Pathologic Lymph Node Staging Practice and Stage- Predicted Survival After Resection of Lung Cancer

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1 ORIGINAL ARTICLES: SURGERY: The Annals of Thoracic Surgery CME Program is located online at 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. Pathologic Lymph Node Staging Practice and Stage- Predicted Survival After Resection of Lung Cancer Raymond U. Osarogiagbon, MD, Jeffrey W. Allen, MD, Aamer Farooq, MD, Allen Berry, MD, and Thomas O Brien, MD Division of Hematology/Medical Oncology, University of Tennessee Health Sciences Center, Memphis; Division of Oncology, Roswell Park Cancer Institute, Buffalo, New York; Department of Pathology, St. Francis Hospital, Memphis; and Duckworth Pathology Group, Memphis, Tennessee Background. Lymph node status is the most important prognostic factor in resectable nonsmall-cell lung cancer (NSCLC). We examined the relationship between the pattern of lymph node examination (including the number and anatomic location of resected lymph nodes), pathologic nodal stage, and survival after NSCLC resection. Methods. Retrospective review of all NSCLC resections in the Memphis Metropolitan Area from January 1, 2004, to December 31, Results. In 656 resections, the number of lymph nodes examined differed significantly between patients grouped by pathologic nodal stage (p < ) and extent of resection (p < 0.001). Thirty-seven percent of mediastinal nodenegative patients had no mediastinal lymph nodes examined. Patients with pn1 and no mediastinal lymph nodes had significantly worse survival than patients with mediastinal lymph node examination (p < 0.02). Approximately 10% of patients with pn0 and pn2 disease had no hilar/ intrapulmonary lymph nodes examined. Conclusions. Suboptimal lymph node staging was prevalent in this cohort. Large proportions of pn1 and pn0 patients were probably understaged. For patients with positive pulmonary/hilar lymph nodes, failure to examine mediastinal lymph nodes was associated with poorer survival. Interventions are needed to improve lymph node staging of NSCLC. (Ann Thorac Surg 2011;91: ) 2011 by The Society of Thoracic Surgeons Only about 28% of all patients with nonsmall-cell lung cancer (NSCLC) are candidates for surgical resection because most present with advanced disease or significant comorbidity that preclude surgery [1]. This minority group eligible for surgery forms the vast majority of long-term survivors. For them, the status of lymph node involvement is the key determinant of prognosis. The location (peripheral/hilar versus mediastinal) and number of lymph nodes with metastasis are related but independent prognostic factors [2, 3]. The median survival of patients with pathologic (p) N0, N1, N2, and N3 disease is 77, 34, 21, and 12 months, respectively [4]. Postoperative adjuvant chemotherapy improves the survival of patients with lymph node metastasis [5 7]; patients with mediastinal lymph node metastasis may also benefit from radiation therapy [8, 9]. Therefore, it is incumbent on surgeons to obtain sufficient lymph nodes from both clusters of stations to enable accurate evaluation of nodal stage [10], and on pathologists to retrieve and examine all lymph nodes in the submitted resection specimen [11]. Heterogeneity in surgical [12] and pathology [13] practice Accepted for publication Nov 29, Address correspondence to Dr Osarogiagbon, University of Tennessee Cancer Institute, 1331 Union Ave, Ste 800, Memphis, TN 38104; rosarogi@uthsc.edu. impairs stage-based prognostication. For example, patients in whom no lymph nodes are examined (pnx) have a significantly worse survival than patients with pn0 who have at least one lymph node examined [14]; and pn0 patients with fewer than 10 lymph nodes examined have worse survival than patients with more than 10 examined lymph nodes [15]. These findings probably reflect differences in the accuracy of staging. We hypothesized that the likelihood of finding lymph node metastasis (and higher pn stage) is directly related to the number and location of lymph nodes examined. We expected that more thorough harvesting of lymph nodes would lead to more accurate reflection of true pathologic stage. We