1. Case Study 60 Kenneth Clark, MD

2. Question 1 This is a 78-year-old woman with a history of CREST syndrome and hypothyroidism who reports 1 month history of neurocognitive decline, personality changes and a mild headache. An MRI of the head was obtained. Describe the MRI findings.

3. Axial T1Axial T1 + ContrastAxial T2 FLAIR Coronal T2 FLAIR Coronal T1 + Contrast

4. Answer Large cystic mass lesion within the right frontal lobe white matter. The lesions show solid areas of diffuse contrast enhancement as well as regions of peripheral rim enhancement. The lesion shows marked surrounding FLAIR signal and associated mass effect.

5. Question 2 What does the T2 FLAIR signal signify?

6. Answer Edema

7. Question 3 What does the surrounding edema tell you about this lesion?

8. Answer That it is infiltrating and very likely a neoplasm.

9. Question 4 A small biopsy was obtained and submitted for intra-operative examination. The surgeon specifically mentions a concern for lymphoma (based on the neuroradiology). Describe the findings. How would you report to the surgeon? Click here to see the smearhere

10. Answer The smear shows a highly cellular lesion comprised of markedly pleomorphic, large, epithelioid cells which are loosely cohesive and appear to be attached to central vascular structures. The cells show round-to-ovoid nuclei with coarsely distributed chromatin, indistinct nuceoli and abundant bright eosinophilic cytoplasm. Numerous cells are wrapped by neighboring tumor cells, forming peculiar whorl- like formations. Sparse mitotic figures are seen. Giant and sparse multinucleate cells are seen. A. Neoplastic B. Favor metastatic tumor versus glioma

11. Question 5 Based on the intra-operative diagnosis, the surgeon resects the lesion and submits it for pathologic examination. How would you describe the histology? Click here to see the H&E slidehere

12. Answer The tissue shows confluent sheets of neoplastic cells that have an epithelioid appearance. The cells show moderate nuclear pleomorphism and relatively abundant pale pink cytoplasm. There are numerous cells that appear to be wrapped by neighboring tumor cells, forming unusual looking concentric structures. Scattered mitotic figures are seen. Endothelial proliferation is seen. No necrosis is evident.

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

14. Answer High grade glioma Metastatic melanoma Metastatic carcinoma

15. Question 6 What immunohistochemical stains would you order to better characterize this lesion?

16. Answer GFAP, IDH1, Vimentin, p53, EGFR (glioma) S100, MelanA, HMB45, Tyrosinase (melanoma) Pankeratin, AE1/3 (carcinoma) CD3, CD20 (r/o lymphoma since surgeon is specifically concerned about this) Ki67 (proliferation index) Click to view vimentin, GFAP, S100, AE1/3, p53, EGFR, Ki67vimentinGFAPS100AE1/3p53 EGFRKi67

17. Question 7 Based on the results of the H&E and immunostains (see below) what is your diagnosis? GFAP & vimentin – strongly positive in tumor cells S100 – positive in tumor cells AE1/3 – light staining of tumor cells P53 - highlights one minute focus of clonality, while the majority of the tumor is negative Tyrosinase, HMB45, pancytokeratin - negative IDH1 - negative. CD3 & CD20 reveal scattered positive cells, with a prominent peri- vascular distribution. Ki67 – proliferation index 10-15% EGFR – strong positive membrane staining

18. Answer Glioblastoma, epithelioid variant, WHO grade 4

19. Question 8 Would any molecular studies be useful in better characterizing this neoplasm? If so, which studies?

20. Answer Fluorescence In Situ Hybridization (FISH) –1p/19q deletion –P16 deletion –EGFR amplification LOH –1p, 19q, 9p (p16), 10q (PTEN), 17p (Tp53) IDH1 mutational analysis

21. Question 9 Molecular studies show the following results: –1p – NO deletion –19q – Deleted –23% p16 deletion by FISH –No EGFR amplification (chromosome 7 hyperploidy rate 33%) –33% 9p deletion by PCR (LOH) –0% p53 deletion by PCR (LOH) –100% 10q deletion by PCR (LOH) –Negative for IDH1 or IDH2 mutation How would you interpret these?

22. Answer Loss of 10q is the most frequent genetic abnormality associated with de novo glioblastomas (60-80%). Also, deletion of 19q occurs in approximately 25% of primary glioblastomas. A subset of glioblastomas have also been shown to have the co-presence of gain of chromosome 7 with loss of chromosome 10. Likewise, the molecular data support the diagnosis of glioblastoma.

23. Question 10 Does the epithelioid variant have prognostic significance?

24. Answer No. Glioblastoma was historically called glioblastoma multiforme, referring to the wide range of histologic appearances. The importance of specifying the subtype is only in distinguishing it from other histologically similar tumors (carcinomas, for instance).

25. Question 11 Are there any histologic subtypes of glioblastoma that have prognostic implications?

26. Answer Giant cell glioblastoma has some distinction from other variants of glioblastoma in that it they show very high levels of p53 mutations (80-90%, less than 30% for conventional primary glioblastomas) and they grow in an expansile manner (rather than infiltrative), resulting in fairly well-circumscribed borders. Some recent reports have indicated that giant cell glioblastoma offers a more favorable prognosis than other forms of glioblastoma.

27. References Louis D, Ohgaki H, Wiestler O, Cavanee W. WHO Classification of Tumours of the Central Nervous System. IARC: Lyon 2007. Von Deimling A, et al. Loci associated with malignant progression in astrocytomas: a candidate on chromosome 19q1 (1994). Cancer Res. 54:1397-1401. Misra A, et al. Array comparative genomic hybridization identifies genetic subgroups in grade 4 human astrocytoma (2005). Clin Cancer Res. 11:2907-2918. Shinojima N, et al. The influence of sex and the presence of giant cells on post-operative long-term survival in adult patients with supratentorial glioblastoma multiforme (2004). J Neurosurg. 101:219-226. Ohgaki H, et al. Genetic pathways to glioblastoma: a population- based study (2004). Cancer Res. 64:6892-6899.