Unraveling the landscape of pediatric pancreatic tumors: Insights from Japan

Abstract

Pediatric pancreatic tumors, though rare, pose significant diagnostic and management challenges. The recent, 22-year nationwide survey on pediatric pancreatic tumors in Japan by Makita et al offers valuable insights into this uncommon entity, revealing striking geographical variations and questioning current treatment paradigms. This editorial commentary analyzes the study's key findings, including the predominance of solid pseudopapillary neoplasms and their younger age of onset, which contrast sharply with Western data. It explores the implications for clinical practice and research, emphasizing the need for population-specific approaches to diagnosis and treatment. The revealed limited institutional experience and surgical management patterns prompt a reevaluation of optimal care delivery for these complex cases, suggesting benefits of centralizing healthcare services. Furthermore, the commentary advocates for international collaborative studies to elucidate the genetic, environmental, and lifestyle factors influencing the development and progression of pediatric pancreatic tumors across diverse populations. It also outlines future directions, calling for advancements in precision medicine and innovative care delivery models to improve global patient outcomes. Unraveling Makita et al's findings within the broader landscape of pediatric oncology can stimulate further research and clinical advancements in managing pancreatic and other rare tumors in children.

Key Words: Child; Epidemiology; Japan; Pancreatic endocrine tumors; Pancreatic neoplasms; Pancreatoblastoma; Pediatric oncology; Solid pseudopapillary neoplasm; Surgical management; Survey

Core Tip: This editorial analyzes a 22-year nationwide survey on pediatric pancreatic tumors in Japan. The predominance of solid pseudopapillary neoplasms and their younger age of onset contrast sharply with Western data, highlighting the need for population-specific approaches. Centralizing healthcare services could address the limited experience with these rare tumors observed at many institutions. The commentary also advocates for precision medicine, innovative care delivery models, and international collaborative studies on genetic and environmental factors across diverse populations. These insights could significantly improve the diagnosis, treatment, and management of pediatric pancreatic and other rare neoplasms globally, stimulating further research and clinical advancements.

INTRODUCTION

Pediatric pancreatic tumors represent rare but formidable adversaries in childhood oncology. These neoplasms, accounting for less than 0.1% of all pediatric cancers, include a diverse spectrum of histological types, each with its own prognostic implications[1-4]. Despite their rarity, most pancreatic tumors present significant diagnostic and therapeutic challenges, frequently resulting in suboptimal outcomes[5,6]. The complex nature of these tumors, coupled with the vital physiological functions of the pancreas, demands a nuanced approach to treatment: One that carefully balances aggressive intervention with organ preservation, particularly in growing children.

In this issue of the World Journal of Gastrointestinal Oncology, Makita et al[7] present a nationwide survey on pediatric pancreatic tumors in Japan, offering a fresh perspective on this uncommon entity. By meticulously documenting 213 cases over a 22-year period, the authors have provided a comprehensive view of the epidemiological landscape, management strategies, and patient outcomes in a large Asian pediatric cohort. The results include a wide range of tumor types, from solid pseudopapillary neoplasms to endocrine tumors and pancreatoblastomas, providing valuable insights into their relative frequencies, clinical presentations, and treatment approaches. The authors also shed light on the surgical experiences across different institutions, highlighting the challenges in managing these rare tumors. This extensive survey not only contributes significantly to our understanding of pediatric pancreatic tumors in Japan but also provides an important point of comparison with data from other countries, revealing important geographical and ethnic variations in disease patterns.

INSIGHTS AND IMPLICATIONS

The striking predominance of solid pseudopapillary neoplasms in the Japanese pediatric population, accounting for 77% of all cases[7], stands as one of the most significant study findings. This figure sharply contrasts with Western data, where solid pseudopapillary neoplasms typically represent only 30%-32% of pediatric pancreatic tumors[1,2]. Such a marked disparity challenges our current understanding of the relevant epidemiology and raises critical questions about underlying causative factors. Genetic predisposition emerges as a potential explanation for this phenomenon. The CTNNB1 gene mutation, affecting β-catenin and considered a hallmark of solid pseudopapillary neoplasms of the pancreas[8,9], may have a higher prevalence or penetrance in the Japanese population. This hypothesis opens new avenues for research into population-specific genetic markers for pancreatic tumor risk. It underscores the need for large-scale genomic studies across diverse populations to illuminate the complex interplay between genetics and tumor development. Environmental factors also warrant investigation. Could distinctive aspects of the Japanese lifestyle, such as dietary habits rich in soy products[10], influence the risk profile for specific pancreatic tumor types? The potential impact of other environmental exposures unique to Japan remains an area ripe for exploration.

