Carcinoid syndrome pathophysiology: Difference between revisions

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==Overview==
==Overview==
The pathophysiology of carcinoid tumor depends on the histological subtype. Genes involved in the pathogenesis of carcinoid tumor are ''[[β-catenin]]'', ''[[NF1]]'', and ''[[MEN1]]''. Carcinoid tumors originate from [[neuroendocrine cells]]. On microscopic histopathological analysis, gastrointestinal carcinoid syndrome is characterized by solid or small trabecular clusters of [[neuroendocrine cells]] with uniform [[nuclei]] and abundant granular or faintly staining (clear) [[cytoplasm]].


==Pathogenesis==
[[Carcinoid Syndrome|Carcinoid syndrome]] (CS) is a [[paraneoplastic Syndromes|paraneoplastic syndrome]] caused by the [[Secretions|secretion]] of [[serotonin]] [[5-hydroxytryptamine|(5-hydroxytrptamine]]) but can be caused by the [[secretion]] of [[histamine|histamine,]] [[kallikrein]], [[prostaglandins]], and tachykinins..[[Carcinoid Syndrome|Carcinoid syndrome]] is most commonly caused by [[neuroendocrine]] [[tumors]] of [[midgut]]. In patients with carcinoid syndrome, 70% of [[tryptophan]] is converted into [[serotonin]] which leads to secondary deficiency of [[niacin]]. [[Serotonin]] is metabolized into 5-hydroxy indoleacetic acid (5-HIAA) by [[aldehyde dehydrogenase]], which is [[eliminated]] into the [[urine]]. Deficiency of [[niacin]] results in [[Pellagra]] which manifests as [[dermatitis]], [[dementia]], and [[diarrhea]]. [[Carcinoid]] [[tumors]] arising in the [[bronchi]] reach the [[systemic]] [[circulation]] before passing through the [[liver]] and may be associated with [[bronchoconstriction]] and manifestations of [[carcinoid]] [[syndrome]] without [[liver]] [[Metastases|metastases.]] [[Bronchospasm]] leading to [[wheezing]] is caused by release of [[histamine]]. [[5-HT2B receptor|5-HT2B]] is the [[receptor]] of [[serotonin]] in the [[cardiovascular]] [[system]] that may be involved in [[fibrogenesis]]. [[Fibrosis]] leads to [[Tricuspid]] and [[Pulmonic Regurgitation|pulmonic]] [[regurgitation]], [[pulmonary stenosis]] and [[Cardiac arrythmia|cardiac arrhythmias]][[arrhythmias|.]] [[Serotonin]] and [[TGF-beta]] are secreted by [[Neuroendocrine tumor|neuroendocrine tumors]]  and appear to play a central role in the development of [[mesenteric]] [[fibrosis]]. [[Carcinoid]] [[tumors]] are normally found throughout the [[gastrointestinal]] [[tract]] from [[mouth]] to [[anus]], with the highest concentration of [[cells]] in the [[appendix]] and [[small intestine]]. [[Lung]] is the second most common site for [[Neuroendocrine tumour|neuroendocrine tumours]] . In the [[gastric]] or [[intestinal]] [[wall]], [[Carcinoid|carcinoids]] may occur as firm [[white]], yellow, or gray [[nodules]] and may be intramural [[masses]] or may protrude into the lumen as [[polypoid]] [[nodules]]. Neuroendocrine tumors arise from [[enterochromaffin]] [[cells]]. The name "[[Enterochromaffin cell|enterochromaffin]]" refers to the ability to stain the cell with [[potassium]] [[chromate]] (chromaffin), a feature of [[cells]] that contain [[serotonin]].
*When the carcinoid tumor is in the [[gastrointestinal tract]], as it is in the great majority of cases, the [[serotonin]] and [[kallikrein]] are inactivated in the [[liver]] and manifestations of carcinoid syndrome do not occur until there are metastases to the liver.  
 
*The [[flushing]] results from secretion of [[kallikrein]], the [[enzyme]] that catalyzes the conversion of [[kininogen]] to lysyl-[[bradykinin]]. The latter is further converted to [[bradykinin]], one of the most powerful [[vasodilators]] known.
=Pathophysiology=
*Large amounts of serotonin produces [[pellagra]]-like features including [[diarrhea]].
* [[Carcinoid Syndrome|Carcinoid syndrome]] (CS) is a [[Paraneoplastic Syndromes|paraneoplastic syndrome]] associated with the [[Secretions|secretion]] of several [[hormones]].<ref name="pmid30133565">{{cite journal |vauthors=Rubin de Celis Ferrari AC, Glasberg J, Riechelmann RP |title=Carcinoid syndrome: update on the pathophysiology and treatment |journal=Clinics (Sao Paulo) |volume=73 |issue=suppl 1 |pages=e490s |date=August 2018 |pmid=30133565 |pmc=6096975 |doi=10.6061/clinics/2018/e490s |url=}}</ref>
*Carcinoid tumors arising in the [[bronchi]], reach the systemic circulation before passing through the [[liver]] and may be associated with [[bronchoconstriction]] and manifestations of carcinoid syndrome without liver metastases.  
 
* The primary marker is [[serotonin]] ([[5-hydroxytryptamine|5-hydroxytrptamine]]) but the syndrome can be caused by the [[secretion]] of [[histamine|histamine,]] [[kallikrein]], [[prostaglandins]], and tachykinins.
 
