (Am J Surg Pathol 1986;10:553)

Differential diagnosis
=========================================================================

Apocrine carcinoma
Clear cell “sugar” tumor: positive for melanocytic markers (Am J Surg Pathol 2002;26:670)
Lipid-rich carcinoma: positive for lipid stains, negative for glycogen
● Myoepithelial lesions
Secretory carcinoma: younger patients, low grade histology

Additional references
=========================================================================

Hum Pathol 1991;22:81, Stanford University



Inflammatory carcinoma


Reviewer: Monika Roychowdhury, M.D., (see Reviewers page)
Revised: 10 October 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● A clinical (not pathologic) diagnosis of an enlarged, erythematous and edematous breast, presumed to be due to dermal plugging of lymphatic vessels by tumor (Breast Cancer Res 2005;7:52, Wikipedia)

Clinical description
=========================================================================

● Mean age 53 years
● Tumor may not be palpable on clinical exam
● Stage T4d in TNM classification
Peau d’orange: lymphatics are so involved by tumor microemboli that skin drainage is blocked, causing lymphedema and thickening of skin of majority of breast

Treatment
=========================================================================

● Aggressive, with 5 year disease free survival < 45%, even if node negative (Arch Surg 2006;141:567)
● Treated with neoadjuvant (pre-operative) chemotherapy

Case reports
=========================================================================

● Breast cancer presenting as subclavian/axillary deep vein thrombosis and upper limb lymphoedema (Ann R Coll Surg Engl 2012;94:e55)

Clinical images
=========================================================================


   
Enlarged erythematous breast

Micro description
=========================================================================

● Usually dermal plugging of lymphatics by tumor, may not be seen in small biopsies
● No specific histology, although usually high grade ductal NOS

Micro images
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Tumor in dermal lymphatics


Fig A: tumor emboli in dermal lymphatic
Fig B: membranous E cadherin staining



Fig A: lobular histology
Fig B: membranous E cadherin staining


   
Post radiation

Positive stains
=========================================================================

● E-cadherin, even if lobular histology (Mod Pathol 2001;14:458)
● High MIB-1 score
● Also HER2 (50%, Breast 2004;13:97), p53 (41%, Breast Cancer 2006;13:172), BP1 (Cancer Biomark 2009;5:9)

Differential diagnosis
=========================================================================

Differential diagnosis (based on clinical findings):
Mastitis: no tumor present
Metastatic carcinoma: tumor present other than in dermal lymphatics (Breast Cancer 2008;15:315, Int J Dermatol 2007;46:303), primary may not be apparent (Breast J 2009;15:176)
● Other primary tumors, including lymphoma (Arch Gynecol Obstet 2009;280:149) and plasmacytoma (Clin Lymphoma Myeloma 2008;8:191)
Nephrogenic systemic fibrosis: different histology (Arch Pathol Lab Med 2007;131:145)
● Post-surgical changes: dilated dermal lymphatics but no tumor (Mayo Clin Proc 1996;71:552)



Intracystic (encysted) papillary carcinoma


Reviewer: Monika Roychowdhury, M.D., (see Reviewers page)
Revised: 10 October 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Terminology
=========================================================================

● Also called encapsulated papillary carcinoma, intracystic papillary ductal carcinoma in situ

Epidemiology
=========================================================================

● Rare, usually seen in elderly women
● 0.5-1% of all breast cancers
● May be associated with conventional DCIS or invasive carcinoma

Clinical description
=========================================================================

● Asymptomatic or presents as breast mass or nipple discharge
● Benign appearance on imaging; on ultrasonography, pure cyst, mixed image or solid mass
● Can be divided into pure form and those associated with ductal carcinoma in situ (DCIS) or invasive carcinoma
● Considered noninvasive or minimally invasive, because there is no infiltrating growth pattern and metastases are rare
● Traditionally considered to lack a myoepithelial layer (Am J Clin Pathol 2005;123:36), but one study found expression of type IV collagen (Am J Clin Pathol 2009;131:228)
● More difficult to diagnose preoperatively than other breast tumors (Surg Today 2009;39:5)
● Pseudo-invasion may be due to prior core biopsy causing epithelial displacement (J Clin Pathol 2002;55:780)

Case reports
=========================================================================

● 44 year old man (J Med Case Reports 2009;13:13)
● 58 year old woman with solid variant (Eur J Gynaecol Oncol 2008;29:545)
● 64 year old man with microinvasive tumor (Breast Cancer 2010;17:146)
● Micrometastases in lymph nodes (Int J Surg Pathol 2007;15:143)
● 3 case (Case Rep Obstet Gynecol 2012;2012:979563)

Treatment
=========================================================================

● Favorable prognosis (Am J Surg Pathol 2006;30:1002), even with invasion (Cancer 2008;113:916, Hum Pathol 1998;29:1097)
● Stromal invasion in 92% with high nuclear grade, frequent mitotic activity, cyclin D1+ or p53+ (Breast J 2005;11:2)
● Treatment is similar to that of DCIS (Am J Surg Pathol 2006;30:1002), namely excision, with possible adjuvant radiation or endocrine therapy (Am J Surg 2007;194:497)

Gross description
=========================================================================

● Mural nodule within a large cystic space; may be encapsulated

Gross images
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Intracystic hemorrhagic tumor with invasion


Thick walled cyst in cystic space


Well defined fibrous margin

Micro images
=========================================================================


       
Papillary tumors

           

           
Classic features


Encapsulated tumor with hemorrhage


Papillary and solid pattern of atypical cells


Focal invasion

   
Core biopsy with luminal calcifications


CK 5/6 negative


Pseudoinvasion due to epithelial displacement post-biopsy

Virtual slides
=========================================================================



Intracystic papillary carcinoma

Positive stains
=========================================================================

● Type IV collagen in one study (Am J Clin Pathol 2009;131:228)

Negative stains
=========================================================================

● CK 5/6, myoepithelial markers except for type IV collagen



Intralymphatic breast carcinoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 10 October 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

See also angiolymphatic invasion, inflammatory carcinoma

● Extensive intralymphatic component with no (pure intralymphatic carcinoma) or only minimal (predominantly pure intralymphatic carcinoma) residual invasive carcinoma (Am J Surg Pathol 2009;33:256)

Clinical description
=========================================================================

● Clinically significant pattern of residual disease post chemotherapy; associated with post-chemotherapy nodal metastases

Treatment
=========================================================================

● Presence of residual intralymphatic tumor is associated with increased mortality

Gross description
=========================================================================

● Pure cases may have no gross findings

Micro description
=========================================================================

● Pure cases have no invasive disease
● Predominantly pure cases have minimal invasive disease

Positive stains
=========================================================================

● D2-40 is helpful to identify lymphatics, although it also stains myoepithelium, particularly in solid DCIS and LCIS (Hum Pathol 2008;39:175)
● E-cadherin is associated with lymphovascular invasion (Cancer 2003;97:2341)

Differential diagnosis
=========================================================================

● Metastatic ovarian serous carcinoma (Breast J 2009;15:176)



Lipid rich carcinoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 10 October 2012, last major update October 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● 90%+ cells have prominent intracytoplasmic neutral lipid

Clinical description
=========================================================================

● 1-2% of breast carcinomas
● Axillary metastases may resemble histiocytes

Treatment
=========================================================================

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

Case reports
=========================================================================

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

Gross description
=========================================================================

● Lobulated, variable circumscription, firm
● 1 to 15 cm

Micro description
=========================================================================

● Nests, cords and sheets of large polygonal cells with foamy or vacuolated cytoplasm containing lipid
● May resemble clear cells or lipoblasts
● Irregular nuclei with coarse chromatin, moderate atypia, prominent nucleoli
● Other patterns are large pleomorphic cells in alveolar pattern with hobnail appearance, oncocytic or apocrine-type change

Micro images
=========================================================================


   
Low power and high power


Fig 1: tumor with pushing borders and lymphoplasmacytic and eosinophilic infiltrate (arrow: high grade comedo DCIS)
Fig 2: tumor composed of sheets and cords of large polyhedral cells with ill-defined borders, fine granular, eosinophilic
cytoplasm and large nuclei with prominent nucleoli and coarse chromatin
Fig 3: also large clear cells with foamy or vacuolated cytoplasm
Fig 4: axillary nodal metastasis



Polygonal tumor cells with distinct cell borders and variable cytoplasmic clearing (AFIP)

Positive stains
=========================================================================

● Lipid stains (Sudan black, Oil red O on fresh tissue)
● HER2 (71%+, Tumori 2008;94:342, Ann Diagn Pathol 2011;15:225)

Negative stains
=========================================================================

● Glycogen (PAS)
● Mucin
● Usually ER, PR
● CK5/6, CK14, p63

Electron microscopic description
=========================================================================

● Numerous intracytoplasmic non-membrane bound lipid droplets, often within autophagocytic vacuoles
● No evidence of lipid synthesis by rough ER or Golgi complexes (Virchows Arch A Pathol Anat Histopathol 1988;413:381)

Electron microscopic images
=========================================================================



Luminal microvilli, lipid droplets and mitochondria

Differential diagnosis
=========================================================================

Apocrine carcinoma: uniformly granular and eosinophilic cytoplasm, GCDFP15+, no lipid
Glycogen-rich carcinoma: clear cytoplasm, secretions are glycogen (PAS+), not lipid
Oncocytic carcinoma: granular and markedly eosinophilic cytoplasm, no lipid
Secretory carcinoma: low grade, PASd+ secretions, no lipid
Xanthogranulomatous mastitis (on core biopsy): not invasive, cells are CD68+, alpha-1-antitrypsin+ histiocytes (Pathol Int 2009;59:234)

