Ann Nucl Med DOI 10.1007/s12149-015-0958-6
ORIGINAL ARTICLE
Update on nodal staging in non-small cell lung cancer with integrated positron emission tomography/computed tomography: a meta-analysis Kyoungjune Pak • Sohyun Park • Gi Jeong Cheon Keon Wook Kang • In-Joo Kim • Dong Soo Lee • E. Edmund Kim • June-Key Chung
•
Received: 4 January 2015 / Accepted: 1 February 2015 Ó The Japanese Society of Nuclear Medicine 2015
Abstract Objectives Nowadays, the number of primary studies on fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) has been increasing rapidly. Thus, we updated meta-analysis to evaluate the test performance of FDG PET/CT for nodal staging in nonsmall cell lung cancer (NSCLC) including the most recent studies. Methods We performed a systematic search of MEDLINE and EMBASE for English publications using keywords ‘‘positron emission tomography’’, ‘‘lung cancer’’, and ‘‘lymph node’’. All searches were limited to human studies. Inclusion criteria were studies of the initial nodal staging of NSCLC with PET/CT. The reasons for exclusion are as follows: (1) studies with PET, (2) previous therapy before PET/CT, (3) nodal staging not confirmed by
histology, and (4) reviews, abstracts, and editorial materials. 786 articles were identified through database searching. Results 28 studies including 3,255 patients and 11,887 lymph nodes (LN) were eligible for this study. The pooled sensitivity was 0.62 (95 % CI 0.54–0.70), widely ranging from 0.13 to 0.98. The specificity ranged between 0.72 and 0.98 with an overall estimated specificity of 0.92 (0.88–0.95) for node-based data. The pooled sensitivity, specificity, positive and negative likelihood ratio were 0.67 (0.54–0.79), 0.87 (0.82–0.91), 5.20 (3.59–7.54), and 0.37 (0.25–0.55) for patient-based data. Studies from tuberculosis (Tb) endemic countries showed lower sensitivity (0.56 vs 0.68, p = 0.03) for node-based data and lower specificity (0.83 vs 0.89, p \ 0.01) for patient-based ones. Conclusions PET/CT has a high specificity, but low sensitivity for detecting LN metastasis in patients with NSCLC. Tb might be one of the main reasons for lower
K. Pak I.-J. Kim Department of Nuclear Medicine and Biomedical Research Institute, Pusan National University Hospital, 179 Gudeok-ro, Seo-gu, Busan 602-739, Korea e-mail:
[email protected]
D. S. Lee e-mail:
[email protected]
I.-J. Kim e-mail:
[email protected];
[email protected]
D. S. Lee E. E. Kim Department of Molecular Medicine and Biopharmaceutical Science, WCU Graduate School of Convergence Science and Technology, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea e-mail:
[email protected]
S. Park G. J. Cheon (&) K. W. Kang D. S. Lee J.-K. Chung Department of Nuclear Medicine and Cancer Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea e-mail:
[email protected] S. Park e-mail:
[email protected]
J.-K. Chung e-mail:
[email protected]
E. E. Kim Department of Radiological Science, University of California at Irvine, Irvine, CA, USA
K. W. Kang e-mail:
[email protected]
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sensitivity of PET/CT in several countries. The primary clinicians of lung cancer should be aware of the possibility of hidden metastatic LNs in bilateral FDG uptake of mediastinal and hilar LNs, especially in the Tb endemic countries. Keywords Positron-emission tomography Carcinoma non-small cell lung Neoplasm staging
Introduction Although estimation of new cases of lung cancer accounts for 13.5 % of all cancer cases, lung cancer is the first leading cause of all cancer deaths in United States [1]. The 5-year survival rates are 54.0 % for localized stage with confined to the primary site, 26.5 % for regional with spreading to regional lymph nodes (LN), 4.0 % for distant with cancer metastasized [2]. However, 15 % are diagnosed as localized stage, 22 % as regional, and 57 % as distant [2]. Surgery, radiation therapy, and chemotherapy are the 3 modalities commonly used to treat patients with non-small cell lung cancer (NSCLC) [3]. The TNM stage at presentation in patients with NSCLC mainly determines patient’s care or treatment [3]. In lung cancer with localized or regional stage, the status of mediastinal or hilar LNs is the most significant factor to determine TNM stage. Computed tomography (CT) is widely used as the standard modality for assessing NSCLC [4]. However, LN size is not a reliable parameter for the evaluation of metastatic involvement in patients with NSCLC [5]. Previous meta-analysis proved that positron emission tomography (PET) is superior to CT for mediastinal staging of NSCLC, which included 14 reports of PET published between 1990 and 1998 with diagnostic accuracy of 92 % [6]. However, the inability to provide anatomical information is a major limitation of dedicated PET. Nowadays, PET is replaced by integrated PET/CT in most clinical settings. Undoubtedly, integrated PET/CT is more accurate for the nodal analysis than dedicated PET alone [7]. It was more sensitive, specific, and had a higher positive predictive value for nodal staging [7]. PET/CT with F-18 fluorodeoxyglucose (FDG) is routinely recommended in the pretreatment evaluation, resulting in sparing patients from stage-inappropriate surgery [3, 8]. Previously, 3 meta-analyses have been evaluated the performance of integrated PET/CT in NSCLC [9–11], however, the number of primary studies has been increasing rapidly nowadays. Therefore, we updated meta-analysis with the most recent studies to evaluate the test performance of integrated PET/CT for nodal staging based on both nodes and patients.
