Background

Endometrial carcinoma, also known as uterine cancer, usually begins in the uterine lining, called the endometrium. It is the most common gynecological malignancies and affects women primarily after menopause. The incidence of endometrial cancer is increasing worldwide, with an estimated about 382,000 new cases and 89,900 deaths in 2020.

It is more common in developed countries, particularly in North America and Europe, and in women with certain risk factors such as obesity, nulliparity, and prolonged exposure to estrogen without progesterone. Early detection and treatment are crucial for improving the prognosis of endometrial cancer. 

Epidemiology

• Incidence: Endometrial carcinoma is the most common gynecological malignancy in the developed countries, with an estimated about 65,620 new cases and 12,590 deaths in the United States in 2021. 
• Age: The incidence of endometrial carcinoma increases with age, with most cases diagnosed in postmenopausal women. The median age to diagnose is 60 years old. 
• Ethnicity: Endometrial carcinoma is more common in white women compared to African American, Asian, and Hispanic women. 
• Geographic location: Endometrial carcinoma is more common in developed countries, with the highest incidence rates in North America and Europe. 
• Obesity: Obesity is a risk factor for endometrial carcinoma, with the incidence of the disease increasing with increasing body mass index (BMI). 
• Hormonal factors: Hormonal factors such as early menarche, late menopause, nulliparity, and use of unopposed estrogen therapy are associated with an increased risk of endometrial carcinoma. 
• Family history: A family history of endometrial carcinoma, hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome is associated with the increased risk of endometrial carcinoma. 

Anatomy

Pathophysiology

The pathophysiology of endometrial carcinoma involves a combination of genetic mutations and hormonal imbalances, leading to the abnormal growth and proliferation of endometrial cells. 

• Genetic Mutations: Endometrial carcinoma is associated with mutations in various genes that control cell growth, differentiation, and apoptosis. These mutations can be sporadic or inherited and may affect genes such as PTEN, TP53, PIK3CA, KRAS, and CTNNB1. 
• Hormonal Imbalances: Estrogen is a key hormone that regulates endometrial growth and proliferation. An excess of estrogen relative to progesterone can lead to unopposed endometrial growth and an increased risk of endometrial carcinoma. Other hormonal imbalances, such as those seen in polycystic ovary syndrome (PCOS), can also increase the risk of endometrial carcinoma. 
• Histopathological Features: Endometrial carcinoma can be classified into various histological subtypes, including endometrioid, serous, clear cell, and mucinous. Endometrioid carcinoma is the most common subtype and is associated with estrogen-driven carcinogenesis. Serous carcinoma, on the other hand, is more aggressive and is typically not associated with hormonal imbalances. 
• Staging: Endometrial carcinoma is staged based on the extent of tumor invasion and spread. Federation of Gynecology and Obstetrics (FIGO) system is commonly used and includes four stages, with stage I being limited to the uterus and stage IV being metastatic disease. 

Etiology

Hormonal etiology: 

• Unopposed estrogen exposure: This is the most significant risk factor for endometrial carcinoma. The risk increases with prolonged exposure to estrogen without progesterone. 
• Hormone replacement therapy (HRT): Women taking estrogen replacement therapy without progesterone have a higher risk of developing endometrial cancer. 
• Polycystic ovarian syndrome (PCOS): Women with PCOS have higher levels of estrogen in their bodies, which increases their risk of endometrial cancer. 
• Obesity: Adipose tissue produces estrogen, and obese women have increased levels of estrogen in their bodies, which increases their risk of endometrial cancer. 

Non-hormonal etiology: 

• Age: Endometrial cancer is mostly diagnosed in postmenopausal women. 
• Diabetes: Women with diabetes have a higher risk of endometrial cancer, due to the high levels of insulin in their bodies. 
• Hypertension: There may be a link between high blood pressure and endometrial cancer. 
• Hereditary nonpolyposis colorectal cancer (HNPCC): This is a genetic syndrome that increases the risk of developing several types of cancer, including endometrial cancer. 

