Despite their reputation of benignity, carcinoid tumors

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1 Operative Risk and Prognostic Factors of Typical Bronchial Carcinoid Tumors Xavier Ducrocq, MD, Pascal Thomas, MD, Gilbert Massard, MD, Pierre Barsotti, MD, Roger Giudicelli, MD, Pierre Fuentes, MD, and Jean-Marie Wihlm, MD Department of Thoracic Surgery, University Hospital of Strasbourg, Strasbourg, and Department of Thoracic Surgery, Hôpital Sainte Marguerite, Marseille, France Background. This study estimated operative risk and examined factors determining long-term survival after resection of typical carcinoid tumors. Methods. From 1976 to 1996, 139 consecutive patients (66 male and 73 female patients with a mean age of years) underwent thoracotomy for typical carcinoid tumor. The tumors were centrally located in 102 patients (73.4%). Results. Radical resection was performed in 106 patients (7 pneumonectomies, 13 bilobectomies, and 86 lobectomies) and conservative resection in 33 (3 segmentectomies, 3 wedge resections, 20 sleeve lobectomies, and 7 sleeve bronchectomies). There were no postoperative deaths. Complications occurred in 19 patients (13.7%). The morbidity rate was not increased after bronchoplastic procedures ( , not significant). Staging was pt1 in 107 patients (77.0%) and pt2 in 32 (23.0%); 13 Despite their reputation of benignity, carcinoid tumors represent a heterogeneous group with a varying prognosis. Warren and colleagues [1] clearly separated typical and atypical carcinoid tumors: the former group is expected to have an excellent prognosis after complete resection, whereas the latter behaves like any bronchogenic carcinoma. Nonetheless, in many recent studies, the results are confusing because the authors included both typical and atypical carcinoid tumors. Questions about typical carcinoid tumors remain. In up to 11% of patients, lymph node metastases are discovered during operation [1, 2], which is a paradox for a mostly benign neoplasm. On rare occasions, distant metastases appear during follow-up. The ideal type of resection, conservative or radical, is still controversial [3 6]. The aim of the following study was to estimate operative risk and long-term survival after resection in a cohort of patients with only typical carcinoid tumors. We also attempted to identify any prognostic factors. Accepted for publication Oct 30, Address reprint requests to Dr Massard, Department of Thoracic Surgery, University Hospital of Strasbourg, F-67091, Strasbourg, France. patients (9.4%) had nodal metastases. Seventeen patients have died (12.2%), during follow-up, but only three deaths were related to the disease. The overall survival rate at 5, 10, and 15 years was estimated to be 92.4%, 88.3%, and 76.4%, respectively; estimated disease-free survival was 100% at 5 years and 91.4% at 10 and 15 years. Estimated survival of patients with lymph node metastasis was 100% at 5, 10, and 15 years. Univariate analysis failed to demonstrate any prognostic significance for sex, tumor size (T1 versus T2), tumor location (central versus peripheral), and type of resection. Conclusions. These data confirm an excellent prognosis after complete resection of typical carcinoid tumors, including those with lymph node metastases. Parenchyma-saving resections should be preferred. (Ann Thorac Surg 1998;65:1410 4) 1998 by The Society of Thoracic Surgeons and Methods This study was restricted to typical carcinoid tumors according to the histologic criteria established by Arrigoni and colleagues [7] and Warren and associates [1]. From 1976 to 1996, 139 consecutive patients underwent thoracotomy for typical carcinoid tumor at our two institutions. There were 66 male and 73 female patients with a mean age of years (range, 14 to 78 years; median age, 50 years). A history of tobacco abuse was identified in 55 patients (39.6%). The diagnosis was made on the basis of routine chest roentgenograms in 38 asymptomatic patients (27.3%). The chief symptom in the remaining 101 patients was obstructive pneumonia in 40 (28.8%), hemoptysis in 33 (23.7%), relentless cough in 14 (10.1%), dyspnea in 9 (6.5%), decline in general health status in 2 (1.4%); and wheezing, chest pain, and Cushing s syndrome in 1 patient (0.7%) each. Methods Patient charts were screened for clinical and radiologic presentation, diagnostic procedures, type of resection, and postoperative complications. Radical resections included lobectomy, bilobectomy, and pneumonectomy according to the principles used for non small cell lung cancer. Conservative resections included parenchymasaving bronchial resections such as sleeve lobectomy and bronchial sleeve resection-anastomosis and limited resections such as segmentectomy and peripheral wedge resection. The choice between radical and conservative resection was made on the basis of bronchoscopic presentation and intraoperative findings. Intraoperatively, frozen-section analysis of resection margins was used 1998 by The Society of Thoracic Surgeons /98/$19.00 Published by Elsevier Science Inc PII S (98)

