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Ann Thorac Surg 2006;81:1969-1973
© 2006 The Society of Thoracic Surgeons

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Original article: General thoracic

Distribution and Likelihood of Lymph Node Metastasis Based on the Lobar Location of Nonsmall-Cell Lung Cancer

^a Section of Thoracic Surgery, University of Alabama at Birmingham, and Division of Cardio-Thoracic Surgery, Birmingham Veterans Administration Hospital, Birmingham, Alabama
^b Department of Epidemiology, School of Public Health, and Department of Surgery, University of Alabama, Birmingham, Alabama

Accepted for publication December 14, 2005.

^_* Address correspondence to Dr Cerfolio, Division of Cardiothoracic Surgery, University of Alabama at Birmingham, 1900 University Blvd, THT 712, Birmingham, AL 35294 (Email: robert.cerfolio{at}ccc.uab.edu).

Presented at the Fifty-second Annual Meeting of the Southern Thoracic Surgical Association, Orlando, FL, Nov 10–12, 2005.

	Abstract

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BACKGROUND: Despite the use of integrated positron emission tomography and computed tomography scans in patients with nonsmall-cell lung cancer, N2 disease is often missed. Knowledge of the N2 station most likely to be malignant based on the lobar location of the primary may help guide biopsies.

METHODS: A retrospective review of an electronic prospective database of patients with nonsmall-cell lung cancer who underwent positron emission tomography and computed tomography clinical staging and had nodal biopsy or resection with complete lymphadenectomy, or both.

RESULTS: The incidence and location of N2 disease of the 954 patients based on the location of the primary tumor was as follows: for right upper lobe cancers, 27% had N2 disease, most commonly in the 4R (23%); right middle lobe, 15%, most commonly in the 4R (8%) and the 7th station (6%); right lower lobe, 30%, most commonly in the 4R (15%) and the 7th station (14%); left upper lobe, 20%, most commonly in the 6 (16%); and left lower lobe, 22%, most commonly in the 7 (8%). Patients with right middle lobe cancer were more likely to have N1 disease (p = 0.014). Skip metastases (no N1, but N2 disease) was most common with left upper lobe lesions. Patients with right-sided cancers were more likely to have N2 disease compared with patients who had left-sided lesions (27% versus 21%, p = 0.02).

CONCLUSIONS: There is a distinct predilection for the location of N2 disease based on the lobar location of primary nonsmall-cell lung cancer. We recommend the consideration of video-assisted thoracoscopy for biopsy of the 5 and 6 stations for patients with left upper lobe lesions, mediastinoscopy for right upper lobe lesions, and esophageal ultrasound with fine-needle aspiration for right lower lobe, left lower lobe, and right middle lobe lesions. Right-sided lesions are more likely to have N2 disease.

	Introduction

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The treatment of nonsmall-cell lung cancer (NSCLC) depends on the stage. The most sophisticated and accurate staging tools used to assess the clinical stage are integrated positron emission tomography (PET) and computed tomography (CT) using F-18 fluorodeoxyglucose (FDG-PET/CT) and CT scan with intravenous contrast and 5-mm collimated cuts. These tests provide targets for potential metastatic sites that should be biopsied using minimally invasive techniques. However, we have shown in a prospective study on 383 patients that even when these two tests are performed in all patients and read in a tertiary center by subspecialties, the clinical stage only accurately reflects the actual pathologic stage in 68%, 84%, and 74% of patients with stage I, II, and III NSCLC, respectively [1]. Mediastinal N2 lymph nodes remain a critical part of staging patients with NSCLC. If they are involved with metastatic cancer, it alters preoperative therapy. For this reason, some surgeons routinely perform mediastinoscopy in all patients with NSCLC. This practice, however, has been shown not to be cost effective [2]. Similarly, when we added the routine use of endoscopic ultrasound with fine-needle aspiration (EUS-FNA) to mediastinoscopy and prospectively studied it in patients who were staged N0 by both integrated PET/CT and by CT scan, we found EUS-FNA to also have a low positive predictive value [3].

The location of the primary NSCLC tumor in the lung affects which N2 nodes are most likely to harbor metastatic cancer [4, 5]. If one reliably knew which unsuspected stations were involved, one could narrow the search for nodal disease and apply the most appropriate test instead of performing all tests in all patients. Different staging procedures—mediastinoscopy, video-assisted thoracoscopy, and EUS-FNA—assess different N2 stations. The objective of this study was to determine the distribution of N2 disease in patients with NSCLC based on the lobar location of the primary lesion to later help direct the best minimally invasive test to discover it.

	Material and Methods

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This is a retrospective cohort study using an electronic prospective database of consecutive patients with NSCLC who underwent lymph node biopsy or complete resection with thoracic lymphadenectomy or both by one surgeon (R.J.C.) at the University of Alabama at Birmingham Hospital. Patients who did not have NSCLC, had biopsy-proven M1 disease, or who did not undergo nodal biopsies were eliminated. Patients who were less than 19 years old or had received neoadjuvant therapy before nodal biopsy were also excluded from the study.

Entry criteria mandated a dedicated FDG-PET scan and a CT scan with intravenous contrast and 5-mm collimated slices no more than 1 month before resection or nodal biopsy. All suspicious sites were investigated. Suspicious sites on FDG-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 greater or called by the radiologist as suspicious. Suspicious sites on CT scan were defined as any site of a possible N2, N3 node if the node was greater than 1.0 cm in its shortest axis, and any M1 as any site called by the radiologists as possible or suspicious for metastatic cancer. Appropriate tests were performed as described previously [1, 6]. This study and the electronic prospective database were approved by the Institutional Review Board at the University of Alabama at Birmingham Hospital, and individual patient consent was obtained for the database.

Data were analyzed using SAS v.9.0 (SAS, Cary, North Carolina). Efficacy was determined for CT and FDG-PET/CT using the pathology or biopsy results as the gold standard. Standard definitions were used for these calculations [7]. Lymph nodes that were not biopsied were not included in the calculations of the incidence as described below in the definition section.

Procedures, Staging, and Surgery
Patients were meticulously staged. All suspicious N2, N3, or M1 areas (maxSUV > 2.5) were biopsied before pulmonary resection. However, if an FDG-PET scan suggested a nodal metastasis and no lymph node was visible on a CT scan that correlated to that area, an exploration was not performed. Selective staging tests were chosen for different patients based on the targets suggested by the FDG-PET or the CT scan. Mediastinoscopy was used to biopsy suspicious lymph nodes in the paratracheal area (stations 2R, 4R, 2L, 4L, and the top of 7) and endoscopic transesophageal ultrasound was used to biopsy suspicious posterior aortopulmonary window nodes (5), subcarinal (7), periesophageal (8), and inferior pulmonary ligament nodes (9), as previously described [8]. Video-assisted thoracoscopy was used to sample the 2R, 4R, 5, 6, 7, 8, and 9 nodes and Chamberlin 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, magnetic resonance imaging was considered the standard reference.

If patients had biopsy proven N3 or M1 disease, the stage was recorded but they were not resected. If there was no evidence of N2 or higher disease, patients underwent thoracotomy, pulmonary resection, and complete thoracic lymphadenectomy. On the right side, all lymph nodes contained in the 2R, 4R, 7, 8, and 9 stations were completely removed. At the time of left thoracotomy, all lymph nodes contained in the 4L, 5, 6, 7, 8, and 9 lymph nodes stations were completely removed. Pathologic review was performed using standard techniques, and immunohistochemical staining was employed when appropriate. The pathologic stage was assessed using the international staging system [9].

Definitions
If a patient had evidence of N2 disease in several locations on the FDG-PET/CT or CT scan and a procedure was performed that biopsied only one N2 nodal station, only the location that was biopsy proven was considered positive in the calculation for the incidence of nodal disease. The other lymph nodes stations that were not biopsied were not considered positive, but also were not considered negative. If N3 disease was suggested, it was examined first and ruled out first (if there was no evidence of M1 disease). At time of mediastinoscopy, all five stations were evaluated and biopsied. However, at EUS-FNA or at video-assisted thoracoscopy, or both, if one station was proven and another lymph node at a different station was difficult to get to for a biopsy, a biopsy was not performed.

Skip metastases was defined as having N2 disease but no N1. If a tumor was located in more than one lobe, the main location of where the tumor appeared to start (where it was predominantly located) was considered its lobe of origin. In this way, every tumor was assigned as originating from only one lobe. If a tumor had features of adenocarcinoma and squamous carcinoma, it was called one or the other based on its predominate histological feature. Immunohistochemical staining was not performed routinely.

	Results

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There were 954 patients (648 men). Patient characteristics are shown in Table 1. The procedures used to prove N2 disease are listed in Table 2. As shown, we had a 6% unsuspected N2 rate at the time of thoracotomy. The incidence of N2, N1, and the histology based on the location of the primary NSCLC is shown in Table 3. Patients with a right lower lobe lesion had the highest incidence (30%) of N2 disease, and those with a right upper lobe were second (27%). Patients with right middle lobe cancers were more likely to have N1 disease than cancers located in other lobes (p = 0.014). Interestingly, patients with right-sided cancers were more likely to have N2 disease than those with left-sided lesions (27% compared with 21%, p = 0.02). Patients with adenocarcinoma were more likely to have N2 (p < 0.001) and N1 (p = 0.039) disease than those with squamous cell.

View larger version (34K): [in this window] [in a new window]   Fig 1. Incidence of the most common nodal stations for patients with proven N2 disease, based on the lobar location of the primary nonsmall cell lung cancer (NSCLC). For example, of the 372 patients who had a right upper lobe NSCLC, 102 patients had N2 disease. It was most commonly (23% of the time) located in the 4R lymph node station. It was located in the 2R nodal station in 17% of those 102 patients.

	Comment

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Our results are similar to those in previous reports. Naruke and associates [5] in 1999, Kotoulas and colleagues [4] in 2003, and Inoue and colleagues [10] in 2004 all reported similar incidence of N2 disease and very similar distribution of N2 disease based on the lobar location of the NSCLC tumor. In general, these four reports had similar findings. The most common mediastinal (N2) nodal metastatic stations were as follows: for right upper lobe cancers, the 4R lymph nodes; for right middle tumors, the 4R and 7 lymph nodes; and for right lower lobe, the 4R and 7 nodes. On the left side, the most common nodal stations were, for left upper lobe cancers, the 5 and 6 lymph nodes, and for left lower lobe cancer, the 6 and 7 stations.

The only finding that currently changes the preoperative management of patients with NSCLC is the discovery of metastatic N2, N3, or M1 disease. The latter two usually remove patients from the surgical arena, at least initially, so the surgeon most often deals with determining the absence or presence of N2 disease. Until future studies are finished and reported, the standard of care for patients with N1 disease is resection followed by adjuvant chemotherapy, although our preference is often to use preoperative chemotherapy. The standard of care for N2 disease known before resection (even for microscopic N2 disease, although solid data are lacking) is neoadjuvant therapy [11, 12]; thus, the search for unsuspected N2 disease remains clinically important.

Figure 2 shows the nodes that are accessible with the different staging procedures currently used and the reported accuracy at each nodal station. Some surgeons use mediastinoscopy routinely, for several reasons: it is safe, accurate, and it can discover unsuspected N2 as well as N3 disease. However, recently Haddad and colleagues [2] found in a prospective study that mediastinoscopy is not cost effective in patients clinically staged as N0 after PET and CT scan. Similarly, we [3] found in a prospective study that added routine EUS-FNA to mediastinoscopy in patients clinically staged as N0 after integrated PET/CT and CT that neither test seemed cost effective. In the Haddad study, only 4 of 149 patients (2.7%) clinically staged as N0 had a positive mediastinoscopy, and a total of only 11 of 195 (5.6%) had unsuspected N2 disease after resection. Our study added the routine use of EUS-FNA to mediastinoscopy in patients who were staged N0 by both integrated PET/CT and by CT scan. We found only 4 of 135 N0 patients (2.9%) had a positive mediastinoscopy, only 5 patients (3.7%) had a positive EUS-FNA, and only 6 of the remaining 126 patients (4.7%) had unsuspected N2 disease after pulmonary resection with complete thoracic lymphadenectomy. In retrospect, however, had we performed mediastinoscopy only for patients with right upper lobe cancers, the yield of routine mediastinoscopy would have tripled to 6%. Similarly, if we had ordered EUS-FNA only for those patients with a right middle, right lower, or left lower lobe cancer, the yield of routine EUS-FNA would have more than doubled to 10%.

View larger version (52K): [in this window] [in a new window]   Fig 2. Types of minimally invasive procedures available for N2 biopsy and the reported accuracy for each test. (* = superior portion only; checkmark = nodal station is accessible by this modality; EUS-FNA = endoscopic ultrasound–fine-needle aspiration; L = left; Med = mediastinoscopy; ? = maybe, conflicting data on the accuracy at these stations; R = right; VATS = video-assisted thoracoscopy.)

	Discussion

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DR DANIEL L. MILLER (Atlanta, GA): Cerf, excellent study. I was very interested to see that in your upper lobe tumors you had no subcarinal involvement at all. Sometimes that occurs on the left, but on the right, a small percentage of those will have disease down below. So I want you to comment on that.

DR CERFOLIO: Thanks, Dan, let me just correct that information. In the slides I am showing you the most prevalent nodes that were involved. There certainly were patients who had No. 7s involved, but I was showing you the two most common locations. Otherwise, the slide would be too busy.

DR MILLER: It would be a Tiki slide.

DR CERFOLIO: Yes, it would be like one of the slides you showed earlier in your talk, too much information. (Laughter)

DR MILLER: Secondly, even if you are biologically staging these patients with PET, surgical staging, you still missed 24% of the lymph nodes, and I wish you would comment on that.

DR CERFOLIO: What do you mean we missed 24% of the lymph nodes?

DR MILLER: I mean 24% of your lymph nodes were positive for N2, which beforehand, you would not have taken them to surgery if they had that.

DR CERFOLIO: Not that is not the data we just presented. Remember, not all these patients went to thoracotomy, some had a med only. 24% had N2 disease but you are asking how many had unsuspected N2 disease at the time of thoracotomy; that is a completely different question. It is not 24%. Now, the question you are asking me is how many patients after we do all these things, med EUS-FNA, etc, have unsuspected N2 disease? It is still high, I am embarrassed to tell you. It is about 5 to 6%, even if you do a mead and an EUS, and it may be 4 or 5%, I have to go back and look, but it's higher than it should be, I concur with your point, but it is not 24%. Some have microscopic N2 and not macroscopic. I will also air some dirty laundry. I had two patients who had false negative med. So I did the mediastinoscopy, I said the 2's and the 4's were negative, and there were two patients at thoracotomy who had a positive 4R that I missed at mediastinoscopy.

DR MILLER: And also I was proud to see that you did VATS staging on the left side.

DR CERFOLIO: Thank you. Yes, L VATS has supplanted the Chamberlain procedure in my practice for most patients to stage the 5 and 6 stations, as I have discussed in the passed. You may sit down now. (Laughter)

DR DAVID R. JONES (Charlottesville, VA): I enjoyed your talk. I take it that location was very important here, but is there any way you could also control for histology. Additionally, what about tumor size? Also, what about whether the tumor is peripheral versus central? Wouldn't these factors also seem to play a role in where the nodes may or may not be positive? Finally, did you look to see which lobar location was more likely to have single-station N2 disease versus multi-station N2 disease? I enjoyed your talk.

DR CERFOLIO: Thanks, Dave, very good questions and I appreciate them. Yes, we did look at size, and certainly a T2 was more likely to have N2 than a T1. The lobar location I showed you. The histology I also mentioned, adeno more commonly involved N2 nodes than squamous. And the location, central versus periphery is a little bit tricky to study because you have got to define where something becomes central and is no longer peripheral. We try to be very academic in these studies and that is not so clearly identified. There are many lesions that we would all agree upon as being central and those that are peripheral, but what about something somewhere in between? So we didn't look exactly at that. And multiple station or skipped stations is in the manuscript.

DR JOHN R. BENFIELD (Los Angeles, CA): You have convinced me that a prospective cooperative trial would be important. I would like to know your proposed study design. What would the controls be? Would you suggest that all patients in the control group have mediastinoscopy and EUS even though that combination is alleged not to be cost effective?

DR CERFOLIO: Thank you, Dr Benfield, for that question. I think the only way to see if a modality is cost effective is to apply it to everybody and critically analyze it. In the study we just finished, not yet published or written yet where we did med and EUS on all patients who were clinically staged after Ct and integrated PET/CT as N0 or N1 (but not N2, I can now say it is not cost effective to med and EUS-FNA those who are N0, but it is for those whoa re PET/CT N1). But that study did not take lobar location into account. So in the multi-institutional study I propose, I would look at all right upper lobes, and every single patient would get a mediastinoscopy, and then we would see if it was cost effective or not. I think that is the only way to judge the cost effectiveness of a modality, to apply it to everybody and see how it works.

	References

Top Abstract Introduction Material and Methods Results Comment Discussion References

 

1. Cerfolio RJ, Bryant AS, Ojha B, et al. Improving the inaccuracies of clinical staging of patients with NSCLCa prospective trial. Ann Thorac Surg 2005;80:1207-1213.[Abstract/Free Full Text]
2. Haddad FJ, Meyers BF, Zoole JB, et al. Should mediastinoscopy be routine for patients with clinical stage I lung cancer by CT and PET scans? A decision analysis. J Cardiothorac Surg. Publication pending..
3. Cerfolio RJ, Bryant AS, Eloubeidi M. Is routine EUS-FNA and mediastinoscopy in patients with clinical staged N0 non-small cell lung cancer cost effective? A prospective study. Publication pending..
4. Kotoulas CS, Foroulis CN, Kostikas K, et al. Involvement of lymphatic metastatic spread in non-small cell lung cancer accordingly to the primary cancer location Lung Cancer 2004;44:183-191.[Medline]
5. Naruke T, Tsuchiya R, Kondo H, et al. Lymph node sampling in lung cancerhow should it be done?. Eur J Cardiothorac Surg 1999(Suppl):S17-S24.
6. Cerfolio RJ, Buddhiwardhan O, Bryant AS, et al. The accuracy of integrated PET/CT compared with dedicated PET alone for the staging of patients with non-small cell lung cancer Ann Thorac Surg 2004;78:1017-1023.[Abstract/Free Full Text]
7. Beck J. Likelihood ratiosanother enhancement of sensitivity and specificity. Arch Pathol Lab Med 1986;110:685-686.[Medline]
8. Hawes RH, Gress F, Kesler KA, Cummings OW, Conces Jr DJ. Endoscopic ultrasound versus computed tomography in the evaluation of the mediastinum in patients with non-small-cell lung cancer Endoscopy 1994;26:784-787.[Medline]
9. Mountain CF. Revisions in the international systems for staging lung cancer Chest 1997;111:1710-1717.[Abstract/Free Full Text]
10. Inoue M, Sawabata N, Takeda S, et al. Results of surgical intervention for p-stage III(N2) non-small cell lung canceracceptable prognosis predicted by complete resection in patients with single N2 disease with primary tumor in upper lobe. J Thorac Cardiovasc Surg 2004;127:1100-1106.[Abstract/Free Full Text]
11. Roth JA, Fossella F, Komaki R, et al. A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small cell lung cancer J Natl Cancer Inst 1994;75:673-680.
12. Rosell R, Gomez-Codina J, Camps C, et al. A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer N Engl J Med 1994;330:153-158.[Abstract/Free Full Text]
13. Cerfolio RJ, Bryant AS, Ojha B, et al. The maximum standardized values after integrated PET/CT predicts the survival, recurrence and in patients with non-small cell lung cancer J Thorac Cardiovasc Surg 2005;130:1551-1559.

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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 Bryant, A. S. Search for Related Content PubMed PubMed Citation Articles by Cerfolio, R. J. Articles by Bryant, A. S. Related Collections Lung - cancer