Tracheobronchopulmonary Carcinoid Tumors: Analysis of 40 Patients

Ann Thorac Cardiovasc Surg 2011; 17: 7 12 Original Article Tracheobronchopulmonary Carcinoid Tumors: Analysis of 40 Patients Reza Bagheri, MD, 1 Mohammad taghi Rajabi Mashhadi, MD, 1 S.Ziaallah Haghi, MD, 1 Ali Sadrizadh, MD, 1 and Fariba Rezaeetalab, MD 2 Introduction: Carcinoid tumors are a type of neuroendocrine tumors which usually involve the upper airways and the patients most often complain of cough and hemoptysis. Materials and Methods: This study was performed from 1990 through 2007 on 40 patients with carcinoid tumor who had been followed up for at least 3 years. The statistical analysis were based on tumor epidemiology, treatment and the 3- year survival. The factors influencing the survival were analyzed using SPSS and exact fisher test. Results: M/F was 16/24 with mean age 34 years. Their most common symptoms were coughing (90%). The left main bronchus was the most common site of involvement (25%). 95% of all the cases underwent surgery and 5% of the patients underwent chemoradiotherapy due to distant metastasis. The most common surgical procedure was lobectomy or biloectomy (57.8%). Bronchial sleeve resection was performed on 10.4% of the patients. The most common pathology was the typical form (90%) and 5% of the madiastinal lymph nodes were involvd all of the atypical type. Carcinoid syndrome was seen in one patient (2.5%) and post operative adjuvant treatment was done in 5% of the patients after surgery because of mediastinal lymph node involvement. Post operative recurrence occurred in one patient (2.6%) of the atypical form with mediastinal lymph nodes involvement. The most common complication of surgery was a long- term air leakage (10.4%) and the surgical death rate was 0%. 3- Year survival was 92.5%. The factors influencing the survival included the pathological type, distant metastasis and mediastinal lymph node involvement. Conclusion: Carcinoid tumors have mostly been responsive to surgical intervention, resulting in a long term survival. Copyright ERS 2009 of the abstract in Eur Respir J 2009, 34, Suppl. 53: P167. Key words: carcinoid tumor, surgical resection, adjuvant therapy 1 Thoracic Surgery, Mashhad University of Medical Sciences, Mashhad, Iran 2 Pulmonary Medicine, Mashhad University of Medical Sciences, Mashhad, Iran (current affiliation) 1 Endoscopic and Minimal Invasive Research Center, 2 Lung Diseases and Tuberculosis Research Center, Mashhad University of Medical Sciences, Mashhad, Iran Received: February 27, 2008; Accepted: January 31, 2010 Corresponding author: Reza Bagheri, MD. (current affiliation) Endoscopic and Minimal Invasive Research Center, Ghaem Hospital, Ahmadabad Street, Mashhad, Iran Email: Bagherir@mums.ac.ir 2011 The Editorial Committee of Annals of Thoracic and Cardiovascular Surgery. All rights reserved. Introduction Pulmonary carcinoid tumors are neuroendocrine malignant tumors that represent 1% to 2% of all lung tumors. According to histopathologic criteria, carcinoids could be divided into typical (TC) and atypical (AC) carcinoids. Carcinoids are in a spectrum of neuroendocrine tumors, ranging from low-grade malignant TC, intermediate AC, high- grade large cell neuroendocrine carcinoma to small cell lung carcinoma. Familial pulmonary carcinoids are rare. The most common symptoms are hemoptysis, cough, recurrent pulmonary infection, 7

Bagheri R et al. Table 1 Prevalence of clinical findings in carcinoid tumor patients (40 patients). fever, chest discomfort and chest pain, unilateral wheezing, and shortness of breath. Paraneoplastic syndromes are rare and include carcinoid syndrome, Cushing s syndrome, and ectopic growth hormone secretion. The diagnosis is usually established by flexible bronchoscopy and biopsy, although occasionally this can result in severe hemorrhage. Immunoscintigraphy by somatostatin analogues can also help in the diagnosis. The treatment of choice is surgical resection, and prognosis is relatively good for TC, though it is not usually favorable for AC. The role of radiotherapy and chemotherapy as a part of multimodality treatment or palliation is still debated. 