*[[Carcinoid Syndrome|Carcinoid syndrome]] is most commonly caused by [[neuroendocrine]] [[tumors]] of the [[midgut]].
*[[Serotonin]] and [[kallikrein]] are inactivated in the [[liver]] and the manifestations of [[Carcinoid Syndrome|carcinoid syndrome]] do not occur until there are [[liver]] [[metastases]].
*Exceptions include circumstances in which [[venous]] [[blood]] draining from a [[carcinoid]] [[tumor]] enters directly into the [[systemic]] [[circulation]]:
#Primary [[pulmonary]] or [[ovarian]] [[carcinoid]]
#[[Pelvic]] or [[retroperitoneal]] involvement by [[metastatic]] or [[locally]] [[invasive]] [[small bowel]] [[Carcinoid Tumor|carcinoid]].
#Extensive [[bone]] [[metastases]]
*Only 1% of dietary [[tryptophan]] is converted into [[serotonin]]. However, in a patient with [[neuroendocrine tumors]], up to 70% of [[tryptophan]] is converted into [[serotonin]]. 
*[[Serotonin]] undergoes [[oxidative]] reaction and leads to the formation of 5-hydroxy indoleacetic acid (5-HIAA) by [[aldehyde dehydrogenase]], which is eliminated into the [[urine]]. 
*[[Serotonin]] causes increased [[motility]] and [[secretions]] of the [[GIT]] resulting in [[diarrhea]]. 
*As most of the body's [[tryptophan]] is diverted to [[serotonin]] formation pathway by [[neuroendocrine]] [[tumors]], [[tryptophan]] (which is needed for [[niacin]] synthesis) becomes deficient. 
*Deficiency of [[niacin]] results in [[Pellagra]] which manifests as [[dermatitis]], [[dementia]], and [[diarrhea]]. 
*[[Prostaglandins]] also mediate increased [[intestinal]] [[motility]] and [[fluid]] [[secretion]] in [[gastrointestinal]] [[tract]] causing [[diarrhea]].
*Skin [[flushing]] results from the [[secretion]] of [[kallikrein]], the [[enzyme]] that [[catalyzes]] the conversion of [[kininogen]] to [[lysyl]]-[[bradykinin]].
*Lysyl-[[bradykinin]]  is further converted to [[bradykinin]], a strong [[vasodilators|vasodilator.]]  
*Large amounts of [[serotonin]] produces [[pellagra]]-like features including [[diarrhea]].
 
===[[Lung]] [[Carcinoid]] [[Tumor]]===
*[[Carcinoid]] [[tumors]] arising in the [[bronchi]] reach the [[systemic]] [[circulation]] before passing through the [[liver]] and may be associated with [[bronchoconstriction]] and manifestations without [[liver]] metastases.
* [[Bronchospasm]] leading to [[wheezing]]  is caused by the crelease of [[histamine]] and [[serotonin]].<ref name="pmid2427948">{{cite journal |vauthors=Kvols LK, Moertel CG, O'Connell MJ, Schutt AJ, Rubin J, Hahn RG |title=Treatment of the malignant carcinoid syndrome. Evaluation of a long-acting somatostatin analogue |journal=N. Engl. J. Med. |volume=315 |issue=11 |pages=663–6 |date=September 1986 |pmid=2427948 |doi=10.1056/NEJM198609113151102 |url=}}</ref>
* Episodes of [[flushing]] and related manifestations are particularly prolonged or severe if [[carcinoid]] [[syndrome]] is caused by a [[lung]] [[neuroendocrine]] [[tumour]].
 
===[[Carcinoid]] [[Heart]] [[Disease]]===
*5-HT2B is the [[receptor]] of [[serotonin]] in the [[cardiovascular]] [[system]] that may be involved in [[fibrogenesis]].<ref name="pmid25871411">{{cite journal |vauthors=Grozinsky-Glasberg S, Grossman AB, Gross DJ |title=Carcinoid Heart Disease: From Pathophysiology to Treatment--'Something in the Way It Moves' |journal=Neuroendocrinology |volume=101 |issue=4 |pages=263–73 |date=2015 |pmid=25871411 |doi=10.1159/000381930 |url=}}</ref>
*Activation of the 5-HT2B [[receptor]] triggers distinct [[intracellular]] [[signaling]] [[pathways]], which in turn may result in a stronger [[inflammatory]] response and release of [[cytokines]] including [[TNF-alpha]], activation of the MAPK signaling pathway and hyperexpression of [[TGF-beta]] leading to to [[cardiac]] [[fibrosis]].<ref name="pmid8621713">{{cite journal |vauthors=Launay JM, Birraux G, Bondoux D, Callebert J, Choi DS, Loric S, Maroteaux L |title=Ras involvement in signal transduction by the serotonin 5-HT2B receptor |journal=J. Biol. Chem. |volume=271 |issue=6 |pages=3141–7 |date=February 1996 |pmid=8621713 |doi= |url=}}</ref><ref name="pmid19023134">{{cite journal |vauthors=Jaffré F, Bonnin P, Callebert J, Debbabi H, Setola V, Doly S, Monassier L, Mettauer B, Blaxall BC, Launay JM, Maroteaux L |title=Serotonin and angiotensin receptors in cardiac fibroblasts coregulate adrenergic-dependent cardiac hypertrophy |journal=Circ. Res. |volume=104 |issue=1 |pages=113–23 |date=January 2009 |pmid=19023134 |doi=10.1161/CIRCRESAHA.108.180976 |url=}}</ref><ref name="pmid12466135">{{cite journal |vauthors=Xu J, Jian B, Chu R, Lu Z, Li Q, Dunlop J, Rosenzweig-Lipson S, McGonigle P, Levy RJ, Liang B |title=Serotonin mechanisms in heart valve disease II: the 5-HT2 receptor and its signaling pathway in aortic valve interstitial cells |journal=Am. J. Pathol. |volume=161 |issue=6 |pages=2209–18 |date=December 2002 |pmid=12466135 |doi=10.1016/S0002-9440(10)64497-5 |url=}}</ref>
*[[Fibrosis]] leads to thickening of mural and [[valvular]] [[endothelial]] surfaces of [[right]]-sided [[cardiac]] structures.<ref>Carcinoid cardiac lesions. Dr Henry Knipe and Dr Yuranga Weerakkody et al. Radiopaedia. http://radiopaedia.org/articles/carcinoid-cardiac-lesions</ref><ref name="pmid26971851">{{cite journal |vauthors=Luis SA, Pellikka PA |title=Carcinoid heart disease: Diagnosis and management |journal=Best Pract. Res. Clin. Endocrinol. Metab. |volume=30 |issue=1 |pages=149–58 |date=January 2016 |pmid=26971851 |doi=10.1016/j.beem.2015.09.005 |url=}}</ref>
* [[Fibrosis]] leads to
#[[Tricuspid]] and [[pulmonic regurgitation]].
#[[Pulmonary stenosis|Pulmonary stenosis.]]
#[[Cardiac arrythmia|Cardiac arhythmias]].
 
