Brain Advance Access originally published online on May 2, 2006
Brain 2006 129(7):1884-1891; doi:10.1093/brain/awl108
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Histological growth patterns and genotype in oligodendroglial tumours: correlation with MRI features
1 Departments of Neurosurgery, University of Liverpool Liverpool 2 Departments of Neuroradiology, The Walton Centre for Neurology and Neurosurgery, Division of Neuroscience, University of Liverpool Liverpool 3 University of Liverpool Liverpool 4 Department of Neuropathology, Hope Hospital Salford 5 Clatterbridge Cancer Research Trust, JK Douglas Laboratories, Clatterbridge Hospital Bebington, Wirral, UK
Correspondence to: Mr Michael D. Jenkinson, Division of Neuroscience, Clinical Sciences Centre, Lower Lane, Liverpool, L9 7LJ, UK E-mail: michael.jenkinson@liv.ac.uk
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Oligodendroglial neoplasms with the –1p/–19q genotype are more indolent with longer survival and increased therapeutic responsiveness than those with intact 1p/19q, but the biological basis for these clinical differences is unclear. Recent research suggests that oligodendrogliomas with and without the –1p/–19q genotype may be distinguished by their magnetic resonance imaging (MRI) appearance, suggesting possible differences in growth characteristics. This study examined the relationship between genotype and histological growth patterns of oligodendroglial neoplasms in association with MR imaging characteristics. Tumour imaging features assessed on MRI included sharp-versus-indistinct border, smooth-versus-irregular contour, homogeneous-versus-heterogeneous signal, contrast enhancement and paramagnetic susceptibility effect. Growth patterns (solid : mixed : infiltrative), tumour-margin transitions in cellularity and calcification were determined histopathologically. Allelic imbalance in chromosomes 1p36 and 19q13 was determined. Thirty-three oligodendrogliomas (25 with 1p/19q loss) and 53 oligoastrocytomas (18 with 1p/19q loss) were investigated. Solid, mixed or infiltrative growth patterns were seen in grade II and grade III tumours with or without 1p/19q loss, but infiltrative growth was more common in tumours with intact 1p/19q (
2: P = 0.029). Grade III tumours were more likely to have a solid growth pattern (2: P = 0.046) associated with contrast enhancement (2: P = 0.011). Transition in cellularity at the radiological margin did not differ according to genotype. All cases with T1 or T2 signal homogeneity had intact 1p/19q. Tumours with sharp/smooth borders were more likely to have intact 1p/19q than those with indistinct/irregular borders (2: P < 0.001), but this was not related to histological growth characteristics. This study identified a group of oligodendroglial tumours with intact 1p/19q displaying distinctive MR imaging features that were unrelated to the histopathology characteristics.
Key Words: brain tumour; MRI; molecular genetics; histopathology
Received June 1, 2005. Revised September 19, 2005. Accepted March 30, 2006.
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Introduction |
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Oligodendroglial neoplasms account for up to 33% of all adult gliomas (Perry, 2001
; Engelhard et al., 2002) and have a more indolent clinical history and prolonged survival (Engelhard et al., 2002, 2003) compared with astrocytic tumours of the same grade. The majority of oligodendrogliomas and some oligoastrocytomas respond to chemotherapy or radiotherapy (Cairncross and Macdonald, 1988; Engelhard et al., 2003), and research suggests that molecular genetic analyses may be the most appropriate way to identify the chemosensitive subgroup (Cairncross et al., 1998; Ino et al., 2001; van den Bent, 2004). Combined loss of heterozygosity (LOH) on chromosome arms 1p and 19q is an early genetic event in the histogenesis of oligodendroglial neoplasms and is considered to be their genetic hallmark, being present in up to 90% of oligodendrogliomas and 50% of oligoastrocytomas (Reifenberger et al., 1994; Kraus et al., 1995; Bigner et al., 1999). The –1p/–19q genotype is associated with longer time to first therapy, therapeutic response to initial therapy, longer progression-free survival, response at recurrence and prolonged overall survival (Bauman et al., 2000; Smith et al., 2000; Ino et al., 2001; Van Den Bent et al., 2003; Fallon et al., 2004; Felsberg et al., 2004; Walker et al., 2005). However, the biological basis for these clinical differences is not well understood. While much of the research effort has been addressed at a molecular level (Kitange et al., 2003; Jeuken et al., 2004), less is known of the comparative pathological and in vivo biology of these tumours in relation to genotype (Megyesi et al., 2004; Walker et al., 2004).
