Expression of Tn and sialyl-Tn antigens in tumor tissues of the ovary.

The expression of sialyl-Tn and Tn antigens in various benign, borderline, and malignant ovarian tumors was examined immunohistochemically using newly developed antibodies specific for sialyl-Tn and Tn antigens. Sialyl-Tn antigen was detected in only one benign tumor, a mucinous adenoma that showed faint cytoplasmic staining in a few cells. However, sialyl-Tn was present in 5 of 12 serous borderline tumors, 10 of 19 mucinous borderline tumors, 10 of 13 serous adenocarcinomas, 15 of 16 mucinous adenocarcinomas, 14 of 15 endometrioid adenocarcinomas, and 7 of 7 clear cell carcinomas of the ovary. The antigen expression was observed throughout the cytoplasm of cancer cells and in the apical cytoplasm and luminal contents of some glands. The incidence and intensity of staining for sialyl-Tn antigen were higher in malignant tumors than in borderline tumors, but these results did not correlate with the histologic classification or differentiation. Coexpression of sialyl-Tn antigen and Tn antigen was observed in two serous adenocarcinomas, six mucinous borderline tumors, five mucinous adenocarcinomas, eight endometrioid, and seven clear cell carcinomas. In no case was Tn antigen expressed without concomitant sialyl-Tn antigen expression. Accumulation of sialyl-Tn antigen seems to be an early event of carcinogenesis of the ovary.     

Expression and mutational analysis of c-kit in ovarian surface epithelial tumors

Coexpression of Kit ligand and c-kit has been reported in some gynecologic tumors. To determine whether imatinib mesylate is useful in ovarian epithelial tumors, we performed immunohistochemical and mutational analysis. The cases consisted of 33 cases, which included 13 serous cystadenocarcinomas, 1 borderline serous tumor, 8 mucinous cystadenocarcinomas, 6 borderline mucinous tumors and 5 clear cell carcinomas. Five cases of serous cystadenoma and 5 cases of mucinous cystadenoma were also included. In the immunohistochemical study, 3 cases (3/6, 50%) of borderline mucinous cystic tumor and two cases (2/8, 25%) of mucinous cystadenocarcinoma show positive staining for KIT protein. Only one case (1/13, 7.7%) of serous cystadenocarcinoma had positive staining. On mutational analysis, no mutation was identified at exon 11. However, two cases of borderline mucinous tumors and one case of mucinous cystadenocarcinoma had mutations at exon 17. In these cases, the immunohistochemistry also shows focal positive staining at epithelial component. Although, KIT protein expression showed higher incidence in mucinous tumors than serous tumors, they lack KIT-activating mutations in exon 11. Thus, ovarian surface epithelial tumors are unlikely to respond to imatinib mesylate.     

Emi1 protein accumulation implicates misregulation of the anaphase promoting complex/cyclosome pathway in ovarian clear cell carcinoma.

Clear cell carcinoma is a clinically and pathologically distinct entity among surface epithelial ovarian neoplasms, recognized for its resistance to standard platinum-based chemotherapy at advanced stage disease and poor prognosis. Despite advances in our understanding of the biology of other surface epithelial ovarian neoplasms, very little is known about the molecular genetic mechanisms that are involved in clear cell tumorigenesis. Early mitotic inhibitor-1 (Emi1) protein is a key cell cycle regulator, that promotes S-phase and mitotic entry by inhibiting the anaphase promoting complex. In cell culture systems, overexpression of Emi1 leads to tetraploidy and genomic instability, especially in the absence of normal p53 function. We investigated Emi1 protein expression in ovarian neoplasms using a tissue microarray constructed from 339 primary ovarian surface epithelial (serous, endometrioid, clear cell, and mucinous) and peritoneal (serous) neoplasms, stromal and mesenchymal tumors, germ cell tumors, and normal ovarian tissue. Significant overexpression of Emi1 protein was present in 82% (27/33) clear cell carcinoma, including one borderline tumor in a diffuse, granular cytoplasmic and perinuclear staining pattern, independent of patient age, presence of ovarian and/or pelvic endometriosis, and FIGO stage. In contrast, only 10% (17/177) primary ovarian and primary peritoneal serous carcinomas, 0% (0/10) mucinous carcinomas, and 19% (6/32) endometrioid carcinomas exhibited significant Emi1 protein overexpression. Accumulation of Emi1 protein was not linked to Ki-67 labeling index, but was directly correlated with cyclin E and inversely correlated with ER in clear cell carcinoma (P<0.001). Emi1 protein expression was present in mixed endometrioid/clear cell tumors but absent in tumors with mixed serous/clear cell histology. These findings represent a potentially important insight into the molecular pathway underlying ovarian carcinogenesis and provide a possible cell cycle model for the development and progression of ovarian clear cell carcinoma.     

