Assessment of the impact of glioma diagnostic reclassification following the new 2016 WHO classification on a series of cases. / Evaluación del impacto del cambio diagnóstico de los gliomas aplicando la nueva clasificación de la OMS de 2016 sobre una serie de casos.

BACKGROUND AND OBJECTIVES: The aim of this project is to assess diagnostic reclassification based on molecular data over morphology in a series of glial tumours since the introduction of the 2016 WHO classification of brain tumours. MATERIALS AND METHODS: Retrospective review of glial tumours (oligodendrogliomas and astrocytomas) treated in our centre between January 2012 and June 2016 in which a review of diagnosis was performed when molecular studies were added. Statistical analysis included evaluation of variables of epidemiology, morphology and molecular data (mainly IDH mutation and 1p19q codeletion), diagnostic changes after new classification was considered, and clinical impact in cases of diagnostic reclassification. RESULTS: From a total of 147 glial tumours reviewed in our centre, molecular diagnosis was obtained in 74 cases (50.3%). Initial diagnosis changed in 23 cases (31%), and 20 (87%) of them had a prior histological diagnosis of oligodendroglioma (69.6% grade ii and 17.4% grade iii). Only 3 of these 23 cases diagnosis changed from astrocytoma to oligodendroglioma. Among reclassified tumours, there was a common molecular pattern, as findings showed mutant IDH in 16 cases (69.6%) and no codeletion in 20 cases (87%). According to the cell of origin, of the whole group of 27 oligodendrogliomas in our series (reclassified and non-reclassifed), 20 cases (74%) became astrocytomas, despite typical oligodendroglial morphology, due to absence of 1p19q codeletion. There was a trend for diagnosis reclassification in younger patients (<40 years), P=.065, mainly in those with a prior diagnosis of oligodendroglioma, with no statistical differences based on gender or clinical data. Besides, reclassification was more common among tumours with mutant IDH (69.6%), P=.003, than those with wild type IDH. In terms of survival, despite receiving different treatments, no significant changes were detected between reclassified and non-reclassified tumours after a mean follow-up of 16 months, partly related to lower grade of these lesions. CONCLUSIONS: Within the spectrum of the glial tumours treated in our institution, this new classification including molecular genetics over morphological data has provided marked diagnostic changes. These changes appear mainly in tumours previously diagnosed as oligodendrogliomas and in younger patients, with molecular patterns of mutant IDH and 1p19q codeletion. Although diagnosis reclassification may affect clinic, prognosis or therapeutic management of these tumours, deeper and prospective studies on these specific aspects are needed.

Diagnosis of oligodendroglioma: molecular and classical histological assessment in the twenty-first century.

Advances in molecular genetics are currently challenging the traditional morphological categorization of gliomas. Recurrent molecular and cytogenetic aberrations add prognostic and predictive information over and above that provided by standard histomorphological techniques and may influence decisions to re-operate or observe, to deliver radiation or not, or to administer chemotherapy to glioma patients. The importance of routine hematoxylin and eosin (H-E pathological stains cannot be underestimated, especially in resource-poor areas and developing countries where there is likely to be a significant economic opportunity cost for molecular diagnosis services. New research tools for image analyses of histological H-E slides, such as the precise measures of cell area, curvature and nuclear roundness, may provide an increased ability to provide an accurate classification for an inherently subjective process of histological assessment. We discuss the current trends, limitations and impact of molecular classification in this mini review.

Magnetic resonance imaging volumetric assessment of the extent of contrast enhancement and resection in oligodendroglial tumors.

