Risk Factors for Occult Mediastinal Metastases in Clinical Stage I Non-Small Cell Lung Cancer

ORIGINAL ARTICLES: 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 nonmember subscription to the journal. Risk Factors for Occult Mediastinal Metastases in Clinical Stage I Non-Small Cell Lung Cancer Paul C. Lee, MD, Jeffrey L. Port, MD, Robert J. Korst, MD, Yaakov Liss, BA, Danish N. Meherally, MPH, and Nasser K. Altorki, MD Division of Thoracic Surgery, Department of Cardiothoracic Surgery, New York Presbyterian Hospital Weill Medical College of Cornell University, New York, New York Background. In patients deemed to have clinical stage I for non-small cell lung cancer (NSCLC) after computerized tomography (CT) and positron emission tomography (PET) scans, the utility of mediastinoscopy to detect occult mediastinal metastases is unclear. The goal of this study was to analyze the risk factors for occult mediastinal metastases in this subset of patients. 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 (SUV max ) of the primary tumors was analyzed, patients with occult N2 metastases had a higher median SUV max 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 SUV max 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. (Ann Thorac Surg 2007;84:177 81) 2007 by The Society of Thoracic Surgeons 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) Accepted for publication March 26, 2007. Presented at the Poster Session of the Forty-third Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Jan 29 31, 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; e-mail: nkaltork@med.cornell.edu. 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 costeffective, 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 2007 by The Society of Thoracic Surgeons 0003-4975/07/$32.00 Published by Elsevier Inc doi:10.1016/j.athoracsur.2007.03.081

178 LEE ET AL Ann Thorac Surg RISKS FOR MEDIASTINAL METASTASES IN NSCLC 2007;84:177 81 Table 1. Pathologic Stages of 224 Resected Clinical Stage 1 Non-Small Cell Lung Cancers Pathologic Stage 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. Material and Methods No. of Patients T1N0M0 a 118 T2N0M0 a 51 T3N0M0 2 T4N0M0 16 T1N1M0 6 T2N1M0 14 T3N1M0 1 T4N1M0 1 T1N2M0 8 T2N2M0 3 T4N2M0 1 M1 3 a Percentage of total patients with pathologic stage I NSCLC: 169/224 75%. We conducted a retrospective review of an institutional review board approved prospective database to identify patients with potentially operable clinical stage I NSCLC with a CT-negative and PET-negative mediastinum from January 2000 to November 2006. This study was approved by the institutional review board of the Weill Medical College of Cornell University, and patient consent was waived. Patients were excluded if both PET and chest CT had not been performed. A total of 224 patients were identified. Hospital and office records of each patient were reviewed for demographic and clinical data, including age, gender, smoking status, preoperative radiologic assessments, associated comorbidities, and clinical stage. Records were also reviewed for surgical data, including use of mediastinoscopy, extent of surgical resection, and method of mediastinal lymph node dissection. Pathologic data were collected, which included tumor size, histology, presence of nodal metastases, and pathologic stage. Radiologic Assessments For radiologic data collection, clinical tumor size, tumor location (central versus peripheral), and PET maximum standardized uptake value (SUV max ) 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 SUV max 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. Results Clinical Findings During the study period from January 2000 to November 2006, 224 patients (87 men, 137 women) were identified. Their median age was 69.5 years (range, 45 to 90 years). Table 2. Tumor Location, Tumor Size, and Prevalence of Occult N2 Metastases Clinical Tumor Size % Occult N2 Metastases for Centrally Located Tumors Peripherally Located Tumors p Value 0 2.0 cm 14.3 (3/21) 2.9 (3/103) 0.068 2.1 3.0 cm 30.0 (3/10) 5.3 (2/38) 0.007 3.0 cm 25.0 (5/20) 0.0 (0/29) 0.010 All tumor sizes 21.6 (11/51) 2.9 (5/170) 0.001

