This is a class of gliomas arising from oligodendrocytes. It has a characteristic histologic appearance with the cells often described as a "fried egg" appearance.
Epidemiology Disease Associations Pathogenesis Laboratory/Radiologic/Other Diagnostic Testing Gross Appearance and Clinical Variants Histopathological Features and Variants Special Stains/
Differential Diagnosis Prognosis Treatment Commonly Used Terms Internet Links
EPIDEMIOLOGY CHARACTERIZATION INCIDENCE 5% of glial neoplasms
PATHOGENESIS CHARACTERIZATION LOSS OF HETEROZYGOSITY
Allelic losses in oligodendroglial and oligodendroglioma-like neoplasms: analysis using microsatellite repeats and polymerase chain reaction.
Johnson MD, Vnencak-Jones CL, Toms SA, Moots PM, Weil R.
Department of Pathology, Vanderbilt Medical School, Nashville, Tenn 37232, USA.
Arch Pathol Lab Med. 2003 Dec;127(12):1573-9. Abstract quote
CONTEXT: Oligodendroglial tumors are heterogenous neoplasms with histologic features shared with other central nervous system tumors, such as dysembryoplastic neuroepithelial tumors.
OBJECTIVE: We examined a series of tumors, identified as possessing oligodendroglial components at the time of intraoperative examination, to see if molecular subsets based on the oligodendroglial component could be recognized.
DESIGN: DNA was extracted from fresh brain tumor tissue and corresponding peripheral blood or normal tissues. Genotypes for multiple loci were determined by polymerase chain reaction amplification using fluorescent-labeled primers for markers on chromosomes 1p, 17p, and 19q.
RESULTS: Of the 12 oligodendrogliomas, 6 (60%) of 10 informative cases for 1p exhibited loss of heterozygosity (LOH). Six (50%) of 12 informative cases for 19q exhibited LOH. Each case also showed LOH at 1p. Three (25%) of 12 informative cases exhibited LOH at 17p for the dinucleotide repeat within the TP53 gene. In oligoastrocytomas, none of 4 informative cases showed LOH at 1p, 1 (25%) showed LOH at 19q, and 2 (50%) at 17p. One case also displayed microsatellite instability at 3 of 8 markers. In the 3 anaplastic oligodendrogliomas, 1 was not informative for 1p and none of the informative tumors exhibited LOH at 1p or 17p; 1 case (33%) exhibited LOH at 19q. Of the 14 informative anaplastic oligoastrocytomas, LOH was seen in 5 (36%) at both 1p and 19q and in 2 (14%) at 17p. Those with allelic loss at TP53 were astrocytoma predominant. No dysembryoplastic neuroepithelial tumors exhibited LOH at any marker on 1p, 17p, or 19q.
CONCLUSIONS: These findings suggest that routine screening for allelic losses, in samples intraoperatively determined to have an oligodendroglial component, will reveal prognostically or therapeutically relevant information in the majority of cases.
- Arch Pathol Lab Med. 2007 Feb;131(2):242-51. Abstract quote
CONTEXT: Significant interobserver variability exists with respect to the diagnosis of oligodendroglial neoplasms, especially their distinction from astrocytoma and mixed oligoastrocytoma. Combined loss of the short arm of chromosome 1 and the long arm of chromosome 19 has been shown to be both relatively specific to oligodendroglioma and, when present, a marker of improved prognosis in patients with these tumors. In addition, 1p/19q loss has been shown to be a marker of "classic" oligodendroglial histology. These findings raise questions as to the role of 1p/19q testing in clinical practice, both as a prognostic marker and as a potential diagnostic marker among infiltrating glial neoplasms.
OBJECTIVE: This review discusses the issues raised above and tries to clarify the current status of 1p/19q evaluation in the diagnosis of oligodendroglioma.
DATA SOURCES: Sources for this review include recent literature as well as the experience of 3 practicing neuropathologists.
CONCLUSIONS: 1p/19q status is an important marker in oligodendroglioma. Loss of 1p/19q is associated with classic oligodendroglioma histology as well as improved prognosis. The combined 1p/19q marker will continue to be a clinically useful marker of prognosis and could potentially be incorporated into diagnostic criteria in the future.
Losses of Chromosomal Arms 1p and 19q in the Diagnosis of Oligodendroglioma. A Study of Paraffin-Embedded Sections
Peter C. Burger, M.D., A. Yuriko Minn, M.S., Justin S. Smith, M.D., Ph.D., Thomas J. Borell, B.S., Anne E. Jedlicka, M.S., Brenda K. Huntley, B.S., Patricia T. Goldthwaite, M.S., Robert B. Jenkins, M.D., Ph. D. and Burt G. Feuerstein, M.D., Ph.D.
