Prognostic Significance of Metastasis to the Highest Mediastinal Lymph Node in Nonsmall Cell Lung Cancer

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1 Prognostic Significance of Metastasis to the Highest Mediastinal Lymph Node in Nonsmall Cell Lung Cancer Yukinori Sakao, MD, PhD, Hideaki Miyamoto, MD, PhD, Akio Yamazaki, MD, PhD, Tsumin Oh, MD, Ryuta Fukai, MD, Kazu Shiomi, MD, and Yuichi Saito, MD Department of General Thoracic Surgery, Juntendo University School of Medicine, Tokyo, Japan Background. We have tried to clarify the prognostic significance of metastasis to the highest mediastinal (HM) lymph node in patients with N2 lung cancer who underwent complete dissection of superior mediastinal (including HM) lymph nodes. Methods. This study analyzed 53 patients with N2 nonsmall cell lung cancer who underwent surgical procedures such as lobectomy plus hilar and mediastinal node dissection (T4, neoadjuvant therapy cases were excluded). For patients whose cancer was in the left lung, we performed surgery through the median sternotomy in order to dissect superior mediastinal nodes. The clinicopathologic records of the patients were examined for prognostic factors such as age, sex, side, histology, tumor location, tumor size, clinical node (cn) number, preoperative serum carcinoembryonic antigen level, number of metastatic stations, and HM lymph node involvement. Results. A univariate analysis showed that tumor size (T1/T2-3), cn factor (cn1-2/cn0), N2 level (multiple/single), and metastasis to the HM node were significant prognostic factors. In the multivariate analysis, metastasis to the HM lymph node remained a significant prognostic factor (p 0.026). The 3-year survival rates were 52% in patients without metastasis to the HM lymph node and 21% in patients with metastasis to the HM lymph node (p < 0.001). Furthermore, when HM nodal involvement was absent, the 5-year survival rate was 33% even in patients with multilevel N2 status, 45% in patients with cn1-2 status, and 47% in patients with pt2-3 tumor status. Conclusions. Highest mediastinal lymph node involvement is prognostic of highly advanced N2 disease resulting in poor outcome. The results also suggest that patients with no involvement of the HM lymph node can experience acceptable postoperative outcomes even if they have multilevel N2 status, positive cn status, or T2-3 tumor status. (Ann Thorac Surg 2006;81:292 7) 2006 by The Society of Thoracic Surgeons The presence of metastasis to the highest mediastinal (HM) lymph node in patients with N2 lung cancer has been defined as a finding of incomplete resection [1, 2]. However, previous studies regarding postoperative prognosis in such patients have not clarified the impact of HM lymph node involvement [3 6]. Recent studies have shown that positive HM nodal status was not related to prognosis after surgery [7]. Thus, the impact of HM lymph node involvement as a prognostic factor in N2 lung cancer is undefined. In this retrospective study, we have tried to clarify the prognostic importance of HM lymph node involvement in patients with N2 lung cancer who underwent complete dissection of the HM lymph node. Patients and Methods Between 1996 and 2003, 433 patients underwent surgical resection of primary lung cancer within our department. Accepted for publication June 24, Address correspondence to Dr Sakao, Department of General Thoracic Surgery, Juntendo University School of Medicine, Hongo, Bunkyoku, Tokyo , Japan; sakao@med.juntendo.ac.jp. Of those, 82 patients were diagnosed as having mediastinal lymph node involvement by pathological examination. The mediastinal nodal status (HM lymph node) was assessed according to the system of Mountain and Dresler [9] and Naruke and coworkers [10]. All the 82 patients underwent ND2a dissection ( for upper lobe: superior and subcarinal nodes; for middle or lower lobes: superior and inferior mediastinal nodes), including complete superior mediastinal (highest mediastinal, upper paratracheal, and lower paratracheal) nodal dissection. The HM lymph node is defined as nodes lying above a horizontal line at the upper rim of the bracheocephalic (left innominate) vein where it ascends to the left, crossing in front of the trachea at its midline [9]. For patients with cancer in the left lung, we performed surgery through a median sternotomy in order to completely dissect superior mediastinal nodes according to Hata s method [11, 12]. Briefly, the anterior mediastinal tissue is removed after the median sternotomy. The lymph nodes around the right and left recurrent laryngeal nerves directly under the thyroid gland, which is the upper limit of mediastinal dissection, and then a series of lymph nodes on the bilateral sides along the trachea were 2006 by The Society of Thoracic Surgeons /06/$32.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg SAKAO ET AL 2006;81:292 7 HIGHEST MEDIASTINAL NODAL INVOLVEMENT 293 Statistical Analysis The duration of survival was defined as the interval between the day of surgery and the date of death by any cause or the last follow-up date. Survival rates were calculated using the Kaplan-Meier method, and univariate analyses were performed using the log-rank test or the logistic regression procedure test. Multivariate analyses were performed by means of the Cox proportional hazards model using Stat View J 5.0 (SAS Institute, Cary, North Carolina) in variables with p value of less than 0.05 in univariate analyses. A pvalue of less than 0.05 was treated as significant. Fig 1. Intraoperative view of mediastinum. After dissection of superior mediastinal lymph nodes through a median sternotomy, the ascending aorta was retracted to the left side. The boxed area shows the anatomical location of highest mediastinal lymph nodes. (BCA brachiocephalic artery; BCV brachiocephalic vein; laryngeal N recurrent laryngeal nerve [taped]; Lt left; PA pulmonary artery; Rt right; Tr trachea; vagal N vagal nerve [taped].) dissected (Fig 1) [11, 14]. When it was difficult to distinguish the ipsilateral lymph nodes from contralateral lymph nodes in the dissected tissue, the lymph nodes around the trachea were included in this study (as N2) for left lung cancer. After exclusion of patients with T4 tumor status, and those who received neoadjuvant therapy, 53 patients remained and were analyzed in this study. None of the 53 patients received any adjuvant therapy. The group comprised 15 female and 38 male patients, with ages ranging from 28 to 80 years (median age, 63). Preoperative staging was performed according to the TNM classification system of the International Union Against Cancer [8] using chest computed tomography (CT), abdominal CT or ultrasonography, brain CT or magnetic resonance imaging, and bone scanning in all patients. Mediastinal and hilar lymph node status was assessed as positive if the chest CT showed that the shorter axis of any node was larger than 1.0 cm. Mediastinoscopy and positron emission tomography (PET) have not been performed routinely in this series. Scalen node biopsy was performed in patients with suspicions of N3 (neck) in physical examination. When N3 (neck) was confirmed pathologically, the patients did not undergo surgery. The follow-up duration ranged from 12 to 96 months (median, 56). The clinicopathological records of each patient were examined for prognostic factors such as age, sex, right or left side cancer, histology, tumor location (upper or lower), tumor size, cn number, preoperative serum carcinoembryonic antigen level, metastatic stations (single or multiple locations) according to Naruke s system [10], and distribution of