Temporal trends in cross-country inequalities of neuroblastoma burden in children under 14 years of age from 1990 to 2021

Introduction

Neuroblastoma is a malignant tumor arising from immature nerve cells, developing from the embryonic neural crest of the peripheral sympathetic nervous system, and can manifest in multiple body areas (1). Due to the similar origin of the adrenal glands and nerve cells, it most commonly appears in the adrenal glands. However, neuroblastoma can also develop in other sites with nerve cell clusters, such as the retroperitoneum, chest, neck, and near the spine. Although children with a family history of neuroblastoma may have an increased risk, most cases are spontaneous, and the initial genetic mutations causing neuroblastoma are still unknown (2). Studies indicate that individuals with specific mutations in genes like TP53, NRAS, BRCA2, and ALK are at higher risk (3,4). Additionally, certain characteristics, such as MYCN oncogene amplification, DNA index, and segmental chromosomal abnormalities, are associated with disease progression and prognosis (5-8).

Neuroblastoma is the most common tumor in infants and the most prevalent extracranial solid tumor in children, primarily affecting those under 5 years (9). It accounts for over 7% of malignant tumors in patients under 15 and 15% of pediatric tumor deaths (1,10). Symptoms vary based on tumor location and can include abdominal distension, pain, constipation, diarrhea, vomiting, difficulty breathing, increased heart rate, and bone pain (11-13). While personalized treatment plans can be tailored based on tumor characteristics, patient age, and genetic mutations, high-risk patients often require intensive multimodal therapies. Despite these approaches, treatment remains challenging, especially for high-risk patients, whose prognosis is poor; survival rates for relapsed or refractory cases remain under 40% for long-term outcomes (14).

The Global Burden of Disease (GBD) study aims to quantify the impact of various diseases and injuries at global and regional levels, offering scientific support for public health policy development worldwide (15-17). Although neuroblastoma is a rare pediatric malignancy, its profound impact on the survival and quality of life of young patients makes it critical to analyze the global burden of this disease. Current research on neuroblastoma predominantly focuses on etiology, genetic mutations, and individualized treatment strategies (18,19). However, comprehensive epidemiological data on global or regional disease burden are limited, with a particular gap in comparisons across countries and regions. Additionally, the burden differences within various socio-demographic index (SDI) contexts are not well understood. This study, by analyzing neuroblastoma data from the GBD 2021 database, systematically characterizes the disease’s epidemiology across different regions and forecasts future trends. The findings aim to support evidence-based policymaking and inform equitable distribution of healthcare resources. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-178/rc).

Methods

Data sources

Data from the GBD 2021 study, accessed via the Global Health Data Exchange platform (https://ghdx.healthdata.org/gbd-2021/sources) (15), were used to evaluate the global burden of neuroblastoma in children under 14 years. This evaluation encompassed prevalence, incidence, mortality, and disability-adjusted life years (DALYs). Additionally, stratified statistical analyses were conducted across different SDI regions. Neuroblastoma-related data were extracted by sex for individuals younger than 14 and further categorized according to the 21 geographical and epidemiologically similar GBD-defined regions or countries. In the GBD 2021, neuroblastoma was coded as C47-C47.9 under the International Classification of Diseases, 10th Revision (ICD-10), and categorized as a level 3 cause within the four-tier GBD cause hierarchy (15,16,20).

SDI

The SDI, developed by the Institute for Health Metrics and Evaluation (IHME) in 2015, serves as a composite measure of a country’s or region’s development status (21). It integrates three key indicators: per capita income, educational attainment, and total fertility rate (22). SDI values range from 0 to 1 and are categorized into five levels: low, low-middle, middle, high-middle, and high (15). Notably, SDI is a dynamic metric, varying by country and year, which means that a region’s classification may shift over time as its socioeconomic conditions evolve.

Disease burden indicator

The GBD study integrates data from diverse sources such as population-based surveys, large epidemiological studies, and hospital records to estimate disease-specific incidence and prevalence globally (23,24). For the majority of conditions, GBD 2021 employs DisMod-MR 2.1—a Bayesian meta-regression tool—to model internally consistent estimates of prevalence, incidence, and mortality across sex, age, location, and year (25). This tool also extrapolates estimates for locations with missing data. Mortality estimates attributable to specific causes are generated using the Cause of Death Ensemble model (CODEm), which systematically evaluates the predictive performance of various statistical models and covariate combinations, ultimately synthesizing them to produce robust cause-specific mortality estimates (26). These estimates are disaggregated by region, age, sex, and calendar year. DALYs—a core metric for assessing disease burden—combine years of life lost due to premature death [years of life lost (YLL)] and years lived with disability [years of disabled life (YLD)], and are similarly stratified by age, sex, time, and geography (16,25).

