7.3.9.2  Systemic Manifestations

CNS Hemangioma

CNS hemangioma is seen in 35–59% of VHL patients [75, 77]. In contrast to sporadic cases, CNS hemangioma in VHL patients tends to be multiple and presents at a younger age. The cumulative probability of developing CNS hemangioma increases with age, from 44% at 30 years to 84% at 60 years. Symptoms of hemangioma depend on its location and size [75, 82, 94–96]. Headache is the most frequent initial symptom in cerebellar hemangioma and radicular pain is common in spinal cord hemangioma. Gadolinium-enhanced magnetic resonance imaging is the best for detecting CNS hemangioma and most frequently shows a small fluidfilled cavity with an enhancing solid nidus [94]. Surgical removal is indicated only in symptomatic lesions [95].

not elevate catecholamines can be detected by contrastenhanced CT and MRI [99]. Small asymptomatic and nonfunctional lesions can be observed. Adrenal-sparing surgery is recommended for functional pheochromocytomas [99, 105, 106].

Pancreatic Cystadenoma and Islet Cell Tumors

Pancreatic lesions in VHL disease are usually classified as nonsecretory (cyst and cystadenoma) or secretory (islet cell tumors). Pancreatic cysts are more common than cystadenomas. These lesions are usually asymptomatic and tend to remain stable. Islet cell carcinomas are neural crest in origin and can secrete various hormones such as glucagon, gastrin, and somatostatin. These lesions frequently coexist with pheochromocytomas­.

Epididymis Cystadenoma

Renal Cell Carcinoma

Renal cell carcinomas (RCC) occur in 24–47% of patients with VHL disease and are the leading cause of mortality [75, 77, 79, 97, 98]. These lesions can arise de novo or from renal cysts [82, 99–101]. The majority of RCC are asymptomatic and screening is critical in VHL patients. Thin section, contrast-enhanced CT is more sensitive than ultrasound in detecting early lesions [102]. RCC less than 3 cm do not metastasize and are managed by observation. Nephron-sparing surgery is preferred for larger tumors [99]. Patients with advanced bilateral RCC may require bilateral nephrectomy and subsequent renal transplantation [103].

Pheochromocytoma

Pheochromocytoma is a rare benign tumor of the adrenal medulla. It arises from neural crest tissue and produces catecholamines, norepinephrine, and epinephrine. Overproduction of catecholamines causes palpitations, anxiety attacks, headaches, and sweating. Most tumors cause labile hypertension and result in life-threatening hypertensive crisis, myocardial infarction, cardiac failure, and cerebrovascular accidents [104]. Diagnosis is based on biochemical and imaging studies. Urinary excretion of epinephrine, norepinephrine, and vanillylmandelic acid over 24 h is measured. Tumors that do

Papillary cystadenoma of the epididymis is a rare benign tumor that is best detected with scrotal sonography. It appears as a solid mass with small cystic components. Rarely, it can cause infertility [107].

7.3.10  Diagnosis and Diagnostic Aids

Strict diagnostic criteria for VHL disease have been set based on the observation of Melmon and Rosen [63]. Three elements are included: RCH or CNS hemangioma, visceral lesions, and family history of similar lesions (Table 7.5).

Table 7.5  Diagnostic criteria for von Hippel-Lindau disease

*Family history of retinal hemangioma, CNS hemangioma, or visceral lesion

**Visceral lesion includes renal cysts, renal cell carcinoma, pheochromocytoma, pancreatic cysts, islet cell tumors, epididymal cystadenoma, endolymphatic sac tumor, adnexal papillary cystadenoma of probable mesonephric origin