Genetics

Prognostic Factors

The prognostic factors for endometrial carcinoma, as reported by Medscape and NIH, are: 

• Tumor grade: The grade of the tumor is based on the appearance of cancer cells under a microscope.  
• Tumor stage: The stage of the tumor refers to the extent of the cancer and whether it has spread beyond the uterus. Higher stage tumors have a worse prognosis. 
• Lymph node involvement: The presence of cancer cells in the lymph nodes is a sign that the cancer spreads beyond the uterus and is associated with a worse prognosis. 
• Age: Younger patients with endometrial cancer have a better prognosis than older patients. 
• Histology: The histology of the cancer refers to the type of cell that the cancer arises from. Different histological subtypes of endometrial cancer have different prognoses. 
• Menopausal status: Postmenopausal women are at higher risk of developing endometrial cancer, and their prognosis may be worse than that of premenopausal women. 
• Comorbidities: The other medical conditions can affect the prognosis of endometrial cancer. 
• Estrogen exposure: Prolonged exposure to estrogen, either through endogenous or exogenous sources, is a risk factor for endometrial cancer and may be associated with a worse prognosis. 
• Genetic mutations: Certain genetic mutations, such as those associated with Lynch syndrome, increase the risk of endometrial cancer and may be associated with a worse prognosis. 
• Response to treatment: The response of the tumor to treatment, such as surgery, radiation therapy, or chemotherapy, can also affect the prognosis. 

Clinical History

Age group: 

• Endometrial carcinoma is more common in postmenopausal women, with a median age of 63 years. 
• However, it can also occur in premenopausal women, especially in those with risk factors such as obesity and polycystic ovary syndrome. 

Physical Examination

• Pelvic examination: The healthcare provider may perform a pelvic examination to check for the abnormalities in the uterus or ovaries. During the pelvic exam, the healthcare provider may insert two fingers into the vagina by pressing on the lower abdomen with the other hand. This allows the healthcare provider to feel for any lumps, growths, or abnormalities in the pelvic area. 
• Speculum examination: The healthcare provider may use a speculum to examine the cervix and vagina. The speculum is a tool that helps to open the vagina so the healthcare provider can see the cervix. 
• Biopsy: If any abnormalities are found during the pelvic exam or speculum examination, the healthcare provider may perform a biopsy.  
• Imaging tests: the tests such as transvaginal ultrasound, CT scan, and MRI may be ordered to determine the extent and spread of the cancer. 
• Blood tests: It is used to check for tumor markers, which are substances that are produced by cancer cells. These tests can help to diagnose and monitor the progress of endometrial cancer. 

Age group

Associated comorbidity

• Obesity is a common risk factor for endometrial carcinoma, as excess adipose tissue leads to increased production of estrogen, which can stimulate the growth of the endometrium. 
• Other risk factors include a history of endometrial hyperplasia, nulliparity, early menarche, late menopause, tamoxifen use, and Lynch syndrome. 
• Women with breast or ovarian cancer may also be at increased risk. 

Associated activity

Acuity of presentation

• The most common presenting symptom of endometrial carcinoma is abnormal uterine bleeding, which can manifest as postmenopausal bleeding, intermenstrual bleeding, or heavy menstrual bleeding. 
• Other symptoms may include pelvic pain or pressure, vaginal discharge, and weight loss. 
• In advanced cases, there may be signs of metastasis, such as abdominal or pelvic masses, ascites, or pleural effusion. 

Differential Diagnoses

• Endometrial hyperplasia: It is condition where the lining of the uterus becomes abnormally thick.  
• Cervical cancer: It develops in the cervix, connects to the vagina.  
• Ovarian cancer: A cancer that develops in the ovaries, the reproductive glands that produce eggs.  
• Uterine fibroids: It is a noncancerous growth in the uterus that can cause heavy bleeding and pain.  
• Adenomyosis: A condition in which the uterine lining grows into muscular walls of the uterus, causing pain and heavy bleeding.  
• Polyps: Abnormal growths that develop in the lining of the uterus.  
• Pelvic inflammatory disease: It is an infection of the female reproductive organs that can cause pain and infertility.  
• Endometriosis: It is a condition in which the uterine lining grows outside of it, causing pain and infertility.  
• Atrophic vaginitis: A condition in which the vaginal walls become thin and dry due to low levels of estrogen. It can cause vaginal dryness, itching, and pain during sex. 

