Real-World Epidemiological Analysis of Gastrointestinal Neuroendocrine Carcinomas: A TriNetX-Based Study

Introduction

The landscape of gastrointestinal neuroendocrine carcinomas (GI-NECs) has undergone significant transformations in recent decades, marked by evolving epidemiological patterns and refined classification systems. Emerging epidemiological data has enhanced our understanding of these complex neoplasms, revealing notable geographic incidence variations. In Norway, GI-NECs have exhibited a remarkable 200% increase from 1993 to 2021, particularly those originating from the gastrointestinal tract [¹]. Similarly, England has suffered from growth, with age-standardized incidence of neuroendocrine neoplasms (NENs) reaching 9 per 100,000 in 2016 [²]. This trend contrasts with data from Switzerland, where despite a steady increase in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) incidence (1.7% annually in men and 1.3% in women), GEP-NEC rates remained relatively stable from 1976 to 2016 [³]. The complexity of these neoplasms is further illustrated by their diverse biological behavior and histopathological characteristics. The World Health Organization’s refined classification system has been instrumental in delineating crucial distinctions between well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs) [⁴]. This classification emphasizes the critical role of proliferation indices and differentiation status, where NETs span grades G1 through G3 based on mitotic counts and Ki-67 indices, while NECs consistently manifest as high-grade (G3) neoplasms [⁵]. The introduction of high-grade well-differentiated tumors (NET G3) as a distinct entity has particularly revolutionized our approach to diagnosis and treatment strategies [⁶].

Our study aims to address several gaps in the current understanding of GI-NECs. While previous studies have documented increasing incidence rates across different geographical regions, real-world data on site-specific survival patterns and TNM staging distributions remain scarce. Existing studies have primarily focused on single-institution experiences or specific anatomical sites, lacking the breadth needed to establish comparative outcomes across different GI locations. Furthermore, while the prognostic implications of tumor grade and differentiation are well-established, the relationship between anatomical location and survival outcomes remains inadequately characterized. By analyzing a large, multi-institutional cohort through TriNetX, our study provides significant insights into site-specific staging patterns, subsite variations in survival, and the prognostic implications of anatomical location. Our paper aims to analyze real-world epidemiological data using the TriNetX platform. We aim to bridge critical knowledge gaps in understanding the contemporary landscape of GI-NECs. This investigation is particularly pertinent given the reported poor prognosis of metastatic cases [⁷] and the imperative need for precise classification to guide treatment decisions [⁸].

Methods

Results

Our analysis encompassed 4,515 patients, who confirmed all bodies from various sites across different anatomical sites. The demographic profile revealed a relatively balanced gender distribution (47.27% male, 47.35% female) with a mean age of 71 ± 14 years (18-90 years). The cohort was predominantly comprised of White patients (52.71%), followed by Black or African American (12.56%) and Asian (1%) populations, with 33.73% categorized as Other/Unknown race. Among those with documented ethnicity, 55.13% were identified as Not Hispanic or Latino, while 3.81% were Hispanic or Latino.

Comparative Insights Across Sites:

A comprehensive analysis revealed that the proportion of advanced-stage (T3/T4) disease was highest in the small intestine and pancreas, with lower stages more common in stomach NECs. Lymph node involvement (N1) was most frequent in small intestine NECs (39%), with markedly lower rates in liver and biliary tract cases.

Discussion

Our analysis of GI-NECs using the TriNetX database uncovers valuable insights into epidemiological trends, staging distributions, and survival outcomes across various anatomical sites. The balanced gender distribution and predominant occurrence in older adults (mean age: 71 ± 14 years) align with previous epidemiological studies. However, our cohort demonstrated a slightly higher mean age compared to the median age of 65 years reported in the Norwegian registry data from 1993 to 2010 [¹⁰]. The racial distribution in our study, with a predominance of White patients (52.71%), reflects similar patterns observed in other large-scale epidemiological studies. However, our cohort demonstrated a higher proportion of Black or African American patients (12.56%) compared to previous reports.

This variation might reflect advancements in diagnostic capabilities for small intestinal NECs, as highlighted by Koffas et al. (2023), or real geographical differences in disease distribution [¹¹]. Our finding of a substantial proportion of cases with unknown primary sites (n=692) underscores the diagnostic challenges emphasized by Koffas et al. (2023), further reinforcing the need for enhanced diagnostic strategies, such as PET/CT imaging and circulating tumor cell analysis [¹¹]. The TNM staging descriptive data revealed important patterns that impact clinical management. The high proportion of TX classification (23%) across all sites in our study underscores persistent challenges in primary tumor assessment, particularly in anatomically challenging locations. These findings align with Merola et al. (2020), who highlighted the complexities of achieving accurate histopathological diagnoses in GEP-NENs, particularly in non-specialist settings [¹²]. Similarly, the higher proportion of T3 tumors in small intestinal NECs (21%) compared to other sites suggests a potential delay in diagnosis, likely due to the anatomical location and nonspecific presenting symptoms, as noted by Lee et al. (2019), who emphasized the advanced presentation of small intestinal NECs due to diagnostic difficulties [¹³].

Survival outcomes in our study demonstrated marked variations across anatomical sites, with small intestinal NECs showing the most favorable five-year survival rate (37.5%). This finding contrasts with earlier studies, such as Alese et al. (2019), which reported poor survival outcomes for high-grade GI NECs overall, emphasizing the aggressive nature of these tumors [¹⁴]. The particularly poor prognosis observed in hepatic and biliary NECs (11.4% five-year survival) is consistent with the aggressive nature of high-grade NECs described by Venizelos et al. (2021), who highlighted their molecular complexity and limited treatment options [¹⁵]. The variation in survival rates between different subsites within the same organ system (e.g., appendiceal NECs at 44.8% versus cecal NECs at 26.4%) highlights the prognostic influence of anatomical location. While our findings may relate to differences in lymphatic drainage patterns and detection timing, site-specific molecular heterogeneity, as discussed by Venizelos et al. (2021), could also play a role [¹⁵].

