Supratentorial Astrocytic Tumors Research Articles

Predicting Isocitrate Dehydrogenase Status in Non-Contrast-Enhanced Adult-Type Astrocytic Tumors Using Diffusion Tensor Imaging and 11C-Methionine, 11C-Choline, and 18F-Fluorodeoxyglucose PET.

We aimed to differentiate the isocitrate dehydrogenase (IDH) status among non-enhanced astrocytic tumors using preoperative MRI and PET. We analyzed 82 patients with non-contrast-enhanced, diffuse, supratentorial astrocytic tumors (IDH mutant [IDH-mut], 55 patients; IDH-wildtype [IDH-wt], 27 patients) who underwent MRI and PET between May 2012 and December 2022. We calculated the fractional anisotropy (FA) and mean diffusivity (MD) values using diffusion tensor imaging. We evaluated the tumor/normal brain uptake (T/N) ratios using 11C-methionine, 11C-choline, and 18F-fluorodeoxyglucose PET; extracted the parameters with significant differences in distinguishing the IDH status; and verified their diagnostic accuracy. Patients with astrocytomas were significantly younger than those with glioblastomas. The following MRI findings were significant predictors of IDH-wt instead of IDH-mut: thalamus invasion, contralateral cerebral hemisphere invasion, location adjacent to the ventricular walls, higher FA value, and lower MD value. The T/N ratio for all tracers was significantly higher for IDH-wt than for IDH-mut. In a composite diagnosis based on nine parameters, including age, 84.4% of cases with 0-4 points were of IDH-mut; conversely, 100% of cases with 6-9 points were of IDH-wt. Composite diagnosis using all parameters, including MRI and PET findings with significant differences, may help guide treatment decisions for early-stage gliomas.

Infratentorial IDH-mutant astrocytoma is a distinct subtype.

Diffuse IDH-mutant astrocytic tumors are rarely diagnosed in the cerebellum or brainstem. In this multi-institutional study, we characterized a series of primary infratentorial IDH-mutant astrocytic tumors with respect to clinical and molecular parameters. We report that about 80% of IDH mutations in these tumors are of non-IDH1-R132H variants which are rare in supratentorial astrocytomas. Most frequently, IDH1-R132C/G and IDH2-R172S/G mutations were present. Moreover, the frequencies of ATRX-loss and MGMT promoter methylation, which are typically associated with IDH mutations in supratentorial astrocytic tumors, were significantly lower in the infratentorial compartment. Gene panel sequencing revealed two samples with IDH1-R132C/H3F3A-K27M co-mutations. Genome-wide DNA methylation as well as chromosomal copy number profiling provided further evidence for a molecular distinctiveness of infratentorial IDH-mutant astrocytomas. Clinical outcome of patients with infratentorial IDH-mutant astrocytomas is significantly better than that of patients with diffuse midline gliomas, H3K27M-mutant (p < 0.005) and significantly worse than that of patients with supratentorial IDH-mutant astrocytomas (p = 0.028). The presented data highlight the very existence and distinctiveness of infratentorial IDH-mutant astrocytomas that have important implications for diagnostics and prognostication. They imply that molecular testing is critical for detection of these tumors, since many of these tumors cannot be identified by immunohistochemistry applied for the mutated IDH1-R132H protein or loss of ATRX.

Vascular endothelial growth factor and KIT expression in relation with microvascular density and tumor grade in supratentorial astrocytic tumors

To evaluate the relationship between microvascular density and the expression of vascular endothelial growth factor (VEGF) and KIT as possible markers of angiogenic stimulus in astrocytic tumors and correlate it with histopathological grading. We enrolled 99 surgical specimens of supratentorial astrocytic tumors for analysis of VEGF and KIT and subsequent correlation with MVD and grading. KIT and VEGF expression correlated with microvascular density (p<0.005) and both VEGF and microvascular density correlated with grading (p<0.005). KIT had no significant relationship with grading (p=0.657). KIT and VEGF constitute important pathways in the angiogenesis of astrocytomas and therefore are promising prognostic tools and options for therapeutic intervention.

