Biomedical subjects

Sydney D Finkelstein

Publications and source records attributed to Sydney D Finkelstein.

53 records · Page 3Linked to original sources

PubMed2003

Molecular evidence of anaplastic transformation in coexisting well-differentiated and anaplastic carcinomas of the thyroid.

Anaplastic thyroid cancer is a rare but nearly universally fatal tumor. Epidemiologic data suggest that many anaplastic thyroid carcinomas arise from transformation of preexisting or coexisting well-differentiated thyroid carcinomas. At the molecular level, the mutations responsible for the anaplastic transformation are incompletely understood, although the mutational events are thought to involve tumor suppressor genes. To examine transformation from a well-differentiated thyroid carcinoma to anaplastic carcinoma, we studied coexisting well-differentiated (Hürthle cell and papillary carcinoma) and anaplastic tumors with a molecular genotyping panel of tumor suppressor genes associated with thyroid neoplasia. The patterns of allelic loss in our results showed that the majority of cases have a core of conserved mutations in the two morphologically distinct areas and substantial increases in mutation rates in the anaplastic components.

Adenoma, Oxyphilic↗

PubMed2003

Widespread molecular alterations present in stage I non-small cell lung carcinoma fail to predict tumor recurrence.

Stage I non-small cell carcinoma (NSCLC) of the lung is typically treated with surgery alone, but with a 30 to 40% recurrence rate. Prognostic factors to stratify these patients into high- and low-risk groups would be of significant clinical value, but published data are conflicting. We studied 39 Stage I NSCLC treated with resection alone, followed for a minimum of 5 years, and divided into recurrent (RC) and non-recurrent (NRC) groups (n = 12 and 27, respectively). Allelic imbalance (loss of heterozygosity, LOH) involving genomic regions containing L-myc (1p32), hOGG1 (3p26), APC/MCC (5q21), c-fms (5q33.3), p53 (17p13), and DCC (18q21), and point mutational change in K-ras-2 (12p12) were studied by PCR-based microsatellite analysis and DNA sequencing. Mutations in k-ras-2 were seen in 25% and 19% of RC and NRC tumors, respectively, most frequently in adenocarcinomas. LOH in the RC and NRC respectively were 50% and 37% for L-myc, 60% and 33% for hOGG1, 60% and 50% for APC, 38% and 35% for c-fms, 78% and 75% for p53, and 17% and 45% for DCC. No statistical significance was seen comparing any of the allelic alterations with recurrence. LOH for hOGG1 and L-myc were more commonly seen in squamous cell carcinomas. Stage I NSCLC are genetically heterogeneous with respect to mutation acquisition. The approach of investigating a panel of genes for alterations can be applied to any given tumor type, and provides information on patterns of mutations/LOH that can help us better understand the molecular biology of tumorigenesis.

Aged↗

PubMed2003

Loss of heterozygosity in the MXI1 gene is a frequent occurrence in melanoma.

Melanoma development and progression is thought to be the result of a multi-step accumulation of genetic damage, with loss of heterozygosity in chromosome 9p (MTS1) frequently described. In addition, chromosome 10q allelic loss has been reported, implicating the tumor suppressor gene PTEN/MMAC1 on 10q23.3. The MXI1 gene at 10q24-25 is another candidate tumor suppressor that has only rarely been studied in melanomas, with conflicting results. We used microdissection-based genotyping to investigate 29 melanomas from 20 patients for loss of heterozygosity in intragenic and flanking microsatellite markers for this latter gene. Concurrently, the MTS1 gene was similarly studied using two flanking microsatellites. Fifty-four percent (15 of 28) of the informative cases showed loss of heterozygosity for one or both MXI1 markers, as compared with 67% (16 of 24) of the informative cases for MTS1. MXI1 allelic loss was seen more frequently in recurrent/metastatic tumors (59%), as compared with in primary (33%) lesions. Eighty percent of the primary tumors showed loss of heterozygosity for MTS1, as well as 63% of recurrent/metastatic ones. We studied more than one tumor in eight patients, with those from three patients showing discordant genetic patterns. One patient showed a metastatic tumor with allelic loss for MXI1 that was not identified in the primary melanoma or a local recurrence. The other two patients showed clonal heterogeneity in MXI1 at synchronous and metachronous metastatic foci. These findings support MXI1 as a putative tumor suppressor gene involved in conventional melanoma progression. Genetic heterogeneity seen in different metastases from the same primary suggests a nonlinear pattern of chromosomal damage, with the development of multiple clones within the primary tumor, each acquiring its own metastatic potential.

