Tumour-associated antigen CA 125 in patients with ovarian cancer

The serum levels of antigen CA 125 expressed by epithelial ovarian carcinoma were measured in 27 postmenopausal women with ovarian tumours and in 16 controls. Increased serum levels of CA 125 were found in nine (75%) out of 12 patients with ovarian cancer; in three with stage I disease levels were not elevated. No significant difference was found in the concentration of CA 125 detected in peripheral or ovarian venous blood. Decreased antigen levels were found 6-30 weeks after radical operation and cytostatic chemotherapy in the ovarian cancer group. The results indicate the value of measuring CA 125 as a tumour marker in the follow-up of ovarian cancer.     

CA125 expression at clinical diagnosis by ovarian carcinoma not detected through antecedent serum CA125 screening

At the time of clinical presentation with ovarian carcinoma, 85% of women have an elevated serum level of the CA125 antigen, but the duration of the preclinical phase of expression of CA125 is unknown. From the database of The Royal London Hospital ovarian cancer screening project, 19 women were identified who had a serum CA125 level <30 IU ml⁻¹, measured between 2 and 24 months prior to their clinical diagnosis of ovarian cancer. Histological sections of tumor removed from these women were reviewed. In 17 cases tumor tissue was immunocytochemically stained for CA125 expression. Tumor blocks of 40 women presenting clinically with ovarian cancer with known preoperative CA125 levels were also stained for CA125 expression. The serum CA125 level at the time of diagnosis was available in six of the 19 screening study cases, four of which had levels> 30 IU ml⁻¹. In five of the 13 cases with unknown serum CA125 levels, ovarian tumor tissue expressed CA125. Among the 40 controls, 24 tumors expressed CA125 and all 24 had a serum level greater than 47 IU ml⁻¹. An annual screening test using serum levels of CA125 at a cut-off of 30 IU ml⁻¹, cannot detect all cases of ovarian cancer that express the antigen at the time of clinical diagnosis. The development of a panel of complementary tumor markers will be necessary to provide a test with a higher sensitivity for the detection of preclinical ovarian cancer.     

Analysis of CA 125 assay system and its diagnostic significance in gynecologic tumors

CA125 antigen levels were measured in patients with ovarian cancer (54 cases) by the RIA method using a monoclonal antibody OC125 and were examined as a marker for ovarian cancer. The upper normal limit of CA125 of 35 U/ml was derived from the mean value (15.7 U/ml)+2SD (9.3 U/ml) of CA125 in healthy controls. The mean value for CA125 in patients with ovarian cancer (1160 +/- 1850 U/ml) was statistically (p less than 0.001) higher than those of healthy controls, benign ovarian tumors (28 +/- 20 U/ml) and cervical cancers (226 +/- 526 U/ml). Elevated CA125 levels were also found in the early pregnant stage and endometriosis, but these cases showed not so high CA125 values as those of ovarian cancers. In addition, CA125 levels were not clearly affected by the menstrual cycle. Among ovarian malignancies, the elevated CA125 values were specifically demonstrated in serous cystadenocarcinoma (positivity 89%) and markedly low in mucinous cystadenocarcinoma (positivity 16%). No positive correlation of CA125 values with the clinical stage (FIGO) were found in any ovarian cancer patients. The rise and fall of CA125 levels corresponded closely with progression and regression of cancer patients with positive CA125 levels. In conclusion, serum CA125 determinations may be useful in patients with ovarian cancer (except for mucinous type) for diagnosis and for monitoring the results of the treatment.     

Clinical usefulness of serum sialyl SSEA-1 antigen levels in patients with epithelial ovarian cancer. Comparative effectiveness of sialyl SSEA-1 and CA 125

The serum levels of sialyl SSEA-1 antigen, a type 2 chain carbohydrate antigen detected using the monoclonal antibody FH-6, were elevated in 47.2% of patients with epithelial ovarian cancer, with the percent positivity increasing with the clinical stage. Of the histological type, it is interesting to note the relatively high sensitivity in patients with mucinous adenocarcinoma and clear cell carcinoma in contrast with the CA 125 antigen levels. Although the percentage of patients with ovarian cancer who had elevated sialyl SSEA-1 antigen levels is lower than that observed with elevated CA 125 antigen levels, the false-positive rate is significantly low in the sialyl SSEA-1 test. Serial sialyl SSEA-1 antigen levels obtained during follow-up were strong predictors of clinical outcome. The combined determination possible with sialyl SSEA-1 and CA 125 did not markedly increase the detection rate because of the overlap in the positivity. However, increased levels of both serum sialyl SSEA-1 antigen and CA 125 antigen indicated the presence of malignancies in pregnant women associated with ovarian tumors.     

