The Significance of One-Station N2 Disease in the Prognosis of Patients With Nonsmall-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 non-member subscription to the journal. The Significance of One-Station N2 Disease in the Prognosis of Patients With Nonsmall-Cell Lung Cancer Panagiotis Misthos, MD, PhD, Evangelos Sepsas, MD, PhD, John Kokotsakis, MD, Ion Skottis, MD, and Achilleas Lioulias, MD, PhD Thoracic Surgery Department, Sismanogleio General Hospital, and Thoracic Surgery Department, General Hospital for Chest Diseases Sotiria, Athens, Greece Background. A retrospective study was conducted to define the characteristics and the prognosis of N2 disease subgroups according to their patterns of spread. Methods. From January 1993 to December 2004, 1,329 patients underwent lung resection for bronchogenic carcinoma The records of all patients with positive mediastinal lymph nodes at the surgical specimen (piiia/n2) after radical resection were analyzed, and the pattern of mediastinal lymphatic spread was classified according to regional spread, to skip metastasis, and to one or two or more lymph node stations, in relation to primary tumor location. Age, sex, type of resection, right or left lesion, T status, primary tumor location, tumor size, tumor central or peripheral location, histology, and survival were recorded and analyzed. Survival was analyzed according to regional spread or not, number of mediastinal lymph node stations involved, and skip metastasis status. Results. Among 302 cases (22.7%) with positive mediastinal lymph nodes piiia/n2, 66 (22%) were skip metastases, 72 (24%) had a nonregional mode of spread, and 199 (66%) included two or more stations of mediastinal lymph node invasion. Cox regression analysis of all cases disclosed malignant invasion in only one mediastinal lymph node station as the only favorable factor of survival (p < 0.001, odds ratio 0.57, 95% confidence interval: 0.42 to 0.78). Conclusions. The presence of one-station mediastinal lymph node metastasis in patients with nonsmall-cell lung cancer who underwent major lung resection with complete mediastinal lymph node dissection proved to be a good prognostic factor that should be taken into account in the future. (Ann Thorac Surg 2008;86:1626 31) 2008 by The Society of Thoracic Surgeons The presence or absence of lymph node metastasis is the single most important factor for estimating the possibility of disease recurrence and prognosis in surgical treatment of nonsmall-cell lung cancer (NSCLC). The typical pattern of the lung s lymphatic drainage suggests a linear model of dissemination malignancy initiating from the tumor, spreading to intrapleural lymph nodes and then to hilar ones (N1). The next station is the ipsilateral mediastinal lymph nodes in a downstream manner, namely, from the closer nodes to the hilum to the most distant [1]. In extremis, the contralateral mediastinal and the extrathoracic lymph nodes are involved (N3). However, great variability exists concerning the patterns of lymphatic drainage from bronchopulmonary segments to mediastinal lymph nodes. The patterns of spread include nonregional or skip metastasis as well as Accepted for publication July 28, 2008. Address correspondence to Dr Misthos, 16-18A Markou Avgeri St, 15343 Agia Paraskevi, Athens, Greece; e-mail: panmisthos@yahoo.gr. involvement of one, two, or more mediastinal lymph node stations. Although several studies have been published during the last few years [2 6], the exact incidence, the clinical significance, and the oncologic interpretation of the different ways of lymphatic spread to the mediastinum remain to be clarified. The authors conducted a retrospective study on a fairly large population to determine the impact on survival of the pattern of NSCLC spread to the mediastinal lymph nodes among patients who underwent major lung resection. Material and Methods From January 1993 to December 2004, 1,329 patients underwent lung resection for bronchogenic carcinoma pathologically staged as pi IIIA. The Scientific and Ethics Committee of Sismanogleio General Hospital has approved the conduction of the study. Individual consent for the study was waived. This group included 1,077 men (81%) and 252 women 2008 by The Society of Thoracic Surgeons 0003-4975/08/$34.00 Published by Elsevier Inc doi:10.1016/j.athoracsur.2008.07.076

