Stefano Restaino, Antonio Raffone, Antonio Travaglino, Federico Paparcura, Martina Arcieri, Alessandro Lucidi, Vito Andrea Capozzi, Emanuela D'Angelo, Elena Thai, Laura Manotti, Angelica Tulisso, Maria Orsaria, Laura Mariuzzi, Lorenza Driul, Roberto Berretta, Giuseppe Vizzielli
Among 201 patients (mean age 57 years), 83 (41.3%) were classified as low-grade, 87 (43.3%) as high-grade, and 31 (15.4%) as confluent glands. Endometrial carcinoma was identified in 42 patients (20.9%). Carcinoma rates were 9.6%, 14.9%, and 64.5% in the low-grade, high-grade, and confluent glands groups, respectively. High-grade atypia was not independently associated with carcinoma compared with low-grade (adjusted odds ratio 1.6, 95% confidence interval 0.6 to 4.0, p = .30), whereas confluent glands showed a strong independent association (adjusted odds ratio 17.0, 95% confidence interval 6.5 to 45.0, p < .001). Inter-observer agreement was substantial for low-grade versus high-grade classification (kappa = 0.76) and excellent for confluent gland identification (kappa = 0.95) CONCLUSIONS: This multi-center external validation confirms that the integrated histological model identifies clinically meaningful sub-groups with distinct risks of concurrent carcinoma. Architectural complexity, rather than cytological atypia alone, is the main determinant of risk, supporting more accurate pre-operative stratification and individualized patient management.
BACKGROUND: Atypical endometrial hyperplasia/endometrioid intra-epithelial neoplasia is the main precursor of endometrioid endometrial carcinoma. Its histopathological spectrum is heterogeneous, and inter-observer reproducibility remains sub-optimal. An integrated histological model combining cytological atypia and architectural complexity has been proposed to improve risk stratification for concurrent carcinoma.
OBJECTIVE: To externally validate the prognostic performance and reproducibility of an integrated histological risk stratification model of atypical endometrial hyperplasia/endometrioid intra-epithelial neoplasia in a multi-center cohort.
METHODS: This multi-center retrospective cohort study included 201 patients with a pre-operative diagnosis of atypical endometrial hyperplasia/endometrioid intra-epithelial neoplasia who underwent hysterectomy between January 2020 and December 2024 at 3 tertiary referral centers. Index biopsies were independently reviewed by 2 blinded pathologist panels and classified into low-grade atypia, high-grade atypia, and confluent glands. The primary outcome was the rate of concurrent endometrial carcinoma at hysterectomy. Inter-observer agreement and multi-variable logistic regression were used to assess reproducibility and identify independent predictors of carcinoma.
RESULTS: Among 201 patients (mean age 57 years), 83 (41.3%) were classified as low-grade, 87 (43.3%) as high-grade, and 31 (15.4%) as confluent glands. Endometrial carcinoma was identified in 42 patients (20.9%). Carcinoma rates were 9.6%, 14.9%, and 64.5% in the low-grade, high-grade, and confluent glands groups, respectively. High-grade atypia was not independently associated with carcinoma compared with low-grade (adjusted odds ratio 1.6, 95% confidence interval 0.6 to 4.0, p = .30), whereas confluent glands showed a strong independent association (adjusted odds ratio 17.0, 95% confidence interval 6.5 to 45.0, p < .001). Inter-observer agreement was substantial for low-grade versus high-grade classification (kappa = 0.76) and excellent for confluent gland identification (kappa = 0.95) CONCLUSIONS: This multi-center external validation confirms that the integrated histological model identifies clinically meaningful sub-groups with distinct risks of concurrent carcinoma. Architectural complexity, rather than cytological atypia alone, is the main determinant of risk, supporting more accurate pre-operative stratification and individualized patient management.