Original ArticlesAtypical Endometrial Hyperplasia, Low-grade “Much ADO About Nothing”D’Angelo, Emanuela MD, PhD*,†; Espinosa, Iñigo MD, PhD‡; Cipriani, Valentina PhD§,∥,¶,#; Szafranska, Justyna MD**; Barbareschi, Mattia MD††; Prat, Jaime MD, PhD, FRCPath**Author Information *Department of Medical, Oral and Biotechnological Sciences, University “G. d’Annunzio” †Laboratory of Diagnostic Molecular Oncology, Center for Advanced Studies and Technology (CAST), Chieti-Pescara ††Department of Pathology, Hospital Santa Chiara, Trento, Italy ‡Department of Pathology, Clínica Universidad de Navarra, Madrid **Department of Pathology, Hospital de la Santa Creu i Sant Pau, Institute of Biomedical Research (IIB Sant Pau), Autonomous University of Barcelona, Barcelona, Spain §William Harvey Research Institute, Queen Mary University of London ∥UCL Institute of Ophthalmology #UCL Genetics Institute, University College London ¶Moorfields Eye Hospital NHS Foundation Trust, London, London, UK Conflicts of Interest and Source of Funding: Supported by Grants FIS PI16-00902 and RTICC RD06/0020/0015, Department of Health, Spain, Fundación de la Asociación Española Contra el Cáncer (AECC), Grupos Estables. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Emanuela D’Angelo, MD, PhD, Department of Medical, Oral and Biotechnological Sciences, University “G. d’Annunzio,” Chieti-Pescara, Italy, Via dei Vestini, 31, Chieti 66100, Italy (e-mail: [email protected]). The American Journal of Surgical Pathology: July 2021 - Volume 45 - Issue 7 - p 988-996 doi: 10.1097/PAS.0000000000001705 Buy Metrics Abstract Atypical endometrial hyperplasia (AEH) is considered a precursor of endometrioid carcinoma. The 2020 World Health Organization (WHO) classification divides endometrial hyperplasia into 2 categories: hyperplasia without atypia and atypical hyperplasia/endometrioid intraepithelial neoplasia (EIN); however, this classification does not consider the degree of nuclear atypia. We graded nuclear atypia for estimating the risk of finding carcinoma at hysterectomy. Also, we investigated genes involved in endometrial carcinogenesis including mismatch repair (MMR) genes and ARID1A, PIK3CA, PTEN, KRAS, and CTNNB1. We reviewed 79 biopsies of AEH from 79 patients who underwent hysterectomy within a 1-year interval. Intraobserver and interobserver agreement of grading nuclear atypia and the relationship between the grade of nuclear atypia at biopsy and the findings at hysterectomy were evaluated. Immunohistochemistry for MMR status was performed in all cases and targeted sequencing in 11. Using low-grade versus high-grade nuclear atypia, κ values ranged from 0.74 to 0.91 (89% to 96%) and from 0.72 to 0.81 (87% to 91%) for the intraobserver and the interobserver agreement, respectively. The degree of nuclear atypia at biopsy was highly predictive of the findings at hysterectomy (P=1.6×10−15). Of 53 patients with low-grade AEH, none had carcinoma at hysterectomy, whereas 6 (6/26; 23%) with high-grade AEH in the biopsy also had high-grade AEH in the uterus and 16 (16/26; 61%) had FIGO grade 1 carcinoma. MMR deficiency was found in 3 of the 79 patients. None of the genes showed a mutational load significantly associated with the degree of nuclear atypia. In summary, our data show high reproducibility within and between observers for the diagnosis of low-grade and high-grade AEH. Most cases of AEH had low-grade nuclear atypia and neither high-grade AEH nor carcinoma was encountered in the corresponding hysterectomy specimens. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.