Current and Future Management of Brain Metastasis

Transcription

1 Progress in Neurological Surgery 25 Current and Future Management of Brain Metastasis Bearbeitet von D.G. Kim, L.D. Lunsford 1. Auflage Buch. XII, 314 S. Hardcover ISBN Gewicht: 980 g Weitere Fachgebiete > Medizin > Chirurgie > Neurochirurgie schnell und portofrei erhältlich bei Die Online-Fachbuchhandlung beck-shop.de ist spezialisiert auf Fachbücher, insbesondere Recht, Steuern und Wirtschaft. Im Sortiment finden Sie alle Medien (Bücher, Zeitschriften, CDs, ebooks, etc.) aller Verlage. Ergänzt wird das Programm durch Services wie Neuerscheinungsdienst oder Zusammenstellungen von Büchern zu Sonderpreisen. Der Shop führt mehr als 8 Millionen Produkte.

2 Understanding Brain Metastasis Kim DG, Lunsford LD (eds): Current and Future Management of Brain Metastasis. Prog Neurol Surg. Basel, Karger, 2012, vol 25, pp Histopathology of Brain Metastases after Radiosurgery György T. Szeifert a Douglas Kondziolka b Marc Levivier c L. Dade Lunsford b a Péterfy Traumatological Center, National Institute of Neurosciences and Department of Neurological Surgery, Semmelweis University of Budapest, Budapest, Hungary; b Center for Image- Guided Neurosurgery, University of Pittsburgh Medical Center, Presbyterian Hospital, Pittsburgh, Pa., USA; c Centre Gamma Knife, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium Abstract 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. Copyright 2012 S. Karger AG, Basel Since the report of Lindquist [1] in 1989, stereotactic radiosurgery [2] has become a rapidly developing treatment modality of the neurosurgical tool for the multidisciplinary management of cerebral metastases [3 10]. Although the number of patients undergoing radiosurgery is increasing continuously, the pathophysiological effect of focused irradiation leading to destruction of the neoplasm, tumor control, or treatment failure is not completely elucidated. The aim of the present study was to explore the histopathological and immunohistochemical findings in a set of cerebral metastatic cancers after Gamma Knife radiosurgery, and to compare them with treatment, imaging and follow- up clinical data.

3 Fig. 1. An illustrative case of failed radiosurgery treatment. Axial T 1 -weighted contrast-enhanced MR images from a patient with melanoma demonstrating enhanced tumor in the right frontal lobe (left). Axial T 1 - weighted contrast- enhanced MRI obtained 2 months after stereotactic radiosurgery showing progression of enhancing tumor before surgical resection (middle). Axial T 2 -weighted MR images obtained 2 months after stereotactic radiosurgery showing iso- intensity with large peritumoral edema before surgical resection (right). Materials and Methods In a series of 7,500 patients who underwent radiosurgery, 2,020 (27%) harbored cerebral metastases. Eighteen of these 2,020 patients (0.9%) underwent 26 subsequent craniotomies for tumor removal because of clinical or imaging evidence of progression between 1 and 59 months after radiosurgery (fig. 1). Eleven patients harbored single, 6 patients two, and 1 patient three metastases. The primary tumor was lung cancer in 9 cases, breast carcinoma in 4 patients, malignant melanoma in 3 and renal cell carcinoma in 2 patients. Radiosurgery was carried out using the Leksell Gamma Knife Model U, B or C (Elekta Instruments AB, Stockholm, Sweden). Dose planning was based on magnetic resonance (MR) imaging or computed tomography (CT) in patients not eligible for MRI. Treated volumes ranged between 35 and 23,600 mm 3 (median 3,800 mm 3 ). Tumors received Gy as the margin dose (median = 18 Gy) at the 30 60% isodose line (median = 50%) with Gy maximal dose (median = 36 Gy).The tumors subsequently were removed using image- guided frameless craniotomy because of neurologic and/or imaging progression after radiosurgery (range 1 59 months, median = 12 months). Representative sections through the resected target volume were used in the pathologic analysis, because the exact spatial location of the removed specimen was difficult to determine precisely. Histopathological investigations were carried out on the surgical pathology materials. The resected specimens were fixed in 10% neutral buffered formaldehyde, processed routinely, and embedded in paraffin. Hematoxylin and eosin, periodic acid- Schiff, Luxol fast blue and Masson trichrome stainings were used for general purposes. Immunohistochemical reactions were carried out for synaptophysin, epithelial membrane antigen, pankeratin, CK7, CK20, CAM5.2, CLA, CD3, CD4, CD8, CD20, CD31, CD34, CD68 (PGM1), CD79, UCHT1, L26 and glial fibrillary acidic protein antigens to characterize phenotypic nature of tumor tissues and the reactive cell population around residual neoplastic islands that were within the original radiosurgery- treated volumes. Biotinstreptavidin- peroxidase complex methods were performed according to standard protocols on 5 μm sections. Five cerebral metastases without previous radiotherapy or radiosurgery that underwent surgical resection served as nonirradiated controls. Histopathology and Radiosurgery of Brain Metastases 31

