International consensus statement on the diagnosis and management of phaeochromocytoma and paraganglioma in children and adolescents.

Phaeochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumours that arise not only in adulthood but also in childhood and adolescence. Up to 70-80% of childhood PPGL are hereditary, accounting for a higher incidence of metastatic and/or multifocal PPGL in paediatric patients than in adult patients. Key differences in the tumour biology and management, together with rare disease incidence and therapeutic challenges in paediatric compared with adult patients, mandate close expert cross-disciplinary teamwork. Teams should ideally include adult and paediatric endocrinologists, oncologists, cardiologists, surgeons, geneticists, pathologists, radiologists, clinical psychologists and nuclear medicine physicians. Provision of an international Consensus Statement should improve care and outcomes for children and adolescents with these tumours.

Assessment of prognostic factors in pediatric adrenocortical tumors: the modified pediatric S-GRAS score in an international multicenter cohort-a work from the ENSAT-PACT working group.

OBJECTIVE: Pediatric adrenocortical carcinoma (pACC) is rare, and prognostic stratification remains challenging. We aimed to confirm the prognostic value of the previously published pediatric scoring system (pS-GRAS) in an international multicenter cohort. DESIGN: Analysis of pS-GRAS items of pACC from 6 countries in collaboration of ENSAT-PACT, GPOH-MET, and IC-PACT. METHODS: We received patient data of the pS-GRAS items including survival information from 9 centers. PS-GRAS score was calculated as a sum of tumor stage (1 = 0; 2-3 = 1; 4 = 2 points), grade (Ki67 index: 0%-9% = 0; 10%-19% = 1; ≥20% = 2 points), resection status (R0 = 0; RX/R1/R2 = 1 point), age (<4 years = 0; ≥4 years = 1 point), and hormone production (androgen production = 0; glucocorticoid-/mixed-/no-hormone production = 1 point) generating 8 scores and 4 groups (1: 0-2, 2: 3-4, 3: 5, 4: 6-7). Primary endpoint was overall survival (OS). RESULTS: We included 268 patients with median age of 4 years. The analysis of the pS-GRAS score showed a significantly favorable prognosis in patients with a lower scoring compared to higher scoring groups (5-year OS: Group 1 98%; group 2 87% [hazard ratio {HR} of death 3.6, 95% CI of HR 1.6-8.2]; group 3 43% [HR of death 2.8, 95% CI 1.9-4.4]; group 4: OS 18% [HR of death 2.1, 95% CI 1.7-2.7]). In the multivariable analysis, age (HR of death 3.5, 95% CI 1.8-7.0), resection status (HR of death 5.5, 95% CI 2.7-11.1), tumor stage (HR of death 1.9, 95% CI of HR 1.2-3.0), and Ki67 index (HR of death 1.7, 95% CI 1.2-2.4) remained strong independent outcome predictors. Especially infants < 4 years showed more often low-risk constellations with a better OS for all tumor stages. CONCLUSION: In an international multicenter study, we confirmed that the pS-GRAS score is strongly associated with overall survival among patients with pACC. Age, resection status, stage, and Ki67 index are important parameters for risk stratification.

International consensus on mitotane treatment in pediatric patients with adrenal cortical tumors: indications, therapy, and management of adverse effects.

