Breast – Malignant, Males, Children - Classic infiltrating lobular carcinoma

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Breast-malignant, males, children

Classic infiltrating lobular carcinoma

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

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

Revised: 22 September 2009

Last major update: September 2009

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

Definition

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● Invasive tumor associated with LCIS, composed of noncohesive cells that are individually dispersed or arranged in a single file pattern

● Minimal desmoplastic response

Features

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● 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

● Often not well seen on mammograms, and may be more extensive than clinically suspected

● Metastasizes to bone marrow, cerebrospinal fluid and leptomeninges (Archives 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 (AJSP 2000;24:1593, Hum Path 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

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● 58 year old man presenting 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 2009 May 23 [Epub ahead of print])

● 88 year old woman with anal metastasis (World J Gastroenterol 2009;15:1388)

● With coexisting DCIS and LCIS, examined by comparative genomic hybridization (Hum Path 2004;35:759)

● Metastases to tamoxifen associated endometrial polyps (Mod Path 2003;16:395)

● Metastasis to uterus in a patient taking anastrozole (related to tamoxifen) therapy (Onkologie 2009;32:424)

Treatment and prognosis

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● Classic variant has better prognosis than non-classic variants overall (Cancer 2008;113:1511)

● 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%, with positive margins, age >50 years and contralateral breast cancer as predictors of relapse (Eur J Surg Oncol 2009 Jul 30 [Epub ahead of print])

Gross description

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● May have mass with ill-defined margins but often no mass because of diffuse growth pattern

Gross images

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Solid firm mass Infiltration into adipose tissue

Anal metastasis

Other images: multiple foci with irregular margins #1; #2

Microscopic description / grading

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● 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; 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

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Single file pattern

Classic features

Single dyscohesive cells

Prominent intracytoplasmic mucin

Targetoid pattern of tumor cells around ducts

Minute focus (arrow) of tumor Classic targetoid (bulls eye)

around a small duct (AFIP) 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

Metastases

Endometrial polyp-AE1/AE3

Lymph node Soft tissue Stomach

Stains

E-cadherin negative H&E (Fig C) and E-cadherin (Fig F)

Other images: single file pattern; prominent intracytoplasmic mucin; targetoid pattern of tumor cells around ducts #1; #2; with LCIS #1; #2

Cytology description

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● 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

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Infiltrating lobular carcinoma

May-Gruenwald-Giemsa staining

Eosinophilic background, small fibrous fragments, altered material mixed with fatty vacuoles; malignant cells are sparse, have eccentric nuclei and intracytoplasmic vacuoles with targetoid appearance

Single cell arrangement Intracytoplasmic vacuole E-cadherin negative

with targetoid appearance

Fig B: FNA shows small cells arranged in linear pattern

Virtual slides

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Lobular carcinoma

With LCIS

Videos

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● Lobular carcinoma

Positive stains

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● ER, PR, HMW keratin (helpful in bone marrow biopsy), mucicarmine (intracellular mucin)

● GCDFP-15 (30%)

Negative stains

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● p53, E-cadherin (complete absence suggests lobular carcinoma, but rarely is positive and may vary by antibody, AJSP 2008;32:773, Mod Path 2008;21:1224)

● HER2

● Ki-67

Molecular / cytogenetics

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● Usually diploid

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

Electron microscopy images

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Line of tumor cells surrounded by collagen, Intracytoplasmic lumina lined by microvilli;

with cytokeratin bundles (arrows), elastic tissue (arrows) and collagen in stroma

but no basement membrane

Intracytoplasmic lumen with numerous microvilli and perinuclear mucin granules

Differential diagnosis

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● Lymphoma - resembles lobular metastases to axillary nodes or eyelid

● Carcinoma with neuroendocrine features

● Invasive ductal adenocarcinoma - may have focal lobular features

Additional references

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

End of Breast – Malignant, Males, Children > Classic infiltrating lobular carcinoma

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