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Eur J Cardiothorac Surg 2001;20:468-475
© 2001 Elsevier Science NL
a Department of Cardio-thoracic Surgery, Université Catholique de Louvain, Brussels, Belgium
b Department of Nuclear Medicine, Université Catholique de Louvain, Brussels, Belgium
c Department of Radiology, Université Catholique de Louvain, Brussels, Belgium
d Department of Pathology, Université Catholique de Louvain, Brussels, Belgium
Received 9 October 2000; received in revised form 25 May 2001; accepted 27 May 2001.
Corresponding author. Tel.: +32-2-7646107; fax: +32-2-7648960
e-mail: poncelet{at}chir.ucl.ac.be
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Abstract |
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 Top Abstract 1. Introduction2. Materials and methods3. Results4. CommentsAppendix A. Conference...References |
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Key Words: PET-FDG scan • Non-small cell lung carcinoma • Mediastinal lymph node
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1. Introduction |
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TopAbstract1. Introduction2. Materials and methods3. Results4. CommentsAppendix A. Conference...References |
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Most recent studies [1,2] have underlined the importance of ipsi-lateral (N2) or contra-lateral (N3) mediastinal lymph node (LN) involvement as a key prognostic factor for long-term survival. Unfortunately, sensitivity and specificity of chest computerized tomography (CT) scan in mediastinal staging for lung cancer has proved to be insufficient. Gambhir et al. [3] reported sensitivity and specificity of 67 and 73%, respectively, whereas more recently, Pieterman et al. [4] reported values of 75 and 66% on a series of 102 patients with a diagnostic accuracy of 69%. Thus, a large percentage of false-positive patients either are overstaged and misclassified or undergo additional surgical diagnostic procedures. Those procedures have their own morbidity, mortality, and costs that one has to account for. Moreover, false-negative patients represent a group of patients likely to benefit more from multimodal treatment than from surgical exploration [5,6].
Positron emission tomography with radiolabeled [18F]-2-fluoro-deoxy-D-glucose (PET-FDG) has been shown to have superior sensitivity and specificity than chest CT-scan in the diagnosis of malignant solitary pulmonary nodule [7] while being an extremely safe non-invasive procedure [8]. Several studies have been conducted on the efficacy of PET-FDG scan in the assessment of mediastinal LN involvement. However, only few of these reported extensive mediastinal pathological results. Chin et al. [9] first reported sensitivity, specificity, diagnostic accuracy, and positive and negative predictive values of 78, 81, 80, 64, and 89%, respectively, in a prospective study of 30 patients. PET-FDG scan results combined with chest CT-scan enhanced the diagnostic accuracy up to 90%.
In our study, we prospectively analyzed the sensitivity, specificity, diagnostic accuracy, and positive and negative predictive values of PET-FDG scanning and compared them to the results of staging by chest CT-scan alone. The integrated results of CT-scan and mediastinal surgical procedures, which represent our conventional staging method, were then compared to PET-FDG scan results.
Endpoints of the study were two-fold: first, to analyze sensitivity, specificity, and accuracy of PET-FDG scan imaging in our institutional series and second, to determine whether this new imaging modality could have a clinical impact on our patient selection and, overall, on our clinical practice.
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2. Materials and methods |
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TopAbstract1. Introduction2. Materials and methods3. Results4. CommentsAppendix A. Conference...References |
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Out of the 92 referred patients, eight patients presented on initial evaluation with such N3 disease and 20 patients presented with metastatic (M1) disease as detected by PET-FDG scanning and correlated with other imaging modalities. These 28 patients were excluded from the present study while the remaining 64 patients represent the study cohort. All data were prospectively entered into our database. Overall, there were 1240 LNs available for pathologic analysis (mean number LN/patient=19.3, range 3–40). This study was approved by our Institutional Review Board.
2.2. Radiological staging
Most CT examinations (42 out of 64) were performed at our institution on a helical scanner (SR 7000, Philips, Eindhoven, The Netherlands). Images were obtained from the lung apices down to the adrenal glands with 6.5-mm-thick sections, after intravenous injection of 60–100 cm3 of contrast medium (Meglumine ioxitalamaat, Telebrix 35, Guerbet, Aulnay-sous-bois, France). All CT-scans were interpreted by one radiologist (E.C.) blinded to the PET-FDG scan imaging results. LNs were considered positive if they were greater than 1.0 cm in their short-axis diameter.