The Departments of Pathology (PCBPTG) and Anesthesiology and Critical Care Medicine (AEJ), Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Pathology and Laboratory Medicine, Mayo Clinic (JSS, TJB, BKH, RBJ), Rochester, Minnesota; and Departments of Laboratory Medicine and Neurosurgery and Brain Tumor Research Center, University of California at San Francisco School of Medicine (BGF, AYM), San Francisco, California
Modern Pathology 14:842-853 (2001) Abstract quote
Comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH), polymerase chain reaction–based microsatellite analysis, and p53 sequencing were performed in paraffin-embedded material from 18 oligodendrogliomas and histologically similar astrocytomas.
The study was undertaken because of evidence that concurrent loss of both the 1p and 19q chromosome arms is a specific marker for oligodendrogliomas.
Of the six lesions with a review diagnosis of oligodendroglioma, all had the predicted loss of 1p and 19q seen by CGH, FISH, and polymerase chain reaction. Other lesions, including some considered oligodendroglioma or mixed glioma by the submitting institution, did not. There were no p53 mutations in any of the six oligodendrogliomas, whereas 5 of the 10 remaining, successfully studied cases did have p53 mutations.
The results suggest that CGH and FISH performed on current or archival tissue can aid in classification of infiltrating gliomas such as oligodendrogliomas and astrocytomas. The results of the p53 studies are consistent with findings of previous investigations that such mutations are less common in oligodendrogliomas than they are in astrocytomas.
PTEN mutation analysis in two genetic subtypes of high-grade oligodendroglial tumors. PTEN is only occasionally mutated in one of the two genetic subtypes.
Jeuken JW, Nelen MR, Vermeer H, van Staveren WC, Kremer H, van Overbeeke JJ, Boerman RH.
Department of Neurosurgery, University Hospital Nijmegen, Nijmegen, The Netherlands.
Cancer Genet Cytogenet 2000 May;119(1):42-7 Abstract quote
We recently identified two genetic subtypes of high-grade oligodendroglial tumors (HG-OT): 1p-/19q- HG-OT are characterized by a loss of chromosome 1p32-36 (del(1)(p32-p36) and/or a del(19)(q13. 3); whereas +7/-10 HG-OT harbor a gain of chromosome 7 (+7) and/or a -10 without a loss of 1p32-36 and 19q13.3. Because a -10 and a +7 are most frequently detected in glioblastomas (GBM), the genotype of +7/-10 HG-OT suggests that these tumors are GBM with a prominent oligodendroglial phenotype rather than anaplastic oligodendrogliomas. PTEN is a tumor suppressor gene, located at 10q23.3, which is involved in tumor progression of GBM and other neoplasms.
In this study, we screened for PTEN mutations in six low-grade oligodendroglial tumors (LG-OT), five 1p-/19q- HG-OT, seven +7/-10 HG-OT, and nine xenografted GBM. PTEN mutations were detected in none of the LG-OT and 1p-/19q- HG-OT, once in +7/-10 HG-OT, and frequently in GBM. As one of the +7/-10 HG-OT harbored a PTEN mutation, this demonstrates that PTEN can be involved in the oncogenesis of this genetic subtype of HG-OT. The lower frequency of PTEN mutations in +7/-10 HG-OT compared to GBM suggests that these tumors are of a distinct tumor type rather than GBM.
CHARACTERIZATION LABORATORY COMPARITIVE GENOMIC HYBRIDIZATION
Identification of subgroups of high-grade oligodendroglial tumors by comparative genomic hybridization.
Jeuken JW, Sprenger SH, Wesseling P, Macville MV, von Deimling A, Teepen HL, van Overbeeke JJ, Boerman RH.
Department of Neurosurgery, University Hospital Nijmegen, The Netherlands.
J Neuropathol Exp Neurol 1999 Jun;58(6):606-12 Abstract quote
In contrast to astrocytic tumors, approximately two thirds of anaplastic oligodendrogliomas are reported to be chemosensitive. Relatively little is known about the genetic aberrations in oligodendroglial tumors (OTs).
In order to elucidate oligodendroglial oncogenesis and to find specific genetic aberrations that may have prognostic and therapeutic implications, we performed comparative genomic hybridization (CGH) to detect chromosomal copy number changes in 17 low-grade OTs (LG-OTs) and 12 high-grade OTs (HG-OTs) lacking a prominent astrocytic component. Loss of chromosome 1p (79%) and 19q (76%) were most frequently detected by CGH, all LG-OTs and 50% of the HG-OTs contained -1p (including 1p36-32), -19q (including 19q13.3), or both, and the rest of the HG-OTs showed +7, -10, or both. Since losses of 1p36-32 and 19q13.3 were mutually exclusive with +7 or -10, the HG-OTs could be divided in -1p/-19q and +7/-10 tumors. While the -1p/-19q tumors can be considered as pure anaplastic oligodendrogliomas, the +7/-10 tumors may rather be glioblastomas with prominent oligodendroglial differentiation.
