Clinical and genetic analysis of patients with pancreatic neuroendocrine tumours associated with von Hippel-Lindau disease

Abstract

Abstract Background Patients with von Hippel-Lindau disease (VHL) are at risk of developing pancreatic cysts, microcystic adenomas and neuroendocrine tumours. Pancreatic neuroendocrine tumours (PNETs) are found in 19 per cent of families with VHL. These tumours can behave in a malignant fashion, with up to 17 per cent of patients developing distant disease. The authors' initial experience with the diagnosis and management of these lesions, with resection based on size greater than 3 cm in imaging studies, has been reported previously. This is a report on their prospective experience using these criteria as well as on the role of genotype/phenotype analysis of germline VHL gene mutations in predicting clinical course. Methods Some 389 patients with VHL were screened between December 1998 and December 1999. The diagnosis of PNET was made by either pathological analysis of tissues or by characteristic radiographic appearance on computed tomography and magnetic resonance imaging. VHL gene germline mutations were determined by quantitative Southern blotting to detect deletions of the gene, Southern blotting to detect gene rearrangements, fluorescence in situ hybridization to confirm deletions and complete gene sequencing. Results Forty-four patients with PNET have been identified. Of these, 25 have undergone definitive surgical resection, five were found to have metastatic disease and 14 are being followed prospectively. No patient who has undergone resection based on the aforementioned tumour size criteria has developed metastatic disease. These patients represent 36 families (19 per cent) of a total of 188 VHL families who have had germline mutation analysis. Compared with all 188 VHL families, those with PNETs are more likely to have missense mutations (58 per cent) and more likely to have intragenic mutations. Four of five patients with metastatic disease have mutations in exon 3 compared with 18 of 39 patients without metastatic disease. Conclusion An aggressive approach to imaging for detection and surgical resection based on established size criteria has resulted in the successful management of patients with VHL and PNETs. Analysis of germline mutations may help predict those patients with VHL who are at risk of developing a PNET and which patients with a PNET may benefit from earlier surgical intervention to prevent spread of disease.