Gastrointestinal cancer with indeterminate ¹⁸F‑FDG PET/CT findings: Diagnostic efficacy analysis of ⁶⁸Ga‑FAPI‑04 PET/MRI

Introduction

Over the past 3 years, gastrointestinal (GI) tumors have contributed markedly to the global cancer burden. Notably, gastric cancer accounted for >970,000 novel cases and ~660,000 mortalities, while >1.9 million novel cases and ~900,000 fatalities were reported for colorectal cancer, thereby representing a severe threat to public health (1). Delays in the diagnosis and treatment of GI cancer are strongly associated with reduced overall survival rates (2).

Fluorine-18 (18F) fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) represents a cornerstone imaging modality for diagnosing GI malignancies (3). Extensively integrated into the routine evaluation and staging of GI cancer (4,5), this technique offers key clinical insights. However, its limitations warrant careful consideration. Firstly, 18F-FDG exhibits extensive and variable physiological uptake within the GI tract (6), complicating the accurate diagnosis of GI tumors (7). Secondly, histological subtypes with low metabolic activity, such as signet-ring cell (8,9) and mucinous (10) adenocarcinomas, show poor 18F-FDG avidity, leading to suboptimal detection rates. Furthermore, postoperative anastomotic healing can cause persistent physiological tracer accumulation, obscuring the identification of anastomotic recurrence. Collectively, these factors contribute to a notable number of cases where 18F-FDG imaging yields inconclusive or atypical results for both primary tumors and metastatic lesions.

These limitations have propelled the continuous innovation of PET tracers. Fibroblast activation protein (FAP) is predominantly upregulated in cancer-associated fibroblasts, which constitute ~90% of tumor stromal cells (11,12). FAP inhibitors (FAPIs) exhibit high specificity in binding to FAP. When FAPI is radiolabeled with gallium-68 (68Ga), it forms a radiotracer capable of detecting FAP+ tumor stroma. In 2018, FAP-related radiotracers were first introduced into clinical practice, with 68Ga-FAPI-04 being the most extensively studied (13,14).

In contrast to 18F-FDG, 68Ga-FAPI-04 does not require pre-imaging preparations such as fasting. Additionally, the administered radioactive dose of 68Ga-FAPI-04 is ~50% of that of 18F-FDG for the same patient. These characteristics markedly reduce patient discomfort and enhance the overall patient experience during the diagnostic process. Previous studies have demonstrated that 68Ga-FAPI-04 outperforms 18F-FDG in diagnosing primary and metastatic lesions in signet ring cell gastric cancer and colorectal cancer (15–18) and exhibits a notable tumor-to-background ratio (TBR) (15,16,19–21).

Although diagnostic research on 68Ga-FAPI-04 in GI cancer has reached a relatively advanced stage, a robust foundation for its clinical implementation remains lacking (22). The present study hypothesized that 68Ga-FAPI-04 could improve the diagnostic accuracy for patients with GI tumors exhibiting atypical or inconclusive 18F-FDG metabolic patterns, potentially serving as a valuable supplement in clinical practice for GI tumors with atypical FDG metabolism. The present prospective study aimed to compare the diagnostic accuracy, staging, restaging and treatment management outcomes of 68Ga-FAPI-04 PET/magnetic resonance imaging (MRI) vs. 18F-FDG PET/CT in such patients with GI cancer.

Patients and methods

Study design and patient recruitment

Data were collected between December 2022 and May 2023. Inclusion criteria for the present study were as follows: i) Patients with pathologically confirmed primary GI cancer (diagnosed via histopathological examination or narrow-band imaging magnification endoscopy); ii) patients with clinical suspicion of recurrence or metastasis supported either by abnormal follow-up CT/MRI findings or other clinical/radiological evidence; iii) patients with atypical 18F-FDG PET findings with either low 18F-FDG uptake in lesions despite radiological/clinical evidence confirming recurrence/metastasis or high 18F-FDG uptake in lesions despite radiological/clinical evidence confirming benign or inflammatory nature; and iv) patients who provided written informed consent for 68Ga-FAPI-04 PET/MRI examination.

All patients were recruited from the First Affiliated Hospital of Anhui Medical University (Hefei, China). Tumor classification was performed according to the World Health Organization Classification of Tumors (23). Exclusion criteria were as follows: i) Failure to provide written informed consent; ii) inability to maintain a supine position for the full duration of the imaging procedure; iii) confirmed claustrophobia (unable to tolerate closed imaging equipment); and iv) concurrent diagnosis of other malignant tumors.

Patients for whom MRI examination was contraindicated (for example, due to implanted pacemakers, metallic intrauterine devices or ferromagnetic hip prostheses) underwent 68Ga-FAPI-04 PET/CT instead of PET/MRI. A flowchart for the patient selection process is depicted in Fig. 1. The present study was performed in line with the principles of the Declaration of Helsinki. Ethics approval for the present study was granted by the Ethics Committee of Anhui Medical University (Hefei, China; date, May 9th 2022; approval no. PJ2022-05-09).

Figure 1. Flowchart of patient selection. FAPI, fibroblast-activation protein inhibitor; 68Ga, gallium 68; FDG, fluorodeoxyglucose; 18F, fluorine 18; PET, positron emission tomography; MRI, magnetic resonance imaging; CT, computed tomography.

Preparation of 68Ga-FAPI-04 and 18F-FDG

FAPI-04 was provided by Jiangsu Huayi Nuclear Medicine Co., Ltd., with a net weight of 872.91 g. The labeling of FAPI with 68Ga was performed using methods previously described by Lindner et al (24) and Chen et al (25), with minor modifications to suit the characteristics of the 68Germanium (68Ge)/68Ga generator (New Radiomedicine Technology Co., Ltd.) and the equipment available at the present study institution (Fig. S1). The 68Ge/68Ga generator was eluted with 0.1 M HCl to obtain 3.0 ml of 68GaCl3 solution. The FAPI-04 precursor (20 µg) was then combined with 375 µl of 1.25 M sodium acetate (pH 4.0), followed by the addition of 3.0 ml of the 68GaCl3 solution previously prepared. The reaction was conducted in a thermostat at 95°C for 10 min. Afterward, the mixture was passed through an activated Sep-Pak® 18C column (Xintuo Trading Co., Ltd.) and washed with 0.8 ml of 80% ethanol. The eluate was then filtered through a 0.2-µm microporous membrane (Pall Corporation) and collected into a sterile, autoclaved vial. The 18F-FDG synthesis was performed by Yantai Dongcheng Pharmaceutical Group Co., Ltd. All products underwent comprehensive quality control, including radiochemical purity, specific activity and sterility tests, and met the required standards before clinical use.

Purity assessment of synthesized 68Ga-FAPI-04 and 18F-FDG

The radiochemical purity of the two radionuclides was assessed using a high-performance liquid chromatograph (HPLC) [model LC-16; Shimadzu Instruments (Suzhou) Co., Ltd.]. The HPLC system conditions were as follows: Voltage, 220±22 V; frequency, ~50±0.5 Hz; power, 150 VA; injection volume, 25 µl; mobile phase A: deionized water containing 0.1% trifluoroacetic acid (TFA), mobile phase B: acetonitrile containing 0.1% TFA; flow rate, 1.0 ml/min; absorption wavelength, 320 nm. The column used was Shim-pack VP-ODS (C18) with a size of 4.6×150 mm and a particle size of 5 µm, manufactured by Shimadzu Instruments (Suzhou) Co., Ltd. The radiochemical purity of 68Ga and 18F was calculated using the area normalization method. The detection conditions of 68Ga and 18F radio-HPLC are shown in Table SI.

