In this study, [68Ga]FAPI-46 PET/CT demonstrated promising results in detecting mediastinal nodal metastasis in a specifically selected group of NSCLC patients, where [18F]FDG PET/CT may exhibit limitations, potentially requiring preoperative EBUS-TBNA. [68Ga]FAPI-46 PET/CT accurately detected eight out of nine N2-metastatic patients while excluding all non-metastatic patients. It exhibited superior discriminative accuracy in the per-station assessment, resulting from a distinct difference in tracer uptake between non-metastatic and metastatic lesions.

Incorporating [68Ga]FAPI-46 PET/CT into clinical practice may offer dual benefits. First, its enhanced sensitivity upstaged 13.0% of patients without compromising specificity, reducing the risk of occult N2 metastases and guiding alternative treatments for high-stage patients who may not benefit from upfront surgery. Second, it distinguished metastatic stations based solely on tracer avidity. FDG is highly accumulated in granulomatous lesions, which necessitates the consideration of calcification and distribution patterns to enhance specificity. That leads to the compensatory expense of sensitivity [7, 8], and EBUS-TBNA is often performed even when observed nodes are considered as inflammation. In this context, [68Ga]FAPI-46 PET/CT has the potential to help avoiding invasive procedures.

Our results suggest the potential of [68Ga]FAPI-46 PET/CT to complement the standard staging process in resectable NSCLC. It is important to emphasize that our study was not designed as a head-to-head comparison with [18F]FDG PET/CT for the general NSCLC population. Instead, we specifically enrolled patients potentially indicated for invasive staging based on the established practice guidelines [2, 28], with the presence of FDG-positive N2 nodes as one of the inclusion criteria. That could impact the straightforward comparison of diagnostic performance between the two tests, and enrolled patients do not represent the entire NSCLC population. Our focus was rather on the specific situation where [18F]FDG PET/CT might have limited diagnostic value and invasive staging should precede the surgery. Our aim was to investigate whether [68Ga]FAPI-46 PET/CT can provide additive value in this situation, thereby correctly guiding the indication for EBUS-TBNA.

The use of FAPI PET/CT for mediastinal nodal staging has been explored in several studies. Wang et al. reported that [68Ga]FAPI PET/CT detected a higher number of metastatic nodes in advanced lung cancer than [18F]FDG PET/CT [24]. This study focused on the advanced stage, including recurrence state, and pathologic reference was not used. Zhou et al., in a post hoc retrospective subgroup analysis of 35 patients, reported accuracies of [68Ga]FAPI-04 and [18F]FDG PET/CT as 0.94 and 0.30, respectively [26], but this analysis only included FDG-avid lesions, producing the exceptionally underestimated accuracy of [18F]FDG PET/CT. Wu et al. reported the superiority of [68Ga]FAPI PET/CT in mediastinal nodal staging in a prospective study with 28 patients [25], demonstrating a sensitivity of 0.818 and specificity of 0.976, but MLND was performed in only ten patients. In contrast, our study specifically focused on its use for preoperative mediastinal nodal staging in operable NSCLC, emphasizing its clinical contribution particularly in guiding management plans for patients with potentially resectable NSCLC and ensuring all lesions are evaluated with postoperative pathologic confirmation.

One of our key objectives was to assess the role of [68Ga]FAPI-46 PET/CT in effectively stratifying patients who may require invasive staging. This goal was indirectly addressed by demonstrating its superior accuracy over [18F]FDG PET/CT and its potential to refine the indication for proceeding to invasive procedures. It is important to note that EBUS-TBNA was not a routine part of our protocol, which precluded a direct comparison in the main analysis. However, we conducted a subgroup analysis on a limited cohort (9 patients with 15 stations) who underwent EBUS-TBNA. The results were somewhat promising, showing a per-station accuracy of 0.93 for both [68Ga]FAPI-46 PET/CT and EBUS-TBNA in detecting N2 metastasis. In addition, the overall sensitivities of [68Ga]FAPI-46 PET/CT in the entire population appear to be not significantly inferior to that of EBUS-TBNA reported in a previous study (a pooled sensitivity of 0.89) [28]. Despite the limited cohort size, these findings may indicate the potential of [68Ga]FAPI-46 PET/CT to refine the existing mediastinal staging process that includes [18F]FDG PET/CT and EBUS-TBNA, warranting the need for further prospective studies to compare its diagnostic accuracy with these conventional tests in a larger population.

We focused on “N2” metastasis in the analyses. The accurate staging of mediastinal nodes is pivotal in determining optimal treatment strategies for patients with resectable NSCLC [1, 2]. In particular, N2 involvement plays a critical role in the decision-making process for curative surgery or adjuvant therapy. Furthermore, focusing specifically on N2 stations enables reliable comparison between PET/CT and postoperative histopathology, because MLND generally covers only N1 and N2 regions and reliable correlation with tomographic locations is limited in N1. For these reasons, we decided to analyze only N2 regions.

The relatively longer intervals between [68Ga]FAPI-46 PET/CT and [18F]FDG PET/CT could potentially impact the comparative results of the two tests. However, it is important to note that our study did not include patients with highly advanced disease stages or poorly differentiated or small cell pathology. This factor reduces the likelihood of rapid tumor progression within this interval. To further address this concern, we performed a supplementary analysis comparing the diameters of metastatic nodes as measured on [68Ga]FAPI-46 PET/CT and [18F]FDG PET/CT (Figure S1). The results showed no significant differences in the diameters measured on both scans, suggesting that any tumor progression during the intervals was not substantial enough to impact the results.

Although CECT is a standard imaging modality in lung cancer staging, it was not part of the analysis in our study. CECT is the most crucial imaging tool in lung cancer, offering the most accurate clinical T stage determination, screening for intrathoracic metastatic lesions, and providing essential anatomical information needed for histologic sampling and surgical approaches. However, the diagnostic efficacy for mediastinal metastasis is acknowledged to be limited, as supported by established practice guidelines [28]. The guideline reported, through meta-analyses, pooled sensitivity and specificity of CECT in mediastinal staging to be 0.55 and 0.81, which were less than those of [18F]FDG PET/CT (0.62 and 0.90). In our study, we excluded CECT from the analyses to focus on the role of [68Ga]FAPI-46 PET/CT as a method to address the limitations of [18F]FDG PET/CT.

This study has limitations to be addressed. As a pilot study, we collected the data from a limited number of patients. As described above, many patients did not undergo EBUS-TBNA. We indirectly showed the feasibility of [68Ga]FAPI-46 PET/CT to reduce the need for EBUS-TBNA by exhibiting its high diagnostic accuracy, but the estimation for this potential is limited due to the lack of sufficient head-to-head comparison. Additionally, mediastinal lymph nodes were resected selectively based on surgeons’ intraoperative assessments as in routine clinical practice, which could influence the precise evaluation of the sensitivity and the false-negative rate. The predominance of patients with adenocarcinoma may also limit the generalizability of the findings and their interpretation across the different pathologic subtypes. The results need to be validated with a larger prospective study designed to encompass broader disease stages and enable the direct comparison among different diagnostic methods.