In the present prospective study, we aimed to investigate the avidity of 68Ga-FAPI-04 in CRC and to explore the potential utility of 68Ga-FAPI PET/CT as the sole imaging modality in primary and recurrent CRC. Our analyses indicated that 68Ga-FAPI PET/CT improved tumor staging in CRC patients because of favorable tumor/background activity and low tracer uptake in the gastrointestinal tract. Moreover, we found signet-ring/mucinous carcinomas accumulated more 68Ga-FAPI than 18F-FDG, while FAPI-avidity was lower than FDG-avidity in poorly differentiated carcinomas.
As key constituents of the tumor stroma, CAFs can support an immunosuppressive microenvironment, tumor cell growth, progression, and metastatic potential. Expressed by CAFs, FAP is an attractive diagnostic and therapeutic target [8, 10, 17, 18]. 68Ga-FAPI PET/CT imaging is characterized by high tumor/background activity and is more sensitive than 18F-FDG PET/CT in identifying primary gastrointestinal carcinoma lesions [12, 19].
The origin, number, and distribution of FAP-expressing CAFs as well as the number of FAP molecules per cell may differ among tumors. Mona et al. [20] reported the presence of a strong association between tumor 68Ga-FAPI uptake intensity and histopathological FAP expression in colon cancer. We expected variations in intratumoral tracer distribution in treatment-naïve patients with specific histopathologic types of CRC. In this study, we firstly demonstrated more FAP expression in signet-ring/mucinous carcinomas, which normal exhibited low 18F-FDG uptake [6, 7, 21, 22]. The finding revealed 68Ga-FAPI PET/CT would have the lower false negative rate in detecting primary and metastatic CRC lesions, comparing to 18F-FDG PET/CT. Interestingly, we also found that poorly differentiated carcinomas exhibited significantly lower 68Ga-FAPI uptake compared with 18F-FDG even though this subtype were both 68Ga-FAPI- and 18F-FDG-avidity.
TNM classification provides the traditional and current guidelines to classify the extent of cancer spread. The degree of tumor progression and invasion at the time of surgical resection, as well as patient outcome, are estimated on the basis of this staging system for CRC. Our study demonstrated that 68Ga-FAPI-PET/CT was able to detect both primary tumors and metastases arising from CRC. The sensitivity was 100% with both 68Ga-FAPI and 18F-FDG PET/CT and no significancy was found in SUV values in 68Ga-FAPI and 18F-FDG PET/CT imagines. Furthermore, we found that FAPI and FDG uptakes in treatment-naïve lesions had no significant difference from those in posttreatment lesions. Thus, 68Ga-FAPI-PET/CT had a similar detecting efficiency to 18F-FDG PET/CT in T stage.
The superiority of 18F-FDG PET/CT in CRC is evident in the detection of lymph nodes and distant metastases and the detection of additional metastases can significantly change treatment plans [23–25]. However, several studies showed that the detection of metastatic regional nodes was low/moderate using 18F-FDG PET/CT, demonstrating the limitations of this method [26, 27]. Several studies suggest that CRC commonly harbor cancer-associated fibroblasts expressing fibroblast activation protein. Thus, this study had explored the reliability of 68Ga-FAPI-PET/CT in detection of metastatic CRC lesions. Our result revealed that 68Ga-FAPI PET/CT identified additional findings in 30 metastatic and 2 inflammatory lymph nodes from 17 patients with CRC, and improved N stage in CRC patients. In addition, the 68Ga-FAPI uptake was higher than the 18F-FDG uptake in abdominal and pelvic involved lymph nodes, whereas thoracic FDG-avid inflammatory/age-related lymph nodes showed FAPI-negative.
According to M stage, early detection of isolated metastasis to the liver or other sites often improves survival following radical resection [28]. Because of the moderate FDG-uptake in liver, 18F-FDG PET/CT was not the first choice for identifying the liver metastasis. Our data showed hepatic background was significantly lower when using 68Ga-FAPI compared to 18F-FDG, in according to the previous study. Thus, FAPI-imaging might be advantageous for patients with suspected liver metastases leading to a potential high detection rate. In the present study, the smallest diameter of the detected lesions was approximately 0.7 cm. Peritoneum is another common site of CRC metastasis [29] and the degree of peritoneal metastasis also determines the choice of treatment [24, 30, 31]. The detection rate of peritoneal metastasis using 18F-FDG PET/CT is not high, primarily due to intestinal inflammatory uptake, small lesions, and other factors including rare pathological types. 68Ga-FAPI is an active fibroblast-targeted imaging agent, and the development of peritoneal metastases is primarily due to active fibroblasts [29], supported by the significantly higher 68Ga-FAPI uptake in peritoneal metastatic lesions compared with 18F-FDG observed in the present study.
In the present study, we also found that the 68Ga-FAPI uptake was significantly higher than that of 18F-FDG in uterus, which might be caused by the presence of active fibroblasts in the uterus [32]. This finding suggests that the SUVmax value of lesions (primary or/and metastases) located in the pelvic area might be affected by a high 68Ga-FAPI uptake, a potential shortcoming of 68Ga-FAPI PET/CT imaging.
This study also has several limitations which should be acknowledged. The cohort size was small, and the number of patients with bone metastases was low. Future studies with larger cohorts are warranted to provide a more comprehensive analyses on the utility of 68Ga-FAPI PET/CT in CRC.