Additional references
=========================================================================

Stanford University



Luminal phenotype


Reviewer: Monika Roychowdhury, M.D., (see Reviewers page)
Revised: 15 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Defining molecular feature is ER expression
● Major difference between luminal A and luminal B breast cancers is degree of proliferation and HER2 expression signature, which is more pronounced in luminal B (Breast Care (Basel) 2011;6:258)

Terminology
=========================================================================

● Not part of current WHO breast classification

Clinical features
=========================================================================

● Classification is based on gene expression (molecular) profile studies; subtype reflects clustering of genes activated by ER signaling pathways
● Distribution by molecular typing is: luminal A: 71%; luminal B: 8%; HER2+: 6%; basal-like: 15% (Ann Surg Oncol 2009;16:2705)
● Luminal subtypes include luminal A (ER+ [strong], PR+, HER2-) and luminal B (ER+ [weak/moderate], PR-, sometimes HER2+)
● Some authors also include categories of luminal A-HER2 and luminal B-HER2 hybrids (Int J Clin Exp Pathol 2009;2:444)
● Luminal cytokeratins are CK7/8, 18 and 19
● Luminal A and B subtypes are associated with mutations in E-cadherin and MAP2K4, and amplifications of Cyclin D1, HER2 and HDM2 (Breast Cancer Res Treat 2010;121:53)
● Luminal A breast cancers are usually low grade, with slow growth and better prognosis than luminal B (J Natl Cancer Inst 2009;101:736)
● Luminal B breast cancers: some are HER2+, but the major biological distinction from Luminal A is the proliferation signature, in which CCNB1, MKI67 and MYBL2 genes have higher expression in luminal B than in luminal A tumors (BMC Genomics 2006 Apr 27;7:96)
● Luminal A and most grade 1 luminal B (HER2+) cases are low proliferative (Breast Cancer 2012 Mar 31 [Epub ahead of print])

Micro images
=========================================================================



Classic Luminal A tumor is ER+ (strong), Ki-67 low


Uncommonly, Luminal A tumor has high Ki-67 index

Various images

Positive stains
=========================================================================

● CK7, CK8/18, ER

Additional references
=========================================================================

Clin Exp Metastasis 2012;29:493, Oncology 2011;81:336



Lymphoepithelioma-like carcinoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 12 December 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare in breast, more common in pharynx

Terminology
=========================================================================

● Not part of WHO breast classification

Epidemiology
=========================================================================

● Usually older patients

Case reports
=========================================================================

● 45 year old woman with possible HPV association (Anticancer Res 2012;32:1435)
● 47 year old woman (Virchows Arch 2005;447:653)
● 50 year old woman with coexisting lymphocytic mastitis (Arch Pathol Lab Med 2001;125:669)
● 53 year old woman with preoperative FNA (Acta Cytol 2012;56:85)
● 65 year old woman (Mod Pathol 1994;7:129)
● HPV18+/HPV33+ tumor (Hum Pathol 2008;39:298)

Gross description
=========================================================================

● Multiple nodules, without circumscription

Micro description
=========================================================================

● Dense inflammatory infiltrate of mature round lymphocytes and lymphoid follicles with occasional plasma cells, histiocytes and 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

Micro images
=========================================================================



Various images

       
Bladder: high grade tumor cells in sheets and nests; AE1/AE3

Other images: Lymphoepithelioma-like carcinoma, Strong cytoplasmic staining

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)

Differential diagnosis
=========================================================================

Medullary carcinoma: circumscribed, syncytial growth pattern

Additional references
=========================================================================

Breast J 2009;15:658



Medullary carcinoma


Reviewer: Monika Roychowdhury, M.D., (see Reviewers page)
Revised: 16 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Well circumscribed, composed of poorly differentiated cells in syncytia or large sheets, with prominent lymphoplasmacytic infiltrate, scant fibrous stroma, no glandular structures, minimal DCIS
● Considered a type of basal-like carcinoma (Breast Cancer Res 2007;9:R24, Am J Surg Pathol 2007;31:501)
● “Medulla” refers to soft structure of marrow (tumors are often soft)

Clinical features
=========================================================================

● Uncommon, <1% of invasive breast carcinomas
● Usually < 50 years old, often < 35 years old, common in Japanese, associated with BRCA1 mutations
● More activated cytotoxic lymphocytes than poorly differentiated ductal carcinomas (Mod Pathol 1999;12:1050, Mod Pathol 2008;21:1101)

Treatment and prognosis
=========================================================================

● Slightly better prognosis than invasive ductal carcinoma NOS, even though high grade, aneuploid, ER/PR negative, p53 positive and high proliferation rates (Hum Pathol 1988;19:1340, Int J Radiat Oncol Biol Phys 2005;62:1040)
● Better prognosis may be due to prominent inflammation (Eur J Cancer 2009;45:1780, Mod Pathol 2010;23:1357)

Case reports
=========================================================================

● 58 year old woman with synchronous bilateral medullary carcinoma (J Cancer Res Ther 2012;8:129)

Gross description
=========================================================================

● Well circumscribed, often large, resembles fibroadenoma but without whorls
● Soft, fleshy, tan-gray
● No desmoplasia
● Easy to cut, large areas of necrosis and hemorrhage

Gross images
=========================================================================



Sharply defined margin with internal nodularity and bosselated surface (AFIP)


Various images

Atypical medullary carcinoma: primary and nodal metastases #1   #2

Other images:: gray-fleshy tumor   tan-pink tumor with circumscribed margin   tumor with extensive hemorrhage

Micro description
=========================================================================

● (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

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

Other features:
● 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

Micro images
=========================================================================


           
High grade tumor cells with syncytial pattern of cells


More distinct cell borders

               
Clusters of sheets of syncytial cells with prominent lymphoplasmacytic infiltrate


Various images


Lymphocytes in micropapillary and medullary carcinomas


Tumor cells have syncytial pattern and high grade nuclei, necrosis
at upper left, lymphoplasmacytic infiltrate at lower right (AFIP)



A lobule with in situ carcinoma in some lobular units;
thick basement membranes, are nonspecific feature (AFIP)



Focal areas of squamous metaplasia with keratin pearls
Note solid growth pattern with distinct cell membranes
(not syncytia) in areas of squamous metaplasia (AFIP)


       
ER neg           p63             p53

       
HER2 staining (usually is negative, in this case, is focally 3+ [see image on right])

Other images: high grade syncytial pattern #1   #2

Atypical medullary carcinoma

Tumor invades fat and is not well circumscribed (AFIP)


Medullary features include poorly differentiated nuclei,
syncytial growth, lymphoplasmacytic infiltrate (AFIP)


Other images: atypical medullary carcinoma because no lymphoplasmacytic infiltrate

Cytology description
=========================================================================

● Cellular smears
● Tumor cells in loosely cohesive sheets and single cells
● Moderate/marked nuclear pleomorphism and nuclear irregularities, mixed with mononuclear inflammation (Diagn Cytopathol 2007;35:408, Acta Cytol 2009;53:165)

Cytology images
=========================================================================



Fig D: FNA shows syncytium of cells with vesicular nuclei and prominent nucleoli in lymphocytic background

Other images: atypical medullary carcinoma #1   #2

Virtual slides
=========================================================================



Medullary carcinoma


Atypical medullary carcinoma

Videos
=========================================================================




Positive stains
=========================================================================

● CK5/6 (94%), p53 (77%)
● High Ki-67 index
● Also HLA-DR, S100

Negative stains
=========================================================================

● ER, PR, HER2 (Arch Pathol Lab Med 2003;127:1458)
● EBV
● Mammaglobin-A (Am J Clin Pathol 2012;137:747)

Molecular / cytogenetic description
=========================================================================

● Microsatellite instability is uncommon, in contrast to medullary colonic tumors (Am J Clin Pathol 2001;115:823)
● Similar genetic alterations as basal-like carcinomas
● Usually aneuploid
● Associated with BRCA1 mutations

Molecular images
=========================================================================



FISH and IHC show HER2 amplification in high grade invasive ductal carcinoma (figures A/B), but not in medullary carcinoma (figures C/D)


CISH - heterogeneous expression of HER2

Differential diagnosis
=========================================================================

Undifferentiated ductal carcinoma: lacks prominent lymphoplasmacytic infiltrate, has infiltrative borders
Lymphoepithelioma-like carcinoma: has infiltrative borders
Lymph node in axillary tail: not circumscribed and may not be syncytial
Collision tumor of invasive ductal NOS and MALT lymphoma: see Arch Pathol Lab Med 2004;128:99

Additional references
=========================================================================

Stanford University



Metastases to breast


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 2 October 2012, last major update October 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

See also metastases to male breast

Clinical features
=========================================================================

● Rare (1-2% of breast tumors), usually from contralateral breast (Arch Pathol Lab Med 2008;132:931)
● Also lung, melanoma, ovary, kidney, stomach and thyroid (World J Surg Oncol 2007;5:74)
● Usually occurs in patients with advanced disease
● In children, rhabdomyosarcoma (alveolar variant) is most common metastasis to breast

Case reports
=========================================================================

