A. When is invasive mediastinal staging indicated?

Background:

As a general rule, invasive staging is typically held to be indicated when the risk of mediastinal lymph node involvement is 10% or greater. There is significant agreement in the existing published guidelines based on moderate to high quality evidence for the following recommendations.

Recommendation

Invasive mediastinal staging is indicated in patients with:

• Primary tumour >/= 3cm ^1-15
• Central tumour* ^{1-3, 7, 13, 16-19}
• CT evidence of enlarged N1/N2/N3 nodes ^{1, 2, 5, 10, 16, 17, 20-23}
• PET evidence of avid N1/N2/N3 nodes ^{1, 2, 5, 16, 17, 22-25}

Note:   Emerging evidence in smaller series has also identified other factors that are associated with an increased risk of mediastinal lymph node involvement. It is not well established if the risk is high enough to justify invasive staging on the basis of these risk factors alone in the absence of the above indications. These additional factors may supplement decision making on a case by case basis:

• Adenocarcinoma histology ^{3, 8, 13, 20, 27-29}
• High SUVmax of the primary tumour** ^{5, 12, 13, 30-34}
• Elevated serum CEA***^{4, 10, 11, 15, 35}

*“Central” is inconsistently defined in the literature²⁶. At the minimum, tumours within the central 1/3 of the chest should undergo invasive staging.
**The threshold value of SUVmax associated with increased risk varies between studies and is poorly defined.
***This test is not a routine part of the work-up of lung cancer in North America

Suggested Reading

1. Silvestri GA, Gonzalez AV, Jantz MA, et al. Methods for staging non-small cell lung cancer: Diagnosis and management of lung cancer, 3^rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143:e211S-50S.
2. Ettinger DS, Wood DE, Aisner DL, et al. NCCN clinical practice guidelines in oncology. Non-small cell lung cancer. Version 4.2018. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf Accessed June 4, 2018.
3. de Leyn P, Dooms C, Kuzdzal J, et al. Revised ESTS guidelines for preoperative mediastinal staging for non-small-cell lung cancer. Eur J Cardiothorac Sur. 2014;45:787-98.
4. Darling G, Dickie A, Malthaner R, Kennedy E, Tey R. Invasive mediastinal staging of non-small-cell lung cancer: A clinical practice guideline. Curr Oncol. 2011;18:e304-9.

