Pancreatic islet cell carcinoma: Difference between revisions

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{{SK}}Islet cell carcinoma of pancreas, Pancreatic islet cell cancer
==Overview==
==Overview==


Cancer of the endocrine pancreas includes a highly treatable and often curable collection of tumors.  
[[Pancreas]] has 2 types of cells, [[acinar]] and [[Islet-cell carcinoma|islet]] that produce [[Exocrine gland|exocrine]] and [[Endocrine system|endocrine]] [[Hormone|hormones]] respectively. The pancreatic islet cell carcinomas are also known as [[neuroendocrine]] tumors. They are of 6 types depending on the type of hormone the tumor produces. They can occur sporadically or in association with other disorders such as [[multiple endocrine neoplasia type 1]], [[Von Hippel-Lindau disease|Von Hippel Lindau disease]], [[Neurofibromatosis type I|neurofibromatosis type 1]] and [[tuberous sclerosis]] which are inherited in an autosomal dominant pattern. The most common [[Metastasis|metastatic]] sites are the liver, the lymph nodes, and the bones. The cancer usually presents with [[jaundice]], [[Acholic stools|light-colored stools]], [[Urine|dark urine]], and [[pain]] in the upper or middle [[abdomen]] and back, unexplained [[weight loss]], [[anorexia]], [[fatigue]] and symptoms according to the hormone produced. The treatment depends on the spread of the cancer and includes both medical and surgical treatment.
 
== Historical perspective ==
In 1869, [[Pancreatic islet cell tumors|pancreatic islet cells]] were discovered by Paul Langerhans and the first [[adenoma]] of islets was discovered by Nicholls in 1902<ref name="pmid20187464">{{cite journal| author=Stamatakos M, Safioleas C, Tsaknaki S, Safioleas P, Iannescu R, Safioleas M| title=Insulinoma: a rare neuroendocrine pancreatic tumor. | journal=Chirurgia (Bucur) | year= 2009 | volume= 104 | issue= 6 | pages= 669-73 | pmid=20187464 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20187464  }} </ref>.


==Classification==
==Classification==
Islet tumors may either be functional (produce one or more hormones) or nonfunctional.  The majority of functioning tumors that produce insulin are benign; however, 90% of non-functioning tumors are malignant.
Many islet cell cancers are nonfunctional and produce symptoms from tumor bulk or metastatic dissemination.  Because of the presence of several cell types in the pancreatic islet cells (alpha, beta, delta, A, B, C, D, E), the term islet cell tumors refers to at least five distinct cancers, which when functional, produce unique metabolic and clinical characteristics<ref>Kent RB 3rd, van Heerden JA, Weiland LH: Nonfunctioning islet cell tumors. Ann Surg 193 (2): 185-90, 1981.</ref>.


==Pathophysiology==
Pancreatic islet cell carcinoma is of 6 types: <ref name="pmid15153416">{{cite journal| author=Klöppel G, Perren A, Heitz PU| title=The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification. | journal=Ann N Y Acad Sci | year= 2004 | volume= 1014 | issue=  | pages= 13-27 | pmid=15153416 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15153416  }} </ref>
Pancreatic islet cell carcinoma is of 6 types:
* [[Gastrinoma]]
* [[Gastrinoma]]
* [[Insulinoma]]
* [[Insulinoma]]
* [[VIPoma|Vasoactive intestinal peptide releasing tumo]]<nowiki/>r ([[VIPoma]])
*<nowiki/><nowiki/><nowiki/><nowiki/><nowiki/><nowiki/><nowiki/>[[VIPoma|Vasoactive intestinal peptide releasing tumo]]<nowiki/>r ([[VIPoma]])
* [[Somatostatinoma]]
*<nowiki/><nowiki/><nowiki/>[[Somatostatinoma]]  
 
* [[Glucagonoma]]
* [[Glucagonoma]]
* Non functional islet cell tumor
* Non fu<nowiki/>nc<nowiki/><nowiki/>tional [[islet cell tumor]]
 
