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Ann Thorac Surg 2005;79:1682-1685
© 2005 The Society of Thoracic Surgeons

Original articles: General thoracic

Problems in Diagnosis and Surgical Management of Clinical N1 Non-small Cell Lung Cancer

Shun-ichi Watanabe, MD*, Hisao Asamura, MD, Kenji Suzuki, MD, Ryosuke Tsuchiya, MD

Division of Thoracic Surgery, National Cancer Center Hospital, Tokyo, Japan

Accepted for publication November 17, 2004.

* Address reprint requests to Dr Watanabe, Division of Thoracic Surgery, National Cancer Center Hospital, Tokyo 104-0045, Japan (E-mail: syuwatan{at}ncc.go.jp).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 References
 
BACKGROUND: Clinical diagnosis of the nodal status is a significant factor in determining the treatment and predicting the prognosis in lung cancer patients. A patient with clinical N1 (cN1) disease is usually considered to be a candidate for surgical intervention in the present staging system in non-small cell lung cancer (NSCLC). However, cN1 disease is a subset for which the method of treatment and surgical results are variable, simply because both upstaging and downstaging can occur. We evaluated the surgical and pathologic results of cN1 NSCLC patients to reveal the problems in diagnosis and surgical management for this subset.

METHODS: From January 1998 to March 2003, 1,606 patients underwent thoracotomy for primary lung cancer at the National Cancer Center Hospital. Among them, the subjects for this study were 168 (10.5%) NSCLC patients who were clinically diagnosed as having N1 disease and underwent surgery without induction therapy.

RESULTS: The tumor cell types of these 168 cN1 NSCLC patients were adenocarcinoma in 73 (44%) and squamous cell carcinoma in 79 (47%). Pneumonectomy was performed in 26% (n = 43) patients, bilobectomy in 15% (n = 25), and exploratory thoracotomy in 11% (n = 19). Of 19 exploratory thoracotomy cases, 10 cases were due to pleural dissemination. The pathologic nodal status of the 135 patients who underwent pulmonary resection and mediastinal dissection was pN0, 19% (n = 25); pN1, 44% (n = 59); and pN2–3, 37% (n = 51). Of the 55 adenocarcinomas, 60% (n = 33) were revealed to be N2 disease on pathologic examination. There were no significant differences in the serum tumor markers between the pN1 and pN2 groups. Among the 25 patients who were downstaged postoperatively (cN1-pN0), 21 patients (84%) showed obstructive pneumonia in the lung.

CONCLUSIONS: In the staging process of cN1 disease, it will be helpful to perform mediastinoscopy and thoracoscopy to avoid unnecessary thoracotomy especially in adenocarcinoma, even though mediastinal nodes and pleural dissemination were negative on computed tomography investigation. Since extensive pulmonary resection (bilobectomy or pneumonectomy) was required in 41% of the patients, preoperative detailed cardiopulmonary function tests should be mandatory to reduce surgical morbidity and mortality. On the other hand, when pneumonia due to airway obstruction by the tumor exists, false-positive hilar nodes can be expected.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 References
 
In the TNM classification of lung cancer, the preoperative evaluation of tumor (T) status is becoming more precise with the development of computed tomography (CT), whereas that of nodal (N) status continues to be unsatisfactory. Clinical diagnosis of N status is a significant factor in determining the method of treatment and predicting the prognosis in non-small cell lung cancer (NSCLC) patients. However, unexpected extensive nodal involvement is occasionally detected in the resected specimen, because the evaluation of clinical N (cN) status is based on the size of lymph nodes on CT. In contrast, tumor involvement sometimes can not be detected in swelling lymph nodes on pathologic examination when the patient had developed pneumonia due to airway obstruction by the tumor. Although most patients with cN1 disease are considered surgical candidates using the present TNM staging system, surgical results in cN1 disease can be variable, simply because both underestimation and overestimation of the N status can occur in this subset. To reveal the problems in diagnosis and surgical management for patients with cN1 disease, we retrospectively evaluated surgical and pathologic results of this subset.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 References
 
From January 1998 to March 2003, 1,606 patients underwent thoracotomy for primary lung cancer at the National Cancer Center Hospital. Among them, the subjects for this study were 168 (10.5%) NSCLC patients who were clinically diagnosed as having N1 disease and underwent thoracotomy without induction therapy. Of these, 33 patients were excluded from pathologic nodal evaluation, consisting of 19 patients who underwent only exploratory thoracotomy, and 14 patients who did not undergo mediastinal nodal dissection because of unfavorable risks.

