CHAPTER 128 Hemangioblastomas
Hemangioblastomas originate nearly exclusively from central nervous system tissues and are rarely found in the peripheral nervous system. They occur sporadically (60% to 75% of cases) or in the context of the neoplasia syndrome, von Hippel-Lindau disease (25% to 40%; [VHL]).1,2 They are World Health Organization (WHO) grade I CNS neoplasms.3 Advances in imaging and development of serial surveillance protocols in VHL patients with CNS hemangioblastomas have given insights into the molecular biology, pathogenesis, natural history, and clinical findings associated with these tumors. These findings have refined indications for treatment and helped define optimal management of hemangioblastomas in sporadic and VHL-related cases. Here, we describe the epidemiology, imaging features, clinical findings, histopathology, pathogenesis, and treatment options of hemangioblastomas.
Epidemiology
Hemangioblastomas are found more frequently (1.5 to 2 times) in males than in females.2–5 Hemangioblastoma-related symptoms typically occur earlier in VHL patients (30 to 40 years) compared with sporadic patients (40 to 50 years).4,6,7 Hemangioblastomas are distributed in a highly conserved region-specific manner within the CNS that includes the brainstem, spinal cord, and cerebellum (about 90% of hemangioblastomas are found in these regions).3,8 Five percent to 10% of hemangioblastomas are found in the supratentorial compartment. When hemangioblastomas are found supratentorially, they most frequently originate in the region of the pituitary stalk and tuber cinereum (30% of supratentorial hemangioblastomas).8 Although hemangioblastomas represent about 2% of all intracranial neoplasms, they account for 7% to 12% of posterior fossa tumors.3,4,9 Two percent to 10% of all primary spinal cord tumors are hemangioblastomas.3,5
Imaging Findings
The most sensitive and accurate imaging modality for discovery and tracking changes in CNS hemangioblastomas is contrast-enhanced magnetic resonance imaging (MRI). Because hemangioblastomas are highly vascular tumors, they vividly and discretely enhance on T1-weighted MRI sequences following gadolinium-based contrast infusion (Fig. 128-1). Even small tumors (2 to 3 mm in diameter) can be detected and precisely measured to determine changes in size or other radiographic characteristics over serial studies. Because hemangioblastomas are frequently associated with peritumoral edema and cysts, imaging designed to detect changes in interstitial fluid is often a sensitive approach for tumor detection. Peritumoral edema and cysts are best detected and followed using fluid-attenuated inversion recovery or T2-weighted MRI sequences (Fig. 128-2). Prominent flow voids are often identified with larger hemangioblastomas on T1- and T2-weighted MRI sequences. Infrequently, arteriography is used to supplement MRI findings. Angiography of vessels supplying and draining a hemangioblastoma reveals a highly vascular tumor nodule with prolonged contrast staining that can be associated with an avascular peritumoral cyst.
Clinical Findings
Clinical findings associated with CNS hemangioblastomas are related to mass effect (tumor mass or peritumoral edema– or cyst-related mass effect) and their anatomic location. Cerebellar hemangioblastomas frequently occur in the posterior and medial portions (70% to 80% of all cerebellar hemangioblastomas) of the cerebellum.2,8,10 Tumors in this anatomic region most frequently cause headache (70% to 80% of patients), gait ataxia (55% to 65%), dysmetria (30% to 65%), hydrocephalus (20% to 30%), or nausea and vomiting (5% to 30%).6,10,11 Brainstem hemangioblastomas frequently occur in the posterior medulla at the obex.8,12,13 Tumors in this anatomic region most frequently cause hypesthesia (40% to 55%), gait ataxia (20% to 30%), dysphagia (20% to 30%), hyperreflexia (20% to 25%), headache (10% to 20%), or disorders of appetite and feeding (2% to 5%).13,14 Spinal cord hemangioblastomas usually arise posterior to the dentate ligament (96% of all spinal cord hemangioblastomas) at the dorsal root entry zone (66% of all posterior spinal cord hemangioblastomas).8,15 Spinal hemangioblastomas most frequently cause hypesthesia (80% to 90%), weakness (60% to 70%), gait ataxia (50% to 65%), hyperreflexia (40% to 60%), or pain (10% to 30%).
Peritumoral Cyst Formation
About 80% of CNS hemangioblastomas are associated with a peritumoral cyst (a cyst that forms at the margin of the tumor). Although signs and symptoms can be related specifically to the mass effect of a hemangioblastoma, neurological dysfunction is most frequently caused by the combined mass effect of the tumor and an associated peritumoral cyst. About 70% of symptomatic cerebellar and brainstem hemangioblastomas are associated with a peritumoral cyst, and more than 90% of symptomatic spinal cord hemangioblastomas are associated with a peritumoral cyst (syringomyelia).15,16 When peritumoral cysts occur with hemangioblastomas, the cyst typically accounts for the bulk of the mass burden. Wanebo and colleagues8 compared tumor volume to associated peritumoral cyst volume and found that cerebellar hemangioblastomas had average cyst volume that was 4 times larger than the associated tumor and that was 12 times larger in the brainstem than the associated tumor in symptomatic VHL patients. Alternatively, asymptomatic cerebellar, brainstem, or spinal cord hemangioblastomas are infrequently associated with peritumoral cysts (only 5% to 10% of tumors with cysts).
