B80-5-14 Not Just Asbestos: Malignant Pleural Mesothelioma as an Unusual Manifestation of Lynch Syndrome

Background Lynch syndrome (LS), caused by germline mutations in DNA mismatch-repair (MMR) genes, is the leading cause of hereditary colorectal cancer and is associated with endometrial and other extracolonic malignancies. Malignant pleural mesothelioma is exceedingly rare in LS, with only a few cases reported worldwide. Because mesothelioma is typically linked to asbestos exposure, distinguishing environmentally induced disease from hereditary predisposition remains challenging and clinically relevant. Case Report A 70 year old woman with a history of endometrial, breast, and colorectal cancers presented with progressive pleuritic chest pain. She had lived for 15 years in a mining region with environmental asbestos exposure. CT of the chest revealed diffuse pleural thickening and bilateral pleural effusions. VATS biopsy showed pleural nodularity and evidence of carcinomatosis. Histopathology demonstrated epithelioid malignant pleural mesothelioma with focal rhabdoid morphology. Immunohistochemistry showed tumor cell positivity for CK7, WT1, and D2-40, and negativity for CK20, GATA3, and TTF1, confirming mesothelioma. Additional staining revealed complete loss of PMS2 expression with retention of MLH1, MSH2, and MSH6, indicating MMR deficiency. The patient underwent multiple thoracic drainages and received systemic chemotherapy followed by immunotherapy with Nivolumab and Ipilimumab. Unfortunately, the patient died from complications within months of diagnosis. Discussion This case represents an exceptionally rare presentation of Lynch syndrome manifesting as malignant pleural mesothelioma. Initially presumed to result from asbestos exposure, subsequent immunohistochemical evidence of PMS2 loss redefined the tumor as Lynch-associated. This diagnostic pivot underscores the importance of considering hereditary cancer syndromes even in malignancies with classic environmental risk factors. The coexistence of MMR deficiency and asbestos exposure suggests a gene-environment synergy, where defective DNA repair may amplify susceptibility to carcinogens at low exposure levels. Recognizing this mechanism expands the tumor spectrum of LS and highlights the clinical imperative of performing MMR testing in atypical thoracic malignancies, particularly when family history suggests a genetic predisposition. Learning Point Not all mesotheliomas are asbestos-induced-some may arise from underlying genomic instability such as Lynch syndrome. Identifying MMR deficiency can change the understanding of disease origin, guide genetic counseling, and inform surveillance for high-risk families.