Introduction

The female reproductive system development can be traced to the paramesonephric duct. Bilateral paramesonephric ducts form the fallopian tubes and then fuse to form the uterus and the upper portion of the vaginal canal. The uterus is held by several ligaments that are responsible for its anteverted and anteflexed position in the pelvis. The embryo embeds and develops into a fetus in the uterus. The placenta attached to the endometrium serves as the port of transfer for nutrition and oxygen between the maternal and fetal blood. Every month in the absence of pregnancy, the endometrium sheds and causes cyclic menstrual bleeding.

The uterus is anatomically divided into three layers, endometrium (innermost), myometrium (middle), and serosa (outermost). Uterine cancer can arise from both the endometrium and the myometrium. Uterine sarcomas arise from the middle muscular layer; these are rare but are often aggressive and need prompt diagnosis and treatment. Among gynecological cancers, Endometrial carcinoma is the most common in developed countries. In developing countries, endometrial carcinoma is the second most common after cervical cancer.[1] 

The age-incidence curve of endometrial cancer suggests that the highest incidence of diagnosis is in the seventh decade of life.[2] The American Cancer Society estimated that about 63,230 new cases of uterine cancer were diagnosed in 2018.[3] Per estimates, 4.6 per 100,000 women die of uterine cancer in the United States of America.[3] These statistics suggest that uterine cancer poses a great burden on the health care system, and timely prevention, diagnosis, and treatment can lead to improved patient outcomes as well as decrease the load on the system.

Etiology

Endometrial adenocarcinoma or endometrioid carcinoma is the most common subtype of endometrial cancer. Endometrial adenocarcinoma develops as a result of unopposed estrogen exposure. Estrogen has a proliferative effect on the endometrium, which leads to endometrial hyperplasia. Unmonitored proliferation leads to dysplasia and later carcinoma. Adipose tissue in the body converts androgens into estrogen and hence conditions like obesity, metabolic syndrome, and diabetes mellitus type II that lead to increased estrogen levels and can increase the risk of endometrial carcinoma. More than 50% of endometrial cancers are attributable to obesity alone.[4] 

The incidence of endometrial cancer has increased over the years, as the incidence of obesity has increased. Early menarche, late menopause, nulliparity, infertility, and polycystic ovarian syndrome all lead to unopposed exposure to estrogen due to an increased number of ovulatory cycles over the lifespan of a patient. These are all considered important risk factors for endometrial cancer.[5] 

Tamoxifen, a drug used for the treatment of breast cancer, also increases the risk of endometrial cancer. Tamoxifen inhibits estrogen receptors in the breast tissue, but at the same time, it has a stimulatory effect on the estrogen receptors in the endometrium.[5] Estrogen-only hormone replacement therapy done in postmenopausal patients can also stimulate the endometrium and can lead to the development of endometrial carcinoma.

Epidemiology

Endometrial carcinoma is among the more common (the fourth most common) cancers in women in developed countries. Every year around 65,000 females develop uterine cancer in the USA alone, out of which more than 90% is of endometrial origin. It is commonly diagnosed in the seventh decade, with the mean age being 61 years. The incidence in Black women is twice that of White women. In addition, Black women with uterine cancer carry a poorer prognosis as compared to White women.[6] Death rates have increased by more than 100% in the last 20 years.[7] 

Even though the death rates from other cancers in women are down, death rates from uterine cancer are increasing. Patients diagnosed with endometrial cancer are most commonly postmenopausal, although 15%-25% of patients are diagnosed before menopause.[8] 

About a quarter are diagnosed between 65 to74 years of age. Also, the percentage of deaths due to uterine cancer is highest amongst women of ages between 65 to 74 years (32%). There are multiple reasons for high mortality in this age group compared to the younger population, e.g., aggressive tumor, advanced disease, reluctance to surgical treatment options, and worse treatment outcomes.[7]

Pathophysiology

Endometrioid cancer develops in response to the exposure of endometrium to unopposed estrogen, which leads to hyperplasia and then dysplasia of the endometrial glands and hence is referred to as adenocarcinoma. Multiple studies have demonstrated a strong association between intrinsic factors that cause increased serum estrogen, e.g., obesity and type II diabetes mellitus with endometrial adenocarcinoma.[9][10][11][12] 

