Comparison of p53, Ki-67, and CD44v6 expression between primary and matched metastatic lesions in ovarian cancer

OBJECTIVE: Many studies have demonstrated that clinically evident tumor cells already carry multiple genetic alterations and further accumulation of genetic alteration causes tumor progression which plays a role in metastasis. Therefore, it could be expected that malignant potential in the metastatic site is more aggressive than that in the primary site. Using several immunohistochemical markers (p53, Ki-67, and CD44v6), we investigated an alteration of malignant potential. METHODS: We immunohistochemically examined expression of p53, Ki-67, and CD44 in primary and metastatic lesions of ovarian cancer. Fifty-six samples of primary lesions and matched metastatic sites from 56 patients with primary epithelial ovarian cancers were included in this study. RESULTS: In 16 cases (28%), the histological grade of the metastatic lesion increased. This difference was statistically significant (P = 0.0232). In 16 cases (28%), the expression of p53 increased in the metastatic lesions, in 5 pairs from negative to positive, whereas the case decrease in the metastatic lesions was only 1. This difference was statistically significant (P = 0.0046). There was no significant difference in Ki-67 labeling indices and expression of CD44v6 between the primary and matched metastatic lesions. The degree of p53 expression in the metastatic lesions significantly correlated with disease-free survival (P = 0.0482), whereas that in the primary lesions did not. Moreover, high p53 expression in the metastatic lesions significantly correlated with disease-free survival in multivariate analysis. CONCLUSIONS: The p53 expression in metastatic lesions may reflect an aggressive biologic behavior in ovarian cancer.     

HER-2/neu及细胞角蛋白在卵巢上皮性肿瘤原发灶和转移灶中表达的检测及临床意义的研究

目的：了解卵巢上皮性肿瘤原发灶和转移灶中癌基因ＨＥＲ－２／ｎｅｕ和细胞角蛋白表达状况及其临床意义。方法：用免疫组化法检测卵巢上皮肿瘤原发灶６９份及转移灶３８份（５１处）标本中ＨＥＲ－２／ｎｅｕ和细胞角蛋白的表达，并与术后组织学分级及患者生存期分析相结合。结果：原发灶中二者阳性表达率与术后患者生存期无相关性（Ｐ＞０．０５）。角蛋白与组织学分级有关（Ｐ＜０．０５），而且在转移灶癌细胞中表达较稳定。在转移灶中ＨＥＲ－２／ｎｅｕ的表达明显低于原发灶中者（Ｐ＜０．０５），在原发灶和转移灶中都呈阳性表达的患者预后较差（Ｐ＜０．０５）。结论：在卵巢上皮性肿瘤原发灶和转移灶中ＨＥＲ－２／ｎｅｕ的表达有显著差别，其原因有待进一步研究。原发灶和转移灶中ＨＥＲ－２／ｎｅｕ都表达的患者提示预后不良。角蛋白与卵巢上皮性肿瘤分化程度有关，在转移灶中表达较稳定     

Conservation of in vitro drug resistance patterns in epithelial ovarian carcinoma

PURPOSE: To compare the in vitro drug resistance profiles of advanced stage primary and recurrent epithelial ovarian cancer specimens using the tritiated thymidine uptake assay. METHODS: Extreme drug resistance (EDR) to cisplatin, paclitaxel, 4-hydroxycyclophosphamide, and topotecan was determined for an unselected population of primary and metastatic malignant ovarian tissues, synchronous tumors (primary and metastatic tissues obtained from the same patient at diagnosis), and metachronous lesions (specimens from the same patient before and after chemotherapy). RESULTS: For the large unselected population of malignant tissues (total, N = 6990; primary ovarian, N = 2031; metastatic ovarian, N = 4959), no statistically significant differences were discovered between primary tissues and metastatic lesions when a comparison was made between the percentage of tumors from each group that exhibited extreme drug resistance to the agents assayed. From the library of 6990 specimens, 119 synchronous pairings were identified. These synchronous lesions did not differ significantly in the %EDR between primary and metastatic sites in the same patient; approximately 10% shifted between low drug resistance and EDR. A total of 334 metachronous pairings were identified and the percentage of tissues that exhibited EDR also failed to show a significant difference when primary tumors were compared with matched recurrences in the same patient. CONCLUSIONS: For the agents studied, acquired resistance was not a function of disease site. In vitro drug resistance observed at recurrence was not influenced significantly by intervening therapy. It is possible that assay results at diagnosis could be used to guide subsequent therapy at relapse, especially when recurrent tissue is not available for analysis.     

