Original article
Is the 1p/19q deletion a diagnostic marker of oligodendrogliomas?

https://doi.org/10.1016/j.cancergencyto.2009.05.004Get rights and content

Abstract

The diagnosis and classification of diffusely infiltrative gliomas are based on their histopathological appearance; however, histopathological delineation of diffuse gliomas can be difficult because of vague and subjective histopathological criteria. Combined loss of chromosome arms 1p and 19q (denoted as 1p−/19q−) has proven to be a powerful predictor of chemotherapeutic response and survival in oligodendrogliomas. We undertook retrospective and prospective studies of brain tumor patients originally diagnosed as oligodendrogliomas or oligoastrocytomas patients followed at our institution using molecular genetic techniques. Fluorescence in situ hybridization using probes specific for chromosomes 1 and 19 was performed on 22 paraffin-embedded tissues retrospectively; 15 touch-preparation smear samples were studied prospectively; and loss of heterozygosity (LOH) screening was performed on 11 samples with microsatellite markers specific to chromosome 1 and chromosome 19. Of the 37 cases, 24 had 1p−/19q−, 1 case had 1p− only, 2 cases had 19q− only, and 10 cases had no deletion. The length of the largest deletion was mapped between markers D1S2795 (1p36.31 locus) and D1S2722 (1p34.2 locus) and between markers D19S416 (19q13.11 locus) and D19S397 (19q13.14 locus), using LOH. All of the pure oligodendrogliomas (n = 7) harbored 1p−/19q−. In light of previous findings, the 1p−/19q− combination appears to be an objective diagnosis marker of classic oligodendrogliomas, one that can be used, in combination with histological examination, to improve the diagnosis of oligodendroglioma. Fluorescence in situ hybridization on touch preparations is a simple way to obtain information on 1p−/19q− in 24 hours.

Introduction

Low-grade oligodendrogliomas constitute ∼2.5% of all primary brain tumors, and their malignant counterpart accounts for 1.2% [1], [2], [3], although more recent studies have reported a much higher incidence (25–33% of all primary brain tumors) based on expanded diagnostic criteria. Histopathological assessment of oligodendroglial tumors remains the gold standard in everyday practice [4]. The triad of uniformly round nuclei, perinuclear haloes, and an even cellular distribution together with a delicate vascular web (the so-called chicken-wire appearance) in a context of infiltration of adjacent brain parenchyma represents the classical criteria for a histopathological diagnosis of oligodendroglioma [1]. In a significant number of these lesions, however, the microscopic morphology is not so clear-cut, and the distinction from other glial lesions may be difficult [5].

The issue is further complicated when histopathological distinction has to be made between oligoastrocytomas and either oligodendrogliomas or astrocytomas, a distinction of clinical importance in terms of prognostic and therapeutic implications. Identification of characteristics inherent to the tumor type is further complicated by regional tumor heterogeneity and sampling error. One consequence of this subjectivity in diagnostic criteria is a high level of intraobserver and interobserver variability, which decreases reproducibility [6], [7], [8], [9]. It is for these reasons that a search for an objective diagnostic tool for the oligodendroglial tumors has been a long one. In 1998, Cairncross et al. [10] identified the combined loss of the short arm chromosome 1 (1p−) and the long arm of chromosome 19 (19q−) as predictive of chemotherapy response and longer survival, in a retrospective study on oligodendroglial tumors. The finding was later confirmed in prospective studies, and this genetic alteration, commonly denoted as 1p−/19q−, has now been reported in up to 85% of oligodendrogliomas and 50% of oligoastrocytomas [11], [12], [13], [14], [15], [16].

Although the combined 1p−/19q− is associated with the oligodendroglial phenotype, these alterations are occasionally encountered in other glioma subtypes, both individually and in combination [17]. Presence of regions of classic histology of oligodendroglioma in a tumor sample is predictive of 1p−/19q− [18], [19]. Nonetheless, oligodendrogliomas do sometimes lack the deletion, and in these cases patient survival is shorter [9], [17], which casts doubt on their true oligodendroglial nature. To date, the 1p−/19q− combination has not been described in hyperplastic, inflammatory, or reactive lesions, and not in neurocytomas, clear-cell ependymomas, dysembryoplastic neuroepithelial tumors (DNETs), and clear-cell meningiomas.

Among available genetic tools, fluorescence in situ hybridization (FISH) and loss of heterozygosity (LOH) techniques are the most widely used for identifying 1p−/19q−. The deletions have been mapped to different areas of chromosome arms 1p and 19q or have involved the whole arm [14]. In most cases, FISH was performed using commercial or bacterial artificial chromosome probes containing the region or gene of interest on paraffin-embedded tissues, and only nonoverlapping nuclei were scored in the great majority of published papers [9], [20], [21], [22], [23], [24], [25]. However, there may be very few nonoverlapping nuclei with tissue sections, depending of the thickness of the section and the focal plane of the hybridization signals, which leads to difficulties of interpretation and could explain nondetection of the deletion in some morphologically typical oligodendroglial tumors. In addition, choosing the right probes to detect all the microdeletions is a hard task. It is also a matter of fact that clear cutoff values for a tumor interpreted as positive for the deletion remain to be defined [19]. Furthermore, adding to the difficulties, a tissue section sometimes has a mixture of normal and tumor cells.

