Sounak Gupta

Expanding the spectrum of paratesticular mullerian-origin tumors: Adenocarcinoma with mixed serous and endometrioid features and clear cell carcinoma

Assessment of trophoblast cell-surface antigen 2 (TROP2) and nectin-4 expression in choriocarcinoma

Choriocarcinoma is associated with high mortality in multiply relapsed patients. Herein, we assessed immunohistochemistry (IHC) expression of TROP2 and nectin-4 in choriocarcinoma and other germ cell tumors (GCT), as antibody drug conjugates (ADCs) targeting these markers are entering the therapeutic landscape of many tumors. Archival cases of choriocarcinoma and controls (non-choriocarcinoma GCT) were evaluated for TROP2 and nectin-4 IHC, performed on whole-slide sections, and results were quantified using H-scores (range: 0-300) based on membranous staining. The cohort included 20 primary GCT and 15 metastases from 34 patients. Of these, 18 specimens were choriocarcinoma (3 primary and 15 metastases), including six women with gestational choriocarcinoma. Median TROP2 and nectin-4 H-scores in choriocarcinomas were 22.5 and 60, respectively. For TROP2 and nectin-4, H-scores>200 were noted in 27.8% of patients, each. There was no correlation between serum beta-hCG levels measured within 2 weeks prior to specimen collection or peak serum beta-hCG levels and TROP2 or nectin-4 expression. The control group consisted of seminoma (n = 10); yolk sac tumor (n = 9), embryonal carcinoma (n = 10), postpubertal teratoma (n = 5), and spermatocytic tumor (n = 2). The median TROP2 H-scores for embryonal carcinoma, teratoma, and yolk sac tumor were 35, 30, and 15, respectively, and 0 for the remainder. The median nectin-4 H-score was 0 for all control group categories. Choriocarcinomas had a higher nectin-4 H-score compared to the control group (p < 0.001). Given the high TROP2 and nectin-4 expression in a subset of choriocarcinoma, ADCs targeting these biomarkers may be a promising therapeutic approach for these tumors, pending additional validation.

A diagnostic approach to paratesticular lesions with tubulopapillary architecture: a series of 16 serous borderline tumors/low-grade serous carcinoma and 14 well-differentiated papillary mesothelial tumors and mesothelioma

As there is limited literature on paratesticular tumors of müllerian and mesothelial origin, we reviewed archived cases of serous borderline tumors (n = 15), low-grade serous carcinoma (n = 1), well-differentiated papillary mesothelial tumors (WDPMTs; n = 2), and mesothelioma (n = 12), for relevant clinicopathologic features. Molecular profiling data from the American Association for Cancer Research (AACR) GENIE registry was accessed for 8 additional patients with testicular mesothelioma. For tumors of mesothelial origin, the median age at surgical excision was 62 years, the median size was 4.5 cm, and they consistently exhibited positivity for mesothelial markers (CK5/6, calretinin, WT1, and D2-40). Recurrent alterations of the NF2 gene were identified in 3 of 8 patients (38%), and alterations of BAP1 and CDKN2A were relatively infrequent. While one patient with WDPMT had a recurrence, a second patient with WDPMT progressed to a biphasic mesothelioma 2 years after initial resection. For tumors of müllerian origin, the median age at surgical excision was 45 years, the median size was 2.5 cm, and these exhibited consistent positivity for ER, WT1, and PAX8. Although no recurrences were documented in patients with serous borderline tumors, a single patient with a low-grade serous carcinoma developed widely metastatic disease and died of disease-related complications. Our study emphasizes the need for close clinical follow-up in patients with WDPMT and highlights the prognostic significance of documenting invasive behavior in tumors of müllerian origin as they can have an aggressive clinical course. Finally, our results suggest that NF2 alterations may play an important role in the pathogenesis of testicular mesothelioma.