Yevgeniya Ioffe, M.D., Clinical Fellow, and Israel Zighelboim, M.D, Assistant Professor, are both in the Division of Gynecologic Oncology, Washington University School of Medicine and Siteman Cancer Center, St. Louis, MO.

The most common form of cancer of the female reproductive tract in the United States is endometrial carcinoma – cancer of the lining of the uterus, or endometrium. Endometrial cancer accounts for over 95% of uterine cancers, which themselves represented approximately 6% of all cancers diagnosed among U.S. women in 2010. It is estimated that 46,470 women will be diagnosed with uterine cancer and that 8,120 will die of this disease in 2011. The median age at which women are diagnosed with endometrial cancer is 63.

Traditionally, women with endometrial cancers have been divided into two groups, depending on the form of cancer they have. Type I tumors are estrogen-dependent, meaning their growth is stimulated by estrogen, like some breast cancers. Usually women with Type I tumors are younger and have a better prognosis. Type II tumors account for 10-20% of all spontaneously occurring endometrial cancers (those without a family history). The prognosis for Type II tumors, unfortunately, tends to be poor.

It is estimated that 46,470 women will be diagnosed with uterine cancer and that 8,120 will die of this disease in 2011. The median age at which women are diagnosed with endometrial cancer is 63.

In this article, we will discuss the risk factors, symptoms, diagnosis, and treatment options for endometrial cancer. We will also go over syndromes that are associated with a higher risk of endometrial cancer, like Lynch syndrome and Cowden syndrome, which also increase one’s risk of other forms of cancer, including breast, ovarian, thyroid, and intestinal. As doctors learn more and more about the genetics and behavior of endometrial cancer, they are better equipped to determine one’s risk of endometrial cancer, diagnose it earlier, and develop more effective means of treatment.

Risk Factors

The risk factors for Type I endometrial cancer include obesity, diabetes, high blood pressure, taking medications like Tamoxifen (a breast cancer medication), estrogen replacement therapy without progesterone, chronic anovulation (lack of periods), never being pregnant, late menopause, and genetics.

Patients with Type II endometrial carcinomas are usually older when they are diagnosed and they typically haven’t had estrogen replacement therapy. The risk factors for Type II tumors are not as well defined as those of Type I endometrial carcinomas. The fact that Type II tumors are less common makes this cancer type more challenging for doctors to study and characterize. Several studies have reported that Type II cases are more likely to occur in older, normal weight women, and those who have been pregnant multiple times or African American women.

The Symptoms of Endometrial Cancer

A case history illustrates the risk factors and the symptoms associated with endometrial cancer:

A 45-year-old female who had been pregnant twice and given birth to one child came to her primary care physician complaining of worsening and excessive bleeding for the last six months. Five years earlier she had had her tubes tied in order to prevent further pregnancies. In the last ten years, the patient had gained weight, her BMI increasing from 29 to 37 (normal is 18.5–24.9), and she developed type II diabetes and high blood pressure.

Upon reviewing her family history, her doctor learns that the patient had family members with cancer: her brother was diagnosed with colon cancer at the age of 47, and her mother was diagnosed with colon cancer at the age of 44. In addition, the patient’s sister and maternal aunt were diagnosed with ovarian and endometrial cancer at the ages of 55 and 38, respectively.

Very long, heavy episodes of bleeding, abdominal or pelvic pain, and clear or white vaginal discharge after menopause are also regular symptoms.

After a thorough evaluation by an Ob/Gyn, the patient was found to have an enlarged uterus, a large fibroid, fluid in the endometrial cavity, and a growth in the lining of the uterus that was about an inch thick. An in-office biopsy revealed that it was indeed endometrial cancer.

One of the most common symptoms of endometrial cancer is abnormal vaginal bleeding, especially bleeding between periods or after menopause. Very long, heavy episodes of bleeding, abdominal or pelvic pain, and clear or white vaginal discharge after menopause are also regular symptoms. However, there can be other causes of any or all of these symptoms, so it is important to see your doctor if you experience any of them. As the case study above suggests, there can be a family or genetic predisposition for endometrial cancer if certain syndromes (like Lynch and Cowden) are present. These syndromes increase risk for a variety of cancers, and are discussed in detail later.

