Pre-managment of Low Grade Glioma- low grade glioma

Pre management of glioma

1. Pre-management of Low Grade Gliomas Presented by Dr. Paritosh Moderated by Dr. Prof. Vipul Nautiyal

2. Topics Epidemiology Introduction and Classification Types of Low Grade Gliomas Pathophysiology and Clinical Features Work up Prognosis

3. Epidemiology Gliomas are the most frequent (75%) tumors of all primary CNS tumors in adults Majority of pediatric gliomas are low grade, slow growing lesions (Grade I or II ) and account for 25%-30% of pediatric CNS tumors Typically affects younger age with a median age of presentation at 35 years Male: Female = 1:1 Particular predilection for the insula and supplementary motor area

4. Introduction Gliomas are tumors of neuro epidermal origin derived from supporting glial cells within CNS or cell precursors They vary in severity ranging from low grade tumors to high grade Glioma is a more inclusive classification encompassing two major basic histopathological subtypes: astrocytoma and oligodendroglioma as per the latest WHO classification

5. CLASSFICATION OF GLIAL TUMORS

6. MOLECULAR CLASSFICATION OF LOW GRADE GLIOMAS Previous WHO Classification included Cytological atypia, Microvascular proliferation, mitotic activity and Necrosis

7. Low Grade Gliomas Premalignant astrocytic tumors that grow slowly and continuously They tend to migrate along the white matter pathways. Over time, more than 70% of these can transform into a higher grade glioma or can become aggressive in behavior within a decade.

8. Types of Low Grade Gliomas Diffuse astrocytoma Oligodendroglioma Oligoastrocytoma

9. Diffuse Astrocytoma Fibrillary Astrocytoma Gemistocytic Astrocytoma Protoplasmic Astrocytoma Ki-67 /MIB index is <4%. Best IHC marker is GFAP (Glial Fibrillary Acidic Protein)

10. Fibrillary Astrocytoma Most common type Characterised by low cellularity with minimal nuclear atypia Expresses intermediate GFAP positivity

11. Fibrillary Astrocytoma

12. Gemistocytic Astroctyoma Characterised by plump, glassy, eosinophilic cell bodies of angular shape Consistently express GFAP More prone to malignant transformation

13. Gemistocytic Astrocytoma

14. Protoplasmic Astrocytoma rarest histological subtype small bodied astrocytes with few processes scant GFAP activity mucoid degeneration and microcystic formation common

15. Protoplasmic Astrocytoma

16. Oligodendrogliomas Characterized by round and regular nuclei, clear perinuclear haloes (fried-eggs) as well as an array of fine, hexagonal capillaries, which are commonly described as a "chicken wire pattern". They are moderately cellular and have a dense network of capillaries and frequently contain calcifications. Occasional mitoses and a Ki-67/MIB-1 labeling index up to 5% are seen There is no immunohistochemical marker specific for oligodendrogliomas.

17. Oligoastrocytoma Mix population of oligodendrocytes and astrocytes

18. IDH: Isocitrate dehydrogenase, TP53: Tumour protein p53, ATRX: Alpha‑thalassemia /mental retardation syndrome X‑linked Molecular Markers

19. Value 1p19q deletion IDH mutation Diagnostic Yes presence confirms oligodendroglioma . Absence diagnosed as diffuse Glioma of oligodendroglial phenotype. Yes, grade II and III gliomas are commonly IDH mutated, while gliosis and other glioma entities are not. Prognostic Yes, patients with codeleted grade II have better prognosis (median overall survival, 8.0 years for 1p19q codeleted and IDH-mutated versus 6.3 years for 1p19q-intact and IDH-mutated low-grade glioma Yes, patients with IDH-mutated gliomas have better prognosis than do those with IDHwt gliomas of similar grade Predictive Yes, patients with grade III co deleted tumors have better survival Probably in grade II and III. Evidence still lacking .

20. Risk Factors FAVOURABLE UNFAVOURABLE Mutations in the IDH gene Age older than 40 years Co- deletion of 1p/19q Presence of neurologic deficits Poor KPS (<70) at time of diagnosis Large tumor crossing the midline Astrocytic histology

21. Pathophysiology Receptor tyrosine kinases (RTKs) are activated in gliomas by epidermal growth factor (EGF), transforming growth factor (TGF) platelet-derived growth factor (PDGF) and insulin-like growth factor IGF 1. These RTKs can then signal through Ras-/MAPK (Ras-/mitogen activated protein kinase), PLC©-PKC (phospholipase C-@/protein kinase C), and PI3K-AKT/PKB pathways. The tyrosine phosphatase (PTEN) protein acts as a tumour suppressor by inhibiting the PI3K/AKT-activated signalling cascade. Ras and PI3K engage the cell cycle machinery through interaction with different regulators that include cyclin D1, MDM2, and p27,which promote cell proliferation, differentiation, anti- apoptosis, migration, and metabolism

