Breast
Lobular carcinoma
Classic
Topic Completed: 1 August 2017
Minor changes: 8 March 2021
Copyright: 2002-2019, PathologyOutlines.com, Inc.
PubMed Search: Invasive lobular carcinoma[TI] free full text[sb]
Table of Contents
Definition / general | Essential features | Etiology | Clinical features | Radiology description | Radiology images | Prognostic factors | Case reports | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Positive stains | Negative stains | Electron microscopy images | Molecular / cytogenetics description | Videos | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1Cite this page: Podoll MB, Reisenbichler ES. Classic. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/breastmalignantlobularclassic.html. Accessed March 9th, 2021.
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
Contributed by Dr. Mark R. Wick
Mammogram
Prognostic factors
- Classic variant of invasive lobular carcinoma of any grade has better prognosis than nonclassic variants overall (Cancer 2008;113:1511, Am J Surg Pathol 1990;14:12)
- May have similar long term prognosis as infiltrating ductal carcinoma (Breast Cancer Res Treat 2009;117:211) but see J Clin Oncol 2008;26:3006 (lobular has better survival at 6 years but worse survival at 10 years)
- In one study, 12 year local relapse free survival was 89%; predictors of relapse were positive margins, age > 50 years and contralateral breast cancer (Eur J Surg Oncol 2010;36:176)
Case reports
- 51 year old woman with colonic metastasis from breast carcinoma (World J Surg Oncol 2017;15:124)
- 56 year old woman with metastasis of lobular breast carcinoma to the uterus (Onkologie 2009;32:424)
- 56 year old woman with breast mass - classical type and solid / alveolar variant (Case of the Week #369)
- 58 year old man with synchronous bilateral invasive lobular breast cancer presenting as carcinomatosis (Am J Surg Pathol 2009;33:470)
- 60 year old woman with lobular carcinoma of the breast with extracellular mucin (Pathol Int 2009;59:405)
- 61 year old woman with c-kit positive gastric metastasis of lobular carcinoma of the breast masquerading as gastrointestinal stromal tumor (Breast Cancer 2010;17:303)
- 62 and 92 year old women with metastatic breast lobular carcinoma involving tamoxifen associated endometrial polyps (Mod Pathol 2003;16:395)
- 70 year old woman with orbital metastasis as the initial presentation of invasive lobular carcinoma of breast (Intern Med 2012;51:1635)
- 70 year old woman with triple negative invasive lobular carcinoma presenting as small bowel obstruction (Int J Surg Case Rep 2017;37:79)
- 88 year old woman with anal metastasis from recurrent breast lobular carcinoma (World J Gastroenterol 2009;15:1388)
Gross description
- Mass with ill defined margins; often no mass because of diffuse growth pattern
Gross images
Images hosted on other servers:
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
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
Case #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)
Cytology description
- Moderate / highly cellular pattern is predominantly or partly dissociated
- Usually small / intermediate cells with intracytoplasmic lumina in 57%, light cytoplasm
- Small, eccentric nuclei with finely granular chromatin (Acta Cytol 2000;44:169, Med Mol Morphol 2008;41:121, Cancer 2008;114:111)
Cytology images
Contributed by Dr. Mark R. Wick
FNAB
Images hosted on other servers:
Small cells arranged in linear pattern (figure B)
Various images
Positive stains
- ER (90%) and PR (80%)
- Cytoplasmic p120 staining
- Cytokeratins
- GATA3
- Mammaglobin
- GCDFP-15 (30%)
- Mucicarmine (highlights the intracellular mucin)
- PLEKHA7 (Hum Pathol 2012;43:1902)
- Pankeratin staining of negative bone marrow biopsies is recommended to detect metastases (Am J Surg Pathol 2000;24:1593, Hum Pathol 1994;25:781) but has minimal value for nodal metastases (Hum Pathol 2008;39:1011)
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
AFIP images
Line of tumor cells
surrounded by collagen,
with cytokeratin bundles (arrows)
but no basement membrane
Intracytoplasmic lumina
lined by microvilli,
elastic tissue (arrows)
and collagen in stroma
Intracytoplasmic lumen
with numerous microvilli
and perinuclear
mucin granules
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
Additional references
Board review style question #1
Which of the following is true of invasive lobular carcinoma?
- Is most commonly associated with cytoplasmic E-cadherin immunostaining
- Is most commonly associated with cytoplasmic p120 immunostaining
- Is most commonly associated with membranous E-cadherin immunostaining
- Is most commonly associated with membranous p120 immunostaining
Board review style 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
