The astrocytoma is a tumor of the central nervous system derived from glial cells. Collectively, these tumors along with ependymomas and oligodendrogliomas, are known as gliomas. All brain tumors manifest symptoms based upon a combination of the tumor size and location. Astrocytomas have a tendency to become progressively anaplastic if left untreated. This transformation may be heralded by a rapid clinical deterioration.
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 SYNONYMS Gliomas GEOGRAPHY Rare in blacks
DISEASE ASSOCIATIONS CHARACTERIZATION Turcot syndrome Ollier disease Mafucci syndrome Radiation treatment
PATHOGENESIS CHARACTERIZATION MOS
Expression of mos in astrocytic tumors and its potential role in neoplastic progression.
Perunovic B, Athanasiou A, Quilty RD, Gorgoulis VG, Kittas C, Love S.
Department of Neuropathology, Frenchay Hospital, Bristol, United Kingdom.
Hum Pathol 2002 Jul;33(7):703-7 Abstract quote
The c-mos gene and its protein product mos, components of the mitogen-activated protein kinase transduction pathway, are known to be involved in the control of meiosis and mitosis. Apart from a study on lung carcinomas, there is little information about its role in human neoplasia.
The aim of this study was to investigate expression of mos in astrocytic tumors and to correlate it with accumulation of p53. We studied expression of mos in 62 cases of supratentorial astrocytic tumor. Intracytoplasmic immunostaining for mos was found in 28 (45%) cases: 3 of 20 (15%) grade 2 astrocytomas, 9 of 20 (45%) grade 3 anaplastic astrocytomas, and 16 of 22 (73%) glioblastomas. Immunopositivity for mos correlated significantly (P < 0.01) with tumor grade but not with p53 expression. In contrast to the findings in relation to lung tumors, immunopositivity for mos in astrocytic tumors did not predict recurrence-free or overall survival time. Cytoplasmic immunostaining was observed in scattered large cortical neurons adjacent to tumors, possibly due to stress-induced abortive entry into the cell cycle. The correlation of mos immunopositivity with tumor grade may reflect the expansion of more malignant mos-positive clones.
This study provides evidence that mos may be involved in the neoplastic progression of a proportion of astrocytic tumors.
CHARACTERIZATION Radiographs CT scan and MRI
Ill defined areas of low density centered in white matter
High grade tumors usually show enhancement with contrast
MRI shows better on T2 weighted secondary to increased water content
PET scan Especially in treated GBM tumors or suspected recurrence, an MRI may show enhancement but this may be due to radionecrosis. A PET scan will be positive indicating recurrent active tumor
Posterior fossa glioblastoma multiforme: MR findings.
Kuroiwa T, Numaguchi Y, Rothman MI, Zoarski GH, Morikawa M, Zagardo MT, Kristt DA.
Department of Diagnostic Radiology, University of Maryland Medical System, Baltimore 21201, USA.
AJNR Am J Neuroradiol 1995 Mar;16(3):583-9 Abstract quote
PURPOSE: To characterize the MR findings of glioblastoma multiforme in the posterior fossa.
METHODS: MR studies of nine patients with surgically proved posterior fossa glioblastoma multiforme were retrospectively evaluated. MR characteristics studied included tumor location, signal intensity, enhancement pattern, and presence of intratumoral hemorrhage, as well as presence of secondary hydrocephalus or metastatic spread.
RESULTS: The tumors were located in the median portion of the cerebellum or brain stem in eight cases. Six extended into the fourth ventricle. Hydrocephalus was seen in four cases. Six cases demonstrated decreased T1- and increased T2-weighted signal intensities. Three cases demonstrated mixed signal intensities suggesting intratumoral hemorrhage. All of the eight patients who received contrast showed moderate to marked heterogeneous ringlike enhancement suggesting intratumoral necrosis. Multicentric/multifocal lesions or extraaxial metastases were identified in three of the nine cases, and there was extracranial extension into the cervical region in one case.
CONCLUSION: Glioblastoma multiforme is a rare tumor in the posterior fossa. Differentiating it from metastatic tumor or malignant astrocytoma was difficult. However, combination of heterogeneous and ringlike enhancement, midline location, poorly defined margin, tumoral hemorrhage, concomitant multicentric/multifocal lesions, and extraaxial or extracranial metastasis may be clues for the prospective diagnosis of glioblastoma multiforme.
Mod Pathol. 2005 Sep;18(9):1258-63. Abstract quote
Astrocytic gliomas are the most common pediatric brain tumors; however, nonbrainstem glioblastomas are extremely rare compared with their adult counterparts. Little information is available on the clinical significance of various molecular markers in pediatric grade IV astrocytomas. The current study was focused on the molecular analysis and clinico-pathological correlations in a set of 44 tumor samples obtained from pediatric patients with nonbrainstem glioblastomas.
Fluorescence in situ hybridization (FISH) with a set of 10 commercial chromosome probes (1p36, 1q25, centromere (CEP)7, EGFR, CEP9, 9p21/p16, CEP10, 10q23/PTEN, 19p13, and 19q13) was performed.
Disclosed molecular abnormalities, in descending order of frequency, included polysomy 7 (72%), loss of 10q23 (61%), loss of 9p21 (52%), loss of 1p36 (41%), gain of 1q25 (25%), polysomy 9 (16%), EGFR amplification (9%), loss of 19q13 (5%), polysomy 19 (5%), and codeletion 1p36/19q13 (2%). The overall survival time was markedly shorter only for those patients whose lesions harbored deletion of 10q23/PTEN locus (log-rank test; P=0.00007). By multivariate analysis, only loss of 10q23 locus reached an independent level of prognostic value (hazard ratio=2.88; P=0.01). There were no significant differences in patient survival for other molecular abnormalities.
In conclusion, a FISH analysis of 10q23 dosage should be recommended as an ancillary laboratory method that allows further clinical subdivision of pediatric glioblastomas.
Favor cerebral hemispheres of young to middle aged adults
Brain stem in children
Pilocytic tumors may occur anywhere but are common in cerebellum and optic nerve
Tumors of the spinal cord usually are fusiform enlargements
Tumors of the brain stem usually in the pons
VARIANTS MULTICENTRIC AND MULTIFOCAL TUMORS
Multicentric and isolated multifocal glioblastoma multiforme simulating metastatic disease.
Prather JL, Long JM, van Heertum R, Hardman J.
Br J Radiol 1975 Jan;48(565):10-5 Abstract quote
Single case reports of multicentric glioblastoma multiforme and multifocal glioblastoma multiforme tumours are presented.
Multicentric glioblastoma multiforme tumours are those which have no macroscopic or microscopic connection. Multifocal gliomatous tumours, on the other hand, are those with either gross or microsopic continuity or evidence of cerebral spinal fluid spread and/or local metastases. The cerebral scintigram findings, cerebral angiogram studies and pathological description of these entities are presented. These lesions may be mistaken for metastases.
In patients with multiple cerebral lesions multiple primary malignancies of brain should be considered when there is no clinical or radiographical evidence for extracranial primary neoplasms.
The incidence of multifocal cerebral gliomas. A histologic study of large hemisphere sections.
Barnard RO, Geddes JF.
Cancer 1987 Oct 1;60(7):1519-31 Abstract quote
A series of 241 gliomas (astrocytomas, oligodendrogliomas, glioblastomas, and subependymal giant-cell astrocytomas) was studied.
This represents all the gliomas examined post mortem over 25 years at one hospital. Two hundred and one cases (85%) were apparently solitary tumors; of the 40 cases with multiple tumor foci, 23 (9.5%) were true multicentric gliomas. After excluding cases in which there was concomitant disease (neurofibromatosis, tuberose sclerosis, or multiple sclerosis), 18 cases of multicentric tumor (7.5%) remained. Multicentric tumors with different histologic appearances accounted for 2.9% of the series. Celloidin-embedded whole brain sections proved invaluable for the detection of microscopic neoplastic foci and unsuspected diffuse spread.
The estimated incidence of multiplicity in gliomas is higher than in most series, but the findings suggest that detection of multifocal neoplastic change in these tumors is directly related to the extent to which the brain is sampled, and that figures obtained in this study may well underestimate the true incidence.
Multicentric gliomas. Report of seven cases.
Salvati M, Oppido PA, Artizzu S, Fiorenza F, Puzzilli F, Orlando ER.
