Japanese Journal of Clinical Oncology Advance Access originally published online on October 26, 2006
Japanese Journal of Clinical Oncology 2006 36(11):694-698; doi:10.1093/jjco/hyl092
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© 2006 Foundation for Promotion of Cancer Research
Characteristics of Advantages of Positron Emission Tomography over Computed Tomography for N-staging in Lung Cancer Patients
1 Department of Internal Medicine, Saiseikai Central Hospital, Tokyo
2 Department of Thoracic Surgery, Saiseikai Central Hospital, Tokyo
3 Department of Thoracic Surgery, Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto,
4 Nishidai Clinic, Tokyo
5 Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan
For reprints and all correspondence: Hiroaki Nomori, Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Kumamoto 860-8556, Japan. E-mail: hnomori{at}kaiju.medic.kumamoto-u.ac.jp
Received March 2, 2006; accepted July 16, 2006
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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OBJECTIVE: We analyzed the characteristics of advantages of positron emission tomography (PET) over computed tomography (CT) for N-staging in lung cancer patients.
METHODS: Preoperative PET and CT scans were performed for 2057 lymph node stations in 205 patients with peripheral-type lung cancer. The advantages of PET over CT for N-staging were analyzed among lymph node locations and histological subtypes.
RESULTS: The pathological N-stages were N0 in 143 patients, N1 in 31, N2 in 24 and N3 in 7. PET was able to diagnose N0, N2 and N3 diseases more accurately than CT (P=0.03, 0.01 and 0.02, respectively), but there was no significant difference between the two modalities for N1 disease. In the upper mediastinal lymph node stations, both false-negative and false-positive were significantly less frequent with PET than with CT (P=0.001). In the lower mediastinal and supra clavicle lymph nodes, PET showed a lower frequency of false-negative than CT (P=0.04 and 0.003, respectively), but there was no significant difference in the frequency of false-positive between the two modalities. Among histological types, PET could stage adenocarcinoma with less frequent false-negative and squamous cell carcinoma with less frequent false-positive than CT (P=0.02 and 0.005, respectively).
CONCLUSION: For N-staging, PET was superior to CT for the following: (1) more accurate for N0, N2 and N3 diseases but not for N1; (2) lower frequency of false-positive in the upper mediastinal nodes; and (3) lower frequencies of false-negative in adenocarcinoma and false-positive in squamous cell carcinoma. Recognizing these advantages of PET could make the N-staging of lung cancer more accurate.
Key Words: positron emission tomography • computed tomography • lymph node stage • lung cancer • adenocarcinoma
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INTRODUCTION |
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CT scanning has been a usual procedure of N-staging of lung cancer. However, CT scanning is not sufficiently sensitive or specific for diagnosing lymph node metastasis, because size is the only criterion used to differentiate benign from malignant lymph nodes (1). In recent years, 18F-fluorodeoxyglucose (FDG)-PET scanning has been used for the staging of lung cancer (2–7). Because of the biological nature of FDG, FDG-PET has been reported to be able to detect metastatic lymph nodes more accurately than CT. A meta-analysis by Dwamena et al. of PET scanning of 514 patients in 14 studies showed that the mean sensitivity and specificity of PET scanning for N-staging were 0.79 (range: 0.62–0.97) and 0.91 (range: 0.79–0.99), respectively, both being superior to those of CT scanning, i.e. 0.60 (range: 0.25–0.89) and 0.77 (range: 0.44–0.95) (1). However, the advantages of PET over CT for lymph node staging of lung cancers have not been fully characterized. In this study we examined the characteristics of advantages of PET over CT for lymph node staging, especially among various lymph node locations and histological types.
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PATIENTS AND METHODS |
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Subjects
Between December 2001 and March 2005, 205 patients with peripheral lung cancer more than 1 cm in size prospectively underwent FDG-PET and CT scanning during the month before surgery. A total of 2057 lymph node stations in these 205 patients were evaluated. The histological type of lung cancer was adenocarcinoma in 151 patients, squamous cell carcinoma in 37, large cell carcinoma in eight, small cell carcinoma in two, adenosquamous carcinoma in four, carcinosarcoma in two and atypical carcinoid in one (Table 1). The histological criteria were based on the 1999 World Health Organization classification (8). The pathological N stages were N0 in 143, N1 in 31, N2 in 24 and N3 in seven. The classification of lymph nodes was done according to the original lymph node map of lung cancer (9). All patients underwent pneumonectomy, lobectomy, or segmentectomy with mediastinal lymph node dissection, except for seven patients with clinical N3 disease in whom pathological N-stages were evaluated by mediastinoscopy and/or scalene node biopsy.
