Capillary Hemangioblastoma Research Articles

Fibrohistiocytic differentiation in capillary hemangioblastoma

Seven cases of capillary hemangioblastoma from the cerebellum and spinal cord were studied by immunohistochemical methods to determine the origin of the stromal cells. A subpopulation of factor XIIIa-positive tumor cells was a constant feature in hemangioblastomas. These stellate or spindle-shaped cells transformed into typical vacuolated stromal cells. Factor VIII-related antigen was limited to the vascular endothelium. Glial fibrillary acidic protein was present only in entrapped astrocytes. Staining for α-1-antitrypsin (α1AT) and α-1-antichymotrypsin (α1ACT) was occasionally observed in stromal cells. It was concluded that the factor XIIIa-positive stromal cells in capillary hemangioblastoma indicate fibrohistiocytic differentiation, which is part of the differentiation spectrum of hemangiopericytomas.

Hepatic Hemangioblastoma

We report a case of multiple capillary hemangioblastomas of the liver occurring in a patient with von Hippel-Lindau disease and a history of previous cerebellar and spinal hemangioblastomas. Although rare examples of this tumor have previously been recorded in the pancreas, kidney, and urinary bladder, this appears to be the first recorded case with hepatic involvement. The histology and immunohistochemical appearance of this neoplasm are identical with those of the cerebellar tumor. We believe it represents a separate primary neoplasm rather than metastatic disease.

Immunohistochemistry of Capillary Hemangioblastoma

We used a battery of antigens to determine whether immunohistochemistry can (a) contribute to resolving the histogenesis of the stromal component of the capillary hemangioblastoma, and (b) answer cases of difficult pathologic differential diagnosis with metastatic clear cell carcinoma. The stromal cells of the capillary hemangioblastoma are antigenically polymorphous and may express immunoreactive erythropoietin, renin, keratin, Leu M1, Leu 7, actin, neuron-specific enolase, S100 protein, and glial fibrillary acidic protein. However, the use of epithelial membrane antigen allows certain histopathologic distinction between capillary hemangioblastoma and metastatic clear cell carcinoma.

Erythropoietin in capillary hemangioblastoma. An immunohistochemical study.

Capillary hemangioblastoma is a tumor known to be associated with secondary polycythemia. Therefore, specimens from ten hemangioblastomas were studied by immunohistochemistry for the presence of erythropoietin, renin substrate, and for various endothelial, histiocytic and glial markers. In all tumors scattered cells among the stromal cells showed a positive-staining reaction with both anti-erythropoietin and anti-renin substrate. The same cells also stained positively for alpha-1-anti-trypsin. It is concluded that, in addition to the capillary endothelial cells, pericytes and stromal cells, capillary hemangioblastomas harbor cells containing and perhaps producing renin substrate and/or erythropoietin or a substance with similar antigenic determinants.

Capillary hemangioblastoma: histogenesis of stromal cells.

The histogenesis of stromal cells in capillary hemangioblastoma has been the subject of debate. The light and electron microscopic studies of hemangioblastomas presented here showed pericytic and leiomyoblastic features in stromal cells. Cells cultured by the monolayer method showed similar features to those of the original tumors. Immunohistochemical studies for glial fibrillary acidic protein and factor VIII/von Willebrand factor indicated that stromal cells were antigenically distinct from astrocytes and endothelial cells. These findings suggest that stromal cells are closely related to pericytes and smooth muscle cells, and support Rhodin's speculation that pericytes serve as a precursor to smooth muscle cells.

Ultrastructure of cerebellar capillary hemangioblastoma. VI. Concentric lamellar bodies of endoplasmic reticulum in stromal cells.