Adult↗

PubMed2003

Granular cell astrocytomas show a high frequency of allelic loss but are not a genetically defined subset.

Granular cell astrocytomas (GCA) are an uncommon morphologic variant of infiltrative glioma that contains a prominent population of atypical granular cells. As a rule, they are biologically aggressive compared to similar tumors without granular features. We sought to determine whether GCAs possess distinct genotypic alterations that might reflect their unique morphology or clinical behavior. Eleven GCAs occurring in 7 men and 4 women ranging in age from 46 to 75 years were investigated for genetic alterations of known significance in glial tumorigenesis, including LOH at 1p, 9p, 10q, 17p, and 19q, point mutations of TP53, deletions of p16(CDKN2A) and p14ARF, as well as EGFR amplifications. Tumors included had an infiltrative growth pattern and consisted of large, round cells packed with eosinophilic, PAS-positive granules that varied in quantity, ranging from 30 to 100% of tumor cells. Three tumors were of WHO grade II, one was grade III, and 7 were grade IV lesions. Overall, the tumors showed higher frequencies of LOH at 1p, 9p, 10q, 17p, and 19q than typical infiltrating astrocytomas of similar grades. Losses on 9p and 10q occurred in nearly all cases, including low grade lesions. TP53 mutations were identified in 2 grade IV GCAs, while combined p14ARF and p16(CDKN2A) homozygous deletions were noted in only one grade IV lesion. None showed EGFR amplification. We found no genetic alterations specific for GCA. Instead, it appears that granular cell change occurs across genetic subsets. The high frequency of allelic loss, especially on 9p and 10q, may confer aggressive growth potential and be related to their rapid clinical progression.

Aged↗

PubMed2003

Association between chromosome 1p and 19q loss and outcome in pediatric malignant gliomas: results from the CCG-945 cohort.

BACKGROUND: Results of recent molecular studies on malignant gliomas in adults showed that deletions within the short arm of chromosome 1 and/or the long arm of chromosome 19 identified a prognostically favorable subgroup of tumors that often respond to conventional chemotherapy. To determine if this association applies to pediatric malignant gliomas, we examined the correlation between 1p and 19q deletions and outcome in the cohort derived from the Children's Cancer Group study 945, the largest randomized trial of such tumors completed to date. METHODS: Archival histopathologic material yielded tissue of sufficient quality and quantity for genotyping in 121 specimens. Sections were examined histologically and targets that contained malignant glioma were isolated by microdissection and subjected to polymerase-chain-reaction-based amplification of microsatellite loci using fluorochrome-labeled primers, followed by capillary electrophoresis, and fluorescent fragment analysis. One hundred and seven specimens had 2 alleles for at least 1 of the 3 1p loci examined, and were therefore informative for determining loss of heterozygosity, defined as at least a twofold difference in fluorescence intensity between the paired allelic bands; 99 were informative at 19q. RESULTS: Thirty-two tumors (29.9%) had loss of heterozygosity involving 1p, 27 (28%) involving 19q, and 13 involving both, an incidence consistent with previous reports involving adult malignant gliomas. However, outcome analyses of the entire cohort found no favorable association between 1p loss, 19q loss, or the combination, and survival. Subset analysis disclosed no association with outcome in either arm of the study (which compared efficacy of 2 chemotherapeutic regimens) or in subgroups stratified by age, tumor location, or tumor histology. CONCLUSION: In contrast to recent observations of adult malignant gliomas, deletions involving chromosomes 1p or 19q did not predict a survival advantage in this series of pediatric high-grade gliomas, which might indicate that frequencies of various histologic and molecular subtypes of malignant gliomas differ between children and adults, and supports further efforts to identify prognostic indicators relevant to pediatric gliomas.

Central Nervous System Neoplasms↗

PubMed2003

A microdissection and molecular genotyping assay to confirm the identity of tissue floaters in paraffin-embedded tissue blocks.

