Hemangioblastoma Of Central Nervous System And Von Hippel-Lindau Disease

Objective: Patients with haemangioblastoma of central nervoussystem have been used to determine the incidence of vonHippel-Lindau disease based of clinical information available at thetime. Method: All cases of haemangioblastoma of central nervoussystem that had presented between 1993 and 2005 and the case notesof these patients were reviewed. The diagnosis of von Hippel-Lindaudisease was made in an individual with >2 manifestations of thisdisease or in patients with isolated lesions and positive family history.The age of presentation of haemangioblastoma occurring as amanifestation of von Hippel-Lindau disease was compared with thatof isolated lesions. In order to develop a screening procedure forfamilies with the disease, age of presentation of other tumorsoccurring as part of the disease complex was calculated, based on ourcases and a review of reported cases in the literature. The G-bandingexamination of chromosome was taken in 3 patients in one family.Result:Between 1993 and 2005 we investigated 73 patients withhaemangioblastoma of central nervous system. The diagnosis of vonHippel-Lindau disease was established in 25(34.2%) although each ofthem had not been considered. The diagnosis of von Hippel-Lindaudisease was made in 14/25 cases because of a previous manifestationof the disease;in 7/25 on the basis of simultaneous involvement oftwo or more organs and in 4/25 on the basis of family history.The type of haemangioblastoma in patients did not differdepending on whether this was isolated or a manifestation of vonHippel-Lindau disease but mean age of presentation respectively was41.6 (22-76) years and 22.8 (8-36) years (P<0.01). The mean age ofeach manifestation of von Hippel-Lindau disease respectively was21years, 27years, 33years, 43years.Discussion: 34.2% of all cases with haemangioblastoma ofcentral nervous system in consecutive 13 years are von Hippel-Lindaudisease. This prevalence compares with figures of 10 to 23% in otherlarger series. The definition of von Hippel-Lindau disease proposed byMelmon and Rosen has been adopted. The previous typicalmanifestation and family history was not given attention. Had patientsbeen aware of this risk and regularly reviewed, the diagnosis wouldhave been made earlier with an associated reduction in morbidity andmortality.There is significant difference in the age at whichhaemangioblastoma of central nervous system presents in patientswith isolated lesions compared with those with von Hippel-Lindaudisease. In the absense of a family history or demonstration ofmultiple tumors, this difference is helpful in distinguishing cases ofvon Hippel-Lindau disease from isolated haemangioblastoma ofcentral nervous system. A screening procedure for asymptomaticlesions is also necessary in patients presenting under the age of50years, which can also be applied in follow-up and their relatives.The mean age of presenting of haemangioblastoma of centralnervous system occurring in 115 cases of von Hippel-Lindau diseaseis 27 years and only two (aged 8 and 9 years) presented before the ageof 10. About 44%-72% cases of von Hippel-Lindau disease withhaemangioblastoma of central nervous system and the most commonplace is cerebellum, accounting for 30% of von Hippel-Lindau disease.Enhanced cranial CT is choiced in screening for haemangioblastoma.In one autopsy series, there are many manifestations unknownthrough their lives. Only 3/8 spinal haemangioblastomas werediagnosed during life. Spinal haemangioblastoma is special in vonHippel-Lindau disease and more than 80% is caused by vonHippel-Lindau disease. 3 cases with spinal haemangioblastoma in ourcases are von Hippel-Lindau diseases. Despite the symptoms causedby these tumors, screening is necessarily invasive and probably notjustified;the role of MRI in this situation is to be developed.The mean age of presentation of retinal haemangioblastomaoccurring in 45 cases of von Hippel-Lindau disease is 21 (8-67) years.Lindau found that 20% of cases with angiomatosis retinae developother manifestations of what is now recognized as part of the vonHippel-Lindau disease and the frequency has not since beenreassessed. For retinal haemangioblastomas, 67% are multiple butonly 21% bilateral;it is not known for certain whether have vonHippel-Lindau disease than cases with isolated retinal lesions.Follow-up of patients with von Hippel-Lindau disease has led toidentification of these lesions at an earlier stage when they appearsimilar to diabetic microaneurysms but lie peripherally between largeaterial and venous