*3.1. Definition, Epidemiology and Classification*

Endometrial cancer is a malignant disease of the inner layer of the uterus (endometrium) [3,78]. It is one of the most common gynecological malignant tumors in developed countries [3,78–80]. In 2012, 527,600 women worldwide were diagnosed with EC, and the mortality rate was 1.7 to 2.4 per 100,000 women [81]. According to the American Cancer Society (ACS), in 2021, there will be an estimated 66,570 new cases of the uterine body cancer diagnosed in the United States and more than 12,940 deaths [82]. These calculations include both EC and uterine sarcomas. Up to 10% of uterine body cancers are sarcomas, so the actual numbers for EC cases and deaths are slightly lower than these estimates [82].

Nowadays, worldwide, EC is the seventh most common malignant disorder, but incidence varies among regions [3]. In less developed countries, risk factors are less common and EC is rare, although specific mortality is higher. Uterine corpus cancer is the 6th leading cause of cancer death among women in the United States and the 8th leading cause of cancer-related death amongst European women [83]. The incidence is ten times higher in North America and Europe than in less developed countries; in these regions, this cancer is the most common of the female genital organs and the 4th most common site after breast, lung, and colorectal cancers [3,83].

During the past two decades, the incidence and mortality rate for EC has increased by more than 100% [80,84,85]. Moreover, the incidence varies ~10-fold worldwide, with estimated age-standardized rates of 15 per 100,000 women and higher in 2018 in Europe and North America (developed countries) [84,85].

EC affects mainly post-menopausal women [86]. The average age of women diagnosed with EC is 60. It is uncommon in women under the age of 45 [82].

ECs are classified into various histological subtypes, including endometrioid EC, serous EC, clear-cell EC, mixed EC, and uterine carcinosarcoma (UCS), which differ in their frequency, clinical presentation, prognosis, and associated epidemiological risk factors [82,83].

Most EC are adenocarcinomas, and endometrioid cancer is the most common type of adenocarcinoma [82]. Endometrioid cancers arise from the glandular cells of the endometrium, and they look like the normal endometrium. There are many variants (or sub-types) of endometrioid cancers including adenocarcinoma (with squamous differentiation), adenoacanthoma, adenosquamous (or mixed cell), secretory carcinoma, ciliated carcinoma, and villoglandular adenocarcinoma [82].

Endometrioid ECs constitute more than 80% of newly diagnosed EC cases [83]. These cancers with its subtypes are generally estrogen-dependent and have a mean age at diagnosis of 62 years [83]. In contrast, serous ECs and clear-cell ECs are relatively uncommon, accounting for ~10% and 3% of newly diagnosed ECs, are generally estrogen-independent, and are diagnosed later in life (mean of 66.5 and 65.6 years, respectively) [82,83].

The prognosis for most newly diagnosed EC patients is good, with a relative 5-year survival rate of 81.1% (2008–2014) [83,87]. The generally high survival rate for EC is largely driven by the frequent early detection of endometrioid ECs, coupled with the effectiveness of surgery for treating many early-stage, low-grade EECs.
