{{Short description|Tumors of the endocrine and nervous systems}} {{Infobox medical condition | name = Neuroendocrine tumor | synonyms = | image = Small intestine neuroendocrine tumour high mag.jpg | caption = Micrograph of a neuroendocrine tumor. H&E stain. | pronounce = | field = | symptoms = | complications = | onset = | duration = | types = | causes = | risks = | diagnosis = | differential = | prevention = | treatment = | medication = | prognosis = | frequency = | deaths = | image_size = 250px }} '''Neuroendocrine tumors''' ('''NETs''') are neoplasms that arise from cells of the endocrine (hormonal) and nervous systems. They most commonly, but not only, occur in the intestine, where they are often called carcinoid tumors.
Although there are many kinds of NETs, they are treated as a group of tissue because the cells of these neoplasms share common features, including a similar histological appearance, having special secretory granules, and often producing biogenic amines and polypeptide hormones.<ref name="Ramage2005">{{cite journal | vauthors = Ramage JK, Davies AH, Ardill J, Bax N, Caplin M, Grossman A, Hawkins R, McNicol AM, Reed N, Sutton R, Thakker R, Aylwin S, Breen D, Britton K, Buchanan K, Corrie P, Gillams A, Lewington V, McCance D, Meeran K, Watkinson A | display-authors = 6 | title = Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours | journal = Gut | volume = 54 | issue = Suppl 4 | pages = iv1–i16 | date = June 2005 | pmid = 15888809 | pmc = 1867801 | doi = 10.1136/gut.2004.053314 | series = 54 }}</ref>
The term "neuro" refers to the dense core granules, similar to those in serotonergic neurons that store monoamines. The term "endocrine" refers to the synthesis and secretion of these monoamines. The neuroendocrine system includes endocrine glands such as the pituitary, the parathyroids and the neuroendocrine adrenals, as well as endocrine islet tissue embedded within glandular tissue such as in the pancreas, and scattered cells in the exocrine parenchyma. The latter is known as the diffuse endocrine system.<ref>{{cite journal | vauthors = Scalettar BA, Jacobs C, Fulwiler A, Prahl L, Simon A, Hilken L, Lochner JE | title = Hindered submicron mobility and long-term storage of presynaptic dense-core granules revealed by single-particle tracking | journal = Developmental Neurobiology | volume = 72 | issue = 9 | pages = 1181–1195 | date = September 2012 | pmid = 21976424 | pmc = 3512567 | doi = 10.1002/dneu.20984 }}</ref><ref>{{cite journal | vauthors = Oronsky B, Ma PC, Morgensztern D, Carter CA | title = Nothing But NET: A Review of Neuroendocrine Tumors and Carcinomas | journal = Neoplasia | volume = 19 | issue = 12 | pages = 991–1002 | date = December 2017 | pmid = 29091800 | pmc = 5678742 | doi = 10.1016/j.neo.2017.09.002 }}</ref>
There are several treatments available for neuroendocrine tumors, including surgery, systemic treatments such as chemotherapy and peptide receptor radionuclide therapy, and others<ref name=":1" />. Treatments may be aimed at curing the disease or at relieving symptoms.<ref name=":1" /> {{TOC limit}}
==Classification==
===WHO=== The World Health Organization (WHO) classification scheme places neuroendocrine tumors into three main categories, which emphasize the tumor grade rather than the anatomical origin:<ref name="Klimstra2010"/><ref name="Tan2011"/> * well-differentiated neuroendocrine tumors, further subdivided into tumors with benign and those with uncertain behavior * well-differentiated (low grade) neuroendocrine carcinomas with low-grade malignant behavior * poorly differentiated (high grade) neuroendocrine carcinomas, which are the large cell neuroendocrine and small cell carcinomas.
Additionally, the WHO scheme recognizes mixed tumors with both neuroendocrine and epithelial carcinoma features, such as goblet cell cancer, a rare gastrointestinal tract tumor.<ref name="vanEeden2007">{{cite journal | vauthors = van Eeden S, Offerhaus GJ, Hart AA, Boerrigter L, Nederlof PM, Porter E, van Velthuysen ML | title = Goblet cell carcinoid of the appendix: a specific type of carcinoma | journal = Histopathology | volume = 51 | issue = 6 | pages = 763–773 | date = December 2007 | pmid = 18042066 | doi = 10.1111/j.1365-2559.2007.02883.x | s2cid = 20185589 }}</ref>
Placing a given tumor into one of these categories depends on well-defined histological features: size, lymphovascular invasion, mitotic count, Ki-67 labelling index, invasion of adjacent organs, presence of metastases and whether they produce hormones.<ref name="Klimstra2010"/><ref name="Tan2011"/>
The WHO grading from 2022 endorses a three-tiered grading system for most NETs, in particular NETs of the gastrointestinal or pancreaticobiliary tract, as well as NETs of the upper aerodigestive tract and the salivary glands. The grading system is based on proliferation assessed by mitotic rate and Ki-67 index and stratifies NETs into grade 1 (G1, low-grade), grade 2 (G2, intermediate-grade) and grade 3 (G3, high-grade). Tumor necrosis, although recognized as a factor associated with a potentially worse prognosis, is not included in the grading of NETs of the gastrointestinal or pancreaticobiliary tract. However, the absence or presence of tumor necrosis is a component of the grading of NETs of many other origins, such as the upper aerodigestive tract, the lung and the thymus.<ref name=":0">{{cite journal | vauthors = Rindi G, Mete O, Uccella S, Basturk O, La Rosa S, Brosens LA, Ezzat S, de Herder WW, Klimstra DS, Papotti M, Asa SL | display-authors = 6 | title = Overview of the 2022 WHO Classification of Neuroendocrine Neoplasms | journal = Endocrine Pathology | volume = 33 | issue = 1 | pages = 115–154 | date = March 2022 | pmid = 35294740 | doi = 10.1007/s12022-022-09708-2 | s2cid = 247455289 }}</ref>
Neuroendocrine carcinomas are poorly differentiated high-grade neuroendocrine neoplasms and a designation of tumor grade is therefore redundant.<ref name=":0" /> Lung and thymic neuroendocrine neoplasms are classified in a similar manner, including typical and atypical carcinoids, small cell and large cell neuroendocrine carincomas.<ref name=":0" />
Furthermore, the 2022 WHO classification introduces a two-tiered grading system for medullary thyroid carcinomas based on mitotic count, Ki-67 index and the absence or presence of tumor necrosis. Here, it may be noted that different cut-offs than with tumors of gastrointestinal, aerodigestive and lung origin are applied.<ref name=":0" />
===Anatomic distribution=== Traditionally, neuroendocrine tumors have been classified by their anatomic site of origin. NETs can arise in many different areas of the body, and are most often located in the intestine, pancreas or the lungs. The various kinds of cells that can give rise to NETs are present in endocrine glands and are also diffusely distributed throughout the body, most commonly Kulchitsky cells or similar enterochromaffin-like cells, that are relatively more common in the gastrointestinal and pulmonary systems.<ref name="Liu2001">{{cite journal | vauthors = Liu Y, Sturgis CD, Grzybicki DM, Jasnosz KM, Olson PR, Tong M, Dabbs DD, Raab SS, Silverman JF | display-authors = 6 | title = Microtubule-associated protein-2: a new sensitive and specific marker for pulmonary carcinoid tumor and small cell carcinoma | journal = Modern Pathology | volume = 14 | issue = 9 | pages = 880–885 | date = September 2001 | pmid = 11557784 | doi = 10.1038/modpathol.3880406 | s2cid = 24740130 | doi-access = free }} </ref>
NETs include certain tumors of the gastrointestinal tract and of the pancreatic islet cells,<ref name="Ramage2005"/> certain thymus and lung tumors, and medullary carcinoma of the parafollicular cells of the thyroid.<ref name="Ramage2005"/> Tumors with similar cellular characteristics in the pituitary, parathyroid, and adrenomedullary glands are sometimes included<ref name="Rufini">{{cite journal | vauthors = Rufini V, Calcagni ML, Baum RP | title = Imaging of neuroendocrine tumors | journal = Seminars in Nuclear Medicine | volume = 36 | issue = 3 | pages = 228–247 | date = July 2006 | pmid = 16762613 | doi = 10.1053/j.semnuclmed.2006.03.007 }}</ref> or excluded.<ref name="Ramage2005"/>
Within the broad category of neuroendocrine tumors there are many different tumor types,<ref>{{cite journal | vauthors = Soga J | title = Carcinoids and their variant endocrinomas. An analysis of 11842 reported cases | journal = Journal of Experimental & Clinical Cancer Research | volume = 22 | issue = 4 | pages = 517–530 | date = December 2003 | pmid = 15053292 }}</ref> representing only a small proportion of the tumors or cancers in most of these tissues{{citation needed|date=July 2021}}: * Pituitary gland: Neuroendocrine tumor of the anterior pituitary * Thyroid gland: Neuroendocrine thyroid tumors, particularly medullary carcinoma * Parathyroid tumors * Thymus and mediastinal carcinoid tumors<ref name="Soga1999">{{cite journal | vauthors = 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 = Annals of Thoracic and Cardiovascular Surgery | volume = 5 | issue = 5 | pages = 285–292 | date = October 1999 | pmid = 10550713 }}</ref><ref name="Öberg2008-BronchThymusESMO">{{cite journal | vauthors = Oberg K, Jelic S | title = Neuroendocrine bronchial and thymic tumors: ESMO clinical recommendation for diagnosis, treatment and follow-up | journal = Annals of Oncology | volume = 19 | issue = Suppl 2 | pages = ii102–ii103 | date = May 2008 | pmid = 18456740 | doi = 10.1093/annonc/mdn116 | doi-access = free }}</ref> * Pulmonary neuroendocrine tumors<ref name="Beasley2005">{{cite journal | vauthors = Beasley MB, Brambilla E, Travis WD | title = The 2004 World Health Organization classification of lung tumors | journal = Seminars in Roentgenology | volume = 40 | issue = 2 | pages = 90–97 | date = April 2005 | pmid = 15898407 | doi = 10.1053/j.ro.2005.01.001 }}</ref><ref name="Gustafsson2008">{{cite journal | vauthors = Gustafsson BI, Kidd M, Chan A, Malfertheiner MV, Modlin IM | title = Bronchopulmonary neuroendocrine tumors | journal = Cancer | volume = 113 | issue = 1 | pages = 5–21 | date = July 2008 | pmid = 18473355 | doi = 