The activation assessed histologically in a single biopsy

The gap

Evidence profile

Sourced from the future work and limitations of the source papers, classified as general, drawn from work published between 2025 and 2026, spanning 3 journals. Those papers have been cited 13 times in total.

Supporting evidence — 3 representative gaps

• Nonmalignant FAPI Uptake on PET/CT: From Diagnostic Pitfall to Fibroblast Biology Insights (2026) · Indian Journal of Nuclear Medicine · cited 1× · doi

  Future research on non-malignant FAPI uptake should aim to better define its biological specificity and clinical utility across inflammatory and fibrotic diseases. Although current evidence shows that FAPI uptake reflects fibroblast activation during tissue remodelling, distinguishing malignant stromal activation from benign fibro-inflammatory processes remains a key diagnostic challenge. Large prospective cohorts are needed to systematically characterise uptake patterns, SUV ranges, and temporal behaviour of FAPI in non-oncologic conditions such as autoimmune diseases, chronic infections, and organ fibrosis. Establishing reference patterns may improve interpretation criteria and reduce false-positive findings during oncologic imaging. e development of standardised interpretation criteria, analogous to PROMISE criteria for PSMA PET, may help reduce variability in FAPI PET interpretation. Beyond diagnostic applications, FAPI imaging may also evolve into a tool for monitoring antifibrotic or immunomodulatory therapies. e ability to noninvasively visualise activated fibroblasts could enable earlier assessment of treatment response before structural changes become apparent on conventional imaging. In addition, the high expression of fibroblast activation protein in fibrotic and fibro-inflammatory tissues raises the possibility of FAPI- based theranostic strategies. Radiolabelled FAP inhibitors such as 177Lu-FAPI could potentially target activated fibroblasts to modulate pathological fibrosis. Another important research priority is determining the optimal timing of imaging for non-malignant conditions. Current protocols typically rely on early imaging after tracer injection, which were largely optimised for oncologic applications. However, inflammatory and fibrotic lesions may demonstrate different tracer kinetics. Future studies should evaluate dual-time-point or delayed imaging to determine whether these approaches improve differentiation between inflammation, fibrosis, and malignancy. formal analysis, validation, Author contributions: AA: Conceptualization, methodology, supervision, investigation, resources, visualization, and writing – review and editing; SM: Conceptualization, methodology, formal analysis, data resources, visualization, writing curation, – original draft, and writing – review and editing; MA: investigation, Al-Ibraheem, et al.: Fibroblast Activation Protein Inhibitor (FAPI) Uptake Beyond Malignancy Conceptualization, methodology, formal analysis, investigation, resources, data curation, visualization, and writing – original draft; SO: Conceptualization, methodology, formal analysis, investigation, resources, visualization, and writing – original draft; MA: Conceptualization, methodology,

  generalfuture work
  Keywords: fapi imaging conceptualization methodology writing uptake inflammatory activation formal investigation resources visualization malignant fibrotic fibroblast
• Nuclear Medicine and Molecular Imaging in Urothelial Cancer: Current Status and Future Directions (2025) · Cancers · cited 12× · doi

