Expansion of EZHIP immunohistochemical profiling to non-germinomatous central nervous system germ cell tumors

To the Editor, Central nervous system (CNS) germ cell tumors (GCTs) are rare neoplasms that predominantly affect children and young adults. They arise mainly in midline locations, most frequently in the pineal and suprasellar regions, and comprise a heterogeneous group of tumors including germinomas and non-germinomatous germ cell tumors (NGGCTs), with germinomas accounting for approximately two-thirds of cases. Histologically, CNS GCTs closely resemble their gonadal and other extragonadal counterparts.1 Accurate pathological classification is essential because treatment strategies and prognosis differ substantially between germinomas and NGGCTs. In routine neuropathological practice, the diagnosis of GCTs frequently relies on small stereotactic biopsies or cytological specimens, particularly for surgically challenging lesions arising in the pineal region in close proximity to the brainstem. In such settings, limited tissue availability and low tumor cell density may complicate morphological assessment; this highlights the need for robust and easily interpretable immunohistochemical markers. Commonly used markers include OCT3/4, SALL4, PLAP, β-HCG, and CD117.2 While OCT3/4 is among the most sensitive markers for germinoma, it is also expressed in embryonal carcinoma. Likewise, SALL4 and PLAP are highly sensitive markers of GCTs but do not reliably distinguish between individual subtypes. Although β-hCG is characteristically expressed in choriocarcinoma, positivity may also be observed in germinomas with syncytiotrophoblastic differentiation. Additional biomarkers with high diagnostic specificity would be valuable.3 Enhancer of zeste homologs inhibitory protein (EZHIP) has recently emerged as a promising diagnostic biomarker in neuropathology. Initially identified as a characteristic marker of posterior fossa ependymoma group A and H3-wildtype diffuse midline glioma, EZHIP has subsequently been reported to be strongly and consistently expressed in CNS germinomas.4 EZHIP is an epigenetic regulator; its physiological expression is largely restricted to germ cells. By inhibiting the Polycomb Repressive Complex 2 (PRC2), it induces a global reduction in histone H3 lysine 27 trimethylation (H3K27me3).5,6 While EZHIP immunohistochemistry has shown considerable promise as a diagnostic tool for germinomas, its expression among CNS NGGCTs has not yet been investigated. Herein we aim to evaluate EZHIP expression in a series of CNS NGGCTs and to assess its diagnostic utility and specificity for distinguishing germinomas from other GCT subtypes.