Extrinsic factors, e.g., estrogen-only hormone replacement therapy and tamoxifen, also increase the risk of developing endometrial adenocarcinoma. Serous carcinoma of the endometrium arises due to atrophy of the endometrium and is often linked to genetic mutations. Based on molecular patterns and estrogen sensitivity, there are two types of uterine cancer. Type I cancer is due to unopposed estrogen, while type II cancer is seen in postmenopausal women, is not estrogen-related, and carries a poorer prognosis. Mutations in PTEN, k-ras, and microsatellite instability inception are common in type I, while p53 and HER2/neu mutations are seen in type II.[13] 

This classification provides important information regarding therapeutics and prognosis as well. The most common mutation is in p53 and HER/neu and has a poor prognosis.[13]

Histopathology

According to the World Health Organization (WHO), the pathological classification of endometrial carcinoma includes nine subtypes. Out of them, endometrioid and serous carcinomas are the most common. Endometrioid carcinoma is further divided into four subtypes based on histopathology - adenocarcinoma with squamous differentiation, villoglandular (papillary subtype with cuboidal/columnar cells), secretory subtype, and ciliated cell subtype. In adenocarcinoma with squamous differentiation (almost 25% of adenocarcinomas), on histological examination keratin pearls, intercellular bridges consisting of ovoid or spindle cells may be seen.[14] 

Serous carcinoma, on histopathology, often contains papillae, which are lined by pleomorphic hyperchromatic cells that contain eosinophilic macronucleoli. Other subtypes include mucinous, clear cell, neuroendocrine, serous endometrial intraepithelial, mixed cell adenocarcinoma, undifferentiated and dedifferentiated carcinomas. Piultas et al. proposed integrating pathological with molecular classification to improve management. Accordingly, molecular classification classifies into four subtypes - group 1 is polymerase epsilon (POLE) ultra-mutated, group 2 with microsatellite instability, group 3 with low copy number alterations, and group 4 with serous-like or high copy number alterations. Groups 1-3 are predominantly endometrioid cancers, and group 4 is serous carcinoma.[15]

History and Physical

Females with endometrial carcinoma most commonly present with postmenopausal bleeding. In premenopausal women, intermenstrual bleeding and irregular menstrual cycles can also be symptoms of endometrial cancer. In a recent study by Megan A Clarke, 34,432 patients with postmenopausal bleeding (PMB) were analyzed. The pooled prevalence of PMB in women positive for endometrial cancer was 91%.[16]

Other important symptoms include vague abdominal pain, pelvic discomfort, nausea, and dysuria. When the tumor has metastasized to other parts of the body, weight loss, anorexia, and changes in bowel and bladder habits may also occur. On physical examination, the patient may appear pale due to the loss of blood caused by abnormal uterine bleeding. The abdominal exam may be normal if the uterus is small in size and non-tender. On vaginal examination, bloody vaginal discharge or blood clots may be present in the vaginal canal.  In the case of uterine sarcoma, postmenopausal bleeding, pelvic pressure, and ascites may be the first presenting complaints. On abdominal examination, the uterus is enlarged and may be tender.

Evaluation

Postmenopausal bleeding is always considered abnormal, and further investigation is needed for the diagnosis. The first line diagnostic test in postmenopausal women is transvaginal ultrasound. The normal endometrial thickness is less than 4mm, and the thickening of the endometrium of more than 4mm should be further investigated with the help of endometrial biopsy. Transvaginal ultrasound has low sensitivity in premenopausal women due to the presence of variations in endometrial thickness during the menstrual cycle. In premenopausal women, endometrial biopsy should be considered as the first-line investigation.

