Underestimated Role of ¹⁸F-FDG PET for HCC Evaluation and Promise of ¹⁸F-FDG PET/MR Imaging in This Setting

TO THE EDITOR: We read with great interest the recent article by Cheung et al. on the utility of ¹¹C-acetate/¹⁸F-FDG PET/CT for clinical staging and appropriate selection of patients with hepatocellular carcinoma (HCC) for liver transplantation based on the Milan criteria (1). The authors of this study were able to show the strength of PET/CT over dynamic contrast-enhanced CT to detect HCCs (particularly small ones measuring 1–2 cm) and to differentiate between benign and malignant hepatic lesions in the cirrhotic liver (1). However, Cheung et al. (1) were unable to show a complementary role for both tracers (i.e., ¹¹C-acetate and ¹⁸F-FDG) in HCC. Apparently, the sensitivity of ¹¹C-acetate PET alone for TNM staging and selection of patients for liver transplantation based on the Milan criteria did not change after ¹⁸F-FDG PET was added to the diagnostic algorithm (1). However, we believe the capabilities of ¹⁸F-FDG PET were not fully exploited in this study. In this communication, we would like to emphasize the unrecognized value of ¹⁸F-FDG PET for the evaluation of HCC and share our view on the promise of ¹⁸F-FDG PET/MR imaging in this setting.

First, ¹⁸F-FDG PET allows not only for tumor detection but also for characterization of cancer biology; that is, aggressive cancers tend to have higher levels of ¹⁸F-FDG uptake whereas less aggressive cancers tend to have lower levels of ¹⁸F-FDG uptake (2). This dimension of diagnostic information provided by ¹⁸F-FDG PET is important because it can be used to improve determination of disease prognosis and treatment planning (2). A study published in JNM in 1995 already showed that ¹⁸F-FDG uptake in HCC correlates with hexokinase/glucose-6-phosphatase activity and differentiation grade (3). These observations have been confirmed by a more recent study published in JNM in 2008 reporting that well-differentiated HCCs have a lower mean ¹⁸F-FDG maximum standardized uptake value (SUV_max) than poorly differentiated HCCs (5.10 vs. 7.66), in contrast to nonsignificant differences in ¹¹C-acetate SUV_max (5.27 vs. 4.94). In addition, patients with ¹⁸F-FDG–positive lesions were reported to have a significantly shorter survival than patients with ¹⁸F-FDG–negative lesions (P < 0.05) (4). In the study by Cheung et al. (1), ¹⁸F-FDG PET was used only for tumor detection rather than tumor detection and characterization. It would be of great interest to incorporate the ¹⁸F-FDG PET information on HCC biology into a predictive model (to select patients for liver-directed interventions) that goes beyond the structural imaging–based Milan criteria (5).

Second, it is important to realize that the absolute accumulation of ¹⁸F-FDG in a cell is a dynamic process, with ¹⁸F-FDG release from the cell depending on the ratio of hexokinase to glucose-6-phosphatase. The dynamics of ¹⁸F-FDG accumulation in HCCs, benign liver lesions, and background tissue go beyond 60 min after ¹⁸F-FDG administration (the conventional time point at which ¹⁸F-FDG PET is routinely performed, as was also done in the study by Cheung et al. (1)) (6–8). Additional PET imaging at a later time point (i.e., dual-time-point or delayed imaging) may be advantageous because ¹⁸F-FDG accumulation in benign liver lesions and background tissue may decrease (7,8) whereas ¹⁸F-FDG accumulation in HCCs may further increase (6). This, in turn, may improve the detection of both HCCs and metastases. Dual-time-point ¹⁸F-FDG PET may also provide additional prognostic information, because more aggressive cancers tend to exhibit increasing ¹⁸F-FDG levels over time, in contrast to less aggressive ones (8,9). For example, in a study published in JNM in 2010, it was reported that lung adenocarcinoma patients with an increase in ¹⁸F-FDG SUV_max of at least 25% between 1 and 1.5 h after injection had a median survival of 15 mo, compared with 39 mo for those with less than a 25% ¹⁸F-FDG SUV_max increase (P < 0.001) (9). Certainly, more work needs to be done to prove the value of dual-time-point ¹⁸F-FDG PET in HCC, but given the potential of this technique (7–9), it would be inappropriate to disregard its value in HCC at this moment.

Third, Cheung et al. (1) compared ¹¹C-acetate/¹⁸F-FDG PET with dynamic contrast-enhanced CT. However, dynamic contrast-enhanced CT has been shown to be inferior to dynamic contrast-enhanced MR imaging with hepatobiliary contrast agents in the cirrhotic liver, especially for the detection of lesions measuring 1–2 cm (10). The sensitivity of MR imaging in this setting was 85%, versus 65% for CT (P < 0.01), whereas specificity (94% and 89%, respectively) was comparable. We envision an important role for combined ¹⁸F-FDG PET/MR imaging for the evaluation of patients with HCC, given the utility of dynamic contrast-enhanced MR imaging with hepatobiliary contrast agents for HCC detection (this technique is already used on a routine clinical basis), the aforementioned unexploited new dimensions of ¹⁸F-FDG PET, and the rise of integrated PET/MR imaging systems. Although the number of clinical PET/MR imaging systems is currently still limited, this technique is rapidly spreading. Thus, it can be expected that the availability of PET/MR imaging to HCC patients will soon increase. At that time, ¹⁸F-FDG PET/MR imaging may well prove to be a more clinically feasible method than a diagnostic approach that uses ¹¹C-acetate PET, requiring an on-site cyclotron.

In conclusion, we believe that ¹⁸F-FDG PET has an important role in the evaluation of HCC, if the information provided in an ¹⁸F-FDG PET scan is correctly interpreted (¹⁸F-FDG uptake reflects HCC biology and should not be used merely for cancer detection) and the technique is optimized (dual-time-point imaging has the potential to improve detection of both primary and metastatic HCC and can provide additional prognostic information). Finally, given the fact that advanced but clinically mature MR imaging techniques are superior to CT for HCC detection, we foresee an important role for ¹⁸F-FDG PET/MR imaging for the evaluation of HCC patients.

• © 2013 by the Society of Nuclear Medicine and Molecular Imaging, Inc.