Anatomical phenotyping and staging of brain tumours

Unlike other tumors, the anatomical extent of brain tumors is not objectified and quantified through staging. Staging systems are based on understanding the anatomical sequence of tumor progression and its relationship to histopathological dedifferentiation and survival. The aim of this study was to describe the spatiotemporal phenotype of the most frequent brain tumor entities, to assess the association of anatomical tumor features with survival probability and to develop a staging system for WHO grade 2 and 3 gliomas and glioblastoma. Anatomical phenotyping was performed on a consecutive cohort of 1000 patients with first diagnosis of a primary or secondary brain tumor. Tumor probability in different topographic, phylogenetic and ontogenetic parcellation units was assessed on preoperative MRI through normalization of the relative tumor prevalence to the relative volume of the respective structure. We analyzed the spatiotemporal tumor dynamics by cross-referencing preoperative against preceding and subsequent MRIs of the respective patient. The association between anatomical phenotype and outcome defined prognostically critical anatomical tumor features at diagnosis. Based on a hypothesized sequence of anatomical tumor progression, we developed a three-level staging system for WHO grade 2 and 3 gliomas and glioblastoma. This staging system was validated internally in the original cohort and externally in an independent cohort of 300 consecutive patients. While primary central nervous system lymphoma showed highest probability along white matter tracts, metastases enriched along terminal arterial flow areas. Neuroepithelial tumors mapped along all sectors of the ventriculocortical axis, while adjacent units were spared, consistent with a transpallial behavior within phylo-ontogenetic radial units. Their topographic pattern correlated with morphogenetic processes of convergence and divergence of radial units during phylo- and ontogenesis. While a ventriculofugal growth dominated in neuroepithelial tumors, a gradual deviation from this neuroepithelial spatiotemporal behavior was found with progressive histopathological dedifferentiation. The proposed three-level staging system for WHO grade 2 and 3 gliomas and glioblastoma correlated with the degree of histological dedifferentiation and proved accurate in terms of survival upon both internal and external validation. In conclusion, this study identified specific spatiotemporal phenotypes in brain tumors through topographic probability and growth pattern assessment. The association of anatomical tumor features with survival defined critical steps in the anatomical sequence of neuroepithelial tumor progression, based on which a staging system for WHO grade 2 and 3 gliomas and glioblastoma was developed and validated

Targeted molecular characterization of adult midline and circumscribed gliomas for the identification of new potential targets for personalized therapy

Diffuse midline gliomas (MLG) are primary brain tumours arising from thalamus, hypothalamus, brainstem, cerebellum or spinal cord, mainly occurring in children. In adults, less than 10% of diffuse gliomas arises in midline structures and recent works suggested that this subset of tumours may present with phenotypic and molecular characteristics differing from both pediatric MLG and adult supratentorial gliomas. Circumscribed gliomas (CG) are low-grade tumours but may progress to anaplasia. They have lower genetic complexity than diffuse gliomas and could be better candidate for targeted therapies, when complete surgical resection is not feasible. Unravelling the genomic landscape of MLG and CG will better define the prognostic value of molecular biomarkers and identify new therapeutic strategies that could improve patient care. Adult patients with diagnosis of MLG and CG were retrospectively identified from \uabMaggiore della Carit\ue0\ubb Hospital and GH Piti\ue9-Salp\ueatri\ue8re (Paris). Mutation analysis was performed by Sanger sequencing of the major hot-spots: IDH1, IDH2, H3F3A, HIST1H3B, FGFR1, TERT promoter. FISH analyses of NTRK1-2-3 rearrangements were performed by break-apart probes on tissue microarray of MLG cases. We identified 116 (French) and 47 (Italian) patients. The two cohorts showed a lower percentage of H3F3A mutations (20% vs 33%), the mutation was not associated to a worse prognosis. FGFR1 mutations were identified in 18% of cases and are restricted to MLG. NTRKs analysis in the Italian cohort showed NTRK1 translocations in 15% of cases. We reported a high rate of FGFR1 mutations in optic nerve pilocytic astrocitomas and the presence of alternative BRAF activating mutations (Thr599_Val600insThr and Val600_Lys601>Glu). Our finding of frequent and potentially targetable FGFR1 and BRAF mutations and NTRK1 translocations have important therapeutical implications in the current context of clinical trials, and further reinforces the need for molecular analyses

