Insulinoma overview

# Overview
Insulinoma is the tumor of  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  5-10 U/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  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  cells with a trabecular arrangement and group B as scarce well-granulated typical  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. 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  5-10 U/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.