OBJECTIVE: Mitotane is an important cornerstone in the treatment of pediatric adrenal cortical tumors (pACC), but experience with the drug in the pediatric age group is still limited and current practice is not guided by robust evidence. Therefore, we have compiled international consensus statements from pACC experts on mitotane indications, therapy, and management of adverse effects. METHODS: A Delphi method with 3 rounds of questionnaires within the pACC expert consortium of the international network groups European Network for the Study of Adrenal Tumors pediatric working group (ENSAT-PACT) and International Consortium of pediatric adrenocortical tumors (ICPACT) was used to create 21 final consensus statements. RESULTS: We divided the statements into 4 groups: environment, indications, therapy, and adverse effects. We reached a clear consensus for mitotane treatment for advanced pACC with stages III and IV and with incomplete resection/tumor spillage. For stage II patients, mitotane is not generally indicated. The timing of initiating mitotane therapy depends on the clinical condition of the patient and the setting of the planned therapy. We recommend a starting dose of 50 mg/kg/d (1500 mg/m²/d) which can be increased up to 4000 mg/m2/d. Blood levels should range between 14 and 20 mg/L. Duration of mitotane treatment depends on the clinical risk profile and tolerability. Mitotane treatment causes adrenal insufficiency in virtually all patients requiring glucocorticoid replacement shortly after beginning. As the spectrum of adverse effects of mitotane is wide-ranging and can be life-threatening, frequent clinical and neurological examinations (every 2-4 weeks), along with evaluation and assessment of laboratory values, are required. CONCLUSIONS: The Delphi method enabled us to propose an expert consensus statement, which may guide clinicians, further adapted by local norms and the individual patient setting. In order to generate evidence, well-constructed studies should be the focus of future efforts.

CXCR4-Directed Imaging and Endoradiotherapy in Desmoplastic Small Round Cell Tumors.

Desmoplastic small round cell tumor (DSRCT) is a rare, radiosensitive, yet difficult-to-treat sarcoma subtype affecting predominantly male adolescents. Extensive intraperitoneal seeding is common and requires multimodal management. With no standard therapy established, the prognosis remains poor, and new treatment options are needed. We demonstrate the clinical potential of C-X-C motif chemokine receptor 4 (CXCR4)-directed imaging and endoradiotherapy in DSRCT. Methods: Eight male patients underwent dual-tracer imaging with [18F]FDG and CXCR4-directed [68Ga]pentixafor PET/CT. A visual comparison of both tracers, along with uptake quantification in active DSRCT lesions, was performed. [68Ga]pentixafor uptake was correlated with immunohistochemical CXCR4 expression on tumor cells. Four patients with end-stage progressive disease underwent CXCR4-based endoradiotherapy. We report the safety, response by RECIST 1.1, and survival after endoradiotherapy. Results: Uptake of [68Ga]pentixafor in tumor lesions was demonstrated in all patients with DSRCT, providing diagnostic power comparable to [18F]FDG PET. Corresponding CXCR4 expression was confirmed by immunohistochemistry in all DSRCT biopsies. Finally, 4 patients were treated with CXCR4-directed [90Y]endoradiotherapy, 3 in a myeloablative dose range with subsequent autologous stem cell transplantation. All 3 required transfusions, and febrile neutropenia occurred in 2 patients (resulting in 1 death). Notably, severe nonhematologic adverse events were absent. We observed signs of response in all 3 patients, translating into disease stabilization in 2 patients for 143 and 176 d, respectively. In the third patient, postmortem autopsy confirmed a partial pathologic response. Conclusion: We validated CXCR4 as a diagnostic biomarker and a promising target for endoradiotherapy in DSRCT, demonstrated its feasibility, and provided the first evidence of its clinical efficacy.

Prognostic value of the Weiss and Wieneke (AFIP) scoring systems in pediatric ACC - a mini review.

Histopathological differentiation in pediatric adrenocortical carcinoma (pACC) is difficult and clinical prediction and stratification scores are not evaluated yet. Therefore, this review aims to summarize current evidence on the value and accuracy of the two commonly used scoring systems (Weiss/Armed Forces Institute of Pathology (AFIP)) pACC. On this base, one might be able to evaluate if patients may benefit from a unique scoring system. For this, we performed a systematic review of the published literature and included 128 patients in our analysis. The majority (72%) of the pACCs had a good clinical course. The follow-up time ranged from 0 to 420 months with a mean age of 5.6 years at diagnosis. Patients with a good clinical course were younger (mean 4.8 years) than patients with a poor outcome (mean 7.6 years). Comparing the two scoring systems, the specificity of the Weiss score was very low (25%), whereas the sensitivity was 100%. According to the AFIP score, specificity (77%) was higher than the Weiss score, whereas the sensitivity of the AFIP score was minimal lower with 92%. Age differences were recognizable as the specificity was lower in infants <4 years (20%) than in older children (32%). In contrast, the specificity of the AFIP score was higher in infants <4 years (82%) than in older age groups (76%). Summarizing our results, we could show that the Weiss score is not a suitable tool for the prediction of malignancy in pACC in comparison with the AFIP score, but further efforts may seek to ensure early and accurate stratification through augmented scoring.