metastatic nodes. Patient characteristics are summarized in Table 1. Results Survival Rate The postoperative prognosis for 53 patients with N2 (without T4) lung cancer is shown in Figure 2. The overall survival rate at 5 years was 41%. Incidence of Highest Mediastinal Lymph Node Involvement Highest mediastinal lymph node involvement according to the primary site is shown in Table 2. The incidence of HM involvement was unrelated to location of the tumor in the right lobe (8 of 37) versus the left lobe (6 of 16), and Table 1. Patient Profile Number Age (years), range (median, 63) Sex, male/female 38/15 Clinical node (cn) factor cn0 30 cn1 11 cn2 12 Pathologic tumor (pt) factor pt1 14 pt2 20 pt3 9 Side Right 37 Left 16 Histology Adeno carcinoma 38 Squamous cell carcinoma 13 Others 2 Highest mediastinal lymph node involvement Yes 14 No 39 Multiple 23 Single 30 Skip N2 Yes 27 No 26

3 294 SAKAO ET AL Ann Thorac Surg HIGHEST MEDIASTINAL NODAL INVOLVEMENT 2006;81:292 7 Table 3. Prognostic Factors in N2 Patients by Univariate Analysis Fig 2. The 5-year survival rate in patients diagnosed with pathologic N2 (pn2) lung cancer. the upper lobe (8 of 33) versus the lower lobe (6 of 16; p 0.31 and p 0.50, respectively). Univariate and Multivariate Analyses of Prognostic Factors A univariate analysis using the variables listed in Table 3 showed that pathologic tumor (pt) size (pt1/pt2-3), cn factor (cn1-2/cn0), N2 level (multiple/single), and metastasis to the HM lymph node were significant prognostic factors. Skip N2 exhibited a trend toward being a significant prognostic factor. In the multivariate analysis (using variables that had a p value less than 0.05 in the univariate analysis), metastasis to the HM lymph node was a significant prognostic factor (Table 4). Survival Rate According to Involvement of Highest Mediastinal Lymph Node Postoperative survival in patients with N2 according to HM lymph node involvement is shown in Figure 3. There was a significant (p 0.001) difference between the two groups; the 3-year survival rates were 52% for patients without metastasis to the highest mediastinal node, and 21% for patients with metastasis to the highest mediastinal node. Highest mediastinal involvement was a prognostic factor even in patients who had other indicators of poor prognosis identified in the univariate analysis. For example, for patients with no HM lymph node involvement, the 5-year survival rate was 33% even for those Table 2. Primary Site and Metastasis to the Highest Mediastinal Lymph Node Highest mediastinal RUL (n 21) RML (n 4) Nodal Station RLL (n 12) LUL (n 12) LLL (n 4) p Value a, 0.50 b a Right lung versus left lung. b Upper lobe versus lower lobe. LLL left lower lobe. LUL left upper lobe; RLL right lower lobe; RML right middle lobe; RUL right upper lobe. with multilevel N2, 45% in cn( ), and 47% in pt2-3 (Fig 4A, B, and C). Association Between Highest Mediastinal Lymph Node Involvement and Other Prognostic Factors A 2 analysis using the variables listed in Table 5 showed that cn factor (cn1-2/cn0), N2 level (multiple/single), and skip N2 were associated with HM lymph node metastasis (p 0.026, p , p 0.023, respectively). Comment Variables Hazard Ratio 95% CI p Value Age (years) Sex Female/male Side Left/right Histology Adenocarcinoma/others Poorly differentiated/others Location Upper/middle or lower lobes Tumor size T1/T T1 2/T Clinical node factor 0/ Carcinoembryonic antigen Multiple/single Skip N2 Nonskip/skip Station Highest mediastinal Our results indicate that HM lymph node involvement was one of the most important prognostic factors for poor Table 4. Prognostic Factors in N2 Patients by Multivariate Analysis Variables Hazard Ratio 95% CI p Value Tumor size T1/T Clinical node factor 0/ Multiple/single Station Highest mediastinal CI confidence interval.

