Patients’ characteristics
The flow diagram of the study design is presented in Fig. 1. 56 patients with gastric cancer confirmed by surgery or gastroscopy were enrolled in this study. A total of 625 abdominal lymph nodes were resected from 17 patients who underwent surgery, of which 16.6% (104/625) metastatic lesions in 11 patients. Patient characteristics are listed in Table 1.
Table 1
Characteristics
|
N (%)
|
Patient No.
|
56
|
Age, years
|
|
Median(range)
|
63.75±14.91 (28-85)
|
Sex
|
|
Male
|
40 (71.4%)
|
Female
|
16 (28.6%)
|
Patient status
|
|
staging
|
45
|
recurrence detection after surgery
|
11
|
Histopathology (n = 45)
|
|
Containing SRCC
|
17 (37.8%)
|
Without SRCC
|
28 (62.3%)
|
T stage (n = 17)
|
|
1
|
2
|
2
|
3
|
3
|
9
|
4
|
3
|
N stage (n = 17)
|
|
0
|
6
|
2
|
5
|
3
|
6
|
Clinical stage (n = 17)
|
|
I
|
5
|
II
|
1
|
III
|
11
|
No., number; SRCC: signet-ring cell carcinoma |
Comparison of [ 68 Ga]Ga-FAPI and [ 18 F]-FDG in the detection of primary tumors
Eleven patients with recurrent lesions after surgery were not included in the semiquantitative analysis of primary lesions which had been surgically removed. Remaining 45 patients which had 46 evaluable primary foci were further included for primary lesion assessment. The depth of primary gastric cancer foci was 1.44 ± 0.45 cm (range 0.60-2.91 cm). The number of positive lesions and the semiquantitative parameters of [68Ga]Ga-FAPI and [18F]-FDG PET/CT are displayed in Table 2. For the patient-based analysis, the primary tumors detection rates were 100% (45/45) for [68Ga]Ga-FAPI PET/CT and 97.8% (44/45) for [18F]-FDG PET/CT. The false-negative tumor from [18F]-FDG PET/CT was gastric signet-ring cell carcinoma (Fig. 2). [68Ga]Ga-FAPI PET/CT showed higher uptake (mean SUVmax, 10.25 vs. 8.13, P = 0.004) and higher tumor-to-background contrast (mean TBR, 11.63 vs. 5.83, P < 0.001) than [18F]-FDG PET/CT. For the lesion-based analysis, the primary tumor detection rates were 97.8% (45/46) for [68Ga]Ga-FAPI PET/CT and 95.7% (44/46) for [18F]-FDG PET/CT. The pathological finding of the lesion, ignored by the two PETs, was high-grade intraepithelial neoplasia with cancerization, and the lesion was also negative on CT.
Table 2
Comparison of [68Ga]Ga-FAPI and [18F]-FDG uptake
|
|
Primary tumor
|
Lymph node
|
Peritoneal
|
Bone
|
Liver
|
Ovary
|
Adrenal gland
|
Erector spinae
|
Lung
|
Patient based analysis
|
45
|
11
|
13
|
4
|
3
|
2
|
1
|
1
|
1
|
Patient No.
