Insulinoma overview: Difference between revisions

Jump to navigation Jump to search
Line 42: Line 42:
Laboratory findings consistent with the diagnosis of insulinoma include serum [[glucose]] < 55 mg/dL<ref name="pmid190881552">{{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>; 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. <ref name="pmid186721442">{{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> 1/3 rd or 33% patients have clinical symptoms with in 12 hours of the fasting; 80% develop within 24 hours; 90% develop within 48 hours and 100% develop within 72 hours.
Laboratory findings consistent with the diagnosis of insulinoma include serum [[glucose]] < 55 mg/dL<ref name="pmid190881552">{{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>; 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. <ref name="pmid186721442">{{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> 1/3 rd or 33% patients have clinical symptoms with in 12 hours of the fasting; 80% develop within 24 hours; 90% develop within 48 hours and 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. 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==
<nowiki>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><nowiki></ref></nowiki>
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 intra-operative [[ultrasound]] (86%). We see hypo-echoic lesions and hypervascular mass on the [[ultrasound]].


==Other Imaging Findings==
==Other Imaging Findings==

Revision as of 16:04, 22 September 2017

Insulinoma Microchapters

Home

Patient Information

Overview

Historical Perspective

Classification

Pathophysiology

Causes

Differentiating Insulinoma from other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

Diagnosis

Staging

Diagnostic Criteria

History and Symptoms

Physical Examination

Laboratory Findings

X-ray

Ultrasound

CT

MRI

Other Imaging Findings

Other Diagnostic Studies

Treatment

Medical Therapy

Surgery

Primary Prevention

Secondary Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

Case Studies

Case #1

Insulinoma overview On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides

Images

American Roentgen Ray Society Images of Insulinoma overview

All Images
X-rays
Echo & Ultrasound
CT Images
MRI

Ongoing Trials at Clinical Trials.gov

US National Guidelines Clearinghouse

NICE Guidance

FDA on Insulinoma overview

CDC on Insulinoma overview

Insulinoma overview in the news

Blogs on Insulinoma overview

Directions to Hospitals Treating Insulinoma

Risk calculators and risk factors for Insulinoma overview

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 MEN1, von Hippel-Lindau, 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 is 72-hour fasting and the laboratory findings include serum glucose < 55 mg/dL[1] . 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.[2] 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]

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 β cells with 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. [4][5] Insulinoma commonly affects individuals 40-60 years of age. Females are more commonly (60-75%) affected by insulinoma than males.[5] 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 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. [6][7].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 serum glucose < 55 mg/dL[8]; 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. [9] 1/3 rd or 33% patients have clinical symptoms with in 12 hours of the 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. 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

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 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 uptakes. The sensitivity of PET is increased by doing a CT scan coupled with PET scan. The sensitivity of SRS is 50-60% as insulinomas have less somatostatin subtype2 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 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 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-Fluoro Uracil, DoxorubicinBevacizumab and Capecitabine in different combinations.For metastasis mainly going to liver regimens include hepatic artery embolization, radiation, chemoembolization, 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.[10][11]

Primary Prevention

There is no established method for prevention of insulinoma.

Secondary Prevention

There are no secondary preventive measures available for insulinoma.

References

  1. 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.
  2. 3.0 3.1
  3. Okabayashi T, Shima Y, Sumiyoshi T, Kozuki A, Ito S, Ogawa Y, Kobayashi M, Hanazaki K (2013). "Diagnosis and management of insulinoma". World J. Gastroenterol. 19 (6): 829–37. doi:10.3748/wjg.v19.i6.829. PMC 3574879. PMID 23430217.
  4. 5.0 5.1 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.
  5. 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.
  6. 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.
  7. 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.
  8. Inulinoma. national library of medicine. https://www.nlm.nih.gov/medlineplus/ency/article/000387.htm