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Ann Thorac Surg 1999;67:903-907
© 1999 The Society of Thoracic Surgeons

Original Articles

Type of lymph node involvement and survival in pathologic N1 stage III non–small cell lung carcinoma

Edwin van Velzen, MDa, Aart Brutel de la Rivière, MD, PhDa, Hans J.J. Elbers, MD, PhDa, Jan-Willem J. Lammers, MD, PhDa, Jules M.M. van den Bosch, MD, PhDa

a Departments of Pulmonology, Thoracic Surgery, and Pathology, Sint Antonius Hospital, Nieuwegein, and Department of Pathology, University Hospital, Utrecht, the Netherlands

Accepted for publication September 24, 1998.

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


   Abstract
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 Abstract
Introduction
 Material and methods
 Results
 Comment
 References
 
Background. Survival of patients with stage II non–small lung cancer by the 1986 classification depends on the type of lymph node involvement (by direct extension or by metastases in lobar or hilar lymph nodes). The influence of these types of lymph node involvement on survival was investigated in pathologic N1 stage III patients.

Methods. Of 2,009 patients having operation from 1977 through 1993, the cases of 123 patients with pathologic N1 stage III disease (80 T3 N1 and 43 T4 N1) were reviewed. The N1 status was refined by the specific type of lymph node involvement.

Results. The cumulative 5-year survival rate of all hospital survivors (n = 111) was 27.2%. A significant difference in mean 5-year survival rate was observed between patients who underwent complete resection and those with incomplete resection (34.4% versus 11.4%; p = 0.0001). Further analysis was performed with hospital survivors having complete resection only (n = 76). The cumulative 5-year survival rate was 34.4%. Type of lymph node involvement did not relate to survival for the group as a whole or for the T3 and T4 subsets. Survival was not related to age, histology, type of resection, or tumor size.

Conclusions. Moderately good results can be obtained with surgical resection for stage III patients with pathologic N1 disease. In contrast with stage II, complete resection of pathologic N1 higher-stage non–small cell lung carcinoma is not influenced by type of lymph node involvement.


   Introduction
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 Introduction
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In the 1986 TNM classification for lung cancer, T1 N1 M0 (formerly stage I) became stage II and stage III was subdivided into IIIA and IIIB [1]. Recently, stage I and stage II were both subdivided into A and B [2]. Subdivision of stage III was done because major differences in survival, particularly in regard to N status, existed within that stage. Stage IIIB, including all pathologic (p) T4 tumors and pN3 nodes, has a survival that is, in some centers, significantly lower than that of stage IIIA [3, 4].

We [5, 6] have previously described different types of pN1 status in T1 and T2 tumors (direct extension or metastases in lobar or hilar nodes) and concluded that 5-year survival is highly related to type of nodal involvement. Patients with metastases in hilar lymph nodes have a significantly worse prognosis compared with patients with lymph node involvement by direct extension or metastases in lobar lymph nodes. The survival outcome at 5 years for patients with hilar lymph node metastases in stage II is less than 30%.

In the T2 group, it was observed that survival is also influenced by factors such as visceral pleural involvement and histology. T3 and T4 tumors invade extrapulmonary structures and organs. The location and the extension of these tumors limit the options of surgical treatment and thereby determine survival [7–9].

To assess whether survival in T3 N1 M0 disease (stage IIIA) and T4 N1 M0 disease (stage IIIB) is also influenced by specific type of lymph node involvement, we reviewed the cases of 80 and 43 patients, respectively.


   Material and methods
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 Abstract
 Introduction
 Material and methods
Results
 Comment
 References
 
From 1977 through 1993, 2,009 patients underwent pulmonary resection because of bronchogenic cancer. Of this group, 80 patients had non–small cell lung carcinoma classified as T3 N1 M0 (T3 for short), and 43 were classified as T4 N1 M0 (T4 for short). Staging was postsurgical and according to the new international staging system for lung cancer [1]. Patients with superior sulcus tumors, two tumors, metastatic carcinomas, and recurrent carcinomas were excluded.

Before operation, all patients underwent cervical mediastinoscopy. Lymph node sampling consisted of stations 2, 4 (both left and right), and 7 in the mapping system of Naruke and colleagues [10]. Because those samples were negative, biopsy specimens were obtained at thoracotomy from the N1 nodes draining from the tumor. In lower lobe operations, biopsy samples from stations 8 and 9 were also taken. Patients with T3 disease were divided into two groups; one with chest wall involvement (n = 24) and the other with invasion of mediastinal structures or the main bronchus (n = 56). T4 patients were not subdivided, as the subsets would be too small for statistical analysis.

