Uterine Cancer

Genetics

Endometrial cancer is uncommon in premenopausal women, and genetic factors account for only 1% of newly diagnosed cases. Lynch syndrome, or hereditary nonpolyposis colorectal cancer syndrome (HNPCC), is associated with a relative risk of 1.5 for the development of endometrial cancer before menopause. Women with Lynch syndrome have a 27% to 71% risk of endometrial cancer. Mutations in the DNA mismatch repair genes impair the ability to maintain genomic integrity. Patients with Lynch syndrome have a germline mutation in one mismatch repair allele, and the second allele is inactivated through mutation, loss of heterozygosity, or epigenetic silencing by promoter hypermethylation. Inactivation of both genes leads to increased DNA mutations and alteration of microsatellite regions in the tumor compared with normal tissue. Microsatellite instability refers to the contraction or expansion of short repetitive DNA sequences and is caused by loss of DNA mismatch repair. Microsatellite instability is found in 90% of tumor tissue from patients with Lynch syndrome. Mutations in MSH2 or MLH1 account for approximately 90% of the identified mutations associated with Lynch syndrome. Mutations in PMS1, MSH6 , and MLH3 have also been described. The age of diagnosis in women with Lynch syndrome is 46 to 54 years. Endometrioid histology is the most common Lynch syndrome–associated endometrial cancer; however, nonendometrioid tumors have been reported. The majority of tumors are diagnosed with early-stage disease, similar to women with sporadic endometrial cancer. Women with Lynch syndrome are at risk for synchronous or metachronous cancers. The Amsterdam Criteria have been developed to identify families at risk for Lynch syndrome ( Table 85.2 ). The Society of Gynecologic Oncologists published a statement for genetic testing of individuals at risk for Lynch syndrome ( Table 85.3 ). Moreover, it released a practice statement suggesting that all women diagnosed with endometrial cancer should undergo a systematic clinical screening (including a review of person and family history), or molecular screening for Lynch syndrome, or both.

Risk Factors

Table 85.4 lists many of the known risk factors for endometrial adenocarcinomas. Endogenous estrogen exposure associated with nulliparity, early menarche, late menopause, obesity, and estrogen-producing tumors are associated with an increased risk of endometrial cancer. Risk factors are associated with the unopposed estrogen effect, or lifetime estrogen exposure. Exposure to unopposed estrogen leads to increased endometrial cell proliferation, resulting in increased DNA replication errors and somatic mutations. Exogenous estrogen sources, such as hormone replacement therapy without progestins, increases the risk for endometrial cancer fivefold. The use of progestins with hormone replacement therapy may decrease the risk of uterine cancer through downregulation of hormone receptors. Cancers that occur in women on combined hormone replacement therapy tend to be of low stage and grade. Endogenous hormones, such as androstenedione, estrone, and estradiol, are associated with a threefold to fourfold increased risk.

The National Surgical Adjuvant Breast Project (NSABP) and the Netherlands Cancer Institute clarified a causal link between the treatment of breast cancer with tamoxifen and endometrial cancer. Tamoxifen, a selective estrogen receptor (ER) modulator, was first described as a risk factor for uterine cancer in 1985. The NSABP evaluated 2834 women treated for breast cancer treated with tamoxifen. Twenty-four cases of endometrial cancer were diagnosed among the study patients. Nearly 96% ( n = 23) of endometrial cancer cases occurred in women taking tamoxifen. The annual hazard rates of endometrial cancer development were 1.6 per 1000 patient-years in the tamoxifen group and 0.2 per 1000 patient-years in the placebo group. In addition, 88% of endometrial cancers diagnosed were stage I, and 78% were of low or intermediate grade. The use of tamoxifen results in a 38% improvement in disease-free survival for breast cancer, which far outweighs the risk of endometrial cancer, from which there were only four deaths. A subsequent analysis by the NSABP showed the risk was predominately in women 50 years of age or older, with an incidence of approximately 2 per 1000. Regular gynecologic follow-up is recommended for patients on tamoxifen.

The Netherlands Cancer Institute performed a case-control study by identifying 98 patients in whom endometrial cancer developed after treatment for breast cancer compared with control participants in whom endometrial cancer did not develop. Twenty-four percent of the patients with endometrial cancer had taken tamoxifen compared with 20% of the control participants. Treatment with tamoxifen for 5 years or more was associated with an increased risk of 3.0-fold for endometrial cancer compared with control participants.

Previous Irradiation

The etiology of uterine sarcomas is not well understood, but it may be related to prior exposure to pelvic irradiation. Uterine sarcomas and carcinomas have been reported after irradiation for cervix and rectal cancer. Radiation-associated uterine cancers are usually of higher grade and stage, with a more unfavorable histology.

Other Comorbidities

Systemic disease and lifestyle factors influence the risk of endometrial cancer. Hypertension, diabetes, and obesity all increase the risk. Nearly 40% of uterine cancers can be attributed to obesity. Increasing body mass indices (BMIs) are associated with higher relative risks of developing a uterine malignancy. Overweight women (BMI, 28 to 29.9) have a relative risk of 1.5 compared with women with a normal BMI. Obese women (BMI, 30 to 33.9) have a relative risk of 2.9, and markedly obese women (BMI >34) have a relative risk of 6.3. The increased risk of endometrial carcinoma associated with increasing BMI may be explained by higher levels of endogenous estrogen. The conversion of androstenedione to estrone and the aromatization of androgens to estradiol occurs in peripheral adipose tissue. Severely obese women are more likely than nonobese women to have a less aggressive histology and present with stage I disease.

Protective Factors

Known protective factors against endometrial cancer include full-term pregnancy, multiparity, older age of menarche, and oral contraceptive use. Use of oral contraceptives for up to 5 years is associated with a relative risk of 0.2, and its use for at least 1 year reduces endometrial cancer risk by approximately 45%. Interestingly, cigarette smoking decreases the risk of endometrial cancer; however, the clear adverse risks of smoking greatly outweigh any potential benefit with respect to endometrial cancer.