Neuroendocrine tumors: Difference between revisions

Jump to navigation Jump to search
No edit summary
 
(173 intermediate revisions by 3 users not shown)
Line 1: Line 1:
__NOTOC__
__NOTOC__
{{Infobox_Disease |
  Name          = Neuroendocrine tumors |
  Image          = |
  Caption        = |
  DiseasesDB    = |
  ICD10          = |
  ICD9          = {{ICD9|209}} |
  ICDO          = M8013/3, M8041/3, M8246/3, M8247/3, M8574/3 |
  OMIM          = |
  MedlinePlus    = 000393|
  eMedicineSubj  = |
  eMedicineTopic = |
  MeshID        = D018358 |
}}
{{Neuroendocrine tumors}}
{{Neuroendocrine tumors}}
'''For patient information, click [[Neuroendocrine tumors (patient information)|here]]'''
'''For patient information, click [[Neuroendocrine tumors (patient information)|here]]'''


{{CMG}} {{AE}}{{S.M.}}
{{CMG}} {{AE}} {{S.M.}}
 
==Overview==
==Overview==


Line 24: Line 9:


==Historical Perspective==
==Historical Perspective==
Siegfried Oberndorfer, in 1907, was the first person to distinguish clearly what we now call GEP-NETs from other forms of cancer. He gave the term "carcinoid" to these tumors, because they were so slow-growing that he considered them to be "cancer-like" rather than truly cancerous.
In 1929, he reported that some such tumors were not so indolent – these he distinguished as what we now call PETs from what most authorities call carcinoids.
Despite the differences between the two categories, some doctors, including oncologists, persist in calling all GEP-NETs "carcinoid", even into the twenty-first century.


The earliest synthetic form of somatostatin used in the treatment of Neuroendocrine tumors was [[octreotide]], first marketed, by [[Sandoz]] as Sandostatin, in 1988.
* In 1907, Siegfried Oberndorfer was the first [[person]] to clearly [[Distinctive feature|distinguish]] GEP-[[NET1|NETs]] from other forms of [[cancer]]. Since they were so [[slow]]-[[Growth|growing]], he considered them to be "[[cancer]]-like" rather than truly [[cancerous]], and hence, he coined the [[Term logic|term]] "[[carcinoid]]" for these [[Tumor|tumors]].
* In 1929, Siegfried Oberndorfer reported that some such [[tumors]] were not so indolent and [[Distinctive feature|distinguished]] them as [[PET|PETs]] (mostly called [[Carcinoid|carcinoids]]). Despite of the [[Difference (philosophy)|differences]] between the two [[categories]],  even in the twenty-first [[century]], some [[doctors]] (including [[oncologists]]) insist on calling all GEP-[[NET1|NETs]] "[[carcinoid]]".
*In 1988, the earliest [[Synthetic element|synthetic]] form of [[somatostatin]] [[Usage analysis|used]] in the [[Treatment Planning|treatment]] of [[neuroendocrine]] [[tumors]] was [[octreotide]], which was first [[Market basket|marketed]] by [[Sandoz]] as [[Sandostatin]].
*In 2006 and 2007, the European [[Neuroendocrine]] [[Tumor]] Society (ENETS) [[Proposition|proposed]] a [[Staging (pathology)|staging]] scheme same as for most other types of [[epithelial]] [[neoplasms]] for GEP NENs, alongwith a [[histologic]] [[Grading (tumors)|grading]] [[system]] [[Applicability Domain|applicable]] to all [[disease]] [[Stages of human development|stages]]. [[American Joint Committee on Cancer]] (AJCC) and the [[UICC|Union for International Cancer Control (UICC)]] later on endorsed this [[Grading (tumors)|grading]] [[Proposition|proposal]] for the [[tumor]], [[Nodal (protein)|node]], [[metastasis]] ([[TNM classification|TNM]]) [[Staging (pathology)|staging]] [[classification]] of [[digestive system]] NENs, after [[Modifications (genetics)|modifying]] the [[Cancer staging|staging]] [[Parameter|parameters]] of the ENETS [[Proposition|proposal]].
*Th 2010 [[World Health Organization|WHO]] [[classification]] of [[tumors]] of the [[gastrointestinal tract]], [[liver]], and [[pancreas]] (which was subsequently updated in 2017) also endorsed the ENETS [[Grading (tumors)|grading]] scheme for NENs of the [[digestive tract]], [[Separation process|separating]] [[WellPoint|well]]-[[Differentiate|differentiated]] [[tumors]] into low-[[Grading (tumors)|grade]] ([[G1]]) and intermediate-[[Grading (tumors)|grade]] ([[G2 phase|G2]]) [[categories]]. All poorly [[Differentiate|differentiated]] [[NET1|NETs]] are high-[[Grading (tumors)|grade]] (G3) NECs according to this [[classification]] scheme.


==Classification==
==Classification==
Line 38: Line 23:
!style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Percentage}}
!style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Percentage}}
|-
|-
| rowspan="2" style="padding: 5px 5px; background: #DCDCDC; font-weight: bold"|'''Carcinoids (about two thirds of GEP-NETs)'''
| rowspan="2" style="padding: 5px 5px; background: #DCDCDC; font-weight: bold"|'''[[Carcinoid|Carcinoids]] (about two thirds of GEP-[[NET1|NETs]])'''
|
|
*With carcinoid syndrome  
*With [[carcinoid syndrome]]
|
|
* About 10 percent of carcinoids
* About 10 [[Percentage|percent]] of [[Carcinoid|carcinoids]]
|-
|-
|
|
* Without carcinoid syndrome  
* Without [[carcinoid syndrome]]
|
|
* About 90 percent of carcinoids
* About 90 [[Percentage|percent]] of [[Carcinoid|carcinoids]]
|-
|-
| rowspan="2" style="padding: 5px 5px; background: #DCDCDC; font-weight: bold"|'''PETs (about one third of GEP-NETs)'''
| rowspan="2" style="padding: 5px 5px; background: #DCDCDC; font-weight: bold"|'''[[PET|PETs]] (about one third of GEP-[[NET1|NETs]])''' <br />
|
|
* Nonfunctioning  
* Nonfunctioning  
|
|
* 15 to 30 percent of PETs
* 15 to 30 [[Percentage|percent]] of [[PET|PETs]]
|-
|-
|
|
* Functioning:
*[[Function (biology)|Functioning]]:
** [[Gastrinoma]] (produces excessive [[gastrin]] and causes [[Zollinger-Ellison Syndrome]] [ZES])
**[[Gastrinoma]] ([[Product (biology)|produces]] [[Excess dose|excessive]] [[gastrin]] and [[causes]] [[Zollinger-Ellison Syndrome]] [<nowiki/>[[Zollinger-Ellison syndrome|ZES]]])
**[[Insulinoma]] (produces excessive [[insulin]])
**[[Insulinoma]] ([[Product (biology)|produces]] [[Excess risk|excessive]] [[insulin]])
**[[Glucagonoma]] (produces excessive [[glucagon]])
**[[Glucagonoma]] ([[Product (biology)|produces]] [[Excess risk|excessive]] [[glucagon]])
**[[Vasoactive intestinal peptideoma]] ([[VIPoma]]) (produces excessive [[vasoactive intestinal peptide]] [VIP])
**[[Vasoactive intestinal peptideoma]] ([[VIPoma]]) ([[Product (biology)|produces]] excessive [[vasoactive intestinal peptide]] [<nowiki/>[[VIP]]])
**[[PPoma]] (produces excessive [[pancreatic polypeptide]] [often classed with nonfunctioning PETs])
**[[PPoma]] ([[Product (biology)|produces]] excessive [[pancreatic polypeptide]] [often [[Class (biology)|classed]] with nonfunctioning [[PET|PETs]]])
**[[Somatostatinoma]] (produces excessive [[somatostatin]])
**[[Somatostatinoma]] ([[Product (biology)|produces]] excessive [[somatostatin]])
**[[Watery diarrhea]], [[hypokalemia]]-[[achlorhydria]] (WDHA)
**[[Watery diarrhea]], [[hypokalemia]]-[[achlorhydria]] ([[WDHA]])
**[[CRHoma]] (produces excessive [[CRH|corticotropin-releasing hormonse]] [CRH])
**[[CRHoma]] ([[Product (biology)|produces]] excessive [[Corticotropin-releasing hormone|corticotropin-releasing hormones]] [<nowiki/>[[CRH]]])
**[[Calcitoninoma]] (produces excessive [[calcitonin]])
**[[Calcitoninoma]] ([[Product (biology)|produces]] excessive [[calcitonin]])
**[[GHRHoma]] (produces excessive [[GHRH|growth-hormone-releasing hormone]] [GHRH])
**[[GHRHoma]] ([[Product (biology)|produces]] excessive [[GHRH|growth-hormone-releasing hormone]] [<nowiki/>[[GHRH]]])
**[[Neurotensinoma]] (produces excessive [[neurotensin]])
**[[Neurotensinoma]] ([[Product (biology)|produces]] excessive [[neurotensin]])
**[[ACTHoma]] (produces excessive [[adrenocorticotropic hormone]] [ACTH])
**[[ACTHoma]] ([[Product (biology)|produces]] excessive [[adrenocorticotropic hormone]] [<nowiki/>[[ACTH]]])
**[[GRFoma]] (produces excessive [[growth hormone]] release factor [GRF])
**[[GRFoma]] ([[Product (biology)|produces]] excessive [[Growth hormone-releasing factor|growth hormone release factor]] [<nowiki/>[[GRF]]])
**[[Parathyroid hormone–related peptide tumor]]
**[[Parathyroid hormone–related peptide tumor|Parathyroid hormone-related peptide tumor]]
|
|
* 70 to 85 percent of PETs
* 70 to 85 [[Percentage|percent]] of [[PET|PETs]]
|-
|-
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |'''Rare GEP-NETs'''
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |'''Rare GEP-[[NET1|NETs]]'''
|
|
*Medullary carcinoma of the [[thyroid]]
*[[Medullary carcinoma of the thyroid]]
*[[Merkel cell cancer]] (trabecular cancer)
*[[Merkel cell cancer]] ([[trabecular cancer]])
*[[Small-cell lung cancer]] (SCLC)
*[[Small-cell lung cancer]] ([[Small cell lung cancer|SCLC]])
* Large-cell neuroendocrine carcinoma (of the lung)
*[[Large-cell neuroendocrine carcinoma]] (of the [[lung]])
* Neuroendocrine carcinoma of the [[cervix]]
*[[Neuroendocrine]] [[carcinoma]] of the [[cervix]]
* Multiple Endocrine Neoplasia type 1 (MEN-1 or MEN1) (usually nonfunctioning) (also causing ZES)
*[[Multiple endocrine neoplasia type 1|Multiple Endocrine Neoplasia type 1]] ([[MEN1|MEN-1]] or [[MEN1]]) (usually nonfunctioning) (also [[Causes|causing]] ZES)
* Multiple Endocrine Neoplasia type 2 (MEN-2 or MEN2)
*[[Multiple endocrine neoplasia type 2|Multiple Endocrine Neoplasia type 2]] ([[MEN2|MEN-2]] or [[MEN2]])
*[[Neurofibromatosis type 1]]
*[[Neurofibromatosis type 1]]
*[[Tuberous sclerosis]]
*[[Tuberous sclerosis]]
*[[Von Hippel-Lindau disease]] (VHL)
*[[Von Hippel-Lindau disease]] ([[VHL]])
*[[Neuroblastoma]]
*[[Neuroblastoma]]
*[[Pheochromocytoma]] (phaeochromocytoma)
*[[Pheochromocytoma]] ([[phaeochromocytoma]])
*[[Paraganglioma]]
*[[Paraganglioma]]
* Neuroendocrine tumor of the anterior [[pituitary]]
*[[Neuroendocrine]] [[tumor]] of the [[Anterior pituitary gland|anterior pituitary]]
* Carney's complex
*[[Carney complex|Carney's complex]]
|
|
|}
|}
Line 99: Line 84:
!style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Name/type of neuroendocrine tumor}}
!style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Name/type of neuroendocrine tumor}}
|-
|-
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |Pituitary gland
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Pituitary gland]]
|
|
* Neuroendocrine tumor of the anterior pituitary
*[[Neuroendocrine]] [[tumor]] of the [[anterior pituitary]]
|-
|-
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |Thyroid gland
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Thyroid gland]]
|
|
* Neuroendocrine thyroid tumors
*[[Neuroendocrine]] [[Thyroid cancer|thyroid tumors]]
** Medullary thyroid carcinoma (particularly)
**[[Medullary thyroid carcinoma]] (particularly)
|-
|-
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |Parathyroid glands
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Parathyroid glands]]
|
|
* Parathyroid tumors
*[[Parathyroid]] [[tumors]]
|-
|-
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |Thymus and mediastinum<ref name="pmid10550713">{{cite journal| author=Soga J, Yakuwa Y, Osaka M| title=Evaluation of 342 cases of mediastinal/thymic carcinoids collected from literature: a comparative study between typical carcinoids and atypical varieties. | journal=Ann Thorac Cardiovasc Surg | year= 1999 | volume= 5 | issue= 5 | pages= 285-92 | pmid=10550713 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10550713  }} </ref><ref name="pmid18456740">{{cite journal| author=Oberg K, Jelic S, ESMO Guidelines Working Group| title=Neuroendocrine bronchial and thymic tumors: ESMO clinical recommendation for diagnosis, treatment and follow-up. | journal=Ann Oncol | year= 2008 | volume= 19 Suppl 2 | issue=  | pages= ii102-3 | pmid=18456740 | doi=10.1093/annonc/mdn116 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18456740  }} </ref>
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Thymus]] and [[mediastinum]]
|
|
* Thymus and mediastinal carcinoid tumors
*[[Thymus cancer|Thymus]] and [[mediastinal]] [[Carcinoid Tumor|carcinoid tumors]]
|-
|-
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |Lungs<ref name="pmid15898407">{{cite journal| author=Beasley MB, Brambilla E, Travis WD| title=The 2004 World Health Organization classification of lung tumors. | journal=Semin Roentgenol | year= 2005 | volume= 40 | issue= 2 | pages= 90-7 | pmid=15898407 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15898407  }} </ref><ref name="pmid18473355">{{cite journal| author=Gustafsson BI, Kidd M, Chan A, Malfertheiner MV, Modlin IM| title=Bronchopulmonary neuroendocrine tumors. | journal=Cancer | year= 2008 | volume= 113 | issue= 1 | pages= 5-21 | pmid=18473355 | doi=10.1002/cncr.23542 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18473355  }} </ref><ref name="pmid18456740">{{cite journal| author=Oberg K, Jelic S, ESMO Guidelines Working Group| title=Neuroendocrine bronchial and thymic tumors: ESMO clinical recommendation for diagnosis, treatment and follow-up. | journal=Ann Oncol | year= 2008 | volume= 19 Suppl 2 | issue=  | pages= ii102-3 | pmid=18456740 | doi=10.1093/annonc/mdn116 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18456740  }} </ref><ref name="pmid1317668">{{cite journal| author=Wick MR, Berg LC, Hertz MI| title=Large cell carcinoma of the lung with neuroendocrine differentiation. A comparison with large cell "undifferentiated" pulmonary tumors. | journal=Am J Clin Pathol | year= 1992 | volume= 97 | issue= 6 | pages= 796-805 | pmid=1317668 | doi=10.1093/ajcp/97.6.796 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1317668  }} </ref>
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Lungs]]
|
|
* Pulmonary neuroendocrine tumors
*[[Pulmonary]] [[neuroendocrine]] [[tumors]]
** Bronchus
**[[Bronchus]]
** Pulmonary carcinoid tumors:
**[[Pulmonary]] [[carcinoid tumors]]:
*** Typical carcinoid (TC; low-grade)  
***[[Typical set|Typical]] [[carcinoid]] (TC; low-[[Grading (tumors)|grade]])
*** Atypical carcinoid (AC; intermediate-grade)
*** Atypical [[carcinoid]] (AC; intermediate-[[Grading (tumors)|grade]])
** Small-cell lung cancer (SCLC)
**[[Small-cell lung cancer]] ([[SCLC]])
** Large cell neuroendocrine carcinoma of the lung (LCNEC)
**[[Large cell neuroendocrine carcinoma of the lung]] ([[LCNEC]])
|-
|-
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |Extrapulmonary  
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |Extrapulmonary  
|
|
* Extrapulmonary small cell carcinomas (ESCC or EPSCC)
* Extrapulmonary [[small cell]] [[carcinomas]] (ESCC or EPSCC)
|-
|-
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |GIT<ref name="pmid11557784">{{cite journal| author=Liu Y, Sturgis CD, Grzybicki DM, Jasnosz KM, Olson PR, Tong M et al.| title=Microtubule-associated protein-2: a new sensitive and specific marker for pulmonary carcinoid tumor and small cell carcinoma. | journal=Mod Pathol | year= 2001 | volume= 14 | issue= 9 | pages= 880-5 | pmid=11557784 | doi=10.1038/modpathol.3880406 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11557784  }} </ref><ref name="pmid15888809">{{cite journal| author=Ramage JK, Davies AH, Ardill J, Bax N, Caplin M, Grossman A et al.| title=Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours. | journal=Gut | year= 2005 | volume= 54 Suppl 4 | issue=  | pages= iv1-16 | pmid=15888809 | doi=10.1136/gut.2004.053314 | pmc=1867801 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15888809  }} </ref><ref name="pmid18803349">{{cite journal| author=Massironi S, Sciola V, Peracchi M, Ciafardini C, Spampatti MP, Conte D| title=Neuroendocrine tumors of the gastro-entero-pancreatic system. | journal=World J Gastroenterol | year= 2008 | volume= 14 | issue= 35 | pages= 5377-84 | pmid=18803349 | doi=10.3748/wjg.14.5377 | pmc=2744160 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18803349  }} </ref><ref name="pmid18177818">{{cite journal| author=Modlin IM, Oberg K, Chung DC, Jensen RT, de Herder WW, Thakker RV et al.| title=Gastroenteropancreatic neuroendocrine tumours. | journal=Lancet Oncol | year= 2008 | volume= 9 | issue= 1 | pages= 61-72 | pmid=18177818 | doi=10.1016/S1470-2045(07)70410-2 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18177818  }} </ref><ref name="pmid18703061">{{cite journal| author=Metz DC, Jensen RT| title=Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors. | journal=Gastroenterology | year= 2008 | volume= 135 | issue= 5 | pages= 1469-92 | pmid=18703061 | doi=10.1053/j.gastro.2008.05.047 | pmc=2612755 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18703061  }} </ref><ref name="pmid21160597">{{cite journal| author=Griniatsos J, Michail O| title=Appendiceal neuroendocrine tumors: Recent insights and clinical implications. | journal=World J Gastrointest Oncol | year= 2010 | volume= 2 | issue= 4 | pages= 192-6 | pmid=21160597 | doi=10.4251/wjgo.v2.i4.192 | pmc=2999180 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21160597  }} </ref><ref name="pmid20380002">{{cite journal| author=Ni SJ, Sheng WQ, Du X| title=Pathologic research update of colorectal neuroendocrine tumors. | journal=World J Gastroenterol | year= 2010 | volume= 16 | issue= 14 | pages= 1713-9 | pmid=20380002 | doi=10.3748/wjg.v16.i14.1713 | pmc=2852818 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20380002  }} </ref><ref name="pmid21160865">{{cite journal| author=Konishi T, Watanabe T, Nagawa H, Oya M, Ueno M, Kuroyanagi H et al.| title=Treatment of colorectal carcinoids: A new paradigm. | journal=World J Gastrointest Surg | year= 2010 | volume= 2 | issue= 5 | pages= 153-6 | pmid=21160865 | doi=10.4240/wjgs.v2.i5.153 | pmc=2999232 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21160865  }} </ref><ref name="pmid12636090">{{cite journal| author=Soga J| title=Primary hepatic endocrinomas (carcinoids and variant neoplasms). A statistical evaluation of 126 reported cases. | journal=J Exp Clin Cancer Res | year= 2002 | volume= 21 | issue= 4 | pages= 457-68 | pmid=12636090 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12636090  }} </ref><ref name="pmid18333038">{{cite journal| author=Nikfarjam M, Muralidharan V, Christophi C| title=Primary hepatic carcinoid tumours. | journal=HPB (Oxford) | year= 2004 | volume= 6 | issue= 1 | pages= 13-7 | pmid=18333038 | doi=10.1080/13651820310017228 | pmc=2020649 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18333038  }} </ref><ref name="pmid8348490">{{cite journal| author=Moriura S, Ikeda S, Hirai M, Naiki K, Fujioka T, Yokochi K et al.| title=Hepatic gastrinoma. | journal=Cancer | year= 1993 | volume= 72 | issue= 5 | pages= 1547-50 | pmid=8348490 | doi=10.1002/1097-0142(19930901)72:5<1547::aid-cncr2820720510>3.0.co;2-c | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8348490  }} </ref><ref name="pmid12725316">{{cite journal| author=Soga J| title=Primary endocrinomas (carcinoids and variant neoplasms) of the gallbladder. A statistical evaluation of 138 reported cases. | journal=J Exp Clin Cancer Res | year= 2003 | volume= 22 | issue= 1 | pages= 5-15 | pmid=12725316 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12725316  }} </ref>
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Gastrointestinal tract|GIT]]
|
|
* Gastroenteropancreatic neuroendocrine tumors (GEP-NET)
* Gastroenteropancreatic [[neuroendocrine]] [[tumors]] (GEP-[[NET1|NET]])
** Foregut GEP-NET (foregut tumors can conceptually encompasses not only NETs of the stomach and proximal duodenum, but also the pancreas, and even thymus, lung and bronchus)
**[[Foregut]] GEP-[[NET1|NET]] ([[foregut]] [[tumors]] can [[Conceptual clustering|conceptually]] encompass not only [[NET1|NETs]] of the [[stomach]] and [[proximal]] [[duodenum]], but also the [[pancreas]], and even [[thymus]], [[lung]] and [[bronchus]])
*** Pancreatic endocrine tumors (if considered separately from foregut GEP-NET)
***[[Pancreatic]] [[endocrine tumors]] (if considered separately from [[foregut]] GEP-[[NET1|NET]])
** Midgut GEP-NET (from distal half of 2nd part of the duodenum to the proximal two-thirds of the transverse colon)
**[[Midgut]] GEP-[[NET1|NET]] (from [[distal]] half of 2nd part of the [[duodenum]] to the [[proximal]] two-thirds of the [[transverse colon]])
*** appendix, including well differentiated NETs (benign); well differentiated NETs (uncertain malignant potential); well differentiated neuroendocrine carcinoma (with low malignant potential); mixed exocrine-neuroendocrine carcinoma (goblet cell carcinoma, also called adenocarcinoid and mucous adenocarcinoid)
***[[Appendix]], including well-[[Differentiate|differentiated]] [[NET1|NETs]] ([[benign]]); well-[[Differentiate|differentiated]] [[NET1|NETs]] (uncertain [[malignant]] [[potential]]); well-[[Differentiate|differentiated]] [[neuroendocrine]] [[carcinoma]] (with low [[malignant]] [[potential]]); [[Mixed-handed|mixed]] [[exocrine]]-[[neuroendocrine]] [[carcinoma]] ([[Goblet cell tumor of appendix|goblet cell carcinoma]], also called adenocarcinoid and [[mucous]] adenocarcinoid)
** Hindgut GEP-NET
**[[Hindgut]] GEP-[[NET1|NET]]
* Liver and gallbladder
*[[Liver]] and [[gallbladder]]
|-
|-
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |Adrenal gland<ref name="pmid16762613">{{cite journal| author=Rufini V, Calcagni ML, Baum RP| title=Imaging of neuroendocrine tumors. | journal=Semin Nucl Med | year= 2006 | volume= 36 | issue= 3 | pages= 228-47 | pmid=16762613 | doi=10.1053/j.semnuclmed.2006.03.007 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16762613  }} </ref><ref name="pmid15053292">{{cite journal| author=Soga J| title=Carcinoids and their variant endocrinomas. An analysis of 11842 reported cases. | journal=J Exp Clin Cancer Res | year= 2003 | volume= 22 | issue= 4 | pages= 517-30 | pmid=15053292 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15053292  }} </ref>
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Adrenal gland]]
|
|
* Adrenal tumors, particularly adrenomedullary tumors
*[[Adrenal tumor|Adrenal tumors]], particularly [[adrenomedullary]] [[tumors]]
* Pheochromocytoma
*[[Pheochromocytoma]]
|-
|-
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |Peripheral nervous system
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Peripheral nervous system]]
|Peripheral nervous system tumors, such as:
|[[Peripheral nervous system]] [[tumors]], such as:
* Schwannoma
 
