Oligodendroglioma: Pathology, Molecular Mechanisms and Markers
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Acta Neuropathol (2015) 129:809–827 DOI 10.1007/s00401-015-1424-1 REVIEW Oligodendroglioma: pathology, molecular mechanisms and markers Pieter Wesseling1,2 · Martin van den Bent3 · Arie Perry4 Received: 12 March 2015 / Revised: 8 April 2015 / Accepted: 10 April 2015 / Published online: 6 May 2015 © The Author(s) 2015. This article is published with open access at Springerlink.com Abstract For nearly a century, the diagnosis and grad- for grading of ‘canonical oligodendrogliomas’ should be ing of oligodendrogliomas and oligoastrocytomas has been adapted, how pediatric oligodendrogliomas (known to lack based on histopathology alone. Roughly 20 years ago, the codeletions) should be defined, which platforms and cut-off first glioma-associated molecular signature was found with levels should ideally be used for demonstration of particu- complete chromosome 1p and 19q codeletion being particu- lar molecular aberrations, and how the diagnosis of oligo- larly common in histologically classic oligodendrogliomas. dendroglioma should be made in centers/countries where Subsequently, this codeletion appeared to not only carry molecular diagnostics is not available. Meanwhile, smart diagnostic, but also prognostic and predictive information, integration of morphological and molecular information the latter aspect only recently resolved after carefully con- will lead to recognition of biologically much more uniform structed clinical trials with very long follow-up times. More groups within the spectrum of diffuse gliomas and thereby recently described biomarkers, including the non-balanced facilitate tailored treatments for individual patients. translocation leading to 1p/19q codeletion, promoter hyper- methylation of the MGMT gene, mutations of the IDH1 or Keywords Oligodendroglioma · Mixed glioma · IDH2 gene, and mutations of FUBP1 (on 1p) or CIC (on Glioblastoma · Histopathology · 1p/19q loss · 19q), have greatly enhanced our understanding of oligo- Molecular marker dendroglioma biology, although their diagnostic, prognos- tic, and predictive roles are less clear. It has therefore been suggested that complete 1p/19q codeletion be required for Introduction the diagnosis of ‘canonical oligodendroglioma’. This tran- sition to an integrated morphological and molecular diag- For over a century, classification of neoplasms has been nosis may result in the disappearance of oligoastrocytoma based on their microscopic characteristics and the histo- as an entity, but brings new challenges as well. For instance pathological diagnosis has provided the cornerstone for it needs to be sorted out how (histopathological) criteria therapeutic decision-making. The ‘taxonomy’ of tumors of the central nervous system (CNS) in the most recent, i.e., 2007 World Health Organization (WHO) classification of * Pieter Wesseling these neoplasms is still largely based on their histopatho- [email protected] logical features as well [73]. Diffuse gliomas are by far the 1 Department of Pathology, VU University Medical Center, most frequent neoplasms originating from the CNS paren- De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands chyma itself. The common denominator of this heterogene- 2 Department of Pathology, Radboud University Medical ous group of neoplasms is extensive, infiltrative growth of Center, Nijmegen, The Netherlands individual tumor cells and/or groups of these cells (‘diffuse 3 Department of Neuro‑Oncology, Erasmus MC Cancer growth’) into the neuropil, i.e., the dense network of neu- Center, Rotterdam, The Netherlands ronal and glial processes of the CNS parenchyma [23]. 4 Department of Pathology and Neurological Surgery, Over 75 % of the diffuse gliomas in adult patients are University of California, San Francisco, CA, USA astrocytic, about two-thirds of these being represented by 1 3 810 Acta Neuropathol (2015) 129:809–827 the most malignant form, glioblastoma. Oligodendroglio- aspect of the microvessel walls), and necrosis [73]. Une- mas and oligoastrocytomas have been generally grouped quivocal histological typing and grading of diffuse gliomas together as oligodendroglial tumors and account for less is challenging however, especially because the biological than 10 % of the diffuse gliomas (Fig. 1). Of note, in chil- diversity of these tumors is difficult to capture in precise dren, glioma variants with a more circumscribed growth microscopic criteria. Also, the samples provided for histo- pattern are more frequent than diffuse gliomas, and oli- pathological analysis are not always (fully) representative. godendroglial tumors are rare (<4 % of the primary CNS This results in a high rate of interobserver variation in the tumors) [85]. According to the WHO 2007 