Ann Thorac Surg LEE ET AL 2007;84:177 81 RISKS FOR MEDIASTINAL METASTASES IN NSCLC 179 Table 3. Tumor Size and Prevalence of Occult N2 Metastases Clinical Tumor Size Overall % Occult N2 Metastases a 0 2.0 cm 4.8 (6/124) 2.1 4.0 cm 6.5 (5/77) 4.1 6.0 cm 6.3 (1/16) 6.0 cm 57.1 (4/7) a By 2 test for overall % N2 metastases and clinical tumor size: p 0.001. All patients were deemed to have clinical stage I NSCLC after radiologic assessments by CT of the chest and upper abdomen (including the adrenals), PET scanning, and any other appropriate imaging modalities including CT or magnetic resonance imaging of the brain. Cervical mediastinoscopies were done in 76 patients (34%), and 11 patients had N2 disease identified by mediastinoscopy. Of these, 7 patients had right paratracheal nodal metastases, 3 had subcarinal nodal metastases, and 1 had both right paratracheal and subcarinal nodal metastases. In 5 additional patients, N2 disease was discovered at the time of surgical resection and mediastinal lymph nodal dissection. Four of those 5 patients had subcarinal nodal metastases, and 1 had level 5 aortopulmonary lymph node metastases. Therefore, 16 patients in our cohort had pathologic N2 disease. The final pathologic stages of all 224 patients are presented Table 1. At surgical resection, 4 of 16 patients had pathologic downstaging of their N2 disease after induction chemotherapy. After surgical resection, 75% of the patients were found to have pathologic stage I disease. Tumor Location The tumor location was classified as central versus peripheral in 221 of the 224 patients. Tumor locations could not be determined in 3 patients because of missing roentgenograms and incomplete radiology reports. Central tumors overall had a significantly higher prevalence of N2 disease compared with peripheral tumors, 21.6% versus 2.9% (p 0.001; Table 2). When categorized by tumor sizes of 0 to 2.0 cm, 2.1 to 3.0 cm, and greater than 3.0 cm, central tumors in each size category had higher prevalence of occult N2 disease compared with peripheral tumors. This was statistically significant for tumors exceeding 2.0 cm. Table 4. Tumor Histology of 224 Resected Clinical Stage 1 Non-Small Cell Lung Cancers Histology No. of Patients Adenocarcinoma 178 Mixed adenocarcinoma/bronchioloalveolar 100 subtype Bronchioloalveolar carcinoma subtype 9 Squamous cell carcinoma 34 Large cell carcinoma 5 Others 7 Table 5. F-18 Fluorodeoxyglucose Positron Emission Tomography Maximum Standardized Uptake Values of Primary Tumor and Prevalence of Occult N2 Metastases Tumor Size All 224 patients had clinically T1 or T2 status assigned preoperatively. There were 155 clinical T1 N0 patients and 69 clinical T2 N0 patients. The overall prevalence of histologically confirmed N2 disease was 6.5% in clinical T1 patients and 8.7% in clinical T2 patients. When clinical tumor sizes were further stratified into 0 to 2.0 cm, 2.1 to 4.0 cm, 4.1 to 6.0 cm, and greater 6.0 cm categories, larger clinical T size significantly predicted a higher prevalence of occult N2 disease (p 0.001; Table 3). Tumor Histology Tumor histologies of all 224 resected clinical stage I NSCLC are summarized in Table 4. All 16 patients with occult N2 metastases had adenocarcinoma as the primary tumor cell type, representing 16 (9.0%) of 178 adenocarcinomas. None of the remaining tumor cell types had any occult N2 metastases. When the incidence of occult N2 metastases between adenocarcinoma and squamous cell carcinoma (9.0% versus 0%) was compared, the Fisher exact test yielded a p 0.082. F-18 Fluorodeoxyglucose Uptake in Primary Tumor Preoperative FDG-PET scans were performed in all 224 clinical stage I NSCLC patients in this cohort. Maximum standardized uptake values (SUV max ) were reported for the primary tumors in 198 patients. The SUV max was not reported in the remaining 26 patients and they were excluded from this analysis. When the SUV max of the primary tumors were analyzed, patients with occult N2 metastases had a significantly higher median SUV max of the primary tumor compared with those without N2 metastases, 6.0 g/ml versus 3.6 g/ml (p 0.017). The prevalence of occult N2 disease increased significantly when SUV max of the primary tumor exceeded 4.0 g/ml (Table 5). Comment SUV max (g/ml) % Occult N2 Metastases a 0 4.0 1.9 (2/103) 4.0 10.5 (10/95) a Fisher exact test of % N2 metastases between tumors with SUV max 0 4.0 and 4.0: p 0.007. SUV max maximum standardized uptake values. The diagnosis of bronchogenic carcinoma carries a dismal prognosis for most patients. The stage of carcinoma at diagnosis remains one of the most important determinants of survival in NSCLC, with earlier stage patients having a better chance of long-term survival [10]. For patients with resectable stage I disease, 5-year survival can be as high as 80% [11]. Patients with metastatic involvement of mediastinal lymph nodes have poor sur-

180 LEE ET AL Ann Thorac Surg RISKS FOR MEDIASTINAL METASTASES IN NSCLC 2007;84:177 81 vival, however, and should not be offered surgical resection as a first-line therapy. 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 SUV max 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 SUV max of the primary tumor exceeded 4.0 g/ml. This finding is corroborated by previous studies. Downey and colleagues [17] have noted that PET SUV max of the primary tumors in patients with pathologic nodal involvement was higher than N0 patients. Cerfolio and colleagues [18] showed that SUV max of the lung tumor increases as tumors progressed from N0 to N3, as well as from M0 to M1. SUV max 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]. SUV max has been identified as an independent prognostic factor correlated with tumor aggressiveness and survival in patients with NSCLC [23 25]. 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