Department of Neurological Sciences-Neurosurgery, University of Rome, La Sapienza, Italy.
Tumori 1991 Dec 31;77(6):518-22 Abstract quote
Multifocal gliomas fall into four main categories: diffuse, multiple, multicentric and multiple-organ. Multicentric gliomas are uncommon lesions of the central nervous system. Even more so are multicentric gliomas lying both above and below the tentorium (16 cases to date, as far we know).
We report a clinical series of 7 cases, including 3 supra-infratentorial tumors. The distinctive features of multicentric gliomas are mainly the absence of gross or microscopic connections and absence of seeding along easily accessible routes like the cerebrospinal fluid pathways or the median commissures.
We consider the pathogenetic hypotheses and problems of diagnosis, especially differential from other multifocal diseases of the central nervous system.
Imaging patterns of multifocal gliomas.
Kyritsis AP, Levin VA, Yung WK, Leeds NE.
Department of Neuro-Oncology, University of Texas, M.D. Anderson Cancer Center, Houston 77030.
Eur J Radiol 1993 Apr;16(3):163-70 Abstract quote
We reviewed the imaging characteristics of 51 consecutive cases of cerebral glioma with multiple foci of involvement.
In 26 patients, multifocality was present at the initial diagnosis, whereas in 25, it developed at a later stage. Thirty-two patients were studied with MRI, 13 with CT, and six with both imaging techniques. In 14 cases, no apparent dissemination route was identified; these tumors were presumed to be true multicentric gliomas. In the rest of the cases, various patterns of spread from a primary site were evident or suggested, and the tumors were denoted as multifocal. The most frequent dissemination route in the latter group was the meningeal-subarachnoid space, followed by the subependymal, intraventricular route and direct brain penetration.
Multifocal gliomas are more frequent than generally believed and, therefore, multiple cerebral masses should be thoroughly evaluated and not always presumed to be of metastatic origin.
Multicentric and multifocal primary cerebral tumours. Methods of diagnosis and treatment.
Salvati M, Cervoni L, Celli P, Caruso R, Gagliardi FM.
Dipartimento di Scienze Neurologiche, Cattedra di Neurochirurgia, Universita di Roma La Sapienza, Italy
Ital J Neurol Sci 1997 Feb;18(1):17-20 Abstract quote
Forty patients with multifocal and multicentric cerebral tumours were retrospectively studied. The patients were divided into two groups: ten patients with multicentric tumours (group A), and 30 patients with multifocal tumours.
As far as their preoperative clinical history and the incidence of the various symptoms and signs are concerned, there were no significant differences between the two groups. CT permitted a correct diagnosis in 90% of the cases. All of the patients underwent the removal of the tumour(s) and received radiotherapy; 30 patients also received chemotherapy.
In group A, nine patients died and one was lost to follow-up one year after treatment; the average survival was ten months from the appearance of the multicentric tumour. In group B, 29 patients died and one is still alive two years after treatment; the average survival was six months. We consider the problems of diagnosis and the long-term follow-up of patients.
Multicentric glioma with unusual clinical presentation.
Zamponi N, Rychlicki F, Ducati A, Regnicolo L, Salvolini U, Ricciuti RA.
Pediatric Neurology Department, Children's Hospital G. Salesi, Ancona, Italy.
Childs Nerv Syst 2001 Jan;17(1-2):101-5 Abstract quote
Multiple glioma is a well-recognized but uncommon entity. They are grouped in two categories: multifocal and multicentric gliomas. Multifocal gliomas grow through dissemination along an established route, spreading through commissural pathways, CSF channels, or the blood or by local extension through satellite formation; at the opposite end of the spectrum, multicentric gliomas are widely separated lesions whose simultaneous presence cannot be attributed to any of the above pathways. Reports in the literature refer to single cases or small series of multicentric gliomas, almost always in adult patients, their occurrence in children being even less frequent.
We report the case of a 12-year-old boy with multicentric glioma, atypical acute clinical onset and fast growth of three other tumors in 8 months, and then discuss the problems of diagnosis and therapy.
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL Fibrillary or diffuse tumors Grading
A variety of systems have been proposed, each using some or all combinations of nuclear atypia, mitoses, vascular proliferation, and necrosis
Well Differentiated Grade I Usually reserved for pilocytic astrocytomas Moderately Differentiated Grade II Well differentiated diffuse astrocytomas
Hypercellular lesions usually in white matter, margins indistinct
Cells usually enlarged and cigar-shaped with irregular hyperchromatic nuclei
Microcystic spaces distinctive, usually in younger patients
Mitoses are not found
Anaplastic Astrocytoma Grade III Atypia with mitotic figures
May have increased gemistocytes
Glioblastoma multiforme Grade IV Atypia, mitotic figures, and necrosis and/or vascular proliferation VARIANTS CHORDOID GLIOMA INFANTILE DESMOPLASTIC ASTROCYTOMA Superficially located hemispheric masses
Elongated glial cells with intense desmoplastic response
May have patchy areas of high cellularity
GEMISTOCYTIC ASTROCYTOMA Plump abundant eosinophilic cytoplasm GLIOFIBROMA Admixture of fibrous connective tissue and glia GLIOMATOSIS CEREBRI Diffusely infiltrating glioma
Computed tomography of gliomatosis cerebri.
Hayek J, Valavanis A.
Comput Radiol 1982 Mar-Apr;6(2):93-8 Abstract quote
Two cases of gliomatosis cerebri which underwent serial CT-examination with contrast enhancement and histological examination of autopsy material are presented. No one single CT showed all the lesions discovered on neuropathological examination, the lesions in the brainstem, basal ganglia and cerebellum being isodense.
The presentation of the lesions on CT was in both cases different. In one case there were several hypodense areas predominantly scattered throughout the white matter of both hemispheres, in the other the main lesion was a "tumor' of the corpus callosum, which lead to the decision for operation. Both cases showed periventricular enhancement expressing the histologically verified periventricular spread of tumor cells. Contrast enhancement appeared in the late stages of the diseases.
In the different diagnosis, pseudotumor cerebri, multiple sclerosis, encephalitis and multiple brain metastases are considered. Bearing the possibility of gliomatosis cerebri in mind, CT would help limit the differential diagnosis, especially on the basis of serial CT examinations and in combination with the clinical course.
Gliomatosis cerebri with secondary glioblastoma formation: report of two cases.
Kannuki S, Hirose T, Horiguchi H, Kageji T, Nagahiro S.
Department of Neurological Surgery, School of Medicine, the University of Tokushima, Japan.
Brain Tumor Pathol 1998;15(2):111-6 Abstract quote
The clinicopathological features of two cases of gliomatosis cerebri associated with secondary glioblastoma formation are reported.
In both cases, glial cells were diffusely distributed in the supra- and infratentorial regions and underlying brain structures were preserved from the onset. In spite of such diffuse distribution of neoplastic glial cells, similar to that observed in low-grade astrocytoma, in both cases the tumor underwent complete remission after radiotherapy. However, the tumor recurred as a localized glioblastoma in both cases, 37 months (case 1) and 7 months (case 2) after the radiotherapy. In both cases, recurrence was accompanied by prominent dissemination of CSF. The recurrent tumors were radiation resistant, and the patients' conditions deteriorated rapidly after recurrence.
The present two cases demonstrated that gliomatosis cerebri, classified among brain tumors of unknown origin by the World Health Organization, may transform into highly proliferative circumscribed tumors, in spite of their good response to radiotherapy. Examination of pathological features and their correlation with MRI findings may allow us to better understand the response to radiotherapy and the process of recurrence.
MENINGEAL GLIOMATOSIS Largely leptomeningeal tumors with only a minor parenchymal component
Range from well differentiated tumors to frankly malignant
- Arch Pathol Lab Med. 2007 Feb;131(2):228-33. Abstract quote
CONTEXT: Several distinctive mixed glioneuronal tumors that warrant recognition as clinicopathologic entities have been recently described by neuropathologists.
OBJECTIVE: To summarize important clinical, radiologic, and pathologic findings for 3 novel glioneuronal tumors (papillary glioneuronal tumor, rosetted glioneuronal tumor, and rosette-forming glioneuronal tumor of the fourth ventricle).