Grading of supratentorial astrocytic tumors by using the difference of ADC value

To investigate the application value of diffusion-weighted imaging (DWI), the difference of apparent diffusion coefficient (ADC(difference)) value calculated from ADC(difference) map was used, in evaluating the pathologic grade of astrocytic tumors. 33 patients with histopathologically proven supratentorial astrocytic tumors were included in this prospective study. All of them received conventional magnetic resonance imaging (MRI), DWI with diffusion factor of 0 and 50s/mm(2) and of 0 and 3,000s/mm(2), and perfusion-weighted imaging (PWI) examinations. Pseudo-color ADC(difference) maps were obtained by means of using ADC map with low b value (0 and 50s/mm(2)) minus ADC map with high b value (0 and 3,000s/mm(2)). The highest ADC(difference) value of grades I-II, grade III, and grade IV was (0.91 ± 0.07) × 10(-3), (1.81 ± 0.38) × 10(-3), and (2.36 ± 0.32) × 10(-3) mm(2)/s, respectively, and there was statistical difference among them (p < 0.001). The highest ADC(difference) value between low-grade (grades I-II) and high-grade (grades III-IV) astrocytic tumors showed statistical difference as well (p < 0.001). The highest ADC(difference) value of astrocytic tumors correlated positively with the pathologic grade of tumor (r = 0.853, p < 0.001). Positive correlation was found between the highest ADC(difference) value and maximum relative cerebral blood volume (rCBV) value (r = 0.829, p < 0.001) in high-grade astrocytic tumors; however, the highest ADC(difference) value and maximum rCBV value had no significant correlation in low-grade astrocytic tumors (r = 0.259, p = 0.536). Quantitative analysis of highest ADC(difference) value of supratentorial astrocytic tumors may provide valuable information of tumor microcirculation and perfusion, thus allowing a promising new method for preoperatively assessing the pathologic grade of tumor.

Expression of vascular endothelial growth factor‐A and mRNA stability factor HuR in human astrocytic tumors

High-grade astrocytic tumors, such as glioblastoma, possess rich vascular components, which are necessary for their growth. VEGF-A is considered to be the major mediator of angiogenesis in malignant neoplasms including high-grade astrocytic tumors. The upregulation of VEGF-A expression in tumor cells is induced by two mechanisms: the transcriptional activation and the post-transcriptional stabilization of VEGF-A mRNA. While the former mechanism mediated by hypoxia inducible factor-1 alpha (HIF-1alpha) has been revealed, the latter mediated by mRNA stability factor HuR remains unclear in astrocytic tumors. In the present study, we investigated the expression of VEGF-A and mRNA stability factor HuR in supratentorial astrocytic tumors of 27 adults using RT-PCR, ELISA, and immunohistochemistry. Furthermore, we studied the involvement of HuR in the upregulation of VEGF-A expression using malignant astrocytoma cell lines. In higher-grade astrocytic tumors, the level of VEGF-A and microvascular density were elevated, cytoplasmic expression of HuR, which potentially means the protection of VEGF-A mRNA from degradation by ribonucleases, appeared, and they were correlated positively. In in vitro experiments, the inhibition of the cytoplasmic translocation of HuR protein by leptomycin B (LMB) reduced the upregulation of VEGF-A expression in malignant astrocytic tumor cells under hypoxic conditions. These findings suggest that the expression of VEGF-A and cytoplasmic translocation of HuR relates to the histological grade, and that HuR is involved in the upregulation of VEGF-A expression, in human astrocytic tumors.

A report of nine newborns with congenital brain tumors

Congenital brain tumors are devastating problems that usually result in the death of the child with a high level of permanent disability in survivors. Most of these children are very large and presentation with macrocephaly is the rule leading to the need for many of these babies to be delivered by caesarian section. For the purpose of communication, it is essential that we use words precisely and that a word means the same thing to all readers. While the classification that the authors suggest is understandable and reasonable, there seems to be an acceptance of the diagnosis of “congenital tumors” to relate to diagnosis in utero or in the first 28 days of life. Is there a compelling reason to change that definition? There is reason to believe that many of the tumors that are found early in life were indeed “congenital,” including most primitive neuroectodermal tumors. The use of the term, though, must mean that the tumor is diagnosed in the perinatal period. This diagnosis carries with it a large number of issues regarding management and the ethics of the treatment of babies diagnosed at this very fragile stage of development. Should any treatment be offered to these babies? In this series, four of the nine patients survived, of which, three are said to have normal development. One of these patients had a posterior fossa capillary hemangioma, which, it might be argued, is not a tumor at all. The surviving patient with an astrocytic tumor and the patient with a capillary hemangioma were managed without adjunctive chemotherapy or radiation therapy. We were not told whether adjunctive chemotherapy was utilized in the patients with intracranial and orbital teratomas who survived with good outcomes. These babies are a great challenge, and in the very young the outcome may not be obvious. We have treated four infants with huge supratentorial malignant astrocytic tumors with staged resection followed by chemotherapy, with longterm survival in three of the patients. It is clear that there is a significant cognitive cost of the treatment of the effect of the tumor. To develop a significant algorithm for the diagnosis and management of these rare and devastating tumors, a great deal of energy would be needed to produce a registry of tumors in the very young. The fact that there were four survivors and that three of these had good developmental outcomes would make it truly valuable to have such a registry, not so much for epidemiology, which would be very difficult, but to find some information to define hopeful cases at the onset. This would be an excellent project for the education committee of the International Society for Pediatric Neurosugery, with the help of the editorial board of Child’s Nervous System. Childs Nerv Syst (2006) 22:1433 DOI 10.1007/s00381-006-0116-5

