Cécile Faure‐Conter

Disorder of sex development with germ cell tumors: Which is uncovered first?

AbstractBackgroundDisorders of sex development (DSD) are rare conditions. Although they are known to predispose to germ cell tumors (GCT), there is a paucity of information regarding the circumstances of DSD discovery.Design/methodsAll patients with DSD registered in two French pediatric GCT protocols (TGM95 and 13) were analyzed.ResultsSixteen patients were identified among 276 ovarian, 160 testicular, and 24 mediastinal GCT. Eleven phenotypic females (median age 15 years) exhibited gonadal GCT, including 10 with a 46,XY karyotype and gonadal dysgenesis and one with 46XX,45X0 mosaicism. None had genital anomalies, seven had spontaneous pubertal changes, and one had spontaneous menarche. The tumors were bilateral in four cases. DSD was diagnosed after the GCT diagnosis in seven cases. The reasons for karyotyping were bilateral tumors (3), gonadoblastoma/streak gonad/absence of egg follicles (3), or systematic for GCT (1). The karyotyping was performed before the GCT diagnosis in four cases: for polymalformative syndrome (2) or primary amenorrhea (2). Four males (median age 14 years) exhibited mediastinal GCT (metastatic in two cases) indicative of Klinefelter syndrome, despite typical phenotypes in all cases. The remaining patient had severe hypospadias, leading to the discovery of 46,XY/45,X0 mosaicism before the diagnosis of testicular nonseminomatous GCT at 16 years of age.ConclusionDSD are often uncovered at the time of GCT diagnosis (11/16 cases). This should prompt oncologists to rule out a DSD in patients with GCT, even in case of pubertal development. Earlier recognition of Klinefelter syndrome could potentially lead to GCT detection at an earlier stage.

Pure pediatric ovarian immature teratomas: The French experience

AbstractObjectiveTo describe characteristics and outcome of pediatric ovarian immature teratomas (IT) to better define the place of chemotherapy.MethodsChildren with ovarian IT enrolled in TGM95 and TGM2013 studies were analyzed. Norris grading and International Federation of Gynecology and Obstetrics staging system were used.ResultsThirty‐six cases were identified with a median age of 11 years (range = 1‐18): 35 of 36 stage I (17 stage IA, 13 stage IC, and 5 stage IX), including seven patients with gliomatosis peritonei (GP), and 1 stage IIIB (IT peritoneal implants). Centrally reviewed Norris grading was performed in 31 cases: 14 grade I and 17 grade II/III tumors. All patients underwent upfront surgery: 19 unilateral oophorectomy, 14 unilateral adnexectomy, 2 unilateral cystectomy, and 1 bilateral cystectomy. No extensive GP surgery was performed. Six patients received adjuvant vinblastin, bleomycin, and cisplatinum because of tumor rupture (n = 5, including two patients with GP) or stage III (n = 1). After a median follow‐up of 39.5 months (range = 6‐238), two events occurred 10 and 11 months after diagnosis: one bilateralization (initial stage IX, grade I) and one IT peritoneal relapse (initial stage IA, grade II), respectively. Both were successfully rescued by platinum‐based chemotherapy and delayed surgery. No stage IC patients treated without adjuvant chemotherapy relapsed (four grade I and three grade III). None of the seven patients with GP progressed. Five‐year event‐free survival and overall survival were 94% (95% CI = 81‐98%) and 100%.ConclusionsThe current series confirms the excellent prognosis of pediatric ovarian IT, arguing for conservative surgical approach in GP and against systematic adjuvant chemotherapy, even in ruptured tumors.

Extracranial germ cell tumours in children and adolescents: Results from the French TGM13 protocol

AbstractBackgroundChemotherapy for non‐seminomatous germ cell tumours (NSGCT) exposes to dose‐dependent toxicities. The TGM13‐NS protocol (EudraCT 2013‐004039‐60) aimed to decrease the chemotherapy burden compared to the previous TGM95 protocol while maintaining the 5‐year event‐free survival (EFS) at 80% or more.ProcedurePatients less than 19 years of age with disseminated NSGCT were enrolled (May 2014 to May 2019) and stratified into four groups: two intermediate‐risk (IR: localised tumour with low tumour markers [TM]) groups treated with VBP (vinblastine–bleomycin–cisplatin): three courses for IR1 (ovarian tumour any age/testis tumour less than or equal to 10 years) and four courses for IR2 (extragonadal tumour 10 years or less) groups, and two high‐risk (HR: metastatic and/or high TM) groups treated with etoposide–cisplatin and either ifosfamide (VIP) or bleomycin (BEP): three courses for HR1 (ovarian tumour any age/testis tumour less than or equal to 10 years and low TM/testis tumour more than 10 years and very low TM) groups and four courses for HR2 (remainder) groups.ResultsOne hundred fifteen patients were included: median age of 12.8 years (0.4–18.9); tumour sites: 44 ovaries, 37 testes and 34 extragonadal. The 5‐year EFS and overall survival (OS) were 87% (95% CI: 80–92) and 95% (89–98), respectively (median follow‐up: 3.5 years, range: 0.2–5.9), similar to those of the TGM95 protocol (5‐year EFS 89% (84–93), 5‐year OS 93% (89–95), p = .561). The 5‐year EFS were 93% (95% CI: 80–98), 88% (71–95) and 79% (62–90) for ovarian, testicular and extragonadal tumours, respectively. The 5‐year EFS varied (p = .02) according to the risk groups: 90% (66–97), 64% (30–85), 95% (72–99) and 87% (74–94) for IR1, IR2, HR1 and HR2, respectively. TM decline adjusted to tumour site, and alpha‐fetoprotein (AFP) level revealed a prognostic impact of time to normalisation on EFS: HR = 1.03 (1.003–1.007).ConclusionRisk‐adapted and globally decreased chemotherapy burden maintains excellent outcomes, exclusive of the IR2 group, which warrants more intensive chemotherapy.

