Ovarian cancer is a common malignancy of the female reproductive system. Tumor markers serve as tools in the diagnosis of the disease. The aim of the present study was to determine the diagnostic value of sera levels of carbohydrate antigen-125 (CA-125), human epididymis protein 4 (HE4) as well as the area under the curve of the receiver operating characteristic (ROC) and the risk of ovarian malignancy algorithm (ROMA) index in ovarian cancer. The sera were measured using an electrochemiluminescence immunoassay on 158 individuals (64 patients with ovarian cancer, 64 with ovarian benign tumor and 30 healthy individuals) between September 2013 and May 2015. The results showed that levels of HE4 and CA-125 in the sera of the ovarian benign tumor group as well as their ROMA index were significantly higher (P<0.05) than those of the ovarian benign tumor and control groups, regardless of pre- or postmenopausal status. However, the level of CA-125 was significantly higher (P<0.05) in the ovarian benign tumor group compared with the healthy group, while the level of HE4 was similar in the two groups. The sensitivity of the ROMA index was higher (P<0.01) with detection of HE4 and CA-125. In the ovarian cancer group, the areas under ROC curves of ROMA, HE4 and CA-125 were 0.994, 0.990 and 0.941, respectively. The specificity and positive predictive value of HE4 in the premenopausal ovarian cancer group reached 98.36 and 95%, respectively. In conclusion, the results showed that the serum level of HE4 and the ROMA index are important indicators in the diagnosis of ovarian cancer. However, in addition to HE4 and CA-125 detection, the ROMA index is extremely valuable in improving the diagnostic efficiency of ovarian cancer.
Ovarian cancer is one of the three most common malignant tumors in the female reproductive system. It has an insidious onset with a difficult early diagnosis (
The tumor marker CA-l25 has been used for 30 years for the monitoring of ovarian cancer, diagnosis, effective evaluation, and recurrence (
The introduction of HE4, a type of gynecological tumor marker, has attracted much attention. HE4 has shown a sensitivity and specificity of 72.9 and 95%, respectively, for differentiating between types of ovarian masses, which is better than that of CA-125 detection (
In total, the present study included 158 cases, which were divided into the ovarian cancer, benign ovarian disease and healthy control groups. Selected patients did not receive chemotherapy or hormonal therapy, or a combination thereof for other tumors or serious heart, liver and kidney disease, or diabetes. A total of 64 patients in the ovarian cancer group were selected between October 2013 and May 2015 in Xuzhou Central Hospital with pelvic mass, which was examined and confirmed by postoperative pathological findings. There were 14 cases of papillary serous cystadenocarcinoma, 1 case of clear cell carcinoma, 7 cases of mucinous cystadenocarcinoma and 42 cases of serous cystadenocarcinoma.
According to the staging method of the International Federation of Gynaecology and Obstetrics, 10 cases were stage I, 18 cases of stage II, 23 cases of stage III and 13 cases of stage IV. The patients were aged 30–51 years with an average age of 55±11.9 years. Twenty-seven patients were in premenopausal status (aged 30–51 years, average age 43.8±6.08 years) while 37 patients were in postmenopausal status (aged 47–81 years, average age 63±7.9 years). The 64 patients were in the benign ovarian disease group (6 cases of ovarian serous cystadenoma, 14 cases of ovarian mucinous cystadenoma, 30 cases of mature ovarian teratoma, 5 cases of theca cell tumor and 9 cases of ovarian endometriosis cyst). The patients were aged 24–82 years, with an average age of 47.81±13.9 years. Of the 64 patients, 40 patients were in premenopausal status (aged 24–47 years, average age 38.9±6.8 years), while 24 patients were in postmenopausal status (aged 50–82 years, average age 62.7±9.2 years). Thirty normal females in the healthy control group identified during the same period with no liver and kidney disease and no tumor history, were included. The patients were aged 30–63 years, with an average age of 45.2±8.25 years. Of the 30 cases, 21 cases were at a premenopausal status, aged 30–49 years with an average age of 40.8±5 years. Nine cases were of postmenopausal status with an age of 51–63 years and an average age of 55.7±3.4 years.
All the subjects provided written inform consent. The study was approved by the Ethics Committee of the Xuzhou Central Hospital.
Samples were collected from all the patients prior to surgery and 3 ml blood was collected. Serum was centrifuged at 2000 × g and stored at −20 and −80°C until use.
Serum CA-125 and HE4 were detected using the full automatic chemiluminescence analyzer Cobs601 and the corresponding kit according to manufacturer's protocol (Roche Diagnostics, Indianapolis, IN, USA). Briefly, serum HE4 and CA-125 levels were calculated for ROMA index value using the Roche ROMA index of ovarian cancer risk assessment software. Serum HE4 and CA-125 reference range was <140 pmol/l and <35 U/ml, respectively.
The ROMA index was calculated according to the levels of HE4 and CA-125. HE4 and CA-125 values were input to the ovarian cancer risk assessment software, followed by automatic calculation of the corresponding ROMA index. The premenopausal calculation formula of the ROMA index was: 12+2.38 × LN(HE4)+0.062 6 × LN(CA-125). The postmenopausal calculation formula of the ROMA index was: 8.09+1.04 × LN(HE4)+0.732 × LN(CA-125). When Roche Elecsys specificity was 75%, premenopausal women with a ROMA value ≥11.4, had a higher risk of ovarian cancer. Postmenopausal women with ROMA value ≥29.9 had a higher risk of ovarian cancer.
