Bronchial neuroendocrine (carcinoid) tumors: Epidemiology, risk factors, classification, histology, diagnosis, and staging
- 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
Bronchial neuroendocrine (carcinoid) tumors (NETs) are an uncommon group of pulmonary neoplasms that are characterized by neuroendocrine differentiation and relatively indolent clinical behavior.
Like neuroendocrine tumors at other body sites, bronchial 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, while lung is the second most common. (See "Clinical characteristics of carcinoid tumors".)
The epidemiology, classification, clinical features, diagnosis, and staging of bronchial NETs will be reviewed here. Treatment and prognosis of bronchial carcinoid tumors, as well as clinical characteristics of carcinoid tumors arising in other sites, are discussed elsewhere. (See "Bronchial neuroendocrine (carcinoid) tumors: Treatment and prognosis" and "Clinical characteristics of carcinoid tumors".)
EPIDEMIOLOGY AND RISK FACTORS
Bronchial neuroendocrine tumors (NETs) account for approximately 1 to 2 percent of all lung malignancies in adults and roughly 20 to 30 percent of all NETs [1-4]. Bronchial NETs are the most common primary lung neoplasm of children, typically presenting in late adolescence. Typical NETs, which are low-grade tumors with a low mitotic rate, are about four times more common than atypical NETs, which are intermediate-grade tumors with a higher mitotic rate and/or necrosis. (See 'Classification, histology, and histochemistry' below.)
Globally, incidence rates range from 0.2 to 2 per 100,000 population per year, and most series suggest a higher incidence in women as compared with men, and in whites as compared with blacks [1-3,5-7].
- Quaedvlieg PF, Visser O, Lamers CB, et al. Epidemiology and survival in patients with carcinoid disease in The Netherlands. An epidemiological study with 2391 patients. Ann Oncol 2001; 12:1295.
- Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer 2003; 97:934.
- Hemminki K, Li X. Incidence trends and risk factors of carcinoid tumors: a nationwide epidemiologic study from Sweden. Cancer 2001; 92:2204.
- Hauso O, Gustafsson BI, Kidd M, et al. Neuroendocrine tumor epidemiology: contrasting Norway and North America. Cancer 2008; 113:2655.
- 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.
- Gatta G, Ciccolallo L, Kunkler I, et al. Survival from rare cancer in adults: a population-based study. Lancet Oncol 2006; 7:132.
- Yao JC, Hassan M, Phan A, et al. One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008; 26:3063.
- 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.
- Cao C, Yan TD, Kennedy C, et al. Bronchopulmonary carcinoid tumors: long-term outcomes after resection. Ann Thorac Surg 2011; 91:339.
- Beasley MB, Thunnissen FB, Brambilla E, et al. Pulmonary atypical carcinoid: predictors of survival in 106 cases. Hum Pathol 2000; 31:1255.
- Erasmus JJ, McAdams HP, Patz EF Jr, et al. Evaluation of primary pulmonary carcinoid tumors using FDG PET. AJR Am J Roentgenol 1998; 170:1369.
- Kayser K, Kayser C, Rahn W, et al. Carcinoid tumors of the lung: immuno- and ligandohistochemistry, analysis of integrated optical density, syntactic structure analysis, clinical data, and prognosis of patients treated surgically. J Surg Oncol 1996; 63:99.
- Froudarakis M, Fournel P, Burgard G, et al. Bronchial carcinoids. A review of 22 cases. Oncology 1996; 53:153.
- Brokx HA, Risse EK, Paul MA, et al. Initial bronchoscopic treatment for patients with intraluminal bronchial carcinoids. J Thorac Cardiovasc Surg 2007; 133:973.
- Hassan MM, Phan A, Li D, et al. Risk factors associated with neuroendocrine tumors: A U.S.-based case-control study. Int J Cancer 2008; 123:867.
- Leoncini E, Carioli G, La Vecchia C, et al. Risk factors for neuroendocrine neoplasms: a systematic review and meta-analysis. Ann Oncol 2016; 27:68.