2 Ann Thorac Surg DUCROCQ ET AL 1998;65: BRONCHIAL CARCINOID TUMORS 1411 liberally. In the standard case, a formal lymph node dissection was performed at the levels of fissure and hilum; mediastinal N2 nodes were sampled or dissected depending on the intraoperative findings. Operative mortality was defined as any death during the first 30 postoperative days or during the initial hospital stay. Medical or surgical complications were defined as any complication requiring specific treatment or prolonging the planned hospital stay. Postoperatively, patients were followed up at the outpatient clinic or by the referring physician. Survival status was updated to January 1, Recurrences were classified as bronchial, nodal, and metastatic. Cause of death was specified whenever possible. Univariate survival analysis was done to identify any prognostic factor such as sex, tumor size, lymph node status, tumor location, or type of resection. Statistical Analysis Quantitative data are expressed as the mean the standard deviation and as the median and were compared using Student s t test for unpaired samples. Qualitative data were compared with the 2 test. Probability of survival was estimated with the Kaplan-Meier model and compared with the log-rank test. A p value of less than 0.05 was considered significant. Results Initial Presentation and Workup Chest roentgenograms were normal in 13 patients (9.4%). Sixty-six patients (47.5%) had a rounded opacity and 59 (42.4%) segmental or lobar atelectasis; 1 patient had a pleural effusion. The tumor was located on the right side in 79 patients: main bronchus in 2 patients, upper lobe in 25, bronchus intermedius in 10, middle lobe in 16, and lower lobe in 26. Sixty patients had a tumor of the left lung: mainstem bronchus in 3, upper lobe in 25, lower lobe in 31, and two simultaneous tumors in both lobes of the left lung in 1. A computed tomographic scan was available for 92 patients (66.2%); substantial enlargement of the hilar or mediastinal lymph nodes was noted in 11 patients. All other patients had coronal tomography. One patient underwent staging mediastinoscopy for bulky N2 disease, which confirmed lymph node metastasis of a typical carcinoid tumor. The results of bronchoscopy were normal in 37 patients (26.6%), who were classified as having peripheral tumors. Tumor was identified at bronchoscopy in 102 patients (73.4%), and they were considered as having a central tumor location. Biopsy was complicated by acute bleeding managed conservatively in 2 patients (2% of all biopsy procedures). A single diagnostic error occurred when a sample was interpreted erroneously as squamous cell carcinoma. Operative Treatment and Immediate Results There were no exploratory thoracotomies. Formal anatomic resection was performed in 106 patients (76%) and included 7 pneumonectomies, 13 bilobectomies, and 86 lobectomies. Thirty-three patients (24%) underwent conservative resection: 3 anatomic segmentectomies, 3 wedge resections, 20 sleeve lobectomies, and 7 segmental bronchectomies without parenchymal resection. The last seven included four bronchial sleeve resectionsanastomoses and three bronchotomies with resection limited to the pars membranalea. A formal mediastinal node dissection was performed in 47 patients (33.8%). There were no postoperative deaths. Nineteen patients (13.7%) sustained postoperative complications. Nine patients experienced prolonged air leaks, and another 6 required tube thoracostomy for pleural space disease. Pleural empyema occurred once after bilobectomy. After a pneumonectomy, 1 patient was seen with unexplained fever, which resolved spontaneously; empyema was ruled out by sampling pleural fluid. Chylothorax developed in 1 patient and was managed conservatively. One patient had supraventricular tachycardia. Sleeve lobectomy did not result in increased operative morbidity. Space problems were observed in 11 patients after 86 formal