Borderline epithelial tumors of the ovary.
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The concept and terminology of borderline epithelial tumors of the ovary have been controversial for over a century, in spite of the acceptance of a borderline category in almost all current classifications of ovarian tumors. Typically, borderline tumors are noninvasive neoplasms that have nuclear abnormalities and mitotic activity intermediate between benign and malignant tumors of similar cell type. Borderline tumors of all surface epithelial cell types have been studied. The most common and best understood are serous borderline tumors and mucinous borderline tumors of intestinal type, which are the subject of this review. Some of the most challenging issues for serous tumors include: the criteria and clinical behavior of stromal microinvasion; the high prevalence of synchronous extraovarian disease; the classification and histopathologic features of associated peritoneal tumor implants, especially invasive implants; and, the prognostic significance of micropapillary tumors. The mucinous borderline tumors of intestinal type have a different set of considerations, including: their frequently heterogeneous composition with coexisting benign, borderline and malignant elements; the classification and significance of accompanying noninvasive carcinoma; the recognition of stromal invasion, including microinvasion and expansile invasion; and, the historically misunderstood relationship to pseudomyxoma peritonei. All of these issues are discussed in this presentation, as are the important gross and microscopic features of serous and mucinous borderline tumors and pertinent information on their treatment and prognosis. (+info)
Gene expression fingerprint of uterine serous papillary carcinoma: identification of novel molecular markers for uterine serous cancer diagnosis and therapy.
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Uterine serous papillary cancer (USPC) represents a rare but highly aggressive variant of endometrial cancer, the most common gynecologic tumour in women. We used oligonucleotide microarrays that interrogate the expression of some 10 000 known genes to profile 10 highly purified primary USPC cultures and five normal endometrial cells (NEC). We report that unsupervised analysis of mRNA fingerprints readily distinguished USPC from normal endometrial epithelial cells and identified 139 and 390 genes that exhibited >5-fold upregulation and downregulation, respectively, in primary USPC when compared to NEC. Many of the genes upregulated in USPC were found to represent adhesion molecules, secreted proteins and oncogenes, such as L1 cell adhesion molecule, claudin-3 and claudin-4, kallikrein 6 (protease M) and kallikrein 10 (NES1), interleukin-6 and c-erbB2. Downregulated genes in USPC included SEMACAP3, ras homolog gene family, member I (ARHI), and differentially downregulated in ovarian carcinoma gene 1. Quantitative RT-PCR was used to validate differences in gene expression between USPC and NEC for several of these genes. Owing to its potential as a novel therapeutic marker, expression of the high-affinity epithelial receptor for Clostridium perfringens enterotoxin (CPE) claudin-4 was further validated through immunohistochemical analysis of formalin-fixed paraffin-embedded specimens from which the primary USPC cultures were obtained, as well as an independent set of archival USPC specimens. Finally, the sensitivity of primary USPC to the administration of scalar doses of CPE in vitro was also demonstrated. Our results highlight the novel molecular features of USPC and provide a foundation for the development of new type-specific therapies against this highly aggressive variant of endometrial cancer. (+info)
Human kallikrein 6: a new potential serum biomarker for uterine serous papillary cancer.
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PURPOSE: The discovery of novel biomarkers might greatly contribute to improve clinical management and outcomes in uterine serous papillary carcinoma (USPC), a highly aggressive variant of endometrial cancer. EXPERIMENTAL DESIGN: Human kallikrein 6 (hK6) gene expression levels were evaluated in 29 snap-frozen endometrial biopsies, including 13 USPC, 13 endometrioid carcinomas, and 3 normal endometrial cells by real-time PCR. Secretion of hK6 protein by 14 tumor cultures, including 3 USPC, 3 endometrioid carcinoma, 5 ovarian serous papillary carcinoma, and 3 cervical cancers, was measured using a sensitive ELISA. Finally, hK6 concentration in 79 serum and plasma samples from 22 healthy women, 20 women with benign diseases, 20 women with endometrioid carcinoma, and 17 USPC patients was studied. RESULTS: hK6 gene expression levels were significantly higher in USPC when compared with endometrioid carcinoma (mean copy number by real-time PCR, 1,927 versus 239, USPC versus endometrioid carcinoma; P < 0.01). In vitro hK6 secretion was detected in all primary USPC cell lines tested (mean, 11.5 microg/L) and the secretion levels were similar to those found in primary ovarian serous papillary carcinoma cultures (mean, 9.6 microg/L). In contrast, no hK6 secretion was detectable in primary endometrioid carcinoma and cervical cancer cultures. hK6 serum and plasma concentrations (mean +/- SE) among normal healthy females (2.7 +/- 0.2 microg/L), patients with benign diseases (2.4 +/- 0.2 microg/L), and patients with endometrioid carcinoma (2.6 +/- 0.2 microg/L) were not significantly different. In contrast, serum and plasma hK6 values in USPC patients (6.1 +/- 1.1) were significantly higher than those in the noncancer group (P = 0.006), benign group (P = 0.003), and endometrioid carcinoma patients (P = 0.005). CONCLUSIONS: hK6 is highly expressed in USPC and is released in the plasma and serum of USPC patients. hK6 may represent a novel biomarker for USPC for monitoring early disease recurrence and response to therapy. (+info)
Microarray analysis of endometrial carcinomas and mixed mullerian tumors reveals distinct gene expression profiles associated with different histologic types of uterine cancer.
