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Breast malignant, males, children

Superpage - In situ carcinoma

Revised: 11 December 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

DCIS - general


Reviewer: Dina Kandil, M.D. (see Reviewers page)
Revised: 19 January 2012, last major update January 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

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

● Neoplastic proliferation with malignant features and ductal phenotype, but confined within spaces bordered by myoepithelium and basement membrane
● May extend into lobules (cancerization of lobules)
● Variable tendency to progress to invasive carcinoma, based on nuclear grade
● Accounts for 15-30% of all breast carcinoma

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

● Mean age 50-59 years
● Five percent of women with DCIS carry a mutation in the BRCA1 or BRCA2 hereditary cancer gene (N Engl J Med 2004;350:1430)

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

● 90% diagnosed while clinically occult because of mammographic detection of microcalcifications (75% of cases), soft-tissue densities (10%), or both (15%)
● 2/3 with low to intermediate grade DCIS have multifocal disease (Hum Pathol 2007;38:1736)
● High grade DCIS tends to be more continuous
● Relative risk for invasive carcinoma of 8-10x compared to general population
● Invasive carcinoma has been reported in 14-60% of untreated women with low grade DCIS after 10 years follow-up (N Engl J Med 2004;350:1430)
● Natural history of untreated high grade DCIS is not well characterized, since most patients have resections
● Ten fold increase in incidence in 1990’s is due to mass screening (Breast Cancer Res Treat 2009;115:181)
● May arise in adenosis, radial scar, fibroadenoma or papilloma; rarely perineural invasion occurs (Hum Pathol 2001;32:785)

Imaging
=========================================================================

● Mammogram shows calcifications in 70%+ of cases
● Linear calcifications are more common in comedo DCIS, while granular calcifications are more common in non-comedo types (AJR Am J Roentgenol 1992;159:483)
● MRI may be a useful adjunct to detect non-calcified DCIS (Breast J 2005;11:382)
● 30% of patients with non-calcified DCIS have false negative imaging (J Ultrasound Med 2009;28:903)

Radiologic images
=========================================================================


   
Clusters of microcalcifications

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

● With osteoclast-like giant cells (Hum Pathol 2006;37:369)
● DCIS skip lesion in nipple (Int J Surg Pathol 2009 Jul 3 [Epub ahead of print])

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

● Surgery: breast conservation therapy with negative margins; mastectomy is reserved for extensive disease
● Radiation therapy after local excision reduces ipsilateral recurrence by 50% (J Clin Oncol 2006;24:3381)
● Tamoxifen further decreases recurrence in patients with ER+ DCIS (Semin Oncol 2006;33:647)
● Possibly sentinel lymph node dissection if patients are planned for mastectomy (Ann Surg Oncol 2008;15:268) or size >5 cm (Am J Surg 2008;196;81), or at high risk of microinvasive carcinoma (Breast J 2008;14:135)
● Approximately half of recurrences are DCIS and half are invasive carcinomas
● Omission of radiotherapy may be considered if DCIS is small size, low grade, and has wide clear margins (J Clin Oncol 2009;27:3211)
● In selected patients with close (< 2 mm) or focally / minimally involved margins, reexcision may be avoided and satisfactory local control achieved by increasing the radiation dose to the tumor bed (Int J Radiat Oncol Biol Phys 2009;75:1021)
● See US National Cancer Institute

Risk factors for local recurrence
=========================================================================

● Positive surgical margins, high nuclear grade and presence of comedo necrosis are the most important predictors of local recurrence after lumpectomy
● Concurrent lobular neoplasia is associated with a higher risk of ipsilateral recurrence in women who receive breast conserving surgery (Cancer 2009;115:1203)

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

● Usually no gross lesion, but high grade DCIS may present as firm gritty mass with multiple areas of round, pale comedonecrosis
● Must carefully examine specimens to exclude small foci of invasive carcinoma
● Difficult to accurately measure size (Arch Pathol Lab Med 2009;133:31, Arch Pathol Lab Med 2009;133:26)

Measuring methods include:
● serial sequential sampling - map each block on sliced specimen radiograph and do 3D reconstruction; accurate but difficult
● calculate size based on areas of calcification
● record number of blocks involved by DCIS and multiply by 0.3 cm to 0.4 cm
● measure largest extent of DCIS on single slide - accurate if DCIS is present on only 1 slide
● mapping method - average thickness of each slice x number of consecutive slices with DCIS

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

● Nuclear grade is determined using 6 morphologic features: nuclear pleomorphism, nuclear size, chromatin, nucleoli, mitosis and polarization
Low grade (grade I): monotonous round cell population with subtle increase in N/C ratio, small (1.5-2.0x normal size) monotonous round nuclei with smooth contours, diffuse fine chromatin, no/indistinct nucleoli; no/rare mitotic figures; polarized toward luminal spaces
High grade (grade III): nuclei are large (2.5x normal size), markedly pleomorphic and angular with irregular contours, coarse chromatin, prominent nucleoli; frequent mitoses; usually not polarized toward luminal spaces
Intermediate grade (grade II): between high grade and low grade
● Grade heterogeneity is common; place cases into higher category if 30% or more ducts are involved by higher grade cells

Specific grading systems (Am J Surg Pathol 2000;24:651):
● Van Nuys:
     1: Non-high grade without necrosis
     2: Non-high grade with necrosis
     3: High grade with or without necrosis
(Lancet 1995;345:1154, table)
● May guide treatment (Cancer 1996;77:2267, World J Surg Oncol 2008 Jun 18;6:61), but validity has been questioned (Cancer 2007;110:2648, Br J Surg 2003;90:426)
● Scott (Modified Lagios system): low, intermediate, high grade; based on nuclear grade and necrosis (absent, focal, extensive, Hum Pathol 1997;28:967)
● European Pathologists Working Group: well, intermediate or poorly differentiated; based on nuclear grade and cell polarization (absent, present/not prominent, prominent, Semin Diagn Pathol 1994;11:167)

● Cancerization of lobules: DCIS growth pattern in which cells fill a lobule, with preservation of normal acinar pattern

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



Grades 1-3 (Van Nuys scoring), p53 staining


DCIS grade 1

   
Low grade


DCIS extending along a duct

       
Cancerization of lobules: extension of DCIS into intralobular ducts


No invasion identified based on myoepithelial markers present

   
Strong E-cadherin staining for DCIS (in background of invasive ductal carcinoma)

Not DCIS:
   
