Low-grade Oligodendrogliomas Research Articles

The Proneural Molecular Signature Is Enriched in Oligodendrogliomas and Predicts Improved Survival among Diffuse Gliomas

The Cancer Genome Atlas Project (TCGA) has produced an extensive collection of ‘-omic’ data on glioblastoma (GBM), resulting in several key insights on expression signatures. Despite the richness of TCGA GBM data, the absence of lower grade gliomas in this data set prevents analysis genes related to progression and the uncovering of predictive signatures. A complementary dataset exists in the form of the NCI Repository for Molecular Brain Neoplasia Data (Rembrandt), which contains molecular and clinical data for diffuse gliomas across the full spectrum of histologic class and grade. Here we present an investigation of the significance of the TCGA consortium's expression classification when applied to Rembrandt gliomas. We demonstrate that the proneural signature predicts improved clinical outcome among 176 Rembrandt gliomas that includes all histologies and grades, including GBMs (log rank test p = 1.16e-6), but also among 75 grade II and grade III samples (p = 2.65e-4). This gene expression signature was enriched in tumors with oligodendroglioma histology and also predicted improved survival in this tumor type (n = 43, p = 1.25e-4). Thus, expression signatures identified in the TCGA analysis of GBMs also have intrinsic prognostic value for lower grade oligodendrogliomas, and likely represent important differences in tumor biology with implications for treatment and therapy. Integrated DNA and RNA analysis of low-grade and high-grade proneural gliomas identified increased expression and gene amplification of several genes including GLIS3, TGFB2, TNC, AURKA, and VEGFA in proneural GBMs, with corresponding loss of DLL3 and HEY2. Pathway analysis highlights the importance of the Notch and Hedgehog pathways in the proneural subtype. This demonstrates that the expression signatures identified in the TCGA analysis of GBMs also have intrinsic prognostic value for low-grade oligodendrogliomas, and likely represent important differences in tumor biology with implications for treatment and therapy.

Favorable long-term outcome of low-grade oligodendrogliomas irrespective of 1p/19q status when treated without radiotherapy

Despite the accumulating evidences of high chemosensitivity especially in anaplastic oligodendrogliomas with loss of chromosomes 1p and 19q, the optimal management strategy for low-grade tumors using the 1p/19q information remains controversial. We have treated all low-grade oligodendrogliomas by a chemotherapy-preceding strategy without radiotherapy, and here we analyzed the survival outcomes of 36 consecutive patients in relation to 1p/19q status. The treatment protocol was as follows: (1) simple observation after gross total resection, and (2) modified PCV chemotherapy for postoperative residual tumors or recurrence after total resection. The 1p and 19q status were analyzed by fluorescence in situ hybridization. The median follow-up period was 7.5 years and no patient was lost during the follow-up periods. 1p/19q co-deletion was observed in 72% of the patients, and there was no significant association between 1p/19q co-deletion and chemotherapy response rate. The 5- and 10-year progression-free survival (PFS) rate was 75.1 and 46.9%, respectively, and the median PFS was 121 months for 1p/19q-deleted tumors and 101 months for non-deleted tumors (log-rank test: P = 0.894). Extent of surgery did not affect PFS (P = 0.685). In contrast, the elder patients (>50) had significantly shorter PFS (P = 0.0458). Recurrent tumors were well controlled by chemotherapy irrespective of 1p/19q status, and 35 out of 36 patients survived without receiving radiotherapy. The 5- and 10-year overall survival rates were 100 and 93.8%, respectively. Two of the patients in their sixties (29%) suffered from severe cognitive dysfunctions and marked brain atrophy following chemotherapy alone. These results show that low-grade oligodendrogliomas could be successfully treated by surgical resection and nitrosourea-based chemotherapy alone without radiotherapy irrespective of 1p/19q status.

