Age groups (years)
Percentage of new cases (%)
<20
0
20–34
1.6
35–44
5.6
45–54
18.4
55–64
33.9
65–74
23.4
75–84
12.6
>84
4.6
Risk Factors for Endometrial Carcinoma
As mentioned, majority of the endometrial cancers are type I tumors with endometrioid histology. The main risk factor for an endometrioid endometrial carcinoma is long-term exposure to excess estrogen, either endogenous or exogenous. Other risk factors include nulliparity and infertility, obesity, hypertension, diabetes, polycystic ovarian syndrome, early menarche, late menopause (after 55 years), and hereditary syndromes like Lynch syndrome, BRCA mutations, etc. [7].
Excess Estrogen Exposure
Excess estrogen exposure can be exogenous or endogenous. The exogenous exposure includes postmenopausal estrogen therapy and tamoxifen use. In a woman with intact uterus, unopposed estrogen therapy causes two to tenfold increases in the risk of endometrial cancer. The risk increases with the increased duration of use [7]. Using combined estrogen–progestin preparation in a woman with intact uterus can reduce the risk. Tamoxifen is a selective estrogen receptor modulator with agonistic action on the endometrium and antagonistic action on the breast. Prospective trials including over 20,000 women have shown that tamoxifen use increased the risk of endometrial cancer [8]. Phytoestrogens that are present in many plants and vegetables like soy have both estrogenic and antiestrogenic properties. Prospective studies have shown significantly higher rate of endometrial hyperplasia in women taking soy isoflavone supplements [9].
Obesity, chronic anovulation, early menarche, late menopause, and rarely estrogen-secreting tumors are causes for excessive endogenous estrogen. In anovulatory women, there is chronic estrogen production unopposed by progesterone allowing continued proliferation of the endometrium leading to endometrial hyperplasia and carcinoma. Polycystic ovary syndrome is the most common endocrine cause of anovulation followed by thyroid dysfunction and hyperprolactinemia. In obese women there is increased conversion of androstenedione to estrone and also increased conversion of androgens to estradiol occurring in the peripheral adipose tissue leading to increased endogenous estrogen. The risk of endometrial carcinoma significantly increased with each increase in body mass index (BMI) of 5 kg/m2 [10]. Obesity is also associated with endometrial carcinoma occurring at a younger age (<45 years) [11]. Early menarche and late menopause result in prolonged estrogen stimulation leading to increased risk of endometrial cancer. Granulosa cell tumors of the ovary secrete excess estrogen and are seen associated with endometrial hyperplasia in 25–50 % and endometrial malignancy in 5–10 % of affected women [12, 13].
Other Risk Factors
Nulliparity and infertility are not independent risk factors for the development of endometrial carcinoma. The risk of developing endometrial carcinoma is inversely related to parity. The risk associated with infertility is related to the increased number of anovulatory cycles in infertile women. Studies have not yet shown an association of infertility treatment and endometrial cancer [14, 15]. The increased endometrial cancer risk seen in diabetes mellitus or hypertension is partly due to the existence of comorbid conditions, mainly obesity [16]. The presence of hyperinsulinemia, insulin resistance, and increased levels of insulin-like growth factors in diabetics may cause endometrial proliferation and lead to the development of endometrial carcinoma [17, 18]. The increased risk of endometrial carcinoma associated with hereditary syndromes is discussed in detail in Chap. 3.
Type II endometrial tumors are typically described as estrogen-independent tumors, but pooled analysis has shown that estrogen-driven proliferation is also important in type II cancers and both type I and type II cancers share common etiologic pathways [19]. Studies have shown the association for BMI with type II tumors though the strength of association is less strong than for type I [19–21]. The relative risk for various risk factors in causing endometrial cancer is summarized in Table 6.2.