Factors influencing seizures in adult patients with supratentorial astrocytic tumors.

Seizures and epilepsy in adults are important and increasingly common clinical problems. Despite this, the investigation of seizures in adults with astrocytic tumors remains a grey area. The incidence and influencing factors of preoperative and postoperative seizures were evaluated in 101 patients of 45 years or older with supratentorial astrocytic tumors. Preoperative seizures occurred in 14 (14%) patients. Seizures at presentation were significantly correlated with pathological grades of astrocytic tumors (p = 0.0318). The risk of seizures at presentation was greatest in patients with well-differentiated astrocytomas as compared with anaplastic astrocytomas (Odds ratio = 4.364, p = 0.056) or glioblastomas multiforme (Odds ratio = 5.673, p = 0.007). There was no association of preoperative seizures with age, sex, location or site of the tumors. Postoperative seizures occurred in 18 (18%) patients, including 8 (8/14, 57%) recurrent seizures and 10 (10/87, 12%) late-onset seizures. Postoperative seizures were significantly correlated with the presence of preoperative seizures (p = 0.0003). The presence of preoperative seizures was potentially predictive of postoperative seizures when evaluated by logistic regression model (Odds ratio = 6.650). Thirteen (72%) of 18 patients with postoperative seizures were associated with tumor recurrence in 7 cases, hemorrhage in 3 cases and malignant progression in 3 cases. There was no association of postoperative seizures with age, sex, location or site of the tumors, grades of tumors, type of preoperative seizures, duration of preoperative seizures, serum level of anticonvulsant drug, extent of surgery, postoperative radiation or chemotherapy. The patients with preoperative seizures had a higher risk of postoperative seizures and should be carefully monitored. Imaging examination of brain to exclude the possibilities of tumor recurrence or hemorrhage is warrantable in supratentorial astrocytoma patients with postoperative seizures.

Limitations of the World Health Organization classification of childhood supratentorial astrocytic tumors

In the context of many implied but not rigorously stated histologic feature combinations, the World Health Organization (WHO) classification of astrocytic tumors specifies only the presence or absence of endothelial proliferation, necrosis, and mitosis to distinguish astrocytoma, anaplastic astrocytoma, and glioblastoma multiforme. The authors examined the effects of these and other reliably recognized histologic features on survival in the Childhood Brain Tumor Consortium (CBTC) sample of 340 children with supratentorial astrocytic tumors. Overall, the WHO criteria distinguished only two prognostically distinct classes of astrocytomas. When the specific combinations of the three features were unambiguously designated, three diagnostic categories resulted. These revised diagnostic categories are consistent with WHO guidelines and have significantly different survival distributions. However, neither the original WHO diagnoses nor the revised categories adequately separated these tumors prognostically, because histologic features other than those specified by WHO were significantly associated with improved or worsened survival. Classifications based on small numbers of specified histologic features may not be feasible because they inadequately separate childhood astrocytic tumors into prognostically homogeneous groups. Preferable classification techniques are those that simultaneously account for all reliably recognized histologic features.

Limitations of the World Health Organization classification of childhood supratentorial astrocytic tumors

Limitations of the World Health Organization classification of childhood supratentorial astrocytic tumors

Limitations of the World Health Organization classification of childhood supratentorial astrocytic tumors

Limitations of the World Health Organization classification of childhood supratentorial astrocytic tumors

The conditional survival statistics for survivors with primary supratentorial astrocytic tumors.