lobectomies and in 3 patients after 20 sleeve lobectomies ( , not significant). Recovery after a sleeve bronchectomy was uneventful. Pathologic Findings Resection was considered radical in all patients. No patient had residual tumor at the resection margins, and the highest lymph node resected was negative in all patients. The tumor was classified T1 in 107 patients (77.0%) and T2 in 32 (23.0%). Ninety-three tumors (66.9%) measured 2 cm or less. Lymph node metastases were identified in 13 patients (9.4%) and were located at the level of the lobar bronchus or fissure in 10 patients, at the hilar level in 1 patient, and in the upper mediastinum in 2. Thus, 126 patients were in stage I, 11 were in stage II, and 2 were in stage IIIA. Long-Term Survival Follow-up exceeded 10 years for 48 patients (34.5%) and 5 years for 83 (59.7%). Seventeen patients (12.2%) have died during follow-up. Only three deaths were related to the disease; these 3 patients had development of liver metastases at 109, 108, and 90 months after initial resection and ultimately died at 185, 168, and 199 months, respectively, after resection. Causes of death in the remaining 14 patients were a second noncarcinoid malignancy in 7, myocardial infarction in 3, disruption of an abdominal aortic aneurysm in 1, acute respiratory failure in 1, chronic renal failure in 1, and complications of diabetes in 1. Besides the three cases of distant metastatic disease, there were two local-regional recurrences. Bronchial recurrence in 1 patient 109 months after left upper lobe resection was managed with left completion pneumonectomy extended to the carina through bilateral thoracotomies; liver metastases were discovered intraoperatively. Mediastinal node recurrence was noted at 84 months in the other patient. As mediastinal node dissection had not

3 1412 DUCROCQ ET AL Ann Thorac Surg BRONCHIAL CARCINOID TUMORS 1998;65: been performed in this patient, we assume that N2 disease was missed during operation. All 4 patients (2.9%) with recurrent disease were male with pn0 status; 3 of them had T2 tumor, central location, or radical resection. Because long-term follow-up is required to recognize recurrent disease, the prevalence of metastatic disease has been 4.8% for the 83 patients followed up for more than 5 years. The overall survival rate at 5, 10, and 15 years was estimated to be 92.4%, 88.3%, and 76.4%, respectively. Estimated disease-free survival was 100% at 5 years and 91.4% at 10 and 15 years. Survival was not calculated according to stage, as only 11 patients were in stage II and only 2 in stage IIIA. Also, there was neither death nor recurrent disease among the patients with lymph node metastases during follow-up. Prognostic Factors Thirteen patients had lymph node metastases. Five were male and 8, female; 11 had a T1 tumor and 2, T2. Ten tumors were centrally located, and only one of them was managed with conservative resection. With a median follow-up of 87 months (range, 10 to 216 months), all 13 patients were alive and free from disease at the conclusion of the study. Univariate analysis was performed on subgroups defined according to tumor size (T1 versus T2), sex, tumor location (central versus peripheral), and type of resection (standard versus conservative). Demographic comparison of these subgroups revealed some differences. Regarding age, patients with centrally located tumors were younger than patients with peripheral tumors (mean age, years versus years; t 5.114, p ). There was a nonsignificant trend toward younger age in patients with positive lymph nodes (t 1.583, p 0.1) and female patients (t 1.405, p 0.1). There was a significantly lower rate of conservative resections in patients with T2 tumors ( , p 0.01) and there was a nonsignificant trend toward less conservative resections in patients with peripheral tumors ( , p 0.1). However, survival studies including mortality not related to the disease failed to identify any significant prognostic factor (Table 1). Because only 4 patients had recurrence and only 3 patients died of disease, survival analysis with exclusion of deaths not related to the disease was not determinate. Comment Table 1. Univariate Survival Analysis a Survival (%) Variable 5 Years 10 Years 15 Years 2 Statistic Tumor size T T Sex Male Female Tumor location Central Peripheral Resection Standard Conservative a This analysis identified no significant prognostic factors. The present series is a collection of patients with typical carcinoid tumors who were