Lobular Proliferation & Breast Cancer Progression

General Information

  • A significant difference between ductal and lobular proliferations involves the presence/absence of epithelial cadherin. Cadherins are a superfamily of transmembrane proteins (encoded by CDH1 gene) used for cell adhesion. Normally, the external portion binds cadherins on other cells forming a tight-knit, cohesive cell group. Epithelial cadherin (e-cadherin) is typically retained in ductal processes, but lost in lobular processes.

  • In ILC, the e-cadherin is lost from the cell membrane and inappropriately expressed in the cytoplasm. The loss of e-cadherin (negative staining) is what allows lobular cells to invade in a “single file” fashion as they lose their cellular adhesion molecule.

  • NOTE: Approximately 16% of ILC tumors still retain their E-cadherin expression!!! It is thought these tumors have a defect in the cytoskeletal proteins that the e-cadherin interacts with, rather than the E-cad itself

  • Molecular testing

  • Molecular Testing for E-cadherin (CDH1 gene)

  • CDH1 mutation testing can be performed in cases of ILC are negative for BRCA1 & BRCA2 testing

  • NOTE: Gastric (signet ring cell) carcinoma also lacks e-cadherin

Simple lobular hyperplasia

(Lobular Neoplasia (LN, grade 1)

  • Mild increase in number of cells lining some acini

  • NO inc risk for cancer

  • No complete filling or expansion of acini

  • No nuclear atypia

Atypical Lobular Hyperplasia (ALH)

(Lobular Neoplasia, grade 2)

  • Shares genetic changes with LCIS & ILC- Cytologically identical to LCIS, but is more limited in extent, hallmark of discohesive round cells

  • 4-5x increased risk of invasive cancer. Slightly inc risk of ipsilateral breast cancer & predictor of bilateral risk.

  • Non-obligate precursor lesion


  • Lobule is expanded, but most acini are not completely filled.

  • Maintains myoepithelial layer

  • Monomorphic proliferation of discohesive small round cells with uniform, round nuclei with dispersed chromatin.

  • The underlying lobular architecture is preserved, as the cells only slightly expand acinar spaces

  • Stains

  • Strong immunoreactivity for ER in all cells (normal ducts show weak, variable staining)

Lobular carcinoma in situ (LCIS)

(Lobular Neoplasia, grade 3)

  • Low grade tumor due to mutation/loss in the E-cadherin gene (CDH1) causing overproliferation of cells in TDLU or acini.

  • Often multicentric and bilateral in 20-40% of cases

  • 8-10x increased risk of invasive cancer

  • Increased risk of developing breast cancer in same or opposite breast; ~1% per year.

Clinical picture

  • Often does NOT form a palpable mass and does NOT form a density or have associated microcalcifications on imaging, thus are often incidental findings on a biopsy for another reason.

LCIS Histology

You must see all 3 components to call it LCIS:
Complete replacement of the lobule by a single cell population of small, uniform, monotonous cells with small nuclei. NOTE: Pleomorphic variant can be seen, look for adjacent pleomorphic invasive lobular carcinoma as a tipoff.
Cells must completely fill all the acini in the lobule
At least ½ of the acini must be distended by the process

Common Histologic Features in LCIS:

  • Solid, monotonous proliferation of small, discohesive cells expanding terminal duct lobular units and small duct (LCIS often tends to have a degree of dyscohesiveness)

  • Clusters of small, round, monomorphic epithelial cells bound by basement membrane (Maintains myoepithelial layer)

  • Signet ring cells often present

  • NOTE: If comedonecrosis present then treat it like DCIS (instead of LCIS)!!!

Staining Pattern:

  • E-cadherin loss of staining

Pleomorphic Variant of LCIS

  • Solid proliferation of epithelial cells distending the lobular acini

  • Dyscohesive tumor cells with abundant cytoplasm and significant nuclear pleomorphism with at least 2 to 3 fold variation in nuclear size, nuclear membrane irregularity and prominent nucleoli

  • Mitotic figures and focal necrosis is present

  • When compared with classic LCIS, Pleomorphic LCIS is more often associated with invasive lobular carcinoma

  • Biological behavior and clinical management of patients with pleomorphic LCIS is similar to patients with DCIS

Tricky Situations

  • Usual lobular hyperplasia vs. ALH

  • Very high relative risk for invasive carcinoma in patients with ALH whereas ULH has no increased risk. So if you see ALH, definitely call it!

  • ALH vs. LCIS

  • Seeing pagetoid spread to the ducts favors LCIS over ALH

  • ALH carries a smaller risk of invasion than LCIS (in about 25% of biopsies, LCIS had invasive carcinoma on resection while ALH did not)

Lobular extension of DCIS

  • Acini filled and distended by cells

  • Nuclei are more pleomorphic than a lobular process

  • Tend to still have second population of cells forming normal lobules in the background

  • (LCIS has a single population of less pleomorphic cells)

  • E-cadherin will be retained (LCIS has loss of staining)

Invasive Lobular Carcinoma (ILC)


  • ALH and LCIS are now thought to be true precursor lesions to invasive carcinoma

  • ILC arises in the TDLU; Characterized by loss of normal cell adhesion (loss of e-cadherin)

  • Accounts for 15-20% of breast cancers

  • Often times, ILC is not detected on imaging

  • Many ILC arise multi centrically in the same breast; There is a 20% chance that the opposite breast will be involved by ILC too.

  • ILC like to metastasize to weird places (peritoneum, retroperitoneum, leptomeninges, GI tract, ovary, uterus).

  • Histology

  • Bland, small, round, discohesive single cells that infiltrate/”march” through the surrounding fibrous stroma

  • Often times these will NOT cause a desmoplastic response to the tumor cells like it does in IDC or other cancers.

  • Typical ILC will have uniform nuclei with minimal pleomorphism, minimal cytoplasm and NO gland formation

  • Cells line up single file as they move through the tissue; very diffuse & stealthy.

  • Often cells form a circumferential pattern around normal ductal structures (“Targetoid lesion”)

  • Signet-ring cells (abundant mucinous cytoplasm with eccentric nuclei) are common

  • Special stains/studies

  • ILC has loss of E-cadherin, a transmembrane cell adhesion protein (CDH1 gene mutation; inc risk of lobular breast & gastric carcinoma)

  • Cytoplasmic p120+ (nuclear staining)

  • Graded using the Modified Bloom-Richardson grading system


Invasive lobular carcinoma- Pleomorphic Type

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These posts contain high yield information collected from various educational resources including textbooks, journal articles, educational websites and more. They are intended for educational use only and should NOT be taken as medical advice. I strongly believe the spreading of knowledge and depth of learned information should be encouraged in today's society rather than coveted. Membership is required to view these posts  and should be used solely for educational purposes only.