Cirrhotic nodules containing hepatocytes are surrounded by perinodular stroma, that consists of an expanded fibrous matrix and epithelial cells with ductular phenotype, the “ductular-reaction”. Stromal invasion is a key histopathologic feature used to differentiate premalignant dysplastic nodules from malignant hepatocellular carcinoma (HCC). K19 immunoreactivity in the stromal compartment in cirrhotic explants was examined. Quantitative differences were manifested in three distinct histologically identifiable patterns: “complex” around cirrhotic nodules, “attenuated” around dysplastic nodules, and “absent” around HCC. These findings suggest marked alterations in cellular identity as an underlying mechanism for the reproducible extralesional K19 pattern that parallels progressive stages of intranodular hepatocarcinogenesis. Paracrine signalling is proposed as a link that emphasizes the importance of the epithelial-stromal compartment in malignant progression of HCC in cirrhosis.