OBJECT: Oligodendrogliomas that enhance on MR images are associated with poor prognosis. However, the importance of the volume of enhancing tumor tissue, and the extent of its resection, is uncertain. The authors examined the prognostic significance of preoperative and residual postoperative enhancing tissue volumes in a large single-center series of patients with oligodendroglioma. They also examined the relationship between enhancement and characteristic genetic signatures in oligodendroglial tumors, specifically deletion of 1p and 19q (del 1p/19q). METHODS: The authors retrospectively analyzed 100 consecutive cases of oligodendroglioma involving patients who had undergone T1-weighted gadolinium-enhanced MRI at diagnosis and immediately after initial surgical intervention. The presence of preoperative enhancement was determined by consensus. Preoperative and residual postoperative volumes were measured using a quantitative, semiautomated method by a single blinded observer. Intrarater reliability for preoperative volumes was confirmed by remeasurement in a subset of patients 3 months later. Intrarater and interrater reliability for residual postoperative volumes was confirmed by remeasurement of these volumes by both the original and a second blinded observer. Multivariate analysis was used to assess the influence of contrast enhancement at diagnosis and the volume of pre- and postoperative contrast-enhancing tumor tissue on time to relapse (TTR) and overall survival (OS), while controlling for confounding clinical, pathological, and genetic factors. RESULTS: Sixty-three of 100 patients had enhancing tumors at initial presentation. Presence of contrast enhancement at diagnosis was related to reduced TTR and OS on univariate analysis but was not significantly related on multivariate analysis. In enhancing tumors, however, greater initial volume of enhancing tissue correlated with shortened TTR (p = 0.00070). Reduced postoperative residual enhancing volume and a relatively greater resection of enhancing tissue correlated with longer OS (p = 0.0012 and 0.0041, respectively). Interestingly, patients in whom 100% of enhancing tumor was resected had significantly longer TTR (174 vs 64 weeks) and OS (392 vs 135 weeks) than those with any residual enhancing tumor postoperatively. This prognostic benefit was not consistently maintained with greater than 90% or even greater than 95% resection of enhancing tissue. There was no relationship between presence or volume of enhancement and del 1p/19q. CONCLUSIONS: In enhancing oligodendrogliomas, completely resecting enhancing tissue independently improves outcome, irrespective of histological grade or genetic status. This finding supports aggressive resection and may impact treatment planning for patients with these tumors.

Rapid and sensitive assessment of the IDH1 and IDH2 mutation status in cerebral gliomas based on DNA pyrosequencing.

Diffusely infiltrating cerebral gliomas frequently carry point mutations in codon 132 of the isocitrate dehydrogenase 1 (IDH1) gene or in codon 172 of the IDH2 gene, which are both clinically important as diagnostic and prognostic markers. Here, we report on a method that allows for the rapid detection of IDH1 and IDH2 mutations based on pyrosequencing. The method is applicable to routinely processed tissue specimens and provides quantitative mutation data within less than one working day. Due to its high sensitivity, the technique may also be used for the diagnostic assessment of IDH1 or IDH2 mutation in tissue samples with low tumor cell content, such as the infiltration zone of diffuse gliomas. Using pyrosequencing and/or conventional cycle sequencing of IDH1 and IDH2 in 262 gliomas, we confirm frequent mutations in diffuse astrocytic and oligodendroglial gliomas, corroborate a prognostic role for IDH1 mutation in primary glioblastomas and show that pleomorphic xanthoastrocytomas generally lack mutations in these genes.

Assessment of tumor angiogenesis as a prognostic factor of survival in patients with oligodendroglioma.

According to World Health Organization (WHO) and Daumas-Duport grading systems, progression of oligodendrogliomas (ODGs) to a higher grade (WHO grade III, grade B) is associated with increased angiogenesis. Based on multivariate assessment of molecular, pathological, and radiological parameters, we further assessed the influence of tumor angiogenesis on tumor progression and patient survival. Patients with a diagnosis of ODG, consecutively treated in a single institution, were reviewed and reclassified according to WHO and Daumas-Duport grading systems. MRI scans were reviewed to assess contrast enhancement and necrosis. Tissue sections were used for pathology review and to evaluate immunostaining of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGF-R), Ki-67, and CD34. Multivariate analysis was performed to assess the impact of tumor angiogenesis-related pathological and radiological factors on patient survival. One hundred thirty-four patients with pure ODG were included in this study. Multivariate analysis identified four independent poor prognostic factors: necrosis, absence of seizure, increased vascularization, and age >55 years. A subgroup of patients with tumor necrosis, increased vascularization, and absence of seizures had a significantly worse outcome than predicted, with a median overall survival of 14.2 months. VEGF expression was significantly higher in this subgroup and correlated with disease progression regardless of histologic grade. Based on the presence of radiological or pathological necrosis, contrast enhancement or endothelial hyperplasia, and absence of seizures, a high risk group of ODG can be identified with significantly worse overall survival. Also, VEGF over-expression in ODG constitutes an early marker for predicting tumor progression.

Role of perfusion-weighted imaging at 3 Tesla in the assessment of malignancy of cerebral gliomas.

