ArticleFrontiers in oncology2026
When Lynch syndrome is not MSI-H: embryonal testicular carcinoma treated with combined BEP chemotherapy and immunotherapy despite MSS/low TMB: a case report.
Article in Frontiers in oncology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Immune checkpoint inhibitors have demonstrated minimal activity in unselected testicular germ cell tumors (GCTs), largely due to low tumor mutational burden (TMB) and immunologically "cold" tumor microenvironments. Microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR), key predictors of response to PD-1 blockade, are exceedingly rare in GCTs. In patients with Lynch syndrome, germline mismatch repair mutations do not uniformly translate to tumor-level MSI-H/dMMR, creating therapeutic uncertainty. Case Presentation: We report a 33-year-old male with germline MSH2-associated Lynch syndrome who presented with metastatic pure embryonal testicular carcinoma and markedly elevated tumor markers. Imaging demonstrated extensive hepatic and nodal metastases. Following orchiectomy, he was treated with bleomycin, etoposide, and cisplatin (BEP). Given his high-risk disease and germline mutation, pembrolizumab was added starting cycle 2 after shared decision-making, prior to tumor molecular results. Treatment was complicated by neutropenic fever and cytopenias requiring dose reductions and supportive care but no unexpected immune-related adverse events. Tumor markers rapidly declined, and interval imaging demonstrated near-complete resolution of hepatic metastases and significant nodal response. Subsequent next-generation sequencing revealed microsatellite stable (MSS) disease with low TMB (2 mutations/Mb), without actionable alterations. The patient completed therapy and transitioned to maintenance pembrolizumab. Conclusion: This case highlights the clinical and biologic discordance between germline Lynch syndrome and tumor-level biomarkers in a non-Lynch spectrum malignancy. While combination chemotherapy and immunotherapy was feasible, the observed response is consistent with expected cisplatin sensitivity, and the contribution of pembrolizumab remains unclear. These findings underscore the importance of tumor-specific molecular testing and caution against extrapolating germline status to guide immunotherapy decisions in germ cell tumors.
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