MR imaging of uterine sarcomas.

OBJECTIVE: The MR imaging appearances of uterine sarcomas are not well described in the literature. We describe the MR imaging features of uterine sarcomas. MATERIALS AND METHODS: MR images from all patients with histologically proven uterine sarcomas scanned between 1993 and 2000 were reviewed. Tumor size, its relationship to the uterus, signal characteristics, and enhancement pattern after IV injection of gadolinium were noted. RESULTS: Twenty-five scans from 22 patients were reviewed. Findings from the scans included 11 leiomyosarcomas, five mixed müllerian tumors, two rhabdosarcomas, and four endometrial stromal sarcomas. Two patterns of disease were observed, including a characteristic large heterogenous pelvic mass (n = 17) and an endometrial mass indistinguishable from endometrial carcinoma (n = 8). On T2-weighted images, the large masses were characteristically of low or intermediate background signal intensity with pockets of very high T2 signal. The areas of high T2 signal corresponded to cystic necrosis in the tumor. Pockets of high T1-weighted signal corresponded to hemorrhage. Gadolinium enhancement was present in the solid components of all tumors. This pattern was observed in all recurrent sarcomas. Some correlation was shown between the histologic subtypes and the MR imaging appearances. CONCLUSION: Uterine sarcomas show two patterns on MR imaging. The most common presentation is a large heterogenous mass. However, sarcomas can mimic endometrial carcinoma.

Radical trachelectomy in early stage carcinoma of the cervix: outcome as judged by recurrence and fertility rates.

The recurrence and fertility rates in 30 women undergoing radical trachelectomy for early stage invasive cervical cancer at St Bartholomew's and Royal Marsden Hospital were reviewed. There were no recurrences, and the mean follow up was 23 months (range 1-64 months). Of 13 women trying to have a baby, eight had conceived with a total of 14 pregnancies and nine live births. Two were still trying and three were experiencing sub-fertility. There were seven premature deliveries and one late miscarriage. Six of the preterm births and the late miscarriage were associated with prelabour spontaneous rupture of membranes. This conservative yet locally radical procedure for a highly selected group of women who wished to preserve their fertility appears to offer a safe alternative to radical hysterectomy in early invasive cervical cancer.

Molecular quantification and mapping of lymph-node micrometastases in cervical cancer.

BACKGROUND: A proportion of patients with cancer and lymph nodes negative on histology will develop recurrence. Reverse-transcriptase PCR (RT-PCR) is a highly sensitive method for detection of lymph-node micrometastases, but accurate quantitative assessment has been difficult. METHODS: We studied primary tumours and 156 lymph nodes from 32 patients with cervical cancer (stage IA2, IB1, and IB2) and 32 lymph nodes from nine patients with benign disease. A fully quantitative, real-time RT-PCR assay was used to document absolute copy numbers of the epithelial marker cytokeratin 19. Primers and probe were designed not to amplify either of the two cytokeratin 19 pseudogenes. FINDINGS: All primary tumours and histologically involved lymph nodes (six) had more than 106 copies of cytokeratin 19 mRNA per microg total RNA. Expression of cytokeratin 19 (up to 1.1 x 10(5) copies per microg RNA) was detected in 66 (44%) of 150 histologically uninvolved lymph nodes, and in nodes from 16 of 32 patients with cervical cancer. 15 of these 16 patients with evidence of micrometastases had the highest cytokeratin 19 transcription level in a first lymph-node drainage station (three obturator, six internal, and six external iliac node). Transcription of cytokeratin 19 was found at a low level in just one of 32 lymph nodes obtained from nine patients with benign disease. Median copy number of cytokeratin 19 transcription was significantly higher (>10(3) copies) in association with adverse prognostic features. INTERPRETATION: The results suggest that about 50% of early-stage cervical cancers shed tumour cells to the pelvic lymph nodes. The amount of cytokeratin 19 expression was related to clinicopathological features. Further studies are required to document the clinical implications of molecular micrometastases.