* Paraganglioma
*[[Schwannoma]]
* Neuroblastoma
*[[Paraganglioma]]
*[[Neuroblastoma]]
|-
|-
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |Mammary gland<ref name="pmid11890336">{{cite journal| author=Soga J, Osaka M, Yakuwa Y| title=Gut-endocrinomas (carcinoids and related endocrine variants) of the breast: an analysis of 310 reported cases. | journal=Int Surg | year= 2001 | volume= 86 | issue= 1 | pages= 26-32 | pmid=11890336 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11890336  }} </ref>
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Mammary gland]]
|
|
* Breast tumors
*[[Breast cancer|Breast tumors]]
|-
|-
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |Genitourinary tract<ref name="pmid17076534">{{cite journal| author=Murali R, Kneale K, Lalak N, Delprado W| title=Carcinoid tumors of the urinary tract and prostate. | journal=Arch Pathol Lab Med | year= 2006 | volume= 130 | issue= 11 | pages= 1693-706 | pmid=17076534 | doi=10.1043/1543-2165(2006)130[1693:CTOTUT]2.0.CO;2 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17076534  }} </ref><ref name="pmid7511278">{{cite journal| author=Mikuz G| title=[Non-urothelial tumors of the urinary tract]. | journal=Verh Dtsch Ges Pathol | year= 1993 | volume= 77 | issue=  | pages= 180-98 | pmid=7511278 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7511278  }} </ref><ref name="pmid11718210">{{cite journal| author=Soga J, Osaka M, Yakuwa Y| title=Gut-endocrinomas (carcinoids and related endocrine variants) of the uterine cervix: an analysis of 205 reported cases. | journal=J Exp Clin Cancer Res | year= 2001 | volume= 20 | issue= 3 | pages= 327-34 | pmid=11718210 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11718210  }} </ref>
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Genitourinary tract]]
|
|
* Urinary tract carcinoid tumor and neuroendocrine carcinoma
*[[Urinary tract]] [[carcinoid tumor]] and [[neuroendocrine]] [[carcinoma]]
* Ovary
*[[Ovary]]
* Neuroendocrine tumor of the cervix
*[[Neuroendocrine]] [[tumor]] of the [[cervix]]
* Testes
*[[Testes]]
|-
|-
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |Skin
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Skin]]
|
|
* Merkel cell carcinoma of skin (trabecular cancer)
*[[Merkel cell carcinoma]] of the [[skin]] ([[trabecular cancer]])
|-
|-
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |Multiple organs involvement in inherited conditions
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |Multiple [[organs]] involvement in [[inherited]] [[conditions]]
|
|
* Several inherited conditions:
* Several [[inherited]] [[conditions]]:
** Multiple endocrine neoplasia type 1 (MEN1)
**[[Multiple endocrine neoplasia type 1]] ([[MEN1]])
** Multiple endocrine neoplasia type 2 (MEN2)
**[[Multiple endocrine neoplasia type 2]] ([[MEN2]])
** Von Hippel-Lindau (VHL) disease
**[[Von Hippel-Lindau Disease|Von Hippel-Lindau (VHL) disease]]
** Neurofibromatosis type 1
**[[Neurofibromatosis type 1]]
** Tuberous sclerosis
**[[Tuberous sclerosis]]
** Carney complex
**[[Carney complex]]
|}
|}


===Classification of GEP-NETs by cell characteristics===
===Classification of GEP-NETs by cell characteristics===


The diverse and amorphous nature of GEP-NETs has led to a confused, overlapping, and changing terminology. In general, aggressiveness (malignancy), secretion (of hormones), and anaplasia (dissimilarity between tumor cells and normal cells) tend to go together, but there are many exceptions, which have contributed to the confusion in terminology. For example, the term ''atypical carcinoid'' is sometimes used to indicate an aggressive tumor without secretions, whether anaplastic or well-differentiated.
* The diverse and [[amorphous]] [[nature]] of GEP-[[NET1|NETs]] has led to a [[Confusion|confused]], overlapping, and [[Change detection|changing]] [[Term logic|terminology]].
 
* In [[General Relativity|general]], [[aggressiveness]] ([[malignancy]]), [[secretion]] (of [[hormones]]), and [[anaplasia]] (dissimilarity between [[Tumor cell|tumor cells]] and [[normal]] [[Cells (biology)|cells]]) tend to go together, but there are many exceptions, which have contributed to the [[confusion]] in [[Term logic|terminology]]. [[Example 1|For example]], the [[Term logic|term]] atypical [[carcinoid]] is sometimes used to [[Indication (medicine)|indicate]] an aggressive [[tumor]] without [[secretions]], whether [[anaplastic]] or well-[[Differentiate|differentiated]].
In 2000, the World Health Organization (WHO) revised the classification of GEP-NETs, abandoning the term ''carcinoid'' in favor of ''neuroendocrine tumor'' (NET) and abandoning ''islet cell tumor'' or ''pancreatic endocrine tumor'' for ''neuroendocrine carcinoma'' (NEC). Judging from papers published into 2006, the medical community is accepting this new terminology with great sluggishness. (Perhaps one reason for the resistance is that the WHO chose to label the least aggressive subclass of neuroendocrine neoplasm with the term&nbsp;&ndash; ''neuroendocrine tumor''&nbsp;&ndash; widely used previously either for the superclass or for the generally aggressive noncarcinoid subclass.)
* In 2000, the [[World Health Organization]] ([[World Health Organization|WHO]]) revised the [[classification]] of GEP-[[NET1|NETs]], abandoning the [[Term logic|term]] [[carcinoid]] in favor of [[neuroendocrine]] [[tumor]] ([[NET1|NET]]) and abandoning [[Islet cell cancer|islet cell tumor]] or [[pancreatic]] [[Endocrine tumors|endocrine tumor]] for [[neuroendocrine]] [[carcinoma]] (NEC).
 
