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Ann Thorac Surg 1996;62:1021-1025
© 1996 The Society of Thoracic Surgeons

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Original Articles: General Thoracic

Skip Metastasis to the Mediastinal Lymph Nodes in Non–Small Cell Lung Cancer

Department of Chest Surgery, National Kyushu Cancer Center, Fukuoka, Japan

Accepted for publication May 8, 1996.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. Whether any difference exists in clinical characteristics between resected non–small cell lung cancer with either skip or ordinary mediastinal lymph node metastases (N2 disease) needs to be clarified.

Methods. There were 110 patients with stage IIIA N2 disease. Thirty-three patients demonstrating no metastasis at the hilar nodes [skip (+) group] were compared with the other 77 patients [skip (-) group]. To investigate the extent of nodal involvement, we classified the mediastinal lymph nodes into three regions (superior, inferior, or aortic).

Results. There were no significant differences regarding histologic type, T status, or the site of the primary tumors between the skip (+) and the skip (-) N2 groups. In the skip (+) group, mediastinal node metastasis was found in only one region (level 1) in 30 patients (90.9%) and in two regions (level 2) in 3 (9.1%), whereas 28 patients (36.4%) from the skip (-) group revealed mediastinal metastasis at two or three regions (level 2 or 3). The overall survival rate at 5 years after operation was 35% in the skip (+) group and 12.7% in the skip (-) group (p = 0.054). This favorable clinical outcome in the skip (+) group could be explained partially by the higher proportion of patients with level 1 metastases. Furthermore, regarding patients with level 1 disease, the skip (+) group tended to have a better prognosis than the skip (-) group (p = 0.096).

Conclusions. These results suggest that patients with skip mediastinal lymph node metastases represent a unique subgroup of N2 disease.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Mediastinal lymph node metastasis (N2 disease) is found in approximately 20% to 40% of patients with non–small cell lung cancer (NSCLC) [1, 2] and is one of the most important adverse factors for prognosis [3]. Until now, many physicians have thought that resection is not indicated when mediastinal lymphatic involvement is found, because of the poor prognostic outcome. However, N2 disease may include various degrees of disease status, such as radiologically detected or undetected disease or mediastinoscopically positive or negative disease, and some of these lesions demonstrate a favorable prognosis after complete surgical resection [4–6]. The hilar lymph nodes are anatomically positioned upstream from the mediastinal lymph nodes; however, N2 disease is also seen without lymph node metastasis in the hilar region, which is called skip metastasis [7, 8]. The clinical significance as well as the basic mechanism of skip metastasis have yet to be clarified.

In this study, skip metastasis was found in approximately 30% of the N2 cases. To elucidate the clinical significance of skip mediastinal lymph node metastasis in NSCLC, we compared N2 patients without hilar lymph node metastasis with other N2 patients in terms of the site and extent of mediastinal lymph node metastasis, the location of the primary tumor, and the overall survival rate. We also discuss the mechanism of skip metastasis.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Patients
Between 1982 and 1993, a total of 619 patients with NSCLC underwent operative resection with mediastinal lymph node dissection at the Department of Chest Surgery, National Kyushu Cancer Center. Of these, 110 patients had stage IIIA with N2 disease based on the TNM classification [3]. Of these 110 patients, 33 were found to have no metastasis in the hilar lymph node upon histopathologic examination; such cases are referred to as "skip metastasis." The patient profiles are shown in Table 1. The histologic diagnosis of the tumors was based on the criteria of the World Health Organization [9].

Classification of Mediastinal Nodes and Grade of Mediastinal Metastases
The mediastinal lymph nodes were identified by the lymph node map for lung cancer [10] and were classified into three regions as follows: (1) superior nodes, consisting of the highest mediastinal, paratracheal, pretracheal or retrotracheal and tracheobronchial nodes; (2) aortic nodes, consisting of the subaortic and paraaortic nodes; and (3) inferior nodes, consisting of the subcarinal, paraesophageal, and pulmonary ligament nodes. The extent of metastasis in the lymph nodes was scored as follows: level 1, mediastinal node metastasis was proved in one region; level 2, metastasis was found in two regions; and level 3, metastasis was seen in three regions.

Follow-Up of Patients
In general, a follow-up examination was done every 2 months for the first 2 years and thereafter every 3 to 4 months. The examination included a physical examination, complete blood count, blood chemistry, and chest roentgenography. Although a few patients routinely received screening examinations by computed tomography or radionuclide bone scanning once or twice per year after the operation, the majority of patients underwent computed tomography or a radionuclide bone scan only when symptoms related to recurrence appeared. Recurrent disease was then confirmed by biopsy if clinically feasible. For patients in whom this was not feasible, radiographic evidence (roentgenography, computed tomography, or radionuclide scan) was accepted.

Statistical Analysis
The skip (+) and skip (-) groups were compared regarding several variables, and the differences between them were evaluated using either Student's t test or the ² test. Survival curves were prepared using the Kaplan-Meier method and were compared using the log-rank test. The data were considered significant when the p value did not exceed 0.05.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Site and Extent of Mediastinal Lymph Node Metastases
The sites of metastases to the mediastinal lymph nodes were similar between the skip (+) and skip (-) groups, as demonstrated in Table 2. Metastasis to the superior nodes was observed predominantly in patients with primary tumors in the right upper lobe, and metastasis to the aortic nodes was found frequently in patients with primary tumors in the left upper lobe. In the patients with primary tumors located in the right middle or lower lobe, both the superior and inferior nodes were involved by tumor metastasis, regardless of the group.

View larger version (16K): [in this window] [in a new window]   Fig 1. . Overall survival curves of the skip (+) and skip (-) groups (p = 0.054).

View larger version (16K): [in this window] [in a new window]   Fig 2. . Survival curves of patients with level 1 mediastinal involvement and those with level 2 or 3 (p = 0.116).

View larger version (15K): [in this window] [in a new window]   Fig 3. . Survival curves of the patients with level 1 mediastinal metastasis in the skip (+) and skip (-) groups (p = 0.096).

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
In the present study, skip metastasis in mediastinal lymph nodes was recognized in approximately 30% of the resected N2 cases, as reported previously [8]. The skip (+) group demonstrated less mediastinal lymph node involvement than the skip (-) group, which may be one of the reasons why the skip (+) group had a better prognosis than the skip (-) group. These findings indicate that skip mediastinal metastasis is a unique subgroup of N2 disease in NSCLC, and this supports complete dissection of the regional lymph nodes as a standard procedure even though no metastasis is apparent in the hilar lymph nodes at the time of thoracotomy.

One possible mechanism of skip metastasis may be the existence of direct lymphatic channels to the mediastinum. Riquet and co-workers [11] reported that subpleural lymphatics have direct passages to the mediastinal lymph nodes in 22.2% of the segments in the right lung and in 25% of the segments in the left lung. These investigators also stated that the direct passages were observed more frequently in the upper lobes [11]. In the present study, however, both the location of the primary tumors and the distribution of the metastatic nodal sites were similar between the skip (+) and the skip (-) groups. These results imply that factors other than anatomic characteristics might also contribute to the skip metastasis phenomenon. For instance, the biologic features of tumor cells or lymph nodes may be considered an important factor of such a phenomenon because the settlement of tumor cells onto lymphatic endothelial cells is mediated by the proliferative potential of tumor cells and by adhesion molecules of both tumor cells and endothelial cells, and thus is affected by the cytokine and growth factor environment [12, 13]. In this study, when comparing patients with the same extent (level 1) of mediastinal metastasis, we found that the skip (+) group showed a longer survival than the skip (-) group. This result suggests that some such biologic factors are likely related to both the phenomenon of skip mediastinal lymph node metastasis and the favorable outcome of patients with skip mediastinal metastases.

Another possible reason for skip nodal metastasis is that small metastatic foci of the hilar lymph nodes are often overlooked in a routine histopathologic examination. In fact, a pathologic examination of the regional lymph nodes is usually performed only at the largest slice of each node, and reevaluations of serial sectioning have revealed up to 20% with false-negative results [14]. Recently, advanced techniques such as immunohistochemistry [15, 16] or polymerase chain reaction [17–19] have been performed in the laboratory to detect micrometastases or circulating tumor cells. Passlik and associates [15] reported that using immunohistochemical techniques, cytokeratin-expressing lung carcinoma cells in the bone marrow were detected in 22.5% of patients who were found to have negative conventional histologic examinations. Gerhard and colleagues [19] demonstrated that polymerase chain reaction techniques can detect a single carcinoembryonic antigen–expressing tumor cell among 2 to 5 x 10⁷ normal bone marrow cells. To clarify this issue, such advanced systems should be introduced to improve the detection of micrometastases in the dissected regional lymph nodes.

In conclusion, patients with NSCLC with skip mediastinal lymph node metastasis are considered to represent a unique subpopulation of N2 disease. Further study is needed to clarify the clinical significance and basic mechanisms of this phenomenon.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
We thank Dr Brian T. Quinn, Kyushu University, for his critical review and Ms Yumiko Oshima for her expert help in the preparation of the manuscript.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr Ichinose, Department of Chest Surgery, National Kyushu Cancer Center, 3-1-1 Notame, Minami-ku, Fukuoka 815, Japan.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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