Molecular Profile of Tumours with an Oligodendroglial Morphology: Clinical Relevance

Abstract

AIM OF THE STUDY: Characterization of the molecular profile of oligodendroglial tumors with relation to 1p/19q status and IDH mutation. OBJECTIVES: 1. To determine the frequency of IDH1 and IDH2 mutations by polymerase chain reaction (PCR) sequencing and IDH1 mutations by immunohistochemistry among 50 cases of oligodendroglial tumours. 2. To calculate the performance indicators of IDH1 immunohistochemistry as a diagnostic marker. 3. To correlate 1p/19q status and IDH1/2 mutations with clinico-pathological variables and measures of outcome. METHODS: 50 oligodendroglial tumours diagnosed from January 2009 to January 2012 were included in the study. These included, 11 WHO grade II Oligodendroglioma, 15 WHO grade III Oliodendroglioma, 7 WHO grade II Oligoastrocytoma, 10 WHO grade III Oligoastrocytoma and 7 Glioblastoma with an oligodendroglial component. 1p/19q status was determined for all cases by Fluorescence in situ hybridization (FISH). Immunohistochemistry was performed for IDH1 mutations. Molecular analysis for IDH1 and IDH2 mutations was done by PCR. Association between combined 1p/19q deletion, polysomy of chromosome 1/19 and IDH mutation with the various clinical, radiological and histopathological parameters was calculated using Pearson’s Chi square test/Fishers exact test. Sensitivity and specificity of IDH1 immunohistochemistry was calculated taking PCR as the gold standard. Odds ratio and risk ratio was calculated for individual risk factors. Logistic regression model was used for multivariate analysis. A p value of ≤ 0.05 was considered significant. RESULTS: 1p/19q co-deletion and polysomy of chromosome 1/19 was seen in 46% (23/50) and 36% (18/50) of the cases respectively. 1p/19q co-deletion was significantly associated with pure oligodendroglial tumours (p = 0.0001), frontal lobe location and classical histology. Polysomy 1/19 was associated with mixed oligoastrocytic tumours (p=<0.00001). IDH1 and IDH2 mutations were seen in 86% and 6% of the cases respectively. The most common type of IDH1 mutation was of IDH1R132H (42 cases) type, followed by IDH1R132C (1 case). All 3 IDH2 mutations were of the IDH2R172H type.IDH1 immunohistochemistry was positive in 42 (84%) cases with IDH1R132H mutation and negative in the remaining cases. The sensitivity and specificity of IDH1 immunohistochemistry was 91.3% and 100% respectively. 23 of the 46 cases with IDH mutation showed 1p/19q co-deletion and all 4 cases negative for IDH mutation were also negative for 1p/19q co-deletion. On univariate analysis, necrosis, WHO grade and IDH mutation were found to have increased risk of recurrence and death. On multivariate analysis, utilizing the following variables, WHO grade (Grade IV vs. Grade II and III combined), classic histology, 1p/19q co-deletion and 1/19 polysomy, only WHO grade was found to be significantly associated with a poor PFS (p = 0.022). CONCLUSION: IDH1/2 mutations were seen with a high frequency in this cohort of oligodendroglial neoplasms. IDH1 immunohistochemistry is a sensitive and specific marker for determining mutational status. There is a role for PCR for detecting IDH mutations in cases that are immunonegative for IDH1