Endometrial cancer

Endometrial cancer is a cancer that arises from the endometrium (the lining of the uterus or womb). It is the result of the abnormal growth of cells that can invade or spread to other parts of the body. The first sign is most often vaginal bleeding not associated with a menstrual period.

Approximately 40% of cases are related to obesity. The most frequent type of endometrial cancer is endometrioid carcinoma, which accounts for more than 80% of cases. Endometrial cancer is commonly diagnosed by endometrial biopsy or by taking samples during a procedure known as dilation and curettage. Regular screening in those at normal risk is not called for.

The leading treatment option for endometrial cancer is abdominal hysterectomy (the total removal by surgery of the uterus), together with removal of the Fallopian tubes and ovaries on both sides, called a bilateral salpingo-oophorectomy.

In 2012, endometrial cancers newly occurred in 320,000 women and caused 76,000 deaths.

thumb|upright=1.3|Video overview of endometrial cancer

Signs and symptoms

Vaginal bleeding or spotting in women after menopause occurs in 90% of endometrial cancer. Bleeding is quite common with adenocarcinoma, occurring in two-thirds of all cases.

Risk factors

Risk factors for endometrial cancer include obesity, insulin resistance and diabetes mellitus, breast cancer, use of tamoxifen, never having had a child, late menopause, high levels of estrogen, and increasing age. These environmental risk factors are not well characterized.

Hormones

Most of the risk factors for endometrial cancer involve high levels of estrogens. An estimated 40% of cases are thought to be related to obesity. Estrogen replacement therapy during menopause when not balanced (or "opposed") with progestin is another risk factor. Higher doses or longer periods of estrogen therapy have higher risks of endometrial cancer. Unopposed estrogen raises an individual's risk of endometrial cancer by 2–10 fold, depending on weight and length of therapy. Higher circulating testosterone levels in women have also been identified as an independent endometrial cancer risk factor.

Genetics

thumb|The autosomal dominant inheritance pattern seen in Lynch syndrome|alt=A diagram of the autosomal dominant inheritance pattern, showing how a gene can be passed from an affected parent to an affected child.

Genetic disorders can also cause endometrial cancer. Overall, hereditary causes contribute to 2–10% of endometrial cancer cases. Carcinogenesis in Lynch syndrome comes from a mutation in MLH1 or MLH2: genes that participate in the process of mismatch repair, which allows a cell to correct mistakes in the DNA. Sixteen genomic regions have been associated with endometrial cancer and the common variants explain up to 7% of the familial relative risk. A one to two-year course of tamoxifen approximately doubles the risk of endometrial cancer, and a five-year course of therapy quadruples that risk. as is having had previous radiotherapy to the pelvis. Specifically, ovarian granulosa cell tumors and thecomas are tumors associated with endometrial cancer.

Low immune function has also been implicated in endometrial cancer.

Protective factors

Smoking and the use of progestin are both protective against endometrial cancer. Smoking protects by altering the metabolism of estrogen and promoting weight loss and early menopause. This protective effect lasts long after smoking is stopped. Progestin is present in the combined oral contraceptive pill and the hormonal intrauterine device (IUD). Combined oral contraceptives reduce risk more the longer they are taken: by 56% after four years, 67% after eight years, and 72% after twelve years. This risk reduction continues for at least fifteen years after contraceptive use has been stopped. Mendelian randomization analyses have established potential protective factors such as LDL cholesterol, later age of menarche and sex hormone binding globulin.

Pathophysiology

{| align=right

|thumb|upright=2|A diagram showing the female reproductive tract with the uterine wall enlarged and normal endometrium visible|alt=A diagram showing the female reproductive tract with histological images of the uterine wall and normal endometrium

{| class="wikitable sortable" align="right"

|+Mutations found in Type I and Type II endometrial cancers]]

PTEN and p27 loss of function mutations are associated with a good prognosis, particularly in obese women. The Her2/neu oncogene, which indicates a poor prognosis, is expressed in 20% of endometrioid and serous carcinomas. CTNNB1 (beta-catenin; a transcription gene) mutations are found in 14–44% of endometrial cancers and may indicate a good prognosis, but the data is unclear. SPOP is another tumor suppressor gene found to be mutated in some cases of endometrial cancer: 9% of clear cell endometrial carcinomas and 8% of serous endometrial carcinomas have mutations in this gene.

Type I and Type II cancers (explained below) tend to have different mutations involved. ARID1A, which often carries a point mutation in Type I endometrial cancer, is also mutated in 26% of clear cell carcinomas of the endometrium and 18% of serous carcinomas. Epigenetic silencing and point mutations of several genes are commonly found in Type I endometrial cancer. An atypical hyperplasia is one with visible abnormalities in the nuclei. Pre-cancerous endometrial hyperplasias are also referred to as endometrial intraepithelial neoplasia. Mutations in the KRAS gene can cause endometrial hyperplasia and therefore Type I endometrial cancer.

