Vaginal malignant germ cell tumors (MGCT) are rare, occurring in children less than 2 years old and raise the question of the optimal local treatment.
We 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) < 10,000 ng/mL) or high risk (HiR: metastatic and/or AFP > 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.
Fourteen 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).
Childhood 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.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Rationale
Sex cord‐stromal tumors (SCST) are hormonally active and rare. The aim was to describe their endocrinological presentation and outcomes.
Method
Patients (< 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.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The diagnosis of multiple or diffuse renal lesions in a child is challenging by imaging and/or pathology. Optimal management requires distinguishing benign lesions such as nephrogenic rests from ...cancerous lesions such as Wilms tumor, but this is often difficult or impossible. This difficulty is compounded by the overlapping nature of our current radiologic and pathologic definitions of lesions along the spectrum of nephrogenic rests/nephroblastomatosis. We provide a review of these issues, as a collaborative effort between the Children's Oncology Group Renal Tumor Committee and International Society of Pediatric Oncology Renal Tumor Study Group. Our aim is to discuss current challenges in diagnosis and management of these renal lesions, encouraging future work toward consensus definitions for research and patient care.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
We report survival and late effects analysis of TGM95 study for childhood (≤18 years) ovarian nonseminomatous germ cell tumors (NS‐GCT). Patients with localized tumors (FIGO‐stage IA) had no adjuvant ...treatment (low‐risk, LR). Patients with advanced‐stage received 3‐5 VBP (vinblastin‐bleomycin‐cisplatin) in intermediate‐risk group (IR: FIGO‐stage IC‐II‐III and AFP < 15 000 ng/mL) or 4‐6 VIP (etoposide‐ifosfamide‐cisplatin) in high‐risk group (HiR: metastatic or AFP ≥ 15 000 ng/mL). Seventy‐seven patients were included (median age = 12 years): 14 LR (13 FIGO‐stage IA, 1 retrospectively IC), 26 IR (12 IC, 12 II‐III, 2 not‐available) and 37 HiR (2 IA with AFP ≥ 15 000 ng/mL, 27 II‐III, 8 IV). After a median follow‐up of 13.4 years, 12 events (eight relapses) and six deaths (two GCT‐related, two due to acute myeloid leukemia and two noncancer related) occurred. All relapses (6 LR, 1 IR) occurred within 2 years. Four contralateral mature teratomas were observed within 8 years. Five‐year EFS and OS were 88.2% (95%CI = 79‐94%) and 94.6% (95%CI = 87‐98%). Seven patients (9%) had bilateral gonadectomy. Among 51 survivors at 2 years aged >15 years (median = 26 years) with remaining ovarian tissue, all had developed spontaneous puberty and 21 (41%) had at least one pregnancy (including two with infertility treatment). Among 69 patients treated with platinum‐based chemotherapy, chronic‐kidney‐disease was diagnosed in four patients (three after VIP) and significant ototoxicity occurred in three (all grade‐2). Childhood ovarian NS‐GCTs have an excellent prognosis with few late effects. The low‐intensive etoposide‐free VBP regimen could be an alternative in children with IR disease especially in cases of tumor rupture. The risk of contralateral mature teratoma needs regular monitoring of the remaining ovary.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Vestibular schwannoma (VS) growth in neurofibromatosis type 2 (NF2) can be responsible for brainstem compression and hearing loss. Surgical removal remains the standard therapy despite potential ...morbidity. Previous studies suggested that the inhibition of the VEGF-pathway with bevacizumab could result in hearing improvement, reduction of the tumor volume or both in adults. We retrospectively describe the French experience of bevacizumab treatment delivered for progressive VS in pediatric NF2 patients. Patients received Bevacizumab 5 or 10 mg/kg every 2 weeks according to the physician’s choice. Follow-up included clinical assessment, audiometry and volumetric MRI every 3–6 months. Seven patients harboring 11 VS were included. The median age at inclusion was 15 years (11.4–18.8), and the median treatment duration was 11.3 months (3.2–55.6). At baseline, the median tumor volume was 1.2 cm
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(0.52–13.5) and the median word recognition score was 90 % (0–100). We observed one major response, two minor responses and a decrease in the rate of tumor growth for the 4 other patients. The median annual growth rate before treatment was significantly higher than after 1 year of treatment (138 vs. 36 %, n = 5, p = 0.043). We noted one hearing improvement over the course of 1 year under treatment (hearing response rate was 14 %). Overall, the treatment was well tolerated. Our study supports that bevacizumab is an attractive therapeutic option for pediatric NF2 patients with growing VS. Thorough multidisciplinary evaluation is necessary to identify the best candidates prior to treatment. It is likely that a better functional outcome would be expected if targeted therapies were discussed early in the management of the disease.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Aims
Translocation renal cell carcinoma (tRCC) is a rare subtype of kidney tumour characterized by translocations involving the transcription factor TFE3 or TFEB. tRCC was introduced into the World ...Health Organization classification in 2004, but much is still unknown about the natural history, clinicopathological features and outcomes of the disease. The aim of this study was to describe the landscape of fusion transcript in a large single‐institution series of fluorescence in‐situ hybridization (FISH)‐confirmed tRCCs and then to compare it to morphological and clinical data.
