Insulinoma overview: Difference between revisions

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==Overview==
==Overview==
An '''insulinoma''' is a [[tumour]] of the [[pancreas]] derived from the [[beta cell]]s which while retaining the ability to synthesize and secrete [[insulin]] is autonomous of the normal feedback mechanisms. Patients present with symptomatic [[hypoglycemia]] which is ameliorated by feeding. The diagnosis of an insulinoma is usually made biochemically with low blood sugar, elevated insulin, pro-insulin and C-peptide levels and confirmed by [[medical imaging]] or angiography. The definitive treatment is surgery. Pancreatic islet cells was first described by Paul Langerhans in 1869, while he was still a medical student. Insulin was first discovered by Frederick Banting and Charles Best in 1922 from a dog’s [[pancreas]]. In 1927, William J Mayo was the first to discover the association between [[hyperinsulinism]] and a functional pancreatic islet cell tumor. In 1929, Roscoe Graham was the first to perform surgical cure of an islet cell tumor. On microscopic histopathological analysis, solid or gyriform patterns, usually without glands are characteristic findings of insulinoma. Insulinoma may occur as part of other genetic syndromes such as [[multiple endocrine neoplasia type 1]] and [[von Hippel-Lindau syndrome]]. Insulinoma must be differentiated from autoimmune [[hypoglycemia]], hypoglycemia due to [[sulfonylurea]] or [[insulin]] abuse, factitious hypoglycemia, noninsulinoma pancreatogenic hypoglycemia syndrome (NIPHS), familial persistent hyperinsulinemia, and [[nesidioblastosis]].<ref name="Abboud2008">{{cite journal|last1=Abboud|first1=Bassam|title=Occult sporadic insulinoma: Localization and surgical strategy|journal=World Journal of Gastroenterology|volume=14|issue=5|year=2008|pages=657|issn=1007-9327|doi=10.3748/wjg.14.657}}</ref> The incidence of insulinoma is approximately 0.1 to 0.4 per 100,000 individuals worldwide. There is no racial predilection to the insulinoma. Females are more commonly affected with insulinoma than males.<ref name="pmid15575328">{{cite journal| author=Vázquez Quintana E| title=The surgical management of insulinoma. | journal=Bol Asoc Med P R | year= 2004 | volume= 96 | issue= 1 | pages= 33-8 | pmid=15575328 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15575328  }} </ref> The male to female ratio is approximately 2 to 3. The median age at diagnosis is 45.5 years.<ref name="pmid15575328">{{cite journal| author=Vázquez Quintana E| title=The surgical management of insulinoma. | journal=Bol Asoc Med P R | year= 2004 | volume= 96 | issue= 1 | pages= 33-8 | pmid=15575328 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15575328  }} </ref> Common risk factors in the development of insulinoma include family history of [[multiple endocrine neoplasia type 1]] and [[von Hippel-Lindau syndrome]], rural population, female gender, and age (40 years or older). According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for insulinoma.<ref>USPTF.http://www.uspreventiveservicestaskforce.org/BrowseRec/Search?s=insulinoma</ref> If left untreated, patients with insulinoma may progress to develop [[autonomic]] symptoms, neuroglycopenenic symptoms, and symptoms of catecholaminergic response. According to The American Joint Committee on Cancer (AJCC), there are four stages of insulinoma based on the TNM staging sysytem. Symptoms of insulinoma include [[diaphoresis]], [[palpitations]], confusions, [[seizures]], [[sweating]], [[tachycardia]], and [[anxiety]]. A positive family history of [[multiple endocrine neoplasia type 1]] or [[von Hippel-Lindau syndrome]] may be present. Common physical examination findings of insulinoma include [[tachycardia]], [[jaundice]], [[diplopia]], [[tremors]], and [[altered mental status]]. Laboratory findings consistent with the diagnosis of insulinoma include 72h suppression test and Whipple's triad. Findings on abdominal CT scan suggestive of insulinoma include calcification and hyper attenuation on arterial phase.<ref name="insulinomaCT">Insulinoma. Dr Yuranga Weerakkody and Dr Frank Gaillard et al. Radiopaedia 2015. http://radiopaedia.org/articles/insulinoma</ref> Findings on abdominal MRI suggestive of insulinoma include signal enhancement on T1 C+ (Gd).<ref name="MRI">Insulinoma. Dr Yuranga Weerakkody and Dr Frank Gaillard et al. http://radiopaedia.org/articles/insulinoma accessed on 10 October, 2015.</ref> Abdominal ultrasound scan may be helpful in the diagnosis of insulinoma. Findings on ultrasound scan suggestive of insulinoma are homogeneously hypoechoic, rounded in shape, and with distinct margins.<ref name="pmid23430217">{{cite journal| author=Okabayashi T, Shima Y, Sumiyoshi T, Kozuki A, Ito S, Ogawa Y et al.| title=Diagnosis and management of insulinoma. | journal=World J Gastroenterol | year= 2013 | volume= 19 | issue= 6 | pages= 829-37 | pmid=23430217 | doi=10.3748/wjg.v19.i6.829 | pmc=PMC3574879 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23430217  }} </ref> Other imaging studies for insulinoma include indium-111 pentetreotide scan. Other diagnostic studies for insulinoma include intra-arterial calcium stimulation test with hepatic venous sampling. The predominant therapy for insulinoma is surgical resection. Supportive therapy for insulinoma includes octerotide, endoscopic ultrasound guided alcohol ablation, radiofrequency ablation, embolization, diazoxide and chemotherapy. Surgery is the mainstay of treatment for insulinoma. The feasibility of surgery depends on the stage of insulinoma at diagnosis.<ref name="pmid23430217">{{cite journal| author=Okabayashi T, Shima Y, Sumiyoshi T, Kozuki A, Ito S, Ogawa Y et al.| title=Diagnosis and management of insulinoma. | journal=World J Gastroenterol | year= 2013 | volume= 19 | issue= 6 | pages= 829-37 | pmid=23430217 | doi=10.3748/wjg.v19.i6.829 | pmc=PMC3574879 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23430217  }} </ref><ref name="surgery">Inulinoma. national library of medicine. https://www.nlm.nih.gov/medlineplus/ency/article/000387.htm</ref> There is no established method for prevention of insulinoma.
Insulinoma is the [[tumor]] of β islet cells of [[pancreas]] involved in the production of [[insulin]]. They are rare tumors and the [[incidence]] varies from 0.1 to 0.4 per 100,000. It commonly affects females in the age group of 40-60 years. It is associated with diseases such as [[MEN1]], [[Von Hippel-Lindau Disease|Von Hippel-Lindau]], and [[Neurofibromatosis]]. The overproduction of [[insulin]] causes [[hypoglycemia]] and manifests as neuroglycopenic symptoms such as [[altered mental status]], [[confusion]], [[coma]] and [[adrenergic]] symptoms such as profuse [[sweating]], [[tremors]] and [[palpitations]]. There are no [[physical exam]] findings usually. It is suspected by the presence of [[Whipple's triad]] which is serum [[glucose]] < 55mg/dL, features/symptoms of [[hypoglycemia]] as described above and resolution of symptoms with administration of [[glucose]]. The [[Gold standard (test)|gold standard]] for diagnosis is 72-hour fasting and the laboratory findings include serum [[glucose]] < 55 mg/dL . [[Insulin]] > 5-10 μU/mL, S. [[C-peptide|C-Peptide]] >200 pmol/L, S. [[proinsulin]] ≥ 22 pmol/L. [[CT scan]] is the first line of investigation. The highest sensitivity is seen in dual-phase [[Helical CT scan|helical CT]] with thin slices up to 94.4%. [[MRI]] is the second line of investigation. Trans-abdominal [[ultrasound]] and [[X-ray]] have less [[sensitivity]] in detecting insulinoma. Invasive modalities like [[endoscopic ultrasound]] are adopted if [[CT]] and [[MRI]] are inconclusive. Other diagnostic modalities include [[PET scan]], intra-operative [[ultrasound]] and arterial calcium stimulation with hepatic vein sampling (ASVS).
 
