Toshihiko Isaka

Expression of thrombomodulin in astrocytomas of various malignancy and in gliotic and normal brains

SummaryA total of 22 surgical specimens, 16 astrocytomas with various malignancy, 3 brains adjacent to tumor and 3 brains with non-neoplastic lesion, was investigated immunohistochemically for the expression of thrombomodulin (TM). This membrane protein is localized on the vascular endothelium of nearly every human tissue and plays a crucial role in the maintenance of antithrombotic property of the endothelial cells. Although the normal cerebral vessels were negative for TM, the tumor vessels were positive for TM. The increased expression of TM was, however, demonstrated not only in glioblastomas but also in low-grade astrocytomas. Furthermore, the vessels in the brains adjacent to tumor and gliotic brains were also positive for TM. Those observations suggested that the tendency of intratumoral bleeding, which is rather characteristic of glioblastomas, is not simply explained by the altered expression of vascular endothelial TM. In two cases of glioblastoma, not only the blood vessels but also the tumor cells were positive. Considering the mitogenic activity of thrombin, a ligand for TM, the increased expression of TM might be related to the tumor neovascularization and also the tumor growth.

Altered expression of antithrombotic molecules in human glioma vessels.

A total of 14 surgical specimens, including 7 glioblastomas, 3 anaplastic astrocytomas, 2 brains adjacent to glioblastoma and 2 grossly normal brains, were investigated immunohistochemically for the expression of antithrombin III (AT-III), heparan sulfate proteoglycan (HSPG) and thrombomodulin (TM) in the endothelium of microvessels. The immunoreaction to AT-III was of moderate intensity in grossly normal brains, brains adjacent to glioblastoma, and anaplastic astrocytomas, but was only weak in glioblastomas, especially in the capillaries. The immunoreaction to HSPG was constantly intense in the microvessels in all the specimens. Although the immunoreaction to TM was negative or only faint in the microvessels in grossly normal brains, it was moderately to strongly intense in anaplastic astrocytomas and brains adjacent to glioblastoma. The intensity of immunoreaction to TM was variable, from faint to strong in the capillaries, and moderate to strong in larger microvessels in glioblastomas. The present study suggested that the alterations in the expression of those antithrombotic molecules could explain, at least in part, the tendencies for intratumoral hemorrhage as well as intravascular thrombosis in the different areas of malignant gliomas.

Skull metastasis from papillary thyroid carcinoma accompanied by neurofibromatosis type 1 and pheochromocytoma: report of a case.

We report here a 74-year-old woman with a skull metastasis from papillary thyroid carcinoma (PTC). In her medical history, she was diagnosed with neurofibromatosis type 1 (NF1) at age 28 years, and she underwent thyroidectomy for PTC at age 52 years and adrenectomy for pheochromocytoma (PC) at age 58 years. She was admitted to our hospital with an increased mass in the forehead. Head computed tomography (CT) showed an expansive, osteolytic, and solid tumor extending from the dura mater into the subcutis, destroying part of the frontal bone. Head magnetic resonance imaging (MRI) revealed that the tumor was chiefly extradural but partially invaded the dura mater. Cerebral angiography showed that the tumor was fed from a branch of the external carotid artery. She underwent surgery, and histological examination revealed that the skull tumor was a metastasis from PTC, indicating that skull metastasis occurred 23 years after curative surgery for PTC. The patient also underwent adjuvant radioiodine therapy. As little is known about skull metastases from PTC, we discuss its characteristics and the extremely rare combined occurrence of PC and PTC in an NF1 patient.

Hemangioblastoma of the third ventricle.

