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.

Histopathology of brain metastases after radiosurgery.

Histopathological investigations revealed acute-, subacute-, and chronic-type tissue responses, accompanied by inflammatory cell reaction in radiosurgery treated cerebral metastases originating from different primary cancers. Immunohistochemistry demonstrated that the preponderance of CD68-positive macrophages and CD3-positive T lymphocytes in the inflammatory infiltration developed in better controlled metastases ( > 5 months). In contrast, it was sparse or absent in poorly controlled neoplasms ( < 5 months) after radiosurgery. This inflammatory reaction may be stimulated by the ionizing energy, probably influenced by the general condition of the patients' immune system as well, and seems to play a role in local tumor control after focused radiation.

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.

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

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 Mallory's 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.

Introduction: the contribution of pathology to radiosurgery.

The term radiosurgery signifies any kind of application of ionizing radiation energy, in experimental biology or clinical medicine, aiming at the precise and complete destruction of chosen target structures containing healthy and/or pathological cells, without significant concomitant or late radiation damage to adjacent tissues. The goal of this study is to explore the short- and long-term pathophysiological effects of high-dose focused irradiation on neural tissue and its pathologies with histological, electron-microscopical tissue culture and biological-biochemical methods. Radiosurgical pathology focuses its scope and microscope on tissue, cellular, genetic and molecular changes in the human organism and experimental animals, or in cell lines and other in vitro experiments, generated by the ionizing radiation delivered from radiosurgical devices.

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.

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.

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.

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.

Pathological findings following trigeminal neuralgia radiosurgery.

Autopsy, 3D MRI and histopathological findings are presented in a patient who had suffered from trigeminal neuralgia and was treated two times by radiosurgery. The first treatment was performed with 90 Gy at the distal part of the nerve. Because of recurrent pain, a second irradiation was carried out delivering 70 Gy at a more proximal segment of the nerve 10 months later. The patient died from a hemorrhagic stroke 26 days following the second intervention. Autopsy revealed a neurovascular conflict close to the second radiosurgery shot. Histopathology demonstrated acute and chronic stage radiation-induced lesions in the trigeminal nerve.

Stereotactic intracavitary irradiation of cystic craniopharyngiomas with yttrium-90 isotope.

The authors analyzed data from nearly 30-year follow-up period to assess the value of intracavitary irradiation with stereotactically implanted beta-emitting radioisotope yttrium- 90 (90Y) silicate colloid for the treatment of cystic craniopharyngiomas. Seventy-three cysts in 60 patients were selected for retrospective analysis. The cumulative dose aimed at the inner surface of the cyst wall was 300 Gy. An average of 79% (mean 88.3%) shrinkage of the initial cyst volume was observed. In 47 cysts, the reduction was more than 80%, and the cyst disappeared totally in 29 out of those 47 cases, usually within a year. Mean survival duration after intracavitary irradiation was 9.4 years. Neuroophthalmological prognosis was only favorable when the optic disc was normal or nearly normal at the time of the treatment. In the presence of preexisting optic atrophy, visual damage proved to be irreversible. The long-term results support the view that intracavitary 90Y irradiation is a noninvasive and effective method for the treatment of craniopharyngioma cysts. Because of the mean penetration pathway of beta irradiation is 3.6mm in the soft tissues (maximum 11 mm) it cannot influence the solid part of the tumor; therefore, the best result can be expected in solitary cysts.

Pathological findings in cystic craniopharyngiomas after stereotactic intracavitary irradiation with yttrium-90 isotope.

Histopathological, ultrastructural and polyacrylamide gel electrophoretic examinations were carried out on biopsy, cyst fluid, surgical pathology and autopsy specimens obtained from 7 cystic craniopharyngioma cases before and after yttrium-90 silicate colloid (90Y) irradiation. Light microscopy revealed that the lining epithelial tumor cell layer of the cyst wall was destroyed, and scar tissue containing large amount of hyaline degenerated collagen bundles replaced it. Proliferative postirradiation vasculopathy was also demonstrated in the cyst wall following 90Y installation. Electrophoretic property of cyst fluid was similar to the normal human serum. Considering that scar tissue has a certain propensity to shrink, the fibrosis in the cyst wall together with destruction of neoplastic epithelium and vascular changes might explain diminished fluid production and cyst volume reduction after 90Y treatment.

Image fusion-guided stereotactic iodine-125 interstitial irradiation of inoperable and recurrent gliomas.

Between 1996 and 2004, 27 patients with low grade gliomas (WHO grade I-II), 10 patients with WHO grade III gliomas and 6 patients with glioblastoma multiforme (WHO grade IV) were treated with stereotactic brachytherapy using low-dose rate iodine-125 (125I) isotope seeds at the Department of Neurosurgery, St. John's Hospital, Budapest, Hungary. In all 43 cases, brachytherapy was used for surgically inoperable gliomas: in 32 cases for recurrent gliomas and in 11 cases as a primary treatment. Results of this study suggest that 125I brachytherapy for inoperable and recurrent gliomas is an effective method and offers a chance for longer-term survival.

Tissue response to iodine-125 interstitial brachytherapy of cerebral gliomas.