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Materials and methods Data search and study selection We performed a systematic search of MEDLINE (inception to April 2014) and EMBASE (inception to April 2014) for English publications using keywords ‘‘PET OR positron emission tomography’’, ‘‘lung cancer’’, and ‘‘lymph node’’. All searches were limited to human studies. Inclusion criteria were studies of the initial nodal staging of NSCLC with integrated F18-FDG PET/CT. Two hundred and ninety-nine studies were excluded. The reasons for exclusion are as follows: (1) studies with PET, (2) previous therapy before PET/CT, (3) nodal staging not confirmed by histology, and (4) reviews, abstracts, and editorial materials. Quality assessment Two reviewers independently assessed study quality using the Quality Assessment of Studies of Diagnostic Accuracy Studies (QUADAS-2) [12]. The QUADAS-2 tool assesses the quality of included studies in terms of the risk of bias and applicability to the clinical question for patient selection, index test, reference standard, and flow/timing. Studies were categorized into low/high/unclear about each domain. Data synthesis and statistical analysis For each study, we constructed a 2 9 2 contingency table with true positive, false positive, false negative, and true negative. Two reviewers independently extracted the relevant data from each study, and a disagreement was resolved by consensus. Pooled sensitivity and specificity were estimated for each cut off and heterogeneity was assessed by I2 statistic, as described by Higgins et al. [13]. Although summary receiver operating characteristic method (SROC) has frequently been used, hierarchical summary receiver operating characteristic model (HSROC) [14] and bivariate model [15] were applied to overcome several limitations of the traditional SROC. Likelihood ratios positive or negative (LR? or LR-) were calculated from the ratio of the probability of a test result (positive or negative) in the patients with disease to the probability of the same test result in the patients without the disease. Diagnostic odds ratio (DOR), a single indicator of test performance was calculated using the ratio of the odds of positivity in disease relative to the odds of positivity in the non-diseased [16]. Publication bias was investigated using Deeks’ funnel plot [17]. Data were analyzed with Stata (version 13.1, StataCorp LP, TX, USA), MedCalc Statistical Software (version 13.1.2, MedCalc Software bvba, Ostend, Belgium) and Revman (version 5.3, Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014).
Ann Nucl Med Fig. 1 Flowchart for the identification of eligible studies
Results Study characteristics and quality assessment Seven hundred and eighty-six articles were identified through database searching. After excluding non-English articles (n = 75) and conference abstracts (n = 335), 166 abstracts were assessed for eligibility. Ninety-seven fulltext articles were reviewed, and 28 studies including 3,255 patients and 11,887 LNs were eligible for this study [4, 18–44]. The detailed procedure is drawn as a flowchart in Fig. 1. Data were analyzed based on node [4, 18, 28, 33, 34, 36, 37, 42–44], patient [21–24, 29, 30, 35, 38, 39], or both [19, 20, 25–27, 31, 32, 40, 41] in each study. The summary of studies included is presented in Table 1. Quality assessment was conducted on all studies included in meta-analysis using QUADAS-2. Generally, studies met most of the quality criteria. Diagnostic performance of PET/CT for nodal staging
7.82 (95 % CI 5.48–11.15) and LR- of 0.41 (95 % CI 0.34–0.50) were calculated, indicating PET/CT may not have the sufficient power either to confirm or to exclude metastasis. The summary DOR was 19.12 (95 % CI 12.77–28.63). The study by Lee et al. [31] showed the lowest sensitivity of 0.13, which included sub-solid adenocarcinoma only in their study. After excluding the study by Lee et al. [31], the pooled sensitivity, DOR was increased by 0.64 (95 % CI 0.57–0.70), and 20.12 (95 % CI 13.54–29.92). The HSROC curves are shown in Fig. 3a. Patient-based Data from 18 studies were analyzed based on patient. The pooled sensitivity, specificity, LR?, and LR- were 0.67 (95 % CI 0.54–0.79), 0.87 (95 % CI 0.82–0.91), 5.20 (95 % CI 3.59–7.54), and 0.37 (95 % CI 0.25–0.55). Figure 2b shows the forest plot of sensitivity and specificity of PET/CT for nodal staging in NSCLC based on patient. The summary DOR was 13.91 (95 % CI 7.20–26.89). The HSROC curves are shown in Fig. 3b. After excluding the study by Lee et al. [31], the pooled sensitivity and DOR were increased by 0.70 (95 % CI 0.58–0.80) and 15.72 (8.32–29.68) (Table 2).