Abstract A third ventricle tumor, in addition to a recurrent cerebellar hemangioblastoma, was found in a 47-year-old woman on follow-up magnetic resonance imaging (MRI) 5 years after operation of the cerebellar tumor. On MRI, the tumor was hypo- to isointense on T1-weighted images and hyperintense on T2-weighted images compared with the normal gray matter, and was strongly enhanced with gadolinium. The tumor was first treated with fractionated conventional external-beam radiation (5120 cGy in 16 fractions over a 4-week period), resulting in a slight decrease in size of the tumor. For a definite diagnosis and mass reduction, surgery was performed using an interhemispheric translamina terminalis approach, resulting in a partial removal of the tumor due to profuse bleeding. Histological diagnosis was hemangioblastoma. Hemangioblastomas of the third ventricle are extremely rare and have not been specifically discussed. We describe the detailed clinicopathological features of the present case together with the possible explanation for the development of this tumor in this rare location.

Direct ethanol injection for skull metastasis from hepatocellular carcinoma. The techniques and consequences of a therapeutic trial

The frequency of skull metastasis from hepatocellular carcinoma (HCC) is increasing together with the recent progress in the management of the primary lesion. Cases are often complicated with poor general conditions or metastasis to the other organs, and not readily indicated for surgery. A direct injection of ethanol to the lesion could be one of the therapeutic options to cope with this complicated situation. To evaluate the feasibility of this technique, we planned a therapeutic trial in a patient with HCC associated with lumbar and skull metastasis, the latter metastasis repeated twice during the past one year. A total of 10 ml of ethanol was injected into the skull metastasis percutaneously under ultrasound (US) guidance. US guidance was very useful in determining the sites of injections and the distribution of ethanol as well as monitoring the blood flow within the tumor vessels. The patient transiently complained of local pain at the injection sites, but there were no other adverse effects. Four days after the injection, the lesion was resected by surgery, which confirmed the pathologic diagnosis as well as the nearly-total necrosis of the tumor. This technique is simple, safe and repeatable with low cost. The technical details and the histologic effects are described.

Brain metastasis from small-cell neuroendocrine carcinoma of the urinary bladder: A case report

Eight months after radical surgery for small-cell neuroendocrine carcinoma (SCNC) of the urinary bladder, a 69-year-old man was admitted with a brain tumor in the left frontal lobe. The tumor, about 5 cm in diameter, was intensely but heterogeneously enhanced on computed tomography and magnetic resonance imaging. The tumor was subtotally removed, leaving only the portion adjacent to the anterior horn of the left lateral ventricle. Microscopically, the tumor was composed of diffuse sheets of small tumor cells with round to spindle-shaped nuclei, indistinct nucleoli, scant or absent cytoplasm, and indistinct cell margins. Immunohistochemically, the tumor cells were positive for synaptophysin, neuron-specific enolase, chromogranin A, and keratin. Ultrastructurally, the tumor cells showed classic neurosecretory granules and microvilli in the cytoplasm. The tumor was diagnosed as a brain metastasis from SCNC of the urinary bladder. After surgery, whole-brain radiation therapy of 40 Gy was performed, which succeeded in controlling the residual tumor. However, 4 months after surgery, the patient died of meningeal carcinomatosis. To our knowledge, this is the first report focusing on brain metastasis from SCNC of the urinary bladder. The clinicopathological features and pathological diagnosis of this tumor are discussed.

Giant cell type of primary intracranial malignant fibrous histiocytoma: a case report.

The primary intracranial giant cell type of malignant fibrous histiocytoma (GC-MFH) is rare, and the resemblance to meningioma causes diagnostic confusion. Discrimination from meningioma bears important therapeutic and prognostic implications. We report one such case in which an extracranial malignant neoplasm was seen after the initial diagnosis and treatment. A 62-year-old woman presented with history of seizure. MRI revealed a huge right frontotemporal, homogeneously enhanced extraaxial lesion with significant mass effect. The main vascular supply was the middle meningeal artery. Workup for lesions elsewhere was negative. Gross total resection including dural attachment was achieved. The histopathological features were consistent with the diagnosis of GC-MFH. Immunohistochemistry disclosed varied reactivity profiles in tumor component cells: the spindle-shaped cells possessed features of mesenchymal and hematopoietic lineage, the histiocytic cells those of mesenchymal and epithelial cells, and the osteoclast-like multinucleated giant cells those of monocyte/macrophage and epithelial cells. Proliferative activity was absent in giant cells. Local irradiation of 60 Gy (linac) was performed. The patient did well for 10 months, and follow-up MRI showed no evidence of tumor recurrence. Subsequently, she developed ascites and died 3 months later as a consequence of end-stage adenocarcinoma (ovary) with peritoneal dissemination. There is no established treatment protocol for primary intracranial MFH. Although gross total resection and local irradiation were effective in the short-term control of local relapse in the present case, occurrence of extracranial neoplasm was fatal. Close follow-up aimed at early detection of local recurrence and distant metastases, as well as extracranial malignancy, remains important.

