Von Hippel-Lindau Disease

Von Hippel-Lindau (VHL) disease is an autosomal dominant genetic condition resulting from a deletion or mutation in the VHL gene. Individuals diagnosed with VHL disease have tumors and cysts in various parts of their bodies and may present with hemangioblastomas, renal cell carcinoma (RCC), pheochromocytoma, endolymphatic sac tumors of the middle ear, pancreatic tumors, and papillary cystadenomas of the epididymis or the broad ligament. The diagnosis is by genetic testing, laboratory evaluation of BUN, laboratory evaluation for the presence of catecholamines in the blood or urine, fundoscopic exam of the eye to detect hemangioblastoma of the retina, and CT/MRI to detect any other tumors. Management of the disease includes surgical removal of tumors. 

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Overview

Definition

Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder characterized by hemangioblastomas of the retina and CNS; cysts involving the kidneys, pancreas, and epididymis; renal cell carcinoma (RCC); pheochromocytomas; and pancreatic islet cell tumors.

Etiology

  • Mutation in the VHL tumor-suppressor gene located on chromosome 3 causes VHL disease.
  • The mutation may be de novo or can occur through autosomal dominant inheritance.
  • 80% of cases are genetically inherited.
  • 20% of cases are new mutations.

Epidemiology

  • Prevalence is estimated to be 1 in 30,000 to 1 in 50,000 live births.
  • Men and women are equally affected.
  • The average age of diagnosis is 26 years; however, individuals are diagnosed at any time from birth to death.
  • VHL disease is the most frequent cause of hereditary renal cancer.
  • The incidence of pheochromocytoma is up to 60% in individuals with VHL disease.

Classification

  • Type 1, without pheochromocytoma
  • Type 2, with pheochromocytoma:
    • Type 2A: Pheochromocytoma is present along with a low incidence of RCC.
    • Type 2B: Pheochromocytoma is present along with a high incidence of RCC.
    • Type 2C: Pheochromocytoma is present without hemangioblastoma or RCC.

Pathophysiology

  • Autosomal dominant mutation of the VHL tumor-suppressor gene on chromosome 3 leads to the formation of abnormal VHL protein (pVHL).
  • Abnormal or absent pVHL results in the uninhibited upregulation of hypoxia-inducible factor (HIF).
  • Upregulated growth factors (e.g., vascular endothelial growth factor, erythropoietin)
  • The above factors lead to the formation of cysts and hypervascular tumors that are characteristic of VHL disease.

Clinical Presentation

The presentation varies depending on the size and location of the tumor. Family history is a key piece of information, as the majority of cases are inherited. Physical examination is usually nonrevealing, with the exception of affected individuals who present with neurologic abnormalities in the setting of hemangioblastomas.

  • Hemangioblastomas:
    • Well-circumscribed, capillary vessel-rich neoplasms
    • Benign, do not invade locally or metastasize
    • Occur in 60%–84% of individuals with VHL disease
    • Common in the retina, cerebellum, and spinal cord
    • May cause visual deficits if present on the retina
    • May cause focal neurologic deficits if present in the cerebellum or spinal cord 
  • RCC:
    • Occurs in ⅔ of affected individuals
    • Clear cell tumors are the most common variant of RCC seen in individuals with VHL disease.
    • Most often multicentric and bilateral
    • Can arise either in conjunction with cysts or de novo from noncystic renal parenchyma
    • Affected individuals present with flank pain, hematuria, and renal dysfunction.
  • Pheochromocytoma:
    • Present in up to 16% of individuals with VHL disease
    • Usually presents in the 2nd decade of life
    • May cause episodic hypertension with palpitations, panic attacks, diaphoresis, and mood changes
  • Endolymphatic sac tumors of the middle ear:
    • Highly vascular lesions arising within the posterior portion of the temporal bone
    • Clinical manifestations include hearing loss, tinnitus, vertigo, and facial muscle weakness.
    • Often bilateral
    • Most commonly seen in the younger age group
  • Pancreatic tumors:
    • Usually asymptomatic
    • Can present with epigastric pain and abdominal discomfort
  • Papillary cystadenoma of the epididymis or broad ligament:
    • Bilateral papillary cystadenomas are almost pathognomonic of VHL disease.
    • Benign and generally asymptomatic; thus, no treatment is required

Mnemonic

HIPPEL:

  • Hemangioblastoma
  • Increased risk of RCC
  • Pheochromocytoma
  • Pancreatic lesions (cysts, cystadenomas, and neuroendocrine tumors)
  • Eye Lesions (retinal angiomas or hemangioblastoma)

Diagnosis

  • Clinical criteria used to diagnose VHL disease:
    • > 1 CNS hemangioblastoma
    • Visceral manifestation of VHL disease
    • VHL manifestation in addition to a family history significant for VHL disease
  • Genetic testing:
    • Heterozygous pathogenic variant of the VHL gene confirms the diagnosis of inherited VHL disease.
    • Pathogenic variants may arise from de novo mutations.
    • Rare cases exhibit clinical features of VHL disease but there are no detectable mutations.
  • Fundoscopic/ophthalmologic eye exam:
    • To detect hemangioblastoma of the eye
    • To detect retinal detachment
    • To check for cataracts
  • Audiometric testing: may show hearing loss secondary to an endolymphatic sac tumor
  • Laboratory tests:
    • BUN and creatinine levels to determine renal involvement
    • Presence of catecholamines and/or their metabolites in blood and/or urine to detect pheochromocytoma
  • CT/MRI imaging studies to detect:
    • RCC
    • Pheochromocytoma
    • Hemangioblastoma
    • Endolymphatic sac tumors of the middle ear

Management

Treatment of VHL disease is tailored depending on the location and size of the lesions, symptoms of the individual, and the extent of the disease.