Whether oligodendroglial neoplasms with or without the –1p/–19q genotype differ in their ‘invasiveness’ or ability to diffusely infiltrate normal brain parenchyma is not known, and the literature evidence is limited, circumstantial and conflicting. Microarray analysis has demonstrated that oligodendrogliomas with loss of 1p and 19q have a similar expression profile to normal brain (Mukasa et al., 2004), which has been hypothesized to occur if normal brain tissue is trapped within an invasive tumour (Megyesi et al., 2004), although this was not assessed histologically. In contrast, using ex vivo rodent organotypic brain slice assays and implanted biopsy samples of gliomas, oligodendroglial tumours with 1p/19q loss were less invasive and grew as compact, hypercellular proliferating masses compared with astrocytic tumours of a similar grade (Palfi et al., 2004). Clinically, untreated newly diagnosed and recurrent oligodendroglial and astrocytic gliomas can show extensive infiltration of brain parenchyma (Kelly et al., 1987; Daumas-Duport et al., 1997b), while multifocal tumours are occasionally found in both lineages (Batzdorf and Malamud, 1963; Barnard and Geddes, 1987). In gliomas, three types of growth pattern have been defined: type I (solid), type II (mixed) and type III (infiltrative) (Kelly et al., 1987; Daumas-Duport et al., 1997a, b), but these have not been studied in oligodendroglial neoplasms classified by genotype. A recent study of oligodendrogliomas has reported associations between genotype and MR imaging; an indistinct tumour border, heterogeneous signal intensity and paramagnetic susceptibility are associated with 1p/19q LOH, which suggests that MRI characteristics may be related to tumour invasiveness (Megyesi et al., 2004).
The aim of this study was to investigate the histological growth characteristics of oligodendroglial neoplasms in relation to the 1p/19q genotype and to relate these findings to MR imaging characteristics.
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Material and methods |
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Case selection
Cases for study were selected from a cohort of primary (previously untreated) and recurrent adult gliomas at the Walton Centre for Neurology and Neurosurgery between July 1999 and July 2005. Eligibility criteria included (i) histological diagnosis of oligodendroglioma or oligoastrocytoma based on the current WHO classification (Kleihues, 2000
); (ii) pre-therapy MRI scan; (iii) known 1p36 and 19q13 status. The local research ethics committee approved the study, and consent was obtained from all patients. Two otherwise eligible cases with post-resection, pre-therapy MRI but insufficient residual tumour were excluded from the study.
Tumour tissue acquisition
Tissue for pathology diagnosis was obtained by serial stereotactic biopsy, image-guided biopsy or resection. Thirteen patients underwent frameless image-guided biopsy or resection using a neuronavigation system (SNN, Toronto, Canada), and samples were taken for intra-operative smear analysis and routine histopathology. Seventy-three patients underwent frame-based, CT or T1-weighted MRI-guided serial stereotactic biopsy. Using the stereotactic planning station (Leibinger, Germany) the tumour volume was calculated with the target position (TP) in the centre of the tumour as determined by volumetry. The biopsy trajectory was calculated to encompass the most aggressive part of the tumour as defined by contrast enhancement or, in non-enhancing cases, to maximize representation of the tumour. Biopsy samples commenced 2–3 mm outside the radiological tumour margin and were taken at 1-mm intervals up to and in some cases beyond the target position. Brain shift and CSF loss were minimized by the use of a 6-mm stereotactic burr hole and a 1-mm internal diameter biopsy cannula. Alternating samples were taken for intra-operative smear diagnosis, formalin fixation and in some cases for snap freezing.
Histopathology
The histopathology diagnosis for each case was made according to current WHO guidelines (Kleihues, 2000) based on examination of all routinely processed tissue taken throughout the biopsy trajectory, or from open surgery. Pathology slides were re-reviewed by a neuropathologist (D.duP.) to assess growth pattern [solid, mixed or infiltrative—respectively corresponding to structure type I, II and III tumours (Daumas-Duport et al., 1997a, b)] and presence of calcification. In the 73 cases diagnosed with frame-based CT or MRI-guided serial stereotactic biopsy, each sample was recorded relative to its position along the biopsy trajectory, enabling assessment of changes in cellularity at the radiological tumour margin within a 5-mm interval. This was scored as ‘marked’, that is, a change in cellularity from normal or low cellularity to high cell density, or ‘insidious’, that is, little or no change in cellularity. The median number of biopsies taken for each case for routine histology was 19 (range: 4–32). Comparison of MRI appearance and histology at the tumour margin was made in the stereotactic group only.
