Results of Systematic Nodal Dissection in Typical and Atypical Carcinoid Tumors of the Lung

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1 ORIGINAL ARTICLE Results of Systematic Nodal Dissection in Typical and Atypical Carcinoid Tumors of the Lung Alain Wurtz, MD,* Lotfi Benhamed, MD,* Massimo Conti, MD,* Brigitte Bouchindhomme, MD, and Henri Porte, MD, PhD* Background: To determine the lymphatic spread frequency and location in patients, who underwent lung resection for carcinoid tumors, associated with systematic nodal dissection. Methods: From January 1998 to June 2007, 54 patients underwent anatomic lung resection associated with systematic nodal dissection for tumors classified as typical (TC) or atypical carcinoid according to 1999 World Health Organization criteria. The number and location of the resected lymph nodes were specified. All patients were followed up. Results: All patients underwent complete resection (R0) that were anatomic in 32 patients (59.2%), and associated with a bronchoplastic procedure in 22 (40.8%). Low morbidity was related to lymphadenectomy. The mean number of resected lymph nodes was of 18 (range, 7 44) per patient, which pathologic studies demonstrated lymphatic spread in 10 patients (18.5%). In the TC group (n 42) 2 patients were classified N1 (4.8%) and 4 N2 (9.5%). In the atypical group (n 12) 2 patients were classified N1 (16.6%) and 2 N2 (16.6%). Five of the 6 N2 patients showed a single skip metastasis not discovered by preoperative evaluation (83.3%). The lymphatic spread was correlated with age 35 years (p 0.01) and a tumor size 3 cm(p 0.002). Median follow-up was 57 months. Nine patients with lymphatic spread are disease free and one died from metastatic disease at 52 months. Conclusion: Systematic nodal dissection showed a high frequency of unpredictable lymphatic spread, mainly in the TC group. This procedure is mandatory to treat carcinoids in a curative intent. Key Words: Carcinoid, Lymph node, Lung cancer. (J Thorac Oncol. 2009;4: ) Carcinoid tumors of the lung are uncommon, constituting 1 to 2% of all pulmonary neoplasms. 1 They have a neuroendocrine differentiation, are associated with relatively slow growth and generally show a favorable outcome. In *Pôle de Chirurgie Thoracique CHRU Lille Lille Cedex France; and Pôle de Pathologie CHRU Lille Lille Cedex France. Disclosure: The authors declare no conflicts of interest. Address for correspondence: Alain Wurtz, MD, Pôle de Chirurgie Thoracique CHRU Lille F LILLE CEDEX France. awurtz@ chru-lille.fr Copyright 2009 by the International Association for the Study of Lung Cancer ISSN: /09/ Arrigoni et al. 2 classified these tumors into two distinctive forms: typical (TC) and atypical carcinoids (AC). This classification has continued to evolve and Warren et al. 3 proposed in 1985 new criteria to separate carcinoids from other neuroendocrine neoplasms. They were later modified by Travis et al. 4 and in 1999 the World Health Organization (WHO) reduced confusion and established a definitive classification 5 based on Travis s works, unchanged in (Table 1). Therefore, the spectrum of neuroendocrine tumors includes four entities of increasing malignancy: TC, AC or well differentiated carcinoma, high grade large-cell neuroendocrine carcinoma and small-cell carcinoma. Carcinoid tumors have a propensity to develop in the right lung 7 and are mainly located in the major bronchi. 8 Approximately 30% of carcinoids are located in the periphery of the lungs. Endocrine manifestations are rare and may reveal a peripheral tumor, especially carcinoid and Cushing s syndromes. 1,8 From literature, AC presents more nodal metastasis and higher recurrence rate than does TC. However, the lymphatic spread frequency of carcinoids is difficult to estimate. First, the classification into two distinctive forms (TC and AC) has changed over the years. Consequently, in series including neuroendocrine tumors classified according to the old classifications, before the 1999 WHO criteria, they are some overlaps among the different entities, leading to significant misleading factors in the lymphatic spread study. 921 Furthermore, other series including TC and AC classified according to the new criteria 7,2229 lack of details 7,27 or homogeneity 23,24,28,29 about the lymphadenectomy performed during surgery. In this field, the aim of our study was to precise the frequency and location of nodal metastasis according to demographic data, macroscopic and microscopic aspect of the carcinoid tumors of the lung in patients who underwent surgical resection including systematic nodal dissection. PATIENTS AND METHODS The study was approved by the institutional review board and from 1998 to June 2007, 54 patients (42 TC and 12 AC) were included. There were 31 women and 23 men aged from 11 to 75 years (mean years). Thirty-eight patients (70.4%) were symptomatic at presentation including recurrent obstructive pneumonia (n 388

