Recurrence in Patients With Lymph Node-Negative Pancreatic Neuroendocrine Tumors

Importance Lymph node (LN) metastasis is a strong predictor of tumor recurrence following pancreatectomy for localized pancreatic neuroendocrine tumors (PanNETs). However, most patients lack LN metastasis and many tumors recur. Tools to guide risk-adapted surveillance in this group are lacking. Objective To develop and validate a tumor recurrence and survival risk score for patients with LN-negative PanNETs. Design, Setting, and Participants This retrospective, case-control study of patients with localized PanNETs took place at 5 high-volume US institutions from 2000 to 2023. Inclusion required 8 or more evaluated LNs and negative nodal status. Median follow-up was 50.6 months. These data were analyzed from March 2025 to May 2025. Exposure Surgical resection of localized PanNETs per clinical guidelines. Main Outcomes and Measures The primary outcome was tumor recurrence. Independent predictors were identified using multivariable logistic regression and used to construct a 13-point composite risk score. Performance was assessed using C statistics. Kaplan-Meier and log-rank methods evaluated disease-free survival (DFS). Genomic profiling was conducted in an external validation cohort to identify and validate recurrence-associated mutational risk scores. Results Of 2024 patients, 770 met inclusion criteria. Median age was 58.7 (IQR, 18.4) years; 405 were male (52.6%) and 365 were female (47.4%). Most tumors were sporadic (94.1%), nonfunctional (90.4%), and located in the body/neck (50.9%). Recurrence occurred in 82 patients (10.6%) at a median of 32.4 (IQR, 16.3-82.0) months after surgery. Independent predictors included male sex (odds ratio [OR], 2.2; 95% CI, 1.3-3.9), tumor size 3 cm or larger (OR, 2.64; 95% CI, 1.5-4.6), World Health Organization grade 2 or higher (OR, 3.70; 95% CI, 1.4-10.0), and lymphovascular invasion (OR, 3.84; 95% CI, 2.1-6.9). The risk score showed strong performance (area under the receiver operating characteristic, 0.83 internally; 0.95 externally). Recurrence rates by risk group were 2.4%, 9.0%, and 27.7% ( P < .001), and 10-year DFS rates of 96.1%, 83.6%, and 51.3%, for low-risk, moderate-risk, and high-risk groups, respectively ( P < .001). Genomic analyses revealed higher tumor mutational burden, somatic mutation count, and somatic mutations in CDC42BPB , DAXX , ERI2 , GALNT9 , MTOR , NUMA1 , and TRPC7 genes among recurrent tumors. Conclusions and Relevance Despite LN-negative status, a subset of patients with PanNETs remained at high risk for recurrence. This validated risk score stratifies recurrence and survival risk showing biological relevance. These findings provide a framework for refining postoperative surveillance and risk-adapted therapeutic strategies.