A 32-year-old BRCA1 mutation carrier undergoes prophylactic mastectomy. Pathological examination of the specimen reveals lobular carcinoma in situ (LCIS). Which molecular alteration is characteristic of LCIS, and how does it relate to the impaired cell-cell adhesion seen?

• A Overexpression of HER2/neu (ERBB2) due to 17q12 amplification — causing excessive proliferation in lobular units
• B Loss of ER (ESR1) expression due to promoter methylation — rendering LCIS hormone-receptor negative
• C p16/CDKN2A deletion causing uncontrolled cell-cycle progression in terminal duct lobular units
• D Loss of E-cadherin (CDH1) expression due to CDH1 mutations or promoter methylation — disrupts cell-cell adhesion, causing dyscohesive cells filling lobular acini ✓

Explanation

LCIS is molecularly defined by loss of E-cadherin (CDH1) expression — either through CDH1 somatic mutations or epigenetic silencing. E-cadherin is the transmembrane glycoprotein that mediates homotypic cell-cell adhesion in epithelial cells via calcium-dependent interactions. Loss of E-cadherin gives lobular lesions their characteristic dyscohesive morphology (cells do not adhere to each other, filling but not distending acini). This same CDH1 loss occurs in invasive lobular carcinoma. LCIS is typically ER-positive and HER2-negative; p16 loss is characteristic of high-grade ductal lesions.

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

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Written and medically reviewed by the StethoPrep medical team.