DATA SOURCES: Recent reports in the pathology literature and the authors' experience with mixed glioneuronal tumors at a major cancer center.
CONCLUSIONS: Histologic features enabling recognition of these recently described glioneuronal tumors are presented along with remarks concerning the classification of mixed neuronal and glial tumors exhibiting unconventional appearances.
GBM with sarcomatoid differentiation
2% of GBM
- Gliosarcoma with epithelial differentiation: immunohistochemical and molecular characterization. A case report and review of the literature.
Ozolek JA, Finkelstein SD, Couce ME.
1Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Mod Pathol. 2004 Jun;17(6):739-45. Abstract quote
Few reported cases of gliosarcomas or glioblastomas with epithelial-like areas exist. Most cases were originally diagnosed as metastatic carcinoma. Focal expression of glial fibrillary acidic protein has helped characterize these tumors as having a glial origin.
We report a case of gliosarcoma with multifocal, extensive areas of well-differentiated carcinoma; demonstrating squamous and glandular differentiation. The expression of glial fibrillary acidic protein and epithelial phenotype were mutually exclusive. We performed extensive immunohistochemical analyses and comparative genotypic analysis using microdissection to secure representative glial and epithelial components. Loss of heterozygosity was analyzed with a panel of 12 polymorphic microsatellite markers designed to indicate allelic loss and situated in proximity to known tumor suppressor genes located on chromosomes 1p, 9p, 10q, 17p and 19q.
We found comparable patterns of acquired allelic loss between the glial and carcinomatous components, strongly supporting the monoclonal origin of this neoplasm. |
This case represents an extreme form of phenotypic divergence in a malignant glioma, and constitutes a difficult diagnostic challenge. This heterogeneity reflects the potential for a range of phenotypic expression in malignant gliomas that needs to be recognized. We suggest microdissection genotyping as a molecular technique to better characterize these tumors.
GRANULAR CELL Granular cells with finely granular cytoplasm
Infiltrative astrocytomas with granular cell features (granular cell astrocytomas): a study of histopathologic features, grading, and outcome.
Brat DJ, Scheithauer BW, Medina-Flores R, Rosenblum MK, Burger PC.
Department of Pathology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Am J Surg Pathol 2002 Jun;26(6):750-7 Abstract quote
Granular cell astrocytomas (GCAs) are rare, incompletely characterized infiltrative gliomas that contain a prominent component of granular cells. Such tumors can readily be mistaken for reactive conditions.
We studied 22 cases to explore their morphologic spectrum, establish features useful in distinguishing GCA from nonneoplastic diseases, and to determine which parameters correlate with biologic behavior. Tumors occurred in 17 men and five women, ranging in age from 29 to 75 years, who presented mainly with seizures, headache, aphasia, or hemiparesis.
Radiologically, high-grade GCAs were contrast-enhancing, cerebral hemispheric masses with prominent peritumoral edema. All contained sheets or interspersed large, round cells packed with eosinophilic, PAS-positive granules. Lymphocytic infiltrates, either perivascular or admixed with neoplastic cells, were present in 14 tumors. Transition to typical infiltrating astrocytoma was noted in 16 cases; of these, granular cells comprised 30-95% of cells. Six tumors consisted almost entirely of atypical granular cells. By WHO criteria, four GCA were grade 2, seven were grade 3, and 11 were grade 4. Glial fibrillary acidic protein staining was seen in all but one tumor, and the majority were immunoreactive for S-100 protein, KP-1, ubiquitin, and epithelial membrane antigen.
Although MIB-1 proliferation indices increased with tumor grade, granular cells accounted for only a minority of immunoreactive cells. Among 18 cases with follow-up, 15 recurred after surgery and resulted in death (mean survival, 7.6 months). Two patients died postoperatively, and one was alive at 51 months. Granular cell astrocytoma is an uncommon morphologic variant that appears to be rapidly progressive and usually fatal.
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.
(Juvenile pilocytic astrocytomas)
Extremely well differentiated, grade I tumors
Children and young adults
Common in the optic nerve and cerebellum
Loosely cohesive stellate astrocytes with microcysts with compact tissue of fibrillated cells
May have prominent hyalinized vessels
Rosenthal fibers may be abundant
PAS positive protein droplets and granular bodies
Filling of perivascular spaces
Adolescents and young adults
Expanding superficial mass in the temporal or parietal region
Often cystic with a mural nodule
Cellular pleomorphism with variable vascular sclerosis and cytoplasmic vacuolization
Eosinophilic granular bodies
Few mitotic figures and absent necrosis
Intercellular pattern of reticulin
Immunophenotype of Pleomorphic Xanthoastrocytoma.
Giannini C, Scheithauer BW, Lopes MB, Hirose T, Kros JM, VandenBerg SR.
Departments of Pathology (C.G., B.W.S.), Mayo Clinic, Rochester, Minnesota, and the University of Virginia (M.B.S.L., S.R.V.), Charlottesville, Virginia, U.S.A.; Saitama Medical School (T.H.), Saitama, Japan; and University Hospital Dijkzigt (J.M.K.), Rotterdam, The Netherlands.
Am J Surg Pathol 2002 Apr;26(4):479-485 Abstract quote
Pleomorphic xanthoastrocytoma (PXA) is an uncommon tumor, often seizure-associated and occurring in the temporal lobe of young adults. Although its cells are considered astrocytic in nature, recent studies suggest the presence of neuronal differentiation and a possible relationship to glioneuronal neoplasms.
We immunostained 40 cases of PXA, including two composite PXA-gangliogliomas (PXA-GG), with a panel of glial (glial fibrillary acidic protein, S-100 protein) and neuronal markers (class III beta-tubulin, synaptophysin, neurofilament proteins, MAP2, and chromogranin A). Conventional PXAs demonstrated immunoreactivity for glial fibrillary acidic protein (100% of cases), S-100 protein (100%), class III beta-tubulin (73%), synaptophysin (38%), NF proteins (18 and 8%), and MAP2 (8%). Chromogranin A stain was absent in all conventional PXA cases. Neoplastic ganglion cells in both PXA-GGs stained with class III beta-tubulin, synaptophysin, and chromogranin A. Ultrastructural studies, performed in nine cases, demonstrated neuronal features including microtubules, dense core granules, and/or clear vesicles largely limited to cell processes (two PXAs) and in the cytoplasm (PXA component of one PXA-GG).
Although the essential nature of PXA is clearly and uniformly glial, the significance of the limited neuronal differentiation is unclear, as it is the relationship between conventional PXA and PXA-GG. We found no evidence that the former is a precursor of the latter.
PROTOPLASMIC ASTROCYTOMA Children and young adults
Low cellularity with cobweb architectural pattern and small, poorly fibrillated cells in a mucoid matrix
Cyclooxygenase-2, Bcl-2, and chromosome 1p analysis in protoplasmic astrocytomas.
Hum Pathol 2004;35:317-321 Abstract quote
Protoplasmic astrocytomas are rare gliomas whose nosology remains enigmatic.
This study retrospectively reviews the clinicopathologic features of eight tumors, including evaluation of these neoplasms for chromosome 1p loss, Bcl-2 immunoreactivity, and cyclooxygenase-2 immunoreactivity. Patients ranged in age from 3 to 49 years (median 25.5 years) and included six males and two females. All patients presented with a period of seizures (median duration of period, 54 months) before surgery. Five tumors were either totally or partially based in the temporal lobe. In the six patients for whom follow-up information was available, there was no evidence of recurrence at last known follow-up (range 5 to 171 months; median 134 months).
Histologically, all tumors were marked by a proliferation of cells with rounded to oval nuclear contours and a paucity of cytoplasmic processes, arranged against a microcystic background. A rare mitotic figure was observed in only one tumor. Vascular proliferative changes and necrosis were not seen in any of the tumors. None of the tumors showed allelic loss on chromosome 1p by fluorescent in situ hybridization (FISH) analysis. Cyclooxygenase-2 (an enzyme involved in the conversion of arachidonate to prostaglandin H(2) and G(2)) immunoreactivity was observed in two tumors. Bcl-2 (an anti-apoptotic protein) immunoreactivity was also confined to two tumors.
In conclusion, protoplasmic astrocytomas appear to be low-grade neoplasms, as evidenced by their relatively benign clinical course. Although they histologically resemble microcystic oligodendrogliomas, none of the tumors showed allelic loss on chromosome 1p, a finding that has been described in the majority of low-grade oligodendrogliomas.
