Abstract
Objectives:
Although FAPI, as a pan-tumor tracer, shows high expression in the malignancy imaging, FAPI uptake is also seen in some benign lesions. The purpose of this study was to retrospectively analyze the characteristics of benign lesions with FAPI uptake on 68Ga-FAPI PET/CT imaging.
Methods:
The electronic medical and imaging records of patients undergoing 68Ga-FAPI PET/CT imaging in the Department of Nuclear Medicine of our hospital from March 2020 to March 2022 were retrospectively analyzed. Patients with benign lesions confirmed by histopathological analysis or long-term follow-up of FAPI-positive lesions were included in the study.
Results:
A total of 44 patients (i.e., 44 benign lesions) were included in this study, including 14 women and 30 men, ranging in age from 19 to 74 years. Benign lesions involved eight systems, including liver (n = 3), tail of pancreas (n = 3), stomach (n = 3), esophagus (n = 1), lung (n = 14), and mediastinum (n = 2), sinuses (n = 1), brain (n = 2), lymph nodes (n = 5), kidneys (n = 4), bones (n = 2), muscles (n = 1), thyroid (n = 1), parathyroid gland (n = 1), and breast (n = 1). The mean SUVmax (p = 0.471) and mean TBR (p = 0.830) of benign lesions in the eight systems were not significantly different.
Conclusion:
Our studies have shown that in addition to malignant tumors, certain benign lesions also show uptake of FAPI, and it is necessary for doctors to distinguish these benign lesions from true malignant tumors.
Advances in knowledge:
Benign lesions may also show FAPI expression, which may make the differential diagnosis of benign and malignant lesions difficult and should be alerted by physicians.
Introduction
Fibroblast activating protein (FAP) is a membrane-bound serine protease belonging to the dipeptidyl peptidase four family that contains both dipeptidyl peptidase (DPP) and endopeptidase activity. This property makes it different from other DPP IV family members and is, therefore, very rare in normal adult tissues. 1 FAP is predominantly expressed in activated fibroblasts, such as cancer-associated fibroblasts (CAFs) from various types of cancer, which are present in more than 90% of epithelial cancers and are distinct from normal fibroblasts. 2 The expression of FAP in CAFs contributes to tumor angiogenesis and the migration and invasion of tumor cells, so the protein can be detected in a variety of malignant tumors and is closely related to poor tumor prognosis. 3–6 Based on this characteristic, FAP has now become a popular molecular target for cancer diagnosis and treatment, attracting widespread attention from the oncology community and nuclear medicine departments. As a result, the development of radionuclide (e.g., 68Ga)-labeled FAP inhibitors (FAPI) has enabled positron emission tomography (PET) imaging of FAP, and 177Lu-labeled FAPI has also been synthesized as a radiographic agent for the treatment of cancer. 7,8 In a variety of tumor entities, including but not limited to tumors in the breast, pancreas and gastrointestinal tract, 68Ga-FAPI PET/CT has excellent tumor uptake capacity and highly sensitive lesion detection ability, even demonstrating a higher tumor-background ratio (TBR) than 18F-FDG PET/CT. 9–12 In addition, the higher target-to-background ratio and the low expression in some normal organs also suggest that FAPI ligands may have potential as therapeutic radioisotopes in the treatment of tumors. 13 In addition to certain epithelial tumors, 68Ga-FAPI PET/CT has also been shown to be effective in imaging other types of cancer, such as lymphoma and sarcoma. 14–16 Therefore, 68Ga-FAPI PET/CT is a promising alternative to 18F-FDG PET/CT in the evaluation of malignant tumors.