Because development and growth of peritumoral cyst frequently underlie the formation of signs and symptoms associated with hemangioblastomas, understanding the mechanism underlying peritumoral cyst development and propagation in CNS hemangioblastomas is critical (Fig. 128-3). Recent studies have shown that development of a peritumoral cyst follows a defined sequence initiated by increased hemangioblastoma vascular permeability.17,18 This results in extravasation of a plasma ultrafiltrate into the interstitial spaces of the tumor, and high interstitial tumor pressure drives this fluid into the surrounding CNS parenchyma. This results in edema formation as the resorptive capacity of the peritumoral tissue is exceeded. As the mismatch between fluid production and tissue resorption increases, the surrounding tissues swell owing to solid stresses (stretching) that favor cyst formation. Formation of the cyst alters interstitial flow patterns so that most excess interstitial fluid flows into the peritumoral cyst (path of least resistance), resulting in cyst expansion.
Based on deeper understanding of the mechanism of peritumoral cyst development and propagation, critical clinical insights have been established. Because the hemangioblastoma is the source of extravasated plasma ultrafiltrate, peritumoral edema and cysts resolve after tumor removal, and treatment does not require cyst wall resection or fenestration. Likewise, increases in tumor vascular permeability can be deleterious because they lead to increased plasma leakage into the surrounding CNS parenchyma and favor edema and cyst formation. Studies have demonstrated that radiation can at least transiently induce increases in vascular permeability, leading to peritumoral edema and cyst formation.19–21 Subsequently, judicious use of irradiation of hemangioblastomas associated with peritumoral edema and cysts is warranted.21–23 Alternatively, a reduction in hemangioblastoma vascular permeability may be beneficial. Anti–vascular endothelial growth factor (VEGF) tumor treatments have been associated with edema reduction and symptom improvement, despite having no effect on tumor size.24,25 Finally, peritumoral cysts stop growing once the surface area of the cyst wall is sufficiently large to absorb the excess fluid and become quiescent. Subsequently, imaging evidence of edema or cyst formation in asymptomatic patients is not an absolute indication for surgery.26
Von Hippel-Lindau Disease
VHL is an autosomal dominant neoplasia syndrome that has a prevalence of 1 in 39,000 live births.27 VHL is the result of a germline mutation of the VHL gene.28,29 Although this disorder has variable expression, it has greater than 90% penetrance by 65 years of age.30 Patients with VHL are predisposed to develop specific CNS and visceral lesions (Table 128-1).6,31,32 CNS manifestations include hemangioblastomas (the most common manifestation of VHL) and endolymphatic sac tumors (ELSTs).33,34 Visceral manifestations include renal cysts, renal carcinomas, pancreatic cysts, pancreatic neuroendocrine tumors, pheochromocytomas, and cystadenomas of the adnexal organs (broad ligament in females and epididymis in males). Before the advent of routine surveillance and better defined treatment recommendations for VHL-associated lesions (Table 128-2), the median survival of VHL patients was less than 50 years of age.32,35 Currently, the primary cause of death is related to renal cell carcinomas or CNS hemangioblastomas.32,35
TABLE 128-1 Approximate Distribution, Mean Age of Onset, Range of Onset Age, and Frequency of Lesions Associated with von Hippel-Lindau Disease
TABLE 128-2 Time Periods Often Recommended for Various Screening Tests in At-Risk Individuals with von Hippel-Lindau Disease
| TEST | START AGE (FREQUENCY) |
|---|---|
| Ophthalmoscopy | Infancy (yearly) |
| Plasma or 24-hr urinary catecholamines and metanephrines | 2 years of age (yearly and when blood pressure is elevated) |
| Magnetic resonance imaging of craniospinal axis* | 11 years of age (yearly) |
| Computed tomography and magnetic resonance imaging of internal auditory canals* | Onset of symptoms (hearing loss, tinnitus, vertigo, or unexplained balance difficulties) |
| Ultrasound of abdomen | 8 years of age (yearly; magnetic resonance imaging as clinically indicated) |
| Computed tomography of abdomen* | 18 years of age or earlier if clinically indicated (yearly) |
| Audiologic function tests | When clinically indicated |
* Precontrast and postcontrast studies are often recommended.
Adapted from Choyke PL, Glenn GM, Walther MM, et al. Von Hippel-Lindau disease: genetic, clinical, and imaging features. Radiology. 1995;194:629.
