This single-center retrospective analysis sought to evaluate the usefulness and impact of 68Ga-FAPI-PET/CT in a cohort of patients with a variety of rare cancer diseases (Figure 2). These are characterized by a common epithelial origin as well as low incidences and are correspondingly frequently neglected as less people are affected. Nevertheless, patients with rare malignancies should yet receive the best possible diagnostic and therapeutic approach, highlighting the immense importance of studies, particularly concerning these tumor entities.
68Ga-FAPI-PET/CT proved to supplement standard diagnostics successfully in several tumor entities such as in pancreaticobiliary and gastrointestinal carcinomas, which also presented the highest uptake of all included subtypes in our analysis. A previously conducted study supports these findings, as it indicates that FAPI scans of patients with hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCC) seem to be equivalent to contrast enhanced computed tomography (CE-CT) and magnetic resonance imaging (MRI) and even superior to FDG-PET/CT (14). Moreover, FAPI-PET/CT imaging of liver lesions was capable of successfully distinguishing between HCC, non-HCC and normal liver parenchyma (15). CCC (n=5) in particular presented an exceedingly high mean uptake with a SUVmax of 11 (range 3.9-26). A possible explanation might be the underlying microenvironment, as CCCs are characterized by a highly desmoplastic reaction, in which cancer associated fibroblasts are among the predominant cell types, possibly contributing to growth and therapeutic resistance (16,17). Simultaneously, CAFs may represent a therapeutic target (18).
Another aspect that has to be considered is the potential of FAPI-PET/CT in primarily detecting peritoneal carcinomatosis and, moreover, in improving the precision of specifying its extent. Furthermore, peritoneal carcinomatosis impressed with not only strong tracer accumulation but also excellent TBRs, allowing an improved tumor delineation. Zhao et al. evaluated the potential of FAPI-PET/CT in patients with peritoneal carcinomatosis in comparison to FDG-PET/CT, showing a clear superior peritoneal cancer index score and a higher sensitivity for FAPI in cancer patients (8). This may be due to low physiological accumulation of 68Ga-FAPI compared with 18F-FDG in the intestinal tract, leading to scarce unspecific uptake in the peritoneal cavity. Exceptionally favorable results regarding peritoneal carcinomatosis were obtained in patients with gastric cancer, which is in concordance with our analyses as the mean SUVmax (10.1) of patients with gastric cancer is stronger than the mean SUVmax (8.5) of all measured peritoneal carcinomatoses, enabling particularly clear imaging contrasts (Figure 3). This may facilitate therapeutic decisions and is of assistance for radiotherapy planning with regard to target volume definition. Within the remaining tumor entities, peritoneal carcinomatosis still presented a rather high uptake, yielding the possibility to enhance standard diagnostic procedure and reduce the amount of missed diagnoses (8).
68Ga-FAPI PET/CT in patients with urinary tract cancer, presented a rather strong mean uptake (SUVmax 9.5) as well. For staging purpose, the European Association of Urology guidelines currently recommends contrast-enhanced CT of the chest and abdomen/pelvis (19,20). However, conventional CT has some limitations due to imprecise determination of the tumor allocation, extent and invasion. As 68Ga-FAPI-PET/CT most clearly demonstrated excellent tumor visualization, it may be able to complement standard diagnostic imaging and improve the precision of tumor detection, delineation and invasion status. Furthermore, one exemplary patient posed to present equally strong uptake in the tumorous lesion only 10 minutes after tracer administration compared with 1-hour, proving the feasibility of FAPI-PET/CT for rapid and adequate images, which may enable reduced radiation burden and improved practical implementation (10,11,12,13) (Figure 4). This patient suffered from neuroendocrine urothelial carcinoma and the favorable strong uptake demonstrates the potential of FAPI in neuroendocrine tumors, which are knowingly associated with the development of fibrosis (21,22) and, therefore, presenting an auspicious target which has been reported in different case reports (23,24).
One patient diagnosed with esthesioneuroblastoma, located retro-maxillary, even achieved higher uptake 10 min after tracer application than 1 h later (Figure 5), representing a prerequisite of the capabilities of FAPI-PET/CT in head-and-neck cancers. This subgroup has proven strong uptakes, which can be interpreted with respect to its mostly epithelial origin, as 90% of all epithelial tumors have shown high FAP expression (5). This is consistent with our analyses where all head-and neck cancers with epithelial origin (n=15) showed a notably higher mean SUVmax (10.11) than those of non-epithelial or unknown origin (n=9) obtaining a SUVmax of 7.5. Head and neck cancers are known to often grow diffusely, making the discrimination between healthy and tumorous tissue difficult. Thus, FAPI-PET/CT might be of help producing sharp imaging contrasts with high tumor uptake and low background activity, represented by high TBRs. This may also facilitate therapy guidance as the main approach is radiotherapy or combined radiochemotherapy, which requires precise and accurate tumor delineation (Figure 6) (25).
To find the most suitable therapeutic approach, knowing the origin of the primary tumor is of inevitable necessity. Lack of knowledge regarding tissue origin leads to a substantially more challenging treatment plan. FAPI-PET/CT, was able to determine the location of the primary tumor and subsequently guide histologically confirmation, in a patient, where standard diagnostic imaging was insufficient beforehand (Figure 7).
This retrospective single-center analysis contains several limitations such as the use of different FAPI-ligands. Nonetheless these ligands share a common backbone and thus early biodistribution and tumor uptake seem to be comparable according to current studies (9,10). The included subgroups differed in the number of patients limiting comparative analysis. No comparison with the current standard oncological tracer 18FDG was conducted. Furthermore, some diseases, even if declared rare by definition, occur fairly frequent such as HCC or urothelial carcinoma. Additionally, a variety of definitions of rare diseases are existing worldwide. However, a prevalence of no more than 1 person out of 2000 seems to be in concordance with the global average prevalence threshold (27). Lacking a gold standard validation of discrepant lesions evaluation of sensitivity, specificity and accuracy was beyond the scope of this work.