Diagnosing Endometrial Cancer

As in the case history above, abnormal bleeding is the first symptom of more than 90% of cases of endometrial carcinomas, which luckily makes early diagnosis somewhat more likely. A physical or pelvic exam does not usually indicate much at all, although one’s doctor might feel a slight enlargement of the uterus. An in-office biopsy of the lining of the uterus is often accurate (more than 90% sensitive) and detects many cases of endometrial carcinoma as well as precancerous lesions that are often precursors to the disease.

Pursuing the Warning Signs
With bleeding as the most common early warning sign, doctors must rule out all possible causes of bleeding, of which there can be several. Unusual bleeding in women over 35, as well as in a younger women who have a history of chronic missed periods are signs that should immediately prompt a doctor to test for endometrial cancer.

Women at risk include those who have a genetic predisposition, postmenopausal women who have been treated with estrogen replacement therapy without progesterone, premenopausal women with chronic missed periods that are untreated and patients with estrogen-producing tumors.

In some instances, women may have a negative biopsy but still have significant symptoms that suggest endometrial cancer. In these cases, doctors will often opt for a procedure called dilation and curettage (D&C), in which the lining of the uterus is scraped and the cells examined more closely. Another technique, called hysteroscopy, in which the uterus is evaluated with an endoscope (a camera on the end of a thin tube, inserted into the uterus through the vagina), may also be recommended.

A transvaginal ultrasound is another common technique, as it is sensitive and noninvasive. It can help evaluate postmenopausal patients with vaginal bleeding, and determine whether the bleeding is worrisome or not. Postmenopausal women who have a minor thickening of the endometrium, as visualized with ultrasound, generally have a low risk of endometrial disease. However, even in this group, if bleeding is recurrent or persistent, endometrial sampling must be carried out to rule out endometrial cancer or its precursor lesions.

After one is diagnosed with endometrial cancer, other lab tests may be done to look at blood counts and liver and kidney function. X-rays may also be taken to determine how advanced the disease is. Chest x-rays are often done to determine whether the cancer has spread to the lungs, since they are a common site of the metastasis of endometrial cancer.

Finally, a specific blood test may be done to measure levels of a glycoprotein called CA-125, since it can be elevated in the presence of endometrial cancer, as well as certain cervical and lung cancers. If it is elevated in endometrial cancer patients, it could mean that there is disease outside the uterus, and knowing this can help determine the best course of treatment.

Screening in High-Risk Women
Some doctors may choose to screen women who are at especially high risk. Women at risk include those who have a genetic predisposition (like those with Lynch or Cowden syndromes, to be discussed shortly), postmenopausal women who have been treated with estrogen replacement therapy without progesterone, premenopausal women with chronic missed periods that are untreated and patients with estrogen-producing tumors. Taking the breast cancer medication Tamoxifen does not mean that a woman should automatically have endometrial “surveillance” with ultrasound or biopsy if they do not have other symptoms that could indicate endometrial cancer.
Treatment Options for Endometrial Cancer
Endometrial cancer can be treated in a number of ways, including surgery, radiation therapy, hormone therapy and chemotherapy. Depending on the type of cancer cell and the stage (I, II, III, or IV), these techniques can either used alone or in combination with one another.

Surgery to Determine the Stage of the Cancer
Patients who are healthy enough to do so typically have exploratory surgery so that one’s doctor can determine how advanced the cancer is (that is, what stage it is), and begin to treat it. The doctor will also determine whether the patient is at low, intermediate or high-risk for cancer recurrence, based on various factors, like the stage of the cancer, the woman’s age, and several variables having to do with the cancer cells themselves and whether or not they have spread. If the woman is determined to be at higher risk, chemotherapy and/or radiation may be required.

Minimally invasive procedures, like laparoscopy, are becoming increasingly common for the initial surgical staging and treatment of endometrial cancer.

There are several components of surgery to determine the stage of the cancer and its early treatment: “pelvic washing” to collect and analyze the cancerous cells, exploration of abdominal cavity with biopsies as needed, hysterectomy, removal of the ovaries, and dissection of the lymph nodes of the pelvis. Removal of the lymph nodes (lymphadenectomy) in patients with early stage cancer is still controversial. Some doctors may opt to skip the lymphadenectomy if the patient is at low-risk for the cancer spreading through the lymph system.