Synthesized 68Ga-FAPI-04 and 18F-FDG purity

The radiochemical purity of 68Ga-FAPI-04 was assessed by radio-HPLC within 10 min. The chromatogram displays a single, sharp peak at 3.1–3.2 min, with a signal intensity of 104.7–104.8 mV, while the 18F-FDG peak appears at 2.5–2.6 min, with a signal intensity of 113.4–113.5 mV. This well-defined peak indicates the presence of a highly pure compound with no detectable impurities or by-products, as evidenced by the stable baseline throughout the chromatogram. The absence of additional peaks confirms the effective separation and successful synthesis of the target radiopharmaceutical Fig. S1.

PET-MRI and PET-CT imaging

PET-MRI imaging was performed using a GE Healthcare scanner (SIGNA™; GE HealthCare) equipped with a dedicated molecular MR coil. 68Ga-FAPI-04 was labeled on-site and used immediately after labeling. The intravenous injection dose was 1.85–3.7 MBq/kg. After 35 min of injection, respiratory gating imaging was initiated. The field of view covered from the skull to the upper part of the thighs. A step-and-shoot acquisition mode was adopted, with five bed positions being acquired, 4–6 min for each bed position and a total scanning duration of ~60 min. Multi-sequence nuclear MRI included T1-weighted imaging (WI), T2-WI and diffusion-WI. Breath-holding was required during the liver acceleration volume acquisition scan. PET/MRI reconstruction was performed using ordered subsets expectation maximization (OSEM) + time-of-flight (TOF) + point spread function (PSF), with two iterations, 28 subsets, a 440×440 matrix and a 5-mm filter.

18F-FDG PET/CT examination was performed using a Biograph Vision 450 PET-CT scanner (Siemens Healthineers). The dose of 18F-FDG was 3.7–5.55 MBq/kg. PET/CT acquisition started 60±20 min after intravenous injection. A CT scan was performed with a table speed of 22.5 mm/sec, followed by a PET scan conducted using a continuous bed movement acquisition mode, with 2–4 min of acquisition for each bed position and a range from the head to the upper part of the thighs. The OSEM algorithm was used for image reconstruction and TOF correction, and PSF modeling were performed. A total of five iterations, four subsets, a 440×440 reconstruction matrix and a 5-mm filter were adopted.

Imaging analysis

Two board-certified nuclear medicine specialists and a nuclear medicine postgraduate student with a medical licensure performed blinded image interpretation, with access to neither pathological findings nor clinical examination data to ensure the objectivity of the analysis. The images were analyzed using the multiple myeloma (MM) oncology-specific software within the Syngo.via VB30 system (2020; Siemens Healthineers). In cases of assessment discrepancies, a third senior nuclear medicine specialist was consulted to reach a final consensus through joint discussion, minimizing subjective bias and ensuring accuracy and consistency in data interpretation.

Anatomical regions evaluated included the primary tumor, anastomotic sites, abdominal incisions, lymph nodes (cervical, thoracic, abdominal and pelvic regions) and distant metastases (for example, brain, bone, liver, spleen, peritoneum, ovary and kidney). For lymph node classification, the cervical region was defined as the area below the line connecting the inferior margin of the mandible, posterior margin of the mandibular process, mastoid process and external occipital protuberance, and the area above the line connecting the suprasternal notch, clavicle, acromion and C7 spinous process. The thoracic region comprised the area within the thoracic cage and diaphragm, with its upper boundary being the thoracic inlet connecting to the cervical region. The abdominal region was defined as the space between the pelvic inlet and diaphragm, while the pelvic region referred to the area within the pelvic girdle.

Lesions with metabolic activity markedly higher compared with adjacent healthy tissues were classified as PET+ and potentially malignant lesions. The criteria for final confirmation of malignant lesions included the following: i) Lesions with malignant biopsy pathology results; ii) abnormal GI vascular patterns observed via standardized narrow-band imaging magnification endoscopy, consistent with histopathology if involving endoscopic biopsy; iii) lesion progression observed using CT or MRI during follow-up; and iv) lesion shrinkage after antitumor therapy. Nuclear medicine specialists qualitatively compared PET+ lesions detected using 18F-FDG PET and 68Ga-FAPI-04 PET with the aforementioned final confirmed malignant lesions to determine the diagnostic accuracy of the two tracers.

In addition, a semi-quantitative comparison of the two radionuclides was also performed. Regions of interest were delineated on the cross-sectional images around the PET+ potentially malignant lesions for semi-quantitative evaluation. The maximum standardized uptake value (SUVmax) was automatically determined using the MM Oncology Syngo software. Due to the differences in the imaging principles, device performance and reconstruction algorithms of PET/CT and PET/MRI, the SUVmax values measured using the two devices could not be directly used for quantitative comparison. Therefore, the tumor-to-blood-pool ratio (TBR_blood_pool) value was used to enhance comparability. The calculation was performed according to a previous study (26) using the following formula: TBR_blood_pool (lesion)=SUVmax (lesion)/mean SUVmax (descending aorta).

For patients with digestive tract tumors detected using 68Ga-FAPI-04 PET or 18F-FDG PET, a board-certified oncologist staged them according to the eighth edition of the American Joint Committee on Cancer guidelines (27). Clinical management and treatment recommendations were put forward based on the staging results. The differences in the staging of 68Ga-FAPI-04 PET/MRI targeted molecular imaging and their impacts on tumor treatment were recorded. The changes in treatment methods were rated based on how much the imaging results influenced clinical decisions. If the modification was made to the treatment plan that the clinician had already anticipated, it was recorded as a minor change. If the FAPI PET results led to a change in the type of treatment or the treatment intent, it was classified as a major change.

Statistical analysis

All statistical analyses were performed using SPSS (version 26.0; IBM Corp.). To determine the diagnostic accuracy of 68Ga-FAPI-04 PET and 18F-FDG PET, the present analysis evaluated the sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) for both imaging modalities, with statistical comparisons conducted using McNemar's test. True-positive (TP) was defined as lesions with significantly elevated SUVmax on FDG or FAPI imaging, confirmed as malignant by pathology or follow-up. True-negative (TN) refers to lesions with no significant SUVmax elevation and verified as disease-free using the gold standard diagnostic method (pathological biopsy) or long-term follow-up. False-positive (FP) denotes focal SUVmax elevation without malignant findings on histopathology or imaging follow-up. False-negative (FN) indicates no significant SUVmax abnormality but evidence of malignancy at corresponding sites per gold standard diagnostic method or follow-up. PPV and NPV were calculated as PPV=TP/(TP + FP) and NPV=TN/(TN + FN), following the method used by Hill et al (28). Compared with 18F-FDG, a significant elevation in TP and TN for 68Ga-FAPI-04 was defined as a statistically significant increase, with P<0.05 considered to indicate a statistically significant difference.

For the semi-quantitative analysis of 68Ga-FAPI-04 and 18F-FDG PET imaging (including TBR_blood_pool), the Shapiro-Wilk test was performed for all subgroups with a sample size of >10. The test results confirmed that the tracer uptake data of target lesions conformed to a normal distribution, and the data were expressed as the mean ± standard deviation. Since all data in this study were obtained from the same subjects who underwent both examinations, the measurements were paired. Therefore, the paired t-test was used to compare the differences in tracer uptake of target lesions between the two imaging modalities and assess the statistical significance of such differences.

