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Ann Thorac Surg 1997;63:1436-1440
© 1997 The Society of Thoracic Surgeons

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Original Article: General Thoracic

Lymph Node Type as a Prognostic Factor for Survival in T2 N1 M0 Non-Small Cell Lung Carcinoma

Departments of Pulmonology, Thoracic Surgery, and Pathology, Sint Antonius Hospital, Nieuwegein, the Netherlands

Accepted for publication December 11, 1996.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Background. Patients with stage II non-small cell lung carcinoma represent a group with varying 5-year survival rates. The influence of specific types of lymph node involvement on survival was investigated.

Methods. Of 2,009 patients operated on from 1977 through 1993, the cases of 391 patients with pathologic T2 N1 M0 disease were reviewed. The N1 status was refined into lymph node involvement by direct extension or by metastases in lobar or hilar lymph nodes.

Results. The cumulative 5-year survival rate of all hospital survivors (n = 369) was 37.8%. The 5-year survival rate of patients with lobar metastases was superior to that of patients with hilar metastases (57.3% versus 30.3%; p = 0.0028) and that of patients with lymph node involvement by direct extension (57.3% versus 39.1%; p = 0.03). The survival rate did not differ between those with hilar metastases and those with direct extension. Survival was significantly poorer in patients with visceral pleural involvement, in patients with adenocarcinoma, and in patients older than 60 years. Survival was not related to sex, type of resection, central growth, or tumor size.

Conclusions. Survival differs according to the type of lymph node involvement: lobar lymph node metastasis seems to be an early stage of the disease, whereas hilar lymph node metastasis represents a more advanced form. However, in T2 N1 M0 disease, other factors besides nodal status also seem to play an important role in postoperative survival.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
In 1986, the TNM classification for lung cancer was revised [1]. In the new international staging system, T1 N1 M0 (formerly stage I) became stage II because survival rates in this subset of patients were more like those of stage II patients. However, the surgical outcome for patients in stage II is highly variable [2, 3], whereas in stage I (T1 N0 and T2 N0), the prognosis is more circumscribed (5-year survival, 60% to 70%) [4, 5]. Possibly, particularly for stage II, nodal status contributes to this variability.

In T1 N1 M0 disease, survival was found to be influenced by type of lymph node involvement [6]. Patients with lymph node involvement by direct extension had a significantly better prognosis than patients with hilar or lobar lymph node metastases (p = 0.0038). The T2 classification depends not only on tumor dimension (as in T1) but also on visceral pleural involvement, endobronchial growth of the tumor, or both, thereby allowing survival to be influenced by other factors than those in T1 N1 M0 disease. To assess whether survival in T2 N1 M0 disease is also influenced by specific type of lymph node involvement, we reviewed the cases of 391 patients in this stage of lung cancer.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
From 1977 through 1993, 2,009 patients underwent pulmonary resection for bronchogenic carcinoma. Of this group, 391 had non-small cell carcinoma classified as T2 N1 M0. Staging was postsurgical according to the new international staging system for lung cancer [1, 7]. Before operation, all but 13 patients underwent a cervical mediastinoscopy. Lymph node sampling consisted of stations 2, 4 (both left and right), and 7 in the mapping system of Naruke and associates [8]. During thoracotomy, as the previous samples were negative, biopsy specimens were obtained from the N1 nodes draining from the tumor. In lower lobe operations, biopsy samples from stations 8 and 9 were also taken. No patient received presurgical or postsurgical radiotherapy.

Mean age of the patients was 56 years. There were 368 men (94%) and 23 women. Tumors were histologically classified as squamous cell carcinoma in 298 patients, adenocarcinoma in 71, adenosquamous in 14, and undifferentiated large cell carcinoma in 8. Tumors were located in the left lung in 188 patients and in the right lung in 203. Complete resection [9, 10] consisted of lobectomy in 169 patients, sleeve lobectomy in 6, bilobectomy in 31, and pneumonectomy in 185. The tumor invaded the visceral pleura in 147 patients and showed central growth (within a lobar bronchus or at least 2 cm distal to the carina, with associated atelectasis, or a combination of these) in 103 patients. Thirty-three patients had both pleural invasion and central growth.

Lymph node involvement was marked using the map of Naruke and colleagues [8]. In addition, lymph node involvement was described with respect to classic anatomic boundaries (lobe and lung hilum). Lymph nodes were characterized as being invaded by direct extension or by metastases (at the lobar level or confined to the lung hilum). The N1 lymph node sites corresponded to those of Naruke and co-workers [8]: lobar included stations 12 and 13, and hilar comprised hilar station 10 and interlobar station 11.

Lymph node involvement in the 391 patients was by metastases in 218 (lobar in 57 and hilar in 161) and by direct extension in 173. The number of involved lymph nodes was not counted, as some of them were massed and therefore hardly identifiable.

The tumor size was 3.0 cm or less in 87 patients, greater than 3.0 cm to 5.0 cm or less in 194, and greater than 5.0 cm in 110. In this last group, 13 patients had lobar lymph node metastases, 46 had hilar node metastases, and 51 had lymph node involvement by direct extension.

Follow-up was complete as of October 1995. Twenty-two patients died in the hospital and were excluded from survival analysis. Eight of them had hilar node metastases, 7 had lobar node metastases, and 7 had lymph node involvement by direct extension.

Survival from the date of operation was estimated using the Kaplan-Meier survival analysis method [11]. Differences in observed survival between groups were tested for significance using the log-rank test [12]. Differences were considered significant when the p value was less than 0.05. Incremental risk factors influencing survival were evaluated using Cox's proportional hazards model [13].