Intraoperative ultrasonographically guided direct ethanol injection for a brain metastasis from renal cell carcinoma: case report

Abstract A 60-year-old man presented with a brain metastasis from renal cell carcinoma (RCC). Computer tomography revealed a homogeneously enhanced tumor, 3.0 cm in maximum diameter, in the right medial temporal lobe. Cerebral angiography revealed that the tumor was mainly fed by the right posterior cerebral artery. Surgery was performed via right temporal craniotomy. After craniotomy, under ultrasonography (US) guidance, a total of 3.0 ml of ethanol was injected into the tumor to diminish the intratumoral vascular flow. Ultrasonographic guidance was very useful in monitoring the intratumoral vascular flow. After a marked decrease in the vascular flow, the tumor was totally removed using piecemeal technique. During surgery, only minimal bleeding from the tumor was noted. The postoperative course was uneventful, with no evidence of injected ethanol-related complications. In conclusion, this can be a safe, easy, and effective therapeutic technique for diminishing vascular flow within brain tumors rich in vascularity, such as brain metastases from RCC.

Cellular targets of exogenous tumour necrosis factor-alpha (TNFα) in human gliomas

SummaryTo identify the cellular targets of TNFα in human gliomas, a total of 30 surgical specimens (12 glioblastomas, 4 anaplastic astrocytomas, 3 astrocytomas, 7 brains adjacent to tumour (BAT), 4 histologically normal-appearing brains) were examined by in vitro binding technique using biotinylated TNFa. The TNF-binding sites (TNF-BS) were recognized in the tumour cells in 8 of the 12 glioblastomas. 3 of the 4 anaplastic astrocytomas and in all the 3 astrocytomas. The TNF-BS were also recognized in the vascular endothelial cells in all these cases. The presence of TNF-BS in blood vessels ranged from 7.7 to 74.4% of the background vessels. This wide range of variation in the presence of TNF-BS within the tumour cells and tumour blood vessels may be relevant to the variable response of individual tumours to TNFα therapy. Since the tissue of normal brain, which lacks TNF-BS, might hardly be affected by this cytokine, administration of TNFa may be considered as an adjuvant therapy in selected groups of patients.

Ultrastructural Changes of the Vascular Endothelium after Intra-arterial Administration of Tumor Necrosis Factor-alpha (TNFα) in Rat Gliomas

The ensuing ultrastructural changes in tumor vascular endothelial cells following intra-arterial administration of tumor necrosis factor-α (TNFα) were studied in an experimental rat glioma model. C6 glioma cells were implanted in Wistar rats and then after 14 days, 5×103 U of human natural-type TNFα (1.7×105 U/m2) was administered through the carotid artery. The animals were sacrificed at 3 or 24 h after TNFα treatment. A detailed examination with transmission electron microscope revealed swelling of the tumor vascular endothelial cell nuclei and mitochondria with matrix densities at 3 h. At 24 h, these cells demonstrated the presence of high amplitude mitochondrial swelling or the violent blebbing characteristic of damaged mitochondria; the cytoplasm was swollen enormously and there were dissolution of cytoplasmic organelles and rupture of the plasma membrane. The observed findings were typical of cell necrosis and confirms yet another mechanism by which TNFα exerts its anti-tumor effects, that is, necrotizing effects on tumor vascular endothelium. The information appears to be important in the context of clinical application of intra-arterial TNFα in the treatment of malignant gliomas.