FAP is not only expressed in CAF, but it can also be expressed in endothelial cells, neovascular cells, embryonic and immune tissues to some extent. FAP also plays a role in wound healing, fibrosis, scar formation, or inflammation. 17 FAP expression is lowest in normal fibroblasts compared to CAF, resulting in extremely low FAP expression in normal human tissues. However, if there is ongoing tissue damage, remodeling or inflammation in the body, the expression of FAP in activated fibroblasts is also increased. 18 Thus despite a growing number of studies have shown that 68Ga-FAPI PET/CT shows clinically promising and clinically effective in oncology imaging, there are still literatures finding possible FAPI uptake in benign tumors and non-neoplastic disease entities, including inflammatory processes, exophytic bone warts, fractures, liver fibrosis, etc. 19,20
It has been reported in the literature that in 68Ga-FAPI PET/CT imaging, for 28 different tumor entities, mean SUVmax (>12) was highest in sarcoma, esophageal, breast, cholangiocarcinoma, and lung cancer; mean SUVmax was moderate (SUV 6–12) in hepatocellular, colorectal, head and neck, ovarian, pancreatic and prostate cancers; and mean SUVmax was lowest in pheochromocytoma, renal cell, differentiated thyroid, adenoid cystic and gastric cancers had the lowest FAPI uptake (mean SUVmax<6). 21 Study in the literature have also found a total of 185 primary malignancies detected with 68Ga-FAPI PET/CT with a median SUVmax of 9.0 (range 0.97 to 25.71). 22 The literature has used quantitative SUVmax to identify benign and malignant lesions on 68Ga-FAPI PET/CT and found that benign lesions exhibited significantly lower FAPI uptake compared to malignant lesions (mean SUVmax for benign vs malignant lesions: 4.2 vs 10.6). 23 Although benign lesions are currently found to have lower SUVmax than malignant lesions, it is inevitable that certain benign lesions have high FAPI uptake on 68Ga-FAPI PET/CT imaging, which may lead to difficulties in differential diagnosis of benign and malignant lesions by radiologists and nuclear medicine physicians. This requires the physician to know which benign lesions show FAPI uptake on 68Ga-FAPI PET/CT imaging, which is essential for clinical diagnosis.
Therefore, in this study, we retrospectively analyzed the characteristics of benign lesions with FAPI uptake in 68Ga-FAPI PET/CT imaging in different systems, including size, site, SUVmax, and TBR, in order to reduce the possibility of misdiagnosis.
Methods and materials
Patients
We conducted a retrospective analysis of patients enrolled in the 68Ga-FAPI PET/CT clinical trial in our department between March 2020 and March 2022, including patients' electronic medical and imaging records. Informed consent was obtained from each participant prior to performing 68Ga-FAPI imaging.
Inclusion criteria: Inclusion criteria: (a) patients with suspected malignancy based on diagnostic imaging (CT, MRI, ultrasound, etc.) and/or clinical symptoms; (b) After 68Ga-FAPI PET/CT examination, the patient underwent biopsy or surgery for suspected FAPI positive lesions to obtain histopathological results; (c) No definite malignant tumor cells were found by histopathological diagnosis; (d) if histopathological diagnosis was not applicable, we requested clinical and/or imaging follow-up data confirming benign lesions, which were obtained after the PET/CT scan. Exclusion criteria: (a) patients with a definite diagnosis of malignancy; (b) Patients without histopathological diagnosis or follow-up of suspected FAPI-positive lesions; (c) Patients who have died.
68Ga-FAPI PET/CT Synthesis
The ligand FAPI containing 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was purchased from CSBio.68 The preparation of 68Ga-FAPI was performed according to a previous protocol. 24 Quality control of the radiosynthesis was performed using UV and radioactive high-performance liquid chromatography (HPLC). The radiochemical purity of 68Ga-FAPI was over 98%. The final product is sterile and pyrogen-free.