This suggests that the protoplasmic astrocytoma is a distinct entity from low-grade oligodendroglioma. Similar to other low-grade astrocytomas, only a minority of tumors show evidence of cyclooxygenase-2 and Bcl-2 immunoreactivity.
SUBEPENDYMAL GIANT CELL ASTROCYTOMA Limited to region around foramen of Monro
Variable histology with usually a uniform cellularity and vasculocentric
Fascicular or swirled appearance with scattered giant cells
CHARACTERIZATION Special stains Immunoperoxidase
In GBM, tumors may be GFAP, CK, and Vimentin positive
S-100 may be positive
Cyclooxygenase-2 (COX-2) expression by immunohistochemistry in glioblastoma multiforme.
Prayson RA, Castilla EA, Vogelbaum MA, Barnett GH.
Brain Tumor Center and the Departments of Pathology and Neurosurgery, Cleveland Clinic Foundation, Cleveland, OH.
Ann Diagn Pathol 2002 Jun;6(3):148-53 Abstract quote
Cyclooxygenase-2 (COX-2) (an enzyme responsible for the conversion of arachidonic acid to prostaglandin) upregulation has been described in association with a variety of tumors including gliomas. This study reviews the immunohistochemical profile of 47 glioblastoma multiforme using COX-2 antibody and correlates the results with MIB-1 (marker of cell proliferation) immunostaining.
Positive staining with COX-2 was observed in 35 tumors (74.5%); more than10% tumor cell positivity was seen in 10 tumors (21.3%). Immunostaining results were as follows: no staining, N = 12 (25.5%); 0% to 5% of tumor cells, N = 20 (42.6%); 5% to 10%, N = 5 (10.6%); 10% to 20%, N = 4 (8.5%); 20% to 50%, N = 4 (8.5%); and greater than 50%, N = 2 (4.3%). The mean MIB-1 labeling index for all tumors ranged from 3.0 to 76.4 (mean, 19.6). Mean MIB-1 labeling indices were higher in tumors with greater than 5% COX-2 immunostaining (mean MIB-1 labeling index, 23.5) versus tumors with 0% to 5% COX-2 immunostaining (mean MIB-1 labeling index, 17.7). There is evidence of COX-2 expression by immunohistochemistry in the majority of glioblastoma multiforme. As a group, tumors with a higher rate of cell proliferation tended to have increased expression of COX-2.
These findings are significant in that therapeutic agents, which inhibit COX-2, are currently available and may play a role in the management of glioblastoma multiforme.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES Cerebral infarcts Macrophages, generally infrequent in brain tumors Demyelinating disease Macrophages Gliosis vs. low grade astrocytoma This is the most difficult distinction, especially on frozen section
- 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.
Gliosis Glioma Nuclei are well spaced and rarely touching
Touch and squash preparations show omnidirectional processes defining spherical domains
Pleomorphic hyperchromatic nuclei with nuclear clustering and molding
Touch preps show shorter and thinner cytoplasmic processes with variable fibrillarity
Microdissection-Based Genotyping Assists Discrimination of Reactive Gliosis From Glioma
Am J Clin Pathl 2004;121:671-678 Abstract quote
We used molecular anatomic pathology to determine the mutational status (loss of heterozygosity [LOH]) to make the distinction between reactive gliosis and glial neoplasia. LOH has been shown to be absent in reactive states and present in neoplastic cellular proliferations.
Three groups of patient specimens were analyzed: group 1, reactive gliosis (n = 15); group 2, gliomas of varying histologic type and grade (n = 54); group 3, diagnostically challenging reactive gliosis vs glioma (n = 16). No group 1 cases (0/15 [0%]) showed allelic loss, whereas all high-grade glial neoplasms, a subset of group 2 (35/35 [100%]) manifested at least 1 allelic loss alteration, with most cases (33/35 [94%]) displaying 2 or more such changes. During a look forward at the group 3 patients, clinical history clarified the problematic diagnosis in a subset of 11 patients: 8 (73%) of 11 clinical outcomes were predicted correctly by our analysis. The molecular anatomic pathology approach outlined herein is designed for minute, formalin-fixed, paraffin-embedded specimens, which are encountered in everyday surgical pathology practice.
Molecular anatomic pathology opens the possibilities of molecular analysis to everyday pathology practice.
Primary Sarcomas of the Brain and Spinal Cord: A Study of 18 Cases
Andre M. Oliveira, M.D.; Bernd W. Scheithauer, M.D.; Diva R. Salomao, M.D.; Joseph E. Parisi, M.D.; Peter C. Burger, M.D.; Antonio G. Nascimento, M.D.
Am J Surg Pathol2002; 26(8):1056-1063 Abstract quote
Primary sarcomas of the central nervous system are exceedingly rare.
We reviewed the clinicopathologic features of 18 primary central nervous system sarcomas diagnosed from 1959 through 1999. Median age at diagnosis of the nine female and nine male patients was 28 years (range 3-63 years). Median tumor size was 4 cm (range 1.3-8 cm). Fifteen tumors arose in the cerebrum (83%), two in the cerebellum, and one in the spinal cord.
Histopathologically, the most common tumor types included fibrosarcoma (six), malignant fibrous histiocytoma (five), and undifferentiated sarcoma (three). Immunohistochemical and ultrastructural studies supported the histologic diagnosis in 17 and six cases, respectively. All patients had subtotal to gross total tumor resection; 16 also received radiotherapy and/or chemotherapy. Twelve tumors (67%) were high-grade. Follow-up was obtained in all instances (median 2.3 years). Nine patients died of the disease, eight with high-grade tumors. Survival at 5 years for patients with high-grade tumors was 28% compared with 83% for those with low-grade neoplasms (p = 0.03).
Primary central nervous system sarcomas most often affect young and middle-aged adults. Most involve the cerebrum and show fibrous, "fibrohistiocytic," or no specific differentiation. The prognosis for high-grade sarcomas seems better than that for glioblastoma multiforme.
Metastatic epithelioid sarcoma to the brain: Palisaded necrosis mimicking glioblastoma multiforme.
Prayson RA, Chahlavi A.
Departments of Anatomic Pathology and Neurosurgery, Cleveland Clinic Foundation, Cleveland, OH.
Ann Diagn Pathol 2002 Oct;6(5):302-6 Abstract quote
Epithelioid sarcomas are rare, morphologically distinct tumors that have a propensity to arise in the extremities. Brain metastasis from epithelioid sarcoma are a relatively rare occurrence.
We report a case of brain metastasis in a 50-year-old man who was previously diagnosed with an epithelioid sarcoma arising in the elbow. Before the diagnosis of brain metastasis, he had developed an axillary lymph node metastasis. He presented with neurologic symptoms of progressively worsening headache and loss of vision on the right side. He underwent gross total resection of an occipital lobe mass.
Histologically, the tumor was focally characterized by prominent perinecrotic pseudopalisading and demonstrated immunoreactivity with antibodies to cytokeratin AE1/3 and CAM5.2; the tumor did not stain with glial fibrillary acidic protein antibody. The literature is reviewed and the morphologic distinction between metastatic epithelioid sarcoma and other central nervous system neoplasms is discussed.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSIS Younger patients do better
Brain stem tumors do better although many are pilocytic
Adequacy of resection
Prognostic implication of clinical, radiologic, and pathologic features in patients with anaplastic gliomas.
Tortosa A, Vinolas N, Villa S, Verger E, Gil JM, Brell M, Caral L, Pujol T, Acebes JJ, Ribalta T, Ferrer I, Graus F.
Neuropathology Institute of Catalonia, Bellvitge Hospital CSUB, L'Hospitalet, Spain.
Cancer 2003 Feb 15;97(4):1063-71 Abstract quote
BACKGROUND: The clinical evolution of anaplastic glioma (anaplastic astrocytoma, oligodendroglioma, and oligoastrocytoma) is variable. Previous studies merged patients with anaplastic glioma and the much more common glioblastoma multiforme. Therefore, the conclusions on prognostic factors reflected in part the consequences of an analysis in a heterogeneous population.