- Oliveira AM, Tazelaar HD, Wentzlaff KA, et al. Familial pulmonary carcinoid tumors. Cancer 2001; 91:2104.
- Klimstra DS, Modlin IR, Coppola D, et al. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. Pancreas 2010; 39:707.
- Travis WB.. The concept of pulmonary neuroendocrine tumors. In: Pathology and genetics of tumours of lung, pleura, thymus, and heart, Travis WB, Brambilla E, Muller-Hermeli, et al. (Eds), IARC Press, Lyon 2004. p.19.
- 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.
- Ruffini E, Bongiovanni M, Cavallo A, et al. The significance of associated pre-invasive lesions in patients resected for primary lung neoplasms. Eur J Cardiothorac Surg 2004; 26:165.
- Rugge M, Fassan M, Clemente R, et al. Bronchopulmonary carcinoid: phenotype and long-term outcome in a single-institution series of Italian patients. Clin Cancer Res 2008; 14:149.
- Gustafsson BI, Kidd M, Chan A, et al. Bronchopulmonary neuroendocrine tumors. Cancer 2008; 113:5.
- Saqi A, Alexis D, Remotti F, Bhagat G. Usefulness of CDX2 and TTF-1 in differentiating gastrointestinal from pulmonary carcinoids. Am J Clin Pathol 2005; 123:394.
- Moore W, Freiberg E, Bishawi M, et al. FDG-PET imaging in patients with pulmonary carcinoid tumor. Clin Nucl Med 2013; 38:501.
- Nessi R, Basso Ricci P, Basso Ricci S, et al. Bronchial carcinoid tumors: radiologic observations in 49 cases. J Thorac Imaging 1991; 6:47.
- Jeung MY, Gasser B, Gangi A, et al. Bronchial carcinoid tumors of the thorax: spectrum of radiologic findings. Radiographics 2002; 22:351.
- Fischer S, Kruger M, McRae K, et al. Giant bronchial carcinoid tumors: a multidisciplinary approach. Ann Thorac Surg 2001; 71:386.
- Karmy-Jones R, Vallières E. Carcinoid crisis after biopsy of a bronchial carcinoid. Ann Thorac Surg 1993; 56:1403.
- Mehta AC, Rafanan AL, Bulkley R, et al. Coronary spasm and cardiac arrest from carcinoid crisis during laser bronchoscopy. Chest 1999; 115:598.
- Limper AH, Carpenter PC, Scheithauer B, Staats BA. The Cushing syndrome induced by bronchial carcinoid tumors. Ann Intern Med 1992; 117:209.
- Jones JE, Shane SR, Gilbert E, Flink EB. Cushing's syndrome induced by the ectopic production of ACTH by a bronchial carcinoid. J Clin Endocrinol Metab 1969; 29:1.
- DeStephano DB, Lloyd RV, Schteingart DE. Cushing's syndrome produced by a bronchial carcinoid tumor. Hum Pathol 1984; 15:890.
- Scanagatta P, Montresor E, Pergher S, et al. Cushing's syndrome induced by bronchopulmonary carcinoid tumours: a review of 98 cases and our experience of two cases. Chir Ital 2004; 56:63.
- Shrager JB, Wright CD, Wain JC, et al. Bronchopulmonary carcinoid tumors associated with Cushing's syndrome: a more aggressive variant of typical carcinoid. J Thorac Cardiovasc Surg 1997; 114:367.
- Pass HI, Doppman JL, Nieman L, et al. Management of the ectopic ACTH syndrome due to thoracic carcinoids. Ann Thorac Surg 1990; 50:52.
- Deb SJ, Nichols FC, Allen MS, et al. Pulmonary carcinoid tumors with Cushing's syndrome: an aggressive variant or not? Ann Thorac Surg 2005; 79:1132.
- 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.
- Phillips JD, Yeldandi A, Blum M, de Hoyos A. Bronchial carcinoid secreting insulin-like growth factor-1 with acromegalic features. Ann Thorac Surg 2009; 88:1350.