Acquisition of 68Ga-FAPI PET/CT Images
The intravenous dose of 68Ga-FAPI was 1.85 MBq/kg depending on the patient’s body weight. 45–60 min after intravenous injection of the tracer, the PET/CT scanner was used for the examination. Participants drank 500 ml of water to stimulate excretion of the tracer and urination prior to undergoing PET/CT. Patients were placed in the supine position and scanned from the head to the upper thighs. The CT scan was performed first; tube voltage, 120 kV; current, 80 mA; slice thickness, 3.75 mm, layer spacing 5 mm, pitch 0.813. PET was performed in a 3D acquisition mode on the same bed as CT. Posterior PET scan, FOV 576 mm, 3 min/bed, included 9–10 beds. All acquired CT and PET data were transferred to a post-processing workstation (uWS-MI, version R002; United Imaging Medical). Reconstruction was performed using the ordered subset maximum expectation method (OSEM) (number of 20 subsets; number of two iterations). Image analysis was performed using fusion software (PHILIPS EBW) after completion of the reconstruction. During and after 120 min of radionuclide injection, the nuclear medicine physician was asked to report any abnormalities in the patient, including mental status, blood pressure, temperature, and heart rate.
68Ga-FAPI PET/CT imaging review
The 68Ga-FAPI PET/CT images were interpreted by two experienced nuclear medicine physicians who have been practicing nuclear medicine for more than 10 years, including visual and semi-quantitative analysis. When there is no agreement on image interpretation, consensus is reached through joint review and discussion within the department. For quantitative analysis, the volume of interest (VOI) was drawn on the transverse axis image around the lesion by automatically calculating the maximum normalized uptake value (SUVmax). The mean normalized uptake value (SUVmean) of a 2 cm diameter sphere in the background blood pool was used as the active background, and the target-to-background ratio (TBR) was calculated by dividing the lesion SUVmax by the SUVmean. We subjectively defined lesion activity on 68Ga-FAPI PET/CT that exceeded the activity of adjacent background tissue (visual interpretation) as a FAPI-positive lesion.
Statistical analyses
All statistical analyses were performed using SPSS 25.0 (IBM, Armonk, NY, USA). Continuous variables were expressed as mean ± SDs. The mean SUVmax and mean TBR of lesions from different systems were compared using a one-way ANOVA test. A two-tailed p < 0.05 indicates statistical significance.
Results
Patients’ characteristics
This study retrospectively counted 670 patients who underwent 68Ga-FAPI PET/CT. According to the inclusion and exclusion criteria, a total of 44 patients were found to meet the requirements (i.e., 44 benign lesions), including 14 women and 30 men, age range for 19–74 years old. Benign lesions were diagnosed based on surgical resection (n = 19), image-guided biopsy (n = 22), and clinical or/and imaging follow-up (n = 3) There were ten cases in the digestive system, seventeen in the respiratory system, two in the nervous system, five in the circulatory system, four in the urinary system, three in the motor system, two in the endocrine system and one in the reproductive system. Patients characteristics and location of lesions with FAPI uptake are shown in Table 1.
Table 1.
Patients characteristics and location of lesions with FAPI uptake.
| Overall (N = 44) | |
|---|---|
| Age | |
| Mean ± SD (rang) | 52 ± 13(19-74) |
| Gender | |
| Female | 14 |
| Male | 30 |
| Number of lesions per system | |
| Digestive System | 10 |
| Respiratory System | 17 |
| Nervous System | 2 |
| Circulation System | 5 |
| Urinary System | 4 |
| Locomotor System | 3 |
| Endocrine System | 2 |
| Reproductive System | 1 |
Characteristics of benign lesions detected by 68Ga-FAPI PET/CT
The sites of benign lesions detected by 68Ga-FAPI PET/CT included the liver, tail of the pancreas, stomach, esophagus, lungs, mediastinum, sinuses, skull, lymph nodes, kidneys, bones, muscles, thyroid, parathyroid and breast, with the lungs being the most numerous. Three cases of pseudocysts in the tail of the pancreas were confirmed by follow-up, and the rest were diagnosed by histopathology. Six of the 44 benign lesions were benign tumors, including three cases of renal angiomyolipoma, one case of inversion papilloma of the sinus, one case of benign nerve sheath tumor of the mediastinum, and one papillary cystadenomatosum of the occlusal muscle. Of these 44 benign lesions, the smallest benign lesion measured 8 × 10 mm and the largest was 99 × 73 mm. The mean SUVmax of the benign lesions detected by 68Ga-FAPI PET/CT was 6.2 (range 2.2–21.8) and the mean TBR value was 5.1 (range 1.9–16.8). benign lesion Characteristics and Semiquantitative Parameters of 68Ga-FAPI PET/CT are shown in Table 2.