Type IV collagen and CD44v6 expression in benign, malignant primary and metastatic ovarian tumors: correlation with Ki-67 and p53 immunoreactivity

OBJECTIVE: Loss of basement membrane (BM) components, such as type IV collagen has been demonstrated in ovarian cancer, but the associations with other molecules like CD44v6, involved in metastatic process of ovarian carcinoma, have not been fully analyzed. This study investigates the expression of type IV collagen, CD44v6 molecule in correlation with p53 and Ki-67 presence in primary and metastatic lesion of ovarian carcinoma to define their role in metastases of ovarian carcinoma. METHODS: The expression of type IV collagen, CD44v6, p53, and Ki-67 was evaluated on frozen tissue sections from primary ovarian tumors (malignant n = 37, benign n = 16), metastatic lesions (n = 29) and ascitic fluid cells (n = 28). Protein expression of all studied biomarkers was evaluated in a subset of specimens using immunohistochemistry (IHC). RESULTS: Type IV collagen expression in the primary ovarian carcinoma was positively correlated with International Federation of Gynecology and Obstetrics (FIGO) stage and tumor grade. Significant difference was observed for type IV collagen immunoreactivity in carcinoma cells in effusions when compared to corresponding primary tumors (P < 0.001) and metastatic lesions (P < 0.001). Likewise down-regulation of type IV collagen expression was seen in primary ovarian carcinomas (P = 0.01), ascitic fluid cells (P < 0.001), and metastases (P = 0.003) when compared to benign ovarian neoplasms. CD44v6 expression was detected in a comparable percentage of primary carcinomas (51%) and metastatic lesions (52%). In cells isolated from ascitic fluid, CD44v6 immunopositivity was observed in 43% of cases. A comparative analysis of primary and metastatic tumors and carcinoma cells in effusion did not reveal differences in expression of CD44v6. Positivity of CD44v6 was found in 2/16 (12%) of benign ovarian neoplasms. There were no significant differences between CD44v6 expression in benign neoplasms compared to primary malignant tumors and metastases (P > 0.05). CD44v6 expression in primary ovarian carcinomas was associated with higher tumor grade (P = 0.01) and histological type of tumors (P = 0.01). An inverse relationship of type IV collagen expression with p53 and CD44v6 positivity in benign and malignant ovarian tumors was found (P > 0.01). Type IV collagen expression was inversely correlated with p53 status (P = 0.03) in metastatic lesions. A slight trend toward an inverse correlation between Ki-67 and type IV collagen expression was observed in both benign and malignant ovarian tumors and metastases. CONCLUSIONS: Our data suggest that observed inverse correlation of type IV collagen expression with p53, CD44v6, and slight with Ki-67 positivity in primary benign and malignant tumors indicates that these molecules may cooperate in the invasion and progression of ovarian carcinomas.     

Analysis of antigen expression at multiple tumor sites in epithelial ovarian cancer.

The question of whether the antigenic phenotype of human epithelial ovarian cancer varies in a given patient between the primary tumor and metastatic sites or among metastatic sites themselves is an important issue in planning potential therapeutic strategies for ovarian cancer. We have obtained tumor specimens from at least two separate sites during operations on 12 patients with epithelial ovarian cancer, and we have typed these specimens with a group of 18 monoclonal antibodies that react with cell-surface glycoprotein and carbohydrate antigens, including blood group antigens. Antibodies with relative specificity for malignant cells as well as those that detect more widely distributed epithelial antigens were used. A total of 31 specimens from 12 patients with advanced adenocarcinoma (8 serous, 3 undifferentiated, 1 endometrioid) of the ovary were studied, including fresh ascites cells in two patients. Frozen sections of tumor specimens were stained with the antibodies by the indirect immunoperoxidase technique and graded semiquantitatively. Little difference was seen in antigenic expression of tumors that were obtained from various sites in the same patient for either the epithelial cell markers or blood group markers. Intratumoral antigenic heterogeneity was seen, but this was generally quite consistent within a given patient's specimens. As anticipated, variations in antigen expression were seen among specimens from different patients. The antigenic phenotype of the tumor specimens in a given patient, as determined immunohistochemically by our group of antibodies, showed only minor variation among primary and metastatic sites.     

