Hemangioblastomas are among the small group of central nervous system (CNS) tumors that often occur in the setting of an inherited tumor predisposition syndrome, with approximately 40% of patients expressing features of the von Hipple–Lindau syndrome (VHL; see below) (1,2). This tumor has a slight predilection for males and may present at any age, but most occur after the age of 21 years (1,3). Common presenting signs and symptoms include headache, nausea/vomiting, and ataxia. Only rare cases hemorrhage (4). The variable secretion of erythropoietin by hemangioblastomas induces an erythrocytosis in a subset of patients (5). Most hemangioblastomas (∼90%) occur in the posterior fossa, but have been described in other sites throughout the CNS. Those in the spinal cord, the second most common site, are more common in patients with VHL and almost always (>95%) noted on the dorsal aspect (2,6). Retinal hemangioblastomas may be seen in VHL patients. Compared with sporadic cases, those in VHL present at a younger age, are more likely multifocal, and more likely to recur.

Neuroimaging reveals two major configurations of hemangioblastoma, “cyst with mural nodule” and solid, although a small number either lack an identifiable solid component or contain internal cystic spaces (7,8). Cystic lesions are more common and can develop over time from solid ones, eliciting symptoms through cyst expansion rather than tumor growth (6,9). Larger vascular channels in the solid portion appear as dark “flow voids” on magnetic resonance imaging (MRI), most notable on T2/FLAIR images against a backdrop of hyperintense tumor (7).

Hemangioblastomas are low-grade neoplasms that are curable by complete excision. The risk of recurrence increases with younger age, VHL diagnosis, and multicentric disease (10). For both recurrent and initial hemangioblastomas, stereotactic radiosurgery is effective at controlling most lesions (11).

VHL syndrome is an autosomal dominant tumor predisposition that results from loss of function mutations in the gene VHL, encoded at locus 3p25. The normal gene product, the protein VHL, is a ubiquitin ligase involved in targeting hypoxia-inducible factor-1α (HIF) for destruction in the proteosome. Loss-of-function mutations in VHL cause a buildup of HIF within cells, triggering a cascade of signals that normally promote the cell’s response to hypoxia, including the excess production of vascular endothelial growth factor (VEGF), accounting for the tumor’s high vascularity and erythropoietin production. Syndromic patients have a heterozygous germline mutation in every cell and develop VHL-associated tumors where a second somatic mutation or deletion of VHL removes the remaining inhibition of HIF. Other tumors in VHL include renal clear cell carcinoma, pheochromocytoma, and papillary endolymphatic sac tumors. Because of its association with VHL, a diagnosis of hemangioblastoma should precipitate genetic testing because VHL patients require lifelong surveillance for malignancy.

Hemangioblastomas comprise two major cellular elements—endothelial cells that form the rich vasculature and stromal cells that occupy the intervascular areas. The endothelial cells are nonneoplastic and form a rich vasculature that grows at least partially in response to VEGF signals from the neoplastic stromal cells. The stromal cells are polygonal with small hyperchromatic nuclei and ample cytoplasm that varies from vacuolated with clear spherical lipid droplets (Figure 17-1) to faintly eosinophilic and
finely granular. These components combine in two major architectural patterns—reticular and cellular. The more common reticular pattern is characterized by a dense network of capillaries with homogenously interspersed stromal cells that are more likely to be vacuolated and lipidized (Figure 17-2). In contrast, the cellular variant has large irregular vascular channels that encircle organoid nests of stromal cells that have a tendency toward smaller amounts of finely granular cytoplasm
(Figure 17-3). Although both are World Health Organization (WHO) grade I, the cellular pattern has features that overlap significantly with some metastatic carcinomas and is more likely to recur than the reticular pattern (10,12).

Mitosis and necrosis are rare in hemangioblastoma, but degenerative nuclear atypia is commonplace (Figure 17-4). Collagen occasionally deposits to form sclerotic tumors. A sparse infiltrate of mast cells is usually present.

Immunohistochemical stains for inhibin and neuron-specific enolase are usually positive, but few other markers react reliably. Glial fibrillary acidic protein (GFAP) is occasionally present within stromal cells and reactive immigrant astrocytes, both more often in the cellular pattern (12). Cytoplasmic staining for the notochordal marker brachyury has been described in hemangioblastoma and suggested as a specific marker (13). Brachyury immunostaining is typically observed in the nuclei of chordomas. Apparent ependymal differentiation has also been described (14,15).

Because of their histologic overlap and tendency to arise in VHL patients, renal clear cell carcinoma and hemangioblastoma are always considered together. At intraoperative consultation, distinguishing these can be very challenging and definitive diagnosis may necessarily await permanent sections and immunohistochemistry. Cytology, architecture, vascular pattern, and mast cell infiltrates are all comparable, but hemangioblastomas are inhibin immunoreactive and epithelial membrane antigen (EMA) negative, whereas renal cell carcinomas show the opposite pattern (16). Pax-8 and Pax-2 are transcription factors expressed in most renal clear cell carcinomas
and not in hemangioblastomas (17,18). Rarely, renal cell carcinoma metastasizes to hemangioblastoma (19).

In young patients, a cerebellar cyst with mural nodule is most often a pilocytic astrocytoma; however, hemangioblastoma may present identically. Inclusion of perilesional tissue can yield piloid gliosis (Figure 17-5) with Rosenthal fibers that may provoke a mistaken intraoperative diagnosis of pilocytic astrocytoma. Simple awareness of this situation and recognition of the histology of hemangioblastoma should mitigate risk of this error.

The cellularity and pleomorphism of hemangioblastoma can cause concern for high-grade glioma intraoperatively, especially with noncystic cases outside of the cerebellum. Tight cohesion on smear preparation, paucity of fibrillar processes, and the presence of lipid droplets and mast cells all strongly favor hemangioblastoma in such a case. Retention of aqueous oil red-O and toluidine blue stains in the frozen section lab facilitates recognition of the latter two (Figure 17-6).

Patients of all ages may present with a chordoma but most are in the third through fifth decades of life. The vast majority of cases occur in the sacrum, clivus, or cervical vertebrae (20), where notochordal cells are seeded during embryogenesis and presumably germinate into chordomas. Clival
cases tend to present with cranial nerve palsies, especially of cranial nerve VI (21). In all locations, the tumor is midline, extradural, and involving bone; the pretest probability of a lesion being chordoma without the three features is low and other tumor types should be expected. Of course, rare chordomas violating these characteristics occur. The radiologic features of chordoma and chondrosarcoma, other than midline location favoring chordoma, are not helpful diagnostically (22).