- Autosomal dominant inheritance
- Occurs in 1 in 36000 people
- 20% are de-novo mutations
The VHL disease was described in von Hippel’s literature in 1911 and Lindau’s literature in 1926. Melmon and Rosen established the notion of the VHL disease in 1964 . The positional cloning for the disease was started by Latif et al. with the accumulation of DNA in VHL families. Identification of the VHL disease gene was published in 1993. The responsible gene was named as ‘VHL tumor suppressor gene’, which is located on the chromosome 3p25–26 . Further studies showed that the VHL gene is also inactivated in sporadic RCC, HB and Pheo.
- Type 1 (without pheochromocytoma)
- Type 2 (with pheochromocytoma):
- Type 2A: Pheochromocytoma + CNS hemangioblastomas – RCC.
- Type 2B: Pheochromocytoma + CNS hemangioblastomas + RCC
- Type 2C: Pheochromocytoma – hemangioblastomas – RCC
Germline mutations of VHL tumor suppressor gene (chromosome 3)Von Hippel-Lindau is caused by autosomal dominant mutation of the von Hippel–Lindau tumor suppressor gene on chromosome 3 that result in an abnormal pVHL. pVHL regulates a protein known as HIF-1-alpha, which is responsible for cellular response to hypoxia. VHL genetic mutations result in alterations to pVHL at the HIF-1-alpha binding site. As a result, pVHL does not bind effectively to HIF-1-alpha which, in turn, leads to the transcription of several genes and subsequent upregulation of growth factors including erythropoietin, vascular endothelial growth factor, platelet-derived growth factor B, and other genes involved in glucose uptake and metabolism.
- pVHL ubiquitinates hypoxia-inducible factor 1a
Common manifestations:Hemangioblastomas of the brain, spinal cord, and retina; pheochromocytoma and paraganglioma; renal cell carcinoma; pancreatic cysts and neuroendocrine tumors; and endolymphatic sac tumors.
- CNS hemangioblastoma (including retinal hemangioblastoma) (M/C, 60% cases)
- Endolymphatic sac tumours (ELST) (25% cases)
- Renal cell carcinoma (RCC) (~60% cases)
- Pheochromocytoma (paraganglioma elsewhere), and/or glomus tumor (20% cases)
- Neuroendocrine neoplasm and/or multiple cysts of the pancreas (15% cases)
CNS hemangioma (M/C, 60% cases):Benign blood vessel tumour (high vascularity with hyperchromatic nuclei) which can cause headaches, vomiting, sensory or motor deficits, and ataxia.
- Brain stem, spine → Mass, focal lesions, CSF flow → ↑ ICP
- Cerebellum → Ataxia (loss of balance), CSF flow block → ↑ ICP
Retinal hemangioblastomas (up to 60%):Although not the most common tumor in VHL, they are often the first manifestation.
- Retinal angioma → Retinal detachment, blindness (5–8%)
Endolymphatic sac tumors (ELST):Develop from endolymphatic epithelium within the vestibular aqueduct which play a role in the production and resorption of endolymph which is found within the cochlea and semicircular canals.
- Ear fullness, disequilibrium, and hearing loss
- Larger lesions (>3 cm): Facial paresis
Renal manifestations:Renal manifestations of VHL include benign renal cysts (50–70%) and clear cell carcinoma (30%)
- RCC: Renal mass with flank pain or hematuria
- Simple renal cysts: Asymptomatic; complex cysts: Solid renal masses
Pheochromocytomas/paragangliomas:They can be bilateral and occasionally multifocal. Pheochromocytomas usually present in the second decade of life in VHL patients and rarely transform into malignant tumors. These tumors produce catecholamines, such as excessive norepinephrine, causing hypertension, tachycardia, palpitations, headaches, sweating, pallor, and nausea
- Pheochromocytomas → ↑ Norepinephrine & epinephrine → Sympathetic overactivity (headaches, sweating, palpitations, HTN)
- Pheo crisis (fatal): ↑↑↑ Catecholamines (noerpinephrine & epinephrine)
Pancreatic neuroendocrine tumors and cysts (35–70%):There are usually multiple cysts that present without symptoms. Serous cystadenomas and neuroendocrine tumors are other manifestations of pancreatic lesions in VHL syndrome
Epididymal cystadenomasMales with VHL can develop cystadenomas in the epididymis. They may arise unilaterally or bilaterally in 25–60% of VHL males (Table 3). They are benign in nature and do not require surgery
Broad ligament cystadenomasPapillary cystadenomas are rare but found in the mesosalpinx and the broad ligament (5, 14, 16). They may be present unilaterally or bilaterally in women with VHL syndrome. The incidence is unknown (Table 3). The tumor may present as an abdominopelvic mass with symptoms of abdominal discomfort or a painful adnexal mass (5, 14, 16).
- At least 2 CNS hemangioblastomas, or
- At least 1 CNS hemangioblastoma + 1 other manifestation, or
- At least 1 of the manifestations described above, and a pathogenic mutation in VHL gene or a first-degree relative with VHL.
- Plasma free metanephrines
- 24-h urinary measurement of catecholamines
Contrast-enhanced MRI:gold standard for detecting and monitoring CNS hemangioblastomas. It is between 90% and 100% sensitive in the detection of these tumors and is the preferred modality compared to CT. Identification of extra-adrenal tumors may benefit from meta-iodobenzylguanidine (MIBG) scintigraphy
- Classic pattern: Small nests (zellballen) of neuroendocrine cells (chief cells) with interspersed small blood vessels
- Variant and combined patterns: Diffuse growth, large zellballen, spindle cells, cell cords, etc
- Surgically resected safely and are often curative.
- Asymptomatic lesions monitored with annual imaging
- Stereotactic radiosurgery (SRS)
Capillary retinal hemangioblastomaManagement depending on the location and size of the lesions
- Laser photocoagulation
- Vitreoretinal surgery
- External beam radiotherapy (refractory cases)
- Surgical resection is the mainstay therapy
- Radiation therapy (unresectable tumors)
- No intervention necessary for tumors < 3 cm
- Partial nephrectomy: Tumors ≥ 3 cm (to reduce the risk of metastasis while maintaining kidney function)
- Percutaneous and laparoscopic radiofrequency ablation therapy: Smaller tumors (<3 cm) with low complication rates
Pancreatic cysts:Do not require surgical intervention
- PNETs with a potential for metastatic disease: Resected with enucleation by Whipple’s procedure or partial pancreatectomy depending on the size and location of the tumor