Biochemically silent abdominal paragangliomas in patients with mutations in the succinate dehydrogenase subunit B gene.
BACKGROUND
Patients with adrenal and extra-adrenal abdominal paraganglioma (PGL) almost invariably have increased plasma and urine concentrations of metanephrines, the O-methylated metabolites of catecholamines. We report four cases of biochemically silent abdominal PGL, in which metanephrines were normal despite extensive disease.


OBJECTIVE
Our objective was to identify the mechanism underlying the lack of catecholamine hypersecretion and metabolism to metanephrines in biochemically silent PGL.


METHODS
This is a descriptive study.


METHODS
The study was performed at a referral center.


METHODS
One index case and three additional patients with large abdominal PGL and metastases but with the lack of evidence of catecholamine production, six patients with metastatic catecholamine-producing PGL and a mutation of the succinate dehydrogenase subunit B (SDHB) gene, and 136 random patients with catecholamine-producing PGL were included in the study.


METHODS
Plasma, urine, and tumor tissue concentrations of catecholamines and metabolites were calculated with electron microscopy and tyrosine hydroxylase immunohistochemistry.


RESULTS
All four patients with biochemically silent PGL had an underlying SDHB mutation. In the index case, the tumor tissue concentration of catecholamines (1.8 nmol/g) was less than 0.01% that of the median (20,410 nmol/g) for the 136 patients with catecholamine-producing tumors. Electron microscopy showed the presence of normal secretory granules in all four biochemically silent PGLs. Tyrosine hydroxylase immunoreactivity was negligible in the four biochemically silent PGLs but abundant in catecholamine-producing PGLs.


CONCLUSIONS
Patients with SDHB mutations may present with biochemically silent abdominal PGLs due to defective catecholamine synthesis resulting from the absence of tyrosine hydroxylase. Screening for tumors in patients with SDHB mutations should not be limited to biochemical tests of catecholamine excess.
Timmers
Henri J L M
HJ
Reproductive Biology and Medicine Branch, National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, Building 10, CRC, Room 1-E 3140, Bethesda Maryland 20892-1109, USA. h.timmers@endo.umcn.nl
Pacak
Karel
K
Huynh
Thanh T
TT
Abu-Asab
Mones
M
Tsokos
Maria
M
Merino
Maria J
MJ
Baysal
Bora E
BE
Adams
Karen T
KT
Eisenhofer
Graeme
G
D000008:Abdominal Neoplasms / Q000235:genetics* / Q000473:pathology; D000328:Adult; D014408:Biomarkers, Tumor; D002395:Catecholamines / Q000378:metabolism; D002648:Child; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008676:Metanephrine / Q000097:blood / Q000652:urine; D008854:Microscopy, Electron; D008875:Middle Aged; D009154:Mutation / Q000235:genetics / Q000502:physiology; D010235:Paraganglioma / Q000235:genetics* / Q000473:pathology; D013385:Succinate Dehydrogenase / Q000235:genetics*; D014057:Tomography, X-Ray Computed; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D055815:Young Adult
D014408:Biomarkers, Tumor; D002395:Catecholamines; C491545:SDHD protein, human; D008676:Metanephrine; D014446:Tyrosine 3-Monooxygenase; D013385:Succinate Dehydrogenase