­­Revisiting the VHL Connection:
How a Common Pathway Now More Closely Links Sporadic RCC,
VHL-Associated Syndromes

Eric Jonasch, MD
Professor, Department of Genitourinary Medical Oncology
Division of Cancer Medicine
The University of Texas MD Anderson Cancer Center
Houston, Texas


Keywords: von Hippel Lindau (VHL) disease; syndrome; hereditary, genetic mutation; hemangioblastoma; retinal; hypoxia inducible factor; VEGF.

Corresponding Author: Eric Jonasch, MD, Department of Genitourinary Medical
Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd # 853, Houston, TX 77030;
email address:


The trajectory of recent work on the pathophysiology of renal cell carcinoma (RCC) suggests the extent to which a spectrum of disorders share a common genetic framework. Although the implications of losing the von Hippel-Lindau (VHL) gene have been clear for a long time, an improved understanding of its precise role in tumorigenesis is now emerging. The challenge now is to take these new findings and extrapolate them to treatment choices as we seek to optimize clinical outcomes, not only in RCC but in VHL-related diseases.

A growing awareness of the interaction between germline mutations and somatic tumor mutations has focused more attention on how distinct phenotypes could provide important new information with implications for earlier diagnosis and potential management strategies in hereditary and sporadic renal cell carcinoma (RCC). Advances in genome-wide sequencing technologies have helped move the discourse beyond core driver mutations, including the VHL gene, to include additional mutations that affect diverse elements of cellular biology, including chromatin homeostasis.  Armed with new data emerging over the last few years, clinicians may have more effective strategies to meet diagnostic, surveillance, and therapeutic challenges in sporadic RCC and in hereditary VHL disease.

Although VHL disease is rare—occurring in roughly 1 in 36,000 births1- this syndrome could yield new clues regarding the molecular pathogenesis of sporadic RCC and could serve as a framework for the application of targeted therapies. As more of the biology of VHL disease has unraveled, the implications for potential therapeutic approaches, including the use of antiangiogenic agents and immunotherapy, suggest that we may have more effective ways to have an impact on downstream targets in RCC.

One of the major themes to emerge from newly published work on VHL disease is the extent to which hereditary and sporadic RCC share common features regarding their molecular pathogenesis. These include dysregulation of the VHL tumor suppressor protein/hypoxia inducible factor axis, ciliogenesis and aberrant tumor meta- bolism.2 As the knowledge base for all genetic RCC syndromes expands, the focus is also shifting toward the development of screening guidelines to identify patients with germline mutations in the absence of secondary clinical manifestations that are at highest risk for potentially lethal disease manifestations. As we learn which elements are necessary to engender early-onset RCC in syndromic patients, it could help identify persons who have an increased risk of developing sporadic RCC.

Understanding VHL Disease, its Genetic
and Pathophysiology
Clear cell RCC can be sporadic (>96%) or familial (<4%). Almost all familial clear cell RCCs arise from an inherited mutation in the VHL tumor suppressor gene located on chromosome 3p.3 Patients with VHL disease develop kidney cysts and multiple bilateral clear cell RCC at an average 37 years of age.4 The second VHL allele has been shown to be inactivated by deletion and less commonly by promoter hypermethylation or rearrangement. The average age of onset of sporadic clear cell RCC is 61 years and it usually presents as a solitary tumor of several centimeters in size.4 Chromosome 3p deletion and inactivation of the VHL gene is the most common genetic alteration.5 The fact that VHL inactivation is so common in sporadic clear cell RCC, including the smallest T1a tumors, and this is also the predisposing factor in familial VHL disease, argues that alteration of VHL is the initiating event in most sporadic clear cell RCC.6

Recent advances in the understanding of cancer as a genetic disease have allowed the identification of clonal genetic and epigenetic alterations, which accumulate during cancer progression, often in a general temporal order. However, relatively little is known about the secondary and later genetic alterations which drive progression after the initiating event of inactivation of VHL in clear cell RCC. Even less is known about the alterations that underlie the initiation and progression of sporadic papillary or chromophobe RCC. It remains that much of what we know of the molecular basis of sporadic RCC arose from identification of the genes predisposing to inherited RCC.7