Molecular genetics
For each case, regions of tumour histology in biopsy specimens representative of the overall pathology diagnosis were selected for study. Laser capture microdissection was used to enrich the tumour component in the samples for analysis, and determination of allelic imbalance was carried out using paired normal and tumour samples and polymerase chain reaction (PCR) amplification of microsatellite markers at 1p36 (D1S2667, D1S508, D1S214) and 19q13 (D19S412, D19S112, D19S596), in a two-round PCR procedure followed by capillary electrophoresis as described previously (Walker et al., 2001, 2003, 2004).
Image analysis
MRI scans were assessed by a neuroradiologist (T.S.S.), neuropathologist (D.duP.) and neurosurgeon (M.D.J.) blinded to the genotype of each case. T1-weighted, T1 post-gadolinium and T2-weighted MR axial images were consistently available for analysis. According to previously described methods (Megyesi et al., 2004) the following magnetic resonance imaging features were evaluated: (i) sharp-versus-indistinct tumour border on T1 and T2; (ii) homogeneous-versus-heterogeneous signal intensity throughout the tumour on T1 and T2; (iii) contrast enhancement, present versus absent; and (iv) paramagnetic susceptibility effect, present versus absent. Additionally, the tumour contour on T2 was also evaluated as smooth versus irregular. Images were scored by consensus.
Statistical analysis
Data were analysed using SPSS for windows (SPSS, UK). Two-tailed Fisher's exact and Pearson's 2 test were used to determine the significance of associations. Probability (P) values < 0.05 were considered significant.
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Results |
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Eighty-six cases were eligible for the study, and the clinicopathological findings are shown in Table 1 (additional data in Supplementary Table 1). Median age at operation was 44 years with 43 males and 43 females in the study. Of the 64 primary, previously untreated cases, 5 had an earlier pathology diagnosis and 59 were newly diagnosed at study. Twenty-two recurrent tumours had received radiotherapy before MRI (median: 69 months; range: 6–165). Complementary T1 and T2 images were not available in 12 cases. 1p/19q loss was present in 15/22 OII, 10/11 OIII, 11/31 OAII and 7/22 OAIII. One patient had loss of 1p without loss of 19q.
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Genotype and histopathology
Solid, mixed or infiltrative growth patterns were seen in tumours with or without 1p/19q loss and in grade II or grade III tumours. Tumours with infiltrative growth were more likely to have intact 1p/19q, and those with mixed or solid growth patterns were more likely to have 1p/19q loss (Table 2). However, these associations were not significant if only primary tumours were analysed (data not shown:
2: P = 0.113). Grade III tumours were more likely to have a solid growth pattern, and grade II tumours, mixed or infiltrative growth patterns in the series (Table 2) and in primary tumours (data not shown: 2: P = 0.009). There was no association between growth pattern and histopathology subtype. When changes in cellularity at the radiological margin were assessed in the 73 cases diagnosed by CT/MRI-guided serial stereotactic biopsy, no differences were observed in relation to genotype. Tumours in the series (Table 2) and primary tumours (data not shown) with and without the –1p/–19q genotype were as likely to show marked or insidious changes in cellularity. There was no correlation between transition in cellularity and histopathology subtypes; however, grade II tumours were weakly associated with insidious margins (Table 2). Calcification was significantly associated with genotype, being present in only 21% of tumours with intact 1p/19q, compared with 42% of –1p/–19q tumours. Calcification was also associated with tumour subtype (Table 2).
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Histopathology and MRI
Solid and mixed tumour growth patterns were associated with contrast enhancement, and infiltrative growth with no contrast enhancement in the series (Table 3) and primary tumours (data not shown:
2: P = 0.011). No other significant associations between imaging characteristics and growth pattern or transitions in cellularity were observed. Only 8 cases had a marked transition in cellularity; 3 out of 7 (43%) of these had a sharp T1 tumour border, while 83% of cases with an insidious transition in cellularity had an indistinct T1 tumour border (Table 4 and Fig. 1). There was no correlation between calcification and paramagnetic susceptibility effect (data not shown: 2: P = 1.0). Tumour border, signal intensity and paramagnetic susceptibility effect did not distinguish histopathological subtype or grade. However, contrast enhancement was present in all grade III tumours, and 53% of grade II tumours in the series (2: P < 0.001) and 46% of primary grade II tumours (2: P < 0.001).
