Molecular analysis of anaplastic oligodendroglial tumors in a prospective randomized study: A report from EORTC study 26951

¹ Department of Neurology, Daniel den Hoed Cancer Center, Erasmus University Hospital, Rotterdam, the Netherlands
² European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium
³ Department of Pathology, Daniel den Hoed Cancer Center, Erasmus University Hospital, Rotterdam, the Netherlands
⁴ Department of Neurology–Mazarin, University Pitié-Salpêtrière Hospital, AP-HP, Paris, France
⁵ Medical Oncology Department Unit, Bellaria-Maggiore Hospital, Bologna, Italy
⁶ Department of Neuropathology, University Pitié-Salpétrière Hospital, AP-HP, Paris, France
⁷ Department of Pathology and Neurology, Leiden University Medical Center, Leiden, the Netherlands
⁸ Department of Pathology, Elisabeth Gasthuis, Tilburg, the Netherlands
⁹ Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
¹⁰ Department of Pathology, University Hospital Center, Nice, France
¹¹ Ludwig Boltzmann Institute for Neurooncology and Kaiser Franz Josef Hospital, Vienna, Austria
¹² National Institute of Neurosurgery, Budapest, Hungary
¹³ Department of Radiotherapy, University Central Hospital Vaudois (CHUV), Lausanne, Switzerland
¹⁴ Department of Neurology, Medical Center Haaglanden, the Hague, the Netherlands

^* To whom correspondence should be addressed. E-mail: m.vandenbent{at}erasmusmc.nl.

	Abstract

Background. Recent studies have shown that the clinical outcome of anaplastic oligodendroglial tumors is variable, but also that the histological diagnosis is subject to interobserver variation. We investigated if the assessment of 1p/19q co-deletion, polysomy of chromosome 7, EGFR gene amplification (EGFR^amp) and loss of chromosome 10 or 10q offers additional prognostic information to the histological diagnosis and would allow molecular subtyping. Methods. For this study the clinical data and tumors samples of the patients included in the multicenter prospective phase III EORTC 26951 trial on the effects of adjuvant procarbazine, CCNU and vincristine chemotherapy in anaplastic oligodendroglial tumors were used. Fluorescent In Situ Hybridization (FISH) was used to assess copy number aberrations of chromosome 1p, 19q, 7, 10 and 10q, and the EGFR gene. Three different analyses were done: on all included patients based on local pathology diagnosis, on the patients with confirmed anaplastic oligodendroglial tumors on central pathology review, and on this latter group but with after exclusion of anaplastic oligoastrocytoma (AOA) with necrosis. As a reference set for glioblastoma, patients from the prospective randomized phase III on glioblastoma (EORTC 26981) were used as a benchmark. Results. In 257 of 368 patients central pathology review confirmed the presence of an anaplastic oligodendroglial tumor. Tumors with combined 1p and 19q loss (1p^loss19q^loss) were histopathologically diagnosed as anaplastic oligodendroglioma (AOD), were more frequently located in the frontal lobe and had a better outcome. Anaplastic oligodendroglial tumors with EGFR^amp were more frequently AOA, were more often localized outside the frontal lobe and have a survival similar to glioblastoma. Survival of patients with AOA harboring necrosis was in a similar range as glioblastoma while patients with AOA with only endothelial proliferation had better overall survival. In univariate analysis all molecular factors except loss of 10q were of prognostic significance, however on multivariate analysis a histopathological diagnosis of AOA, necrosis and 1p^loss19q^loss remained independent prognostic factors. Conclusion. AOA with necrosis are to be considered WHO grade IV tumors (glioblastoma). Of all molecular markers analyzed in this study especially loss of 1p/19q carried prognostic significance, while the others contributed little prognostic value to classical histology.

Key Words: anaplastic oligodendroglioma, anaplastic oligoastrocytoma, prognosi, 1p, 19q, EGFR, monosomy 10, polysomy 7.

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