Pathology of Infratentorial Hemangioblastomas in Children

Pathophysiology

• Noninfiltrative growth: Hemangioblastomas typically remain asymptomatic until the intracranial compliance is overcome. Tumor growth mainly results from enlargement of the peritumoral cyst, which is filled with xanthochromic fluid produced by the tumoral capillary network (51). Clinical onset may be abrupt.

• Cyst formation: Cysts develop from a vicious circle starting from the peritumoral edema that surrounds hemangioblastomas. The edema increases the vascular permeability with consequent plasma extravasation and increased hydrodynamic extravascular forces. These events further amplify the peritumoral edema, and the fluid extravasation exceeds the reabsorbing properties of the neural tissue with subsequent cyst formation (29). Intratumoral cysts as a result of tumor necrosis also may be present.

Molecular/Genetic Pathology

• Mutation in 3p25-26 gene (VHL suppressor gene): VHL-related hemangioblastoma shows a germline mutation of the VHL tumor suppressor gene (3p25-26) (24). Such a mutation encompasses both small intragenic mutations (60%) and partial or even total gene deletion (30%) (58).

• VHL suppressor protein (pVHL): The VHL suppressor gene encodes for a protein that is involved in the degradation of factors coordinating the cellular response to hypoxia and the transcription regulation of angiogenesis (8). Stromal cells overexpress vascular endothelial growth factor (VEGF) due to the inhibition of pVHL, thus inducing an abundant capillary network. The VHL gene is altered not only in the germline of patients with VHL but also in the somatic line of their tumors according to Knudson’s two-hit hypothesis (inherited germline mutation + acquired somatic DNA alteration) (11).

• Inactivation of VHL gene in sporadic hemangioblastoma: 30–50% of sporadic cases result from the inactivation of the VHL gene; somatic mutations are prevalent (18, 20, 49). Overexpression of cyclin D1, a pVHL-modulated protein regulating the cell cycle, has been demonstrated (9). Loss of heterozygosity on chromosomes 3, 6, 9, and 18, and a gain on chromosome 19 are found in the remaining cases (27).

Histopathology

• WHO grade I: The WHO classification includes hemangioblastomas among the “neoplasms related to the meninges” (WHO grade I) (30). There are no histological differences between sporadic and VHL-related forms.

• Two variants, reticular and cellular: Hemangioblastomas that consist of stromal cells located within and around a well-defined capillary network are termed the “reticular” variant. In the “cellular” variant, areas with high cellular density alternate with regions with a paucity of cells that contain only the vascular nidus and cyst-like spaces.

Hemangioblastoma (H&E): Note the large number of stromal cells, which are characterized by variable size, vacuolated, lipid-like cytoplasm, and hyperchromatic nuclei, and the capillary network (numerous lumina containing red blood cells).

• Stromal cells have hyperchromatic nuclei, clear cytoplasm, and variable size: Stromal cells are polyedric, lipid-laden cells containing clear cytoplasmatic vacuoles. They show atypia, are highly variable in size, and have hyperchromatic nuclei with rare mitoses (MIB-1 index < 3%).

• Stromal cells are neoplastic component: Microdissection and in situ hybridization demonstrates that the neoplastic component is represented by the stromal cells (25). These stromal cells may originate from hemangioblast progenitor cells based on similar expressed proteins (12, 38).

• Immunohistochemical findings: Stromal cells variably immunostain for vimentin (100%), S-100 protein (80%), neuron-specific enolase, glial fibrillary acid protein, and erythropoietin.  Hemangioblastomas are often positive for VEGF, while they are immunonegative for vascular (CD31) and epithelial markers (keratin, epithelial membrane antigen).

• Mast cells scattered throughout: Mast cells are frequently found among the stromal cells and the capillary network.

• Gliotic rim surrounds: Both tumor and peritumoral cysts do not present a true capsule and are surrounded by a layer of gliosis containing rare astrocytes and Rosenthal fibers.

• Rests of renal cell carcinoma and pheochromocytoma within hemangioblastomas: Metastatic deposits of other VHL tumors (e.g., renal carcinoma or pheochromocytoma) may be present within hemangioblastomas (16).