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Endometrial Cancer

by Pedro T. Ramirez, MD, David M. Gershenson, MD

Endometrial cancer is usually endometrioid 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, and may become even more common as prevalence of the metabolic syndrome increases. In 2013, it was estimated that endometrial cancer was diagnosed in 49,560 women and that 8190 women died 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 are

  • Obesity

  • Diabetes

  • Hypertension

Other risk factors include

  • Unopposed estrogen

  • 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

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 up to 10% of cases; about half of these cases occur in families with hereditary nonpolyposis colorectal cancer (Lynch syndrome).

Pathology

Endometrial cancer is usually preceded by endometrial hyperplasia. Adenocarcinomas account for > 80% of endometrial cancers. Endometrial adenocarcinoma is commonly classified into 2 types.

Type I tumors are more common, are commonly estrogen-responsive, and are usually diagnosed in younger, obese, or perimenopausal women. These tumors are usually low-grade. Endometroid 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 adenocarcinomas are type II.

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); 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 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 cancer is diagnosed, pretreatment evaluation includes serum electrolytes, kidney and liver function tests, CBC, chest x-ray, and ECG. 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)

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 ( 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 can be done via laparotomy, laparoscopy, or a robotics surgical system.

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

Involvement of the uterus and cervix but no extension outside the uterus

III

Local 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 or 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 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

*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 deep (> 50% myometrial invasion) grade 1 or 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 carboplatin plus paclitaxel) are effective. They are given mainly to women with metastatic or recurrent cancer. Another option is doxorubicin 60 mg/m 2 plus cisplatin 60 mg/m 2 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.

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 robotics surgical system.

  • Treatment is usually total hysterectomy and bilateral salpingo-oophorectomy, sometimes with lymph node dissection, radiation therapy, and/or chemotherapy.

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • NOLVADEX
  • CRINONE
  • No US brand name
  • PLATINOL
  • TAXOL

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