Pheochromocytoma/Paraganglioma
Update on Genetic Mutations Associated With
Pheochromocytomas(PCCs)
Paragangliomas (PGLs) – cathecholalamine – producing neuroendocrine
tumors arising from chromaffin cells of the extra-adrenal gland .
Head and neck PGL ( HNPGL ) - derived from parasympathetic ganglia and
often nonsecretory.
WHO: definition of malignant PCC/PGL is the presence of distant metastases
at sites where chromaffin tissue is not normally present. (1 )
The most common sites of metastatic disease are lymph nodes, bones, liver,
lung.
-SDHB mutation carry a higher risk of malignancy.
GENETICS
30% of PCCs/PGLs have a germline mutation in known susceptibility genes .(2)
There are currently 10 well-characterized PCC/PGL susceptibility genes (Table I)
SDHB, SDHD, VHL and RET genes, Three genes cause well known cancer
susceptibility syndromes : NF1 ,VHL ,RET (MEN 2) .
In addition, mutations in any of the succinate dehydrogenase (SDH) complex
subunits (SDHA,SDHB,SDHC,SDHD) .
Mutations in SDHB lead most commonly to extra-adrenal PGL.
The risk of malignancy with SDHB mutations : A recent meta-analysis suggests
that the risk may be less than previously ~13%–23% when accounting for
incident and prevalent cases.(3)
Since 2010, two more susceptibility genes have been identified ;
TMEM127 mutation ,and MAX mutation .
Indication for genetic testing.
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Young pt (<50 yr).
Positive family history.
Presence of syndromic features of VHL or MEN2.
Multifocal or bilat PCC/PGL. Metastasis PCC/PGL.(4)
FIGURE. Synthesis and metabolism of catecholamines
CATECHOLAMINES
VHL
-low expression of phenylethanolamine- N-methyltransferase (PNMT)
normetanephrine and norepinephrine, rather than the metabolites
metanephrine and epinephrine.
RET mutations often overexpress PNMT and, therefore, have high levels of
epinephrine. (5)
SDHB-associated tumors have a normetanephrine and dopamine
predominance. (5)
Tumors with SDHC, SDHD, and SDHAF2 are often nonsecretory since they are
most commonly derived from parasympathetic ganglia in the head and neck .
The biochemical profiles of tumors associated with mutations in TMEM127,
MAX, and SDHA have not been well-defined
References
1. DeLellis RA, Lloyd RV, Heitz PU, et al. World Health OrganizationClassification of
Tumours. Pathology and Genetics of Tumours of Endocrine Organs. Lyon, France:
IARC Press; 2004.
2. Fishbein L, Nathanson KL. Pheochromocytoma and paraganglioma: understanding
the complexities of the genetic background. Cancer Genet. 2012;205:1–11
3. van Hulsteijn LT, Dekkers OM, Hes FJ, et al. Risk of malignant
paraganglioma in SDHB-mutation and SDHD-mutation carriers: asystematic review
and meta-analysis. J Med Genet. 2012;49:768–76
4. Endo 2013 MEET -THE – PROFESSOR ,Adrenal 2013-23 .
5. Eisenhofer G, Lenders JW, Timmers H, et al. Measurements of
plasma methoxytyramine, normetanephrine, and metanephrine as discriminators of
different hereditary forms of pheochromocytoma.Clin Chem. 2011;57:411–20.