10.1002/cncr.23542 | s2cid = 22143641 | doi-access = free }}</ref> ** bronchus<ref name="Öberg2008-BronchThymusESMO"/> ** pulmonary carcinoid tumors: typical carcinoid (TC; low-grade); atypical carcinoid (AC; intermediate-grade) ** small-cell lung cancer (SCLC) ** large cell neuroendocrine carcinoma of the lung (LCNEC)<ref name="Wick1992">{{cite journal | vauthors = 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 = American Journal of Clinical Pathology | volume = 97 | issue = 6 | pages = 796–805 | date = June 1992 | pmid = 1317668 | doi = 10.1093/ajcp/97.6.796 }}</ref> * Extrapulmonary small cell carcinomas (ESCC or EPSCC) * Gastroenteropancreatic neuroendocrine tumors (GEP-NET)<ref name="Massironi2008">{{cite journal | vauthors = Massironi S, Sciola V, Peracchi M, Ciafardini C, Spampatti MP, Conte D | title = Neuroendocrine tumors of the gastro-entero-pancreatic system | journal = World Journal of Gastroenterology | volume = 14 | issue = 35 | pages = 5377–5384 | date = September 2008 | pmid = 18803349 | pmc = 2744160 | doi = 10.3748/wjg.14.5377 | doi-access = free }}</ref><ref name="Modlin2008">{{cite journal | vauthors = Modlin IM, Oberg K, Chung DC, Jensen RT, de Herder WW, Thakker RV, Caplin M, Delle Fave G, Kaltsas GA, Krenning EP, Moss SF, Nilsson O, Rindi G, Salazar R, Ruszniewski P, Sundin A | display-authors = 6 | title = Gastroenteropancreatic neuroendocrine tumours | journal = The Lancet. Oncology | volume = 9 | issue = 1 | pages = 61–72 | date = January 2008 | pmid = 18177818 | doi = 10.1016/S1470-2045(07)70410-2 | s2cid = 46127116 | author-link6 = Rajesh Thakker }}</ref> ** 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){{citation needed|date=June 2013}} *** Pancreatic endocrine tumors (if considered separately from foregut GEP-NET)<ref name="Metz2008">{{cite journal | vauthors = Metz DC, Jensen RT | title = Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors | journal = Gastroenterology | volume = 135 | issue = 5 | pages = 1469–1492 | date = November 2008 | pmid = 18703061 | pmc = 2612755 | doi = 10.1053/j.gastro.2008.05.047 }}</ref> ** Midgut GEP-NET (from distal half of 2nd part of the duodenum to the proximal two-thirds of the transverse colon) *** appendix,<ref name="Griniatsos2010">{{cite journal | vauthors = Griniatsos J, Michail O | title = Appendiceal neuroendocrine tumors: Recent insights and clinical implications | journal = World Journal of Gastrointestinal Oncology | volume = 2 | issue = 4 | pages = 192–196 | date = April 2010 | pmid = 21160597 | pmc = 2999180 | doi = 10.4251/wjgo.v2.i4.192 | doi-access = free }}</ref> 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) ** Hindgut GEP-NET<ref name="Ni2010">{{cite journal | vauthors = Ni SJ, Sheng WQ, Du X | title = Pathologic research update of colorectal neuroendocrine tumors | journal = World Journal of Gastroenterology | volume = 16 | issue = 14 | pages = 1713–1719 | date = April 2010 | pmid = 20380002 | pmc = 2852818 | doi = 10.3748/wjg.v16.i14.1713 | doi-access = free }}</ref><ref name="Konishi2010">{{cite journal | vauthors = Konishi T, Watanabe T, Nagawa H, Oya M, Ueno M, Kuroyanagi H, Fujimoto Y, Akiyoshi T, Yamaguchi T, Muto T | display-authors = 6 | title = Treatment of colorectal carcinoids: A new paradigm | journal = World Journal of Gastrointestinal Surgery | volume = 2 | issue = 5 | pages = 153–156 | date = May 2010 | pmid = 21160865 | pmc = 2999232 | doi = 10.4240/wjgs.v2.i5.153 | doi-access = free }}</ref> * Liver<ref name="Soga2002">{{cite journal | vauthors = Soga J | title = Primary hepatic endocrinomas (carcinoids and variant neoplasms). A statistical evaluation of 126 reported cases | journal = Journal of Experimental & Clinical Cancer Research | volume = 21 | issue = 4 | pages = 457–468 | date = December 2002 | pmid = 12636090 }}</ref><ref>{{cite journal | vauthors = Nikfarjam M, Muralidharan V, Christophi C | title = Primary hepatic carcinoid tumours | journal = HPB | volume = 6 | issue = 1 | pages = 13–17 | year = 2004 | pmid = 18333038 | pmc = 2020649 | doi = 10.1080/13651820310017228 }}</ref><ref>{{cite journal | vauthors = Moriura S, Ikeda S, Hirai M, Naiki K, Fujioka T, Yokochi K, Gotou S | title = Hepatic gastrinoma | journal = Cancer | volume = 72 | issue = 5 | pages = 1547–1550 | date = September 1993 | pmid = 8348490 | doi = 10.1002/1097-0142(19930901)72:5<1547::AID-CNCR2820720510>3.0.CO;2-C | doi-access = free }}</ref> and gallbladder<ref>{{cite journal | vauthors = Soga J | title = Primary endocrinomas (carcinoids and variant neoplasms) of the gallbladder. A statistical evaluation of 138 reported cases | journal = Journal of Experimental & Clinical Cancer Research | volume = 22 | issue = 1 | pages = 5–15 | date = March 2003 | pmid = 12725316 }}</ref> * Adrenal tumors, particularly adrenomedullary tumors * Pheochromocytoma * Peripheral nervous system tumors, such as: ** Schwannoma ** paraganglioma ** neuroblastoma * Breast<ref>{{cite journal | vauthors = Soga J, Osaka M, Yakuwa Y | title = Gut-endocrinomas (carcinoids and related endocrine variants) of the breast: an analysis of 310 reported cases | journal = International Surgery | volume = 86 | issue = 1 | pages = 26–32 | year = 2001 | pmid = 11890336 }}</ref> * Genitourinary tract ** urinary tract carcinoid tumor and neuroendocrine carcinoma<ref name="Murali2006">{{cite journal | vauthors = Murali R, Kneale K, Lalak N, Delprado W | title = Carcinoid tumors of the urinary tract and prostate | journal = Archives of Pathology & Laboratory Medicine | volume = 130 | issue = 11 | pages = 1693–1706 | date = November 2006 | pmid = 17076534 | doi = 10.5858/2006-130-1693-CTOTUT }}</ref><ref name="Mikuz1993">{{cite journal | vauthors = Mikuz G | title = [Non-urothelial tumors of the urinary tract] | journal = Verhandlungen der Deutschen Gesellschaft für Pathologie | volume = 77 | pages = 180–198 | year = 1993 | pmid = 7511278 }}</ref> ** ovary ** neuroendocrine tumor of the cervix<ref name="Soga2001Cerv">{{cite journal | vauthors = 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 = Journal of Experimental & Clinical Cancer Research | volume = 20 | issue = 3 | pages = 327–334 | date = September 2001 | pmid = 11718210 }}</ref> ** Prostate tumor with neuroendocrine differentiation<ref>{{cite journal | vauthors = Usmani S, Orevi M, Stefanelli A, Zaniboni A, Gofrit ON, Bnà C, Illuminati S, Lojacono G, Noventa S, Savelli G | display-authors = 6 | title = Neuroendocrine differentiation in castration resistant prostate cancer. Nuclear medicine radiopharmaceuticals and imaging techniques: A narrative review | journal = Critical Reviews in Oncology/Hematology | volume = 138 | pages = 29–37 | date = June 2019 | pmid = 31092382 | doi = 10.1016/j.critrevonc.2019.03.005 | s2cid = 131934021 }}</ref><ref>{{cite journal | vauthors = Davies AH, Beltran H, Zoubeidi A | title = Cellular plasticity and the neuroendocrine phenotype in prostate cancer | journal = Nature Reviews. Urology | volume = 15 | issue = 5 | pages = 271–286 | date = May 2018 | pmid = 29460922 | doi = 10.1038/nrurol.2018.22 | s2cid = 4732323 | author-link3 = Amina Zoubeidi }}</ref> ** testes * Merkel cell carcinoma of skin (trabecular cancer) * Inherited conditions:<ref name="Jensen2008">{{cite journal | vauthors = Jensen RT, Berna MJ, Bingham DB, Norton JA | title = Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management, and controversies | journal = Cancer | volume = 113 | issue = 7 Suppl | pages = 1807–1843 | date = October 2008 | pmid = 18798544 | pmc = 2574000 | doi = 10.1002/cncr.23648 }}</ref> ** multiple endocrine neoplasia type 1 (MEN1) ** multiple endocrine neoplasia type 2 (MEN2) ** von Hippel-Lindau (VHL) disease<ref name="Jensen2008"/> ** neurofibromatosis type 1<ref name="Hirsch2001">{{cite journal | vauthors = Hirsch NP, Murphy A, Radcliffe JJ | title = Neurofibromatosis: clinical presentations and anaesthetic implications | journal = British Journal of Anaesthesia | volume = 86 | issue = 4 | pages = 555–564 | date = April 2001 | pmid = 11573632 | doi = 10.1093/bja/86.4.555 | doi-access = free }}</ref><ref name="Lodish2010">{{cite journal | vauthors = Lodish MB, Stratakis CA | title = Endocrine tumours in neurofibromatosis type 1, tuberous sclerosis and related syndromes | journal = Best Practice & Research. Clinical Endocrinology & Metabolism | volume = 24 | issue = 3 | pages = 439–449 | date = June 2010 | pmid = 20833335 | pmc = 2939061 | doi = 10.1016/j.beem.2010.02.002 }}</ref> ** tuberous sclerosis<ref name="Lodish2010"/><ref name="Dworakowska2008">{{cite journal | vauthors = Dworakowska D, Grossman AB | title = Are neuroendocrine tumours a feature of tuberous sclerosis? A systematic review | journal = Endocrine-Related Cancer | volume = 16 | issue = 1 | pages = 45–58 | date = March 2009 | pmid = 18978035 | doi = 10.1677/ERC-08-0142 | doi-access = free }}</ref> ** Carney complex<ref name="OMIM160980">{{cite web | work = OMIM - Online Mendelian Inheritance in Man. | title = Carney Complex, type 1; CNC1 | id = OMIM 160980 | url = http://www.omim.org/entry/160980 }}</ref><ref name="OMIM605244">{{cite web | work = OMIM - Online Mendelian Inheritance in Man. | title = Carney Complex, type 2; CNC2 | id = OMIM 605244 | url = http://www.omim.org/entry/605244 }}</ref>
===Grading=== Neuroendocrine lesions are graded histologically according to markers of cellular proliferation, rather than cellular polymorphism. The following grading scheme is currently recommended for all gastroenteropancreatic neuroendocrine neoplasms by the World Health Organization:<ref name="WHO grade">{{cite book | veditors = Bosman FT, Carneiro F, Hruban RH, Theise ND |year=2010 |title=WHO Classification of Tumours of the Digestive System|publisher=International Agency for Research on Cancer |location=Lyon |isbn=978-92-832-2432-7 |pages=13–14 |edition=4 }}</ref>
thumb|Mitosis in a neuroendocrine tumor.
{| class="wikitable" |- ! G !! Mitotic count (per 10 HPF) !! Ki-67 index (%) |- | GX || colspan=2 | Grade cannot be assessed |- | G1 || < 2 || < 3% |- | G2 || 2 to 20 || 3–20% |- | G3 || > 20 || > 20% |}
If mitotic count and Ki-67 are discordant, the figure which gives the highest grade is used.
