Endometrial cancer is the fourth-most-common cancer diagnosed in women in the United States, following breast, lung, and colorectal cancer in frequency. It accounts for 6% of all cancers in women, with an estimated 54,870 new cases in 2015. It is the most common gynecologic malignancy in the United States. One in 40 women will develop endometrial cancer in their lifetime, and the American Cancer Society estimated there would be 10,470 deaths from this disease in 2016. Endometrial cancer is typically a disease seen in perimenopausal and postmenopausal women. The likelihood of developing an endometrial cancer is rare before the age of 40 (<5%), and the risk increases thereafter, with median age at diagnosis of 63. Caucasian women are twice as likely to be affected.

Endometrial cancers can be divided into 2 categories: type 1 and type 2.¹ Type 1 endometrial cancer includes endometrioid adenocarcinoma grades 1 and 2 and is more frequent. It is recognized to be estrogen related and hormonally dependent. It typically arises in patients with a hyperestrogenic state. Excess estrogen exposure can result from a variation of the normal reproductive physiology, as is seen in anovulatory cycles, polycystic ovary disease, prolonged perimenopause or late menopause with anovulatory bleeding pattern, or obesity. Alternatively, estrogen excess can be the result of iatrogenic administration or estrogen-secreting ovarian tumors. The risk of endometrial neoplasia is greater for nulliparous women. It is hypothesized that this process may be related to prolonged periods of infertility, correlating with anovulatory menstrual cycles, excessive serum levels of androstenedione, and lack of monthly sloughing of the endometrial lining. These tumors are typically estrogen and progesterone receptor (PR) positive and have a high sensitivity to progestins. Patients have a favorable prognosis, and 5-year survival of approximately 85%. Obesity in particular increases the risk of type 1 endometrial cancers.

Type 2 endometrial cancers represent the opposite end of the spectrum. These tumors are typically more aggressive. They do not need a hyperestrogenic environment for development. These cancers are high grade, display high-risk cell types, and are not hormonally driven. Examples include grade 3 endometrioid adenocarcinomas and serous, clear cell, and undifferentiated cancers. Type 2 tumors have a higher incidence of deep myometrial invasion and, in comparison to type 1, a higher metastatic potential. Because these tumors are frequently estrogen receptor negative, they have low response rates to progestins. They have a relatively poor prognosis, with a 5-year survival of 58%. Patients with type 2 cancers are typically thinner and older and have no apparent stigmata or history to suggest a hyperestrogenic state. Type 2 tumors are not associated with obesity.

Over 60% of adults in the United States have a body mass index (BMI) over 25, making them either overweight or obese. In a UK study, data from the Clinical Practice Research Datalink (CPRD) was utilized to examine associations between BMI and risk of individual cancers, adjusting for potential confounders. Each 5-kg/m² increase in BMI was linearly associated with cancers of the uterus, gallbladder, kidney, cervix, and thyroid and leukemia. Of endometrial cancers in this study, 41% could be attributable to excess weight.²

In the United States, the incidence of endometrial cancer increased every year from 1987 to 1998, and the disease-specific mortality has doubled, paralleling the rise in obesity during the same time frame.³ From 1999 to 2011, the incidence of endometrial cancer has increased within African Americans, Latinos, and Asian Pacific Islanders, while it has stayed relatively stable in whites (Figure 34-1). Decreases in the use of unopposed estrogen for hormone replacement therapy in the United States should have resulted in a decrease in endometrial cancer. But, this anticipated decrease was not seen and has been attributed to the rising incidence of obesity. It is estimated that 70%–90% of patients with type 1 endometrial cancer are obese.⁴ Obesity is a risk factor for neoplasia in both pre- and postmenopausal patients. Obesity and nulliparity are dominant risk factors for premenopausal endometrial cancer.⁵

Several studies have evaluated the relationship of obesity indices to the risk of endometrial cancer.^6,7 These studies showed that obesity increases the risk of endometrial neoplasia in a dose-dependent fashion; that is, women with a weight exceeding 78 kg (171 lb) are at a 2.3-fold increased risk over women with a weight of 58 kg (127 lb). A large meta-analysis of prospective studies that included 22,300 patients analyzed the association between anthropometric measures and endometrial cancers; it found that the relative risk (RR) for a 5-unit increment in the BMI was 1.54. The risk curve was nonlinear, with a steeper increase in risk in the overweight and obese BMI ranges.⁸

Adult weight gain increases risk, and avoidance of weight gain may be protective. Baseline weight and weight gain in adulthood are associated with increased endometrial cancer risk.⁹ A 20-kg (45-lb) weight gain has an RR of 2.75. In 2 large studies, current weight and adult weight gain conferred greater risk of endometrial cancer in never users of postmenopausal hormonal therapy (RR = 5.35) compared to ever users (RR = 2.53) or current users (RR = 1.44).^8,9

Body fat distribution also appears to have an effect on the risk of endometrial cancer. Patients with a greater waist-to-hip circumference ratio, abdomen-to-thigh skin ratio, and suprailiac-to-thigh skin ratio have an increased risk of endometrial cancer. This suggests that increased upper body fat localization increases the risk for endometrial cancer.

