Our study demonstrated that pancreatic alpha cells normally express FAP. Indeed, all the patients (40/40) resulted positive at immunohistochemistry. Additionally, no difference in FAP expression was found according to different pancreatic cancer types (NET vs adenocarcinoma) nor according to neoadjuvant chemotherapy in the adenocarcinoma cohort (received or not received).
Our results are in line with data from Busek et al. [9], who demonstrated the co-expression of FAP and dipeptidyl peptidase-IV (DPP-IV) in pancreatic alpha cells in adult humans, potentially implying modulation of the paracrine signaling in the human Langerhans islets.
The implications for FAPI-PET/CT imaging are expected to be limited since Langerhans insulae are definitely smaller (mean islet diameter of 108.92 µm (± 6.27 µm) [10] than the resolution limit of a PET scanner (2.36 mm FWHM)[11]. According to biodistribution studies, Mona et al. found average [68Ga]Ga-FAPi-46 SUVmean at the pancreas to be < 2.5 [12]. Additionally, in the head-to-head comparison, Giesel et al. found that mean SUVmax in the pancreas was significantly lower for [68Ga]Ga-FAPI than [18F]FDG (1.82 vs. 1.99; p = 0.027)[13]. Figure 5 shows no significantly increased uptake in the pancreas as compared to background in the rectal cancer patient scanned by our group at Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology in Wuhan, China.
Consequently, alpha cells uptake does not affect primary pancreas neoplasms detection. According to the recent paper from Hirmas et al., mean primary exocrine pancreatic cancer tumor-to-background ratio was prominent, and significantly higher for [68Ga]Ga-FAPI than [18F]FDG (14.7 vs. 3.0, p < 0.001) [14].
Indeed, FAP expression by cancer lesions confirms the opportunity to detect and stage malignant lesions, both NET and adenocarcinoma lesions. FAPI uptake has been demonstrated by initial investigations [15, 16] in NET patients. Kratochwil et al. reported NET lesions to display an average SUVmax ranging between 6 and 12 [16]. A case of a NET patient, scanned by our group at Department of Nuclear Medicine and Minnan PET Center, Xiamen University, is illustrated in Fig. 6.
Moreover, Kreppel suggested FAPI PET/CT-derived parameters for patient risk-stratification. Indeed, they found ratio between volumes of liver metastases positive on FAPI and DOTATOC scans to be significantly and strongly correlated with Ki-67 (rho = 0.808, p < 0.01)[17]. In pancreatic ductal carcinoma Kratochwil et al. reported that average SUVmax ranged between 6 and 12, while the tumor-to-background ratios were more than 3 [18]. Hirmas et al. found mean primary tumor and metastatic lesions SUVmax to be 13.2 and 9.4, respectively[14]. These high uptake values result in high image contrast and excellent tumor delineation. Moreover, in the study by Röhrich et al. the authors found FAPI PET/CT changed TNM staging in 10/19 patients compared to the contrast-enhanced CT [19].
The implications for FAPI-targeted treatments on glucose metabolism have not been elucidated yet. The initial reports in a variety of cancer types have not reported increased glucose levels interpreted as radioligand treatment related. Ballal et al. in a cohort of 15 radioiodine-refractory differentiated thyroid cancer found that none of the patients experienced grade 3 or 4 hematological, renal, or liver toxicity after [177Lu]Lu-DOTAGA.(SA.FAPi)2[20]. In the study by Fendler et al. [90Y]-FAPI-46 treatment-related grade 3 or 4 adverse events were observed in 38% of patients being thrombocytopenia and anemia the most prevalent [21].
As for dosimetric assessments, in a recent study dose-limiting organ with [177Lu]Lu-DOTA.SA.FAPi was found to be the kidney, followed by colon. While the highest estimated absorbed radiation dose by [177Lu]Lu-DOTAGA.(SA.FAPi)2 was observed in the colon, followed by gall bladder, pancreas, and kidneys[22]. The dosimetric assessments in the study be Fendler et al. focused on bone marrow, liver, lung and kidneys[21]. In view of the peculiar Langerhans insulae anatomy, future microdosimetry studies might elucidate properly the absorbed dose to the endocrine component of the pancreas and eventually establish with radionuclide holds the best properties for FAPI-targeted treatments.
We acknowledged some limitations in our study. Firstly, the retrospective design; however, multicenter data availability provided robustness to the results. Some of the included patients received different chemotherapy regiments before surgery which might have influenced the results; however, immunohistochemistry demonstrated score 2 expression of FAP in both treatment naïve and treated groups, suggesting expression is not significantly related to treatment. We have not performed PET/CT imaging since it was out of scope of the present study.
In conclusion, pancreatic Langerhans islets alpha cells normally express FAP, in both chemotherapy treated and treatment naïve patients. In view of promising anticancer activity using FAP-targeting radioligands as reported in recent literature these radiopharmaceuticals are expected to be increasingly used and early translated to clinics. Our results suggest the need to better elucidate FAPI radioligand therapy effects on the Langerhans insulae function and establish the limit absorbed dose.