The loss of succinate dehydrogenase B expression is frequently identified in hemangioblastoma of the central nervous system.

Succinate dehydrogenase (SDH) is a mitochondrial enzyme that plays an important role in both the Krebs cycle and the electron transport chain. SDH inactivation is associated with tumorigenesis in certain types of tumor. SDH consists of subunits A, B, C and D (SDHA, SDHB, SDHC, and SDHD, respectively). Immunohistochemistry for SDHB is a reliable method for detecting the inactivation of SDH by mutations in SDHA, SDHB, SDHC, SDHD and SDH complex assembly factor 2 (SDHAF2) genes with high sensitivity and specificity. SDHB immunohistochemistry has been used to examine the inactivation of SDH in various types of tumors. However, data on central nervous system (CNS) tumors are very limited. In the present study, we investigated the loss of SDHB immunoexpression in 90 cases of CNS tumors. Among the 90 cases of CNS tumors, only three cases of hemangioblastoma showed loss of SDHB immunoexpression. We further investigated SDHB immunoexpression in 35 cases of hemangioblastoma and found that 28 (80%) showed either negative or weak-diffuse pattern of SDHB immunoexpression, which suggests the inactivation of SDH. Our results suggest that SDH inactivation may represent an alternative pathway in the tumorigenesis of hemangioblastoma.

Specific immunohistochemical pattern of carbonic anhydrase IX is helpful for the diagnosis of CNS hemangioblastoma.

Hemangioblastomas are rare capillary-rich tumors predominantly found in the CNS. The histological appearance of these tumors varies across a broad spectrum. Several entities show considerable histomorphological similarities to hemangioblastomas. Therefore, morphological evaluation can be challenging. In this study, we evaluated the diagnostic utility of immunohistochemistry using antibodies against carbonic anhydrase IX and cytokeratin staining. Within our files, we identified 20 hemangioblastomas. A collection of 46 other tumors relevant to the differential diagnosis (12 pilocytic astrocytomas, 11 meningiomas, one pleomorphic xanthoastrocytoma, one angiomatous fibrous histiocytoma, 14 carcinoma metastases and seven gliomas grades II-IX) served as control. The pattern of strong, diffuse expression of carbonic anhydrase IX with membranous accentuation in combination with keratin negativity was considered diagnostic for hemangioblastomas. It was found in 18 out of 20 (90%) hemangioblastomas and in none of the control cases (P < 0.001). This resulted in a sensitivity of 90% and a specificity of 100%. The positive and negative predictive values were 100% and 96%, respectively. Carbonic anhydrase IX with cytokeratin is thus a highly sensitive and specific marker combination for hemangioblastomas. It is therefore very helpful in the diagnosis of these tumors and in their discrimination from other entities.

Sulfotransferase 1A1 (SULT1A1) polymorphism and susceptibility to primary brain tumors.

PURPOSE: Sulfotransferase 1A1 is a member of sulfotransferase family that plays an important role in the biotransformation of numerous carcinogenic and mutagenic compounds through sulfation. The present study has investigated the association between SULT1A1 polymorphism and primary brain tumor incidence. METHODS: SULT1A1 genotypes were successfully detected using the PCR-RFLP assay in 60 primary brain tumor patients and 156 hospital-based healthy control individuals with no history of cancer or precancerous disorder. RESULTS: There was a significant difference in genotypes distribution (GG vs. GA + AA) between brain tumor patients (GG genotype frequency = 48.3%) and control population (GG genotype frequency = 65.4%; OR = 2.019, 95% CI = 1.103-3.695; P = 0.022). In order to determine the association between SULT1A1 polymorphism and specific types of brain tumors, the patients were classified according to the type of brain tumors they suffer from: glial and non-glial. Results of the statistical analyses of each group of patients in comparison with the control individuals showed a significant difference only between SULT1A1 polymorphism and non-glial brain tumors (OR = 2.615; 95% CI = 1.192-5.739; P = 0.014) but glial tumors (OR = 1.535; 95% CI = 0.688-3.425; P = 0.293). When non-glial tumors were classified as meningiomal and others (pituitary adenoma, craniopharyngioma, acoustic neuroma and hemangioblastoma), statistical analysis showed that this significance is only due to the meningiomal tumors (OR = 3.238; CI = 1.205-8.704; P = 0.015). We also estimated a reduced risk of brain tumor in non-smokers (OR = 1.700; CI = 0.800-3.615) in comparison to smokers (OR = 2.773; CI = 0.993-7.749), but this was not statistically significant. CONCLUSION: Our findings have suggested that there was a significant association between brain tumor and SULT1A1*2 allele (A allele that is also known as His allele) and this allele is an important risk factor in the development of meningiomal brain tumors.

Hemangioblastomas share protein expression with embryonal hemangioblast progenitor cell.

Hemangioblastomas are central nervous system (CNS) tumors of unknown histogenesis, which can occur sporadically or in von Hippel-Lindau disease. Hemangioblastomas are composed of neoplastic "stromal" cells of unknown origin, accompanied by intensive reactive angiogenesis. Failure to specify the cytologic origin of the stromal cell has precluded the development of nonsurgical therapies and limits understanding of its basic biology. We report that the stromal cells express proteins (Scl, brachyury, Csf-1R, Gata-1, Flk-1, and Tie-2) that characterize embryonic progenitor cells with hemangioblastic differentiation potential and conclude that embryonic progenitors with hemangioblast potential represent a possible cytologic equivalent of the stromal cell. We also identified a new autocrine/paracrine stimulatory loop between the receptor Tie-2 and the hypoxia-inducible factor target Ang-1, which, combined with previous observations, suggests that a variety of autocrine loops may be initiated in hemangioblastomas, depending on the differentiation status of the tumor cells and the extent of HIF downstream activation. Finally, the consistent identification of Scl in the stromal cells may help explain the unique and characteristic topographical distribution of hemangioblastomas within the CNS.

Expression of hypoxia-inducible carbonic anhydrases in brain tumors.

Malignant brain tumors exhibit distinct metabolic characteristics. Despite high levels of lactate, the intracellular pH of brain tumors is more alkaline than normal brain. Additionally, with increasing malignancy, brain tumors display intratumoral hypoxia. Carbonic anhydrase (CA) IX and XII are transmembrane isoenzymes that are induced by tissue hypoxia. They participate in regulation of pH homeostasis by catalyzing the reversible hydration of carbon dioxide. The aim of our study was to investigate whether brain tumors of different histology and grade of malignancy express elevated levels of CA IX and XII as compared to normal brain. We analyzed 120 tissue specimens from brain tumors (primary and metastatic) and normal brain for CA IX and XII expression by immunohistochemistry, Western blot, and in situ hybridization. Whereas normal brain tissue showed minimal levels of CA IX and XII expression, expression in tumors was found to be upregulated with increased level of malignancy. Hemangioblastomas, from patients with von Hippel-Lindau disease, also displayed high levels of CA IX and XII expression. Comparison of CA IX and XII staining with HIF-1alpha staining revealed a similar microanatomical distribution, indicating hypoxia as a major, but not the only, induction factor. The extent of CA IX and XII staining correlated with cell proliferation, as indicated by Ki67 labeling. The results demonstrate that CA IX and XII are upregulated in intrinsic and metastatic brain tumors as compared to normal brain tissue. This may contribute to the management of tumor-specific acid load and provide a therapeutic target.