For subgroups with a sample size of ≤10, including primary lesions, anastomotic recurrence, abdominal wall recurrence, preoperative metastatic lymph nodes, cervical, thoracic and pelvic metastatic lymph nodes, as well as liver, kidney, peritoneal, bone and splenic metastases, the normality of the data could not be validly verified. The semi-quantitative analysis results of 68Ga-FAPI-04 and 18F-FDG PET imaging for these subgroups were expressed as median (lower quartile-upper quartile). The Wilcoxon signed-rank test was adopted for non-parametric analysis to compare the differences in tracer uptake of target lesions between the two imaging modalities and further evaluate the statistical significance of the differences.

Fisher's exact test was used to verify the associations between different pathological subtypes and the changes in tumor staging and treatment decisions indicated by 68Ga-FAPI-04 PET imaging. Simple ratio calculations were employed to determine the number of patients with stage changes and the impact rate on subsequent treatment due to 68Ga-FAPI-04 PET, demonstrating its effect on staging and therapy planning. Two-tailed P<0.05 was considered to indicate a statistically significant difference.

Cost-benefit analysis

The use of 68Ga-FAPI-04 PET/MRI is associated with high equipment and drug costs and whether such high costs can bring tangible diagnostic value to patients is a key concern in clinical applications. Therefore, based on data from 22 patients, the present study conducted a preliminary comparison of the hospital operating costs and patient-derived medical benefits between 68Ga-FAPI-04 PET/MRI and 18F-FDG PET/CT.

The hospital operating costs were defined as experiment-related hospital expenditures (rounded to the nearest whole number), which included only medication, equipment and labor costs. The direct costs of 68Ga-FAPI-04 PET/MRI covered the consumption of 68Ge/68Ga generators, the cost of FAPI-04 precursor drugs, the depreciation of PET/MRI equipment and the salary of the technicians. For 18F-FDG PET/CT, the costs included the direct purchase cost of 18F-FDG, the depreciation of PET/CT equipment and the salary of the technicians.

Since 68Ga-FAPI-04 PET/MRI is part of a clinical trial with no requirements for report writing, miscellaneous clinical expenses, such as fees paid to physicians for report preparation, hospital utility consumption, equipment maintenance, consumables for report printing and monitor repair, were not included in the calculation.

Results

Patient demographics

The present study included 22 participants, 12 men and 10 women, with a median age of 62 years (range, 51–77 years). The demographic and clinical characteristics of the patients are summarized in Table I. Specifically, there were 7 (31.8%) patients with esophageal cancer, 7 (31.8%) with gastric cancer, 5 (22.7%) with colon cancer and 3 (13.6%) with rectal cancer. Furthermore, 20 (90.9%) patients received treatments such as surgery, chemotherapy, radiotherapy or immunotherapy.

Table I. Clinical characteristics of patients with gastrointestinal cancer (n=22).

Table I.

Clinical characteristics of patients with gastrointestinal cancer (n=22).

Characteristic	Value
Age, years
Median	60.24
Range	6.89
Sex, n (%)
Male	12 (54.55)
Female	10 (45.46)
Primary site of cancer, n (%)
Esophagus	7 (31.82)
Stomach	7 (31.82)
Colon	5 (22.73)
Rectum	3 (13.64)
Role of PET, n (%)
Primary staging/treatment-naive	2 (9.09)
Recurrence detection/restaging	20 (90.91)
Squamous cell carcinoma	6 (27.27)
Adenocarcinoma	9 (40.91)
Mucinous cancer	3 (13.64)
Miscellaneous	4 (18.18)
Degree of differentiation, n (%)
Fully or partially moderately	10 (45.45)
Fully or partially poorly	6 (27.27)
NA	6 (27.27)

[i] NA, not applicable; PET, positron emission tomography.

The present study aimed to explore the diagnostic value of 68Ga-FAPI-04 PET/MRI and 18F-FDG PET/CT in the detection of recurrent and metastatic diseases in patients with GI cancer. A comparison of partial maximum intensity projection images obtained from representative 18F-FDG and 68Ga-FAPI-04 scans is presented in Fig. 2.

Figure 2. Comparison of 18F-FDG and 68Ga-FAPI-04 MIP images. MIP images of 5 patients clearly demonstrating marked differences between the two tracers, including visualization of (A) metastasis in the pancreaticoduodenum, (B) anastomotic recurrence, (C) cerebellar metastasis, (D) splenic metastasis and (E) peritoneal metastasis. Two orange arrows (upper and lower) constitute a pair, indicating the visual comparison of the same lesion in the same patient on MIP images obtained with two different tracers. MIP, maximum intensity projection; FAPI, fibroblast-activation protein inhibitor; 68Ga, gallium 68; FDG, fluorodeoxyglucose; 18F, fluorine 18.

Primary tumors

The lesion-based analysis demonstrated that the sensitivity for diagnosing primary tumors was 50.0% (3/6) for 18F-FDG PET/CT and 83.3% (5/6) for 68Ga-FAPI-04 PET/MRI (Table II). For cancer types with low 18F-FDG uptake, such as mucinous cancer (MC) and GI stromal tumors (GIST), 18F-FDG PET/CT generated more FN results.

Table II. Qualitative evaluation of lesions by 68Ga-FAPI-04 PET/magnetic resonance imaging vs. 18F-FDG PET/computed tomography.

Table II.

Qualitative evaluation of lesions by 68Ga-FAPI-04 PET/magnetic resonance imaging vs. 18F-FDG PET/computed tomography.

Lesion category	Sensitivity, (n/total n) %	Specificity, (n/total n) %	Accuracy, (n/total n) %	PPV, (n/total n) %	NPV, (n/total n) %
Primary tumor
n0
68Ga-FAPI-04	(5/6) 83.33	NA	(5/6) 83.33	(5/5)100.00	NA
18F-FDG	(3/6) 50.00	NA	(3/6) 50.00	(3/3) 100.00	NA
P-value	0.55	NA	0.55	NA	NA
Anastomotic recurrence and abdominal wall incisions
n1
68Ga-FAPI-04	(2/3) 66.67	(11/14) 78.57	(13/17) 76.47	(2/5) 40.00	(11/12) 91.67
18F-FDG	(0/3) 0.00	(7/14) 50.00	(7/16) 43.75	(0/8) 0.00	(7/8) 87.50
P-value	0.4	0.24	0.08	0.13	1.0
Lymph node metastasis
n0
68Ga-FAPI-04	(9/9) 100.00	(24/36) 66.67	(33/45) 73.33	(9/21) 42.86	(24/24) 100.00
18F-FDG	(9/9) 100.00	(13/36) 36.11	(22/45) 48.89	(9/32) 28.13	(13/13) 100.00
P-value	NA	0.009a	0.02a	0.27	NA
n1
68Ga-FAPI-04	(82/82) 100.00	(22/29) 75.86	(104/111) 93.69	(82/89) 92.13	(22/22) 100.00
18F-FDG	(73/82) 89.02	(16/29) 55.17	(89/111) 80.18	(73/86) 84.88	(16/25) 64.00
P-value	0.002a	0.10	0.003a	0.13	0.002a
n
68Ga-FAPI-04	(91/91) 100.00	(47/65) 72.31	(138/156) 88.46	(91/109) 83.49	(47/47) 100.00
18F-FDG	(81/91) 89.01	(31/65) 47.69	(112/156) 71.79	(81/107) 75.70	(31/49) 63.27
P-value	0.001a	0.004a	0.0002a	0.16	<0.001a
Distant organ metastasis
n
68Ga-FAPI-04	(24/26) 92.31	NA	(24/27) 88.89	(24/25) 96.00	NA
18F-FDG	(16/26) 61.54	NA	(17/27) 62.96	(16/16) 100.00	NA
P-value	0.008a	NA	0.03a	>0.99	NA

a P<0.05. n0, participants who had not undergone surgery or therapy, n1=participants who had undergone surgery or therapy, n=n0+n1. ¹⁸F, fluorine 18; FDG, fluorodeoxyglucose; ⁶⁸Ga, gallium 68; FAPI, fibroblast-activation protein inhibitor; NA, not applicable; PPV, positive predictive value; NPV, negative predictive value; PET, positron emission tomography.

