György T. Szeifert

The potential role of myofibroblasts in the obliteration of arteriovenous malformations after radiosurgery.

OBJECTIVES To examine the structural changes in arteriovenous malformations (AVMs) after stereotactic radiosurgery and to identify the cytoskeletal antigen phenotype of the proliferating cells to gain information about the possible mechanism of obliteration. METHODS We conducted immunohistochemical and electromicroscopic investigations of surgical material that was removed from seven patients. The patients were harboring cerebral AVMs that had been previously treated with gamma knife irradiation, and they experienced subsequent bleeding 10 to 52 months after treatment. RESULTS Light microscopy revealed spindle-shaped cell proliferation in the connective tissue stroma and in the subendothelial region of the vessels. The ultrastructural and immunohistochemical characteristics of these spindle cells were identical to those designated as myofibroblasts in wound healing processes and pathological fibromatoses. Whereas in nonirradiated specimens of AVMs, similar cells expressed vimentin and desmin positivity, in irradiated cases, alpha-smooth muscle actin activity was also observed. CONCLUSION In view of the contractile activity of myofibroblasts, the proliferation generated by irradiation and the transformation of the resting cells into an activated form could be relevant to the shrinking process and eventual occlusion of AVMs after radiosurgery.

Long-term results and late complications after intracavitary yttrium-90 colloid irradiation of recurrent cystic craniopharyngiomas.

OBJECTIVE Data were analyzed to assess the value of stereotactically applied intracystic colloidal yttrium-90 (YTx) for the treatment of recurrent cystic craniopharyngiomas during a 30-year period. METHODS This article compares data from 73 YTx procedures in 60 patients between 1975 and 2006. The cumulative beta dose aimed at the inner surface of the cyst wall was 300 Gy. RESULTS After YTx, the initial cyst volumes decreased an average of 79%. In 47, the reduction was more than 80%; in 27 of them, the cyst disappeared completely within 1 year. The mean survival after YTx was 9.4 years (range, 0.7–30 yr). Actuarial survival rates at 5, 10, 15, 20, 25, and 30 years were 81, 61, 45, 18, 2, and 0%, respectively. Late complications of YTx were related to the anatomic localization of the cyst, either presellar and retrosellar, e.g., a presellar (prechiasmatic/suprasellar) localization caused neuro-ophthalmological complications in 5.8% and internal carotid artery injury in 1.6%. The treatment of retrosellar (retrochiasmatic, suprasellar) tumors occasionally induced hypothalamic and/or pontomesencephalothalamic damage obviously by untoward radiation to the so-called perforating arteries. This occurred in 3.2% of these latter patients. CONCLUSION Despite sporadic complications, intracavitary YTx irradiation is a valuable treatment alternative for craniopharyngioma cysts, sometimes as part of a multimodality management in these tumors, especially in precarious surgical cases.

Bilateral supraorbital keyhole approach for multiple aneurysms via superciliary skin incisions