To provide insights into the relative frequency of different tumor types, the findings from Japan can be contextualized by comparing them with data from other regions. In the United States, the Surveillance, Epidemiology, and End Results database[1] reveals a more balanced distribution of tumor types, with neuroendocrine tumors (33.8%) and solid pseudopapillary neoplasms (32.3%) occurring at almost equal rates. Additionally, a National Cancer Database study[2] in the United States reported a higher frequency of pancreatoblastoma (15.6%) compared to Japan (7.5%). European data also demonstrate variations. For instance, the Italian Tumori Rari in Età Pediatrica project documented an intermediate prevalence of solid pseudopapillary tumors (12 of 21 cases) over a 10-year period, while pancreatoblastomas were relatively more common (4 of 21 cases) than in Japan[11]. Interestingly, a single-institution study from China, conducted over 15 years, found that 5 out of 11 adolescents with pancreatic tumors treated with resection were diagnosed with solid pseudopapillary neoplasms, a finding that aligns more closely with the Japanese data[12]. In this study, the same number of patients were found to have neuroendocrine tumors, while one patient was diagnosed with pancreatic ductal adenocarcinoma. These comparisons highlight the geographical variations in pediatric pancreatic tumor distribution and show the importance of region-specific epidemiological understanding.

The high relative frequency of solid pseudopapillary neoplasms in Japanese children carries significant implications also for clinical practice. It suggests that clinicians in Japan should maintain a high level of suspicion for this histological type when evaluating pediatric pancreatic tumors. Conversely, clinicians in Western countries, such as the United States and United Kingdom, should remain vigilant for other tumor types that are equally or more prevalent in their populations, including endocrine tumors and pancreatoblastoma[1,2]. This geographical variation in tumor type distribution highlights the need for region-specific clinical approaches to diagnosis and management. From a research standpoint, this difference underscores the importance of international studies to elucidate the global landscape of pediatric pancreatic tumors. Such collaborative efforts could pave the way for the development of population-specific risk assessment tools, potentially improving early detection and patient outcomes across different ethnic groups.

Another key finding in the study by Makita et al[7] is the relatively young age at onset for solid pseudopapillary neoplasms in the Japanese cohort. The median presentation age of approximately 12 years is significantly lower than that reported in Western and Taiwanese data[1,2,13,14], revealing variations even within Asian populations. This earlier presentation has important implications for early detection strategies and challenges current screening practices for high-risk groups. Moreover, this gap in age of onset suggests that a uniform strategy for managing pediatric pancreatic tumors may be insufficient. This finding also prompts questions about potential modifiable risk factors contributing to earlier onset in certain populations. Tailored, population-based approaches should be employed to enhance prevention, early detection, and overall outcomes.

The surgical management patterns revealed in the study by Makita et al[7] highlight a significant challenge in pediatric oncology. Nearly 52% of the surveyed institutions across Japan had no experience with pancreatic tumor surgery in children over the study period. This striking statistic mirrors trends in the United States, where even the largest children's hospitals report an average of only 1-2 patients with pancreatic neoplasms per year[15,16]. This paucity of cases presents a serious obstacle to developing and maintaining surgical expertise, supporting the argument for centralization of care for these rare and complex cases. Centralization could concentrate expertise, thereby improving outcomes through higher case volumes and standardized care protocols[17,18]. Nevertheless, this approach raises questions about maintaining a distributed knowledge base within the broader pediatric surgical community, crucial for initial recognition and appropriate referral of these rare cases. Consequently, it may lead to delayed diagnosis and treatment, especially in geographically diverse countries like Japan[18,19]. Balancing the concentration of expertise with accessibility of care represents a key challenge in optimizing the management of rare pediatric cancers, such as pancreatic tumors.

Building on the challenges of surgical management, the study by Makita et al[7] further reveals that adult gastrointestinal surgeons were involved in roughly 40% of pediatric pancreatic tumor cases. This pattern highlights the need for cross-specialty expertise and prompts a reevaluation of training requirements for these complex procedures. While the current collaborative model between pediatric and adult specialists has yielded favorable outcomes, as evidenced by the reported survival rates, there remains scope for improvement. Developing specialized training programs for pediatric pancreatic surgery could strengthen the expertise of pediatric surgeons in this rare but critical field. However, the rarity of these tumors poses challenges in maintaining proficiency. A more pragmatic approach may involve establishing centers of excellence where pediatric surgeons can gain focused experience in pancreatic procedures while leveraging the expertise of adult gastrointestinal surgeons. This hybrid model could synergize pediatric-specific knowledge of child physiology and care with the technical proficiency of high-volume pancreatic surgeons. This integrated approach aligns with the concept of centralization discussed earlier, offering a potential solution to balance the concentration of expertise with the need for comprehensive pediatric care. By fostering collaboration between pediatric and adult specialists, such centers could address both the surgical complexity of these rare tumors and the unique needs of pediatric patients.

While the study by Makita et al[7] offers valuable insights, it is important to acknowledge and analyze its limitations. The retrospective, questionnaire-based design introduces several potential biases. Recall bias may affect the accuracy of data, particularly for cases from the earlier years of the 22-year study period. Additionally, there is a risk of selection bias favoring high-volume centers, potentially skewing the data towards more complex cases. The extended study period also raises concerns about the consistency of diagnostic criteria across different centers and over time, which may impact the comparability of cases.