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.

Outcome and late effects of patients treated for childhood vaginal malignant germ cell tumors

AbstractPurposeVaginal malignant germ cell tumors (MGCT) are rare, occurring in children less than 2 years old and raise the question of the optimal local treatment.MethodsWe included children treated for vaginal MGCT according to the French TGM‐95/2013 regimen. Patients were classified as standard risk (SR: localized disease and alpha‐fetoprotein (AFP) &lt; 10,000 ng/mL) or high risk (HiR: metastatic and/or AFP &gt; 10,000 ng/mL) and were treated, respectively, with three to five VBP (vinblastine–bleomycin–cisplatin) or four to six VIP (etoposide–ifosfamide–cisplatin), followed by conservative surgery and/or brachytherapy in case of post‐chemotherapy residuum.ResultsFourteen patients were included (median age = 12 months), of which six (43%) were classified as HiR. AFP levels were normalized after first‐line chemotherapy in all cases but one. A vaginal post‐chemotherapy residuum (median size = 8 mm, range: 1–24 mm) was observed in 13/14 patients, treated by complete resection in seven of 13 (viable cells in three of seven), incomplete resection in four of 13 (viable cells in two of four), with adjuvant brachytherapy in two of 13, and exclusive brachytherapy in two of 13 (viable cells in one of six). Among the six patients with viable disease, four patients received adjuvant chemotherapy. One patient (SR) experienced immediate postoperative relapse despite presenting no viable residual cells and was treated with four VIP cycles and brachytherapy. At last follow‐up (median = 4.6 years, range: 0.5–16), all patients were alive in complete remission. Five patients suffered from vaginal sequelae with synechiae and/or stenosis (of whom four had undergone brachytherapy).ConclusionChildhood vaginal MGCTs show a highly favorable prognosis with risk‐adapted chemotherapy and local treatment of post‐chemotherapy residuum (preferably by conservative surgery with partial vaginectomy). Brachytherapy could be an alternative when conservative surgery is not deemed possible or in cases of incomplete resection with residual viable cells.

Oncological and endocrinological outcomes for children and adolescents with testicular and ovarian sex cord‐stromal tumors. Results of the TGM13 National Registry

Abstract Rationale Sex cord‐stromal tumors (SCST) are hormonally active and rare. The aim was to describe their endocrinological presentation and outcomes. Method Patients (&lt; 19 years) registered in the TGM13 registry between 2014 and 2021 for SCST were selected. Results Sixty‐three ovarian SCST (juvenile granulosa tumor (JGT) n  = 34, Sertoli‐Leydig cell tumor (SLCT) n  = 17, other SCST n  = 12) were included. Median age was 13.1 years (0.4‐17.4). Germline DICER1 pathogenic variant was present in 9/17 SLCT. Sixty‐one were FIGO stage I (IC n  = 14). Adjuvant chemotherapy was administered for 15. Seven had recurrence (FIGO IA n  = 3, IX n  = 2, III n  = 2), leading to one death. With a median follow‐up of 42 months (2.5‐92), the 3‐year progression‐free survival (PFS) was 89% (95% CI 76%‐95%). Median age was 6.4 years (0.1‐12.9) among the 15 testicular SCST (Leydig cell tumor n  = 6, JGT n  = 5, Sertoli cell tumor n  = 3, mixed SCST n  = 1). Tumor‐nodes‐metastases (TNM) stage was pSI in 14. Eight underwent a tumorectomy, 7 an orchiectomy. None experienced recurrence. Endocrinological data were reviewed for 41 patients (18 prepubescent). Endocrine symptoms were present at diagnosis in 29/34 females and 2/7 males (gynecomastia). After a median follow‐up of 11 months, 15 patients had persistent endocrine abnormalities: gynecomastia/breast growth (2 males, 1 prepubescent female), precocious/advanced puberty (4 prepubescent females), and hirsutism/menstruation disorders/voice hoarseness/hot flashes (8 pubescent females). The mean height at the last follow‐up was within normal ranges (+0.3 standard deviation). Conclusions SCSTs have a favorable prognosis. Tumorectomy appears safe with testicular primary. Endocrinological disorders, common at diagnosis, may persist warranting endocrinological follow‐up.