==Historical Perspective==
==Historical Perspective==
In 1869, pancreatic islet cells were discovered by Paul Langerhans and the first adenoma of islets was discovered by Nicholls in 1902. Insulin was first discovered by Banting and Best in 1922. Association between hyperinsulinism and functional islet tumor was described in 1926 by Wilder. In 1927 the insulinoma was first described in Mayo clinic which was dissected in 1929 in Toronto.<ref name="pmid20187464" />In 1929, the first surgical cure was performed by Roscoe Graham.<ref name="pmid17856569" />In 1935, Whipple suggested a diagnostic criterion for the diagnosis of Insulinoma called as Whipple's triad.<ref name="pmid17856569" />
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. [[Insulin]] was first discovered by Banting and Best in 1922. Association between [[hyperinsulinism]] and functional islet tumor was described in 1926 by Wilder. In 1927, the insulinoma was first described in Mayo clinic which was dissected in 1929 in Toronto. In 1929, the first surgical cure was performed by Roscoe Graham. In 1935, Whipple suggested a diagnostic criterion for the diagnosis of insulinoma called as [[Whipple's triad]].
 
==Classification==
Insulinoma may be classified according to their [[malignant]] potential into 2 sub-types: [[Benign]] (90%) and [[malignant]] (10%). It is also classified into 2 subtypes based on the number: solitary (90%) and multiple (10%). Previously, insulinoma was classified into 2 subtypes based on [[hormonal]] level as determined by [[radioimmunoassay]] into group A and group B. The staging of [[malignant]] insulinoma is based on the [[AJCC|AJCC 2010]], ENETS and modified ENETS staging classification.