The value of CA 125 determination in the serum of patients with ovarian cancer

The circulating ovarian cancer associated antigen CA 125 was determined in serum of 63 patients with ovarian malignancies by radioimmunometric solid phase assay using the monoclonal antibody OC 125 as catcher and tracer. The results of 41 patients with 43 active tumour situations were compared with the CA 125 serum levels of 27 patients without recurrence after therapy of ovarian cancer and 49 benign ovarian tumours. Significant differences exist between these three groups (p less than 0.001) with elevated values (greater than 35 U/ml) in 84 per cent in ovarian carcinoma, 22 per cent in benign tumours and nought per cent in woman without recurrence in follow-up. The pre-operative sensitivity in ovarian cancer is 93 per cent (in epithelial carcinoma 96 per cent) with a distinct dependence of the CA 125 serum levels on the stage of the disease (stage III and IV versus stage I and II; p less than 0.01). A positive correlation of CA 125 values to clinical status was found in 82 per cent in follow-up. Increasing values of CA 125 can detect the recurrence any months earlier than the clinical examination. Decreasing serum levels in chemotherapy don't reflect the objective tumour remission in every case. Because of elevated values in benign and inflammatory adnexal tumours and the relative low sensitivity in borderline cases (three of seven patients greater than 35 U/ml) the CA 125 assay seems not be suitable for a screening method. However it is a substantial amplification in control of therapeutic success and an early detection of recurrence of ovarian cancer disease.     

The concomitant determination of different serum tumor markers in epithelial ovarian cancer: relevance for monitoring the response to chemotherapy and follow-up of patients.

The levels of CA125, CA19.9, CA15.3 CA72.4, and TATI were serially measured during and after chemotherapy in 43 patients with epithelial ovarian cancer having elevated concentrations of one or more of the antigens before initial surgery. The value of 35 U/ml was chosen as cutoff level of CA125 for the monitoring of disease. Changes in the serum levels of CA125, CA19.9, CA15.3, CA72.4, and TATI correlated with the clinical course of disease in 87.4% of 215, 76.3% of 80, 71.3% of 122, 76.0% of 167, and 48.5% of 101 instances, respectively. After the sixth course of monthly primary chemotherapy, elevated antigen levels were strong predictors of persistent disease, while normal antigen values were associated with both positive and negative second-look findings. It is worth noting that antigen levels above the cut-off limits before the third course, but still in the normal range after the sixth course, seemed to be predictive of positive second-look findings. Among patients with elevated antigen levels at diagnosis, clinical detection of neoplastic progression after treatment was stopped was preceded by an elevation of serum CA125 in 93.3% of 15 patients, of serum CA19.9 in 80.0% of 5 patients, of serum CA15.3 in 66.7% of 9 patients, of serum CA72.4 in 81.8% of 11 patients, and of serum TATI in 40% of 10 patients. In patients with positive CA125 assay at diagnosis, the concomitant evaluation of the other antigens did not seem to be of additional benefit for monitoring epithelial ovarian cancer. However, the measurement of the other tumor markers could represent an interesting biochemical tool for the management of patients with negative CA125 assay. In particular the evaluation of serum CA19.9 or CA72.4 could be very useful in the monitoring of patients with mucinous ovarian cancer, which often fails to express CA125 antigen.     

The clinical significance of pre-operative serum CA 125 in ovarian cancer

In a prospective study of 52 patients with ovarian malignancy followed up for 3-18 months the clinical significance of pre-operative serum CA 125 as a tumour marker was assessed. In 41 patients with epithelial ovarian cancer, the level of CA 125 correlated well with tumour load as indicated by FIGO stage. All epithelial histological types, including mucinous, released CA 125 although serous and undifferentiated tumours produced quantitatively more antigen. There was, however, no correlation between CA 125 concentration and histopathological grade, nor did CA 125 level appear to be of any prognostic value in epithelial ovarian cancer. Elevated CA 125 levels were also found in patients with sex cord/stromal tumours. Krukenberg tumours, an ovarian sarcoma and a serous carcinoma of low malignant potential.     

