Correlation of Histologic Features with Gene Alterations in Pleural Mesothelioma

Histologic features, including architectural patterns, cytologic features, and 2021 World Health Organization nuclear grade have been shown to have prognostic significance in epithelioid diffuse pleural mesothelioma (DPM). Biphasic and sarcomatoid DPM, regardless of morphology, have worse outcomes. These prognostic findings are well-established but correlation of architectural patterns, cytologic features, and nuclear grade with genetic alterations has not been well studied. To investigate relationships between histologic findings and genomic alterations, 128 treatment-naïve DPM specimens (70% epithelioid, 23% biphasic and 6.3% sarcomatoid) with next generation sequencing data were retrospectively reviewed. Alterations in BAP1 were the most common genomic alteration (n=62, 48%), followed by CDKN2A (n=49, 38%) and NF2 (n=38, 30%). NF2 alterations were significantly more frequent in biphasic DPM (53% in biphasic versus 25% in sarcomatoid and 22% in epithelioid; p=0.005). In epithelioid DPM, TP53 alterations were associated with presence of prognostically unfavorable histology, including micropapillary or solid architecture, pleomorphic features and high nuclear grade. Tumors with low tumor infiltrating lymphocytes had a higher rate of BAP1 alterations compared to tumors with higher levels of tumor infiltrating lymphocytes (67% versus 30%; p=0.002). The findings of this study enhance our understanding of the relationships among prognostically significant histologic and molecular features of DPM and provide preliminary data to support increased integration of these findings in clinical diagnosis of pleural mesothelioma.