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

Treatment and management of endometrial carcinoma may depend on the stage of the cancer, the patient’s age and overall health, and other factors. Treatment options include: 

Modification of environment: There are no specific environmental modifications to prevent or treat endometrial carcinoma, but maintaining a healthy lifestyle and weight may reduce the risk of developing the disease. 

Administration of a pharmaceutical agent with drugs: 

• Hormonal therapy: It is used to treat early-stage endometrial carcinoma or to relieve symptoms in advanced cases. It may involve the use of progesterone alone or in combination with estrogen. 
• Chemotherapy: Chemotherapy may be used in advanced cases of endometrial carcinoma to help control the growth and spread of cancer cells. Chemotherapy drugs are usually given intravenously. 
• Targeted therapy: Targeted therapeutic drugs may be used in cases of advanced endometrial carcinoma that have certain genetic mutations. These drugs target specific proteins or pathways that are involved in the growth and the spread of cancer cells. 

Intervention with a procedure: 

• Surgery: It may involve a total hysterectomy, bilateral salpingo-oophorectomy, and/or removal of nearby lymph nodes. 
• Radiation therapy: Radiation therapy may be used in combination with surgery or chemotherapy to treat endometrial carcinoma. 

Phase of management: 

• Follow-up care: After treatment, patients with endometrial carcinoma will need regular follow-up care to monitor for recurrence and manage any side effects of treatment. This may involve regular physical exams, imaging tests, and blood tests. 

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

non-pharmacological-treatment-of-endometrial-carcinoma

Lifestyle modifications: 

• Adopting a Healthy Diet:A diet including vegetables, fruits, whole grains & lean proteins. Limit the intake of processed meats, as it leads to increased risk of colorectal cancer. Adequate fiber intake can contribute to regular bowel movements and overall digestive health. 
• Maintaining a Healthy Weight: Strive for a healthy body weight through regular physical activity and balanced nutrition. Obesity has an increased risk of colorectal cancer, and maintaining the healthy weight can positively impact treatment outcomes. 
• Control Blood Sugar Levels: Manage and control blood sugar levels through regular exercise and balanced diet. High levels of insulin, often associated with conditions like insulin resistance, may contribute to an increased risk of endometrial cancer. 
• Hormone Replacement Therapy (HRT): If considering hormone replacement therapy, discuss the risks and benefits with a healthcare provider. Long-term use of estrogen-only HRT may be associated with an increased risk of endometrial cancer. 
• Regular Gynecological Check-ups: Attend regular gynecological check-ups and screenings. Report any abnormal bleeding, pelvic pain, or other concerning symptoms promptly. 
• Smoking Cessation: Quit smoking, as smoking is associated with an increased risk of endometrial cancer. 
• Limit Alcohol Consumption: Limit alcohol intake. Excessive alcohol consumption may have an increased risk of endometrial cancer. 
• Sun Protection: Practice sun safety to reduce the risk of developing skin cancer, which can also affect the reproductive organs. 
• Stay Informed: Stay informed about your family history and any hereditary conditions that may contribute to cancer risk. Discuss genetic counseling and testing options with healthcare providers when appropriate. 

Use of Hormone therapy in the treatment of Endometrial Carcinoma

Hormone therapy is not typically the primary treatment for endometrial carcinoma. However, it may be considered in certain situations, especially for specific types of endometrial cancer.

Hormone therapy is often used as part of a comprehensive treatment plan, and its appropriateness depends on the characteristics of the tumor and the overall health of the patient. 

Type of Endometrial Cancer: 

• Well-Differentiated Endometrioid Carcinoma: Hormone therapy may be considered for well-differentiated endometrioid carcinomas, especially those that are estrogen receptor or progesterone receptor. 
• Low-Grade Endometrial Stromal Sarcoma: Hormone therapy may be used for low-grade endometrial stromal sarcomas, as they often express hormone receptors. 

Treatment Goals: 

• Fertility Preservation: In younger women with early-stage, well-differentiated endometrial cancer who wish to preserve fertility, hormone therapy may be considered as alternative to surgery. 
• Disease Control: For women who are not surgical candidates or have advanced disease, hormone therapy can be employed to control the growth of the tumor and manage symptoms. 

