Ottó Major

Histopathological findings in a surgically resected thalamic cavernous hemangioma 1 year after 40-Gy irradiation

✓ Stereotactic radiosurgery is a controversial treatment modality in the management of cerebral cavernous hemangiomas (CHs), and results vary from center to center. Even the interpretation of treatment failure is controversial. It is suggested that the systematic pathological investigation of irradiated specimens could help to resolve the controversy. A hemorrhagic lesion in the posterior part of the thalamus had been diagnosed as a tumor and was treated with 40-Gy fractionated radiotherapy. One year after this treatment the case was reconsidered based on new imaging evidence, and the lesion was removed by conventional craniotomy. Histopathological examination revealed a CH with postirradiation changes. Compared with nonirradiated control CH tissue samples, there was endothelial cell destruction and marked fibrosis with scar tissue formation in the stroma of the treated lesion. The histopathological findings in this specimen were similar to those described in arteriovenous malformations after gamma knife surgery. The results of light microscopic investigations suggest that the ionizing effect of radiation energy evokes vascular and connective tissue stroma changes in CHs as well.

Stereotactic radiosurgery for arteriovenous malformations located in deep critical regions.

BACKGROUND Radiosurgery is widely used to treat deep eloquent arteriovenous malformations (AVMs). OBJECTIVE To evaluate how anatomic location, AVM size, and treatment parameters define outcome. METHODS Retrospective analysis of 356 thalamic/basal ganglia and 160 brainstem AVMs treated with gamma knife radiosurgery. RESULTS Median volume was 2 cm (range, 0.02-50) for supratentorial and 0.5 cm (range, 0.01-40) for brainstem AVMs; the marginal treatment doses were 17.5 to 25 Gy. After single treatment, obliteration was achieved in 65% of the brainstem, in 69% of the supratentorial, and 40% of the peritectal AVMs. Obliteration of lesions <4 cm was better in the brainstem (70%) and in the supratentorium (80%), but not in the peritectal region (40%). Complications were rare (6%-15%) and mild (≤ modified Rankin scale [MRS] 2). Rebleed rate increased with size, but was not higher than before treatment. AVMs >4 cm in the brainstem were treated with unacceptable morbidity and low cure rate. Obliteration of large supratentorial AVMs was 65% to 47% with more complications ≥ MRS3. Repeat radiosurgical treatment led to obliteration in 66% of the cases with minor morbidity. CONCLUSION Deep eloquent AVMs <4 cm can be treated safely and effectively with radiosurgery. Obliteration of peritectal AVMs is significantly lower after a single treatment. However, morbidity is low, and repeat treatment leads to good obliteration. Radiosurgical treatment >4 cm in the brainstem is not recommended. Supratentorial deep AVMs >8 cm can be treated with radiosurgery with higher risk and lower obliteration rate. However, these lesions are difficult to treat with other treatment modalities, and a 50% success rate makes radiosurgery a good alternative even in this challenging group.

Ultrastructural changes in arteriovenous malformations after gamma knife surgery: an electron microscopic study

OBJECT The authors analyzed morphological alterations at the subcellular level by undertaking transmission electron microscopy in arteriovenous malformations (AVMs) after gamma knife surgery (GKS). METHODS Histological, immunohistochemical, and electron microscopic investigations were performed in a series of pathological specimens obtained in seven patients. The patients harbored cerebral AVMs that had been previously treated with GKS and had suffered subsequent bleeding 10 to 52 months after treatment. Histological studies revealed spindle cell proliferation in the connective tissue stroma and in the subendothelial region of the irradiated AVM vessels. Electron microscopy demonstrated different ultrastructural characteristics of this spindle cell population. There were cells with a smooth-edged oval nuclei surrounded by massive bundles of collagen fibers in the extracellular matrix. Other cells with the same nuclear morphology contained abundant intracytoplasmic filaments. Nuclear deformation was connected to a fibrillary system developed within the cytoplasm, and peripheral attachment sites were related to an extracellular layer of basement membrane-like material arranged parallel to the cell border. Also present were cells containing well-developed cisterns of rough endoplasmic reticulum and dense bodies at the periphery of the cytoplasm with folded, irregular nuclei. CONCLUSIONS The ultrastructural and histological characteristics of the spindle cell population in the GKS-treated AVMs are similar to those designated as myofibroblasts in wound healing processes and pathological fibromatoses. Because similar cell modifications have not been demonstrated in control nonirradiated AVM specimens, these myofibroblasts may contribute to the shrinking process and final occlusion of AVMs after radiosurgery.

