In the United States, endometrial cancer is the most common female malignancy, with an estimated mortality of 7950 women in 2010, ranking eighth for cancer-related deaths.1 Although endometrial cancer tends to be diagnosed in older postmenopausal women with a median age of 61 years, conditions of approximately 20% to 25% of the patients are diagnosed before menopause.2 In Taiwan, the mean age of menopause is 50 years. The 2010 annual report of the Taiwan Department of Health (DOH) estimated that up to 35% of the cases of endometrial cancer occurred in women aged 50 years or younger.3 Therefore, ovarian preservation and lymphadenectomy should be an issue that requires consideration, especially in young women. Several studies have compared younger and older endometrial cancer patients to estimate whether there were any differences in the outcome. Some reports have shown that a more favorable prognosis was most commonly encountered in younger patients.2,4,5 To date, the number of published studies examining this population of premenopausal women has been limited,6 and few studies have focused on the risk factors associated with endometrial cancer in women diagnosed at a young age.
The incidence of endometrial cancer has progressively increased in Taiwan, and the number of cases of endometrial cancer in younger premenopausal women has increased simultaneously. The development of endometrial cancer is predominantly related to excess estrogen exposure. The risk factors for endometrial cancer include obesity, nulliparity, late menopause, diabetes mellitus, unopposed estrogen therapy, tamoxifen therapy, and use of sequential oral contraception. Excess estrogen from any of these sources produces continued stimulation of the endometrial lining, which can result in endometrial hyperplasia and, potentially, endometrial cancer. Obesity has the highest associated risk ratio. The risk is increased 3-fold in women 9 to 23 kg heavier than the ideal body weight and 10-fold in women more than 23 kg heavier than the ideal body weight. Diabetes has been found to have a relative risk (RR) of 2.7, and nulliparity has been associated with an RR of 2.0.7 Noda et al8 reported that no history of pregnancy, a small number of pregnancies or births, no experience with contraception, and a history of hormone therapy in Asian women carried high RRs of endometrial cancer. The purpose of this study was to review the 10-year clinical and pathologic characteristics of a retrospective cohort of young Taiwanese women with the diagnosis of endometrial cancer.
MATERIALS AND METHODS
After obtaining approval from the institutional review board, 512 patients with histologically confirmed adenocarcinoma of the endometrium evaluated and treated at the Taipei Veterans General Hospital from 2001 to 2010 were enrolled into the study. Of the 512 patients, 146 (28.5%) were both premenopausal (ie, cessation of menstruation less than 1 year) and younger than 50 years at the time of diagnosis.
Clinical data, including age at diagnosis, presenting symptoms, body mass index (BMI), gravidity, parity, menopausal status, oral contraceptive pill use, history of diabetes, hypertension, and history of cancer, were obtained from medical records. The BMI was calculated by weight in kilograms divided by the height squared in meters. Subjects were classified into normal weight (BMI, 18–22.9 kg/m2) and overweight (BMI, ≥23 kg/m2) at baseline based on the definition of overweight and obesity suggested by the 2000 World Health Organization Asia-Pacific Guideline.9 Pathologic information, such as histology, tumor grade, depth of myometrial invasion, vascular space invasion, and lymph node involvement, was collected from surgical pathology reports generated by our gynecologic pathology department at the time of diagnosis or referral. The diagnosis of synchronous ovarian and endometrial cancers was made based on the criteria outlined by Scully et al10 in the Atlas of Tumor Pathology. The surgical staging criteria set forth by the International Federation for Gynecology and Obstetrics in 2009 were used. Survival and time to recurrence were also evaluated.
In all, 508 patients underwent surgical treatment with hysterectomy and bilateral salpingo-oophorectomy, and 4 patients underwent ovarian preservation surgery. The pathologic specimen was evaluated by gynecologic pathologists. Patients with carcinosarcoma of the uterus were excluded from the study.
Data were analyzed using the SPSS Software Version 17.0 for Windows (SPSS Inc, Chicago, IL). The χ2 test was used to assess the significance of differences in categorical clinical and pathologic variables. Continuous variables were analyzed using t tests and analysis of variance. Kaplan-Meier survival analyses were generated and compared using the log-rank test. Cox regression was used for multivariate analysis to determine independent prognostic factors for survival. P < 0.05 was used to determine statistical significance.