Age ranged from 34 to 82 years (Table 1). There were 76 men (95%) in the T3 group. In this group, the primary tumor was located in the left lung in 39 patients. The tumors were histologically classified as squamous cell carcinoma in 59 patients, adenocarcinoma in 10, adenosquamous in 8, and undifferentiated large cell carcinoma in 3.


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  		Table 1. Data for Patients With T3 N1 M0 and T4 N1 M0 Disease

 
The T4 group consisted of 38 men (88%). The primary tumor was located in the left lung in 22 patients. The histologic classification was squamous cell carcinoma in 37 patients, adenocarcinoma in 4, adenosquamous in 1 patient, and undifferentiated large cell carcinoma in 1.

Resection was considered complete when the surgeon was as certain as possible that all known disease was removed, resection margins were free at histopathologic examination, and the highest mediastinal lymph node was negative by microscopy. Sixty-two patients (77.5%) in the T3 group and 22 (51.2%) in the T4 group had a complete resection. Most of the resections were pneumonectomies: 57 patients (71.3%) and 34 patients (79.1%) in groups T3 and T4, respectively (see Table 1).

Lymph node involvement was subdivided as described previously, ie, coding lymph node invasion by direct extension and by metastases, at either the lobar level or to the lung hilum [4, 6]. Lymph node involvement in the 80 patients with T3 disease was by metastases in 36 (lobar in 16 and hilar in 20) and by direct extension in 44 patients (see Table 1). Only 10 patients with T4 disease had lymph node involvement by metastases (lobar in 3 and hilar in 7); the other 33 had involvement by direct extension. The number of involved lymph nodes was not counted, as some of them were coalesced and therefore barely identifiable.

The tumor size was less than or equal to 3.0 cm in 17 patients (T3 group, 14, and T4 group, 3), between 3.0 and 5.0 cm in 53 (T3, 31, and T4, 22), and larger than 5.0 cm in 53 (T3, 35, and T4, 18).

One patient with T3 disease received presurgical radiotherapy, whereas 22 received postsurgical radiotherapy. Four patients were postsurgically treated with chemotherapy. In the T4 group, 1 patient received presurgical and 14 patients, postsurgical radiotherapy. Two patients underwent postsurgical chemotherapy. None of the 123 patients received neoadjuvant induction chemotherapy. Follow-up was complete as of November 1995. There were four hospital deaths in the T3 group and eight in the T4 group. These 12 patients were excluded from the survival analysis.

Survival was estimated from the date of operation 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
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 Introduction
 Material and methods
 Results
Comment
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Twelve patients died in the hospital, for a hospital mortality rate of 9.8%. The hospital mortality rate was 5.0% (4 of 80) for T3 patients and 18.6% (8 of 43) for T4 patients. The cumulative postoperative survival rate at 5 years for hospital survivors was 27.2%. It was 27.6% in the T3 group and 26.7% in the T4 group (Fig 1).



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  		Fig 1. Cumulative 5-year survival curves for patients with pathologic N1 T3 disease (solid line) and T4 disease (broken line). (+ = censored patient; T3: 17 patients censored; T4: 10 patients censored.)

 
A significant difference in mean 5-year survival rate was found between patients who underwent complete resection and those having incomplete resection (34.4% versus 11.4%; p = 0.0001) (Table 2). Therefore, further statistical analysis was performed with hospital survivors having complete resection only (n = 76). A nonsignificant difference in survival between patients with T3 disease (n = 59) and T4 disease (n = 17) was observed (32.3% versus 42%; p = 0.34). Nineteen of the 76 patients received radiotherapy (T3 group, 14, and T4 group, 5), and 1 T3 patient underwent chemotherapy. Only 4 of the T3 patients who received radiotherapy survived more than 5 years, and another patient was alive when follow-up was completed (3 years after operation). Of T4 patients, 2 survived more than 5 years after radiotherapy, and 1 other patient had a 3-year survival by the end of follow-up. The T3 patient treated with adjuvant chemotherapy died 4 years after operation.


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  		Table 2. Estimated Mean 5-Year Survival Rates for Hospital Survivors With Complete or Incomplete Resection Associated With Pathologic N1 Disease

 
Survival of patients according to type of lymph node involvement
The 5-year survival rate of pN1 stage III patients with nodal involvement by direct extension (n = 47) did not differ from that of patients with lymph node metastases (n = 29) (34.7% versus 34.1%; p = 0.92) (Table 3). Likewise, when patients with nodal metastases were subdivided into patients with hilar metastases and those with lobar metastases and subsequently compared with each other and with patients with nodal involvement by direct extension, no significant differences in survival were found (p > 0.05).


