Pheochromocytoma pathophysiology: Difference between revisions

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==Overview==
==Overview==
Pheochromocytoma arises from [[chromaffin cells]] of the [[adrenal medulla]]. On [[gross pathology]], pheochromocytoma has a [[Nodule (medicine)|multinodular]] and a multicentric pattern of [[growth]]. On [[microscopic|microscopic histopathological]] analysis, nesting (Zellballen) pattern composed of well-defined clusters of [[Tumor cell|tumor cells]] separated by fibrovascular [[stroma]] may be seen. It may be [[benign]], [[malignant]], familial([[multiple endocrine neoplasia]] 1 and [[Multiple endocrine neoplasia type 2|type 2B]]) or sporadic. All of these forms have [[genetic]] origin depending on a large number of [[genes]], for example, [[Von Hippel-Lindau tumor suppressor|VHL]], [[SDH|SDH,]] [[NF1]], [[RET proto-oncogene|RET]] [[Gene|genes]].
 
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 ganglion|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, [[Von Hippel-Lindau tumor suppressor|VHL]], [[SDH|SDH,]] [[NF1]], [[RET proto-oncogene|RET]] [[Gene|genes]]. It is associated with conditions like MEN 2A syndrome, MEN 2B syndrome, VHL disease, and NF1.


==Pathophysiology==
==Pathophysiology==
* Pheochromocytoma arises from [[chromaffin cells]] of the [[adrenal medulla]] and [[Sympathetic ganglion|sympathetic ganglia]]. [[Malignant]] and [[benign]] pheochromocytomas share the same [[biochemical]] and [[histological]] features, the only difference is to have a distant spread or be locally invasive. <ref name="pmid10363888">{{cite journal| author=Goldstein RE, O'Neill JA, Holcomb GW, Morgan WM, Neblett WW, Oates JA et al.| title=Clinical experience over 48 years with pheochromocytoma. | journal=Ann Surg | year= 1999 | volume= 229 | issue= 6 | pages= 755-64; discussion 764-6 | pmid=10363888 | doi= | pmc=1420821 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10363888  }}</ref>
===Physiology===
'''<u>Basic physiology of [[catecholamines]]</u>'''<ref name="pmid1900669">{{cite journal| author=Raz I, Katz A, Spencer MK| title=Epinephrine inhibits insulin-mediated glycogenesis but enhances glycolysis in human skeletal muscle. | journal=Am J Physiol | year= 1991 | volume= 260 | issue= 3 Pt 1 | pages= E430-5 | pmid=1900669 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1900669  }}</ref><ref name="pmid3521311">{{cite journal| author=Arnall DA, Marker JC, Conlee RK, Winder WW| title=Effect of infusing epinephrine on liver and muscle glycogenolysis during exercise in rats. | journal=Am J Physiol | year= 1986 | volume= 250 | issue= 6 Pt 1 | pages= E641-9 | pmid=3521311 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3521311  }}</ref>
Pheochromocytoma is not associated with normal physiology.
* [[Epinephrine]] acts on nearly all body tissues. Its actions vary by tissue type and tissue expression of [[adrenergic receptors]].
 
