Breast – Malignant, Males, Children - Lobular carcinoma in situ (LCIS)

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Breast-malignant, males, children

Morphologic variants of DCIS

Lobular carcinoma in situ (LCIS)

Author: Nat Pernick, M.D, PathologyOutlines.com, Inc.

Reviewer: Daniel Visscher, M.D., University of Michigan Hospitals, February 2009 (see Reviewers page)

Revised: 6 September 2009

Last major update: September 2009

Definition

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● Lobulocentric proliferation of small, monotonous, loosely cohesive cells

● Must fill or distend lobular unit, in contrast to atypical lobular hyperplasia (ALH)

Terminology

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● “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

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● 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

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● 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 year, 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 (AJSP 1981;5:233)

● Not in nipple and only rarely in large lactiferous ducts

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

Treatment and prognosis

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● 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% (Archives 2008;132:979, AJSP 2005;29:534) but see AJCP 2006;126:310-low risk of DCIS or invasive disease at excision

● Higher risk of invasive disease if neoplastic epithelial microcalcifications present (AJSP 2007;31:717) or if associated with a mass lesion (Mod Path 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

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

Gross images

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No distinct gross features

Microscopic description / grading

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● 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

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“Subgross” image

Lobules are distended by monomorphic cells

Intracytoplasmic lumina Core biopsy

Involving several closely situated terminal duct lobular units

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 Discrete acini have haphazardly arranged

uniform cells that fill acini, individual monomorphic cells with scant

glands are round and discrete cytoplasm and dark nuclei

Monomorphic cells have no specific Pagetoid spread of LCIS cells

orientation to basement membrane into normal acini (arrow)

Type A (central) and type B Involvement of duct and lobule,

(peripheral) cells with pagetoid extension beneath duct

epithelium in lower left

Layer of LCIS cells beneath Cytoplasmic vacuoles (arrows)

attenuated ductal epithelium

Signet ring cells Serrated (sawtooth) pattern with LCIS

involvement of ducts and ductules only

Cloverleaf pattern in atrophic Resembles invasive carcinoma

TDLU in post-menopausal woman but has alveolar pattern of LCIS

Merging with DCIS With microinvasion (linear strands

or single cells)

Other sources

Mucicarmine+ ER+ Fig 3a: Factor VIII staining shows reduced

vascular proliferation; Fig 3b: low MIB1 staining

LCIS focus is E-cadherin negative (Fig 2C) E-cadherin negative (fig a-d)

but CK903+ (Fig 2D)

E-cadherin staining of E-cadherin negative (fig g) and

mixed LCIS and DCIS 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

Cytology description

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● 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)

Cytology images

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Virtual slides

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LCIS

DCIS and LCIS

Videos

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● LCIS #1; #2

Positive stains

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● 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 (AJSP 2007;31:427)

● EMA

● Milk fat globule membrane antigen

Negative stains

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● E-cadherin (Hum Path 2002;33:620, AJSP 2001;25:229)

● CK 5/6, p53, HER2

Molecular / cytogenetics

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● 16q- (88%, Hum Path 2001;32:292, Breast Cancer Res Treat 2009;113:59)

● 17p- (18%), 8p- (12%), 12q24- (12%)

Differential diagnosis

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● 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

End of Breast – Malignant, Males, Children > Lobular carcinoma in situ (LCIS)

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