Vaginal bleeding? Beware of endometrial cancer

Endometrial cancer (EC) is a common malignant tumor of the female reproductive system. It originates from the endometrial epithelium and is divided into estrogen-dependent (type I) and estrogen-independent (type II). Most type I endometrial cancers are moderately or highly differentiated endometrial adenocarcinomas, accounting for 65% of all endometrial cancers. They are sensitive to progesterone therapy and have a good prognosis, with a 5-year survival rate of more than 80% [1]. Type II endometrial cancers are mostly poorly differentiated tumors, including serous carcinomas and clear cell carcinomas. They are prone to deep myometrial invasion and lymph node metastasis, have a poor prognosis, and are not sensitive to progesterone therapy. The early symptoms of endometrial cancer are non-specific, mostly manifested as irregular vaginal bleeding and abnormal vaginal discharge. About 73% of endometrial cancer patients can be diagnosed in stage I, and the 5-year overall survival rate after surgery is 85% to 91% [2]. Therefore, early prevention, early detection, and early treatment are very important for the prognosis of endometrial cancer patients.

Risk factors for endometrial cancer

(1) Patients with reproductive endocrine disorders, such as anovulatory menstrual abnormalities, anovulatory infertility, polycystic ovary syndrome (PCOS), etc.

(2) Obesity, hypertension, and diabetes[4]: also known as the endometrial cancer triad. Studies have shown that for every 1 kg/m2 increase in body mass index (BMI), the relative risk of endometrial cancer increases by 9%. Compared with women with a BMI of less than 25 kg/m2, women with a BMI of 30-35 kg/m2 have a 1.6-fold increased risk of endometrial cancer, while women with a BMI of more than 35 kg/m2 have a 3.7-fold increased risk of endometrial cancer. Patients with diabetes or impaired glucose tolerance have a 2.8-fold increased risk of endometrial cancer compared to normal people. Patients with hypertension have a 1.8-fold increased risk of endometrial cancer compared to normal people.

(3) Those with early menarche, late menopause, or infertility.

(4) Patients with ovarian tumors.

(5) When single exogenous estrogen therapy is used for more than 5 years, the risk of endometrial cancer increases by 10 to 30 times, but the risk of endometrial cancer does not increase if estrogen-progestin combined replacement therapy is used.

(6) Genetic factors. About 20% of endometrial cancer patients have a family history. Women whose first-degree family members have endometrial cancer have an approximately 1.5-fold increased risk of developing endometrial cancer.

(7) In addition, lifestyle factors such as eating habits, exercise, drinking, and smoking may also be related to endometrial cancer.

Clinical manifestations of endometrial cancer

70% to 75% of endometrial cancer patients are postmenopausal women, 20% are perimenopausal women, and only 5% to 10% are under 40 years old [4]. The average age is about 55 years old. The symptoms that patients with endometrial cancer may experience are as follows:

(1) Vaginal bleeding. A small number of early-stage endometrial cancers may not have any symptoms and are difficult to detect clinically. However, the main symptom of 90% of endometrial cancers is various vaginal bleeding, such as postmenopausal vaginal bleeding in postmenopausal patients, and perimenopausal patients and patients under 40 years old may experience menstrual cycle disorders and continuous bleeding.

(2) Abnormal vaginal discharge.

(3) Pain in the lower abdomen, lower limbs, or lumbar region.

(4) In the late stage, symptoms of systemic failure such as anemia, weight loss, fever, and cachexia may appear.

Staging criteria for endometrial cancer

According to the "International Federation of Gynecology and Obstetrics (FIGO) 2018 Cancer Report: Guidelines for the Diagnosis and Treatment of Endometrial Cancer", the staging standards for endometrial cancer follow the surgical-pathological staging standards released by FIGO in 2009, as shown in the figure below.

Figure 1 International Federation of Gynecology and Obstetrics (FIGO 2009) surgical-pathological staging criteria for endometrial cancer

However, not all patients with endometrial cancer are suitable for the above staging standards, such as some young patients who wish to retain their fertility, patients with serious medical diseases and contraindications to surgery, and patients who need radiotherapy alone or preoperative radiotherapy due to cervical tumor involvement. The above patients use the clinical staging standards published by FIGO in 1971, as shown in the figure below.

Figure 2 Clinical staging of endometrial cancer (FIGO 1971)

In recent years, with the breakthrough progress in the fields of molecular biology and genomics, molecular targeted therapy has gradually become a new effective treatment strategy for malignant tumors. Based on 373 cases of endometrial cancer, the Cancer Genome Atlas (TCGA) project integrated the characteristics of tumor genome, transcriptome and proteome, and divided endometrial cancer into four molecular subtypes: (1) Polymerase ε (POLE) gene hypermutation type: accounting for 7% of endometrial cancer, all accompanied by mutations in the POLE exonuclease domain (POLE EDM). Patients with this type of tumor are younger, and most tumors are G1 grade. Almost all of them are endometrial adenocarcinomas. Serous carcinoma and clear cell carcinoma are extremely rare. Deep myometrial invasion and lymphovascular invasion rarely occur, and the prognosis is good. At the same time, the tumor cytotoxic T cell response is enhanced, suggesting that immune checkpoint inhibitor therapy may be effective for it. (2) Microsatellite instability (MSI) type: Microsatellites are also called "short tandem repeat sequences". MSI endometrial cancer accounts for 28% of all endometrial cancers. (3) Low copy number type: mainly including MSS type tumors, accounting for 39% of endometrial cancer, this type of tumor has a good response to hormone therapy. (4) High copy number type: accounting for 26% of endometrial cancer, this subtype includes serous carcinoma and 25% high-grade endometrioid carcinoma other than all the above subtypes. Patients of this type can refer to the treatment plan for serous carcinoma.