Hormonal Agents Used: 

• Progestins (Progesterone): Progestins are the most common hormonal agents used in the treatment of endometrial carcinoma. They work by promoting differentiation of endometrial cells and inducing apoptosis (programmed cell death). 
• Gonadotropin-Releasing Hormone (GnRH) Agonists: GnRH agonists may be used to suppress ovarian function, reducing estrogen levels in the body. 
• Aromatase Inhibitors: Aromatase inhibitors, which block the conversion of androgens to estrogen, may be considered in certain cases. 

Administration and Monitoring: 

• Oral or Injectable Forms: Hormone therapy can be administered orally or through injectable forms, depending on the specific agent. 
• Regular Monitoring: Patients undergoing hormone therapy are regularly monitored through imaging studies and biopsies to assess the response to treatment. 

Use of Biological therapy in the treatment of Endometrial Carcinoma

Biological therapies, including mTOR inhibitors and Bevacizumab, are sometimes used in the treatment of endometrial carcinoma, especially in advanced or recurrent cases.  

mTOR Inhibitors: 

Role: 

• mTOR (mammalian target of rapamycin): The mTOR is a protein kinase which regulates cell growth and proliferation. Abnormal activation of the mTOR pathway is observed in some cancers, including endometrial carcinoma. 
• Inhibition of mTOR: mTOR inhibitors, such as everolimus, work by inhibiting the mTOR pathway, thereby slowing down the growth of cancer cells. 

Indications: 

• Advanced or Recurrent Disease: mTOR inhibitors may be considered in patients with advanced or recurrent endometrial carcinoma that is not responding to conventional therapies. 
• Specific Molecular Characteristics: Some tumors with specific molecular characteristics, such as mutations in the PI3K/AKT/mTOR pathway, may be more responsive to mTOR inhibitors. 

Administration: 

• Oral Medication: mTOR inhibitors are typically administered orally, and the treatment is closely monitored for effectiveness and side effects. 

Bevacizumab: 

• It is a monoclonal antibody that targets vascular endothelial growth factor (VEGF), a protein involved in angiogenesis (formation of new blood vessels). By inhibiting VEGF, Bevacizumab aims to disrupt the tumor’s blood supply, limiting its ability to grow and spread. 

Indications: 

• Advanced or Recurrent Disease: Bevacizumab may be used in combination with chemotherapy for the treatment of advanced or recurrent endometrial carcinoma. 
• Maintenance Therapy: In some cases, Bevacizumab may be used as maintenance therapy after initial treatment to delay disease progression. 

Administration: 

• Intravenous Infusion: Bevacizumab is administered through intravenous infusion, typically in combination with other chemotherapy agents. 

use of chemotherapy in the treatment of Endometrial Carcinoma

Chemotherapy is a systemic treatment option commonly used in the treatment of endometrial carcinoma, especially in cases of advanced or recurrent disease.

The decision to use chemotherapy is typically based on the stage and characteristics of the cancer, as well as individual patient factors. Here’s an overview of the use of chemotherapy in the treatment of endometrial carcinoma: 

• Advanced Stage Disease: Chemotherapy may be recommended for patients with advanced-stage endometrial carcinoma, where the cancer has spread beyond the uterus. 
• High-Grade Tumors: High-grade tumors that are more aggressive may be candidates for chemotherapy. 

Commonly Used Chemotherapy Drugs: 

• Paclitaxel: Paclitaxel is a taxane drug that interferes with cell division, preventing cancer cells from multiplying. 
• Carboplatin: Carboplatin is a platinum-based chemotherapy drug that disrupts DNA function in cancer cells, inhibiting their ability to divide and grow. 
• Doxorubicin: Doxorubicin is an anthracycline drug that works by intercalating DNA strands and inhibiting the enzyme topoisomerase II, leading to cell death. 
• Cisplatin: Cisplatin is another platinum-based drug that forms cross-links in DNA, preventing cell replication. 
• Combination Therapies: Often, a combination of chemotherapy drugs is used to enhance effectiveness and reduce the risk of resistance. 

use-of-hysterectomy-in-the-treatment-of-endometrial-carcinoma

Hysterectomy with bilateral salpingo-oophorectomy is a common surgical procedure used in the treatment of endometrial carcinoma, particularly when the cancer has not spread beyond the uterus.

