Expression of glucose transporters and hexokinase II in cholangiocellular carcinoma compared using [18F]-2-fluro-2-deoxy-D-glucose positron emission tomography

Abstract

Cholangiocellular carcinoma (CCC) has been reported to have a high glucose uptake; however, the mechanism of glucose entry into these cells is still unclear. We investigated the relationship between [(18)F]-2-fluro-2-deoxy-D-glucose ((18)F-FDG) uptake and the expression of facilitative glucose transporters (Glut) and hexokinase (HK) II, as well as the association between the expression of different histological types of CCC. The expression of Glut (1-5) and HK II was studied using immunohistochemistry of 26 patients with CCC who underwent whole-body (18)F-FDG positron emission tomography before surgery or biopsy. CCC expressed immunohistochemically detectable Glut 1 in 81%, Glut 2 in 54%, Glut 3 in 19%, and HK II in 77% of the total cases. Glut 1, Glut 2, Glut 3, and HK II were more often detected in moderately differentiated and poorly differentiated than in well-differentiated CCC. A significant correlation was observed between (18)F-FDG uptake and the staining scores of Glut 1 and HK II (P = 0.02, rho = 0.45 and P = 0.001, rho = 0.59). The staining scores of Glut 1 and HK II were also significantly correlated (P = 0.002, rho = 0.3). Multivariate regression analysis revealed that lymph-node metastasis was independently associated with (18)F-FDG uptake. Our study showed a significant association between the expression of Glut 1 and HK II with (18)F-FDG uptake, indicating that Glut 1 is a major glucose transporter expressed in CCC and that HK II contributes to the increased metabolism of glucose, especially in moderately and poorly differentiated CCC.

Figure 1

Comparison between [¹⁸F]‐2‐fluro‐2‐deoxy‐d‐glucose (FDG) uptake and different histological types of cholangiocellular carcinoma (CCC). A significant difference was seen between well‐differentiated and moderately differentiated CCC, and also between well‐differentiated and poorly differentiated CCC. However, no significant difference (NS) was noted between poorly differentiated CCC and moderately differentiated CCC.

Figure 2

[¹⁸F]‐2‐fluro‐2‐deoxy‐d‐glucose (FDG) positron emission tomography, corresponding computed tomography (CT), and expression of glucose transporters (Glut) in cholangiocellular carcinoma (CCC). (a) High ¹⁸F‐FDG uptake (standardized uptake value = 3.64) was noted in the tumor (arrow). (b) CT showed a heterogeneously enhanced mass (arrow) with dilated intrahepatic bile ducts, which is consistent with CCC. (c) Hematoxylin–eosin staining confirmed the histological diagnosis of CCC. (d) Immunohistochemical staining showed strong Glut 1 expression in the cell membranes (short arrow) and a few positive granules in the cytoplasm (long arrow). Red blood cells (arrowhead) showed strong staining and served as an internal positive control. (e) Immunohistochemical staining showed strong expression of Glut 2. (f) Immunohistochemical staining of hexokinase (HK) II showed strong expression of HK II (original magnification ×400).

Figure 3

Relationship between [¹⁸F]‐2‐fluro‐2‐deoxy‐d‐glucose (FDG) uptake and intensity (negative, weak, or strong) of glucose transporter (Glut) 1, Glut 2, and hexokinase (HK) II expression in cholangiocellular carcinoma (CCC). A statistically significant difference in ¹⁸F‐FDG uptake was noted between the negatively and weakly stained cells, and between the negatively and strongly stained cells for Glut 1 and HK II. However, no significant difference (NS) was observed between ¹⁸F‐FDG uptake and the expression of Glut 2. SUV, standardized uptake value.

Figure 4

Relationship between intensity score of glucose transporter (Glut) 1 and hexokinase (HK) II expression in cholangiocellular carcinoma. A weak correlation was noted between Glut 1 and HK II.