2 Systematic Nodal Dissection in Carcinoid TABLE World Health Organization Criteria for Carcinoid Tumors of the Lung Classification Typical carcinoid A tumor with carcinoid morphology with fewer than 2 mitoses per 2mm 2 (10 high power fields) and lacking necrosis. Atypical carcinoid A tumor with carcinoid morphology with 210 mitoses per 2 mm 2 (10 high power fields) and or foci of necrosis. 14), hemoptysis (n 10), persistent cough (n 9), asthma (n 3), Cushing s syndrome (n 2). Patients underwent routine preoperative evaluation, including physical examination, chest and upper abdominal computed tomography. Positron emission tomography was performed in 11 patients and was positive in 7 (63.6%), without significant fixation in hilar or mediastinal lymph node in all of them. Fiber optic bronchoscopy was performed in all patients and rigid bronchoscopy in 14, for proper histologic diagnosis in 10, and to restore airway patency prior to surgery in 4. Tumors visualized at bronchoscopy were classified as central (n 48), 89%. Biopsies were performed in 37 patients and 3 of them (5.7%) who underwent biopsies with fiber optic bronchoscopy before surgery were misdiagnosed: one as a well differentiated adenocarcinoma and two as a small-cell carcinoma. (The later received chemo-radiotherapy before referral to our institution). The remaining 6 tumors (11%) were classified as peripheral and transthoracic needle biopsy was never performed in these cases. Lastly, 34 patients (63%) were correctly diagnosed prior to surgery. No evidence of mediastinal lymphadenopathy was identified in any patient, by computed or positron emission tomography, so that mediastinoscopy was never performed. Surgical Management All patients underwent anatomic resection. For centrally located tumors, bronchoplastic procedures were considered to spare the distal functional lung tissue 11 and formal anatomic resections were performed mainly when distal parenchyma was destroyed, due to chronic obstruction. Frozen section analysis of the bronchial margins were routinely performed. In case of peripheral tumors, segmentectomy or lobectomy was considered, according to tumor location. The resection of hilar, intrapulmonary, and mediastinal lymph nodes, including at least three mediastinal stations, one of which being station seven, 30 was routinely performed even in peripheral tumors. Operative Complications Operative complications were classified as pulmonary (air leak 7 days, pneumonia, pleural effusions, atelectasis), cardiovascular complications (myocardial infarction, arrhythmia, pulmonary embolism) and complications related to systematic nodal dissection (recurrent nerve palsy, chylothorax). Operative mortality included the patients who died during hospitalization. Pathologic Data Pathology slide blocks of six patients who underwent surgical resection before 1999 where reviewed by a pathologist with a special interest in lung tumors, using the criteria outlined by Travis. 4 Overall, all the tumors were classified according to the new 1999 WHO criteria for neuroendocrine tumors. 5,6 (Table 1) The size, location, macroscopic and microscopic aspects were studied to classify tumors as intraluminal (tumor invading the overlying mucosa), mural (tumor invading the bronchus wall) or iceberg tumor (tumor with an extra wall component). Lymphadenectomy s specimens were analyzed with special attention to the number and location of the metastatic and non metastatic resected lymph nodes, according to the American Thoracic Society map. 31 Definitive staging was determined according to the Revisited International Clinical Staging System. 