The respective uptake of FAMT was lower in both metastatic liver lesions and normal tissues compared with that of FDG. However, most liver metastases were recognized on FAMT-PET images, except NET lesions. Differential diagnosis among various tissues using T/L ratio might be useful, particularly for comparison between SCC and AC on FAMT-PET. In FDG and FAMT combinations, tissues tended to be distributed on the basis of their histology (Fig. 2).
Both FDG and FAMT uptakes for SCC were relatively higher than those for AC. Only two lesions of AC in one patient showed higher SUVmax compared with that in SCC; however, excluding these two lesions, the T/L ratio of FDG revealed no significant difference between SCC and AC (p = 0.063). This patient was the only case of esophageal adenocarcinoma. We speculated that this cancer lesion might have included adenosquamous components. Further investigations of LAT1 expression based on histology will be required to demonstrate the utility of FDG-PET or FAMT-PET for differentiating between SCC and AC. FDG uptakes of CAR tumors had relatively low T/L ratios, resulting in difficulty to differentiate metastatic liver lesions from liver parenchymal tissues on FDG-PET. In contrast, CAR tumors were detected on FAMT-PET and FAMT-PET was superior to FDG-PET in this point.
In this study, FDG uptake in the liver parenchymal tissues ranged from 1.36 to 4.50, and the median value of SUVmax (2.60) was already over the upper limit of the general threshold between benign and malignant lesions. FDG uptake in the liver parenchyma was higher than that of FAMT because glucose was metabolized and stored in the liver. In general, hepatocytes have glucose-6-phosphatase that can reverse FDG-6-phosphate to FDG, thus reducing FDG uptake in the hepatocyte (Torizuka et al. 1995; Khan et al. 2000; Yen et al. 2004). Therefore, FDG accumulation was relatively lower than what was expected of a glucose analog.
The differences between FDG and FAMT may be because of not only metabolism but also retention. Because FDG was taken up by GLUT1 and trapped into cells after phosphorylation, it accumulated in a linear fashion and was eventually retained. Conversely, after FAMT transport into cells by LAT1, relatively rapid clearance of FAMT can be observed in even tumor cells; this means that LAT1 function of FAMT transport was not one way but was reversible. These mechanisms may explain the lower SUVmax of FAMT.
Alpha-methylation of FAMT reduces liver accumulation and increases renal excretion, whereas the analog of FAMT, l-tyrosine, has been well known to be one of the aromatic amino acids that are metabolized in the liver. This is an advantage of FAMT over the most commonly studied MET, which strongly accumulates in both the normal and metastatic liver tissues (Wiriyasermkul et al. 2012). Another analog of tyrosine and a well-known amino acid tracer, O-(2-18F-fluoroethyl)-l-tyrosine (FET), has been shown to have low accumulation in murine liver and a higher specificity than FDG (Ishiwata et al. 2004). Although FET would be a good candidate for detecting liver metastasis, most reports on its application were for brain tumors, and there has been no report on liver metastasis.
Wiriyasermkul et al. (2012) revealed that FAMT had two potential benefits: one was the reduced uptake in the liver and another was the specific transport via LAT1 without the need to go through other types of amino acid transporters, such as the system ASC amino acid transporter-2 (ASCT2). The details of the mechanisms for uptake of FAMT or methionine in normal liver are not clear; however, FAMT is transported only via L-amino acid transporter-1 (LAT1), while methionine is transported via LAT-1, LAT-2, and some other transporters (Singhal et al. 2008). LAT1 specificity of FAMT may increase the possibility of detecting metastatic liver lesions.
Nevertheless, because FDG strongly accumulated in the metastatic liver lesions, T/L ratios were still higher than those of FAMT. In this study, T/L ratio indicated the specific features based on histological origins. Although FAMT uptake was detected in metastatic liver lesions from NETs, FDG accumulation was very high (median; 7.28, ranging from 5.50 to 12.45). Our clinical experiences revealed that FAMT-PET had a difficulty in the detecting pheochromocytoma lesions (unpublished data), whereas FDG had an advantage. In contrast, the detection of liver metastasis from CAR tumors using FDG-PET was difficult because FDG uptake was low; thus, for these lesions, FAMT-PET could be more useful. According to the International Union Against Cancer classification of neuroendocrine tumors, CAR belongs to G1 and NET belongs to G2 or G3. Because the uptake of FDG generally reflects the grading of tumor differentiation, FDG-PET should have shown higher accumulations in NET than in CAR. Low-grade tumors, such as NET, show a high uptake of FDG compared with well-differentiated tumors such as CAR. In our case, two lesions were detected using only FAMT-PET not FDG-PET.
The limitation of this study was that patients with colorectal cancer were not included. Although most metastatic liver lesions from colorectal cancer would be AC, our AC group included metastasis from lung cancers. However, some reports revealed high expressions of GLUT1 and high FDG uptake in SCC (Yen et al. 2004; Fletcher et al. 2008). Our comparison between SCC and AC may not be different from that for colorectal cancer. FAMT-PET was performed not for conventional clinical examinations but for study purposes; this study did not include metastatic liver lesions from colorectal cancers. Therefore, the number of patients who underwent both FDG-PET and FAMT-PET was small, and this would be a limitation for statistical analysis. In further investigations, the time of PET acquisition after tracer administration can be changed to an earlier time. It would have an advantage with obtaining high FAMT uptakes in liver lesions. However, the high T/L ratio would be required to depict liver lesions more clearly. Because of the background signals, including normal liver uptakes is another important factor and should be investigated for an optimal time.