Endometrial Carcinoma

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Epidemiology of the carcinoma of the lining of the uterus

• Most common gynecologic malignancy, accounts for about 6 percent of all malignancies occurring in women. There will be an estimated 38,000 cases of endometrial cancer diagnosed in the United States in 2002.
• Fortunately, because the cancer causes bleeding so early in its growth, most women are alerted to see their physicians for early diagnosis, with a five-year survival of 85%.
• Risk factors – conferred by unopposed estrogen effect. Estrogen, which dominates during the first half of the menstrual cycle, causes increased mitotic activity, cell growth, thickening of the endometrial lining, and up-regulates cell sensitivity to itself. Progesterone is secreted by ovulation and dominates in the second half of the menstrual cycle, inhibiting cell growth, promoting maturation of the lining stopping the growth of the lining and decreasing overall sensitivity to estrogen.
• Increasing risk – more exposure to estrogen:
• Obesity by >50 lbs (10x) Fat cells convert adrenal hormones into estrogens (androstenedione into estrone)
• Estrogen replacement without progestins (7-10x)
• Age >70 (2-4x)
• Tamoxifen, a weak estrogen (6x)
• Anovulation – no progesterones (5x)
• Late menopause – less progesterones secreted in 50’s (2.5x)
• No children – less progesterone exposure (2x)
• Hypertension (2x)
• Diabetes (3x)

• Decreasing risk – more exposure to progestins
  
• Birth control pills – all contain good progestin levels (.5x).
• Post menopausal progestogens reduce risk to (.25x)

Screening and prevention of uterine cancers

Screening for endometrial carcinoma is not as easy as screening for cancer of the cervix because the uterine cavity is well above the cervix, and can only be reached by biopsy with a special suction device that is associated with significant cramping. Pap smears cannot be relied upon to detect endometrial cancers because they sample only the cervix and inner cervix, the lowermost portion of the uterus.

There have been studies showing the benefit of using endometrial biopsies to screen high-risk women who have no symptoms, or women who cannot take progesterones with their estrogens (“unbalanced”).

A sonogram of the uterus with measurement of the endometrial thickness may be suggestive of uterine cancer if the lining of the uterus cavity demonstrates increased thickness. Likewise, if the lining is 4.0 mm or thinner, a biopsy can be avoided. Screening for endometrial carcinoma by yearly biopsy is not currently done, even in high-risk women who are obese, or taking Tamoxifen. Pap smear is performed on the cervix but still detects only about 10% of endometrial cancers because the uterine cavity is higher up and not included in the Pap smear scraping. Routine annual screening for women without symptoms is not recommended by the American College of Obstetricians and Gynecologists.

All women who are at high risk for uterine cancer should be given cycles of progesterones. It has been known since the late 1970’s that obese women, women under age 50 who do not ovulate either because they are in early menopause or have ovarian dysfunction, or women taking only estrogen hormones have a much higher risk of uterine cancers. Prevention must be offered by balancing the body’s levels of estrogen with cycles of progesterones at least every three months.

Signs and symptoms of endometrial carcinoma most commonly include vaginal staining or bleeding, however short-lived or slight, in a postmenopausal woman. Most postmenopausal women recognize these symptoms and have a biopsy, which gives an early diagnosis and a high cure probability. However, pre-menopausal and peri-menopausal women with irregular bleeding also should have a biopsy. Other symptoms may include pain in the pelvis, back or legs, bladder or rectal pressure symptoms, weight loss and general weakness, which may indicate more widespread disease. Five percent of women will have no symptoms.

Diagnosis of Endometrial cancer is made by microscopic exam of the cells of the uterine lining, obtained by suction of scraping biopsy.

• The definitive diagnosis is made by an endometrial biopsy, which involves a small scraping of the uterus and is usually performed in the doctor's office. A dilation and curettage (D&C) is required for some women who can't have an endometrial biopsy done in the office because of a small cervical opening or discomfort.
• Hysteroscopy should not be performed in women in whom cancer is part of the differential– as the fluid used to distend the uterine cavity for visual inspection can disseminate the cancer cells through the fallopian tubes into the peritoneal cavity.
• A pelvic sonogram can reveal the possibility of uterine cancer if the lining of the uterus cavity demonstrates either normal or increased thickness. If an endometrial stripe is very thin, 4mm or less, most studies indicate that no cancer exists, and no biopsy is needed.

Workup and Physical Examination must be thorough to include evaluation of co-morbidities as well as the gynecologic exam.