粘附分子CE44v6表达和p53基因突变与卵巢癌转移关系的研究

目的 探索卵巢癌粘附分子ＣＤ４４和变构体ＣＤ４４ｖ６表达和Ｐ５３基因突变与卵巢癌转移之间的关系和作用柚是。方法 选择正常卵巢２０例,良性卵巢肿瘤２０例、卵巢癌４５例（其中２０例肿瘤无转移,２５例肿瘤有转移）,应用流式细胞仪测定卵巢癌细胞ＤＮＡ含量及其在细胞周期各相中的分布;应用逆转录－聚合酶链反应（ＲＴ－ＰＣＲ）及特异探针Ｄ３对卵巢癌细胞进行ＤＮＡ印溃杂交分析,并对杂交条带进行辉度扫描;应用银染聚     

Epidermal growth factor receptor expression in gynecological malignancies

Epidermal growth factor receptor (IEGF-R) levels were analyzed in 72 gynecological tumor specimens. Measurable EGR-R levels were found in a significant percentage of ovarian and uterine tumors. Moreover, all vulvar epidermoid carcinomas and uterine sarcomas analyzed were EGF-R positive. In all tumor types examined, scattered EGF-R levels were observed. Higher EGF-R levels were found in metastatic than in primary ovarian tumors. Moreover, EGF-R were found to be more expressed in less differentiated than in well-moderately differentiated endometrial tumors. Our results suggest a role of EGF or EGF-like substances in regulating the growth of gynecological malignancies, and indicate EGF-R expression as a possible prognostic factor.     

Estrogen receptor expression and increased risk of lymphovascular space invasion in high-grade serous ovarian carcinoma

Objective

Recent studies have demonstrated that lymphovascular space invasion (LVSI) is associated with increased risk of hematogenous and lymphatic metastasis and poor clinical outcome of women with epithelial ovarian cancer. Given the suspected role of estrogen in promoting ovarian cancer metastasis, we examined potential links between estrogen receptor and LVSI in high-grade serous ovarian carcinoma.

Methods

Tumoral expression of ER, PR, p53, MDR1, EGFR, HER2, DNA ploidy, and S-phase fraction was examined for 121 cases of stage I–IV high-grade serous ovarian carcinoma samples obtained at primary cytoreductive surgery. Biomarker expression was correlated to LVSI and survival outcomes.

Results

LVSI was observed in 101 (83.5%) of all cases. Immunohistochemistry of tested biomarkers showed ER (86.7%) to be the most commonly expressed followed by p53 (71.4%), HER2 (68.3%), EGFR (52.1%), MDR-1 (14.3%), and PR (8.9%). ER expression was positively correlated to PR expression (r = 0.31, p = 0.001). LVSI was only correlated with ER (odds ratio 6.27, 95%CI 1.93–20.4, p = 0.002) but not with other biomarkers. In multivariate analysis, ER remained significantly associated with LVSI (p = 0.039). LVSI remained a significant prognostic factor for decreased progression-free survival (HR 3.01, 95%CI 1.54–5.88, p = 0.001) and overall survival (HR 2.69, 95%CI 1.18–6.23, p = 0.021) while ER-expression did not remain as a significant variable in multivariate analysis.

Conclusion

Our data demonstrated that estrogen receptor was positively correlated with LVSI that was an independent prognostic indicator of poor survival outcomes of high-grade serous ovarian carcinoma. This study emphasizes the importance of estrogen pathway in promoting lymphatic or vascular spread of high-grade serous ovarian carcinoma.     

Epidermal Growth Factor Receptor in Vulvar Malignancies and Its Relationship to Metastasis and Patient Survival

