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Ann Thorac Surg 2007;84:177-181
© 2007 The Society of Thoracic Surgeons
Division of Thoracic Surgery, Department of Cardiothoracic Surgery, New York Presbyterian Hospital–Weill Medical College of Cornell University, New York, New York
Accepted for publication March 26, 2007.
* Address correspondence to Dr Altorki, Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Suite M404, Weill Medical College of Cornell University, 525 E 68th St, New York, NY 10021 (Email: nkaltork{at}med.cornell.edu).
Presented at the Poster Session of the Forty-third Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Jan 29–31, 2007.
| General thoracic surgery:
The Annals of Thoracic Surgery CME Program is located online at http://cme.ctsnetjournals.org. To take the CME activity related to this article, you must have either an STS member or an individual non-member subscription to the journal.
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Abstract |
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Methods: We conducted a retrospective review during a 7-year period to identify patients with potentially operable clinical stage I NSCLC screened by CT and PET scans. Medical records were reviewed, and the prevalence of pathologic N2 disease was analyzed according to clinical tumor location, size, histology, and PET uptake of the primary tumor.
Results: Of 224 patients identified with clinical stage I NSCLC with a CT-negative and PET-negative mediastinum, 16 patients had pathologic N2 disease proven by mediastinoscopy (n = 11) or after resection (n = 5). The overall prevalence of histologically confirmed N2 disease was 6.5% in clinical T1 patients and 8.7% in clinical T2 patients. Central tumors had a higher prevalence of N2 disease compared with peripheral tumors, 21.6% versus 2.9% (p < 0.001). Larger clinical T size predicted a higher prevalence of occult N2 disease (p < 0.001). All 16 patients with occult N2 metastases had adenocarcinoma as the primary tumor cell type. When the PET maximum standardized uptake value (SUVmax) of the primary tumors was analyzed, patients with occult N2 metastases had a higher median SUVmax of the primary tumor compared with patients without N2 metastases, 6.0 g/mL versus 3.6 g/mL (p = 0.017).
Conclusions: For patients deemed at clinical stage I NSCLC by CT and PET, the prevalence of missed N2 metastases increased significantly with larger tumor size and central location. Adenocarcinoma cell type and a high PET SUVmax of the primary tumor were other risk factors. Mediastinoscopy may have improved yield in the select subset of patients with one or more risk factor.
Lung cancer is the leading cause of cancer deaths in the United States. In 2005, an estimated 173,000 Americans were diagnosed with lung cancer, and 164,000 died of their disease [1]. Most patients with non-small cell lung cancer (NSCLC) have metastatic or locally advanced disease at presentation, and less than 15% present with stage I disease where surgical resection results in a 5-year survival of 60% to 80%. Accurate clinical tumor staging therefore is paramount in reserving surgical resection as a first-line therapy to those with early stage disease with no distant or mediastinal metastases.
Before the era of positron emission tomography (PET) with F-18 fluorodeoxyglucose (FDG-PET), computed tomography (CT) of the chest and cervical mediastinoscopy were the conventional methods in staging the mediastinum. PET recently has become an important noninvasive tool in mediastinal staging for NSCLC, with reported sensitivity of 61% to 88% and specificity of 77% to 96% [2–7].
In patients deemed at clinical stage I NSCLC by CT and PET, some surgeons have advocated forgoing a cervical mediastinoscopy before thoracotomy and surgical resection. Meyers and colleagues [8] have suggested that the use of routine mediastinoscopy in CT and PET screened patients with stage I NSCLC is not cost-effective, with occult mediastinal lymph node metastases found in only 5.6% of patients. However, stage I NSCLC represents a heterogeneous group of tumors, and characteristics such as large tumor size and central locations have been shown to be risk factors for mediastinal metastases [9].
In this study, we examined the risk factors for occult mediastinal metastases in clinical stage I NSCLC by CT and PET. Guidelines are suggested for selective use of cervical mediastinoscopy in patients with such risk factors where the use of cervical mediastinoscopy might have improved yield.
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Material and Methods |
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Radiologic Assessments
For radiologic data collection, clinical tumor size, tumor location (central versus peripheral), and PET maximum standardized uptake value (SUVmax) were recorded. Clinical tumor size and tumor location were determined by direct review of available chest CT images (71% of patients) or review of radiology reports by one of the authors (PCL). A tumor was considered peripheral if the center of the tumor was located within the outer one third of the lung field as determined from the radial distance from the hilum to the lung periphery. All PET scan reports were reviewed. A SUVmax was reported in 198 patients. The remaining 26 patients were excluded from the PET data analysis because standardized uptakes values were not reported for the primary tumors.
Cervical Mediastinoscopy
All of the cervical mediastinoscopies were done by thoracic surgeons (PCL, JLP, RJK, NKA) at New York Presbyterian Hospital–Weill Cornell Medical College. Techniques of cervical mediastinoscopies were standardized with biopsy of lymph nodes in at least three nodal stations, including the paratracheal nodes (4R, 4L) and the subcarinal nodes (7). When indicated, biopsies were also obtained in the 2R or 2L nodal stations.
Mediastinal Lymph Node Dissection
All of the surgical resections and mediastinal nodal dissections were done by thoracic surgeons (PCL, JLP, RJK, NKA) at New York Presbyterian Hospital–Weill Cornell Medical College. Techniques of mediastinal nodal dissection at the time of surgical resection were standardized as well. For right-sided tumors, lymph node stations 2R, 4R, 7, 9, and 10R were dissected. For left sided tumors, lymph node stations 5, 6, 7, 9, and 10L were dissected. The combined results of mediastinoscopy and mediastinal lymph node dissection were used to calculate the prevalence of mediastinal metastasis in patients with NSCLC. Staging was done according to the Tumor-Node-Metastasis (TNM) classification of the American Joint Committee for Cancer Staging and Revised International System for Staging Lung Cancer [10].
