Kenneth Clark, MD

Question 1
• This is a 40-year-old woman who 2004 had a right temporal lobe tumor resected which was signed out as a WHO grade 2 oligodendroglioma. On follow-up surveillance
MRI she was found to have a new lesion since her last exam (2 years).
• Describe the MRI findings (films of original lesion also provided for comparison).

Answer
• 2004 – Fairly well circumscribed, T1 hypointense, non-contrast enhancing lesion with subtle FLAIR signal near temporal pole.
• 2011 – Postoperative changes from remote right temporal lobe oligodendroglioma resection. New irregular region of ring-enhancement posterior to resection bed with adjacent area of FLAIR signal immediately adjacent to posterior aspect of resection cavity anterior to region of enhancement.

Question 2
• What is the differential diagnosis of a ringenhancing lesion?

Answer

Question 3
• The lesion was resected and submitted for pathological examination. Describe the histologic findings.
• Click here to view the slide

Answer
• Sections show an infiltrating glial tumor with predominantly oligodendroglial morphology (round nuclei with perinuclear clearing). There is also a subset of tumor cells that show astrocytic morphology with larger hyperchromatic nuclei with irregular nuclear contours and ill-defined eosinophilic cytoplasm. In many regions cells appear gemistocytic with small eccentric nuclei, sharp cell borders and homogeneous glassy eosinophilic cytoplasm. Scattered mitoses can be seen. Multifocal glomeruloid endothelial proliferation is seen. Many of the vessels have sclerotic hyalinizing basement membranes.
In the most cellular area of tumor a small focus of incomplete necrosis without palisading is seen.

Question 4
• What is your diagnostic impression?

Answer
• Recurrent glioma, high grade, with oligodendroglial and astrocytic morphologies

Question 5
• What immunohistochemical stains would you order to further characterize this lesion?

Answer
• GFAP
• IDH1
• EGFR
• P53
• Ki67
• Click to see GFAP , IDH1 , EGFR , p53 , Ki67

Question 6
• The immunohistochemical findings support the impression of oligoastrocytoma. Would any molecular studies be useful in better characterizing this neoplasm? If so, which studies?

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

Question 7
• Molecular studies show the following results:
– 1p/19q – NO deletion
– 74% p16 deletion by FISH (hemizygous)
– No EGFR amplification
– 100% 9p deletion by PCR (LOH)
– 100% p53 deletion by PCR (LOH)
– 33% 10q deletion by PCR (LOH)
– Positive for IDH1 mutation (p.R132H, c.395G>A)
• How would you interpret these?

Answer
• The absence of 1p/19q deletion is seen in 50-
70% of oligoastrocytomas and less than 10% of pure oligodendrogliomas
• P53 mutation is commonly seen in oligoastrocytomas, while rare in pure oligodendrogliomas
• 10q loss (PTEN) is also more frequently seen in oligoastrocytomas, rare in pure oligos
• EGFR amplification is rare in both tumors
• Taken together, these molecular data support the diagnosis of high grade oligoastrocytoma.

Question 8
• The tumor does show focal necrosis. Is it a grade 3 or 4 (glioblastoma)

Answer
• The tumor shows numerous mitoses, clear endothelial proliferation and foci of necrosis; likewise it would formally meet the criteria for glioblastoma, WHO Grade 4. However, the patient has received radiation therapy and the necrosis seen isn ’ t typical (non-palisading, incomplete) of a glioblastoma. The extent to which the necrosis can be attributed to radiation vasculopathy is unclear but a reasonable possibility. Because of this it could still be classified as a Grade 3 lesion as it is in the oligodendroglial lineage.

Question 9
• What is the significance of the IDH1 mutation?

Answer
• Mutations of the isocitrate dehydrogenase enzyme isoform 1 (IDH1) have recently been identified in a high percentage of infiltrating glial neoplasms. Approximately 90% of all IDH1 mutations affect amino amino acid 132 (R132H).
Although the mutational analysis is not needed for the diagnosis of glioma in this case, it is a useful prognostic marker as patients who harbor the mutation have better clinical outcomes than those without. IDH1 is particularly useful in small biopsies of low cellularity which are difficult to interpret.

Question 10
• What is the prognosis of this patient?

Answer
• Anaplastic oligoastrocytoma has a median survival of 2.8 years and 5- and 10-year survival rates of 36% and 9%, respectively following resection and radiation only. The addition of chemotherapy increases the median survival to almost 50 months.

Question 11
• Two factors have shown to have independent prognostic implications – necrosis and 1p deletion
• Necrosis – Anaplastic oligoastroctyomas with necrosis are associated with worse outcomes than those without, leading some to classify any oligoastrocytoma with necrosis as “ glioblastoma with oligodendroglial component ”
• 1p deletion – Independently associated with increased progression-free and overall survival

References
• Louis D, Ohgaki H, Wiestler O, Cavanee W. WHO Classification of
Tumours of the Central Nervous System. IARC: Lyon 2007.
• Yan H, et al. IDH1 and IDH2 Mutations in Gliomas (2009). N Engl J
Med .360:765-773.
• Eoli M, et al. Reclassification of oligoastrocytomas by loss of heterozygosity studies (2006). Int J Cancer . 119:84-90.
• Miller C, Dunham C, Scheithauer B, Perry A. Significance of necrosis is grading of oligodendroglial neoplasms: A clinicopathologic and genetic study of 1093 newly-diagnosed high grade gliomas (2006). J Clin Oncol . 24:5419-5426.
• Mueller W, et al. Genetic signature of oligoastrocytomas correlates with tumor location and denotes distinct molecular subsets (2002).
Am J Pathol . 161:313-319.