Relative survival rates can offer a general description of tumor outcome and, traditionally, are used for surveillance and comparison purposes. However, they are not informative for individual tumor survivors. Conditional survival estimates can calculate the probability of surviving next some years given survival to a specific period of time after craniotomy for individual tumor survivors. However, clinically, they have not been used for predicting the tumor outcome. We calculated conditional probabilities of survival within 6 years after craniotomy in 112 patients with primary supratentorial astrocytic tumors and evaluated factors affecting the survival time more than 2 years after craniotomy. Our data showed that the conditional probability of survival can predict yearly survival rate when patients survive for a specific period of time. The conditional survival rates within 6 years after craniotomy were always higher than those evaluated by relative survival rates. Overall, the longer the patients survived, the higher the conditional probabilities of surviving sixth year postoperatively were. Our study demonstrates the conditional probabilities of survival have good availability and are important estimates for individual tumor survivors.

Surgical management for supratentorial astrocytic tumors.

To compare the surgical treatment of supratentorial astrocytic tumors, various methods were performed by the same surgeon. Removal of the tumor was performed using stereotactic open surgery, the fluorescein surgical microscope, and a frameless stereotactic system, and these methods were compared. The method using the stereotactic technique was useful because there was no disturbance by the shifting of the brain during the operation. However, its limitation was that only points can be marked. The fluorescein surgical microscope was very useful in the cases where neuroradiological images were enhanced by the contrast medium, but deep lesions could not be identified from the brain surface. This method could not be used, either, in the case of images that were not enhanced. By the method using the frameless stereotactic system, identification of tumors including deep lesions was possible from every direction, but the problems were the mobility of the registered skin and the shifting of the brain during the operation. On the basis of these results, the combined method of the fluorescein surgical microscope and the frameless stereotactic system appeared to be useful when neuroradiological images of lesions were enhanced because these methods were complementary towards each other, and the frameless stereotactic system supplemented by the stereotactic open surgery technique (such as leaving a marker in deep lesions just before the start of microsurgery) seemed useful when images could not be enhanced.

Endothelial nitric oxide synthase expression in tumor vasculature is correlated with malignancy in human supratentorial astrocytic tumors.

Endothelial nitric oxide synthase (eNOS) may play an important role in the regulation of tumor blood flow and vascular permeability. However, there have been no reports describing alterations of eNOS expression in relation to malignant progression in human astrocytic tumors. We immunohistochemically studied the relationship between eNOS expression in tumor vasculature and malignancy in supratentorial astrocytic tumors. Tissue samples were obtained from 12 patients with low-grade astrocytomas, 10 with anaplastic astrocytomas, and 17 with glioblastomas. Normal brain tissue samples were obtained from four patients with other brain diseases. Immunohistochemical staining was performed using the avidin-biotin complex method, with polyclonal anti-eNOS antibody, and the levels of eNOS expression in endothelial cells were evaluated as slight, moderate, or intense on the basis of eNOS immunoreactivity. The proliferative potential was assessed as the MIB-1 staining index for tumor cells. The expression of eNOS was slight in all specimens of normal brain tissue, slight in 7 and moderate in 5 specimens of low-grade astrocytoma, slight in 2, moderate in 6, and intense in 2 specimens of anaplastic astrocytoma, and moderate in 5 and intense in 12 specimens of glioblastoma. The MIB-1 staining index (mean+/-standard deviation) was 0.2+/-0.2% for normal specimens, 1.8+/-0.6% for low-grade astrocytomas, 9.6+/-6.9% for anaplastic astrocytomas, and 18.5+/-7.7% for glioblastomas. The MIB-1 staining indices for slight, moderate, and intense eNOS expression were 2.0+/-2.3%, 10.8+/-9.8%, and 16.9+/-7.7%, respectively. Expression of eNOS in tumor vessels was significantly correlated with histological grade and proliferative potential. These findings suggest that astrocytic tumor vessels possess higher activity for nitric oxide production than do normal vessels.

Endothelial Nitric Oxide Synthase Expression in Tumor Vasculature Is Correlated with Malignancy in Human Supratentorial Astrocytic Tumors

Endothelial Nitric Oxide Synthase Expression in Tumor Vasculature Is Correlated with Malignancy in Human Supratentorial Astrocytic Tumors

Improving morphology-based malignancy grading schemes in astrocytic tumors by means of computer-assisted techniques.

