Thymic neuroendocrine (carcinoid) tumors
- Jonathan R Strosberg, MD
Jonathan R Strosberg, MD
- Associate Professor
- Department of Gastrointestinal Oncology
- H. Lee Moffitt Cancer Center
- Mark F Berry, MD
Mark F Berry, MD
- Associate Professor
- Department of Cardiothoracic Surgery
- Stanford University
- Henry D Tazelaar, MD
Henry D Tazelaar, MD
- Mayo Clinic Arizona
- Professor of Pathology
- Mayo Clinic College of Medicine
- Chair of the Department of Laboratory Medicine and Pathology
- Mayo Clinic Arizona
- Section Editors
- James R Jett, MD
James R Jett, MD
- Section Editor — Lung Cancer
- Professor of Medicine Emeritus
- National Jewish Health
- Sally E Carty, MD, FACS
Sally E Carty, MD, FACS
- Section Editor — Endocrine Surgery
- Professor, Chief, Division of Endocrine Surgery
- University of Pittsburgh School of Medicine
- Joseph S Friedberg, MD
Joseph S Friedberg, MD
- Section Editor — Thoracic Surgery
- Charles Reid Edwards Professor of Surgery
- University of Maryland
Thymic neuroendocrine tumors (NETs), otherwise known as thymic carcinoid tumors, are uncommon primary thymic neoplasms with neuroendocrine differentiation that generally present as a mass within the anterior mediastinum. This topic review will cover the epidemiology, pathology, classification, clinical presentation, staging, and treatment of NETs arising in the thymus. Thymomas and thymic carcinomas are addressed separately, as are the diagnostic evaluation of patients with a mediastinal mass and the differential diagnosis of an anterior mediastinal mass. (See "Clinical presentation and management of thymoma and thymic carcinoma" and "Approach to the adult patient with a mediastinal mass".)
The thymus is an anterior mediastinal organ that weighs 12 to 15 grams at birth, reaches its maximum weight of 40 grams around puberty, and then involutes and persists in an atrophic state into old age. The gland is composed of a central medulla and an outer cortex, surrounded by an outer capsule. The thymus consists primarily of epithelial cells, keratinized epithelial cells (Hassall's corpuscles), myoid cells, thymic lymphocytes ("thymocytes"), and B-lymphocytes, which may rarely form germinal centers. The thymus is primarily involved in the processing and maturation of lymphocytes, which become T-lymphocytes upon release into the circulation. (See "Normal B and T lymphocyte development", section on 'T cell development'.)
Thymic malignancies as a group are relatively rare (0.2 to 1.5 percent of all malignancies, 0.13 cases per 100,000 population in the United States), but they are among the most common mediastinal primary tumors [1,2].
Of the primary thymic malignancies, neuroendocrine tumors (NETs) are the least common, accounting for 2 to 5 percent of thymic tumors [3,4]. A thymic primary site accounts for approximately 0.4 percent of all carcinoid tumors; this corresponds to an estimated annual incidence in the United States of approximately 0.2 per million [5,6]. (See "Pathology of mediastinal tumors".)
Almost all cases have been reported in adults, with a median age of approximately 54 years and a strong male preponderance [4,5,7-11]. The largest reported series of thymic NETs consists of 160 patients who were reported to the Surveillance, Epidemiology, and End Results (SEER) database over a 33-year period . The median age at presentation was 57, and the male to female ratio was 3:1. Disease was confined to the thymus, locally invasive (or involving regional lymph nodes), or distantly metastatic in 27, 36, and 28 percent of cases, respectively. Histologically, tumors were classified as well-differentiated, moderately-differentiated, or poorly-differentiated/anaplastic in 58, 10, and 12 percent of cases, respectively.
- Engels EA. Epidemiology of thymoma and associated malignancies. J Thorac Oncol 2010; 5:S260.