trunks and are usually only seen by indirectophthalmoscopy. Retinal angiomas usually progress, causingblindness in the affected eye. Cryotherapy or photocoagulation,particularly of smaller lesions, can cause complete degradationwithout visual loss.Renal cancer and phaeochromocytoma are the abdominalmanifestations of von Hippel-Lindau disease which can lead to seriousmorbidity and mortality, whereas pancreatic and renal cysts rarelyproduce symptoms. But they can prove useful in identifying affectedindividuals before other manifestations appear.The mean age of presentation of renal carcinoma occurring in 38cases of von Hippel-Lindau disease is 43 (31-69) years. Renalcarcinoma was found in 1/4 of affected patients from nine families ofvon Hippel-Lindau disease. Metastases were presented in 50% and thecause of death in nearly 1/3 of the patients. Renal carcinoma occurredin at least 4/25 affected individuals in our cases. Renal carcinoma ofpatients with von Hippel-Lindau disease is distinguished fromsporadic cases by its earlier age of onset, multifocal nature and equalsex distribution. The prognosis for all patients with renal carcinoma isdependent on size at diagnosis;since patients with von Hippel-Lindaudisease are at risk of developing multiple renal tumors, screeningtechniques must demonstrate small tumors that can be treated by localexcision in order to conserve as much normal renal tissue as possible.IVP only detects small tumors if they are peripheral and renalultrasound may not detect lesions less than 2cm in diameter. Theinvestigation of choice is abdominal CT which has the addedadvantage of visualizing the adrenal gland and pancreas. Theestimation of urinary VMA is an additional screening procedure forphaeochromocytoma.The age at which pancreatic and renal cysts develop in patientswith von Hippel-Lindau disease is not known and these are almostasymptomatic. They are frequently present at autopsy and are bestdetected by abdominal CT. Phaeochromocytoma is uncommon in vonHippel-Lindau disease, occurring only 10% of patients reported byliterature. 4/5 cases are from the same family, indicating that onlycertain pedigrees are predisposed to development of thismanifestation.In the absence of a laboratory test for von Hippel-Lindau disease,several problems arise in genetic counseling of patients and theirrelatives. The inheritance is autosomal dominant but with incompletegene penetrance. This is assessed to be 80% to 90% in a retrospectivefamily survey that involved no presymptomatic screening, althoughpenetrance is difficult to determine because of the variations in age ofpenetration and natural history has shown that 95% of patients withvon Hippel-Lindau disease will have developed one or moremanifestations of the disease by 50 years.Conclusion: The developing curve of manifestations of vonHippel-Lindau disease changes with age increasing. The retinallesions appear earliest, then the haemangioblastoma of central nervoussystem, the renal carcinoma develops later. The mean ages ofpresentation of these manifestations are 21years, 27years, 33years and43years, respectively. Through critical review of our cases andprevious literatures, the screening protocol of von Hippel-Lindaudisease and relatives at risk is proposed as following.1. Annual clinical assessment including indirect ophthalmoscopyfrom the age of 5years because the retinal haemangioblastomas are thefirst manifestation to appear.2. Urinary VMA estimation should be introduced from the age of10years.3. Biennial cranial CT from the age of 10years.4. Although renal carcinomas rarely produce symptoms before30years, they have long natural history and only cause symptoms at anadvanced stage so that we should suggest that biennial abdominal CTof the kidneys, adrenal and pancreas is undertaken from the age of20years.5. At-risk relatives of newly diagnosed cases should be screenedaccording to these guidelines.6. Once the diagnosis of von Hippel-Lindau disease is made, thefollow-up must be life-long, but if at-risk relatives have nomanifestations by the age of 50years, it is unlikely that they will beaffected.In view of the high incidence of von Hippel-Lindau disease inour cases presenting with appearantly isolated haemangioblastomas ofcentral nervous system, this protocol should be extended to all patientspresenting with haemangioblastomas of central nervous system orretina under the age of 50 years. The chromosome G-bandingexamination is completely normal. In order to propose the geneticscreening technique of von Hippel-Lindau disease, the notation ofmolecular diagnosis should be sought.