==Pathophysiology==
==Pathophysiology==
 
Insulinoma arises from [[Beta cell|β islet cells]], which are [[endocrine]] cells that are normally involved in the production of [[insulin]]. It is thought that insulinoma is mediated by [[mTOR]]/P70S6K [[signaling pathway]]. Thus, inhibitors of [[mTOR]] ([[rapamycin]]) or dual [[PI3K]]/[[Mammalian target of rapamycin|mTOR]] (NVP-BEZ2235) have become new drugs for treating insulinoma. [[YY1]] [[gene]] is [[mutated]] by T372R [[mutation]] that causes a defect in [[mitochondrial]] function for [[glucose|glucose-]]<nowiki/>stimulated [[insulin]] action which is thought to be involved in [[MTOR|mTOR pathway]]. The progression to [[hypoglycemia]] is actually because of decreased [[glucose]] synthesis rather than increased use due to the direct effect of [[insulin]] on the [[liver]]. Insulinoma is transmitted in an [[Autosomal dominant inheritance|autosomal dominant]] pattern when it is associated with [[MEN 1 syndrome]]. They are usually small (90%), sporadic (90%), solitary (90%) and [[benign]] (90%) [[tumors]]. On [[gross pathology]] insulinomas are encapsulated and have a gray to red-brown appearance. On microscopic [[histopathological]] analysis, patterns like [[Trabecular meshwork|trabecular]], gyriform, [[lobular]] and solid structures, particularly with [[amyloid]] in the fibrovascular [[stroma]], are characteristic findings of insulinoma. It is also evaluated for the [[mitotic index]] ([[mitosis]] per 10 high power field) and [[immunohistochemistry]] staining by [[Chromogranin A]], [[synaptophysin]], and [[Ki-67]] index. The structure of tumor cells observed under [[electron microscopy]] as group A characterized by abundant well-granulated typical [[Beta cells|β cells]] with a [[Trabecula|trabecular]] arrangement and group B as scarce well-granulated typical [[B cells|β cells]] and a [[medullary]] arrangement.
*Insulinoma arises from β [[Islets of Langerhans|islet]] cells, which are [[endocrine]] cells that are normally involved in the production of [[insulin]]. It is thought that insulinoma is mediated by mTOR/P70S6K [[signaling pathway]]. Inhibitors of mTOR ([[rapamycin]]) or dual PI3K/mTOR (NVP-BEZ2235) thus have become new drugs for treating insulinoma. [[YY1]] gene is mutated by T372R [[mutation]] that causes a defect in [[mitochondrial]] function for glucose stimulated insulin action which is thought to be involved in mTOR pathway.The progression to [[hypoglycemia]] is actually because of decreased glucose synthesis rather than increased use due to the direct effect of insulin on the liver. Insulinoma is transmitted in an [[Autosomal dominant inheritance|autosomal dominant]] pattern when it is associated with MEN 1 syndrome.They are usually small (90%), sporadic (90%), solitary (90%) and [[benign]] (90%) tumors.On gross pathology insulinomas have a gray to red-brown appearance, encapsulated.On microscopic histopathological analysis, patterns like [[Trabecular meshwork|trabecular]], gyriform, [[lobular]] and solid structures, particularly with [[amyloid]] in the fibrovascular stroma, are characteristic findings of insulinoma. It is also evaluated for the [[mitotic index]] ([[mitosis]] per 10 high power field) and [[immunohistochemistry]] staining by [[Chromogranin A]], [[synaptophysin]], and [[Ki-67]] index.The structure of tumor cells observed under [[electron microscopy]] as Group A characterized by abundant well-granulated typical B cells with [[Trabecular meshwork|trabecular]] arrangement and Group B as scarce well -granulated typical B cells and a [[medullary]] arrangement


==Causes==
==Causes==
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==Differential Diagnosis==
==Differential Diagnosis==
Insulinoma must be differentiated from other diseases that cause features of [[hypoglycemia]] like [[altered mental status]]/[[confusion]], profuse [[sweating]] and visual disturbances ([[Blurred vision|blurring]]/[[diplopia]]). These are classified on the basis of laboratory findings into exogenous [[insulin]], [[oral hypoglycemic agent]]<nowiki/>s (e.g. [[sulphonylurea]]<nowiki/>s), [[nesidioblastosis]], [[insulin autoimmune hypoglycemia]].
Insulinoma must be differentiated from other diseases that cause features of [[hypoglycemia]] like [[altered mental status]]/[[confusion]], profuse [[sweating]] and visual disturbances ([[Blurred vision|blurring]]/[[diplopia]]). These are classified on the basis of [[laboratory]] findings into exogenous [[insulin]], [[oral hypoglycemic agent]]<nowiki/>s (e.g. [[sulphonylurea]]<nowiki/>s), [[nesidioblastosis]], insulin autoimmune hypoglycemia.