4 Ann Thorac Surg SAKAO ET AL 2006;81:292 7 HIGHEST MEDIASTINAL NODAL INVOLVEMENT 295 Fig 3. The 5-year survival rate in patients diagnosed with N2 lung cancer depending on involvement of the highest mediastinal (HM) lymph node. acceptable postoperative outcomes (at least 30% 5-year survival rate). It is difficult to perform complete dissection of the superior mediastinal nodes through the left thoracotomy used for resection of tumor in the left lung; it is comparatively easier with a right thoracotomy. Since the favorable postoperative outcome in N2/N3 lung cancer reported by Hata and colleagues [11], we have performed a median sternotomy in patients with lung cancer in the left lobe in order to completely dissect the superior mediastinal nodes. The Japan Clinical Oncology Group reported the incidence of HM lymph node involvement outcome after surgery in patients with N2 disease. Several factors such as cn factor, N2 level, tumor size, tumor location, and skip N2 have been reported as being important postoperative prognostic factors in N2 patients [3 6, 9, 10]. However, the impact of the location of involved mediastinal nodes (stations), in particular HM node involvement, has been defined as a finding of incomplete resection [1, 2], the prognostic significance of this factor has been unclear [7]. The present study showed that cn status (cn0 versus cn1-2), involvement of multiple lymph node levels, T status (T1 versus T2-3), as well as HM nodal involvement were significant (p 0.05) prognostic factors in a univariate analysis. Tumor location was not a significant prognostic factor in this study. Furthermore, multivariate analysis confirmed that HM nodal involvement was a significant prognostic factor. In the N2 patients, the 3-year and 5-year survival rates were 35% and 0% (no patient lived beyond 40 months) in those with HM lymph node involvement, but 60% and 55% in those without HM lymph node involvement (p 0.001). The 5-year survival rate was 35% when HM lymph node was not involved, even for patients with multilevel N2. However, the 3-year survival was 20% and the 5-year survival was 0% for patients with multilevel N2 and HM lymph node involvement. Similarly, even in cn positive or T2-3 patients, the 5-year survival rate was greater than 40% when the HM lymph node was not involved. In contrast, when the HM lymph node was involved in otherwise similar patients, the prognosis was very poor (0% at 5-year survival; Fig 4A through C). Thus, HM nodal involvement was a very strong prognostic factor for poor outcome in N2 patients. Highest mediastinal lymph node involvement was also associated with cn factor (cn1-2), N2 level (multiple station metastases), and skip N2 (nonskip N2). These factors have been recognized as indicators of more advanced N2 resulting in poor outcome [3 6]. According to these results, HM lymph node involvement can be recognized as a simple and reliable finding that indicates highly advanced N2 lung cancer. Without HM involvement, even among patients with multilevel N2 nodal status, with positive cn status, or with T2-3 tumor status, surgical resection can lead to Fig 4. (A) The 5-year survival rate in patients diagnosed with N2 lung cancer depended on highest mediastinal (HM) lymph node involvement and involved station levels. (B) The 5-year survival rate in patients diagnosed with N2 lung cancer depended on HM lymph node involvement and pt status. (C) The 5-year survival rate in patients diagnosed with N2 lung cancer depended on HM lymph node involvement and CN status. (CN clinical node; meta metastasis; pt tumor pathology.)

5 296 SAKAO ET AL Ann Thorac Surg HIGHEST MEDIASTINAL NODAL INVOLVEMENT 2006;81:292 7 Table 5. Association Between Highest Mediastinal Nodal Involvement (HM) and Clinical Variables Variables HM Positive (n 14) HM Negative (n 39) p Value Age 58 / / Sex Female/male 3/11 12/ Side Left/right 6/8 10/ Histology Adenocarcinoma/others 11/3 27/ Poorly differentiated/others 6/8 12/ Location Upper/middle or lower lobes 8/6 25/ Tumor size (mm) 37 / / Clinical node factor 0/1 2 4/10 26/ Carcinoembryonic antigen (ng/ml) 1.7 / / Multiple/single 14/0 9/ Skip N2 Nonskip/skip 14/0 12/ in patients with multilevel N2. They reported that patients who received the standard ND2a dissection through the thoracotomy exhibited HM involvement in 46% of cases (52 of 113) of right