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FDG-PET Scanning
Patients were instructed to fast for at least 4 h prior to intravenous (IV) administration of 18F-FDG. The administered dosage of 18F-FDG was 125 µCi/kg (4.6 MBq/kg) for non-diabetic patients and 150 µCi/kg (5.6 MBq/kg) for diabetic patients. PET imaging was performed approximately 60 min after administration of the FDG with a POSICAM.HZL m-POWER (Positron Co., Houston, Texas, USA). Initially no attenuation-corrected emission scans were obtained during the two-dimensional, high-sensitivity mode for 4 min per bed position, taken from the vertical-skull through the mid-thighs. Immediately thereafter, a two-bed-position attenuation-corrected examination was performed with 6 min for the emission sequence and 6 min for the transmission sequence at each bed position. The images were usually reconstructed in a 256x256 matrix by using ordered subset expectation maximization corresponding to a pixel size of 4x4 mm, with section spacing of 2.66 mm.
N Staging by PET Scanning
PET data were evaluated visually and/or semi-quantitatively. Based on visual findings, the lymph nodes showing clearly greater or less FDG-uptake than the mediastinal blood pool were diagnosed as positive and negative, respectively. Two examiners (A.E. and K.U.), who were blinded for the pathological N-stage, evaluated the visual findings of PET. For the lymph nodes showing similar FDG-uptake to the mediastinal blood pool or where there was disagreement between the two examiners, semi-quantitative analysis was used as reported previously (10). Briefly, the regions of interest (ROIs) were placed in the lymph nodes and cerebellum. The highest activities in both the lymph node ROI (L) and the cerebellum ROI (C) were measured. The contrast ratio (CR) was calculated by L/C in each lymph node as an index of FDG uptake. The cut-off value was determined as 0.25, i.e. lymph nodes with CR
0.25 were defined as positive and those with CR<0.25 as negative.
N Staging by CT Scanning
Spiral CT was performed using a ProSeed SA (General Electric Medical System, Milwaukee, USA). The following acquisition parameters were used: high voltage (120 kV), tube load 160 mA, window level –500 Hounsfield units (HU) and window width 1500 HU. The entire thorax was scanned with 0.5 or 1-cm thick sections at 1 breath hold with maximum inspiration. The criterion of CT definition for suspected metastasis of the lymph node was a short-axis diameter of 1.0 cm or larger. Enhanced CT was additionally conducted for patients with CT-negative and PET-positive lymph nodes. The same two examiners for N-staging by PET evaluated the CT findings. For lymph nodes showing disagreement between the two examiners, N-sages were determined after their discussion.
Statistical Analysis
True-positive (TP), true-negative (TN), false-positive (FP) and false-negative (FN) results of PET and CT scanning for lymph node metastasis were compared with the results of pathological diagnosis. Sensitivity was calculated as TP/TP+FN, specificity as TN/TN+FP, positive predictive value as TP/TP+FP, negative predictive value as TN/TN+FN and accuracy as TP+TN/Total. The advantages of PET over CT were evaluated for each pathological N-stage, lymph node location and each histological type. All data were analyzed for significance by using the Stat View software 
2 test. Differences at P<0.05 were accepted as significant. All values in the text and tables are given as mean±SD.
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Table 2 shows the correlation between the N-staging by PET and CT and pathological N-stage. PET was able to diagnose N0, N2 and N3 diseases more accurately than CT with significant difference (P=0.03, 0.01 and 0.02, respectively). However, there was no difference between PET and CT in the accuracy in diagnosing N1 disease (P=0.4).
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Of the 2057 lymph node stations examined, 15 showed similar FDG-uptake to the mediastinal blood pool. Of those 15 lymph nodes, six showed CR
0.25 (positive) and the remaining nine showed CR<0.25 (negative). PET scanning yielded TP in 85 lymph node stations, FN in 46, FP in 11 and TN in 1915 (Table 3). For the same lymph node stations, CT scanning yielded TP in 49 lymph node stations, FN in 82, FP in 22 and TN in 1904. As a result, the sensitivity of PET was 0.65, which was significantly higher than 0.37 of CT (P<0.0001). The positive predictive value of PET was 0.89, which was significantly higher than 0.7 of CT (P=0.02). However, there was no significant difference in specificity, accuracy and negative predictive value between the two diagnostic modalities.