==Epidemiology and Demographics==
==Epidemiology and Demographics==
The incidence of insulinoma is approximately 0.1-0.4 per 100,000 individuals that constitute 1-2% of all pancreatic neoplasms.<ref name="pmid23430217">{{cite journal |vauthors=Okabayashi T, Shima Y, Sumiyoshi T, Kozuki A, Ito S, Ogawa Y, Kobayashi M, Hanazaki K |title=Diagnosis and management of insulinoma |journal=World J. Gastroenterol. |volume=19 |issue=6 |pages=829–37 |year=2013 |pmid=23430217 |pmc=3574879 |doi=10.3748/wjg.v19.i6.829 |url=}}</ref><ref name="pmid1677058">{{cite journal |vauthors=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. |volume=66 |issue=7 |pages=711–9 |year=1991 |pmid=1677058 |doi= |url=}}</ref>Insulinoma commonly affects individuals 40-60 years of age. Females are more commonly (60-75%)<ref name="pmid1677058">{{cite journal |vauthors=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. |volume=66 |issue=7 |pages=711–9 |year=1991 |pmid=1677058 |doi= |url=}}</ref> affected by insulinoma than males. The female to male ratio is approximately 3:2.There is no regional predisposition.
The [[incidence]] of insulinoma is approximately 0.1-0.4 per 100,000 individuals that constitute 1-2% of all [[Pancreatic neoplasm|pancreatic neoplasms]]. The female to male ratio is approximately 3:2. There is no regional predisposition.


==Risk Factors==
==Risk Factors==


Common risk factors in the development of insulinoma include gender: woman, age:40-60 years, [[Multiple endocrine neoplasia type 1|MEN1]] syndrome, [[Von Hippel-Lindau Disease|von Hippel-Lindau]] disease, and [[Neurofibromatosis type I|Neurofibromatosis 1]]
Common risk factors in the development of insulinoma include female gender, age:40-60 years, [[Multiple endocrine neoplasia type 1|MEN1 syndrome]], [[Von Hippel-Lindau Disease|Von Hippel-Lindau]] disease, and [[Neurofibromatosis type I|Neurofibromatosis 1]]. 
<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


==Screening==
== Screening ==
According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for insulinoma.<nowiki><ref>USPTF.</nowiki>http://www.uspreventiveservicestaskforce.org/BrowseRec/Search?s=insulinoma</ref>
There is insufficient evidence to recommend routine [[screening]] for insulinoma.


==Natural History, Complications and Prognosis==
==Natural History, Complications and Prognosis==
If left untreated, patients with insulinoma may progress to develop [[seizures]], [[coma]] and may be even death. Prognosis is generally excellent for benign insulinoma after the removal of the tumor. Recurrence rates are higher in those associated with [[MEN1]] syndrome.
If left untreated, patients with insulinoma may progress to develop [[seizures]], [[coma]] and even death. Prognosis is generally excellent for [[benign]] insulinoma after the removal of the tumor. Recurrence rates are higher in those associated with [[MEN1 syndrome]].


==Staging==
==Staging==
The staging had been done according to American Joint Cancer Committee(AJCC) 7th edition 2010. <ref name="pmid27646952" /><ref name="pmid25816036" />.Being a pancreatic neuroendocrine tumor, it is also staged by European Neuroendocrine Tumor Society (ENETS).In its new 8th edition of AJCC which is planned to be published on January 1, 2018; AJCC[1] had developed a modified ENETS (mENETS) staging classification.
The staging had been done according to American Joint Cancer Committee (AJCC) 7th edition 2010. Being a [[pancreatic neuroendocrine tumor]], it is also staged by European Neuroendocrine Tumor Society (ENETS). In its new 8th edition of AJCC which is planned to be published on January 1, 2018; AJCC had developed a modified ENETS (mENETS) staging classification.


==History and Symptoms==
==History and Symptoms==
A positive long history of frequent episodes of [[altered mental status]]/[[confusion]], visual disturbances and sweating is suggestive of insulinoma. The most common symptoms of insulinoma include [[altered mental status]]/[[confusion]], visual disturbances like [[blurred vision]]/[[diplopia]], [[sweating]],[[hyperphagia]] and [[coma]]. Less common symptoms of insulinoma include [[palpitations]], [[seizures]], [[tremor|Tremors]], behavioral disturbances and [[weakness]].
A positive long history of frequent episodes of [[altered mental status]]/[[confusion]], [[visual]] disturbances and [[sweating]] is suggestive of insulinoma. The most common symptoms of insulinoma include [[altered mental status]]/[[confusion]], [[visual]] disturbances like [[blurred vision]]/[[diplopia]], [[sweating]], [[hyperphagia]] and [[coma]]. Less common symptoms of insulinoma include [[palpitations]], [[seizures]], [[Tremor|tremors]], behavioral disturbances and [[weakness]].


