Endometrial Cancer

What is Endometrial Cancer?

Uterine corpus cancer is the most common type of cancer affecting women’s reproductive organs in the United States. In 2023, it was estimated that over 66,000 people were newly diagnosed and over 13,000 deaths were attributed to this cancer. More than 83% of all uterine corpus cancers are classified as endometrial carcinomas, a specific type of cancer that forms in the lining of the uterus, leaving less than 10% as sarcomas, another type of cancer originating in the uterus.

In more severe cases, serous and papillary serous carcinomas (a very aggressive form of cancer cells) constitute 4% to 6% of endometrial carcinomas, and 1% to 2% are clear cell carcinomas (cancer cells that appear clear under a microscope).

Endometrial cancer starts in the cells that make up the lining of the uterus. It has typically been separated in type 1 and type 2, based on what the cells look like under a microscope. But new research tends to classify it based on the specific cellular behavior (molecular subgrouping system). The majority, or 80%, are type 1 tumors that originate from a specific type of cell called endometrioid. Type 2 tumors, however, primarily come from serous or clear cells. The greatest risk factors linked to endometrial cancer are those that allow a long-term exposure to unbalanced estrogen, like obesity and artificial estrogen. It’s vital to be able to differentiate between the type 1 and type 2 endometrial cancers and particularly invasive types to appropriately deal with and potentially prevent these diseases.

Symptoms of this condition often include abnormal uterine bleeding, pain in the lower abdomen, and a swollen uterus. The initial assessment for endometrial cancer includes an ultrasound performed through the vagina, followed by a biopsy where a small piece of the uterine lining is removed to confirm diagnosis. Alternatively, the biopsy may be done first. Additional imaging studies might be carried out to check if the cancer has spread. The treatment usually involves surgery, removal of uterus and ovaries, removal of lymph nodes, and washing the abdominal cavity. If the cancer is found to be limited to the uterus and the muscular layer surrounding it, further treatments might not be necessary. But for advanced cases, a combination of surgery and additional treatments like radiation therapy, hormone therapy, or chemotherapy are often needed. Usually, the outlook is good if the cancer is detected at an early stage.

What Causes Endometrial Cancer?

The development of most low-grade endometrial cancers, a type of cancer that begins in the lining of the womb, is believed to start from continuous uncontrolled growth of the womb lining. This growth is stimulated by hormones, namely estrogen, which could be present naturally in the body or taken as medication, and are not balanced by the presence of progesterone or progestin hormones. This growth can advance from simple to complex forms of endometrial hyperplasia, which means an excessive growth of cells in the womb lining. If this occurs, unusual, potential precancerous changes, known as endometrial intraepithelial neoplasia (EIN) or previously called atypical endometrial hyperplasia, may develop into endometrioid carcinoma, a type of cancer that invades the tissue of the womb. Other contributing factors to this cancer include PTEN and KRAS2 gene mutations, microsatellite instability (which is a condition where the DNA sequences change), commonly found in Lynch syndrome, and specific chromosome abnormalities.

Endometrial cancers are generally classified according to molecular subgroups based on the number of genetic mutations and changes in the number of copies of a gene, rather than just what the cells look like under a microscope. Since the cause of EIN and endometrioid carcinomas is usually hormonal, these tend to show a presence of estrogen and progesterone hormone receptors. There have been other possibilities like insulin resistance and hyperandrogenemia, which is an excessive amount of male hormones in the body, associated with the development of endometrial cancers, but these connections are not fully understood. Non-endometrioid endometrial adenocarcinoma, another subtype of endometrial cancer, doesn’t necessarily relate to hormonal factors, but to genetic and physical changes happening in the cells.