We propose an original methodology which improves the accuracy of the prognostic values associated with conventional morphologically-based classifications in supratentorial astrocytic tumors in the adult. This methodology may well help neuropathologists, who must determine the aggressiveness of astrocytic tumors on the basis of morphological criteria. The proposed methodology comprises two distinct steps, i.e. i) the production of descriptive quantitative variables (related to DNA ploidy level and morphonuclear aspects) by means of computer-assisted microscopy and ii) data analysis based on an artificial intelligence-related method, i.e. the decision tree approach. Three prognostic problems were considered on a series of 250 astrocytic tumors including 39 astrocytomas (AST), 47 anaplastic astrocytomas (ANA) and 164 glioblastomas (GBM) identified in accordance with the WHO classification. These three problems concern i) variations in the aggressiveness level of the high-grade tumors (ANA and GBM), ii) the detection of the aggressive as opposed to the less aggressive low-grade astrocytomas (AST), and iii) the detection of the aggressive as opposed to the less aggressive anaplastic astrocytomas (ANA). Our results show that the proposed computer-aided methodology improves conventional prognosis based on conventional morphologically-based classifications. In particular, this methodology enables some reference points to be established on the biological continuum according to the sequence AST-->ANA-->GBM.

The combined determination of proliferative activity and cell density in the prognosis of adult patients with supratentorial high-grade astrocytic tumors.

Tumor growth represents the ratio between cell gain (number of mitoses per unit of time, i.e., proliferative activity) and cell loss (number of cell deaths during the same unit of time). While in adults, proliferative activity parallels the level of malignancy in astrocytic tumors and therefore represents a useful diagnostic marker, cell loss has never been concomitantly assessed in tumors of this type. We hypothesize that cell density assessable on histologic slides represents the ratio between cell gain and cell loss. This hypothesis concerns only the diffuse type of astrocytic tumors. Proliferative activity (assessed by MIB1 antigen immunostain) and cell density were thus quantitatively assessed by means of a cell image processor in a series of 54 supratentorial astrocytic tumors of adult patients, which included 15 astrocytomas (ASTs), 18 anaplastic astrocytomas (ANAs), and 21 glioblastomas (GBMs). The results show that proliferative activity and cell density were highly correlated (P = .003) and that both correlated with histopathologic grade. The patients with a high-grade astrocytic tumor (i.e., ANA or GBM) that exhibited a low level of proliferative activity but high cell density survived for significantly shorter periods than did patients with a tumor that exhibited low proliferative activity and low cell density (P = .002). The patients with a high-grade astrocytic tumor that exhibited high proliferative activity and high cell density survived for significantly less time than did the patients with a tumor that exhibited high proliferative activity but low cell density (P < .05). A marked difference in survival periods was observed between the patients with a high-grade astrocytic tumor that exhibited a low level of proliferative activity and low cell density and the patients with a tumor that exhibited a high level of proliferative activity and high cell density (P < .001). The concomitant determination of proliferative activity and cell density seems likely to enable determination of the few adult patients who have high-grade astrocytic tumors and who will survive for a considerable period (several years).

Nearest-neighbor classification for identification of aggressive versus nonaggressive low-grade astrocytic tumors by means of image cytometry-generated variables.

The authors investigated whether cytometry-related variables generated by means of computer-assisted microscopic analysis of Feulgen-stained nuclei can contribute significant information toward the characterization of low-grade astrocytic tumor aggressiveness. This investigation was conducted using the nearest-neighbor rule (a traditional classification method used in pattern recognition) to analyze a series of 250 supratentorial astrocytic tumors from adult patients. This series included 39 low-grade astrocytomas and 211 high-grade astrocytic tumors (including 47 anaplastic astrocytomas and 164 glioblastomas multiforme [GBMs]). The results show that the 3-nearest-neighbors rule enabled a subgroup of "atypical" astrocytomas to be distinguished from the "typical" tumors. The atypical astrocytoma species exhibited a DNA content (DNA ploidy level) and morphonuclear characteristics that were statistically more similar to the characteristics of GBMs than to those exhibited by the typical astrocytomas. An analysis of survival data revealed that patients with atypical astrocytomas survived for a significantly shorter period (p < 0.001) than patients with typical lesions of this kind. In fact, patients with atypical astrocytomas had a survival period similar to that of patients with anaplastic astrocytomas, whereas patients with typical astrocytomas had a survival period significantly longer (p < 0.0001) than those associated with anaplastic astrocytomas and GBMs.

