Pediatric Oncology Research Research Articles

Current Management of Pulmonary Relapse in Ewing Sarcoma: A Report from the Pediatric Surgical Oncology Research Collaborative

Current Management of Pulmonary Relapse in Ewing Sarcoma: A Report from the Pediatric Surgical Oncology Research Collaborative

Pharmacogenomics in Pediatric Oncology Research and Treatment

Pharmacogenomics in Pediatric Oncology Research and Treatment

Safety and outcome of children, adolescents and young adults participating in phase I/II clinical oncology trials: a 9-year center experience.

Enrolling children with cancer in early phase trials is crucial to access innovative treatments, contributing to advancing pediatric oncology research and providing tailored therapeutic options. Our objective is to analyze the impact of these trials on patient outcomes and safety, and to examine the evolution and feasibility of trials in pediatric cancer over the past decade. All patients recruited in pediatric anticancer phase I/II clinical trials from January 2014 to December 2022 were included. Clinical records and trial protocols were analyzed. A total of 215 patients (median age 11.2 years, range 1-29.5) were included in 52 trials (258 inclusions). Patients with extracranial solid tumors (67%), central nervous system (CNS) tumors (24%), and leukemia (9%) were included. The most common investigational drugs were small molecules (28.3%) and antibodies (20.5%). Serious adverse events were experienced by 41% of patients, 4.4% discontinued treatment because of toxicity and two had toxic deaths. Median event-free survival was 3.7 months (95%CI: 2.8-4.5), longer in phase II trials than in phase I (2 vs. 6.3 months; p ≤ 0.001). Median overall survival was 12 months (95%CI: 9-15), higher in target-specific vs. non-target-specific trials (14 vs. 6 months; p ≤ 0.001). A significant and increasing number of patients have been included in early clinical trials, suggesting that both oncologists and families consider it valuable to be referred to specialized Units to access new therapies. Moreover, our data suggests that participation in early clinical trials, although not without potential toxicities, might have a positive impact on individual outcomes.

Delving into the clinical impact of NETs in pediatric cancer.

Pediatric cancer, a complex and heterogeneous group of diseases, continues to challenge medical research and treatment strategies. Despite advances in precision medicine and immunotherapy, certain aggressive subtypes of pediatric cancer are resistant to conventional therapies, requiring further exploration of potential therapeutic targets. Neutrophil extracellular traps (NETs), net-like structures released by neutrophils, have emerged as a potential player in the pediatric cancer landscape. However, our understanding of their role in pediatric oncology remains limited. This systematic review examines the current state of the NETs literature in pediatric cancer, focusing on the most frequent subtypes. The review reveals the scarcity of research in this area, highlighting the need for further investigation. The few studies available suggest that NETs may influence infection risk, treatment resistance and prognosis in certain pediatric malignancies. Although the field is still in its infancy, it holds great promise for advancing our understanding of pediatric cancer biology and potential therapeutic pathways. IMPACT: This review identifies a significant gap in research on neutrophil extracellular traps (NETs) in pediatric cancer. It provides a summary of existing studies and their promising findings and potential, as well as a comprehensive overview of current research on NETs in certain tumor types. It also emphasizes the lack of specific studies in pediatric cancer. The review encourages the prioritization of NET research in pediatric oncology, with the aim of improving prognosis and developing new treatments through increased understanding and targeted studies.

The Crucial Role of Patient Advocates in Pediatric Oncology Research—Insights From ACCELERATE

This Viewpoint explores the important role that patient advocates play in pediatric oncology as exemplified by ACCELERATE, a multiparty collaboration that centers advocate involvement in pediatric oncology research.

The importance of basic and translational research in caring for children with malignant solid tumors in Latin America.