Volume-outcome relationship in adrenal surgery from 2009-2017 in Germany-a retrospective study.

OBJECTIVE: Adrenal resections are rare procedures of a heterogeneous nature. While recent European guidelines advocate a minimum annual caseload for adrenalectomies (6 per surgeon), evidence for a volume-outcome relationship for this surgery remains limited. DESIGN: A retrospective analysis of all adrenal resections in Germany between 2009 and 2017 using hospital billing data was performed. Hospitals were grouped into three tertiles of approximately equal patient volume. METHODS: Descriptive, univariate, and multivariate analyses were applied to identify a possible volume-outcome relationship (complications, complication management, and mortality). RESULTS: Around 17 040 primary adrenal resections were included. Benign adrenal tumors (n = 8,213, 48.2%) and adrenal metastases of extra-adrenal malignancies (n = 3582, 21.0%) were the most common diagnoses. Six hundred and thirty-two low-volume hospitals performed an equal number of resections as 23 high-volume hospitals (median surgeries/hospital/year 3 versus 31, P < .001). Complications were less frequent in high-volume hospitals (23.1% in low-volume hospitals versus 17.3% in high-volume hospitals, P < .001). The most common complication was bleeding in 2027 cases (11.9%) with a mortality of 4.6% (94 patients). Overall in-house mortality was 0.7% (n = 126). Age, malignancy, an accompanying resection, complications, and open surgery were associated with in-house mortality. In univariate analysis, surgery in high-volume hospitals was associated with lower mortality (OR: 0.47, P < .001). In a multivariate model, the tendency remained equal (OR: 0.59, P = .104). Regarding failure to rescue (death in case of complications), there was a trend toward lower mortality in high-volume hospitals. CONCLUSIONS: The annual caseload of adrenal resections varies considerably among German hospitals. Our findings suggest that surgery in high-volume centers is advantageous for patient outcomes although fatal complications are rare.

Assessment of prognostic factors in pediatric adrenocortical tumors: a systematic review and evaluation of a modified S-GRAS score.

Objective: Pediatric adrenocortical carcinoma (pACC) is rare and prognostic stratification remains challenging. We summarized the clinical prognostic factors of pACC and determined the prognostic value of the pediatric scoring system (pS-GRAS) in adaption to the recommendation (S-GRAS) of the European Network for the Study of Adrenal Tumors for the classification of adult ACC. Design: Analysis of pACC patients of 33 available retrospective studies in the literature. Methods: We searched the PubMed and Embase databases for manuscripts regarding pACC. The pS-GRAS score was calculated as a sum of tumor stage (1 = 0; 2-3 = 1; 4 = 2 points), grade (Ki67 index/rate of mitosis 0-9%/low = 0; 10-19%/intermediate = 1; ≥20%/high = 2 points), resection status (R0 = 0; RX = 1; R1 = 2; R2 = 3 points), age (<4 years = 0; ≥4 years = 1 point), hormone-related symptoms (androgen production = 0; glucocorticoid/mixed/no hormone production = 1 point) generating 10 scores and 4 groups (1: 0-2, 2: 3-4, 3: 5, 4: 6-9). The primary endpoint was overall survival (OS). Results: We included 733 patients. The median age was 2.5 years and >85% of pACC showed hormone activity (mixed 50%, androgen 29%, glucocorticoid 21%). Androgen production was associated with a superior OS. Increasing age correlated with higher rates of inactive or only glucocorticoid-producing tumors, advanced tumor stage, and case fatality. Especially infants < 4 years showed more often low-risk constellations with an increased OS for all tumor stages. The pS-GRAS score correlated with clinical outcome; median OS was 133 months (95% CI: 36-283) in group 1 (n = 49), 110 months (95% CI: 2.9-314) in group 2 (n = 57), 49 months (95% CI: 5.8-278) in group 3 (n = 18), and 16 months (95% CI: 2.4-267) in group 4; (n = 11) P < 0.05). Conclusion: The pS-GRAS score seems to have a high predictive value in the pACC patients, may serve as a helpful tool for risk stratification in future studies, and should be evaluated prospectively in an international context.

