- Multidisciplinary evaluation: The diagnostic evaluation should include genetic evaluation and tests for VHL, ophthalmological examination (detection of presence of retinal hemangioblastomas), neuropsychological tests (possible developmental delay/regression), and possibly electrodiagnostic tests in case of brainstem/spinal cord involvement.
- Diagnostic criteria for VHL: The diagnostic criteria for VHL include the following: more than one hemangioblastoma of the CNS, one isolated hemangioblastoma associated with pheochromocytoma and/or renal carcinoma and/or pancreatic islet cell tumor or cyst, or one first-degree relative affected by VHL and one condition of the disease (31).
- VHL subtypes: VHL can be divided into two types on the basis of the genetic mutation present and the risk for developing pheochromocytomas. VHL complex type 1 (VHL gene deletion) is not associated with pheochromocytomas, whereas VHL complex type 2 is associated with a high risk for the development of pheochromocytoma (VHL intragenic mutations).
- Family history: Familial hemangioblastomas are part of the VHL complex. About 80% of patients with VHL have an affected parent, while 20% show a de novo mutation (46).
- VHL is an autosomal dominant cancer predisposition syndrome: There is a relatively high penetrance of clinical expression of the syndrome (90% by 65 years of age) characterized by the development of hemangioblastomas in the CNS (brain, cerebellum, and retina), endolymphatic sac tumor, and tumors of the kidney, pancreas, and adrenal gland. Its clinical expression is highly variable.
- Hematologic tests: Standard hematologic tests are used for screening and to prepare the patient for surgery.
- Systematic screening for VHL: Patients with newly diagnosed hemangioblastoma are systematically screened for VHL.
- Erythrocythemia with elevated hematocrit: 10–20% of patients with hemangioblastomas (especially cerebellar ones) have erythrocythemia with an elevated hematocrit as a result of unregulated secretion of erythropoietin by neoplastic cells (23). This rate is lower in patients with small and/or incidentally discovered tumors (15).
- Cystic tumors in the cerebellum, solid tumors in the brainstem: Cystic hemangioblastomas predominate in the cerebellum, while solid hemangioblastomas are more common in the brainstem (where they may be associated with syringobulbia and/or syringomyelia).
- Leptomeningeal dissemination is rare (57).
- Location: The posterior fossa is involved in 80% of cases (spinal cord: 15–20%; supratentorial space: 1–3%) (45). Posterior fossa hemangioblastomas are located in the cerebellum in 90–95% of cases, with a 9/1 hemispheres/vermis ratio. The floor of the fourth ventricle, dorsal aspect of the medulla oblongata, and cervicomedullary junction are other sites of occurrence (5–10%). Location within the cerebellopontine angle is rare (3).
- Four radiological tumor types: Four types of hemangioblastomas can be differentiated radiographically (44). Type 1: The lesion appears as a totally cystic tumor since the solid component is too small to be visualized. This type is rare (5% of the cases). Type 2: This is the characteristic and most common tumor (60%), consisting of a large cyst (diameter up to 7–8 cm) with a 0.5–2.5 cm mural nodule (see photo below). Type 3: These are totally solid tumors (25%). Type 4: These tumors have numerous small internal cysts (10%).
MRI of the brain and total spine with and without gadolinium is recommended.
- T1-weighted images: The solid nodule is round or oval-shaped, isointense > hypointense. The cyst appears grossly round and hypointense.
- T2-weighted images: The nodule is hypointense, while the cyst shows a CSF-like signal (brilliantly hyperintense). Feeding vessels are visualized as serpiginous flow voids (similarly in T1-weighted images). Peritumoral edema is often present.
- T1-weighted image after gadolinium: Strong contrast enhancement of the solid portion is seen; intratumoral as well as peritumoral cysts do not enhance.
- Multiple tumors typical of VHL: Multiple tumors are characteristic of patients with VHL.
- Rich, abnormal vascularity: MRI-angiography demonstrates the rich and abnormal tumor vascularization, thus helping in the differential diagnosis. Digital subtraction angiography is performed when a preoperative embolization is planned. An intense tumor flush is visualized along with the feeding arteries and the draining veins.
Radiological differential diagnosis
The differential diagnosis includes other cystic lesions of the posterior fossa:
- Pilocytic astrocytoma: Larger mural nodule, absence of flow voids, sometimes not differentiable from hemangioblastoma.
- Arachnoid cyst: No mural nodule, mass effect on the vermis.
- Epidermoid cyst: Cerebellopontine angle, totally cystic, usually smaller.
- Dermoid cyst: Midline fatty mass, dermal sinus often present, fat droplets if ruptured.
- Choroid plexus tumors: Solid hemangioblastomas are difficult to distinguish from choroid plexus tumors, which show strong contrast enhancement and flow voids but usually appear as frond-like masses within the fourth ventricle.
- Metastatic clear-cell carcinoma or endolymphatic sac tumor: In patients with VHL, metastasis from clear cell renal carcinoma or endolymphatic sac tumor should be considered.
Nuclear Medicine Tests
- Usually not indicated
- SPECT may be helpful: Thallium-201-single-photon emission computerized tomography (SPECT) can be useful in the differential diagnosis between hemangioblastoma and glioma of the posterior fossa (22). Thallium-201 washout is significantly faster in hemangioblastoma because of its hypervascular tumor bed.
- Baseline intraoperative monitoring: Evoked potentials (BAERs, MEPs and SEPs) may be useful at the time of surgery when there is brainstem involvement and their use in intraoperative monitoring is anticipated. It can be helpful to have baseline studies for purposes of comparison, but usually these are obtained after the patient is asleep in the operating room prior to entry into the brainstem.
- Postoperative assessment: These tests may be considered for patients with perceived postoperative cognitive deficits.
Correlation of Tests
- Familial history and multiple tumors=VHL: The diagnosis of hemangioblastoma is obtained by combining information from clinical evaluation, laboratory tests, and neuroimaging. A familial inheritance as well as the presence of multiple hemangioblastomas (especially in the retina) and/or pheochromocytoma/renal/pancreatic tumors both are strongly suggestive of VHL, which can be confirmed by laboratory genetic investigations. MRI is able to verify the presence of a posterior fossa hemangioblastoma in patients with cerebellar syndrome or brainstem dysfunction.
- Surgery for growth or symptoms: Surgery is planned for symptomatic patients or for those with enlarging isolated hemangioblastomas. Radiological examinations and electrodiagnostic and neuropsychological tests may help to detect tumor evolution before the occurrence of clinical signs or symptoms. They are also useful for monitoring patients with multiple hemangioblastomas.