operated on at one of two institutions over a 20-year period. Data on patient age, sex ratio, presenting symptoms, and tumor location are consistent with those in previously published series. The mean age is typically between 45 and 50 years [2, 8, 9], although Rea and colleagues [10] reported a mean age of 39 years. Sex ratio is close to 1 [2, 8, 9]. A central location involving lobar or segmental bronchi is more common, being observed in 75% to 85% of patients [8]. About 25% of patients are asymptomatic; the most frequent symptoms are obstructive pneumonia and hemoptysis [8, 11]. Although numerous publications have stressed the importance of these symptoms, many patients still undergo exploratory procedures only after a symptomatic course of several months. Because treatment philosophy differs from that for non small cell lung cancer and even atypical carcinoid tumor, a preoperative tissue diagnosis should be obtained to plan a conservative resection in the case of a centrally located tumor. The risk of hemorrhage after endoscopic biopsy has been overemphasized. In 1980, Todd and colleagues [12] recommended routine biopsy; 6 of 23 patients experienced moderate to severe bleeding, but none required either blood transfusion or emergency operation. Hurt and Bates [13] reported that only 2 of 62 patients had bleeding. In the present series, only 2 of 102 patients who underwent biopsy experienced major bleeding. Our results confirm that the operative risk is acceptable. As in several other series [9, 10, 12, 14], there were no operative deaths. Postoperative complications were mainly space problems after lobectomy. The fact that bronchoplastic procedures did not increase the operative risk is a strong argument in favor of parenchymal preservation when feasible. Mainstem bronchial resection without parenchymal resection, performed in 7 patients in this series, has proved to be a safe operation [4, 6]. The present study corroborates the favorable prognosis for typical carcinoid tumors after complete resection. Our 5-, 10-, and 15-year survival rates are similar to those in other reported series [2, 9 12, 14, 15] (Table 2). Regarding the low incidence of recurrent disease, it is not surprising that our study did not clearly identify any adverse prognostic factor. Age does not appear to be a prognostic factor per se; however, patients with typical carcinoid tumors are younger by 10 years than patients with atypical carcinoid tumors [9, 15]. This also applies to our experience (nonpublished data). Sex has no prognostic significance; it is noteworthy that the sex ratio is close to 1, which is unlike the findings for primary bronchogenic carcinoma.

4 Ann Thorac Surg DUCROCQ ET AL 1998;65: BRONCHIAL CARCINOID TUMORS 1413 Table 2. Long-Term Survival After Resection of Typical Bronchial Carcinoid Tumors No. of Survival (%) Reference 5 Years 10 Years 15 Years Okike et al [8] Wilkins et al [11] Hurt and Bates [13] MacCaughan et al [2] Rea et al [10] Marty-Ané et al [9] Ducrocq et al [this series] Martini et al [15] a a had lymph node metastases. One series [14] credits a prognostic value to tumor size, but this series included both typical and atypical tumors. Most large series in the literature conclude that tumor size has no influence on survival. Tumor location apparently has no influence on survival. We observed a less favorable survival for patients with peripheral tumors, a finding mentioned by Okike and colleagues [8]; this difference did not reach significance. However, patients with peripheral tumors were significantly older, which might explain the difference in the 15-year survival rate. A large review of the literature by Åberg and colleagues [3] in 1981 concluded that radical resections are preferable; although 5-year survival was similar compared with that for conservative resections, survival curves began to show a difference starting 8 years postoperatively, with a significantly lower 20-year survival after conservative resection. However, this considerable work included historic series, and therefore the population under investigation may have been contaminated by inclusion of patients with atypical tumors. Other recent publications [4 6, 9, 12] advocate parenchyma-saving resections, including isolated sleeve bronchectomy, which achieve very satisfactory local control of the disease. Our series shows similar survival rates for conservative and radical resection. Local-regional recurrence is most likely related to unrecognized nodal