Adrenalectomies in children and adolescents in Germany - a diagnose related groups based analysis from 2009-2017.

Background: Adrenalectomies are rare procedures especially in childhood. So far, no large cohort study on this topic has been published with data on to age distribution, operative procedures, hospital volume and operative outcome. Methods: This is a retrospective analysis of anonymized nationwide hospital billing data (DRG data, 2009-2017). All adrenal surgeries (defined by OPS codes) of patients between the age 0 and 21 years in Germany were included. Results: A total of 523 patient records were identified. The mean age was 8.6 ± 7.7 years and 262 patients were female (50.1%). The majority of patients were between 0 and 5 years old (52% overall), while 11.1% were between 6 and 11 and 38.8% older than 12 years. The most common diagnoses were malignant neoplasms of the adrenal gland (56%, mostly neuroblastoma) with the majority being younger than 5 years. Benign neoplasms in the adrenal gland (D350) account for 29% of all cases with the majority of affected patients being 12 years or older. 15% were not defined regarding tumor behavior. Overall complication rate was 27% with a clear higher complication rate in resection for malignant neoplasia of the adrenal gland. Bleeding occurrence and transfusions are the main complications, followed by the necessary of relaparotomy. There was an uneven patient distribution between hospital tertiles (low volume, medium and high volume tertile). While 164 patients received surgery in 85 different "low volume" hospitals (0.2 cases per hospital per year), 205 patients received surgery in 8 different "high volume" hospitals (2.8 cases per hospital per year; p<0.001). Patients in high volume centers were significant younger, had more extended resections and more often malignant neoplasia. In multivariable analysis younger age, extended resections and open procedures were independent predictors for occurrence of postoperative complications. Conclusion: Overall complication rate of adrenalectomies in the pediatric population in Germany is low, demonstrating good therapeutic quality. Our analysis revealed a very uneven distribution of patient volume among hospitals.

Case Report: Multifocal EBV-Associated Diffuse Large B-Cell Lymphoma in a Patient With 6-MP Associated Lymphopenia With TPMT Deficiency.

Introduction: EBV associated lymphoproliferative disorders (EBV LPD) are a known complication following solid organ or hematopoietic stem cell transplantation. The disturbance of the immune system leads to a lack of control of latent EBV-infected B-cells, as control by T-cells is mandatory to prevent uninhibited cell proliferation. EBV LPD in other settings is less frequent and etiology and pathogenesis are not completely understood. Case Presentation: We present the case of an 18-year old adolescent suffering from lymphoblastic T-cell lymphoma who developed a life-threatening EBV associated B-cell lymphoma while he was under therapy with 6-MP (6- mercaptopurine). An underlying homozygous TPMT (thiopurine S-methyltransferase) deficiency with subsequent insufficient degradation of 6-MP was identified as contributory for the development of a distinct lymphopenia leading to EBV LPD. The patient was successfully treated by discontinuation of 6-MP and initiating rituximab monotherapy. Discussion: Rare cases of EBV LPD during therapy with 6-MP are reported in patients with leukemia, but no data about TPMT pharmacogenomics are available. In contrast the disease development in the presented case may be explained by the iatrogenic immunosuppression in the context of TPMT deficiency. While using 6-MP testing of genetic variations is not required for every protocol, although the use of thiopurines in patients with TPMT deficiency can cause severe immunosuppression. Our case suggests that insufficient degradation of 6-MP can have significant consequences despite dose reduction. Conclusion: When using thiopurines, TPMT genetics should be initiated and strict drug monitoring and dose adjusting must be performed by a specialized center.

Radiotherapy for pediatric adrenocortical carcinoma - Review of the literature.

