Cutaneous melanoma in children and adolescents is an extremely rare malignancy that poses significant diagnostic and therapeutic challenges due to limited clinical evidence and a lack of specific treatment guidelines. This document, developed by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT), updates and systematizes previous recommendations by integrating recent advances. It particularly emphasizes the need for accurate diagnosis through expert pathology review, multidisciplinary discussion, appropriate surgical management, and the important role of systemic treatments now available, also in pediatric age. A strengthened collaboration with adult oncologists is fundamental to optimizing strategies and improving outcomes.

Primary lung carcinomas and bronchial carcinoid tumors (BC) are very rare malignancies in childhood. While typical BC and mucoepidermoid carcinomas are mostly low-grade, localized tumors with a more favorable prognosis than in adults, necessitating avoidance of overtreatment, adenocarcinomas of the lung are often diagnosed at advanced disease stages with low survival rates. This paper presents consensus recommendations on the diagnosis and treatment of pediatric patients with primary lung carcinomas and BC, established by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) in collaboration with the European Reference Network for Pediatric Oncology (ERN PaedCan).

OBJECTIVE:The efficacy of adjuvant chemotherapy (AC) in improving survival for patients with sarcoma is debated. We performed a cost-effectiveness analysis (CEA) comparing AC vs. no AC for non-metastatic sarcoma based on the nationwide retrospective study DEEPSARC. METHODS:The CEA was carried out over a 1-, 3-, and five-year horizon, using data from the French NETSARC+ database linked to the French national health data system (SNDS).There was no age limit and no specific histological type selection in the reference case analysis. Costs (expressed in 2021 EUR) were provided by the SNDS from the French national health insurance perspective. Incremental cost effectiveness ratios (ICER) were expressed in cost per life-year gained (LYG). Propensity score analysis with 1:1 matching was undertaken. Sensitivity and subgroup analyses were performed. RESULTS:Of the 33,548 patients from the French NETSARC+ database, 24,539 were linked to the SNDS. A total of 14,808 patients diagnosed between 2012 and 2017 were included in the reference case analysis with 2,784 patients after propensity score matching. Mean costs (SD) [95% CI] differences per patient between AC and no AC were €12,826 (36,758) [10,883-14,719], €15,706 (49,849) [13,330-18,383], and €16,841 (56,060) [13,590-19,657] at 1, 3, and 5 years, respectively. Mean overall survival differences per patient (in years) were 0.0066 (0.1685) [-0.0021 to 0.0157], -0.0728 (0.9336) [-0.1237 to -0.0229], and -0.1204 (1.3595) [-0.1926 to -0.0475] at 1, 3, and 5 years, respectively. ICER was €1,934,511 [-11,767,351-15,829,959] per LYG at 1 year. AC lagged behind at 3 and 5 years. CONCLUSIONS:In the reference case analysis, AC outperformed its use in terms of outcomes at 1 year, but a high level of willingness to pay would be required for AC to be cost-effective. At 3 and 5 years, AC was deemed to be not cost-effective for patients with non-metastatic sarcoma.

Background: Larotrectinib is a selective tropomyosin receptor kinase (TRK) inhibitor approved for the treatment of NTRK fusion-positive tumors. Although its efficacy has been demonstrated in clinical trials, particularly in infantile fibrosarcoma (IFS), real-world data in pediatric populations remain limited. Methods: We conducted a prospective observational study within the SACHA- France study, including patients < 25 years treated with larotrectinib outside clinical trials between April 2019 and September 2025. Clinical characteristics, molecular data, treatment indications, responses, survival outcomes, toxicity, treatment discontinuation, and resistance were analyzed. Results: Twenty-five patients were included (median age 2.8 years): IFS (n = 9), extra-CNS tumors (n = 10) and CNS tumors (n = 6). Twelve patients were treated at progression, nine to avoid mutilating surgery, two for multifocal/metastatic disease, and two as maintenance for high relapse risk; five received upfront larotrectinib. The overall response rate was 70% (95% CI: 47-87), with a median time to best response of 2 months. Two-year event-free and overall survival rates were 61.3% (95% CI: 38.3-77.7) and 74.9% (95% CI: 52.4-87.9) respectively. A trend toward higher 2-year EFS was observed in IFS versus CNS tumors (72.9% [95% CI: 26.7-92.9] vs 33% [95% CI: 10.5-80]). Treatment-related adverse events were reported in 8% of patients. Disease progression occurred in five patients, with acquired resistance mutations in the kinase domain confirmed in two. Conclusion: Larotrectinib shows meaningful efficacy and favorable tolerance across NTRK fusion-positive malignancies beyond IFS. These real-world data support early molecular testing, highlight histology-dependent outcomes, and inform clinical management strategies.