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Previous studies using cDNA microarray have indicated that distinct gene expression profiles characterize endometrioid and papillary serous carcinomas of the endometrium. Molecular studies have observed that mixed mullerian tumors, characterized by both carcinomatous and sarcomatous components, share features that are characteristic of endometrial carcinomas. The objective of this analysis was to more precisely define gene expression patterns that distinguish endometrioid and papillary serous histologies of endometrial carcinoma and mixed mullerian tumors of the uterus. One hundred nineteen pathologically confirmed uterine cancer samples were studied (66 endometrioid, 24 papillary serous, and 29 mixed mullerian tumors). Gene expressions were analyzed using the Affymetrix Human Genome Arrays U133A and U133B Genechip set. Unsupervised analysis revealed distinct global gene expression patterns of endometrioid, papillary serous, mixed mullerian tumors, and normal tissues as grossly separated clusters. Two-sample t tests comparing endometrioid and papillary serous, endometrioid and mixed mullerian tumor, and papillary serous and mixed mullerian tumor pairs identified 1,055, 5,212, and 1,208 differentially expressed genes at P < 0.001, respectively. These data revealed that distinct patterns of gene expression characterize various histologic types of uterine cancer. Gene expression profiles for select genes were confirmed using quantitative PCR. An understanding of the molecular heterogeneity of various histologic types of endometrial cancer has the potential to lead to better individualization of treatment in the future. (+info)
Amplification of c-erbB2 oncogene: a major prognostic indicator in uterine serous papillary carcinoma.
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BACKGROUND: Overexpression of the epidermal growth factor type II receptor HER-2/neu has been associated with resistance to chemotherapy and poor survival in several human tumors. In the current study, the authors have determined the frequency and clinical significance of HER-2/neu gene amplification in uterine serous papillary endometrial carcinoma (USPC), a highly aggressive variant of endometrial carcinoma. METHODS: Fluorescence in situ hybridization (FISH) assay was used to analyze gene amplification in paraffin blocks from 30 women harboring Stage IA-IV USPC treated at the University of Arkansas for Medical Sciences (Little Rock, AR) from 1997 to 2004. Chromosome 17 polysomy status by FISH was also assessed in all specimens. USPC patient survival in relation to HER-2/neu gene amplification was analyzed using Kaplan-Meier curves in conjunction with the log-rank test. RESULTS: Amplification of the HER-2/neu gene by FISH was observed in 14 of the 30 (47%) cases. Heterogeneity was noted in 4 of 14 cases in the amplification of the HER-2/neu gene within the same tumor samples with pockets of amplified tumor cells amidst nonamplified tumor cells. Patients with USPC harboring tumors with HER-2/neu gene amplification had a significantly shorter survival time from diagnosis to disease-related death when compared with FISH-negative patients (P = 0.0008). African-American (AA) patients were found to have a poorer prognosis compared with Caucasian (C) women (P = 0.01) and to harbor USPC with significantly higher levels of HER-2/neu gene amplification (P = 0.02). CONCLUSIONS: HER-2/neu gene amplification in USPC was found to be an important prognostic indicator for poor outcome that occurs more frequently in AA when compared with C patients. Determination of HER-2/neu gene amplification may guide clinical management of patients with USPC and may have important implications for the implementation of novel treatment strategies. (+info)
p53 and bcl-2 expression in invasive and pre-invasive uterine papillary serous carcinoma and atrophic endometrium.