Histopathological study of Gliomas and Evaluation of IDH – 1 Expression in Glioblastoma by Immunohistochemistry

INTRODUCTION: The recent WHO 2016 CLASSIFICATION OF CNS TUMORS incorporates molecular parameters for classification of gliomas. • Accordingly, all diffusely infiltrating gliomas (Grades II –IV) have been grouped together based on histopathological assessment and IDH – (Isocitrate dehydrogenase) mutation status. • IDH mutant, IDH wildtype- diffuse gliomas & glioblastomas are among the few new entities included in this classification. • Utility of assessment of IDH mutation status: • To identify reactive gliosis from gliomas in difficult cases. • To differentiate infiltrating and non infiltrative gliomas in adults. • IDH mutant gliomas are associated with better prognosis. • Can provide ground for novel treatment strategies targeting IDH mutations. AIMS AND OBJECTIVES: 1. To study the frequency of occurrence of gliomas in specimens received from Government Rajaji hospital, Madurai to the Department of pathology, Madurai Medical College. 2. To study the incidence in relation to age and sex in gliomas. 3. To study the histopathological classification of gliomas. 4. To analyse the expression of immunohistochemical marker Isocitrate dehydrogenase (IDH -1) in glioblastomas – utility in identifying glioblastomas with better prognosis. BACKGROUND OF STUDY: • Histopathological study to morphologically classify gliomas and to know the incidence of the same in a population of different age and sex. • Immunohistochemical marker study with IDH-1(R132H) as an independent predictor of better prognosis in gliobastomas. • Place of study: Madurai Medical College. • Study design: Prospective study. • Sample size: 50. INCLUSION CRITERIA: • Biopsy specimens of space occupying lesions (SOL) of brain EXCLUSION CRITERIA: • Benign tumors. • Neoplastic lesions other than gliomas. SUMMARY: In the present prospective study of 96 cases of brain SOLs, the following results were obtained: • Out of the 96 cases, 92% were neoplastic lesions and 97% were primary brain tumors. • Gliomas comprised of 50 cases out of the 96 brain SOLs and were the commonest among the primary CNS tumors. • Of the non glial tumors, meningiomas were the commonest constituting 28.2%. • The commonest glioma was glioblastoma accounting for 42%. • The most common age group affected by gliomas was 40-59 years with an overall frequency of 46% and the glioblastomas was 50 -59 years accounting for 38.1%. • Males had a definite sex predilection for both gliomas overall and glioblastomas specifically, accounting for 62% and 71.4% respectively. • The commonest location of all gliomas and glioblastomas in specific was the frontal lobe. • Unusual sites of distribution of gliomas were – corpus callosum and cerebellum. • The analysis of IDH1mutation showed IDH wild type glioblastomas as the most predominant, comprising 71.4% of the glioblastomas. The results were statistically significant with a p value of 0.0327 (p<0.05). • The most common sex affected in IDH1 mutant glioblastomas was male and the most common age group was 50-59 years. The results were statistically significant with a p value of 0.0464(p<0.05). • IDH wild type glioblastomas accounted for 26.7% of the seventh decade patients. • Frontal lobe was the predilected site for IDH1 mutant glioblastomas. The results were statistically significant with a p value of 0.028. • The analysis of EGFR mutation in all IDH wild type glioblastomas showed 40% positivity

