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==Introduction==
[[Image:Islet cell tumour.jpg|right|thumb|100px|<small><center>Islet cell tumour (Image sourced from Bristol Biomed Image Archive with permission)</center></small>]]
'''Insulinomas''' are slow growing, well-encapsulated, functional tumours of the [[Pancreas - Anatomy & Physiology#Endocrine|beta cells]] of the pancreatic islets. They secrete inappropriately high amounts of [[Pancreas - Anatomy & Physiology#Insulin|insulin]], irrespective of the serum glucose concentration. They are often malignant, with a high metastatic rate to regional lymph nodes, [[Liver - Anatomy & Physiology|liver]] and omentum. 60% of insulinomas are carcinomas, which are more likely to be endocrinologically active whereas the others are adenomas.
Blood glucose concentration is normally maintained within a narrow homeostatic range because several tissues are able to use only glucose as an energetic substrate. These tissues are particularly affected by the hypoglycaemia which occurs with hyperinsulinaemia and they include neurones, blood cells, renal medullary cells and fibroblasts in healing wounds. The release of hormones antagonistic to insulin (such as glucagon, growth hormone, glucocorticoids and catecholamines) also contributes to the pathogenesis and clinical signs observed in animals with insulinoma.
==Signalment==
==Signalment==
Insulinomas occur most commonly in middle-aged or older dogs of the larger breeds. There is no sex predilection and the condition occurs less commonly in cats. Older cattle may rarely develop insulin-secreting tumours.
==Diagnosis==
==Diagnosis==
===Clinical Signs===
===Clinical Signs===
The following signs are related to hypoglycaemia:
The following signs are related primarily to '''hypoglycaemia''' but the release of catecholamines during episodes of hypogylcaemia may be contributory:
*collapse
*'''Collapse'''
*seizures
*'''Seizures'''
*muscle tremor
*'''Muscle tremors and weakness'''
*'''Ataxia'''
*ataxia
*'''Lethargy and depression'''
*lethagy and depression
*'''Exercise intolerance'''
*exercise intolerance
These signs may be intermittent at the beginning of the disease, but they become more often with time. In between hypoglycaemic episodes, the animals are generally normal. A presumptive diagnosis can be made on the demonstration of the Wipple's triad. This includes the presence of clinical signs associated with hypoglycaemia, fasting hypoglycaemia and amelioration of clinical signs with the administration of glucose. Insulinoma should always be considered when clinical signs are associated with exercise, fasting, excitement or feeding.
These signs may be intermittent early in the course of the disease, but they become more frequent and sustained with time. In between hypoglycaemic episodes, the animals often appear to be normal. Hypoglycaemic episodes may occur shortly after feeding (as insulin secretion is stimulated) or a long time after feeding (as the animal cannot maintain its blood glucose in the acceptable range) and they may also be associated with exercise or excitement.
A presumptive diagnosis can be made on the basis of '''Wipple's triad''', which refers to the presence of:
*Clinical signs associated with hypoglycaemia
*Fasting hypoglycaemia
*Amelioration of clinical signs with the administration of glucose
===Laboratory Tests===
===Laboratory Tests===
====Biochemistry====
====Biochemistry====
*Hypoglycemia
*'''Hypoglycaemia''' which should be a persistent finding during fasting.
*'''Serum ALT and ALK''' are often elevated but the significance of these findings is not known.
====Other Tests====
====Other Tests====
*A tentative diagnosis can be made if an inappropriately high serum insulin level in the presence of a hypoglycaemia is shown.
*'''Serum insulin concentration''' is usually elevated in the face of profound hypoglycaemia, with an '''insulin: glucose ratio''' of >4.2 considered to be diagnostic for insulinoma.
*'''Serum fructosamine levels''' can also be assessed to gauge whether the animal has been persistently hypoglycaemic over the previous 2-3 weeks. A level <250-350 umol/l is suggestive of insulinoma
===Histopathology===
===Pathology===
Collection and examination of a biopsy is needed for definitive confirmation of the diagnosis. The following features may be identified: usually single, or less often multiple, small (1-3cm) spherical nodules, yellow to dark red, in one or more lobes.
Histologically, small islets of acinar tissue are sometimes present within the neoplasm.
Pancreatic beta cells can readily be identified using immunocytochemistry.
===Diagnostic Imaging===
===Diagnostic Imaging===
====Radiography====
====Radiography====
Thoracic radiographs may be used to identify any pulmonary metastases, but it is uncommon for insulinomas to metastasise to the lungs.
====Ultrasonography====
====Ultrasonography====
Occasionally, it may be possible to visualise the location of the tumour on the [[Pancreas - Anatomy & Physiology|pancreas]]. However, this may not always be possible, especially if the tumour is too small. Metastases to [[Lymph Nodes - Anatomy & Physiology|lymph nodes]] and [[Liver - Anatomy & Physiology|liver]] can sometimes be seen.
Occasionally, it may be possible to visualise the location of the neoplasm on the [[Pancreas - Anatomy & Physiology|pancreas]] as a hypoechoic nodule. However, this may not always be possible, especially if the tumour is very small. Metastases to [[Lymph Nodes - Anatomy & Physiology|lymph nodes]] and [[Liver - Anatomy & Physiology|liver]] can sometimes be identified but suspected hepatic metastases should always be biopsied.
