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{{CMG}}; {{AE}} {{PSD}} {{MAD}}
{{CMG}}; {{AE}} {{PSD}} {{MAD}}
==Overview==
==Overview==
A glucagonoma is a rare tumor of the [[alpha cells]] of the [[pancreas]] that results in the overproduction of the hormone [[glucagon]]. Glucagon increases glycogenolysis, gluconeogenesis from amino acid substrates and inhibits glycolysis. This causes weight loss due to the [[Catabolism|catabolic]] action of glucagon. Glucagonoma may be part of multiple endocrine neoplasia type1 (MEN1). It is an autosomal dominant syndrome that is usually caused by mutations in the [[MEN1 syndrome|''MEN1'' gene]]. Glucagonomas are generally large tumors at diagnosis with a mean diameter of 5 cm, Most tuomrs have evidence of [[Metastasis|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. On the microscopic picture, glucagonomas are [[Pleomorphism|pleomorphic]] with cells containing granules that stain for other peptides, most frequently [[pancreatic polypeptide]]. Glucagon is usually detectable within the tumor cells by [[Immunoperoxidase|immunoperoxidase staining]], and glucagon [[mRNA]] may be detected.  
''Glucagonoma'' is a rare tumor of the [[alpha cells]] of the [[pancreas]] that results in the overproduction of the hormone [[glucagon]]. Glucagonoma causes hyperglucagonemia, [[zinc deficiency]], [[fatty acid]] deficiency, [[Aminoacid|hypoaminoacidemia]] that may cause [[necrolytic migratory erythema]]. Glucagonoma may be part of multiple endocrine neoplasia type1 (MEN1). It is an autosomal dominant syndrome that is usually caused by mutations in the [[MEN1 syndrome|''MEN1'' gene]]. ''MEN1'' [[gene]] is a [[tumor suppressor gene]] and causes type 1 multiple endocrine neoplasia by Knudson's "two hits" model for [[tumor]] development. 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. Glucoganoma can metastasize mainly to liver. Glucagonomas consist of [[Pleomorphism|pleomorphic]] cells containing granules that stain for other peptides, most frequently [[pancreatic polypeptide]]. [[Immunoperoxidase|Immunoperoxidase staining]] can detect glucagon within the tumor cells and glucagon.  


