Disclosure
Background: Hemangioblastomas are considered to be benign neoplasms and represent 1-2% of all primary central tumors. Historically, hemangioblastomas are linked to von Hippel-Lindau (VHL) disease. In 1927, Arvid Lindau reported the connection between retinal angiomas and hemangiomas of the cerebellum. VHL is an autosomal dominant condition involving chromosome 3 characterized by specific benign and malignant tumors with variable expressivity (Couch, 2000; Richard, 1998). Cerebellar hemangioblastoma is the most common initial manifestation, affecting 64% of patients with VHL (Conway, 2001). In many series, cerebellar hemangioblastoma is the most important cause of mortality, affecting 47.7% of patients with VHL (Friedrich, 1999), followed by renal cell carcinoma (Friedrich, 1999; Plowman, 1997). In patients with a positive family history, a single cerebellar hemangioblastoma is sufficient to make the diagnosis. If no known family history exists, at least 2 cerebellar hemangioblastomas or 1 hemangioblastoma plus 1 visceral tumor are necessary to justify the diagnosis of VHL. Various organs can be involved (Friedrich, 1999) (see Image 1). Of patients presenting with hemangioblastomas, 70% do not have a family history, and 3- 25% these patients have tumors associated with VHL. Hemangioblastoma appears to be associated more with VHL than previously reported, and it has been suggested that all patients with sporadic nonhereditary tumors should be evaluated for evidence of VHL disease (Conway, 2001; Neumann, 1989; Plowman, 1997). For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education article Brain Cancer. Pathophysiology: Hemangioblastomas are highly vascular tumors with 2 principal components, ie, capillaries and stromal cells. The origin of the stromal cells is not well defined. The expression of transthyretin and transferrin has been reported in these cells, and the possibility exists that they may originate from embryonic plexus epithelium (Bleistein, 2000). The controversial origin has resulted in the classification of hemangioblastoma as a single entity in the category of tumors of uncertain histogenesis in the current World Health Organization system (Lach, 1999). Etiopathogenic studies on VHL demonstrate that the VHL gene (located on bands 3p25-26) acts as a tumor suppressor that binds the transcription factors elongin B and elongin C and inhibits transcriptional elongation. Germ-line mutation in patients with VHL and somatic mutations in different tumors have been identified (Tampieri, 1993). The development of tumors requires the inactivation of the 2 copies of the VHL gene. In patients with VHL, only 1 somatic mutation on the remaining allele is required for tumors to develop. In patients with sporadic cases, the 2 VHL gene mutations are seen. The hallmark of VHL tumors is high vascularization, which arises from increased levels of vascular endothelial growth factor (VEGF). Patients with hemangioblastomas present with high levels of VEGF. The principal function of the VHL protein (pVHL) is negative regulation of hypoxia-inducible messenger RNA (mRNA), such as the mRNA encoding VEGF. The activity of pVHL has been linked to the targeting of specific proteins for proteolysis. When the VHL gene is mutated, absence of hypoxia-inducible transcription factor degradation (target of the proteolytic enzymes) is responsible for the accumulation of VEGF (Maxwell, 1999) (see Image 2). Hemangioblastomas are slow-growing tumors of endothelial cells with high tendency to be cystic (60%). The solid component is composed of capillaries, which are tightly packed blood vessels lined by endothelial cells. The blood vessels vary in size from capillary to cavernous. Abundant intercapillary tissue is seen with swollen fat-laden endothelial cells that allow differentiation from angioma (see Images 3-4). A small cyst may exist in the mass, but more often, the cyst is situated adjacent to the tumor (Hasso, 1994). The tumor does not have a capsule, and no mitotic changes are seen. The wall of the cystic component is composed of neural glial cells, with proteinaceous content that is rarely hemorrhagic. The cystic fluid is xanthochromic, with a concentration of amino acids, alkaline phosphates, and mucoproteins similar to blood, suggesting that they originate by diffusion from the vascular component of the solid tumor (Ho, 1992). Frequency:
Mortality/Morbidity: Morbidity and mortality rates have been reduced as a result of diagnostic and therapeutic advances in the last 25 years. Morbidity and mortality are related to the risk of rapidly enlarging cysts and the tendency for multiple recurrences. Morbidity and mortality rates are higher in patients with VHL, in whom it is the first cause of death in many series, with an average rate of 40-60%.