Tumor vascular leakiness and blood volume estimates in oligodendrogliomas using perfusion CT: an analysis of perfusion parameters helping further characterize genetic subtypes as well as differentiate from astroglial tumors

The purpose of this study was to determine the usefulness of perfusion CT (PCT) parameters particularly blood volume and neovascular permeability estimates (permeability surface area-product, PS) in the evaluation of oligodendrogliomas (OG), correlation with genetic subtypes of OGs (with or without loss of heterozygosity/LOH on 1p/19q) as well as comparison of perfusion parameters of OGs with astroglial tumors. Pre-operative PCT done in 21 patients with OGs was retrospectively correlated with our previously published PCT data for 32 patients with astroglial neoplasms (Jain R et al., AJNR Am J Neuroradiol 29:694-700, 2008). All OGs were also analyzed for genetic subtypes of with or without LOH. PCT parameters PS and cerebral blood volume (CBV) were obtained for the entire lesion and a statistical analysis done to correlate various histopathological variants. Low grade OGs (n=13) showed slightly lower CBV (1.42 vs. 1.72ml/100g; P value 0.391) and PS (0.56 vs. 0.95ml/100g/min; P value 0.099) as compared to high grade OGs (n=8), though not statistically significant. LOH positive OGs (n=13) showed higher mean CBV (1.59 vs. 1.45; P value 0.712) and slightly lower PS (0.68 vs. 0.75; P value 0.718) as compared to LOH negative OGs (n=8), although not statistically significant. Low grade OGs (n=13) showed higher mean CBV 1.42ml/100g as compared to low grade astroglial tumors (n=8) 0.95ml/100g (P value=0.08), however no statistically significant difference was noted for PS (0.56 vs. 0.52ml/100g/min, P value 0.695). Statistically significant differences were observed in CBV and PS values of high grade OGs and high grade astroglial tumors with the high grade glial tumors showing higher mean CBV (2.79 vs. 1.72; P value 0.03) as well as higher PS (2.37 vs. 0.95; P value<0.01), however this difference was not significant if only comparing grade III OGs with grade III astroglial tumors. PCT perfusion parameters including PS values do not help grade OGs despite showing a trend for higher CBV and PS in higher grade OGs. Similarly LOH positive OGs also showed slightly higher CBV, but again failed to reach any statistically significant level. Low grade OGs showed slightly higher CBV as compared to low grade astroglial tumors, whereas higher grade OGs showed significantly lower PS values as compared to higher grade astroglial tumors despite showing high CBV.

Tumours arising in the setting of paediatric chronic epilepsy

Along with malformations of cortical development or cortical dysplasia, hippocampal sclerosis, and remote ischaemic damage, tumours are among the more commonly identifiable causes of medically intractable seizures in paediatric age patients. This study reviews one institution's 20 year experience with tumours arising in this clinical setting. Retrospective review of 129 paediatric patients [less than 19 years of age, 65 females (50.4%)] with tumours and medically intractable seizures encountered during a 20 year period of time (1989-2009). Using the most recent World Health Organization (WHO) classification of brain tumours, tumour type and grade were assessed. The most common sites of origin included temporal lobe (n = 77, 59.7%), parietal lobe (n = 20, 15.5%), and frontal lobe (n = 15, 11.6%). WHO grade included 73 (56.6%) grade I tumours, 32 (24.8%) grade II tumours, and 18 (14%) grade I/II tumours. In six cases (4.7%), a WHO grade was not associated with mass. Tumour types included: ganglioglioma (n = 48, 37.2%), dysembryoplastic neuroepithelial tumour (n = 17, 13.2%), low grade astrocytoma (n = 15, 11.6%), low grade mixed glioma (n = 8, 6.2%), low grade oligodendroglioma (n = 5, 3.9%), meningioangiomatosis (n = 4, 3.1%) angiocentric glioma (n = 3, 2.3%), and dysembryoplastic neuroepithelial tumour/ganglioglioma composite tumour (n = 3, 2.3%). Less frequently observed lesions (n = 1 or 2) included pilocytic astrocytoma, protoplasmic astrocytoma, pleomorphic xanthoastrocytoma, and glioneuronal hamartoma. In 18 cases, distinction between low grade glioma and low grade glioneuronal tumour could not be definitively made. Coexisting malformation of cortical development/cortical dysplasia was noted in 29.8% of evaluable cases. In four tumours, coexistent hippocampal sclerosis was identified. Ki-67 labelling indices were less than 5% in all (n = 51) cases assessed. Of 25 tumours evaluated for chromosome 1p status, only one low grade mixed glioma demonstrated evidence of deletion; only one of 22 evaluated tumours (a low grade mixed glioma) showed evidence of chromosome 19q deletion. Collectively, WHO grade I glioneuronal tumours account for slightly more than half of all neoplasms which cause intractable epilepsy in paediatric patients. A significant minority of tumours (n = 18, 14%) were difficult to definitively classify as glioma versus glioneuronal tumour, due to extent of sampling. Coexistent pathologies including malformation of cortical development/cortical dysplasia may be observed in a significant minority of tumours, suggesting a possible developmental origin for some tumours arising in this setting.

