 |
|
|
|
|
|
|
|
|
|
 |
 |
 |
 |
 |
 |
 |
 |
|
Background
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.
OUTLINE
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.1p/19q DELETIONS
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 MUTATIONS
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.
LABORATORY/
RADIOLOGIC/OTHERCHARACTERIZATION 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.
FISH
- 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
M. Eva Alonso, PhD, etal.
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 fewGrading 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.
SARCOMA (OLIGOSARCOMA)
- 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.
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
Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.
Basic Principles of Disease
Learn the basic disease classifications of cancers, infections, and inflammation
Commonly Used Terms
This is a glossary of terms often found in a pathology report.Diagnostic Process
Learn how a pathologist makes a diagnosis using a microscopeSurgical Pathology Report
Examine an actual biopsy report to understand what each section meansSpecial Stains
Understand the tools the pathologist utilizes to aid in the diagnosisHow Accurate is My Report?
Pathologists actively oversee every area of the laboratory to ensure your report is accurateGot Path?
Recent teaching cases and lectures presented in conferences
Last Updated March 13, 2007
Send mail to The Doctor's Doctor with questions or comments about this web site.
Read the Medical Disclaimer.
Copyright © The Doctor's Doctor