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.     

LMX1A as a prognostic marker in ovarian mucinous cystadenocarcinoma

This study aimed to evaluate the relationship of LMX1A and osteopontin (OPN) expression with clinicopathologic parameters for the 4 most common ovarian surface epithelial carcinomas. Both biomarkers were investigated immunohistochemically using tissue microarrays of 249 specimens including 91 serous cystadenocarcinomas, 56 mucinous cystadenocarcinomas, 64 endometrioid adenocarcinomas, 26 clear cell carcinomas, and 12 normal ovarian tissues. All 4 carcinomas showed significant expression of LMX1A and OPN. In addition, higher immunostaining scores and percentage of cells stained for LMX1A in mucinous cystadenocarcinomas correlated with T stage, American Joint Committee on Cancer clinical stage, poorer tumor differentiation, and poorer survival rate. In serous cystadenocarcinoma, higher percentage of staining for OPN and higher intensity or immunostaining scores for LMX1A correlated with poorer tumor differentiation. Thus, the expression of LMX1A may be an independent prognostic risk factor in mucinous cystadenocarcinoma and a helpful marker in evaluating this tumor's aggressiveness.     

The correlation of cortactin and fascin‐1 expression with clinicopathological parameters in pancreatic and ampulla of Vater adenocarcinoma

Cortactin and fascin‐1 are important factors affecting progression and metastasis of carcinomas. We tested the hypothesis that cortactin and fascin expression has significant correlation with clinicopathological parameters in pancreatic and ampulla of Vater adenocarcinomas. Immunohistochemical analysis of cortactin and fascin‐1 was performed in 50 pancreatic and 40 ampulla of Vater adenocarcinomas. The specimens were from 29 R0, 8 R1, and 13 palliative resections of pancreatic adenocarcinomas and 18 R0, 14 R1, and 8 palliative resections of ampulla of Vater adenocarcinomas. ‘R0’ resection is defined by complete removal of the tumor and histologically negative surgical margins and ‘R1’ resection indicates the presence of microscopically residual disease at the surgical margins. The level of expression was assessed by scoring the intensity of cytoplasmic or membranous immunostaining on a 4‐point scale. Higher immunostaining scores of cortactin and fascin‐1 were both significantly correlated with histological grade, American Joint Committee on Cancer (AJCC) stage, and survival rate in all patients. In conclusion, overexpression of cortactin and fascin‐1 implies poorer tumor differentiation, advanced AJCC stage, and shorter survival rate in pancreatic and ampulla of Vater adenocarcinomas.     

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.     

Expression of Survivin and Cortactin in Colorectal Adenocarcinoma: Association with Clinicopathological Parameters

Objective: Survivin and cortactin are factors that promote tumor progression. We tested the hypothesis that survivin and cortactin expressions correlate with the clinico-pathological parameters of colorectal adenocarcinomas and survival time. Methods: Immunohistochemical analysis of survivin and cortactin were performed using tissue microarrays of 119 specimens from 18 well, 50 moderately, and 27 poorly differentiated colorectal adenocarcinomas and 24 colorectal adenomas with dysplasia. As control, 10 specimens of normal colorectal epithelia were included. Results: The percentage of cells immunostained and the immunostaining scores for survivin and cortactin were all significantly higher in well-, moderately, and poorly differentiated colorectal adenocarcinomas than in normal colorectal epithelia. The survivin immunostaining score was significantly correlated with T, M, and AJCC/TNM stages (p `0.05). For cortactin, the score was significantly correlated with T and M stages (p ` 0.05). Higher survivin immunostaining score was associated with higher mortality. Conclusions: Higher expression of survivin and cortactin correlates significantly with tumor stages and shorter survival time. Survivin and cortactin may be good biomarkers of aggressiveness of colorectal adenocarcinomas. Our findings require validation in independent cohorts and these data support the potential targeting of survivin and cortactin for the development of novel therapeutic strategies.     

