Lung neuroendocrine (carcinoid) tumors: Treatment and prognosis
- Charles F Thomas, Jr, MD
Charles F Thomas, Jr, MD
- Associate Professor of Medicine
- Mayo Clinic College of Medicine
- James R Jett, MD
James R Jett, MD
- Section Editor — Lung Cancer
- Professor of Medicine Emeritus
- National Jewish Health
- Jonathan R Strosberg, MD
Jonathan R Strosberg, MD
- Associate Professor
- Department of Gastrointestinal Oncology
- H. Lee Moffitt Cancer Center
Lung neuroendocrine (bronchial carcinoid) tumors (NETs) are a rare group of pulmonary neoplasms that are often characterized by indolent clinical behavior. Like other carcinoid tumors, lung NETs are thought to derive from peptide- and amine-producing neuroendocrine cells. NETs can arise at a number of sites throughout the body, including the thymus, lung, gastrointestinal (GI) tract, and ovary. The GI tract is the most frequently involved site for NETs, while the lung is the second most common. (See "Clinical characteristics of carcinoid tumors".)
Lung NETs are characterized by strikingly heterogeneous pathological features and clinical behavior. At one end of the spectrum are the so-called typical carcinoids, which are well-differentiated, low-grade, slowly growing neoplasms that seldom metastasize to extrathoracic structures. At the other end of the spectrum are the poorly differentiated and high-grade neuroendocrine carcinomas, as typified by small cell lung cancer (SCLC), which behaves aggressively, with rapid tumor growth and early distant dissemination. The biologic behavior of atypical carcinoid tumors, which are of intermediate grade and differentiation, is intermediate between typical carcinoid tumors and SCLC. The terms "typical" and "atypical" carcinoid of the lung correspond roughly to the terms "grade 1" and "grade 2," which are used more commonly in extrathoracic NETs. (See "Lung neuroendocrine (carcinoid) tumors: Epidemiology, risk factors, classification, histology, diagnosis, and staging", section on 'Classification, histology, and histochemistry' and "Pathobiology and staging of small cell carcinoma of the lung" and "Pathology, classification, and grading of neuroendocrine tumors arising in the digestive system", section on 'Classification and terminology'.)
Multifocal disease is relatively common in patients with low-grade lung NETs. An extreme example is diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH), a benign condition characterized by diffuse hyperplasia of pulmonary neuroendocrine cells and formation of multiple carcinoid tumorlets. (See "Pathology of lung malignancies", section on 'DIPNECH'.)
The treatment and prognosis of both typical and atypical lung NETs (carcinoid tumors) will be discussed here. The epidemiology, classification, clinical features, diagnosis, and staging of these tumors is discussed elsewhere, as is treatment of well-differentiated NETs arising in other sites and poorly differentiated neuroendocrine cancers arising in the lung. (See "Lung neuroendocrine (carcinoid) tumors: Epidemiology, risk factors, classification, histology, diagnosis, and staging" and "Staging, treatment, and posttreatment surveillance of nonmetastatic, well-differentiated gastrointestinal tract neuroendocrine (carcinoid) tumors" and "Extensive stage small cell lung cancer: Initial management" and "Role of surgery in multimodality therapy for small cell lung cancer".)
For patients with localized lung neuroendocrine tumors (NETs), surgical resection is the preferred treatment approach, assuming adequate pulmonary reserve. For patients whose condition does not permit complete resection and for exceptional low-grade cases where the lesion is entirely endobronchial, transbronchoscopic resection may be an alternative. (See 'Endobronchial management' below.)
- Terzi A, Lonardoni A, Feil B, et al. Bronchoplastic procedures for central carcinoid tumors: clinical experience. Eur J Cardiothorac Surg 2004; 26:1196.
- El Jamal M, Nicholson AG, Goldstraw P. The feasibility of conservative resection for carcinoid tumours: is pneumonectomy ever necessary for uncomplicated cases? Eur J Cardiothorac Surg 2000; 18:301.
