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Ann Thorac Surg 2007;84:940-945
© 2007 The Society of Thoracic Surgeons

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Original Articles: General Thoracic

Accessing the Aortopulmonary Window (#5) and the Paraaortic (#6) Lymph Nodes in Patients With Non-Small Cell Lung Cancer

^a Department of Surgery, Division of Cardiothoracic Surgery, The University of Alabama at Birmingham, Birmingham, Alabama
^b Department of Epidemiology, Division of Cardiothoracic Surgery, The University of Alabama at Birmingham, Birmingham, Alabama
^c Division of Gastroenterology and Hepatology, The University of Alabama at Birmingham, Birmingham, Alabama

Accepted for publication April 23, 2007.

^_* Address correspondence to Dr Cerfolio, Division of Cardiothoracic Surgery, University of Alabama at Birmingham, 703 19th St S, ZRB 739, Birmingham, AL 35294 (Email: robert.cerfolio{at}ccc.uab.edu).

Presented at the Poster Session of the Forty-third Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Jan 29–31, 2007.

	Abstract

Top Abstract Introduction Material and Methods Results Comment References

 
Background: The purpose of this study was to assess the efficacy of the different techniques of lymph node biopsies in patients with suspected metastatic non-small cell lung cancer (NSCLC) in the subaortic (station #5) and paraaortic (station #6) lymph nodes.

Methods: This was a retrospective cohort study conducted of a prospective database of patients between January 2003 and June 2006 with suspected N2 disease only in the #5 or #6 lymph nodes, or both. All patients had integrated 2-deoxy-2-fluoro-D-glucose positron emission tomography/computed tomography, and nodal biopsy or thoracotomy, or both, with complete thoracic lymphadenectomy.

Results: There were 112 patients with clinically suspected N2 disease in lymph node stations #5 or #6, or both. The primary tumor was in the left upper lobe in 98 (88%) and in the left lower lobe in 14 (13%), and 58 had pathologic N2 disease in #5 or #6 lymph node stations only. Mediastinoscopy, used in all patients found, unsuspected N3 disease in 4 patients (3.6%) and N2 (#4L) disease in 12 (11%). Endoscopic ultrasound with fine needle aspiration (EUS-FNA), implemented in 62 patients (56%), correctly identified 41 patients (66%). Left single-incision video-assisted thoracic surgery (VATS) was used in 39 patients and was correct in 100%. Of the 58 patients, 53 (91%) completed neoadjuvant chemoradiotherapy, followed by resection, and their 5-year survival was 64%.

Conclusions: EUS-FNA is less accurate for the #5 and #6 lymph node stations than left VATS. We prefer left VATS over the Chamberlain procedure for patients with suspected nodal metastases isolated only to #5 or #6 stations, and if positive, we prefer neoadjuvant therapy. The advantage of neoadjuvant therapy followed by resection compared with resection followed by adjuvant therapy remains controversial; and hence, the role for biopsy of these nodes is also controversial.

	Introduction

Top Abstract Introduction Material and Methods Results Comment References

 
Non-small cell lung cancer (NSCLC) is the number one cause of cancer deaths worldwide [1]. An estimated 162,460 deaths from NSCLC (29% of all cancer deaths) occurred in 2006 in the United States alone [2]. Surgical resection, which is offered for early stage lung cancer, can be curative. However, if there is metastatic disease to the mediastinal (N2) lymph node stations, which represents stage IIIa disease, resection is often preceded by chemoradiotherapy and the overall survival is lower [3].

In addition, N2 disease represents an extremely diverse, heterogeneous group of patients; thus, the ideal treatment for these patients is controversial. For example, some patients have bulky N2 disease that involves many different N2 lymph node stations, and others have only microscopic disease that is found after resection. The survival of these two groups of patients is quite different, and thus, perhaps their treatment strategies should be different as well.

Another example of this heterogenicity is the variation in survival by involvement isolated to specific nodal stations. N2 disease isolated to the lymph nodes near the aortopulmonary window, namely lymph node #5 (the subaortic or aortopulmonary window nodes) and #6 (the paraaortic or ascending aortic or phrenic nodes) [4], has been reported to have a better prognosis compared with involvement of other N2 nodal stations [5–8].