There are generally two main types of endometrial cancer based on their cause. Type 1 cancers, which are primarily caused by factors that increase estrogen exposure without balancing hormones, and Type 2 cancers, which are not linked to such unregulated estrogen. Risk factors for the more common Type 1 cancer include obesity, taking estrogen hormone therapy, estrogen-secreting tumors, chronic lack of ovulation, tamoxifen therapy, early onset of periods, and late menopause, all of which increase the exposure to natural or added estrogen. On the other hand, risks for Type 2 cancers include a lower body weight, older age, a prior history of breast cancer, and being older than 55 at the time of diagnosis.

A family history of endometrial, colorectal, ovarian, and other cancers can increase the risks for endometrial cancer. This is especially true for cancers that establish the presence of Lynch syndrome, a genetic condition that raises your risk of certain types of cancer. Lynch syndrome is associated with mutations in specific genes like MLH1, MSH2, MSH6, and PMS2. By the age of 70, the chance of getting endometrial cancer for those carrying these mutations ranges from 13% to 60%, depending on the specific gene that’s mutated. If you carry PTEN mutations, which happens in a condition called Cowden syndrome, you may also be at a higher risk for endometrial cancers and other malignancies like the breast and thyroid cancer.

Having a high body mass index (BMI), type II diabetes and insulin resistance, lack of ovulation, irregular periods, absence of periods, or not being able to conceive, these factors consistently increase risks for endometrioid carcinoma, a type of endometrial cancer. Moreover, being overweight or obese raises the chances of getting endometrial cancer because excessive fat and a condition of uncontrolled blood sugar often seen in type II diabetes can lower the levels of a protein that binds sex hormones, resulting in higher levels of free estrogen that can stimulate the womb lining. Even having type I diabetes, which needs insulin treatment, was found to be associated with an even higher risk of endometrial cancer.

Male hormones, produced by polycystic ovaries, or the adrenal glands, can be converted to estrogen in body fat tissues. Thus, if there’s a lot of subcutaneous fat tissue and an efficient conversion of male to female hormones, there may be constant unbalanced exposure to estrogen, which affects early ovulation and stimulates endometrial growth without proper shedding of womb lining during periods. After menopause, the ovaries and adrenal glands can still produce male hormones that would be converted to estrogens in fat tissues, leading to continuous growth and excessive cell production.

On a positive note, some lifestyle factors may decrease the risk of endometrial cancers. Use of combination oral contraceptives or intrauterine devices that contain levonorgestrel, a hormone, can reduce the risk for endometrial cancer by about 33% for every five years of usage, and this decrease in risk can still be-present even 30 years after stopping the use of these contraceptives. Drinking coffee and tea might also decrease your chances of getting endometrial cancer. Meanwhile, smoking, despite its harmful effects, was associated with a large risk reduction for endometrial cancer, but it’s not recommended as a protective measure against the disease.

Finding from a large-scale study showed that the risk for all types of endometrial cancers decreases with older age when giving birth for the first time. It established that women who had their first child after 40 had their risk lowered by 44% as compared to their counterparts who gave birth before they turned 25. Furthermore, other studies noted that advancing birth frequency and short gaps between births and between the last birth and menopause reduced the risks of endometrial cancer. Additionally, breastfeeding was found to decrease the risk of developing endometrial cancer by 11% as per another large-scale study.

Risk Factors and Frequency for Endometrial Cancer

Endometrial cancer, a form of cancer affecting the female reproductive system, is the fourth most common cancer among women in the United States. Each year, about 61,880 new cases are diagnosed and 12,160 deaths are reported. This type of cancer primarily affects women between the ages of 65 and 75. Though the highest number of cases is found in North America, the global incidence has surged by over 130% in the past 30 years.

The average age for diagnosis of type 1 endometrial cancer in the U.S has dropped from 64 to 61, possibly due to the rise in obesity rates. Studies estimate that the number of endometrial cancer cases may double by 2030, reaching an estimated 122,000 cases annually.

• Endometrial cancer incidence rates are growing more rapidly among Hispanic, Asian, Pacific Islander, and Black women, compared to non-Hispanic White women.
• Black women have been found to be more likely to be diagnosed with advanced, high-grade cancers, compared to non-Hispanic White women.
• Furthermore, Black women often have poorer outcomes, possibly due to disparities in socio-economic status and access to healthcare.

