Endometrial cancer is usually endometrioid adenocarcinoma. Typically, postmenopausal vaginal bleeding occurs. Diagnosis is by biopsy. Staging is surgical. Treatment requires hysterectomy, bilateral salpingo-oophorectomy, and, in high-risk patients, usually pelvic and para-aortic lymphadenectomy. For advanced cancer, radiation, hormone, or cytotoxic therapy is usually indicated.
Endometrial cancer is more common in developed countries where the diet is high in fat. In the US, this cancer is the 4th most common cancer among women, affecting 1 in 50. The American Cancer Society estimates that in 2017, about 61,380 new cases of endometrial cancer will be diagnosed and that about 10,920 women will die of this cancer.
Endometrial cancer affects mainly postmenopausal women. Mean patient age at diagnosis is 61 yr. Most cases are diagnosed in women aged 50 to 60 yr; 92% of cases occur in women > 50 yr.
Major risk factors for endometrial cancer are
Other risk factors include
Unopposed estrogen (high circulating levels of estrogen with no or low levels of progesterone) may be associated with obesity, polycystic ovary syndrome, nulliparity, late menopause, estrogen-producing tumors, anovulation (ovulatory dysfunction), and estrogen therapy without progesterone.
Most endometrial cancer is caused by sporadic mutations. However, in about 5% of patients, inherited mutations cause endometrial cancer; endometrial cancer due to inherited mutations tends to occur earlier and is often diagnosed 10 to 20 yr earlier than sporadic cancer. About half of cases that involve heredity occur in families with hereditary nonpolyposis colorectal cancer (HNPCC; Lynch syndrome). Patients who have HNPCC have a high risk of developing a second cancer (eg, colorectal cancer, ovarian cancer).
Endometrial cancer is usually preceded by endometrial hyperplasia. Endometrial carcinoma is commonly classified into 2 types.
Type I tumors are more common, are usually estrogen-responsive, and are usually diagnosed in younger, obese, or perimenopausal women. These tumors are usually low-grade. Endometrioid adenocarcinoma is the most common histology. These tumors may show microsatellite instability and have mutations in PTEN, PIK3CA, KRAS, and CTNNBI.
Type II tumors are usually high-grade (eg, serous or clear cell histology). They tend to occur in older women. About 10 to 30% have p53 mutations. Up to 10% of endometrial carcinomas are type II.
Endometrioid adenocarcinomas account for about 75 to 80% of endometrial cancers.
Uterine papillary serous carcinomas, clear cell carcinomas, and carcinosarcomas are considered more aggressive, high-risk histologies and are thus associated with a higher incidence of extrauterine disease at presentation. Carcinosarcomas have been reclassified as high-risk malignant epithelial tumors.
Endometrial cancer may spread as follows:
The higher (more undifferentiated) the grade of the tumor, the greater the likelihood of deep myometrial invasion, pelvic or para-aortic lymph node metastases, or extrauterine spread.
The following suggest endometrial cancer:
If endometrial cancer is suspected, outpatient endometrial biopsy is done; it is > 90% accurate. Endometrial sampling is also recommended for women with abnormal bleeding, particularly those > 40 yr. If results are inconclusive or suggest cancer (eg, complex hyperplasia with atypia), outpatient fractional D & C with hysteroscopy is done. An alternative is transvaginal ultrasonography; however, a histologic diagnosis is required.
Once endometrial cancer is diagnosed, pretreatment evaluation includes serum electrolytes, kidney and liver function tests, CBC, chest x-ray, and ECG.
Because endometrial cancer sometimes results from an inherited mutation, genetic counseling and/or testing should be considered if patients are < 50 yr or have a significant family history of endometrial cancer and/or HNPCC.
Pelvic and abdominal CT are also done to check for extrauterine or metastatic cancer in patients with any of the following:
Staging of endometrial cancer is based on histologic differentiation (grade 1 [least aggressive] to 3 [most aggressive]) and extent of spread, including invasion depth, cervical involvement (glandular involvement vs stromal invasion), and extrauterine metastases (see Table: FIGO Staging of Endometrial Carcinoma).
Staging is surgical and includes exploration of the abdomen and pelvis, biopsy or excision of suspicious extrauterine lesions, total abdominal hysterectomy, and, in patients with high-risk features (grade 1 or 2 cancer plus deep myometrial invasion, grade 3 cancer, all cancers with high-risk histology), pelvic and para-aortic lymphadenectomy. Staging can be done via laparotomy, laparoscopy, or robotic-assisted surgery.
FIGO Staging of Endometrial Carcinoma
Usually total hysterectomy and bilateral salpingo-oophorectomy
Pelvic and para-aortic lymphadenectomy for grade 1 or 2 with deep (> 50%) myometrial invasion, for any grade 3, and for all cancers with high-risk histology
Pelvic radiation therapy with or without chemotherapy for stage II or III
Multimodal therapy usually recommended for stage IV
In patients with grade 1 or 2 endometrial cancer and < 50% invasion, the probability of lymph node metastasis is < 2%. In these patients, treatment is usually total hysterectomy and bilateral salpingo-oophorectomy via laparotomy, laparoscopy, or robotic-assisted surgery. However, for young women with stage IA or IB endometrioid adenocarcinoma, ovarian preservation is usually safe and recommended to preserve fertility.
