The Netherlands Journal of Medicine
Invited ReviewClinical management of Von Hippel–Lindau (VHL) disease
Introduction
Von Hippel–Lindau (VHL) disease is named after the German ophthalmologist Eugen von Hippel, who described retinal haemangioblastoma in 1904 and the Swedish pathologist Arvid Lindau who associated retinal and CNS haemangioblastoma with cysts of the kidneys, pancreas and epididymis in 1926 (Fig. 1) [1], [2], [3]. The first report on phaeochromocytoma in VHL disease appeared in 1953 [4], and in 1964 Melmon and Rosen published the first major literature review [5]. The most recently discovered VHL-related tumours are the endolymphatic sac tumour of the inner ear and the adnexal papillary tumour of probable mesonephric origin (APMO) [6], [7].
In the presence of a positive family history, VHL disease can be diagnosed in a patient with at least one typical VHL tumour [5], [8]. Typical VHL tumours are retinal and cerebellar haemangioblastoma, renal cell carcinoma, and phaeochromocytoma [8]. Endolymphatic sac tumours and multiple pancreatic cysts suggest a positive carrier status (in the presence of a positive VHL family history), since they are uncommon in the general population [6], [8]. In contrast, renal and epididymal cysts occur very frequently in the general population and are, as sole manifestation, no reliable indicators of the carrier status [9]. Apparently sporadic cases of VHL disease may be under-ascertained as a result of the requirement of a positive family history to define the disease [10]. Therefore, a diagnosis can also be made for isolated cases of VHL disease when two or more haemangioblastomas, or a single haemangioblastoma in association with a visceral manifestation, are present in a sporadic patient [8].
Current estimates of the prevalence of VHL disease range between two and three per 100 000 persons [11], [12], [13]. Studies of selected VHL families indicate that most manifestations occur at a young age, i.e. between 20 and 40 years and the penetrance of the disease is usually complete by the age of 60 years [10]. In a study carried out in the beginning of the 90’s, without intervention an average age of death of 41±14.3 years was observed [10], [12]. Metastases from renal cell carcinoma and neurological complications from cerebellar haemangioblastoma are the most common causes of death in VHL disease. However, early detection of tumours by intensive radiological and clinical screening, together with advanced operation techniques are likely to reduce both morbidity and mortality in VHL disease [8], [14], [15], [16].
Early identification is now facilitated by presymptomatic detection of VHL germline mutations. Family members who are non-carriers are relieved from the burden of repeated clinical monitoring. Since the necessity for costly and time-consuming surveillance programs can be reduced and monitoring can be directed at those carrying the mutation [17], the ratio between cost and effectiveness is expected to improve. Guidelines for clinical monitoring of VHL patients and eligibility for VHL gene mutation analysis are drawn by the Dutch VHL working group [18].
This article reviews the natural history, pathology, diagnosis, treatment and clinical monitoring of tumours occurring in VHL disease.
Section snippets
Ocular haemangioblastoma
Haemangioblastoma is the most common and early tumour in VHL disease [10], [19]. In VHL patients it may occur in the eye and central nervous system. On histopathological examination retinal tumours are identical to the cerebellar haemangioblastomas [20]. Ocular haemangioblastoma is considered to be the first manifestation of the disease in 43–68% of the VHL patients and the mean age at diagnosis is 24 years [10], [21]. Most ocular haemangioblastomas occur peripherally, 8% occur on the optical
Acknowledgements
F.J. Hes received grants from Zorg Onderzoek Nederland and the Janivo Foundation.
References (73)
- et al.
Pheochromocytoma. Its relationship to the neurocutaneous syndromes
Am. J. Med.
(1953) - et al.
Lindau’s disease: review of the literature and study of a large kindred
Am. J. Med.
(1964) - et al.
Clustering of features of von Hippel–Lindau syndrome: evidence for a complex genetic locus
Lancet
(1991) - et al.
Light and electron microscopic study of early lesions in angiomatosis retinae
Am. J. Ophthalmol.
(1976) - et al.
Ruthenium-106 brachytherapy for peripheral retinal capillary hemangioma
Ophthalmology
(1998) - et al.
Radiosurgery for hemangioblastoma: results of a multiinstitutional experience
Int. J. Radiat. Oncol. Biol. Phys.
(1996) - et al.
Characterization of the renal pathology of a familial form of renal cell carcinoma associated with von Hippel–Lindau disease: clinical and molecular genetic implications
J. Urol.
(1995) - et al.
Histopathology and classification of renal cell tumors (adenomas, oncocytomas and carcinomas). The basic cytological and histopathological elements and their use for diagnostics
Pathol. Res. Pract.
(1986) Molecular cytogenetics of renal cell tumors
Adv. Cancer Res.
(1993)- et al.