- Lucchi M, Melfi F, Ribechini A, et al. Sleeve and wedge parenchyma-sparing bronchial resections in low-grade neoplasms of the bronchial airway. J Thorac Cardiovasc Surg 2007; 134:373.
- Stefani A, Morandi U, Urgese AL, et al. Carcinoid tumors of the lung. An analysis of 65 operated cases. J Cardiovasc Surg (Torino) 1999; 40:607.
- Morandi U, Casali C, Rossi G. Bronchial typical carcinoid tumors. Semin Thorac Cardiovasc Surg 2006; 18:191.
- Cerfolio RJ, Deschamps C, Allen MS, et al. Mainstem bronchial sleeve resection with pulmonary preservation. Ann Thorac Surg 1996; 61:1458.
- Ferguson MK, Landreneau RJ, Hazelrigg SR, et al. Long-term outcome after resection for bronchial carcinoid tumors. Eur J Cardiothorac Surg 2000; 18:156.
- Gustafsson BI, Kidd M, Chan A, et al. Bronchopulmonary neuroendocrine tumors. Cancer 2008; 113:5.
- Filosso PL, Oliaro A, Ruffini E, et al. Outcome and prognostic factors in bronchial carcinoids: a single-center experience. J Thorac Oncol 2013; 8:1282.
- Phan AT, Oberg K, Choi J, et al. NANETS consensus guideline for the diagnosis and management of neuroendocrine tumors: well-differentiated neuroendocrine tumors of the thorax (includes lung and thymus). Pancreas 2010; 39:784.
- Darling GE, Allen MS, Decker PA, et al. Randomized trial of mediastinal lymph node sampling versus complete lymphadenectomy during pulmonary resection in the patient with N0 or N1 (less than hilar) non-small cell carcinoma: results of the American College of Surgery Oncology Group Z0030 Trial. J Thorac Cardiovasc Surg 2011; 141:662.
- Fink G, Krelbaum T, Yellin A, et al. Pulmonary carcinoid: presentation, diagnosis, and outcome in 142 cases in Israel and review of 640 cases from the literature. Chest 2001; 119:1647.
- Skuladottir H, Hirsch FR, Hansen HH, Olsen JH. Pulmonary neuroendocrine tumors: incidence and prognosis of histological subtypes. A population-based study in Denmark. Lung Cancer 2002; 37:127.
- Divisi D, Crisci R. Carcinoid tumors of the lung and multimodal therapy. Thorac Cardiovasc Surg 2005; 53:168.
- 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.
- Cardillo G, Sera F, Di Martino M, et al. Bronchial carcinoid tumors: nodal status and long-term survival after resection. Ann Thorac Surg 2004; 77:1781.
- Ducrocq X, Thomas P, Massard G, et al. Operative risk and prognostic factors of typical bronchial carcinoid tumors. Ann Thorac Surg 1998; 65:1410.
- Asamura H, Kameya T, Matsuno Y, et al. Neuroendocrine neoplasms of the lung: a prognostic spectrum. J Clin Oncol 2006; 24:70.
- Soga J, Yakuwa Y. Bronchopulmonary carcinoids: An analysis of 1,875 reported cases with special reference to a comparison between typical carcinoids and atypical varieties. Ann Thorac Cardiovasc Surg 1999; 5:211.
- Matilla Gonzalez J, Garcia-Yuste M, Moreno-Mata N, et al. Typical and atypical carcinoid tumors (NEC grades 1 and 2): Prognostic factiors in metastaes and local recurrence (abstract). Lung Cancer 2005; 49(2 suppl):S60.
- Lou F, Sarkaria I, Pietanza C, et al. Recurrence of pulmonary carcinoid tumors after resection: implications for postoperative surveillance. Ann Thorac Surg 2013; 96:1156.