==Pathophysiology==
* [[Acinus|Acinar]] cells and Islet cells are the 2 types of cells in pancreas<ref name="pmid18703061">{{cite journal| author=Metz DC, Jensen RT| title=Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors. | journal=Gastroenterology | year= 2008 | volume= 135 | issue= 5 | pages= 1469-92 | pmid=18703061 | doi=10.1053/j.gastro.2008.05.047 | pmc=2612755 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18703061  }} </ref>.
* Acinar cells are responsible for secretion of [[enzymes]] and [[bicarbonate]] involved in the digestion process.
* Islet cells of pancreas play the endocrine organ role, by producing hormones such as [[insulin]], [[gastrin]], [[glucagon]], [[somatostatin]], and [[Vasoactive intestinal peptide|vasoactive intestinal polypeptide]].
* The pancreatic islet cell carcinomas are also known as neuroendocrine tumors<ref name="pmid17312380">{{cite journal| author=Falconi M, Plockinger U, Kwekkeboom DJ, Manfredi R, Korner M, Kvols L et al.| title=Well-differentiated pancreatic nonfunctioning tumors/carcinoma. | journal=Neuroendocrinology | year= 2006 | volume= 84 | issue= 3 | pages= 196-211 | pmid=17312380 | doi=10.1159/000098012 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17312380  }} </ref>.
* They can occur sporadically or in association with other disorders such as [[multiple endocrine neoplasia type 1]], [[VonRecklinghausen's Disease|Von Hippel Lindau disease]], [[Neurofibromatosis type I|neurofibromatosis type 1]] and [[tuberous sclerosis]] which are inherited in an autosomal dominant pattern.
* Islet cell carcinoma is divided into 6 types depending on the type of hormone produced.
* These tumors produce excessive amounts of hormones and cause symptoms similar to the hormones' action.
** [[Insulinoma]] - [[hypoglycemia]] due to decreased [[glucose]] synthesis in liver<ref name="pmid1677058">{{cite journal| author=Service FJ, McMahon MM, O'Brien PC, Ballard DJ| title=Functioning insulinoma--incidence, recurrence, and long-term survival of patients: a 60-year study. | journal=Mayo Clin Proc | year= 1991 | volume= 66 | issue= 7 | pages= 711-9 | pmid=1677058 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1677058  }} </ref>.
** [[Zollinger-Ellison syndrome|Gastrinom]]<nowiki/>a - [[Zollinger-Ellison syndrome]], in which hypersecretion of gastrin causes hydrochloric acid release which causes [[Peptic ulcer|peptic ulcers]].
** [[Glucagonoma]] - hyperglucagonemia, [[zinc deficiency]], [[fatty acid]] deficiency, [[Aminoacid|hypoaminoacidemia]] that may cause [[necrolytic migratory erythema]]<ref name="pmid9113318">{{cite journal| author=Frankton S, Bloom SR| title=Gastrointestinal endocrine tumours. Glucagonomas. | journal=Baillieres Clin Gastroenterol | year= 1996 | volume= 10 | issue= 4 | pages= 697-705 | pmid=9113318 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9113318  }} </ref>.
** [[VIPoma]] - Elevated serum VIP levels leads to increased intracellular [[Cyclic adenosine monophosphate|cAMP]] which causes increased intestinal secretion of water along with Na+, K+, [[HCO3]] -, and Cl- in the intestinal lumen, causing diarrhea and [[Hypokalemia|hypokalemia.]]
** [[Somatostatinoma]] - increased release of somatostatin causes [[Gallstone disease|gallstones]], [[diarrhea]] and fat [[malabsorption]] resulting in [[steatorrhea]].
** Non functional islet cell tumor- These do not produce any hormones, symptoms depend on the size and metastasis. <ref name="pmid9202529">{{cite journal| author=Madura JA, Cummings OW, Wiebke EA, Broadie TA, Goulet RL, Howard TJ| title=Nonfunctioning islet cell tumors of the pancreas: a difficult diagnosis but one worth the effort. | journal=Am Surg | year= 1997 | volume= 63 | issue= 7 | pages= 573-7; discussion 577-8 | pmid=9202529 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9202529  }} </ref>
* The tumor cells are usually round with regular bland nuclei which produce large number of secretory granules with diffuse immunoexpression of [[neuroendocrine]]<nowiki/>markers.
* The poorly differentiated [[neuroendocrine tumor]] (NET) shows an atypical, sheet-like, diffuse and irregular nuclei, less cytoplasmic secretory granules, and limited biomarker immunoexpression.
* Head of the pancreas is most commonly involved (75% of cases) followed by the tail.
* The most common [[metastatic]] sites are the liver, the lymph nodes, and the bones.
* Pancreatic islet cell carcinoma is divided into 3 grades by [[World Health Organization|WHO]].<ref name="pmid22592847">{{cite journal| author=Bond-Smith G, Banga N, Hammond TM, Imber CJ| title=Pancreatic adenocarcinoma. | journal=BMJ | year= 2012 | volume= 344 | issue=  | pages= e2476 | pmid=22592847 | doi=10.1136/bmj.e2476 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22592847  }} </ref>
 
