Glucagonoma pathophysiology: Difference between revisions
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** The mechanism for [[necrolytic migratory erythema]] involves excessive inflammation in the epidermis in response to trauma and to the necrolysis. | ** The mechanism for [[necrolytic migratory erythema]] involves excessive inflammation in the epidermis in response to trauma and to the necrolysis. | ||
** [[Necrolytic migratory erythema]] (NME) probably results from hyponutrition and [[amino acid]] deficiency. It can be caused by the loss of [[tryptophan]] in cutaneous tissues as a result of the excess circulating [[glucagon]]. [[Tryptophan]] is responsible for [[niacin]] function, which regulates cell turnover and the maturation of the epidermis and mucosal epithelia. | ** [[Necrolytic migratory erythema]] (NME) probably results from hyponutrition and [[amino acid]] deficiency. It can be caused by the loss of [[tryptophan]] in cutaneous tissues as a result of the excess circulating [[glucagon]]. [[Tryptophan]] is responsible for [[niacin]] function, which regulates cell turnover and the maturation of the epidermis and mucosal epithelia. | ||
** [[Diarrhea]] may result from the secretion of [[gastrin]] occurs with glucagonoma. | ** [[Diarrhea]] may result from the secretion of [[gastrin]] which occurs with glucagonoma. | ||
== Genetics == | == Genetics == | ||
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The gross pathology of glucagonoma may show:<ref name="pmid21859461">{{cite journal| author=Castro PG, de León AM, Trancón JG, Martínez PA, Alvarez Pérez JA, Fernández Fernández JC et al.| title=Glucagonoma syndrome: a case report. | journal=J Med Case Rep | year= 2011 | volume= 5 | issue= | pages= 402 | pmid=21859461 | doi=10.1186/1752-1947-5-402 | pmc=PMC3171381 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21859461 }} </ref><ref name="pmid9880781">{{cite journal| author=Soga J, Yakuwa Y| title=Glucagonomas/diabetico-dermatogenic syndrome (DDS): a statistical evaluation of 407 reported cases. | journal=J Hepatobiliary Pancreat Surg | year= 1998 | volume= 5 | issue= 3 | pages= 312-9 | pmid=9880781 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9880781 }}</ref><ref name="pmid25152626">{{cite journal| author=Fang S, Li S, Cai T| title=Glucagonoma syndrome: a case report with focus on skin disorders. | journal=Onco Targets Ther | year= 2014 | volume= 7 | issue= | pages= 1449-53 | pmid=25152626 | doi=10.2147/OTT.S66285 | pmc=PMC4140234 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25152626 }} </ref> | The gross pathology of glucagonoma may show:<ref name="pmid21859461">{{cite journal| author=Castro PG, de León AM, Trancón JG, Martínez PA, Alvarez Pérez JA, Fernández Fernández JC et al.| title=Glucagonoma syndrome: a case report. | journal=J Med Case Rep | year= 2011 | volume= 5 | issue= | pages= 402 | pmid=21859461 | doi=10.1186/1752-1947-5-402 | pmc=PMC3171381 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21859461 }} </ref><ref name="pmid9880781">{{cite journal| author=Soga J, Yakuwa Y| title=Glucagonomas/diabetico-dermatogenic syndrome (DDS): a statistical evaluation of 407 reported cases. | journal=J Hepatobiliary Pancreat Surg | year= 1998 | volume= 5 | issue= 3 | pages= 312-9 | pmid=9880781 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9880781 }}</ref><ref name="pmid25152626">{{cite journal| author=Fang S, Li S, Cai T| title=Glucagonoma syndrome: a case report with focus on skin disorders. | journal=Onco Targets Ther | year= 2014 | volume= 7 | issue= | pages= 1449-53 | pmid=25152626 | doi=10.2147/OTT.S66285 | pmc=PMC4140234 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25152626 }} </ref> | ||
* Large tumors at diagnosis with a mean diameter of 5 cm | * Large tumors at diagnosis with a mean diameter of 5 cm. About 50 to 82% 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. | * 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, | * In few patients, location can be [[extrapancreatic]], such as in [[Kidney|kidney,]] [[duodenum]], [[lung]], [[Accessory pancreas|accessory pancreatic tissue]]. | ||
* Metastasis usually occurs to [[Liver|the liver]]. Other sites are [[Lymph node|lymph nodes]], [[bone]], [[lung]], and [[Adrenal gland|adrenals]]. | * Metastasis usually occurs to [[Liver|the liver]]. Other sites are [[Lymph node|lymph nodes]], [[bone]], [[lung]], and [[Adrenal gland|adrenals]]. | ||
*Tumors smaller than 2 cm in diameter are associated with a very low chance of malignancy. | *Tumors smaller than 2 cm in diameter are associated with a very low chance of [[malignancy]]. | ||