studied the relationship between pathologic nodal stage and the number of lymph nodes examined to determine if patients with more lymph nodes examined were more likely to have node-positive disease. We also investigated the factors associated with increased lymph node examination and compared the survival of patients with and without mediastinal lymph node examination. Patients and Methods We conducted a retrospective review of the Memphis Metropolitan Area Quality of Surgical Resection (MMA by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg OSAROGIAGBON ET AL 2011;91: LYMPH NODE STAGING PRACTICE AND SURVIVAL 1487 QSR) cohort, a community-wide database from all hospitals where lung cancer surgery was routinely performed in the greater Memphis Metropolitan Area from January 1, 2004, to December 31, The dataset includes details about patients, their surgeons, lung resection procedures, and pathology examination. The Institutional Review Boards of the University of Tennessee and all participating hospitals approved this study and waived the informed consent requirement. For this analysis, we excluded patients who received preoperative chemotherapy or radiation therapy. We also excluded those who had no lymph nodes examined, because we have previously reported their inferior survival statistics [14]. Patients with incomplete resections and patients with metastatic disease were excluded from analyses of survival. We compared the demographic and clinical characteristics of patients with the different pn stages. We also compared the survival of patients in the pn subgroups according to the number and location of examined lymph nodes. All references to TNM staging are to the sixth edition of the American Joint Commission on Cancer system, which was in use during the time span of this study. Statistical Analysis Categorical variables were compared by the 2 test, or Fishers exact test when the expected cell frequencies were low. Differences in medians were tested by the Wilcoxon- Mann-Whitney test when there were two groups, or the Kruskal-Wallis test when there were more than two groups. Survival was estimated by the Kaplan-Meier method, and survival curves were compared by the log rank test. All tests of statistical significance were two-sided. The level of significance was set at 0.05, with no adjustments for multiple testing. Results MMA-QSR Cohort A total of 806 patients had a curative-intent resection for primary lung cancer. We excluded 60 patients who had preoperative chemotherapy or radiation therapy, or both, and 90 with no lymph nodes examined from further analysis, leaving a final cohort of 656 patients. Ninety-five percent of the resections were performed by board-certified cardiothoracic surgeons. No resections were performed by general surgeons. All institutions contributing to the MMA- QSR dataset were in urban or suburban locations. Patient and Disease Characteristics The majority of patients (77%) had pn0 disease; none had pn3 disease (Table 1). Patient characteristics were similar across the pn stage groups. Adenocarcinoma was more frequent than other histologic types in the pn2 subset (p 0.003). Although the T-stage distribution was similar among patients in the three N-stage subgroups, the pneumonectomy rate was significantly higher in patients with nodepositive disease (pn1 and pn2), as was the rate of resection with positive margins (Table 2). Extent of Resection and Lymph Node Examination The number of lymph nodes examined was significantly associated with the extent of resection (Table 3). Patients undergoing pneumonectomy had a higher median number of lymph nodes examined (9) compared with patients undergoing lobectomy/bilobectomy (5) and patients with sublobar resection (3; p ). This pattern was consistent within each pathologic nodal stage (Table 3). The likelihood of finding lymph node metastasis was greatest in patients who underwent a pneumonectomy (51%) compared with lobectomy/bilobectomy (19%) or sublobar resection (22%; p for comparison be- Table 1. Demographic and Disease Characteristics Characteristic pn0 Disease n 506 (77%) pn1 Disease n 94 (14%) pn2 Disease n 56 (9%) Age, years, median (range) 68 (42 89) 66 (27 84) 65 (39 85) 0.15 Sex, n (%) 0.52 Female 240 (47) 40 (43) 29 (51) Male 266 (53) 54 (58) 27 (48) Race 0.11 Black 106 (20) 25 (27) 18 (32) White 397 (79) 67 (71) 38 (68) Histology Adenocarcinoma 218 (43) 37 (39) 39 (66) Squamous 192 (37.9) 39 (42) 7 (13) Other 96 (19) 18 (19) 12 (21) T stage (49) 38 (40) 23 (41) (38) 43 (46) 24 (43) 3 18 (4) 5 (5) 4 (7) 4 40 (8) 8 (9) 5 (9)