Malignant Gliomas: A Case Study

Malignant gliomas, of grade III and grade IV malignancy, are incurable neoplasms that arise from cells with several well-characterized genetic profile abnormalities that cause uncontrollable growth and infiltration in the brain. Presenting symptoms of both generalized and focal neurological abnormalities are induced by increased intracranial pressure and focal neuronal dysfunction, respectively. On average, patients experience 3 months or less of clinical history before receiving diagnosis based on multifactorial comparison of clinical and pathological presentation of the tumor. Following diagnosis, maximal safe resection and adjuvant radiotherapy and concurrent chemotherapy typically ensues with subsequent management chemotherapy regimens. Despite aggressive treatment approaches, progression or recurrence is highly typical based on 5-yr survival rates of 5.1% and 27.9% of grade IV glioblastoma multiforme (GBM) and grade III anaplastic astrocytoma (AA), respectively, the two most common malignant gliomas. Severely progressive clinical and functional deterioration in the terminal stage of care may warrant cessation of curative care replaced with maximal palliative care. Brain tumor patients experience the burden of terminal illness as other cancer patients do, but with added neurological-specific impairments that reduce quality of life. Possible causes of death include herniation, tumor progression, and systemic illness, but can be potentially multifactorial. The following manuscript characterizes the pathological mechanisms of oncogenesis and growth, followed by a comprehensive review of the clinical care for brain tumor patients from symptom onset to cause of death. To aid in the clinical applicability of these concepts, a case study of a single patient “WL”, who received a diagnosis of grade III anaplastic astrocytoma following 3 months of visual deterioration, will prompt the clinical review by illustration of disease course and treatment

Diffusion Tensor Imaging of the Brain: Background and Review of Clinical Applications

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75192/1/j.1617-0830.2005.00036.x.pd

CNS High Grade Glioma

Since the publication of the 2016 edition of the WHO Classification of CNS Tumors, advances in neuropathology have enhanced our understanding of the molecular underpinnings of CNS tumors, providing new elements to refine their classification and improve pathological diagnosis of these neoplasms. This chapter will review the highlights of the updated recommendations which provide guidance for how even in the absence of histopathological characteristics of the highest malignancy grade, molecular markers can be used to reach a diagnosis of glioblastoma, IDH–wild-type or astrocytoma, IDH-mutant, grade IV. These changes have important implications for the management of patients with CNS tumors in current neuro-oncology practice

Risk Assessment by Pre-surgical Tractography in Left Hemisphere Low-Grade Gliomas

Background: Tracking the white matter principal tracts is routinely typically included during the pre-surgery planning examinations and has revealed to limit functional resection of low-grade gliomas (LGGs) in eloquent areas. Objective: We examined the integrity of the Superior Longitudinal Fasciculus (SLF) and Inferior Fronto-Occipital Fasciculus (IFOF), both known to be part of the language-related network in patients with LGGs involving the temporo-insular cortex. In a comparative approach, we contrasted the main quantitative fiber tracking values in the tumoral (T) and healthy (H) hemispheres to test whether or not this ratio could discriminate amongst patients with different post-operative outcomes. Methods: Twenty-six patients with LGGs were included. We obtained quantitative fiber tracking values in the tumoral and healthy hemispheres and calculated the ratio (HIFOF\u2013TIFOF)/HIFOF and the ratio (HSLF\u2013TSLF)/HSLF on the number of streamlines. We analyzed how these values varied between patients with and without post-operative neurological outcomes and between patients with different post-operative Engel classes. Results: The ratio for both IFOF and SLF significantly differed between patient with and without post-operative neurological language deficits. No associations were found between white matter structural changes and post-operative seizure outcomes. Conclusions: Calculating the ratio on the number of streamlines and fractional anisotropy between the tumoral and the healthy hemispheres resulted to be a useful approach, which can prove to be useful during the pre-operative planning examination, as it gives a glimpse on the potential clinical outcomes in patients with LGGs involving the left temporo-insular cortex

Survival signalling and apoptosis resistance in glioblastomas: opportunities for targeted therapeutics