2.3. PET-FDG acquisition
2-[18F]Fluoro-2-deoxy-D-glucose (FDG) was produced by an automated nucleophilic method based on the Hamacher procedure [10]. Sixty minutes after injection of 370 MBq FDG, patients were positioned on the PET device (ECAT EXACT HR, CTI, Knoxville, TN, USA). Attenuated and non-attenuated images were simultaneously displayed on a high-resolution color monitor and interpreted by one nuclear medicine physician (M.L.) blinded to the results of other imaging modalities. Nodes were described as ipsi- or contra-lateral to the primary tumor and whenever possible, were labeled according to the American Thoracic Society (ATS) classification [11]. In this study, there were neither ‘co-registration’ nor ‘co-lecture’ of CT-scan and PET-FDG scans. Unexpected findings from the PET-FDG scan (extra-thoracic and/or contra-lateral lung uptake) were reported to the responsible physician.
2.4. Surgical staging
Surgical mediastinal staging diagnostic procedures were performed according to the following criteria: (1) patients with ipsi- or contra-lateral mediastinal LN with a diameter >10 mm in its shorter axis on chest CT-scan; (2) patients with a histology of adenocarcinoma on bronchoscopy or transthoracic needle biopsy; or (3) high-risk surgical candidates (associated co-morbidities, elderly patients, etc.). Patients with early stage NSCLC (I–II) and squamous histology were not routinely submitted to mediastinal surgical procedures. All nodal stations were labeled according to the ATS guideline [11]. Biopsy and/or removal of LNs from stations 1–4 and station 7 were routinely performed through a cervical mediastinoscopy. For left-sided tumors and/or stations 5 and 6 sampling, left anterior mediastinotomy was performed as well.
At the time of surgical resection, surgeons were aware of the results of both conventional staging and PET-FDG scan, but regardless of the imaging results, all ipsi-lateral mediastinal LNs stations were systematically sampled. Histologically documented nodal involvement by tumor was the standard criterion to which CT-scan and PET-FDG scan results were compared.
2.5. Statistical analysis
All data were dichotomized with respect to the accurate diagnosis of mediastinal LN involvement (N0–N1 vs. N2 disease). Diagnostic efficacy of CT-scan, PET-FDG imaging and surgical diagnostic procedures was determined by calculating sensitivity, specificity, overall predictive accuracy, and positive and negative predictive values as follows:
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The McNemar test was used to compare the effectiveness of chest CT-scan vs. PET-FDG scan in the detection of pathologic N2 disease. A probability value of less than 0.05 was considered significant.
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3. Results |
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TopAbstract1. Introduction2. Materials and methods3. Results4. CommentsAppendix A. Conference...References |
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pN2) is summarized in Table 3. Sensitivity, specificity, overall accuracy, positive predictive value (+PV), and negative predictive value (-PV) for CT-scan were 55, 68, 66, 23, and 90%; and for PET-FDG scan they were 67, 85, 82, 43, and 93.6%, respectively. With respect to the 28 patients who underwent mediastinal surgical staging, the results obtained were 27, 100, 82, 100, and 80%. For CT-scan and mediastinoscopy/mediastinotomy together, sensitivity, specificity, accuracy, +PV, and -PV results were 33, 90.6, 82, 37, and 89%. Statistical analysis of the diagnostic accuracy of nodal involvement by CT-scan alone or PET-FDG scan alone showed that, even with PET-FDG scan greater sensitivity, the P value was only of borderline significance (McNemar's test, P=0.08). Conventional staging (CT-scan and mediastinoscopy) statistically improved diagnostic accuracy when compared to CT-scan staging alone (P=0.02). Finally, comparison between conventional staging and PET-FDG staging showed that PET-FDG scan did not improve diagnostic accuracy significantly (P=0.79, NS). Based on our current algorithm, six out of 64 patients (9.3%) were primarily operated on for N2 disease though our current practice would have been to offer the patient a multimodal treatment with induction chemotherapy. Relying on PET-FDG scan results, only three patients with N2 disease out of the 64 patients (4.7%) would not have been detected prior to surgery.
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Table 4 shows the details of the eight false-positive patients that were encountered in the study group. Out of these eight patients, three had centrally located tumors and two others had an active inflammatory process (one had active granulomatous disease and another had severe anthroco-silicotic disease on pathological examination of mediastinal LNs).