1) This study was aimed to assess the result of treatment and 3-year survival rate of patients with carcinoid tumors. Materials and Methods This is a descriptive study which was performed on 40 patients admitted to Qhaem and Omid hospitals of Mashhad University of Medical Sciences from 1990 to 2007. They were evaluated after appropriate treatment (38 patients had undergone surgery and 2 patients underwent chemoradiotherapy without surgery because of distant metastasis at the time of admission). They were followed up for at least 3 years. Average time of follow up was 9.5 ± 0.6 years (3 17 years). The following factors were statically analyzed: age, sex, clinical symptoms, tumor location, diagnostic procedures before treatment, therapeutic method and its complications and 3-year survival. The factors influenced 3-year survival rate were also studied by Statistical Package for the Social Sciences (SPSS) version 11.5 and Fisher s exact test. Results Percent Number Clinical finding 95% 38 Cough 75% 30 Hemoptysis 55% 22 Dyspnea 27.5% 11 Wheezing Table 2 Prevalence of involved airways in carcinoid tumor (40 patients). percent Num Location 5% 2 Trachea 25% 10 Left main bronchus 20% 8 Right main bronchus 12.5% 5 Left upper lobe bronchus 5% 2 Right upper lobe bronchus 12.5% 5 Left lower lobe bronchus 10% 4 Right lower lobe bronchus 5% 2 Right middle lobe bronchus 2.5% 1 Lingual 2.5% 1 Miliary pattern 40 patients were enrolled in the study, including 16 males and 24 females (M/F = 0.66). their age ranged from 12 to 88 years with a mean age of 34 years. The most common symptoms were cough (40%) and hemoptysis (25%). The prevalence of the clinical findings in carcinoid tumor patients is shown in Table 1. Chest X-ray and CT scan were used as diagnostic tools in all patients. Flexible bronchoscopy was performed in all patients as a standard diagnostic procedure before treatment. A biopsy sample with a definitive pathological report was taken from 32 patients (80%); however, because of the risk of severe hemorrhage, a biopsy was not performed, and surgery was performed without biopsy on the other 8 (20%) patients. The most common location of the tumor was in the left main bronchus (25%). Table 2 shows the prevalence of involved airways in carcinoid tumor. Generally the tumor most commonly involved the proximal airway on the left side. Bilateral form was not observed in our study. Thirty-eight patients (95%) underwent surgical operation. Only 2 cases (5%) showed distant metastasis on admission and did not undergo surgery. In one patient a miliary pattern of lung involvement was seen, in addition to the distant metastasis. The most common surgical technique was lobectomy, which was performed in 14 cases (37%). Table 3 shows the prevalence of the technical procedures used in the 38 surgical cases. We performed bronchial sleeve resection in four patients in whom three underwent bronchial sleeve upper lobectomy and one, bronchial sleeve lower lobectomy. On pathological examination, 36 patients had the typical carcinoid form (90%) and 4 had the atypical carcinoid form (10%). Classical mediastinal lymphadenectomy was performed on 4 patients during operation, because of 8

Table 3 Prevalence of technical procedures (38 patients). Percent Num Technique 37% 14 Lobectomy 20.8% 8 Bilobectomy 20.8% 8 Pneumonectomy 10.4% 4 Bronchial sleeve resection 5.2% 2 Segmentectomy 5.2% 2 Tracheal resection Tracheobronchopulmonary Carcinoid Tumors mediastinal lymphatic involvement; however, in 2 patients (5%), metastatic lymphatic involvement was seen after the pathological report both of whom had the atypical carcinoid form. Only one of the cases showed the clinical symptoms of carcinoid syndrome in which hepatic metastasis occurred. Postoperative adjuvant therapy was required in 2 patients (5%) with atypical carcinoid form and mediastinal lymphatic involvement, (chemoradiotherapy); however, in 2 patients (5%) who had distant metastasis on admission, chemoradiotherapy was performed without an operation. Chemotrapeutic regimens were cisplatin with etopside which was given in 6 courses with 3 weeks interval and in each course cisplaten was given with the dose of 80 mg/m 2 and etopside with the dose of 100 mg/m 2. The dosage of radiotherapy was 5000 rad which was given in 5 weeks (5 times each week). Also in cases with unresectable tumor and in patients who could not tolerate surgery, the dosage of radiotherapy was enhanced, but only if the tumor has an acceptable response to it. Postoperative recurrence was seen in form of distant metastasis in one case (2.5%) in atypical carcinoid form with mediastinal lymphatic involvement. 37 (92.5%) patients had no recurrence after surgery. In the 3-year evaluation for survival, 37 patients (92.5%) were still alive while 3 (7.5%) patients died, in whom 2 cases had distant metastasis at the time of admission and one patient went to the US, 1.5 years after the initial surgery with distant metastasis. All the patients who underwent sleeve resection were still alive with no sign of recurrence on follow up. Regarding factors affecting the survival, patients were placed into two groups (more and less than 3 years survival), and were evaluated for parameters such as age, sex, side of involvement, type of pathology, mediastinal lymph node involvement and distant metastasis (early and late). All patients with typical carcinoid were alive after 3 years and only one patient with atypical carcinoid