With regard to the clinical characteristics of the 512 patients, the mean age of the younger women (aged <50 years) and older women (aged ≥50 years) was 42.7 ± 5.2 years (range, 26–49 years) versus 60.1 ± 8.4 years (range, 50–89 years), respectively, and the median follow-up was 36.5 months (range, 0.9–121.7 months) versus 29.6 months (range, 0.2–122.6 months), respectively. Body mass index less than 23 kg/m2 (P < 0.001), nulliparity (P < 0.001), less medical illness (P < 0.001), and less adjuvant treatment (P < 0.001) were more common in the younger women (Table 1).
Twenty patients (3.9%), 12 younger and 8 older, had a primary ovarian cancer (P = 0.001). Among the young patients with synchronous primary ovarian cancer (n = 11), 9 (81.8%) had an endometrioid histology for both the endometrium and the ovary, 1 had an endometrioid histology for the endometrium and an endometrioid/mucinous histology for the ovary, and 1 patient had mixed endometrioid/neuroendocrine tumors of the endometrium, with an endometrioid histology of the ovary. At the time of surgery, gross ovarian disease was found in 10 (90.9%) of 11 patients, and microscopic disease was identified in 1 (9.1%) of 11 patients. The condition of the other patient with metachronous primary ovarian cancer was diagnosed with disease 2 years before the endometrial cancer diagnosis.
Younger women seemed to have had a greater association with many favorable pathological characteristic features compared with older women. However, the associations were significant only for endometrioid histology, tumor grade, lymph node status, depth of myometrial invasion, and vascular space invasion. Early stage was also common in younger women but without statistical significance (P = 0.147). Survival was then examined. Kaplan-Meier analysis revealed that the disease-free survival (P = 0.006, log-rank statistic; Fig. 1) and the overall survival (P = 0.004, log-rank statistic; Fig. 2) were better in young women than in older women (Table 2).
Univariate Cox regression analysis was used for the variables of age, histological type, stage, tumor grade, pelvic lymph node involvement, para-aortic lymph node involvement, cervical and adnexal involvement, tumor size, depth of myometrial invasion, lymphovascular space invasion, and peritoneal cytology. Stage was a significant factor associated with disease-free survival (hazards ratio [HR], 4.53; 95% CI, 1.60–12.84; P = 0.004) and overall survival (HR, 2.73; 95% CI, 0.96–7.76; P = 0.050). Moreover, lymph vascular space invasion was related to disease-free survival (HR, 2.69; 95% CI, 1.17–6.19; P = 0.019), and young age was related to overall survival (HR, 0.10; 95% CI, 0.01–0.78; P = 0.028; Table 3).
In Taiwan, endometrial cancer is traditionally considered a disease of the fifth and sixth decades of life; however, a considerable number of patients are with the diagnosis before the age of 40. According to the annual report of the DOH, there were 1424 new cases in 2008, and the incidence rate had increased to 9.75 per 100,000. The median age of endometrial cancer patients was 52–54 years.3 The incidence of endometrial cancer diagnosed in young patients (<40 years) was reported to be up to 10%, which was comparable to that in our institution (7.5%) in 2008. The mean age at menopause in Taiwan is 50 years; therefore, we chose to evaluate the conditions of patients diagnosed with endometrial cancer who were aged younger than 50 years and premenopausal. We found that a high number of patients (28.5%) were younger than 50 years and premenopausal at the time of diagnosis. We performed an analysis comparing patients aged younger than 50 years and those 50 years and older; there were significant differences in nulliparity, BMI, diabetes, hypertension, hormone treatment, and synchronous/metachronous ovarian cancer among the 2 groups.
