Only about 16% of the approximately 200,000 persons

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1 GENERAL THORACIC Nonexamination of Lymph Nodes and Survival After Resection of Non-Small Cell Lung Cancer Raymond U. Osarogiagbon, MBBS, and Xinhua Yu, MD, PhD Multidisciplinary Thoracic Oncology Program, Baptist Cancer Center, and Division of Epidemiology and Biostatistics, School of Public Health, University of Memphis, Memphis, Tennessee Background. Nonexamination of lymph nodes is an extreme example of the variability of pathologic nodal staging of non-small cell lung cancer. We compared the prevalence, characteristics, and survival of patients without lymph nodes (pnx) to patients with documented pathologic N0 and pathologic N1 non-small cell lung cancer. Methods. A retrospective analysis was done of nonsmall cell lung cancer resections in the US Surveillance, Epidemiology, and End Results database from 1998 to Results. Thirteen percent of all resections (18% of node negative resections) were pnx, including 6% of all nodenegative lobar or greater resections and 51% of sublobar resections. Thirty-five percent of pnx resections were lobar or greater compared with 90% of pathologic N0 (p < ). Advanced age and surgery in rural locations were also significantly associated with pnx resection. The Only about 16% of the approximately 200,000 persons diagnosed annually in the United States with nonsmall cell lung cancer (NSCLC) survive beyond 5 years [1]. Most long-term survivors are recipients of curative-intent surgery. For patients undergoing surgery, the number and anatomic location of lymph nodes with metastasis profoundly influence the odds of long-term survival [2 7]. But long-term survival outcomes are highly variable after curative-intent lung resection, even in patients with ostensibly similar stage of disease [8 10]. Thatispartlydueto variability in the quality of lymph node examination [10]. Patients with lymph node metastasis benefit frompost- operative adjuvant therapy [11, 12]. In theory, missed lymph node metastasis can impair survival because of misclassification of risk, and in the modern era, failure to provide effective postoperative adjuvant therapy. To examine the impact of variability, we examined patients at one extreme of the quality spectrum: those in whom no lymph nodes were examined after lung cancer resection (pathology [p] NX). These patients are usually treated as though they were known to be free of lymph node metastasis. However, a cohort without pathologic nodal staging might include a sufficient number of patients with undiagnosed lymph node metastasis to median duration of survival was 3 years in the pnx cohort, 6.4 years in the N0 cohort (p < ), and 2.8 years in the N1 group, with respective 5-year survival rates of 47%, 67%, and 45% (p < ). These survival differences remained after adjustment for potentially confounding factors. Conclusions. Patients with pnx resections are a highrisk subset, with survival approximating pathologic N1, not N0. They should have further attempts at retrieving lymph nodes for examination or be offered postoperative adjuvant chemotherapy. We predict that treatment modalities that fail to address lymph nodes are likely to yield inferior survival in comparison to surgery with proper lymph node examination. The proportion of pnx lung resections may be a sentinel quality indicator for lung cancer programs. (Ann Thorac Surg 2013;96: ) Ó 2013 by The Society of Thoracic Surgeons significantly impair the long-term survival of the whole group. Our prior test of this hypothesis in a citywide database suggested that pnx patients may be at inordinately high risk for early death, when compared with matched node-negative patients with examination of at least one lymph node (pn0) [13]. In this study, we examined the prevalence of pnx resections in a representative national sample, identified factors associated with pnx resections, and attempted to quantify the pnx survival deficit by comparison to patients with pn0 and hilar/intrapulmonary nodal metastasis (pn1). Patients and Methods With the permission of the University of Tennessee Institutional Review Board, we conducted a retrospective analysis of the US Surveillance, Epidemiology, and End Results (SEER) database of lung cancer resections over 12 years, from 1998 to 2009, with survival updated to December 31, The characteristics of the SEER database have been well described [14]. Briefly, SEER is a population-based dataset constructed to be representative Accepted for publication May 10, Address correspondence to Dr Osarogiagbon, Multidisciplinary Thoracic Oncology Program, Baptist Cancer Center, 6027 Walnut Grove Rd, Ste 201, Memphis, TN 38120; rosarogi@bmg.md. Dr Osarogiagbon has a patent application under consideration for a surgical lymph node specimen collection kit. Ó 2013 by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc

2 Ann Thorac Surg OSAROGIAGBON AND YU 2013;96: LYMPH NODE NONEXAMINATION AND SURVIVAL of the US population. It includes detailed sociodemographic, disease, treatment, and survival information reported in a standardized format. Mortality information is abstracted from death certificates, thereby providing the opportunity to analyze cause-specific mortality. Over the time span included in our study, SEER included as many as 28% of the US population Patient Selection Criteria Patients who had a first primary lung cancer treated from 1998 to 2009 were eligible for this study. We excluded patients with bronchioloalveolar carcinoma, carcinoid tumors, and small cell lung cancer (because lymph node status has less impact on survival in these cases), patients who did not undergo surgical resection, and patients GENERAL THORACIC Fig 1. Cohort selection. (NSCLC ¼ non-small cell lung cancer.)

