John Broome

Cerebral blood volume, genotype and chemosensitivity in oligodendroglial tumours.

IntroductionThe biological factors responsible for differential chemoresponsiveness in oligodendroglial tumours with or without the −1p/−19q genotype are unknown, but tumour vascularity may contribute. We aimed to determine whether dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) could distinguish molecular subtypes of oligodendroglial tumour, and examined the relationship between relative cerebral blood volume (rCBV) and outcome following procarbazine, lomustine and vincristine (PCV) chemotherapy.MethodsPretherapy rCBV was calculated and inter- and intraobserver variability assessed. Allelic imbalance in 1p36, 19q13, 17p13, 10p12–15, and 10q22–26 and p53 mutation (exons 5–8) were determined. rCBV was compared with genotype and clinicopathological characteristics (n=37) and outcome following PCV chemotherapy (n=33).Results1p/19q loss was seen in 6/9 grade II oligodendrogliomas, 6/14 grade II oligoastrocytomas, 4/4 grade III oligodendrogliomas, and 3/10 grade III oligoastrocytomas. rCBV measurements had good inter- and intraobserver variability, but did not distinguish histology subtype or grade. Tumours with 1p/19q loss had higher rCBV values (Student’s t-test P=0.001). Receiver operating characteristic analysis revealed a cut-off of 1.59 for identifying genotype (sensitivity 92%, specificity 76%). Tumours with high and low rCBV showed response to chemotherapy. The −1p/−19q genotype, but not rCBV, was strongly associated with response, progression-free and overall survival following PCV chemotherapy. Tumours with high rCBV and intact 1p/19q were associated with shorter progression-free and overall patient survival than those with intact 1p/19q and low rCBV or high rCBV and 1p/19q loss.ConclusionrCBV identifies oligodendroglial tumours with 1p/19q loss, but does not predict chemosensitivity. The prognostic significance of rCBV may differ in oligodendroglial tumours with or without the −1p/−19q genotype.

Molecular pathology and clinical characteristics of oligodendroglial neoplasms

To evaluate the role of molecular genetics in the routine clinic, we investigated allelic imbalance at 1p36, 19q13, 17p13, 10p12‐15, and 10q22‐26 and p53 mutation in 100 oligodendroglial neoplasms diagnosed at a single treatment center between 2000 and 2003. The ‐1p/‐19q genotype, seen in 64, 34, 77, and 30% of OII, OAII, OIII, and OAIII respectively, was inversely related to p53 mutation and 17p13 loss. Genotype was unrelated to tumor location and could not distinguish high‐grade tumors that presented de novo from those that progressed from a previous lower grade malignancy. Presentation with seizures was more common in cases with the ‐1p/‐19q genotype, and these remained stable for longer before treatment. In longitudinal samples, 74% retained their initial histological differentiation, whereas 29% showed new genetic alterations, the ‐1p/‐19q genotype being acquired in three cases. Loss of 1p36 and 19q13, 17p13, chromosome 10, and p53 mutation were significantly associated with survival from presentation in Kaplan–Meier analysis (p < 0.01), and loss of 1p36 and 19q13 and loss of 17p13 retained significance in multivariate analysis. In this recently diagnosed unselected series, clinical differences in tumors with and without the ‐1p/‐19q genotype support a genetic approach to aid diagnosis and prognostication for oligodendroglial neoplasms. Ann Neurol 2005;57:855–865

Correlation of Molecular Genetics with Molecular and Morphological Imaging in Gliomas with an Oligodendroglial Component

Purpose: Since the recognition that oligodendrogliomas may be chemosensitive, their diagnosis and clinical management has become highly controversial. Histopathology diagnosis remains challenging and new tools such as molecular genetics or molecular imaging require evaluation. Experimental Design: In a single-center, population-based prospective study, allelic imbalance in chromosomes 1p36, 19q13, 17p13, 10p12–15, and 10q22–26 has been investigated in 19 oligodendroglioma WHO grade 2 (OII), 20 oligoastrocytoma WHO grade 2 (OAII), 8 oligodendroglioma WHO grade 3 (OIII), and 12 oligoastrocytoma WHO grade 3 (OAIII), and compared with pretherapy histopathology, computed tomography and/or magnetic resonance (CT and/or MR), [fluorine-18]fluoro-2-deoxyglucose (18F-FDG), and thallium-201 single-photon emission computed tomography (201Tl SPECT). Results: In 50 cases, 18F-FDG uptake correlated with 201Tl uptake; however, 8 cases had increased 201Tl uptake but were hypometabolic for 18F-FDG, and 1 case was hypermetabolic with normal 201Tl uptake. Sixteen cases enhanced on CT/MR but failed to show 201Tl uptake; and 2 low-grade non-enhancing oligodendrogliomas had increased 201Tl uptake. Increased metabolism was more likely in high-grade cases, with 201Tl uptake more strongly correlated with grade than was 18F-FDG uptake. Tumors with 1p/19q loss were more likely to show increased 201Tl uptake and, to a lesser degree, increased 18F-FDG uptake than those without these losses. Elevated metabolism in 28% of low-grade tumors was significantly more common in tumors with 1p/19q loss, and increased uptake of both 18F-FDG and 201Tl in low-grade cases was found only in those with 1p/19q loss. Conclusions: In this study, dissociation of uptake of contrast agents and radiotracers suggests independent deregulation of the blood–brain barrier breakdown and metabolism during disease progression of oligodendroglial neoplasms, and the association of elevated metabolism with 1p/19q loss, particularly in low-grade tumors, may have implications for clinical management.

