Insulinoma overview
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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
An insulinoma is a tumour of the pancreas derived from the beta cells 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.[1] 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.[2] The male to female ratio is approximately 2 to 3. The median age at diagnosis is 45.5 years.[2] 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.[3] 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.[4] Findings on abdominal MRI suggestive of insulinoma include signal enhancement on T1 C+ (Gd).[5] 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.[6] 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.[6][7] There is no established method for prevention of insulinoma.
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.[8]In 1929, the first surgical cure was performed by Roscoe Graham.[9]In 1935, Whipple suggested a diagnostic criterion for the diagnosis of Insulinoma called as Whipple's triad.[9]
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. 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 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, 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 arrangement and Group B as scarce well -granulated typical B 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 insulin, oral 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.[6][10]Insulinoma commonly affects individuals 40-60 years of age. Females are more commonly (60-75%)[10] affected by insulinoma than males. 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 gender: woman, age:40-60 years, MEN1 syndrome, von Hippel-Lindau disease, and Neurofibromatosis 1
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.
Staging
The staging had been done according to American Joint Cancer Committee(AJCC) 7th edition 2010. [11][12].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.
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 S. glucose <55 mg/dL[13] S. Insulin >5-10 μU/mL S. 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.[14] 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 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 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.
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.
Ultrasonography
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.[6]
Other Imaging Findings
Other imaging studies for insulinoma include indium-111 pentetreotide scan.
Other Diagnostic Studies
Other diagnostic studies for insulinoma include intra-arterial calcium stimulation test with hepatic venous sampling.
Medical Therapy
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
Surgery is the mainstay of treatment for insulinoma. The feasibility of surgery depends on the stage of insulinoma at diagnosis.[6][7]
Primary Prevention
There is no established method for prevention of insulinoma.
Secondary Prevention
There are no secondary preventive measures available for insulinoma.
References
- ↑ Abboud, Bassam (2008). "Occult sporadic insulinoma: Localization and surgical strategy". World Journal of Gastroenterology. 14 (5): 657. doi:10.3748/wjg.14.657. ISSN 1007-9327.
- ↑ 2.0 2.1 Vázquez Quintana E (2004). "The surgical management of insulinoma". Bol Asoc Med P R. 96 (1): 33–8. PMID 15575328.
- ↑ USPTF.http://www.uspreventiveservicestaskforce.org/BrowseRec/Search?s=insulinoma
- ↑ Insulinoma. Dr Yuranga Weerakkody and Dr Frank Gaillard et al. Radiopaedia 2015. http://radiopaedia.org/articles/insulinoma
- ↑ Insulinoma. Dr Yuranga Weerakkody and Dr Frank Gaillard et al. http://radiopaedia.org/articles/insulinoma accessed on 10 October, 2015.
- ↑ 6.0 6.1 6.2 6.3 6.4 Okabayashi T, Shima Y, Sumiyoshi T, Kozuki A, Ito S, Ogawa Y; et al. (2013). "Diagnosis and management of insulinoma". World J Gastroenterol. 19 (6): 829–37. doi:10.3748/wjg.v19.i6.829. PMC 3574879. PMID 23430217.
- ↑ 7.0 7.1 Inulinoma. national library of medicine. https://www.nlm.nih.gov/medlineplus/ency/article/000387.htm
- ↑
- ↑ 9.0 9.1
- ↑ 10.0 10.1 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.
- ↑
- ↑
- ↑ Cryer PE, Axelrod L, Grossman AB, Heller SR, Montori VM, Seaquist ER; et al. (2009). "Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline". J Clin Endocrinol Metab. 94 (3): 709–28. doi:10.1210/jc.2008-1410. PMID 19088155.
- ↑ Callender GG, Rich TA, Perrier ND (2008). "Multiple endocrine neoplasia syndromes". Surg Clin North Am. 88 (4): 863–95, viii. doi:10.1016/j.suc.2008.05.001. PMID 18672144.