Endoscopic ultrasound-guided ablation of small pancreatic neuroendocrine neoplasms: Bridging the gap between surveillance and surgery

Table 1 Comparison of endoscopic ultrasound-guided ablative techniques for small pancreatic neuroendocrine neoplasms

Parameter	EUS-guided ethanol injection	EUS-RFA	Emerging EUS-guided techniques
Mechanism of action	Chemical coagulative necrosis through protein denaturation and vascular thrombosis	Thermal coagulative necrosis induced by high-frequency alternating current	Hybrid cryothermal or laser-induced thermal ablation
Technical complexity	Low	Moderate to high	High; experimental
Equipment	Standard 22-gauge or 25-gauge EUS needle	Dedicated needle-based or catheter-based RFA system and generator	Dedicated probes or optical fibers with limited availability
Technical success	Approximately 90%-100%	Approximately 95%-100%	Insufficient panNEN-specific data
Complete radiological response	Approximately 50%-70%; may increase with repeat treatment	Approximately 80%-90%	Unknown
Clinical success in functioning tumors	High, particularly in insulinomas	Very high, generally > 90% in insulinomas	Unknown
Number of sessions	Frequently more than one	Usually, one or two	Not standardized
Main adverse events	Pancreatitis, abdominal pain, ethanol leakage, pancreatic tissue injury	Pancreatitis, abdominal pain, pancreatic duct injury or stenosis	Safety profile not established in panNENs
Main procedural risk factor	Excessive or extratumoral ethanol diffusion	Close proximity to the MPD, particularly ≤ 1 mm	Not defined
Control of ablation volume	Limited and diffusion-dependent	More predictable and energy-controlled	Potentially precise, but not clinically validated
Most established clinical setting	Small insulinomas and selected small NF-panNENs	Small, well-differentiated insulinomas and selected NF-panNENs	Investigational
Main limitation	Unpredictable ethanol distribution and frequent need for repeat treatment	Requirement for dedicated equipment, expertise, and careful ductal assessment	Lack of dedicated clinical evidence in panNENs

EUS: Endoscopic ultrasound; panNENs: Pancreatic neuroendocrine neoplasms; NF-panNENs: Non-functioning pancreatic neuroendocrine neoplasms; EUS-RFA: Endoscopic ultrasound-guided radiofrequency ablation; MPD: Main pancreatic duct.

Table 2 Proposed criteria for patient selection for endoscopic ultrasound-guided ablative treatment in small pancreatic neuroendocrine neoplasms

Parameter	More favorable candidate	Borderline candidate (case-by-case)	Generally unsuitable candidate
Tumor size	≤ 15 mm	15-20 mm	> 20 mm
Differentiation	Well-differentiated NET	Well-differentiated NET	Poorly differentiated NEC
Tumor grade	G1, Ki-67 < 3%	Selected low-G2 tumor (Ki-67 ≤ 5%), after multidisciplinary review	G3 or clearly high-proliferative G2 tumor
Functionality	Insulinoma	Other functioning tumors are considered only for symptom control in exceptional circumstances	Functioning tumor with multifocal, nodal, or metastatic disease
Nodal or distant disease	Absent	Indeterminate findings requiring further staging	Present
Behavior during surveillance	No clear evidence of aggressive behavior	Limited interval growth requiring repeat staging and reassessment	Rapid growth or other evidence of progression
Tumor margins and local invasion	Well-defined, confined lesion	Uncertain local relationships	Vascular invasion, perineural invasion, or infiltrative margins
EUS accessibility	Safe and straightforward access	Technically feasible but challenging	Unsafe or impossible access
Relationship with MPD	Clear separation from the duct	Close proximity requiring increased caution	Direct contact, duct involvement, or inability to preserve a safe margin
Pancreatic duct dilation	Absent	Equivocal or unrelated dilation requiring clarification	Dilation attributable to tumor obstruction
NF-panNENs	Active treatment considered appropriate despite disproportionate surgical morbidity	Uncertain balance between surveillance, ablation, and surgery	Stable low-risk lesion appropriately managed by surveillance
Surgical risk	High surgical risk or relevant comorbidities	Intermediate risk	Fit patient with a clear surgical indication
Patient preference	Declines surgery after informed counseling	Preference uncertain or evolving	Prefers surgery or does not accept structured follow-up
Treatment setting	Expert tertiary center with multidisciplinary NET expertise	Expert center after extended multidisciplinary discussion	Center without advanced EUS and pancreatic support
Post-treatment surveillance	Accepts structured long-term follow-up	Potential concerns regarding adherence	Unable or unwilling to undergo surveillance