● Chordoma in 74 year old woman (APMIS 2006;114:726)
● Choriocarcinoma in 27 year old woman (AJR Am J Roentgenol 2005;184(3 Suppl):S53)
● Colonic adenocarcinoma in 63 year old woman (J Korean Surg Soc 2011;81 Suppl 1:S43)
● Colonic carcinoid in 53 year old woman (Arch Pathol Lab Med 2003;127:1373)
● GI (World J Gastroenterol 2006;12:2958, Am J Clin Pathol 2004;121:884, Asian J Surg 2006;29:95)
● Lung: small cell carcinoma in 50 year old woman (Diagn Cytopathol 2009;37:208) or squamous cell carcinoma in 48 year old woman (Anticancer Res 2008;28:1299)
● Melanoma in 47 year old woman (Diagn Cytopathol 2000;22:246)
● Neuroendocrine tumor (Histopathology 2011;59:619)
● Osteosarcoma in 15 year old girl (Australas Radiol 1999;43:108)
● Pancreatic islet cell tumor (Am J Surg Pathol 2006;30:912)
● Primary peritoneal carcinoma (Ann R Coll Surg Engl 2012;94:e57)
● Renal carcinoid tumor (Am J Surg 2006;191:799, Diagn Cytopathol 2007;35:306)
● Renal cell carcinoma in 81 year old woman (World J Surg Oncol 2007;5:25)
● Retroperitoneal leiomyosarcoma (Diagn Cytopathol 2007;35:508)
● Rhabdomyosarcoma (Pediatr Hematol Oncol 1996;13:277)
● Salivary gland tumor (Acta Cytol 2002;46:377)
● Small intestinal carcinoid (Arch Pathol Lab Med 2004;128:292, World J Surg Oncol 2006;4:15)
● Thyroid in 59 year old woman (Ann Pathol 1998;18:130)
● Various metastases may resemble inflammatory breast cancer (Breast Cancer 2008;15:315, Int J Dermatol 2007;46:303, Breast J 2009;15:176)

Gross description
=========================================================================

● Often superficial (in soft tissue), well-circumscribed firm nodules without skin retraction or peau d’orange

Gross images
=========================================================================



Colonic adenocarcinoma

Micro description
=========================================================================

● Most important feature is that it does not resemble a primary breast carcinoma
● Usually no ductal carcinoma in situ (DCIS), although infiltrative pattern may resemble DCIS (Ann Diagn Pathol 2001;5:15)

Metastatic ovarian or peritoneal serous carcinoma to breast or axilla:
● Rare, but may resemble poorly differentiated ductal carcinoma or micropapillary carcinoma
● Tumors have papillary architecture, often WT1+ and GCDFP15 negative (Am J Surg Pathol 2004;28:1646, Am J Surg Pathol 1993;17:193), although breast mucinous carcinomas may also be WT1+ (Mod Pathol 2008;21:1217)

Micro images
=========================================================================



Choriocarcinoma: antibody to hCG

   
Colonic adenocarcinoma


Colonic carcinoid

                                         
Lung: neuroendocrine carcinoma      Chromogranin+             Synaptophisin+


Renal cell carcinoma

           
Small intestinal carcinoid


Small intestinal carcinoid-chromogranin+

Cytology images
=========================================================================


   
Left: medulloblastoma; right: melanoma

Negative stains
=========================================================================

● GCDFP15
● ER, PR (usually)



Micropapillary carcinoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 6 October 2012, last major update September 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● Tumor composed of small clusters of cells within clear stromal spaces resembling dilated vascular channels
● First described by Tavassoli (Mod Pathol 1993;6:660)

Epidemiology
=========================================================================

● Rare, < 2% of invasive breast cancers have substantial micropapillary pattern
● Mean age 59 years, range 25-92 years

Clinical features
=========================================================================

● Morphologically similar to micropapillary tumors of bladder, lung and major salivary glands
● May be caused by reversal of cell polarity and MUC1 expression, resulting in detachment of tumor cells from stroma, promoting their spread and leading to early nodal metastases (Mod Pathol 2004;17:1045)
● Sialyl Lewis X/CD15s, the ligand of E-selectin, also exhibits reversed cell polarity in these tumors (Int J Surg Pathol 2010;18:193)
● Tumor infiltrating lymphocytes usually lack cytotoxic phenotype (Mod Pathol 2008;21:1101)
● Increased expression of CD146 and microvessel density (Pathol Res Pract 2011;207:739)

Prognostic features
=========================================================================

● Very aggressive with poor prognosis (Adv Anat Pathol 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 Pathol 1999;30:1459)
● Focal component found in 6% of all breast carcinomas - these cases have same poor prognosis regardless of amount of micropapillary component (Mod Pathol 2001;14:836, Am J Clin Pathol 2006;126:740); exception is that presence of micropapillary pattern in mucinous / colloid carcinoma of breast may have no clinical significance (Int J Surg Pathol 2008;16:251)
● Presence of micropapillary features and retraction artifact in core biopsies predicts nodal metastases (Am J Surg Pathol 2009;33:202)

Case reports
=========================================================================

● 35 year old woman with multifocal grade III invasive micropapillary carcinoma associated with metaplastic breast carcinoma (Int J Surg Pathol 2012;20:488)
● 51 year-old woman with myoepithelial carcinoma and contralateral invasive micropapillary carcinoma of the breast (J Korean Surg Soc 2011;81:211)
● 59 year old woman with a 2 cm breast mass, who underwent lumpectomy and axillary dissection (Case of the Week #4)
● 66 year old man with pure invasive micropapillary carcinoma of breast (Can J Surg 2005;48:156)
● Series of eight cases of invasive micropapillary carcinoma of breast (Breast J 2012;18:267)
● Invasive micropapillary carcinoma of the male breast with neuroendocrine differentiation (Zhonghua Bing Li Xue Za Zhi 2011;40:704)

Gross description
=========================================================================

● Mean tumor size 2 cm, range 0.1 to 10 cm
● Lobulated outline

Micro description
=========================================================================

● Well formed, angular and 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 and no lymphocytic inflammation

Micro images
=========================================================================


       
Low power

                                        
High power                       Well defined margins                     Tumor cell nests within fine reticular stroma

                                        
Various images                Tumor infiltrating lymphocytes      With siliconoma

                                                                      
Nested pattern with intervening clear spaces                         Nodal metastases


Infiltrating ductal carcinoma with focal micropapillary features

                                                                      
Tumor cell clusters are surrounded by clear                          Tumor cells have some features
empty spaces, cells have abundant mildly                             of colloid / mucinous carcinoma
granular cytoplasm and nuclear clearing

                                          
MUC1 stain                       Highlights tumor cell clusters       In breast and bladder tumors

Low power

Tumor cell clusters are surrounded by clear empty spaces, cells have abundant mildly granular cytoplasm and nuclear clearing

Cytology description
=========================================================================

● Increased cellularity, angulated clusters, abortive papillae and isolated malignant cells
● Staghorn epithelial structures in 35% (Pathology 2007;39:401)
● May have few malignant appearing multinucleated giant cells or focal mucin (Acta Cytol 2009;53:463)
● No fibrovascular cores (Cancer 2002;96:280)

Positive stains
=========================================================================

● 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 (20-80%) and GCDFP-15 (30%)

Negative stains
=========================================================================

● MUC2, CK5, CK20, c-kit/CD117, EGFR (Arch Pathol Lab Med 2005;129:1277) and WT1 (usually)

Molecular description
=========================================================================

● Mixed tumors have genetic profiles more similar to pure tumors than to ductal carcinoma (J Pathol 2009;218:301)
● High cyclin D1 expression, high proliferation rates and MYC (8q24) amplification (J Pathol 2008;215:398)

Electron microscopy description
=========================================================================

● Secretory activity in stroma-facing surface of tumor cells

Differential diagnosis
=========================================================================

● Metastatic ovarian papillary serous carcinoma: WT1+, GCDFP15- (Hum Pathol 2008;39:666)
● Metastatic micropapillary carcinoma: breast primaries are ER+, mammaglobin+, PAX8/WT1-, other primaries have different patterns (Am J Surg Pathol 2009;33:1037)
● Extensive lymphovascular invasion by a primary or metastatic breast carcinoma

Additional references
=========================================================================

Mod Pathol 1999;12:499, Am J Clin Pathol 2004;121:857, AJR Am J Roentgenol 2002;179:927, Stanford University



Mixed ductal and lobular carcinoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 14 October 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● Mixture of ductal carcinoma NOS and lobular carcinoma

Terminology
=========================================================================

● Not part of WHO breast classification

Clinical features
=========================================================================

● Age of onset similar to infiltrating ductal carcinoma
● Survival similar to pure ductal or lobular types
● Compared to pure ductal carcinomas, have higher rate of second primary breast cancers (World J Surg Oncol 2010;8:51, Breast Cancer Res Treat 2009;114:243
● Compared to pure lobular carcinomas, have lower rate of synchronous contralateral breast cancer
● 4% of breast carcinomas
● 89% have DCIS, 31% have LCIS
● 41% have positive lymph nodes at diagnosis
● May have higher plasma levels of Soluble human leukocyte antigen s(HLA)-G (Anticancer Res 2012;32:1021)

Micro description
=========================================================================

● Definite features of invasive ductal carcinoma and invasive lobular carcinoma in same tumor

Micro images
=========================================================================


   
Mixed ductal / lobular tumor

   
E-cadherin immunostaining of ductal components of tumor

Positive stains
=========================================================================

