[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 high throughput screening compounds 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 ATM/ATR mutation 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 Inositol oxygenase 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.