Pheochromocytoma pathophysiology: Difference between revisions

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* Genes involved in the pathogenesis of pheochromocytoma include:  
* Genes involved in the pathogenesis of pheochromocytoma include:  
** RET gene (MEN 2A, MEN 2B syndromes)
**[[RET gene|RET]] gene ([[MEN, type 2a|MEN 2A]], [[Multiple endocrine neoplasia type 2|MEN 2B]] [[Syndrome|syndromes]])
** NF1 gene
**[[NF1|NF1 gene]]
** VHL gene (VHL disease)
**[[Von Hippel-Lindau tumor suppressor|VHL gene]] ([[Von Hippel-Lindau disease|VHL disease]])
** SDHD, SDHB, and SDHC genes of the mitochondrial complex <ref name="pmid15883706">{{cite journal| author=Gimm O| title=Pheochromocytoma-associated syndromes: genes, proteins and functions of RET, VHL and SDHx. | journal=Fam Cancer | year= 2005 | volume= 4 | issue= 1 | pages= 17-23 | pmid=15883706 | doi=10.1007/s10689-004-5740-1 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15883706  }} </ref>
**[[SDHD]], [[SDHB]], and [[SDHC]] genes of the [[Mitochondrial|mitochondrial complex]] <ref name="pmid15883706">{{cite journal| author=Gimm O| title=Pheochromocytoma-associated syndromes: genes, proteins and functions of RET, VHL and SDHx. | journal=Fam Cancer | year= 2005 | volume= 4 | issue= 1 | pages= 17-23 | pmid=15883706 | doi=10.1007/s10689-004-5740-1 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15883706  }} </ref>
** SDHA, SDHAF2, TMEM127 (transmembrane protein 127), MAX (myc-associated factor X), FH (fumarate hydratase), PDH1, PDH2 (pyruvate dehydrogenase), HIF1alpha (hypoxia-inducible factor), MDH2 (malate dehydrogenase), and KIF1Bß (kinesin family member) genes. <ref>{{cite book | last = Jameson | first = J | title = Harrison's Principles of Internal Medicine 19th Edition and Harrison's Manual of Medicine 19th Edition VAL PAK | publisher = McGraw-Hill Medical | location = New York | year = 2017 | isbn = 978-1260128857 }} </ref>
**[[SDHA]], [[SDHAF2]], [[TMEM127]] (transmembrane protein 127), [[MAX (gene)|MAX]] (myc-associated factor X), [[Fumarate hydratase|FH]] (fumarate hydratase), [[PDH complex|PDH1]], PDH2 (pyruvate dehydrogenase), [[Hypoxia inducible factors|HIF1alpha]] (hypoxia-inducible factor), [[MDH1|MDH2]] (malate dehydrogenase), and KIF1Bß (kinesin family member) genes. <ref>{{cite book | last = Jameson | first = J | title = Harrison's Principles of Internal Medicine 19th Edition and Harrison's Manual of Medicine 19th Edition VAL PAK | publisher = McGraw-Hill Medical | location = New York | year = 2017 | isbn = 978-1260128857 }} </ref>
Pheochromocytoma and paragangliomas  (PPGL) susceptibility genes can be classified into the following clusters- <ref>{{cite book | last = Jameson | first = J | title = Harrison's Principles of Internal Medicine 19th Edition and Harrison's Manual of Medicine 19th Edition VAL PAK | publisher = McGraw-Hill Medical | location = New York | year = 2017 | isbn = 978-1260128857 }} </ref> <ref name="pmid15613462">{{cite journal| author=Eisenhofer G, Huynh TT, Pacak K, Brouwers FM, Walther MM, Linehan WM | display-authors=etal| title=Distinct gene expression profiles in norepinephrine- and epinephrine-producing hereditary and sporadic pheochromocytomas: activation of hypoxia-driven angiogenic pathways in von Hippel-Lindau syndrome. | journal=Endocr Relat Cancer | year= 2004 | volume= 11 | issue= 4 | pages= 897-911 | pmid=15613462 | doi=10.1677/erc.1.00838 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15613462  }} </ref>  <ref name="pmid28477311">{{cite journal| author=Lam AK| title=Update on Adrenal Tumours in 2017 World Health Organization (WHO) of Endocrine Tumours. | journal=Endocr Pathol | year= 2017 | volume= 28 | issue= 3 | pages= 213-227 | pmid=28477311 | doi=10.1007/s12022-017-9484-5 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28477311  }} </ref>
 