* [[Epinephrine]] is a nonselective agonist of all [[adrenergic receptors]], including the major subtypes [[Alpha-1 adrenergic receptor|α<sub>1</sub>]], [[Alpha-2 adrenergic receptor|α<sub>2</sub>]], [[Β1-adrenoreceptors|β<sub>1</sub>]], [[Beta-2 adrenergic receptor|β<sub>2</sub>]], and [[Beta-3 adrenergic receptor|β<sub>3:</sub>]]
===Pathology===
**Binding to [[Alpha-1 adrenergic receptor|α<sub>1</sub>]] receptors causes [[vasoconstriction]]. [[Blood vessels]] with α<sub>1</sub>-adrenergic receptors are present in the skin, the sphincters of the [[gastrointestinal system]], [[kidney]] (renal artery) and [[brain]]. During the fight-or-flight response vasoconstriction results in decreased blood flow to these organs.
* It is understood that pheochromocytoma is the is mediated by excessive secretion of [[catecholamines]] and subsequent stimulation of [[adrenergic receptors]].
**Binding to [[Alpha-2 adrenergic receptor|α2]] receptors inhibits [[insulin]] secretion by the [[pancreas]], stimulates [[glycogenolysis]] in the liver and muscle, and stimulates [[glycolysis]] and inhibits [[insulin]]-mediated [[glycogenesis]] in muscle. It suppresses the release of [[norepinephrine]] by negative feedback.
* Commonly secreted [[catecholamines]] include [[norepinephrine]] (predominant) and [[epinephrine]]. Some [[tumors]] may also secrete [[dopamine]]. <ref name="pmidorcid.org/0000-0003-2771-564X">{{cite journal| author=Smith RJ, Bryant RG| title=Metal substitutions incarbonic anhydrase: a halide ion probe study. | journal=Biochem Biophys Res Commun | year= 1975 | volume= 66 | issue= 4 | pages= 1281-6 | pmid=orcid.org/0000-0003-2771-564X | doi=10.1016/0006-291x(75)90498-2 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3  }} </ref>
**Binding to [[Beta-2 adrenergic receptor|β<sub>2</sub>]] receptors causes Smooth muscle relaxation in the uterus, GI tract, [[Detrusor urinae muscle|detrusor urinae]] muscle of [[Urinary bladder|bladder]] wall, and bronchi. It also causes dilatation of smaller [[Coronary circulation|coronary]] arteries, [[hepatic artery]], arteries to skeletal muscle.
* Excessive secretion of [[catecholamines]] may be either continuous or intermittent.
**Binding to [[Β1-adrenoreceptors|β<sub>1</sub>]] receptors causes [[renin]] release from [[juxtaglomerular cells]] and [[lipolysis]] in [[adipose tissue]]. It Increases [[cardiac output]] by:
*Pheochromocytoma is a [[tumor]] which arises from the [[chromaffin cells]] of the [[adrenal medulla]] and [[Sympathetic ganglion|sympathetic ganglia]].
***Increase in [[heart rate]] in [[sinoatrial node]]  
*The pathophysiology of pheochromocytoma does not depend on the histological subtype. [[Malignant]] and [[benign]] pheochromocytomas share the same [[biochemical]] and [[histological]] features. <ref name="pmid10363888">{{cite journal| author=Goldstein RE, O'Neill JA, Holcomb GW, Morgan WM, Neblett WW, Oates JA et al.| title=Clinical experience over 48 years with pheochromocytoma. | journal=Ann Surg | year= 1999 | volume= 229 | issue= 6 | pages= 755-64; discussion 764-6 | pmid=10363888 | doi= | pmc=1420821 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10363888  }}</ref><ref name="pmid1900669">{{cite journal| author=Raz I, Katz A, Spencer MK| title=Epinephrine inhibits insulin-mediated glycogenesis but enhances glycolysis in human skeletal muscle. | journal=Am J Physiol | year= 1991 | volume= 260 | issue= 3 Pt 1 | pages= E430-5 | pmid=1900669 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1900669  }}</ref><ref name="pmid3521311">{{cite journal| author=Arnall DA, Marker JC, Conlee RK, Winder WW| title=Effect of infusing epinephrine on liver and muscle glycogenolysis during exercise in rats. | journal=Am J Physiol | year= 1986 | volume= 250 | issue= 6 Pt 1 | pages= E641-9 | pmid=3521311 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3521311  }}</ref>
***Increase in [[atrial]] cardiac muscle [[contractility]]
* The exact mechanism responsible for surge in [[catecholamine]] secretion remains unclear but it has been postulated that certain [[medications]] (such as [[opiates]], [[metoclopramide]] or [[beta blockers]]) and changes in [[tumor]] [[blood flow]] and [[pressure]] could be responsible factors.
***Increases in [[contractility]] and [[automaticity]] of [[ventricular]] cardiac muscle
*Binding to [[Β1-adrenoreceptors|β<sub>1</sub>]] receptors causes [[renin]] release from [[juxtaglomerular cells]] and [[lipolysis]] in [[adipose tissue]]. It Increases [[cardiac output]] by:
***Increases in [[Electrical conduction system of the heart|conduction]] and [[automaticity]] of [[atrioventricular node]]
**Increase in [[heart rate]] in [[sinoatrial node]]  
**Increase in [[atrial]] cardiac muscle [[contractility]]
**Increases in [[contractility]] and [[automaticity]] of [[ventricular]] cardiac muscle
**Increases in [[Electrical conduction system of the heart|conduction]] and [[automaticity]] of [[atrioventricular node]]