Loss of DNA mismatch repair protein hMSH6 in ovarian cancer is histotype-specific

Microsatellite instability (MSI) due to defects in DNA mismatch repair genes may be involved in the development of a subset of human ovarian carcinomas. The role of one such gene, hMSH6, in ovarian cancer is not well documented. We investigated the expression of hMSH6 protein in different histotypes of ovarian carcinoma and the associations between loss of hMSH6 protein and tumor grade, disease stage, familial history of cancer and patient survival. We stained an ovarian carcinoma tissue microarray consisting of formalin-fixed, paraffin-embedded tissue samples from 322 patients with an anti-hMSH6 antibody and scored the results semiquantitatively as negative or positive. Twelve cases were excluded owing to loss of cores during staining. Absence of hMSH6 protein was noted in 20 of 230 serous carcinomas (8.7%), in 7 of 16 clear cell carcinomas (43.7%), in 4 of 34 endometrioid carcinomas (11.7%), in 1 of 14 malignant mixed Müllerian tumors, 2 of 6 mucinous carcinomas, 0 of 2 transitional cell carcinomas and in 0 of 8 undifferentiated carcinomas. Loss of hMSH6 protein was not associated with survival, patient age, tumor grade, or disease stage but was associated with clear cell, mucinous and endometrioid carcinoma histology (P<0.007). These findings indicate that loss of hMSH6 expression in ovarian carcinoma is more common in certain histologic subtypes, particularly in clear cell, endometrioid, and mucinous carcinoma, suggesting that loss of hMSH6 function may participate in the pathogenesis of these subtypes of cancer. Loss of hMSH6 expression did not predict survival and was not associated with disease stage, tumor grade, patient age or family history of cancer.     

Expression of Rsf-1, a chromatin-remodeling gene, in ovarian and breast carcinoma

Rsf-1 protein is a member of a chromatin-remodeling complex that plays an important role in regulating gene expression and cell proliferation. Our previous study showed that Rsf-1 was an amplified gene that participated in the development of ovarian serous carcinoma. To further elucidate the role of Rsf-1 in ovarian cancer, we studied Rsf-1 immunoreactivity in 294 ovarian tumors of various histologic types. Because the Rsf-1 amplicon overlaps an amplified region reported in breast cancer, we included 782 neoplastic and normal breast tissues for comparison. Immunohistochemistry was performed on tissue microarrays using a 4-tiered scoring system. Overexpression of Rsf-1 was defined as a nuclear immunointensity of 3+ to 4+ because of a strong correlation between 3+ and 4+ immunointensity and Rsf-1 gene amplification, based on our previous fluorescence in situ hybridization analysis. Rsf-1 overexpression was observed in 25% of high-grade ovarian serous carcinomas and in only rare cases (<7%) of low-grade ovarian serous, ovarian endometrioid, and invasive breast carcinomas but not in any ovarian serous borderline tumors, ovarian clear cell carcinomas, ovarian mucinous carcinomas, intraductal carcinomas of the breast, and normal ovaries and breast tissues. Thus, overexpression of Rsf-1 was significantly associated with high-grade ovarian serous carcinoma (P < .05), as compared with other types of ovarian tumors and breast carcinomas. Our results provide evidence that Rsf-1 expression is primarily confined to high-grade serous carcinoma, the most aggressive ovarian cancer. Because Rsf-1 overexpression occurs in only a small number of breast carcinomas, it is unlikely that Rsf-1 is a critical gene in the development of breast carcinoma.     

