Treatment of clinically localized Von Hippel–Lindau (VHL)–associated renal cell carcinoma (RCC) involves a nuanced multidisciplinary approach balancing surveillance, surgery, and, more recently, systemic therapy. The optimal treatment paradigm is evolving, but the primary goal remains unchanged: provide oncologic control while preserving renal function over a lifetime of tumor development.

VHL disease is an autosomal dominant hereditary syndrome caused by germline mutations in the VHL tumor suppressor gene (3p25-26), resulting in an inability to form the E3 ubiquitin ligase complex that regulates the degradation of regulatory proteins, including hypoxia inducible factors (HIFs).¹ Constitutive activation of HIF and overproduction of HIF-related proteins, including vascular endothelial growth factor, drive angiogenesis in RCC. Consequently, most patients (40%-70%) with VHL disease develop multiple clear cell RCCs at early age of onset (third to fifth decade), among other benign and malignant tumors in multiple organ systems (eg, pancreatic cysts and neuroendocrine tumors, retinal and central nervous system hemangioblastomas, endolymphatic sac tumors, and epididymal and broad ligament cysts).^2,3

VHL-associated RCC presents a unique clinical challenge due to the multifocal, bilateral, and recurrent nature of renal tumors, coupled with the need to preserve renal function across a lifetime. While there are multiple genotype-phenotype subtypes within VHL disease, surveillance guidelines are similar. Abdominal MRI or CT scans (MRI may be preferred given high lifetime radiation exposure), obtained with and without IV contrast, are used to assess kidneys, pancreas, and adrenals every 2 years starting at age 15 years.³ If there is a family member with an earlier diagnosis, screening should begin 10 years before the earliest age of diagnosis. Imaging frequency increases with lesion detection. There is variability in how often lesions should be reimaged at this point. Some experts recommend if masses are found (<3 cm), the kidneys should be reimaged every 3 to 6 months to determine stability; if stability occurs over 3 consecutive scans, imaging can return back to every 2 years.² Others may survey less frequently than annually depending on the size and location of tumors, given the slow growth rate of VHL-deficient tumors (median 4 mm/yr) as long as tumors are projected to be less than 3 cm during that interval.⁴

Prior studies have suggested surgical intervention at a threshold of 3-cm tumor diameter.⁵ Referral to centers with expertise in VHL-associated RCC may be beneficial because repeated treatment of multifocal tumors is lifelong and may be complicated. Even with successful initial surgery, a high rate of recurrence necessitates repeat intervention, which carries an increased risk of renal insufficiency and morbidity. Given these challenges, alternative approaches like percutaneous renal mass ablation offer another nephron-sparing approach with minimal procedural morbidity, which is beneficial given that multiple kidney tumors may need treatment during a patient’s lifetime.⁶

Systemic therapy was historically reserved for metastatic disease and focuses on combinations of targeted therapies and immune checkpoint inhibitors. However, VHL patients with earlier-stage RCC may also benefit from systemic therapy as demonstrated in LITESPARK-004, which was an open-label phase 2 trial.⁷ Sixty-one patients with VHL-associated RCC were given 120 mg of belzutifan (HIF-2α inhibitor) daily. Over a median of 21.8 months, 49% demonstrated an objective response (complete or partial response), and an additional 49% had stable disease, which led to Food and Drug Administration approval in 2021 for nonmetastatic VHL-associated RCC not requiring immediate surgery. Overall, belzutifan is well tolerated, with predominantly grade 1 and 2 adverse events including anemia (90%) and fatigue (66%). Belzutifan is now considered category 2A and is a preferred systemic option for patients with VHL-associated RCC not requiring immediate surgery.⁸ Additionally, pazopanib has been studied in a VHL population, with a 42% objective response rate in a phase 2 clinical trial of 32 patients. High-grade treatment-related adverse events were significant, and the study was stopped before planned accrual goals because of high rates of discontinuing treatment due to adverse events.^8,9

The development of belzutifan has raised new questions such as when to start systemic treatment, how long to continue treatment, and when to surgically intervene. Given the high efficacy and low toxicity of belzutifan, many experts anticipate a shift in the treatment paradigm toward increasing systemic therapy use to further delay surgical intervention. A treatment approach is outlined in the Figure. In 2022, experts in VHL were polled to assess their practice managements.¹⁰ In those tumors eligible for active surveillance (<3 cm), 36% would initiate belzutifan to prevent growth, 36% still recommend routine surveillance, and 28% recommend surveillance with consideration of belzutifan only if the lesion surpassed the surgical threshold. For those lesions that classically met the threshold for surgery (>3 cm), 54% of providers recommend initiation of belzutifan instead of surgery. In more complex situations with multifocality and growth of a solitary tumor on belzutifan, 50% would proceed with only treatment of that site, although this was heavily favored by medical oncologists (90%), whereas urologists were more likely to treat all tumors and stop belzutifan (60%). Opinions vary considerably, but 87% of respondents agreed to initiate belzutifan in patients with high risk of morbidity from local therapy, and 98% of respondents agreed that belzutifan should not be used prophylactically to prevent the development of new tumors. Belzutifan also may treat extrarenal manifestations of VHL disease in the pancreas, central nervous system, adrenal glands, and retinas. Opinions regarding the optimal duration of belzutifan treatment is widely disputed and should be made on an individual basis.

Continued translational clinical trials and comprehensive multidisciplinary care are critical to achieve optimal outcomes in a new era of precision oncology for VHL patients. Balancing the current surveillance regimen, surgical management, and systemic therapies in the nonmetastatic setting requires individualized decision-making. Currently, opinions vary widely on when to initiate belzutifan vs operate, how to best salvage patients who progress on belzutifan, and the long-term toxicities of belzutifan. Therefore, collaborative multidisciplinary efforts are needed to consider nonrenal manifestations of VHL, as well as RCC tumor size, multifocality, growth kinetics, anatomical considerations, prior interventions, and patient preferences to allow for further optimization of care.