CONTEXT: A recurring problem in surgical pathology practice is specimen mix-up and floater contamination. While many cases can be resolved histologically, a significant number remain unclear and may have serious clinical and medicolegal implications. OBJECTIVES: To design a microdissection and genotyping assay to identify contaminating floater tissues in paraffin-embedded tissues that is optimized for small samples, and to use the assay to resolve a series of clinical cases with floater tissues. MATERIALS AND METHODS: Twenty-one cases of possible tissue floater contamination in paraffin-embedded tissue blocks were included. Using 4 unstained, 4-microm-thick histologic sections, multiple sites were microdissected under direct visualization either by hand or by laser capture microdissection. Nonneoplastic and neoplastic tissues were sampled. Polymerase chain reaction was performed for a panel of 10 polymorphic microsatellite markers at 1p34, 3p26, 5q21, 9p21, 10q23, and 17p13. Allele size and content were analyzed semiquantitatively by fluorescent capillary electrophoresis, and the genotypes for the tissues in the paraffin-embedded tissue blocks were compared for identity. RESULTS: Tissue identification was successful in all cases, despite small tissue sample size and fixation effects. Comparative analysis of neoplastic tissue floaters and the presumptive source tumor was performed when possible to control for possible allelic loss or microsatellite instability. CONCLUSIONS: Microdissection and genotyping are effective and reliable means to objectively resolve problems of possible floater contamination. Even minute tissue samples provide sufficient DNA template for polymerase chain reaction microsatellite analysis. Because of the potential clinical implications of floaters, we recommend that all suspected floaters that would change a diagnosis from benign to malignant be subjected to genotyping assay to confirm the identity of the floater tissue.

Biopsy↗

PubMed2003

Primary duodenal carcinoma showing divergent growth patterns as determined by microdissection-based mutational genotyping.

Primary duodenal adenocarcinoma accounts for less than 0.5% of all gastrointestinal cancers. We report a case of duodenal adenocarcinoma with highly divergent growth patterns consisting of poorly differentiated adenocarcinoma and neuroendocrine carcinoma proven to arise as a single neoplasm of monoclonal origin, as demonstrated by microdissection-based mutational profiling. Multicomponent growth patterns, as seen in this case, can occasionally be encountered in gastrointestinal malignancies and have led to speculation about the pathogenesis. The methods used to clearly establish monoclonal origin based on the unique profiling of mutational damage can address fundamental issues related to tumor development and progression, while providing cogent clinical information. Our findings confirm the great potential for intestinal epithelial cells to differentiate along different histogenetic lines during tumor progression.

Adenocarcinoma↗

PubMed2002

Frequencies of tetramer+ T cells specific for the wild-type sequence p53(264-272) peptide in the circulation of patients with head and neck cancer.

Immunization with wild-type sequence (wt) p53 epitopes represents a novel therapeutic strategy for cancer patients with tumors accumulating mutant p53. To evaluate usefulness of p53-derived peptides as future cancer vaccines, frequencies of wt p53(264-272) peptide-specific CD8+ T cells were determined in the peripheral circulation of patients with squamous cell carcinoma of the head and neck (SCCHN). T cells of 30 HLA-A2.1+ patients and 31 HLA-A2.1+ healthy individuals were evaluated by multicolor flow cytometry analysis using peptide-HLA-A2.1 complexes (tetramers). T cells specific for an influenza matrix peptide (a model recall antigen) or an HIV reverse transcriptase peptide (a model novel antigen) were studied in parallel. Patients with SCCHN had a significantly higher mean frequency of CD8+ T cells specific for wt p53(264-272) than normal donors (P = 0.0041). Surprisingly, the frequency of epitope-specific T cells in the circulation of patients did not correlate with p53 accumulation in the tumor. In patients whose tumors had normal p53 expression or had p53 gene mutations preventing presentation of this epitope, high frequencies of wt p53(264-272)-specific CD8+ T cells were found, of which many were memory T cells. In contrast, patients whose tumors accumulated p53 had low frequencies of wt p53(264-272)-specific CD8+ T cells, which predominantly had a naive phenotype and were unable to proliferate ex vivo in response to the epitope, as reported by us previously (T. K. Hoffmann, J. Immunol., 165: 5938-5944, 2000). This seemingly contradictory relationship between the high frequency of epitope-specific T cells and wt p53 expression in the tumor suggests that other factors may contribute to the observed anti-p53 responses. Human papillomavirus-16 E6/E7 expression is common in SCCHN, and E6 is known to promote presentation of wt p53 epitopes. Although human papillomavirus-16 E6/E7 expression was detected in 46% of the tumors, it did not correlate with the frequency of wt p53(264-272)-specific CD8+ T cells or with p53 expression in the tumor. These findings emphasize the complexity of interactions between the tumor and the host immune system, and, thus, have particularly important implications for future p53-based immunization strategies.

