Oestrogen and progesterone receptor content as a prognostic factor in advanced epithelial ovarian carcinoma.

Levels of oestrogen receptor (ER) and progesterone receptor (PgR) in ovarian cancer tissue were examined with regard to their prognostic importance for survival in 179 patients with primary epithelial ovarian cancer stage III or IV in relation to: FIGO-stage, histological type, histological grade, age, ascites, and postoperative residual tumour. Hormone receptor content was determined with the DCC-method, receptor values higher than 9 fmol/mg protein were considered positive. Response to postoperative chemotherapy was significantly correlated with PgR content (80% responders in the group with PgR positive tumours and only 61% responders in the group with PgR negative tumours). A Cox proportional hazards regression model identified histological grade, residual tumour, age and PgR content as independent prognostic factors for survival in advanced epithelial ovarian carcinoma. PgR content had particularly significant prognostic relevance for patients with postoperative residual tumour mass less than or equal to 2 cm in diameter. Within this group of patients, those who are PgR positive have a 2-years survival probability of 83% compared with only 51% in the PgR-negative group.

Prognostic significance of estrogen and progesterone receptors in epithelial ovarian cancer.

Estrogen and progesterone receptor assays were analyzed from epithelial ovarian cancer in 123 patients to determine the prognostic significance of receptor results. In 110 (89%), assays were performed at diagnosis and in 13, assays were performed after previous therapy. Estrogen receptor determinations were positive (above 10 fmol/mg) in 75 cases (61%), progesterone receptor determinations were positive (above 3 fmol/mg) in 35 (28%), and both were positive in 20 (16%). Progesterone receptors were more frequently positive (53%) in tumors of endometrioid histology than with other histologic types (P = .01). Thirty-one subjects had a second assay; estrogen receptors were positive in 16 cases (52%), progesterone receptors were positive in five (17%), and both were positive in five (17%). Synchronous and metachronous assays were in agreement in 60-79% of the cases. By multivariate analysis, positive estrogen receptor, progesterone receptor, or both did not predict response to chemotherapy, negative second-look findings, or survival. Thirty-one women received hormonal therapy; one of 26 evaluable subjects had a partial response and four (13%) maintained stable disease for at least 6 months (6-21 months). Positive receptors did not predict hormonal response or disease stabilization.

Serological mapping of the TAG-72 tumor-associated antigen using 19 distinct monoclonal antibodies.

Monoclonal antibody (MAb) B72.3 has been shown to be of potential utility in the management of human carcinoma via its use in (a) the targeting of carcinoma lesions in colorectal and ovarian cancer patients, (b) immunohistochemical analyses of biopsies and effusions, and (c) serum assays to help define the presence of carcinoma. The B72.3-reactive antigen, designated tumor-associated glycoprotein 72 (TAG-72), has been characterized as a high molecular weight glycoprotein with the properties of a mucin. We report here the utilization of MAb B72.3 and 18 second generation MAbs (generated using purified TAG-72 obtained from a colon carcinoma xenograft as immunogen) to construct a serological map of the TAG-72 molecule. The generation and initial characterization of 10 of the second generation MAbs have been described previously; in addition, eight previously unreported MAbs were used. All 19 MAbs produced immune precipitate lines against purified TAG-72 in double immunodiffusion, indicating that each epitope recognized by a single MAb is present at least twice on the TAG-72 molecule. Immunodepletion analyses utilizing 11 of the anti-TAG-72 MAbs indicated that each recognizes the same molecule or population of molecules. Nineteen competition radioimmunoassays were developed and 19 purified competitor immunoglobulins were used in each assay. The patterns of cross-competition indicated the presence of a complex array of tumor-associated epitopes on the TAG-72 molecule. Some of the MAbs recognized epitopes that were structurally or spatially related to one another, but none appeared to recognize identical epitopes. The spectrum of inhibitory reactivities of these MAbs for TAG-72 binding varied from extremely restricted to more broad inhibition. The serological mapping studies reported here provide information as to the range and nature of the epitopes expressed on the TAG-72 molecule, help form the basis for selecting alternative anti-TAG-72 MAbs for use in potential clinical applications, and further define the nature of this oncofetal antigen.

Selective over-expression of mRNA coding for 90 KDa stress-protein in human ovarian cancer.

The mRNA expression of the KDa stress-protein (SP) was assayed in normal and neoplastic human ovary. It was found that the expression level is low in normal ovary and in benign tumors and increases in the more advanced stages of ovarian cancer. A low level of mRNA coding for the 70 KDa SP--the most prominent among the inducible SPs-was constantly found in all specimens. No relationship was observed between SP 90 mRNA abundance and the receptor status of epidermal growth factor, estrogen and progesterone.

Ovarian adenocarcinomas express fms-complementary transcripts and fms antigen, often with coexpression of CSF-1.

