Clinical characteristics of well-differentiated neuroendocrine (carcinoid) tumors arising in the tubular digestive tract, lung, and genitourinary tract
- Jonathan R Strosberg, MD
Jonathan R Strosberg, MD
- Associate Professor
- Department of Gastrointestinal Oncology
- H. Lee Moffitt Cancer Center
- Section Editors
- Kenneth K Tanabe, MD
Kenneth K Tanabe, MD
- Section Editor — Gastrointestinal Malignancies
- Professor of Surgery
- Harvard Medical School
- David C Whitcomb, MD, PhD
David C Whitcomb, MD, PhD
- Section Editor — Pancreatic Diseases
- Professor of Medicine
- University of Pittsburgh School of Medicine
The term "carcinoid" is generally applied to well-differentiated neuroendocrine tumors (NETs) originating in the tubular digestive tract, lungs, or rare primary sites, such as the kidneys or ovaries. Use of the term carcinoid implies well-differentiated (low- to intermediate-grade) histology and is not traditionally used to describe high-grade poorly differentiated NETs, which are now classified as neuroendocrine carcinomas. Well-differentiated NETs that arise in the pancreas, while histologically similar to those arising in the tubular portion of the gastrointestinal tract, are not referred to as "carcinoids" but instead as pancreatic NETs (table 1). (See "Pathology, classification, and grading of neuroendocrine tumors arising in the digestive system", section on 'Pathology, tumor classification, and nomenclature'.)
"Carcinoid syndrome" is the term applied to a constellation of symptoms mediated by various humoral factors that are elaborated by some well-differentiated NETs arising in the gastrointestinal tract (GINETs) (table 2) . Typical carcinoid syndrome, consisting primarily of flushing and diarrhea (table 3), occurs predominantly in patients with metastatic NETs originating in the small intestine. Carcinoid syndrome is rare with lung or genitourinary well-differentiated NETs. (See "Clinical features of the carcinoid syndrome".)
Well-differentiated NETs are rare overall, but their age-adjusted incidence in the United States has increased significantly, partly due to increased detection on radiographic imaging and endoscopy.
This topic will cover the epidemiology, classification, and clinical features of primary well-differentiated NETs (carcinoid tumors) arising in the gastrointestinal and genitourinary systems. The pathology and nomenclature of digestive tract NETs; clinical features and diagnosis of carcinoid syndrome; issues related to tumor localization in well-differentiated GINETs; features and management of high-grade gastroenteropancreatic neuroendocrine carcinoma, bronchial NETs, and thymic NETs; and the management of patients with nonmetastatic and metastatic well-differentiated GINETs are discussed separately.To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Kulke MH, Mayer RJ. Carcinoid tumors. N Engl J Med 1999; 340:858.
- 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.
- Hemminki K, Li X. Incidence trends and risk factors of carcinoid tumors: a nationwide epidemiologic study from Sweden. Cancer 2001; 92:2204.
- Garcia-Carbonero R, Capdevila J, Crespo-Herrero G, et al. Incidence, patterns of care and prognostic factors for outcome of gastroenteropancreatic neuroendocrine tumors (GEP-NETs): results from the National Cancer Registry of Spain (RGETNE). Ann Oncol 2010; 21:1794.
- Mocellin S, Nitti D. Gastrointestinal carcinoid: epidemiological and survival evidence from a large population-based study (n = 25 531). Ann Oncol 2013; 24:3040.
- Hallet J, Law CH, Cukier M, et al. Exploring the rising incidence of neuroendocrine tumors: a population-based analysis of epidemiology, metastatic presentation, and outcomes. Cancer 2015; 121:589.
- Dasari A, Shen C, Halperin D, et al. Trends in the Incidence, Prevalence, and Survival Outcomes in Patients With Neuroendocrine Tumors in the United States. JAMA Oncol 2017; 3:1335.
- Maggard MA, O'Connell JB, Ko CY. Updated population-based review of carcinoid tumors. Ann Surg 2004; 240:117.
- Taghavi S, Jayarajan SN, Powers BD, et al. Examining rectal carcinoids in the era of screening colonoscopy: a surveillance, epidemiology, and end results analysis. Dis Colon Rectum 2013; 56:952.
- Ito T, Sasano H, Tanaka M, et al. Epidemiological study of gastroenteropancreatic neuroendocrine tumors in Japan. J Gastroenterol 2010; 45:234.
