Identical TP53 mutations have been found in foci of benign-appearing endometrium (“p53 signatures”), endometrial glandular dysplasia (EmGD) and associated serous endometrial intraepithelial carcinoma (EIC) and invasive ESC, giving credence to a concept of endometrial serous carcinogenesis with accumulation of TP53 mutations recognized first as p53 signatures, progressing to EmGD, to EIC, and ultimately to ESC. In postmenopausal women on exogenous hormone replacement therapy, ESC may be diagnosed in a background of the proliferative endometrium and rarely even in the hyperplastic endometrium. In contrast to low-grade endometrioid carcinomas, ESC typically arises in atrophic, resting, or weakly proliferative endometrium. Mutations in TP53 with loss of heterozygosity, identified by DNA sequencing and/or aberrant immunohistochemical (IHC) expression of p53, are present in some 90% or more of endometrial serous carcinomas (ESC). While the aggressive nature of these major high-grade endometrial cancer histotypes is similar, the prevailing evidence indicates that at least early carcinogenesis differs. Whether confined or spread beyond the uterine corpus when diagnosed, clear cell carcinomas have been associated with higher 5-year survival rates than serous carcinomas however, together, type 2 endometrial serous and clear cell carcinomas are associated with significantly poorer survival rates than high-grade endometrioid carcinoma. High-grade serous and clear cell carcinomas overall have been associated with significantly poorer 5-year survival rates than high-grade endometrioid carcinomas. The most prevalent non-endometrioid, type 2 endometrial cancers are high-grade, serous, undifferentiated, and clear cell carcinomas. Aggressively malignant high-grade endometrioid carcinomas with such poor prognosis are more akin to type 2, high-grade non-endometrioid histotypes than they are to low-grade endometrioid carcinomas. Using binary grading, endometrioid carcinomas classified as high grade on the basis of 2 or more architectural features, which included greater than 50% solid growth pattern without distinction between squamous or non-squamous differentiation, diffuse infiltrative growth and/or tumor necrosis, were associated with only 46% 5-year survival rates compared to 93% 5-year survival rates in patients with low grade endometrioid carcinomas. Low-grade endometrioid carcinomas with more than 50% myometrium invasion and high-grade endometrial cancer have much poorer prognoses with higher proportions of lymph node metastases and post-treatment recurrences. Type 1, low-grade endometrial endometrioid carcinomas with less than 50% myometrium invasion have favorable prognosis approaching 100% 5-year survival rates. This system classifies endometrioid carcinomas with less than 50% solid component and absence of marked nuclear atypia as low-grade, and those with greater than 50% solid component and/or marked nuclear atypia are graded as high-grade carcinomas with either endometrioid, serous, clear cell or undifferentiated histology. Grade 3: Greater than 50% solid non-squamous growth pattern, upgrading by 1 grade when there is notable nuclear atypia Grade 2: Six percent to 50% solid non-squamous growth pattern Grade 1: Less than or equal to 5% solid non-squamous growth pattern International Federation of Gynecology and Obstetrics (FIGO) 3-Grade Assessment of the Glandular Component Most endometrial endometrioid carcinomas are lower grade cancers. Other suspect etiologic factors, including insulin resistance and hyperandrogenemia, are being investigated, but these endometrial carcinogenic mechanisms have not be worked out. Given the hormonal etiology, EIN and endometrial endometrioid carcinomas usually express estrogen and progesterone receptors (ER and PR). Arising in this milieu, histologically recognizable atypical premalignant lesions, defined as endometrial intraepithelial neoplasia (EIN), may transform to endometrioid carcinoma, characterized by stromal and/or myometrial invasion, PTEN mutations, and often KRAS2 mutations, microsatellite instability caused by mismatch repair (MMR) defects, and near-diploid karyotype. Present consensus holds that pathogenesis of most endometrial endometrioid carcinomas begins with uninterrupted endometrial proliferation, hormonally stimulated by endogenous or exogenous estrogen unopposed by progesterone or progestins, progressing through states of simple to complex forms of endometrial hyperplasia (EH).
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