Objective The radiological characteristics of World Health Organization grade III oligodendroglial tumours in relation to chromosome 1p and 19q deletions were analysed.
Methods 56 patients recently diagnosed with anaplastic oligodendroglioma (AO, n=49) or anaplastic oligoastrocytoma (AOA, n=7) were studied. Their preoperative magnetic resonance images were examined. Deletions of chromosome 1p and 19q were determined using the fluorescence in situ hybridisation method. Both 1p and 19q chromosomes had deletions (1p19q codeletion) in 39 patients (36 AO and 3 AOA).
Results Tumors associated with the 1p19q codeletion were predominantly located in the frontal lobe (p=0.044). The magnetic resonance image characteristics of indistinct tumour borders (p=0.005 on T1, p=0.036 on T2) and a heterogeneous intratumoural signal intensity (p=0.033 on T1, p=0.041 on T2) were significantly correlated with the 1p19q codeletion. Analysis of patient survival showed those with the 1p19q-codeleted tumours survived significantly longer than those lacking the 1p19q codeletion (p=0.042). The presence of a heterogeneous signal intensity in T2-weighted images, a characteristic significantly related to the 1p19q codeletion, indicated a favourable prognosis for patients' survival (HR; 0.125, 95% CI, 0.016 to 0.963, p=0.046) based on multivariate analysis.
Conclusion A relationship between radiological characteristics and molecular signatures in AO/AOAs was shown. It is believed that radiological characteristics have prognostic value as a surrogate marker for molecular characteristics.
- Anaplastic oligodendroglioma
- anaplastic oligoastrocytoma
- radiological characteristics
- 1p19q deletion
- surrogate marker
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- Anaplastic oligodendroglioma
- anaplastic oligoastrocytoma
- radiological characteristics
- 1p19q deletion
- surrogate marker
In addition to the traditional histopathological classification, meaningful molecular markers that can predict the prognosis for patients with glioma are currently under vigorous investigation. Oligodendroglial tumours are the first gliomas known to have specific molecular signatures that can predict the response to chemotherapy and survival.1–3 Evidence of longer survival times and a better response to chemotherapy in patients with oligodendrogliomas and the 1p19q codeletion is well established.4–6 The 1p19q codeletion may be a prognostic marker as well as predictive marker for responses to chemotherapy.4
Along with progress in molecular genetics, advanced imaging technology has improved the diagnostic accuracy and provided additional biological information about malignant gliomas.3 7 8 Recent investigations have examined the correlation between 1p19q chromosomal status and radiological features based on magnetic resonance images of oligodendroglial tumours.2 3 9–12 We confirm the relationship between the 1p19q chromosomal status and radiological characteristics of high-grade oligodendroglial tumours such as anaplastic oligodendrogliomas (AOs) and anaplastic oligoastrocytomas (AOAs).
We retrospectively assessed patients with high-grade oligodendroglial tumours who were surgically treated between 1995 and 2008. Only those patients who met the following criteria were included: (a) a newly diagnosed AO or AOA based on World Health Organization (WHO) 2000 classification, (b) available appropriate preoperative imaging studies and (c) available tumour samples for genetic analyses of chromosomes 1p and 19q.
Fifty-six patients (32 men and 24 women), with a mean age at diagnosis of 40 years (range 20–62 years), were eligible for this study. Forty-nine patients had AOs and seven had AOAs. The 1p19q chromosomal deletion status was assessed by fluorescence in situ hybridisation on paraffin sections obtained during surgery, as previously described.13
Preoperative magnetic resonance images with contrast enhancement were obtained using a 1.5 or 3.0-T unit (Signa or CV/I, Signa Excite, GE Medical Systems, Milwaukee, WI, USA). Magnetic resonance images were analysed by a neuroradiologist and a neurosurgeon, both of whom had no knowledge of the histology or 1p19q deletion status. The following radiological characteristics were noted: (a) tumour location; (b) cortex involvement; (c) tumour border (sharp vs indistinct); (d) signal intensity (homogeneous vs heterogeneous); (e) contrast enhancement; and (f) other radiological features such as calcification, haemorrhage, cyst, oedema.
Examples of classification using signal intensity and tumour border are shown in figure 1. We defined the tumour border as “sharp” rather than “indistinct” if most of the tumour margin was well defined and most of the tumour–brain parenchyma interface was not blurred. If the signal intensity within the tumour, apart from the surrounding peritumoural oedema, was uniform, it was defined as being of “homogeneous” signal intensity.
Statistics and survival analysis
Fisher's exact test and Pearson's χ2 test were used to analyse the relationship between radiological variables and chromosome 1p19q status. Kaplan–Meier method and log-rank test was performed to determine the overall survival of the patients according to 1p19q deletion status. The Cox proportional hazards model was fitted to assess the direct predictive value of the radiological observations on patient survival together with potential prognostic factors such as the extent of resection. Statistical significance was accepted for p values <0.05, using the SPSS V.12.0 (SPSS).
The 1p19q codeletion occurred in 39 patients (69.6%), whereas 14 patients (25.0%) had both 1p and 19q intact. Chromosome 1p deletion only was found in one patient and 19q deletion only in two patients. The results of radiological analysis and its relationship to the 1p19q codeletion are shown in table 1.
