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	====Features in common====		====Features in common====
	Neuroendocrine tumors, despite differing [[embryology\|embryological]] origin, have common [[phenotypic]] characteristics. NETs show [[tissue (biology)\|tissue]] immunoreactivity for markers of neuroendocrine [[cellular differentiation\|differentiation]] (pan-neuroendocrine tissue markers) and may secrete various peptides and hormones. There is a lengthy list of potential markers in neuroendocrine tumors; several reviews provide assistance in understanding these markers.<ref name="Berretta2010">{{Cite journal\|last1=Berretta\|first1=M.\|doi=10.2741/s68\|pmid=20036951\|title=Biomarkers in neuroendocrine tumors\|journal=Frontiers in Bioscience\|volume=S2\|pages=332–42\|year=2010}}</ref><ref name="Ferolla2008">{{Cite journal\|last1=Ferolla\|first1=P.\|last2=Faggiano\|first2=A.\|last3=Mansueto\|first3=G.\|last4=Avenia\|first4=N.\|last5=Cantelmi\|first5=M.\|last6=Giovenali\|first6=P.\|author7=Del Basso De Caro ML\|last8=Milone\|first8=F.\|last9=Scarpelli\|first9=G.\|last10=Masone\|first10=S.\|last11=Santeusanio\|first11=F.\|last12=Lombardi\|first12=G.\|last13=Angeletti\|first13=G.\|last14=Colao\|first14=A.\|title=The biological characterization of neuroendocrine tumors: The role of neuroendocrine markers\|journal=[[Journal of Endocrinological Investigation]]\|volume=31\|issue=3\|pages=277–86\|year=2008\|pmid=18401212\|doi=10.1007/bf03345602\|s2cid=25108086}}</ref> Widely used neuroendocrine tissue markers are various [[chromogranin]]s, [[synaptophysin]] and [[PGP9.5]].<!--? add ??PAX5 and CD56/NCAM--> [[Neuron-specific enolase]] (NSE) is less [[Sensitivity and specificity\|specific]].<ref name="Ramage2005"/><ref name="Liu2001"/> The nuclear neuroendocrine marker insulinoma-associated protein-1 (INSM1) has proven to be sensitive as well as highly specific for neuroendocrine differentiation.<ref>{{cite journal \| vauthors = Mukhopadhyay S, Dermawan JK, Lanigan CP, Farver CF \| title = Insulinoma-associated protein 1 (INSM1) is a sensitive and highly specific marker of neuroendocrine differentiation in primary lung neoplasms: an immunohistochemical study of 345 cases, including 292 whole-tissue sections \| journal = Modern Pathology \| volume = 32 \| issue = 1 \| pages = 100–09 \| date = August 2018 \| pmid = 30154579 \| doi = 10.1038/s41379-018-0122-7 \| s2cid = 52110673 \| doi-access = free }}</ref>		Neuroendocrine tumors, despite differing [[embryology\|embryological]] origin, have common [[phenotypic]] characteristics. NETs show [[tissue (biology)\|tissue]] immunoreactivity for markers of neuroendocrine [[cellular differentiation\|differentiation]] (pan-neuroendocrine tissue markers) and may secrete various peptides and hormones. There is a lengthy list of potential markers in neuroendocrine tumors; several reviews provide assistance in understanding these markers.<ref name="Ferolla2008">{{Cite journal\|last1=Ferolla\|first1=P.\|last2=Faggiano\|first2=A.\|last3=Mansueto\|first3=G.\|last4=Avenia\|first4=N.\|last5=Cantelmi\|first5=M.\|last6=Giovenali\|first6=P.\|author7=Del Basso De Caro ML\|last8=Milone\|first8=F.\|last9=Scarpelli\|first9=G.\|last10=Masone\|first10=S.\|last11=Santeusanio\|first11=F.\|last12=Lombardi\|first12=G.\|last13=Angeletti\|first13=G.\|last14=Colao\|first14=A.\|title=The biological characterization of neuroendocrine tumors: The role of neuroendocrine markers\|journal=[[Journal of Endocrinological Investigation]]\|volume=31\|issue=3\|pages=277–86\|year=2008\|pmid=18401212\|doi=10.1007/bf03345602\|s2cid=25108086}}</ref><ref name="Berretta2010">{{Cite journal\|last1=Berretta\|first1=M.\|doi=10.2741/s68\|pmid=20036951\|title=Biomarkers in neuroendocrine tumors\|journal=Frontiers in Bioscience\|volume=S2\|pages=332–42\|year=2010}}</ref> Widely used neuroendocrine tissue markers are various [[chromogranin]]s, [[synaptophysin]] and [[PGP9.5]].<!--? add ??PAX5 and CD56/NCAM--> [[Neuron-specific enolase]] (NSE) is less [[Sensitivity and specificity\|specific]].<ref name="Ramage2005"/><ref name="Liu2001"/> The nuclear neuroendocrine marker insulinoma-associated protein-1 (INSM1) has proven to be sensitive as well as highly specific for neuroendocrine differentiation.<ref>{{cite journal \| vauthors = Mukhopadhyay S, Dermawan JK, Lanigan CP, Farver CF \| title = Insulinoma-associated protein 1 (INSM1) is a sensitive and highly specific marker of neuroendocrine differentiation in primary lung neoplasms: an immunohistochemical study of 345 cases, including 292 whole-tissue sections \| journal = Modern Pathology \| volume = 32 \| issue = 1 \| pages = 100–09 \| date = August 2018 \| pmid = 30154579 \| doi = 10.1038/s41379-018-0122-7 \| s2cid = 52110673 \| doi-access = free }}</ref>