==Microscopic Pathology== | ==Microscopic Pathology== | ||
The microscopic pathology of glucagonoma tumors in pancreas usually show intense staining for [[glucagon]].<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><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> | The microscopic pathology of glucagonoma tumors in [[pancreas]] usually show intense staining for [[glucagon]].<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><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> | ||
* Many glucagonomas are [[Pleomorphism|pleomorphic]] with cells containing granules that stain for other peptides, most frequently [[pancreatic polypeptide]]. | * Many glucagonomas are [[Pleomorphism|pleomorphic]] with cells containing [[granules]] that stain for other [[peptides]], most frequently [[pancreatic polypeptide]]. | ||
* [[Immunoperoxidase|Immunoperoxidase staining]] can detect glucagon within the tumor cells and glucagon [[mRNA]] also may be detected. | * [[Immunoperoxidase|Immunoperoxidase staining]] can detect glucagon within the tumor cells and glucagon [[mRNA]] also may be detected. | ||
* [[Electron|Electron microscopy]] shows secretory granules indicating the origin of glucagonoma from [[alpha cells]]. | * [[Electron|Electron microscopy]] shows secretory granules indicating the origin of glucagonoma from [[alpha cells]]. | ||
* Benign tumors are usually fully granulated and malignant cells have fewer granules. | * Benign tumors are usually fully granulated and [[malignant]] cells have fewer granules. | ||
*Skin biopsy may depict epidermal necrosis. | *[[Skin biopsy]] may depict [[Epidermal|epidermal necrosis]]. | ||
===Images=== | ===Images=== | ||
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Image:1024px-Confluent epidermal necrosis - intermed mag.jpg|'''Histology of confluent epidermal necrosis''' '''(intermed mag)'''<small>Source:By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=16874054</small><ref name=picture>Glucagonoma. Wikimedia Commons. https://commons.wikimedia.org/wiki/File:Confluent_epidermal_necrosis_-_high_mag.jpg</ref> | Image:1024px-Confluent epidermal necrosis - intermed mag.jpg|'''Histology of confluent epidermal necrosis''' '''(intermed mag)'''<small>Source:By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=16874054</small><ref name=picture>Glucagonoma. Wikimedia Commons. https://commons.wikimedia.org/wiki/File:Confluent_epidermal_necrosis_-_high_mag.jpg</ref> | ||
</gallery> | </gallery> | ||
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[[Category:Medicine]] | [[Category:Medicine]] | ||
[[Category:Endocrinology]] | [[Category:Endocrinology]] | ||
[[Category:Up-To-Date]] | |||
[[Category:Oncology]] | |||
[[Category:Medicine]] | |||
[[Category:Gastroenterology]] | |||
[[Category:Surgery]] | |||
Latest revision as of 22:28, 30 May 2019
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Glucagonoma Microchapters |
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Glucagonoma pathophysiology On the Web |
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American Roentgen Ray Society Images of Glucagonoma pathophysiology |
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Risk calculators and risk factors for Glucagonoma pathophysiology |
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 tumor of the alpha cells of the pancreas characterized by the excessive secretion of glucagon and necrolytic migratory erythema. Glucagonoma causes hyperglucagonemia, zinc deficiency, fatty acid deficiency, hypoaminoacidemia that may cause necrolytic migratory erythema. Glucagonoma may be a part of type 1 multiple endocrine neoplasia. 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. Glucagonoma can metastasize mainly to the 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
- Glucagonoma is a rare tumor of the alpha cells of the pancreas that results in the overproduction of the hormone glucagon. Glucagonomas are neuroendocrine tumors derived from multipotential stem cells.[1][2][3][4][5][6]
- Glucagon increases glycogenolysis, gluconeogenesis from amino acid substrates and inhibits glycolysis. This causes weight loss due to the catabolic action of glucagon.
- 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, hypoaminoacidemia that may cause necrolytic migratory erythema.
- The mechanism for necrolytic migratory erythema involves excessive inflammation in the epidermis in response to trauma and to the necrolysis.