The utility of calretinin, inhibin, and WT1 immunohistochemical staining in the differential diagnosis of ovarian tumors

Calretinin has been proposed as a novel marker of ovarian sex cord-stromal tumors (SCST); this study aims to determine whether calretinin can complement or supplant the established utility of inhibin in the differential diagnosis of SCST. WT1 has been shown to be expressed in ovarian serous, but not mucinous neoplasms; its expression in a variety of ovarian tumors is also examined. Formalin-fixed, paraffin-embedded archival tissues from 111 primary ovarian tumors were analyzed with commercially available antibodies using semi-automated immunohistochemistry. Results were graded on a 4-tiered scale with staining of more than 0 but less than 5% of cells considered focal. Of 27 SCST, 56% were calretinin and 56% inhibin positive overall; 90% of granulosa cell tumors, 57% of Sertoli-Leydig cell tumors, 33% of thecomas, and 14% of fibromas were calretinin positive. Inhibin was expressed in 60% of granulosa cell tumors, 71% of Sertoli-Leydig cell tumors, 43% of fibromas, and 33% of thecomas. Of 35 surface epithelial tumors (SET), 8% of serous papillary tumors were calretinin positive, whereas 8% of serous papillary tumors and 13% of poorly differentiated carcinomas expressed inhibin. WT1 was expressed in 29% of all endometrioid carcinomas, 10% of borderline mucinous tumors, and no mucinous carcinomas; however, most of the other SETs were positive (77% serous papillary and 88% poorly differentiated carcinomas). Among the SCST, WT1 stained only granulosa cell tumors (75%), though often weakly or variably. Calretinin has only slightly greater sensitivity (76% versus 65%) and equal specificity to inhibin (92%) in the differential staining of granulosa or Sertoli-Leydig cell tumors, that is, nonstromal SCST. Hence, calretinin cannot replace but could complement inhibin as part of an immunohistochemical panel used for diagnostically challenging SCST. Although WT1 should be reliably positive in non-mucinous SET, staining of granulosa cell tumors and lack of expression in a sizable subset of endometrioid carcinomas may confound interpretation.     

Ovarian atypical endometriosis: its close association with malignant epithelial tumours

The incidence of ovarian atypical endometriosis and its association with malignant epithelial tumours in a consecutive series of cases during the period 1987 to 1995 were studied. Atypical glandular changes were observed in four (1.7%) of 255 ovarian endometriosis cases and one patient with ovarian atypical endometriosis developed subsequent endometrioid carcinoma in the abdominal wall. Fifty-four (24.1%) of the 224 ovarian cancers were associated with ovarian endometriosis; 21 with typical and 33 with atypical endometriosis. Clear cell carcinomas and endometrioid carcinomas were most frequently associated with endometriosis, with 54% (27 of 50 cases) and 41.9% (13 of 31), respectively. Atypical endometriosis was found in 18 clear cell carcinomas, in seven endometrioid carcinomas, in four serous carcinomas, in three mucinous borderline tumours, and in one serous borderline tumour. In 13 cases, the atypical endometriosis was in contiguity with malignant epithelial tumours. We consider that atypical endometriosis possesses a precancerous potential or is most frequently associated with clear cell and endometrioid carcinomas. Close screening of cellular atypia or hyperplasia in ovarian endometriosis and careful long-term follow-up of patients with atypical endometriosis is required.     

Insulin-like growth factor-binding protein 2 and 5 are differentially regulated in ovarian cancer of different histologic types.

The family of insulin-like growth factor-binding proteins (IGFBPs) comprises six members, which bind and regulate the functions of insulin-like growth factors. Overexpression of IGFBP2 and IGFBP5 contributes to the invasiveness and progression of several human cancers, but their role and clinical significance in ovarian cancer has not been investigated in detail. We examined IGFBP2 and IGFBP5 expression levels using two tissue microarrays, one containing six normal surface epithelium, six benign serous cysts, 10 serous borderline tumors, eight low-grade, and 20 high-grade serous carcinomas. The other comprising 441 ovarian cancers of different histologic types linked to a clinicopathologic database. Each tumor was sampled in duplicate with a 1.0-mm punch core needle. Immunohistochemical staining was performed using antibodies against IGFBP2 or IGFBP5. The staining intensity was scored semiquantitatively as negative (0), weak (1-10%), moderate (10-50%), or strong (50-100%) using computerized image analysis. Statistical analyses used Fisher's exact test and Kaplan-Meier method. IGFBP2 and IGFBP5 were overexpressed in high-grade serous carcinomas compared to normal surface epithelium, benign serous cysts, serous borderline tumors, or low-grade serous carcinoma. They were differentially expressed in different types of ovarian carcinomas, being more often expressed at high levels in high-grade serous carcinoma, malignant mixed mullerian tumors and undifferentiated carcinoma, and more often expressed at low levels or not at all in clear cell and mucinous carcinomas. We concluded that IGFBP2 and IGFBP5 might play a role in the development of high-grade ovarian serous carcinoma, but not in mucinous or clear cell ovarian carcinomas.     

