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Farewell to Oligoastrocytoma: in Situ Molecular Genetics Favor Classification As Either Oligodendroglioma Or Astrocytoma

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Farewell to Oligoastrocytoma: in Situ Molecular Genetics Favor Classification As Either Oligodendroglioma Or Astrocytoma Acta Neuropathol (2014) 128:551–559 DOI 10.1007/s00401-014-1326-7 ORIGinaL PAPER Farewell to oligoastrocytoma: in situ molecular genetics favor classification as either oligodendroglioma or astrocytoma Felix Sahm · David Reuss · Christian Koelsche · David Capper · Jens Schittenhelm · Stephanie Heim · David T. W. Jones · Stefan M. Pfister · Christel Herold‑Mende · Wolfgang Wick · Wolf Mueller · Christian Hartmann · Werner Paulus · Andreas von Deimling Received: 29 April 2014 / Revised: 23 July 2014 / Accepted: 23 July 2014 / Published online: 21 August 2014 © Springer-Verlag Berlin Heidelberg 2014 Abstract Astrocytoma and oligodendroglioma are histo- in different institutions employing histology, immunohisto- logically and genetically well-defined entities. The majority chemistry and in situ hybridization addressing surrogates of astrocytomas harbor concurrent TP53 and ATRX muta- for the molecular genetic markers IDH1R132H, TP53, tions, while most oligodendrogliomas carry the 1p/19q ATRX and 1p/19q loss. In all but one OA the combination co-deletion. Both entities share high frequencies of IDH of nuclear p53 accumulation and ATRX loss was mutually mutations. In contrast, oligoastrocytomas (OA) appear less exclusive with 1p/19q co-deletion. In 31/43 OA, only altera- clearly defined and, therefore, there is an ongoing debate tions typical for oligodendroglioma were observed, while in whether these tumors indeed constitute an entity or whether 11/43 OA, only indicators for mutations typical for astrocy- they represent a mixed bag containing both astrocytomas tomas were detected. A single case exhibited a distinct pat- and oligodendrogliomas. We investigated 43 OA diagnosed tern, nuclear expression of p53, ATRX loss, IDH1 mutation and partial 1p/19q loss. However, this was the only patient undergoing radiotherapy prior to surgery, possibly contrib- Electronic supplementary material The online version of this article (doi:10.1007/s00401-014-1326-7) contains supplementary uting to the acquisition of this uncommon combination. In material, which is available to authorized users. F. Sahm · D. Reuss · C. Koelsche · D. Capper · S. M. Pfister A. von Deimling (*) Department of Pediatric Oncology, Haematology Department of Neuropathology, Institute of Pathology, Ruprecht- and Immunology, Heidelberg University Hospital, Im Karls-University Heidelberg, INF 224, 69120 Heidelberg, Neuenheimer Feld 224, 69120 Heidelberg, Germany Germany e-mail: [email protected] C. Herold-Mende Department of Neurosurgery, University Hospital Heidelberg, F. Sahm · D. Reuss · C. Koelsche · D. Capper · A. von Deimling INF 400, 69120 Heidelberg, Germany Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), W. Wick Im Neuenheimer Feld 224, 69120 Heidelberg, Germany Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), J. Schittenhelm Heidelberg, Germany Department of Neuropathology, Institute of Pathology and Neuropathology, University Tübingen, Calwerstraße 3, W. Wick 72076 Tübingen, Germany Department of Neurooncology at the National Center for Tumor Diseases, Heidelberg University Hospital, INF 400, S. Heim · W. Paulus 69120 Heidelberg, Germany Institute of Neuropathology, University Hospital Münster, Pottkamp 2, 48149 Münster, Germany W. Mueller Department of Neuropathology, University Hospital Leipzig, D. T. W. Jones · S. M. Pfister Liebigstr. 24, 04103 Leipzig, Germany Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany 1 3 552 Acta Neuropathol (2014) 128:551–559 OA with oligodendroglioma typical alterations, the portions separated. Intriguingly, the author already considered corresponding to astrocytic part were determined as reac- whether the astrocytic component might be purely reac- tive, while in OA with astrocytoma typical alterations the tive. In 1974, Hart and colleagues expanded on this study portions corresponding to oligodendroglial differentiation in their work “Mixed Gliomas” [15], coining the different were neoplastic. These data provide strong evidence against distributions of cell compartments as of the diffuse and of the existence of an independent OA entity. the compact type. Cooper’s consideration that astrocytic portions could also be reactive has later on been expanded Keywords Mixed glioma · Oligoastrocytoma · 1p/19q · in the classification system by Daumas–Duport, culminat- ATRX · TP53 · IDH1 ing in the hypothesis that all diffuse gliomas represent oli- godendrogliomas with reactive astrocytosis [12]. Molecular genetic analyses early on casted doubt on Introduction the