● E-cadherin patterns include no staining (similar to lobular), full staining (similar to ductal) or staining of ductal areas only (Am J Clin Pathol 2001;115:85)

Differential diagnosis
=========================================================================

Tubulolobular carcinoma: typical areas of invasive lobular carcinoma with cords of single file cells, which merge with small round to angulated tubules with minute or undetectable lumina
● Collision of two separate neoplasms



Mucin producing carcinomas


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 14 October 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Mucin producing carcinomas
=========================================================================

● Columnar cell mucinous carcinoma
● Cystadenocarcinoma
● Ductal carcinoma NOS with focal mucin production
● Lobular carcinoma (rarely, Pathol Int 2009;59:405)
● Metastatic tumors, include GI and chordoma (APMIS 2006;114:726)
● Mucinous / colloid carcinoma
● Mucinous cystadenocarcinoma
● Mucoepidermoid carcinoma
● Neuroendocrine carcinoma (Am J Surg Pathol 1991;15:677)
● Signet ring carcinoma



Mucinous / colloid carcinoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 14 October 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● Clusters of small uniform cells floating in lakes of extracellular mucin
● Mucin accumulation may be due to inversion of polarity in cell, with mucin secretion directed towards base of cell / stroma, rather than luminal border
● Tumor cells also produce MUC2, a distinctive mucin type (Am J Surg Pathol 2003;27:571, Hum Pathol 1998;29:1517, Histopathology 2003;42:26)
● Classified as type A (paucicellular / no neuroendocrine differentiation), type B (hypercellular / neuroendocrine differentiation) or type AB (intermediate form), although no clinical significance
● Based on molecular studies, mucinous type A is distinct from mucinous type B, and mucinous type B is part of a spectrum with neuroendocrine carcinoma (Mod Pathol 2009;22:1401)
● Pure if 90% of more mucinous / colloid component
● Cases with 75-90% mucinous / colloid component are considered a mixed variant with a prognosis worse than pure mucinous carcinoma, and dependent on the grade of the remaining carcinoma component
● Dictionary definition of colloid: (a) gelatinous material resulting from colloid degeneration in diseased tissue; (b) resembling product of thyroid gland; (c) system in which finely divided particles are dispersed within a continuous medium in a manner that prevents them from being filtered easily or settled rapidly

Terminology
=========================================================================

● Also called gelatinous carcinoma

Epidemiology
=========================================================================

● 0.5 to 3% of breast carcinomas (Cancer Radiother 2009;13:37)
● Usually older women (mean age 71 years, Breast Cancer Res Treat 2008;111:541) with slow growing tumor

Clinical features
=========================================================================

● Nodal metastases are rare (2-4%), but important prognostic factor (Am J Surg 2004;187:528)
● Usually no nodal metastases for tumors < 1 cm (Am J Surg 2008;196:549)
● Micropapillary architecture has no clincal significance (Int J Surg Pathol 2008;16:251, but see Breast J 2008;14:412)

Prognostic features
=========================================================================

● 10 year survival for pure form is > 90% (much better than ductal carcinoma NOS)
● Death may occur late, although 20 year breast cancer specific survival is still > 80%

Case reports
=========================================================================

● 35 year old woman with locally advanced tumor and sudden growth (Jpn J Clin Oncol 2002;32:64)
● 36 year old woman with tumor arising within fibroadenoma (Pathologica 2008;100:199)
● 42 year old woman with aggressive, HER2+ tumor (Am Surg 2008;74:113)
● 47 year old woman with vulvar tumor due to ectopic breast tissue (Arch Pathol Lab Med 2002;126:1216)
● 64 year old woman with giant (17 cm) tumor (Breast Cancer 2005;12:337)
● 74 year old man with rapidly growing retroareolar tumor in left breast (Gac Med Mex 2007;143:79)
● 86 year old man with tumor presenting as Paget’s disease of nipple (Diagn Pathol 2008;3:42)
● Woman in 60's with a breast mass (Case of the Week #11)

Treatment
=========================================================================

● Pure cases may not need axillary staging (Ann Surg Oncol 2002;9:161)

Gross description
=========================================================================

● Soft, pale, gray-blue, gelatin-like and well-circumscribed
● Frequently hemorrhagic

Gross images
=========================================================================


                 
Soft, gelatinous mass          AFIP


Tumor with positive margin (Fig 1A/1B)

Soft, gelatinous mass #1#2

Micro description
=========================================================================

● Well-differentiated (low grade) tumor cells floating in a sea of lightly staining amorphous mucin
● Tumor cells may be solid, acinar or detached
● Often surrounded by connective tissue bands
● Recommended that at least 1/3 of tumor volume should consist of mucin, and that no areas of typical invasion should be present (Stanford Universtiy)
● No / rare mitotic figures
● Usually no in-situ epithelial component
Note: recommended to designate tumors as pure (at least 90% mucinous component) or mixed

Micro images
=========================================================================


   
Images from Case of the Week #11

           

           
Abundant mucinous stroma containing epithelial tumor cells with at most mild atypia

AFIP images:
                                                  
Clusters of tumor cells                         Alveolar and festoon            Sparse epithelial
in mucinous secretion                          patterns surrounded            component (arrow-DCIS)
surround a duct                                                                                    by mucin

                                 
Clusters of tumor cells

                                 
ER+, PR+, chromogranin+                   Tumor cells are ER+
and synaptophysin+

                                 
Grimelius staining (an agryophilic silver stain) denotes neuroendocrine differentiation


Ectopic breast tissue in vulva:
Figure 1: mucinous lakes with clusters of tumor cells and adjacent benign breast tissue
Figure 2: ER+
Figure 3: BRST1+


Various images: fig 2, 4

Cytology description
=========================================================================

● Highly cellular, loosely cohesive clusters and dissociated cells with intact cytoplasm and nuclei with mild atypia, no oval bare nuclei
● Also thin walled capillaries, micropapillary pattern of angulated clusters or abortive papillae and ball-like clusters (Acta Cytol 2007;51:25), abundant extracellular mucin (Malays J Pathol 2000;22:65)
● May have spindle cells at edge of nests and in background, which represent either tumor cells compressed by mucin or fibroblasts (Diagn Cytopathol 2009;37:393)
● Variable psammoma bodies (Diagn Cytopathol 2007;35:230)

Cytology images
=========================================================================


                                    
Fig C: FNA shows tightly                         Fig C: FNA shows carcinoma
cohesive tumor cells in                           cells embedded in mucin
mucinous background

Various images: fig 5-9

Colloid carcinoma

Virtual slides
=========================================================================



Mucinous / colloid carcinoma

Videos
=========================================================================


Mucinous / colloid carcinoma

Positive stains
=========================================================================

● ER, PR (< 70%) and MUC2
● Neuroendocrine differentiation (chromogranin, synaptophysin, neuron-specific enolase) in 15-50% (Am J Surg Pathol 1994;18:702)
● Mucin stains with PAS, Alcian blue and mucicarmine
● Also WT1 (65%, Mod Pathol 2008;21:1217), androgen receptor (42%, Ann Oncol 2010;21:488)

Negative stains
=========================================================================

● MUC1 (or low, Histopathology 2003;42:26)
● p53
● HER2 (Kaohsiung J Med Sci 2005;21:197)

Molecular description
=========================================================================

● Usually diploid

Electron microscopy description
=========================================================================

● Differences exist between cells of pure and mixed forms (Ultrastruct Pathol 2007;31:263)

Electron microscopy images
=========================================================================


   
Cytoplasmic mucigen granules

Differential diagnosis
=========================================================================

● Infiltrating ductal carcinoma with focal mucinous change
Invasive micropapillary carcinoma: less extracellular mucin than mucinous carcinoma; cells have abundant eosinophilic cytoplasm, round vesicular nuclei and prominent nucleoli; extensive true angiolymphatic invasion; often psammoma bodies
● Metastatic mucinous carcinoma (rectum-Asian J Surg 2006;29:95)
Mucinous ductal carcinoma in situ: non-invasive, myoepithelial cells (calponin+, p63+) are present
Mucocele-like lesion: myoepithelial cells are present and adherent to strips of cells floating in mucin, also ducts extended by mucinous material
● Myxoid fibroadenoma - has compressed spaces lined by 2 layers
Signet ring carcinoma: intracellular mucin only
● FNA: infiltrating ductal carcinoma - marked atypia (Am J Clin Pathol 2003;120:194)
● FNA: myxoid fibroadenoma - stromal fragments and oval bare nuclei in every case



Mucinous cystadenocarcinoma and columnar cell mucinous carcinoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 6 October 2012, last major update September 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● Very rare as primary breast tumor (< 50 cases reported)
● Carcinoma composed of tall columnar cells with basal, bland nuclei and abundant intracytoplasmic and extracytoplasmic mucin (as opposed to mucinous / colloid carcinoma with only extracellular mucin, and signet ring cell carcinoma with only intracellular mucin)
● Either grossly cystic (mucinous cystadenocarcinoma) or solid (columnar cell mucinous carcinoma)
● Resembles similar tumors of ovary, pancreas and appendix (Am J Surg Pathol 1998;22:698)

Epidemiology
=========================================================================

● Mean age 58-68 years, range 49-96 years

Case reports
=========================================================================