Tumours with the 1p19q codeletions were predominantly located in the frontal lobe, whereas the others were more often located in the temporoinsular lobe (p=0.044). There was no significant relationship between 1p19q codeletion and tumour enhancement (p=0.727) or cortical involvement (p=0.960). Forty-five tumours were confined to a single lobe, and 11 were located in multiple lobes. Tumour border shapes in the magnetic resonance images showed significant associations with the 1p19q codeletion. Tumours with the 1p19q codeletion tended to have an indistinct border in both T1-weighted (p=0.005) and T2-weighted images (p=0.036), whereas the others were more likely to have a sharp border. Of the 1p19q-codeleted tumours, 80.6% of T1-weighted images and 67.6% of T2-weighted images had an indistinct tumour border. Also, tumours with the 1p19q codeletion were more likely to show a heterogeneous signal intensity on both T1-weighted (p=0.033) and T2-weighted images (p=0.041) compared with tumours lacking the 1p19q codeletion. There was no relationship between the presence of the 1p19q codeletion and other radiological features including calcification, intratumoural haemorrhage, cystic formation and peritumoural oedema.
The tumours were completely removed in 17 of 39 patients (43.6%) with the 1p19q codeletion and in 7 of 17 patients (41.2%) without codeletion. There was no difference in removal extent according to 1p19q codeletion (p=0.867). Forty-two patients (75%) underwent radiotherapy (59.0–61.2 Gy) and PCV (procarbazine, lomustine and vincristine) chemotherapy after resection; 12 patients (21%) underwent radiotherapy alone (59.0–61.2 Gy). The analysis of overall survival revealed by the Kaplan–Meier and log-rank methods showed that patients whose tumours had the 1p19q codeletion survived significantly longer than those without the 1p19q codeletion (p=0.042). Overall survival rates of patients with 1p19q-codeleted tumours were 95% at 5 years, 72% at 10 years, whereas those without the 1p19q codeletion were 67% and 45%, respectively (data not shown).
Multivariate analysis, including radiological characteristics significantly related to the 1p19q codeletion as well as to the extent of removal, showed that the presence of heterogeneous signal intensity on T2-weighted images appears to be a favourable sign for patient survival (HR; 0.125, 95% CI; 0.016 to 0.963, p=0.046). Other radiological characteristics did not show a direct correlation with survival.
Significant relationships between the 1p19q codeletion and magnetic resonance image characteristics in oligodendroglial tumours such as frontal location, bifrontal growth pattern, diffuse and patchy enhancement, heterogeneous signal intensity, and an indistinct tumour border were previously reported.2 3 9–11 However, most of these studies included both WHO grade II and III oligodendroglial tumours.3 9–11 Although the role of the 1p19q codeletion as a prognostic marker is not limited to anaplastic oligodendroglial tumours, the radiological characteristics of high-grade oligodendroglial tumours separately from low-grade ones is worth analysing because their radiological features are quite distinct. Therefore, we confined our study to newly diagnosed AO/AOAs.
We found several significant radiological characteristics associated with the 1p19q codeletion. First, the AO/AOAs with the 1p19q codeletion had indistinct tumour borders in both T1-weighted and T2-weighted images. Jenkinson et al11 reported similar results in WHO grade II or III oligodendroglial tumours. Megyesi et al3 observed a significant association between the 1p19q codeletion and an indistinct tumour border on T1-weighted images but not T2-weighted images. The reason that 1p19q-codeleted tumours have indistinct borders in magnetic resonance images is not known. A study using microarray analysis suggested that oligodendroglial tumours lacking 1p have similar expression profiles to those of normal brain tissues.14 Based on these findings, Megyesi et al3 suggested that the reason for the indistinct border around the 1p19q-codeleted tumours was that normal brain tissue was surrounded by an invasive 1p19q-codeleted tumour. Second, analysis of the intratumoural signal intensity showed that AO/AOAs with the 1p19q codeletion displayed greater heterogeneous signal intensity than those without a deletion. The intratumoural heterogeneous signal may result from intratumoural haemorrhage, necrosis or calcification. This observation is consistent with previous reports showing that the 1p19q codeletion was associated with calcification and paramagnetic susceptibility in oligodendroglial tumours.3 11 The absence of information on the functional consequences of the 1p19q codeletion makes it difficult to provide a plausible explanation for the presence of intratumoural heterogeneity in magnetic resonance images. However, our observation that heterogeneous signal intensity in T2-weighted images was directly correlated with increased survival as well as with 1p19q codeletion is worth emphasising. This is more evidence of a relationship between radiological characteristics, molecular signatures and prognosis in central nervous system tumours. Third, the predominant location of the 1p19q-codeleted tumours in the frontal lobe is consistent with previous studies.2 10 Zlatescu et al2 have suggested that each oligodendroglial tumour subtype may develop in different lobes and have different growth patterns because they arise from different regionally specific precursor cells.
Other imaging methods such as diffusion or perfusion magnetic resonance imaging as well as conventional magnetic resonance imaging have been used to define more accurately the molecular subtypes of oligodendroglial tumours.12 15 As shown in the present study, it appears that molecular changes can be reflected in image characteristics. Therefore, radiological characteristics may used as a surrogate marker for the molecular signatures that can predict the prognosis of patients with AO/AOAs.
Our observations show that radiological characteristics are associated with molecular signatures in AO/AOAs and they have prognostic value as a surrogate marker for the molecular characteristics. Further investigations on the underlying mechanisms linking radiological and molecular characteristics are needed to provide better understanding of the nature of these tumours.
This study was supported by a grant of the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A090676).
Competing interests None.
Patient consent Obtained.
Ethics approval This study was conducted with the approval of the Seoul National University Hospital Institutional Review Board.
Provenance and peer review Not commissioned; externally peer reviewed.
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