Signs and Symptoms of Endometrial Cancer

A careful health review and physical exam are essential for women who may have genital cancer or precancerous lesions. This is usually based on their medical history, like the symptoms they’ve been experiencing, any risk factors, and if they have a family history of cancer. Their health history should involve their personal lifestyle habits and a detailed family history of cancer, which can help predict any risk factors. If a hereditary disease like Lynch syndrome is suspected, then genetic counseling is recommended.

Endometrial cancer, which is cancer confined to the uterus, might produce mild symptoms like abnormal uterine bleeding (AUB). This is the most common symptom. However, for advanced endometrial cancer there might be additional issues like complications in the pelvic-abdominal area or widespread cancer. Rare cases may even show extra-abdominal metastases. This abnormal uterine bleeding associated with endometrial cancer can happen to women at any age, and it becomes more prevalent with women older than 45 years. As such, any woman who is postmenopausal or has AUB and is 45 or older ought to get an endometrial evaluation.

Endometrial cancer could also occur in women before menopause, especially those with risk factors for endometrial hyperplasia. In fact, about 75% of women who were diagnosed with endometrial cancer before they were 25 also had a body mass index of over 30. So, any woman before menopause who has AUB and risk factors for endometrial cancer, or is exposed to uncontrolled estrogen (like obesity, exogenous estrogen, and polycystic ovarian syndrome), or has constant or recurrent AUB should get an endometrial assessment. This allows doctors to rule out hyperplasia, malignancy, and other diagnoses. Less common symptoms of endometrial cancer include abnormal vaginal discharge, pelvic pain, constipation, or diarrhea. Typically, nothing unusual is found during a physical exam, although those with advanced disease might show an enlarged uterus.

Testing for Endometrial Cancer

The diagnosis of endometrial cancer, or cancer of the lining of the uterus, is determined by evaluating tissue samples under a microscope. Other lab tests and imaging studies are also performed to help rule out other possible conditions and to help plan for surgery if needed. In women who have undergone menopause, either an ultrasound done through the vagina or a sample of the endometrial tissue may be used as the first step in testing for endometrial cancer. However, in women who haven’t undergone menopause yet, ultrasound through the vagina is not recommended for diagnosing endometrial cancer. There’s no specific thickness of the uterine lining that can help identify an increased risk of cancer in such women, unlike in postmenopausal women.

For patients with abnormal uterine bleeding, blood tests including a urine pregnancy test and complete blood count (to count all different cells in the blood), are usually done. These tests are used to rule out other conditions and complications due to bleeding, like anemia. A cervical screening (pap smear) test might also be done if it’s not up to date, as recommended by current guidelines. Certain results on the screening test in women aged 35 years or older, or those younger but with risk factors, will require further evaluation of the endometrial tissue.

The endometrial tissue can be sampled using various methods. The method chosen depends on various factors, including the need to visualize the inside of the uterus, expertise of the doctor and the patient’s preference. The most frequently used techniques consist of a minor procedure that uses a small, thin tube to suck a small piece of the endometrial tissue called aspiration biopsy and a slightly more invasive procedure that involves dilating the cervix and scraping the lining of the uterus known as dilation and curettage. This sample is checked for cancer cells.

If less tissue is sampled than needed in women with postmenopausal bleeding during the initial biopsy, usually an ultrasound through the vagina is recommended. In some cases, hysteroscopy (a procedure that allows the doctor to look inside your uterus in order to diagnose and treat causes of abnormal bleeding) is also recommended as it helps the doctor to clearly visualize the inside of the uterus.

Once the tissue samples are obtained, several studies are performed to determine the type of cancer cells, cellular characteristics of the tissue samples, and any specific gene or protein changes in the cancer cells. These changes can provide information about the prognosis (possible outcomes) and best treatment options.