- Chughtai TS, Morin JE, Sheiner NM, et al. Bronchial carcinoid--twenty years' experience defines a selective surgical approach. Surgery 1997; 122:801.
- Harpole DH Jr, Feldman JM, Buchanan S, et al. Bronchial carcinoid tumors: a retrospective analysis of 126 patients. Ann Thorac Surg 1992; 54:50.
- Aubry MC, Thomas CF Jr, Jett JR, et al. Significance of multiple carcinoid tumors and tumorlets in surgical lung specimens: analysis of 28 patients. Chest 2007; 131:1635.
- Fiala P, Petrásková K, Cernohorský S, et al. Bronchial carcinoid tumors: long-term outcome after surgery. Neoplasma 2003; 50:60.
- Martini N, Zaman MB, Bains MS, et al. Treatment and prognosis in bronchial carcinoids involving regional lymph nodes. J Thorac Cardiovasc Surg 1994; 107:1.
- Filosso PL, Guerrera F, Evangelista A, et al. Prognostic model of survival for typical bronchial carcinoid tumours: analysis of 1109 patients on behalf of the European Association of Thoracic Surgeons (ESTS) Neuroendocrine Tumours Working Group. Eur J Cardiothorac Surg 2015; 48:441.
- Beasley MB, Thunnissen FB, Brambilla E, et al. Pulmonary atypical carcinoid: predictors of survival in 106 cases. Hum Pathol 2000; 31:1255.
- Gould PM, Bonner JA, Sawyer TE, et al. Bronchial carcinoid tumors: importance of prognostic factors that influence patterns of recurrence and overall survival. Radiology 1998; 208:181.
- Filosso PL, Rena O, Donati G, et al. Bronchial carcinoid tumors: surgical management and long-term outcome. J Thorac Cardiovasc Surg 2002; 123:303.
- García-Yuste M, Matilla JM, Alvarez-Gago T, et al. Prognostic factors in neuroendocrine lung tumors: a Spanish Multicenter Study. Spanish Multicenter Study of Neuroendocrine Tumors of the Lung of the Spanish Society of Pneumonology and Thoracic Surgery (EMETNE-SEPAR). Ann Thorac Surg 2000; 70:258.
- Rea F, Rizzardi G, Zuin A, et al. Outcome and surgical strategy in bronchial carcinoid tumors: single institution experience with 252 patients. Eur J Cardiothorac Surg 2007; 31:186.
- Kaplan B, Stevens CW, Allen P, et al. Outcomes and patterns of failure in bronchial carcinoid tumors. Int J Radiat Oncol Biol Phys 2003; 55:125.
- Machuca TN, Cardoso PF, Camargo SM, et al. Surgical treatment of bronchial carcinoid tumors: a single-center experience. Lung Cancer 2010; 70:158.
- Mackley HB, Videtic GM. Primary carcinoid tumors of the lung: a role for radiotherapy. Oncology (Williston Park) 2006; 20:1537.
- Marty-Ané CH, Costes V, Pujol JL, et al. Carcinoid tumors of the lung: do atypical features require aggressive management? Ann Thorac Surg 1995; 59:78.
- Cooper WA, Thourani VH, Gal AA, et al. The surgical spectrum of pulmonary neuroendocrine neoplasms. Chest 2001; 119:14.
- Carretta A, Ceresoli GL, Arrigoni G, et al. Diagnostic and therapeutic management of neuroendocrine lung tumors: a clinical study of 44 cases. Lung Cancer 2000; 29:217.
- Perkins P, Kemp BL, Putnam JB Jr, Cox JD. Pretreatment characteristics of carcinoid tumors of the lung which predict aggressive behavior. Am J Clin Oncol 1997; 20:285.
- Nussbaum DP, Speicher PJ, Gulack BC, et al. Defining the role of adjuvant chemotherapy after lobectomy for typical bronchopulmonary carcinoid tumors. Ann Thorac Surg 2015; 99:428.