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MRI and genotype
Significant associations were seen when imaging characteristics were correlated with genotype; 14 out of 16 cases with a sharp T1 border had intact 1p/19q (Table 5 and Fig. 2A–D). However, intact 1p/19q was also seen in 38% with an indistinct T1 border, which suggests that individually the presence of a sharp border is not specific for intact alleles. Similar findings were also seen with the T2 border and T2 contour (Table 5). When an indistinct tumour border on both T1 and T2 was identified, it was always associated with an irregular T2 contour (n = 60). Likewise, a sharp tumour border on both T1 and T2 was always associated with a smooth T2 contour (n = 14) (Fisher's exact: P < 0.001). These combined imaging features were significantly correlated with genotype in the series, tumours with sharp/smooth imaging being more likely to have intact 1p/19q (Table 5). However, 38% of tumours with an indistinct/irregular imaging appearance also had intact 1p/19q. There were no significant associations between genotype and contrast enhancement or paramagnetic susceptibility effect (Table 5). All tumours with homogeneous signal intensity on T1 (n = 7) and T2 (n = 8) imaging had intact 1p/19q.
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In the 14 cases with a sharp, smooth border, all were previously untreated; 12 were oligoastrocytomas; 13 had intact 1p/19q; 1 had solid, eight infiltrative and five mixed growth patterns; and 2 had marked transition in cellularity at the radiological margin. No unifying features were identified, and tumours with sharp borders were not influenced by their relationship to the grey/white matter interface or location (Table 6).
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Discussion |
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This is the first study correlating MRI features at the tumour border with actual histology from this imaging area in a cohort of oligodendroglial neoplasms classified according to genotype. The principal findings are that tumours with or without 1p/19q loss showed solid, mixed and infiltrative growth patterns, but infiltrative growth was more common in those with intact 1p/19q. Transition in cellularity at the margin was similar, irrespective of genotype; however, tumours with a sharp, smooth border and homogeneous signal intensity were more likely to have intact 1p/19q.
Gliomas have a propensity to be diffusely infiltrative, and it is now known that these migratory cells are refractory to conventional therapy, which may contribute to treatment failure (Giese et al., 2003). Investigation of growth patterns is therefore fundamental to understanding the cellular interactions and tissue organization of these tumours. Diagnosis through frame-based serial stereotactic biopsy has proven diagnostic accuracy (Tilgner et al., 2005) and was used in 85% of cases in this study. As in previous studies (Kelly et al., 1987; Daumas-Duport et al., 1997a, b), this permits the assessment of in vivo histopathological growth pattern and transition in cellularity in relation to co-registered clinical imaging characteristics. Oligodendroglial neoplasms irrespective of genotype displayed solid, mixed or infiltrative growth patterns, although in the series overall, infiltrative growth was associated with intact 1p/19q. Growth pattern correlated with WHO tumour grade, grade III tumours being more likely to exhibit solid tumour tissue and grade II tumours, infiltrative tissue. Consistent with previous observations, solid growth patterns were also associated with contrast enhancement, and infiltrative growth patterns with no contrast enhancement (Daumas-Duport et al., 1997a). It has been suggested that the combined features of contrast enhancement and solid growth pattern reflect neovascularization enabling rapid growth of the developing tumour, with new blood vessels absent in regions of infiltration (Daumas-Duport et al., 1997a, b). Our data suggest that tumourigenesis in oligodendroglial neoplasms of both genetic lineages is similar with respect to both growth pattern and contrast enhancement, although there may be a tendency for tumours with intact 1p/19q to more commonly show infiltrative growth patterns.
In our study, 12 cases showed only a solid growth pattern, which contrasts with previously published series of oligodendrogliomas (Daumas-Duport et al., 1997b) that may have included some oligoastrocytomas if current WHO guidelines were applied (Kleihues, 2000). The apparent disparity in growth pattern may be due to differences in the image guidance used for stereotactic biopsy in the two studies. We used the radiological tumour margin visible on CT or T1-weighted MRI to calculate the initial sampling point along the stereotactic biopsy trajectory, whereas previous studies used the T2 margin (Daumas-Duport et al., 1997b). Although there is a good correlation between CT and T1-weighted MRI for assessing tumour margins, the area of T2 hyperintensity, which usually contains infiltrating tumour cells, often extends beyond this visible margin (Kelly et al., 1987), and may not have been sampled in all cases in our series. In this study, tumours with an indistinct border tended towards an insidious transition in cellularity; however, this did not reach statistical significance. Similar findings were not evident on the T2-weighted images, which highlights the discrepancy between tumour margin assessed using CT or T1-weighted MRI and T2 sequences (Kelly et al., 1987).