Basic and translational research in pediatric cancer are essential to improve patient care. To critically assess the developments achieved in these areas in Latin America, we systematically reviewed information published between 2013 and 2023. Studies of basic and translational research performed by investigators in Latin America evaluating pediatric malignant solid and central nervous system tumors were retrieved from PubMed. Original articles published in English between 2013 and 2023 were included. Collaborations among Latin American authors or among Latin American authors working with researchers from other continents were also included. Studies were excluded if they focused only on adults or on basic research in tumor biology not specifically related to the tumor types analyzed in this review. A total of 550 articles were retrieved, but after removal of duplicates, 514 articles were included in the analysis, the majority of which were authored by researchers affiliated with institutions in Argentina, Brazil and Mexico. These countries also had the highest number of collaborations on original articles published with authors from Europe and North America. Argentina had the highest number of collaborations on original publications, with coauthors from Brazil and Uruguay. The median impact factor of the 244 journals in which articles were published was 3.5. The most commonly studied tumors were osteosarcomas, neuroblastomas and medulloblastomas; the most commonly studied areas were molecular analysis, tumor cell biology and biomarkers. In Latin America, research in pediatric oncology is on the agenda, despite a notable disparity in publication rates and frequency of collaboration between countries. There is a need to strengthen scientific collaboration within Latin America and with countries from other continents to promote research and to develop novel treatment strategies that reflect the local needs of children in Latin America who have solid tumors and brain cancer.

Survival outcomes in pediatric patients with metastatic Ewing sarcoma who achieve a rapid complete response of pulmonary metastases.

Our objectives were to compare overall survival (OS) and pulmonary relapse between patients with metastatic Ewing sarcoma (EWS) at diagnosis who achieve rapid complete response (RCR) and those with residual pulmonary nodules after induction chemotherapy (non-RCR). This retrospective cohort study included children under 20years with metastatic EWS treated from 2007 to 2020 at 19 institutions in the Pediatric Surgical Oncology Research Collaborative. Chi-square tests were conducted for differences among groups. Kaplan-Meier curves were generated for OS and pulmonary relapse. Among 148 patients with metastatic EWS at diagnosis, 61 (41.2%) achieved RCR. Five-year OS was 71.2% for patients who achieved RCR, and 50.2% for those without RCR (p=.04), and in multivariable regression among patients with isolated pulmonary metastases, RCR (hazards ratio [HR] 0.42; 95% confidence interval [CI]: 0.17-0.99) and whole lung irradiation (WLI) (HR 0.35; 95% CI: 0.16-0.77) were associated with improved survival. Pulmonary relapse occurred in 57 (37%) patients, including 18 (29%) in the RCR and 36 (41%) in the non-RCR groups (p=.14). Five-year pulmonary relapse rates did not significantly differ based on RCR (33.0%) versus non-RCR (47.0%, p=.13), or WLI (38.8%) versus no WLI (46.0%, p=.32). Patients with EWS who had isolated pulmonary metastases at diagnosis had improved OS if they achieved RCR and received WLI, despite having no significant differences in rates of pulmonary relapse.

Cancer symptom cluster research in pediatric oncology: a work in progress.

In the 21st century, advances in basic research have provided new insights in the field of pediatric oncology. Pediatric patients tend to experience higher levels of distressing symptoms, which together form a symptom cluster. In clinical practice, these symptom clusters are reported daily by children and adolescents with cancer. Translational research has emerged as the translation of new knowledge from basic science into clinical practice. Understanding how neuroimmunoendocrine pathways regulate cancer development and the aspects underlying the specific therapies, such as chemotherapy and immunotherapy, is an important frontier for future research in pediatric oncology. The goal of translational research is to show how different variables in tumor and patient characteristics explain the differential effects of interventions, as translational research provides new insights into the management of cancer symptoms in children and adolescents with cancer. Together, this approach could lead to improvements in pediatric oncology care worldwide.

Management of undifferentiated embryonal sarcoma of the liver: A Pediatric Surgical Oncology Research Collaborative study.