- Caplin ME, Baudin E, Ferolla P, et al. Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids. Ann Oncol 2015; 26:1604.
- Brokx HA, Risse EK, Paul MA, et al. Initial bronchoscopic treatment for patients with intraluminal bronchial carcinoids. J Thorac Cardiovasc Surg 2007; 133:973.
- van Boxem TJ, Golding RP, Venmans BJ, et al. High-resolution CT in patients with intraluminal typical bronchial carcinoid tumors treated with bronchoscopic therapy. Chest 2000; 117:125.
- Brokx HA, Paul MA, Postmus PE, Sutedja TG. Long-term follow-up after first-line bronchoscopic therapy in patients with bronchial carcinoids. Thorax 2015; 70:468.
- Berendsen HH, Postmus PE, Edens ET, Sluiter HJ. Irresectable bronchial carcinoid with a 32-year natural history. A report of two cases treated with Neodymium-YAG-laser, initially misinterpreted as small cell lung cancer. Eur J Respir Dis 1986; 68:151.
- Díaz-Jiménez JP, Canela-Cardona M, Maestre-Alcacer J. Nd:YAG laser photoresection of low-grade malignant tumors of the tracheobronchial tree. Chest 1990; 97:920.
- Orino K, Kawai H, Ogawa J. Bronchoscopic treatment with argon plasma coagulation for recurrent typical carcinoids: report of a case. Anticancer Res 2004; 24:4073.
- Schreurs AJ, Westermann CJ, van den Bosch JM, et al. A twenty-five-year follow-up of ninety-three resected typical carcinoid tumors of the lung. J Thorac Cardiovasc Surg 1992; 104:1470.
- Bertoletti L, Elleuch R, Kaczmarek D, et al. Bronchoscopic cryotherapy treatment of isolated endoluminal typical carcinoid tumor. Chest 2006; 130:1405.
- Chakravarthy A, Abrams RA. Radiation therapy in the management of patients with malignant carcinoid tumors. Cancer 1995; 75:1386.
- Colaco RJ, Decker RH. Stereotactic radiotherapy in the treatment of primary bronchial carcinoid tumor. Clin Lung Cancer 2015; 16:e11.
- Wirth LJ, Carter MR, Jänne PA, Johnson BE. Outcome of patients with pulmonary carcinoid tumors receiving chemotherapy or chemoradiotherapy. Lung Cancer 2004; 44:213.
- Krenning EP, Kwekkeboom DJ, Bakker WH, et al. Somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients. Eur J Nucl Med 1993; 20:716.
- Fischer S, Kruger M, McRae K, et al. Giant bronchial carcinoid tumors: a multidisciplinary approach. Ann Thorac Surg 2001; 71:386.
- Rinke A, Müller HH, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol 2009; 27:4656.
- Caplin ME, Pavel M, Ruszniewski P. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 2014; 371:1556.
- Sullivan I, Le Teuff G, Guigay J, et al. Antitumour activity of somatostatin analogues in sporadic, progressive, metastatic pulmonary carcinoids. Eur J Cancer 2017; 75:259.
- Jermendy G, Kónya A, Kárpáti P. Hepatic artery embolisation--new approach for treatment of malignant carcinoid syndrome. Dtsch Z Verdau Stoffwechselkr 1986; 46:130.
- Sayeg Y, Sayeg M, Baum RP, et al. [Pulmonary neuroendocrine neoplasms]. Pneumologie 2014; 68:456.
- Milkiewicz P, Olliff S, Johnson AP, Elias E. Obstructive sleep apnoea syndrome (OSAS) as a complication of carcinoid syndrome treated successfully by hepatic artery embolization. Eur J Gastroenterol Hepatol 1997; 9:217.
- Yao JC, Fazio N, Singh S, et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet 2016; 387:968.
- Fan JT, Ortiz RG, Buettner H. Regression of choroidal metastases from a bronchial carcinoid tumor after chemotherapy with cisplatin and etoposide. Am J Ophthalmol 1994; 117:111.