PURPOSE: This study was performed to clarify the role of perfusion-weighted imaging (PWI) at 3 Tesla in the characterisation of haemodynamic heterogeneity within gliomas and surrounding tissues and in the differentiation of high-grade from low-grade gliomas. MATERIALS AND METHODS: We examined 36 patients with histologically verified gliomas (25 with high-grade and 11 with low-grade gliomas). PWI was performed by first-pass gadopentetate dimeglumine T2*-weighted echo-planar images, and cerebral blood volume (CBV) maps were computed with a nondiffusible tracer model. Relative CBV (rCBV) was calculated by dividing CBV in pathological areas by that in contralateral white matter. RESULTS: In high-grade gliomas, rCBV were markedly increased in mass [mean+/-standard deviation (SD), 4.3+/-1.2] and margins (4.0+/-1.1) and reduced in necrotic areas (0.3+/-0.3). Oedematous-appearing areas were divided in two groups according to signal intensity on T2-weighted images: tumour with lower (nearly isointense to grey matter) and oedema with higher (scarcely isointense to cerebrospinal fluid) signal intensity. Tumour showed significantly higher rCBV than did oedema (1.8+/-0.5 vs. 0.5+/-0.2; p<0.001) areas. In low-grade gliomas, mass (2.0+/-1.5) and margin (2.2+/-1.2) rCBV were significantly lower than in high-grade gliomas (p<0.001). CONCLUSIONS: Three-Tesla PWI helps to distinguish necrosis from tumour mass, infiltrating tumour from oedema and high-grade from low-grade gliomas. It enhances the magnetic resonance (MR) assessment of cerebral gliomas and provides useful information for planning surgical and radiation treatment.

Qualitative and quantitative analysis of cytologic assessment of astrocytoma, oligodendroglioma and oligoastrocytoma.

OBJECTIVE: To evaluate the usefulness of intraoperative cytology for differential diagnoses of astrocytoma, oligodendroglioma and oligoastrocytoma. STUDY DESIGN: Qualitative analysis of cytologic features of the 3 brain tumors was conducted using intraoperative touch or squash preparations that were stained with the Papanicolaou method, targeting the cellular density, cytoplasmic and nuclear profiles and blood vessel morphology. In addition, we attempted a computer-assisted image analysis of tumor cell nuclei and compared the results with qualitative observations. RESULTS: Astrocytomas were characterized by many fibrillary cytoplasmic processes and large, irregular nuclei. Oligodendrogliomas were characterized by small, round nuclei and a fine, delicate capillary network. In both tumors of a higher grade, anaplastic large nuclei and proliferating endothelial cells were noted. Oligoastrocytomas showed combined cytologic profiles of astrocytomas and oligodendrogliomas. Quantitative studies suggested that nuclei of oligodendroglial tumors were significantly rounder than those of astrocytomas. In general, the quantitative results were consistent with the qualitative observations. CONCLUSION; Cytologic evaluation using touch or squash preparations is of great help for intraoperative differential diagnosis of astrocytoma, oligodendroglioma and oligoastrocytoma. Cytologic as well as histologic assessment should be conducted at the intraoperative diagnosis of these tumors.

Proliferation (MIB-1 expression) in oligodendrogliomas: assessment of quantitative methods and prognostic significance.

Expression of to nuclear antigen Ki-67 (MIB-1) has been linked to proliferative activity and prognosis in a variety of tumors. The authors assessed three techniques for quantitating MIB-1 (expression in oligodendrogliomas, correlating results with mitotic activity and prognosis. Formalin-fixed, paraffin-embedded sections of 38 oligodendrogliomas were immunostained using monoclonal MIB-l. Proliferation index (PI) was quantitated by visual estimation, CAS-200, and AC1S image analysis. MIB-1 expression and mitotic count were correlated with overall survival and recurrence (disease-free survival), defined clinically and radiographically as new tumor growth. Mean follow-up was 54 months (range 1-276). Mean PI quantitated by the three methods was statistically similar (Visual 10.5%, CAS-200, 12.2%, CAIS 11.2%). PI results by all three techniques correlated significantly with each other; visual and CAS-200 PI correlated with mitotic index. Overall and disease-free survivals were similar for patients with PIs above and below the mean by both image cytometric assays; visually estimated PIs below the mean, versus above the mean, correlated with improved disease-free survival. The authors show a significant correlation between MIB-1 PI using the visual method and recurrence in patients with oligodendrogliomas. The objectivity and speed of the image analysis systems make them an attractive alternative to visual estimation, and larger series should be analyzed for prognostic value.

Fluid-attenuated inversion-recovery MR imaging in assessment of intracranial oligodendrogliomas.

This retrospective study consisted of 17 consecutive patients with oligodendrogliomas. We qualitatively and quantitatively assessed the diagnostic value of fluid-attenuated inversion-recovery (FLAIR) images compared with T2-weighted fast spin-echo (FSE) images for evaluating intracranial oligodendrogliomas. Qualitative evaluations of signal intensity, tumor conspicuity, definition of tumor margin, distinction between solid and cystic-like parts within tumor, and calcification were performed. Quantitative criteria comparing FLAIR to T2-weighted FSE images included tumor-to-background contrast and contrast-to-noise ratio (CNR) and tumor-to-cerebrospinal fluid (CSF) contrast and CNR. Our results demonstrate that the FLAIR sequence can replace the T2-weighted FSE sequence for evaluating oligodendrogliomas.