3 GENERAL THORACIC 1180 OSAROGIAGBON AND YU Ann Thorac Surg LYMPH NODE NONEXAMINATION AND SURVIVAL 2013;96: without pathologic confirmation of disease (Fig 1). We also excluded patients with stage IV disease or unknown stage, with unknown number of examined lymph nodes, and with mediastinal lymph node metastasis. To limit potential bias, we eliminated patients who received preoperative radiation therapy and patients who died within 30 days of surgery. We could not account for the impact of chemotherapy because SEER does not provide this information. All remaining patients were separated into a cohort with no lymph node metastasis after examination of one or more nodes (pn0), a cohort with hilar/intrapulmonary lymph node metastasis (pn1), and a cohort with no lymph nodes examined (pnx). The pn0 cohort was the primary comparison group for the pnx cohort because of the prevailing clinical tendency to treat them alike. We used the pn1 group to put the survival experience of the pnx cohort into a defined context. Statistical Analysis For descriptive analyses, we used the c 2 test to examine the difference between categorical variables, and the t test and trend test for continuous variables. We used the Kaplan-Meier method to construct unadjusted survival curves for visualization, and the log rank test to compare unadjusted survival curves. The Cox proportional hazards model was used to determine the effect of lymph node examination on overall survival, adjusted for patient sociodemographic factors, tumor characteristics, and clinical treatment. We used the Fine and Gray competing risk model to examine lung cancer specific survival [15]. We conducted additional analyses in which we excluded recipients of sublobar resection, because the need for limited resection may have been driven by significant comorbidities, which independently connote a higher mortality risk. For similar reasons, we also tested the impact of excluding recipients of postoperative radiation therapy. During the period 1998 to 2004, SEER did not explicitly report details of tumor, node, and metastasis (TNM) stage except for summary stage information (I to IV). Therefore, we reconstructed the TNM stage based on the sixth edition of the American Joint Committee on Cancer staging guidelines by using the descriptors tumor extension, lymph node involvement, tumor size, and metastasis from information in the guidelines specified in the SEER documents. For comparison, we applied the same algorithm to the cases after 2004 and found that our method yielded almost identical TNM stages to that reported in the SEER database. Finally, we matched pnx cases with pn0 controls based on propensity score (defined as the probability of having pnx, adjusted for race, age, sex, and clinical factors). The determination of rural areas was based on county urbanity as defined by the US Census Bureau. days. Of these patients, 12,768 (29%) had node-positive disease (pn1, N2, or N3), and 32,032 (71%) had nodenegative disease. In the node-positive group, 7,008 patients (55%) had pn1; in the node-negative group, 26,300 (82%) were pn0 and 5,732 (18%) were pnx (Fig 1). The pnx population represented 13% of the whole surgical resection cohort. The distribution of the number of lymph nodes examined in the node-negative population is shown in Figure 2. Factors Associated With pnx Resections Key patient demographic, tumor and treatment characteristics of the pn0 and