Uptake of amino acids and glucose in cancer cells is elevated to maintain rapid cell proliferation and intracellular metabolism [14]. Increased amino acid metabolism is mediated by elevated activity and expression of transporters, which are responsible for cellular uptake of nutrients [15], while glucose is transported into normal cells and cancer cells via the glucose transporter (GLUT) 1 [16]. Glucose metabolism is accelerated in malignant tumors, and PET uses a radioactive agent to visualize the status of metabolism [17]. 18F-FDG is a substrate for GLUT1 and is taken up by normal tissues such as the brain, resulting in high background values. Therefore, 18F-FDG PET has limited utility in diagnosis of malignant brain tumors [18, 19]. Granulation tissue, macrophages, and neutrophils also have elevated glucose metabolism, so high uptake of 18F-FDG occurs in inflammatory lesions in which these cells are proliferating. Kubota et al. found higher uptake of 18F-FDG in macrophages around necrotic tissue and in juvenile granulation tissue around tumors, rather than in the tumor cells themselves [20]. Thus, 18F-FDG PET/CT is limited for differential diagnosis of tumors and other lesions, especially in cases with active inflammation. The present results showed no significant difference in SUVmax of 18F-FDG PET/CT for malignant tumors and benign lesions (10.9 ± 6.3 vs. 9.1 ± 2.7, P = 0.62), indicating that differentiation is difficult, as also found in previous reports [21–23].
The amino acid transport system includes a large number of amino acid transporters, and the molecular properties of amino acids vary greatly depending on their side chains. Recently, LAT1 of the L-type family of amino acid transporters has been shown to be present in tumor cells, while LAT2 is found in normal cells [24]. LAT1 is upregulated in many cancer cells and is highly correlated with the cell proliferation index, disease stage and poor prognosis. However, LAT1 is also expressed, although to a lesser extent, in cells and tissues with high proliferative and differentiation potential, such as the normal blood-brain barrier, blood-retina-brain barrier, placental barrier, endocrine glands and activated T cells. LAT2 is a neutral amino acid transporter that is mainly responsible for amino acid transport in the small intestine, where nutrients are absorbed, and in mucosal epithelial cells of the kidney, where amino acids are reabsorbed from urine [24].
There are several amino acid PET tracers in clinical use, including 11C-MET (methionine), 18F-FAMT (methyltyrosine) and 18F-FBPA. 11C-MET is taken up by multiple amino acid transporters in normal cells since it is a natural amino acid used for protein synthesis in the cell, which leads to high background values in the liver, pancreas, and salivary gland tissue on PET [25, 26]. In contrast, 18F-FAMT is specific for LAT1 and is not transported by LAT2 [25]. Results from 18F-FAMT PET in patients with lung cancer showed accumulation of 18F- FAMT in cancer foci that correlated with the LAT1 expression level, while normal tissue, inflammatory sites and benign lesions showed little accumulation of 18F-FAMT [27]. 18F-FAMT PET is superior to 18F-FDG PET for detection of malignant tumors in some cancer types [28, 29]. Kim et al. found that the SUV of 18F-FAMT is smaller than that of 18F-FDG [30] because 18F-FDG also has uptake due to inflammatory processes in the tumor, whereas 18F-FAMT does not. However, although 18F-FAMT has promise for specific diagnosis of cancer, the compound is difficult to synthesize and label, and development of a simple and efficient method for F-18 labeling is needed for clinical application [28, 29].
BPA used in boron neutron capture therapy (BNCT) is transported by LAT1, LAT2 and another transporter of neutral amino acids, amino acid transporter B0 (ATB0). BPA is not specific for LAT1, but is mainly transported into cancer cells via LAT1. In contrast, 18F-FBPA used in PET has been reported to be highly specific for LAT1 [31] and has been found to be useful in differential diagnosis of tumors and inflammation in animal models [6]. In the current study, 18F-FBPA uptake was visualized in many tumors, although 18F-FBPA tended not to show as high an uptake as 18F-FDG. A few tumors showed stronger accumulation of 18F-FBPA than 18F-FDG (SUVmax: external auditory canal cancer 13.3 vs. 11.6, breast cancer 4.5 vs. 3.7), but others showed low 18F-FBPA accumulation (SUVmax: mantle lymphoma 1.5–2.4, olfactory neuroblastoma 2.4) and could not be visualized (false-negative on PET). Conversely, a small number of cases of granulomatous inflammatory disease in the brainstem and cervical lymph node areas gave false-positive results. In such cases, it is important to evaluate the results in conjunction with other examinations and the clinical course. The expression level of LATI was not examined in this study, but is likely to vary among types of tumor, and this may also have caused differences in accumulation of 18F-FBPA. Well-differentiated lung cancers with frosted appearances on CT and 18F-FDG PET have low accumulation and cannot be visualized. This suggests that tumor size, cell density, and the limited spatial resolution of PET can also affect the diagnostic performance.
18F-FDG PET/CT has the advantage of capturing metabolic changes that precede morphological changes caused by therapeutic interventions, allowing early assessment of the effect of treatment. In malignant lymphoma, 18F-FDG PET/CT has been used to determine the response to treatment and to diagnose residual active disease [32]. However, since 18F-FDG is also taken up by inflammatory lesions, it is limited for differentiating tumor and inflammatory responses to treatment, especially in patients with persistent inflammation [33]. The present study suggests that this distinction may be possible under certain conditions, especially in the presence of inflammation after radiotherapy (Fig. 6).
Fibroblast activation protein (FAP) is a type II membrane-bound glycoprotein belonging to the dipeptidylpeptidase 4 family and is highly expressed in many epithelial cancer-associated fibroblasts. It is characterized by a strong desmoplastic response, and the association between FAP overexpression and a poor cancer prognosis has led to development of FAP-specific inhibitors (FAPIs) [21]. In recent years, FAPIs labeled with 67Ga- or 18F and detected by PET have been used to provide information on tumor diagnosis and radiotherapy planning [34, 35]. However, this technique (which is referred to as tumor stromal imaging) is intended to detect pathological conditions associated with tumors and does not directly depict the tumor cells themselves. In contrast, 18F-FBPA PET directly depicts tumor cells and has a different target dimension. In the context of treatment, 18F-FBPA PET allows for appropriate selection of patients for BNCT and accurate treatment planning [36]. In particular, prediction of boron concentrations in tumors is needed for accurate dose prediction and efficacy assessment in BNCT. Therefore, use of 18F- FBPA PET is important for further development of BNCT [37], and in this sense, the value of 18F-FBPA PET is extremely high. In this study, we mainly examined tumors and inflammation in the trunk region. There were some false-negative and false-positive cases, but SUVmax for 18F-FBPA PET differed significantly in tumors and inflammatory lesions, indicating sufficient discriminatory ability for clinical use.