Significance of Metastatic Disease

Significance of Metastatic Disease in Subaortic Lymph Nodes G. A. Patterson, M.D., D. Piazza, M.D., F. G. Pearson, M.D., T. R. J. Todd, M.D., R. J. Ginsberg, M.D., M. Goldberg, M.D., P. Waters, M.D., D. Jones, M.D., R. Ilves, M.D., and J. D. Cooper, M.D. ABSTRACT Thirtyfive patients underwent resection of primary bronchogenic carcinoma of the left upper lobe or left main bronchus in the presence of metastatic disease in subaortic lymph nodes. No patient had metastatic disease in other mediastinal node stations. There was 1 postoperative death. Complete followup is available on 34 patients. Threeyear and fiveyear actuarial survival for the entire group is 44% and 28%, respectively. For 23 patients undergoing complete resection, fiveyear actuarial survival is 42%. Resection of primary bronchogenic carcinoma in the presence of subaortic nodal metastases is associated with improved survival relative to reports of survival following resection of metastatic disease in other mediastinal node stations. Resection should be undertaken in these patients especially when it is judged that the resection is likely to be complete. There is controversy regarding the benefit of surgical resection for bronchogenic carcinoma in the presence of metastatic disease in mediastinal lymph nodes (N2 disease). Martini and associates [l] reported a fiveyear actuarial survival of 29% in patients undergoing complete resection in the presence of N2 disease. Kirsh and coworkers [2] reported a 30% absolute survival for 32 patients treated with resection and postoperative irradiation for N2 squamous carcinoma. A fiveyear actuarial survival of 24% was noted by Pearson and colleagues [3] in patients who underwent resection of N2 disease discovered at thoracotomy following negative cervical mediastinoscopy. In that same report, a 9% fiveyear survival was described following resection of N2 disease discovered at mediastinoscopy. Other authors [4] obtained similarly poor results in patients undergoing resection in the presence of N2 disease. Despite these reports, enthusiasm exists for radical resection in the presence of known subaortic lymph node metastases from left upper lobe or left main bronchial tumors. In spite of our reservations regarding resection in the face of N2 disease detected by cervical mediastinoscopy, we usually opt for resection in the From the Division of Thoracic Surgery, Department of Surgery, University of Toronto. Toronto, Ont, Canada. Presented at the Twentysecond Annual Meeting of The Society of Thoracic Surgeons, Washington, DC, Jan 2729, 1986. Address reprint requests to Dr. Patterson, Division of Thoracic Surgery, Toronto General Hospital, Eaton Building N 10230, Toronto, Ont, Canada M5G 1L7. presence of subaortic metastases when no higher mediastinal nodes are involved. This review was undertaken to determine the outcome for patients undergoing resection for primary bronchogenic carcinoma in the presence of N2 disease restricted to the subaortic window. It represents a retrospective analysis of a very select group of patients with N2 disease. Material and Methods Between January, 1968, and February, 1985, 35 patients underwent thoracotomy and resection of primary bronchogenic carcinoma in the presence of subaortic nodal metastases. Patients with metastatic disease in mediastinal nodes at any other location were excluded from analysis. All patients were judged to be Mo (no distant metastasis) at the time of resection. There were 24 men and 11 women with a mean age of 60.1 years (range, 42 to 75 years). The T (tumor) status of the primary lesions was T1 in 6 patients, T2 in 17, and T3 in 12. Fifteen patients had peripheral primary bronchogenic tumors (Fig l), and 20 patients had central primary tumors (Fig 2). Seventeen squamous carcinomas, 16 adenocarcinomas, and 2 small cell carcinomas were resected in these 35 patients. Nodal disease was confined by the capsule of the node (intranodal) in 30 patients, and 5 patients had extranodal extension into mediastinal tissues as judged by the gross findings of the operating surgeon or by the pathologist on examination of excised nodes. Seven patients had direct primary tumor extension into mediastinal structures. The tumor involved the pericardium in 3 patients, and in 1 of these patients, the superior portion of the left atrial wall was also involved. In 4 patients, the tumor involved the phrenic nerve. Cervical mediastinoscopy was carried out in 33 patients and was negative in every instance. Twenty patients underwent anterior mediastinotomy or extended cervical mediastinoscopy. One patient underwent anterior mediastinotomy alone. Nineteen patients required pneumonectomy, and 16 underwent lobectomy. Twentythree of the 35 patients had complete resection of the primary tumor and mediastinal nodal metastases as judged by the operating surgeon. Twelve patients had known residual microscopic disease at the completion of resection. This determination was made by the operating surgeon and by the pathologist, who based his decision on the finding of microscopic residual disease in a resection margin. Mediastinal irradiation was employed in 20 patients. Four patients received preoperative irradiation, 15 pa 155 Ann Thorac Surg 43:155159, Feb 1987

156 The Annals of Thoracic Surgery Vol 43 No 2 February 1987 Fig 1. Findings in 15 patients; peripheral prima y bronchogenic carcinoma with metastatic subaortic nodal disease and other mediastinal nodes negative. Fig 2. Findings in 20 patients; central prima y tumor with metastatic subaortic nodal disease and other mediastinal nodes negative. tients had radiation treatment postoperatively, and 1 patient received preoperative and postoperative irradiation. Ten of the 12 patients with incomplete resections received perioperative irradiation. The timing and dose of irradiation (2,000 to 5,000 cgy) were not uniform. Results Followup is available on 34 patients. One patient died of respiratory failure in the first postoperative month. One patient was lost to followup at 50 months. In the immediate postoperative period, 8 patients had a documented left recurrent nerve palsy following resection. The presence of intranodal or extranodal disease did not appear to influence the completeness of resection. Of the 5 patients with extranodal disease, 3 had a complete resection and 2, an incomplete resection. Among the 30 patients with intranodal disease, 20 underwent a complete resection and 10 had an incomplete resection. In only 7 of the 12 patients with an incomplete resection was microscopic disease left at the nodal site. Four patients had microscopic disease in the region of the primary tumor, and 1 patient had a positive bronchial resection margin. The threeyear and fiveyear actuarial survival for the entire group was 44% and 28%, respectively (Fig 3). Of 16 patients eligible for absolute fiveyear survival, 6 (37.5%) survived. Three and fiveyear actuarial survival for patients undergoing complete resection was 52% and 42%, respectively (see Fig 3). Eleven of the 23 patients undergoing complete resection are currently alive (6 to 156 months), but only 2 of 12 patients are alive after an incomplete resection (26 and 127 months). Only 2 of the 22 deaths were not cancer related. Eighteen patients died with distant metastatic disease; only 4 patients died with locally recurrent carcinoma. Because of the nonuniform selection of patients for radiotherapy, as well as the variability and timing in dose, it is not possible to draw any meaningful conclusion as to the value of radiotherapy in this group of patients. There was no appreciable difference in survival for patients with squamous tumors versus those with adenocarcinoma. Of the 2 patients with small cell carcinoma, 1 died at 12 months following resection and the other was lost to followup at 50 months after resection. Comment Longterm survival is decreased following resection for bronchogenic carcinoma in the presence of N2 disease. The best reported results range from a fiveyear survival of 25 to 30%. However, selection of patients and methods for reporting survival figures vary widely, thereby making comparisons between reported series difficult, if not impossible. An example is the 29% fiveyear actuarial survival reported by Martini and coworkers [ 11; it excludes incomplete resections, operative deaths, and noncancerrelated deaths. A previous study by our own group (31 described a fiveyear actuarial survival of 24% in patients with N2 disease whose disease was identified at thoracotomy following a negative cervical mediastinoscopy. In that same report, a fiveyear survival of 9% was recorded in patients whose N2 disease was identified at mediastinoscopy and who underwent subsequent resection. Pearson [5] recently reanalyzed his previously reported series and noted a 24% fiveyear actuarial survival among patients who

157 Patterson, Piazza, Pearson, et al: Metastatic Disease in Subaortic Lymph Nodes % 100 v, so:\ 80 70 60 50 40 13 All Resectlons IN=351 Complete Resections INS31 '? 6 8 ** % \ l, * a\o 0 42% \\ 3 30 a\ 28% Years Fig 3. Actuarial survival curve for all patients and those undergoing complete resection in the presence of subaortic nodal metastases. underwent complete resection of N2 disease discovered at mediastinoscopy or at subsequent thoracotomy. Our selective attitude regarding resection for patients with N2 disease has been relaxed, as a rule, in patients with N2 disease located in the subaortic window. The identification of subaortic nodal disease, even at the time of mediastinoscopy, has not dissuaded us from radical resection when we thought that the disease was technically resectable. The results in the present series support this practice. Our fiveyear actuarial survival of 28% for the entire group compares very favorably with the survival in other reports of resection in the presence of metastatic mediastinal nodal disease. Certainly, the fiveyear actuarial survival of 42% seen in those patients undergoing complete resection compares very favorably with the figures in other reports of resection for N2 disease at other node stations. Indeed, in these patients undergoing curative resection, survival almost equals that reported following resection in the presence of N1 disease (hilar, interlobar, peribronchial, or segmental nodal metastases). Martini and associates [6] reported a fiveyear survival of 49% in 75 patients undergoing resection in the presence of N1 disease. Without supplying data regarding survival for individual N1 locations, the authors concluded that specific N1 location is not important in determining survival. Our own unpublished fiveyear actuarial survival for resected N1 disease (peribronchial nodes only) is 51% following pneumonectomy and lobectomy and 40% following sleeve lobectomy. It is quite possible that the good results obtained in other studies have been due in part to the presence of patients with subaortic N2 disease. In the report of Pearson and coworkers [3], 3 of 8 absolute fiveyear survivors with negative mediastinoscopy had subaortic nodes as the only site of metastatic mediastinal disease. In an earlier report by Martini and colleagues [7], 6 of 32 twoyear survivors with resected mediastinal nodal disease had metastatic disease in the subaortic window only. Martini and coworkers (11 observed that the pres ence of a single station of nodal involvement was perhaps of more importance than the site of mediastinal nodal disease. In this series, T status had obvious influence on survival, since 5 of 6 patients with T1 disease are still alive, whereas only 4 of 17 patients with T2 N2 disease and 4 of 12 patients with T3 N2 disease are still living. There is no difference in actuarial survival between patients with T2 and T3 disease in this series. There does not appear to be any benefit obtained by the use of perioperative mediastinal irradiation; however, the dose and timing of radiotherapy were quite variable. In addition, patients with more extensive disease tended to be referred for perioperative irradiation. Twelve of 20 patients with central tumors and 10 of 12 patients with incomplete resections received perioperative irradion. Therefore, it is not surprising that 7 of 14 patients receiving no irradiation are still living, whereas only 6 of 20 patients undergoing radiation therapy are still alive. In keeping with'our longheld belief that all patients should have accurate staging of mediastinal nodes before the appropriate therapy is selected, 33 of these 35 patients underwent preoperative cervical mediastinoscopy. In all patients this examination was negative. Twenty patients underwent concomitant anterior mediastinotomy or extended cervical mediastinoscopy [8] for the purpose of exploring the subaortic window. One patient underwent anterior mediastinoscopy alone. Anterior mediastinotomy as described by McNeill and Chamberlain [9] is invaluable in the assessment of the extent of primary and metastatic disease originating from the left upper lobe and left main bronchus. We perform biopsy through an anterior mediastinoscopy when nodes are readily visible and easily accessible. Although valuable for preoperative staging, subaortic nodal biopsy is not essential to determine resectability. A judgment as to the gross extent of subaortic nodal disease and its resectability can be made by palpation, particularly when access is also available through a cervical mediastinoscopy so that bimanual palpation of the subaortic window can be performed with one finger inserted behind the aortic arch from the neck incision and the other, inferior to the arch through the anterior incision. Of the 12 patients with microscopic residual disease, 7 had residual disease in the region of subaortic nodal metastases. A judgment of resectability could presumably have been made in these 7 patients by anterior mediastinotomy. However, only 2 of these patients underwent this procedure. In this select group of patients, a correct assessment of technical resectability of nodal disease was made by anterior mediastinal exploration in 18 of 20 patients undergoing resection. Involvement of subaortic mediastinal nodes by metastatic spread from primary left upper lobe or left main bronchogenic carcinoma is not a contraindication to resection. Indeed, acceptable survival can be expected following radical resection. Survival exceeding that ob

158 The Annals of Thoracic Surgery Vol 43 No 2 February 1987 served in the presence of metastatic disease in other mediastinal nodal sites and approaching that reported for N1 disease can be expected if a complete resection is performed. We acknowledge the assistance of Gisela Schloegl in the preparation of the manuscript. References 1. Martini N, Flehinger BJ, Zaman MB, Beattie EJ Jr: Results of resection in nonoat cell carcinoma of the lung with mediastinal lymph node metastases. Ann Surg 198:386, 1983 2. Kirsh MM, Kahn DR, Gago 0, et al: Treatment of bronchogenic carcinoma with mediastinal metastases. Ann Thorac Surg 12:11, 1971 3. Pearson FG, Delarue NC, Ilves R, et al: Significance of positive superior mediastinal nodes identified at mediastinoscopy in patients with resectable cancer of the lung. J Thorac Cardiovasc Surg 83:1, 1982 4. Paulson DL, Urshel HC Jr: Selectivity in the surgical treatment of bronchogenic carcinoma. J Thorac Cardiovasc Surg 62554, 1971 5. Pearson FG: Lung cancer: the past 25 years. Chest 89:200S, 1986 6. Martini N, Flehinger BJ, Nagasaki F, Hart B: Prognostic significance of N1 disease in carcinoma of the lung. J Thorac Cardiovasc Surg 86546, 1983 7. Martini N, Flehinger J, Zaman MB, Beattie EJ: Prospective study of 445 lung carcinomas with mediastinal lymph node metastases. J Thorac Cardiovasc Surg 80:390, 1980 8. Rice TW, Goldberg M, Waters P, et al: Extended cervical mediastinoscopy: a single procedure for staging left upper lobe bronchogenic carcinomas. Chest 88:44S, 1985 9. McNeill TM, Chamberlain JM: Diagnostic anterior mediastinotomy. Ann Thorac Surg 2:532, 1966 Discussion DR. JOHN R. BENFIELD (Duarte, CA): This is a remarkable series of patients, but it is important to critically analyze what the results mean. Whereas twothirds of patients whose bronchogenic carcinomas were Stage 111 because of N2 metastases in the subaortic location enjoyed a 52% 5year survival after resection, and onethird of patients who had incomplete resections survived for 5 years, nearly twothirds of patients in the series were dead at the time of writing; 91% of the deaths were from recurrent or metastatic carcinoma. Protagonists of resection take this evidence to mean that resection should be accomplished whenever possible and that subaortic lymph node metastases are not as ominous as nodal spread elsewhere in the mediastinum. Antagonists can maintain that retrospective review of results with this highly selected series of patients probably attests more to the clinical acumen of the physicians and surgeons in selecting goodrisk patients with slowgrowing cancers than to the wisdom of proceeding with resection. Neither position can be scientifically substantiated from the data presented. There are no true controls. From the data presented today, we cannot exclude the possibility (perhaps likelihood) that the patients referred to surgeons are a select group with relatively slowgrowing cancers. It is a common denominator of cancer biology that regional metastases substantially impair prognosis and that there is at least roughly proportional correlation between the number of lymph nodes involved and the lethality of the cancer. This is in keeping with the Toronto General Hospital observation that mediastinal metastases limited to the subaortic location are associated with a better prognosis than is more extensive N2 disease. Therefore, 1 accept the data from Toronto as a most worthwhile hypothesis, on the basis of which it is reasonable to continue to resect lung cancers in patients with N2 subaortic metastases when the spread is detected at the time of thoracotomy in goodrisk patients. The question is, Why do a mediastinotomy if one is going to proceed anyway with resection, even when there is Nz disease? Our current practice is to proceed to thoracotomy without mediastinotomy in goodrisk patients whose mediastina are apparently free from enlarged nodes by computed tomographic (CT) scan. In patients with mediastinal adenopathy by CT scan and in patients whose cardiopulmonary function makes them poor risks, we continue to use mediastinotomies liberally. In such patients, we do not recommend thoracotomies when there is evidence of N2 disease, and subaortic nodal spread alone would suffice to deter us from thoracotomy. Were we not to find subaortic nodal metastasis in a poorrisk patient until the time of thoracotomy, we would generally proceed with complete resection by segmentectomy or lobectomy, but we would usually refrain from pneumonectomy. 1 would appreciate hearing from Dr. Patterson and his colleagues under what circumstances, if any, they would decline to resect a bronchogenic carcinoma on the basis of finding subaortic nodal metastases. DR. NAEL MARTINI (New York, NY): Both the Toronto group and one group in New York have long realized that a select group of patients with N2 disease benefit from surgical treatment. The point we have differed on all along is the size of this group. We continue to believe that in nonsmall cell lung cancer, as many as 20% of all patients with N2 disease can derive benefit from operation. This surgical group includes patients with positive paratracheal nodes as well as patients with nodes in the aortopulmonary window and in the subcarinal region. Our results in 46 patients, with N2 nodes in the aortopulmonary window treated from 1974 to 1981 by complete resection have been essentially similar to the results presented by Dr. Patterson. The survival in our 46 patients was 50% at 2 years and 34% at 5 years. However, there are differences between the two groups. First, included in our patient group are 14 patients who also had positive N2 disease in the subcarinal or supraaortic regions. Their survival following complete resection has been essentially the same. Second, all 46 of our patients have had a complete, potentially curative resection. It has been our experience in patients with carcinoma of the lung that no benefit is derived from operation when the resection performed is incomplete or palliative. I have two questions for the authors. First, have you operated on patients with N2 disease extending to other nodes of the mediastinum, in addition to those noted in the aortopulmonary window, and if so, what was the survival following resection? Second, I believe that the denominator of all patients seen is essential to assess how many were indeed offered resection. Was surgical treatment offered only to patients whose nodes in the aortopulmonary window were not detected preoperatively? If not, what proportion of patients with known N2 disease at this location were offered thoracotomy? DR. c. FREDERICK KITTLE (Chicago, IL): 1 congratulate Dr. Patterson and his colleagues on this fine presentation. I also have

159 Patterson, Piazza, Pearson, et al: Metastatic Disease in Subaortic Lymph Nodes several questions to ask. I am confused about your use of the term subaortic lymph nodes. Do some of these patients have recurrent laryngeal nerve paralysis or are these patients with a particular degree of subaortic lymph node involvement? What is your practice about operating on patients with recurrent nerve involvement? In removing the subaortic nodes, do you sacrifice the vagus? Last, was any attempt made to determine by examination of the lymph nodes whether there was extracapsular spread of tumor or was the metastatic growth contained within the node capsule? DR. PATTERSON: I thank the discussants for their remarks. Dr. Benfield, this series suffers from the problems of any retrospective analysisthere are no controls. 1 do not have the number of patients who were considered for resection and who refused or the number of patients who had subaortic nodal metastases and were thought not to be candidates for operation for other reasons, physiological or otherwise. 1 can but agree with your statements about slowgrowing tumors in general. We did not measure doubling times in these tumors. Although these patients were highly selected, that selection was done retrospectively in a certain sense, and I do not really see what the rate of tumor growth has to do with the site of single nodal metastasis; it has more perhaps to do with the timing of their presentation. In regard to our choice of resection in patients with known subaortic disease, we never undertake a resection if it is our judgment that a complete resection is unlikely. There were patients who underwent incomplete resection. That is true of all series of patients with extensive tumors. Certainly we would not embark on a resection with the anticipation that gross tumor would be left behind. Usually we use anterior mediastinoscopy to make that judgment. Some of these patients did have radiographic evidence of tumor in the hilum of the lung, and many of these patients were found at preoperative mediastinoscopy to have mobile intranodal disease in the subaortic window. Those patients were selected for operation based on the judgment concerning technical resectability made at mediastinoscopy. That technical judgment is easily made with the right index finger in the mediastinoscopy incision and posterior to the aortic arch and the left index finger in the subaortic window through the anterior mediastinotomy incision. Resection of central lesions involving mediastinal structures or large nodal masses in the subaortic window is technically difficult. Resection of peripheral lesions associated with mobile intranodal nodes in the subaortic window is not technically difficult. We certainly advocate resection in these patients. In regard to Dr. Martini s comments, we can only admire his experience in the surgery of lung cancer and N2 disease in particular. Many patients not included in this series did have subaortic nodal disease detected at mediastinoscopy or by radiography preoperatively and were not offered resection. 1 do not have these numbers. Although the figures Dr. Martini supplied are impressive, they represent only those patients with N2 disease undergoing complete, potentially curative resection. We have similar results for all patients with isolated subaortic nodal disease and better survival in those patients who had complete, potentially curative resection. Dr. Kittle, most patients whom we see with recurrent laryngeal nerve invasion do have metastatic disease elsewhere in the mediastinum and are therefore not candidates for resection. One patient in this series had a preoperative left recurrent nerve palsy but did not have evidence of other mediastinal disease as judged by mediastinoscopy. The determination of intranodal versus extranodal disease was made by the operating surgeon at mediastinoscopy and thoracotomy as well as by the pathologist in his examination of the excised specimen.