Endometrial Hyperplasia and Cancer

What is Endometrial Cancer?

Endometrial cancer is a cancer arising from the Endometrium (the lining of the uterus). The uterus has three layers: the endometrium (or inner lining), the myometrium (muscle), and the serosa (outer surface lining, the same as the lining of the abdominal cavity).

The endometrium typically grows thicker in response to Estrogen stimulation. Estrogen is produced by the ovary as the egg is growing within it. However, it may also be produced by conversion of male hormones (androgens) to female estrogens in fatty tissues in the body. Normally, after an egg is released (ovulation) the ovary converts over to the production of progesterone. Progesterone then causes the endometrium to mature and eventually shed- resulting in a "period" or menstrual cycle. Chronic lack of progesterone (patients who fail to ovulate regularly) or overstimulation with estrogen (overweight patients and those taking oral estrogen supplements) can cause unregulated growth of the endometrium. This can lead to Hyperplasia- an abnormal thickened growth of the lining of the uterus which is a pre-cursor to endometrial cancer.

Endometrial Hyperplasia and its relation to Cancer

Endometrial hyperplasia is an abnormal thickening or growth of the lining of the uterus. There are several varieties:

Simple hyperplasia- this is simply an increased thickness in the endometrium with an increased number of glands. There is no cytological atypia (abnormal, malignant appearing cells). Treatment is usually  with progesterone supplementation and there is a <1% chance of progression to cancer.

Complex hyperplasia without atypia- this type is a little thicker than simple hyperplasia, and has more crowding and abnormal architecture to the glands. Without treatment, about 10% of patients will progress to endometrial cancer. Treatment is typically with progesterone, although hysterectomy is an option in women who have completed childbearing and are at acceptable surgical risk.

Complex hyperplasia with atypia- similar architectural abnormalities as complex hyperplasia without atypia, only the cells have bizarre appearances. Unfortunately, if the diagnosis is made by D&C or endometrial biopsy, it is virtually impossible to distinguish between this and invasive endometrial cancer, as they look very similar. This has become a perplexing problem recently, as most patients are treated with a hysterectomy. However, 30-40% of patients will be found to have an invasive cancer instead of hyperplasia, a large proportion of who have significant amounts of invasion. Since patients with invasive cancer normally have lymph nodes removed as part of their surgical staging, this presents a dilemma- should lymph nodes be removed at the time of surgery for complex hyperplasia with atypia? Some physicians are using frozen section (looking at the pathology during surgery) but this may fail to yield a correct diagnosis in as high as 20% of patients. Because of the significant risk of invasive endometrial cancer, all patients with this diagnosis should have a consultation with and/or be managed by a surgeon capable of performing complete surgical staging (such as a gynecologic oncologist).

Statistics of Endometrial Cancer

Endometrial cancer is the most common Gynecologic malignancy in the United States, and the fourth most common female malignancy. This year an estimated 41,000 women will be diagnosed with the disease.

Overall survival is excellent since 75% of patients have disease confined to the uterus.

Risk Factors

In addition to genetic pre-disposition to endometrial cancer- anything that increases the amount of time the endometrium is exposed to un-opposed estrogen will increase the risk of endometrial cancer. This includes:

• Obesity
  • If you are >30 pounds overweight you have triple the risk of endometrial cancer compared to the normal population
  • If you are >50 pounds overweight, you have 10 times the risk
  • Nulliparity (never had children)-  2x increased risk; usually because it is associated with chronic anovulation (failure to ovulate)
  • Late menopause or early menarche (onset of menses)- 2.5x increased risk
  • Diabetes-2.8x increased risk
  • High Blood Pressure- 1.5x increased risk
  • Exogenous estrogen use (taking estrogen supplements without progesterone)- 10 time increased risk

Special Considerations:

• Tamoxifen use- tamoxifen is known to increase the risk of endometrial cancer up to three-fold. However, this results in only 6-7 endometrial cancers per 1000 women taking tamoxifen compared to 121 fewer breast cancer recurrences per 1000 women. Therefore, despite its associated risks, tamoxifen is overall beneficial for breast cancer patients.
• Hereditary Non-Polyposis Colorectal Cancer Syndrome (HNPCC or Lynch type II)- These patients have an inherited genetic disorder that is associated with an increased risk of colon cancer (lifetime risk 80%), endometrial cancer (risk 60%), stomach cancer (13%), ovarian cancer (10%), as well as urinary tract, small bowel cancer, and brain cancers. If you have a significant family history of any of these cancers, you should consider genetic testing.
  • Patients with HNPCC mutations should have annual exam with CA125 level and annual endometrial biopsy starting at age 35. Consideration should be given to prophylactic hysterectomy and salpingo-oophorectomy (removal of the ovaries) once child bearing is complete.

Symptoms of Endometrial Cancer

• Irregular, unusual, or heavy vaginal bleeding
• Any amount of bleeding or spotting after you have gone through menopause
• Pain with intercourse
• Pain with urination
• Lower abdominal or pelvic pain

While these symptoms may be caused by other conditions besides endometrial cancer, if you experience any of these, you may want to contact your physician. This is especially true for bleeding after menopause.

Diagnosis of Endometrial Cancer

• If you have any of the above symptoms, your doctor may recommend either an Endometrial Biopsy or a Hysteroscopy with Dilation and Curettage (D&C). An endometrial biopsy uses a small flexible suction straw that is inserted through your cervix into your uterus to obtain a sample of the endometrial lining. This is done in the office and is accompanied by minimal discomfort. A D&C is usually performed as an outpatient surgical procedure. An endometrial biopsy is 95% as sensitive for detecting cancer as a D&C and is usually considered adequate for diagnosis, although certain situations may require an additional D&C as well.

Treatment Options for Endometrial Cancer

• The mainstay of treatment for endometrial cancer is surgery. Here is a link to an article on the importance of surgery and staging for endometrial cancer. The following procedures should be included:
  • Complete Hysterectomy (removal of uterus, both tubes and ovaries, and cervix)
  • Surgical Staging- complete removal (not just sampling) of pelvic and para-aortic lymph nodes. These should include the external iliac nodes, internal iliac nodes, obturator nodes, common iliac nodes, and para-aortic nodes. For certain cell types (papillary serous endometrial cancer) removal of the omentum should be performed as well.
• Surgical staging benefits:
  • 20% of patients with tumors apparently limited to the uterus will have disease outside the uterus (in the lymph nodes, ovaries, or other tissues) when full surgical staging is performed
  • If surgical staging is not done, the majority of these patients would require radiation in addition to surgery, as the true extent of disease would be unknown. By removing lymph nodes, further therapy can be avoided in the 80% of patients who don't need it, while allowing tailoring of therapy to patients with spread of disease outside the uterus.
  • Surgical staging, if done by competent physicians, has not been shown to increase blood loss, or surgical complication rates compared to simple hysterectomy.
• Additional treatment of endometrial cancer
  • Spread to cervix
    • This is treated with additional radiation to the top of the vagina to prevent local recurrence
  • Spread to lymph nodes
    • This is usually treated with chemotherapy in combination with radiation therapy. Oftentimes this involves 9 weeks of chemotherapy, followed by 6 weeks of radiation therapy, followed by an additional 9 weeks of chemotherapy.

Robotic/Laparoscopic Surgery for Endometrial Cancer

• Previously, endometrial cancer was managed by operating through a large abdominal incision. This required 3-5 days in the hospital, with usual recovery period lasting 4-6 weeks.
• Recent technologic advances have led to the use of robotic assisted laparoscopy for management of this condition
  • 4-5 "band-aid" sized incisions Patients able to go home the next day and resume normal activities in 1-2 weeks Less blood loss Less post-operative complications

Stages of Endometrial Cancer