==Pathogenesis==
==Pathogenesis==
* A ''glucagonoma'' is a rare tumor of the [[alpha cells]] of the [[pancreas]] that results in the overproduction of the hormone [[glucagon]].  
* ''Glucagonoma'' is a rare tumor of the [[alpha cells]] of the [[pancreas]] that results in the overproduction of the hormone [[glucagon]].  
* Glucagon increases glycogenolysis, gluconeogenesis from amino acid substrates and inhibits glycolysis. This causes weight loss due to the [[Catabolism|catabolic]] action of glucagon.<ref name="pmid6127984">{{cite journal| author=Braverman IM| title="Cutaneous manifestations of internal malignant tumors" by Becker, Kahn and Rothman, June 1942. Commentary: Migratory necrolytic erythema. | journal=Arch Dermatol | year= 1982 | volume= 118 | issue= 10 | pages= 784-98 | pmid=6127984 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6127984  }}</ref>
* [[Glucagon]] increases [[glycogenolysis]], [[gluconeogenesis]] from amino acid substrates and inhibits [[glycolysis]]. This causes weight loss due to the [[Catabolism|catabolic]] action of [[glucagon]].<ref name="pmid6127984">{{cite journal| author=Braverman IM| title="Cutaneous manifestations of internal malignant tumors" by Becker, Kahn and Rothman, June 1942. Commentary: Migratory necrolytic erythema. | journal=Arch Dermatol | year= 1982 | volume= 118 | issue= 10 | pages= 784-98 | pmid=6127984 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6127984  }}</ref>
* When glucagon is secreted by a tumor, it becomes independent and is no longer influenced by feedback control mechanisms.
* When [[glucagon]] is secreted by a tumor, it becomes independent and is no longer influenced by feedback control mechanisms.
* Glucagonoma causes hyperglucagonemia, [[zinc deficiency]], [[fatty acid]] deficiency, [[Aminoacid|hypoaminoacidemia]] that may cause [[necrolytic migratory erythema]].
* Glucagonoma causes hyperglucagonemia, [[zinc deficiency]], [[fatty acid]] deficiency, [[Aminoacid|hypoaminoacidemia]] that may cause [[necrolytic migratory erythema]].
* The postulated mechanism for [[necrolytic migratory erythema]] involves 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>
* The mechanism for [[necrolytic migratory erythema]] involves 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>
* [[Necrolytic migratory erythema]] (NME) probably results from hyponutrition and amino acid deficiency. It can be caused by a tryptophan loss in cutaneous tissues because of the excess circulating glucagon. Tryptophan is responsible for niacin function, which regulates cell turnover and the maturation of the epidermis and mucosal epithelia.<ref name="pmid13978995">{{cite journal| author=STURZBECHER M| title=[8 letters of Ferdinand von HEBRAS on his contributin to Virchow's Handbuch der Speziellen Pathologie and Therapie]. | journal=Z Haut Geschlechtskr | year= 1963 | volume= 34 | issue=  | pages= 281-6 | pmid=13978995 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13978995  }}</ref><ref name="pmid14356022">{{cite journal| author=Wilson LA, Kuhn JA, Corbisiero RM, Smith M, Beatty JD, Williams LE et al.| title=A technical analysis of an intraoperative radiation detection probe. | journal=Med Phys | year= 1992 | volume= 19 | issue= 5 | pages= 1219-23 | pmid=1435602 | doi=10.1118/1.596754 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1435602  }}</ref>
* [[Necrolytic migratory erythema]] (NME) probably results from hyponutrition and [[amino acid]] deficiency. It can be caused by a [[tryptophan]] loss in cutaneous tissues because of the excess circulating [[glucagon]]. [[Tryptophan]] is responsible for niacin function, which regulates cell turnover and the maturation of the epidermis and mucosal epithelia.<ref name="pmid13978995">{{cite journal| author=STURZBECHER M| title=[8 letters of Ferdinand von HEBRAS on his contributin to Virchow's Handbuch der Speziellen Pathologie and Therapie]. | journal=Z Haut Geschlechtskr | year= 1963 | volume= 34 | issue=  | pages= 281-6 | pmid=13978995 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13978995  }}</ref><ref name="pmid14356022">{{cite journal| author=Wilson LA, Kuhn JA, Corbisiero RM, Smith M, Beatty JD, Williams LE et al.| title=A technical analysis of an intraoperative radiation detection probe. | journal=Med Phys | year= 1992 | volume= 19 | issue= 5 | pages= 1219-23 | pmid=1435602 | doi=10.1118/1.596754 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1435602  }}</ref>
* [[Diarrhea]] may result from the secretion of [[gastrin]] occurs with hyperglucagonoma.
* [[Diarrhea]] may result from the secretion of [[gastrin]] occurs with glucagonoma.


== Genetics ==
== Genetics ==
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* [[Parathyroid]] [[hyperplasia]] with resulting [[hyperparathyroidism]]
* [[Parathyroid]] [[hyperplasia]] with resulting [[hyperparathyroidism]]
* The [[gene]] [[locus]] causing [[multiple endocrine neoplasia type 1]] has been localized to [[chromosome]] 11q13 by studies of [[loss of heterozygosity]] on [[multiple endocrine neoplasia type 1]]-associated [[Tumor|tumors]] and by linkage analysis in [[multiple endocrine neoplasia type 1]] families.<sup>[[Multiple endocrine neoplasia type 1 pathophysiology#cite note-pmid17014705-2|[2]]][[Multiple endocrine neoplasia type 1 pathophysiology#cite note-pmid2894610-3|[3]]][[Multiple endocrine neoplasia type 1 pathophysiology#cite note-pmid2568587-4|[4]]][[Multiple endocrine neoplasia type 1 pathophysiology#cite note-pmid2568586-5|[5]]][[Multiple endocrine neoplasia type 1 pathophysiology#cite note-pmid1968641-6|[6]]]</sup>''MEN1'', spans about 10 Kb and consists of ten exons encoding a 610 [[amino acid]] nuclear protein, named menin.<sup>[[Multiple endocrine neoplasia type 1 pathophysiology#cite note-pmid17014705-2|[2]]]</sup>
* The [[gene]] [[locus]] causing [[multiple endocrine neoplasia type 1]] has been localized to [[chromosome]] 11q13 by studies of [[loss of heterozygosity]] on [[multiple endocrine neoplasia type 1]]-associated [[Tumor|tumors]] and by linkage analysis in [[multiple endocrine neoplasia type 1]] families.<sup>[[Multiple endocrine neoplasia type 1 pathophysiology#cite note-pmid17014705-2|[2]]][[Multiple endocrine neoplasia type 1 pathophysiology#cite note-pmid2894610-3|[3]]][[Multiple endocrine neoplasia type 1 pathophysiology#cite note-pmid2568587-4|[4]]][[Multiple endocrine neoplasia type 1 pathophysiology#cite note-pmid2568586-5|[5]]][[Multiple endocrine neoplasia type 1 pathophysiology#cite note-pmid1968641-6|[6]]]</sup>''MEN1'', spans about 10 Kb and consists of ten exons encoding a 610 [[amino acid]] nuclear protein, named menin.<sup>[[Multiple endocrine neoplasia type 1 pathophysiology#cite note-pmid17014705-2|[2]]]</sup>
* ''MEN1'' [[gene]] is a putative [[tumor suppressor gene]] and causes type 1 multiple endocrine neoplasia by Knudson's "two hits" model for [[tumor]] development.<sup>[[Multiple endocrine neoplasia type 1 pathophysiology#cite note-pmid7902574-7|[7]]]</sup>
* ''MEN1'' [[gene]] is a [[tumor suppressor gene]] and causes type 1 multiple endocrine neoplasia by Knudson's "two hits" model for [[tumor]] development.<sup>[[Multiple endocrine neoplasia type 1 pathophysiology#cite note-pmid7902574-7|[7]]]</sup>
* two hits model for [[tumor]] development suggests that there is a [[germline mutation]] present in all [[Cell|cells]] at birth and the second [[mutation]] is a somatic [[mutation]] that occurs in the predisposed [[endocrine]] [[cell]] and leads to loss of the remaining wild type [[allele]]. This "two hits" model gives [[Cell|cells]] the survival advantage needed for [[tumor]] development.
* Two hits model for [[tumor]] development suggests that there is a [[germline mutation]] present in all [[Cell|cells]] at birth and the second [[mutation]] is a somatic [[mutation]] that occurs in the predisposed [[endocrine]] [[cell]] and leads to loss of the remaining wild type [[allele]]. This "two hits" model gives [[Cell|cells]] the survival advantage needed for [[tumor]] development.