Renal cancer in families with hereditary renal cancer: prospective analysis of a tumor size threshold for renal parenchymal sparing surgery
J. Urol.
(1999)
Clinical and genetic characterization of pheochromocytoma in von Hippel–Lindau families: comparison with sporadic pheochromocytoma gives insight into natural history of pheochromocytoma
J. Urol.
Von Hippel–Lindau disease: new strategies in early detection and treatment
Am. J. Med.
Pregnancy in von Hippel–Lindau disease
Am. J. Obstet. Gynecol.
Management of hereditary pheochromocytoma in von Hippel–Lindau kindreds with partial adrenalectomy
J. Urol.
Pancreatic lesions in the von Hippel–Lindau syndrome
Gastroenterology
Pancreatic neuroendocrine tumors associated with von Hippel Lindau disease: diagnostic and management recommendations
Surgery
Multiple neuroendocrine tumors of the pancreas in von Hippel–Lindau disease patients: histopathological and molecular genetic analysis
Am. J. Pathol.
Somatic von Hippel–Lindau mutation in clear cell papillary cystadenoma of the epididymis
Hum. Pathol.
Epididymal cystadenomas in von Hippel–Lindau disease
Urology
Bilateral clear cell papillary cystadenoma of the epididymides presenting as infertility: an early manifestation of von Hippel–Lindau’s syndrome
J. Urol.
Papillary cystadenoma of the broad ligament in von Hippel–Lindau disease
Am. J. Obstet. Gynecol.
Uber eine sehr seltene Erkrankung der Netzhaut
von Graefes Arch. Ophth.
Die anatomische Grundlage der von mir beschriebenen ‘sehr seltenen Erkrankung der Netzhaut’
von Graefes Arch. Ophth.
Studien uber kleinhirncysten. Bau, pathogenese und beziehungen zur angiomatosis retinae
Acta Pathet Microbiol Scandinav
Endolymphatic sac tumors. A source of morbid hearing loss in von Hippel–Lindau disease
J Am Med Assoc
Third international meeting on von Hippel–Lindau disease
Cancer Res.
von Hippel–Lindau disease
Medicine (Baltimore)
Genetic flanking markers refine diagnostic criteria and provide insights into the genetics of Von Hippel Lindau disease
Proc. Natl. Acad. Sci. USA
Clinical features and natural history of von Hippel–Lindau disease
Q. J. Med.
Von Hippel–Lindau disease: a genetic study
J. Med. Genet.
Pheochromocytomas multiple endocrine neoplasia type 2 and von Hippel–Lindau disease
New Engl. J. Med.
Molecular genetic analysis of von Hippel–Lindau disease
J. Intern. Med.
Nephron-sparing surgery and renal transplantation in patients with renal cell carcinoma and von Hippel–Lindau disease
J. Intern. Med.
Treatment of hemangioblastomas in von Hippel–Lindau disease with linear accelerator-based radiosurgery
Neurosurgery
Efficacy of gene testing for von Hippel–Lindau disease
Med. J. Aust.
Von Hippel–Lindau disease: protocols for diagnosis and periodical clinical monitoring. National Von Hippel–Lindau Disease Working Group
Ned. Tijdschr. Geneeskd.
Cited by (52)
Consensus Guidelines for Ocular Surveillance of von Hippel-Lindau Disease
2024, Ophthalmologyvon Hippel-Lindau disease: Updated guideline for diagnosis and surveillance
2022, European Journal of Medical GeneticsCitation Excerpt :PNETs rarely develop during childhood although PNET has been reported as early as 16 years of age in vHL patients (Blansfield et al., 2007). Our recommendations are in line with a recent consensus statement from the Pancreatic Manifestation Subcommittee of the VHL Alliance Surveillance Guidelines Consortium who recommend gadolinium enhanced MRI every second year from of the age of 15 (Laks et al., 2021), and with most previous vHL surveillance guidelines (Kruizinga et al., 2014; TheAlliance, 2015), although some have proposed even lower starting ages of regular abdominal imaging (Hes et al., 2001; Rednam et al., 2017). In the previous edition of this guideline, we recommended measurement of plasma-chromogranin A (Binderup et al., 2013).
Vhl-related neuroendocrine neoplasms and beyond: An Israeli specialized center real-life report
2020, Endocrine PracticeNeurologic Diseases
2012, Anesthesia and Uncommon Diseases: Sixth EditionCompliance with periodic surveillance for Von-Hippel-Lindau disease
2011, Genetics in MedicineCitation Excerpt :However, early diagnosis and treatment, such as laser treatment for retinal hemangioblastomas at an asymptomatic stage, may affect prognosis positively. Therefore, high-risk individuals are advised to undergo periodic, multidisciplinary surveillance according to published, national guidelines.9 These national guidelines are largely in line with international guidelines.2,9,10
<sup>68</sup>Ga-DOTANOC PET/CT for Screening and Surveillance of Von Hippel-Lindau (VHL) disease
2023, Nuclear Medicine and Molecular Imaging
- 1
Present address: Department of Clinical Genetics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. Tel.: +31-71-526-8033.