von Hippel Lindau disease

Introduction of von Hippel Lindau disease

The Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder where patients have central nervous system hemangioblastoma (cerebellar, cerebral and spinal), retinal angioma, renal cysts and renal carcinoma, endolymphatic sac tumors, neuroendocrine tumors and cysts of the pancreas, epididymal cystadenoma, and pheochromocytoma in varying combinations. The incidence has been estimated to 1/36000. Patients have been classified as VHL type 1 without pheochromocytoma, and VHL type 2 with pheochromocytoma. Type 2A appears without renal carcinoma (and low frequency of hemangioblastoma and retinal angioma); type 2B have renal carcinoma (and high frequency of other manifestations), and type 2C have only pheochromocytoma. Deaths have been due to complications of cerebellar hemangioblastoma, or metastatic clear cell renal carcinoma. Retinal lesions may cause blindness due to retinal detachment or hemorrhage, but usually responds to treatment with laser or cryotherapy. Pheochromocytomas have been found in altogether 7-20% of VHL families, and in 15% of VHL patients. VHL germ-line mutations may cause at least 10-20% of all pheochromocytomas, and many cases represent de novo mutations, with unrecognized VHL disease.

Genetics of von Hippel Lindaus disease
The VHL gene located on chromosome 3p25-26 is a tumor suppressor gene. VHL type 1 families most often have larger deletions of the VHL gene, with a resulting non-functioning protein. VHL type 2 families with pheochromocytoma often have missense mutations (92%), with a functioning VHL protein, which may be necessary to develop pheochromocytoma. Among mutation carriers in type 2 families 60-80% risk to develop pheochromocytoma. Missense mutations in codon 167 have been found in 33% of VHL patients with type 2 disease and pheochromocytoma.

Pheochromocytomas may be the first manifestation of VHL. The disease has often presented in young patients, median age ∼28 years, and is a common cause of pheochromocytomas in children. The pheochromocytomas are often small, multifocal and bilateral (50%) at time of diagnosis. Extraadrenal pheochromocytomas occur in 12%, most of them abdominal, but rare thoracic, neck and middle ear paraganglioma have also been reported. Thus, multifocal tumors can be expected in >60% of VHL patients. Malignant pheochromocytoma have been encountered in 3%, the risk is higher with large tumors (>5 cm). Rare patients present with spread malignant disease.

Many VHL pheochromocytomas are small and functionally inactive, and patients are often normotensive and asymptomatic, especially when detected by screening. They still constitute a serious threat because sudden release of catecholamines may occur during surgery or pregnancy and cause unexpected death. VHL pheochromocytomas mainly release norepinehprine, indicating a biochemical noradrenergic phenotype.

Recommendations infer that life-long monitoring of all VHL patients, apart from ophthalmologic examination and MRI of brain and spine, should include screening for pheochromocytoma. This may be done by determination of urinary catecholamines (or plasma metanephrines), and abdominal CT (or ultrasound in young individuals) every 1-2 year. Screening for pheochromocytoma should begin at the earliest reported age of diagnosis, which has been 4 years. A large proportion of VHL patients (35%) with smaller pheochromocytoma initially have normal urinary catecholamines. Plasma metanephrines may be better for screening and have demonstrated 97% sensitivity for pheochromocytoma. MIBG may be negative in 40% of VHL pheochromocytoma, and functional diagnosis may be efficiently made by [11C]-hydroxyephedrine PET.

Surgical treatment of von Hippel Lindaus disease
When evaluating VHL patients for surgery it is important to ensure that other VHL manifestations are correctly treated. VHL patients may have pheochromocytomas and concomitant extraadrenal paraganglioma, and also renal carcinoma and endocrine pancreatic tumors (most likely to be non-functioning).

Small, apparently non-functioning and slow growing VHL pheochromocytomas may be followed without surgery, if urinary catecholamines and plasma metanephrines are normal. Surgery is recommended for larger (>2 cm), and symptomatic tumors, but should also be considered when other surgery is indicated or pregnancy planned. Prior to surgery the patients should be treated with α-blockade as other pheochromocytoma patients.

Laparoscopic removal is recommended for both unilateral and bilateral tumors. After unilateral adrenalectomy new pheochromocytomas have developed in the remaining adrenal gland in 19-33% of patients after median 4 years. Laparopscopic partial adrenalectomy has been advocated and half to one third of one adrenal has appeared sufficient to avoid corticoid replacement therapy. The partial adrenalectomy may be especially well suited for smaller VHL pheochromocytoma, since VHL patients generally lack adrenal medullary hyperplasia. Recurrence can be expected after partial resection, but generally with delay, and then require repeated surgery.