4 a b Fig. 2. Histological characteristics of acute- type tissue reaction in brain metastasis after Gamma Knife radiosurgery. a Homogeneous coagulation necrosis is seen in the central part and residual cancer nests at the periphery of the lesion in a small cell lung carcinoma metastasis 3 months after RS. HE b Scattered, pyknotic, apoptotic cells, endothelial destruction and fibrinoid necrosis from vessel wall are seen in the radiolesion. HE Results Three basic histologic responses were encountered in the surgical pathology samples of the irradiated metastatic tumors: acute type, subacute type, and chronic type. The acute-type postradiosurgery tissue reaction was characterized by a sharply demarcated coagulation necrosis in the parenchyma and stroma of the metastases. The center of the lesion consisted of homogeneous eosinophilic fibrin strands intermingled with some tissue debris (fig. 2a). There was usually a faint to moderate cellular accumulation at the periphery of the necrosis containing pyknotic and apoptotic elements accompanied with an inflammatory reaction, mostly polymorphonuclear leukocytes. The acute- type histologic response was observed in 8 of 26 specimens, and occurred at intervals from 1 to 17 months (median, 4 months) after radiosurgery. Specimens from the 2 patients who had the shortest local tumor control (1 and 3 months) did not exhibit any cellular response. Three other specimens from patients who required craniotomy for tumor progression <5 months after radiosurgery revealed only a minimal inflammatory reaction. There were residual neoplastic tissue islands recognized outside of the radiosurgery lesions in 6 of 8 patients with acute- type tissue reactions. Gliosis around the radiolesions was not remarkable. In specimens from 3 patients, acute vasculopathy with endothelial destruction and different degrees of fibrinoid necrosis in the vessel walls was expressed (fig. 2b). This vasculopathy was seen in the central areas of the radiosurgery target that received the highest doses of irradiation. These inflammatory and vasculopathic changes were not seen in control specimens. The subacute-type postradiosurgery tissue reactions were characterized by central necrosis surrounded by granulation tissue infiltrated with inflammatory cells, consisting mainly of macrophages with loaded cytoplasm that expressed phagocytic 32 Szeifert Kondziolka Levivier Lunsford

5 activity (fig. 3a, b). Immunohistochemical reactions demonstrated CD68 (PGM1) positivity in the great majority of these macrophages (fig. 3c), but CD31 positivity also was present in a moderate number of specimens. Macrophages seemed to originate from the perivascular spaces of the granulation tissue and surrounding brain parenchyma (fig. 3d). Gliosis appeared at a mild- to- moderate extent and demarcated the periphery of the radiosurgery target volume from surrounding tissues (fig 3e). Vasculopathy was present within the irradiated area in the majority of specimens. This vasculopathy was characterized by different degrees of endothelial destruction accompanied with subendothelial spindle- shaped cell proliferation that narrowed the lumina (fig. 3f). The subacute- type histologic response was observed in 18 of 26 specimens and occurred at intervals from 5 to 59 months (median, 16 months) after radiosurgery. Complete tumor destruction was realized in 5 tissue samples; however, in the remaining 13 specimens, small areas of residual tumor cell nests were observed within the radiosurgery- treated volume. These small nests comprised <5% of the total area analyzed. Five specimens evolved partial or complete chronic-type histologic responses in metastases at intervals from 9 to 33 months (median, 17 months) after radiosurgery. In these specimens, the majority of coagulation necrosis was replaced by hypocellular, gliotic, or collagen- rich scar tissue undergoing various degrees of hyaline degeneration, calcification or even ossification (fig. 4a). A moderate- to- intense inflammatory cellular reaction, which consisted mainly of lymphocytes, infiltrated these lesions (fig. 4b). Immunohistochemistry revealed a prominent presence of CD3- positive T lymphocytes (fig. 4c). Postradiosurgery vasculopathy with various degrees of endothelial damage and subendothelial spindle cell proliferation that narrowed the lumen, accompanied by perivascular fibrosis or scar tissue formation, was seen frequently (fig. 4d). It is noteworthy that we observed 1 specimen that had both acute and subacute findings, while 4 specimens with both subacute and chronic histologic changes on pathologic examination. No association was observed between the radiosurgery- treated volume and the histologic type of metastases or the duration of local tumor control. Discussion Radiosurgery may destroy or inactivate the targeted neoplastic cell proliferation either by direct, early cytotoxic effects (coagulation necrosis, apoptosis) or by late vascular changes. It has been suggested that the radiobiologic mechanism of radiosurgery on benign tumors is a combination of both cytotoxic and vascular effects [11]. The direct cellular influence may be the consequence of DNA damage by the ionizing energy of the intersection of the converging gamma rays. This high dose to a small target volume leads to cell death at the start of the next cell cycle (apoptosis, i.e. programmed cell death). It is for this reason that rapidly proliferating tumors with high cellular mitosis rates, such as metastases or malignant gliomas, react earlier to radiosurgery Histopathology and Radiosurgery of Brain Metastases 33

6 a b c d e f Fig. 3. Morphologic appearance of subacute- type pathologic lesions that evolved in secondary cerebral neoplasms after Gamma Knife radiosurgery (GKRS). a Central necrosis is surrounded by an inflammatory cell reaction from a renal cell carcinoma metastasis 7 months after GKRS. HE b Highly cellular granulation tissue is seen around the necrotic core. HE c Immunohistochemistry demonstrated the conspicuous presence of CD68- positive macrophages in the inflammatory cell reaction d Macrophages appear to originate from a perivascular space. HE e A gliotic rim demarcates the target of radiation. Glial fibrillary acidic protein stain. 40. f Subendothelial proliferation narrows vessel lumen. HE Szeifert Kondziolka Levivier Lunsford