Redefining therapeutic thresholds and global guidelines: Toward precision management of intermediate-sized rectal neuroendocrine tumors

Abstract

With the widespread adoption of colonoscopic screening, the detection rate of rectal neuroendocrine tumors (rNETs) has risen year by year. Treatment strategies for small (< 1 cm) and large (> 2 cm) lesions are relatively well established, but the optimal management pathway for intermediate-sized (1-2 cm) rNETs remains controversial. Inspired by the recent study by Kim et al, this editorial summarizes differences among international guidelines for managing intermediate-sized rNETs, the selection and latest advances in endoscopic techniques, and examines the feasibility and oncologic safety of endoscopic resection for intermediate-sized rNETs. We contend that future management should focus on the clinical application of molecular stratification, biomarkers, and dynamic risk modeling to enable individualized decision-making. Given global disparities in medical resources, a tiered care system based on risk stratification and resource availability should be established to ensure the safety, equity, and accessibility of rNETs treatment.

Key Words: Rectal neuroendocrine tumor; Endoscopic resection; Endoscopic mucosal resection; Endoscopic submucosal dissection; Guideline; Precision management; Risk stratification; Global accessibility

Core Tip: The management strategy for medium-sized rectal neuroendocrine tumors (rNETs) remains a subject of debate. Inspired by the latest research by Kim et al, this editorial summarizes the differences in international guidelines regarding management strategies, recent advances in endoscopic resection techniques, and their oncological safety. This editorial posits that, for medium-sized rNETs, endoscopic resection is emerging as a highly promising therapeutic option due to its minimally invasive nature, lower incidence of postoperative complications, and greater cost and time effectiveness.

INTRODUCTION

Rectal neuroendocrine tumors (rNETs) are detected in approximately 0.17% of colonoscopic screening examinations[1], accounting for 12%-27% of all neuroendocrine tumors (NETs) and about 20% of gastrointestinal NETs[2]. With the increasing use of endoscopic screening techniques and the expansion of cancer screening programs, the incidence of rNETs has shown a steady rise[3,4]. Owing to advances in endoscopic resection, surgical techniques, and systemic therapies, the overall survival of patients with rNETs has also improved[4]. Tumor size, depth of invasion, histological grade, mitotic index, and lymphovascular invasion (LVI) remain the key determinants of prognosis.

The therapeutic approach for localized rNETs should be determined according to tumor size and other risk factors associated with lymph node metastasis. Most international guidelines recommend standard endoscopic resection for tumors smaller than 1 cm that are confined to the mucosa or submucosa (T1 stage). For lesions larger than 2 cm, those staged as T2 or beyond, or those with confirmed lymph node metastasis, consensus across guidelines favors radical surgical resection comparable to that for rectal adenocarcinoma, including regional lymph node dissection. In patients with advanced rNETs characterized by distant metastases or unresectable disease, treatment strategies focus on systemic therapy and locoregional management of metastatic sites, as outlined in the American Society of Clinical Oncology guidelines[5] and the United Kingdom’s National Institute for Health and Care Excellence recommendations[6].

However, the optimal management of intermediate-sized (1-2 cm) rNETs remains controversial. Inspired by the recent retrospective study by Kim et al[7], published in World Journal of Gastroenterology, which demonstrated favorable outcomes of endoscopic treatment for these intermediate lesions, this editorial aims to summarize the current international differences in management strategies for intermediate-sized rNETs, review the selection and advancement of endoscopic techniques, and discuss the advantages, limitations, and future research directions of endoscopic therapy, as well as the disparities in accessibility across low and middle income countries and regions.

INTERNATIONAL VARIATIONS IN THE MANAGEMENT STRATEGIES FOR INTERMEDIATE-SIZED rNETS

rNETs represent a heterogeneous group of diseases, and a globally unified management strategy has not yet been established. While authoritative international guidelines demonstrate a consensus on core principles, such as risk stratification based on tumor size and the application of local excision for small, low-risk lesions, significant discrepancies exist in the specific details of execution. These differences are particularly prominent in the management of intermediate-sized tumors.

The primary point of divergence in management strategies concerns intermediate-sized tumors, defined as those 1-2 cm in diameter. The Japanese Neuroendocrine Tumor Society guidelines[8] advocate for the most aggressive approach, strongly recommending direct radical surgery with lymph node dissection, citing the high risk of lymph node metastasis (18.5%-30.4%) associated with tumors of this size.

In contrast, the European Neuroendocrine Tumor Society guidelines[9] emphasize individualized decision-making. They recommend a comprehensive imaging evaluation for such lesions, followed by a discussion within a multidisciplinary team. The final decision between a more extensive endoscopic resection or surgical intervention is based on risk factors such as muscularis propria invasion, LVI, and a G2/G3 grade.