was alive after 3 years which shows that type of pathology affects survival (P <0.05). Other factors such as mediastinal lymph node involvement (P = 0.001) and early distant metastasis (P = 0.004) were also effective on survival, but other factors were not meaningful statistically. Table 4 shows the role of various factors in the survival of 40 patients with carcinoid tumors. We also determined 3 years survival according to Kaplan Meier method for the patients whom underwent appropriate treatment (Fig. 1). Postoperative complications were seen in 6 (15.6%) out of 38 patients and the most common were: prolonged air leakage in 4 patients (10.5%) which was controlled with conservative treatments (use of low suction), and wound infection in 2 patients (5.2%) which responded to usual treatments (opening the wound, washing and secondary repair). In one patient who had been discharged, empyema occurred after 3 months because of persistent space formation (from the prolonged air leakage group), and it was controlled by operation and using decortications and muscular flap. No surgical mortality occurred. Discussion Carcinoid tumors are malignant neuroendocrine tumors, first described in 1888 in the ileum. When neuroendocrine cells were first discovered, they were called clear cells and, later, amine precursor uptake and decarboxylation (APUD) system cells. The term neuroendocrine was introduced because of capability to synthesizing hormonal products and numbers of these 9

Bagheri R et al. Table 4 Studying the role of effective factors in the survival of pulmonary carcinoid patients (40 patients). Variables More than 3-years survey Less than 3-years survey Fisher exact test (37 patients) (3 patients) (P-value) Age Less than 60 y 30 (81%) 2 (66.6% ) More than 60 y 7 (19%) 1 (33.3%) Sex M 15 (40.5%) 1 (33.3%) F 22 (59.5%) 2 (66.6%) Tumor location Left side 20 (54%) 1 (33.3%) Right side 15 (40.5%) 1 (33.3%) Tracheal 2 (5.5%) 0 (0%) Miliary 0 (0%) 1 (33.3%) P >0.05 P >0.05 P >0.05 Mediastinal lymph node involvement 0 (0%) 3 (100%) P = 0.001 Metastasis Early 0 (0%) 2 (66.6%) P = 0.004 Delay 0 (0%) 1 (33.3% ) P = 0.075 Metastasis 0 (0%) 3 (100%) P = 0.001 Tumor pathology Typical 36 (97.3%) 0 Atypical 1 (2.7%) 3 (100%) P <0.05 Fig. 1 3 years survival of 40 patients with tracheobronchopulmonary Carcinoid Tumor cases according to Kaplan Meier method. products are identical to the nervous system. 2) Carcinoid tumors can be placed in the spectrum of neuroendocrine tumors, from low grade malignant typical carcinoids to intermediate atypical carcinoid to high grade small cell lung cancer (SCLC). 3) Bronchial carcinoids occur in any age but usually in the middle of 5th- decade of life equally in both sexes. 4) In our study the median age was 34 years and male to female ration was 0.66. In a study performed by Modlin et al, 25% of patient s were asymptomatic but in the symptomatic cases cough and hemoptysis were the most common symptoms. 5) In our study all the patients were symptomatic and cough 10

Tracheobronchopulmonary Carcinoid Tumors and hemoptysis were the most common symptoms. Bronchial carcinoids mostly occur in major airways (central airways). These tumors are highly vascular and originate submucusally. The carcinoid syndrome is rare, presents at diagnosis (1% 2% incidence) and is severe in patients with large primary tumors or extensive hepatic metastases. 6) Diagnosis is usually established by fibreoptic bronchoscopy and biopsy, although it can occasionally result in severe hemorrhage. 7) In our study the most common location of tumor was in the left main bronchus, and only one case (2.5%) showed the clinical symptoms of carcinoid syndrome with hepatic metastasis. All patients underwent flexible bronchoscopy but the biopsy was taken in 80% of patients before surgery. But because of the occurrence of severe hemorrhage, biopsy was not performed, and surgery performed without biopsy in (20%) patients. Biological behavior and prognosis of bronchial cacinoid tumors are better than other lung cancers. 8) The best method in treatment of carcinoid tumors is surgical resection with lymph node sampling. Surgery and long terms outcome are significantly related to histological type, node involvement and pathological status. 9) Because of the central localization of these tumors, for saving the pulmonary parenchyma, sleeve resection was performed in these tumors. Sleeve resection achieves local tumor control and is associated with a low mortality and bronchial anostomatic complication rate as well as excellent long term survival. 