Jed-Sian Cheng, MD, MPH
Gennady Bratslavsky, MD
BASICS
DESCRIPTION
• Von Hippel–Lindau (VHL) disease is a multisystem autosomal dominant neoplastic syndrome with a predisposition to develop:
– Clear cell renal cell carcinoma (ccRCC) and cystic lesions
– Pancreatic neuroendocrine tumors (NET) and cystic lesions
– Pheochromocytomas
– Central nervous system (CNS) hemangioblastomas
– Retinal angiomas
– Endolymphatic sac tumors (ELST)
– Cystadenomas of the epididymis (males) or broad ligament (females)
EPIDEMIOLOGY
Incidence
Rare: 1 in 35,000 live births
Prevalence
Prevalence in USA: About 7,000 people
RISK FACTORS
• Inheritance of a mutated VHL allele
• No gender or racial predilection
Genetics
• Autosomal dominant inheritance pattern
• VHL is a tumor suppression gene on chromosome 3p25–26 (3)
• Affected individuals inherit 1 copy of a mutated VHL from the affected parent
• The loss or mutation of the 2nd (initially normal) allele in the cell leads to tumor formation (mechanism known as a 2-hit model)
• Present technology identifies the mutated gene in 100%
PATHOPHYSIOLOGY
• Mutated VHL leads to aberrant VHL protein (pVHL)
• Abnormal pVHL is unable to target hypoxia inducible factor (HIF) for degradation
• Accumulation of HIF protein upregulates downstream genes such as VEGF, GLUT-1, PDGF, TGF-α, Epo, and many others, leading to tumor formation
ASSOCIATED CONDITIONS
• Multifocal and bilateral ccRCC in 50%
• Renal cysts seen in up to 70%
• Pheochromocytomas in about 20%
– Extra-adrenal pheochromocytomas in <5%
• CNS hemangioblastomas in 75%
• Retinal angiomas in 50–55%
• Pancreatic NET in 15–20%
• Pancreatic cysts are seen in up to 60%
• ELST in 5–10%
• Papillary cystadenomas of the epididymis or broad ligament in <5%
• VHL-associated lung cysts/tumors in <1%
• VHL-associated ovarian tumors in <1%
GENERAL PREVENTION
• Close surveillance of affected individuals and timely intervention
• Genetic screening of family to initiate early surveillance
DIAGNOSIS
HISTORY
• Family history of RCC or pheochromocytoma, CNS or pancreatic surgeries, hearing or vision problems is often elicited
• Patients may present with ≥1 symptoms related to the organ involved
• Renal tumors and cysts:
– Usually detected incidentally or during screening by imaging in VHL patients
– May present with hematuria, flank pain, abdominal fullness, weight loss, cachexia in advanced disease
• Pheochromocytoma:
– Headaches, palpitations, episodic sweating, anxiety attacks, personality changes
– Severe hypertension (HTN) leading to hemorrhagic stroke
– Rarely may present with weight loss, cachexia, bone pain, or cough in setting of metastatic disease
– May be asymptomatic
• CNS hemangioblastomas:
– Often asymptomatic
– Headaches, vertigo, ataxia, vomiting, wide-based gait, sensory loss, seizures
– Size and location of the lesion(s) often determine symptoms
• Retinal angiomas:
– Blurred or decreased vision, eye pain
– If undetected, may present with blindness
• Pancreatic NET and cysts:
– Most are asymptomatic
– Diarrhea, steatorrhea, and diabetes may occur if pancreas is replaced by cysts
– Early satiety if pancreatic cysts are large and compressing the stomach
– Bone pain and painless jaundice in rare cases of extrinsic compression of the biliary system or metastatic disease
• ELST:
– Hearing decrease or loss, tinnitus, vertigo
• Cystadenomas of epididymis:
– Scrotal or testicular tenderness or mass
PHYSICAL EXAM
• Careful urologic, neurologic, and ophthalmologic exam can often help with diagnosis of VHL
• ccRCCs:
– Undetected unless large in size
– May cause marked varicocele
– Occasionally, skin lesions or jaundice may be appreciated in metastatic RCC
• Pheochromocytoma:
– HTN, tachycardia, arrhythmias
• CNS hemangioblastomas:
– Nystagmus, papilledema, loss of proprioception, and sensory deficits
• Retinal angiomas:
– Decreased visual acuity, characteristic retinal hemangiomas, and retinal detachment
• Pancreatic NET:
– Undetected on exam unless large in size, metastatic, or causing obstruction
• ELST:
– Decrease or loss of hearing
• Papillary cystadenomas of the epididymis:
– Paratesticular tenderness and palpable epididymal masses
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Elevated plasma and urine catecholamines are seen in patients with pheochromocytoma:
– Norepinephrine or normetanephrine are most commonly elevated in VHL patients
– Other catecholamines may also be elevated
• Similar to sporadic ccRCC:
– Hypercalcemia, erythrocytosis, anemia, or elevated liver function tests (LFTs) may be seen as paraneoplastic lab abnormalities
• Elevated erythropoietin levels or erythrocytosis may be seen with CNS involvement
Imaging
• Brain and spine magnetic resonance imaging (MRI) for detection of CNS hemangioblastomas and ELSTs
• Abdominal imaging: Ultrasound (US) in children, and computed tomography (CT) or MRI in adults for detection of renal or pancreatic masses, as well as adrenal and extra-adrenal pheochromocytomas
• Metaiodobenzylguanidine scan (MIBG) scan is helpful in localizing active pheochromocytoma
• Chest CT or MIBG may be helpful for extra-abdominal pheochromocytomas
Diagnostic Procedures/Surgery
• Genetic testing
• Occasionally, the glucagon stimulation test or clonidine suppression for pheochromocytoma
Pathologic Findings
• ccRCCs:
– Usually multifocal and bilateral
– May be several hundreds of gross and microscopic lesions in a single kidney
– Most commonly Fuhrman nuclear grade II
– Cysts commonly lined by clear cells
• Pheochromocytoma:
– Encapsulated and vascular
– Frequently multifocal and bilateral
– Microscopic: Nests of cells in round clusters
• CNS hemangioblastomas:
– Solitary or multiple lesions in cerebellum, spinal cord, brainstem, or cerebrum
– Benign vascular lesions
• Pancreatic NET:
– Usually multifocal intermixed with cysts
– May metastasize to liver or bones unless resected in timely manner
– Well-demarcated, unencapsulated nodules
– Microscopic: Nests of polygonal cells with vesicular nuclei
• ELST:
– Locally aggressive; usually slow growing
– Microscopic: Low-grade papillary adenocarcinomas
• Papillary cystadenomas of the epididymis or the broad ligament:
– Benign lesions
– Well circumscribed but unencapsulated
– Microscopic: Papillary and tubular architecture with a fibrous stroma
DIFFERENTIAL DIAGNOSIS
• Metastatic RCC or other primary
• Multiple endocrine neoplasia type 2 (MEN-2)
• Non-VHL familial bilateral multifocal RCC
• Other familial types of hereditary renal carcinoma syndromes
• Polycystic kidney disease
• Sporadic form of bilateral RCC
• Succinate dehydrogenase B (SDHB) deficiency syndrome in the presence of pheochromocytoma and renal masses
TREATMENT
GENERAL MEASURES
• Vigilant surveillance of kidneys, adrenals, pancreas, retina, brain, and spinal cord are the most important measures for timely intervention
• Surgery is still the mainstay of VHL treatment
• Nephron-sparing surgery is recommended when the largest solid tumor reaches 3 cm in the largest dimension
MEDICATION
First Line
• No VHL-specific medical treatment
• Treatment directed to address immediate presenting symptoms (eg, antihypertensives in patients presenting with pheochromocytoma)
• Other agents may be necessary for the management of related diseases such as RCC
• Preoperative blockade in a patient with a known pheochromocytoma
– National Cancer Institute (NCI) regimen: Phenoxybenzamine 10 mg BID and metyrosine 250 mg TID for 2 wk preop
Second Line
N/A
SURGERY/OTHER PROCEDURES
• ccRCC:
– Dozens of tumors may be resected in a single setting with adequate renal preservation
– To minimize renal ischemia, most of the surgery is performed without hilar clamping
– Select patients may benefit from laparoscopic or robotic surgery
– Prior renal surgery or ablation makes surgery more challenging and increases morbidity
– Bilateral nephrectomies and renal transplantation may be a valid option for occasional patients
