Prof. Yusuf Yıldırım

CAUSES & RISK FACTORS

Endometrial cancer occurs when cells in the endometrium, the lining of the uterus, begin to grow out of control. Endometrial cancers are divided into different (histological) types depending on how the cells look under the microscope. Most endometrial cancers are adenocarcinomas. There are also several types of adenocarcinomas. These are: Endometrioid-type adenocarcinoma (EEC), Mucinous carcinoma (constitutes 1-2% of endometrial cancers and has a very good prognosis), Serous carcinoma (SC) (also called papillary-serous or serous-papillary carcinoma), Clear-Cell carcinoma (CCC), Undifferentiated adenocarcinoma, and Mixed type adenocarcinoma (if a second type accounts for more than 10% of the tumor). Uterine carcinosarcoma (UCS) begins in the endometrium and has features of both endometrial carcinoma and sarcoma (sarcoma is a type of non-epithelial cancer). UCS is also known as malignant mixed mesodermal/mullerian tumor (MMMT). It is accountable for about 3% of uterine cancers. There are other rare types of endometrial cancer.

Endometrial cancers are grouped as Type 1 and Type 2 based on clinical, histopathological and molecular features. Type 1 endometrial cancers are more common (85% vs 15%) and include grade 1 and 2 Endometrioid type carcinomas (and mucinous carcinoma). It is believed to be caused by excess estrogen (it is an estrogen-dependent tumor) and responds well to treatment with the anti-estrogen hormone “progesterone”. They develop from atypical hyperplasia (AH), which is an abnormal overgrowth of cells in the endometrium or from endometrial intraepithelial neoplasia (EIN). They usually have a nonspecific molecular profile (NSMP) or are associated with DNA mismatch repair genes disorder (dMMR) or POLE/PTEN/KRAS gene mutations. It typically presents with abnormal vaginal bleeding in the early stages. Type 1 cancers are usually not very aggressive and do not spread quickly to other tissues. Type 2 cancers include non-endometrioid endometrial cancer (NEEC) types such as serous carcinoma (SC), clear cell carcinoma (CCC), undifferentiated carcinoma and uterine carcinoma (UCS/MMMT) and grade 3 endometrioid type endometrial carcinoma. These cancers are called poorly differentiated or high grade. They do not appear to be as a result of excess estrogen and often arise from an atrophic endometrial background. Common genetic/molecular changes are p53 mutation, Her2 over expression and loss of E-cadherin. Generally, hormone receptors (ER/PR) in tumor cells are negative. Type 2 cancers are more likely to grow and spread outside the uterus and have a worse prognosis. Thus, there is a tendency to treat these cancers more aggressively. Current molecular classification of endometrial cancer is as follows:

• POLE mutant: It accounts for 7% of cases. It has a good prognosis.
• P53 abn: It constitutes 25% of the cases. It has a poor prognosis.
• MMRd/MSI-H: It constitutes 28% of the cases. It has an intermediate prognosis.
• NSMP (Non-specific molecular profile): 40% of cases. Moderate prognosis.

Endometrial cancer is the most common gynecological cancer in developed countries and the second most common gynecological cancer in developing countries. It mainly affects postmenopausal women, and the average age of women diagnosed is 62. Only 5% of cases are under the age of 45. According to the latest data, the lifetime risk of developing endometrial cancer in a woman is around 2.8%.

Hormonal and genetic factors play a major role in the development of endometrial cancer. Most of the known endometrial cancer risk factors affect the balance between estrogen and progesterone in the body. The main risk factor for type 1 endometrial cancers is endogenous (e.g., obesity, polycystic ovarian syndrome, hormone-secreting ovarian cyst or tumor) or exogenous (e.g., postmenopausal hormone therapy) “prolonged exposure to excessive estrogen” unbalanced by the progesterone hormone. There are other risk factors, including genetic factors. List of the risk factors for type 1 cancers are;

