Breast malignant, males, children
Carcinoma subtypes
Classic infiltrating lobular carcinoma

Author: Mirna B. Podoll, M.D. (see Authors page)
Editor: Emily S. Reisenbichler, M.D.

Revised: 20 August 2017, last major update August 2017

Copyright: (c) 2002-2017, PathologyOutlines.com, Inc.

PubMed Search: Lobular carcinoma [title] classic

Cite this page: Podoll, M.B., Reisenbichler, E.S. Classic infiltrating lobular carcinoma. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/breastmalignantlobularclassic.html. Accessed October 17th, 2017.
Definition / general
  • Invasive mammary carcinoma lacking cellular adhesion proteins
Essential features
  • Tumor is composed of noncohesive cells that are individually dispersed or arranged in a single file pattern with a minimal desmoplastic response
  • Often associated with lobular carcinoma in situ (LCIS)
  • Displays a loss of adhesion proteins, resulting in a discohesive morphologic pattern (~85% lack E-cadherin)
  • May form spiculated masses or asymmetry on mammography; sometimes are not well seen
Etiology
  • Invasive lobular carcinoma comprises between 5 - 15% of all breast carcinomas
  • More commonly multifocal than invasive ductal carcinoma, no special type
  • E-cadherin (CDH1) germline mutation is seen in many tumors, resulting in the loss of E-cadherin gene expression
Clinical features
  • Most tumors form mass-like lesions or result in architectural distortion
  • May be difficult to identify clinically due to the lack of strong desmoplastic response
  • Multicentricity within same breast is more common than invasive ductal carcinoma
  • More likely to be multifocal and confer a 0.5 - 1% yearly risk of contralateral breast involvement (10 - 20% are bilateral)
  • Metastasizes to bone marrow, cerebrospinal fluid and leptomeninges (Arch Pathol Lab Med 1991;115:507), GI tract, ovary, serosal surfaces, uterus and retroperitoneum (resembles low grade stromal sarcoma) more than other subtypes
  • Variants usually coexist with classic pattern
Radiology description
  • Tumors are most commonly detected as spiculated mass lesions on mammography, followed by findings of asymmetric densities and opacities
  • Approximately 15% of cases may be difficult to identify on imaging or may present with benign findings
  • Since these tumors are more commonly multicentric and bilateral, evaluation of both breasts is critical
  • Use of magnetic resonance imaging can aid in the detection of multicentric and contralateral lesions
Radiology images

Images hosted on PathOut server:

Mammogram, contributed by Dr. Mark R. Wick

Prognostic factors
Case reports
Gross description
  • Mass with ill defined margins; often no mass because of diffuse growth pattern
Gross images

Images hosted on other servers:

Solid firm mass

Infiltration into adipose tissue

Anal metastasis

Multiple foci with irregular margins

Microscopic (histologic) description
  • Cells grow in single file, linear pattern and are loosely dispersed throughout fibrous matrix
  • Cells can often be seen encircling normal ducts (onion skin pattern)
  • Variable dense fibrous stroma with periductal and perivenous elastosis
  • Dense lymphoid infiltrate may accompany tumor at periphery
  • Classic invasive lobular carcinomas will not show tubule formation and will commonly be given a tubule score of 3 ( < 10% tubule formation)
  • Tumor cells are usually small, uniform, round with minimal pleomorphism, evenly dispersed chromatin and no nucleoli (nuclear grade 1 or 2, like LCIS cells)
  • Commonly signet ring cells, intracellular lumina and targetoid cytoplasmic mucin can be seen
  • Typically not very mitotically active with < 10 mitoses/10 HPF without necrosis and usually given a mitotic score of 1
  • Most commonly tumors are of intermediate histologic grade (Nottingham grade 2)
  • Lymph node metastasis:
    • Metastatic tumor cells may resemble histiocytes or lymphocytes; the use of cytokeratins may help highlight the malignant cells
  • 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
  • Metastasis to other sites:
    • Leptomeningies and cerebrospinal fluid
    • Gastrointestinal tract: the differentiation from primary gastric tumors can be difficult histologically; immunohistochemistry may be necessary
    • Ovary, uterus and retroperitoneum
Microscopic (histologic) images