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The locations of FP lymph node stations revealed by PET and CT are shown in Table 4. Of the 670 upper mediastinal lymph node stations without metastasis, PET showed FP less frequently than CT (P=0.001). One FP upper mediastinal lymph node, demonstrated by PET was Botallo's lymph node, showed lymphadenitis probably as a result of tuberculosis accompanying the adenocarcinoma. The other locations of FP lymph nodes did not show any difference between PET and CT.
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The locations of FN lymph node stations revealed by PET and CT are shown in Table 5. For the upper mediastinal, lower mediastinal and supra-clavicle lymph nodes with metastasis, PET showed FN less frequently than CT (P=0.001, 0.04 and 0.003). However, for hilar lymph nodes, there was no significant difference of FN between PET and CT.
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The difference of histological types in patients who were understaged or overstaged by PET and CT are shown in Tables 6 and 7. For adenocarcinoma, PET showed significantly less understaging than CT (P=0.02) (Table 6). For squamous cell carcinoma, PET showed significantly less overstaging than CT (Table 7) (P=0.005). All seven squamous cell carcinoma patients who were overstaged by CT were heavy smokers, whose Brinkman Index was 680–2400 (mean±SD: 1444±525).
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Several criteria have been used to detect lymph node metastases of lung cancer using PET scanning, including accumulation of FDG without objective criteria (6, 11), accumulation greater than mediastinal blood flow (2–4), and CR with the paravertebral muscles (12). We evaluated the lymph nodes with similar FDG-uptake to mediastinal blood pool by using the activity ratio in comparison to the cerebellum, as reported previously (10), because accumulation of FDG in the cerebellum was more stable than that in mediastinal blood flow or muscle.
While several authors have reported the superiority of PET over CT for N-staging of lung cancer (1–7), the present study showed that PET was able to identify N0, N2 and N3 diseases significantly more accurately than CT. However, there was no difference between the two modalities for N1 disease. These results appeared to be supported by data obtained by Vesselle et al., who reported that PET scanning could not reliably identify N1 disease, with only 6 of 21 cases identified (13).
It is well known that the inflammatory condition of lymph nodes can cause FP results of FDG-PET in lung cancer. Takamochi et al. reported that 10 of 71 patients (14%) with NSCLC showed FP lymph nodes with PET (14). While they did not show the location of the FP lymph nodes, the present study demonstrated that PET showed a lower frequency of FP in the upper mediastinal lymph nodes than CT. Thus we concluded that PET-positive lymph nodes in the upper mediastinum could be truly positive for metastasis, making it possible to reduce the need of mediastinoscopy in such patients. However, because there was some possibility of FP in the lower mediastinum and hilar nodes, transbronchial needle or thoracoscopic biopsy is recommended for these regions.
In the analysis of histological types, the present study showed that PET was able to reduce the incidences of FN in adenocarcinoma and FP in squamous cell carcinoma in comparison with CT. Ohta et al. reported that nodal micrometastasis was detected by immunohistochemistry in 20% of patients with adenocarcinoma 1–2 cm in size, whereas it was not found in any patients with squamous cell carcinoma of the same size (15). Mori et al. reported that lymph node metastases from adenocarcinoma frequently showed normal size, resulting in lower sensitivity of N-staging by CT than those from squamous cell carcinoma (16). They also reported that CT scanning showed FP lymph nodes more frequently in squamous cell carcinoma than in adenocarcinoma (16). Because the present study examined peripheral-type lung cancer, there were no enlarged lymph nodes caused by inflammation, such as obstructive pneumonia and atelectasis. Because all seven patients with squamous cell carcinoma whose N-stages were overstaged by CT smoked heavily, the enlarged lymph nodes could be caused by smoking.
We conclude that PET is more advantageous for lymph node staging than CT. However, the advantage depends on the lymph node locations and histological types. Realizing the characteristic advantages of PET is useful for accurate lymph node staging in lung cancer.
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References |
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