Cancer of the corpus uteri

Endometrial cancer is the most common gynecological malignancy in high‐income countries. Although the overall prognosis is relatively good, high‐grade endometrial cancers have a tendency to recur. Recurrence needs to be prevented since the prognosis for recurrent endometrial cancer is dismal. Treatment tailored to tumor biology is the optimal strategy to balance treatment efficacy against toxicity. Standard treatment consists of hysterectomy and bilateral salpingo‐oophorectomy. Lymphadenectomy (with ongoing studies of sentinel node biopsy) enables identification of lymph node positive patients who need adjuvant treatment, including radiotherapy and chemotherapy. Adjuvant radiotherapy is used for Stage I–II patients with high‐risk factors and Stage III lymph node negative patients. In advanced disease, a combination of surgery to no residual disease and chemotherapy results in the best outcome. Surgery for recurrent disease is only advocated in patients with a good performance status with a relatively long disease‐free interval.

in 2009. Rules for classification include histologic verification of grading and extent of the tumor.

| Histopathologic types (according to WHO/ International Society of Gynecological Pathology classification)
All tumors are to be microscopically verified.
The histopathologic types of endometrial carcinomas are 2 : 1. Endometrioid carcinoma: adenocarcinoma; adenocarcinoma-variants (with squamous differentiation; secretory variant; villoglandular variant; and ciliated cell variant). Endometrial cancers have traditionally been classified in one of the following two categories: 1. Types 1 (grade 1 and 2 endometrioid carcinoma) are the most common endometrial cancers. They may arise from complex atypical hyperplasia and are linked to excess of estrogen stimulation. As they are usually diagnosed at early stages, they present a relatively good prognosis.
2. Types 2 are the least common endometrial tumors. They include grade 3 endometrioid tumors as well as tumors of nonendometrioid histology, and develop from atrophic endometrium. Type 2 tumors are less hormone sensitive. Since they are diagnosed in later stages, they are generally more aggressive and have a poorer prognosis than Type 1 endometrial cancer.
However, the Cancer Genome Atlas studies have identified four molecular subgroups characterized, respectively, by POLE mutation, mismatch repair deficiency, TP53 mutation, and a copy number low group without a specific driver mutation, each with a distinct prognosis. 3,4 1.3.2 | Histopathologic grades (G) 1. GX: Grade cannot be assessed. Degree of differentiation of the adenocarcinoma is another basis for classification carcinoma of the corpus, which are grouped as follows: 1. G1: less than 5% of a nonsquamous or nonmorular solid growth pattern.

| Pathologic grading notes
Notable nuclear atypia (pleomorphism and prominent nucleoli), inappropriate for the architectural grade, raises the grade of a grade 1 or grade 2 tumor by 1. However, this should not be done too easily as grade 2 will then lose its discriminative power. 5 Most authors consider serous and clear cell carcinomas high grade by definition.
Grading of adenocarcinomas with squamous differentiation is allocated according to the nuclear grade of the glandular component. Table 1 shows the current FIGO staging classification for cancer of the corpus uteri. Comparison of the stage groupings with the TNM classification is represented in Table 2. 1.4.1 | Regional lymph nodes (N) 1. NX: Regional lymph nodes cannot be assessed.
3. N1: Regional lymph node metastasis to pelvic lymph nodes. 4. N2: Regional lymph node metastasis to para-aortic lymph nodes, with or without positive pelvic lymph nodes.

| Rules related to staging
During staging, distance from tumor to serosa should be measured.
Other features should also be reported in the pathologic report of the hysterectomy specimen. For instance, the presence of lymphovascular space invasion (LVSI) should also be indicated, as patients with LVSI-positive tumors have a significantly worse prognosis, especially if extensive LVSI is found. 6 The distinction made using LVSI status could be more relevant than the distinction between Stages IA and IB for predicting survival in Stage I endometrial cancer. 7 As a minimum, any enlarged or suspicious lymph nodes should be removed in all patients. For high-risk patients (grade 3, deep myometrial invasion, cervical extension, serous or clear cell histology), complete pelvic lymphadenectomy and resection of any enlarged para-aortic nodes is recommended.
Clinical staging, as designated by FIGO in 1971, applies to a small percentage of corpus cancers that are primarily treated with radiation therapy. In those instances, the designation of that staging system should be noted.