==Physical Examination==
==Physical Examination==
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==Laboratory Findings==
==Laboratory Findings==
Laboratory findings consistent with the diagnosis of insulinoma include
Laboratory findings consistent with the diagnosis of insulinoma include serum [[glucose]] < 55 mg/dL; serum [[insulin]] > 5-10 μU/mL; serum [[C-peptide|C-Peptide]] > 200 pmol/L and serum [[proinsulin]] ≥ 22 pmol/L. Patients with insulinoma may have elevated [[insulin]] to [[glucose]] ratio > 0.4, which is usually suggestive of insulinoma after a 72-hour fast test as a [[Gold standard (test)|gold standard]] test. One-thirds or 33% patients have clinical symptoms within 12 hours of fasting, 80% develop within 24 hours, 90% develop within 48 hours and 100% develop within 72 hours.
S. [[glucose]] <55 mg/dL<ref name="pmid19088155">{{cite journal| author=Cryer PE, Axelrod L, Grossman AB, Heller SR, Montori VM, Seaquist ER et al.| title=Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. | journal=J Clin Endocrinol Metab | year= 2009 | volume= 94 | issue= 3 | pages= 709-28 | pmid=19088155 | doi=10.1210/jc.2008-1410 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19088155  }} </ref>
S. [[Insulin]] >5-10 μU/mL
S. [[C-peptide|C-Peptide]] >200 pmol/L
S. [[proinsulin]] ≥ 22 pmol/L
Patients with insulinoma may have elevated insulin to glucose ratio >0.4, which is usually suggestive of insulinoma after a 72-hour fast test.It is a [[Gold standard (test)|gold standard]] test.<ref name="pmid18672144">{{cite journal| author=Callender GG, Rich TA, Perrier ND| title=Multiple endocrine neoplasia syndromes. | journal=Surg Clin North Am | year= 2008 | volume= 88 | issue= 4 | pages= 863-95, viii | pmid=18672144 | doi=10.1016/j.suc.2008.05.001 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18672144  }} </ref>
1/3rd or 33% patients have clinical symptoms with in 12 hours of the fasting.
80% develop within 24 hours
90% develop within 48 hours
100% develop within 72 hours.
==CT==
==CT==
CT scan is currently accepted as the first line of investigation for diagnosing insulinoma. Currently, with the advances in technology, the [[Sensitivity (tests)|sensitivity]] has risen to 80% and 94.4% for [[helical CT scan]] with dual-phase multidetector CT scan. Insulinoma is hypervascular and thus CT shows greater enhancement (hyper-attenuation) than rest of the pancreatic [[parenchyma]]. Cystic and nodular masses with calcification indicates malignant insulinoma. Metastasis can be detected by CT scan.
CT scan is currently accepted as the first line of investigation for diagnosing insulinoma. Currently, with the advances in technology, the [[Sensitivity (tests)|sensitivity]] has risen to 80% and 94.4% for [[helical CT scan]] with dual-phase multi-detector [[CT scan]]. Insulinoma is hypervascular and thus CT shows greater enhancement (hyper-attenuation) than rest of the pancreatic [[parenchyma]]. Cystic and nodular masses with [[calcification]] indicates [[malignant]] insulinoma. [[Metastasis]] can be detected by CT scan.
==MRI==
==MRI==
MRI has better sensitivity than CT scan. It is still considered as the second line of investigation due to cost and availability. Insulinoma shows low intensity on T1 weighted and high intensity on T2 weighted signals, having better visualization on T1 and T2 weighted images with fat suppression.They exhibit typically homogenous enhancement when small and ring enhancement when more than 2 cm. A similar pattern is seen in metastatic lesion as of primary tumor.
MRI has better [[sensitivity]] than CT scan. However, it is still considered as the second line of investigation due to cost and availability. Insulinoma shows low intensity on T1 weighted and high intensity on T2 weighted signals, having better visualization on T1 and T2 weighted images with fat suppression.They exhibit typically homogenous enhancement when small and ring enhancement when more than 2 cm. A similar pattern is seen in [[metastatic]] lesion as of primary tumor.


==Ultrasonography==
==Ultrasonography==
Transabdominal ultrasound has low sensitivity varying between 0-66% in detecting insulinoma. The sensitivity increases with the use of more invasive endoscopic ultrasound (93%) and intraoperative ultrasound (86%).We see hypoechoic lesions and hypervascular mass on the ultrasound.rlinks&id=23430217  }} <nowiki></ref></nowiki>
Trans-abdominal [[ultrasound]] has low [[sensitivity]] varying between 0 to 66% in detecting insulinoma. The [[sensitivity]] increases with the use of more invasive technique including [[endoscopic ultrasound]] (93%) and intra-operative [[ultrasound]] (86%). We see hypo-echoic lesions and hypervascular mass on the [[ultrasound]].