==Treatment==
==Treatment==
===Emergency===
===Emergency Stabilisation===
In the event of a hypoglycaemic episode, a bolus of 50% dextrose solution should be given immediately by the intra-venous route. Glucose syrup can also be rubbed onto the gums of an affected animal or a meal could be provided and this approach may reduce the risk of rebound hypoglycaemia encountered with administration of 50% dextrose solution. Intra-venous fluid therapy can then be maintained using 2.5% dextrose solution.
===Medical===
===Medical Management===
This is more suitable for patients in which surgery has been declined or when surgery is inappropriate or fails due to the presence of metastasis.
This is suitable for patients in which surgery has been declined or when clinical signs recur after surgical treatment due to the presence of metastases. A suitable regime would include:
*Small and frequent meals (3-6 times/day) of complex carbohydrate content.
*'''Small and frequent meals''' (3-6 times/day) of with high fat and protein content and some complex carbohydrate.
*Exercise restriction.
*'''Exercise restriction'''.
*[[Steroids|Glucocorticoid]] such as prednisolone to increase hepatic glucose production and decrease cellular glucose uptake.
*[[Steroids|'''Glucocorticoids''']] such as prednisolone prescribed to increase hepatic gluconeogenesis and to decrease cellular glucose uptake.
*Diazoxide, an oral hyperglycaemic drug, to inhibit pancreatic insulin secretion and tissue glucose uptake.
*'''Diazoxide''', an oral hyperglycaemic drug, used to inhibit pancreatic insulin secretion and tissue glucose uptake.
*'''Octreotide''', a somatostatin analogue which reduces the synthesis of insulin but which is rarely used for management of insulinomas.
===Surgical Management===
A '''partial pancreatectomy''' is suitable for patients with a solitary tumour and any suspected metastases may be removed or biopsied during the procedure. An intra-operative ultrasound scan can be performed if the mass is not evident when the pancreas has been exposed. Possible post-operative complications include:
*'''Persistent hypoglycaemia''', probably due to the presence of unidentified metastases.
*[[Pancreatitis|'''Pancreatitis]]''' or '''[[Diabetes Mellitus|Diabetes mellitus]]''' due to disruption to the pancreatic parenchyma during the procedure.
*'''Epilepsy''' and '''diffuse polyneuropathy''' due to chronic hypoglycaemia.
*'''Duodenal necrosis and perforation''' as the cranial pancreatico-duodenal artery may be disrupted when the right limb of the pancreas is dissected away from the duodenum.
==Prognosis==
==Prognosis==
This is dependent on the WHO staging of the tumour. A stage I and II can expect a median survival time of 18 months whereas it is only 6 months for a stage III. Patients suitable for surgical excision has better prognosis than those treated medically.
This is related to the WHO stage of the tumour at diagnosis. An animal with a stage I and II neoplastic process could expect a median survival time of 18 months but this falls to only 6 months for an animal with stage III disease. Patients which undergo surgery to remove an insulinoma have a better prognosis than those treated medically but the condition will recur invariably after surgical removal. Those animals which show a recurrence of clinical signs after surgery may then be treated medically, an approach that produces a significant increase in median survival time (from approximately 2 years to 4 years).
{{Learning
|Vetstream = [https://www.vetstream.com/felis/Content/Disease/dis02122.asp Insulinoma]
|literature search = [http://www.cabdirect.org/search.html?rowId=1&options1=AND&q1=Insulinoma&occuring1=title&rowId=2&options2=AND&q2=&occuring2=freetext&rowId=3&options3=AND&q3=&occuring3=freetext&x=44&y=8&publishedstart=yyyy&publishedend=yyyy&calendarInput=yyyy-mm-dd&la=any&it=any&show=all Insulinoma publications]
}}
==References==
==References==
*Polton, G. A., White, R. N., Brearley, M. J. and Eastwood, J. M. (2007) '''Improved survival in a retrospective cohort of 28 dogs with insulinoma''' ''Journal of Small Animal Practice'' 48:151-156 [http://www3.interscience.wiley.com/cgi-bin/fulltext/117961667/PDFSTART]
*Polton, G. A., White, R. N., Brearley, M. J. and Eastwood, J. M. (2007) '''Improved survival in a retrospective cohort of 28 dogs with insulinoma''' ''Journal of Small Animal Practice'' 48:151-156 [http://www3.interscience.wiley.com/cgi-bin/fulltext/117961667/PDFSTART]
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[[Category:Pancreas_-_Hyperplastic_and_Neoplastic_Pathology]][[Category:Endocrine_System_-_Pathology]]
[[Category:Pancreas_-_Hyperplastic_and_Neoplastic_Pathology]][[Category:Endocrine_System_-_Pathology]]
[[Category:To_Do_-_Clinical]]
[[Category:Neoplasia]][[Category:Pancreas_-_Hyperplastic_and_Neoplastic_Pathology]][[Category:Endocrine_System_-_Pathology]]
[[Category:Endocrine Diseases - Dog]][[Category:Neurological Diseases - Dog]][[Category:Pancreatic Diseases - Dog]]
[[Category:Endocrine Diseases - Cat]][[Category:Neurological Diseases - Cat]][[Category:Pancreatic Diseases - Cat]]
[[Category:Expert_Review]]