Antibodies, Neoplasm↗

PubMed2002

Comparison of accumulated allele loss between primary tumor and lymph node metastasis in stage II non-small cell lung carcinoma: implications for the timing of lymph node metastasis and prognostic value.

Although the Tumor-Node-Metastasis staging of non-small cell lung carcinoma (NSCLC) is the most effective predictor of survival, the clinical outcome of patients at each stage is variable on an individual case basis. We tested the value of incorporating information about the tumor heterogeneity of NSCLC into microsatellite allelotyping in a cohort of 48 node-positive stage II patients (T1N1M0 and T2N1M0). Microsatellite allelotyping involved microdissection of the invasive component of primary tumor and lymph node metastasis at multiple target sites followed by loss of heterozygosity (LOH) analysis at specific regions on chromosomes 1p, 3p, 5q, 7q, 8q, 9p, 10q, 17p, and 18q using 16 markers. All microsatellites manifested LOH ranging from 44 to 76% in primary tumor and showed various degree of heterogeneity between primary tumor and lymph node metastasis. LOH on 3p and 5q in the lymph node metastases was associated significantly with shortened survival of the patients (P = 0.033 and 0.004, respectively), whereas no single LOH in the primary tumors showed association with prognosis. For the analysis of the accumulated load of allele loss, fractional allele loss (FAL) was calculated for each sample. The maximal FAL of lymph node metastasis was significantly lower than that of primary tumor (P = 0.0015), possibly reflecting the early lymphatic spread. High maximal FAL of lymph node metastasis was significantly correlated with an adverse outcome (P = 0.012), whereas maximal FAL of primary tumor did not show any prognostic significance (P = 0.552). A composite mutational profile for each patient based on the allelotyping of the primary tumor and lymph node deposits may make a significant contribution to a more accurate prognosis of stage II NSCLC.

Aged↗

PubMed2002

Expression of p53 and prognosis in children with malignant gliomas.

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.

Adolescent↗

PubMed2002

Multiple loss of heterozygosity without K-ras mutation identified by molecular analysis on fine-needle aspiration cytology specimen of acinar cell carcinoma of pancreas.

Fine-needle aspiration diagnosis of pancreatic acinar cell carcinoma (PAC) is challenging. Typically, the cytologic findings in PAC are described as a cellular population of loosely cohesive clusters and single neoplastic cells. The individual cells have granular cytoplasm, uniform nuclei, a fine chromatin pattern, and occasional prominent nucleoli. These features are suggestive of PAC but not diagnostic. We illustrate a case in which the combination of cytopathologic findings, clinical information, and molecular analysis enabled us to arrive at the diagnosis of PAC. Although the cytomorphologic features alone were not specific, the presence of a markedly elevated serum lipase level, cutaneous lesions of fat necrosis, and loss of heterozygosity at 1p, 5q25 at the APC locus, 9p21 at the p16 locus, and 17p13 at the p53 locus were essential in excluding the main differential diagnostic entities including pancreatic ductal carcinoma, pancreatic endocrine tumor, and pancreatoblastoma.

Adenocarcinoma↗

PubMed2002

Pathologic features of early inflammatory bowel disease.

Often the pathologic changes of IBD are subtle and may not be present in a proportion of biopsy specimens. In cases of early disease, the changes may be missed, and additional specimens should be taken after a period of time. Modifying factors, such as prebiopsy treatment and coexisting disease, should be considered. A forum to review cases and allow for communication between gastroenterologists and pathologists is especially useful for clinicopathologic correlation and assignment of a working diagnosis to each case. Careful attention to the pathologic features of early UC and CD would be most useful when evaluating new therapies for IBD.

Biomarkers↗

PubMed2002

Molecular abnormalities and correlations with tumor response and outcome in glioma patients.

Molecular analysis approaches hold promise to refine the management of patients with malignant gliomas. An important step in the application of these techniques to guide clinical decision-making involves transitioning these approaches from the research setting into the clinical diagnostic arena, using methods that can be performed rapidly and reliably on surgically obtained tumor specimens. Many centers have begun this process for the detection of chromosome 1p and 19q deletions in oligodendroglial neoplasms. It is likely that the current limited portfolio of prognostic markers will be increased substantially during the next several years as innovative techniques for tumor genotyping and gene expression profiling help to identify additional correlates of tumor prognosis. An associated challenge involves demonstrating that biological stratification can support therapeutic stratification that will influence, rather than merely predict, the outcome of patients with brain tumors. The realization of this long-range goal will require the identification of novel therapeutic strategies that hold promise for improving the outcome of molecularly defined subsets of high-grade gliomas, which as a group remain largely resistant to conventional therapies.