The effect of diet and dietary interventions in the obese population and the risk of endometrial cancer have been evaluated. A higher rate of endometrial cancer in the West and lower rates in Eastern societies suggest a role for nutrition due to the presence of a higher amount of animal fat in the typical Western diet. Both total energy intake and diet components seem to have an effect on risk. Meats, sugar, and eggs increase risk. Fruits, vegetables, and whole grain breads are protective, especially if the foods are high in beta carotene or lutein. Exercise is inversely related to endometrial cancer risk, especially in the overweight and obese patient. The protection is dose dependent, with women who exercise 5 times/week at lower risk than women who never or occasionally exercise (hazard ratio = 0.77).¹⁰

The biologic basis for the increased risk of endometrial neoplasia from obesity may be manifold—related to endocrine, metabolic, and inflammatory effects. These effects are felt to be dose dependent. The endocrine effects of obesity are related to estrogen excess. Adipose tissue expresses aromatase, an enzyme that converts adrenally secreted peripheral androstenedione to estrone. Estrone is then converted by 17-hydroxysteroid dehydrogenase into estradiol, the dominant postmenopausal estrogen. The excessive total aromatase levels found in the obese patient lead to excessive circulating estrogen. Estrogen stimulates proliferation in normal endometrium and consequently is considered mitogenic. In the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial, use of unopposed estrogen for 3 years led to the development of endometrial hyperplasia in 62% of study participants.¹¹ Chronic anovulation is common in obese premenopausal women, resulting in prolonged low progesterone levels. Coupled with unopposed estrogen from increased aromatase, an increased risk of neoplasia results. There is also increased androgen production, which negatively affects the circulating sex hormone–binding globulin (SHBG) levels by inhibiting synthesis in the liver. This leads to an increased level of unbound, and therefore bioavailable, estrogen. In the postmenopausal woman, high baseline follicle-stimulating hormone (FSH) levels stimulate aromatase, contributing further to higher levels and greater bioavailability of estradiol.

Obesity can lead to insulin resistance, diabetes, or metabolic syndrome. Insulin resistance is associated with elevated levels of insulinlike growth factor 1 (IGF-1). IGF-1 is a stimulus for proliferative activity in breast, colon, and endometrial tissue, leading to an increased risk of neoplasia. Progesterone deficiency can also affect IGF-1 activity due to lower levels of IGF-1–binding proteins (IGFBPs) and higher circulating free IGF-1 levels.¹² In the premenopausal female, hyperinsulinemia can cause stimulation of the hypothalamic-pituitary axis, leading to increased luteinizing hormone (LH) levels and hypersecretion of the ovarian androgens. This in turn causes anovulatory cycles and polycystic ovary disease. Hyperinsulinemia also decreases the amount of SHBG synthesis, which again leads to increased levels of bioavailable estrogen.

Inflammation has a key role in the normal menstrual cycle, and chronic inflammation has an indirect role in tumor initiation and progression, potentially by affecting insulin sensitivity.¹² Adiponectin, a cytokine, is an inverse marker for insulin resistance.¹³ Levels of adiponectin are inversely proportional to the risk of endometrial cancer¹⁴; that is, lower levels indicate insulin resistance and a high risk of endometrial cancer.¹⁵ Conversely, high levels of adiponectin have decreased endometrial cancer risk.¹²

Pro-inflammatory cytokines like tumor necrosis factor alpha (TNF-α), C-reactive protein, interleukin 6, and cytokine receptors like soluble TNF receptors 1 and 2 and interleukin 1 receptor antagonist have all been shown to have a positive correlation with the risk of endometrial cancer in postmenopausal women.¹²

Adipose-derived stem cells (ASCs) are cells within the adipose tissue vascular stroma that have plasticity and can differentiate into many different tissues, such as adipose tissue, heart muscle, cartilage, and so on. ASCs secrete growth factors, cytokines, and inflammatory cells and interact with cancer cells and may thereby have a role in tumor initiation, metastasis, and survival. Numerous studies have looked the role of ASCs in breast, ovarian, lung, pancreatic, and other cancers. There has been a study evaluating ASCs in endometrial cancer in a mouse model; it demonstrated that visceral adiposity increased the omental adipose stem cells and increased tumor vascularity.^13,16,17 The exact mechanism by which ASCs may contribute to tumor initiation or progression in endometrial cancer remains to be elucidated.