Objective.To evaluate the level of epidermal growth factor receptor (EGF-R) expression in vulvar malignancies and to determine if a correlation exists between EGF-R levels and metastasis or patient survival.Methods.All patients with a diagnosis of invasive squamous cell carcinoma of the vulva who were treated at our institution with a primary radical vulvectomy and inguinal lymph node dissection from 1983 to 1993 were eligible for the study. Sixty-one patients with available tissue blocks of benign vulvar epithelium, the primary malignant vulvar lesion, and groin node metastasis (when positive) were included in the study. Semiquantitative EGF-R expression was determined in a blinded fashion utilizing immunohistochemical staining of appropriate tissue samples. Survival was calculated utilizing Kaplan–Meier life table analysis based upon disease-free survival.Results.A significant increase (P< 0.001) in mean EGF-R levels was demonstrated in the primary tumor (67%) versus benign vulvar epithelium (31%). In the 14 patients with lymph node metastasis, the mean EGF-R level in the primary tumor was 65% versus 88% in the metastatic lesion (P< 0.001). The likelihood of lymph node metastasis was elevated in those patients with a benign tissue EGF-R level ≥40% (P< 0.03) and in those patients with a primary tumor EGF-R level ≥90% (P< 0.025). Life table analysis revealed a cumulative disease-free survival of 45% for all patients. Disease-free survival in those patients with EGF-R levels ≥90% in the primary tumor was 25%, contrasting with a disease-free survival of 54% in those patients with EGF-R levels <90% (P< 0.05).Conclusions.There is a progressive increase in EGF-R expression from benign vulvar epithelium to primary malignant tissue to metastatic lesions within the same patient. Increased expression of EGF-R in the primary vulvar malignancy is significantly associated with lymph node metastasis and decreased patient survival. Increased expression of EGF-R in histologically benign vulvar epithelium has a significant association with lymph node metastasis and may predict decreased patient survival.     

Identification of genes associated with ovarian cancer metastasis using microarray expression analysis

Although the transition from early- to advanced-stage ovarian cancer is a critical determinant of survival, little is known about the molecular underpinnings of ovarian metastasis. We hypothesize that microarray analysis of global gene expression patterns in primary ovarian cancer and metastatic omental implants can identify genes that underlie the metastatic process in epithelial ovarian cancer. We utilized Affymetrix U95Av2 microarrays to characterize the molecular alterations that underlie omental metastasis from 47 epithelial ovarian cancer samples collected from multiple sites in 20 patients undergoing primary surgical cytoreduction for advanced-stage (IIIC/IV) serous ovarian cancer. Fifty-six genes demonstrated differential expression between ovarian and omental samples (P < 0.01), and twenty of these 56 differentially expressed genes have previously been implicated in metastasis, cell motility, or cytoskeletal function. Ten of the 56 genes are involved in p53 gene pathways. A Bayesian statistical tree analysis was used to identify a 27-gene expression pattern that could accurately predict the site of tumor (ovary versus omentum). This predictive model was evaluated using an external data set. Nine of the 27 predictive genes have previously been shown to be involved in oncogenesis and/or metastasis, and 10/27 genes have been implicated in p53 pathways. Microarray findings were validated by real-time quantitative PCR. We conclude that gene expression patterns that distinguish omental metastasis from primary epithelial ovarian cancer can be identified and that many of the genes have functions that are biologically consistent with a role in oncogenesis, metastasis, and p53 gene networks.     

Frequent and increased expression of human METCAM/MUC18 in cancer tissues and metastatic lesions is associated with the clinical progression of human ovarian carcinoma

ObjectivesHuman METCAM/MUC18 (huMETCAM/MUC18), a cell adhesion molecule, plays an important role in the progression of several epithelial cancers; however, its role in the progression of epithelial ovarian cancers is unknown. To initiate the study we determined expression of this protein in normal and cancerous ovarian tissues, cystadenomas, metastatic lesions, and ovarian cancer cell lines.Materials and methodsImmunoblotting and immunohistochemical (IHC) methods were used to determine huMETCAM/MUC18 expression in lysates of frozen and formalin-fixed, paraffin-embedded tissue sections of normal human ovaries, and ovarian (benign) cystadenomas, carcinomas and metastatic lesions. We also determined expression levels of several downstream effectors of METCAM/MUC18 in these tissues.ResultsHuMETCAM/MUC18 levels in ovarian carcinomas and metastatic lesions were significantly higher than in normal tissues and cystadenomas. IHC results showed that expression of huMETCAM/MUC18 in normal tissues and cystadenomas was mostly absent from epithelial cells, but in carcinomas and metastatic lesions it was localized to epithelial cells. In higher pathological grades of ovarian cancer and metastatic lesions, the percentage of cells stained in IHC was increased. Thirty percent of normal tissues weakly expressed the huMETCAM/MUC18 antigen, but 70% of cancer tissues and 100% of metastatic lesions expressed the antigen. Expression levels of several downstream effectors of huMETCAM/MUC18, Bcl2, PCNA and VEGF, were elevated in cancerous tissues, however, not that of Bax. The phospho-AKT/AKT ratio was elevated in metastatic lesions.ConclusionUpexpression of huMETCAM/MUC18 may be a marker for the malignant potential of ovarian carcinomas. Progression of ovarian cancer may involve increased signaling in anti-apoptosis, proliferation, survival/proliferation pathway, and angiogenesis.     