Risk factor | Relative risk (RR) |
|---|---|
Unopposed estrogen therapy | 2–10 |
Tamoxifen | 2 |
Late menopause | 2 |
Nulliparity | 2 |
Polycystic ovarian syndrome | 3 |
Obesity | 2–4 |
Diabetes mellitus | 2 |
Clinical Presentation
More than 90 % of endometrial cancers occur in women above 45 years with the majority diagnosed between the ages of 55 and 64 [2]. Abnormal uterine bleeding including postmenopausal bleeding, heavy menstrual bleeding, or intermenstrual bleeding is the most common presenting symptoms with about 75–90 % of women with endometrial cancer presenting similarly [22]. Rarely, women affected with endometrial cancer can present with atypical glandular cells on regular screening cervical cytology. Any bleeding occurring in postmenopausal women including mild spotting should be evaluated as about 3–20 % of women presenting with postmenopausal bleeding are found to have endometrial carcinoma [23]. Abnormal uterine bleeding occurring in women who are above the age of 45 should be evaluated with an endometrial biopsy to rule out carcinoma. In women who are younger than 45 years, abnormal uterine bleeding which occurs in a background of unopposed estrogen as in obesity or polycystic ovarian disease or in patients with a family history of Lynch syndrome or BRCA mutation must be evaluated immediately. Also, persistent abnormal uterine bleeding not responding to medical management in women younger than 45 years should be viewed with suspicion as about 7 % of endometrial carcinomas occur in this age group. A thickened endometrial lining seen on pelvic imaging for other causes also warrants evaluation to rule out endometrial carcinoma. At the time of diagnosis, two-thirds of patients with endometrial cancer have disease confined to the uterus [2].
Evaluation of a Patient with Suspected Endometrial Carcinoma
A patient with suspected endometrial carcinoma should be subjected to a thorough physical and pelvic examination. The size and mobility of the uterus and the presence or absence of gross cervical involvement, extrauterine mass, or ascites should all be assessed. The supraclavicular area must be examined to rule out enlarged nodes. Pelvic sonography, especially transvaginal ultrasound (TVS), is often the first line of investigation used in a woman with abnormal uterine bleeding. Hysterosonography, where sterile saline is placed within the endometrial cavity and uterus imaged using TVS, can help distinguish diffuse or focal thickening of endometrium and endometrial polyps. In a postmenopausal woman endometrial thickness more than 4 mm warrants a biopsy to rule out malignancy.
Endometrial biopsy is the gold standard test, which can help to confirm the presence of endometrial carcinoma. It can be done as an outpatient/office procedure without anesthesia or under local anesthesia, by using Pipelle sampling device. This is the least invasive technique for obtaining an endometrial biopsy and has a sensitivity of 73 % and specificity of 100 % for detecting endometrial disease [24]. A dilatation and curettage (D&C) needs to be performed only if the office endometrial biopsy shows insufficient endometrial cells for evaluation. Hysteroscopy can assist to identify focal lesions in the endometrium and ensure biopsy of them and thus can be helpful when ultrasound results are inconclusive. There have been concerns about the possibility of spill of malignant cells into the peritoneal cavity by the high pressure induced in the uterine cavity during the procedure and thereby worsening the prognosis [25, 26]. But the published data presently available in the literature seems to indicate that hysteroscopy is not statistically associated with worse outcome, and based on this most authors conclude that hysteroscopy can be used in patients with endometrial cancer without adversely affecting the prognosis [27–29]. Endocervical curettage at the time of endometrial biopsy can help to rule out cervical involvement in endometrial cancer. Cervical cytology used to be recommended in the initial evaluation of a patient with endometrial cancer but was removed in the revised National Comprehensive Cancer Network (NCCN) guideline [30].
Preoperative Evaluation
Women with endometrial cancer are likely to have medical comorbidities like diabetes mellitus, hypertension, or coronary artery disease that will need optimization prior to surgery. Preoperative elevated CA125 levels have been shown to be an important factor predictive of extrauterine disease in women with endometrial cancer [31, 32]. Preoperative pelvic and abdominal imaging is helpful to rule out cervical involvement and extrauterine disease. Although of value in selected cases, routine preoperative imaging is of arguable cost-effectiveness, as most patients will undergo surgery and endocervical curettage at the time of endometrial biopsy, and intraoperative findings will guide therapeutic decisions in the majority of cases without the need for imaging.