Statistical analysis

In this analysis, we assessed the global and regional burden of neuroblastoma in children under 14 years by calculating age-standardized rates (ASRs) and their corresponding 95% uncertainty intervals (UIs) for prevalence, incidence, mortality, and DALYs. Specifically, we computed the age-standardized incidence rate (ASIR), prevalence rate (ASPR), mortality rate (ASMR), and DALY rate (ASDR). To evaluate temporal trends from 1990 to 2021, we estimated the estimated annual percentage change (EAPC) (27). A positive EAPC with a 95% confidence interval (CI) lower bound exceeding zero was interpreted as a significant increasing trend, while a negative EAPC with the upper CI bound below zero indicated a significant decline. If the 95% CI of the EAPC included zero, the trend was considered statistically stable.

To better understand the factors driving changes in the neuroblastoma burden from 1990 to 2021, we conducted a decomposition analysis with a gender-stratified approach. This analysis examined the roles of population growth, population aging, and epidemiological shifts in influencing changes in the neuroblastoma burden over time (27,28).

To support universal health coverage and inform policy, planning, and practice aimed at reducing health disparities, we conducted both absolute and relative inequality assessments of neuroblastoma using the slope index of inequality (SII) and the concentration index, respectively (29,30). The SII was derived by regressing national DALY values against each country’s relative SDI position, defined by the midpoint of its cumulative population distribution based on SDI ranking. The concentration index, reflecting relative inequality, was computed as the ratio of the area between the Lorenz curve—constructed from cumulative SDI rank and cumulative DALY burden—and the line of equality (31). Additionally, we projected global trends in incidence, prevalence, mortality, and DALYs for neuroblastoma through 2036. These forecasts were based on global population projections for 2017–2100 and age-standardized neuroblastoma data spanning 1990–2021. The model is implemented in R via the autoregressive integrated moving average (ARIMA) model (32,33). All statistical analyses and visualizations were processed using R software; P<0.05 was considered statistically significant.

Ethics statement

The study is an integrated and anonymous analysis based on the open-source data from the GBD database. The waiver of informed consent has been approved by the University of Washington Institutional Review Board (IRB). It does not involve randomized controlled trials nor human subjects directly; therefore, IRB approval is not applicable. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Results

Neuroblastoma burden at global, regional, and national levels

Globally, the incidence, prevalence, mortality rate, and DALYs of neuroblastoma have shown an increasing trend, with the burden in males consistently higher than in females. Examining across the five SDI regions, we observed that, except in the high-SDI region where incidence, prevalence, mortality, and DALYs have decreased, the disease burden in the other four SDI regions continues to rise (Tables 1-4).

Among the 21 GBD regions, South Asia had the highest number of neuroblastoma cases, incidence, mortality, and DALYs cases in 2021, with these metrics continuing to increase (Tables 1-4). On a national level, there are substantial variations in neuroblastoma burden worldwide. India reported the highest case count, prevalence, and mortality, while Pakistan recorded the highest DALYs cases (Figure 1).

Figure 1 Neuroblastoma burden for 204 countries or regions worldwide in 2021. ASDR, age-standardized disability-adjusted life years rate; ASIR, age-standardized incidence rate; ASMR, age-standardized mortality rate; ASPR, age-standardized prevalence rate.

Decomposition analysis

The decomposition analysis highlighted the relative contributions of population aging, population growth, and prevalence changes to the increase in neuroblastoma incidence, prevalence, mortality, and DALYs globally and across the five SDI regions (Figure 2). Among these disease burden indicators, epidemiological changes and population growth emerged as the primary drivers of growth, while aging consistently contributed negatively across all indicators.

Figure 2 Changes in DALYs (A), incidence (B), prevalence (C) and deaths (D) of neuroblastoma according to aging, population growth and epidemiological change from 1990 to 2021 at global level by SDI quintile and by subgroups of sexes. The black dot denotes the overall value of the change resulting from all three components. For each component, the magnitude of a positive value suggests a corresponding increase in neuroblastoma DALYs attributed to the component; the magnitude of a negative value suggests a corresponding decrease in neuroblastoma DALYs attributed to the component. DALY, disability-adjusted life year; SDI, socio-demographic index.

Inequality analysis

Inequality analysis of neuroblastoma burden associated with SDI revealed a decreasing disparity between the highest and lowest SDI countries, with the DALYs ratio declining from 6.23 in 1990 to 4.55 in 2021. Additionally, the concentration index rose from −0.02 in 1990 to −0.21 in 2021 (Figure 3). These findings suggest that both absolute and relative inequalities in neuroblastoma burden are shifting, with an increasingly greater burden falling on lower-SDI countries over time.

