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Extracranial spread of neuroectodermal tumors is an unusual event, most frequently expected from glioblastomas and medulloblastomas. Single cases of metastatic oligodendrogliomas have been described, but no genetic data are reported. Oligodendrogliomas are characterized by distinct genetic alterations, i.e. loss of heterozygosity (LOH) of 1p and 19q; therefore, molecular genetic analysis of metastatic cases is of considerable interest. It may be instrumental in defining the distant tumor as metastatic oligodendroglioma and give clues to the genetic events associated with the highly malignant transformation. We present the case of a patient with multiple bone metastases from a cerebral oligodendroglioma. Oligodendroglioma grade II was the diagnosis both at original and second operation, performed 7 and 1 years before the extracranial dissemination. The extraneural spread presented before the local intracranial recurrence. The patient received procarbazine, lomustine, vincristine chemotherapy and radiotherapy after the second surgery. The computed tomography-guided biopsy of the bone lesions revealed tumor cells positive for GFAP, S-100 and Leu-7 and negative for cytokeratin, LCA and EMA. The genetic analysis of DNA from the original tumor, the bone metastasis and the autoptic brain tumor showed LOH of 1p; heterozygous deletion of CDKN2A/p 16 was detected as additional alteration in the metastasis and in the intracranial tumor at autopsy. TP53, MDM2 and CDKN2A/p14ARF genes were unchanged. Repeated brain surgery and extended survival may have acted as promoter of extraneural dissemination. Loss of CDKN2A most probably played an important role in the malignant progression: its involvement in metastatic potential remains to be clarified. Our data confirm that malignant transformation of oliogodendrogliomas may be undetected by histology and underscore the importance of genetic analysis. Coincidentally with intensive anticancer therapy, chemotherapy included, employed in patients with oligodendroglioma and the ensuing long survival, the frequency of metastatic oliogodendrogliomas may increase.

Symptomatic brain metastases of carcinomas in patients without a previously diagnosed malignancy are frequent in neurosurgical series. Such tumors often lack distinctive morphological characteristics so that the routine histological examination can be unsuccessful in identifying the site of origin. Objectives of the present study were to evaluate the frequency of brain metastases as the only manifestation of an unknown primary cancer by the retrospective analysis of a series of consecutively operated single cerebral metastases; to verify the efficacy of clinical investigations in detecting the site of origin; to investigate whether the primary site can be identified by the immunohistochemical study of the neurosurgical specimens. Antibodies to the following antigens were used: carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 19.9, CA 125, BCA-225, cytokeratin 20, PSA, HMB-45. Out of 181 patients operated for single cerebral metastasis of carcinoma, 99 (54.7%) were in patients without any previously diagnosed systemic neoplasm. In 26.7% the primary remained undiagnosed after clinical investigations, in 9 cases even at autopsy. PSA and HMB45 antibodies specifically identified metastases from prostate carcinomas and skin melanomas, respectively. No other specific immunophenotype was identified; the immunoreactivity of the single cases was more or less suggestive for a primary site. Precocious metastases of lung carcinomas expressed CEA more frequently than late metastases. It has been hypothesized that CEA plays some role as a contact mediating device. CEA expression can have some link with the tendency to metastasize precociously to the brain. No major difference of p53 and k-ras expression has been found in precocious versus late brain metastases.

The appearance of medulloblastoma in adult age and the uncertain overlapping of prognostic factors in pediatric and adult populations stimulate the question of whether medulloblastoma is different in adults and in children. The pathologic features, proliferation potential and glial/neuronal differentiation have been investigated in 42 adult medulloblastomas and 42 medulloblastomas of children; the quantitative data have been compared between the two groups of age. Homer-Wright rosettes, nuclear polymorphism and histologic signs of neuronal differentiation were more frequent in children cases; GFAP-positive tumor cells and desmoplastic type were more frequent in adult cases. The mean, median and rage of Lis, with PCNA and MIB-1 were significantly (p < 0.05) higher in adults than in children. All cases, independently from age of the patients were immunoreactive with markers of neuronal commitment (class III beta tubulin isotype, MAP-2, neurofilaments). The immunoreactivity pattern suggested a more mature neuronal character in desmoplastic cases of adults than of children and in classic cases of children than of adults. In conclusion, some phenotypic differences between childhood and adult medulloblastoma exist, but do not support a substantially different course of the disease. The higher proliferation potential in adult than in childhood cases is unexpected in a tumor of embryonal origin, and reduces the applicability of Collin's law to medulloblastoma.