By contrast, the lesions on 68Ga-FAPI-04 PET/MRI were more clearly defined their semi-quantitative assessment was also significantly improved compared with that of 18F-FDG PET/CT imaging [TBR_blood_pool, 6.13 (5.71–7.57) vs. 2.62 (1.82–3.03); P=0.004; Fig. 3F]. This difference was even more pronounced (TBR_blood_pool, 5.82 vs. 1.12) in patients with gastric GIST (Fig. 3A).

Figure 3. 68Ga-FAPI-04 PET/MRI vs. 18F-FDG PET/CT: Quantitative comparison of primary tumors and anastomotic sites. Primary tumor focus of (A) a patient with gastrointestinal cancer, (B) the anastomotic recurrence of 1 patient, (C) the metastatic abdominal wall incision of 1 patient and (D and E) the benign anastomoses of 2 patients. The white arrows appear in paired upper and lower positions, indicating the uptake comparison of the two tracers at the same anatomical site. The orange arrows also appear in paired upper and lower positions, corresponding to the MRI T1WI and T2WI signals of the same lesion, respectively. The color bar shows a consistent color scale (7.0) for all images. Histograms are respectively used to display the statistical differences in the TBR_blood_pool of the primary tumor foci of (F) the two tracers, (G) the recurrent anastomoses and the metastatic abdominal wall incisions, as well as (H) the benign anastomoses. The numbers on the histograms represent the sample size of each group. **P<0.01. TBR_blood_pool, tumor-to-blood-pool ratio; ns, not significant; FAPI, fibroblast-activation protein inhibitor; 68Ga, gallium 68; FDG, fluorodeoxyglucose; 18F, fluorine 18; PET, positron emission tomography; MRI, magnetic resonance imaging; CT, computed tomography.

Anastomotic recurrence

Anastomotic stroma and abdominal wall incisions were evaluated using two radionuclides, 68Ga-FAPI-04 and 18F-FDG. Anastomotic sites and abdominal wall incisions from 17 patients were included in the evaluation, with 3 patients presenting with recurrence and metastasis. While 18F-FDG PET/CT failed to detect these recurrences, 68Ga-FAPI-04 PET/MRI identified two of them (Fig. 3B). 68Ga-FAPI-04 improved the diagnostic accuracy to 66.67% for anastomotic recurrences that remained undetectable using 18F-FDG (Table II).

Although it is well known that 68Ga-FAPI-04 is likely to be taken up due to the fibrous remodeling at the anastomotic healing site, thus affecting the examination results (29), 68Ga-FAPI-04 still exhibits certain advantages compared with 18F-FDG in detecting anastomotic recurrence of pathological types with low 18F-FDG metabolism, such as mucinous adenocarcinoma and poorly differentiated adenocarcinoma (PDA).

The tracer uptake [TBR_blood_pool, 7.79 (5.97–8.58)] at the recurrent anastomotic sites of two patients and the metastatic abdominal wall incision of 1 patient, as shown by 68Ga-FAPI-04 PET, was markedly higher compared with that of 18F-FDG PET [TBR_blood_pool, 2.00 (1.83–1.92)]. 18F-FDG had almost no uptake at the recurrent anastomotic sites of the 2 patients and had a little uptake at the metastatic abdominal wall incision (Table III).

Table III. Quantitative assessment of diagnosed lesions in organs and lymph nodes by 68Ga-FAPI-04 PET-magnetic resonance imaging vs. 18F-FDG PET-computed tomography.

Table III.

Quantitative assessment of diagnosed lesions in organs and lymph nodes by 68Ga-FAPI-04 PET-magnetic resonance imaging vs. 18F-FDG PET-computed tomography.

	Malignant lesions			Benign lesions
	TBR_blood_pool			TBR_blood_pool
Lesion site	68Ga-FAPI-04	18F-FDG	P-value	68Ga-FAPI-04	18F-FDG	P-value
Primary tumor	6.13 (5.71–7.57)	2.62 (1.82–3.03)	0.004a	NA
Anastomotic recurrence and abdominal wall incisions	6.48 (5.97–7.79)	1.94 (1.83–2.11)	0.05	2.64±1.89	1.57±0.55	0.10
Lymph node (treatment-naive)	6.07 (5.77–6.37)	1.94 (1.92–1.97)	<0.001a	2.42±1.59	2.80±1.29	0.27
Lymph node (postoperative metastasis)	9.13±2.93	4.01±1.72	<0.001a	2.01±1.26	2.04±0.65	0.93
Lymph node (cervical)	16.23	7.25 (5.91–8.66)	<0.001a	2.55	2.03	0.59
	(14.47–16.95)			(2.04–3.05)	(1.53–2.53)
Lymph node (thoracic)	10.00 (8.06–12.00)	4.87 (3.47–6.81)	<0.001a	1.88±0.87	2.71±1.14	<0.001a
Lymph node (abdomen)	8.52±2.29	3.67±1.33	<0.001a	2.24±1.88	1.84±0.73	0.59
Lymph node (pelvis)	4.11 (3.86–4.49)	1.55 (1.41–1.67)	<0.001a	1.25	1.69	0.13
				(0.85–1.63)	(1.45–1.81)
Lymph node (all)	9.07±2.93	3.96±1.73	<0.001a	2.24±1.46	2.46±1.11	0.33
Liver	3.45 (2.23–5.81)	2.58 (1.92–2.69)	0.047a	NA
Kidney	9.91 (6.20–10.08)	1.13 (1.09–5.48)	0.13	NA
Peritoneum	9.19,3.88	3.05,3.02	<0.001a	NA
Bones	10.84 (9.90–12.11)	5.60 (5.36–6.40)	<0.001a	NA
Spleen	4.48 (4.13–4.71)	1.12 (1.09–1.16)	0.01a	NA
Distant organ metastasis (all)	3.31±2.19	6.87±4.16	<0.001b	NA

a P<0.05. P-values are for comparison of TBR_blood_pool with FDG and FAPI. Data are presented as mean ± SD and median (lower quartile-upper quartile). ¹⁸F, fluorine 18; FDG, fluorodeoxyglucose; ⁶⁸Ga, gallium 68; FAPI, fibroblast-activation protein inhibitor; NA, not applicable; PPV, positive predictive value; NPV, negative predictive value; PET, positron emission tomography.

The imaging effect of 68Ga-FAPI-04 PET was also enhanced, allowing for a clearer scope delineation of the lesions (Fig. 3G). However, there was no comparable difference in the accuracy and semi-quantitative parameters of the two radionuclides in detecting anastomotic recurrence and abdominal wall incisions. This may be due to the low anastomotic recurrence rate of the patients and the small sample size in the present study (P>0.05).

