Hemangioblastomas are uncommon in the general population, with an overall incidence of 0.141 per 100,000 person-years in the United States [3]. They account for less than 2% of all CNS neoplasms but comprise an estimated 11% of primary posterior fossa tumors [4-6]. Some studies suggest a slightly higher incidence in male than in female patients, while others report no significant sex predilection [3,7,8]. Approximately 70% of cases are believed to be sporadic with the remaining 30% representing VHL-associated familial cases [9,10]. An estimated 60%–80% of patients with VHL disease develop CNS hemangioblastoma during their lifetime [11,12]. The average patient age at presentation varies by genetic subgroup, with VHL-associated tumors presenting on average two decades earlier than sporadic tumors; the mean age of onset is approximately 29 years in VHL-associated hemangioblastomas compared to 47 years in sporadic cases [9]. A comparison of epidemiologic data for sporadic and hereditary hemangioblastomas is summarized in Table 1.

Hemangioblastomas may arise throughout the CNS, most commonly involve the cerebellum, brainstem, and spinal cord, in order of descending frequency [3]. Less common sites of involvement include the supratentorial compartment and spinal nerve roots [13]. Cases of extraneural hemangioblastomas are rare [14,15]. While the cerebellum is still the most common site of hemangioblastoma in VHL patients, a higher proportion of extra-cerebellar sites are seen in VHL-associated cases, including retinal involvement in 28%–50% [16,17]. Patients with VHL disease are more likely to present with multiple hemangioblastomas [10,13,18]. Other VHL-associated neoplasms and their common sites of involvement include clear cell renal cell carcinoma (CCRCC) of the kidneys, paragangliomas of the head and neck, pheochromocytoma of the adrenal gland, neuroendocrine islet cell tumors of the pancreas, endolymphatic sac tumors of the inner ear, and cystadenomas of the epididymis and broad ligament [19].

Loss of function of the VHL tumor suppressor gene is implicated in most cases of hemangioblastoma, both familial and sporadic. VHL disease is an autosomal dominant tumor predisposition syndrome resulting from inactivating germline mutation in the VHL tumor suppressor gene [19,20]. This gene is located on the short arm of chromosome 3 (3p25-26) [21]. Biallelic inactivation of VHL is frequently found in familial cases of hemangioblastoma, according to Knudson’s “two-hit” hypothesis [22,23]. Under this system, a germline loss of function variant inactivates one copy of the VHL gene—the first hit—and loss of function of the remaining functional copy—the second hit—occurs prior to tumorigenesis [22]. The normally functioning VHL protein (pVHL) is involved in multiple cellular functions, including cell cycle regulation, apoptosis, and extracellular matrix formation [24-26]. pVHL also regulates cellular hypoxia signaling via the hypoxia-inducible factor (HIF) complex. Under normoxic conditions, the HIFα subunit undergoes hydroxylation creating a high affinity pVHL binding site [27,28]. As part of a multi-subunit ubiquitin ligase complex, pVHL facilitates HIFα polyubiquitylation and targeting for degradation [27-29]. In contrast, under hypoxic conditions, the HIF complex avoids hydroxylation and ubiquitin-associated degradation [30]. The stabilized complex serves as a transcription factor, upregulating the transcription of multiple growth factors to promote cell survival [31].

While hemangioblastoma pathogenesis is not yet fully understood, the pseudohypoxia hypothesis proposes a mechanism by which VHL loss promotes downstream tumorigenesis. Under this proposed pathway, VHL loss of function leads to loss of regulation of the HIF complex, which in turn promotes increased expression of growth factors in the absence of hypoxia, resulting in increased angiogenesis and conditions suitable for neoplastic growth [32].

HIF-independent pathways may also contribute to VHL disease and hemangioblastoma formation. VHL protein has been implicated in several other cellular functions, including regulation of apoptosis, microtubule stabilization, extracellular matrix formation, and cell-cell adhesion; loss of these functions could also contribute to tumorigenesis [33].

While the majority of familial cases demonstrate germline VHL loss, most studies indicate a smaller proportion of sporadic cases show VHL loss of function [34-36]. Historical studies of sporadic hemangioblastomas demonstrated VHL alterations in a minority of cases, although more recent investigation places the rate as high as 78% [36]. Older studies of sporadic hemangioblastoma may have shown erroneously low proportions of VHL loss due to low tumor purity. Since only the neoplastic stromal cells harbor the genetic alterations in sporadic cases, some alterations may evade detection when the stromal cells comprise a small fraction of the sampled tissue [36].

Epigenetic suppression may play a more prominent role in sporadic hemangioblastoma than in familial cases. One investigation found VHL promoter hypermethylation in 33% of sporadic hemangioblastomas but none of the VHL disease-associated cases [37]. Further studies are needed on sporadic cases without demonstrable VHL alterations to elucidate whether VHL loss is present but has not yet been detected, or if alternative pathways are responsible.

Clinical signs and symptoms of hemangioblastoma are mainly attributed to the tumor’s mass effect on adjacent regions, generalized increase in intracranial pressure, or obstruction of cerebrospinal fluid flow. General symptoms may include manifestations of increased intracranial pressure such as headaches, nausea, and emesis [10,38]. Secondary polycythemia may occur in approximately 5%–40% of cases, owing to ectopic production of erythropoietin [39,40].