G1 and G2 neuroendocrine neoplasms are called neuroendocrine tumors (NETs) – formerly called carcinoid tumours. G3 neoplasms are called neuroendocrine carcinomas (NECs).{{citation needed|date=May 2021}}
It has been proposed that the current G3 category be further separated into histologically well-differentiated and poorly-differentiated neoplasms to better reflect prognosis.<ref>{{cite journal | vauthors = Basturk O, Yang Z, Tang LH, Hruban RH, Adsay V, McCall CM, Krasinskas AM, Jang KT, Frankel WL, Balci S, Sigel C, Klimstra DS | display-authors = 6 | 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 = The American Journal of Surgical Pathology | volume = 39 | issue = 5 | pages = 683–690 | date = May 2015 | pmid = 25723112 | pmc = 4398606 | doi = 10.1097/PAS.0000000000000408 }}</ref>
===Staging=== thumb|Lymph node metastasis of a neuroendocrine tumor Currently there is no one staging system for all neuroendocrine neoplasms. Well-differentiated lesions generally have their own staging system based on anatomical location, whereas poorly differentiated and mixed lesions are staged as carcinomas of that location. For example, gastric NEC and mixed adenoneuroendocrine cancers are staged as primary carcinoma of the stomach.<ref>{{cite book | veditors = Amin MB |year=2017 |title=AJCC Cancer Staging Manual |publisher=Springer |isbn=978-3-319-40617-6 |page=351 |edition=8 }}</ref>
TNM staging of gastroenteropancreatic Grade 1 and Grade 2 neuroendocrine tumors are as follows:
{| class="wikitable mw-collapsible mw-collapsed" |+ class="nowrap" style="text-align: left;" | Stomach<ref>{{cite book | veditors = Amin MB |year=2017 |title=AJCC Cancer Staging Manual |publisher=Springer |isbn=978-3-319-40617-6 |page=355 | chapter=29 – Neuroendocrine Tumors of the Stomach |edition=8 }}</ref> |- ! scope="col" colspan=2 style="background: #D8F8FB;" | Primary Tumor (T) |- |- ! scope="col" | T Category ! scope="col" | Tumor Criteria |- | TX || Primary tumour cannot be assessed |- | T0 || No evidence of primary tumour |- | T1 || Invades the lamina propria or submucosa, and less than or equal to 1 cm in size |- | T2 || Invades the muscularis propria, or greater than 1 cm in size |- | T3 || Invades through the muscularis propria into subserosal tissue without penetration of overlying serosa |- | T4 || Invades visceral peritoneum (serosal) or other organs or adjacent structures |- ! scope="col" colspan=2 style="background: #F8E147;" | Regional Lymph Node (N) |- |- ! scope="col" | N Category ! scope="col" | N Criteria |- | NX || Regional lymph nodes cannot be assessed |- | N0 || No regional lymph node metastasis |- | N1 || Regional lymph node metastasis |- ! scope="col" colspan=2 style="background: #B0FD70;" | Distant Metastasis (M) |- |- ! scope="col" | M Category ! scope="col" | M Criteria |- | M0 || No distant metastasis |- | M1 || Distant metastasis |- | M1a || Metastasis confined to liver |- | M1b || Metastasis in at least one extra-hepatic site |- | M1c || Both hepatic and extra-hepatic metastases |- ! scope="col" colspan=2 style="background: #FDD1CE;" | AJCC Prognostic Stage Groups |- |- ! scope="col" | Stage ! scope="col" | Criteria |- | I || T1, N0, M0 |- | II || T2 or T3, N0, M0 |- | III || Any T, N1, M0; T4, N0, M0 |- | IV || Any T, any N, M1 |}
{| class="wikitable mw-collapsible mw-collapsed" |+ class="nowrap" style="text-align: left;" | Duodenum / Ampulla of Vater<ref>{{cite book | vauthors = Amin MB |year=2017 |title=AJCC Cancer Staging Manual |publisher=Springer |isbn=978-3-319-40617-6 |page=369 | chapter=30 – Neuroendocrine Tumors of the Duodenum & Ampulla of Vater |edition=8 }}</ref> |- ! scope="col" colspan=2 style="background: #D8F8FB;" | Primary Tumor (T) |- |- ! scope="col" | T Category ! scope="col" | Tumor Criteria |- | TX || Primary tumour cannot be assessed |- | T1 || Invades the mucosa or submucosa only, and less than or equal to 1 cm in size (duodenal tumors)<br />Confined within the sphincter of Oddi, and less than or equal to 1 cm in size (ampullary tumors) |- | T2 || Invades the muscularis propria, or is > 1 cm (duodenal)<br />Invades through sphincter into duodenal submucosa or muscularis propria, or is > 1 cm (ampullary) |- | T3 || Invades the pancreas or peripancreatic adipose tissue |- | T4 || Invades visceral peritoneum (serosal) or other organs |- ! scope="col" colspan=2 style="background: #F8E147;" | Regional Lymph Node (N) |- |- ! scope="col" | N Category ! scope="col" | N Criteria |- | NX || Regional lymph nodes cannot be assessed |- | N0 || No regional lymph node metastasis |- | N1 || Regional lymph node metastasis |- ! scope="col" colspan=2 style="background: #B0FD70;" | Distant Metastasis (M) |- |- ! scope="col" | M Category ! scope="col" | M Criteria |- | M0 || No distant metastasis |- | M1 || Distant metastasis |- | M1a || Metastasis confined to liver |- | M1b || Metastasis in at least one extra-hepatic site |- | M1c || Both hepatic and extra-hepatic metastases |- ! scope="col" colspan=2 style="background: #FDD1CE;" | AJCC Prognostic Stage Groups |- |- ! scope="col" | Stage ! scope="col" | Criteria |- | I || T1, N0, M0 |- | II || T2 or T3, N0, M0 |- | III || T4, N0, M0; Any T, N1, M0 |- | IV || Any T, any N, M1 |}
{| class="wikitable mw-collapsible mw-collapsed" |+ class="nowrap" style="text-align: left;" | Jejunum and Ileum<ref>AJCC, 8th edition: {{cite web|url=https://www.uptodate.com/contents/pathology-classification-and-grading-of-neuroendocrine-neoplasms-arising-in-the-digestive-system|title=Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system| vauthors = Klimstra DS, Yang Z |website=UpToDate | date = 29 October 2019 }}</ref> |- ! scope="col" colspan=2 style="background: #D8F8FB;" | Primary Tumor (T) |- |- ! scope="col" | T Category ! scope="col" | Tumor Criteria |- | TX || Primary tumour cannot be assessed |- | T0 || No evidence of primary tumour |- | T1 || Invades the lamina propria or submucosa, and less than or equal to 1 cm in size |- | T2 || Invades the muscularis propria, or greater than 1 cm in size |- | T3 || Invades through the muscularis propria into subserosal tissue without penetration of overlying serosa |- | T4 || Invades visceral peritoneum (serosal) or other organs or adjacent structures |- ! scope="col" colspan=2 style="background: #F8E147;" | Regional Lymph Node (N) |- |- ! scope="col" | N Category ! scope="col" | N Criteria |- | NX || Regional lymph nodes cannot be assessed |- | N0 || No regional lymph node metastasis |- | N1 || Regional lymph node metastasis less than 12 nodes |- | N2 || Large mesenteric masses (> 2 cm) and / or extensive nodal deposits (12 or greater), especially those that encase the superior mesenteric vessels |- ! scope="col" colspan=2 style="background: #B0FD70;" | Distant Metastasis (M) |- |- ! scope="col" | M Category ! scope="col" | M Criteria |- | M0 || No distant metastasis |- | M1 || Distant metastasis |- | M1a || Metastasis confined to liver |- | M1b || Metastasis in at least one extra-hepatic site |- | M1c || Both hepatic and extra-hepatic metastases |- ! scope="col" colspan=2 style="background: #FDD1CE;" | AJCC Prognostic Stage Groups |- |- ! scope="col" | Stage ! scope="col" | Criteria |- | I || T1, N0, M0 |- | II || T2 or T3, N0, M0 |- | III || Any T, N1 or N2, M0; T4, N0, M0; |- | IV || Any T, any N, M1 |}
{| class="wikitable mw-collapsible mw-collapsed" |+ class="nowrap" style="text-align: left;" | Appendix<ref>{{cite book | vauthors = Amin MB |year=2017 |title=AJCC Cancer Staging Manual |publisher=Springer |isbn=978-3-319-40617-6 |page=392 | chapter=32 – Neuroendocrine Tumors of the Appendix |edition=8 }}</ref> |- ! scope="col" colspan=2 style="background: #D8F8FB;" | Primary Tumor (T) |- |- ! scope="col" | T Category ! scope="col" | Tumor Criteria |- | TX || Primary tumour cannot be assessed |- | T0 || No evidence of primary tumour |- | T1 || 2 cm or less in greatest dimension |- | T2 || Tumor more than 2 cm but less than or equal to 4 cm |- | T3 || Tumor more than 4 cm or with subserosal invasion or involvement of the mesoappendix |- | T4 || Perforates the peritoneum or directly invades other organs or structures (excluding direct mural extension to adjacent subserosa of adjacent bowel) |- ! scope="col" colspan=2 style="background: #F8E147;" | Regional Lymph Node (N) |- |- ! scope="col" | N Category ! scope="col" | N Criteria |- | NX || Regional lymph nodes cannot be assessed |- | N0 || No regional lymph node metastasis |- | N1 || Regional lymph node metastasis |- ! scope="col" colspan=2 style="background: #B0FD70;" | Distant Metastasis (M) |- |- ! scope="col" | M Category ! scope="col" | M Criteria |- | M0 || No distant metastasis |- | M1 || Distant metastasis |- | M1a || Metastasis confined to liver |- | M1b || Metastasis in at least one extra-hepatic site |- | M1c || Both hepatic and extra-hepatic metastases |- ! scope="col" colspan=2 style="background: #FDD1CE;" | AJCC Prognostic Stage Groups |- |- ! scope="col" | Stage ! scope="col" | Criteria |- | I || T1, N0, M0 |- | II || T2 or T3, N0, M0 |- | III || Any T, N1, M0; T4, N1, M0 |- | IV || Any T, any N, M1 |}
{| class="wikitable mw-collapsible mw-collapsed" |+ class="nowrap" style="text-align: left;" | Colon and Rectum<ref>{{cite book | vauthors = Amin MB |year=2017 |title=AJCC Cancer Staging Manual |publisher=Springer |isbn=978-3-319-40617-6 |page=399 | chapter=33 – Neuroendocrine Tumors of the Colon and Rectum |edition=8 }}</ref> |- ! scope="col" colspan=2 style="background: #D8F8FB;" | Primary Tumor (T) |- |- ! scope="col" | T Category ! scope="col" | Tumor Criteria |- | TX || Primary tumour cannot be assessed |- | T0 || No evidence of primary tumour |- | T1 || Invades the lamina propria or submucosa, and less than or equal to 2 cm |- | T1a || Less than 1 cm in greatest dimension |- | T1b || 1–2 cm in greatest dimension |- | T2 || Invades the muscularis propria, or greater than 2 cm in size with invasion of the lamina propria or submucosa |- | T3 || Invades through the muscularis propria into subserosal tissue without penetration of overlying serosa |- | T4 || Invades visceral peritoneum (serosal) or other organs or adjacent structures |- ! scope="col" colspan=2 style="background: #F8E147;" | Regional Lymph Node (N) |- |- ! scope="col" | N Category ! scope="col" | N Criteria |- | NX || Regional lymph nodes cannot be assessed |- | N0 || No regional lymph node metastasis |- | N1 || Regional lymph node metastasis |- ! scope="col" colspan=2 style="background: #B0FD70;" | Distant Metastasis (M) |- |- ! scope="col" | M Category ! scope="col" | M Criteria |- | M0 || No distant metastasis |- | M1 || Distant metastasis |- | M1a || Metastasis confined to liver |- | M1b || Metastasis in at least one extra-hepatic site |- | M1c || Both hepatic and extra-hepatic metastases |- ! scope="col" colspan=2 style="background: #FDD1CE;" | AJCC Prognostic Stage Groups |- |- ! scope="col" | Stage ! scope="col" | Criteria |- | I || T1, N0, M0 |- | IIA || T2, N0, M0 |- | IIB || T3, N0, M0 |- | IIIA || T4, N0, M0 |- | IIIB || Any T, N1, M0 |- | IV || Any T, any N, M1 |}