==Genetics==
==Genetics==
* 60-65 percent of pheochromocytomas are sporadic.<ref name="pmid6103678">{{cite journal |vauthors=Webb TA, Sheps SG, Carney JA |title=Differences between sporadic pheochromocytoma and pheochromocytoma in multiple endocrime neoplasia, type 2 |journal=Am. J. Surg. Pathol. |volume=4 |issue=2 |pages=121–6 |year=1980 |pmid=6103678 |doi= |url=}}</ref><ref name="pmid3474647">{{cite journal |vauthors=Yee JK, Moores JC, Jolly DJ, Wolff JA, Respess JG, Friedmann T |title=Gene expression from transcriptionally disabled retroviral vectors |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=84 |issue=15 |pages=5197–201 |year=1987 |pmid=3474647 |pmc=298821 |doi= |url=}}</ref>
* Pheochromocytoma can be transmitted in a sporadic(60-65%) or familial pattern. <ref name="pmid6103678">{{cite journal |vauthors=Webb TA, Sheps SG, Carney JA |title=Differences between sporadic pheochromocytoma and pheochromocytoma in multiple endocrime neoplasia, type 2 |journal=Am. J. Surg. Pathol. |volume=4 |issue=2 |pages=121–6 |year=1980 |pmid=6103678 |doi= |url=}}</ref><ref name="pmid3474647">{{cite journal |vauthors=Yee JK, Moores JC, Jolly DJ, Wolff JA, Respess JG, Friedmann T |title=Gene expression from transcriptionally disabled retroviral vectors |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=84 |issue=15 |pages=5197–201 |year=1987 |pmid=3474647 |pmc=298821 |doi= |url=}}</ref>
 
* Pheochromocytomas can be familial and occur in patients with [[multiple endocrine neoplasia]]<nowiki/> ([[Multiple endocrine neoplasia type 1|MEN1]] and [[Multiple endocrine neoplasia type 2|MEN 2B]]).
* Patients with [[Von Hippel-Lindau disease|Von Hippel Lindau disease]] ([[VHL]]) may also develop pheochromocytoma.<ref name="pmid24642075">{{cite journal| author=Shuch B, Ricketts CJ, Metwalli AR, Pacak K, Linehan WM| title=The genetic basis of pheochromocytoma and paraganglioma: implications for management. | journal=Urology | year= 2014 | volume= 83 | issue= 6 | pages= 1225-32 | pmid=24642075 | doi=10.1016/j.urology.2014.01.007 | pmc=4572836 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24642075  }}</ref>
* It has [[Autosomal dominant inheritance|autosomal dominant]] inheritance and has two pathways of [[tumor]] pathogenesis. Cluster 1 tumors are [[noradrenergic]]. Cluster 2 tumors are [[adrenergic]].<ref name="pmid23933153">{{cite journal| author=King KS, Pacak K| title=Familial pheochromocytomas and paragangliomas. | journal=Mol Cell Endocrinol | year= 2014 | volume= 386 | issue= 1-2 | pages= 92-100 | pmid=23933153 | doi=10.1016/j.mce.2013.07.032 | pmc=3917973 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23933153  }}</ref>
{| class="wikitable"
! colspan="2" |Familial pheocromocytoma
|-
!Cluster 1 (Noradrenergic)
!Cluster 2 (Adrenergic)
|-
!
* [[Succinate dehydrogenase]] (SDH) subunit genes
* [[Von Hippel-Lindau Disease|Von Hippel-Lindau]] (VHL) disease
* [[Fumarate hydratase|Fumarate hydratase gene]] mutations
|
* '''[[Multiple endocrine neoplasia, type 2|Multiple endocrine neoplasia]] type 2A'''
* '''[[Multiple endocrine neoplasia (MEN 2b),|Multiple endocrine neoplasia]] type 2B'''
* '''[[Neurofibromatosis type I|Neurofibromatosis type 1]] (NF1)'''
|}
* Patients with the [[Succinate dehydrogenase|succinate dehydrogenase B]] [[mutations]] are likely to develop a [[malignant]] disease.<ref name="pmid15328326">{{cite journal| author=Neumann HP, Pawlu C, Peczkowska M, Bausch B, McWhinney SR, Muresan M et al.| title=Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. | journal=JAMA | year= 2004 | volume= 292 | issue= 8 | pages= 943-51 | pmid=15328326 | doi=10.1001/jama.292.8.943 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15328326  }}</ref>


