Soliman, Pamela T. MD; Oh, Jonathan C. MD; Schmeler, Kathleen M. MD; Sun, Charlotte C. DrPh; Slomovitz, Brian M. MD; Gershenson, David M. MD; Burke, Thomas W. MD; Lu, Karen H. MD
In the United States endometrial cancer is the most common malignancy of the female genital tract, with 40,320 new cases and 7,090 cancer-related deaths estimated for 2004.1 Although endometrial cancer tends to be diagnosed in older, postmenopausal women with a mean age of 61 years, between 5% and 30% of endometrial cancers are diagnosed in “young” women.2–6 Several studies have compared “young” and older endometrial cancer patients to estimate whether there was any differences in outcome. Although some reports have shown that younger women diagnosed with endometrial cancer have a more favorable prognosis,6–8 other studies have reported no differences between these groups.4,9 To date, the published studies examining this population of young women have been limited by small numbers. In addition, few studies have focused on the risk factors associated with endometrial cancer in women diagnosed at a young age.
The development of endometrial cancer is predominantly related to excess estrogen exposure. Risk factors 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 9–23 kg more than ideal body weight, and 10-fold in women more than 23 kg heavier than ideal body weight. Diabetes has been found to have a relative risk (RR) of 2.7, and nulliparity has been associated with a RR of 2.0.10 The purpose of this study was to review the clinical and pathologic characteristics in a large cohort of women diagnosed with endometrial cancer aged younger than 50 years. We hypothesize that risk factors such as obesity, nulliparity, irregular menses, and possibly polycystic ovary syndrome (PCOS) are also relevant in the development of endometrial cancer in this group of women.
MATERIALS AND METHODS
After obtaining approval from the Institutional Review Board, our study population was identified through a search of the Tumor Registry database maintained by the Department of Medical Informatics. Between 1989 and 2003, 1,531 patients with histologically confirmed adenocarcinoma of the endometrium were evaluated and treated at the University of Texas M. D. Anderson Cancer Center. Of the 1,531 patients, 188 women (12.3%) were both premenopausal and aged younger than 50 years at the time of diagnosis.
Clinical data, including age at diagnosis, presenting symptoms, race, body mass index (BMI), gravidity, parity, menstrual history, oral contraceptive pill use, history of diabetes, hypertension, and personal and family history of cancer were obtained from medical records. Pathologic information such as histology, grade, depth of myometrial invasion, lymph-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. Endometrial cancer stage was assigned based on the surgical staging criteria set forth by the International Federation for Gynecology and Obstetrics.11 Survival and time to recurrence were also evaluated.
One hundred eighty-seven patients underwent surgical evaluation with hysterectomy and bilateral salpingo-oophorectomy. One patient did not undergo hysterectomy to preserve fertility and is being followed. The primary surgical management was performed at the M. D. Anderson Cancer Center in 112 of the patients. The remaining 75 patients were referred after initial surgical management at an outside institution. The pathologic specimens for all 187 cases were reviewed by gynecologic pathologists at our institution. Patients with malignant mixed mesodermal tumors of the uterus were excluded from the study.
Data were analyzed using SPSS 11.5 software (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. A P value of less than .05 was used to determine statistical significance.
The clinical characteristics of all 188 patients are shown in Table 1. The mean age at the time of diagnosis was 41 years (median 42, range 21 to 49 years). All of the patients were premenopausal. The mean BMI was 34.2 kg/m2 (median 33, range 18 to 68). Forty-seven patients (25%) were in the normal weight range (BMI < 25), 31 patients (17%) were overweight (25 ≤ BMI < 30), and 106 patients (58%) met criteria for obesity (BMI ≥ 30).12
One hundred two women (54%) were nulliparous. Twenty-five patients reported a history of infertility. Seventy-three women (39%) had a history of irregular menstrual cycles. Fourteen patients reported a history of PCOS. Six patients had pathologic findings consistent with the diagnosis; more than 12 follicles in each ovary measuring 2–9 mm in diameter or increased ovarian volume (> 10 mL).13 Twenty-three percent (44/144) of patients had diabetes, and 23% (43/144) had hypertension. Sixty-four patients (34%) reported taking oral contraceptive pills for at least 1 year. When patients were divided into groups based on age at the time of diagnosis, there were no significant differences among the subgroups (Table 1).