Table 2.
Benign lesion Characteristics and Semiquantitative Parameters of 68Ga-FAPI PET/CT.
| No. | Lesion site | Lesion size (mm) | 68Ga-FAPI | Final diagnosis | |
|---|---|---|---|---|---|
| SUVmax | TBR | ||||
| 1 | Left lobe of liver | 36✕65 | 10.7 | 5.9 | Viral hepatitis |
| 2 | Left lobe of liver | 42✕79 | 5.5 | 3.7 | Liver cirrhosis |
| 3 | Left lobe of liver | 27✕35 | 4.5 | 4.1 | Focal nodular hyperplasia of the liver |
| 4 | Pancreatic tail | 65✕48 | 5.3 | 4.8 | Pseudocyst |
| 5 | Pancreatic tail | 41✕42 | 21.8 | 16.8 | Pseudocyst |
| 6 | Pancreatic tail | 15✕17 | 4.4 | 5.5 | Pseudocyst |
| 7 | Stomach | 27✕17 | 3.3 | 2.5 | No malignant tumor cells |
| 8 | Esophagus | - | 5.3 | 3.5 | No malignant tumor cells |
| 9 | Stomach | - | 3 | 3.0 | Ulcer |
| 10 | Stomach | 31✕29 | 7.8 | 7.8 | Granulomatous inflammation |
| 11 | Upper lobe of right lung | 9✕13 | 2.3 | 2.1 | No malignant tumor cells |
| 12 | Middle lobe of right lung | 29✕39 | 5.1 | 4.6 | No malignant tumor cells |
| 13 | Upper lobe of right lung | 14✕13 | 12.3 | 8.8 | Fibrous connective tissue hyperplasia |
| 14 | Upper lobe of left lung | 8✕10 | 2.5 | 2.5 | Langerhans cell histiocytosis |
| 15 | Middle lobe of right lung | 52✕37 | 3.0 | 2.5 | Chronic inflammation |
| 16 | Lower lobe of left lung | 16✕17 | 6.0 | 6.0 | Chronic inflammation |
| 17 | Lower lobe of left lung | 19✕15 | 9.1 | 7.0 | Chronic inflammation |
| 18 | Upper lobe of left lung | 10✕15 | 3.0 | 2.5 | No malignant tumor cells |
| 19 | Upper lobe of left lung | 23✕18 | 2.5 | 2.1 | Tuberculosis |
| 20 | Upper lobe of left lung | 12✕14 | 6.3 | 4.8 | Tuberculosis |
| 21 | Lower lobe of left lung | 10✕10 | 2.3 | 2.1 | No malignant tumor cells |
| 22 | Lower lobe of right lung | 14✕20 | 3.0 | 2.7 | Chronic inflammation |
| 23 | Upper lobe of left lung | 19✕30 | 9.0 | 10.0 | Chronic inflammation |
| 24 | Lower lobe of right lung | 11✕11 | 9.3 | 9.3 | Granulomatous inflammation |
| 25 | Right upper mediastinum | 99✕73 | 3.5 | 2.7 | Benign nerve sheath tumor |
| 26 | Middle mediastinum | 50✕57 | 2.2 | 2.4 | Goiter |
| 27 | Left sinus | 28✕37 | 5.8 | 4.8 | Inverted papilloma |
| 28 | Right frontal lobe | 14✕14 | 5.7 | 3.8 | Parasitic infection |
| 29 | Right occipital lobe | 35✕26 | 4.0 | 2.4 | Inflammatory lesion |
| 30 | Left side-of neck | 17✕13 | 5.0 | 10.0 | Granulomatous inflammation |
| 31 | Right supraclavicular fossa | 10✕18 | 5.5 | 3.2 | IgG4-related lymph node disease |
| 32 | Right supraclavicular fossa | 11✕13 | 2.8 | 1.9 | Lymph node reactive hyperplasia |
| 33 | Right supraclavicular fossa | 28✕12 | 9.8 | 5.7 | Lymph node reactive hyperplasia |
| 34 | Retroperitoneal | 21✕30 | 17.9 | 11.9 | Lymph node reactive hyperplasia |
| 35 | Left kidney | 22✕30 | 2.4 | 4.0 | Cystic nodule |
| 36 | Left kidney | 23✕20 | 11.2 | 10.2 | Angiomyolipoma |
| 37 | Left kidney | 62✕55 | 3.8 | 3.5 | Angiomyolipoma |
| 38 | Right kidney | 15✕17 | 2.4 | 4.0 | Angiomyolipoma |
| 39 | vertebral body | 15✕15 | 14.3 | 10.2 | Granulomatous inflammation |
| 40 | Occipital bone | - | 12.2 | 6.8 | Eosinophilic granuloma |
| 41 | Right side-bite muscle | 34✕39 | 2.3 | 2.1 | Papillary cystadenomatosum |
| 42 | Left lobe of thyroid | 13✕15 | 7.7 | 5.5 | Nodular goiter |
| 43 | Right parathyroid | 11✕13 | 3.4 | 2.8 | Parathyroid hyperplasia |
| 44 | Left brea | 12✕10 | 3.6 | 2.8 | Fibrous fat |
Note:—The size of some lesions cannot be measured.
FAPI-positive benign lesions in different systems
Digestive system
There were 10 benign lesions, including one case of viral hepatitis of the liver, one case of liver cirrhosis and one case of focal nodular hyperplasia of the liver (Figure 1), three cases of caudal pancreatic pseudocysts, one case of gastric ulcer, one case of gastric granulomatous inflammation, and two gastric lesions and one esophageal lesion that were biopsied without finding malignant cells. The mean SUVmax and TBR of these 10 lesions were 7.2 ± 5.6 and 5.8 ± 4.2, respectively.
Figure 1.
A 56-year-old male patient underwent 68Ga-FAPI PET/CT for a patchy abnormal enhancing shadow (arterial phase) seen in the left inner lobe of the liver on enhanced CT. A whole-body PET coronal maximum intensity projection image (A) and axial cross-sectional images (B-C) showed localized FAPI activity in the left lobe of the liver. The patient then underwent a biopsy of the lesion and the pathology was consistent with focal nodular hyperplasia of the liver.
Respiratory system
There was one case of sinus invagination papilloma, one case of goiter in the mediastinal, one case of benign mediastinal nerve sheath tumor and the remaining 14 cases were benign lesions of the lung. Among the 14 cases, five cases had chronic inflammation, four cases had no malignant tumor cells detected by needle biopsy, two cases had tuberculosis, one case had fibrous connective tissue hyperplasia (Figure 2), and one case had Langerhans cells Histiocytosis, one case of granulomatous inflammation. The mean SUVmax and TBR of the 17 lesions were 5.1 ± 3.1 and 4.5 ± 2.7, respectively, while the mean SUVmax and TBR of the 14 lung lesions were 5.4 ± 3.3 and 4.8 ± 2.9, respectively.
Figure 2.
A 68-year-old male patient underwent 68Ga-FAPI PET/CT for a solid subpleural nodule in the approximately anterior segment of the right upper lobe of the lung detected on chest CT. Whole-body PET coronal maximum intensity projection images (A) and axial cross-sectional images (B-C) showed localized FAPI activity in the nodule in the upper lobe of the right lung. The patient then underwent television-assisted thoracoscopic surgery (VATS) for resection of a right upper lobe nodule, which showed fibrous connective tissue hyperplasia and hyalinosis with carbon deposits and inflammatory cell infiltration
Nervous system
By retrospective analysis, only two cases of benign cranial lesions were identified, including one parasitic infection and one case of inflammatory lesion. Their average SUVmax and TBR were 4.9 ± 1.2 and 3.1 ± 1.0 respectively.
Circulatory system
A total of five isolated enlarged lymph nodes were diagnosed as benign lesions by histopathological examination, including three cases of reactive hyperplasia, one case of granulomatous inflammation and one case of IgG4-related lymph node disease. The mean SUVmax and TBR of these five lesions were 8.2 ± 6.0 and 6.5 ± 4.3, respectively.
Urinary system
There were one cystic nodule and three angiomyolipoma, of which one angiomyolipoma lesion had an SUVmax of 11.2 (Figure 3). The mean SUVmax and TBR of these four lesions were 5.0 ± 4.2 and 5.4 ± 3.2, respectively.
Figure 3.
A 63-year-old female patient who underwent abdominal CT for acute pancreatitis was found to have a left renal lesion. She underwent 68Ga-FAPI PET/CT for further clarification. A whole-body PET coronal maximum intensity projection image (A) and axial cross-sectional images (B-C) showed a left renal lesion with increased FAPI expression The patient subsequently underwent surgery and the postoperative pathology showed: left suprarenal pole vascular smooth muscle lipoma.
Locomotor system
Includes one case of granulomatous inflammation of the vertebral body, one case of eosinophilic granuloma of the occipital bone and one case of papillary cystadenomatosum of the occipital muscle. Their mean SUVmax and TBR were 9.6 ± 6.4 and 4.2 ± 1.9, respectively.
Endocrine system
One case of nodular goiter (Figure 4) and one case of parathyroid hyperplasia were identified by retrospective analysis. The mean SUVmax and TBR were 5.6 ± 3.0 and 4.2 ± 1.9, respectively.
Figure 4.
A 51-year-old male patient underwent 68Ga-FAPI PET/CT for a mixed cystic solid echogenicity with calcification in the left lobe of the thyroid gland detected by thyroid ultrasound. A whole-body PET coronal maximum intensity projection image (A) and axial cross-sectional images (B-C) showed a nodule in the left lobe of the thyroid with increased FAPI expression. The patient then underwent excision of the left lobe of the thyroid and isthmus under general anesthesia. Postoperative pathology showed a nodular goiter with fibrosis and calcification.
Reproductive system
Only one case of left breast fibrofatty nodule was found, with a SUVmax of 3.6 and a TBR of 2.8.
Comparison of mean SUVmax and mean TBR of benign lesions in different systems
The mean SUVmax values of the 44 benign lesions in the eight systems were 6.2 ± 4.4 and there was no significant difference in the SUVmax of benign lesions in the eight systems (p = 0.471); their mean TBR was also not significantly different (5.1 ± 3.3, p = 0.830). SUVmax and TBR in benign lesions of different systems are shown in Table 3.
Table 3.
The mean SUVmax and TBR in benign lesions of different systems
| Different systems | Number of patient | 68Ga-FAPI PET/CT | P | ||
|---|---|---|---|---|---|
| SUVmax | TBR | SUVmax | TBR | ||
| Digestive System | 10 | 7.2 ± 5.6 | 5.8 ± 4.2 | ||
| Respiratory System | 17 | 5.1 ± 3.1 | 4.5 ± 2.7 | ||
| Nervous System | 2 | 4.9 ± 1.2 | 3.1 ± 1.0 | ||
| Circulation System | 5 | 8.2 ± 6.0 | 6.5 ± 4.3 | ||
| Urinary System | 4 | 5.0 ± 4.2 | 5.4 ± 3.2 | ||
| Locomotor System | 3 | 9.6 ± 6.4 | 6.4 ± 4.1 | ||
| Endocrine System | 2 | 5.6 ± 3.0 | 4.2 ± 1.9 | ||
| Reproductive System | 1 | 3.6 | 2.8 | ||
| Sum | 44 | 6.2 ± 4.4 | 5.1 ± 3.3 | 0.471 | 0.830 |
Discussion
Cancer-associated fibroblasts (CAFs) constitute a major component of the tumor microenvironment and overexpression of FAP protein is a distinctive feature of cancer-associated fibroblasts that is not found in normal fibroblasts. 7,8 FAP-targeted radiopharmaceuticals have therefore recently been developed on the basis of FAP-specific inhibitors (FAPI). Studies have shown that 68Ga-FAPI PET/CT enables rapid imaging in 28 tumor entities with particularly sharp tumor contours and high tumor-to-background contrast. 21 However, FAP expression is not cancer specific and many activated fibroblasts can also express FAP in wound healing and non-malignant diseases such as pulmonary fibrosis or cirrhosis, chronic inflammation, rheumatic diseases, and myocardial infarction. 1,25 Inevitably, elevated FAPI uptake is also found in some benign lesions. 22 In this study, we use tables and associated images to illustrate benign lesions with FAPI uptake that may be encountered when reporting 68Ga-FAPI PET/CT to help avoid misdiagnosis and mistreatment. Our retrospective analysis showed that FAPI uptake by benign lesions occurred in all the eight systems, and no significant differences were found in SUVmax and TBR for benign lesions in each system. We included a total of 44 benign lesions, of which the smallest benign lesion measured 8 × 10 mm and the largest 99 × 73 mm. The mean SUVmax of the benign lesions detected by 68Ga-FAPI PET/CT was 6.2 (range 2.2–21.8) and the mean TBR was 5.1 (range 1.9–16.8).