• Pheochromocytoma:
– Laparoscopic, robot-assisted, or open partial adrenalectomies are performed to preserve maximal adrenal function and avoid steroid dependence (1)
• Pancreatic NET:
– Resection is the most definitive treatment
– The type of surgical resection and procedure is determined by tumor size and location
• ELSTs or hemangiomas: Surgical resection
• Retinal angiomas: Laser ablation or cryotherapy
ADDITIONAL TREATMENT
Radiation Therapy
Occasional stereotactic irradiation of the metastatic disease or CNS hemangioblastomas not amendable to surgical resection
Additional Therapies
• A few clinical trials are presently in progress for treatment of VHL-associated tumors
• Genetic counseling, ophthalmology, neurosurgery, and otolaryngology support as needed
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• Much depends on the stage of the renal lesions at presentation
• Growth rate similar to sporadic counterpart of about 3 mm on average per year
• No metastasis with solid RCC lesions <3 cm (2)
• Metastatic potential of RCC lesions increases with increase in the size of the lesion, with up to 50% metastasis in those with tumors >6 cm
• Pancreatic NET also increase metastatic potential with increase in size
COMPLICATIONS
• Hypertensive crisis resulting in hemorrhagic stroke
• Severe neurologic deficit or paralysis
• Blindness
• Metastatic disease from either RCC, pheochromocytoma, or pancreatic NET
FOLLOW-UP
Patient Monitoring
• Radiographic surveillance is performed every 1–2 yr with CT or MRI for kidneys, adrenal, pancreas; and MRI for brain or spinal cord
– More frequent for faster-growing lesions
• Ophthalmology exams yearly
• Otology exams every 5 yr
• Pediatric considerations
– Yearly ophthalmologic exam from birth
– Yearly urinary catecholamines from age 2 yr
– Yearly abdominal US from age 10 yr
• Pregnancy considerations
– Higher risk of miscarriage with active pheochromocytoma
– Treatment of pheochromocytoma is preferred before pregnancy or early in the pregnancy
Patient Resources
www.vhl.org
REFERENCES
1. Benhammou JN, Boris RS, Pacak K, et al. Functional and oncologicoutcomes of partial adrenalectomy for pheochromocytoma in patients with von Hippel-Lindau syndrome after at least 5 yearsof follow up. Urology. 2005;66(1):19–23.
2. Duffey BG, Choyke PL, Glenn G, et al. The relationship between renal tumor size and metastases in patients with von Hippel-Lindau disease. J Urol. 2005;72(1):63–65.
3. Linehan WM, Vasselli J, Srinivasan R, et al. Genetic basis of cancer of the kidney: Disease-specific approaches to therapy. Clin Cancer Res. 2004;15(10 Pt 2):6282S–6289S.
ADDITIONAL READING
• Shuch B, Linehan WM, Bratslavsky G. Repeat partialnephrectomy: Surgical, functional and oncologicaloutcomes. Curr Opin Urol. 2011;21(5):368–375.
• Singer EA, Vourganti S, Lin KY, et al. Outcomes ofpatients with surgically treated bilateral renalmasses and a minimum of 10 years of follow up. J Urol. 2012;188(6):2084–2088.
• Zbar B, Glenn G, Merino M, et al. Familial renal carcinoma: Clinical evaluation, clinical subtypes and risk of renal carcinoma development. J Urol.2007;177(2):461–465.
See Also (Topic, Algorithm, Media)
• Adrenal Mass
• Epididymis, Mass (Epididymal Tumor and Cysts)
• Pheochromocytoma
• Renal Cell Carcinoma, General
• Renal Cell Carcinoma, Localized (T1–T2)
• Renal Cysts (Intrarenal, Peripelvic, and Parapelvic)
• Renal Mass
• Von Hippel-Lindau Disease/Syndrome Image 
CODES
ICD9
• 189.0 Malignant neoplasm of kidney, except pelvis
• 209.60 Benign carcinoid tumor of unknown primary site
• 759.6 Other hamartoses, not elsewhere classified
ICD10
• C64.9 Malignant neoplasm of unsp kidney, except renal pelvis
• D3A.8 Other benign neuroendocrine tumors
• Q85.8 Other phakomatoses, not elsewhere classified
CLINICAL/SURGICAL PEARLS
Suspect VHL in a patient with strong family history of RCC or pheochromocytoma, CNS or pancreatic surgeries, hearing or vision problems.