Some authors have suggested that this molecular and chromosomal signature, the combined 1p−/19q−, represents a diagnostic hallmark of oligodendrogliomas, rather than being a marker only of therapeutic sensitivity [6], [7]. Because the proportion of oligodendroglial tumors that express the deletion corresponds to the typical chemosensitive tumor described by Cairncross and Macdonald [26] in 1988, we wondered whether the deletion might not be a better diagnostic criterion than the traditional morphological analysis. Accordingly, we hypothesized that this molecular signature might be a more significant prognostic and diagnostic factor than morphological characterization. This is exemplified by archetypical gene fusions such as BCR–ABL (the Philadelphia chromosome, which is pathognomonic for chronic myeloid leukemia and is also present in a subset of acute lymphocytic leukemia [27]) and PML–RARA (which is pathognomonic for acute promyelocytic leukemia). We therefore retrospectively and prospectively studied brain tumor patients originally diagnosed as oligodendrogliomas or oligoastrocytomas patients followed at our institution using cytogenetic and molecular genetic techniques, and we propose a simple approach to including 1p−/19q− as an assay suitable for routine oligodendroglial diagnosis.

Section snippets

Patients and samples

Patients undergoing or having undergone surgery for an initially diagnosed oligodendroglial or oligoastrocytomal brain tumor at the Sherbrooke University hospital (CHUS) were enrolled in this study after consent approval by the human ethical committee Board. The patient population was composed of 37 individuals: 13 men (35.1%) and 24 women (64.9%) ranging in age from 18 to 77 years (median, 40.9 years).

A total of 23 paraffin-embedded oligodendroglial tumors were collected retrospectively from

Pathological diagnosis

Data were collected on a total of 37 patients operated, from 1993 to 2007. All of these 37 patients were initially diagnosed with an oligodendroglial tumor. Specifically, 7 oligodendrogliomas, 15 anaplastic oligodendrogliomas, 7 oligoastrocytomas, and 8 anaplastic oligoastrocytomas were classified based on traditional morphological analysis; upon review for this study, however, 5 of the 7 oligoastrocytoma cases were reclassified as malignant astrocytic tumors (Table 1, Table 2).

The final

Discussion

In everyday practice, the diagnosis and the classification of diffusely infiltrative gliomas is based on histopathological appearance, which is considered the gold standard for management decisions and prognostication [4], [29]. The histopathological delineation of diffuse gliomas can be difficult, however, because of vague and subjective criteria. In a study on diagnostic concordance among four neuropathologists reviewing gliomas, the interobserver agreement peaked at 69%; the inclusion of

Conclusions

Although histological evaluation should remain the chief support of brain tumor classification, the growing list of options for cytogenetic analysis has improved the understanding of chromosomal changes in disease initiation, progression, and response to treatment. Based on both FISH and LOH findings, the present study suggests that the 1p−/19q− codeletion in pure oligodendroglial tumors can be considered as a diagnostic, rather than a prognostic marker. The touch preparation technique

Acknowledgments

The authors are grateful to Dr. Joe T.R. Clarke for careful review of the manuscript and important comments, to Mrs. Sylvie Breton and Marie Boudrias for their excellent technical help, and to Mrs. Marie-Pierre Garrant and Nathalie Carrier for their help with the statistical analyses. This study was supported in part by grant from the Canada Research Chairs Program to R.D. Public Health Minister (MSP) and the National Center of Blood Transfusion (CNTS) of Senegal to M.G. M.G. holds a

References (50)

  • L.B. Rorke

    Pathologic diagnosis as the gold standard

    Cancer

    (1997)
  • P.C. Burger

    What is an oligodendroglioma?

    Brain Pathol

    (2002)
  • S.H. Bigner et al.

    Morphologic and molecular genetic aspects of oligodendroglial neoplasms

    Neuro Oncol

    (1999)
  • C. Giannini et al.

    Anaplastic oligodendroglial tumors: refining the correlation among histopathology, 1p 19q deletion and clinical outcome in Intergroup Radiation Therapy Oncology Group Trial 9402

    Brain Pathol

    (2008)
  • J.G. Cairncross et al.

    Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas

    J Natl Cancer Inst

    (1998)
  • H. Sasaki et al.

    Histopathological-molecular genetic correlations in referral pathologist-diagnosed low-grade oligodendroglioma

    J Neuropathol Exp Neurol

    (2002)
  • K. Ueki et al.

    Correlation of histology and molecular genetic analysis of 1p, 19q, 10q, TP53, EGFR, CDK4, and CDKN2A in 91 astrocytic and oligodendroglial tumors

    Clin Cancer Res

    (2002)
  • J.W. Jeuken et al.

    Molecular pathogenesis of oligodendroglial tumors

    J Neurooncol

    (2004)
  • Y. Okamoto et al.

    Population-based study on incidence, survival rates, and genetic alterations of low-grade diffuse astrocytomas and oligodendrogliomas

    Acta Neuropathol

    (2004)
  • G. Reifenberger et al.

    Oligodendroglioma: toward molecular definitions in diagnostic neuro-oncology

    J Neuropathol Exp Neurol

    (2003)
  • J.S. Smith et al.

    Alterations of chromosome arms 1p and 19q as predictors of survival in oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas

    J Clin Oncol

    (2000)
  • C. Godfraind et al.

    Tumour necrosis and microvascular proliferation are associated with 9p deletion and CDKN2A alterations in 1p/19q−deleted oligodendrogliomas

    Neuropathol Appl Neurobiol

    (2003)
  • F.M. Iwamoto et al.

    Clinical relevance of 1p and 19q deletion for patients with WHO grade 2 and 3 gliomas

    J Neurooncol

    (2008)
  • C. Bouvier et al.

    Deletions of chromosomes 1p and 19q are detectable on frozen smears of gliomas by FISH: usefulness for stereotactic biopsies

    J Neurooncol

    (2004)
  • A. Perry et al.

    Ancillary FISH analysis for 1p and 19q status: preliminary observations in 287 gliomas and oligodendroglioma mimics

    Front Biosci

    (2003)
  • Cited by (0)

    View full text