== Gross Pathology ==
== Gross Pathology ==
Line 40: Line 40:
==Microscopic Pathology==
==Microscopic Pathology==
* Many glucagonomas are [[Pleomorphism|pleomorphic]]<ref name="pmid6295622" /> with cells containing granules that stain for other peptides, most frequently [[pancreatic polypeptide]].<ref name="pmid6295622">{{cite journal| author=Warner TF, Block M, Hafez GR, Mack E, Lloyd RV, Bloom SR| title=Glucagonomas. Ultrastructure and immunocytochemistry. | journal=Cancer | year= 1983 | volume= 51 | issue= 6 | pages= 1091-6 | pmid=6295622 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6295622  }}</ref>  
* Many glucagonomas are [[Pleomorphism|pleomorphic]]<ref name="pmid6295622" /> with cells containing granules that stain for other peptides, most frequently [[pancreatic polypeptide]].<ref name="pmid6295622">{{cite journal| author=Warner TF, Block M, Hafez GR, Mack E, Lloyd RV, Bloom SR| title=Glucagonomas. Ultrastructure and immunocytochemistry. | journal=Cancer | year= 1983 | volume= 51 | issue= 6 | pages= 1091-6 | pmid=6295622 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6295622  }}</ref>  
* Glucagon is usually detectable within the tumor cells by [[Immunoperoxidase|immunoperoxidase staining]], and glucagon [[mRNA]] may be detected.
* [[Immunoperoxidase|Immunoperoxidase staining]] can detect glucagon within the tumor cells and glucagon [[mRNA]] also may be detected.
* [[Electron|Electron microscopy]] reveals a variable number of secretory granules, indicative of their [[alpha cell]] origin.
* [[Electron|Electron microscopy]] shows secretory granules indicating the origin of glucagonoma from [[alpha cells]].
* Benign tumors are usually fully granulated, whereas malignant cells have fewer granules.<ref name="pmid1973365">{{cite journal| author=Mozell E, Stenzel P, Woltering EA, Rösch J, O'Dorisio TM| title=Functional endocrine tumors of the pancreas: clinical presentation, diagnosis, and treatment. | journal=Curr Probl Surg | year= 1990 | volume= 27 | issue= 6 | pages= 301-86 | pmid=1973365 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1973365  }}</ref>
* Benign tumors are usually fully granulated and malignant cells have fewer granules.<ref name="pmid1973365">{{cite journal| author=Mozell E, Stenzel P, Woltering EA, Rösch J, O'Dorisio TM| title=Functional endocrine tumors of the pancreas: clinical presentation, diagnosis, and treatment. | journal=Curr Probl Surg | year= 1990 | volume= 27 | issue= 6 | pages= 301-86 | pmid=1973365 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1973365  }}</ref>


===Images===
===Images===

Revision as of 20:41, 4 August 2017


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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] Mohammed Abdelwahed M.D[3]

Overview

Glucagonoma is a rare tumor of the alpha cells of the pancreas that results in the overproduction of the hormone glucagon. Glucagonoma causes hyperglucagonemia, zinc deficiency, fatty acid deficiency, hypoaminoacidemia that may cause necrolytic migratory erythema. Glucagonoma may be part of multiple endocrine neoplasia type1 (MEN1). It is an autosomal dominant syndrome that is usually caused by mutations in the MEN1 gene. MEN1 gene is a tumor suppressor gene and causes type 1 multiple endocrine neoplasia by Knudson's "two hits" model for tumor development. 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. Glucoganoma can metastasize mainly to liver. Glucagonomas consist of pleomorphic cells containing granules that stain for other peptides, most frequently pancreatic polypeptide. Immunoperoxidase staining can detect glucagon within the tumor cells and glucagon.

Pathogenesis

Genetics

Glucagonoma may be part of multiple endocrine neoplasia type1 (MEN1). It is an autosomal dominant syndrome that is usually caused by mutations in the MEN1 gene.

Gross Pathology

  • 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.
  • Tumors below 2 cm in diameter are associated with a very low chance of malignancy.

Microscopic Pathology

Images

  • Confluent epidermal necrosis (high mag)[9]

    Confluent epidermal necrosis (high mag)[9]

  • Confluent epidermal necrosis (very high mag)[9]

    Confluent epidermal necrosis (very high mag)[9]

  • Confluent epidermal necrosis (intermed mag)[9]

    Confluent epidermal necrosis (intermed mag)[9]

  • Confluent epidermal necrosis (low mag)[9]

    Confluent epidermal necrosis (low mag)[9]

  • (A) Skin lesions affecting pretibial area. (B) Skin biopsy in necrolytic migratory erythema showing a zone of necrolysis and vacuolated keratinocytes[10]

    (A) Skin lesions affecting pretibial area. (B) Skin biopsy in necrolytic migratory erythema showing a zone of necrolysis and vacuolated keratinocytes[10]

  • Skin biopsy in necrolytic migratory erythema showing a large zone of necrolysis in the upper epidermis (arrow)[11]

    Skin biopsy in necrolytic migratory erythema showing a large zone of necrolysis in the upper epidermis (arrow)[11]

  • 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).[12]

    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).[12]

  • 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.[12]

    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.[12]

  • 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)[12]

    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)[12]

References

  1. ↑ Braverman IM (1982). ""Cutaneous manifestations of internal malignant tumors" by Becker, Kahn and Rothman, June 1942. Commentary: Migratory necrolytic erythema". Arch Dermatol. 118 (10): 784–98. PMID 6127984.
  2. ↑ Necrolytic migratory erythema. Wikipedia. https://en.wikipedia.org/wiki/Necrolytic_migratory_erythema. Accessed on October 13, 2015.
  3. ↑ 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.
  4. ↑ STURZBECHER M (1963). "[8 letters of Ferdinand von HEBRAS on his contributin to Virchow's Handbuch der Speziellen Pathologie and Therapie]". Z Haut Geschlechtskr. 34: 281–6. PMID 13978995.
  5. ↑ Wilson LA, Kuhn JA, Corbisiero RM, Smith M, Beatty JD, Williams LE; et al. (1992). "A technical analysis of an intraoperative radiation detection probe". Med Phys. 19 (5): 1219–23. doi:10.1118/1.596754. PMID 1435602.
  6. ↑ Soga J, Yakuwa Y (1998). "Glucagonomas/diabetico-dermatogenic syndrome (DDS): a statistical evaluation of 407 reported cases". J Hepatobiliary Pancreat Surg. 5 (3): 312–9. PMID 9880781.
  7. ↑ 7.0 7.1 Warner TF, Block M, Hafez GR, Mack E, Lloyd RV, Bloom SR (1983). "Glucagonomas. Ultrastructure and immunocytochemistry". Cancer. 51 (6): 1091–6. PMID 6295622.
  8. ↑ Mozell E, Stenzel P, Woltering EA, Rösch J, O'Dorisio TM (1990). "Functional endocrine tumors of the pancreas: clinical presentation, diagnosis, and treatment". Curr Probl Surg. 27 (6): 301–86. PMID 1973365.
  9. ↑ 9.0 9.1 9.2 9.3 Glucagonoma. Wikimedia Commons. https://commons.wikimedia.org/wiki/File:Confluent_epidermal_necrosis_-_high_mag.jpg
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 12.0 12.1 12.2 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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