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Objective: Our objective was to determine if the level of Her-2/neu expression in advanced ovarian cancer changed after platinum-based chemotherapy., Methods: Tissue samples from 43 patients who had surgery for ovarian cancer between 1991 and 2001 at the Mayo Clinic were stained for Her-2/neu expression using the DAKO kit and reviewed independently by two pathologists. Patient charts were reviewed for demographic data, clinical course, chemotherapy, and survival times., Results: Her-2/neu expression was 0 in 30 patients (69.76%), 1+ in 12 patients (27.9%), and 3+ in 1 patient (2.32%) before chemotherapy. After platinum chemotherapy, Her-2/neu expression changed from 0 to 1+ in 7 patients, from 1+ to 0 in 4 patients, 0 to 2+ in 1 patient, and 1+ to 2+ in 2 patients and no change was seen in 29 patients. Both pathologists agreed in all instances when the score was 0 or 1+ and disagreed in two instances between a negative and a weakly positive staining., Conclusions: Our findings indicate a low level of overexpression of Her-2/neu at the time of primary diagnosis of epithelial ovarian cancer. Relapsing tumors show no significant change in the intensity of Her-2/neu expression after platinum-based chemotherapy. Further prospective studies are needed to confirm these findings and to ascertain whether platinum chemotherapy indeed has no effect on Her-2/neu expression.

The insulin receptor mediates a proliferative response in certain transformed cells, but little is known about its function in ovarian cancer. We used human epithelial ovarian carcinoma cell lines and lifespan-extended normal ovarian surface epithelial (OSE) cells to examine (125)I-insulin binding and mitogenic responses to insulin. All cancer cell and OSE cultures specifically bound (125)I-insulin. Except for OV202, the carcinoma lines had elevated insulin binding compared with OSE cells. All carcinoma lines except OV202 expressed insulin receptor as detected by flow cytometry and increased (3)H-thymidine incorporation or cell number in response to 0.1-10 nM insulin. Interestingly, similar concentrations of IGF-II also induced proliferation of the insulin-responsive cancer cell lines and displaced (125)I-insulin binding. Direct binding of (125)I-IGF-II to the insulin receptor was visualized by cross-linking and immunoprecipitation. Binding of IGF-II to the insulin receptor and a proliferative effect of insulin suggest the presence of insulin receptor isoform A. Real-time PCR analyses confirm that insulin receptor isoform A expression predominates over isoform B expression in the ovarian carcinoma cell lines. This report suggests that the insulin receptor may play a role in the regulation of ovarian cancer cell growth.

Objectives: The expression of messenger RNA (mRNA) for the LH (LHR) and FSH receptors (FSHR) was examined in normal human corpora lutea and granulosa cell tumors., Methods: Expression was examined by RT/PCR and DNA sequencing techniques., Results: The full-length (FL) coding region and seven additional isoforms were identified for normal LHR mRNA. Isoform 1 had portions of exons II and III deleted, and isoform 2 had exon IX omitted. Isoform 3 also had portions of exons II and III deleted and all of exon IX deleted. Exons III through VI were missing in isoforms 4-7. Isoform 5 also had exon IX omitted, and isoform 6 also had part of exon XI missing. Isoform 7 also had exon IX and part of exon XI deleted. An aberrant migration pattern of the LHR mRNA isoforms was observed for granulosa cell tumors with FIGO Stage I-IV. Five tumor samples of Stage III-IV had many isoforms absent. Seven Stage I samples had aberrant migration patterns that depended on the size of the tumor. As the size of the tumor increased the aberrant migration pattern of the LHR mRNA isoforms was more pronounced and some isoforms were not detected. The FL and at least one additional isoform were identified for FSHR mRNA. Isoform 1 had regions of exons IV and V deleted. The FSHR mRNA isoforms had a similar migration pattern for the normal ovary and the granulosa cell tumors., Conclusions: Alternately spliced forms of mRNA for the LHR and FSHR exist for normal human ovary and granulosa cell tumors. The aberrant migration and missing LHR mRNA isoforms in granulosa cell tumors do not appear to result from general genomic instability associated with tumor progression. These findings are important to understand the role of alternate splicing in the regulation of LHR and FSHR expression in different pathological states., (Copyright 2000 Academic Press.)