- Niederle MB, Hackl M, Kaserer K, Niederle B. Gastroenteropancreatic neuroendocrine tumours: the current incidence and staging based on the WHO and European Neuroendocrine Tumour Society classification: an analysis based on prospectively collected parameters. Endocr Relat Cancer 2010; 17:909.
- Caplin ME, Buscombe JR, Hilson AJ, et al. Carcinoid tumour. Lancet 1998; 352:799.
- 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.
- Rindi G, Arnold R, Bosman FT, et al. Nomenclature and classification of neuroendocrine neoplasms of the digestive system. In: WHO Classification of Tumours of the Digestive System, 4th ed, Bosman TF, Carneiro F, Hruban RH, Theise ND (Eds), International Agency for Research on cancer (IARC), Lyon 2010. p.13.
- Gustafsson BI, Kidd M, Chan A, et al. Bronchopulmonary neuroendocrine tumors. Cancer 2008; 113:5.
- WILLIAMS ED, SANDLER M. The classification of carcinoid tum ours. Lancet 1963; 1:238.
- Bordi C. Endocrine tumours of the stomach. Pathol Res Pract 1995; 191:373.
- Borch K, Ahrén B, Ahlman H, et al. Gastric carcinoids: biologic behavior and prognosis after differentiated treatment in relation to type. Ann Surg 2005; 242:64.
- Sculco D, Bilgrami S. Pernicious anemia and gastric carcinoid tumor: case report and review. Am J Gastroenterol 1997; 92:1378.
- Hirschowitz BI, Griffith J, Pellegrin D, Cummings OW. Rapid regression of enterochromaffinlike cell gastric carcinoids in pernicious anemia after antrectomy. Gastroenterology 1992; 102:1409.
- Rindi G, Bordi C, Rappel S, et al. Gastric carcinoids and neuroendocrine carcinomas: pathogenesis, pathology, and behavior. World J Surg 1996; 20:168.
- Thomas RM, Baybick JH, Elsayed AM, Sobin LH. Gastric carcinoids. An immunohistochemical and clinicopathologic study of 104 patients. Cancer 1994; 73:2053.
- Dakin GF, Warner RR, Pomp A, et al. Presentation, treatment, and outcome of type 1 gastric carcinoid tumors. J Surg Oncol 2006; 93:368.
- Havu N. Enterochromaffin-like cell carcinoids of gastric mucosa in rats after life-long inhibition of gastric secretion. Digestion 1986; 35 Suppl 1:42.
- Soga J. Early-stage carcinoids of the gastrointestinal tract: an analysis of 1914 reported cases. Cancer 2005; 103:1587.
- Gilligan CJ, Lawton GP, Tang LH, et al. Gastric carcinoid tumors: the biology and therapy of an enigmatic and controversial lesion. Am J Gastroenterol 1995; 90:338.
- Modlin IM, Champaneria MC, Chan AK, Kidd M. A three-decade analysis of 3,911 small intestinal neuroendocrine tumors: the rapid pace of no progress. Am J Gastroenterol 2007; 102:1464.
- Bilimoria KY, Bentrem DJ, Wayne JD, et al. Small bowel cancer in the United States: changes in epidemiology, treatment, and survival over the last 20 years. Ann Surg 2009; 249:63.
- Capella C, Heitz PU, Höfler H, et al. Revised classification of neuroendocrine tumours of the lung, pancreas and gut. Virchows Arch 1995; 425:547.
- Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer 2003; 97:934.
- Solcia E, Fiocca R, Rindi G, et al. Endocrine tumors of the small and large intestine. Pathol Res Pract 1995; 191:366.
- Wolff BG, Park JJ. Meckel's diverticulum, a "hot spot" for cancer. Ann Surg 2011; 253:231.
- Pape UF, Perren A, Niederle B, et al. ENETS Consensus Guidelines for the management of patients with neuroendocrine neoplasms from the jejuno-ileum and the appendix including goblet cell carcinomas. Neuroendocrinology 2012; 95:135.
- Saha S, Hoda S, Godfrey R, et al. Carcinoid tumors of the gastrointestinal tract: a 44-year experience. South Med J 1989; 82:1501.
- Eckhauser FE, Argenta LC, Strodel WE, et al. Mesenteric angiopathy, intestinal gangrene, and midgut carcinoids. Surgery 1981; 90:720.
- Laskaratos FM, Rombouts K, Caplin M, et al. Neuroendocrine tumors and fibrosis: An unsolved mystery? Cancer 2017; 123:4770.
