Selection of carbohydrate antigens in human epithelial ovarian cancers as targets for immunotherapy: serous and mucinous tumors exhibit distinctive patterns of expression

Expression of blood group-related carbohydrate antigens was examined in frozen sections from a series of ovarian carcinomas of different histological types using an indirect immunoperoxidase technique. Antigenic specificities belonging to the O(H) and Lewis blood group families (H-1, H-2, Le(a), sLe(a), Le(x), sLe(x), Le(b) and Le(y)) or the mucin-core family (Tn, sTn and TF) were studied. A distinct difference in antigen expression between mucinous and other ovarian carcinomas (serous and endometrioid) was observed. Specifically, mucinous tumors tended to express sTn, Le(a) and sLe(a) strongly and homogeneously, whereas serous and endometrioid tumors rarely expressed these specificities and, in contrast, expressed Le(y) and H type 2 antigen strongly. When expressed in serous tumors, sTn was usually distributed in a heterogeneous pattern, whereas sTn expression in mucinous tumors was much more homogeneous. The distribution of Le(y) in serous tumors was noticeably homogeneous. H-1, Le(x), sLe(x), Le(b), TF and Tn specificities were rarely expressed in any type of ovarian carcinoma. Our results provide further support for the different histogenesis of mucinous and non-mucinous tumors and indicate alternative differentiation pathways for the 3 pathological subtypes of ovarian tumor. They also provide the basis for the choice of carbohydrate antigens for active and passive immunotherapy of ovarian carcinomas.     

Identification of two different surface epitopes of human ovarian epithelial carcinomas by monoclonal antibodies

Monoclonal antibodies (Mabs) against human ovarian mucinous and serous carcinoma were obtained by the Mab technique. Their reactivities against human tumors were tested by indirect immunofluorescence. One of the Mabs, named 4C7, derived from the spleen cells of mice immunized with mucinous carcinoma line OVA-1, reacted to ovarian mucinous carcinoma, endometrioid carcinoma, and mesonephroid carcinoma but did not react to ovarian serous carcinoma. Another Mab, 3C2, obtained from the spleen cells of mice immunized with serous carcinoma line HOC-21, reacted to serous carcinoma and endometrioid carcinoma of ovary, but never reacted to mucinous carcinoma or mesonephroid carcinoma. Neither of the Mabs reacted to other types of ovarian carcinomas such as undifferentiated carcinoma, dysgerminoma, endodermal sinus tumor, and malignant teratoma of ovary, and also did not react to any benign ovarian tumors or other normal human tissues. Both Mabs 3C2 and 4C7 had no reactivity to carcinoma of other organs such as stomach, colon, lung, lymphoid system, and kidney and also did not react to human lymphocytic or carcinoembryonic antigen as confirmed by using many human cell lines and surgically resected samples. Since the cross-reactivities of these Mabs were limited within the ovarian epithelial carcinomas, it is suggested that two distinct epitopes are expressed on the ovarian epithelial carcinomas. One epitope, identified by Mab 4C7, is expressed only on mucinous carcinoma, endometrioid carcinoma, and mesonephroid carcinoma, while the epitope, identified by Mab 3C2, appears only on serous and endometrioid carcinoma.     

Monoclonal antibody against human ovarian tumor-associated antigens

Mouse monoclonal antibodies (OV-TL 3) were raised against human ovarian tumor-associated antigens for diagnostic purposes. A cloned hybridoma cell line was obtained by fusion of murine myeloma cells with spleen lymphocytes from BALB/c mice immunized with a tumor cell suspension prepared from an ovarian endometrioid carcinoma. The antibodies were initially screened for their ability to bind on frozen sections of human ovarian carcinoma tissue and a negative reaction on gastric carcinoma tissue by indirect immunofluorescence. The reactivity of the selected OV-TL 3 clone (IgG1 subclass) was studied on normal and neoplastic tissues as well as on a cell line derived from the original tumor cell suspension used for immunization. OV-TL 3 antibodies stained frozen sections of human ovarian carcinomas of the following histological types: serous, mucinous, endometrioid, and clear cell. No reaction was found with breast cancers or other nongynecological tumors. No differences in staining pattern were observed between primary and metastatic ovarian carcinomas. OV-TL 3 antibodies brightly stained ovarian carcinoma cell clusters in ascitic fluids and left unstained mesothelial cells and peripheral blood cells. The OV-TL 3-defined antigen also remained strongly expressed on a cell line derived from the endometrioid ovarian carcinoma originally used for generation of OV-TL 3 clone. Reactivity was weak and irregular in a few ovarian cysts, while traces of fluorescence were sometimes detected in epithelial cells lining the female genital tract. In only 3 specimens of 15 endometrium carcinomas was weak focal reactivity with OV-TL 3 antibodies observed. The results of the immunofluorescence study were confirmed by the more sensitive avidin-biotin method and by 125I-labeled OV-TL 3 antibodies. Thus OV-TL 3 recognizes a common antigen for most ovarian carcinomas and may be a useful tool for rapid diagnosis of ovarian carcinomas.     