Thus, the role of neoadjuvant chemoradiotherapy in these patients remains controversial. If one favors pathologically proving this type of N2 disease before resection to offer neoadjuvant therapy, the best procedure to choose is also controversial. Some prefer an anterior mediastinotomy (Chamberlain procedure), others prefer video-assisted thoracic surgery (VATS) and some choose endoscopic ultrasound with fine needle aspiration (EUS-FNA). Therefore, we evaluated the outcomes and the efficacy of these biopsy methods in a cohort of patients clinically staged with N2 disease isolated to the #5 or #6 lymph nodes.

	Material and Methods

Top Abstract Introduction Material and Methods Results Comment References

 
This is a retrospective cohort study using an electronic prospective database consisting of a series of consecutive patients during a 3-year period from January 2003 to June 2006. Patients who were younger than 19 years old or who had diabetes mellitus were excluded from the study. This study and the electronic prospective database used for data compilation were both approved by the Institutional Review Board (IRB) at the University of Alabama at Birmingham. Patient consent for participation in the prospective database was obtained; however, individual consent for participation in this retrospective study was waived by the IRB.

The entry criteria mandated that patients have NSCLC and clinical evidence of metastatic lymph node disease in the mediastinal lymph node stations #5 or #6, or both, based on dedicated 2-deoxy-2-fluoro-D-glucose (FDG) positron emission tomography (PET) or by computed tomography (CT), or both. Patients who had pathologic N2 disease in these stations that was not suggested by clinical staging before resection were eliminated from this study as were patients who had clinical evidence of N2 disease in stations #5 or #6, or both, and who also had evidence of N2 disease in other stations.

Staging
Patients were staged as we previously reported in 2005 [9]. Entry criteria for this study mandated a FDG PET/CT scan and CT scan with intravenous contrast and 5-mm collimated slices no more than 1 month before resection or nodal biopsy. All sites suggestive for disease were investigated. Suspicious sites on PET were defined as any site of a possible N2, N3, or M1 lesion that had a maximum standardized uptake value (maxSUV) of 2.5 or more or called suspicious by the radiologist. Suspicious sites on CT scan were defined as any site of a possible N2, N3 node if the node was more than 1.0 cm in its shortest axis, and any site called by the radiologists as possible or suspicious for metastatic cancer (M1). Appropriate tests were performed as described previously [10]. (For this study, patients with questions of N3 or M1 disease were eliminated.)

Mediastinoscopy was used to biopsy suspicious lymph nodes in the paratracheal area (stations #2R, #4R, #2L, #4L, and the superior portion of #7), and EUS-FNA was used to biopsy suspicious posterior subaortic (aortopulmonary) window (#5), subcarinal (#7), periesophageal (#8), and inferior pulmonary ligament lymph nodes (#9), as previously described [11]. VATS was used in this study to sample the #5, #6, #7, #8, and #9 lymph nodes on the left, and a Chamberlain procedure was used to sample the #5 and #6 lymph node stations. All #10R and #10L nodes were considered N1 nodes for this study. Patients with suspected M1 disease in the liver, adrenal, or contralateral lung underwent definitive biopsy to prove or disprove M1 cancer. If the bone or brain was suspected to harbor metastases, MRI was considered the standard reference.

Patients who had biopsy-proven N2 disease before thoracotomy underwent neoadjuvant chemoradiotherapy as previously described [12]. In general, patients with N2 disease underwent neoadjuvant radiation using doses of 60 Gy or higher and cisplatinum-based chemotherapy. All patients were restaged after neoadjuvant therapy, and resection was generally reserved for those who were down-staged as previously described [13].

At the time of left thoracotomy, all lymph nodes contained in the #4L, #5, #6, #7, #8, and #9 lymph node stations were completely removed. Pathologic review was performed by using standard techniques, and immunohistochemical staining was used selectively. The pathologic stage was assessed using the international staging system. Operative morbidity was defined as previously described [12]. Operative mortality was defined as death within 30 days of the surgical procedure from any cause or during the same hospital admission.

