Endometrial cancer: An increasingly common gynecologic malignancy

Endometrial cancer is the most common gynecologic malignancy in the U.S. and is second only to cervical cancer worldwide. Endometrioid adenocarcinoma is the most common subtype and portends a positive prognostic factor when low- or intermediate-grade and compared with other histopathologies. Important risk factors for endometrial cancer include age, predisposing genetic syndromes, and prolonged exposure to estrogen in the absence of progestins. Obesity is a modifiable risk factor for endometrial cancer and is becoming increasingly important in counseling patients in the setting of the international obesity epidemic. Treatment typically includes surgery, with radiation or chemotherapy reserved for high-risk lesions. In counseling patients with endometrial cancer, it is important that care be coordinated by a gynecologic oncologist.

Epidemiology, risk factors, and genetics

Approximately 600,000 new cases of endometrial cancer are diagnosed worldwide each year, with more than 60,000 occurring in the U.S.¹ Per 100,000 women, the mortality rate of uterine cancer is 1.7 to 2.4 per 100,000 women, with individual risk dependent on demographic, histopathologic, stage, and genetic factors. Because most women are diagnosed at an early stage with disease confined to the uterus, the five-year survival rate can exceed 90 percent.^2,3 Women in the U.S. have a 2.8 percent lifetime risk of being diagnosed with uterine cancer, with an average age of diagnosis of 62 years. At diagnosis, only about 21 percent of women will have evidence of regional spread or lymph node involvement, with distant metastasis evident in 8 percent.³ Although some women are diagnosed due to incidental findings on cervical pathology or imaging, the cardinal symptom of endometrial cancer is abnormal uterine bleeding and is the presenting symptom of 75 to 90 percent of patients.^3,4

Endometrial adenocarcinoma is the most common subtype and confers the most favorable prognosis. Endometrial cancers are defined into two histologic categories (type I and type II tumors) and help to stratify risk and clinical features.⁵ Type I cancers include grade 1 or 2 endometrioid adenocarcinomas and typically have the favorable prognosis previously described. They may be preceded by endometrial hyperplasia and are estrogen-responsive. Type II malignancies are high-risk lesions and include grade 3 endometrioid adenocarcinoma and those of nonendometrioid histology, such as serous, clear cell, mucinous, squamous, transitional cell, mesonephric, and undifferentiated. Type II cancers account for 10 to 20 percent of all endometrial carcinomas.

Because type I tumors are hormone-sensitive, main risk factors include exposure to unopposed (in excess of progestin) endogenous or exogenous estrogen, such as polycystic ovarian syndrome, obesity, and nulliparity. Similarly, increased risk occurs in conditions affecting the metabolism of hormones or production of sex hormone-binding globulin, which increases the circulating levels of bio-available estrogen. Such conditions include age, tamoxifen therapy, diabetes mellitus, hypertension, and liver dysfunction.^6,7

Several genetic syndromes have been linked to an increased risk of endometrial cancer. Lynch syndrome, or hereditary nonpolyposis colorectal cancer, is an autosomal dominant genetic condition attributed to a mutation in DNA mismatch repair genes. Although most commonly associated with colorectal cancer, endometrial cancer is the second most common associated malignancy, with a lifetime risk of 12 to 54 percent.⁸ Cowden syndrome results in a mutation in the PTEN tumor suppressor gene; women with Cowden syndrome have a lifetime risk of 13 to 28 percent.⁹

Obesity and endometrial cancer

Though the lifetime risk of endometrial cancer is low, both incidence and mortality rates have increased over the last few decades in large part due to the obesity epidemic, with about 57 percent of diagnoses in the U.S. attributable to being overweight or obese.¹⁰ Following diagnosis, obesity is considered a poor prognostic factor. When compared with women with normal body mass index (BMI), the relative risk (RR) for obese women with BMI of 30 to 34.9 kg/m2 is 2.53; the RR is 6.25 for women with BMI greater than 40 kg/m2.^11,12 Linear regression models predict the incidence of endometrial cancer will nearly double within the next 10 to 15 years.¹³