An endometrial biopsy is obtained with the help of dilation and curettage, and the biopsy is then evaluated by a histopathologist for the presence of hyperplasia, dysplasia, or carcinoma. Uterine sarcomas may be detected on transvaginal or transabdominal ultrasound, but a definitive diagnosis is only made on the microscopic examination of the tumor cells. There is no evidence that the screening for endometrial cancer in asymptomatic patients is of any benefit.[5]

Treatment / Management

If the histopathological examination of the endometrial biopsy shows hyperplasia without atypia, there is less than a 3% chance of developing cancer, and hence progestin therapy is considered appropriate. Progestin stimulates progesterone receptors in the endometrium and causes the decidualization of the stroma and thinning of the endometrium. If hyperplasia with atypia is present, the chances of developing endometrial carcinoma increase by up to 30%.

In women considering future pregnancy, progestins can also be used in the presence of atypia, but if the patient has no plans for pregnancy, hysterectomy should be considered. It is important to stage the disease and plan the treatment accordingly in the presence of carcinoma. For endometrial carcinoma stage I, transabdominal hysterectomy with bilateral salpingo-oophorectomy is the treatment of choice.

For stage II, radical or simple hysterectomy along with adjuvant radiotherapy is preferred. Stage III endometrial carcinoma is treated with transabdominal hysterectomy with bilateral salpingo-oophorectomy and pelvic radiation, while for stage IV, cancer surgery and radiation therapy are the mainstays of treatment. Patients with stage IV cancer might also require palliative care to improve their quality of life.

Differential Diagnosis

Several medical conditions might mimic the signs and symptoms of endometrial carcinoma. In premenopausal women, abnormal uterine bleeding might be a result of endometriosis, fibroids, adenomyosis, and ovulatory dysfunction. Conditions such as atrophic vaginitis, endometrial atrophy, endometrial hyperplasia, and endometrial/cervical polyps are more common in postmenopausal women and are the potential differential diagnosis for endometrial carcinoma. Systemic conditions such as coagulopathy and infection must also be ruled out in both groups.

Surgical Oncology

Surgical oncologists play a very important role in the management of patients with endometrial carcinoma. Total abdominal hysterectomy with bilateral salpingo-oophorectomy is the treatment of choice in patients with stage I disease. The most common complication associated with total abdominal hysterectomy is an excessive loss of blood. Other complications include infection, side effects of anesthesia, bladder rupture, and ureter damage. Sexual function remains unaffected after treatment.[17]

Radical hysterectomies done for stage II cancer involves the removal of the uterus along with all the ligaments and the upper one third or half of the vaginal canal. Stage III and IV are most commonly treated with hysterectomy plus bilateral salpingo-oophorectomy and radiation. Laparoscopic surgery has been found to have an equal risk of death compared to laparotomy and hence is now often performed.[18][19]

Radiation Oncology

Radiation therapy is given in two forms to patients with endometrial carcinoma - brachytherapy and external beam radiation. In vaginal brachytherapy, a radiation-emitting source is placed inside the vaginal canal, and this can be a high or low dose rate brachytherapy.[20] High dose rate brachytherapy is done at the clinic and does not take more than half an hour, and the patient has to come to the clinic weekly or even daily in some cases. Low dose rate (LDR) brachytherapy is less potent, and the radiation-emitting device is placed in the vagina for 1 to 4 days. The patient is admitted to the hospital for this. For the efficient working of LDR brachytherapy, the patient must not be mobile, which leads to an increased risk of DVT. In external beam therapy, the radiation source is outside the body, the area of the body receiving the radiation is marked and radiated five days a week for at least 5 to 6 weeks.

The most common complication of radiation therapy is skin changes. The skin may become red and dry, leading to scarring and infection. Radiation cystitis, proctitis, and vaginitis can also occur. In the long run, the inflamed tissue may scar and cause stenosis of the vaginal and anal canal. A communication between the vagina, bowel, and skin called a fistula can also form. Radiation leads to inflammation and damage to ovaries and can cause premature ovarian failure leading to premature menopause.[20][21]

Medical Oncology

While a large randomized trial demonstrated that chemotherapy adjuvant to external beam radiotherapy did not improve survival in patients with endometrial carcinoma, it is still used in certain patients with stage III and IV endometrial carcinomas.[22] Systemic therapy is required when the tumor has spread to other parts of the body. Chemotherapy is most commonly given in the form of a combination of two drugs. The most commonly used drugs include carboplatin, cisplatin, paclitaxel, docetaxel, and doxorubicin.[23] 

Paclitaxel and docetaxel inhibit the cytoskeletal protein called tubulin and prevents it from making the mitotic spindle, which is an essential component of cell division. Platinum-based drugs such as carboplatin and cisplatin render the DNA inactive by aquation. The common side effects of chemotherapy are nausea, vomiting, hair loss, and bone marrow suppression.

