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| | ===Famous Cases=== |
| | The following are a few famous cases of narcolepsy: |
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| '''Editor-In-Chief:''' [[User:C Michael Gibson|C. Michael Gibson, M.S., M.D.]] [[Mailto:charlesmichaelgibson@gmail.com|[1]]]; '''Associate Editor(s)-in-Chief:''' [[User:Amandeep Singh|Amandeep Singh M.D.]][[Mailto:samadee@bidmc.harvard.edu|[2]]] | | *'''Jimmy Kimmel''', American late-night talk show host, actor, producer, comedian, and writer |
| | *'''Harold M. Ickes''', former deputy White House chief of staff for President Bill Clinton and a leading figure in the His administration's [[healthcare]] reform initiative |
| | *'''Arthur Lowe''', a British actor who played iconic Captain Mainwaring in the British sitcom ''Dad's Army'' |
| | *'''Nastassja Aglaia Kinski''', German actress, and former model |
| | *'''George M. Church''', molecular geneticist, molecular engineer, and chemist, who is a Professor of Genetics and Professor of Health Sciences at Harvard |
| | *'''Teresa Nielsen Hayden''', American science fiction editor, fanzine writer, and essayist who has a famous weblog, named Making Light |
| | *'''Franck Bouyer''', French former road racing cyclist who was unable to compete or train without treatment with Modafinil |
| | *'''Gabe Barham''', former Drummer for American post-hardcore band Sleeping With Sirens |
| | *'''Jinkx Monsoon''' (real name is Jerick Hoffer), Seattle Drag Queen, stage performer, comedian and singer who is the winner of the fifth season of ''RuPaul's Drag Race'' |
| | *'''Aaron Flahavan''', former English (Portsmouth) football Goalkeeper |
| | *'''Paul Gonsalves''', Jazz tenor saxophonist |
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| '''''Synonyms and Keywords:''''' Pancreatic beta cell tumor; tumor of beta cells; beta cell tumor; cancer of beta cells
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| == Overview ==
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| 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).
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| == Historical Perspective[edit | edit source] ==
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| 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]].
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| == Classification[edit | edit source] ==
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| 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.
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| == Pathophysiology[edit | edit source] ==
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| 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.
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| == Causes[edit | edit source] ==
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| There are no established causes for insulinoma.
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| == Differential Diagnosis[edit | edit source] ==
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| 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.
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| == Epidemiology and Demographics[edit | edit source] ==
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| 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.
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| == Risk Factors[edit | edit source] ==
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| 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]].
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| == Screening[edit | edit source] ==
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| There is insufficient evidence to recommend routine [[screening]] for insulinoma.
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| == Natural History, Complications and Prognosis[edit | edit source] ==
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| 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]].
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| == Staging[edit | edit source] ==
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| 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.
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| == History and Symptoms[edit | edit source] ==
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| 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]].
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| == Physical Examination[edit | edit source] ==
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| Physical examination of patients with insulinoma is usually unremarkable.
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| == Laboratory Findings[edit | edit source] ==
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| 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.
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| == CT[edit | edit source] ==
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| 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.
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| == MRI[edit | edit source] ==
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| 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.
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| == Ultrasonography[edit | edit source] ==
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| 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]].
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| == Other Imaging Findings[edit | edit source] ==
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| 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.
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| == Other Diagnostic Studies[edit | edit source] ==
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| 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.
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| == Medical Therapy[edit | edit source] ==
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| 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]].
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| == Surgery[edit | edit source] ==
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| [[Surgery]] is the mainstay of treatment for insulinoma. The feasibility of [[surgery]] depends on the stage of insulinoma at diagnosis.
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| == Primary Prevention[edit | edit source] ==
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| There is no established method for prevention of insulinoma.
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| == Secondary Prevention[edit | edit source] ==
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| There are no secondary preventive measures available for insulinoma.
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| == References ==
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