Basically, only CT was employed to determine clinical N status. Our criterion for lymph node enlargement is greater than 1.0 cm in the short axis of each nodal station on CT. Mediastinoscopy or positron emission tomography scan was not routinely employed preoperatively. Pathologic confirmation of lung cancer was not made if the nodule is highly suspected as lung cancer on CT scan.

Tumors were removed through posterolateral thoracotomy. A Naruke map in the classification of lung cancer issued by the Japan Lung Cancer Society was used for the designation of dissected nodal stations.

The serum carcinoembryonic antigen (CEA) level was measured in adenocarcinoma patients, and cytokeratine fragment (CYFRA) or squamous cell carcinoma antigen (SCC), or both, were measured in squamous cell carcinoma by enzyme immunoassay. The cut-off value was 5 ng/mL for CEA, 2.2 ng/mL for CYFRA, and 1.5 ng/mL for SCC.

Mean values are expressed as mean ± standard deviation throughout the article. The {chi}2 test was used for statistical analyses, and a value of p less than 0.05 was considered to be significant.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 References
 
Patient Characteristics
The patient characteristics of the 168 patients are shown in Table 1. The patients consisted of 138 men and 30 women with a mean age of 62.5 years (range, 26 to 81). The tumor cell types of these 168 cN1 NSCLC patients were adenocarcinoma in 73 (43%), squamous cell carcinoma in 79 (47%), and other cell types in 16 (10%). Preoperative evaluation of T status by CT was T1 in 27 cases, T2 in 90, T3 in 38, and T4 in 13. The mean tumor diameter was 5.2 ± 2.3 cm.


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  		Table 1. Patient Characteristics in Clinical N1 Nonsmall Cell Lung Cancer Patients
 
Surgical Procedure
Pneumonectomy was performed in 43 patients (26%), bilobectomy in 25 (15%), lobectomy in 80 (48%), segmentectomy in 1, and exploratory thoracotomy in 19 (11%). Among the 80 lobectomy patients, 19 (24%) underwent plasty of the bronchus or pulmonary artery, or both (Table 2). The reasons for the 19 exploratory thoracotomies were unresectable T4 disease in 13 patients (pleural dissemination in 10, aortic invasion in 2, and vertebral invasion in 1) and extensive nodal involvement in 6 (Table 2).


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  		Table 2. Surgical Procedures in Clinical N1 Nonsmall Cell Lung Cancer Patients
 
Tumor Cell Type and Nodal Status
The tumor cell type, clinical T status, and pathologic nodal status in the 135 patients who underwent pulmonary resection and mediastinal nodal dissection are shown in Table 3. The nodal status of these 135 cases was pN0, 25 (19%); pN1, 59 (44%); and pN2-3, 51 (37%). The incidence of pN2-3 was not influenced by T status (T1-2, 38%; T3-4, 37%). Sixty percent of all adenocarcinomas (33 of 55) and 68% of T1-2 adenocarcinomas (27 of 40) were revealed to be N2 on pathology examination. On the other hand, among 68 squamous cell carcinomas, 79% (n = 54) were pN0-1.


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  		Table 3. Cell Types, Clinical T Status, and Pathological N Status in 135 Patients Who Underwent Pulmonary Resection and Mediastinal Dissection
 
Serum Tumor Markers
Of 55 adenocarcinoma patients, 26 patients (47%) showed an abnormal level of CEA, and consisted of 3 N0 patients (41%), 7 N1 (44%), and 16 N2 (49%). Among the 68 squamous cell carcinoma patients, 43 patients (63%) showed an abnormal level of serum tumor marker (CYFRA or SCC), and consisted of 7 N0 patients (41%), 27 N1 (73%), and 9 N2 (64%). There were no significant differences in the serum tumor markers between the pN1 and pN2 groups in each cell type.

Incidence of Obstructive Pneumonia in Downstaged Cases
Table 4 shows the incidence of obstructive pneumonia in patients with false-positive N1 nodes (cN1-pN0). In total, 25 patients (19%) were downstaged postoperatively, and 23 of these 25 patients (84%) were histologically proven to have obstructive pneumonia in the resected lungs.


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  		Table 4. The Incidence of Obstructive Pneumonia in Downstaged (cN1–pN0) Patients
 

   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
References
 
In the article by Mountain [1] on revision of the lung cancer staging system, only 5% had cN1 disease in surgical patients, showing cN1 disease is a minor entity in surgical candidates. Clinical diagnosis of the nodal status is a significant factor to decide the treatment and predict the prognosis in NSCLC patients. In the present staging system, most of the clinical N0 and N1 disease is basically considered to be a candidate for surgical resection unless the tumor is unresectable T4 disease, whereas N2 disease is to be a candidate for chemoradiotherapy. Therefore, cN1 disease is a borderline subset for which the treatment can go different ways, simply because both underestimation and overestimation of the nodal status can easily occur in this group of patients.

Computed tomography scan has been used for the clinical diagnosis of nodal status in the staging system. In spite of the development of the helical CT scanner, the preoperative evaluation of intrathoracic nodal status by CT scan remains difficult, mainly because many cancer-positive nodes of normal size exist, especially in adenocarcinoma cases [2–5]. The overall sensitivities of CT scan for N factor is reportedly about 64% to 79% [6, 7]. About 20% of false-negative nodes on CT scan have been reported, even in small-sized adenocarcinoma cases [8, 9]. As shown in Table 3, 60% of all cN1 adenocarcinoma and 68% of cT1-2N1 adenocarcinoma patients were histologically revealed to be N2 after thoracotomy in our series. Preoperative evaluation of nodal status by CT scan is thus not accurate enough to establish the appropriate therapeutic strategy [5, 6]. Furthermore, 11.3% of cN1 patients (19 of 168) in our series underwent only exploratory thoracotomy because of unresectable T4 disease (n = 13) or extensive nodal involvement (n = 6) as shown in Table 2. Among the 13 cases of unresectable T4 disease, 10 (77%) were due to pleural dissemination. Preoperative evaluation of T status is also revealed to be unsatisfactory, especially for pleural dissemination. Although the clinical N1 NSCLC patient is a candidate for surgical resection in the present staging system, it would be helpful to perform mediastinoscopy and thoracoscopy for cN1 disease to avoid unnecessary thoracotomy, even though mediastinal nodes or pleural dissemination were negative on CT investigation [10].

Riquet and associates [11] reported that lung cancer easily metastasizes to the mediastinum. Keller and associates (Eastern Cooperative Oncology Group) [12] reported that complete mediastinal lymph node dissection had identified significantly more levels of mediastinal involvement than systematic sampling. Systematic nodal dissection will be indispensable in adenocarcinoma patients for accurate intrathoracic staging [13].

In contrast with the above, the existence of obstructive pneumonia sometimes caused overestimation of nodal involvement, that is, a false-positive node, as shown in Table 4. Takamochi and coworkers [14] reported that smoking history, presence of obstructive pneumonia, or other factors were significant factors of false-positive scans in mediastinal nodes on CT. Also regarding the hilar nodes, we consider that false-positive nodes can be expected if the obstructive pneumonia exists within the lung.

Regarding the preoperative serum tumor marker investigation, we failed to show the usefulness of serum tumor marker measurement for discrimination of N1 and N2 disease in all cell types. Carcinoembryonic antigen is an antibody extracted from colon cancer [15], and has been used as a specific tumor marker for digestive cancers and lung cancer [16, 17]. In this study, 49% of pN2 and 44% of pN1 adenocarcinoma patients showed elevated serum CEA levels, with no significant differences. These incidences are similar to that of stage IIIA patients with mediastinal involvement reported by Vincent and coworkers [16]. The combination of SCC and CYFRA also revealed not to be useful tumor marker for discrimination of N1 and N2 disease in squamous cell carcinoma.

The type of resection can also be variable in this subset, such as lobectomy, bilobectomy, or pneumonectomy, depending on intraoperative findings of nodal status. We do not perform pneumonectomy when the N1 node is mobile. In our series of resected cases, 41% of patients (68 of 135) underwent extensive resection of lung parenchyma (pneumonectomy, 26%; and bilobectomy, 15%), despite of our aggressive attitude to perform the plasty of the bronchus or pulmonary artery as shown in Table 2. In view of perioperative cardiopulmonary management, preoperative meticulous evaluation of pulmonary and cardiac function test will be mandatory for cN1 disease [18].

Collectively, in staging process of cN1 disease, meticulous evaluation of N and T status using mediastinoscopy and thoracoscopy will be necessary to avoid unnecessary thoracotomy. Because bilobectomy or more resection is often required, preoperative detailed cardiopulmonary function tests will be mandatory to reduce the morbidity and mortality. On the other hand, when the obstructive pneumonia exists within the lung, false-positive nodes can be expected.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 References
 

  1. Mountain CF. Revision in the international system for staging lung cancer Chest 1997;111:1710-1717.[Abstract/Free Full Text]
  2. Oda M, Watanabe Y, Shimizu J, et al. Extent of mediastinal node metastasis in clinical stage I non-small-cell lung cancer: the role of systematic nodal dissection Lung Cancer 1998;22:23-30.[Medline]
  3. Izbicki JR, Thetter O, Karg O, et al. Accuracy of computed tomographic scan and surgical assessment for staging of bronchial carcinoma J Thorac Cardiovasc Surg 1992;104:413-420.[Abstract]
  4. Ichinose Y, Yano T, Yokoyama H, Inoue T, Asoh H, Katsuda Y. The correlation between tumor size and lymphatic vessel invasion in resected peripheral stage I non-small-cell lung cancer J Thorac Cardiovasc Surg 1994;108:684-686.[Abstract/Free Full Text]
  5. Asamura H, Nakayama H, Kondo H, Tsuchiya R, Shimosato Y, Naruke T. Lymph node involvement, recurrence, and prognosis in resected small, peripheral, non-small-cell lung carcinomas: are these candidates for video-assisted lobectomy? J Thorac Cardiovasc Surg 1996;111:1125-1134.[Abstract/Free Full Text]
  6. Goldstraw P, Kurzer M, Edwards D. Preoperative staging of lung cancer: accuracy of computed tomography versus mediastinoscopy Thorax 1983;38:10-15.[Abstract/Free Full Text]
  7. Izbiki JR, Thetter O, Karg O, et al. Accuracy of computed tomographic scan and surgical assessment for staging of bronchial carcinoma J Thorac Cardiovasc Surg 1992;104:413-420.
  8. Watanabe S, Oda M, Go T, et al. Should mediastinal nodal dissection be routinely undertaken in patients with peripheral small-sized lung cancer? Retrospective analysis of 225 patients Eur J Cardiothorac Surg 2001;20:1007-1011.[Abstract/Free Full Text]
  9. Koike T, Terashima M, Takizawa T, Watanabe T, Kurita Y, Yokoyama A. Clinical analysis of small-sized peripheral lung cancer J Thorac Cardiovasc Surg 1998;115:1015-1020.[Abstract/Free Full Text]
  10. Dwamena BA, Sonnad SS, Angobaldo JO, et al. Metastasis from non-small cell lung cancer: mediastinal staging in the 1990s; meta-analytic comparison of PET and CT Radiology 1999;213:530-536.[Abstract/Free Full Text]
  11. Riquet M, Hidden G, Debesse B. Direct lymphatic drainage of lung segments to the mediastinal nodes J Thorac Cardiovasc Surg 1989;97:623-632.[Abstract]
  12. Keller SM, Adak S, Wagner H, Johnson DH. Mediastinal lymph node dissection improves survival in patients with stage II and IIIa non-small cell lung cancer Ann Thorac Surg 2000;70:358-366.[Abstract/Free Full Text]
  13. Graham ANJ, Chan KJM, Pastorino U, Galdstraw P. Systematic nodal dissection in the intrathoracic staging of patients with non-small cell lung cancer J Thorac Cardiovasc Surg 1999;117:246-251.[Abstract/Free Full Text]
  14. Takamochi K, Nagai K, Yoshida J, et al. The role of computed tomographic scanning in diagnosing mediastinal node involvement in non-small cell lung cancer J Thorac Cardiovasc Surg 2000;119:1135-1140.[Abstract/Free Full Text]
  15. Gold P, Freedman SO. Demonstration of tumor-specific antigen in human colonic carcinomata by immunological tolerance and absorption techniques J Exp Med 1969;121:439-462.
  16. Vincent RG, Chu TM, Lane WW. The value of carcinoembryonic antigen in patients with carcinoma of the lung Cancer 1979;44:685-691.[Medline]
  17. Concannon JP, Dalbow MH, Hodgson SE, et al. Prognostic value of preoperative carcinoembryonic antigen (CEA) plasma levels in patients with bronchogenic carcinoma Cancer 1978;42:1477-1483.[Medline]
  18. Watanabe S, Asamura H, Suzuki K, Tsuchiya R. Recent results of postoperative mortality for surgical resections in lung cancer Ann Thorac Surg 2004;78:999-1003.[Abstract/Free Full Text]



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