• The gynecologic examination is often normal. However there may be metastatic invasion of the cervix (Stage II), and the vagina may also be involved (Stage III).
• Occasionally the uterus will be enlarged or softened and masses may be detected in the ovaries, parametrium, pelvic lymph nodes, groin nodes, supraclavicular nodes.
• In rare cases there is upper abdominal spread, with ascites, or a palpable mass
• Personal and Family history should be obtained for all cases of endometrial and colon cancers (rule out Hereditary Non-Polyposis Coli; Familial Endometrial Carcinoma syndrome is very, very rare) Get colonoscopy if heme positive.
• Standard blood count, liver, renal, and electrolyte panels are obtained.
• Serum CA-125 is rarely produced with endometrial carcinoma, but can be elevated with disease beyond the uterus and can be useful in follow up to detect recurrences.
• If extra-uterine disease is suspected based on exam or by elevated Ca125, a CT scan of the abdomen and MRI scan of the pelvis may be useful for determining the extent of the cancer in the pelvis, the presence of ovarian disease and the presence of involved pelvic and aortic lymph nodes and liver metastases.
• Pre-operative Chest x-ray is always obtained, but is positive in only 2%.

Classification: Cancer is classified the degree of spread (the stage) and the appearance of the cells (the grade), and by the type of cells overgrowing (histologic type).
Staging – endometrial cancer cells grow slowly, into the muscular wall of the uterus, deeply into the lymphatic channels, then into the lymph nodes, down to the cervical opening, or out through the fallopian tubes to the ovaries or the fluid in the peritoneal cavity. Rarely the cancer cells can travel through the blood to the lungs and bones.

Stage is the physical extent of spread
of cancer and is assigned from the surgical and pathological data. The International Federation of Gynecologists and Obstetricians makes the rules of staging so that therapy data can be compared throughout the world.

Grading of cancer - Grade is a ranking between 1 and 3 of the degree of similarity of cancer cells’ microscopic appearance to normal endometrial cells. The pathologist examines and reports the appearance of the nucleus and the architectural arrangements of the cells, assigning the grade. Higher grade means a more virulent cancer with higher likelihood of early metastatic spread and recurrence. Survival of all types of endometrial cancer is affected by grade.

Histologic Types - Histotype is based on the type of cell the cancer arose from. The uterus has an endometrial lining, supporting endometrial stromal cells, a tubal lining and a muscular wall. Tumors can arise from any of these three areas, usually alone, but occasionally in combination.

• Villoglandular Adenocarcinoma – (80%) arises from endometrial glands. These may contain squamous cells, which do not impact survival.
• Papillary Serous – (5-10%) looks like fallopian tube serous cells and can mimic ovarian cancer spread and appear similar under the microscope, often with early spread out to the abdomen. This type has a poorer prognosis and is almost always grade 3.
• Clear cell carcinoma – (3%) This type is almost always grade 3.
• Endometrial stromal sarcoma arises from stromal supporting cells around glands.
• Leiomyosarcoma arises from the muscular wall of the uterus.

Endometrial cancer precursors, called Endometrial hyperplasia, an overgrowth of the lining of the uterus, is a precursor to the development of cancer. This disorder tends to progress from a simple, benign hyperplasia confined to the lining of the uterus, to more severe atypical forms of hyperplasia and eventually to an invasive malignancy. The risk factors for endometrial hyperplasia are similar to those of endometrial carcinoma.

Abnormal uterine bleeding is usually the first symptom. The diagnosis is made by evaluating the lining of the uterus by office biopsy or dilation and curettage (D&C).

Treatment depends on the degree of hyperplasia, the age of the woman and her reproductive desires. Total abdominal hysterectomy and removal of both tubes and both ovaries is recommended for postmenopausal women and women who have completed childbearing. Women who want to keep their reproductive organs can be treated with oral progesterones. These hormones are taken for three months and then the uterine lining is re-evaluated by another biopsy. If the pre-cancer is gone, then cycles of progesterones are given for life. If the pre-cancer is still there, then either another cycle of progesterone is tried and a third biopsy is performed or a hysterectomy is done. A hysterectomy should be done if the pre-cancer remains.

Surgical Treatment of cancer - The standard therapy for early low-grade cancer is a hysterectomy with removal of both fallopian tubes and ovaries, and obtaining of fluid washings from the abdominal cavity to look for malignant cells. Once the uterus is removed, it is given to the pathologist to examine for high-risk factors for lymph node invasion. Removal of pelvic and aortic lymph nodes is done when/if the pathologist finds high-grade cancer, deep invasion into the muscular wall of the uterus, spread down to the cervix, or invasion into the lymphatic channels of the wall of the uterus.

Complications of hysterectomy include infection, bleeding and injury to the bladder, rectum or ureter causing a leak (all thankfully rare). There may also be blood clots in the legs, occasionally dislodging and traveling to the lungs (pulmonary embolism).

