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Eur J Cardiothorac Surg 2002;21:520-526
© 2002 Elsevier Science NL

Mediastinal lymphadenectomy in non-small cell lung cancer: effectiveness in patients with or without nodal micrometastases — results of a preliminary study

^a Department of Surgery, University of Munich, Munich, Germany
^b Department of Thoracic Surgery, Asklepios Fachklinik Munich-Gauting, Munich, Germany
^c Division of Molecular Oncology, University of Hamburg, Hamburg, Germany
^d Department of Surgery, University of Hamburg, Hamburg, Germany

Received 12 September 2001; received in revised form 12 December 2001; accepted 20 December 2001.

* Corresponding author. Department of Surgery, Klinikum Innenstadt, Ludwig-Maximilians-University, Nußbaumstrasse 20, D-80336 Munich, Germany. Tel.: +49-89-85791-7333; fax: +49-89-85791-7335
e-mail: passlick{at}lrz.uni-muenchen.de

	Abstract

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion Appendix A. Conference... References

 
Objectives: So far it has not clearly been demonstrated that systematic mediastinal lymphadenectomy improves survival in patients with non-small cell lung cancer. One explanation might be that in some patients an early spread of tumor cells has occurred which might not be curable by surgical means. To test this hypothesis lymph nodes of patients which were treated either by lymph node sampling or systematic lymphadenectomy were screened for micrometastatic spread of tumor cells and the influence of nodal micrometastases on the efficacy of lymphadenectomy was analyzed. Methods: Lymph nodes from patients (n=94) which were included in a randomized trial of lymph node sampling (LS, n=41) versus radical systematic lymphadenectomy (LA, n=53) were screened by immunohistochemistry for disseminated tumor cells using the antibody Ber-Ep4. The median observation time was longer than 5 years and follow-up data were available from all 94 patients. Kaplan–Meier curves were calculated and tested for statistical significance using the log-rank test. Results: Standard histopathological analysis revealed no lymph node involvement (pN0) in 61 patients, pN1 disease in 13 patients and pN2 disease in 20 patients without significant differences between LA and LS with respect to T-stage, N-stage or age and sex of the patients. By immunohistochemistry a minimal nodal spread of tumor cells was detected in 21 out of 94 patients (LS, n=10 (24%); LA, n=11 (21%)). Similar to the entire group of patients also in the subset of patients with nodal micrometastases the type of lymphadenectomy did not significantly influence the long-term survival (P=0.27 and P=0.39, respectively). In contrast, in patients with a negative immunohistochemical analysis systematic lymphadenectomy resulted in an improved overall survival (P=0.044). Conclusions: Our data provide some evidence that systematic lymphadenectomy improves survival in patients without an early locoregional spread of cancer cells. As long as these patients can not be identified preoperatively all patients should undergo a systematic mediastinal lymphadenectomy.

Key Words: Lymphadenectomy • Micrometastases • Non-small cell lung cancer • Prognosis

	1. Introduction

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion Appendix A. Conference... References

 
The role of mediastinal lymphadenectomy in non-small cell lung cancer (NSCLC) is still a matter of controversy. While it is commonly accepted that for an appropriate staging a minimum of hilar and mediastinal lymph nodes has to be removed and examined, the therapeutic efficacy of mediastinal lymphadenectomy is still under debate. In a recent study published by Keller et al. [1] it has been postulated that a systematic lymphadenectomy improves long-term survival in stage II and IIIA lung cancer patients. However, the study has been performed in a non-randomized fashion and more than 190 surgeons have entered patients into the study; 131 of them entered only one patient.

Our group has performed a prospective randomized trial in order to investigate the effect of systematic lymphadenectomy on staging and long-term outcome [2]. The results of that trial demonstrated that patients after systematic mediastinal lymphadenectomy did not show a significantly improved outcome as compared to patients with lymph node sampling only.

Recently, it has been shown that in some NSCLC patients an early micrometastatic spread of tumor cells to the regional lymph nodes occurs [3–6]. Even in patients with small primary tumors such a tumor cell dissemination can be detected in about 20% of the patients by using immunohistochemical methods [3]. The detection of nodal micrometastases is associated with a poor clinical outcome [3–6], indicating that these primary tumors have high metastatic potential.

We speculated that the therapeutic effect of systematic mediastinal lymphadenectomy might be influenced by the presence of micrometastatic cells in lymph nodes. We tested this hypothesis in a subset of patients of the original lymphadenectomy trial from which data of the immunohistological analysis of lymph nodes cells were available.

	2. Patients and methods

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion Appendix A. Conference... References

 
2.1. Patients and data collection
At our institution a prospective randomized trial had been performed analyzing the effect of systematic mediastinal lymphadenectomy on tumor staging and survival in patients with pathological stage I–IIIA NSCLC [2]. Two hundred one patients were recruited for the study and randomly assigned to be treated either by radical systematic mediastinal lymphadenectomy (LA, n=100) or by mediastinal lymph node sampling (LS, n=101). After randomization 32 patients were excluded from analysis (for details see Ref. [2]). Hence, 169 eligible patients (LS, n=93; LA, n=76) remained for the final analysis of that trial.

At the same time we studied the occurrence and prognostic significance of isolated micrometastatic tumor cells in lymph nodes of patients undergoing resection for NSCLC by using immunohistochemical methods [4]. A total number of 125 patients were enrolled in that study. For the present analysis we identified all patients of the lymphadenectomy trial from which the lymph nodes have been analyzed in addition to the conventional histopathological analysis by immunohistochemistry. Ninety-four patients were identified (LS, n=41; LA, n=53) corresponding to 57% of 169 eligible patients of the lymphadenectomy trial. The follow-up was complete in all patients and ranged from 39 to 82 months (median 72 months).

Adjuvant postoperative percutaneous radiation therapy (50 Gy) was applied to all patients whose primary tumor was classified by the pathologist as T₃ or T₄ tumor and all patients with involvement of nodes of the N₂ region by conventional histopathology. This therapeutic regimen was followed in both groups.

2.2. Operative technique
The operative technique for lymph node sampling or systematic mediastinal lymphadenectomy has been described previously [2]. Briefly, in patients randomized to the LS group the resection was combined with a regional lymphadenectomy of interlobular, peribronchial and hilar nodes representing nodes 10, 11 and 12 according to the lymph node mapping of the American Thoracic Society [7]. A mediastinotomy was performed via longitudinal incision of the mediastinal pleura and nodes of regions 2–9 were explored. Any nodes suspicious of cancer were removed and submitted to patho-histological analysis. Nodes of regions 4, 5, and 7 were removed routinely in all patients.

In the LA group, the resection was combined with a radical systematic en-bloc-mediastinal lymphadenectomy as described by Naruke [8] and Martini [9]. Briefly, in right-sided tumors the superior mediastinal compartment contained between trachea, superior vena cava from the level of the azygos vein to the right subclavian artery and right recurrent laryngeal nerve was dissected and the trachea, azygos vein, superior vena cava and ascending aorta were completely freed from all tissue. Azygos vein and vagus nerve were generally spared and the right laryngeal nerve exposed. Subcarinal, paraesophageal and inferior pulmonary lymph nodes were removed en-bloc, exposing the entire thoracic esophagus and the vagal nerve.

In left-sided cancers the subaortic compartment – contained between the left pulmonary artery, the aortic arch, the left recurrent laryngeal, and the phrenic nerve – was dissected by completely freeing the left vagal nerve and the recurrent laryngeal nerve. Thereafter the aorto-pulmonary ligament of Botalli was ligated and divided and the aortic arch was mobilized anteriorly to facilitate dissection of paratracheal nodes (nodes 2, 3 and 4).

2.3. Immunohistochemical analysis of lymph nodes
Our immunohistochemical assay for the detection of disseminated micrometastatic tumor cells in lymph nodes has been described previously [4]. Briefly, at primary surgery, all resected and clearly identifiable lymph nodes were divided into two parts. One part was embedded in paraffin for histopathological routine staging (HE), and the other part was snap-frozen in liquid nitrogen and stored at -80 °C until use. Lymph nodes which had no evidence of nodal metastases by routine histopathology were screened by immunohistochemistry, using the anti-epithelial mAb Ber-Ep4 for the detection of disseminated tumor cells. Ber-Ep4 (IgG1; Dako, Hamburg, Germany) is directed against two glycopolypeptides of 34 and 49 kDa present on the surface and in the cytoplasm of all epithelial cells except the superficial layers of squamous epithelia, hepatocytes, and parietal cells [10]. The monoclonal antibody Ber-Ep4 bas been described to be highly sensitive for the detection of tumor cells derived form NSCLC [11]. From each lymph node 4–6 µm cryostat sections were cut from three different levels and were stained immunohistochemically using the alkaline phosphatase anti-alkaline phosphatase (APAAP) technique. Only the presence of Ber-Ep4 positive cells within the body of the lymph nodes was accepted as disseminated tumor cells.

2.4. Statistical analysis
Classified data were analyzed with the Pearson ²-test. Postoperative survival was calculated by the Kaplan–Meier method and analyzed by the log-rank test. The level of significance was set at P<0.05. All procedures were performed using statistical software package SPSS (SPSS Software, Munich, Germany).

	3. Results

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion Appendix A. Conference... References

 
3.1. Patient characteristics
The characteristics of the study population are shown in Table 1. There were no statistically significant differences between the lymph node sampling group (LS) and the systematic lymphadenectomy group (LA) with respect to T-stage, N-stage or age and sex of the patients. However, there were more patients with squamous cell carcinomas in the LS group (54%) as compared to the LS group (36%; P=0.03).

View larger version (13K): [in this window] [in a new window]   Fig. 1. Cumulative survival of 94 patients with NSCLC after lymph node sampling (LS, n=41, dashed line) or systematic mediastinal lymphadenectomy (LA, n=53, solid line). Kaplan–Meier analysis; log-rank test: P=0.27.

View larger version (13K): [in this window] [in a new window]   Fig. 2. Cumulative survival of 73 patients with NSCLC and without nodal micrometastases after lymph node sampling (LS, n=31, dashed line) or systematic mediastinal lymphadenectomy (LA, n=42, solid line). Kaplan–Meier analysis; log-rank test: P=0.044.

View larger version (13K): [in this window] [in a new window]   Fig. 3. Cumulative survival of 21 patients with NSCLC after lymph node sampling and with nodal micrometastases (LS, n=10, dashed line) or systematic mediastinal lymphadenectomy (LA, n=11, solid line). Kaplan–Meier analysis; log-rank test: P=0.39.

	4. Discussion

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion Appendix A. Conference... References

In the present report we compared the therapeutic effectiveness of systematic mediastinal lymphadenectomy in patients with and without nodal micrometastases. While in patients with early disseminated tumor cells in lymph nodes the survival was not influenced by the type of lymphadenectomy, patients without nodal micrometastases lived after systematic lymphadenectomy considerably longer than patients after lymph node sampling only. Therefore, it can be assumed that the effectiveness of mediastinal lymphadenectomy might be influenced by the presence of disseminated tumor cells in the regional lymph nodes. Furthermore, these cells can be considered as a marker for primary tumors with a high metastatic potential, which might not be curable by surgery alone.

Our data seem to be compatible with the recently published work by Asamura et al. [19]. They pointed out that the prognosis of patients with apparently resectable NSCLC is substantially influenced by the extent of mediastinal lymph node involvement. Despite a systematic mediastinal and hilar lymphadenectomy, patients with multiple mediastinal lymph node metastases had an extremely poor outcome, while patients with a so-called minimal N2 disease showed a 5-year survival rate of 48%. Therefore, patients with multiple mediastinal lymph node involvement or disseminated tumor cells in lymph nodes as detected by immunohistochemistry might be candidates for preoperative adjuvant systemic therapy. Recently, it has been shown that the immunohistochemical approach is also applicable to mediastinoscopy biopsy specimens and can result in an improved staging before surgical resection [20].

Unfortunately our present work has some limitations. We have analyzed a subset of patients from an existing trial and the data on lymph node micrometastases have been added retrospectively. Furthermore, the evidence of our findings is limited by the relatively low number of patients in each group. Therefore, the possibility of a false significant result can not be fully excluded and the data should be interpreted with caution. Additionally, one might speculate that the so-called ‘Will–Rogers effect’ is responsible for the poor outcome of the LS group as compared to the LA group [21]. That means that due to the incomplete lymph node dissection in the LS group, some patients with more advanced lymph node disease have not been detected, since some of the mediastinal lymph nodes have not been removed and consequently not examined. This argument is supported by the finding that systematic mediastinal lymphadenectomy indeed results in a more detailed staging of the mediastinal lymph node involvement if conventional histopathological staining methods are used [22]. However, by immunohistochemistry most of the micrometastatically involved lymph nodes were detected in lymph node levels which would have been removed anyway routinely in all patients (Tables 2 and 3). Therefore, the Will–Rogers argument does not seem to be applicable in this context.

Additionally, there was an imbalance between both groups with respect to the distribution of adeno and squamous cell carcinomas (Table 1). However, since there were more squamous cell carcinomas, which are known to have less lymph node and skip metastases [19] in the LS group, we do not believe that this imbalance has markedly influenced the results.

In conclusion, our report provides first evidence that the effectiveness of lymphadenectomy is influenced by the tumor biological characteristics of the primary tumor. Since these characteristics can currently not be determined preoperatively, all patients should undergo a systematic mediastinal lymphadenectomy. However, future strategies should focus on the attempt to identify parameters which allow the classification of primary tumors early in the diagnostic work up by tumor biopsy into tumors with a low or high metastatic potential in order to allow the design of a customized treatment strategy, including the extent of lymphadenectomy.

	Footnotes

 
Presented at the joint 15th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 9th Annual Meeting of the European Society of Thoracic Surgeons, Lisbon, Portugal, September 16–19, 2001.

	Appendix A. Conference discussion

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion Appendix A. Conference... References

 
Mr D. Waller (Leicester, UK): Could I ask you what you think is the effect of mediastinal lymphadenectomy? Does it reduce local disease recurrence or do you think it prevents systemic recurrence?

Dr Passlick: I believe we should differentiate between primary tumors with a high metastatic potential and primary tumors with a low metastatic potential. Our assumption is that there is a biological difference between these primary tumors. There will be some primary tumors which are suitable for a surgical resection also if there are some lymph node metastases. This is also reflected by our clinical experience. For example, primary tumors with squamous cell characteristics with some lymph node metastases are often curable by surgical means, while small adenocarcinomas metastasize early to other distant organs.

I believe the first aim of mediastinal lymphadenectomy is to prevent local recurrences within the mediastinum, but the second is also to eradicate metastases which by themselves could be the source of additional metastases to other distant organs.

Mr Waller: That was the point. You believe that metastases metastasize.

Dr Passlick: We don't know that.

Mr Waller: That is your inference, isn't it? You do a mediastinal lymphadenectomy to prevent systemic recurrence, so you must believe that metastases metastasize.

Dr Passlick: That is what it looks like, yes.

Mr Waller: Do you have any evidence for that?

Dr Passlick: Not yet.

Mr A. Morgan (Bristol, UK): I have been fascinated by this work for a long time. What implications do you think your findings have of these micrometastases on the use of either preoperative or postoperative chemotherapy?

Dr Passlick: We have done a lot of work in the field of early micrometastases in bone marrow and also in lymph nodes, and my colleagues from the experimental institutes are trying to characterize these cells a little more in detail. Their studies demonstrated that most of these cells are in a nonproliferative state, so they are not dividing themselves very rapidly. Therefore, our assumption is that the standard chemotherapeutic agents alone are not the best treatment option in these patients. Therefore, we are evaluating other types of treatment for minimal residual diseases after surgery, including biological principles, like monoclonal antibodies. These studies are currently running.

Mr R. Qureshi (Birmingham, UK): There have been a number of studies done about mediastinal lymphadenectomy causing ARDS, and there has been a randomized trial in Canada stating that mediastinal lymphadenectomy and mediastinal lymph node sampling does not make any difference in the staging. Would you comment on that before recommending this mediastinal lymphadenectomy?

Dr Passlick: You mean the effect of mediastinal lymphadenectomy on staging?

Mr Qureshi: On the staging and therapeutic benefit.

Dr Passlick: We analyzed the effect of systematic mediastinal lymphadenectomy, first on staging and also on overall survival. Our results demonstrated that it is possible to determine the N stage sufficiently by lymph node sampling. However, by an extended mediastinal lymphadenectomy, you will get more information on the distribution of the lymph node involvement. For example, it is possible to identify patients with a multiple N2 involvement. If you are interested in a detailed staging of the mediastinum and this information influences the clinical decisions, a systematic lymphadenectomy should be done.

Mr Qureshi: And how about the related complication like ARDS, which Mr Peter Goldstraw has mentioned and has studied?

Dr Passlick: We looked in our original lymphadenectomy trial also for complications. A comparison between systematic lymphadenectomy and lymph node sampling revealed that there were some more bleeding complications and more recurrent nerve injuries. However, these differences were not statistically significant. The operating time in the systematic lymphadenectomy group was 20 min longer than in the lymph node sampling group.

Dr H. Ris (Lausanne, Switzerland): You showed us that patients without lymph node involvement, detection by lymphadenectomy or sampling, do better by lymphadenectomy than by sampling. Do you have an explanation for this? Is that because the sampling leaves a tumor behind or do you have other evidence for this?

Dr Passlick: You mean the effect of our assay on the staging of the patients? Well, we looked in our study population in which lymph node levels we find these micrometastatic cells. The micrometastatic cells were generally in hilar and mediastinal lymph nodes. There was only one patient in the systematic lymphadenectomy group in which micrometastatic tumor cells were found in a lymph node level which was exclusively resected in the systematic group. So we don't believe that the detection rate in both groups is different. Was that the question?

Dr Ris: The question was why does an operation where you remove healthy tissue reduce survival in these patients? Why do we have better results after a wide resection than a small resection in patients without this kind of lymph node involvement?

Dr Passlick: Two points should be considered. The first is that we believe that some patients are not correctly staged by the routine histopathological approach. Normally, only one section per lymph node or lymph node level is analyzed in order to detect a tumor involvement. This seems to be not sufficient to detect all patients with mediastinal lymph node involvement. Therefore, some patients seem to be understaged by the current analyses and the correct stage is not reflected by the pathological report. Another point is the survival analysis in the subgroups of patients with or without lymph node involvement. In the systematic lymphadenectomy group as well as in the lymph node sampling group there were about 60% of patients with uninvolved lymph nodes and 30% of patients with lymph node involvement. The survival analysis revealed that the death rate in patients without lymph node involvement was 30% in both groups. But the survival in the lymph node sampling group in patients with N1 or N2 disease was very, very low, while in patients with proven N1 or N2 disease in the systematic lymphadenectomy group it was much better. We only had a 20% death rate in the N2 involvement group with systematic lymphadenectomy.

So I believe some patients with mediastinal lymph node involvement can be cured by a radical approach.

Professor A. Yim (Hong Kong): I just want to ask what is your policy on mediastinoscopy? Do you do it routinely on all your patients?

Dr Passlick: Right now it is still the old criterion. We do a mediastinoscopy in patients which have enlarged lymph nodes on the CT scan of more than 1 cm in diameter.

Professor Yim: So for the two groups, is it the same?

Dr Passlick: The policy was the same in both groups.

	References

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion Appendix A. Conference... References

 

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