We conclude that CGH is a powerful tool to assist in the identification of 2 major subgroups of HG-OTs with prognostic and possibly therapeutic relevance.
- Fluorescence In Situ Hybridization (FISH) on Touch Preparations: A Reliable Method for Detecting Loss of Heterozygosity at 1p and 19q in Oligodendroglial Tumors.
Scheie D, Andresen PA, Cvancarova M, Bo AS, Helseth E, Skullerud K, Beiske K.
*The Pathology Clinic, Departments of Pathology daggerBiostatistics double daggerNeurosurgery, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway.
Am J Surg Pathol. 2006 Jul;30(7):828-837. Abstract quote
Combined loss of heterozygosity (LOH) on 1p and 19q is reported in 50% to 90% of oligodendroglial tumors and has emerged as a strong and favorable prognostic factor. Fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR) are the most widely used techniques.
The aim of this study was to evaluate the reliability of FISH to predict LOH at 1p and 19q when performed on touch preparations from 40 oligodendroglial tumors, even if the majority of the nuclei showed chromosomal imbalance. PCR was used as the gold standard. The presence of none or one target signal was reported as FISH-LOH, whereas all other losses were defined as FISH-imbalance. The sum of nuclei with FISH-LOH and imbalance was calculated in each case (FISH-sum) and cut-off values were defined as the mean FISH-sum value in controls plus 3 standard deviations; 27.7% for 1p and 33.2% for 19q. These corresponded well with the optimal cut-off values for our data, calculated using the minimum error rate classification procedure (35.6% for 1p and 33.1% for 19q). Concurrent FISH and PCR results were encountered in 95% for 1p and 87.5% for 19q. FISH-sum was the best and simplest discriminating variable for correct classification of LOH status.
Under these conditions, even a dominant population of nuclei showing FISH-imbalance represented an LOH status in the tumor cells. FISH on touch preparations is a quick and reliable method for 1p/19q testing, does not require normal DNA and can be easily performed in an immunohistochemistry unit.
POLYMERASE CHAIN REACTION Real-Time Quantitative PCR Analysis of Gene Dosages Reveals Gene Amplification in Low-Grade Oligodendrogliomas
M. Eva Alonso, PhD, etal.
Am J Clin Pathol 2005;123:900-906 Abstract quote
Proto-oncogene amplification is an important alteration that is present in about 45% to 50% of high-grade human gliomas. We studied this mechanism in 8 genes (cyclin-dependent kinase-4 [CDK4], MDM2, MDM4, renin-angiotensin system-1, ELF3, GAC1, human epidermal growth factor receptor-2, and platelet-derived growth factor receptor-A gene) in a series of 40 oligodendrogliomas (World Health Organization (WHO) grade II, 21; WHO grade III, 13; and WHO grade II-III oligoastrocytomas, 6) using real-time quantitative polymerase chain reaction.
Amplification of at least 1 of these genes was detected in 58% of samples (23/40). By histopathologic grade, 67% of grade II oligodendrogliomas (14/21), 46% of grade III anaplastic oligodendrogliomas (6/13), and 50% of mixed oligoastrocytomas (3/6) were positive for amplification of at least 1 gene. CDK4, MDM2, and GAC1 were the most frequently involved genes (12/40 [30%], 12/40 [30%], and 13/40 [33%], respectively).
Our findings demonstrate gene amplification in low-grade samples indicating that it is an important alteration in the early steps of oligodendroglioma development and, therefore, might be considered a molecular mechanism leading to malignant progression toward anaplastic forms.
CLINICAL VARIANTS CHARACTERIZATION DISSEMINATED
- Disseminating anaplastic brainstem oligodendroglioma associated with allelic loss in the tumor suppressor candidate region D19S246 of chromosome 19 mimicking an inflammatory central nervous system disease in a 9-year-old boy.
Mittelbronn M, Wolff M, Bultmann E, Nagele T, Capper D, Beck R, Meyermann R, Beschorner R.
Institute of Brain Research, University of Tuebingen, D-72076 Tuebingen, Germany.
Hum Pathol. 2005 Jul;36(7):854-7. Abstract quote
We report the case of a 9-year-old boy clinically presenting with severe headache, vomiting, head retroflexion, nystagmus, and ataxia. Magnetic resonance imaging showed brainstem enlargement leading to the diagnosis of an inflammatory process. In addition, the clinical picture, a monocytic cerebrospinal fluid pleocytosis with elevated protein and lactate and serum IgM antibodies to Mycoplasma pneumoniae favored this diagnosis. Subsequently, corticosteroid treatment rapidly improved clinical symptoms, and lesions declined in subsequent neuroradiological examinations. However, 2 months later, fulminant disease progression led to brain death.