Another limitation of the study is the exclusion of non-surgically treated cases. This approach may underestimate the true incidence of pancreatic tumors, particularly advanced or unresectable cases, leading to an incomplete picture of the full spectrum of pediatric pancreatic tumors in Japan. The study's focus on surgical cases omits valuable information about tumors managed non-operatively, potentially biasing the overall understanding of disease presentation and management.

The limited institutional experience highlighted in the study is also noteworthy. With 75 of 145 responding facilities reporting no experience with pediatric pancreatic tumor surgery over the 22-year period, and only 4 facilities managing more than 10 cases, the rarity of these tumors and the challenge in building expertise become apparent. This disparity in experience may influence the generalizability of the findings and highlights the need for centralized expertise in managing these rare cases.

Another limitation is the potential underrepresentation of certain patient groups. The survey was administered only to pediatric surgical units, potentially missing cases treated solely by adult gastrointestinal surgeons. This may particularly affect the representation of solid pseudopapillary neoplasms in older teenagers, whose care might be managed by adult surgeons due to their physical maturity. Consequently, the study might not capture the full spectrum of pediatric pancreatic tumors, especially in the adolescent population.

The lack of standardized data collection across institutions poses another challenge. This may result in inconsistencies in reporting and limit the ability to perform more granular analyses of factors such as specific surgical techniques or detailed pathological findings. The variability in data reporting could impact the reliability and comparability of the results across different centers.

To address these limitations and improve future studies, several strategies can be implemented. Establishing a prospective, multi-institutional registry with standardized data collection protocols would ensure consistency across centers and reduce recall bias. Such a registry should include all cases of pediatric pancreatic tumors, regardless of treatment approach, and incorporate regular quality checks and data audits to maintain accuracy.

Expanding data collection to include detailed pathological and molecular profiling of tumors, long-term follow-up data, and quality of life measures would provide a more comprehensive understanding of disease progression and treatment outcomes. Collaboration with adult gastrointestinal surgery departments is necessary to ensure comprehensive coverage of all pediatric cases, including those treated by adult surgeons.

Utilization of national databases, such as the National Clinical Database in Japan, would allow for more comprehensive case capture and validation of questionnaire-based data. This integration would provide a more accurate representation of the incidence and management of pediatric pancreatic tumors across all healthcare settings. Furthermore, establishing an international collaborative network would facilitate standardized data collection across different countries, enabling more robust international comparisons. Such collaboration could also pool resources for centralized pathology review and molecular analysis, ensuring consistency in diagnosis and classification across diverse populations.

FUTURE DIRECTIONS

The study by Makita et al[7] catalyzes broader discussions regarding rare pediatric neoplasms, such as pancreatic tumors. Their findings highlight the importance of understanding genetic, environmental, and lifestyle factors influencing these rare tumors across diverse populations. By pooling global data and resources, we can construct a more comprehensive picture of pediatric pancreatic tumors, aligning with the growing emphasis on precision medicine in oncology. Advanced genomic and proteomic profiling could reveal early detection biomarkers and novel therapeutic targets, paving the way for personalized treatment strategies that can improve outcomes while minimizing toxicity in young patients. The marked differences in tumor type distribution between Japanese and Western populations underscore the significance of geographic and ethnic variations in disease patterns, echoing recent calls for more diverse representation in cancer genomics studies[20]. As precision medicine advances, understanding these population-specific differences becomes crucial for developing targeted therapies and personalized treatment approaches, potentially revolutionizing pediatric oncology.

The insights from Makita et al[7] extend beyond scientific understanding. The study's revelation of limited institutional experience with rare pediatric pancreatic tumors highlights the importance of democratizing access to expertise. Virtual tumor boards and telemedicine networks could ensure that every child, regardless of location, benefits from the collective knowledge of the pediatric oncology community[21,22]. Coupled with standardized treatment protocols and quality metrics specific to pediatric pancreatic tumors, this approach could bridge the gap between high-volume centers and community hospitals, enhancing care quality and consistency across diverse healthcare settings.

As we look to the future, the work of Makita et al[7] serves as both a valuable resource and a call to action. It challenges us to think globally while acting locally. By embracing a holistic approach that combines collaborative research, precision medicine, and innovative care delivery, we can work towards a future where every child with a pancreatic tumor has access to optimal, evidence-based care. While the path forward may be challenging, the potential to transform outcomes for these young patients makes it a journey worth undertaking. As we advance, it is essential to maintain focus on the individual child at the center of our efforts, ensuring that our scientific and clinical progress translates into tangible benefits for patients and their families.

CONCLUSION

The nationwide survey by Makita et al[7] provides crucial insights into pediatric pancreatic tumors in Japan, highlighting important trends and challenges in their management. The predominance of solid pseudopapillary neoplasms in the Japanese cohort and the varying surgical experiences across institutions emphasize the need for further research and international collaboration. This study should serve as a steppingstone for more comprehensive, prospective investigations to validate and expand upon these findings. By integrating the lessons learned from this survey with ongoing advances in molecular diagnostics and precision medicine, we can work towards improving outcomes for children with rare tumors worldwide. The pediatric oncology community must continue to foster global collaboration and knowledge sharing to address the unique challenges posed by rare but impactful neoplasms.