BACKGROUND Considering that multiple aneurysms carry a high risk for fatal rupture, there is a need for complete treatment of all lesions in one surgical session using either unilateral-contralateral or bilateral approaches. Contralateral approaches have been used mainly for small anteriorly projecting middle cerebral and medially expanding ophthalmic types of aneurysms. They are limited by the narrow space for surgical manipulation, forced elevation of frontal lobes, and stretching of the olfactory nerves. These problems might result in damage to structures along the unusually long intracranial way of the approach. The complications associated with the unnecessarily large conventional fronto-temporal and bifrontal craniotomies, and the developments in visualization, neuroanaesthesia, microneurosurgery, cerebrospinal fluid (CSF) drainage, and brain protection have led to less invasive methods in cerebral base surgery. These achievements have supplied the background for the supraorbital keyhole approach to aneurysms of the anterior circulation or basilar tip. Because the supraorbital keyhole approach offers several advantages over the classic fronto-temporal craniotomies to the anterior skull base, it was extended for both sides in one surgical session to treat bilateral multiple aneurysms as well. METHODS Out of a series of 150 patients harboring 188 saccular aneurysms operated on via a supraorbital keyhole approach with a superciliar skin incision, 36 had multiple aneurysms. Thirty patients with multiple aneurysms underwent surgery for their ruptured aneurysms (17 cases in the acute phase and 13 patients during the chronic stage); in 6 cases silent aneurysms were operated on. The multiple aneurysms were managed from one side in 18 cases. A bilateral supraorbital keyhole approach was performed during one surgical session in 11 patients, and in 7 cases the unilateral supraorbital keyhole approach was combined with contralateral fronto-temporal (3 cases), suboccipital (2 cases), or frontal-parasagittal (2 cases) exploration. The operations were carried out through an approximately 2.5 x 3 cm supraorbital keyhole craniotomy following a skin incision just above the eyebrow. The roughly 4 cm superciliar skin incision begins medial to the supraorbital nerve and ends 3 to 10 mm beyond the lateral edge of the eyebrow. The technical details of the method are presented, and the benefits, limitations, and complications are discussed. RESULTS In the 36 patients operated on via the supraorbital keyhole approach 74 aneurysms were clipped successfully. In 2 cases premature intraoperative rupture of the aneurysms occurred, but these events were managed successfully. Despite the small size of the craniotomy the approach allows enough room for intracranial manipulation with maximal protection of the brain and other intracranial structures. One patient died because of pulmonary embolism. There were no craniotomy-related complications in the present series. CONCLUSION The supraorbital keyhole approach together with the advent of the modern neuroanaesthesia, CSF drainage, and microsurgical techniques is a safe approach in the hands of experienced neurosurgeons for the treatment of supratentorial or basilar tip aneurysms. Because the approach is simple and swift, the bilateral single-session craniotomy does not have any disadvantages compared to two-stage procedures. However, the one-sitting surgery reduces the high risk of fatal rupture in the perioperative period associated with multiple aneurysms.

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.

Histopathological changes in cerebral arteriovenous malformations following Gamma Knife radiosurgery.

Histological, immunohistochemical and electron microscopic investigations were carried out in a series of surgical pathology material that was removed from 7 patients. They were harboring cerebral arteriovenous malformations (AVMs) that had been previously treated with Leksell Gamma Knife radiosurgery, and presented subsequent bleeding 10-52 months after treatment. Light microscopic studies revealed a spindle cell proliferation in the connective tissue stroma and in the subendothelial region of the irradiated AVM vessels. The histological, immunohistochemical and ultrastructural characteristics of the spindle cell population in the Leksell Gamma Knife-treated AVMs are similar to those designated as myofibroblasts in wound healing processes and pathological fibromatoses. Considering that similar cell modifications have not been demonstrated in control, nonirradiated AVM specimens, these myofibroblasts might contribute to the shrinking process and final occlusion of AVMs after radiosurgery.

The Role of the Gamma Knife in the Management of Cerebral Astrocytomas

The aim of this study was to assess the role of Gamma Knife radiosurgery in the complex management of cerebral astrocytomas. Out of a series with more than 1,000 brain tumor cases treated at the Lars Leksell Center for Gamma Knife Surgery, UVA, 74 astrocytomas were selected for the present review. The tumor either disappeared or decreased in 60% of grade 1 astrocytomas (n = 15), and 71% tumor control was achieved in grade 2 astrocytomas (n = 17) following radiosurgery. In the high-grade glioma group (grades 3 and 4; n = 42) median survival time was 14 (range 2-58) months, and 25% of the patients were alive at 5 years after the treatment. The best results were presented by the subgroup wherein previous craniotomy and debulking of the tumor were followed by radiosurgery (n = 7) with a median survival period of 24 (range 2-53) months. Results of the present analysis suggest that stereotactic radiosurgery represents an alternative or supplementary treatment modality to conventional surgery in small-volume low-grade astrocytomas especially in deep-seated critical locations. There is also evidence for the beneficial effect of radiosurgery on the survival of patients with high-grade gliomas; however, the limitations of a focused irradiation technique on a malignant infiltrative process are obvious.