===Mesentric fibrosis===
* [[Serotonin]] and [[TGF-beta]] secreted by [[Neuroendocrine tumor|neuroendocrine tumours]] appears to play a central role in the development of [[mesenteric]] [[fibrosis]].<ref name="pmid20123681">{{cite journal |vauthors=Druce MR, Bharwani N, Akker SA, Drake WM, Rockall A, Grossman AB |title=Intra-abdominal fibrosis in a recent cohort of patients with neuroendocrine ('carcinoid') tumours of the small bowel |journal=QJM |volume=103 |issue=3 |pages=177–85 |date=March 2010 |pmid=20123681 |doi=10.1093/qjmed/hcp191 |url=}}</ref>
* It is another complication of uncontrolled [[carcinoid syndrome]].
* There is a fibrotic and [[desmoplastic]] reaction around [[metastatic]] [[mesenteric]] [[lymph nodes]].
* [[Mesenteric]]  [[fibrosis]] is a [[pathognomonic]] [[radiological]] sign of midgut NET, which can be observed on [[CT]], and nuclear [[MRI]].
* [[Mesenteric]]  [[fibrosis]] can lead to [[ischemia]] of [[vessels]] and [[intestinal obstruction]].
* [[Vascular]] [[ischemia]] can lead to [[bowel]] [[congestion]] and result in decreased [[Absorption (digestive)|absorption]] of [[nutrients]] and can also cause [[ascites]] and more severe cases of [[mesenteric]] ischemia.<ref name="pmid7839976">{{cite journal |vauthors=Pantongrag-Brown L, Buetow PC, Carr NJ, Lichtenstein JE, Buck JL |title=Calcification and fibrosis in mesenteric carcinoid tumor: CT findings and pathologic correlation |journal=AJR Am J Roentgenol |volume=164 |issue=2 |pages=387–91 |date=February 1995 |pmid=7839976 |doi=10.2214/ajr.164.2.7839976 |url=}}</ref><ref name="pmid27861745">{{cite journal |vauthors=Daskalakis K, Karakatsanis A, Stålberg P, Norlén O, Hellman P |title=Clinical signs of fibrosis in small intestinal neuroendocrine tumours |journal=Br J Surg |volume=104 |issue=1 |pages=69–75 |date=January 2017 |pmid=27861745 |doi=10.1002/bjs.10333 |url=}}</ref>
==Genetics==
==Genetics==
*Gastrointestinal carcinoids occur in association with inherited syndromes, such as [[multiple endocrine neoplasia type 1]] and [[neurofibromatosis type 1]].<ref name=aaa> General Information About Gastrointestinal (GI) Carcinoid Tumors
*Gastrointestinal carcinoids occur in association with inherited syndromes, such as [[multiple endocrine neoplasia type 1]] and [[neurofibromatosis type 1]].<ref name="aaa">General Information About Gastrointestinal (GI) Carcinoid Tumors.<nowiki><ref name="pmid2886072"></nowiki>{{cite journal |vauthors=Duh QY, Hybarger CP, Geist R, Gamsu G, Goodman PC, Gooding GA, Clark OH |title=Carcinoids associated with multiple endocrine neoplasia syndromes |journal=Am. J. Surg. |volume=154 |issue=1 |pages=142–8 |date=July 1987 |pmid=2886072 |doi= |url=}}</ref>
. National Cancer Institute. http://www.cancer.gov/types/gi-carcinoid-tumors/hp/gi-carcinoid-treatment-pdq#link/_49_toc Accessed on September 24, 2015</ref>
*[[Multiple endocrine neoplasia type 1]] is caused by alterations of the [[MEN1]] [[gene]] located at [[chromosomal]] region 11q13.
*[[Multiple endocrine neoplasia type 1]] is caused by alterations of the MEN1 gene located at chromosomal region 11q13. Most carcinoids associated with Multiple endocrine neoplasia type 1 appear to be of foregut origin.
*Most [[Carcinoid|carcinoids]] that are associated with [[multiple endocrine neoplasia type 1]] appear to be of [[foregut]] origin.
*[[Neurofibromatosis type 1]] is an [[autosomal dominant]] genetic disorder caused by alteration of the ''[[NF1]]'' gene at chromosome 17q11. Carcinoids in patients with neurofibromatosis type 1 appear to arise primarily in the periampullary region.
*[[Neurofibromatosis type 1]] is an [[autosomal dominant]] [[genetic]] [[disorder]] caused by alteration of the ''[[NF1]]'' [[gene]] at [[chromosome]] 17q11.
*In sporadic gastrointestinal carcinoids, numerous chromosomal imbalances have been found by comparative genome hybridization analysis. Gains involving chromosomes 5, 14, 17 (especially 17q), and 19 and losses involving chromosomes 11 (especially 11q) and 18 appear to be the most common.
*[[Carcinoid|Carcinoids]] in patients with [[neurofibromatosis type 1]] appear to arise primarily in the periampullary region.<ref name="pmid10873367">{{cite journal |vauthors=Karatzas G, Kouraklis G, Karayiannakis A, Patapis P, Givalos N, Kaperonis E |title=Ampullary carcinoid and jejunal stromal tumour associated with von Recklinghausen's disease presenting as gastrointestinal bleeding and jaundice |journal=Eur J Surg Oncol |volume=26 |issue=4 |pages=428–9 |date=June 2000 |pmid=10873367 |doi=10.1053/ejso.1999.0911 |url=}}</ref>
*The most frequently reported mutated gene in gastrointestinal carcinoids is ''[[β-catenin]]'' (CTNNB1).
* A [[hereditary]] form of [[small intestinal]] [[carcinoid]] [[Tumour|tumour has]] been found which is caused by a [[Mutations|mutation]] in the IPMK [[gene]] leads to higher risk of developing [[carcinoid]] [[tumors]] in the [[Small intestinal|small intestine]].<ref name="pmid25865046">{{cite journal |vauthors=Sei Y, Zhao X, Forbes J, Szymczak S, Li Q, Trivedi A, Voellinger M, Joy G, Feng J, Whatley M, Jones MS, Harper UL, Marx SJ, Venkatesan AM, Chandrasekharappa SC, Raffeld M, Quezado MM, Louie A, Chen CC, Lim RM, Agarwala R, Schäffer AA, Hughes MS, Bailey-Wilson JE, Wank SA |title=A Hereditary Form of Small Intestinal Carcinoid Associated With a Germline Mutation in Inositol Polyphosphate Multikinase |journal=Gastroenterology |volume=149 |issue=1 |pages=67–78 |date=July 2015 |pmid=25865046 |pmc=4858647 |doi=10.1053/j.gastro.2015.04.008 |url=}}</ref>
*The most frequently reported [[mutated]] [[gene]] in [[gastrointestinal]] carcinoids is [[β-catenin|''β-catenin'']] (CTNNB1).<ref name="pmid11559529">{{cite journal |vauthors=Fujimori M, Ikeda S, Shimizu Y, Okajima M, Asahara T |title=Accumulation of beta-catenin protein and mutations in exon 3 of beta-catenin gene in gastrointestinal carcinoid tumor |journal=Cancer Res. |volume=61 |issue=18 |pages=6656–9 |date=September 2001 |pmid=11559529 |doi= |url=}}</ref>