| Incidence
Endometrial cancer represents the sixth most common malignant disorder worldwide. An estimated 320 000 new cases are diagnosed with this malignancy annually. High-income countries have a greater incidence of endometrial cancer (5.9%) compared with low-resource countries (4.0%), although specific mortality is higher in the latter.
The cumulative risk of endometrial cancer up to the age of 75 years has been estimated as 1.6% for high-income regions and 0.7% for low-income countries. 8 This might be attributable to high rates of obesity and physical inactivity-two major risk factors in highincome countries. Specifically, elevated estrogen levels are known to be the most likely cause of the increased risk of endometrial cancer for postmenopausal obese women. 9 Conversely, physical activity and long-term use of continuous combined estrogen-progestin therapy are associated with a reduced risk of endometrial cancer. 10,11 Interestingly, obesity is associated with earlier age at diagnosis, and with endometrioid-type endometrial cancers. Similar associations were not observed with nonendometrioid cancers, consistent with different pathways of tumorigenesis. 12 North America and Europe have the highest incidence of endometrial cancer, where it is the most frequent cancer of the female genital tract and the fourth most common site in women after breast, lung, and colorectal cancer. 13 In Europe, it represents the eighth most common cancer death in women, with a reported 23 700 women dying in 2012. 7 In North America, it is the sixth most frequent cause of death, with approximately 55 000 new cases and 11 000 estimated new deaths each year. 3 The two major factors that contribute to an increase in the incidence of endometrial cancer in high-income countries are increased prevalence of obesity and extended life expectancy. Other determinants-such as the widespread decrease in use of estrogen plus progestin menopausal hormone therapy-have also been proposed as the cause of the increased incidence rates for endometrial cancer in North America. 14 Mortality rates for endometrial cancer showed a decrease in most European Union member states among women born before 1940. Improved cancer treatment and access to health care have been suggested as contributing to this decrease in cancer mortality. 8

| Diagnosis
The utility of population screening for endometrial cancer remains to be fully substantiated. 17

| PROGNOSTIC TUMOR CHARACTERISTICS FOR HIGH-RISK DISEASE
Its early presentation following postmenopausal bleeding results in a generally good prognosis, but it should be treated using evidencebased protocols, and where appropriate, by expert multidisciplinary teams. Four main histopathologic criteria are recommended to determine high-risk disease: 1. Tumor grade 3 (poorly differentiated).

Cervical stromal involvement.
MRI scanning and intraoperative frozen section represent the most accurate means of assessing both the depth of myometrial invasion and cervical involvement. [22][23][24] Although CT and MRI are equivalent in terms of evaluating nodal metastases, neither is suitable to replace surgical lymph node assessment, which provides histological confirmation. 25,26 PET-CT is the best imaging method to evaluate lymph node and distant metastases, and could be considered in high-risk or advanced stage disease. The role of PET-MRI is currently being investigated.
Nonsurgical staging for endometrial cancer, where extrauterine disease exists, is inherently inaccurate. This is particularly the case for the detection of small nodal involvement, intraperitoneal implants, and adnexal metastasis.

| SURGICAL STAGING PROCEDURE FOR ENDOMETRIAL CANCER
Staging of endometrial cancer was changed from clinical to surgical in 1988, by the FIGO Gynecologic Oncology Committee. This recommendation has led to considerable debate and effort to define surgical staging procedures that can be implemented internationally. A generally recommended protocol includes opening of the abdomen with a vertical midline incision and peritoneal washings taken immediately from the pelvis and abdomen, followed by careful exploration of the intra-abdominal contents. The omentum, liver, peritoneal cul-de-sac, and adnexal surfaces should be examined and palpated for any possible metastases. These procedures should be followed by careful palpation for suspicious or enlarged nodes in the aortic and pelvic areas.
However, laparoscopic procedures have increasingly been introduced as standard, especially for early stage disease, as these have been proven safe and reduce acute treatment-related complications. 27,28 The recommended standard surgical procedure is an extra-fascial total hysterectomy with bilateral salpingo-oophorectomy. Adnexal removal is recommended even if the tubes and ovaries appear normal, as they may contain micrometastases. In premenopausal women with low-grade early stage disease, ovarian preservation could be considered. 29 The utility of lymphadenectomy of the pelvic and para-aortic areas is disputed, albeit it is currently mandated through the staging system. Currently, it is advised that complete lymphadenectomy is reserved for cases with high-risk features. In contrast, selective node sampling has been deemed dubious as a routine approach.
Since many individuals with endometrial cancer are obese or elderly, with concomitant medical problems, clinical judgment is required to determine if additional surgery is warranted. Any deeply invasive tumor or radiological suggestion of positive nodes is an indication for retroperitoneal lymph node evaluation, which might be followed by removal of any enlarged or suspicious nodes. Documentation of positive nodes identifies a high-risk population and helps to tailor adjuvant treatment. Nodal resection also allows identification of node negative patients, potentially reducing the need for external beam radiotherapy. 19 Several parameters advocate for aortic node sampling. These include suspicious aortic or common iliac nodes, grossly positive adnexae, grossly positive pelvic nodes, and high-grade tumors showing full thickness myometrial invasion. Patients with clear cell, papillary serous, or carcinosarcoma histologic subtypes are also candidates for aortic node sampling.