Undifferentiated embryonal sarcoma of the liver (UESL) is a rare tumor for which there are few evidence-based guidelines. The aim of this study was to define current management strategies and outcomes for these patients using a multi-institutional dataset curated by the Pediatric Surgical Oncology Research Collaborative. Data were collected retrospectively for patients with UESL treated across 17 children's hospitals in North America from 1989 to 2019. Factors analyzed included patient and tumor characteristics, PRETEXT group, operative details, and neoadjuvant/adjuvant regimens. Event-free and overall survival (EFS, OS) were the primary and secondary outcomes, respectively. Seventy-eight patients were identified with a median age of 9.9years [interquartile range [IQR): 7-12]. Twenty-seven patients underwent resection at diagnosis, and 47 patients underwent delayed resection, including eight liver transplants. Neoadjuvant chemotherapy led to a median change in maximum tumor diameter of 1.6cm [IQR: 0.0-4.4] and greater than 90% tumor necrosis in 79% of the patients undergoing delayed resection. R0 resections were accomplished in 63 patients (81%). Univariate analysis found that metastatic disease impacted OS, and completeness of resection impacted both EFS and OS, while multivariate analysis revealed that R0 resection was associated with decreased expected hazards of experiencing an event [hazard ratio (HR): 0.14, 95% confidence interval (CI): 0.04-0.6]. At a median follow-up of 4years [IQR: 2-8], the EFS was 70.0% [95% CI: 60%-82%] and OS was 83% [95% CI: 75%-93%]. Complete resection is associated with improved survival for patients with UESL. Neoadjuvant chemotherapy causes minimal radiographic response, but significant tumor necrosis.

Robotic-assisted laparoscopy in pediatric surgical oncology: a narrative review.

Robotic surgical oncology in children calls for experienced surgeons in minimally invasive surgery (MIS) and a solid oncological background. The aim of this review was to analyze the current state of robotic-assisted laparoscopy in pediatric tumor resection, assess the necessary framework of minimally invasive surgical oncology and describe future developments of the robotic technology. A literature search of the MEDLINE/PubMed database was conducted, using the terms "robotic surgery", "pediatric" or "children" and "oncology" or "tumor". All relevant English-language studies published between 2008 and 2022 were reviewed. Although concerns have been raised regarding the use of MIS in surgical oncology, current literature reports similar oncological outcome if surgeons comply with the oncologic principles. The benefits of MIS have been established for robotic surgery in adult studies, including a shorter time to adjuvant chemotherapy. Surgical feasibility should be assessed based on tumor characteristics, preoperative imaging focusing on vascular involvement and surgeon's experience until clear guidelines are issued. The difficulties in establishing eligibility criteria for robotic resection of pediatric tumors lie in the great variability of indications, heterogeneity in tumor histology with their own surgical specificities, and wide range of age and weight, as shown by the literature review we performed. Between 2008 and 2022, 31 studies reported 171 cases with three studies including at least ten patients. The most reported procedure was adrenalectomy (41 cases). Current research in pediatric surgical oncology focuses on intraoperative locoregional treatment, improved vision with fluorescence and dyed-loaded specific probes and the many possibilities of enhancement software using the robotic console. The robotic technology allows the surgeon to push the boundaries of conventional laparoscopy. Specific surgical guidelines are necessary.

Disorders of mental health in children and adolescents with hematological malignancies

