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ORIGINAL ARTICLE |
Seoul National University Hospital Seoul, South Korea
Young Tae Kim, MD, Tel: 82 2 2072 3161 Fax: +82 2 765 7117 Email: ytkim{at}snu.ac.kr, Department of Thoracic and Cardiovascular Surgery, Clinical Research Institute, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, 103 Daehangno Jongno-gu, Seoul 110-744, South Korea.
ABSTRACT
As lymph node metastasis is the most important factor determining the surgical outcome of lung cancer, we evaluated the accuracy and clinical usefulness of functional imaging with integrated positron-emission tomography and computed tomography in nodal staging of non-small-cell lung cancer. Between October 2003 and August 2004, 43 newly diagnosed patients underwent curative surgical resection or mediastinoscopic nodal biopsy after chest computed tomography as well as whole-body functional imaging for clinical staging. Based on histopathologic findings in the lymph nodes, we compared the diagnostic usefulness of computed tomography and functional imaging. Twenty-two patients were N0 stage, 6 were N1, 11 were N2, and 4 were N3. Although functional imaging seemed to be superior for evaluation of N2 nodes, there were no significant differences in the sensitivity, specificity, positive-predictive value, negative-predictive value, or accuracy. The situation was similar for N1 nodes, and there were no significant differences except for the false-negative rate. High false-positive and negative-rates for N2 lymph nodes suggest that functional imaging should not replace mediastinoscopy.
Key Words: Lung Neoplasms • Lymph Nodes • Neoplasm Staging • Positron-Emission Tomography • Tomography • X-Ray Computed
INTRODUCTION
The outcome of non-small-cell lung cancer (NSCLC) depends on the stage of the cancer, thus accurate clinical staging is important to determine the appropriate treatment strategy. A recent neoadjuvant therapeutic protocol has demonstrated the importance of mediastinal lymph node status, so there is greater need for a more accurate, less invasive, and reproducible diagnostic method of mediastinal lymph node staging.1 Despite recent developments in imaging technology, mediastinoscopic biopsy remains the most accurate means of determining lymph node stage. Conventional computed tomography (CT) provides clear anatomical information on the mediastinal lymph nodes; however, high rates of false-positive and false-negative results limit its clinical usefulness. 18F-labeled fluorodeoxyglucose (FDG) positron-emission tomography (PET) provides functional images of glucose metabolism for mediastinal evaluation and seemed initially promising, but the high rate of false-positive results became a limitation of this technique.2,3 To combine anatomic and metabolic information, integrated PET/CT was developed with the anticipation that it would be superior to single studies. We investigated the role of integrated PET/CT in lymph node staging of NSCLC, and compared this method with the gold standard of the surgical pathologic result.
PATIENTS AND METHODS
Our institutional review board approved our study, and written informed consent was obtained from all patients (IRB no. 0601-063-167). From October 2003 to August 2004, we selected newly diagnosed NSCLC patients admitted to Seoul National University Hospital. All patients were histologically diagnosed with NSCLC, and underwent enhanced chest CT and whole-body PET/CT for clinical staging. This method of cancer staging was followed by the TNM and American Joint Committee on Cancer staging systems.4 Surgically resectable patients underwent curative pulmonary resection including complete mediastinal lymph node dissection. If there was any suspicion of N2 or N3 lymph node involvement on CT or PET/CT, a mediastinoscopic biopsy was performed before proceeding to thoracotomy. We compared the results of preoperative staging by CT with those of PET/CT and the pathologic lymph node status. Patients who had neoadjuvant chemotherapy or radiotherapy before thoracotomy or mediastinoscopy, or previous history of malignancy or pulmonary resection were excluded.
Contrast-enhanced CT scans were carried out using a Somatom Plus 4 (Siemens Medical Solutions) and a HighSpeed Advantage scanner (GE Healthcare). CT provided full images of the liver, both adrenal glands and kidneys, with intravenous contrast medium. A significant metastatic lymph node was defined as a short-axis diameter >1 cm at each nodal station. All results were reviewed by an experienced radiologist. PET/CT was undertaken with a Gemini PET/CT system (Philips, Milpitas). All PET/CT images were evaluated by an experienced nuclear medicine physician. Hypermetabolic activity with a standardized uptake value >2.5 was regarded as a positive finding. On several occasions, the decision was modified based on known decision criteria distinguishing physiologic uptake from pathologic uptake.5–9 Mediastinal nodal status was analyzed at each mediastinal lymph node station and at N1 nodes in the hilar and peribronchial areas. If a distant metastatic lesion was found on PET/CT, brain magnetic resonance imaging, bone scan, or tissue biopsy was carried out for further evaluation. Mediastinoscopy was performed only in patients with suspected metastatic nodes. All accessible nodes (2R, 2L, 4R, 4L, 7) were biopsied, and more than one node was biopsied at each station. If there was no mediastinal metastasis on CT or PET/CT, we performed curative resection and lymphadenectomy without mediastinoscopy. The lymphadenectomy included the 2R, 3, 4R, 7, 8, 9 nodes, and regional lymph nodes on the right side, and 4L, 5, 6, 7, 8, 9, and regional lymph nodes on the left side.
For comparison of CT and PET/CT findings with the surgical pathologic results, we calculated sensitivity, specificity, positive-predictive value, negative-predictive value, false-positive rate, false-negative rate, and accuracy at each lymph node station. The statistical analysis was carried out using the McNemar test or Fisher’s exact test. A p value less than 0.05 was regarded as significant.