• Advanced age
• Unopposed estrogen therapy
• Tamoxifen use:
• High total number of menstrual cycles: Early menarche and late menopause) are associated with increased risk.
• Not giving birth & not breastfeeding
• Estrogen-producing tumor
• History of endometrial hyperplasia
• Polycystic ovary syndrome (PCOS)
• Obesity
• Diabetes
• High-fat diet and reduced physical activity
• Hypertension
• Family history and hereditary cancer syndromes: The relative risk of having endometrial cancer in the family without any hereditary cancer syndrome is approximately 1.8. In the case of hereditary cancer syndrome, the risk is much higher. Hereditary cancers are responsible for approximately 5% of endometrial cancers.
• Being North American, Western European or Caucasian
• High socioeconomic/educational level
• History of breast and ovarian cancer
• Pelvic radiotherapy history

The risk factors for Type 2 cancers may be different from Type 1 cancers.

SYMPTOMS, DIAGNOSIS & STAGES

75-90% of patients with endometrial cancer are symptomatic. Endometrial cancer often presents with abnormal vaginal bleeding. there may be additional or other abdominal or extra-abdominal symptoms depending on the extent (stage) of the disease. Among these, the most frequently reported ones are;

• Difficulty urinating
• Pain while urinating (painful urination)
• Pain during sexual intercourse
• Pelvic pain and pressure/mass sensation (usually in advanced stages of the disease)
• Unexplained weight loss (usually in advanced stages of the disease).

Diagnostic (and disease assessment) methods for endometrial cancer include:

• Physical examination
• Ultrasound (pelvic or vaginal)
• Sonohysterography (ultrasound by injecting fluid into the uterus)
• Cervical cytology (pap-test)
• Hysteroscopy   
• Biopsy — The definitive diagnosis is made by histopathological examination of the tissue obtained by biopsy.
• Advanced imaging methods 
• Cystoscopy and proctoscopy 
• Blood tests (tumor markers) 

The TNM staging system recommended by AJCC (American Joint Committee on Cancer) and FIGO (the International Federation of Gynecology & Obstetrics) is used in the staging of endometrial cancer (T-the size of the primary tumor and its relationship with neighboring structures and organs; N-whether there is spread to lymph nodes; M-distant metastasis). Although a “clinical stage” (cTNM) estimation can be made on the basis of preoperative clinical and radiological findings, staging in endometrial cancer is mainly based on surgical data (and pathological data obtained as a result of this surgery). In other words, in cases where there is no obvious distant metastasis, the actual stage is determined by surgery. The current (FIGO 2021) “pathological stages” (pTNM) of endometrial cancer are as follows:

• Stage I – Tumor confined to the corpus uteri (T1-N0-M0). This stage has two substages: Stage IA, Stage IB
• Stage II – Tumor invades cervical stroma, but does not extend beyond the uterus (T2-N0-M0)
• Stage III – Local and/or regional spread of the tumor (T3-N0/1-M0). This stage has three substages: Stage IIIA, Stage IIIB, Stage IIIC (IIIC1/IIIC2)
• Stage IV – Tumor invades bladder and/or bowel mucosa, and/or distant metastases. This stage has two substages: Stage IVA, Stage IVB (distant metastasis)

TREATMENT & PROGNOSIS

The most important factor in the choice of treatment for endometrial cancer is the stage of the disease. However, other factors such as the type of cancer (histological and molecular type), age, general health and whether there is a desire for fertility can also affect treatment options.

Traditionally, various “prognostic risk groups” have been identified that are used to guide treatment in endometrial cancer. In January 2021 the European Society of Gynecological Oncology (ESGO), the European Society for Radiotherapy and Oncology (ESTRO) and the European Society of Pathology (ESP) published an updated guideline for risk group determination in endometrial cancer, integrating both molecular diagnostics and clinicopathologic variables, with the goal of improving treatment outcomes. According to the ESGO/ESTRO/ESP guide, the risk groups are as follows:

• Low risk group: Stage IA “MMRd/NSMP” EEC grade 1/2 without substantial LVSI (LVSI negative or focal) -or- Stage I–II “POLEmut” endometrial carcinoma
• Intermediate risk group: Stage IB “MMRd/NSMP” EEC grade 1/2 without substantial LVSI -or- Stage IA “MMRd/NSMP” EEC grade 3 without substantial LVSI -or- Stage IA NEEC without myometrial invasion -or- Stage IA “p53abn” without myometrial invasion
• High–intermediate risk group: Stage I “MMRd/NSMP” EEC with substantial LVSI regardless of grade and substage (depth of invasion) -or- Stage IB “MMRd/NSMP” EEC grade 3 regardless of LVSI status -or- Stage II “MMRd/NSMP” EEC
• High risk group: Stage III–IVA “MMRd/NSMP” EEC with no residual disease (optimally debulked) -or- Stage I–IVA “p53abn” endometrial carcinoma with myometrial invasion, and with no residual disease -or- Stage I–IVA “NSMP/MMRd” NEEC with myometrial invasion, and with no residual disease
• Advanced/Metastatic disease: Stage III-IVA with residual disease of any molecular type -or- Stage IVB regardless molecular type (Abbreviations: EEC: endometrioid endometrial cancer; LVSI: lymph-vascular space invasion; NEEC: non-endometrioid endometrial cancer).

Treatment in Early (Stage I-II) Endometrial Cancer

Surgery is the first treatment for almost all women with early-stage endometrial cancer and is simply called surgical staging (or staging surgery). This operation includes removal of the uterus, fallopian tubes and ovaries (total hysterectomy + bilateral salpingo-oophorectomy-TH/BSO), removal of the pelvic and aortic lymph nodes (pelvic and para-aortic lymph node dissection) and removal of the omentum. Peritoneal washing is done, and a sample is taken for cytological examination. There are those who advocate that the hysterectomy stage of surgery in stage II disease is Radical Hysterectomy (Type 3 Hysterectomy) however, this view is not accepted by all professionals. Others recommend standard hysterectomy (Type 1 Hysterectomy) followed by neoadjuvant radiation therapy. There is also controversy regarding the lymphadenectomy part of surgery. In order to avoid the risks associated with lymphadenectomy, some circles tend not to perform lymphadenectomy in clinical Stage IA cases, provided they have low grade endometrioid histology. Others prefer lymph node sampling over systematic lymphadenectomy. Finally, preserving the ovaries in young (<45 years) patients to avoid premature menopause is also a topic that has been frequently discussed recently. In clinical Stage IA disease, the ovaries can be left in place (with the consent of the patient), provided there is no evidence/suspect of ovarian and extrauterine disease and low grade (grade 1/2) endometrioid histology. Salpingectomy is recommended when the ovaries are spared. Ovary preservation is not recommended in patients with a strong family history of ovarian cancer or hereditary cancer syndrome (e.g., BRCA mutation, Lynch Syndrome).

Surgically removed tissue is tested to see how far the cancer has spread (stage) and to understand its molecular characteristics (type). Thus, the prognostic risk group of the disease is determined. The decision for adjuvant (post-operative/additional) treatment for early-stage endometrial cancer depends on which risk group the patient belongs to. In addition, lower uterine segment involvement, tumor diameter, patient age and positive peritoneal cytology are parameters that can be considered when deciding on adjuvant therapy. According to this:

• Low risk group patients: They are usually only followed up without additional (adjuvant) treatment (Patients in this group have a recurrence risk of less than 5% after staging surgery).
• Intermediate risk group patients: This group of patients has a slightly higher risk of locoregional (regional) recurrence compared to the patients in the low-risk group thus there is a tendency to give adjuvant radiotherapy (RT). RT is given as vaginal brachytherapy (VBT).
• High-intermediate risk group patients: Adjuvant VBT is given to achieve optimal local control. External pelvic radiotherapy (EBRT) is also given to patients who have not been surgically staged (understaging). Chemotherapy is considered for high grade (grade 3) and LVSI positive cases.
• High risk group patients: This group of patients has a significantly higher risk of recurrence and loss from disease and therefore almost all patients receive EBRT+chemotherapy (concurrent or sequential) or alternatively only chemotherapy after surgery. In chemotherapy, “paclitaxel+carboplatin” combination is mostly favored and given as 6 cycles.

