Distinguishing Benign and Malignant Findings on [68 Ga]-FAPI PET/CT Based on Quantitative SUV Measurements

This retrospective study primarily aimed to provide an overview of the frequency and clinical significance of incidental benign findings in [68 Ga]-FAPI PET/CT. Additionally, we sought to determine a reliable, accurate parameter or assessment method to facilitate imaging-based differentiation of those lesions. To this end, we analyzed a large patient cohort with a broad spectrum of histopathological verified cancer entities accompanied by confounding equivocal findings.

To distinguish between FAP expression of CAFs and the reactivation of the so-called quiescent fibroblasts in benign remodeling processes, i.e., wound healing and fibrotic changes, or physiological changes in hormone sensitive organs such as breast or uterus [2627] is still a clinical challenge.

Studies with smooth muscle cells and formation of atherosclerotic plaques revealed a strong correlation between an increase of FAP expression and atherosclerotic changes in arteries which seems to be a poor prognostic factor because of the formation of thin-cap human coronary plaques [26]. In our evaluation, we observed 59 cases with moderately elevated FAPI uptake not only at sites of visible atherosclerotic plaques, but also in the thoracic and abdominal arteries as well as coronary arteries that showed no detectable signs of arteriosclerosis. Presumably, the macrophage infiltration due to a subclinical atherogenesis leads to an increased FAP expression by TNFα-secretion [28]. However, this hypothesis requires further research to determine whether a decent increase of FAPI uptake within the vessel walls is a suitable predictive/prognostic factor for the atherosclerotic plaque formation and development of clinical manifestations.

As for FAPI uptake of the testicles, it has been established that seminiferous tubules are surrounded by the lamina propria, which consists of the basement membrane and the outer layers of myoid cells, connective tissue, and fibroblasts, whereas the outmost layers consist of mainly fibroblasts [29]. The composition of the peritubular wall can undergo dramatic changes. A study suggested that tryptase produced by peritubular mast cells may be directly involved in the development fibrosis, in particular the fibrotic thickening of the walls of the seminiferous tubules, causing infertility [30]. It might be possible, considering the advanced age of most male patients included in our study, that moderate FAPI uptake in the testicles might be associated with the these changes.

Among the benign lesions shown on [68 Ga]-FAPI PET/CT, we observed 50 cases with moderate to diffusely high FAPI uptake in the pancreas. Some of these patients have had a prior cancer surgery, e.g., partial resection or postoperative pancreatitis as surgical complication. In other cases, without a surgical history and no clinical information suggesting acute pancreatitis, this appears to be related to chronic pancreatitis or fibrotic changes within the parenchyma. Furthermore, 25 patients were identified demonstrating moderate FAPI uptake at the site of active wound healing after operation (i.e., laparotomy). Overall, the diagnosis of an early tumor recurrence at sites of wound healing might be challenging due to high background activity of the target organ during the early postoperative period.

Several studies report an upregulation of FAPI in patients with thyroiditis and fibrotic changes in the thyroid parenchyma whereas FAPI uptake in differentiated thyroid cancers remains low [1921]. We had a confirmed case of Hashimoto’s thyroiditis in a patient with a diffuse increased FAPI uptake. Yet, 75 patients without history of thyroid pathologies demonstrated a diffuse or focal, moderate FAPI uptake in the thyroid parenchyma. Diffuse uptake of the thyroid might be linked to fibrotic changes of the thyroid architecture (e.g., lymphocyte and fibroblast infiltration) due to undiagnosed autoimmune diseases, like Hashimoto thyroiditis [31], Graves’ disease [32], or immune-related thyroiditis caused by immunosuppressive therapy [33]. A recently published study supports this assumption [16].

Similarly, in 33 cases or 42% of male patients of our cohort, we noticed diffuse moderate uptake of FAPI in the prostate. The prevalence of prostatitis is estimated to range from 2.2 to 9.7% [34]; hence, a fourfold increase of incidental prostatitis seems very unlikely. Moreover, FAP expression in the benign prostate is shown to be relatively low. However, several studies report a crucial role of inflammation for the development and progression of benign prostatic hyperplasia (BPH) which has a high prevalence of more than 50% after 6th decade [35]. Hesterberg et al. demonstrated that FAP expression is significantly increased in the tumor microenvironment adjacent to Gleason grade 4 prostate cancer compared to benign prostate. Therefore, even a moderate, focal uptake of FAPI in the prostate should initiate diagnostic work-up in order to rule out prostate cancer [36] and an even distributed moderate to high FAPI uptake in the prostate might be assigned to BPH.