Infiltrative carcinoma with central necrosis


With axillary nodal metastasis


Negative staining for myoepithelial markers

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


       

Other images: #1; #2; high grade

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



DCIS


DCIS and LCIS

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

● E-cadherin (Am J Surg Pathol 2001;25:229)
● ER/PR (strong and diffuse positivity in low grade cases / variable in high grade cases (Mod Pathol 2005;18:615)
● p53 is positive in some high grade DCIS myoepithelial cells
● Positive stains are less positive in DCIS myoepithelial cells than in those surrounding normal mammary ductal-lobular structures (Am J Surg Pathol 2009;33:227)

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

● High molecular weight cytokeratin / 34betaE12 (Hum Pathol 2002;33:620, Am J Surg Pathol 1999;23:1048)

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

● Allelic imbalance in region of BRCA1 gene in 74% of DCIS cases (Br J Cancer 1996;73:636)
● Low grade DCIS and high grade DCIS appear to be genetically distinct disorders
● Low grade DCIS show chromosomal losses at 16q and 17p and gains at 1 q
● High grade DCIS shows losses at 8p, 11q, 13q and 14q, and gains at 5p, 8q and 17q (J Pathol 2005;205:248)

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

Lobular carcinoma in situ: E cadherin negative
Atypical ductal hyperplasia: immunohistochemistry has no value in differentiating from low grade DCIS
Invasive cribriform carcinoma or infiltrative ductal carcinoma with comedonecrosis: immunostains for myoepithelial cells are negative (J Pathol 2005;205:248)

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

Protocol for the Examination of Specimens from Patients with Ductal Carcinoma In Situ (DCIS) of the Breast (CAP)



Apocrine DCIS


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

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

● DCIS with cells containing abundant eosinophilic cytoplasm, vesicular nuclei and prominent nucleoli
● Uncommon variant; clinical behavior similar to classic DCIS

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

● Growth pattern may be solid, cribriform or micropapillary
● Tumor grade is based on nuclear features and presence of comedo-type necrosis (Hum Pathol 2001;32:487)
● Nuclei are graded 1-3 based on nuclear size, pleomorphism and nucleoli
● Nuclear size (compared to benign apocrine cells) is either small (1-2x), intermediate (3-4x) or large (5x or larger)
Grade 1 nuclei: low pleomorphism, small/intermediate size, usually single prominent nucleolus
Grade 2 nuclei: moderate pleomorphism, small/intermediate size, multiple nucleoli; may have occasional large nuclei or multinucleated cells
Grade 3 nuclei: intermediate/large size, marked pleomorphism, coarse chromatin, irregular nuclear contour, frequently multiple nucleoli
Necrosis: punctuate or comedo necrosis
Low-grade: nuclear grade 1 or 2 without necrosis
High-grade: tumors with grade 3 nuclei and necrosis; similar to high grade nonapocrine DCIS, but with cytoplasmic apocrine features and 10%+ nuclei with single large nucleolus and vesicular chromatin
Intermediate-grade: cases not classified as low or high histologic grade

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


   
Various images

       
Low, intermediate and high power


Granular cytoplasm


Involving lobules


Forming tufts

               
Secretory features

       
Cells have abundant cytoplasm, vesicular nuclei and prominent nucleoli (AFIP)


Micropapillary pattern


Cribriform pattern


Androgen receptor staining


p53

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



High grade apocrine DCIS

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

● Androgen receptor, B72.3 (92%, APMIS 2006;114:712), ER-beta (73%, Histopathology 2007;50:425)
● p53 (62%), HER2 (47%), Ki-67 (5% of cells) (Mod Pathol 2000;13:13)

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

● ER-alpha, PR, bcl2

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

● Atypical apocrine hyperplasia: difficult to distinguish from low-grade apocrine DCIS; absence of fully-developed architectural features of DCIS

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

Hum Pathol 1994;25:164; Mod Pathol 1994;7:813; Stanford University



Basal-like DCIS


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

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

● Classified based on immunohistochemistry or gene expression profiling (Breast Cancer Res 2006;8:R61), not morphology
● 8% of DCIS
● Of academic interest only, not currently used clinically

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

● Associated with high grade nuclei, p53 overexpression, increased Ki-67 index (Hum Pathol 2007;38:197), but only a small percentage of high grade DCIS has basal-like phenotype (Mod Pathol 2006;19:617)
● Commonly found with invasive basal-like carcinomas (Mod Pathol 2006;19:1506)
● DCIS lesions in BRCA1 mutation carriers are mostly basal-like (J Clin Pathol 2009;62:926)

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

● Solid, flat or micropapillary
● High nuclear grade, comedonecrosis, intense lymphocytic infiltrate

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


   
H&E and stains


H&E and variable CK5/6 staining

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

● CK5/6, CK14 or CK17
● Usually EGFR or c-kit/CD117
● Also vimentin, alphaB-crystallin (Ann Diagn Pathol 2008;12:33), P-cadherin (Virchows Arch 2007;450:73)

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

● By definition is ER-, PR- and HER2-



Clinging DCIS


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

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

● Terminology is no longer widely used
● Typically used to describe high-grade DCIS with comedonecrosis, in which the necrosis is so extensive that only 1 or 2 layers are present at the periphery
● Although controversial, it is preferable not to use this term to describe columnar cell hyperplasia with atypia or flat epithelial lesion, to avoid overtreatment (Breast Cancer Res 2003;5:263)

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

● 1-2 layers of malignant cells lining a gland with a large empty lumen
● Tumor cells are highly atypical and often associated with extensive comedo necrosis

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

Flat epithelial atypia: dilated ducts lined by 1 or several layers of cuboidal or columnar cells with atypia resembling low-grade DCIS; prominent apical cytoplasmic snouts are very common



Comedo DCIS / comedocarcinoma


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

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

● High grade DCIS with central expansile comedonecrosis (central necrosis within involved ducts)
● Necrosis is due to apoptosis and oncosis (passive cell death, Ultrastruct Pathol 2000;24:135)

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

● Has similar hormonal and reproductive risk factors as invasive ductal carcinoma, unlike non-comedo DCIS (Cancer Epidemiol Biomarkers Prev 2009;18:1507)

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

● 1/3 appear multicentric, but many are actually continuous in 3 dimensions, as demonstrated by serial section mapping studies
● 10% are bilateral
● 1-3% of patients have axillary nodal metastases, even without evidence of invasive carcinoma
● Lesions may be extensive (>5 cm); must examine carefully for invasive carcinoma

