von Hippel–Lindau (VHL) disease is a hereditary tumor susceptibility syndrome which was initially described by Dr. Eugen von Hippel in 1904, followed by the description by Dr. Arvid Lindau in 1926.1,2 It is most commonly due to germline loss-of-function variants in VHL.3 Affected individuals are at risk for asynchronous or synchronous occurrence of numerous cysts and tumors involving multiple organs.4 On histopathologic examination, the findings of a clear cell component and prominent vascularity are shared by most of the VHL tumors, which can pose a diagnostic challenge.5 Distinguishing primary tumors from metastatic renal cell carcinoma (RCC) is particularly important because the latter represents the leading cause of mortality in VHL patients.6,7 In up to three quarters of individuals with VHL disease RCC occurs by the seventh decade.8 From a management perspective, nephron-sparing surgery is the treatment of choice.9,10 However, repeated partial nephrectomies for multifocal tumors may result in end-stage renal disease, which is a major source of morbidity and mortality.3 More recently, the advent of targeted therapies has given rise to a paradigm shift in the management of RCCs in patients with VHL disease.11, 12, 13 This review covers the neoplastic conditions associated with this syndrome and focuses on renal neoplasia.

VHL disease has an incidence of approximately one in 36,000 to 50,000 live births.8,13,14 Based on a recent epidemiologic study in the United States, it was estimated that there were 7,001 individuals with VHL disease in 2019.15 VHL disease is characterized by autosomal dominant inheritance, and has a penetrance greater than 90%.13,16

Following Knudson's “two-hit” hypothesis, tumors generally develop after biallelic VHL inactivation. The first hit occurs when a germline alteration involving the VHL gene results in a defective allele in all cells of the patient. In the cancer cells of origin, this is followed by a somatic event inactivating the wild-type allele, resulting in loss of heterozygosity (second hit).8,17 Biallelic inactivation leads to abnormal or absent VHL protein (pVHL) function, and constitutive activation of hypoxia-inducible factors (HIF) that promote oncogenic signaling.18,19 Until recently, only variants in the VHL gene had been demonstrated to cause VHL disease. In 2022, however, a novel pathogenic variant involving the ELOC gene (also referred to as TCEB1), which encodes elongin C, was linked to VHL disease.20

Based on genotypic–phenotypic correlation studies, VHL has been divided into two clinical subtypes: type 1, manifesting with a relatively decreased risk of paraganglioma compared to type 2, which is associated with a higher risk of paraganglioma. The latter has been subclassified into type 2A (relatively decreased risk of RCC); type 2B (high risk of RCC); and type 2C (risk of paraganglioma only).12

In humans, VHL is a tumor suppressor gene on chromosome 3p25.3, that is highly conserved across species.21,22 Missense alterations are the most frequent germline genetic events, followed by truncating/nonsense alterations.8,23,24

Under normoxic conditions, pVHL plays a role in sensing of oxygen on a cellular level by acting as the substrate recognition component of a ubiquitin ligase complex that also includes elongin B, elongin C, cullin 2, and ring box 1, and promotes proteasomal breakdown of HIF-α subunits.20,25 In the presence of a defective pVHL or under hypoxic conditions, HIFs escape degradation, which results in stabilization and accumulation of HIFα subunits HIF1α and HIF2α.3,11 Downstream signaling includes upregulation of HIF2α-target genes that regulate angiogenesis, cell cycle, proliferation, and glucose metabolism.7 Proteins that are frequently upregulated by activation of this pathway include carbonic anhydrase 9 (CA9), glucose transporter 1 (GLUT-1), erythropoietin, platelet-derived growth factor-β, transforming growth factor-α, and vascular endothelial growth factor (VEGF), among others.5,16,26 Constitutive overproduction of these proteins in VHL disease leads to tumorigenesis.7