1. Patients’ characteristics
One hundred and three patients who were suspected of primary tumor and twenty patients with a previously treated cancer were included in this prospective study. The inclusion criteria was that at least one nonphysiological focus greater than blood-pool activity or adjacent normal tissue background on 18F-FDG or 68Ga-FAPI-04 PET was found. The study subjects comprised 69 men and 54 women, with an average age of 56.11±11.94 years (range, 28-83 years). Among the 123 patients, 13 patients were confirmed with non-malignant oncological diseases. A total of 84 patients with 88 solid primary malignant tumors, 8 patients with hematological neoplasms, 58 patients with 376 nodal metastases, 43 patients with 406 distant metastases and 52 patients with 145 non-oncological lesions and benign tumors were detected (Table 1).
2. Malignant tumor
2.1 Solid tumor
2.1.1 Detection of primary malignant cancer
For primary malignant cancer detection, eighty-two patients with 18 types of newly diagnosed tumor underwent PET/CT for an initial staging, and 20 patients with 14 types of previously treated cancer underwent PET/CT for recurrence detection (restaging). A total of 84 patients with 88 primary tumors were detected (Table 2). Among the 84 patients with 18 types of cancers, 2 patients had two primary tumors each and 1 patient had three primary lesions. Eighty-two patients had newly diagnosed tumor and two patients underwent tumor recurrence. For individual primary tumor analysis, the 68Ga-FAPI-04 PET-derived SUVmax were significantly higher than the SUVmax of 18F-FDG PET in liver cancer, stomach tumor, and pancreatic tumor (p = 0.007, 0.005, and 0.011, respectively). For all 88 primary tumors, 68Ga-FAPI-04 PET showed significantly higher SUVmax value than 18F-FDG PET (10.98±5.83 vs. 8.36±6.43, p<0.001).
The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of 18F-FDG PET/CT for primary malignant tumor detection was 84.89% (73/86), 0.00%, 97.33%, 0.00%, and 82.95%, respectively (Table 3). The corresponding value of 68Ga-FAPI-04 PET/CT was 97.67% (84/86), 50.00%, 98.82%, 33.33%, and 96.59%, respectively. There were 13 primary tumors that were not visualized by 18F-FDG but visualized by 68Ga-FAPI-04 PET/CT [including 4 hepatocellular cancers (Figure 1), 1 stomach cancer, 1 gastric stromal tumor (Figure 2), 1 pancreatic adenocarcinoma, 1 pancreatic neuroendocrine tumor, 1 mucous adenocarcinoma of the appendix (Figure 3), 1 appendix cancer, 1 ovarian cancer, 1 breast cancer, and 1 papillary carcinoma of the thyroid]. Only two primary tumors (1 pancreatic mucinous cystadenoma and 1 pancreatic cancer) were not visualized by 68Ga-FAPI-04 PET/CT. One colonic lesion was misdiagnosed as colon cancer both by 18F-FDG and 68Ga-FAPI-04 PET/CT. One nasopharyngeal uptake was misdiagnosed as nasopharyngeal carcinoma by 18F-FDG PET/CT, but 68Ga-FAPI-04 PET/CT demonstrated no abdominal tracer uptake. Finally, nasopharyngoscopy confirmed chronic nasopharyngitis. The diagnostic efficacy of 18F-FDG and 68Ga-FAPI-04 PET/CT for primary malignant tumor detection was compared using McNemar’s test. 68Ga-FAPI-04 PET/CT demonstrated a higher diagnostic efficacy (Pearson X2 = 0.538, p = 0.021).