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.     

Differential expression of MUC2 and MUC5AC mucin genes in primary ovarian and metastatic colonic carcinoma

Colonic adenocarcinoma, the most common tumor metastatic to the ovary, may closely mimic primary ovarian adenocarcinoma, especially that of mucinous or endometrioid histology. The differential diagnosis is important for therapeutic considerations. Mucin gene expression is relatively organ-specific and may therefore have use in distinguishing between colonic carcinomas metastatic to the ovary and primary ovarian tumors. In this study, we compared the expression of MUC2 and MUC5AC apomucins in 10 colonic adenocarcinomas metastatic with the ovary, 10 ovarian endometrioid carcinomas (4 primary, 6 metastatic), and 32 primary mucinous ovarian tumors (12 cystadenomas, 10 borderline tumors, and 10 cystadenocarcinomas). Monoclonal antibodies CCP58 and 45M1 were used for immunostains of MUC2 and MUC5AC apomucin, respectively. All but 1 of the 10 metastatic colon adenocarcinomas expressed MUC2, whereas none expressed MUC5AC. None of the 10 endometrioid carcinomas expressed MUC2, and only 2 showed weak immunoreactivity with MUC5AC. All 32 primary mucinous ovarian tumors expressed MUC5AC. The percentages of MUC2-positive immunostaining for cystadenomas, borderline tumors, and cystadenocarcinomas were 0% (0/12), 50% (5/10), and 70% (7/10) respectively. These studies show that MUC2 and MUC5AC are useful markers in the distinction between colonic carcinoma metastatic to the ovary and primary ovarian carcinoma.     

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.     

Loss of cables, a novel gene on chromosome 18q, in ovarian cancer.

Cables, a cyclin-dependent kinase (cdk) interacting protein, has recently been identified and mapped to human chromosome 18q11. Cables appears to be primarily involved in cell cycle regulation and cell proliferation. Overexpression of Cables in Hela and other cell lines inhibits cell proliferation and tumor formation. We hypothesize that loss of Cables expression is associated with ovarian cancer. To test our hypothesis, we examined Cables expression in the four most common subtypes of ovarian carcinomas: serous, endometrioid, mucinous, and clear cell. In addition, mucinous and serous borderline tumors were also included. Loss of Cables expression was observed at high frequency in ovarian serous (11 of 14 cases, 79%) and endometrioid (5 of 10 cases, 50%) carcinomas. In contrast, strong Cables staining was detected in all clear cell carcinomas (10 cases) and mucinous tumors (5 carcinomas and 5 borderline tumors). The majority of serous borderline tumors (11 of 14 cases, 79%) showed positive Cables staining, with the rest showing focal loss of Cables expression. Furthermore, RT-PCR revealed the lack of Cables mRNA in a human ovarian cancer xenograft. No correlation was noted between loss of Cables and histologic grade, tumor stage, and survival. In conclusion, our results indicate that loss of Cables is common in ovarian serous and endometrioid carcinomas and imply that Cables may be involved in the pathogenesis of these two types of ovarian carcinomas.     

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.     

Utility of hepatocyte nuclear factor‐1β as a diagnostic marker in ovarian carcinomas with clear cells