Ann Thorac Surg MISTHOS ET AL 2008;86:1626 31 MEDIASTINAL LYMPHATIC SPREAD OF LUNG CANCER 1627 (19%), aged 44 tp 78 years (median, 62). The types of resection included 372 pneumonectomies (27.9%), 219 right (59%) and 153 left (41%), and 957 lobectomies (72.1%). The patients were staged preoperatively by different means of chest imaging (radiography, computed tomography, magnetic resonance imaging) and invasive procedures (medistinoscopy, anterior mediastinotomy, and so forth). Positron emission tomography scan was not available. The findings of pathologic staging consisted of 90 cases (6.7%) with pia/b, 213 (16%) with piia, 699 (52.7%) with piib, and 327 (24.6%) with piiia. All piiia/n2 cases were due to unsuspected N2 disease. Thus, no patient had induction therapy. All patients with N2 disease received platinum-based adjuvant therapy. The records of all patients with NSCLC with positive mediastinal lymph nodes at the surgical specimen (piiia/n2) after radical resection were analyzed. Complete resection was defined as removal of the primary tumor and all accessible hilar and mediastinal lymph nodes, with no residual tumor left behind (resection of all macroscopic tumor and resection margins free of tumor Table 1. Demographic Data and Oncologic Characteristics Number of patients 302 Age (median), years 62 Sex Male 240 (79%) Female 62 (21%) Type of resection Pneumonectomies 98 (32.5%) Lobectomies 204 (67.5%) Side Right 184 (61%) Left 118 (39%) T status T1 8 (2.5%) T2 180 (60%) T3 114 (37.5%) Primary tumor location Right upper 103 (34%) Right middle 22 (7.4%) Right lower 59 (19.5%) Left upper 80 (26.5%) Left lower 38 (12.6%) Tumor size 1cm 0 1 to 2 cm 2 (0.5%) 2 to 3 cm 6 (2%) 3 to 4 cm 146 (48.5%) 4 cm 148 (49%) Tumor Central 98 (32.5%) Peripheral 204 (67.5%) Histology Adenocarcinoma 142 (47%) Squamous carcinoma 144 (47.7%) Other 16 (5.3%) Table 2. Lymph Node Involvement According to Primary Tumor Location Upper Lower Upper and Lower Right upper, n 103 83 (80.6%) 7 (6.8%) 13 (12.6%) Right middle, n 22 8 (36%) 9 (41%) 5 (23%) Right lower, n 59 17 (29%) 29 (49%) 13 (22%) Left upper, n 80 62 (78%) 3 (4%) 15 (18%) Left lower, n 38 8 (21%) 20 (53%) 10 (26%) at microscopic analysis). All patients underwent standard resections (lobectomy, bilobectomy, or pneumonectomy). Patients who underwent minor resections were excluded from the study. A complete mediastinal lymphadenectomy was routinely performed. The following lymph nodes compartments were routinely dissected: superior mediastinal and paratracheal on the right side; aortopulmonary window and preaortic on the left side, subcarinal and lower mediastinal on both sides. Left paratracheal nodes were not routinely included in the dissection. Only palpable lymph nodes in this region were surgically removed when encountered. Age, sex, type of resection, right or left lesion, T status, primary tumor location, tumor size, tumor central or peripheral location, histology, and survival were recorded and analyzed. Mediastinal lymph node involvement was classified as upper or lower level and was grouped according to primary tumor location. All patients were postsurgically staged according to the 1997 TNM classification [7]. Lymph node levels were classified according to the American Thoracic Society system [8]. Hence, upper mediastinal lymph nodes were 1, 2, 3, 4, 5, and 6; and lower mediastinal lymph nodes were 7, 8, and 9. Furthermore, the pattern of mediastinal lymphatic spread was classified according to regional spread, to skip metastasis, and to one, two, or more lymph node stations, in relation to primary tumor location. Several studies [5, 6, 9, 10] have showed that the location of the primary tumor corresponds to the mediastinal areas where lymph nodes are likely to be diseased. The corresponding areas were the upper mediastinum for right upper lobe lesions, lower mediastinum for right lower lobe lesions, and subaortic component Table 3. Mode of Spread in Mediastinal Lymph Nodes Skip Nonregional One Station Total 66 (22%) 72 (24%) 103 (34%) Right 54 (29%) 45 (25%) 51 (28%) Left 12 (10%) 27 (23%) 52 (44%) Right upper 33 (32%) 22 (21%) 30 (29%) Right middle 3 (14%) 4 (18%) 5 (23%) Right lower 18 (31%) 19 (32%) 16 (27%) Left upper 3 (4%) 19 (24%) 35 (44%) Left lower 9 (24%) 8 (21%) 17 (45%)