Histologic type, organ of origin, and Wnt pathway status: effect on gene expression in ovarian and uterine carcinomas.

PURPOSE: Ovarian and uterine carcinomas manifest several differentiation patterns resembling those seen in nonneoplastic epithelia of the gynecologic tract. Specific oncogene and tumor suppressor gene defects have been associated with particular differentiation patterns in carcinomas arising in either the uterus or ovary. For instance, ovarian and uterine carcinomas with endometrioid differentiation frequently show beta-catenin mutations. Whereas type of differentiation is considered in the treatment of uterine carcinomas, it does not presently contribute to decisions about treatment of ovarian carcinomas. A widely accepted view is that the accumulation of specific gene defects and gene expression changes underlies phenotypic traits of cancers, including their response to treatment. EXPERIMENTAL DESIGN: Using oligonucleotide microarrays to assess gene expression in 103 primary ovarian and uterine carcinomas, we sought to address whether organ of origin or type of differentiation (histotype; endometrioid versus serous) had a more substantial effect on gene expression patterns. RESULTS: We found that effects on gene expression due to organ of origin and histotype are similar in magnitude and are parallel in that organ effects are similar in the two histotypes and histotype effects are similar in the two organs. In addition, ovarian and uterine endometrioid adenocarcinomas with beta-catenin defects show a common gene expression signature largely distinct from that seen in tumors lacking such defects. CONCLUSIONS: Our results illustrate how organ of origin, type of differentiation, and specific molecular defects all contribute to gene expression in the most common types of ovarian and uterine cancers. The findings also imply gene expression data will be of value for stratifying ovarian cancer patients for new treatment approaches.     

Tumor-associated glycoprotein (TAG-72) in ovarian carcinomas defined by monoclonal antibody B72.3

Murine IgG1 monoclonal antibody (MoAb) B72.3, reactive with a high molecular weight glycoprotein complex [designated tumor-associated glycoprotein-72 (TAG-72)] was shown, with the use of the avidin-biotin-complex-immunoperoxidase technique and surgically resected tissues, to be reactive with a variety of histologic tumor types. TAG-72 is expressed in at least 5% (and up to 100%) of the malignant epithelial cells in 77% (n = 52) of human primary cancers and 71% (n = 31) of metastatic ovarian cancers of the common "epithelia" histologic category. Of these, several histologic types, including serous and mucinous cystadenocarcinomas, undifferentiated carcinomas, and less common types of ovarian carcinoma, were all shown to express TAG-72. In contrast, normal ovarian tissues and 26 of 27 benign ovarian tumors of various histologic types failed to express similar levels of TAG-72. Of interest is the 1 benign tumor that demonstrated unusual glandular complexity, as well as 3 tumors designated as borderline malignancy, that contained elevated TAG-72 expression. MoAb B72.3 also was used successfully to detect ovarian carcinoma cells in 28 cytologic preparations of human serous effusions and peritoneal washings. The reactivity of MoAb B72.3 was shown to be distinct from that of MoAb OC125 and an anti-CEA MoAb B1.1. The potential applications of MoAb B72.3 in the study of human ovarian cancer cell populations, as well as in several aspects of the management of human ovarian cancer, are discussed.     