References

5. Ettinger DS, Wood DE, Aisner DL, et al. NCCN clinical practice guidelines in oncology. Non-small cell lung cancer. Version 4.2018. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf Accessed June 4, 2018.
6. Darling G, Dickie A, Malthaner R, Kennedy E, Tey R. Invasive mediastinal staging of non-small-cell lung cancer: A clinical practice guideline. Curr Oncol. 2011;18:e304-9.
7. ­Chen K, Yang F, Jiang G, Li J, Wang J. Development and validation of a clinical prediction model for N2 lymph node metastasis in non-small cell lung cancer. Ann Thorac Surg. 2013;96:1761-8.
8. Cho S, Song IH, Yang HC, Kim K, Jheon S. Predictive factors for node metastasis in patients with clinical stage I non-small cell lung cancer. Ann Thorac Surg. 2013;96:239-46.
9. Farjah F, Lou F, SIma C, Rusch V, Rizk N. A prediction model for pathologic N2 disease in lung cancer patients with a negative mediastinum by positron emission tomorgraphy. J Thorac Oncol. 2013;8:1170-80.
10. Fernandez FG, Kozower BD, Crabtree TD, et al. Utility of mediastinoscopy in clinical stage I lung cancers at risk for occult mediastinal nodal metastases. J Thorac Cardiovasc Surg. 2014;149:35-42.
11. Gao SJ, Kim AW, Puchalski JT, et al. Indications for invasive mediastinal staging in patients with early non-small cell lung cancer staged with PET-CT. Lung Cancer. 2017;109:36-41.
12. Gomez-Caro A, Boada M, Cabanas M, et al. False-negative rate after positron emission tomography/computer tomography scan for mediastinal staging in c) stage non-small-cell lung cancer. Eur J Cardiothorac Surg. 2012;42:93-100.
13. Kanzaki R, Higashiyama M, Fujiwara A, et al. Occult mediastinal lymph node metastasis in NSCLC patients diagnosed as clinical N0-1 by preoperative integrated FDG-PET/CT and CT: Risk factors, pattern and histopathological study. Lung Cancer. 2011;71:333-7.
14. Kimura H, Iwai N, Ando S, et al. A prospective study of indications for mediastinoscopy in lung cancer with CT findings, tumor size, and tumor markers. Ann Thorac Surg. 2003;75:1734-9.
15. Koike T, Koike T, Yamato Y, Yoshia K, Tohabe SI. Predictive risk factors for mediastinal lymph node metastases in clinical stage IA non-small-cell lung cancer patients. J Thorac Oncol. 2012;7:1246-51.
16. Li L, Ren S, Zhang Y, et al. Risk factors for predicting the occult nodal metastasis in T1-2N0M0 NSCLC patients staged by PET/CT: Potential value in the clinic. Lung Cancer. 2013;81:213-7.
17. Lee PC, Port JL, Korst RJ, et al. Risk factors for occult mediastinal metastases in clinical stage I non-small cell lung cancer. Ann Thorac Surg. 2007;84:177-81.
18. Park HK, Jeon K, Koh WJ, et al. Occult nodal metastasis in patients with non-small cell lung cancer at clinical stage IA by PET/CT. Respir. 2010;15:1179-84.
19. Suzuki K, Nagai K, Yoshida J, et al. Clinical predictors of N2 disease in the setting of a negative computed tomographic scan in patients with lung cancer. J Thorac Cardiovasc Surg. 1999;117:593-8.
20. Silvestri GA, Gonzalez AV, Jantz MA, et al. Methods for staging non-small cell lung cancer: Diagnosis and management of lung cancer, 3^rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143:e211S-50S.
21. de Leyn P, Dooms C, Kuzdzal J, et al. Revised ESTS guidelines for preoperative mediastinal staging for non-small-cell lung cancer. Eur J Cardiothorac Sur. 2014;45:787-98.
22. Al-Sarraf N, Aziz R, Gately K, et al. Pattern and predictors of occult mediastinal lymph node involvement in non-small cell lung cancer patients with negative mediastinal uptake on positron emission tomography. Eur J Cardiothorac Surg. 2012;144:1360-4.