3 1488 OSAROGIAGBON ET AL Ann Thorac Surg LYMPH NODE STAGING PRACTICE AND SURVIVAL 2011;91: Table 2. Comparison of Surgical and Lymph Node Examination Details pn0 Disease n 506 (77%) pn1 Disease n 94 (14%) pn2 Disease n 56 (9%) Extent of resection Pneumonectomy 40 (8) 27 (29) 14 (25) Lobe/bilobectomy 438 (87) 66 (70) 35 (63) Segmental/wedge 28 (6) 1 (1) 7 (13) Resection margins R0 474 (95) 83 (91) 43 (80) R1/R2 23 (5) 8 (9) 11 (20) Number of lymph nodes examined, median (range) All stations 5 (1 45) 6 (1 28) 7 (1 35) Hilar/intrapulmonary, stations 10 to 14 3 (0 38) 4 (1 22) 3 (0 24) Mediastinal, stations 1 to 9 1 (0 29) 1 (0 10) 3 (1 12) Percentage with 10 lymph nodes Number with no lymph nodes from 10 to 14, n (%) 46 (9) 0 (0) 6 (11) Number with no lymph nodes from 1 to 9, n (%) 179 (35) 45 (48) 0 (0) tween pneumonectomy and both types of lesser resection). Number, Location of Examined Lymph Nodes, and pn Stage The median number of lymph nodes examined in the whole cohort was 5 (range, 1 to 45). It generally increased with increasing pn stage (Table 2). Although patients with pn0 and pn1 had similar total number of lymph nodes (p 0.07), the location differed. Patients with pn1 had significantly more nodes examined from the hilar/ intrapulmonary stations than patients with pn0 (p ), whereas patients with pn0 had slightly more mediastinal lymph nodes examined (p 0.03). Patients with pn1 and pn2 disease had slight differences in the numbers of total and hilar/intrapulmonary lymph nodes examined (p 0.14 and 0.29, respectively), but those with pn2 had significantly more mediastinal lymph nodes examined (p ). There were significantly more total and mediastinal lymph nodes examined in patients with pn2 than in patients with pn0 (p and , respectively), whereas there was no difference in the number of hilar/intrapulmonary lymph nodes examined (p 0.2). The median number of mediastinal lymph nodes examined in the whole cohort was 1 (range, 0 to 29). Thirty-seven percent of the 600 patients without mediastinal lymph node metastasis had no mediastinal lymph nodes examined (35% of pn0 and 48% of pn1 patients). Conversely, 9% of patients with pn0 and 11% with pn2 had no N1 lymph nodes examined. Nineteen of the 50 pn2 patients (38%) with both N1 and N2 lymph nodes examined had negative N1 lymph nodes (mediastinal skip metastasis). Number of Lymph Nodes and Likelihood of Lymph Node Positivity The proportion of patients with more than 10 lymph nodes examined increased significantly with advancing pn stage (p 0.02; Table 2). Twenty-one percent of patients with 10 or fewer lymph nodes had node positive disease, whereas 32% with more than 10 lymph nodes had lymph node metastasis. The likelihood that lymph nodes from both N1 and N2 stations were examined increased significantly with the number of lymph nodes examined, ranging from 37% in the 1 to 5 lymph node group, to 97% in the more than 15 lymph node group (p ; Table 4). The proportion of patients with lymph node metastasis also increased in direct association with the number of lymph nodes examined. Whereas 19% of the lowest cohort had any detected lymph node metastasis, 39% of the highest cohort did (p 0.035). Characteristics of Patients With High and Low Lymph Node Counts Patient characteristics were similar across the lymph node examination cohorts with the exception of median tumor size, which increased with increasing number of lymph nodes (p ). However, the incremental change in Table 3. Extent of Resection, Number of Examined Lymph Nodes, and Pathologic Nodal Stage Number of Lymph Nodes Examined Median (Range) Type of Resection N (%) All pn0 pn1 pn2 Pneumonectomy 81 (12) 9 (1 45) 7.5 (1 45) 8 (3 28) 10.5 (2 35) 0.52 Bilobectomy/lobectomy 539 (82) 5 (1 36) 5 (1 36) 5 (1 18) 7 (1 17) Segmentectomy/wedge 36 (5) 3 (1 13) 3 (1 13) 1 3 (1 5) 0.49