Expression of heparanase, Mdm2, and erbB2 in ovarian cancer

Ovarian cancer is the most lethal of gynecological malignancies. Yet early diagnosis and prognosis are far from being satisfactory. Degradation of heparan sulfate proteoglycans by heparanase appears to play an important role in the invasiveness of tumor cells through the basement membrane and into the extracellular matrix. Recent cloning of the heparanase gene and generation of monoclonal antibodies against the enzyme permit to examine tumor cell expression of the enzyme. The aim of the present study was to assess heparanase activity and localization in various subtypes of epithelial ovarian cancer in correlation with oncogene expression. Histologically confirmed malignant ovarian tissue from ten women and tissue from 2 benign ovarian tumors and 4 normal ovaries were assessed for heparanase presence, activity and localization, incidence of apoptosis and expression of the oncogenes erbB2 and Mdm2. Heparanase immunohistostaining and activity were present in mucinous carcinomas and were more intense than in endometrioid and in serous carcinomas. The lowest activity was observed in benign ovarian tumors and normal ovaries. In ovarian carcinomas the enzyme was intensely concentrated in the cytoplasm of the cancerous cells. In contrast, in normal ovaries and benign tumors the enzyme was predominantly localized in endothelial cells lining blood capillaries. The rate of apoptosis was considerably higher in mucinous and endometrioid carcinomas, and was lower in serous and primary peritoneal carcinomas. Extremely high concentration of heparanase was often demonstrated in apoptotic cells. Endometrioid and serous carcinomas showed high expression of Mdm2 and erbB2 while mucinous carcinomas showed low expression. In benign ovarian tumors and normal ovaries the expression of both oncoproteins was extremely low. In conclusion ovarian carcinomas demonstrate higher levels of heparanase than benign tumors and normal ovaries suggesting that the enzyme may play an important role in metastatic spread of the cancerous cells. Apoptosis may be a significant part of the mechanism of the enzyme release into the extracellular space. Although heparanase activity seems to play an essential role in tumor progression, expression of oncogenes, such as erbB2 and Mdm2 seems to play the dominant role in the development of ovarian cancer.     

Immunohistochemical demonstration of neuron-specific enolase in gynecologic malignant tumors

Gynecologic malignant tumors were studied by the immunoperoxidase method for neuron-specific enolase (NSE). They included 22 argyrophil cell carcinomas of the endometrium, 6 argyrophil small cell carcinomas of the cervix, 21 argyrophil cell adenocarcinomas of the ovary (endometrioid type, 10; mucinous type, 11) and 3 ovarian carcinoids (strumal type, 2; insular type, 1). NSE was demonstrated in all cases of argyrophil small cell carcinomas of the cervix and ovarian carcinoids. On the other hand, NSE was positive only in four cases of endometrial carcinomas with argyrophil cells. Argyrophil cell adenocarcinomas of the cervix and the ovary were immunohistochemically negative for NSE. The current results suggest that argyrophil small cell carcinoma of the cervix, ovarian carcinoid, and some endometrial argyrophil cell carcinomas are related to APUDoma.     

Immunological reactivity of mucinous and serous ovarian adenocarcinomas

Comparison of immunological reactivity of glycoprotein antigens extracted from individual cases of mucinous and serous ovarian adenocarcinomas was performed taking into account the immunological relationship with carcinoembryonic antigen (CEA), nonspecific cross-reacting antigen (NCA), alpha-1-antichymotrypsin, and alpha-1-acid glycoprotein. In all immunological tests, the specific immune sera against perchloric acid extracts of ovarian mucinous and serous cystadenocarcinomas and antisera against the reference antigens mentioned above were used. It was established that: 1) ovarian mucinous and serous adenocarcinomas are immunologically different and possess various tumor-associated antigens, 2) ovarian mucinous adenocarcinomas contain considerable amounts of CEA and NCA, whereas serous type neoplasms show negligible amounts or lack of these antigens; and 3) in both types of tumors, alpha-1-antichymotrypsin and alpha-1-acid glycoprotein activities are found. Immunological data indicate that ovarian mucinous and serous adenocarcinomas derive from separate lineages of epithelium.     