Kao Y‐C, Lin M‐C, Lin W‐C, Jeng Y‐M & Mao T‐L
(2012) Histopathology  61, 760–768 Utility of hepatocyte nuclear factor‐1β as a diagnostic marker in ovarian carcinomas with clear cells Aims: Overexpression of hepatocyte nuclear factor‐1β (HNF‐1β) has been found in ovarian clear cell carcinoma (OCCC) but not in other types of ovarian carcinoma. The aim of this study was to clarify whether the overexpression of HNF‐1β is specific for OCCC, and does not occur in ovarian carcinoma with clear cell change. Methods and results: Immunohistochemistry was performed on 178 ovarian carcinomas with clear cells (80 OCCCs, 60 high‐grade serous, 25 endometrioid, and 13 mixed endometrioid and clear cell), 22 ovarian high‐grade serous carcinomas without clear cells, 41 renal cell carcinomas (RCCs) and 20 hepatocellular carcinomas (HCCs) with clear cytoplasm. Results were evaluated using an H‐score (percentage × intensity). Most OCCCs were diffusely and strongly positive (mean H‐score 15.1). High‐grade serous carcinoma and endometrioid carcinoma with clear cells were usually negative or focally and weakly positive (mean H‐scores 1.5 and 1.7, respectively). High‐grade serous carcinoma without clear cells had a mean H‐score of 0.77. The mean H‐scores of the endometrioid and clear cell components in mixed endometrioid and clear cell carcinoma were 6.2 and 15.7, respectively. HNF‐1β was expressed in 95.1% of RCCs and in 30% of HCCs. Conclusions: The diagnosis of ovarian carcinomas with clear cells can be made with greater accuracy by using the intensity and extent of immunoreactivity for HNF‐1β.     

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.     

Mucosal carcinoma of the fallopian tube coexists with ovarian cancer of serous subtype only: a study of Japanese cases

Previous studies in Western countries have revealed that mucosal carcinoma of the fallopian tube frequently coexists with pelvic (ovarian, tubal, and peritoneal) serous carcinomas, and early tubal carcinoma is now regarded as a possible origin of these tumors. However, the relationship between early tubal carcinoma and non-serous ovarian cancer, such as clear cell adenocarcinoma, has not been studied in detail. In this study, we sought to examine the coexistence of mucosal carcinoma of the fallopian tube in Japanese ovarian cancer cases. We submitted the fallopian tubes in toto for histological examination in 52 ovarian carcinoma cases and three peritoneal serous carcinoma cases. The ovarian tumors included 12 serous adenocarcinomas, 23 clear cell adenocarcinomas, nine endometrioid adenocarcinomas, three mucinous adenocarcinomas, and four mixed epithelial carcinomas. Mucosal carcinoma of the fallopian tube did not coexist with non-serous adenocarcinoma (n = 40). In contrast, mucosal carcinoma of the fallopian tube was observed in six cases of ovarian serous adenocarcinoma and one case of peritoneal serous adenocarcinoma. In these cases, the p53 immunophenotypes were similar in tubal lesions and invasive ovarian or peritoneal carcinomas. Tumors were negative for p53 in four of seven cases, and one of the p53-negative serous adenocarcinomas showed low-grade morphology. We believe that some ovarian and peritoneal serous adenocarcinomas develop from early tubal carcinomas. However, it should be noted that early tubal carcinomas are not always p53-positive immunohistochemically. Finally, it is unlikely that early tubal lesions are involved in the carcinogenesis of clear cell adenocarcinoma and other non-serous adenocarcinomas.     

Monoclonal antibody SM047 as an immunohistochemical marker of ovarian adenocarcinoma

AIMS: This study describes the generation of a monoclonal antibody designated SM047 which binds to an epitope that is displayed by a multivalent antigen associated with the glycocalyx of ovarian adenocarcinoma cells. The study also investigates SM047 staining in adenocarcinomas of diverse sites in order to determine whether the antibody is specific for ovarian adenocarcinoma and of value in the confirmation of an ovarian origin when the site of primary tumour is unknown. METHODS AND RESULTS: SM047, an IgM monoclonal antibody, was the product of hybridoma cells derived from fusion of SP2 myeloma cells with splenocytes of a mouse that had been immunized with a membrane preparation of tumour (ovarian serous cystadenocarcinoma) and boosted with cells from a cell line established from a similar tumour in a different patient. Sixty-two primary ovarian adenocarcinomas (28 serous, 23 mucinous, five endometrioid and six clear cell), 69 adenocarcinomas arising primary at other sites and 10 mesotheliomas were stained with SM047. There was positive membrane staining, which was usually strong and widespread, in 27 of 28 ovarian serous carcinomas and in all ovarian endometrioid and clear cell carcinomas. Most ovarian mucinous tumours were negative or exhibited weak cytoplasmic staining. Staining was variable in the other tumours but there was positive staining of most endometrial, endocervical and pancreatic adenocarcinomas. Most colonic adenocarcinomas were negative or exhibited weak cytoplasmic staining. CONCLUSIONS: SM047 is strongly expressed in most ovarian serous adenocarcinomas and in other female genital tract adenocarcinomas, with the exception of ovarian mucinous tumours. The antibody may be useful in confirming the ovarian origin of an adenocarcinoma when used as part of a larger panel. This is especially so in the distinction between a non-mucinous ovarian adenocarcinoma, which usually exhibits strong membranous staining, and a colonic adenocarcinoma which is usually negative or exhibits weak cytoplasmic staining. These findings need to be confirmed by further study of larger numbers of cases.     