Pediatric very rare tumors (VRTs) are a highly heterogeneous group of neoplasms defined by an annual incidence of <2 cases per million children under 18 years. Their rarity precludes prospective clinical trials, resulting in limited evidence-based guidelines and largely individualized treatment approaches. Olfactory neuroblastoma (ON) is an exceptionally rare pediatric VRT arising from the olfactory neuroepithelium, typically affecting adults. In children, ON is locally aggressive and may present with regional or distant metastases. Prognosis depends on stage, histology, and multimodal treatment. Owing to the absence of pediatric-specific guidelines, this project aims to develop internationally harmonized consensus recommendations for diagnosis and management.

Background. DICER1 syndrome is an autosomal dominant disorder predisposing to a broad spectrum of malignant and benign neoplasms, caused by germline pathogenic variants (PVs) in the DICER1 gene. We aimed to characterize the clinical features of DICER1 syndrome in a national referral cohort and to estimate neoplasm risk.Materials and Methods. This retrospective study was conducted in a cohort of 945 patients who underwent DICER1 genetic testing at Institut Curie, Paris, using Sanger sequencing from 2012 to 2014 and Next Generation Sequencing from 2015 to 2023.Results. Among 584 index cases evaluated for DICER1 syndrome, 91 (16%) carried a germline DICER1 PV and 31 (5%) harbored only somatic DICER1 PVs. Several tumors that were not previously part of the DICER1 tumor spectrum were identified. ETMR-like brain tumor and testicular Sertoli cell tumor are now recognized as DICER1-related neoplasms, and schwannoma is a strong candidate. The neoplasm risk was estimated in 170 relatives carrying a germline DICER1 PV. The cumulative incidence of malignant neoplasms was 4.8% [95% CI: 2.1% – 9.1%] at 10 years and 15.8% [95% CI: 8.9% – 24.7%] at 50 years. Overall neoplasm risk was significantly higher in females, primarily driven by the higher incidence of multinodular goiter.Conclusion. This large cohort study provides a comprehensive overview of the distribution of neoplasms associated with DICER1 syndrome. Broader genetic testing identified additional DICER1-related neoplasms, and schwannoma emerged as a candidate association. Finally, this study confirms the moderate penetrance of germline DICER1 PVs.