X-ray
=========================================================================

● Mammography usually shows linear and branching microcalcifications due to calcification of necrotic material, more often central than other tumors
● Occasionally lacks calcifications

X-ray images
=========================================================================


Linear and branching microcalcifications

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

● Cheesy appearance (resembling comedones) due to plugging of thick walled ducts with necrotic material

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

● Solid growth of large, pleomorphic, high grade cells with central expansile necrosis
● Frequent mitotic figures
● Myoepithelial cell layer may be attenuated
● Coarse microcalcifications are common
● Periductal fibrosis and inflammation are common
● Often cancerization of lobules
● May have branching and budding

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



Central necrosis with dystrophic calcifications (AFIP)

       
Classic features


Periductal fibrosis


Involving lobules


Cancerization of lobules

   
HER2+


Androgen receptor+

Other images: central necrosis #1, #2

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


Other images: low power; atypical cells with large nuclei #1; #2; #3

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



DCIS and LCIS


Calponin

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

● HER2 amplification (Cancer 2000;89:2153), p53 (Lab Invest 1994;71:67)
● Also P-cadherin (Virchows Arch 2007;450:73)

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

● ER, PR (Br J Surg 2005;92:429)

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

● Aneuploid
● Multicentric tumors were monoclonal in one study (Hum Pathol 2003;34:1163)

Molecular/cytogenetics images
=========================================================================



Tetraploid DNA


Aneuploid DNA

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

● Invasive ductal carcinoma with central necrosis (J Med Case Reports 2007;1:83)
● Intraductal papilloma with comedo-like necrosis (Ann Diagn Pathol 2004;8:276)

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

Arch Pathol Lab Med 1996;120:81



Cribriform DCIS


Reviewer: Dina Kandil, M.D. (see Reviewers page)
Revised: 8 November 2012, last major update January 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

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

● Multiple secondary lumens having round, regular spaces with sharp borders that appear to be made from “cookie-cutters,” usually low grade (image)
● Nuclear palisading around the lumens (the long axes of the nuclei are perpendicular to the lumens
● May have small, regular fenestrations (Latin, the arrangement of windows in a building), giving a sieve-like appearance
● Nuclei are usually small and uniform, equidistant from each other; usually no necrosis
Trabecular bars: rigid rows of cells with long axes perpendicular or at least not parallel to long axis of the bar (not just partial detachments of duct lining)
Roman bridges: curvilinear trabecular bars connecting two portions of the epithelial lining (image)

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


   
Uniform cells either haphazard or at right angles to long axis of intraductal columns (AFIP)


Prominent Roman bridge (AFIP)


Cribriform growth due to merging of intraductal epithelial bridges


Regular punched out fenestrations and distension of duct


Rigid microlumina

           

           
Glandular spaces and monotonous epithelial cells


Round fenestrations


Fenestrations, Roman bridges and trabecular bars

   
Prominent roman bridges


Classic area (fig c) and areas resembling low grade clinging carcinoma (fig a) and ADH (fig b)

   
With microcalcifications


ER+


Factor VIII staining shows only rare vascular proliferation (fig 2a); low MIB1 staining (fig 2b)

Other images: glandular spaces and monotonous epithelial cells; low grade cytology but with comedonecrosis #1;; #2; post-chemotherapy

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

● Three dimensional structures, occasionally with tumor cells bordering central lumina
● Few single tumor cells
● Clear or slightly hemorrhagic background without necrosis
● Tumor cells are uniform and oval, with round/oval nuclei, finely granular chromatin, indistinct nucleoli, slight nuclear membrane condensation (Acta Cytol 1992;36:48)

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


Various images #1   #2   #3

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



Cribriform and solid DCIS

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

● ER and PR

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

Atypical ductal hyperplasia: cells are pleomorphic and occupy less than 2 duct spaces
Collagenous spherulosis: intraductal lumina of hyaline, acellular eosinophilic spherules lined by myoepithelial cells
Adenoid cystic carcinoma: true glandular lumina lined by ductal epithelium and eosinophilic “cylinders” with basement membrane material lined by basal cells; usually ER- and PR- CD117+ luminal cells, p63+, calponin and smooth muscle actin negative



Cystic hypersecretory DCIS


Reviewer: Dina Kandil, M.D. (see Reviewers page)
Revised: 12 January 2012, last major update January 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

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

● First described in 1984 by Rosen and Scott (Am J Surg Pathol 1984;8:31)

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

● Rare (<100 cases described); usually large palpable mass with pain
● Mean age 55 years, range 32-79 years
● 20% are associated with an invasive component, usually poorly differentiated ductal carcinoma with solid growth pattern and no secretory features

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

● Excision with careful search for invasive component
● May recur as in situ or invasive disease (Ceska Gynekol 2005;70:73, Cancer 1988;61:1611)

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

● 40 year old woman with cystic, ill-defined breast mass and invasive carcinoma (Arch Pathol Lab Med 2005;129:e79)
● 54 year old woman with large breast mass (Case of the week #35)

X-ray
=========================================================================

● Single, irregular, spiculated mass with occasional calcifications

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

● Numerous cysts with sticky, mucoid or gelatinous secretions

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

● Dilated ducts and cysts containing homogenous eosinophilic secretions resembling thyroid colloid
● Secretions may retract from epithelium, causing smooth or scalloped margin
● Lining epithelium usually grows as micropapillary DCIS
● DCIS is usually low grade

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



Variably sized cysts


Cysts lined by flattened epithelium


Intraluminal secretions show cracks and shrinkage of cyst content with peripheral scalloping


Cysts lined by micropapillary projections with atypical cells containing pleomorphic nuclei

       
Cysts contain colloid type material, and epithelium has changes of DCIS


Fig 1: color Doppler is suggestive of cancer
Fig 2: FNA shows sparsely cellular smears with groups of cells in 3 dimensional clusters, papillary formation and granular background (inset: hyperchromatic cell with increased N/C ratio)
Fig 3: core biopsy shows dilated ducts with papillary proliferation
Fig 4: excision shows dilated ducts with micropapillary architecture and eosinophilic colloid-like material



Micropapillary intraductal carcinoma and sparse secretion retracted from epithelium


Micropapillary type pattern with prominent secretion


Hobnail type cells

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

● Distinct granular, colloid-like material in background
● Often reported as negative or suggestive of malignancy

