Insulinoma

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

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).

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.

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.

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.

There are no established causes for insulinoma.

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.

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.

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

There is insufficient evidence to recommend routine screening for insulinoma.

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.

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.

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 of patients with insulinoma is usually unremarkable.

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 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 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.

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.

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.

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

There is no established method for prevention of insulinoma.

There are no secondary preventive measures available for insulinoma.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Amandeep Singh M.D.[2], Parminder Dhingra, M.D. [3]

In 1869, pancreatic islet cells were discovered by Paul Langerhans. 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.

• Pancreatic islet cells were first described by Paul Langerhans in 1869 when he was still a medical student.
• In 1902, the first adenoma of pancreatic islets was discovered by Nicholls.^[1]
• Insulin was first discovered by Frederick Banting and Charles Best in 1922 from a dog’s pancreas.
• The association between hyperinsulinism and functional islet tumor was made in 1926 by Wilder-et-al after a surgery on a person who had hypoglycemia and found an islet cell cancer with liver metastasis.^[2]

• In 1927, William J Mayo was the first to discover the association between hyperinsulinism and a functional pancreatic islet cell tumor. In 1927 the insulinoma was first described in Mayo clinic which was dissected in 1929 in Toronto.^[1]

• In 1929, the first surgical cure was performed by Roscoe Graham.^[3]

• In 1935, Whipple suggested a diagnostic criterion for the diagnosis of insulinoma called as Whipple’s triad. ^[3]

• William J Mayo did the first operation for insulinoma in 1927 and found it to be unresectable. Two years later, Roscoe Graham successfully completed the first surgical cure of an islet cell tumor.
• In 1935, Whipple’s triad was developed by Virginia Kneeland Frantz and Allen O. Whipple to diagnose insulinoma.

• Steve Jobs, the founder, and CEO of Apple Inc. had died on Oct 5,2011 due to pancreatic neuroendocrine cancer.
• Dag Kittlaus, the creator of “Siri” had been diagnosed with a pancreatic neuroendocrine tumor in 2016.

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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]

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.

The staging of malignant insulinoma being a pancreatic neuroendocrine tumor may be classified into several subtypes based on American Joint Cancer Committee (AJCC) 7th edition 2010: ^[9][10]

Being a pancreatic neuroendocrine tumor, it is also staged by European Neuroendocrine Tumor Society (ENETS) as: ^[9][10]

• WHO classification system combined differentiation and grading characteristics to classify the belligerence of a pancreatic neuroendocrine tumor.
• The aggressiveness of tumor was expressed in form of mitotic count and staining of a nuclear antigen called Ki-67: ^[11][6]

• Grade 1 and 2 tumors were classified as neuroendocrine neoplasm (NET) and grade 3 were classified as neuroendocrine carcinoma (NEC).

• 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:^[9]

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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]

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.

• Insulinoma is a rare benign pancreatic neuroendocrine tumor that arises from β islet cells, which are cells that are normally involved in the production of insulin. Few insulinomas can also produce other hormones such as Serotonin, gastrin, ACTH, glucagon, and somatostatin. ^[1]
• They are usually small (90%), sporadic (90%), solitary (90%) and benign (90%) tumors.
• It usually occurs sporadically (90%) but 10% are found to be associated with MEN 1 syndrome.^[2] Those associated with the MEN1 syndrome are usually malignant and higher recurrence rate (21% at 10 and 20 years) than in those without MEN 1 (5% at 10 and 7% at 20 years). ^[3]

• 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.
• Everolimus (an oral mTOR inhibitor) has a better glycemic control in people having an insulinoma.^[4][5]

• Mitochondria play a key role in glucose and insulin coupling to assure insulin secretion after glucose stimulation in pancreatic β cells. Coupling is impaired due to abnormal mitochondrial function in β cells causing the death of the cell.^[6] This mitochondrial function is regulated by YY1.^[7]
• T372R mutation increases the transcription of YY1.^[8]

• The progression to hypoglycemia is the result of decreased glucose synthesis rather than increased use due to the direct effect of insulin on the liver.^[9]
• The neuroglycopenic symptoms appear eventually due to decreased blood glucose. Hypoglycemia stimulates catecholamine release which produces adrenergic symptoms.^[10]

• Insulinoma is transmitted in an autosomal dominant pattern when it is associated with MEN 1 syndrome.
• Genes involved in the pathogenesis of insulinoma include MEN1 gene. Loss of heterozygosity of MEN1 gene takes place on chromosome 11q13. ^[11]

The following conditions are associated with insulinomas:

• Pancreatic neuroendocrine tumors such as:^[3]
  • Gastrinoma
  • Glucagonoma
  • VIPoma
  • Somatostatinoma
• MEN 1
• Von Hippel-Lindau
• Neurofibromatosis type 1