METHODS: To identify clinical, neuroradiologic, pathologic, and molecular factors with prognostic significance, we analyzed 95 treated patients with a histologic diagnosis of anaplastic glioma. Variables included age, gender, clinical manifestations at diagnosis (seizures, focal neurologic deficit, and cognitive changes), computed tomographic (CT) scan characteristics (diffuse, ring, and no enhancement), tumor location, extent of resection, histopathology, postoperative Karnofsky performance status (KPS) score, adjuvant chemotherapy, tumor response, proliferation index (Ki-67 expression), and p53, p16, pRb, and epidermal growth factor receptor immunohistochemical expression.
RESULTS: Ninety-five patients with a histologic diagnosis of anaplastic astrocytoma (73%), anaplastic oligoastrocytoma (16.6%), or anaplastic oligodendroglioma (10.4%) constituted the basis of this study. Median overall survival was 29 months. Multivariate analysis revealed that an age of 49 years or younger (P < 0.03), postoperative KPS score of 80 or higher (P < 0.007), absence of ring enhancement (P = 0.03), and a proliferation index of 5.1% or lower (P = 0.044) were independently associated with longer survival. The presence of an oligodendroglial component was associated with better prognosis in the univariate analysis (P = 0.009), although this lost power in the multivariate analysis.
CONCLUSIONS: In addition to previously recognized prognostic variables such as age and KPS score, CT ring enhancement and tumor proliferation index were identified as independent predictors of survival in a homogeneous series of patients with anaplastic gliomas.
A prospective study on glioblastoma in the elderly.
Brandes AA, Vastola F, Basso U, Berti F, Pinna G, Rotilio A, Gardiman M, Scienza R, Monfardini S, Ermani M.
Department of Medical Oncology, Azienda Ospedale-Universita, Padova, Italy.
Cancer 2003 Feb 1;97(3):657-62 Abstract quote
BACKGROUND: Elderly patients (age > 65 years) with glioblastoma multiforme frequently are excluded from clinical studies, and prospective trials for patients with this age group do not exist to date.
METHODS: The authors conducted a prospective trial in 79 consecutive elderly patients with glioblastoma who underwent surgery and received radiotherapy (59.44 grays in 33 fractions; Group A; n = 24 patients) or received the same radiotherapy plus adjuvant chemotherapy with procarbizine, lomustine, and vincristine (PCV; lomustine 110 mg/m(2) on Day 1, procarbazine 60 mg/m(2) on Days 8-21, and vincristine 1.4 mg/m(2) on Days 8 and 29 every 42 days; Group B; n = 32 patients), or received the same radiotherapy plus adjuvant temozolomide (150 mg/m(2) for 5 days every 28 days; Group C; n = 22 patients).
RESULTS: The median time to disease progression (TTP) and median survival MST were 7.2 months (95% confidence interval [95%CI], 6.34-8.64) and 12.5 months (95%CI, 11.6-14.8), respectively. The TTP was significantly better for Group C compared with Groups A and B (10.7 months vs. 5.3 months and 6.9 months, respectively; P = 0.0002). Karnofsky performance status (KPS) (P < 0.001) and temozolomide (P < 0.001) were the only independent prognostic factors. Overall survival was better in Group C compared with Group A (14.9 months vs. 11.2 months; P = 0.002), but there were no statistical differences found between Groups A and B or between Groups B and C. Only KPS (P < 0.001) was predictive of overall survival, even if temozolomide chemotherapy was very close to the significance level (P = 0.058). Hematologic Grade 3-4 toxicity was higher with the PCV chemotherapy regimen compared with the temozolomide chemotherapy regimen.
CONCLUSIONS: Age alone should not preclude appropriate treatment in elderly patients with good performance status, for whom definitive radiation therapy and adjuvant chemotherapy with temozolomide is advised.
Management of patients aged >60 years with malignant glioma: good clinical status and radiotherapy determine outcome.
Whittle IR, Basu N, Grant R, Walker M, Gregor A.
Edinburgh Centre for Neuro-oncology, Department of Clinical Neurosciences, Western General Hospital, UK.
Br J Neurosurg 2002 Aug;16(4):343-7 Abstract quote
Many clinical trials have shown that the most important prognostic variable in patients with malignant glioma is advanced age. However, can some patients aged >60 years still have relatively good outcomes with conventional surgical and radiotherapeutic treatment? A previous audit of practice (1983-89) suggested that functional status was an important prognostic variable in the elderly.
We have reviewed a further cohort (1989-96) to evaluate changes in practice and outcomes given advances in neuroimaging, neurosurgery and radiotherapy. The major findings in this series of 80 patients aged over 60 years with a histological diagnosis of supratentorial malignant glioma were: (i) There was a relationship between management undertaken and clinical status of the patients (p < 0.01), i.e. patients in good grade generally had tumour debulking and radiotherapy, whilst those in poor grade generally had only biopsy. (ii) There was a significant increase in survival of patients in the second period who received surgical debulking and post-operative radiotherapy (from a median of 23 to 41 weeks (p < 0.05). (iii) It is likely that case selection accounted for much of this improvement since there was a direct relationship between median survival time and good clinical grade using the WHO performance scale. (iv) A shorter radiotherapy course (30 Gy in six fractions) was as efficacious as a conventional course (60 Gy in 30 fractions), and those patients having radiotherapy survived significantly longer than those not having this treatment (p = 0.001). This study has again demonstrated the importance of preoperative clinical grade and radiotherapy treatment in determining outcomes in patients >60 years.
To put these data in a societal context a recent prospective multicentre audit of patients with malignant glioma in Scotland, and another audit from our unit, showed that between 24 and 65% of patients aged >60 years, with a CT diagnosis of malignant glioma do not undergo either surgery or radiotherapy. Advanced age per se should not be a bar to interventional treatment in patients aged >60 years with suspected malignant glioma.
- Microdissection genotyping of mixed glial and primitive neuroectodermal central nervous system neoplasm.
Mohan D, Rao GR, Swalsky PA, Bakker A, Martinez AJ, Finkelstein SD.
Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pa, USA.
Arch Pathol Lab Med. 2004 Oct;128(10):1161-4. Abstract quote
A 22-year-old man with previous radiation treatment for childhood astrocytoma underwent resection of a right parietooccipital lesion. Histopathology revealed a malignant neoplasm with areas of astrocytic and primitive neuroectodermal components.
To resolve the relationship and cellular origin, representative tissue was microdissected from several targets, obtaining a balanced mixture of each element. Nonneoplastic brain parenchyma was separately microdissected to determine polymorphic marker informativeness and to serve as an internal negative control. Despite the relatively small quantity of tissue removed for each microdissection target, sufficient material was available for reliable, balanced, polymerase chain reaction-format genotyping encompassing a panel of tumor suppressor genes and genetic loci associated with these forms of neoplasia.
The findings revealed distinct discordant genotypic profiles for each of the neoplastic components. The efficacy of the approach used for molecular analysis of this complex neoplasm and the implication of the genotypic findings are discussed.
Hum Pathol. 2005 Sep;36(9):1008-15. Abstract quote
Cathepsin B, one of the lysosomal cysteine proteases, has been related to tumor invasiveness. Cystatin C is the strongest inhibitor of cathepsin B. Knowledge of its participation in the progression of gliomas is limited.
We investigated the expression of cystatin C and its association with the clinicopathologic features of 57 gliomas. Cystatin C and cathepsin B expressions were evaluated by immunohistochemical methods and by semiquantitative real-time polymerase chain reaction analysis for the corresponding messenger RNA. Disease-free survival was analyzed by the Kaplan-Meier method. Tumors with low cystatin C protein expression and high cathepsin B protein expression were significantly more likely to be of high grade, and this pattern was significantly correlated with high Ki-67 LI and tumor recurrence. Depressed expression of cystatin C messenger RNA in glioblastomas compared with low-grade astrocytomas was demonstrated. Multivariate analysis demonstrated high tumor grade, high Ki-67 labeling index, high cathepsin B expression, and low cystatin C expression correlated significantly with shorter disease-free survival.
These results suggest that gliomas in patients with an unfavorable clinical outcome are characterized by depressed expression of cystatin C. Evaluation of cystatin C expression in gliomas provides useful clinical information, especially as a prognostic indicator.
EPIDERMAL GROWTH FACTOR RECEPTOR
- Glioblastomas in the older old.
Kleinschmidt-DeMasters BK, Lillehei KO, Varella-Garcia M.