The approach to patients who are surgically understaged (e.g., endometrial cancer was found incidentally in the pathological examination after TH-BSO was performed for other reasons) is also made according to risk groups. Low risk group patients are only followed up. “Pelvic radiotherapy (EBRT)” is generally the treatment of choice for the intermediate risk group patients. “Re-staging surgery” is applied to high-intermediate or high-risk patients.

The person with early-stage disease may, in some cases, be too old, frail or co-morbid (medically inoperable) to be able to have surgery safely. In this case, the patient is treated with RT (EBRT + VBT).

Fertility Preserving Approach

For young women with stage IA grade 1 endometrioid cancer who wish to have children, progestin therapy may be used to treat the cancer and delay surgery. Progestin therapy can cause the cancer to shrink or even disappear for a while, giving a woman a chance to become pregnant. In a previous multicenter study, we achieved approximately 81% response rate and 42% pregnancy rate with fertility-sparing treatment (Reference: A Turkish Gynecologic Oncology Group study of fertility-sparing treatment for early-stage endometrial cancer. Int J Gynaecol Obstet 2012; 119 :270-3). However, this form of treatment is experimental and can be risky if the patient is not closely monitored. It is crucial to inform the patient that the fertility-preserving approach is not a standard treatment and may increase the risk of cancer growth and spread. If it does not clear up within 6-9 months, surgery (TH-BSO) is recommended to remove and stage the cancer.

Treatment in Locally Advanced (Stage III-IVA) Endometrial Cancer

The treatment approach for tumors at this stage depends on whether the tumor is surgically removable (resectable) and the patient's surgical condition:

• In patients whose disease appears resectable: Surgery (surgical staging or cytoreductive surgery) + Adjuvant Chemotherapy+/-VBT (depending on residual disease status) is considered. EBRT is preferred as radiotherapy in patients who cannot receive chemotherapy for any reason. After the GOG-258 study revealed no difference between postoperative only RT+CT and CT in terms of recurrence of the disease (relapse-free survival) in Stage III or IVA cases, a tendency for adjuvant chemotherapy rather than adjuvate RT emerged. In patients whose condition is not suitable for primary surgery, interval cytoreductive surgery can be applied after neoadjuvant chemotherapy. Rarely, pelvic exenteration may be the appropriate surgical approach.
• In patients whose disease is not resectable: Neoadjuvant RT + Surgery + Adjuvant Chemotherapy
• In patients who are in very poor surgical condition (medically inoperable): In some cases, the person may be too old, debilitated or with co-morbid to have surgery safely. These women are treated with Radiation therapy (EBRT+VBT).

For some people, targeted (smart) drug therapy and/or immunotherapy with or without chemotherapy could be appropriate.

Treatment in Metastatic (Stage IVB) Endometrial Cancer

Here the treatment aim is not cure but palliation. The type of treatment depends on resectablity of the tumor, histology, previous treatment and the molecular characteristics of the tumor (e.g., MMR defectivity status, tumor mutational burden and Her2 and hormone receptor status).

Resection of isolated pulmonary or liver metastases can be considered. In the case of peritoneal disease, cytoreductive surgery (SRC) can be applied to reduce the tumor burden and increase the effectiveness of systemic therapy in cases whose tumor appears to be resectable and it has been shown to have survival benefits in selected cases. RT may be beneficial in bone and brain metastases.

Platinum-based combination chemotherapy (paclitaxel+carboplatin) is often used. However, in patients who wish to avoid the toxicity of combination chemotherapy, hormone therapy (or single-agent chemotherapy) may be an important alternative. Hormonotherapy is particularly effective in asymptomatic or minimally symptomatic patients with grade 1/2 endometrioid histology, positive hormone receptors (ER/PR+). Megestrol acetate (alternating with Tamoxifen) is commonly used as hormone therapy. Chemotherapy can be used in cases that do not respond to hormone therapy or whose disease progresses while under hormone therapy. Since the aim of the treatment is palliation, a single-agent (e.g., doxorubicin or paclitaxel) chemotherapy protocol is a reasonable option instead of combination chemotherapy. Treatment should be individualized according to the clinical situation and patient preference.