entity of OA. Analyses of small series of OA detected 1p/19q losses in neither or both astrocytic and oligoden- According to the World Health Organization (WHO) clas- droglial portions. Further, OA without 1p/19q loss fre- sification of central nervous system tumors diffuse astro- quently harbored TP53 mutations again in both tumor cytomas of grades II and III share infiltrative growth with portions [27]. Another study addressing 1p/19q status and astrocytic differentiation and the most frequent molecu- other molecular aberrations by in situ hybridization sup- lar alteration in these tumors is TP53 mutation which is ported the finding that the majority of cells in mixed glio- observed in 60–70 % [25]. More recent findings include mas homogenously share aberrations and concluded that mutations in the isocitrate-dehydrogenases 1 and 2 polyclonal origin is rather unlikely. However, the authors (IDH1;IDH2) as well as in the alpha-thalassemia/mental state that this does not abrogate the possibility that the cells retardation syndrome X-linked gene (ATRX) in the majority might cytologically differentiate along either astrocytic or of the cases [1, 16, 18, 19, 29, 35, 46]. Oligodendrogliomas oligodendroglial lineage [14]. of grades II and III share a typical morphological fried egg Moreover, emergent clinical data contribute to the debate pattern and combined losses of chromosomal arms 1p and on the existence of OA: recent results from clinical studies 19q. Likewise, recent studies reported a high frequency of demonstrated the overwhelming importance of 1p/19q loss IDH1 and IDH2 mutations of about 80–88 % also in oligo- for therapy prediction and prognosis which was independent dendroglioma [16, 46]. The WHO classification also recog- of the histological diagnoses of OA and oligodendroglioma nizes the tumor entity oligoastrocytoma (OA) also termed [5, 39, 41]. These findings obviously reduce the relevance mixed gliomas of grades II and III. However, this tumor for the morphological distinction of the entity OA. entity is poorly defined merely by the presence of both Recent developments in neuropathology now provide tumor cells with astrocytic and oligodendroglial differentia- tools to resolve this discrepancy. The major genetic hall- tion. No guidelines are given regarding the minimal percent- marks for oligodendroglioma and astrocytoma can nowa- ages of either part required for the diagnosis of OA. This is days be identified in tissue sections on the single-cell level. good practice in light of modern surgical procedures apply- This includes H09 staining demonstrating the IDH1R132H ing aspiration and coagulation, thus resulting in submission mutation [8, 9], p53 upregulation associated with TP53 of only a minor tumor fraction for neuropathological exami- mutation [24, 26, 33], loss of ATRX expression indicating nation. Further aggravation to the diagnostician derives ATRX mutation [23] and in situ hybridization for 1p/19q from the diversion of material to biobanks. In consequence, providing information on chromosome copy numbers. the pathologist is left clueless on the representative nature of To systematically address the question toward the exist- the material finally submitted. Therefore, it is not surprising ence of OA molecularly distinct from both, oligodendro- to see the diagnosis of OA made with extraordinary varying glioma or astrocytoma, we collected a series of 43 tumors frequencies in different institutions [10, 14, 30]. diagnosed at different institutions and assessed the hall- Originally, the term OA was coined in 1935 by Eugenia mark genetic aberrations in tissue section in the context Cooper in the seminal work “The relation of oligocytes with morphology. and astrocytes in cerebral tumors” [11]. The analysis describes for the first time mixed gliomas with astrocytic and oligodendroglial cells either intermingled or regionally Materials and methods Tissue C. Hartmann Department for Neuropathology, Institute of Pathology, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625, Formalin-fixed paraffin-embedded tissue of 43 oligoastro- Hannover, Germany cytomas diagnosed between 1989 and 2013 was obtained 1 3 Acta Neuropathol (2014) 128:551–559 553 from the Departments and Institutes of Neuropathology 482,421 CpG sites (Illumina, San Diego, USA) according Muenster (12 cases), Tuebingen (11 cases) and Heidel- to the manufacturer’s instructions at the Core Facility of the berg (20 cases) in accordance with local ethical approval. DKFZ. The array data were used to calculate a low-resolu- All cases were centrally reviewed at the Dept. of Neuro- tion copy number profile as previously described [37]. pathology Heidelberg. For inclusion the cases had to meet two criteria: presence of IDH1R132H mutation allowing Sequencing for the unequivocal identification
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