Keratin 19 epithelial patterns in cirrhotic stroma parallel hepatocarcinogenesis

Area of Science:

• Hepatology and Cancer Biology
• Cellular and Molecular Pathology

Background:

• The ductular reaction (DR) in cirrhosis comprises various cells within septa.
• The absence of DR in the stroma around hepatocellular carcinoma (HCC) is known.
• The role of keratin 19 (K19) structures in the DR and HCC progression is unexplored.

Purpose of the Study:

• To investigate the relationship between K19 structures in the stromal compartment and the progression of liver carcinogenesis.
• To analyze the immunophenotypic and cytomorphologic changes in the DR during hepatocarcinogenesis.

Main Methods:

• Examined K19 immunoreactivity in the stromal compartment around 176 nodules in cirrhotic explants.
• Utilized multicolor immunolabeling for K19, vimentin, E-Cadherin, SNAIL, and fibroblast-specific protein 1 (FSP-1).
• Assessed transforming growth factor-β (TGF-β) signaling components (TGFβR1, SMAD3, pSMAD2/3).

Main Results:

• Identified three distinct K19 patterns: complex (cirrhotic nodules, CN), attenuated (dysplastic nodules, DN), and absent (HCC).
• Observed decreased epithelial markers and increased SNAIL and FSP-1 positive cells in DR around DN compared to CN (P < 0.0001).
• Found increased pSMAD2/3 in DR around DN compared to CN (P < 0.0001).

Conclusions:

• Extralesional K19 patterns correlate with progressive stages of hepatocarcinogenesis.
• Alterations in cellular identity and paracrine signaling in the epithelial-stromal compartment are key mechanisms in HCC progression.
• The study highlights the importance of the epithelial-stromal interaction in malignant progression of HCC in cirrhosis.