Nakao, Masayuki MD*; Yoshida, Junji MD, PhD*; Ishii, Genichiro MD, PhD†; Hishida, Tomoyuki MD, PhD*; Nishimura, Mitsuyo MD*; Nagai, Kanji MD, PhD*
Lymph node involvement is one of the most important prognostic factors in cancer patients and is categorized based on the anatomic extent by the N classification in the tumor, node, metastasis (TNM) classification of the Union Internationale Contre le Cancer.1 For lung cancer, the International Association for the Study of Lung Cancer has proposed a new lymph node map, reconciling the Naruke et al.2 and American Joint Committee on Cancer3 maps for the 7th edition of the TNM classification.4 However, nothing has been suggested regarding N1 (peribronchial, interlobar, or perihilar) lymph node involvement patterns. To metastasize to a lymph node separate from the primary tumor, cancer cells have to invade lymphatic ducts, travel along the lymphatic flow, and implant in the lymph node tissue, whereas direct involvement of an adjacent node is probably simple invasion. The prognostic impact of node involvement directly by the main tumor may be different from that of involved node separate from the primary tumor.
Squamous cell carcinoma (SCC) accounts for approximately 30% of all lung cancers and is the second most common histologic type of lung cancer, following adenocarcinoma.5 SCC arises in central airways adjacent to hilar lymph nodes, more frequently than the other histologic types.6–8 Lymph nodes directly involved by the main tumor are expected to be more often observed in SCC than other histologic types.
The purpose of this study was to evaluate the prognostic impact of N1 lymph node involvement patterns in pulmonary SCC patients pathologically classified as N1 (pN1).
PATIENTS AND METHODS
From July 1992 through December 2005, 2546 consecutive primary lung cancer patients underwent surgical resection at our hospital. Among them, a total of 124 patients whose resection was considered complete and disease was pathologically diagnosed as N1 SCC were identified. We defined complete resection as lobectomy or more extensive resection with systematic ipsilateral hilar and mediastinal lymph node dissection and absence of residual cancer both macroscopically and histologically. Patients who underwent any preoperative anticancer treatments or a limited resection less than lobectomy were excluded from this study. After excluding four patients because of incomplete pathologic records, the remaining 120 patients were included in this study. To compare the survival probability, 302 and 59 patients undergoing complete resection during the same period for pathologic N0 (pN0) and N2 (pN2) SCC, respectively, were also investigated. We reviewed their medical records for the following clinicopathologic factors: age, sex, location, type of resection, pathologic T classification, tumor size, clinical N classification, node involvement pattern, #10 node involvement, number of metastatic N1 nodes, lymphatic permeation, vascular invasion, and pleural invasion.
All surgical specimens were fixed with 10% formalin and embedded in paraffin. The tumors were sliced at approximately 5-mm intervals, and serial 4-μm sections were stained using hematoxylin and eosin for routine pathologic evaluation and Elastica-van Gieson or Victoria blue-van Gieson staining method for elastic fibers. Lymphatic infiltration was considered to be present when tumor cells were identified floating in lymphatic vessels defined by the lack of supporting smooth muscles or elastic fibers in the vessel wall. Vascular invasion was considered to be present when tumor cells were identified floating in blood vessels defined by supporting elastic fibers in the vessel wall. Pleural invasion was considered to be present when tumor cells were identified beyond the elastic layer of the visceral pleura regardless of tumor exposure on the pleural surface.9 Histologic classification of the resected specimens was determined according to the World Health Organization International Histologic Classification of Tumors.5 Lymph nodes were clinically diagnosed as involved when larger than 1.0 cm in the shortest axis on preoperative contrast-enhanced computed tomography (CT). Clinical N classification and pathologic stage were determined according to the Union Internationale Contre le Cancer TNM classification.1 Tumor location was defined as central if the primary tumor arose in the main bronchus or segmental bronchi and as peripheral if the primary tumor was located distally to the subsegmental bronchi.
