Nodal upstaging: effects of instrumentation and three-dimensional view in clinical stage I lung cancer

Introduction

Definition of the ideal surgery for lung cancer patients could be concluded as follows: an approach with minimal morbidity allowing patients to return to daily activities in short time, but without any compromises in the oncologic principles. Minimally invasive surgeries are performed to the lung cancer patients with abovementioned expectations. Unfortunately, very few data exists to define the oncologic quality and equivalence of the minimally invasive surgery versus open surgery.

To define the oncologic equivalence, the prevalence of pathologic nodal upstaging is used as a quality measure for the definition of the completeness of the nodal dissection, and surgery by comparing video-assisted thoracoscopic surgery (VATS) and thoracotomy patients (1,2). Several studies have shown that VATS has less nodal upstaging than thoracotomy, suggesting a difference in the completeness of nodal evaluation. However, none has demonstrated a difference in overall or disease-free survival (2).

Here, in this study we will try to define the effects of instrumentation and three-dimensional view in clinical stage I lung cancer for nodal upstaging.

How is nodal upstaging for lung cancer defined?

Nodal upstaging after surgical intervention for non-small cell lung cancer (NSCLC) is defined as the presence of unsuspected pathologic hilar (pN1) or mediastinal (pN2) disease detected during the final histopathologic evaluation of surgical specimens, in patients presumed to have clinical N0 diseases (1,2). Nodal upstaging may occur in a significant proportion of the patients. According to Cancer and Leukemia Group B prospective clinical trial (CALGB 9761), 28% of clinical stage I lung cancer patients were upstaged (14% stage II and 14% stage III) (3).

Are there any predictors for nodal upstaging in lung cancer?

Hilar and mediastinal lymph nodes can be evaluated either by non-invasive (chest computed tomography, positron emission tomography, etc.) or by invasive (mediastinoscopy, endobronchial ultrasound, VATS, etc.) methods. Each of these techniques has its own false-positive or negative predictive rates. As imaging did not identify the nodal metastases, nodal upstaging is likely dependent on the efficacy of the surgical lymph node evaluation. Therefore, the prevalence of nodal upstaging may be a landmark for the completeness of nodal evaluation (1,2). Incomplete staging might also happen since invasive staging of both hilar and peribronchial lymph nodes remains challenging with more recent techniques including endobronchial or endoscopic ultrasound (2).

Rocha et al. (4) investigated the predictors of upstaging in 109 patients with clinical stage I/II lung cancer. Their study is of limited value, since the authors did not analyse specifically the predictors of upstaging due to N stage, but included patients upstaging due to T stage. They concluded that early-stage NSCLC located in the lower lobes was associated with upstaging after surgery. Another study investigating nodal upstaging was reported by Al-Sarraf et al. (5). This is study evaluated the risk factors of inaccuracy in N staging (both downstaging and upstaging), and concluded that inaccurate nodal staging was common in patients with history of tuberculosis, rheumatoid arthritis, and diabetes mellitus. In patients with abovementioned co-morbidities, especially interlobar lymph nodes are adhesive to pulmonary artery and its branches. Many times surgeons would not perform a proper dissection in the benefit of the patient to prevent bleeding. Robotic surgery is an excellent type of surgery to dissect these adhesive nodes in our experience.

Contrary to the abovementioned studies, the study of Lee et al. (6) is more specific. The authors investigated the risk factors of occult mediastinal metastases in clinical stage I NSCLC patients (n=224) with CT and PET-CT negative results for mediastinal lymph nodes. According to this study, risk factors for N2 upstaging in stage I NSCLC were the presence of a central tumor, tumor size larger than 2 cm, and a SUVmax value of more than 4 for primary tumor. Besides, the authors concluded that there was a trend to occult nodal mediastinal metastasis in patients with adenocarcinoma. In a recent study, Decaluwé and colleagues (7) pointed out that centrally located tumors had a significant impact on N1 upstaging.

Some other studies also reported that the rate of nodal upstaging generally may increase with increasing clinical T stage (2,8-10). Licht et al. (2) also reported a significant nodal upstaging in lower lobe tumors. The type of the operation also affected the rate of nodal upstaging. Khullar and colleagues (11) demonstrated that lobar resections was associated with a higher rate of nodal upstaging compared to sublobar resections.