1628 MISTHOS ET AL Ann Thorac Surg MEDIASTINAL LYMPHATIC SPREAD OF LUNG CANCER 2008;86:1626 31 Table 4. Three-Year Survival Rates According to Mode of Spread in Mediastinal Lymph Nodes Ordinary Skip Regional Nonregional One Station Two Stations Total 82 (27.15%) 57 (24%) 25 (38%) 69 (30%) 13 (18%) 44 (43%) 38 (19%) Right 45 (24.4%) 24 (18.5%) 21 (39%) 39 (28%) 6 (13.3%) 20 (39%) 25 (19%) Left 37 (31.3%) 33 (31%) 4 (33.3%) 30 (33%) 7 (26%) 24 (46%) 13 (20%) Right upper, n 103 23 (22.3%) 9 (13%) 14 (42.5%) 22 (27%) 1 (5%) 14 (47%) 9 (12%) Right middle, n 22 9 (41%) 8 (42%) 1 (33%) 8 (38%) 1 (100%) 2 (40%) 7 (41%) Right lower, n 59 13 (22%) 7 (17%) 6 (33%) 9 (24%) 4 (18%) 4 (25%) 9 (21%) Left upper, n 80 22 (27.5%) 21 (27.2%) 1 (33%) 21 (30%) 1 (10%) 16 (46%) 6 (13%) Left lower, n 38 15 (39%) 12 (41%) 3 (33%) 9 (43%) 6 (35%) 8 (47%) 7 (30%) (levels 4 through 6) and lower mediastinum for left lower lobe lesions. If a tumor was located in more than one lobe, the main location of where the tumor appeared to start (where it was predominantly located) was considered its lobe of origin. In this way, every tumor was assigned as originating from only one lobe. Therefore, regional spread was defined for upper lobe tumors as invasion to levels 1 through 6, and for lower lobe tumors to levels 7 through 9. Skip metastasis was defined as the presence of mediastinal lymph node metastasis without intralobar, scissural, or hilar lymph node involvement (N2 without N1). Survival analysis referred to the 3-year survival rate, because the study has not matured for 5-year survival estimation. Survival was studied according to right or left lesion and primary tumor location. Moreover, survival was analyzed according to regional spread or not, number of mediastinal lymph node stations involved, and skip metastasis status. Frequencies were compared with the 2 test for categorical variables; Fisher s exact test was used for small samples. Survival was calculated by the Kaplan-Meier method; it included all cancer-related deaths and excluded all postoperative ones. The deaths for causes other than the tumor and postoperative deaths were considered as withdrawals, the date of death representing the endpoint of follow-up. Multivariate Cox regression was used to test the relationship of survival to mode of spread to the mediastinal lymph nodes. Age, sex, type of resection, right or left lesion, histology, nonregional spread, skip metastasis, and spread to two or more lymph node stations were matched in a multivariate analysis. A p value less than 0.05 was treated as significant. Results Patients at stage piiia/n2 were the target group to be studied. This group consisted of 302 patients (22.7%). The demographic and clinicopathologic characteristics of this group are fully described in Table 1. The incidence of mediastinal lymph node involvement according to primary tumor location was studied (Table 2). In 59% of the cases, the upper mediastinal lymph nodes were invaded, 22.5% of the lower ones and 18.5% of both the upper and lower lymph node stations. Positive lymph nodes belonged to the upper mediastinal group when the primary tumor was located at right or left upper lobes, whereas tumors of right middle, right lower, and left lower lobe metastasize more often to the lower one. Apart from the right upper lobe (12.6%), all other lobar locations of the primary tumor disclosed almost the same tendency (18% to 26%) to mestasize to both upper and lower mediastinal lymph nodes. Among 302 cases with positive mediastinal lymph nodes, 66 were skip metastases (22%), 72 had a nonregional mode of spread (24%), and 199 (66%) cases included two or more stations of mediastinal lymph node invasion (Table 3). Skip metastases were more frequently found in tumors of the right upper lobe. Nonregional mode of spread was more Table 5. Cox Regression Analysis Results p Value Odds Ratio 95% CI Sex (male, female) 0.07 0.62 0.38 1.03 Peripheral/central location 0.35 2.81 0.31 25.32 Side (right, left) 0.44 2.14 0.28 16.33 Histology (adenocarcinoma, 0.73 0.81 0.14 3.92 squamous) Type of resection (lobectomy/ 0.62 0.55 0.04 6.27 pneumonectomy) Regional/nonregional 0.583 0.91 0.68 1.24 Skip/ordianry 0.081 1.35 0.96 1.90 One station/multiple stations 0.000 0.57 0.42 0.78 CI confidence interval.

