*3.3. Pathophysiology of Endometrial Cancer*

Based on epidemiology, histopathology, prognosis, and treatment, EC can appear as type 1 (endometrioid), affecting approximately 80% of patients, and type 2 (nonendometrioid), affecting approximately 20% of patients [78,85,88]. Type 1 tumors develop from atypical glandular hyperplasia. This type is related to long-lasting unopposed estrogen stimulation and often preceded by endometrial hyperplasia [3,90]. The molecular basis of this process is not clear yet [3].

Carcinomas of type 1 are associated with significant incidences of *CTNNB1*, *KRAS*, and *POLE* oncogene mutations; phosphatase and tensin homolog (*PTEN*) tumor suppressor gene; defects in deoxyribonucleic acid (DNA) mismatch repair; and near-diploid karyotype (Table 2) [3,88,104]. From a molecular point of view, ECs resemble proliferative rather than secretory endometrium [3,78]. Specific tumor suppressor gene, *PTEN* that is expressed most highly in an estrogen-rich environment, could be responsible for the disease development. Progestogens affect *PTEN* expression and promote involution of *PTEN*-mutated endometrial cells in various histopathological settings [3,78]. This hypothesis can explain therapeutic effect of progestogens in EC cases.


**Table 2.** Molecular mechanisms of endometrial cancer development.

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Type 2 tumors include predominantly unspecified EC, clear-cell, carcinosarcoma and high-grade EC, and mixed (typically endometrioid and a high-grade non-endometrioid pattern) variants [103]. Type 2 tumors are associated with mutations in TP53 and *ERBB-2 (HER2/neu)* overexpression (Table 2) [3]. The features of endometrial serous carcinomas are the following: presence of *TP53* mutations, an overall low mutation rate, and frequent copy-number alterations [88].

For the majority of EC cases, sporadic mutations are responsible; however, approximately 5% of EC cases are caused by inherited genetic mutations. EC caused by genetic predispositions typically occur 10 to 20 years before sporadic EC [90]. The following syndromes are known to predispose to EC:


Currently, there is no approved effective screening program for EC. However, for patients with genetic syndromes, because of the significantly increased risk of the disease onset in reproductive age, the ACS recommends annual EC screening with endometrial biopsies starting at age 35 [85,90,105].