This procedure involves the removal of uterus along with the fallopian tubes (salpingectomy) and both ovaries (oophorectomy). The primary goal is to eliminate the cancer and prevent its further spread. 

During the surgery, the surgeon may also perform lymph node dissection to assess the cancer has spread to nearby lymph nodes. By eliminating the ovaries, the production of estrogen is drastically reduced, helping to control the progression of the disease. 

This surgical intervention is often considered the initial and definitive treatment for early-stage endometrial carcinoma. In cases where the cancer has spread beyond the uterus, additional therapies such as chemotherapy or radiation may be recommended after surgery.

The decision to perform a hysterectomy with bilateral salpingo-oophorectomy is based on the specific characteristics of the tumor, the stage of the cancer, and the overall health of the patient.

It is a critical component of a comprehensive treatment plan, and patients should discuss the potential benefits and risks with their healthcare team. After the procedure, patients may experience changes in hormonal balance, and hormone replacement therapy may be considered based on individual factors and menopausal status. 

use-of-radiation-therapy-in-the-treatment-of-endometrial-carcinomaradiation-therapy-is-a-valuable-treatment-modality-in-the-comprehensive-management-of-endometrial-carcinoma-it-involves-the-targeted

Radiation therapy is a valuable treatment modality in the comprehensive management of endometrial carcinoma. It involves the targeted use of high-energy beams to destroy or damage cancer cells, preventing their ability to grow and divide.

Radiation therapy is employed in different scenarios based on the characteristics of the cancer, its stage, and the overall treatment plan.  

• Postoperative Treatment: After surgical interventions like hysterectomy with bilateral salpingo-oophorectomy, adjuvant radiation therapy may be recommended to eliminate remaining cancer cells & reduce the risk of local recurrence. 
• Lymph Node Involvement: If there is evidence of lymph node involvement or a higher risk of recurrence, pelvic or para-aortic radiation may be considered to target these areas. 
• Localized Disease: For localized disease confined to the uterus, radiation therapy can be directed specifically to the affected area, aiming to eradicate cancer cells. 

• External Beam Radiation: Delivered from outside the body using a machine, external beam radiation is commonly used in endometrial carcinoma treatment. It precisely targets the pelvic area where the cancer is located. 
• Internal Radiation (Brachytherapy): It involves placing a radiation source directly inside or very close to the tumor. In endometrial carcinoma, vaginal brachytherapy may be utilized to target the upper part of the vagina and surrounding tissues. 

management-of-endometrial-carcinoma

Acute Phase: 

• Diagnosis: The acute phase begins with the diagnosis, involving a thorough clinical evaluation, imaging studies (such as MRI or CT scans), and often a biopsy to confirm the presence and type of endometrial carcinoma. 
• Surgery: For many cases, surgery is an immediate consideration, and a hysterectomy with bilateral salpingo-oophorectomy may be performed to remove uterus and surrounding structures. 
• Chemotherapy or Radiation: Neoadjuvant chemotherapy or radiation therapy may be administered before surgery and improve surgical outcomes, especially in cases of locally advanced disease. 
• Symptom Management: In cases where the disease is advanced or metastatic, palliative care aims at managing symptoms, improving quality of life, and providing psychosocial support. 

Chronic Phase: 

• Chemotherapy: After surgery, adjuvant therapies such as chemotherapy or radiation may be recommended based on the pathological findings to eliminate residual cancer cells & reduce the risk of recurrence. 
• Hormonal Therapy: It may be considered for tumors that express hormone receptors. Progestins, GnRH agonists, or aromatase inhibitors may be used to control the growth of cancer cells. 
• Physical Therapy: Rehabilitation programs may be recommended to address physical challenges, particularly for patients who have undergone surgery or radiation. 
• Psychosocial Support: Addressing emotional and psychosocial aspects of recovery is integral, including support for anxiety or depression that may accompany a cancer diagnosis. 
• Hormone Replacement Therapy (HRT): For women who experience menopausal symptoms after surgery, discussions about the potential use of hormone replacement therapy (HRT) are important. 

Medication

Future Trends

Media Gallary

References

Endometrial Cancer – StatPearls 

Endometrial Cancer Treatment (PDQ®)–Health Professional Version