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Uterine tumour resembling ovarian sex cord tumour (UTROSCT) are a histological variant of endometrial stromal sarcomas (ESS). There is no established medical management of metastatic UTROSCT or ESS, although there is evidence supporting the use of hormonal therapy. Given the success of aromatase inhibitors in breast cancer, their potential role in ESS and UTROSCT is of current interest. We report the first case of response to second-line, single agent anastrazole in a patient with metastatic UTROSCT.

The expression of Fas and FasL was studied in 86 patients with benign, borderline, and malignant serous ovarian lesions. Four normal ovaries, and monolayer epithelial cultures from a human fetal ovary, a borderline, and a serous adenocarcinoma were used for comparison. Expression of Fas and FasL was studied immunohistochemically and flowcytometrically. Fas was expressed in all 90 lesions; FasL in 57 lesions, including 2 normal ovaries. Fas expression was significantly increased in borderline tumors compared with benign (P = 0.005, t = -2.94) or malignant serous tumors (P = 0.0001, t = 4.15). FasL expression was significantly increased in malignant tumors compared with benign (P = 0.039, t = -2.10) and borderline tumors (P = 0.0016, t = -3.33). Flow cytometry showed a range of Fas expression in short-term cultures isolated from normal, borderline, and malignant ovarian serous tissue; in the few samples studied, FasL was not expressed. Expression in three serous ovarian cell lines was similar. Fas and FasL expression differed throughout the spectrum of ovarian lesions. FasL expression was increased in malignant tumors, and Fas expression was increased in borderline tumors. Changes in Fas/FasL expression in ovarian surface epithelium might play a functional role in the biology of ovarian tumors., (Copyright 2003, Elsevier Science (USA). All rights reserved.)

Of 369 patients with apparent advanced ovarian cancer entered on a randomized trial between September 1979 and June 1983, 56 survived more than 5 years. Central pathology review confirmed the diagnosis in 318 cases (15 cases not ovarian primary, 36 slides did not reach central review). Two hundred ninety-eight were invasive cancer and 34 of these (11.4%) patients were alive at 5 years. The remaining 20 cases were tumors of low malignant potential and 17 (85%) were alive at 5 years. The clinical, pathological, and treatment characteristics of these long-term survivors has been ascertained. No significant difference in survival has emerged between the two treatment arms being compared--combination chlorambucil and cisplatin versus sequential chlorambucil followed by cisplatin on treatment failure. Of 298 cases of invasive cancer there were 133 with residuum less than 2 cm after initial surgery and 20 of these (15%) survived 5 years compared with 14/165 (8.5%) of those with more tumor residuum. Clinical response was a poor indicator of survival. Only 7 of 46 (15%) patients with complete clinical response survived 5 years; however, of 44 patients with complete surgical response, 29 (65.9%) were alive at 5 years. These results highlight the improved survival prospects of women with low-potential malignancy, even in advanced stage, compared to those with invasive tumors and make a strong case for central pathology review of all cases of apparent ovarian cancer entered on randomized trials.

With the use of a short-term tissue culture method, 27 solid ovarian tumor specimens (from 22 patients) were successfully karyotyped. The majority of the specimens were from serous carcinoma (18 specimens, 2 of which were not invasive). Adenocarcinomas (two specimens), two endometrioid carcinomas, and one each of clear cell, mucinous, sarcoma, squamous carcinoma, and an unclassified sex cord carcinoma were also analyzed. The specimens showed marked cytogenetic heterogeneity, ranging from a normal karyotype (46,XX) to very grossly aneuploid, with multiple rearrangements. All chromosomes, excepting 13, 15, 19, 20, and 21 were positively identified in at least one rearrangement. Chromosomes 1, 6, and 7 were most commonly involved. Identified rearrangements were not limited to one carcinoma type. The most common deletions of 1p and 6q were identified in both serous carcinoma and adenocarcinoma. Deletion of 7q,(del(7)(q32)), was observed only in serous carcinoma but was limited to three patients. Correlations of modal chromosome count and number of marker chromosomes appeared to be associated with good prognosis for patients with serous carcinoma.