Clinical presentation may vary widely based on anatomic localization of the tumor. Cerebellar tumors often present with dysmetria and ataxia [38]. In contrast, patients with spinal hemangioblastomas often present with symptoms associated with radiculopathy and myelopathy, including hypesthesia, weakness, hyperreflexia, pain, and incontinence [41,42]. Patients with brainstem hemangioblastomas may show evidence of cranial nerve impingement as well as increased intracranial pressure [43].

Some radiographic findings appear to correlate with symptomatology. Peritumoral cysts frequently underlie the clinical findings associated with hemangioblastomas, with at least 72% of symptomatic tumors but only 13% of asymptomatic tumors containing cysts [43]. In rare cases, hemangioblastomas may present with intraparenchymal, subarachnoid, or ventricular hemorrhage [44-46].

Radiologic studies of hemangioblastoma generally show a welldemarcated enhancing mass ranging from solid to cystic, frequently presenting as a cyst with an enhancing mural nodule (Fig. 1) [47]. Tumors in the spinal cord are often associated with syrinx formation [48]. Computed tomography imaging demonstrates isodense signal compared to brain within the solid component [49]. Calcification is usually absent [49]. On magnetic resonance imaging, hemangioblastomas tend to appear as a T1 hypointense to isointense, T2 hyperintense nodule (Fig. 1) with serpentine flow voids in the nodular portion [47]. These tumors are often seen abutting the pia [50]. If a cystic component is present, the cyst wall rarely enhances [50].

Grossly, hemangioblastomas appear as solid and/or cystic masses, often seen as a cyst with a mural nodule [43]. The tumors tend to be well-circumscribed and surrounded by a pseudocapsule [43]. Given the highly vascular nature of the neoplasm, cut surfaces may appear red in color, with yellow and orange variegation attributed to the high lipid content in neoplastic cells [51].

Cytologic examination via direct smear or squash preparation can be a useful diagnostic aid at the time of intraoperative consultation. Unfortunately, hemangioblastoma samples are frequently resistant to squash preparation, resulting in thick clumps of tissue which may obfuscate cytologic detail (Fig. 2A) [52]. In the case of a successful cytologic smear preparation (or frozen section) with clearly visualized cells, the cytoplasm of neoplastic cells should demonstrate a characteristic foamy or finely vacuolated appearance (Fig. 2B) [52] . Cytoplasmic borders often appear indistinct, and nuclei may be mildly pleomorphic with hyperchromatic, speckled chromatin and occasional nuclear grooves [52]. Hemosiderin deposition is frequently seen, indicative of prior hemorrhage or red blood cell extravasation within these highly vascularized tumors [52].

On histologic sections, hemangioblastomas demonstrate compact, generally non-infiltrative growth patterns with variable lobularity [51]. The neoplastic component of these tumors are the stromal cells which are arranged within a rich network of thinwalled vessels (Fig. 3A) [51]. In these highly vascular tumors, there may be larger branching type vessels (Fig. 3B) and/or areas of hemorrhage (Fig. 3C). The neoplastic stromal cells classically contain clear, foamy cytoplasm with lipid-containing vacuoles (Fig. 3D) [51]. Nuclei may show mild pleomorphism, particularly in cases with degenerative atypia (Fig. 3E). Rare cytoplasmic hyaline globules may also be found [53,54].

Two histologic variants of hemangioblastoma have been described. The first is the more common reticular variant, characterized by a predominance of capillary vessels over stromal cells, and the second and less common variant is the cellular variant, marked by a preponderance of stromal cells and a less prominent vascular component [55].

If present, adjacent neural parenchyma maintains a well-demarcated border with the neoplasm (Fig. 3F), and may show marked reactive changes, including piloid gliosis with Rosenthal fibers [56]. Other helpful but non-essential features include the presence of intratumoral hemorrhage, mast cells, and cyst-like spaces. Extramedullary hematopoiesis may be found in approximately 15% of cases [57]. Mitotic figures are rare to absent.

Immunohistochemistry provides a useful and in some cases essential role in the diagnosis of hemangioblastoma and discrimination from histologic mimics.

Several entities must be considered in the differential diagnosis of hemangioblastoma on a histopathologic basis. In the VHL disease patient, special care must be taken to exclude certain histologic mimics that are of greater risk due to genetic predisposition.

Hemangioblastoma is assigned a CNS WHO grade of 1, as complete excision is curative in most cases [2]. Surgical resection is considered the standard of care [94]. However, depending on the location of the tumor, excision may not be feasible. In the case of a symptomatic nonresectable tumor, stereotactic radiosurgery may provide some short-term control, but data on safety and long-term efficacy is currently limited [95-97].

Prospective natural history studies reveal unpredictable growth patterns in CNS hemangioblastoma. The predominant pattern is saltatory with intermittent periods of growth and quiescence [13,98]. Since it is difficult to predict the timeline of tumor growth, and because surgical intervention is not without risk of morbidity and mortality, treatment is often reserved for symptomatic tumors [94,98].

CNS hemangioblastoma carries a good prognosis with complete surgical excision, with significantly longer overall survival observed in patients who underwent gross total resection versus those who did not [96]. Compared to sporadic cases, outcomes are poorer in VHL patients; in this population, CNS hemangioblastomas remain the primary cause of mortality [99,100].

CNS hemangioblastoma is an important cause of morbidity and mortality in patients with VHL disease. Further studies are needed to clarify the pathogenesis of this disease, particularly in sporadic cases. Recognizing the basic clinical, radiographic, and pathologic features and considering a relevant differential diagnosis is crucial for making a correct diagnosis and guiding disease management.