The role of microglia/macrophage system in the tissue response to I-125 interstitial brachytherapy of cerebral gliomas

Abstract Objective: To study histopathologic changes and the role of the microglia/macrophage cell in the therapeutic effect of I-125 interstitial brachytherapy on the cerebral gliomas. Methods: Out of a series of 60 cases with cerebral astrocytomas and other brain tumors treated with I-125 interstitial brachytherapy, autopsy materials were available in ten cases 0.75 and 60 months after irradiation. The patients were treated with the maximum dosage (60 Gy) on the tumor periphery. Besides the routine hematoxylin-eosine and Mallorys PTAH trichrome staining, immunohistochemical reactions were carried out for CD15, CD31, CD34, CD45, CD68, CPM, HAM56 and HLR-DR antigens on paraffin sections to study immunologic phenotypic characteristics of the reaction cell population around gliomas after I-125 treatment. Result: One month after irradiation, a necrotic zone developed around the I-125 seeds within the 72 Gy isodose curve. Histologically, there was a fresh coagulation necrosis in the center of the lesion. Reactive zone has not yet developed but scattered interstitial and perivascular CD68 positive macrophages were present in the surrounding brain tissues. Six months after the I-125 isotope treatment, a reactive zone developed: a microglial rim around the necrosis tissue, and a broad area of proliferating vessels and glial fibrillary acidic protein (GFAP) positive astroglial cells which contained CD68 positive activated microglial and macrophage cells. Fifty-four months after I-125 interstitial irradiation, the necrotic center became colliquative and cystic. The microglial rim was replaced by round end stage (HLR-DR and CD31 positive) macrophages. The reactive zone was characterized by astrocytic gliosis but vascular proliferation and macrophages were lacking. Conclusion: Results of the present immunohistochemical study suggest that the early lesions are characterized by migrating macrophages apparently concerned with the removal of necrotic debris. The established phase of reactive zone around the necrotic center is characterized by a narrow inner rim of microglial accumulation and a broad outer area characterized by astrocytic gliosis, vascular proliferation, activated microglia and infiltration by macrophages. In the burned-out phases of I-125 interstitial brachytherapy of gliomas, the necrosis undergoes liquefaction and the microglial rim is replaced by astrocytic gliosis which can be considered as equivalent to the scar tissue formed around necrosis outside the central nervous system.

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.

Radiosurgical Pathology of Brain Tumors: Metastases, Schwannomas, Meningiomas, Astrocytomas, Hemangioblastomas

Systematic human pathological background to brain tumor radiosurgery explaining biological and pathophysiological effects of focused irradiation barely exists. The goal of this study was to explore histopathological changes evoked by single high-dose irradiation in a set of different brain tumors following Gamma Knife radiosurgery (GKRS). Light microscopy revealed that GKRS evokes degenerative and proliferative pathological changes in the parenchyma, stroma and vessels of the irradiated tumors. Three main histological types of gamma radiolesions, that is acute, subacute and chronic variants of tissue reactions were recognized in different neoplasms irrespective of their ontogenetic nature. Acute type gamma radiolesions were characterized mainly with necrotic changes and appeared either early or in a delayed time interval. Subacute type gamma radiolesions expressed resorptive activity also with early or delayed chronology. Chronic type lesions showed a reparative tendency but presented only at the delayed stage. These changes seem to follow each other consecutively. There was no significant relation between morphological characteristics of the generated tissue reaction and the time interval elapsed after GKRS. This relative time and environment autonomy of the developed pathological lesions with similar histological picture in different neoplasms suggests either a vascular mechanism or/and a genetically directed origin presumably induced by the ionizing energy of high-dose irradiation.

Could craniopharyngiomas produce pituitary hormones

The authors have studied the endocrinological characteristics of 13 craniopharyngioma biopsy specimens in paraffin embedded histological sections with immunohistochemical methods for pituitary hormones (GH, PRL, ACTH, TSH, F5H and LH). Scattered cell groups with mild to moderate positivity for at least one hormone were found in all but one case. This finding supplies further evidence to the hypothesis which suggests the Rathkes pouch origin of craniopharyngiomas. Beside the hypothalamic-hypohyseal lesion it might explain the endocrinological disturbances accompanying the patients suffering from these tumours. [Neurol Res 1993; 15: 68-69].