Clinical and pathologic phenotyping of mesotheliomas developing in carriers of germline BAP1 mutations

Abstract

ABSTRACTIntroduction: Mesothelioma is frequent among carriers of inactivating heterozygous germline BAP1 mutations (BAP1+/-). We studied whether the natural history and the pathology of mesotheliomas in BAP1+/- carriers differed from sporadic, not-genetically related, mesotheliomas. Methods: During 1999-2024, we studied 47 families carrying BAP1+/- transmitted in a Mendelian fashion. We characterized these mutations, collected family history, clinical records, prepared family pedigrees and diagnosed their mesotheliomas. Results: We identified 34 different germline inactivating mutations. Among 238 BAP1+/- carriers aged 27-81, 84 were diagnosed with mesothelioma (35%), 1/84 had evidence of asbestos exposure. No mesothelioma was recorded among 123 siblings/relatives who did not inherit BAP1+/- p < 0.0001. The 84 BAP1+/- patients developed mesothelioma at a relatively young age; 45.2% developed multiple cancers. BAP1+/- patients had a florid, diffuse mesothelial hyperplasia often present in both pleural cavities, peritoneum and pericardium. Thoracoscopy and laparoscopy showed several multi-cavity ~1-3 mm whitish flat lesions, imaging was usually negative for cancer. Histology revealed epithelioid cells lacking BAP1 nuclear staining arranged in tubulo-papillary and trabecular architectures, focally invading sub-mesothelial adipose tissue. These findings may lead to the diagnosis of stage IV metastatic mesothelioma. However, we found that these tumors remain indolent for years and, at this early stage, patients do not require aggressive therapy. We refer to these tumors as “Low-grade-germline-mutant-BAP1-associated-mesotheliomas, L-BAM” to distinguish them from aggressive, therapy-resistant, sporadic mesotheliomas. For the 1/3 of patients who develop lesions visible by imaging, surgery and/or chemotherapy leads to survival of several years, some were cured. Deep invasion by mesothelioma cells with a solid architecture is rare: these cases have poor survival. Conclusions: Compared to sporadic mesotheliomas, mesotheliomas developing in BAP1+/- carriers are a different disease, biologically, histologically and clinically: these patients require a tailored clinical approach.