4 Ann Thorac Surg OSAROGIAGBON ET AL 2011;91: LYMPH NODE STAGING PRACTICE AND SURVIVAL 1489 Table 4. Comparison of Patients Sorted Into Categories According to Number of Lymph Nodes Examined, Whole Cohort Number of Lymph Nodes Examined, n (%) Variable 1 5 n 333 (51) 6 10 n 211 (32) n 74 (11) 15 n 38 (6) Age, median (range) 68 (42 86) 67 (37 89) 66 (42 86) 67 (50 83) 0.56 Sex 0.36 Female 163 (49) 100 (47) 33 (45) 13 (34) Male 170 (51) 111 (53) 41 (55) 25 (66) Race 0.16 African American 69 (21) 54 (26) 21 (28) 5 (13) Caucasian 262 (79) 154 (73) 53 (72) 33 (87) Other 2 (1) 3 (1) 0 0 Histology 0.11 Adeno 154 (46) 91 (43) 34 (46) 13 (34) Squamous 114 (34) 74 (35) 28 (38) 22 (58) Other 65 (20) 46 (22) 12 (16) 3 (8) Tumor size, median (range) 2.5 ( ) 2.7 ( ) 3.0 ( ) 3.5 ( ) T stage (55) 87 (41) 36 (49) 6 (16) (32) 99 (47) 31 (42) 26 (68) 3 14 (4) 8 (4) 3 (4) 2 (5) 4 29 (9) 16 (8) 4 (5) 4 (11) X 3 (1) 1 (0) 0 0 No N1 nodes 44 (13) 6 (3) 2 (3) No N2 nodes 165 (50) 49 (23) 9 (12) 1 (3) N1 and N2 present 124 (37) 156 (74) 63 (85) 37 (97) Percent with any positive nodes N stage (81) 161 (76) 53 (72) 23 (61) 1 43 (13) 31 (15) 11 (15) 9 (24) 2 21 (6) 19 (9) 10 (14) 6 (16) Extent of resection Bilobectomy/lobectomy 279 (84) 182 (86) 61 (82) 17 (45) Pneumonectomy 26 (8) 22 (10) 12 (16) 21 (55) Segmentectomy/wedge 28 (8) 7 (3) 1 (1) 0 median tumor size was small (Table 4), and despite this difference, the rates of pneumonectomy, lobectomy, or sublobar resection were similar, except for the cohort with more than 15 lymph nodes, in which the pneumonectomy rate was higher (55%, versus 8% for the 1 to 5 node group). When we restricted analysis to the lobectomy/bilobectomy population to eliminate the impact of extent of resection, we found no sequential difference in tumor size between patients in the various lymph node examination cohorts (Table 5). However, there continued to be significant differences in the likelihood of examination of lymph nodes from both N1 and N2 stations (p ) and a sequential, but statistically insignificant (p 0.32), increase in the identification of lymph node metastasis, ranging from 16% in the 1 to 5 lymph node group to 29% in the more than 15 node group. Survival Patients with pn0 had significantly better survival than patients with pn1 and pn2 disease (p ; Fig 1). However, there was no survival difference between patients with pn1 and pn2 (p 0.17). Patients with pn1 and no mediastinal lymph nodes examined had significantly worse survival than patients with at least one examined mediastinal node (p 0.02). These patients, with no mediastinal lymph nodes examined, had a survival curve that was very similar to that of patients with pn2 disease (Fig 2). This was dissimilar to the pn0 group, in which there was no difference between patients with or without mediastinal lymph nodes examined (Fig 3). Comment A large proportion of patients who underwent surgical resection for lung cancer in our community-based cohort did not have sufficient lymph nodes examined, irrespective of attributed pn stage. The median number of lymph nodes and the proportion of patients with more than 10 lymph nodes examined, a significant threshold for survival in patients with node-negative disease [15 18],

5 1490 OSAROGIAGBON ET AL Ann Thorac Surg LYMPH NODE STAGING PRACTICE AND SURVIVAL 2011;91: Table 5. Comparison of Patients Sorted Into Categories According to Number of Lymph Nodes Examined, Lobectomy/Bilobectomy Cohort Only Number of Lymph Nodes Examined, n (%) Variable 1 5 n n n n 17 Age 68 (42 85) 68 (39 89) 66 (42 86) 69 (50 83) 0.52 Sex 0.92 Female 138 (49) 86 (47) 28 (46) 9 (53) Male 141 (51) 96 (53) 33 (54) 8 (47) Race 0.30 African American 60 (22) 47 (26) 18 (30) 2 (12) Caucasian 217 (78) 133 (73) 43 (70) 15 (88) Other 2 (1) 2 (1) 0 (0) 0 (0) Tumor diameter 2.5 ( ) 2.5 ( ) 2.5 ( ) 3.4 ( ) T stage (55) 79 (43) 35 (57) 5 (29) 2 88 (32) 84 (46) 22 (36) 11 (65) 3 10 (4) 2 (1) 2 (3) 1 (6) 4 24 (9) 16 (9) 2 (3) 0 (0) X 3 (1) 1 (1) 0 (0) 0 (0) No N1 nodes 30 (11) 4 (2) 1 (2) 0 (0) No N2 nodes 152 (54) 42 (23) 8 (13) 1 (6) N1 and 2 nodes present 97 (32) 136 (75) 52 (85) 16 (94) N stage (84) 145 (80) 47 (77) 12 (71) 1 34 (12) 22 (12) 7 (11) 3 (18) 2 11 (4) 15 (8) 7 (11) 2 (12) were