SPSS 16.0 statistical software (SPSS, Inc., Chicago, IL, USA) was used for statistical analysis. HE4, CA-125, ROMA index and other non-normal measurement data were shown as the quartile interval. The count data were shown using rate. The use of the rank sum test (Man-whitney U test) and Chi-square test data were statistically analyzed. The area under curve (AUC) of receiver operating characteristic (ROC) were calculated for a comparison of the three test methods. P<0.05 was considered to indicate a statistically significant difference.
The serum levels of HE4, CA-125 and ROMA index in the ovarian cancer group were significantly higher than those in the benign tumor and healthy control groups, and there was significant difference (P<0.05). The expression level of HE4 and ROMA index in the benign tumor group was not significantly different. The expression level of CA-125 in serum was significantly higher than that in the healthy control group (P<0.05,
The patients in the ovarian benign disease and healthy control groups were further divided into the pre- and postmenopausal groups. The patients with ovarian cancer were divided into the pre- and postmenopausal groups. The serum levels of HE4, CA-125 and ROMA index were detected to evaluate the sensitivity, specificity, positive predictive value and negative predictive value of HE4, CA-125 and ROMA standardized with pathological diagnosis (
The early diagnosis of ovarian malignancies is one of the key factors for improving the survival rate of patients (
In conclusion, application of the ROMA index and HE4 for the diagnosis of ovarian cancer was found to be effective and it has good clinical application value, which may be useful for clinicians.
The receiver operating characteristic of risk of ovarian malignancy algorithm (ROMA) index, human epididymis secretory protein 4 (HE4) and carbohydrate antigen-125 (CA-125) in the diagnosis of ovarian cancer.
Sera levels of HE4, CA-125 and ROMA index of three groups.
Parameters | Healthy control group | Benign tumor group | Ovarian cancer group |
---|---|---|---|
Cases | 30 | 64 | 64 |
HE4 | 39.04±8.38 | 54.76±42.35 | 739.03±860.04 |
CA-125 | 15.08±5.28 | 49.07±175.61 |
868.85±1204.08 |
ROMA index | 6.18±2.21 | 10.15±11.98 | 76.30±28.57 |
The three parameters were significantly increased in the ovarian cancer group while only CA-125 was significantly increased in the benign tumor group relative to the healthy control group.
Compared with those of the control group, P<0.05
Compared with those of the benign tumor group, P<0.05. HE4, human epididymis protein 4; CA-125, carbohydrate antigen-125; ROMA, risk of ovarian malignancy algorithm.
The diagnostic values of CA-125, HE4 and ROMA in ovarian cancer compared with the golden standard.
Characteristics | Sensitivity (%) | Specificity (%) | Positive predictive value (%) | Negative predictive value (%) |
---|---|---|---|---|
Total | ||||
CA-125 | 85.07 (57/64) | 92.31 (84/94) | 90.6 (57/67) | 89.36 (84/91) |
HE4 | 75 (48/64) | 97.87 (92/94) | 96 (48/50) | 85.19 (92/108) |
ROMA index | 93.75 (60/64) | 92.55 (87/94) | 89.55 (60/67) | 86.14 (87/101) |
Premenopausal | ||||
CA-125 | 92.59 (25/27) | 88.52 (54/61) | 78.13 (25/32) | 96.43 (54/56) |
HE4 | 70.37 (19/27) | 98.36 (60/61) | 95.00 (19/20) | 88.24 (60/68) |
ROMA index | 96.3 (26/27) | 88.52 (54/61) | 78.79 (26/33) | 98.18 (54/55) |
Postmenopausal | ||||
CA-125 | 86.49 (32/37) | 90.9 (30/33) | 91.43 (32/35) | 90.90 (30/35) |
HE4 | 78.38 (29/37) | 96.97 (32/33) | 96.67 (29/30) | 80.00 (32/40) |
ROMA index | 91.89 (34/37) | 96.97 (32/33) | 97.14 (34/35) | 91.43 (32/35) |
Sensitivity and specificity of the positive and negative predictive values of HE4, CA-125 and ROMA standardized with pathological diagnosis were comparable between the groups. HE4, human epididymis protein 4; CA-125, carbohydrate antigen-125; ROMA, risk of ovarian malignancy algorithm.
The diagnostic values of CA-125, HE4 and ROMA in ovarian cancer.
CA-125 | HE4 | |||
---|---|---|---|---|
Characteristics | Positive | Negative | Positive | Negative |
Total | ||||
ROMA index | ||||
Positive | 57 | 10 | 48 | 18 |
Negative | 10 | 81 | 2 | 90 |
χ2 | 86.721 | 89.755 | ||
P-value | <0.001 | <0.001 | ||
Premenopausal | ||||
ROMA index | ||||
Positive | 25 | 8 | 19 | 13 |
Negative | 7 | 48 | 1 | 55 |
χ2 | 35.41 | 39.27 | ||
P-value | <0.001 | <0.001 | ||
Postmenopausal | ||||
ROMA index | ||||
Positive | 32 | 2 | 29 | 5 |
Negative | 3 | 33 | 1 | 35 |
χ2 | 51.47 | 48.62 | ||
P-value | <0.001 | <0.001 |
The ROMA index and a comparison of the sera levels of CA-125 and HE4 in the diagnosis of ovarian cancer between the three groups were significantly different. HE4, human epididymis protein 4; CA-125, carbohydrate antigen-125; ROMA, risk of ovarian malignancy algorithm.