Pooled data Subgroup analyses Node-based Data from 19 studies were analyzed based on node. The pooled sensitivity was 0.62 (95 % CI 0.54–0.70), widely ranging from 0.13 to 0.98. The specificity ranged between 0.72 and 0.98 with an overall estimated specificity of 0.92 (95 % CI 0.88–0.95). Forest plot of 19 studies are presented in Fig. 2a. An overall LR? of
Studies were analyzed according to tuberculosis (Tb) prevalence, contrast enhancement, time interval between injection and PET scan, criteria for positive LNs, nodal stations, and pathology. Tb endemic country is defined as Tb case rate of 50 or more per 100,000 people according to
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123
Korea
Korea
Taiwan Korea
China
Kim [25]
Kim [4]
Kuo [27] Lee [31]
Li [32]
Canada
Darling [22]
Egypt
USA
Ventura [43]
El-Hariri [35]
Japan
Toba [41]
Japan
Turkey
Tasci [40]
Turkey
Denmark
Fischer [23]
Ceylan [21]
China
Liu [34]
Ohno [37]
Korea
Lee [30]
Germany
Korea
Korea
Japan
An [18]
Nomori H [36] Plathow [39]
Italy
Siemens
Belgium
Tournoy [42]
Hwangbo B [24]
GE
GE
USA
Lee [29]
Bille [19]
Philips
Korea
Kim [26]
Discovery ST
GE
GE Philips
GE
Siemens
Siemens
Philips
GE
Siemens
Toshiba
Siemens
GE
Siemens
Discovery
Discovery ST Gemini
Discovery STE
Biograph sensation
Biograph
Gemini
Discovery ST
Biograph sensation
Aquiduo
Biograph
Discovery LS
Biograph sensation
Gemini
Biograph LSO Duo
Siemens
Philips
Discovery LS
Discovery ST
Biograph LSO Duo
Discovery LS
GE
GE
ECAT Gemini
Discovery LS
GE
Discovery LS
Model
Siemens
GE
Company
PET machine
Country
References
Table 1 Studies included in meta-analysis
200
102 160
49
69
33
57
250
149
19
42
127
60
39
43
117
159
52
88
124
52
126
674
No. of patients
Y
N Y
Y
Y
N
Y
N
N
N
N
Y
N
Y
Y
Y
N
N
N
Y
N
N
Y
Tb endemic (Y/N)
61/137
14/74 0/160
14/32
31/33
17/27
23/218
24/64
8/30
69/54
20/29
7/29
21/20
53/55
100/38
14/62
69/43
20/17
271/347
Pathology (SCC/ ADC)
1132
118 599
206
268
457
52
217
826
208
1404
223
1001
734
396
105
2477
No. of LNs
N/P
N/P N/P
N
N/P
P
P
N
P
N
N/P
N/P
P
N
P
P
N/P
P
N
N
N
P
N/P
(N/P)
Analysis
LN [ 2.5
LN [ 3.15 LN [ 3.5
LN [ mediastinum
LN [ 3.4
LN [ surrounding tissue & 2.5
LN [ surrounding tissue & 2.5
Visual assessment
visual assessment
Visual assessment ? short axis [ 10 mm
LN [ surrounding tissue
LN [ mediastinum
?
LN [ mediastinum
LN [ 2.5
LN [ 2.5
LN [ surrounding tissue
?
LN/cerebellum [ 0.26
LN [ 4.4
LN [ 2.9 ? short axis [ 10 mm
benign calcification, high attenuation [70HU
Benign calcification, high attenuation [ 70HU
Benign calcification, high attenuation [70HU
benign calcification, high attenuation [70HU
LN [ surrounding tissue LN [ mediastinum
Negative finding
Positive finding
Criteria
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China Xu [44]
PET positron emission tomography, Tb tuberculosis, SCC squamous cell carcinoma, ADC adenocarcinoma, LN lymph node, N node-based, P patient-based, HU hounsfield unit
LN [ surrounding tissue N 528 30/68 Y 101
LN [ 2.9 N 372 31/65 Y 104 Discovery STE Korea Lee [28]
GE Japan
Ireland
Ose N [38]
Booth [20]
GE
Visual assessment
LN [ 2.5 P
N/P 200
16/84
36/25 N
N 112
Discovery LS
64
LN [ 2, 1.6 364 Discovery VCT GE Taiwan Lin [33]
Company
Model
83
N
11/68
Pathology (SCC/ ADC) Tb endemic (Y/N) No. of patients PET machine Country References
Table 1 continued
N
Positive finding (N/P)
No. of LNs
Analysis
Criteria
Negative finding
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data from World Health Organization [45]. Results of subgroup analyses are presented in Table 3. Node-based Studies from Tb endemic countries showed lower sensitivity for nodal staging (0.56 vs 0.68, p = 0.03) (Fig. 4). In 10 studies, LNs were visually assessed with mediastinal blood pool or background activity, which showed higher specificity (0.94 vs 0.87, p = 0.04) than other criteria. Subgroup analysis according to nodal stations (N1 vs N2/3) did not show any significant difference. Patient-based Six Studies from Tb endemic countries showed lower specificity (0.83 vs 0.89, p \ 0.01), and trend toward lower sensitivity (0.53 vs 0.74, p = 0.09) (Fig. 4). Subgroup analyses according to criteria for positivity and pathology (adenocarcinoma vs squamous cell carcinoma) did not show any significant difference.