Of these 44 benign lesions, pulmonary lesions accounted for 14 (31.8%), including 12 isolated pulmonary nodules less than 3 cm in diameter and two masses greater than 3 cm in diameter. This may be due to the fact that lung nodules are gradually causing concern for clinicians and patients, especially isolated lung nodules (SPN). A pulmonary nodule is defined as a well-margined round or ovoid shadow less than 30 mm in diameter, completely surrounded by lung parenchyma and not associated with lymphadenopathy, atelectasis, pneumonia, or pleural effusion. 26 With the application of high resolution CT and the popularization of lung cancer screening, more and more lung nodules are being detected. In the United States, approximately 1.6 million lung nodules are detected each year, and about 30% are detected by chest computed tomography (CT) images. 27 SPN are classified as solid, sub-solid, or hairy glass nodules. The differential diagnosis of SPN is broad, including neoplastic, inflammatory, infectious, congenital, and vascular lesions. 28 The incidental discovery of SPN are an increasingly common clinical challenge for clinicians, particularly in the identification of benign and malignant. High-resolution CT is generally considered to be the conventional method for identifying GGN. However, the imaging features of benign and malignant GGN overlap, and the judgement of lesion features is susceptible to subjective factors. Therefore, the diagnostic efficiency of HRCT needs to be improved. One study used the SUVmax of 18F-FDG PET imaging to identify benign and malignant lung nodules, but there are still some limitations. 29 As a pan-tumor PET tracer, 68Ga-FAPI is highly expressed in a variety of malignant tumors, including lung cancer, and one study found that the mean SUVmax of lung cancer on 68Ga-FAPI PET/CT imaging was >12. 21 However, our study found high FAPI uptake in benign isolated lung nodules as well, with the highest SUVmax of 12.3 and the lowest of 2.3, and the most common isolated lung nodules were inflammatory in nature. Therefore, when high FAPI uptake occurs in isolated lung nodules, using SUVmax alone as a criterion, we cannot directly diagnose malignancy and should assess multiple aspects.
FAP is associated with scar formation, and up-regulation of FAPI can be observed in fibrotic diseases, such as liver fibrosis resulting from chronic injury caused by viral hepatitis. One case of viral hepatitis in our study exhibited high FAPI uptake, possibly because hepatic stellate cells were activated and generated extracellular matrix due to hepatic fibrosis, thus contributing to the formation of FAP-expressing scarring in the liver. 20 Of note is a case report by Zhao et al describing a patient with cirrhosis who presented with multiple liver nodules of unknown origin, and 68Ga-FAPI PET/CT showing increased uptake by the liver due to cirrhosis 30 This is consistent with our case of a cirrhotic nodule with high FAPI expression. The overexpression of FAP in benign fibrosis may present a new challenge for 68Ga-FAPI PET/CT in identifying benign and malignant liver tumors. It has also recently been found that pancreatitis causes intense uptake of 68Ga-FAPI throughout the pancreas. 31 In our study we also observed Avid- FAPI uptake in three cases suffering from pancreatic pseudocysts, and by reviewing the electronic medical records we found that the patients had a previous history of pancreatitis. This may be due to fibrin formation as a result of chronic inflammation, and post-drainage pancreatic tissue may express FAP through wound healing. Therefore, we cannot ignore the patient’s past medical history when making the diagnosis.