23. Zhang Y, Sun Y, Xiang J, et al. A prediction model for N2 disease in T1 non-small cell lung cancer. J Thorac Cardiovasc Surg. 2012;144:1360-4.
24. Fibla JJ, Molins L, Simon C, Perez J, Vidal G. The yield of mediastinoscopy with respect to lymph node size, cell type, and the location of the primary tumor. J Thorac Oncol. 2006;1:430-3.
25. Gurses A, Turna A, Bedirhan MA, et al. The value of mediastinoscopy in preoperative evaluation of mediastinal involvement in non-small-cell lung cancer patients with clinical N0 disease. J Thorac Cardiovasc Surg. 2002;50:174-7.
26. Pozo-Rodriguez F, Martin de Nicolás JL, Sánchez-Nistal MA, et al. Accuracy of helical computed tomography at [18F] fluorodeoxyglucose positron emission tomography for identifying lymph node mediastinal metastases in potentially resectable non-small-cell lung cancer. J Clin Oncol. 2005;23:8348-56.
27. Wang L, Jian W, Zhang C, et al. Lymph node metastasis in clinical stage IA peripheral lung cancer. Lung Cancer. 2015;90:41-6.
28. Yap KK, Yap KS, Byrne AJ, et al. Positron emission tomography with selected mediastinoscopy compared to routine mediastinoscopy offers cost and clinical outcome benefits for pre-operative staging of non-small cell lung cancer. Eur J Nucl Med Mol Imaging. 2005;32:1033-40.
29. Billé A, Pelosi E, Skanjeti A, et al. Preoperative intrathoracic lymph node staging in patients with non-small-cell lung cancer: accuracy of integrated positron emission tomography and computed tomography. Eur J Cardiothorac Surg. 2009:36:440-5.
30. Casal RF, Vial MR, Miller R, et al. What exactly is a centrally located lung tumor? Results of an online survey. Ann Am Thorac Soc. 2017;14:118-23.
31. Billé A, Okiror L, Skanjeti A, et al. Evaluation of integrated positron emission tomography and computed tomography accuracy in detecting lymph node metastasis in patients with adenocarcinoma vs squamous cell carcinoma. Eur J Cardiothorac Surg. 2013;43:574-9.
32. Choi YS, Shim YM, Kim J, Kim K. Mediastinoscopy in patients with clinical stage I non-small cell lung cancer. Ann Thorac Surg. 2003;73-364-6.
33. Mizuno T, Arimura T, Kuroda H, et al. Histological type predicts mediastinal metastasis and surgical outcome in resected cN1 non-small cell lung cancer. Gen Thorac Cardiovasc Surg. 20017;65:519-26.
34. Cerfolio RJ, Bryant AS, Eloubeidi MA. Routine mediastinoscopy and esophageal ultrasound fine-needle aspiration in patients with non-small cell lung cancer who are clinically N2 negative: A prospective study. Chest. 2006;130:1791-5.
35. Cerfolio RJ, Bryant AS, Ohja B, Bartolucci AA. The maximum standardized uptake values on positron emission tomography of a non-small cell lung cancer predict stage, recurrence, and survival. J Thorac Cardiovasc Surg. 2005;13-:151-9
36. Li M, Liu N, Hu M, et al. Relationship between primary tumor fluorodeoxyglucose uptake and nodal or distant metastases at presentation in T1 stage non-small cell lung cancer. Lung Cancer. 2009;63:383-6.
37. Lin JT, Yang XN, Zhing WZ, et al. Association of maximum standardized uptake value with mediastinal lymph node metastases in cN0 non-small cell lung cancer. Eur J Cardiothorac Surg. 2016;50:914-9.
38. Miyasaka Y, Suzuki K, Tamakochi K, Matsunaga T, Oh S. The maximum standardized uptake value of fluorodeoxyglucose positron emission tomography of the primary tumour is a good predictor of pathological nodal involvement in clinical N0 non-small-cell lung cancer. Eur J Cardiothorac Surg. 2013;44:83-7.
39. Ye B, Cheng M, Li W, et al. Predictive factors for lymph node metastasis in clinical stage IA lung adenocarcinoma. Ann Thorac Surg. 2014;98:217-23.