Well-differentiated astrocytomas may transform into malignant astrocytomas in time. In surgical specimens, when the histological picture strictly corresponds to that of grade II glioma, the transformation is unpredictable. Clinically, the bad outcome of a quota of astrocytomas is a well known phenomenon. The use of proliferation markers, and recently of MIB-1 LI, for detecting the proliferation potential comes out to be a useful tool for prognosis. A survival analysis of fifty astrocytomas grade II according to the WHO classification was performed with univariate and multivariate analysis of a series of clinical and histological parameters. MIB-1 LI was calculated and compared with all the other parameters. A cut-off of 8% of MIB-1 LI divided the astrocytomas in two groups with significantly different survival (p = 0.0066): median survival time of 1062 versus 1686 days. According to multivariate analysis MIB-1 LI resulted to be an independent factor (p = 0.002) along with extension of surgical removal (partial versus total), postoperative Karnofsky status (> or = 70 versus < 70) and age (< or = 30 versus > 30). The interpretation of well-differentiated astrocytomas with high MIB-1 LI is that the increasing number of cycling cells precedes phenotypic transformation. MIB-1 LI can be used as a prognostic factor.

Bcl-2 proto-oncogene prevents apoptosis in many conditions. First detected in lymphomas, it has been also described in non-lymphoid tissues. The immunohistochemical distribution of bcl-2 protein in 100 neuroepithelial tumors is presented. Bcl-2 was positive in some neurons of normal nervous tissue, in reactive astrocytes and variably in all neuroepithelial tumor. The reaction product was either diffuse or granular, due to bcl-21 protein localization on cytoplasmic, nuclear and mitochondrial membranes. The positivity was high in medulloblastomas and in astrocytic tumors. In the latter, the strongest staining was found in cells retaining the astrocytic aspect. Oligodendroglial cells were minimally stained. No correlation of bcl-2 staining with survival was found in each tumor type. The interpretation of the results is based on the one side on the constitutive role played by bcl-2 in the nervous tissue and its neoplastic derivatives. On the other side, in tumors bcl-2 acts by preventing tumor cells from undergoing apoptosis. BCl-2 expression in brain tumors, therefore, receives a dual interpretation. For this reason and for the lacking of correlation with survival, bcl-2 expression cannot be regarded as a prognostic factor.

A case of primary diffuse leptomeningeal gliomatosis with anaplastic features, diagnosed during life and confirmed at autopsy, is presented. The clinical, radiological and pathological features are compared with those of the very few cases reported in the literature. Early papilloedema and hydrocephalus were followed by spinal and cranial nerve palsies. The NMR images and the tissue biopsy turned out to be useful for reaching an in vivo diagnosis. While in the previously reported cases the glial proliferation was microscopically a slow growing astrocytoma, the present case was histologically malignant and had a high labelling index (LIs) for proliferation markers (PCNA and KI-67). The high growth rate and the wide diffusion of the tumour at presentation may account for the poor prognosis of diffuse leptomeningeal gliomatosis and the inefficacy of radiotherapy and chemotherapy. The presence of basal lamina arount tumour cells and the immunohistochemical distribution of the proliferation markers are consistent with the origin of primary leptomeningeal gliomatosis from ectopic glia.

The vascular response to irradiation was studied in peritumoral cortex and tumor areas in 9 autopsied cases of glioblastoma multiforme and in 10 biopsies of reoperated cases. The study was carried out by histological, immunohistochemical and electron microscope procedures. Hyaline thickening of the vessel walls with deformation and impoverishment of endothelial nuclei are the most striking features. Formation of large PAS-positive areas from the confluence of thickened vessel walls and development of a fibroblastic proliferation follow. Fibroblastic areas may entrap tumor glial cells. In PAS-positive areas a special population resembles myofibroblasts of tissue scars. Electron microscope reveals the production of collagen fibrils in and outside vessel walls. The presence of collagen III and IV is in line with the present interpretation of the mesodermic component.

Tumours of the nervous system have been induced by transplacental ENU. Until the fourth month of life the tumoural lesions appear as mixed glial proliferations or oligodendroglial foci. From the fourth month on they develop as glial micro- and macrotumours or as isomorphic and polymorphic oligodendrogliomas. The adenylate cyclase activity studied during these two distinct phases of tumour development was markedly reduced in brain tumours, independent of their cellular origin, compared with the level in the normal brain. On the other hand, the activity of the enzyme responsible for the synthesis of cyclic AMP is significantly increased during the first period of tumour development when early neoplastic proliferations are present.

Little is known of the histological effects of radiation on low grade astrocytomas, whereas the clinical efficacy of radiotherapy on these tumors is still a matter of discussion. Since it is difficult to have large series of autoptic brains harboring astrocytomas, the wide astrocytomatous areas of conventionally irradiated secondary glioblastomas have been studied in whole mount preparations. It was assumed that these areas were already present at the time of irradiation. In these areas no histologic changes referable to 'short-term' effect of radiation have been found. When the astrocytomatous areas were located in the white matter, they were affected by chronic edema, which usually occurs in periglioblastomatous tissue. In one case necrotic foci in the astrocytomatous areas were interpreted as anaplastic foci damaged by radiation; radiotherapy of astrocytomas might therefore result in the eradication of undetected anaplastic foci.