- Strollo DC, Rosado de Christenson ML, Jett JR. Primary mediastinal tumors. Part 1: tumors of the anterior mediastinum. Chest 1997; 112:511.
- Goto K, Kodama T, Matsuno Y, et al. Clinicopathologic and DNA cytometric analysis of carcinoid tumors of the thymus. Mod Pathol 2001; 14:985.
- Chaer R, Massad MG, Evans A, et al. Primary neuroendocrine tumors of the thymus. Ann Thorac Surg 2002; 74:1733.
- Gaur P, Leary C, Yao JC. Thymic neuroendocrine tumors: a SEER database analysis of 160 patients. Ann Surg 2010; 251:1117.
- 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.
- Rosai J, Higa E. Mediastinal endocrine neoplasm, of probable thymic origin, related to carcinoid tumor. Clinicopathologic study of 8 cases. Cancer 1972; 29:1061.
- de Montpréville VT, Macchiarini P, Dulmet E. Thymic neuroendocrine carcinoma (carcinoid): a clinicopathologic study of fourteen cases. J Thorac Cardiovasc Surg 1996; 111:134.
- Wick MR, Scheithauer BW. Thymic carcinoid. A histologic, immunohistochemical, and ultrastructural study of 12 cases. Cancer 1984; 53:475.
- Economopoulos GC, Lewis JW Jr, Lee MW, Silverman NA. Carcinoid tumors of the thymus. Ann Thorac Surg 1990; 50:58.
- Valli M, Fabris GA, Dewar A, et al. Atypical carcinoid tumour of the thymus: a study of eight cases. Histopathology 1994; 24:371.
- Teh BT, McArdle J, Chan SP, et al. Clinicopathologic studies of thymic carcinoids in multiple endocrine neoplasia type 1. Medicine (Baltimore) 1997; 76:21.
- Gibril F, Chen YJ, Schrump DS, et al. Prospective study of thymic carcinoids in patients with multiple endocrine neoplasia type 1. J Clin Endocrinol Metab 2003; 88:1066.
- Ferolla P, Falchetti A, Filosso P, et al. Thymic neuroendocrine carcinoma (carcinoid) in multiple endocrine neoplasia type 1 syndrome: the Italian series. J Clin Endocrinol Metab 2005; 90:2603.
- Ferolla P, Urbani M, Ascani S, et al. [Prevalence of the neuroendocrine phenotype in thymus neoplasms]. Chir Ital 2002; 54:351.
- Duh QY, Hybarger CP, Geist R, et al. Carcinoids associated with multiple endocrine neoplasia syndromes. Am J Surg 1987; 154:142.
- Powell AC, Alexander HR, Pingpank JF, et al. The utility of routine transcervical thymectomy for multiple endocrine neoplasia 1-related hyperparathyroidism. Surgery 2008; 144:878.
- Burgess JR, Giles N, Shepherd JJ. Malignant thymic carcinoid is not prevented by transcervical thymectomy in multiple endocrine neoplasia type 1. Clin Endocrinol (Oxf) 2001; 55:689.
- Strobel P, Marx A, Chan JKC, et al. Thymid neuroendocrine tumours:Typical and atypical carcinoid. In: WHO Classification of Tumours opf the lung, pleura, thymus, and heart, 4th, Travis WD, Brambilla E, Buirke AP, et al. (Eds), International AGency for Research on Cancer, Lyon 2015. p.234.
- Marx A, Shimosato Y, Kuo TT, et al. Thymic neuroendocrine tumours. In: Pathology & genetics: Tumours of the lung, pleura, thymus and heart, Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC (Eds), IARC Press, Lyon, France 2004.
- Moran CA, Suster S. Spindle-cell neuroendocrine carcinomas of the thymus (spindle-cell thymic carcinoid): a clinicopathologic and immunohistochemical study of seven cases. Mod Pathol 1999; 12:587.
- Rosai J. Histological Typing of Tumours of the Thymus, 2nd, Springer, Berlin 1999.