Detection of histological anaplasia in gliomas with oligodendroglial components using positron emission tomography with 18F-FDG and 11C-methionine: report of two cases

Gliomas are regionally heterogeneous tumors. Positron emission tomography (PET) with (18)F-fluorodeoxyglucose (FDG) and (11)C-methionine (MET) evaluates the heterogeneity of histological malignancy within the tumor. We present two patients with oligodendrocytic tumors that showed discrepancies in the highest uptake areas with these two tracers. PET studies with MET and FDG were performed on the same day, 2 weeks before surgery. In both cases, biopsy specimens were separately obtained from the highest MET and FDG uptake areas guided by intraoperative neuronavigation. Histological examinations demonstrated that the specimens from the highest MET uptake area revealed low-grade oligoastrocytoma or oligodendroglioma, whereas histological anaplasias were contained in the specimens from the highest FDG uptake area. With gliomas with oligodendroglial components, the MET uptake ratio does not always correspond to histological anaplasia, which can be detected only by FDG PET. Sole application of MET PET for preoperative evaluation may lead to misunderstanding of histological heterogeneity in gliomas, especially those with oligodendroglial components. FDG and MET tracers play complementary roles in preoperative evaluation of gliomas.

Reconsidering the lifetime deferral of blood donation by men who have sex with men

Although leptomeningeal spread (LMS) of primary CNS tumors in children has been well documented in the literature, it has rarely been reported in children with low-grade gliomas. Between 1975 and 1985, 6 of 162 children (3.7%) with low-grade gliomas treated at Children9s Hospital of Philadelphia had LMS. LMS was present at diagnosis of the original tumor in one patient, was the first sign of relapse in one patient, occurred simultaneously with local relapse in two patients, and after local relapse in two patients. Pathology of the original tumor was low-grade astrocytoma in five and low-grade oligodendroglioma in one. Primary tumor site was cervical cord in three, chiasm in one, frontal lobe in one, and cerebellum in one. All of the children with LMS had undergone surgical treatment at the time of diagnosis of the primary tumor; four had total resections at some point in their course. Three of the six patients died; three are still alive after treatment with radiation therapy and/or chemotherapy. The longest survival to date has been 3¹/₂ years after diagnosis of LMS. We compared clinical characteristics of these six patients with 131 children with low-grade tumors without dissemination treated at our institution during the same time period. LMS, although relatively infrequent, does occur in children with low-grade gliomas, especially spinal cord tumors. LMS may occur at any time during illness and diagnosis may be difficult unless LMS is suspected. Treatment, at times, results in clinical improvement and considerable disease control.

Low-grade astrocytoma, anaplastic oligodendroglioma or astrocytoma, and glioblastoma: The clinical trial portfolio of the EORTC Brain Tumor and Radiation Oncology Groups for newly diagnosed patients.

e12551 Background: Better understanding of underlying molecular mechanisms and alterations have led to substantial improvements in classification and therapy of gliomas. Grouping of patients, based...