Cytogenetic analyses of solid tumors are hampered both by the difficulties in preparing high-quality banded metaphases and the high degree of karyotypic heterogeneity. Three specimens were obtained from a single patient with serous carcinoma for karyotyping and compared to determine whether the tumor was multifocal or metastatic. All three specimens were hypodiploid, sharing marker chromosomes, thus indicating metastasis. To simplify comparison between the specimens, a diagram of the inferred cytogenetic evolution of the cells analysed was developed. This method afforded a simple means of comparing the different tumor sites in a single patient and might also be applied to sequential samples from patients.

Cytogenetic studies of human solid tumor tissue are hampered by poor quality preparations. Using a method of short-term tissue culture developed for ovarian carcinoma specimens, we have obtained large numbers of high quality metaphases suitable for analysis from 19 of 28 ovarian tumors studied.

Magnetic resonance spectroscopy (MRS) can identify abnormal lipoproteins in the plasma of patients with premalignant and malignant tumours. Proteolipid complexes, 8-11 nm and 25-28 nm in size, were isolated from the plasma of a patient with a borderline ovarian tumour. These complexes, which generated a characteristically long MRS T2 relaxation value (greater than 400 ms), were disrupted by ribonuclease. None of the conventional lipoproteins had a T2 value above 160 ms. Chemical analysis of the proteolipid complexes showed a 20% glycolipid component, and MRS identified a fucosylated molecule as the origin of the long T2 value. 9 months after resection of all tumour, a visible lipoprotein band, possibly lipoprotein (a), persisted in the plasma but neither the long T2 relaxation value nor the 8-11 nm or 25-28 nm particles were present. The long T2 relaxation value in the MRS profile, found in isolated proteolipid and unfractionated plasma and serum of other patients with carcinoma of the ovary and colon, provides a non-invasive method of assaying for cancer.

The proportion of proliferating tumour cells in a tumour ('growth fraction') was estimated in 30 patients with primary ovarian carcinoma, using monoclonal antibody Ki-67 which reacts with a nuclear antigen present only in proliferating cells. A positive correlation between the 'growth fraction' and both the clinical stage and histological grade of the tumours was observed. A high 'growth fraction' was observed in advanced, metastatic and poorly differentiated tumours and a low 'growth fraction' with early stage, well-differentiated tumours. This information which has not been available previously to clinicians may be of practical value for determining the prognosis, and influencing treatment recommendation.

Flow cytometric analysis of cellular DNA content was performed on tissue from 44 borderline ovarian tumours (tumours of low malignant potential). Forty-two tumours (95%) were diploid and associated with both an indolent biological behaviour and good prognosis. Aneuploidy was identified in only 2 tumours (5%), and one of the associated patients died of progressive disease within months of the initial diagnosis. Careful review of the histopathology of these 2 aneuploid tumours revealed areas of invasion in the omental and peritoneal "implants" of each. This study has reinforced the currently advocated separation of so-called borderline tumours from invasive ovarian carcinomas and the interpretation of the pathological criteria used to categorize such neoplasms. Our results indicate that flow cytometric analysis of cellular DNA content may complement conventional histopathological diagnosis by providing an objective parameter which correlates with biological behaviour and may identify the few genuine borderline ovarian epithelial neoplasms which show clinical progression.

Six cell lines, established from four primary ovarian carcinomas were examined cytogenetically. The lines varied greatly in their chromosome complement. All cells from the lines were aneuploid, although one cell line contained two populations having a pseudodiploid and a pseudotetraploid modal chromosome number. Every chromosome group was involved with loss and gain of chromosomes, but some individual chromosomes were more prone to aneuploidy than others. Chromosome #6 was the most stable throughout. Structural changes gave rise to many marker chromosomes. Although most markers were random and the majority unidentifiable, some abnormalities of clonal origin were found. Deletions especially of chromosome #1, were the most common change. Further sequential studies may elicit the origin, stability, and timing of the chromosome abnormalities.