==Embryology==
==Embryology==
Carcinoid tumours originate from [[neuroendocrine cells]] ([[Enterochromaffin]] or amine precursor uptake and decarboxylase [APUD] cells), which embryologically are of neural crest origin. Gastrointestinal carcinoids derive from cells that migrate from the neural crest to the [[foregut]], [[midgut]] and [[hindgut]].
*[[Carcinoid tumors]] originate from [[neuroendocrine cells]] ([[enterochromaffin]] or [[amine]] precursor uptake and [[decarboxylase]] [[APUD cell|[APUD]]<nowiki>] </nowiki>[[cells]]) which are derived from [[neural crest cells]] embrologically.
 
*[[Gastrointestinal|Gastrointestina]]<nowiki/>l [[Carcinoid tumors|carcinoids]] derive from [[cells]] that migrate from the [[Neural crest cell|neural crest]] to the [[foregut]], [[midgut]] and [[hindgut]].<ref name="pmid17114072">{{cite journal| author=Reznek RH| title=CT/MRI of neuroendocrine tumours. | journal=Cancer Imaging | year= 2006 | volume= 6 | issue=  | pages= S163-77 | pmid=17114072 | doi=10.1102/1470-7330.2006.9037 | pmc=PMC1805060 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17114072  }} </ref>
==Associated Conditions==
'''Goblet Cell Carcinoid''' is considered to be a hybrid between an [[exocrine]] and [[endocrine]] tumor derived from crypt cells of the [[appendix]]. They behave in a more aggressive manner than do classical appendiceal carcinoids. Spread is usually to regional [[lymph nodes]], [[peritoneum]], and particularly the [[ovary]]. They do not produce sufficient hormonal substances to cause the carcinoid or other endocrine syndromes. In fact, they more closely resemble [[exocrine]] than [[endocrine tumors]]. The term 'crypt cell carcinoma' has been used for them, and though perhaps more accurate than considering them carcinoids, has not been a successful competitor.


==Location==
==Location==
Carcinoid tumors are normally found throughout the gastrointestinal tract from [[mouth]] to [[anus]], with the highest concentration of cells in the [[appendix]] and [[small intestine]]. The [[pancreas]] contains a large number of these cells, the [[biliary tree]] only a few and the [[liver]] normally contains none. Fibrotic lesions are found on [[endocardium]], particularly on the right side of the [[heart]].
[[Carcinoid tumors]] are normally found throughout the [[gastrointestinal]] tract from [[mouth]] to [[anus]], with the highest concentration of [[cells]] in the [[appendix]] and [[small intestine]]. The [[pancreas]] contains a large number of these [[cells]], the [[biliary tree]] only a few and the [[liver]] normally contains none. [[Fibrosis|Fibrotic]] lesions are found on [[endocardium]], particularly on the right side of the [[heart]].


==Gross Pathology==
==Gross Pathology==
===Gastrointestinal Carcinoid===
===Gastrointestinal Carcinoid===
In the gastric or intestinal wall, carcinoids may occur as firm white, yellow, or gray nodules and may be intramural masses or may protrude into the lumen as polypoid nodules, the overlying [[gastric]] or [[intestinal mucosa]] may be intact or have focal ulceration.
In the [[gastric]] or [[intestinal]] wall, [[Carcinoid tumors|carcinoids tumors]] may occur as firm white, yellow, or gray nodule. The lesions may be intramural masses or may protrude into the [[lumen]] as polypoid [[nodules]]. The overlying [[gastric]] or [[intestinal mucosa]] may be intact or have focal [[ulceration]].
*Well-differentiated [[neuroendocrine tumors]] of the [[tubular]] [[gastrointestinal tract]] are often well-circumscribed round lesions in the [[Submucosal|submucosa]] or extending to the [[Muscular|muscular layer]].
*The cut surface appears red to tan, reflecting the abundant [[microvasculature]], or sometimes yellow because of the high [[lipid]] content.
 
{| align=""
|- valign="top"
| [[Image:Terminal-ileum-carcinoid-well-differentiated-neuroendocrine-tumour_(1).JPG|thumb|500px|Terminal ileal carcinoid gross pathology<ref name="radio">Image courtesy of Dr Henry Knipe and Dr Yuranga Weerakkody et al. [http://www.radiopaedia.org Radiopaedia] (original file [http://radiopaedia.org/articles/carcinoid-tumours-1]). [http://radiopaedia.org/licence Creative Commons BY-SA-NC</ref>]]
|}