Clinical criteria or genetic testing can be used to establish the diagnosis of VHL. Patients with a family history of VHL and CNS hemangioblastoma (including retinal hemangioblastomas), clear cell renal carcinoma, pheochromocytoma, or ELST are diagnosed with the disease. Twenty percent of VHL patients do not have a family history but fulfill the clinical diagnostic criteria for VHL by having two or more CNS hemangioblastomas or one CNS hemangioblastoma and a VHL-associated visceral tumor.35,36 At-risk patients, including patients with isolated CNS hemangioblastoma37 and undiagnosed family members of VHL patients, now frequently undergo testing for a germline VHL mutation. Blood samples can tested for the VHL mutation at a number reference laboratories internationally. The detection rate of VHL mutations in patients with a family history of VHL is nearly 100%.38 However, mutations in de novo patients without a family history may result in a disease mosaicism, whereby some tissues carry the mutation.39 These patients may test negative if their peripheral blood leukocytes do not carry the VHL gene mutation.
Natural History
Understanding the natural history of CNS hemangioblastomas is critical for optimizing treatment and for determining the efficacy of various therapies. It is especially important for VHL patients with CNS hemangioblastomas because they may have multiple hemangioblastomas along the neuraxis at any point in time and may develop new tumors over their lifetime. Wanebo and colleagues8 examined the natural history of 665 CNS hemangioblastomas in 160 consecutive VHL patients. Symptoms in patients with CNS hemangioblastomas were related to tumor size and cyst-associated mass effect. As a result, symptom formation in patients with CNS hemangioblastomas was associated with lesions with peritumoral cysts and with more rapid rates of hemangioblastoma growth. However, the pattern of growth of CNS hemangioblastomas is variable and is often marked by prolonged (years) periods of quiescence.8 Ammerman and colleagues,16 by examining patients with VHL and hemangioblastomas who had been followed with serial MRI for at least 10 years, identified certain thresholds of tumor size and threshold rates of growth that were associated with development of symptoms, but because of the relatively small number of patients, no recommendations resulted for management of individual lesions. Thus, neither tumor size nor rate of growth currently permits an argument for early intervention, a circumstance in which a tumor may be smaller and potentially more easily amenable to surgery or medical therapy. Thus, in the setting of VHL, it is probably best to reserve treatment of hemangioblastomas until they produce symptoms.
Pathologic Findings
Hemangioblastomas are bright red or red-orange and are invariably associated with intense vascularity (Fig. 128-4). Typically, large abnormal veins are found draining these tumors during resection. They are well-circumscribed, encapsulated tumors that occasionally have intratumoral cysts but more frequently are associated with peritumoral cysts whose walls are composed of compressed brain tissue and reactive gliosis. Histologically, the tumors are characterized by proliferation of stromal cells and endothelial cells. The endothelial cells surrounded by pericytes form extensive vascular channels that surround the bland, polygonal, vacuolated stromal cells (see Fig. 128-4).40
Because the stromal cells have numerous lipid-containing vacuoles that have a clear cell morphology similar to renal cell carcinoma, these tumors often appear histologically similar to renal cell carcinoma metastases. Further, because VHL patients often have contemporaneous renal cell carcinomas that can metastasize to the CNS or metastasize to hemangioblastomas,3,41 immunohistochemical differentiation between renal cell carcinoma and hemangioblastoma may be necessary. Jarrell and colleagues41 reported that 8% of a series of CNS hemangioblastomas removed from consecutive VHL patients harbored either a renal cell carcinoma or pancreatic neuroendocrine tumor that had metastasized to a coexisting hemangioblastoma.
Pathogenesis
Based on embryologic studies, as well as morphologic and molecular analyses of CNS hemangioblastomas, the origin of these tumors has recently been established. From her detailed analysis of chick embryo development, Sabin hypothesized, in 1917, that a single multipotent embryologic precursor cell was responsible for forming both blood and vessels.42 After comprehensive histomorphologic studies in VHL patients, Lindau suggested, in 1931, that hemangioblastomas arise from a congenital analage and have an embryologic cell origin.43 In 1960, Stein and colleagues44 described islands of blood formation and vessel formation in CNS hemangioblastomas and, based on Sabin’s embryologic studies, speculated that these tumors may be the result of arrested defective embryonic development. In 2003, Vortmeyer and colleagues45 discovered that hemangioblastomas contain regions of extramedullary hematopoiesis and that the hematopoietic cells in these regions of the tumor are VHL gene deficient. The same group also detected numerous microscopic nests of hemangioblastomas (tumorlets) in the same unique CNS distribution that characterizes hemangioblastomas in VHL patients at autopsy.46
Developmental data, combined with evidence of intratumoral hematopoiesis and vessel formation, as well as microscopic primordial hemangioblastomas in patients with VHL, suggested that hemangioblastomas may derive from an embryologic cell capable of blood and vessel formation. Until Choi and colleagues,47