This framework reflects the authors’ interpretation of the available evidence and should not be regarded as a validated guideline. Eligibility should be determined within an experienced multidisciplinary team. EUS: Endoscopic ultrasound; NF-panNENs: Non-functioning pancreatic neuroendocrine neoplasms; NET: Neuroendocrine tumour; NEC: Neuroendocrine carcinoma; MPD: Main pancreatic duct.

Table 3 Comparison of active surveillance, endoscopic ultrasound-guided ablation, and surgery for small pancreatic neuroendocrine neoplasms

Parameter	Active surveillance	EUS-guided ablation	Surgery
Main clinical role	Observation of low-risk lesions	Minimally invasive local treatment in selected patients	Definitive treatment when oncological resection is indicated
Most appropriate setting	Small, asymptomatic, NF, well-differentiated, stable panNENs	Small insulinomas and selected localized low-grade NF-panNENs	Tumors with higher-risk biological or anatomical features
Pathological confirmation	Based on biopsy when performed	Pretreatment biopsy required; no resection specimen	Complete surgical specimen available
Assessment of margins	Not applicable	Not available	Available
Lymph-node assessment	Not available	Not available	Available when lymphadenectomy is performed
Oncological certainty	Limited during observation	Limited; imaging response does not prove eradication	Highest among the three strategies
Procedure-related morbidity	None	Generally lower than surgery, but pancreatitis, pain, and ductal injury may occur	Substantial, depending on procedure type and location
Hospital stay	None	Usually short	Usually longer
Pancreatic preservation	Complete	Usually preserved	Variable; risk of endocrine and exocrine insufficiency
Local residual or recurrent disease	Tumor remains untreated and monitored	Possible; repeat ablation may be required	Lower after complete resection, although recurrence remains possible
Need for repeat intervention	Possible if growth or progression occurs	Relatively common after incomplete response or recurrence	Usually not required for local control after complete resection
Main advantage	Avoids overtreatment and procedural morbidity	Pancreas-preserving local treatment with lower short-term burden	Definitive pathology and oncological resection
Main limitation	Persistent uncertainty and need for long-term follow-up	No nodal staging or confirmation of complete microscopic eradication	Operative morbidity and potential long-term pancreatic dysfunction
Evidence base	Supported by prospective observational data in selected NF-panNENs	Mainly retrospective series, small prospective cohorts, and limited comparative data	Established standard for tumors requiring active definitive treatment

EUS: Endoscopic ultrasound; NF-panNENs: Non-functioning pancreatic neuroendocrine neoplasms; NF: Non-functioning; panNENs: Pancreatic neuroendocrine neoplasms.

Table 4 Main clinical studies of endoscopic ultrasound-guided ablation in pancreatic neuroendocrine neoplasms