TFF3 Expression as Stratification Marker in Borderline Epithelial Tumors of the Ovary

Borderline tumors (BOT) of the ovary account for 10% to 20% of ovarian neoplasms. Like ovarian cancer, BOT encompass several different histological subtypes (serous, mucinous, endometrioid, clear cell, transitional cell and mixed) with serous (SBOT) and mucinous (MBOT) the most common. Current hypotheses suggest low-grade serous carcinoma may develop in a stepwise fashion from SBOT whereas the majority of high grade serous carcinomas develop rapidly presumably from inclusion cysts or ovarian surface epithelium. The pathogenesis of mucinous ovarian tumors is still puzzling. Molecular markers could help to better define relationships between such entities. Trefoil factor-3 (TFF3) is an estrogen-regulated gene associated with prognosis in different types of cancer. It has also been included in a recent marker panel predicting subtypes of ovarian carcinoma. We analyzed the expression of TFF3 by immunohistochemistry in a cohort of 137 BOT and its association with histopathological features. Overall expression rate of TFF3 was 21.9%. None of the BOT with serous and endometrioid histology displayed strong TFF3 expression. On the other hand, TFF3 was highly expressed in 61.4% of MBOT cases and 33.3% of BOT with mixed histology (P < 0.001) suggesting a potential function of the protein in that subtypes. Associations of TFF3 expression with FIGO stage and micropapillary pattern were significant in the overall cohort but confounded by their correlation with histological subtypes. The highly specific expression of TFF3 in MBOT may help to further clarify potential relationships of tumors with mucinous histology and warrants further studies.     

Common epithelial ovarian tumors. Immunohistochemical intermediate filament profiles

The authors studied 79 common epithelial ovarian tumors in order to ascertain the intermediate filament profiles in formalin-fixed and methacarn-fixed, paraffin-embedded surgical pathology materials. Ultra-structural correlations were attempted with several tumors. All categories of common benign and malignant epithelial tumors were examined. Antibodies used in the study included antikeratins (AE1/AE3, 35BH11, 34BE12), carcinoembryonic antigen (CEA), and vimentin. All ovarian epithelial tumors expressed keratin in uniform fashion, except high molecular weight keratin (34BE12) which was focal. Vimentin was coexpressed with cytokeratins in 42% of serous carcinomas, 71% of endometrioid carcinomas, and 7% of clear cell carcinomas. Vimentin decoration in serous carcinoma was very focal, whereas endometrioid decoration tended to involve larger areas, similar to uterine-based endometrial adenocarcinoma. Mucinous, Brenner, and solid (not otherwise specified) ovarian tumors were positive only for cytokeratin. Carcinoembryonic antigen luminal staining was present in 52% of serous carcinomas and 87% of mucinous carcinomas. Whereas there are distinct differences in intermediate filament expression among ovarian carcinomas, these differences do not allow for specific categorization of ovarian neoplasms because there is some overlap of intermediate filament expression. In order to differentiate ovarian carcinoma from other carcinomas and mesothelioma, other methods of study would be necessary in addition to intermediate filament profiles, such as CEA immunohistochemistry, mucin histochemistry, and ultrastructural study.     

Advanced stage mucinous adenocarcinoma of the ovary is both rare and highly lethal

BACKGROUND:

Primary mucinous adenocarcinomas of the ovary are uncommon, and their biological behavior is uncertain. Retrospective studies have suggested that many mucinous carcinomas initially diagnosed as primary to the ovary have in fact metastasized from another site. A prospective randomized trial provided an opportunity to estimate the frequency of mucinous tumors, diagnostic reproducibility, and clinical outcomes.

METHODS:

A phase 3 trial enrolled 4000 women with stage III or IV ovarian carcinoma, treated by surgical staging and debulking, with randomization to one of five chemotherapeutic arms. Slides and pathology reports classified as primary mucinous carcinoma were reviewed independently by three pathologists. Cases were reclassified as primary or metastatic to the ovary according to two methods. Overall survival (OS) of reclassified groups was compared within the groups and with that of patients with serous carcinomas.

RESULTS:

Forty‐four cases were classified as mucinous adenocarcinoma upon review. Using either method, only about one third were interpreted by the three reviewers as primary mucinous carcinomas. Reproducibility of interpretations among the reviewers was high, with unanimity of opinion in 30 (68%) cases. The median survival (MS) did not differ significantly between the groups interpreted as primary or metastatic, but the OS was significantly less than that for women with serous carcinoma (14 vs 42 months, P < 0.001).

CONCLUSION:

Advanced stage mucinous carcinoma of the ovary is very rare and is associated with poor OS. Many mucinous adenocarcinomas that are diagnosed as primary ovarian neoplasms appear to be metastatic to the ovary. Cancer 2011. © 2010 American Cancer Society.     