Clinical use of genotype to predict chemosensitivity in oligodendroglial tumors

Background: The −1p/−19q genotype has been associated with prolonged survival and chemosensitivity in oligodendroglial neoplasms, but the predictive and prognostic significance of genotype in the routine clinic is not established. Methods: The authors investigated allelic imbalance in 1p36, 19q13, 17p13, 10p12-15, and 10q22-26 and p53 mutation in a cohort representative of clinical practice at their center (50 primary, 26 recurrent cases) given PCV chemotherapy between 2000 and 2003 and compared with response and outcome following PCV. Results: 1p/19q loss was found in 12/19 OII, 10/23 OAII, 11/13 OIII, and 6/21 OAIII. Response, seen in 92% with 1p/19q loss, was associated with the −1p/−19q genotype (Fisher exact: p < 0.001) regardless of WHO grade or whether primary or recurrent. 1p/19q loss was an independent prognostic factor associated with longer progression-free (PFS) and overall survival (OS) (Cox regression: PFS and OS p < 0.001), with greater impact on PFS than OS in primary tumors, and OS at recurrence. 17p13 loss and p53 mutation were associated with poor prognosis in recurrent tumors and chromosome 10 loss was associated with short PFS and OS in primary tumors. Histologic subtype did not influence outcome in tumors of equivalent genotype. Genotype had greater association with response and outcome than conventional clinical factors. A total of 29% with intact 1p/19q and a variety of genetic or clinicopathologic characteristics responded in association with increased PFS and OS. Conclusions: The −1p/−19q genotype predicted response and favorable outcome following PCV chemotherapy corroborating genetic analysis to guide routine clinical management. However, some cases with intact 1p/19q also had clinical benefit.

Characterisation of molecular alterations in microdissected archival gliomas.

Abstract. Classification of gliomas according to their molecular characteristics may be important in future histopathological diagnosis. However, gliomas frequently display heterogeneity at the histological, biological and molecular level. In this study of archival diagnostic gliomas, precision microdissection was used to enrich samples in the most malignant cells or to investigate intratumoural histological heterogeneity. Analysis of tumour samples microdissected from the most aggressive regions, representative of the histopathological diagnosis, revealed PTEN mutations in 4/14 anaplastic astrocytomas, 4/13 glioblastomas and 1 gliosarcoma, but not in 19 low-grade gliomas. Using a novel PCR procedure and direct sequence analysis of the entire coding sequence, TP53 mutations were detected in 1/3 pilocytic astrocytomas, 3/13 astrocytomas, 4/14 anaplastic astrocytomas, 5/13 glioblastomas and 1 gliosarcoma. All but one of the tumours with TP53 mutation showed p53 immunopositivity, but 5 low-grade and 10 high-grade gliomas had p53 protein nuclear accumulation in the absence of detectable mutation. p53 status was unrelated to p21 expression. Neither PTEN nor TP53 mutations influenced the proliferative index or microvessel density of high-grade astrocytomas. Unusual findings include: TP53 mutation in a juvenile pilocytic astrocytoma; TP53 and PTEN mutations in a de novo glioblastoma, a gliosarcoma with identical mutations in gliomatous and sarcomatous components, and an infratentorial anaplastic astrocytoma with an earlier supratentorial grade II astrocytoma bearing the same TP53 mutation but not the PTEN mutation or loss of heterozygosity (LOH) of 10q23. Similarly, the transition to high-grade histology was associated with acquisition of PTEN mutations and 10q23.3 LOH in two de novo high-grade tumours with regions of low-grade histology.