● 41 year old woman with a basal-like immunophenotype (Pathol Int 2012;62:429)
● 52 year old woman (Case Rep Oncol 2009;2:210)
● 65 year old woman whose tumor coexisted with infiltrating ductal carcinoma (Pathol Int 2004;54:781)
● 65 year old woman with primary mammary mucinous cystadenocarcinoma (Diagn Cytopathol 2012;40:624)
● 96 year old woman with mucinous cystadenocarcinoma of breast (Arch Pathol Lab Med 2003;127:1031)
● Mucinous cystadenocarcinoma of the breast with Her2 amplification (Hum Pathol 2010;41:910)

Gross description
=========================================================================

● Multicystic, up to 19 cm
● Resembles ovarian and pancreatic cystadenocarcinoma, cystic hypersecretory carcinoma of breast

Gross images
=========================================================================



Ovary - multicystic tumor

Micro description
=========================================================================

● Cystic spaces lined by bland, tall columnar cells with abundant intracytoplasmic mucin
● Tumor cells exhibit stratification, tufting and papillary formation
● Variable cytologic atypia
● Gradual loss of intracytoplasmic mucin and transformation to eosinophilic squamoid cells that are focally invasive
● Columnar cell variant has round and convoluted glands in loose aggregates, lined by tall columnar mucinous epithelium with basal bland nuclei
● Demonstrates both intracellular and extracellular mucin

Micro images
=========================================================================


       
Mucinous cystadenocarcinoma of breast with estrogen receptor expression


Breast - various images


Retroperitoneal tumor

Positive stains
=========================================================================

● CK7, Ki-67 (high % of cells) and ER (rarely positive, Case Rep Oncol 2009;2:210)

Negative stains
=========================================================================

● CK20, CDX2, ER and PR

Differential diagnosis
=========================================================================

Colloid / mucinous carcinoma: clusters of tumor cells floating in lakes of extracellular mucin
Cystic hypersecretory carcinoma: prominent epithelial hyperplasia and eosinophilic secretions
● Metastatic tumor



Mucoepidermoid carcinoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 6 October 2012, last major update September 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Terminology
=========================================================================

● See also adenosquamous carcinoma; also called adenoacanthoma

Clinical features
=========================================================================

● Very rare
● Grading system used for salivary gland tumors is recommended (Virchows Arch 2004;444:13)

Case reports
=========================================================================

● 46 year old woman with high grade tumor and axillary metastases (Arch Pathol Lab Med 1981;105:612)
● 54 year old woman with mucoepidermoid carcinoma of breast (Pathol Int 2006;56:549)
● Two low grade tumors (Arch Pathol Lab Med 1979;103:196)
● High grade and low grade tumors (Neoplasma 2007;54:168)

Micro description
=========================================================================

● Resembles salivary gland counterpart (Virchows Arch 2004;444:13)
● Mixture of neoplastic mucus-secreting, squamous and intermediate cells

Micro images
=========================================================================


       
In breast affected by burn scars

       
Salivary gland tumors: H&E and Alcian blue-PAS

Cytology description
=========================================================================

High grade tumors:
● Clusters of epithelial ductal cells with mixed glandular, squamous and intermediate cells
● May be scant intra- and extracellular mucin (Acta Cytol 2006;50:344)

Positive stains
=========================================================================

● Keratin, EMA and CEA
● Mucin is PAS+
● Have basal-like phenotype: strong and diffuse expression of CK5/6, p-cadherin, p63, EGFR (Appl Immunohistochem Mol Morphol 2012 Aug 29 [Epub ahead of print])

Negative stains
=========================================================================

● ER, PR and Her2 (Mod Pathol 2010;23:951)

Electron microscopy description
=========================================================================

● Intermediate cells are modified myoepithelial cells (Hum Pathol 1985;16:941)

Differential diagnosis
=========================================================================

Metastatic salivary gland tumor (Acta Cytol 2002;46:377)



Myoepithelial carcinoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 6 October 2012, last major update September 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● Rare tumor composed solely of cytologically malignant myoepithelial cells with mitotic activity

Terminology
=========================================================================

● Also called malignant myoepithelioma

Epidemiology
=========================================================================

● Median age 60 years

Prognostic features
=========================================================================

● 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)
● 69 year old woman with tumor arising in adenomyoepithelioma (Pathol Int 2006;56:211)
● 70 year old woman with myoepithelial carcinoma of the breast (Br J Radiol 2005;78:444)

Treatment
=========================================================================

● Complete excision with negative margins

Gross description
=========================================================================

● Up to 21 cm, well-defined with focal marginal irregularity and may be stellate
● Large tumors may have hemorrhage and necrosis

Micro description
=========================================================================

● 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), due to glycogen (J Clin Pathol 1997;50:700)
● May have necrosis
● Infiltrative growth pattern most frequently with thin anastomosing cords of tumor cells associated with an intimately admixed reactive spindle cell stroma (Virchows Arch 2010;457:337)

Micro images
=========================================================================


                                                   
Irregular dense proliferation        Tumor cells invade normal           Tumor infiltration of stroma
of pleomorphic spindle cells        breast tissue

                         
Myoepithelial carcinoma in          Foci of epithelioid cells
adenomyoepithelioma with
spindle cell elements

                         
S100+                                             p63+

       
Various images

Cytology description
=========================================================================

● Cohesive cell groups composed of spindle cells with atypical cigar-shaped nuclei
● Also epithelioid cells, mitotic figures

Cytology images
=========================================================================


                               
Crowded haphazard cluster of          Nest of pleomorphic cells is composed
cells in metachromatic stroma          of large epithelioid, plasmacytoid and spindle cells

Positive stains
=========================================================================

Myoepithelial markers: smooth muscle actin, S100 and p63
● Also CD10, cytokeratin (pankeratin, CK5 and CK14), vimentin, EGFR
● Reactive stroma: weak positivity for calponin, S100 and smooth muscle actin (Virchows Arch 2010;457:337)

Negative stains
=========================================================================

● ER, PR, HER2

Electron microscopy description
=========================================================================

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

Differential diagnosis
=========================================================================

Spindle cell carcinoma: negative for myoepithelial markers
Fibromatosis: no dominant nodule
Myofibroblastic lesions: usually no dominant nodule, keratin negative

Additional references
=========================================================================

J Clin Pathol 2003;56:497, Pathol Res Pract 2012;208:147



Oncocytic carcinoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 3 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● Composed of 70%+ oncocytic cells
● Also called malignant oncocytoma

Epidemiology
=========================================================================

● Very rare (< 20 cases reported), usually age 60+ years

Prognostic factors
=========================================================================

● Usually high grade (grade 3)

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 (Arch Pathol Lab Med 1989;113:1396)

Micro description
=========================================================================

● Well-circumscribed, abundant granular eosinophilic cytoplasm and low grade nuclei with conspicuous nucleoli (Am J Surg Pathol 1998;22:221)
● Similar to apocrine carcinoma on H&E, but different staining pattern
● No / rare mitotic figures

Micro images
=========================================================================



Salivary gland oncocytic carcinoma

Virtual slides
=========================================================================



Virtual slide

Positive stains
=========================================================================

● Anti-mitochondrial antibody, HER2 (Hum Pathol 2011;42:166)

Negative stains
=========================================================================

● GCDFP-15

Electron microscopy description
=========================================================================

● Numerous mitochondria dispersed throughout cell, occupying 60%+ of cytoplasm

Differential diagnosis
=========================================================================

Apocrine carcinoma: GCDFP-15+, negative for antimitochondrial antibody

Additional references
=========================================================================

Stanford University



Papillary carcinoma - invasive


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 4 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

● See also papillary DCIS, intracystic papillary carcinoma

Terminology
=========================================================================

● Literature often does NOT clearly differentiate between in situ and invasive papillary tumors

Clinical features
=========================================================================

● Rare; invasive and in-situ papillary tumors together are 1-2% of breast carcinomas in women
● Average age 63-67 years
● Present with bloody nipple discharge, abnormal mass or radiographic abnormalities (rounded and circumscribed)
● 50% arise in central part of breast; 25-33% associated with nipple discharge
● Most papillary carcinomas are in situ and are not invasive
● Invasive carcinoma can arise in papillomas
● Invasive portions of papillary DCIS are either papillary carcinoma or ductal carcinoma NOS
● Often, clinical axillary metastases are actually sinus histiocytosis (Am J Clin Pathol 1980;73:313)
● Circumscribed tumors with no apparent invasion may lack myoepithelial markers at tumor-stromal interface (Histopathology 2007;51:657)

Prognostic features
=========================================================================

● 5 year survival is 90%, better than invasive ductal NOS (although some of the papillary cases may, in fact, be in situ only)

Case reports
=========================================================================

● 35 year old man with invasive papillary carcinoma and infiltrating ductal carcinoma (Int J Surg Pathol 2008;16:311)
● 44 year old woman with painless breast lump (Biomed Imaging Interv J 2005;1:e5)
● 63 year old woman with post-traumatic hemorrhagic cyst (The Internet Journal of Surgery;11:1)
● 96 year old woman with solid variant (Arch Pathol Lab Med 2005;129:e128)
● Elderly woman with rare bilateral tumor (Clin Imaging 2007;31:419)

Gross description
=========================================================================

● Often grossly circumscribed

Gross images
=========================================================================



Thick cyst wall with nodular lesions


Circumscribed and partially cystic lesion contains round fleshy papillary nodules (AFIP)

Hemorrhagic tumor nodule with focal infiltration

Micro description
=========================================================================