Minimally invasive procedures, like laparoscopy, are becoming increasingly common for the initial surgical staging and treatment of endometrial cancer. Complications during the surgery tend to be about the same for laparoscopy and regular surgery (laparotomy). But laparoscopy patients may have fewer adverse events after surgery and had a lower risk for having a prolonged hospital stay, compared to women who have conventional surgery, which suggests that laparoscopy may be an effective alternative.

Radiation Therapy
Radiation therapy may be used in addition to surgery. There has been a lot of debate about whether it really helps the outcome, however. Some studies have found that it can help control the cancer in an immediate way, but the likelihood of metastasis, recurrence of the cancer at the site at which it started, and one’s five-year survival odds may not be significantly affected by radiation. Some studies found that despite a decrease in local recurrence, there was also an increase in gastrointestinal toxicities.

Other methods like vaginal brachytherapy, in which radioactive material is placed directly in the body, were linked to significantly reduced rates of gastrointestinal toxicity, so doctors may opt for this treatment over conventional (external beam) radiation. Each case of endometrial cancer is different, and doctors will look at all the variables and weigh all the options before determining an appropriate course of treatment.

Chemotherapy
Chemotherapy is another common treatment for endometrial cancer, especially in later stages of the disease (stages III and IV). Many studies have looked at the effectiveness and the adverse effects of chemotherapy in endometrial cancer treatment, and the debate is ongoing. The three most effective chemotherapeutic compounds are platinum (cisplatin and carboplatin), taxanes (paclitaxel) and doxorubicin. They are commonly used alone or in combination for the treatment of advanced cases of cancer. The response rates (how likely the cancer is to be affected by the chemicals) ranges from 20% to >40%. Other cytotoxic agents including 5-fluorouracil, vincristine, ifosfamide and ixabepilone are less supported by the research, but may be somewhat effective as well.

Studies comparing the different forms of chemotherapy against one another have found that there are pros and cons to each. In one study, women who got by cisplatin and doxorubin (AP) or cisplatin plus doxorubicin plus paclitaxel (TAP) had about the same rates of survival and of recurrence. But in further analysis, TAP was linked to a 50% reduction in the risk of recurrence or death in patients cancer recurrence, but it also carried a greater risk of serious side effects. Other studies are currently underway to determine the effectiveness and adverse events associated with other combinations of chemotherapy drugs.

Hormone Therapy
Hormonal therapy using high doses of progestins (progesterone) is another treatment option for patients with advanced or recurrent endometrial cancers. Before hormonal therapy can be used, however, the tumor has to be tested for expression of estrogen and progesterone receptors. The response rates approach 20% in the presence of estrogen and progesterone receptors., but some research has found that this form of therapy is not useful in preventing relapse or prolonging lifespan, although there were some shortcomings in the design of the study. Combining daily tamoxifen with weekly progesterone may be more effective treatment option for advanced or recurrent endometrial cancer.

Biologics Could Be Promising in the Future
Over the past several years, there has been increasing interest in biological therapy for treating cancer, especially in advanced and recurrent endometrial cancer. Biologics don’t attack the cancer cells directly, as with chemotherapy – rather, they help the immune system fight the cancer more effectively. Some trials have shown promise for a drug called bevacizumab, administered to patients with recurrent or persistent endometrial cancer. But these methods are still new, and more research needs to be done to determine how safe they are, and how effective.

Recurrent Endometrial Cancers
For women who have recurring endometrial cancer, the treatment options are somewhat limited. Vaginal recurrences can often be treated with radiation therapy. For women who initially under go surgery, radiation can be an effective option if the cancer reoccurs in the vagina.

For cancers that occur at a single site, surgery and/or radiation may be successful. For cancers that occur at distant sites from the original location, chemotherapy, biologic or hormonal agents, as previously discussed, can be used.

Syndromes That Raise One’s Risk for Endometrial Cancer

A small percentage (3-5%) of women who have endometrial cancer may have what is known as “site-specific cancer susceptibility syndromes.” These syndromes elevate one’s risk for developing several forms of cancer, including endometrial, and involve specific gene mutations. They also increase one’s risk for developing cancers at an earlier age than the average. The two discussed here are Lynch syndrome and Cowden syndrome.

Lynch Syndrome
Lynch syndrome is a genetic condition that increases one’s risk for a specific type of colorectal cancer known as hereditary nonpolyposis colorectal cancer (HNPCC), and accounts for the majority of inherited cases of endometrial cancer. It can affect both women and men. The average age of diagnosis of endometrial cancer in patients with Lynch syndrome is 46 years old. Individuals affected by this syndrome are at risk for a number of cancers, including colon, endometrial, ovarian, gastric, intestinal, hepatobilliary tract, upper urinary tract, brain, and skin cancers.