Figure 3 Health inequality slope index (A) and concentration index (B) for the DALYs of neuroblastoma from 1990 to 2021 across the world. DALY, disability-adjusted life year; SDI, socio-demographic index.

GBD future forecast for global neuroblastoma

Future projections for neuroblastoma indicate that while the global ASIR, ASPR, ASMR, and ASDR will stabilize and gradually decline, the absolute numbers of incidence, prevalence, mortality, and DALY cases are expected to rise (Figure 4). By 2036, the ASPR for males is projected to be 2.83 per 100,000 people and for females, 2.18 per 100,000. Additionally, the ASIR, ASMR, and ASDR for neuroblastoma from 2021 to 2036 are anticipated to decline, with a notably sharper reduction in ASDR and ASMR among males.

Figure 4 Future forecasts of GBD in neuroblastoma. ASDR, age-standardized disability-adjusted life years rate; ASIR, age-standardized incidence rate; ASMR, age-standardized mortality rate; ASPR, age-standardized prevalence rate; GBD, Global Burden of Disease.

Discussion

In this study, we analyzed data on neuroblastoma from the GBD 2021 database, systematically describing its epidemiological characteristics at global and regional levels and forecasting future disease burden trends. The findings reveal that although neuroblastoma has a relatively low incidence rate, it significantly impacts survival rates and quality of life in pediatric patients, with the burden being particularly pronounced in low-SDI countries.

The disease burden of neuroblastoma exhibits significant disparities globally, particularly in low-SDI regions, where incidence, mortality, and DALYs rates are on the rise. These differences are closely linked to the accessibility of regional healthcare resources, the level of early screening and diagnostic capabilities, and variations in health policies (34). High-SDI regions benefit from adequate medical resources and effective early diagnosis and intervention measures, which help reduce the disease burden (35). In contrast, low-SDI regions face notable shortcomings in screening and treatment. This situation highlights the importance of strengthening early screening and diagnostic systems in low-SDI areas as a crucial step to effectively reduce the burden of this disease.

While early screening programs have been widely advocated as a means to reduce the burden of childhood cancers, their effectiveness in improving the prognosis of neuroblastoma remains a subject of debate. Historically, early screening programs for neuroblastoma have been implemented in several countries, notably in Japan. The mass screening program introduced in Japan in the 1980s led to the early detection of neuroblastoma in infants, allowing for timely intervention and treatment. However, the effectiveness of this approach in improving long-term survival rates has been questioned. In 2004, Japan discontinued its nationwide screening program, citing a lack of conclusive evidence showing significant improvements in overall survival rates or a reduction in mortality due to early detection of asymptomatic cases. The decision to halt the screening program was also influenced by concerns about the psychological burden on families, the high cost of screening, and the potential for overdiagnosis and overtreatment in low-risk cases (35).

Moreover, studies examining the long-term effects of early screening have shown mixed results. While some research suggests that early detection can lead to a reduction in mortality, other studies point to the limited impact on overall survival, especially in high-risk cases where prognosis remains poor despite early intervention. This discrepancy may be attributed to the fact that neuroblastoma is a heterogeneous disease with varying biological behavior. In low-risk cases, early detection may indeed offer a survival benefit; however, for high-risk cases, the disease may progress aggressively despite early intervention, resulting in poor prognosis and survival outcomes (14).

Given these challenges, the question of whether early screening for neuroblastoma is a universally beneficial strategy remains unresolved. Rather than relying solely on screening programs, there is a growing recognition of the need for a more nuanced approach that includes improving access to quality healthcare, advancing diagnostic technologies, and focusing on targeted therapies. Additionally, efforts should be made to improve risk stratification and better understand the molecular and genetic factors associated with neuroblastoma. This will help in identifying high-risk populations who may benefit most from early screening or more aggressive treatment strategies.

Our study also analyzed the gender differences in the disease burden of neuroblastoma, revealing that the burden is higher in males than in females (36). Although neuroblastoma typically arises non-hereditarily, the genetic patterns are less correlated with gender. However, social gender differences may indirectly influence the timing of diagnosis and treatment through social, cultural, and economic factors (37). Currently, the global birth rate for males is higher than that for females, which is particularly pronounced in regions with a high burden of neuroblastoma. In these areas, due to social, cultural, and economic constraints, males often receive earlier diagnoses and better access to medical resources. This results in a higher incidence rate among males and a more significant decrease in mortality compared to females.

