Background: Despite advancements in treatment of advanced testicular germ cell tumors (GCT), metastatic teratoma remains a significant challenge due to its intrinsic chemo- and radioresistance. Claudin-6 (CLDN6), a tumor-specific antigen, has shown promise in targeted therapies for various solid tumors, including metastatic GCT in early phase trials. Testicular GCT frequently exhibit a unique cytogenetic hallmark, isochromosome 12p (i12p), which is associated with tumor development and progression, underscoring its significance in oncogenesis and diagnosis, and potential as a potential biomarker. Objectives: We aimed to understand the expression of CLDN6 during progression from germ cell neoplasia in situ (GCNIS) to primary GCT and postchemotherapy teratoma, and to investigate persistence of i12p in postchemotherapy teratoma. Design: An observational cohort study. Methods: Using matched pre- and postchemotherapy formalin-fixed paraffin-embedded tumor tissue from patients with primary GCT and postchemotherapy teratoma identified from a national GCT registry, iTestis, CLDN6 expression, and presence of i12p were evaluated. Results: Twenty-two patients were eligible. The majority were diagnosed with mixed primary GCT (20/22, 91%) with teratoma the sole histologic component in 86% of postchemotherapy samples (19/22). CLDN6 expression was consistently observed in GCNIS (16/16, 100%) and primary nonteratoma GCT (20/20, 100%) though significantly lower in primary teratoma components (4/10, 40%) and metastatic teratomas (5/22, 23%). The mean proportion of CLDN6-positive cells was higher in primary nonteratoma components (87.5%) compared to primary (6.5%) and postchemotherapy teratoma (4.6%). i12p was also common in primary GCT (18/22, 82%), including pure teratoma (2/2, 100%), though concordance between i12p in primary orchidectomy and metastatic samples was lower (13/18, 72%). Conclusion: Our results demonstrate early overexpression of CLDN6 in GCNIS and high expression in nonteratoma components in primary GCTs, but limited expression in primary and posttreatment teratomas. CLDN6-targeted therapies may not be effective for teratoma. In contrast, i12p was prevalent across all stages of GCT progression, suggesting its potential as a biomarker for identifying viable GCT.
Conduit et al. (Sun,) studied this question.