A review of 128 cases of "primary" ovarian müllerian carcinoma treated at the King George V Memorial Hospital was undertaken to determine the relative frequency with which such tumors were associated with evidence of multifocal primary neoplasia. Of the 128 cases studied, 115 were invasive carcinomas and 13 were noninvasive or borderline ovarian tumors ("tumors of low malignant potential"). Eight of 10 borderline serous ovarian tumors (80%) and 37 of 75 invasive serous carcinomas (49%) exhibited evidence of independent primary neoplasia at more than one anatomical site in the biopsy material available for review. Many of these cases represented bilateral primary ovarian tumors, but autochthonous extraovarian neoplasia was also commonly encountered. A single borderline endometrioid ovarian tumor and six of 15 endometrioid carcinomas (40%) were associated with biopsy-proven multifocal primary tumorigenesis. These were predominantly neoplasms in one or both ovaries plus adenocarcinoma in the uterine corpus. Other histological types of malignant common epithelial tumors of the ovaries did not demonstrate any such tendency, highlighting major differences in pathogenesis between members of this loosely associated group of ovarian cancers. Our study suggests that gynecological endometrioid and serous malignancies are commonly multifocal and we feel this has significant implications for the way these neoplasms are staged and therefore treated.

Human ovarian cancers of four different histological types have been cultured in vitro and in nude mice. Nineteen tumor specimens (11 solid tumors and eight malignant effusions) were obtained from 14 patients. Tumor lines from ten of these patients were established after several subpassages, and six xenograft lines have been grown, all of them from tumors of which a cell line exists in vitro. In all, 14 lines have been successfully cultured from the 19 tumor specimens. The morphology (studied by light and electron microscopy) of the established lines in vitro and in vivo resembles that of the original tumors in all cases. Flow cytometric studies of DNA content of the original tumor specimens and the cell culture and xenograft lines were performed. In all lines in both culture systems, aneuploid cells became predominant after the first to fourth passages, despite an aneuploid peak having been evident in only nine of the 19 initial specimens. Four of the original tumor specimens contained measurable estrogen receptors and five progesterone receptors, but none of the established cell lines expressed these hormone receptors. These results indicate that, while morphological features are similar in the initial tumor specimens and in the established lines in vitro and in vivo, flow cytometric and steroid hormone receptor data suggest selection of aneuploid and receptor-negative cells.

Detailed flow cytometric analysis of cellular DNA content was performed on neoplastic tissue from 33 patients with malignant common epithelial ovarian tumours in order to investigate the intratumoral stability of ploidy and proliferative fraction. There was a remarkable stability, both spatial and temporal, in the DNA pattern for any particular tumour. Of 24 tumours that were analysed in multiple areas tumour ploidy was found to be a stable marker in all but 3 cases where regional variations were evident. In 9 patients serial analyses were performed on tumour obtained either at initial diagnosis (6 patients) or second look laparotomy (3 patients) and then some time later (7-17 months) at relapse or death and in all cases the tumour ploidy remained unchanged. In addition, 10 ovarian carcinomas established in nude mice have maintained a DNA content during serial passage similar to that of the original implanted tumour. In contrast in 50% of tumours that were evaluable for S-phase analysis we demonstrated a considerable intratumoral variability in the S-phase fraction. We conclude that cellular DNA content is a stable feature of ovarian carcinoma while S-phase fraction is commonly subject to intratumoral variation.

Tumor cellular DNA content was measured by flow cytometry in 91 patients with advanced ovarian cancer, using a new and simple technique which allows archival paraffin-embedded tissue to be studied; 69% of the tumors were aneuploid, and 31% were diploid. Tumor ploidy was shown by multivariate Cox model analysis to be an independent prognostic variable and the major determinant of survival. Patients with diploid tumors survived significantly longer than did those with aneuploid tumors (p much less than 0.0001; X2 = 25.44; d.f. = 1).