Prognostic significance of tumor ploidy in patients with advanced ovarian carcinoma

Fresh tumor specimens obtained from 53 consecutive patients with FIGO Stage III ovarian carcinoma were analyzed by flow cytometry. All patients were treated by a standard protocol: maximal tumor excision and cisplatin/cyclophosphamide/adriamycin chemotherapy, and followed-up for at least 24 months. Thirty-two percent of tumors were diploid (DNA index = 1.00) and 68% aneuploid (DNA index greater than 1.00), with more aneuploid tumors being associated with larger residual tumor and poor cellular differentiation. Patients with diploid tumors were found to survive significantly better than those with aneuploid tumors, in terms of survival rate (65% versus 31%), median survival time (33 months versus 13 months), and mean disease-free interval (17.8 months versus 8.2 months). The influence of the amount of residual tumor after primary surgery on survival was only significant in patients with diploid tumors. Our results support previous findings that tumor ploidy is an important prognostic indicator in ovarian cancer. We found aneuploidy to be associated with a poorer clinical outcome in Stage III disease, regardless of the amount of residual tumor after primary surgery and the degree of cellular differentiation.     

Expression of MUC1 in primary and metastatic human epithelial ovarian cancer and its therapeutic significance

BACKGROUND: MUC1 is associated with cellular transformation and tumorigenicity and is considered as an important tumor-associated antigen (TAA) for cancer therapy. The objective of this study was to evaluate the patterns of MUC1 expression in primary tumors and metastatic lesions in the advanced stages of epithelial ovarian cancers (EOCs) and correlate the expression with clinicopathological features. METHODS: The expression of MUC1 was examined on frozen tissue sections from primary EOC (n=42), the matched metastatic lesions (n=30) and paraffin-embedded tissue sections from primary EOC (n=60), normal ovarian tissues (n=20) using immunohistochemistry (IHC) by monoclonal antibody (MAb) C595. RESULTS: The expression of MUC1 was found in 92% (39/42) of EOC and 90% (27/30) of the matched metastatic lesions in frozen tissue sections respectively while the expression of MUC1 was found in 95% (57/60) of EOC and 5% (1/20) of normal ovarian tissues in paraffin-embedded sections respectively. Most of the tumors showed moderate to strong intensity staining while normal ovarian tissues only showed weak intensity staining. The overexpression of MUC1 was significantly associated with various progression parameters such as tumor stage, grade, residual disease status and presence of ascites (P<0.05). CONCLUSIONS: MUC1 is overexpressed in above 90% of late stage of EOC and of metastatic lesions but not in normal ovarian tissues, and the high expression of MUC1 is correlated with EOC progression. MUC1 antigen may be a useful therapeutic target to prevent the development of incurable, recurrent metastatic EOC.     

原发上皮性卵巢癌组织中多药耐药基因表达及其临床意义

目的探讨多药耐药（ＭＤＲ１）基因表达与原发性上皮性卵巢癌（ＰＥＯＣ）耐药的关系及其临床意义。方法应用半定量逆转录—聚合酶链反应（ＲＴ－ＰＣＲ）技术,对３７例ＰＥＯＣ、１０例正常卵巢上皮组织和２０例正常女性外周血单核细胞（ＰＢＭＣ）新鲜标本ＭＤＲ１基因表达进行了检测;并用四氮唑蓝（ＭＴＴ）法,检测了这３７例ＰＥＯＣ患者的原代癌细胞对临床常用抗癌药物的敏感性。结果ＰＥＯＣ标本中ＭＤＲ１基因阳性表达率为３０％,而正常卵巢上皮组织和ＰＢＭＣ则无ＭＤＲ１基因表达;ＭＤＲ１基因表达与ＰＥＯＣ临床期别及组织学类型无关,而与组织学级别有关,且有随级别升高而升高的趋势;ＭＤＲ１基因阳性表达组与阴性组比较,ＤＡＣＴ、ＡＤＭ、Ｅ－ＡＤＭ、ＶＣＲ和ＶＰ１６对ＰＥＯＣ细胞抑制率差异有显著性,其余则无显著性;ＭＤＲ１基因表达与无进展生存期有关,而与总体生存期无关。结论ＭＤＲ１基因表达与ＰＥＯＣ耐药有关,是抗ＭＤＲ相关药物的主要原因;ＭＤＲ１基因表达的检测,对临床用药有指导意义,对临床疗效判断和患者预后预测有一定价值。     