Abstract 113: The TCGA proneural subtype predicts improved clinical outcome for low-grade oligodendrogliomas

Abstract The Cancer Genome Atlas Project (TCGA) has produced a wide array of omic data on glioblastoma multiforme (GBM) tumors, and has resulted in several works on the molecular subtyping of GBM tumors. Despite its richness, the TCGA dataset currently contains very limited data for low-grade gliomas and progressive GBMs, preventing analysis of progression models and prognostic biomarker discovery for these tumor types. A complementary dataset, the NCI Repository for Molecular Brain Neoplasia Data (REMBRANDT), includes a collection of samples for low-grade and progressive gliomas. This data contains some paired tumors that progressed to GBM and like TCGA, includes pathological and survival information. Our in silico study of low-grade and progressive gliomas has leveraged this complementary data to examine the progression of low-grade gliomas to GBM. The REMBRANDT dataset includes 176 samples with survival outcome data, including 101 grade IV GBM, 32 astrocytomas, and 43 oligodendrogliomas. Of the astrocytomas and oligodendrogliomas, there are 31 grade II samples and 31 grade III samples, with the remainder lacking grade data. We have investigated the gene expression profiles of the REMBRANDT samples to compare them to the established classes from TCGA and other studies. Candidate prognostic biomarkers have been identified to predict the progression of low-grade gliomas. We have found that the TCGA Proneural subtype predicts improved clinical outcome for low-grade oligodendrogliomas, with significantly better survival among all 176 low and high-grade samples (log rank test p = 1.27e-08). Moreover, analysis of 62 grade II and grade III samples determined that the Proneural class still has significantly better outcome (p= 0.0033). Further sub-analysis to control for oligodendrogliomas and grade, found that grade III oligodendrogliomas with the Proneural signature still had significantly improved survival (p &amp;lt; 0.05, n = 12). Stratification using the signatures developed by Li et al that define six oligodendrioma and glioma subtypes demonstrated that the OA subclass had significantly better survival (log rank test p = 9.14e-08). However, these signatures were not significant in multivariate analysis after controlling for grade and disease subtype. Thus, the gene expression patterns identified in the TCGA analysis of GMB has intrinsic prognostic value for low-grade oligondendriomas, and likely represents important differences in tumor biology with implications for treatment and therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 113.

A case report of pseudoprogression followed by complete remission after proton-beam irradiation for a low-grade glioma in a teenager: the value of dynamic contrast-enhanced MRI

A fourteen years-old boy was treated post-operatively with proton therapy for a recurrent low-grade oligodendroglioma located in the tectal region. Six months after the end of irradiation (RT), a new enhancing lesion appeared within the radiation fields. To differentiate disease progression from radiation-induced changes, dynamic susceptibility contrast-enhanced (DSCE) MRI was used with a T2* sequence to study perfusion and permeability characteristics simultaneously. Typically, the lesion showed hypoperfusion and hyperpermeability compared to the controlateral normal brain. Without additional treatment but a short course of steroids, the image disappeared over a six months period allowing us to conclude for a pseudo-progression. The patient is alive in complete remission more than 2 years post-RT.

Spontaneous canine gliomas: overexpression of EGFR, PDGFRα and IGFBP2 demonstrated by tissue microarray immunophenotyping

Fifty-seven spontaneous canine gliomas were histologically classified and graded using the latest World Health Organization (WHO 2007) criteria for classification of human gliomas. A total of 19 canine astrocytomas were classified as follows: grade IV (GBM) n = 7; grade III n = 5; and grade II, n = 7. Thirty-eight oligodendrogliomas were classified as either grade III (anaplastic) n = 35 or low grade II n = 3. Tissue microarray (TMA) immunohistochemistry was used to evaluate tumor expression of EGFR, PDGFRa and IGFBP2, three key molecules of known pathophysiological importance in human gliomas. Findings were correlated with tumor classification and grade. Increased EGFR expression was demonstrated in 57% of GBMs, 40% of grade III and 28% of grade II astrocytomas. EGFR expression occurred in only 3% of grade III oligodendrogliomas. Increased expression of PDGFRalpha was demonstrated in 43% of GBMs, 20% of grade III, and 14% of grade II astrocytomas. In the oligodendroglioma series, 94% of grade III tumors overexpressed PDGFRalpha. IGFBP2 expression was detected in 71, 60 and 28% of GBMs, grade III and grade II astrocytomas respectively. IGFBP2 expression occurred in 48% of anaplastic and in 33% of low grade oligodendrogliomas. Expression of EGFR, PDGFRalpha or IGFBP2 was not detected in normal canine CNS control TMA cores. The incidence of overexpression of EGFR, PDGFRalpha and IGFBP2 in these canine gliomas closely parallels that in human tumors of similar type and grade. These findings support a role for the spontaneous canine glioma model in directed pathway-targeting therapeutic studies.