===Ovarian Carcinoid===
===Neuroendocrine tumours of the lung===
Lesions can markedly vary in size. Metastatic carcinoids are nearly always bilateral with scattered tumor deposits present throughout both ovaries. Primary carcinoids of the ovary are invariably unilateral. They form a solid nodule within a cystic teratoma, or form a pure solid hypervascular mass. They can be  indistinguishable from other solid neoplasms of the ovary. Lesions can markedly vary in size. Metastatic carcinoids are nearly always bilateral with scattered tumor deposits present throughout both ovaries.<ref> Ovarian carcinoid tumours. Dr Aditya Shetty and Dr Yuranga Weerakkody et al. Radiopaedia 2015. http://radiopaedia.org/articles/ovarian-carcinoid-tumours</ref>
*[[Pulmonary]] [[neoplasms]] that are characterized by [[Neuroendocrine|neuroendocrin]]<nowiki/>[[Neuroendocrine|e]] differentiation and relatively indolent [[clinical]] behavior.
*Lung is the second most common site for [[neuroendocrine tumor]].
*[[Lung]] [[Neuroendocrine tumor|neuroendocrine tumors]] are classified on the basis of [[Histology|histology:]]<ref name="pmid20664470">{{cite journal |vauthors=Klimstra DS, Modlin IR, Coppola D, Lloyd RV, Suster S |title=The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems |journal=Pancreas |volume=39 |issue=6 |pages=707–12 |date=August 2010 |pmid=20664470 |doi=10.1097/MPA.0b013e3181ec124e |url=}}</ref><ref name="pmid17400673">{{cite journal |vauthors=Aubry MC, Thomas CF, Jett JR, Swensen SJ, Myers JL |title=Significance of multiple carcinoid tumors and tumorlets in surgical lung specimens: analysis of 28 patients |journal=Chest |volume=131 |issue=6 |pages=1635–43 |date=June 2007 |pmid=17400673 |doi=10.1378/chest.06-2788 |url=}}</ref>
#Typical [[neuroendocrine tumor]] : well-differentiated, low-grade, slowly growing [[neoplasms]] that are localized and rarely [[metastasize]] to extrathoracic structures.
#Poorly differentiated and high-grade [[Neuroendocrine tumor|neuroendocrine carcinomas]], as typified by [[small cell lung cancer]] and large cell carcinomas which behave aggressively, with rapid [[tumor]] growth and early distant [[dissemination]].
#Atypical [[neuroendocrine tumor]], which are of intermediate grade and differentiation, is intermediate between typical [[neuroendocrine tumor]] and [[small cell lung cancer]].
*Based on the location:
[[Carcinoid tumor]] of the [[lung]] may be classified based on the location into two subtypes:
#[[Bronchial]] [[carcinoid tumors]]: central lesions
#Peripheral [[pulmonary]] [[carcinoid tumors]]: peripheral lesions
*[[Carcinoid syndrome]] is encountered uncommonly and most often with tumors of the large size (>5 cm).


==Microscopic Pathology==
===Goblet Cell Carcinoid===
Histologically, globet cell carcinoid forms clusters of [[goblet cells]] containing [[mucin]] with a minor admixture of [[paneth cells]] and [[endocrine cells]]. The growth pattern is distinctive: typically producing a concentric band of tumour nests interspersed among the [[muscle]] and [[stroma]] of the appendiceal wall extending up the shaft of the [[appendix]]. This makes the lesion difficult to suspect grossly and difficult to measure. Small tumor nests may be camouflaged amongst the [[muscle]] or in periappendiceal fat, [[cytokeratin]] preparations best demonstrate the tumor cells; [[mucin]] stains are also helpful in identifying them.


===Gastric or Intestinal Carcinoid===
[[Image:Bronchial carcinoid tumor Gross pathology.jpeg|thumb|left|500px|Left upper lobe": A lung lobe 185x110x55mm with bronchovascular remnants up to 25mm. Arising in the hilum and involving the bronchus is a rubbery tan-pink tumor 21x20x19mm. The tumor is 6mm from the bronchovascular margins and 3mm from the hilar margin. 26mm from the tumor and 1mm from the pleura there is a firm white nodule 6mm. Peripheral to the tumor is an area where the lung shows dilated bronchi up to 12mm in diameter which lie 2mm from the pleura.[https://radiopaedia.org/cases/obstructing-typical-carcinoid-causing-bronchoceles?lang=us#googDisableSync Source: Radiopedia]]]
[[Neuroendocrine cells]] have uniform nuclei and abundant granular or faintly staining (clear) cytoplasm, and are present as solid or small trabecular clusters, or are dispersed among other cells, which may make them difficult to recognize in sections stained with [[hematoxylin]] and [[eosin]], immunostaining enables their exact identification. At the ultrastructural level, [[neuroendocrine cells]] contain cytoplasmic membrane-bound dense-cored secretory granules (diameter >80 nm) and may also contain small clear vesicles (diameter 40–80 nm) that correspond to the synaptic vesicles of neurons.<ref name=aaa> General Information About Gastrointestinal (GI) Carcinoid Tumors
. National Cancer Institute. http://www.cancer.gov/types/gi-carcinoid-tumors/hp/gi-carcinoid-treatment-pdq#link/_49_toc Accessed on September 24, 2015</ref>
[[file:Terminal-ileum-carcinoid-well-differentiated-neuroendocrine-tumour.jpg]]


===Hepatic Carcinoid===
==Microscopic Pathology==
Histologically, the tumor has features of classic carcinoid (i.e. trabecular and pseudoglandular pattern) and dense core granules demonstrated by electron microscopy or by immunohistochemistry (i.e. positive staining by chromogranin antibody).<ref> Hepatic carcinoid. Dr Henry Knipe and Dr Yuranga Weerakkody et al. Radiopaedia 2015. http://radiopaedia.org/articles/bronchial-carcinoid-tumour</ref>
* [[Neuroendocrine tumor]] arises from [[Enterochromaffin cells|enterochromaffin]] ([[Neuroendocrine cells|neuroendocrine) cells]] of the [[Gastrointestinal|gastrointestinal tract.]]


===Video===
*The term [[enterochromaffin]] refers to the ability to stain with [[Potassium chromate|potassium chromate (chromaffin]]), a feature of [[cells]] that contain [[serotonin]].
On [[electron microscopy]], the tumor cells are found to contain [[membrane]]-bound [[Granules|secretory granules]] with dense-core [[granules]] in the [[cytoplasm]].[[File:Typical carcinoid histopathology.jpg|thumb|left|700px| Typical carcinoid histopathology-The nuclei of the tumor cells are uniform with a stippled chromatin pattern. There is no mitotic activity or necrosis. https://commons.wikimedia.org/wiki/File:Typical_carcinoid_(3931156341).jpg source Case courtesy of Dr Yale Rosen, from wikicommons]]The most recent nomenclature for [[neuroendocrine tumor]]<nowiki/>s of the [[Digestive systems|digestive system]] from the [[World Health Organization]] (WHO) distinguishes two broad subgroups:<ref name="pmid21629514">{{cite journal |vauthors=Schott M, Klöppel G, Raffel A, Saleh A, Knoefel WT, Scherbaum WA |title=Neuroendocrine neoplasms of the gastrointestinal tract |journal=Dtsch Arztebl Int |volume=108 |issue=18 |pages=305–12 |date=May 2011 |pmid=21629514 |pmc=3103981 |doi=10.3238/arztebl.2011.0305 |url=}}</ref><ref name="pmid28837143">{{cite journal |vauthors=Cavalcanti E, Armentano R, Valentini AM, Chieppa M, Caruso ML |title=Role of PD-L1 expression as a biomarker for GEP neuroendocrine neoplasm grading |journal=Cell Death Dis |volume=8 |issue=8 |pages=e3004 |date=August 2017 |pmid=28837143 |pmc=5596583 |doi=10.1038/cddis.2017.401 |url=}}</ref><ref name="pmid25412850">{{cite journal |vauthors=Reid MD, Bagci P, Ohike N, Saka B, Erbarut Seven I, Dursun N, Balci S, Gucer H, Jang KT, Tajiri T, Basturk O, Kong SY, Goodman M, Akkas G, Adsay V |title=Calculation of the Ki67 index in pancreatic neuroendocrine tumors: a comparative analysis of four counting methodologies |journal=Mod. Pathol. |volume=28 |issue=5 |pages=686–94 |date=May 2015 |pmid=25412850 |pmc=4460192 |doi=10.1038/modpathol.2014.156 |url=}}</ref>