How to diagnose endometrial cancer

Histological diagnosis and cytological screening:

(1) Endometrial biopsy is a relatively direct, easy and efficient method for evaluating the pathological status of endometrial cancer, but it has disadvantages such as low accuracy and limitations.

(2) Diagnostic curettage. Diagnostic curettage is a classic procedure for the diagnosis and treatment of abnormal vaginal bleeding. It has the characteristics of segmented curettage and is objective in diagnosing endometrial cancer in terms of pathology. It is simple and easy to perform. However, it is a blind curettage operation and may miss smaller lesions located in the uterine horns. Curettage cannot determine myometrial invasion and staging. In addition, it is an invasive examination and causes great pain to the patient. Comprehensive considerations are required when choosing it.

(3) Intrauterine brush, intrauterine cell aspirator, uterine flushing and other methods can be used as important means of cytological screening, and the screening accuracy is relatively objective.

Hysteroscopic endometrial biopsy:

Hysteroscopic biopsy has the advantages of being intuitive and having a clear field of vision, and is of great value for some patients with early latent cancer. For example, it can be considered for perimenopausal patients with normal endometrial thickness on vaginal B-ultrasound, or with symptoms such as bleeding after a negative diagnostic curettage or biopsy.

Imaging diagnosis:

Transvaginal ultrasound can provide a preliminary understanding of uterine size, endometrial thickness, lesion distribution, and hemodynamics. It is inexpensive, noninvasive, and highly repeatable, and has become the preferred examination method for many gynecological diseases. However, transvaginal ultrasound is prone to miss diagnosis when the endometrial thickness is less than 5 mm, and it is first used to evaluate premenopausal endometrial lesions. Therefore, it is often combined with other examinations in clinical application.

Spiral CT/magnetic resonance imaging is widely used in the preoperative staging evaluation of EC. Although CT is relatively cheap, not affected by metal substances in the body, and can show the structural characteristics of the tumor, it is inferior to magnetic resonance imaging in terms of soft tissue resolution, and has low sensitivity and specificity in terms of the degree of cervical involvement and depth of myometrial invasion in EC. Magnetic resonance imaging examinations have no bone artifacts, and its multi-directional, multi-angle, and multi-plane imaging can provide a more accurate understanding of the diameter, nature, myometrial invasion, and lymph node metastasis of the tumor. It is widely used in the preoperative diagnosis, evaluation, treatment plan formulation, and follow-up review of EC. Based on the accuracy of magnetic resonance imaging in disease assessment, the American Society of Imaging recommends it as the preferred preoperative examination method.

In addition, serum tumor marker testing (serum cancer antigen 125, human epididymis protein 4, etc.) and genetic testing can be used to diagnose endometrial cancer.

Treatment principles for endometrial cancer

The treatment principle of endometrial cancer is mainly surgical treatment, supplemented by comprehensive treatment such as radiotherapy, chemotherapy and hormone therapy. The treatment plan should be formulated based on a comprehensive assessment of the pathological diagnosis and histological type, as well as the patient's age, general condition, fertility requirements, surgical contraindications, and medical complications.

The treatment is mainly total hysterectomy, bilateral adnexa plus lymph node resection, combined with brachytherapy, pelvic external radiotherapy or chemotherapy according to whether there are high-risk factors in the pathology report. For patients who meet the criteria (well-differentiated endometrioid adenocarcinoma, imaging shows that the lesions are limited to the endometrium, there is no suspected metastasis, and there are no contraindications to drug treatment and pregnancy) and who wish to retain their fertility, after consultation, the uterus can be removed after giving birth.

References:

[1] Qian Qiuhong, Song Kun. Research progress in endometrial cancer[J]. Chinese Journal of Medical Frontiers (Electronic Edition), 2020, 12(5): 1-6.

[2] Peng Duanlong, Huang Hao. Research on diagnosis and treatment of early endometrial cancer[J]. Medical Information, 2020, 33(1): 51-53.

[3] Bao Yuanyuan, Luo Ruoyu. Research progress in early screening and diagnosis of endometrial cancer[J]. Medical Review, 2020, 26(1): 76-85.

[4] National Health Commission of the People's Republic of China. Guidelines for the diagnosis and treatment of endometrial cancer (2018 edition)[J]. Electronic Journal of Comprehensive Oncology Treatment, 2020, 6(4): 25-35.

[5] Jin Mingzhu, Di Wen. Research progress on endometrial cancer classification[J]. International Journal of Obstetrics and Gynecology, 2020, 47(1): 15-18.