• On gross pathology insulinoma is encapsulated and have a gray to red brown appearance.^[12]
• They are usually small and solitary tumors, although there is a case report of a large (9 cm), pedunculated insulinoma and weighing more than 100 grams.^[13]

• Almost all insulinomas are present throughout the pancreas and extrapancreatic ones causing hypoglycemia are rare (<2%)^[15]

• Various other findings are noted on gross pathology are: ^[16]
  • Size of the tumor
  • Metastasis to lymph nodes
  • Extrapancreatic involvement
  • Distant metastasis

• On microscopic histopathological analysis, patterns like trabecular, gyriform, lobular and solid structures particularly with amyloid in fibrovascular stroma are characteristic findings of insulinoma.^[17]
• 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.^[16]
• The structure of tumor cells observed under electron microscopy as:
  • Group A characterized by abundant well-granulated typical β cells with trabecular arrangement.
  • Group B as scarce well-granulated typical β cells and a medullary arrangement. ^[18]

• 
  Histopathology of a pancreatic endocrine tumor (insulinoma). Source:https://librepathology.org/wiki/Neuroendocrine_tumour_of_the_pancreas^[19]
• 
  Histopathology of a pancreatic endocrine tumor (insulinoma). Chromogranin A immunostain. Source:https://librepathology.org/wiki/Neuroendocrine_tumour_of_the_pancreas^[19]
• 
  Histopathology of a pancreatic endocrine tumor (insulinoma). Insulin immunostain. Source:https://librepathology.org/wiki/Neuroendocrine_tumour_of_the_pancreas^[19]

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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]

The cause of insulinoma has not been identified. To review risk factors for the development of insulinoma, click here.

There are no established causes of insulinoma but there is an association with MEN 1 syndrome and rarely with Von Hippel-Lindau disease, Neurofibromatosis-1 and Tuberous sclerosis. ^[1][2][3]

• To review risk factors for the development of insulinoma, click here.

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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]

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.

Insulinoma must be differentiated from other diseases that cause features of hypoglycemia. These are classified on the basis of laboratory findings.

Differentials for Hypoglycemia on the basis of Laboratory findings:^[1]

Differentiating hypoglycemia from other diseases that cause autonomic hyperactivity symptoms :

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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]

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.

• The incidence of insulinoma is approximately 0.1-0.4 per 100,000 individuals that constitute 1-2% of all pancreatic neoplasms.^[1][2]

• Patients of all age groups may develop insulinoma.
• Insulinoma commonly affects individuals 40-60 years of age.

• There is no racial predilection to insulinoma.

• Females (60-75%) are more commonly affected by insulinoma than males. The female to male ratio is approximately 3:2.^[2]

• There is no regional predisposition but it was described according to local studies. One of the best studies ever conducted for insulinoma, by Mayo clinic, showed the incidence of insulinoma in residents of Olmsted County, Minnesota over the time frame of 60 years.

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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]

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

Common risk factors in the development of insulinoma include:

• Gender
  • Females are more at risk of developing insulinoma than males.
• Age
  • People who are in the age range of 40-60 years.
• Genetics
  • Persons with family history of pancreatic neuroendocrine tumors are at higher risk of developing insulinomas. ^[1]
  • People with associated Multiple endocrine neoplasia type 1 syndrome (MEN 1).^[1][2][3][4]

Less common risk factors in the development of insulinoma include:

• Von Hippel-Lindau disease
• Neurofibromatosis type 1 ^[1][4]

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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]

There is insufficient evidence to recommend routine screening for insulinoma.

• There is insufficient evidence to recommend routine screening for insulinoma.

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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]

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.

• The symptoms of insulinoma are found in any age group and start with neuroglycopenic symptoms such as altered mental status, visual disturbances, confusion and adrenergic symptoms such as profuse sweating, palpitations and tremors.
• If left untreated, hypoglycemic episodes progresses in frequency, although the tumor size remains small. ^[1]

• Common complications of insulinoma are due to hypoglycemia include:^[2]
  • Seizures
  • Coma
  • Death

• 90% insulinomas are benign and they are generally cured after the removal of the tumor, so benign insulinoma is associated with the most favorable prognosis. ^[3]
• The prognosis varies with the malignant potential of the tumor; grade 1 and 2 tumor have the most favorable prognosis.
• Malignant insulinomas: In a study of 10 patients, the first 4 who presented with lymph node metastasis after surgical excision, maintained a prolonged tumor-free survival. The next four patients presented with metastasis to the liver, which appeared years after the initial diagnosis and presumed curative surgery. One patient presented with a large α-fetoprotein-secreting liver mass. Finally, 9 of the 10 patients had a prolonged survival.^[4]

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