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INTRODUCTION: Uterine papillary serous carcinoma (UPSC), a high-grade tumour, is known to be associated in some cases with an identifiable intraepithelial neoplasia (IEN) component. Biomarker studies incorporating this latter component are not well documented. One aim of the present study was to compare levels of immunohistochemical (IHC) expression of p53 tumour suppressor gene and bcl-2 oncoprotein between UPSC and IEN, as well as normal endometrium to determine its biologic significance. The other major aim was to determine if these IHC results have any bearing on survival data in this tumour. MATERIALS AND METHODS: An immunoreactivity score was assigned for examination of p53 and bcl-2 expression in a total of 21 cases of UPSC, 9 with an evaluable IEN component and 11 with associated non-neoplastic endometrium. Statistical analysis of IHC results was performed, in addition to correlation with survival data and disease stage. RESULTS: p53 was identified in 16/21 cases of UPSC (76%) and 8/9 cases of IEN (89%), and no cases of normal endometrium. By contrast, bcl-2 was positive in all normal endometria with less expression in UPSC leaving 15/21 (71%) cases positive, and in IEN, leaving 5/9 (55%) of cases positive. Differences in immunoreactive scores for both p53 and bcl-2 between UPSC and benign glands, as well as between IEN and benign glands reached statistical significance with P values of 0.006 and 0.014 for p53, and 0.003 and 0.027 for bcl-2 respectively. There was no statistical significance between values for UPSC and IEN. Cox regression analysis found no statistically significant relationship between patient survival time in early and late stages of disease, and p53 and bcl-2 immunoscores. CONCLUSIONS: The lack of a significant difference between the bcl-2 and p53 values for both UPSC and IEN suggests that these molecular alterations occur at an early stage of tumour pathogenesis. A potential advantage of the use of immunohistochemical markers is their application to routinely processed surgical specimens. In this case, bcl-2 and p53 were applied in UPSC to determine any potential significance, but neither marker proved to be a useful predictor of survival time or disease stage. (+info)
Peritoneal serous papillary adenocarcinoma: report of four cases.
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We report four cases of peritoneal serous papillary adenocarcinoma (PSPC), a rare disease; all patients had ascites and high levels of serum CA125. Clinical and radiological examinations could not differentiate the disease from peritoneal metastatic tumors and mesothelioma, and histopathological analysis including immunochemistry on the specimen obtained at laparotomy or laparoscopy was necessary for the diagnosis. One patient lived for 58 months with cytoreductive surgery and chemotherapy, and another is still living after 20 months by chemotherapy alone. In patients with peritoneal tumors of unknown origin and a high level of serum CA125, taking PSPC into consideration in the differential diagnosis, histopathological examination should be performed. (+info)
The value of serum and tissular expression of CA 125 antigen, in evaluation of the response to second line chemotherapy for the relapsed ovarian carcinoma.
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PURPOSE: The purpose of this study is to compare the predicted value of the blood levels variations of CA 125 antigen and the imunohistochemical expression of CA 125, with imagistic criteria (The Response Evaluation Criteran in Solid Tumor--RECIST) regarding the survival estimation of female patients with relapsed ovarian carcinoma which undergo to second line chemotherapy. MATERIAL AND METHOD: We included in this study 40 female patients diagnosed with ovarian carcinoma in the Oncology Clinic of the Emergency County Hospital Craiova, in a period of two years (from 2000 to 2002), which have fulfilled the following criteria: ovarian carcinoma IC-IV stage, according to FIGO system, first line treatment represented by the association between paclitaxel and a platinum salt, refractory or recurrent disease, indications for beginning the second line chemotherapy represented by topotecan or paclitaxel and carboplatin. The serial CA 125 antigen was determined in all patients before starting the chemotherapy and after each two sequences of chemotherapy, and the imunohistochemical expression of CA 125 was evaluated from surgery extracts before the second line chemotherapy (11 cases). The imagistic evaluation of the treatment response was done after 4 sequences of chemotherapy. RESULTS: All patients had measurable disease according to RECIST criteria and had high values (at least double) of the CA 125 antigen blood level at the time of diagnosis. The imunohistochemically expression of CA 125 was correlated in most cases with the blood level of CA 125. The evaluation criterion of the CA 125 antigen has been shown to be more efficient in estimation the survival rate compared with the RECIST system. In a various analysis, which included numerous potential prognostic factors, only the variation of blood levels of these antigen and the free disease interval from the finalization of the first line chemotherapy have been identified as predictive factors of survival, while the other variables, including the RECIST criteria, had no impact on the prognosis regarding the survival. CONCLUSIONS: The response evaluation criteria based on the blood levels variations of CA 125 antigen are a better instrument for the estimation of the compared prognosis with the RECIST criteria, for patients on second line chemotherapy for relapsed ovarian carcinoma. (+info)