* Judging from papers published into 2006, the [[medical]] community is [[Acceptor|accepting]] this [[new]] [[Term logic|terminology]] with great [[sluggishness]]. (Perhaps one [[Reasoning|reason]] for the [[resistance]] is that the [[World Health Organization|WHO]] chose to [[label]] the least aggressive [[Subclass (biology)|subclass]] of [[neuroendocrine]] [[neoplasm]] with the [[Term logic|term]]&nbsp;&ndash; [[neuroendocrine]] [[tumor]]&nbsp;&ndash; [[Wide and fast|widely]] [[Usage analysis|used]] previously either for the [[Superclass (biology)|superclass]] or for the [[General Relativity|generally]] aggressive noncarcinoid [[Subclass (biology)|subclass]]).
Klöppel ''et alia'' have written an overview that clarifies the WHO classification and bridges the gap to the old terminology (Klöppel, Perren, and Heitz 2004). In this article we conform to the old terminology.
* Klöppel ''et alia'' have [[Writing|written]] an [[overview]] that clarifies the [[World Health Organization|WHO]] [[classification]] and [[Bridge (chemical)|bridges]] the gap to the old [[Term logic|terminology]] (Klöppel, Perren, and Heitz 2004), this old [[Term logic|terminology]] is given in the table below:


====Summary of classification by cell characteristics (the WHO classification)====
====Summary of classification by cell characteristics (the WHO classification)====


* GEP-NETs are also sometimes called ''APUDomas'', but that term is now considered to be misleading, since it is based on a discredited theory of the development of the tumors<ref>
* This classification was done due to peripheral receptors.
*GEP-[[NET1|NETs]] receptors  (''[[APUDoma of skin|APUDomas]]) are the main detected receptors.''  
*That [[Term logic|term]] is now misleading, since it is [[Base|based]] on a discredited [[theory]] of the [[development]] of the [[tumors]].
*It is now known that this receptor may not be indicator of cell origin.<ref>
"The APUD concept led to the belief that these cells arise from the embryologic neural crest. This hypothesis eventually was found to be incorrect" (Warner 2005, 2).
"The APUD concept led to the belief that these cells arise from the embryologic neural crest. This hypothesis eventually was found to be incorrect" (Warner 2005, 2).
<p>
<p>
Line 197: Line 186:
! colspan="5" style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Superclass:Öberg, WHO, Klöppel ''et alia'': Gastro-entero-pancreatic neuroendocrine tumor (GEP-NET)}}
! colspan="5" style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Superclass:Öberg, WHO, Klöppel ''et alia'': Gastro-entero-pancreatic neuroendocrine tumor (GEP-NET)}}
|-
|-
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |'''Subclass 1 (less malignant)'''
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |'''[[Subclass (biology)|Subclass]] 1 (less [[malignant]])'''
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |'''Subclass 2 (more malignant)'''
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |'''[[Subclass (biology)|Subclass]] 2 (more [[malignant]])'''
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |'''Subclass 3 (most malignant)'''
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |'''[[Subclass (biology)|Subclass]] 3 (most [[malignant]])'''
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |'''Subclass 4 (mixed)'''
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |'''[[Subclass (biology)|Subclass]] 4 ([[Mixed-handed|mixed]])'''
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |'''Subclass 5 (miscellaneous)'''
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |'''[[Subclass (biology)|Subclass]] 5 (miscellaneous)'''
|-
|-
|
|
*'''Öberg:''' Carcinoid
*'''Öberg:''' [[Carcinoid]]
*'''WHO:''' Neuroendocrine tumor (NET)
*'''[[WHO]]:''' [[Neuroendocrine]] [[tumor]] ([[NET1|NET]])
*'''Klöppel ''et alia'':''' Well-differentiated neuroendocrine tumor (NET) (carcinoid)
*'''Klöppel ''et alia'':''' Well-[[Differentiate|differentiated]] [[neuroendocrine]] [[tumor]] ([[NET1|NET]]) ([[carcinoid]])
*'''this article:''' Carcinoid
*'''This article:''' [[Carcinoid]]
|
|
*'''Öberg:''' Endocrine pancreatic tumor
*'''Öberg:''' [[Endocrine]] [[pancreatic tumor]]
*'''WHO:''' Neuroendocrine carcinoma (NEC)
*'''[[WHO]]:''' [[Neuroendocrine]] [[carcinoma]] (NEC)
*'''Klöppel ''et alia'':''' Well-differentiated neuroendocrine carcinoma (NEC) (malignant carcinoid)
*'''Klöppel ''et alia'':''' Well-[[Differentiate|differentiated]] [[neuroendocrine]] [[carcinoma]] (NEC) ([[malignant]] [[carcinoid]])
*'''this article:''' Pancreatic endocrine tumor (PET) or endocrine pancreatic tumor (EPT) or islet cell tumor or noncarcinoid GEP-NET
*'''This article:''' [[Pancreatic]] [[Endocrine tumors|endocrine tumor]] ([[PET]]) or [[endocrine]] [[pancreatic tumor]] ([[EPT]]) or [[Pancreatic islet cell carcinoma|islet cell tumor]] or noncarcinoid GEP-[[NET1|NET]]
|
|
*'''WHO:''' Poorly-differentiated neuroendocrine carcinoma
*'''[[WHO]]:''' Poorly-[[Differentiate|differentiated]] [[neuroendocrine]] [[carcinoma]]
*'''Klöppel ''et alia'':''' Poorly-differentiated neuroendocrine carcinoma (high-grade malignant carcinoid)
*'''Klöppel ''et alia'':''' Poorly-[[Differentiate|differentiated]] [[neuroendocrine]] [[carcinoma]] (high-[[Grading (tumors)|grade]] [[malignant]] [[carcinoid]])
|
|
* '''WHO:''' Mixed endocrine/exocrine tumor
* '''[[WHO]]:''' [[Mixed-handed|Mixed]] [[endocrine]]/[[exocrine]] [[tumor]]
|
|
* '''WHO:''' Rare neuroendocrine-like lesions
* '''[[WHO]]:''' [[Rare]] [[neuroendocrine]]-like [[lesions]]
|}
===2010 WHO Classification Of NET===
*2010 [[World Health Organization|WHO]] [[Classification]] of [[neuroendocrine]] [[Tumor|tumors]] with their ICD-O-3 [[Code|codes]] is given below:
{| class="wikitable"
|+2010 World Health Organization International Classification and Distribution of Diseases for Oncology (3rd Ed. (ICD-O-3) Codes of Neuroendocrine Tumors (NETs) in the Gastrointestinal and Pancreatobiliary Tracts)
! colspan="2" style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|NET (Neuroendocrine Tumor) Classification}}
!style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Location}}
!style="background: #4479BA; width: 100px;" | {{fontcolor|#FFF|ICD-O-3 Code}}
|-
| colspan="2" style="padding: 5px 5px; background: #DCDCDC; font-weight: bold"|[[NET1|NET]] [[G1]] ([[Grading (tumors)|Grade]] 1)
|All [[organs]]
|8240/3
|-
| colspan="2" style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[NET1|NET]] [[G2 phase|G2]] ([[Grading (tumors)|Grade]] 2)
|All [[organs]]
|8249/3
|-
| rowspan="3" style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Neuroendocrine]] [[carcinoma]]
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |
|All [[organs]]
|8246/3
|-
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Large cell]] NEC
|All [[organs]]
|8013/3
|-
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Small cell]] NEC
|All [[organs]]
|8041/3
|-
| colspan="2" style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Enterochromaffin cell]] [[serotonin]]-[[Product (biology)|producing]] [[NET1|NET]]
|All [[organs]]
|8241/3
|-
| colspan="2" style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Gastrin]]-[[Product (biology)|producing]] [[NET1|NET]] ([[gastrinoma]])
|[[Stomach]], [[ampulla]], [[small intestine]], [[pancreas]]
|8153/3
|-
| colspan="2" style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Glucagon]]-[[Product (biology)|producing]] [[NET1|NET]] ([[glucagonoma]])
|[[Pancreas]]
|8152/3
|-
| colspan="2" style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |Gangliocytic [[paraganglioma]]
|[[Ampulla]], [[small intestine]]
|8683/0
|-
| colspan="2" style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Somatostatin]]-[[Product (biology)|producing]] [[NET1|NET]] (somatostatinoma)
|[[Ampulla]], [[small intestine]], [[pancreas]]
|8156/3
|-
| colspan="2" style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Insulin]]-[[Product (biology)|producing]] [[NET1|NET]] ([[insulinoma]])
|[[Pancreas]]
|8151/3
|-
| colspan="2" style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[VIPoma]]
|[[Pancreas]]
|8155/3
|-
| colspan="2" style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |L [[Cell (biology)|cell]], [[Glucagon-like peptide-1|Glucagon-like peptide]], and [[PP]]/[[Peptide YY|PYY]]-[[Product (biology)|producing]] [[NET1|NETs]]
|[[Small intestine]], [[appendix]], colorectum
|8152/1
|-
| colspan="2" style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Goblet cell]] [[carcinoid]]
|[[Appendix]], [[Extrahepatic bile ducts|extrahepatic bile duct]]
|8241/3
|-
| colspan="2" style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Tubular]] [[carcinoid]]
|[[Appendix]], [[Extrahepatic bile ducts|extrahepatic bile duct]]
|8245/1
|-
| colspan="2" style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Mixed-handed|Mixed]] adenoneuroendocrine [[carcinoma]] (MANEC)
|All [[organs]]
|8244/3
|-
| colspan="2" style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Neuroendocrine]] microadenoma
|[[Pancreas]]
|8150/0
|}
|}
===WHO Grading criteria for neuroendocrine neoplasms===
*[[WHO]] [[Grading (tumors)|grading]] [[criteria]] for [[neuroendocrine]] [[neoplasms]] is [[Base|based]] upon [[histological]] [[Marker|markers]] for [[cellular]] [[proliferation]] (rather than [[cellular]] [[polymorphism]])<ref name="pmid27259015">{{cite journal| author=Tang LH, Basturk O, Sue JJ, Klimstra DS| title=A Practical Approach to the Classification of WHO Grade 3 (G3) Well-differentiated Neuroendocrine Tumor (WD-NET) and Poorly Differentiated Neuroendocrine Carcinoma (PD-NEC) of the Pancreas. | journal=Am J Surg Pathol | year= 2016 | volume= 40 | issue= 9 | pages= 1192-202 | pmid=27259015 | doi=10.1097/PAS.0000000000000662 | pmc=4988129 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27259015  }} </ref>
* Following table shows the currently recommended [[World Health Organization|WHO]] [[Grading (tumors)|grading]] [[criteria]] for all gastroenteropancreatic [[neuroendocrine]] [[neoplasms]]:<ref name="pmid30098710">{{cite journal| author=Inzani F, Petrone G, Rindi G| title=The New World Health Organization Classification for Pancreatic Neuroendocrine Neoplasia. | journal=Endocrinol Metab Clin North Am | year= 2018 | volume= 47 | issue= 3 | pages= 463-470 | pmid=30098710 | doi=10.1016/j.ecl.2018.04.008 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=30098710  }} </ref><ref name="pmid22967994">{{cite journal| author=Sorbye H, Welin S, Langer SW, Vestermark LW, Holt N, Osterlund P et al.| title=Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. | journal=Ann Oncol | year= 2013 | volume= 24 | issue= 1 | pages= 152-60 | pmid=22967994 | doi=10.1093/annonc/mds276 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22967994  }} </ref><ref name="pmid26113608">{{cite journal| author=Heetfeld M, Chougnet CN, Olsen IH, Rinke A, Borbath I, Crespo G et al.| title=Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms. | journal=Endocr Relat Cancer | year= 2015 | volume= 22 | issue= 4 | pages= 657-64 | pmid=26113608 | doi=10.1530/ERC-15-0119 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26113608  }} </ref><ref name="pmid25723112">{{cite journal| author=Basturk O, Yang Z, Tang LH, Hruban RH, Adsay V, McCall CM et al.| title=The high-grade (WHO G3) pancreatic neuroendocrine tumor category is morphologically and biologically heterogenous and includes both well differentiated and poorly differentiated neoplasms. | journal=Am J Surg Pathol | year= 2015 | volume= 39 | issue= 5 | pages= 683-90 | pmid=25723112 | doi=10.1097/PAS.0000000000000408 | pmc=4398606 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25723112  }} </ref><ref name="pmid26482044">{{cite journal| author=Tang LH, Untch BR, Reidy DL, O'Reilly E, Dhall D, Jih L et al.| title=Well-Differentiated Neuroendocrine Tumors with a Morphologically Apparent High-Grade Component: A Pathway Distinct from Poorly Differentiated Neuroendocrine Carcinomas. | journal=Clin Cancer Res | year= 2016 | volume= 22 | issue= 4 | pages= 1011-7 | pmid=26482044 | doi=10.1158/1078-0432.CCR-15-0548 | pmc=4988130 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26482044  }} </ref><ref name="pmid27169712">{{cite journal| author=La Rosa S, Sessa F, Uccella S| title=Mixed Neuroendocrine-Nonneuroendocrine Neoplasms (MiNENs): Unifying the Concept of a Heterogeneous Group of Neoplasms. | journal=Endocr Pathol | year= 2016 | volume= 27 | issue= 4 | pages= 284-311 | pmid=27169712 | doi=10.1007/s12022-016-9432-9 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27169712  }} </ref><ref name="pmid18360283">{{cite journal| author=Shia J, Tang LH, Weiser MR, Brenner B, Adsay NV, Stelow EB et al.| title=Is nonsmall cell type high-grade neuroendocrine carcinoma of the tubular gastrointestinal tract a distinct disease entity? | journal=Am J Surg Pathol | year= 2008 | volume= 32 | issue= 5 | pages= 719-31 | pmid=18360283 | doi=10.1097/PAS.0b013e318159371c | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18360283  }} </ref><ref name="pmid22967994">{{cite journal| author=Sorbye H, Welin S, Langer SW, Vestermark LW, Holt N, Osterlund P et al.| title=Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. | journal=Ann Oncol | year= 2013 | volume= 24 | issue= 1 | pages= 152-60 | pmid=22967994 | doi=10.1093/annonc/mds276 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22967994  }} </ref><ref name="pmid26482044">{{cite journal| author=Tang LH, Untch BR, Reidy DL, O'Reilly E, Dhall D, Jih L et al.| title=Well-Differentiated Neuroendocrine Tumors with a Morphologically Apparent High-Grade Component: A Pathway Distinct from Poorly Differentiated Neuroendocrine Carcinomas. | journal=Clin Cancer Res | year= 2016 | volume= 22 | issue= 4 | pages= 1011-7 | pmid=26482044 | doi=10.1158/1078-0432.CCR-15-0548 | pmc=4988130 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26482044  }} </ref><ref name="pmid24503751">{{cite journal| author=Basturk O, Tang L, Hruban RH, Adsay V, Yang Z, Krasinskas AM et al.| title=Poorly differentiated neuroendocrine carcinomas of the pancreas: a clinicopathologic analysis of 44 cases. | journal=Am J Surg Pathol | year= 2014 | volume= 38 | issue= 4 | pages= 437-47 | pmid=24503751 | doi=10.1097/PAS.0000000000000169 | pmc=3977000 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24503751  }} </ref>


==Pathophysiology==
{| class="wikitable"
===The neuroendocrine system===
|+2017 World Health Organization Classification of Neuroendocrine Tumors (NETs) in the GIT and Pancreatobiliary Tracts (PanNETs)
! style="background: #4479BA; width: 150px;" | {{fontcolor|#FFF|Grade/Classification}}
!style="background: #4479BA; width: 100px;" | {{fontcolor|#FFF|Mitotic Count/ 10 HPFs (High-Power Field)}}
!style="background: #4479BA; width: 100px;" | {{fontcolor|#FFF|Ki-67 Labeling Index, %}}
!style="background: #4479BA; width: 150px;" | {{fontcolor|#FFF|Traditional}}
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Neuroendocrine]] [[neoplasm]] GX
| colspan="3" |[[Grading (tumors)|Grade]] cannot be [[Assessment and Plan|assessed]]
|-
| colspan="4" style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |'''Well-[[Differentiate|differentiated]] [[GIT]] [[NET1|NETs]] & PanNENs: [[Pancreatic]] [[neuroendocrine]] [[tumors]] (PanNETs)'''
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Neuroendocrine]] [[tumor]], [[Grading (tumors)|Grade]] 1 and PanNET G1 (low [[Grading (tumors)|grade]])
|<2
|<3
|
*[[Carcinoid tumor]]
*[[Pancreatic islet cell carcinoma|Islet cell neuroendocrine tumor]]
*[[Pancreatic]] [[neuroendocrine]] [[tumor]]
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Neuroendocrine]] [[tumor]], [[Grading (tumors)|Grade]] 2 and PanNET G2 (intermediate [[Grading (tumors)|grade]])
|2–20
|3–20
|
*[[Carcinoid tumor]]
* Atypical [[carcinoid tumor]] (intermediate-[[Grading (tumors)|grade]] [[neuroendocrine]] [[tumors]] of the [[lung]])
*[[Pancreatic islet cell carcinoma|Islet cell neuroendocrine tumor]]
*[[Pancreatic]] [[neuroendocrine]] [[tumor]]
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |PanNET G3
|>20
|>20
|_
|-
| colspan="4" style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |'''Poorly [[Differentiate|differentiated]] PanNENs: [[Pancreatic]] [[neuroendocrine]] [[carcinomas]] (PanNECs)'''
|-
| rowspan="2" style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |'''[[Neuroendocrine]] [[carcinoma]], [[Grading (tumors)|Grade]] 3''' and
'''PanNEC G3 (high [[Grading (tumors)|grade]])'''
| rowspan="2" |>20
| rowspan="2" |>20
|[[Small cell]] [[carcinoma]]
|-
|[[Large cell]] [[neuroendocrine]] [[carcinoma]]
|-
| colspan="4" style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |'''[[Mixed-handed|Mixed]] [[neuroendocrine]]-non-[[neuroendocrine]] [[neoplasm]] (MiNEN)'''
|}