{{#ev:youtube|hTSHJBAD3C4}}
[[Neuroendocrine tumor|Neuroendocrine tumor:]] which are further subdivided according to their proliferative rate:<ref name="KlöppelAnlauf2005">{{cite journal|last1=Klöppel|first1=Günter|last2=Anlauf|first2=Martin|title=Epidemiology, tumour biology and histopathological classification of neuroendocrine tumours of the gastrointestinal tract|journal=Best Practice & Research Clinical Gastroenterology|volume=19|issue=4|year=2005|pages=507–517|issn=15216918|doi=10.1016/j.bpg.2005.02.010}}</ref>




#Well-differentiated :Low grade also known as typical neuroendocrine tumors.
#Intermediate grade.(Intermediate-grade [[neuroendocrine tumor]] arising in the [[lung]] (but not elsewhere) are referred to as atypical [[Carcinoid|carcinoid.]]
*Poorly differentiated [[Neuroendocrine tumor|neuroendocrine carcinomas]]: High grade
*They are high-grade [[carcinomas]] that resemble [[Small cell carcinoma of the lung|small cell carcinoma]] or [[large cell neuroendocrine carcinoma of the lung]].
*Histoloigically, well-differentiated [[neuroendocrine tumor]] have characteristic "[[organoid]]" arrangements of [[Tumor cell|tumor]] [[cells]], with solid/nesting, trabecular, gyriform, or sometimes, [[glandular]] patterns.
*The [[cells]] are relatively uniform, and they have round to oval nuclei, coarsely stippled [[Chromatin|chromatin,]] and finely [[Granularity|granular]] [[Cytoplasmic|cytoplasm]].
*The [[cells]] produce abundant neurosecretory granules, as reflected in the strong and diffuse [[immunohistochemical]] expression of [[Neuroendocrine cells|neuroendocrine markers]] such as [[synaptophysin]], [[neuron-specific enolase]] and  [[chromogranin]].<ref name="pmid15104570">{{cite journal |vauthors=Nehar D, Lombard-Bohas C, Olivieri S, Claustrat B, Chayvialle JA, Penes MC, Sassolas G, Borson-Chazot F |title=Interest of Chromogranin A for diagnosis and follow-up of endocrine tumours |journal=Clin. Endocrinol. (Oxf) |volume=60 |issue=5 |pages=644–52 |date=May 2004 |pmid=15104570 |doi=10.1111/j.1365-2265.2004.02030.x |url=}}</ref><ref name="pmid20217257">{{cite journal |vauthors=Modlin IM, Gustafsson BI, Moss SF, Pavel M, Tsolakis AV, Kidd M |title=Chromogranin A--biological function and clinical utility in neuro endocrine tumor disease |journal=Ann. Surg. Oncol. |volume=17 |issue=9 |pages=2427–43 |date=September 2010 |pmid=20217257 |doi=10.1245/s10434-010-1006-3 |url=}}</ref>
*Well-differentiated [[neuroendocrine tumor]] of the [[midgut]] [[Ileum|(ileum]] in particular) also have a very characteristic pattern of [[solid]] or cribriform nests punctuated by sharply outlined luminal spaces with peripheral [[nuclear]] [[palisading]] and [[Granular cell|granular]] [[eosinophilic]] [[Cytoplasmic|cytoplasm]].
*Poorly differentiated [[Neuroendocrine tumor|neuroendocrine carcinomas]] (NECs) less closely resemble [[nonneoplastic]] [[neuroendocrine cells]] and have a more sheet-like or diffuse architecture, irregular [[nuclei]], and less [[cytoplasmic]] [[granularity]]. [[Immunohistochemical|Immunohistochemica]]<nowiki/>l expression of [[Neuroendocrine cells|neuroendocrine]] markers is generally more limited in extent and intensity.


==References==
==References==
{{reflist|2}}
{{reflist|2}}


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Latest revision as of 16:45, 7 May 2019

Carcinoid syndrome Microchapters

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [3]

Overview

Carcinoid syndrome (CS) is a paraneoplastic syndrome caused by the secretion of serotonin (5-hydroxytrptamine) but can be caused by the secretion of histamine, kallikrein, prostaglandins, and tachykinins..Carcinoid syndrome is most commonly caused by neuroendocrine tumors of midgut. In patients with carcinoid syndrome, 70% of tryptophan is converted into serotonin which leads to secondary deficiency of niacin. Serotonin is metabolized into 5-hydroxy indoleacetic acid (5-HIAA) by aldehyde dehydrogenase, which is eliminated into the urine. Deficiency of niacin results in Pellagra which manifests as dermatitis, dementia, and diarrhea. Carcinoid tumors arising in the bronchi reach the systemic circulation before passing through the liver and may be associated with bronchoconstriction and manifestations of carcinoid syndrome without liver metastases. Bronchospasm leading to wheezing is caused by release of histamine. 5-HT2B is the receptor of serotonin in the cardiovascular system that may be involved in fibrogenesis. Fibrosis leads to Tricuspid and pulmonic regurgitation, pulmonary stenosis and cardiac arrhythmias. Serotonin and TGF-beta are secreted by neuroendocrine tumors and appear to play a central role in the development of mesenteric fibrosis. Carcinoid tumors are normally found throughout the gastrointestinal tract from mouth to anus, with the highest concentration of cells in the appendix and small intestine. Lung is the second most common site for neuroendocrine tumours . In the gastric or intestinal wall, carcinoids may occur as firm white, yellow, or gray nodules and may be intramural masses or may protrude into the lumen as polypoid nodules. Neuroendocrine tumors arise from enterochromaffin cells. The name "enterochromaffin" refers to the ability to stain the cell with potassium chromate (chromaffin), a feature of cells that contain serotonin.