| WHO SHOULD PERFORM THE SURGERY?
Full surgical staging is not required for low-risk tumors, defined as well-differentiated tumors with less than 50% myometrial invasion, with positive nodes in less than 5% of cases. Women with these tumors can be safely operated on by a general gynecologist. Patients at greater risk of extrauterine disease who may require lymphadenectomy should, in contrast, be operated on by gynecological oncologists. Care provided by gynecologic oncologists has been associated with better survival in high-risk cancers 40 and results in efficient use of healthcare resources and minimization of the potential morbidity associated with adjuvant radiation. 41 A thorough preoperative assessment, with particular attention to the pathology and to radiological features has been defined as the most effective strategy for the triaging of these patients. Triaging for lymphadenectomy is also possible during surgery. Intraoperative assessment mainly involves assessment of myometrial invasion. 22,24,39 Grading on frozen section is possible, though suboptimal compared with preoperative grading. 24 Concerning sentinel lymph node biopsy, several key surgical points should be respected 42 : 1. Expertise of the surgeon and attention to technical detail.
2. Superficial and deep cervical injection of dye.
3. Complete evaluation of the peritoneal cavity (sentinel lymph node mapping is for clinical Stage I, apparent uterine-confined disease).
4. Sentinel lymph node dissection begins with evaluation of the retroperitoneal spaces and identification of the sentinel drainage pathways that emanate from the parametria, followed by excision of the most proximal lymph nodes in the sentinel pathway. 5. Any suspicious lymph nodes should be removed regardless of sentinel lymph node mapping and frozen section analysis may influence the decision to perform para-aortic lymphadenectomy in some cases.
6. Performance of hemipelvic side-specific lymphadenectomy for mapping failure has been shown to reduce false-negative staging.
7. Enhanced pathology evaluation of sentinel lymph nodes with serial sectioning and immunohistochemistry stains increases the detection of low-volume metastasis.

| WHEN SHOULD SURGERY BE PERFORMED?
The effect of waiting time for surgical staging on survival outcome for endometrial cancer is controversial. It has been suggested that a longer waiting time for surgical staging was associated with worse survival outcomes in uterine cancer 43 and the delay between diagnosis and surgery should not exceed 6 weeks. 44 However, when focusing on type 1 endometrial cancer only, the waiting time for surgical staging was not associated with decreased survival outcome, presumably owing to its indolent growth and resulting excellent prognosis. 45

| IS LYMPHADENECTOMY THERAPEUTIC?
Lymphadenectomy is required for accurate staging, yet its therapeutic benefits remain controversial. Historically, one case-control study suggested that lymphadenectomy may be beneficial therapeutically 46 and another showed it improved prognosis even in node-positive women. 47  Sentinel lymph node mapping has been introduced into the surgical staging of endometrial cancer with the goal to reduce morbidity associated with comprehensive lymphadenectomy and to obtain prognostic information from lymph node status. A recent metaanalysis reported overall detection rates higher than 80%, with 50% bilateral pelvic node detection rate and 17% para-aortic detection rate. 53 Use of indocyanine green increases the bilateral detection rate compared with blue dye. Additionally, cervical injection increases the bilateral sentinel lymph node detection rate but decreases the paraaortic detection rate compared with alternative injection techniques.
The sensitivity of sentinel lymph node mapping to detect metastases is higher than 90%, reaching almost 100% in a meta-analysis. 53 Randomized studies have suggested that sentinel lymph node mapping can safely replace lymphadenectomy in the staging of endometrial cancer. 54,55 Apart from the historical distinction between type 1 and 2 endo-

| PROGESTOGEN THERAPY
Although the use of progesterone therapy has been widely recognized in the past, a meta-analysis of six randomized trials totalizing 3339 women has shown no survival benefit for adjuvant progestogen therapy in endometrial cancer. 81

| Occult Stage II disease
Therapeutic management of patients with clinically occult Stage II disease is similar to that of patients with Stage I disease.

| Clinical overt Stage II disease
In these cases, radical hysterectomy, bilateral salpingooophorectomy, bilateral pelvic lymphadenectomy, and selective aortic node dissection have been historically used as primary treatment. However, it is important to note that this strategy has

| STAGE III
Most patients with Stage III endometrial cancer are managed by complete surgical resection of all pelvic and/or nodal disease, followed by postoperative EBRT and/or chemotherapy.
As primary tumors of both the ovary and the endometrium may be present in patients with presumed Stage III disease with adnexal involvement, full surgical staging and expert pathologic examination of the specimen is recommended in these cases.
Adjuvant treatment is indicated for women with Stage III disease as detailed in Section 8 above.
Patients with clinical Stage III endometrial carcinoma in which surgical resection is not possible are treated primarily by pelvic irradiation, with or without chemotherapy. 89 Once therapy has been completed, exploratory laparotomy should be considered for those patients whose disease now appears to be resectable.