The endocrine system is a communication system in which [[hormones]] act as biochemical messengers to regulate physiological events in living organisms. The nervous system performs the same functions using electrical impulses as messengers. The [[neuroendocrine system]] is the combination of those two systems, or more specifically, the various interfaces between the two systems. A GEP-NET is a tumor of any such interface.
{| class="wikitable"
|+Classification of Gastric Enterochromaffin-Like Cell Histamine-Producing Neuroendocrine Tumors
!style="background: #4479BA; width: 150px;" | {{fontcolor|#FFF|Classification}}
!style="background: #4479BA; width: 100px;" | {{fontcolor|#FFF|I}}
!style="background: #4479BA; width: 100px;" | {{fontcolor|#FFF|II}}
!style="background: #4479BA; width: 100px;" | {{fontcolor|#FFF|III}}
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Incidence]], %
|55–88
|8–13
|12–23
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |Multifocality
|Multiple
|Multiple
|Single
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |Peritumoral [[Oxyntic cells|oxyntic]] [[mucosa]]
|[[Atrophic]]
|[[Hypertrophic]]
|[[Normal]]
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Size consistency|Size]], [[Centimetre|cm]]
|0.5–1
|<2
|>2
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Location parameter|Location]]
|Corpus
|Corpus
|Any
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Sex (activity)|Sex]]
|[[Male|M]] < [[Female|F]]
|[[Male|M]] = [[Female|F]]
|[[Male|M]] > [[Female|F]]
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |Hypergastrinemia
|Yes
|Yes
|No
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Antrum|Antral]] [[G-cells|G-cell]] [[hyperplasia]]
|Yes
|No
|No
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Association (statistics)|Associated]] [[disease]]
|
*[[Chronic atrophic gastritis]]
|
*[[Multiple endocrine neoplasia type 1|Multiple endocrine neoplasia 1]]
*[[Zollinger-Ellison syndrome|Zollinger–Ellison syndrome]]
|No
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Precursor]] [[lesion]]
|Yes
|Yes
|No
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[World Health Organization|WHO]] 2010 [[classification]]
|[[Grading (tumors)|Grade]] 1
|[[Grading (tumors)|Grades]] 1 or 2
|[[Grading (tumors)|Grades]] 1–3
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Lymph node]] [[metastasis]], %
|5
|30
|70
|}<br />
{| class="wikitable"
|+'''Comparison of the WHO classifications of pancreatic neuroendocrine neoplasms'''
!style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|'''WHO 1980'''}}
!style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|'''WHO 2000/2004'''}}
!style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|'''WHO 2010'''}}
!style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|'''WHO 2017'''}}
|-
|[[Pancreatic islet cell carcinoma|Islet cell tumor]] ([[adenoma]]/[[carcinoma]])
|Well-[[Differentiate|differentiated]] [[Endocrine tumors|endocrine tumor]]/[[carcinoma]] (WDET/WDEC)
|[[NET1|NET]] [[G1]]/[[G2 phase|G2]]
|[[NET1|NET]] [[G1]]/[[G2 phase|G2]]/G3 (well-[[Differentiate|differentiated]] NEN)
|-
|Poorly [[Differentiate|differentiated]] [[endocrine]] [[carcinoma]]
|Poorly [[Differentiate|differentiated]] [[endocrine]] [[carcinoma]]/[[small cell]] [[carcinoma]] (PDEC)
|NEC (G3), [[large cell]] or [[small cell]] type
|NEC (G3), [[large cell]] or [[small cell]] type (poorly [[Differentiate|differentiated]] NEN)
|-
|_
|[[Mixed-handed|Mixed]] [[exocrine]]-[[endocrine]] [[carcinoma]] (MEEC)
|[[Mixed-handed|Mixed]] adenoneuroendocrine [[carcinoma]]
|[[Mixed-handed|Mixed]] [[neuroendocrine]]-non-[[neuroendocrine]] [[neoplasm]]
|-
|Pseudotumor [[lesions]]
|[[Tumor]]-like [[lesions]] (TLLs)
|[[Hyperplastic]] and preneoplastic [[lesions]]
|_
|}


More specifically, the endocrine system is primarily a network of glands that produce and secrete hormones, usually into the bloodstream. It also includes cells that are not part of glands: the diffuse neuroendocrine system, scattered throughout other organs.
==Pathophysiology==
 
===Neuroendocrine system===
A hormone is a chemical that delivers a particular message to a particular organ, typically remote from the hormone's origin. For example, the hormone [[insulin]], secreted by the [[pancreas]], acts primarily to allow glucose to enter the body's cells for use as fuel. The hormone [[gastrin]] is secreted by the [[stomach]] to tell the stomach to produce acids to digest food.
 
Hormones can be divided into subtypes such as [[peptides]], [[steroids]], and [[amine|neuroamines]]. For some researchers, there is no clear distinction between peptide hormones and peptides; the hormones are simply longer than other peptides. In the context of GEP-NETs, the terms ''hormone'' and ''peptide'' are often used interchangeably.
 
The vast majority of GEP-NETs fall into two nearly distinct categories: [[carcinoid]]s, and pancreatic endocrine tumors (PETs). Despite great behavioral differences between the two, they are grouped together as GEP-NETs because of similarities in cell structure.


<ref>
*[[Endocrine system]] is a signaling [[system]] made of a [[Network effect|network]] of [[glands]] that metabolize hormones.
*It secrete hormones in order to lead a series of [[intracellular]] [[cascade]] to get an appropriate response .<ref name="pmid25161467">{{cite journal |vauthors=Oladejo AO |title=GASTROENTEROPANCREATIC NEUROENDOCRINE TUMORS (GEP-NETs) - APPROACH TO DIAGNOSIS AND MANAGEMENT |journal=Ann Ib Postgrad Med |volume=7 |issue=2 |pages=29–33 |date=December 2009 |pmid=25161467 |pmc=4111010 |doi= |url=}}</ref>
*[[Neuroendocrine system]] is actually a [[Combination tone|combination]] of both endocrine and nervous system.
*these two [[systems]] have various [[interfaces]] in order to control many functions, specially in [[Gastrointestinal]] system.
*Gastrointestinal neuroendocrine sustem (GEP-[[NET1|NET]]) is a [[tumor]] of gastrointestinal and neuroendocrine system.
* Some of these malignant cells do not form a [[gland]] and are consistent in organ as different cells. (Like G cells in [[stomach]].)
*[[Hormones]] are divided into further sub-types based on their chemical structure:
**[[Peptides]]/[[peptide hormones]]
**[[steroids]]
**[[amine|neuroamines]]
* The vast majority of GEP-[[NET1|NETs]] [[fall]] are further devided in two [[Distinctive feature|distinct]] [[categories]]:
**[[carcinoid]]s
**[[pancreatic]] [[endocrine tumors]] ([[PET|PETs]]).
* Despite great difference in hormone made and the action of these two , they are [[Group (sociology)|grouped]] together as GEP-[[NET1|NETs]] because of [[Similarity matrix|similarities]] in [[cell]] [[Structure factor|structure]].<ref>
"The main two groups of neuroendocrine GEP tumours are so-called carcinoid tumours and endocrine pancreatic tumours" (Öberg 2005a, 90, ).
"The main two groups of neuroendocrine GEP tumours are so-called carcinoid tumours and endocrine pancreatic tumours" (Öberg 2005a, 90, ).
<p>
<p>
Line 246: Line 463:
Another way to classify GEP-NETs is to separate those that begin in the glandular neuroendocrine system from those that begin in the diffuse neuroendocrine system. "Neuroendocrine tumors generally may be classified into two categories. The first category is an organ-specific group arising from neuroendocrine organs such as pituitary gland, thyroid, pancreas, and adrenal gland. The second group arises from the diffuse neuroendocrine cells/Kulchitsky cells that are widely distributed throughout the body and are highly concentrated in the pulmonary and gastrointestinal systems" (Liu ''et al.'' 2001, [http://www.nature.com/modpathol/journal/v14/n9/full/3880406a.html]).
Another way to classify GEP-NETs is to separate those that begin in the glandular neuroendocrine system from those that begin in the diffuse neuroendocrine system. "Neuroendocrine tumors generally may be classified into two categories. The first category is an organ-specific group arising from neuroendocrine organs such as pituitary gland, thyroid, pancreas, and adrenal gland. The second group arises from the diffuse neuroendocrine cells/Kulchitsky cells that are widely distributed throughout the body and are highly concentrated in the pulmonary and gastrointestinal systems" (Liu ''et al.'' 2001, [http://www.nature.com/modpathol/journal/v14/n9/full/3880406a.html]).
</ref>
</ref>
*<nowiki/>[[Pancreatic]] [[endocrine tumors]] (PETs) are also known as [[endocrine]] [[Pancreatic tumor|pancreatic tumors]] (EPTs) or [[Pancreatic islet cell carcinoma|islet cell tumors]].
*further classification of gasterointestinal  neuroendocrine tumors is based on:
**[[Secretory component|Secretory]] [[tumors]] are [[Classification|classified]] by the dominant [[hormone]] secreted hormone.
**[[Origin (anatomy)|origin]], as [[foregut]] ([[lung]], [[thymus]], [[stomach]], and [[duodenum]]) or [[midgut]] ([[distal]] [[ileum]] and [[proximal]] [[Colon (anatomy)|colon]]) or [[hindgut]] ([[distal]] [[Colon (anatomy)|colon]] and [[rectum]]).
*[[Carcinoid tumors]] ([[serotonin]] secreting) tend to [[Growth|grow]] much more [[Slow|slowly]] than PETs.


Pancreatic endocrine tumors (PETs) are also known as endocrine pancreatic tumors (EPTs) or islet cell tumors. PETs are assumed to originate generally in the [[islets of Langerhans]] within the pancreas&nbsp;&ndash; or, Arnold ''et alia'' suggest, from endocrine pancreatic precursor cells (Arnold ''et al.'' 2004, 199) &nbsp;&ndash; though they may originate outside of the pancreas. (The term ''[[pancreatic cancer]]'' almost always refers to ''adenopancreatic cancer'', also known as ''exocrine pancreatic cancer''. Adenopancreatic cancers are generally very aggressive, and are not a neuroendocrine cancers. About 95 percent of pancreatic tumors are adenopancreatic; about 1 or 2 percent are GEP-NETs.)
* In the context of GEP-[[NET1|NETs]], the [[Term logic|terms]] ''[[metastatic]]'' and ''[[malignant]]'' are often [[Usage analysis|used]] interchangeably.
* GEP-[[NET1|NETs]] are often [[malignant]], since the primary site often eludes [[Detection theory|detection]] for [[Year|years]], sometimes decades&nbsp;&ndash; during which [[Time constant|time]] the [[tumor]] has the opportunity to [[metastasize]].
*[[Research|Researchers]] [[Difference (philosophy)|differ]] [[Wide and fast|widely]] in their [[Estimate|estimates]] of [[malignancy]] [[rates]], especially at the [[Level of measurement|level]] of the [[Secretory component|secretory]] subtypes (the various "-omas").
* The most common [[metastatic]] sites are the [[liver]], the [[lymph nodes]], and the [[bones]].
*[[Liver]] [[metastases]] are so [[Frequentist|frequent]] and so [[WellPoint|well]]-fed that for many [[patients]], they dominate the [[Course (medicine)|course]] of the [[Cancer (disease)|cancer]].
* For a [[patient]] with a nonsecretory [[PET]], for [[Example 1|example]], the primary threat to [[life]] may be the sheer bulk of the [[tumor]] [[Loading dose|load]] in the [[liver]].


==Causes==
* In the [[normal]] [[pancreas]], [[Islet cell|islet cells]] [[Product (biology)|produce]] [[hormones]] that [[Regulatory elements|regulate]] a variety of [[Human body|bodily]] [[Function (biology)|functions]], such as the [[control]] of [[blood sugar]] [[Leveling effect|level]] and [[stomach]] [[acid]] [[Product (chemistry)|production]].
*[[Islet cell]] [[tumors]] include:
**[[Gastrinoma|Gastrinomas]] ([[Zollinger-Ellison syndrome]])
**[[Glucagonoma|Glucagonomas]]
**[[Insulinoma|Insulinomas]]
*The [[Exact test|exact]] [[Causes|cause]] of [[neuroendocrine]] [[tumors]] is [[Cancer of unknown primary origin|unknown]].
*Different [[DNA mutations]] in [[neuroendocrine cells]] is supposed to be one of the [[causes]] of [[neuroendocrine]] [[tumors]].
*Various [[hereditary]] [[syndromes]] [[Association (statistics)|associated]] with [[Gastrointestinal tract|GIT]] and pancreatobiliary [[Tract (anatomy)|tract]] [[NET1|NETs]] are mentioned in [[Detailed balance|detail]] in the table below:


PETs may secrete hormones (as a result, perhaps, of impaired storage ability), and those hormones can wreak symptomatic havoc on the body. Those PETs that do not secrete hormones are called ''nonsecretory'' or ''nonfunctioning'' or ''nonfunctional'' tumors. Secretory tumors are classified by the hormone most strongly secreted&nbsp;&ndash; for example, insulinoma, which produces excessive insulin, and gastrinoma, which produces excessive gastrin (see more detail in the summary below).  
{| class="wikitable"
|+Hereditary Syndromes Associated With Gastrointestinal (GI) and Pancreatobiliary Tract Neuroendocrine Tumors (NETs)
!style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Name of the syndrome}}
!style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Pattern of inheritance}}
!style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Chromosomal Band Location}}
!style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Gene/ Protein Involved}}
!style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|GIT and Pancreatobiliary Tract NETs}}
!style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Other Tumors of GIT and Pancreatobiliary Tract}}
!style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Clinical Presentation Outside GIT and Pancreatobiliary Tract}}
|-
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Multiple endocrine neoplasia type 1|Multiple endocrine neoplasia 1]] ([[MEN 1]])
|
*[[Autosomal]] [[Dominant]]
|
* 11q13.1
|
*[[MEN1]]/ menin
|
* Nonfunctional


Carcinoid tumors are further classified, depending on the point of origin, as foregut ([[lung]], [[thymus]], [[stomach]], and [[duodenum]]) or midgut (distal [[ileum]] and proximal [[Colon (anatomy)|colon]]) or hindgut (distal colon and [[rectum]]). Less than one percent of carcinoid tumors originate in the pancreas. But for many tumors, the point of origin is unknown.
Maybe [[Association (statistics)|associated]] with multiple:


Carcinoid tumors, which secrete serotonin tend to grow much more slowly than PETs. Although this serotonin secretion is entirely different from a secretory PET's hormone secretion, [[carcinoid tumors]] with carcinoid syndrome are nevertheless sometimes called ''functioning'', adding to the frequent confusion of carcinoids with PETs. Carcinoid syndrome is primarily associated with midgut carcinoids. A severe episode of carcinoid syndrome is called ''carcinoid crisis''; it can be triggered by surgery or chemotherapy, among other factors. <ref>Larry Kvols, of the [[Moffitt Cancer Center and Research Institute]] in Tampa, Florida, lists flushing, diarrhea, CHF, and asthma as the four critical characteristics of carcinoid syndrome (Kvols 2002, [http://www.carcinoid.org/pcf/lectures/docs/KVOLS.htm]). </ref>
*[[Gastric]] [[NET1|NETs]] ([[gastrinoma]])
*[[Duodenal]] [[NET1|NETs]]
*[[Pancreatic]] [[NET1|NETs]] ([[insulinoma]])
|
*[[Esophageal]] [[leiomyoma]]
|More commonly:


The mildest of the carcinoids are discovered only upon surgery for unrelated causes. These ''coincidental carcinoids'' are common; one study found that one person in ten has them. <ref>
*[[Pituitary adenoma]]
"[In] 800 autopsy cases, ... incidence of tumor was 10% (6/60) in individuals having histological studies of all sections of the pancreas" (Kimura, Kuroda, and Morioka 1991, [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=2070707]).
*[[Parathyroid]] [[hyperplasia]] [[Lead|leading]] to [[primary hyperparathyroidism]]
<p>
Small tumors are not necessarily harmless: Rodney Pommier tells of a "chick pea-sized tumor causing [so much] hormonal effect" that the patient was wheelchair-bound, unable to walk (Pommier 2003, [http://www.carcinoid.org/pcf/lectures/docs/Pommier.htm]).
</ref>


Neuroendocrine tumors other than coincidental carcinoids are rare. Incidence of PETs is estimated at one new case per 100,000 people per year; incidence of clinically significant carcinoids is twice that. Thus the total incidence of GEP-NETs in the United States would be about 9,000 new cases per year. But researchers differ widely in their estimates of incidence, especially at the level of the secretory subtypes (the various "-omas").
Less commonly:


*[[Bronchial]] [[NET1|NET]]
*[[Thymic]] [[NET1|NET]]
*[[Adrenal]] [[Cortical area|cortical]] [[adenoma]]/[[tumors]]
*[[Carcinoid tumors]]
*Nonmedullary [[Thyroid tumor|thyroid tumors]]
|-
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Von Hippel-Lindau disease|von Hippel-Lindau disease/syndrome]] ([[VHL]])
|
*[[Autosomal]] [[Dominant]]
|
* 3p25.3
|
*[[VHL]]/ [[VHL]]
|
* Nonfunctional or
*[[Pancreatic]] [[clear cell]] [[NET1|NETs]]
|
*[[Pancreas]] [[serous]] [[cyst]] [[adenomas]]
|
*[[CNS]] or [[cerebellar]] [[Hemangioblastoma|hemangioblastomas]]
*[[Retinal]] [[Hemangioblastoma|hemangioblastomas]]
*[[Renal]] [[Clear cell tumor|clear cell carcinomas]]
*[[Pheochromocytoma|Pheochromocytomas]] (often [[bilateral]])
*[[Adrenal]] [[Cortical area|cortical]] [[adenomas]]
|-
|style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Neurofibromatosis type I|Neurofibromatosis 1]]
([[von Recklinghausen disease]])
|
*[[Autosomal]] [[Dominant]]
|
* 17q11.2
|
*[[NF1]]/ [[neurofibromin]]
|
*[[Duodenal]] [[somatostatin]] [[Product (biology)|producing]] [[NET1|NETs]]
*[[Pancreatic]] [[somatostatin]] [[Product (biology)|producing]] [[NET1|NETs]]
|
*[[Gastrointestinal stromal tumor]] ([[GIST]])
*[[Neurofibroma|Neurofibromas]]
|
*[[Neurofibromatosis]]
*[[Café au lait spot|Cafe´ au lait spots]]
*[[Optic nerve gliomas]]
*[[Pheochromocytoma]]
|-
| rowspan="2" style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Tuberous sclerosis]]
| rowspan="2" |
*[[Autosomal]] [[Dominant]]
|
* 9q34.13
|
*[[TSC1]]/ [[hamartin]]
| rowspan="2" |
*[[Pancreatic]] [[insulin]] [[Product (biology)|producing]] [[NET1|NETs]]
*[[Pancreatic]] [[somatostatin]] [[Product (biology)|producing]] [[NET1|NETs]]
| rowspan="2" |
*[[Hamartomatous]] [[polyp]]
| rowspan="2" |
*[[Hamartomas]] involving multiple [[organs]]
*[[Cardiac rhabdomyoma|Cardiac rhabdomyomas]]
*[[Angiomyolipoma|Angiomyolipomas]]
*[[Renal cysts]]
|-
|
* 16p13.3
|
*[[TSC2]]/ [[tuberin]]
|}
Other [[familial]] [[syndromes]] [[Association (statistics)|associated]] with [[neuroendocrine]] [[neoplasms]] are:


In addition to the two main categories, there are even rarer forms of GEP-NETs. At least one form&nbsp;&ndash; neuroendocrine lung tumors&nbsp;&ndash; arises from the respiratory rather than the gastro-entero-pancreatic system.
*[[Multiple endocrine neoplasia, type 2|Multiple Endocrine Neoplasia type 2]] ([[MEN2]])
*[[Carney complex]]


Non-human animals also suffer from GEP-NETs; for example, neuroendocrine cancer of the liver is a disease of dogs, and Devil facial tumor disease is a neuroendocrine tumor of Tasmanian Devils.  
==Epidemiology and Demographics==
===Lung NETs===
*The portion of [[lung]] [[neuroendocrine]] [[tumors]] ([[NET1|NETs]]) is approximately 1 to 2% of [[lung]] [[malignancies|malignancy]] in [[Adult|adults]] and  30% of [[neuroendocrine]] tumores.<ref name="pmid28448665">{{cite journal| author=Dasari A, Shen C, Halperin D, Zhao B, Zhou S, Xu Y et al.| title=Trends in the Incidence, Prevalence, and Survival Outcomes in Patients With Neuroendocrine Tumors in the United States. | journal=JAMA Oncol | year= 2017 | volume= 3 | issue= 10 | pages= 1335-1342 | pmid=28448665 | doi=10.1001/jamaoncol.2017.0589 | pmc=5824320 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28448665  }} </ref>
*Annual [[incidence]] of [[lung]] [[NET1|NETs]] was 1.49 per 100,000 [[population]] between 2000 and 2012 according to the [[United States]] Surveillance, [[Epidemiology]], and [[End-group|End]] [[Result|Results]] ([[SEER]]) [[database]].
*[[Lung]] [[NET1|NETs]] are considered to be the most common primary [[lung neoplasm]] in [[children]] with [[Typical set|typical]] [[Presenting symptom|presentation]] in [[late adolescence]].<ref name="pmid11697843">{{cite journal| author=Quaedvlieg PF, Visser O, Lamers CB, Janssen-Heijen ML, Taal BG| title=Epidemiology and survival in patients with carcinoid disease in The Netherlands. An epidemiological study with 2391 patients. | journal=Ann Oncol | year= 2001 | volume= 12 | issue= 9 | pages= 1295-300 | pmid=11697843 | doi=10.1023/a:1012272314550 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11697843  }} </ref><ref name="pmid12569593">{{cite journal| author=Modlin IM, Lye KD, Kidd M| title=A 5-decade analysis of 13,715 carcinoid tumors. | journal=Cancer | year= 2003 | volume= 97 | issue= 4 | pages= 934-59 | pmid=12569593 | doi=10.1002/cncr.11105 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12569593  }} </ref><ref name="pmid11596039">{{cite journal| author=Hemminki K, Li X| title=Incidence trends and risk factors of carcinoid tumors: a nationwide epidemiologic study from Sweden. | journal=Cancer | year= 2001 | volume= 92 | issue= 8 | pages= 2204-10 | pmid=11596039 | doi=10.1002/1097-0142(20011015)92:8<2204::aid-cncr1564>3.0.co;2-r | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11596039  }} </ref><ref name="pmid18853416">{{cite journal| author=Hauso O, Gustafsson BI, Kidd M, Waldum HL, Drozdov I, Chan AK et al.| title=Neuroendocrine tumor epidemiology: contrasting Norway and North America. | journal=Cancer | year= 2008 | volume= 113 | issue= 10 | pages= 2655-64 | pmid=18853416 | doi=10.1002/cncr.23883 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18853416  }} </ref>
*[[Average]] [[adult]] [[age]] at the [[Time constant|time]] of [[diagnosis]] of a [[Typical set|typical]] [[lung]] [[NET1|NET]] is 45 [[Year|years]], whereas [[patients]] with atypical [[tumors]] are approximately 10 [[Year|years]] [[Old age|older]].<ref name="pmid12140134">{{cite journal| author=Skuladottir H, Hirsch FR, Hansen HH, Olsen JH| title=Pulmonary neuroendocrine tumors: incidence and prognosis of histological subtypes. A population-based study in Denmark. | journal=Lung Cancer | year= 2002 | volume= 37 | issue= 2 | pages= 127-35 | pmid=12140134 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12140134  }} </ref><ref name="pmid21256263">{{cite journal| author=Cao C, Yan TD, Kennedy C, Hendel N, Bannon PG, McCaughan BC| title=Bronchopulmonary carcinoid tumors: long-term outcomes after resection. | journal=Ann Thorac Surg | year= 2011 | volume= 91 | issue= 2 | pages= 339-43 | pmid=21256263 | doi=10.1016/j.athoracsur.2010.08.062 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21256263  }} </ref>
*[[Incidence rate|Incidence]]  of [[lung]] [[NET1|NETs]] differs  from 0.2 to 2 per 100,000 [[population]] per [[year]] .
*There's a [[Higher Power|higher]] [[incidence]] of [[lung]] [[NET1|NETs]] in [[Womens Pack|women]] as [[Comparability|compared]] to [[men]].
*Lung NET has annual [[Incidence rate|incidence rates]] of 0.2 and 1.3 per 100,000 [[population]] among [[men]] and [[Womens Pack|women]] respectively.
*[[White (mutation)|White]] [[People's Solidarity|people]] have [[Higher Power|higher]] [[incidence]] of [[lung]] [[NET1|NETs]] as [[Comparability|compared]] to [[black]] [[People's Solidarity|people]].<ref name="pmid11399686">{{cite journal| author=Fink G, Krelbaum T, Yellin A, Bendayan D, Saute M, Glazer M et al.| title=Pulmonary carcinoid: presentation, diagnosis, and outcome in 142 cases in Israel and review of 640 cases from the literature. | journal=Chest | year= 2001 | volume= 119 | issue= 6 | pages= 1647-51 | pmid=11399686 | doi=10.1378/chest.119.6.1647 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11399686  }} </ref><ref name="pmid16455477">{{cite journal| author=Gatta G, Ciccolallo L, Kunkler I, Capocaccia R, Berrino F, Coleman MP et al.| title=Survival from rare cancer in adults: a population-based study. | journal=Lancet Oncol | year= 2006 | volume= 7 | issue= 2 | pages= 132-40 | pmid=16455477 | doi=10.1016/S1470-2045(05)70471-X | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16455477  }} </ref><ref name="pmid28448665">{{cite journal| author=Dasari A, Shen C, Halperin D, Zhao B, Zhou S, Xu Y et al.| title=Trends in the Incidence, Prevalence, and Survival Outcomes in Patients With Neuroendocrine Tumors in the United States. | journal=JAMA Oncol | year= 2017 | volume= 3 | issue= 10 | pages= 1335-1342 | pmid=28448665 | doi=10.1001/jamaoncol.2017.0589 | pmc=5824320 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28448665  }} </ref>


===Digestive system NETs===
*Annual [[incidence]] of [[digestive system]] [[NET1|NETs]] is 3.56 per 100,000 in United States approximately.
*[[Digestive system]] [[NET1|NENs]] of the [[tubular]] [[gastrointestinal tract]] and [[pancreas]] are [[Relatively compact|relatively]] rare with an [[incidence]] of ≤1 case per 100,000 [[Individual growth|individuals]] per [[year]]..<ref name="pmid28448665">{{cite journal| author=Dasari A, Shen C, Halperin D, Zhao B, Zhou S, Xu Y et al.| title=Trends in the Incidence, Prevalence, and Survival Outcomes in Patients With Neuroendocrine Tumors in the United States. | journal=JAMA Oncol | year= 2017 | volume= 3 | issue= 10 | pages= 1335-1342 | pmid=28448665 | doi=10.1001/jamaoncol.2017.0589 | pmc=5824320 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28448665  }} </ref>
*[[Pancreatic]] [[NET1|NETs]] account for 1 to 2% (<3%) of all primary [[Pancreatic neoplasm|pancreatic neoplasms]].<ref name="pmid20058030">{{cite journal| author=Ito T, Sasano H, Tanaka M, Osamura RY, Sasaki I, Kimura W et al.| title=Epidemiological study of gastroenteropancreatic neuroendocrine  tumors in Japan. | journal=J Gastroenterol | year= 2010 | volume= 45 | issue= 2 | pages= 234-43 | pmid=20058030 | doi=10.1007/s00535-009-0194-8 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20058030  }} </ref><ref name="pmid24499825">{{cite journal| author=Ito T, Igarashi H, Nakamura K, Sasano H, Okusaka T, Takano K et al.| title=Epidemiological trends of pancreatic and gastrointestinal neuroendocrine tumors in Japan: a nationwide survey analysis. | journal=J Gastroenterol | year= 2015 | volume= 50 | issue= 1 | pages= 58-64 | pmid=24499825 | doi=10.1007/s00535-014-0934-2 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24499825  }} </ref><ref name="pmid18536315">{{cite journal| author=Ito T, Tanaka M, Imamura M, Neuroendocrine Tumor Workshop Japan| title=[Results of a nationwide survey of gastrointestinal tumors in Japan]. | journal=Nihon Geka Gakkai Zasshi | year= 2008 | volume= 109 | issue= 3 | pages= 128-32 | pmid=18536315 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18536315  }} </ref><ref name="pmid17671766">{{cite journal| author=Ito T, Tanaka M, Sasano H, Osamura YR, Sasaki I, Kimura W et al.| title=Preliminary results of a Japanese nationwide survey of neuroendocrine gastrointestinal tumors. | journal=J Gastroenterol | year= 2007 | volume= 42 | issue= 6 | pages= 497-500 | pmid=17671766 | doi=10.1007/s00535-007-2056-6 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17671766  }} </ref>
*Following is a table that shows [[Association (statistics)|association]] of different [[diseases]] with the [[incidence]] of [[pancreatic]] [[NET1|NETs]]:


Rufini ''et alia'' summarize: "Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms originating from endocrine cells, which are characterized by the presence of secretory granules as well as the ability to produce biogenic amines and polypeptide hormones. These tumors originate from endocrine glands such as the adrenal medulla, the pituitary, and the parathyroids, as well as endocrine islets within the thyroid or the pancreas, and dispersed endocrine cells in the respiratory and gastrointestinal tract. The clinical behavior of NETs is extremely variable; they may be functioning or not functioning, ranging from very slow-growing tumors (well-differentiated NETs), which are the majority, to highly aggressive and very malignant tumors (poorly differentiated NETs).... Classically, NETs of the gastrointestinal tract are classified into 2 main groups: (1) carcinoids,&nbsp;... and (2) endocrine pancreatic tumors (EPTs)" (Rufini, Calcagni, and Baum 2006). (Note that the definition of ''well-differentiated'' may be counterintuitive: a tumor is well-differentiated if its cells are similar to normal cells, which have a well-differentiated structure of nucleus, cytoplasm, membrane, etc.)
{| class="wikitable"
|+
! style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Disease/Syndrome}}
! style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|% chance of developing Pancreatic NET}}
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Multiple endocrine neoplasia type 1|Multiple endocrine neoplasia 1]] '''('''[[MEN 1]]''')'''
|80-100%
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Von Hippel-Lindau disease|von Hippel-Lindau disease/syndrome]] '''('''[[VHL]]''')'''
|20%
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Neurofibromatosis type I|Neurofibromatosis 1]]
([[von Recklinghausen disease]])
|10%
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Tuberous sclerosis]]
|1%
|}


Ramage ''et alia'' provide a summary that differs somewhat from that of Rufini ''et alia'': "NETs ... originate from pancreatic islet cells, gastroenteric tissue (from diffuse neuroendocrine cells distributed throughout the gut), neuroendocrine cells within the respiratory epithelium, and parafollicullar cells distributed within the thyroid (the tumours being referred to as medullary carcinomas of the thyroid). Pituitary, parathyroid, and adrenomedullary neoplasms have certain common characteristics with these tumours but are considered separately" (Ramage ''et al.'' 2005, [http://gut.bmj.com/cgi/content/full/54/suppl_4/iv1]).
==Risk factors==
[[Fewmets|Few]] of the [[risk factors]] for [[neuroendocrine]] [[tumors]] include:


===Metastases and malignancy===
*[[Smoking]] is a [[risk factor]] for both [[lung]] and [[pancreatic]] [[NET1|NETs]] especially in case of atypical [[tumors]].<ref name="pmid11399686">{{cite journal| author=Fink G, Krelbaum T, Yellin A, Bendayan D, Saute M, Glazer M et al.| title=Pulmonary carcinoid: presentation, diagnosis, and outcome in 142 cases in Israel and review of 640 cases from the literature. | journal=Chest | year= 2001 | volume= 119 | issue= 6 | pages= 1647-51 | pmid=11399686 | doi=10.1378/chest.119.6.1647 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11399686  }} </ref><ref name="pmid8604242">{{cite journal| author=Froudarakis M, Fournel P, Burgard G, Bouros D, Boucheron S, Siafakas NM et al.| title=Bronchial carcinoids. A review of 22 cases. | journal=Oncology | year= 1996 | volume= 53 | issue= 2 | pages= 153-8 | pmid=8604242 | doi=10.1159/000227552 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8604242  }} </ref><ref name="pmid18491401">{{cite journal| author=Hassan MM, Phan A, Li D, Dagohoy CG, Leary C, Yao JC| title=Risk factors associated with neuroendocrine tumors: A U.S.-based case-control study. | journal=Int J Cancer | year= 2008 | volume= 123 | issue= 4 | pages= 867-73 | pmid=18491401 | doi=10.1002/ijc.23529 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18491401  }} </ref>
*[[Genetic predisposition|Inherited predisposition]] is one of the [[risk factors]] especially in the case of [[lung]] [[NET1|NETs]] (not [[Related phenomena|related]] to [[MEN syndromes|MEN syndrome]]).<ref name="pmid11391591">{{cite journal| author=Oliveira AM, Tazelaar HD, Wentzlaff KA, Kosugi NS, Hai N, Benson A et al.| title=Familial pulmonary carcinoid tumors. | journal=Cancer | year= 2001 | volume= 91 | issue= 11 | pages= 2104-9 | pmid=11391591 | doi=10.1002/1097-0142(20010601)91:11<2104::aid-cncr1238>3.0.co;2-i | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11391591  }} </ref>
*[[Diabetes]] is [[Association (statistics)|associated]] with increased [[RiskMetrics|risk]] of [[pancreatic]] [[NET1|NETs]].
*[[Chronic pancreatitis]] is [[Association (statistics)|associated]] with increased [[RiskMetrics|risk]] of [[pancreatic]] [[NET1|NETs]].
*The [[inherited]] [[Genetic Disorders|genetic]] [[syndromes]] [[Association (statistics)|associated]] with increased [[Risk factor|risk]] of [[Causes|causing]] [[neuroendocrine]] [[tumors]] include:
**[[Multiple endocrine neoplasia type 1|Multiple Endocrine Neoplasia type 1]] ([[MEN1]])
**[[Multiple endocrine neoplasia type 2|Multiple Endocrine Neoplasia type 2]] ([[MEN2]])
**[[Von Hippel-Lindau syndrome]]
**[[Neurofibromatosis]]
**[[Tuberous sclerosis]]


In the context of GEP-NETs, the terms ''[[metastatic]]'' and ''[[malignant]]'' are often used interchangeably.
==Natural History, Complications and Prognosis==
 
GEP-NETs are often malignant, since the primary site often eludes detection for years, sometimes decades&nbsp;&ndash; during which time the tumor has the opportunity to metastasize. Researchers differ widely in their estimates of malignancy rates, especially at the level of the secretory subtypes (the various "-omas").