2.1.2 Detection of nodal metastasis
18F-FDG or 68Ga-FAPI-04 PET-positive lymph nodes were classified into 4 regions by anatomical regions, including head and neck, thoracic, abdominal, and pelvic regions. Among the 102 patients with either newly diagnosed or previously treated cancers, a total 58 patients with 376 lymph node metastases were examined. As shown in Table 4, lymph nodes in two regions (head and neck and pelvic regions) showed concordant SUVmax uptake of both 18F-FDG and 68Ga-FAPI-04, whereas lymph nodes in the other two regions (thoracic and abdominal regions) demonstrated discordant tracer activity. Indeed, thoracic and abdominal nodal metastases demonstrated significantly higher 68Ga-FAPI-04 PET-derived SUVmax than 18F-FDG SUVmax. For all 376 nodal metastases, 68Ga-FAPI-04 PET showed significantly higher SUVmax value than 18F-FDG PET (10.50±5.98 vs. 8.20±6.29, p=0.011). The sensitivity, specificity, PPV, NPV, and accuracy of detecting metastatic lymph nodes were 84.72%, 33.33%, 99.37%, 1.72%, and 84.31% for 18F-FDG PET/CT and 97.59%, 66.67%, 99.73%, 18.18%, and 97.34% for 68Ga-FAPI-04 PET/CT, respectively (Table 3). 68Ga-FAPI-04 PET/CT demonstrated a higher diagnostic efficacy (Pearson X2=2.067, p<0.001) for metastatic lymph node detection compared to 18F-FDG PET/CT. In the nodal region-based analysis, there were 11 head and neck, 18 thoracic, 21 abdominal (Figure 3), and 6 pelvic lymph node metastases that were not visualized by 18F-FDG but visualized by 68Ga-FAPI-04 PET/CT. Only 3 head and neck, 2 thoracic, 3 abdominal, and 1 pelvic lymph node metastases were not detected by 68Ga-FAPI-04 but detected by 18F-FDG PET/CT. Two head and neck lymph nodes were misdiagnosed as nodal metastasis by 18F-FDG PET, but demonstrated no 68Ga-FAPI-04 uptake. One abdominal lymph node was misdiagnosed as nodal metastasis by positive 68Ga-FAPI-04 uptake. The abdominal lymph node and the two head and neck lymph nodes were finally confirmed as lymphnoditis.
2.1.3 Detection of distant metastasis
A total of 13 different distant involvement sites with 406 metastases were defined in 43 solid tumor patients based on the reference standard. The most common site of metastases was axial skeleton, followed by liver, lung metastasis and peritoneal, omentum, and mesenteric metastasis. As shown in Table 5, the metastatic lesions in skeleton, liver, peritoneum, omentum, and mesentery demonstrated about 2 times greater 68Ga-FAPI-derived SUVmax than the 18F-FDG-derived SUVmax. Furthermore, more metastases in these sites were discovered with 68Ga-FAPI-04 than with 18F-FDG. 18F-FDG PET/CT was false negative for 22 skeletal metastases (Figure 4), 29 liver metastases, 10 lung metastases and 75 peritoneal, omentum, and mesenteric metastases (Figure 3). Only 5 lung metastases and 2 peritoneal, omentum, and mesenteric metastases were false negative on 68Ga-FAPI-04 PET/CT. Distant metastasis in other involvement sites showed concordant SUVmax uptake of both 18F-FDG and 68Ga-FAPI-04. However, the metastases in these sites were too few to make a convincing and firm conclusion. Based on all metastases analysis, 68Ga-FAPI-04 PET showed significantly higher SUVmax value than 18F-FDG PET (9.64±6.45 vs. 6.74±4.83, p<0.001). The overall sensitivity, specificity, predictive values and accuracy of 18F-FDG and 68Ga-FAPI-04 PET/CT for all detecting metastatic diseases were presented in Table 3. 68Ga-FAPI-04 PET/CT demonstrated a higher diagnostic efficacy (Pearson X2=4.897, p<0.001) for distant metastasis detection compared to 18F-FDG PET/CT.
2.2 Hematological neoplasm
Eight patients with hematological neoplasm (3 multiple myelomas and 5 lymphomas) were included in the study. A total 39 myeloma and 117 lymphoma lesions were examined (Table 6). Myeloma lesions showed concordant SUVmax uptake of both 18F-FDG and 68Ga-FAPI-04. Lymphoma lesions demonstrated significantly higher 18F-FDG PET-derived SUVmax than 68Ga-FAPI-04 SUVmax (13.74±7.09 vs. 5.95±3.82, p<0.001). For both myeloma and lymphoma lesions, 18F-FDG PET showed significantly higher SUVmax value than 68Ga-FAPI-04 PET (6.84±4.67 vs. 13.09±7.29, p<0.001).
The sensitivity of 18F-FDG and 68Ga-FAPI-04 PET/CT detecting hematological neoplasm lesions were 96.75% (149/154) and 50.65% (78/154), respectively (Table 3). For detecting all 156 myeloma and lymphoma lesions, 18F-FDG PET/CT demonstrated a higher diagnostic efficacy (Pearson X2=5.166, p<0.001) compared to 68Ga-FAPI-04 PET/CT. There were 20 myeloma lesions and 56 lymphoma lesions (including 53 lymph nodes, 2 marrow infiltrations and 1 splenic infiltraion) that were not visualized by 68Ga-FAPI-04 PET (Figure 5). However, only five lymphoma lesions were not visualized by 18F-FDG PET. Two cervical lymph nodes were misdiagnosed as lymphoma lesions by 18F-FDG PET/CT, but 68Ga-FAPI-04 PET/CT demonstrated no abdominal tracer uptake. After the patent received CHOP chemotherapy, 18F-FDG PET/CT follow-up demonstrated complete remission of other enlarged lymph node lesions, but the two cervical lymph nodes still accumulated 18F-FDG. Finally, a lymph node biopsy was performed and confirmed the diagnosis of lymphnoditis.