pnx cohorts are compared in Table 1. The pnx cohort was older (median age 71 versus 68 years, p < 0.001) and had significantly less extensive lung resections than the pn0 cohort (p < 0.001). The difference in sublobar resection rate was particularly striking: 54% of pnx patients had a sublobar resection compared with only 10% of the pn0 cohort; however, 35% of the pnx cohort had a lobar or greater resection. There was significant heterogeneity in the pnx rate between the 18 SEER registries contributing to the dataset, ranging from 8% of eligible resections in Utah to 24% of eligible resections in rural Georgia (Table 2). The pnx rate was 17.1% for resections performed in rural areas compared with 14.2% in metropolitan areas (p < 0.001). For example, the pnx rate was 24.4% in rural Georgia compared with 12.2% in Metropolitan Atlanta. Information on preoperative lymph node examination is available only for the 1998 to 2002 subpopulation in the SEER database. Of 13,405 patients eligible during this 5-year time span, only 650 (5%) had lymph nodes examined before surgery, of which 464 (71%) were pn0, 178 (27%) were pn1, and 8 (2%) were pnx. Impact on Survival The median overall survival of the pnx cohort was 3 years (interquartile range, 1.3 to 7.7), compared with 6.4 years (interquartile range, 2.4 to not reached) for the pn0 cohort (p < 0.001), and 2.8 years (interquartile range, Results Prevalence of pnx Resections From 1998 to 2009, 408,215 patients in the SEER database were treated for a first primary lung cancer, of whom 44,800 had pathologically confirmed NSCLC after primary surgical resection and survived past 30 postoperative Fig 2. Distribution of the number of lymph nodes examined in patients with pathologic node-negative non-small cell lung cancer: US Surveillance, Epidemiology, and End Results database 1998 to 2009.

4 Ann Thorac Surg OSAROGIAGBON AND YU 2013;96: LYMPH NODE NONEXAMINATION AND SURVIVAL Table 1. Characteristics of Patients With Resected pn0, pn1, and pnx Non-Small Cell Lung Cancer in the US Surveillance, Epidemiology, and End Results Database: 1998 to 2009 Characteristics pn0 pn1 pnx n ¼ 26,300 (67%) a n ¼ 7,008 (18%) a n ¼ 5,732 (15%) a 1181 p Value b GENERAL THORACIC Demographic characteristics Age, years, mean (SD) 67 (10) 65 (10) 69 (10) <0.001 <50 1,480 (6) 513 (7) 247 (4) < ,619 (33) 2,559 (37) 1,515 (26) ,809 (37) 2,514 (36) 2,070 (36) >74 6,392 (24) 1,422 (20) 1,900 (33) Sex Male 13,743 (52) 4,029 (57) 2,983 (52) <0.001 Female 12,557 (48) 2,979 (43) 2,749 (48) Race White 23,543 (86) 5,937 (85) 4,944 (86) <0.001 Black 2,205 (8) 603 (9) 516 (9) Other 1,552 (6) 468 (7) 272 (5) Marital status Married 15,347 (58) 4,289 (61) 3,019 (53) <0.001 Living alone 10,953 (42) 2,719 (39) 2,713 (47) Metropolitan status No 3,812 (15) 1,173 (17) 1,208 (18) <0.001 Yes 22,488 (85) 5,835 (83) 4,704 (82) Tumor characteristics Histology Adenocarcinoma 13,046 (50) 3,342 (48) 2,634 (46) <0.001 Squamous 8,570 (33) 2,488 (36) 1,673 (30) Large cell 1,388 (5) 366 (5) 294 (5) Other 3,296 (12) 812 (11) 1,131 (18) Grade 1 2,469 (9) 263 (4) 470 (8) < ,645 (40) 2,548 (36) 1,889 (34) 3 10,635 (40) 3,444 (49) 1,996 (35) (4) 295 (4) 200 (4) Unknown 1,566 (6) 458 (6) 1,177 (21) Size <3 20,676 (79) 4,643 (66) 4,356 (76) < ,358 (13) 1,232 (18) 584 (11) >5 2,058 (8) 1,014 (14) 249 (4) Unknown 208 (1) 119 (2) 543 (9) Location Upper 16,279 (62) 3, 987 (54) 3,222 (57) <0.001 Middle 1,253 (5) 314 (5) 324 (6) Lower 7,886 (30) 2,350 (34) 1,726 (31) Unknown 882 (3) 546 (8) 460 (7) T category 1 15,800 (60) 2,973 (42) 2,853 (50) < ,724 (29) 2,678 (38) 1,504 (26) 3 1,513 (6) 607 (9) 332 (6) 4 1,211 (5) 699 (10) 563 (10) Unknown 52 (0) 51 (1) 480 (8) Treatment characteristics Extent of resection Lobectomy 22,089 (84) 5,146 (73) 1,838 (32) <0.001 (Continued)