Statistical Analysis
Analysis was performed using SAS 9.0 software (SAS Inc, Cary, NC). Accuracy (defined as true negative plus the true positive results divided by the sum of all true and false results) was determined using the pathology or biopsy results as the gold standard. Nonparametric estimates of survival were obtained by the Kaplan-Meier analysis. A parametric method was used to estimate shaping parameters and project survival [14]. A value of p 0.05 was considered to indicate a statistically significant outcome unlikely due to chance.

	Results

Top Abstract Introduction Material and Methods Results Comment References

 
There were 112 patients (73 men) with a median age of 64 years who were clinically staged with N2 disease that was located only in lymph node stations #5 or #6, or both. The primary tumor was in the left upper lobe in 98 (88%) and in the left lower lobe in 14 (13%). After definitive biopsy, only 58 (52%) of the 112 patients were pathologically confirmed as having metastatic disease only in these nodal stations (group A). Of the 54 patients who had different pathology (group B), 15 were pathologically staged as N0 or N1, and 39 had N2 disease in other nodal stations. Table 1 summarizes the pathologic characteristics of the tumors of these 112 patients. Figure 1 depicts the study algorithm and results.

View larger version (30K): [in this window] [in a new window]   Fig 1. Algorithm used in this study. Shaded boxes consist of patients in group B from Table 1 only. *Five patients did not return for restaging after neoadjuvant therapy. (EUS-FNA = endoscopic ultrasound with fine needle aspiration; LN = lymph node; PET/CT = positron emission tomography/computed tomography; VATS = video-assisted thoracic surgery.)

View larger version (10K): [in this window] [in a new window]   Fig 2. Depicts the overall survival of the 58 patients (group A) with N2 disease at the #5 or #6 lymph nodes only. Circles are Kaplan-Meier estimates at 1-year intervals with confidence intervals. Solid line represents parametric survival estimates. Number of patients at risk is shown for each year.

	Comment

Top Abstract Introduction Material and Methods Results Comment References

If the presence of N2 disease did not change management, then there would be little role for mediastinoscopy unless ones argues that it is only performed to ensure N3 disease is not present, which is very infrequent (only 3.6% in our series). Therefore, most physicians who suspect N2 disease before resection according to the clinical stage as suggested after PET and CT scan will prove or disprove it using minimally invasive techniques.

If the patient is pathologically proven to have N2 disease, most recommend neoadjuvant chemotherapy or chemoradiotherapy before resection; however, even these statements are controversial. Microscopic unsuspected N2 disease, which is usually not detected by PET, may be best treated by resection with complete thoracic lymphadenectomy, followed by adjuvant therapy. Thus, several controversies still exist over the ideal therapy for patients with N2 NSCLC.

Patients with stage IIIa NSCLC from N2 lymph node disease that is isolated to the #5 (subaortic) and #6 (paraaortic) lymph nodes represents an even more controversial and unique group. Our series evaluated patients with clinically suspicious N2 disease in those two lymph node stations only. Only about half (52%) had it, and this further supports the relative inaccuracy of clinical staging compared with pathologic staging, as we have previously reported [9].

As shown in Figure 1, we prefer neoadjuvant chemoradiotherapy for these patients. The 5-year survival was 64%. The survival of the 10 patients who received adjuvant chemotherapy was slightly greater at 70%. The 5 patients who were complete responders in this series are all still alive, with a median follow-up of 2.7 years. We have used induction chemotherapy and high-dose radiation (60 Gy or higher) because it leads to higher complete response rates, and patients who have a complete response have been shown to have higher survival [17, 18]. We also prefer it because if patients get the standard 4500 Gy dose and then after restaging are found to have recalcitrant N2 and are not resected, the large time gaps in the completion of the radiotherapy, which diminishes its efficacy, are avoided.

The survival rate of patients in our series who had disease isolated to these two nodal stations who underwent resection after neoadjuvant therapy is higher than Paterson and colleagues [19] reported in 1987 (the second largest series in the literature). They reported a 5-year overall survival rate of 42% in 35 patients with disease isolated to this nodal station.

