Published online Jun 24, 2020. doi: 10.5306/wjco.v11.i6.378
Peer-review started: December 20, 2019
First decision: April 2, 2020
Revised: May 11, 2020
Accepted: June 2, 2020
Article in press: June 2, 2020
Published online: June 24, 2020
Standard surgical treatment in endometrial cancer consists of hysterectomy with bilateral salpingo-oophorectomy. Node dissection is performed in selected patients with high-risk features such as grade 3 tumors, large tumor sizes (more than 2 cm), deep myometrial invasion (more than 50%), lymphovascular space invasion (LVSI), cervical involvement, and extrauterine involvement. Preoperative evaluation aiming to assess high-risk features in clinical stage 1 endometrial cancer patients are crucial. Preoperative imaging still has some limitations in assessing microscopic node metastasis. Intraopeative frozen section has been accepted as the most reliable method but it is not widely available especially in developing countries.
Cancer antigen 125 (CA125) and human epididymis protein 4 (HE4) have been reported in endometrial cancer patients with poor prognostic factors. These serum tumor markers can be used as biomarkers to stratify patients preoperatively into high-risk and low-risk groups aiming to refer high-risk patients to gynecologic oncologists for complete surgical staging.
The objective of this study was to assess the association between preoperative levels of CA125 and HE4 and high-risk features, including grade 3 tumors, large tumor sizes (more than 2 cm), deep myometrial invasion, LVSI, cervical involvement, extrauterine metastasis and node metastasis. The cut-off values of each tumor marker were analyzed to predict high-risk features in clinical stage 1 endometrial cancer patients.
This retrospective study was conducted on 128 clinical stage 1 endometrioid endometrial cancer patients were included. Patients with advanced stages, the nonendometrioid subtype, synchronous ovarian or colorectal cancers and incomplete medical records were excluded. The patients’ demographic data, clinicopathological characteristics, and preoperative serum biomarkers, including CA125 and HE4 levels, were collected. High-risk features included grade 3 tumors, large tumor sizes (more than 2 cm), deep myometrial invasion (more than 50%), LVSI, cervical involvement, extrauterine involvement and node metastasis. Receiver operating characteristic (ROC) curves were generated to analyze the optimal cut-off values.
The mean age of the patients was 57.4 years, and 69.5% of them were postmenopausal. Most patients presented with stage I disease (67.2%) and had the endometrioid subtype (97.7%). The median CA125 and HE4 levels in all patients were 22.1 U/mL and 104.7 pmol/L, respectively. CA125 and HE4 levels were significantly elevated in those with large tumor sizes, deep myometrial invasion, LVSI, extrauterine metastasis, and advanced stage, but node metastasis was associated with elevated CA125 only. According to the ROC curve, both serum markers had statistical significance for the prediction of high-risk features only in postmenopausal patients, with an optimal cut-off value of 20 U/mL for CA125 (AUC = 0.72, P = 0.002) and 113 pmol/L for HE4 (AUC = 0.70, P = 0.006). The combination of both serum markers had 80% sensitivity and 64.4% positive predictive value. Significantly worse 5-year disease-free survival was observed in patients with high levels of CA125 and HE4 (78.4% and 100%, respectively; P = 0.01).
Preoperative CA125 levels above 20 U/mL or HE4 levels above 113 pmol/L can predict high-risk features such as large tumor sizes, deep myometrial invasion, LVSI, advanced stage, and extrauterine metastasis in clinical stage 1 postmenopausal endometrial cancer patients. However, only a high level of CA125 was associated with node metastasis. Combining elevated levels of CA125 with HE4 preoperatively enhanced the sensitivity to 80% and PPV to 64.4%. It may be a helpful tool to direct patients to gynecologic oncologists to perform complete surgical staging. This result is clinically useful for individualized treatment and provides information about the prognosis of disease.
Elevated CA125 and HE4 levels were associated with high-risk features and had worse prognosis in clinical stage 1 endometrial cancer patients, the cut-off values could be analyzed only in postmenopausal patients in this study. Because high-risk features were less common in premenopausal patients, a larger sample size should be further evaluated and the optimal cut-off values should be evaluated in premenopausal endometrial cancer patients. Furthermore, combination with novel biomarkers should be further investigated aiming to increase efficacy.