Immunohistochemical expression of EZH2 in germ cell tumors of the testis: New insights into the genesis and epigenetic reprogramming of these fascinating tumors

Objective: Several studies analyzed the "reprogramming" of germ cell tumors of the testis (GCTT), known to be an epigenetic process that results in the preservation of stem cell features and/or differentiation of GCTT. EZH2 is a methyltransferase involved in the epigenetic regulation of tumors and has become a promising therapeutic target, but few studies have analyzed its expression in GCTT, germ cell neoplasia in situ (GCNIS), and adjacent testis. Methods: We tested 131, 36, and 29 GCTT components, GCNIS, and adjacent testes, respectively. EZH2 expression was evaluated by H-score and compared between different subgroups by adopting median values and the Fisher exact test. Results: We found that EZH2 was more highly expressed by adjacent testis/GCNIS rather than by GCTT (P < .001), with adjacent testis showing the highest values and being statistically significant compared to GCNIS (P < .001). In adjacent testis, EZH2 expression was mainly detected in spermatocytes (primary and secondary) and spermatids, with scattered positive spermatogonia. Seminoma/embryonal carcinoma showed statistically significantly higher EZH2 expression compared to the other nonseminomatous GCTT (P = .027). Conclusions: EZH2 is differentially expressed during GCTT reprogramming (adjacent testis [very high levels] → GCNIS [high levels] → seminoma/embryonal carcinoma [moderate levels] → other nonseminomatous GCTT [low/absent levels]), supporting its involvement in the epigenetic regulation for determining the fate of GCTT.