Objective: The goal of this work was to determine the cellular content of inhibin and p53 in granulosa cell tumors (GCTs)., Methods: Clinical records of 47 patients (mean age, 54 years; range, 20-85 years) presenting with GCT surgically managed at our institution were abstracted. International Federation of Gynecology stage I was assigned in 39 patients, stage II in 2, and stage III in 6. Concomitant endometrial carcinoma was identified in 6 patients. Mean follow-up was 13.6 years (range, 1 day to 37.6 years). Sections from paraffin-embedded tissue blocks were analyzed immunohistochemically for expression of tissue inhibin and p53 levels. Inhibin expression was graded by intensity and reactivity, and p53, by its presence or absence., Results: The tumors of 27 patients (57%) stained strongly for inhibin intensity and showed >60% reactivity. Decreased intensity and reactivity of inhibin expression were associated with advanced-stage disease (P = 0.05 and P < 0.01, respectively, by Fisher exact test). Expression of p53 was detected in tumors from 27 patients (57%), and immunoreactivity was associated with compromised progression-free survival (P = 0.016, log-rank test). However, the association between p53 immunoreactivity and disease stage was not significant. Absence of p53 expression was significantly associated with concurrent endometrial carcinoma (P = 0.022), suggesting more molecularly intact tumors that retain functional activity., Conclusions: Although the majority of GCTs show strong expression of inhibin with regard to intensity and reactivity, weak expression is associated with advanced disease but not with decreased progression-free survival. By contrast, expression of p53 is not significantly associated with stage, but increased expression is associated with decreased disease-free survival. Absence of p53 expression appears to be associated with concurrent endometrial carcinoma., (Copyright 2000 Academic Press.)

Objective: To investigate the role of expression of p34cdc2 protein kinase in normal, benign, and malignant ovarian epithelium., Material and Methods: Tissue sections from 24 patients with epithelial ovarian carcinoma (EOC) along with 6 normal ovarian specimens and 12 benign cystadenomas were incubated with mouse IgG monoclonal antibody to human p34cdc2 protein kinase, followed by detection with use of a standard peroxidase-labeled streptavidin-biotin technique. Immunohistochemical staining was graded and compared. Clinical data were also reviewed., Results: Normal surface epithelium and 10 of 12 benign cystadenomas failed to stain for p34cdc2 protein kinase. Of the 24 EOC specimens, however, 19 (79%) stained positively. The staining pattern or intensity was not associated with the histologic grade or surgical stage., Conclusion: Expression of p34cdc2 protein kinase is strongly up-regulated in most cases of EOC but not in normal epithelial ovarian tissue or in most cases of benign epithelial tumors evaluated. Therefore, it may be associated with early events in carcinogenesis. Redundant overexpression of cyclin-dependent kinases such as p34cdc2 may contribute to deranged cell cycle progression and proliferation of EOC. Observation of overexpression of p34cdc2 protein kinase in other malignant lesions suggests a common mechanism.