'''2010 WHO grading system for pNETs'''
{| class="wikitable"
! colspan="1" rowspan="1" |
! colspan="1" rowspan="1" |Grade 1 (G1)
! colspan="1" rowspan="1" |Grade 2 (G2)
! colspan="1" rowspan="1" |Grade 3 (G3)
|-
| colspan="1" rowspan="1" |Ki-67 index
| colspan="1" rowspan="1" |<3%
| colspan="1" rowspan="1" |3-20%
| colspan="1" rowspan="1" |>20%
|-
| colspan="1" rowspan="1" |Mitotic count
| colspan="1" rowspan="1" |<2/10 HPF
| colspan="1" rowspan="1" |2-20/10 HPF
| colspan="1" rowspan="1" |>20/10 HPF
|-
| colspan="1" rowspan="1" |Differentiation
| colspan="1" rowspan="1" |Well differentiated
| colspan="1" rowspan="1" |Well differentiated
| colspan="1" rowspan="1" |Poorly differentiated
|-
| colspan="1" rowspan="1" |5-year survival rate
| colspan="1" rowspan="1" |85%
| colspan="1" rowspan="1" |78%
| colspan="1" rowspan="1" |9%
|}
 
== Causes ==
There are no established causes of pancreatic islet cell carcinoma but there is an association with [[MEN 1 syndrome]] and rarely with [[Von Hippel-Lindau disease]], [[Neurofibromatosis 1|Neurofibromatosis-1]] and [[Tuberous sclerosis]]<ref name="pmid26487581">{{cite journal| author=Leoncini E, Carioli G, La Vecchia C, Boccia S, Rindi G| title=Risk factors for neuroendocrine neoplasms: a systematic review and meta-analysis. | journal=Ann Oncol | year= 2016 | volume= 27 | issue= 1 | pages= 68-81 | pmid=26487581 | doi=10.1093/annonc/mdv505 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26487581  }} </ref>.
 
== Epidemiology and Demographics ==
* The incidence of pancreatic islet cell carcinoma is 1 in 100000 people<ref name="pmid25312765">{{cite journal| author=Hallet J, Law CH, Cukier M, Saskin R, Liu N, Singh S| title=Exploring the rising incidence of neuroendocrine tumors: a population-based analysis of epidemiology, metastatic presentation, and outcomes. | journal=Cancer | year= 2015 | volume= 121 | issue= 4 | pages= 589-97 | pmid=25312765 | doi=10.1002/cncr.29099 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25312765  }} </ref>.
 
=== Age ===
* It mostly occurs in fourth to sixth decades of life.
 
=== Gender ===
* Its incidence is equal in both males and females.


==Epidemiology and Demographics==
=== Race ===
They are uncommon cancers with 200 to 1,000 new cases per year and occur in only 1.5% of detailed autopsy series.  
* Race has no effect on the incidence.  


==Staging==
==Staging==
Pancreatic cancer is staged according to the TNM staging system based on the primary tumor, lymph nodes involved and distant metastasis.
Pancreatic cancer is staged according to the TNM staging system based on the [[primary tumor]], [[lymph nodes]] involved and distant [[metastasis]].<ref name="pmid25207767">{{cite journal| author=Ryan DP, Hong TS, Bardeesy N| title=Pancreatic adenocarcinoma. | journal=N Engl J Med | year= 2014 | volume= 371 | issue= 11 | pages= 1039-49 | pmid=25207767 | doi=10.1056/NEJMra1404198 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25207767  }} </ref><ref name="pmid20664470">{{cite journal| author=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 | year= 2010 | volume= 39 | issue= 6 | pages= 707-12 | pmid=20664470 | doi=10.1097/MPA.0b013e3181ec124e | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20664470  }} </ref>