Evaluation for endometrial neoplasms is prompted by abnormal uterine bleeding, typically postmenopausal bleeding. Routine screening for endometrial neoplasms is not currently recommended except in patients known to have Lynch syndrome, who have a 40%–60% lifetime risk of endometrial cancer. Lynch syndrome is an autosomal dominant genetic condition resulting from defects in DNA-mismatch repair genes (such as MLH1, MSH2, MSH6, PMS2, EPCAM) that results in an increased predisposition to cancers of colon, rectum, uterus, ovaries, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. To date, although it is recognized that overweight and obese women are at increased risk for endometrial cancer, there are no preventive or enhanced screening guidelines for this patient population. A high degree of suspicion should be maintained and diagnostic evaluation performed in patients with abnormal bleeding over 40 years. In addition, patients with an increased risk of endometrial neoplasms such as hyperestrogenic states (obesity, polycystic ovary syndrome [PCOS], chronic anovulation, tamoxifen exposure) with prolonged unexplained bleeding should be assessed. The typical diagnostic evaluation includes an ultrasound-based assessment of the endometrial thickness and an endometrial sampling.

Imaging

Ultrasound evaluation of endometrial thickness can be used in the assessment of abnormal uterine bleeding. In the postmenopausal woman, an endometrial thickness of 4 mm or greater is considered abnormal and may prompt further evaluation, such as endometrial sampling. An ultrasound is readily available in gynecology offices and is commonly used for this assessment. In the obese patient, the thickness of subcutaneous fat and resulting sound attenuation present diagnostic challenges. Transabdominal imaging using a standard 7-mHz ultrasound transducer can be 94% attenuated in a patient with 8-cm subcutaneous tissue before it reaches the peritoneal cavity. Using “penetration mode” by lowering the frequency of the transducer to allow better penetration and using a technique called “tissue harmonic imaging,” by which the presence of fat actually increases the beam frequency and image quality, may improve imaging. Also, placing the patient in a modified lateral decubitus position may help displace the fatty tissue and aid in transabdominal scanning.¹⁸

Transvaginal scanning is superior to transabdominal studies for evaluation of endometrial thickness, especially in the obese patient. The transvaginal route avoids the problem of adipose attenuation by the thickened abdominal wall. Visualization of the adnexa in obese women using a transvaginal ultrasound can be more difficult. In the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) study, visualization of the ovaries in postmenopausal women decreased with being overweight (odds ratio [OR] = 0.953) or obese (OR = 0.715).¹⁹ Due to these considerations, a combination of both transabdominal and transvaginal ultrasound evaluation should be considered on a case-by-case basis for complete assessment of the pelvic structures.

A higher BMI is independently associated with thicker endometrium, and the degree of endometrial thickness correlates to the BMI.^20,21 This may affect interpretation using the standard criterion of 4 mm for endometrial thickness and lead to additional and potentially unnecessary procedures.

Although computerized tomographic (CT) imaging is not the initial study of choice to evaluate the endometrium, occasionally CT studies will be used for further evaluation. CT imaging is also used for assessment of metastatic endometrial cancer. In this scenario, the quality of CT imaging is affected by obesity and may require utilization of specialized obesity protocols. Most modern CT machinery has software algorithms designed to adjust for obesity that employ noise reduction techniques.²² Obese patients receive a higher dose of radiation for CT scans and radiography compared to the nonobese patient. It is estimated that diagnostic CT scans increase exposure of target tissue to radiation by as much as 62% due to the higher-power settings required to obtain imaging.

Endometrial Sampling

Endometrial sampling with an office biopsy or with curettage is the standard for establishing the diagnosis of hyperplasia/cancer. An office endometrial biopsy has 91%–99% accuracy in diagnosis of cancer and correlates well with endometrial curettings.²³ A histologic evaluation allows confirmation of the diagnosis, assigns a grade for the cancer, and allows for evaluation for other sources for bleeding, such as polyps, atrophy, endometritis, and cervical cancer. As most endometrial cancers in obese patients are type 1, a simple office biopsy is typically sufficient to make the diagnosis. There are, however, challenges in obtaining an adequate endometrial sample, particularly with an office biopsy alone. In many cases, sampling will require a procedure in the operating room with additional staff and equipment that can meet the challenges that morbidly obese patients present. When an office biopsy is nondiagnostic or inadequate or if the patient symptoms are not congruent with the pathology, formal dilation and curettage are required. Hysteroscopy can provide confirmation that the endometrial cavity was accessed and can allow for a visually directed biopsy. Complete assessment of cavities that are distorted by anatomical obstacles such as leiomyoma or scarring from previous endometrial ablations can be difficult. Stenosis of the cervix from atrophy or previous treatment for dysplasia can also contribute to difficulty in obtaining a sample.