B. Choice of invasive modality

Background

When invasive mediastinal staging is required. Various modalities maybe utilized including, but not limited to cervical mediastinoscopy (CM), endobronchial ultrasound (EBUS) and endoscopic ultrasound (EUS). This set of recommendations will compare these techniques and attempt to set some parameters regarding required nodal stations. In doing so, we are very cognizant of the variation in the technology and expertise available at the various Thoracic Surgery centres across the country.

Recommendations

1. Both cervical mediastinoscopy (CM) and needle (FNA) techniques (EBUS with or without EUS) have excellent reported sensitivity, negative predictive value and accuracy.

Initial reports on the accuracy of EBUS and EUS in lung cancer staging yielded disappointing results with unacceptably high false negative rates. However, more contemporary reports have shown equivalence. Indeed, with wider access to mediastinal lymph node staging, needle techniques may prove to be superior to conventional surgical staging. Combined EBUS and EUS, for example, affords access at lymph nodes from station 2R, 2L, 3p, 4R, 4L, 5, 6, 7, 8R, 8L, 9R, 9L, 10R, 10L, 11R and 11L.

2. We recommend that invasive mediastinal staging, whether with mediastinoscopy or needle techniques should include sampling of at least the right paratracheal lymph node station (station 4R), left paratracheal lymph node station (station 4L) and subcarinal lymph node (station 7), as well as any other suspicious lymph node station by CT or PET criteria

Conventional reports of adequate mediastinoscopy in invasive staging of the mediastinum stipulate that both lower paratracheal lymph node stations and the subcarinal lymph node station should be sampled. While there may not be a lot of evidence that support this convention, it does seem like a reasonable and valid recommendation. This same rule should apply to needle techniques for the same reasons. Therefore, regardless of procedure, an invasive mediastinal staging procedure should only be considered adequate if it samples lymphoid tissue from both lower paratracheal lymph nodes and subcarinal lymph node, and any lymph nodes that are considered suspicions by CT or PET. For example, in a patient with a right upper lobe tumor and a suspicious high paratracheal lymph node by PET, and adequate mediastinoscopy or EBUS would include lymphoid tissue sampled from at least stations 4R, 4L, 7 and 2R.

3. If both procedures are readily available at an institution, then needle techniques (preferably under sedation in an endoscopy suite) should preferentially be selected to cervical mediastinoscopy

The most important factors in selecting which procedure to use is whether the selected procedure is performed adequately with good results, and whether the target lymph nodes are within reach of that procedure. For example, using mediastinoscopy alone in a patient with left lower lobe tumor and a suspicious lower paraesophageal lymph node (station 8L) would not be considered adequate even if lymph node tissue is adequately obtained from stations 4R, 4L and 7. However, in situations where both procedures can be used safely and adequately, the panel recommends a needle technique. This is because of the lower incidence of devastating complications and the lower cost associated with needle techniques. One should note, that the cost advantage of needle techniques is more pronounced when they are performed in an endoscopy suite.

4. In an institution where needle techniques are available with high quality, there is no need to confirm negative results with a more invasive procedure.

Given the equivalent results obtained by both procedures in the right setting, the practice of routinely confirming negative EBUS or EUS resulted is not supported by the current literature and is not necessary. There are situations where a negative EBUS or EUS result may require confirmation with a more invasive technique, such as CM or thoracoscopy. This includes inadequate samples or highly suspicious lymph nodes by imaging criteria that are unexpectedly negative.

Suggested reading

1. Silvestri GA, Gonzalez AV, Jantz MA, Margolis ML, Gould MK, Tanoue LT, Harris LJ, Detterbeck FC. Methods for staging 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 May;143(5 Suppl):e211S-e250S
2. Yasufuku K, Pierre A, Darling G, de Perrot M, Waddell T, Johnston M, da Cunha Santos G, Geddie W, Boerner S, Le LW, Keshavjee S. A prospective controlled trial of endobronchial ultrasound-guided transbronchial needle aspiration compared with mediastinoscopy for mediastinal lymph node staging of lung cancer. J Thorac Cardiovasc Surg. 2011 Dec;142(6): 1393-400
3. Liberman M, Sampalis J, Duranceau A, Thiffault V, Hadjeres R, Ferraro P. Endosonographic mediastinal lymph node staging of lung cancer. Chest. 2014 Aug;146(2):389-397
4. Czarnecka-Kujawa K, Rochau U, Siebert U, Atenafu E, Darling G, Waddell TK, Pierre A, De Perrot M, Cypel M, Keshavjee S, Yasufuku K. Cost-effectiveness of mediastinal lymph node staging in non-small cell lung cancer. J Thorac Cardiovasc Surg. 2017 Jun;153(6):1567-1578
5. Nasir BS, Yasufuku K, Liberman M. When should negative endobronchial ultrasound findings be confirmed by a more invasive procedure? Ann Surg Oncol. 2018 Jan;25(1):68-75