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 is composed of well-defined clusters of [[Tumor cell|tumor cells]] separated by fibrovascular [[stroma]]. 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>'''
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 α<sub>1</sub>, α<sub>2</sub>, β<sub>1</sub>, β<sub>2</sub>, and β<sub>3:</sub>
**Binding to 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.
**Binding to 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.
**Binding to B2 receptors causes Smooth muscle relaxation in the uterus, GI tract, detrusor urinae muscle of bladder wall, and bronchi. It also causes dilatation of smaller coronary arteries, hepatic artery, arteries to skeletal muscle.
**Binding to B1 receptors causes renin release from juxtaglomerular cells and lipolysis in adipose tissue. It Increases cardiac output by:
***Increase in heart rate in sinoatrial node
***Increase in atrial cardiac muscle contractility
***Increases in contractility and automaticity of ventricular cardiac muscle
***Increases in conduction and automaticity of atrioventricular node


== Pathogenesis ==
===Pathology===
* It is understood that pheochromocytoma is the is mediated by excessive secretion of [[catecholamines]] and subsequent stimulation of [[adrenergic receptors]].
* 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>
* Excessive secretion of [[catecholamines]] may be either continuous or intermittent.
*Pheochromocytoma is a [[tumor]] which 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. <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>
* 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.
*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:
**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/>s ([[Multiple endocrine neoplasia type 1|MEN1]] and [[Multiple endocrine neoplasia type 2|MEN 2B]]).
* Genes involved in the pathogenesis of pheochromocytoma include:
* Patients with 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>
**[[RET gene|RET]] gene ([[MEN, type 2a|MEN 2A]], [[Multiple endocrine neoplasia type 2|MEN 2B]] [[Syndrome|syndromes]])
* 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>
**[[NF1|NF1 gene]]
{| class="wikitable"
**[[Von Hippel-Lindau tumor suppressor|VHL gene]] ([[Von Hippel-Lindau disease|VHL disease]])
! colspan="2" |Familial pheocromocytomas
**[[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 (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>
!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]] (VHL) disease
*PCCs arise in about 10–20% of patients with VHL disease.  VHL tumor suppressor protein is the main cause of the disease. There are more than 500 different germ-line ''VHL'' mutations linked to VHL disease have been reported.<ref name="pmid8956040">{{cite journal| author=Zbar B, Kishida T, Chen F, Schmidt L, Maher ER, Richards FM et al.| title=Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan. | journal=Hum Mutat | year= 1996 | volume= 8 | issue= 4 | pages= 348-57 | pmid=8956040 | doi=10.1002/(SICI)1098-1004(1996)8:4<348::AID-HUMU8>3.0.CO;2-3 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8956040  }}</ref>  Missense, nonsense, splice site mutations, microdeletions, and insertions are detected in about two-thirds of the patients.
*The VHL 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>
*HIF-1 is involved in erythropoiesis through its ability to induce 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>
*Deletions in ''VHL'' and nonsense and 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>  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 protein is a transmembrane receptor of the tyrosine kinase family.
**It is expressed in cell lineages derived from the neural crest and has a key role in regulating cell proliferation, migration, differentiation, 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 receptor can be activated through various factors such as 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>
**Germline mutations of the ''RET'' proto-oncogene cause constitutive activation of the RET receptor and of intracellular signaling pathways (“gain of function”), 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 protein were found to be associated with Hirschsprung's disease, a developmental disorder characterized by the absence of enteric ganglia in the 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>
**The ''NF1'' gene has been localized on chromosome 17qll.2 and encodes its protein product, neurofibromin.<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>
* Cluster 1
**Most mutations in the ''NF1'' gene result in the truncation of neurofibromin and thus in the loss of functional protein causing the wide spectrum of clinical findings.
**[[Mutation|Mutations]] involving in [[overexpression]] of [[Vascular endothelial growth factor (VEGF) IRES A|vascular endothelial growth factor (VEGF)]] as a result of pseudohypoxia
**In the absence or at decreased levels of neurofibromin in NF1, 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>
** Impaired [[DNA]] [[methylation]] leading to increased vascularization
**The ''NF1'' mutations include translocations, splicing, deletions, duplications, insertions, point mutations, and substitutions. NF1 also has a high rate of new mutations of about 50%. 
* Cluster 2
**The GAP (Ras-GTPase-activating protein)-related domain (GRD) is a small part of and has the important role of stimulating the intrinsic GTPase of p21-Ras''-''GTP to hydrolyze GTP to GDP, thus inactivating p21-Ras.
** Activating [[Mutation|mutations]] of [[Wnt signaling pathway|Wnt-signaling pathway]] including Wnt receptor signaling and [[Hedgehog signaling pathway|Hedgehog]] signaling.
**P21-Ras is a key component of many growth factor signaling pathways, and neurofibromin acts therefore as a tumor suppressor protein.
** Mutations of [[CSDE1]] (Cold shock domain containing E1) and [[MAML2|MAML3]] (Mastermind like transcriptional coactivator 3) genes7.
**It seems that in the pathogenesis of NF1-associated PCC, the cysteine-serine-rich domain (CSR) of neurofibromin plays a more important role than the GRD.<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>
* Cluster 3
**In the pathogenesis of PCC in NF1 patients, Knudson's two-hit tumor suppressor model could be applied, resulting in a loss of heterozygosity at tumor level. This process leads to the lack of expression of neurofibromin in PCCs.<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>
** 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 neoplasias]] ([[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 86: Line 69:


==Gross Pathology==
==Gross Pathology==
On gross pathology, A multinodular and multicentric pattern of growth of pheochromocytoma may be seen.
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>
* Usually [[Lobule|lobulated]]
*[[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.
<gallery>
<gallery>
Image:Bilateral pheo MEN2.jpg|Bilateral pheochromocytoma in [[Multiple_endocrine_neoplasia_type_2|MEN2]]. Gross image.
Image:Bilateral pheo MEN2.jpg|Bilateral pheochromocytoma in [[Multiple_endocrine_neoplasia_type_2|MEN2]]. Gross image. Source: https://upload.wikimedia.org/wikipedia/commons/5/5f/Bilateral_pheo_MEN2.jpg
</gallery>
</gallery>


==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.
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 (3) histopathology.jpg|Histopathology of adrenal pheochromocytoma. Adrenectomy specimen.
Image:Adrenal pheochromocytoma (3) histopathology.jpg|Histopathology of adrenal pheochromocytoma. Adrenectomy specimen. Source: CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=535945
Image:Adrenal pheochromocytoma (2) histopathology.jpg|Micrograph of pheochromocytoma.
Image:Adrenal pheochromocytoma (2) histopathology.jpg|Micrograph of pheochromocytoma. Source: CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=535944
Image:Adrenal pheochromocytoma (3) histopathology.jpg|Micrograph of pheochromocytoma.
</gallery>
</gallery>


Latest revision as of 23:28, 24 July 2020

Pheochromocytoma Microchapters

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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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