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| {{Pancreatic neuroendocrine tumor}} | | {{Pancreatic neuroendocrine tumor}} |
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| | '''For patient information on this page, click [[Pancreatic neuroendocrine tumor (patient information)|here]]''' |
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| {{CMG}} | | {{CMG}} |
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| ==Overview== | | {{SK}} Islet-cell carcinoma |
| '''Pancreatic neuroendocrine tumors''' ('''PanNETs''', '''PETs''', or '''PNETs'''), often referred to as "islet cell tumors", or "pancreatic endocrine tumors" are [[neuroendocrine cell|neuroendocrine]] [[neoplasm]]s that arise from [[Cell (biology)|cell]]s of the [[endocrine]] ([[hormonal]]) and [[nervous system]] within the [[pancreas]].
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| | ==[[Pancreatic neuroendocrine tumor overview|Overview]]== |
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| PanNETs are a type of [[neuroendocrine tumor]], representing about one third of [[neuroendocrine tumor#gastroenteropancreatic neuroendocrine tumors (GEP-NET)|gastroenteropancreatic neuroendocrine tumor]]s (GEP-NETs). Many PanNETs are [[benign]], while some are [[malignant]]. Aggressive PanNET tumors have traditionally been termed "islet cell carcinoma".
| | ==[[Pancreatic neuroendocrine tumor historical perspective|Historical Perspective]]== |
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| PanNETs are quite distinct from the usual form of [[pancreatic cancer]], the majority of which are [[adenocarcinoma]]s, which arises in the exocrine pancreas. Only 1 or 2% of clinically significant pancreas neoplasms are PanNETs.
| | ==[[Pancreatic neuroendocrine tumor classification|Classification]]== |
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| ==Types== | | ==[[Pancreatic neuroendocrine tumor pathophysiology|Pathophysiology]]== |
| PanNETs are sometimes abbreviated as PETs or PNETs: such use should not to be confused with the [[primitive neuroectodermal tumor]] (PNET).
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| The majority of PanNETs are [[benign]], while some are [[malignant]]. The World Health Organization (WHO) classification scheme places neuroendocrine tumors into three main categories, which emphasize the [[Grading (tumors)|tumor grade]] rather than the [[anatomy|anatomical origin]]. In practice, those tumors termed well or intermediately [[Grading (tumors)|differentiated]] PanNETs in the WHO scheme are sometimes called "[[islet cell]] tumors." The high grade subtype, termed neuroendocrine cancer (NEC) in the WHO scheme, is synonymous with "islet cell carcinoma".
| | ==[[Pancreatic neuroendocrine tumor causes|Causes]]== |
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| ==Signs and symptoms== | | ==[[Pancreatic neuroendocrine tumor differential diagnosis|Differentiating Pancreatic neuroendocrine tumor from other Diseases]]== |
| Some PanNETs do not cause any symptoms, in which case they may be discovered incidentally on a CT scan performed for a different purpose. Symptoms such as abdominal or back pain or pressure, diarrhea, indigestion, or yellowing of the skin and whites of the eyes can arise from the effects of a larger PanNET tumor, either locally or at a [[metastasis]].<ref>Pancreatic Neuroendocrine Tumors (Islet Cell Tumors) Treatment (PDQ®) National Cancer Institute [http://www.cancer.gov/cancertopics/pdq/treatment/isletcell/Patient/page1]</ref>{{medical citation needed|date=December 2014}}<!--add Burns etc--> About 40%{{medical citation needed|date=December 2014}}<!--NCCN page 66 states 40 to 91%, with their recent series = 22%--> of PanNETS have symptoms related to excessive secretion of [[hormone]]s or active [[polypeptide]]s and are accordingly labeled as "functional"; the symptoms reflect the type of hormone secreted, as discussed below. Up to 60%{{medical citation needed|date=December 2014}} of PanNETs are nonsecretory or nonfunctional, in which there is no secretion, 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. In total, 85% of PanNETs have an elevated blood marker.
