Hemangioblastoma and von Hippel-Lindau disease: genetic background, spectrum of disease, and neurosurgical treatment

Abstract

Introduction: Hemangioblastomas are rare, histologically benign, highly vascularized tumors of the brain, the spinal cord, and the retina, occurring sporadically or associated with the autosomal dominant inherited von Hippel-Lindau (VHL) disease. Children or adults with VHL disease have one of > 300 known germline mutations of the VHL gene located on chromosome 3. They are prone to develop hemangioblastomas, extremely rarely starting at age 6, rarely at age 12-18, and, typically and almost all, as adults. There is a plethora of VHL-associated tumors and cysts, mainly in the kidney, pancreas, adrenals, reproductive organs, and central nervous system. Due to a lack of causal treatment, alleviation of symptoms and prevention of permanent neurological deficits as well as malignant transformation are the main task. Paucity of data and the nonlinear course of tumor progression make management of pediatric VHL patients with hemangioblastomas challenging.

Methods: The Freiburg surveillance protocol was developed by combining data from the literature and our experience of examinations of > 300 VHL patients per year at our university VHL center.

Results: Key recommendations are to start screening of patients at risk by funduscopy with dilated pupils for retinal tumors with admission to school and with MRI of the brain and spinal cord at age 14, then continue biannually until age 18, with emergency MRI in case of neurological symptoms. Indication for surgery remains personalized and should be approved by an experienced VHL board, but we regard neurological symptoms, rapid tumor growth, or critically large tumor/cyst sizes as the key indications to remove hemangioblastomas. Since repeated surgery on hemangioblastomas in VHL patients is not rare, modern neurosurgical techniques should encompass microsurgery, neuronavigation, intraoperative neuromonitoring, fluorescein dye-based intraoperative angiography, intraoperative ultrasound, and minimally invasive approaches, preceded in selected cases by endovascular embolization. Highly specialized neurosurgeons are able to achieve a very low risk of permanent morbidity for the removal of hemangioblastomas from the cerebellum and spinal cord. Small retinal tumors of the peripheral retina can be treated by laser coagulation, larger tumors by cryocoagulation or brachytherapy.

Conclusion: We consider management at experienced VHL centers mandatory and careful surveillance and monitoring of asymptomatic lesions are required to prevent unnecessary operations and minimize morbidity.

Keywords: Adolescence; Childhood; Hemangioblastoma; Screening; Surgery; VHL; von Hippel-Lindau.

Fig. 1

Histology of a hemangioblastoma of the central nervous system showing foamy stromal cells and abundant vessels

Fig. 2

Tiny hemangioblastoma in the left cerebellar hemisphere in a patient with VHL disease (a–c: hollow arrow). In order to distinguish this tiny lesion from a vessel, high-resolution images allowing multiplanar reformations are needed. An example is the vessel (c, d: arrow), which in axial reformation is displayed as a tubular structure

Fig. 3

Patient with VHL disease and multiple hemangioblastomas in the obex and the dorsal aspect of the spinal cord. All lesions have a pial contact. The one at level Th1 (a–c: hollow arrow) has caused a spinal cord edema. Axial T1-weighted contrast-enhanced images with fat sat also show a left-sided retinal “angioma” (d: arrow)

Fig. 4

Multiple cerebellar hemangioblastomas remained stable for several years (a). In 1 year, especially cystic portions in the left inferior vermis (b: arrow) and afterwards in the right hemisphere got larger (c: arrow). Some years later, solid and cystic (d, e: arrows) and cystic hemangioblastoma portions (f: arrow) started to grow

Fig. 5

Endolymphatic sac tumor (ELST) in a typical location with strong enhancement (a), calcific spiculae on CT (b: arrow), inhomogeneous signal due to calcifications and cysts on T2-weighted images (c), and intense vascular blush with supply via branches of the ICA (d), ascending pharyngeal artery (e), and middle meningeal artery (f)

Fig. 6

Surgical case illustration. The 10-year-old VHL patient had a previously known small intramedullary hemangioblastoma at Th9-Th10 (encircled in A). Meanwhile the patient developed progressive painful dysesthesia in the right leg. The current MRI (B) showed the solid tumor progressive from 6 × 5 mm to 15 × 10 mm, now with peritumoral myelon edema ranging from Th4 to the conus medullaris. Intraoperative radiographic confirmation of the target level must be as radiation minimized as possible in pediatric patients (here: only 2 single X-ray images taken, note the applied beam collimation). Under microscopic magnification (D1), the dura is opened lengthwise after laminotomy, revealing abundant pathological vessels on the surface of the myelon (arrows). The next crucial step is to identify and incise the junction between the tumor surface and the surrounding neural tissue (D2; asterisk: tumor; hollow arrows: junction). Step by step (D3), the tumor is circumferentially dissected en bloc (asterisk: cauterized tumor surface; black arrow: natural, typically reddish tumor surface; white hollow arrows: plane of dissection between tumor and neural tissue). With this technique (D4), the tumor (asterisk) can be gently dissected from the surrounding neural tissue

Fig. 7

Intraoperative 3D neuronavigation. A preoperatively obtained, high-resolution MRI scan can be used for intraoperative 3D neuronavigation in triplanar visualization. The oblique turquoise line corresponds to a navigation pointer inserted into the posterior fossa, which harbors multiple hemangioblastomas in solid and cystic formation

Fig. 8

Intraoperative ultrasound. Intraoperative ultrasound showing multiple cerebellar hemangioblastomas with tumor-associated cysts (a). The color flow feature (b) allows visualization of the blood flow including the high vascularization of the solid tumor component as well as pathological blood vessels supplying the hemangioblastoma

Fig. 9

Intraoperative ultrasound-guided cyst evacuation. Intraoperatively, it may be advantageous to first evacuate a large tumor-associated cyst in order to reduce the intraparenchymal pressure. Therefore, after minimal incision of the dura, a cannula is advanced into the cyst under ultrasound guidance (a) with sequential outflow of the cyst fluid (b–e)

Fig. 10

Minimally invasive tumor removal. a Intraoperative anterior-posterior X-ray image confirming the installed operating tube at the correct level Th1. b Magnified microscopic view through an 18-mm diameter operating tube onto the opened dura mater and the exposed spinal hemangioblastoma at the dorsal root entry zone

Fig. 11

Intraoperative indocyanine green (ICG) videoangiography. The microscope image (a) shows a spinal hemangioblastoma and indistinguishable pathological blood vessels. Especially in spinal hemangioblastomas, it is important to cauterize and sever the feeding vessels first, and not the draining vessels. Otherwise, swelling or even hemorrhage out of the tumor might occur. Intraoperative videoangiography with snapshots at 12, 15, and 23 s after ICG injection (b, c, d) allows the identification of a thin feeding vessel after 12 s (b) and major draining vessel after 23 s (d). Post-processing color coding according to the injection time indicates the feeding vessel in red and the major draining vessel in yellow/green (e)

Fig. 12

Preoperative embolization. Triplanar contrast-enhanced, T1-weighted MRI scan (a, b, c) predominantly showing a large solid tumor of the right posterior fossa in a VHL patient. Notice the large pathological blood vessels in and around the tumor (black) (b). Preoperative angiography (d) depicting a large tumor blush of the hemangioblastoma that is mainly nourished from the superior cerebellar artery. After particle embolization (e), the blood supply has been completely eliminated