{| class="wikitable"
{| class="wikitable"
Line 89: Line 150:
|Distant [[metastasis]]
|Distant [[metastasis]]
|}
|}
==Screening==
Screening for pancreatic islet cell carcinoma is not done.
== Natural history, complications and prognosis ==
=== Natural history ===
* The cancer usually presents with [[jaundice]], [[Acholic stools|light-colored stools]], [[Urine|dark urine]], [[pain]] in the upper or middle [[abdomen]] and back, unexplained [[weight loss]], [[anorexia]], [[fatigue]] and symptoms according to the hormone produced.<ref name="pmid15258206">{{cite journal| author=Graves TD, Gandhi S, Smith SJ, Sisodiya SM, Conway GS| title=Misdiagnosis of seizures: insulinoma presenting as adult-onset seizure disorder. | journal=J Neurol Neurosurg Psychiatry | year= 2004 | volume= 75 | issue= 8 | pages= 1091-2 | pmid=15258206 | doi=10.1136/jnnp.2003.029249 | pmc=1739168 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15258206  }} </ref><ref name="pmid25984844">{{cite journal| author=de Mestier L, Hentic O, Cros J, Walter T, Roquin G, Brixi H et al.| title=Metachronous hormonal syndromes in patients with pancreatic neuroendocrine tumors: a case-series study. | journal=Ann Intern Med | year= 2015 | volume= 162 | issue= 10 | pages= 682-9 | pmid=25984844 | doi=10.7326/M14-2132 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25984844  }} </ref><ref name="pmid20087335">{{cite journal| author=Zerbi A, Falconi M, Rindi G, Delle Fave G, Tomassetti P, Pasquali C et al.| title=Clinicopathological features of pancreatic endocrine tumors: a prospective multicenter study in Italy of 297 sporadic cases. | journal=Am J Gastroenterol | year= 2010 | volume= 105 | issue= 6 | pages= 1421-9 | pmid=20087335 | doi=10.1038/ajg.2009.747 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20087335  }} </ref>
* Patients with VIPoma may progress to develop watery [[diarrhea]], [[abdominal pain]], [[bloating]], [[nausea]], [[vomiting]], [[skin rash]], [[backache]], [[flushing]], and [[lethargy]].
* The symptoms of insulinoma are found in any age group and start with [[Insulinoma history and symptoms|neuroglycopenic symptoms]] such as [[altered mental status]], [[Visual disturbance|visual disturbances]], [[confusion]] and [[adrenergic]] symptoms such as profuse [[sweating]], [[palpitations]] and [[tremors]].
* Zollinger Ellison syndrome presents with refractory [[peptic ulcer disease]], severe [[gastroesophageal reflux disease]] ([[GERD]]), [[diarrhea]], and finally death, mainly due to complications of the refractory [[peptic ulcer disease]].
* Patients with [[glucagonoma]] may progress to develop [[necrolytic migratory erythema]], [[cheilosis]], [[stomatitis]], [[diarrhea]], [[polyuria]], and [[polydipsia]].
* Patients with [[somatostatinoma]] present with headaches, frequent urination, dry skin and mouth, or feeling hungry, thirsty, tired, or weak, diarrhea, steatorrhea and gallstones.
* If left untreated, patients may progress to develop [[Exocrine gland|exocrine]] [[pancreatic insufficiency]] arising from [[pancreatic duct]] [[obstruction]] leading to [[malabsorption]], [[malnutrition]] and [[cachexia]]. Dudodenal [[obstruction]] and [[Bile duct|biliary]] [[obstruction]] may cause symptoms of [[Intestine|bowel]] [[obstruction]] and [[jaundice]].
* [[Metastasis]] may occur to different sites.
=== Complications ===
* [[Hematemesis]]
* [[Anemia]]
* [[Duodenal ulcer perforation]]
* [[Weight loss]]
* [[Seizure|Seizures]]
* [[Coma]]
* [[Neuropsychiatric]] manifestations include [[depression]], [[dementia]], [[psychosis]], and [[agitation]]
* D[[Dilated cardiomyopathy|ilated cardiomyopathy]]
* [[Cardiac arrest]] from low blood [[potassium]] level
* [[Dehydration]]
* [[Jaundice|Obstructive jaundice]] can present with features of [[cholangitis]]:
* [[Duodenum|Duodenal]] [[obstruction]]
=== Prognosis ===
Prognosis of pancreatic [[islet cell]] carcinoma depends on the following: <ref name="pmid18515795">{{cite journal| author=Halfdanarson TR, Rabe KG, Rubin J, Petersen GM| title=Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival. | journal=Ann Oncol | year= 2008 | volume= 19 | issue= 10 | pages= 1727-33 | pmid=18515795 | doi=10.1093/annonc/mdn351 | pmc=2735065 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18515795  }} </ref>
* Whether or not the [[tumor]] can be removed by [[surgery]].
* The stage of the [[tumor]], the size of the [[tumor]], whether [[cancer]] has spread outside the [[pancreas]].
* The patient’s general health.
* Whether the [[tumor]] has just been diagnosed or has recurred.
* The presence of [[metastasis]] is associated with a particularly poor prognosis. Grade 1 and 2 [[tumor]] have the most favorable prognosis.