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  		Table 3. Results of Univariate Analysis of Factors Influencing Postoperative Survival

 
Survival according to type of lymph node involvement in T3 and T4 subsets
For T3 disease, no significant difference in survival was found between patients with lymph node involvement by direct extension or by metastases (see Table 3). In addition, no significant differences in 5-year survival rates were found between patients with direct extension (n = 33) and patients with hilar metastases (n = 15) (34.4% versus 26.7%; p = 0.57), between patients with direct extension and patients with lobar metastases (n = 11) (p = 0.90), and between patients with lobar or hilar metastases (p = 0.52).

With respect to the T4 subsets lobar and hilar metastases, no reliable 5-year survival data were obtained because of the small numbers of patients. A 5-year survival rate of 37.5% was observed in patients with lymph node involvement by direct extension.

Survival of T3 N1 M0 patients according to involvement of chest wall versus mediastinal structures or main bronchus
The cumulative 5-year survival rate for patients with chest wall involvement was 23.0% versus 36.7% for patients with tumor invasion of mediastinal structures or the main bronchus (p = 0.39).

Factors influencing survival
Univariate analysis of factors that could have influenced survival, including age, type of resection, histology, and tumor size, did not show significant denominators. However, differences in the mean 5-year survival rate between patients with a tumor size of 3.0 cm or smaller and those with a size greater than 5.0 cm approached significance (57.1% versus 20.4%; p = 0.055). A difference in survival rate was also observed between patients with a tumor size of greater than 3.0 to 5.0 cm and those with a tumor larger than 5.0 cm (39.2% versus 20.4%; p = 0.067) (Table 3).


   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
References
 
Staging non–small cell lung cancer is important in planning treatment. Staging relies heavily on the nodal descriptor N [1, 3, 7, 14]. Previously, we [5, 6] described the pN1 status of stage II patients. A new subdivision based on lymph node involvement by direct extension or metastases, either lobar or hilar, was presented. Highly significant differences in survival were observed in favor of patients with lobar lymph node metastases. In this review of 123 patients with either T3 N1 M0 or T4 N1 M0 non–small cell lung cancer, it became clear that in these subsets of patients, type of lymph node involvement did not relate to survival. Overall survival at 5 years for all hospital survivors was 27.2%, which is comparable with the findings of Naruke and associates [3]. Survival did not differ between T3 and T4 patients.

A highly significant difference in mean 5-year survival rate was observed between patients who underwent a complete resection versus those with an incomplete resection (34.4% versus 11.4%). When all patients having incomplete resections were excluded from the statistical analysis, the overall 5-year survival rate was 34.4%, which is consistent with survival rates found by others [4, 15] and comparable with survival rates reported for stage II [3, 10, 16, 17].

No significant difference in cumulative 5-year survival was observed between patients with chest wall invasion and those with central tumors in the T3 group. The same survival results have been presented in other reports [4, 18–21], although comparison is sometimes difficult because of differences in nodal status and patient selection.

In contrast with other studies [4, 22–24], a high survival rate at 5 years after complete resection was found in T4 patients (42%). However, hospital mortality was high in the T4 group (18.6%). Both findings are possibly due to a fairly aggressive approach, with tracheal sleeve pneumonectomy the most frequently used type of resection.

Lymph node involvement by direct extension was seen more frequently than involvement by metastases. This could be related to the large tumors, often invading adjacent (lymphoid) tissue [25]. Survival rates for patients with direct extension did not differ between stage IIIA and stage IIIB. As shown in Table 4, patients with hilar lymph node metastases have the worst survival in all stages. Only in stage II patients (n = 391) did this finding reach significance (direct extension versus hilar metastases, p = 0.013; lobar metastases versus hilar metastases, p = 0.0005) [5, 6]. Mean 5-year survival rates for stage III lymph node types are nearly the same, which suggests that in this higher stage of lung cancer, N1 involvement does not have a significant influence on survival. However, when a comparison is made between N0 or N1 and N2, nodal status does influence the prognosis significantly [3, 7].


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  		Table 4. Estimated Mean 5-Year Survival by Type of Lymph Node Involvement Associated With Pathologic N1 Disease After Complete Resection

 
Radiotherapy and chemotherapy did not seem to improve 5-year survival in this group of patients. Apart from complete resection, no other prognostic factors were found. This is in contrast with our pN1 stage II population, in whom age, histology, and tumor size influenced survival significantly [5, 6].

We concluded that 5-year survival after complete resection of pN1 higher-stage (ie, > T2) non–small cell lung carcinoma is not affected by type of lymph node involvement. In contrast to stage II, other factors seem to influence survival, although in our population, only tumor size approached significance. Our study also demonstrated that in select patients with stage III non–small cell bronchogenic carcinoma, moderately good results can be obtained with surgical intervention.


   References
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 Abstract
 Introduction
 Material and methods
 Results
 Comment
 References
 

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