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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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