* [[Von Hippel-Lindau Disease|Von Hippel-Lindau]] ([[Von Hippel-Lindau tumor suppressor|VHL]]) disease
* Genes involved in the pathogenesis of pheochromocytoma include:
**PCCs arise in about 10–20% of patients with [[VHL]] disease. 
**[[RET gene|RET]] gene ([[MEN, type 2a|MEN 2A]], [[Multiple endocrine neoplasia type 2|MEN 2B]] [[Syndrome|syndromes]])
**VHL [[Tumor suppressor gene|tumor suppressor protein]] is the main cause of the disease.tcted.
**[[NF1|NF1 gene]]
**The [[VHL]] [[Tumor suppressor gene|tumor suppressor protein]] targets especially hypoxia-inducible factor-1 (HIF-1), [[MMP]] inhibitors, and atypical [[protein kinase C]].<ref name="pmid12209156">{{cite journal| author=Kaelin WG| title=Molecular basis of the VHL hereditary cancer syndrome. | journal=Nat Rev Cancer | year= 2002 | volume= 2 | issue= 9 | pages= 673-82 | pmid=12209156 | doi=10.1038/nrc885 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12209156  }}</ref>
**[[Von Hippel-Lindau tumor suppressor|VHL gene]] ([[Von Hippel-Lindau disease|VHL disease]])
**HIF-1 is involved in [[erythropoiesis]] through its ability to induce [[Transcription (genetics)|transcription]] of [[mRNA]] coding for [[erythropoietin]]. it regulates several [[growth factors]], such as [[vascular endothelial growth factor]] (VEGF), [[platelet-derived growth factor]] (PDGF)-beta, and [[transforming growth factor]] (TGF-alpha).<ref name="pmid15350900">{{cite journal| author=Barry RE, Krek W| title=The von Hippel-Lindau tumour suppressor: a multi-faceted inhibitor of tumourigenesis. | journal=Trends Mol Med | year= 2004 | volume= 10 | issue= 9 | pages= 466-72 | pmid=15350900 | doi=10.1016/j.molmed.2004.07.008 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15350900  }}</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>
**[[Deletion (genetics)|Deletions]] in ''[[VHL]]'' and [[Nonsense mutation|nonsense]] and [[Frameshift mutation|frameshift mutations]] appear to be more common in type 1 disease, while [[missense mutations]] may be more common in type 2 disease.<ref name="pmid9681856">{{cite journal| author=Neumann HP, Bender BU| title=Genotype-phenotype correlations in von Hippel-Lindau disease. | journal=J Intern Med | year= 1998 | volume= 243 | issue= 6 | pages= 541-5 | pmid=9681856 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9681856  }}</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>
**[[Missense mutations]] at codon 167 are associated with a particularly high risk of PCC.<ref name="pmid8730290">{{cite journal| author=Maher ER, Webster AR, Richards FM, Green JS, Crossey PA, Payne SJ et al.| title=Phenotypic expression in von Hippel-Lindau disease: correlations with germline VHL gene mutations. | journal=J Med Genet | year= 1996 | volume= 33 | issue= 4 | pages= 328-32 | pmid=8730290 | doi= | pmc=1050584 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8730290  }}</ref>
*'''[[Multiple endocrine neoplasia, type 2|Multiple endocrine neoplasia]] type 2A'''
**The [[RET gene|RET]] protein is a transmembrane [[receptor]] of the [[tyrosine kinase]] family.
**It is derived from the [[neural crest]] and has a key role in regulating [[cell proliferation]] and survival during [[embryogenesis]].<ref name="pmid7907913">{{cite journal| author=Mulligan LM, Eng C, Healey CS, Clayton D, Kwok JB, Gardner E et al.| title=Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. | journal=Nat Genet | year= 1994 | volume= 6 | issue= 1 | pages= 70-4 | pmid=7907913 | doi=10.1038/ng0194-70 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7907913 }}</ref>
**The [[RET gene|RET]] receptor can be activated through various factors such as [[Glial cell line-derived neurotrophic factor|glial-cell-line-derived neurotrophic factor]] ([[GDNF]]), [[neurturin]], [[artemin]], and [[persephin]].<ref name="pmid11073534">{{cite journal| author=Hansford JR, Mulligan LM| title=Multiple endocrine neoplasia type 2 and RET: from neoplasia to neurogenesis. | journal=J Med Genet | year= 2000 | volume= 37 | issue= 11 | pages= 817-27 | pmid=11073534 | doi= | pmc=1734482 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11073534  }}</ref>
**[[Mutations]] of the [[RET proto-oncogene|''RET'' proto-oncogene]] cause constitutive activation of the [[RET gene|RET]] receptor and of intracellular signaling pathways, ultimately resulting in the cellular transformation.<ref name="pmid7532281">{{cite journal| author=Asai N, Iwashita T, Matsuyama M, Takahashi M| title=Mechanism of activation of the ret proto-oncogene by multiple endocrine neoplasia 2A mutations. | journal=Mol Cell Biol | year= 1995 | volume= 15 | issue= 3 | pages= 1613-9 | pmid=7532281 | doi= | pmc=230385 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7532281  }}</ref>
**[[Mutations]] causing loss of function of the [[RET gene|RET]] protein were found to be associated with [[Hirschsprung's disease]], a disorder characterized by the absence of [[enteric ganglia]] in the [[Gastrointestinal tract|intestinal tract]].<ref name="pmid16448984">{{cite journal| author=Lantieri F, Griseri P, Ceccherini I| title=Molecular mechanisms of RET-induced Hirschsprung pathogenesis. | journal=Ann Med | year= 2006 | volume= 38 | issue= 1 | pages= 11-9 | pmid=16448984 | doi=10.1080/07853890500442758 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16448984  }}</ref>