Post-operative radiation - If the cancer is limited to the inner portion of the uterine muscular wall, not invading the lymphatics or the cervix, with no evidence of spread to the upper abdomen, then the cure probability is over 90%. With limited volume cancers the cure is as high as 98%. These early cancers require no radiation.

Women who have uterine cancer that is high grade, invading the lymphatics, involving the cervix or spread to the ovaries, tubes or elsewhere have a higher probability of recurrence of the cancer and need radiation to the entire pelvis and upper vagina. Cure rates are only about 50-70% without radiation, but are as high as 85% with radiation. The invisible external beam radiation is given daily, five days a week for four to five weeks. Pelvic external beam radiation therapy will decrease the frequency of recurrences in the pelvis and vagina, and improve the overall cure rate.

Side effects of radiation are rare but can include diarrhea, nausea and vomiting, bleeding from the bladder or rectum, vagina, scarring, intestinal obstruction, or leaks (fistulas) in the urinary or intestinal tracts.

Chemotherapy Treatment with chemotherapy after surgery is being evaluated for higher stages of the disease.

Peritoneal fluid involvement: The chance of malignant cells being present within the abdominal cavity (Stage lIIa) increases with higher grades of cancer and with deeper invasion of the tumor into the uterine wall. Treatment after surgery, with chemotherapy or radiation is controversial and should be considered investigational. Many gynecologic oncologists recommend treatment with radiation therapy to the entire abdomen, intra-abdominal radioactive substances such as chromic phosphate, progestational hormone therapy or combination chemotherapy.

Vaginal Metastases: This stage (IIIb) is generally treated by abdominal hysterectomy, removal of the tubes and ovaries on both sides, thorough staging and, occasionally, surgical excision of the metastases.

These cases are then usually treated with external beam radiation therapy to the pelvis and vagina, five days a week for four to five weeks. This is followed by either a temporary insertion of radioactive cesium or iridium directly into the cancer (interstitial implant). Sometimes radiation therapy is employed before surgery.

Endometrial cancer that extends locally outside the uterus is usually treated with radiation therapy-five weeks of external radiation therapy to the pelvis followed by two temporary cesium insertions two weeks apart or by a radioactive interstitial implant-followed by surgery, if possible.

Tumor invading the bladder or rectum IVA: External radiation therapy to the pelvis followed surgical removal of the uterus, upper vagina, possible some or all of the bladder and/or rectum.

Distant metastases, intra-abdominal spread or groin nodes IVB- Standard Treatment is based on the location of the distant metastasis, with the most common sites being the lungs or liver. Therapy is rarely curative, but may be prolong life.

There is a 20-to 30 percent response rate to the hormone progesterone. If the cancer contains progesterone receptors, then progesterone can be tried. Similarly, if the tumor contains many estrogen receptors, then an anti-estrogen hormone can be tried also with a response rate of 20 to 30 percent.

Most women with a recurrence will receive chemotherapy with Taxol + Carboplatin every three to four weeks has been shown to be effective in some patients, with tumor shrinkage in about 65% of women.

Treatment follow-up - Most gynecologic oncologists recommend a general physical and pelvic examination including a Pap smear every three months for the first two years, then every six months for another three years.

The serum CA-125 level is monitored among high risk patients. X-ray studies, such as CT scans, are done only when specific signs and symptoms warrant.

Recurrent cancer - Most recurrences take place within three years of completing the initial therapy. Symptoms of recurrent cancer may include vaginal bleeding or discharge, pain in the pelvis, abdomen, back or legs, leg swelling (edema), weight loss and chronic cough.

Local recurrences-those in the pelvic wall, vagina and the tissue surrounding the cervix and uterus (parametrium)-are the most common sites in women who have not received pelvic radiation; distant metastases to the lung, liver or abdominal cavity are more common in women who have received radiation.

Radiation therapy, if not given previously, may cure those women with a vaginal or parametrial recurrence. In women who have localized vaginal recurrence involving the bladder or rectum, the removal of the bladder and/or rectum and vagina (total pelvic exenteration) can be curative in 40 to 50 percent of cases.

Unfortunately, most women with recurrent endometrial cancer outside the pelvis cannot be cured. But symptoms may be relieved with progestational therapy, anti-estrogen therapy or chemotherapy as noted above.

THE MOST IMPORTANT QUESTIONS YOU CAN ASK YOUR DOCTOR:

1. What qualifications do you have for treating cancer? Are you trained and able to perform every step that may be necessary in my case?
2. Can my surgery be performed using minimally invasive surgical techniques (laparoscopy)?
3. Do you know already if I will need radiation therapy or do I need to wait until the tissue pathology is analysed and reported? When will I find out?
4. What can I do to improve my health to prevent recurrences of this cancer and the development of other cancers?

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