Final neuroradiological examination favored meningoencephalitis. The autopsy revealed brain swelling and brainstem softening with a superficial gelatinous mass extending along the spinal cord. Finally, a disseminating anaplastic oligodendroglioma with allelic loss of the D19S246 tumor suppressor candidate locus of chromosome 19 was diagnosed.
To our knowledge, this is the first case of a disseminating anaplastic brainstem oligodendroglioma associated with this specific allelic loss occurring in childhood.
HISTOLOGICAL TYPES CHARACTERIZATION General Tumor tends to infiltrate the cortical gray matter with perineuronal satellitosis, subpial accumulation, and perivascular aggregation
Round uniform nuclei with sparse mitotic figures
May have microcysts, palisading, and islands and lobules of clustered cells
Fried egg artifact is caused by fixation artifact but is not always present, frequently absent in frozen sections and in tumors previously frozen and then later fixed and paraffin embedded
Calcifications may be abundant
Chicken wire vasculature
Mitoses are usually few
Grading Variables include increased cellularity, microcysts, cytologic atypia, mitotic activity, vascular proliferation, pleomorphism, and necrosis VARIANTS OLIGOASTROCYTOMA
Clonality of oligoastrocytomas.
Dong ZQ, Pang JC, Tong CY, Zhou LF, Ng HK.
Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, China.
Hum Pathol 2002 May;33(5):528-35 Abstract quote
Oligoastrocytomas (OA) are mixed glial tumors that show morphologic features of both oligodendrogliomas and astrocytomas. The histogenesis of these tumors remains undefined. The aim of this study was to investigate the clonality of OA on the basis of tumor-dependent genetic alterations and tumor-independent X-chromosome inactivation.
We microdissected 11 biphasic OA and subjected the oligodendroglial and astrocytic components to allelic loss analysis of chromosomes 1p, 9p21, 10q, 13q, 17p, and 19q; TP53 immunohistochemical and mutation analyses; and X-linked HUMARA gene methylation study. On the basis of the genetic findings, we categorized these tumors into 3 groups. Group 1 consisted of 4 tumors that showed identical genetic aberrations in the 2 histologic elements, characterized by allelic loss on 1p and 19q. These results suggest that group 1 tumors are of monoclonal origin and share a precursor cell with oligodendrogliomas. Group 2 consisted of 5 tumors characterized by losses on 1p and 19q, with additional allelic losses on chromosomes 9p, 10q, 13q and/or 17p. Four of these tumors were of the anaplastic type. Thus, group 2 tumors may be regarded as advanced variants of group 1 OA with heterogeneous genetic changes during clonal expansion. The X-chromosome inactivation analysis confirmed the monoclonality of groups 1 and 2 OA. Group 3 consisted of two tumors that showed divergent allelic loss patterns in the 2 histologic components. Mutation and overexpression of TP53 were detectable in the astrocytic components only.
These findings raise the possibility that group 3 tumors have a biclonal origin. In conclusion, our results suggest that OA are predominantly of monoclonal origin but that a small subset of tumors may be derived from different precursors.
- Gliosarcoma Arising in Oligodendroglial Tumors ("Oligosarcoma"): A Clinicopathologic Study.
- Rodriguez FJ,
- Scheithauer BW,
- Jenkins R,
- Burger PC,
- Rudzinskiy P,
- Vlodavsky E,
- Schooley A,
- Landolfi J.
*Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN daggerDepartment of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD double daggerJFK Medical Center, Neuroscience Institute Edison, NJ section signRambam Medical Center, Haifa, Israel.
- Am J Surg Pathol. 2007 Mar;31(3):351-362. Abstract quote
Gliosarcomas are morphologically biphasic tumors composed of glial and sarcomatous elements. Only rare examples of gliosarcoma with oligodendroglial components have been reported. Seven patients with oligodendroglial tumors and a sarcomatous component were identified. Fluorescence in situ hybridization for 1p/19q was sought in glial and sarcomatous regions in all cases. Their mean age at diagnosis of gliosarcoma was 48 years (range 36 to 68) (F:M ratio=5:2).
At first resection, the tumors included grade II oligodendroglioma (n=3), grade III oligodendroglioma (n=1), grade II oligoastrocytoma (n=1), and grade III oligoastrocytoma (n=2). The sarcomatous component developed in recurrent/progressive tumors in 6 cases but was a focal finding at first tumor resection in 1 and included fibrosarcoma (n=5), leiomyosarcoma (n=1), or pleomorphic myogenic sarcoma (n=1). Rhabdoid change was a focal finding in the sarcomatous component of 1 tumor. The glial component expressed both glial fibrillary acidic protein and S-100 in all cases, whereas the sarcomatous component at least focally showed smooth muscle actin (n=6), CD34 (n=4), S-100 protein (n=3), and epithelial membrane antigen (n=2) reactivity.