* '''[[Neurofibromatosis type I|Neurofibromatosis type 1]] (NF1)'''
[[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>
**[[Mutations]] in the [[NF1|''NF1'' gene]] result in loss of functional [[protein]] causing the wide spectrum of clinical findings.
* Cluster 1
**The ''[[NF1]]'' gene has been localized on [[chromosome]] 17qll.2 and encodes [[neurofibromin]]. In the absence or at decreased levels of [[neurofibromin]], [[Signaling pathway|signaling]] is increased through various pathways resulting in the [[cell proliferation]] and inhibited [[apoptosis]].<ref name="pmid7926784">{{cite journal| author=Brannan CI, Perkins AS, Vogel KS, Ratner N, Nordlund ML, Reid SW et al.| title=Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues. | journal=Genes Dev | year= 1994 | volume= 8 | issue= 9 | pages= 1019-29 | pmid=7926784 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7926784  }}</ref><ref name="pmid8825042">{{cite journal| author=Shen MH, Harper PS, Upadhyaya M| title=Molecular genetics of neurofibromatosis type 1 (NF1). | journal=J Med Genet | year= 1996 | volume= 33 | issue= 1 | pages= 2-17 | pmid=8825042 | doi= | pmc=1051805 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8825042 }}</ref>
**[[Mutation|Mutations]] involving in [[overexpression]] of [[Vascular endothelial growth factor (VEGF) IRES A|vascular endothelial growth factor (VEGF)]] as a result of pseudohypoxia
**[[Knudson hypothesis|Knudson's two-hit tumor suppressor model]] could be applied, resulting in a [[loss of heterozygosity]] at tumor level. <ref name="pmid7519874">{{cite journal| author=Gutmann DH, Cole JL, Stone WJ, Ponder BA, Collins FS| title=Loss of neurofibromin in adrenal gland tumors from patients with neurofibromatosis type I. | journal=Genes Chromosomes Cancer | year= 1994 | volume= 10 | issue= 1 | pages= 55-8 | pmid=7519874 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7519874 }}</ref>The [[mutations]] include [[translocations]], [[Splicing (genetics)|splicing]], [[Deletion (genetics)|deletions]], [[insertions]], and [[point mutations]].
** Impaired [[DNA]] [[methylation]] leading to increased vascularization
**The Ras-GTPase-activating protein-related domain has the important role of stimulating the intrinsic [[GTPase]] of p21-Ras''-''GTP to hydrolyze GTP to GDP and inactivating p21-Ras. .[[P21|P21-Ras]] is a key component of many [[growth factors]] signaling pathways, and [[neurofibromin]] acts as a [[Tumor suppressor|tumor suppressor protein]].  
* Cluster 2
**The cysteine-serine-rich domain ([[CSR]]) of [[neurofibromin]] plays an important role in the pathogenesis of NF1.<ref name="pmid17426081">{{cite journal| author=Bausch B, Borozdin W, Mautner VF, Hoffmann MM, Boehm D, Robledo M et al.| title=Germline NF1 mutational spectra and loss-of-heterozygosity analyses in patients with pheochromocytoma and neurofibromatosis type 1. | journal=J Clin Endocrinol Metab | year= 2007 | volume= 92 | issue= 7 | pages= 2784-92 | pmid=17426081 | doi=10.1210/jc.2006-2833 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17426081  }}</ref>
** Activating [[Mutation|mutations]] of [[Wnt signaling pathway|Wnt-signaling pathway]] including Wnt receptor signaling and [[Hedgehog signaling pathway|Hedgehog]] signaling.
** Mutations of [[CSDE1]] (Cold shock domain containing E1) and [[MAML2|MAML3]] (Mastermind like transcriptional coactivator 3) genes7.
* Cluster 3
** Abnormal activation of [[Kinase|kinase signaling pathways]] like PI3Kinase/[[AKT]], [[RAS]]/RAF/ERK, and [[mTOR]] pathways.


