In the present study, we conduct a comprehensive analysis of survival rates in adrenal and non-adrenal pediatric neuroblastomas in the United States. Among the most important findings were the higher survival rates in non-adrenal NB, marked improvements in survival rates and hazard reduction for diagnoses made post-2000 and cases undergoing surgery.
The presented study found that non-adrenal neuroblastoma cases had significantly better survival rates compared to adrenal cases after adjusting of sex, race, year of diagnosis, and treatment modality. These findings are consistent with previous studies that have also reported better outcomes in non-adrenal neuroblastoma cases [5, 20]. The explanation for this disparity is that adrenal neuroblastoma is often associated with negative prognostic markers such as metastasis at diagnosis, presence of MYC-N amplification[20, 21], 1p loss, 11q loss, 17q gain, or DNA copy number alterations [21, 22]. Adrenal cases predominantly manifested at a distant stage (73.1%), in contrast to non-adrenal cases (34.7%). Adrenal cases were also more likely to present with undifferentiated grade. The significant divergence in tumor stage and grade suggests that adrenal neuroblastomas may inherently be more aggressive or have delayed clinical manifestations, leading to advanced-stage presentation, and necessitating more aggressive diagnostic and treatment methods [21]. It is worth noting that stage and grade analysis was limited due to the unavailability of related data in many cases.
Adrenal cases underwent radiotherapy and chemotherapy more frequently than non-adrenal cases (31.5% and 76.3% vs 19.7% and 58.5%, respectively, consistent with previously reported studies [23]. Chemotherapy and radiotherapy were associated with lower survival rates as these treatments are reserved for intermediate to high-risk neuroblastoma cases [24]. Conversely, surgical intervention showed the best survival outcomes, likely due to the fact that it is recommended as the frontline treatment in low-risk neuroblastoma [25].
Both adrenal and non-adrenal neuroblastoma cases exhibited an overall balanced sex distribution. Although adrenal neuroblastoma showed a slight predominance in males (55.7%). The analysis further shows that females have a higher mean survival time than males. When stratified by site, this difference was statistically significant in non-adrenal NB only. Overall, the influence of sex on neuroblastoma survival is not clear. While some studies have found that sex is not a significant prognostic factor [26], others reported that the association between sex and survival is mediated by the stage of disease [27]. In our study, males were more likely to present with adrenal NB, distant stage and undifferentiated grade than females, potentially explaining the survival difference. Further analysis of prognostic markers and genetic mutations between males and females is warranted.
Similarly, race was associated with survival in non-adrenal NB only. White patients may have higher survival compared to other races, although this difference was not significant on multivariate analysis. A previous study found that Black patients with neuroblastoma have a higher prevalence of high-risk disease than white patients[28]. Another study suggested that the poorer outcomes might be due to higher incidence of high-risk NB among black patients [29]. According to a recent study, no association between race and survival was concluded. Nevertheless, the survival rates of patients treated during 2000–2004 and 2005–2015 showed improvement compared to those treated prior to 2000 suggesting reduction of the racial disparity in survival rates [26]. Around the year 2000, there were significant changes in the understanding and management of neuroblastoma [14, 30]. Some of the major changes that occurred around this time includes the development of more intensive, multimodality approaches to treat patients who are classified as high risk [12]. The discovery of genetic alterations that drive tumor growth resulted in the development of targeted therapies that exploit these alterations [14]. Further prognostic refinement might be attributed to the development of the International Neuroblastoma Risk Group Staging System (INRGSS), which was first proposed in 2009 [11]. Multiple biologic and immunologic agents were developed over the recent years for treatment of NB. For example, dinutuximab and eflornithine were approved for high-risk NB by the FDA on March 2015 [31] and December 2023 [32], respectively. These multimodal approaches have significantly increased long-term survival, with recent studies reporting long-term survival up to 50% compared with 15% prior to their implementation[33–37].
While this study offers valuable insights, it is not without limitations. The database provides limited information on the status of radiotherapy and chemotherapy treatments, which consequently restricts the extent to which definitive conclusions can be drawn concerning these variables. Additionally, the SEER database lacks data on adjunctive therapies that may have been administered in conjunction with primary treatments, thereby potentially impacting the interpretation of treatment efficacy. The SEER database accounts for approximately 48% of cancer cases in the United States, which may limit the generalizability of our findings. Moreover, the absence of tumor grading and staging information for a significant proportion of cases limits the comprehensiveness of the study.
In summary, this study establishes the primary tumor site as a significant predictor of survival outcomes in pediatric neuroblastoma in the US. We provide a stratified analysis of risk factors associated with adrenal vs nonadrenal NB. Survival rates of patients with neuroblastoma continues to improve over the past years owing to improved diagnostic and treatment modalities.