Diagnosis

Diagnosis of endometrial cancer is made first by a physical examination, endometrial biopsy, or dilation and curettage (removal of endometrial tissue; D&C). This tissue is then examined histologically for characteristics of cancer. If cancer is found, medical imaging may be done to see whether the cancer has spread or invaded tissues like the myometrium (the muscular wall of the womb) or the uterine cervix. A study from 2024 indicates that transvaginal ultrasound provides diagnostic performance comparable to magnetic resonance imaging regarding the myometrial infiltration assessment. However, magnetic resonance imaging showed significantly better specificity in low-grade endometrial cancer.

Examination

thumb|[[Vaginal ultrasonography with an endometrial fluid accumulation (darker area) in a postmenopausal uterus, a finding that is highly suspicious for endometrial cancer|alt=An ultrasound image showing an endometrial fluid accumulation (darker area) in a postmenopausal uterus, a finding that is highly suspicious for endometrial cancer]]

thumb|Polypoidal endometrial carcinoma

Routine screening of asymptomatic people is not indicated since the disease is highly curable in its early, symptomatic stages. Instead, women, particularly menopausal women, should be aware of the symptoms and risk factors of endometrial cancer. A cervical screening test, such as a Pap smear, is not a useful diagnostic tool for endometrial cancer because the smear will be normal 50% of the time.

Women with Lynch syndrome should begin to have annual biopsy screening at the age of 35. Some women with Lynch syndrome elect to have a prophylactic hysterectomy and salpingo-oophorectomy to greatly reduce the risk of endometrial and ovarian cancer. In the United Kingdom, both an endometrial biopsy and a transvaginal ultrasound used in conjunction are the standard of care for diagnosing endometrial cancer. They can also be used to investigate extrapelvic disease.

thumb|Relative incidences of endometrial carcinomas by histopathology

Traditional classification of endometrial carcinomas is based either on clinical and endocrine features (Type I and Type II) or histopathological characteristics (endometrioid, serous, and clear-cell). Some tumors are difficult to classify and have features overlapping more than one category. High-grade endometrioid tumors, in particular, tend to have both type I and type II features. They tend to present later than Type I tumors and are more aggressive, with a greater risk of relapse and/or metastasis.

The genetic mutations most commonly associated with endometrioid adenocarcinoma are in the genes PTEN, a tumor suppressor; PIK3CA, a kinase; KRAS, a GTPase that functions in signal transduction; and CTNNB1, involved in adhesion and cell signaling. The CTNNB1 (beta-catenin) gene is most commonly mutated in the squamous subtype of endometrioid adenocarcinoma.

Serous carcinoma

Serous carcinoma is a Type II endometrial tumor that makes up 5–10% of diagnosed endometrial cancer and is common in postmenopausal women with atrophied endometrium and black women. Serous endometrial carcinoma is aggressive and often invades the myometrium and metastasizes within the peritoneum (seen as omental caking) or the lymphatic system. Histologically, it appears with many atypical nuclei, papillary structures, and, in contrast to endometrioid adenocarcinomas, rounded cells instead of columnar cells. Roughly 30% of endometrial serous carcinomas also have psammoma bodies.

Undifferentiated endometrial carcinomas make up less than 1–2% of diagnosed endometrial cancers. They have a worse prognosis than grade III tumors. Histologically, these tumors show sheets of identical epithelial cells with no identifiable pattern. Primary transitional cell carcinomas of the endometrium are even more rare; 16 cases had been reported . Its pathophysiology and treatments have not been characterized. Histologically, TCCE resembles endometrioid carcinoma and is distinct from other transitional cell carcinomas.

Sarcoma

thumb|alt=Image of the histology of an endometrioid endometrial adenocarcinoma|Endometrioid endometrial adenocarcinoma—very high magnification—H&E stain

In contrast to endometrial carcinomas, the uncommon endometrial stromal sarcomas are cancers that originate in the non-glandular connective tissue of the endometrium. They are generally non-aggressive and, if they recur, can take decades. Metastases to the lungs and pelvic or peritoneal cavities are the most frequent. The prognosis for low-grade endometrial stromal sarcoma is good, with 60–90% five-year survival. High-grade undifferentiated endometrial sarcoma (HGUS) has a worse prognosis, with high rates of recurrence and 25% five-year survival. HGUS prognosis is dictated by whether or not the cancer has invaded the arteries and veins. Without vascular invasion, the five-year survival is 83%; it drops to 17% when vascular invasion is observed. Stage I ESS has the best prognosis, with a five-year survival rate of 98% and a ten-year survival rate of 89%. ESS makes up 0.2% of uterine cancers.

