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==Overview==
Pheochromocytomas and paragangliomas (collectively referred to as PPGLs) are rare [[tumors]] that originate from [[chromaffin cells]] in the [[adrenal medulla]] (pheochromocytoma) or in the extra-adrenal [[Ganglion|neural ganglia]] ([[paraganglioma]]). These [[tumors]] can be either biochemically active (producing a [[catecholamine]] like [[epinephrine]], [[Norepinephrine|nor-epinephrine]] and [[dopamine]]) or biochemically silent. PPGLs can be either sporadic or genetic, with association to several familial syndromes. PPGLs can also be classified according to their spread into local, regional, or [[Metastasis|metastatic.]] The defining characteristic of [[malignancy]] in PPGLs is the presence of [[metastasis]].
==Classification==
 
Pheochromocytoma and paragangliomas may be classified into several subtypes based on:
* Type of cells
* Nature of tumor
* Location
* Biochemical secretory patterns
* Genetics
* Mutations and pathogenetic pathways
 
=== Classification based on type of cells the tumor is derived from===
[[Pheochromocytoma|Pheochromocytomas]] and [[Paraganglioma|paragangliomas]] may be classified according to the cells they are derived from: <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>
*[[Sympathetic nervous system|Sympathetic]]- adrenal medulla or sympathetic trunk
*[[Parasympathetic nervous system|Parasympathetic]]- [[carotid body]], glomus tympanicum, [[Glomus jugulare tumor|glomus jugulare]], [[Glomus tumor|glomus vagale]].


{{PleaseHelp}}
=== Classification based on nature of tumor ===
* [[benign|Benign]]
*[[Metastatic]]/ [[Malignant]]


==Overview==
[[Malignant]] and [[benign]] [[Tumor|tumors]] share the same [[biochemical]] and [[histological]] characters. The only difference is the ability of the [[malignant]] [[tumor]] to [[metastasize]] to distant [[Tissue (biology)|tissues]] and have high rates of recurrence.
Pheochromocytoma can be either [[benign]] or [[malignant]] and can be localized, regional, or [[metastatic]]. It can be familial, non-familial and sporadic.  
* According to the WHO 2017 Classification of Tumors of Endocrine Organs, all parangangliomas have metastatic potential and hence the term "malignant" was replaced with "metastatic". <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>
* Common sites of metastasis include:
** [[Lung]]
** [[Bone]]
** [[Head]]
** [[Thorax]]
** [[Liver]]
 
=== Classification based on location===
 
* 95% of pheochromocytomas are found in the [[abdomen]]
* '''Intra-[[Adrenal gland|adrenal]]'''- 85-90%
* '''Extra-[[Adrenal gland|adrenal]] ([[Paraganglioma|paragangliomas]])'''- 10-15% are prevertebral and paravertebral sympathetic ganglia of the chest, abdomen, and pelvis.
** The tumors in the abdomen most commonly arise from the organ of Zuckerkandl which is a collection of chromaffin tissue around the origin of the inferior mesenteric artery or the bifurcation of aorta. <ref name="pmid11903030">{{cite journal| author=Lenders JW, Pacak K, Walther MM, Linehan WM, Mannelli M, Friberg P | display-authors=etal| title=Biochemical diagnosis of pheochromocytoma: which test is best? | journal=JAMA | year= 2002 | volume= 287 | issue= 11 | pages= 1427-34 | pmid=11903030 | doi=10.1001/jama.287.11.1427 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11903030  }} </ref> <ref name="pmid16112304">{{cite journal| author=Lenders JW, Eisenhofer G, Mannelli M, Pacak K| title=Phaeochromocytoma. | journal=Lancet | year= 2005 | volume= 366 | issue= 9486 | pages= 665-75 | pmid=16112304 | doi=10.1016/S0140-6736(05)67139-5 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16112304  }} </ref>
 
=== Classification based on biochemical secretory pattern===
 
Pheochromocytoma and paragangliomas (PPGL) can be classified based on the biochemical secretory pattern: <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>
*[[Noradrenergic]] [[phenotype]] (predominant [[norepinephrine]] secreting)- associated with  [[Von Hippel-Lindau disease|Von Hippel-Lindau syndrome]]
*[[Adrenergic]] [[phenotype]] (predominant [[epinephrine]] secreting)- associated with [[Multiple endocrine neoplasia type 2|MEN2]] or [[neurofibromatosis type 1]] (NF1)
*[[Dopamine]] secreting- associated with [[SDHB]], [[SDHD]] or [[SDHC]] [[Mutation|mutations]] and potentially [[Metastasis|metastatic]] tumors.


