1. Case Study 58 Kenneth Clark, MD

2. Question 1 This is a 4-year-old boy with refractory epilepsy attributable to the right temporal region. An MRI as well as PET CT showed subtle changes in the right temporal lobe consistent with the origin of his seizures. He underwent an uncomplicated right-sided grids placement for mapping of his seizures. Several days later he returned to the OR for removal of grids and for right-sided temporal lobectomy. Describe the subtle MRI and PET findings.

3. Axial T1Axial T1 + ContrastAxial T2 FLAIR PET CT Scan

4. Answer MRI - Increased T2 FLAIR signal in the cortex and subcortical region of the superior gyrus of the posterior right temporal lobe, minute cystic areas in this same region. No discrete lesions or areas of enhancement. PET CT - Diffuse hypometabolism involving the entire right temporal lobe. Remaining cerebral cortex, subcortical structures and the cerebellum show no metabolic abnormalities.

5. Question 2 What is the differential diagnosis of a temporal lobe lesion in a child with epilepsy?

6. Answer Cortical Dysplasia Ganglioglioma Dysembryoplastic Neuroepithelial Tumor (DNET) Xanthoastrocytoma

7. Question 3 The lesion was resected. Describe the findings. Click here to view the slidehere

8. Answer The tissue shows a large segment of hypercellular grey matter with predominantly small and irregularly shaped neurons admixed with increased numbers of atypical astrocytes and increased background vascularity. Within this region of cortex and adjacent white matter are multiple well-circumscribed glial nodules comprised of oligodendroglia-like cells with small round nuclei and perinuclear cytoplasmic clearings. The background within the nodules shows rich thin-walled vascular networks and rare entrapped neurons. The periphery of the lesion shows foci of severe cortical dysplasia including small regions with balloon cell change.

9. Question 4 What is your diagnostic impression?

10. Answer Dysembryoplastic Neuroepithelial Tumor (DNET), Complex Type

11. Question 5 What additional immunohistochemical stains would you order to better characterize this lesion?

12. Answer GFAP (glial elements) NeuN (neuronal elements) Synaptophysin (help characterize degree of neuronal aberrancy in lesional cortex) Ki67 (proliferation index) Neurofilament (axonal pathology) Click to see GFAP, NeuN, Synaptophysin, Neurofilament, Ki67GFAPNeuNSynaptophysin NeurofilamentKi67

13. Question 6 How would you describe the immunohistochemical findings?

14. Answer GFAP - highlights astrocytic component of cortical glioneuronal element; negative in glial nodules Synaptophysin - reduced staining within glioneuronal region (compared to unaffected cortex); slight staining within white matter NeuN - highlights small, round, dysplastic neurons and effaced laminar structure in glioneuronal region; also reveals scattered small neurons in white matter tracts; negative in glial nodules Neurofilament - highlights white matter axons Ki67 - stains less than 1% of glioneuronal cells; highlights numerous proliferating inflammatory cells & macrophages near grid wire insertion tracts

15. Question 7 Do these stains confirm your diagnosis? Explain.

16. Answer Yes. The NeuN staining highlights severe neuronal cortical dysplasia within the glioneuronal neoplastic element as well as numerous scattered neurons in the subcortical white matter. This is further confirmed by the reduced synaptophysin staining in the affected regions. Furthermore, the GFAP staining highlights the glial component of the neoplasm and absent staining of the oligodendroglial nodules typify the complex DNET variant.

17. Question 8 What grade is a dysembryoplastic neuroepithelial tumor?

18. Answer DNETs, both classic and complex, are considered WHO grade 1 lesions.

19. Question 9 How often is cortical dysplasia found in association with this tumor?

20. Answer Some studies have shown that cortical dysplasia can be found in as many as 80% of DNETs.

21. Question 10 What is the primary differential diagnosis with a DNET? How would you make the distinction?

22. Answer The main differential with DNET is ganglioglioma. They are both WHO grade 1 lesions with neoplastic neuronal elements. Similarities: –Variable numbers of neoplastic ganglion cells –Multinodular structures –Very similar clinical presentations Differences: –Gangliogliomas more often have large cystic components than DNET. –Gangliogliomas often have perivascular lymphocytic infiltrates where DNETs do not. –Gangliogliomas demonstrate a rich background of reticulin fibers where DNETs do not.

23. Question 11 Why is the distinction between DNET and ganglioglioma important?

24. Answer Making the distinction between DNET and ganglioglioma is important because gangliogliomas can undergo malignant transformation with anaplastic changes in the glial component of the tumor (resembling high grade glioma), whereas DNETs do not. This has prognostic and follow-up implications.

25. References Louis D, Ohgaki H, Wiestler O, Cavanee W. WHO Classification of Tumours of the Central Nervous System. IARC: Lyon 2007. Pasquier B, Peoch M, Fabre-Bocquentin B, Bensaadi L, Pasquier D, Hoffmann D, Kahane P, Tassi L, Le Bas J, Benabid A. Surgical pathology of drug resistant partial epilepsy. A 10-year-experience with a series of 327 consecutive resections (2002). Epileptic Disorders. 4:99-119. Prayson R, Khajavi K, Comair Y. Cortical architectural abnormalities and MIB1 immunoreactivity in gangliogliomas: a study of 60 patients with intracranial tumors (1995). Neuropathol Exp Neurol. 54:513- 520. Daumas-Duport C, Varlet P, Bacha S, Beuvon F, Cervera-Pierot P, Chodkiewicz J. Dysembryoplastic neuroepithelial tumors: non- specific histological forms – a study of 40 cases. J Neurooncol. 41:267-280.