The association between obesity and endometrial cancer is strongest with type I tumors, with oncogenesis thought to be due to a variety of mechanisms. Visceral fat contains adipocytes and preadipocytes, as well as cells of hematologic, interstitial, and lymphocytic origin that increase endometrial proliferation and promote oncogenesis.¹⁴ Adipose tissue contains aromatase, leading to the conversion of androgens to estrogens, leading to endometrial proliferation and upregulation in the expression of pro-proliferation genes. Furthermore, increasing adiposity decreases serum levels of sex hormone-binding globulin, thereby increasing bio-available estrogen without a net increase of synthesis.¹⁵ Lifestyle modifications to decrease BMI are recommended, particularly to decrease risk associated with surgical morbidity; however, the associated risk reduction with weight loss for the development of endometrial cancer has yet to be determined.

Management of endometrial cancer

Like other gynecologic malignancies, endometrial cancer is treated with a combination of surgery, adjuvant chemotherapy, and/or radiation and is surgically staged according to the International Federation of Gynecology and Obstetrics/Tumor, Node, Metastasis classification system.¹⁶ For women for whom optimal debulking to no residual disease (R0) is considered feasible, surgery includes, at minimum, peritoneal washings, total hysterectomy, bilateral salpingo-oophorectomy, bilateral pelvic/paraaortic lymphadenectomy, peritoneal biopsies, and removal of any other lesions suspicious for tumor. Laparoscopic-assisted vaginal, laparoscopic, and robotic-assisted procedures may be indicated in lieu of laparotomy and have been shown to decrease length of stay, surgical morbidity, and increase short-term patient satisfaction.¹⁷ More recently, it has been suggested that the use of bilateral sentinel node mapping and biopsies, rather than traditional lymphadenectomies, may be sufficient for staging and detection of extrauterine lymphovascular disease; this practice is rapidly becoming a part of clinical practice.¹⁸

The decision for adjuvant therapy is based on clinical and pathologic factors that are used to determine risk of disease recurrence. Low-risk lesions include low-grade endometrioid cancers confined to the endometrium and are treated with surgery alone, followed with surveillance. Patients with advanced stage (III or IV) disease or who have type II uterine cancers are considered high-risk and are typically offered adjuvant chemotherapy. For women who fall in the intermediate-risk category, further characteristics are used to stratify for the need of adjuvant chemotherapy or radiation, including histologic grade, depth of tumor invasion, and the presence of lymphovascular space invasion. Other prognostic factors, such as involvement beyond the endometrium, peritoneal cytology, and age, can be considered.^19,20

Patients with low-risk endometrial cancer or precancerous pathology, such as complex hyperplasia, may be candidates for conservative management, particularly in patients for whom surgery may present increased relative risk of morbidity or for those who desire future fertility. As these lesions are type I and confined to the uterus, progestin therapy, such as megestrol acetate or insertion of a levonorgestrel intrauterine device, may be considered.²¹ When counseling these patients, however, it is important to consider that high-risk features ultimately may be present at the time of surgery.²²

Trends and access to gynecologic cancer care

With the incorporation of minimally invasive procedures, novel chemotherapeutic agents, and newer surgical techniques, the American College of Obstetrics and Gynecology recommends referral to gynecologic oncologists for the treatment of endometrial cancer. Recent retrospective studies suggest improved patient outcomes among high-volume surgeons and high-volume institutions.^23,24 Consultation with a gynecologic oncologist is recommended to improve the preoperative decision process, facilitate conversations regarding the benefit of adjuvant therapy, and prepare for comprehensive staging. Population studies indicated that gynecologic oncologists now provide the majority of care for women with endometrial cancer or endometrial hyperplasia who undergo hysterectomy in the U.S., with approximately 90 percent of women receiving care from a specialist.²⁵

Despite the increasing incidence of endometrial cancer, it is estimated that up to 9 percent of the women in the U.S. may experience geographic barriers to access to a gynecologic oncologist.²⁶ Similarly, even when controlling for histologic subtype, racial disparities persist despite equal access to care.²⁷ The differences in outcomes between white and black women remain when accounting for social or economic imbalances and cannot be adequately explained by a higher incidence of high-risk tumors in black patients.^28,29

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