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| Functional tumors are often classified by the hormone most strongly secreted, for example:
| | ==[[Pancreatic neuroendocrine tumor epidemiology and demographics|Epidemiology and Demographics]]== |
| * [[gastrinoma]]: the excessive [[gastrin]] causes [[Zollinger–Ellison syndrome]] (ZES) with [[peptic ulcer]]s and [[diarrhea]]
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| * [[insulinoma]]: [[hypoglycemia]] occurs with concurrent elevations of [[insulin]], [[proinsulin]] and [[C peptide]]
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| * [[glucagonoma]]: the symptoms are not all due to glucagon elevations, and include a [[Necrolytic migratory erythema|rash]], sore mouth, altered bowel habits, venous [[thrombosis]], and high blood glucose levels
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| * [[VIPoma]], producing excessive [[vasoactive intestinal peptide]], which may cause profound chronic '''<u>w</u>'''atery <u>'''d'''</u>[[diarrhea|iarrhea]] and resultant [[dehydration]], <u>'''h'''</u>[[hypokalemia|ypokalemia]], and '''<u>a</u>'''[[achlorhydria|chlorhydria]] (WDHA or pancreatic cholera syndrome)
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| * [[somatostatinoma]]: these rare tumors are associated with elevated blood glucose levels, [[achlorhydria]], [[cholelithiasis]], and [[diarrhea]]
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| * less common types include [[adrenocorticotropic hormone|ACTHoma]], [[Corticotropin-releasing hormone|CRH]]oma, [[calcitonin]]oma, [[GHRH]]oma, [[Growth hormone-releasing factor|GRFoma]], and [[parathyroid]] hormone–related peptide tumor
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| In these various types of functional tumors, the frequency of malignancy and the survival [[prognosis]] have been estimated dissimilarly, but a pertinent accessible summary is available.
| | ==[[Pancreatic neuroendocrine tumor risk factors|Risk Factors]]== |
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| ==Staging== | | ==[[Pancreatic neuroendocrine tumor natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
| The 2010 WHO classification of tumors of the digestive system grades all the [[neuroendocrine tumor]]s into three categories, based on their degree of [[Grading (tumors)|cellular differentiation]] (from well-differentiated "NET G1" through to poorly-differentiated "NET G3"). The NCCN recommends use of the same AJCC-UICC staging system as pancreatic adenocarcinoma. Using this scheme, the stage by stage outcomes for PanNETs are dissimilar to pancreatic exocrine cancers.<ref name="NCI_FIG1">National Cancer Institute. Pancreatic Neuroendocrine Tumors (Islet Cell Tumors) Treatment (PDQ®) Incidence and Mortality [http://www.cancer.gov/cancertopics/pdq/treatment/isletcell/HealthProfessional/page1]</ref> A different TNM system for PanNETs has been proposed by The European Neuroendocrine Tumor Society.
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| <gallery class="center" caption="Pancreatic neuroendocrine tumor staging ([[American Joint Committee on Cancer|AJCC]])">
| | ==Diagnosis== |
| File:Pancrea2.png|Stage T1
| | [[Pancreatic neuroendocrine tumor staging| Staging]] | [[Pancreatic neuroendocrine tumor history and symptoms| History and Symptoms]] | [[Pancreatic neuroendocrine tumor physical examination | Physical Examination]] | [[Pancreatic neuroendocrine tumor laboratory findings|Laboratory Findings]] | [[Pancreatic neuroendocrine tumor other imaging findings|Other Imaging Findings]] | [[Pancreatic neuroendocrine tumor other diagnostic studies|Other Diagnostic Studies]] |
| File:Pancrea3.png|Stage T2
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| File:Pancrea4.png|Stage T3
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| File:Pancrea5.png|Stage T4
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| File:Pancrea5.png|Involvement of nearby lymph nodes – Stage N1
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| File:Pancrea7.png|Metastasis – stage M1
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| </gallery>
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| ==Treatment== | | ==Treatment== |
| {{Main|Neuroendocrine tumor}}
| | [[Pancreatic neuroendocrine tumor medical therapy|Medical Therapy]] | [[Pancreatic neuroendocrine tumor surgery|Surgery]] | [[Pancreatic neuroendocrine tumor primary prevention|Primary Prevention]] | [[Pancreatic neuroendocrine tumor secondary prevention|Secondary Prevention]] | [[Pancreatic neuroendocrine tumor future or investigational therapies|Future or Investigational Therapies]] |
| In general, treatment for PanNET encompasses the same array of options as other [[neuroendocrine tumor]]s, as discussed in that main article.<!--duplication of that content here is probably unnecessary – see the main article link--> However, there are some specific differences, which are discussed here.