- Necrolytic migratory erythema (NME) probably results from hyponutrition and amino acid deficiency. It can be caused by the loss of tryptophan in cutaneous tissues as a result of the excess circulating glucagon. Tryptophan is responsible for niacin function, which regulates cell turnover and the maturation of the epidermis and mucosal epithelia.
- Diarrhea may result from the secretion of gastrin which occurs with glucagonoma.
Genetics
Glucagonoma may be part of type 1 multiple endocrine neoplasia. It is an autosomal dominant syndrome that is usually caused by mutations in the MEN1 gene.[1][2][3][4][5][6][7]
- It is characterized by the development of the following tumors:
- Pituitary adenomas
- Islet cell tumors of the pancreas (commonly gastrinoma and glucagonoma)
- 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 tumors and by linkage analysis in multiple endocrine neoplasia type 1 families. MEN1, spans about 10 Kb and consists of ten exons encoding a 610 amino acid nuclear protein, named menin.
- MEN1 gene is a tumor suppressor gene and causes type 1 multiple endocrine neoplasia by Knudson's "two hits" model for tumor development.
- Two hits model for tumor development suggests that there is a germline mutation present in all 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 cells the survival advantage needed for tumor development.
Gross Pathology
The gross pathology of glucagonoma may show:[7][8][9]
- Large tumors at diagnosis with a mean diameter of 5 cm. About 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, location can be extrapancreatic, such as in kidney, duodenum, lung, accessory pancreatic tissue.
- Metastasis usually occurs to the liver. Other sites are lymph nodes, bone, lung, and adrenals.
- Tumors smaller than 2 cm in diameter are associated with a very low chance of malignancy.
Microscopic Pathology
The microscopic pathology of glucagonoma tumors in pancreas usually show intense staining for glucagon.[10][11]
- Many glucagonomas are pleomorphic with cells containing granules that stain for other peptides, most frequently pancreatic polypeptide.
- Immunoperoxidase staining can detect glucagon within the tumor cells and glucagon mRNA also may be detected.
- Electron microscopy shows secretory granules indicating the origin of glucagonoma from alpha cells.
- Benign tumors are usually fully granulated and malignant cells have fewer granules.
- Skin biopsy may depict epidermal necrosis.
Images
-
![Histology of confluent epidermal necrosis (high mag),Source:By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=16874054[12]](/images/2/2d/800px-Confluent_epidermal_necrosis_-_high_mag.jpg)
Histology of confluent epidermal necrosis (high mag),Source:By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=16874054[12]
-
![Histology of confluent epidermal necrosis (very high mag)Source:By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=16874054[12]](/images/f/ff/1024px-Confluent_epidermal_necrosis_-_very_high_mag.jpg)
Histology of confluent epidermal necrosis (very high mag)Source:By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=16874054[12]
-
![Histology of confluent epidermal necrosis (intermed mag)Source:By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=16874054[12]](/images/7/70/1024px-Confluent_epidermal_necrosis_-_intermed_mag.jpg)
Histology of confluent epidermal necrosis (intermed mag)Source:By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=16874054[12]
![Histology of confluent epidermal necrosis (high mag),Source:By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=16874054[12]](/index.php/File:800px-Confluent_epidermal_necrosis_-_high_mag.jpg)
![Histology of confluent epidermal necrosis (very high mag)Source:By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=16874054[12]](/index.php/File:1024px-Confluent_epidermal_necrosis_-_very_high_mag.jpg)
![Histology of confluent epidermal necrosis (intermed mag)Source:By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=16874054[12]](/index.php/File:1024px-Confluent_epidermal_necrosis_-_intermed_mag.jpg)
References
- ↑ Frankton S, Bloom SR (1996). "Gastrointestinal endocrine tumours. Glucagonomas". Baillieres Clin Gastroenterol. 10 (4): 697–705. PMID 9113318.
- ↑ 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.
- ↑ Necrolytic migratory erythema. Wikipedia. https://en.wikipedia.org/wiki/Necrolytic_migratory_erythema. Accessed on October 13, 2015.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Warner TF, Block M, Hafez GR, Mack E, Lloyd RV, Bloom SR (1983). "Glucagonomas. Ultrastructure and immunocytochemistry". Cancer. 51 (6): 1091–6. PMID 6295622.
- ↑ 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.
- ↑ 12.0 12.1 12.2 Glucagonoma. Wikimedia Commons. https://commons.wikimedia.org/wiki/File:Confluent_epidermal_necrosis_-_high_mag.jpg
