IMR Press / EJGO / Volume 40 / Issue 2 / DOI: 10.12892/ejgo4495.2019
Open Access Original Research
CA 125 and Grade 1 endometrial cancer: analyzing the risk of metastases
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1 Division of Gynecologic Oncology, Cancer Treatment Centers of America, Newnan, Georgia, USA
Eur. J. Gynaecol. Oncol. 2019 , 40(2), 246–248; https://doi.org/10.12892/ejgo4495.2019
Published: 10 April 2019
Abstract

Background: The purpose of this article was to relate preoperative serum CA 125 to risk of nodal metastases in women with Grade 1 endometrial cancer that were fully surgically staged. Materials and Methods: Charts were reviewed to determine all patients with preoperative Grade 1 endometrial carcinoma and a serum CA 125 undergoing complete surgical staging. Charts were also reviewed for final stage, grade, and site of metastases. All serum CA 125s were drawn within four weeks of definitive surgery. Results: Analysis was completed on 737 patients with Grade 1 endometrial cancer. The mean age of the population was 61.9 years (95% CI 61.3-62.4). Extrauterine disease was found in 14.7% of patients and nodal disease in 12.6%. A significant difference in BMI was seen between those not having lymph node metastases (mean 38.7 kg/m2; 95% CI 38.1, 39.3) and those having positive nodes (mean 35.3 kg/m2; 95% CI 34.3-36.3) (p < 0.001). The mean CA 125 for the cohort was 25.6 mIU/ml (95% CI 22.0-29.2). No patients with preoperative Grade 1 disease and a CA 125 < 15 mIU/ml (0/239) had nodal disease at surgical staging while 18.7% (93/498) with a CA 125 ≥ 15 mIU/ml had nodal metastases (p < 0.001). Conclusion: In patients with Grade 1 endometrial adenocarcinomas, CA 125 can be used to determine who needs full surgical staging with minimal risk of missing nodal positive patients.

Keywords
Endometrial cancer
CA 125
Grade 1
Introduction

Endometrial cancer is the most common gynecologic malignancy in the United States. In 2014, 52,630 women were diagnosed with uterine cancer and 8,590 died from their disease [1].

Because women often present with abnormal uterine bleeding, 75% are diagnosed at an early stage, leading to a favorable prognosis [2]. Most women are diagnosed after menopause, at an average age of 60-years-old. The major risk factor is unopposed estrogen, either from obesity or from exogenous estrogen given without simultaneous progestin administration [3]. This is consistent with the fact that Type 1, estrogen-dependent cancer, is the most common variety.

The staging of endometrial cancer has undergone significant change over time, and it is currently staged surgically according to the 2010 International Federation of Gynecology and Obstetrics (FIGO)/TNM classification system. This system calls for routine total extrafascial hysterectomy with bilateral salpingo-oophorectomy with both pelvic and para-aortic lymph node dissection [4]. To achieve accurate disease assessment, extensive surgical staging is done in all patients in some centers. Under the current staging standards, many patients suffer the associated morbidity of the extensive surgery without an improvement in their survival.

If there was a strategy to stratify patients into likelihood of extra-uterine spread, then costly and unnecessary surgical staging procedures could be avoided. In these low-risk patients, hysterectomy and bilateral salpingo-oophorectomy could be performed without the risk of missing advanced disease. The purpose of this paper was to analyze whether CA 125 could be used to help stratify patients with preoperative Grade 1 endometrial cancer into those at risk for metastases and those not as risk or at extremely low risk.

Materials and Methods

This study was approved by the institutional review board. CA 125 was ordered on all patients with endometrial cancer since 2000. Data were collected on all patients with undergoing surgery for Grade 1 endometrial adenocarcinomas from July 2003 until December 2013. Only patients who underwent full surgical staging were included in analysis. There was no differentiation of data by procedure used for diagnosis (office biopsy versus dilation and curettage). All specimens were reviewed by a gynecologic pathologist and at institutional tumor boards before surgery.

Statistical analyses were conducted using the SPSS. The independent t-test was used to compare baseline variables and Fisher’s exact test to analyze categorical and normally distributed numerical data. The Shapiro-Wilk test was used to test for normality, and for data with a skewed distribution, the Mann-Whitney U test was used. A p value of 0.05 was considered significant, corresponding to 95% confidence intervals (CIs). All tests were two-tailed. Results for normally distributed numerical data are presented as the mean with standard deviation (SD), and results for skewed numerical data are presented as the median.