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



33 year old woman

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

Epithelial cells - EMA, androgen receptor (Histopathology 2005;46:43), variable ER and PR
Myoepithelial cells - S100, smooth muscle actin, p63, CD10, heavy chain myosin, calponin
Secretions - EMA, PAS, Alcian blue (focal)

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

Secretions - thyroglobulin
● ER/PR - usually negative

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

Cystic hypersecretory hyperplasia: lining cells are flat cuboidal or columnar without atypia
Fibrocystic disease with microcyst formation: apocrine metaplasia, benign epithelial lining, no micropapillary formation or colloid-like secretions within cysts, no atypia
Juvenile papillomatosis: teenagers with "Swiss cheese" pattern of ductal papillomatosis, papillary hyperplasia, sclerosing adenosis; variable atypia
Metastatic thyroid carcinoma: history, thyroglobulin+
Mucocele-like lesions: mucin containing cysts that often rupture, with extravasation of mucin into surrounding stroma
Mucinous cystadenocarcinoma: at least focal invasion, no prominent secretions
Secretory/juvenile carcinoma: invasive, usually no prominent cystic areas



Micropapillary DCIS


Reviewer: Dina Kandil, M.D. (see Reviewers page)
Revised: 8 November 2012, last major update January 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Gross
=========================================================================

● 25% of cases involve multiple quadrants of breast (multicentric)

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

● Tufts of proliferating epithelial cells projecting into the ductal lumen, without fibrovascular cores, characteristic of true papillary lesions
● These micropapillae are narrow at the base and have bulbous expansion at the tip resembling a club
● Tips of epithelial tufts may fuse together, forming “bridges” and “arcades”
● Cells are uniform and evenly distributed
● Usually low grade DCIS without necrosis
● Can be associated with flat epithelial atypia (Mod Pathol 2007;20:1149)

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


           

           
Various images

   
No true fibrovascular cores


Roman bridges

           
Within a papilloma

       
Apocrine features


With cribriform DCIS


With hypersecretory features

   
With columnar cell change


Discontinuous fragments related to plane of sectioning


Micropapillae lack fibrovascular cores, cells are homogeneous

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



Nipple discharge shows high nuclear grade micropapillary DCIS (Giemsa stain)



Mucinous DCIS


Reviewer: Dina Kandil, M.D. (see Reviewers page)
Revised: 14 January 2012, last major update January 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

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

● DCIS with extracellular mucin production
● Mucin is usually in lumens of ducts involved by DCIS; also in vessels
● There are few studies of this entity (Histopathology 1996;29:533)

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

● Mean age 62 years
● Predominant histologic types are solid, cribriform and micropapillary
● DCIS grading - low grade/1 (29%), intermediate grade/2 (61%), high grade/3 (10%)

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

● Often associated with neovascularization in intraluminal mucin, although the presence of vascularized mucin in a needle biopsy cannot differentiate between in situ and invasive disease (Histopathology 2008;53:545)

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



DCIS (micropapillary) with invasive mucinous carcinoma

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

Invasive mucinous carcinoma: mucin is in direct contact with stroma, and tumor cells are floating in mucin



Neuroendocrine DCIS


Reviewer: Dina Kandil, M.D. (see Reviewers page)
Revised: 8 November 2012, last major update January 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

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

● DCIS in which 50% or more cells express neuroendocrine markers (Histopathology 2008;53:288)
● Regarded by some as DCIS with neuroendocrine features rather than a distinct type

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

● First described in 1985 (Histopathology 1985;9:21)
● Also called endocrine DCIS, intraductal or solid papillary carcinoma (Am J Surg Pathol 1995;19:1237)

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

● 7% of DCIS cases
● Mean age 70 years, usually > age 60 years (Zhonghua Bing Li Xue Za Zhi 2006;35:594)

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

● May have associated invasive component, either mucinous (colloid) or with neuroendocrine features (Am J Surg Pathol 1996;20:921)
● Presents as breast mass or nipple discharge (Am J Surg Pathol 1996;20:921)
● Associated with intraductal papilloma and pagetoid involvement by tumor cells
● Neuroendocrine markers are expressed in 67% of solid intraductal papillary carcinomas (Virchows Arch 2007;450:539)
● Almost all DCIS with spindle cells have neuroendocrine differentiation (Histopathology 2004;45:343)

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

● 68 year old woman with 1.5 cm breast nodule (Am Surg 2000;66:1163)
● 72 year old woman with breast mass (Case of the Week #45)

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

● Solid lobular growth, neuroendocrine-like festoons and rosettes and prominent fibrovascular septa
● Cells are polygonal, oval or spindled with abundant granular eosinophilic cytoplasm and bland ovoid nuclei
● Accumulation of basophilic intracellular mucin
● Often pagetoid spread and well developed vascular network
● Variable stromal sclerosis or signet ring cells
● Usually no necrosis

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


           

           
Case of the Week #45

   
Synaptophysin

   
Solid proliferation


Cribriform pattern


Small cells with dense, deeply stained amphophilic cytoplasm and uniform round nuclei


Focal Grimelius+ cells

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

● Plasmacytoid tumor cells and arborizing papillary fronds (Cancer 2000;90:286)

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


Various images

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



Two cases

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

● Chromogranin, synaptophysin, neuron-specific enolase
● ER, PR (Histopathology 2004;45:343)
● Low Ki-67

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

● p53, HER2

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

● Dense core neurosecretory granules, larger mucigen granules

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

● Florid epithelial hyperplasia and papilloma; lacks the monomorphic cell population associated with DCIS, negative for neuroendocrine markers



Papillary DCIS


Reviewer: Dina Kandil, M.D. (see Reviewers page)
Revised: 8 November 2012, last major update January 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

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

● DCIS with fibrovascular stalks
● Traditionally, a myoepithelial cell layer is not considered to be present

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

● Also called noninvasive papillary carcinoma
● Different from intraductal papilloma with DCIS

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

● Mean age is 65 years, older than DCIS overall

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

● 90% of lesions are low grade, so outcome is favorable
● Thought to arise from large ducts
● Associated with multiple papillomas
● Involves multiple ducts, unlike intracystic papillary carcinoma, but there is partial overlap between these lesions

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

● Well circumscribed mass within a distended duct or may extend throughout ducts to involve a large area
● Mean 2 cm

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



Circumscribed and partially cystic lesion contains round fleshy papillary nodules (AFIP)

