Association of VHL Genotype With Pancreatic Neuroendocrine Tumor Phenotype in Patients With von Hippel–Lindau Disease

Von Hippel–Lindau (VHL) disease is a familial cancer syndrome caused by a germline mutation in the VHL tumor suppressor gene (OMIM 193300).¹ The prevalence of pancreatic neuroendocrine tumors (PNETs) in VHL disease ranges from 9% to 17% and is characterized by a better prognosis compared with sporadic PNETs.^2,3 Several risk factors for PNET metastasis in VHL disease have been reported⁴ but have not been validated. We conducted a prospective study (NCT00062166) to evaluate the natural history of VHL disease–associated pancreatic lesions to determine what factors were associated with PNET phenotype and prognosis.

Patients were enrolled from January 1, 2010, to January 1, 2017, based on the following eligibility criteria: age of 12 years or older, a diagnosis of VHL disease based on germline VHL mutation or clinical criteria,⁵ and a pancreatic manifestation of VHL disease. Pancreatic protocol (2-mm section) abdominal computed tomography and pelvis computed tomography with intravenous contrast material were performed annually or every 2 years in patients with solid or cystic pancreatic lesions, respectively. Each imaging study was assessed by at least 2 independent reviewers. The criteria for surgical resection of pancreatic solid lesions were reported previously.² Disease-free interval and progression-free interval were defined as the time from inclusion without PNET and with no tumor growth (>5 mm and >20%), respectively.

Patients diagnosed with VHL disease underwent genetic testing for mutations in the 3 coding exons and exon-intron boundaries of the VHL gene and for partial or complete deletion or duplication of the VHL gene in Clinical Laboratory Improvement Amendments–approved laboratories.⁶ This study was approved by the institutional review board of the National Cancer Institute, and written informed consent was obtained from all patients enrolled in the study. All data were deidentified.

The current analysis included 229 patients (mean [SD] age, 49.6 [12.7] years, 110 [48.0%] male and 119 [52.0%] female); 54 patients had only cystic lesions, and 175 had solid pancreatic lesions consistent with PNETs (median of 2 PNETs per patient; range, 1-10; total, 489). Patients with VHL mutations in exon 3 vs exons 1 or 2 had a higher rate of PNETs on univariate (odds ratio, 3.0; 95% CI, 1.4-6.5; P = .006) and multivariable analyses (odds ratio, 2.8; 95% CI, 1.3-6.1; P = .01).

Among patients with PNETs (median follow-up, 53.0 months; range, 12-84 months), 29 (16.6%) required surgical intervention. VHL gene sequencing was performed in 156 patients, 7 (4.5%) of whom had metastatic disease during follow-up. Patients with missense vs other VHL mutation types had a larger PNET diameter (mean [SD] diameter, 1.6 [1.1] vs 1.4 [1.0] cm; P = .05, Mann-Whitney test), but this finding did not reach statistical significance (Table).

Patients with a greatest tumor diameter less than 1.2 cm had a 100% negative predictive value for developing metastasis and requiring a surgical intervention during follow-up, whereas patients with a tumor diameter greater than 3.0 cm had a high risk of metastatic disease on univariate (hazard ratio [HR], 8.6; 95% CI, 2.1-34.9; P = .003) and multivariable analyses (HR, 8.6; 95% CI, 1.7-43.2; P = .009).

Among patients with a PNET diameter of 1.2 cm or greater and 3 cm or less, only those with a VHL missense mutation developed metastatic disease during follow-up (5 [12.5%] vs 0 patients with missense vs other type of VHL gene mutation; log-rank test, P = .04). Patients with a VHL missense mutation had a higher rate of requiring a surgical intervention compared with other mutation types(16 [40.0%] with missense vs 5 [16.1%] with other VHL gene mutation type; log-rank test, P = .04), and patients with a VHL gene mutation located in exon 3 vs exon 1 or 2 had a higher rate of requiring a surgical intervention during follow-up (13 [44.8%] vs 8 patients [23.5%], P = .02). Patients with a missense VHL mutation or any mutation type in exon 3 had a higher rate of surgical intervention compared with other VHL genotypes on univariate (HR, 9.2; 95% CI, 1.2-68.7; P = .03) and multivariable analyses (HR, 8.8; 95% CI, 1.2-66.3; P = .04).

Our study findings support an evidence-based algorithm for risk stratification and surveillance of patients with VHL-associated pancreatic lesions (Figure). Such an approach would provide precision medicine for patients with VHL disease–associated pancreatic lesions based on VHL genotype and tumor size. These results should be validated in future studies because of the rate of metastatic disease observed in our cohort.

Corresponding Author: Electron Kebebew, MD, Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, 10 Center Dr, Bldg 10, Room 4W-5952, MSC-1201, Bethesda, MD 20892-1201 (electron.kebebew@nih.gov).

Published Online: October 26, 2017. doi:10.1001/jamaoncol.2017.3428

Author Contributions: Dr Tirosh had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Tirosh, Libutti, Kebebew.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Tirosh, Kebebew.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Tirosh, Patel.

Obtained funding: Kebebew.

Administrative, technical, or material support: Tirosh, Linehan, Libutti, Nilubol, Kebebew.

Study supervision: Sadowski, Kebebew.

Conflict of Interest Disclosures: None reported.

Funding/Support: The study was funded by the grant 1ZIA BCO1127507 from the Intramural Research Program of the National Cancer Institute (Dr Kebebew).

Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.