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| In functioning PanNETs, [[octreotide]] is usually recommended prior to biopsy or surgery but is generally avoided in [[insulinoma]]s to avoid profound [[hypoglycemia]].
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| PanNETs in [[MEN1]] are often multiple, and thus require different treatment and surveillance strategies.
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| Some PanNETs are more responsive to [[chemotherapy]] than are gastroenteric [[carcinoid]] tumors. Several agents have shown activity. In well differentiated PanNETs, chemotherapy is generally reserved for when there are no other treatment options. Combinations of several medicines have been used, such as [[doxorubicin]] with [[streptozocin]] and [[fluorouracil]] (5-FU) and capecitabine with temozolomide. Although marginally effective in well-differentiated PETs, [[cisplatin]] with [[etoposide]] has some activity in poorly differentiated neuroendocrine cancers (PDNECs), particularly if the PDNEC has an extremely high [[Ki-67 (protein)|Ki-67]] score of over 50%.
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| Several [[targeted therapy]] agents have been approved in PanNETs by the [[Food and Drug Administration|FDA]] based on improved [[progression-free survival]] (PFS):
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| * [[everolimus]] (Afinitor) is labeled for treatment of progressive neuroendocrine tumors of pancreatic origin in patients with unresectable, locally advanced or metastatic disease. The safety and effectiveness of everolimus in carcinoid tumors have not been established.
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| * [[sunitinib]] (Sutent) is labeled for treatment of progressive, well-differentiated pancreatic neuroendocrine tumors in patients with unresectable locally advanced or metastatic disease. Sutent also has approval from the European Commission for the treatment of 'unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumors with disease progression in adults'. A phase III study of sunitinib treatment in well differentiated pNET that had worsened within the past 12 months (either advanced or metastatic disease) showed that sunitinib treatment improved [[progression-free survival]] (11.4 months vs. 5.5 months), [[overall survival]], and the [[objective response rate]] (9.3% vs. 0.0%) when compared with placebo.
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| ==Genetics==
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| [[DNA]] [[mutation]] analysis in well-differentiated pancreatic neuroendocrine tumors identified four important findings:<ref name="Jiao2011">{{cite journal |author= Jiao, Y.; Shi, C.; Edil, B. H.; De Wilde, R. F.; Klimstra, D. S.; Maitra, A.; Schulick, R. D.; Tang, L. H.; Wolfgang, C. L.; Choti, M. A.; Velculescu, V. E.; Diaz Jr, L. A.; Vogelstein, B.; Kinzler, K. W.; Hruban, R. H.; Papadopoulos, N.|title= DAXX/ATRX, MEN1, and mTOR Pathway Genes Are Frequently Altered in Pancreatic Neuroendocrine Tumors|journal= Science |volume= 331|issue=6021 |pages=1199–1203|year=2011 |pmid= 21252315|doi= 10.1126/science.1200609}}</ref><ref name=" McKenna2014">{{cite journal |author= McKenna, L. R.; Edil, B. H. |title= Update on pancreatic neuroendocrine tumors |journal= Gland surgery |volume= 3|issue=4 |pages=258–275|year=2014 |pmid=25493258|doi= 10.3978/j.issn.2227-684X.2014.06.03}}</ref>
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| * as expected, the [[gene]]s mutated in NETs, [[MEN1]], [[ATRX]], [[DAXX]], [[TSC2]], [[PTEN (gene)|PTEN]] and [[PIK3CA]],<ref name="Jiao2011" /> are different from the mutated genes previously found in [[pancreatic cancer|pancreatic]] [[adenocarcinoma]].<ref name="Jones2008">{{cite pmid|18772397}}</ref><ref name="Harada2009">{{cite pmid|19077451}}</ref>
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| * one in six well-differentiated pancreatic NETs have mutations in [[mTOR]] pathway genes, such as [[TSC2]], [[PTEN (gene)|PTEN]] and [[PIK3CA]].<ref name="Jiao2011" /> The sequencing discovery might allow selection of which NETs would benefit from mTOR inhibition such as with [[everolimus]], but this awaits validation in a [[clinical trial]].