Ann Thorac Surg MISTHOS ET AL 2008;86:1626 31 MEDIASTINAL LYMPHATIC SPREAD OF LUNG CANCER 1629 common among the tumors of the left lower lobe. Tumors of the right middle and lower lobe metastasize more easily to more than two mediastinal lymph node stations. Onestation involvement cases included 16 cases of skip metastasis (15.5%) and 21 cases of nonregional spread (20%). Univariate analysis of 3-year survival rates (Table 4) disclosed better survival after skip metastasis (p 0.027), regional lymph node spread (p 0.047), and one-station invasion (p 0.001) (Fig 1). Skip metastasis and regional lymph node spread had improved survival rates for patients with right-sided tumors (p 0.003 and p 0.046, respectively). The number of stations of mediastinal lymph node metastasis seemed to influence survival of both right- and left-sided tumors (p 0.004 and p 0.002, respectively). Lobe-specific survival analysis revealed that skip metastasis, regional lymph node invasion, and one-station metastasis were statistically significant favorable factors for survival only for right upper lobe tumors (p 0.001, p 0.024, p 0.001, respectively). Cox regression analysis (Table 5) of all cases disclosed malignant invasion in only one mediastinal lymph node station as the only independent favorable factor of survival (p 0.001, odds ratio 0.57, 95% confidence interval: 0.42 to 0.78). Comment One should not take for granted that cancer lymphatic spread follows a linear model from intraparenchymal nodes to hilar, mediastinal, and extrathoracic ones. The lymphatic network draining the lung is extensive and variability is probably the rule. Riquet and colleagues [11] have reported direct lymph passages from each lobe to the mediastinum. More commonly, these communications were observed in the upper lobes. This provides multiple pathways for dissemination, creating a complicated model to be used for clinical assessment. It is wise not to underestimate the genetic profile of the primary tumor, which might keep a central role to the mode of tumor s lymphatic spread [12]. Surgical resection remains the cornerstone of management for NSCLC. Among other factors, the prognosis of these patients depends on metastasis to the lymph nodes, especially the ipsilateral (N2) or contralateral (N3) mediastinal lymph nodes [13 15]. Nonsmall-cell lung cancer with N2 lymph nodes positive for metastases (approximately 20% to 40% of all patients with NSCLC) shows extremely low survival rates. Preoperative staging detecting positive N2 lymph nodes renders surgical resection not useful, and these patients should be given neoadjuvant therapy and reconsidered for surgical treatment [16, 17]. Most clinicians dealing with thoracic oncology agree that patients who have NSCLC with ipsilateral mediastinal lymph node (N2) involvement are a heterogeneous group [18 21]. This heterogeneity involves factors such as preoperative detection, susceptibility to neoadjuvant treatment, clinically unsuspected N2 disease, and level/site and number, or both, of involved mediastinal lymph nodes [1, 22, 23]. Therefore, stage IIIA/N2 is characterized by several subgroups with variable survival rates. For example level 5, 6 N2 nodes have better prognosis, cn2 worse than respective unsuspected pn2, single versus multiple N2 stations, the number of involved lymph nodes, the extracapsular spread, the presence of subcarinal node metastasis, skip metastasis, and so forth [24, 25]. Each of these subclassifications should be considered as a completely different subpopulation of positive mediastinal lymph nodes, and highly selected patients with N2 disease achieve better 5-year results in this group [13 15]. The patterns of mediastinal lymph node metastasis reported in other reports are relatively similar to our results [2 4, 6, 26]. In our study, skip metastasis, regional spread, and one-station metastasis to mediastinal lymph nodes disclosed a clear advantage in survival rates. However, multivariate analysis established mediastinal lymph node spread at one station as the only independent favorable prognostic factor. One station favorable results are in agreement with previous reports [27 32]. Although skip metastasis and regional spread are considered significantly favorable factors in the current literature, our study reliably proves that only one-station metastasis has a positive impact on 3-year survival and nothing else. The latter challenges the results of previous studies. One-station involvement cases did not include more cases of skip metastasis (15.5%) or cases of nonregional spread (20%) in comparison to overall incidence of these favorable factors. Thus, this particular pattern of mediastinal spread may be considered as a condition with the lower possibility for systematic extension of the malignancy. One-station metastasis should be evaluated as a solitary intrathoracic metastasis with good prognosis if it is removed along with the primary tumor. Extraregional spread was significant as in other studies [33]. Therefore, we challenge the recommendation of a more targeted approach based on, at least partly, the Fig 1. Kaplan-Meier plots and life tables of regional (squares), skip (diamonds), and one-station (triangles) mode of spread (3-year survival).

1630 MISTHOS ET AL Ann Thorac Surg MEDIASTINAL LYMPHATIC SPREAD OF LUNG CANCER 2008;86:1626 31 lobar location of the primary tumor or with sentinel node. Complete nodal dissection or meticulous sampling of all stations in the mediastinal stations is imperative, even though for tumors small in size. Limitations of the present study include the retrospective nature of the analysis and that the total number of nodes removed at the time of surgery is not available. Further prospective studies should be conducted using immunohistochemical node examination to detect micrometastases and to define the exact incidence of one-station N2 disease. Finally, in a future revision of the current TNM system, N2 disease should be classified into more subgroups. 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