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A glucagonoma is a rare tumor of the alpha cells of the pancreas that results in the overproduction of the hormone [[glucagon]]. On microscopic histopathological analysis, findings of glucagonoma are epidermal necrosis, subcorneal pustules, confluent parakeratosis, epidermal hyperplasia and marked papillary dermal angioplasia, and suppurative folliculitis.
A glucagonoma is a rare tumor of the alpha cells of the pancreas that results in the overproduction of the hormone [[glucagon]]. On microscopic histopathological analysis, findings of glucagonoma are epidermal necrosis, subcorneal pustules, confluent parakeratosis, epidermal hyperplasia and marked papillary dermal angioplasia, and suppurative folliculitis.


==Pathophysiology==
==Pathogenesis==
*A glucagonoma is a rare tumor of the alpha cells of the pancreas that results in the overproduction of the hormone [[glucagon]]. Alpha cell tumors are commonly associated with glucagonoma syndrome, though similar symptoms are present in cases of pseudoglucagonoma syndrome in the absence of a glucagon-secreting tumor.<ref>Glucagonoma. Wikipedia. https://en.wikipedia.org/wiki/Glucagonoma. Accessed on October 13, 2015.</ref>
All cases of the glucagonoma have been associated with tumors originating in the alpha cells of the pancreas. Glucagon, acting on the liver, increases both amino acid oxidation and gluconeogenesis from amino acid substrates [6]. The weight loss characteristic of glucagonoma may result from the catabolic action of glucagon and through glucagon-like peptides such as GLP-1. Necrolytic migratory erythema probably results from hyponutrition and amino acid deficiency [7]. Diarrhea may result from hyperglucagonemia and co-secretion of gastrin, vasoactive intestinal peptide, serotonin, or calcitonin [2].
*The primary [[physiology|physiological]] effect of glucagonoma is an overproduction of the [[peptide]] hormone [[glucagon]], which enhances [[blood glucose]] levels through the activation of [[catabolism|catabolic]] processes including [[gluconeogenesis]] and [[lipolysis]].
*Gluconeogenesis produces [[glucose]] from [[protein]] and [[amino acid]] materials. Lipolysis is the breakdown of [[adipose tissue|fat]].
*[[Diabetes mellitus]] also frequently results from the [[insulin]] and [[glucagon]] imbalance that occurs in glucagonoma.<ref>{{cite journal |author=Koike N, Hatori T, Imaizumi T, ''et al'' |title=Malignant glucagonoma of the pancreas diagnoses through anemia and diabetes mellitus |journal=Journal of hepato-biliary-pancreatic surgery |volume=10 |issue=1 |pages=101-5 |year=2003 |pmid=12918465 |doi=}}</ref>
*Pathogenesis of [[necrolytic migratory erythema]] is ill defined. The postulated mechanism for necrolytic migratory erythema involves the combined effect of hyperglucagonemia, [[zinc deficiency]], [[fatty acid]] deficiency, hypoaminoacidemia, and liver disease, that lead to excessive inflammation in the epidermis in response to trauma and to the necrolysis.<ref>Necrolytic migratory erythema. Wikipedia. https://en.wikipedia.org/wiki/Necrolytic_migratory_erythema. Accessed on October 13, 2015.</ref><ref name="pmid9591806">{{cite journal| author=Mullans EA, Cohen PR| title=Iatrogenic necrolytic migratory erythema: a case report and review of nonglucagonoma-associated necrolytic migratory erythema. | journal=J Am Acad Dermatol | year= 1998 | volume= 38 | issue= 5 Pt 2 | pages= 866-73 | pmid=9591806 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9591806  }} </ref>


==Microscopic Pathology==
Pathogenesis of [[necrolytic migratory erythema]] is ill defined. The postulated mechanism for necrolytic migratory erythema involves the combined effect of hyperglucagonemia, [[zinc deficiency]], [[fatty acid]] deficiency, hypoaminoacidemia, and liver disease, that lead to excessive inflammation in the epidermis in response to trauma and to the necrolysis.<ref>Necrolytic migratory erythema. Wikipedia. https://en.wikipedia.org/wiki/Necrolytic_migratory_erythema. Accessed on October 13, 2015.</ref><ref name="pmid9591806">{{cite journal| author=Mullans EA, Cohen PR| title=Iatrogenic necrolytic migratory erythema: a case report and review of nonglucagonoma-associated necrolytic migratory erythema. | journal=J Am Acad Dermatol | year= 1998 | volume= 38 | issue= 5 Pt 2 | pages= 866-73 | pmid=9591806 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9591806 }} </ref>
On microscopic histopathological analysis, findings of glucagonoma are:<ref name="pmid3014912">{{cite journal| author=Kheir SM, Omura EF, Grizzle WE, Herrera GA, Lee I| title=Histologic variation in the skin lesions of the glucagonoma syndrome. | journal=Am J Surg Pathol | year= 1986 | volume= 10 | issue= 7 | pages= 445-53 | pmid=3014912 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3014912 }} </ref>
 
== Genetics ==
 
== Associated Conditions ==
 
== Gross Pathology ==
Glucagonomas are neuroendocrine tumors derived from multipotential stem cells of endodermal origin. The World Health Organization classifies NETs arising within the digestive system into two broad categories based upon the extent to which they resemble their normal non-neoplastic counterparts
* Glucagonomas are usually solitary, and the majority are located in the distal pancreas.