Interobserver variability in the radiological assessment of response to chemotherapy in glioma.

OBJECTIVE: To assess the interobserver variability in the radiologic assessment of response to chemotherapy in patients with recurrent glioma. METHODS: Five clinicians with experience in the treatment and follow-up of patients with glioma measured tumor size in 20 pairs of CT and 20 pairs of MRI scans of 35 patients who had been treated with chemotherapy for recurrent glioma. Tumor size was defined as the product of the two largest perpendicular enhancing tumor diameters on the postcontrast images. To assess the interobserver variability in the measurements of tumor size, and in the classification according to the widely used Macdonald response criteria, intraclass correlation coefficients (ICC) and weighted kappa values were calculated. RESULTS: Substantial interobserver agreement was noted in the manual, two-dimensional measurements of tumor size on CT and MRI in patients treated with chemotherapy for recurrent glioma (overall ICC 0.64). Classification of response to chemotherapy according to the Macdonald criteria resulted in moderate interobserver agreement (overall weighted kappa 0.51). In 65% of evaluated CT and in 55% of evaluated MRI studies, no complete consensus was found for the categorical tumor response measurement. CONCLUSION: The radiologic assessment of response to chemotherapy in patients with recurrent glioma is susceptible to considerable interobserver variability. This underlines the difficulties that arise in scoring response to chemotherapy by conventional radiologic techniques.

Magnetic source imaging of late evoked field responses to vowels: toward an assessment of hemispheric dominance for language.

OBJECT: The goal of this study was to determine whether the late neuromagnetic field elicited by simple speech sounds, which is detected by magnetoencephalography, may be used to estimate hemispheric dominance for language and to guide or constrain the intraoperative search for essential language sites. If sufficiently robust, a noninvasive method for assessing hemispheric dominance for language could reduce the necessity for amobarbital testing and the extent of intraoperative cortical stimulation-based mapping, both of which carry the risk of morbidity. METHODS: Fifteen patients undergoing surgery for tumors during which intraoperative language mapping would be performed and two additional patients in whom intracarotid amobarbital testing confirmed right-hemisphere language dominance participated. Following a primary auditory response sources of late neuromagnetic fields elicited by vowel stimuli were modeled and coregistered using magnetic resonance images to form magnetic source (MS) images. A laterality index (LI) was calculated by summing the number of equivalent current dipolar sources in the late fields detected from each hemisphere. In 14 right-handed patients, 10 displayed left asymmetric LIs (0.37 +/- 0.16. mean +/- standard error of the mean in 14 patients). For both right-hemisphere dominant patients in whom an LI was obtainable, the LI was rightward. Stimulation-mapped essential language sites were found in 7 of 15 patients. For six of these seven patients, the MS image-derived LI was leftward. CONCLUSIONS: Asymmetry in single equivalent dipole modeling of the late neuromagnetic field evoked by simple speech sounds correlates with hemispheric language dominance, although not to the degree necessary for individual clinical predictions. With further development, MS imaging of simple language tasks may be used preoperatively to predict language dominance and even to identify or constrain the intraoperative search for likely sites of essential language cortex.

An assessment of the accuracy of computerized transverse axial scanning (EMI scanner) in the diagnosis of intracranial tumour. A review of 366 patients.

The computerized transverse axial (CTA) scans of 366 patients with intracranial tumours and 267 patients without tumours, but with similar presenting features, were analyzed. In all cases the definitive diagnosis was established either by histological or neurological methods. Most tumours were found to be of low tissue density, but a gradation from low through normal to a high density appearance was recognized. Tissue density enhancement with sodium iothalamate was achieved in 63-9% of supratentorial and 62-4% of infratentorial tumours, and usually allowed a more accurate determination to be made of the boundary between the tumour and the surrounding oedema. The accuracy of the CTA scanner as a screening technique was found to be 96%, this being superior to either clinical evaluation or rectilinear isotope scanning. When assessed on the basis of structural abnormalities demonstrated in the same groups of patients, the CTA scans enabled a diagnosis to be made or a lesion excluded in 92-3% of the patients, a figure which bears comparison with arteriography and pneumo-encephalography. It is anticipated that the simplicity and superior sensitivity of the system should decrease the necessity for invasive techniques such as angiography and pneumo-encephalography in the future.