* The 10-year event free [[survival rate]] is less than 51.6% with [[metastasis]] and 64.3% without [[metastasis]].
== Diagnosis ==
=== Diagnostic findings ===
* The dynamic spiral [[Computed tomography|CT scan]] with contrast media (oral and IV) enhancement is the gold standard test for the [[diagnosis]] and [[Cancer staging|staging]] of [[pancreatic cancer]]. <ref name="pmid17438169">{{cite journal| author=Vagefi PA, Razo O, Deshpande V, McGrath DJ, Lauwers GY, Thayer SP et al.| title=Evolving patterns in the detection and outcomes of pancreatic neuroendocrine neoplasms: the Massachusetts General Hospital experience from 1977 to 2005. | journal=Arch Surg | year= 2007 | volume= 142 | issue= 4 | pages= 347-54 | pmid=17438169 | doi=10.1001/archsurg.142.4.347 | pmc=3979851 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17438169  }} </ref><ref name="pmid19129613">{{cite journal| author=Horwhat JD, Gerke H, Acosta RD, Pavey DA, Jowell PS| title=Focal or diffuse "fullness" of the pancreas on CT. Usually benign, but EUS plus/minus FNA is warranted to identify malignancy. | journal=JOP | year= 2009 | volume= 10 | issue= 1 | pages= 37-42 | pmid=19129613 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19129613  }} </ref>
** [[Morphology|Morphological]] changes of the [[gland]]
** Destruction of the peripancreatic fat and loss of the sharp margins with surrounding structures
** Involvement of the regional [[Lymph node|lymph nodes]] and adjacent [[Circulatory system|vasculature]]
** [[Pancreatic duct|Pancreatic ductal]] [[Dilation|dilatation]]
** [[Pancreas|Pancreatic]] atrophy
** [[Obstruction]] of the [[common bile duct]] ([[CBD]])
* Measuring hormone levels for specific tumor.
=== History and symptoms ===
History includes: <ref name="pmid20087335">{{cite journal| author=Zerbi A, Falconi M, Rindi G, Delle Fave G, Tomassetti P, Pasquali C et al.| title=Clinicopathological features of pancreatic endocrine tumors: a prospective multicenter study in Italy of 297 sporadic cases. | journal=Am J Gastroenterol | year= 2010 | volume= 105 | issue= 6 | pages= 1421-9 | pmid=20087335 | doi=10.1038/ajg.2009.747 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20087335  }} </ref><ref name="pmid17312380">{{cite journal| author=Falconi M, Plockinger U, Kwekkeboom DJ, Manfredi R, Korner M, Kvols L et al.| title=Well-differentiated pancreatic nonfunctioning tumors/carcinoma. | journal=Neuroendocrinology | year= 2006 | volume= 84 | issue= 3 | pages= 196-211 | pmid=17312380 | doi=10.1159/000098012 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17312380  }} </ref><ref name="pmid15522652">{{cite journal| author=Khorana AA, Fine RL| title=Pancreatic cancer and thromboembolic disease. | journal=Lancet Oncol | year= 2004 | volume= 5 | issue= 11 | pages= 655-63 | pmid=15522652 | doi=10.1016/S1470-2045(04)01606-7 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15522652  }} </ref>
* episodes of [[altered mental status]]/[[confusion]]
* [[Visual]] disturbances
* [[Sweating]]
* Negative history for exogenous [[insulin]] or oral [[hypoglycemic]] agents such as [[Sulfonylureas]]
* [[Palpitations]]
* [[Seizures]]
* [[Tremor|Tremors]]
* Behavioral disturbances
* [[Weakness]]
* [[Abdominal pain]]
* [[Weight loss]]
* [[Loss of appetite]]
* [[Diarrheal|Diarrhea]]
* Heart burn
* [[Necrolytic migratory erythema]] (NME) is a classical symptom observed in patients with glucagonoma and is present in 80% of cases. Associated NME is characterized by the spread of [[Erythematous rash|erythematous blisters]] and swelling across areas subject to greater friction and pressure, including the lower [[abdomen]], [[Buttock|buttocks]], [[perineum]], and [[groin]].
* [[Polyuria]]
* Polydypsia
* [[Weight loss]]
* [[Numbness]] caused due to [[hypokalaemia]]
* [[Flushing|Flushin]]<nowiki/>[[Flushing|g]]
=== Physical examination ===
* [[Jaundice]]
* [[Excoriation|Excoriations]] of the [[skin]] from unrelenting [[Itch|pruritus]]
* [[Pallor]] ±
* [[Thrombophlebitis|Migratory superficial thrombophlebitis]] (classic [[Trousseau's syndrome]])
* [[Abdominal distension]]
* [[Abdominal tenderness]]
* [[Hepatomegaly]]
* [[Splenomegaly]]
* Fluid thrill and percussion depending on [[ascites]]
* [[Erythematous]], ring shaped [[rash]] that [[Blister|blisters]], erodes, and crusts over suggesting [[necrolytic migratory erythema]].
* [[Ophthalmoscopy|Ophthalmoscopic]] exam may be abnormal with findings of [[cotton wool spots]], [[Flame hemorrhages|flame hemorrhage]], and dot and blot [[Bleeding|hemorrhage]]
* Muscle [[atrophy]] may be present
* [[Altered mental status]] in [[insulinoma]]
* [[Tremor|Tremors]]
*
*