PAX2, PAX8 and CDX2 Expression in Metastatic Mucinous,Primary Ovarian Mucinous and Seromucinous Tumors and Review of the Literature

Ovarian cancer is the most common cause of gynecologic cancer death. Both morphologically and immunohistochemically, metastatic mucinous tumors are the best mimickers of mucinous ovarian tumors; its pathogenesis still remains a mystery. PAX2 and PAX8 immunohisyochemistries are useful for differentiating numerous primary tumour types from metastatic ones. There are few studies in literature about PAX expressions in mucinous and seromucinous tumors. None of these are takes into account the histologic type (whether it is seromucinous or mucinous) or the metastatic origin. With this purpose hematoxylin and eosine slides of ovarian mucinous and seromucinous tumors were re-evaluated and one block was chosen for each case. The study included 76 ovarian mucinous and seromucinous tumors of the ovary reported in Hacettepe University department of pathology between 2000 and 2013. Tissue microarray (TMA) was designed from the chosen blocks, PAX2, PAX8, CDX2 immunostains was preformed to the TMA slides. As a result, most of the metastatic cases were negative for PAX2 (91.2 %) and PAX8 (86.3 %), many were diffusely and strongly positive for CDX2 (68.2 %). Seromucinous tumors were devoid of CDX2 expression; but all cases (except one) displayed strong and diffuse positivity with PAX8. In other words differing from mucinous tumors, seromucinous tumors show strong PAX8 positivity–similar to serous tumors. This study shows that PAX8 and CDX2 could be useful in differentiating primary mucinous from metastatic tumor. Furthermore unlike the homogeneity in seromucinous tumors for PAX8 and CDX2 mucinous tumors shows heterogeneity with different expression patterns.     

Immunohistochemical staining of GLUT1 in benign, borderline, and malignant ovarian epithelia

BACKGROUND: Aberrant expression of the facilitative glucose transporter GLUT1 is found in a wide spectrum of epithelial malignancies. The authors describe an immunohistochemical study of GLUT1 expression in benign, borderline, and malignant ovarian epithelia. METHODS: One hundred forty one formalin-fixed, paraffin-embedded sections were immunostained with rabbit anti-GLUT1 using the streptavidin-biotin method. The samples were as follows: 3 endometriotic cysts, 9 serous cystadenomas, 15 mucinous cystadenomas, 17 noninvasive borderline implants, 3 invasive borderline implants, and 3 endosalpingiosis. In addition, 35 borderline tumors (26 serous, 7 mucinous, 2 seromucinous) and 56 adenocarcinomas (50 serous, 4 endometrioid, 2 mucinous) were stained. RESULTS: Benign serous and mucinous cystadenomas and endosalpingiosis were non-staining with GLUT1 antiserum. Twenty-eight of 35 borderline tumors (80%) stained positively, with weak to moderate (1-2+ out of 3) staining intensity and focal or patchy distribution. Seventeen noninvasive serous borderline implants were negatively stained; however, three invasive serous borderline implants were positively stained with GLUT1 antiserum. Fifty four of 56 ovarian carcinomas (96%) stained positively, with moderate to strong (2-3+ out of 3) intensity and multifocal distribution. CONCLUSIONS: GLUT1 is a consistent marker of ovarian epithelial malignancy. GLUT1 staining is absent in benign ovarian epithelial tumors, and shows progressively more staining in invasive tumors as compared to borderline tumors. Anti-GLUT1 antibody may be useful in distinguishing invasive from noninvasive serous borderline implants.     

Reactivity of monoclonal antibody DF3 with a high molecular weight antigen expressed in human ovarian carcinomas