	NETs are often small, yellow or tan masses, often located in the [[submucosa]] or more deeply intramurally, and they can be very firm due to an accompanying intense [[Desmoplasia\|desmoplastic]] reaction. The overlying mucosa may be either intact or [[ulcer (dermatology)\|ulcer]]ated. Some GEP-NETs invade deeply to involve the [[mesentery]].{{citation needed\|date=November 2015}} Histologically, NETs are an example of "small blue cell tumors," showing uniform cells which have a round to oval stippled nucleus and scant, pink granular cytoplasm. The cells may align variously in islands, glands or sheets. High power examination shows bland cytopathology. Electron microscopy can identify secretory granules. There is usually minimal [[pleomorphism (cytology)\|pleomorphism]] but less commonly there can be [[anaplasia]], [[mitosis\|mitotic]] activity, and [[necrosis]].{{citation needed\|date=November 2015}}		NETs are often small, yellow or tan masses, often located in the [[submucosa]] or more deeply intramurally, and they can be very firm due to an accompanying intense [[Desmoplasia\|desmoplastic]] reaction. The overlying mucosa may be either intact or [[ulcer (dermatology)\|ulcer]]ated. Some GEP-NETs invade deeply to involve the [[mesentery]].{{citation needed\|date=November 2015}} Histologically, NETs are an example of "small blue cell tumors," showing uniform cells which have a round to oval stippled nucleus and scant, pink granular cytoplasm. The cells may align variously in islands, glands or sheets. High power examination shows bland cytopathology. Electron microscopy can identify secretory granules. There is usually minimal [[pleomorphism (cytology)\|pleomorphism]] but less commonly there can be [[anaplasia]], [[mitosis\|mitotic]] activity, and [[necrosis]].{{citation needed\|date=November 2015}}
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	AdVince, a type of [[gene therapy]] using a genetically modified [[oncolytic adenovirus]]<ref>{{Cite web\|url=http://mosaicscience.com/story/plutocratic-proposal\|title=A plutocratic proposal\|last=Masters\|first=Alexander\|date=2014-10-14\|website=Mosaic\|publisher=The Wellcome Trust\|access-date=2016-07-03\|url-status=live\|archive-url=https://web.archive.org/web/20160529021009/http://mosaicscience.com/story/plutocratic-proposal\|archive-date=2016-05-29}}</ref> and supported by the [[crowdfunding]] campaign iCancer<ref>{{Cite web\|url=http://icancer.org.uk/about/\|title=iCancer web site\|website=icancer.org.uk\|access-date=2016-07-03\|url-status=live\|archive-url=https://web.archive.org/web/20160714143714/http://icancer.org.uk/about/\|archive-date=2016-07-14}}</ref> was used in a Phase 1 trial against NET in 2016.<ref>{{Cite web\|url=https://www.telegraph.co.uk/men/health/can-crowdfunding-really-cure-cancer-alexander-masters-investigat/\|title=Can crowdfunding really cure cancer? Alexander Masters investigates a pioneering new project\|last=Masters\|first=Alexander\|author-link=Alexander Masters\|date=2016-07-02\|publisher=The Telegraph\|access-date=2016-07-03\|url-status=dead\|archive-url=https://web.archive.org/web/20160703115042/http://www.telegraph.co.uk/men/health/can-crowdfunding-really-cure-cancer-alexander-masters-investigat/\|archive-date=2016-07-03}}</ref>		AdVince, a type of [[gene therapy]] using a genetically modified [[oncolytic adenovirus]]<ref>{{Cite web\|url=http://mosaicscience.com/story/plutocratic-proposal\|title=A plutocratic proposal\|last=Masters\|first=Alexander\|date=2014-10-14\|website=Mosaic\|publisher=The Wellcome Trust\|access-date=2016-07-03\|url-status=live\|archive-url=https://web.archive.org/web/20160529021009/http://mosaicscience.com/story/plutocratic-proposal\|archive-date=2016-05-29}}</ref> and supported by the [[crowdfunding]] campaign iCancer<ref>{{Cite web\|url=http://icancer.org.uk/about/\|title=iCancer web site\|website=icancer.org.uk\|access-date=2016-07-03\|url-status=live\|archive-url=https://web.archive.org/web/20160714143714/http://icancer.org.uk/about/\|archive-date=2016-07-14}}</ref> was used in a Phase 1 trial against NET in 2016.<ref>{{Cite web\|url=https://www.telegraph.co.uk/men/health/can-crowdfunding-really-cure-cancer-alexander-masters-investigat/\|title=Can crowdfunding really cure cancer? Alexander Masters investigates a pioneering new project\|last=Masters\|first=Alexander\|author-link=Alexander Masters\|date=2016-07-02\|publisher=The Telegraph\|access-date=2016-07-03\|url-status=dead\|archive-url=https://web.archive.org/web/20160703115042/http://www.telegraph.co.uk/men/health/can-crowdfunding-really-cure-cancer-alexander-masters-investigat/\|archive-date=2016-07-03}}</ref>

