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
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
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.
Case #369
Classical type and solid / alveolar variant
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
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
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