Ref.	Design	Population	Technique	Main efficacy and safety outcomes	Follow-up	Main limitations
Park et al[70], 2015	Retrospective, single center	11 patients; 14 panNENs < 20 mm; 10 NF-panNENs, 4 insulinomas; 2 MEN1; mean size 12.3 mm	EUS-EA; 18 sessions	Technical success 100%; complete radiological response 53.8% after one session and 61.5% after retreatment; symptom resolution in 2/2 insulinomas; pancreatitis in 3 patients and 1 duct stricture	Median 370 days	Small uncontrolled cohort; mixed tumors; variable ethanol dose and sessions; imaging-based response; short follow-up
Choi et al[71], 2018	Prospective, single center	33 patients; 40 panNENs < 20 mm; 39 NF-panNENs, 1 insulinoma; median size 11 mm; 3 hereditary cases	EUS ethanol-lipiodol ablation; 63 sessions	Technical success 100%; complete ablation 60%; pancreatitis in 2/63 sessions; radiological-pathological concordance 86% in 22 reassessed tumors	Median 42 months	No control group; single expert operator; repeat FNB available in only 22/40 tumors; 3 radiological complete responses reclassified as incomplete
Barthet et al[84], 2021	Prospective, multicenter, non-randomized	12 patients; 14 G1 NF-panNENs < 20 mm; mean size 13.1 mm; 1 MEN1	EUS-RFA	Complete disappearance/necrosis 85.7% at 1 year and final follow-up; 1 late recurrence, 1 delayed response, and 1 persistent failure followed by liver metastases after initial undergrading	Mean 45.6 months	Very small panNEN subgroup; mixed study cohort; no control group; protocol evolved during the study; response mainly imaging based
Marx et al[35], 2022	Retrospective, two centers	27 patients with sporadic G1 NF-panNENs; mean size 14.0 mm, range 7-25	EUS-RFA	Technical success 100%; complete radiological response 85.2% after one session and 92.6% overall; pancreatitis 14.8%; 3 grade IIIb complications; surgical specimen in 1 patient showed 3-mm residual tumor	Mean 15.7 months	Small selected cohort; no comparator; short and heterogeneous follow-up; imaging-based response; clinically relevant AE rate
Napoléon et al[75], 2023	National, multicenter, retrospective	100 patients; 104 pancreatic neoplasms, including 64 panNENs and 16 functioning tumors; median overall size 15 mm	EUS-RFA; 116 sessions	Technical success 97%; overall complete response 60.2%; panNEN histology and size < 20 mm predicted complete response; 22 AEs; MPD distance ≤ 1 mm independently predicted AEs	Imaging planned at 1 month, 6 months, and 12 months	Heterogeneous tumor types; panNEN-specific outcomes incompletely separated; variable protocols across 20 centers; non-standardized longer-term follow-up
Yan et al[99], 2023	Prospective, single center	9 high-risk or surgery-refusing patients with symptomatic insulinomas; 5 previously operated; 1 multifocal case	EUS-EA; 14 procedures	Initial clinical response 77.8%; relapse in 55.6%; 4 patients remained relapse-free long term; repeat-ablation response 40%; pancreatitis in 1/14 procedures	Median 994 days	Very small cohort; no control group; highly selected patients; heterogeneous tumor burden; clinical rather than oncological endpoint
Crinò et al[36], 2023	International, multicenter, retrospective propensity-matched study	178 patients with sporadic insulinomas: 89 EUS-RFA and 89 surgery; mean size 13.5 mm	EUS-RFA vs surgery	AEs 18.0% vs 61.8%; severe AEs 0% vs 15.7%; clinical efficacy 95.5% vs 100%; shorter hospital stay after RFA; recurrence after RFA 16.9%	Median 23 vs 37 months	Non-randomized design; residual confounding possible; shorter follow-up after RFA; clinical rather than histological efficacy endpoint
Matsumoto et al[72], 2025	Prospective, multicenter, single arm with historical surgical comparison	25 patients with G1 NF-panNENs ≤ 15 mm; median size 10.1 mm; MPD distance ≤ 2 mm excluded	Standardized EUS-EA with early reassessment and retreatment	Complete ablation 88% at 1 month and 6 months; 32% required early retreatment; severe AEs 4%; pancreatitis 20%; new or worsening diabetes 12%; no conversion to surgery	6 months	Small single-arm cohort; historical control; very short follow-up; imaging-based endpoint; highly selected tumors
Okasha et al[100], 2025	Prospective, multicenter cohort	27 patients: RFA group included 11 insulinomas and 2 PDACs; EA group included 13 insulinomas and 1 NF-panNEN	EUS-RFA or EUS-EA	RFA: Complete insulinoma response 10/11 and partial response 1/11, with no reported AEs. EA: Complete response 8/14, partial response 2/14, failure 4/14; pancreatitis in 4/14	Mean 12.0 months for RFA and 9.6 months for EA	Small heterogeneous cohort; non-comparative groups; unclear grading; clinical endpoints; short follow-up; internal reporting inconsistencies

AEs: Adverse events; EA: Ethanol ablation; EUS: Endoscopic ultrasound; MEN1: Multiple endocrine neoplasia type 1; MPD: Main pancreatic duct; NF-panNENs: Non-functioning pancreatic neuroendocrine neoplasms; panNENs: Pancreatic neuroendocrine neoplasms; PDACs: Pancreatic ductal adenocarcinomas; RFA: Radiofrequency ablation; EUS-RFA: Endoscopic ultrasound-guided radiofrequency ablation; EUS-EA: Endoscopic ultrasound-guided ethanol ablation; FNB: Fine-needle biopsy.