Surgical and Endoscopic Resection of Duodenal Neuroendocrine Tumors Have Similar Disease-Specific Survival Outcome

Data were extracted from SEER using SEER*Stat 8.4.0.1 and International Classification of Diseases for Oncology, Third Edition (ICD-O-3) codes. Inclusion criteria were “8240/3: Carcinoid tumor, NOS” histology type, and “C17.0-Duodenum” primary site. Exclusion criteria consisted of patients with tumor types “neuroendocrine carcinoma” and “atypical carcinoid tumor,” unavailable survival information, patients with no intervention and tumor only found on autopsy, unknown tumor size, and unknown metastasis. We decided to only include patients with dNETs listed on SEER from 2010 to 2015 to allow for data maturity and meaningful survival analysis. Demographic and tumor-related data were collected for each patient including age, tumor primary site, histologic type, grade, stage, tumor size, number of nodes surgically resected, number of nodes positive for cancer, method of tumor removal including endoscopic or surgical resection, disease-specific survival (DSS) in months, and vital status. The SEER database surgery codes were used based on the American College of Surgeons Commission on Cancer’s Facility Oncology Registry Data System, with supplementary annotations from the SEER Program Coding and Staging Manual.⁸ Patients not undergoing any procedures were excluded, and surgery codes were categorized as endoscopic resection or surgical resection. Furthermore, the status of lymph node resection was also considered when assessing the resection approach. Based on the AJCC TNM staging, N0 was defined as dNETs with no positive nodes detected, N1 as tumor with any nodal involvement, and Nx patients who had endoscopic tumor resection without node removal.⁹ In addition, M0 was defined as tumor with no metastasis, and M1 as tumor with distant metastasis.⁹

This study is exempt from IRB approval.

Four hundred and sixty-five patients with dNETs listed on SEER from 2010 to 2015 were identified. The median (IQR) patient follow-up was 5.5 (4.3–7.5) years. The average age of the cohort was 61.9 years. Tumor sizes ranged from 0.1 to 10.5 cm. A total of 124 (26.7%) of the patients underwent surgical tumor resection, and the remaining patients had endoscopic tumor resection. Compared to the endoscopic group, the surgery cohort had a higher percentage of tumors sized between 2 to 3 cm (p < 0.001) and tumors larger than 3 cm (p < 0.001), while the endoscopic cohort had a higher percentage of tumors smaller than 0.5 cm (p < 0.001) and between 0.5 to 1 cm (p = 0.015). Among the surgery group, 60 (48.4%) had positive lymph nodes. Ninety-nine (79.8%) of the surgical cohort had histologically low-grade tumors, and 117 (94.4%) had no metastasis at the time of resection (Table 1).

Among the patients who underwent surgical tumor resection, tumor size groups—(0–0.5), (0.5–1), (1–2), (2–3), (> 3)—were found to have similar DSS (Fig. 1). In the surgical group, the percentage of node positivity was not associated with size (Fig. 2).

On univariate analysis, age, histologically advanced tumor grade, and nodal involvement were not associated with DSS in patients who underwent surgery. At all size ranges of dNETs, patients had comparable survival after surgical resection regardless of nodal status, tumor grade, or tumor size (Table 2). The hazard ratio for tumor size groups—(0–0.5), (0.5–1), (1–2), (2–3), and (> 3)—and DSS was not statistically significant. In addition, tumor grades 1, 2, and 3, as well as nodal involvement, and distant metastasis did not have a significant hazard ratio with DSS.

Subsequently, to assess the predictive value of clinically significant variables in determining survival after surgical tumor resection, a Cox multivariable regression model was constructed. In this model, age, tumor grade or level of differentiation, tumor size, and node positivity did not predict DSS after surgery (Table 3).

At each size range, KM curves were made to compare survival for N1, N0, and Nx. At various size groups—(0–0.5), (0.5–1), (1–2), (2–3), and (> 3)—DSS was similar between N1, N0, and Nx, indicating comparable survival outcomes between surgical and endoscopic tumor resection in this cohort (Fig. 3A–E). When assessing all tumor sizes combined, patients who underwent surgical tumor resection had a mean DSS of 67.3 months and median (IQR; interquartile) of 55.0 (19.0–111.0), which was lower than patients undergoing endoscopic resection with a mean DSS of 71.1 months and median of 69.0 (55.0–88.0). While the mean DSS difference was statistically significant (p = 0.017), the 3.8 months survival advantage was not clinically significant (Fig. 3F).

