Expression of K19 and K7 in dysplastic nodules and hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most common types of malignant tumors characterized by a multistep process of tumor development. Nodular lesions that differ from the surrounding liver parenchyma and are characterized by cytological or structural atypia are termed dysplastic nodules (DNs). DNs are well-known precancerous HCC lesions. Expression of keratin (K) 19 and K7, molecular markers of hepatic progenitor cells and cholangiocytes, has been reported in certain HCCs. However, it remains unclear whether K19-positive HCC cells are derived from true hepatic progenitor cells or mature cells that have undergone a dedifferentiation or a transdifferentiation process. In total, 107 tissue sections (13 low-grade DNs, 15 high-grade DNs, 27 small HCCs and 52 large HCCs) from resected liver samples and 132 HCC tissue microarray (TMA) cores were subjected to immunohistochemical analysis for K19 and K7. Clinicopathological data of the HCC patients were evaluated. K19 expression was found in 0% of DNs, 19% of small HCCs (≤2 cm), 8% of large HCCs (>2 cm) and 8% of TMA samples. K7 expression was found in 14% of DNs, 41% of small HCCs, 15% of large HCCs and 6% of TMA samples. Among the five K19-positive small HCCs, four were distinctly nodular and one tumor was an infiltrative type. No vaguely nodular HCC was positive for K19. K19 expression was significantly associated with histological grade (P=0.023), serum α-fetoprotein level (P=0.001) and K7 expression (P=0.001) in HCC. K19 expression was an independent prognostic factor for overall survival in non-viral HCC patients (P=0.003). K19 expression is extremely rare in DNs and occurs in progressed small HCCs. Our results suggest that K19 expression may be an acquired feature of carcinoma cells during HCC progression in certain HCCs.

Figure 1

Hematoxylin and eosin staining and immunohistochemical results of K19 and K7 expression in cirrhotic liver, DNs and HCC. (A and B) Ductular cells surrounding the portal tract and in the interface between hepatocytes and stroma demonstrated strong K19 immunoreactivity in cirrhotic livers are shown. (C and D) K7 expression in low-grade DN is shown. K7 demonstrated a geographic pattern of intermediate hepatocyte-like cells and small cells in low-grade DNs. (E and F) K19 immunoreactivity shows small HCC cells with diffuse and intense cytoplasmic reactivity. K, keratin; DN, dysplastic nodules; HCC, hepatocellular carcinoma.

Figure 2

Kaplan-Meier analysis of overall survival in patients with K19-positive HCC. HCC, hepatocellular carcinoma; K, keratin.