Staging

Grading and staging the disease before proceeding towards treatment is essential. The grading of endometrial cancer is based on the presence of a solid component. If the adenocarcinoma contains 5% or less of the solid component, it is graded as grade I. Presence of 6% - 50% of solid component is labeled as grade II, and tumors that have more than 50% of the solid component are referred to as grade III. Staging of endometrial cancer is done based on the extent of the spread of the disease. Stage I endometrial carcinoma is limited to the uterus. If cancer extends into the cervix, it is labeled as Stage II. Metastasis of the tumor into serosa, vagina, and pelvic lymph nodes is labeled as stage III, whereas metastasis to distant sites (bowel/bladder) or abdominal or inguinal lymph nodes is labeled as stage IV.[24]

According to staging as per International Federation of Gynecology and Obstetrics Staging System for Endometrial Cancer, 2009, the staging is as follows:[24]

Stage I- Limited to the uterus

• IA- Limited to the endometrium, no invasion or invasion of less than half of the myometrium
• IB- Invasion of more than half of the myometrium

Stage II- Invasion into the cervical stroma

Stage III- Extension into pelvis or vagina

• IIIA- Invasion into the serosa or adnexa
• IIIB- Vaginal or parametrial involvement
• IIIC- Spread to pelvic (III C1) or para-aortic lymph nodes (III C2)

Stage IV- Extension into bladder/rectum or distant metastasis

• IVA- Extension into bladder/bowel mucosa
• IVB- Distant metastasis into omental or inguinal lymph nodes

Prognosis

Based on the data available from 2009 to 2015, women diagnosed with localized, regionally extended, and distantly metastasized endometrial carcinoma had a 5-year survival rate of 95%, 69%, and 17%, respectively. For all stages taken together, the overall 5-year survival is around 80%.[2] Some biochemical markers such as carbohydrate antigen 125 (CA 125), estrogen and progesterone receptor expression, presence of mutations (e.g., PTEN, TP53), E-cadherin (CDH1), and neural cell adhesion molecule L1 (L1CAM) are useful prognostic factors.[25]

Complications

One of the potential complications of endometrial carcinoma itself is anemia. Due to the excessive loss of blood from the uterus, symptoms such as shortness of breath, fatigue, and palpitations may arise. Each treatment modality has its complications, and there is a high risk of developing vaginal stenosis, vaginal atrophy, and bowel/bladder fistula post-irradiation. Surgical treatment may lead to bladder instability, sexual dysfunction, and lymphedema, while chemotherapy has its own side effects, but these are usually limited and easily treated with medication. When the tumor metastasizes to distant organs, it can cause symptoms of weight loss, shortness of breath, and bone pain.

Deterrence and Patient Education

It is important and essential to educate patients about lifestyle modifications such as a balanced diet, regular exercise, and abstinence of tobacco, which can be effective in preventing the development of uterine cancer.[5][26][27][28] Once a patient is diagnosed with uterine cancer, it is essential to discuss all available treatment options and the associated risks and benefits.

Enhancing Healthcare Team Outcomes

Diagnosis and management of endometrial cancer require combined efforts of health care professionals from different fields. It is important that the communication between these individuals is uninterrupted and accurate transfer of information is assured. Nursing staff plays an important role in carefully curating and administering treatment regimens, following up on patients, and monitoring adverse events related to the treatment. In order to improve treatment outcomes and ensure patient safety, the interprofessional team should discuss the patient's responses to treatment regularly. The social, psychological, and financial needs of the patient should be taken into consideration, and help should be offered when needed.

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Disclosure: Unaiza Faizan declares no relevant financial relationships with ineligible companies.

Disclosure: Vijayadershan Muppidi declares no relevant financial relationships with ineligible companies.