Divergent biology and outcomes of somatic transformations (SM) in germ cell tumors (GCT).

Abstract

613 Background: Somatic transformation (SM) of teratoma, defined by dedifferentiation and expansile overgrowth of teratomatous elements, is rare yet clinically significant due to its aggressive behavior and metastatic potential. Differences by primary site, time to transformation, and outcomes remain poorly characterized. Optimal management and molecular insights are underexplored. Methods: We reviewed clinical and molecular data of all patients diagnosed with SM from June 2016 to May 2025. Time from initial GCT diagnosis to SM detection was defined as time to somatic transformation (TST). SM detected before first relapse was classified as “de-novo,” all others as “evolved.” Overall survival (OS) was measured from SM detection. Descriptive statistics, Kaplan-Meier estimates, and Cox proportional hazards analyses were used. Results: Seventy-two patients were identified: 40 (56%) testicular and 24 (33%) mediastinal primaries. Over 90% of mediastinal tumors showed sarcomatous transformation and were de-novo. Rhabdomyosarcoma (RMS) was enriched in de-novo cases with faster TST, whereas adenocarcinoma predominated in evolved cases with longer TST. (See Table) Primitive neuroectodermal tumor (PNET) histology carried the worst prognosis compared to non-PNET SM (median OS 1.8 vs 8 years; HR 1.94, 95% CI 0.88–4.31; p = 0.1), particularly in testicular primaries (HR 3.81, 95% CI 1.28–11.32; p = 0.01). Relapses within three months of chemotherapy in de-novo SM were associated with inferior OS (HR 2.65, 95% CI 1.01–6.92; p = 0.04). Among those who progressed, salvage surgery was associated with improved OS (HR 0.28, 95% CI 0.13–0.59; p = 0.008). Genomic data was available in 40 patients (55%). TP53 mutations occurred in 35%, enriched in extragonadal primaries (OR 20.8; 95% CI 2.3–184.4; p = 0.0006) and associated with faster progression (HR 3.6; 95% CI 1.7–7.9; p = 0.0009) without OS differences. PTEN/AKT pathway mutations (32%) correlated with sarcomatous transformation (OR 5.11; 95% CI 1.1–37.23; p = 0.05). ctDNA was detected in three relapsed patients; two cleared with salvage therapy, one remains on treatment. Conclusions: SM in GCT demonstrates temporal, histologic, and molecular distinctions across primary sites. PNET histology and chemotherapy resistance in de-novo SM portend worse outcomes. The feasibility of salvage surgery is consequential for those who experience relapse. Extragonadal SM, particularly mediastinal primaries, are enriched for TP53 mutations, and sarcomatous elements. Feature OR/95%CI/ p value Testicular vs extragonadal primaries: sarcomatous elements Frequency (%) 15/40 (37%) vs 27/32 (84%) OR: 9; 95% CI: 2.85–28.4; p < 0.0001 RMS vs non-RMS Mean TST in years (SD) 0.2 (0.5) vs 4.6 (9.4) p = 0.0007 Adenocarcinoma vs non-adenocarcinoma Mean TST in years (SD) 19.4 (13.3) vs 2.4 (6.7) p = 0.02