We have previously described the monoclonal antibody (MAb) DF3, prepared against a human breast carcinoma. MAb DF3 reacts with a high molecular weight glycoprotein detectable in human breast carcinomas and in human milk. Previous studies have demonstrated that DF3 antigen levels are elevated in the plasma of patients with breast and ovarian cancer. The present study has further examined the reactivity of MAb DF3 with human ovarian carcinomas. Immunoperoxidase staining demonstrated reactivity of MAb DF3 with 95% of benign, borderline, and malignant tumors (serous, mucinous, and endometrioid) of the ovary. Furthermore, malignant tumors contained cytoplasmic DF3 antigen while benign tumors expressed the antigen only on apical surfaces. Western blot analyses demonstrated that the MAb DF3 reactive ovarian antigen (DF3-O) was a glycoprotein with a heterogenous molecular weight ranging between 300,000 and 450,000. This antigen was detectable by immunofluorescence on the cell surface of five of six cultured human ovarian carcinoma cell lines. The extent of cell surface reactivity with MAb DF3 was equivalent to or greater than that obtained with MAb OC125, an antibody generated against coelomic epithelium and developmental amnion. Furthermore, uptake of 125I-labeled MAb DF3 by human ovarian carcinoma xenografts in athymic mice was 5.4- and 6.2-fold higher than the respective uptake noted in liver and control tumor (P = 0.031). These findings suggest that DF3-O antigen is similar if not identical to the antigen detected in human breast carcinomas by MAb DF3. Thus, MAb DF3 may be a useful reagent in immunodiagnostic evaluation of patients with ovarian cancer.     

Alteration of the p53 Tumor Suppressor Gene Occurs Independently of K-ras Activation and More Frequently in Serous Adenocarcinomas than in Other Common Epithelial Tumors of the Human Ovary

To clarify the role of the p53 tumor suppressor gene in the development of human ovarian epithelial tumors and to study the association of p53 alterations with K-ras activation, a series of 70 common epithelial ovarian tumors from Japanese patients was studied. These included 31 serous adenocarcinomas, 12 mucinous adenocarcinomas, 5 mutinous tumors of borderline malignancy, 13 endometrioid adenocarcinomas, and 9 clear cell carcinomas. Allelic loss, recognized at the polymorphic site in codon 72 of the p53 gene, was detected in 14 of 36 (39%) informative cases by restriction fragment length polymorphism analysis and by single-strand conformation polymorphism (SSCP) analysis of polymerase chain reaction(PCR)-amplified DNA fragments. Mutations in the highly conserved regions of the p53 gene were detected by SSCP analysis of PCR-amplifled fragments. Mutations were found in 22 of 70 (31%) ovarian tumors, including 1 of 5 mucinous tumors of borderline malignancy. Mutations were subsequently characterized by direct sequencing. Single missense base substitutions were detected in 13 ovarian carcinomas and in one case of mucinous tumor of borderline malignancy. Short (1-8 bp) deletions and insertions were found in 8 cases. Mutations in the p53 gene occurred more frequently in serous adenocarcinomas (14/31, 45%) than in all nonserous types of malignant epithelial tumors combined (7/34, 21%;P=0.032). Point mutations in K-ras were identified by dot blot hybridization analysis of PCR-amplified fragments with mutation-specific oligonucleotides and by direct sequencing. The overall frequency of K-ras mutations was 19/70 (27%).K-ras mutations were found in 12 of 17 (71%) mucinous tumors (8/12 mucinous carcinomas [67%] and 4/5 mucinous tumors of borderline malignancy [80%]), and occurred more frequently than in serous carcinomas (4/31, 13%;P=0.00009) or in all nonmucinous types of ovarian epithelial tumors combined (7/53, 13%; p=0.00002). These data suggest that different combinations of oncogenes and/or tumor suppressor genes may be involved in the genesis and development of histologically distinct categories of common epithelial tumors of the human ovary.     

Nuclear localization of phosphorylated ERK1 and ERK2 as markers for the progression of ovarian cancer

We examined the possibility that the localization of phosphorylated ERK1 and ERK2 (pERK1/2) can serve as a marker for the development of benign and borderline tumors as well as carcinoma of the ovary by an immunohistochemical method on ovarian paraffin sections, obtained from women aged 41-83 years. In normal tissue, 28.3% of nuclei were labeled, mainly confined to the epithelial cells at the surface of the ovary. In benign serous tumors, the label rose to 55.0%, while the intensity of the staining was weak. In contrast, in borderline serous tumors and in ovarian serous carcinoma (stage II) 52.1% and 70.3% of nuclei, respectively, were labeled with a high intensity. In mucinous benign tumors, the number of labeled nuclei was as in the control, but in addition, 49.4% of the cells demonstrated high concentration of pERK1/2 in aggregated form that was evident in the cytoplasm of the cells. In the mucinous and endometrioid ovarian carcinomas (stage II) very intensive labeling was found in 60% and 77.3% of cells, respectively. It is, therefore, suggested that since nuclear pERK1/2 can be mitogenic, it can serve as a reliable marker for the progression of ovarian cancer. Interestingly, the intense labeling of pERK1/2 was mainly confined to the peripheral areas of ovarian endometrioid carcinoma (stage II). In addition, all tumor cells in this class of cancer were positively stained with mutated p53. It seems, therefore, that immunohistochemical staining of normal and ovarian tumor cells with anti-pERK1/2 is a reliable marker for early detection of the cancer, which may assist in the early diagnosis and prognosis of this lethal disease.     