Introduction. The success in pediatric oncohematological disorders treatment cause increasing scrutiny not only to remission achievement and long-term patient survival, but also to supportive dysfunctions, which go with malignancy and anti-tumor treatment. Blood tumors cause all organs and systems disorders, and psychic dysfunctions of these are not in the last place.Aim. To characterize mental health and psychic disorders types in children and adolescents with oncohematological diseases during hospital stay.Materials and methods. It was analyzed mental health of 169 children and adolescents with hemoblastoses, who were treated at Pediatric Oncology and Hematology Research Institute of National Research Cancer Centre n. a. N. N. Blokhin (Moscow, Russia) in 2022 year. 50 (29.6 %) patients needed a psychiatric consultation. Among oncohematological disorders acute lymphoblastic leukemia was predominated – 25 (50 %), lymphomas – 17 (34 %) and acute myeloid leukemia – 8 (16 %) patients. Mental health data assessed after examination/consultation of clinical psychologist and psychiatrist.Results. Asthenia was found in all 50 (100 %) patients, who were recommended a psychiatrist consultation, in 47 (94 %) – adjustment disorder, in 15 (30 %) – vexatious and neurotic disorder, in 16 (32 %) – affective syndromes, less often (18 and 14 % respectively) – behavioral deviations and eating disorders. As single cases in 2 (4 %) patients an intellectual disability and in 1 (2 %) a psychotic syndrome were diagnosed. As a role the most pronounced psychopathological conditions were upon admission to the hospital and decreased during the treatment and adaptation.Conclusions. One third of children and adolescents, hospitalizing to oncohematological clinic need a psychiatrist consultation. Multidisciplinary care for such patients with pediatric oncologist, psychiatrist and clinical psychologist can cure psychogenic disorder effectively, improving the stay of patient at the hospital and best compliance between the doctor and patient.

Designing and validating novel communication measures for pediatric, adolescent, and young adult oncology care and research: The PedCOM measures.

High-quality communication in pediatric and adolescent cancer is the standard of care. Yet, we lack pediatric-specific communication measures. We designed self-report and caregiver-report communication measures for use in pediatric oncology settings. We recruited adolescent and young adults (AYAs; 12-24years) with cancer and parents of children and AYAs between 1month post-diagnosis and 2months after completing treatment. Participants completed measures including 58 questions addressing eight previously characterized communication functions. For each function, we conducted factor analysis, and assessed reliability and construct validity. Based on psychometric properties, we created final long-form (31 items) and short-form (eight items) communication measures (PedCOM) for both self- and caregiver-report. Participants included 200 parents and 88 AYAs. The final 31-item and eight-item PedCOM measures for parents and AYAs demonstrated good unidimensional model fit. Each communication function (e.g., building relationships) demonstrated high reliability, coefficient alphas ranged from .83 to .93 for parents and .85 to .93 for AYAs. The overall 31-item and eight-item PedCOM measures also demonstrated high reliability (alphas >.9). For construct validity, PedCOM-Parent-31 and PedCOM-Parent-8 correlated positively with satisfaction with care, trust, emotional self-management, and decisional satisfaction, and negatively with anxiety and caregiver burden. PedCOM-AYA-31 and PedCOM-AYA-8 correlated positively with satisfaction with care, trust, emotional self-management, symptoms self-management, and decisional satisfaction, and negatively with anxiety. We developed valid and reliable measures of communication functions for parents and AYAs with cancer. These measures can support organizations and stakeholder groups that are striving to improve the quality of cancer care.

Management and Outcomes of Wilms Tumor With Suprarenal Intravascular Extension: A Pediatric Surgical Oncology Research Collaborative Study.

The purpose of this study was to describe management and outcomes from a contemporary cohort of children with Wilms tumor complicated by inferior vena caval thrombus. The largest series of these patients was published almost 2 decades ago. Since then, neoadjuvant chemotherapy has been commonly used to manage these patients, and outcomes have not been reported. Retrospective review of 19 North American centers between 2009 and 2019. Patient and disease characteristics, management, and outcomes were investigated and analyzed. Of 124 patients, 81% had favorable histology (FH), and 52% were stage IV. IVC thrombus level was infrahepatic in 53 (43%), intrahepatic in 32 (26%), suprahepatic in 14 (11%), and cardiac in 24 (19%). Neoadjuvant chemotherapy using a 3-drug regimen was administered in 82% and postresection radiation in 90%. Thrombus level regression was 45% overall, with suprahepatic level showing the best response (62%). Cardiopulmonary bypass (CPB) was potentially avoided in 67%. The perioperative complication rate was significantly lower after neoadjuvant chemotherapy [(25%) vs upfront surgery (55%); P =0.005]. CPB was not associated with higher complications [CPB (50%) vs no CPB (27%); P =0.08]. Two-year event-free survival was 93% and overall survival was 96%, higher in FH cases (FH 98% vs unfavorable histology/anaplastic 82%; P =0.73). Neither incomplete resection nor viable thrombus cells affected event-free survival or overall survival. Multimodal therapy resulted in excellent outcomes, even with advanced-stage disease and cardiac extension. Neoadjuvant chemotherapy decreased the need for CPB to facilitate resection. Complete thrombectomy may not always be necessary.