==Associated conditions==
==Associated conditions==
* Pheochromocytoma can be part of other syndromes named [[Multiple endocrine neoplasia|multiple endocrine neoplasia]] ([[Multiple endocrine neoplasia type 1|MEN1]] and [[MEN2|MEN2B]]), which are [[Autosomal dominant inheritance|autosomal dominant]] syndromes controlled by [[RET proto-oncogene|RET gene]]. Pheochromocytoma occurs in 50% of patients with [[MEN2]] as follows:
Conditions associated with pheochromocytoma include:
*[[Multiple endocrine neoplasia]] ([[Multiple endocrine neoplasia type 1|MEN1]])
*[[Multiple endocrine neoplasia (MEN 2b)|Multiple endocrine neoplasia]] ([[MEN2|MEN2B]])
*[[Von Hippel-Lindau disease|Von-Hippel Lindau disease]] (VHL)
*[[Neurofibromatosis type I|Neurofibromatosis 1]] (NF1)
 
{| class="wikitable"
{| class="wikitable"
!MEN1
! align="center" style="background:#4479BA; color: #FFFFFF;" + |MEN 1
|'''MEN2'''
| align="center" style="background:#4479BA; color: #FFFFFF;" + |'''MEN 2'''
|-
|-
| rowspan="3" |
| rowspan="3" |
Line 84: Line 69:


==Gross Pathology==
==Gross Pathology==
*On [[gross pathology]], pheochromocytoma varies from small to large and 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>
On [[gross pathology]], the characteristic findings of pheochromocytoma are:
*Pheochromocytoma is usually lobulated and small [[tumors]] have compressed [[adrenal gland]].
* 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>
*Familial [[Tumor|tumors]] are bilateral.
* Usually [[Lobule|lobulated]]
*It may be associated with hyperplasia in the adjacent [[medulla]].
*[[Bilateral]] when [[familial]] [[Tumor|tumors]]
* 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>
Line 94: Line 80:


==Microscopic Pathology==
==Microscopic Pathology==
On microscopic pathology, Pheochromocytoma typically demonstrates a nesting (Zellballen) pattern on microscopy. This pattern is composed of well-defined clusters of tumor cells containing eosinophilic cytoplasm separated by fibrovascular stroma.
On microscopic histopathological analysis, the characterisitc findings of pheochromocytoma typically include: <ref name="pmid2912871">{{cite journal| author=Kliewer KE, Wen DR, Cancilla PA, Cochran AJ| title=Paragangliomas: assessment of prognosis by histologic, immunohistochemical, and ultrastructural techniques. | journal=Hum Pathol | year= 1989 | volume= 20 | issue= 1 | pages= 29-39 | pmid=2912871 | doi=10.1016/0046-8177(89)90199-8 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2912871  }} </ref> <ref name="pmid2684087">{{cite journal| author=Kliewer KE, Cochran AJ| title=A review of the histology, ultrastructure, immunohistology, and molecular biology of extra-adrenal paragangliomas. | journal=Arch Pathol Lab Med | year= 1989 | volume= 113 | issue= 11 | pages= 1209-18 | pmid=2684087 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2684087  }} </ref>
* 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.
 
<gallery>
<gallery>
Image:Adrenal pheochromocytoma (1) histopathology.jpg|[[Micrograph]] of pheochromocytoma. Source: By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=5938524
Image:Adrenal pheochromocytoma (1) histopathology.jpg|[[Micrograph]] of pheochromocytoma. Source: By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=5938524

Latest revision as of 23:28, 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.
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