Pleural Mesothelioma With Unusual Squamous Differentiation: A Clinicopathological Case Report With Molecular Insights From Whole-Exome Sequencing.

Pleural mesothelioma is an aggressive tumor with a poor prognosis and limited therapeutic options. While histological heterogeneity is common, true squamous differentiation is extremely rare and diagnostically challenging. We report an 81-year-old man with asbestos exposure who presented with recurrent right-sided pleural effusion. Thoracoscopic biopsies revealed two distinct tumor components. The first expressed mesothelial immunohistochemical markers, whereas the second showed a squamous profile. Both components demonstrated loss of BAP1 expression and homozygous deletion of CDKN2A, supporting a common mesothelial origin. Whole-exome sequencing revealed a tumor mutational burden above the average reported for mesothelioma (8-9 mutations per megabase), with 69 somatic mutations in total, 43 shared between the two components. In addition to canonical mesothelioma alterations (BAP1, CHEK2), the squamous component harbored 18 unique variants, including oncogenic alterations in NFE2L2 and PIK3CA. A novel SOX9 missense variant of uncertain significance (p. Thr243Pro) was also identified within the transactivation middle (TAM) domain; its functional consequence remains unknown. This case highlights a rare histological variant of pleural mesothelioma with partially squamous differentiation, characterized by a mutational burden above the mesothelioma average and squamous carcinoma-associated alterations. Integrated histology, immunohistochemistry, and genomic profiling are essential to avoid misdiagnosis and to improve understanding of tumor plasticity in mesothelioma.