Objective
We sought to assess the ability of human epididymis protein 4 (HE4) and CA-125 to distinguish among benign, borderline, and malignant pelvic masses in premenopausal women.
Study Design
We conducted a subset analysis of data from a prospective clinical trial that enrolled women undergoing surgery for an adnexal mass. Diagnostic performance of CA-125 and HE4 for epithelial ovarian cancer (EOC) detection in premenopausal women was determined.
Results
Of 229 premenopausal patients, 195 (85%) had benign masses, 18 (8%) had EOC, and 16 (7%) had borderline ovarian tumor. The sensitivity of CA-125 and HE4 for EOC detection was 83.3% and 88.9%, respectively. The specificity of CA-125 and HE4 was 59.5% and 91.8%, respectively. A normal HE4 level ruled out invasive cancer in 98% of women with an elevated CA-125.
Conclusion
HE4 offers superior specificity compared to CA-125 for the differentiation of benign and malignant adnexal masses in premenopausal women.
The evaluation of a woman with an adnexal mass is a common clinical circumstance facing the obstetrician/gynecologist. It is estimated that 5-10% of women in the United States will undergo a surgical procedure for a suspected ovarian neoplasm during their lifetime and 13-21% of these women will be found to have an ovarian malignancy. The challenges facing the gynecologist include the selection of patients appropriate for expectant management or minimally invasive surgical procedures. It is necessary to optimize the surgical management of an adnexal carcinoma, should one be discovered.
Several means of investigation have been employed, with varying success, to aid the clinician in distinguishing between benign and malignant adnexal masses. Currently, the combination of physical examination, serum CA-125 level, and imaging affords the highest positive predictive value. While CA-125 measurement is an important component in the workup of a woman with an adnexal mass, its utility is hindered by low specificity, especially in premenopausal women where it is elevated above the normal level in common benign conditions such as pelvic endometriosis, follicular cysts, cystadenoma, tuboovarian abscess, and pregnancy. In addition, the association of an elevated CA-125 level with malignancy is not limited to primary gynecologic cancers. Cancers of the pancreas, stomach, colon, and rectum have all been associated with elevated CA-125, particularly in cases involving metastatic disease.
Although only a limited number of studies examined the predictive value of CA-125 in women with an adnexal mass stratified by menopausal status, the data consistently demonstrated higher positive predictive value for ovarian cancer detection in postmenopausal women. Malkasian et al evaluated 158 women with pelvic masses preoperatively with CA-125 to distinguish benign from malignant disease. The positive predictive value of CA-125 in postmenopausal women was 98% compared with 49% in premenopausal women. Given the lack of a more sensitive and specific marker, CA-125 still remains the most commonly used blood test in premenopausal women. The American Congress of Obstetrics and Gynecology acknowledges that in premenopausal women with symptoms, a CA-125 measurement is not useful in most circumstances because elevated levels are associated with a variety of benign adnexal conditions.
In an effort to improve the management of premenopausal women with an adnexal mass, we evaluated human epididymis protein 4 (HE4) and CA-125 to determine if the addition of HE4 increased the sensitivity and specificity for ovarian cancer detection in this population. HE4, a novel biomarker that is expressed in normal glandular epithelium of the female genital tract and breast as well as in a number of glandular carcinomas, has the potential to achieve increased sensitivity and specificity in premenopausal women. In a study of 67 malignant and 166 benign pelvic masses the combination of HE4 and CA-125 produced the highest sensitivity of any single marker or dual-marker combination. The purpose of the present study is to assess the ability of HE4 alone and in combination with CA-125 to distinguish among benign, borderline, and malignant pelvic masses in premenopausal women presenting with a pelvic mass.
Materials and Methods
The study is a subset analysis of serum samples from a prospective, multicenter, double-blind clinical trial that enrolled women ≥18 years of age presenting with a pelvic mass who were scheduled to undergo surgery ( ClinicalTrial.gov identifier NCT00315692 ). It was conducted at 14 clinical sites across the United States from December 2005 through February 2007. The pelvic mass had to be demonstrable on pelvic sonogram, computed tomography scan, or magnetic resonance imaging. Women with a history of cancer within the last 5 years (excluding nonmelanoma skin cancer), those receiving cytotoxic chemotherapy, and pregnant women were excluded. Serum was collected from all study participants not >30 days prior to the planned surgery for the pelvic mass and analyzed for CA-125 and HE4 concentrations using the Architect assay (Abbott, Abbott Park, IL). Using the Architect HE4 assay results (expressed as pmol/L) obtained from 210 premenopausal and 190 postmenopausal healthy women, the upper limits of normal (95th percentile) were determined to be ≥70 pmol/L for premenopausal and ≥140 pmol/L for postmenopausal women. The threshold for Architect CA-125 was ≥35 U/mL for both premenopausal and postmenopausal women. Women >55 years of age and those with cessation of menses for at least 12 consecutive months were considered postmenopausal. If the menopausal status was unclear, follicle-stimulating hormone levels were determined (Abbott) and a level >22 mIU/mL was considered postmenopausal. All study participants underwent either laparoscopy or laparotomy for resection of their pelvic mass and all pathology specimens were centrally reviewed. Women diagnosed at surgery with nongynecological malignancies were excluded from the analysis. Using the predetermined cutoff values, the proportions of premenopausal women with elevated CA-125 and HE4 levels were calculated and compared using χ 2 tests. Sensitivity, specificity, and negative and positive predictive values were calculated for CA-125 and HE4 in the detection of borderline and invasive tumors. Fisher’s exact test was used to compare proportions of benign or cancer patients with and without elevations in the markers. P < .05 was considered significant for all tests.
Results
In all, 229 premenopausal (46%) and 265 postmenopausal (54%) women comprised the entire study protocol population. The histologic findings stratified by menopausal status are shown in Table 1 . Benign masses were predominant in premenopausal women with only 8% being diagnosed with epithelial ovarian cancers (EOC) and 7% with borderline ovarian tumors (BOT). Further analysis was limited to the premenopausal group only. The median serum CA-125 value in the benign cases was 25.6 U/mL (5.1-2462.2 U/mL) vs 187.4 U/mL (7.6-741.8 U/mL) in BOT and 204.7 U/mL (19.2-3345.4 U/mL) in EOC. The median HE4 values were 37.9 pmol/L (17.2-1529.8 pmol/L) in benign conditions vs 57.3 pmol/L (28.9-387.8 pmol/L) in BOT and 281.7 pmol/L (33.1-839.0 pmol/L) in EOC ( Figure 1 ).
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