lung cancer, but in only 3.8% of cases (3 of 80) of left lung cancer [4]. In the present study, there was no difference in the incidence of HM lymph node involvement comparing patients with right and left side tumors (Table 2). The difference in the incidence of HM involvement between right and left lung cancer reported in the previous study [4] supports the idea that HM node dissection cannot be performed adequately through a left thoracotomy. If the impact of HM metastasis were analyzed using data only from patients with right lung cancer, results similar to those of the present study may be demonstrated. However, we are unaware of such an analysis in the literature. In our study, the prognostic importance of HM lymph node involvement was independent of whether the primary tumor was in the left or right lung (data not shown). Hata and coworkers [13] used scintigraphy in healthy volunteers to show that the main lymphatic route from any pulmonary lobe was connected with both sides of the supraclavicular lymph nodes through the superior mediastinal nodes. The HM lymph node is the nearest mediastinal station that connects with the venous angle (supraclavicular lymph nodes), which is the entrance to the major systemic blood vessels. Furthermore, Miyamoto and associates [14] reported that 8 of 10 patients with HM lymph node involvement (cn0, 2 cases, and cn2, 8 cases) had neck (including supraclavicular) lymph node metastases; these patients exhibited very poor outcome in an analysis of patients who underwent neck and mediastinal dissection. Thus, HM lymph node involvement implies the presence of metastases to the neck lymph nodes or spreading of the tumor cells into the blood stream through the supraclavicular lymph nodes. Thus, patients with HM lymph node metastasis must be candidates for multimodal therapy due to its poor outcome after surgery, and recent diagnostic modality such as positron emission tomography may be able to detect patients with HM involvement without surgery. Limitations of this study include its being a retrospective one and the small sample size. In summary, our results suggest that metastasis to HM lymph node implies incomplete resection, and should be considered prognostic of poor outcome after surgery. Patients with such findings should be classified as having highly advanced N2 disease. The results also suggest that patients with no involvement of the HM lymph node can experience acceptable postoperative outcomes (at least 30% 5-year survival rate) even if they have multilevel N2 status, positive cn status, or pt2-3 tumor status. We thank Enjo Hata, Chief, Surgical Department of Respiratory Center, Mitsui Memorial Hospital, and Edmund J Miller, Chief, Surgical Immunology, North Shore University Hospital, for critical reviews. References 1. Mountain CF. Expanded possibilities for surgical treatment of lung cancer survival in stage IIIa disease. Chest 1990;97: Thomas L, Lawrence R, Ahmad S, for the Lung Study Group. The benefit of adjuvant treatment for resected locally advanced non-small-cell lung cancer. J Clin Oncol 1988;6: Watanabe Y, Hayashi Y, Shimizu J, Oda M, Iwa T. Mediastinal nodal involvement and prognosis of non-small cell lung cancer. Chest 1991;100: Ichinose Y, Kato H, Koike T, et al. Completely resected stage IIIA non-small cell lung cancer: the significance of primary

6 Ann Thorac Surg SAKAO ET AL 2006;81:292 7 HIGHEST MEDIASTINAL NODAL INVOLVEMENT 297 tumor location and N2 station. J Thorac Cardovasc Surg 2001;122: Inoue M, Sawabata N, Takeda S, Ohta M, Ohno Y, Maeda H. Results of surgical intervention for p-stage IIIA (N2) nonsmall cell lung cancer: acceptable prognosis predicted by complete resection in patients with single N2 disease with primary tumor in the upper lobe. J Thorac Cardiovasc Surg 2004;127: Marc R, Jalal A, Patrick B, et al. Skip mediastinal lymph node metastasis and lung cancer: a particular N2 subgroup with a better prognosis. Ann Thorac Surg 2005;79: Lacasse Y, Bucher HC, Wrong E, et al, for the Canadian Lung Oncology Group. Incomplete resection in non-small cell lung cancer: need for a new definition. Ann Thorac Surg 1998;65: Hermanek P, Sobin LH. UICC TNM classification of malignant tumors.4th ed.berlin: Splinger-Verlag, Mountain CF, Dresler CM. Regional lymph node classification for lung cancer staging. Chest 1997;111: Naruke T, Suemasu