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

● Solid lobular growth, neuroendocrine-like festoons and rosettes and prominent fibrovascular septa
● Cells are polygonal, oval or spindled with abundant granular eosinophilic cytoplasm and bland ovoid nuclei
● Accumulation of basophilic intracellular mucin
● Often pagetoid spread and well developed vascular network
● Variable stromal sclerosis or signet ring cells
● Usually no necrosis

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



Complex architecture


Globoid cells are present


Multiple finger like projections in dilated ducts


High power demonstrates lack of fibrovascular cores

   
Fusion of papillae


Intraductal tumor


Complex papillary branching


Nuclear atypia

   
Atypical epithelial proliferation


Papillary carcinoma with fibroadenoma


Complex compact papillary pattern


Columnar cell nuclei have variable staining


Overlapping and crowded nuclei


Solid apocrine carcinomatous area


Apocrine papillary carcinoma with cribriform area (arrows at apocrine snouts)


Inconspicuous myoepithelial cells (arrows)

                 
Irregular sclerotic border     Trapped neoplastic glands in sclerotic reaction
*Neither of these examples constitutes invasion

Other images: high power #1; #2; post-biopsy hemorrhage #1;; #2

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

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

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


Various images

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



Papillary carcinoma

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

● Myoepithelial cell markers are negative within the papillae but present at the periphery (Histopathology 2007;51:657, Am J Clin Pathol 2005;123:36)

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

Intraductal papilloma: variably fibrotic fibrovascular cores covered by both epithelial and myoepithelial cells; myoepithelial cell markers are positive both at the periphery of the duct space and within the papillae
Apocrine metaplasia
Encapsulated papillary carcinoma: myoepithelial cells are absent both within the papillae and at the periphery of the duct spaces



Signet ring cell DCIS


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

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

● Not a distinct subtype of DCIS (Am J Clin Pathol 1980;73:31, Cancer 1985;55:2533)
● Signet ring cells are usually associated with LCIS, but can be seen in DCIS as well; signet ring cells are very rare in benign ductal proliferation

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

● Cells have eccentric nuclei that are indented at the nuclear border by a cytoplasmic vacuole with a central minute secretion droplet

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

● Mucicarmine, Alcian blue, PAS-diastase

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

● Clear cells of normal nipple-areola complex: varied morphology but no atypia; usually morphology consistent with pagetoid dyskeratosis, HMW CK+ (Histol Histopathol 2009;24:367)
● Non-specific cytoplasmic halos: usually a fixation artifact, mucin negative
● Histiocytes: may appear in lymph nodes too; mucin negative, CD68+ (Am J Clin Pathol 1989;92:509)



Solid DCIS


Reviewer: Dina Kandil, M.D. (see Reviewers page)
Revised: 26 January 2012, last major update January 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

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

● Ducts filled with uniform neoplastic cells without microlumina or papillary structures

Drawings
=========================================================================



Drawing

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

● The lumen of the duct is filled by small to medium, uniform polygonal cells
● May produce a microacinar or rosette-like pattern
● Cells are larger than LCIS but smaller and more uniform than comedocarcinoma
● Cytoplasm can show a spectrum of changes including clear, granular and apocrine change
● Comedonecrosis is usually absent but small foci of necrosis may be present
● Usually low or intermediate grade (Anal Quant Cytol Histol 2001;23:418)

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


   
AFIP images: solid growth pattern with occlusion and distension of ducts by proliferation of cells with prominent nuclear pleomorphism (note: high grade features are not common in solid DCIS)

       

       
Various images


Solid pattern with central mucin


Intermediate grade based on cytologic features

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

● E-cadherin, ER, PR

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

Lobular carcinoma in situ: sharp cell borders, dyshesive, E-cadherin negative (Semin Diagn Pathol 2004;21:25)
Neuroendocrine carcinoma: chromatin has salt and pepper pattern, usually other neuroendocrine features



Solid papillary DCIS


Reviewer: Dina Kandil, M.D. (see Reviewers page)
Revised: 8 November 2012, last major update January 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

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

Clinical behavior:
● Indolent behavior if no invasion
● Can be associated with invasive colloid/mucinous or neuroendocrine carcinomas (Am J Surg Pathol 1995;19:1237, Pathol Int 2007;57:421)
● With invasion, patients often die of disease (Am J Surg Pathol 2006;30:501)

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

● Also called neuroendocrine DCIS

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

● Uncommon (2% of breast cancer)
● Age 60+ years

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

● Solid and cystic papillary carcinoma (Ann Diagn Pathol 2004;8:126)

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

● Circumscribed, large cellular nodules separated by bands of dense fibrosis
● Network of fibrovascular cores, but discrete papillae are not identified
● Solid growth with cellular streaming and low grade, ovoid or spindled cells, resembling usual ductal hyperplasia
● Cells may have endocrine features with granular eosinophilic cytoplasm and fine chromatin
● May have pseudorosettes with palisading around small vascular spaces
● Often mitotic figures
● May have intracytoplasmic and extracellular mucin

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



Solid tumor with focal fibrovascular stroma


Solid variant with spindling


Inconspicuous fronds centrally (AFIP)

Tumor cells in cords and festoons, with well-defined fibrovascular septa and vascular cores

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



Two cases

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

● Malignant features include hypercellularity, highly discohesive clusters, numerous isolated cells and severe overcrowding
● Benign features include small and bland nuclei, low nuclear-cytoplasmic ratio and inconspicuous nucleoli (Diagn Cytopathol 2007;35:417)

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

● Chromogranin or synaptophysin in 50%, ER and PR

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

● Usually negative for myoepithelial markers (Histopathology 2007;51:657), including CK5/6, but entrapped benign and myoepithelial cells may be positive (Hum Pathol 2006;37:787)
● 34betaE12 (Virchows Arch 2007;450:539), HER2

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

● Usually ductal hyperplasia involving a papilloma: no atypia, mosaic staining pattern with CK5/6+
LCIS: no fibrovascular septa, no papillary features
Solid variant of adenoid cystic carcinoma: biphasic with small inconspicuous intercalated ducts mixed with myoepithelium and small collagenous spherules
● Metastatic carcinoid: clinical history of primary, may not be papillary, usually ER negative



Spindle cell ductal carcinoma in situ


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 26 January 2012, last major update January 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

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

● May be a variant of neuroendocrine DCIS (Zhonghua Bing Li Xue Za Zhi 2006;35:13)
● Invasive tumors are considered a subset of metaplastic carcinoma

