Subsolid Lung Nodule, Invasive Lung Cancer & Metastatetomy

Mediastinal lymph node biopsy (sampling or dissection) may not be indicated for pure ground glass or ground glass predominant lung nodules <3cm (C:T < 0.5).

1. 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).
2. 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.
3. We recommend against the use of non-systemic or selective lymph node biopsy in patients undergoing curative-intent surgery for NSCLC.

1. Based on the current literature, the committee cannot recommend routine lymph node dissection or sampling in patients undergoing pulmonary metastesectomy
2. Thoracic lymph node sampling may be reasonable in situations where the presence of lymph node disease may impact decision making.

Background

The risk of mediastinal node involvement in subsolid lung lesions is related to the extent of the solid component, as measured by the consolidation:tumour size ratio or the absolute size of the solid component. For pure ground glass or ground glass predominant (C:T<0.5) nodules less than 3cm in total size, the risk of mediastinal node involvement is low, and may approach zero. The limited utility of mediastinal node sampling or dissection in this setting should be weighed against the limited, but non-zero, morbidity and cost of the procedure. The prognostic value of mediastinal node biopsy should also be taken into account in select circumstances such as bilateral lesions where there is a question about multiple primaries vs metastatic disease. The evidence for this recommendation comes predominantly from retrospective single centre studies in Asian countries and the applicability to Canadian practice is not known at this time.  The risk of nodal involvement for ground glass lesions >3cm is less well studied but also appears low.

Recommendation

Mediastinal lymph node biopsy (sampling or dissection) may not be indicated for pure ground glass or ground glass predominant lung nodules <3cm (C:T < 0.5).

Suggested Reading

• Moon Y, Park JK, Lee KY, Namkoong M, Ahn S. Consolidation/tumor ratio on chest computed tomography as predictor of postoperative nodal upstaging in clinical T1N0 lung cancer. World J Surg. 2018;42:2872-8.
• Hattori A, Matsunaga, Takamochi K, Oh S, Suzuki K. Significance of lymphadenectomy in part-solid lung adenocarcinoma: Propensity score matched analysis. Ann Thorac Surg. 2018;106:989-97
• Suzuki S, Sakurai H, Yotsukura M, et al. Clinical features of ground glass opacity-dominant lung cancer exceeding 3.0 cm in the whole tumor size. Ann Thorac Oncol. 208;105:1499-506.

References

1. Moon Y, Shung SW, Namkoon M, Park JK. The effectiveness of mediastinal lymph node evaluation in a patient with ground glass opacity tumor. J Thorac Dis. 2016;8:2617-25.
2. Haruki T, Aokage K, Miyoshi T, et al. Mediastinal nodal involvement in patients with clinical stage I non-small-cell lung cancer. Possibility of rational lymph node dissection. J Thorac Oncol. 2015;20:930-6.
3. Nakamura S, Fukui T, Kawaguchi K, et al. Does ground glass opacity-dominant feature have a prognostic significance even in clinical T2aN0M0 ling adenocarcinoma? Lung Cancer. 2015;89:38-42.
4. Hattori A, Matsunaga, Takamochi K, Oh S, Suzuki K. Importance of ground glass opacity component in clinical stage IA radiologic invasive lung cancer. Ann Thorac Surg. 2017;104:313-20. J Thorac Cardiovasc Surg. 2017;154:2102-10.
5. Hattori A, Matsunaga, Takamochi K, Oh S, Suzuki K. Prognostic impact of a ground glass opacity in the clinical T classification of non-small cell lung cancer.
6. Tsutani Y, Miyata Y, Nakayama H, et al. Prediction of pathologic node-negative clinical stage IA lung adenocarcinoma for optimal candidates undergoing sublobar resection. J Thorac Cardiovasc Surg. 2012;144:1365-71.
7. Berry MR, Gao R, Kunder CA, et al. Presence of even a small ground-glass component in lung adenocarcinoma predicts better survival. Clin Lung Cancer. 2017;19:e47-51.
8. Hayashi H, Ashizawa K, Ogihara Y, et al. Comparison between solid component size on thin-section CT and pathologic lymph node metastasis and local invasion in T1 lung adenocarcinoma. Jpn J Radiol. 2017;35:109-15.
9. Sim HJ, Choi SH, Chae EJ, et al. Surgical management of pulmonary adenocarcinoma presenting as a pure ground-glass nodule. Eur J Cardio-Thorac Surg. 2014;46:632-6.
10. Tsutani Y, Miyata Y, Nakayama H, et al. Appropriate sublobar resection choice for ground glass opacity-dominant clinical stage IA lung adenocarcinoma: Wedge resection or segmentectomy. Chest. 2014;145:66-71.

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 making^1,2. 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 table^4-13. 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

1. 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 characteristics^5,10. 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 MLND^5,9. 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 cancers^2,12.  In these patients, an MLNS may be a reasonable alternative.

2. 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.

3. 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

References

1. 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
2. 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
3. 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
4. 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.
5. 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.
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-
7. 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
8. 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
9. 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
10. 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
11. 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.
12. 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
13. 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.
14. 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
15. 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
16. 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.
17. 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
18. 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
19. National Comprehensive Cancer Network (NCCN) guidelines. Lung Cancer. www.nccn.org
20. Maconachie R, Mercer T, Navani N, McVeigh G. Lung Cancer: Diagnosis and Management: summary of updated NICE guidelines. BMJ 2019; 28:364-1049
21. Scottish Intercollegiate Guidelines Network (SIGN). Management of Lung Cancer. Edinburgh: SIGN 2014. SIGN publication No. 137. Available from URL http://www.sign.ac.uk

Background

Pulmonary metastesectomy in selected patients is associated with improved survival¹. The role for lymph node sampling or dissection during curative intent surgery for lung cancer has been established². However, the role of lymph node evaluation during pulmonary metastesectomy for extrathoracic malignancy is not well defined. Many questions remain unanswered, such as the need for routine versus selective mediastinal lymph node evaluation and whether a lymph node dissection is needed or is sampling enough. Most importantly, and perhaps even more difficult to answer, is there a therapeutic benefit to mediastinal lymph nodes that contain metastases from extrathoracic malignancy?

We have made a few observations form examining the literature. First, the icnidecne o f lymph node metastases are highest in series that perform an extensive lymph node dissection³. The most commonly examined histology is colorectal primary tumors, which have an incidence of thoracic lymph node metastases of 7-16%^4-9.

Second, that presence of thoracic lymph node metastases significantly impacts survival negatively. In ost series, the overall survival drops by approximately 50%^3-9. Additionally, 5 year survival approaches zero in some series^6,8.

Third, there is no conclusive evidence that resecting lymph nodes with metastatic deposits improves survival. There is no comparison or randomized trial that shows improvement if a lymph node dissection will result in better control, and based on the one series, the majority of patients will progress in distant sites⁸.

Recommendations

1. Based on the current literature, the committee cannot recommend routine lymph node dissection or sampling in patients undergoing pulmonary metastesectomy
2. Thoracic lymph node sampling may be reasonable in situations where the presence of lymph node disease may impact decision making.

There may be situations where the presence of lymph node metastases may impact decision making. For example, the decision to give additional systemic therapy or the decision to proceed with contralateral metastesectomy in the setting bilateral pulmonary metastases. It may be reasonable in theses situations to abort a contralateral metastesectomy if thoracic lymph node metastases are identified. Therefore, a mediastinal dissection or sampling may be beneficial to help with the decision making.

Summary of Literature

References

1. Pastorino U, Buyse M, Friedel G, et al. Long-term results of lung metastasectomy: prognostic analysis based on 5206 cases. J Thorac Cardiovasc Surg 1997;113:37–49.
2. 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
3. Kudelin N, Bölükbas S, Eberlein M, Schirren J. Metastasectomy with standardized lymph node dissection for metastatic renal cell carcinoma: an 11-year single-center experience. Ann Thorac Surg. 2013 Jul;96(1):265-70
4. Loehe F, Kobinger S, Hatz RA, Helmberger T, Loehrs U, Fuerst H. Value of systematic mediastinal lymph node dissection during pulmonary metastasectomy. Ann Thorac Surg. 2001 Jul;72(1):225-9
5. Saito Y, Omiya H, Kohno K, Kobayashi T, Itoi K, Teramachi M, Sasaki M, Suzuki H, Takao H, Nakade M. Pulmonary metastasectomy for 165 patients with colorectal carcinoma: A prognostic assessment. J Thorac Cardiovasc Surg. 2002 Nov;124(5):1007-13.
6. Ercan S, Nichols FC 3rd, Trastek VF, Deschamps C, Allen MS, Miller DL, Schleck CD, Pairolero PC. Prognostic Significance of Lymph Node Metastasis Found During Pulmonary Metastasectomy for Extrapulmonary Carcinoma. Ann Thorac Surg 2004;77:1786 –91.
7. Pfannschmidt J, Klode J, Muley T, Dienemann H, Hoffmann H. Nodal Involvement at the Time of Pulmonary Metastasectomy: Experiences in 245 Patients. Ann Thorac Surg 2006;81:448 –54
8. Welter S, Jacobs J, Krbek T, Poettgen C, Stamatis G. Prognostic impact of lymph node involvement in pulmonary metastases from colorectal cancer. Eur J Cardiothorac Surg. 2007 Feb;31(2):167-72
9. Hamaji M1, Cassivi SD, Shen KR, Allen MS, Nichols FC, Deschamps C, Wigle DA. Is lymph node dissection required in pulmonary metastasectomy for colorectal adenocarcinoma? Ann Thorac Surg. 2012 Dec;94(6):1796-800