Concentric lamellar bodies of endoplasmic reticulum (CLB) were found in the stromal cells of all five cases of cerebellar capillary hemangioblastoma studied ultrastructurally. CLB were often present in the stromal cells with voluminous loose cytoplasm, particularly those close to the capillaries. They were rarely seen in small stromal cells with abundant organelles and stromal cells distended by large lipid droplets. Small lipid droplets were usually present in the center or in the vicinity of CLB. Vesiculation and vacuolization of the lamellar arrays of CLB were common. Some vacuolized CLB were transformed into large, varying-shaped, multilocular bodies. Some stromal cells were markedly distended by numerous large vacuoles derived from CLB. Granulo-fibrillary material was frequently present in the vacuolized lamellae. Discharge of vacuoles into the interstitial space was observed. It is suggested that CLB is one of the characteristic ultrastructural features of the stromal cells. They may represent a special type of hyperplasia of the endoplasmic reticulum, but their functional significance is not known.

Capillary hemangioblastoma. An immunohistochemical study.

Previous studies using immunohistochemical methods to determine the presence of glial fibrillary acidic protein (GFAP) and Factor VIII-related antigen (FVIIIR:Ag) in stromal cells of capillary hemangioblastomas have yielded conflicting results with respect to the possible astrocytic and endothelial origins of these cells. This study included Ulex europaeus I lectin (UEAI), a more sensitive marker of endothelial cells. Antibodies were also used as markers of pericytes and a variety of markers were employed to identify different populations of histiocytes. Results of this investigation indicate that FVIIIR:Ag and UEAI are limited only to endothelial cells, and that GFAP is present in entrapped astrocytes only. Positivity of stromal cells was found with some of the histiocytic markers, but the authors were unable to conclude that these cells have a histiocytic origin. It was concluded that currently there is no evidence that stromal cells are derived from endothelial, pericytic, or astrocytic cells-their origin remains uncertain.

Ultrastructure of cerebellar capillary hemangioblastoma. III. Crystalloid bodies in endothelial cells.

The endothelial cells of three cases of cerebellar capillary hemangioblastoma were studied by means of electron microscopy. Crystalloid bodies, not previously described in the vessels of the central nervous system (CNS), were found in 5%-10% of the endothelial cells, more often in the capillaries with small irregular lumens. They were not observed in the pericytes or stromal cells. They were round to polygonal, 0.5-1.0 micron in size and composed of substructural units of parallel thick and thin electron-dense lines with a periodicity of 180-220 A. They coexisted occasionally with Weibel-Palade bodies but shared no structural correlation with them. The nature and significance of these crystalloid bodies are as yet unknown. Their close association with pinocytic vesicles suggests that the substructural crystalline might be the result of reconstruction of absorbed material from either the vascular lumen or the interstitium. Their subsequent development, associated with lysosomal activity, into intracytoplasmic dense bodies is postulated. Since crystalloid bodies were found only in endothelial cells, particularly those active in proliferation, they may play a pathophysiologic role in relation to angiogenesis.

Ultrastructure of cerebellar capillary hemangioblastoma. IV. Pericytes and their relationship to endothelial cells.

Electron microscopy and computerized morphometric techniques were employed to examine pericyte ultrastructure and to assess quantitatively their relationship to endothelial cells in five cases of cerebellar capillary hemangioblastoma. A total of 97 cross-sectioned capillary profiles were studied. Pericyte coverage of capillary ranged from 30.2% to 97.3% with a mean value of 68.7%, which is higher as compared with the available data from the cerebral cortex, skeletal and cardiac muscle, and pulmonary capillaries. The higher pericyte coverage of capillary suggests that pericyte is an active component of cerebellar capillary hemangioblastoma and may have a close functional relationship to endothelial cells. Pericytes contained bundles of parallel microfilaments along the adluminal side and in the terminal processes, and exhibited an intimate "peg-and-socket" relationship with endothelial cells, suggesting a contractile function of pericytes and their possible role in regulating capillary lumina and focal blood flow. The finding of abundant micropinocytic vesicles along the abluminal side of the cytoplasmic membrane indicates an active metabolic exchange between pericytes and the interstitium. It is possible that in cerebellar hemangioblastoma pericytes may act as a mechanical and metabolic monitor barrier for endothelial cells.