*Epidermal necrosis
* Glucagonomas are generally large tumors at diagnosis with a mean diameter of 5 cm, From 50 to 82% have evidence of metastatic spread at presentation.


*Subcorneal pustules, either isolated or associated with necrosis of the epidermis
* Nearly all glucagonomas are located in the pancreas,  50–80% occur in the pancreatic tail, 32.2% in the body and 21.9% in the head.
* In few patients, the location was extrapancreatic, such as in kidney, duodenum, lung, accessory pancreatic tissue.


*Confluent parakeratosis
* Metastasis usually occurs to the liver. The most common site for distal metastases is the liver
* Other sites are lymph nodes, bone, mesentery, lung, and adrenals. 22
*


*Epidermal hyperplasia, and marked papillary dermal angioplasia
*Tumors below 2 cm in diameter are associated with a very low chance of malignancy.


*Suppurative folliculitis
==Microscopic Pathology==
*Tumors consist of cords and nests of well-differentiated that is similar to that of other pancreatic NETs.
*Immunostaining is positive for glucagon containing  granules, indicative of their alpha cell origin.  Many glucagonomas re pleomorphic36,37 with  cells containing granules that stain for other peptides,  most frequently pancreatic polypeptide.36,38  Electron microscopy reveals a variable number of secretory granules.  Benign tumors are usually fully granulated, whereas  malignant cells have fewer granules.35,39  Histology of skin lesions. The histologic appearance he histologic appearance  by superficial spongiosis and necrosis in the upper layers of the stratum Malpighi and subcorneal blis-
===Images===
===Images===
<gallery>Image:800px-Confluent epidermal necrosis - high mag.jpg|Confluent epidermal necrosis (high mag)<ref name=picture>Glucagonoma. Wikimedia Commons. https://commons.wikimedia.org/wiki/File:Confluent_epidermal_necrosis_-_high_mag.jpg</ref>
<gallery>Image:800px-Confluent epidermal necrosis - high mag.jpg|Confluent epidermal necrosis (high mag)<ref name=picture>Glucagonoma. Wikimedia Commons. https://commons.wikimedia.org/wiki/File:Confluent_epidermal_necrosis_-_high_mag.jpg</ref>

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

Overview

A glucagonoma is a rare tumor of the alpha cells of the pancreas that results in the overproduction of the hormone glucagon. On microscopic histopathological analysis, findings of glucagonoma are epidermal necrosis, subcorneal pustules, confluent parakeratosis, epidermal hyperplasia and marked papillary dermal angioplasia, and suppurative folliculitis.

Pathogenesis

All cases of the glucagonoma have been associated with tumors originating in the alpha cells of the pancreas. Glucagon, acting on the liver, increases both amino acid oxidation and gluconeogenesis from amino acid substrates [6]. The weight loss characteristic of glucagonoma may result from the catabolic action of glucagon and through glucagon-like peptides such as GLP-1. Necrolytic migratory erythema probably results from hyponutrition and amino acid deficiency [7]. Diarrhea may result from hyperglucagonemia and co-secretion of gastrin, vasoactive intestinal peptide, serotonin, or calcitonin [2].

Pathogenesis of necrolytic migratory erythema is ill defined. The postulated mechanism for necrolytic migratory erythema involves the combined effect of hyperglucagonemia, zinc deficiency, fatty acid deficiency, hypoaminoacidemia, and liver disease, that lead to excessive inflammation in the epidermis in response to trauma and to the necrolysis.[1][2]

Genetics

Associated Conditions

Gross Pathology

Glucagonomas are neuroendocrine tumors derived from multipotential stem cells of endodermal origin. The World Health Organization classifies NETs arising within the digestive system into two broad categories based upon the extent to which they resemble their normal non-neoplastic counterparts

  • Glucagonomas are usually solitary, and the majority are located in the distal pancreas.
  • Glucagonomas are generally large tumors at diagnosis with a mean diameter of 5 cm, From 50 to 82% have evidence of metastatic spread at presentation.
  • Nearly all glucagonomas are located in the pancreas, 50–80% occur in the pancreatic tail, 32.2% in the body and 21.9% in the head.
  • In few patients, the location was extrapancreatic, such as in kidney, duodenum, lung, accessory pancreatic tissue.
  • Metastasis usually occurs to the liver. The most common site for distal metastases is the liver
  • Other sites are lymph nodes, bone, mesentery, lung, and adrenals. 22
  • Tumors below 2 cm in diameter are associated with a very low chance of malignancy.