Brain Neoplasms↗

PubMed2002

Small-cell neuroendocrine carcinoma displays unique profiles of tumor-suppressor gene loss in relationship to the primary site of formation.

Small-cell neuroendocrine carcinoma (SCNC) is a well characterized malignancy with distinctive cellular morphology and aggressive biologic behavior most frequently encountered in the lung but also noted for origin from other sites. The basis for this difference in incidence and the impact of primary site location on the molecular pathogenesis of the neoplasm is not well understood. To address this issue and to identify reliable molecular markers of potential diagnostic value for primary site localization of this tumor, we have compared the genetic profile of cancer-related gene damage of SCNC arising from a variety of organ sites. The analysis involved microdissected paraffin-embedded formalin fixed specimens of SCNC. Tumors were organized into 3 groups: lung (n = 18), head and neck region (n = 5), and gastrointestinal tract (n = 5). Genotyping evaluated allelic imbalance (loss of heterozygosity) involving genomic regions containing p53 (17p13), L-myc (1p34), OGG1 (3p26), MCC/APC (5q21), p16 (9p21), PTEN (10q23), and point mutational change in K-ras-2 (12p12) using polymerase chain reaction-based microsatellite analysis and DNA sequencing. Distinct genotypic profiles of allelic imbalance using this panel was seen for each group of SCNC enabling primary site determination to be suggested based on genotypic profiling of microdissected tissue samples. Despite similarity in histologic appearance, our study suggests that SCNC have a unique pattern of acquired allelic damage that is determined in part by primary site of tumor development. These attributes can be effectively used for primary localization of metastatic SCNC, thereby assisting in the diagnosis and classification of this neoplasm.

Carcinoma, Small Cell↗

PubMed2002

Rapid, quantitative reverse transcriptase-polymerase chain reaction: application to intraoperative molecular detection of occult metastases in esophageal cancer.

OBJECTIVE: Our earlier data showed that quantitative reverse transcriptase-polymerase chain reaction can discriminate patients with node-negative cancer who are at high risk for recurrence. The objective of this study was to determine whether a new, more rapid quantitative reverse transcriptase-polymerase chain reaction assay could provide this information in a time frame suitable for intraoperative decision making. METHODS: We studied formalin-fixed, archived lymph nodes from 30 patients with histologically determined node-negative esophageal cancer with rapid quantitative reverse transcriptase-polymerase chain reaction to measure expression of carcinoembryonic antigen messenger RNA. We also performed rapid quantitative reverse transcriptase-polymerase chain reaction on 37 snap-frozen lymph nodes from 23 patients. Eleven of the 23 patients had benign esophageal disorders (negative control group). The other 12 had esophageal cancer, 6 with histologically determined positive lymph nodes and 6 with histologically determined negative lymph nodes. RESULTS: In the retrospective analysis of archival tissue from 30 patients with esophageal cancer with histologically determined negative lymph nodes, rapid quantitative reverse transcriptase-polymerase chain reaction predicted disease recurrence with a sensitivity and a specificity of 90% and 80%, respectively, and was comparable to conventional quantitative reverse transcriptase-polymerase chain reaction. In the frozen-tissue analysis rapid quantitative reverse transcriptase-polymerase chain reaction detected significantly higher levels of carcinoembryonic antigen expression in all 12 of the histologically determined positive lymph nodes than in the benign nodes. For 2 of these 12 nodes the intraoperative frozen-section analysis had negative histologic results, and N1 status was determined only on final pathologic examination. Rapid (intraoperative) quantitative reverse transcriptase-polymerase chain reaction discriminated both nodes as positive. Among the 14 histologically determined negative nodes, 1 of 3 nodes from 1 patient showed increased carcinoembryonic antigen according to rapid quantitative reverse transcriptase-polymerase chain reaction, and this patient had a clinical recurrence. CONCLUSIONS: In our study we were able to rapidly discriminate patients with node negative-esophageal cancer who had a high risk of recurrence. In frozen tissues rapid quantitative reverse transcriptase-polymerase chain reaction correlated with final pathologic report for 11 of 12 patients. In the 1 discordant case, the quantitative reverse transcriptase-polymerase chain reaction result was positive and may have detected microscopically occult metastasis, because this patient did have disease recurrence. Rapid quantitative reverse transcriptase-polymerase chain reaction was more sensitive than intraoperative frozen sections for detecting metastatic disease. These data suggest that rapid quantitative reverse transcriptase-polymerase chain reaction may have a prognostic role and could guide intraoperative decisions.