Morphological Observations in Brain Arteriovenous Malformations after Gamma Knife Radiosurgery

Morphological studies after Gamma Knife radiosurgery (GKRS) revealed endothelial destruction followed by spindle-shaped cell proliferation in the subendothelial region and in the connective tissue stroma of arteriovenous malformation (AVM) vessels. Histological, immunohistochemical and ultrastructural characteristics of this spindle-shaped cell population in the irradiated AVMs were reminiscent of those described as myofibroblasts in wound healing processes and pathological fibromatoses. These modified fibroblasts have contractile capacity, therefore this might contribute to the vessel occlusion, shrinking process and final volume reduction of AVMs after GKRS. Similar histopathological changes were observed in a cavernous malformation following high-dose irradiation.

Experimental stereotactic gamma knife radiosurgery. Vascular contractility studies of the rat middle cerebral artery after chronic survival

Abstract In vitro isometric small vessel myograph experiments and pathological investigations were performed on rat middle cerebral arteries. Thirty-four animals provided 68 normal vessels, six further rats had the endothelial layer mechanically removed from their 12 arteries. Eighteen animals received gamma knife irradiation to the middle cerebral arteries. Fifteen of these received 50 Gray, and three 25 Gray dose to the 50% isodose and the contralateral vessels offered 20 Gray and 15 Gray irradiated specimens. Survival times varied from 12 weeks to 18 months. In the acute stage, abolition of potassium-induced relaxation occurred as early as 24 h after irradiation whilst in one year this reaction seemed to recover and remained active to 18 months. The contraction response to prostaglandin F2 α was diminished at six weeks in the 50 Gray-irradiated vessels. However, from one year further reduction was seen and by 18 months this response was totally abolished. We demonstrated reduction of contractile capability of the irradiated normal vessels while the vessels remained patent. When using low irradiation dose there were no pathological changes even at 18 months, but marked physiological changes could be demonstrated. Different vessel wall functions appear to have different radiosensitivity, time course and capability for regeneration [Neurol Res 2002; 24: 191-198]

Physiological and pathological observations on rat middle cerebral arteries and human AVM tissue cultures following single high-dose gamma irradiation.

In vitro isometric myograph and histopathological studies were performed on rat middle cerebral arteries (MCAs) to explore changes in contractile capacity following experimental Gamma Knife radiosurgery. Right MCAs were treated with 25 Gy and 50 Gy at the 50% isodose line, while contralateral vessels received 15 Gy and 20 Gy at the 20% isodose region. Survival period varied from 3 to 18 months. Reduction in contractile capacity of irradiated normal rat MCAs was detected but their lumina remained patent. In another study, we investigated human AVM tissue cultures in order to detect genetic and phenotypic modifications contributing to vessel occlusion after irradiation. In culture, the proliferation index decreased considerably following 15-, 20-, 25- or 50-Gy irradiation at the 5th posttreatment day and remained depressed during the observation period of 14 days. P53, p21Waf-1 and mdm-2 mRNA contents were elevated significantly after irradiation, indicating enhanced apoptosis. Immunohistochemistry revealed vigorous vimentin positivity in the nonirradiated control AVM cultures, which gradually decreased by the time in the irradiated specimens. Smooth muscle alpha-actin positivity was prominent in the irradiated cultivated samples, suggesting transformation of resting fibroblasts onto activated myofibroblastic elements with contractile capacity. This transformation process was confirmed by the appearance of TGF-Beta in the irradiated AVM cell lines also. These data support the hypothesis that one of the contributing factors to AVM shrinkage and obliteration after radiosurgery might be fibrocyte-myofibroblastic cell transformation in the vessel wall.

Pathological Considerations to Irradiation of Cavernous Malformations

Stereotactic radiosurgery is a controversial treatment modality in the management of cerebral cavernous malformations (CVMs). Systematic pathological studies of irradiated specimens probably could help to resolve the controversy. Light microscopic investigation of a surgically resected thalamic CVM 1 year after 40-Gy irradiation revealed endothelial cell destruction in the cavernous channels, and marked fibrosis with scar tissue formation in the connective stroma of the lesion. These histopathological findings were similar to those described in arteriovenous malformations after Gamma Knife surgery, and suggest that the ionizing effect of radiation energy evokes vascular and connective tissue stroma changes in CVMs as well.