Ultrasonography is the most inexpensive imaging modality available, and TVS can predict myometrial or cervical invasion better than a computerized tomography (CT) scan. But it is not as sensitive as CT scan or magnetic resonance imaging (MRI) in detecting the abdominopelvic lymph nodes or omental/peritoneal metastases and results are operator dependent. CT scan and MRI are more accurate in the radiological staging of endometrial cancer. MRI has a very good soft-tissue contrast resolution and can predict the cervical involvement and myometrial invasion better than a CT scan or ultrasound [33]. MRI/CT can be done to look for the presence of ascites or omental/peritoneal/nodal/ovarian disease [34]. A prospective multicenter study evaluating the diagnostic performance of PET/CT and MRI found that both modalities have equal sensitivities in predicting myometrial invasion, cervical involvement, and lymph node metastases in endometrial cancer [35]. Initial evaluation also should include an imaging of the chest. NCCN recommends genetic counseling and testing for all patients with endometrial cancer below the age of 50 years and also in patients with a significant family history of endometrial or colorectal cancer [30].
Staging
FIGO staging for endometrial carcinoma was adopted initially in 1950 to include just two criteria—tumors clinically confined to the uterine corpus and extending outside. Both the categories were subdivided into medically operable or not. This was modified in 1961 to include cervical involvement (stage II), disease confined to the pelvis (stage III), and disease extending beyond the pelvis or involving the bladder and rectum (stage IV). In 1971 the staging was changed to incorporate the depth of the uterine cavity (as it was ascertained that the virulence of the tumor increased with the increasing size of the uterus) as well as the grade of the tumor. After the surgicopathological staging trial of the Gynecologic Oncology Group (GOG) [36], the primary treatment for endometrial carcinoma is surgical and the staging was changed to a surgicopathological one in 1988 which divided uterine-confined cancers into three substages [37].
Presently endometrial carcinoma is surgically staged according to the joint 2010 International Federation of Gynecology and Obstetrics (FIGO)/TNM classification system [38, 39]. They are represented in Table 6.3. The revised staging eliminated the cervical glandular involvement and ascitic fluid cytology from the staging, grouped together both IA and IB of the previous staging as IA, and substratified stage IIIC. This staging system for endometrial cancers has been found to be highly prognostic in the case of endometrioid tumors [40]. But the size of the tumor and lymphovascular space invasion (LVSI), which are also considered as prognostic factors, are not included in the current staging.
Primary tumor (T) (surgicopathologic findings) | ||
|---|---|---|
TNM categories | FIGO stages | Definition |
TX | Primary tumor cannot be assessed | |
T0 | No evidence of primary tumor | |
Tis | Carcinoma in situ (preinvasive carcinoma) | |
T1 | I | Tumor confined to corpus uteri |
T1a | IA | Tumor limited to endometrium or invades less than one-half of the myometrium |
T1b | IB | Tumor invades one-half or more of the myometrium |
T2 | II | Tumor invades stromal connective tissue of the cervix but does not extend beyond uterus |
T3a | IIIA | Tumor involves serosa and/or adnexa (direct extension or metastasis) |
T3b | IIIB | Vaginal involvement (direct extension or metastasis) or parametrial involvement |
T4 | IVA | Tumor invades bladder mucosa and/or bowel mucosa |
Regional lymph nodes (N) | ||
NX | Regional lymph nodes cannot be assessed | |
N0 | No regional lymph node metastasis | |
N1 | IIIC1 | Regional lymph node metastasis to pelvic lymph nodes |
N2 | IIIC2 | Regional lymph node metastasis to para-aortic lymph nodes, with or without positive pelvic lymph nodes |
Distant metastasis (M) | ||
M0 | No distant metastasis | |
M1 | IVB | Distant metastasis (includes metastasis to inguinal lymph nodes, intraperitoneal disease, or the lung, liver, or bone. It excludes metastasis to para-aortic lymph nodes, vagina, pelvic serosa, or adnexa) |
Anatomic stage/prognostic groups | ||
Stage I | T1 N0M0 | |