Tumor size, grade, and stage, as well as LN positivity, are often utilized to determine disease severity, prognosis, and management plan. Previously, Untch et al. demonstrated that in dNETs, tumor size is associated with recurrence-free survival.⁴ In nonfunctional pancreatic NETs, tumors less or equal to 2 cm with histologic grades of I or II have a low probability of aggressive behavior.¹⁰ Kim et al. demonstrated that in small intestinal NETs, a higher LN positivity ratio was associated with worse NET cancer-specific survival.¹¹

NCCN and ENETS make some recommendations regarding the management of dNETs; however, the role of novel endoscopic approaches in various dNET sizes is still a controversial topic.^6,7 There is emerging evidence that endoscopic resection of dNETs is as effective in improving patient survival as surgical resection methods.^4,12‐14 In 2021, Tran et al. examined dNETs of different sizes in their cohort (n = 104) and found that after adjusting for age, the method of resection had no significant association with survival.¹² Similarly, Untch et al. (n = 75) and Margonis et al. (n = 146) suggested that patients undergoing local surgical resection of dNETs had similar survival rates to patients with endoscopic resection.^4,13 Our findings from a large US national database (n = 465) corroborated these recent studies demonstrating that patients undergoing both endoscopic and surgical resection had comparable DSS.

Factors associated with lymph node metastasis in dNETs are a topic of debate. ENETS guidelines recommend surgical resection of dNETs larger than 2 cm, in the presence of nodal involvement. Some studies suggest that the size of neuroendocrine tumors may not reliably predict nodal metastasis.¹⁵ Furthermore, the role of nodal metastasis on survival has also been a controversial topic.^16‐18 While some older studies suggest a role for nodal metastasis on survival of NETs, recently there has been conflicting evidence that suggests otherwise.16–18 The result of our study is in congruence with the recent data as it elucidated that nodal involvement did not predict worse DSS.

Some factors that could be considered regarding lymph node resection include tumor type. Resection of tumor-draining lymph nodes is controversial, particularly in superficial tumors, as extensive lymph node dissection can lead to significant morbidity.¹⁹ In dNETs, the removal of regional mesenteric lymph nodes has been associated with higher DSS. It is possible that patients would be under-staged if too few lymph nodes are resected, but removing a larger number of lymph nodes may allow for the identification of lymph node metastases that are not clinically detectable.¹⁹ A study investigated the association of lymph node metastasis on overall survival of dNET patients (n = 7613), and their results showed that there was no significant difference in survival between N0 and N1, and even diminished survival for patients who underwent radical lymph node resection compared to local resection.²⁰

This study had several limitations that warrant consideration. The distribution of the sample size was such that it limited the granular analysis of tumors larger than 3 cm. However, since in general dNETs tend to be small, then this limitation may have low clinical implications. We collected the patient data from SEER, and due to the limited information on this database, we were unable to account for the effect of other factors on survival such as patient comorbidities, readmissions, and further complications that may have partially explained the differences in survival between endoscopic and surgical cohorts. An important limitation is the lack of comparative analysis between endoscopic and surgical resection in terms of complications, such as the increased risk of perforation associated with larger sizes after endoscopic treatment; therefore, further studies are required to explore this aspect. In addition, the survival difference for surgical resection in larger tumor sizes may have been influenced by selection bias for healthier individuals to undergo endoscopy. Furthermore, an important limitation in the analysis of the endoscopic cohort is their unknown nodal status. Another limitation is the lack of data on SEER regarding the endoscopic cases that required later surgical resection as the database only provides information about the primary procedure. Despite these limitations, this study is clinically important as it investigates the validity of NCCN and ENETS guidelines, which are widely used in clinical practice.

In our study, we found that endoscopic resection of dNETs has a comparable survival outcome to surgical resection at all tumor sizes. This is in contrast to NCCN and ENETS guidelines which do not recommend endoscopic resection for larger tumors. In addition, our results showed that nodal involvement does not significantly impact survival of dNETs of various sizes after surgical resection. Due to the rarity of dNETs, and the relative novelty of endoscopic approaches, there is limited data regarding this topic; however, proper selection of management may have a significant impact on patient care and quality of life. There is robust evidence in the literature that show a higher probability for complications following surgery compared to less invasive endoscopic methods.^21,22 Because of this, it is pertinent to consider endoscopic resection as a primary approach for dNETs irrespective of tumor size or node positivity, when possible. Further studies need to investigate the validity of current guidelines for dNETs. Additionally, since both endoscopic and surgical resection have similar survival outcomes when correcting for confounders, another important consideration for future studies is direct cost-effectiveness and resources allocation analyses in endoscopic tumor resection compared to a surgical approach.