Department of Pathology, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Arch Pathol Lab Med. 2005 May;129(5):624-31. Abstract quote
CONTEXT: Recent studies have identified fundamental biological differences in the effects of epidermal growth factor receptor (EGFR) amplification on survival in older versus younger patients with glioblastoma multiforme (GBM). Cell cycle labeling indices have also been found to be inordinately high in older GBM patients and may contribute to the known adverse prognosis in this cohort. However, testing has not been conducted on significant numbers of patients of very advanced age, in whom these features might be expected to emerge as even more significant factors.
OBJECTIVE: To assess EGFR amplification status and MIB-1 indices in patients with GBM who are older than 75 years.
DESIGN: We identified 20 patients (female-male ratio, 11:9; 11 aged 75-79 years and 9 aged 80-87 years) and studied tumor tissue samples with immunohistochemistry for cell cycle labeling index and by fluorescence in situ hybridization for EGFR amplification. Survival data were obtained from the Colorado Tumor Registry.
RESULTS: Mean MIB-1 index was high (24.8%), but individual indices did not correlate with survival. EGFR amplification was detected in 25% of cases, with gain of chromosome 7 in all but one of the remaining patients. Ninety-five percent of patients manifested EGFR amplification and/or polysomy of chromosome 7. Heterogeneity was found within a given tumor, with 10% to 60% of cells showing gain of chromosome 7. Overall patient survival was poor (mean, 4.6 months), but was significantly longer in those with EGFR gene amplification (mean, 8.3 months; median, 10.5 months) versus those without (mean, 3.2 months; median, 2.0 months) (P = .04).
CONCLUSION: The presence of EGFR amplification is a significant predictor of survival time in older old patients.
Ann Diagn Pathol. 2005 Dec;9(6):307-11. Abstract quote
Fascin is a protein that serves to aggregate F actin into bundles that rearrange the cytoskeleton and promote cellular motility. Fascin has been linked to the invasive behavior of some tumors. Fascin immunohistochemical analysis was performed in 90 glioblastoma multiforme, including 53 males and 37 females (mean age, 58.3 years).
All patients had tumors that demonstrated positive fascin staining. Nineteen tumors showed more than 75% positive staining tumor cells, 14 tumors had more than 50% to 75% staining, 23 tumors had more than 25% to 50% staining, 26 tumors had more than 5% to 25% staining, and 8 tumors had less than 5% staining. In comparison, 9 of 11 low-grade astrocytomas had 50% or less staining for fascin. Eight of 10 anaplastic astrocytomas had more than 50% fascin staining. All gliomas studied expressed fascin by immunohistochemistry. Higher grade tumors generally expressed a greater degree of fascin staining.
There was no obvious correlation with the extent of staining and survival among glioblastoma multiforme. Fascin may play a role in tumor cell infiltration.
METASTASIS Rare cases of organ visceral metastasis PROLIFERATION MARKERS
Cellular proliferation in pilocytic and diffuse astrocytomas.
Giannini C, Scheithauer BW, Burger PC, Christensen MR, Wollan PC, Sebo TJ, Forsyth PA, Hayostek CJ.
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA
J Neuropathol Exp Neurol 1999 Jan;58(1):46-53 Abstract quote
Using quantitative image analysis, we evaluated the MIB-1 labeling index (LI) in a large population of pilocytic (n = 131) and diffuse astrocytomas (n = 140), explored its significance as a prognostic predictor of survival, and compared it to other commonly accepted predictors, including grade and its histologic determinants, atypia, mitoses, endothelial proliferation, and necrosis.
Diffuse astrocytomas were graded according to the St Anne-Mayo scheme and included 45 grade 2, 50 grade 3, and 45 grade 4 astrocytomas. In pilocytic astrocytomas, mean, median, and range of MIB-1 LIs were 1.1, 0.9, and 0-3.9%, respectively. In diffuse astrocytomas, these values were 2.3, 2, and 0-7.6% in grade 2; 6, 4.4, and 0.1-25.7% in grade 3; 9.1, 6, and 0.3-36% in grade 4. There was a significant difference in the distribution of MIB-1 LIs between pilocytic and diffuse grade 2 astrocytomas (p < 0.001), between grade 2 and grade 3 (p < 0.001), and between tumors of grade 3 and 4 (p = 0.014). Among pilocytic astrocytomas there was no association between survival and MIB-1 LI or any histologic parameter. In diffuse astrocytomas, MIB-1 LI was significantly correlated with grade as well as with mitotic activity (<0.001) and survival. While in diffuse astrocytomas of all grades, necrosis was the strongest factor associated with survival, in tumors of grades 2 and 3 the MIB-1 LI preceded other histologic parameters and, on multivariate analysis, remained the only feature predictive of survival. Grade 3 astrocytomas with a single "solitary" mitosis had a significantly lower MIB-I LI than did grade 3 tumors with >1 mitosis and, compared to the latter, had a significantly longer survival (p = 0.013), one not significantly different from patients with grade 2 astrocytomas.
These findings suggest that the cutoff point between grade 2 and 3 in the St. Anne-Mayo scheme may not be optimal and may need to be revised.
Evaluation of Molecular Markers in Low-Grade Diffuse Astrocytomas: Loss of p16 and Retinoblastoma Protein Expression Is Associated With Short Survival.
Hilton DA, Penney M, Evans B, Sanders H, Love S.
Department of Histopathology (D.A.H., M.P., B.E.), Derriford Hospital, Plymouth, U.K.; the Department of Neuropathology (S.L.), Frenchay Hospital, Bristol, U.K.; and the Department of Mathematics and Statistics (H.S.), University of Plymouth, Plymouth, U.K.
Am J Surg Pathol 2002 Apr;26(4):472-478 Abstract quote
Diffuse astrocytomas have a median survival of 6-8 years. However, in a minority of cases that are histologically low grade, progression is rapid, leading to death within 2 years. Loss of p16, retinoblastoma protein, and deleted-in-colon-carcinoma protein expression, and monosomy of chromosome 10 have been shown to occur in malignant astrocytic tumors.
We have investigated the prognostic value of expression of these markers, using techniques applicable in many histopathology laboratories, in diffuse astrocytomas that are histologically low grade. Paraffin sections from 71 diffuse, supratentorial, low-grade astrocytomas, from patients with at least 8-year survival data, were immunostained with antibodies to p16, deleted-in-colon-carcinoma protein, p53, Ki67, and retinoblastoma protein. In situ hybridization with a digoxigenin-labeled probe to chromosome 10 was used to assess chromosomal loss. In most cases there was immunostaining of virtually all tumor cell nuclei with antibodies to p16 and retinoblastoma protein. Three of the 68 tumors in which assessment of p16 was possible included discrete foci with lack of detectable immunoreactivity in tumor cells. The three patients concerned had a significantly shortened median survival (1.1 years vs 4.4 years in those without loss of p16; p <0.01). In six of the 61 cases where assessment of retinoblastoma protein was possible, <70% of tumor cell nuclei showed immunoreactivity. These six patients had a shorter survival (4.0 years) than had the remaining patients (5.4 years), although this difference was not statistically significant. The tumor from one of these patients included areas where only 36% of tumor cells showed retinoblastoma protein immunoreactivity, and this patient survived only 1.5 years. Tumors showing loss of both p16 and retinoblastoma were not seen. p53 and deleted-in-colon-carcinoma protein expression was highly variable and did not correlate with survival. Tumors with monosomy for chromosome 10 were not identified. Both polyploidy and the Ki67 labeling index were significantly associated with the p53 labeling index but not with survival. Focal loss of p16 or retinoblastoma protein is demonstrable in approximately 5% and 10% of diffuse low-grade diffuse astrocytomas, respectively.
Tumors with focal loss of immunoreactivity for these proteins are associated with shorter survival than those without, suggesting that immunohistochemistry for p16 and retinoblastoma protein may be a useful adjunct to other methods for assessing the prognosis of astrocytomas.
Expression of p27KIP1 in human gliomas: Relationship between tumor grade, proliferation index, and patient survival.
Zagzag D, Blanco C, Friedlander DR, Miller DC, Newcomb EW.
Departments of Pathology and Neurosurgery and the New York University Cancer Institute, New York University School of Medicine, New York, NY.