The most common metastatic sites are the liver, the lymph nodes, and the bones. Liver metastases are so frequent and so well-fed that for many patients, they dominate the course of the cancer. For a patient with a nonsecretory PET, for example, the primary threat to life may be the sheer bulk of the tumor load in the liver.
* [[Neuroendocrine]] [[tumors]] are [[slow]] [[Growth|growing]] [[tumors]] but they can [[Product (biology)|produce]] [[amino acids]] that can [[Causes|cause]] severe [[symptoms]].


==Causes==
===Complications===
In the normal [[pancreas]], cells called [[islet cells]] produce hormones that regulate a variety of bodily functions, such as blood sugar level and the production of [[stomach]] [[acid]].
*Common [[complications]] of [[neuroendocrine]] [[tumors]] include the following:
**[[Diabetes]]
**[[Hormone]] [[Crisis (charity)|crisis]] (if the [[tumor]] [[Release (information centre)|releases]] certain types of [[hormones]])
** Severe [[low blood sugar]] (from [[Insulinoma|insulinomas]])
** Severe [[ulcers]] in the [[stomach]] and [[small intestine]] (from [[Gastrinoma|gastrinomas]])
**[[Spread of the cancer|Spread of the tumor]] to the [[liver]]


Islet cell tumors include:
* Gastrinomas (Zollinger-Ellison syndrome)
* Glucagonomas
* Insulinomas
==Natural History, Complications and Prognosis==
* Diabetes
* Hormone crises (if the tumor releases certain types of hormones)
* Severe low blood sugar (from insulinomas)
* Severe ulcers in the stomach and small intestine (from gastrinomas)
* Spread of the tumor to the liver
===Prognosis===
===Prognosis===
You may be cured if the tumors are surgically removed before they have spread to other organs. If tumors are cancerous, chemotherapy may be used, but it usually cannot cure patients.
*[[Neuroendocrine]] [[tumors]] can be [[Cure for cancer|cured]] if they are removed [[Surgery operation|surgically]] before their [[Spread of the cancer|spread]] to the other [[organs]].
*[[Chemotherapy]] can be [[Usage analysis|used]] in case of [[cancerous]] [[tumors]] but it usually doesn't [[cure]] the [[patients]].
*[[Life]]-threatening [[Problem Solved|problems]] (such as a very [[Low blood sugar|low blood sugar level]]) can occur due to [[Excess risk|excess]] [[hormone]] [[Product (biology)|production]], or if [[Spread of the cancer|cancer spreads]] throughout the [[Human body|body]].
*[[Fewmets|Few]] of the [[prognostic]] [[Fact table|facts]] about poorly [[Differentiate|differentiated]] [[pancreatic]] NEC are given below:<ref name="pmid24503751" />
**88% of the [[patients]] have [[lymph node]] or [[Distance matrix|distant]] [[metastatic disease]] at the [[Time constant|time]] of [[tumor]] [[Presenting symptom|presentation]].
**7% of the [[patients]] subsequently [[Development (biology)|develop]] [[metastases]].
**The [[median]] [[Survival analysis|survival]] is 11 months, [[Range (statistics)|ranging]] from 0 to 104 months.
**The two-[[year]] [[survival rate]] is 22.5%.
**The [[five-year survival rate]] is 16.1%.


Life-threatening problems (such as very low blood sugar) can occur due to excess hormone production, or if the cancer spreads throughout the body.
==History and Symptoms==
==History and Symptoms==
According to Arnold ''et alia'', "many tumors are asymptomatic even in the presence of metastases" (Arnold ''et al.'' 2004, 197).
A carcinoid tumor may produce serotonin ([[5-HT]]), a biogenic [[amine]] that causes a specific set of symptoms including


* [[Flushing]]
* Initially, many of the [[neuroendocrine]] [[tumors]] mostly remain [[asymptomatic]].
* [[Diarrhea]] or increase in number of bowel movements
*When they [[Causes|cause]] [[symptoms]], it is usually due to the following two [[Reasoning|reasons]]:
* [[Weight loss]]
**[[Tumor]] [[Location parameter|location]] [[Causality|causing]]:
* [[Weight gain]]
***[[Feeling]] of a [[Growth|growing]] [[lump]] under the [[skin]]
* [[Palpitations]]
***Persistent [[pain]] occurring from increasing [[tumor]] [[Size consistency|size]] during its [[growth]] in [[Specific activity|specific]] [[area]]
* [[Congestive heart failure]] ([[CHF]])
***Unusually [[tired feeling]] ([[fatigue]])
* [[Asthma]]
***[[Unintentional weight loss]]
* [[Acromegaly]]
***[[Loss of appetite]]
* [[Cushing's syndrome]]
***[[Headache]]
***[[Jaundice]]
***[[Changes in bowel habits|Changes in bowel]] or [[Urinary bladder|bladder]] habits
***Unusual [[discharge]] or [[bleeding]]
***[[Persistent cough]] or [[hoarseness]]
***Persistent [[fever]] or [[night sweats]]
**Particular [[Excess risk|excessive]] [[hormone]] [[Product (biology)|production]] by the [[tumor]] ([[Function (biology)|functional]] [[tumor]])
===Carcinoid tumor===
*[[Carcinoid tumors]] may [[Product (biology)|produce]] [[serotonin]] ([[5-HT]]), a [[biogenic amine]] [[Lead|leading]] to the following [[Specific activity|specific]] [[set]] of [[symptoms]] which are collectively known as [[Carcinoid syndrome]]:
**[[Unusual warmth and flushing of skin|Flushing of skin]]
**[[Diarrhea]] (or increase in the [[number]] of [[bowel]] movements)
**[[Weight loss]]
**[[Weight gain]]
**[[Palpitations]]
**[[Congestive heart failure]] ([[CHF]])
**[[Asthma]]
**[[Acromegaly]]
**[[Cushing's syndrome]]
===Pancreatic NETs===
*According to the [[Recent changes|recent]] [[Study design|studies]], 50 to 85% of the [[pancreatic]] [[NET1|NETs]] are nonfunctioning.
*Functioning [[pancreatic]] [[NET1|NETs]] include the following:
**'''[[Insulinoma|Insulinomas]]''' with [[Typical set|typical]] [[Presenting symptom|presentation]] of episodic [[hypoglycemia]] [[Lead|leading]] to:
***[[Confusion]]
***[[Amnesia]] (during [[hypoglycemic]] [[Phase (waves)|phase]] is common)
***[[Visual]] [[Change detection|changes]]
***[[Palpitations]]
***[[Trembling|Tremulousness]]
***[[Diaphoresis]]
***Unusual [[behavior]]
**'''[[Gastrinoma|Gastrinomas]]''' with [[Typical set|typical]] [[Presenting symptoms|presentation]] of:
***[[Peptic ulcer disease]]
***[[Diarrhea]] (prominent [[Features (pattern recognition)|feature]] too sometimes)
**'''[[Glucagonoma]]''' [[Causes|causing]] classical [[clinical]] [[syndrome]] which includes:
***[[Necrolytic migratory erythema]]
***[[Cheilitis]]
***[[Diabetes mellitus]]
***[[Anemia]]
***[[Weight loss]]
***[[Diarrhea]]
***[[Venous thrombosis]]
***[[Neuropsychiatric]] [[symptoms]]
**'''[[VIPoma]]''' [[syndrome]] [[Presenting symptom|presents]] with the following main [[clinical]] [[symptoms]]:
***[[Watery diarrhea]]
***[[Hypokalemia]]
***[[Hypochlorhydria]]


This set of symptoms is called ''[[Carcinoid syndrome]]''.
==Laboratory Findings==
==Laboratory Findings==


* Cells that receive hormonal messages do so through receptors on the surface of the cells. For reasons that are not understood, many neuroendocrine tumor cells possess especially strong receptors; for example, PETs often have strong receptors for [[somatostatin]], a very common hormone in the body. We say that such tumor cells ''overexpress'' the somatostatin receptors (SSTRs) and are thus ''avid for'' the hormone; their ''uptake'' of the hormone is strong. This avidity for somatostatin is a key for diagnosis&nbsp;&ndash; and it makes the tumors vulnerable to certain ''targeted therapies''.
* Many [[neuroendocrine]] [[Tumor cell|tumor cells]] especially possess [[strong]] [[receptors]] on their [[Surface chemistry|surfaces]] through which they receive [[hormonal]] [[Message-passing method|messages]] such as:
**[[PET|PETs]] often have [[strong]] [[receptors]] for [[somatostatin]].
**Such [[Tumor cell|tumor cells]] ''[[overexpress]]'' the [[somatostatin receptors]] (SSTRs) and are thus considered to be ''[[Avidity|avid]] for'' this [[hormone]], hence, their ''[[Uptake signal sequence|uptake]]'' of [[somatostatin]] is [[strong]].
**This [[avidity]] for [[somatostatin]] is the key factor for the [[PET|PETs']] [[diagnosis]]&nbsp;and it also [[MakeBot|makes]] the [[tumors]] [[Vulnerable populations|vulnerable]] to [[Certain safety factor|certain]] ''[[Targeted therapy|targeted therapies]]''.


* Aside from their use in diagnosis, some markers can track the progress of therapy while the patient avoids the detrimental side-effects of CT-scan contrast.
*[[Generality|Generally]], the important common [[Usage analysis|uses]] of [[tumor markers]] include:
**[[Help Menu|Helpful]] in the [[Specific activity|specific]] [[tumor]] [[diagnosis]].
**[[Help Menu|Helpful]] in [[Tracking changes|tracking]] the progress of [[tumor]] [[therapy]] hence, the detrimental [[side effects]] of [[Contrast agent|contrast]] [[CT scan]] on the [[patient]] can be [[Avoidance reaction|avoided]].


{| class="wikitable"
{| class="wikitable"
Line 330: Line 742:
|-
|-
|
|
*[[Chromogranin]] A (CgA)
*[[Chromogranin A]] (CgA)
* Urine 5-hydroxy indole acetic acid (5-HIAA) (grade C)
*[[Urine]] [[5-Hydroxyindoleacetic acid|5-hydroxy indole acetic acid]] ([[5-HIAA]]) ([[Grading (tumors)|grade]] C)
* Neuron-specific enolase (NSE, gamma-gamma dimer)
*[[Neuron-specific enolase]] (NSE, [[gamma]]-[[gamma]] [[dimer]])
* Synaptophysin (P38)
*[[Synaptophysin]] ([[P38]])
|
|
*Synaptobrevin (VAMP-1)
*[[Synaptobrevin]] ([[VAMP1|VAMP-1]])
* Synapsin (1A, 1B, 2A, 2B)
*[[Synapsin]] ([[Synapsin I|1A]], [[Synapsin I|1B]], [[Synapsin 2|2A]], [[Synapsin 2|2B]])
* SV2
*[[SV2A|SV2]]
* Protein P65
*[[Protein]] P65
* Protein S-100
*[[S-100 protein|Protein S-100]]
* Protein gene product (PGP) 9.5
*[[Protein]] [[gene product]] ([[PGPEP1|PGP]]) 9.5
* Intermediate filaments (cytokeratins, vimentin, neurofilaments)
*[[Intermediate filaments]] ([[Cytokeratin|cytokeratins]], [[vimentin]], [[Neurofilament|neurofilaments]])
* Protein 7B2
*[[Protein]] 7B2
* Chromogranin B (secretogranin I)
*[[Chromogranin]] B (secretogranin I)
* Chromogranin C (secretogranin II)
*[[Chromogranin]] C (secretogranin II)
* Pancreastatin
*[[Pancreastatin]]
* Vasostatin
* Vasostatin
* Cytochrome b561
*[[Cytochrome]] b561
* Leu-7 (HNK-1)
* Leu-7 (HNK-1)
* Calcitonin
*[[Calcitonin]]
* Human chorionic gonadotropin-alpha (HCG-α)
*[[Human chorionic gonadotropin]]-alpha ([[HCG]]-α)
* Human chorionic gonadotropin-beta (HCG-β)
*[[Human chorionic gonadotropin]]-beta ([[HCG]]-β)
* Thyroid function tests (TFTs)
*[[Thyroid function tests]] ([[TFTs]])
* Parathyroid hormone (PTH)
*[[Parathyroid hormone]] ([[PTH]])
* Calcium
*[[Calcium]]
|
|
*Prolactin
*[[Prolactin]]
* {Alpha}-fetoprotein
*[[Alpha-fetoprotein]]
* Carcinoembryonic antigen (CEA)
*[[Carcinoembryonic antigen]] ([[CEA]])


*ß-human chorionic gonadotrophin (ß-HCG) (grade D)
*ß-[[human chorionic gonadotrophin]] (ß-[[HCG]]) ([[Grading (tumors)|grade]] D)
* CGRP
*[[CGRP]]
* GRP
* GRP
* PYY
*[[Peptide YY|PYY]]
* hCGα
*[[HCG|hCGα]]
* N Peptide K
* N [[Peptide]] K
* Neurokinin A
*[[Neurokinin A]]
* Serotonin
*[[Serotonin]]
* Neurotensin
*[[Neurotensin]]
* Motilin
*[[Motilin]]
* Substance P
*[[Substance P]]
* Histamine
*[[Histamine]]
* Catecholamines
*[[Catecholamines]]
* Dopa
*[[Dopamine|Dopa]]
* Various rarer peptide hormones
* Various [[Rare|rarer]] [[peptide hormones]]
* Synaptotagmin
*[[Synaptotagmin]]
* HISL-19
* HISL-19
|
|
*N-terminally truncated variant of heat shock protein 70 (Hsp70)
*N-terminally [[Truncated distribution|truncated]] variant of [[Heat shock protein 70 (Hsp70) internal ribosome entry site (IRES)|heat shock protein 70]] ([[Hsp70]])
* CDX-2, a homeobox gene product
*[[CDX2|CDX-2]], a [[homeobox gene]] [[Product (biology)|product]]
* Neuroendocrine secretory protein-55
*[[Neuroendocrine]] [[secretory protein]]-55
|}
|}


==CT Scan==
==CT Scan==
*[[CT-scan]] is a common diagnostic tool in the diagnosis of Neuroendocrine tumors.
*CT scan is one of the most common diagnostic tool used for diagnosing of Neuroendocrine tumors.
*CT-scans using contrast medium can detect 95 percent of tumors over 3 cm in size, and no tumors under 1 cm (University of Michigan Medical School n. d., [http://www.med.umich.edu/lrc/presentation/endo/islet.htm]).
*CT scan with contrast medium can detect 95% of the tumors with size of >3 cm in size, and no tumors under 1 cm (University of Michigan Medical School n. d., [http://www.med.umich.edu/lrc/presentation/endo/islet.htm]).