The purpose of this study was to investigate histopathological changes and the role of the microglia/macrophage cell system in the therapeutic effect of iodine-125 (125I) interstitial brachytherapy on cerebral gliomas. Out of a series of 60 cases harboring cerebral astrocytomas and other brain tumors treated with 125I interstitial brachytherapy, autopsy material was available in 10 cases between 0.75 and 60 months after irradiation. The patients were treated with 60-Gy maximum doses at the tumor periphery. Besides the routine HE and Mallory's PTAH trichrome staining, immunohistochemical reactions were carried out for CD15, CD31, CD34, CD45, CD68 (PG-M1), CPM, HAM 56 and HLA-DR antigens to study immunological characteristics of the reactive cell population around gliomas after 125I treatment. The present immunohistochemical study demonstrated that the early lesions following 125I interstitial brachytherapy of gliomas are characterized by migrating macrophages apparently concerned with the removal of necrotic debris. The established phase of reactive zone around the necrotic center disclosed a narrow inner rim of microglial accumulation, and a broad outer area consisting of astrocytic gliosis, vascular proliferation, activated microglia and infiltration by macrophages. In the burned-out phase, the necrosis undergoes liquefaction, the microglial rim is replaced by end-stage macrophages, and the reactive zone is transformed into astrocytic gliosis, which can be considered as equivalent to scar tissue formed around necrosis outside of the central nervous system.

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.

Cerebral metastases pathology after radiosurgery: a multicenter study.

BACKGROUND: To the authors' knowledge, comprehensive human pathologic investigations that explore fundamental radiosurgical effects on metastatic brain tumors are sparse in the literature. The objective of this study was to analyze histopathologic findings in a set of clinically recurrent cerebral metastases after patients underwent stereotactic radiosurgery (SRS). METHODS: In a series of 7500 patients who underwent radiosurgery, 2020 patients (27%) harbored cerebral metastases. Eighteen of 2020 patients (0.9%) underwent subsequent craniotomy for tumor removal anywhere from 1 month to 59 months after they received high-dose irradiation. Histologic and immunohistochemical investigations were performed on the surgically resected tissue specimens. These specimens were within the radiosurgical treatment volume of the metastatic tumor. RESULTS: Light microscopy revealed 3 basic categories of histologic responses: acute-type, subacute-type, and chronic-type tissue reactions. A moderate-to-intense inflammatory cell reaction was seen in the tissue responses of well controlled neoplasms (i.e., in patients who had neoplasms that required craniotomy for recurrent disease > 5 months after SRS), whereas the inflammatory reaction was missing or sparse in poorly controlled neoplasms (patients who required craniotomy for recurrent disease < 5 months after SRS). This reaction was seen within the irradiated tumor volume and not in the peritumoral area nor in areas remote from the radiosurgical treatment volume. Immunohistochemical characterization demonstrated the presence of prominent CD68-positive macrophage and CD3-positive T-lymphocyte populations. A progressively severe vasculopathy also was observed with increasing time after radiosurgery. CONCLUSIONS: Although causality has not been established, a brisk inflammatory response and more severe vasculopathy were observed in lesions in which recurrences were more delayed.

The role of the superciliary approach in the surgical management of intracranial neoplasms.

OBJECTIVE: The authors present and evaluate the experiences with 76 frontolateral keyhole craniotomies performed for supratentorial intracranial tumors via superciliary skin incisions. METHOD: The exploration is a modification of the generally used pterional approach. Out of a series of 302 cases operated on with frontolateral keyhole craniotomies via superciliary skin incisions, 76 had various tumors at the frontal base, intra-, supra-, parasellar and intraorbital regions. The operations were carried out through a approximately 2.5 x 3 cm frontolateral miniaturized craniotomy following a skin incision at the upper edge of the eyebrow. CONCLUSION: Despite the small size of craniotomy the superciliary approach is a suitable technique for resection of skull base tumors in the anterior fossa, orbit, sellar, parasellar and suprasellar regions. The exploration allows enough room for intracranial surgical manipulation with maximal protection of normal brain, vessel and nerve structures. The presented patients did not have any craniotomy-related complication.

Treatment of pituitary tumors: radiation.

In this paper, the role of conventional radiotherapy and radiosurgery in the management of pituitary tumors is reviewed. After a short summary of the mechanism of action of irradiation therapy and the types of different irradiation techniques, the therapeutic effects and side effects are analyzed in patients with different types of pituitary tumors, including our own experience with conventional radiotherapy and radiosurgery in patients with acromegaly. Conventional fractionated radiotherapy has long been used to control growth and/or hormonal secretion of residual or recurrent pituitary tumors. However, patient selection for conventional radiotherapy still remains a controversial issue, because a number of potentially significant side effects, including hypopituitarism and other complications, have been described. Stereotactic radiotherapy/radiosurgery methods have several potential advantages over conventional radiotherapy, including their use in patients with residual or recurrent pituitary tumors who had previously been treated by conventional radiotherapy, but long-term follow-up data with these relatively new techniques are still limited.

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.

Does gamma knife surgery stimulate cellular immune response to metastatic brain tumors? A histopathological and immunohistochemical study.

OBJECT: The aim of this study was to analyze the cellular immune response and histopathological changes in secondary brain tumors after gamma knife surgery (GKS). METHODS: Two hundred ten patients with cerebral metastases underwent GKS. Seven patients underwent subsequent craniotomy for tumor removal between 1 and 33 months after GKS. Four of these patients had one tumor, two patients had two tumors, and one patient had three. Histological and immunohistochemical investigations were performed. In addition to routine H & E and Mallory trichrome staining, immunohistochemical reactions were conducted to characterize the phenotypic nature of the cell population contributing to the tissue immune response to neoplastic deposits after radiosurgery. Light microscopy revealed an intensive lymphocytic infiltration in the parenchyma and stroma of tumor samples obtained in patients in whom surgery was performed over 6 months after GKS. Contrary to this, extensive areas of tissue necrosis with either an absent or scanty lymphoid population were observed in the poorly controlled neoplastic specimens obtained in cases in which surgery was undertaken in patients less than 6 months after GKS. Immunohistochemical characterization demonstrated the predominance of CD3-positive T cells in the lymphoid infiltration. CONCLUSIONS: Histopathological findings of the present study are consistent with a cellular immune response of natural killer cells against metastatic brain tumors, presumably stimulated by the ionizing energy of focused radiation.