Microscopic Pathology

  • Tumors consist of cords and nests of well-differentiated that is similar to that of other pancreatic NETs.
  • Immunostaining is positive for glucagon containing granules, indicative of their alpha cell origin. Many glucagonomas re pleomorphic36,37 with cells containing granules that stain for other peptides, most frequently pancreatic polypeptide.36,38 Electron microscopy reveals a variable number of secretory granules. Benign tumors are usually fully granulated, whereas malignant cells have fewer granules.35,39 Histology of skin lesions. The histologic appearance he histologic appearance by superficial spongiosis and necrosis in the upper layers of the stratum Malpighi and subcorneal blis-

Images

  • Confluent epidermal necrosis (high mag)[3]

    Confluent epidermal necrosis (high mag)[3]

  • Confluent epidermal necrosis (very high mag)[3]

    Confluent epidermal necrosis (very high mag)[3]

  • Confluent epidermal necrosis (intermed mag)[3]

    Confluent epidermal necrosis (intermed mag)[3]

  • Confluent epidermal necrosis (low mag)[3]

    Confluent epidermal necrosis (low mag)[3]

  • (A) Skin lesions affecting pretibial area. (B) Skin biopsy in necrolytic migratory erythema showing a zone of necrolysis and vacuolated keratinocytes[4]

    (A) Skin lesions affecting pretibial area. (B) Skin biopsy in necrolytic migratory erythema showing a zone of necrolysis and vacuolated keratinocytes[4]

  • Skin biopsy in necrolytic migratory erythema showing a large zone of necrolysis in the upper epidermis (arrow)[5]

    Skin biopsy in necrolytic migratory erythema showing a large zone of necrolysis in the upper epidermis (arrow)[5]

  • A) Psoriasiform hyperplasia of the epidermis with overlying parakeratosis and mild perivascular infiltrate of lymphocytes in the upper dermis (HE 5 X). B) Vascular dilatation (HE 20 X).[6]

    A) Psoriasiform hyperplasia of the epidermis with overlying parakeratosis and mild perivascular infiltrate of lymphocytes in the upper dermis (HE 5 X). B) Vascular dilatation (HE 20 X).[6]

  • Specimen from distal splenopancreatectomy.A) The neoplasia is located in the inferior border of the pancreas (arrow); it shows an exophytic growth but appears well circumscribed. B) The cut surface is whitish-yellow in color with focal areas of hemorrhage.[6]

    Specimen from distal splenopancreatectomy.A) The neoplasia is located in the inferior border of the pancreas (arrow); it shows an exophytic growth but appears well circumscribed. B) The cut surface is whitish-yellow in color with focal areas of hemorrhage.[6]

  • Histopathological examination of the pancreatic tumor.A) The tumor appears encapsulated and composed of polygonal cells with trabecular or ribbon-like proliferation (HE 5 X). B) At immunohistochemistry, neoplastic cells showed an intense diffuse staining for glucagon (Anti-glucagon antibody 5 X)[6]

    Histopathological examination of the pancreatic tumor.A) The tumor appears encapsulated and composed of polygonal cells with trabecular or ribbon-like proliferation (HE 5 X). B) At immunohistochemistry, neoplastic cells showed an intense diffuse staining for glucagon (Anti-glucagon antibody 5 X)[6]

References

  1. ↑ Necrolytic migratory erythema. Wikipedia. https://en.wikipedia.org/wiki/Necrolytic_migratory_erythema. Accessed on October 13, 2015.
  2. ↑ Mullans EA, Cohen PR (1998). "Iatrogenic necrolytic migratory erythema: a case report and review of nonglucagonoma-associated necrolytic migratory erythema". J Am Acad Dermatol. 38 (5 Pt 2): 866–73. PMID 9591806.
  3. ↑ 3.0 3.1 3.2 3.3 Glucagonoma. Wikimedia Commons. https://commons.wikimedia.org/wiki/File:Confluent_epidermal_necrosis_-_high_mag.jpg
  4. ↑ Castro PG, de León AM, Trancón JG, Martínez PA, Alvarez Pérez JA, Fernández Fernández JC; et al. (2011). "Glucagonoma syndrome: a case report". J Med Case Rep. 5: 402. doi:10.1186/1752-1947-5-402. PMC 3171381. PMID 21859461.
  5. ↑ Fang S, Li S, Cai T (2014). "Glucagonoma syndrome: a case report with focus on skin disorders". Onco Targets Ther. 7: 1449–53. doi:10.2147/OTT.S66285. PMC 4140234. PMID 25152626.
  6. ↑ 6.0 6.1 6.2 Erdas E, Aste N, Pilloni L, Nicolosi A, Licheri S, Cappai A; et al. (2012). "Functioning glucagonoma associated with primary hyperparathyroidism: multiple endocrine neoplasia type 1 or incidental association?". BMC Cancer. 12: 614. doi:10.1186/1471-2407-12-614. PMC 3543729. PMID 23259638.


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