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4. Comments |
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TopAbstract1. Introduction2. Materials and methods3. Results4. CommentsAppendix A. Conference...References |
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Our results concerning the PET-FDG scan, 67, 85, 82, 43, and 93.6%, respectively, are slightly inferior to those found in the most recent published series. Scott et al. [14] reported values of 100, 98, 99, 91, and 100% in a series of 27 patients. However, only 2.8 LNs were sampled per patient on average and one could argue that some nodal stations remained unexplored, leading to optimistic results. Gupta et al. [15] reported a series of 71 patients with 126 LNs sampled (less than two per patient) with respective values of 93, 94, 96, 92, and 96%. In their series, there were four false-positive and four false-negative results. Finally, Kernstine et al. [16] recently reported their experience in a series of 64 patients and 122 LNs. Sensitivity, specificity, and diagnostic accuracy of PET-FDG scan were 70, 86, and 84% (vs. 65, 79, and 76% for CT-scan) with an 8% (two out of 25) false-negative rate.
In the current study, all 64 patients had complete mediastinal surgical staging with 1240 LNs available for pathological examination (19.4 nodes/patient). Therefore, we believe that the reported results are rather realistic and that there should be minimal bias with respect to the completeness of mediastinal pathological staging. We do not have a clear explanation for the false-negative results of PET-FDG scan. In a previous report, Vansteenkiste et al. [17] suggested that their five false-negative node results (two out of 68 patients) were due to microscopic tumor burden in the mediastinal LNs and the current limits of the PET-FDG technique. However, in our series, the three false-negative patients had metastatic mediastinal LNs with tumor burden ranging from 0.9 to more than 2 cm in diameter. Thus, it is likely that the biological behavior of the tumor cells has also to be accounted for when considering potential limitations of this non-invasive technique.
Importantly, in our series, eight false-positive patients (eight out of 64), or 12.5% of all patients, would have been denied surgical exploration with a curative intent if no further diagnostic procedures had been performed. In our experience, seven out of the eight false-positive PET-FDG scan patients were correctly staged after mediastinoscopy (Table 4).
The potential impact of PET-FDG scan on the overall preoperative work-up is illustrated in Table 5 which represents a comparison between our current strategy and a hypothetical setting with the study group population. Based on our criteria described in Section 2, 17 patients (Group I) should not have had mediastinal staging as part of preoperative work-up whereas 47 patients (Groups II and III) should have undergone mediastioscopy or anterior mediastinotomy, in 13 cases for clinical T3 or T4 tumors and/or enlarged mediastinal LNs on CT-scan (Group II), and in 34 patients for a non-small and non-SCC histology (Group III). Adding the PET-FDG scan to the preoperative work-up, and taking into consideration its very accurate negative predictive value and its relatively low specificity would have modified our strategy in the initial work-up in such a way that out of the 17 patients of Group I, only three would have undergone mediastinal surgical staging. Out of the 13 patients of Group II, five would have had mediastinoscopy/mediastinotomy and finally, out of the 34 patients from Group III, only seven were PET-FDG scan positive and would have undergone mediastinal surgical staging. Of the 64 patients, 49 patients had negative PET-FDG scan. Three out of these were false-negative (one patient in each group) whereas in one patient, the PET-FDG scan could not differentiate the hilar location of the primary tumor from an ipsi-lateral mediastinal LN. Thus, taking into account the results of the PET-FDG scan and its high negative predictive value, only 15 mediastinal surgical staging procedures would have been performed. This represents a three-fold decrease in the amount of invasive procedures NSCLC patients would have to undergo.
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Following the inclusion criteria for surgical staging strictly, our study group should have had 47 mediastinal surgical procedures out of the 64 patients (total cost=116 509 euro).
However, 28 surgical staging procedures only were performed in addition to the PET-FDG scan studies, revealing the selection bias in this non-controlled non-randomized trial where throughout the study period, our growing confidence in a negative PET-FDG scan study increased our threshold for invasive surgical staging.
Following strictly PET-FDG scan results and pursuing investigations only with positive results, our study group should have had 15 mediastinal surgical staging procedures out of the 64 patients (37 184 euro), in addition to the PET-FDG scan studies (37 184 euro) (total cost=89 539 euro).
As shown in Tables 5 and 6, this could have reduced overall staging costs by about 23%, in addition to a three-fold reduction in the number of surgical procedures required, sparing patients surgical stress, associated morbidities, and the theoretical risk of mortality.