Survival outcomes in pediatric patients with metastatic Ewing sarcoma who achieve a rapid complete response of pulmonary metastases.

11535 Background: Twenty-five percent of patients with Ewing Sarcoma (EWS) have metastatic disease at diagnosis, most commonly in the lungs. Our objectives were to compare overall (OS) and pulmonary disease-free survival (PDFS) between patients with metastatic EWS at diagnosis who achieve rapid complete response (RCR), defined as radiographic resolution of all pulmonary nodules at the end of induction chemotherapy, and those with residual pulmonary nodules after induction chemotherapy (non-RCR). Methods: This multi-center, retrospective cohort study included children under 20 years of age with metastatic EWS treated from 2007-2020 at 19 institutions participating in the Pediatric Surgical Oncology Research Collaborative. Chi-square tests were conducted for differences among groups, and p < 0.05 was considered significant. Kaplan-Meier curves were generated for OS and PDFS. Cox regression was performed for OS, controlling for whole lung irradiation (WLI), extrapulmonary metastases, and age. Results: Among 153 patients with metastatic EWS at diagnosis, 61 (40%) achieved RCR, and 87 (57%) did not (5 unknown). The median number of pulmonary nodules was 3.5 in the RCR vs 5 in the non-RCR groups (p = 0.02), while bilateral disease was present in 44 (72%) RCR vs 75 (86%) non-RCR patients (p = 0.03). Pulmonary relapse occurred in 58 (38%) patients, including 18 (29%) in the RCR and 36 (41%) in the non-RCR groups (p = 0.14). Factors associated with pulmonary relapse in the univariate analysis include median age [15 years (IQR: 12-17) with pulmonary relapse vs 12 years (IQR: 9-16) without (p = 0.03)] and extrapulmonary metastases at diagnosis [24 (41%) patients with pulmonary relapse vs 26 (27%) patients without pulmonary relapse (p = 0.05)]. WLI was performed in 100 patients and was not associated with a reduction in pulmonary relapse (p = 0.93). Complete surgical clearance of pulmonary disease was attempted in 29 (19%) patients, including 17 of the patients who met the criteria for RCR. On Kaplan-Meier analyses, 5-year PDFS did not significantly differ based on RCR (67%) vs. non-RCR (53%, p = 0.13), or WLI (61%) vs. no WLI (54%, p = 0.32). However, 5-year OS did vary significantly between patients with RCR and WLI (85%), RCR without WLI (55%), non-RCR with WLI (60%), and non-RCR without WLI (25%; p < 0.01). In Cox regression analysis, RCR was associated with improved OS after controlling for WLI, extrapulmonary metastases, and patient age (HR 0.51, p = 0.03). Conclusions: Patients with EWS who had pulmonary metastases at diagnosis had improved OS if they achieved RCR and received WLI, despite having no significant differences in rates of pulmonary relapse. Further research is needed to determine whether clearance of pulmonary disease achieved through surgical metastasectomy provides a comparable survival benefit and if any subsets of patients have a reduced risk of pulmonary relapse after resection.

