Alok Bansal

BASICS

DESCRIPTION

• Von Hippel-Lindau (VHL) disease is an inherited cancer predisposition syndrome characterized by various tumors affecting multiple organ systems (see ‘Commonly Associated Conditions’).

• The primary ophthalmic finding, retinal capillary hemangioblastoma, is common; it is frequently an early manifestation of VHL disease.

EPIDEMIOLOGY

Incidence

1 in 40,000–54,000 live births (1,2)

Prevalence

• VHL disease is rare, affecting approximately 7,000 patients in the US (3)

• Retinal capillary hemangioblastomas is found in approximately 37–59% of patients with VHL (3,4)

RISK FACTORS

Genetics

• Autosomal dominant

• High penetrance

• Chromosome 3 (3p25–26)

GENERAL PREVENTION

Genetic counseling

PATHOPHYSIOLOGY

• The VHL gene functions as a tumor suppressor gene.

• Tumor formation results from lack of function of the gene.

• Tumor formation thought to follow two-hit model (similar to retinoblastoma).

• Clinical phenotype of ocular manifestations in VHL may vary based on precise gene mutation (4).

COMMONLY ASSOCIATED CONDITIONS

• Hemangioblastoma

– Retinal

– Cerebellar

– Spinal cord

• Visceral lesions

– Renal cell carcinoma

– Pheochromocytoma

– Renal cysts

– Pancreatic cysts

– Islet cell tumors

– Epididymal cystadenoma

– Bilateral endolymphatic sac tumors

– Adnexal papillary cystadenoma of probable mesonephric origin (APMO)

DIAGNOSIS

HISTORY

• Family history is paramount as VHL is inherited in an autosomal dominant manner, however, full penetrance does not occur until approximately age 65 years. If history is equivocal consider examination of family members.

• A detailed review of systems may reveal complaints related to any of the potential associated disorders (see ‘Commonly Associated Conditions’). However, many of the associated conditions are asymptomatic in VHL disease and therefore screening protocols have been developed (see “Follow-up Recommendations’).

PHYSICAL EXAM

• Classification of retinal capillary hemangioblastomas is based on location.

• Peripheral endophytic

– Most common

– Reddish–orange circumscribed tumor (one or more)

– Progressive enlargement

– Dilated, tortuous feeding, and draining vessels

– Intraretinal and subretinal exudation (frequently in macula)

– Possible tractional retinal detachment

• Juxtapapillary

– Less common

– May appear as discrete red/pink lesions at the disc margin (endophytic) or as diffuse gray/pink thickening that may blur the disc borders (exophytic)

• Systemic/visceral

– CNS hemangioblastoma

Cerebellum (75%) and spinal cord (15%) are most common locations

– Pheochromocytoma

Typically bilateral and multiple in VHL disease

Palpitations, anxiety, headaches, sweating, hypertension

– Renal cysts

Potential malignant transformation

– Renal cell carcinoma

Bilateral in large majority (90%) of cases in VHL disease

Typically lack pain or hematuria

– Pancreatic cysts

– Secretory versus non-secretory

– Cystadenoma of epididymis or broad ligament

Asymptomatic and largely benign

Rarely a cause of infertility

– Endolymphatic sac tumor

Locally aggressive, benign cystadenoma

May present with impaired hearing, tinnitus, and vertigo

DIAGNOSTIC TESTS & INTERPRETATION

Lab

• Urinary catecholamines

• Genetic evaluation

Imaging

Initial approach

– Fundus photos

• Fluorescein angiography (FA)

– Rapid arterial phase

– Diffuse leakage in mid and late frames

• Systemic evaluation

– Brain/spine MRI

– Abdominal CT/MRI/ultrasound

Follow-up & special considerations

May use retinal fundus photos to follow progression or assess response to treatment for retinal capillary hemangioblastoma.

Diagnostic Procedures/Other

• Ultrasonography (ocular)

– Acoustically solid with variable reflectivity (medium or high reflectivity)

• CT

– Thin section, contrast enhanced CT is sensitive for early renal lesions

• MRI

– Most useful for detecting CNS hemangioblastoma

– Hyperintense on T1

– Hypointense on T2

– Enhance with contrast

• Diagnostic Criteria

– Based upon presence of retinal or CNS capillary hemangioblastoma, visceral lesions, and family history

– With positive family history, only 1 hemangioblastoma (retinal or CNS) or visceral lesion required

– Negative family history requires 2 hemangioblastomas or a hemangioblastoma and a visceral lesion

• National Cancer Institute classification

– Type I – Pheochromocytoma absent

– Type II – Pheochromocytoma present (further subdivisions of Type II exist)

Pathological Findings

• Spindle cells, small blood vessels, clear stromal cells

• Stromal cells appear to be cells of origin

DIFFERENTIAL DIAGNOSIS

Retinal Capillary Hemangioblastoma

• Coats’ disease

• Racemose hemangioma

• Retinal arterial macroaneurysm

• Retinal cavernous hemangioma

• Vasoproliferative tumor

TREATMENT

SURGERY/OTHER PROCEDURES

• Most common procedures/therapy

– Laser photocoagulation

– Cryotherapy

• Less common procedures/therapy

– Photodynamic therapy

– External beam radiotherapy

– Proton beam radiotherapy

– Plaque radiotherapy

• New or experimental therapy (4)

– Systemic anti-VEGF

– Local anti-VEGF

• Visceral/systemic

– CNS angiomas are typically observed but may be surgically excised if symptomatic

– Small renal cell carcinomas (<3 cm) may be observed, larger lesions are typically removed with nephron-sparing surgery

– Functional pheochromocytomas are excised with adrenal sparing surgery

– Early removal of endolymphatic sac tumors may prevent hearing loss

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

• Patients with or at risk for VHL (5)

– Ophthalmoscopy yearly

– Urinary catecholamine yearly

– MRI of brain and spine every 2 years

– Abdominal ultrasound every year

– Abdominal CT every 1–2 years

• Ophthalmologist (likely retina or oncology) to follow ocular lesions and implement treatment when appropriate

• Referral to geneticist and/or oncologist with an interest/expertise in VHL

PROGNOSIS

• Risk of severe bilateral vision loss (legal blindness) is low (approximately 5%).

• Risk of severe unilateral vision loss (20/200) is approximately 25%.

– Risk increases with age, juxtapapillary tumors, and increased tumor number.

• Morbidity/mortality commonly associated with CNS lesions or renal cell carcinoma.

– Average life expectancy of approximately 50 years

– Appropriate screening may reduce morbidity and mortality.

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