	Further efforts towards more [[Precision medicine\|personalized therapies]] in neuroendocrine tumors are undertaken <ref>{{Cite journal\|last=Detjen\|first=Katharina\|last2=Hammerich\|first2=Linda\|last3=Özdirik\|first3=Burcin\|last4=Demir\|first4=Muenevver\|last5=Wiedenmann\|first5=Bertram\|last6=Tacke\|first6=Frank\|last7=Jann\|first7=Henning\|last8=Roderburg\|first8=Christoph\|date=2020-07-02\|title=Models of gastroenteropancreatic neuroendocrine neoplasms – Current status and future directions\|url=https://www.karger.com/Article/FullText/509864\|journal=Neuroendocrinology\|language=en\|doi=10.1159/000509864\|issn=0028-3835\|doi-access=free}}</ref> i.a. combining [[Drug test\|drug screening]] platforms and patient-derived ''[[ex vivo]]'' [[~~Cell~~ culture~~\|cell cultures~~]] that mimic relevant aspects of the original [[Neoplasm\|tumors]].<ref>{{Cite journal\|last=April-Monn\|first=Simon Leonhard\|last2=Wiedmer\|first2=Tabea\|last3=Skowronska\|first3=Magdalena\|last4=Maire\|first4=Renaud\|last5=Schiavo Lena\|first5=Marco\|last6=Trippel\|first6=Mafalda\|last7=Di Domenico\|first7=Annunziata\|last8=Muffatti\|first8=Francesca\|last9=Andreasi\|first9=Valentina\|last10=Capurso\|first10=Gabriele\|last11=Doglioni\|first11=Claudio\|date=2020-04-03\|title=3D Primary Cell Culture: A Novel Preclinical Model For Pancreatic Neuroendocrine Tumors (PanNETs)\|url=https://www.karger.com/Article/FullText/507669\|journal=Neuroendocrinology\|language=en\|doi=10.1159/000507669\|issn=0028-3835}}</ref>		Further efforts towards more [[Precision medicine\|personalized therapies]] in neuroendocrine tumors are undertaken <ref>{{Cite journal\|last=Detjen\|first=Katharina\|last2=Hammerich\|first2=Linda\|last3=Özdirik\|first3=Burcin\|last4=Demir\|first4=Muenevver\|last5=Wiedenmann\|first5=Bertram\|last6=Tacke\|first6=Frank\|last7=Jann\|first7=Henning\|last8=Roderburg\|first8=Christoph\|date=2020-07-02\|title=Models of gastroenteropancreatic neuroendocrine neoplasms – Current status and future directions\|url=https://www.karger.com/Article/FullText/509864\|journal=Neuroendocrinology\|language=en\|doi=10.1159/000509864\|issn=0028-3835\|doi-access=free}}</ref> i.a. combining [[Drug test\|drug screening]] platforms and patient-derived ''[[ex vivo]]'' [[cell culture]]s that mimic relevant aspects of the original [[Neoplasm\|tumors]].<ref>{{Cite journal\|last=April-Monn\|first=Simon Leonhard\|last2=Wiedmer\|first2=Tabea\|last3=Skowronska\|first3=Magdalena\|last4=Maire\|first4=Renaud\|last5=Schiavo Lena\|first5=Marco\|last6=Trippel\|first6=Mafalda\|last7=Di Domenico\|first7=Annunziata\|last8=Muffatti\|first8=Francesca\|last9=Andreasi\|first9=Valentina\|last10=Capurso\|first10=Gabriele\|last11=Doglioni\|first11=Claudio\|date=2020-04-03\|title=3D Primary Cell Culture: A Novel Preclinical Model For Pancreatic Neuroendocrine Tumors (PanNETs)\|url=https://www.karger.com/Article/FullText/507669\|journal=Neuroendocrinology\|language=en\|doi=10.1159/000507669\|issn=0028-3835}}</ref>

