A. Lindsay Frazier

Standard‐Dose Versus High‐Dose Cisplatin for Intermediate/Poor‐Risk Extracranial Malignant Germ Cell Tumors: Re‐Analysis of Pediatric Oncology Group 9049 and Children's Cancer Group 8882 Trial Using Updated MaGIC Risk Stratification

ABSTRACTBackgroundCisplatin, etoposide, and bleomycin (PEb) have been the standard of care for patients with germ cell tumors (GCT). In the 1990s, an intergroup trial (POG9049/CCG8882) randomized patients with high‐risk GCT, as defined by the 1990 criteria, to high‐dose (HDPEb) versus standard‐dose PEb. HDPEb resulted in improved event‐free survival (EFS), but no difference in overall survival (OS), thus standard‐dose PEb has remained the standard of care. Subsequently, the Malignant Germ Cell International Consortium (MaGIC) updated the risk stratification for pediatric and adolescent patients with GCT. Currently, patients are categorized as intermediate or poor risk if they are ≥11 years of age with Stage IV ovarian GCT, or testicular, mediastinal, or retroperitoneal GCT with intermediate or poor prognosis using the International Germ Cell Consensus Classification criteria.MethodsWe re‐analyzed data from the POG9049/CCG8882 trial using the updated MaGIC risk stratification to determine whether HDPEb improved outcomes over PEb in patients with intermediate/poor‐risk GCTs.ResultsAmong 299 patients in the trial, 57 patients (48 males, nine females) met the inclusion criteria for this analysis. There were no statistically significant differences in 5‐year EFS (0.72 vs. 0.70, p‐value = 0.82) or OS (0.76 vs. 0.74, p‐value = 0.91) among patients treated with HDPEb versus PEb, respectively. Also, of note patients with mediastinal primaries had significantly worse 5‐year EFS (0.51 vs. 0.83, p‐value = 0.0062) and OS (0.49 vs. 0.89, p‐value = 0.0013) compared to other sites, with no difference in outcome between HDPEb and PEb.ConclusionsTreatment with HDPEb did not improve outcomes for intermediate/poor‐risk GCT patients compared to standard‐dose PEb.

Prognostic Significance of Germline DICER1 Pathogenic or Likely Pathogenic Variants in Outcomes of Ovarian Sertoli-Leydig Cell Tumor

PURPOSE Sertoli-Leydig cell tumors (SLCTs) are rare sex cord-stromal tumors, representing <0.5% of all ovarian tumors. We analyze the role of germline DICER1 status in outcomes of ovarian SLCT. METHODS Patients with SLCT were enrolled in the International Pleuropulmonary Blastoma/ DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry. Medical records were systematically abstracted, and those with known germline DICER1 status were selected for analysis. RESULTS Of 162 patients with SLCT, 60% had a germline DICER1 pathogenic or likely pathogenic (P/LP) variant. The adjusted 3-year recurrence-free survival (RFS) was 87.2% (95% CI, 79.4 to 95.8) for patients with a germline DICER1 P/LP variant compared with 78.1% (95% CI, 66.4 to 91.9) for those without a germline DICER1 P/LP variant ( P = .043). The adjusted 3-year and 5-year overall survival (OS) was 93.9% (95% CI, 87.3 to 100.0) for those with a germline DICER1 P/LP variant compared with the 3-year OS of 91.3% (95% CI, 83.4 to 100.0) and the 5-year OS of 78.2% (95% CI, 63.8 to 95.9) for those without a germline DICER1 P/LP variant ( P = .021). Among patients with a germline DICER1 P/LP variant, the risk of a subsequent, nonrecurrent event was 36.2% (95% CI, 21.4 to 48.1) within 10 years. Previous/concurrent and subsequent neoplasms were rare among those without a germline DICER1 P/LP variant. CONCLUSION This cohort study of patients with SLCT demonstrated that those with germline DICER1 P/LP variants had superior RFS and OS even when adjusting for other prognostic factors. Beyond prognostic implications of a germline DICER1 P/LP variant, germline testing helps identify patients at risk of subsequent neoplasms, including metachronous SLCT.

Vaginal germ cell tumors: results from the international retrospective VAGIPED study

Vaginal malignant germ cell tumors (MGCTs), predominantly yolk sac tumors, are extremely rare, with no established consensus on optimal management. This study evaluated whether post-chemotherapy surgery is necessary for vaginal MGCTs. A retrospective analysis was conducted on patients diagnosed with vaginal MGCTs from 1996 to 2023. Progression-free survival (PFS), overall survival (OS), the impact of surgical intervention, and the presence of post-chemotherapy residual mass (RM) were assessed. Seventy-five patients (median age:11 months) were included. Six underwent initial tumor resection, and all received platinum-based chemotherapy. RM was detected post-chemotherapy in 57% of evaluable cases (40/70), with vaginoscopy outperforming standard imaging in detection (p < 0.001). The 5-year PFS and OS rates were 83% (95%CI: 71-90) and 94% (95%CI: 84-98), respectively. Neither RM (p = 0.64) nor delayed surgical intervention (5-year PFS: 77% (95%CI: 54-90) without surgery versus 85% (95%CI: 70-92) with surgery; log-rank test p = 0.72) significantly impacted PFS. Neoadjuvant platinum-based chemotherapy yields excellent survival outcomes in vaginal MGCTs. Vaginoscopy appears more sensitive than standard imaging for RM detection and is recommended for post-chemotherapy evaluation. In the absence of RM on vaginoscopy and with negative tumor markers, systematic post-chemotherapy surgery may be unnecessary. A global consensual framework for managing is proposed.

DICER1-Related Tumor Predisposition: Identification of At-risk Individuals and Recommended Surveillance Strategies

Abstract Purpose: DICER1-related tumor predisposition increases risk for a spectrum of benign and malignant tumors. In 2018, the International Pleuropulmonary Blastoma (PPB)/DICER1 Registry published guidelines for testing- and imaging-based surveillance of individuals with a known or suspected germline DICER1 pathogenic or likely pathogenic (P/LP) variant. One of the goals of the Registry is to continue to refine these guidelines as additional data become available. Experimental Design: Individuals were enrolled in the International PPB/DICER1 Registry, the International Ovarian and Testicular Stromal Tumor Registry, and/or the NCI Natural History of DICER1 Syndrome study. Results: Review of participant records identified 713 participants with a germline DICER1 P/LP variant from 38 countries. To date, 5 cases of type I and 29 cases of type Ir PPB have been diagnosed by surveillance in enrolled individuals. One hundred and three individuals with a germline P/LP variant developed a primary ovarian Sertoli–Leydig cell tumor at a median age of 14 years (range: 11 months–66 years); 13% were diagnosed before 8 years of age, the current age of onset of pelvic surveillance. Additionally, 4% of Sertoli–Leydig cell tumors were diagnosed before 4 years of age. Conclusions: Ongoing data collection highlights the role of lung surveillance in the early detection of PPB and suggests that imaging-based detection and early resection may decrease the risk of advanced PPB. DICER1-related ovarian tumors were detected before 8 years of age, prompting the Registry to recommend earlier initiation of ovarian surveillance with pelvic ultrasound beginning at the time of detection of a germline DICER1 P/LP variant.