  • CNS hemangiomas are surgically removed:
    • Recurrence is possible after surgical removal.
    • Gamma knife radiosurgery is an alternative treatment.
  • Retinal capillary hemangiomas are usually treated with diathermy, xenon, laser photocoagulation, and external beam radiotherapy:
    • Small hemangiomas that do not interfere with vision can be observed.
    • Laser photocoagulation is the preferred treatment for small lesions.
    • Cryotherapy is the preferred treatment when fluid is present underneath the retina.
  • Nephrectomy:
    • The preferred approach in cases of RCC associated with VHL disease
    • Cryoablation and radiofrequency ablation are preferred for small tumors.
  • The preferred treatment for symptomatic pheochromocytoma is the surgical removal after appropriate supportive therapy:
    • Preoperative alpha-adrenoceptor and beta-adrenoceptor blockers are prescribed to avoid excess catecholamines.
    • Laparoscopic adrenalectomy is the preferred surgical approach except in cases where the tumor is invasive or > 6.0 cm.
  • Treatment of endolymphatic sac tumors of the middle ear is primarily by surgical removal to prevent hearing loss.
  • Surgical resection is preferred for pancreatic neuroendocrine tumors:
    • Indicated for tumors > 3 cm
    • Indicated if the tumor-doubling rate is < 500 days
Surgically removed pheochromocytoma

Surgically removed pheochromocytoma

Image: “Adrenal paraganglioma clinical Pheochromocytoma” by Michael Feldman. License: CC BY 2.0

Differential Diagnosis

  • MEN2: an autosomal dominant inherited condition characterized by a hormone-producing tumor. The MEN2A variant is associated with primary hyperparathyroidism, whereas MEN2B is associated with neuromas and Marfanoid habitus. Neck mass, lymph node enlargement, hypertension, tachycardia, headache, and pheochromocytoma are the presenting symptoms. Diagnosis is based on lab studies, CT, and RET mutation analysis. Surgical removal of the tumor is the primary treatment modality.
  • Pheochromocytoma: a catecholamine-secreting tumor derived from chromaffin cells. Symptoms result from excessive catecholamine production and include hypertension, tachycardia, headache, and sweating. Diagnosis is made on the basis of clinical examination, laboratory studies, and CT. Approximately 90% of pheochromocytomas are benign, and surgical resection is the only curative treatment. Pheochromocytomas are associated with VHL disease but some cases present in isolation without other findings of VHL disease.
  • Neurofibromatosis type 1 (NF1): an autosomal dominant inherited condition characterized by an abnormality in the tumor-suppressor gene, giving rise to nerve tumors. Affected individuals present with café au lait spots, neurofibroma, skinfold freckling, optical pathway gliomas, and Lisch nodules. The diagnosis is based on the NIH clinical criteria and imaging studies. Selumetinib and surgery are the treatment modalities.
  • RCC: the most common cancer of the kidney. Renal cell carcinomas are often asymptomatic and can present with hematuria, flank pain, and an abdominal mass. Diagnosis is based on imaging studies and biopsy. Treatment is by removing the kidney in part or entirety. In addition to being associated with VHL disease, RCC is also encountered in several paraneoplastic syndromes that cause hypercalcemia, anemia, and amyloidosis.

References

  1. Plon, E.S., Jonasch, E. (2020). Clinical features, diagnosis, and management of von Hippel-Lindau disease. UpToDate. Retrieved August 21, 2021, from https://www.uptodate.com/contents/clinical-features-diagnosis-and-management-of-von-hippel-lindau-disease
  2. Plon, E.S., Jonasch, E. (2020). Molecular biology and pathogenesis of von Hippel-Lindau disease. UpToDate. Retrieved August 21, 2021, from https://www.uptodate.com/contents/molecular-biology-and-pathogenesis-of-von-hippel-lindau-disease
  3. Mikhail, M.I., Singh, A.K. (2021). Von Hippel Lindau Syndrome. NCBI. Retrieved August 21, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK459242/
  4. Leeuwaarde, R.S., Ahmad, S., Links, T.P., Giles, R.H. (2018). Von Hippel-Lindau Syndrome. NCBI. Retrieved August 21, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK1463/
  5. Chittiboina, P., Lonser, R.R. (2016). Von Hippel–Lindau disease. NCBI. Retrieved August 21, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5121930/
  6. Gulani, A.C., Defendi, G.L. (2019). von Hippel-Lindau Disease. MedScape. Retrieved August 21, 2021, from https://emedicine.medscape.com/article/1219430

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