A 45-year-old woman undergoes excision of a breast mass showing lobular carcinoma in situ (LCIS). Molecular analysis confirms E-cadherin loss. What is the mechanistic basis for the lack of cohesion in lobular neoplasia, and how does this differ from ductal carcinoma in situ (DCIS)?

• A In LCIS, CDH1 (E-cadherin gene) mutations or promoter methylation cause loss of the transmembrane calcium-dependent adhesion molecule E-cadherin; without E-cadherin, the p120-catenin cannot form the E-cadherin/β-catenin/α-catenin cytoskeletal link, and cells lose cohesion, producing the characteristic discohesive single-file infiltrative pattern; DCIS retains E-cadherin and maintains cohesive growth ✓
• B LCIS has gain-of-function N-cadherin expression that replaces E-cadherin, causing a mesenchymal-like pattern; DCIS lacks any cadherin switching
• C LCIS loses BRCA1 expression which normally anchors E-cadherin to the cytoskeleton; DCIS has BRCA2 mutation and retains E-cadherin
• D Loss of MUC1 in LCIS destabilizes the acinar architecture, while DCIS retains MUC1-mediated cohesion

Explanation

E-cadherin (encoded by CDH1) is a Ca2+-dependent transmembrane adhesion molecule that forms homodimers between adjacent epithelial cells and connects intracellularly to the actin cytoskeleton via β-catenin and α-catenin. Loss of E-cadherin in LCIS (due to CDH1 mutations or, more commonly, promoter hypermethylation and allelic loss) disrupts intercellular adhesion complexes — p120-catenin, which normally binds the E-cadherin cytoplasmic domain to prevent its degradation, is now cytoplasmic and activates Rho GTPase pathways promoting cell motility. The result is the characteristic discohesive, single-file (Indian file) and targetoid infiltrating pattern of lobular carcinoma. DCIS uniformly retains E-cadherin expression and grows in cohesive solid, cribriform, or comedo patterns — making E-cadherin IHC a key diagnostic discriminator.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

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Written and medically reviewed by the StethoPrep medical team.