==Other Imaging Findings==
==Other Imaging Findings==
The other imaging studies include [[Positron Emission Tomography]] (PET) and Somatostatin Receptor Scintigraphy (SRS) which are nuclear studies used for detecting [[Somatostatin receptor 2|somatostatin receptor]] especially subtype 2 using radioisotopes of Gallium. The increased uptake of radioligands is suggestive of insulinoma. The metastasis also shows the increased uptakes. The sensitivity of PET is increased by doing a CT scan coupled with PET scan. The [[Sensitivity (tests)|sensitivity]] of SRS is 50-60% as insulinomas have less somatostatin subtype2 receptor which is detected by the test.
The other imaging studies include [[Positron Emission Tomography|positron emission tomography]] ([[PET]]) and [[somatostatin receptor]] [[Scintigraphy]] (SRS) which are [[nuclear]] studies used for detecting [[Somatostatin receptor 2|somatostatin receptor especially subtype 2]] using radioisotopes of [[Gallium]]. The increased uptake of [[Radioligand|radioligands]] is suggestive of [[insulinoma]]. The [[metastasis]] also shows the increased uptake. The [[sensitivity]] of [[PET]] is increased by doing a [[CT scan]] coupled with [[PET]] scan. The [[Sensitivity (tests)|sensitivity]] of SRS is 50 to 60% as insulinomas have less [[Somatostatin receptor 2|somatostatin subtype 2 receptor]] which is detected by the test.


==Other Diagnostic Studies==
==Other Diagnostic Studies==
Arterial calcium Stimulation with hepatic Venous Sampling (ASVS) is an invasive diagnostic study which is used when all other imaging studies are inconclusive. Findings are noted after [[Calcium-activated potassium channel|calcium]] stimulation of tumor supplying [[arteries]] and in the [[Hepatic veins|hepatic venous]] samples which show the positive response of a two-fold or greater increase in insulin levelsArterial calcium Stimulation with hepatic Venous Sampling (ASVS) is an invasive diagnostic study which is used when all other imaging studies are inconclusive. Findings are noted after [[Calcium-activated potassium channel|calcium]] stimulation of tumor supplying [[arteries]] and in the [[Hepatic veins|hepatic venous]] samples which show the positive response of a two-fold or greater increase in insulin levels.
Arterial calcium stimulation with hepatic venous sampling (ASVS) is an invasive diagnostic study which is used when all other imaging studies are inconclusive. Findings are noted after [[Calcium-activated potassium channel|calcium]] stimulation of [[tumor]] supplying [[arteries]] and in the [[Hepatic veins|hepatic venous]] samples which show the positive response of a two-fold or greater increase in [[insulin]] levels.


==Medical Therapy==
==Medical Therapy==
Medical therapy is reserved for those who can't undergo the primary surgical therapy. Drugs commonly used for benign insulinoma are [[Diazoxide]], [[Octreotide]]/Lanreotide, [[Phenytoin]] , Verapamil and Everolimus. For malignant insulinoma, these drugs are used with the chemotherapy drugs [[Streptozocin]], 5-Fluoro Uracil, [[Doxorubicin]][[Bevacizumab]] and [[Capecitabine]] in different combinations.For metastasis mainly going to liver regimens include hepatic artery embolization, radiation, chemoembolization, ethanol ablation [[Radiofrequency ablation]] and [[Cryoablation]].
Medical therapy is reserved for those who can't undergo the primary surgical therapy. Drugs commonly used for benign insulinoma are [[diazoxide]], [[octreotide]]/lanreotide, [[Phenytoin]], verapamil and everolimus. For malignant insulinoma, these drugs are used with the [[chemotherapy]] drugs [[streptozocin]], 5-[[fluorouracil]], [[doxorubicin]][[Bevacizumab|, bevacizumab]] and [[capecitabine]] in different combinations. For [[metastasis]] mainly going to [[liver]] regimens include [[hepatic artery]] [[embolization]], [[Radiation therapy|radiation]], chemo-embolization, [[ethanol]] ablation [[radiofrequency ablation]] and [[cryoablation]].


==Surgery==
==Surgery==
Surgery is the mainstay of treatment for insulinoma. The feasibility of surgery depends on the stage of insulinoma at diagnosis.<ref name="pmid23430217">{{cite journal| author=Okabayashi T, Shima Y, Sumiyoshi T, Kozuki A, Ito S, Ogawa Y et al.| title=Diagnosis and management of insulinoma. | journal=World J Gastroenterol | year= 2013 | volume= 19 | issue= 6 | pages= 829-37 | pmid=23430217 | doi=10.3748/wjg.v19.i6.829 | pmc=PMC3574879 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23430217  }} </ref><ref name="surgery">Inulinoma. national library of medicine. https://www.nlm.nih.gov/medlineplus/ency/article/000387.htm</ref>
[[Surgery]] is the mainstay of treatment for insulinoma. The feasibility of [[surgery]] depends on the stage of insulinoma at diagnosis.