● Circumscribed, delicate fibrovascular stroma in arborizing pattern
● Either papillary or solid foci formed by ducts nearly or completely filled by a solid neoplastic proliferation
● Also ribbons or trabeculae
● Cells have moderate to abundant cytoplasm, low/intermediate histologic grade, moderate or marked mucin, often papillary DCIS (at periphery), microcalcifications
● May have solid pattern with no discrete papillary pattern, but an underlying fibrovascular stromal network is seen
● May have neuroendocrine features, extracellular or intracellular mucin
● Variable collagen
● Rarely cribriform or comedonecrosis
● Papillae often lack myoepithelial cells

Micro images
=========================================================================



Various images

            
Complex papillary structures         Invasion intro stroma (lower right)
supported by delicate fibrous stalks

            
Core biopsy shows papillary architecture, monotonous cells with nuclear hyperchromasia


Apocrine change

AFIP images:
   
Papillary DCIS with            Residual papilloma in a malignant lesion
invasion above fat


Figure 1: papillary carcinoma
Figure 2: recurrence in myocutaneous flap
Figure 3: recurrent invasive ductal carcinoma


Cytology description
=========================================================================

● Hypercellular, papillary clusters, hemorrhagic background, palisading rows of tall columnar cells, cellular atypia, calcification and eosinophilic, bipolar, cytoplasmic granules (Acta Cytol 1999;43:767)

Positive stains
=========================================================================

● Mucin stains with mucicarmine, Alcian blue and PAS
● ER and GCDFP-15
● Variable synaptophysin, neuron-specific enolase

Negative stains
=========================================================================

● Myoepithelial markers: calponin, smooth muscle myosin heavy chain, p63

Differential diagnosis
=========================================================================

● Fibroadenoma at FNA (Arch Pathol Lab Med 2000;124:1667)
● Metastatic papillary carcinoma

Additional references
=========================================================================

Breast Cancer Res Treat 2010;122:637, Arch Pathol Lab Med 2009;133:893



Sebaceous carcinoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 4 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● Very rare primary breast carcinoma resembling skin adnexal tumor with sebaceous differentiation, but no evidence of cutaneous derivation (see J Med Case Rep 2008;2:276 for cutaneous tumor of breast)

Clinical features
=========================================================================

● Associated with Muir-Torre syndrome (Cancer 2005;103:1018)

Case reports
=========================================================================

● 45 year old woman with extensive metastatic disease (Pathol Int 2000;50:63)
● 46 year old woman with Muir-Torre syndrome (AJR Am J Roentgenol 2000;174:541)
● 50 year old woman (Pathol Int 2009;59:188)
● 63 year old woman (Virchows Arch 2006;449:484)
● 83 year old woman with tumor of nipple (J Cutan Pathol 2008;35:608)

Micro description
=========================================================================

● Well-defined solid sheets or lobules of atypical epithelial cells, including large, pale or clear cells with coarsely vacuolated cytoplasm, containing Oil red O staining lipid and often scalloped nuclei
● Often focal squamous morules

Micro images
=========================================================================



Malignant cells with sebaceous gland differentiation.


Focal calcification and necrosis

Conjunctiva:

Sebaceous carcinoma

Skin:

Various images

Positive stains
=========================================================================

● Cytokeratin, including 35betaH11 (Pathol Res Pract 1993;189:888), EMA
● ER, PR, Oil Red O
● Mismatch repair genes: MLH1, PMS2, MSH2, MSH6 (Ceska Gynekol 2010;75:50)
● Some cells may express neuroendocrine markers

Negative stains
=========================================================================

● GCDFP-15, CEA, S100 and vimentin
● Alpha smooth muscle actin, p63, androgen receptor (usually), mucins, HER2 and CK15

Electron microscopy description
=========================================================================

● Empty appearing, non-membrane bound vacuoles

Differential diagnosis
=========================================================================

Apocrine carcinoma: >90% of tumor cells have cytologic or immunohistochemical features of apocrine cells
Lipid rich carcinoma: usually not coarsely vacuolated, often squamous morules, usually HER2+, ER-, PR-



Secretory carcinoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 29 October 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● Tumor cells with granular eosinophilic cytoplasm and prominent intracellular and extracellular milk-like secretion
● First described in 1966 as juvenile carcinoma by McDivitt and Stewart (JAMA 1966;195:388)
● A type of basal-like carcinoma (triple negative with expression of basal cytokeratins, Mod Pathol 2009;22:291)

Terminology
=========================================================================

● Also called juvenile carcinoma

Epidemiology
=========================================================================

● Rare, usually children (most common form of breast carcinoma in children), but can occur in adults
● Rare in males

Prognostic features
=========================================================================

● Excellent prognosis, although nodal metastases occur even in tumors < 2 cm (Ann Surg Oncol 2002;9:663, Cancer 1980;45:2404)
● 5 year survival near 100% in children; in women, poorer prognosis in women age 30+ years due to late recurrence and nodal metastases, but death due to disease is rare
● More aggressive in men (Ann Surg Oncol 2002;9:663)

Case reports
=========================================================================

● 7 year old girl with axillary nodal metastases (Ethiop Med J 2012;50:89)
● 17 year old boy with recurrent breast swelling (World J Surg Oncol 2004;2:17)
● 23 year old man with unilateral gynecomastia (Am J Surg Pathol 1988;12:150)
● 27 year old woman with recurrent tumor after mastectomy (Am J Surg Pathol 1993;17:715)
● 33 year old woman with positive sentinel node (World J Surg Oncol 2006;4:88)
● 40 year old woman with tumor arising within radial scar (Indian J Pathol Microbiol 2009;52:83)
● 46 year old woman with axillary tumor (Arch Pathol Lab Med 2001;125:1372)
● 52 year old man with recurrent tumor at chest wall and lung metastases (World J Surg Oncol 2005;3:35)
● 52 year old woman with breast mass and two positive axillary lymph nodes (Case of the Week #8)
● 60 year old woman with tumor ulcerating through skin (Arch Pathol Lab Med 2006;130:1073)
● 61 year old woman with tumor exhibiting apocrine differentiation (Arch Pathol Lab Med 2006;130:e50)
● Young girl with axillary tumor (Am J Surg Pathol 2009;33:950)

Clinical images
=========================================================================



17 year old boy with breast mass and skin involvement


7 year old Ethiopian girl with breast mass present for 2 years

Gross description
=========================================================================

● Small, well-circumscribed and often near areola

Micro description
=========================================================================

● Sheet-like growth, usually circumscribed, pushing margins, occasional foci of infiltration (Stanford University)
● Tubuloalveolar and focally papillary formations composed of relatively bland cells with uniform, low-grade nuclei
● Abundant pale to eosinophilic, often vacuolated cytoplasm, but little pleomorphism
● Prominent nucleoli
● PAS+ diastase resistant eosinophilic secretions
● Also prominent hyalinization centrally, in situ component
● No atypia, no / rare mitotic figures
● May be difficult to differentiate in situ from invasive disease

Micro images
=========================================================================



Case of Week #8


Arising within radial scar


Intracytoplasmic lumina with secretions


AFIP images:
      
Intraductal component      Microcystic pattern below,
with microcystic features    solid apocrine pattern above


Secretion tends to shrink toward center of lumen, may have a scalloped border in larger microcysts


Various images


PAS+ diastase resistant secretions


Various immunostains


Figure 1: solid and cystic tumor with brown-yellow mucoid material in cysts
Figure 2: tumor cells are arranged in glandular pattern with eosinophilic secretions in lumen
Figure 3: focally are vacuolated secretory cells
Figure 4: secretions are PAS+ diastase resistant



Figure 1: FNA shows abundant, granular and vacuolated cytoplasm
Figure 2: firm white cut surface
Figure 3: tumor cells have abundant pale to pink or amphophilic cytoplasm and prominent nucleoli
Figure 4: secretions are PAS+


Cytology description
=========================================================================

● Cohesive sheets of monotonous cells with intracytoplasmic vacuoles, round nuclei and small nucleoli (Diagn Cytopathol 2005;32:47)

Positive stains
=========================================================================

● Keratin, EMA, S100, alpha-lactalbumin and mucicarmine
● Variable GCDFP-15 and CEA
● Secretions are Alcian blue+, PAS+
● Variable intranuclear or cytoplasmic p63 (Int J Surg Pathol 2012;20:367)

Negative stains
=========================================================================

● Usually ER, PR and HER2 (triple negative)

Molecular description
=========================================================================

● Usually t(12;15)(p13;q25), producing ETV6-NTRK3 fusion gene that is also seen in cellular mesoblastic nephroma and infantile fibrosarcoma (Hum Pathol 2003;34:1299, Semin Cancer Biol 2005;15:215, Genes Chromosomes Cancer 2004;40:152, AtlasGeneticsOncology.org)

Molecular images
=========================================================================


   
FISH shows t(12;15)   t(12;15) in 6 year old girl

Electron microscopy description
=========================================================================

● Numerous, membrane-bound, intracytoplasmic secretory vacuoles

Electron microscopy images
=========================================================================



Large irregular cytoplasmic vacuoles lined by villi (AFIP)

Differential diagnosis
=========================================================================

Acinic cell carcinoma: no t(12;15) (Histopathology 2008;52:840)

Additional references
=========================================================================

Am J Surg Pathol 1980;4:465, Arch Pathol Lab Med 1991;115:141, Mod Pathol 1994;7:475
Stanford University, Int J Breast Cancer 2011;2011:704657



