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

Abstract

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 (PPGL) 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% confidence interval (CI)=15.9-23.6%, I²=86.1%). The frequency increased to 60.0% in patients with vHL type 2 (95%CI=53.4-66.3%, I²=54.6%) and was determined to be of 58.2% in patients with vHL type 2A (95%CI=49.7-66.3%, I²=36.2%), compared to 49.8% in vHL type 2B (95%CI=39.9-59.7%, I²=42.7%), and 84.1% in vHL type 2C (95%CI=75.1-93.1%, I²=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: PPGL 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.

Patient Sex and Origin Influence Distribution of Driver Genes and Clinical Presentation of Paraganglioma

“…Nevertheless, more men than women were reported to have PPGL due to VHL PVs irrespective of germline or somatic status. The same observation was made in a meta-analysis focused specifically on PPGL patients with VHL disease [ 102 ]. Other studies found that the involved organs in germline VHL -mutated patients are not associated with sex but rather with age and mutation type [ 103-105 ].…”

Current prospects of hereditary adrenal tumors: towards better clinical management

“…Regarding PPGL, the estimated lifetime risk is 10–25% [ 11 ]. According to a systematic review and meta-analysis of VHL-associated PPGL that included 4263 VHL cases, the pooled frequency of PPGL was 19.4% [ 12 ]. VHL is classified into types 1 and 2; only patients with type 2 VHL develop PPGL.…”

Hypoxia signaling pathway: A central mediator in endocrine tumors

“…Germline and somatic mutations in major susceptibility genes associated with hypoxia signaling involved in the PCC development, include the tumor suppressors such as VHL1 , the SDH complex (genes encoding the four subunits, A,B,C,D) and occasionally, the egl-9 family hypoxia-inducible factor 1/Prolyl hydroxylase domain 2 protein ( EGLN1/ PHD2) ( 62 , 63 ). Recently, ten new genes have been added to this list and those associated with the hypoxia pathway include HIF-2α (endothelial PAS domain containing protein 1, EPAS1 ) ( 64 , 65 ), FH ( 66 ), and PHD1 (egl nine homolog 2, EGLN2 ) ( 67 ), suggesting that a mutation in any of these major genes involved in the VHL-HIF axis can lead to PCC or PGL development.…”