A 65-year-old man with a history of asbestos exposure develops a pleural mass. Histology shows biphasic pattern with both epithelioid (tubular) and spindle cell (sarcomatoid) components. Immunohistochemistry: calretinin+, WT1+, CK5/6+, CEA−, TTF-1−. What is this diagnosis and the most relevant oncogenic mechanism?
- A Malignant mesothelioma; driven by BAP1 inactivation and NF2/Merlin loss ✓
- B Pleural adenocarcinoma; driven by EGFR mutation
- C Synovial sarcoma; driven by SS18-SSX fusion
- D Sarcomatoid carcinoma; driven by TP53 mutation exclusively
Correct answer: A. Malignant mesothelioma; driven by BAP1 inactivation and NF2/Merlin loss
Explanation
The IHC profile (calretinin+, WT1+, CK5/6+, CEA−, TTF-1−) is characteristic of malignant mesothelioma. The biphasic pattern with both epithelioid and sarcomatoid elements confirms biphasic mesothelioma. Key molecular events include loss of NF2 (Merlin) via deletion/mutation (seen in ~40–50%), loss of CDKN2A (p16), and BAP1 inactivation (BRCA1-associated protein 1 on chromosome 3p21 — a chromatin remodeling factor). Asbestos fibers generate ROS that drive these mutations. BAP1 germline mutations predispose to mesothelioma and uveal melanoma.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.