Signet ring cell variant of invasive ductal carcinoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 4 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● Ductal carcinoma with cells resembling gastric carcinoma due to acidic mucin that fills cytoplasm and displaces nucleus
● Excludes cases with lobular features (signet ring variant of lobular carcinoma)

Case reports
=========================================================================

● 40 year old woman presenting with cystic pelvic mass (Acta Chir Belg 2005;105:224)
● 52 year old woman with associated invasive ductal carcinoma (Breast Cancer 1999;6:223)
● 54 year old woman with uterine metastases (J Obstet Gynaecol Res 2012;38:948)
● 68 year old woman (Pathol Int 2000;50:67)
● 73 year old woman with invasive ductal carcinoma with signet ring cell and mucinous carcinoma components (Diagn Cytopathol 2007;35:171)
● 74 year old woman with metastatic breast cancer to stomach resembling early gastric cancer (Case Rep Oncol 2010;3:142)
● Ductal type signet ring cell carcinoma of breast (Pathology 2011;43:282)

Micro description
=========================================================================

● Mucin fills cytoplasm and displaces nucleus
● Usually coexists with invasive ductal NOS
● High nuclear grade; DCIS may be present, but no lobular features (by definition)

Micro images
=========================================================================



Breast metastasis to stomach

Cytology description
=========================================================================

● Look for signet ring cells if plasmacytoid cells are identified
● Favor ductal carcinoma if hypercellular, single signet ring cells, high nuclear grade and tubule formation
● Favor lobular carcinoma if hypocellular, single signet ring cells and mild / moderate nuclear grade (Cytopathology 2009;20:321)

Differential diagnosis
=========================================================================

Signet ring variant of lobular carcinoma: usually classic lobular component present, no DCIS, ER+ and E-cadherin negative
● Metastatic GI signet ring carcinoma: history, no DCIS, CDX2+ and ER- (Am J Clin Pathol 2004;121:884, ISRN Obstet Gynecol 2011;2011:426150)



Small cell carcinoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 29 October 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● Similar morphologically to lung tumor
● Diagnosis requires exclusion of other primaries or presence of DCIS
● Also known as oat cell carcinomas, high-grade neuroendocrine carcinoma, small cell undifferentiated carcinoma
● May arise as variant of metaplastic carcinoma or from multipotential stem cells capable of divergent differentiation (Surg Today 2008;38:734)
● Prognosis may not be as poor as previously thought (Am J Surg Pathol 2000;24:1231)

Epidemiology
=========================================================================

● Rare, usually ages 43-70 years

Case reports
=========================================================================

● 60 year old woman with multiple axillary nodal metastases (Arch Pathol Lab Med 2000;124:296)
● 61 year old woman with E-cadherin negative tumor (Am J Clin Pathol 2004;121:117)
● 64 year old woman (J Korean Surg Soc 2012;82:116)
● Merging with solid variant of adenoid cystic carcinoma (Pathol Res Pract 2005;201:705)

Treatment
=========================================================================

● Surgery, possibly chemotherapy (Breast Cancer 2009;16:68)

Gross description
=========================================================================

● Mean 3 cm, range 1-5 cm

Micro description
=========================================================================

● Typical small cell carcinoma features of scant cytoplasm, small (diameter of three lymphocytes) nuclei with finely granular, evenly distributed chromatin and absent or inconspicuous nucleoli
● Frequent mitoses
● Frequent crush artifact or nuclear streaming
● Infiltrative borders, lymphatic tumor emboli and necrosis
● Associated with invasive poorly differentiated carcinoma and lobular carcinoma
● Associated with small cell in situ carcinoma and high grade DCIS

Micro images
=========================================================================



Classic features


Immunostains

Lung:

Classic features  H&E, CD117    Flow, H&E and stains (site unknown)

Cytology description
=========================================================================

● Resembles small cell carcinoma of lung (Breast Cancer 2007;14:414)

Cytology images
=========================================================================



Clusters of monotonous neoplastic cells, some with nuclear molding

Positive stains
=========================================================================

● CK7, E-cadherin (100%, Am J Surg Pathol 2001;25:831)
● ER or PR (35-50%, Semin Oncol 2007;34:64)
● BCL2, TTF1 (20%)
● Variable neuroendocrine staining (neuron specific enolase, synaptophysin, chromogranin)
● May have basal-like phenotype due to expression of EGFR and basal type keratins (Int J Surg Pathol 2009;17:368), or “triple negative” pattern (Med Mol Morphol 2009;42:58)

Negative stains
=========================================================================

● CK20, HER2

Molecular description
=========================================================================

● Small study shows similar genetic changes as both invasive ductal carcinoma and lung small cell carcinoma (Hum Pathol 2001;32:753)

Differential diagnosis
=========================================================================

Invasive lobular carcinoma: single file or targetoid patterns, cells have low grade features with occasional intracytoplasmic vacuoles, no nuclear molding and are E-cadherin negative
Metastatic tumor from lung or elsewhere: see Diagn Cytopathol 2009;37:208

Additional references
=========================================================================

Stanford University, J Clin Pathol 2005;58:775



Squamous cell carcinoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 4 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

See also acantholytic subtype

Definition
=========================================================================

● Primary breast carcinoma composed entirely of metaplastic squamous cells with variable keratin or spindle cells

Clinical features
=========================================================================

● Very rare (< 0.2% of breast primaries) if exclude cutaneous tumors, squamous component of phyllodes tumors and squamous-like areas of medullary carcinoma (Hum Pathol 1984;15:526)
● Aggressive and often refractory to treatment (Eur J Obstet Gynecol Reprod Biol 2008;137:222, J Clin Oncol 2005;23:7827)

Case reports
=========================================================================

● 32 year old lactating woman (Jpn J Clin Oncol 2000;30:279)
● 55 year old woman with cerebellar metastases (Fukushima J Med Sci 2005;51:105)
● 61 year old woman presenting with breast abscess (Breast Dis 2011;33:125); another case presenting as abscess (Clin Breast Cancer 2007;7:713)
● 71 year old woman with intracystic tumor (Breast Cancer 2007;14:109)
● 82 year old woman (World J Surg Oncol 2008;6:135)
● Two cases (Arch Pathol Lab Med 1984;108:893)

Treatment
=========================================================================

● Possibly cisplatin based chemotherapy (Clin Breast Cancer 2009;9:187)

Gross description
=========================================================================

● May have central cyst with keratin

Gross images
=========================================================================



Circumscribed and hemorrhagic tumor


Partially cystic tumor (arrows at margins, AFIP)

Micro description
=========================================================================

● Tumor composed entirely of malignant squamous cells with variable keratinization and spindle cells
● Bland squamous cells may line cystic spaces
● May represent squamous metaplasia in ductal carcinoma
● May have prominent myxoid stroma

Micro images
=========================================================================


    
Keratinizing tumor     Non-keratinizing tumor

AFIP images:
    
Poorly differentiated tumor with acantholysis and keratin pearl


Squamous cell carcinoma with transition to metaplastic spindle cells and early acantholytic changes


Spaces between tumor cells may be mistaken for vessels

Non-keratinizing tumor #1;   #2

Cytology description
=========================================================================

● Squamous cells, isolated and in aggregates and at various stages of maturation (Diagn Cytopathol 2007;35:429)

Cytology images
=========================================================================


Polygonal tumor cells with abundant eosinophilic cytoplasm and nucleus hyperchromasia #1;   #2

Positive stains
=========================================================================

● EGFR (85%, Int J Surg Pathol 2005;13:319), 34betaE12, CK5/6 (75%), p63 (70%)
● High Ki-67 (Anticancer Res 2007;27:547)

Negative stains
=========================================================================

● ER, PR and HER2 (93%)
● Mucin, CEA and vascular markers

Electron microscopy description
=========================================================================

● May have glandular features ultrastructurally (Arch Pathol Lab Med 1980;104:130)

Differential diagnosis
=========================================================================

● Post-traumatic lobular squamous metaplasia (Mod Pathol 1988;1:385)
● Other squamous metaplasia (Eur J Cancer Care (Engl) 2009;18:650)
Metastasis to breast: see Anticancer Res 2008;28:1299



Acantholytic subtype of squamous cell carcinoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 4 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● Acantholysis (lack of cell adhesion) is due to a desmosomal defect, possibly alteration in keratins (Cell Cycle 2008;7:2021)
● May be very aggressive

Terminology
=========================================================================

● Also called pseudoglandular or adenoid squamous cell carcinoma

Case reports
=========================================================================

● 57 year old woman (Cesk Patol 2011;47:184)
● 60 year old woman (Ecancermedicalscience 2011;5:214)

Gross images
=========================================================================



Cystic area with necrosis (upper), gray white solid area (below)

Micro description
=========================================================================

● Pseudovascular or pseudoglandular appearance due to tumor cell discohesiveness
● Lining is composed of squamous epithelium and spaces with necrotic debris and keratin

Micro images
=========================================================================


Breast:

Various images

Conjunctival tumor:

Pseudoglandular pattern due to acantholysis of neoplastic squamous cells

Head and neck:
       
Pseudolumina are present, but no true glands

Skin:
           
Various images

Positive stains
=========================================================================

● Myoepithelial markers: CK14, CD10, p63 (Cesk Patol 2011;47:184)
● May have EGRF overexpression (Virchows Arch 2005;446:305)

Negative stains
=========================================================================

● EMA, factor VIII, PAS and Alcian blue

Differential diagnosis
=========================================================================

