Endometrial cancer is usually adenocarcinoma. Typically, postmenopausal vaginal bleeding occurs. Diagnosis is by biopsy. Staging is surgical. Treatment requires hysterectomy, bilateral salpingo-oophorectomy, usually pelvic and para-aortic lymph node dissection, and excision of all tissue likely to be involved. 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.

Etiology

Endometrial cancer affects mainly postmenopausal women, particularly those aged 50 to 65. Major risk factors are

• Obesity
• Diabetes
• Hypertension

Other risk factors include

• Unopposed estrogen
• TamoxifenSome Trade Names
  NOLVADEX
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  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

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. Heredity contributes to endometrial cancer in about 6% of cases, usually in families with hereditary nonpolyposis colorectal cancer (HNPCC) syndrome.

Pathology

Endometrial cancer is usually preceded by endometrial hyperplasia. Adenocarcinoma accounts for > 80% of endometrial cancers. Other types include papillary serous, clear cell, squamous, mucinous carcinoma, and sarcomas.

The cancer may spread 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; or 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 have abnormal uterine bleeding (eg, postmenopausal bleeding, premenopausal recurrent metrorrhagia); ¹/₃ 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 cancer is suspected, outpatient endometrial biopsy is done; it is > 90% accurate. If results are inconclusive or suggest cancer, outpatient fractional D & C with hysteroscopy is done. An alternative is transvaginal ultrasonography; however, a histologic diagnosis is required.

Once cancer is diagnosed, pretreatment evaluation includes serum electrolytes, kidney and liver function tests, CBC, chest x-ray, and ECG. If an abdominal mass or hepatomegaly is detected during physical examination or if liver function tests are abnormal, pelvic and abdominal CT are also done to check for extrauterine or metastatic cancer.

Staging: Staging 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 4: Gynecologic Tumors: Staging of Endometrial Carcinoma*). Staging is surgical and includes peritoneal fluid cytology, exploration of the abdomen and pelvis, and biopsy or excision of suspect extrauterine lesions. Pelvic and para-aortic lymph nodes are removed. During staging, a total abdominal hysterectomy and bilateral salpingo-oophorectomy are done. Surgical staging is traditionally done via laparotomy but may be done via laparoscopy or use of a robotics surgical system.

Table 4
PrintOpen table
Staging of Endometrial Carcinoma* Stage† Definition I Confined to the uterine corpus IA Tumor limited to endometrium IB Invasion of more than half of the myometrium IC Invasion of more than half of the myometrium II Involvement of the uterus and cervix but no extension outside the uterus IIA Involvement of endocervical glands IIB Invasion of cervical stroma III Extension beyond the uterus but not beyond the true pelvis IIIA Invasion of serosa, adnexa, or both and/or positive peritoneal cytologic results IIIB Metastases to vagina IIIC Metastases to pelvic or para-aortic lymph nodes or both IV Involvement of the bladder or intestinal mucosa 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 *Based on staging established by the International Federation of Gynecology and Obstetrics (FIGO) and American Joint Committee on Cancer (AJCC), 1989, 1992, and 1997. 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. Staging of Endometrial Carcinoma* Stage† Definition I Confined to the uterine corpus IA Tumor limited to endometrium IB Invasion of more than half of the myometrium IC Invasion of more than half of the myometrium II Involvement of the uterus and cervix but no extension outside the uterus IIA Involvement of endocervical glands IIB Invasion of cervical stroma III Extension beyond the uterus but not beyond the true pelvis IIIA Invasion of serosa, adnexa, or both and/or positive peritoneal cytologic results IIIB Metastases to vagina IIIC Metastases to pelvic or para-aortic lymph nodes or both IV Involvement of the bladder or intestinal mucosa 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 *Based on staging established by the International Federation of Gynecology and Obstetrics (FIGO) and American Joint Committee on Cancer (AJCC), 1989, 1992, and 1997. 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.

Prognosis

Prognosis is worse with higher-grade tumors, more extensive spread, and older patient age. Average 5-yr survival rates are 70 to 95% with stage I or II and 10 to 60% with stage III or IV. 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 deep (> 50% myometrial invasion) grade 1 and 2 and for grade 3
• Pelvic radiation therapy with or without chemotherapy for stage II or III
• Multimodal, individualized therapy for stage IV

If cancer appears to be stage I/grade 1 without deep myometrial invasion, the probability of unrecognized lymph node metastasis is < 2%. Treatment is usually total hysterectomy and bilateral salpingo-oophorectomy via laparotomy, laparoscopy, or robotics.

For grade 1 or 2 with ≥ 50% myometrial invasion or grade 3, complete pelvic and para-aortic lymphadenectomy is also done. Whether the extent of para-aortic node dissection 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.

Hormone therapy with a progestin causes regression for up to 3 yr in 20 to 25% of patients. Pulmonary, vaginal, and mediastinal metastases may regress. Treatment continues as long as the response is favorable.

Several cytotoxic drugs (particularly carboplatinSome Trade Names
PARAPLATIN
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plus paclitaxelSome Trade Names
TAXOL
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) are effective. They are given mainly to women with metastatic or recurrent cancer. With monthly regimens of doxorubicinSome Trade Names
ADRIAMYCIN
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60 mg/m² plus cisplatinSome Trade Names
PLATINOL
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60 mg/m² IV, overall response rate may be ≥ 50%.

Treatment of endometrial hyperplasia consists of progestins or surgery (eg, D & C), depending on the complexity of the lesion and the patient's desire to avoid hysterectomy. 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 on average. After 3 mo, patients should be evaluated via D & C rather than endometrial biopsy.

Last full review/revision November 2008 by David M. Gershenson, MD; Pedro T. Ramirez, MD

Content last modified February 2012