Hemangioblastoma of the central nervous system: Nature of the stromal cells as studied by the immunoperoxidase technique

Ten hemangioblastomas of the central nervous system were examined by an immunoperoxidase technique for glial fibrillary acidic protein (GFAP), S-100 protein, and Factor VIII-related antigen to determine the origin of the stromal cells. In seven cases scattered stromal cells were positive for GFAP, and eight cases showed variable numbers of S-100 protein-positive cells. These positive cells were present throughout the tumors. S-100 protein-positive stromal cells corresponded to GFAP-positive cells, but the former were more numerous than the latter. Staining for Factor VIII-related antigen was negative in stromal cells, except in endothelial cells lining capillaries. It was suggested that stromal cells of capillary hemangioblastomas are composed by heterogeneous cell populations.

Ultrastructure of cerebellar capillary hemangioblastoma. II. Mast cells and angiogenesis.

The topographic distribution, population density, and ultrastructural features of mast cells were studied in six cases of cerebellar capillary hemangioblastoma. The vascular area of tumor tissue contained large numbers of mast cells (6.3 cells/high power field, X 400) in comparison with hyalinized area (0.3 cell) and adjacent cerebellar tissue (less than 0.1 cell). Close association of mast cells with endothelial cells and stromal cells was found. The morphology of mast cell granules and their degranulation through dissolution of granule contents and exocytosis were illustrated. The findings suggest that an increased number of mast cells may represent one of the characteristic histological features of capillary hemangioblastoma, and continuous degranulation of mast cell granules with release of heparin may play an important pathophysiologic role in the vascular proliferation and expansion of the tumor.

Mixed Capillary Hemangioblastoma and Glioma

The histopathologic features of four cases of mixed capillary hemangioblastoma and glioma are described. In three cases, two of which arose in the cerebellum and one in the spinal cord, the hemangioblastic component may have originated from a neoplastic proliferation of the exuberant vascular stroma in a glial tumor. In a fourth case, a cerebellar hemangioblastoma was surrounded by a peripheral rim of atypical neoplastic-looking astrocytes ("reactive glioma"). The controversial concept of the "angioglioma" is reviewed, and it is proposed that the term be used to designate only true mixed tumors of glial and vascular tissue origin whose histologic features conform to the examples described in this report.

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We experienced a case of capillary hemangioblastoma forming the dumbbell shape. This tumor is rare and interesting form of the spinal cord tumors.A 51 year old male has been suffering from lumbar pain. About 9 months ago he developed so-called SHIBIRE-feeling in his feet and weakness of the extrimities.X-ray showed the enlargement of the right intervertebral formen of L1-2.The Th12-L2 laminectomy was performed and the dural canal was opened. The tumor was situated within the vertebral canal and was partially intradural, partially extradural, as if it was constricted by the dura.Histologically, the tumor was a capillary hemangioblastoma.

Cells constituting cerebellar hemangioblastomas. Ultrastructural study.

Five capillary hemangioblastomas exhibiting a range of histologic variations common to this tumor were studied using electron microscopy. The capillary hemangioblastoma were composed commonly of three cell lines -- stromal cells, endothelial cells and pericytes. In addition, extramedullary hematopoietic foci were seen in the tissue of one case. We regarded all these cellular elements as neoplastic components. The interconvertibility among them was not confirmed. The capillary hemangioblastomas were highly organized by those multiple cell lines. The histologic pattern of growth was arbitrarily subgrouped into stromal cell prominent type and capillary prominent type. Intermediate features between the two types were observed. These different types would depend on relative proportions and the degree of maturity of the constituting cell elements. From the histogenetic point of view, we considered capillary hemangioblastomas as being a hamartomatous tumor.

Primary intracranial tumors: analysis of a series of consecutive autopsies and biopsies