Evaluation of health-related quality of life and its domains in pediatric patients with cancer

BackgroundHealth-related quality of life has emerged as a significant component in pediatric oncology research during the last several decades. Measures of health-related quality of life provide a thorough assessment of the child’s response to medical therapy, disease course, and adjustment outcomes in the context of pediatric oncology.MethodsThe aim of the present study was to assess the cancer-specific health-related quality of life in cancer pediatric patients and to evaluate the contribution of its domains and some of the anthropometric, sociodemographic, and treatment-related variables on the overall quality of life, by using the PedsQL™ 3.0 Cancer Module.ResultsThe study included 110 cases. The mean value of the PedsQL™ 3.0 Cancer Module score was 49.3 ± 12.0. The lowest mean score of quality of life was for the “procedure anxiety” (8.7 ± 23.9), followed by the “worry” domains (16.6 ± 28.5). Higher “frequency of hospital visits” was associated with increased feeling of pain and treatment anxiety yet decrease in suffering from nausea and vice versa. The longer period of hospital admission for more than half of the recommended treatment period was associated with reduced pain suffering on the expense of increase in feeling of worry as well as communication problems. The perceived physical appearance was better among those patients who spent a treatment period for 3–6 months when compared to those who spent a treatment period less than 3 months or more than 6 months. There was a highly significant association between all the eight-cancer-specific quality-of-life domains except the pain domain- and the overall quality-of-life log scores. Nausea problem followed by worry and cognitive problems was the most effective domains on the overall quality-of-life score.ConclusionCancer pediatric patients suffered low quality of life especially for anxiety procedure and worry domains with special consideration for the impact of nausea, worry, and cognitive problems on their perception of quality of life.

Single-cell technologies uncover intra-tumor heterogeneity in childhood cancers.

Childhood cancer is the second leading cause of death in children aged 1 to 14. Although survival rates have vastly improved over the past 40years, cancer resistance and relapse remain a significant challenge. Advances in single-cell technologies enable dissection of tumors to unprecedented resolution. This facilitates unraveling the heterogeneity of childhood cancers to identify cell subtypes that are prone to treatment resistance. The rapid accumulation of single-cell data from different modalities necessitates the development of novel computational approaches for processing, visualizing, and analyzing single-cell data. Here, we review single-cell approaches utilized or under development in the context of childhood cancers. We review computational methods for analyzing single-cell data and discuss best practices for their application. Finally, we review the impact of several studies of childhood tumors analyzed with these approaches and future directions to implement single-cell studies into translational cancer research in pediatric oncology.

Data standards in pediatric oncology: Past, present, and future.

In this commentary, we highlight the central role that data standards play in facilitating data-driven efforts to advance research in pediatric oncology. We discuss the current state of data standards for pediatric oncology and propose five steps to achieve an improved future state with benefits for clinicians, researchers, and patients.

Incidence and management of pleural effusions in patients with Wilms tumor: A Pediatric Surgical Oncology Research Collaborative study.

Wilms tumor (WT) is the most common renal malignancy in children. Children with favorable histology WT achieve survival rates of over 90%. Twelve percent of patients present with metastatic disease, most commonly to the lungs. The presence of a pleural effusion at the time of diagnosis of WT may be noted on staging imaging; however, minimal data exist regarding the significance and prognostic importance of this finding. The objectives of our study are to identify the incidence of pleural effusions in patients with WT, and to determine the potential impact on oncologic outcomes. A multi-institutional retrospective review was performed from January 2009 to December 2019, including children with WT and a pleural effusion on diagnostic imaging treated at Pediatric Surgical Oncology Research Collaborative (PSORC) participating institutions. Of 1259 children with a new WT diagnosis, 94 (7.5%) had a pleural effusion. Patients with a pleural effusion were older than those without (median 4.3 vs 3.5 years; P=.004), and advanced stages were more common (local stage III 85.9% vs 51.9%; P < .0001). Only 14 patients underwent a thoracentesis for fluid evaluation; 3 had cytopathologic evidence of malignant cells. Event-free and overall survival of all children with WT and pleural effusions was 86.2% and 91.5%, respectively. The rate and significance of malignant cells present in pleural fluid is unknown due to low incidence of cytopathologic analysis in our cohort; therefore, the presence of an effusion does not appear to necessitate a change in therapy. Excellent survival can be expected with current stage-specific treatment regimens.