Stage IA | T1a N0M0 | |
Stage IB | T1b N0M0 | |
Stage II | T2 N0M0 | |
Stage III | T3 N0M0 | |
Stage IIIA | T3a N0M0 | |
Stage IIIB | T3bN0M0 | |
Stage IIIC1 | T1-T3N1M0 | |
Stage IIIC2 | T1-T3N2M0 | |
Stage IVA | T4 any N M0 | |
Stage IVB | Any T any N M1 | |
Complete surgical staging for endometrial carcinoma includes total hysterectomy, bilateral salpingo-oophorectomy, and bilateral pelvic and para-aortic lymphadenectomy. If there is cervical involvement, radical hysterectomy is recommended and serous or clear cell cancers are staged like ovarian cancer including omentectomy and peritoneal biopsies [30]. Thorough visual evaluation of the peritoneal and bowel surfaces with biopsy of any suspicious lesions is important to exclude extrauterine disease [41]. In the case of ascites, peritoneal or ovarian disease, omental thickening, or obvious nodal involvement, complete surgical debulking is recommended. If there is initially unresectable disease involving the vagina or parametrium, or infiltrating the bladder, bowel, or rectum, radiation or chemotherapy is preferred over surgery [30].
Pelvic lymphadenectomy involves the removal of the nodal tissue over the distal half of common iliac arteries, around the external iliac vessels unto the circumflex iliac veins, and removal of the nodal tissue around the internal iliac vessels and also obturator pad of fat above the obturator nerve. Ten percent of women with endometrial cancer apparently confined to the uterus have lymph node metastases [42]. Para-aortic lymph node involvement occurs in 50 % of women with positive pelvic nodes, but isolated para-aortic involvement can occur (up to 6 %). Higher histologic grade, deep myometrial invasion, cervical involvement, and lymphovascular space involvement are the other factors that can predict a para-aortic nodal involvement [42]. Para-aortic node dissection involves the removal of the nodal tissue over the inferior vena cava and aorta from the level of renal veins unto the level of mid-common iliac arteries. Many surgeons limit the para-aortic nodal dissection up to the level of inferior mesenteric artery (IMA). But about 77 % of patients with para-aortic nodal involvement are found to have positive nodes above the level of IMA [42]. Patients with serous or clear cell cancers are staged as with ovarian cancer including omentectomy and peritoneal biopsies. Though peritoneal cytology does not affect staging, FIGO and AJCC continue to recommend that it may be obtained and reported.
Traditionally the staging for endometrial carcinoma has been done through a large incision, but the advancement in minimally invasive surgery has made laparoscopic staging possible. Since Childers et al. first described the use of laparoscopy for staging endometrial cancer in 1993, many studies have been published describing the use of laparoscopic or a combined laparoscopic and vaginal approach to completely stage endometrial cancer [43–45]. Laparoscopically assisted vaginal hysterectomy (LAVH) was found to have fewer complications and decreased hospital stay [46]. Kohler et al. and Eltabbakh et al. have demonstrated the adequacy of lymphadenectomy with the laparoscopic approach [45, 47]. Recurrence rates and 5-year survival rates were also found to be similar to that achieved by laparotomy [48, 49]. The randomized LAP-2 trial involving 2,616 patients was conducted by the GOG to compare laparoscopic and open approaches in surgical staging of uterine cancers. The laparoscopic group had fewer adverse events, shorter hospital stay, and an improved quality of life [50, 51]. The recurrence rates and 5-year survival rates were similar in both arms [52].
The last decade saw the emergence of robotic-assisted surgery in oncology. The use of a robotic platform reduced surgical morbidity and hospital stay and also reduced conversions to laparotomy [53]. Leitao et al. reported that among patients undergoing robotic surgery, there were a higher proportion of obese patients, but overall the robotic surgery group had a shorter hospital stay and similar pelvic nodal counts when compared to laparoscopy [54]. For further details on the role of minimally invasive surgery in the treatment of endometrial cancer, please refer to Chaps. 20 and 21.
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