In concordance with previously conducted studies, we also noted a high, diffuse FAPI uptake in patients with fibrotic lung (12 cases) and liver diseases (9 cases). The application of FAPI for the diagnosis of primary or secondary hepatic malignancy is expected to be a promising diagnostic tool because of very low background uptake in liver tissue and thus excellent target-to-background ratio. However, the primary hepatic malignancies usually emerge in patients with fibrotic changes or advanced cirrhosis, which still might act as a limiting factor [37]. Moreover, intrahepatic expression of FAP seems to correlate with the degree of fibrosis [38]. Our evaluation seems to support these findings, as Fig. 3 shows a patient with liver cirrhosis demonstrating high FAPI uptake in the liver. In addition, the conditions with chronic inflammation or infection in the lung, such as bronchiectasis, rheumatological disorders with pulmonary manifestations, restrictive lung disease or infections might represent, among others, a limiting factor for pulmonary tumor diagnostic.

Most of our patient cohort showed a moderate uptake in the rectum without any known underlying pathology. Zheng et al. reported of this phenomenon and postulated that mild fibrous tissue hyperplasia associated with varicose veins and the inflammation as a cause of increased FAP expression [18]. Undoubtedly, persistent straining, pressure, and microinjuries in the epithelium of the anal canal might cause a certain kind of the so-called never healing wound which, as we know, leads to a stronger FAP expression. Moreover, the increased glucose metabolism that is often detected by high FDG uptake also supports the hypothesis of chronic inflammatory changes of the epithelium in the anal canal. However, to our knowledge, there is no significant literature data supporting the correlation between fibrous tissue hyperplasia in varicose veins and FAP expression. Similarly, in 57 out of 155 patients, we identified moderate uptake in the esophagus, predominantly in the lower third of the esophagus. Gastroesophageal reflux disease (GERD) is one of the most predominant gastrointestinal diseases with a prevalence in the US between 18.1–27.8% and 8.8–25.9% in Europe (an even higher incidence is to be assumed due to an availability of over-the-counter anti-acidic medication) [39, 40]. Studies suggest that cell damage and inflammation caused by gastric fluid may trigger the wound healing process and subsequent immunomodulation, promoted by inflammatory cytokines and chemokine activation [41]. Inflammatory cytokines cause fibroblast to myofibroblast transition, leading to fibrosis [42].

Beyond the characterization of benign findings in this study, we elaborated on the equivocal findings and classified them into benign and malignant lesions according to their etiology, which was determined by analyzing and crosschecking the electronic medical records including available pathology reports or reports of other imaging modalities. To our knowledge, a reliable parameter, or a diagnostic criterion such as a cutoff value for FAPI uptake is still missing. Our aim was to identify a pattern of FAPI uptake in benign lesions that could reliably predict the accurate diagnosis of equivocal findings in the clinical setting and thereby largely prevent misdiagnosis and mismanagement. Although there was sporadically overlap in the tracer uptake between benign and malignant lesions in some patients, we detected statistically significant differences in SUVmax, SUVmean, and LBR in accordance with previous studies.

We performed ROC analysis to evaluate the diagnostic performance of [68 Ga]-FAPI PET/CT by assessing the semiquantitative metabolic parameters (SUVmax, SUVmean, and LBR) in differentiation of equivocal findings on [68 Ga]-FAPI PET/CT, which yielded an excellent trade-off between sensitivity and specificity. We found a sensitivity of 78.8% and specificity of 85,8% at a SUVmax cutoff value of 5.5 under AUC of 0.89. Our evaluation showed better diagnostic accuracy at a SUVmean cutoff value of 3.3 with a sensitivity of 84.9% and a specificity of 85,3% under AUC of 0.916. The cumulative accuracy and negative predictive factor for all three parameters are 82,8% and 89,7% respectively. Furthermore, the comparison of the ROC curves yielded a favorable result for the SUVmean, which, however, can be regarded as equivalent to other parameters. However, since the SUVmax and SUVmean are not always comparable between different PET centers without cross-calibration of scanner hardware and reconstruction algorithms, the LBR might be a more reproducible predictive factor for the clinical and research setting as well. Since the FAP ligands, FAPI-02 and FAPI-04 are considered interchangeable due to comparable biodistribution at 1 h p.i. and similar diagnostic performance, no relevant influence on our analysis is expected [1].

Thus, our findings suggest rather promising, accurate diagnostic criteria for [68 Ga]-FAPI PET/CT distinguishing equivocal lesions based on semiquantitative metabolic parameters. We suggest that our findings can facilitate diagnostics by establishing predictable patterns of FAPI accumulation, especially while taking patient history into account. We have solely used semiquantitative parameters for the assessment, but if qualitative criteria such as the pattern and location of lesions, which can be evaluated only by a nuclear medicine physician, are also used, the diagnostic accuracy will probably increase further.

This investigation contained several limitations including its retrospective study design, with the associated risks of selection bias, since the cohort only consistsed of patients with known malignancies, frequently at advanced stages. Furthermore, the study is lacking a gold standard test for the validation of benign lesions. On the other hand, pathological analysis of every equivocal finding on [68 Ga]-FAPI PET/CT would be unfeasible and unethical. Finally, our results were obtained from a single institution and further multicenter studies are warranted to validate the utility of these metabolic threshold or cutoff values for differentiation of equivocal findings on [68 Ga]-FAPI PET/CT.

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