5 GENERAL THORACIC 1182 OSAROGIAGBON AND YU Ann Thorac Surg LYMPH NODE NONEXAMINATION AND SURVIVAL 2013;96: Table 1. Continued Characteristics pn0 pn1 pnx n ¼ 26,300 (67%) a n ¼ 7,008 (18%) a n ¼ 5,732 (15%) a p Value b Pneumonectomy 1,438 (5) 1,425 (20) 195 (3) Sublobar 2,647 (10) 357 (5) 3,109 (54) Other 126 (0) 80 (1) 590 (10) Postoperative adjuvant radiation No 24,228 (92) 5,117 (73) 4,665 (81) <0.001 Yes 2,072 (8) 1,891 (27) 1,067 (19) a Row percentage. b Statistical comparison of all three groups. All numbers in parentheses are column percentages unless otherwise indicated. 1.3 to 7.7, p < 0.001) for the pn1 cohort. The respective 5-year overall survival rates were 47% for pnx, 45% for pn1, and 67% for pn0 (Fig 3A). This striking difference in survival was consistent across all T categories (Fig 4). Separation of the pn0 cohort into patients with examination of the recommended six or more lymph nodes and patients with only one to five lymph nodes examined reveals that the median overall survival of the pn0 subcohort with six or more lymph nodes was 7.4 years, compared with 6.0 years for patients with one to five nodes (p < 0.001; Fig 5). The lung cancer specific survival plots show similar patterns to overall survival plots (Fig 3B, Fig 6). However, the non-lung cancer specific survival rate, while similar between pn0 and pn1 cohorts, was significantly worse in the pnx cohort (Fig 3C). Therefore, we performed the survival analysis after excluding all patients who had sublobar resection. In the group of patients with lobectomy or greater resection, the overall and lung cancer specific survival of patients with pnx approximated closely to that of patients with pn1, and there was no difference in non-lung cancer survival (Fig 7). In the multivariate analysis including age, race, sex, histology, tumor size, tumor grade, T category, tumor location, and use of radiation as potential confounders, pnx status was associated with a 36% higher risk of allcause mortality in comparison to pn0 (hazard ratio 1.36, 95% confidence interval: 1.30 to 1.43, p < 0.001). Even after excluding all patients with sublobar resection (to eliminate potential bias from excess mortality of patients who are candidates only for limited lung resections), the hazard ratio was 1.37 (95% confidence interval: 1.28 to 1.46, p < 0.001). The results for lung cancer specific mortality were very similar to those of overall survival (Table 3). Table 2. Geographic Variation of pnx rate by Surveillance, Epidemiology, and End Results Registry pn0 pn1 pnx SEER Registry n % n % n % Total Utah San Jose-Monterey Hawaii Metropolitan Detroit 2, ,862 Metropolitan Atlanta ,219 Greater Georgia a 2, ,416 Connecticut 1, ,534 Los Angeles 2, ,076 Seattle (Puget Sound) 1, ,598 Louisiana 1, ,903 Iowa 1, ,985 San Francisco-Oakland 1, ,797 Greater California b 5, , , ,459 New Jersey 2, ,664 Alaska Kentucky 2, ,656 New Mexico Rural Georgia Total 26, , , ,040 a Excluding Atlanta. b Excluding San Francisco, Los Angeles, San Jose-Monterey. Rural areas are defined by Census Bureau based on county urbanity.