Glioblastoma multiforme (GBM) is the most common primary brain tumour in adults and one of the most aggressive cancers in man. Despite technological advances in surgical management, combined regimens of radiotherapy with new generation chemotherapy, the median survival for these patients is 14.6 months. This is largely due to a highly deregulated tumour genome with opportunistic deletion of tumour suppressor genes, amplification and/or mutational hyper-activation of receptor tyrosine kinase receptors. The net result of these genetic changes is augmented survival pathways and systematic defects in the apoptosis signalling machinery. The only randomised, controlled phase II trial conducted targeting the epidermal growth factor receptor (EGFR) signalling with the small molecule inhibitor, erlotinib, has showed no therapeutic benefit. Survival signalling and apoptosis resistance in GBMs can be viewed as two sides of the same coin. Targeting increased survival is unlikely to be efficacious without at the same time targeting apoptosis resistance. We have critically reviewed the literature regarding survival and apoptosis signalling in GBM, and highlighted experimental, preclinical and recent clinical trials attempting to target these pathways. Combined therapies simultaneously targeting apoptosis and survival signalling defects might shift the balance from tumour growth stasis to cytotoxic therapeutic responses that might be associated with greater therapeutic benefits

Development and Characterization of Mouse Models of Human Glioblastoma

Glioblastoma multiforme (GBM) is a very challenging disease clinically because of lacking effective treatments. Accurate and accessible preclinical models of GBM are required to both understand these diseases and facilitate development of diagnostic tests and therapies. Recently, genetic mutations in human gliomas are better understood and techniques to generate genetically engineered mice (GEM) are more sophisticated, which makes it possible to mimic those mutations in the mouse in an accurate way. Here, we developed mouse models of human GBM by simulating most common genetic mutations in human GBMs, including abnormal RTK-Ras signal, Rb pathway, and Pten locus. In the beginning, the model was manipulated so that the mutation (K-RasG12D) was transferred to astrocytes using an hGFAP-Cre allele, which resulted in primary GBMs. This model is valuable for understanding the role of K-Ras overactivation in primary GBM's formation and cell-oforigin. However, developmental phenotypes other than GBM in this model restrict its further uses in mechanistic studies and combinations with other mutations. In subsequent models, we modified the strategy and generated an inducible system, in which genetic changes can be spatially and temporally induced in adult astrocytes, thus avoiding developmental defects. Induction is elicited by activation of CreERtam, expressed from the human GFAP promoter, after intraperitoneal 4OH-tamoxifen injection. With high penetrance and reproducible timing, the combination of all three events induces tumors that possess all common histological features of human GBM, including brain invasion, high mitotic indexes, angiogenesis, and necrosis. Furthermore, analysis of event combinations provides insight into disease etiology. For example, without Pten inactivation, pRb inactivation and K-Ras activation predispose to high-grade astrocytic tumors that lack the necrotic phenotype characteristic of GBM. Neither activation of K-Ras nor inactivation of Pten alone produces detectable pathology, and thus are involved in tumor progression. In contrast, inactivation of pRb function initiates disease that does not progress to high-grade tumors. Because of their inducibility, high-penetrance and molecular and histological similarity to human high-grade astrocytomas, these models are extremely promising for both further mechanistic analyses and for preclinical studies, including the validation of potential drug targets and diagnostic and therapeutic development

Advanced imaging and artificial intelligence for diagnostic and prognostic biomarkers in glioblastoma

Conventional magnetic resonance imaging (MRI) has a pivotal role in diagnosis and post-treatment management of glioblastoma, however it has limitations. This work investigates the use of advanced MRI techniques that assess the tumour microenvironment, and artificial intelligence (AI) techniques that compute quantitative features, as potential imaging biomarkers in key clinical issues faced by clinicians, through several retrospective studies. Results show that advanced multiparametric MRI is superior to current standard-of-care imaging for the diagnosis of glioblastoma, and in treatment response assessment. Results of AI techniques on pre-operative imaging show the ability to differentiate between glioblastoma and metastasis with an accuracy of 88.7%, prediction of overall survival with a high level of accuracy, and stratification of patients into high- and low-level groups of MGMT promoter methylation with accuracies between 45-67%. In the early post-treatment phase, AI analysis of imaging can distinguish between disease progression and pseudoprogression with an accuracy of 73.7%, compared to neuroradiologist accuracy of 32.9%. Integrating these techniques into routine clinical practice is essential to improve patient outcomes. Further work is required to validate advanced imaging and AI biomarkers, towards the longer-term goal of using these as clinical decision support tools, to benefit patients with glioblastoma and other brain tumours