Flow cytometric analysis of lymph node metastases in advanced ovarian cancer: Clinical and biologic significance

OBJECTIVE: This study was undertaken to evaluate the deoxyribonucleic acid content and S-phase fraction in advanced epithelial ovarian carcinomas to determine whether lymph node metastases are biologically distinct from peritoneal sites of metastases.STUDY DESIGN: Thirty-five patients with stage III or IV epithelial ovarian cancer who had undergone complete pelvic and paraaortic lymphadenectomy had representative samples from the primary ovarian tumor, peritoneal metastases, and lymph node metastases analyzed by flow cytometry for deoxyribonucleic acid nuclear content and S-phase fraction.RESULTS: Diploid cell lines are found in metastatic lymph nodes (52%) significantly more frequently than in peritoneal metastases (25%, p < 0.02) or in primary ovarian tumors (26%, p < 0.001). The ploidy category frequency distribution of peritoneal metastases mirrors that found in the primary tumor, and both are significantly different from the ploidy category frequency distribution found in metastatic lymph nodes. Heterogeneity among sites is common, being identified in 54% of patients. Peritoneal metastases are more likely to be concordant with the primary tumor (69%) than are lymph node metastases (39%, p < 0.001). Mean S-phase fraction did not differ overall by site but was significantly different between diploid and aneuploid samples by site. Diploid lymph node metastases were found to have the lowest mean S-phase fraction (7.2% ± 3.3%), and aneuploid lymph node metastases had the highest mean S-phase fraction (22.3% ± 10.2%). Diploidy of the primary tumor is a positive predictor of long-term survival. Tumoral heterogeneity and lymph node metastases are not related to survival in this group of patients who underwent therapeutic pelvic and aortic lymphadenectomy.CONCLUSIONS: A high proportion of tumor deposits found in metastatic lymph nodes are diploid with a low S-phase fraction. Therapeutic pelvic and aortic lymph node dissection removes disease that, on the basis of flow cytometric characteristics, may be predicted to be resistant to chemotherapy and radiation therapy. (Am J Obstet Gynecol 1997;176:1319-27.)     

The relationship of steroid receptor expression to nuclear DNA distribution and clinicopathological characteristics in epithelial ovarian tumors

Tumor specimens from 92 patients with ovarian carcinoma were analyzed for estrogen receptor (ER), progesterone receptor (PR), proliferative fraction, and ploidy. Seventy-one percent of tumors were either ER+ (greater than 5 fmole/mg protein) or PR+ (greater than 10 fmole/mg protein) with 27% of tumors overall being both ER+ and PR+. There was no significant relationship between receptor expression and stage, grade, or histological subtype. Thirteen percent of diploid tumors were receptor negative in contrast to 38% of aneuploid tumors (P less than 0.01). There was no significant association between ER status and ploidy, but 60% of diploid tumors were PR+ in contrast to 33% of aneuploid tumors (P less than 0.02). Eleven percent of tumors overall were both ER rich and PR rich and comprised 23% of diploid and 5% of aneuploid tumors (P less than 0.01). Receptor-negative tumors had a median S phase of 18.8% which was significantly higher than the median S phase of 12% in receptor-positive tumors (P less than 0.02). A similar analysis was also performed on specimens from 9 patients with borderline epithelial ovarian tumors and 12 with benign epithelial ovarian tumors. Up to 50% of benign and borderline epithelial tumors had measurable receptors, but all were diploid with a relatively low S phase fraction. The functional significance of steroid receptor expression in ovarian cancer is unclear, but the association with ploidy and proliferative activity particularly in patients with malignant ovarian tumors may allow better identification of prognostic subsets and aid in selection of patients for hormonal therapy.     

