In sharp contrast to many other cancer types, the incidence and mortality of endometrial cancer continue to grow. This unfortunate trend is, in no small part, a result of the worldwide obesity epidemic. More than half of endometrial cancers are currently attributable to obesity, which is recognized as an independent risk factor for this disease. In this review, we identify the molecular mechanisms by which obesity and adipose tissue contribute to the pathogenesis of endometrial cancer. We further discuss the impact of obesity on the clinical management of the disease and examine the development of rational behavioral and pharmaceutical interventions aimed at reducing endometrial cancer risk, improving cancer outcomes, and preserving fertility in an increasingly younger population of patients with endometrial cancer.

OBJECTIVE: Women with hereditary nonpolyposis colorectal cancer syndrome have a 40–60% lifetime risk for colon cancer, a 40–60% lifetime risk for endometrial cancer, and a 12% lifetime risk for ovarian cancer. A number of women with hereditary nonpolyposis colorectal cancer syndrome will have more than one cancer in their lifetime. The purpose of this study was to estimate whether women with hereditary nonpolyposis colorectal cancer syndrome who develop 2 primary cancers present with gynecologic or colon cancer as their “sentinel cancer.” METHODS: Women whose families fulfilled Amsterdam criteria for hereditary nonpolyposis colorectal cancer syndrome and who developed 2 primary colorectal/gynecologic cancers in their lifetime were identified from 5 large hereditary nonpolyposis colorectal cancer syndrome registries. Information on age at cancer diagnoses and which cancer (colon cancer or endometrial cancer/ovarian cancer) developed first was obtained. RESULTS: A total of 117 women with dual primary cancers from 223 Amsterdam families were identified. In 16 women, colon cancer and endometrial cancer/ovarian cancer were diagnosed simultaneously. Of the remaining 101 women, 52 (51%) women had an endometrial or ovarian cancer diagnosed first. Forty-nine (49%) women had a colon cancer diagnosed first. For women who developed endometrial cancer/ovarian cancer first, mean age at diagnosis of endometrial cancer/ovarian cancer was 44. For women who developed colon cancer first, the mean age at diagnosis of colon cancer was 40. CONCLUSION: In this large series of women with hereditary nonpolyposis colorectal cancer syndrome who developed 2 primary colorectal/gynecologic cancers, endometrial cancer/ovarian cancer was the “sentinel cancer,” preceding the development of colon cancer, in half of the cases. Therefore, gynecologists and gynecologic oncologists play a pivotal role in the identification of women with hereditary nonpolyposis colorectal cancer syndrome. LEVEL OF EVIDENCE: II-3

OBJECTIVE: Endometrial cancer is the most common gynecologic malignancy in the United States. The mean age at diagnosis is 61 years; however, 5–30% of women are aged younger than 50 years at the time of diagnosis. The objective of this study was to conduct a clinical and pathologic review of endometrial cancers diagnosed in premenopausal women aged younger than 50 years, to better identify the risk factors for this subgroup of women. METHODS: We conducted a retrospective cohort study of patients with histologically confirmed endometrial cancer treated at the University of Texas, M. D. Anderson Cancer Center from 1989 to 2003. Clinical characteristics including age, body mass index (BMI), parity, diabetes, and personal or family history of cancer were obtained from the medical record. Pathologic information was obtained from pathology reports. RESULTS: Twelve percent (188/1531) of all patients with endometrial adenocarcinoma were aged younger than 50 years. The mean age at diagnosis was 41 years (range 21–49 years). Mean BMI was 34 kg/m² (range 18–68); 58% of patients had a BMI of 30 or greater. Fifty-five percent were nulliparous and 39% reported irregular menstrual cycles. The incidence of both diabetes and hypertension was 23%. Thirty-six patients (19%) had synchronous ovarian cancers. CONCLUSION: We found that the majority of patients diagnosed with endometrial cancer at a young age were obese and nulliparous. In addition, we found a high incidence of synchronous primary ovarian cancers in this cohort of young, premenopausal women. LEVEL OF EVIDENCE: III

Background: Approximately 2% to 5% of endometrial cancers may be due to an inherited susceptibility. Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, an autosomal-dominant inherited cancer susceptibility syndrome caused by a germline mutation in one of the DNA mismatch repair genes, accounts for the majority of inherited cases. Lynch syndrome is associated with early onset of cancer and the development of multiple cancer types, particularly colon and endometrial cancer. Methods: The current status of knowledge regarding Lynch syndrome-associated endometrial cancer and methods for diagnosis, screening, and prevention of cancers is reviewed. Results: The lifetime cumulative risk of endometrial cancer for women with Lynch syndrome is 40% to 60%, which equals or exceeds their risk of colorectal cancer. No current evidence suggests either a survival advantage or disadvantage to endometrial cancer that is associated with Lynch syndrome when these cases are compared with sporadic cases. A combination of family and personal medical history and tumor testing provides an efficient basis for diagnosing Lynch syndrome in women with endometrial cancer. Current gynecologic cancer screening guidelines for women with Lynch syndrome include annual endometrial sampling and transvaginal ultrasonography beginning at age 30 to 35 years. Conclusions: Diagnosing endometrial cancer patients with Lynch syndrome has important clinical implications for the individual and family members. Screening and prevention practices can decrease the likelihood of developing additional cancers.

Purpose: Age younger than 50 years at the time of colon cancer diagnosis is often used as a screening criterion for Lynch syndrome (hereditary nonpolyposis colorectal cancer syndrome). The purpose of this study was to determine the prevalence of MLH1, MSH2, and MSH6 mutations in an unselected cohort of women diagnosed with endometrial cancer at age younger than 50 years. Methods: A prospective, multicenter study was performed at three institutions. After written consent was obtained, germline mutation testing by full sequencing and large deletion analysis of the MLH1, MSH2, and MSH6 genes was performed. Tumor studies included immunohistochemistry of MLH1, MSH2, and MSH6; microsatellite instability analysis; and hypermethylation of the MLH1 promoter. Results: Of the 100 women, nine (9%; 95% CI, 4.2 to 16.4) carried a deleterious germline mutation: seven women with mutations in MSH2, one woman with a mutation in MLH1, and one woman with a mutation in MSH6. Two additional women had molecular studies consistent with the diagnosis of Lynch syndrome. The mean body mass index (BMI) for the entire cohort was 34.4, which is significantly higher than 29.2, the mean BMI for the mutation carriers. Predictors of finding a germline mutation included having a first-degree relative with a Lynch syndrome–associated cancer, endometrial tumor with loss of MSH2 expression, tumors with high microsatellite instability, and lower BMI. Conclusion: In this prospective study of endometrial cancer patients younger than age 50 years, 9% were found to carry germline Lynch syndrome–associated mutations. In addition to young age of onset, family history, BMI, and molecular tumor studies can improve the likelihood of identifying a Lynch syndrome–associated germline mutation in MLH1, MSH2, and MSH6.