Lymph Node Involvement
Lymph node stations were designated according to the lymph node map by Naruke et al.,2 and #10 nodes were defined as main bronchial nodes. We classified N1 involvement into two patterns according to the relationship between the main tumor and N1 node on resected specimens. We defined a “direct N1” node as an N1 node completely inside of, or partly connected to, the primary tumor (Figures 1A, B). Because the resected specimens were sliced at approximately 5-mm intervals, N1 nodes, which were 3 mm or less apart from the main tumor, were also classified as direct N1 even if the tumor did not seem to be in direct contact with the N1 nodes on the resected specimen. The other pattern, a “separate N1” node, was defined as an N1 node connected with the primary tumor only by preexisting normal bronchovascular structure and located more than 3 mm away from the main tumor (Figures 1C, D). We classified the 120 pN1 patients into two groups: patients whose involved N1 nodes were all direct N1 nodes as the direct group and those with at least one separate N1 node as the separate group.
The N1 node involvement patterns and clinicopathologic factors were analyzed for correlation by the χ2 test or Fisher's exact test, as appropriate. Cox's proportional hazards regression model was used to identify statistically significant differences in survival and estimate hazard ratios and 95% confidence intervals. Survival curves were plotted using the Kaplan-Meier method, and the statistical significances of differences between subgroups were determined using the log-rank test. The end point for analyses was overall survival, measured from the date of surgery to the date of death, from any cause. The last follow-up observation was censored when the patient was alive or lost to follow-up. All p values were two-sided and p values less than 0.05 were considered statistically significant. Statistical analysis software (Dr. SPSS II for Windows, standard Version 11.0, SPSS Inc., Chicago, IL) was used for these analyses. Data collection and analyses were approved, and the need for obtaining informed consent from each patient was waived by the institutional review board in August 2009.
N1 Node Involvement Patterns and Clinicopathologic Factors
The clinicopathologic characteristics of the 120 pN1 patients are shown in Tables 1 and 2, and the correlations between the node involvement patterns and other clinicopathologic factors are shown in Table 3. We chose 5.0 cm as the tumor size cutoff, because the median tumor size was 4.2 cm and 5 cm is one of the tumor size cutoffs in the 7th edition of the TNM classification.10 Because the median number of metastatic N1 node was 2, we divided the patients into single or multiple node involvement groups. The direct N1 node involvement pattern was significantly correlated with central location, larger size, and positive pleural invasion of the main tumor.
Prognostic Impact of N1 Node Involvement Pattern on Survival
The median length of overall follow-up period for the censored patients was 5.4 years. Univariate analyses showed that patient survival significantly associated with N1 node involvement pattern, as well as the location and vascular invasion, and marginally associated with tumor size and pleural invasion (Table 4). Among these 5 factors, multivariate analysis proved that the separate N1 node involvement pattern was the only independent predictor of poor outcome (hazard ratio: 1.839, 95% confidence interval: 1.015–3.333; Table 5).
Survival curves are shown in Figure 2. The 5-year overall survival rate of pN1 patients (55.7%) was marginally lower than that of pN0 patients (61.7%, p = 0.05) and significantly higher than that of pN2 patients (25.5%, p < 0.01; Figure 2A). When the direct and separate N1 groups were compared, the direct N1 group had a much better 5-year overall survival rate of 67.7% compared with 32.4% of the separate N1 group, and the log-rank test showed statistically significant difference (p < 0.01; Figure 2B). The direct N1 group survival curve almost overlapped with the pN0 curve, whereas the separate N1 group curve overlapped with the pN2 curve (log-rank test: p = 0.679 and 0.914, respectively; Figure 2B).
Figure 3 shows the results of stratified analysis according to pathologic T classification. In pT2 and pT3 patients, the direct N1 group showed significantly better outcomes than the separate N1 group (p = 0.01 and <0.01, respectively; Figures 3B, C). Although significance was not reached in pT1 patients (p = 0.17; Figure 3A), this was probably due to the small number of patients in each group.