Hum Pathol 2003 Jan;34(1):48-53 Abstract quote
Numerous studies examining the prognostic significance of p27KIP1 expression in human cancer have shown that decreased expression often is an independent prognostic factor associated with worse survival. However, the prognostic value of p27KIP1 expression in gliomas is less well established.
To further address this issue, we evaluated the relationship between p27KIP1 protein expression in a series of 50 astrocytomas with clinicopathologic parameters including age, tumor grade, MIB-1 proliferation index, and patient survival using both Western blot analysis and immunohistochemistry. The level of p27KIP1 protein expression in 9 nonneoplastic brain tissue specimens served as a control. Sixteen high-grade astrocytomas were analyzed by Western blot, and 26 high-grade astrocytomas were analyzed by immunohistochemistry for levels of p27KIP1 protein expression. Regardless of the technique used to measure p27KIP1, approximately 50% of the high-grade tumors were low expressors and the other 50% were high expressors.
Thus, expression of p27KIP1 was independent of tumor grade. Loss of p27KIP1 expression is often associated with an increase in proliferative activity. We measured the rate of tumor cell proliferation using MIB-1 immunostaining in 16 high-grade astrocytomas to determine whether there was an inverse correlation between p27KIP1 expression and proliferation. No correlation between p27KIP1 expression and MIB-1 labeling index or patient survival was found.
Using immunohistochemistry, we noted that the staining pattern of p27KIP1 in glioblastomas was mainly in the pseudopalisading cells that outline areas of necrosis. Because p27KIP1 can be up-regulated by hypoxia, this staining pattern would be consistent with our observation that hypoxia-inducible factor 1alpha is expressed primarily in pseudopalisading tumor cells around necrotic zones. It has been shown that a high level of p27KIP1 prevents apoptosis in hypoxic cells.
Thus, maintenance of high levels of p27KIP1 in gliomas could result from the hypoxic microenvironment present within the tumor. No correlation was found between p27KIP1 expression and any of the clinicopatholgic parameters tested, including patient age and tumor grade, the 2 strongest predictors of survival among glioma patients.
Expression of p53 and prognosis in children with malignant gliomas.
Pollack IF, Finkelstein SD, Woods J, Burnham J, Holmes EJ, Hamilton RL, Yates AJ, Boyett JM, Finlay JL, Sposto R; The Children's Cancer Group.
Department of Neurosurgery, University of Pittsburgh Medical Center and Children's Hospital of Pittsburgh, Pittsburgh, PA 15213, USA
N Engl J Med 2002 Feb 7;346(6):420-7 Abstract quote
BACKGROUND: The prognosis of children with high-grade gliomas is uncertain, even when clinical and histologic findings are considered. We investigated whether mutations in the TP53 gene or the degree of expression of p53 protein in high-grade gliomas is associated with progression-free survival in children with these tumors.
METHODS: Paraffin-embedded specimens of malignant gliomas from children treated in the Children's Cancer Group study CCG-945 were assessed by mutational analysis of TP53 (121 specimens) and immunohistochemical analysis of p53 (115 specimens). For mutational studies, areas of tissue that contained malignant glioma were isolated by microdissection, and the DNA was subjected to polymerase-chain-reaction-based amplification and sequencing of TP53 exons 5, 6, 7, and 8. Immunohistochemical analysis was performed with the use of a microwave-enhanced antigen retrieval and an antibody that bound both wild-type and mutant p53.
RESULTS: We found a significant association between overexpression of p53 and outcome; this association was independent of histologic features, age, sex, the extent of resection, and tumor location. The rate ( +/- SE) of progression-free survival at five years was 44 +/- 6 percent in the group of 74 patients whose tumors had low levels of expression of p53 and 17 +/- 6 percent in the group of 41 patients whose tumors had overexpression of p53 (P<0.001). A nonsignificant association was observed between mutations in TP53 and outcome.
CONCLUSIONS: Overexpression of p53 in malignant gliomas during childhood is strongly associated with an adverse outcome, independently of clinical prognostic factors and histologic findings.
TOPOISOMERASE MIB-1 and DNA Topoisomerase IIa Could Be Helpful for Predicting Long-Term Survival of Patients With Glioblastoma
Donald Ming-Tak Ho, MD, FRCPC, FCAP, Chih-Yi Hsu, MD, MHA, Ling-Tan Ting, MSc, and Hung Chiang, MD
Am J Clin Pathol 2003;119:715-722 Abstract quote
Approximately 10% of patients with glioblastoma survive more than 2 years after diagnosis. Distinguishing these patients from those who died within 2 years of diagnosis is clinically significant.
We studied the MIB-1 labeling index (LI) and DNA topoisomerase IIa LI of glioblastomas from 34 patients who lived for more than 2 years after diagnosis and of glioblastomas from 34 age- and sex-matched control patients who died within 2 years of diagnosis. The means of MIB-1 and topoisomerase IIa LIs of the group with a better outcome were lower. With 35 as the cutoff point for the MIB-1 LI and 26 as the cutoff point for the topoisomerase IIa LI, both MIB-1 and topoisomerase IIa LIs were related significantly to survival.
Our study showed that both MIB-1 and topoisomerase IIa could help predict long-term survival of patients with glioblastomas. Multivariate analyses revealed that MIB-1 was a better prognostic marker than topoisomerase IIa.
SURVIVAL Well differentiated astrocytomas
Mean of >5 years, most die by 10 years
Majority of cases show progression to more anaplastic tumors
Pilocytic tumors may have survival as long as 20 years
Anaplastic astrocytomas Median survival following surgery and radiation of 2-3 years GBM
Even with combined chemotherapy, radiation, and surgery, 8-10 months
<10% are alive at 2 years
Tumors of giant cell type fare better
Brain stem tumors are poor prognosis
Recurrent tumors may exhibit malignant transformation in 10-25% of cases
Survivin in glioblastomas. Protein and messenger RNA expression and comparison with telomerase levels.
Kleinschmidt-DeMasters BK, Heinz D, McCarthy PJ, Bobak JB, Lillehei KO, Shroyer AL, Shroyer KR.
Department of Pathology, University of Colorado Health Sciences Center, Denver, USA.
Arch Pathol Lab Med. 2003 Jul;127(7):826-33 Abstract quote
CONTEXT: Survivin is a novel inhibitor of apoptosis that acts via a pathway independent of bcl-2. Little is known about its distribution in brain tumors or how it correlates with other biomarkers of malignancy, such as telomerase, an enzyme that plays a critical role in cellular immortalization and cancer biology.
OBJECTIVES: To assess survivin protein expression in gliomas and to compare expression with that of telomerase.
DESIGN: Immunohistochemical staining for survivin protein expression was performed using an antibody developed in our laboratory. Quantitative survivin messenger RNA (mRNA) levels were assessed by reverse transcriptase-polymerase chain reaction. In selected cases, survivin results were compared with quantitative telomerase values analyzed by polymerase chain reaction-based telomerase repeat amplification protocol (TRAP) assay. Twenty-five tumor tissue samples from 16 cases of glioblastoma multiforme (GBM; including multiple tissue samples in 6 patients), 2 grade II gliomas, 4 grade III gliomas, and 3 control temporal lobectomy specimens were studied.
RESULTS: Nuclear immunoreactivity for survivin protein and survivin mRNA were detectable in most glioma samples, regardless of grade. Glioblastoma multiforme demonstrated moderate protein expression and survivin mRNA levels compared to epithelial malignancies previously tested in our laboratory. Although the association of survivin mRNA with the levels of telomerase within the GBM cases did not reach statistical significance, most GBMs also expressed survivin. The quantitative score for survivin mRNA was higher in GBMs than in grade II and III gliomas (P =.02), after accounting for multiple specimens per patient.
CONCLUSIONS: Quantitative survivin mRNA analysis, but not immunohistochemistry, distinguished GBMs from lower grade gliomas. Mechanisms that promote both cell proliferation (telomerase expression) and cell survival (survivin expression) are often activated in GBMs.
RECURRENCE GBM tend to recur in and around tumor bed but contralateral occurrence in lesions close to corpus callosum may occur
May have extensive subependymal spread
CSF dissemination in 10%
Recurrent malignant glioma in adults.
Department of Neurosurgery, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1029, USA. Dexamethasone (used for the shortest time in the lowest effective doses) can provide symptomatic benefits. Osmotic diuretics such as mannitol reduce cytotoxic edema more rapidly.