Discussion The pooled sensitivity, and specificity of integrated PET/ CT for nodal staging in NSCLC was 0.62, and 0.92 for node-based data, 0.67, and 0.87 for patient-based. Sensitivities were low across studies, ranging between 0.13 and 0.98. After excluding the study with sub-solid adenocarcinoma, the pooled sensitivity, and specificity were 0.64, and 0.92 for node-based data, 0.70, and 0.87 for patientbased. Studies from Tb endemic countries showed significantly lower sensitivity for node-based analysis, and trend toward lower sensitivity for patient-based. The TNM stage at presentation in patients with NSCLC is the factor that has the greatest impact on prognosis [3], and the status of LNs is the most significant factor to determine TNM stage. PET/CT has become the routine workup of NSCLC due to its superior diagnostic performance over CT [6]. In this meta-analysis, specificity is satisfactory, while sensitivity seems to be disappointing for nodal staging. Considering the definitions of sensitivity; a proportion of test positives among the people known to have the disease, and specificity; a proportion of test negatives among the healthy patients known not to have the disease, there might be relatively a large number of false negatives and a small number of false positives. There have been several reports regarding false positives in nodal staging on PET/CT [19, 28, 33, 34]. Anthracosis, inflammation, or concomitant infection is mainly responsible for hypermetabolism of LNs in PET scans, which mimic metastasis from NSCLC [19, 28, 33, 34]. According to current study, nuclear medicine physicians need to be more focused on false negatives, which results in decrease of sensitivity of PET/CT. There are several reasons for these false negatives. False negatives may occur from micrometastasis from primary tumor [38], which means too small to be detected on any kinds of scans. In addition,
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Fig. 2 a Node-based, and b patient-based forest plots of sensitivity and specificity for LN metastasis in patients with NSCLC
partial volume effect is one of the important factors in false negatives for small-sized LNs [46]. Thus, FDG uptake needs to be interpreted according to the size of LNs. In a certain clinical setting, nuclear medicine physicians often encounter the PET scans of bilateral symmetric FDG uptake in mediastinal and hilar LNs, which are one of the frequent reasons for false positives. Those may be regarded as false-positive findings as a result of chronic inflammatory process. However, metastatic LNs can be hidden among the concurrent infection or inflammation, which might be one of the reasons of low sensitivity of PET/CT for nodal staging. Bilateral symmetric FDG uptake of mediastinal and hilar LNs with or without calcification is much more common in Tb endemic countries. In addition, sensitivity in Tb endemic countries was 12 percentage point lower than that in Tb non-endemics for node-based analysis in this study. Therefore, Tb, a chronic granulomatous inflammation, might be one of the main reasons for lower sensitivity of PET/CT in several countries.
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Although there is no cut off of LR, a good diagnostic test may have LR? greater than 10, LR- less than 0.1 to have a greatest diagnostic value [9]. However, the LR syntheses gave an overall LR? of 7.82 and LR- of 0.41 for node-based studies, and LR? of 5.20 and LR- of 0.37 for patient based. Therefore, PET/CT can neither rule in nor rule out metastasis of LNs in NSCLC. The DOR is a single summary measure, independent of prevalence [47]. It shows how much greater the odds of having the disease are for the people with a positive test result than for the people with a negative test result [47]. The higher the DOR is, the better it discriminates test performance [9]. The summary DOR were 19.1 for node-based and 13.9 for patient-based. Standards of cutoff values for metastasis in LN vary considerably among studies. Mediastinal blood pool or surrounding tissue was visually assessed with activity of LNs in 14 of 28 studies. ROC analysis was adopted to select cutoff values, ranging from 2.9 to 4.4. Specific cutoff
Ann Nucl Med
Fig. 3 a Node-based, and b patient-based Hierarchical summary receiver operating characteristic curves
Table 2 Pooled diagnostic performance No. of studies
Sensitivity (95 % CI)
Specificity (95 % CI)
DOR (95 % CI)
LR? (95 % CI)
LR- (95 % CI)
Node-based
19
0.62 (0.54–0.70)
0.92 (0.88–0.95)
19.12 (12.77–28.63)
7.82 (5.48–11.15)
0.41 (0.34–0.50)
Patient-based
18
0.67 (0.54–0.79)
0.87 (0.82–0.91)
13.91 (7.20–26.89)
5.20 (3.59–7.54)
0.37 (0.25–0.55)
DOR diagnostic odds ratio, LR likelihood ratio, CI confidence interval