==PET Scan==
==PET Scan==
Line 417: Line 829:
Two tricky issues in evaluating therapies are durability (is the therapy long-lasting?) and stasis (are the tumors neither growing nor shrinking?). For example, one therapy might give good initial results&nbsp;&ndash; but within months the benefit evaporates. And another therapy might be disparaged by some for causing very little tumor shrinkage, but be championed by others for causing significant tumoristasis.
Two tricky issues in evaluating therapies are durability (is the therapy long-lasting?) and stasis (are the tumors neither growing nor shrinking?). For example, one therapy might give good initial results&nbsp;&ndash; but within months the benefit evaporates. And another therapy might be disparaged by some for causing very little tumor shrinkage, but be championed by others for causing significant tumoristasis.


The half-life of somatostatin in circulation is under three minutes, making it useless for diagnosis and targeted therapies. For this reason,  The synthetic forms are typically called ''somatostatin analogs'' (''somatostatin analogues''), but according to the US [[Food and Drug Administration]] (FDA), the proper term is ''somatostatin congeners''. (In this article we conform to the old terminology, as the medical community has been slow to adopt the term ''[[congener]]''.) The analogs have a much longer half-life than somatostatin, and other properties that make them more suitable for diagnosis and therapy.
The half-life of somatostatin in circulation is under three minutes, making it useless for diagnosis and targeted therapies. For this reason,  The synthetic forms are typically called ''somatostatin analogs'' (''somatostatin analogues''), but according to the US [[Food and Drug Administration]] (FDA), the proper term is somatostatin congeners. (In this article we conform to the old terminology, as the medical community has been slow to adopt the term ''[[congener]]''.) The analogs have a much longer half-life than somatostatin, and other properties that make them more suitable for diagnosis and therapy.


===Chemotherapy===
===Chemotherapy===
Line 474: Line 886:
</ref>
</ref>


====Other therapies====
====Other Therapies====


* '''Radiofrequency ablation''' (RFA) is used when a patient has relatively few metastases. In RFA, a needle is inserted into the center of the lesion and is vibrated at high frequency to generate heat; the tumor cells are killed by cooking.  
* '''Radiofrequency ablation''' (RFA) is used when a patient has relatively few metastases. In RFA, a needle is inserted into the center of the lesion and is vibrated at high frequency to generate heat; the tumor cells are killed by cooking.  
Line 508: Line 920:
[[Category:Oncology]]
[[Category:Oncology]]
[[Category:Endocrinology]]
[[Category:Endocrinology]]
[[Category:Up-To-Date]]
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Medicine]]
[[Category:Endocrinology]]
[[Category:Endocrinology]]
[[Category:Surgery]]
[[Category:Surgery]]
<references />
==References==
{{Reflist|2}}

Latest revision as of 18:45, 22 September 2020

Neuroendocrine tumors Microchapters

Patient Information

Overview

Historical Perspective

Classification

Pathophysiology

Causes

Epidemiology and Demographics

Risk factors

Natural History, Complications and Prognosis

History and Symptoms

Laboratory Findings

CT scan

PET scan

Medical Therapy

Surgery

For patient information, click here

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [9] Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[10]

Overview

Neuroendocrine tumors, or more properly gastro-entero-pancreatic or gastroenteropancreatic neuroendocrine tumors (GEP-NETs), are cancers of the interface between the endocrine (hormonal) system and the nervous system.

Historical Perspective

Classification

Human GEP-NETs by Site of Origin and by Symptom

Human GEP-NETs by Site of Origin and by Symptom Percentage
Carcinoids (about two thirds of GEP-NETs)
PETs (about one third of GEP-NETs)
  • Nonfunctioning
Rare GEP-NETs

Simplified classification according to anatomic distribution

Simplified classification of Neuroendocrine tumors according to anatomic distribution
Involved organ Name/type of neuroendocrine tumor
Pituitary gland
Thyroid gland
Parathyroid glands
Thymus and mediastinum
Lungs
Extrapulmonary
GIT
Adrenal gland
Peripheral nervous system Peripheral nervous system tumors, such as:
Mammary gland
Genitourinary tract
Skin
Multiple organs involvement in inherited conditions

Classification of GEP-NETs by cell characteristics

Summary of classification by cell characteristics (the WHO classification)

  • This classification was done due to peripheral receptors.
  • GEP-NETs receptors (APUDomas) are the main detected receptors.
  • That term is now misleading, since it is based on a discredited theory of the development of the tumors.
  • It is now known that this receptor may not be indicator of cell origin.[1]
Superclass:Öberg, WHO, Klöppel et alia: Gastro-entero-pancreatic neuroendocrine tumor (GEP-NET)
Subclass 1 (less malignant) Subclass 2 (more malignant) Subclass 3 (most malignant) Subclass 4 (mixed) Subclass 5 (miscellaneous)

2010 WHO Classification Of NET

2010 World Health Organization International Classification and Distribution of Diseases for Oncology (3rd Ed. (ICD-O-3) Codes of Neuroendocrine Tumors (NETs) in the Gastrointestinal and Pancreatobiliary Tracts)
NET (Neuroendocrine Tumor) Classification Location ICD-O-3 Code
NET G1 (Grade 1) All organs 8240/3
NET G2 (Grade 2) All organs 8249/3
Neuroendocrine carcinoma All organs 8246/3
Large cell NEC All organs 8013/3
Small cell NEC All organs 8041/3
Enterochromaffin cell serotonin-producing NET All organs 8241/3
Gastrin-producing NET (gastrinoma) Stomach, ampulla, small intestine, pancreas 8153/3
Glucagon-producing NET (glucagonoma) Pancreas 8152/3
Gangliocytic paraganglioma Ampulla, small intestine 8683/0
Somatostatin-producing NET (somatostatinoma) Ampulla, small intestine, pancreas 8156/3
Insulin-producing NET (insulinoma) Pancreas 8151/3
VIPoma Pancreas 8155/3
L cell, Glucagon-like peptide, and PP/PYY-producing NETs Small intestine, appendix, colorectum 8152/1
Goblet cell carcinoid Appendix, extrahepatic bile duct 8241/3
Tubular carcinoid Appendix, extrahepatic bile duct 8245/1
Mixed adenoneuroendocrine carcinoma (MANEC) All organs 8244/3
Neuroendocrine microadenoma Pancreas 8150/0

WHO Grading criteria for neuroendocrine neoplasms

2017 World Health Organization Classification of Neuroendocrine Tumors (NETs) in the GIT and Pancreatobiliary Tracts (PanNETs)
Grade/Classification Mitotic Count/ 10 HPFs (High-Power Field) Ki-67 Labeling Index, % Traditional
Neuroendocrine neoplasm GX Grade cannot be assessed
Well-differentiated GIT NETs & PanNENs: Pancreatic neuroendocrine tumors (PanNETs)
Neuroendocrine tumor, Grade 1 and PanNET G1 (low grade) <2 <3
Neuroendocrine tumor, Grade 2 and PanNET G2 (intermediate grade) 2–20 3–20
PanNET G3 >20 >20 _
Poorly differentiated PanNENs: Pancreatic neuroendocrine carcinomas (PanNECs)
Neuroendocrine carcinoma, Grade 3 and

PanNEC G3 (high grade)

>20 >20 Small cell carcinoma
Large cell neuroendocrine carcinoma
Mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN)
Classification of Gastric Enterochromaffin-Like Cell Histamine-Producing Neuroendocrine Tumors
Classification I II III
Incidence, % 55–88 8–13 12–23
Multifocality Multiple Multiple Single
Peritumoral oxyntic mucosa Atrophic Hypertrophic Normal
Size, cm 0.5–1 <2 >2
Location Corpus Corpus Any
Sex M < F M = F M > F
Hypergastrinemia Yes Yes No
Antral G-cell hyperplasia Yes No No
Associated disease No
Precursor lesion Yes Yes No
WHO 2010 classification Grade 1 Grades 1 or 2 Grades 1–3
Lymph node metastasis, % 5 30 70


Comparison of the WHO classifications of pancreatic neuroendocrine neoplasms
WHO 1980 WHO 2000/2004 WHO 2010 WHO 2017
Islet cell tumor (adenoma/carcinoma) Well-differentiated endocrine tumor/carcinoma (WDET/WDEC) NET G1/G2 NET G1/G2/G3 (well-differentiated NEN)
Poorly differentiated endocrine carcinoma Poorly differentiated endocrine carcinoma/small cell carcinoma (PDEC) NEC (G3), large cell or small cell type NEC (G3), large cell or small cell type (poorly differentiated NEN)
_ Mixed exocrine-endocrine carcinoma (MEEC) Mixed adenoneuroendocrine carcinoma Mixed neuroendocrine-non-neuroendocrine neoplasm
Pseudotumor lesions Tumor-like lesions (TLLs) Hyperplastic and preneoplastic lesions _

Pathophysiology

Neuroendocrine system

Causes

Hereditary Syndromes Associated With Gastrointestinal (GI) and Pancreatobiliary Tract Neuroendocrine Tumors (NETs)
Name of the syndrome Pattern of inheritance Chromosomal Band Location Gene/ Protein Involved GIT and Pancreatobiliary Tract NETs Other Tumors of GIT and Pancreatobiliary Tract Clinical Presentation Outside GIT and Pancreatobiliary Tract
Multiple endocrine neoplasia 1 (MEN 1)
  • 11q13.1
  • Nonfunctional

Maybe associated with multiple:

More commonly:

Less commonly:

von Hippel-Lindau disease/syndrome (VHL)
  • 3p25.3
Neurofibromatosis 1

(von Recklinghausen disease)

  • 17q11.2
Tuberous sclerosis
  • 9q34.13
  • 16p13.3

Other familial syndromes associated with neuroendocrine neoplasms are:

Epidemiology and Demographics

Lung NETs

Digestive system NETs

Disease/Syndrome % chance of developing Pancreatic NET
Multiple endocrine neoplasia 1 (MEN 1) 80-100%
von Hippel-Lindau disease/syndrome (VHL) 20%
Neurofibromatosis 1

(von Recklinghausen disease)

10%
Tuberous sclerosis 1%

Risk factors

Few of the risk factors for neuroendocrine tumors include:

Natural History, Complications and Prognosis

Complications

Prognosis

History and Symptoms

Carcinoid tumor

Pancreatic NETs

Laboratory Findings

List of potential markers for GEP-NETs apart from hormones of secretory tumors
Most important markers Other markers Newer (as of 2005) markers

CT Scan

  • CT scan is one of the most common diagnostic tool used for diagnosing of Neuroendocrine tumors.
  • CT scan with contrast medium can detect 95% of the tumors with size of >3 cm in size, and no tumors under 1 cm (University of Michigan Medical School n. d., [11]).

PET Scan

A gallium-68 receptor PET-CT, integrating a PET image with a CT image, is much more senstitive than an OctreoScan, and it generates objective (quantified) results in the form of a standardized uptake value (SUV).

Octreoscan

The diagnostic procedure that utilizes a somatostatin analog is the OctreoScan, also called somatostatin receptor scintigraphy (SRS or SSRS): a patient is injected with octreotide chemically bound to a radioactive substance, often indium-111; for those patients whose tumor cells are avid for octreotide, a radiation-sensitive scan can then indicate the locations of the larger lesions.

An OctreoScan is a relatively crude test that generates subjective results.

Images courtesy of RadsWiki

OctreoScan demonstrates abnormal uptake in the liver and abdominal lymph nodes


OctreoScan demonstrates abnormal uptake in the liver and abdominal lymph nodes


OctreoScan demonstrates abnormal uptake in the head of the pancreas


OctreoScan demonstrates abnormal uptake in the head of the pancreas


OctreoScan demonstrates abnormal uptake in the head of the pancreas


Medical Therapy

Approach

According to Warner, the best care, at least for noncarcinoid GEP-NETs, is provided by "an active [as opposed to wait-and-see] approach using sequential multimodality treatment" delivered by a "multidisciplinary team, which also may include a surgeon, endocrinologist, oncologist, interventional radiologist, and other specialists". This recommendation is based on his view that, except for most insulinomas, "almost all" PETs "have long-term malignant potential" – and in sixty percent of cases, that potential is already manifest. "Indeed, the most common cause of death from PETs is hepatic [that is, liver] failure" (Warner 2005, 4).

Two tricky issues in evaluating therapies are durability (is the therapy long-lasting?) and stasis (are the tumors neither growing nor shrinking?). For example, one therapy might give good initial results – but within months the benefit evaporates. And another therapy might be disparaged by some for causing very little tumor shrinkage, but be championed by others for causing significant tumoristasis.

The half-life of somatostatin in circulation is under three minutes, making it useless for diagnosis and targeted therapies. For this reason, The synthetic forms are typically called somatostatin analogs (somatostatin analogues), but according to the US Food and Drug Administration (FDA), the proper term is somatostatin congeners. (In this article we conform to the old terminology, as the medical community has been slow to adopt the term congener.) The analogs have a much longer half-life than somatostatin, and other properties that make them more suitable for diagnosis and therapy.

Chemotherapy

The most common nonsurgical therapy for all GEP-NETs is chemotherapy, although chemotherapy is reported to be largely ineffective for carcinoids, not particularly durable (long-lasting) for PETs, and inappropriate for PETs of nonpancreatic origin. [29]

When chemotherapy fails, the most common therapy, in the United States, is more chemotherapy, with a different set of agents. Some studies have shown that the benefit from one agent is not highly predictive of the benefit from another agent, except that the long-term benefit of any agent is likely to be low.

Strong uptake of somatostatin analogs is a negative indication for chemo.

Symptomatic relief

There are two major somatostatin-analog-based targeted therapies. The first of the two therapies provides symptomatic relief for patients with secretory tumors. In effect, somatostatin given subcutaneously or intramuscularly "clogs up" the receptors, blocking the secretion of hormones from the tumor cells. Thus a patient who might otherwise die from severe diarrhea caused by a secretory tumor can gain additional years of life.

Specific counter-hormones or other hormone-blocking medications are sometimes also used to provide symptomatic relief.

Hormone-delivered radiotherapy – PRRT

The second of the two major somatostatin-analog-based targeted therapies is called peptide receptor radionuclide therapy (PRRT), though we might simply call it hormone-delivered radiotherapy. In this form of radioisotope therapy (RIT), radioactive substances (called radionuclides or radioligands) are chemically conjugated with hormones (peptides or neuroamines); the combination is given intravenously to a patient who has good uptake of the chosen hormone. The radioactive labelled hormones enter the tumor cells, and the attached radiation damages the tumor- and nearby cells. Not all cells are immediately killed this way. The process of tumor cells dying as result of this therapy can go on for several months, even up to two years. In patients with strongly overexpressing tumor cells, nearly all the radiation either gets into the tumors or is excreted in urine. As Rufini et alia say, GEP-NETs "are characterized by the presence of neuroamine uptake mechanisms and/or peptide receptors at the cell membrane, and these features constitute the basis of the clinical use of specific radiolabeled ligands, both for imaging and therapy" (Rufini, Calcagni, and Baum 2006, [12]).

The use of PRRT for GEP-NETs is similar to the use of iodine-131 as a standard therapy (in use since 1943) for nonmedullary thyroid tumors (which are not GEP-NETs). Thyroid cells (whether normal or neoplastic) tend to be avid for iodine, and nearby cells are killed when iodine-131 is infused into the bloodstream and is soon attracted to thyroid cells. Similarly, overexpressing GEP-NET cells (neoplastic cells only) are avid for somatostatin analogs, and nearby cells are killed when radionuclides attached to somatostatin analogs are infused into the bloodstream and are soon attracted to the tumor cells. In both therapies, hormonal targeting delivers a much higher dose of radiation than external beam radiation could safely deliver.

As of 2006, PRRT is available in at least dozen medical centers in Europe. In the USA it is FDA-approved, and available at the MD Anderson Cancer Center, but using a radionuclide, indium-111, that is much weaker than the lutetium-177 and the even stronger yttrium-90 used on the European continent. In the UK, only the radionuclide metaiodobenzylguanidine (I-MIBG) is licensed (but GEP-NETs are rarely avid for MIBG). Most patients (from all over the world) are treated (with lutetium-177) in The Netherlands, at the Erasmus Medical Center. PRRT with lutetium or yttrium is nowhere an "approved" therapy, but the German health insurance system, for example, covers the cost for German citizens.

