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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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| 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 overview|Overview]]== |
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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 historical perspective|Historical Perspective]]== |
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| ==Types== | | ==[[Pancreatic neuroendocrine tumor classification|Classification]]== |
| 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 pathophysiology|Pathophysiology]]== |
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| ==Signs and symptoms== | | ==[[Pancreatic neuroendocrine tumor causes|Causes]]== |
| 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 differential diagnosis|Differentiating Pancreatic neuroendocrine tumor from other Diseases]]== |
| * [[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 epidemiology and demographics|Epidemiology and Demographics]]== |
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| ==Diagnosis== | | ==[[Pancreatic neuroendocrine tumor risk factors|Risk Factors]]== |
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| ===Imaging=== | | ==[[Pancreatic neuroendocrine tumor natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
| {{expand section|date=December 2014|needs explanation of which studies}}
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| *CT, MRI, EUS, SRS<ref>[http://emedicine.medscape.com/article/276943-workup#a0720 Ong, ES Neoplasms of the Endocrine Pancreas Workup - Imaging Studies]</ref>
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| *[[Octreotide scan]]ing
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| ===Biochemical evaluation=== | | ==Diagnosis== |
| {{expand section|date=December 2014}}
| | [[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]] |
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| ===MEN1===
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| {{expand section|date=December 2014|also potentially mention MEN2 and Hippel}}
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| Personal and family history should be evaluated for [[MEN1]].
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| ==Staging==
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| 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.<ref name="NCCN_NET201501"/>{{rp|52}} 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.<ref name=Oberg-2012 />
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| <gallery class="center" caption="Pancreatic neuroendocrine tumor staging ([[American Joint Committee on Cancer|AJCC]])">
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| File:Pancrea2.png|Stage T1
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| 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.<ref name="NCCN_NET201501" />
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| In functioning PanNETs, [[octreotide]] is usually recommended prior to biopsy<ref name="NCCN_NET201501" />{{rp|21}} or surgery<ref name="NCCN_NET201501" />{{rp|45}} but is generally avoided in [[insulinoma]]s to avoid profound [[hypoglycemia]].<ref name="NCCN_NET201501" />{{rp|69}}
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| PanNETs in [[MEN1]] are often multiple, and thus require different treatment and surveillance strategies.<ref name="NCCN_NET201501" />
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| Some PanNETs are more responsive to [[chemotherapy]] than are gastroenteric [[carcinoid]] tumors. Several agents have shown activity.<ref name="Benson2010" /> 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)<ref name="Benson2010" /><ref name="Tejani2014" /> and capecitabine with temozolomide.<ref name="Tejani2014" /> Although marginally effective in well-differentiated PETs, [[cisplatin]] with [[etoposide]] has some activity in poorly differentiated neuroendocrine cancers (PDNECs),<ref name="Benson2010" /> particularly if the PDNEC has an extremely high [[Ki-67 (protein)|Ki-67]] score of over 50%.<ref name="NCCN_NET201501" />{{rp|30}}
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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.<ref name="ASCOPost20110515Evero" /><ref name="Afinitor-PI" /> The safety and effectiveness of everolimus in carcinoid tumors have not been established.<ref name="ASCOPost20110515Evero" /><ref name="Afinitor-PI" />
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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.<ref name="NCIPET" /><ref name="Sutent-PI" /> 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'.<ref name="EU2010" /> 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.<ref name= "Raymond2011" />
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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;<ref name="Heaphy2011" /> 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]].<ref name="Heaphy2011" />
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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>
| | ==Case Studies== |
| | [[Pancreatic neuroendocrine tumor case study one|Case#1]] |
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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>
| | ==Related chapters== |
| | | * [[Pancreatic cancer]] |
| <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>
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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/}} |
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| {{Endocrine gland neoplasia}}
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| {{Epithelial neoplasms}}
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