Uterine Cancer
Uterine endometrial cancer, the most prevalent gynecologic malignancy in the US, presents concerning trends with rising incidence rates, particularly among black women, and a strong association with obesity as a significant risk factor. Predominantly affecting menopausal women, although younger individuals can also be affected due to hereditary factors or excess estrogen expression, this cancer originates from the endometrium, the mucosal lining of the uterus. Endometrioid carcinomas constitute the majority of cases, driven by estrogen stimulation without progesterone balance, leading to abnormal cellular growth and potential malignancy. While endometrioid cancers are common, more aggressive adenocarcinomas such as clear cell and serous types exist, necessitating prompt evaluation upon suspicion, especially in cases of abnormal bleeding, for early detection and improved survival rates. Understanding hormonal influences on the uterus underscores the dynamics of endometrial cancer development, emphasizing the importance of recognizing symptoms and seeking timely medical attention for optimal prognosis.
Executive Summary
Uterine endometrial cancer is the most common gynecologic malignancy in the US, with 66,000 new cases and 13,000 deaths last year. There's a concerning trend of increasing incidence, particularly among black women, who have a 1.5 times faster rising rate and twice the likelihood of death compared to white women. Obesity is a significant risk factor, and while the average age at diagnosis is 60, younger women can develop the disease due to hereditary factors or excess estrogen exposure.
The uterus consists of an inner mucosal lining (endometrium) and an outer muscular layer (myometrium). Endometrial cancer primarily develops in the endometrium, with endometrioid carcinomas being the most common type, accounting for 80% of cases. These cancers are often driven by excess estrogen without sufficient progesterone balance, leading to abnormal cell growth.
Risk factors for endometrial cancer include obesity, hormone replacement therapy without progesterone, diabetes, early menstruation, late menopause, and certain genetic conditions like Lynch Syndrome. Protective factors include oral contraceptives, multiple pregnancies, breastfeeding, and increased physical activity. There's also growing concern about the potential role of environmental toxins like xenoestrogens in cancer development.
The primary symptom of endometrial cancer is abnormal uterine bleeding, occurring in 90% of cases. This can present as bleeding between periods, irregular or heavy periods, or postmenopausal bleeding. Any such symptoms should prompt immediate medical evaluation, as early detection significantly improves survival rates.
Diagnosis typically involves a combination of pelvic exams, transvaginal ultrasound, and endometrial biopsy. The cancer is then staged and graded based on how far it has spread and how abnormal the cells appear. This information is crucial for determining the appropriate treatment plan.
Treatment for endometrial cancer usually begins with surgery to remove the uterus, cervix, ovaries, and fallopian tubes (total hysterectomy with bilateral salpingo-oophorectomy). Lymph node evaluation may also be performed, often using a sentinel lymph node biopsy technique. Minimally invasive approaches like laparoscopic or robotic surgery are preferred when possible.
After surgery, additional treatments may be recommended based on the cancer's risk of recurrence. Low-risk cancers may not require further treatment. Intermediate-risk cancers often receive vaginal brachytherapy (internal radiation). High-risk cancers may require a combination of external beam radiation, brachytherapy, and chemotherapy.
For advanced or recurrent endometrial cancer, treatment options include chemotherapy (often with carboplatin and paclitaxel), immunotherapy (like Keytruda/pembrolizumab), and targeted therapies. The choice of treatment depends on factors like the cancer's genetic profile, including mismatch repair status and HER2 expression.
Newer approaches to treatment are focusing on molecular subtypes of endometrial cancer. For example, cancers with mismatch repair deficiency may respond well to immunotherapy, while HER2-positive serous carcinomas may benefit from targeted therapies like Herceptin (trastuzumab).
Side effects of treatment can be significant and vary depending on the specific therapies used. Common side effects of chemotherapy include fatigue, nausea, hair loss, and increased risk of infections. Radiation therapy can cause urinary and gastrointestinal symptoms, as well as vaginal changes. It's important for patients to discuss potential side effects and management strategies with their healthcare team.
Lifestyle modifications play a crucial role in both prevention and management of endometrial cancer. Maintaining a healthy weight, engaging in regular physical activity, and following a balanced diet rich in fruits and vegetables can help reduce risk. Some studies suggest that certain supplements like curcumin, green tea extract, and mushroom extracts may have beneficial effects, though more research is needed to confirm their efficacy.
For younger women with early-stage, low-grade endometrial cancer who wish to preserve fertility, conservative management with hormonal therapy may be an option. This approach requires close monitoring and is not suitable for all patients.
Follow-up care after treatment is crucial. This includes regular check-ups, imaging studies, and monitoring for potential recurrence or side effects of treatment. Survivorship care also addresses quality of life issues, including sexual health, menopausal symptoms, and psychosocial support.
Research in endometrial cancer is ongoing, with focus areas including improved molecular classification, development of targeted therapies, and strategies to reduce disparities in outcomes among different populations. Clinical trials offer opportunities for patients to access new treatments and contribute to advancing care for future patients.
Introduction
Uterine endometrial cancer is the most common gynecologic malignancy in the US. Last year there were 66,000 new cases and 13,000 deaths. There is a concerning trend toward an increasing number of women diagnosed with this disease, with rates in black women rising one- and one-half times faster than white women, and their likelihood of death being twice as great. There is also an association between endometrial cancer and the rising rate of obesity as being a significant risk factor. Endometrial cancer (EC) mainly affects menopausal woman, with 60 being the average age of presentation. It is uncommon in women less than 45 years old, but younger people can still present with disease from hereditary causes or from cancer developing from premalignant cells associated with excess estrogen expression.