Loss of VHL function is associated with several events that can predispose to tumorigenesis. The protein product VHL serves as an E3 ubiquitin ligase, and regulates degradation of hypoxia-inducible factors (HIF) under normoxic conditions.1 There are two main HIF transcription factors, HIF-1alpha and HIF-2alpha. Under hypoxic conditions, these HIF isoforms regulate a large number of overlapping and unique target genes, including vascular endothelial growth factor (VEGF).8,9  This interaction plays a role in cellular adaptation to hypoxia. VEGF is well recognized as an important factor in promoting tumorigenesis. A number of additional VHL functions exist whose loss may also engender tumo-rigenesis.10,11

As outlined below, multiple cancerous and non-cancerous organ-specific manifestations arise in VHL patients, with the only known initiating factor being a germ-line VHL mutation. It will be critical to perform cross-lesion analyses to identify the common as well as the discordant features responsible for producing such discrepant phenotypic manifestations.

The Spectrum of Manifestations and Presentations
The clinical manifestations of VHL disease include hemangioblastomas, pheochromo-cytomas, endolymphatic sac tumors, pheo-chromocytomas, epididymal cystadenomas, pancreatic and renal cysts, pancreatic neuroendocrine tumors and clear cell RCC. The mean age of onset of RCC is 37 years and RCC is the leading cause of death in patients with VHL disease. The most common manifestation is CNS hemangioblastoma, (Fig. 1) found in 60% to 80% of all VHL patients, according to a review by Kim et al.12 CNS hemangioblastomas can be located anywhere along the neural axis, but most of them are localized in the eye, the cerebellum and the spinal cord (Fig. 2). This review will focus primarily on RCC and hemangioblastomas in view of their most common occurrence compared to the other VHL-related syndromes, and their relative morbidity.

Figure 1

Figure 1. (A) Axial T1 postcontrast images demonstrate an enhancing mural nodule (white arrow) with accompanying cyst (*) in the right cerebellar hemisphere exerting a mass effect upon the midline and fourth ventricle (double white arrow). (B) Hematoxylin-eosin staining showing scattered large hyperchromatic nuclei, vacuolated cells, and multiple capillaries which are classic features of the cellular type of hemangioblastoma. From: Varshney N, Kebede AA, Owusu-Dapaah H, et al. A review of von-Hippel-Lindau syndrome. J Kidney Cancer VHL. 2017;4:20-29.

Figure 2

Figure 2. Clinical manifestations of von Hippel-Lindau disease. Sites indicate where an increased risk for tumor development is likely to occur. From: Ho TH, Jonasch E. Genetic kidney cancer syndromes. J Natl Compr Cancer Netw. 20144;12:1347-1355.


Treatment: Studies Still Investigational but
Antiangiogenic Approaches Look Promising
Since acquired dysregulation of VHL-dependent pathways is often apparent in patients with sporadic RCC treated with tyrosine kinase inhibitors (TKIs) the same rationale has been extrapolated for treating VHL patients with progressive disease in the kidneys or other sites.13 This approach has been delineated in numerous trials. These reports share a common hypothesis: the most important mechanism involved in the pathogenesis of sporadic and VHL-related RCC is the overexpression of angiogenic growth factors stimulated by HIF-1 alpha and HIF-2 alpha after inactivation of VHL (Fig. 3). Thus, a growing literature has drawn a connection between the treatment of sporadic RCC and the VHL-related syndromes. For example, in a landmark paper, Kaelin,13 suggested that mutations or promoter hypermethylation of the VHL gene may be frequently found in sporadic clear cell RCC. It is a logical step then to suggest there may be a correlation with sensitivity to antiangiogenic treatment.

Figure 3

Figure 3. Genes mutated in hereditary kidney cancer syndromes. Mutations (blue) in MET, PTEN, TSC1/TSC2, FLCN, VHL, SDH, FH, and BAP1, are linked to sporadic RCC and hereditary kidney cancer syndromes. VHL mutations play a role in tumorigenesis by affecting hypoxia-inducible factor and cellular adaptation to hypoxia. From: Ho TH, Jonasch E. Genetic kidney cancer syndromes. J Natl Compr Cancer Netw. 20144;12:1347-1355.