|
[68Ga]Ga-FAPI PET/CT
|
45
|
5
|
13
|
4
|
3
|
2
|
1
|
1
|
1
|
[18F]-FDG PET/CT
|
44
|
5
|
9
|
4
|
3
|
2
|
1
|
1
|
1
|
P Value
|
1.000
|
NA
|
0.096
|
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
SUVmax
|
[68Ga]Ga-FAPI PET/CT
|
10.25±3.84
|
7.36±3.89
|
8.24±4.46
|
6.99±3.44
|
9.01±6.13
|
4.92±1.35
|
4.10
|
6.79
|
2.74
|
[18F]-FDG PET/CT
|
8.13±4.85
|
7.64±4.21
|
5.96±2.14
|
8.67±5.24
|
15.19±16.02
|
4.42±1.00
|
10.21
|
9.67
|
2.85
|
Z
|
-2.843
|
-0.313
|
-1.035
|
-0.289
|
-0.218
|
-0.775
|
NA
|
NA
|
NA
|
P Value
|
0.004
|
0.754
|
0.324
|
0.886
|
1.000
|
0.667
|
NA
|
NA
|
NA
|
TBR
|
[68Ga]Ga-FAPI PET/CT
|
11.63±5.42
|
8.83±4.62
|
9.47±5.85
|
6.95±4.58
|
9.27±6.37
|
5.21±0.18
|
4.10
|
6.79
|
2.45
|
[18F]-FDG PET/CT
|
5.83±3.62
|
5.21±3.47
|
4.41±1.86
|
7.28±4.26
|
9.88±8.22
|
3.12±0.18
|
10.86
|
10.29
|
1.64
|
Z
|
-5.375
|
-1.567
|
-2.170
|
0.000
|
-0.218
|
-1.549
|
NA
|
NA
|
NA
|
P Value
|
<0.001
|
0.117
|
0.030
|
1.000
|
1.000
|
0.333
|
NA
|
NA
|
NA
|
Lesion based analysis
|
46
|
104
|
159
|
64
|
7
|
4
|
1
|
1
|
1
|
Lesion No.
|
[68Ga]Ga-FAPI PET/CT
|
45
|
20
|
159
|
64
|
7
|
4
|
1
|
1
|
1
|
[18F]-FDG PET/CT
|
44
|
16
|
47
|
55
|
5
|
4
|
1
|
1
|
1
|
P Value
|
1.000
|
0.538
|
<0.001
|
0.003
|
0.462
|
NA
|
NA
|
NA
|
NA
|
SUVmax
|
[68Ga]Ga-FAPI PET/CT
|
10.25±3.84
|
6.27±2.13
|
7.10±3.73
|
6.44±2.36
|
7.50±5.25
|
3.86±1.48
|
4.1
|
6.79
|
2.74
|
[18F]-FDG PET/C
|
8.13±4.85
|
6.08±3.72
|
4.48±1.78
|
7.05±3.83
|
20.40±13.40
|
3.43±1.33
|
10.21
|
9.67
|
2.85
|
Z
|
-2.843
|
-1.178
|
-3.036
|
-0.221
|
-1.543
|
-0.577
|
NA
|
NA
|
NA
|
P Value
|
0.004
|
0.239
|
0.002
|
0.839
|
0.149
|
0.686
|
NA
|
NA
|
NA
|
TBR
|
[68Ga]Ga-FAPI PET/CT
|
11.63±5.42
|
8.03±2.66
|
8.05±4.79
|
6.29±3.07
|
7.40±5.05
|
4.11±1.28
|
4.10
|
6.79
|
2.45
|
[18F]-FDG PET/CT
|
5.83±3.62
|
3.73±2.69
|
3.22±1.38
|
5.72±3.09
|
12.41±6.78
|
2.37±1.22
|
10.86
|
10.29
|
1.64
|
Z
|
<0.001
|
-3.677
|
-4.654
|
0.591
|
-1.543
|
-1.732
|
NA
|
NA
|
NA
|
P Value
|
<0.001
|
<0.001
|
<0.001
|
0.606
|
0.149
|
0.114
|
NA
|
NA
|
NA
|
No., number; NA, not applicable |
SUVmax-FAPI and TBR-FAPI both showed positive correlations with primary tumor depth (r = 0.303, P = 0.043 for SUVmax-FAPI; r = 0.471, P = 0.001 for TBR-FAPI). However, primary tumor depth had no correlations with SUVmax-FDG or TBR-FDG (r = 0.201, P = 0.190 for SUVmax-FDG; r = 0.270, P = 0.077 for TBR-FDG). Pathological results showed 17 patients with signet-ring cell carcinoma (SRCC) and the remaining 28 patients without SRCC. In SRCC group, SUVmax and TBR of [68Ga]Ga-FAPI were significantly higher than those of [18F]-FDG (mean SUVmax, 10.38 vs. 6.17, P = 0.001; mean TBR, 11.52 vs. 4.92, P < 0.001). In non-SRCC group, only the TBR of [68Ga]Ga-FAPI was significantly higher than that of [18F]-FDG (11.69 vs. 6.35, P < 0.001), whereas the difference of SUVmax was not significant (10.16 vs. 9.25, P = 0.248).