Aged↗

PubMed2002

Molecular pathogenesis of pulmonary carcinosarcoma as determined by microdissection-based allelotyping.

Pulmonary carcinosarcoma is a rare, biphasic tumor composed of malignant epithelial and mesenchymal elements. Its histogenesis is controversial in light of the presence of divergent cell lineages and the clonal nature of malignancy. To address these issues, we performed an extensive comparative genotypic analysis using microdissection to secure representative mesenchymal and epithelial components from each of six cases of pulmonary carcinosarcoma. 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 1p, 3p, 5q, 9p, 10q, and 17p. In accordance with the relatively greater biologic aggressiveness of this tumor type, both the epithelial and mesenchymal components showed extensive allelic loss, most notably for 3p, 5q, and 17p. More importantly, we found overall equivalent patterns of acquired allelic loss between the two components on an individual case basis, strongly supporting the monoclonal origin of these neoplasms. Minor differences in the allelic fingerprint between the two cell lineages could be explained by progressive accumulation of allelic loss alterations that appear to occur more frequently in the mesenchymal component of the tumor. The data support the efficacy of microdissection-based allelic fingerprinting to delineate the relationship between different morphologic components of a single neoplasm.

Carcinosarcoma↗

PubMed2002

Impact of proliferation index on outcome in childhood malignant gliomas: results in a multi-institutional cohort.

OBJECTIVE: Prognoses of pediatric high-grade gliomas are unpredictable, even when clinical and histological factors are taken into account. In preliminary studies with an institutional cohort of pediatric high-grade gliomas, we observed a strong association between outcome and proliferation index, as assessed by immunolabeling with the MIB-1 antibody. To determine whether this marker could provide prognostically useful information independent of tumor histology, we examined the prognostic usefulness of this marker in the multi-institutional cohort of Children's Cancer Group Study 945, the largest group of childhood high-grade gliomas analyzed to date. METHODS: The study group consisted of tumors within this cohort that were classified as high-grade gliomas on central review according to contemporary World Health Organization guidelines and that had sufficient histopathological material to permit proliferation index assessment. Paraffin-embedded sections were cut and processed, microwave antigen enhancement was used, and MIB-1 indices were calculated by percent labeling in approximately 2000 cells (5-10 high-power fields) in the areas with greatest labeling. To ensure that the review diagnostic classification and proliferation labeling index were assigned independently for each tumor, these analyses were performed by two different neuropathologists at separate institutions, and each was blinded to the results of the other. RESULTS: Ninety-eight tumors met eligibility criteria for this study. Among these high-grade gliomas, there was a strong association between MIB-1 labeling and patient outcome: 5-year progression-free survival was 33 +/- 7% in 43 patients whose tumors had MIB-1 indices of less than 18%, 22 +/- 8% in the 27 patients whose tumors had indices between 18 and 36%, and 11 +/- 6% in the 28 patients whose tumors had indices greater than 36% (P = 0.003). As anticipated, a strong association was also observed between histology and MIB-1 labeling index in these cases. Mean labeling indices were 19.4 +/- 2.66 for tumors classified as anaplastic astrocytoma versus 32.1 +/- 3.08 for those classified as glioblastoma multiforme (P = 0.0024). Notwithstanding this correlation, a significant association was noted between labeling index and progression-free survival, even after the analysis had been stratified by histology (P = 0.001). Although histology had an independent association with outcome, the prognostic value of MIB-1 labeling transcended histological subgrouping and was apparent both in tumors classified as anaplastic astrocytoma (P = 0.02) and in those classified as glioblastoma multiforme (P = 0.046). Multivariate regression modeling confirmed the strong independent association between MIB-1 labeling index and outcome. As a group, tumors with labeling indices higher than 36% had an almost uniformly poor outcome, regardless of histology. CONCLUSION: MIB-1 labeling index and histological categorization are each prognostically relevant in childhood high-grade gliomas. MIB-1 labeling index can help to refine the accuracy of histologically based prognostic assessments.

Antigens, Nuclear↗