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Endometrial Cancer

(Uterine Cancer)

By Pedro T. Ramirez, MD, Professor, Department of Gynecologic Oncology and Reproductive Medicine, David M. Gershenson Distinguished Professor in Ovarian Cancer Research, and Director of Minimally Invasive Surgical Research and Education, The University of Texas MD Anderson Cancer Center ; David M. Gershenson, MD, Professor and Chairman, Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center ; Gloria Salvo, MD, Rotating Research Resident, Department of Gynecologic Oncology and Reproductive Medicine, MD Anderson Cancer Center

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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.

Etiology

Major risk factors for endometrial cancer are

  • Unopposed estrogen

  • Age > 50

  • Obesity

  • Diabetes

Other risk factors include

  • Tamoxifen use for > 5 yr

  • Previous pelvic radiation therapy

  • A personal or family history of breast or ovarian cancer

  • Family history of hereditary nonpolyposis colorectal cancer or possibly, among 1st-degree relatives, endometrial cancer

  • Hypertension

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).

Pathology

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:

  • From the surface of the uterine cavity to the cervical canal

  • Through the myometrium to the serosa and into the peritoneal cavity

  • Via the lumen of the fallopian tube to the ovary, broad ligament, and peritoneal surfaces

  • Via the bloodstream, leading to distant metastases

  • Via the lymphatics

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.

Symptoms and Signs

Most (> 90%) women with endometrial cancer have abnormal uterine bleeding (eg, postmenopausal bleeding, premenopausal recurrent metrorrhagia); one third of women with postmenopausal bleeding have endometrial cancer. A vaginal discharge may occur weeks or months before postmenopausal bleeding.

Diagnosis

  • Endometrial biopsy

  • Surgical staging

The following suggest endometrial cancer:

  • Postmenopausal bleeding

  • Abnormal bleeding in premenopausal women

  • A routine Papanicolaou (Pap) test showing endometrial cells in postmenopausal women

  • A routine Pap test showing atypical endometrial cells in any woman

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:

  • An abdominal mass or hepatomegaly detected during physical examination

  • Abnormal liver function test results

  • A high-risk histologic subtype of cancer (eg, papillary serous carcinoma, clear cell carcinoma, carcinosarcoma)

Staging

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

Stage*,†

Definition

I

Confined to the uterine corpus

IA

Limited to endometrium or involves less than half of the myometrium

IB

Invasion of half or more of the myometrium

II

Invasion of the cervical stroma but no extension outside the uterus

III

Local and/or regional spread of the tumor

IIIA

Invasion of serosa, adnexa, or both (direct extension or metastasis)

IIIB

Metastases or direct spread to the vagina and/or spread to the parametria

IIIC

Metastases to pelvic or para-aortic lymph nodes or to both

IIIC1

Metastases to pelvic lymph nodes

IIIC2

Metastases to para-aortic lymph nodes, with or without metastases to pelvic lymph nodes

IV

Involvement of the bladder and/or intestinal mucosa and/or distant metastases

IVA

Invasion of the bladder, intestinal mucosa, or both

IVB

Distant metastases, including to intra-abdominal or inguinal lymph nodes or both

*Endometrial cancer is usually surgically staged.

For all but stage IVB, grade (G) indicates percentage of tumor with a nonsquamous or nonmorular solid growth pattern:

  • G1: 5%

  • G2: 6–50%

  • G3: > 50%

Nuclear atypia excessive for the grade raises the grade of a G1 or G2 tumor by 1. In serous adenocarcinomas, clear cell adenocarcinomas, and squamous cell carcinomas, nuclear grading takes precedence. Adenocarcinomas with squamous differentiation are graded according to the nuclear grade of the glandular component.

*Based on staging established by the International Federation of Gynecology and Obstetrics (FIGO) and American Joint Committee on Cancer (AJCC), AJCC Cancer Staging Manual, ed. 7. New York, Springer, 2010.

Prognosis

Prognosis is worse with higher-grade tumors, more extensive spread, and older patient age.

Average 5-yr survival rates are

  • Stage I or II: 70 to 95%

  • Stage III or IV: 10 to 60%

Overall, 63% of patients are cancer-free 5 yr after treatment.

Treatment

  • 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:

  • Grade 1 or 2 cancer with deep (> 50%) myometrial invasion

  • Any grade 3 cancer

  • All cancers with high-risk histology (papillary serous carcinoma, clear cell carcinoma, carcinosarcoma)

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.

Sentinel lymph node mapping in endometrial cancer

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

  • Medial to the external iliac blood vessels

  • Ventral to the internal iliac blood vessels

  • In the superior part of the obturator region

Less common locations are the iliac and/or presacral regions.

A complete pelvic lymphadenectomy should be done when any of the following occur:

  • Mapping does not detect any SLNs.

  • A hemipelvis cannot be mapped.

  • There are any suspicious or grossly enlarged nodes, regardless of mapping.

Fertility preservation in endometrial hyperplasia and early endometrial cancer

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.

General measures

Because obesity and hypertension increase the risk of endometrial cancer and because evidence suggests that certain lifestyle choices may help prevent endometrial cancer, patients should be counseled about the importance of exercise, weight loss, and an adequate diet.

High-risk histologies

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:

  • Stage IA without myometrial invasion and without residual disease in the hysterectomy specimen: Observation and close follow-up (an acceptable approach)

  • All other stages: Usually systemic chemotherapy with ifosfamide plus paclitaxel

Key Points

  • 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).

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