Curr Treat Options Oncol 2002 Dec;3(6):509-24 Abstract quote
Meaningful palliation is possible for selected patients with recurrent malignant glioma (glioblastoma multiforme, anaplastic astrocytoma, anaplastic oligodendroglioma, or anaplastic mixed oligoastrocytoma) using aggressive treatment. Although long-term disease-free survival occurs in fewer than 10% of patients, most who achieve such survival have been treated for multiple recurrences. Surgical resection with the placement of lomustine-releasing wafers is the only therapy proven in randomized trials to be beneficial for recurrent malignant gliomas. Reoperation is indicated when local mass effect limits the quality of life.
Reoperation may make other treatments more effective by removing treatment-resistant hypoxic cells and thereby prolonging high-quality survival. Combination chemotherapy (including procarbazine and a nitrosourea) provides dramatic benefit for many recurrent anaplastic or aggressively behaving oligodendrogliomas and anaplastic mixed oligoastrocytomas. For other recurrent malignant gliomas, single-agent cytotoxic chemotherapy (eg, intravenous lomustine or platinums, oral carmustine, temozolomide, or procarbazine) appears to provide equivalent results and better quality of life at a lower cost than do the combinations of cytotoxic drugs. A randomized phase II trial demonstrates that temozolomide provides longer progression-free survival and better quality of life than standard-dose procarbazine in patients with recurrent glioblastoma multiforme. Because benefits of available cytotoxic chemotherapy for anaplastic astrocytoma and glioblastoma are small, participation in clinical trials is appropriate for most patients. Reirradiation (using stereotactic or three-dimensional conformal techniques with or without concomitant cytotoxic chemotherapy) as radiation sensitization can prolong high-quality survival in selected patients.
Specific examples include radiosurgery with the gamma knife or with linear accelerators, intracavitary radiation with the newly US Food and Drug Administration-approved GliaSite (Proxima Therapeutics, Alpharetta, GA) radiation therapy system, low dose rate permanent-seed brachytherapy, and high dose rate stereotactic brachytherapy. Dexamethasone (used for the shortest time in the lowest effective doses) can provide symptomatic benefits. Osmotic diuretics such as mannitol reduce cytotoxic edema more rapidly.
TREATMENT Combined chemotherapy, surgical resection, and radiation therapy CHEMOTHERAPY
Phase II study of chemotherapy with ACNU plus cisplatin followed by cranial irradiation in patients with newly diagnosed glioblastoma multiforme.
Choi IS, Lee SH, Kim TY, Bang JS, Paek SH, Kim S, Kim IH, Heo DS, Bang YJ, Kim DG, Jung HW, Kim NK.
Department of Internal Medicine, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
J Neurooncol 2002 Nov;60(2):171-6 Abstract quote
PURPOSE: To evaluate the efficacy and toxicity of chemotherapy with ACNU (1-(4-amino-2-methyl-5-pyrimidinyl)-methyl-(2-chloroethyl)-3-nitrosourea) plus cisplatin followed by cranial irradiation in patients with newly diagnosed glioblastoma multiforme.
PATIENTS AND METHODS: Between August 1999 and July 2001, previously untreated 30 patients with histologically confirmed glioblastoma multiforme were treated. Chemotherapy consisting of up to 2 cycles of 72 h of continuous intravenous infusion of ACNU (40 mg/m2/day) and cisplatin (40 mg/m2/d) was given over a 6-week period. Radiation was begun 6 weeks after the second cycle of chemotherapy.
RESULTS: Median age was 48 years (range 18-66 years) and 22 patients with residual measurable disease after surgery were eligible for response analysis. One (5%) had a complete response (CR), 36% partial response (PR), 14% stable disease (SD), and 45% progressive disease (PD) after chemotherapy. After additional radiation, 22% had CR, 22% PR, 16% SD, and 42% PD. Grades III and IV leukopenia and thrombocytopenia occurred in 18 cycles (36%) and 15 cycles (30%), respectively. No fatal complications occurred. Median time to progression was 5.9 months (95% CI 5.1-6.8 months) and median overall survival was 14.9 months (95% CI 9.1-20.7 months).
CONCLUSIONS: Preradiation chemotherapy with ACNU plus cisplatin is effective and feasible in patients with gliobiastoma multiforme.
A phase II study of radiotherapy after hyperbaric oxygenation combined with interferon-beta and nimustine hydrochloride to treat supratentorial malignant gliomas.
Beppu T, Kamada K, Nakamura R, Oikawa H, Takeda M, Fukuda T, Arai H, Ogasawara K, Ogawa A.
Department of Neurosurgery, Iwate Medical University, Morioka, Japan
J Neurooncol 2003 Jan;61(2):161-70 Abstract quote
Hypoxic cells play a key role in the radioresistance of malignant glioma. Interferon-beta, ACNU as nimustine hydrochloride and radiotherapy (IAR) is a common therapy for malignant glioma in Japan. Since hyperbaric oxygenation (HBO) increases oxygen pressure in glioma tissue, we applied a modified IAR therapy, radiotherapy after HBO combined with interferon-beta and ACNU (HBO/IAR therapy), for supratentorial malignant gliomas. Daily radiation therapy was completed within 15 min after HBO.
We assessed HBO/IAR with respect to toxicity, response rates and the time of tumor progression (TTP). We also examined the incidence of responses by some prognostic factors before HBO/IAR, namely, age, Karnofsky performance scale (KPS), histological type, tumor size, tumor site and operation type. Of 39 patients who participated in this study, 35 underwent a complete schedule of HBO/IAR therapy in which toxicity was permissible. Thirty patients (76.9%) either maintained or increased KPS during HBO/IAR with a mean duration of 68 +/- 14 days. The response rates (CR + PR%) for glioblastoma, anaplastic astrocytoma and overall were 50%, 30% and 43%, respectively. The incidence of therapeutic responses among all prognostic factors before HBO/IAR did not significantly differ. Median TTP for patients with glioblastoma, patients with anaplastic astrocytoma, and overall were 38, 56 and 43 weeks, respectively.
The present study suggested that HBO/IAR therapy could be applied to especially patients with poor prognostic factors, because of its short treatment period, its permissible toxicity and identical response to patients with good prognostic factors.
Treatment of recurrent malignant gliomas with stereotactic intensity modulated radiation therapy.
Voynov G, Kaufman S, Hong T, Pinkerton A, Simon R, Dowsett R.
Department of Radiation Oncology, University of Connecticut Health Center, Farmington, Connecticut 06030-2930, USA.
Am J Clin Oncol 2002 Dec;25(6):606-11 Abstract quote
Malignant gliomas are usually refractory to aggressive combined-modality therapy, and the incidence of recurrence and death after treatment is very high. State-of-the-art techniques such as stereotactic intensity-modulated radiation therapy (IMRT) are now available to deliver a high dose of radiation to the tumor with relative preservation of surrounding tissues to achieve optimal tumor coverage with minimal toxicity.
We report 10 patients (median age 48 years) with recurrent malignant gliomas that were treated with stereotactic directed IMRT. Initial tumor histologies included one low grade glioma (upgraded to anaplastic astrocytoma at recurrence), four anaplastic astrocytomas, and four glioblastomas multiforme. One patient was originally presumed to have a brain metastasis secondary to renal cell carcinoma but was pathologically confirmed as having glioblastoma multiforme at the time of recurrence. Before recurrence, all patients had been treated with external beam radiation therapy (median 59.7 Gy).
All recurrences were confirmed by a subtotal resection (5/10) or by imaging (5/10). The median Karnofsky performance score at the time of IMRT was 80. The median tumor volume was 34.69 cm. Treatment was delivered on a 10-MV linear accelerator with a mini-multileaf collimator, MIMiC, and planned with Peacock/Corvus software. Radiation was delivered in daily fractions of 5 Gy, to a total median dose of 30 Gy at the 71% to 93% median isodose line. Median overall survival time was 10.1 months from the date of stereotactic treatment, with 1- and 2-year survival rates of 50% and 33.3%, respectively.
Fractionated stereotactic intensity modulated radiation therapy is a novel technique used in the treatment of recurrent malignant gliomas, which produces results comparable to other currently used stereotactic techniques.
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