PRRT using yttrium or lutetium was first applied to humans about 1999. Practitioners continue to refine their choices of radionuclides to maximize damage to tumors, of somatostatin analogs to maximize delivery, of chelators to bind the radionuclides with the hormones (and chelators can also increase uptake), and of protective mechanisms to minimize damage to healthy tissues (especially the kidneys).


Hepatic artery-delivered therapies

  • One therapy for liver metastases of GEP-NETs is hepatic artery embolization (HAE). Larry Kvols, of the Moffitt Cancer Center and Research Institute in Tampa, Florida, says that "hepatic artery embolization has been quite successful. During that procedure a catheter is placed in the groin and then threaded up to the hepatic artery that supplies the tumors in the liver. We inject a material called embospheres [tiny spheres of glass or resin, also called microspheres] into the artery and it occludes the blood flow to the tumors, and in more than 80% of patients the tumors will show significant tumor shrinkage" (Kvols 2002, [13]). HAE is based on the observation that tumor cells get nearly all their nutrients from the hepatic artery, while the normal cells of the liver get about 75 percent of their nutrients (and about half of their oxygen) from the portal vein, and thus can survive with the hepatic artery effectively blocked.

[30]

  • Another therapy is hepatic artery chemoinfusion, the injection of chemotherapy agents into the hepatic artery. Compared with systemic chemotherapy, a higher proportion of the chemotherapy agents are (in theory) delivered to the lesions in the liver.

[31]

  • Hepatic artery chemoembolization (HACE), sometimes called transarterial chemoembolization (TACE), combines hepatic artery embolization with hepatic artery chemoinfusion: embospheres bound with chemotherapy agents, injected into the hepatic artery, lodge in downstream capillaries. The spheres not only block blood flow to the lesions, but by halting the chemotherapy agents in the neighborhood of the lesions, they provide a much better targeting leverage than chemoinfusion provides.
  • Radioactive microsphere therapy (RMT) combines hepatic artery embolization with radiation therapy – microspheres bound with radionuclides, injected into the hepatic artery, lodge (as with HAE and HACE) in downstream capillaries. This therapy is also called selective internal radiation therapy, or SIRT. In contrast with PRRT, the lesions need not overexpress peptide receptors. (But PRRT can attack all lesions in the body, not just liver metastases.) Due to the mechanical targeting, the yttrium-labeled microspheres "are selectively taken up by the tumors, thus preserving normal liver" (Salem et al. 2002, [14]).

[32]

Other Therapies

  • Radiofrequency ablation (RFA) is used when a patient has relatively few metastases. In RFA, a needle is inserted into the center of the lesion and is vibrated at high frequency to generate heat; the tumor cells are killed by cooking.
  • Cryoablation is similar to RFA; an endothermic substance is injected into the tumors to kill by freezing. Cryoablation has been considerably less successful for GEP-NETs than RFA.
  • Interferon is sometimes used to treat GEP-NETs; its use was pioneered by Dr. Kjell Öberg at Uppsala. For GEP-NETs, Interferon is often used at low doses and in combination with other agents (especially somatostatin analogs such as octreotide). But some researchers claim that Interferon provides little value aside from symptom control.
  • As described above, somatostatin analogs have been used for about two decades to alleviate symptoms by blocking the production of hormones from secretory tumors. They are also integral to PRRT. In addition, some doctors claim that, even without radiolabeling, even patients with nonsecretory tumors can benefit from somatostatin analogs, which purportedly can shrink or stabilize GEP-NETs. But some researchers claim that this "cold" octreotide provides little value aside from symptom control.

Surgery

Surgery is the only therapy that can cure GEP-NETs. However, the typical delay in diagnosis, giving the tumor the opportunity to metastasize, makes most GEP-NETs ineligible for surgery (non-resectable).

Case Studies

Case #1

External links

Acknowledgements

The content on this page was first contributed by: C. Michael Gibson, M.S., M.D.

Template:Epithelial neoplasms


Template:WikiDoc Sources

References

  1. "The APUD concept led to the belief that these cells arise from the embryologic neural crest. This hypothesis eventually was found to be incorrect" (Warner 2005, 2).

    "The APUD-concept is currently abandoned" (Öberg 1998, 2, [1]).

  2. Tang LH, Basturk O, Sue JJ, Klimstra DS (2016). "A Practical Approach to the Classification of WHO Grade 3 (G3) Well-differentiated Neuroendocrine Tumor (WD-NET) and Poorly Differentiated Neuroendocrine Carcinoma (PD-NEC) of the Pancreas". Am J Surg Pathol. 40 (9): 1192–202. doi:10.1097/PAS.0000000000000662. PMC 4988129. PMID 27259015.
  3. Inzani F, Petrone G, Rindi G (2018). "The New World Health Organization Classification for Pancreatic Neuroendocrine Neoplasia". Endocrinol Metab Clin North Am. 47 (3): 463–470. doi:10.1016/j.ecl.2018.04.008. PMID 30098710.
  4. 4.0 4.1 Sorbye H, Welin S, Langer SW, Vestermark LW, Holt N, Osterlund P; et al. (2013). "Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study". Ann Oncol. 24 (1): 152–60. doi:10.1093/annonc/mds276. PMID 22967994.
  5. Heetfeld M, Chougnet CN, Olsen IH, Rinke A, Borbath I, Crespo G; et al. (2015). "Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms". Endocr Relat Cancer. 22 (4): 657–64. doi:10.1530/ERC-15-0119. PMID 26113608.
  6. Basturk O, Yang Z, Tang LH, Hruban RH, Adsay V, McCall CM; et al. (2015). "The high-grade (WHO G3) pancreatic neuroendocrine tumor category is morphologically and biologically heterogenous and includes both well differentiated and poorly differentiated neoplasms". Am J Surg Pathol. 39 (5): 683–90. doi:10.1097/PAS.0000000000000408. PMC 4398606. PMID 25723112.
  7. 7.0 7.1 Tang LH, Untch BR, Reidy DL, O'Reilly E, Dhall D, Jih L; et al. (2016). "Well-Differentiated Neuroendocrine Tumors with a Morphologically Apparent High-Grade Component: A Pathway Distinct from Poorly Differentiated Neuroendocrine Carcinomas". Clin Cancer Res. 22 (4): 1011–7. doi:10.1158/1078-0432.CCR-15-0548. PMC 4988130. PMID 26482044.
  8. La Rosa S, Sessa F, Uccella S (2016). "Mixed Neuroendocrine-Nonneuroendocrine Neoplasms (MiNENs): Unifying the Concept of a Heterogeneous Group of Neoplasms". Endocr Pathol. 27 (4): 284–311. doi:10.1007/s12022-016-9432-9. PMID 27169712.
  9. Shia J, Tang LH, Weiser MR, Brenner B, Adsay NV, Stelow EB; et al. (2008). "Is nonsmall cell type high-grade neuroendocrine carcinoma of the tubular gastrointestinal tract a distinct disease entity?". Am J Surg Pathol. 32 (5): 719–31. doi:10.1097/PAS.0b013e318159371c. PMID 18360283.
  10. 10.0 10.1 Basturk O, Tang L, Hruban RH, Adsay V, Yang Z, Krasinskas AM; et al. (2014). "Poorly differentiated neuroendocrine carcinomas of the pancreas: a clinicopathologic analysis of 44 cases". Am J Surg Pathol. 38 (4): 437–47. doi:10.1097/PAS.0000000000000169. PMC 3977000. PMID 24503751.
  11. Oladejo AO (December 2009). "GASTROENTEROPANCREATIC NEUROENDOCRINE TUMORS (GEP-NETs) - APPROACH TO DIAGNOSIS AND MANAGEMENT". Ann Ib Postgrad Med. 7 (2): 29–33. PMC 4111010. PMID 25161467.
  12. "The main two groups of neuroendocrine GEP tumours are so-called carcinoid tumours and endocrine pancreatic tumours" (Öberg 2005a, 90, ).

    "Less than 1% of carcinoids arise in the pancreas" (Warner 2005, 9).

    Arnold et alia in effect define carcinoids as "extra-pancreatic endocrine gastronintestinal tumors" (Arnold et al. 2004, 196).

    Some doctors believe that there is significant overlap between PETs and carcinoids. For example, endocrine surgeon Rodney Pommier says that "there are pancreatic carcinoids" (Pommier 2003, [2]). However, Pommier made his statement in a talk at a conference on carcinoids, not in a peer-reviewed journal; and in his talk he did not define the word carcinoid.

    Another way to classify GEP-NETs is to separate those that begin in the glandular neuroendocrine system from those that begin in the diffuse neuroendocrine system. "Neuroendocrine tumors generally may be classified into two categories. The first category is an organ-specific group arising from neuroendocrine organs such as pituitary gland, thyroid, pancreas, and adrenal gland. The second group arises from the diffuse neuroendocrine cells/Kulchitsky cells that are widely distributed throughout the body and are highly concentrated in the pulmonary and gastrointestinal systems" (Liu et al. 2001, [3]).

  13. 13.0 13.1 13.2 Dasari A, Shen C, Halperin D, Zhao B, Zhou S, Xu Y; et al. (2017). "Trends in the Incidence, Prevalence, and Survival Outcomes in Patients With Neuroendocrine Tumors in the United States". JAMA Oncol. 3 (10): 1335–1342. doi:10.1001/jamaoncol.2017.0589. PMC 5824320. PMID 28448665.
  14. Quaedvlieg PF, Visser O, Lamers CB, Janssen-Heijen ML, Taal BG (2001). "Epidemiology and survival in patients with carcinoid disease in The Netherlands. An epidemiological study with 2391 patients". Ann Oncol. 12 (9): 1295–300. doi:10.1023/a:1012272314550. PMID 11697843.
  15. Modlin IM, Lye KD, Kidd M (2003). "A 5-decade analysis of 13,715 carcinoid tumors". Cancer. 97 (4): 934–59. doi:10.1002/cncr.11105. PMID 12569593.
  16. Hemminki K, Li X (2001). "Incidence trends and risk factors of carcinoid tumors: a nationwide epidemiologic study from Sweden". Cancer. 92 (8): 2204–10. doi:10.1002/1097-0142(20011015)92:8<2204::aid-cncr1564>3.0.co;2-r. PMID 11596039.
  17. Hauso O, Gustafsson BI, Kidd M, Waldum HL, Drozdov I, Chan AK; et al. (2008). "Neuroendocrine tumor epidemiology: contrasting Norway and North America". Cancer. 113 (10): 2655–64. doi:10.1002/cncr.23883. PMID 18853416.
  18. Skuladottir H, Hirsch FR, Hansen HH, Olsen JH (2002). "Pulmonary neuroendocrine tumors: incidence and prognosis of histological subtypes. A population-based study in Denmark". Lung Cancer. 37 (2): 127–35. PMID 12140134.
  19. Cao C, Yan TD, Kennedy C, Hendel N, Bannon PG, McCaughan BC (2011). "Bronchopulmonary carcinoid tumors: long-term outcomes after resection". Ann Thorac Surg. 91 (2): 339–43. doi:10.1016/j.athoracsur.2010.08.062. PMID 21256263.
  20. 20.0 20.1 Fink G, Krelbaum T, Yellin A, Bendayan D, Saute M, Glazer M; et al. (2001). "Pulmonary carcinoid: presentation, diagnosis, and outcome in 142 cases in Israel and review of 640 cases from the literature". Chest. 119 (6): 1647–51. doi:10.1378/chest.119.6.1647. PMID 11399686.
  21. Gatta G, Ciccolallo L, Kunkler I, Capocaccia R, Berrino F, Coleman MP; et al. (2006). "Survival from rare cancer in adults: a population-based study". Lancet Oncol. 7 (2): 132–40. doi:10.1016/S1470-2045(05)70471-X. PMID 16455477.
  22. Ito T, Sasano H, Tanaka M, Osamura RY, Sasaki I, Kimura W; et al. (2010). "Epidemiological study of gastroenteropancreatic neuroendocrine tumors in Japan". J Gastroenterol. 45 (2): 234–43. doi:10.1007/s00535-009-0194-8. PMID 20058030.
  23. Ito T, Igarashi H, Nakamura K, Sasano H, Okusaka T, Takano K; et al. (2015). "Epidemiological trends of pancreatic and gastrointestinal neuroendocrine tumors in Japan: a nationwide survey analysis". J Gastroenterol. 50 (1): 58–64. doi:10.1007/s00535-014-0934-2. PMID 24499825.
  24. Ito T, Tanaka M, Imamura M, Neuroendocrine Tumor Workshop Japan (2008). "[Results of a nationwide survey of gastrointestinal tumors in Japan]". Nihon Geka Gakkai Zasshi. 109 (3): 128–32. PMID 18536315.
  25. Ito T, Tanaka M, Sasano H, Osamura YR, Sasaki I, Kimura W; et al. (2007). "Preliminary results of a Japanese nationwide survey of neuroendocrine gastrointestinal tumors". J Gastroenterol. 42 (6): 497–500. doi:10.1007/s00535-007-2056-6. PMID 17671766.
  26. Froudarakis M, Fournel P, Burgard G, Bouros D, Boucheron S, Siafakas NM; et al. (1996). "Bronchial carcinoids. A review of 22 cases". Oncology. 53 (2): 153–8. doi:10.1159/000227552. PMID 8604242.
  27. Hassan MM, Phan A, Li D, Dagohoy CG, Leary C, Yao JC (2008). "Risk factors associated with neuroendocrine tumors: A U.S.-based case-control study". Int J Cancer. 123 (4): 867–73. doi:10.1002/ijc.23529. PMID 18491401.
  28. Oliveira AM, Tazelaar HD, Wentzlaff KA, Kosugi NS, Hai N, Benson A; et al. (2001). "Familial pulmonary carcinoid tumors". Cancer. 91 (11): 2104–9. doi:10.1002/1097-0142(20010601)91:11<2104::aid-cncr1238>3.0.co;2-i. PMID 11391591.
  29. Ramage et alia say that "response to chemotherapy in patients with strongly positive carcinoid tumours was of the order of only 10% whereas patients with SSRS negative tumours had a response rate in excess of 70%. The highest response rates with chemotherapy are seen in the poorly differentiated and anaplastic NETs: response rates of 70% or more have been seen with cisplatin and etoposide based combinations. These responses may be relatively short lasting in the order of only 8–10 months. Response rates for pancreatic islet cell tumours vary between 40% and 70% and usually involve combinations of streptozotocin (or lomustine), dacarbazine, 5-fluorouracil, and adriamycin. However, the best results have been seen from the Mayo clinic where up to 70% response rates with remissions lasting several years have been seen by combining chemoembolisation of the hepatic artery with chemotherapy. The use of chemotherapy for midgut carcinoids has a much lower response rate, with 15–30% of patients deriving benefit, which may only last 6–8 months (Ramage et al. 2005, [4]).

    For 125 patients with histologically proven unresectable islet-cell carcinomas, "median duration of regression was 18 months for the doxorubicin combination and 14 months for the 5-FU combination" (Arnold et al. 2004, 230).

  30. "The liver gets about 80% of its blood and half the oxygen from the portal vein, and only 20% of the blood and the other 50% of the oxygen from the artery.... The liver gets 80% of its blood from the portal vein and 20% from that little hepatic artery. But tumors get 100% of their blood off the hepatic artery, and this has been shown by multiple lines of evidence (Pommier 2003, [5]).

    "The normal liver gets its blood supply from two sources; the portal vein (about 70%) and the hepatic artery (30%)" (Fong and Schoenfield n. d., [6]).

  31. "The theoretical advantage is that higher concentrations of the agents can be delivered to the tumors without subjecting the patients to the systemic toxicity of the agents.... In reality, however, much of the chemotherapeutic agents does end up in the rest of the body" (Fong and Schoenfield, [7]).
  32. The "microspheres preferentially cluster around the periphery of tumor nodules with a high tumor:normal tissue ratio of up to 200:1". The SIRT-spheres therapy is not FDA-approved for GEP-NETs; "it is FDA approved for liver metastases secondary to colorectal carcinoma and is under investigation for treatment of other liver malignancies, such as hepatocellular carcinoma and neuroendocrine malignancies" (Welsh, Kennedy, and Thomadsen 2006, [8]).