Gastric cancer is one of the most common cancers and the third leading cause of cancer-related death worldwide . Early and accurate diagnosis is extremely important for its treatment and prognosis. 68Ga-FAPI-04 PET has achieved good outcomes for diagnosis in various tumors [12, 16-18]. These include high expression across a wide range of cancer types including several with typically low FDG‐avidity, low uptake in almost all normal tissues, where high physiological uptake can obscure primary or metastatic disease . However, the usefulness of 68Ga-FAPI-04 for the detection of primary gastric cancer remains unclear. In this study, we aimed to evaluate the usefulness of 68Ga-FAPI-04 PET for the detection of gastric cancer compared with that of 18F-FDG PET.
Our results demonstrated the potential advantage of 68Ga-FAPI-04 PET over 18F-FDG PET for the detection of primary gastric cancer. In all 38 patients with gastric cancer, all primary tumors were detected by 68Ga-FAPI-04 PET. 68Ga-FAPI-04 PET (100%, 38/38) provided better sensitivity than 18F-FDG PET (82%, 31/38), consistent with a previous study reporting that more positive lesions on other type of tumors were discovered with 68Ga-FAPI-04 than with 18F-FDG, especially in gastric cancer . In the present study, 68Ga-FAPI-04 PET detected signet ring cell carcinoma of the stomach in one case that was missed by 18F-FDG PET (Fig. 3). Furthermore, in another patient with gastric adenocarcinoma, 68Ga-FAPI-04 displayed focal uptake in the primary tumor, whereas 18F-FDG showed slightly and diffusely elevated uptake in the gastric wall (Fig. 4). As a result, 68Ga-FAPI-04 could provide better surgery determination for gastric cancer. Moreover, the background activity of 68Ga-FAPI-04 was low, resulting in a higher tumor-to-background contrast than 18F-FDG.
Previous studies have shown that the sensitivity of 18F-FDG PET in the detection of gastric cancer ranges from 47% to 96% . One of the reasons for this disparity may be the different histologic types of gastric cancer. 18F-FDG showed lower sensitivity and uptake in signet ring cell carcinoma and mucinous carcinoma than in conventional adenocarcinoma [8-10]. This is due to the relatively low expression level of glucose transporter 1 (GLUT-1) in signet ring cell and mucinous carcinomas . These results are consistent with our finding that signet ring cell carcinoma had lower 18F-FDG uptake than adenocarcinoma, although the difference was not statistically significant. In our study, 68Ga-FAPI-04 detected 3 cases of signet ring cell carcinoma that were negative in 18F-FDG, resulting in a sensitivity of 100% (7/7) in detecting signet ring cell carcinoma and outperforming 18F-FDG (57%, 4/7). Therefore, 68Ga-FAPI-04 PET has an obvious advantage for the detection of signet ring cell carcinoma, especially when negative with 18F-FDG. But the sensitivity of 68Ga-FAPI-04 on signet ring cell carcinoma need larger samples to evaluate.
Tumor size is also an important factor influencing the detection rate of gastric cancer in PET scans. Nakajo et al.  examined the relationship between the SUVmax of primary gastric cancers and the size of visible tumors and found that the 18F-FDG uptake of primary tumors was significantly associated with tumor size. In another study, small gastric cancers were reported to be difficult to detect by 18F-FDG PET . Interestingly, for detection of tumors less than 4 cm, 68Ga-FAPI-04 PET also provided a better sensitivity than (100% vs. 70%, P = 0.062) 18F-FDG, although the difference is not significant. All 17 tumors ≤ 4 cm in size, including 5 with negative 18F-FDG uptake, were detected by 68Ga-FAPI-04 PET in our study. The uptake of 68Ga-FAPI-04 in small gastric cancers (≤ 4 cm in diameter) was lower than that in large gastric cancers (> 4 cm in diameter), it needs to be further confirmed whether 68Ga-FAPI-04 PET has advantages in detecting small gastric cancers.
The depth of invasion in primary gastric cancer is essential for prognosis and therapy. The results from previous studies have shown that the SUVmax of 18F-FDG does not correlate with the degree of infiltration [31, 33, 34]. In addition, other tracers used to detect gastric cancer, such as 18F-FLT, are not suitable for evaluating the degree of infiltration in gastric cancers . In our study, the SUVmax of 68Ga-FAPI-04 in pathologically T4 tumors was significantly higher than that in T1 and T2 tumors (10.9 ± 4.3 vs. 3.8 ± 2.1, P = 0.0002). Thus, 68Ga-FAPI-04 PET could provide insight into the degree of tumor invasion in gastric cancer.
In our patient-based analysis, the sensitivity of 18F-FDG PET for detecting regional metastatic lymph nodes was 50% (5/10), which is in line with previous studies of 18F-FDG PET for detecting lymph node metastasis (mean sensitivity: 45%) . The sensitivity of 68Ga-FAPI-04 PET for the detection of regional metastatic lymph nodes was 60% (6/10). As shown in Fig. 5, lymph node metastasis at the lesser curvature of the stomach in one patient with moderately differentiated adenocarcinoma presented elevated uptake of 68Ga-FAPI-04 but negative uptake of 18F-FDG. Chen et al.  reported 12 cases of gastric cancer (4 signet ring cell carcinomas and 8 adenocarcinomas) and found that 68Ga-FAPI-04 PET/CT showed higher sensitivity than 18F-FDG PET/CT for the detection of lymph node metastases of gastric cancer from their lesion-based analysis.
In addition, in contrast to 18F-FDG PET, 68Ga-FAPI-04 PET has an advantage in detecting distant metastasis in gastric cancer. Although pathological analysis of a biopsy serves as the gold standard for the diagnosis of metastases in gastric cancer, the noninvasive imaging technique has become a standard modality for staging before treatment. In this study, distant lymph nodes in 3 patients showed high 68Ga-FAPI-04 uptake but negative 18F-FDG uptake. These distant lymph nodes, which included the posterior peritoneum lymph nodes and supraclavicular lymph nodes, are prevalent metastatic sites of gastric cancer. As shown in Fig. 6, one patient displayed discernible 68Ga-FAPI-04 uptake in the peritoneum that was not detected by 18F-FDG PET. It is known that distant metastasis has an important impact on treatment and prognosis. In gastric cancer, peritoneal metastasis is associated with a poor prognosis . According to previous studies, the sensitivity of 18F-FDG PET for the detection of metastatic peritoneal disease is low [36, 37]. Overall, 68Ga-FAPI-04 PET may play an important role in detecting metastases of gastric cancer with or without confirmation by pathological biopsy.
There were several limitations to our study. The small sample size limited the power of the analysis, and not all histological types of gastric cancer were analyzed. Moreover, as there was no histological verification available for some cases of highly suspicious distant metastases, latent bias may be present. We also intended to investigate the advantage of PET/MR in the detection of gastric cancer metastases, but it seems infeasible due to the lack of contrast-enhanced MRI data in this study. Nevertheless, the usefulness of 68Ga-FAPI-04 PET for the detection of distant metastases of gastric cancer needs to be further investigated on a larger cohort.