32 Follow-Up All patients were followed up by physical examination and chest radiograph 3 months after the operation, fiber optic bronchoscopy, chest and upper abdominal computed tomography at 6 months, and then every year. Survival and tumor recurrence were measured from the date of operation. Statistical Analysis Patients were evaluated for demographic data, tumor location, surgical, and pathologic variables. The distributions were compared using the 2 test or Fisher s exact test for discrete variables and unpaired Student t test for continuous variables. Odds ratio and 95% confidence intervals were calculated to assess the relationship between each variable and the lymphatic spread. Quantitative data were expressed as the mean SD. Two sets of survival curves - one based on the pathologic diagnosis and another one based on lymphatic spread - were generated using the Kaplan-Meier method, and compared with the log-rank test. A p value lower than 0.05 was considered statistically significant. All data were analyzed with the Statistical Package for Social Sciences software. RESULTS A complete resection (R0) was performed in all patients, including anatomic resection in 32 of them (59.2%): lobectomy (n 18), bilobectomy (n 10), standard pneumonectomy (n 2), segmentectomy (n 2) and a bronchoplastic procedure in 22 of them (40.8%) : sleeve upper lobectomy (n 15), sleeve middle or lower lobectomy (n 3), right pneumonectomy with carinal resection (n 3), left main stem bronchial sleeve resection (n 1). 33 A mean of (range, 35) lymph node stations were dissected and nodes (range, 744) resected per patient. The postoperative course was uneventful in 38 patients, including both with ACTH-secreting AC who became eucortisolemic immediately after operation (70.4%). Fifteen patients presented postoperative complications (morbidity rate: 27.8%), related to lung resection in 7 (13%), including prolonged air leaks (n 4) or pleural effusion (n 1) Copyright 2009 by the International Association for the Study of Lung Cancer 389

3 Wurtz et al. requiring prolonged chest tube drainage, pneumonia (n 1) requiring prolonged mechanical ventilation, atelectasis requiring fiberoptic desobstruction (n 1). In 8 cases (14.8%), postoperative complications were related to lymphadenectomy: chylothorax (n 1, 1.8%), which pharmacologically recovered; recurrent nerve palsy (n 7, 13%) with total symptom s regression 3 months later, in all but one case. Ninety days after resection, a 74-year-old patient, who underwent right pneumonectomy for a 9 cm diameter hilar TC, died of adult respiratory distress syndrome (in hospital mortality rate, 1.8%). Pathologic Findings According to new WHO criteria, 42 tumors were classified as TC and 12 as AC, which size varied from 0.5 to 9 cm (mean 2, 1.6 cm). They were located in the right lung in 33 cases (61%) and in the left lung in 21 cases (39%). The location, the macroscopic and microscopic aspect of the carcinoid tumors are summarized in Table 2. Among the TC group (n 42), 2 patients were classified N1 (4.8%) and 4 N2 (9.5%). Among the AC group (n 12), 2 patients were classified N1 (16.6%) and 2 N2 (16.6%). In both groups a single skip metastasis was found in 5 of 6 N2 patients (83.3%) (Table 3). The definitive staging of 54 patients is summarized in Table 4. TABLE 2. Location, Macroscopic and Microscopic Aspect of Carcinoid Tumors of the Lung Location Macroscopic and Microscopic Aspect TC (42) AC (12) Total % Central Endoluminal Mural Iceberg Peripheral TC, typical carcinoid; AC, atypical carcinoid. Follow-Up No patient was lost for follow-up, with a months (range, 9124) median time of observation. In the TC group, 2 N0 patients died of metastatic disease respectively at 36 and 76 months (mortality rate, 4.8%) and there was another death not related to the disease. Among survivors (n 39), one patient is alive with liver metastasis that appeared 12 months after surgery. In the AC group, all but one patient are alive and disease free. A 79-year-old woman (Table 3, patient n 7) who showed multiple nodal metastasis, died of metastatic disease at 52 months (mortality rate, 8.3%). Overall survival was 50 out of 54 patients (92.6%). Statistical Analysis Significantly higher frequency of lymphatic spread was observed in patients aged 35 years (p 0.01, Odds Ratio 7.95% CI ) and tumor size 3 cm(p 0.002, Odds Ratio 12.3, 95% CI ). No further relationship was demonstrated between lymphatic spread and sex, tumor location, macroscopic and microscopic