Methods and results
Paired‐end RNA sequencing was performed within a prospective database of the Department of Pathology, Centre Hospitalier Régional Universitaire (Lille, France). The diagnosis of tRCC was confirmed by FISH. Among a total of 1130 identified renal cell carcinomas, 21 cases (1.9%) showed rearrangement of the TFE3 (n = 20) or (TFEB) (n = 1) gene. Median patient age was 31 years (range = 15–47), and the female‐to‐male ratio was 6:1. Five different TFE3 fusion transcripts were identified; the most frequent TFE3 partners were PRCC (n = 4) and SFPQ (n = 4). The other partners involved were ASPCR1 (n = 1) and MED15 (n = 1) genes as well as a novel TFE3 partner, GRIPAP1.
Conclusions
We identified a new fusion partner, GRIPAP1. The prognostic role of transcript type could not be determined because our number of cases was too small. Four patients (19%) died of the disease, all of which presented with a lymph node involvement at diagnosis. We confirm that tRCC can be an aggressive tumour, especially those of advanced clinical stage.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Background
Chemotherapy 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.
Procedure
Patients 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.
Results
One 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).
Conclusion
Risk‐adapted and globally decreased chemotherapy burden maintains excellent outcomes, exclusive of the IR2 group, which warrants more intensive chemotherapy.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background
WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays) is a rare contiguous gene deletion syndrome with a 45% to 60% risk of developing Wilms ...tumor (WT). Currently, surveillance and treatment recommendations are based on limited evidence.
Methods
Clinical characteristics, treatments, and outcomes were analyzed for patients with WAGR and WT/nephroblastomatosis who were identified through International Society of Pediatric Oncology Renal Tumor Study Group (SIOP‐RTSG) registries and the SIOP‐RTSG network (1989‐2019). Events were defined as relapse, metachronous tumors, or death.
Results
Forty‐three patients were identified. The median age at WT/nephroblastomatosis diagnosis was 22 months (range, 6‐44 months). The overall stage was available for 40 patients, including 15 (37.5%) with bilateral disease and none with metastatic disease. Histology was available for 42 patients; 6 nephroblastomatosis without further WT and 36 WT, including 19 stromal WT (52.8%), 12 mixed WT (33.3%), 1 regressive WT (2.8%) and 2 other/indeterminable WT (5.6%). Blastemal type WT occurred in 2 patients (5.6%) after prolonged treatment for nephroblastomatosis; anaplasia was not reported. Nephrogenic rests were present in 78.9%. Among patients with WT, the 5‐year event‐free survival rate was 84.3% (95% confidence interval, 72.4%‐98.1%), and the overall survival rate was 91.2% (95% confidence interval, 82.1%‐100%). Events (n = 6) did not include relapse, but contralateral tumor development (n = 3) occurred up to 7 years after the initial diagnosis, and 3 deaths were related to hepatotoxicity (n = 2) and obstructive ileus (n = 1).
Conclusions
Patients with WAGR have a high rate of bilateral disease and no metastatic or anaplastic tumors. Although they can be treated according to existing WT protocols, intensive monitoring of toxicity and surveillance of the remaining kidney(s) are advised.
Lay Summary
WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays) is a rare genetic condition with an increased risk of developing Wilms tumor.