{| class="wikitable mw-collapsible mw-collapsed" |+ class="nowrap" style="text-align: left;" | Pancreas<ref>{{cite book | vauthors = Amin MB |year=2017 |title=AJCC Cancer Staging Manual |publisher=Springer |isbn=978-3-319-40617-6 |pages=415–16 | chapter=30 – Neuroendocrine Tumors of the Pancreas |edition=8 }}</ref> |- ! scope="col" colspan=2 style="background: #D8F8FB;" | Primary Tumor (T) |- |- ! scope="col" | T Category ! scope="col" | Tumor Criteria |- | TX || Primary tumour cannot be assessed |- | T1 || Limited to the pancreas, less than or equal to 2 cm in size |- | T2 || Limited to the pancreas, 2–4 cm in size |- | T3 || Limited to the pancreas, > 4 cm; or invading the duodenum or bile duct |- | T4 || Invading adjacent organs or the wall of large vessels |- ! scope="col" colspan=2 style="background: #F8E147;" | Regional Lymph Node (N) |- |- ! scope="col" | N Category ! scope="col" | N Criteria |- | NX || Regional lymph nodes cannot be assessed |- | N0 || No regional lymph node involvement |- | N1 || Regional lymph node involvement |- ! scope="col" colspan=2 style="background: #B0FD70;" | Distant Metastasis (M) |- |- ! scope="col" | M Category ! scope="col" | M Criteria |- | M0 || No distant metastasis |- | M1 || Distant metastasis |- | M1a || Metastasis confined to liver |- | M1b || Metastasis in at least one extra-hepatic site |- | M1c || Both hepatic and extra-hepatic metastases |- ! scope="col" colspan=2 style="background: #FDD1CE;" | AJCC Prognostic Stage Groups |- |- ! scope="col" | Stage ! scope="col" | Criteria |- | I || T1, N0, M0 |- | II || T2 or T3, N0, M0 |- | III || Any T, N1, M0; T4, N0, M0 |- | IV || Any T, any N, M1 |}
==Signs and symptoms==
===Gastroenteropancreatic=== Conceptually, there are two main types of NET within the gastroenteropancreatic neuroendocrine tumors (GEP-NET) category: those that arise from the gastrointestinal (GI) system and those that arise from the pancreas. In usage, the term "carcinoid" has often been applied to both, although sometimes it is restrictively applied to NETs of GI origin (as herein), or alternatively to those tumors which secrete functional hormones or polypeptides associated with clinical symptoms, as discussed.{{citation needed|date=November 2015}}
====Carcinoid tumors==== {{Main|Carcinoid}} Carcinoids most commonly affect the small bowel, particularly the ileum, and are the most common malignancy of the appendix. Many carcinoids are asymptomatic and are discovered only upon surgery for unrelated causes. These coincidental carcinoids are common; one study found that one person in ten has them.<ref name="Kimura1991">{{cite journal | vauthors = Kimura W, Kuroda A, Morioka Y | title = Clinical pathology of endocrine tumors of the pancreas. Analysis of autopsy cases | journal = Digestive Diseases and Sciences | volume = 36 | issue = 7 | pages = 933–942 | date = July 1991 | pmid = 2070707 | doi = 10.1007/BF01297144 | s2cid = 20567425 }} "[In] 800 autopsy cases, ... incidence of tumor was 10% (6/60) in individuals having histiological studies of all sections of the pancreas"</ref> Many tumors do not cause symptoms even when they have metastasized.<ref name="Arnold"/> Other tumors, even if very small, can produce adverse effects by secreting hormones.<ref name="Pommier"/>
Ten percent (10%)<ref name="HC">{{cite web | work = Health Communities. | title = Carcinoid Tumor Overview. | url = http://www.healthcommunities.com/carcinoid-malignancy/carcinoid-malignancy-overview.shtml | archive-url = https://web.archive.org/web/20120303205216/http://www.healthcommunities.com/carcinoid-malignancy/carcinoid-malignancy-overview.shtml | archive-date = 2012-03-03 }}</ref> or less of carcinoids, primarily some midgut carcinoids, secrete excessive levels of a range of hormones, most notably serotonin (5-HT) or substance P,<ref name="Kvols">{{cite web | vauthors = Kvols LK | date = 2002 | title = Carcinoid Tumors and the Carcinoid Syndrome: What's New in the Therapeutic Pipeline. | publisher = The Carcinoid Cancer Foundation | work = Carcinoid Symposium 2002 | url = http://www.carcinoid.org/content/carcinoid-tumors-and-carcinoid-syndrome-whats-new-therapeutic-pipeline | archive-url = https://web.archive.org/web/20150105014851/http://www.carcinoid.org/content/carcinoid-tumors-and-carcinoid-syndrome-whats-new-therapeutic-pipeline | archive-date=2015-01-05 }}</ref> causing a constellation of symptoms called carcinoid syndrome:{{citation needed|date=May 2022}} * flushing * diarrhea * asthma or wheezing * congestive heart failure (CHF) * abdominal cramping * peripheral edema * heart palpitations
A carcinoid crisis with profound flushing, bronchospasm, tachycardia, and widely and rapidly fluctuating blood pressure<ref name="Ramage2005"/> can occur if large amounts of hormone are acutely secreted,<ref name="Kvols"/> which is occasionally triggered by factors such as diet,<ref name="Kvols"/> alcohol use,<ref name="Kvols"/> surgery,<ref name="Ramage2005"/><ref name="Kvols"/> chemotherapy,<ref name="Kvols"/> embolization therapy, or radiofrequency ablation.<ref name="Ramage2005"/>
Chronic exposure to high levels of serotonin causes thickening of the heart valves, particularly the tricuspid and the pulmonary valves, and over a long period can lead to congestive heart failure.<ref name="Kvols"/> However, valve replacement is rarely needed.<ref name="Benson2010"/> The excessive outflow of serotonin can cause a depletion of tryptophan leading to niacin deficiency, and thus pellagra,<ref name="Ramage2005"/> which is associated with dermatitis, dementia, and diarrhea. Many other hormones can be secreted by some of these tumors, most commonly growth hormone that can cause acromegaly, or cortisol, that can cause Cushing's syndrome.<ref>{{cite web |url= https://www.lecturio.com/concepts/cushings-syndrome/| title= Cushing's Syndrome|website=The Lecturio Medical Concept Library |access-date= 28 September 2021}}</ref>
Occasionally, haemorrhage or the effects of tumor bulk are the presenting symptoms. Bowel obstruction can occur, sometimes due to fibrosing effects of NET secretory products<ref name="Pommier"/> with an intense desmoplastic reaction at the tumor site, or of the mesentery.
====Pancreatic neuroendocrine tumors==== {{Main|Pancreatic neuroendocrine tumor}}
Pancreatic neuroendocrine tumors (PanNETs) are often referred to as "islet cell tumors",<ref name=PDQ/><ref name="Burns2012">{{cite journal | vauthors = Burns WR, Edil BH | title = Neuroendocrine pancreatic tumors: guidelines for management and update | journal = Current Treatment Options in Oncology | volume = 13 | issue = 1 | pages = 24–34 | date = March 2012 | pmid = 22198808 | doi = 10.1007/s11864-011-0172-2 | s2cid = 7329783 }}</ref> or "pancreatic endocrine tumors".<ref name="Klimstra2010"/>
The PanNET denomination aligns with current WHO guidelines. Historically, PanNETs have also been referred to by a variety of terms, and are still often called "islet cell tumors" or "pancreatic endocrine tumors",<ref name="Klimstra2010"/> given that they originate within the pancreas. PanNETs are quite distinct from the usual form of pancreatic cancer, adenocarcinoma, which arises in the exocrine pancreas. About 95% of pancreatic tumors are adenocarcinoma; only 1–2% of clinically significant pancreas neoplasms are GEP-NETs.{{citation needed|date=November 2015}}
Well- or intermediately-differentiated PanNETs are sometimes called islet cell tumors; neuroendocrine cancer (NEC) (synonymous with islet cell carcinoma) is more aggressive. Up to 60% of PanNETs are nonsecretory or nonfunctional, which either don't secrete, or the quantity or type of products such as pancreatic polypeptide (PPoma), chromogranin A, and neurotensin do not cause a clinical syndrome, although blood levels may be elevated.<ref name="Jensen2008"/> Functional tumors are often classified by the hormone most strongly secreted by the pancreatic neuroendocrine tumor, as discussed in that main article.{{citation needed|date=May 2021}}
===Other=== In addition to the two main categories of GEP-NET, rarer forms of neuroendocrine tumors arise anywhere in the body, including within the lung, thymus, and parathyroid. Bronchial carcinoid can cause airway obstruction, pneumonia, pleurisy, difficulty with breathing, cough, and hemoptysis, or may be associated with weakness, nausea, weight loss, night sweats, neuralgia, and Cushing's syndrome. Some are asymptomatic.{{citation needed|date=November 2015}}Animal neuroendocrine tumors include neuroendocrine cancer of the liver in dogs, and devil facial tumor disease in Tasmanian devils.<ref name="Bostanci">{{cite journal | vauthors = Bostanci A | title = Wildlife biology. A devil of a disease | journal = Science | volume = 307 | issue = 5712 | page = 1035 | date = February 2005 | pmid = 15718445 | doi = 10.1126/science.307.5712.1035 | quote = The tumors [of Devil facial tumor disease] have been characterized as a neuroendocrine cancer | s2cid = 54100368 }}</ref><ref name=BBC_2010>{{Cite news|url=https://news.bbc.co.uk/2/hi/science/nature/8433645.stm|title=Tasmanian devil facial cancer origins 'identified'| vauthors = Kinver M |publisher=BBC|date=January 1, 2010|url-status=live|archive-url=https://web.archive.org/web/20100102052045/http://news.bbc.co.uk/2/hi/science/nature/8433645.stm|archive-date=January 2, 2010}}</ref><ref name=Time_2010>{{Cite news|title=Decoding the Tasmanian Devil's Deadly Cancer|url=http://www.time.com/time/health/article/0,8599,1950787,00.html?xid=rss-topstories| vauthors = Walsh B |publisher=Time|date=January 1, 2010|archive-url=https://web.archive.org/web/20100108083306/http://www.time.com/time/health/article/0,8599,1950787,00.html?xid=rss-topstories|archive-date=January 8, 2010}}</ref>