  6.1. FAPI PET An area of exciting ongoing research in PET imaging is the use of fibroblast activation protein inhibitors (FAPIs), which have demonstrated good results in a range of tumours and appear promising in urothelial cancer. 68Ga-labelled FAPI PET specifically targets FAP, which is highly expressed by cancer-associated fibroblasts in the tumour stroma. This tracer rapidly accumulates in lesions while maintaining low background activity, resulting in a high tumour-to-background ratio and improved lesion detection. Unlike many targets, FAP is minimally expressed in healthy tissue, making it a promising candidate for both diagnostic and therapeutic applications [53,54]. Although strong evidence for the use of this novel technique in urothelial cancer is still lacking, several small studies highlight the advantages of 68Ga FAPI PET-CT over traditional imaging. Unterrainer et al. found that in a small patient group retrospectively assessed, FAPI PET-CT identified lesions in 26.7% of patients that were missed by conventional CT. Furthermore, in this study, 68Ga FAPI PET-CT was able to accurately exclude malignancy for patients previously labelled as having suspicious pelvic lymph nodes and pulmonary nodules on conventional imaging [55,56]. Novruzov et al. demonstrated that 68Ga FAPI PET-CT had a higher tumour uptake and mean SUVmax than 18F FDG PET-CT, with an additional nine lesions detected exclusively by FAPI PET [57]. Similarly, a small study by Koshkin et al. noted that FAPI PET-CT detected small nodal metastases in patients with both localised and metastatic urothelial cancer, that would not otherwise meet Response Evaluation Criteria In Solid Tumours (RECIST) criteria for malignancy, impacting clinical decisions [58,59]. These findings indicate that FAPI PET-CT could enhance staging accuracy and guide treatment. 6.2. Carbonic Anhydrase IX (CAIX) CAIX is expressed in 70% to 90% of bladder cancers, but not in normal urothelial tis- sue [60]. It is a promising tumour marker for urothelial carcinoma and is hoped to be a target for the development of new treatments [61]. Several biodistribution studies have already eval- uated 89Zirconium (89Zr)-labelled girentuximab, an anti-CAIX monoclonal antibody (mAb) in renal cell carcinoma [62–64]. A similar approach is being tested in urothelial cancer in the Cancers 2025, 17, 232 8 of 16 phase 1 ZIPUP trial, which is currently examining the feasibility, safety, and utility of PET-CT using 89Zr girentuximab (89Zr TLX250) in patients either undergoing pre-operative staging of urothelial carcinoma or bladder cancer for curative intent, or with known metastatic urothelial carcinoma. 89Zr TLX250 may have utility in the accurate staging of bladder and urothelial carcinomas, with less renal excretion compared to FDG [65]. Hofman et al. recently published a first-in-human study looking at the safety, imaging, and dosimetry of a CAIX-targeting peptide, 68Ga DPI-4452, in patients with clear cell renal

  generalfuture work
  Keywords: fapi urothelial cancer patients imaging tumour small caix carcinoma promising labelled expressed lesions staging bladder
• Prognostic impact of discordant lesions on [18F]FDG and [68Ga]Ga-FAPI-04 PET/CT compared to histological FAP expression in neuroendocrine neoplasms (2026) · Frontiers in Nuclear Medicine · doi

  the activation assessed histologically in a single biopsy. However, in addition to to immunohistochemistry (32), the spatial mismatch between biopsy sites and imaging-defined discordant lesions represents an important methodological limitation. Among patients with FDG+/FAPI− discordant lesions, biopsies were obtained from the same organ in only a minority of cases, and even in those cases, lesion-level correspondence could not be confirmed. In most patients, biopsies originated from anatomically distinct lesion-by-lesion comparison tumor sites, precluding direct between histological FAP expression and PET imaging findings. Given intrapatient heterogeneity of aggressive NENs, this mismatch may substantially limit the between biological immunohistochemistry parameters. Consequently, histological FAP expression from a single biopsy site may not adequately reflect the spatial heterogeneity of tumor burden stromal activation across of imaging-derived interpretability and the whole-body the known correlations interest increasing in stroma-targeted assessed by PET/CT. Future prospective studies with spatially matched biopsies are therefore essential to validate the tissue– imaging relationship at the lesion level, especially in view of the therapies and theranostic approaches with FAP-directed radioligands (10, 33). Regarding prognosis, our data showed that, in addition to the presence of discordant lesions and the expected patient age, [18F]FDG-derived tumor burden metrics ([18F]FDG-TV and [18F]FDG-TLU) were significantly associated with shorter PFS, whereas histological FAP expression (IRS-FAP) was not. These results are consistent with previous reports highlighting the prognostic value of [18F]FDG uptake in aggressive NENs (5) and suggest that tumor metabolism remains a more reliable predictor of outcome than stromal activity in this patient population. It also indicates that (dual-tracer) PET/CT with [18F]FDG and [68Ga]Ga-FAPI-04 as a whole-body diagnostic tool provides deeper insights into tumor phenotype in all lesions and may be superior for estimating prognosis in patients with aggressive NENs.

  generallimitationsevidence 5/5
  Keywords: tumor imaging lesions lesion biopsy discordant patients biopsies histological expression aggressive nens activation assessed single

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