metastases, and therefore, extensive lymph node dissection is encouraged. Operative strategy is complicated by the fact that a preoperative positive diagnosis of typical carcinoid tumor is subject to some diagnostic error. Clearly, atypical characteristics such as necrosis or mitoses may appear only on large samples. Tissue specimens harvested at bronchoscopy appear to be reliable, but reliability is less certain with needle aspiration. Intraoperative frozensection analysis may also lack precision. Therefore, for peripheral tumors, we believe that at the least, resection should be anatomic segmentectomy with careful lymph node dissection; lobectomy is the preferred standard. On the other hand, with centrally located tumors, bronchoplastic lobectomy is routinely preferable to pneumonectomy. As most tumors are small, the resection would still follow the principles of oncology if further analysis revealed an atypical carcinoid tumor. Small mainstem bronchial tumors are rare and usually typical carcinoids; a conservative resection is the rule. The most fascinating problem is lymph node involvement. Its true incidence depends on the extent of lymph node dissection, which may be neglected when benign disease is assumed. The incidence ranges from 2.3% to 11% (Table 3). Most probably, this disparity is explained by a different strategy of lymph node resection. As carcinoid tumors are renowned for their benign course, many surgeons might be tempted to omit formal lymph node dissection and thus miss positive lymph nodes; local recurrence from these nodes may be found more than 10 to 15 years postoperatively and therefore be unrecognized at 5- and 10-year follow-up studies. Further, bronchoplastic procedures may lead the surgeon to a lesser lymph node dissection with the intent of preserving bronchial vascularization. When present, lymph node metastases should not be considered an adverse prognostic factor. In the current series, there was no recurrent disease after a median follow-up of 87 months among the 13 patients with lymph node metastases. Seven patients in the study of Todd and colleagues [12] survived for at least 5 years, as did 5 patients reported by Wilkins and associates [11]. The 5-year survival rate for 12 patients in a series from Martini and coworkers [15] was 92%. In a series from the Mayo Clinic [8], 11 patients had lymph node involvement, with a 5-year survival rate of 71%. Metaanalysis of these combined 48 patients with positive lymph nodes shows an estimated 5-year survival of 91.7%. We conclude that the prognosis is excellent provided a complete resection has been performed. Distant metastases can appear at long-term follow-up, although the reported rates are regularly less than 5% [1, 8]. The preferential location is the liver. A useful diagnostic tool is radionuclide imaging with indium 111 labeled octreotid [16]. However, there is no evidence of an effective chemotherapy regimen; the spontaneous evolution of recurrent disease from diagnosis to death has been 76, 78, and 90 months in our experience. In conclusion, our data confirm a most favorable prognosis, but we failed to identify any prognostic factors. Nodal involvement is not an adverse prognostic factor when resection is complete, although our 100% survival rate is certainly due to a short sample artifact. When the Table 3. Incidence of Lymph Node Metastases in Typical Carcinoid Tumors Reference No. of With N Disease (%) Okike et al [8] Wilkins et al [11] MacCaughan et al [2] Rea et al [10] Marty-Ané et al [9] 52 4 Ducrocq et al [this series]

5 1414 DUCROCQ ET AL Ann Thorac Surg BRONCHIAL CARCINOID TUMORS 1998;65: diagnosis of typical carcinoid tumor has been ascertained preoperatively, maximal preservation of functional lung tissue should be the goal. Bronchoplastic procedures are preferable to pneumonectomy. Routine lymph node dissection has to be performed to achieve adequate staging and, most importantly, complete resection of all diseased tissue, which is the ultimate guarantee of long-term survival. References 1. Warren WH, Gould VE, Faber LP, et al. Neuroendocrine neoplasms of the bronchopulmonary tract: a classification of the spectrum of carcinoid to small cell carcinoma and intervening variants. J Thorac Cardiovasc Surg 1985;89: MacCaughan BC, Martini N, Bains MS. Bronchial carcinoids: a review of 124 cases. J Thorac Cardiovasc Surg 1985;89: Åberg T, Blöndal T, Nõu E, Malmaeus J. The choice of operation for bronchial carcinoids. Ann Thorac Surg 1981;32: Frist