There are emerging data on the benefit of TKIs in VHL disease patients with progressive disease in the kidneys or other sites. The clinical trials have primarily focused on the use of two TKIs, sunitinib and pazopanib; however, other agents have also undergone study such as bevacizumab and ranibizumab. In their retrospective analysis, Roma et al14 evaluated progression-free survival in 14 patients with genetically-confirmed VHL treated for a histological diagnosis of multifocal or advanced RCC. After administering sunitinib as a first systemic treatment, Roma et al recorded 9 partial responses (64.3%) and 5 stabilizations of disease with a PFS of 71.4% at 2 years. All evaluable hemangioblastomas remained stable. More encouraging were the radiological responses observed not only in renal lesions but also in pancreatic, adrenal, hepatic, pulmonary and subcutaneous nodules as well as in some cystic lesions, which represents a wide spectrum of VHL-related lesions.

In a prospective trial,15 we evaluated the safety and efficacy of sunitinib in VHL patients (NCT00330564) and examined the expression of various receptors in archived tissue. Of 18 RCCs, 33% responded favorably although none of the hemangioblastomas did. One intriguing finding con- cerned the results of biomarker expression: mean levels of VEGF receptors were lower in hemangioblastoma than in RCC and mean fibroblast growth factor receptor (FGFR) activation state was higher in hemangioblastomas. Why do organ-specific VHL-derived lesions respond differently to therapy? And what of the findings on fibroblast growth factor (FGF) axis? To what effect does do these differences affect organ specific response rates? At this point in time, we do not have clear answers to these questions, but as previously stated, RCCs are true cancers, whereas hemangioblastomas have no metastatic potential. It could be that the differences are due to cancer-specific genetic lesions or tissue-specific endothelial differences. The results on FGF raise the possibility that further studies should examine whether hemangioblastomas could depend on FGF signaling and whether we can identify biomarkers that will help us determine whether agents will yield some benefit.

To that end, we launched a phase II study14 (NCT01-266070) in VHL patients to test the hypothesis that hemangioblastomas would respond to dovitinib, which blocks FGFR in addition to VEGF receptors.  Unfortunately, this study was closed after six patients were enrolled as the toxicity stopping rule was met, mainly because of the development of rash.  No responses were observed and this agent was not considered for further development in this indication.

Tracing the Origins of VHL Disease to the Work of Two Physicians

von Hippel and LindauThe investigative work of two physicians began more than 100 years ago, each working independently and unaware of the other’s research. Today, the condition they observed bears both of their names, reflecting the discoveries of these two pioneers. They were Eugen von Hippel and Arvid Lindau. When their revelations were further validated, the disease became known as von Hippel-Lindau (VHL) disease.

In 1904, Eugen von Hippel , a German ophthalmologist, described a rare disorder of the retina, and in 1911 discovered the anatomical basis of this disease, which he named “angiomatosis retinae.” However, it was not until 1926 that Swedish pathologist Arvid Lindau recognized an association between angiomatosis of the retina with hemangioblastomas of the cerebellum and other parts of the central nervous system. Thus the condition is known today as VHL disease.

Lindau was the first to describe a coherent link between the retinal, cerebellar and visceral components of a disease he called “angiomatosis of the central nervous system.” This disease is characterized by tumors of the retina and the brain, along with cysts and tumors of several visceral organs such as the kidneys, pancreas and adrenal glands. Lindau’s research soon attracted the attention of famed neurosurgeon Harvey Cushing, who named the disorder, “Lindau’s disease.” By 1964 the medical community had become more aware of early 20th century research on retinal angiomata conducted by von Hippel, and both men were recognized for their contribution in describing the condition.