Results from other series that evaluated similar patients are summarized in Table 3. The variability in survival rates may be attributed to several reasons. The first is that most series consisted of a relatively small number of patients over a wide range of times; therefore, the death of even 1 patient would significantly alter the survival rate.

Finally, variability in study methods, such as diagnosis and treatment protocols, between series may also contribute. For example, the differences in survival between our report and others may not only be secondary to the use of neoadjuvant therapy but also due to the lack of stage migration seen in our cohort. All patients in our series had a dedicated PET before their operation and underwent complete thoracic lymphadenectomy. Despite the differences, one consistency remains for all of these series: the survival rate of patients with metastatic disease in stations #5 and #6 only was considerably higher than in those patients who also had other N2 station involved.

Why Prove N2 Disease in the #5 or #6 Lymph Nodes?
Does proving N2 disease in the #5 and #6 lymph node stations to offer therapy before resection offer a true survival advantage compared with resection, followed by adjuvant therapy? Do our relatively favorable results suggest that we should continue to try to prove it before resection? There are no randomized data to fully answer these questions.

How Best to Prove N2 Disease in the #5 or #6 Lymph Nodes
If one believes that neoadjuvant therapy is best for these patients, then the next controversial issue is how best to biopsy these nodes. Chamberlain described performing a left anterior mediastinotomy and it is named after him. This technique is commonly used, but many surgeons perform a large anterior thoracotomy. It is anything but minimally invasive. They often remove a rib or piece of cartilage and make a long 5-cm to 8-cm incision. Patients often have large left upper lobe tumors and this can make the Chamberlain more difficult. In addition, a significant number of patients have had a coronary artery bypass procedure that has used the left internal mammary artery for grafting, and this can make Chamberlain not only difficult but also dangerous.

Within the past decade, we have come to favor left VATS as our preferred staging procedure to prove or disprove cancer in the #5 or #6 nodal stations. As shown in the results from this study, it is very accurate. We find it easier and less invasive to get to these nodes with VATS compared with Chamberlain. VATS also allows for inspection of the pleural space, and if needed, it can also reliably ascertain mediastinal invasion. In addition, VATS may also require less time compared with the Chamberlain procedure [20].

EUS-FNA does not reliably assess the #5 or #6 nodal stations, but like mediastinoscopy, it can accurately assess the 4L lymph node station.

Oftentimes a language or labeling problem exists. A surgeon may call a specific lymph node a #5 or #6 node, but the endosonographer or radiologist assigns it a different number. This problem also exists between surgeons. This obviously represents a major problem in any study on this issue, and we all need to talk the same language.

Conclusion
Our recommendations for patients with NSCLC who have suspected N2 disease in the #5 (subaortic or aortopulmonary window nodes) or the #6 (paraaortic, ascending aortic or phrenic nodes) are outlined in Figure 3. We prefer preoperative clinical staging using CT scan with intravenous contrast and 5-mm collimated cuts. In addition, we prefer integrated PET/CT because it is superior to dedicated PET [10, 21]. If metastatic disease is suspected in these stations, we prefer left VATS to biopsy these nodes. If the nodes are negative for metastatic cancer, we perform a left thoracotomy, lobectomy, R0 resection, and complete thoracic lymphadenectomy. If the nodes are positive for metastatic cancer, we prefer induction chemoradiotherapy, followed by repeat staging and complete resection in properly selected patients, as we have previously described [22].

View larger version (17K): [in this window] [in a new window]   Fig 3. Our recommended staging algorithm for patients with suspected N2 disease at the aortopulmonary window lymph nodes. (EUS-FNA = endoscopic ultrasound with fine needle aspiration; LN = lymph node; L VATS = left video assisted thoracic surgery; NSCLC = non-small cell lung canger; PET/CT = positron emission tomography/computed tomography; VATS = video-assisted thoracic surgery.)

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Robert J. Cerfolio Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cerfolio, R. J. Articles by Eloubeidi, M. A. Search for Related Content PubMed PubMed Citation Articles by Cerfolio, R. J. Articles by Eloubeidi, M. A. Related Collections Lung - cancer