6 Ann Thorac Surg OSAROGIAGBON AND YU 2013;96: LYMPH NODE NONEXAMINATION AND SURVIVAL 1183 Fig 3. Unadjusted survival in all eligible patients: (A) overall; (B) lung cancer specific; (C) non-lung cancer specific. (Green lines ¼ pnx; blue lines ¼ pn0; red lines ¼ pn1.) GENERAL THORACIC

7 GENERAL THORACIC 1184 OSAROGIAGBON AND YU Ann Thorac Surg LYMPH NODE NONEXAMINATION AND SURVIVAL 2013;96: Fig 4. T-category adjusted survival, all eligible patients. (A) Overall survival, T ¼ 1; (B) overall survival, T ¼ 2; (C) overall survival, T ¼ 3; (D) overall survival, T ¼ 4; (E) overall survival, T ¼ unknown. (Green lines ¼ pnx; blue lines ¼ pn0; red lines ¼ pn1.) The additional analysis in which pnx cases were matched with pn0 cases based on propensity score yielded almost identical results to the Cox proportional hazards model. For example, in the propensity score stratified analysis for all-cause mortality, the hazard ratio for the pnx population in comparison to the pn0 cohort was 1.36 (95% confidence interval: 1.29 to 1.42, p < 0.001), which is almost identical to the Cox model. Fig 5. Survival of node-negative cohorts based on number of lymph nodes (LN) examined, in comparison to pathologic N1 cohort. (pnx ¼ no lymph nodes examined [blue line]; LN 1 5 ¼ pn0 with 1 to 5 lymph nodes [red line]; LN6 ¼ pn0 with 6 or more lymph nodes [green line]; pn1 ¼ hilar or intrapulmonary lymph node metastasis [yellow line].)

8 Ann Thorac Surg OSAROGIAGBON AND YU 2013;96: LYMPH NODE NONEXAMINATION AND SURVIVAL 1185 GENERAL THORACIC Fig 6. T-category adjusted lung cancer specific survival (LCSS), all eligible patients: (A) LCSS, T ¼ 1; (B) LCSS, T ¼ 2; (C) LCSS, T ¼ 3; (D) LCSS, T ¼ 4; (E) LCSS, T ¼ unknown. (Green lines ¼ pnx; blue lines ¼ pn0; red lines ¼ pn1.) Comment As with our examination of the Memphis Metropolitan Area quality of surgical resection cohort [13], we found that 13% of resections for NSCLC and 18% of all resections for node-negative NSCLC in the SEER database had no lymph nodes examined. The present report validates our prior report in a much larger, nationally representative sample that allowed for multiple adjustments for the influence of potential confounders, including T category, extent of resection, and geographic region. This report indicates the national span of the suboptimal lymph node examination problem. On the surface, this pathologic NX phenomenon, seems to be at the extreme end of the surgical lymph node staging quality spectrum. The slightly older age and predominance of sublobar resection in the pnx cohort suggest a difference in the physiologic state of patients within the two cohorts, such as a difference in residual lung function or cardiac comorbidity [16, 17]. It is also possible that some of these patients did not undergo a curative-intent procedure, but rather, had an open biopsy. However, 35% of patients in the pnx cohort were deemed healthy enough to undergo a lobectomy or greater resection. In these patients, nonexamination of lymph nodes may be a sign of systemic failure in the provision of care. For example, a judicious decision to avoid operative complications in patients too frail for mediastinal lymph node sampling will not explain the concurrent failure of thorough pathology examination of the resected lung specimen. The negative impact of nonexamination of lymph nodes is evident in patients with lobar or greater resections. Because non-lung cancer survival is similar between these patients and patients with pn0 and pn1 (Fig 7C), a higher rate of competing causes of mortality will not explain the difference in overall and lung cancer specific survival. These resections cannot be said to have been noncurative in intent, as may be said of the wedge resections. The close approximation between the pnx and pn1 survival curves (Fig 7A, 7B), and the differences between pn0 subsets with and without six or more lymph nodes (Fig 5), suggests that the most plausible etiology of the survival disparity between the pnx and pn0 cohorts is the presence of missed lymph node metastasis in a significant proportion of the pnx patients. In the modern era, it is likely that such patients would be deprived of postoperative adjuvant therapy, which would normally be indicated if their lymph node metastasis had been detected. Therefore, the dual failure of surgery and pathology processes to identify their true risk level will probably be compounded by inadvertent failure to offer beneficial postresection therapy.

9 GENERAL THORACIC 1186 OSAROGIAGBON AND YU Ann Thorac Surg LYMPH NODE NONEXAMINATION AND SURVIVAL 2013;96: Fig 7. Unadjusted survival in recipients of lobar or greater resection: (A) overall; (B) lung cancer specific; (C) non-lung cancer specific. (Green lines ¼ pnx; blue lines ¼ pn0; red lines ¼ pn1.)