value of SUV 3.5 or 2.5 was applied in 5 studies. However, subgroup analysis including studies with cutoff values of mediastinal blood pool, surrounding tissues or visual assessment showed no significant difference in diagnostic performance with those of other criteria. In addition, the proportion of criteria adopted in each subgroup according to Tb prevalence was similar. Six of 11 studies from Tb endemic countries, and 4 of 9 from Tb non-endemics adopted the cutoff value of mediastinal blood pool, surrounding tissues or visual assessment. Until now, no standard criteria for LN metastasis on PET/CT have been reached consensus. The universal criterion for interpreting LN metastasis will be needed. In addition, various parameters of PET including LN heterogeneity should be incorporated into criteria to achieve better performance for nodal staging [48]. In this respect, diffusion-weighted imaging of magnetic resonance imaging (MRI) might have a role in nodal staging of NSCLC [36]. In addition, dual time point PET/CT, obtaining delayed images might have a complementary role in nodal staging [25]. Although none
of the studies included in this meta-analysis stated the use of time-of-flight (TOF) PET, TOF PET has known to provide a gain in image signal-to-noise ratio, lesion detectability, and accuracy of lesion uptake measurement [49]. Therefore, further studies should be done to propose the ideal criteria for interpreting PET/CT. Several previous meta-analyses of diagnostic performance of PET/CT in NSCLC have been published since 1999 [6, 50–56]. Most studies analyzed the reports of dedicated PET only [6, 50] or both PET and PET/CT [51, 57, 58]. Three meta-analyses from China included 7 (1,248 patients), 14 (2,550 patients), and 19 (2,733 patients) reports of integrated PET/CT [9–11]. As the number of primary studies has been increasing rapidly nowadays, we could update and include total 28 studies, 3,255 patients and 11,887 LNs in this current study. However, this study has several limitations. First, criteria for positive LN vary among studies. Second, until now, there are few studies comparing the diagnostic performance of mediastinoscopy, endoscopic ultrasound biopsy, and endobronchial
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Ann Nucl Med Table 3 Subgroup analyses Factor
No. of studies
Sensitivity (95 % CI)
p
Specificity (95 % CI)
p
Node-based Tuberculosis endemic 9
0.56 (0.46–0.67)
No
10
0.68 (0.59–0.78)
Contrast enhancement 1
0.95(0.85–1.00)
No
18
0.61(0.54–0.68)
Time interval Others (30/45/50 min)
0.92(0.87–0.96) 0.11 0.73(0.37–1.00) 0.93(0.90–0.95) 0.43
14
0.66(0.58–0.74)
3
0.48(0.28–0.69)
Criteria for positivity Mediastinal blood pool
0.92(0.88–0.97) 0.01
Yes
60 min
\0.01
0.03
Yes
0.04 0.91(0.87–0.95) 0.94(0.87–1.00)
0.40
0.04
10
0.62(0.51–0.73)
0.94(0.91–0.97)
8
0.62(0.49–0.74)
0.87(0.81–0.93)
6
0.55(0.43–0.67)
0.91(0.84–0.98)
9
0.50(0.43–0.58)
0.95(0.91–0.98)
Yes
6
0.53(0.31–0.76)
No
12
0.74(0.61–0.87)
Others Nodal stations N1 N2/3
0.47
0.19
Patient-based Tuberculosis endemic
Contrast enhancement 3
0.89(0.76–1.00)
No
15
0.62(0.50–0.74)
Time interval Others (30/45/50 min)
0.83(0.74–0.92) 0.89(0.84–0.94) 0.17
Yes
60 min
\0.01
0.09
0.34 0.97(0.92–1.00) 0.85(0.80–0.90)
0.82 10
0.69(0.52–0.86)
5
0.67(0.43–0.92)
Criteria for positivity
0.03 0.87(0.79–0.94) 0.88(0.80–0.96)
0.44
0.13
Mediastinal blood pool
7
0.71(0.56–0.85)
0.89(0.84–0.94)
Others
7
0.51(0.34–0.69)
0.79(0.71–0.88)
3
0.47(0.09–0.85)
0.81(0.71–0.91)
2
0.48(0.04–0.99)
0.67(0.49–0.84)
Pathology Adenocarcinoma Squamous cell carcinoma
Fig. 4 Subgroup analysis of a sensitivity and b specificity according to Tb prevalence
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0.97
0.94
Ann Nucl Med
ultrasound biopsy with that of PET/CT. Therefore, further studies to compare the test performances among modalities and to suggest algorithms of staging in NSCLC are needed. In addition, as non-English articles were excluded in this study, the potential impact of language bias should be considered. In conclusion, PET/CT has a high specificity, but low sensitivity for detecting LN metastasis in patients with NSCLC. Tb might be one of the main reasons for lower sensitivity of PET/CT in several countries. Primary clinicians as well as nuclear medicine physicians at initial staging of lung cancer should be aware of the possibility of hidden metastatic LNs in bilateral FDG uptake of mediastinal and hilar LNs, especially in the Tb endemic countries. Acknowledgments This study was supported by the National Research Fund (Grant No. HI13C-1299-020013) of Korea Health Industry Development Institute (KHIDI) and Ministry of Health & Welfare of Korea. Conflict of interest
11.
12.
13. 14.
15.
16. 17.
Nothing to declare. 18.