Inhibitory role of prohibitin in human ovarian epithelial cancer

Objectives: To characterize the exact individual roles of gonadotropins on ovarian epithelial carcinogenesis, an earlier study showed that prohibitin was significantly up-regulated by luteinizing hormone (LH). To further clarify the role of prohibitin in ovarian carcinogenesis and its association with LH, herein we studied the expression of prohibitin in various ovarian tissues including different developmental stages of ovarian epithelial tumors. Methods: A total of 135 samples were studied by immunohistochemistry. These included benign ovarian cases with follicles, ovarian surface epithelia and ovarian epithelial inclusions (OEI) (n=30), serous cystadenoma (n=14), serous borderline tumor (n=12), serous carcinoma (n=20), mucinous cystadenoma (n=10), mucinous borderline tumor (n=10), mucinous carcinomas (n=10), endometrioid carcinomas (n=12), poorly/undifferentiated carcinomas (n=5), and fallopian tube (n=12). Results: Strong and diffuse staining of prohibitin was detected in luteinized ovarian stromal cells, follicular cells, fallopian tube, and OEI with serous differentiation. A significantly higher prohibitin expression in luteinized stromal cells than in non-luteinized stromal cells was observed (P<.01). Within the ovarian epithelium, the level of prohibitin expression was basically negative in ovarian surface epithelia, but highly expressed in OEI. However, compared to the level of prohibitin expression in OEI, it showed a trend of gradual loss from benign ovarian tumors, to borderline tumors and to carcinomas (P<.0001). Compared to the serous tumors, epithelial tumors with mucinous differentiation showed a significant lower level of prohibitin (P<.0001). An inverse correlation was noted between prohibitin expression and cancer grade. It is interesting to note that a high prohibitin expression level was seen in the fallopian tube, which is similar to OEI. Conclusions: These data further suggest that prohibitin plays a tumor suppressing role, which is probably associated with LH mediated protection role against ovarian epithelial carcinoma. In addition to the tumor suppressive role of prohibitin, it also plays a role in cellular differentiation, which may be helpful to differentiate ovarian mucinous tumors from the tumors with serous differentiation in clinical settings. More importantly, our findings are supportive that the ovarian epithelial cancers, particularly the serous cancers including those precursors with serous differentiation are likely to be derived from fallopian tube instead of ovarian surface epithelia.     

Histological classification of ovarian cancer

The histology of ovarian tumors exhibits a wide variety of histological features. The histological classification of ovarian tumors by the World Health Organization (WHO) is based on histogenetic principles, and this classification categorizes ovarian tumors with regard to their derivation from coelomic surface epithelial cells, germ cells, and mesenchyme (the stroma and the sex cord). Epithelial ovarian tumors, which are the majority of malignant ovarian tumors, are further grouped into histological types as follows: serous, mucinous, endometrioid, clear cell, transitional cell tumors (Brenner tumors), carcinosarcoma, mixed epithelial tumor, undifferentiated carcinoma, and others. Clear cell and endometrioid carcinomas are highly associated with endometriosis. In stage distribution, serous carcinoma is found predominantly is stage III or IV. In contrast, clear cell and endometrioid carcinomas tend to remain confined to the ovary. Clear cell and endometrioid carcinomas may be unique histological types compared with serous carcinomas with respect to stage distribution and association with endometriosis.     

卵巢上皮性肿瘤肠粘液抗原和癌胚抗原的免疫组织化学研究

应用两种肠粘液抗原（ＬａｒｇｅＩｎｔｅｓｔｉｎａｌＭｕｃｉｎｏｕｓＡｎｔｉｇｅｎ，ＬＩＭＡ，ＳｍａｌｌＩｎｔｅｓｄｔｉｎａｌＡｎｔｉ－ｇｅｎ，ＳＩＭＡ）和ＣＥＡ对７８例卵巢上皮性肿瘤石蜡标本进行免疫组化染色。三种抗原在良性和交界性肿瘤中以腔缘型分布为主，可见恶性肿瘤腔缘、胞浆弥漫分布并随组织学分级的增高趋向于胞浆分布；三种抗原的阳性率在浆液性癌和粘液性癌中的差别不显著，但ＣＥＡ在浆液性癌中表达强度低于粘液性癌（Ｐ＜０．０５）；在子宫内膜样癌中三抗原之阳性率和表达强度均较低，故可以辅助鉴别浆液性癌、粘液性癌和官内膜样癌。ＣＥＡ和ＬＩＭＡ大量出现于癌细胞内的肿瘤更具侵袭性，易致肿瘤扩散转移，预后较差。     