Chromosome 1p and 19q evaluation in low-grade oligodendrogliomas: A descriptive study

Oligodendrogliomas are rare primary brain tumors with variable patient outcomes which are not always adequately accounted for by clinical or pathological variables. The present study evaluated the prognostic implications of chromosome 1p and 19q status in a set of 23 low grade oligodendrogliomas (OGD II), and correlated the results with patient outcome. Loss of heterozygosity (LOH) and fluorescent in situ hybridization (FISH) analyses, the most widely used standard procedures, were used. 1p and 19q deletions were found in 65 and 61% of cases, respectively, using FISH and in 78 and 72% of cases using LOH. Both deletions were found in 56 and 64% of patients using FISH and LOH, respectively. Concordance between the results from the two techniques, determined by the Kappa statistics, ranged from fair to substantial depending on whether single or combined deletions were considered. Our results showed that the molecular alterations are associated with age and tumor localization. With regard to the impact of chromosomal alterations on clinical outcome, chromosome 19q deletions detected by LOH would seem to indicate a subgroup of patients at a higher risk of relapse, although the small number of patients recruited does not permit any definitive conclusions to be drawn. Further studies are now ongoing to determine whether this methodological approach could be potentially useful in low grade oligodendrogliomas to better characterize chromosomal alterations of 1p/19q and identify subgroups of patients with a higher risk of disease recurrence.

Prognosis and patterns of care in elderly patients with glioma

The current study was conducted to evaluate the patterns of care and survival of older adults with oligodendroglioma (OLI) and astrocytoma (AST) from a large population-based registry. The authors identified a cohort of OLI and AST patients aged >or=65 years from Surveillance, Epidemiology and End Results (SEER) cancer registry data linked with Medicare claims between 1994 and 2002. Patients with a diagnosis of glioblastoma were excluded. The impact of demographic characteristics and comorbidities on the probability of undergoing surgical resection, radiotherapy (RT), and chemotherapy within 6 months of diagnosis was assessed using multivariate logistic regression. A total of 1067 patients (891 with AST and 176 with OLI) were included; the median survival was 9 months for patients with low-grade AST, 4 months for patients with anaplastic AST, 57 months for patients with low-grade OLI, and 9 months for patients with anaplastic OLI. Approximately 54% of patients underwent resection at the time of diagnosis; 66% received RT, and 13% received chemotherapy within 6 months of diagnosis. In a multivariate regression analysis, age and tumor grade were found to be the most significant predictors of resection, RT, or chemotherapy. Patients with anaplastic tumors were treated with resection, RT, and chemotherapy more often than patients with low-grade tumors, and OLI patients received chemotherapy more frequently than AST. Data from the current study suggested that histologic diagnosis and tumor grade retained significant prognostic value in this elderly AST and OLI population. Furthermore, age and tumor grade were found to influence the probability of undergoing surgery, RT, and chemotherapy in this cohort.

Genetic alterations and signaling pathways in the evolution of gliomas

Gliomas are the most common primary brain tumors. They account for more than 70% of all neoplasms of the central nervous system and vary considerably in morphology, location, genetic alterations, and response to therapy. Most frequent and malignant are glioblastomas. The vast majority (>90%) develops rapidly after a short clinical history and without evidence of a less malignant precursor lesion (primary or de novo glioblastoma). Secondary glioblastomas develop more slowly through progression from low-grade or anaplastic astrocytoma. These glioblastoma subtypes constitute distinct disease entities that affect patients of different age, develop through distinct genetic pathways, show different RNA and protein expression profiles, and may differ in their response to radio- and chemotherapy. Recently, isocitrate dehydrogenase 1 (IDH1) mutations have been identified as a very early and frequent genetic alteration in the pathway to secondary glioblastomas as well as that in oligodendroglial tumors, providing the first evidence that low-grade astrocytomas and oligodendrogliomas may share common cells of origin. In contrast, primary glioblastomas very rarely contain IDH1 mutations, suggesting that primary and secondary glioblastomas may originate from different progenitor cells, despite the fact that they are histologically largely indistinguishable. In this review, we summarize the current status of genetic alterations and signaling pathways operative in the evolution of astrocytic and oligodendroglial tumors.