==Treatment==
==Treatment==
===Medical Therapy===
===Medical Therapy===
Combination [[chemotherapy]] may provide effective palliation as well as increased survival in selected patients. In patients with indolent, slow-growing metastatic islet cell tumors, the best therapy may be careful observation and no treatment until palliation is required.
 
==== Chemotherapy: <ref name="pmid22996141">{{cite journal| author=Tas F, Sen F, Odabas H, Kılıc L, Keskın S, Yıldız I| title=Performance status of patients is the major prognostic factor at all stages of pancreatic cancer. | journal=Int J Clin Oncol | year= 2013 | volume= 18 | issue= 5 | pages= 839-46 | pmid=22996141 | doi=10.1007/s10147-012-0474-9 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22996141  }} </ref><ref name="pmid19307501">{{cite journal| author=Huguet F, Girard N, Guerche CS, Hennequin C, Mornex F, Azria D| title=Chemoradiotherapy in the management of locally advanced pancreatic carcinoma: a qualitative systematic review. | journal=J Clin Oncol | year= 2009 | volume= 27 | issue= 13 | pages= 2269-77 | pmid=19307501 | doi=10.1200/JCO.2008.19.7921 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19307501  }} </ref><ref name="pmid17986845">{{cite journal| author=Brasiūniene B, Juozaityte E| title=The effect of combined treatment methods on survival and toxicity in patients with pancreatic cancer. | journal=Medicina (Kaunas) | year= 2007 | volume= 43 | issue= 9 | pages= 716-25 | pmid=17986845 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17986845  }} </ref> ====
* [[Paclitaxel]]
* [[Gemcitabine]]
* [[Erlotinib]]
* [[Streptozocin]]
* [[Doxorubicin hydrochloride|Doxorubicin]]
 
==== Symptomatic treatment ====
* [[Octreotide]]
* [[Hepatic artery]] [[embolization]]
* [[Radiation therapy|Radiation]]
* Percutaneous [[ethanol]] injection/ [[Ethanol]] ablation
* [[Radiofrequency ablation]] ([[RFA]])
* [[Cryoablation]]


===Surgery===
===Surgery===
Surgery is the only curative modality.[4,5] Even in those cases not resectable for cure, effective palliation may be achieved because of the slow-growing nature of the majority of these tumors and the potential use of antihormonal pharmacologic therapy (for example, [[cimetidine]] in the ulcer-producing [[Zollinger-Ellison]] syndrome).   
* The different surgical techniques that may be used for resectable [[pancreatic cancer]] include [[pancreaticoduodenectomy]] (Whipple Procedure), pylorus sparing [[Pancreaticoduodenectomy|Whipple procedure]], distal [[pancreatectomy]] and total [[pancreatectomy]]. <ref name="pmid1493387">{{cite journal| author=Bancroft J| title=Sexual behaviour in Britain and France. | journal=BMJ | year= 1992 | volume= 305 | issue= 6867 | pages= 1447-8 | pmid=1493387  | doi= | pmc=1884127 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1493387 }} </ref>


Patients with [[multiple endocrine neoplasia]] syndrome type 1, an [[autosomal dominant]] condition in which 85% have pancreatic islet cell tumors, 90% have hyperparathyroidism, and 65% have pituitary tumors, are less likely to be cured by pancreatic resection than are patients with sporadic islet cell tumors. With the exception of pain relief from bone metastases, radiation therapy has a limited role in this disease<ref>Modlin IM, Lewis JJ, Ahlman H, et al.: Management of unresectable malignant endocrine tumors of the pancreas. Surg Gynecol Obstet 176 (5): 507-18, 1993</ref>.
*<nowiki/>The method of [[Resection|surgical resection]]<nowiki/>depends on the locally invasive characteristics and [[Size consistency|size]] of the [[neoplasm]].
* Minimal [[invasive]] surgery such as<nowiki/> [[laparoscopic surgery]] is preferred especially for small tumors.


==References==
==References==

Latest revision as of 14:37, 9 April 2019

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Jogeet Singh Sekhon, M.D. [2]

Synonyms and keywords:Islet cell carcinoma of pancreas, Pancreatic islet cell cancer

Overview

Pancreas has 2 types of cells, acinar and islet that produce exocrine and endocrine hormones respectively. The pancreatic islet cell carcinomas are also known as neuroendocrine tumors. They are of 6 types depending on the type of hormone the tumor produces. They can occur sporadically or in association with other disorders such as multiple endocrine neoplasia type 1, Von Hippel Lindau disease, neurofibromatosis type 1 and tuberous sclerosis which are inherited in an autosomal dominant pattern. The most common metastatic sites are the liver, the lymph nodes, and the bones. The cancer usually presents with jaundice, light-colored stools, dark urine, and pain in the upper or middle abdomen and back, unexplained weight loss, anorexia, fatigue and symptoms according to the hormone produced. The treatment depends on the spread of the cancer and includes both medical and surgical treatment.