WH, Mathisen DJ, Hilgenberg AD, Grillo HC. Bronchial sleeve resection with and without pulmonary resection. J Thorac Cardiovasc Surg 1987;93: Okike N, Bernatz PE, Payne WS, et al. Bronchoplastic procedures in the treatment of carcinoid tumors of the tracheobronchial tree. J Thorac Cardiovasc Surg 1978;76: Cerfolio RJ, Deschamps C, Allen MS, Trastek VF, Pairolero PC. Mainstem bronchial sleeve resection with pulmonary preservation. Ann Thorac Surg 1996;61: Arrigoni MG, Woolner LB, Bernatz PE. Atypical carcinoid tumors of the lung. J Thorac Cardiovasc Surg 1972;64: Okike N, Bernatz PE, Woolner LB. Carcinoid tumors of the lung. Ann Thorac Surg 1976;22: Marty-Ané C-H, Costes V, Pujol J-L, Alauzen M, Baldet P, Mary H. Carcinoid tumors of the lung: do atypical features require aggressive management? Ann Thorac Surg 1995;59: Rea F, Binda R, Spreafico G, et al. Bronchial carcinoids: a review of 60 patients. Ann Thorac Surg 1989;47: Wilkins EW Jr, Grillo HC, Moncure AC, Scannell JG. Changing times in surgical management of bronchopulmonary carcinoid tumor. Ann Thorac Surg 1984;38: Todd TR, Cooper JD, Weissberg D, et al. Bronchial carcinoid tumors. J Thorac Cardiovasc Surg 1980;79: Hurt R, Bates M. Carcinoid tumors of the bronchus: a 33 years experience. Thorax 1984;39: Harpole DH Jr, Feldman JM, Buchanan S, Young WG, Wolfe WG. Bronchial carcinoid tumors: a retrospective analysis of 126 patients. Ann Thorac Surg 1992;54: Martini N, Zaman MB, Bains MS. Treatment and prognosis in bronchial carcinoids involving regional lymph nodes. J Thorac Cardiovasc Surg 1994;107: Philipponneau M, Nocaudie M, Epelbaum, et al. Somatostatin analogs for the localization and preoperative treatment of an adrenocorticotropin secreting bronchial carcinoid tumor. J Clin Endocrinol Metab 1994;78:20 4. INVITED COMMENTARY This article by Ducrocq and associates has clearly listed what is believed to be the current view on bronchial carcinoids. Nevertheless, certain points deserve emphasis. Bronchial carcinoids are now recognized as malignant tumors because of their potential to metastasize. Both typical and atypical carcinoids metastasize to regional lymph nodes; both are treated by resection even if lymph node metastases exist. Although the treatment is primarily surgical, complete resection is essential. When resection is complete, survival free of cancer is assured in nearly all patients even if N2 metastases are present. It is important to stress that preoperative nodal assessment by mediastinoscopy is not essential and, if done, is not intended as a deterrent to surgical management, but as an emphasis on the need of mediastinal lymph node dissection to effect a curative resection. A sleeve lobectomy, segmentectomy, and even a generous wedge resection are acceptable alternatives to conserve lung tissue provided the resection is complete and is combined with a meticulous mediastinal lymph node dissection. Bronchotomy, however, is not an acceptable alternative and should be limited in use to patients with severe pulmonary compromise because the risk of local recurrence is real. It is not justified in patients with adequate lung reserve. Controversy remains regarding the extent of resection necessary to obtain the most favorable results. I agree with Ducrocq and associates that the least amount of resection for peripheral tumors should be a segmentectomy with lymph node dissection, although a lobectomy is the preferable option. For centrally placed tumors, a sleeve lobectomy is preferred over a bronchotomy whenever possible. Locoregional occurrence should not occur in bronchial carcinoids if resection is complete and lymph node dissection or evaluation is carefully undertaken. If lesser resections are under consideration, one must remember that there can be a sampling error in the preoperative or intraoperative pathologic diagnosis of a typical as opposed to an atypical carcinoid. No correlation exists between the history of smoking and the development of carcinoids. Carcinoids are generally unresponsive to radiation or chemotherapy. Resection remains their only effective treatment, and if lymph node metastases exist, their presence does not preclude surgical treatment because long-term survival is still possible for both typical and atypical carcinoids treated with resection. Nael Martini, MD Department of Thoracic Surgery Memorial Sloan-Kettering Cancer Center 1275 York Ave New York, NY by The Society of Thoracic Surgeons /98/$19.00 Published by Elsevier Science Inc PII S (98)