Construction of an immunoradiometric assay for ovarian cancer associated antigen CA125 recognizing different antigenic determinant.

We generated five murine monoclonal antibodies reactive with ovarian cancer-associated antigen CA125. These monoclonal antibodies seemed to bind to separate epitopes from OC125 antibody, known to recognize CA125. A series of immunoradiometric assays for measuring serum CA125 values rapidly and sensitively were devised using these monoclonal antibodies. The antigenic determinant of a new immunoradiometric assay was different from that of a currently used CA125 kit employing OC125 both as a catcher and a tracer. However, serum antigen levels were closely correlated to each other and were elevated not only in patients with ovarian cancer, but also in patients with endometriosis and in some normal females during menstruation. These results suggest that CA125 has at least two antigenic determinants close to each other and this new rapid assay is useful, although not specific for ovarian cancer, in patients with gynecological disorders.     

Monitoring human ovarian carcinoma with a combination of CA 125, CA 19-9, and carcinoembryonic antigen

CA 125 and CA 19-9 are antigenic determinants associated with human epithelial ovarian carcinomas. Murine monoclonal antibodies have been raised against these determinants, and immunoradiometric assays have been developed to monitor antigen levels in the serum of cancer patients. This study was undertaken to determine whether concomitant measurement of CA 125, CA 19-9, and carcinoembryonic antigen would provide a more precise correlation with tumor progression or regression than could be obtained with any single assay. Among 105 patients with surgically demonstrable epithelial ovarian carcinoma, serum CA 125 levels were elevated (greater than 35 U/ml) in 83%, CA 19-9, levels (greater than 37 U/ml) in 17%, and carcinoembryonic antigen levels (greater than or equal to 2.5 ng/ml) in 37%. Within individual samples, no correlation was found among values for the three markers, but patients with elevated CA 19-9 levels also had increased levels of CA 125. At least one of the three markers was elevated in 90% of the subjects. When 41 patients were monitored serially over 2 to 60 months, alterations in CA 125 levels correlated with disease progression or regression in 94% of instances, whereas alterations in CA 19-9 levels correlated in 33% and alterations in carcinoembryonic antigen levels in 25% of instances. Concomitant measurement of CA 125, CA 19-9, and carcinoembryonic antigen did not prove superior to measurement of CA 125 alone in the monitoring of patients with epithelial ovarian carcinoma.     

Clinical usefulness of sialyl SSEA-1 antigen as tumor marker for ovarian cancer as compared with CA125, CA19-9, TPA, IAP, CEA and ferritin

In order to determine the clinical significance of sialyl SSEA-1 antigen, we compared its usefulness as a tumor marker for ovarian cancer with simultaneously measured CA125, CA19-9, TPA, IAP, CEA and ferritin. The sialyl SSEA-1 antigen in serum was measured by radioimmunoassay with an "FH-6" Otsuka Kit. The immunohistochemical localization of sialyl SSEA-1 antigen in ovarian carcinoma tissues was determined by an immunoperoxidase method using FH-6 monoclonal antibody. Among fifty-one patients with ovarian cancer, the incidence of elevated serum levels was 54.9% with sialyl SSEA-1 antigen, 90.2% with CA125, 48.8% with CA19-9, 78.0% with TPA, 73.1% with IAP, 17.1% with CEA and 63.4% with ferritin. On the other hand, among the patients with uterine malignancies and gynecologic benign tumors, the incidence of elevated sialyl SSEA-1 antigen levels in serum was lower than that of other tumour markers. In the patients with ovarian cancer, the serum levels of sialyl SSEA-1 antigen increased in accordance with the advance of the clinical stage and were also correlated with the effect of therapy. In the examination of immunohistochemical localization of sialyl SSEA-1 antigen, a positive reaction occurred in 10 out of 30 ovarian carcinoma specimens. Intense staining appeared in the secretory materials, in the luminal surface of the glands, and in the cytoplasm of cells. Thus, sialyl SSEA-1 antigen appears to be a useful tumor marker for the diagnosis of ovarian cancer, especially when measured simultaneously with CA125, CA19-9, TPA, ferritin and IAP.     