Background and purpose: Pediatric adrenocortical carcinoma (pACC) is a rare disease with poor prognosis. Publications on radiotherapy (RT) are scarce. This review summarizes the current data on RT for pACC and possibly provides first evidence to justify its use in this setting. Materials and methods: We searched the PubMed and Embase database for manuscripts regarding RT for pACC. Results: We included 17 manuscripts reporting on 76 patients treated with RT, after screening 2961 references and 269 full articles. In addition, we added data of 4 unreported pACC patients treated by co-authors. All reports based on retrospective data. Median age at first diagnosis was 11.1 years (70% female); 78% of patients presented with hormonal activity. RT was mostly performed for curative intent (78%). 88% of RT were administered during primary therapy. The site of RT was predominantly the local tumor bed (76%). Doses of RT ranged from 15 to 62 Gy (median 50 Gy). Information on target volumes or fractionation were lacking. Median follow-up was 6,9 years and 64% of the patients died of disease, with 33% alive without disease. In 16 of 48 patients with available follow-up data after adjuvant RT (33%) no recurrence was reported and in 3 of 9 patients palliative RT seemed to induce some benefit for the patient. Conclusions: Our first systematic review on RT for pACC provides too few data for any general recommendation, but adjuvant RT in patients with high risk might be considered. International collaborative studies are urgently needed to establish better evidence on the role of RT in this rare malignancy.

Differences in morbidity and mortality between unilateral adrenalectomy for adrenal Cushing's syndrome and bilateral adrenalectomy for therapy refractory extra-adrenal Cushing's syndrome.

PURPOSE: In selected cases of severe Cushing's syndrome due to uncontrolled ACTH secretion, bilateral adrenalectomy appears unavoidable. Compared with unilateral adrenalectomy (for adrenal Cushing's syndrome), bilateral adrenalectomy has a perceived higher perioperative morbidity. The aim of the current study was to compare both interventions in endogenous Cushing's syndrome regarding postoperative outcomes. METHODS: We report a single-center, retrospective cohort study comparing patients with hypercortisolism undergoing bilateral vs. unilateral adrenalectomy during 2008-2021. Patients with adrenal Cushing's syndrome due to adenoma were compared with patients with ACTH-dependent Cushing's syndrome (Cushing's disease and ectopic ACTH production) focusing on postoperative morbidity and mortality as well as long-term survival. RESULTS: Of 83 patients with adrenalectomy for hypercortisolism (65.1% female, median age 53 years), the indication for adrenalectomy was due to adrenal Cushing's syndrome in 60 patients (72.2%; 59 unilateral and one bilateral), and due to hypercortisolism caused by Cushing's disease (n = 16) or non-pituitary uncontrolled ACTH secretion of unknown origin (n = 7) (27.7% of all adrenalectomies). Compared with unilateral adrenalectomy (n = 59), patients with bilateral adrenalectomy (n = 24) had a higher rate of severe complications (0% vs. 33%; p < 0.001) and delayed recovery (median: 10.2% vs. 79.2%; p < 0.001). Using the MTL30 marker, patients with bilateral adrenalectomy fared worse than patients after unilateral surgery (MTL30 positive: 7.2% vs. 25.0% p < 0.001). Postoperative mortality was increased in patients with bilateral adrenalectomy (0% vs. 8.3%; p = 0.081). CONCLUSION: While unilateral adrenalectomy for adrenal Cushing's syndrome represents a safe and definitive therapeutic option, bilateral adrenalectomy to control ACTH-dependent extra-adrenal Cushing's syndrome or Cushing's disease is a more complicated intervention with a mortality of nearly 10%.

Percutaneous implantation of peripherally inserted totally implantable venous access systems in the forearm in adolescent patients.

