Von Hippel-Lindau gene alterations in sporadic benign and malignant pheochromocytomas

The Von Hippel-Lindau (VHL) gene product has a wide spectrum of tissue-specific functions, and specific germline mutations are associated with clinical phenotypes in VHL disease. In particular, missense mutations are correlated with the susceptibility to pheochromocytomas. An association between VHL aberrations and prognosis has been suggested in renal clear cell carcinoma but has not been studied in pheochromocytomas. We studied the frequency and spectrum of VHL alterations in apparently sporadic pheochromocytomas in relation to the clinical behavior in 72 patients, including 48 patients with clinically benign and 24 patients with malignant pheochromocytomas. Single-strand conformation polymorphism (SSCP) analysis followed by DNA sequencing, loss of heterozygosity analysis of the VHL locus and immunohistochemistry for VHL protein expression were used to investigate somatic VHL gene alterations. In 2 patients, I with a malignant tumor, germline mutations were identified in the stop codon. Tumor-specific intragenic VHL mutations and accompanying loss of heterozygosity were identified in 2 (4.3%) of 47 sporadic benign pheochromocytomas compared to 4 (17.4%) of 23 malignant tumors (p = 0.064). Only one of these mutations has been previously described, in a renal clear cell carcinoma. Expression of the VHL protein was observed in all pheochromocytomas. No distinction in the nature of VHL alterations between benign and malignant pheochromocytomas and no correlation with histopathologic or clinical features was observed. We report novel VHL mutations in sporadic pheochromocytomas, which are slightly correlated with malignancy. VHL mutations may have some impact on the malignant transformation of pheochromocytomas.