Statistical Analysis
Statistical analysis was performed using SPSS statistical software (SPSS Inc, Chicago, IL). Independent t tests were used for two-group comparisons of continuous variables. Categoric data in cross-tabulation tables were compared using the Fisher exact test or Pearson’s 
2 test. Nonparametric data were analyzed with the Mann-Whitney U test. Results were considered significant for p 
0.05.
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Comment |
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TopAbstractIntroductionMaterial and MethodsResultsCommentReferences |
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Careful mediastinal staging therefore is essential, and chest CT and cervical mediastinoscopy have been the traditional gold standards. FDG-PET recently has become an important noninvasive tool in mediastinal staging for NSCLC, with reported sensitivity as high as 88% and specificity as high as 96% [2–7]. Some surgeons have argued against a cervical mediastinoscopy in patients deemed clinical stage I NSCLC screened by CT and PET. Meyers and colleagues [8] have reported that occult mediastinal lymph node metastases were found in only 5.6% of patients with clinical stage I lung cancer screened by CT and PET. Furthermore, the authors suggested that the use of routine mediastinoscopy in these patients is not cost-effective secondary to the low prevalence of occult mediastinal lymph node metastases.
However, stage I lung cancer represents a heterogeneous group of patients with various tumor sizes, cell types, and location. It is well established that tumor size is an important prognostic factor for survival in NSCLC [12–15]. The prevalence of mediastinal metastases increases with tumor size [16]. Asamura and colleagues [16] have found that among patients with resected peripheral NSCLC, the prevalence of lymph node metastases increased from 19.5% in tumors 2.0 cm or smaller to 32.5% in tumors 2 to 3.0 cm in diameter [16]. In the current study, large clinical tumor size was a significant factor for increased prevalence of occult mediastinal metastases.
The traditional TNM classification does not consider tumor location as a prognostic factor. Current evidence suggests that central tumors, regardless of size, have a higher incidence of lymph node metastases and a poorer prognosis [9]. For example, Ketchedjian and colleagues [9] have demonstrated that the incidence of lymph node involvement in central T1 tumors was as high as 50% [9]. In the current study, a direct correlation was found between tumor size, central location, and the prevalence of occult N2 mediastinal metastases. For centrally located tumors, the incidence of occult N2 disease was 21.6% and was as high as 26.7% for tumors exceeding 2 cm in size. For peripherally located tumors, the incidence was 2.9%. Certainly, given the high rate of occult N2 disease, the selective use of cervical mediastinoscopy in patients with centrally located tumors and large primary tumor size is warranted and justified.
It is interesting to note that all 16 patients in our series with occult N2 disease had adenocarcinoma as the primary tumor cell type. None of the 34 patients with squamous cell carcinomas harbored any occult N2 metastases. Although this was not statistically significant (p = 0.082), the trend certainly suggests that adenocarcinoma cell type compared with squamous cell carcinoma is a relative risk factor for N2 metastases. Asamura and colleagues [16] examined 337 patients with peripheral resected NSCLC for lymph node involvement. They found that lymph node involvement was very rare among squamous cell carcinoma of 2.0 cm or less in diameter, and concluded that the rarity of lymphatic spread might justify not performing a lymphadenectomy in this subset of patients.
Finally, when PET uptake values of primary tumors were analyzed, tumors with occult N2 metastases had a significantly higher median SUVmax compared with those tumors without N2 disease, 6.0 g/mL versus 3.6 g/mL. The prevalence of occult N2 disease increased significantly from 1.9% to 10.5% when SUVmax of the primary tumor exceeded 4.0 g/mL. This finding is corroborated by previous studies. Downey and colleagues [17] have noted that PET SUVmax of the primary tumors in patients with pathologic nodal involvement was higher than N0 patients. Cerfolio and colleagues [18] showed that SUVmax of the lung tumor increases as tumors progressed from N0 to N3, as well as from M0 to M1. SUVmax also independently predicted the likelihood of lymphovascular invasion [18].
NSCLC is characterized by glucose metabolic derangements. Increased glycolysis results in the upregulation of glucose transporter proteins (especially subtype Glut-1) and increased hexokinase activity [19]. These glucose metabolic derangements can be measured quantitatively in vivo by PET after administration of F18-FDG. F18-FDG uptake in NSCLC has been correlated with tumor growth rate and proliferation capacity [20–22]. SUVmax has been identified as an independent prognostic factor correlated with tumor aggressiveness and survival in patients with NSCLC [23–25]. Hence, in addition to large tumor size, central location, and adenocarcinoma cell type, a high PET SUVmax of the primary tumor appears to be another risk factor for occult mediastinal metastases.
In summary, for patients with clinical stage I NSCLC screened by CT and PET, the prevalence of occult N2 metastases increased significantly with larger tumor size and central location. Adenocarcinoma cell type and a high PET SUVmax of the primary tumor were other risk factors. Selective use of mediastinoscopy in patients with one or more risk factors may have improved yield. Routine use of mediastinoscopy in those patients with small peripherally located tumors or tumors with SUVmax of 4.0 g/mL or less is not justified owing to low incidence of occult N2 metastases.
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