Dual NF2-YAP/TAZ immunohistochemistry is a reliable marker for the detection of NF2 alterations in diffuse pleural mesothelioma

Abstract NF2 loss occurs in about 30 - 50% of diffuse pleural mesothelioma (DPM) with accumulation of YAP and TAZ in tumor nuclei. NF2 and YAP/TAZ represent potential therapeutic targets. We investigate the performance of NF2-YAP/TAZ dual immunohistochemistry (IHC) in identifying DPM that harbors NF2 alterations and in distinguishing DPM from benign mesothelial proliferations. NF2-YAP/TAZ IHC was subsequently performed on a Discovery cohort of DPM with (n=10) or without (n=10) NF2 alterations by next generation sequencing (NGS) and 9 benign cases. Cutoff values for loss of NF2 expression and YAP/TAZ overexpression by IHC were determined in Discovery cohort. Performance characteristics of NF2-YAP/TAZ IHC were investigated in a Validation cohort (20 DPMs and 10 benign cases). In the Discovery cohort, all DPMs with NF2 alterations by NGS showed NF2 IHC scores of <2 while all NF2-wildtype DPMs showed scores of >2. NF2-altered DPMs had significantly higher YAP/TAZ H-scores (p<0.001) than NF2-wildtype DPM and benign pleura (median H-scores: 237.5 (range 185-275), 130.0 (40-225), and 10.0 (0-75), respectively). NF2-YAP/TAZ IHC demonstrated 95.2%, 100%, 100% and 95%, sensitivity, specificity, positive predictive and negative predictive values respectively, for detecting NF2 alterations in DPM (n=40) with NGS as gold standard and 87.5% sensitivity and 100% specificity for distinguishing DPM (n=40) from benign mesothelial proliferations (n=19). NF2-YAP/TAZ IHC has high sensitivity and specificity for detecting NF2 alterations in DPM and high specificity for malignancy, highlighting potential utility for guiding NF2-targeted therapies and distinguishing DPM from benign mimics.