22. Clinical Features Seizures: most common (80 to 90%) Can present as GTCS or partial/ focal type Seen in gliomas of mediotemporal and insular/paralimbic locations. More frequently associated with oligodendrogliomas Headache Fatigue Nausea and Vomiting Neurologic deficits are rare but if present, they are associated with poor prognosis Personality changes and mood fluctuation

23. Location Specific Symptoms Frontal Temporal Parietal Occipital Personality changes Auditory hallucinations Homonymous quadrantopia Visual aberrations Abulia Impaired perception of verbal commands Hemianesthesia Perceptual disruption of color Memory loss Dysgraphia Apraxia

24. Work Up Detailed History and Examination behavioral changes are present in frontal lobe tumors receptive aphasia in temporal lobe mass parietal lobe tumors can vary in presentation

25. However, these tumors are relatively less common to present with focal neurological deficits such as unilateral weakness or aphasia. Cognitive dysfunction may develop over time and is mainly influenced by tumor location and size . Therefore a detailed Neurological Examination is necessary.

26. Imaging CT Scan MRI MRS DTI PETCT

27. CT Scan First-line diagnostic imaging modality Because most of these tumours are slow growing, they may cause expansion, remodelling, or erosion of the calvarium. Contrast enhancement: Non/mildly enhancing LGGs rarely cause significant peritumoral edema

28. Calcifications: Hallmark seen in 70%-90% Cystic component (20%) Haemorrhage: uncommon Low-grade diffuse astrocytomas - Ill-defined homogenous masses with rare calcification Contrast enhancement: Suspect secondary high-grade glioma. (LGG -> HGG)

29. MRI Homogeneously isointense to hypointense on T1-weighted images and hyperintense on T2/fluid-attenuated inversion recovery (FLAIR) weighted images Calcifications manifest as areas of low-intensity on T2 images Mostly non-enhancing When a nodular contrast enhancement is present, it indicates a focal area of malignant transformation

30. Dynamic Susceptibility MRI Dynamic susceptibility contrast MRI (DSC-MRI) enables the measurement of relative cerebral blood volume ( rCBV ), which is associated with vascularity. In astrocytoma, increase in rCBV in LGG predicts malignant transformation before contrast enhancement occurs.

31. MR Spectroscopy Proton magnetic resonance spectroscopy measures major metabolites in tumoral tissue The typical (but not specific) spectrum of an LGG Elevated choline (+ membrane turnover) Decreased N-acetyl aspartate (neuronal loss). The presence of lactate and lipids is correlated to a more aggressive tumour

32. Diffusion Tensor Imaging Diffusion tensor imaging (DTI) enables the identification of the tractography of the main fiber bundles. DTI enables the study of the sole anatomy of the subcortical pathways DTI indices (mean diffusivity [MD] and fractional anisotropy [FA]) maybe used to distinguish between LGGs and HGGs

33. PETCT LGGs are hypometabolic in contrast to HGGs, which are hypermetabolic uptake of radiolabelled amino acids Increased uptake of amino acids is seen in LGGs 18F-FET PET ( Fluoro ethyl tyrosine) - used in LGG for predicting outcome.

34. Workup ( contd ) Histopathology Stereotactic Biopsy : The procedure is performed with a stereotactic device that uses a coordinate-based navigation system equipped with a patient’s brain images (MRI, CT) and fine needle is inserted to obtain samples. Open Biopsy : samples are taken during craniotomy Biomarker Testing by IHC, FISH, PCR and DNA sampling to detect mutations such as IDH1/2, ATRX, 1p,19q codeletion and TERT promoter gene

35. Stereotactic Biopsy

36. Prognosis EORTC Guidelines De Differentiation

37. EORTC (European Organization for Research and Treatment of Cancer) Prognostic Scoring System Adverse Factors Age > 40 yrs. Astrocytic tumour type Tumour size > 6cm Tumour crossing the midline Neurological deficit at diagnosis Favourable prognosis: no more than 2 of the adverse factors - median survival of 7.7 yrs. 3 - 5 adverse factors - median survival of 3.2 yrs.

38. The major cause of morbidity with low-grade astrocytoma is de-differentiation to a more malignant grade. LGG  HGG Genetic markers that correlate with a higher degree of malignant degeneration Loss of heterozygosity on chromosomes 10 &17 Alteration in tumor suppressor genes at 9p. 13q. 19q &22q Changes in epidermal growth factor receptor (EGRF) and platelet-derived growth factor (PDGF) Mutation of the TP53 gene located on chromosome 17p Transformation of the p53 suppressor gene lsocitrate dehydrogenase (IDH) mutations — genetic aberrations that lead to epigenetic machinery dysfunction De Differentiation

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