- Filosso PL, Donati G, Rena O, Oliaro A. Acromegaly as manifestation of a bronchial carcinoid tumour. Asian Cardiovasc Thorac Ann 2003; 11:189.
- Scheithauer BW, Carpenter PC, Bloch B, Brazeau P. Ectopic secretion of a growth hormone-releasing factor. Report of a case of acromegaly with bronchial carcinoid tumor. Am J Med 1984; 76:605.
- Athanassiadi K, Exarchos D, Tsagarakis S, Bellenis I. Acromegaly caused by ectopic growth hormone-releasing hormone secretion by a carcinoid bronchial tumor: a rare entity. J Thorac Cardiovasc Surg 2004; 128:631.
- Osella G, Orlandi F, Caraci P, et al. Acromegaly due to ectopic secretion of GHRH by bronchial carcinoid in a patient with empty sella. J Endocrinol Invest 2003; 26:163.
- Bhansali A, Rana SS, Bhattacharya S, et al. Acromegaly: a rare manifestation of bronchial carcinoid. Asian Cardiovasc Thorac Ann 2002; 10:273.
- Zatelli MC, Maffei P, Piccin D, et al. Somatostatin analogs in vitro effects in a growth hormone-releasing hormone-secreting bronchial carcinoid. J Clin Endocrinol Metab 2005; 90:2104.
- Biermasz NR, Smit JW, Pereira AM, et al. Acromegaly caused by growth hormone-releasing hormone-producing tumors: long-term observational studies in three patients. Pituitary 2007; 10:237.
- American Joint Committee on Cancer Staging Manual, 7th, Edge SB, Byrd DR, Compton CC, et al (Eds), Springer, New York 2010. p.253.
- Rami-Porta R, Asamura H, Travis WD, Rusch VW.. Lung. In: AJCC Cancer Staging Manual, 8th, Amin MB. (Ed), AJCC, Chicago 2017. p.431.
- Magid D, Siegelman SS, Eggleston JC, et al. Pulmonary carcinoid tumors: CT assessment. J Comput Assist Tomogr 1989; 13:244.
- Zwiebel BR, Austin JH, Grimes MM. Bronchial carcinoid tumors: assessment with CT of location and intratumoral calcification in 31 patients. Radiology 1991; 179:483.
- Divisi D, Crisci R. Carcinoid tumors of the lung and multimodal therapy. Thorac Cardiovasc Surg 2005; 53:168.
- Granberg D, Sundin A, Janson ET, et al. Octreoscan in patients with bronchial carcinoid tumours. Clin Endocrinol (Oxf) 2003; 59:793.
- Reubi JC, Kvols LK, Waser B, et al. Detection of somatostatin receptors in surgical and percutaneous needle biopsy samples of carcinoids and islet cell carcinomas. Cancer Res 1990; 50:5969.
- Weiss M, Yellin A, Husza'r M, et al. Localization of adrenocorticotropic hormone-secreting bronchial carcinoid tumor by somatostatin-receptor scintigraphy. Ann Intern Med 1994; 121:198.
- Yellin A, Zwas ST, Rozenman J, et al. Experience with somatostatin receptor scintigraphy in the management of pulmonary carcinoid tumors. Isr Med Assoc J 2005; 7:712.
- Righi L, Volante M, Tavaglione V, et al. Somatostatin receptor tissue distribution in lung neuroendocrine tumours: a clinicopathologic and immunohistochemical study of 218 'clinically aggressive' cases. Ann Oncol 2010; 21:548.
- Buchmann I, Henze M, Engelbrecht S, et al. Comparison of 68Ga-DOTATOC PET and 111In-DTPAOC (Octreoscan) SPECT in patients with neuroendocrine tumours. Eur J Nucl Med Mol Imaging 2007; 34:1617.
- http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm504524.htm (Accessed on June 07, 2016).
- Janson ET, Westlin JE, Eriksson B, et al. [111In-DTPA-D-Phe1]octreotide scintigraphy in patients with carcinoid tumours: the predictive value for somatostatin analogue treatment. Eur J Endocrinol 1994; 131:577.