Seventeen patients had pathological TNM stage, who underwent surgery due to early imaging stages. The TBR-FAPI of T3-4, N1-3 and III-IV groups were significantly higher than that of T1-2, N0 and I-II groups, respectively (Z = -2.319, -2.111 and -2.111, P = 0.019, 0.037 and 0.037, respectively). No significant differences were observed in other semiquantitative parameters, such as SUV-FAPI, SUVmax-FDG and TBR-FDG in these groups (Table 3).
Table 3
Comparison of [68Ga]Ga-FAPI and [18F]-FDG primary lesions uptake in different stages
Stages
(No.)
|
[68Ga]Ga-FAPI PET/CT
|
[18F]-FDG PET/CT
|
SUVmax-FAPI
|
TBR-FAPI
|
SUVmax-FDG
|
TBR-FDG
|
T1-2 (5)
|
7.65±3.84
|
7.00±3.17
|
9.25±4.89
|
5.78±2.94
|
T3-4 (12)
|
12.04±4.22
|
14.16±6.05
|
6.83±3.69
|
4.53±1.94
|
Z
|
-1.792
|
-2.319
|
-1.055
|
-0.843
|
P
|
0.082
|
0.019
|
0.328
|
0.442
|
N0 (6)
|
8.09±3.59
|
7.82±3.47
|
8.69±4.59
|
5.45±2.76
|
N1-3 (11)
|
12.20±4.38
|
14.37±6.30
|
6.91±3.85
|
4.60±2.02
|
Z
|
-1.809
|
-2.111
|
-1.006
|
-0.603
|
P
|
0.078
|
0.037
|
0.350
|
0.591
|
I-II (6)
|
8.09±3.59
|
7.82±3.47
|
8.69±4.59
|
5.45±2.76
|
III-IV (11)
|
12.20±4.38
|
14.37±6.30
|
6.91±3.85
|
4.60±2.02
|
Z
|
-1.809
|
-2.111
|
-1.006
|
-0.603
|
P
|
0.078
|
0.037
|
0.350
|
0.591
|
No., number |
Comparison of [ 68 Ga]Ga-FAPI and [ 18 F]-FDG in the detection of lymph nodal metastases
The number of LN metastases and the semiquantitative parameters of [68Ga]Ga-FAPI and [18F]-FDG PET/CT are demonstrated in Table 2. 16.6% (104/625) LN metastases in 11 patients was confirmed by the pathological findings obtaining from 17 patients who underwent surgery. For the patient-based analysis, [68Ga]Ga-FAPI and [18F]-FDG PET/CT both correctly identified 45.5% (5/11) of patients of LN metastases. The mean SUVmax and TBR of [68Ga]Ga-FAPI were comparable to [18F]-FDG without significant differences (SUVmax, 7.36 ± 3.89 vs. 7.64 ± 4.21, P = 0.754; TBR, 8.83 ± 4.62 vs. 5.21 ± 3.47, P = 0.117).