Forty-eight patients (26%) had a second primary cancer (Table 2). Thirty-six patients (19%) were noted to have synchronous ovarian cancer at the time of their endometrial cancer diagnosis. The diagnosis of synchronous ovarian and endometrial cancers was made based on the criteria outlined by Scully et al14 in the Atlas of Tumor Pathology.
One of these patients also had a prior history of colon cancer. One patient was diagnosed with ovarian cancer 8 years before her endometrial cancer diagnosis. Two patients had a history of colon cancer. Three patients had a history of breast cancer and 1 patient had a history of ductal carcinoma in situ. None of these patients were treated with tamoxifen. The other second primary cancers were cervical cancer, fallopian tube cancer, renal cell carcinoma, urachal adenocarcinoma, and neuroblastoma.
Family history data were available for 177 patients. Three percent (6/177) reported a family history that met the revised Amsterdam criteria for hereditary nonpolyposis colorectal cancer (HNPCC).15 An additional 23 patients (13%) reported having at least one first-degree relative with an HNPCC-related cancer (colon, endometrial, ovarian, gastric, or small bowel).
One hundred sixty-eight patients (89%) had pure endometrioid histology (Table 3). Six patients (3.5%) had at least a component of papillary serous carcinoma and 7 patients (3.5%) had a component of clear cell carcinoma. The remaining 7 patients had either mixed or undifferentiated histology. Forty-five percent of patients had grade 1 tumors, 40% had grade 2 tumors, and 15% had grade 3 or undifferentiated tumors. Twenty-eight percent of patients had disease confined to the endometrium, 48% had superficial myometrial invasion, and 22% had deep myometrial invasion. Lymph-vascular space invasion was present in 31% of tumors. The stage distribution is shown in Table 4. Sixty-one percent of patients were stage I, 12% were stage II, 18% were stage III, and 8% were stage IV.
In the subgroup of patients with synchronous primary cancers of the ovary (n = 36), 21 patients (58%) had endometrioid histology of both the endometrium and the ovary. Of the remaining 15 patients, 13 had endometrioid histology of the endometrium and nonendometrioid histology of the ovary. Two patients had mixed endometrioid/clear cell tumors of the endometrium, with endometrioid/clear cell and endometrioid/clear cell/serous tumors of the ovary. At the time of surgery, gross ovarian disease was found in 28/36 (78%) of patients and microscopic disease was identified in 4/36 (11%) of patients. Information was not available on 4 patients.
For all patients, median follow-up was 32 months (range 1–166 months). Ninety-five patients received adjuvant therapy. Forty-eight patients were treated with radiation, 31 patients were treated with chemotherapy, and 16 patients received a combination of radiation and chemotherapy. Twenty-eight patients (15%) developed recurrent disease. The median time to recurrence was 24 months (range 4 to 99 months). Advanced stage disease was a poor prognostic factor (median survival was not reached for stage I compared with 24 months for stage IV, P < .001). At the time of analysis, 33 patients were deceased. Median overall survival in this subgroup was 25 months (range 2 to 124 months). Causes of death included uterine cancer (n = 13), synchronous uterine and ovarian cancer (n = 11), colon cancer (n = 1), cervical cancer (n = 1), and fallopian tube cancer (n = 1). The cause of death was unknown in 6 patients.
Endometrial cancer is traditionally considered a disease of the sixth and seventh decades of life; however, there are a considerable number of patients who are diagnosed before the age of 50 years. Previous studies have reported a wide range in the incidence of endometrial cancers diagnosed in young patients. This variation may be related to the definition of “young” in this study population. Gallup et al3 described a cohort of patients who were less than 40 years of age at the time of diagnosis. Several other authors have included patients younger than the age of 45 at the time of diagnosis.4,5,7–9,16 In our study, we chose to evaluate patients diagnosed with endometrial cancer aged younger than 50 years because it is the criterion generally used for hereditary cancer syndromes. In addition, the mean age of menopause in the United States is 51 years, and our intent was to capture patients who were premenopausal at the time of diagnosis. We performed a subset analysis comparing patients aged 40 and younger, 41 to 45, and 46 to 49 years and found no significant differences in nulliparity, obesity, diabetes, hypertension and family history among the 3 subgroups.