Efforts to avoid unnecessary surgery for asymptomatic cerebellar hemangioblastomas have also focused on the use of pazopanib. Three case reports have helped provide an avenue for further investigation of this TKI in this setting. The first report from MD Anderson by Kim et al12 provided evidence demonstrating clinical and radiological anti-tumor response using pazopanib in a patient with treatment-refractory VHL-associated CNS hemangioblastoma. Treatment with 800mg/day of pazopanib resulted in significant neurologic improvement and radiologic tumor volume reduction in a 47-year-old African-American male. This case report represented the first time any agent had demonstrated clinical benefit for CNS hemangioblastomas. With the exception of neutropenia, the patient experienced only mild adverse events (grade 1 and 2.)

In a second case report, Swiss authors17 reported on pazopanib treatment in a 37-year-old female patient with recurrent and rapidly progressive VHL-associated hemangioblastomas that caused severe disability. A 24-month treatment with pazopanib achieved progressive improvement in her condition. Radiological findings did not show significant changes in the size of target lesions and did not reveal any new lesion in contrast to the continuous multifocal progression prior to therapy. The report offers further evidence supporting the use of a TKI in this setting and underscoring the rationale of such treatment because RCC harbors the same molecular abnormalities as CNS hemangioblastoma. A third, more recent case report demonstrated heterogeneous response in a patient with multiple CNS hemangioblastomas.18

We presented a phase II study testing pazopanib in VHL patients (NCT01436227) at the 2017 ASCO meeting.19 In this trial, 31 VHL patients were treated with pazopanib. The objective response rate was 42%, with a greater than 50% response rate in RCCs and in pancreatic lesions. Hemangioblastomas demonstrated a response rate of 4%, but disease stabilization was noted in a number of patients. Two cases of bleeding were reported in hemangioblastomas. This study represents the largest prospective study using an antiangiogenic agent in VHL patients, with a number of individuals remaining on study for several years.

Treatment of Retinal Hemangioblastoma
Treatment of retinal hemangioblastomas with intravitreal or systemic antiangiogenic agents has shown limited success. The hallmark ocular lesion associated with VHL disease is the retinal capillary hemangioblastoma, present in about 37% of VHL patients.20 Investigative work, such as the study by Wong et al,21 used intravitreal ranibizumab a VEGF trapping agent. In the Wong study,21 five patients received an average of 10 intravitreal injections over an average of 47 weeks. Unfortunately, ranibizumab had minimal beneficial effect on most VHL-associated retinal hemangioblastomas, although there was possible efficacy in a patient with the smallest lesion with less exudation. More promising results were achieved in a second study in which bevacizumab was used over 60 months in a patient with progressive visual loss to a VHL-associated macular and optic nerve hemangioblastoma.22 After under- going a treatment regimen of 15 injections, visual acuity improved 25 letters, ocular coherence thickness improved from 646 um to 4244 um; structural lesions stabilized while exudates and edema resolved. Although the results are somewhat encouraging, it remains to be seen whether localized VEGF blocking therapy with either bevacizumab or ranibizumab will be more than an interim solution.

Novel Treatments for VHL disease
The ideal treatment for VHL patients would be gene replacement therapy, whereby copies of a normal VHL gene can be introduced into patient’s cells, thereby normalizing them. At this time, such technology has not yet been developed for patients with VHL disease, although the “CRISPR” Cas9 gene editing technology23 shows promise in an increasingly large number of applications, and could be adapted for this purpose. Short of replacing defective VHL, the next best approach would be to block the HIF transcription factor itself.  Two HIF2 alpha blocking agents PT2385, and the more recent version PT2977, are in clinical development. PT2385 demonstrated promising results in a recently published phase I clinical trial in patients with advanced malignancies.24  PT2977 is being tested in a phase I clinical study25 (NCT02974738) and a second study was launched to test this agent in patients with VHL disease26 (NCT03401788).  This latter study holds great promise for patients with VHL disease, as HIF blockade would theoretically inhibit development of all VHL organ manifestations.

Despite the heterogeneous nature of hereditary and sporadic clear cell RCC, their pathophysiology shares a common dysregulation of the HIF-VEGF axis. The recognition of a shared pathway offers the potential to develop an understanding of the common drivers of tumor progression and lethality in sporadic and hereditary VHL-related disease. Although still investigational, ongoing trials using TKIs and HIF-targeted therapy will hopefully provide the compelling data needed to support the use of such therapies in the hereditary VHL patient population.

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