==Classification==
=== Classification based on genetics ===


=== '''Pheochromocytoma can be classified either [[benign]] or [[malignant]]:''' ===
==== Familial pheochromocytoma ====
Malignant and benign tumours are the same on biochemical and histological bases. The only difference is the ability of the malignant one to invade local and distatant tissues (pathology and Genetics of Tumours of the Endocrine Organs. WHO Classification of Tumours, DeLellis RA, Lloyd RV, Heitz PU, Eng C. (Eds), IARC press, Lyon, France 2004). So, most cases need follow up for long durations. 10% of pheochromocytomas are malignant.
* Familial pheochromocytoma is associated with several hereditary disorders such as:
**[[MEN2a|Multiple Endocrine Neoplasia types 2A]]
** [[MEN2b|2B]] ([[Multiple endocrine neoplasia type 2|MEN2]]) (caused by mutations of the [[RET gene]])
**[[Von Hippel-Lindau Disease|Von Hippel-Lindau]] (VHL) disease (caused by mutations of the [[VHL gene]])
** Familial paraganglioma of the neck (cause by [[mutations]] of the gene for [[succinate dehydrogenase]] subunit D (SDHD))  
** [[Neurofibromatosis type 1]] (NF1)


=== '''Pheochromocytomas can be localized, regional, or [[metastatic]]:''' ===
==== Non-familial pheochromocytoma====
* 95 *% of pheochromocytomas are in the abdomen, 85 to 90 % are intraadrenal  and 5 to 10 percent are multiple, 10% are extraadrenal and are referred to as catecholamine-secreting paragangliomas.
* Resulting from sporadic [[Germline mutation|germ-line mutations]], which have been documented in about 20% of cases.
* The majority of them are positive for [[C-kit|KIT]] expression. A partial explanation was provided by the finding of activating mutations in another [[gene]] encoding an RTK, the [[Platelet-derived growth factor receptor|platelet-derived growth factor receptor alpha]] (''PDGFRA'') gene in some [[Gastrointestinal stromal tumor|KIT-negative GISTs]]


=== '''Pheochromocytoma can be either familial,non-familial or sporadic:''' ===
==== Sporadic====
<u>'''''Familial pheochromocytoma'''''</u> is an autosomal dominant disorder characterized by skull, neck, thorax, abdomen and urinary bladder. They are associated with other syndromes named Multiple endocrien neoplasia (MEN2) Which are autosomal dominant syndromes controlled by RET gene. Pheochromocytoma occurs in 50% of patients with MEN2 as follows:
* Most [[catecholamine]]-secreting tumors are sporadic. [[Mutation|Mutations]] have been identified in most of the sporadic cases.  
{| class="wikitable"
!MEN1
|'''MEN2'''
|-
| rowspan="3" |
* Medullary thyroid cancer,
* Pheochromocytoma
* Primary hyperparathyroidism
|
* Medullary thyroid cancer
* Pheochromocytoma
* Mucosal neuromas
* Marfanoid habitus
|}
'''''<u>Non-familial</u> pheochromocytomas:''''' include cholelithiasis, renal artery stenosis,  (gastrointestinal stromal tumor [GIST], paraganglioma, adrenal cortical adenoma Majority of them are positive for KIT expression, some are not. A partial explanation was provided by the finding of activating mutations in another gene encoding an RTK, the platelet-derived growth factor receptor alpha (''PDGFRA'') gene in some KIT-negative GISTs.