==Primary Prevention==
==Primary Prevention==
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==References==
==References==
{{Reflist|2}}
{{Reflist|2}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Gastroenterology]]
[[Category:Surgery]]

Latest revision as of 14:23, 5 December 2017

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

Overview

Insulinoma is the tumor of β islet cells of pancreas involved in the production of insulin. They are rare tumors and the incidence varies from 0.1 to 0.4 per 100,000. It commonly affects females in the age group of 40-60 years. It is associated with diseases such as MEN1, Von Hippel-Lindau, and Neurofibromatosis. The overproduction of insulin causes hypoglycemia and manifests as neuroglycopenic symptoms such as altered mental status, confusion, coma and adrenergic symptoms such as profuse sweating, tremors and palpitations. There are no physical exam findings usually. It is suspected by the presence of Whipple's triad which is serum glucose < 55mg/dL, features/symptoms of hypoglycemia as described above and resolution of symptoms with administration of glucose. The gold standard for diagnosis is 72-hour fasting and the laboratory findings include serum glucose < 55 mg/dL . Insulin > 5-10 μU/mL, S. C-Peptide >200 pmol/L, S. proinsulin ≥ 22 pmol/L. CT scan is the first line of investigation. The highest sensitivity is seen in dual-phase helical CT with thin slices up to 94.4%. MRI is the second line of investigation. Trans-abdominal ultrasound and X-ray have less sensitivity in detecting insulinoma. Invasive modalities like endoscopic ultrasound are adopted if CT and MRI are inconclusive. Other diagnostic modalities include PET scan, intra-operative ultrasound and arterial calcium stimulation with hepatic vein sampling (ASVS).

Historical Perspective

In 1869, pancreatic islet cells were discovered by Paul Langerhans and the first adenoma of islets was discovered by Nicholls in 1902. Insulin was first discovered by Banting and Best in 1922. Association between hyperinsulinism and functional islet tumor was described in 1926 by Wilder. In 1927, the insulinoma was first described in Mayo clinic which was dissected in 1929 in Toronto. In 1929, the first surgical cure was performed by Roscoe Graham. In 1935, Whipple suggested a diagnostic criterion for the diagnosis of insulinoma called as Whipple's triad.

Classification

Insulinoma may be classified according to their malignant potential into 2 sub-types: Benign (90%) and malignant (10%). It is also classified into 2 subtypes based on the number: solitary (90%) and multiple (10%). Previously, insulinoma was classified into 2 subtypes based on hormonal level as determined by radioimmunoassay into group A and group B. The staging of malignant insulinoma is based on the AJCC 2010, ENETS and modified ENETS staging classification.

Pathophysiology

Insulinoma arises from β islet cells, which are endocrine cells that are normally involved in the production of insulin. It is thought that insulinoma is mediated by mTOR/P70S6K signaling pathway. Thus, inhibitors of mTOR (rapamycin) or dual PI3K/mTOR (NVP-BEZ2235) have become new drugs for treating insulinoma. YY1 gene is mutated by T372R mutation that causes a defect in mitochondrial function for glucose-stimulated insulin action which is thought to be involved in mTOR pathway. The progression to hypoglycemia is actually because of decreased glucose synthesis rather than increased use due to the direct effect of insulin on the liver. Insulinoma is transmitted in an autosomal dominant pattern when it is associated with MEN 1 syndrome. They are usually small (90%), sporadic (90%), solitary (90%) and benign (90%) tumors. On gross pathology insulinomas are encapsulated and have a gray to red-brown appearance. On microscopic histopathological analysis, patterns like trabecular, gyriform, lobular and solid structures, particularly with amyloid in the fibrovascular stroma, are characteristic findings of insulinoma. It is also evaluated for the mitotic index (mitosis per 10 high power field) and immunohistochemistry staining by Chromogranin A, synaptophysin, and Ki-67 index. The structure of tumor cells observed under electron microscopy as group A characterized by abundant well-granulated typical β cells with a trabecular arrangement and group B as scarce well-granulated typical β cells and a medullary arrangement.

Causes

There are no established causes for insulinoma.

Differential Diagnosis

Insulinoma must be differentiated from other diseases that cause features of hypoglycemia like altered mental status/confusion, profuse sweating and visual disturbances (blurring/diplopia). These are classified on the basis of laboratory findings into exogenous insulinoral hypoglycemic agents (e.g. sulphonylureas), nesidioblastosis, insulin autoimmune hypoglycemia.

Epidemiology and Demographics

The incidence of insulinoma is approximately 0.1-0.4 per 100,000 individuals that constitute 1-2% of all pancreatic neoplasms. The female to male ratio is approximately 3:2. There is no regional predisposition.