Fluorescence in situ hybridization studies demonstrated 1p/19q codeletion in 5 cases, showed no evidence of deletion in 1 case, and technically failed in 1 case. Three of the 5 cases demonstrated 1p/19q codeletion in the sarcomatous component as well. Gliosarcomas with oligodendroglial elements are rare.
The relatively frequent presence of 1p/19q codeletion in both glial and sarcomatous components supports the notion that the sarcomatous component represents a metaplastic change occurring in the glial element, the same mechanism active in classic astrocytic gliosarcomas.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES GLIOMAS
- Clarifying the diffuse gliomas: an update on the morphologic features and markers that discriminate oligodendroglioma from astrocytoma.
Gupta M, Djalilvand A, Brat DJ.
Department of Pathology and Laboratory Medicine and the Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
Am J Clin Pathol. 2005 Nov;124(5):755-68. Abstract quote
Diffuse gliomas are the most common brain tumors and include astrocytomas, oligodendrogliomas, and oligoastrocytomas. Their correct pathologic diagnosis requires the ability to distinguish astrocytic from oligodendroglial differentiation in histologic sections, a challenging feat even for the most experienced neuropathologist.
Interobserver variability in the diagnosis of diffuse gliomas has been high owing to subjective diagnostic criteria, overlapping morphologic features, and variations in training and practice among pathologists. A select, albeit imperfect, group of molecular and immunohistochemical tests are available to assist in diagnosis of these lesions. Combined loss of chromosomes 1p and 19q is a genetic signature of oligodendrogliomas, whereas gains of chromosome 7 in the setting of intact 1p/19q are more typical of astrocytomas. Detection of amplified epidermal growth factor receptor favors the diagnosis of high-grade astrocytomas over anaplastic oligodendroglioma, which is especially relevant for small cell astrocytomas. Strong nuclear staining for p53 often reflects TP53 mutation and is typical of low-grade astrocytomas.
The Olig family of transcription factors has not demonstrated their diagnostic usefulness. Diffuse gliomas remain a diagnostic challenge, and new markers are needed for proper classification and directed therapies.
NEUROCYTOMA Positive for synaptophysin and NSE
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSTIC FACTORS Like gliomas, these tumors exhibit histologic progression to anaplasia and malignancy, but occurs at a slower pace 1p/19q DELETIONS
Pilot evaluation of 1p and 19q deletions in anaplastic oligodendrogliomas collected by a national cooperative cancer treatment group.
Jenkins RB, Curran W, Scott CB, Cairncross G.
Department of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA
Am J Clin Oncol 2001 Oct;24(5):506-8 Abstract quote
Radiation Therapy Oncology Group (RTOG) trial 94-02 is designed to compare the effectiveness of radiation therapy alone with radiation therapy plus procarbazine, lomustine, and vincristine (PCV) chemotherapy in patients with anaplastic oligodendrogliomas and mixed oligoastrocytomas.
This prospectively collected, randomly treated, prospectively followed cohort is the ideal set of patients to validate the observation that anaplastic oligodendrogliomas with 1p and 19q deletions have a prolonged survival and a better response to chemotherapy. For patients entered on RTOG 94-02, fresh blood specimens, as well as slides and paraffin blocks, have been obtained (with informed consent) on enrollment. Peripheral blood leukocytes (buffy coats) have been frozen and stored and Epstein-Barr-virus-immortalized lymphoblastoid lines have been prepared from the blood specimens. In this report, the authors describe a pilot 1p/19q deletion analysis of 26 tumors from RTOG trial 94-02. In this analysis, it is shown that 1p/19q deletion analysis by fluorescence in situ hybridization is feasible on blocks collected from this trial. Also demonstrated is that the incidence of 1p and 19q deletions in this pilot series of anaplastic oligodendrogliomas and mixed oligoastrocytomas is similar to that reported in previous studies.
When the clinical follow-up on this prospective trial is mature and the deletion studies have been completed, the authors should be able to determine whether 1p and 19q deletions predict a prolonged survival and/or responsiveness to PCV chemotherapy plus radiation in patients with anaplastic oligodendrogliomas and mixed oligoastrocytomas.
BETA III TUBULIN
Localization of the neuronal class III beta-tubulin in oligodendrogliomas: comparison with Ki-67 proliferative index and 1p/19q status.
Katsetos CD, Del VL, Geddes JF, Aldape K, Boyd JC, Legido A, Khalili K, Perentes E, Mork SJ.
Department of Pediatrics, St Christopher's Hospital for Children, Philadelhpia, PA 19134, USA.