- Hishima T, Fukayama M, Hayashi Y, et al. Neuroendocrine differentiation in thymic epithelial tumors with special reference to thymic carcinoma and atypical thymoma. Hum Pathol 1998; 29:330.
- Moran CA, Suster S, Fishback N, Koss MN. Mediastinal paragangliomas. A clinicopathologic and immunohistochemical study of 16 cases. Cancer 1993; 72:2358.
- Miettinen M, McCue PA, Sarlomo-Rikala M, et al. GATA3: a multispecific but potentially useful marker in surgical pathology: a systematic analysis of 2500 epithelial and nonepithelial tumors. Am J Surg Pathol 2014; 38:13.
- Weissferdt A, Kalhor N, Liu H, et al. Thymic neuroendocrine tumors (paraganglioma and carcinoid tumors): a comparative immunohistochemical study of 46 cases. Hum Pathol 2014; 45:2463.
- Shimosato Y, Mukai K. Tumors of the Mediastinum, 3rd, Armed Forces Institute of Pathology, Washington, DC 1995.
- Fukai I, Masaoka A, Fujii Y, et al. Thymic neuroendocrine tumor (thymic carcinoid): a clinicopathologic study in 15 patients. Ann Thorac Surg 1999; 67:208.
- Wick MR, Carney JA, Bernatz PE, Brown LR. Primary mediastinal carcinoid tumors. Am J Surg Pathol 1982; 6:195.
- Moran CA, Suster S. Neuroendocrine carcinomas (carcinoid tumor) of the thymus. A clinicopathologic analysis of 80 cases. Am J Clin Pathol 2000; 114:100.
- Wang DY, Chang DB, Kuo SH, et al. Carcinoid tumours of the thymus. Thorax 1994; 49:357.
- Tiffet O, Nicholson AG, Ladas G, et al. A clinicopathologic study of 12 neuroendocrine tumors arising in the thymus. Chest 2003; 124:141.
- Soga J, Yakuwa Y, Osaka M. Evaluation of 342 cases of mediastinal/thymic carcinoids collected from literature: a comparative study between typical carcinoids and atypical varieties. Ann Thorac Cardiovasc Surg 1999; 5:285.
- Wick MR, Rosai J. Neuroendocrine neoplasms of the thymus. Pathol Res Pract 1988; 183:188.
- de Perrot M, Spiliopoulos A, Fischer S, et al. Neuroendocrine carcinoma (carcinoid) of the thymus associated with Cushing's syndrome. Ann Thorac Surg 2002; 73:675.
- Gal AA, Kornstein MJ, Cohen C, et al. Neuroendocrine tumors of the thymus: a clinicopathological and prognostic study. Ann Thorac Surg 2001; 72:1179.
- Dixon JL, Borgaonkar SP, Patel AK, et al. Thymic neuroendocrine carcinoma producing ectopic adrenocorticotropic hormone and Cushing's syndrome. Ann Thorac Surg 2013; 96:e81.
- Neary NM, Lopez-Chavez A, Abel BS, et al. Neuroendocrine ACTH-producing tumor of the thymus--experience with 12 patients over 25 years. J Clin Endocrinol Metab 2012; 97:2223.
- Ghazi AA, Dezfooli AA, Mohamadi F, et al. Cushing syndrome secondary to a thymic carcinoid tumor due to multiple endocrine neoplasia type 1. Endocr Pract 2011; 17:e92.
- Jansson JO, Svensson J, Bengtsson BA, et al. Acromegaly and Cushing's syndrome due to ectopic production of GHRH and ACTH by a thymic carcinoid tumour: in vitro responses to GHRH and GHRP-6. Clin Endocrinol (Oxf) 1998; 48:243.
- Okada S, Ohshima K, Mori M. The Cushing syndrome induced by atrial natriuretic peptide-producing thymic carcinoid. Ann Intern Med 1994; 121:75.