If patients have any of the following, pelvic and para-aortic lymphadenectomy is also done:
Whether the extent of para-aortic lymphadenectomy should reach the inferior mesenteric artery vs the renal vessels remains a topic of debate.
Stage II or III cancer requires pelvic radiation therapy with or without chemotherapy. Treatment of stage III cancer must be individualized, but surgery is an option; generally, patients who undergo combined surgery and radiation therapy have a better prognosis. Except in patients with bulky parametrial disease, a total abdominal hysterectomy and bilateral salpingo-oophorectomy should be done.
Treatment of stage IV is variable and patient-dependent but typically involves a combination of surgery, radiation therapy, and chemotherapy. Occasionally, hormonal therapy should also be considered.
Tumors respond to hormone therapy with a progestin in 20 to 25% of patients.
Several cytotoxic drugs (particularly carboplatin plus paclitaxel) are effective. They are given mainly to women with metastatic or recurrent cancer. Another option is doxorubicin.
The role of sentinel lymph node (SLN) mapping in endometrial cancer is currently being evaluated. SLN mapping is done as for cervical cancer using the same tracers (blue dye, technetium-99 [99Tc], indocyanine green [ICG]).
SLN mapping can be considered for the surgical staging of cancer that appears confined to the uterus. SLN mapping in cancers with high-risk histology (papillary serous carcinoma, clear cell carcinoma, carcinosarcomas) should be done with caution.
Where to inject the tracer in patients with endometrial carcinoma is controversial; however, injecting dye into the cervix is a useful and validated technique for identifying lymph nodes. Dye is usually injected into the cervix both superficially (1 to 3 mm) and deep (1 to 2 cm) at 3 and 9 o’clock. With this technique, dye penetrates to the uterine lymphatic trunks (which meet in the parametria) and appears in the broad ligament leading to pelvic and occasionally para-aortic SLNs.
The most common locations of pelvic SLNs are
Less common locations are the iliac and/or presacral regions.
A complete pelvic lymphadenectomy should be done when any of the following occur:
Patients with complex endometrial hyperplasia and atypia have up to a 50% risk of having concurrent endometrial cancer. Treatment of endometrial hyperplasia consists of progestins or definitive surgery, depending on the complexity of the lesion and the patient’s desire to preserve fertility.
If young patients with grade 1 tumors and no myometrial invasion (documented by MRI) wish to preserve fertility, progestin alone is an option. About 46 to 80% of patients have a complete response within 3 mo of initiation of therapy. After 3 mo, patients should be evaluated via D & C rather than endometrial biopsy.
Alternatively, use of a levonorgestrel-releasing intrauterine device (IUD) is being increasingly used to treat patients with complex atypical hyperplasia or grade 1 endometrial cancer.
Surgery is recommended if conservative treatment is not effective (endometrial cancer is still present after 6 to 9 mo of treatment) or if patients have completed childbearing. Fertility-sparing treatment is contraindicated in patients with high-grade endometrioid adenocarcinomas, uterine papillary serous carcinoma, clear cell carcinoma, or carcinosarcoma.
In young women with stage IA or IB endometrioid adenocarcinoma, ovarian preservation is safe and recommended.
Uterine papillary serous carcinoma, clear cell carcinomas, and carcinosarcomas (reclassified as high-risk malignant epithelial tumors) are considered histologically aggressive, high-risk cancers and are thus more likely to have spread outside the uterus at presentation.
Multimodality therapy is typically recommended for these histologically aggressive endometrial tumors. Primary treatment includes abdominal hysterectomy, bilateral salpingo-oophorectomy with pelvic and para-aortic lymphadenectomy, and omental and peritoneal biopsies.
In patients with gross extrauterine disease, cytoreduction should be done to reduce the bulk of the tumor to no gross residual disease.
Adjuvant therapy for papillary serous and clear cell carcinomas depends on the stage:
Stage IA without myometrial invasion and without residual disease in the hysterectomy specimen: Observation and close follow-up (an acceptable approach)
Other stage IA and IB or stage II cancers: Usually vaginal brachytherapy followed by systemic chemotherapy with carboplatin and paclitaxel
More advanced disease: Chemotherapy
Adjuvant therapy for carcinosarcoma also depends on the stage:
Endometrial cancer is one of the most common cancers among women and, as prevalence of the metabolic syndrome increases, may become more common.
Prognosis is better with type I tumors, which tend to be diagnosed in younger or perimenopausal women, to be estrogen-responsive, and to have more benign histologic features.
Recommend endometrial sampling for women with abnormal bleeding, particularly those > 40 yr.
Stage endometrial cancer surgically via laparotomy, laparoscopy, or a robotic-assisted surgery.
Treatment is usually total hysterectomy, bilateral salpingo-oophorectomy, and lymphadenectomy and sometimes radiation therapy and/or chemotherapy.
Consider sentinel lymph node mapping for cancers that appear to be confined to the uterus.
Consider fertility-sparing treatment for certain patients with grade 1 endometrioid adenocarcinoma or endometrial complex atypical hyperplasia.
Consider genetic counseling and testing for patients < 50 yr and those with a significant family history of endometrial and/or colorectal cancer (hereditary nonpolyposis colorectal cancer).