Pheochromocytoma classification: Difference between revisions

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Latest revision as of 20:35, 24 July 2020

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]

Sympathetic- adrenal medulla or sympathetic trunk
Parasympathetic- carotid body, glomus tympanicum, glomus jugulare, glomus vagale.

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:
- Lung
- Bone
- Head
- Thorax
- Liver

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]

Noradrenergic phenotype (predominant norepinephrine secreting)- associated with Von Hippel-Lindau syndrome
Adrenergic phenotype (predominant epinephrine secreting)- associated with MEN2 or neurofibromatosis type 1 (NF1)
Dopamine secreting- associated with SDHB, SDHD or SDHC mutations and potentially metastatic tumors.

Classification based on genetics

Familial pheochromocytoma

Familial pheochromocytoma is associated with several hereditary disorders such as:
- Multiple Endocrine Neoplasia types 2A
- 2B (MEN2) (caused by mutations of the RET gene)
- 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)

Non-familial pheochromocytoma

Resulting from sporadic germ-line mutations, which have been documented in about 20% of cases.
The majority of them are positive for 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 alpha (PDGFRA) gene in some KIT-negative GISTs

Sporadic

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

Sporadic tumors may be due to spontaneous mutation, decreased penetrance or maternal imprinting.^[5]
50% of patients had a pathogenic mutation in SDHB, SDHD, or VHL.^[6]

Classification based on mutations and pathogenetic pathways

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

Cluster 1
- Mutations involving in overexpression of vascular endothelial growth factor (VEGF) as a result of pseudohypoxia
- Impaired DNA methylation leading to increased vascularization
Cluster 2
- Activating mutations of Wnt-signaling pathway including Wnt receptor signaling and Hedgehog signaling.
- Mutations of CSDE1 (Cold shock domain containing E1) and MAML3 (Mastermind like transcriptional coactivator 3) genes7.
Cluster 3
- Abnormal activation of kinase signaling pathways like PI3Kinase/AKT, RAS/RAF/ERK, and mTOR pathways.

References

↑ 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.
↑ ^2.0 ^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).
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.

[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.

[pmidorcid.org/0000-0003-2771-564X-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).

[pmid11903030-3] 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.

[pmid16112304-4] 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.

[pmid22517557-5] 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.

[pmid230723242-6] 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.

[pmid15613462-8] 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.

[pmid28477311-9] 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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@@ Line 3: / Line 3: @@
 {{CMG}}; {{AE}} {{AAM}} {{MAD}}
 ==Overview==
- Pheochromocytoma may be classified by nature into [[benign]] and [[malignant]] and can be classified by spread into local, regional, and [[Metastasis|metastatic.]]Another classification by origin is '''[[Familial|familial,]] non-familial, and sporadic.'''
+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 may be classified by nature either: ===
+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]].
+=== Classification based on nature of tumor ===
 * [[benign|Benign]]
-* [[malignant]]: 10% of pheochromocytomas are malignant.
+*[[Metastatic]]/ [[Malignant]]
-* Malignant and benign tumors share the same biochemical and histological characters. The only difference is the ability of the malignant tumor to invade local and distant tissues according to WHO Classification of Tumours in 2004.<ref name="pmid26291008">{{cite journal| author=Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JH, Beasley MB et al.| title=The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification. | journal=J Thorac Oncol | year= 2015 | volume= 10 | issue= 9 | pages= 1243-60 | pmid=26291008 | doi=10.1097/JTO.0000000000000630 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26291008  }}</ref>
+[[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.
-* Most cases need to follow up for long durations.
+* 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]]
-=== '''Pheochromocytomas can be classified by spread ability either:'''  ===
+=== Classification based on location===
-* Localized: 95% of pheochromocytomas are in the [[abdomen]], 85 to 90 % are intra-adrenal and 5 to 10 percent are multiple, 10% are extra-adrenal and are referred to as catecholamine-secreting paragangliomas.
-* Regional
-* [[metastatic]]: to [[lung]], [[Bone|bone,]] [[head]], [[thorax]], and [[liver]]
-=== '''Pheochromocytoma can be either familial, non-familial, and sporadic:''' ===
+* 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 based on genetics ===
 ==== Familial pheochromocytoma ====
-* They are associated with other syndromes named [[Multiple endocrine neoplasia|Multiple endocrine neoplasia 2]] (MEN2) Which are autosomal dominant syndromes controlled by RET gene. Pheochromocytoma occurs in 50% of patients with MEN2 as follows:
+* Familial pheochromocytoma is associated with several hereditary disorders such as:
-{| class="wikitable"
+**[[MEN2a|Multiple Endocrine Neoplasia types 2A]]
-!MEN1
+** [[MEN2b|2B]] ([[Multiple endocrine neoplasia type 2|MEN2]]) (caused by mutations of the [[RET gene]])
-|'''MEN2'''
+**[[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))
-| rowspan="3" |
+** [[Neurofibromatosis type 1]] (NF1)
-* [[Medullary thyroid cancer]]
-* Pheochromocytoma
-* [[Primary hyperparathyroidism]]
-|
-* [[Medullary thyroid cancer]]
-* Pheochromocytoma
-* [[Neuroma|Mucosal neuromas]]
-* [[Marfan's syndrome|Marfanoid habitus]]
-|}
-==== Non-familial pheochromocytoma: ====
-the majority of them are positive fo[[KIT|r 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|platelet-derived growth factor receptor alpha]] (''PDGFRA'') gene in some [[Gastrointestinal stromal tumor|KIT-negative GISTs]]:
-* [[Cholelithiasis]]
-* [[Renal artery stenosis]]
-* [[Paraganglioma]]
-* [[Adrenal cortical cancer|Adrenal cortical adenoma]]
-==== Sporadic''''':''''' ====
+==== Non-familial pheochromocytoma====
-Most [[Catecholamine secreting|catecholamine-secreting tumors]] are sporadic. Mutations were identified in most of the 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 ''[[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>
+* 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 classified on genetic basis into cluster 1 and cluster 2''':''' ===
+==== Sporadic====
-{| class="wikitable"
+* Most [[catecholamine]]-secreting tumors are sporadic. [[Mutation|Mutations]] have been identified in most of the sporadic cases.
-!Cluster 1
-!Cluster 2
-|-
-!
-* '''[[Norepinephrine|Noradrenergic]]'''
-* [[Succinate dehydrogenase|Succinate dehydrogenase (]]SDH) subunit genes
+* 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>
-* [[Von Hippel-Lindau Disease|Von Hippel-Lindau]] (VHL) disease
+* 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>
-* [[Fumarate hydratase]] gene mutations
-|
-* '''[[Adrenergic|Adrenergic.]]<sup>[[Pheochromocytoma pathophysiology#cite note-pmid23933153-3|[3]]]</sup>'''
-* '''Multiple endocrine neoplasia type 2A'''
+===Classification based on mutations and pathogenetic pathways===
-* '''Multiple endocrine neoplasia type 2B'''
+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>
-* '''[[Neurofibromatosis type I|Neurofibromatosis type 1]] (NF1)'''
+* 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
-. Patients with the [[succinate dehydrogenase]] B mutations are likely to develop a malignant disease.<sup>[[Pheochromocytoma pathophysiology#cite note-pmid15328326-4|[4]]]</sup>
+** 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.
+** 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.
 == References ==