OBJECTIVE:To map real-world management of paediatric differentiated thyroid carcinoma (DTC) across Europe and identify targets for harmonization. DESIGN:Cross-sectional, web-based survey of centres providing paediatric DTC care. SETTING & PARTICIPANTS:One consolidated response per centre was requested from a clinician overseeing paediatric DTC. The instrument covered centre profile/multidisciplinary tumour (MDT) board organization; staging and guideline use; risk stratification and dynamic response; diagnostics; surgery/lymph node management; radioactive iodine therapy (RAIT) policy and activity selection; and thyroid-stimulating hormone targets, follow-up, shared-care/transition. Analyses were descriptive at centre level. RESULTS:Forty-two centres from 18 countries participated in the survey. Response denominators varied by item. Among responding centres, ≈75% were university or academic hospitals, ≈70% used a paediatric age cut-off of ≤18 years, and ≈60% reported having a dedicated MDT board. Staging and guideline use were heterogeneous: centres most often reported mixed or centre-specific guidance, followed by the American Thyroid Association (ATA) 2015 guideline, national guidelines, and the European Thyroid Association (ETA) 2022 guideline. Dynamic response-to-therapy categories were commonly used. For unilateral presumed low-risk disease, hemithyroidectomy was the usual initial surgery in approximately two-thirds to three-quarters of centres, whereas total thyroidectomy was less common. For low-risk patients, RAIT policy were split between de-escalation and risk-adapted use. When administered, RAIT activity was determined using weight-based, dosimetric, or fixed empirical approaches. Country-level patterns suggested clustering around ETA-leaning, ATA-leaning, and national guideline frameworks. CONCLUSIONS:Across Europe, centres broadly endorse risk-adapted care but diverge at key decision nodes-extent of surgery, formal risk framework, and RAIT in low-risk disease-reflecting guidance plurality and organizational context. Leveraging existing infrastructures offers pragmatic avenues to reduce unwarranted variation while generating paediatric-specific evidence to refine recommendations.

Non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) are a heterogeneous malignancies with different histopathological characteristics. Distinct molecular findings help to classify NRSTS into subtypes. Further new molecular subtypes give insight into the heterogeneity of these rare tumours. Over the past 25 years, five large international prospective clinical trials have been conducted to improve prognosis for pediatric, adolescent, and young adult patients (< 25 years) with NRSTS and rare soft tissue neoplasms. The overall cure rate is around 70% but varies dramatically between the different entities. New treatment approaches are still needed for some histotypes and for metastatic tumors to improve outcome.The European paediatric soft tissue sarcoma study Group (EpSSG) proposes guidelines developed by an European NRSTS group supported by the European Reference Network on Paediatric Cancer (ERN PaedCan). This consensus summarizes the standard of care, diagnostic work up, multimodal treatment and surveillance recommendations for pediatric, adolescent, and young adult patients with NRSTS and rare soft tissue neoplasms, according to the Consensus Conference Standard Operating Procedure methodology. The unique features of selected histotypes are discussed.

As part of the European Cooperative Study Group for Paediatric Rare Tumours initiative, we developed standard clinical practice guidelines for ovarian sex cord stromal tumors, based on comprehensive national and international cohort analyses, literature review, and a final expert consensus conference. Complete tumor resection is the cornerstone of treatment, with meticulous attention to preventing tumor spillage. Risk stratification of adjuvant chemotherapy decisions incorporates tumor stage and critical parameters, including histological differentiation and mitotic rate. Optimal patient management requires treatment within cooperative networks providing centralized histopathological review and comprehensive genetic testing, multidisciplinary tumor board evaluation, and prospective registry enrollment to advance knowledge for these exceptionally rare malignancies.

Solid pseudopapillary neoplasm of the pancreas (SPN) is a rare low-grade malignant exocrine pancreatic tumor, mostly discovered during the second decade of life in females, with a very good prognosis, provided microscopically complete surgical excision is achieved. This manuscript presents harmonized recommendations for the diagnosis, treatment, and long-term management of pediatric SPN established by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) in collaboration with the European Reference Network for Pediatric Oncology (ERN PaedCan) after careful review of the literature and experts' opinions refined by selected external reviewers.