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

● Very rare (0.1% of breast carcinomas)
● Mean age 59 years

Symptoms
=========================================================================

● Nipple discharge, breast lump or mammographic abnormality

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

● 3 to 41 mm

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

● 10-80% of DCIS cells are spindled; patterns are fascicular, streaming or papillary
● Solid growth pattern, lack of secondary spaces or peripheral fenestrations
● Usually low to intermediate nuclear grade, with variable necrosis and microinvasion (Histopathology 2004;45:343)

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

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

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

● Usually synaptophysin or chromogranin
● ER, PR

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

● HER2, HMW keratin, smooth muscle actin

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

● Florid hyperplasia: HMW keratin+
Intraductal papilloma: no atypia
● Metaplastic spindle cell tumors associated with fibrosclerotic lesions: Mod Pathol 2003;16:893
● Myoepithelial hyperplasia: p63+, S100+, smooth muscle actin+

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

Virchows Arch 2001;439:70



Squamous cell carcinoma in situ / Bowen’s disease


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

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

● Either intraepidermal tumor of nipple, or rarely a tumor of breast parenchyma (Am J Surg Pathol 2007;31:1414)

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

● 69 year old woman with coexisting basaloid carcinoma of nipple (Breast J 2009;15:409)
● Tumor of nipple (Hum Pathol 1994;25:1371)
● Tumor of nipple in young man with HIV (Clin Breast Cancer 2009;9:53)

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

● Nipple tumor - wide local excision, possibly phototherapy (Breast 2005;14:65)
● Breast parenchyma tumor - standard treatment for DCIS (excision, possible radiotherapy)

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

● Obvious squamous features with diffuse atypia
● May be extensive, but no dermal or myoepithelial invasion

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


   
Contributed by Dr. Amy Lynn, Toledo, Ohio - skin (not necessarily breast)

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

● High molecular weight keratin

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

● Mucin, melanin

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

Paget’s disease: CK7+, CAM5.2+ (J Cutan Pathol 2003;30:449)



Lobular carcinoma in situ (LCIS)


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

See also: Pleomorphic lobular carcinoma in situ

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

● Lobulocentric proliferation of small, monotonous, loosely cohesive cells
● Must fill or distend lobular unit, in contrast to atypical lobular hyperplasia (ALH)

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

● “Lobular neoplasia” terminology is used by some authors to denote the histologic overlap / frequent co-existence of ALH and LCIS (Cancer 1978;42:737)

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

● Estimated incidence of 2.8 per 100K
● Present in 0.5 to 8% of benign breast biopsies
● Mean age 53 years
● Diagnosed as an incidental microscopic finding since no distinguishing features on gross examination and usually not associated with microcalcifications

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

● 30-70% are bilateral (vs. 20% for invasive lobular carcinoma and 10% for DCIS)
● 75% are multicentric; 5% have coexisting invasive carcinoma in another quadrant or opposite breast
● 20-30% risk of subsequent breast cancer, which may occur in either breast (8-10x relative risk) but is slightly more likely in ipsilateral breast, often develops after long follow up (up to 10 years, J Clin Oncol 2005;23:5534)
● Risk of invasive lobular carcinoma after LCIS is 5x risk after DCIS (Cancer 2006;106:2104)
● LCIS is considered to be a precursor of some invasive lobular carcinomas (Verh Dtsch Ges Pathol 2007;91:208, Breast Cancer Res Treat 2008;107:331)
● May be present in fibroadenomas or sclerosing adenosis (Am J Surg Pathol 1981;5:233)
● Not in nipple and only rarely in large lactiferous ducts
● Minimal risk of dying from breast cancer since most subsequent tumors are treatable and low stage

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

● Watchful waiting (Cancer 2004;100:238), possibly with tamoxifen
● An alternative treatment to waiting is ipsilateral or bilateral mastectomy (if strong family history of carcinoma)
● Presence of LCIS at excision margin is not a risk factor for recurrence of DCIS or invasive carcinoma (Ann Surg Oncol 2008;15:2263, Cancer 2006;106:28) but see Int J Radiat Oncol Biol Phys 2006;66:365
● If LCIS in core biopsy, excision recommended due to subsequent invasive ductal or lobular carcinoma in 10-31% (Arch Pathol Lab Med 2008;132:979, Am J Surg Pathol 2005;29:534) but see Am J Clin Pathol 2006;126:310 - low risk of DCIS or invasive disease at excision
● Higher risk of invasive disease if neoplastic epithelial microcalcifications present (Am J Surg Pathol 2007;31:717) or if associated with a mass lesion (Mod Pathol 2003;16:120)
● If radiologic: pathologic discordance, pleomorphic features or necrosis (Mod Pathol 2008;21:1208)
● Note: residual LCIS is usually present at excisional biopsy

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

● Occurring within a fibroadenoma (Postgrad Med J 1999;75:293)

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



No distinct gross features

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

● LCIS affects terminal duct lobular unit (TDLU) with expansion / effacement of acini
● Proliferation of monomorphic, evenly spaced cells that are loosely cohesive and slightly larger than normal with uniform nuclei, evenly distributed chromatin and small / no nucleoli
● Resembles “marbles in a bag”
● Intracytoplasmic lumina are common, but are not specific for LCIS
● Signet ring cells with mucin are common
● Classic type of LCIS lacks pleomorphism / necrosis
● “Pagetoid growth” refers to continuous row of tumor cells beneath adjacent terminal duct epithelium, causing cloverleaf or necklace patterns
● Myoepithelial cells may be replaced or unchanged
● Minimal mitotic figures
● May involve / arise in sclerosing adenosis, radial scar, fibroadenoma, collagenous spherulosis, papillary lesions
● Type A pattern: small, round, bland cells; diploid
● Type B pattern: larger cells with more cytoplasm, less uniform nuclei and distinct nucleoli
● By definition, E-cadherin negative (DCIS is positive)
Page criteria for LCIS: cells must fill ALL acini, expand or distort 50%+ acini in lobule, otherwise call atypical lobular hyperplasia

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



“Subgross” image

           
Lobules are distended by monomorphic cells


Intracytoplasmic lumina


Core biopsy

   
Involving adenosis, with microcalcifications in biopsy


Involving sclerosing adenosis (Fig 4A/B)


With adjacent infiltrating lobular carcinoma


Comparison with low grade DCIS


Various images

Lobular neoplasia:

Monotonous cells obliterate lumina


Involving a micropapilloma

               
Involving foci of florid hyperplasia

AFIP Fascicle images (3rd Series):