The DOH in Taiwan has defined overweight as BMI greater than or equal to 24 kg/m2 and obesity as BMI greater than or equal to 27 kg/m2. This differs from the criteria of the World Health Organization Asia, which define overweight as BMI greater than or equal to 23 kg/m2 and obesity as BMI greater than or equal to 25 kg/m2.11 Obesity is an epidemic problem in the industrialized world12–15 and is also a growing problem in Taiwan.16 Choo17 suggested that the range for acceptable, normal, or optimum BMI for Asian populations should be narrowed to 18.5 to 23 kg/m2. Anuurad et al18 also reported a higher prevalence of metabolic syndrome because of the increasing risks of “overweight” with a BMI based on Asian criteria. We found that 51.4% of our younger patients had a BMI greater than or equal to 23 kg/m2, and 33.6% met the Asian criteria for obesity (BMI ≥25 kg/m2). These findings were comparable to those reported in previous studies.4,19,20 However, the higher percentage of older women with BMI greater than or equal to 23 kg/m2 (73%) compared with younger women was significant, and as a result, low BMI was commonly found in premenopausal women with endometrial cancer.
We found that 45.9% of patients were nulliparous, with an incidence of 61.7% in women aged 40 years or younger and 58.2% in women aged 45 years or younger. This incidence was slightly higher than that in previous studies.4,19,20 However, Soliman et al6 reported similar findings in a large cohort study, with up to 55% of patients being nulliparous and 71% of the women aged 40 years and younger. These results may reflect the change in lifestyle and behavior during the last decade. A history of irregular menstrual cycles of at least 1 year before the time of diagnosis was reported by 50% (73) of our patients. This information has been available in only a limited number of large studies.6 About 6.8% and 9.6% of our cohort reported a history of diabetes and hypertension, respectively, similar to a previous large study.20
Varying results suggest a relationship between endometrial cancer and tamoxifen use. Longer duration of tamoxifen use has also been associated with the development of endometrial cancer.21,22 In our cohort, 4 younger women and 1 older woman with a history of breast cancer and who received tamoxifen treatment developed type I uterine cancer within 2 years. Tamoxifen use was likely to be associated with a shorter interval to the development of uterine cancer and less aggressive histological types, especially in younger women. However, this result was not significantly associated with the limited number of patients.
Sixteen younger women had coexisting adnexa malignancies. Eleven of these patients had synchronous ovarian cancer, 1 had metachronous ovarian cancer, and 4 had metastatic disease. Previous studies have reported an incidence of synchronous primary ovarian cancers ranging from 7% to 29% in young endometrial cancer patients.6,19 In our study, a higher number of patients aged younger than 50 years than those aged 50 years or older (8.8% vs 2.2%, P = 0.001) were found to have synchronous ovarian cancer. In addition, 91% of patients with synchronous ovarian cancer were noted to have gross ovarian disease at the time of surgery, This finding highlights the need for careful evaluation of the adnexa at the time of surgery for young women with a preoperative diagnosis of endometrial cancer, and especially for those who undergo ovarian preservation surgery.
Most studies found low-risk features in young endometrial cancer patients, for example, low-grade tumor, endometrioid histology, early-stage disease, and less myometrial invasion.5,23 However, some studies found no difference in the prognostic factors between younger and older patients, in terms of grade, histology, or stage.24,25 Our study found that younger women seemed to have a greater association with favorable surgical-pathological characteristics than older women. The associations were statistically significant for endometrioid type, grade, lymph node status, depth of myometrial invasion, and vascular space invasion, but not for stage and tumor size.
This study included a large cohort of endometrial cancer patients aged younger than 50 years who were treated at a single institution. There was a high incidence of early stage and irregular menstrual cycles among these younger women. In addition, there was significantly more nulliparity, more endometrioid-type and low-grade tumor, no vascular space invasion, less lymph node metastasis, less myometrial invasion, and favorable disease-free and overall survival in the younger women compared with the older women. Moreover, synchronous primary ovarian cancer patients are commonly younger women, so hormonal factors may play a role in the development of endometrial cancer. These findings might help the physician counsel young endometrial cancer patients in terms of tailoring their treatment and achieving a favorable prognosis. However, careful intraoperative assessment of the adnexa is mandatory in young women with endometrial cancer who desire ovarian preservation. These women should be counseled regarding the high rate of coexisting ovarian malignancy.
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