Loss of expression and altered localization of KAI1 and CD9 protein are associated with epithelial ovarian cancer progression

OBJECTIVE: Impairment of cell adhesion plays a vital role in tumor progression. E- and N-cadherin, CD9, and KAI1 are all adhesion molecules that have been implicated in the progression of several different tumor types. To help explain the potential role these adhesion molecules have in ovarian cancer, comparisons were made between expression patterns in normal ovary and various grades of primary and metastatic epithelial ovarian cancers. METHODS: Thirty-two primary and 8 metastatic human ovarian epithelial carcinomas and 18 samples of normal ovarian tissue were examined for adhesion molecule expression using immunohistochemistry. RESULTS: KAI1 and CD9 revealed an inverse relationship between tumor grade and expression levels, characterized by high expression in low-grade tumors and low expression in high-grade tumors and metastases. KAI1 and CD9 also demonstrated a shift in cellular localization from the membrane in grade 1 tumors to the cytoplasm in grade 3 tumors. N-cadherin expression showed a positive trend between expression levels and tumor grade. E-cadherin expression varied little between different tumor grades and metastases. Inclusion cysts (n = 6) and surface invaginations often strongly expressed KAI1, CD9, and E-cadherin. KAI1 expression was variable in ovarian follicles and corpora lutea depending on their stage of development. CONCLUSIONS: Although sample size is limited, these findings suggest that progression of ovarian epithelial carcinomas is associated with down-regulation and altered cellular localization of KAI1 and CD9. In addition, variable KAI1 expression during follicular and luteal development suggests that it has a physiological function in the ovary. Further investigation will be needed to see if it is also regulated this way during progression of ovarian cancers.     

Cyclooxygenase-1 and 2 in normal and malignant human ovarian epithelium

OBJECTIVES: Cyclooxygenase-1 and 2 (COX-1 and COX-2) play important roles in normal physiology and are often dysregulated in neoplastic tissues. The present study determines whether COX-1 and COX-2 are expressed in ovarian cancers and whether the pattern of expression of these enzymes reveals clues to their roles in this cancer. METHODS: The expression of COX-1 and COX-2 proteins in 9 normal human ovaries, in 137 cases of ovarian cancers of epithelial origin (83 primary and 54 metastatic), and in 7 ovarian cancer cell lines was examined by immunohistochemistry and western analysis. RESULTS: COX-1 protein was present in 95/137 (69.3%) of the total cancers studied, with 55/83 (66.3%) of the primary cancers and 40/54 (74.1%) of the metastatic cancers positive for protein. COX-2 was present in 97/137 (70.8%) of all cancers studied, with 53/83 (63.9%) of the primary cancers and 44/54 (81.5%) of the metastatic cancers positive for protein. Notably, the quickscores for COX-2-positive staining were significantly higher in metastatic cancers. Moreover, COX-2 immunostaining was frequently found at the advancing margin of tumor invasion or in new metastatic loci. COX-1 protein expression was observed in the ovarian surface epithelial cells, especially that of the inclusion cysts. COX-1 was also detected by western blot in seven of nine ovarian cancer cell lines. However, no COX-2 was detected in either normal epithelium or cancer cell lines. CONCLUSION: COX-1 and COX-2 were expressed in every type of ovarian epithelial cancer, suggesting that each may contribute to the cancer development or progression.     

Metastatic tumors to the ovaries: a study of 170 cases in northern Thailand

Abstract.   Khunamornpong S, Suprasert P, Na Chiangmai W, Siriaunkgul S. Metastatic tumors to the ovaries: a study of 170 cases in northern Thailand. Int J Gynecol Cancer 2006; 16(Suppl. 1): 132–138.
The cases of malignant ovarian tumors treated at Chiang Mai University hospital between 1992 and 2003 were histologically reviewed. The medical records, the radiologic findings, and the follow-up outcome in the cases suspicious or diagnostic of metastases were reviewed to confirm the diagnosis and to determine the primary sites. Metastatic tumors accounted for 30% of malignant ovarian tumors. A total of 170 cases of metastatic tumors included 117 cases with nongynecologic origin and 53 cases with gynecologic origin. Nongynecologic metastatic tumors were from large intestine (31%), stomach (14%), intrahepatic bile duct (10%), breast (9%), extrahepatic bile duct/gallbladder (7%), appendix (5%), hematologic tumors (3%), others (4%), and unknown primary site (16%). Metastatic gynecologic tumors were from cervix (53%), corpus (34%), fallopian tube (11%), and gestational trophoblastic disease (2%). The proportion of metastatic tumors to malignant ovarian tumors in northern Thailand was comparable to those of the Western or Japanese studies. However, the distribution of the primary sites was different and was correlated with the cancer incidence in Thai women. The majority of mucin-producing adenocarcinomas involving the ovaries were metastatic tumors.