The expression of six biomarkers in the four most common ovarian cancers: correlation with clinicopathological parameters

This study aimed to evaluate the relationship of fascin‐1, matrix metalloproteinase (MMP)‐2, MMP‐9, cortactin, survivin, and epidermal growth factor receptor (EGFR) expression with clinicopathological parameters for the four most common ovarian surface epithelial carcinomas. Six biomarkers were investigated immunohistochemically using tissue microarrays of 185 specimens including 79 serous cystadenocarcinomas, 47 mucinous cystadenocarcinomas, 45 endometrioid adenocarcinomas, and 14 clear cell carcinomas. The four most common ovarian carcinomas showed significant expression of fascin‐1, cortactin, survivin, and EGFR, but not of MMP‐2 and MMP‐9. In addition, higher immunostaining scores for fascin‐1 in mucinous cystadenocarcinomas correlated with T stage, N stage, American Joint Committee on Cancer AJCC clinical stage, and a poorer survival rate; for cortactin in serous cystadenocarcinomas correlated with T stage; for cortactin in clear cell carcinomas correlated with T and clinical AJCC stages; and for survivin in clear cell carcinomas correlated with T stage and AJCC clinical stage. In addition, higher immunostaining scores for fascin‐1, cortactin, and survivin correlated with poorer tumor differentiation in serous, mucinous, and endometrioid adenocarcinomas. Thus, the expression of fascin‐1, cortactin, and survivin may be helpful in evaluating the aggressiveness of ovarian mucinous, serous, and clear cell adenocarcinoma. Additionally, the expression of fascin‐1 may be an independent prognostic risk factor in mucinous cystadenocarcinoma.     

β-Catenin Expression Pattern in Stage I and II Ovarian Carcinomas : Relationship with β-Catenin Gene Mutations, Clinicopathological Features, and Clinical Outcome

The immunohistochemical expression pattern of beta-catenin has been correlated with beta-catenin gene mutations, clinicopathological features, and disease outcome in 69 stage I and II ovarian carcinomas. beta-Catenin expression was localized in the nuclei, in addition to the cytoplasm and membrane, in 11 tumors (16%): nine endometrioid carcinomas with widespread nuclear expression and two serous carcinomas with focal nuclear expression. The remaining 58 carcinomas (84%) only had membranous beta-catenin expression. All but one of the endometrioid carcinomas with nuclear beta-catenin expression had considerable squamous metaplasia, and five of these cases had large areas of endometrioid tumor of low malignant potential. In addition, beta-catenin nuclear expression was observed in atypical epithelial cells in endometriotic glands adjacent to an endometrioid carcinoma. Sequencing was performed on 25 tumors and corresponding normal tissue: all 13 endometrioid tumors as well as 12 carcinomas of other histological types (four serous, two clear cell, two mucinous, and two mixed). There were oncogenic mutations in the phosphorylation sequence for GSK-3beta in exon 3 of the beta-catenin gene in seven endometrioid carcinomas with beta-catenin nuclear expression. Three mutations affected codon 32 (D32G, D32Y, and D32Y), one affected codon 33 (S33C), two affected codon 37 (S37C and S37F), and one affected codon 41 (T41A). No mutations were observed in the other 18 carcinomas analyzed, comprising two endometrioid and two serous carcinomas with beta-catenin nuclear expression, and 14 carcinomas of different histological types with only membranous expression. In the univariate and multivariate survival analyses, beta-catenin nuclear expression was selected as an indicator of good prognosis, because no patient whose tumor expressed beta-catenin in the nuclei showed relapses or died, in contrast to the 19 relapses and deaths among patients with tumors that only had beta-catenin membranous expression, including three of the four patients with endometrioid carcinomas. Oncogenic beta-catenin mutation is characteristic of a group of endometrioid carcinomas with a good prognosis, most of which originate from previous benign or borderline lesions. Endometrioid carcinomas with exclusively membranous expression of beta-catenin seem to represent a different subgroup of carcinomas that probably have a worse prognosis. In early-stage ovarian cancer, determination of the beta-catenin expression pattern could prove to be a useful marker for selecting low-risk patients.     