In our cohort of 188 patients, we found that 56% met criteria for obesity (BMI ≥ 30 kg/m2). The incidence of obesity was slightly higher in the subset of patients aged 40 years or younger at the time of diagnosis (n = 79, 62%). These findings were consistently higher than the incidence of obesity reported in previous studies (Table 5). The referral pattern at our institution may contribute to the higher percentage of obese patients in this cohort. In addition, several of the other studies were performed in countries with lower rates of obesity, such as Japan, Denmark, Italy, and Australia.7,8,16,17 The 2 larger studies conducted in the United States focused primarily on outcome, and information on obesity was not available for comparison.4,9
We found that 55% of patients were nulliparous, with an incidence of 71% in women aged 40 years or younger. Previous studies have reported similar findings, with the exception of a study by Parslov et al17 who reported nulliparity in only 19% of young endometrial cancer patients in Denmark. Thirty-nine percent of our patients reported a history of irregular menstrual cycles defined as irregular periods for at least 1 year before the time of diagnosis. This information was only available in a limited number of the previous studies. Twenty-three percent of our cohort reported a history of diabetes. This is significantly higher than previous studies, and is likely related to our higher percentage of obese patients.
It is clear from our study that a high proportion of young women who develop endometrial cancer are obese, nulliparous, and report irregular menstrual cycles. Historically, these characteristics, coupled with hirsutism and infertility, have been associated with polycystic ovarian syndrome.13 The association between endometrial cancer and PCOS has been suggested for many years;18 however, the diagnostic criteria used to define PCOS have varied, making it difficult to assess the relationship between PCOS and endometrial cancer risk.19 Despite the recent revision in the diagnostic criteria for PCOS, it is difficult to evaluate this disease retrospectively. Although some of our findings may suggest that PCOS may be a risk factor for these women, prospective evaluation of young patients with endometrial cancer would be necessary to define the relationship between PCOS and endometrial cancer risk.
A high number of patients in our study (19%) were found to have synchronous ovarian cancer at the time of surgery. Previous studies have reported an incidence of synchronous primary ovarian cancers in young endometrial cancer patients ranging from 7% to 29%.4,8,9 In our previous review of patients with synchronous primary cancers of the endometrium and ovary, we found that 50% of these women were aged younger than 50 years at the time of diagnosis.20 In our current study, 78% 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. In addition, 4 patients had microscopic ovarian cancer noted at the time of pathologic review. It is unclear whether bilateral oophorectomy should be offered to all young patients with endometrial cancer.
In young patients diagnosed with cancer, and in particular those diagnosed with multiple primary cancers, familial cancer syndromes should be considered. Women with HNPCC have up to a 60% lifetime risk of developing endometrial cancer.21 In our cohort of patients, only 6 patients (3%) reported a family history that met the revised Amsterdam Criteria for the diagnosis of HNPCC. Two of these patients had synchronous ovarian cancers, and 1 had metachronous colon cancer. Similar to previous reports, our findings indicate that it is unlikely that HNPCC accounts for a significant number of young, endometrial cancer patients.22 Although family history data has several limitations, at the present time this is the primary source of information used to determine whether patients are at risk for HNPCC. We are currently conducting a prospective clinical trial evaluating the prevalence of HNPCC mutations in women diagnosed with endometrial cancer aged younger than 50 years, regardless of family history. This will help determine whether diagnosis at a young age alone warrants genetic testing.
In summary, our study represents a large cohort of endometrial cancer patients aged younger than 50 years treated at a single institution. We found that 12% of patients evaluated with endometrial cancer between 1989 and 2003 at our institution were younger than age 50 years at the time of diagnosis. In this cohort, there was a high incidence of obesity, nulliparity, and irregular menstrual cycles. In addition, there were a high number of synchronous primary ovarian cancers. These findings suggest that hormonal factors may play a role in the development of endometrial cancer. Further studies are needed to better understand the causes and risk factors of endometrial cancer in young women.
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