| STAGE IV
Optimal management in women with Stage IV endometrial cancer includes cytoreductive surgery, which is associated with superior overall survival outcome. 90 In advanced disease, neoadjuvant chemotherapy is also an option, particularly if postoperative morbidity is considered likely and/or ascites is present. 91  The better tolerability profile of carboplatin-paclitaxel has led to the recommendation of the use of carboplatin and paclitaxel as the standard for adjuvant treatment in Stage III and IV disease.
Pelvic radiotherapy in Stage IV disease is sometimes considered to provide local tumor control. Similarly, it has also been suggested that patients with vaginal bleeding or pain from a local tumor mass, or with leg edema due to lymph node involvement, should be treated with pelvic radiotherapy. Palliation of brain or bone metastases can be effectively obtained with short courses (1-5 fractions) of radiotherapy.

| Diagnosis post hysterectomy
Several therapeutic management problems have been reported to arise from post hysterectomy diagnosis. This is particularly true in cases where the adnexae have not been removed, which most often arises following vaginal hysterectomy for pelvic organ prolapse.

| Medically inoperable patients
The most common reasons for endometrial carcinoma to be deemed medically inoperable are morbid obesity and severe cardiopulmonary disease. In such cases, uterine brachytherapy is advised and has been shown to achieve cure rates in excess of 70%. In the presence of prognostic factors suggesting a high risk of involved nodes it can be combined with EBRT. 88 Primary radiation therapy for medically inoperable patients with clinical Stage I and II endometrial adenocarcinoma provides disease control, with fewer than 16% of surviving patients experiencing recurrence. 99 For patients with a well-differentiated lesion, contraindications to general anesthesia, and who are unsuitable for radiotherapy, high-dose progestins may be used. Trials using intrauterine hormone releasing devices instead of oral progestins are underway. In patients with contraindications to high-dose progestins, the uterine hormone releasing device can be considered.

| Diagnosis in young women
Since endometrial carcinoma is uncommon in women the age of 35

| FOLLOW-UP
The objectives of follow-up care for treated endometrial cancer patients are to provide reassurance, diagnose early recurrence, and collect data. The clinical and cost-effectiveness of follow-up implementation has been addressed internationally in one prospective 102 and several retrospective studies. [103][104][105] Overall, these studies found that about 75% of recurrences in endometrial cancer patients are symptomatic and 25% asymptomatic. Neither recurrence-free nor overall survival was improved in asymptomatic cases compared with those detected at clinical presentation. Most (65%-85%) recurrences were diagnosed within 3 years of primary treatment, and 40% of recurrences were local. Another important finding of those studies was that the use of routine follow-up Pap smears and chest X-rays is not costeffective. Given the high salvage rate following radiotherapy, it has been suggested that nonirradiated patients are a group that would benefit from regular follow-up to detect early vaginal recurrence. 106 Two systematic reviews 107,108 documented evidence for the utility of follow-up examinations, and concluded that follow-up should be practical and directed by symptoms and pelvic examination. These studies also recommend reduction in the frequency of follow-up visits for low-risk patients. Given the low risk of recurrence, vaginal cytology can be omitted, resulting in reduced healthcare costs. 109 It appears that visual inspection is sufficient, since positive cytology is merely diagnosed in cases of symptomatic recurrence. 104,110,111 More recently, studies of minimal follow-up (nurse led, telephone based) after the first year have been done and results are awaited. 112,113 First results suggest good patient acceptability once prompt access to evaluation in case of symptoms is ensured.
Follow-up care should also include patient counseling as these patients are at risk of second cancers following their primary endometrial cancer. For instance, the estimated incidence rate of Lynch syndrome in an unselected endometrial cancer population is 3%-6%. 114 Routine pathologic screening of mismatch repair deficiencies in the endometrial cancer specimen, similar to colorectal cancer, has been advocated and is increasingly being introduced in practice. 115 However, in most women with mismatch repair deficiency this is caused by MLH1 promoter hypermethylation and a test of this before referring a patient to a clinical geneticist is recommended. Survivors of endometrial cancer have a three-fold increased risk of second cancer when compared with a matched population. This risk increase seems mainly related to lifestyle factors and genetic susceptibility. 116 These women should be counseled on exercise and weight loss programs.

| RECURRENCE
The therapeutic management for localized recurrences includes surgery, radiation therapy, or a combination of both.