'''''<u>Sporadic</u>:''''' Most catecholamine-secreting tumors are sporadic.Mutations were identified in most of sporadic cases. May be due to spontaneous mutation, decreased penetrance, maternal imprinting.<ref name="pmid22517557">{{cite journal| author=Buffet A, Venisse A, Nau V, Roncellin I, Boccio V, Le Pottier N et al.| title=A decade (2001-2010) of genetic testing for pheochromocytoma and paraganglioma. | journal=Horm Metab Res | year= 2012 | volume= 44 | issue= 5 | pages= 359-66 | pmid=22517557 | doi=10.1055/s-0032-1304594 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22517557  }}</ref> 50% of patients had a pathogenic mutation in ''SDHB'', ''SDHD'', or ''VHL''<ref name="pmid230723242">{{cite journal| author=Jafri M, Whitworth J, Rattenberry E, Vialard L, Kilby G, Kumar AV et al.| title=Evaluation of SDHB, SDHD and VHL gene susceptibility testing in the assessment of individuals with non-syndromic phaeochromocytoma, paraganglioma and head and neck paraganglioma. | journal=Clin Endocrinol (Oxf) | year= 2013 | volume= 78 | issue= 6 | pages= 898-906 | pmid=23072324 | doi=10.1111/cen.12074 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23072324  }}</ref>
* Sporadic tumors may be due to spontaneous mutation, decreased penetrance or [[Genomic imprinting|maternal imprinting]].<ref name="pmid22517557">{{cite journal| author=Buffet A, Venisse A, Nau V, Roncellin I, Boccio V, Le Pottier N et al.| title=A decade (2001-2010) of genetic testing for pheochromocytoma and paraganglioma. | journal=Horm Metab Res | year= 2012 | volume= 44 | issue= 5 | pages= 359-66 | pmid=22517557 | doi=10.1055/s-0032-1304594 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22517557  }}</ref>
* 50% of patients had a pathogenic [[mutation]] in ''[[SDHB]]'', ''[[SDHD]]'', or ''[[Von Hippel-Lindau tumor suppressor|VHL.]]''<ref name="pmid230723242">{{cite journal| author=Jafri M, Whitworth J, Rattenberry E, Vialard L, Kilby G, Kumar AV et al.| title=Evaluation of SDHB, SDHD and VHL gene susceptibility testing in the assessment of individuals with non-syndromic phaeochromocytoma, paraganglioma and head and neck paraganglioma. | journal=Clin Endocrinol (Oxf) | year= 2013 | volume= 78 | issue= 6 | pages= 898-906 | pmid=23072324 | doi=10.1111/cen.12074 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23072324  }}</ref>


=== '''Pheochromocytoma can be classified on genetic basis into cluster 1 and cluster 2 :''' ===
===Classification based on mutations and pathogenetic pathways===
Cluster 1 tumorsare noradrenergic. Cluster 2 tumors are adrenergic.<sup>[[Pheochromocytoma pathophysiology#cite note-pmid23933153-3|[3]]]</sup>
Pheochromocytoma and paragangliomas  (PPGL) 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>
{| class="wikitable"
* 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
!Cluster 2
** Impaired [[DNA]] [[methylation]] leading to increased vascularization
|-
* Cluster 2
!
** Activating [[Mutation|mutations]] of [[Wnt signaling pathway|Wnt-signaling pathway]] including Wnt receptor signaling and [[Hedgehog signaling pathway|Hedgehog]] signaling.
* Succinate dehydrogenase (SDH) subunit genes
** Mutations of [[CSDE1]] (Cold shock domain containing E1) and [[MAML2|MAML3]] (Mastermind like transcriptional coactivator 3) genes7.
* Von Hippel-Lindau (VHL) disease
* Cluster 3
* Fumarate hydratase gene mutations
** Abnormal activation of [[Kinase|kinase signaling pathways]] like PI3Kinase/[[AKT]], [[RAS]]/RAF/ERK, and [[mTOR]] pathways.
|
* '''Multiple endocrine neoplasia type 2A'''
* '''Multiple endocrine neoplasia type 2B'''
* '''Neurofibromatosis type 1 (NF1)'''
|}
. Patients with the succinate dehydrogenase B mutations are likely to develop malignant disease.<sup>[[Pheochromocytoma pathophysiology#cite note-pmid15328326-4|[4]]]</sup>