Results

Seven hundred thirty-seven patients with Grade 1 endometrial adenocarcinomas had a preoperative CA 125 and underwent full surgical treatment and subsequent analysis. Another 53 patients underwent nonsurgical management of their Grade 1 disease because of medical comorbidities or patient request. Preoperative CA 125 could not be documented in 23 patients. The results will focus upon the 737 that underwent full staging and had a preoperative CA 125 within four weeks of surgery.

Analysis was completed on 737 patients with Grade 1 endometrial cancer. The mean age of the population was 61.9 years (95% CI 61.3, 62.4). The mean age of patients with a CA 125 <15 mIU/ml (63.4 years; 95%CI 62.5, 64.3) was higher than the mean age of patients with CA 125 ≥15 mIU/ml (61.8 years; 95%CI 61.2, 62.4) (p = 0.002).

The mean CA 125 for the cohort was 25.6 mIU/ml (95% CI 22.0, 29.2). Figure 1 demonstrates a receiver operator characteristic (ROC) curve. With this curve, CA 125 of 15 mIU/ml was shown to be the most important cut off. No patients with preoperative Grade 1 disease and a CA 125< 15 mIU/ml (0/239) had nodal disease at surgical staging, while 18.7% (93/498) with a CA 125 ≥ 15 mIU/ml had nodal metastases (p < 0.001) (Table 1). There was a direct correlation between CA 125 over 35 and metastatic disease being found (p <0.001). Extra-uterine disease was found in 14.7% of patients and nodal disease in 12.6%. The relationships among CA 125 and both lymph node metastases and any extrauterine metastases can be seen in Table 2.

Figure 1.

— Receiver operator characteristic (ROC) curve showing the sensitivity and 1-specificity for various CA 125 levels. At a CA 125 of below 15 mIU/ml, there are no positive lymph nodes found (100% sensitivity).

Table 1Serum CA 125 levels and number of patients.
CA 125 mIU/ml n CA 125 mIU/ml n
< 15 238 ≥ 15 498
< 35 708 ≥ 35 29
< 60 712 ≥ 60 25
Table 2CA 125 and metastatic disease (nodal or extrauterine including nodes).
CA 125 mIU/ml Negative nodes (n) Positive nodes (n) p value Negative for metastases (n) Positive for metastases (n) p value
< 15 239 0 < 0.001 239 0 < 0.001
≥ 15 405 93 380 108
< 35 626 65 < 0.001 625 66 < 0.001
≥ 35 18 28 4 42
< 60 630 70 < 0.001 628 72 < 0.001
≥ 60 14 23 1 36

A significant difference in BMI was seen between those not having lymph node metastases (mean 38.7 kg/m2; 95% CI 38.1, 39.3) and those having positive nodes (mean 35.3 kg/m2; 95% CI 34.3, 36.3) (p < 0.001).

Discussion

The risk of lymph node metastases corresponds with increasing grade and depth of invasion and ranges from 35% in well differentiated tumors with only superficial myometrial invasion to 20% in poorly differentiated tumors with deep myometrial invasion [5-9]. Lymph node metastases is highly correlated with prognosis, but because so many women with low grade disease do not have lymph node metastases, the approach to lymph node assessment is controversial and has prompted research into risk factors for nodal metastases that would allow for more selective staging procedures.

CA 125 is a tumor antigen first discovered in 1981 when it was found to be elevated in the serum of patients with epithelial ovarian cancer [10]. Since then, it has become key in the management of patients with ovarian cancer, and is now widely used to predict treatment response and prognosis. Several years after its discovery, CA 125 was found to be elevated not only in ovarian cancer, but also in patients with recurrent or widespread endometrial cancer [11], and was suggested as a method of follow up in patients after treatment of endometrial cancer. In 1997, Sood et al. found that CA 125 was the most significant predictor of extrauterine disease, correlating with not only increasing stage, but also increasing grade, positive peritoneal cytology, and positive pelvic nodes [12]. These results led to the proposal that CA 125 should be part of the preoperative workup for uterine cancer and help guide treatment decisions. Sood et al. predicted that by considering vaginal hysterectomy alone for patients with a CA 125 less than 20 U/mL and favorable histology, 24% of staging surgeries could be prevented with only a 3% risk of extrauterine disease [12]. Sood et al. also found that CA 125 levels correspond with survival rates, and therefore could serve an important prognostic role [12]. Although CA 125 is now commonly incorporated into the preoperative workup, it is not routinely used to plan for the degree of surgical staging. In this study, the authors assessed CA 125 in patients with Grade 1 endometrial cancer, and showed that preoperative CA 125 levels can be used to avoid lymphadenectomy in patients with low-risk of nodal metastases.

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