Through decomposition analysis, we found that population growth and epidemiological changes are the primary drivers of the increasing burden of neuroblastoma, particularly in low-SDI and low-middle SDI regions. Given that this disease primarily affects children, an increase in the population directly correlates with a rise in the number of cases. Additionally, environmental pollution and changes in lifestyle may also contribute to an increased risk of developing the disease (38). Epidemiological changes have been associated with environmental factors, especially regarding industrial pollution, environmental exposure, and lifestyle during pregnancy (39-41). Therefore, future disease prevention and control efforts should consider the impact of population policies while also focusing on improving lifestyle factors to reduce the incidence of new cases.

While the development of neuroblastoma is primarily associated with genetic factors, increasing attention is being paid to the potential role of environmental and lifestyle factors in its pathogenesis. Although the evidence in this area remains limited, and these factors have not yet been widely accepted as contributing to neuroblastoma development, several environmental exposures and lifestyle choices have been suggested as potential risk factors for this malignancy. Research has indicated that exposure to toxic chemicals such as pesticides and heavy metals (e.g., lead and mercury) during pregnancy may increase the risk of neuroblastoma in offspring (38). Additionally, exposure to harmful gases like nitrogen oxides and sulfur dioxide may also be associated with higher incidence rates of neuroblastoma, particularly in regions with significant air pollution (39).

Inequality analysis indicates that the burden of neuroblastoma is gradually increasing in low-SDI countries, reflecting the uneven distribution of healthcare resources. This phenomenon may stem from the lack of essential medical facilities and specialists in low-SDI countries, making it difficult for patients to receive timely diagnosis and treatment (42-44). Therefore, international health organizations and governments should enhance resource support and policy interventions in low-SDI regions, promoting equitable distribution of healthcare resources to reduce the disease burden in these areas.

Future projections indicate that while the ASIR and ASMR of neuroblastoma are expected to stabilize or decline globally, the number of cases will continue to rise due to population growth. To address this trend, governments and health organizations should continue to invest in early screening, the development of innovative treatment methods, and effective health education campaigns, especially in low-SDI regions with a heavy disease burden, to effectively manage the impending healthcare challenges.

Treatment for neuroblastoma typically involves a combination of surgery, chemotherapy, and radiotherapy. High-SDI countries have access to advanced multimodal treatment protocols, but these remain less accessible in low-middle and low-SDI countries. Drugs like cisplatin, cyclophosphamide, and etoposide are standard in treating neuroblastoma. Increasing access to affordable chemotherapy drugs and improving distribution channels would help ensure that children in these areas receive adequate treatment. Early and complete surgical resection remains a cornerstone of neuroblastoma treatment, particularly for localized cases. Improving access to surgical interventions by training more pediatric surgeons and providing necessary surgical equipment is crucial in low-middle and low-SDI countries. Additionally, international collaboration is essential for addressing these challenges. Increasing the number of trained oncologists, pediatricians, and surgeons who specialize in childhood cancers is crucial. International training programs, workshops, and partnerships can help build local expertise and improve the quality of care.

Drugs like anti-GD2 monoclonal antibody (dinutuximab) have shown promise in improving survival rates, particularly for high-risk neuroblastoma (18,19). Efforts should be made to reduce the cost of these therapies through international collaboration, drug subsidies, or the development of generic versions to make them accessible in low-middle and low-SDI countries.

This study primarily relies on data from GBD 2021, which may contain incomplete or inconsistent information, particularly in low-SDI regions, potentially leading to biased estimates. Additionally, the assumptions made in the GBD model could affect the accuracy of the predictions. Future research should incorporate micro-mechanism studies to further elucidate the specific causes of the increasing burden of neuroblastoma. Moreover, cross-national and cross-regional collaboration will facilitate the collection of more comprehensive disease data, enhancing the accuracy and applicability of global neuroblastoma burden research.

Conclusions

This study provides an in-depth exploration of the global and regional disease burden of neuroblastoma, offering important insights for further public health interventions. Although neuroblastoma is a relatively rare childhood malignancy, its impact on survival rates and quality of life is significant. We found that children in low-SDI regions are disproportionately affected by neuroblastoma, highlighting the need for policymakers to implement effective measures to improve the allocation and accessibility of medical resources, thereby reducing the disease burden in these areas. Future research should focus on deeper mechanistic investigations and international collaboration to better understand and address the burden of neuroblastoma.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-178/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-178/prf

Funding: This work was supported by the Capital’s Funds for Health Improvement (No. 2022-2-5083), the Youth Support Fund of Chinese PLA General Hospital (No. 22QNFC112), and the Construction Project for High-Level Clinical Specialties in Public Hospitals in Hohhot Capital Region (No. 2024-BFXM-02014).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-178/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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