Scroll to see all images:


Images hosted on PathOut server:

Images contributed by Mirna B. Podoll, M.D.:

Adjacent to LCIS

Pleomorphic cells with cytoplasmic mucin

Single cells around normal duct

Lymph node macrometastasis

Macrometastatic focus


Cytoplasmic p120 staining

Surrounding normal duct (p120)

Loss of E-cadherin



AFIP images:

Targetoid pattern

Minute focus (arrow) of tumor around a small duct



Case of the Week #369 - classical type and solid / alveolar variant:

H&E images



Pancytokeratin (positive)

E-cadherin (negative)

ER (positive: 25 - 75% tumor cells)

PR (positive: 25 - 75% tumor cells)


HER2 (negative)

Chromogranin (negative)

Synaptophysin (negative)



Images contributed by Dr. Mark R. Wick:

Sheet-like

Alcian blue stain

Estrogen receptor

Type 3



Images contributed by Dr. Semir Vranić, University of Sarajevo:

H&E

ER

CK5 / 6

E-cadherin



Images hosted on other servers:

Single dyscohesive cells


Classic features

Targetoid pattern


Foci of tumor cells may be inconspicuous

Mimicking fat necrosis

Prominent intracytoplasmic mucin

Tumor of male breast


With LCIS


Grade I of III - minimal nuclear pleomorphism

Grade II of III - moderate nuclear pleomorphism

Grade III of III - severe nuclear pleomorphism



Metastases:

Endometrial polyp: H&E and AE1 / AE3


Soft tissue

Stomach

Cytology description
Cytology images

Images hosted on PathOut server:

FNAB, contributed by Dr. Mark R. Wick



Images hosted on other servers:

Small cells arranged in linear pattern (figure B)

Various images

Positive stains
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)
  • Ki67 shows low proliferation rate (typically putting these tumors in mitotic score of 1)
  • HER2 is typically negative although 25 - 50% grade 3 invasive lobular carcinomas can be HER2+
Electron microscopy images

Images hosted on PathOut server:
   

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

Molecular / cytogenetics description
  • Usually diploid
  • Truncation mutations in E-cadherin gene (16q) or inactivation of wild type allele
  • Loss of adhesion proteins are seen in the invasive lobular carcinoma as well as its precursor lesions, atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS)
  • E-cadherin binds actin cytoskeleton through interaction with p120 and alpha, beta and gamma catenins; loss of chromosome 16q22.1, the E-cadherin locus, confers loss of protein
  • Typically are luminal A category (Gene Expr 2011;15:105)
Videos


Histopathology breast - lobular carcinoma
Differential diagnosis
  • Gastric carcinoma: may also display loss of E-cadherin proteins, immunohistochemical stains such as mammaglobin and GATA3 may be of use
  • Histiocytes of a lymph node: will display positivity for histocytic markers such as CD68 and will be negative for cytokeratins
  • Invasive ductal carcinoma: may have focal lobular features but will show more cohesion between tumor cells, a retained membranous E-cadherin staining and will membranous p120 staining
  • Lymphoma: less cytoplasm without cytoplasmic mucin, positive for CD45 and other lymphoma markers
  • Melanoma: will display positivity for melanocytic markers such as MelanA and HMB45
    • Note that SOX10 positivity can be seen in both breast carcinoma and melanoma
    • Cytokeratins should be negative
  • Myofibroblastoma: epithelioid variant may mimic malignancy but will be well circumscribed often and will not show a spiculated mass-like lesion seen with invasive carcinoma
Board review question #1
Which of the following is true of invasive lobular carcinoma?

  1. Is most commonly associated with cytoplasmic E-cadherin immunostaining
  2. Is most commonly associated with cytoplasmic p120 immunostaining
  3. Is most commonly associated with membranous E-cadherin immunostaining
  4. Is most commonly associated with membranous p120 immunostaining
Board review answer #1
B. Is most commonly associated with cytoplasmic p120 immunostaining; invasive lobular carcinomas commonly have a CDH1 germline mutation, causing the cells to lose membranous E-cadherin staining and resulting in cytoplasmic p120 expression