J Neuropathol Exp Neurol 2002 Apr;61(4):307-20 Abstract quote
The class III beta-tubulin isotype (betaIII) is widely regarded as a neuronal marker in development and neoplasia. Whereas the expression of betaIII in neuronal/neuroblastic tumors is differentiation-dependent, the aberrant expression of this cytoskeletal protein in astrocytomas is associated with an ascending gradient of malignancy.
To test the generality of this observation we have compared the immunoreactivity (IR) profiles of the betaIII isotype with the Ki-67 nuclear antigen proliferative index in 41 archival, surgically excised oligodendrogliomas (32 classical [WHO grade II] and 9 anaplastic [WHO grade III]). Seventeen of 41 tumors were examined by quantitative microsatellite analysis for loss of 1p and/or 19q. Minimal deletion regions were defined on 1p (D1S468, D1S214) and 19q (D19S408, D19S867).
Three of 10 classical oligodendrogliomas had combined 1p/19q loss, while 2 exhibited loss of either 1p or 19q. Three of 7 anaplastic tumors had combined 1p/19q loss. BetaIII IR was present in all tumors, but was significantly greater in the anaplastic (median labeling index [MLI] 61%, interquartile range [IQR] 55%-64%) as compared with the classical variants (MLI, 19%, IQR, 11-36%) (p < 0.0001).
A highly significant relationship was found to exist between betaIII and Ki-67 LIs (betaIII, p < 0.0001 and Ki-67, p < 0.0001. r = 0.809). BetaIII localization delineated hitherto understated unipolar or bipolar tumor phenotypes with growth cones and leading cell processes resembling migrating oligodendrocyte progenitor cells. Codistribution of betaIII and GFAP IR was present in "gliofibrillary" tumor areas. Synaptophysin IR was detected in rare tumor cells (mean LI, 0.7%), and only in 4/41 samples (10%), denoting a lack of relationship between betaIII and synaptophysin expression. No significant differences in betaIII LIs were observed in tumors with 1p and/or 19q loss as compared to those with 1p/19q intact status. Increased betaIII IR in oligodendrogliomas is associated with an ascending degree of malignancy and thus is a potentially useful tumor marker.
However, the significance of high betaIII LIs in low-grade oligodendrogliomas with respect to prognostic and predictive value requires further evaluation. Class III beta-tubulin expression in oligodendrogliomas should not be construed as a priori evidence of divergent neuronal differentiation.
Interobserver variability in determining MIB-1 labeling indices in oligodendrogliomas.
Prayson RA, Castilla EA, Hembury TA, Liu W, Noga CM, Prok AL.
Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, OH.
Ann Diagn Pathol 2003 Feb;7(1):9-13 Abstract quote
Several studies have shown that MIB-1 labeling indices correlate well with tumor grade and prognosis in a variety of tumor types. Several factors are responsible for some degree of variability in the determination of labeling indices. Interobserver variability is one of the factors often cited as responsible for this variability. A slide from each of 30 oligodendrogliomas, stained with MIB-1 antibody, was distributed to six pathologists.
The same set of slides was reviewed by each individual. Each pathologist was instructed to determine a MIB-1 labeling index by evaluating 1,000 tumor cell nuclei from the area of the slide with the most staining. The labeling index record reflected a percentage of positive-staining tumor cells. Interobserver agreement was compared. MIB-1 labeling indices ranged from 0 to 45.7. Overall agreement was good (>/=0.75) with a concordance coefficient of 0.832 (confidence interval, 0.700 to 0.909). Variability was greater among tumors with higher labeling indices as compared with tumors with labeling indices closer to 0. The overall agreement of MIB-1 labeling indices, while not perfect, was good.
The generally minor variability among observers may be related to differences in the area of the slide evaluated and in differing lower thresholds for interpreting positivity. Further improvement of concordance may theoretically be attainable by further training and discussion among observers.
Immunohistochemical Analysis of p18INK4C and p14ARF Protein Expression in 117 Oligodendrogliomas Correlation With Tumor Grade and Clinical Outcome
Andrey Korshunov, MD, DSc and Andrey Golanov, MD, DSc
From the Departments of Neuropathology (Dr Korshunov) and Neuro-oncological Surgery (Dr Golanov), Burdenko Neurosurgical Institute, Moscow, Russia.
Arch Pathol Lab Med 2002;Vol. 126, No. 1, pp. 42–48. Abstract quote
Objective.—To investigate immunoexpression of 2 cyclin-dependent kinase inhibitors, p18INK4C (p18) and p14ARF (p14), in oligodendrogliomas and to evaluate the possible association with tumor grade and clinical outcome.
Design.—One hundred seventeen specially selected cases of cerebral oligodendrogliomas were studied retrospectively. Tumor specimens were immunohistochemically examined with antibodies to p18INK4C (118.2) and p14ARF (FL-132) proteins. A computerized color image analyzer was used to count immunostained nuclei.