Low-grade oligodendroglioma: current treatments and future hopes

Current treatment modalities for low-grade gliomas include surgery, radiotherapy and chemotherapy. Management of these ultimately incurable tumors remains controversial, particularly the timing and extent of surgery, and the optimal sequence of radiotherapy and chemotherapy thereafter. Two ongoing Phase III trials should provide definitive answers to some of these controversial issues in the treatment of low-grade gliomas and confirm the impact of molecular predictors of response and outcome. This review will discuss recent progress and topical issues in the treatment of low-grade gliomas.

Predictive value of multimodality MRI using conventional, perfusion, and spectroscopy MR in anaplastic transformation of low-grade oligodendrogliomas

The aim of our study was to evaluate the role of proton magnetic resonance (MR) spectroscopy and MR perfusion in the follow-up of low-grade gliomas, since conventional MR imaging (MRI) is not reliable in detecting the passage from a low- to high-grade tumor. Twenty-one patients with a World Health Organisation (WHO) grade II glioma were followed up using proton MR spectroscopy, perfusion, and conventional MRIs. Follow-up MRIs had been performed at the third month of evolution and then twice a year, with an average of five MR studies per patient. Five out of the 21 patients had an anaplastic transformation. A choline to creatine ratio (choline/creatine ratio) above 2.4 is associated with an 83% risk of a malignant transformation in an average delay of 15.4 months. The choline/creatine ratio at this threshold was more efficient than perfusion MR in detecting the anaplastic transformation, with sensitivity of 80% and specificity of 94%. An increased choline/creatine ratio seemed to occur an average 15 months before the elevation of relative cerebral blood volume (rCBV). The mean annual growth of low-grade glioma was 3.65 mm. A growth rate higher than 3 mm per year was also correlated with greater risk of anaplastic transformation. Proton magnetic resonance spectroscopy should be recommended in the follow-up of low-grade gliomas since the choline/creatine ratio can predict anaplastic transformation before perfusion abnormalities, with high positive predictive value of 83%.

Low-grade oligodendroglioma: an indolent but incurable disease?

The authors reviewed their institutional experience with pure low-grade oligodendroglioma (LGO), correlating outcomes with several variables of possible prognostic values. Sixty-nine patients with WHO-classified LGOs were treated between 1992 and 2006 at the McGill University Health Center. Clinical, pathological, and radiological records were carefully reviewed. Demographic characteristics; the nature and duration of presenting symptoms; baseline neurological function; extent of resection; Karnofsky Performance Scale score; preoperative radiological findings including tumor size, location, and absence/presence of enhancement; and pathological data including chromosome arms 1p/19q codeletion and O-methylguanine-DNA methyltransferase promoter gene methylation status were all compiled. The timing and dose of radio- and/or chemotherapy, date of tumor progression, pathological finding at disease progression, treatment at time of disease progression, and status at the last follow-up were also recorded. The median follow-up period was 6.1 years (range 1.3-16.3 years). The majority (78%) of patients presented with seizures; contrast enhancement was initially seen in 16 patients (25%). All patients had undergone an initial surgical procedure: gross-total resection in 27%, partial resection in 59%, and biopsy only in the remaining 13%. Fifteen patients received adjuvant radiotherapy. Data on O-methylguanine-DNA methyltransferase promoter gene methylation status was available in 47 patients (68%) and in all but 1 patient for 1p/19q status. Survival at 5, 10, and 15 years was 83, 63, and 29%, respectively. Multivariate analysis showed that seizures at presentation and the absence of contrast enhancement were the only independent favorable prognostic factors for survival. The 5-, 10-, and 15-year progression-free survival rates were 46, 7.7, and 0%, respectively. This retrospective review confirms the indolent but progressively fatal nature of LGOs. Contrast enhancement was the most evident single prognostic factor. New treatment strategies are clearly needed in the management of this disease.

