Pancreatic Neuroendocrine Tumors in French VHL Mutation Carriers

Abstract

Context: Von Hippel-Lindau disease (VHL) is a rare, autosomal-dominant hereditary cancer-predisposition syndrome caused by germline pathogenic variants (PVs) in the VHL gene. It is associated with a high penetrance of benign and malignant vascular tumors in multiple organs, including pancreatic neuroendocrine tumors (PanNETs), whose long-term natural history is ill-known.

Objective: The aim of this study was to identify prognostic factors associated with VHL-related PanNETs, notably the role of genotype-phenotype correlations.

Methods: Patients with both documented germline PV in the VHL gene and PanNETs included in the French PREDIR database between 1995 and 2022 were included. The primary end point was the proportion of patients with PanNET-related metastases, and the secondary end point was overall survival (OS). Genotype/phenotype correlations were studied.

Results: We included 121 patients with 259 PanNETs. Median age at diagnosis was 38 years. Median follow-up was 89.5 months. PanNET surgical resection was performed in 51 patients. Overall, 29 patients (24%) had metastases (5 synchronous, 10 metachronous), with a higher risk in case of larger PanNET size (P = .0089; best threshold 28 mm) and grade 2 PanNET (P = .048), and a pejorative prognostic impact (P = .043). Patients with PV in VHL exon 1 had larger PanNETs (P = .018), more often metastatic disease (48% vs 11.5%; P < .001) and a trend toward shorter OS (P = .16).

Conclusion: The risk of metastases associated with VHL-related PanNETs remains low (24%) but increases with tumor size greater than 28 mm, higher grade, and in case of PV, located in VHL exon 1. These data might help improve the management of these patients, who should be referred to an expert center.

Keywords: VHL gene; hereditary neoplastic syndromes; pancreatic neuroendocrine tumors; von Hippel-Lindau disease.