Historical perspective

In 1869, pancreatic islet cells were discovered by Paul Langerhans and the first adenoma of islets was discovered by Nicholls in 1902[1].

Classification

Pancreatic islet cell carcinoma is of 6 types: [2]

Pathophysiology

2010 WHO grading system for pNETs

Grade 1 (G1) Grade 2 (G2) Grade 3 (G3)
Ki-67 index <3% 3-20% >20%
Mitotic count <2/10 HPF 2-20/10 HPF >20/10 HPF
Differentiation Well differentiated Well differentiated Poorly differentiated
5-year survival rate 85% 78% 9%

Causes

There are no established causes of pancreatic islet cell carcinoma but there is an association with MEN 1 syndrome and rarely with Von Hippel-Lindau disease, Neurofibromatosis-1 and Tuberous sclerosis[9].

Epidemiology and Demographics

  • The incidence of pancreatic islet cell carcinoma is 1 in 100000 people[10].

Age

  • It mostly occurs in fourth to sixth decades of life.

Gender

  • Its incidence is equal in both males and females.

Race

  • Race has no effect on the incidence.

Staging

Pancreatic cancer is staged according to the TNM staging system based on the primary tumor, lymph nodes involved and distant metastasis.[11][12]

TNM Classification for Pancreatic Cancer:
Primary tumor
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ
T1 Tumor limited to the pancreas, ≤2 cm in greatest dimension
T2 Tumor limited to the pancreas, >2 cm in greatest dimension
T3 Tumor extends beyond the pancreas but without involvement of the celiac axis or the superior mesenteric artery
T4 Tumor involves the celiac axis or the superior mesenteric artery (unresectable primary tumor)
Regional lymph nodes
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis
Distant metastases
MX Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis

Screening

Screening for pancreatic islet cell carcinoma is not done.

Natural history, complications and prognosis

Natural history

Complications

Prognosis

Prognosis of pancreatic islet cell carcinoma depends on the following: [16]

  • Whether or not the tumor can be removed by surgery.
  • The stage of the tumor, the size of the tumor, whether cancer has spread outside the pancreas.
  • The patient’s general health.
  • Whether the tumor has just been diagnosed or has recurred.
  • The presence of metastasis is associated with a particularly poor prognosis. Grade 1 and 2 tumor have the most favorable prognosis.
  • The 10-year event free survival rate is less than 51.6% with metastasis and 64.3% without metastasis.

Diagnosis

Diagnostic findings

History and symptoms

History includes: [15][4][19]

Physical examination

Treatment

Medical Therapy

Chemotherapy: [20][21][22]