- Granberg D, Eriksson B, Wilander E, et al. Experience in treatment of metastatic pulmonary carcinoid tumors. Ann Oncol 2001; 12:1383.
- Crona J, Fanola I, Lindholm DP, et al. Effect of temozolomide in patients with metastatic bronchial carcinoids. Neuroendocrinology 2013; 98:151.
- Masi G, Fornaro L, Cupini S, et al. Refractory neuroendocrine tumor-response to liposomal doxorubicin and capecitabine. Nat Rev Clin Oncol 2009; 6:670.
- Bajetta E, Rimassa L, Carnaghi C, et al. 5-Fluorouracil, dacarbazine, and epirubicin in the treatment of patients with neuroendocrine tumors. Cancer 1998; 83:372.
- Bajetta E, Catena L, Procopio G, et al. Are capecitabine and oxaliplatin (XELOX) suitable treatments for progressing low-grade and high-grade neuroendocrine tumours? Cancer Chemother Pharmacol 2007; 59:637.
- De Dosso S, Bajetta E, Procopio G, et al. Pulmonary carcinoid tumours: indolent but not benign. Oncology 2007; 73:162.
- Lo Russo G, Pusceddu S, Prinzi N, et al. Peptide receptor radionuclide therapy: focus on bronchial neuroendocrine tumors. Tumour Biol 2016; 37:12991.
- Ianniello A, Sansovini M, Severi S, et al. Peptide receptor radionuclide therapy with (177)Lu-DOTATATE in advanced bronchial carcinoids: prognostic role of thyroid transcription factor 1 and (18)F-FDG PET. Eur J Nucl Med Mol Imaging 2016; 43:1040.
- Mariniello A, Bodei L, Tinelli C, et al. Long-term results of PRRT in advanced bronchopulmonary carcinoid. Eur J Nucl Med Mol Imaging 2016; 43:441.
- van Vliet EI, Krenning EP, Teunissen JJ, et al. Comparison of response evaluation in patients with gastroenteropancreatic and thoracic neuroendocrine tumors after treatment with [177Lu-DOTA0,Tyr3]octreotate. J Nucl Med 2013; 54:1689.
- Imhof A, Brunner P, Marincek N, et al. Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue [90Y-DOTA]-TOC in metastasized neuroendocrine cancers. J Clin Oncol 2011; 29:2416.
- Brabander T, Van der Zwan WA, Teunissen JJ, et al. Long-term efficacy, survival and safety of [177Lu-DOTA0,Tyr3]octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors. Clin Cancer Res 2017.
- Zuetenhorst JM, Hoefnageli CA, Boot H, et al. Evaluation of (111)In-pentetreotide, (131)I-MIBG and bone scintigraphy in the detection and clinical management of bone metastases in carcinoid disease. Nucl Med Commun 2002; 23:735.
- LOCALIZED DISEASE
- Surgical resection
- - Proximal tumors
- - Peripheral tumors
- - Role of lymph node dissection
- - Prognosis
- Typical lung NETs
- Atypical lung NETs
- - Role of adjuvant therapy
- Recommendations of expert groups
- Endobronchial management
- - Resection
- - Cryotherapy
- Inoperable and locally advanced unresectable disease
- Posttreatment surveillance
- - Guidelines from expert groups
- MANAGEMENT OF CARCINOID SYNDROME
- Potentially resectable locoregional disease
- Unresectable disease
- - Somatostatin analogs
- - Refractory symptoms
- ANTITUMOR THERAPY FOR ADVANCED DISEASE
- Initial therapy for slowly progressive disease
- Liver-dominant metastatic disease
- Progressive, disseminated, or SSA-refractory disease
- - Everolimus
- - Cytotoxic chemotherapy
- - Peptide receptor radioligand therapy
- Painful bone metastases
- Recommendations from expert groups
- SUMMARY AND RECOMMENDATIONS