[[Pheochromocytoma]] and [[Paraganglioma|paragangliomas]] (PPGL) susceptibility genes can be classified into the following clusters- <ref>{{cite book | last = Jameson | first = J | title = Harrison's Principles of Internal Medicine 19th Edition and Harrison's Manual of Medicine 19th Edition VAL PAK | publisher = McGraw-Hill Medical | location = New York | year = 2017 | isbn = 978-1260128857 }} </ref> <ref name="pmid15613462">{{cite journal| author=Eisenhofer G, Huynh TT, Pacak K, Brouwers FM, Walther MM, Linehan WM | display-authors=etal| title=Distinct gene expression profiles in norepinephrine- and epinephrine-producing hereditary and sporadic pheochromocytomas: activation of hypoxia-driven angiogenic pathways in von Hippel-Lindau syndrome. | journal=Endocr Relat Cancer | year= 2004 | volume= 11 | issue= 4 | pages= 897-911 | pmid=15613462 | doi=10.1677/erc.1.00838 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15613462  }} </ref>  <ref name="pmid28477311">{{cite journal| author=Lam AK| title=Update on Adrenal Tumours in 2017 World Health Organization (WHO) of Endocrine Tumours. | journal=Endocr Pathol | year= 2017 | volume= 28 | issue= 3 | pages= 213-227 | pmid=28477311 | doi=10.1007/s12022-017-9484-5 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28477311  }} </ref>
* Cluster 1
* Cluster 1
**[[Mutation|Mutations]] involving in [[overexpression]] of [[Vascular endothelial growth factor (VEGF) IRES A|vascular endothelial growth factor (VEGF)]] as a result of pseudohypoxia
**[[Mutation|Mutations]] involving in [[overexpression]] of [[Vascular endothelial growth factor (VEGF) IRES A|vascular endothelial growth factor (VEGF)]] as a result of pseudohypoxia
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Conditions associated with pheochromocytoma include:
Conditions associated with pheochromocytoma include:
*[[Multiple endocrine neoplasia]] ([[Multiple endocrine neoplasia type 1|MEN1]])
*[[Multiple endocrine neoplasia]] ([[Multiple endocrine neoplasia type 1|MEN1]])
* Multiple endocrine neoplasia ([[MEN2|MEN2B]])
*[[Multiple endocrine neoplasia (MEN 2b)|Multiple endocrine neoplasia]] ([[MEN2|MEN2B]])
* Von-Hippel Lindau (VHL) disease (VHL)
* Von-Hippel Lindau disease (VHL)
* Neufibromatosis 1 (NF1)
*[[Neurofibromatosis type I|Neurofibromatosis 1]] (NF1)


{| class="wikitable"
{| class="wikitable"
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On [[gross pathology]], the characteristic findings of pheochromocytoma are:
On [[gross pathology]], the characteristic findings of pheochromocytoma are:
* Small to large tumors usually associated with [[hemorrhage]] and [[necrosis]].<ref name="pmid26266130">{{cite journal| author=Sajjanar AB, Athanikar VS, Dinesh US, Nanjappa B, Patil PB| title=Non Functional Unilateral Adrenal Myelolipoma, A Case Report. | journal=J Clin Diagn Res | year= 2015 | volume= 9 | issue= 6 | pages= ED03-4 | pmid=26266130 | doi=10.7860/JCDR/2015/13209.6070 | pmc=4525519 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26266130  }}</ref>
* Small to large tumors usually associated with [[hemorrhage]] and [[necrosis]].<ref name="pmid26266130">{{cite journal| author=Sajjanar AB, Athanikar VS, Dinesh US, Nanjappa B, Patil PB| title=Non Functional Unilateral Adrenal Myelolipoma, A Case Report. | journal=J Clin Diagn Res | year= 2015 | volume= 9 | issue= 6 | pages= ED03-4 | pmid=26266130 | doi=10.7860/JCDR/2015/13209.6070 | pmc=4525519 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26266130  }}</ref>
* Usually lobulated
* Usually [[Lobule|lobulated]]
* Bilateral when familial [[Tumor|tumors]]
*[[Bilateral]] when [[familial]] [[Tumor|tumors]]
* Associated with hyperplasia in the adjacent [[medulla]].
* Associated with [[hyperplasia]] in the adjacent [[medulla]].
*[[Chromaffin]] reaction: fresh [[tumor]] cut section turns dark brown if add [[potassium dichromate]] at pH 5-6.
*[[Chromaffin]] reaction: fresh [[tumor]] cut section turns dark brown if add [[potassium dichromate]] at pH 5-6.
<gallery>
<gallery>

Revision as of 23:27, 24 July 2020

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmad Al Maradni, M.D. [2] Mohammed Abdelwahed M.D[3]

Overview

It is understood that pheochromocytoma is mediated by excessive secretion of catecholamines and subsequent stimulation of adrenergic receptors. It arises from the chromaffin cells of the adrenal medulla and sympathetic ganglia. The pathophysiology of pheochromocytoma does not depend on the histological subtype. Malignant and benign pheochromocytomas share the same biochemical and histological features. It may be sporadic or familial. All of these forms have genetic origin depending on a large number of genes, for example, VHL, SDH, NF1, RET genes. It is associated with conditions like MEN 2A syndrome, MEN 2B syndrome, VHL disease, and NF1.

Pathophysiology

Physiology

Pheochromocytoma is not associated with normal physiology.