North American guidelines offer an intermediate pathway. The Canadian Neuroendocrine Tumor Society consensus[10] recommends an individualized risk assessment for tumors in this size range. Local excision may be considered for patients without risk factors, but radical surgery is favored if any risk factors are present. The United States National Comprehensive Cancer Network guidelines[11] recommend initial local excision, followed by a mandatory one-year period of close surveillance, including both endoscopic and imaging follow-up.

The Chinese Society of Clinical Oncology consensus[12] recommends transanal local excision for T1, G1/G2 tumors of this size, an approach with an intervention level between that of endoscopic therapy and radical surgery. To more clearly illustrate the core differences among the various guidelines, the management recommendations for 1-2 cm rNETs are summarized in the Table 1.

Table 1 Comparison of international guideline strategies for the management of 1-2 cm rectal neuroendocrine tumors.

Guideline	Primary recommendation for 1-2 cm rectal neuroendocrine tumors	Key considerations
Japan (JNETS)	Radical surgical resection + lymph node dissection	The most aggressive strategy. Considers the risk of metastasis in this size range to be sufficiently high to warrant a radical approach
Europe (ENETS)	Individualized decision-making (endoscopy or surgery) after multidisciplinary team discussion	Offers the highest degree of flexibility; decisions are heavily dependent on risk factors (lymphovascular invasion, muscularis invasion, grade)
Canada (Canadian Neuroendocrine Tumor Society)	Individualized assessment; local excision considered if no risk factors, radical surgery if risk factors are present	Employs a risk-stratified approach positioned between ENETS and JNETS, emphasizing shared decision-making with the patient
North America (National Comprehensive Cancer Network)	Local excision followed by 1 year of close surveillance	Accepts local excision as the initial treatment but mandates subsequent imaging and endoscopic follow-up
China (Chinese Society of Clinical Oncology)	Local excision (transanal)	Favors a more thorough local excision than endoscopic methods; recommends radical surgery directly for higher stages

ENETS: European Neuroendocrine Tumor Society; JNETS: Japanese Neuroendocrine Tumor Society.

SELECTION AND ADVANCEMENTS OF ENDOSCOPIC RESECTION TECHNIQUES FOR rNETS

Selection of endoscopic techniques

The success of the study by Kim et al[7] hinged on the selection of endoscopic techniques based on accurate preoperative assessment. According to Kim et al[7] study, all patients underwent colonoscopy prior to intervention, with endoscopic ultrasound used to evaluate the depth of tumor invasion before resection, and computed tomography (CT) scanning employed to identify distant organ or lymph node metastasis. For rNETs measuring 1-2 cm, when the tumor was deemed localized and the patient was unwilling to undergo surgery, experienced endoscopists selected the most appropriate resection method based on various modified techniques of standard endoscopic mucosal resection (EMR), such as pre-cut EMR, band ligation EMR, or endoscopic submucosal dissection (ESD). Therefore, we advocate a risk-based strategy, emphasizing that experienced endoscopists should select the most suitable endoscopic resection method for each patient based on rigorous preoperative assessments and the various modified techniques derived from standard EMR.

Ultimately, the selection of an appropriate endoscopic technique is a multifactorial decision[13-15]. This therapeutic decision should be individualized, based on a comprehensive evaluation of tumor size, histological characteristics, institutional resources, endoscopist expertise, as well as patient comorbidities and preferences. Furthermore, continued surveillance and long-term follow-up after endoscopic resection are necessary to better assess the oncological safety and long-term outcomes for patients with intermediate-sized rNETs treated endoscopically.

Advancements in endoscopic technology

With advancements in endoscopic technology, a spectrum of modified and advanced techniques has been developed, each presenting a unique profile of therapeutic efficacy, safety, and technical feasibility[14,15]. For instance, modified EMR techniques, such as cap-assisted EMR and EMR with ligation (ESMR-L), have demonstrated enhanced en-bloc resection capabilities for tumors up to 15 mm, with R0 rates frequently exceeding 90% and favorable safety profiles[15,16].

While being technically more demanding and associated with higher risks of bleeding and perforation, ESD remains a cornerstone for larger lesions (approaching 20 mm) or those with suspected submucosal fibrosis[13,17]. Its versatility allows for precise dissection and high R0 resection rates. A meta-analysis comparing outcomes for rNETs smaller than 16 mm substantiated the superiority of both ESMR-L and ESD over conventional EMR in achieving complete resection[18]. The analysis reported R0 rates of 94.5% for ESMR-L and 92.3% for ESD, compared to 72.3% for conventional EMR, highlighting ESMR-L's excellent balance of efficacy and safety[18]. Further comparisons from systematic reviews and network meta-analyses continue to refine the relative merits of these different endoscopic approaches[19].