Based on the abovementioned studies, we can specifically describe the candidate patients for nodal upstaging. N1 and N2 level proper lymph node dissection should be a must in lung cancer patients to define the adjuvant treatment after the surgery.

VATS as a minimally invasive technique and its effects on nodal upstaging compared to thoracotomy

Too many articles have been published on VATS lobectomy during the past two decades. VATS has been generally shown to have its benefits, including decreased pain, lesser trauma, shortened length of postoperative stay, and increased compliance to adjuvant chemotherapy compared to thoracotomy. But the level of evidence for its superiority is low.

Survival rates of VATS are similar with those of thoracotomy, but orthodox surgeons maintained the criticisms for VATS resections as if there is a concern for a less systematic lymph node dissection. There are many studies which have demonstrated no difference in the number of lymph nodes and lymph node stations dissected (12-14). Some other groups have found the LN dissection to be incomplete during VATS (15).

Several studies compared VATS with thoracotomy in terms of nodal upstaging, and reported that the rate of both techniques were similar (12,16-18). Contrary to these studies, there are major studies based on larger number of patients favored thoracotomy to detect unsuspected nodal metastasis. Boffa et al. (1) investigated 11,513 patients from the Society of Thoracic Surgeons database undergoing anatomical pulmonary resections in clinical stage T1N0M0 or T2N0M0 lung cancer. They concluded that upstaging from N0 to N1 was more common in the thoracotomy group, however upstaging from N0 to N2 was similar between both approaches. Licht et al. (2) recruited their patients from the Danish Lung Cancer Registy database (n=1,513). The authors demonstrated that the rates of upstaging from N0 to both N1 and N2 were higher in patients undergoing thoracotomy. A very recent study reported by Medbery and colleagues (19) consisted of 16,983 patients collected from the National Cancer database undergoing lobectomy for early stage lung cancer revealed that the overall nodal upstaging was more common in thoracotomy group.

We can claim that expert VATS surgeons could provide similar lymph node dissection with VATS techniques. However, novice VATS surgeons may not provide similar capabilities, as they could do in open techniques. One other possible explanation for lower rate of nodal upstaging in VATS may be the selection of fissureless technique to prevent air-leak after VATS surgery. In this technique, as the fissure is not dissected, lymph node may remain undissected.

Theoretical superiorities of robotic surgery and its possible reflections

In the past decade, robotic assisted thoracic surgery (RATS) approach to anatomic lung resection became the newest minimally invasive technique, and studies have shown its feasibility and safety (20-22). Three-dimensional high-definition camera, dexterity, and precision in dissection are its superiorities compared with VATS. An important aspect of the RATS is the depth and accuracy of hilar and mediastinal nodal dissection (23). In comparative studies by Veronesi et al. (20) and Cerfolio et al. (21) the median numbers of lymph nodes removed by RATS and thoracotomy procedures were closely similar, suggesting that RATS achieves similar oncological radicality to that achieved by thoracotomy. In our recent study comparing three approaches (thoracotomy vs. VATS vs. RATS), we demonstrated that RATS could yield more peribronchial (number 11 and 12) compared to the other two techniques (24). We believe that this higher rate of interlobar lymph node dissection is due to our preference in performing segmentectomy operations more often which increases the number of dissected level 11 and 12 nodes. Another reason may be the fact that as the table surgeon staples the vessels, the console surgeon wants to provide a very clean field around the vessels for an easy stapling.

The reflections of RATS in the nodal upstaging remains controversial. Wilson and colleagues (25) reported that the rate of nodal upstaging of RATS was greater than that of VATS. Contrary to this study, Lee et al. (26) demonstrated that both techniques achieved similar rates of nodal upstaging. A very recent study by Yang et al. (27) compared 7,824 VATS and 2,025 RATS lobectomy patients using propensity score matching, and concluded that both approaches yielded similar results in terms of nodal upstaging.

The only study comparing three approaches (RATS, VATS and thoracotomy) in terms of nodal upstaging was recently reported. In their study, Martin et al. (10) demonstrated that nodal upstaging rates of RATS and thoracotomy were similar, but there was a lower upstaging rate with VATS. This study and our study claims that the robotic surgery even in the earliest experience may replicate the open surgery results.

