Pheochromocytoma pathophysiology: Difference between revisions

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* '''[[Neurofibromatosis type I|Neurofibromatosis type 1]] (NF1)'''
* '''[[Neurofibromatosis type I|Neurofibromatosis type 1]] (NF1)'''
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* 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
**PCCs arise in about 10–20% of patients with [[VHL]] disease.
**VHL [[Tumor suppressor gene|tumor suppressor protein]] is the main cause for [[VHL]] disease.
**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>
**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>
**[[Deletion (genetics)|Deletions]] in ''[[VHL]]'' from [[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>
**[[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.
**[[RET gene|RET]] protein 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)'''
**[[Mutations]] in the [[NF1|''NF1'' gene]] result in loss of functional [[protein]] causing the wide spectrum of clinical findings.
**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>
**[[Knudson hypothesis|Knudson's two-hit tumor suppressor model]] could be applied, resulting in a [[loss of heterozygosity]] at tumor level. The [[mutations]] include [[translocations]], [[Splicing (genetics)|splicing]], [[Deletion (genetics)|deletions]], [[insertions]], and [[point mutations]].<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 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]].
**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>


==Associated conditions==
==Associated conditions==

Revision as of 05:08, 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

Pheochromocytoma arises from chromaffin cells of the adrenal medulla. On gross pathology, pheochromocytoma has a multinodular and a multicentric pattern of growth. On microscopic histopathological analysis, nesting (Zellballen) pattern composed of well-defined clusters of tumor cells separated by fibrovascular stroma may be seen. It may be benign, malignant, familial (multiple endocrine neoplasia 1 and type 2B) or sporadic. All of these forms have genetic origin depending on a large number of genes, for example, VHL, SDH, NF1, RET genes.

Pathophysiology

The pathophysiology associated with pheochromocytoma is as follow:[1] [2][3]

Effects of adrenergic stimulation by pheochromocytoma

Genetics

  • Pheochromocytoma can be transmitted in a sporadic(60-65%) or familial pattern. [4][5]
  • Genes involved in the pathogenesis of pheochromocytoma include:
    • RET gene (MEN 2A, MEN 2B syndromes)
    • VHL gene (VHL disease)
    • SDHD, SDHB, and SDHC genes of the mitochondrial complex [6]
Familial pheocromocytoma
Cluster 1 (Noradrenergic) Cluster 2 (Adrenergic)

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:

  • A nesting (Zellballen) pattern- this pattern is composed of well-defined clusters of tumor cells containing eosinophilic cytoplasm separated by fibrovascular stroma.

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References

  1. ↑ 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.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ King KS, Pacak K (2014). "Familial pheochromocytomas and paragangliomas". Mol Cell Endocrinol. 386 (1–2): 92–100. doi:10.1016/j.mce.2013.07.032. PMC 3917973. PMID 23933153.
  8. ↑ 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.
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