Normal Serum CA-125 Research Articles

Well-differentiated papillary mesothelioma of the peritoneum: A pathological analysis and review of the literature

Background Well-differentiated papillary mesothelioma (WDPM) of the peritoneum is a rare subtype of peritoneal epithelioid mesothelioma which typically has low malignant potential. It most commonly occurs in young women lacking a history of asbestos exposure. Only 38 female patients with peritoneal WPDM have been reported in the literature, and no uniform treatment recommendation has been established. Case report A 74-year-old asymptomatic woman without significant past medical history underwent workup and subsequent surgery for an adnexal mass with a normal serum CA-125 level. Exploratory laparotomy identified an ovarian serous cystadenoma and an incidental multifocal peritoneal neoplasm with extensive calcifications. Histology and cytology confirmed WDPM with extensive, intimately associated mesothelial cystic inclusions and zonal calcifications with osseous metaplasia. Our patient did not receive adjuvant therapy and was without clinical or radiologic evidence of disease 12 months after diagnosis. Conclusion WDPM of the peritoneum in women is frequently asymptomatic and associated with an indolent course. Patient outcomes are usually favorable after tumor-debulking surgery without adjuvant therapy.

Management of Ovarian Cysts with Aspiration and Methotrexate Injection

To evaluate prospectively ultrasonography (US)-guided cyst aspiration and methotrexate injection in the management of simple and endometriotic ovarian cysts in selected patients. Authors obtained informed patient consent and approval from hospital ethics committee. Study included 162 female patients (aged 15-77 years) with simple or endometriotic ovarian cysts (3.0-10.6 cm) at a tertiary hospital. Criteria for inclusion in the study were (a) persistence of the cyst for at least 6 months, (b) benign appearance of the cyst at US, and (c) normal serum CA-125 level measurement before the procedure. Authors performed transabdominal aspiration of the cysts with direct US guidance and injection of methotrexate (30 mg). Cytologic examination was performed in all cases. Follow-up US was performed at 1, 3, and 6 months. If the cyst persisted, the procedure could be repeated. Main outcome measure was resolution or persistence of cysts. chi(2) Test or Mantel-Haentszel chi(2) tests for univariate analysis and multiple logistic regression were used for multivariate statistical analysis. Of 162 patients, 148 were available for follow-up. Malignant cells were not found in any of the cases at cytologic examination. At follow-up US, cysts had disappeared in 124 patients (83.8%) and persisted in 24 (16.2%). Cyst diameter proved to be a significant prognostic factor for cyst resolution (P = .01). No major complications were observed. Patients received neither analgesia nor antibiotics. US-guided transabdominal aspiration of cyst fluid and subsequent methotrexate injection appears to be an alternative treatment for both simple and endometriotic ovarian cysts in selected cases.

Gene expression profiling of epithelial ovarian tumours correlated with malignant potential

BackgroundEpithelial ovarian tumours exhibit a range of malignant potential, presenting distinct clinical phenotypes. Improved knowledge of gene expression changes and functional pathways associated with these clinical phenotypes may lead to new treatment targets, markers for early detection and a better understanding of disease progression.ResultsGene expression profiling (Affymetrix, U95Av2) was carried out on 18 ovarian tumours including benign adenomas, borderline adenocarcinomas of low malignant potential and malignant adenocarcinomas. Clustering the expression profiles of samples from patients not treated with chemotherapy prior to surgery effectively classified 92% of samples into their proper histopathological group. Some cancer samples from patients treated with chemotherapy prior to surgery clustered with the benign adenomas. Chemotherapy patients whose tumours exhibited benign-like expression patterns remained disease free for the duration of this study as indicated by continued normal serum CA-125 levels. Statistical analysis identified 163 differentially expressed genes: 61 genes under-expressed in cancer and 102 genes over-expressed in cancer. Profiling the functional categories of co-ordinately expressed genes within this list revealed significant correlation between increased malignant potential and loss of both IGF binding proteins and cell adhesion molecules. Interestingly, in several instances co-ordinately expressed genes sharing biological function also shared chromosomal location.ConclusionOur findings indicate that gene expression profiling can reliably distinguish between benign and malignant ovarian tumours. Expression profiles of samples from patients pre-treated with chemotherapy may be useful in predicting disease free survival and the likelihood of recurrence. Loss of expression of IGF binding proteins as well as specific cell adhesion molecules may be a significant mechanism of disease progression in ovarian cancer. Expression levels in borderline tumours were intermediate between benign adenomas and malignant adenocarcinomas for a significant portion of the differentially expressed genes, suggesting that borderline tumours are a transitional state between benign and malignant tumours. Finally, genes displaying coordinated changes in gene expression were often genetically linked, suggesting that changes in expression for these genes are the consequence of regional duplications, deletions or epigenetic events.

Clinical implications of a rising serum CA-125 within the normal range in patients with epithelial ovarian cancer: a preliminary investigation☆

Objective The goal of this study was to determine the clinical implications of a progressively rising serum CA-125 level in the normal (< 35 U/ml) range in ovarian cancer patients with complete response to therapy. Methods A multi-institutional investigation was undertaken to identify patients with CA-125-producing epithelial ovarian cancers who experienced progressively rising antigen levels in the normal (<35 U/ml) range after completion of therapy. All patients had (1) histologic documentation of epithelial ovarian cancer and (2) complete clinical remission (CR) as defined by negative imaging studies, normal clinical examination, and a normal (<35 U/ml) serum CA-125 value. All patients had serum CA-125 determinations at 1- to 3-month intervals after treatment. A rising serum CA-125 level was defined as a progressive increase in at least three CA-125 values above the coefficient of variation (CV) for the assay. No patient had a known episode of pelvic or gastrointestinal inflammatory disease during the period when the progressive rise in serum CA-125 took place. Results Eleven patients with rising serum CA-125 levels in the normal range were identified. Original stage of disease was as follows: stage IIA, 1; stage IIIC, 10. Cell type was as follows: endometrioid adenocarcinoma, 4; serous adenocarcinoma, 6; clear cell carcinoma, 1. Of the 11 patients identified, all developed recurrent ovarian cancer. Tumor recurrence was documented either by new lesions appearing on imaging studies (6/11) or by histologic confirmation (5/11). The mean time from CR to recurrence was 21 months (median = 22, range = 12–33). The mean time from the third early rising serum CA 125 value to clinical or radiographic confirmation of recurrence was 189 days (range = 84–518). All recurrences were intraabdominal with the exception of one axillary recurrence. Conclusion In patients with a history of ovarian cancer, three progressively rising serum CA-125 values in the normal range (< 35 U/ml) at 1- to 3-month intervals are associated with a high likelihood of tumor recurrence. Patients with such a pattern should undergo immediate investigation to rule out and/or identify recurrent cancer.

Evaluation of serum CEA and CA19-9 levels as prognostic factors in patients with gastric cancer.

BACKGROUND: This clinicopathological study evaluated the utility of serum carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 as predictors of locoregional recurrence and long-term disease-free survival in patients with gastric cancer.METHODS: During the period January 1989 to December 1994, 485 patients with primary gastric cancer were evaluated. Gastrectomies were performed in 434 patients. Prognostic factors were analyzed by the Kaplan-Meier method and multivariate analysis, using Cox regression.RESULTS: Elevated serum CEA and CA19-9 levels were observed in 92 of the 485 patients (19.0%), and in 95 of the 435 patients (21.8%), respectively, and both markers were elevated in 29 of these 435 patients (6.7%). Elevated serum CEA and CA19-9 levels correlated well with lymph node metastasis, lymphatic invasion, vessel invasion, stage grouping, depth of invasion, and curability. Patients with elevated serum CEA levels were at significantly higher risk of having all recurrence factors than were those with normal serum CEA levels. Patients with elevated serum CA19-9 levels were at significantly higher risk of having peritoneal metastases and distant metastases than were those with normal serum CA19-9 levels. A significant difference in the cumulative survival curves of patients was demonstrated between those with elevated and those with normal serum CEA or CA19-9 levels, even for patients at the same disease stage (stage III). Patients with elevated levels of both markers had a significantly worse prognosis than patients in whom the levels of both markers were normal. In patients who underwent gastrectomy, elevated serum CEA levels either preoperatively or within 3 weeks after gastrectomy were associated with significantly worse prognosis than were normal levels. When the cutoff level of serum CEA was increased to 10 ng/ml, serum CEA, age, lymph node metastasis, and surgical stage grouping were selected as independent prognostic factors by multivariate analysis of 14 prognostic factors, using Cox regression.CONCLUSION: Serum CEA and CA19-9 levels provide additional prognostic information in patients with primary gastric cancer. In particular, an elevated serum CEA level provides additional prognostic information and is a useful indicator of curability in patients who undergo gastrectomy. Serum CEA level is an independent prognostic factor in patients with primary gastric cancer.

Follow Up of Women With Simple Ovarian Cysts Detected by Transvaginal Sonography in the Tokyo Metropolitan Area

From late 1990 through 1991, 10,294 asymptomatic women participated in a screening program for ovarian tumors at the Tokyo Metropolitan Cancer Detection Center. The screening examination included a Papanicolaou test, colposcopy, digital vaginal examination, and transvaginal ultrasonography using a 5.0-MHz transducer with a 100-Hz sump filter to eliminate low-frequency sounds. Women with abnormalities (ovary greater than 2 cm in diameter, ovarian cyst or mass) underwent a second scan 6 weeks later to exclude functional cysts. Apparent simple cysts in premenopausal women (no papillary component, thick septa, or solid tumor) were rescanned every 3 months and watched carefully for any changes in the nature or size of the cyst. Women with other abnormalities underwent further evaluation, including measurement of serum levels of CA-125, CA-199, and carcinoembryonic antigens (CEAs) and in some cases computed tomographic scanning. Results of the screening program are presented in Figure 1. Of the 372 women with abnormal findings, 32 were diagnosed with a uterine fibroid, and 340 were found to have an adnexal mass. Of these patients, 115 had either an ovarian mass larger than 6 cm in diameter or an elevated blood serum CA-125 level and were referred for exploratory surgery. Eight women refused to undergo surgery and were followed up elsewhere. In the remaining 107, two stage Ia mucinous cyst adenocarcinomas, one stage Ic endometrioid adenocarcinoma, and one endometrial carcinoma metastatic to the ovary were found. In addition, three borderline malignancies were diagnosed.Fig. 1: Breakdown of patients with adnexal masses screened by transvaginal ultrasonography (TV-UST).Two hundred twenty-five of the 340 women had an adnexal mass less than 6 cm in diameter with normal blood serum CA-125 levels and were followed up every 3 months for 75 months. One hundred sixty-five (73 percent) of the masses had regressed by the end of the follow-up period, 80 at the first follow-up examination and most (146) within 12 months. None of the cysts recurred. In 31 (41 percent) women, the mass persisted throughout the follow-up period, and in 29 (13 percent), progression of the adnexal mass occurred, most often (21) within 24 months. Three cysts persisted for 5 years before beginning to grow; one of these was found to have enlarged in the 75th month. Of the 29 women with progression, 9 had either rising CA-125 levels, greatly enlarged cysts (>6 cm), or a multiloculated cyst and underwent surgery. Three women were diagnosed with endometriosis, three with mature teratoma, two with cystadenoma (one serous and one mucinous), and one with an endosalpingeal cyst. In women with normal blood serum CA-125 levels and cysts less than 6 cm in diameter at the time of initial diagnosis, the outcome at 75 months was significantly correlated with ultrasound findings (cystic mass vs. solid or mixed mass, P = .01), mass diameter (<4 cm compared with >5 cm, P = .05), blood serum CEA levels (<0.7 vs. >1.0, P = .02), and blood serum CA-199 levels (<7 vs. >20, P = .001). A multivariate analysis of risk factors for tumor growth was conducted for the 140 women with complete information recorded. Blood serum CA-199 and CEA levels at the time of initial diagnosis were found to be significant predictors of tumor regression (P = .004 and P = .02, respectively). A CA-199 level of 20 IU/mL or higher had a relative probability of tumor regression of 0.34. Similarly, a CEA level of 1.0 IU/mL or higher had relative probability of regression of 0.53.

Tumor tissue CA125 in ovarian carcinoma patients with normal serum levels

A good correlation between elevated serum CA125 and its immunolocalization in ovarian tumor tissue has been reported. This study was undertaken in order to assess the presence of CA125 in tumor tissue obtained from ovarian carcinoma patients with normal serum levels. Eleven such ovarian carcinoma patients (nine of them serous) were identified. In seven the level was normal prior to the initial operation, and in four, prior to a positive second-look operation. Immunohistochemical staining of paraffin sections for CA125 was positive in seven of the tumor tissue samples. Tumor tissue of most ovarian carcinoma patients with a preoperative normal serum CA125 contains the antigen, but an undetermined mechanism prevents elevated serum levels.

CA19-9: a possible serum marker for embryonal carcinoma.

We determined whether a carbohydrate antigen in serum, CA19-9, serves as a marker for embryonal carcinoma. Serum CA19-9 was serially measured in 18 male patients with a germ cell tumor. Five of 8 patients with an embryonal carcinoma had an elevated serum CA19-9. The elevated serum CA19-9 returned to normal in parallel to the clinical response to the treatment. Patients with a seminoma had a normal serum CA19-9 irrespective of their tumor size. Paraffin-embedded specimens of germ cell tumors from 9 of the 18 patients and 10 other patients were stained with the monoclonal antibody against CA19-9. These immunohistochemical stainings showed that embryonal carcinomas and mature teratomas were consistently positive and seminomas were often faintly positive for CA19-9, whereas choriocarcinomas, yolk sac tumors and immature teratomas were negative for CA19-9. These results indicate that serum CA19-9 may be a useful serum marker for embryonal carcinomas.

Identification of rhesus macaques with spontaneous endometriosis.

Rhesus macaques (Macaca mulatta) with endometriosis were identified using reproductive histories, serum levels CA-125, pelvic ultrasonography, laparoscopy, and histopathology. All animals were evaluated from a large breeding colony and had a history of infertility and/ or spontaneous abortions. Laparoscopy and ultrasonography were performed on 40 macaques: 27 macaques from the breeding colony with elevated CA-125 levels, ten macaques from the breeding colony with normal or low serum CA-125 levels, and three macaques from another facility with previously diagnosed spontaneous endometriosis. Clinical endometriosis was diagnosed by laparoscopy in 16/37 (43%) macaques from the breeding colony and was confirmed by histologic examination in all animals biopsied. The disease was classified as minimal (40%), mild (25%), moderate (10%), or severe (25%). The most common sites of endometriosis were the serosal surface of the uterus (75%) and the posterior cul-de-sac (75%). In this study, CA-125 levels were useful in identifying animals from the breeding colony with endometriosis. The rhesus macaque provides a valuable animal model to study endometriosis and potentially to assess efficacy of therapeutic agents for this disease condition.

Plasma D‐dimer and peritoneal CA‐125 levels as predictors of disease status in ovarian carcinoma

Although serum CA-125 has improved our ability to monitor tumor response in ovarian carcinoma, approximately 50% of patients with normalization of CA-125 have persistent disease at second look laparotomy. Peritoneal CA-125 and plasma D-Dimer levels were studied to determine if their use could increase the sensitivity for persistent ovarian carcinoma in a population of patients with normal physical examinations, radiologic studies, and serum CA-125 values. Plasma D-Dimer levels were obtained prior to second look laparotomy. The results of peritoneal CA-125 and plasma D-Dimer studies were compared to second look laparotomy results. Differences were evaluated with a one-way analysis of variance. Twenty-seven patients were studied. Peritoneal CA-125 was evaluated in 23 patients and ranged from < 6.3-223 U/ml. There was no statistical difference in peritoneal CA-125 levels between patients whose second look laparotomies were negative, or microscopically or macroscopically positive. D-Dimer was elevated in three patients, all of whom had macroscopically positive second look findings. The sensitivity for positive second look findings was only 27%. Minimally elevated plasma D-Dimer levels were specific but not sensitive for persistent disease and peritoneal CA-125 was not predictive of disease status.

Ovarian Cancer Screening in Asymptomatic Postmenopausal Women

From 1987 to 1992, 3220 asymptomatic postmenopausal women underwent screening with transvaginal sonography (TVS) as part of the University of Kentucky Ovarian Cancer Screening Project. Ovarian volume was calculated using the prolate ellipsoid formula (length x height x width x 0.523). An abnormal sonogram was defined by (1) an ovarian volume > 10cm3 or (2) a papillary projection into a cystic ovarian tumor. All women with an abnormal TVS had a repeat sonogram in 4-6 weeks. If the repeat sonogram was abnormal, a morphology index score was assigned to each tumor, and a serum CA-125 was obtained. The patient then had a pelvic examination and an exploratory laparotomy. Forty-four patients (1.4%) with a persisting abnormality on TVS underwent exploratory laparotomy. Twenty-one patients had serous cystadenomas and 3 had primary ovarian cancers. Two patients with primary ovarian cancer had Stage IA disease and one had Stage IIIB disease. All patients with ovarian cancer had normal pelvic examinations and normal serum CA-125 levels, and are presently alive and well 32, 31, and 8 months after conventional therapy. Over 5000 screening years have been accumulated at this institution, and there have been no ovarian cancer deaths in the screened population. TVS screening has produced a decrease in stage at detection and case-specific mortality from ovarian cancer. A multi-institutional trial to test the efficacy of TVS as a screening method for ovarian cancer is indicated.

What Is a Normal CA125 Level?

CA125 is a coelomic epithelial antigen which is widely used to monitor residual disease in patients undergoing chemotherapy for ovarian cancer. Interpretation of serum CA125 levels has been based on a normal value of 35 U/ml which was derived by screening a young, general population of blood donors which included women with intact reproductive systems. This study addresses the issue of what constitutes a normal serum CA125 level following successful surgical therapy for gynecologic malignancy. Three hundred ninety-three CA125 values were measured in 145 patients after an elapsed time of at least 1 year following completion of surgical therapy for early-stage endometrial or cervical adenocarcinoma. All patients were without evidence of recurrent disease. The mean duration of follow-up was 4.3 years with a median of 3.7 years. Sixty-seven percent of the CA125 values were less than 10 U/ml; 95% were less than or equal to 20 U/ml. The median value for this patient population was 7.5 U/ml with a mode of 7.1 U/ml. There was no correlation between patient age and CA125 levels. These data suggest that the normal value for CA125 used for patient follow-up after treatment for gynecologic adenocarcinoma needs to be redefined. Our data support an upper limit of normal of 20 U/ml and encourage further study on the clinical impact of this new definition.

Ovarian Cancer Screening in Asymptomatic Postmenopausal Women

From 1987 to 1992, 3220 asymptomatic postmenopausal women underwent screening with transvaginal sonography (TVS) as part of the University of Kentucky Ovarian Cancer Screening Project. Ovarian volume was calculated using the prolate ellipsoid formula (length × height × width × 0.523). An abnormal sonogram was defined by (1) an ovarian volume >10cm 3 or (2) a papillary projection into a cystic ovarian tumor. All women with an abnormal TVS had a repeat sonogram in 4-6 weeks. If the repeat sonogram was abnormal, a morphology index score was assigned to each tumor, and a serum CA-125 was obtained. The patient then had a pelvic examination and an exploratory laparotomy. Forty-four patients (1.4%) with a persisting abnormality on TVS underwent exploratory laparotomy. Twenty-one patients had serous cystadenomas and 3 had primary ovarian cancers. Two patients with primary ovarian cancer had Stage IA disease and one had Stage IIIB disease. All patients with ovarian cancer had normal pelvic examinations and normal serum CA-125 levels, and are presently alive and well 32, 31, and 8 months after conventional therapy. Over 5000 screening years have been accumulated at this institution, and there have been no ovarian cancer deaths in the screened population. TVS screening has produced a decrease in stage at detection and case-specific mortality from ovarian cancer. A multi-institutional trial to test the efficacy of TVS as a screening method for ovarian cancer is indicated.

Serum CA125 regression in epithelial ovarian cancer: Correlation with reassessment findings and survival

Findings at reassessment laparotomy and disease-free survival are reported for a group of patients with advanced-stage epithelial ovarian cancer who have had a complete clinical response to cytoreductive surgery and multiagent platinum-based chemotherapy. The predictive value of the number of chemotherapy cycles to achieve a serum CA125 of <35 U/ml is compared to the predictive value of s, the rate of achieving a normal serum CA125. s is generated from an exponential regression model. This study suggests that s accurately predicts which patients have residual disease at reassessment laparotomy, who will be free of disease, and, of those in the latter group, who are at greatest risk to recur, as well as overall survival. If these observations are confirmed, physicians may base further therapeutic intervention on the basis of a calculated parameter following complete clinical response to first-line treatment rather than relying on findings at reassessment laparotomy.

Ovarian cancer screening in asymptomatic postmenopausal women by transvaginal sonography

From November 1987 to January 1991, 1300 postmenopausal women underwent screening with transvaginal sonography (TVS). Women eligible for screening were all asymptomatic with no known ovarian tumors. Ovarian volume was calculated using the prolate ellipsoid formula, and a value in excess of 8.0 cm3 was considered abnormal. Ovarian abnormalities were detected in 33 women (2.5%), and 27 underwent exploratory laparotomy. Ovarian tumors were noted in all 27 patients, including 2 primary carcinomas and 14 serous cystadenomas. The two women with ovarian carcinomas had normal results of pelvic examinations and normal serum CA-125 levels. Both women had Stage I disease, and are alive and well after conventional therapy. TVS was time efficient, easy to perform, and well-accepted by patients. Currently, there are more than 3000 patient years of follow-up in the screened population, and there have been no deaths due to ovarian cancer. A multi-institutional trial to determine the efficacy of TVS as a screening method for ovarian cancer is indicated.

Does serum CA-125 level prior to second-look laparotomy for invasive ovarian adenocarcinoma predict size of residual disease?

The records of 125 patients with nonmucinous invasive ovarian adenocarcinoma who underwent cytoreductive surgery, cisplatinbased combination chemotherapy, and second-look laparotomy were analyzed to correlate pre-second-look serum CA-125 levels with the size of residual ovarian cancer. The majority of patients with negative second-look laparotomy had normal serum CA-125 levels ( 46 50 or 92%). Of the 75 patients with positive secondlook, 56 (75%) had normal CA-125 levels preoperatively. Twentythree of twenty-four (96%) patients with residual disease less than or equal to 1 cm had normal CA-125 levels as did 20 of 28 (71%) patients with disease 1.1–2.0 cm. Although elevated serum CA-125 levels were invariably associated with visible/gross disease and increasing size of residual disease tended to be associated with increasing elevations of CA-125, normal CA-125 levels often occurred in the presence of large-volume (>2 cm) disease ( 13 23 , 57% of patients). The considerable overlap of serum CA-125 levels for all sizes of residual disease precluded precise prediction of residual disease size based on serum CA-125 level alone.

Does serum CA-125 level prior to second-look laparotomy for invasive ovarian adenocarcinoma predict size of residual disease?

The records of 125 patients with nonmucinous invasive ovarian adenocarcinoma who underwent cytoreductive surgery, cisplatin-based combination chemotherapy, and second-look laparotomy were analyzed to correlate pre-second-look serum CA-125 levels with the size of residual ovarian cancer. The majority of patients with negative second-look laparotomy had normal serum CA-125 levels ( 46 50 or 92%). Of the 75 patients with positive second-look, 56 (75%) had normal CA-125 levels preoperatively. Twenty-three of twenty-four (96%) patients with residual disease less than or equal to 1 cm had normal CA-125 levels as did 20 of 28 (71%) patients with disease 1.1–2.0 cm. Although elevated serum CA-125 levels were invariably associated with visible/gross disease and increasing size of residual disease tended to be associated with increasing elevations of CA-125, normal CA-125 levels often occurred in the presence of large-volume (>2 cm) disease ( 13 23 , 57%). The considerable overlap of serum CA-125 levels for all sizes of residual disease precluded precise prediction of residual disease size based on serum CA-125 level alone.

Immunoscintigraphy of ovarian endometriosis. A preliminary study.

CA-125 is a membrane antigen detected in the serum of some women with gynaecological disease including endometriosis. We attempted to use a radioiodinated anti-CA-125 monoclonal antibody, OC-125, to image ovarian endometriosis using immunoscintigraphy. Two women with significant endometriosis and normal serum CA-125 levels had positive immunoscintigraphy. In one woman, all areas of endometriosis were imaged; in the other, endometriosis in one affected ovary was seen, but uptake in the other ovary was less than the extent of the disease.