The cellular DNA content of 50 ovarian common epithelial carcinomas was determined by flow cytometry, and tumours were classified as being either diploid or aneuploid. A significant association between tumour stage and ploidy was demonstrated, with all diploid tumours being of an early stage (p less than 0.001). Forty percent of early-stage tumours (FIGO stages I and II) and all late-stage tumours (FIGO stages III and IV) were aneuploid. This heterogeneity with respect to DNA content among tumours of a similar stage may allow the identification of neoplasms with a different natural history. The proportion of S-phase cells determined by flow cytometry is a measure of cellular proliferation and may also be of prognostic significance. Diploid tumours had a median S phase of 9.8% (2.4-14.1%), while aneuploid tumours had a significantly higher S phase of 19.6% (7-24.7%; p less than 0.05). In this study there was no relationship between histological grading of invasive carcinomas and ploidy, but in view of the relatively small numbers and limited follow-up, it was not possible to perform a multivariate analysis of all known prognostic factors in ovarian cancer. Our results suggest that ploidy reflects tumour behaviour, but prolonged follow-up and increased patient accrual is necessary to assess whether the flow cytometric analysis of DNA content will provide clinically important information in ovarian cancer.

Thirty-seven patients with advanced ovarian cancer were treated in a prospective, randomised trial comparing chlorambucil with a combination of cyclophosphamide and cis-diamminedichloroplatinum (cis DDP). Treatment with the combination was associated with an increased overall response rate (69% versus 23%) (p = 0.04). A response was associated with a longer median survival but no survival advantage was demonstrated for patients who received cyclophosphamide/cis DDP. A larger study is needed to evaluate fully the potential of regimens containing cis DDP in the management of advanced ovarian cancer.

In a consecutive series of 163 patients referred with malignant ovarian tumours there were 24 (14.7%) who developed major bowel complications; 21 patients were operated upon for bowel obstruction and had a mean survival time of 8.1 months; 8 of the 24 patients are alive with cancer and 4 are alive without evidence of residual tumour. It is concluded that laparotomy is indicated when bowel complications occur in patients with ovarian carcinoma.

Twenty-seven patients with advanced ovarian cancer were treated with a total of 80 courses of cis-dichlorodiammine platinum (II) (cisplatin). The doses in three courses were less than 50 mg/m2, in 64 courses they were 50 mg/m2, and in eight courses they were 100 mg/m2. In addition, five courses of low-dose daily treatment (20 mg/m2 for five days) were administered. Twelve patients received cisplatin alone, 12 received cisplatin and cyclophosphamide (750 mg/m2), and three patients received cisplatin with other drugs. There were eight responders (33%) in the 24 evaluable patients. Renal toxicity occurred in four patients, ototoxicity in four, and leucopenia (which was life-threatening in one patient) occurred in 16 patients (white cell count less than 3.0 X 10(9)/L). There were two early drug-related deaths. The median survival of patients who responded to cisplatin treatment was longer than 30 weeks compared with nine weeks for non-responders.

Thirty-five patients with advanced epithelial ovarian carcinoma (24 untreated, 11 previously treated with alkylating agents) were treated with a combination of cisplatin and etoposide (VP16-213). Tumor response (i.e., complete response and partial response) was seen in 16 of the 35 patients (i.e., 46%), with 5 complete responses. The response rate in previously untreated patients was 54%, but only 27% in previously treated patients. The median survival was 42 weeks. The toxicity of this regimen was severe. Twelve patients became severely myelosuppressed, including one septic death while severely neutropenic. Treatment with cisplatin and etoposide produces only average tumor response rates and patient survival, but is associated with severe toxicity. There is no evidence of synergy between cisplatin and VP16 in this study.

