Endoscopic ultrasonography ablation for small pancreatic neuroendocrine tumors

Introduction

The optimal management of small pancreatic neuroendocrine tumors (pNETs) remains one of the most debated questions in contemporary pancreatic oncology. pNETs are uncommon neoplasms accounting for approximately 1–2% of pancreatic malignancies, yet their incidence has increased substantially over the past two decades, largely due to the widespread use of high-resolution cross-sectional imaging and endoscopic ultrasonography (EUS) (1-3). This trend has led to a growing number of incidentally detected small pNETs (<2 cm), many of which are asymptomatic at diagnosis. Management of these lesions remains controversial, balancing the risks of surgical morbidity against the possibility of underestimating malignant potential. In this setting, EUS-guided ablative therapies have emerged as a minimally invasive alternative to surgery that may provide local tumor control while preserving pancreatic function. Among these techniques, EUS-guided ethanol injection (EUS-EI) induces coagulative necrosis through intratumoral ethanol delivery and has shown promising results in early clinical studies. In a recent prospective multicenter study, Matsumoto et al. demonstrated high rates of complete radiographic ablation with a favorable safety profile for EUS-EI in patients with small, grade 1 pancreatic neuroendocrine neoplasms ≤15 mm, highlighting the potential role of endoscopic ablation in the management of carefully selected tumors (4).

Guidelines for management of pNETs ≤2 cm

Historically, surgical resection was considered the standard of care for localized pNETs, based on early series demonstrating metastatic potential even among small tumors. However, pancreatic surgery is associated with significant morbidity, including pancreatic fistula, delayed gastric emptying, and long-term endocrine and exocrine insufficiency, even when performed at high-volume centers (5). As natural history data accumulated, it became evident that many small, well-differentiated pNETs follow an indolent course, prompting a shift toward more selective, biology-driven management strategies. Current management recommendations are informed by major guideline bodies, including the National Comprehensive Cancer Network (NCCN), the European Neuroendocrine Tumor Society (ENETS), and the North American Neuroendocrine Tumor Society (NANETS).

Across guidelines, active surveillance is considered an acceptable approach for asymptomatic, nonfunctional, well-differentiated grade 1 pNETs <2 cm in the absence of radiographic evidence of nodal or distant metastasis. Surgical resection is generally recommended for functional tumors regardless of size and for nonfunctional tumors demonstrating higher grade, interval growth, or adverse imaging features such as pancreatic ductal dilation or vascular involvement. While ENETS guidelines most strongly favor observation in low-risk tumors, NCCN and NANETS endorse a more individualized, risk-adapted approach that incorporates patient age, comorbidities, surgical risk, and patient preference. Despite nuanced differences, all guideline frameworks acknowledge a substantial therapeutic gray zone for small pNETs, particularly in younger patients with long life expectancy who may otherwise face decades of surveillance or the morbidity of pancreatic resection. Figure 1 summarizes surveillance, endoscopic ablation, and surgery as competing strategies within this therapeutic continuum.

Figure 1 Overview of management strategies for small pNETs ≤2 cm, highlighting surveillance, endoscopic ablation, and surgical resection with their respective advantages, limitations, and roles within the therapeutic continuum. pNET, pancreatic neuroendocrine tumor.

Natural history of pNETs ≤2 cm

Natural history studies demonstrate that although most pNETs ≤2 cm exhibit indolent behavior, a clinically meaningful minority display invasive or metastatic potential. Population-based analyses from the National Cancer Database report lymph node metastases in approximately 6–10% of patients with small nonfunctional pNETs, with higher rates observed in tumors measuring 1.1–2.0 cm compared with those ≤1.0 cm (6). SEER-based analyses similarly demonstrate that up to 24% of pNETs ≤2 cm exhibit invasive disease, including lymph node metastasis, regional organ invasion, or distant metastasis, underscoring the limitations of tumor size alone as a risk stratification tool (7). Tumor grade further refines prognosis, with surgical cohorts demonstrating that approximately 80–85% of small pNETs are grade 1, 14–18% grade 2, and fewer than 2% grade 3, with increasing grade associated with higher rates of nodal metastasis (8). Prospective surveillance studies such as the PANDORA trial show that many small nonfunctional pNETs demonstrate minimal short-term growth, supporting the safety of initial observation in carefully selected patients (9). Similarly, findings from the ASPEN prospective cohort suggest that active surveillance can be a safe initial management strategy for small, low-grade nonfunctional pNETs, although a subset of tumors ultimately demonstrate progression requiring delayed intervention (10). Importantly, PANDORA and ASPEN differ in study design and progression criteria, but both show that a subset of carefully observed small nonfunctional pNETs ultimately progresses or requires delayed intervention, supporting selective rather than reflexive use of preemptive ablation (9,10).

Novel ablation techniques for pNETs ≤2 cm

EUS-guided ablative therapies are increasingly being explored as an intermediate treatment strategy for small pNETs, particularly in patients who fall between the extremes of long-term surveillance and surgical resection. Although many pNETs ≤2 cm exhibit indolent behavior, several natural history studies have demonstrated that a subset of these tumors can develop nodal or metastatic disease, providing a rationale for considering local therapy in selected patients (11). Early endoscopic treatment approaches focused on EUS-EI, which induces tumor necrosis through cellular dehydration and vascular thrombosis following direct intratumoral alcohol injection (12). EUS-guided ethanol ablation was first reported in 2006 and gained early interest due to its relative technical simplicity and low cost compared with surgical or device-based therapies (13). However, concerns regarding chemical diffusion beyond the tumor margin and subsequent pancreatitis have limited widespread adoption. More broadly, EUS-guided ablation has been evaluated across pancreatic lesions, including solid tumors, cystic lesions, and pNETs, although the strongest rationale for routine clinical adoption remains in highly selected, small, well-differentiated pNETs treated at experienced centers (14,15).