In earlier studies of oncogene expression in ovarian and endometrial neoplasms, the authors reported that high tumor levels of fms-complementary transcripts correlate with high histologic grade and advanced clinical stage presentations. In this communication, they pursue these initial clinicopathologic investigations to demonstrate by in situ hybridization and immunohistochemistry that malignant epithelial cells of 14 of 14 invasive adenocarcinomas of the ovary express fms-complementary transcripts. By Northern blotting and by reverse transcription, followed by polymerase chain reaction amplification, the authors also were able to demonstrate fms transcript expression in several ovarian and endometrial carcinoma-derived cell lines. Because about half (6/14) of the invasive adenocarcinoma specimens were shown to coexpress fms and colony-stimulating factor 1, the authors propose that the expression of this lymphohematopoietic cytokine and its receptor by ovarian adenocarcinomas could contribute to their proliferative and invasive characteristics in vivo.

Overexpression of HER-2/neu is associated with poor survival in advanced epithelial ovarian cancer.

Previous studies have suggested that overexpression of HER-2/neu oncogene occurs in 15-40% of breast cancers and that overexpression is associated with poor prognosis. In the present report, we have used an immunohistochemical technique involving a monoclonal antibody specifically reactive with the external domain of HER-2/neu to study expression of HER-2/neu in frozen sections of normal ovary and advanced epithelial ovarian cancer. The intensity of staining for HER-2neu was always moderate or less (0-2+) in normal ovarian epithelium. Among 73 ovarian cancers, 50 (68%) had staining similar to that for normal ovarian epithelium (0-2+) while 23 (32%) stained heavily (3+). Survival of the 23 patients with high HER-2/neu expression (median, 15.7 months) was significantly worse (P = 0.001) than that of the 50 patients (median, 32.8 months) with normal HER-2/neu expression. In addition, patients whose tumors had high HER-2/neu expression were significantly less likely to have a complete response to primary therapy (P less than 0.05) or have a negative second-look laparotomy when serum CA 125 levels were normal preoperatively (P less than 0.05). These findings suggest that HER-2/neu deserves further evaluation as a prognostic marker in epithelial ovarian cancer.

Follicular and luteal cysts after treatment with gonadotropin-releasing hormone analog for in vitro fertilization.

Ovarian cysts are a common complication of GnRH-a administration. We followed 98 patients who were suppressed with GnRH-a before ovarian stimulation with hMG for IVF treatment. Approximately 20% of the patients receiving GnRH-a during the follicular or luteal phase had developed ovarian cysts. However, the number of cysts per patient was significantly higher in the follicular phase compared with luteal phase. Systematic aspiration of those cysts under local anesthesia permitted the start of ovarian stimulation with hMG as scheduled on day 16 after GnRH-a administration. Follicular fluid content of the cysts revealed similar levels of steroids to those in normal follicles. These cysts contained few cells and no egg. In vitro fertilization treatment was more successful in patients whose cysts were aspirated during the luteal phase than in those with cysts during the follicular phase. We concluded that luteal phase cysts are more benign than follicular phase cysts, and it is possible that they represent an enlargement of pre-existing corpora lutea.

Flow cytometric evaluation of epithelial ovarian cancer.

We investigated the prognostic significance of deoxyribonucleic acid content and proliferative activity of tumor cell populations as measured by flow cytometry of the tumor specimens from 115 women with epithelial ovarian cancer. Deoxyribonucleic acid aneuploidy was found in 87 of 115 (76%) of these cancers with a mean deoxyribonucleic acid index of 1.6 and S-phase fraction of 14.7%. The S-phase fraction of the 28 (24%) diploid tumors was 7.0%. Deoxyribonucleic acid ploidy was significantly correlated with survival. S-phase fraction was significantly correlated with ploidy, residual tumor, histology, grade, ascites, time to recurrence, and survival. Diploidy versus aneuploidy were the best discriminating values for deoxyribonucleic acid index and an S-phase fraction of greater or less than 18% for that parameter. Multivariate analysis revealed stage, S-phase fraction, residual tumor, and grade to be independently associated with time to recurrence, and stage, age, S-phase fraction, and largest metastases were factors associated with survival. Deoxyribonucleic acid ploidy did not significantly improve either model. These results suggest that abnormalities of deoxyribonucleic acid content and the proliferative activity of tumor cell populations are reflective of their biologic activity.

[Detection of trophoblastic beta 1-glycoprotein in tumor tissue and blood in ovarian neoplasms]. / Opredelenie trofoblasticheskogo beta 1-glikoproteina v opukholevoi tkani i syvorotke krovi pri rake iaichnika.