Our observation of higher nodal involvement in small intestinal NECs (39% N1 disease) emphasizes the aggressive nature of these tumors. While Burkart et al. (2018) primarily explored molecular targets like BRAF mutations, their findings highlight the metastatic potential of gastrointestinal NECs, which may correlate with lymphotropic behavior [¹⁶]. The presence of metastatic disease in 27% of all cases at diagnosis underscores the aggressive nature of GI-NECs and aligns with observations by Chen et al. (2021) regarding late-stage presentation [¹⁷]. The particularly poor outcomes in hepatic and biliary NECs (8.9% five-year survival for intrahepatic lesions) reflect the challenges in managing these anatomically complex tumors. Mestre-Alagarda et al. (2023) highlighted the molecular heterogeneity and poor prognosis associated with aggressive NETs and NECs, which likely contribute to the difficulties in treatment [¹⁸]. The significant variation in survival outcomes between different anatomical subsites highlights the importance of site-specific approaches to management. For instance, the relatively better outcomes in appendiceal NECs (44.8% five-year survival) than other colorectal sites suggest potential biological differences warrant further investigation. The gradual deterioration in survival rates from proximal to distal pancreatic NECs (tail 17.1% vs. head 13.8%) may reflect differences in presentation timing and surgical accessibility.

Our study has several important limitations that warrant consideration. First, the predominant representation of U.S. healthcare organizations in the TriNetX database may introduce geographic and demographic biases. While our cohort showed diversity in racial distribution (52.71% White, 12.56% Black or African American), these proportions may not accurately reflect global population demographics, potentially limiting generalizability to other geographic regions, particularly Asia and South America, where GI-NEC epidemiology may differ substantially. Second, our analysis is subject to several potential biases inherent to retrospective database studies. Coding inaccuracies and misclassification errors may exist, particularly in distinguishing between well-differentiated NETs and poorly differentiated NECs, as this distinction often requires detailed histopathological review. The high proportion of unknown primary sites (n=692) and TX classification (23%) might reflect both genuine diagnostic challenges and documentation limitations within the database. Third, our study’s temporal scope may not fully capture recent advances in diagnostic techniques and therapeutic approaches. The rapid evolution of molecular profiling and targeted therapies in NECs means that some patients in our cohort may have received different standard-of-care treatments depending on their diagnosis date. Advanced molecular techniques, such as the use of liquid biopsies to complement solid tumor analyses, as suggested by Knappskog et al. (2023), could improve the identification of targetable mutations and enhance biomarker assessment, particularly in patients with limited tumor tissue availability [¹⁹].

The applicability of our findings across different healthcare settings requires careful consideration. While our results demonstrate clear anatomical site-specific survival patterns, these outcomes may vary in healthcare systems with different diagnostic capabilities and treatment accessibility. For instance, the superior survival rates observed in small intestinal NECs (37.5%) may reflect earlier detection in well-resourced healthcare settings, and these outcomes might not be reproducible in regions with limited access to advanced imaging or surgical expertise. The demographic characteristics of our cohort, particularly the mean age of 71 years and racial distribution should be considered when applying these findings to different populations. Healthcare systems serving younger populations or different ethnic compositions may observe varying patterns of disease presentation and outcomes. Additionally, the treatment patterns and survival outcomes observed in our U.S.-predominant cohort may not directly translate to healthcare systems with different organizational structures or resource availability.

Despite these limitations, our study’s large sample size and detailed anatomical analysis provide valuable insights for clinical practice. The observed survival differences between subsites within organs (e.g., appendiceal versus cecal NECs) remain relevant across different healthcare settings, as they likely reflect underlying biological differences rather than treatment variations. Furthermore, our findings regarding the poor prognosis of hepatic and biliary NECs (11.4% survival) highlight a universal need for improved therapeutic strategies for these anatomical locations, regardless of geographic setting.

Conclusions

Our large-scale analysis of GI-NECs through the TriNetX database reveals critical patterns that significantly impact patient care and outcomes. The marked variations in survival rates across anatomical sites, ranging from 44.8% in appendiceal NECs to 8.9% in intrahepatic lesions, emphasize the necessity for site-specific treatment approaches rather than a one-size-fits-all strategy. The high proportion of advanced-stage disease at diagnosis, particularly in small intestinal NECs, with 39% showing N1 disease, underscores the urgent need for improved early detection methods. The high number of cases with unknown primary sites (n=692) and high TX classification rates (23%) highlights a critical gap in current diagnostic capabilities. This finding suggests the potential value of implementing standardized diagnostic algorithms incorporating advanced imaging techniques and molecular profiling. Furthermore, the notably poor outcomes in hepatic and biliary NECs (11.4% five-year survival) identify a specific patient subgroup requiring innovative therapeutic strategies. Our findings directly impact clinical practice, supporting the development of anatomical site-specific treatment protocols and suggesting the need for more aggressive surveillance in high-risk anatomical locations. The significant survival differences between subsites within the same organ system, such as the variance between appendiceal and cecal NECs, indicate that tumor location should be a key consideration in prognostication and treatment planning. Our epidemiological results raise an important concern in targeted therapies according to anatomical regions and biomolecular profiles, particularly in investigating the biological basis for site-specific outcome variations and developing targeted therapeutic approaches. Integrating these findings with emerging molecular and genetic data could further refine our understanding of GI-NECs and lead to more effective, personalized treatment strategies.