Clinico-Radio-Pathological and Molecular Features of Hepatocellular Carcinomas with Keratin 19 Expression

Abstract

Hepatocellular carcinoma (HCC) is a heterogeneous neoplasm, both from the molecular and histomorphological aspects. One example of heterogeneity is the expression of keratin 19 (K19) in a subset (4-28%) of HCCs. The presence of K19 expression in HCCs has important clinical implications, as K19-positive HCCs have been associated with aggressive tumor biology and poor prognosis. Histomorphologically, K19-positive HCCs demonstrate a more infiltrative appearance, poor histological differentiation, more frequent vascular invasion, and more intratumoral fibrous stroma than K19-negative conventional HCCs. From the molecular aspect, K19-positive HCCs have been matched with various gene signatures that have been associated with stemness and poor prognosis, including the G1-3 groups, S2 class, cluster A, proliferation signature, and vascular invasion signature. K19-positive HCCs also show upregulated signatures related to transforming growth factor-β pathway and epithelial-to-mesenchymal transition. The main regulators of K19 expression include hepatocyte growth factor-MET paracrine signaling by cancer-associated fibroblast, epidermal growth factor-epidermal growth factor receptor signaling, laminin, and DNA methylation. Clinically, higher serum alpha-fetoprotein levels, frequent association with chronic hepatitis B, more invasive growth, and lymph node metastasis have been shown to be characteristics of K19-positive HCCs. Radiologic features including atypical enhancement patterns, absence of tumor capsules, and irregular tumor margins can be a clue for K19-positive HCCs. From a therapeutic standpoint, K19-positive HCCs have been associated with poor outcomes after curative resection or liver transplantation, and resistance to systemic chemotherapy and locoregional treatment, including transarterial chemoembolization and radiofrequency ablation. In this review, we summarize the currently available knowledge on the clinico-radio-pathological and molecular features of K19-expressing HCCs, including a detailed discussion on the regulation mechanism of these tumors.

Keywords: Hepatocellular carcinoma; Invasiveness; Keratin 19; Poor prognosis; Treatment resistance.

Fig. 1

Morphological features of K19-expressing HCCs. An infiltrative growth pattern is seen on both macroscopic (a) and microscopic (b) examination. Frequent vascular invasion (b) and intratumoral fibrous stroma (c) are also features of these tumors. d K19 expression in the tumor cells. Portal vein invasion is marked by arrows. b, c Hematoxylin-eosin. d immunohistochemistry for K19; original magnification, ×10 (b), ×100 (c, d). K19, keratin 19; HCC, hepatocellular carcinoma.

Fig. 2

Morphological features of K19-expressing HCCs. K19-expressing HCC cells are frequently poorly differentiated (a); however, those with lower histological grade may also express K19 (b). K19 expression is also frequently observed in the smaller “hepatic progenitor cell-like” tumor cells at the periphery of tumor nests, facing the fibrous stroma (c) (upper row: hematoxylin-eosin, lower row: immunohistochemical stain for K19; original magnification, ×400). K19, keratin 19; HCC, hepatocellular carcinoma.

Fig. 3

Regulatory mechanism of KRT19 expression in HCC. Expression of KRT19 is regulated at the transcriptional level by various external signals. HGF secreted from CAF activates the MET-MEK-ERK1/2 pathway and transcriptional factors JUN/FOSL1 and SP1 which upregulate KRT19 transcription. EGF secreted from HCC cells also acts in an autocrine manner to upregulate KRT19 through the EGFR-JNK pathway and unknown TF. Laminins also play an important role in KRT19 regulation. Laminin-332 and laminin-111 upregulate KRT19 through the mTORC complex and the integrin-FAK-SRC pathway, respectively. Epigenetic regulation of KRT19 is also important for KRT19 expression; the dense methylation of the KRT19 promoter decreases the expression of KRT19. HGF, hepatocyte growth factor; CAF, cancer-associated fibroblast; EGF, epidermal growth factor; FAK, focal adhesion kinase; TF, transcription factor; JNK, Jun N-terminal kinase; EGFR, epidermal growth factor receptor; HCC, hepatocellular carcinoma.

Fig. 4

Gadoxetic acid-enhanced MRI of K19-expressing HCC. The lesion shows a low signal intensity in the precontrast T1-weighted image (a), rim-like enhancement in the arterial phase (b), absence of enhancing capsule in the portal phase (c), and low signal intensity and delayed enhancement of central area (white arrows) in the hepatobiliary phase (d). Targetoid restriction on diffusion-weighted image (e, b = 800) and apparent diffusion coefficient image (f). On microscopy, this HCC demonstrates a macrotrabecular pattern (g), focal area of fibrous stroma (h), and K19 expression (i, j) (g, h: hematoxylin-eosin; i, j: immunohistochemical stain for K19, original magnification, ×100). K19, keratin 19; HCC, hepatocellular carcinoma.

Fig. 5

Model of treatment resistance to TACE in K19-expressing HCC. HCC cells without K19 expression are more susceptible to TACE with a higher chance of near total necrosis than those with K19 expression. In contrast, HCC cells with K19 expression may be resistant to a hypoxic tumor microenvironment induced by TACE and have higher chance of incomplete necrosis. In addition, they can proliferate with altered tumor stroma after TACE. TACE, transarterial chemoembolization; K19, keratin 19; HCC, hepatocellular carcinoma.