How Doctors Recognize and Diagnose Different Types of Endometrial Cancer

“A patient who is coming into my office with a new diagnosis of endometrial cancer is going to have a consultation with me regarding what’s on their pathology report.  If their diagnosis was achieved by getting a uterine biopsy, for example, or an endometrial biopsy, then we’re going to talk about what that pathology shows and what the next steps in treatment would be,” she says.

“If the diagnosis has been made after a hysterectomy [the removal of the uterus and cervix], then we’re going to talk a little bit about what that diagnosis shows and what the stage, grade or extent of disease might be and how we proceed for treatment from there,” she adds.

Related: Understanding the Risks and Symptoms of Uterine Cancer

Types of Endometrial cancer

The 5th edition of the World Health Organization (WHO) system, was published in 2020, and it classifies endometrial cancer into the following subgroups:

• Endometrioid carcinoma: The most common type, typically linked to excess estrogen and often presents with less aggressive behavior.
• Serous carcinoma: A highly aggressive and more likely to spread type, associated with older age and atrophic endometrium.
• Clear cell carcinoma: Known for its clear and cells packed with a form of sugar known as glycogen, this type is rare and has a poorer prognosis.
• Mixed carcinoma: Features characteristics of more than one type of endometrial cancer, varying widely in behavior and treatment response.
• Undifferentiated/dedifferentiated carcinoma: Lacks specific tissue features, typically very aggressive and difficult to treat.
• Carcinosarcoma: Also known as malignant mixed müllerian tumor, includes both carcinomatous (epithelial) and sarcomatous (connective tissue) components, often very aggressive.
• Rare endometrial cancers: Includes less common subtypes like small cell carcinoma, transitional cell carcinoma, among others

Doctors also recommend the integration of molecular characteristics to further categorize these tumors and to help predict prognosis.

“If you do have a defect in one of those genes, you could have Lynch syndrome, which is a common cause hereditarily for endometrial cancer,” Dr. Toboni, an assistant professor of gynologic oncology at University of Alabama Medicine.  “MMR proficient is when you do not have a defect in one of those genes, which is the majority of endometrial cancers, approximately 70%.”

Molecular classification

Doctors and scientists use a special way to understand and sort endometrial cancer into groups, just like sorting tools into boxes based on their type and what they do. This helps them figure out how serious the cancer is and the best way to treat it. They get this information by looking at the cancer’s genes, which are like tiny, detailed instruction books inside every cell.

When doctors understand which group the cancer belongs to, they can tell how it might act, like whether it will grow quickly or slowly, and if it will respond well to certain treatments like radiation (using high energy to kill cancer cells), chemotherapy (special medicine to kill cancer cells), or other special medicines aimed directly at the cancer, like immunotherapy.

Doctors find out about these groups by removing a small piece of the cancer as a sample and testing it, which is usually with a procedure known as a biopsy or with surgery.

Sometimes, they find out that a cancer fits into more than one group, which is pretty rare — about 3 times out of 100. So, knowing about these groups is really helpful for doctors to treat their patients in the most beneficial way possible.

There are four main types of endometrial cancer, all of which start in the lining of the womb. Here’s how doctors group them:

1. POLE-mutated: this type is very rare and happens when there’s a mistake in the POLE gene, which helps copy DNA when cells divide. This mistake causes the cancer numerous other tiny mistakes in its genes. Even though this type can look serious under a microscope, people with this cancer usually do really well and live a long time after treatment.
2. Mismatch repair-deficient (dMMR): This type happens when the cancer cells can’t fix mistakes in their DNA properly and this leads to the cancer having lots of mistakes in its genes. These cancers are not good at fixing themselves, so they have lots of errors and tend to be found because they cause the immune system to react strongly. This type of cancer often happens with a condition called Lynch syndrome, which can also lead to other types of cancer.
3. No specific molecular profile (previously also known as p53 wild-type [“p53wt”]: This type doesn’t have a lot of big changes in its genes and doesn’t fit into the other groups. It’s sort of a middle-of-the-road type, not too aggressive but not the easiest to treat either. This type tends to respond well to hormone therapy if the cancer cells have hormone receptors.
4. p53 abnormal: This type is more serious and has lots of changes in its genes. It’s similar to some aggressive types of ovarian and breast cancers. This type can be pretty tough to treat and is a common reason why endometrial cancer can be deadly.

Related: Exciting New Combination Therapy Gives Hope To Women With Advanced Endometrial Cancer

Symptoms of Endometrial Cancer

The earlier doctors spot endometrial cancer, the better the chances are that treatment will be successful.

The number one symptom most women notice is irregular bleeding.

“It’s important for women that haven’t gone through menopause yet … like if you’ve always had normal periods, they’ve always come every 28 days, for example, and all of a sudden for the last couple months you’re having bleeding in between periods. I would encourage you to go to the doctor and discuss that because that could lead them to want to do an endometrial biopsy,” – says Dr Dana Chase, an associate professor of UCLA Obstetrics and Gynecology in the Division of Gynecologic Oncology. 

• More than 90% of women with endometrial cancer experience abnormal vaginal bleeding.
• If you are still having periods, abnormal bleeding might mean bleeding between periods or having very heavy periods.
• If you have gone through menopause and stopped having periods, any amount of vaginal bleeding is considered unusual. This is even more important if you are not taking hormone therapy for menopause symptoms like hot flashes or vaginal dryness.
• It’s normal for people who are taking hormone therapy for menopause to experience some bleeding in the first few months of treatment. But, if you are on hormone therapy and notice any bleeding, it’s still something you should talk to your doctor about.

Dr. Chase says that if you’ve always had irregular periods it’s less likely that that you have endometrial cancer. However, doctors won’t rule it out so be sure to have that discussion.

Other symptoms of endometrial cancer may include:

• Pelvic pain: Some women may experience pain or discomfort in the pelvic area.
• Pain during intercourse: This symptom is less common but can occur in some cases.
• Unusual vaginal discharge: Watery or blood-tinged discharge may be a sign of endometrial cancer.
• Weight loss: Unexplained weight loss can sometimes be associated with cancer.
• Urinary problems: Difficulty or pain when urinating.

Many of these symptoms could generally be a sign that something is wrong and don’t necessarily point to endometrial cancer. All the more reason to proactively seek a medical opinion when you notice something unusual happening with your health.

Diagnosis of Endometrial Cancer

Here are the primary diagnostic tools and methods used:

• Pelvic Examination: A physical exam to check for any abnormalities in the uterus, ovaries, and other nearby organs.
• Transvaginal Ultrasound: A type of ultrasound where a probe is inserted into the vagina to get a clear image of the uterus and detect any irregularities in the endometrial lining.
• Endometrial Biopsy: A procedure where a small sample of the endometrial tissue is removed and examined under a microscope for cancer cells. This is considered the most definitive way to diagnose endometrial cancer.
• Hysteroscopy: A procedure that allows the doctor to look inside the uterus with a thin, lighted tube to check for abnormal growths.
• Dilation and Curettage (D&C): A surgical procedure to remove a sample of the endometrial tissue. It’s often performed in conjunction with a hysteroscopy.
• Imaging Tests Beyond Ultrasound: Your doctor may sometimes order a CT scan or an MRI to evaluate the extent of the cancer, especially to see if it has spread beyond the uterus.

Dr. Rimel emphasizes the growing importance of genetic testing and counseling for women who have a history of endometrial cancer in their family or who they suspect may have a genetic mutation like Lynch Syndrome that increases their risk of endometrial cancer because cells are unable to repair themselves properly. Understanding the characteristics of your tumor can lead to treatments that target your tumor more precisely.

For example, Dr. Rimel strongly recommends getting tested to see whether or not your cancer is high in HER2, or Human Epidermal Growth Factor Receptor 2.

Tumors where HER2 is present in high amounts could point to a more aggressive cancer that may respond differently to certain treatment. HER2 serves as a specific target for therapies including a new targeted drug known as Enhertu that can block the growth signals sent by this protein, potentially slowing or stopping the progression of the cancer.

“Testing that’s required for seeing if a tumor has HER2 is very easy to get,” Rimel says. “Most pathology departments where patients have their tumors stored after surgery or after biopsy can perform this test, and any patient can ask for this test of their doctor and their doctor can submit a request. It’s a very commonly done test so it’s available almost everywhere.”

Questions to Ask Your Doctor

• What type of endometrial cancer do I have?
• What diagnostic and treatment options will we consider?
• What is my prognosis?
• What will insurance cover and what will I pay out of pocket?

Related: Immunotherapy, PARP Inhibitor Drug Combination Shows Promise for Endometrial Cancer

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