Prognostic significance of CK7, CK20, and CDX2 expression in small intestinal adenocarcinoma

Background: Small intestinal adenocarcinoma (SIA) is a rare gastrointestinal malignancy for which prognostic biomarkers remain poorly defined. Immunohistochemical markers cytokeratin 7 (CK7), cytokeratin 20 (CK20), and caudal-type homeobox transcription factor 2 (CDX2) are diagnostic markers that are prognostic in other intestinal cancers, but their prognostic significance in SIA has not been studied before. Patients and methods: This nationwide, retrospective, population-based cohort study used data from the Netherlands Cancer Registry and the Dutch pathology database. Patients diagnosed with primary SIA between 1999 and 2019 and with registered CK7, CK20, or CDX2 expression levels were included. Overall survival (OS) was analyzed using Kaplan–Meier curves and multivariable Cox regression models adjusted for age, sex, stage, tumor location, and treatment. The findings were validated in a detailed cohort of 128 SIA patients. Results: Of 2697 patients diagnosed with SIA, expression data were available for 691 patients. CK7 positivity was associated with more proximal, advanced, and microsatellite stable tumors. CK7-negative, CK20-positive, and CDX2-positive tumors demonstrated significantly improved OS (all P = 0.002). In multivariable analysis, lack of CK20 and CDX2 expression were independent predictors of poorer survival [hazard ratio (HR) 1.37, 95% confidence interval (CI) 1.02-1.83 and HR 1.51, 95% CI 1.06-2.17, respectively]. Combined expression profiles identified distinct prognostic subgroups, which were confirmed in the validation cohort. Conclusion: CK20 and CDX2 expression are independent prognostic biomarkers in SIA, regardless of primary tumor location. Their assessment may improve risk stratification and refine disease classification, bridging diagnostic and prognostic utility in this rare cancer type.