Malignant tumours yield a high-resolution proton magnetic resonance (MR) spectrum. Fifty-one tumour biopsy specimens from patients with cancer of the ovary or colon were examined by magnetic resonance spectroscopy (MRS) to determine whether it was possible to identify tumour subtypes with metastatic potential. Relaxation parameters (T2) for visible lipid methylene protons were within the range of those measured for three animal metastasis models. Primary carcinomas with metastases gave T2 values greater than 350 ms, whereas carcinomas not associated with known metastases at the time of tumour excision gave a range of values from 150 to 1500 ms. All but two carcinomas gave a long T2 (greater than 350 ms) indicating metastatic potential. The MRS method designated five of six histologically borderline epithelial ovarian tumours as malignant with metastatic potential. MRS may be sensitive enough to detect malignant cells in a tumour which is of intermediate or borderline malignancy by light microscopy. Malignancy without a potential for metastasis is uncommon.

Cytogenetic studies of fresh solid tumours are hampered by the small numbers of poor quality metaphases which are obtained through direct preparations. The proportion of cycling cells in freshly excised tumours have been identified by measuring the incorporation of the nucleoside analogue 5-bromo-2'deoxyuridine (BrUdR) into DNA. We have developed an immunochemical method using a mouse monoclonal antibody directed against BrUdR which stains nuclei of cells which have incorporated this nucleoside. Using this method, optimal culture conditions and harvest times may be identified, to provide greater numbers of high quality metaphases, suitable for karyotyping solid tumours.

Human epithelial ovarian tumours were successfully established as xenografts in nude mice in 54% of cases. An evaluation of the biological characteristics of tumours propagated in nude mice was carried out and the functions investigated included morphology, growth kinetics, cellular DNA content, cell surface antigen expression and sensitivity to chemotherapy. To allow a more detailed study of the influence of ploidy on biological behaviour, xenografted tumour with varying degrees of aneuploidy and tumours with a common ancestry but different ploidies were also established. Although this is a highly selective model system favouring the growth of biologically aggressive tumours the xenografts, in general, reflect many of the characteristics of the tumours from which they were derived and are likely to provide a useful model for investigating the biology of ovarian cancer.

We have analyzed the patterns of disease progression in patients with advanced breast and ovarian cancer receiving systemic therapy. Approximately 50% of patients developed progressive disease in a new, rather than a previously documented, disease site. Even when disease progressed in a previously involved disease site, in only half the cases was this identified as the bulk disease site before commencing treatment. The CNS was rarely a new site of disease progression in our patients, a finding that contrasts with a report that identified the CNS as the predominant new disease site in advanced breast cancer patients relapsing following a complete response. Progression of disease on second line treatment commonly occurred at sites of known disease. A number of factors influencing the pattern of disease progression have been examined. Disease progression on endocrine therapy tended to be more common in a previously involved disease site than in patients receiving cytotoxic therapy. There was a trend for patients who progressed within 6 months of chemotherapy to do so in an old site, whereas new disease sites predominated among those progressing later. Strategies for overcoming the causes of treatment failure should take account of the patterns of disease progression. Our results question the wisdom of always ceasing existing therapy when progressive disease is first documented.

Seventeen patients with advanced ovarian adenocarcinoma recurring or progressing after prior treatment with chlorambucil and cis-platinum were treated with cyclophosphamide, adriamycin, and cis-platinum (CAP) every 3 weeks. In seven patients there was objective tumor response (41%) with a median response duration of 7.6 months and a survival advantage over nonresponders. Patients whose tumors had previously responded to chlorambucil or cis-platinum were less likely to respond to CAP than those who had not responded. Myelosuppression was the main toxicity, febrile neutropenia occurring after 8% of treatments.

Twenty patients with ovarian cancer, who following reexploration were left with residual disease nodules of less than 2 cm diameter, received abdominopelvic irradiation. Of these patients 18 had previous chemotherapy. Fifteen patients completed treatment, 13 of whom had prior chemotherapy. Six of the 18 patients with invasive tumors were alive and disease free 18-53 months postradiotherapy, while only 4 patients had died at the time of follow-up. No patient with residual nodules greater than 1 cm remained disease free. There was no difference in outcome between patients with microscopic or macroscopic less than 1 cm residuum. Complications were acceptable with 3/20 (15%) developing treatment-related intestinal obstruction.