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| * mutations affecting a new cancer pathway involving [[ATRX]] and [[DAXX]] genes were found in about 40% of pancreatic NETs.<ref name="Jiao2011" /> The proteins encoded by ATRX and DAXX participate in [[chromatin]] remodeling of [[telomere]]s; these mutations are associated with a [[telomerase]]-independent maintenance mechanism termed ALT (alternative lengthening of telomeres) that results in abnormally long telomeric ends of [[chromosomes]].
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| * [[ATRX]]/[[DAXX]] and [[MEN1]] mutations were associated with a better [[prognosis]].<ref name="Jiao2011" />
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| ==References==
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| {{Reflist|2|refs=
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| <--This reference list is organized alphanumerically by arbitrary ref name-->
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| <ref name="Afinitor-PI">http://www.pharma.us.novartis.com/product/pi/pdf/afinitor.pdf</ref>
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| <ref name="ASCOPost20110515Evero">Everolimus Approved for Pancreatic Neuroendocrine Tumors. The ASCO Post. May 15, 2011, Volume 2, Issue 8 http://ascopost.com/articles/may-15-2011/everolimus-approved-for-pancreatic-neuroendocrine-tumors/</ref>
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| <ref name="Benson2010">Benson AB, Myerson RJ, and Sasson AR. Pancreatic, neuroendocrine GI, and adrenal cancers. Cancer Management: A Multidisciplinary Approach 13th edition 2010. ISBN 978-0-615-41824-7 Text is available electronically (but may require free registration) at http://www.cancernetwork.com/cancer-management/pancreatic/article/10165/1802606</ref>
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| <ref name="Burns2012">{{cite journal| author=Burns WR, Edil BH| title=Neuroendocrine pancreatic tumors: guidelines for management and update| journal=Current treatment options in oncology| date=March 2012 |volume=13| issue=1| pages=24–34| pmid=22198808| doi=10.1007/s11864-011-0172-2}}</ref>
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| <ref name="EU2010">{{cite news|url=http://www.genengnews.com/gen-news-highlights/pfizer-scores-new-approval-for-sutent-in-europe/81244326/ |title=Pfizer Scores New Approval for Sutent in Europe |date=2 Dec 2010 }}</ref>
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| <ref name="Grant2005">{{cite journal| author=Grant C | title=Insulinoma| journal= Best Practice & Research Clinical Gastroenterology | date=2005|volume=19 | issue=5| pages=783–798 | pmid=16253900| doi=10.1016/j.bpg.2005.05.008}}</ref>
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| <ref name="Heaphy2011">{{cite journal| author=Heaphy CM, De Wilde RF, Jiao Y, et al | date=2011| title=Altered Telomeres in Tumors with ATRX and DAXX Mutations| journal=Science |volume=333| issue=6041| pages= 425| doi=10.1126/science.1207313 | pmid=3174141 | pmid=21719641}}</ref>
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| <ref name="Jensen2008">{{cite journal| author=Jensen RT, Berna MJ, Bingham DB, Norton JA | title=Inherited pancreatic endocrine tumor syndromes: Advances in molecular pathogenesis, diagnosis, management, and controversies| journal= Cancer | date=2008|volume=113| issue=7 Suppl| pages= 1807–1843| pmid=18798544|pmc=2574000| doi=10.1002/cncr.23648}}</ref>