RESULTS
During the study period, 63 newly diagnosed NSCLC patients underwent both CT and integrated PET/CT for the clinical staging. Among them, 43 patients underwent surgical procedures including mediastinoscopy, which allowed pathologic evaluation of the mediastinal nodes. There were 34 men and 9 women; their median age was 64.0 years (range, 32.9–83.1 years). The characteristics of the patients are summarized in Table 1
. Squamous cell carcinoma was the most common histology, followed by adenocarcinoma; one patient had both squamous cell carcinoma and adenocarcinoma. Patients underwent surgery within a mean of 8 days after the PET/CT study. Eleven patients underwent mediastinoscopy for mediastinal lymph node evaluation, and 5 were referred for chemotherapy due to N2 or N3 nodes involvement. The remaining patients underwent curative resection and mediastinal lymphadenectomy. The surgical treatments are summarized in Table 1.
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). There was no difference according to nodal station, except for the false-negative rate (Table 3). Among 43 patients, only 26 (63.4%) were correctly diagnosed by PET/CT at nodal stage, 3 were over-staged, and 12 were under-staged (Table 4). Three cases of extrathoracic metastasis were undetected by PET/CT. Brain metastases were detected in 2 patients one month after pulmonary resection. Both bone and spleen metastases were detected in another patient. They had normal images and no symptoms except for the pulmonary lesion found at the previous PET/CT.
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The use of integrated FDG PET/CT for preoperative diagnosis of NSCLC is increasing. There have been several studies on the role of PET/CT in NSCLC. Cerfolio and colleagues10 performed a similar study of PET/CT in 129 patients, and reported that it had better predictability compared to dedicated PET alone. Their data showed that PET/CT was superior in sensitivity (69% vs. 62%) and accuracy (96% vs. 93%) but not in specificity (94% vs. 97%). The nodal distribution in patients who underwent surgery was similar to that in our series, but their study included neoadjuvant chemotherapy and distant metastatic cases. They presented the results of 382 patients at the 41st Society of Thoracic Surgeons Annual Meeting, which indicated that the predictability of PET/CT was no different to that of CT (62% vs. 52%) for stage III disease. Shim and colleagues11 compared PET/CT and CT in 106 patients, and suggested that PET/CT was superior for the depiction of malignant nodes, with specificity of 84% vs. 69%, and accuracy of 84% vs. 69%. The sensitivity rate in our study was lower than that of other studies.10–14 This discrepancy may have resulted from a difference in the study population. Our study population included those who had early disease and were considered initially as surgically resectable. Thus we included more clinical N0 than N2 or N3 patients. We excluded patients who had undergone previous lung surgery or neoadjuvant therapy because these situations can influence the PET/CT results. This finding agrees with the recent data of Kim and colleagues14 that for T1 NSCLC, the sensitivity and specificity of integrated PET/CT were 47% (16/34) and 100% (116/116). Although the total N2 lesions showed no significant advantages on the CT scan, level 7 nodes showed good results.
Considering our population, PET/CT had a limited role in mediastinal evaluation in early stage NSCLC, and level 7 nodal station had more accuracy than other stations (Table 3
). In spite of the high accuracy, PET/CT had many false-positive and false-negative cases. In our study of N2 lesions, the 16.7% false-positive rate and 18.9% false-negative rate in the PET/CT study erroneously diagnosed 1 out of 3 patients (Tables 3 and 4). Hence, one can say that histologic confirmation is necessary regardless of the PET/CT finding. For N1 lesions, PET/CT showed a significantly lower false-negative rate than that of CT, and we believe it can be useful for staging. As a result, PET/CT would not be the appropriate choice to replace the tissue biopsy. Endobronchial ultrasonography is a recently introduced technique that improves transbronchial needle aspiration results in lung cancer staging, thanks to the visualization of mediastinal and lobar lymph nodes.15 Herth and colleagues16 performed endobronchial ultrasonography and transbronchial needle aspiration of lymph nodes in the radiologically and PET-normal mediastinum in patients with lung cancer, and detected 9 nodal metastases among 100 patients, with sensitivity of 89%, specificity of 100%, and a negative-predictive value of 98.9%. Since endobronchial ultrasonography has several advantages, such as access to posterior mediastinal level 7 and hilar nodes and examination of small-sized lymph nodes, it can be considered an additional method of mediastinal staging.
When we analyzed the N status, it was important to access each nodal station separately. Even if the pathologic staging and preoperative clinical staging resulted in the same N2 disease, we looked back at individual lymph node stations separately because the purpose of this study was to evaluate the diagnostic usefulness of the 2 techniques. We regarded the results as incorrect if the individual positive nodal number was different, or another node in other nodal numbers was positive, even if the N stage was the same. False-negative or false-positive cases were also found for the distant metastases. There were 3 patients with undetected extrathoracic metastases. Two were cases of brain metastasis and one had bone and spleen metastases. As brain metastasis is known to exhibit heterogeneous findings on PET/CT, we should evaluate the brain with another study if there is any neurologic symptom.17
Our results demonstrate that although PET/CT seems to offer an improved method to evaluate mediastinal lymph nodes, mediastinoscopic biopsy currently remains the standard method. A high false-positive rate for N2 lymph nodes on PET/CT limits its use for selecting patients for neoadjuvant treatments, and as a result, PET/CT would not be an appropriate choice to replace mediastinoscopy.
ACKNOWLEDGMENTS
This work was supported by the Korea Science & Engineering Foundation (KOSEF) through the Tumor Immunity Medical Research Center (TIMRC) at Seoul National University College of Medicine (R13-2002-025-03002-0); and by the grant no. 800-2005-0144 from Seoul National University (Sang Koo Hahn Research Fund).
REFERENCES
Asian Cardiovasc Thorac Ann 2009;
17:622-626
© 2009 by SAGE Publications
DOI: 10.1177/0218492309349253
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