For the lesion-based analysis, [68Ga]Ga-FAPI PET/CT revealed 19.2% (20/104) of LN metastases with a mean SUVmax and TBR of 6.27 ± 2.13 (range, 0.99-11.30) and 8.03 ± 2.66 (range, 1.16-13.23). [18F]-FDG PET/CT was inferior to [68Ga]Ga-FAPI PET/CT in detecting LN metastases with 15.4% (16/104) and the mean SUVmax and TBR were 6.08 ± 3.72 (range, 1.75-13.00) and 3.73 ± 2.69 (range, 0.89-9.49). The difference of mean SUVmax between [68Ga]Ga-FAPI and [18F]-FDG was not significant (6.27 vs. 6.08, P = 0.239); however, the mean TBR displayed significant difference between the two PETs (8.03 vs. 2.66, P < 0.001). Table 4 exhibits results of N-Staging according to [18F]-FDG and [68Ga]Ga-FAPI PET/CT in 17 patients who underwent the surgery. Of these 625 resected lymph nodes, there were 16 true-positive, 12 false-positive, 509 true-negative and 88 false-negative findings on [18F]-FDG PET/CT and 20 true-positive, non-false-positive, 521 true-negative and 84 false-negative findings on [68Ga]Ga-FAPI PET/CT. The sensitivity, specificity, accuracy, PPV and NPV of [68Ga]Ga-FAPI were all higher than those of [18F]-FDG (19.2% vs. 15.4%, P = 0.463; 100.0% vs. 97.7%, P < 0.001; 86.6% vs. 84.0%, P = 0.202; 100.0% vs. 57.1%, P = 0.001; 86.1% vs. 85.3%, P = 0.672), but only the difference in specificity and PPV was significant.
Table 4
Results of N-Staging according to [18F]-FDG and [68Ga]Ga-FAPI PET/CT
No.
|
LN
(Mets/total)
|
|
[18F]-FDG
|
|
|
[68Ga]Ga-FAPI
|
|
|
|
N-P
|
TP
|
FP
|
TN
|
FN
|
N-FAPI
|
Effect
|
|
TP
|
FP
|
TN
|
FN
|
N-FDG
|
Effect
|
1
|
0/32
|
0
|
0
|
2
|
30
|
0
|
1
|
↑
|
|
0
|
0
|
32
|
0
|
0
|
→
|
2
|
8/34
|
3a
|
0
|
0
|
26
|
8
|
0
|
↓
|
|
0
|
0
|
26
|
8
|
0
|
↓
|
3
|
0/37
|
0
|
0
|
1
|
36
|
0
|
1
|
↑
|
|
0
|
0
|
37
|
0
|
0
|
→
|
4
|
6/49
|
2
|
2
|
0
|
43
|
4
|
1
|
↓
|
|
4
|
0
|
43
|
2
|
2
|
→
|
5
|
4/37
|
2
|
0
|
4
|
29
|
4
|
2
|
|
|
0
|
0
|
33
|
4
|
0
|
↓
|
6
|
0/30
|
0
|
0
|
0
|
30
|
0
|
0
|
→
|
|
0
|
0
|
30
|
0
|
0
|
→
|
7
|
0/48
|
0
|
0
|
0
|
48
|
0
|
0
|
→
|
|
0
|
0
|
48
|
0
|
0
|
→
|
8
|
8/45
|
3a
|
1
|
0
|
37
|
7
|
1
|
↓
|
|
1
|
0
|
37
|
7
|
1
|
↓
|
9
|
10/23
|
3a
|
0
|
0
|
13
|
10
|
0
|
↓
|
|
0
|
0
|
13
|
10
|
0
|
↓
|
10
|
12/49
|
3a
|
7
|
2
|
35
|
5
|
3a
|
→
|
|
7
|
0
|
37
|
5
|
3a
|
→
|
11
|
16/45
|
3b
|
1
|
0
|
29
|
15
|
1
|
↓
|
|
1
|
0
|
29
|
15
|
0
|
↓
|
12
|
2/22
|
2
|
0
|
0
|
20
|
2
|
0
|
↓
|
|
0
|
0
|
20
|
2
|
0
|
↓
|
13
|
28/60
|
3b
|
5
|
0
|
32
|
23
|
2
|
↓
|
|
7
|
0
|
32
|
21
|
3a
|
↓
|
14
|
0/10
|
0
|
0
|
0
|
10
|
0
|
0
|
→
|
|
0
|
0
|
10
|
0
|
0
|
→
|
15
|
6/59
|
2
|
0
|
1
|
52
|
6
|
1
|
↓
|
|
0
|
0
|
53
|
6
|
0
|
↓
|
16
|
0/22
|
0
|
0
|
2
|
20
|
0
|
1
|
↑
|
|
0
|
0
|
22
|
0
|
0
|
→
|
17
|
4/23
|
2
|
0
|
0
|
19
|
4
|
0
|
↓
|
|
0
|
0
|
19
|
4
|
0
|
↓
|
|
104/625
|
|
16
|
12
|
509
|
88
|
|
|
|
20
|
0
|
521
|
84
|
|
|