Angiosarcoma: endothelial cells line spaces and are CD31+, CD34+, keratin- (Am J Surg Pathol 1986;10:855, Head Face Med 2008;4:17)
Phyllodes tumor
Sarcoma



Tall-cell like tumors


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 4 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● Very rare tumor resembling tall cell variant of papillary thyroid carcinoma, first described in 2003 (Am J Surg Pathol 2003;27:1114)

Terminology
=========================================================================

● Not part of WHO breast classification

Clinical features
=========================================================================

● Presents with palpable nodule
● May have nodal metastases (Int J Surg Pathol 2007;15:14)

Micro description
=========================================================================

● Solid or papillary nests of columnar / cuboidal cells with eosinophilic granular cytoplasm, round / oval nuclei with sharply defined nuclear membrane, nuclear grooves and eosinophilic pseudoinclusions
● Also psammoma bodies

Cytology description
=========================================================================

● Abundant cellularity with isolated cells, sheets and papillary formations of epithelial cells with nuclear grooves (Int J Surg Pathol 2006;14:79)

Positive stains
=========================================================================

● Keratin, ER (alpha and beta), PR
● Also androgen receptor, CEA, bcl2

Negative stains
=========================================================================

● Thyroglobulin, TTF1

Molecular description
=========================================================================

● No BRAF mutations of thyroid carcinoma

Electron microscopy description
=========================================================================

● Cytoplasmic granules are mitochondria

Differential diagnosis
=========================================================================

● Metastatic tall cell variant of papillary thyroid carcinoma: clinical history of thyroid disease, thyroglobulin+, TTF1+ (Ann Pathol 1998;18:130)



Tubular carcinoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 7 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● Special type of breast carcinoma with favorable prognosis, composed of distinct, well-differentiated angular tubular structures (90%+ according to WHO) with open lumina, lined by a single layer of epithelial cells
● Not actually tubular - pattern is better described as a necklace formed by a string of beads (Stanford University)

Clinical features
=========================================================================

● 2-6% of all malignant breast tumors
● Often multifocal / multicentric (20-55%, Am J Surg Pathol 1997;21:653), family history of breast carcinoma (40%)
● Usually presents with pT1 and pN0 disease (Int J Radiat Oncol Biol Phys 2009;75:1304)

Prognostic features
=========================================================================

● A well-differentiated variant with very favorable prognosis (low rate of recurrence or metastasis) and only rare deaths (Am J Surg 2009;197:674)
● Excellent prognosis is restricted to tumors with 70%+ tubules, pure grade 1 nuclei and no / rare mitoses (Am J Clin Pathol 2004;122:728)
● Mixture with ordinary ductal carcinoma has worse prognosis (Hum Pathol 1983;14:694)
● Cause specific survival is 97% at 10 years (Eur J Surg Oncol 2005;31:9)
● 10-27% have axillary metastases, often micrometastases (Eur J Surg Oncol 2006;32:488), but still have excellent prognosis (Breast J 2003;9:298)

Treatment
=========================================================================

● Surgery, long term followup for local recurrence and possibly radiation therapy (Breast Cancer Res Treat 2005;93:199, Breast J 2005;11:129)

Gross description
=========================================================================

● Poorly circumscribed margins, hard consistency, mean size 1 cm

Gross images
=========================================================================



Yellow-white sclerotic mass

Micro description
=========================================================================

● 90%+ tubules with low grade features, irregular angulated contours of glands (“teardrop-like”), open lumina with apocrine-like snouts and basophilic secretions / columnar cell lesions in almost all cases (Adv Anat Pathol 2008;15:140), usually with flat epithelial atypia (Am J Surg Pathol 2007;31:417, Pathol Int 2008;58:620)
● Also desmoplastic stroma
● May form trabecular bars
● Frequently invades fat at periphery
● Fibrous, cellular and elastotic stroma
● Associated with low grade DCIS in 40-65% (micropapillary or cribriform), less often LCIS
● Minimal pleomorphism
● No myoepithelial layer, no mitotic figures, no necrosis, no angiolymphatic or perineural invasion and no basement membrane after PAS or type IV collagen staining

Micro images
=========================================================================


           

           

           
Various images


           
Angular glands with cytoplasmic snouts         With cribriform DCIS

           
Core biopsy     Blue: malignant  Tumor is CK5/6-; normal myoepithelial cells are CK5/6+
          Red: benign


p63 negative (fig e)

AFIP images:
              
Angular glands with    With collagenous and elastotic  With < 90% tubular component,
cytoplasmic snouts    stroma and micropapillary DCIS  arrows point to ductal-type

           
Perineural invasion      Axillary nodal metastasis         Reticulin stains stromal fibers, but fibers do not completely
                                   surround neoplastic glands

Cells in tubules have same morphology as lobular carcinoma cells

Virtual slides
=========================================================================


Tubular carcinoma

Cytology description
=========================================================================

● Increased cellularity, somewhat angular epithelial clusters and single epithelial cells
● Cells are bland and orderly with variable atypia and variable number of prominent myoepithelial cells (Acta Cytol 1997;41:1139, Am J Clin Pathol 1994;101:488)

Positive stains
=========================================================================

● ER, PR and E-cadherin (but reduced)

Negative stains
=========================================================================

● HER2 (Am J Clin Pathol 2006;126:55), p53 and EGFR
● Myoepithelial markers (p63, CD10, smooth muscle actin, CK5/6)

Molecular description
=========================================================================

● Usually diploid
● 16q- (78% of tumors), 1q+ (50%), but fewer overall chromosomal changes than ductal NOS (Hum Pathol 2001;32:222)
● Clonally related to flat epithelial atypia and low grade DCIS (Am J Surg Pathol 2009;33:1646)

Electron microscopy description
=========================================================================

● Ductal differentiation, no myoepithelial cells and no basement membrane

Differential diagnosis
=========================================================================

Benign sclerosing lesion: overall lobular architecture, compression of glandular structures, positive for myoepithelial markers p63 and CD10 or smooth muscle actin (Appl Immunohistochem Mol Morphol 2006;14:71)
Fibroadenoma: biphasic tumor with overgrowth of epithelial and stromal tissue; no true angulated contours of cells (may be compressed by stroma), no desmoplastic stroma
Microglandular adenosis: more rounded tubules, often with colloid-like secretory material (Am J Surg Pathol 1982;6:401)
Ductal carcinoma, low grade: actual tubules, not angular; usually no apocrine-like snouts with basophilic secretions / columnar cell lesions



Tubulolobular carcinoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 7 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● Rare, first described in 1977 (Hum Pathol 1977;8:679)
● Also occurs in anogenital region (Am J Surg Pathol 2006;30:1193)
● May be a well-differentiated ductal carcinoma with a lobular growth pattern, or a tubular variant of lobular carcinoma (Virchows Arch 2006;448:500)

Terminology
=========================================================================

● Not part of WHO breast classification

Epidemiology
=========================================================================

● Median age 60 years, range 43-79 years

Prognostic features
=========================================================================

● Intermediate prognostic features between lobular and ductal carcinoma
● Best prognosis if unilateral and < 2 cm
● 25% present with greater than stage I disease, compared to 0% with tubular and 60% with lobular carcinoma (Mod Pathol 2007;20:130)
● Axillary nodal metastases in 13-43%

Case reports
=========================================================================

● 69 year old woman with tubulobular carcinoma of the breast with grooved and cerebriform nuclei (Diagn Cytopathol 2011;39:54)

Gross description
=========================================================================

● 0.5 to 2.5 cm, usually unilateral and 19-30% multifocal

Micro description
=========================================================================

● Typical areas of invasive lobular carcinoma with cords of single file cells, which merge with small, round to angulated tubules with minute or undetectable lumina
● Usually accompanied by DCIS, LCIS or both
● Tumors are usually well differentiated with small, round nuclei and indistinct nucleoli
● Stroma is densely collagenous with prominent elastosis

Micro images
=========================================================================


       
Mixed tubular and lobular components      Fig a-d

                
Axillary nodal metastasis           Involving complex sclerosing lesion

                
E-cadherin (Fig 3a)              34betaE12 (negative in Fig 4a although usually positive)

       
Beta-catenin+ (Fig 6a) p120 catenin+ (Fig 7a) Tubulolobular breast immunophenotype

       
Small infiltrative glands

AFIP images:
   
             Arrow at tubules

Mixed tubular and lobular components #1;   #2;   #3;   #4

Virtual slides
=========================================================================



Tubulolobular carcinoma

Cytology description
=========================================================================

● Single filing of cells and tubular structures
● Tumor cells have intracytoplasmic vacuoles, low nuclear grade and low mitotic activity
● Relatively clean background
● Variable apocrine cells (Acta Cytol 1996;40:465)

Positive stains
=========================================================================

● E-cadherin (75-100%), 34betaE12 (93%) and Catenins (alpha, beta or gamma-membranous staining in 100%)
● Usually ER+ and PR+
● Aberrant overexpression of CD133 / Prominin-1, collagen IV (basement membrane like pattern, Breast Care (Basel) 2008;3:423)

Differential diagnosis
=========================================================================

Mixed ductal and lobular carcinoma: may lack small, round to angulated tubules with minute or undetectable lumina; may lack prominent elastosis

Additional references
=========================================================================

Am J Surg Pathol 2004;28:1587, Am J Surg Pathol 1997;21:653, Stanford University

End of Breast malignant, males, children > Superpage > Carcinoma subtypes


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