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.     

Ephrin B expression in epithelial ovarian neoplasms correlates with tumor differentiation and angiogenesis

Differential gene expression studies are identifying new sets of genes with a role in the classification, differential diagnosis, and prognosis of some human tumors. Ephrin B1, a factor involved in angiogenesis, has been shown to be up-regulated in ovarian carcinomas, making it a potential target for cancer treatment. This study investigates ephrin B expression in ovarian tumors to validate results from gene expression studies and evaluates its significance with a clinical-pathological correlation. Specimens from 112 benign, borderline, and malignant epithelial ovarian tumors were examined. Tissue microarrays were constructed, and ephrin B expression was studied by immunohistochemistry. To correlate ephrin B expression with angiogenesis, CD31 immunostaining was performed to assess microvessel density. Ephrin B was detected in 50% of ovarian tumors: clear cell carcinomas (93%), serous carcinomas (74%), mucinous carcinomas (29%), and endometrioid carcinomas (27%). High-grade carcinomas showed greatest ephrin B expression, whereas benign tumors and low-grade carcinomas were rarely positive. A correlation was found between ephrin B expression and microvessel density, supporting the angiogenic role of this factor in ovarian carcinomas. Ephrin B expression was associated with higher rates of disease recurrence and a decrease in overall survival. A distinctive pattern of ephrin B expression was observed in ovarian tumors: high-grade tumors and clear cell and serous carcinomas show higher expression, correlating with the aggressiveness. On the other hand, ephrin B expression correlated with microvessel density of the tumors. Because Eph receptors and ephrins are targets for new therapeutic inhibitors, this pattern of ephrin B expression should be considered in future clinical studies.     

Expression of aberrantly glycosylated Mucin-1 in ovarian cancer

Van Elssen C H M J, Frings P W H, Bot F J, Van de Vijver K K, Huls M B, Meek B, Hupperets P, Germeraad W T V & Bos G M J
(2010) Histopathology 57 , 597–606
Expression of aberrantly glycosylated Mucin‐1 in ovarian cancer Aims: Mucin 1 (MUC1) is an important tumour‐associated antigen (TAA), both overexpressed and aberrantly glycosylated in adenocarcinomas. The aim of this study was to examine the MUC1‐glycosylation status of primary ovarian adenocarcinomas and metastatic lesions. Methods and results: Paraffin‐embedded tissue sections of 37 primary ovarian adenocarcinomas representing all histotypes (22 serous, five mucinous, two clear‐cell, eight endometrioid), four serous borderline tumours with intraepithelial carcinoma, seven sections of ovarian endometriosis and 13 metastatic lesions were analysed by immunohistochemistry. Non‐neoplastic ovarian surface epithelium and serous cystadenomas were used as controls. All epithelia expressed MUC1 protein. Of primary tumours, 76% expressed the differentiation‐dependent glycoform and 84% the cancer‐associated glycoform (Tn/Sialyl‐Tn‐epitopes). In metastatic lesions this was 77% and 85%, respectively. Notably, in 57% of ovarian endometriosis and 75% of intraepithelial lesions, the cancer‐associated MUC1 epitopes were expressed, whereas normal ovarian surface epithelium and serous cystadenomas did not express these epitopes. Conclusions: The underglycosylated MUC1 epitopes are expressed by all histotypes of primary ovarian adenocarcinomas, by the vast majority of metastatic lesions and by possible ovarian cancer precursor lesions, but not by normal ovarian tissue. These results indicate that MUC1‐associated Tn/STn‐epitopes are important targets for immunotherapy and diagnostic imaging in ovarian cancer patients.     