Results.—p18 nuclear immunoexpression was found in 57 (49%) of the oligodendrogliomas we studied. p18 immunoreactivity exhibited a clear tendency to elevate with increasing tumor grade, and the mean p18 labeling index was 9.7% for low-grade (World Health Organization [WHO] grade II) and 19.2% for high-grade (WHO III) tumors. p14-immunopositive nuclei were found in 87 (74%) tumors, and p14 immunoreactivity showed no correlation with oligodendroglioma histological malignancy. Survival times were significantly reduced for p18-positive tumors, and risk of death was independently associated with p18 expression (hazard ratio = 2.48; P = .01). There was no difference in survival times in patients with or without p14 immunoreactivity.
Conclusions.—p18 protein expression is closely associated with malignant oligodendrogliomas and worse clinical outcome. It seems unlikely that p14 immunohistochemistry will be of value in assessing individual prognosis for these tumors.
TREATMENT After surgery, some tumors may respond to chemotherapy
Radiotherapy may be most efficacious in partially resected tumors
CHEMOTHERAPY PCV (procarbazine, lomustine, and vincristine)
Anaplastic oligodendrogliomas respond 50% of the time to this combination of drugs
PCV chemotherapy for recurrent oligodendrogliomas and oligoastrocytomas.
Soffietti R, Ruda R, Bradac GB, Schiffer D.
Department of Neuroscience, University of Torino, Italy.
Neurosurgery 1998 Nov;43(5):1066-73 Abstract quote
OBJECTIVE: The role of chemotherapy in the treatment of low-grade oligodendrogliomas and oligoastrocytomas is still unclear. A Phase II study was conducted to determine the benefits and toxicity of the procarbazine, lomustine, and vincristine (PCV) regimen in patients with low-grade oligodendrogliomas and oligoastrocytomas recurrent after surgery alone or surgery with radiotherapy.
METHODS: Patients with both enhancing and nonenhancing tumors were treated with up to six cycles of standard PCV, and response was evaluated by conventional criteria based on computed tomography or magnetic resonance imaging.
RESULTS: Sixteen of 26 patients (62%) responded to PCV: 3 (12%) experienced complete response, 13 (50%) experienced partial response, 8 (31%) had stable disease, and 2 (8%) had progressive disease. All symptomatic patients who responded and three with stable disease improved in seizure frequency, lateralizing signs, and symptoms of intracranial hypertension. The response rate for patients with enhancing lesions revealed by computed tomography or magnetic resonance imaging (74%) was significantly higher than that of patients with nonenhancing lesions (29%) (P < 0.05). Both oligodendrogliomas and oligoastrocytomas responded to PCV, with complete responses occurring in association with pure tumors only. The median time to tumor progression of all 26 patients was 24 months and was significantly longer for those with oligodendrogliomas compared with those with oligoastrocytomas (32 versus 12 mo) (P < 0.001). Chemotherapy was well tolerated, with mild hematological toxicity and rare skin rashes being the most frequent sequelae.
CONCLUSION: These results suggest that chemotherapy with PCV is effective in the treatment of recurrent low-grade oligodendrogliomas and oligoastrocytomas.
PCV for oligodendroglial tumors: in search of prognostic factors for response and survival.
Fortin D, Macdonald DR, Stitt L, Cairncross JG.
Department of Neurosurgery and Neuro-oncology, Centre Universitaire de Sante de l'Estrie, Sherbrooke University, Quebec, Canada.
Can J Neurol Sci 2001 Aug;28(3):215-23 Abstract quote
BACKGROUND: We report survival and pretreatment prognostic factors for survival and chemosensitivity in 53 oligodendrogliomas treated with PCV (procarbazine, lomustine and vincristine) chemotherapy.
METHODS: A total of 53 patients with histologically proven oligodendroglioma, anaplastic oligodendroglioma or oligo-astrocytoma and treated with PCV were extracted from the London Regional Cancer Center database. A retrospective review was conducted to evaluate overall survival and pretreatment prognostic factors for survival and chemosensitivity.
RESULTS: The median survival time from diagnosis was 123.6 months. The overall five- and ten-year survival rates were 72.7% and 52.7% respectively. Age <40, seizure as an initial symptom, absence of cognitive deficit and presence of a homogeneous hypodense lesion without contrast enhancement on the initial pretreatment CT scan were all factors independently associated with favorable outcome. The presence of increased cellularity, pleomorphism, mitosis, vascular proliferation and grading as an anaplastic lesion using these surrogates on pathological assessment, were all associated with an unfavorable outcome in univariable analysis. In multivariable analysis, only the anaplastic grading and presence of increased cellularity were significant determinants of unfavorable survival. The only factor adversely associated with chemosensitivity was the presence of a focal symptom at presentation.