===Familial syndromes=== Most pancreatic NETs are sporadic.<ref name="PDQ">{{cite journal | author = PDQ Adult Treatment Editorial Board | title = Pancreatic Neuroendocrine Tumors (Islet Cell Tumors) Treatment (PDQ®): Health Professional Version | date = August 2022 | journal = PDQ Cancer Information Summaries [Internet]. | location = Bethesda (MD) | publisher = National Cancer Institute | pmid = 26389309 | url = https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0032521/ }}{{dead link|date=July 2025|bot=medic}}{{cbignore|bot=medic}}</ref> However, neuroendocrine tumors can be seen in several inherited familial syndromes, including:<ref name="Jensen2008"/> * multiple endocrine neoplasia type 1 (MEN1) * multiple endocrine neoplasia type 2 (MEN2) * von Hippel-Lindau (VHL) disease<ref name="Jensen2008"/> * neurofibromatosis type 1<ref name="Hirsch2001"/> * tuberous sclerosis<ref name="Lodish2010"/><ref name="Dworakowska2008"/> * Carney complex<ref name="OMIM160980"/><ref name="OMIM605244"/>
Given these associations, recommendations in NET include family history evaluation, evaluation for second tumors, and in selected circumstances testing for germline mutations such as for MEN1.<ref name="Ramage2005"/>
==Pathophysiology== NETs are believed to arise from various neuroendocrine cells whose normal function is to serve at the neuroendocrine interface. Neuroendocrine cells are present not only in endocrine glands throughout the body that produce hormones, but are found in all body tissues.<ref name="Langley1994">{{cite journal | vauthors = Langley K | title = The neuroendocrine concept today | journal = Annals of the New York Academy of Sciences | volume = 733 | issue = 1 | pages = 1–17 | date = September 1994 | pmid = 7978856 | doi = 10.1111/j.1749-6632.1994.tb17251.x | s2cid = 33139633 | bibcode = 1994NYASA.733....1L }}</ref>
==Diagnosis== {{more citations needed section|date=November 2020}}
===Markers=== Symptoms from secreted hormones may prompt measurement of the corresponding hormones in the blood or their associated urinary products, for initial diagnosis or to assess the interval change in the tumor. Secretory activity of the tumor cells is sometimes dissimilar to the tissue immunoreactivity to particular hormones.<ref name="Ferolla2008"/> [[File:Synaptophysin immunohistochemistry of neuroendocrine tumor.jpg|thumb|Synaptophysin immunohistochemistry of neuroendocrine tumor, staining positively]] Given the diverse secretory activity of NETs there are many other potential markers, but a limited panel is usually sufficient for clinical purposes.<ref name="Ramage2005"/> Aside from the hormones of secretory tumors, the most important markers are: * chromogranin A (CgA), present in 99% of metastatic carcinoid tumors<ref>{{Cite web |url= http://www.gpnotebook.co.uk/simplepage.cfm?ID=953155609| title=investigations – General Practice Notebook | vauthors = McMorran J, Crowther DC, McMorran S, Prince C, YoungMin S, Pleat J, Wacogne I |website= www.gpnotebook.co.uk |language=en |access-date=23 February 2017 |url-status=live |archive-url= https://web.archive.org/web/20170224053811/http://www.gpnotebook.co.uk/simplepage.cfm?ID=953155609 |archive-date= 24 February 2017 }}</ref> * urine 5-hydroxyindoleacetic acid (5-HIAA) * neuron-specific enolase (NSE, gamma-gamma dimer) * synaptophysin (P38)
Newer markers include N-terminally truncated variant of Hsp70 is present in NETs but absent in normal pancreatic islets.<ref name="Öberg2005b">{{cite journal | vauthors = Oberg K | title = Neuroendocrine tumors of the gastrointestinal tract: recent advances in molecular genetics, diagnosis, and treatment | journal = Current Opinion in Oncology | volume = 17 | issue = 4 | pages = 386–391 | date = July 2005 | pmid = 15933475 | doi = 10.1097/01.cco.0000167739.56948.a9 | s2cid = 208286399 }}</ref> High levels of CDX2, a homeobox gene product essential for intestinal development and differentiation, are seen in intestinal NETs. Neuroendocrine secretory protein-55, a member of the chromogranin family, is seen in pancreatic endocrine tumors but not intestinal NETs.<ref name="Öberg2005b"/>
===Imaging=== For morphological imaging, CT-scans, MRIs, sonography (ultrasound), and endoscopy (including endoscopic ultrasound) are commonly used. Multiphase CT and MRI are typically used both for diagnostics and for evaluation of therapy. The multiphase CT should be performed before and after an intravenous injection of an iodine-based contrast agent, both in the late arterial phase and in the portal venous phase (triple-phase study). While MRI is generally superior to CT, both for detection of the primary tumor and for evaluation of metastases, CECT is more widely available, even at academic institutions. Therefore, multiphase CT is often the modality of choice.<ref name="Tan2011">{{cite journal | vauthors = Tan EH, Tan CH | title = Imaging of gastroenteropancreatic neuroendocrine tumors | journal = World Journal of Clinical Oncology | volume = 2 | issue = 1 | pages = 28–43 | date = January 2011 | pmid = 21603312 | pmc = 3095463 | doi = 10.5306/wjco.v2.i1.28 | doi-access = free }}</ref><ref>{{cite journal | vauthors = van Essen M, Sundin A, Krenning EP, Kwekkeboom DJ | title = Neuroendocrine tumours: the role of imaging for diagnosis and therapy | journal = Nature Reviews. Endocrinology | volume = 10 | issue = 2 | pages = 102–114 | date = February 2014 | pmid = 24322649 | doi = 10.1038/nrendo.2013.246 | s2cid = 40129404 }}</ref>
Advances in nuclear medicine imaging, also known as molecular imaging, have improved diagnostic and treatment paradigms in patients with neuroendocrine tumors. This is because of its ability to not only identify sites of disease but also characterize them. Neuroendocrine tumours express somatostatin receptors providing a unique target for imaging. Octreotide is a synthetic modification of somatostatin with a longer half-life.{{citation needed|date=November 2015}} OctreoScan, also called somatostatin receptor scintigraphy (SRS or SSRS), utilizes intravenously administered octreotide that is chemically bound to a radioactive substance, often indium-111, to detect larger lesions with tumor cells that are avid for octreotide.{{citation needed|date=November 2015}}
Somatostatin receptor imaging can now be performed with positron emission tomography (PET) which offers higher resolution, three-dimensional and more rapid imaging. Gallium-68 receptor PET-CT is much more accurate than an Octreotide scan.<ref name="Ga68SSTR">{{cite journal | vauthors = Hofman MS, Kong G, Neels OC, Eu P, Hong E, Hicks RJ | title = High management impact of Ga-68 DOTATATE (GaTate) PET/CT for imaging neuroendocrine and other somatostatin expressing tumours | journal = Journal of Medical Imaging and Radiation Oncology | volume = 56 | issue = 1 | pages = 40–47 | date = February 2012 | pmid = 22339744 | doi = 10.1111/j.1754-9485.2011.02327.x | s2cid = 21843609 | doi-access = free }}</ref> Thus, octreotide scanning for NET tumors is being increasingly replaced by gallium-68 DOTATOC scan.<ref name="NETONC">{{cite journal | vauthors = Scott AT, Howe JR | title = Management of Small Bowel Neuroendocrine Tumors | journal = Journal of Oncology Practice | volume = 14 | issue = 8 | pages = 471–482 | date = August 2018 | pmid = 30096273 | pmc = 6091496 | doi = 10.1200/JOP.18.00135 }}</ref><ref>{{Cite journal |last1=Harbi |first1=Emirhan |last2=Aschner |first2=Michael |date=2025 |title=Nuclear medicine and perspective thoughts in the diagnosis and treatment of pheochromocytoma and paraganglioma |url=https://onlinelibrary.wiley.com/doi/abs/10.1111/jne.70017 |journal=Journal of Neuroendocrinology |language=en |volume=37 |issue=8 |article-number=e70017 |doi=10.1111/jne.70017 |pmid=40042101 |issn=1365-2826}}</ref>
Imaging with fluorine-18 fluorodeoxyglucose (FDG) PET may be valuable to image some neuroendocrine tumors.<ref name="FDGPET">{{cite journal | vauthors = Hofman MS, Hicks RJ | title = Changing paradigms with molecular imaging of neuroendocrine tumors | journal = Discovery Medicine | volume = 14 | issue = 74 | pages = 71–81 | date = July 2012 | pmid = 22846204 | url = http://www.discoverymedicine.com/Michael-S-Hofman/2012/07/26/changing-paradigms-with-molecular-imaging-of-neuroendocrine-tumors | access-date = November 8, 2015 }}</ref> This scan is performed by injected radioactive sugar intravenously. Tumors that grow more quickly use more sugar. Using this scan, the aggressiveness of the tumor can be assessed.{{citation needed|date=November 2015}} However, neuroendocrine tumors are often slow growing and indolent, and these do not show well on FDG-PET.
Functional imaging with gallium-labelled somatostatin analog and 18F-FDG PET tracers ensures better staging and prognostication of neuroendocrine neoplasms.<ref>{{cite journal | vauthors = Hofland J, Kaltsas G, de Herder WW | title = Advances in the Diagnosis and Management of Well-Differentiated Neuroendocrine Neoplasms | journal = Endocrine Reviews | volume = 41 | issue = 2 | pages = 371–403 | date = April 2020 | pmid = 31555796 | pmc = 7080342 | doi = 10.1210/endrev/bnz004 }}</ref>
The combination of somatostatin receptor and FDG PET imaging is able to quantify somatostatin receptor cell surface (SSTR) expression and glycolytic metabolism, respectively.<ref name="FDGPET"/> The ability to perform this as a whole body study is highlighting the limitations of relying on histopathology obtained from a single site. This is enabling better selection of the most appropriate therapy for an individual patient.<ref>{{cite journal | vauthors = Nilica B, Waitz D, Stevanovic V, Uprimny C, Kendler D, Buxbaum S, Warwitz B, Gerardo L, Henninger B, Virgolini I, Rodrigues M | display-authors = 6 | title = Direct comparison of (68)Ga-DOTA-TOC and (18)F-FDG PET/CT in the follow-up of patients with neuroendocrine tumour treated with the first full peptide receptor radionuclide therapy cycle | journal = European Journal of Nuclear Medicine and Molecular Imaging | volume = 43 | issue = 9 | pages = 1585–1592 | date = August 2016 | pmid = 26922350 | pmc = 4932132 | doi = 10.1007/s00259-016-3328-2 }}</ref>
===Histopathology=== [[File:Well-differentiated neuroendocrine tumor with salt-and-pepper chromatin.png|thumb|250px|Nuclei of neuroendocrine tumors often show granular "salt-and-pepper" chromatin, as seen here on H&E stain and Pap stain.<ref>{{cite journal | vauthors = Van Buren G, Rashid A, Yang AD, Abdalla EK, Gray MJ, Liu W, Somcio R, Fan F, Camp ER, Yao JC, Ellis LM | display-authors = 6 | title = The development and characterization of a human midgut carcinoid cell line | journal = Clinical Cancer Research | volume = 13 | issue = 16 | pages = 4704–4712 | date = August 2007 | pmid = 17699847 | doi = 10.1158/1078-0432.CCR-06-2723 | doi-access = free }}</ref>]] [[File:Small intestine neuroendocrine tumour low mag.jpg|thumb|right|200px|Small intestinal neuroendocrine tumor at bottom third of image, showing the typical intramural (within the wall) location, and overlying intact epithelium. H&E stain.]]