In this study, 43 patients with WAGR and Wilms tumor (or Wilms tumor precursor lesions/nephroblastomatosis) were identified through the international registry of the International Society of Pediatric Oncology Renal Tumor Study Group (SIOP‐RTSG) and the SIOP‐RTSG network. In many patients (37.5%), both kidneys were affected. Disease spread to other organs (metastases) did not occur.
Overall, this study demonstrates that patients with WAGR syndrome and Wilms tumor can be treated according to existing protocols. However, intensive monitoring of treatment complications and surveillance of the remaining kidney(s) are advised.
Patients with WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays) and Wilms tumor/nephroblastomatosis, identified through the International Society of Pediatric Oncology Renal Tumor Study Group registries and network, have a high rate of bilateral disease and no metastatic or anaplastic tumors. Although they can be treated according to existing Wilms tumor protocols, intensive monitoring of toxicity and surveillance of the remaining kidney(s) are advised.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background
Heterogeneous data have been reported on high‐dose chemotherapy (HDCT) with autologous stem cell rescue (ASCR) in Wilms tumors (WTs). We aimed to define its safety and efficacy in the ...French cohort, and to compare this management to current international recommendations.
Methods
Data prospectively collected from children, adolescents, and young adults with WT treated with HDCT/ASCR between 2000 and 2016 in French centers were retrospectively analyzed. Toxicity was reported according to CTCAE v4.03.
Results
Fifty‐four patients received HDCT/ASCR (first line, n = 13; recurrence, n = 41). Their median age at the time of ASCR was 5.3 years (range 2.2–21.6). Main nonhematological acute grades 3–4 toxicities were digestive and renal. No significant difference of toxicity rate was observed among HDCT regimens and schedules. Two patients died shortly after ASCR (renal and multiorgan failure), and one heavily pretreated patient died of late respiratory failure. The selection criteria applied to define those patients eligible for HDCT/ASCR retrospectively matched to those currently used in the International Society of Pediatric Oncology (SIOP) UMBRELLA protocol for 38 patients, with encouraging survival rates compared to published data. The objective response rate to HDCT was 21%, with a disease control rate after HDCT of 85%. After a median follow‐up of 7 years, the 5‐year event‐free survival (EFS) and overall survival (OS) were 54% (95% CI: 32%–76%) and 62% (95% CI: 31%–82%) for frontline patients, and 57% (95% CI: 39%–71%) and 69% (95% CI: 52%–81%) at recurrence.
Conclusion
HDCT was feasible and showed encouraging results in well‐defined settings. Data from the current prospective protocol will help to better evaluate HDCT impact on survival.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Purpose
To examine the clinical presentation, treatment and results in children and adolescents with primary mediastinal (PM) and retroperitoneal (RP) germ cell tumors (GCTs).
Methods
The TGM95 trial ...for malignant GCTs was conducted in France between 1995 and 2005 to evaluate a strategy adapted to prognostic factors with cisplatin‐based chemotherapy and surgical management. We reviewed patients with TGCTs at PM and RP sites.
Results
Among 239 patients, there were 16 patients with PM and 5 with RP tumors, which represent 9% of all patients, highlighting the rarity of these extragonadal locations. A bimodal demographic distribution was observed (11/21 patients <5 years old and 7/21 patients >12 years old). A majority of patients presented with bulky tumors that required urgent care with neoadjuvant chemotherapy. In all patients, elevation of alpha‐fetoprotein indicated a yolk sac tumor component. Human chorionic gonadotrophin was elevated in five patients (four adolescents), suggesting a choriocarcinoma or seminoma component. The diagnosis was based on elevation of these tumor markers in addition to imaging. Chemosensitivity was observed for a majority of patients. An aggressive surgical approach allowed a microscopic complete resection in 12/15 patients with PM tumors and 4/5 with RP tumors. Overall, 14/16 and 4/5 patients survived, respectively. Three adolescents died of tumor progression.
Conclusion
In children with mediastinal or RP GCTs, the prognosis is favorable when a strategy of delayed aggressive surgery is performed after cisplatin‐based chemotherapy. Younger patients have a better prognosis. Relapses were observed only in adolescents and could not be cured.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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