Objectives: The role of the candidate metastasis-suppressor gene nm23-H1 first characterized in breast cancer remains controversial, with both metastasis suppression and disease progression being linked to elevated nm23-H1 gene expression in different human tumor types. We sought to characterize (1) the pattern and intensity of nm23-H1/nucleoside diphosphate (NDP) kinase expression in human epithelial ovarian carcinoma (EOC) and (2) the relationship between nm23-H1/NDP kinase expression and tumor extent at diagnosis (FIGO stage) and response to treatment as defined by progression-free survival and actuarial survival., Methods: Twenty-four patients with EOC aged 61.1 +/- 13.0 (mean +/- SD) years were followed for 614.0 +/- 289.7 days after a debulking procedure, cisplatin-based chemotherapy (19 of 24), and second-look laparotomy (9 of 24). After the primary debulking procedure, 63% of patients had no or microscopic residual disease. Overnight incubation of formalin-fixed tumor sections at 4 degree C with primary rabbit polyclonal IgG antibody to human nm23-H1/NDP kinase was followed by detection with standard ABC method. Nonimmune rabbit serum and normal breast tissue served as controls. Immunohistochemical staining was graded by a clinically blinded observer for intensity of staining (0, negative; 1, weak; 3, strong), pattern of staining (focal or diffuse), and histologic grade of tumor (1 through 4)., Results: Of the EOCs, 54% were histologic grade 3 or 4 and 58% were FIGO stage III; 88% (21 of 24) stained positively, and 18 of 21 stained strongly and 14 of 21 stained diffusely. No correlation was found between either intensity or pattern of nm23-H1/NDP kinase immunostaining and histologic grade. No correlation was found between either staining pattern or intensity and FIGO stage. There was a trend toward decreased actuarial survival with both focal pattern (P = 0.12, log-rank test) and strong intensity (P = 0.15, log-rank test) of nm23-H1 staining. Decreased progression-free survival was likewise correlated with focal nm23-H1/NDP kinase immunostaining pattern (P = 0.02, log-rank test) and strong intensity of nm23-H1/NDP kinase staining (P = 0.08, log-rank test)., Conclusions: Expression of nm23-H1/NDP kinase is strongly upregulated in most EOCs. Redundant overexpression of nm23-H1/NDP kinase may contribute to deranged cell cycle progression and EOC proliferation. Pattern and intensity of nm23-H1/NDP kinase immunostaining of EOC tissue retrieved at primary operation may identify patients at risk for tumor progression and help guide treatment strategies. These findings suggest that nm23-H1 gene expression may have distinct if not opposite biologic functions in EOC and breast carcinoma.

Purpose: To evaluate the prognostic significance of p53 expression in epithelial ovarian cancer, including a subset of stage I patients, and to look for correlations between p53 expression and other disease parameters, including stage, grade, age, histologic subtype, second-look results, ploidy, and percent S phase., Patients and Methods: We analyzed p53 expression in 284 patients with epithelial ovarian cancer using immunohistochemical techniques in paraffin-embedded specimens. There were 36 patients with stage I disease, 20 with stage II disease, 186 with stage III disease, and 42 with stage IV disease., Results: p53 immunoreactivity was present in 177 cases (62%). p53 expression was associated with grade 3 to 4 disease (P = .003). The following factors were associated with a decrease in overall survival in a univarate analysis: stage III or IV disease (P = .0001), grade 3 or 4 disease (P = .0001), age above the median (P = .0002), and p53 reactivity (P = .04). In a multivariate analysis, stage, grade, and age retained independent prognostic significance. In the subset of 36 stage I patients, p53 positively approached statistical significance (P = .10) as a negative prognostic factor in a univariate analysis., Conclusion: Abnormalities of p53 expression occur commonly in epithelial ovarian cancer. Although associated with decreased survival in a univariate analysis, this biologic marker did not retain independent prognostic significance in a multivariate analysis. p53 expression should be studied in a larger cohort of early-stage patients, where accurate prognostic information is needed to direct therapy.

We determined the proliferative index (PI) of 92 previously untreated advanced epithelial ovarian cancers using PCNA/cyclin immunostaining and image analysis quantitation. In this retrospective study, there was a relationship between tumor PI and 5-year survival. For patients with a tumor PI greater than the median, the estimated 5-year survival was 44%; for patients with a tumor PI below the median, the estimated 5-year survival was 15% (P = 0.003). This may partly reflect sensitivity to chemotherapy, as those patients with more rapidly proliferating tumors were more likely to achieve a pathologic complete response to platinum-based therapy.