INTRODUCTION:We evaluated the survival rate/survivor characteristics following first progression/relapse of metastatic rhabdomyosarcoma (M1 RMS), using pooled European and US collaborative group data from the INternational Soft Tissue saRcoma ConsorTium (INSTRuCT). METHODS:Patients with first diagnosis of M1 RMS aged 0-40 years were identified within the INSTRuCT database (Upfront Cohort; UC). The First Event Cohort (FEC) included UC patients with first event of disease progression/relapse. Clinical features and survival of FEC patients were described. RESULTS:UC included 1095 eligible M1 RMS patients. 5-year Overall and Event Free Survival were 32.0% (95% Confidence Interval (CI) 29.2-34.9) and 27.5% (95% CI 24.8-30.2) respectively. Median time to event was 13.9 months (range 1 day-172.6 months). Among UC patients, 727 with first event of progression/relapse were included in FEC. 3-year Overall Survival for FEC from first event was 8.0% (95% CI 6.1-10.2). Thirty-four (4.7%) FEC patients were alive with > 3 years follow up ("disease free") and 16 (2.2%) with < 3 years follow up. FEC patients alive > 3 years were significantly more likely than deceased FEC patients to have: younger age (p = 0.0031); no locoregional lymph node involvement (p = 0.0013); fewer metastatic sites (p = 0.006); no bone and/or bone marrow disease (p < 0.001 for each); lower Oberlin scores (p < 0.0001); time to first event > 18 months (p < 0.0001). Univariate and multivariable analyses conducted in FEC to investigate factors impacting OS showed that Oberlin score ≥ 2 (Hazard Ratio (HR) 1.295, 95% Confidence Limits (CL) 1.07-1.57, p = 0.0074) and involvement of loco-regional lymph nodes at diagnosis (HR 1.28, 95% CL 1.08-1.52, p = 0.0053) were associated with worse outcome. CONCLUSIONS:Outcomes following first progression/relapse of M1 RMS are dismal. Survivors had fewer adverse prognostic features at first presentation and later first events. Further work is required to predict survivors of first relapse more reliably.

Desmoplastic Small Round Cell Tumor (DSRCT) is an ultra-rare, highly aggressive sarcoma that predominantly affects young individuals. DSRCT is defined by the characteristic chromosomal translocation t(11;22) (p13;q12), which results in the oncogenic EWSR1::WT1 fusion gene. DSRCT typically presents as multiple, disseminated nodules within the abdominopelvic cavity. Patients with DSRCT typically receive an intensive multimodal treatment regimen comprising multi-agent chemotherapy, extensive cytoreductive surgery, that could be followed by whole abdominopelvic radiotherapy. Attempts to improve patient outcomes over the past two decades have yielded limited results, leading to a persistent lack of improvement in prognosis. There is an urgent, unmet clinical need for innovative and effective treatments guided by a deeper understanding of DSRCT biology. Recent efforts have successfully generated extensive multi-omic data and a growing number of patient-derived models. This information has deepened our understanding of the EWSR1::WT1 translocation's oncogenic mechanisms and revealed critical DSRCT dependencies, leading to the identification of several putative therapeutic targets. Clinical translation of these findings as well as conduction of further preclinical research requires an international, multidisciplinary collaborative effort to propel preclinical and clinical studies. This review was conducted by the DSRCT Working Group of OCTOPUS ("Optimising Combination Therapy fOr Paediatric, adolescent and yoUng adult patients with non-rhabdomyosarcoma soft tissue Sarcomas") to consolidate existing knowledge on preclinical translational aspects of DSRCT and guide future cooperative research.

Few innovative treatments were developed for patients with non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) in the past decades. The paper describes the OCTOPUS project (Optimising Combination Therapy fOr Paediatric, adolescent and yoUng adult patients with non-rhabdomyosarcoma soft tissue Sarcomas), a master protocol and includes an adaptive platform trial comprising different sub-trials, a real-world data registry, translational studies, and overarching study questions assessing local therapy issues and patient reported outcome measures (PROMs). The OCTOPUS consortium will provide an operational framework including a legal consortium structure, a network of national coordinating centres (NCCs) and sites within the EpSSG (European paediatric Soft tissue sarcoma Study Group) and ITCC (Innovative Therapies for Children and adolescents with Cancer) network. The overarching aim of the platform is to improve outcome and quality of life for patients with NRSTS by providing access to innovative treatments. Every sub-trial will have a unique design, tailored to the needs of the patients, the characteristics of the disease, and the stage of development of the experimental compound(s). Depending on the medical need in a specific patient population and the expected activity of a compound (or a combination), the innovative treatment(s) will be offered to patients with relapsed/refractory disease or placed in frontline treatment when appropriate.

