Prospective natural history study of central nervous system hemangioblastomas in von Hippel-Lindau disease

Abstract

Object: The tumors most frequently associated with von Hippel-Lindau (VHL) disease are hemangioblastomas. While they are associated with significant neurological impairment and mortality, their natural history and optimal management have not been fully defined.

Methods: Patients with VHL were enrolled in a prospective study designed to define the natural history of CNS hemangioblastomas. In the present analysis, serial imaging, laboratory, genetic, and clinical data were evaluated in those with at least 2 years of follow-up data.

Results: At study entrance 225 patients (111 males, 114 females) harbored 1921 CNS hemangioblastomas in the supratentorial compartment (21 tumors [1%]), cerebellum (865 [45%]), brainstem (129 [7%]), spinal cord (689 [36%]), cauda equina (212 [11%]), and nerve roots (5 [0.3%]; follow-up 15,819 hemangioblastoma-years). Increased tumor burden was associated with partial deletions in the VHL gene (p = 0.005) and male sex (p = 0.002). Hemangioblastoma development (median 0.3 new tumors/year) was associated with younger age (p < 0.0001) and more tumors at study entrance (p < 0.0001). While 1278 hemangioblastomas (51%) did not grow, 1227 hemangioblastomas (49%) grew in a saltatory (886 [72%]), linear (76 [6%]), or exponential (264 [22%]) pattern. Faster tumor growth was associated with male sex (p = 0.001), symptomatic tumors (p < 0.0001), and tumors associated with cysts (p < 0.0001). Location-dependent tumor size was the primary predictor of eventual symptom formation (159 symptomatic tumors [6.3%]; area under the curve > 0.9).

Conclusions: Central nervous system hemangioblastoma burden in VHL is associated with partial germline deletions and male sex. Unpredictable growth of hemangioblastomas compromises assessment of nonsurgical therapies. The judicious treatment of symptom-producing hemangioblastomas, while avoiding unnecessary treatment of asymptomatic tumors that may not progress, can provide clinical stability.

Trial registration: ClinicalTrials.gov NCT00005902.

Figures

Fig. 1

Kaplan-Meier analysis of hemangioblastoma progression over an 8-year period in patients with VHL disease. Left: Fifty percent of (nongrowing) hemangioblastomas located in the brainstem progressed in 5.6 years. Twenty-five percent of hemangioblastomas located in the cauda equina progressed in 5.0 years. Fifty percent of hemangioblastomas located in the cerebellum progressed in 6.2 years. Fifty percent of hemangioblastomas located in the spine progressed in 8.9 years. Right: Twenty-five percent of hemangioblastomas at all tumor locations progressed in 2.5 years and 50% in 7.5 years. No. at risk = tumors at risk for growing. The numbers of tumors at risk refer to the years on the x-axis under which they align.

Fig. 2

Characteristic patterns of growth associated with CNS hemangioblastomas in patients with VHL disease. Left: Axial contrast-enhanced MR image of the cerebellum in a patient showing 5 tumors (A–E) that demonstrated 3 growth patterns. Right: Tumor growth patterns, including saltatory (A–C), linear (D), and stable (E).