Innovations in technique are ongoing. Notably, a recent multicenter, randomized controlled trial investigating traction-assisted ESD (TA-ESD) demonstrated a significant reduction in procedure time (median 7.3 minutes vs 12.2 minutes, P = 0.0054) and achieved a 100% R0 resection rate, comparable to conventional ESD, without any instances of perforation or postoperative complications[20]. The use of a floss-assisted traction mechanism in TA-ESD was shown to improve visualization of the submucosal plane, thereby facilitating a safer and more efficient dissection[20]. These findings suggest TA-ESD may represent a promising and practical alternative to conventional ESD, particularly for challenging lesions or in centers with requisite expertise.

Advantages and limitations of endoscopic techniques

For medium-sized rNETs, endoscopic resection is emerging as a highly promising treatment option due to its minimally invasive nature, fewer postoperative complications, and cost and time effectiveness; the findings of Kim et al[7] support this view. However, several limitations exist. The single-center, retrospective design of the study limits the generalizability of the findings and the control of confounding factors that could influence the results. The small sample size reduces statistical power and may be insufficient to detect subtle yet clinically significant differences. Furthermore, there is a lack of long-term prospective validation to assess the long-term prognosis of patients with medium-sized rNETs. Given the slow-growing biological nature of these tumors, the current evidence is insufficient to completely rule out the risk of long-term recurrence. Prospective multicenter studies with larger sample sizes are needed to evaluate the long-term efficacy of this approach, thereby providing an evidentiary basis for refining treatment guidelines.

FUTURE PERSPECTIVES

Looking forward, the management of rNETs is entering a phase of refinement that emphasizes precision over generalization. One critical direction involves molecular stratification, where biomarkers such as Ki-67 index, chromogranin A, synaptophysin, and caudal-related homeobox transcription factor 2 contribute to more accurate prognostic assessment[21,22]. In addition, emerging molecular targets including delta-like ligand 3 expression, O6-methylguanine-DNA methyl-transferase methylation, and somatostatin receptor subtypes may inform therapeutic responsiveness and guide the selection of systemic or targeted therapies[23,24].

Alongside molecular advances, the therapeutic landscape is expanding to include novel modalities. Peptide receptor radionuclide therapy (PRRT) using ¹⁷⁷Lu-DOTATATE, previously reserved for metastatic disease, is now being explored in high-risk localized tumors and as a potential adjuvant strategy following incomplete resection[25]. Furthermore, agents such as everolimus and immune checkpoint inhibitors are under investigation for their role in selected cases with atypical histology or treatment resistance, offering new possibilities for individualized care[26].

To support this evolving paradigm, dynamic risk modeling is gaining importance. Traditional criteria based solely on tumor size and depth of invasion may fail to capture the full spectrum of recurrence risk. By integrating molecular features, imaging characteristics, and longitudinal surveillance data, clinicians can develop adaptive algorithms that personalize follow-up intensity and reduce unnecessary interventions[27-29].

Taken together, these developments signal a transition toward mechanism-informed, patient-centered management of rNETs. Continued research and international collaboration will be essential to translate these innovations into standardized practice and improve long-term outcomes across diverse clinical settings.

However, any shift toward endoscopic management for medium-sized rNETs must consider the disparities in access to experienced endoscopists, endoscopic techniques like ESD, and advanced treatments such as PRRT in low-income and middle-income countries and regions. We therefore propose the establishment of a tiered management system based on risk stratification and resource availability. For small, low-risk rNETs in primary or resource-limited settings, EMR and its modified techniques, which are simpler to perform and have a shorter learning curve, should be prioritized to improve treatment accessibility and safety. For medium-sized rNETs or those with a risk of deep invasion, clear referral criteria should be established to centralize their management at regional medical centers equipped with ESD capabilities and multidisciplinary support. This will ensure complete resection and reduce the risk of complications. Notably, precise staging evaluations, including colonoscopy, endoscopic ultrasound, and CT scans, should be routinely performed before treatment to scientifically identify patients suitable for endoscopic therapy, thereby preventing tumor residue or recurrence due to improper technique selection. Concurrently, the global imbalance in healthcare resources must be fully considered. In high-resource areas, advanced treatments such as ESD and PRRT can be further promoted. In low-income and middle-income countries and regions, gradual improvements in technological accessibility and quality can be achieved by strengthening physician training, establishing regional centers, and enhancing referral networks. Overall, a tiered management model guided by risk and grounded in resource availability has the potential to enhance the precision, safety, and equity of rNET treatment on a global scale.

CONCLUSION

For moderately sized rNETs, endoscopic resection is a feasible and oncologically safe treatment option when performed after rigorous preoperative assessment by experienced endoscopists, offering clear advantages of minimal invasiveness, safety, and cost effectiveness. However, current evidence is still primarily derived from retrospective single-center studies and lacks prospective validation with large samples and long-term follow-up. Future multicenter collaborative studies should further define the optimal management pathway for moderately sized rNETs and promote the integration of molecular stratification, biomarkers, and dynamic risk models into clinical decision-making. At the same time, attention must be paid to global disparities in healthcare resources by establishing a tiered care system based on risk stratification and resource matching to achieve safe, accessible, and equitable worldwide management of rNETs.