Melanotic neuroectodermal tumor of infancy (MNTI) is a rare neoplasm primarily affecting the craniofacial skeleton in infants. Management can be challenging in unresectable, multiply recurrent, or metastatic cases. Diagnosis requires local imaging assessment with magnetic resonance imaging (MRI) and computed tomography (CT) and histopathological confirmation. Surgery is the mainstay of treatment, achieving 80%-90% cure rates. Chemotherapy may be considered for advanced disease, whereas radiotherapy is generally avoided in young children. These recommendations were developed within European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) and European Reference Network Paediatric Cancer (ERN PaedCan) using a structured consensus process based on focused literature review and expert agreement. Multidisciplinary, risk-adapted management, and structured follow-up are essential.

INTRODUCTION:Extracranial malignant germ cell tumors represent approximately 3% of cancers in children and adolescents. Their age distribution is bimodal, with a first peak in early childhood and a second after puberty, extending into adulthood. Non-seminomatous germ cell tumors (NSGCTs), characterized by tumor markers secretion, predominate. Treatment strategies have evolved over successive clinical protocols. METHODS:Subsequent studies, particularly the Franco-Belgian TGM95 and TGM13-NS protocols, have demonstrated an excellent overall prognosis for NSGCTs. Management is primarily based on a surgical approach aiming to achieve oncologic control while preserving organ function whenever feasible, coupled, when indicated, with platinum-based chemotherapy tailored to the risk group. To minimize treatment-related toxicities, chemotherapy regimens and the number of cycles have been progressively optimized. RESULTS:We present the current national therapeutic recommendations for NSGCTs. Tumor stage and site, initial tumor marker levels, and patient age allow risk stratification and guide treatment decision. Adolescents should benefit from coordinated care between pediatric and adult oncology teams and be included in clinical trials whenever possible. CONCLUSION:Following completion of the TGM13-NS protocol, the Germ Cell Tumor Group of the French Society of Childhood Cancer developed updated management guidelines and is simultaneously involved in international collaborations to establish larger-scale studies, justified by the rarity of these cancers.

BACKGROUND:Desmoid-type fibromatosis (DTF) is a rare intermediate malignancy with high local aggressiveness and recurrence in children after first-line methotrexate-vinblastine (Mtx-Vbl) regimen. The objective is to describe refractory DTF to standardize second-line therapy. METHODS:This national multicenter retrospective study included patients (<25 years) with progressive/refractory DTF after Mtx-Vbl first-line. The primary objective was to evaluate response rate (RR: complete/partial response [CR/PR]) and progression-free survival (PFS2) following second-line treatments. Secondary objectives included overall burden of therapy and predictive factors for therapeutic efficacy analysis. RESULTS:From 2000 to 2022, 50 patients fulfilled inclusion criteria. Median age at first relapse was 15.6 years [range: 0.9-24.8]. Second-line treatments included exclusive medical treatment for 86%-majority alkaloid-based re-challenge (60%)-exclusive local therapy in 8%, both (4%) and observation (2%). RR to any medical therapy was 30% [95% CI: 16-44], specifically 35% [95% CI: 15-55] for alkaloid-based regimens with clinical benefit (CR/PR or stabilization) in 85%. The 5-year PFS2 was 44% [95% CI: 30-58]. Limb location was the only significant predictive factor for PFS2 (p < 0.01). Overall treatment load comprised a median of three lines [range: 2-8] over 27 months median duration [range: 4-90]. Local therapy was done for 50% of patients. One patient died from secondary digestive infection. CONCLUSIONS:Refractory DTF should be considered as a chronic disease with significant treatment burden where objectives should be regularly reassessed. Even for refractory disease, local therapy might be avoided in half of cases. Authors propose a second-line treatment algorithm for pediatric refractory DTF.

Supplementary Table 3 shows the estimated adjusted relative risks of renal hospitalisation by exposure to ifosfamide (stratified by cumulative dose) according to nephrectomy status.