Immunohistological characterization of a monoclonal antibody (OV632) against epithelial ovarian carcinomas

Summary A hybridoma cell line (OV632) producing monoclonal antibody against ovarian carcinomas was developed from the spleen cells of a mouse immunized with cystic fluid from a serous cystadenocarcinoma. Immunohistological studies in frozen sections showed that 22 out of 28 nonmucinous ovarian carcinomas, which included serous, endometrioid, clear cell, and undifferentiated tumours, reacted with this antibody. Three out of 7 mucinous ovarian carcinomas were positive, whereas only 7 out of 122 extra-genital malignant lesions, predominantly adenocarcinomas, were positive. The negative cases included 38 breast carcinomas and 24 colon carcinomas, tumours which are responsible for most of metastatic disease in the ovary. On the basis of these findings, the antibody OV632 is considered appropriate for histodiagnostic purposes as an aid in the distinction between primary and secondary ovarian cancer.     

Morphological subtypes of ovarian carcinoma: a review with emphasis on new developments and pathogenesis

Ovarian carcinomas comprise a heterogeneous group of neoplasms, the four most common subtypes being serous, endometrioid, clear cell and mucinous. In recent years, our understanding of the underlying pathogenesis and initiating molecular events in the different tumour subtypes has greatly increased, and although ovarian carcinoma is often considered clinically as one disease, there is now a much greater realisation that the various subtypes have a different natural behaviour and prognosis. At present, adjuvant therapy is mainly dependent upon tumour stage and grade rather than type; however, this is likely to change in the future with the development of new chemotherapeutic agents and targeted therapies and clinical trials are necessary to evaluate the efficacy of different agents in clear cell, mucinous and low grade serous carcinomas, neoplasms which are considered relatively resistant to traditional chemotherapeutic regimes. In this review, the major subtypes of ovarian carcinoma are discussed. It is now firmly established that there are two distinct types of ovarian serous carcinoma, low grade and high grade, the former being much less common and arising in many cases from a serous borderline tumour. Low grade and high grade serous carcinoma represent two distinct tumour types with a different underlying pathogenesis rather than low grade and high grade variants of the same neoplasm. Both are usually advanced stage (stage III or IV) at diagnosis. B-raf and k-ras mutations are important molecular events in low grade serous carcinomas while high grade serous carcinomas are almost always associated with TP53 mutation. There is now emerging and compelling evidence that many high grade serous carcinomas (by far the most common subtype of ovarian carcinoma) actually arise from the epithelium of the distal fallopian tube. Future studies regarding the initiating molecular events in the development of this aggressive neoplasm should concentrate on this site. Primary ovarian mucinous carcinomas are uncommon, almost always unilateral and stage I, and largely of so-called intestinal or enteric type. Most arise in a stepwise manner from a pre-existing mucinous cystadenoma and mucinous borderline tumour. Endometrioid and clear cell carcinomas typically present as low stage neoplasms and in many, or most, cases arise from endometriosis; the former are usually well differentiated and there is now evidence that the majority of neoplasms reported in the past as high grade endometrioid carcinoma are of serous type. WT1 is useful in this regard since it is a relatively specific marker of a serous phenotype. It is recommended that different subtypes of ovarian carcinoma are graded using different systems rather than employing a universal grading system.