Anatomically, the uterus is composed of a mucosal inner lining of glandular tissue, the endometrium, and an outer adjacent layer of muscular and fibrous tissue and blood vessels, the myometrium. The upper inner part of the uterus is called the body, and the lower part is the cervix, which joins to the vagina. The uterus is directly influenced by a woman’s hormonal cycle of estrogen and progesterone, with each cycle following a pattern of potentially preparing for pregnancy. Estrogen causes the lining, the endometrium, to grow and thicken for implementation and support or maintenance if pregnancy were to occur and is the stimulus for both the production of the egg and ovulation. After ovulation, estrogen levels decrease, and the post ovulation cystic structure, the corpus luteum, produces the hormone progesterone which rises for two weeks to support the endometrial lining, again in preparation for pregnancy. Without pregnancy, at the end of cycle, all levels decrease, triggering the shedding of the uterine lining and the initiation of menstruation.
The majority of uterine cancers develop in the endometrium from the surface type epithelial cells and are called endometrioid carcinomas. They called adenocarcinomas or glandular cancers based on their histology or microscopic appearance, and are the most common endometrial cancers comprising eighty percent.
The etiology or cause of endometroid cancer is considered to be the result of the intake of excess estrogen either into the body from outside sources, like hormone replacement, or from excess production by the body, without the presence of progesterone to balance it out. It appears that this causes the growth and number of new endometrial cells, called endometrial hyperplasia. With continued unopposed cellular growth some cells can change and become premalignant, called endometrial intraepithelial neoplasm (EIN), or actually become cancer, with the potential for spread and invasion.
While endometroid cancers are the most common there are other adenocarcinomas called, clear cell, serous, undifferentiated, dedifferentiated, and mucinous which are more aggressive types of adenocarcinoma that grow and spread rapidly, often having grown outside of the uterus before a diagnosis is made.
Abnormal bleeding and bleeding patterns in both younger women and after menopause suggest the possibility of endometrial cancer. Further evaluation of these symptoms offers the potential for early detection of cancer in 75% of women.
In addition, if your age is less than 60years old and cancer is the low grade and confined to the uterine lining, the endometrium, there is a 90% five-year survival. Therefore, any suspicious bleeding should be promptly evaluated for endometrial cancer, as early diagnosis offers an excellent prognosis.
Risk Factors for Endometrial Cancer & Protective Factors
Associated with estrogen excess include:
Hormone replacement therapies that do not include a progesterone component
Tamoxifen treatment for breast cancer. The use of this drug is for its antiestrogenic activity, but it still has estrogenic activity that are associated with endometrial cancer, polyps, and uterine sarcomas.
Obesity -The risk of endometrial cancer rises 3-fold with obesity and an elevated BMI is associated with cancer before menopause. The explanation is that adipose cells can synthesize estrogens and also produce the aromatase enzyme that converts androgens, male hormones, to estrogen without out the buffering effect of progesterone.
Type 2 diabetes with elevated insulin levels.
Diets that are composed of excessive animal fats are considered at higher risk.
Anovulatory cycles are cycles in which no corpus luteum is created resulting in low levels of progesterone and allowing for increased estrogen stimulation.
PCOS, polycystic ovarian disease occurs in obese and non-obese women which results in anovulatory cycles, no progesterone, and other hormonal imbalances. These women produce excessive amounts of testosterone which is converted to estrogen by the aromatase enzyme in the endometrium and can raise the risk of endometrial cancer up to 5X greater.
African American women are more likely to be diagnosed with aggressive types of uterine cancer; serous carcinoma and carcinosarcoma which have the TP53 mutation.
This gene, is a tumor suppressor gene that codes proteins that function in DNA repair or if damage is to extensive trigger cell death, called apoptosis. This ensures abnormal cells don’t become cancer. A TP53 mutation prevents these processes and seventy percent of black women versus half that number of white women have this mutation. This mutation is associated with higher cancer risk as well as posing greater difficulties for treatment. It should be noted that some while people have this mutation some cancers are actually able to cause inactivation of this gene allowing increased growth and progression of disease.
It is imperative therefore for earlier more aggressive screening of black women with any suggestive symptoms.
Early menstruation and late menopause
Older age, disease occurs primarily over the age of 50.
There is a potential risk factor, which while unproven in studies is worth mentioning. Carcinogenic effects have been shown from the presence of xenoestrogens, foreign synthesized estrogens that are found in Bisphenol A (BPA) and phalates, which are plasticizers and parabens and triclosan, which are preservatives. Some scientists believe that these chemicals are a plausible risk factor for endometrial carcinoma and more data needs to be generated. These chemicals have been associated with breast cancer, so avoidance of exposure is wise. BPA can be found in plastic water bottles and the others are used in many cosmetic products.
Hereditary Risks
Lynch Syndrome
This is an inherited cancer mutation syndrome that is associated with several different mutations, increasing the risk of not only endometrial cancer but ovarian/fallopian tube cancer, stomach, urinary tract, and bile duct cancers. With a family history of any of these cancers, genetic testing is indicated. If Lynch syndrome is diagnosed, surveillance for any of these potential cancers can be used to possibly diagnosis them at an early stage.
