Retinoblastoma Protein Loss in p53 Abnormal Endometrial Carcinoma: Histologic and Clinicopathological Correlates

Abstract

Of the 4 molecular subtypes of endometrial cancer (EC), p53-abnormal (p53abn) EC is associated with abundant copy number alterations and the worst clinical outcome. Patients with p53abn EC have the highest risk of disease recurrence and death, independent of tumor grade and histologic subtype. Currently, all invasive p53abn ECs are considered high risk, and no prognostic biomarkers have yet been found that can aid in clinical management. Here, we aimed to test whether loss of retinoblastoma (RB) protein expression using immunohistochemistry has the potential for prognostic refinement of p53abn EC. A large cohort of 227 p53abn ECs collected from the PORTEC-1/2/3 clinical trials and the Medisch Spectrum Twente cohort study was investigated, and RB loss was identified in 7.0% (n = 16/227). RB-lost p53abn ECs were predominantly high-grade endometrioid ECs (n = 6, 37.5%) and carcinosarcomas with endometrioid-type epithelial component (n = 5, 31.3%). Histologically, RB-lost p53abn ECs were typified by high-grade nuclear atypia (n = 16, 100%), predominantly solid growth pattern (n = 15/16, 93.8%), and polypoid growth (n = 9/16, 56.3%). Copy number loss involving the RB1 locus was identified in the majority of RB-lost p53abn EC (n = 13/14, 92.9%), explaining the loss of RB expression. Comparative analysis also showed that RB-lost p53abn ECs were diagnosed at earlier stages than RB-retained p53abn EC (P = .014). Interestingly, RB-lost p53abn EC showed prolonged time to overall recurrence (P = .038), even within stage I alone (P = .040). These findings highlight distinct morphomolecular features in RB-lost p53abn ECs and confirm the utility of RB immunohistochemistry as a surrogate for underlying molecular RB1 alterations. To our knowledge, this is the first study to show the potential use of RB in prognostic refinement of p53abn EC, although validation is warranted.