- Burke AP, Thomas RM, Elsayed AM, Sobin LH. Carcinoids of the jejunum and ileum: an immunohistochemical and clinicopathologic study of 167 cases. Cancer 1997; 79:1086.
- Loftus JP, van Heerden JA. Surgical management of gastrointestinal carcinoid tumors. Adv Surg 1995; 28:317.
- MOERTEL CG, SAUER WG, DOCKERTY MB, BAGGENSTOSS AH. Life history of the carcinoid tumor of the small intestine. Cancer 1961; 14:901.
- Strosberg J, Gardner N, Kvols L. Survival and prognostic factor analysis of 146 metastatic neuroendocrine tumors of the mid-gut. Neuroendocrinology 2009; 89:471.
- Jann H, Roll S, Couvelard A, et al. Neuroendocrine tumors of midgut and hindgut origin: tumor-node-metastasis classification determines clinical outcome. Cancer 2011; 117:3332.
- Rosenberg JM, Welch JP. Carcinoid tumors of the colon. A study of 72 patients. Am J Surg 1985; 149:775.
- Caplin M, Sundin A, Nillson O, et al. ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms: colorectal neuroendocrine neoplasms. Neuroendocrinology 2012; 95:88.
- Spread C, Berkel H, Jewell L, et al. Colon carcinoid tumors. A population-based study. Dis Colon Rectum 1994; 37:482.
- Ballantyne GH, Savoca PE, Flannery JT, et al. Incidence and mortality of carcinoids of the colon. Data from the Connecticut Tumor Registry. Cancer 1992; 69:2400.
- Jetmore AB, Ray JE, Gathright JB Jr, et al. Rectal carcinoids: the most frequent carcinoid tumor. Dis Colon Rectum 1992; 35:717.
- Modlin IM, Sandor A. An analysis of 8305 cases of carcinoid tumors. Cancer 1997; 79:813.
- Koura AN, Giacco GG, Curley SA, et al. Carcinoid tumors of the rectum: effect of size, histopathology, and surgical treatment on metastasis free survival. Cancer 1997; 79:1294.
- Mani S, Modlin IM, Ballantyne G, et al. Carcinoids of the rectum. J Am Coll Surg 1994; 179:231.
- Shields CJ, Tiret E, Winter DC, International Rectal Carcinoid Study Group. Carcinoid tumors of the rectum: a multi-institutional international collaboration. Ann Surg 2010; 252:750.
- Fahy BN, Tang LH, Klimstra D, et al. Carcinoid of the rectum risk stratification (CaRRs): a strategy for preoperative outcome assessment. Ann Surg Oncol 2007; 14:1735.
- Hansel DE, Epstein JI, Berbescu E, et al. Renal carcinoid tumor: a clinicopathologic study of 21 cases. Am J Surg Pathol 2007; 31:1539.
- Shurtleff BT, Shvarts O, Rajfer J. Carcinoid tumor of the kidney: case report and review of the literature. Rev Urol 2005; 7:229.
- Zavala-Pompa A, Ro JY, el-Naggar A, et al. Primary carcinoid tumor of testis. Immunohistochemical, ultrastructural, and DNA flow cytometric study of three cases with a review of the literature. Cancer 1993; 72:1726.
- Stroosma OB, Delaere KP. Carcinoid tumours of the testis. BJU Int 2008; 101:1101.
- Tal R, Lask DM, Livne PM. Metastatic renal carcinoid: case report and review of the literature. Urology 2003; 61:838.
- Davis KP, Hartmann LK, Keeney GL, Shapiro H. Primary ovarian carcinoid tumors. Gynecol Oncol 1996; 61:259.
- Soga J, Osaka M, Yakuwa Y. Carcinoids of the ovary: an analysis of 329 reported cases. J Exp Clin Cancer Res 2000; 19:271.
- Strosberg J, Nasir A, Cragun J, et al. Metastatic carcinoid tumor to the ovary: a clinicopathologic analysis of seventeen cases. Gynecol Oncol 2007; 106:65.
- Pappa I, Peros G, Lappas C, et al. Management of ovarian carcinoid syndrome. Int J Gynaecol Obstet 2011; 115:205.
- Muller KE, Tafe LJ, Gonzalez JL, et al. Ovarian strumal carcinoid producing peptide YY associated with severe constipation: a case report and review of the literature. Int J Gynecol Pathol 2015; 34:30.
- 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.