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In conclusion, the current study suggests that PET-FDG scan is a valuable adjunct in the preoperative diagnostic staging of NSCLC even though the overall accuracy (82%) was lower than data previously reported by others. PET-FDG scan strength lies mostly in its very high negative predictive value. This should alleviate the need for surgical staging procedures in patients whose PET-FDG scan studies are negative. We believe that with a positive PET-FDG scan result, every effort should be pursued to confirm or infirm mediastinal LN involvement so as not to exclude false-positive patients who otherwise would be denied surgical exploration with a curative intent.
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Footnotes |
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1 Members of the ‘Groupe d'Oncologie Thoracique des Cliniques Universitaires Saint-Luc, Université catholique de Louvain’ and co-operating in the study are E. Coche, Ph. Collard, Y. Humblet, G. Liistro, M. Lonneux, Ph. Noirhomme, Th. Pieters, A. Poncelet, D. Rodenstein, P. Scaillet, and B. Weynand. 
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Appendix A. Conference discussion |
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TopAbstract1. Introduction2. Materials and methods3. Results4. CommentsAppendix A. Conference...References |
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Can I ask you what your current policy is in a patient with a central tumor and a negative PET-scan on the mediastinum?
Dr Poncelet: In this study, in fact, we did not do co-registration of CT-scan and PET-FDG, so that we believe that our false-positive rate is higher than what was published previously. So our aim now would be first to do co-registration. However, we probably would go to mediastinoscopy.
Dr van Raemdonck: It's also our practice for central tumors to still do a mediastinoscopy because the PET-scan is having difficulties in distinguishing lymph nodes from the primary tumor.
Dr Poncelet: That is correct.
Dr T. Dosios (Athens, Greece): Do you think that every patient who is going to be operated on should have a PET-scan preoperatively from now on, and, if so, what about the cost?
Dr Poncelet: What was not studied in this presentation is the number of positive findings outside of the thoracic wall and parenchyma. Several studies have shown that there is probably more than 10% of patients who would be initially operated on without a PET-FDG and who would prove to be metastatic by PET-FDG and histology. So I believe that PET-FDG should be done in every patient, even for the N0 patient. Currently the cost in Belgium is about $700.
Dr A. Imdahl (Freiburg, Germany): I understand that you miss N1 disease with a PET-scan because N1 is localized near the tumor and you get one hot spot, but I have difficulty understanding why N2 was false-negative. It might be worth it to look at markers, for instance, the proliferation index or whatever. Have you done that?
Dr Poncelet: As we have seen on the slide, we have looked into the diameter of the metastatic cell islets within the lymph nodes, and in contrary to what was published by the Leuven group, in our cases there was a large amount of metastatic cells within the nodes. We haven't studied the biological behavior of these tumors.
Dr K. Jeyasingham (Winterbourne Down, UK): You mentioned that you would do PET-scan for all cases. If you were going to do PET-scan and CT-scan, at what point would you do the PET-scan and at what point would you do the CT-scan in order to reduce cost and time?
Dr Poncelet: I would probably say that with a peripheral small tumor that you see on the chest X-ray and which is centrally located in comparison to the chest wall, you might think that just doing the PET-scan as a preoperative work-up would be enough just because you know that the resection would probably be easy. Now, the CT is an indication for the local information when you need to know whether the chest wall or the mediastinum is invaded.
Dr van Raemdonck: If I can add to this comment, I also agree that PET-scan and CT-scan should be added together because you still need anatomical information next to the biochemical information. So I think you still need both investigations if you have the money to do it.
Dr K. Al Kattan (Riyadh, Saudi Arabia): Obviously we have a bit different type of population because we have a higher incidence of TB, which makes the diagnostic differentiation a bit more difficult. But when we started the biologic study using PET-scan, we noted that, yes, we can save some money by detecting extra-thoracic lesions which you wouldn't detect before, but also we started doing too many investigations for suspicious lesions that would have not been significant on CT alone; contra-lateral lymph node, for example, or on the other side or a small old TB on another lobe, that you need also to do further investigation, and I think we used to have this when we used to do routine brain CT and bone scan and details for lung cancer, and then we stopped because it's not cost-effective and we started to do it only on symptomatic patients. So I think routine use of PET can have advantages but can also have a lot of disadvantages costwise, even if you bring the cost up to $700, as you said.
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References |
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TopAbstract1. Introduction2. Materials and methods3. Results4. CommentsAppendix A. Conference...References |
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