Pheochromocytomas and paragangliomas in von Hippel–Lindau disease: not a needle in a haystack

OBJECTIVE: Pheochromocytomas are a hallmark feature of von Hippel–Lindau disease (vHL). To our knowledge, this is the first systematic review with meta-analysis evaluating the frequency of pheochromocytomas and/or paragangliomas (PPGLs) in patients with vHL, as well as among patients with different vHL subtypes. DESIGN: Systematic review with meta-analysis. METHODS: We searched on MEDLINE, Scopus, and Web of Science. We included primary studies assessing participants with vHL and reporting on the frequency of PPGL. We performed random-effects meta-analysis to quantitatively assess the frequency of PPGL, followed by meta-regression and subgroup analysis. Risk of bias analysis was performed to assess primary studies’ methodological quality. RESULTS: We included 80 primary studies. In 4263 patients with vHL, the pooled frequency of PPGL was 19.4% (95% CI = 15.9–23.6%, I(2) = 86.1%). The frequency increased to 60.0% in patients with vHL type 2 (95% CI = 53.4–66.3%, I(2) = 54.6%) and was determined to be of 58.2% in patients with vHL type 2A (95% CI = 49.7–66.3%, I(2) = 36.2%), compared to 49.8% in vHL type 2B (95% CI = 39.9–59.7%, I(2) = 42.7%), and 84.1% in vHL type 2C (95% CI = 75.1–93.1%, I(2) = 0%). In meta-regression analysis, more recent studies were associated with a higher frequency of PPGL. All studies had at least one internal validity item classified as 'high risk of bias,' with 13% studies having low risk of bias in all external validity items. CONCLUSIONS: PPGLs are a common manifestation of vHL. Despite methodological limitations and differences across primary studies, our results point to the importance of PPGL screening in patients with vHL.