Pathophysiology

  1. Primary pulmonary or ovarian carcinoid
  2. Pelvic or retroperitoneal involvement by metastatic or locally invasive small bowel carcinoid.
  3. Extensive bone metastases

Lung Carcinoid Tumor

Carcinoid Heart Disease

  1. Tricuspid and pulmonic regurgitation.
  2. Pulmonary stenosis.
  3. Cardiac arhythmias.

Mesentric fibrosis

Genetics

Embryology

Location

Carcinoid tumors are normally found throughout the gastrointestinal tract from mouth to anus, with the highest concentration of cells in the appendix and small intestine. The pancreas contains a large number of these cells, the biliary tree only a few and the liver normally contains none. Fibrotic lesions are found on endocardium, particularly on the right side of the heart.

Gross Pathology

Gastrointestinal Carcinoid

In the gastric or intestinal wall, carcinoids tumors may occur as firm white, yellow, or gray nodule. The lesions may be intramural masses or may protrude into the lumen as polypoid nodules. The overlying gastric or intestinal mucosa may be intact or have focal ulceration.

Terminal ileal carcinoid gross pathology[17]

Neuroendocrine tumours of the lung

  1. Typical neuroendocrine tumor : well-differentiated, low-grade, slowly growing neoplasms that are localized and rarely metastasize to extrathoracic structures.
  2. Poorly differentiated and high-grade neuroendocrine carcinomas, as typified by small cell lung cancer and large cell carcinomas which behave aggressively, with rapid tumor growth and early distant dissemination.
  3. Atypical neuroendocrine tumor, which are of intermediate grade and differentiation, is intermediate between typical neuroendocrine tumor and small cell lung cancer.
  • Based on the location:

Carcinoid tumor of the lung may be classified based on the location into two subtypes:

  1. Bronchial carcinoid tumors: central lesions
  2. Peripheral pulmonary carcinoid tumors: peripheral lesions
  • Carcinoid syndrome is encountered uncommonly and most often with tumors of the large size (>5 cm).


Left upper lobe": A lung lobe 185x110x55mm with bronchovascular remnants up to 25mm. Arising in the hilum and involving the bronchus is a rubbery tan-pink tumor 21x20x19mm. The tumor is 6mm from the bronchovascular margins and 3mm from the hilar margin. 26mm from the tumor and 1mm from the pleura there is a firm white nodule 6mm. Peripheral to the tumor is an area where the lung shows dilated bronchi up to 12mm in diameter which lie 2mm from the pleura.Source: Radiopedia

Microscopic Pathology

On electron microscopy, the tumor cells are found to contain membrane-bound secretory granules with dense-core granules in the cytoplasm.

Typical carcinoid histopathology-The nuclei of the tumor cells are uniform with a stippled chromatin pattern. There is no mitotic activity or necrosis. https://commons.wikimedia.org/wiki/File:Typical_carcinoid_(3931156341).jpg source Case courtesy of Dr Yale Rosen, from wikicommons

The most recent nomenclature for neuroendocrine tumors of the digestive system from the World Health Organization (WHO) distinguishes two broad subgroups:[20][21][22]

Neuroendocrine tumor: which are further subdivided according to their proliferative rate:[23]


  1. Well-differentiated :Low grade also known as typical neuroendocrine tumors.
  2. Intermediate grade.(Intermediate-grade neuroendocrine tumor arising in the lung (but not elsewhere) are referred to as atypical carcinoid.

