New insights into Nectin-4 expression in testicular choriocarcinoma and its potential treatment with Enfortumab Vedotin: analysis of a multi-institutional series and association with clinical-pathological features.

Choriocarcinoma (CHC) is an aggressive tumor that expresses Nectin-4, which makes it a potential target for enfortumab vedotin (EV). However, only a few cases have been analyzed so far, and the correlation between Nectin-4 and clinical-pathological features has never been investigated. Twenty-one testicular CHCs were collected and stained for Nectin-4. Cytoplasmatic expression was positive in 17/20 primary CHCs (4/20: moderate expression). Membrane expression was positive in 16/20 primary CHCs (5/20: moderate expression). Cytoplasmatic expression was associated with higher % of CHC (p = 0.028) and β-HCG serum levels (p = 0.007); moderate/strong cytoplasmatic expression was associated with younger age (p = 0.0039). The only post-chemotherapy and metastatic CHC showed the highest membrane expression (H-score: 155), especially if paired with its primary (H-score: 33). The Nectin-4 stain was primarily confined to syncytiotrophoblasts rather than to cytotrophoblasts/intermediate trophoblasts. These findings confirm that testicular CHC expresses Nectin-4 and may be potentially targetable with EV. Future studies are needed to verify whether metastasis and chemotherapy up-regulate Nectin-4 and increase the sensitivity to EV, and whether the absence of Nectin-4 expression by cytotrophoblasts (the proliferative population of CHC) influences its potential efficacy.