CONCLUSION: Overall survival is significantly longer in oligodendroglial lesions than in fibrillary astrocytic tumors. A two tier grading system using standard morphological features seems accurate in predicting outcome in these patients. The presence of a neoplastic astrocytic component does not seem to impact the outcome. No clinical, radiological or pathological factor could be identified to reliably predict chemotherapy response.
Phase II study of accelerated fractionation radiation therapy with carboplatin followed by PCV chemotherapy for the treatment of anaplastic gliomas.
Levin VA, Yung WK, Bruner J, Kyritsis A, Leeds N, Gleason MJ, Hess KR, Meyers CA, Ictech SA, Chang E, Maor MH.
Department of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Int J Radiat Oncol Biol Phys 2002 May 1;53(1):58-66 Abstract quote
PURPOSE: To conduct a Phase II one-arm study to evaluate the long-term efficacy and safety of accelerated fractionated radiotherapy combined with i.v. carboplatin for patients with previously untreated anaplastic gliomas.
METHODS AND MATERIALS: Between 1988 and 1992, 90 patients received 1.9-2.0-Gy radiation 3 times a day with 2-h infusions of 33 g/m(2) carboplatin for two 5-day cycles separated by 2 weeks. After radiotherapy, patients received procarbazine, lomustine (CCNU), and vincristine (PCV) for 1 year or until the tumor progressed.
RESULTS: Ninety patients were evaluable for analysis. Histologically, 69 had anaplastic astrocytoma; 14, anaplastic oligoastrocytoma; and 7, anaplastic oligodendroglioma. Gross total resection was performed in 20 (22%), subtotal resection in 45 (50%), and biopsy in 25 (28%); reoperation (total or subtotal resection) was performed in 50 (56%) patients. A multivariate analysis showed that a younger age (p = 0.026), Karnofsky performance score (KPS; p = 0.009), and brain necrosis (p = 0.0002) were predictive of a better survival. Results from analysis of extent of surgery (biopsy, subtotal resection, gross total resection) approached significance (p = 0.058). Radiation dose, irradiated tumor volume, and techniques used (boost and fields) were not significant variables. The median survival (MS) of all anaplastic glioma patients was 28.1 months; for anaplastic astrocytoma patients, MS was 28.7 months and 40.8 months for the combined anaplastic oligodendroglioma/oligoastrocytoma patients. Long-term survival occurred in 25% of anaplastic glioma patients who were alive 8.6 years after treatment was initiated. Treatment-induced necrosis was documented by surgery or autopsy in 19 (21%) patients; 21 (23%) had a mixed pattern of necrosis and tumor; and an additional 13 (14%) patients who did not have surgical or autopsy demonstration of predominant radiation necrosis had magnetic resonance imaging (MRI) evidence of radiation necrosis. Serious clinical neurologic deterioration and/or dementia requiring full-time caregiver attention were observed in 9 (10%) patients.
CONCLUSION: When comparable selection criteria are applied, the rate of MS in this study is inferior to results attainable with current radiation and chemotherapy approaches, although the rates of long-term survival are comparable. Theoretically, patients failing therapy and dying earlier than anticipated may be because of excessive central nervous system (CNS) toxicity resulting from the combination of accelerated fractionated irradiation, intensive carboplatin chemotherapy before each radiation fraction, and postirradiation PCV chemotherapy. On the other hand, patients with treatment-induced necrosis survived significantly longer than patients who did not demonstrate MRI or histologic evidence of necrosis (MS, 106 months vs. 18-33 months).
Intensified PCV-chemotherapy with optional stem cell support in recurrent malignant oligodendroglioma.
Zander T, Nettekoven W, Kraus JA, Pels H, Ko YD, Vetter H, Klockgether T, Schlegel U.
Department of Neurology University Bonn Sigmund-Freud-Str. 25 53105 Bonn, Germany.
J Neurol 2002 Jul;249(8):1055-1057 Abstract quote
Six patients with recurrent or progressive anaplastic oligodendroglial tumors after surgical treatment and irradiation were treated with six/seven cycles of intensified PCV: Vincristine (1 mg/m(2)), CCNU (50 mg/m(2)) d.1,15 and procarbazine (75 mg/m(2)) d.2 to 29. If leukocytopenia (< 2.500/&mgr;l) or thrombocytopenia (< 75.000/&mgr;l) developed, 1 x 10(6) CD34(+) autologous stem cells/ kg body weight were reinfused three days after completion of subsequent cycles.
Complete response was seen in 2/6 and partial response in 4/6 patients. Median follow up from time of recurrence was 35 months, progression free survival was 18 to > 39 months and overall survival 23 to > 39 months.
We conclude that intensified PCV with stem cell support is feasable in recurrent/progressive anaplastic oligodendroglial tumors and appears to be sufficiently well tolerated to allow further study.
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