AN AGGRESSIVE TEMPORAL BONE SDHC PARAGANGLIOMA ASSOCIATED WITH INCREASED HIF-2α SIGNALING.
OBJECTIVE
To describe a patient with a germline succinate dehydrogenase (SDHC) gene mutation presenting with primary hyperparathyroidism and a large catecholamine-producing temporal bone paraganglioma (PGL).


METHODS
Evaluation of a SDHC mutation-positive PGL tumor biology using staining for tyrosine hydroxylase (TH), hypoxia-inducible factors 1α (HIF-1α) and 2α (HIF-2α).


RESULTS
A 66-year-old man was noted to have a lytic skull base mass during work-up for his primary hyperparathyroidism. Biochemical evaluation with 24-hour urine catecholamines and metanephrines revealed marked elevation of norepinephrine and normetanephrine. Genetic testing revealed a germline SDHC mutation. A partial excision of skull base tumor was performed, which upon further examination revealed PGL. Immunohistochemistry of skull base PGL demonstrated heavy expression of TH and HIF-2α but reduced expression of HIF-1α. The remaining skull base PGL was treated with adjuvant radiation therapy. The patient's normetanephrine levels significantly decreased after surgery and radiation.


CONCLUSIONS
Here, we report an unusual case of a patient presenting with a germline SDHC mutation-related functional PGL along with concomitant primary hyperparathyroidism. The present case illustrates that overexpression of HIF-2α but not of HIF-1α is linked to the pathogenesis of SDHC mutation-related PGL, and it may be responsible for the aggressive clinical behavior of a usually indolent course of SDHC-related PGLs.
Brandon
B
Isaacson
Petra
P
Bullova
Megan
M
Frone
Arielle
A
Click
Barbora
B
Hamplova
Jennifer
J
Rabaglia
Stacey
S
Woodruff
Fiemu
F
Nwariaku
Amita
A
Kathuria
Karel
K
Pacak
Hans K
HK
Ghayee
D000368:Aged; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009361:Neoplasm Invasiveness; D010235:Paraganglioma / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011877:Radionuclide Imaging; D015398:Signal Transduction; D012888:Skull Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D013701:Temporal Bone / Q000473:pathology*; D015854:Up-Regulation; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D008565:Membrane Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1; C108096:SDHC protein, human