Eur J Cardiothorac Surg 2007;32:868-872. doi:10.1016/j.ejcts.2007.09.007
Copyright © 2007, European Association for Cardio-thoracic Surgery. Published by Elsevier. All rights reserved.
Systematic mediastinal lymphadenectomy does not increase postoperative immune response after major lung resections
Tomasz Jaros
aw Szcz
snya,d,*,
Robert Sotwi
skib,e,f,
Bruno Szczygiec,
Aleksander Stankiewiczd,
Marzanna Zaleskae,
Maria Kopaczf,
Aleksandra Olesiska-Grod
g
a Department of Thoracic Surgery, Regional Lung Diseases Hospital, Prabuty, Poland
b Department of Immunology and Nutrition, Medical University, Warsaw, Poland
c Department of Human Nutrition, Medical University, Warsaw, Poland
d Olsztyn City Hospital, Olsztyn, Poland
e Department of Surgical Research and Transplantology, Medical Research Center, Polish Academy of Sciences, Warsaw, Poland
f Department of General, Gastroenterologic Surgery and Nutrition, Medical University, Warsaw, Poland
g Hospital Laboratory, Regional Lung Diseases Hospital, Prabuty, Poland
Received 2 June 2007;
received in revised form 28 August 2007;
accepted 3 September 2007.
* Corresponding author. Address: Department of Thoracic Surgery, Regional Lung Diseases Hospital, 30 Kuracyjna Str., 82-550 Prabuty, Poland. Tel.: +48 55 2624 377; fax: +48 55 2782 435. (Email: szczesny{at}lungcancer.med.pl).
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Abstract
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Objective: To assess the influence of mediastinal lymphadenectomy on postoperative concentration of interleukin 6 (IL-6) and interleukin 1 receptor antagonist (IL-1ra) in serum, sputum, and pleural fluid, in patients operated upon due to lung cancer and benign pulmonary diseases. Methods: Thirty-three patients undergoing uncomplicated resections, including 23 with lung cancer and 10 with benign diseases, were analyzed. In patients with right lung cancer we performed a systematic lymphadenectomy, while in patients with left lung cancer systematic sampling was performed. Serum IL-6 and IL-1ra concentration was measured before and after surgery, and on postoperative days 1, 3, and 7, as well as in sputum at the end of surgery and in pleural fluid on postoperative day 1, by ELISA test. Results: In 23 patients with cancer, 19.0 ± 11.43 mediastinal lymph nodes were removed (in 11 patients with right lung cancer 27.6 ± 7.6 and in 12 patients with left lung cancer 11.1 ± 8.1). No differences were found in serum and sputum concentration of IL-6 and IL-1ra between patients after right and left thoracotomy due to cancer and between patients with cancer and patients with benign diseases. Patients with cancer had a lower concentration of IL-1ra in pleural fluid (median 16950, range 16050–45470.05 pg/ml) than patients with benign diseases (76665.6 pg/ml (range 53618–89617.9); p
= 0.0008). In 23 cancer patients a negative correlation between concentration of cytokines in pleural fluid and a number of mediastinal lymph nodes resected was observed (Spearman correlation coefficient for IL-6: r
= –0.44, p
= 0.04; for IL-1ra: r
= –0.57, p
= 0.01). Such correlation was not observed for a number of positive N2 lymph nodes. Conclusions: Systematic lymphadenectomy added to major lung resection does not increase postoperative humoral immune response in uncomplicated cases, as measured by levels of IL-6 and IL-1ra in serum, pleural fluid, and sputum.
Key Words: NSCLC • Lung cancer • Mediastinal lymphadenectomy • IL-6 • IL-1ra
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1. Introduction
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Systematic mediastinal lymphadenectomy is a recommended completion of radical surgical resection of lung cancer [1]. However, with the introduction of computerized tomography for lung cancer screening, a growing number of small pulmonary neoplasms have been observed which could be treated with less invasive methods. Surgeons’ efforts to minimize surgical injury concentrate on three fields: surgical approach, extent of pulmonary resection, and extent of mediastinal lymphadenectomy. The first goal was achieved by developing the technique of VATS lobectomy [2–4]. To reach the second goal, multicenter surgical trials assessing the value of conservative pulmonary resections (segmentectomies and wedge resections) for lung cancer are organized [5,6]. To achieve the third goal, sentinel node technique has been investigated [7] to establish in which cases mediastinal lymphadenectomy could be avoided. Avoiding lymphadenectomy would not merely decrease the time of operation, but even more importantly, it is believed to diminish the amount of surgical injury. Even with good availability of immunological tests, it is still difficult to assess how much of an immune response is the result of lymphadenectomy, because lymphadenectomy is not a separate procedure, but is always performed together with thoracic incision and pulmonary resection.
The aim of this study was to estimate the amount of surgical injury caused by systematic lymphadenectomy of mediastinum in patients with cancer of the right lung, compared with surgical injury in patients with cancer of the left lung (where systematic sampling of mediastinal lymph nodes was performed) and benign pulmonary diseases (no mediastinal lymphadenectomy).
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2. Material and methods
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Clinical data were collected prospectively from 84 patients (17 women, 67 men; age 29 through 75 years, mean 60.4 ± 9.6 years) treated with anatomical pulmonary resections (at least lobectomy) due to lung cancer or non-malignant diseases. In 69 patients (48 without and 21 with postoperative complications) the operation was performed due to lung cancer, while in 15 (13 without and 2 with complications) it was performed due to non-malignant diseases. The majority of patients with complications were operated upon due to diseases of the right lung (17 cancer patients and 1 aspergilloma patient). Because immune response to lymphadenectomy is much smaller than immune response to infection or hemorrhage, only patients with an uneventful postoperative course were included for further analysis. To avoid the influence of different surgical approaches and different types of anesthesia, only patients who were operated through muscle-sparing postero-lateral thoracotomy and without epidural analgesia were selected. Immunological studies were only performed in patients with lung cancer of the right lung who had systematic lymphadenectomy (group 1), in patients with cancer of the left lung who had systematic sampling (group 2), and in patients with non-malignant diseases who did not have any mediastinal nodal dissection (group 3). Patients who had preoperative invasive staging more extensive than bronchoscopy and transthoracic fine needle aspiration (mediastinoscopy, mediastinotomy, thoracoscopy, Daniels procedure) within a month before curative resection were excluded. Finally, out of the primary group 33 patients who underwent uncomplicated resections, including 23 with lung cancer (3 women, 20 men; age 58.3 ± 8.8 years) and 10 with benign diseases (3 women, 7 men; age 57.5 ± 12.8 years), fulfilled inclusion and exclusion criteria for immunological studies. In 23 patients with lung cancer 16 lobectomies (1 left lower, 3 right lower, 7 left upper, 4 right upper, 1 right lower bilobectomy) and 7 pneumonectomies (3 right and 4 left) were performed. In all lung cancer patients mediastinal nodal dissection was performed by the same surgeon (T.S.). In patients with non-malignant diseases (age 57.5 ± 12.8 years) 10 lobectomies (3 left lower, 2 right lower, 3 right upper, and 2 medial) were performed.
Serum IL-6 and IL-1ra concentrations were measured before surgery, at the end of surgery, and on postoperative days 1, 3, and 7, as well as in sputum at the end of operation and in pleural fluid on postoperative day 1. After obtaining, venous blood and pleural fluid were cooled to 4 °C, centrifuged at a speed of 2500/min for 10 min, and then preserved at –80 °C until further investigations. Sputum was obtained just before extubation, by washing routinely used catheter with saline. Diluted sputum was frozen at –80 °C. Before freezing, mucus was removed by centrifuging and filtering through gauze. Concentrations of IL-6 and IL-1ra were determined using enzyme immunoassay kits (Quantikine R&D Systems Europe Ltd., Barton Lane Abingdon, Oxon, UK). Immunological studies were performed with STAT FAX 2100 device.
Degree of dilution of sputum was assessed by comparing the concentration of urea in sputum and serum, collected at the end of operation, with urease method (Olympus Diagnostica GmbH, Lismeehan, O’Callaghan Mills, Co., Clare, Ireland). Tests were performed with OLYMPUS AU400 device.
The number of peripheral blood lymphocytes was measured with flow cytometry on postoperative day 1 with ACT 5DIFF Beckman-Coulter device.
Informed consent was obtained from every patient accrued. The study was approved by the local ethics committee.
2.1 Statistical analysis
Results were expressed as median and first and third quartile, or mean values ± SD or as number and percentage. To evaluate statistical significance of the difference between preoperative and postoperative results of cytokine concentration, Wilcoxon test with Bonferroni correction was used. For categorical parameters Fisher's exact test was used. The differences between groups were analyzed with the Mann–Whitney U-test. Computations were performed using SPSS 12.0 statistical package.
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3. Results
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Clinical characteristics of patients from three analyzed groups are presented in Table 1
.
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Table 1 Clinical parameters in patients with systematic lymphadenectomy, in patients with systematic sampling, and in patients without lymphadenectomy (n
= 33)
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Before surgery, the number of peripheral blood lymphocytes (PBL) in the whole group, in patients with cancer, in patients without cancer, and in patients with cancer of the right and left lung was 1.9 ± 0.6, 1.9 ± 0.5, 2.0 ± 0.7, 1.9 ± 0.4, and 2.0 ± 0.5 (x109), respectively. Differences among groups were not significant. After the operation, the number of PBL was 1.5 ± 0.6, 1.5 ± 0.6, 1.4 ± 0.5, 1.2 ± 0.4, and 1.7 ± 0.6 (x109), respectively. In all groups, significant increase of neutrophil count on postoperative day 1 was noted (p
= 0.0000002, 0.00002, 0.005, 0.004, and 0.002, respectively). Patients from group 1 had lower postoperative number of PBL than patients from group 2 (1.2 ± 0.37 vs 1.7 ± 0.64 (x109); p
= 0.04). Decrease in PBL was significant in the whole group of 33 patients (p
= 0.001), in 23 patients with cancer (p
= 0.02), and in patients with cancer of the right lung (p
= 0.003). Decrease of PBL was not significant in patients with cancer of the left lung (p
= 0.3) and in patients with benign diseases (p
= 0.05).
In the whole group, median serum concentration of IL-6 before surgery, at the end of operation, and on postoperative days 1, 3, and 7 was 6.5 pg/ml (range 2.8–17.8), 73.3 pg/ml (range 32.1–123.5), 206.1 pg/ml (range 139.8–350.7), 82.9 pg/ml (range 41.1–130.4), and 27.4 pg/ml (range 12.5–36.6), respectively. Serum concentrations of IL-6 before the operation and on all subsequent days, as well as concentrations of IL-6 in sputum, were not statistically different among groups. Pleural fluid concentration of IL-6 was higher in group 3 than in group 1 (22,975 pg/ml (range 19,980–37,613) vs 2080 pg/ml (range 1942–12,297); p
= 0.0003). The difference between groups 2 and 1 was not significant (17,282 pg/ml (range 2128–23,881) vs 2080 pg/ml (range 1942–12,297); p
= 0.09) (Fig. 1
).
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Fig. 1. Concentration of IL-6 in serum, pleural fluid, and sputum in patients after systematic lymphadenectomy, systematic sampling, and no lymphadenectomy of superior mediastinum. (*) p
< 0.05 between groups 1 and 3.
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Median serum concentration of IL-1ra was 436.5 pg/ml (range 262.6–540), 955.6 pg/ml (range 441.9–1581.4), 944.9 pg/ml (range 782.9–1447.5), 848.6 pg/ml (range 562.5–1302.5), and 662.6 pg/ml (range 408.8–1205.2), respectively. Serum concentrations of IL-1ra before the operation and on all subsequent days, as well as concentrations of IL-1ra in sputum, were not different among groups. In pleural fluid on postoperative day 1, the level of IL-1ra was significantly higher in group 3 than in group 1 (76,666 pg/ml (range 53,618–89,618) vs 16,560 pg/ml (range 15,840–18,333); p
= 0.0004). The difference between group 2 and 1 was not significant (35,026 pg/ml (16,740–50,515) vs 16,560 pg/ml (15,840–18,333); p
= 0.09) (Fig. 2
).
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Fig. 2. Concentration of IL-1ra in serum, pleural fluid, and sputum in patients after systematic lymphadenectomy, systematic sampling, and no lymphadenectomy of superior mediastinum. (*) p
< 0.05 between groups 1 and 3.
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A significant negative correlation between the number of resected mediastinal (N2) lymph nodes and level of cytokines in pleural fluid was observed in 23 lung cancer patients (for IL-6: r
= –0.44, p
= 0.04; for IL-1ra: r
= –0.57, p
= 0.01) (Fig. 3
). No significant correlation between the level of cytokines and number of resected intrapulmonary lymph nodes (N1), number of positive N2 nodes, and number of positive N1 lymph nodes was observed.
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Fig. 3. Correlation between concentration of IL-6 and IL-1ra in pleural fluid and the number of resected mediastinal lymph nodes (N2) in 23 patients with lung cancer without complications.
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4. Discussion
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Assessing serum concentration of immune response mediators is a widely recognized method of measurement of the amount of surgical injury and SIRS-type reaction (systemic inflammatory response syndrome) [8–10].
Mediastinal lymph node dissection, first described over 50 years ago [11,12], is a mandatory completion of radical resection of lung cancer, according to current recommendations. However, it is a different procedure in patients with cancer of right and left lung, due to two main reasons: (1) predominant lymphatic drainage of both lungs through right paratracheal lymph nodes and (2) impaired access to paratracheal lymph nodes through left thoracotomy, due to the aortic arch and its large branches. In patients with cancer of the left lung, systematic lymphadenectomy consists of transsection of superior pulmonary ligament and the removal of all fatty tissue including lymph nodes, which is considered by some surgeons to be a challenging and time-consuming procedure. Additionally, in patients with cancer of the left lung, lymphadenectomy does not influence the late outcome as much as lymphadenectomy in patients with cancer of the right lung [13]. Due to all these reasons, in patients with cancer of the left lung, systematic sampling (consisting of removal of 2–3 lymph nodes from groups 5, 6, and 7, without transsection of superior pulmonary ligament and without removal of left inferior paratracheal lymph nodes – group 4L) is widely accepted. In the background of this study was the assumption that systematic sampling, as a less extensive procedure, causes a smaller immune response than systematic lymphadenectomy, and therefore can serve as a control group in the study evaluating the amount of surgical injury caused by systematic lymphadenectomy. Another control group consisted of patients operated upon due to benign pulmonary diseases, with no mediastinal nodal dissection performed.
From the analysis of patients with complications who were excluded from the current study, we learned that elevated concentration of IL-6 and IL-1ra in pleural fluid on postoperative day 1 is a sensitive early marker of postoperative complications [14]. Therefore, negative correlation between the number of resected N2 lymph nodes and concentration of these cytokines in pleural fluid of lung cancer patients (Fig. 3) might paradoxically suggest that patients who had more extensive lymphadenectomy were at a lower risk of developing complications.
Several explanations of this fact are possible: (1) majority of patients with complications were operated upon due to cancer of the right lung and due to squamous cell carcinoma (differences were not significant) and excluding these patients from the current study might influence its results; (2) excised lymph nodes or removed lymphatic vessels can be the source of cytokines in pleural fluid; (3) higher number of mediastinal lymph nodes are found in the resected specimen of patients with more advanced cancer which causes more pronounced immunosuppression; (4) at least some cytokines are produced by pneumocytes in the operated lung [15], therefore concentration of cytokines is lower when the route of lymphatic drainage is transsected or removed; (5) lymphadenectomy decreases the number of mediastinal dendritic cells which play a major role in presenting inhaled bacterial antigens to T cells [16].
The fact that no significant correlations were found between concentration of IL-6 and IL-1ra in pleural fluid and number of positive N1 and N2 lymph nodes suggests that the third explanation is not valid. We did not find any other studies in the literature assessing immune response to mediastinal lymphadenectomy.
Another symptom of immunosuppression in patients after systematic lymphadenectomy of the mediastinum (cancer of the right lung) may be a significant decrease of PBL after surgery. Decrease of PBL was highly significant in patients after surgery of right lung and not significant in patients after resections of cancer of left lung. Therefore, we believe that a negative correlation between concentration of IL-6 and IL-1ra in pleural fluid and the number of resected N2 lymph nodes should be interpreted as immunosuppression (which can predispose to postoperative complications), not as a decreased risk of development of postoperative complications (in analogy to increased concentration of IL-6 and IL-1ra in pleural fluid observed by us in the study concerning patients with complications).
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5. Conclusions
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Systematic lymphadenectomy performed in patients with cancer of the right lung, in comparison with patients with cancer of the left lung, does not result in elevation of IL-6 and IL-1ra concentration in serum, sputum, or pleural fluid which indicates that this procedure is not a major factor in influencing changes in the immune response. Systematic lymphadenectomy is accompanied by immunosuppression, as measured by negative correlation between the number of resected N2 nodes and concentration of IL-6 and IL-1ra in pleural fluid on postoperative day 1, and by a decreased number of peripheral blood lymphocytes in comparison with patients after systematic sampling which means that in certain situations mediastinal lymphadenectomy can tip the balance and trigger processes leading to the development of postoperative complications (in patients with diabetes, liver cirrhosis, etc.).
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Footnotes
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\#9734; Presented at the 15th European Conference on General Thoracic Surgery, Leuven, Belgium, June 3–6, 2007.
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References
|
|---|
- Lardinois D, DeLeyn P, Van Schil P, Rami-Porta R, Waller David, Passlick B, Zielinski M, Junker K, Rendina EA, Ris H-B, Hasse J, Detterbeck F, Lerut T, Weder W. ESTS guidelines for intraoperative lymph node staging in non-small cell lung cancer. Eur J Cardiothorac Surg 2006;30:787-792.[Abstract/Free Full Text]
- Craig SR, Leaver HA, Yap PL, Pugh GC, Walker WS. Acute phase responses following minimal access and conventional thoracic surgery. Eur J Cardiothorac Surg 2001;20(3):455-463.[Abstract/Free Full Text]
- Inada K, Shirakusa T, Yoshinaga Y, Yoneda S, Shiraishi T, Okabayashi K, Iwasaki A, Kawahara K. The role of video-assisted thoracic surgery for the treatment of lung cancer: lung lobectomy by thoracoscopy versus the standard thoracotomy approach. Int Surg 2000;85(1):6-12.[Medline]
- Sugi K, Kaneda Y, Esato K. Video-assisted thoracoscopic lobectomy reduces cytokine production more than conventional open lobectomy. Jpn J Thorac Cardiovasc Surg 2000;48(3):161-165.[CrossRef][Medline]
- Pass HI, Altorki NK. Computerized tomographic nodule heterogeneity: present and future impact on indications for sublobar resections. Clin Lung Cancer 2004;6(1):20-27.[Medline]
- Koike T, Yamato Y, Yoshiya K, Shimoyama T, Suzuki R. Intentional limited pulmonary resection for peripheral T1 N0 M0 small-sized lung cancer. J Thorac Cardiovasc Surg 2003;125(4):924-928.[Abstract/Free Full Text]
- Tiffet O, Nicholson AG, Khaddage A, Prevot N, Ladas G, Dubois F, Goldstraw P. Feasibility of the detection of the sentinel lymph node in peripheral non-small cell lung cancer with radio isotopic and blue dye techniques. Chest 2005;127(2):443-448.[CrossRef][Medline]
- Biffl WL, Moore EE, Moore FA, Peterson VM. Interleukin-6 in the injured patient. Marker of injury or mediator of inflammation?. Ann Surg 1996;224:647-664.[CrossRef][Medline]
- Lin E, Calvano SE, Lowry SF. Inflammatory cytokines and cell response in surgery. Surgery 2000;127:117-126.[CrossRef][Medline]
- Slotwinski R, Olszewski WL, Paluszkiewicz R, Zieniewicz K, Hevelke P, Zaleska M, Krawczyk M, Krasnodebski IW. Serum cytokine concentration after liver lobe harvesting for transplantation. Ann Transplant 2002;7(3):36-39.[Medline]
- Cahan WG. Radical lobectomy. J Thorac Cardiovasc Surg 1960;39:555-572.[Medline]
- Cahan WG, Watson WL, Pool JL. Radical pneumonectomy. J Thorac Surg 1951;22:449-473.[Medline]
- Keller SM, Adak S, Wagner H, Johnson DH. Mediastinal lymph node dissection improves survival in patients with stages II and IIIa non-small cell lung cancer. Eastern Cooperative Oncology Group. Ann Thorac Surg 2000;70(2):358-365[discussion 365–366].[Abstract/Free Full Text]
- Szczesny TJ, Slotwinski R, Stankiewicz A, Szczygiel B, Zaleska M, Kopacz M. Interleukin 6 and interleukin 1 receptor antagonist as early markers of postoperative complications after lung cancer surgery. Eur J Cardiothorac Surg 2007;31:719-724.[Abstract/Free Full Text]
- Abe T, Oka M, Tangoku A, Hayashi H, Yamamoto K, Yahara N, Morita K, Tabata T, Ohmoto Y. Interleukin-6 production in lung tissue after transthoracic esophagectomy. J Am Coll Surg 2001;192(3):322-329.[CrossRef][Medline]
- van Rijt LS, Vos N, Hijdra D, de Vries VC, Hoogsteden HC, Lambrecht BN. Airway eosinophils accumulate in the mediastinal lymph nodes but lack antigen-presenting potential for naive T cells. J Immunol 2003;171:3372-3378.[Abstract/Free Full Text]
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Abstract
1. Introduction