Risk Factors

Common risk factors in the development of insulinoma include female gender, age:40-60 years, MEN1 syndrome, Von Hippel-Lindau disease, and Neurofibromatosis 1

Screening

There is insufficient evidence to recommend routine screening for insulinoma.

Natural History, Complications and Prognosis

If left untreated, patients with insulinoma may progress to develop seizures, coma and even death. Prognosis is generally excellent for benign insulinoma after the removal of the tumor. Recurrence rates are higher in those associated with MEN1 syndrome.

Staging

The staging had been done according to American Joint Cancer Committee (AJCC) 7th edition 2010. Being a pancreatic neuroendocrine tumor, it is also staged by European Neuroendocrine Tumor Society (ENETS). In its new 8th edition of AJCC which is planned to be published on January 1, 2018; AJCC had developed a modified ENETS (mENETS) staging classification.

History and Symptoms

A positive long history of frequent episodes of altered mental status/confusion, visual disturbances and sweating is suggestive of insulinoma. The most common symptoms of insulinoma include altered mental status/confusion, visual disturbances like blurred vision/diplopia, sweating, hyperphagia and coma. Less common symptoms of insulinoma include palpitations, seizures, tremors, behavioral disturbances and weakness.

Physical Examination

Physical examination of patients with insulinoma is usually unremarkable.

Laboratory Findings

Laboratory findings consistent with the diagnosis of insulinoma include serum glucose < 55 mg/dL; serum insulin > 5-10 μU/mL; serum C-Peptide > 200 pmol/L and serum proinsulin ≥ 22 pmol/L. Patients with insulinoma may have elevated insulin to glucose ratio > 0.4, which is usually suggestive of insulinoma after a 72-hour fast test as a gold standard test. One-thirds or 33% patients have clinical symptoms within 12 hours of fasting, 80% develop within 24 hours, 90% develop within 48 hours and 100% develop within 72 hours.

CT

CT scan is currently accepted as the first line of investigation for diagnosing insulinoma. Currently, with the advances in technology, the sensitivity has risen to 80% and 94.4% for helical CT scan with dual-phase multi-detector CT scan. Insulinoma is hypervascular and thus CT shows greater enhancement (hyper-attenuation) than rest of the pancreatic parenchyma. Cystic and nodular masses with calcification indicates malignant insulinoma. Metastasis can be detected by CT scan.

MRI

MRI has better sensitivity than CT scan. However, it is still considered as the second line of investigation due to cost and availability. Insulinoma shows low intensity on T1 weighted and high intensity on T2 weighted signals, having better visualization on T1 and T2 weighted images with fat suppression.They exhibit typically homogenous enhancement when small and ring enhancement when more than 2 cm. A similar pattern is seen in metastatic lesion as of primary tumor.

Ultrasonography

Trans-abdominal ultrasound has low sensitivity varying between 0 to 66% in detecting insulinoma. The sensitivity increases with the use of more invasive technique including endoscopic ultrasound (93%) and intra-operative ultrasound (86%). We see hypo-echoic lesions and hypervascular mass on the ultrasound.

Other Imaging Findings

The other imaging studies include positron emission tomography (PET) and somatostatin receptor Scintigraphy (SRS) which are nuclear studies used for detecting somatostatin receptor especially subtype 2 using radioisotopes of Gallium. The increased uptake of radioligands is suggestive of insulinoma. The metastasis also shows the increased uptake. The sensitivity of PET is increased by doing a CT scan coupled with PET scan. The sensitivity of SRS is 50 to 60% as insulinomas have less somatostatin subtype 2 receptor which is detected by the test.

Other Diagnostic Studies

Arterial calcium stimulation with hepatic venous sampling (ASVS) is an invasive diagnostic study which is used when all other imaging studies are inconclusive. Findings are noted after calcium stimulation of tumor supplying arteries and in the hepatic venous samples which show the positive response of a two-fold or greater increase in insulin levels.

Medical Therapy

Medical therapy is reserved for those who can't undergo the primary surgical therapy. Drugs commonly used for benign insulinoma are diazoxide, octreotide/lanreotide, Phenytoin, verapamil and everolimus. For malignant insulinoma, these drugs are used with the chemotherapy drugs streptozocin, 5-fluorouracil, doxorubicin, bevacizumab and capecitabine in different combinations. For metastasis mainly going to liver regimens include hepatic artery embolization, radiation, chemo-embolization, ethanol ablation radiofrequency ablation and cryoablation.

Surgery

Surgery is the mainstay of treatment for insulinoma. The feasibility of surgery depends on the stage of insulinoma at diagnosis.

Primary Prevention

There is no established method for prevention of insulinoma.

Secondary Prevention

There are no secondary preventive measures available for insulinoma.

References