Markers of Proliferative Activity Are Predictors of Patient Outcome for Low-Grade Endometrioid Adenocarcinoma But Not Papillary Serous Carcinoma of Endometrium

Kushi, Abdulmohsen Al; Lim, Peter; Aquino‐Parsons, Christina; Gilks, C. Blake

doi:10.1038/modpathol.3880531

Cited by 40 publications

(29 citation statements)

References 42 publications

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“…2,4 A dualistic model of endometrial carcinogenesis is widely accepted. 5,[28][29][30][31][32][33][34] Most endometrial carcinomas are of type I, arising from precursor hyperplasia driven by estrogen excess. These tumors express ER and PR, may have microsatellite instability (20%), and may have PTEN mutation (40%).…”

Section: Discussionmentioning

confidence: 99%

“…We did not use MIB-1 (Ki67) immunostaining as we have previously shown that it shows only a weak correlation with mitotic activity in uterine serous carcinomas. 28 Additional markers included proteins implicated in regulation of hormone response (Gfi-1 47 ), markers of squamous differentiation (and thus possible markers of endometrioid cell type; CK5/6 and p63 48,49 ), and a protein associated with serous differentiation (B72.3 50 ). Not surprisingly, given the criteria for selection of the immunopanel, most markers studied were prognostically significant in univariate analysis.…”

Section: Discussionmentioning

confidence: 99%

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Identification of prognostically relevant and reproducible subsets of endometrial adenocarcinoma based on clustering analysis of immunostaining data

et al. 2007

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Panels of immunomarkers can provide greater information than single markers, but the problem of how to optimally interpret data from multiple immunomarkers is unresolved. We examined the expression profile of 12 immunomarkers in 200 endometrial carcinomas using a tissue microarray. The outcomes of groups of patients were analyzed by using the Kaplan-Meier method, using the log-rank statistic for comparison of survival curves. Correlation between clustering results and traditional prognosticators of endometrial carcinoma was examined by either Fisher's exact test or v 2 -test. Multivariate analysis was performed using a proportional hazards method (Cox regression modeling). Seven of the 12 immunomarkers studied showed prognostic significance in univariate analysis (Po0.05) and 1 marker showed a trend toward significance (P ¼ 0.06). These eight markers were used in unsupervised hierarchical clustering of the cases, and resulted in identification of three cluster groups. There was a statistically significant difference in patient survival between these cluster groups (P ¼ 0.0001). The prognostic significance of the cluster groups was independent of tumor stage and patient age on multivariate analysis (P ¼ 0.014), but was not of independent significance when either tumor grade or cell type was added to the model. The cluster group designation was strongly correlated with tumor grade, stage, and cell type (Po0.0001 for each). Interlaboratory reproducibility of subclassification of endometrial adenocarcinoma by hierarchical clustering analysis was verified by showing highly reproducible assignment of individual cases to specific cluster groups when the immunostaining was performed, interpreted, and clustered in a second laboratory (j ¼ 0.79, concordance rate ¼ 89.6%). Unsupervised hierarchical clustering of immunostaining data identifies prognostically relevant subsets of endometrial adenocarcinoma. Such analysis is reproducible, showing less interobserver variability than histopathological assessment of tumor cell type or grade.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Identification of prognostically relevant and reproducible subsets of endometrial adenocarcinoma based on clustering analysis of immunostaining data

et al. 2007

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“…The effect of the mutation of PTEN remains controversial, since this has been found to be positively associated with prognosis, whereas the loss of expression and methylation of PTEN are negatively associated with prognosis (54). A high proliferative activity of tumor cells based on Ki-67 expression and the number of mitoses is associated with a poor prognosis in endometrial cancer; however, the multivariate survival analyses do not show concordant results, which may be due to technical differences in measuring Ki-67 (55,56). The loss of expression of Bcl-2 and the resultant reduced apoptosis are also associated with a poor prognosis (39).…”

Section: Biomarkers For Prognosis and Treatmentmentioning

confidence: 99%

Biomarkers in endometrial cancer: Possible clinical applications (Review)