- 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.
- Daniels CE, Lowe VJ, Aubry MC, et al. The utility of fluorodeoxyglucose positron emission tomography in the evaluation of carcinoid tumors presenting as pulmonary nodules. Chest 2007; 131:255.
- Rege SD, Hoh CK, Glaspy JA, et al. Imaging of pulmonary mass lesions with whole-body positron emission tomography and fluorodeoxyglucose. Cancer 1993; 72:82.
- Chong S, Lee KS, Kim BT, et al. Integrated PET/CT of pulmonary neuroendocrine tumors: diagnostic and prognostic implications. AJR Am J Roentgenol 2007; 188:1223.
- Granberg D, Eriksson B, Wilander E, et al. Experience in treatment of metastatic pulmonary carcinoid tumors. Ann Oncol 2001; 12:1383.
- Campana D, Nori F, Piscitelli L, et al. Chromogranin A: is it a useful marker of neuroendocrine tumors? J Clin Oncol 2007; 25:1967.
- Nehar D, Lombard-Bohas C, Olivieri S, et al. Interest of Chromogranin A for diagnosis and follow-up of endocrine tumours. Clin Endocrinol (Oxf) 2004; 60:644.
- Modlin IM, Gustafsson BI, Moss SF, et al. Chromogranin A--biological function and clinical utility in neuro endocrine tumor disease. Ann Surg Oncol 2010; 17:2427.
- Aron M, Kapila K, Verma K. Carcinoid tumors of the lung: a diagnostic challenge in bronchial washings. Diagn Cytopathol 2004; 30:62.
- Okike N, Bernatz PE, Woolner LB. Carcinoid tumors of the lung. Ann Thorac Surg 1976; 22:270.
- Nguyen GK. Cytopathology of pulmonary carcinoid tumors in sputum and bronchial brushings. Acta Cytol 1995; 39:1152.
- Todd TR, Cooper JD, Weissberg D, et al. Bronchial carcinoid tumors: twenty years' experience. J Thorac Cardiovasc Surg 1980; 79:532.
- Kurul IC, Topçu S, Taştepe I, et al. Surgery in bronchial carcinoids: experience with 83 patients. Eur J Cardiothorac Surg 2002; 21:883.
- Malchoff CD, Orth DN, Abboud C, et al. Ectopic ACTH syndrome caused by a bronchial carcinoid tumor responsive to dexamethasone, metyrapone, and corticotropin-releasing factor. Am J Med 1988; 84:760.
- Vincent JM, Trainer PJ, Reznek RH, et al. The radiological investigation of occult ectopic ACTH-dependent Cushing's syndrome. Clin Radiol 1993; 48:11.
- Tsagarakis S, Christoforaki M, Giannopoulou H, et al. A reappraisal of the utility of somatostatin receptor scintigraphy in patients with ectopic adrenocorticotropin Cushing's syndrome. J Clin Endocrinol Metab 2003; 88:4754.
- EPIDEMIOLOGY AND RISK FACTORS
- Risk factors
- - Inherited predisposition
- CLASSIFICATION, HISTOLOGY, AND HISTOCHEMISTRY
- WHO classification
- CLINICAL FEATURES
- Presenting signs and symptoms
- Clinical syndromes related to peptide production
- - Carcinoid syndrome and carcinoid crisis
- - Cushing's syndrome
- - Acromegaly
- DIAGNOSTIC AND STAGING WORKUP
- Staging system
- Cross sectional imaging
- Other imaging procedures
- - Somatostatin receptor-based imaging techniques
- Clinical utility
- - FDG-PET scans
- - Liver imaging
- Tumor markers
- Bronchoscopy and biopsy
- - Peripheral pulmonary nodules
- DIFFERENTIAL DIAGNOSIS
- Disorders with similar clinical manifestations
- Disorders with similar radiographic manifestations
- SUMMARY AND RECOMMENDATIONS