In ovarian neoplasms, BRAF, but not KRAS, mutations are restricted to low-grade serous tumours

Genes of the RAF family, which mediate cellular responses to growth signals, encode kinases that are regulated by RAS and participate in the RAS/RAF/MEK/ERK/MAP-kinase pathway. Activating mutations in BRAF have recently been identified in melanomas, colorectal cancers, and thyroid and ovarian tumours. In the present study, an extensive characterization of BRAF and KRAS mutations has been performed in 264 epithelial and non-epithelial ovarian neoplasms. The epithelial tumours ranged from adenomas and borderline neoplasms to invasive carcinomas including serous, mucinous, clear cell, and endometrioid lesions. It is shown that BRAF mutations in ovarian tumours occur exclusively in low-grade serous neoplasms (33 of 91, 36%); these included serous borderline tumours (typical and micropapillary variants), an invasive micropapillary carcinoma and a psammocarcinoma. KRAS mutations were identified in 26 of 91 (29.5%) low-grade serous tumours, 7 of 49 (12%) high-grade serous carcinomas, 2 of 6 mucinous adenomas, 22 of 28 mucinous borderline tumours, and 10 of 18 mucinous carcinomas. Of note, two serous borderline tumours were found to harbour both BRAF and KRAS mutations. The finding that at least 60% of serous borderline tumours harbour mutations in two members of the ERK-MAP-kinase pathway (BRAF 36%, KRAS 30%) compared with 12% of high-grade serous carcinomas (BRAF 0%, KRAS 12%) indicates that the majority of serous borderline tumours do not progress to serous carcinomas. Furthermore, no BRAF mutations were detected in the other 173 ovarian tumours in this study.     

Ovarian carcinomas: five distinct diseases with different origins,genetic alterations,and clinicopathological features

Malignant epithelial tumors (carcinomas) are the most common ovarian cancers and also the most lethal gynecological malignancies. Based on histopathology and molecular genetic alterations, ovarian carcinomas are divided into five main types (high-grade serous (70%), endometrioid (10%), clear cell (10%), mucinous (3%), and low-grade serous carcinomas (<5%)) that account for over 95% of cases. These types are essentially distinct diseases, as indicated by differences in epidemiological and genetic risk factors, precursor lesions, patterns of spread, and molecular events during oncogenesis, response to chemotherapy, and prognosis. For a successful specific treatment, reproducible histopathological diagnosis of the tumor cell type is critical. The five tumor types are morphologically diverse and resemble carcinomas of the uterus. Actually, recent investigations have demonstrated that a significant number of cancers, traditionally thought to be primary ovarian tumors (particularly serous, endometrioid, and clear cell carcinomas), originate in the fallopian tube and the endometrium and involve the ovary secondarily. This review summarizes recent advances in the molecular pathology which have greatly improved our understanding of the biology of ovarian carcinoma and are also relevant to patient management.     

Uncommon ovarian epithelial tumours

Epithelial ovarian tumours represent the most common type of ovarian tumour. Most of malignant cases represent high-grade serous, clear cell and endometrioid carcinomas; borderline serous and mucinous tumours of intestinal type are less common. This review focuses on the uncommon or rare epithelial tumours of the ovary which include borderline and malignant Brenner tumours, the recently-described mesonephric-like carcinoma of the ovary, and primary ovarian neuroendocrine tumours, with emphasis on helpful and diagnostic features.     

Increasing expression of serine protease matriptase in ovarian tumors: tissue microarray analysis of immunostaining score with clinicopathological parameters.