Microvessel density is a prognostic indicator for patients with astroglial brain tumors.

Microvessel density in tumors, a measure of angiogenesis, has been shown to be a prognostic indicator that correlates with an increased risk of metastasis in various epithelial cancers and with overall and relapse free survival in patients with breast cancer. Astrocytic brain tumors, particularly malignant astrocytomas, are recognized to be highly vascular tumors with potent angiogenic activity. However, the prognostic significance of microvessel density in these tumors is not known. Sections from formalin fixed paraffin embedded tumor tissue from 93 unselected adult patients with supratentorial astrocytic brain tumors were immunostained for factor VIII-related antigen in order to highlight microvessel endothelial cells. Microvessels were counted at 200x and 400x magnification. Microvessel density was graded as 1+ to 4+ on 1 low power field, without knowledge of clinical outcome. Microvessel count and microvessel grade were correlated with postoperative survival using the Cox proportional hazards regression model. The prognostic significance of microvessel count and grade were also compared with established prognostic indicators, including patient age, Karnofsky performance status, and tumor histology using multivariate analyses. Both microvessel grade and microvessel count correlated significantly with postoperative survival by univariate analysis in both previously untreated and treated patients. Patients with tumors containing a microvessel Grade of 3+ or 4+ had significantly shorter survival time than patients with a microvessel Grade of 1+ or 2+ (P = 0.0022). Likewise, patients with microvessel counts of 70 or greater had significantly shorter survival than those with microvessel counts of fewer than 70 (P = 0.041). Patient age, Karnofsky performance status, tumor histology, and extent of resection were also correlated with survival by univariate analysis. Microvessel count was further shown to be an independent prognostic indicator by multivariate analyses. There were correlations between microvessel density and patient age and between microvessel density and astrocytic tumor grade. These findings support the importance of microvessel density as a prognostic indicator of postoperative survival of patients with astroglial brain tumors. Regional tumor heterogeneity may limit the use of these techniques for routine pathologic examination.

Identification of High Versus Lower Risk Clinical Subgroups in a Group of Adult Patients with Supratentorial Anaplastic Astrocytomas

The present work investigates whether computer-assisted techniques can contribute any significant information to the characterization of astrocytic tumor aggressiveness. Two complementary computer-assisted methods were used. The first method made use of the digital image analysis of Feulgen-stained nuclei, making it possible to compute 15 morphonuclear and 8 nuclear DNA content-related (ploidy level) parameters. The second method enabled the most discriminatory parameters to be determined. This second method is the Decision Tree technique, which forms part of the Supervised Learning Algorithms. These two techniques were applied to a series of 250 supratentorial astrocytic tumors of the adult. This series included 39 low-grade (astrocytomas, AST) and 211 high-grade (47 anaplastic astrocytomas, ANA, and 164 glioblastomas, GBM) astrocytic tumors. The results show that some AST, ANA and GBM did not fit within simple logical rules. These "complex" cases were labeled NC-AST, NC-ANA and NC-GBM because they were "non-classical" (NC) with respect to their cytological features. An analysis of survival data revealed that the patients with NC-GBM had the same survival period as patients with GBM. In sharp contrast, patients with ANA survived significantly longer than patients with NC-ANA. In fact, the patients with ANA had the same survival period as patients who died from AST, while the patients with NC-ANA had a survival period similar to those with GBM. All these data show that the computer-assisted techniques used in this study can actually provide the pathologist with significant information on the characterization of astrocytic tumor aggressiveness.

Histologic and non-histologic factors correlated with survival time in supratentorial astrocytic tumors.

One hundred and ninety-two cases of supratentorial astrocytic tumors are classified in 4 groups according to the presence or absence in the pathological material of simple morphological criteria: abnormal cellular density, nuclear pleomorphism, neovascularization, necrosis. Each one of these criteria is strongly correlated with prognosis. Nevertheless only a simple classification in low and high grade lesions has a definite predictive value. A multivariate analysis utilizing Cox's hazard function confronts these histological findings with a number of clinical and etiological possible factors of prognosis. Age and performance status at the time of diagnosis are the best predictors of survival time. The clinical use of a predictive model derived from Cox's function analysis is discussed.