Cowan’s Disease Is an inherited genetic disease that causes non-cancerous growths over parts of the body and increases the risk of endometrial cancer.
BRCA, breast cancer genes 1& 2 are associated with a 2% risk of uterine cancer, especially BRCA 1 and if present is a more aggressive serous type carcinoma.
Protective Factors
Oral contraceptives can balance estrogen and progesterone
Multiple pregnancies
Breastfeeding
Smoking
Lifestyle, diet, and exercise
Increased physical activity raises sex hormone binding globulin which can act to bind estrogens.
In women who have similar activity levels, the risk of EC increases with those who spend larger amounts of time sitting.
Mediterranean diet is associated with lower risk of endometrial cancer compared to western diets, especially those with high amounts of red meat and processed foods.
One study revealed a substantial increase in EC with greater than 3-4 oz of red meat a day. However, it did not state if it was free range beef or commercially raised beef given antibiotics, GMO grains and hormones.
A higher fruit and vegetable diet may offer greater protection. A study, while not statistically significant, revealed that over a 10-year period Seventh Day Adventists in California that were vegetarians or vegans had a lower incidence of EC.
Women that had higher levels of EPA and DHA, fish oil, had a lower risk of EC
Symptoms of Uterine Cancer
Abnormal or unusual Uterine Bleeding is a cardinal symptom that occurs in 90% of women with endometrial cancer. It occurs symptomatically as bleeding between periods which is unscheduled, irregular cycles often with heavy bleeding, bleeding after menopause, and persistent bloody and non-bloody vaginal discharge, or in menopausal women on hormone replacement therapy without progesterone. Because these symptoms can be associated with endometrial cancer evaluation by a physician is essential.
Clinically, the following situations indicate the need for an ultrasound, pelvic exam, and often an endometrial biopsy, to determine and separate endometrial hyperplasia ,endometrial intra epithelial neoplasia, and endometrial cancer.
Based on age:
Any post-menopausal bleeding requires an ultrasound and examination and commonly a biopsy.
Age 45- menopause, biopsy is performed in situations of frequent cycles of heavy bleeding or other unexpected patterns of bleeding. See symptoms as discussed above.
Less than age 45 requires evaluation for abnormal bleeding especially when the BMI (body mass index) is > 30. BMI is measure of body fat based on height and weight and is related to increased production of estrogen in the body. If the BMI is < 30, evaluation is done when there is persistently abnormal bleeding or unscheduled bleeding in situations where there are anovulatory cycles or a woman is on estrogen replacement.
Endometrial Hyperplasia (EH)
Abnormal uterine bleeding caused by excessive growth of the endometrial lining, often is not cancerous, but can signal premalignant development of endometrial cancer. There are two types that can be determined by biopsy.
Benign EH is growth of the endometrial lining caused by prolonged estrogen exposure, often due to anovulation, obesity, or estrogen only replacement use. There is an approximate 5% risk of endometrial cancer over the next two decades but by re-establishing the hormonal balance the risk can be markedly decreased.
In women without risk factors who resume normal cycles observation is an accepted treatment option.
In women with associated risk factors, lifestyle changes to decrease weight can help lower estrogen. Medication can also be used. Whereas estrogen encourages rapid endometrial cell growth, progestins oppose this growth. Progesterone, or progestins, can be utilized on a continuous basis orally, or an IUD with progestin. They are effective and will correct the problem, in benign disease, in approximately 70+% of women.
Endometrial Intraepithelial Neoplasia (EIN) is endometrial hyperplasia with anormal atypical cells which are considered premalignant and can progress to endometrial cancer. Endometrial cancer is four times more likely than when there is no atypia. Therefore, EIN on tissue evaluation is a precursor to endometrial cancer, and the recommended definitive treatment is a hysterectomy
Other features that should not be ignored are pelvic pain, any sense of mass in the lower abdomen or unexplained weight loss should prompt a medical visit. These symptoms often present in later stages of disease so prompt attention may prevent further progression.
Sometimes uterine cancer is discovered when unanticipated from a pap smear, during imaging for another problem or with the removal of the uterus for non-cancerous reasons.
In Younger women:
In adolescence and the twenties, the development of the hormonal menstrual rhythms are commonly irregular and these types of cycles often do produce ovulation. Normally after ovulation, progesterone is produced to support a potential pregnancy, and at the end of a non-pregnant cycle both estrogen and progesterone decline and a period starts. Without ovulation, estrogen alone is produced stimulating the lining of the uterus to grow until it becomes too thick and starts to bleed. This commonly resolves as cycles self-regulate. Sometimes hormones are used to temporarily create regular cycles.
Often the symptoms associated with uterine cancer are nondescript as they can be attributed to a number of different problems, many of which are non-cancerous.
Pelvic pain can represent:
Infection
Menstrual pain
Endometriosis
Ovulatory pain
Fibroids
Scar tissue
Ectopic pregnancy
Digestive symptoms can be associated with endometrial disease or:
Irritable bowel
Diverticulosis
Colitis
Hernia
Appendicitis
Diagnostic Methods
When there is a concern, based on symptoms or pelvic exam, the first choice for evaluation is pelvic ultrasound which uses sound waves to image the uterus, ovaries and fallopian tubes, and bladder. It can be performed on the outer abdomen, or via a probe that can be placed in the vagina for better uterine images. Using this technique information can reveal the thickness of the uterine wall, any masses, or polyps, and if an abnormality is seen it can pinpoint its location for biopsy.
Biopsy
Endometrial biopsy can be performed by inserting a tube through the cervix and obtaining tissue from the lining of the uterus by using suction through the tube. This is a common approach in postmenopausal bleeding.
Hysteroscopy involves placing a small telescope through the cervix into the uterus Salt water is instilled for improved definition of the terrain as the doctor then looks for any abnormalities.
Dilatation and Curettage (D&C) is performed if enough tissue isn’t obtained from the other mentioned procedures or even with tissue is obtained when the diagnosis is unclear. In this situation the cervix is dilated, enlarged and instruments are used to scrap the lining for tissue.
Grade and Type of cancer
From this information if the biopsy confirms cancer, it will state the type and the grade of disease.
The grade of cancer is from 1-3 and indicates how close to normal endometrium the tissue is.
Grade 1 indicates that 95% are organized in glandular structures
Grade 2 indicates that between 50% and 94% of cells form glands
Grade 3 tumors are more aggressive and have < 50% that are glandular cells. These tumors grow and spread more quickly.
The implication is that the closer the appearance of the cancer cell is to normal the less invasive and progressive it is.
Types of Endometrial Cancer
There are two divisions of uterine cancer:
Type 1 Endometrial Cancers
Grade 1 and 2 endometroid cancers are Type 1 endometrial cancers. They are usually not aggressive in nature and tend to not spread rapidly. They are stimulated by an excess of estrogen, from prolonged exposure, with insufficient progesterone. This causes excessive glandular growth of endometrial cells and ultimately is associated with endometrial cancer. This is the case with some of the above-mentioned risk factors.
Type 2 Endometrial Cancers
Are less common and less frequent than type1 but not driven to grow by excess estrogen. The cells appear much less like normal cells, called undifferentiated, and tend to be more aggressive, grow and spread faster, and result in lower long-term survival. They are associated with the following mutations that are non hereditary.
High Ki67, a measure of growth
TP53 mutations, a tumor suppression gene
Increased HER2, (epidermal growth factor receptor) associated with greater risk of metastasis
Inactivation of cancer suppressor gene, Cadherin 1 gene which prevents rapid growth and increased replication of cancer cells.
Tumor suppressor gene 16 inactivation
Another important categorization of endometrial cancer is based on four molecular subtypes that predict growth patterns, provide information for both prognosis and the response of different therapies, and can potentially direct women with progression toward clinical trials with newer treatments.
These are:
DNA polymerase epsilon (POLE) mutated subtype
These women are young and while the cancer is aggressive, survival is excellent.
Mismatched repair deficient subtype
Aggressive and does recur and progress but these women can have better outcomes with checkpoint inhibitor therapies.
Nonspecific subtype
Often have estrogen and progesterone receptors and respond to hormonal treatments
P53 abnormal
These women have poor prognosis and responsible for 50-70% of endometrial deaths as P53 has become an ineffective tumor suppressor gene.
Histology or Cellular appearance of Endometrial cancers when viewed under the microscope, or
Adenocarcinoma- in this type of endometroid cancer the cells look similar to normal ones, and it is the most common type. The cancer originates and grows from the lining glandular cells.
Clear Cell Carcinoma accounts for 5-10% of endometrial cancer. its cell type is more aggressive and shown in Its clinical course of rapid progression and poor outcome.
Serous carcinoma occurs in < 10% of women but is associated with 40% of uterine cancer deaths. It is commonly seen in black women and is diagnosed late in the disease. Risks include a history of breast cancer and the treatment of breast cancer with tamoxifen and increasing age.
Treatments with Epidermal Growth factor Inhibitors, discussed in the treatment section, have been beneficial.
Carcinosarcoma is a combination of a carcinoma, epithelial cells on the uterine lining and a sarcoma which originates in muscle. It is a highly aggressive and high grade.
Squamous Cell carcinoma is so rare, <1% of uterine cancer that few cases are known. The cells do not resemble glands but are flat. It is important to distinguish it from squamous cell cervical cancer.
Transitional carcinoma is another very rare endometrial cancer seen infrequently.
Uterine Sarcomas are much rarer cancers involving the the myometrium(muscle) or connective tissue of the uterus, where endometrial cancers are glandular or adenocarcinomas. They are considered more aggressive with a poorer prognosis than endometrial cancers. Some of the tumors are comprised of the expected tissues of the uterus, muscle, connective tissue, endometrium, and blood vessels while others are aggressive and made up of undifferentiated connective tissue stem cells that become skeletal muscle, bone and fat suggesting a very aberrant process in the cancer cells.
Presentation is in the premenopausal and postmenopausal ages of 40-60 and are often associated with other cancer treatments
Including:
Tamoxifen, the selective estrogen receptor modular which blocks the effects of estrogen on breast cancer growth, when used for > five years.
Pelvic radiation
Clinically, the diagnosis is made after the uterus, or a mass is removed for what is thought to be a benign fibroid growth. Both benign and malignant lesions present with bleeding. It is an abnormal pattern in premenopausal women, and bleeding after menopause that has started in generally older women. Both conditions can also present with abdominal complaints of pain and /or distention.
Imaging with ultrasound often looks like a fibroid, appearing as a uterine mass, and differentiation cannot be made on the growth pattern as they are similar.
Biopsy is needed to determine the diagnosis and if it is a sarcoma, prognostic features relate to how rapidly cells are replicating, and how abnormal they look, and the tissue damage occurring from the growth process.
Treatment will be discussed in a later article.
Staging of Uterine Cancer
Radiologic Imaging is then utilized to determine Staging of Uterine Cancer
Stage 1- Confined to the body of the uterus and ovary with no lymph node or distant spread
Stage1A- the cancer is limited to the lining of the uterus or is nonaggressive, considered low grade endometroid, and has grown less than halfway into the underlying muscular layer called the myometrium. There is no LVSI. Endometroid tumors are cancers that resemble the glandular structures that make up the lining of the uterus.
1A1 is nonaggressive histological type limited to an endometrial polyp or the endometrium, the lining of the uterus
1A2 is nonaggressive involving less than half the myometrium with no focal LVSI
1A3 low grade endometroid carcinomas limited to the uterus or ovary.
1B is nonaggressive cellular histology with invasion of half or more of the myometrium (muscle) and no focal LVSI
1C is an aggressive type but limited to a polyp or the endometrium alone.
Stage 3- Local or regional spread of the tumor regardless of its aggressiveness
Stage 3A -Cancer has spread to the surface of the uterus (the serosa) and/or the ovaries and fallopian tubes by direct extension or metastasis
3A1 -Spread to ovary or fallopian tube, but not like initial Stage 1A3 which is the initial nonaggressive limited type of cancer
3A2- Involvement of the tissue at the outer areas of the uterus, the subserosa or spread through this outer membrane.
Stage 3B – the cancer has spread to the vagina and /or the tissue adjacent and peritoneum or abdominal lining cells
3B1 -Metastasis to the vagina or adjacent tissues
3B2 -Metastasis to the peritoneum
Stage 3C- Spread to the pelvic or para-aortic lymph nodes or both.
3C1 -Metastasis to pelvic lymph nodes, with subtypes either microscopic spread or visible spread
3C2- metastasis to para-aortic lymph nodes up to the kidney vessels, with or without spread to the pelvic nodes, either microscopic or visible.
Stage 2- cancer has spread from the uterine body and is growing into the supportive tissue of the cervix, the cervical stroma, but not spread outside the uterus, with substantial LVSI or an aggressive subtype involving the myometrium. LVSI is considered lymph vascular space invasion implying that cancer cells seen under the microscope are spreading into the lymph or blood vessels in the tissue making metastasis a much higher risk. No lymph node involvement or distant spread.
Stage2A- Cervical stromal invasion that does not involve an aggressive type of cancer cell
Stage2B- Significant LVSI but again a non-aggressive type of cancer cells
Stage2C- Aggressive cancer cells with myometrial involvement
Stage 4- Cancer is spread to the lining (the mucosa) of the bladder or rectum and/or has spread to distant areas.
Stage4A- invasion of the bladder and/or bowel mucosa
Stage4B- Metastasis into the peritoneum outside the pelvis. The peritoneum is a serous membrane or lining that secretes serum the covers the pelvis and abdomen and provides lubrication.
Stage4C- Metastasis to distant organs and lymph nodes including lymph nodes above the kidney vessels, lungs, liver ,brain or bone.
As the result of evaluation—symptoms, pelvic exam and ultrasound, tissue biopsy, testing, and Imaging and surgery will provide information as to:
Histologic cellular appearance, types of endometrial adenocarcinomas or sarcoma
Type 1, estrogen excess or Type 2, associated with mutations making them more aggressive
Grade of cells
Molecular subtypes
Mutations
These provide the necessary information to form a plan of treatment, predict potential for progression and survival. While as discussed below, some aspects of treatment will be standard for all, but then complex decision making will go into decisions as to how to proceed with chemotherapy, immunotherapies, and radiation.
Treatments
Surgery
Surgery is considered the primary modality of treatment for endometrial cancer (EC) and allows for staging of the disease. The procedure done is the removal of the uterus and cervix, and both ovaries and fallopian tubes, called a bilateral salpingo-oophorectomy. Many physicians will also perform lymph node biopsy which can provide information if there is concern of possible extension beyond the uterus, which affects prognosis and the types of therapies.
Years ago, EC surgery was performed by opening the abdomen at the midline called an exploratory laparotomy. Today surgery is considered minimally invasive and can be performed as Laparoscopic surgery, in which small incisions are made and tubes inserted in the abdomen through which the instruments can be used for the procedure,
or as Robotic surgery in which the surgeon operates the robotic instruments from a control panel.
These techniques offer less postoperative complications and shorter hospitalizations and comparable outcomes to laparotomy. However, minimally invasive techniques are more difficult to perform on obese people and while attempted may need to be changed to a laparotomy.
Approach to Lymph Node Disease
The removal of the lymph nodes of the pelvis and around the aorta can be performed with either robotic or laparoscopic surgery. This is done to evaluate whether the cancer has spread outside the uterus and helps determine the stage of disease and the appropriate treatment that is needed.
The terms used are, lymph node sampling where a few nodes are removed or lymph node dissection where all of the nodes in an area are removed.
The removal of lymph nodes is based on the type and grade of cancer, its depth of penetration into the muscle of the uterus and the results of any imaging.
A technique called sentinel node biopsy is now being used commonly, as is the case in breast cancer. If imaging is inconclusive as to any spread of the cancer to the lymph nodes, then a colored dye is injected into the cancer area and traced to the nodes that are considered to be the first nodes that the cancer would drain to. If it is normal, then no further nodes are removed. If positive, then further node dissection is performed. This procedure is done at the time of the initial hysterectomy.
If there is apparent spread, locally or distant nodes might not need to be taken
Therapeutic Approaches to Endometroid, Low, Intermediate, and High-Risk Disease
Based on the initial diagnosis and
While the cancer is localized to the endometrium and has not spread to other local and distant areas, surgery does not confer safety from further progression. It is an essential step, but there are characteristics of the cancer that can be categorized as being low, intermediate, or high risk of spread and studies and data support the following approach to each of these situations.
Low Risk Disease involves cells that are Grade 1 or 2, or looking similar to normal cells, and limited to the endometrium, endometroid, with none of the characteristics listed for intermediate. The risk of progression is low and adjuvant therapy is therefore not recommended.
There is a subgroup of women with low-risk disease that wish to preserve their fertility and to avoid a hysterectomy if at all feasible. The treatment of this group is being reevaluated based on current studies. Medroxyprogesterone can be used in fertility sparing treatment for EC or endometrial hyperplasia with atypia. These issues are from excess estrogen and medroxyprogesterone is used to counter estrogen. However, it has been noted that it also increases insulin like growth factor that can stimulate cancer and stimulate prolactin which can stimulate endometrial growth. Adding metformin, used in diabetes, can reverse these effects making it a possibility to improve treatment in fertility sparing situations.
Following surgery, if the cancer is characterized, based on stage of disease and histology subtype as having a low, intermediate, or high risk of recurrence. Adjuvant treatments are the secondary therapies that follow the primary treatment. In endometrial cancer the initial therapy is surgery followed by the following recommendations.
Intermediate Risk of Disease implies that there is a risk of Recurrence based on local extension of the cancer. They are not the subtypes of serous carcinoma, clear cell carcinoma or carcinosarcoma which are associated with a high risk of recurrence. However, there is an increased risk but without evidence of lymph node involvement or distant spread. It is different than low risk as:
Cells are Grade 1 or 2 and < half the myometrium is invaded but with lymph/ vascular invasion.
Cells are grade 1 or 2, with > than half the myometrium involved (stage 1B), or invasion of the cervical fibrous tissue or stroma is present.
Cells are grade 3 and < half the myometrium is invaded
Treatment of High Intermediate Risk Disease is radiation therapy, which decreases the risk of recurrence but does not seem to improve overall long-term survival. The recommended form of radiation is brachytherapy, in which low radiation in a cylinder is placed in the vagina either weekly or sometimes over a shorter daily regime. It affects the area of the vagina. It is done rather than pelvic external beam radiation which can potentially injure the bladder or bowel.
However, listed below are other subtypes of endometrial cancer that pose a higher risk of progression and spread and a poorer prognosis and require more intensive treatments.
High Risk Disease
Recently, in 2023, the International Federation of gynecology and Obstetrics updated the staging of Endometrial cancer, EC. Women with EC categorized as being high risk for recurrence, with surgery alone, and have a lower survival. Therefore, adjuvant therapies are secondary treatments following primary treatment, which in this situation is surgery.
Information as to specific protocols are not uniform but oncologists use current research and experience to make decisions as to therapies.
Having the following are considered high risk of recurrence:
Serous endometrial cancer
Clear cell endometrial cancer
Grade 3 abnormality of cells
Stage 3 or 4 disease
Treatment recommendations for these are as follow:
Early Stage 1 or 2 but with serous or clear cell endometrial carcinoma, pose a much higher risk of progression.
Stage 1A1 -when confined to the lining of the endometrium treatment can be observation, but some oncologists recommend brachytherapy. In this situation there is no invasion into the myometrium of the uterus. See below for information on radiation.
Stage 1A2,1B both of which involve the myometrium (muscle) or grade 3 cellular appearance -the treatment recommendation is pelvic radiation alone or with the addition of chemotherapy with or without vaginal brachytherapy. So, there is invasion in this setting of treatment.
Locally advanced Stage 3 or 4 – requires, if possible, surgery to reduce or remove tumor burden followed with chemotherapy and vaginal brachytherapy. If tumors cannot be removed, then chemotherapy.
Chemotherapies:
The chemotherapies recommended for these situations are:
Cisplatin and Paclitaxel (Taxol)
Platinum Drugs- These drugs activate inside the cancer cell and binds to DNA linkages, causing damage to the DNA and inducing self-destruction and cell death.
The two used are:
Cisplatin
Major Side effects include:
>40% up to 80% peripheral neuropathy, drug manufacture sites 0%
28% Kidney dysfunction
31% Hearing loss
30% Marrow suppression
Taxol (Paclitaxel)
Major side effects include:
90% Low white count
87% Hair Loss
78% Anemia
60% Peripheral Neuropathy and Muscle Pain
58% nausea and Vomiting
Monoclonal Antibodies
In women with high-risk Stage 3 or 4 serous carcinoma or with Grade 3 cells a percentage of women in this situation have positive HER 2 receptors.
Women overexpress a cell protein called Human Epidermal Growth Factor Receptor (HER2). Having this positive receptor tends to make these cancers grow and spread more aggressively than patients who lack this receptor. Treatment to stop the amplification of growth rely primarily on the manufactured monoclonal antibodies, Herceptin (Trastuzumab)
Major Side effects of Herceptin (Trastuzumab)
47%, pain
36%, chills and fever
22%, abdominal or back pain
25%, vomiting or diarrhea
26%, cough
18%, rash
Radiation
Radiation Side effects happen more often than reported and the level of side effects varies depending on the target organs or area being treated, the total dose required and
External Beam Radiation Therapy is directed from an external source outside the body at tumor areas and the margin around it. Treatment is given on a daily basis, using measured increments of radiation until the calculated therapeutic dose is achieved. It is often 4-6 weeks, but newer protocols are shorter in duration.
Side Effects
Urinary symptoms occur with dysuria, urgency, and cystitis. These issues resolve the bladder inflammation heals
Gastrointestinal side effects that can occur in women with pain, cramps, urgency and frequent stools and it can persist. If the nodes are radiated there can also be inflammation of the intestines, called enteritis.
Brachytherapy
Brachytherapy is the more commonly used treatment, in which a plastic tube or applicator is inserted in the vagina. Two methods of treatment are available, low dose in which an implant is placed usually for 1-4 days and delivers a low continuous dose of radiation. It requires hospitalization, or more commonly high dose radiation put in for about an hour daily or weekly for a minimum of 3 doses.
Side Effects:
Early Symptoms include vaginal bleeding or discharge
Urinary frequency, burning and pain
Long Term
Vaginal ulcers
Fibrous or scarring of the vagina causing it to narrow or shorten with pain with intercourse
Bladder symptoms
Fatigue
Bowel Blockage
Current therapies used in older women, when > 65 years old need to take into account overall health and disease status. Many women have high risk disease, high grade cells or advanced disease with invasion. In these situations, balancing the benefits of treatment which will involve chemotherapy and possible radiation and the ensuing side effects need to be considered as recovery will be slower and longer than in younger women. And what are the percentages of improved longevity of survival with treatment.
Metastatic Disease
Treatment for Recurrence or Progression
In this situation, treatment based on the initial diagnosis will have been completed.
Cancer that subsequently appears is considered a recurrence and is in the pelvis and/or has spread to distant areas, but sometimes it is a woman’s initial presentation of endometrial cancer.
Symptom presentation can be systemic, with diminished appetite, weight loss and fatigue but often there is abdominal and/or pelvic pain, lower extremity swelling and /or bleeding from the rectum, bladder, or vagina. Since distant metastasis is often to the lungs cough and shortness of breath can be seen.
Radiologic evaluation requires imaging of all possible areas of extension or spread, which requires whole body imaging of the chest, abdomen, and pelvis using CT, MRI, or PET/CT. This allows for staging of the disease, and if possible, to obtain a conformational biopsy to confirm the disease allows for the addition of genomic testing to assist in focused treatment decisions.
But in these situations, women need to understand this is a palliative treatment, or one to relieve symptoms but is not curative.
If it has been Less than 6 months since completing Carboplatin and Paclitaxel or while they are still receiving it, then the next treatment options are evaluating for:
Mismatch Subtypes
DNA Mismatch Repair Deficiency Genes (MMR) are found in endometrial cancer, and are also associated with ovarian cancer, 15% of certain colon cancers, and other cancers. It relates to an aberrant mechanism of DNA repair that creates a large number of mutations. Its importance in EC is that having these markers allows targeted treatments with immune checkpoint inhibitors that can unleash the immune system on this cancer.
There are MMR proficient and MMR deficient subtypes. If the woman has the deficient subtype, then the treatment would be, Keytruda (Pembrolizumab). And if not a candidate for Keytruda then endocrine therapy, discussed below, is a possibility.
If relapse has occurred and it has been Less than 6 months since completing Carboplatin and Paclitaxel or while they are still receiving it the treatments recommended are Keytruda (Pembrolizumab) and Lenvima (Levatinib) a vascular endothelial Growth Factor inhibitor (VEGF).
Subtypes that can be tested for that can offer additional potential therapies.
These include:
Estrogen/progesterone receptor status
Herceptin (HER-2) status
Mismatch somatic mutations to assess the use of immunotherapy or targeted therapy in treatment.
Metastatic Disease Associated with Recurrence or Disease Progression
Women that have had recurrence after being treated with Carboplatin and Paclitaxel and have been off it for > 6 months, can be retreated with these same chemotherapy agents. It is possible that they may have already had treatment with an immunotherapy agent for an earlier recurrence. If they have not had immunotherapy, then along with chemotherapy an immune checkpoint inhibitor, Keytruda (Pembrolizumab) is added for therapy.
Keytruda (Pembrolizumab) a PDL-1 (Programmed Cell Death Ligand) drugs, Checkpoint Inhibitors. These drugs take the brakes off of the immune system and allow it to more actively engage in fighting the cancer
Major Side effects listed as up to:
92% Anemia
71% Rash or elevated liver functions
80% Elevated blood sugar
61% Alopecia
62% Enteritis
70% Fatigue
48% Weight loss
Potential autoimmune disease
Lenvima (Levatinib)
Metastatic Disease that is the initial presentation of Endometrial Cancer
In this situation, the recommendation is for surgery to remove as much tumor as possible and then the initiation of systemic chemotherapy which may or may not include immunotherapy, dependent on hormone receptor and genetic profiles. If surgery is not possible, women are still offered chemotherapy, with or without immunotherapy.
Chemotherapy currently involves a minimum of two chemotherapy drugs together, but sometimes triple therapy with the addition of doxorubicin is used.
Using:
Carboplatin and Paclitaxel (Taxol)
Platinum Drugs- These drugs activate inside the cancer cell and binds to DNA linkages, causing damage to the DNA and inducing self-destruction and cell death.
The two used are:
Carboplatin
Major side effects include:
5% Peripheral neuropathy
10% Nephrotoxicity
93% Nausea
84% Vomiting
44% Pain
Taxane Drugs-These drugs interfere with normal cell division inducing death
The two used are:
Taxotere (Docetaxel) is 2x as potent as Taxol
Major side effects:
98% Low white blood cell count
94% Anemia
98% Hair loss
60% Fluid retention
54% Rash
Or
Taxol (Paclitaxel)
Major side effects include:
90% Low white count
87% Hair Loss
78% Anemia
60% Peripheral Neuropathy and Muscle Pain
58% nausea and Vomiting
Adriamycin (Doxorubicin) inserts within the DNA, in the lipid layers, and prevents DNA replication. It is another choice which
Pegylated Liposomal Doxorubicin is the chemotherapy drug packed inside spheres of lipid so that it remains in the blood to be transported to areas where the cancer cells are.
Major side effects are many, but often frequencies are not given, these include:
60-80% Low White Blood Cell Counts
80% Stomatitis
20-85% Nausea
1-10% Myocardial Damage, Heart Failure, Abnormal Rhythm
1-10% secondary acute myelogenous leukemia or myelodysplastic syndrome
Newly Diagnosed Metastatic Disease with Mismatch Subtypes
The protocol is the same as for recurrent disease, if a woman has been off Carboplatin and Paclitaxel > 6months. Retreat with those drugs and add Keytruda (Pembrolizumab).
If it is less than six months since that initial treatment, then a decision of treatment is determined by the amount of tumor that has these mismatch mutations. If it is dMMR then Keytruda (Pembrolizumab) is indicated, with pMMR disease multiple chemotherapy agents used together is recommended.
Serous endometrial cancer, with HER2 Receptors are treated with Carboplatin and Paclitaxel (Taxol) and Herceptin (Trastuzumab), a HER2 inhibitor.
Human Epidermal Growth Factor Receptors (HER2)
Is a monoclonal antibody, but it does not specifically activate the immune system but rather binds to that HER 2 receptors to inhibit its action. Women that overexpress this cell protein have a positive receptor that tends to make serous endometrial cancer grow and spread more aggressively than patients who lack this receptor. Treatment to stop the amplification of growth rely primarily on the manufactured monoclonal antibodies, Herceptin (Trastuzumab).
Quercetin down regulates both HER 2 and PI3K which is the pathway which signals HER 2 overexpression.
If progression occurs, and it has been greater than six months since treatment then these same drugs are used again. If the tumor has MMR deficient mutations, then the above protocols are used.
Keytruda (Pembrolizumab) a PDL-1 (Programmed Cell Death Ligand) drugs, Checkpoint Inhibitors. These drugs take the brakes off of the immune system and allow it to more actively engage in fighting the cancer
Major Side effects listed as up to:
92% Anemia
71% Rash or elevated liver functions
80% Elevated blood sugar
61% Alopecia
62% Enteritis
70% Fatigue
48% Weight loss
Potential autoimmune disease
Herceptin (Trastuzumab)
Major Side effects of
47%, pain
36%, chills and fever
22%, abdominal or back pain
25%, vomiting or diarrhea
26%, cough
18%, rash
Integrated Recommendations specifically for Endometrial Cancer
Curcumin (Diferuloylmethane)
In laboratory studies on endometrial cancer cells lines:
curcumin was anti proliferative on replication of endometrial cancer cells
inhibited tumor growth
prevented migration of endometrial cancer cells to reduce metastasis
Please see the resource monograph on curcumin to see the impressive effects of curcumin in cancer care.
Green Tea (EGCG-Epigallocatechin- Gallate)
Studies using endometrial cancer cells, the lab, reveal EGCG:
Inhibits cellular growth and multiplication
Induces cancer cell death
Agaricus Mushroom
Enhances natural killer cell activity
Decreases the side effects from ongoing chemotherapy with carboplatin and paclitaxel.
Dang-Kuei
Is a common herb ingredient in many menopausal Chinese herbal formulas. A studied reviewed three thousand women after tamoxifen treatment for breast cancer was completed. Taking Dang-kuei decreased the risk of endometrial cancer compared to those that had not taken it.
Indole-3 Carbinol (I-3C)
In animal studies I-3-C was associated with the reduction in the growth of endometrial cells and the formation of new blood vessels, angiogenesis. The recommendation was for further studies to assess its effectiveness for therapy and in prevention of endometrial cancer.
Genistein
Progesterone binding at its receptor site has been shown to have an anti-cancer effect on the endometrial cell and has been shown to increase progression free and overall survival.
Genistein an isoflavone found in soy products, and in limited amounts in beans and chickpeas has been shown in studies to also increase progesterone by upregulating the progesterone receptor. Recent studies suggest more evidence might provide an indication for genistein as maintenance therapy in early-stage disease, in women < 40 who wish to maintain fertility. It is safe and non-teratogenic to women in the diet, but optimal safe dosages related to supplemental intake are unknown.
A clinical trial of medroxyprogesterone and metformin has been shown to be effective in relapse free survival for maintaining fertility after initial treatment.
Evaluation of multiple studies has also shown that isoflavones from soy reduces the risk of endometrial cancer by almost 20%.