Surgery

Surgery is the mainstay of treatment for endometrial cancer. Patients undergoing standard treatment using surgery followed by adjuvant therapy based on risk factors have comparatively high disease-specific survival. Surgery has the advantage of immediate and effective palliation of bleeding and pain-related symptoms. Standard surgical treatment of endometrial cancer includes a hysterectomy, bilateral salpingo-oophorectomy, and staging with lymphadenectomy. The extent of surgical staging and the need for lymphadenectomy with endometrial cancer are major controversies in the field of gynecologic oncology. Although a thorough discussion of this issue is beyond the scope of this chapter, it should be noted that performing a formal retroperitoneal node dissection in obese patients can be challenging and may not be warranted.

A higher incidence of medical comorbidities, including hypertension, diabetes mellitus, obstructive sleep apnea, and venous stasis, requires preoperative optimization to improve outcomes. A consultation with an anesthesiologist, careful history, and airway assessment for difficult intubation should be considered in all obese patients. Special attention should be given to the possibility of obstructive sleep apnea. Obesity increases complications such as surgical site infection, venous thromboembolism, and wound complications. Informed consent for these increased risks should be part of preoperative counseling.²⁴ A detailed description of perioperative considerations in the obese patient is discussed in Chapters 25 and 32.

Surgical staging can be accomplished via a laparotomy or a minimally invasive surgical technique. Compared to laparotomy, minimally invasive surgery offers advantages in the obese patient. Minimally invasive techniques are considered to be feasible, safe, and comparable in staging with the added advantage of decreased postoperative complications, such as would healing and infection rates, and quicker return to baseline function.

In the Lap2 trial, 2616 patients were randomized to surgical staging of endometrial cancer by laparotomy (920 patients) or laparoscopy (1696 patients). The majority of patients were successfully staged laparoscopically, with an overall conversion rate of 26% from laparoscopy to laparotomy, demonstrating the feasibility of comprehensive surgical staging using laparoscopy. The conversion rates were associated with the BMI, with an increase from 17.5% in patients with a BMI of 25 to 57.1% in patients with a BMI greater than 40. The operative times were longer for the laparoscopy group. However, the laparoscopic group had a shorter hospital stay and fewer postoperative complications.

In several reported studies, and in my own experience, there is a lower conversion rate (6%) from robotic-assisted laparoscopic staging to laparotomy. In our study, the operating room times were longer, but surgical times were similar between laparoscopy and laparotomy, due to increased setup time prior to start of surgery.²⁵ Rates of completion of the surgery laparoscopically, performance of lymphadenectomy, and lymph node counts were not affected by BMI. Similar findings have been reported in other large series.^26,27,28 In a retrospective study comparing survival after robotic surgery with standard laparoscopy, there was no significant difference in survival (3-year survival 93.3% and 93.6%), disease-free survival (DFS) (3-year DFS 83.3% and 88.4%, respectively), or tumor recurrence (14.8% and 12.1).²⁹ Outcomes from robotic surgery have also been shown to be comparable to those reported in the Surveillance, Epidemiology, and End Results database from the National Cancer Institute (NCI), with 88.7% overall survival at 5 years.³⁰ In conclusion, the oncologic outcome of robotic-assisted laparoscopic staging and feasibility of completion of surgery are equal to laparoscopy and the surgical parameters such as operative time, blood loss, conversion rates, and complications have been reported to be lower, making it the most used platform for endometrial cancer staging.

A Society of Gynecologic Oncology (SGO) task force white paper in 2012 reviewed use of the robotic platform for endometrial cancer in several large retrospective studies and accepted it as an alternative standard-of-care platform for minimally invasive surgery for staging of endometrial cancer.³¹ Further, the task force consensus appears to be that a prospective trial evaluation of robotic surgery may not be feasible. Surgical staging in the obese patient is possible and should be considered the initial step in management in all patients unless there are specific contraindications. This is particularly relevant in this patient group as they are more likely to have disease with a good prognosis.

Chemotherapy for Endometrial Cancer

Chemotherapy is used in endometrial cancer in the presence of early-stage disease with adverse histology, advanced-stage disease, or with recurrent disease. Cancer outcomes are directly related to adequate dosage and frequency of chemotherapy. There is growing evidence of underdosing of chemotherapy in obese patients, with poorer outcomes noted posttreatment in breast, colon, and gynecologic malignancies.^{32,33,34,35,36} With some exceptions, chemotherapy drug-dosing calculations are typically performed using the body surface area (BSA), which is calculated from patient weight and height. Numerous formulas are available for chemotherapy dosing and may have some variation in the calculation of BSA. The American Society of Clinical Oncology (ASCO) does not recommend any particular formula.