The occurrence, distribution and concentration of GAGs in ENU and MNU experimental brain tumors induced in the rat are reported. GAGs have been histochemically studied by Alcian Blue methods; they have been quantified and qualitatively evaluated by electrophoresis of brain extracts. The pattern of GAGs in normal rats is consistent with the data of the literature. No GAG accumulation precedes the tumor development. Early neoplastic proliferations, oligodendroglial and mixed glial microtumors are strongly alcian-positive; the alcianophilia spares clusters of cells developing a cytoplasm. In large tumors, GAGs are histochemically demonstrable in the honey-comb areas of oligodendrogliomas and in peripheral infiltration areas of polymorphic gliomas. The role of the normal nervous tissue and oligodendroglial cells in the accumulation of the GAGs is discussed. The accumulated GAGs seem to rise from the nervous tissue included in the tumors, rather than from the metabolism of tumor cells.

The pathological effects of radio- and chemotherapy on the normal nervous tissue have been studied in 42 brains with malignant gliomas. The brains have been examined by means of the complete study technique. In seven cases the picture of delayed radionecrosis has been found. Apart from this, many histological features have been related to post-operative survival, radiation dose, interval between radiation and death, chemotherapy, steroids, size and activity of the tumour. Some alterations, such as peritumoural necroses, macrophage areas, vessel wall degenerations etc. result from radiotherapy. The relations and pathogenesis are discussed.

The pathological effects of radio- and chemotherapy have been studied in 31 malignant gliomas. The brains have been examined by means of the complete study technique. Many histological features have been related to surgery, localization, preoperative duration, postoperative survival, irradiation, and chemotherapy. No specific alterations have been found, but some positive correlations have been established: decrease of mitoses, occurrence of macrophages and vessel degeneration after radiation, increase of monstrous cells after chemotherapy.

It is well known that the system of cyclic nucleotides plays an important role in cell differentiation and proliferation. Cyclic AMP is capable of stimulating cell growth, and cyclic GMP is thought to control cell division and growth. The authors measured adenylcyclase activity (AC) and cGMP content in the tumor latency period and in early neoplastic proliferations in rats with brain tumors induced by transplacental ethylnitrosourea (ENU). AC activity, which is high during the first days of life, decreases until it reaches, at the 60th day, levels lower than those in control animals. Cyclic GMP, on the contrary, increases during the first month in treated animals and remains consistently higher than controls up to the 45th day. In fully developed experimental brain tumors (mixed gliomas, isomorphic and polymorphic oligodendrogliomas) the percentage of reduction in AC activity is significantly higher. AC activity was measured also in human tumoral tissue. In malignant tumors it is markedly lower than in benign tumors. In the same patients cAMP in the cerebrospinal fluid was measured with results similar to those obtained in tissues. These findings confirm that the system of cyclic nucleotides is implicated in all the developmental phases of brain tumors and therefore may reveal how research can clarify the first transformations of tumoral cells.

Neoplasms of the third ventricle are lesions arising within the ventricular cavity, often free but more often pedunculated. True third ventricle tumours are surgically removable. In a consecutive surgical series of 580 intracranial tumours the authors operated on 27 lesions of the third ventricle, 7 of which were benign gliomas. The histological diagnosis was polar spongioblastoma in 5 cases and fibrillar subependymal astrocytoma in 2 cases. The dominant clinical features were a slowly progressive or intermittently increased intracranial pressure syndrome, and mental and visual disturbances. CT and CSF contrastographic studies provided the essential diagnostic data for the therapeutic plan. CT scans at follow-up studies confirmed the successful removal of the lesions. A right trans-ventricular approach was employed in all cases. Depending on the size and position of the lesion, removal was performed through the foramen of Monro or through a sub-choroidal approach. In two patients a ventriculo-atrial shunt was necessary in spite of tumour removal. No surgical mortality occurred and patients are well at a follow-up time of from 2 to 6 years.

Out of 107 pts. treated with radio- and chemotherapy for low and high grade gliomas (TD: 45-65Gy), 3 cases developed pathologically documented radionecrosis (coagulative necrosis with minimal or no persistent tumor). Clinico-therapeutic modalities were analyzed for all cases and biologically equivalent doses were calculated according to NSD, ED and btu formulas. All cases of radionecrosis fell into the group of doses close to 60Gy/30fx./42d. and NSD = 1758, ED = 1340 and btu = 1161. Isodose curve reconstruction on planes corresponding to histological sections of brains with radionecrosis demonstrated that doses received by areas of necrosis were higher than the calculated mid-plane doses in two cases. Clinical and autoptic incidence of radionecrosis were 2.8% and 10% respectively. High doses of steroids during RT seemed to offer some protection against radionecrosis, while number of chemotherapy cycles did not influence the risk of radionecrosis. A higher autoptic rate of irradiated gliomas is needed in order to obtain a better understanding of a number of unresolved problems.