Symptomatic treatment

Surgery

References

  1. ↑ Stamatakos M, Safioleas C, Tsaknaki S, Safioleas P, Iannescu R, Safioleas M (2009). "Insulinoma: a rare neuroendocrine pancreatic tumor". Chirurgia (Bucur). 104 (6): 669–73. PMID 20187464.
  2. ↑ Klöppel G, Perren A, Heitz PU (2004). "The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification". Ann N Y Acad Sci. 1014: 13–27. PMID 15153416.
  3. ↑ Metz DC, Jensen RT (2008). "Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors". Gastroenterology. 135 (5): 1469–92. doi:10.1053/j.gastro.2008.05.047. PMC 2612755. PMID 18703061.
  4. ↑ 4.0 4.1 Falconi M, Plockinger U, Kwekkeboom DJ, Manfredi R, Korner M, Kvols L; et al. (2006). "Well-differentiated pancreatic nonfunctioning tumors/carcinoma". Neuroendocrinology. 84 (3): 196–211. doi:10.1159/000098012. PMID 17312380.
  5. ↑ Service FJ, McMahon MM, O'Brien PC, Ballard DJ (1991). "Functioning insulinoma--incidence, recurrence, and long-term survival of patients: a 60-year study". Mayo Clin Proc. 66 (7): 711–9. PMID 1677058.
  6. ↑ Frankton S, Bloom SR (1996). "Gastrointestinal endocrine tumours. Glucagonomas". Baillieres Clin Gastroenterol. 10 (4): 697–705. PMID 9113318.
  7. ↑ Madura JA, Cummings OW, Wiebke EA, Broadie TA, Goulet RL, Howard TJ (1997). "Nonfunctioning islet cell tumors of the pancreas: a difficult diagnosis but one worth the effort". Am Surg. 63 (7): 573–7, discussion 577-8. PMID 9202529.
  8. ↑ Bond-Smith G, Banga N, Hammond TM, Imber CJ (2012). "Pancreatic adenocarcinoma". BMJ. 344: e2476. doi:10.1136/bmj.e2476. PMID 22592847.
  9. ↑ Leoncini E, Carioli G, La Vecchia C, Boccia S, Rindi G (2016). "Risk factors for neuroendocrine neoplasms: a systematic review and meta-analysis". Ann Oncol. 27 (1): 68–81. doi:10.1093/annonc/mdv505. PMID 26487581.
  10. ↑ Hallet J, Law CH, Cukier M, Saskin R, Liu N, Singh S (2015). "Exploring the rising incidence of neuroendocrine tumors: a population-based analysis of epidemiology, metastatic presentation, and outcomes". Cancer. 121 (4): 589–97. doi:10.1002/cncr.29099. PMID 25312765.
  11. ↑ Ryan DP, Hong TS, Bardeesy N (2014). "Pancreatic adenocarcinoma". N Engl J Med. 371 (11): 1039–49. doi:10.1056/NEJMra1404198. PMID 25207767.
  12. ↑ Klimstra DS, Modlin IR, Coppola D, Lloyd RV, Suster S (2010). "The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems". Pancreas. 39 (6): 707–12. doi:10.1097/MPA.0b013e3181ec124e. PMID 20664470.
  13. ↑ Graves TD, Gandhi S, Smith SJ, Sisodiya SM, Conway GS (2004). "Misdiagnosis of seizures: insulinoma presenting as adult-onset seizure disorder". J Neurol Neurosurg Psychiatry. 75 (8): 1091–2. doi:10.1136/jnnp.2003.029249. PMC 1739168. PMID 15258206.
  14. ↑ de Mestier L, Hentic O, Cros J, Walter T, Roquin G, Brixi H; et al. (2015). "Metachronous hormonal syndromes in patients with pancreatic neuroendocrine tumors: a case-series study". Ann Intern Med. 162 (10): 682–9. doi:10.7326/M14-2132. PMID 25984844.
  15. ↑ 15.0 15.1 Zerbi A, Falconi M, Rindi G, Delle Fave G, Tomassetti P, Pasquali C; et al. (2010). "Clinicopathological features of pancreatic endocrine tumors: a prospective multicenter study in Italy of 297 sporadic cases". Am J Gastroenterol. 105 (6): 1421–9. doi:10.1038/ajg.2009.747. PMID 20087335.
  16. ↑ Halfdanarson TR, Rabe KG, Rubin J, Petersen GM (2008). "Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival". Ann Oncol. 19 (10): 1727–33. doi:10.1093/annonc/mdn351. PMC 2735065. PMID 18515795.
  17. ↑ Vagefi PA, Razo O, Deshpande V, McGrath DJ, Lauwers GY, Thayer SP; et al. (2007). "Evolving patterns in the detection and outcomes of pancreatic neuroendocrine neoplasms: the Massachusetts General Hospital experience from 1977 to 2005". Arch Surg. 142 (4): 347–54. doi:10.1001/archsurg.142.4.347. PMC 3979851. PMID 17438169.
  18. ↑ Horwhat JD, Gerke H, Acosta RD, Pavey DA, Jowell PS (2009). "Focal or diffuse "fullness" of the pancreas on CT. Usually benign, but EUS plus/minus FNA is warranted to identify malignancy". JOP. 10 (1): 37–42. PMID 19129613.
  19. ↑ Khorana AA, Fine RL (2004). "Pancreatic cancer and thromboembolic disease". Lancet Oncol. 5 (11): 655–63. doi:10.1016/S1470-2045(04)01606-7. PMID 15522652.
  20. ↑ Tas F, Sen F, Odabas H, Kılıc L, Keskın S, Yıldız I (2013). "Performance status of patients is the major prognostic factor at all stages of pancreatic cancer". Int J Clin Oncol. 18 (5): 839–46. doi:10.1007/s10147-012-0474-9. PMID 22996141.
  21. ↑ Huguet F, Girard N, Guerche CS, Hennequin C, Mornex F, Azria D (2009). "Chemoradiotherapy in the management of locally advanced pancreatic carcinoma: a qualitative systematic review". J Clin Oncol. 27 (13): 2269–77. doi:10.1200/JCO.2008.19.7921. PMID 19307501.
  22. ↑ Brasiūniene B, Juozaityte E (2007). "The effect of combined treatment methods on survival and toxicity in patients with pancreatic cancer". Medicina (Kaunas). 43 (9): 716–25. PMID 17986845.
  23. ↑ Bancroft J (1992). "Sexual behaviour in Britain and France". BMJ. 305 (6867): 1447–8. PMC 1884127. PMID 1493387  Check |pmid= value (help).


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