American Association of Neuropathologists, Inc. Abstracts of the 88th Annual Meeting June 21–24, 2012 Chicago, IL
Journal of Neuropathology and Experimental Neurology
High-grade astrocytomas (HGAs) corresponding to WHO grades III (AA) and IV (GBM), are highly aggressive and therapeutically challenging. Recently, studies have associated PDGFRA gains/amplifications with: 1) the proneural subtype in adult GBMs, 2) poor prognosis in IDH1 wild-type adult primary GBMs, 3) childhood onset, especially in the brainstem, and 4) potential pharmacological inhibition for therapy. The simplest and most sensitive technique for detecting copy number gains in routinely
... sed pathology specimens is FISH, although interpretive guidelines are currently lacking. We therefore studied 184 adult (101 AA, 83 GBM) and 90 pediatric (42 AA, 48 GBM) HGAs, pairing a home brew PDGFRA probe with a commercial centromere 4 reference probe. A wide range of FISH patterns were identified and cases were scored as: normal (40% adult, 38% pediatric), polysomy (910% cells with 92 signals; 38% adult, 26% pediatric), low-level amplification (innumerable signals in G10% of cells or 940% cells with 96 signals; 12% adult, 18% pediatric), and high-level amplification ABSTRACTS 547 (910% cells with innumerable signals; 11% adult, 19% pediatric), the latter two groups considered as BFISH positive[. FISH positivity was more common in pediatric (37%) than adult (23%) HGAs (p=0.0157). There were no statistically significant associations between positive cases and grade, gender, location, or institution. Our data suggests that FISH reliably detects PDGFRA gains in formalin-fixed paraffin-embedded samples. In contrast to EGFR FISH in adult HGAs where widespread high-level amplification is the rule, focal or low-level PDGFRA amplifications are common. As such, this alteration is probably more prevalent than previously reported with dose averaging techniques, such as PCR and array CGH. To our knowledge, this study represents the largest survey of PDGFRA status in adult and pediatric HGAs, with gene amplifications being relatively common, especially in pediatric cases. Clinical follow-up is currently being obtained and prognostic associations will be explored. Introduction: Glioblastoma with oligodendroglial component (GBMO) has been recognised in the WHO classification, however the diagnostic criteria, molecular biology and the clinical outcome of primary GBMO remains unclear. Aims: To investigate whether primary GBMO is a distinct clinicopathological subgroup of GBM and to determine the relative frequency of prognostic markers such as loss of heterozygosity (LOH) on 1p and/or 19q, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and isocitrate dehydrogenase 1 (IDH1) mutation. Methods: We examined 288 cases of primary GBM and assessed the molecular markers in 57 GBMO and 50 cases of other primary GBM, correlating the data with clinical parameters and outcome. Results: GBMO comprised 21.5% of GBM and show significantly longer survival compared to the other GBM (12 months vs. 5.8 months, p = 0.006); there was also a strong correlation with younger age at diagnosis (56.4 yrs vs. 60.6 yrs, p = 0.005). Singular LOH of 19q (P= 0.04) to confers 1.9 fold increased hazard of shorter survival. There was no difference in the frequencies of 1p or 19q deletion, MGMT promoter methylation, or IDH1 mutation (p = 0.8, p = 1, p = 1, respectively). Conclusions: Primary GBMO is a subgroup of GBM associated with longer survival and a younger age group but shows no difference in the frequency of LOH of 1p/19q, MGMT and IDH1 mutation compared with other primary GBM and is different from oligoastrocytoma with necrosis.