References 1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics. 2014. CA Cancer J Clin. 2014;64(1):9–29. 2. Health NIo. Surveillance, Epidemiology, and End Results Program: National Cancer Institue; [cited 2014]. 3. Ettinger DS, Akerley W, Bepler G, Blum MG, Chang A, Cheney RT, et al. Non-small cell lung cancer. J Natl Compr Cancer Netw JNCCN. 2010;8(7):740–801. 4. Kim YN, Yi CA, Lee KS, Kwon OJ, Lee HY, Kim BT, et al. A proposal for combined MRI and PET/CT interpretation criteria for preoperative nodal staging in non-small-cell lung cancer. Eur Radiol. 2012;22(7):1537–46. 5. Prenzel KL, Monig SP, Sinning JM, Baldus SE, Brochhagen HG, Schneider PM, et al. Lymph node size and metastatic infiltration in non-small cell lung cancer. Chest. 2003;123(2):463–7. 6. Dwamena BA, Sonnad SS, Angobaldo JO, Wahl RL. Metastases from non-small cell lung cancer: mediastinal staging in the 1990s—meta-analytic comparison of PET and CT. Radiology. 1999;213(2):530–6. 7. Cerfolio RJ, Ojha B, Bryant AS, Raghuveer V, Mountz JM, Bartolucci AA. The accuracy of integrated PET-CT compared with dedicated PET alone for the staging of patients with nonsmall cell lung cancer. Ann Thorac surg. 2004;78(3):1017–23 (discussion 1027-23). 8. Maziak DE, Darling GE, Inculet RI, Gulenchyn KY, Driedger AA, Ung YC, et al. Positron emission tomography in staging early lung cancer: a randomized trial. Ann Intern Med. 2009;151(4):221–8 W-48. 9. Lv YL, Yuan DM, Wang K, Miao XH, Qian Q, Wei SZ, et al. Diagnostic performance of integrated positron emission tomography/computed tomography for mediastinal lymph node staging in non-small cell lung cancer: a bivariate systematic review and meta-analysis. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer. 2011;6(8):1350–8. 10. Liao CY, Chen JH, Liang JA, Yeh JJ, Kao CH. Meta-analysis study of lymph node staging by 18 F-FDG PET/CT scan in non-
19.
20.
21.
22.
23.
24.
25.
26.
small cell lung cancer: comparison of TB and non-TB endemic regions. Eur J Radiol. 2012;81(11):3518–23. Wu LM, Xu JR, Gu HY, Hua J, Chen J, Zhang W, et al. Preoperative mediastinal and hilar nodal staging with diffusionweighted magnetic resonance imaging and fluorodeoxyglucose positron emission tomography/computed tomography in patients with non-small-cell lung cancer: which is better? J Surg Res. 2012;178(1):304–14. Whiting PF, Rutjes AW, Westwood ME, Mallett S, Deeks JJ, Reitsma JB, et al. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med. 2011;155(8):529–36. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–60. Rutter CM, Gatsonis CA. A hierarchical regression approach to meta-analysis of diagnostic test accuracy evaluations. Stat Med. 2001;20(19):2865–84. Reitsma JB, Glas AS, Rutjes AW, Scholten RJ, Bossuyt PM, Zwinderman AH. Bivariate analysis of sensitivity and specificity produces informative summary measures in diagnostic reviews. J Clin Epidemiol. 2005;58(10):982–90. Kraemer HC. Evaluating medical tests: objective and quantitative guidelines. Newbury Park, CA: SAGE; 1992. Deeks JJ, Macaskill P, Irwig L. The performance of tests of publication bias and other sample size effects in systematic reviews of diagnostic test accuracy was assessed. J Clin Epidemiol. 2005;58(9):882–93. An YS, Sun JS, Park KJ, Hwang SC, Park KJ, Sheen SS, et al. Diagnostic performance of (18)F-FDG PET/CT for lymph node staging in patients with operable non-small-cell lung cancer and inflammatory lung disease. Lung. 2008;186(5):327–36. Bille A, Pelosi E, Skanjeti A, Arena V, Errico L, Borasio P, et al. Preoperative intrathoracic lymph node staging in patients with non-small-cell lung cancer: accuracy of integrated positron emission tomography and computed tomography. Eur Journal Cardio-thorac Surg Off J Eur Assoc Cardio-thorac Surg. 2009;36(3):440–5. Booth K, Hanna GG, McGonigle N, McManus KG, McGuigan J, O’Sullivan J, et al. The mediastinal staging accuracy of 18FFluorodeoxyglycose positron emission tomography/computed tomography in non-small cell lung cancer with variable time intervals to surgery. Ulst Med J. 2013;82(2):75–81. Ceylan N, Dogan S, Kocacelebi K, Savas R, Cakan A, Cagrici U. Contrast enhanced CT versus integrated PET-CT in pre-operative nodal staging of non-small cell lung cancer. Diagn Interv Radiol. 2012;18(5):435–40. Darling GE, Maziak DE, Inculet RI, Gulenchyn KY, Driedger AA, Ung YC, et al. Positron emission tomography-computed tomography compared with invasive mediastinal staging in nonsmall cell lung cancer: results of mediastinal staging in the early lung positron emission tomography trial. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer. 2011;6(8):1367–72. Fischer BM, Mortensen J, Hansen H, Vilmann P, Larsen SS, Loft A, et al. Multimodality approach to mediastinal staging in nonsmall cell lung cancer. Faults and benefits of PET-CT: a randomised trial. Thorax. 2011;66(4):294–300. Hwangbo B, Kim SK, Lee HS, Lee HS, Kim MS, Lee JM, et al. Application of endobronchial ultrasound-guided transbronchial needle aspiration following integrated PET/CT in mediastinal staging of potentially operable non-small cell lung cancer. Chest. 2009;135(5):1280–7. Kim DW, Kim WH, Kim CG. Dual-time-point FDG PET/CT: is it useful for lymph node staging in patients with non-small-cell lung cancer? Nucl Med Mol Imaging. 2012;46(3):196–200. Kim YK, Lee KS, Kim BT, Choi JY, Kim H, Kwon OJ, et al. Mediastinal nodal staging of nonsmall cell lung cancer using
123
Ann Nucl Med
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
integrated 18F-FDG PET/CT in a tuberculosis-endemic country: diagnostic efficacy in 674 patients. Cancer. 2007;109(6):1068–77. Kuo WH, Wu YC, Wu CY, Ho KC, Chiu PH, Wang CW, et al. Node/aorta and node/liver SUV ratios from (18)F-FDG PET/CT may improve the detection of occult mediastinal lymph node metastases in patients with non-small cell lung carcinoma. Acad Radiol. 2012;19(6):685–92. Lee AY, Choi SJ, Jung KP, Park JS, Lee SM, Bae SK. Characteristics of metastatic mediastinal lymph nodes of non-small cell lung cancer on preoperative F-18 FDG PET/CT. Nucl Med Mol Imaging. 2014;48(1):41–6. Lee BE, von Haag D, Lown T, Lau D, Calhoun R, Follette D. Advances in positron emission tomography technology have increased the need for surgical staging in non-small cell lung cancer. J Thorac Cardiovasc Surg. 2007;133(3):746–52. Lee HJ, Kim YT, Kang WJ, Lee HJ, Kang CH, Kim JH. Integrated positron-emission tomography for nodal staging in lung cancer. Asian Cardiovasc Thorac Ann. 2009;17(6):622–6. Lee SM, Park CM, Paeng JC, Im HJ, Goo JM, Lee HJ, et al. Accuracy and predictive features of FDG-PET/CT and CT for diagnosis of lymph node metastasis of T1 non-small-cell lung cancer manifesting as a subsolid nodule. Eur Radiol. 2012;22(7):1556–63. Li X, Zhang H, Xing L, Ma H, Xie P, Zhang L, et al. Mediastinal lymph nodes staging by 18F-FDG PET/CT for early stage nonsmall cell lung cancer: a multicenter study. Radiother Oncol J Eur Soc Ther Radiol Oncol. 2012;102(2):246–50. Lin WY, Hsu WH, Lin KH, Wang SJ. Role of preoperative PETCT in assessing mediastinal and hilar lymph node status in early stage lung cancer. J Chin Med Assoc JCMA. 2012;75(5):203–8. Liu BJ, Dong JC, Xu CQ, Zuo CT, Le JJ, Guan YH, et al. Accuracy of 18F-FDG PET/CT for lymph node staging in nonsmall-cell lung cancers. Chin Med J. 2009;122(15):1749–54. Mona A, El-Hariri GKG, Ali M. Refat. Integrated PET/CT in the preoperative staging of lung cancer: a prospective comparison of CT, PET and integrated PET/CT. Egypt J Radiol Nucl Med. 2012;43(4):613–21. Nomori H, Mori T, Ikeda K, Kawanaka K, Shiraishi S, Katahira K, et al. Diffusion-weighted magnetic resonance imaging can be used in place of positron emission tomography for N staging of non-small cell lung cancer with fewer false-positive results. J Thorac Cardiovasc Surg. 2008;135(4):816–22. Ohno Y, Koyama H, Yoshikawa T, Nishio M, Aoyama N, Onishi Y, et al. N stage disease in patients with non-small cell lung cancer: efficacy of quantitative and qualitative assessment with STIR turbo spin-echo imaging, diffusion-weighted MR imaging, and fluorodeoxyglucose PET/CT. Radiology. 2011;261(2):605–15. Ose N, Sawabata N, Minami M, Inoue M, Shintani Y, Kadota Y, et al. Lymph node metastasis diagnosis using positron emission tomography with 2-[18F] fluoro-2-deoxy-D-glucose as a tracer and computed tomography in surgical cases of non-small cell lung cancer. Eur J Cardio-thorac Surg Off J Eur Assoc Cardiothorac Surg. 2012;42(1):89–92. Plathow C, Aschoff P, Lichy MP, Eschmann S, Hehr T, Brink I, et al. Positron emission tomography/computed tomography and whole-body magnetic resonance imaging in staging of advanced nonsmall cell lung cancer—initial results. Invest Radiol. 2008;43(5):290–7. Tasci E, Tezel C, Orki A, Akin O, Falay O, Kutlu CA. The role of integrated positron emission tomography and computed tomography in the assessment of nodal spread in cases with non-small cell lung cancer. Interact CardioVasc Thorac Surg. 2010;10(2):200–3.