Pathology

Genetics

  • Pheochromocytoma can be transmitted in a sporadic(60-65%) or familial pattern. [5][6]

Pheochromocytoma and paragangliomas (PPGL) susceptibility genes can be classified into the following clusters- [9] [10] [11]

Associated conditions

Conditions associated with pheochromocytoma include:

MEN 1 MEN 2

Gross Pathology

On gross pathology, the characteristic findings of pheochromocytoma are:

Microscopic Pathology

On microscopic histopathological analysis, the characterisitc findings of pheochromocytoma typically include: [13] [14]

  • A nesting (Zellballen) pattern- this pattern is composed of well-defined clusters of tumor cells (round or polygonal epithelioid cells) containing eosinophilic cytoplasm separated by fibrovascular stroma.
  • These cells have a central nucleus with an eosinophilic, granular cytoplasm, and clumped chromatin.
  • At the periphery, spindle-shaped sustentacular or supporting cells are seen.

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References

  1. Smith RJ, Bryant RG (1975). "Metal substitutions incarbonic anhydrase: a halide ion probe study". Biochem Biophys Res Commun. 66 (4): 1281–6. doi:10.1016/0006-291x(75)90498-2. PMID orcid.org/0000-0003-2771-564X Check |pmid= value (help).
  2. Goldstein RE, O'Neill JA, Holcomb GW, Morgan WM, Neblett WW, Oates JA; et al. (1999). "Clinical experience over 48 years with pheochromocytoma". Ann Surg. 229 (6): 755–64, discussion 764-6. PMC 1420821. PMID 10363888.
  3. Raz I, Katz A, Spencer MK (1991). "Epinephrine inhibits insulin-mediated glycogenesis but enhances glycolysis in human skeletal muscle". Am J Physiol. 260 (3 Pt 1): E430–5. PMID 1900669.
  4. Arnall DA, Marker JC, Conlee RK, Winder WW (1986). "Effect of infusing epinephrine on liver and muscle glycogenolysis during exercise in rats". Am J Physiol. 250 (6 Pt 1): E641–9. PMID 3521311.
  5. Webb TA, Sheps SG, Carney JA (1980). "Differences between sporadic pheochromocytoma and pheochromocytoma in multiple endocrime neoplasia, type 2". Am. J. Surg. Pathol. 4 (2): 121–6. PMID 6103678.
  6. Yee JK, Moores JC, Jolly DJ, Wolff JA, Respess JG, Friedmann T (1987). "Gene expression from transcriptionally disabled retroviral vectors". Proc. Natl. Acad. Sci. U.S.A. 84 (15): 5197–201. PMC 298821. PMID 3474647.
  7. Gimm O (2005). "Pheochromocytoma-associated syndromes: genes, proteins and functions of RET, VHL and SDHx". Fam Cancer. 4 (1): 17–23. doi:10.1007/s10689-004-5740-1. PMID 15883706.
  8. Jameson, J (2017). Harrison's Principles of Internal Medicine 19th Edition and Harrison's Manual of Medicine 19th Edition VAL PAK. New York: McGraw-Hill Medical. ISBN 978-1260128857.
  9. Jameson, J (2017). Harrison's Principles of Internal Medicine 19th Edition and Harrison's Manual of Medicine 19th Edition VAL PAK. New York: McGraw-Hill Medical. ISBN 978-1260128857.
  10. Eisenhofer G, Huynh TT, Pacak K, Brouwers FM, Walther MM, Linehan WM; et al. (2004). "Distinct gene expression profiles in norepinephrine- and epinephrine-producing hereditary and sporadic pheochromocytomas: activation of hypoxia-driven angiogenic pathways in von Hippel-Lindau syndrome". Endocr Relat Cancer. 11 (4): 897–911. doi:10.1677/erc.1.00838. PMID 15613462.
  11. Lam AK (2017). "Update on Adrenal Tumours in 2017 World Health Organization (WHO) of Endocrine Tumours". Endocr Pathol. 28 (3): 213–227. doi:10.1007/s12022-017-9484-5. PMID 28477311.
  12. Sajjanar AB, Athanikar VS, Dinesh US, Nanjappa B, Patil PB (2015). "Non Functional Unilateral Adrenal Myelolipoma, A Case Report". J Clin Diagn Res. 9 (6): ED03–4. doi:10.7860/JCDR/2015/13209.6070. PMC 4525519. PMID 26266130.
  13. Kliewer KE, Wen DR, Cancilla PA, Cochran AJ (1989). "Paragangliomas: assessment of prognosis by histologic, immunohistochemical, and ultrastructural techniques". Hum Pathol. 20 (1): 29–39. doi:10.1016/0046-8177(89)90199-8. PMID 2912871.
  14. Kliewer KE, Cochran AJ (1989). "A review of the histology, ultrastructure, immunohistology, and molecular biology of extra-adrenal paragangliomas". Arch Pathol Lab Med. 113 (11): 1209–18. PMID 2684087.