== References ==
== References ==
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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

Pheochromocytomas and paragangliomas (collectively referred to as PPGLs) are rare tumors that originate from chromaffin cells in the adrenal medulla (pheochromocytoma) or in the extra-adrenal neural ganglia (paraganglioma). These tumors can be either biochemically active (producing a catecholamine like epinephrine, nor-epinephrine and dopamine) or biochemically silent. PPGLs can be either sporadic or genetic, with association to several familial syndromes. PPGLs can also be classified according to their spread into local, regional, or metastatic. The defining characteristic of malignancy in PPGLs is the presence of metastasis.

Classification

Pheochromocytoma and paragangliomas may be classified into several subtypes based on:

  • Type of cells
  • Nature of tumor
  • Location
  • Biochemical secretory patterns
  • Genetics
  • Mutations and pathogenetic pathways

Classification based on type of cells the tumor is derived from

Pheochromocytomas and paragangliomas may be classified according to the cells they are derived from: [1]

Classification based on nature of tumor

Malignant and benign tumors share the same biochemical and histological characters. The only difference is the ability of the malignant tumor to metastasize to distant tissues and have high rates of recurrence.

  • According to the WHO 2017 Classification of Tumors of Endocrine Organs, all parangangliomas have metastatic potential and hence the term "malignant" was replaced with "metastatic". [2]
  • Common sites of metastasis include:

Classification based on location

  • 95% of pheochromocytomas are found in the abdomen
  • Intra-adrenal- 85-90%
  • Extra-adrenal (paragangliomas)- 10-15% are prevertebral and paravertebral sympathetic ganglia of the chest, abdomen, and pelvis.
    • The tumors in the abdomen most commonly arise from the organ of Zuckerkandl which is a collection of chromaffin tissue around the origin of the inferior mesenteric artery or the bifurcation of aorta. [3] [4]

Classification based on biochemical secretory pattern

Pheochromocytoma and paragangliomas (PPGL) can be classified based on the biochemical secretory pattern: [2]

Classification based on genetics

Familial pheochromocytoma

Non-familial pheochromocytoma

Sporadic

  • Most catecholamine-secreting tumors are sporadic. Mutations have been identified in most of the sporadic cases.

Classification based on mutations and pathogenetic pathways

Pheochromocytoma and paragangliomas (PPGL) can be classified into the following clusters- [7] [8] [9]

References

  1. ↑ 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.
  2. ↑ 2.0 2.1 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).
  3. ↑ Lenders JW, Pacak K, Walther MM, Linehan WM, Mannelli M, Friberg P; et al. (2002). "Biochemical diagnosis of pheochromocytoma: which test is best?". JAMA. 287 (11): 1427–34. doi:10.1001/jama.287.11.1427. PMID 11903030.
  4. ↑ Lenders JW, Eisenhofer G, Mannelli M, Pacak K (2005). "Phaeochromocytoma". Lancet. 366 (9486): 665–75. doi:10.1016/S0140-6736(05)67139-5. PMID 16112304.
  5. ↑ Buffet A, Venisse A, Nau V, Roncellin I, Boccio V, Le Pottier N; et al. (2012). "A decade (2001-2010) of genetic testing for pheochromocytoma and paraganglioma". Horm Metab Res. 44 (5): 359–66. doi:10.1055/s-0032-1304594. PMID 22517557.
  6. ↑ Jafri M, Whitworth J, Rattenberry E, Vialard L, Kilby G, Kumar AV; et al. (2013). "Evaluation of SDHB, SDHD and VHL gene susceptibility testing in the assessment of individuals with non-syndromic phaeochromocytoma, paraganglioma and head and neck paraganglioma". Clin Endocrinol (Oxf). 78 (6): 898–906. doi:10.1111/cen.12074. PMID 23072324.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
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