Clinical presentation, genotype-phenotype correlations, and outcome of pancreatic neuroendocrine tumors in Von Hippel-Lindau syndrome

Endocrine. 2021 Oct;74(1):180-187. doi: 10.1007/s12020-021-02752-8. Epub 2021 May 25.


Purpose: Data regarding the clinical management and follow-up of pancreatic neuroendocrine tumors (PanNETs) associated with Von Hippel-Lindau (VHL) syndrome are limited. This study aimed to assess clinical presentation, genotype-phenotype correlations, treatment and prognosis of PanNETs in a series of VHL syndrome patients.

Methods: Retrospective analysis of data of patients observed between 2005 and 2020.

Results: Seventeen patients, including 12 probands and 5 relatives (mean age 30.8 ± 18.4; 7 males), were recruited. PanNETs were found in 13/17 patients (77.5%) at a median age of 37 years: 4/13 (30.7%) at the time of VHL diagnosis and 9 (69.3%) during follow up. Six (46.1%) PanNET patients underwent surgery, whereas seven were conservatively treated (mean tumor diameter: 40 ± 10.9 vs. 15 ± 5.3 mm respectively). Four patients (30.7%) had lymph node metastases and a mean tumor diameter significantly larger than the nonmetastatic PanNETs (44.2 ± 9.3 vs. 17.4 ± 7 mm, p = 0.00049, respectively). Five (83.3%) operated patients had stable disease after a median follow up of 3 years whereas one patient showed liver metastases. Six (85.7%) non-resected PanNETs were stable after a median follow-up of 2 years, whereas one patient developed a new small PanNET and a slight increase in diameter of a pre-existing PanNET. No correlation was found between the type of germline mutation and malignant behavior of PanNETs.

Conclusions: PanNETs are a common disease of the VHL syndrome and can be the presenting feature. Tumor size rather than genetic mutation is a prognostic factor of malignancy.

Keywords: Clinical presentation; Genotype–phenotype correlations; Pancreatic neuroendocrine tumors; Von Hippel–Lindau syndrome.

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Genetic Association Studies
  • Humans
  • Male
  • Middle Aged
  • Neuroendocrine Tumors* / genetics
  • Pancreatic Neoplasms* / genetics
  • Retrospective Studies
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics
  • Young Adult
  • von Hippel-Lindau Disease* / complications
  • von Hippel-Lindau Disease* / genetics


  • Von Hippel-Lindau Tumor Suppressor Protein