Researchers have outlined the gene mutations involved in Lynch syndrome, which occur in the repair system of the DNA. The inheritance pattern for the disorder is autosomal dominant, meaning that only one parent needs to have the mutation in order for a child to inherit it.

The average age of diagnosis of endometrial cancer in patients with Lynch syndrome is 46 years old. Individuals affected by this syndrome are at risk for a number of cancers, including colon, endometrial, ovarian, gastric, intestinal, hepatobilliary tract, upper urinary tract, brain, and skin cancers.

The estimated risk of developing colon cancer in women affected with Lynch syndrome is 40% to 60%. Additionally, for women with Lynch syndrome, their lifetime endometrial cancer risk equals or exceeds their risk of developing colon cancer. Based on the specific types of genetic mutations a woman has, her risk for developing endometrial cancer is between 40 and 70%.

Cowden Syndrome
Cowden syndrome was first described in 1963 and is named after a last name of a patient. It is a rare inherited disorder that can affect both sexes, and the criteria doctors use for diagnosis continue to evolve. Individuals afflicted with Cowden syndrome (CS) have an increased risk of developing several types of cancer: breast, thyroid, and uterus. Women who have CS have a higher risk – 19% – of developing endometrial cancer by age 70.

Signs and symptoms of CS include lesions on the mucous membranes of the nose and mouth, growths in the gastrointestinal system (called hamartomatous gastrointenstinal polyps), enlarged head (macrocephaly), thyroid disease, benign breast disease, breast cancer and endometrial cancer. The overwhelming majority of patients will show clinical signs (lesions of the mucous membranes) by age 29.

Approximately one in 200,000 people have CS. Like Lynch syndrome, in CS only one parent has to have the mutation to pass it on to the child, making it an autosomal dominant mutation. Researchers have uncovered the specific mutations involved in CD: a particular mutation in PTEN, a tumor suppressor is found in approximately 80% of patients with CS. Mutations in the gene are found in an array of sporadic tumors, such as thyroid, endometrium, prostate, breast, brain, and endometrial cancer.

Diagnosis and Management for Lynch and Cowden Syndromes
A detailed family history helps doctors identify patients and their families who may have a genetic cancer predisposition, like Lynch or Cowden syndromes. Genetic testing can be done for women thought to be at risk for having Lynch syndrome. Sometimes hysterectomy along with removal of the ovaries may be recommended for women with Lynch syndrome in order to prevent endometrial and ovarian cancers from occurring.

Diagnostic criteria for Cowden syndrome have evolved over the years. The most recent is the Cleveland Clinic scoring system in 2011. For an individual patient, the probability of a relevant gene mutation may be evaluated by the Cleveland Clinic web calculator to derive.

Outcomes for Patients and Future Directions

Endometrial cancer patients tend to experience vaginal bleeding and pelvic discomfort early in the disease process which, fortunately, leads to early diagnosis. As a result, 75% of the patients are diagnosed with early-stage carcinomas and will survive their disease. The survival rate by the stage of the cancer approaches 85% for stage I, 75% for stage II, 45% for stage III and 25% for stage IV disease. However, these rates can vary considerably, as they depend on many variables, like the type of cancer cells that are present, and other clinical variables.

Several factors are associated with prognosis for women with endometrial cancer. These include histologic type, the woman’s age at diagnosis, tumor grade and stage, how deep into the uterus the cancer cells have grown, and whether or not the cancer has invaded the lymph or vascular systems.

Endometrial cancer patients tend to experience vaginal bleeding and pelvic discomfort early in the disease process which, fortunately, leads to early diagnosis.

Much is known about endometrial cancer, but there is also much about it that is still a mystery. The risk models are imperfect, and can make treatment difficult. For example, some women who are thought to be at low risk may experience recurrences, while others probably receive unnecessary, costly and potentially toxic treatments. In the future, a better understanding of the biomarkers associated with endometrial cancer is expected to help doctors determine a woman’s risk more accurately, and develop the best method of treatment. Learning more about the genetics of endometrial cancer should also lead to earlier detection, and an even better prognosis for patients who are affected by it.