====Features in common==== Neuroendocrine tumors, despite differing embryological origin, have common phenotypic characteristics. NETs show tissue immunoreactivity for markers of neuroendocrine differentiation (pan-neuroendocrine tissue markers) and may secrete various peptides and hormones. There is a lengthy list of potential markers in neuroendocrine tumors; several reviews provide assistance in understanding these markers.<ref name="Berretta2010">{{cite journal | vauthors = Berretta M, Cappellani A, Di Vita M, Berretta S, Nasti G, Bearz A, Tirelli U, Canzonieri V | display-authors = 6 | title = Biomarkers in neuroendocrine tumors | journal = Frontiers in Bioscience | volume = 2 | issue = 1 | pages = 332–342 | date = January 2010 | article-number = 68 | pmid = 20036951 | doi = 10.2741/s68 | doi-access = free }}</ref><ref name="Ferolla2008">{{cite journal | vauthors = Ferolla P, Faggiano A, Mansueto G, Avenia N, Cantelmi MG, Giovenali P, Del Basso De Caro ML, Milone F, Scarpelli G, Masone S, Santeusanio F, Lombardi G, Angeletti G, Colao A | display-authors = 6 | title = The biological characterization of neuroendocrine tumors: the role of neuroendocrine markers | journal = Journal of Endocrinological Investigation | volume = 31 | issue = 3 | pages = 277–286 | date = March 2008 | pmid = 18401212 | doi = 10.1007/bf03345602 | s2cid = 25108086 }}</ref> Widely used neuroendocrine tissue markers are various chromogranins, synaptophysin and PGP9.5.<!--? add ??PAX5 and CD56/NCAM--> Neuron-specific enolase (NSE) is less specific.<ref name="Ramage2005"/><ref name="Liu2001"/> The nuclear neuroendocrine marker insulinoma-associated protein-1 (INSM1) has proven to be sensitive as well as highly specific for neuroendocrine differentiation.<ref>{{cite journal | vauthors = Mukhopadhyay S, Dermawan JK, Lanigan CP, Farver CF | title = Insulinoma-associated protein 1 (INSM1) is a sensitive and highly specific marker of neuroendocrine differentiation in primary lung neoplasms: an immunohistochemical study of 345 cases, including 292 whole-tissue sections | journal = Modern Pathology | volume = 32 | issue = 1 | pages = 100–109 | date = January 2019 | pmid = 30154579 | doi = 10.1038/s41379-018-0122-7 | s2cid = 52110673 | doi-access = free }}</ref>
NETs are often small, yellow or tan masses, often located in the submucosa or more deeply intramurally, and they can be very firm due to an accompanying intense desmoplastic reaction. The overlying mucosa may be either intact or ulcerated. Some GEP-NETs invade deeply to involve the mesentery.<ref>{{Cite news|url=https://www.medicinenet.com/script/main/art.asp?articlekey=4356|title=Definition of Mesentery|work=MedicineNet|access-date=2018-04-21|language=en}}</ref> Histologically, NETs are an example of "small blue cell tumors," showing uniform cells which have a round to oval stippled nucleus and scant, pink granular cytoplasm. The cells may align variously in islands, glands or sheets. High power examination shows bland cytopathology. Electron microscopy can identify secretory granules. There is usually minimal pleomorphism but less commonly there can be anaplasia, mitotic activity, and necrosis.{{citation needed|date=November 2015}}
Some neuroendocrine tumor cells possess especially strong hormone receptors, such as somatostatin receptors and uptake hormones strongly. This avidity can assist in diagnosis and may make some tumors vulnerable to hormone targeted therapies.{{citation needed|date=November 2015}}
====Argentaffin and hormone secretion====
NETs from a particular anatomical origin often show similar behavior as a group, such as the foregut (which conceptually includes pancreas, and even thymus, airway and lung NETs), midgut and hindgut; individual tumors within these sites can differ from these group benchmarks:{{citation needed|date=July 2021}} * Foregut NETs are argentaffin negative. Despite low serotonin content, they often secrete 5-hydroxytryptophan (5-HTP), histamine, and several polypeptide hormones. There may be associated atypical carcinoid syndrome, acromegaly, Cushing disease, other endocrine disorders, telangiectasia, or hypertrophy of the skin in the face and upper neck.<ref>{{cite web|title=Carcinoid Tumor| vauthors = Tebbi CK, Windle ML, Cripe TP, Sakamoto KM | veditors = Coppes MJ |url= http://emedicine.medscape.com/article/986050-overview|work=Medscape.com|publisher=WebMD LLC|date=1 April 2014|access-date=3 September 2014 |url-status=live|archive-url=https://web.archive.org/web/20141215204328/http://emedicine.medscape.com/article/986050-overview|archive-date=15 December 2014}}</ref> These tumors can metastasize to bone. * Midgut NETs are argentaffin positive, can produce high levels of serotonin 5-hydroxytryptamine (5-HT), kinins, prostaglandins, substance P (SP), and other vasoactive peptides, and sometimes produce corticotropic hormone (previously adrenocorticotropic hormone [ACTH]). Bone metastasis is uncommon. * Hindgut NETs are argentaffin negative and rarely secrete 5-HT, 5-HTP, or any other vasoactive peptides. Bone metastases are not uncommon.
==Treatment== Several tumor characteristics guide appropriate treatment of a neuroendocrine tumor, including its location, invasiveness, hormone secretion, and metastasis. Treatments may be aimed at curing the disease or at relieving symptoms (palliation).
Treatments can be broadly divided into surgery to remove the tumor or its metastases, systemic therapies which travel throughout the bloodstream to treat the tumor, and locoregional therapies, which target the tumor or its metastases in a specific region e.g. targeted liver therapies to treat liver metastases<ref name=":1" />
Observation may be feasible for non-functioning low-grade neuroendocrine tumors. If the tumor is locally advanced or has metastasized, but is nonetheless slowly growing, treatment that relieves symptoms may often be preferred over immediate challenging surgeries.{{citation needed|date=May 2011}}
Intermediate and high grade tumors (noncarcinoids) are usually best treated by various early interventions (active therapy) rather than observation (wait-and-see approach).<ref name="Warner">{{cite journal | vauthors = Warner RR | title = Enteroendocrine tumors other than carcinoid: a review of clinically significant advances | journal = Gastroenterology | volume = 128 | issue = 6 | pages = 1668–1684 | date = May 2005 | pmid = 15887158 | doi = 10.1053/j.gastro.2005.03.078 | doi-access = free }}</ref>
Treatments have improved over the past several decades, and outcomes are improving.<ref name="Pommier"/> In malignant carcinoid tumors with carcinoid syndrome, the median survival has improved from two years to more than eight years.<ref name="Öberg1998"/>
Detailed guidelines for managing neuroendocrine tumors are available from ESMO,<ref>{{Cite journal |last1=Pavel |first1=M. |last2=Öberg |first2=K. |last3=Falconi |first3=M. |last4=Krenning |first4=E. P. |last5=Sundin |first5=A. |last6=Perren |first6=A. |last7=Berruti |first7=A. |date=2020-07-01 |title=Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up† |url=https://www.annalsofoncology.org/article/S0923-7534(20)36394-8/fulltext |journal=Annals of Oncology |language=English |volume=31 |issue=7 |pages=844–860 |doi=10.1016/j.annonc.2020.03.304 |issn=0923-7534 |pmid=32272208|hdl=11379/532638 |hdl-access=free }}</ref> NCCN,<ref>NCCN Clinical Practice Guidelines in Oncology. Neuroendocrine and Adrenal Tumors. Version 3.2025 October 1, 2025</ref> [https://nanets.net NANETS]<ref>NANETS Guidelines 2025 Edition https://nanets.net/images/NANETS_2025_Symposium_Guidelines_Compendium.pdf</ref>, and [https://www.enets.org ENETS]<ref>{{Cite web |title=ENETS Guidelines & Standards of Care |url=https://www.enets.org/guidelines.html |access-date=2025-11-18 |website=enets.org |language=en}}</ref><ref>{{Cite journal |last1=Kos-Kudła |first1=Beata |last2=Castaño |first2=Justo P. |last3=Denecke |first3=Timm |last4=Grande |first4=Enrique |last5=Kjaer |first5=Andreas |last6=Koumarianou |first6=Anna |last7=de Mestier |first7=Louis |last8=Partelli |first8=Stefano |last9=Perren |first9=Aurel |last10=Stättner |first10=Stefan |last11=Valle |first11=Juan W. |last12=Fazio |first12=Nicola |date=December 2023 |title=European Neuroendocrine Tumour Society (ENETS) 2023 guidance paper for nonfunctioning pancreatic neuroendocrine tumours |journal=Journal of Neuroendocrinology |volume=35 |issue=12 |article-number=e13343 |doi=10.1111/jne.13343 |issn=1365-2826 |pmid=37877341}}</ref><ref>{{Cite journal |last1=Hofland |first1=Johannes |last2=Falconi |first2=Massimo |last3=Christ |first3=Emanuel |last4=Castaño |first4=Justo P. |last5=Faggiano |first5=Antongiulio |last6=Lamarca |first6=Angela |last7=Perren |first7=Aurel |last8=Petrucci |first8=Simona |last9=Prasad |first9=Vikas |last10=Ruszniewski |first10=Philippe |last11=Thirlwell |first11=Christina |last12=Vullierme |first12=Marie-Pierre |last13=Welin |first13=Staffan |last14=Bartsch |first14=Detlef K. |date=August 2023 |title=European Neuroendocrine Tumor Society 2023 guidance paper for functioning pancreatic neuroendocrine tumour syndromes |journal=Journal of Neuroendocrinology |volume=35 |issue=8 |article-number=e13318 |doi=10.1111/jne.13318 |issn=1365-2826 |pmid=37578384|hdl=11573/1686370 |hdl-access=free }}</ref>. The NCI has guidelines for several categories of NET: islet cell tumors of the pancreas,<ref name="NCI-ICT">{{cite web | work = National Cancer Institute | title = Islet Cell Tumors (Endocrine Pancreas) | url = http://www.cancer.gov/cancertopics/types/isletcell | archive-url = https://web.archive.org/web/20110607014639/http://www.cancer.gov/cancertopics/types/isletcell | archive-date = 2011-06-07 }}</ref> gastrointestinal carcinoids,<ref name="NCI-GICarcin">{{cite web | work = National Cancer Institute | title = Gastrointestinal Carcinoid Tumors Treatment | url = http://www.cancer.gov/cancertopics/pdq/treatment/gastrointestinalcarcinoid/HealthProfessional | archive-url = https://web.archive.org/web/20110627175816/http://www.cancer.gov/cancertopics/pdq/treatment/gastrointestinalcarcinoid/HealthProfessional | archive-date=2011-06-27 }}</ref> Merkel cell tumors<ref name="NCI-Merkel">{{cite web | work = National Cancer Institute | title = Merkel cell tumors | date = 21 February 2006 | url = http://www.cancer.gov/cancertopics/pdq/treatment/merkelcell/Patient | archive-url = https://web.archive.org/web/20110607040331/http://www.cancer.gov/cancertopics/pdq/treatment/merkelcell/Patient | archive-date=2011-06-07 }}</ref> and pheochromocytoma/paraganglioma.<ref name="NCI-PheoParag">{{cite web | work = National Cancer Institute | title = Pheochromocytoma and Paraganglioma | url = http://www.cancer.gov/cancertopics/types/pheochromocytoma | archive-url = https://web.archive.org/web/20110607014552/http://www.cancer.gov/cancertopics/types/pheochromocytoma | archive-date=2011-06-07 }}</ref> However, effective predictive biomarkers are yet to be discovered. Similarly, recent advances in understanding neuroendocrine tumor's molecular and genomic alterations still have to find their ways into a definitive management strategy.<ref>{{cite journal | vauthors = Rinke A, Auernhammer CJ, Bodei L, Kidd M, Krug S, Lawlor R, Marinoni I, Perren A, Scarpa A, Sorbye H, Pavel ME, Weber MM, Modlin I, Gress TM | display-authors = 6 | title = Treatment of advanced gastroenteropancreatic neuroendocrine neoplasia, are we on the way to personalised medicine? | journal = Gut | volume = 70 | issue = 9 | pages = 1768–1781 | date = September 2021 | pmid = 33692095 | doi = 10.1136/gutjnl-2020-321300 | s2cid = 232172557 }}</ref>