- Boix E, Picó A, Pinedo R, et al. Ectopic growth hormone-releasing hormone secretion by thymic carcinoid tumour. Clin Endocrinol (Oxf) 2002; 57:131.
- Takagi J, Otake K, Morishita M, et al. Multiple endocrine neoplasia type I and Cushing's syndrome due to an aggressive ACTH producing thymic carcinoid. Intern Med 2006; 45:81.
- Lowenthal RM, Gumpel JM, Kreel L, et al. Carcinoid tumour of the thymus with systemic manifestations: a radiological and pathological study. Thorax 1974; 29:553.
- Strollo DC, Rosado-de-Christenson ML. Tumors of the thymus. J Thorac Imaging 1999; 14:152.
- Ferrozzi F, Ganzetti A, Mugnoli E, et al. [Thymic carcinoid: CT and MR findings]. Radiol Med 1997; 94:652.
- Adolph JM, Kimmig BN, Georgi P, zum Winkel K. Carcinoid tumors: CT and I-131 meta-iodo-benzylguanidine scintigraphy. Radiology 1987; 164:199.
- Guidoccio F, Grosso M, Maccauro M, et al. Current role of 111In-DTPA-octreotide scintigraphy in diagnosis of thymic masses. Tumori 2011; 97:191.
- 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.
- Lastoria S, Vergara E, Palmieri G, et al. In vivo detection of malignant thymic masses by indium-111-DTPA-D-Phe1-octreotide scintigraphy. J Nucl Med 1998; 39:634.
- Nilsson O, Kölby L, Wängberg B, et al. Comparative studies on the expression of somatostatin receptor subtypes, outcome of octreotide scintigraphy and response to octreotide treatment in patients with carcinoid tumours. Br J Cancer 1998; 77:632.
- Silva F, Vázquez-Sellés J, Aguilö F, et al. Recurrent ectopic adrenocorticotropic hormone producing thymic carcinoid detected with octreotide imaging. Clin Nucl Med 1999; 24:109.
- Granberg D, Sundin A, Janson ET, et al. Octreoscan in patients with bronchial carcinoid tumours. Clin Endocrinol (Oxf) 2003; 59:793.
- Whitaker D, Dussek J. PET scanning in thymic neuroendocrine tumors. Chest 2004; 125:2368.
- Groves AM, Mohan HK, Wegner EA, et al. Positron emission tomography with FDG to show thymic carcinoid. AJR Am J Roentgenol 2004; 182:511.
- Fujishita T, Kishida M, Taki H, et al. Detection of primary and metastatic lesions by [18F]fluoro-2-deoxy-D-glucose PET in a patient with thymic carcinoid. Respirology 2007; 12:928.
- Kunz PL, Reidy-Lagunes D, Anthony LB, et al. Consensus guidelines for the management and treatment of neuroendocrine tumors. Pancreas 2013; 42:557.
- Kaiser LR. Surgical treatment of thymic epithelial neoplasms. Hematol Oncol Clin North Am 2008; 22:475.
- Shabb NS, Fahl M, Shabb B, et al. Fine-needle aspiration of the mediastinum: a clinical, radiologic, cytologic, and histologic study of 42 cases. Diagn Cytopathol 1998; 19:428.
- Zakowski MF, Huang J, Bramlage MP. The role of fine needle aspiration cytology in the diagnosis and management of thymic neoplasia. J Thorac Oncol 2010; 5:S281.
- Wakely PE Jr. Fine needle aspiration in the diagnosis of thymic epithelial neoplasms. Hematol Oncol Clin North Am 2008; 22:433.
- Filosso PL, Yao X, Ahmad U, et al. Outcome of primary neuroendocrine tumors of the thymus: a joint analysis of the International Thymic Malignancy Interest Group and the European Society of Thoracic Surgeons databases. J Thorac Cardiovasc Surg 2015; 149:103.