Normal epithelium is replaced by uniform cells that fill acini,
individual glands are round and discrete



Discrete acini have haphazardly arranged monomorphic cells
with scant cytoplasm and dark nuclei



Monomorphic cells have no specific orientation to basement membrane


Pagetoid spread of LCIS cells into normal acini (arrow)


Type A (central) and type B (peripheral) cells


Involvement of duct and lobule, with pagetoid extension beneath duct epithelium in lower left


Layer of LCIS cells beneath attenuated ductal epithelium

       
Cytoplasmic vacuoles (arrows)


Signet ring cells


Serrated (sawtooth) pattern with LCIS involvement of ducts and ductules only


Cloverleaf pattern in atrophic TDLU in post-menopausal woman


Resembles invasive carcinoma but has alveolar pattern of LCIS


Merging with DCIS


With microinvasion (linear strands or single cells)

Stains:

Mucicarmine+


ER+


Fig 3a: Factor VIII staining shows reduced vascular proliferation; Fig 3b: low MIB1 staining

       
LCIS is E-cadherin negative


E-cadherin staining of mixed LCIS and DCIS


E-cadherin negative (Fig. G) and p-120 catenin positive (Fig. J)

Other images: lobules are distended by monomorphic cells #1; #2; with comedonecrosis #1; #2; high power shows prominent intracytoplasmic vacuoles; various images

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

● Commonly either (a) benign appearing / nondiagnostic or (b) cell groups diagnostic or consistent with LCIS due to loosely cohesive cell groups of uniform cells with occasional intracytoplasmic lumina and slightly irregular and eccentric nuclei
● May have hypercellular, dissociated, pleomorphic tumor cells (Diagn Cytopathol 2002;27:22)
Thin-Prep: tight or loosely cohesive clusters of crowded mildly enlarged nuclei with at least moderate cellularity; occasional single epithelial cells, small but prominent nucleoli, intracytoplasmic lumina (Diagn Cytopathol 2005;32:276)

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


   
LCIS


DCIS and LCIS

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


LCIS #1; #2

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

● ER (60-90%, both alpha and beta forms, Histopathology 2007;50:875)
● Usually PR
● 75% mucin positive (Alcian blue, mucicarmine)
● High molecular weight cytokeratin (34betaE12 / CK903-perinuclear)
● S100 (60%)
● p120 catenin (Am J Surg Pathol 2007;31:427)
● EMA
● Milk fat globule membrane antigen (Am J Surg Pathol 2007;31:427)

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

● E-cadherin (Hum Pathol 2002;33:620, Am J Surg Pathol 2001;25:229)
● CK 5/6, p53, HER2

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

● 16q- (88%, Hum Pathol 2001;32:292, Breast Cancer Res Treat 2009;113:59)
● 17p- (18%), 8p- (12%), 12q24- (12%)

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

● Cancerization of lobules by DCIS: has high grade cytology, necrosis, different architecture
Atypical lobular hyperplasia: normal sized lobules, central lumina still present
Pregnancy-like or pseudolactational hyperplasia: premenopausal women who aren’t pregnant
● Myoepithelial hyperplasia: normal glandular cells remain with clear cytoplasm, small, round, hyperchromatic nuclei, image
● Clear cell change
● Poor tissue preservation: loosely cohesive cells but no lobular distension




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

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

● Also called ductal-lobular carcinoma in situ
● Has features distinct from classic LCIS (Am J Surg Pathol 2009;33:1683)

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

● 67 year old woman with mammographic calcifications, in situ and invasive disease (Case of Week #168)
● Almost pure signet ring cell morphology (Pathol Int 2006;56:683)

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

● May have more aggressive behavior than classic LCIS
● Treated similar to DCIS (excision with negative margins, variable radiation)
● Responded to trastuzumab in 4 cases (J Clin Oncol 2008;26:5823)

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

● One or more lobular units with distended terminal ducts and acini
● Medium/large dyscohesive cells with eosinophilic, granular and occasionally vacuolated cytoplasm
● Often apocrine features (Hum Pathol 1992;23:655, Pathol Oncol Res 2002;8:151)
● Eccentrically placed nuclei are 4x size of lymphocytes, exhibit moderate/marked pleomorphism, distinct nucleoli
● Central necrosis in 60%, microcalcifications in 40%
● “Classic” LCIS is often seen
● Morphologic features of pleomorphic LCIS and coexisting invasive disease (if present) are similar

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


           
Various images


Central necrosis and calcification


With infiltrating lobular carcinoma


Needle biopsy

           
In situ and invasive disease

           
E-cadherin: in situ and invasive disease


Fig A: moderate Ki-67, Fig B: E-cadherin negative


Negative E-cadherin with internal control (normal breast)


E-cadherin: LCIS vs. DCIS

Other images: Plasmacytoid cells in linear pattern (PDF)

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

● Features are hybrid of ductal and lobular tumor cells - cellular smears with tumor cells 2-3x size of classic invasive lobular, with moderate to abundant eosinophilic, granular/apocrine to finely vacuolated cytoplasm, moderate nuclear pleomorphism, prominent nucleoli; may have plasmacytoid appearance due to eccentric nuclear location (Journal of Cytology 2007; 24:193 - PDF)
Ductal lavage: epithelial cells in small clusters, single file arrangement or solitary, cytoplasmic vacuoles and nuclear atypia (Acta Cytol 2008;52:207)

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


Plasmacytoid cells (PDF)

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

● ER (90-100%), P120 catenin (cytoplasmic-dominant, Am J Surg Pathol 2008;32:1721)
● GCDFP-15 (74%), PR (50%), HER2 (5-25%), Ki-67 > 20% (47%)

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

● E-cadherin (100%), p53 (75%)

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

● Molecular features are distinct from classic LCIS (Am J Surg Pathol 2009;33:1683), but resemble invasive lobular carcinoma more than invasive ductal carcinoma (J Pathol 2008;215:231)

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

● DCIS: no lobular involvement, cells are cohesive, nuclei not eccentric, strongly E-cadherin+ (Arch Pathol Lab Med 2009;133:1116), pleomorphic cells are ER-, HER2+

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

Mod Pathol 2002;15:1044



Ductal intraepithelial neoplasia (DIN)


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

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

● This terminology avoids use of “carcinoma”, but is not widely used
● Proponents claim it reduces the “artificial separation” between ADH and low grade DCIS (Virchows Arch 2006;449:609)
● If DIN terminology is used in a report, recommended to also reference traditional terminology