As in previous studies, calcification assessed histologically was associated with genotype (Megyesi et al., 2004); 18 out of 27 calcified tumours had 1p/19q loss. However, not all tumours with the –1p/–19q genotype were calcified, and calcification was also present in nine tumours with intact 1p and 19q. It is therefore unlikely that calcification is a direct biological effect of 1p/19q loss; indeed, calcification is also seen in pure astrocytomas (Kleihues, 2000).
Previous studies have postulated that the MR imaging characteristics of indistinct T1 border and mixed signal intensity reflect increased ‘invasiveness’ associated with the –1p/–19q genotype in newly diagnosed, untreated oligodendrogliomas (Megyesi et al., 2004). The present series included examples with and without the –1p/–19q genotype with MRI characteristics considered by neuroradiologists as typical of diffusely infiltrative tumours. Significant associations between genotype and radiological tumour border were found in the present study, tumours with a sharp border being likely to have intact 1p and 19q. Indeed, when all tumour border parameters were assessable (T1 and T2 border and T2 contour), 93% of tumours with a sharp, smooth border had intact 1p and 19q alleles. No features of neuroanatomy were evident to account for these sharp tumour boundaries. However, these imaging characteristics were not diagnostic of genotype, and 38% of tumours with indistinct, irregular margins also had intact 1p and 19q. The previous study described the association in reverse, that is, an indistinct T1 border in 17 of 26 cases was associated with 1p and 19q loss (Megyesi et al., 2004). Whilst we found this feature in 40 of 42 cases with 1p and 19q loss, it was also present in 24 of 38 cases with intact alleles. In keeping with previous studies, loss of 1p and 19q was rarely associated with a sharp border, and no association between contrast enhancement and genotype was observed (Megyesi et al., 2004). In addition, all cases with homogeneous signal intensity on T1 and T2-weighted imaging had intact 1p/19q, and whilst heterogeneous signal intensity was present in both genotypes, it was more likely in tumours with 1p/19q loss. We did not find any associations between paramagnetic susceptibility effect and genotype (Megyesi et al., 2004). Paramagnetic susceptibility was only assessable in 56% of our series as magnetization transfer was applied to T1-weighted images in the remainder. We used the images illustrated in the previous study (Megyesi et al., 2004) as a benchmark for assessment of all imaging parameters, but, nevertheless, such judgements are subjective and may be influenced by differences in image processing between different neuroradiology departments. Direct comparison with the previous study (Megyesi et al., 2004) would require analysis of the newly diagnosed, previously untreated oligodendroglioma subgroup. Although this was not possible owing to sample size and the small number of cases with intact 1p/19q (6 out of 23), the imaging characteristics were similar to those of the series (Supplementary Table 1). In our study, the imaging features of sharp borders and signal homogeneity associated with intact 1p/19q were more common in oligoastrocytomas, but represented only 23% (12 out of 53) of oligoastrocytomas, 30% (13 out of 43) of those with intact 1p/19q and 16% (14 out of 86) of the series overall. Furthermore, although we have confirmed these imaging characteristics in a larger series, combined analysis of these and other series is necessary to establish further the relationship between MRI features and genotype in oligodendroglial tumours.
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Conclusions |
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Tumours with and without the 1p/19q genotype show similar cellularity transition at the radiological margin, and showed solid, mixed and infiltrative growth patterns, but infiltrative growth was more common in those with intact 1p/19q. Tumours with sharp, smooth imaging features and homogeneous signal intensity were more likely to have intact 1p/19q, which may be clinically useful in the absence of genetic testing, but these imaging factors were not related to histological growth characteristics. The lack of strong associations between genotype, imaging and growth suggests that these features are unlikely to account for the differences in clinical behaviour of these genetic subtypes of oligodendroglial neoplasms.
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Acknowledgements |
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We acknowledge the support of the Neuroradiology and Neuropathology departments at The Walton Centre and funding from Clatterbridge Cancer Research Trust, The Walton Centre for Neurology and Neurosurgery, and The Royal Colleges of Surgeons of Edinburgh and Ireland.
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References |
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M. Eoli, F. Menghi, M. G. Bruzzone, T. De Simone, L. Valletta, B. Pollo, L. Bissola, A. Silvani, D. Bianchessi, L. D'Incerti, et al. Methylation of O6-Methylguanine DNA Methyltransferase and Loss of Heterozygosity on 19q and/or 17p Are Overlapping Features of Secondary Glioblastomas with Prolonged Survival Clin. Cancer Res., May 1, 2007; 13(9): 2606 - 2613. [Abstract] [Full Text] [PDF]
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