Metastasis

Endometrial cancer frequently metastasizes to the ovaries and Fallopian tubes Endometrial cancer metastasizes to the lungs 20–25% of the time, more than any other gynecologic cancer. There is also a separate "nuclear grade" system, where grade 1 tumors have inconspicuous cell nuclei, whereas grade 3 tumors have highly atypical nuclei.

The histopathology of endometrial cancers is highly diverse. The most common finding is a well-differentiated endometrioid adenocarcinoma,

File:Endometrioid adenocarcinoma of the uterus FIGO grade III.jpg|A stage III endometrioid adenocarcinoma that has invaded the myometrium

File:Metastatic endometrial carcinoma (3944215367).jpg|Metastatic endometrial cancer seen in a removed lung

File:Histopathology of FIGO (architectural) grade 1 endometrial adenocarcinoma.png|Grade 1: ≤5% solid non-glandular, non-squamous growth.

File:FIGO grade 2 endometrial adenocarcinoma.jpg|Grade 2: >5% and ≤50% solid non-glandular, non-squamous growth.

File:Histopathology of endometrioid cancer, grade 1, nuclear grade 2.jpg|Nuclear grade 2: Intermediate features. The 2009 FIGO staging system is as follows:

{| class="wikitable"

!Stage

!Description

|IA

|Tumor is confined to the uterus with less than half myometrial invasion

|IB

|Tumor is confined to the uterus with more than half myometrial invasion

|II

|Tumor involves the uterus and the cervical stroma

|IIIA

|Tumor invades serosa or adnexa

|IIIB

|Vaginal and/or parametrial involvement

|IIIC1

|Pelvic lymph node involvement

|IIIC2

|Para-aortic lymph node involvement, with or without pelvic node involvement

|IVA

|Tumor invades bladder mucosa and/or bowel mucosa

|IVB

|Distant metastases including abdominal metastases and/or inguinal lymph nodes

thumb|250px|[[Histopathology of pelvic lymph node involvement in a patient with endometrial adenocarcinoma (FIGO grade 1):<br />- Left panel shows H&E staining and low magnification, where presence of small metastases is hard to see.<br />- Middle panel shows immunohistochemistry for CK AE1/AE3, which highlights even small tumor nests.<br />- The right panel shows high magnification on a positive area, confirming adenocarcinoma, as it shows tumor cells with large nuclei and prominent nucleoli.]]

thumb|In contrast, isolated tumor cells do not count as lymph node metastasis. ITCs for endometrial cancers are defined as less than or equal to 0.2 mm or single cells or clusters of cells less than or equal to 200 cells in a single lymph node cross section.

Myometrial invasion and involvement of the pelvic and para-aortic lymph nodes are the most commonly seen patterns of spread.

Surgery

thumb|A keyhole hysterectomy, one possible surgery to treat endometrial cancer|alt=

The initial treatment for endometrial cancer is surgery; 90% of women with endometrial cancer are treated with some form of surgery. Women who undergo lymphadenectomy are more likely to experience systemic morbidity related to surgery or lymphoedema/lymphocyst formation. Removal of the uterus via the abdomen is recommended over removal of the uterus via the vagina because it allows examining and obtaining washings of the abdominal cavity to detect any further evidence of cancer. Staging of the cancer is done during the surgery.

The few contraindications to surgery include inoperable tumor, massive obesity, a particularly high-risk operation, or a desire to preserve fertility. Uterine perforation may occur during a D&C or an endometrial biopsy. Side effects of surgery to remove endometrial cancer can specifically include sexual dysfunction, temporary incontinence, and lymphedema, along with more common side effects of any surgery, including constipation. Mutations in mismatch repair genes, like those found in Lynch syndrome, can lead to resistance against platins, meaning that chemotherapy with platins is ineffective in people with these mutations. Side effects of chemotherapy are common. These include hair loss, low neutrophil levels in the blood, and gastrointestinal problems.

Radiotherapy

Adjuvant radiotherapy is commonly used in early-stage (stage I or II) endometrial cancer. It can be delivered through vaginal brachytherapy (VBT), which is becoming the preferred route due to its reduced toxicity, or external beam radiotherapy (EBRT). Brachytherapy involves placing a radiation source in the organ affected; in the case of endometrial cancer a radiation source is placed directly in the vagina. External beam radiotherapy involves a beam of radiation aimed at the affected area from outside the body. VBT is used to treat any remaining cancer solely in the vagina, whereas EBRT can be used to treat remaining cancer elsewhere in the pelvis following surgery. However, the benefits of adjuvant radiotherapy are controversial. Though EBRT significantly reduces the rate of relapse in the pelvis, overall survival and metastasis rates are not improved. About 25% of metastatic endometrioid cancers show a response to progestins. Also, endometrial stromal sarcomas can be treated with hormonal agents, including tamoxifen, hydroxyprogesterone caproate, letrozole, megestrol acetate, and medroxyprogesterone. Preliminary research and clinical trials have shown these treatments to have a high rate of response even in metastatic disease. There is insufficient evidence to inform women considering hormone replacement therapy after treatment for endometrial cancer.