3. Non-oncological lesion and benign tumor
Among the 123 included patients, a total of 23 different kinds of 145 non-oncological lesions and benign tumors were detected in 52 patients (Table 7). For more than 5 foci non-oncological lesion, fracture (10), fibrosis (8), and arthritis (14) demonstrated discordant activity between 18F-FDG and 68Ga-FAPI-04 uptake. Indeed, the 68Ga-FAPI-04 PET-derived SUVmax were significantly higher than the SUVmax of 18F-FDG PET (The p values were 0.005, 0.022 and <0.001 for fracture (Figure 1), fibrosis and arthritis, respectively). Pneumonia (10), tuberculosis (14) and lymphnoditis (61, Figure 1-2) demonstrated concordant uptake of both 18F-FDG and 68Ga-FAPI-04 (The all p values were >0.05). For all 145 non-oncological lesions, 68Ga-FAPI-04 PET showed no significantly higher SUVmax value than 18F-FDG PET (6.40±3.95 vs. 5.74±15.78, p = 0.729). The sensitivity, specificity, PPV, NPV, and accuracy of 18F-FDG PET/CT for non-oncological lesion and benign tumor detection was 72.34%, 75.00%, 99.03%, 7.14%, and 72.41%, respectively (Table 3). The corresponding value of 68Ga-FAPI-04 PET/CT was 86.52%, 25.00%, 97.60%, 5.00%, and 84.83%, respectively. There were 39 non-oncological lesions that were not visualized by 18F-FDG PET (including 4 fractures, 3 pulmonary bacterial infections, 2 pulmonary fibrosis, 3 renal fibrosises, 3 liver fibrosises, 7 arthritis, 1 thyroiditis, 1 splenic hemangioma, 2 liver hemangioma, 1 esophagitis, 1 pancreatitis, 7 lymphnoditis, 1 parotitis, 2 pleuritis, 1 lipoma). Nineteen non-oncological lesions or and benign tumors (including 2 pulmonary bacterial infections, 1 myoma of uterus, 11 lymphnoditis, 1 adult Still’s disease, 1 reactive lymph node hyperplasia, 1 splenomegaly of unknown origin, 1 silicosis nodule, 1 bone marrow reactive hyperplasia) were not visualized by 68Ga-FAPI-04 PET. One osteophyte was misdiagnosed as arthritis by 18F-FDG but was invisible on 68Ga-FAPI-04 PET. Three pancreatic intensive tracer uptakes were misdiagnosed as pancreatitis by 68Ga-FAPI-04 PET/CT. However, the blood amylase level of the three patients was not increased and MRI scans demonstrated no abnormal signal change in the pancreas. The intensive pancreatic 68Ga-FAPI-04 uptake can’t be reasonably explained. Based on all 145 non-oncological lesions and benign tumors analysis, 68Ga-FAPI-04 PET/CT demonstrated a higher diagnostic efficacy (Pearson X2 = 9.460, p = 0.007) for lesion detection compared to 18F-FDG PET/CT.
4. Interfering factors
For 18F-FDG PET/CT, besides the common physiological 18F-FDG uptake of brain tissue, oropharynx, laryngopharynx, salivary glands and so on, there were 26 patients with segmental physiological uptake of the intestinal tract, 3 patients with uptake in brown adipose tissue and 1 patient with left ovary uptake. For 68Ga-FAPI-04 PET/CT, varying degree of 68Ga-FAPI-04 uptake in uterus was found for all female patients. A moderately negative correlation was observed between patient age and the 68Ga-FAPI-04 SUVmax (rs=-0.536, p<0.001). In addition, varying degree of bilateral breast 68Ga-FAPI-04 uptake was found in 5 female patients and diffuse pancreas 68Ga-FAPI-04 uptake of unknown origin in 3 patient. These physiological or non-physiological tracer uptakes might have an interfering effect on the PET/CT imaging analysis especially for nearby lesions (Figure 6-7).