Notably, a patient with colon cancer (patient 21) exhibited mild 18F-FDG uptake (TBR_blood_pool, 2.28) at the abdominal wall incision 9 months after surgery. Ordinarily, this would not be considered a metastasis at the abdominal wall incision due to the potential for physiological uptake in the surgical area. Nevertheless, the uptake of 68Ga-FAPI-04 was higher (TBR_blood_pool, 6.48), and a low signal on T1WI and a high signal on T2WI were observed on PET/MRI (Fig. 3C). Considering factors such as fibrosis, this specific case was not defined as metastasis due to the high uptake of 68Ga-FAPI-04 at that time. The pathological results obtained after a 2-month follow-up confirmed that the abnormal uptake and signals in the abdominal wall indicated the presence of metastasis.

Lymph nodes

Among the included patients, 45.45% (10/22) were diagnosed with lymph node involvement. Using pathological sections or subsequent imaging follow-up, 91 TP lymph nodes were identified and used as the control standard. The TBR_blood_pool of 68Ga-FAPI-04 used for imaging of metastatic lymph nodes was notably increased compared with that of 18F-FDG and the imaging effect was notable (Fig. 4E-G). There was no significant difference in the uptake of 18F-FDG and 68Ga-FAPI-04 in inflammatory lymph nodes (Fig. 5E-G).

Figure 4. 68Ga-FAPI-04 PET/MRI vs. 18F-FDG PET/CT: Quantitative comparison of metastatic lymph nodes. Comparison between 68Ga-FAPI-04 PET/MRI and 18F-FDG PET/CT for metastatic lymph nodes located in the (A) cervical, (B) thoracic, (C) abdominal and (D) pelvic regions, respectively. The white arrows appear in paired upper and lower positions, indicating the uptake comparison of the two tracers at the same anatomical site. The orange arrows also appear in paired upper and lower positions, corresponding to the MRI T1WI and T2WI signals of the same lesion, respectively. The color bar shows a consistent color scale (7.0) for all images. Histograms show the statistical differences in TBR_blood_pool between the two tracers for metastatic lymph nodes: (E) Treatment-naive lymph nodes, (F) postsurgical and other treated lymph nodes, (G) all metastatic lymph nodes, as well as for (H) cervical, (I) thoracic, (J) abdominal and (K) pelvic regions, respectively. The numbers on the histograms represent the sample size of each group. ***P<0.001. TBR_blood_pool, tumor-to-blood-pool ratio; FAPI, fibroblast-activation protein inhibitor; 68Ga, gallium 68; FDG, fluorodeoxyglucose; 18F, fluorine 18; PET, positron emission tomography; MRI, magnetic resonance imaging; CT, computed tomography.

Figure 5. 68Ga-FAPI-04 PET/MRI vs. 18F-FDG PET/CT: quantitative comparison of benign lymph nodes. Comparison between 68Ga-FAPI-04 PET/MRI and 18F-FDG PET/CT for benign lymph nodes located in the (A) cervical, (B) thoracic, (C) abdominal and (D) pelvic regions, respectively. The white arrows appear in paired upper and lower positions, indicating the uptake comparison of the two tracers at the same anatomical site. The orange arrows also appear in paired upper and lower positions, corresponding to the MRI T1WI and T2WI signals of the same lesion, respectively. The color bar shows a consistent color scale (7.0) for all images. Histograms show the statistical differences in TBR_blood_pool between the two tracers for benign lymph nodes: (E) Treatment-naive lymph nodes, (F) postsurgical and other treated lymph nodes, (G) all benign lymph nodes, as well as for (H) cervical, (I) thoracic, (J) abdominal and (K) pelvic regions, respectively. The numbers on the histograms represent the sample size of each group. ***P<0.001. ns, not significant; TBR_blood_pool, tumor-to-blood-pool ratio; FAPI, fibroblast-activation protein inhibitor; 68Ga, gallium 68; FDG, fluorodeoxyglucose; 18F, fluorine 18; PET, positron emission tomography; MRI, magnetic resonance imaging; CT, computed tomography.

Treatment-naive and postoperative metastatic lymph nodes

When evaluating imaging modalities for the detection of untreated lymph node metastases, 18F-FDG demonstrated limitations. Among patients followed up for 1 year after 18F-FDG imaging, non-metastatic lymph nodes were misdiagnosed as metastatic, leading to overestimation of lymph node involvement compared with histopathological findings (the gold standard). Accordingly, the diagnostic accuracy of 18F-FDG was lower than that of 68Ga-FAPI-04 (71.79 vs 88.46%; P<0.001) (Table II). By contrast, 68Ga-FAPI-04 exhibited significantly improved diagnostic performance, with higher specificity (66.67 vs. 36.11%; P=0.009) and accuracy (73.33 vs. 48.89%; P=0.02) compared with 18F-FDG (Table II). Semi-quantitatively, 68Ga-FAPI-04 exhibited a significantly higher TBR_blood_pool [6.07 (5.77–6.37) vs. 1.94 (1.92–1.97); P<0.001; Fig. 4E].

Among treated patients, 18F-FDG failed to detect 9 cases of lymph node metastases. 68Ga-FAPI-04 exhibited significantly higher diagnostic sensitivity (100 vs. 89.02%; P=0.002) accuracy (93.69 vs. 80.18%; P=0.003) and NPV (100.00 vs. 64.00%; P=0.002) compared with 18F-FDG (Table II). The TBR_blood_pool of 68Ga-FAPI-04 (9.13±2.93 vs. 4.01±1.72; P<0.001) (Table III) was also significantly higher, indicating stronger imaging and diagnostic capabilities (Fig. 4F) (17,27).

Lymph nodes in different body regions

The present study evaluated the detection of metastatic (Fig. 4) and non-metastatic lymph nodes in four regions (Fig. 5). The qualitative comparison results of the diagnosis of lymph nodes in these four regions are shown in Table IV.

Table IV. Qualitative evaluation of detected lesions with regional lymph node metastasis by 68Ga-FAPI-04 PET/magnetic resonance imaging vs. 18F-FDG PET/computed tomography.

Table IV.

Qualitative evaluation of detected lesions with regional lymph node metastasis by 68Ga-FAPI-04 PET/magnetic resonance imaging vs. 18F-FDG PET/computed tomography.

Lymph node site	Sensitivity, (n/total n) %	Specificity, (n/total n) %	Accuracy, (n/total n) %	PPV, (n/total n) %	NPV, (n/total n) %
Cervical
68Ga-FAPI-04	(9/9) 100.00	(1/4) 25.00	(10/13) 76.92	(9/12) 75.00	(1/1) 100.00
18F-FDG	(9/9) 100.00	(3/4) 75.00	(12/13) 92.31	(9/10) 90.00	(3/3) 100.00
P-value	NA	0.49	0.59	0.59	NA
Thoracic
68Ga-FAPI-04	(4/4) 100.00	(33/47) 70.21	(37/51) 72.55	(4/17) 23.53	(33/33) 100.00
18F-FDG	(4/4) 100.00	(0/47) 0.00	(4/51) 7.84	(4/51) 7.84	(0/0) 00.00
P-value	NA	<0.001a	<0.001a	0.08	NA
Abdominal
68Ga-FAPI-04	(72/72) 100.00	(8/10) 80.00	(80/82) 97.56	(72/74) 97.30	(8/8) 100.00
18F-FDG	(63/72) 87.50	(8/10) 80.00	(71/82) 86.59	(63/65) 96.92	(8/17) 47.06
P-value	0.002a	>0.99	0.02a	0.90	0.02a
Pelvic
68Ga-FAPI-04	(6/6) 100.00	(4/9) 44.44	(10/15) 66.67	(6/11) 54.55	(4/4) 100.00
18F-FDG	(6/6) 100.00	(3/4) 75.00	(9/10) 90.00	(6/7) 85.71	(3/3) 100.00
P-value	NA	0.56	0.35	0.32	NA

a P<0.05. ¹⁸F, fluorine 18; FDG, fluorodeoxyglucose; ⁶⁸Ga, gallium 68; FAPI, fibroblast-activation protein inhibitor; NA, not applicable; PPV, positive predictive value; NPV, negative predictive value; PET, positron emission tomography.