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Twenty-two patients died within 30 days of the operation, for a hospital mortality rate of 5.6%. Survival analysis was performed with hospital survivors only (n = 369). The cumulative postoperative survival rate at 5 years was 37.8% (Fig 1).

View larger version (15K): [in this window] [in a new window]   Fig 1. . Overall survival at 5 years for 369 patients with pathologic T2 N1 M0 non-small cell lung carcinoma. (+ = censored cases.)

View larger version (19K): [in this window] [in a new window]   Fig 2. . Five-year survival curves for patients with lobar lymph node metastases (solid line), direct extension (dotted line), and hilar lymph node metastases (broken line). (+ = censored cases.)

To eliminate the influence of pleural invasion and central growth on survival of patients with different types of lymph node involvement, patients with pleural invasion, central growth, or both were excluded from further statistical analysis. This made the T2 N1 M0 group comparable to our former T1 N1 M0 group. There then were 36 patients with lymph node involvement by direct extension, 16 with lobar node metastases, and 46 with hilar node metastases. Comparing these three groups, different survival rates at 5 years were found (Fig 3). No significant difference was observed between patients with direct extension and those with lobar node metastases (p = 0.23). The significance in survival rate between the group with lobar metastases and the group with hilar metastases did not change (65.3% versus 21.0%; p = 0.0029), but there was a change between the direct-extension and the hilar metastases groups. Patients with lymph node involvement by direct extension had a significantly better 5-year survival rate than those with hilar lymph node metastases (44.6% versus 21.0%; p = 0.032) (see Table 1).

View larger version (18K): [in this window] [in a new window]   Fig 3. . Five-year survival curves by type of lymph node involvement—lobar (solid line), direct extension (dotted line), and hilar (broken line)—after exclusion of patients with visceral pleural involvement, central growth, or both. (+ = censored cases.)

Multivariate analysis using Cox's proportional hazards model showed the two variables type of lymph node involvement and age to be prognostic factors for survival. Lobar lymph node invasion has a relative risk of 0.62, a 95% confidence interval of 0.41 to 0.93, and a p value of 0.022. Age of 60 years or less has a relative risk of 0.64, a 95% confidence interval of 0.49 to 0.85, and a p value of 0.0015 (Table 3).

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment References

In the present investigation comprising 391 patients with completely resected stage II disease (pathologic T2 N1 M0), the usefulness of this refined nodal classification was studied. The set of patients compared well with recently published stage II series [2, 14]. Survival was comparable. In addition, a relationship between tumor size and survival was found, thus corroborating the results of Martini and co-workers [14]. Martini and Beattie [4] also found a significantly better survival rate in the absence of pleural involvement, as we did. These two findings underscore the heterogeneity of the stage II group. Moreover, we found a relationship between survival and both age and histology.

However, this study aimed at examining the influence of nodal involvement by metastases or by direct extension on survival. The difference in 5-year survival rate between patients with lobar metastases and patients with direct extension was significant (p = 0.03). Patients with lobar metastases survived highly significantly longer than patients with hilar metastases (p = 0.0028), as Yano and co-workers [3] also found, again stressing the disparity within the N1 group, ie, stage II. However, they did not differentiate between nodal involvement by direct extension and nodal involvement by metastases. Nor did they describe the possible influence of visceral pleural involvement, central growth, or tumor size on survival.

Patients with nodal disease caused by direct extension had a survival comparable to that of patients with hilar nodal metastases but inferior to survival of patients with lobar metastases. This is in contrast to survival rates in our former study group (pathologic T1 N1 M0) in whom no significant difference between patients with lobar metastases (n = 9) and those with direct extension (n = 23) and a highly significant difference between patients with direct extension and those with hilar metastases (n = 25) were observed (68.6% versus 23.3%; p = 0.0006).

In T2 N1 M0 disease compared with T1 N1 M0 disease, other factors seem to play a role. When patients with visceral pleural invasion, central growth, or both were excluded from further analysis, the same outcome as in T1 N1 M0 disease was observed, despite an equal distribution of patients with pleural invasion and patients with central growth among the three lymph node groups. Still, there was a slightly better prognosis for lobar metastases than for direct extension. This may be caused by the smaller percentage of patients in the lobar metastases group with a larger tumor (>5.0 cm). Although not significant (p = 0.055), 5-year survival of patients with a tumor greater than 5.0 cm is worse than that of patients with a smaller tumor (3.0 cm).

We conclude that 5-year survival after resection of a bronchogenic carcinoma in T2 N1 M0 disease is affected by the type of lymph node involvement. Patients with metastatic invasion of lobar lymph nodes have a significantly better prognosis than do patients with other types of lymph node involvement, and the survival is comparable to that of patients with stage I disease [2, 4, 5]. In patients with N1 hilar lymph node involvement, underestimated N2 disease may be present. Adjuvant therapy should be considered in patients with hilar nodal disease [15, 16].

Besides type of lymph node invasion, other factors such as age, pleural infiltration, histology, and tumor size influence survival of patients with pathologic T2 N1 M0 disease. Restaging of stage II patients may be useful in the future to provide better treatment and improve survival. Our refined nodal classification can be of use, although more research, eg, on recurrence of malignancy, has to be done.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Address reprint requests to Dr van den Bosch, Department of Pulmonology, Sint Antonius Hospital, PO Box 2500, 3430 EM Nieuwegein, the Netherlands.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 

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