- Weksler B, Holden A, Sullivan JL. Impact of Positive Nodal Metastases in Patients with Thymic Carcinoma and Thymic Neuroendocrine Tumors. J Thorac Oncol 2015; 10:1642.
- Hayashi R, Hanyu N, Moriyama S. Efficacy of steroid therapy on liver metastasis of thymic carcinoid. Intern Med 1994; 33:45.
- Sugiura H, Morikawa T, Itoh K, et al. Thymic neuroendocrine carcinoma: a clinicopathologic study in four patients. Ann Thorac Cardiovasc Surg 2000; 6:304.
- Tsuchida M, Yamato Y, Hashimoto T, et al. Recurrent thymic carcinoid tumor in the pleural cavity. 2 cases of long-term survivors. Jpn J Thorac Cardiovasc Surg 2001; 49:666.
- Asbun HJ, Calabria RP, Calmes S, et al. Thymic carcinoid. Am Surg 1991; 57:442.
- Lin FC, Lin CM, Hsieh CC, et al. Atypical thymic carcinoid and malignant somatostatinoma in type I multiple endocrine neoplasia syndrome: case report. Am J Clin Oncol 2003; 26:270.
- Filosso PL, Actis Dato GM, Ruffini E, et al. Multidisciplinary treatment of advanced thymic neuroendocrine carcinoma (carcinoid): report of a successful case and review of the literature. J Thorac Cardiovasc Surg 2004; 127:1215.
- Dham A, Truskinovsky AM, Dudek AZ. Thymic carcinoid responds to neoadjuvant therapy with sunitinib and octreotide: a case report. J Thorac Oncol 2008; 3:94.
- 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.
- Ekeblad S, Sundin A, Janson ET, et al. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res 2007; 13:2986.
- Crona J, Björklund P, Welin S, et al. Treatment, prognostic markers and survival in thymic neuroendocrine tumours. a study from a single tertiary referral centre. Lung Cancer 2013; 79:289.
- Saranga-Perry V, Morse B, Centeno B, et al. Treatment of metastatic neuroendocrine tumors of the thymus with capecitabine and temozolomide: a case series. Neuroendocrinology 2013; 97:318.
- Takahashi T, Hatao K, Yamashita Y, Tanizawa Y. Ectopic ACTH syndrome due to thymic atypical carcinoid treated with combination chemotherapy of cisplatin and etoposide. Intern Med 2003; 42:1197.
- van Essen M, Krenning EP, Bakker WH, et al. Peptide receptor radionuclide therapy with 177Lu-octreotate in patients with foregut carcinoid tumours of bronchial, gastric and thymic origin. Eur J Nucl Med Mol Imaging 2007; 34:1219.
- Oberg K, Jelic S, ESMO Guidelines Working Group. Neuroendocrine bronchial and thymic tumors: ESMO clinical recommendation for diagnosis, treatment and follow-up. Ann Oncol 2008; 19 Suppl 2:ii102.
- Screening in MEN1
- PATHOLOGY AND CLASSIFICATION
- Histologic differential diagnosis
- CLINICAL PRESENTATION
- Paraneoplastic conditions
- DIFFERENTIAL DIAGNOSIS
- EVALUATION AND STAGING
- Cross-sectional imaging
- Somatostatin receptor-based diagnostic imaging
- Laboratory testing
- Need for biopsy
- Staging classification
- PROGNOSIS AND MANAGEMENT
- Treatment for locoregional disease
- - Resection
- - Role of RT
- - Neoadjuvant therapy for locally advanced disease
- Treatment of recurrent and metastatic disease
- - Potentially resectable recurrent disease
- - Metastatic/unresectable disease
- Systemic therapy
- - Somatostatin analog therapy
- - Everolimus
- - Cytotoxic chemotherapy
- - Peptide receptor radiotherapy
- POSTTREATMENT SURVEILLANCE
- SUMMARY AND RECOMMENDATIONS