BACKGROUND: Children with different underlying malignant diseases require long-term central venous access. As for port systems in a pectoral position, peripherally implanted port systems in the forearm revealed high levels of technical and clinical success in adult cohorts. OBJECTIVE: To investigate the technical and clinical outcomes of percutaneous central venous port implantation in the forearm in adolescents. MATERIALS AND METHODS: Between April 2010 and August 2020, 32 children ages 9 to 17 years with underlying malignancy received 35 totally implantable venous access ports (TIVAPs) in the forearm. All venous port systems were peripherally inserted under ultrasound guidance. Correct catheter placement was controlled by fluoroscopy. As primary endpoints, the technical success, rate of complications and catheter maintenance were analyzed. Secondary endpoints were the side of implantation, vein of catheter access, laboratory results on the day of the procedure, procedural radiation exposure, amount of contrast agent and reasons for port device removal. RESULTS: Percutaneous TIVAP placement under sonographic guidance was technically successful in 34 of 35 procedures (97.1%). Procedure-related complications did not occur. During the follow-up, 13,684 catheter days were analyzed, revealing 11 complications (0.8 per 1,000 catheter-duration days), Of these 11 complications, 7 were major and 10 occurred late. In seven cases, the port device had to be removed; removal-related complications did not occur. CONCLUSION: Peripheral TIVAP placement in the forearms of children is a feasible, effective and safe technique with good midterm outcome. As results are comparable with standard access routes, this technique may be offered as an alternative when intermittent venous access is required.

Impact of Lymphadenectomy on the Oncologic Outcome of Patients with Adrenocortical Carcinoma-A Systematic Review and Meta-Analysis.

(1) Background: Locoregional lymphadenectomy (LND) in adrenocortical carcinoma (ACC) may impact oncological outcome, but the findings from individual studies are conflicting. The aim of this systematic review and meta-analysis was to determine the oncological value of LND in ACC by summarizing the available literature. (2) Methods: A systematic search on studies published until December 2020 was performed according to the PRISMA statement. The primary outcome was the impact of lymphadenectomy on overall survival (OS). Two separate meta-analyses were performed for studies including patients with localized ACC (stage I-III) and those including all tumor stages (I-IV). Secondary endpoints included postoperative mortality and length of hospital stay (LOS). (3) Results: 11 publications were identified for inclusion. All studies were retrospective studies, published between 2001-2020, and 5 were included in the meta-analysis. Three studies (N = 807 patients) reported the impact of LND on disease-specific survival in patients with stage I-III ACC and revealed a survival benefit of LND (hazard ratio (HR) = 0.42, 95% confidence interval (95% CI): 0.26-0.68). Based on results of studies including patients with ACC stage I-IV (2 studies, N = 3934 patients), LND was not associated with a survival benefit (HR = 1.00, 95% CI: 0.70-1.42). None of the included studies showed an association between LND and postoperative mortality or LOS. (4) Conclusion: Locoregional lymphadenectomy seems to offer an oncologic benefit in patients undergoing curative-intended surgery for localized ACC (stage I-III).

ALK-positive histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition.

ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in 3 infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (7 and 12 from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one-third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated extracellular signal-regulated kinase, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, whereas CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK, and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, 10 with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-positive histiocytosis and provides guidance for the clinical management of this emerging histiocytic entity.

Adrenocortical Carcinoma in Childhood: A Systematic Review.

Adrenocortical tumors are rare in children. This systematic review summarizes the published evidence on pediatric adrenocortical carcinoma (ACC) to provide a basis for a better understanding of the disease, investigate new molecular biomarkers and therapeutic targets, and define which patients may benefit from a more aggressive therapeutic approach. We included 137 studies with 3680 ACC patients (~65% female) in our analysis. We found no randomized controlled trials, so this review mainly reflects retrospective data. Due to a specific mutation in the TP53 gene in ~80% of Brazilian patients, that cohort was analyzed separately from series from other countries. Hormone analysis was described in 2569 of the 2874 patients (89%). Most patients were diagnosed with localized disease, whereas 23% had metastasis at primary diagnosis. Only 72% of the patients achieved complete resection. In 334 children (23%), recurrent disease was reported: 81%-local recurrence, 19% (n = 65)-distant metastases at relapse. Patients < 4 years old had a different distribution of tumor stages and hormone activity and better overall survival (p < 0.001). Although therapeutic approaches are typically multimodal, no consensus is available on effective standard treatments for advanced ACC. Thus, knowledge regarding pediatric ACC is still scarce and international prospective studies are needed to implement standardized clinical stratifications and risk-adapted therapeutic strategies.