Fibroblasts play a key role in granuloma formation and there are increasing reports that high FAPI uptake may be closely associated with granulomatous diseases similar to malignancy, such as tuberculosis. 32 In contrast, our study also identified four cases of granulomatous inflammation and two cases of tuberculosis mimicking malignancy with increased uptake on 68Ga-FAPI PET/CT, with the highest SUVmax value of 14.3 and the lowest of 5.0. IgG4 is a disease that affects multiple organs and is associated with fibrosis, and FAPI exhibits high expression in such lesions. 33 And we confirmed a case of IgG4-associated lymph node disease with high FAPI uptake. An increased accumulation of 68Ga-FAPI in recurrent renal angiomyolipoma has also been reported. 34 Our retrospective analysis also identified increased FAPI uptake in 3 cases of renal angiomyolipoma. This may be because fibroblasts are one of the cell types in renal angiomyolipoma, and fibroblast-like cells are present in the abnormally thickened subendothelial space of renal angiomyolipoma. 35 Thus not only do benign lesions such as inflammation and scarring lead to increased FAPI expression, but certain benign tumors can also show a similar picture.
Based on the analysis of these 44 benign lesions, we found that FAPI-positive benign lesions can occur in a variety of systems. FAPI is not a specific tracer only for malignant tumors, but it can also be used as a broad-spectrum inflammatory imaging agent to detect a variety of non-neoplastic lesions. This makes it necessary to distinguish these benign lesions from true malignant tumors when interpreting 68Ga-FAPI PET/CT images. In such cases, we can resort to morphological features of the CT scan or certain clinical tests to help in the differential diagnosis.
However, there are still some limitations to this study. Firstly, the patient population we studied was relatively small (n = 44) and not enough benign lesions were found in each system, so this may introduce statistical uncertainty. Second, it would be unethical to perform histopathological biopsies on all suspicious lesions with abnormally high FAPI uptake, and therefore we had three pancreatic lesions as a follow-up result. Third, this study was a retrospective analysis and did not examine the ability of 68Ga-FAPI PET/CT in the differential diagnosis of benign and malignant lesions.
Conclusion
In conclusion, lesions with increased FAPI uptake are not necessarily malignant. Certain benign lesions with FAPI uptake can be diagnosed by combining the CT presentation, specific location and clinical information. However, benign lesions with FAPI uptake remain indistinguishable from malignant tumors, which may make diagnosis difficult. We report 44 cases of benign lesions with FAPI uptake as a way to bring them to the attention of imaging physicians.
Footnotes
Competing interests: None of the authors have any conflict of interest.
Funding: Sichuan Provincial Science and Technology Department (Grant No.2022NSFSC0827) and Luzhou Science and Technology Bureau (Grant No.2021CDLZ-9) provided financial support for this study.
Patient consent: The patient gave informed consent to using clinical data for research and scientifc purposes.
Ethics approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional.
Contributors: All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Qiaoqiao Shu, YuDi Wang, Maoxue Deng, MengNa Liu, Xi Chen, Liang Cai. The first draft of the manuscript was written by Qiaoqiao Shu, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Contributor Information
Qiaoqiao Shu, Email: 1466683748@qq.com.
Yudi Wang, Email: wyd290023@163.com.
Maoxue Deng, Email: dengmaoxue711@163.com.
Xi Chen, Email: chenxi000127@163.com.
Mengna Liu, Email: 2323034044@qq.com.
Liang Cai, Email: cllc131420@sina.com.
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