Targeted therapy

Dostarlimab has been approved by the FDA for therapy of endometrial cancer with specific biomarker

Monitoring

The tumor marker CA-125 is frequently elevated in endometrial cancer and can be used to monitor response to treatment, particularly in serous cell cancer or advanced disease. Periodic MRIs or CT scans may be recommended in advanced disease and women with a history of endometrial cancer should receive more frequent pelvic examinations for the five years following treatment. If a recurrence is suspected, PET/CT scanning is recommended.

! Stage

! 5-year survival rate

| I-A

| 88%

| I-B

| 75%

| II

| 69%

| III-A

| 58%

| III-B

| 50%

| III-C

| 47%

| IV-A

| 17%

| IV-B

| 15%

The five-year survival rate for endometrial adenocarcinoma following appropriate treatment is 80%. More than 70% of women diagnosed have FIGO stage I cancer, which has the best prognosis. Stage III and especially Stage IV cancers have a worse prognosis, but these are relatively rare, occurring in only 13% of cases. The median survival time for stage III–IV endometrial cancer is nine to ten months. Older age indicates a worse prognosis. Tumors with high progesterone receptor expression have a good prognosis compared to tumors with low progesterone receptor expression; 93% of women with high progesterone receptor disease survived to three years, compared with 36% of women with low progesterone receptor disease. with other obesity-related health problems also being common. Following diagnosis, quality of life is also positively associated with a healthy lifestyle (no obesity, high-quality diet, physical activity).

Recurrence rates

Recurrence of early-stage endometrial cancer ranges from 3% to 17%, depending on primary and adjuvant treatment. Radiation therapy (VBT and EBRT) for a local vaginal recurrence has a 50% five-year survival rate. Pelvic recurrences are treated with surgery and radiation, and abdominal recurrences are treated with radiation and, if possible, chemotherapy.

Epidemiology

, approximately 320,000 women are diagnosed with endometrial cancer worldwide each year and 76,000 die, making it the sixth most common cancer in women. representing 6% of all cancer cases in women. In that country, it was estimated that 52,630 women were diagnosed yearly and 8,590 would die from the disease. Northern Europe, Eastern Europe, and North America have the highest rates of endometrial cancer, whereas Africa and West Asia have the lowest rates. Asia saw 41% of the world's endometrial cancer diagnoses in 2012, whereas Northern Europe, Eastern Europe, and North America together comprised 48% of diagnoses.

Endometrial cancer appears most frequently during perimenopause (the period just before, just after, and during menopause), between the ages of 50 and 65;

Research is ongoing on the use of metformin, a diabetes medication, in obese women with endometrial cancer before surgery. Early research has shown it to be effective in slowing the rate of cancer cell proliferation. Preliminary research has shown that preoperative metformin administration can reduce the expression of tumor markers. Long-term use of metformin has not been shown to have a preventative effect against developing cancer, but it may improve overall survival.

Temsirolimus, an mTOR inhibitor, is under investigation as a potential treatment. An experimental drug that combines a hormone with doxorubicin is also under investigation for greater efficacy in cancers with hormone receptors. Hormone therapy that is effective in treating breast cancer, including the use of aromatase inhibitors, is also being investigated for use in endometrial cancer. One such drug is anastrozole, which is currently being researched in hormone-positive recurrences after chemotherapy. Research into hormonal treatments for endometrial stromal sarcomas is ongoing as well. It includes trials of drugs like mifepristone, a progestin antagonist, and aminoglutethimide and letrozole, two aromatase inhibitors. In surgery, research has shown that complete pelvic lymphadenectomy along with hysterectomy in stage 1 endometrial cancer does not improve survival and increases the risk of negative side effects, including lymphedema. Other research is exploring the potential of identifying the sentinel lymph nodes for biopsy by injecting the tumor with dye that shines under infrared light. Intensity modulated radiation therapy is currently under investigation and already used in some centers for application in endometrial cancer to reduce side effects from traditional radiotherapy. Its risk of recurrence has not yet been quantified. Research on hyperbaric oxygen therapy to reduce side effects is also ongoing. The results of the PORTEC 3 trial assessing combining adjuvant radiotherapy with chemotherapy were awaited in late 2014.

History and culture

Endometrial cancer is not widely known by the general populace despite its frequency. There is low awareness of the symptoms, which can lead to later diagnosis and worse survival.

References

External links

American Cancer Society's Detailed Guide: Endometrial Cancer
U.S. National Cancer Institute: Uterine cancer
Anatomical pathology images