Matriptase is a type II transmembrane serine protease expressed by cells of surface epithelial origin, including epithelial ovarian tumor cells. Matriptase cleaves and activates proteins implicated in the progression of cancer and represents a potential prognostic and therapeutic target. The aim of this study was to examine the expression of matriptase in ovarian tumors and to assign clinicopathological correlations. Immunohistochemical analysis of matriptase was performed in tissue microarrays of 164 ovarian neoplasms including 84 serous adenocarcinomas, 23 mucinous adenocarcinomas, 10 endometrioid adenocarcinomas, six yolk sac tumors, 12 clear cell carcinomas, six dysgerminomas, eight granulosa cell tumors, four transitional cell carcinomas, five fibromas, and six Brenner tumors. All ovarian tumors except the fibromas and Brenner tumors showed significant expression of matriptase. The matriptase scores were significantly higher in the tumors than in their nontumor counterparts (304+/-26 for serous adenocarcinoma; 361+/-28 for mucinous adenocarcinoma; 254+/-17 for endometrioid adenocarcinoma; 205+/-19 for yolk sac tumor; 162+/-16 for clear cell carcinoma; 109+/-11 for dysgerminoma; 105+/-9 for granulosa cell tumor; and 226+/-18 for transitional cell carcinoma). Matriptase scores in serous adenocarcinoma were correlated with TNM stage and FIGO stage. Our findings demonstrate for the first time that matriptase is overexpressed in many malignant ovarian tumors. It may be a novel biomarker for diagnosis and treatment of malignant ovarian tumors.     

Nuclear findings of ovarian surface epithelial tumors

While cytoplasmic features of ovarian surface epithelial tumors are well-known, the nuclear findings have received little attention. We reviewed imprint cytology materials of the ovary which were collected at the Kawasaki Medical School Hospital between January 1989-July 1999, and identified 15 mucinous cystadenomas, 3 borderline mucinous tumors, 4 mucinous cystadenocarcinomas, 4 serous cystadenomas, 4 borderline serous tumors, 7 serous cystadenocarcinomas, 6 endometrioid carcinomas, and 2 clear-cell adenocarcinomas. We microscopically observed nuclear findings of the 45 cases. Coffee-bean nuclei were observed in 15.0%, 15.8%, and 10.1% of the tumor cells in mucinous adenomas, borderline mucinous tumors, and borderline serous tumors, respectively. The frequencies of the coffee-bean nuclei in the three tumors were higher than in the remaining tumors (P < 0.001). Intranuclear cytoplasmic inclusions were observed in 2.1% of the tumor cells in mucinous cystadenoma, and their frequency was significantly higher than that in cases of other surface epithelial ovarian tumors (P < 0.001). Semilunar-shaped nuclei were seen in all cases of mucinous cystadenomas and borderline mucinous tumors, and in 3 of 4 mucinous adenocarcinomas. The remaining surface epithelial tumors did not reveal the semilunar-shaped nuclei. In the cytology of the ovary, the semilunar nuclei are characteristic of mucinous tumors, and the intranuclear cytoplasmic inclusion may be a diagnostic clue to mucinous cystadenoma, when it is conspicuous. The coffee-bean nuclei can be seen in mucinous cystadenoma, borderline mucinous tumors, and borderline serous tumors.     

Association of cortactin, fascin-1 and epidermal growth factor receptor (EGFR) expression in ovarian carcinomas: correlation with clinicopathological parameters

Cortactin, fascin-1 and EGFR are recognized as important factors in tumor progression. We tested the hypothesis that cortactin, fascin-1 and EGFR expression correlates with clinicopathological parameters of the four most common ovarian surface epithelial carcinomas--serous cystadenocarcinoma, mucinous cystadenocarcinoma, endometrioid adenocarcinoma, and clear cell carcinoma. Immunohistochemical analysis of cortactin, fascin-1 and EGFR was performed using tissue microarrays of 172 specimens comprising 69 serous cystadenocarcinomas, 44 mucinous cystadenocarcinomas, 45 endometrioid adenocarcinomas and 14 clear cell carcinomas. All ovarian carcinomas showed significant expression of cortactin, fascin-1 and EGFR in staining intensity, tumor percentages and immunostaining scores. In addition, higher immunostaining scores of fascin-1 correlated with more advanced cancer stages (TNM), poorer histological differentiation and poorer survival rate of mucinous cystadenocarcinoma. Similarly, higher immunostaining scores of cortactin correlated with T stages and histological differentiation of serous cystadenocarcinoma. The immunostaining scores of EGFR did not correlate with TNM stages, tumor differentiation or prognosis in the four ovarian surface epithelial carcinomas. Our findings suggest that cortactin and fascin-1 may serve as good biomarkers in evaluating aggressiveness of ovarian serous and mucinous cystadenocarcinoma. And the pharmacological inhibitors of fascin-1 activity may slow down tumor progression and prolong survival time in patients with mucinous cystadenocarcinoma.