classification, diagnosis of diffuse gliomas, including oligodendroglial after typing a diffuse glioma as astrocytic, oligodendro- tumors [36, 65, 117]. glial, or mixed, these neoplasms are graded as WHO grade For the past 20 years, the knowledge on the genetic/ II/low grade, WHO grade III/anaplastic or WHO grade IV/ molecular underpinnings of gliomagenesis is rapidly glioblastoma (WHO grade I being reserved for more cir- expanding. It is now fully clear that certain molecular cumscribed gliomas, such as pilocytic astrocytoma). Micro- aberrations carry important diagnostic, prognostic and/or scopic features used for grading are the presence/absence predictive information because they provide clinically rel- of marked mitotic activity, florid microvascular prolifera- evant information on tumor type, biological behavior, and/ tion (MVP, i.e., marked hypertrophy and hyperplasia of or expected response to a particular treatment regimen, endothelial cells and pericytes resulting in a multilayered respectively. It is therefore to be expected that (like, e.g., Fig. 1 Relative frequency of a anaplastic astrocytoma histopathologically diagnosed 6.1% oligodendroglial and oligoas- diffuse astrocytoma trocytic tumors in the spectrum 9.0% of glial tumors of the CNS: a oligoastrocytic tumors in 95,564 patients of all age 3.3% groups; b in 10,274 children and adolescents (0–19 years). oligodendrogliomas Information extracted from 5.9% CBTRUS statistical report: glioblastoma 55.2% NPCR and SEER, 2007–2011 [85] ependymal tumors 6.8% pilocytic astrocytoma 5.9% ‘unique astrocytoma variants’ 1.0% malignant glioma, NOS 7.4% b glioblastoma 6.3% anaplastic astrocytoma 3.6% diffuse astrocytoma 11.1% oligoastrocytic tumors 1.4% malignant glioma, oligodendrogliomas 2.5% NOS 25.7% ependymal tumors 11.4% ‘unique astrocytoma variants’ pilocytic astrocytoma 4.2% 33.8% 1 3 Acta Neuropathol (2015) 129:809–827 811 sarcomas and hematological malignancies) classification longer, but sooner or later such tumors generally progress of CNS tumors will increasingly be based on the presence to a high-grade malignant glioma as well. Given the often of particular molecular aberrations, and oligodendroglial young age at presentation, however, this patient category tumors are amongst the first in line for such a change. still substantially contributes to the high average number of In this review, we reconstruct the transition from a ‘years of life lost’ for patients suffering from a CNS tumor purely morphological to an integrated morphological and [17]. Rarely, extracranial metastases of oligodendroglial molecular scheme for classification of the heterogeneous tumors occur (for recent reviews, see [71, 78]). Only a tiny group of oligodendroglial tumors. After summarizing clini- fraction of oligodendroglial tumors is thought to be due to cal, radiological and histopathological aspects of these neo- single-gene hereditary syndromes such as biallelic Lynch plasms (‘Setting the stage’), the molecular underpinnings syndrome [37, 42]. of oligodendroglial tumors and the diagnostic, prognostic As originally described by Bailey and Bucy [7], nuclear and/or predictive value of these aberrations will be dis- features are key for microscopic recognition of an oligo- cussed (‘Molecular mechanisms and markers’). In the last dendroglial phenotype, although some architectural growth part of this article (‘WHO’s next?’), we elaborate on how patterns also provide useful clues (Fig. 2). In low-grade oli- these markers can be used to reclassify oligodendroglial godendrogliomas, the nuclei are generally round and uni- tumors more objectively, but with some challenges and form with crisp nuclear membranes, delicate chromatin and unanswered questions remaining. For a review on similar small-to-inconspicuous nucleoli. In anaplastic examples, aspects concerning diffuse astrocytomas, glioblastomas, cells are frequently enlarged and epithelioid with nuclei and pilocytic astrocytomas the reader is referred to com- that often show increased size and pleomorphism, a more panion articles in the present cluster. vesicular chromatin pattern and more prominent nucleoli, but the tumor still maintains an overall sense of regularity and nuclear roundness [80, 81]. The clear, perinuclear halo Setting the stage that often is seen in oligodendroglial tumor cells is in fact an artifact of formalin fixation, which is typically absent in Gliomas originate from neural stem cells or glial progeni- frozen sections and rapidly fixed specimens. The combina- tor cells that develop or maintain glial characteristics [136]. tion of the round nuclei and perinuclear haloes results in According to the WHO 2007 classification, based on the a fried-egg appearance of individual cells and in a honey- resemblance of the tumor cells with non-neoplastic glial comb architectural pattern of