High-grade Endometrial Carcinomas: Morphologic and Immunohistochemical Features, Diagnostic Challenges and Recommendations

Abstract

This review of challenging diagnostic issues concerning high-grade endometrial carcinomas is derived from the authors' review of the literature followed by discussions at the Endometrial Cancer Workshop sponsored by the International Society of Gynecological Pathologists in 2016. Recommendations presented are evidence-based, insofar as this is possible, given that the levels of evidence are weak or moderate due to small sample sizes and non-uniform diagnostic criteria used in many studies. High grade endometrioid carcinomas include FIGO grade 3 endometrioid carcinomas, serous carcinomas, clear cell carcinomas, undifferentiated carcinomas and carcinosarcomas. FIGO grade 3 endometrioid carcinoma is diagnosed when an endometrioid carcinoma exhibits more than 50% solid architecture (excluding squamous areas), or when an architecturally FIGO grade 2 endometrioid carcinoma exhibits marked cytologic atypia, provided that a glandular variant of serous carcinoma has been excluded. The most useful immunohistochemical studies to make the distinction between these two histotypes are p53, p16, DNA mismatch repair proteins, PTEN and ARID1A. Endometrial clear cell carcinomas must display prototypical architectural and cytologic features for diagnosis. Immunohistochemical stains, including, Napsin A and p504s can be used as ancillary diagnostic tools; p53 expression is aberrant in a minority of clear cell carcinomas. Of note, clear cells are found in all types of high-grade endometrial carcinomas, leading to a tendency to overdiagnose clear cell carcinoma. Undifferentiated carcinoma (which when associated with a component of low-grade endometrioid carcinoma is termed ‘dedifferentiated carcinoma’) is composed of sheets of monotonous, typically dyscohesive cells, which can have a rhabdoid appearance; they often exhibit limited expression of cytokeratins and epithelial membrane antigen, are usually negative for PAX8 and hormone receptors, lack membranous e-cadherin and commonly demonstrate loss of expression of DNA mismatch repair proteins and SWI-SNF chromatin remodeling proteins. Carcinosarcomas must show unequivocal morphologic evidence of malignant epithelial and mesenchymal differentiation.

Unique Molecular Features in High-Risk Histology Endometrial Cancers

“…Table 1 highlights the general clinical features of low- and high-risk histologic endometrial carcinomas. First, high-risk histologic carcinomas are high-grade carcinomas [12]. High tumor grade is the most significant risk factor for subsequent death and disease recurrence [13,14].…”

KAT6A amplifications are associated with shorter progression-free survival and overall survival in patients with endometrial serous carcinoma

“…As a matter of fact, ESC overlap with the "copy number (CN) high group" at the molecular level to such an extent; in the current molecular classification of EC the CN-high group is also known "serous-like" carcinoma [6]. ESC is one of the high-grade EC with a worse clinical outcome compared to low-grade (type 1) EC [7].…”

Endometrial Histology and Safety on Non-Oral Routes of Hormone Therapy for Perimenopausal/Early Menopausal Women: Transdermal Estrogens and Vaginal Micronized Progesterone

“…There are many pathologists involved in endometrial assessment on/after MHT in Europe, USA, Canada, South Africa. Table 4 presents an adaption of endometrial changes on MHT according to International Society of Gynecological Pathologists (2019) [112,113], WHO (2014) cited by [123], British Society for Gynecological Endoscopy (2014) [120], FIGO (2009, 2012) cited by [119]. Deligdish [104], Feeley and Wells [94] present very understandable the endometrial effects of MHT, including a wide spectrum of morphologic features, known since long time on oral MHT, and less on non-oral routes, which are.…”

“…According to the molecular mechanisms, to the dualistic model of endometrial cancer development, first time described by Bokhman [111], the last classification at the Endometrial Cancer Workshop sponsored by the International Society of Gynecological Pathologists in 2016 [112], and the most recent discussion of the International Society of Gynecological Pathologists in 2019 [113] describes low grade and high grade endometrial cancers, both types being discussed to have MHT in perimenopause and late postmenopausal stages of women's life.…”