low in our cohort. The number of lymph nodes examined in each cluster of node stations was directly proportional to the pn stage. Patients with pn1 disease were more likely than patients with pn0 disease to have had hilar/intrapulmonary lymph nodes examined, and those with pn2 disease were more likely than those with pn0 or pn1 to have had mediastinal lymph nodes examined. This suggests an effect of sampling variation on the attribution of lymph node stage, raising questions about possible understaging of some patients with pn0 and pn1. Illustrative of the enormity of this risk is that 35% of pn0 and 48% of pn1 patients had no mediastinal lymph nodes examined. Although disappointing, the characteristics of the MMA-QSR cohort mirror national NSCLC surgical resection cohorts [14, 19]. Little and colleagues [12], in a Fig 1. Survival by pathologic N stage: N0 (blue line); N1 (red line); N2 (green line). p for comparison N0 versus N1 and N2. Fig 2. Survival of pathologic N1 patients with mediastinal (Med) lymph node examination (blue line) and without mediastinal lymph node examination (red line), compared with pathologic N2 patients (green line). p 0.02 for comparison N1 with mediastinal lymph node examination versus N1 without mediastinal lymph node examination.

6 Ann Thorac Surg OSAROGIAGBON ET AL 2011;91: LYMPH NODE STAGING PRACTICE AND SURVIVAL 1491 Fig 3. Survival of pathologic N0 patients with mediastinal (Med) lymph node examination (blue line) and without mediastinal lymph node examination (red line), compared with pathologic N2 patients (green line). p for comparison N0 with or without mediastinal lymph node examination versus N Patient Care Evaluation of the National Cancer Data Base, reported that 42% of NSCLC resections had no mediastinal lymph nodes examined. Ludwig and coworkers [15] reported that 42% of node-negative NSCLC resections with at least 1 examined lymph node in the 1990 to 2000 Surveillance, Epidemiology and End Results (SEER) cohort had only 1 to 4 total lymph nodes examined [15]. Varlotto and associates [18], reviewing SEER data from 1992 to 2002, showed that 49% of stage I NSCLC resections had no mediastinal lymph nodes examined, 83% had fewer than 10 total lymph nodes, and the median number of lymph nodes examined was between 4 and 6. We found an association between the extent of resection and likelihood of lymph node examination on the one hand, and extent of resection and advanced N stage, on the other hand. This cannot be satisfactorily explained by differences in T stage between patients who had more extensive resection and those with lesser resections, given the minimal differences in T-stage distribution between these patients (Table 1). Our finding that 20% and 25% of patients with T1 and T2 tumors, respectively, had positive lymph nodes suggests that T stage cannot be used to determine the need for systematic nodal evaluation. This point, previously made by others [20], is emphasized because of suggestions that patients with small peripheral tumors without hilar lymph node metastasis might not need mediastinal lymph node examination [21, 22]. The occurrence of skip metastases in 38% of the pn2 cohort indicates why avoiding mediastinal examination is risky. Theoretically, if the mediastinal nodes had not been examined, these patients would have been erroneously assumed to be pn0, with negative implications for subsequent therapy and outcomes. Although the similarity in survival between pn0 patients with and without examined mediastinal lymph nodes seems to support the idea that there is no need for mediastinal lymph node examination in patients with small peripheral T1 lesions in the absence of N1 lymph node involvement [21], the high skip metastasis rate coupled with the fact that 41% of the pn2 cohort had a T1 lesion argues against this idea. Interestingly, 9% of the pn0 group and 11% of the pn2 group had no lymph nodes examined from stations 10 to 14. The existence of this small group of patients suggests that pathologists bear some responsibility for suboptimal lymph node staging. Lymph nodes from peripheral stations are present in the resection specimen, irrespective of the surgeon s mediastinal lymph node harvest