Inflammatory myofibroblastic tumor: A multi-institutional study from the Pediatric Surgical Oncology Research Collaborative.

Inflammatory myofibroblastic tumor (IMT) is a mesenchymal neoplasm of intermediate malignancy. We describe the largest cohort of IMT patients to date, aiming to further characterize this rare, poorly understood tumor. This is a multi-institutional review of IMT patients ≤39 years, from 2000 to 2018, at 18 hospitals in the Pediatric Surgical Oncology Research Collaborative. One hundred and eighty-two patients were identified with median age of 11 years. Thirty-three percent of tumors were thoracic in origin. Presenting signs/symptoms included pain (29%), respiratory symptoms (25%) and constitutional symptoms (20%). Median tumor size was 3.9cm. Anaplastic lymphoma kinase (ALK) overexpression was identified in 53% of patients. Seven percent of patients had distant disease at diagnosis. Ninety-one percent of patients underwent resection: 14% received neoadjuvant treatment and 22% adjuvant treatment. Twelve percent of patients received an ALK inhibitor. Sixty-six percent of surgical patients had complete resection, with 20% positive microscopic margins and 14% gross residual disease. Approximately 40% had en bloc resection of involved organs. Median follow-up time was 36 months. Overall 5-year survival was 95% and 5-year event-free survival was 80%. Predictors of recurrence included respiratory symptoms, tumor size and distant disease. Gross or microscopic margins were not associated with recurrence, suggesting that aggressive attempts at resection may not be warranted.

Histologic type predicts disparate outcomes in pediatric hepatocellular neoplasms: A Pediatric Surgical Oncology Research Collaborative study.

Hepatocellular carcinoma (HCC) is a rare cancer in children, with various histologic subtypes and a paucity of data to guide clinical management and predict prognosis. A multi-institutional review of children with hepatocellular neoplasms was performed, including demographic, staging, treatment, and outcomes data. Patients were categorized as having conventional HCC (cHCC) with or without underlying liver disease, fibrolamellar carcinoma (FLC), and hepatoblastoma with HCC features (HB-HCC). Univariate and multivariate analyses identified predictors of mortality and relapse. In total, 262 children were identified; and an institutional histologic review revealed 110 cHCCs (42%; 69 normal background liver, 34 inflammatory/cirrhotic, 7 unknown), 119 FLCs (45%), and 33 HB-HCCs (12%). The authors observed notable differences in presentation and behavior among tumor subtypes, including increased lymph node involvement in FLC and higher stage in cHCC. Factors associated with mortality included cHCC (hazard ratio [HR], 1.63; P = .038), elevated α-fetoprotein (HR, 3.1; P = .014), multifocality (HR, 2.4; P < .001), and PRETEXT (pretreatment extent of disease) stage IV (HR, 5.76; P < .001). Multivariate analysis identified increased mortality in cHCC versus FLC (HR, 2.2; P = .004) and in unresectable tumors (HR, 3.4; P < .001). Disease-free status at any point predicted survival. This multi-institutional, detailed data set allowed a comprehensive analysis of outcomes for children with these rare hepatocellular neoplasms. The current data demonstrated that pediatric HCC subtypes are not equivalent entities because FLC and cHCC have distinct anatomic patterns and outcomes in concert with their known molecular differences. This data set will be further used to elucidate the impact of histology on specific treatment responses, with the goal of designing risk-stratified algorithms for children with HCC. This is the largest reported granular data set on children with hepatocellular carcinoma. The study evaluates different subtypes of hepatocellular carcinoma and identifies key differences between subtypes. This information is pivotal in improving understanding of these rare cancers and may be used to improve clinical management and subsequent outcome in children with these rare malignancies.