Using immunochemical analysis methods (the reaction of precipitation in agar, immunoenzymatic method, immunofluorescence), trophoblastic beta 1-glycoprotein (TBG) concentration in tumour tissue and in the blood serum of patients with ovarian cancer was studied. By rabbits immunization with glycoprotein fraction of ovarian adenocarcinoma, dissolved in 0.6 M sulfosalicylic acid, the authors obtained antibodies to TBG. Immunoenzymatic method showed, that TBG level is raised during ovarian cancer (more than 3 micrograms/l): in 18% of tumour extracts, in 12.5% of blood sera samples and in 41.6% of cases in ascites fluid. Utilizing indirect immunofluorescence method morphological structures of trophoblastic type were identified in paraffin sections of ovarian adenocarcinoma. The authors suppose, that such structures may be responsible for TBG biosynthesis in ovarian tumours.

[Immunohistological coexpression of keratin and vimentin in the epithelial neoplastic cells].

Filed formalin-fixed paraffin blocks of 128 cases of epithelial neoplasms were selected for immunohistochemical study of keratin and vimentin expression. The results showed that 35.1% (45/128) of different carcinomas expressed vimentin. The immuno-positivity of vimentin in thyroid carcinomas, ovarian carcinomas, prostatic adenocarcinomas, pulmonary carcinomas and malignant mesotheliomas were 81.8%, 42.8%, 66.7%, 30.5% and 53.4%, respectively. Carcinomas of breast, kidneys, salivary glands, adrenal glands and nasopharyngeal carcinomas also showed various degrees of positive reaction. The results suggest that an immunohistochemical positive vimentin reaction does not exclude histopathological diagnosis of carcinomas. The significance and noticeable aspects of immunohistochemical methods in histopathological diagnosis are also discussed.

Glial fibrillary acidic protein immunoreactivity of chondrocytes in immature and mature teratomas.

The immunoreactivity of chondrocytes for glial fibrillary acidic protein (GFAP), other intermediate filament proteins and S-100 protein was studied in formalin-fixed paraffin-embedded sections. A total of 95 cartilage specimens were examined from five immature teratomas, 12 mature teratomas, and a teratocarcinoma. GFAP-immunoreactive chondrocytes were abundant in immature cartilages, and as the cartilages maturated, these chondrocytes decreased and became distributed peripherally. Elastic cartilage had more GFAP-immunoreactive chondrocytes than non-elastic cartilage. GFAP-immunoreactive cartilage was often located close to central nervous tissue. Immunostaining for vimentin and S-100 protein revealed extensive distribution of immunoreactive chondrocytes in immature and mature cartilages, but in mature cartilage, chondrocytes at the center had less vimentin immunoreactivity. GFAP-immunoreactive chondrocytes also showed apparent immunostaining for vimentin. There was no difference in immunohistochemical staining for the alpha and beta subunits of S-100 protein. The immunoreactivities of teratoma cartilage specimens were quite similar to those of respiratory tract cartilage.

Monoclonal antibody C219 detection of the multidrug-resistant protein P-glycoprotein in routinely processed tissues: a study of 36 cases of ovarian carcinoma.

P-glycoprotein is a membrane protein found in high levels in multidrug-resistant (MDR) tumor cells and is associated with in vitro and clinical resistance of neoplasms to a wide variety of structurally unrelated oncolytic agents. We retrospectively investigated the presence of P-glycoprotein in 36 patients with treated, high grade ovarian carcinomas by using a murine monoclonal antibody (C219). The patients were selected on the basis of their complete response (11 patients) or nonresponse (25 patients) to chemotherapy. Routinely processed tissue sections from pre- and postchemotherapy surgical tissue samples were processed by a standard immunohistochemical method. Sections of tumor from both pre- and postchemotherapy specimens from the responder group were all negative, as were the prechemotherapy specimens from the nonresponder group. Four of the 25 (15%) nonresponders' postchemotherapy tissues were positive, predominantly in areas of histologically undifferentiated tumor. The cellular localization of P-glycoprotein in normal, untreated tissues was also investigated using C219, and its presence in various luminal epithelia of the gastrointestinal tract, kidney, and liver are consistent with its proposed normal function as a toxin/drug-export protein. Our overall results indicate that P-glycoprotein can be detected in routinely processed tissues by standard methods. The presence of P-glycoprotein in some patients with treated ovarian carcinomas is associated with nonresponse to standard chemotherapy treatment.

Two homologous mixed müllerian tumor lines of the ovary and their characteristics.

Two cell lines, NF and JoN, derived from human ovarian carcinosarcomas, were established in tissue culture and in nude mice. Both lines, growing in monolayers, showed morphologic features of adenocarcinoma cells (NF being aneuploid with a modal number of 53, and JoN being pseudodiploid with a modal number of 44). Intermediate filaments were demonstrated immunohistochemically; the JoN line expressed keratin, but not vimentin or desmin, whereas the NF line expressed vimentin and desmin, but not keratin. Plasminogen activator activity was found in both lines. It is concluded that both of these lines are potentially useful models for studying the diverse characteristics of malignant mixed Müllerian tumors.