Race: No racial difference has been reported. Sex: Hemangioblastomas are slightly more common in men than in women, with a male-to-female ratio of 1.3-2.6:1 in sporadic cases. Patients with hemangioblastomas related to VHL present with no sex differences in frequency. Age: Hemangioblastomas occur more often in middle-aged adults aged 30-50 years. Patients with VHL present at a younger age than patients with sporadic cases, with an age range of 25-40 years (Conway, 2001). Anatomy: The nidus of the tumor abuts the pia matter, from which the tumor receives its vascular supply. The tumor is more frequently superficial than deep. Of hemangioblastomas, 60-70% are cystic, and the remainder are solid. Solid tumors are more common in the brainstem and supratentorial locations than elsewhere. The mural nodule is hypervascular and relatively small, less than 15 mm in diameter. From a macroscopic point of view, hemangioblastomas can appear as solid or cystic tumors with mixed forms. Four types can be distinguished, as follows:
Clinical Details: Clinical symptoms depend on the site and size of the lesion because it is a slow-growing tumor. The patient can present with minor neurologic symptoms for months, followed by a sudden exacerbation. In infratentorial localizations, headache is the most common symptom as a result of increased intracranial pressure. Other symptoms include vomiting, giddiness, ataxia, and gait disturbances. Neurologic examination results are normal or include cerebellar signs, but hydrocephalus results in rapid decompensation with papilledema. Polycythemia occurs in approximately 20% of cerebellar hemangioblastomas and is more common with solid hemangioblastomas (Friedrich, 1999; Richard, 1998). Polycythemia is caused by tumoral production of erythropoietin. Subarachnoid or intra-axial hemorrhages are rare. Subarachnoid hemorrhages occur as a result of the subpial localization. Hemangioblastoma is the most common presenting manifestation of VHL, revealing the disease in 30-50% of cases (Richard, 1998). Preferred Examination: Contrast-enhanced MRI is considered the best method for screening patients with VHL and the first evaluation used in symptomatic patients. However, preoperative angiography remains important for defining feeding vessels and aiding in embolization (Filling-Katz, 1989; Lee, 1989). Prior to MRI, contrast-enhanced CT scanning was performed frequently; however, beam-hardening artifacts produced by the petrous and vertebral bone limited its use. MRI is superior to CT in the detection of vascular components of the tumor. Contrast-enhanced CT has the same sensitivity as nonenhanced MRI; however, it is inferior to contrast-enhanced MRI (Filling-Katz, 1989). Contrast-enhanced MRI permits the identification of small tumor nodules. In addition, MRI is helpful in separating cystic and solid components of the tumor from edema. Patients with VHL should be screened, and follow-up studies should be performed at 6 months. Further follow-up studies should be performed at 1-year intervals to detect the development of additional tumors and monitor progression of existing lesions (Filling-Katz, 1989). Early treatment improves the outcome. Using MRI and CT at 1- to 2-year intervals, Conway et al identified 74% of lesions that required surgery before the patients became symptomatic (Conway, 2001). Limitations of Techniques: MRI is superior to nonenhanced CT in the detection of vascular components of the tumor (Filling-Katz, 1989; Sanders, 1986). Contrast-enhanced CT has the same sensitivity as nonenhanced MRI. The sensitivity of MRI increases with the use of gadolinium-based contrast material. Angiography is better in the detection of small (< 1 cm) vascular tumor components, and it is better for showing the vascular nature, supply, and drainage of tumors, compared with CT (Sato, 1988). However, CT and MRI depict tumor cysts better (Guhl, 1987).
Arachnoid Cyst
Findings: On CT scans, the tumor appears well circumscribed, solid, or cystic, with a mural nodule. Usually, the nodule is smaller that the cyst. This feature helps in differentiating it from cystic astrocytoma, which tends to have a larger nodule.
Degree of Confidence: CT shows all the clinically significant features of hemangioblastoma, along with secondary features such as hydrocephalus and edema. False Positives/Negatives: False-negative results are found in patients with small nodules (<5 mm) that can be obscured by posterior fossa artifacts; therefore, CT is not a sensitive screening procedure. False-positive results are rare. Metastases and cystic astrocytoma can appear similar. A diagnostic pitfall is the hemangioblastoma with a small central lucency, which can be interpreted as a necrotic metastasis. In this case, the ringlike enhancement of the necrotic nodule is thick and irregular (Ganti, 1982). |
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Findings: Intracranial hemangioblastomas can manifest 3 morphologic patterns based on the macroscopic pathology. These are well correlated with the MRI findings and include (1) cyst with a small mural nodule, (2) solid mass with a central cystic component, and (3) solid tumor without a cystic component (Ho, 1992; Lee, 1989).