Primary Intradural Classic Chondrosarcoma: Case Report and Literature Review

OBJECTIVE AND IMPORTANCE The exact origin of rare intradural chondrosarcomas remains obscure. We present a case report of an intradural classic chondrosarcoma (a very rare subtype of chondrosarcoma in this location), with a review of the literature, in an attempt to clarify the histogenesis of these tumors. CLINICAL PRESENTATION A 48-year-old man presented with a 12-month history of progressive right hemiparesis. Computed tomography and magnetic resonance imaging demonstrated a left parietal space-occupying lesion. INTERVENTIONThe patient underwent an image-guided, left parietal parasagittal craniotomy. An extrinsic tumor, which seemed to arise from the dura, was macroscopically removed. There was no bone involvement. The histological examination revealed a Grade II classic chondrosarcoma with tumor infiltration into the dura. Adjuvant radiotherapy was administered. CONCLUSIONIntradural chondrosarcomas are rare tumors, the majority of which are mesenchymal. Classic chondrosarcomas in this location are much rarer. Their histogenesis is uncertain. In this case, the origin seems to be from the dura. Because of the malignant potential of these tumors, radical extirpation whenever possible, followed by radiotherapy, is indicated.

Traumatic cerebral aneurysm formation following ventriculoperitoneal shunt insertion

IntroductionIatrogenic intracranial aneurysms are rare in children.Case reportA 15-year-old girl presented in coma with a fixed dilated left pupil six weeks following removal of a long-standing left-sided ventriculoperitoneal shunt. Computed tomography (CT) and cerebral angiography revealed a left temporoparietal intracerebral haemorrhage with a fusiform distal middle cerebral artery aneurysm. The patient underwent image-guided localisation of the aneurysm to enable evacuation of the haemorrhage and resection of the fusiform aneurysm.ConclusionA high index of suspicion is required for diagnosis and early treatment to prevent unnecessary morbidity and mortality.

Molecular genetic analysis of archival gliomas using diagnostic smears.

Investigation of the clinical significance of genetic alterations in gliomas requires molecular genetic analysis using samples from retrospective or prospective clinical studies. However, diagnostic tissue is often severely limited and because of fixation, paraffin‐embedded tissues (PET) contain degraded DNA. Intra‐operative cytological preparations (smears) archived after diagnosis may represent an additional source of clinical material for genetic analysis. In this study, tissue samples were obtained by precision microdissection of archived diagnostic smears from 20 cases (1961–1999). All samples produced polymerase chain reaction (PCR) products for the β globin gene, but the most recent samples amplified best and gave longer amplimers. For six cases, direct comparison was made between samples microdissected from smears and the corresponding PET. Samples from smears showed improved PCR performance and similar alleles on microsatellite marker analysis. One case, with smears of uninvolved cortex and tumour tissue available for microdissection, showed allelic imbalance at 10q23 on the basis of the smear results alone. PCR products from smears were shown to be suitable for direct sequence analysis (p53 gene). A PTEN mutation, found previously in an anaplastic astrocytoma by analysis of PET, was detected in the corresponding diagnostic smear. The results of this study indicate that tissue samples microdissected from diagnostic intra‐operative cytological preparations may be suitable for molecular genetic analysis of gliomas.

Genetic and metabolic predictors of chemosensitivity in oligodendroglial neoplasms

The −1p/−19q genotype predicts chemosensitivity in oligodendroglial neoplasms, but some with intact 1p/19q also respond and not all with 1p/19q loss derive durable benefit from chemotherapy. We have evaluated the predictive and prognostic significance of pretherapy 201Tl and 18F-FDG SPECT and genotype in 38 primary and 10 recurrent oligodendroglial neoplasms following PCV chemotherapy. 1p/19q loss was seen in 8/15 OII, 6/15 OAII, 7/7 OIII, 3/11 OAIII and was associated with response (Fisher-Exact: P=0.000) and prolonged progression-free (log-rank: P=0.002) and overall survival (OS) (log-rank: P=0.0048). Response was unrelated to metabolism, with tumours with high or low metabolism showing response. Increased 18F-FDG or 201Tl uptake predicted shorter progression-free survival (PFS) in the series (log-rank: 201Tl P=0.0097, 18F-FDG P=0.0170) and in cases with or without the −1p/−19q genotype. Elevated metabolism was associated with shorter OS in cases with intact 1p/19q (log-rank: 18F-FDG P=0.0077; 201Tl P=0.0004) and shorter PFS in responders (log-rank: 18F-FDG P=0.005; 201Tl P=0.0132). 201Tl uptake and 1p/19q loss were independent predictors of survival in multivariate analysis. In this initial study, 201Tl and 18F-FDG uptake did not predict response to PCV, but may be associated with poor survival following therapy irrespective of genotype. This may be clinically useful warranting further study.