Fibroblast activation protein (FAP)–targeted PET imaging with radiolabeled fibroblast activation protein inhibitors (FAPI) has emerged as a promising modality in oncologic imaging due to its high tumor-to-background contrast. However, increasing evidence indicates that FAPI uptake is not tumor-specific and may occur in a wide range of non-malignant conditions. This narrative review summarizes the current evidence on non-malignant FAPI uptake patterns. A literature search was conducted using PubMed, Scopus, and Web of Science up to January 2026, including studies reporting FAPI uptake in inflammatory diseases, fibrotic disorders, physiological conditions, post-interventional changes, and benign stromal lesions. Non-malignant FAPI uptake reflects activated fibroblasts involved in tissue repair, fibrosis, and extracellular matrix remodeling across multiple organ systems. Reported entities include infectious and autoimmune diseases, IgG4-related disease, vasculitis, interstitial lung disease, hepatic and renal fibrosis, and myocardial remodeling. Uptake is also observed in benign tumors such as leiomyomas, schwannomas, and fibroadenomas. In addition, physiological uptake in hormonally responsive tissues, reactive lymph nodes, and post-procedural changes may further complicate interpretation. A notable overlap in standardized uptake values between benign and malignant lesions represents a key diagnostic limitation. Recognition of these patterns is essential to avoid false-positive oncologic interpretations. Standardized interpretation frameworks, prospective validation, and increased histopathologic correlation are needed to improve diagnostic specificity and support safe clinical implementation, including potential theranostic applications.
Al-Ibraheem et al. (Fri,) studied this question.