Scrutiny of robotic surgeons

The systematic lymph node sampling or complete lymphadenectomy were accepted as the standarts for lymph evaluation after a resection either with VATS or RATS. Many times the comparisons are retrospective, however, the participating surgeons in these studies, in common, share similar philosophy regarding the role of hilar and mediastinal lymph node dissection. When VATS lobectomy was accused for not having any possibility for complete lymph evaluation, all VATS surgeons tried to demonstrate that the lymph node dissection was equal to open surgery (28). Having such an experience before, the robotic surgeons did their best to prevent the claims of incomplete lymph node dissection before any suspects rose.

Conclusions

One of the oncologic quality predictor of a resection is the lymph node dissection. Actually, the theorical superiority of a minimally invasive resections to recently developed radiotherapy techniques is the lymph node dissection. Nodal upstaging in clinical stage I lung cancer has been shown to be around 10–30%. Studies performed up to now, may suggest that, expert VATS surgeon could do similar lymph node dissection as it is done in open. Robotic surgeons, even in the early experience may replicate the results of lymph node dissection in the open techniques. The possible reason for this is the instrumental superiority provided by the high technology.

Acknowledgements

None.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

References

1. Boffa DJ, Kosinski AS, Paul S, et al. Lymph node evaluation by open or video-assisted approaches in 11,500 anatomic lung cancer resections. Ann Thorac Surg 2012;94:347-53; discussion 353. [Crossref] [PubMed]
2. Licht PB, Jørgensen OD, Ladegaard L, et al. A national study of nodal upstaging after thoracoscopic versus open lobectomy for clinical stage I lung cancer. Ann Thorac Surg 2013;96:943-9; discussion 949-50. [Crossref] [PubMed]
3. D'Cunha J, Herndon JE 2nd, Herzan DL, et al. Poor correspondence between clinical and pathologic staging in stage 1 non-small cell lung cancer: results from CALGB 9761, a prospective trial. Lung Cancer 2005;48:241-6. [Crossref] [PubMed]
4. Rocha AT, McCormack M, Montana G, et al. Association between lower lobe location and upstaging for early-stage non-small cell lung cancer. Chest 2004;125:1424-30. [Crossref] [PubMed]
5. Al-Sarraf N, Aziz R, Doddakula K, et al. Factors causing inaccurate staging of mediastinal nodal involvement in non-small cell lung cancer patients staged by positron emission tomography. Interact Cardiovasc Thorac Surg 2007;6:350-3. [Crossref] [PubMed]
6. 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. [Crossref] [PubMed]
7. Decaluwé H, Stanzi A, Dooms C, et al. Central tumour location should be considered when comparing N1 upstaging between thoracoscopic and open surgery for clinical stage I non-small-cell lung cancer. Eur J Cardiothorac Surg 2016;50:110-7. [Crossref] [PubMed]
8. Asamura H, Nakayama H, Kondo H, et al. Lymph node involvement, recurrence, and prognosis in resected small, peripheral, non-small-cell lung carcinomas: are these carcinomas candidates for video-assisted lobectomy? J Thorac Cardiovasc Surg 1996;111:1125-34. [Crossref] [PubMed]
9. Downey RJ, Akhurst T, Gonen M, et al. Preoperative F-18 fluorodeoxyglucose-positron emission tomography maximal standardized uptake value predicts survival after lung cancer resection. J Clin Oncol 2004;22:3255-60. [Crossref] [PubMed]
10. Martin JT, Durbin EB, Chen L, et al. Nodal Upstaging During Lung Cancer Resection Is Associated With Surgical Approach. Ann Thorac Surg 2016;101:238-44; discussion 44-5. [Crossref] [PubMed]
11. Khullar OV, Liu Y, Gillespie T, et al. Survival After Sublobar Resection versus Lobectomy for Clinical Stage IA Lung Cancer: An Analysis from the National Cancer Data Base. J Thorac Oncol 2015;10:1625-33. [Crossref] [PubMed]