Trastuzumab (Herceptin®) can be added to chemotherapy in patients with human epidermal growth factor receptor 2 (Her2) positive serous papillary tumors.

In “Mismatch repair-deficient (MMRd)” or “microsatellite-instable (MSI-H)” tumors or in tumors with high Tumor Mutation Burden (TMB-H), if there is progression despite chemotherapy, the immunotherapy agent Pembrolizumab (Keytruda®) can be utilized instead of further chemotherapy or hormone therapy.

Treatment in Recurrent Endometrial Cancer

The treatment approach in distant recurrences is similar to the treatment of metastatic (Stage IVB) disease and the results are not very good. Platinum-based chemotherapy (paclitaxel+carboplatin) is again chosen over endocrine therapy as a systemic treatment in chemotherapy-sensitive (platinum sensitive: at least 6 months since the last platinum administration) distant recurrences (whether surgical cytoreduction is performed or not). However, in patients who wish to avoid the toxicity of combination chemotherapy, hormone therapy (or single-agent chemotherapy) may be an important alternative. Trastuzumab (Herceptin®) can be added to chemotherapy in patients with human epidermal growth factor receptor 2 (Her2) positive serous papillary tumors. In “mismatch repair-deficient (MMRd)” or “microsatellite-instable (MSI-H)” tumors, or in tumors with high tumor mutation burden (TMB-H), if there is progression despite chemotherapy, the immunotherapy agent Pembrolizumab (Keytruda®) can be tried. It may also be an option to include these patients in clinical trials testing new drugs.

In regional (locoregional: i.e., vaginal and pelvic) recurrences, good results can be obtained with aggressive regional treatment approaches. The approach varies depending on what treatment the patient has previously received:

• Many clinicians prefer RT rather than surgery in the treatment of regional recurrences of patients who have not received RT before. Surgery is a logical alternative for patients who do not want RT or for whom RT is not suitable.
• In patients who have received RT before surgical resection is preferred if possible. For vaginal recurrence, this is a radical operation called pelvic exenteration. Following this surgery, adjuvant (chemo- or hormone-) therapy is preferred instead of just monitoring in high-risk patients (pelvic recurrence, incomplete resection, LVSI positive, grade 3 tumor, not isolated vaginal recurrence).
• In patients with regional recurrence who are not candidates for surgical resection or RT, medical treatments (chemotherapy or hormone therapy) are given, as in primary (initial diagnosis) metastatic disease or distant site recurrence.

Treatment Success & Prognosis (outlook)

Factors affecting treatment success and prognosis are as follows:

• Stage – Stage is one of the three most important prognostic factors (the other two are histologic type and grade).
• Histological type and grade 
• Lymphovascular space invasion (LVSI) 
• Condition of the non-neoplastic endometrium 
• Lower uterine segment involvement 
• Peritoneal cytology: The prognostic significance of isolated positive peritoneal cytology in cases without signs of extrauterine spread is controversial.
• Age 
• Race 
• Molecular prognostic factors – Numerous molecular factors are being used more and more in addition to clinicopathologic factors. The most commonly used are: POLE (Polymerase Epsilon) gene mutation (POLE mutant tumors have good prognosis), MSI-H/MMRd (moderate prognosis), TP53 mutation (p53abn) (poor prognosis), CTNNB1 mutations (poor prognosis), mutations in other tumor suppressor genes (PTEN, KRAS) (poor prognosis), hormone receptors (ER/PR) expression (good prognosis), overexpression of Her2 (human epidermal growth factor receptor 2) (poor prognosis), and high Ki 67 proliferation index (poor prognosis).

You can visit our current website “oncosurgery.com.tr” for further information about endometrial cancer and its surgery.