practice. This is probably one extreme end of a continuum of poor lymph node retrieval and examination practices in the pathology laboratory, which may have contributed to the low median number of N1 lymph nodes in the whole cohort (Table 2). Strategies to limit the extent of lymph node examination during lung cancer resection by either visual/ textural indicators [23, 24] or sentinel lymph node examination [25] fail to eliminate the need for systematic dissection of lymph nodes. Although it is not clear that radical mediastinal lymph node dissection is superior to systematic mediastinal lymph node sampling [22, 26 29], the studies that suggest equivalency between both types of surgical practice [22, 26] used a control arm with significantly more extensive mediastinal lymph node sampling than what we found in our cohort and what appears to be prevalent in routine US practice. Our study is limited by its retrospective design. Unexplained factors may account for the differences we have found in the number of lymph nodes between patients in the pn subgroups. For example, we cannot separate the effect of lymph node appearance and size on surgeon practice in collecting or not collecting certain lymph nodes, irrespective of their location; we may have missed information about preoperative mediastinoscopy that might have influenced surgeons intraoperative decisions; finally, we are unable to accurately distinguish between the relative weight of surgeon and pathologist practice. The practice of pathologic lymph node staging in this community-based cohort was poor, but reflective of overall US practice [12, 15, 18]. A large proportion of patients are exposed to the danger of underestimation of pn stage, with likely consequent failure to follow up with appropriate postoperative adjuvant therapy. Interventions are needed in the operating room and pathology laboratory to improve the examination of lymph nodes in patients who undergo lung cancer resection. One set of interventions must target intraoperative collection and mapping of lymph nodes, and another set of interventions must be directed at the retrieval and examination of lymph nodes from resection specimens in the pathology laboratory. Clinical trials of lung cancer resection and therapy after resection need to balance lymph node entry criteria to account for the heterogeneity of surgical and pathology practice, while avoiding the negative effect of excessively stringent entry criteria on patient accrual. We recommend stratification by quality of lymph node examination.

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Ann Thorac Surg 2000;70: Lardinois D, Suter H, Hakki H, Rousson V, Betticher D, Ris H. Morbidity, survival, and site of recurrence after mediastinal lymph-node dissection versus systematic sampling after complete resection for nonsmall-cell lung cancer. Ann Thorac Surg 2005;80: Allen MS, Darlin GE, Pechet TTV, et al. Morbidity and mortality of major pulmonary resections in patients with early-stage lung cancer: initial results of the randomized, prospective ACOSOG Z0030 trial. Ann Thorac Surg 2006;81: INVITED COMMENTARY This retrospective review by Osarogiagbon and colleagues [1] of all non-small cell lung cancer resections, performed in the Memphis Metropolitan area during a 4-year time span, addresses an important issue affecting patients with resectable lung cancer. Adequacy of lymph node staging is crucial, because it provides the most important prognostic information in patients with locoregional non-small cell lung cancer. This is typically accomplished by a combination of imaging and surgical sampling. The extent of lymphadenectomy has been controversial, but at a minimum, systematic lymph node sampling is considered vital for adequate staging [2, 3]. Unfortunately, a large number of patients are inadequately staged [4]. This may negatively impact survival by depriving understaged patients of the potential benefits of adjuvant therapy. The National Comprehensive Cancer Network Guidelines (version ) for treatment of non-small cell lung cancer includes recommendations for the sampling of at least three N2 stations or complete 2011 by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur