Von Hippel-Lindau (VHL) syndrome is a rare genetic disorder that increases the risk of developing tumors and cysts in multiple organs, including the kidneys, pancreas, adrenal glands, retina, and central nervous system. Among the most common and clinically significant manifestations are kidney tumors, which can arise at a young age and develop in a multifocal and bilateral manner over the course of a person’s life.
The complexity and multisystem nature of the disease require specialized, multidisciplinary management involving various healthcare professionals, including urologists, oncologists, radiologists, neurosurgeons, endocrinologists, and geneticists. The goal is to optimize disease control while preserving the function of the affected organs and minimizing treatment-related morbidity.
The management of kidney lesions in VHL is based on a fundamental principle: preserving kidney function as much as possible without compromising cancer control. Since patients may develop new tumors over time, subjecting them to early or repeated surgeries exposes them to the risk of progressive loss of renal parenchyma and, in the most severe cases, chronic kidney disease. For this reason, leading international centers have adopted active surveillance strategies, monitoring lesion growth through periodic radiological follow-up and intervening only when the risk of progression becomes significant.
Numerous studies have shown that this approach is safe: most small renal masses associated with VHL grow slowly and present an extremely low risk of metastasis when their diameter remains less than 3 cm. Active surveillance therefore makes it possible to delay interventions without compromising oncological outcomes, thereby reducing the number of procedures a patient will undergo over the course of their lifetime.
In recent years, the introduction of Belzutifan has further changed the therapeutic paradigm for VHL. By inhibiting the HIF-2α factor, the drug has been shown to reduce or stabilize the growth of renal lesions and to exert a significant effect on other manifestations of the disease as well. In particular, the LITESPARK-004 trial, designed to evaluate the efficacy and safety of Belzutifan in von Hippel-Lindau syndrome, demonstrated significant clinical activity across all major manifestations of the disease. The treatment resulted in an objective response rate of 67% in patients with renal cell carcinoma, 48% in central nervous system hemangioblastomas, 91% in pancreatic neuroendocrine tumors, and 93% in retinal hemangioblastomas.
The availability of an effective systemic therapy makes it possible, in many cases, to further delay the need for local treatments, thereby reducing exposure to repeated procedures and preserving organ function.
Consequently, modern management of VHL syndrome is no longer based on a simple alternation between surveillance and surgery, but on a multidisciplinary and personalized approach that integrates active surveillance, local treatments, and systemic therapy. The choice of treatment is determined on a case-by-case basis, taking into account the number and location of lesions, their progression over time, the patient’s characteristics, and the cumulative effects of treatments. The goal is no longer merely to treat individual manifestations, but to optimize clinical outcomes by preserving organ function, minimizing treatment-related toxicity, and improving patients’ long-term quality of life.
Reference: Jonasch E, et al. Belzutifan for von Hippel-Lindau disease-associated renal cell carcinoma and other neoplasms (LITESPARK-004): 50-month follow-up from a single-arm, phase 2 study. Lancet Oncol 2025; 26: 571–82.
Larcher A, et al. Real-world challenges and considerations in treating von Hippel-Lindau disease with HIF-2α inhibitors. Lancet Oncol. July 2025;26(7):e347.
Von Hippel-Lindau (VHL) syndrome is a rare genetic disorder that increases the risk of developing tumors and cysts in multiple organs, including the kidneys, pancreas, adrenal glands, retina, and central nervous system. Among the most common and clinically significant manifestations are kidney tumors, which can arise at a young age and develop in a multifocal and bilateral manner over the course of a person’s life.
The complexity and multisystem nature of the disease require specialized, multidisciplinary management involving various healthcare professionals, including urologists, oncologists, radiologists, neurosurgeons, endocrinologists, and geneticists. The goal is to optimize disease control while preserving the function of the affected organs and minimizing treatment-related morbidity.
The management of kidney lesions in VHL is based on a fundamental principle: preserving kidney function as much as possible without compromising cancer control. Since patients may develop new tumors over time, subjecting them to early or repeated surgeries exposes them to the risk of progressive loss of renal parenchyma and, in the most severe cases, chronic kidney disease. For this reason, leading international centers have adopted active surveillance strategies, monitoring lesion growth through periodic radiological follow-up and intervening only when the risk of progression becomes significant.
Numerous studies have shown that this approach is safe: most small renal masses associated with VHL grow slowly and present an extremely low risk of metastasis when their diameter remains less than 3 cm. Active surveillance therefore makes it possible to delay interventions without compromising oncological outcomes, thereby reducing the number of procedures a patient will undergo over the course of their lifetime.
In recent years, the introduction of Belzutifan has further changed the therapeutic paradigm for VHL. By inhibiting the HIF-2α factor, the drug has been shown to reduce or stabilize the growth of renal lesions and to exert a significant effect on other manifestations of the disease as well. In particular, the LITESPARK-004 trial, designed to evaluate the efficacy and safety of Belzutifan in von Hippel-Lindau syndrome, demonstrated significant clinical activity across all major manifestations of the disease. The treatment resulted in an objective response rate of 67% in patients with renal cell carcinoma, 48% in central nervous system hemangioblastomas, 91% in pancreatic neuroendocrine tumors, and 93% in retinal hemangioblastomas.
The availability of an effective systemic therapy makes it possible, in many cases, to further delay the need for local treatments, thereby reducing exposure to repeated procedures and preserving organ function.
Consequently, modern management of VHL syndrome is no longer based on a simple alternation between surveillance and surgery, but on a multidisciplinary and personalized approach that integrates active surveillance, local treatments, and systemic therapy. The choice of treatment is determined on a case-by-case basis, taking into account the number and location of lesions, their progression over time, the patient’s characteristics, and the cumulative effects of treatments. The goal is no longer merely to treat individual manifestations, but to optimize clinical outcomes by preserving organ function, minimizing treatment-related toxicity, and improving patients’ long-term quality of life.
Jonasch E, et al. Belzutifan for von Hippel-Lindau disease-associated renal cell carcinoma and other neoplasms (LITESPARK-004): 50-month follow-up from a single-arm, phase 2 study. Lancet Oncol 2025; 26: 571–82.
Larcher A, et al. Real-world challenges and considerations in treating von Hippel-Lindau disease with HIF-2α inhibitors. Lancet Oncol. July 2025;26(7):e347.