In the recent prospective multicenter study by Matsumoto and colleagues, EUS-EI for small, well-differentiated pancreatic neuroendocrine neoplasms demonstrated complete ablation in 88% of patients with low rates of severe adverse events, supporting the feasibility of chemical ablation as a minimally invasive alternative to surgery in carefully selected patients (4). In that cohort, procedure-related pancreatitis occurred in approximately 20% of patients, although most cases were mild and only one severe adverse event was reported, suggesting that ethanol ablation can be performed safely when careful injection volumes and technique are used (4). These findings are consistent with earlier ethanol-ablation series, which demonstrated meaningful tumor regression but reported pancreatitis rates of approximately 12.5% in early case series, likely related to uncontrolled ethanol diffusion into surrounding pancreatic parenchyma (16). However, Matsumoto’s findings should be interpreted in light of several limitations: the study included only 25 patients, used a single-arm uncontrolled design, had a maximum follow-up of 6 months, and enrolled a highly selected population with grade 1 tumors ≤15 mm without nodal involvement. These constraints limit assessment of recurrence prevention and generalizability, which Matsumoto et al. also acknowledged in the published study protocol (17).

In parallel with chemical ablation strategies, thermal ablation techniques, most notably EUS-guided radiofrequency ablation (EUS-RFA), have emerged as an alternative method for local tumor destruction. RFA induces coagulative necrosis through delivery of high-frequency alternating current, allowing for a more controlled ablation zone compared with injectate-based approaches (18). Multicenter series evaluating EUS-RFA for nonfunctional pNETs have demonstrated technical success approaching 100% and overall response rates exceeding 90%, suggesting that thermal ablation may be an effective treatment modality for small lesions (19,20). Recent prospective multicenter data and updated meta-analytic evidence further support EUS-RFA as a feasible treatment option for selected patients with pNETs, demonstrating high technical success, favorable overall response, and acceptable adverse event rates (21-24).

Comparative evidence between ablation and surgery remains limited but is beginning to emerge. In a propensity score-matched study of pancreatic insulinoma, Crino et al. reported comparable clinical efficacy between EUS-RFA and surgery, with fewer adverse events and shorter hospitalization after EUS-RFA, although recurrence was more frequent and often managed with repeat ablation (25). A multicenter randomized trial, ERASIN-RCT, is now underway to compare EUS-RFA with surgical resection for pancreatic insulinoma and will help define whether ablation can be incorporated into first-line or step-up treatment strategies (26).

When comparing EUS-RFA and EUS-guided ethanol ablation, the adverse-effect profiles appear to differ mechanistically rather than dramatically in magnitude. Ethanol ablation is primarily associated with chemical pancreatitis resulting from extralesional alcohol diffusion, whereas thermal ablation carries risks related to heat-mediated tissue injury, including pancreatitis, bleeding, pancreatic necrosis, and infection (27). Overall adverse event rates reported in pooled analyses are broadly comparable between modalities, generally ranging from 10–20%, although most events are mild and self-limited (28). For EUS-RFA specifically, favorable response is most likely in carefully selected patients with smaller, solitary functional tumors that have a measurable hormonal endpoint, adequate distance from the main pancreatic duct, and complete ablation coverage, whereas larger tumor size, multifocal disease, ductal proximity, underlying genetic tumor syndromes, and higher grade or Ki-67 may increase the risk of incomplete response or recurrence (21,22,28,29).

An additional technical consideration raised by Matsumoto et al. is the potential role of contrast-enhanced EUS (CE-EUS) in guiding ablation therapy. CE-EUS can help identify residual vascularized tumor following treatment and may improve the accuracy of post-ablation assessment, particularly when conventional B-mode imaging is inconclusive (4). Furthermore, emerging experience with endoscopic ablation suggests that treatment response may evolve gradually over time, with some lesions demonstrating delayed radiographic regression or eventual complete response following an initially partial response. This observation raises the possibility that early post-treatment imaging may underestimate ultimate therapeutic efficacy and highlights the importance of careful longitudinal surveillance following ablative therapy.

Taken together, these data suggest that EUS-guided ablation, whether chemical or thermal, may ultimately occupy an important role within the management spectrum of small pNETs, particularly for patients who fall within the therapeutic gray zone between surveillance and surgical resection. While the prospective results reported by Matsumoto et al. provide compelling evidence supporting ethanol-based ablation, continued advances in thermal technologies, imaging guidance, and procedural standardization will be essential to define the optimal role of endoscopic therapies for these tumors. Ultimately, future management of small pNETs may increasingly rely on a biology-driven approach in which minimally invasive ablative techniques complement both surveillance and surgical strategies, offering individualized treatment options tailored to patient risk and tumor behavior.

Conclusions

Contemporary guideline recommendations and natural history data highlight the heterogeneous biology of pNETs ≤2 cm and the limitations of a binary surveillance-vs.-surgery paradigm. EUS-guided ablative therapies, including ethanol injection and radiofrequency ablation, may offer a minimally invasive option for carefully selected patients who fall within this therapeutic gray zone. However, broader adoption will require clearer patient-selection criteria, standardized procedural techniques, and longer-term oncologic follow-up to determine durability of response and recurrence risk. Ongoing comparative studies, including randomized evaluation of EUS-RFA vs. surgery for insulinoma, will be important in defining whether endoscopic ablation should remain a niche alternative for select patients or become an integrated component of routine management for small pNETs.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Gastrointestinal Oncology. The article has undergone external peer review.

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0289/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0289/coif). The authors have no conflicts of interest to declare.

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