Abstract
INTRODUCTION: 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 to 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 to 81 years, 84 were diagnosed with mesothelioma (35%) and one of 84 had evidence of asbestos exposure. No mesothelioma was recorded among 123 siblings, first- or second-degree relatives who did not inherit BAP1(+/-) (p < 0.0001). The 84 patients with BAP1(+/-) developed mesothelioma at a relatively young age; 45.2% developed multiple cancers. Patients with BAP1(+/-) had a florid, diffuse mesothelial hyperplasia often present in both pleural cavities, peritoneum and pericardium. Thoracoscopy and laparoscopy results revealed several multicavity approximately 1 to 3 mm whitish flat lesions, but imaging result was usually negative for cancer. Histology results revealed epithelioid cells lacking BAP1 nuclear staining arranged in tubulopapillary and trabecular architectures, focally invading submesothelial 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 developed lesions visible by imaging, surgery, chemotherapy, or a combination of both led to survival of several years, and some were cured. Deep invasion by mesothelioma cells with a solid architecture is rare: these cases have poor survival. CONCLUSIONS: Compared with sporadic mesotheliomas, mesotheliomas developing in BAP1(+/-) carriers are a different disease, biologically, histologically, and clinically; these patients require a tailored clinical approach.