===Surgery=== Surgery is typically the treatment of choice for neuroendocrine tumors that can be completely removed, .<ref name=":1">{{Cite web |last=NCCN |title=NCCN Guidelines for Patients: Neuroendocrine Tumors |url=https://www.nccn.org/patients/guidelines/content/PDF/neuroendocrine-patient.pdf |access-date=November 11, 2025}}</ref> Even if the tumor has advanced and metastasized to the point where curative surgery is not possible, surgery often has a role for palliation of symptoms and possibly increased lifespan.<ref name="Warner"/>
Cholecystectomy is recommended if there is a consideration of long-term treatment with somatostatin analogs.<ref name="NCCN_NET201501">{{cite web|title=Neuroendocrine tumors, NCCN Guidelines Version 1.2015|website=NCCN Guidelines|publisher=National Comprehensive Cancer Network, Inc.|url=http://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf|access-date=December 25, 2014|date=November 11, 2014}}</ref>{{rp|46}}
===Systemic Therapies===
==== Somatostatin analogs ==== Somatostatin analogs help relieve hormonal symptoms by blocking hormone release from secretory tumors<ref name=":2" />. They can be given by injection under the skin or into the muscle<ref name=":2" />. Octreotide and Lanreotide are the two somatostatin analogs currently approved by the Food and Drug Administration (FDA) and European Medicines Agency as anti-tumor therapies.<ref name=":2">{{Cite journal |last1=La Salvia |first1=A. |last2=Modica |first2=R. |last3=Rossi |first3=R. E. |last4=Spada |first4=F. |last5=Rinzivillo |first5=M. |last6=Panzuto |first6=F. |last7=Faggiano |first7=A. |last8=Cinieri |first8=S. |last9=Fazio |first9=N. |date=2023-06-01 |title=Targeting neuroendocrine tumors with octreotide and lanreotide: Key points for clinical practice from NET specialists |url=https://www.sciencedirect.com/science/article/pii/S0305737223000518 |journal=Cancer Treatment Reviews |volume=117 |article-number=102560 |doi=10.1016/j.ctrv.2023.102560 |pmid=37088017 |issn=0305-7372|url-access=subscription }}</ref> A consensus review has reported on the use of somatostatin analogs for GEP-NETs.<ref name="Öberg2004">{{cite journal | vauthors = Oberg K, Kvols L, Caplin M, Delle Fave G, de Herder W, Rindi G, Ruszniewski P, Woltering EA, Wiedenmann B | display-authors = 6 | title = Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system | journal = Annals of Oncology | volume = 15 | issue = 6 | pages = 966–973 | date = June 2004 | pmid = 15151956 | doi = 10.1093/annonc/mdh216 | doi-access = free }}</ref> These medications may also anatomically stabilize or shrink tumors, and increase progression-free survival.<ref name="pmid19704057">{{cite journal | vauthors = Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Bläker M, Harder J, Arnold C, Gress T, Arnold R | display-authors = 6 | title = Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group | journal = Journal of Clinical Oncology | volume = 27 | issue = 28 | pages = 4656–4663 | date = October 2009 | pmid = 19704057 | doi = 10.1200/JCO.2009.22.8510 }}</ref><ref>{{cite journal | vauthors = Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, Sedláčková E, Cadiot G, Wolin EM, Capdevila J, Wall L, Rindi G, Langley A, Martinez S, Blumberg J, Ruszniewski P | display-authors = 6 | title = Lanreotide in metastatic enteropancreatic neuroendocrine tumors | journal = The New England Journal of Medicine | volume = 371 | issue = 3 | pages = 224–233 | date = July 2014 | pmid = 25014687 | doi = 10.1056/NEJMoa1316158 | doi-access = free }}</ref><ref>{{Cite journal |last1=Kuiper |first1=Jelka |last2=Zoetelief |first2=Eline |last3=Brabander |first3=Tessa |last4=de Herder |first4=Wouter W. |last5=Hofland |first5=Johannes |date=2025 |title=Current status of peptide receptor radionuclide therapy in grade 1 and 2 gastroenteropancreatic neuroendocrine tumours |journal=Journal of Neuroendocrinology |language=en |volume=37 |issue=3 |article-number=e13469 |doi=10.1111/jne.13469 |pmid=39563515 |issn=1365-2826|pmc=11919478 }}</ref>
==== Chemotherapy ==== Chemotherapy treatments work by killing or stopping the growth of fast growing cells, including cancer cells.<ref>{{Cite web |date=2015-04-29 |title=Chemotherapy to Treat Cancer - NCI |url=https://www.cancer.gov/about-cancer/treatment/types/chemotherapy |access-date=2025-11-18 |website=www.cancer.gov |language=en}}</ref> Different chemotherapy drugs can be used depending on the type of NET being treated. Examples of chemotherapy treatments used for neuroendocrine tumors include Carboplatin, Cisplatin, Fluorouracil, and Irinotecan<ref name=":1" />
===== Gastrointestinal neuroendocrine tumors ===== Most gastrointestinal carcinoid tumors tend not to respond to chemotherapy agents,<ref name="Benson2010">{{cite book | vauthors = Benson AB, Myerson RJ, Sasson AR | chapter = Pancreatic, neuroendocrine GI, and adrenal cancers. | title = Cancer Management: A Multidisciplinary Approach | date = March 2011 | publisher = UBM Medica | edition = 13th | isbn = 978-0-615-41824-7 | chapter-url = http://www.cancernetwork.com/cancer-management/pancreatic/article/10165/1802606 | archive-url = https://web.archive.org/web/20110515111725/http://www.cancernetwork.com/cancer-management/pancreatic/article/10165/1802606 | archive-date=2011-05-15 }}, cancernetwork.com; accessed November 8, 2015.</ref> showing 10 to 20% response rates that are typically less than 6 months. Combining chemotherapy medications has not usually been of significant improvement<ref name="Benson2010"/> showing 25 to 35% response rates that are typically less than 9 months.
The exceptions are poorly differentiated (high-grade or anaplastic) metastatic disease, where cisplatin with etoposide may be used<ref name="Benson2010"/> and Somatostatin Receptor Scintigraphy (SSRS) negative tumors which had a response rate in excess of 70% compared to 10% in strongly positive SRSS carcinoid tumors.<ref name="Ramage2005"/>
===== PanNETs ===== {{Main|Pancreatic neuroendocrine tumor#Treatment}}
Targeted therapy with everolimus (Afinitor) and sunitinib (Sutent) is approved by the FDA in unresectable, locally advanced or metastatic PanNETs. Some PanNETs are more responsive to chemotherapy than gastroenteric carcinoid tumors. Several agents have shown activity<ref name="Benson2010"/> and combining several medicines, particularly doxorubicin with streptozocin and fluorouracil (5-FU or f5U), is often more effective. Although marginally effective in well-differentiated PETs, cisplatin with etoposide is active in poorly differentiated neuroendocrine cancers (PDNECs).<ref name="Benson2010"/>
==== Radionuclide therapy ==== thumb|CT scan of a patient with a non-functioning pancreatic NET before and 6 months after treatment with four cycles of peptide receptor radionuclide therapy. The size of the liver is reduced and almost all metastases have disappeared. Peptide receptor radionuclide therapy (PRRT) is a type of radioisotope therapy (RIT)<ref name="Rufini"/> in which a peptide or hormone conjugated to a radionuclide or radioligand is given intravenously. The peptide or hormone needs to have previously shown good uptake of a tracer dose using Somatostatin receptor imaging as detailed above. This type of radiotherapy is a systemic therapy and will impact somatostatin positive disease.<ref>{{cite journal | vauthors = Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH, Jacene H, Bushnell D, O'Dorisio TM, Baum RP, Kulkarni HR, Caplin M, Lebtahi R, Hobday T, Delpassand E, Van Cutsem E, Benson A, Srirajaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Öberg K, Lopera Sierra M, Santoro P, Thevenet T, Erion JL, Ruszniewski P, Kwekkeboom D, Krenning E | display-authors = 6 | title = Phase 3 Trial of <sup>177</sup>Lu-Dotatate for Midgut Neuroendocrine Tumors | language = EN | journal = The New England Journal of Medicine | volume = 376 | issue = 2 | pages = 125–135 | date = January 2017 | pmid = 28076709 | pmc = 5895095 | doi = 10.1056/nejmoa1607427 | hdl = 2445/125256 }}</ref> The peptide receptor may be bound to lutetium-177, yttrium-90, indium-111 and other isotopes including alpha emitters.<ref>{{cite journal | vauthors = Kratochwil C, Giesel FL, Bruchertseifer F, Mier W, Apostolidis C, Boll R, Murphy K, Haberkorn U, Morgenstern A | display-authors = 6 | title = ²¹³Bi-DOTATOC receptor-targeted alpha-radionuclide therapy induces remission in neuroendocrine tumours refractory to beta radiation: a first-in-human experience | journal = European Journal of Nuclear Medicine and Molecular Imaging | volume = 41 | issue = 11 | pages = 2106–2119 | date = November 2014 | pmid = 25070685 | pmc = 4525192 | doi = 10.1007/s00259-014-2857-9 }}</ref> This is a highly targeted and effective therapy with minimal side effects in tumors with high levels of somatostatin cell surface expression, because the radiation is absorbed at the sites of the tumor, or excreted in the urine. The radioactively labelled hormones enter the tumor cells which, together with nearby cells, are damaged by the attached radiation.
PRRT was initially used for low grade NETs. It is also very useful in more aggressive NETs such as Grade 2 and 3 NETs<ref>{{cite journal | vauthors = Kashyap R, Hofman MS, Michael M, Kong G, Akhurst T, Eu P, Zannino D, Hicks RJ | display-authors = 6 | title = Favourable outcomes of (177)Lu-octreotate peptide receptor chemoradionuclide therapy in patients with FDG-avid neuroendocrine tumours | journal = European Journal of Nuclear Medicine and Molecular Imaging | volume = 42 | issue = 2 | pages = 176–185 | date = February 2015 | pmid = 25209134 | doi = 10.1007/s00259-014-2906-4 | s2cid = 20740102 }}</ref><ref>{{cite journal | vauthors = Hofman MS, Michael M, Kashyap R, Hicks RJ | title = Modifying the Poor Prognosis Associated with 18F-FDG-Avid NET with Peptide Receptor Chemo-Radionuclide Therapy (PRCRT) | journal = Journal of Nuclear Medicine | volume = 56 | issue = 6 | pages = 968–969 | date = June 2015 | pmid = 25814516 | doi = 10.2967/jnumed.115.154500 | s2cid = 207407820 | doi-access = free }}</ref> provided they demonstrate high uptake on SSTR imaging to suggest benefit.
