Gene expression and immunohistochemical phenotypes of high-grade epithelioid mesothelioma

Grading of epithelioid mesothelioma (EM) has recently been reported to be predictive of survival. We investigated whether RNA expression profiles and immunohistochemical (IHC) markers could refine EG grading and potentially identify therapeutic targets. Forty-seven pleural mesothelioma biopsies were studied, including 6 sarcomatoid/desmoplastic mesothelioma (SM), 6 biphasic mesothelioma (BM), and 35 EM. We subclassified EM cases into low-(LG) and high-grade (HG) based on WHO classification. FFPE slides were used for RNA expression and IHC (BAP1, EZH2 and PD-L1) studies. RNA expression was profiled by nCounter PanCancer Pathways Panel (NanoString, 770 genes). In 35 EM, 14 were classified as EM-HG and 21 as EM-LG. RNA expression heat mapping demonstrated that EM-LG predominantly cluster together while EM-HG exhibit more heterogeneity with some cases exhibiting proximity to SM/BM. SM/BM demonstrated a noticeable different IHC profile compared to EM-LG: fewer BAP1 loss (25% vs 86%), higher expression of PD-L1 (mean 30.1%, range 0-80% vs mean 1.3%, 0-10%) and higher EZH2 (mean H score 136.3, 10-250 vs mean 57.1, 5-150). Similarly to EM-LG, EM-HG exhibited low PD-L1 expression with a mean TPS of 1.2%, suggesting limited clinical utility for PD-L1 IHC for EM-LG and EM-HG. A non-statistically significant trend for higher EZH2 expression in EM-HG (mean H score 88.3, 60-140) compared to EM-LG was seen. In conclusion, in addition to supporting histology grading of EM, our findings highlight that EM-HG cases display more heterogeneous expression profiles than EM-LG with some features in between EM-LG and SM/BM. Further data is needed to explore the potential clinical utility EZH2 IHC in the clinical management of pleural mesothelioma.