When evaluating abdominal metastatic lymph nodes, 68Ga-FAPI-04 demonstrated significantly higher diagnostic sensitivity (100 vs. 87.5%; P=0.002), accuracy (97.56 vs. 86.59%; P=0.02) and NPV (100 vs. 47.06%; P=0.02) compared with 18F-FDG.

In semi-quantitative parameter comparisons, 68Ga-FAPI-04 demonstrated significantly higher uptake compared with 18F-FDG in metastatic lymph nodes across all anatomical regions: Cervical [7 nodes, TBR_blood_pool, 16.23 (14.47–16.95) vs. 7.25 (5.911–8.66); P<0.001], thoracic [4 nodes, 10.00 (8.06–12.00) vs. 4.87 (3.47–6.81); P<0.001], abdominal (72 nodes, 8.52±2.29 vs. 3.67±1.33; P<0.001) and pelvic [6 nodes, 4.11 (3.86–4.49) vs. 1.55 (1.41–1.67); P<0.001] (Fig. 4A-D and H-K).

For non-metastatic (inflammatory/benign) lymph nodes, 18F-FDG frequently exhibited FP uptake in thoracic lymph nodes due to inflammation, whereas 68Ga-FAPI-04 achieved significantly higher diagnostic accuracy in thoracic lymph nodes (72.55 vs. 7.84%; P<0.001). In semi-quantitative analysis of benign lymph nodes, 68Ga-FAPI-04 exhibited significantly lower TBR_blood_pool in inflammatory thoracic lymph nodes compared with 18F-FDG (1.88±0.87 vs. 2.71±1.14; P<0.001) (Fig. 5B and I), with no significant differences in uptake between the two tracers observed in cervical, abdominal or pelvic benign lymph nodes.

Distant metastases

In total, 12 patients had distant organ metastases in various sites, including the liver, kidney, pancreatic head, lung, peritoneum, bone, brain, ovary and spleen. Notably, 1 patient had simultaneous liver and spleen metastases. 18F-FDG missed one peritoneal metastasis, one bone metastasis, one pancreatic head with surrounding peritoneal involvement, three splenic metastases, three liver metastases and one renal metastasis, whereas 68Ga-FAPI-04 clearly detected all these metastatic lesions except for one renal metastasis and one small liver metastasis. However, for lung metastases, 18F-FDG PET/CT exhibited improved imaging performance compared with 68Ga-FAPI-04 PET/MRI.

In detecting distant organ metastases in GI tumors with atypical metabolism, 68Ga-FAPI-04 demonstrated significantly higher sensitivity (92.31 vs. 61.54%; P=0.008) and accuracy (88.89 vs. 62.96%; P=0.03) compared with 18F-FDG (Table II). 68Ga-FAPI-04 also exhibited significantly higher uptake in distant metastases (TBR_blood_pool, 6.87±4.16 vs. 3.31±2.19; P<0.001) as well as in the liver, peritoneum, bone and spleen. A comparison of all TBR_blood_pool values is listed in Table III.

Staging impact

Compared with 18F-FDG PET, 68Ga-FAPI-04 PET induced staging changes in 36.4% of cases (8/22). Among these, 31.8% (7/22) had an upstaging. Specifically, 57.1% (4/7) were whole or partial PDA, 28.6% (2/7) were whole or partial MC and 14.3% (1/7) were adenocarcinoma with unclear differentiation. In 4.5% (1/22) of cases, a downstaging was noted, specifically in a case of metastatic duodenal adenocarcinoma.

68Ga-FAPI-04 PET detected M stage upgrading in 22.7% of cases (5/22) and N stage upgrading in 9.1% (2/22). The comparison between 68Ga-FAPI-04 and 18F-FDG imaging revealed statistically significant differences in the disease stage (P=0.004). However, there was no significant difference in N stage staging between the two imaging modalities. These data were derived from Table V.

Table V. Staging changes and treatment changes of patients.

Table V.

Staging changes and treatment changes of patients.

Patient no.	Pathology	18F-FDG staging	68Ga-FAPI-04 staging	Staging change	Additional findings	Previous treatment	Therapeutic management change
1	*	TxN0M1	TxN0M1	-	-	Total gastrectomy + CT	-
2	MDA, partial MC	T3N1bM0	T3N1bM0	-	-	Right colectomy + TT + IT + CT	-
3	PDA	T3N1b3aM0	T3N1b3aM1	M; upgrade	PM, LNM	Total gastrectomy + partial duodenectomy + TT + IT + CT	-
4	MDA	T3N1M1	T3N1M1	-	LM and RM	Palliative surgery for right colon cancer + IT + CT	-
5	MDA, PDA	T3N3M0	T3N3M1	M; upgrade	Recurrence	Esophageal cancer radical surgery + CT	Changed (major)
6	PDA, partial MDA	T4N0M1	T4N0M1	-	-	Partial resection of the small bowel + bilateral salpingo-ovariectomy + CT	-
7	*	T4N0M0	T4N0M0	-	-	-	-
8	Adenocarcinoma	T3N1bM0	T3N2aM0	N; upgrade	LNM	Total mesorectal excision + CT	-
9	SCC (MD)	T2N2M1	T2N2M1	-	-	Esophageal cancer radical surgery + CT + IT	-
10	PDA	T3N3M0	T3N3aM0	N; upgrade	LNM	Total gastrectomy + IT	-
11	SCC	T1aN0M0	T1aN0M0	-	-	Esophageal ESD	-
12	MDA	T3N1M0	T3N0M0	N; degradation	-	Right colectomy + CT	-
13	Gastric GIST	TxN0M0	TxN0M0	-	-	-	-
14	Adenocarcinoma	T3N0M0	T3N0M0	-	-	Radical operation of sigmoid colon carcinoma	-
15	SCC (PD)	T2N1M1	T2N1M1	-	-	Esophageal cancer radical surgery + CT + RT + IT	-
16	MC	TxN0M0	TxN0M1	M; upgrade	PDM	Radical resection of rectal carcinoma + CT + RT + IT	Changed (major)
17	SCC (MD)	T4N1M1	T4N1M1	-	-	Esophageal cancer radical surgery + CT + RT	-
18	SCC (MD)	T3N1M1	T3N1M1	-	-	Esophageal cancer radical surgery + CT + IT	-
19	SCC (MD)	T1bN0M1	T1bN0M1	-	BM	Esophageal cancer radical surgery + CT + IT	Changed (minor)
20	PDA	T4aN0M0	T4aN0M1	M; upgrade	Recurrence	Subtotal gastrectomy + total hysterectomy and bilateral adnexectomy + CT + IT	Changed (major)
21	MDA, partial MC	T3N1M0	T3N1M1	M; upgrade	AM, LM	Left hemicolectomy + CT	Changed (major)
22	*	TxN0M1	TxN0M1	-	LM, SM	CT + IT + RT	Changed (minor)

