Pathology Review of Low Grade Gliomas

1. Pathology Reviewof Low Grade Gliomas Kara Wyant MD Clayton A. Wiley MD, PhD

2. Case 1 Mrs. S is a 58 year old woman with a history of right frontotemporaloligodendrogliomaand seizure disorder secondary to the mass lesion. The patient first presented to an OSH in 1994 following witnessed seizure-like activity associated with lateral tongue bites and incontinence. Her initial exam was significant left sided weakness, and MRI revealed for a right frontotemporal mass lesion. She underwent stereotactic biopsy which was consistent with a low-grade oligodendroglioma. She was treated with XRT in 1995, but declined chemotherapy at that time. Twelve years later progression was seen on her surveillance scans.

3. Case 1 In 2008 she underwent a second stereotactic biopsy. Pathology was consistent with WHO grade II oligodendroglioma. Molecular diagnostics: 1p/19q co-deletion Ki-67 was less than 5% MGMT low-grade promoter methylation Due to the fact that the lesion progressed, despite its low grade features , she was treated with low dose continuous temozolamide from Sept 2008- June 2009. The planned treatment course of 12 months was stopped early due to myelosuppression.

4. MRI Brain 2007 & 2010

5. MRI Brain 2007 & 2010

6. Case 1 Her lesion remained stable on serial scans, but she continued to have frequent seizures, so she was referred to Dr. Ghearing for evaluation of epilepsy surgery. Her initial evaluation included EMU admission Feb 2010 which suggested a seizure focus in the right temporal lobe. She was also evaluated with neuropsychological testing and fMRI to help localize her language function, but she declined further testing and surgery.

7. Case 1 At her follow up visits she reported frequent break through seizures, despite multiple medication adjustments; and she continued to decline surgical treatment of her epilepsy. She was again admitted to the EMU in August 2013 for seizure localization. Nine habitual seizures were captured and were localized to the right frontal head region. She also underwent SPECT imaging to help with seizure localization.

8. Axial SPECT Images

9. Sagittal SPECT Images

10. Case 1 Following her evaluation she again declined surgical treatment. She continued to decline clinically, and tumor progression was noted on serial MRIs.

11. MRI Brain 2012 & 2014

12. MRI Brain 2012 & 2014

13. Case 1 She was admitted June 30 for stereotactic EEG monitoring. The seizure focus was localized to the right hippocampal region.

14. Stereotactic EEG Monitoring

15. Case 1 She underwent anterior temporal lobectomy 7/8 for resection of her seizure focus.

16. MRI Two Days Post-op

17. Case 1 Surgical Pathology Report: Two of the five parts examined were significant for recurrent glioma without progression past grade II. Microscopic analysis: Hypercellular Round non-hyperchromaticnuclei with perinuclear halos. No mitoses, endothelial proliferation and necrosis were noted.

18. Case 1 Molecular analysis: Ki-67 proliferation index in this tumor is ~5%. GFAP: strong background staining and minor population with cytoplasmic staining. EGFR: moderately and diffusely positive IDH1 and p53: positive MGMT promoter shows low level of methylation Chromosome 1p: Complex abnormality Chromosome 19q: Deletion IS NOT detected Chromosome 9p (p16/CDKN2A): Fractional Allelic Loss is 0% Chromosome 10q (PTEN): Fractional Allelic Loss is 0% Chromosome 17p (TP53): Fractional Allelic Loss is 100%

19. Pathology Review Origin of Low Grade Gliomas Classification of Gliomas Clinical Presentation Imaging Features Pathology Overview Treatment

20. Origin of Low Grade Gliomas Ref: British J Radiology 2011 84: S90-S106

21. Glial Cell Tumor Classification Oligodendroglial: • Oligodendroglioma, WHO grade II • Anaplastic Oligodendroglioma, WHO grade III • GBM-O, WHO grade IV Mixed: • Oligoastrocytoma, WHO grade II • Anaplastic Oligoastrocytomas, WHO grade III

22. Glial Cell Tumor Classification “Circumscribed” Astrocytic Tumors: • Pilocytic astrocytoma, WHO grade I • Pleomorphic xanthoastrocytoma, WHO grade I • Subependymal giant cell astrocytoma, WHO grade I Diffuse Astrocytic Tumors: • Diffuse Astrocytoma, WHO grade II • Anaplastic astrocytoma, WHO grade III • Glioblastoma, WHO grade IV

23. Clinical Presentation Non-specific and depend upon location • ICP Elevation: Headache, nausea, vomiting • Generalized: cognitive dysfunction, dizziness • Focal: weakness, sensory abnormalities, aphasia, seizures

24. Imaging Features

25. Features of Low Grade Glioma • Pathology • Mild increase in cellularity • No to rare mitoses • Low Ki67 proliferation index • No anaplasia • No necrosis

26. Oligodendroglioma • H&E • GFAP • Ki67 • Molecular • IDH mutation • 1p 19q deletion • NO- ATRX mutation, EGFR amplification or mutation

27. Low versus High Grade Glioma • H&E • GFAP • Ki67 • H&E • GFAP • Ki67

28. Pathologic Features

29. Treatment of LGG Symptoms management: 1) Seizure Management • Prophylactic AEDs • AED choice • Surgical Evaluation 2) Cerebral Edema 3) Obstructive Hydrocephalus

30. Treatment in LGG Timing of Treatment • Biopsy • Watch and Wait • Early treatment

31. Treatment of LGG • Surgical Resection • Radiation Therapy • EORTC Study • Chemotherapy • PVC • Temozolamide

32. Questions? Thank you for your attention. Please complete the survey and post-test questions.