Diagnostic implications of IDH1-R132H and OLIG2 expression patterns in rare and challenging glioblastoma variants

Modern Pathology (2013) 26, 315–326 & 2013 USCAP, Inc. All rights reserved 0893-3952/13 $32.00 Diagnostic implications of IDH1-R132H and OLIG2 expression patterns in rare and challenging glioblastoma variants Nancy M Joseph1, Joanna Phillips1,2, Sonika Dahiya3, Michelle M Felicella1, Tarik Tihan1, Daniel J Brat4 and Arie Perry1,2 1Department of Pathology, University of California San Francisco (UCSF), San Francisco, CA, USA; 2Department of Neurological Surgery, University of California San Francisco (UCSF), San Francisco, CA, USA; 3Department of Pathology and Immunology, Division of Neuropathology, Washington University School of Medicine, St Louis, MO, USA and 4Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA Recent work has demonstrated that nearly all diffuse gliomas display nuclear immunoreactivity for the bHLH transcription factor OLIG2, and the R132H mutant isocitrate dehydrogenase 1 (IDH1) protein is expressed in the majority of diffuse gliomas other than primary glioblastoma. However, these antibodies have not been widely applied to rarer glioblastoma variants, which can be diagnostically challenging when the astrocytic features are subtle. We therefore surveyed the expression patterns of OLIG2 and IDH1 in 167 non-conventional glioblastomas, including 45 small cell glioblastomas, 45 gliosarcomas, 34 glioblastomas with primitive neuroectodermal tumor-like foci (PNET-like foci), 23 with an oligodendroglial component, 11 granular cell glioblastomas, and 9 giant cell glioblastomas. OLIG2 was strongly expressed in all glioblastomas with oligodendroglial component, 98% of small cell glioblastomas, and all granular cell glioblastomas, the latter being particularly helpful in ruling out macrophage-rich lesions. In 74% of glioblastomas with PNET-like foci, OLIG2 expression was retained in the PNET-like foci, providing a useful distinction from central nervous system PNETs. The glial component of gliosarcomas was OLIG2 positive in 93% of cases, but only 14% retained focal expression in the sarcomatous component; as such this marker would not reliably distinguish these from pure sarcoma in most cases. OLIG2 was expressed in 67% of giant cell glioblastomas. IDH1 was expressed in 55% of glioblastomas with oligodendroglial component, 15% of glioblastomas with PNET-like foci, 7% of gliosarcomas, and none of the small cell, granular cell, or giant cell glioblastomas. This provides further support for the notion that most glioblastomas with oligodendroglial component are secondary, while small cell glioblastomas, granular cell glioblastomas, and giant cell glioblastomas are primary variants. Therefore, in one of the most challenging differential diagnoses, IDH1 positivity could provide strong support for glioblastoma with oligodendroglial component, while essentially excluding small cell glioblastoma. Modern Pathology (2013) 26, 315–326; doi:10.1038/modpathol.2012.173; published online 5 October 2012 Keywords: glioblastoma; IDH1; OLIG2 In 2008, whole genome analysis of human glioblastomas led to the discovery of recurrent mutations in the active site of isocitrate dehydrogenase 1 (IDH1) in secondary (those progressing from lower grade gliomas) rather than in primary glioblastomas.1 This discovery was subsequently validated and expanded in larger series of human gliomas, Correspondence: Dr A Perry, MD, Department of Pathology, UCSF, 505 Parnassus Avenue, #M551, Box #0102, San Francisco, CA 94143, USA. E-mail: Received 30 April 2012; revised 27 June 2012; accepted 29 June 2012; published online 5 October 2012 www.modernpathology.org establishing that roughly 80% of all WHO grade II– III infiltrating/diffuse gliomas (astrocytomas, oligodendrogliomas, and oligoastrocytomas) and secondary glioblastomas show mutations in IDH1 and to a lesser extent, IDH2;2–4 these mutations correlate with enhanced patient survival, and by far the most common alteration is the R132H mutation in IDH1.5,6 Immunohistochemistry (IHC) for expression of R132H IDH1 mutant protein7 is increasingly performed in the routine pathologic evaluation of glioblastoma and lower grade diffuse gliomas because of its prognostic significance. In glioblastomas, immunoreactivity for IDH1 mutant protein suggests that the tumor is secondary, even 315 IDH1 and OLIG2 expression in glioblastoma variants 316 NM Joseph et al without the appropriate history of a preceding lower grade glial neoplasm.6,8 In support of this notion, such patients tend to be younger and enjoy similarly prolonged survival times as those of more classically defined secondary glioblastomas. IDH1 mutant protein expression has also proven to be diagnostically useful in the distinction of entrapped dysmorphic cortical neurons in low-grade infiltrative gliomas from gangliogliomas, the majority of which do not show IDH1 mutations.9 Similarly, IDH1 is useful in the distinction of diffuse low-grade gliomas from reactive astrocytosis.10,11 Lastly, immunopositivity may be useful in distinguishing diagnostically challenging diffuse gliomas from other tumor types, given that other primary central nervous system (CNS) tumors and metastatic malignancies are typically negative.2,12–15 The only other tumor type currently known to have a significant rate of IDH1 mutations is acute myelogenous leukemia.16,17 Although the frequency of IDH1 mutation is well established in the most common forms of WHO grade II–IV gliomas, IDH1 mutant protein expression has not been widely examined in rare glioblastoma variants. A few limited studies have recently suggested that such mutations may be higher in some of the rare variants compared with conventional glioblastomas. For example, a recent case report of granular cell glioblastoma demonstrated R132H IDH1 mutation,18 another study found it in 2 of 8 glioblastomas with PNET-like foci,19 and another study found it in 31% of glioblastomas with an oligodenodroglial component.20 R132H IDH1 mutation was recently reported in gliosarcomas at a similar rate to glioblastomas, with 2 out of 26 (7.7%) cases being positive.21 However, larger series are still needed to confirm these results and to additionally screen other challenging subtypes, such as small cell glioblastoma and giant cell glioblastoma. Another potentially useful immunostain in the diagnostic workup of gliomas is OLIG2. Recent work has shown that although this oligodendroglial lineage marker, a bHLH transcription factor, is restricted to oligodendroglia and their progenitors in normal human brain, it is nearly universally expressed in diffuse human gliomas.22 Thus, OLIG2 is not useful in the distinction of astrocytomas from oligodendrogliomas as was originally hoped, but can potentially help distinguish gliomas from other high-grade CNS and non-CNS malignancies, including sarcomas and primitive neuroectodermal tumors (PNET).22 Additionally, OLIG2 is a particularly useful diagnostic marker for infiltrative tumors, such as gliomas becau (...truncated)