Case Study 61

1. Case Study 61 Kenneth Clark, MD

2. Question 1 • This is a 31-year-old asymptomatic man who was found to have papilledema on a routine ophthalmologic examination. He was subsequently sent for an MRI. • Describe the MRI findings.

4. Answer • A large, well-circumscribed cystic lesion with a mural nodule of the left parietal-occipital lobe. The mural nodule shows diffuse homogeneous contrast enhancement. The cystic component shows hyperintense signal on T2. No FLAIR signal is seen.

5. Question 2 • What is the differential diagnosis of a cystic lesion with a mural nodule?

6. Answer • Ganglioglioma • Hemangioblastoma • Pilocytic astrocytoma • Pleomorphic Xanthoastrocytoma

7. Question 3 • The lesion was biopsied and submitted for an intra-operative evaluation. Describe the intra-operative smear. How would you report to the surgeon? • Click here to see the smear

8. Answer • The smear shows a polymorphous cellular neoplasm comprised of small and large cells in a dense glial background. The small cells show ovoid-to-elongated hyperchromatic nuclei with angular nuclear contours, evenly distributed chromatin and indistinct cytoplasm; many of these cells show thin processes. The large cells show more abundant cytoplasm, finely stippled chromatin and prominent nucleoli; numerous markedly enlarged and multinucleated forms are seen. These cells also show processes. The background numerous globules of dense eosinophilic material. No mitotic figures are seen. • A. Neoplastic • B. Defer to permanent sections, favor ganglioglioma

9. Question 4 • The lesion was resected and submitted for pathologic examination. Describe the findings. • Click here to see the H&E slide

10. Answer • Sections show a neuroglial tumor comprised of neoplastic astrocytes and neurons. The majority of astrocytes show nuclear pleomorphism with angular contours, hyperchromasia and scant amounts of light eosinophilic cytoplasm; sparse scattered gemistocytes are also seen. The neurons show markedly enlarged nuclei with significant contour irregularities, prominent nucleoli, marked variation in size and shape, and moderate amounts of pale pink flocculent cytoplasm. Numerous bi-nucleate and giant multinucleate forms are seen. No mitotic activity is seen. The background shows very abundant granular eosinophilic bodies and occasional Rosenthal fibers in the more purely glial areas. There is significant degenerative nuclear atypia in the larger cells both glial and neuronal.

11. Question 5 • What is your differential diagnosis based on these findings?

12. Answer • Ganglioglioma, WHO grade 1 • Pleomorphic Xanthoastrocytoma (PXA) • Large cells show flocculent cytoplasm, many giant multinucleate cells have astrocytic appearance, and eosinophilic granular bodies/Rosenthal fibers are numerous; although unlikely, pleomorphic xanthoastrocytoma (PXA) needs to be ruled out

13. Question 6 • What immunohistochemical stains would you order to firmly establish the diagnosis?

14. Answer • GFAP (identify glial component) • Synaptophysin (identify neuronal component) • NeuN (identify neoplastic neuronal component) • IDH1 • Ki67 (proliferation index) • Reticulin (abundant fibers with pericellular staining in PXA, not ganglioglioma) • Click to view GFAP, Synaptophysin, NeuN, IDH1, Ki67, Reticulin

15. Question 7 • Based on the H&E and immunohistochemical findings (see below), what is your final diagnosis? • GFAP – strong staining of glial tumor cells; negative in large and giant multinucleated cells • NeuN – highlights non-neoplastic neurons in adjacent cortex; negative in neuronal cells and giant cells within the tumor  • IDH1 – negative • Synaptophysin – stains the cytoplasm of large and multinucleated tumor cells • Ki67 - the proliferative index is less than 2%. • Reticulin – low background deposition in majority of tumor; rich perivascular deposition; no conclusive pericellular deposition

16. Answer • Ganglioglioma, WHO grade 1

17. Question 8 • Where do the majority of gangliogliomas typically occur?

18. Answer • Temporal Lobe – 86% • Frontal Lobe – 7% • Parietal Lobe – 3% • Occipital Lobe – 3% • Other Areas – 1% • The predominant temporal lobe involvement explains the common association of ganglioglioma and epilepsy

19. Question 9 • How typical are the neuroradiologic findings in this case?

20. Answer • The neuroradiology in this case are classic for ganglioglioma. MRI typically shows a well-circumscribed, T1-weighted hypointense/T2-weighted hyperintense lesion with a mural nodule that shows contrast enhancement (variable).

21. Question 10 • Are there genetic abnormalities associated with ganglioglioma?

22. Answer • Only about 1/3 of gangliogliomas show a cytogenetic abnormality. Of these, gain of chromosome 7 and partial loss of chromosome 9p are the most common. • Recent studies have shown BRAF mutations in approximately 20% of gangliogliomas, 10% of pilocytic astrocytomas and almost 70% of PXAs; this may be useful in diagnostically challenging / borderline cases.

23. Question 11 • What is the prognosis of ganglioglioma?

24. Answer • Generally, gangliogliomas are considered benign lesions with 7.5-year recurrence-free survival rates approaching 95%. However, anaplastic change in the glial component is known to occur (mitotic activity, endothelial hyperplasia, necrosis). In these transformed lesions Ki67 indices are high and p53 clonality may be present.

25. References • Schindler G, et al. Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma (2011). Acta Neuropathol. 121(3):397-405. • Louis D, Ohgaki H, Wiestler O, Cavanee W. WHO Classification of Tumours of the Central Nervous System. IARC: Lyon 2007. • Prayson R, et al. Cortical architectural abnormalities and MIB1 immunoreactivity in gangliogliomas: a study of 60 patients with intracranial tumors (1995). J Neuropathol Exp Neurol. 54:513-520. • Squire J, et al. Molecular cytogenetic analysis of glial tumors using spectral karyotyping and comparative genomic hybridization (2001). Mol Diagn. 6:93-108.