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

● Most invasive breast cancer cases are associated with more than one type of DIN
Morphologic subtypes:
     ● Solid
     ● Cribriform
     ● Comedo
     ● Micropapillary
     ● Papillary
     ● Flat

Grades:
     ● UDH: usual ductal hyperplasia
     ● DIN 1A: flat epithelial atypia
     ● DIN 1B: atypical ductal hyperplasia
     ● DIN 1C: DCIS grade 1 (low grade)
     ● DIN2: DCIS grade 2 (intermediate grade)
     ● DIN3: DCIS grade 3 (high grade)
Source: Tavassoli: Tumours of the Breast and Female Genital Organs (WHO, 2003)

● Initial version as proposed by Tavassoli is below (Mod Pathol 1998;11:140), but was subsequently modified to above:
     ● DIN 1a: usual ductal hyperplasia
     ● Din 1b: flat epithelial atypia
     ● Din 1c: ADH and small grade I DCIS
     ● DIN 2: large grade I and grade II DCIS
     ● DIN 3: grade III DCIS

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

Histologic Subtypes of ductal intraepithelial neoplasia of the breast (DIN): Characteristics and Biology (2009 ASCO Annual meeting)



Mammary intraepithelial neoplasia (MIN)


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

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

● A general term to include both ductal and lobular intraepithelial neoplasia (Am J Surg Pathol 1991;15:209)
● Mammary intraepithelial neoplasia, NOS refers to lesions with intermediate or overlapping ductal and lobular features (Hum Pathol 2002;33:620)
● Some can be classified based on immunostains as ductal (E-cadherin+, high MW keratin-) or lobular (E-cadherin-, HMW keratin+), but others cannot
● May have classic histological changes of DCIS and LCIS merging in single lobular-duct systems (Am J Surg Pathol 1980;4:241)
● Terminology is also used to describe type of mice (multiple intestinal neoplasia)



Paget’s disease


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

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

● Malignant epithelial cells randomly disposed within epidermis of nipple / areola
● A type of in situ carcinoma that arises in or involves the main excretory (lactiferous) ducts
● Associated with underlying DCIS or invasive disease in almost all cases (Breast Cancer Res Treat 2008;112:513, Ann Surg Oncol 2005;12:391)
● Described by Sir James Paget in 1874 as a crusted lesion of nipple caused by breast carcinoma
● May derive from Toker cells (clear cells in nipple), or from epidermotropism of existing carcinoma (Hum Pathol 2003;34:1321)
● Present in 1-4% of all patients with breast carcinoma; age ranges from 26 to 88, median age 54 years

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

● Differs from Paget’s disease of vulva (usually not associated with underlying carcinoma) and Paget’s disease of bone
● "Anaplastic Paget's", based on markedly atypical cells, is occasionally described (Am J Surg Pathol 1992;16:1085, J Cutan Pathol 2009;36:374, Turkish Journal of Cancer 2003;33:158 [PDF]), but not widely accepted as a distinct entity

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

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

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

● Mastectomy or possibly breast conserving surgery
● Prognosis depends on underlying DCIS or invasive carcinoma

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

● 53 year old woman with bilateral Paget’s disease derived from LCIS (Arch Pathol Lab Med 2002;126:90)
● 58 year old woman with vulvar and breast disease and invasive disease at both sites (Arch Gynecol Obstet 2009;280:313)
● 64 year old woman with nipple discharge and inverted nipple (Univ Pittsburgh Case #331)
● 83 year old woman with acinar pattern (Breast J 2007;13:520)

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



Eczematoid lesion


Pigmented lesion

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

● Skin is fissured, oozing, ulcerated
● Resembles eczema (Breast Cancer Res Treat 2008;111:313)

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

● Single cells, groups or rarely tubules
● Cells are large, atypical and spread throughout epidermis
● Cells have abundant clear or light staining cytoplasm, abundant mucin and occasionally intracytoplasmic melanin (Melanoma Res 2004;14:S13, Am J Dermatopathol 2009;31:223)
● Nucleus is large and vesicular with prominent nucleolus
● DCIS is usually present and may also have invasive component
● Underlying breast carcinoma is usually adjacent to Paget’s disease if one takes enough sections

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


       
Large atypical cells in epidermis


With hyperkeratosis and dermal inflammation


With underlying comedo DCIS


H&E and stains


With melanin pigment


Derived from LCIS


CK7+, E-cadherin negative

       
CK7+


Involvement of entire thickness of epidermis, with pseudoepitheliomatous hyperplasia and
hyperkeratosis with involved area, but not in normal appearing area (AFIP)



Large atypical cells in epidermis have round nuclei and prominent nucleoli (AFIP)


Involvement of terminal portion of lactiferous duct (AFIP)


HER2+ (AFIP)

Contributed by Dr. Semir Vranic: Paget’s with underlying DCIS:
           
Paget’s (left to right): H&E, CK8+, HER2+, S100-

           
Underlying DCIS (left to right): H&E, ER alpha, CK8, HER2

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



Paget's disease

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


Paget's disease

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

● AE1/3, CK7 (also stains Toker and Merkel cells, Am J Surg Pathol 1999;23:212)
● Low molecular weight keratin (CAM 5.2, AE1, Am J Surg Pathol 1992;16:58)
● EMA, CEA / MUC1 (Am J Surg Pathol 2001;25:1469, Am J Surg Pathol 2002;26:617)
● HER2 and androgen receptor (Mod Pathol 2005;18:1283)
● GCDFP-15 (50%)
● Variable p53, ER and PR

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

● MUC2, MUC5AC (mucin expressed in extramammary Paget’s disease), S100, HMB45

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

● Intracytoplasmic lumina with microvilli, evidence of glandular differentiation

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

● Carcinoma in situ of skin / Bowen’s disease: has individual cell keratinization and multinucleated giant cells, CK7-, mucin-, HER2-
● Superficial spreading melanoma: tumor cells invade dermis, S100+, HMB45+, AE1/3- (Dermatology Online Journal 13(2):18)
● Benign proliferative nipple duct lesions or Toker cells: mucin- (APMIS 2008;116:139, Breast J 2009;15:394)
● Pemphigus vulgaris: clinically different (Breast J 2003;9:319)
● Clear cell keratinocytes: image

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

eMedicine

End of Breast malignant, males, children > Superpage > In situ carcinoma


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