[Separation of Thomsen-Friedenreich (T) antigen and N antigen precursor glycoproteins from perchloric acid-soluble fraction of cyst fluid of human ovarian clear cell carcinoma and their some chemical and serological properties].

One M perchloric acid-soluble fraction separated from cyst fluid of a patient (blood group AB) with ovarian clear cell carcinoma in malignant was subjected to Sephacryl S-200 gel filtration and Fraction 1 which was eluted at void volume, reacted with both of the lectins of Vicia unijuga and Arachis hypogaea. This fraction was then separated into 6 fractions (DEAE-Frs. 1-6) in a DEAE-Sephacel column chromatography. DEAE-Frs. 3-6 were sugar-rich glycoprotein fractions which contained galactose and N-acetylglucosamine in remarkably high percentages, respectively. Reactivities against various hemagglutinins of these four fractions suggest that DEAE-Fr. 3 is a Thomsen-Friedenreich (T) glycoprotein fraction with AB activity and weak N antigen precursor activity and DEAE-Fr. 4 is an N antigen precursor glycoprotein fraction with AB activity and weak T activity.

Protooncogene amplification and tumor ploidy in human ovarian neoplasms.

DNA from 24 ovarian tumors, including 16 carcinomas, was examined for amplification of the proto-oncogenes c-myc, int-2, and rc-erbB-2. All cases of carcinoma were also examined by flow cytometry for DNA ploidy and cell cycle analysis, and eight cases of carcinoma were examined for estrogen and progesterone receptors. Protooncogene amplification was not detected in the DNA of benign ovarian neoplasms, or of ovarian carcinomas with low malignant potential. Amplification of c-myc was detected in six of 12 cases of invasive carcinoma, int-2 amplification was present in one case, and c-erbB-2 amplification was not detected in any case. Among the seven cases evidencing protooncogene amplification, three cases showed aneuploidy in tumor DNA, while four showed diploidy. Two cases which showed aneuploidy in tumor DNA did not demonstrate any degree of protooncogene amplification. Protooncogene amplification was frequently associated with morphologic nuclear anaplasia and high mitotic count. Six of the seven cases demonstrating c-myc or int-2 were of the serous type or showed some degree of serous differentiation, while none of the four cases of purely mucinous carcinoma had evidence of amplification. While the total number of cases in the study was limited, it would appear from the trend demonstrated by the data that protooncogene amplification (particularly c-myc) may be involved in the pathogenesis of aggressive common epithelial tumors of the ovary.

Tumor markers in gynecologic neoplasms.

The applications of tumor markers and steroid receptors in gynecologic neoplasms are described. The value of immunohistologic techniques in the histogenetic assessment of gynecologic neoplasms is examined. Approaches to the diagnosis of similar-appearing lesions are presented.

[Lactating mammary tissue in a mature cystic teratoma of the ovary].

Discussed is a mature cystic teratoma that was surgically removed from the left ovary, said teratoma containing lactating mammary tissue of a 30-year-old Japanese lady, primigravida and in her 36th gestation week. The tumor measuring 3 X 3 X 3 cm, was accidently found when she underwent a cesarian section. In the lactating glandular tissue of the teratoma, the application of an anti-alpha-lactalbumin serum revealed diffuse and/or reticular cytoplasmic stainings of almost all the luminal cells and secretory materials. Further, myoepitheliall cells were clearly visualized with anti-actin serum. References are made to 2 other case reports of similar tumoral tissue.

Detection of pS2 messenger RNA in gynecological cancers.

Estrogen-inducible pS2 mRNA was previously detected in human cancer cell lines the growth of which was sensitive to estrogen. In the present study, the expression of the pS2 gene was analyzed in 111 gynecological carcinomas. The pS2 message was detected in greatest abundance in 6 primary carcinomas of the ovary (6 of 29), 4 of these being mucinous cystadenocarcinomas. A secondary carcinoma of the ovary, and another of the omentum (1 of 4), also contained detectable levels of pS2 mRNA. Weak pS2 mRNA signals were occasionally observed in endometrial (2 of 55) and cervical carcinomas (2 of 33) as well. There was a poor correlation between estrogen receptor and pS2 mRNA in ovarian carcinomas.

Embryonal carcinoma of the ovary: a six-year survival.

We report a case of embryonal carcinoma, stage II, arising in the right ovary of an 18-year-old woman. The elevated serum levels of alpha-fetoprotein (AFP) and urinary human chorionic gonadotropin (hCG) rapidly normalized after conservative surgery followed by combination chemotherapy. The tumor was composed of large primitive cells and some multinucleated giant cells. AFP and hCG were demonstrated immunohistochemically in each type of cells. She has been disease-free for 6 years.