No., number; LN, lymph node(s); Mets, metastases; Total, total number of resected lymph nodes; |
N-P, N-staging according to postoperative pathological results; N-FAPI, N-staging according to [68Ga]Ga-FAPI PET/CT; N-FDG, N-staging according to [18F]-FDG PET/CT; |
→, unchanged; ↑, upgraded; ↓, degraded; |
, unchanged, but due to false positive lymph node; |
TP, true positive; FP, false positive; TN, true negative; FN, false negative |
In contrast to pathological staging, [68Ga]Ga-FAPI accurately predicted N stages of 47.1% (8/17) of patients and degraded N stages of 52.9% (9/17) of patients. [18F]-FDG accurately predicted N stages of 29.4% (5/17) of patients, degraded N stages of 52.9% (9/17) of patients and upgraded N stages of 17.7% (3/17) of patients. Noteworthily, of these five patients with correct N stages, patient# 5 was accurately staged N2 due to 4 false positive lymph nodes. Therefore, [68Ga]Ga-FAPI PET/CT was superior to [18F]-FDG PET/CT in N-staging of gastric cancer patients (47.1% [8/17] vs. 23.5% [4/17]), but no significant difference was observed (P = 0.282).
Comparison of [ 68 Ga]Ga-FAPI and [ 18 F]-FDG in the detection of other metastases
The number and semiquantitative parameters of positive metastasis are shown in Table 2. For the patient-based analysis, the TBR of [68Ga]Ga-FAPI was significantly higher than that of [18F]-FDG in the peritoneal metastases (mean TBR, 9.47 vs. 4.41, P = 0.030). For the lesion-based analysis, [68Ga]Ga-FAPI PET/CT detected more metastatic lesions in peritoneal and bone (159 vs. 47, P < 0.001; 64 vs. 55, P = 0.003). However, only the SUVmax and TBR of peritoneal metastases derived from [68Ga]Ga-FAPI significantly higher than those derived from [18F]-FDG (7.10 vs. 4.48, P = 0.002; 8.05 vs. 3.22, P < 0.001).
Comparison of [ 68 Ga]Ga-FAPI and [ 18 F]-FDG in the detection of recurrence
Regarding the 11 patients with recurrence after surgery, [68Ga]Ga-FAPI PET/CT detected positive lesions in all patients, while [18F]-FDG PET/CT detected positive lesions in only 9 patients. Moreover, [68Ga]Ga-FAPI PET/CT showed more positive lesions and clearer tumor delineation (Fig. 3).
76.5% (13/17) of gastric tumor showed markedly positive FAP immunostaining (scored 3); meanwhile, 5.9% (1/17) and 17.6% (3/17) showed moderately (scored 2) and slightly (scored 1) FAP immunostaining. Furthermore, the SUVmax and TBR of [68Ga]Ga-FAPI were positively correlated with FAP expression (r = 0.503, P = 0.040; r = 0.539, P = 0.026, respectively). The FAP expression showed no correlation with the tumor depth and the number of LN metastases (r = 0.336, P = 0.187; r = 0.336, P = 0.609). FAP was overexpressed on the cell surface of CAFs in all tumor specimens (Fig. 5), and the expression of FAP could also be observed in tumor cells cytoplasm in one patient.