References

  1. ↑ Rubin de Celis Ferrari AC, Glasberg J, Riechelmann RP (August 2018). "Carcinoid syndrome: update on the pathophysiology and treatment". Clinics (Sao Paulo). 73 (suppl 1): e490s. doi:10.6061/clinics/2018/e490s. PMC 6096975. PMID 30133565.
  2. ↑ Kvols LK, Moertel CG, O'Connell MJ, Schutt AJ, Rubin J, Hahn RG (September 1986). "Treatment of the malignant carcinoid syndrome. Evaluation of a long-acting somatostatin analogue". N. Engl. J. Med. 315 (11): 663–6. doi:10.1056/NEJM198609113151102. PMID 2427948.
  3. ↑ Grozinsky-Glasberg S, Grossman AB, Gross DJ (2015). "Carcinoid Heart Disease: From Pathophysiology to Treatment--'Something in the Way It Moves'". Neuroendocrinology. 101 (4): 263–73. doi:10.1159/000381930. PMID 25871411.
  4. ↑ Launay JM, Birraux G, Bondoux D, Callebert J, Choi DS, Loric S, Maroteaux L (February 1996). "Ras involvement in signal transduction by the serotonin 5-HT2B receptor". J. Biol. Chem. 271 (6): 3141–7. PMID 8621713.
  5. ↑ Jaffré F, Bonnin P, Callebert J, Debbabi H, Setola V, Doly S, Monassier L, Mettauer B, Blaxall BC, Launay JM, Maroteaux L (January 2009). "Serotonin and angiotensin receptors in cardiac fibroblasts coregulate adrenergic-dependent cardiac hypertrophy". Circ. Res. 104 (1): 113–23. doi:10.1161/CIRCRESAHA.108.180976. PMID 19023134.
  6. ↑ Xu J, Jian B, Chu R, Lu Z, Li Q, Dunlop J, Rosenzweig-Lipson S, McGonigle P, Levy RJ, Liang B (December 2002). "Serotonin mechanisms in heart valve disease II: the 5-HT2 receptor and its signaling pathway in aortic valve interstitial cells". Am. J. Pathol. 161 (6): 2209–18. doi:10.1016/S0002-9440(10)64497-5. PMID 12466135.
  7. ↑ Carcinoid cardiac lesions. Dr Henry Knipe and Dr Yuranga Weerakkody et al. Radiopaedia. http://radiopaedia.org/articles/carcinoid-cardiac-lesions
  8. ↑ Luis SA, Pellikka PA (January 2016). "Carcinoid heart disease: Diagnosis and management". Best Pract. Res. Clin. Endocrinol. Metab. 30 (1): 149–58. doi:10.1016/j.beem.2015.09.005. PMID 26971851.
  9. ↑ Druce MR, Bharwani N, Akker SA, Drake WM, Rockall A, Grossman AB (March 2010). "Intra-abdominal fibrosis in a recent cohort of patients with neuroendocrine ('carcinoid') tumours of the small bowel". QJM. 103 (3): 177–85. doi:10.1093/qjmed/hcp191. PMID 20123681.
  10. ↑ Pantongrag-Brown L, Buetow PC, Carr NJ, Lichtenstein JE, Buck JL (February 1995). "Calcification and fibrosis in mesenteric carcinoid tumor: CT findings and pathologic correlation". AJR Am J Roentgenol. 164 (2): 387–91. doi:10.2214/ajr.164.2.7839976. PMID 7839976.
  11. ↑ Daskalakis K, Karakatsanis A, Stålberg P, Norlén O, Hellman P (January 2017). "Clinical signs of fibrosis in small intestinal neuroendocrine tumours". Br J Surg. 104 (1): 69–75. doi:10.1002/bjs.10333. PMID 27861745.
  12. ↑ General Information About Gastrointestinal (GI) Carcinoid Tumors.<ref name="pmid2886072">Duh QY, Hybarger CP, Geist R, Gamsu G, Goodman PC, Gooding GA, Clark OH (July 1987). "Carcinoids associated with multiple endocrine neoplasia syndromes". Am. J. Surg. 154 (1): 142–8. PMID 2886072.
  13. ↑ Karatzas G, Kouraklis G, Karayiannakis A, Patapis P, Givalos N, Kaperonis E (June 2000). "Ampullary carcinoid and jejunal stromal tumour associated with von Recklinghausen's disease presenting as gastrointestinal bleeding and jaundice". Eur J Surg Oncol. 26 (4): 428–9. doi:10.1053/ejso.1999.0911. PMID 10873367.
  14. ↑ Sei Y, Zhao X, Forbes J, Szymczak S, Li Q, Trivedi A, Voellinger M, Joy G, Feng J, Whatley M, Jones MS, Harper UL, Marx SJ, Venkatesan AM, Chandrasekharappa SC, Raffeld M, Quezado MM, Louie A, Chen CC, Lim RM, Agarwala R, Schäffer AA, Hughes MS, Bailey-Wilson JE, Wank SA (July 2015). "A Hereditary Form of Small Intestinal Carcinoid Associated With a Germline Mutation in Inositol Polyphosphate Multikinase". Gastroenterology. 149 (1): 67–78. doi:10.1053/j.gastro.2015.04.008. PMC 4858647. PMID 25865046.
  15. ↑ Fujimori M, Ikeda S, Shimizu Y, Okajima M, Asahara T (September 2001). "Accumulation of beta-catenin protein and mutations in exon 3 of beta-catenin gene in gastrointestinal carcinoid tumor". Cancer Res. 61 (18): 6656–9. PMID 11559529.
  16. ↑ Reznek RH (2006). "CT/MRI of neuroendocrine tumours". Cancer Imaging. 6: S163–77. doi:10.1102/1470-7330.2006.9037. PMC 1805060. PMID 17114072.
  17. ↑ Image courtesy of Dr Henry Knipe and Dr Yuranga Weerakkody et al. Radiopaedia (original file [1]). [http://radiopaedia.org/licence Creative Commons BY-SA-NC
  18. ↑ Klimstra DS, Modlin IR, Coppola D, Lloyd RV, Suster S (August 2010). "The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems". Pancreas. 39 (6): 707–12. doi:10.1097/MPA.0b013e3181ec124e. PMID 20664470.
  19. ↑ Aubry MC, Thomas CF, Jett JR, Swensen SJ, Myers JL (June 2007). "Significance of multiple carcinoid tumors and tumorlets in surgical lung specimens: analysis of 28 patients". Chest. 131 (6): 1635–43. doi:10.1378/chest.06-2788. PMID 17400673.
  20. ↑ Schott M, Klöppel G, Raffel A, Saleh A, Knoefel WT, Scherbaum WA (May 2011). "Neuroendocrine neoplasms of the gastrointestinal tract". Dtsch Arztebl Int. 108 (18): 305–12. doi:10.3238/arztebl.2011.0305. PMC 3103981. PMID 21629514.
  21. ↑ Cavalcanti E, Armentano R, Valentini AM, Chieppa M, Caruso ML (August 2017). "Role of PD-L1 expression as a biomarker for GEP neuroendocrine neoplasm grading". Cell Death Dis. 8 (8): e3004. doi:10.1038/cddis.2017.401. PMC 5596583. PMID 28837143.
  22. ↑ Reid MD, Bagci P, Ohike N, Saka B, Erbarut Seven I, Dursun N, Balci S, Gucer H, Jang KT, Tajiri T, Basturk O, Kong SY, Goodman M, Akkas G, Adsay V (May 2015). "Calculation of the Ki67 index in pancreatic neuroendocrine tumors: a comparative analysis of four counting methodologies". Mod. Pathol. 28 (5): 686–94. doi:10.1038/modpathol.2014.156. PMC 4460192. PMID 25412850.
  23. ↑ Klöppel, Günter; Anlauf, Martin (2005). "Epidemiology, tumour biology and histopathological classification of neuroendocrine tumours of the gastrointestinal tract". Best Practice & Research Clinical Gastroenterology. 19 (4): 507–517. doi:10.1016/j.bpg.2005.02.010. ISSN 1521-6918.
  24. ↑ Nehar D, Lombard-Bohas C, Olivieri S, Claustrat B, Chayvialle JA, Penes MC, Sassolas G, Borson-Chazot F (May 2004). "Interest of Chromogranin A for diagnosis and follow-up of endocrine tumours". Clin. Endocrinol. (Oxf). 60 (5): 644–52. doi:10.1111/j.1365-2265.2004.02030.x. PMID 15104570.
  25. ↑ Modlin IM, Gustafsson BI, Moss SF, Pavel M, Tsolakis AV, Kidd M (September 2010). "Chromogranin A--biological function and clinical utility in neuro endocrine tumor disease". Ann. Surg. Oncol. 17 (9): 2427–43. doi:10.1245/s10434-010-1006-3. PMID 20217257.


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