K, Ishikawa S. Lymph node mapping and curability at various levels of metastasis in resected lung cancer. J Thorac Cardovasc Surg 1978;76: Hata E, Hayakawa K, Miyamoto H, Hayashida R. Rationale for extended lymphadenectomy for lung cancer. Thorac Surg 1990;5: Kawano R, Hata E, Ikeda S, Sakaguchi H. Micrometastasis to lymph node in stage I left lung cancer patients. Ann Thorac Surg 2002;73: Hata E, Troidl H, Hasegawa T. In vivo Untersuchungen der Lymph drainage des Bronchialsystems beim Menschen mit der Lympho-Szintigraphie: Eine neue diagnostische Technik. In: Hammelmann H, Troidl H, eds. Behandlung des Bronchhialkarzinoms.Stuttgart:Thieme, Miyamoto H, Hata E, Sakao Y, Harada R, Hamada T. Evaluation of neck lymph node dissection and extended lymphadenectomy through a collar incision and median sternotomy for lung cancer. Jpn J Thorac Cardiovasc Surg 1995;16: INVITED COMMENTARY Each year 40,000 Americans present with locally advanced nonsmall cell lung cancer (NSCLC). Only a small percentage of stage IIIA and very few IIIB patients achieve long-term survival. Most research in this country concentrates on preoperative chemotherapy in stage III, whereas the contributions of pulmonary resection, mediastinal node dissection, and postoperative radiation therapy receive less attention. After the introduction of mediastinoscopy in Scandanavia in the 1950s, it became generally accepted by most American thoracic surgeons that N2 metastasis was a contraindication to primary pulmonary resection, and many publications refer to such resections as futile. However, primary pulmonary resection and mediastinal node dissection has been widely applied in many Japanese and European surgical centers continuously since the 1970s. Data from these groups indicates that patients with limited N2 benefit from pulmonary resection and mediastinal node dissection, and since there are long-term survivors even after resection of multiple, large N2 nodes, it is difficult to set exact limits on the size and number of N2 nodes that should contraindicate the primary resection. Patients with cn2 disease must be carefully selected before considering pulmonary resection and mediastinal node dissection as first line therapy. Preoperative computed tomography and positron emission tomographic scans, mediastinoscopy, and endoscopic ultrasound techniques facilitate recognition of T3-4, large or extranodal N2, multi-station N2 and N3 disease that identify questionable candidates for primary resection. Sakao and his colleagues [1] from the Juntendo University School of Medicine examine the question of whether surgical treatment plays a potentially curative role in patients with involvement of the highest mediastinal nodes (ie, those lying above a horizontal line at the upper rim of the left brachiocephalic (left innominate) vein where it ascends to the left crossing in front of the trachea at its midline. It is generally considered that metastatic involvement of these nodes indicates incomplete (R1) resection and carries a poor prognosis. The Juntendo group has adopted a technique originally described by Hata, in extending their mediastinal dissections to the apex of the right pleura and through a median sternotomy to the upper left mediastinum and lower neck in the case of left-sided lung cancers. They report on survival in a group of 53 patients (T1-3 N2) who were not treated with preoperative chemotherapy. They confirm the adverse prognostic significance of involvement of the highest nodes. There were no long-term survivors in this group, even with extended nodal dissection. However, they do make the important additional observation that absence of metastasis in these nodes is an important prognosticator. They observed substantial 5-year survival in patients with N2 disease, even when clinically enlarged, multiple nodes, in multiple nodal stations were involved, as long as the highest nodes remained uninvolved. Frederic Grannis, Jr, MD Department of General and Oncologic Surgery City of Hope National Medical Center 1500 E Duarte Rd Duarte, CA fgrannis@coh.org Reference 1. Sakao Y, Miyamoto H, Yamazaki A, et al. The prognostic significance of metastasis to the highest mediastinal lymph node in non-small cell lung cancer. Ann Thorac Surg 2006;81: by The Society of Thoracic Surgeons /06/$32.00 Published by Elsevier Inc doi: /j.athoracsur