123
41. Toba H, Kondo K, Otsuka H, Takizawa H, Kenzaki K, Sakiyama S, et al. Diagnosis of the presence of lymph node metastasis and decision of operative indication using fluorodeoxyglucose-positron emission tomography and computed tomography in patients with primary lung cancer. J Med Invest JMI. 2010;57(3–4):305–13. 42. Tournoy KG, Maddens S, Gosselin R, Van Maele G, van Meerbeeck JP, Kelles A. Integrated FDG-PET/CT does not make invasive staging of the intrathoracic lymph nodes in non-small cell lung cancer redundant: a prospective study. Thorax. 2007;62(8):696–701. 43. Ventura E, Islam T, Gee MS, Mahmood U, Braschi M, Harisinghani MG. Detection of nodal metastatic disease in patients with non-small cell lung cancer: comparison of positron emission tomography (PET), contrast-enhanced computed tomography (CT), and combined PET-CT. Clin Imaging. 2010;34(1):20–8. 44. Xu N, Wang M, Zhu Z, Zhang Y, Jiao Y, Fang W. Integrated positron emission tomography and computed tomography in preoperative lymph node staging of non-small cell lung cancer. Chin Med J. 2014;127(4):607–13. 45. World Health Organization WHO. TB data: World health organization. http://www.who.int/tb/country/data/download/en/. Accessed 1 Jan 2015. 46. Soret M, Bacharach SL, Buvat I. Partial-volume effect in PET tumor imaging. J Nucl Med. 2007;48(6):932–45. 47. Glas AS, Lijmer JG, Prins MH, Bonsel GJ, Bossuyt PM. The diagnostic odds ratio: a single indicator of test performance. J Clin Epidemiol. 2003;56(11):1129–35. 48. Ha S, Choi H, Cheon GJ, Kang KW, Chung JK, Kim EE, Lee DS. Autoclustering of Non-small Cell Lung Carcinoma Subtypes on 18F-FDG PET Using Texture Analysis: a Preliminary Result. Nucl Med Mol Imaging. 2014;48(4):278–86. 49. Surti S. Update on Time-of-Flight PET Imaging. J Nucl Med. 2015;56(1):98–105. 50. Gould MK, Kuschner WG, Rydzak CE, Maclean CC, Demas AN, Shigemitsu H, et al. Test performance of positron emission tomography and computed tomography for mediastinal staging in patients with non-small-cell lung cancer: a meta-analysis. Ann Intern Med. 2003;139(11):879–92. 51. Birim O, Kappetein AP, Stijnen T, Bogers AJ. Meta-analysis of positron emission tomographic and computed tomographic imaging in detecting mediastinal lymph node metastases in nonsmall cell lung cancer. Ann Thorac Surg. 2005;79(1):375–82. 52. Alongi F, Ragusa P, Montemaggi P, Bona CM. Combining independent studies of diagnostic fluorodeoxyglucose positron-emission tomography and computed tomography in mediastinal lymph node staging for non-small cell lung cancer. Tumori. 2006;92(4):327–33. 53. Lv YL, Yuan DM, Wang K, Miao XH, Qian Q, Wei SZ, et al. Diagnostic performance of integrated positron emission tomography/computed tomography for mediastinal lymph node staging in non-small cell lung cancer: a bivariate systematic review and meta-analysis. J Thorac Oncol. 2011;6(8):1350–8. 54. Liao CY, Chen JH, Liang JA, Yeh JJ, Kao CH. Meta-analysis study of lymph node staging by 18 F-FDG PET/CT scan in nonsmall cell lung cancer: comparison of TB and non-TB endemic regions. Eur J Radiol. 2012;81(11):3518–23. 55. Wang J, Welch K, Wang L, Kong FMS. Negative predictive value of positron emission tomography and computed tomography for stage T1-2N0 nonsmall-cell lung cancer: a meta-analysis. Clin Lung Cancer. 2012;13(2):81–9. 56. Wu LM, Xu JR, Gu HY, Hua J, Chen J, Zhang W, et al. Preoperative mediastinal and hilar nodal staging with diffusionweighted magnetic resonance imaging and fluorodeoxyglucose positron emission tomography/computed tomography in patients
Ann Nucl Med with non-small-cell lung cancer: which is better? J Surg Res. 2012;178(1):304–14. 57. Alongi F, Ragusa P, Montemaggi P, Bona CM. Combining independent studies of diagnostic fluorodeoxyglucose positron-emission tomography and computed tomography in mediastinal lymph node staging for non-small cell lung cancer. Tumori. 2006;92(4):327–33.
58. Wang J, Welch K, Wang L, Kong FM. Negative predictive value of positron emission tomography and computed tomography for stage T1-2N0 non-small-cell lung cancer: a meta-analysis. Clin Lung Cancer. 2012;13(2):81–9.
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