aspect (TC or AC). Kaplan-Meier survival and statistical comparative analysis did not show any difference according to histologic type (p 0.264, Figure 1) and nodal status (p 0.518, Figure 2). DISCUSSION The real frequency of lymphatic spread in carcinoid tumors of the lung is difficult to estimate and we here report a series carried out to answer the question, by studying the number and location of nodal metastatis. Indeed, all articles before 1999 are inaccurate for this purpose, including carcinoids classified according to the old classifications 2,3 leading to overlaps among the different entities (TC, AC and highgrade large-cell neuroendocrine carcinoma). 921 In other series including newly classified carcinoids, the lymphadenectomy was not described 7,27 or heterogeneously performed. 23,24,28,29 In a retrospective series of 517 carcinoids that specifically addressed the outcome in patients presenting with lymphatic spread, 34 the low percentage of lymph node TABLE 3. Age yr Lymphatic Spread Sex Macroscopic Aspect (Tumor Size) Procedure (Number of Resected Lymph Nodes) Hilar and Intrapulmonary Nodal Status (Location) Mediastinal Nodal Status (Location) Single Skip Metastasis TNM Classification Typical Carcinoids with Lymphatic Spread (6/42:14.3%) 1 32 M Mural (3 cm) SRUL (12) 2N 9N; 1N (4R) T2N2M M Iceberg tumor (3.8 cm) RLL (11) 2N 8N; 1N (7) T2N2M M Endoluminal (1.9 cm) SRUL (20) 2N; 1N (11R) 17N T1N1MO 4 15 F Endoluminal (0.7 cm) RLL, ML (24) 4N 19 N; 1N (8R) T1N2MO 5 49 F Iceberg tumor (4.5cm) SLUL (10) 3N 6N ; 1N (6L) T2N2MO 6 20 F Iceberg tumor (5 cm) RLL, ML (31) 6N; 1N (11R) 24 N T2N1MO Atypical carcinoids with lymphatic spread (4/12:33.3%) 7 71 F Iceberg tumor (6 cm) LP (13) 2N; 1N (10L) 2N; 8N (4L, 7) T2N2M F Peripheral (1.5 cm) LUL (9) 2N 7N T1N1M F Mural (3 cm) SRUL (23) 8N 14N; 1N (4R) T2N2M M Iceberg tumor (3.5 cm) SRP (41) 14N; 2N (10R, 11R) 25N T4N1M0 M, male; F, female; SRUL, sleeve right upper lobectomy; RLL, right lower lobectomy; ML, middle lobectomy; SLUL, sleeve left upper lobectomy; LP, left pneumonectomy; LUL, left upper lobectomy; SRP, sleeve right pneumonectomy; N, no nodal metastasis; N, nodal metastasis; TNM, tumor, node, metastasis. 390 Copyright 2009 by the International Association for the Study of Lung Cancer

4 Systematic Nodal Dissection in Carcinoid metastases (5.99%) raises some doubt regarding the effectiveness and the completeness of lymphadenectomy. 25 Furthermore, there was no information about the lymphatic spread distribution between TC and AC respectively. Only Cardillo et al. 25 and Mineo et al. 26 reported relevant series in which all patients underwent formal lung resection associated with systematic nodal dissection (Table 5). In Cardillo s series reporting 163 patients, the mean number of resected lymph nodes was specified (12 7 per patient). In the TC group (n 121) the percentage of lymphatic spread was 11.6% (14 N1) and 63.2% in the AC TABLE 4. TNM Classification According to the Revisited International Clinical Staging System Stage (%) TC AC Total I (76) T1N0M T2N0M0 6 6 II (7.4) T1N1M T2N1M IIIA (9.2) T1N2M0 1 1 T2N2M IIIB (7.4) T4N0M T4N1M0 1 1 TNM, tumor node metastasis; TC, typical carcinoid; AC, atypical carcinoid. group (n 42), with 18 N1 and 9 N2. 25 Furthermore, the pathologic diagnosis of nodal metastasis was increased by Mineo et al., 26 who emphasized the relevance of micrometastasis detection by immunohistochemical techniques: from 17 to 27.6% increase in TC group and from 50 to 87.5% increase in AC group. With a lymphatic spread of 14.3% in the TC group and 33.3% in the AC group (p 0.05) we did not confirm the sparse data from literature. In this field, literature (Table 5) shows a small percentage (mean 2.3, range, 05.3%) of N2 patients in TC group: that was rather higher in our experience i.e., 4 N2 patients (9.5%), all with a single skip metastasis that could have been resected only after a complete clearance of the mediastinal stations. In AC group, the higher percentage of N2 patients (mean 17.9, range, %), is confirmed by our study: 2 N2 patients (16.6%) with a single skip metastasis in one (Table 5). Another issue concerns the lymphatic spread predictability. El Jamal et al. 22 did not find any correlation between tumor size and lymphatic spread risk. However, in our experience a tumor size 3 cm was significantly correlated with a lymphatic spread (p 0.01) and age 35 years (p 0.002) and we did not find any correlation between location, macroscopic or microscopic aspect (TC or AC) and lymphatic spread risk. Nonetheless, in Cardillo s series the difference in lymphatic spread between TC and AC (11.57 versus 64.28%) was highly significant (p ). Risks and Benefits of Surgery Including Systematic Nodal Dissection The surgical strategy to resect carcinoids is lung preservation whenever possible. Out of 54 patients, 22 broncho- FIGURE 1. Kaplan-Meier curves: survival in patients comparing those with typical carcinoids to those with atypical carcinoids; Logrank p AC, atypical carcinoid; TC, typical carcinoid. Copyright 2009 by the International Association for the Study of Lung Cancer 391

5 Wurtz et al. FIGURE 2. Kaplan-Meier curves: survival in patients comparing those without lymphatic spread and those with lymphatic spread; Logrank p LS, lymphatic spread. plastic procedures (40.8%) were performed with satisfactory long-term results, in line with other authors. 11,13,22 Confirming literature data, 25 lymphadenectomy led to low morbidity in our experience and neither fistula nor ischemic damage to the airway was observed. In TC, mediastinal relapses are quite rare and appear in the long-term. Rea et al. 28 observed two nodal relapses (carinal and paratracheal) in patients in whom a systematic nodal dissection was not performed. Bernstein et al. 35 found recurrences 18 and 32 years after pneumonectomy. El Jamal et al. 22 had one recurrence 18 years after surgery and emphasized the need for extraordinarily long follow-up to establish the results of surgery. Consequently, we stress on the potentially curative aspect of systematic nodal dissection in TC, even if it will be difficult to prove in the near future the impact upon the survival. In AC, the lymphatic spread has been shown to be a factor of worse prognosis as demonstrated by Garcia-Yuste et al. Furthermore, they found a significant improvement in patients survival with lymphatic spread between the retrospective group (without systematic nodal dissection) and the prospective group (following systematic nodal dissection). 29 Systematic nodal dissection plays a crucial role to cure ACTH-secreting carcinoid as well. In Pass s series of 13 patients, the first underwent a wedge resection without lymphadenectomy and all subsequent patients underwent systematic lymph node dissection in addition to the lobectomy. Six of 13 patients had metastatic mediastinal lymph nodes (46%) and among the 10 patients who became eucortisolemic immediately after operation, five of them were found to have positive lymph nodes (50%). Consequently the author emphazises the curative aspect of compulsive lymph node resection. 36 In Shrager s series of 7 patients, mediastinal lymphadenectomy was not systematicaly performed and 3 patients (43%) required a second operation to resect metastatic lymph node relapses. 37 Only Debetal. 38 found a lower rate of lymph node metastases (32%) and N2 disease (5.5%) in ACTH-secreting carcinoids. However they concluded that these tumors should be treated with formal anatomic resection and mediastinal lymphadenectomy. So far, in both groups of our series, all but one patient with metastatic lymph nodes, including one case of ACTHsecreting AC, are still alive and disease free. Furthermore we did not find any significant survival difference according to histologic type and nodal status. These results suggest the role of systematic nodal dissection in survival s improvement in carcinoid tumors of the lung, even so we acknowledge the limitation of this hypothesis in regard to the small number of patients, mainly in AC, and the relatively short length of follow-up. Some authors advocate for a bronchoscopic removal associated with Nd-YAG laser, electrocautery 39,40 or cryotherapy 41 to treat patients with intraluminal carcinoid in a curative intent. In the van Boxem s pilot study, tumor s eradication was effective in 14 of 19 patients (76.6%), with a median follow-up of 29 months. In the remaining 5 patients, radical resection was performed afterward with confirming the presence of residual carcinoid of atypical feature, with positive hilar node in one case, in contrast to the diagnosis 392 Copyright 2009 by the International Association for the Study of Lung Cancer

6 Systematic Nodal Dissection in Carcinoid TABLE 5. Lymphatic Spread of Carcinoid Tumors (Series Including Tumors Classified According to the 1999 WHO Histopathological Classification of Lung Tumors) Author/yr No. of Patients No. of N (%) No. of N1 (%) No. of N2 (%) El Jamal TC:81 AC:14 Cooper TC:50 AC:5 Filosso TC:75 AC:38 Mezzetti TC:88 AC:10 Cardillo TC:121 AC:42 Mineo TC:47 AC:8 Asamura TC:55 AC:9 Rea TC:174 AC:78 Garcia Yuste TC:569 AC:92 Present study TC:42 AC:12 11 (13.6) 4 (28.5) 2 (4) 2 (40) 6 (8) 14 (36.8) 18 (20.4) 5 (50) 14 (11.6) 27 (64.3) 13 (27.6) 7 (87.5) 2 (3.6) 4 (44.4) 7 (4) 22 (28.2) 52 (9.1) 33 (35.9) 6 (14.3) 4 (33.3) 11 (13.6) 2 (14.2) 2 (2,7) 7 (18.4) 16 (18) 3 (30) 14 (11.6) 18 (42.8) 13 (27.6) 5 (62.5) 1 (1.8) 2 (22.2) 6 (3.4) 13 (16.6) 32 (5,6) 14 (15) 2 (4.8) 2 (16.6) 0 2 (14.2) 4 (5,3) 7 (18.4) 2 (2.2) 2 (20) 0 9 (21.4) 0 2 (25) 1 (1.8) 2 (22.2) 1 (0.6) 9 (11.6) 20 (3.5) 19 (20.6) 4 (9.5) 2 (16.6) S Type of Lymphadenectomy S (no lymphadenectomy in 13 patients) S or SND, in case of macroscopic involvement SND SND Remarks 60/77 tumors reclassified according to the 1999 WHO classification Location of lymphatic spread specified Number of resected lymph nodes specified (12 7) Micrometastasis included Multicenter study From 1968 to 1989: S From 1990 to 2005: SND From 1980 to 1997: S From 1998 to 2002: SND SND Multicenter study Number of resected lymph nodes and location of lymphatic spread specified TC, typical carcinoid; AC, atypical carcinoid; N, nodal metastasis; N1, hilar and/or interlobar nodal metastasis; N2, mediastinal nodal metastasis; S, lymph node sampling; SND, systematic nodal dissection;, no reported data; WHO, World Health Organization. ascertained before resection. 39 Bertoletti et al. 41 reported a series of 19 patients treated with bronchoscopic removal plus cryotherapy. Median follow-up was 55 months and a single local recurrence (5.3%) was observed 7 years after the initial treatment, requiring surgery for TC. Brokx et al. applied an initial bronchoscopic treatment in 72 patients with intraluminal bronchial carcinoids, to improve presurgical condition and to enable less extensive parenchymal resection. Tumor eradication was attempted in 35 of them, but not achieved in two. In the other patients follow-up was stopped after the fifth year and 2 of them showed late recurrence ( 100 months), requiring further surgical resection. 40 In these series, the relatively short length of median follow-up (up to 55 months), in regard to late nodal relapse possibility even in atypical feature, 42 raises some doubt regarding the effectiveness of bronchoscopic treatment in a curative intent. In our series, among 10 patients showing strictly endoluminal TC 41 who were potentially eligible for bronchoscopic treatment, surgery discovered N1 or N2 lymphatic spread in 2 of them (20%) who were 29 and 15-year-old respectively (Table 3, patients n 3, 4). Accordingly, bronchoscopic treatment of carcinoid should be restricted to elderly patients or patients with a high operative risk. In other situations carcinoids tumors demand a surgical treatment by lung resection with bronchoplastic procedure whenever possible, associated with systematic nodal dissection, as non-small cell bronchic carcinomas, even so the impact upon the survival is currently difficult to estimate. REFERENCES 1. Morandi U, Casali C, Rossi G. Bronchial typical carcinoid tumors. Sem Thorac Cardiovasc Surg 2006;18: Arrigoni MG, Woolner LB, Bernatz PE. Atypical carcinoid tumors of the lung. J Thorac Cardiovasc Surg 1972;64: 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: Travis WD, Rush W, Flieder DB, et al. Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid. Am J Surg Pathol 1998;22: World Health Organization. Histologic Typing of Lung and Pleural Tumours, 3rd Ed. Geneva: The Organization, World Health Organization. Classification of tumours. Pathology and Genetics of Tumours of the lung, Pleura, Thymus and Heart. Lyon: IARC Press, Cooper WA, Thourani VH, Gal AA, et al. The surgical spectrum of pulmonary neuroendocrine neoplasms. Chest 2001;119: Hage R, Brutel de la Rivière A, Seldenrijk A, et al. Update in pulmonary carcinoid tumors: a review article. Ann Surg Oncol 2003;10: Copyright 2009 by the International Association for the Study of Lung Cancer 393

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