A 32-year-old woman with cervical carcinoma in situ (CIN 3/HSIL) shows diffuse p16 block staining on IHC. The mechanism of p16 overexpression in HPV-driven dysplasia is:

• A HPV E6 protein degrades Rb, releasing E2F, which transcriptionally activates p16 as a compensatory negative feedback
• B HPV E5 protein directly activates the p16 promoter via EGFR-MAPK signaling
• C p16 overexpression reflects amplification of chromosome 9p21 in HPV-infected cells
• D HPV E7 protein binds and inactivates Rb; free E2F upregulates transcription of p16 (CDKN2A) as compensatory feedback ✓

Explanation

HPV E7 oncoprotein binds and degrades pRb (retinoblastoma protein) through an LxCxE motif, releasing E2F transcription factors to drive cell cycle progression. Loss of functional pRb removes the feedback suppression of p16 (CDKN2A), which normally inhibits CDK4/6 to phosphorylate Rb; without Rb as a target, p16 accumulates massively. This paradoxical p16 overexpression in the context of Rb loss is why diffuse block-positive p16 IHC is a surrogate marker for transcriptionally active high-risk HPV infection and distinguishes CIN 2-3/HSIL from reactive squamous changes.

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

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Written and medically reviewed by the StethoPrep medical team.