12. Denlinger CE, Fernandez F, Meyers BF, et al. Lymph node evaluation in video-assisted thoracoscopic lobectomy versus lobectomy by thoracotomy. Ann Thorac Surg 2010;89:1730-5; discussion 1736.
13. Sagawa M, Sato M, Sakurada A, et al. A prospective trial of systematic nodal dissection for lung cancer by video-assisted thoracic surgery: can it be perfect? Ann Thorac Surg 2002;73:900-4. [Crossref] [PubMed]
14. Shigemura N, Akashi A, Funaki S, et al. Long-term outcomes after a variety of video-assisted thoracoscopic lobectomy approaches for clinical stage IA lung cancer: a multi-institutional study. J Thorac Cardiovasc Surg 2006;132:507-12. [Crossref] [PubMed]
15. Okada M, Sakamoto T, Yuki T, et al. Hybrid surgical approach of video-assisted minithoracotomy for lung cancer: significance of direct visualization on quality of surgery. Chest 2005;128:2696-701. [Crossref] [PubMed]
16. Watanabe A, Koyanagi T, Ohsawa H, et al. Systematic node dissection by VATS is not inferior to that through an open thoracotomy: a comparative clinicopathologic retrospective study. Surgery 2005;138:510-7. [Crossref] [PubMed]
17. D'Amico TA, Niland J, Mamet R, et al. Efficacy of mediastinal lymph node dissection during lobectomy for lung cancer by thoracoscopy and thoracotomy. Ann Thorac Surg 2011;92:226-31; discussion 231-2. [Crossref] [PubMed]
18. Stephens N, Rice D, Correa A, et al. Thoracoscopic lobectomy is associated with improved short-term and equivalent oncological outcomes compared with open lobectomy for clinical Stage I non-small-cell lung cancer: a propensity-matched analysis of 963 cases. Eur J Cardiothorac Surg 2014;46:607-13. [Crossref] [PubMed]
19. Medbery RL, Gillespie TW, Liu Y, et al. Nodal Upstaging Is More Common with Thoracotomy than with VATS During Lobectomy for Early-Stage Lung Cancer: An Analysis from the National Cancer Data Base. J Thorac Oncol 2016;11:222-33. [Crossref] [PubMed]
20. Veronesi G, Galetta D, Maisonneuve P, et al. Four-arm robotic lobectomy for the treatment of early-stage lung cancer. J Thorac Cardiovasc Surg 2010;140:19-25. [Crossref] [PubMed]
21. Cerfolio RJ, Bryant AS, Skylizard L, et al. Initial consecutive experience of completely portal robotic pulmonary resection with 4 arms. J Thorac Cardiovasc Surg 2011;142:740-6. [Crossref] [PubMed]
22. Louie BE, Farivar AS, Aye RW, et al. Early experience with robotic lung resection results in similar operative outcomes and morbidity when compared with matched video-assisted thoracoscopic surgery cases. Ann Thorac Surg 2012;93:1598-604; discussion 1604-5. [Crossref] [PubMed]
23. Gharagozloo F, Margolis M, Tempesta B. Robot-assisted thoracoscopic lobectomy for early-stage lung cancer. Ann Thorac Surg 2008;85:1880-5; discussion 1885-6.
24. Toker A, Özyurtkan MO, Demirhan Ö, et al. Lymph Node Dissection in Surgery for Lung Cancer: Comparison of Open vs. Video-Assisted vs. Robotic-Assisted Approaches. Ann Thorac Cardiovasc Surg 2016;22:284-290. [Crossref] [PubMed]
25. Wilson JL, Louie BE, Cerfolio RJ, et al. The prevalence of nodal upstaging during robotic lung resection in early stage non-small cell lung cancer. Ann Thorac Surg 2014;97:1901-6; discussion 1906-7.
26. Lee BE, Shapiro M, Rutledge JR, et al. Nodal Upstaging in Robotic and Video Assisted Thoracic Surgery Lobectomy for Clinical N0 Lung Cancer. Ann Thorac Surg 2015;100:229-33; discussion 233-4. [Crossref] [PubMed]
27. Yang CF, Sun Z, Speicher PJ, et al. Use and Outcomes of Minimally Invasive Lobectomy for Stage I Non-Small Cell Lung Cancer in the National Cancer Data Base. Ann Thorac Surg 2016;101:1037-42. [Crossref] [PubMed]
28. Ramos R, Girard P, Masuet C, et al. Mediastinal lymph node dissection in early-stage non-small cell lung cancer: totally thoracoscopic vs thoracotomy. Eur J Cardiothorac Surg 2012;41:1342-8; discussion 1348. [Crossref] [PubMed]