- Endometrial cancer is the most common gynecologic malignancy in developed countries and primarily arises from the lining of the uterus (the endometrium).
- It most often affects women after menopause, though it can also occur in younger women, particularly those with risk factors such as obesity, unopposed estrogen exposure, or hereditary cancer syndromes. Clinically, it most frequently presents with abnormal uterine bleeding, which allows for relatively early detection compared to other gynecologic cancers. Despite this, endometrial cancer remains a significant cause of morbidity and mortality, especially in advanced stages or aggressive histologic subtypes.
- At the molecular and pathological level, endometrial cancer is broadly divided into two major types, reflecting distinct pathogenetic pathways. Type I endometrial cancer, the more common form, is often estrogen-dependent and associated with endometrial hyperplasia. It typically arises in the setting of chronic unopposed estrogen stimulation, such as in obesity, polycystic ovary syndrome (PCOS), nulliparity, early menarche, late menopause, and estrogen therapy without progesterone. These tumors are usually endometrioid adenocarcinomas, well to moderately differentiated, and carry a relatively favorable prognosis. Molecularly, they are associated with mutations in PTEN, KRAS, PIK3CA, and ARID1A, as well as microsatellite instability (MSI).
- In contrast, Type II endometrial cancer is not related to estrogen stimulation and arises in an atrophic endometrium, usually in older women. It includes aggressive histologies such as serous carcinoma, clear cell carcinoma, and carcinosarcoma. These tumors are typically poorly differentiated, exhibit early spread, and are associated with a poor prognosis. Molecularly, Type II cancers are characterized by TP53 mutations, HER2 amplification, and chromosomal instability. They behave more aggressively and account for a disproportionate share of endometrial cancer deaths, despite being less common overall.
- The genomic classification of endometrial cancer, based on The Cancer Genome Atlas (TCGA), has refined this dualistic model into four molecular subgroups: (1) POLE ultramutated tumors, which have an excellent prognosis despite high mutation rates; (2) MSI-high tumors, caused by mismatch repair deficiency, often associated with Lynch syndrome; (3) copy-number low tumors (mostly low-grade endometrioid cancers); and (4) copy-number high tumors, corresponding to serous-like cancers with poor outcomes. This molecular stratification is increasingly used to guide prognosis and therapy.
- Clinically, the hallmark symptom is abnormal uterine bleeding, particularly postmenopausal bleeding, which warrants evaluation. Other symptoms may include pelvic pain, weight loss, or abnormal vaginal discharge in more advanced cases. Diagnosis is established through endometrial sampling or biopsy, often followed by imaging (transvaginal ultrasound, MRI, or CT) to assess spread and staging. Staging is surgical and determined by the FIGO system, which considers depth of myometrial invasion, cervical involvement, lymph node spread, and distant metastasis.
- Treatment of endometrial cancer depends on stage, histology, and molecular subtype. For most patients with early-stage disease, the mainstay of treatment is surgery: total hysterectomy with bilateral salpingo-oophorectomy, often with lymph node assessment. High-risk or advanced cases may require adjuvant therapy, including radiation, chemotherapy (commonly carboplatin and paclitaxel), or both. Hormonal therapy with progestins or agents targeting estrogen signaling may be used in selected patients, especially those with Type I tumors or those desiring fertility preservation. In recent years, immunotherapy has emerged as a major advance, particularly for tumors with mismatch repair deficiency (dMMR) or MSI-high status, which respond well to immune checkpoint inhibitors such as pembrolizumab or dostarlimab.
- Risk factors for endometrial cancer align closely with hormonal and metabolic influences. Obesity is the single strongest modifiable risk factor, as excess adipose tissue increases peripheral conversion of androgens to estrogens. Other risk factors include diabetes, hypertension, tamoxifen use, and Lynch syndrome. Conversely, protective factors include combined oral contraceptive use, multiparity, and physical activity. Genetic counseling and prophylactic hysterectomy are often considered in women with Lynch syndrome to prevent endometrial and ovarian cancers.
- In summary, endometrial cancer is a hormonally influenced and genetically heterogeneous malignancy with two broad clinicopathological types and more refined molecular subgroups. While most cases are detected early due to abnormal bleeding and have good outcomes with surgery, aggressive subtypes remain challenging and account for significant mortality. Advances in molecular classification, targeted therapies, and immunotherapy are transforming the management of this disease, moving toward a more personalized approach to care.
