[99] During the serial histogenetic pathway in this model, in addition to p53 mutation, IMP3 overexpression and loss of ER/PgR expression, p16 overexpression and HER2

amplification are likely involved. Endometrial glandular dysplasia is considered to be a morphologically and biologically distinctive putative precursor lesion of CCA as well as SEA.[74] Serous EIC has been newly added in the tumors of the uterine AZD8055 corpus in the WHO 2014 classification.[100] A question about whether G3 EMA should be regarded as type I or II is not only a controversial pathological issue but is of clinical significance.[12,

21] Some G3 EMA can be consistently categorized as type I, while others can be categorized as type II, based on the variable clinicopathologic Epacadostat datasheet parameters, such as age, tumor size, myometrial invasion, lymphovascular space invasion, lymph node metastasis, extranodal metastasis, and immunohistochemical expressions of ER, PgR, p53 and Ki-67.[12] Comprehensively, on average, G3 EMA may be identical to an intermediate lesion between types I and II. In practice, however, a considerable portion of G3 EMA should be treated as type II, namely, high-grade endometrial carcinoma. G3 EMA has two tumorigenic pathways: (i) continuous development from G1/2 EMA preceded/accompanied by endometrial

hyperplasia; and (ii) de novo cancer arising in the atrophic endometrial background L-gulonolactone oxidase in association with mutations in p53 and HER-2 and expression decrease in E-cadherin.[4, 101-105] As differential diagnoses for G3 EMA, undifferentiated carcinoma and dedifferentiated carcinoma should be raised from the significant viewpoint of the difference in the prognosis.[106] Carcinosarcoma/malignant mixed Müllerian tumor remains an occasionally confusing diagnostic consideration for G3 EMA because the minimum amount of a high-grade mesenchymal component necessary for diagnostic confirmation of carcinosarcoma/malignant mixed Müllerian tumor has not been established.[84] Therefore, some of the G3 EMA may contain undifferentiated carcinoma, dedifferentiated carcinoma and carcinosarcoma/malignant mixed Müllerian tumor. To improve the diagnostic validations for G3 EMA with a decrease in the interobserver difference, they may need to be re-subclassified with the setting of a more detailed definition.