Performance of ultrasound as a second line test to serum CA125 in ovarian cancer screening.

OBJECTIVE: To assess the performance of ultrasonography in a multimodal ovarian cancer screening strategy. DESIGN: Prospective ovarian cancer screening trial between December 1986 and June 1993. SETTING: General practice, occupational health departments and an ovarian cancer screening clinic at a London teaching hospital. POPULATION: Postmenopausal women, > or = 45 years with a raised CA125. METHODS: Volunteers with a CA125 > or = 30 U/mL underwent a pelvic ultrasound. Scans were classified as normal, abnormal (ovarian volume > or = 8.8 mL) or equivocal (normal volume with abnormal morphology). Abnormal ovarian morphology was subclassified as simple cyst (single, thin walled cyst with no septa or papillary projections) or complex (all other abnormalities). Volunteers with abnormal scans were referred for a gynaecological opinion. Follow up was via the cancer registry and postal questionnaires. MAIN OUTCOME MEASURES: Sensitivity, specificity and positive predictive value of different ultrasound criteria for detection of index cancer (e.g. primary invasive epithelial carcinoma of the ovary and fallopian tube). RESULTS: Seven hundred and forty-one women underwent 1,219 scans and 20 index cancers occurred during a median follow up of 6 x 8 years. The sensitivity for detection of ovarian cancer of different ultrasound criteria was 100% for abnormal morphology, 89 x 5% for abnormal volume and 84% for complex morphology. The highest specificity (97%) and positive predictive value (37 x 2%) was achieved using complex morphology. CONCLUSION: A variety of ultrasound criteria can achieve high sensitivity, specificity and positive predictive value for index cancers in postmenopausal women with an elevated CA125. Use of ovarian morphology to interpret ultrasound may increase sensitivity and use of complex ovarian morphology may increase the positive predictive value.

Role of MR imaging in the selection of patients with early cervical carcinoma for fertility-preserving surgery: initial experience.

PURPOSE: To assess whether magnetic resonance (MR) imaging can be used for reliable prediction of proximal extension of cervical carcinoma into the myometrium. MATERIALS AND METHODS: Thirty patients with early cervical carcinoma underwent MR imaging with use of a 1.5-T magnet prior to surgery. The MR images were analyzed by two radiologists, unaware of the histopathologic findings, for the relationship of the tumor to the internal os and extension of the tumor into the myometrium. Findings at MR imaging were compared with those at histopathologic examination. RESULTS: At MR imaging, 24 patients were considered not to have tumor extension proximal to the internal os and into the myometrium. All tumors were confirmed histopathologically. In six patients thought to have myometrial tumor invasion at MR imaging, five tumors were confirmed histopathologically; in one, tumor extended up to the internal os but did not involve the myometrium. CONCLUSION: This is a small study, but MR imaging appears accurate in the prediction of myometrial tumor involvement and in showing the relationship of cervical carcinoma to the internal os and, hence, the patient's suitability for trachelectomy.

Ultrasound assessment of ovarian cancer risk in postmenopausal women with CA125 elevation.

We have previously shown that, in asymptomatic post-menopausal women, serum CA125 elevation is associated with a 36-fold increase in risk of ovarian cancer. This study was undertaken to assess the value of pelvic ultrasound for further stratification of ovarian cancer risk. Of 22,000 post-menopausal women, aged > or = 45 participating in an Ovarian Cancer Screening Trial, 741 with a CA125 > or = 30 U ml(-1) underwent pelvic ultrasonography. Twenty index cancers (primary invasive epithelial carcinomas of the ovary and fallopian tube) were diagnosed amongst these 741 women during a median follow-up of 6.8 years. Ultrasound results separated the women with CA125 elevation into two groups. Those with normal ovarian morphology had a cumulative risk (CR) of index cancer of 0.15% (95% confidence interval (CI) 0.02-1.12) which is similar to that of the entire population of 22,000 women (0.22%, 95% CI 0.18-0.30). In contrast, women with abnormal ovarian morphology had a CR of 24% (15-37) and a significantly increased relative risk (RR) of 327 (156-683). Ultrasound can effectively separate post-menopausal women with raised CA125 levels into those with normal scan findings who are not at increased risk of index cancer and those with abnormal findings who are at substantially increased risk of index cancer.

Serum CA125 elevation and risk of clinical detection of cancer in asymptomatic postmenopausal women.

BACKGROUND: This study was undertaken to assess the correlation between CA125 elevation, a past history of cancer, and future risk of a diagnosis of cancer among asymptomatic postmenopausal women. METHODS: The subjects consisted of a study group of 771 women with elevated CA125 (> or =30 U/mL) and a control group of 771 women with CA125 <30 U/mL. They were selected from a prospective ovarian carcinoma screening trial of 22,000 postmenopausal women followed for a mean of 2269 days. RESULTS: Subjects in the study group were more likely to have a past history of cancer than subjects in the control group (odds ratio [OR] 2.31, 95% confidence interval [CI] 1.49-3.58). Much of the difference in cancer risk prior to CA125 testing was attributable to a past history of breast carcinoma (OR 2.53, 95% CI 1.45-4.42), but CA125 elevation did not predict recurrence of breast carcinoma. Subjects in the study group were also more likely to develop cancer in the future (OR 2.53, 95% CI 1.61-3.97). This difference was due to an increased risk of gynecologic cancer (OR 30.09, 95% CI 4.09-221.59). CA125 elevation was not associated with an increase in the future risk of developing breast carcinoma (OR 1.19, 95% CI 0.53-2.66) or nongynecologic cancer (OR 1.43, 95% CI 0.86-2.36). CONCLUSIONS: Elevated CA125 in asymptomatic postmenopausal women is not a predictor of nongynecologic cancer or recurrence of cancer, and further investigation should be limited to the detection of gynecologic cancers.

Increased mortality in postmenopausal women with serum CA125 elevation.

OBJECTIVES: Serum CA125 is used in monitoring treatment and detecting recurrence in ovarian cancer (OC). We have also shown that CA125 can be used with ultrasound for the early detection of OC. However, physiological, benign, and malignant conditions are also associated with CA125 elevation. The aim of the study was to determine the prognostic implications of CA125 elevation in asymptomatic postmenopausal women. METHODS: The study involved 771 volunteers in an OC screening trial of 22,000 women who had elevated serum CA125 levels (>/=30 U/ml). The control group consisted of an equal number of volunteers with normal levels. Survival was analyzed from the first point of CA125 elevation. Univariate analyses utilized the log-rank chi2 test. A logistic model was constructed for the multivariate analyses. RESULTS: The mean duration of follow-up was 1614 days (SD 897 days). Eighty-four women died (elevated CA125 group-62, control group-22). Univariate analyses showed that mortality in the elevated CA125 group was significantly greater (log-rank chi2 = 23.556, P < 0.0001, RR = 2.76), even when preexisting morbid conditions were excluded (log-rank chi2 = 14.644, P = 0.0001, RR = 2.4). Multivariate analysis showed that CA125 elevation, age (>60 years), and a prior history of cancer were associated with a poor prognosis. CONCLUSIONS: Serum CA125 elevation is associated with a significantly increased risk of death from all causes in the next 5 years. These findings may have implications for asymptomatic postmenopausal women with CA125 elevation.

Screening for ovarian cancer: a pilot randomised controlled trial.

BACKGROUND: The value of screening for ovarian cancer is uncertain. We did a pilot randomised trial to assess multimodal screening with sequential CA 125 antigen and ultrasonography. METHODS: Postmenopausal women aged 45 years or older were randomised to a control group (n=10,977) or screened group (n=10,958). Women randomised to screening were offered three annual screens that involved measurement of serum CA 125, pelvic ultrasonography if CA 125 was 30 U/mL or more, and referral for gynaecological opinion if ovarian volume was 8.8 mL or more on ultrasonography. All women were followed up to see whether they developed invasive epithelial cancers of the ovary or fallopian tube (index cancers). FINDINGS: Of 468 women in the screened group with a raised CA 125, 29 were referred for a gynaecological opinion; screening detected an index cancer in six and 23 had false-positive screening results. The positive predictive value was 20.7%. During 7-year follow-up, ten further women with index cancers were identified in the screened group and 20 in the control group. Median survival of women with index cancers in the screened group was 72.9 months and in the control group was 41.8 months (p=0.0112). The number of deaths from an index cancer did not differ significantly between the control and screened groups (18 of 10,977 vs nine of 10,958, relative risk 2.0 [95% CI 0.78-5.13]). INTERPRETATION: These results show that a multimodal approach to ovarian cancer screening in a randomised trial is feasible and justify a larger randomised trial to see whether screening affects mortality.

Ovarian cancer identified through screening with serum markers but not by pelvic imaging.

Woolas RP, Oram DH, Jeyarajah AR, Bast RC Jr, Jacobs IJ. Ovarian cancer identified through screening with serum markers but not by pelvic imaging. This study evaluated the possible role of 3 additional tumor markers to CA 125 among postmenopausal volunteers participating in a sequential multimodal ovarian cancer screening study. In 82 asymptomatic women the finding of a serum CA 125 level of > 30 U/ml precipitated pelvic ultrasound examination. Levels of CA15-3, CA72-4 and CA19-9 were subsequently determined in sera stored from the time of the CA 125 assay. Following ultrasound 29 women underwent surgery for benign conditions. The remaining 53 women underwent 2 years of surveillance. In 5 of these women a diagnosis of ovarian cancer was established between 6 and 10 months after their initial investigation. Elevated levels of at least one of the 3 additional tumor markers were present in the serum, prior to ultrasound abnormalities being detected, in 4 (80%) of the women who developed cancer. At least one of this 3-marker panel was elevated in 29% of the 48 women who have not developed cancer and 14% of the 29 women undergoing surgery for benign conditions. Information complementary to pelvic ultrasound examination for the preclinical detection of ovarian cancer could be obtained through multiple marker assay. Coordinated elevated serum levels of tumor markers could increase the sensitivity of this sequential screening protocol.

Radical trachelectomy: a way to preserve fertility in the treatment of early cervical cancer.

In the Centenary year of Wertheim's hysterectomy for the treatment of invasive cervical cancer, it is appropriate to look at less radical methods of managing early stage disease. Radical trachelectomy with pelvic lymphadenectomy is a conservative but locally radical procedure, preserving the corpus uteri and therefore fertility potential. The first 10 cases in a pilot study are presented. One patient has required post-operative radiotherapy and another a completion radical hysterectomy. Three live births by caesarean section and three other pregnancies have resulted. Careful selection within strict criteria may allow this more conservative approach without compromising cure. These procedures should be carried out in referral centres with continuing follow up and review.

Risk of diagnosis of ovarian cancer after raised serum CA 125 concentration: a prospective cohort study.

OBJECTIVE: To determine the risk of invasive epithelial ovarian cancer and fallopian tube cancer associated with a raised concentration of the tumour marker CA 125 in asymptomatic postmenopausal women. DESIGN: Serum CA 125 concentration was measured annually in study participants for one to four years. Participants with a concentration > or = 30 U/ml were recalled for abdominal ultrasonography. Follow up was by annual postal questionnaire. SETTING: General practice, occupational health departments, ovarian cancer screening unit in a teaching hospital. SUBJECTS: 22,000 volunteers, all postmenopausal women > or = 45 years of age; recruited between 1 June 1986 and 1 May 1990. INTERVENTION: Surgical investigation if the ultrasound examination was abnormal. MAIN OUTCOME MEASURES: Cumulative and relative risk of developing an index cancer (invasive epithelial cancer of the ovary or fallopian tube) after a specified CA 125 result. RESULTS: 49 index cancers developed in the study population during a mean follow up of 6.76 years. The overall cumulative risk of developing an index cancer was 0.0022 for the entire study population and was lower for women with a serum CA 125 concentration < 30 U/ml (cumulative risk 0.0012) but was appreciably increased for women with a concentration > or = 30 U/ml (0.030) and > 100 U/ml (0.149). Compared with the entire study population the relative risk of developing an index cancer within one year and five years was increased 35.9-fold (95% confidence interval 18.3 to 70.4) and 14.3-fold (8.5 to 24.3) respectively after a serum CA 125 concentration > or = 30 U/ml and 204.8-fold (79.0 to 530.7) and 74.5-fold (31.1 to 178.3) respectively after a concentration > or = 100 U/ml. CONCLUSION: CA 125 is a powerful index of risk of ovarian and fallopian tube cancer in asymptomatic postmenopausal women.

Long-term follow-up of gonadotrophin-releasing hormone analog treatment for recurrent endometrial cancer.

To test the antitumor effect of gonadotrophin-releasing hormone (GnRH) analogs, 32 consecutive patients with recurrent endometrial cancer that had progressed through conventional treatments were entered into an open observational trial of treatment with this class of compounds. Patients recruited had progressive, symptomatic, and measurable disease. Treatment was with monthly subcutaneous injections of GnRH analog. Measurements of gonadotrophins, sex hormones, and tumor dimensions were made together with repeat biopsy when possible to assess response to treatment. An objective response was seen in nine patients (28%, 95% CI 13-43%). Responses were seen within the first 2 months of treatment and included pelvic as well as distant sites of recurrence. Significantly greater response rates were seen in previously irradiated sites when compared with nonirradiated sites of recurrence (0.01 > P > 0.001). There was no significant difference between the response in patients with G3 lesions compared with patients with G1/G2 lesions (P > 0.5). Response did not correlate with previous progestogen exposure. No evidence of disease flare or drug toxicity was observed. GnRH analogs have a significant and durable antitumor effect in recurrent endometrial cancer which warrants further examination in comparison with progestogens.

Serum CA 125 in a pregnancy generated by ovum donation.

Serum CA 125 was measured by radioimmunoassay during the first trimester at intervals of 2 weeks in a woman with Turner's syndrome, who conceived following ovum donation from a healthy anonymous donor. Serum CA 125 concentrations were lower than or at the 10th percentile of the normal range. These findings imply that CA 125 may be secreted from the ovary in the first trimester, or produced at another site in response to stimuli from the ovary.

Immunocytochemical and serological expression of CA 125: a clinicopathological study of 40 malignant ovarian epithelial tumours.

Elevated serum levels of the tumour-associated antigen CA 125 occur in more than 80% of cases of ovarian carcinoma. The antigen can be demonstrated in formalin-fixed tissue using the monoclonal antibody OC 125, which localizes it to the surface membrane or cytoplasm. This study was performed to determine the relationship between pre-operative serum levels of CA 125 and the subsequent immunocytochemical findings in the surgical specimen. Paraffin-wax embedded sections from 40 consecutive borderline and frankly malignant ovarian epithelial tumours were stained with OC 125. The pattern and distribution of immunostaining were investigated in relation to histological appearances. Serous tumours showed a 100% correlation between immunocytochemical findings and elevated serum levels of CA 125. Amongst the other histological types, correlation was less good; mucinous tumours and undifferentiated carcinomas showed a poor correlation. Immunostaining within tumours was heterogeneous and only loosely related to morphological appearances. Our finding suggests that, with the exception of serous tumours, immunolocalization of CA 125 is insufficiently sensitive to provide reliable clinical guidance to the likely value of serum CA 125 monitoring on follow-up.

Differential diagnosis of ovarian cancer with tumour markers CA 125, CA 15-3 and TAG 72.3.

OBJECTIVE: To determine the accuracy of tumour associated antigens CA 125, CA 15-3 and TAG 72.3 in the differential diagnosis of benign and malignant pelvic masses and to compare the results with a previously defined risk of malignancy index (RMI). DESIGN: Retrospective analysis of samples collected during a prospective observational study. SETTING: Department of Obstetrics and Gynaecology, the Royal London Hospital and Duke University Medical Center. SUBJECTS: One hundred and forty-three consecutive patients undergoing surgery for an adnexal mass. METHOD: Tumour marker levels were determined by radio-immunoassay in stored serum samples obtained from 143 study subjects. RESULTS: The highest diagnostic accuracy of the tumour marker panel was achieved by defining a positive result as elevation of any two of CA 125 (> 30 u/ml), CA 15-3 (> 30 u/ml) and TAG 72.3 (> 10 u/ml), (sensitivity 66.7%, specificity 93.1%). Similar diagnostic accuracy could be achieved by CA 125 alone using an upper limit of 50 u/ml (sensitivity 66.7%, specificity 94.1%). Inclusion of CA 15-3 or TAG 72.3 in stepwise logistic regression analysis did not improve the discriminative performance of the RMI. CONCLUSION: The risk of malignancy index incorporating CA 125, menopausal status and ultrasound is superior to the panel of three tumour markers for pre-operative differential diagnosis of the pelvic mass.

Elevation of multiple serum markers in patients with stage I ovarian cancer.

BACKGROUND: The high overall mortality from ovarian cancer (> 60%) relates, in part, to delays in diagnosis. When ovarian cancer is detected in stage I (International Federation of Gynecology and Obstetrics staging), up to 90% of patients can be cured. Transvaginal sonography can detect early-stage disease with great sensitivity, but it is expensive and lacks specificity. Although serum marker assays could provide a less expensive and more convenient initial screening test, the sensitivity of assays varies. Measurement of serum CA 125 in conjunction with ultrasound screening as a second-line test confers high specificity but detects only about one half of early stage ovarian carcinomas. PURPOSE: The purpose of this retrospective study was to determine whether assays of multiple serum markers would improve sensitivity by detecting a higher percentage of stage I ovarian cancers than the CA 125 assay alone. METHODS: Using immunoradiometric assays, we measured preoperative serum levels of CA 125 tumor-associated antigen, macrophage colony-stimulating factor (M-CSF), and OVX1 in 46 patients with stage I ovarian cancer of different histologies and 237 patients with benign pelvic masses. We also assayed sera from 204 apparently healthy women who had participated in a screening trial and remained free from cancer at 1 year of followup. All specimens were obtained from cryopreserved aliquots. Marker levels were considered to be elevated when levels of CA 125 were greater than 30 U/mL, M-CSF levels were greater than 3.1 ng/mL, or OVX1 levels were greater than 12.1 U/mL. RESULTS: At least one of the serum markers was elevated in 98% of patients with stage I ovarian cancer; CA 125 levels were elevated in 67%. By the same criteria, 11% of healthy individuals and 51% of patients with benign pelvic masses had at least one elevated marker value. Thus, the sensitivity of the combination of assays for the three serum markers was significantly greater than the sensitivity of the CA 125 assay (P < .0005) and specificity was moderate. CONCLUSION: A panel of these three tumor markers can identify early-stage ovarian cancer with extremely high sensitivity and moderate specificity. IMPLICATIONS: Elevation of one or more serum markers should be evaluated further as an indication for transvaginal sonography in apparently healthy women. Such a strategy might substantially reduce the expense and improve the specificity of screening compared to the use of ultrasound alone. Prospective studies with a large cohort of patients at high risk for ovarian cancer will be required to confirm these findings.