A retrospective study of primary intracranial tumors found in 19.760 consecutive autopsies and 72.972 consecutive biopsies during a period of over 41 years was carried out. Two hundred and five neoplasms comprising 69,7% of the primary intracranial tumors were located in the supratentorial compartment whereas 84 tumors (28,6%) were infratentorial in site. Gliomas constituted the largest group of primary tumors comprising 60,9% of the intracranial primary neoplasms. Most of gliomas were found in the cerebral hemispheres, particularly in the frontal lobes. Of the total number of gliomas 40,2% were astrocytomas, 29,6% glioblastomas, 10,6% ependymomas, 10,1% medulloblastomas, 5% oligodendrogliomas and 2,2% choroid plexus papillomas. Meningiomas constituted the second most common primary intracranial tumors being found in 56 cases (19%), most of them in parasagittal region, sphenoid ridge and anterior fossa. In the sella region there were 39 neoplasms including 21 pituitary adenomas, seven meningiomas, five craniopharyngiomas, four epidermoid cysts and two teratomas. Six capillary hemangioblastomas of the cerebellum and two chordomas of the clivus were also found. Sixty-five tumors occurred in patients under 15 years of age, 53,3% of them infratentorial in location--36% in the cerebellum, 9,3% in the brainstem and 8% in the fourth ventricle. The majority of these tumors were astrocytomas, medulloblastomas and ependymomas. The present data are discussed in relation to other pathological series found in the literature.

Glial fibrillary acidic protein in stromal cells of some capillary hemangioblastomas: significance and possible implications of an immunoperoxidase study.

Thirty-nine hemangioblastomas from 26 patients were studied by the immunoperoxidase method for GFA protein. Reactive gliosis in the form of trapped GFA protein-positive astrocytes or astrocytic cell processes penetrated the margins of all the neuraxial tumors and none of those occurring on nerve roots or in the tumor explants maintained in an organ culture system. Gliosis was especially prominent in tumors recurring after surgical excision or in patients with a long history of tumor. In six tumors, representing both the reticular and the cellular variants of hemangioblastoma, GFA protein-positive stromal cells were also found, chiefly in the periphery of the neoplasma: all these tumors were surrounded by dense reactive gliosis. Four hypotheses accounting for the presence of GFA protein-positive stromal cells are considered: (1) The tumors are astrocytomas. (2) The GFA protein-positive cells are not neoplastic but lipidized or altered reactive astrocytes. (3) The tumors are mixed and partly composed of neoplastic astrocytes. (4) The stromal cells are capable of taking up extracellular GFA protein derived from the adjacent reactive astrocytes. The last of these hypotheses is the most consistent with the collective evidence derived from the histological findings. It implies that the presence of GFA protein in the cytoplasm of a cell does not necessarily establish that the cell is glial. The possibility of uptake of GFA protein by non-glial cells must be considered if dense gliosis is present in the vicinity.

Cerebellar capillary hemangioblastoma: Its histogenesis studied by organ culture and electron microscopy

A capillary hemangioblastoma from the vermis of a 21-year-old man with von Hippel-Lindau's disease was successfully maintained in organ culture systems on Millipore filter platforms and gelatin sponge foam matrices up to 48 days. Three cell types--endothelial cells, pericytes, and stromal cells--identified by their fine structural features and their architectural relationships to vascular lumens and to the extracellular space were recognized in the original tumor. By light microscopy the explants showed, in the late stages, increased lipid droplets in the stromal cells and perivascular hyaline thickening. By electron microscopy, endothelial cells, pericytes, and stromal cells remained distinguishable as cell types. However, the stromal cells demonstrated, in addition to an increase of their normal complement of microfilaments and lipid droplets, features that were more characteristic of the two other cell types, i.e. micropinocytotic vesicles and the formation of zonula occludens junctions and hemidesmosomes. Basement membranes also became more apparent around the stromal cells. With increasing time in vitro, there was a striking increase in mature collagen fibers in the extracellular space. The roles of the different cell types in capillary hemangioblastoma and the histogenesis of the stromal cells are discussed in light of these observations. It is concluded that the capillary hemangioblastoma consists of multiple cell lines--endothelial cells, pericytes, stromal cells and, occasionally, hematopoietic cells--all of which are neoplastic and replicate in parallel with one another. Stromal cells may be regarded as an aberrant monopotential cell type which shares with the endothelial cell and pericyte a common mesenchymal, presumably angiogenic, ancestry, and may, on occasion, display morphological features, such as increased basement membrane formation and the formation of zonula occludens junctions, which recall its angiogenic lineage. However, interconvertibility between endothelial cells and stromal cells does not appear to occur in vivo or in vitro.