Is nestin a diagnostic marker for combined hepatocellular–cholangiocarcinoma?

BACKGROUND AND AIMS: The type IV intermediate filament, nestin, may be a candidate diagnostic marker for combined hepatocellular-cholangiocarcinoma (cHCC-CCA). Therefore, the significance of nestin as a diagnostic marker for cHCC-CCA categorized by the World Health Organization (WHO) 2019 classification and its relationship with clinicopathological features were examined in the present study. METHODS AND RESULTS: Nestin expression was immunohistochemically assessed in the liver sections from 75 patients with cHCC-CCA, 22 with small duct-type intrahepatic cholangiocarcinoma (iCCA), 20 with large duct-type iCCA and 35 with hepatocellular carcinoma (HCC). Nestin expression and its relationship with clinicopathological features and genetic alterations were investigated in cHCC-CCA. Nestin expression was detected in significantly more patients with cHCC-CCA (66.7%) than in those with large duct-type iCCA (5%) (P < 0.01), HCC (2.9%) (P < 0.01) and small duct-type iCCA (40.9%) (P < 0.05). Nestin expression was partly associated with neural cell adhesion molecule (NCAM) and vimentin expression. Nestin expression was also observed in significantly more patients with small duct-type iCCA than in those with large duct-type iCCA and HCC (P < 0.01). Nestin-positive cHCC-CCA was characterized by a smaller tumour size, the more frequent presence of cholangiolocellular carcinoma (CLC) components, a higher rate of p53 overexpression and a higher rate of multiple genetic alterations (P < 0.05). Furthermore, p53 overexpression was associated with a higher histological grade and multiple genetic alterations (P < 0.05) in nestin-positive cHCC-CCA. CONCLUSION: Nestin may be a useful diagnostic marker for a specific subgroup of cHCC-CCA and small duct-type iCCA associated with CLC components, p53 mutations and multiple genetic alterations, which are related to stemness and multipotent differentiation.