10 Ann Thorac Surg OSAROGIAGBON AND YU 2013;96: LYMPH NODE NONEXAMINATION AND SURVIVAL Table 3. Multivariate Analysis of Factors Influencing Long-Term Postoperative Mortality of Patients With Early Stage Non-Small Cell Lung Cancer in the US Surveillance, Epidemiology and End Results Database: 1998 to 2009 Characteristics Overall Survival Lung Cancer Specific Survival HR (95% CI) p Value HR (95% CI) p Value 1187 GENERAL THORACIC Lymph node status pn0 Reference Reference pn ( ) < ( ) <0.001 pnx 1.36 ( ) < ( ) <0.001 Age 1.03 ( ) < ( ) <0.001 Race White Reference Reference Black 1.12 ( ) < ( ) Other 0.90 ( ) < ( ) Sex Male Reference Reference Female 0.75 ( ) < ( ) <0.001 Marriage Married Reference Reference Living alone 1.18 ( ) < ( ) <0.001 Metropolitan status No Reference Reference Yes 0.92 ( ) < ( ) Histology Adenocarcinoma Reference Reference Squamous 1.04 ( ) ( ) <0.001 Large cell 1.16 ( ) < ( ) 0.02 Other 1.03 ( ) ( ) Tumor size <3 Reference Reference ( ) < ( ) <0.001 > ( ) < ( ) <0.001 Unknown 1.43 ( ) < ( ) <0.001 Tumor grade 1 Reference Reference ( ) < ( ) < ( ) < ( ) < ( ) < ( ) <0.001 Unknown 1.48 ( ) < ( ) <0.001 Tumor extension 1 Reference Reference ( ) < ( ) < ( ) < ( ) < ( ) < ( ) <0.001 Unknown 1.09 ( ) ( ) Tumor location Upper Reference Reference Middle 1.10 ( ) ( ) Lower 1.13 ( ) < ( ) <0.001 Unknown 1.16 ( ) < ( ) <0.001 Postop adjuvant radiation No Reference Reference Yes 1.31 ( ) < ( ) <0.001 (Continued)

11 GENERAL THORACIC 1188 OSAROGIAGBON AND YU Ann Thorac Surg LYMPH NODE NONEXAMINATION AND SURVIVAL 2013;96: Table 3. Continued Characteristics Overall Survival Lung Cancer Specific Survival HR (95% CI) p Value HR (95% CI) p Value Extent of resection Lobectomy Reference Reference Pneumonectomy 1.11 ( ) < ( ) Sublobar 1.24 ( ) < ( ) <0.001 Other 1.56 ( ) < ( ) <0.001 CI ¼ confidence interval; HR ¼ hazard ratio; Postop ¼ postoperative. The SEER database does not provide information on performance status and preoperative comorbidity, including pulmonary function. The higher sublobar resection rate in the pnx population probably indicates a more physiologically fragile population, with a higher prevalence of competing risk for mortality. The poorer non-lung cancer survival of the overall pnx population supports this notion (Fig 3C). Therefore, we repeated the survival comparisons after eliminating all patients who had sublobar resection. The results were very similar, except that in the reanalysis, there was no difference in non-lung cancer survival, suggesting that eliminating the sublobar population indeed enabled a more balanced comparison, probably by correcting for imbalances in cardiopulmonary comorbidity (Fig 7). In the multivariate analysis, inclusion or exclusion of the sublobar resection population had no impact on the hazard ratio for mortality. The matched analysis based on propensity scoring corroborates this. The SEER database does not provide information on chemotherapy use. However, preoperative adjuvant chemotherapy was not commonly used during the time of our study, and the penetrance of postoperative adjuvant chemotherapy was almost certainly low, given the timing of publications of successful landmark postoperative adjuvant chemotherapy trials [18, 19]. Even in contemporary practice, 87% of the node-negative patients who had T1 or T2 disease would probably not undergo chemotherapy. Therefore, it seems unlikely that differences in adjuvant chemotherapy use account for the survival differences we report. We speculate that the pnx population, with resection of tumor without reference to lymph node status, is akin to a population of radiologically early stage NSCLC patients treated with localized, lymph node-neutral therapy such as stereotactic body radiation therapy. Indeed, because pnx lobectomy, or greater, cases have the benefit of removal of any intrapulmonary lymph node metastases, the outcome of this subset of pnx patients might be better than that of patients treated with stereotactic radiation. Therefore, we predict from our results that on-going randomized controlled trials of surgical resection versus stereotactic radiation will show resection to be the superior