Oligodendroglioma Arising in an Ovarian Mature Cystic Teratoma

We describe a case of oligodendroglioma arising in an ovarian mature cystic teratoma associated with a loss of heterozygosity on the long arm of chromosomes 19 and 10. To our knowledge it is the second case reported in the literature at this site and the first one described in association with a characterized genetic alteration. The patient was 29 years old and presented with a history of 4 months of pelvic pain. Ultrasound examination showed a cystic mass arising in the left adnexa suggesting a teratoma. At laparotomy a cystic ovoid mass was found arising from the left adnexa, completely replacing the ovary. An ovariectomy was performed. Macroscopically a multilocular cyst containing hair, sebum, and a relatively well-defined solid zone of grayish-pink color strongly suggestive of a cerebral tissue, was observed. Microscopic analyses confirmed the teratomatous nature of the cyst. The solid area was composed of mature glial tissue in which was observed a proliferation of monotonous cells with round and homogenous nuclei, surrounded by a clear halo of cytoplasm ("honeycomb appearance") which immunohistochemically showed positivity for glial fibrilar acidic protein and for neurofilament protein. Ki-67 labeling index was about 3%. These findings were consistent with a low-grade oligodendroglioma arising in a mature ovarian cystic teratoma. Reverse transcription-polymerase chain reaction analysis showed a characterized loss of heterozygosity occurring in tumor DNA on chromosomes 10q and 19q13.

Primary leptomeningeal oligodendroglioma with documented progression to anaplasia and t(1;19)(q10;p10) in a child

Oligodendrogliomas are infiltrating gliomas typically arising in the cerebral cortex and white matter. Rare examples present with diffuse leptomeningeal involvement in the absence of a clinically/radiologically detectable intraparenchymal tumor [1–5, 7, 8, 10, 14, 15]. Although oligodendrogliomas are rare in children, most primary leptomeningeal oligodendrogliomas have occurred in the first decade of life (Table 1). We report the case of a 3-year-old girl, who presented with progressive regression of her ability to walk and an increase of cranial circumference. MRI showed marked hydrocephalus and diffuse leptomeningeal enhancement without supratentorial intraparenchymal lesions (Fig. 1a–c). A C3–C4 mildly enhancing 5 mm nodule was present, which could not be defined with certainty as meningeal or intraparenchymal (Fig. 1c). Cerebrospinal fluid (CSF) was xanthochromic, with high protein (177 mg/dl), normal glucose (63 mg/dl) and increased white blood cells (47 cells/mm, 50% mononuclear). Bacterial cultures were negative, but polymerase chain reaction showed CSF positivity for M. tuberculosis. A diagnosis of basal meningitis was made and the child was unsuccessfully treated with anti-tuberculosis therapy. When a meningeal biopsy demonstrated a low-grade neuroectodermal tumor consistent with low-grade oligodendroglioma, the patient was started on chemotherapy, according to the SIOP protocol for low-grade gliomas, based on vincristine and carboplatin, changed later to vincristine and cisplatin alternating with cyclophosphamide every 6 weeks due to an allergic reaction to carboplatin. Chemotherapy was suspended at 18 months, after remarkable improvement of her clinical condition. She also received radiotherapy at the level of C2–C4, because of the gradual increase of the cervical nodule (54 Gy in 30 fractions). The child remained stable for the following 3 years, when her tumor progressed to anaplastic oligodendroglioma, as confirmed by a new biopsy of a left frontal paraventricular nodule. At this time, MRIs demonstrated multiple enhancing nodules filling the ventricles, suggesting involvement of the sub-ependymal parenchyma (Fig. 1d–f). The patient received temozolomide, but her clinical condition continued to deteriorate and she expired, 7 years from the original diagnosis. The first biopsy consisted of a very small fragment of leptomeninges showing dominant reactive changes with hyperplastic meningothelial cells and inflammation. A small focus of monomorphous cells with round nuclei diffusely expressing S100 protein and focally GFAP was seen (Fig. 2a). The second biopsy revealed a highly cellular neoplasm with small cells with hyperchromatic round nuclei and perinuclear halos similar to the original ones (Fig. 2b). Numerous mitoses were identified (up to 8/10 HPF). S100 protein expression was extensive, GFAP was focal. Neu-N, synaptophysin, EMA and CKAE1/AE3 stains were negative. p53 was expressed in rare nuclei. MIB-1 labeling index was high (up to 50%). Electron microscopy demonstrated round cells with scant organelles lacking ependymal features. 1p/19q co-deletion and S. Rossi A. P. Dei Tos F. D. Paola M. Bendini S. Agostini P. Longatti Departments of Pathology, Neuroradiology, Pediatrics and Neurosurgery, Regional Hospital, Treviso, Italy

Retrospective review of prognostic factors, including 1p19q deletion, in low‐grade oligodendrogliomas and a review of recent published works

The purpose of the present study was to investigate potential prognostic factors in low-grade oligodendrogliomas (LGOs), particularly 1p19q deletion, due to its proven prognostic significance in anaplastic oligodendrogliomas. We carried out a retrospective review of patients with a histological diagnosis of LGO between 1990 and 2000 in Auckland and Wellington, New Zealand. All cases underwent central histopathological review and FISH testing for 1p19q status. Univariate analysis of potential prognostic factors including 1p19q status, age, tumour size, tumour crossing midline, tumour enhancement, extent of surgery and seizures at diagnosis was carried out. Thirty-one patients were eligible and FISH testing was successful in 28 specimens (90%). Twenty-three specimens (82%) had 1p19q deletion; four (14%) had no 1p19q deletion; and one (4%) had 1p deletion alone. At a median follow-up of 87 months (0-147 months), median survival had not been reached and no significant difference in overall survival (OS) based on 1p19q status was detected (1p19q deletion OS 56%; 1p19q intact OS 0%; 1p deletion alone 100% (P = 0.38)). None of the other prognostic factors investigated reached statistical significance. We confirmed the high incidence (82%) of combined 1p19q deletion in LGOs and the feasibility of successful FISH testing in paraffin embedded specimens up to 10-years-old. Analysis of potential prognostic factors was limited by the lack of events during the follow-up period.

Phase II trial of temozolomide (TMZ) followed by myeloablative chemotherapy with autologous peripheral blood progenitor cell rescue (APBPCR) for newly diagnosed anaplastic oligodendroglioma: An Oligodendroglioma Study Group trial

2055 Background: Treatment of anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytomas (AOA) is controversial. Radiotherapy (RT) remains the standard therapy, but not without toxicity. Exploiting the chemosensitivity of these tumors using myeloablative chemotherapy with APBPCR is a potential strategy to defer RT. We previously reported results using induction PCV chemotherapy; subsequently the induction regimen was changed to temozolomide (TMZ) which is reported here. Methods: Patients were treated with six cycles of TMZ at 200mg/m2 on standard 5/28 day schedule. MRI was performed after three cycles and then after six cycles. Patients with surgical gross total resection who maintained response or patients who responded to temozolomide (CR or PR defined as &gt;50% reduction in tumor) were eligible for myeloablative chemotherapy with thiotepa 250mg/m2/day for three days followed by busulfan 3.2mg/kg/day for three days, followed by APBPCR. 1p19q status was analyzed prospectively; however, patients were enrolled without regard to deletion status. Results: 19 patients (16 AO, 2 AOA, 1 low-grade oligodendroglioma with radiographic features suggestive of high-grade tumor) with a median age of 42 (28–56) and KPS of 90 (70–100) were enrolled. 13 patients had co-deletion of 1p/19q, 2 had intact 1p/19q, 1 pt had biopsy without enough tissue, and pending in 3. Eleven patients were eligible for APBPCR: 10 patients either maintained surgical CR (9) or had a response to TMZ (1) and went on to transplant; one surgical CR pt refused transplant. Six patients were ineligible for transplant because best response of SD (2), PD (2, both 1p19q intact), insurance denial (2). Two patients are still receiving induction TMZ. Median progression-free (PFS) and overall survivals (OS) have not been reached at a median follow-up of 20 months. 2 of the 10 patients who underwent APBPCR recurred, one at 16.1 and one at 34.2 months. No veno-occlusive disease was observed during transplant and no treatment-related deaths occurred. Conclusions: TMZ followed by myeloablative chemotherapy with APBPCR can be safely administered to newly diagnosed AO patients. [Table: see text]