[i] ‘*’ denotes that the pathological subtype was not provided despite a basic pathological diagnosis. Metastasis was confirmed by the comprehensive consideration of imaging findings. If the modification was made to the treatment plan that the clinician had already anticipated, it was recorded as a minor change. If the FAPI PET results led to a change in the type of treatment or the treatment intent, it was classified as a major change. N, lymph node status; M, distant metastasis status; MDA, moderately differentiated adenocarcinoma; MC, mucinous carcinoma; PDA, poorly differentiated adenocarcinoma; SCC, squamous cell carcinoma; MD, moderately differentiated; PD, poorly differentiated; GIST, GI stromal tumor; PM, peritoneal metastasis; LNM, lymph node metastasis; PDM, pancreaticoduodenal metastasis; LM, liver metastasis; RM, renal metastasis; BM, bone metastasis; AM, abdominal wall metastasis; SM, splenic metastasis; CT, chemotherapy; TT, targeted therapy; IT, immunotherapy; RT, radiotherapy; ESD, endoscopic submucosal dissection; ¹⁸F, fluorine 18; FDG, fluorodeoxyglucose; ⁶⁸Ga, gallium 68; FAPI, fibroblast-activation protein inhibitor.

The present study also conducted an analysis between biopsy results and staging changes indicated by 68Ga-FAPI-04 PET. Fisher's exact test was performed to evaluate the associations. The results demonstrated that mucinous (P=0.018), poorly differentiated (P=0.005), and adenocarcinoma (P=0.004) pathological subtypes were all significantly associated with staging changes indicated by 68Ga-FAPI-04 PET (Table VI). The results demonstrated that the coincidence rate between pathological findings and the diagnostic results of lesion staging changes detected by 68Ga-FAPI-04 PET was 62.5% (5/8), indicating a high degree of consistency between its staging judgments and the pathological gold standard. The nature of the remaining lesions was confirmed using imaging follow-up.

Table VI. Association of pathological subtypes with changes in tumor staging and treatment decisions indicated by gallium 68Ga-fibroblast-activation protein inhibitor-04 positron emission tomography imaging.

Table VI.

Association of pathological subtypes with changes in tumor staging and treatment decisions indicated by gallium 68Ga-fibroblast-activation protein inhibitor-04 positron emission tomography imaging.

	Tumor staging			Treatment decision
Pathology	Stage change, (n/total n) %	No stage change, (n/total n) %	P-value	Treatment decision change, (n/total n) %	No treatment decision change, (n/total n) %	P-value
Mucinous subtype	(2/3) 66.67	(1/3) 33.33	0.018a	(2/3) 66.67	(1/3) 33.33	0.01a
Non-mucinous subtype	(6/19) 31.58	(13/19) 68.42		(4/19) 21.05	(15/19) 78.95
Poorly differentiated subtype	(4/6) 66.67	(2/6) 33.33	0.005a	(2/6) 33.33	(4/6) 66.67	<0.001a
Non-poorly differentiated subtype	(4/16) 25.00	(11/16) 68.75		(4/16) 25.00	(12/16) 75.00
Adenocarcinoma	(7/11) 63.64	(4/11) 36.36	0.004a	(3/11) 27.28	(8/11) 72.73	<0.001a
Non-adenocarcinoma	(1/11) 9.09	(10/11) 90.91		(3/11) 27.28	(8/11) 72.73

a P<0.05.

According to the subgroup analysis, among these lesions whose staging was changed based on 68Ga-FAPI-04 PET detection, 62.5% (5/8) were poorly differentiated adenocarcinoma or MC. This suggested that 18F-FDG PET uptake is atypical in poorly differentiated adenocarcinoma or MC and these subtypes are more likely to achieve medical benefits in staging via 68Ga-FAPI-04 PET detection.

The influence of 68Ga-FAPI-04 PET on staging is summarized in Table V. The analysis presented in the current study focuses on the differences in N and M staging, as well as overall staging.

Treatment impact

68Ga-FAPI-04 influenced the management of subsequent oncological treatments in 27.3% of cases (6/22). Among them, 66.7% (4/6) experienced major treatment changes and 33.3% (2/6) had minor changes (these data were calculated from Table V). Overall, patients diagnosed with PDC and MC had the highest proportion of treatment changes, accounting for 83.3% (5/6).

The following patient-level changes were documented in detail: 68Ga-FAPI-04 successfully detected early local recurrence of PDA and MC (Fig. 3B) and pancreaticoduodenal metastases (Fig. 6C). These findings prompted notable modifications to the therapeutic strategy at the initiation of systemic chemotherapy. Notably, the recurrent metastases were confirmed via gastroscopic follow-up 1 month after initial assessment and the patient was followed up for a total of 1 year.

Figure 6. 68Ga-FAPI-04 PET/MRI vs. 18F-FDG PET/CT: Quantitative comparison of distant metastasis. Comparison between 68Ga-FAPI-04 PET/MRI and 18F-FDG PET/CT for the metastases of gastrointestinal tumors in the (A) peritoneum, (B) spleen, (C) pancreatic head and peritoneum metastasis, (D) liver, (E) bone, (F) cerebellum and (G) kidney. The color bar shows a consistent color scale (7.0) for all images. (H) The histogram shows the comparison of the TBR_blood_pool of the two tracers for distant organ metastases. The numbers on the histograms represent the sample size of each group. ***P<0.001. TBR_blood_pool, tumor-to-blood-pool ratio; FAPI, fibroblast-activation protein inhibitor; 68Ga, gallium 68; FDG, fluorodeoxyglucose; 18F, fluorine 18; PET, positron emission tomography; MRI, magnetic resonance imaging; CT, computed tomography.

In patients with metastatic moderately differentiated esophageal and rectal cancer (patients 19 and 22), 68Ga-FAPI-04 PET/MRI demonstrated increased involvement of the bones, liver and spleen, while 18F-FDG PET/CT failed to detect evident tumors. This discrepancy led to the recommendation of additional systemic therapy, which was regarded as a minor adjustment to the existing treatment plan.

The present study also conducted an analysis between biopsy results and changes in treatment decisions induced by 68Ga-FAPI-04 PET. Fisher's exact test was subsequently performed for statistical analysis, and the results revealed that pathological features, including mucinous subtype (P=0.01), poorly differentiated histology (P<0.001) and adenocarcinoma (P<0.001), were all associated with changes in treatment decisions indicated by 68Ga-FAPI-04 PET (Table VI). The results demonstrated that the coincidence rate between pathological findings and the diagnostic results of 68Ga-FAPI-04 PET for lesions leading to treatment decision changes was 83.3% (5/6), indicating a high degree of consistency between its treatment-related judgments and the pathological gold standard. The nature of the remaining lesion was determined based on follow-up.

According to the subgroup analysis, among these lesions for which treatment plans were adjusted based on 68Ga-FAPI-04 PET detection, 83.3% (5/6) were poorly differentiated adenocarcinoma or MC. This suggested that 18FDG PET uptake is atypical in poorly differentiated adenocarcinoma or MC and these subtypes are more likely to achieve medical benefits in terms of treatment plan adjustment via 68Ga-FAPI-04 PET detection.

Table V summarizes the subsequent impact of FAP-targeted molecular imaging on treatment decisions.

Additional value of MRI

In PET/MRI, the multiple signal sequences of MRI can provide additional imaging parameters and offer high soft-tissue resolution, which aids in accurate diagnosis and confers added value to the detection of primary and metastatic lesions in abdominal and pelvic tumors.