In 80 direct N1 patients, 42 (53%) had more than two involved N1 nodes, but the 5-year overall survival rate of these multiple node involvement patients (62%) was comparable with that of the 38 single node involvement patients (74%, p = 0.64).
N1 nodes in lung cancer patients include peribronchial, interlobar, and perihilar lymph nodes. The survival probability of pN1 patients is evidently lower than that of pN0 patients, and adjuvant chemotherapy is recommended after complete resection.11–13 The reported 5-year survival rates of pN1 patients range from 38% to 67%.14–19 The wide range suggests that pN1 patients are heterogeneous, and various prognostic factors have been reported. In the previous studies, pN1 node involvement pattern was reported to be associated with patient prognosis.16,17,20–22 van Velzen et al.20–22 analyzed the association between pN1 involvement patterns and non-small cell lung cancer (NSCLC) patient survival in T1, T2, and T3-4 patients separately. They found significant association only in pT1N1M0 patients but did not compare them with pN0 or pN2 patients. In their study, the prognostic impact of lymph node involvement patterns in comparison with the other nodal involvement classifications was not clarified.
In our current study, the overall survival rates were significantly different between the direct and separate pN1 groups for all patients, pT2 patients, and also for pT3 patients. The direct group outcome was comparable with that of pN0 patients. In this group, N1 involvement may be due to direct cancer invasion and not due to cancer cells exfoliated and transported by lymphatic flow. Although they are classified as pN1, the main tumor and involved nodes may remain local without lymphatic extension, and when completely resected, the disease is expected to be highly curable. In contrast, the separate N1 group outcome was as poor as that of pN2 patients. In this group, although cancer cells were not observed in the dissected mediastinal lymph nodes, cancer cells may have been transported further by lymphatic flow. Separate N1 status may be a sign of systemic disease and result in an outcome similar to pN2 disease.
Centrally located SCC and peripheral SCC have been reported to differ in clinicopathologic and biologic characters but not in survival.7,8 In our study, survival was significantly different between these two groups in univariate analysis but not in multivariate analysis. There were more direct pN1 patients in the centrally located group than in the peripherally located group. The node involvement pattern and main tumor location (central versus peripheral) significantly correlated (p < 0.01). These results suggest that better survival of centrally located pN1 SCC patients compared with peripheral patients in our series may be explained by the predominance of direct pN1 pattern in the centrally located group.
In pN1 NSCLC patients, #10 node involvement has been reported to be a poor prognostic factor.17–19 Although #10 node involvement was not associated with poor survival in our study, the 5-year overall survival rate was significantly higher in patients with direct #10 node involvement (66.7%, n = 9) than in patients with separate #10 node involvement (0%, n = 9, p = 0.02). The number of patients was small, but these results may strengthen the suggestion that node involvement through lymphatic flow, separate N1, has stronger unfavorable impact on survival than node involvement by direct invasion, direct N1.
The number of involved nodes has been reported to be associated with poor patient outcome in pN1-2 NSCLC patients.23–25 In our study, however, there was no significant difference in survival between single and multiple node involvement patients. In the direct N1 group, the 5-year overall survival rate of multiple node involvement patients was comparable with that of single node involvement patients. In direct N1 group, when complete resection is performed, a favorable outcome can be expected even if multiple nodes are involved.
Lymph node involvement pattern had significant outcome impact on pulmonary pN1 SCC patients. The direct N1 group outcome was comparable with that of pN0 patients, whereas the separate N1 group outcome was as poor as pN2 patients. These results suggest that direct N1 disease is local and separate N1 disease is systemic, although they are currently categorized in the same N1 classification. Further study including other histologic type is essential to verify our findings and to incorporate N1 involvement pattern in future NSCLC staging systems.
Supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare, Japan.
The authors thank Prof. J. Patrick Barron of the Department of International Medical Communications of Tokyo Medical University for his review of the manuscript.
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