Antigen CA125 in tumor tissue and serum from patients with adenocarcinoma of the ovary

The presence of cancer antigen CA125 has been assessed immunohistologically in formalin-fixed tumor tissue and immunoradiometrically in serum from 41 women with residual epithelial ovarian carcinoma after diagnostic laparotomy. CA125 was detected in tumor tissue from the majority of patients (34/41), including those with normal serum levels (15/18). The major determinant of serum CA125 concentration appears to be the size of the residual tumor. The results suggest that in the majority of patients with small residual tumor masses and normal postoperative serum antigen levels, progressive disease may well be associated with increasing serum CA125 levels.     

Meigs' syndrome with elevated serum cancer antigen 125 levels in a case of ovarian sclerosing stromal tumor

ObjectiveMeigs’ syndrome presenting as an ovarian tumor with elevated serum cancer antigen 125 (CA 125) levels is unusual. Only 37 cases have been reported, including three cases of ovarian sclerosing stromal tumor (SCT). Many reports have suggested that the presence of ascites is the major factor inducing mesothelial expression of CA 125.Case ReportAn 18-year-old woman presented with massive ascites, elevated serum CA 125 levels, and radiographic evidence of ovarian tumor. The histological and immunohistochemical examinations revealed a benign SCT.ConclusionSCT is a benign ovarian tumor and complete excision is curative. We also review all 37 cases and discuss possible mechanisms of Meigs’ syndrome and elevated serum CA 125 level.     

组织多肽抗原在卵巢癌诊断及监测中的应用

目的评价组织多肽抗原（ＴＰＡ）在卵巢癌诊断和监测中的临床价值。方法应用放射免疫方法测定了２４例正常妇女、２７例妇科良性疾患及６０例卵巢癌患者的血清ＴＰＡ及ＣＡ１２５值并进行比较分析。结果ＴＰＡ在卵巢上皮性癌患者中的异常检出率为８２％,ＣＡ１２５为７０％,二者总的异常检出率为９２％。在绝大多数正常妇女和卵巢良性肿瘤患者中,ＣＡ１２５和ＴＰＡ在正常范围。作为卵巢癌相关标志物,ＴＰＡ与ＣＡ１２５具有相似敏感性。１９例动态观察结果显示,ＴＰＡ和ＣＡ１２５二者与病情转归是一致的。结论ＴＰＡ和ＣＡ１２５联合应用对卵巢癌的鉴别诊断及提高总的异常检出率具有价值。     

Evaluation of two new assays for tumor-associated antigens, CASA and OSA, found in the serum of patients with epithelial ovarian carcinoma--comparison with CA125.

Two new assays have been developed to measure tumor-associated antigens designated ovarian serum antigen (OSA) and cancer-associated serum antigen (CASA). Both assays are dual epitope ELISAs using the same capture monoclonal antibody (BC2); the second antibodies in the OSA and CASA assays are OM-1 and BC3, respectively. Using arbitrary cutoffs of 2.5 and 3.0 units/ml, 82 and 76% of 80 serum samples from ovarian cancer patients were positive for OSA and CASA, respectively, compared with 5 and 2.5% of samples from a control population of 40 women. A strong correlation was found between the two assays (r = 0.80, P less than 0.001). CA125 levels were obtained from 49 of the 80 samples; 82% of these samples were positive for CA125 (greater than 35 U/ml), 82% for OSA and 73% for CASA. Of the 9 samples negative for CA125, 3 were positive for OSA and 3 were positive for CASA. Serum OSA, CASA, and CA125 levels were determined in serial samples from 20 ovarian carcinoma patients throughout the course of their treatment. Clinical course was accurately reflected by CA125 levels in 85% of patients, by CASA in 65%, and by OSA in 75%. In 4 patients, a rise in CASA levels and, in 2 patients, a rise in OSA levels significantly predated rising CA125 levels to predict recurrence. Six of 7 serum samples obtained prior to positive second-look laparotomy were negative for CA125, while 4 were positive for OSA and 6 were positive for CASA. These results indicate that the OSA and CASA assays could be superior to CA125 for detection of small volume occult ovarian carcinoma.     

Clinical evaluation of specificity of serum CA125 as a tumor marker of ovarian carcinoma

To evaluate whether elevated serum CA125 levels have specificity to ovarian malignancies, CA125 levels were measured in sera of 48 malignancies, 56 benign diseases and 40 healthy women. Furthermore serum CA125 levels were serially followed up in all the patients with positive serum CA125 levels (35 U/ml less than or equal to) to evaluate the correlation between serum CA125 levels and the response to treatment. Results obtained were as follows. A significantly higher positive rate (91%) of serum CA125 levels was observed in patients with ovarian malignancies than that (30%) in patients with other malignancies. Positive serum CA125 levels were also observed in patients with endometriosis, benign ovarian tumor, hydrosalpinx, uterine myoma and peritoneal tuberculosis. Serum CA125 levels in patients with malignancies depend on the volume of the solid part of the tumor irrespective of the tumor type. In patients with positive serum CA125 levels, rising or falling of the serum levels of this antigen correlated well with progression or regression of all kinds of diseases. These results suggested that a high positive rate of this antigen in patients with ovarian malignancies was not merely derived from the tumor specificity of this marker but partly from the fact that tumor sizes of ovarian malignancies were generally larger than those of other malignancies.     

Elevated serum levels of macrophage colony-stimulating factor and OVX1, 11 months prior to the diagnosis of stage IC ovarian cancer

In published trials, CA125 has been utilized to trigger ultrasound examination for the early detection of ovarian cancer. Although serum CA125 levels can be elevated prior to clinical detection of ovarian cancer, only approximately half of patients with stage I disease will have an abnormal value. A combination of CA125, macrophage colony-stimulating factor (M-CSF) and the mucin marker OVX1 will detect> 95% of stage I patients, but it is not known whether the markers can be elevated prior to clinical detection of the disease. A postmenopausal patient was found to have small unilocular bilateral cystic adnexal lesions during an abdominal ultrasound examination. No pelvic abnormality could be palpated. Serum levels of the CA125 antigen were within the normal range. Progressive ultrasound changes prompted a laparotomy II months later, and the diagnosis of a stage IC serous cystadenocarcinoma of the ovary was established. A retrospective analysis of stored serum samples revealed that this patient had elevated serum levels of M-CSF and OVX1 at the time of the original ultrasound scan. Interpreted within the context of a potential screening strategy for ovarian cancer, these data illustrate that either or both of these tumor markers and/or ultrasound could have identified this ovarian cancer many months prior to the actual diagnosis, while the disease was at an early stage.     

Differential diagnosis of ovarian cancer, benign ovarian tumor and endometriosis by a combination assay of serum sialyl SSEA-1 antigen and CA125 levels

We used a combination assay of serum sialyl SSEA-1 antigen (SLX) and CA125 levels, and evaluated the clinical usefulness of this technique for a differential diagnosis of ovarian cancer, benign ovarian tumor and endometriosis. In 82 patients with ovarian tumors, the sera of 20 (64.5%) of 31 with ovarian cancer and 15 (48.4%) of the 31 with endometriosis (endometrial cyst) were positive for both SLX and CA125, but serum SLX level was 5 U/ml or less in these 14 SLX- and CA125-positive patients with endometriosis. The sera of 16 (80.0%) patients with benign ovarian tumor were negative for both tumor markers. The sera of 3 (9.7%) of 31 with ovarian cancer and the sera of 2 (6.5%) of 31 with endometriosis were negative for both markers. The diagnostic accuracy (true positive rate X true negative rate) of the combination assay for ovarian cancer was 49.0% when the cutoff value of the serum SLX was 38 U/ml but improved to 78.5% when the value was set at 50 U/ml. When the cutoff value of serum SLX was set at 50 U/ml and that of serum CA125 at 35 U/ml, 27 of 37 patients who were positive only for CA125 had endometriosis. From the above observations, a combination assay of serum SLX and CA125 is a promising method for the differential diagnosis of malignant and benign ovarian tumors. Our results also suggest that to improve the diagnostic accuracy, the cutoff value of the serum SLX level should be 50 U/ml for ovarian tumors alone.     

LPA、CA125与经阴道彩色多普勒超声联合诊断卵巢上皮癌的临床价值

目的:探讨血浆溶血磷脂酸(LPA)在卵巢上皮癌患者血浆中的表达水平,及其与血清CA125和经阴道彩色多普勒超声(TV-CDUS)联合应用诊断卵巢上皮癌的临床价值。方法:术前检测卵巢上皮癌48例,卵巢良性肿瘤30例的LPA、CA125,以20例健康者作为对照,卵巢肿瘤患者同时经阴道超声评分和TV-CDUS检查。结果:卵巢癌患者LPA水平明显高于卵巢良性肿瘤组和健康对照组,差异有统计学意义(P0.05),LPA水平在良性肿瘤组与健康对照组之间无显著差异(P0.05)。单独应用LPA、CA125、TV-CDUS检测诊断卵巢癌的敏感性和特异性分别为87.5%、79.16%、81.25%和80%、70%、86%,各组间敏感性和特异性比较,无显著差异(P0.05)。LPA、CA125、TV-CDUS 3项联合检测诊断卵巢癌的敏感性和特异性为95.80%和94%,与单独应用CA125检测特异性比较,差异有统计学意义(P0.05)。LPA诊断卵巢癌的敏感性和特异性与卵巢癌分期和病理类型无关(P0.05),CA125诊断卵巢癌的敏感性和特异性与卵巢癌的分期和病理类型有关(P0.05)。结论:卵巢上皮癌患者血浆LPA水平明显升高,有望成为卵巢上皮癌诊断的敏感指标,联合检测血浆LPA、血清CA125与TV-CDUS有助于术前卵巢癌的诊断。     

Evaluation of HE4 as an extrabiomarker to CA125 to improve detection of ovarian carcinoma: is it time for a step forward?

Purpose

To evaluate human epididymis protein 4 (HE4) as an extrabiomarker to cancer antigen 125 (CA125) to improve the detection of ovarian carcinoma.

Methods

Sixty patients with ovarian carcinoma, 50 patients with benign ovarian tumors and 30 healthy women were included in the present study. Serum concentration of HE4 was assayed using ELISA technique, while CA125 was assayed using chemiluminescent enzyme immunoassay.

Results

The median CA125 and HE4 serum values were significantly higher among ovarian cancer patients when compared with healthy control However, the median serum levels of CA125 but not HE4 were significantly higher among patients with benign ovarian tumors as compared to healthy women. Based on the receiver operator characteristics curve analysis, HE4 had higher sensitivities than CA125 for the detection of ovarian cancer at 90, 95 and 98 % specificities and the combination of both markers yielded a higher sensitivity than either alone. However, CA125 but not HE4 had higher sensitivities for the detection of benign ovarian tumors at the same specificities. In addition, a positive correlation was observed between HE4 and CA125 among patients with ovarian carcinoma.

Conclusion

HE4 is a valuable marker for ovarian cancer diagnosis and when combined with CA125, they had a higher sensitivity at a set specificity, thus providing a more accurate predictor of ovarian cancer than either alone.     

CA 125 in peritoneal fluid: reliable values at high dilutions.

Forty-three samples of peritoneal fluid from women undergoing laparotomy or laparoscopy for various gynecologic diseases were examined to determine and characterize CA 125 antigen. The data were compared with the corresponding serum levels. CA 125 levels in undiluted peritoneal fluid ranged between 41-301 U/mL and were significantly higher than levels in serum, except in cases of ovarian carcinoma. However, when CA 125 of peritoneal fluid was measured at dilutions greater than 1:50, higher antigen levels were measured (1120-31,500 U/mL), with the highest CA 125 values in patients with ovarian carcinoma. Measurements at dilutions of less than 1:50 were also affected but did not show any decreased binding of the antigen. Immunoblotting analysis of serum and peritoneal fluid indicated the presence of two main bands in each. The monoclonal antibody OC 125 reacted strongly with peritoneal fluid CA 125, in agreement with the CA 125 values obtained by immunoradiometric assay using high dilutions. These data suggest that CA 125 measurements in peritoneal fluid are unreliable unless the samples are diluted 1:50 or more. Furthermore, the statistical difference found between patients with benign and malignant tumors and those with leiomyomata uteri and controls suggests that diluted peritoneal fluid could have a role in identifying abnormal antigen levels.