Commonly (60-69%), hemangioblastomas have associated internal or peripheral serpentine signal voids, which represent dilated afferent and efferent vessels (Elster, 1988). Therefore, the presence of a peripheral cyst with a mural nodule surrounded by signal voids is characteristic of hemangioblastoma (Lee, 1989). Pathologic dilated vessels can be demonstrated as hyperintense structures on flow-enhanced gadolinium studies. MRI with intravenous contrast enhancement shows enhancing nodules well because of their vascularity (Ho, 1992) (see Image 11). Degree of Confidence: MRI is the preferred screening study. Gadolinium enhancement increases the sensitivity (Anson, 1991; Filling-Katz, 1989; Guhl, 1987; Maeda, 1993). MRI with gadolinium enhancement is the best study for screening, with the highest sensitivity and specificity compared with CT and nonenhanced MRI. Large studies are necessary to achieve a high degree of confidence; however, the advantages are obvious. False Positives/Negatives: False-negative results can be seen with small lesions (<5 mm) and with delayed imaging because of the early enhancement of the lesions. False-positive findings are rare. Most false-positive findings lead to an inadequate diagnosis. For solid and multiple enhancing lesions, metastases are the most important differential diagnosis; supratentorial lesions are more common in metastases. The visualization of associated abnormal vessels helps in differentiating hemangioblastomas from other cystic lesions.
Findings: Gray-scale ultrasonography has been useful in the intraoperative evaluation of cerebellar and spinal hemangioblastomas by shortening and simplifying the surgical procedure. Most hemangioblastomas appear hyperechoic to adjacent neural tissue. Most studied cases have involved spinal hemangioblastomas. The use of ultrasonography is limited in brain lesions. Doppler color flow images can be helpful in patients with isoechoic lesions, showing increase of vascularity as a tightly packed tangle of vessels. The technique can also demonstrate areas without flow that correspond to cystic areas (Avila, 1993; Rosenthal, 1998).
Findings: No helpful findings have been described.
Findings: For many years, angiography was the primary diagnostic modality and still is a preoperative requisite in many patients. Infratentorial hemangioblastomas are evaluated by using vertebral angiography, which provides a selective opacification of both vertebral arteries by arterial femoral catheterization. Subtraction and magnification are necessary (Sato, 1988). Angiography provides detection, exact localization, and definition of the vascularity of tumors in the vertebrobasilar system. Findings are specific, and the diagnosis can be made with confidence. Nodules usually stain intensely with either a homogeneous or mottled appearance (see Images 9-10). The tumor has irregular vessels. The largest tumors are associated with 1 or more enlarged feeding arteries and draining veins and can demonstrate arteriovenous shunting. When a cyst is present, it can be seen as an avascular area producing vascular displacement (Archer, 1972; Sato, 1988). Angiography is superior to CT in defining the vascular nodule and in characterizing occult and multiple lesions. The relationship of the nodule with the cyst is not demonstrated as well on angiograms as on MRI or CT scans (Sato, 1988). Imaging of the neck with injection of each vertebral artery should be routine in patients with VHL complex or a posterior fossa hemangioblastoma. The blood supply is usually received through the pia mater; however, external carotid angiography provides valuable preoperative information in selected patients in whom a hemangioblastoma is superficial and abuts the dura (which is usually supplied by meningeal branches of the carotid system).
Intervention: Surgical excision has been the treatment of choice for these tumors. Several factors should be considered in surgical planning, including the site, vascularity, recurrence, and multiplicity of the tumor. Usually, total resection of solid tumors is more difficult, making them more likely to recur, compared with cystic forms (Julow, 1994). The surgeon must perform careful research on the mural nodule. If the cyst wall does not contain macroscopic tumor, it does not have to be removed. When the tumor is invading the brainstem, total excision is impossible. Postoperative mortality rates can be as high as 24% (Julow, 1994). Hemangioblastomas are highly vascular tumors. When they are large, resection can be difficult because of excessive bleeding. The addition of a preoperative embolization procedure decreases the blood loss and allows more complete resection (Sung, 1982). Recurrence is the rule after partial removal, and the multicentric nature of the tumor also predisposes patients to recurrence, with an overall recurrence rate of 8-16%. In cases of multiplicity, stereotactic radiosurgery was introduced as treatment in view of the otherwise high surgical risks (Pinto, 1987). Stereotactic radiosurgery has been performed with satisfactory results. Small hemangioblastomas are ideal targets for radiosurgery. Jawahar et al showed a 5-year rate of freedom from progression of 75% and a 10-year rate of 67% (Jawahar, 2000). Fractionated radiation therapy has not been rigidly evaluated, but it appears to be partly effective. Sung et al reported good responses with 4500-5000 cGy (Sung, 1982). In patients with VHL, metastases from renal clear cell carcinoma can occur within a hemangioblastoma (Sato, 1988). Hematogenous metastases are more likely to occur in highly vascularized tissues, making the diagnosis difficult (Richard, 2000). This situation is rare, and only a few cases have been reported. It is more common in meningiomas. Medical/Legal Pitfalls:
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