Transvaginal ultrasound can be used to evaluate postmenopausal bleeding; if the lining of the uterus is less than 4mm thick, there’s generally no need for a biopsy as the risk for having endometrial cancer is very low, less than 1%. However, even in those with a thinner lining, if postmenopausal bleeding continues, further tissue sample assessment is needed. Other findings on ultrasound that can suggest endometrial cancer include uneven or irregular thickening of the endometrial lining, fluid accumulation in the uterus (especially in postmenopausal women) or invasion of the muscle layer of the uterus by a tumor.

If the tissue sample reveals a high-grade (more aggressive) type of cancer, a Computerized Tomography (CT) scan (a type of imaging that uses many X-rays and a computer to create detailed images) of the chest, abdomen, and pelvis are performed to look for any spread of the cancer and assist with surgical planning. Magnetic Resonance Imaging (MRI) (type of imaging using a magnetic field and radio waves to create detailed images) are sometimes used for staging in patients who can’t handle surgical staging or to look at suspicious areas seen on CT scans. In certain cases, a Positron Emission Tomography/CT scan (a type of nuclear imaging that uses a small amount of a radioactive drug to help evaluate functioning of organs and tissues) may be used to look at the lymph nodes.

Treatment Options for Endometrial Cancer

Treatment for endometrial neoplasms, a type of growth found in the lining of a woman’s uterus, should be tailored to the patient’s specific needs and desires. The decisions are made after considering many factors, such as the cancer stage, subtype, the patient’s age, other health conditions, and whether the patient wants to have children in the future. This process involves lots of open conversation between the patient and the healthcare team, which can include gynecologic oncologists, medical oncologists, radiation oncologists, and pathologists.

The Gynecologic Oncology Group (a medical group specializing in studying and treating cancers that affect women) uses various criteria to classify the risk level of the disease to determine the best management route. This could include surgery, radiation therapy or chemotherapy, hormone treatment, and targeted therapy.

The primary treatment for endometrial cancer that hasn’t spread beyond the uterus is surgery, often involving removal of the uterus and the ovaries. Doctors try to use minimally invasive techniques where possible – this means less scarring and quicker recovery times. The surgical team evaluates whether the cancer has spread to other parts of the body, particularly the lymph nodes, which can guide further treatment decisions.

Once the surgery is complete, the team may suggest additional therapies depending on the risk level of the disease. This could include radiation therapy or chemotherapy. Hormone therapy may be an option for women with low-grade cancer who want to have children in the future or who are not suitable for surgery. However, there’s a high recurrence rate, so it’s often seen as a temporary solution.

As science advances, doctors are testing new “targeted therapies,” like immune system checkpoint inhibitors and DNA repair inhibitors. These treatments aim specifically at particular abnormalities in recurrent or advanced endometrial cancers. However, their use is mainly limited to trials at the moment.

Finally, for those with advanced and recurrent endometrial cancers, options include surgery, radiation therapy, chemotherapy, hormone therapy, or a combination of those. The decision will be based on the individual patient’s circumstances. It’s important to note that many treatments aim to relieve symptoms and improve the quality of life rather than providing a cure.

What else can Endometrial Cancer be?

When a doctor is trying to diagnose common symptoms of endometrial cancer like abnormal vaginal bleeding and pelvic masses, they have to consider a range of possible causes. These could be anything from simple localized abnormalities, to system-wide diseases, and even other types of cancer. When evaluating these potential causes, doctors often refer to a classification system for abnormal uterine bleeding, known as the FIGO classification. This includes problems like polyps, adenomyosis, leiomyoma, malignancies, blood clotting disorders, disruptions in the ovulation process, problems starting in the endometrium, iatrogenic causes, and those that aren’t easily classified.

For women of childbearing age with abnormal bleeding, doctors should also consider possibilities such as intrauterine pregnancies, pregnancies outside the uterus (ectopic pregnancies), and gestational trophoblastic diseases.