et al. 2012

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Abstract. The number of cases of endometrial cancer has shown a tendency to increase in recent years. Endometrial cancer originates from the endometrium and is classified, based on the development mechanism, into types 1 and 2, which are responsive and non-responsive to estrogen, respectively, and have significantly different gene expression profiles. Studies of genes with abnormal expression in endometrial cancer have identified multiple oncogenes, tumor suppressors, mismatch repair genes, apoptosis-associated genes, levels of hormone receptors and DNA ploidy and aneuploidy as biomarkers of endometrial cancer. The use of these molecules and genes may facilitate accurate diagnosis and prognostic prediction and contribute to individualized treatment. Trials of drugs which target these biomarkers and searches for new biomarkers using cDNA microarrays and RT-qPCR are ongoing and it is likely that these findings can be translated to clinical use. Contents1. Introduction 2. Differences in biomarkers in subtypes of endometrial cancer 3. Oncogenes 4. Tumor suppressors 5. Mismatch repair genes and microsatellite instability 6. Other biomarkers 7. Biomarkers for prognosis and treatment 8. Conclusion IntroductionEndometrial cancer is the seventh most common cancer worldwide in women (1). The incidence differs depending on the region: in developed countries, 10-20 in 100,000 women have endometrial cancer, whereas the incidence is approximately one-tenth this level in developing countries. The number of cases is rapidly increasing in Japan. Obesity, nulliparity and the administration of tamoxifen have been identified as risk factors for endometrial cancer (2).In the last 10 years, numerous studies have aimed to identify tumor biomarkers. The US National Cancer Institute (NCI) defines a biomarker as ʻa biological molecule found in blood, other body fluids, or tissues that is a sign of a normal or abnormal process, or of a condition or diseaseʼ. According to this definition, a biomarker includes not only the proteins normally used as tumor markers, such as CA-125, but also genes and chromosomes. Biomarkers of endometrial cancer that have been identified include the K-ras, HER2/neu, epithelial growth factor receptor (EGFR), phosphatidylinositol 3-kinase catalytic subunit (PI3KCA) and fibroblast growth factor receptor 2 (FGFR2) oncogenes; the phosphatase and tensin homolog (PTEN), p53, p21 and cyclin-dependent kinase inhibitor 2A (CDKN2A) cancer suppressor genes; the hMLH1, hMSH2, hMSH6, PMS1 and PMS2 mismatch repair genes; Ki-67, an index of cell proliferation; BCL2-associated X protein (Bax), an apoptosis promotor gene; Bcl-2, an apoptosis suppressor; expression levels of estrogen and progesterone receptors; microvascular density (MVD); and vascular endothelial growth factor A (VEGF-A), which are all indices of angiogenesis; expression changes in E/P-cadherin and β-catenin, which are associated with infiltration and metastatic capacity; and ploidy and aneuploidy of DNA. The characteristics and functions of each of these bioma...

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“…1,50 High proliferation index by MIB-1 stain has been shown to be of prognostic significance in endometrial carcinomas in some studies, [51][52][53] whereas others have shown no prognostic significance of MIB-1 in high-grade carcinomas of the endometrium. 54 We use MIB-1 in endometrial cancers that show complete absence of staining for p53 (p53 null), a pattern that has been shown to correlate with the presence of frameshift or nonsense p53 mutations. If such tumors show a very high proliferative rate (480%), we favor a diagnosis of serous carcinoma in the appropriate clinical and morphologic context.…”

Section: Pfs -Morphologymentioning

confidence: 99%

p53 overexpression in morphologically ambiguous endometrial carcinomas correlates with adverse clinical outcomes

et al. 2010

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The distinction between uterine serous and endometrioid carcinomas can usually be achieved by morphologic examination alone. However, there are occasional 'morphologically ambiguous endometrial carcinomas' that show overlapping serous and endometrioid features and defy histologic classification. The primary aim of this study was to assess the clinical significance of p53 overexpression using immunohistochemistry in such tumors. Related aims included (1) assessing interobserver diagnostic concordance for histologic subclassification of these tumors using a panel of pathologists with and without gynecologic pathology expertise and (2) elucidating the histologic features that correlate with p53 status. Thirty-five such cases were identified during the study period. p53 overexpression was seen in 17 of 35 cases. Tumors with p53 overexpression were associated with a significantly inferior progression-free survival and disease-specific survival compared with those that lacked p53 overexpression (3-year progression-free survival and disease-specific survival were 94 and 100% in patients with no p53 overexpression, and 52 and 54% in patients with p53 overexpression; P ¼ 0.02 and 0.003, respectively). The consensus diagnosis rendered by gynecologic pathologists was predictive of disease-specific survival (P ¼ 0.002), but not progression-free survival (P ¼ 0.11). Although the interobserver diagnostic concordance (kappa ¼ 0.70) was substantial for gynecologic pathologists, and highly associated with p53 status (77% of 'favor serous' cases showed p53 overexpression, whereas only 25% of 'favor endometrioid' cases showed p53 overexpression; P ¼ 0.005), the concordance between the consensus diagnosis of the two specialized pathologists versus each of three non-specialized pathologists was poor (kappa ¼ 0.13-0.25). The histologic feature that correlated most with p53 overexpression was the presence of diffuse high nuclear grade. p53 immunohistochemistry assays in morphologically ambiguous endometrial carcinomas are roughly as clinically informative as gynecologic pathology consultation and can be helpful for prognostic assessment and therapeutic decision making in difficult endometrial carcinomas.

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Markers of Proliferative Activity Are Predictors of Patient Outcome for Low-Grade Endometrioid Adenocarcinoma But Not Papillary Serous Carcinoma of Endometrium

Cited by 40 publications

References 42 publications

Identification of prognostically relevant and reproducible subsets of endometrial adenocarcinoma based on clustering analysis of immunostaining data

Identification of prognostically relevant and reproducible subsets of endometrial adenocarcinoma based on clustering analysis of immunostaining data

Biomarkers in endometrial cancer: Possible clinical applications (Review)

p53 overexpression in morphologically ambiguous endometrial carcinomas correlates with adverse clinical outcomes

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