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| <ref name="Klimstra2010">The PanNET denomination is in line 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". See: {{cite journal |author=Klimstra DS, Modlin IR, Coppola D, et al. |title=The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems |journal=Pancreas |volume=39 |issue=6 |pages=707–12 | date=August 2010 |pmid=20664470 |doi=10.1097/MPA.0b013e3181ec124e |url=http://www.seen.es/docs/apartados/470/The_Pathologic_Classification_of_Neuroendocrine.2.pdf}}</ref>
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| <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|accessdate=December 25, 2014|date=November 11, 2014}}</ref>
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| <ref name="NCIPET">National Cancer Institute. Cancer Drug Information. FDA Approval for Sunitinib Malate. Pancreatic Neuroendocrine Tumors http://www.cancer.gov/cancertopics/druginfo/fda-sunitinib-malate</ref>
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| <ref name=Oberg-2012>{{cite journal |author=Öberg K, Knigge U, Kwekkeboom D, Perren A |title=Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up |journal=Annals of Oncology: Official Journal of the European Society for Medical Oncology / ESMO |volume=23 Suppl 7 |issue= |pages=vii124–30 | date=October 2012 |pmid=22997445 |doi=10.1093/annonc/mds295 |url=http://annonc.oxfordjournals.org/content/23/suppl_7/vii124.long#T2}} ([http://annonc.oxfordjournals.org/content/23/suppl_7/vii124/T5.expansion.html Table 5] outlines the proposed TNM staging system for PanNETs.)</ref>
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| <ref name="PDQ">Pancreatic Neuroendocrine Tumors (Islet Cell Tumors) Treatment (PDQ) Health Professional Version. National Cancer Institute. March 7, 2014. [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0032521/can]</ref>
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| <ref name="Ramage2005">{{cite journal |author=Ramage JK, Davies AH, Ardill J, et al.|title=Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours |journal=Gut |volume=Suppl 4 |issue= suppl_4|pages=iv1–16 |date=Jun 2005 |series=54 |pmid=15888809|pmc=1867801|doi=10.1136/gut.2004.053314|url=http://gut.bmj.com/cgi/content/full/54/suppl_4/iv1}}</ref>
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| <ref name= "Raymond2011">{{cite journal | author = Raymond E, Dahan L, Raoul JL, et al. | year = 2011 | title = Sunitinib malate for the treatment of pancreatic neuroendocrine tumors | url = | journal = N Engl J Med | volume = 364 | issue = 6| pages = 501–13 | pmid = 21306237 | doi=10.1056/NEJMoa1003825}}</ref>
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| <ref name="Sutent-PI">http://labeling.pfizer.com/ShowLabeling.aspx?id=607</ref>
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| <ref name="Tejani2014">{{cite journal| author=Tejani MA, Saif MW (2014). "Pancreatic neuroendocrine tumors: Does chemotherapy work?". JOP : Journal of the pancreas 15 (2): 132–4. doi:10.6092/1590-8577/2301 (inactive 2014-12-26). PMID 24618436}}</ref>
| | ==Case Studies== |
| | [[Pancreatic neuroendocrine tumor case study one|Case#1]] |
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| | ==Related chapters== |
| | * [[Pancreatic cancer]] |
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| ==External links== | | ==External links== |
| * {{DMOZ|Health/Conditions_and_Diseases/Cancer/Gastrointestinal/Pancreatic/Neuroendocrine/}} | | * {{DMOZ|Health/Conditions_and_Diseases/Cancer/Gastrointestinal/Pancreatic/Neuroendocrine/}} |