Abnormal uterine bleeding can also be caused by hormones, such as estrogen, progesterone and progestogens, androgens, and tamoxifen, acting on the lining of the uterus. This can happen in both women of childbearing age and women who have undergone menopause.

Doctors should consider diseases and conditions that disrupt ovulation. These can include eating disorders, obesity, and polycystic ovarian disease, as well as hormone-secreting tumors in the ovaries, thyroid problems, adrenal gland tumors, and pituitary gland tumors. Signs that a woman’s body is losing female characteristics or developing male characteristics may indicate a problem with the body’s production of androgens.

Finally, if the doctor physically detects a mass in the pelvis, their list of potential causes would include:

• Metastatic cancer
• Fluid-filled fallopian tubes (hydrosalpinx)
• Fallopian tube tumors
• Ovarian and broad ligament cysts and tumors
• Leiomyomas
• Tissue that sticks together after surgery (pelvic adhesions)
• Displaced kidneys (retroperitoneal kidneys)
• Dermoid tumors
• Enlarged lymph nodes (tumorous nodes)
• Primary colorectal and stomach cancers
• Abnormalities in the urinary system

Surgical Treatment of Endometrial Cancer

Endometrial cancer, which starts in the inner lining of the uterus, is typically first identified (or “staged”) using surgery. Indeed, surgery is the main treatment for this type of cancer when it’s still in the early stages and hasn’t spread to other parts of the body. The usual surgical procedure is a total hysterectomy with bilateral salpingo-oophorectomy, essentially meaning that the uterus and both ovaries are removed. Doctors prefer to use a minimally invasive technique if possible, to reduce health risks and the recovery period.

Research has shown that minimally invasive surgery often results in shorter hospital stays and less chance of complications such as infection, blood clots, and fistulas (abnormal connections between organs or vessels). The risk of bleeding and bowel injury during the operation is not significantly greater than with more invasive surgery. However, minimally invasive surgery does require skilled surgeons and the ability to remove the uterus in one piece.

The decision to use surgery for advanced or recurrent endometrial cancer isn’t as straightforward, and the most effective approach isn’t well-defined. Some studies suggest that a procedure called surgical cytoreduction, which attempts to remove as much of the cancer as possible, could be beneficial when the disease can be totally removed. Based on the results of the surgery, doctors can then determine whether additional treatment is needed and what kind might be best.

What to expect with Endometrial Cancer

The survival rate for patients diagnosed with stage 1 endometrial cancer is very promising, with over 95% living beyond five years after their diagnosis. Additionally, more than 80% of patients are able to catch this cancer early, which helps their chances.

The type of endometrial cancer can impact survival rates. For example, patients with endometrial cancer of the POLE type have a 5-year survival rate of 98% without the cancer returning. On the other hand, the p53abn type, which carries the highest risk of spreading to other parts of the body, has a lower rate of 46.6%.

Another two kinds, known as MMRd and NSMP, have survival rates of 77.1% and 74.4% respectively, without the cancer coming back within 5 years.

Unfortunately, for women whose cancer has spread to other parts of the body or comes back after treatment, the prognosis is usually not as hopeful. On average, these patients live for about 15 months after chemotherapy, based on the results of a study conducted in 2020.

Possible Complications When Diagnosed with Endometrial Cancer

Endometrial cancer treatment comes with several possible side effects. Those being treated could experience:

• Lymphedema, or swelling in the limbs due to damage to the lymphatic system
• Neurotoxicity, or harm to the nervous system
• Fatigue or significant tiredness
• Problems with bowel and bladder functioning
• A diminished quality of life
• Osteoporosis, or weakening of the bones
• Intense hot flashes and other symptoms due to menopause brought on by surgery

Moreover, younger women under the age of 50 who have had both their ovaries removed (bilateral salpingo-oophorectomy) face increased risks. These include a higher likelihood of passing away, suffering a heart attack, or experiencing a stroke. For women who have survived endometrial cancer, the leading cause of death is, in fact, heart disease.

Recovery from Endometrial Cancer

About 10% of endometrial cancer, a type of cancer that begins in the lining of the uterus, may return within 3 to 5 years after initial treatment. Because of this, medical experts suggest that those who have been treated for endometrial cancer should have regular check-ups. These check-ups are recommended every 3 months in the first year, every 4 months in the second year, and then twice a year until 5 years after the treatment is completed.

For patients with high-risk endometrial cancer, the European Society for Medical Oncology (ESMO) advises that they should have check-ups every 3 months for the first 3 years and then twice a year until 5 years after treatment. But for those with low-risk disease, check-ups every 6 months for the first 2 years should be enough.

Patients should also be aware of symptoms like vaginal bleeding and pelvic pain, which could indicate a recurrence of the cancer and should be reported immediately. Routine CT scans, a type of imaging test, are not usually recommended unless the patient is showing suspicious symptoms or irregular results in their regular check-ups.

Other tests such as PET-CT, a scan that combines images from a positron emission tomography (PET) scan and a computed tomography (CT) scan, the measurement of cancer antigen 125, a protein that can be found in higher levels in some cancer patients, and Pap smears, a test used to detect precancerous or cancerous cells in the cervix, are not routinely recommended for detecting a recurrence of endometrial cancer.

Preventing Endometrial Cancer

Women with a Body Mass Index (BMI) of over 30, a measurement that indicates whether a person’s weight is healthy for their height, have about 2.5 times the risk of developing endometrial cancer compared to women with a healthy BMI. Since weight gain and obesity are linked to endometrial cancer, maintaining a healthy BMI through a balanced diet and regular exercise is an effective way to lower the risk. Moreover, low physical activity levels and high-fat, high-sugar diets can increase this risk. Women with insulin resistance and metabolic syndrome, conditions that involve problems with the body’s usual way of converting food into energy, face double the risk of endometrial cancer. Losing significant weight can also reduce the risk as every pound gained increases this risk. For instance, women after menopause who lost 5% or more of their body weight had a 30% lower chance of developing endometrial cancer.

Once regular, ovulatory menstrual cycles are established during teenage years, women who develop less frequent or absent periods and signs of excess androgen or estrogen, such as excessive facial hair growth, hair loss in specific body areas, should be evaluated for conditions like polycystic ovarian syndrome and hormonal-secreting tumors. These conditions can lead to endometrial hyperplasia, an overgrowth of the lining of the uterus, and should be adequately treated to ensure a regular menstrual cycle and fertility.

Keeping documented family medical history up to date is vital. If a personal or family history suggests a hereditary cancer syndrome, the patient should receive genetic counseling. This process includes analyzing their family’s cancer history, evaluating risks, educating the patient, testing for genes associated with cancer, and planning management strategies. A high occurrence of endometrial, colon, ovarian, and other cancers, especially those associated with Lynch syndrome and several consecutive generations developing these at younger ages, indicate a strong possibility of certain mutations.

Certain individuals with Lynch syndrome, a hereditary condition that increases the risk of many types of cancer, should consider preventative surgery due to their increased risk of ovarian and endometrial cancer. In a study over 12 years, no cancers were diagnosed in individuals with Lynch syndrome mutation who chose preventive surgery, compared to a 33% and 26% diagnosis rate of endometrial and ovarian cancers, respectively, in those who did not select surgery. This surgery ideally should be completed after childbearing is over but before their 60s, when these cancer risks increase. If these individuals are undergoing surgery for primary colorectal cancer, they should be evaluated for gynecological cancers beforehand, and possible consideration given to preventive hysterectomy and removal of both ovaries if they are done with childbearing.

While techniques like transvaginal ultrasound and sampling of the uterine lining can be useful in identifying abnormal gynecological symptoms and abnormal uterine bleeding, they haven’t proved effective as screening tests for endometrial cancer in women without symptoms at low-risk. Women with Lynch syndrome should start screening from ages 30 to 35 with these methods while they wait for risk-reducing surgery.