	==Epidemiology==		==Epidemiology==
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	==History==		==History==
	Small intestinal neuroendocrine tumors were first distinguished from other tumors in 1907.<ref name="Modlin">{{Cite journal\|last1=Modlin\|first1=I.M.\|last2=Shapiro\|first2=M.D.\|last3=Kidd\|first3=M.\|doi=10.1016/j.humpath.2004.09.018\|title=Siegfried oberndorfer: Origins and perspectives of carcinoid tumors\|journal=Human Pathology\|volume=35\|issue=12\|pages=1440–51\|year=2004\|pmid=15619202}}</ref><ref name="Arnold">{{cite book\|vauthors=Arnold R, Göke R, Wied M, Behr T \|chapter=Chapter 15 Neuroendocrine Gastro-Entero-Pancreatic (GEP) Tumors\|veditors=Scheppach W, Bresalier RS, Tytgat GN \|title=Gastrointestinal and Liver Tumors\|publisher=Springer\|location=Berlin\|year=2003\|pages=195–233\|isbn=978-3-540-43462-7}}</ref> They were named carcinoid tumors because their slow growth was considered to be "cancer-like" rather than truly cancerous.<ref name="Arnold"/>		Small intestinal neuroendocrine tumors were first distinguished from other tumors in 1907.<ref name="Arnold">{{cite book\|vauthors=Arnold R, Göke R, Wied M, Behr T \|chapter=Chapter 15 Neuroendocrine Gastro-Entero-Pancreatic (GEP) Tumors\|veditors=Scheppach W, Bresalier RS, Tytgat GN \|title=Gastrointestinal and Liver Tumors\|publisher=Springer\|location=Berlin\|year=2003\|pages=195–233\|isbn=978-3-540-43462-7}}</ref><ref name="Modlin">{{Cite journal\|last1=Modlin\|first1=I.M.\|last2=Shapiro\|first2=M.D.\|last3=Kidd\|first3=M.\|doi=10.1016/j.humpath.2004.09.018\|title=Siegfried oberndorfer: Origins and perspectives of carcinoid tumors\|journal=Human Pathology\|volume=35\|issue=12\|pages=1440–51\|year=2004\|pmid=15619202}}</ref> They were named carcinoid tumors because their slow growth was considered to be "cancer-like" rather than truly cancerous.<ref name="Arnold"/>

	However, in 1938 it was recognized that some of these small bowel tumors could be malignant.<ref name="~~Modlin~~"/><ref name="~~Arnold~~"/> Despite the differences between these two original categories, and further complexities due to subsequent inclusion of other NETs of pancreas and pulmonary origin, all NETs are sometimes (incorrectly) subsumed into the term "carcinoid".{{citation needed\|date=November 2015}}		However, in 1938 it was recognized that some of these small bowel tumors could be malignant.<ref name="Arnold"/><ref name="Modlin"/> Despite the differences between these two original categories, and further complexities due to subsequent inclusion of other NETs of pancreas and pulmonary origin, all NETs are sometimes (incorrectly) subsumed into the term "carcinoid".{{citation needed\|date=November 2015}}

	[[Enterochromaffin]] cells, which give rise to carcinoid tumors, were identified in 1897 by [[Nikolai Kulchitsky]] and their secretion of [[serotonin]] was established in 1953<ref name="Modlin"/> when the "flushing" effect of serotonin had become clinically recognized. Carcinoid heart disease was identified in 1952, and carcinoid fibrosis in 1961.<ref name="Modlin"/>		[[Enterochromaffin]] cells, which give rise to carcinoid tumors, were identified in 1897 by [[Nikolai Kulchitsky]] and their secretion of [[serotonin]] was established in 1953<ref name="Modlin"/> when the "flushing" effect of serotonin had become clinically recognized. Carcinoid heart disease was identified in 1952, and carcinoid fibrosis in 1961.<ref name="Modlin"/>

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Neuroendocrine tumor - Revision history

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