Highly expressed EZH2 in combination with BAP1 and MTAP loss, as detected by immunohistochemistry, is useful for differentiating malignant pleural mesothelioma from reactive mesothelial hyperplasia

Masayo Yoshimura, Yoshiaki Kinoshita, Makoto Hamasaki, Shinji Matsumoto, Tomoyuki Hida, Yoshinao Oda, Akinori Iwasaki, Kazuki Nabeshima
Lung Cancer: Journal of the International Association for the Study of Lung Cancer 2019, 130: 187-193

OBJECTIVE: Malignant pleural mesothelioma (MPM) is an aggressive neoplasm with poor prognosis. Loss of BRCA-associated protein 1 (BAP1) protein expression as detected by immunohistochemistry (IHC) and homozygous deletion (HD) of the 9p21 locus as detected by fluorescence in situ hybridization (FISH) permits differentiation of MPM from reactive mesothelial hyperplasia (RMH). We have previously reported that detecting the loss of methylthioadenosine phosphorylase (MTAP) using IHC is a surrogate assay for 9p21 FISH. Furthermore, enhancer of zeste homolog 2 (EZH2), which encodes a component of polycomb repressor complex 2 (PRC-2), has been overexpressed in various tumors as well as MPM. In the current study, we investigated whether EZH2 IHC assay, alone or in combination with BAP1 and MTAP IHC, is useful for distinguishing MPM from RMH.

MATERIALS AND METHODS: We examined IHC expression of EZH2, BAP1, and MTAP, and 9p21 FISH in MPM (n = 38) and RMH (n = 29) and analyzed the sensitivity and specificity of each detection assay for distinguishing MPM from RMH.

RESULTS AND CONCLUSION: EZH2, BAP1, and MTAP IHC, and 9p21 FISH were characterized by a 100% specificity each and 44.7%, 52.6%, 47.4%, and 65.8% sensitivities, respectively. A combination of EZH2 and BAP1 IHC, and 9p21 FISH showed the greatest sensitivity (89.5%). Using IHC alone (EZH2, BAP1, and MTAP IHC) also yielded a good sensitivity of 86.9%; this level is high enough for routine diagnostics. There were no statistically significant associations between expression of EZH2 and that of other markers (BAP1 and MTAP IHC) or 9p21 HD. However, a high expression level of EZH2 was significantly associated with short survival (P = 0.025). In conclusion, adding a high expression level of EZH2 to a combination of BAP1 and MTAP loss, all detected by IHC, demonstrated useful for discriminating MPM from RMH.

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