=== Locoregional Therapies ===
==== External beam radiation therapy ==== External beam radiation therapy can be used to treat neuroendocrine tumors. This treatment involves using a machine to deliver a beam of radiation targeted to the region of the tumor or metastases in order to kill the tumor cells. Treatments typically take place on scheduled days over several weeks.<ref name=":1" /><ref>{{Cite web |date=2018-05-01 |title=External Beam Radiation Therapy for Cancer - NCI |url=https://www.cancer.gov/about-cancer/treatment/types/radiation-therapy/external-beam |access-date=2025-11-18 |website=www.cancer.gov |language=en}}</ref>
==== Hepatic artery embolization ==== Hepatic artery treatments are performed by placing a small catheter into a blood vessel, guiding it into the hepatic artery, then delivering treatments directly into the hepatic artery (or arteries) to target the tumor or metastases in the liver. Neuroendocrine metastases to the liver can be treated by hepatic artery treatments 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 70–80 percent of their nutrients and 50% their oxygen supply from the portal vein, and thus can survive with the hepatic artery effectively blocked.<ref name="Pommier">{{cite conference | vauthors = Pommier R | date = October 2003 | title = The role of surgery and chemoembolization in the management of carcinoid. | conference = California Carcinoid Fighters Conference. | url = http://www.carcinoid.org/content/role-surgery-and-chemoembolization-management-carcinoid | archive-url = https://web.archive.org/web/20150915090206/http://www.carcinoid.org/content/role-surgery-and-chemoembolization-management-carcinoid | archive-date=2015-09-15 }}</ref><ref name="Fong">{{cite news | vauthors = Fong T, Schoenfield LJ | title = Arterial Chemotherapy Infusion of the Liver (and) Chemoembolization of the Liver (TACE) | url = http://www.medicinenet.com/chemo_infusion_and_chemoembolization_of_liver/article.htm | work = medicinenet.com | archive-url = https://web.archive.org/web/20141224070514/http://www.medicinenet.com/chemo_infusion_and_chemoembolization_of_liver/article.htm | archive-date=2014-12-24 | access-date = 8 November 2015 }}</ref> * [https://www.cancer.gov/publications/dictionaries/cancer-terms/def/transarterial-embolization '''Transarterial embolization'''] (TAE) occludes blood flow to the tumors by injecting small particles (embospheres) into the artery which lodge in downstream capillaries. * [https://www.cancer.gov/publications/dictionaries/cancer-terms/def/transarterial-chemoembolization '''Transarterial chemoembolization'''] (TACE) combines transarterial embolization with chemotherapy delivery: embospheres bound with chemotherapy agents are injected into the hepatic artery and lodge in downstream capillaries. * '''Transarterial radioembolization''' (TACE), also called '''selective internal radiation therapy''' (SIRT)<ref name="Welsh2006">{{cite journal | vauthors = Welsh JS, Kennedy AS, Thomadsen B | title = Selective Internal Radiation Therapy (SIRT) for liver metastases secondary to colorectal adenocarcinoma | journal = International Journal of Radiation Oncology, Biology, Physics | volume = 66 | issue = 2 Suppl | pages = S62–S73 | year = 2006 | pmid = 16979443 | doi = 10.1016/j.ijrobp.2005.09.011 | doi-access = free }}</ref><ref name="VdW2009-page321">{{cite journal | vauthors = Van De Wiele C, Defreyne L, Peeters M, Lambert B | title = Yttrium-90 labelled resin microspheres for treatment of primary and secondary malignant liver tumors | journal = The Quarterly Journal of Nuclear Medicine and Molecular Imaging | volume = 53 | issue = 3 | pages = 317–324 | date = June 2009 | pmid = 19521311 }}</ref> delivers radioactive microsphere therapy (RMT) by injection into the hepatic artery, lodging (as with TAE and TACE) in downstream capillaries. In contrast to hormone-delivered radiotherapy, the lesions need not overexpress peptide receptors. The mechanical targeting delivers the radiation from the yttrium-labeled microspheres selectively to the tumors without unduly affecting the normal liver.<ref name="Salem2002">{{cite journal | vauthors = Salem R, Thurston KG, Carr BI, Goin JE, Geschwind JF | title = Yttrium-90 microspheres: radiation therapy for unresectable liver cancer | journal = Journal of Vascular and Interventional Radiology | volume = 13 | issue = 9 Pt 2 | pages = S223–S229 | date = September 2002 | pmid = 12354840 | doi = 10.1016/S1051-0443(07)61790-4 }}</ref> This type of treatment is FDA approved for liver metastases secondary to colorectal carcinoma and is under investigation for treatment of other liver malignancies, including neuroendocrine malignancies.<ref name="Welsh2006" />thumb|Radiofrequency ablation of a liver tumor
==== Ablation therapy ==== Ablation therapy involves using cold temperatures (cryoablation), heat (thermal ablation), microwaves, radiowaves or ultrasonic waves (histiotripsy) delivered directly to the tumor or metastasis site to kill cancer cells. Ultrasound or CT imaging is used to ensure the correct anatomic region is targeted.<ref name=":1" />
===Other therapies=== AdVince, a type of gene therapy using a genetically modified oncolytic adenovirus<ref>{{Cite web|url=http://mosaicscience.com/story/plutocratic-proposal|title=A plutocratic proposal| vauthors = Masters A |date=2014-10-14|website=Mosaic|publisher=The Wellcome Trust|access-date=2016-07-03|url-status=live|archive-url=https://web.archive.org/web/20160529021009/http://mosaicscience.com/story/plutocratic-proposal|archive-date=2016-05-29}}</ref> and supported by the crowdfunding campaign iCancer<ref>{{Cite web|url=http://icancer.org.uk/about/|title=iCancer web site|website=icancer.org.uk|access-date=2016-07-03|url-status=live|archive-url=https://web.archive.org/web/20160714143714/http://icancer.org.uk/about/|archive-date=2016-07-14}}</ref> was used in a Phase 1 trial against NET in 2016.<ref>{{Cite web|url=https://www.telegraph.co.uk/men/health/can-crowdfunding-really-cure-cancer-alexander-masters-investigat/|title=Can crowdfunding really cure cancer? Alexander Masters investigates a pioneering new project| vauthors = Masters A |author-link=Alexander Masters|date=2016-07-02|publisher=The Telegraph|access-date=2016-07-03|archive-url=https://web.archive.org/web/20160703115042/http://www.telegraph.co.uk/men/health/can-crowdfunding-really-cure-cancer-alexander-masters-investigat/|archive-date=2016-07-03}}</ref>
Further efforts towards more personalized therapies in neuroendocrine tumors are undertaken <ref>{{cite journal | vauthors = Detjen K, Hammerich L, Özdirik B, Demir M, Wiedenmann B, Tacke F, Jann H, Roderburg C | display-authors = 6 | title = Models of Gastroenteropancreatic Neuroendocrine Neoplasms: Current Status and Future Directions | journal = Neuroendocrinology | volume = 111 | issue = 3 | pages = 217–236 | date = 2020-07-02 | pmid = 32615560 | doi = 10.1159/000509864 | doi-access = free }}</ref> i.a. combining drug screening platforms and patient-derived ''ex vivo'' cell cultures that mimic relevant aspects of the original tumors.<ref>{{cite journal | vauthors = April-Monn SL, Kirchner P, Detjen K, Bräutigam K, Trippel MA, Grob T, Statzer C, Maire RS, Kollàr A, Chouchane A, Kunze CA, Horst D, Sadowski MC, Schrader J, Marinoni I, Wiedenmann B, Perren A | display-authors = 6 | title = Patient derived tumoroids of high grade neuroendocrine neoplasms for more personalized therapies | journal = npj Precision Oncology | volume = 8 | issue = 1 | article-number = 59 | date = March 2024 | pmid = 38429350 | pmc = 10907580 | doi = 10.1038/s41698-024-00549-2 }}</ref><ref>{{cite journal | vauthors = April-Monn SL, Wiedmer T, Skowronska M, Maire R, Schiavo Lena M, Trippel M, Di Domenico A, Muffatti F, Andreasi V, Capurso G, Doglioni C, Kim-Fuchs C, Gloor B, Zatelli MC, Partelli S, Falconi M, Perren A, Marinoni I | display-authors = 6 | title = Three-Dimensional Primary Cell Culture: A Novel Preclinical Model for Pancreatic Neuroendocrine Tumors | journal = Neuroendocrinology | volume = 111 | issue = 3 | pages = 273–287 | date = 2020-04-03 | pmid = 32241015 | doi = 10.1159/000507669 | s2cid = 214768622 | doi-access = free | hdl = 11392/2447420 | hdl-access = free }}</ref>
==Epidemiology== Although estimates vary, the annual incidence of clinically significant neuroendocrine tumors is approximately 2.5–5 per 100,000;<ref name="Öberg2011">{{cite journal | vauthors = Oberg K, Castellano D | title = Current knowledge on diagnosis and staging of neuroendocrine tumors | journal = Cancer and Metastasis Reviews | volume = 30 | issue = Suppl 1 | pages = 3–7 | date = March 2011 | pmid = 21311954 | doi = 10.1007/s10555-011-9292-1 | s2cid = 29720754 }}</ref> two thirds are carcinoid tumors and one third are other NETs.
The prevalence has been estimated as 35 per 100,000,<ref name="Öberg2011"/> and may be considerably higher if clinically silent tumors are included. An autopsy study of the pancreas in people who died from unrelated causes discovered a remarkably high incidence of tiny asymptomatic NETs. Routine microscopic study of three random sections of the pancreas found NETs in 1.6%, and multiple sections identified NETs in 10%.<ref>{{cite journal | vauthors = Kimura W, Kuroda A, Morioka Y | title = Clinical pathology of endocrine tumors of the pancreas. Analysis of autopsy cases | journal = Digestive Diseases and Sciences | volume = 36 | issue = 7 | pages = 933–942 | date = July 1991 | pmid = 2070707 | doi = 10.1007/BF01297144 | s2cid = 20567425 }}</ref> As diagnostic imaging increases in sensitivity, such as endoscopic ultrasonography, very small, clinically insignificant NETs may be coincidentally discovered; being unrelated to symptoms, such neoplasms may not require surgical excision.{{citation needed|date=November 2015}}
==History== Small intestinal neuroendocrine tumors were first distinguished from other tumors in 1907.<ref name="Modlin">{{cite journal | vauthors = Modlin IM, Shapiro MD, Kidd M | title = Siegfried Oberndorfer: origins and perspectives of carcinoid tumors | journal = Human Pathology | volume = 35 | issue = 12 | pages = 1440–1451 | date = December 2004 | pmid = 15619202 | doi = 10.1016/j.humpath.2004.09.018 }}</ref><ref name="Arnold">{{cite book|vauthors=Arnold R, Göke R, Wied M, Behr T |chapter=Chapter 15 Neuroendocrine Gastro-Entero-Pancreatic (GEP) Tumors|veditors=Scheppach W, Bresalier RS, Tytgat GN |title=Gastrointestinal and Liver Tumors|publisher=Springer|location=Berlin|year=2003|pages=195–233|isbn=978-3-540-43462-7}}</ref> They were named carcinoid tumors because their slow growth was considered to be "cancer-like" rather than truly cancerous.<ref name="Arnold"/>
However, in 1938 it was recognized that some of these small bowel tumors could be malignant.<ref name="Modlin"/><ref name="Arnold"/> Despite the differences between these two original categories, and further complexities due to subsequent inclusion of other NETs of pancreas and pulmonary origin, all NETs are sometimes (incorrectly) subsumed into the term "carcinoid".{{citation needed|date=November 2015}}
Enterochromaffin cells, which give rise to carcinoid tumors, were identified in 1897 by Nikolai Kulchitsky and their secretion of serotonin was established in 1953<ref name="Modlin"/> when the "flushing" effect of serotonin had become clinically recognized. Carcinoid heart disease was identified in 1952, and carcinoid fibrosis in 1961.<ref name="Modlin"/>
Neuroendocrine tumors were sometimes called APUDomas because these cells often show <u>'''a'''</u>mine <u>'''p'''</u>recursor (L-DOPA and 5-hydroxytryptophan) <u>'''u'''</u>ptake and <u>'''d'''</u>ecarboxylation to produce biogenic amines such as catecholamines and serotonin. Although this behavior was also part of the disproven hypothesis that these cells might all embryologically arise from the neural crest,<ref name="Langley1994"/><ref name="Warner"/><ref name="Öberg1998">{{cite journal | vauthors = Öberg K | title = Carcinoid Tumors: Current Concepts in Diagnosis and Treatment | journal = The Oncologist | volume = 3 | issue = 5 | pages = 339–345 | year = 1998 | pmid = 10388123 | doi = 10.1634/theoncologist.3-5-339 | doi-access = free }}</ref> neuroendocrine cells sometimes produce various types of hormones and amines,<ref name="Öberg1998"/> and they can also have strong receptors for other hormones to which they respond.
There have been multiple nomenclature systems for these tumors,<ref name="Klimstra2010">{{cite journal | vauthors = Klimstra DS, Modlin IR, Coppola D, Lloyd RV, Suster S | title = The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems | journal = Pancreas | volume = 39 | issue = 6 | pages = 707–712 | date = August 2010 | pmid = 20664470 | doi = 10.1097/MPA.0b013e3181ec124e | s2cid = 3735444 | doi-access = free }}</ref> and the differences between these schema have often been confusing. Nonetheless, these systems all distinguish between well-differentiated (low and intermediate-grade) and poorly differentiated (high-grade) NETs. Cellular proliferative rate is of considerable significance in this prognostic assessment.<ref name="Klimstra2010"/>
== References == {{Reflist}}
== External links == {{Commons category|Neuroendocrine tumors}}
{{Medical resources | DiseasesDB = | ICD10 = | ICD10CM = {{ICD10CM|C7A.0}}-{{ICD10CM|C7A.8}}, {{ICD10CM|C7B.0}}-{{ICD10CM|C7B.8}} | ICD9 = {{ICD9|209}} | ICDO = {{ICDO|8013|3}}, {{ICDO|8041|3}}, {{ICDO|8246|3}}, {{ICDO|8247|3}}, {{ICDO|8574|3}} | OMIM = | MedlinePlus = | eMedicineSubj = | eMedicineTopic = | MeshID = D018358 }} {{Epithelial neoplasms|state=collapsed}} {{Authority control}}
{{DEFAULTSORT:Neuroendocrine Tumor}} Category:Nervous system neoplasia Category:Endocrine neoplasia Category:Pancreatic cancer Category:Infectious causes of cancer Category:Neuroendocrinology