10) In our study, 38 patients (95%) underwent surgical operation, and lobectomy was the most common surgical technique (37%). Sleeve resection was performed in (10.4%) of patient with excellent long term results with no mortality or recurrence. All patients in whom sleeve resection was performed had typical carcinoid tumor. A study comparing typical and atypical carcinoid tumors showed that typical carcinoid tumors had more significant endobronchial polypoid growth and better survival than atypical carcinoid tumors, but mediastinal lymph node involvement had been more significant in atypical carcinoid tumors. 11) Patients with atypical carcinoid tumors and regional lymph node metastasis have a high likelihood of developing recurrent disease, if treated with surgical resection alone, and have a significantly worse outcome. 12) In our study, 90% of patients had typical carcinoid form but mediastinal lymph node involvement was seen in 2 patients with atypical carcinoid tumor with worse prognosis than the typical carcinoid tumor. Although surgery remains the standard of treatment for operable disease, histology is the most important factor in determining the role of adjuvant therapy. Completely resected typical or atypical carcinoid tumors without mediastinal lymph node involvement do not require adjuvant therapy but resected atypical carcinoid with mediastinal lymph node involvement or unresectable cases requires adjuvant therapy. 13) In our study, post operative adjuvant therapy was performed in atypical carcinoid tumors with positive mediastinal lymph node involvement in 2 patients (5%) and in those with metastatic lesions on admission in 2 patients (5%) In a Spanish multicentric study (2007) histology and node involvements appeared as the most important factors influencing the prognosis. 14) In another studies histological type, pathological stage and lymph node 8, 15) involvement affected the prognosis. In our study, histology, lymph node involvement and early distant metastasis appeared as the most important factors affecting the prognosis. Conclusion Based on good postoperative results in carcinoid tumor patients, surgical resection has been the treatment of choice in these tumors. Factors which appear to influence the prognosis are the pathological form, mediastinal lymph node involvement and distant metastasis in carcinoid tumor patients. Acknowledgement The authors wish to thank Vice Chancellery of Research of Mashhad University of Medical Sciences, Dr Amir Asnaashari, Dr. Mozhgan Bahadorinia, Dr. Reza Shojaeyan, Dr. Seyed Reza Hosseini, and Toktam Moghiman for their support and cooperation in accomplishing the study. The authors also appreciate Dr. Nurshafiee for composing and edition of this article. References 1) Hage R, de la Rivière AB, Seldenrijk CA, van den Bosch JM. Update in pulmonary carcinoid tumors: a reviw article. Ann Surg Oncol 2003; 10: 697 704. 2) Kulke MH, Mayer RJ. Carcinoid tumors. N Engl J Med 1999; 340: 858 68. 3) Rena O, Filosso PL, Ruffini E, Oliaro A. Bronchopulmonary carcinoid tumors. Minerva Chir 2002 57: 11

Bagheri R et al. 403 23. 4) Paladugu RR, Benfield JR, Pak HY, Ross RK, Teplitz RL. Bronchopulmonary Kulchitzky cell carcinomas. A new classification scheme for typical and atypical carcinoids. Cancer 1985; 55: 1303 11. 5) Modlin IM, Sandor A. An Analysis of 835 cases of carcinoid tumors. Cancer 1997; 79: 813 29. 6) 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: 50 4. 7) van Boxem TJ, Venmans BJ, van Mourik JC, Postmus PE, Sutedja TG. Bronchoscopic treatment of intraluminal typical carcinoid: a pilot study. J Thorac Cardiovasc Surg 1998; 116: 402 6. 8) Ferguson MK, Landreneau RJ, Hazelrigg SR, Altorki NK, Naunheim KS, et al. Long-term outcome after resection for bronchial carcinoid tumors. Eur J Cardiothorac Surg 2000; 18: 156 61. 9) Martini N, Zaman M B, Bains M, A Manjti S, Bains M, et al. Treatment and prognosis in bronchial carcinoids involving regional lymph nodes. J Thorac Cardiovasc Surg 1994; 107: 1 7. 10) Fadel E, Yildizeli B, Chapelier AR, D Centa I, Mussot S, et al. Sleeve lobectomy for brochogenic cancers factor affecting survival. Ann Thorac Surg 2002; 74: 851 8. 11) Akiba T, Naruke T, Kondo H, Goya T, Tsuchiya R, et al. Carcinoid tumor of the lung: clinicopathological study of 32 cases. J Clin Oncol 1992; 22: 92 5. 12) Thomas CF Jr, Tazelaar HD, Jett JR. Typical and atypical pulmonary carcinoids : outcome in patients presenting with regional lymph node involvement. Chest 2001; 119: 1143 50. 13) Mackley HB, Videtic GM. Primary carcinoid tumors of the lung: a role for radiotherapy. Oncology 2006; 20: 1537 43. 14) García-Yuste M, Matilla JM, Cueto A, Paniagua JM, Ramos G, et al. Typical and atypical carcinoid tumours: analysis of the experience of the Spanish Multi-centric Study of Neuroendocrine Tumours of the Lung. Eur J Cardiothorac Surg 2007; 31: 192 7. 15) Chughtai TS, Morin JE, Sheiner NM, Wilson JA, Mulder DS. Bronchial carcinoid--twenty years experience defines a selective surgical approach. Surgery 1997; 122: 801 8. 12