Gene expression profiles of serous, endometrioid, and clear cell subtypes of ovarian and endometrial cancer.

PURPOSE: The presence of similar histologic subtypes of epithelial ovarian and endometrial cancers has long been noted, although the relevance of this finding to pathogenesis and clinical management is unclear. Despite similar clinical characteristics, histologic subtypes of cancers of the ovary and endometrium are treated according to organ of origin. This study compares the gene expression profiles of analogous histologic subtypes of cancers of the ovary and endometrium using the same genomic platform to determine the similarities and differences between these tumors. EXPERIMENTAL DESIGN: Gene expression profiles of 75 cancers (endometrioid, serous, and clear cell) of the ovary and endometrium, five renal clear cell cancers, and seven normal epithelial brushings were determined using a 11,000-element cDNA array. All images were analyzed using BRB ArrayTools. Validation was done using real-time PCR on select genes and immunohistochemical staining. RESULTS: Comparison across endometrial and ovarian cancers and serous and endometrioid tumors showed expression patterns reflecting their organ of origin. Clear cell tumors, however, showed remarkably similar expression patterns regardless of their origin, even when compared with renal clear cell samples. A set of 43 genes was common to comparisons of each of the three histologic subtypes of ovarian cancer with normal ovarian surface epithelium. CONCLUSIONS: The comparison of the gene expression profiles of endometrioid and serous subtypes of ovarian and endometrial cancer are largely unique to the combination of a particular subtype in a specific organ. In contrast, clear cell cancers show a remarkable similarity in gene expression profiles across organs (including kidney) and could not be statistically distinguished.     

Alteration of BRCA-1 tumor suppressor gene expression in serous and mucinous ovarian neoplasms in the benign-borderline-malignant pathway

Alteration of expression of the tumor suppressor gene BRCA-1 has been widely studied in breast and ovarian carcinoma. However, pattern of this alteration in the benign-borderline-carcinoma sequence in serous and mucinous ovarian neoplasms have not yet fully described. Tissue sections from 214 formalin-fixed paraffin-embedded ovarian specimens were stained immunohistochemically with BRCA-1 antibody. Specimens were 10 normal ovarian surface epithelium, 10 fallopian tube epithelium, 70 benign adenoma (50 serous and 20 mucinous), 28 borderline (13 serous and 15 mucinous), 78 carcinoma (58 serous and 20 mucinous), and 18 metastatic deposit (13 serous and 5 mucinous). Expression was evaluated into 0, +1, +2, and +3. Score +3 staining similar to normal tissues was considered normal and other scores were considered altered expression. Strong expression was seen in all normal epithelium specimens. Altered expression was seen in 34 serous neoplasms; 17 of 50 (34%) of benign cystadenomas, 6 of 13 (46%) of borderline tumors, 43 of 58 (74%) of primary carcinoma, and in 8 of 13 (62%) of metastatic carcinoma. This alteration was significantly associated with higher histopathologic grade (P = 0.049), presence of necrosis (P = 0.0001), and higher proliferation rate (P = 0.001). In mucinous neoplasms; altered BRCA-1 was detected in 25 specimens; 7 of 20 (41%) of benign cystadenomas, 5 of 15 (33%) of borderline neoplasms, 9 of 20 (45%) of primary carcinoma, and 4 of 5 (80%) of the metastatic deposits. This alteration was not associated with any of the clinicopathologic tumor characteristics. In conclusion, alteration of BRCA-1 expression is more frequent in serous than in mucinous carcinomas and is associated with tumors of higher grades and high proliferation rate.