therapeutic modality. The prevalence of poor lymph node examination practice (Fig 2) and its profoundly negative impact on survival must be acknowledged. Only then can successful efforts be made to eradicate this quality of care deficit. Measures to improve the intraoperative collection and mapping of hilar and mediastinal lymph nodes by use of specially designed surgical lymph node specimen collection kits will help [20], as will efforts to improve the gross dissection of lung resection specimens, which increase the detection rate of lymph node metastasis, including detection of missed lymph node metastasis in as many as 12% of pn0 patients [21]. Wider adoption of these quality improvement practices can eliminate the pnx phenomenon, with the promise of more accurate stage classification, risk attribution, and selection of patients for postoperative adjuvant therapy, and clinical trials of novel adjuvant therapies [20 22]. References 1. Siegel R, Naishadham D, Jemal A. Cancer statistics, CA Cancer J Clin 2012;62: Fukui T, Mori S, Yokoi K, Mitsudomi T. Significance of the number of positive lymph nodes in resected non-small cell lung cancer. J Thorac Oncol 2006;1: Lee JG, Lee CY, Park IK, et al. Number of metastatic lymph nodes in resected non-small cell lung cancer predicts patient survival. Ann Thorac Surg 2008;85: Wei S, Asamura H, Kawachi R, Sakurai H, Watanabe S. Which is the better prognostic factor for resected non-small cell lung cancer: the number of metastatic lymph nodes or the currently used nodal stage classification? J Thorac Oncol 2011;6: Rusch VW, Giroux DJ. Nodal staging in lung cancer lymph node location or number? J Thorac Oncol 2011;6: Jonnalagadda S, Smith C, Mhango G, Wisnivesky JP. The number of lymph node metastases as a prognostic factor in patients with N1 non-small cell lung cancer. Chest 2011;140: Nwogu CE, Groman A, Hahey D, et al. Number of lymph nodes and metastatic lymph node ratio are associated with survival in lung cancer. Ann Thorac Surg 2012;93: Ludwig MS, Goodman M, Miller DL, Johnstone PAS. Postoperative survival and the number of lymph nodes sampled during resection of node-negative non-small cell lung cancer. Chest 2005;128: Ou SI, Zell JA. Prognostic significance of the number of lymph nodes removed at lobectomy in stage IA non-small cell lung cancer. J Thorac Oncol 2008;3: Osarogiagbon RU, Yu X. Mediastinal lymph node examination and survival in resected early-stage non-small cell lung cancer in the Surveillance, Epidemiology, and End Results database. J Thorac Oncol 2012;7: Pignon J, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 2008;26: Lally BE, Zelterman D, Colasanto JM, Haffty BG, Detterbeck FC, Wilson LD. Postoperative radiotherapy for stage II or III non-small-cell lung cancer using the

12 Ann Thorac Surg OSAROGIAGBON AND YU 2013;96: LYMPH NODE NONEXAMINATION AND SURVIVAL Surveillance, Epidemiology, and End Results database. J Clin Oncol 2006;24: Osarogiagbon RU, Allen JW, Farooq A, et al. Outcome of surgical resection for pathologic N0 and NX non-small cell lung cancer. J Thorac Oncol 2010;5: Overview of the SEER program. Available at: cancer.gov/about/overview.html. Accessed November 6, Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999;94: Mery CM, Pappas AN, Bueno R, et al. Similar long-term survival of elderly patients with non-small cell lung cancer treated with lobectomy or wedge resection within the Surveillance, Epidemiology, and End Results database. Chest 2005;128: Rami-Porta R, Tsuboi M. Sublobar resection for lung cancer. Eur Respir J 2009;33: The International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients 1189 with completely resected non-small-cell lung cancer. N Engl J Med 2004;350: Winton T, Livingston R, Johnson D, et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005;352: Osarogiagbon RU, Miller LE, Ramirez RA, et al. Use of a surgical specimen-collection kit to improve mediastinal lymph-node examination of resectable lung cancer. J Thorac Oncol 2012;7: Ramirez RA, Wang CG, Miller LE, et al. Incomplete intrapulmonary lymph node retrieval after routine pathologic examination of resected lung cancer. J Clin Oncol 2012;30: Osarogiagbon RU, Ramirez RA, Wang CG, et al. A comparison of interventions to improve intraoperative lymph lode (LN) collection and pathologic examination of lung resection specimens. J Thorac Oncol 2011;6(Suppl): GENERAL THORACIC INVITED COMMENTARY In this article, Osarogiagbon and Yu [1] extend prior work examining patterns of care for lung cancer resection within the Memphis, Tennessee, metropolitan area [2, 3] and nationally, through the Surveillance, Epidemiology, and End Results database [4]. They show that intraoperative hilar and mediastinal lymph node assessment is frequently incomplete or not performed at all, and that pathologic examination is often inconsistent. Patients who do not have lymph nodes pathologically examined (pnx) have a 5-year survival approximating that of pn1 disease, not pn0, suggesting that their cancers have been significantly understaged. Previously, Osarogiagbon and Yu [5] described the creation of a prelabeled specimen collection kit as a way to standardize surgical and pathologic practice and to improve lymph node staging. The staging manuals of the International Union Against Cancer (UICC) and the American Joint Commission on Cancer (AJCC) have long recommended the removal of six lymph nodes as a minimum requirement for adequate staging of lung cancers. In 1996, the International Association for the Study of Lung Cancer (IASLC) defined systematic nodal dissection (SND), the en-bloc removal of all hilar and mediastinal nodes, as the optimal approach for staging lung cancers. The removal of at least three mediastinal and three N1 lymph nodes was considered minimum acceptable staging. These standards are widely practiced by European and Canadian thoracic surgeons. In Japan, meticulous SND performed according to uniform anatomic nomenclature has been standard care for decades. The suboptimal surgical (and pathologic) practices reported by Osarogiagbon and Yu make the United States an outlier. Although there is controversy among experts about whether SND (versus lobe-specific nodal dissection or nodal sampling) is required for all patients, a lack of adherence to a minimal standard for nodal staging should no longer be tolerated because it adversely affects oncologic outcomes. Patients whose survival might be improved through adjuvant postoperative chemotherapy will not be identified if the nodal assessment is inadequate. Recently, these issues have been complicated by the increasing detection of very early lung cancers (ie, tumors less than 2 cm) through computed tomographic screening. Some of these tumors have an indolent behavior because they are low-grade adenocarcinomas. A few of them, usually seen on computed tomographic scans as ground-glass opacities, prove to be adenocarcinomas of a purely lepidic or minimally invasive pattern, with essentially no risk of lymph node metastases. Figuring out which of these small cancers need lesser resections and less extensive lymph node assessment is the subject of ongoing investigations. For the moment, nodal staging as defined by the IASLC, UICC, and AJCC is still the standard. Valerie W. Rusch, MD Thoracic Service Department of Surgery Memorial Sloan-Kettering Cancer Center 1275 York Ave New York, NY ruschv@mskcc.org References 1. Osarogiagbon RU, Yu X. Nonexamination of lymph nodes and survival after resection of non-small cell lung cancer. Ann Thorac Surg 2013;96: Osarogiagbon RU, Allen JW, Farooq A, et al. Pathologic lymph node staging practice and stage-predicted survival after resection of lung cancer. Ann Thorac Surg 2011;91: Osarogiagbon RU, Allen JW, Farooq A, et al. Objective review of mediastinal lymph node examination in a lung cancer resection cohort. J Thorac Oncol 2012;7: Osarogiagbon RU, Yu X. Mediastinal lymph node examination and survival in resected early-stage non-small cell lung cancer in the Surveillance, Epidemiology, and End Results database. J Thorac Oncol 2012;7: Osarogiagbon RU, Miller LE, Ramirez RA, et al. Use of a surgical specimen-collection kit to improve mediastinal lymph-node examination of resectable lung cancer. J Thorac Oncol 2012;7: Ó 2013 by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc