Background
Surgical resection is established as a standard treatment for stage I non-small cell lung cancer (NSCLC). Upstaging of the tumor by the identification of lymph node disease has a significant impact on survival and therapeutic decision making1,2. The presence of hilar or mediastinal lymph node disease renders surgical resection alone less efficacious, and typically, systemic therapy is recommended. Therefore, the identification of lymph node disease is of utmost importance. Current preoperative staging techniques have reduced the number of cases with ‘surprise N2’. Despite optimal preoperative staging with positron emission tomography (PET) and invasive mediastinal staging, a small percentage of patients with preoperative clinical node-negative status will have lymph node metastases on final pathology3.
The question of whether a mediastinal lymph node dissection provides any advantage over a systemic sampling has been debated rigorously. In this publication, we have summarized the literature and provided our interpretation and recommendations on how to handle the mediastinum during curative intent surgery for NSCLC. Studies comparing mediastinal lymph node dissection (MLND) to mediastinal lymph node sampling (MLNS) are summarized in the table4-13. We also included studies which compared MLND to lobe-specific lymph node dissection (LSD)14-18. It should be noted that many of these studies were published more than 10 years ago.
Search strategy
We conducted a Medline search of English-language studies published from 1998 to 2019. We used the Medical Subject Heading term “lymph node dissection” and then “lymph node sampling”; the terms “lung cancer,” “non-small lung cancer,” were introduced to limit the number of studies identified. Of the 106 abstracts we reviewed, 2 studies did not include a surgical population, 80 articles were excluded because they did not include a long-term comparison of MLND versus MLNS. A careful review of the remaining 24 articles was conducted, and 13 articles were excluded because of methodological issues. The remaining 11 articles were included in this analysis. The references for each of those articles were searched, yielding an additional 2 articles that were included.
Definitions
Non-systemic or selective lymph node biopsy: In this procedure, one or multiple suspicious lymph node(s) are biopsied.
Systemic mediastinal lymph node sampling: Sampling is the removal of one or more lymph nodes guided by preoperative or intraoperative findings which are thought to be representative. Systematic sampling means a predetermined selection of the lymph node stations specified by the surgeon.
In Z0030, the definition included: For tumors in the right lung lymph node stations 2R, 4R, 7, and 10R were sampled. For tumors in the left lung, stations 5, 6, 7, and 10L were sampled. Any suspicious lymph nodes were also biopsied.
Systematic mediastinal lymph nodal dissection: All the mediastinal tissue containing the lymph nodes is dissected and removed systematically within anatomical landmarks Beside the mediastinal nodes, the hilar and the intrapulmonary lymph nodes are dissected as well
In Z0030, the definition included: For tumors on the right, all lymph tissue was removed from an area bounded by the takeoff of the right upper lobe bronchus, the innominate artery, the superior vena cava and the trachea (stations 2R and 4R). Lymph nodes in the prevascular area, adjacent to the superior vena cava, and retrotracheal nodes were removed. Complete MLND for tumors on the left involved removing all lymph tissue between the phrenic and vagus nerves extending down to the left main stem bronchus (stations 5 and 6). At the completion of the dissection, the aortopulmonary window was free of lymph tissue and the recurrent nerve was preserved. Regardless of the side of the tumor, complete subcarinal lymph node dissection was performed removing all lymph tissue caudal to the carina and both left and right mainstem bronchi (station 7). Lymph nodes in the inferior pulmonary ligament and adjacent to the caudal half of the esophagus were also removed (stations 8 and 9). When the dissection was complete, mainstem bronchi, posterior pericardium, and the esophagus were free of all lymph tissue
Lobe-specific systematic node dissection: In this procedure, the mediastinal tissue containing specific lymph node stations are excised, depending on the lobar location of the primary tumor. All ipsilateral hilar lymph node stations are dissected, but only specific mediastinal lymph node stations are resected depending on the lobar location of the primary tumor [stations 2R and 4R for right upper lobe (RUL), stations 5 and 6 left upper lobe (LUL) tumors; stations 7, 8R and 9R for right lower lobe (RLL) tumors; stations 7, 8L and 9L for left lower lobe (LLL) tumors; and stations 2R, 4R, 7, 8R and 9R for right middle lobe (RML) tumors].
Recommendations
- In patients with clinical stage I NSCLC, either a lymph node sampling, lobe-specific lymph node dissection or mediastinal lymph node dissection is recommended, with a preference given to dissection. A systemic lymph node sampling is equivalent to dissection if there is pathologic confirmation of negative mediastinal lymph nodes (either with preoperative invasive mediastinal staging or intraoperative frozen section).
Most studies demonstrate a higher incidence of N2 disease in MLND compared to MLNS, despite having similar demographics and tumor characteristics5,10. This would suggest that MLND may be better at detecting occult nodal disease. However, most studies that compare MLND to MLNS did not demonstrate an advantage in overall or progression-free survival. Furthermore, some studies show lower incidence of local relapse and increased cancer upstaging with MLND, and in one of these studies, there was a survival advantage to MLND5,9. Taking all these observations into consideration, one can deduce that MLND may result in better identification of occult N2 disease, perhaps better local control, but with no major impact on overall or cancer-specific survival.
The results of ACOSOG Z0030 trial have been used to justify MLNS as an alternative to MLND. This should be interpreted with caution because patients (cT1/2N0/1-less than hilar) were randomized only after a thorough mediastinal lymph node sampling and intraoperative frozen section analysis showed no evidence of lymph node disease. Therefore, the results of this study are not applicable to patients who have not had a systematic lymph node sampling which was negative, or tumors with higher T or N stage on preoperative imaging, as they were excluded from the study. Taking this into consideration, an MLNS may only be equivalent to MLND if intraoperative frozen section shows no evidence of nodal disease after systematic sampling.
All studies comparing lobe-specific lymph node dissection to MLND have shown equivalent rates of nodal detection, overall survival, and cancer-specific survival. Therefore, the committee suggests that a lobe-specific systemic dissection is equivalent to a mediastinal lymph node dissection in patients with clinical stage I NSCLC.
There are situations, however, where the incidence of nodal disease approaches zero, such as patients with semisolid nodules and small (< 2 cm), peripheral squamous cell cancers2,12. In these patients, an MLNS may be a reasonable alternative.
- In patients with clinical stage II and III NSCLC undergoing surgery (including patients who undergo preoperative chemotherapy or chemoradiation), we recommend a systemic mediastinal lymph node dissection or lobe-specific systemic lymph node dissection.
Given the lack of robust data showing equivalency of MLND and MLNS in patients with known nodal disease (stage IIIA) or at high risk of having nodal disease (stage II), the committee suggests that there is insufficient evidence to show that MLNS is equivalent to MLND is these patients.
- We recommend against the use of non-systemic or selective lymph node biopsy in patients undergoing curative-intent surgery for NSCLC.
Reference to Other Guidelines
- The committee fully endorses the ACCP guidlines1
- The committee fully endorses the National Comprehensive Cancer Network (NCCN) guidelines19
- The committee fully endorses the National Institute for Health and Care Excellence (NICE) guidelines20
- The ESTS recommends a lymph node dissection in most cases of NSCLC undergoing curative-intent surgery2. The Scottish Intercollegiate Guidelines Network (SIGN) guidelines also suggest that lymph node sampling is inadequate21. The committee does recognize that there are situations where a dissection might be favored over a sampling. However, after reviewing the literature, we have found that the evidence was not strong enough to recommend a blanket statement. The committee disagrees with the ESTS and SIGN guidelines in recommending a dissection over sampling in all cases.
Summary of Literature
Study |
N |
Preoperative evaluation |
Type |
Rate of lymph node disease |
Upstaging |
Survival |
Darling et al (Z0030) 2011 |
1,023 (498 MLNS, 525 MLND) |
CT, PET, selective invasive mediastinal staging
Only included patients who were pN0 |
Randomized controlled |
N2 4%
N1 12% |
N2 4%
N1 12% |
Median survival
MLNS 8.1 years
MLND 8.5 years |
Wu 2002 |
532
(MLNS 264
MLND 268) |
CT |
Randomized controlled |
N2 38% |
N2
MLNS 28%
MLND 48% |
Median survival
MLNS 34
MLND 59 |
Sugi 1998 |
115
(56 MLNS, 59 MLND) |
CT
Only included patients with tumor < 2 cm |
Randomized controlled |
22% |
MLNS
N1 5%
N2 14%
MLND
N1 7%
N2 15% |
5-year survival
MLNS 84%
MLND 81% |
Izbicki 1998 |
169
(93 MLNS, 76 MLND) |
Bronchoscopy, CT, abdominal ultrasound, bone scan |
Randomized controlled |
Not stated |
Not stated |
Median disease-free interval
MLNS 24 months
MLND 48 months
(p=0.233) |
Keller 2000 |
373
(MLNS 187
MLND 186) |
CT, selective invasive mediastinal staging
Stage II and IIIa |
Prospective nonrandomized |
100% |
MLNS
N1 40%
N2 39%
Skip N2 21%
MLND
N1 41%
N2 39%
Skip N2 20% |
Median survival
MLNS 29.2 months
MLND 57.5 months
Disease free survival
MLNS 21.4 months
MLND 33.2 months
(p = 0.086) |
Lardinosis 2005 |
100 (MLNS 50 MLND 50) |
CT, brain CT, bone scan, CM |
Prospective nonrandomized |
46% |
MLNS
N1 12%
N2 9%
MLND
N1 13%
N2 12% |
Median survival
MLNS 50.9 months
MLND 51.7 months
(p = 0.4) |
Massard 2006 |
208 (patients served as their own controls) |
Not stated |
Prospective nonrandomized |
N2 29%
N1 17%
“Skip N2” 12% |
MLNS 15%
MLND 29% |
Not stated |
Su 2008 |
319(MLNS 180, MLND 136) |
CT, Brain CT, abdominal US |
Retrospective |
Not stated |
Not stated |
5-year survival
MLNS 65.9%
MLND 76.4$
(p = 0.015) |
Ma 2008 |
105
(MLNS 63
MLND
42) |
Not stated
Included pathologic stage I patients only |
Retrospective |
0 |
N/A |
For tumors 2-3 cm
5 year survival
MLNS 55.8%
MLND 81.6%
For tumors < 2cm
No difference |
Takizawa 2008 |
119
(61 MLNS, 58 MLND) |
CT, selective invasive mediastinal staging |
Retrospective |
12.6% |
N2 = 13.8% in MLND
N2 = 11.5% in MLNS |
5-year cancer specific survival
MLNS 76.2%
MLND 78% |
Lobe-specific dissection (LSD) versus mediastinal lymph node dissection (MLND) |
Okada 2006 |
LSD 377
MLND 358 |
Not stated
Included only clinical stage I |
Retrospective |
6.1 |
LSD
N1 5.6%
N2 0.5 %
MLND
N1 5.3%
N2 0.8% |
5-year disease free survival
LNS 76.4%
MLND 73.4% (p = NS)
5-year survival
LNS 83.2 %
MLND 79.7%
(P = NS) |
Ishiguro 2010 |
LSD 137
MLND 625 |
Not states
Included stage cIA – cIIIB |
Retrospective |
Not stated |
N/A |
5 year survival
LSD 76%
MLND 71.9%
(p = NS) |
Maniwa 2013 |
335
LSD 129
MLND 206 |
CT, PET, Brain MRI
Included stage I-II |
Retrospective |
N1 7%
N2 6% |
LSD
N1 8.2%
N2 4.2 %
MLND
N1 8.3%
N2 7.7% |
5 year survival
LNS 89.7%
MLND 86.6%
(p = NS)
5 year disease free survival
LNS 76.4%
MLND 77.7%
(p = NS) |
Hishida 2016 |
5392
LSD 1268
MLND 4124 |
CT, selective PET and invasive mediastinal staging
Included stage cI-cII |
Retrospective |
Not stated |
N2
LSD 8.4%
MLND 12.7%
pN2 disease outside the LSD area and accessible only by SND = 3.2% |
5-year survival
LSD 81.5%
MLND 75.9%
(p = |
Adachi 2017 |
488
MLNS 153
LSD 145
MLND 190 |
CT, PET
Included cT1a–2b N0–1 M0 |
Retrospective |
N1 9%
N2 9% |
N1
MLNS 7.2%
LSD 7.6%
MLND 11.1%
N2
MLNS 3,3%
LSD 9%
MLND 13.1% |
5-year survival
MLNS 70.9%
LSD 74.7%
MLND 73.8%
(p = NS) |
References
- Howington JA, Blum MG, Chang AC, Balekian AA, Murthy SC. Treatment of Stage I and II Non-small Cell Lung Cancer; Diagnosis and Management of Lung Cancer,3rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST 2013; 143(5)(Suppl):e278S–e313S
- Lardinois D, De Leyn P, Van Schil P, Porta RR, Waller D, Passlick B, Zielinski M, Lerut T, Weder W. ESTS guidelines for intraoperative lymph node staging in non-small cell lung cancer. Eur J Cardiothorac Surg. 2006 Nov;30(5):787-92
- Nasir BS, Yasufuku K, Liberman M. When Should Negative Endobronchial Ultrasonography Findings be Confirmed by a More Invasive Procedure? Ann Surg Oncol. 2018 Jan;25(1):68-75
- Darling GE , Allen MS , Decker PA , et al . Number of lymph nodes harvested from a mediastinal lymphadenectomy: results of the randomized, prospective American College of Surgeons Oncology Group Z0030 trial. Chest. 2011;139(5):1124-1129.
- Wu Yl, Huang ZF, Wang SY, Yang XN, Ou W. A randomized trial of systematic nodal dissection in resectable non-small cell lung cancer. Lung Cancer. 2002 Apr;36(1):1-6.
- Sugi K, Nawata K, Fujita N, Ueda K, Tanaka T, Matsuoka T, Kaneda Y, Esato K. Systematic lymph node dissection for clinically diagnosed peripheral non-small-cell lung cancer less than 2 cm in diameter. World J Surg. 1998 Mar; 22(3):290-
- Izbicki JR, Passlick B, Pantel K, Pichlmeier U, Hosch SB, Karg O, Thetter O. Effectiveness of radical systematic mediastinal lymphadenectomy in patients with resectable non-small cell lung cancer: results of a prospective randomized trial. Ann Surg. 1998 Jan; 227(1):138-44
- 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 Aug;70(2):358-65
- Lardinois D, Suter H, Hakki H, Rousson V, Betticher D, Ris HB. Morbidity, survival, and site of recurrence after mediastinal lymph-node dissection versus systematic sampling after complete resection for non-small cell lung cancer. Ann Thorac Surg. 2005 Jul; 80(1):268-74
- Massard G, Ducrocq X, Kochetkova EA, Porhanov VA, Riquet M. Sampling or node dissection for intraoperative staging of lung cancer: a multicentric cross-sectional study. Eur J Cardiothorac Surg. 2006 Jul;30(1):164-7
- Su X , Wang X, Long H, Fu J, Lin P, Zhang Let al. . Mediastinal lymph node dissection affects survival in patients with stage I non-small cell lung cancer. Thorac Cardiovasc Surg 2008;56:226–30.
- Ma K, Chang D, He B, Gong M, Tian F, Hu X, Ji Z, Wang T. Radical systematic mediastinal lymphadenectomy versus mediastinal lymph node sampling in patients with clinical stage IA and pathological stage T1 non-small cell lung cancer. J Cancer Res Clin Oncol. 2008 Dec; 134(12):1289-9
- Takizawa H, Kondo K, Matsuoka H, Uyama K, Toba H, Kenzaki K, Sakiyama S, Tangoku A, Miura K, Yoshizawa K, Morita J. Effect of mediastinal lymph nodes sampling in patients with clinical stage I non-small cell lung cancer. J Med Invest. 2008 Feb;55(1-2):37-43.
- Okada M, Sakamoto T, Yuki T, et al. Selective mediastinal lymphadenectomy for clinico-surgical stage I non-small cell lung cancer. Ann Thorac Surg 2006;81:1028-32
- Ishiguro F, Matsuo K, Fukui T, et al. Effect of selective lymph node dissection based on patterns of lobe-specific lymph node metastases on patient outcome in patients with resectable non-small cell lung cancer: a large-scale retrospective cohort study applying a propensity score. J Thorac Cardiovasc Surg
- Maniwa T, Okumura T, Isaka M, et al. Recurrence of mediastinal node cancer after lobe-specific systematic nodal dissection for non-small-cell lung cancer. Eur J Cardiothorac Surg 2013;44:e59-64.
- Hishida T, Miyaoka E, Yokoi K, et al. Lobe-Specific Nodal Dissection for Clinical Stage I and II NSCLC: Japanese Multi-Institutional Retrospective Study Using a Propensity Score Analysis. J Thorac Oncol 2016;11:1529-37
- Adachi H, Sakamaki K, Nishii T, et al. Lobe-specific lymph node dissection as a standard procedure in surgery for non-small-cell lung cancer: A propensity score matching study. J Thorac Oncol 2017;12:85-93
- National Comprehensive Cancer Network (NCCN) guidelines. Lung Cancer. www.nccn.org
- Maconachie R, Mercer T, Navani N, McVeigh G. Lung Cancer: Diagnosis and Management: summary of updated NICE guidelines. BMJ 2019; 28:364-1049
- Scottish Intercollegiate Guidelines Network (SIGN). Management of Lung Cancer. Edinburgh: SIGN 2014. SIGN publication No. 137. Available from URL http://www.sign.ac.uk