Von Hippel-Lindau disease (VHL) is an autosomal dominant disease that can predispose individuals to multiple neoplasms. Germline pathogenic variants in the VHLgene predispose individuals to specific types of benign tumors, malignant tumors, and cysts in many organ systems. These include central nervous system hemangioblastomas; retinal hemangioblastomas; clear cell renal cell carcinomas and renal cysts; pheochromocytomas, cysts, cystadenomas, and neuroendocrine tumors of the pancreas; endolymphatic sac tumors; and cystadenomas of the epididymis (males) and of the broad ligament (females).[
The VHLgene is a tumor suppressor gene located on the short arm of chromosome 3 at cytoband 3p25-26.[
Prevalence and rare founder effects
The incidence of VHL is estimated to be between 1 case per 27,000 and 1 case per 43,000 live births in the general population.[
Penetrance of pathogenic variants
VHL pathogenic variants are highly penetrant, with manifestations found in more than 90% of carriers by age 65 years.[
Risk factors for VHL
Each offspring of an individual with VHL has a 50% chance of inheriting the VHL pathogenic variant allele from their affected parent. For more information, see the Genetic diagnosis section.
The following types of pathogenic variants can lead to VHL clinical manifestations: missense, nonsense, frameshifts, insertions, partial and complete deletions, and splice-site variants. The specific type of pathogenic variant seen in the patient may influence which clinical manifestations occur. Two major clinical VHL phenotypes have been described. Individuals with type 1 VHL often have large deletions in the VHL gene and can develop all VHL-associated lesions. However, these individuals often have a lower incidence of pheochromocytomas (PHEOs) than individuals with type 2 VHL.[
De novo pathogenic variants and mosaicism
In some cases, an individual can be diagnosed with VHL, even when this disease is not present in other family members. This scenario can occur when an affected individual has a de novo (new) pathogenic variant in the VHL gene. Patients who were diagnosed with VHL and have no family history of VHL comprise about 23% of VHL kindreds.[
Depending on the embryogenesis stage at which the new variant occurs, there may be different somatic cell lineages carrying the variant. This influences the extent of mosaicism seen in the cell lineages. Mosaicism occurs when two or more cell lines in an individual differ by genotype. These differing cell lines all arise from the same zygote.[
VHL-associated polycythemia (also known as familial erythrocytosis type 2 or Chuvash polycythemia) is a rare, autosomal recessive blood disorder caused by homozygous or compound heterozygous pathogenic variants in VHL in which affected individuals develop abnormally high numbers of red blood cells (polycythemia). The affected individuals have biallelic pathogenic variants in the VHL gene. It had been originally thought that the typical VHL syndromic tumors do not occur in these affected individuals.[
Other Genetic Alterations
In sporadic RCC, mutational inactivation of the VHL gene is the most frequent molecular event that occurs. In addition to VHL inactivation, sporadic clear cell renal cell carcinoma (ccRCC) tumors harbor frequent variants in other genes, including PBRM1, SETD2, and BAP1.[
The VHLtumor suppressor gene encodes two proteins: a 213 amino acid protein (pVHL30) and a 154 amino acid protein, which is the product of internal translation.[
HIF1-Alpha and HIF2-Alpha
pVHL regulates protein levels of HIF1-alpha and HIF2-alpha in the cell by acting as a substrate recognition site for HIF as part of an E3 ubiquitin ligase complex.[
Hypoxia inactivates prolyl hydroxylases, leading to lack of HIF hydroxylation. Nonhydroxylated HIF1-alpha and HIF2-alpha are not bound to the VHL protein complex for ubiquitination, and therefore, accumulate. The resulting constitutively high levels of HIF1-alpha and HIF2-alpha drive increased transcription of a variety of genes, including growth and angiogenic factors, enzymes of the intermediary metabolism, and genes promoting stemness-like cellular phenotypes.[
HIF1-alpha and HIF2-alpha possess distinct and partially contrasting functional characteristics. In the context of renal cell carcinoma (RCC), it appears that the EPAS1 gene, also known as HIF2A, acts as an oncogene, and HIF1A acts as a tumor suppressor gene. HIF2-alpha may preferentially upregulate Myc activity, whereas HIF1-alpha may inhibit Myc activity.[
Numerous studies using xenografted or transgenic animal models have shown that inactivation of HIF2-alpha by pVHL is necessary and sufficient for tumor suppression by the pVHL proteins. HIF2-alpha is now an established therapeutic target for von Hippel-Lindau disease (VHL)-related malignancies.[
Microtubule Regulation and Cilia Centrosome Control
Emerging data point to the importance of pVHL-mediated control of the primary cilium and the cilia centrosome cycle. The nonmotile primary cilium acts as a mechanosensor, regulates cell signaling, and controls cellular entry into mitosis.[
Cell Cycle Control
pVHL reintroduction induces cell cycle arrest and p27 upregulation after serum withdrawal in VHL-null cell lines.[
Extracellular Matrix Control
Functional pVHL is needed for appropriate assembly of an extracellular fibronectin matrix.[
Regulation of Oncogenic Autophagy
In clear cell renal cell carcinoma (ccRCC), oncogenic autophagy dependent on microtubule-associated protein 1 light chain 3 alpha and beta (LC3A and LC3B) is stimulated by activity of the transient receptor potential melastatin 3 (TRPM3) channel through multiple complementary mechanisms. The VHL tumor suppressor represses this oncogenic autophagy in a coordinated manner through the activity of miR-204, which is expressed from intron 6 of the gene encoding TRPM3. TRPM3 represents an actionable target for ccRCC treatment.[
Animal Models of VHL
Vhl-knockout mice die in utero. Heterozygous Vhl mice develop vascular liver lesions reminiscent of hemangioblastomas.[
Age Ranges and Cumulative Risk of Different Syndrome-related Neoplasms
The age of onset for von Hippel-Lindau disease (VHL) varies both between different families and between members of the same family. This fact informs the guidelines for starting age and frequency of presymptomatic surveillance examinations. Of all VHL manifestations, retinal hemangioblastomas and pheochromocytomas (PHEOs) have the youngest age of onset; hence, targeted screening is recommended in children younger than 10 years. At least one study has demonstrated that the incidence of new lesions varies depending on patient age, the underlying pathogenic variant, and the organ involved.[
|Neoplasm||Mean Age (Range) in y||Cumulative Risk (%)|
|PHEO = pheochromocytoma|
| a Adapted from Choyke et al.[
|b Limited data are available for cystadenomas of the broad/round ligament and epididymis.|
|Renal cell carcinoma||37 (16–67)||24–45|
|Pancreatic tumor or cyst||36 (5–70)||35–70|
|Retinal hemangioblastoma||25 (1–67)||25–60|
|Cerebellar hemangioblastoma||33 (9–78)||44–72|
|Brainstem hemangioblastoma||32 (12–46)||10–25|
|Spinal cord hemangioblastoma||33 (12–66)||13–50|
|Endolymphatic sac tumor||22 (12–50)||10|
For more information, see the Clinical diagnosis section.
VHL Familial Phenotypes
Four clinical types of VHL have been described. In 1991, researchers classified VHL as type 1 (without PHEOs) and type 2 (with PHEOs).[
|PHEO = pheochromocytoma; RCC = renal cell carcinoma.|
|a Each of the VHL subtypes can include other manifestations, such as central nervous system hemangioblastomas; retinal hemangioblastomas; renal cysts; cysts, cystadenomas, and neuroendocrine tumors of the pancreas; endolymphatic sac tumors; and cystadenomas of the epididymis (males) and of the broad ligament (females).|
|1||Absence of PHEOs|
|Low risk of RCC|
|High risk of RCC|
|Absence of RCC|
More than 55% of von Hippel-Lindau disease (VHL)-affected individuals only develop multiple renal cell cysts. The VHL-associated renal cell carcinomas (RCCs) that occur are characteristically multifocal and bilateral; these RCCs present as combined cystic and solid masses.[
Figure 1. von Hippel-Lindau disease–associated renal cell cancers are characteristically multifocal and bilateral and present as a combined cystic and solid mass. Red arrow indicates a lesion with a solid and cystic component, and white arrow indicates a predominantly solid lesion.
Tumors larger than 3 cm may increase in grade as they grow, and metastasis may occur.[
Patients can also develop pancreatic cysts, cystadenomas, and pancreatic neuroendocrine tumors (NETs).[
Retinal manifestations, which were first reported more than a century ago, were one of the first recognized VHL features. Retinal hemangioblastomas (also known as capillary retinal angiomas) are one of the most common manifestations of VHL and are present in more than 50% of patients.[
Retinal hemangioblastomas occur most frequently in the periphery of the retina; they can also occur in other locations like the optic nerve, which is a more difficult area to treat. Retinal hemangioblastomas are bright orange spherical tumors that are supplied by a tortuous vascular supply. Nearly 50% of patients have bilateral retinal hemangioblastomas.[
Longitudinal studies help explain the natural history of these tumors. If left untreated, retinal hemangioblastomas can be a major source of morbidity in patients with VHL. Approximately 8% of patients [
Cerebellar and Spinal Hemangioblastomas
Hemangioblastomas are the most common disease manifestation in patients with VHL, affecting more than 70% of individuals. A prospective study assessed the natural history of hemangioblastomas.[
Figure 2. Hemangioblastomas are the most common disease manifestation in patients with von Hippel-Lindau disease. The left panel shows a sagittal view of brainstem and cerebellar lesions. The middle panel shows an axial view of a brainstem lesion. The right panel shows a cerebellar lesion (red arrow) with a dominant cystic component (white arrow).
Figure 3. Hemangioblastomas are the most common disease manifestation in patients with von Hippel-Lindau disease. Multiple spinal cord hemangioblastomas are shown.
Pheochromocytomas and Paragangliomas
The rate of pheochromocytoma (PHEO) formation in the VHL patient population is 25% to 30%.[
PGLs are rare in VHL patients but can occur in the head and neck or in the abdomen.[
The mean age at diagnosis of VHL-related PHEOs and PGLs is approximately 30 years.[
VHL patients may develop multiple serous cystadenomas, pancreatic NETs, and simple pancreatic cysts.[
Pancreatic NETs are usually nonfunctional, but they can metastasize (to the lymph nodes and the liver). The risk of pancreatic NET metastasis was analyzed in a large cohort of patients, in which the mean age of pancreatic NET diagnosis was 38 years (range, 16–68 y).[
Endolymphatic Sac Tumors (ELSTs)
ELSTs are adenomatous tumors arising from the endolymphatic duct or sac within the posterior part of the petrous bone.[
ELSTs are an important cause of morbidity in VHL patients. ELSTs evident on imaging are associated with a variety of symptoms, including hearing loss (95% of patients), tinnitus (92%), vestibular symptoms (such as vertigo or disequilibrium) (62%), aural fullness (29%), and facial paresis (8%).[
Hearing loss related to ELSTs is typically irreversible; serial imaging to enable early detection of ELSTs in asymptomatic patients and resection of radiologically evident lesions are important components in the management of VHL patients.[
Broad/Round Ligament Papillary Cystadenomas
Tumors of the broad ligament can occur in females with VHL and are known as papillary cystadenomas. These tumors are extremely rare, and fewer than 20 have been reported in the literature.[
Fluid-filled epididymal cysts, or spermatoceles, are very common in adult men. In VHL, the epididymis can contain more complex cystic neoplasms known as papillary cystadenomas, which are rare in the general population. More than one-third of all cases of epididymal cystadenomas reported in the literature and most cases of bilateral cystadenomas have been reported in patients with VHL.[
In a small series, histological analysis did not reveal features typically associated with malignancy, such as mitotic figures, nuclear pleomorphism, and necrosis. Lesions were strongly positive for CK7 and negative for RCC. Carbonic anhydrase IX (CAIX) was positive in all tumors. PAX8 was positive in most cases. These features were reminiscent of clear cell papillary RCC, a relatively benign form of RCC without known metastatic potential.[
Genetic Risk Assessment for von Hippel-Lindau Disease (VHL)
The primary risk factor for VHL (or any of the hereditary forms of renal cancer under consideration) is the presence of a family member affected with the disease. Risk assessment should also consider gender and age for some specific VHL-related neoplasms. For example, pheochromocytomas (PHEOs) may have onset in early childhood,[
Each offspring of an individual with VHL has a 50% chance of inheriting the VHLvariant allele from their affected parent. Diagnosis of VHL is frequently based on clinical criteria. If there is family history of VHL, then a patient with one or more specific VHL-type tumors (e.g., hemangioblastoma of the central nervous system [CNS] or retina, PHEO, or clear cell renal cell carcinoma [ccRCC]) may be diagnosed with VHL.
Diagnosis of VHL is frequently based on clinical criteria. If there is family history of VHL, a previously unevaluated family member can be clinically diagnosed with VHL if this person presents with one or more VHL-related tumors (e.g., CNS/retinal hemangioblastomas, PHEOs, ccRCCs, or endolymphatic sac tumors). If a patient does not have a family history of VHL, he/she must meet one of the following criteria: (1) two or more CNS hemangioblastomas, or (2) one CNS hemangioblastoma and either (a) a visceral tumor or (b) an endolymphatic sac tumor. For more information about VHL diagnostic details, see Table 3.[
In 1998, all germline pathogenic variants identified in a cohort of 93 VHL families were reported. Since then, VHL diagnosis has been based on a combination of the following: (1) identifying clinical VHL-associated manifestations, and (2) conducting genetic testing for VHL pathogenic variants identified within families. This diagnostic strategy can differ among individual family members. Table 3 summarizes a combined approach that uses both methods mentioned above (i.e., identifying VHL clinical manifestations and VHL genetic testing).
|Family History of VHL||Genetic Testing||Scenarios for Clinical Diagnosis||Requirements for Clinical Diagnosis|
|CNS = central nervous system; ccRCC = clear cell renal cell carcinoma; PHEO = pheochromocytoma.|
|Adapted and updated from Glenn et al.[
|With a family history of VHL||Test DNA for the sameVHLgene pathogenic variant as previously identified in an affected biologic relative(s)||WhenVHLgene pathogenic variant is unknown for a biologic relative||One or more of the following is required for a clinical diagnosis:|
|- Epididymal or broad ligament cystadenoma|
|- CNS hemangioblastoma|
|- Multifocal ccRCC|
|- Retinal hemangioblastoma|
|- Pancreatic neuroendocrine tumor|
|- Pancreatic cysts and/or cystadenoma|
|- Endolymphatic sac tumor|
|Without a family history of VHL||Genetics test result may be negative if theVHLpathogenic variant occurred postzygotically (e.g.,VHLmosaicism)||WhenVHLpathogenic variant is unknown or germline negative, but there are clinical signs of VHL||At least one of the following are required for a clinical diagnosis:|
|- CNS hemangioblastoma|
|- Retinal hemangioblastomas|
|If only one of the above is present, then one of the following is also required for a clinical diagnosis:|
|- Pancreatic cysts and/or cystadenomas|
|- Endolymphatic sac tumor|
|- Epididymal or broad ligament cystadenomas|
At-risk family members should be informed that genetic testing for VHL is available. A family member with a clinical diagnosis of VHL or who is showing signs and symptoms of VHL is initially offered genetic testing. Germline pathogenic variants in VHL are detected in more than 99% of families affected by VHL. Sequence analysis of all three exons detect point variants in the VHLgene (~72% of all pathogenic variants).[
Genetic counseling is first provided, including discussion of the medical, economic, and psychosocial implications for the patient and their bloodline relatives. After counseling, the patient may choose to voluntarily undergo testing, after providing informed consent. Additional counseling is given at the time results are reported to the patient. When a VHL pathogenic variant is identified in a family member, this person's biologic relatives who then test negative for the same pathogenic variant are not carriers of the trait (i.e., they are true negatives) and are not predisposed to developing VHL manifestations. Equally important, the children of true-negative family members are not at risk of VHL either. Clinical testing throughout their lifetime is therefore unnecessary.[
A germline pathogenic variant in the VHL gene is considered a genetic diagnosis. Hence, it predisposes an individual to clinical VHL and confers a 50% risk among offspring to inherit the VHL pathogenic variant. Approximately 400 unique pathogenic variants in the VHL gene have been associated with clinical VHL, and their presence verifies the disease-causing capability of the variant. The diagnostic genetic evaluation in a previously untested family generally begins with a clinically diagnosed individual. If a VHL pathogenic variant is identified, that specific pathogenic variant becomes the DNA marker for which other biological relatives may be tested. Cases can present where an individual meets VHL clinical criteria for diagnosis, but this individual does not test positive for a VHL pathogenic variant; when these individuals also do not have family history of VHL, a de novo pathogenic variant or mosaicism may be the cause. The latter may be detected by performing genetic testing on other bodily tissues, such as skin fibroblasts or exfoliated buccal cells.
Screening for Early Detection of VHL Manifestations
Screening guidelines have been suggested for various manifestations of VHL. In general, these recommendations are based on expert opinion and consensus. Most of these recommendations are not evidence-based. Several VHL screening and surveillance guidelines are available.[
|Examination/Test||Condition Screened For|
|CNS = central nervous system; IAC = internal auditory canal; MRI = magnetic resonance imaging.|
| a Adapted from VHL Alliance.[
|b Age-appropriate history and physical examination includes the following: neurological examination, auditory/vestibuloneural questioning and testing, visual symptoms, catecholamine-excess symptom assessment (headaches, palpitations, diaphoresis, hyperactivity, anxiety, polyuria, and abdominal pain).|
|History and physical examinationb||All conditions listed in this table|
|Dilated, in-person eye examination with ophthalmoscopy||Retinal hemangioblastoma|
|Blood pressure and pulse measurements, plasma free metanephrines or fractionated 24-hour urinary free metanephrines test||Pheochromocytoma/paraganglioma|
|MRI of brain and total spine with and without contrast||CNS hemangioblastoma|
|MRI of abdomen with and without contrast||Renal cell carcinoma, pheochromocytoma/paraganglioma, pancreatic neuroendocrine tumor/cyst|
|Audiological exam, MRI of IAC||Endolymphatic sac tumor|
Level of evidence: 5
Treatment of Disease Manifestations
Treatment of renal tumors
The management of VHL has changed significantly as clinicians have learned how to balance the risk of cancer dissemination while minimizing renal morbidity. Some of the initial surgical series focused on performing a bilateral radical nephrectomy for renal tumors followed by a renal transplantation.[
Patients with VHL can have dozens of renal tumors; therefore, resection of all evidence of disease may not be feasible. To minimize the morbidity of multiple surgical procedures, loss of kidney function, and the risk of distant progression, a method to balance over- and under-treatment was sought. The National Cancer Institute (NCI) evaluated a specific size threshold to trigger surgical intervention. An evaluation of 52 patients treated when the largest solid lesion reached 3 cm demonstrated no evidence of distant metastases or need for renal replacement therapy at a median follow-up of 60 months.[
Many patients with VHL develop new RCCs on an ongoing basis and may require further intervention. Adhesions and perinephric scarring make subsequent surgical procedures more challenging. While a radical nephrectomy could be considered, NSS remains the preferred approach, when feasible. While there may be a higher incidence of complications, repeat and salvage NSS can enable patients to maintain excellent renal function and provide promising oncologic outcomes at intermediate follow-up.[
Level of evidence: 3di
Ablative techniques for renal tumors
Thermal ablative techniques use either extreme heating or cooling of a mass to destroy it. Cryoablation (CA) and radiofrequency ablation (RFA) were introduced to manage small renal masses in the late 1990s.[
Thermal ablation may play an increasing role in the salvage therapy setting for individuals with a high risk of morbidity from surgery. CA was evaluated as a salvage therapy in a series of 14 patients to avoid the morbidity associated with repeated NSS. Results showed minimal change in renal function after treatment with CA. At a median follow-up period of 37 months, there was suspicion for lesion recurrence in only 4 of 33 tumors (12.1%).[
The clinical applications of ablative techniques are not clearly defined in VHL, and surgery remains the most-studied intervention. The available clinical evidence suggests that ablative approaches are only recommended for small (≤3 cm), solid-enhancing renal masses in older patients with high operative risk—especially in those facing salvage renal surgery because of a high complication rate. Young age, tumors larger than 4 cm, hilar tumors, and cystic lesions are relative contraindications for thermal ablation.[
Level of evidence: 3di
Treatment of pheochromocytomas
Surveillance of pheochromocytomas
PHEOs can be a significant source of morbidity in patients with VHL because excess catecholamines can cause significant cardiovascular effects. PHEOs can be detected early when key tests like catecholamine/metanephrine levels and cross-sectional abdominal imaging are done. Most small (≤1 cm) PHEOs can have undetectable levels of catecholamines/metanephrines, thus catecholamine/metanephrine levels can increase with PHEO tumor progression.[
Biochemical testing remains critical to the evaluation of individuals with VHL as levels can often be elevated in the absence of anatomic imaging findings. Assessment begins in childhood with some guidelines recommending initiation at age 5 years. Clinicians have the option of performing plasma testing, urinary testing, or both. The levels of catecholamines can greatly vary as a result of diet and medications; measurement of their metabolites, metanephrines, is suggested because of higher performance metrics. A fourfold, or greater, elevation of metanephrines is suggestive of the presence of a PHEO or paraganglioma (PGL).[
Imaging of pheochromocytomas
Cross-sectional imaging is initiated early in the second decade of life to evaluate the kidneys, adrenal glands, and pancreas. Both magnetic resonance imaging (MRI) and computed tomography (CT) scans have excellent performance characteristics for the detection of PHEOs with a sensitivity of greater than 90%.[
Surgical resection is an important tool for managing PHEOs in individuals with VHL. It is important that all patients have detailed endocrine evaluations and preoperative alpha-blockades prior to surgical resection of PHEOs. Medications are often initiated and carefully titrated prior to surgery to prevent potentially life-threatening cardiovascular complications. For more information, see the Preoperative management section in Genetics of Endocrine and Neuroendocrine Neoplasias.
PHEOs in patients with VHL may have different management than in individuals with sporadic tumors or other hereditary cancer syndromes. The incidence of bilaterality and multifocality is nearly 50%, and historically many patients underwent bilateral adrenalectomy and required lifelong steroid replacement.[
Leaving residual cancer behind is a concern with a partial adrenalectomy in patients with a malignant PHEO; however, in the VHL population, the malignancy rate is extremely low (<5%).[
In a total adrenalectomy, the adrenal vein is generally divided early to limit catecholamine release with gland mobilization. In a partial adrenalectomy, this can lead to venous congestion and gland compromise.[
Both open resection and laparoscopic approaches are safe, but if feasible, laparoscopic removal is preferred.[
Treatment of pancreatic manifestations
VHL-related tumors such as pancreatic neuroendocrine tumors (NETs) may be identified during incidental imaging or during lifelong surveillance protocols.[
Workup and imaging
Pancreatic cysts are benign and rarely require any intervention. Pancreatic cysts in VHL demonstrate no enhancement in imaging and have no malignant potential regardless of size. Diffuse cystic disease rarely affects endocrine function. Infrequently, cystic replacement of the normal pancreas can lead to loss of exocrine function. When bloating, cramping, diarrhea, or abdominal pain occurs with fatty meals, enzymatic studies on the stool could be employed to determine if exocrine supplementation is indicated. Solid or mixed pancreatic lesions require specialized evaluation and treatment as they may represent cystadenomas or pancreatic NETs. The majority of pancreatic NETs are nonfunctional but laboratory evaluation with biochemical markers such as chromogranin A could be considered during the workup or during follow-up. Imaging evaluation with a contrast-enhanced CT or MRI are both excellent modalities to characterize pancreatic lesions. Gallium Ga 68-DOTATATE PET/CT has also been used in the detection of VHL-associated tumors.[
Surveillance of pancreatic manifestations
Serous cystadenomas do not have malignant potential and can be safely observed. Local obstruction of the bile or pancreatic duct is rare. Solid pancreatic NETs have low metastatic potential and if localized, small, and asymptomatic, can be safely observed without concerns. The duration and modality for imaging is center dependent, but the general principles are to perform imaging every 1 to 2 years with the same examination method to allow meaningful comparisons. Lesions with slow doubling times, sizes less than 3 cm, and no exon 3 pathogenic variants have the most favorable outcomes.[
Pancreatic cysts rarely need intervention except when exerting a mass effect. Aspiration or decortication can be considered in these rare cases. Indications for surgery for pancreatic NETs can vary, but intervention is offered to lower the risk of dissemination. Tumor enucleation is safe and effective if the lesion is away from the pancreatic duct. Lesions in the body or tail of the pancreas are removed when they are 3 cm or larger in diameter. If it is not safe to enucleate, a distal pancreatectomy is performed. Tumors of the head that are 2 cm or larger are also evaluated for resection, as larger lesions in this location are more challenging to enucleate. If there is concern with regards to the location of the pancreatic duct, a Whipple procedure is offered. For rare situations where there are large multifocal lesions, a total pancreatectomy could be considered. After surgery, if patients develop exocrine dysfunction, enzyme supplementation may improve gastrointestinal symptoms and nutritional status.
Positive lymph nodes should be removed when found at the time of surgery. For individuals with locally advanced or metastatic pancreatic NETs, surgery is still considered if significant debulking can be offered. Metastatic liver lesions can often be treated with local ablative techniques or resection in select VHL patients.
Treatment of retinal hemangioblastomas
Treatment of retinal hemangioblastomas includes laser treatment, photodynamic therapy, and vitrectomy. Efforts have also been made to use either local or systemic therapy.
Laser photocoagulation is extensively used for retinal hemangioblastomas in patients with VHL disease. A retrospective review of 304 treated retinal hemangioblastomas in 100 eyes showed that laser photocoagulation had a control rate greater than 90%, and was most effective in smaller lesions measuring up to 1 disk diameter.[
Twenty-one patients with severe retinal detachment achieved varying degrees of visual preservation when treated with pars plana vitrectomy with posterior hyaloid detachment, epiretinal membrane dissection, and silicone oil or gas injection with retinectomy or photocoagulation/cryotherapy to remove the retinal hemangioblastoma.[
Photodynamic therapy reduced macular edema in a case series of two patients with bilateral retinal hemangioblastoma involvement; these patients had minimal, if any, benefit in visual acuity.[
Case reports of intravitreal treatment with bevacizumab resulted in stabilization for over 2 years in one case report,[
A case study of proton therapy of eight eyes in eight patients demonstrated resolution of macular edema in seven of eight patients, and all treated eyes experienced preservation of vision after a median follow-up of 84 months.[
Treatment of CNS hemangioblastomas
Surveillance of CNS hemangioblastomas
Many small lesions are found incidentally with screening, and patients may remain asymptomatic for a long period of time. In a study with a short-term follow-up, 35.5% to 51% of CNS hemangioblastomas remained stable.[
In a National Institutes of Health series, the researchers noted that the pattern of growth for CNS hemangioblastoma can vary with saltatory growth most commonly observed (72%), but other patterns such as linear growth (6%) and exponential growth (22%) were also observed.[
Another small series (n = 52) aimed to evaluate growth rates under surveillance. Researchers identified symptomatic presentation as the only independent predictor of growth.[
Surgical resection of cerebellar or spinal hemangioblastomas has been the standard treatment approach. While surgical resection of tumors is generally performed prior to the onset of neurologic symptoms,[
Because patients may have multiple tumors and require several surgical procedures, external beam radiation therapy has emerged as an alternative when surgical resection is not feasible. Stereotactic radiosurgery has become a commonly utilized approach for hemangioblastoma treatment.[
Treatment of endolymphatic sac tumors (ELSTs)
There are limited data on the management of ELSTs, consisting largely of case series detailing surgical management of sporadic and VHL-associated tumors. The largest series details the outcomes in 31 patients treated with surveillance and surgical resection.[
VHL-specific systemic therapy for localized disease
Patients with VHL often require multiple local treatments for their disease manifestations. Recurrent surgical intervention contributes to morbidity and can often cause irreversible damage to affected organs. This can result in a permanent loss of function in the following organs: visual impairment (retina), chronic kidney disease (kidney), adrenal insufficiency (adrenal glands), diabetes and pancreatic exocrine deficiency (pancreas), and neurologic complications such as motor or sensory deficits (brain and spine). Researchers have sought a systemic therapy option that can reduce or eliminate the need for local interventions. Understanding the biology of VHL has led to the development of targeted therapies that interfere with the downstream signaling cascade that is associated with tumorigenesis.[
Initial tanespimycin (17-AAG) therapy research highlighted that intravenous administration of medication may not be preferred by some patients. The modest toxicity and poor tolerability associated with 17-AAG may deter healthy patients (with other surgical options) from using this treatment.[
While anti-VEGF therapy is administered systemically for most VHL-associated neoplasms, in VHL-associated retinal tumors, there is the potential to deliver anti-VEGF therapy directly into the eye. A study of intravitreally-administered pegaptanib (an anti-VEGF therapy) was evaluated in five patients with VHL-associated retinal hemangioblastomas.[
Research targeting downstream consequences of HIF upregulation (due to inactivation of the VHL gene) have only had modest success. Hence, recent efforts have focused on targeting direct consequences of VHL loss. Multiple studies have demonstrated that multiple HIF molecules differentially regulate tumorigenesis, with HIF2 being the most critical mediator.[
VHL in Pregnancy
Two studies have examined the effect of pregnancy on hemangioblastoma progression in patients with VHL.[
Historically, patients with von Hippel-Lindau disease (VHL) had poor survival when compared with the general population, because of the morbidity and mortality of the various disease manifestations and the resultant management.[
In the past, metastatic renal cell carcinoma (RCC) has caused about one-third of deaths in patients with VHL and, in some reports, it was the leading cause of death in VHL patients.[
Morbidity and mortality in VHL vary and are influenced by the individual and the family's VHL phenotype (e.g., type 1, 2A, 2B, or 2C). For more information, see the VHL Familial Phenotypes section. The Danish study reported an increased hazard ratio for death in women,[
Currently, the renal manifestations of von Hippel-Lindau disease (VHL) are generally managed surgically or with thermal ablation. There is a clear need for better management strategies and development of targeted systemic therapy. These will include defining the molecular biology and genetics of kidney cancer formation, which may lead to the development of effective prevention or early intervention therapies. In addition, the evolving understanding of the molecular biology of established kidney cancers may provide opportunities to phenotypically normalize the cancer by modulating residual VHLgene function, identifying new targets for treatment, and discovering synthetic lethal strategies that can effectively eradicate renal cell carcinoma.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Added text to state that a case manager or nurse navigator may be helpful in certain scenarios (cited Wolters et al. as reference 5).
Added text to state that several von Hippel-Lindau (VHL) screening and surveillance guidelines are available (cited Wolters et al. as reference 8 and Binderup et al. as reference 9).
The Ablative techniques for renal tumors subsection was renamed from, "Ablative techniques."
Added Chan et al. as reference 34.
Added VHL-specific systemic therapy for localized disease as a new subsection.
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Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of von Hippel-Lindau disease. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
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Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Cancer Genetics Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
PDQ® Cancer Genetics Editorial Board. PDQ Von Hippel-Lindau Disease. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/kidney/hp/renal-cell-carcinoma-genetics/vhl-syndrome. Accessed <MM/DD/YYYY>. [PMID: 33724751]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
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Last Revised: 2023-04-18
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