In the present study, MRI identified a renal metastasis in patient 4, who was diagnosed with differentiated adenocarcinoma of the ascending colon. However, this metastatic lesion was not detected by either of the two radiotracers.

Cost-benefit analysis

Regarding the potential cost benefit of 68Ga-FAPI-04 PET/MRI compared with 18F-FDG PET/CT in diagnosing atypical GI tumors, calculations show that the hospital cost of 68Ga-FAPI-04 PET/MRI was higher (RMB 98,583 for 22 patients; RMB 4,481 per person) than that of 18F-FDG PET/CT (RMB 24,347 for 22 patients; RMB 1,107 per person), resulting in a total cost difference of RMB 98,583. However, for 6 patients whose treatment decisions were altered based on PET/MRI findings, the indirect benefits largely offset this cost difference, generating greater overall value.

In patients 5 and 20, 68Ga-FAPI-04 PET/MRI detected anastomotic recurrences missed by both 18F-FDG and initial pathology, eliminating the need for subsequent gastroscopy follow-ups and pathological examinations. This saved ~RMB 2,200 per patient (for gastroscopy, anesthesia, pathology and staining), totaling RMB 4,400 for both. It also avoided one subsequent hospitalization for each patient (~RMB 8,000 per hospitalization) and one follow-up PET/CT scan (RMB 7,000 per scan), resulting in total savings of RMB 34,400.

In patients 16, 19, 21 and 22, 68Ga-FAPI-04 PET/MRI identified additional metastases (pancreatic head, multiple bone lesions, abdominal wall nodules and liver/spleen metastases, respectively). This reduced the need for three subsequent CT follow-ups per patient (~RMB 500 per CT), saving RMB 1,500 per patient. It also avoided one hospitalization (RMB 8,000 each) and one PET/CT follow-up scan (RMB 7,000 for 1 patient), generating total savings of RMB 66,000 for these 4 patients.

For the 22 patients, the additional hospital cost of 68Ga-FAPI-04 PET/MRI over 18F-FDG PET/CT was ~RMB 98,583, while the total benefits from altered management amounted to RMB 100,400, thus covering the cost difference. Additionally, patients saved considerable time and reduced the risk of disease progression.

These findings suggest that although 68Ga-FAPI-04 PET/MRI has higher initial costs, its long-term economic benefits through optimized treatment decisions support its clinical adoption in cases where 18F-FDG results are inconclusive for GI tumors.

Discussion

18F-FDG has limitations in diagnosing GI tumors with atypical glucose metabolism, demonstrating low sensitivity for primary and metastatic lesions with low metabolic activity, such as GI stromal tumors (30), mucinous adenocarcinoma (31) or signet-ring cell carcinoma (32). Regarding lymph node staging, 18F-FDG often yields FP results in the mediastinal and bilateral hilar regions due to inflammatory hypermetabolism. For distant metastases, 18F-FDG shows lower target-to-background ratios than 68Ga-FAPI-04 in extra-pulmonary sites (for example, the liver, peritoneum and spleen). The present findings confirm that 68Ga-FAPI-04 PET/MRI is a valuable complementary tool for detecting such GI tumors, which is consistent with the findings by Pang et al (29). Moreover, by being less affected by postsurgical inflammation, this imaging modality allows for more accurate identification of nodal metastases, thereby avoiding inappropriate adjustments to tumor staging and clinical management in a notable proportion of patients.

Although the present study highlights the advantages of 68Ga-FAPI-04 and supports its clinical value in GI tumors with atypical or equivocal 18F-FDG metabolism, 68Ga-FAPI-04 remains an imperfect radiotracer for malignant lesions due to FP uptake in fibrotic or healing tissues. For instance, anastomotic sites with fibrotic tissue proliferation can exhibit varying degrees of tracer uptake, as demonstrated by the findings of Li et al (33). Beyond these anastomotic FPs, studies such as that by Mori et al (11) indicate that conditions such as arthritis, myocardial fibrosis and uterine fibroids may also lead to FP FAPI uptake. In future studies, the underlying causes of FAPI FPs in benign lesions, specific semi-quantitative uptake parameters and imaging patterns will be further investigated.

The present study has several limitations. First, the sample size was relatively small (n=22), primarily due to the lengthy 68Ga-FAPI-04 PET/MRI protocol (60 min), the limited scanner availability, the high cost of 68Ga-FAPI-04 tracer production requiring a 68Ge/68Ga generator and the stringent inclusion criteria. Of 112 cases that were potentially eligible during the study period, only 22 completed the entire protocol. Accordingly, given the relatively small analyzable sample, no significant differences were observed in the diagnostic accuracy and semi-quantitative parameters of the two radionuclides for detecting anastomotic recurrence and abdominal wall incision lesions. Second, inherent differences in imaging and reconstruction between PET/MRI and PET/CT may lead to non-comparable SUV measurements. To mitigate this, the present study applied the TBR_blood_pool for semi-quantitative correction, a validated method consistent with the study by Qin et al (26). Furthermore, to prevent potential MRI signal gain from exaggerating 68Ga-FAPI-04 results, only CT and MRI for anatomical localization were used in the direct tracer comparison. Specifically, hyperintense MRI findings were discussed separately in the results. Lastly, the present study was registered as retrospective, as registration occurred after its initiation, although the methodology was prospectively applied.

Future large-scale, multi-center studies are required to validate these findings. The present preliminary cost-effectiveness analysis supports the value of 68Ga-FAPI-04, demonstrating benefits for both hospital resource allocation and patient outcomes. As the role of 68Ga-FAPI-04 in GI tumors becomes clearer, this radiotracer is poised for gradual integration into clinical workflows.

In summary, 68Ga-FAPI-04 demonstrates notably increased diagnostic performance in comparison to 18F-FDG in GI cancer with atypical metabolic activity, particularly in poorly differentiated and mucinous subtypes, and exhibits favorable cost-effectiveness. The ability of 68Ga-FAPI-04 to improve staging accuracy and guide treatment modifications underscores its significant potential as a clinical imaging tool.

Supplementary Material

Supporting Data

Supporting Data

Acknowledgements

Not applicable.

Funding

The present study was supported by the National Natural Science Foundation of China (grant no. 81801736).

Availability of data and materials

The data generated in the present study are not publicly available due to restrictions by the Institutional Review Board of the First Affiliated Hospital of Anhui Medical University (Hefei, China) to protect participant privacy, but may be requested from the corresponding author.

Authors' contributions

JM, YX, FQ, NC, MK, YZ and HW contributed to the study conception and design. Material preparation, data collection and analysis were performed by YX, FQ and NC. The first draft of the manuscript was written by JM, and all authors commented on previous versions of the manuscript. All authors have read and approved the final manuscript. JM, YX and HW confirm the authenticity of all the raw data.

Ethics approval and consent to participate

The present study was performed in line with the principles of the Declaration of Helsinki. Ethics approval was granted for the present study by the Ethics Committee of Anhui Medical University (Hefei, China; date, 9th May 2022; approval no. PJ2022-05-09). Informed consent was obtained from all individual participants included in the present study.

Patient consent for publication

Written informed consent was provided by the affected patients for publication of the images in Fig. 2, Fig. 3, Fig. 4, Fig. 5, Fig. 6.

Competing interests

The authors declare that they have no competing interests.

Authors' information

ORCID: JM, 0000-0002-0368-0748; HW, 0000-0002-5753-4420.

References