Original ArticlesAN AGGRESSIVE TEMPORAL BONE SDHC PARAGANGLIOMA ASSOCIATED WITH INCREASED HIF-2α SIGNALING
Section snippets
INTRODUCTION
Pheochromocytomas (PCCs) are catecholamine-producing tumors, which arise from chromaffin cells in the adrenal medulla. Extra-adrenal PCCs are also known as paragangliomas (PGLs), which may variably produce catecholamines depending on the genetic mutation. Patients with catecholamine-producing PCC/PGL demonstrate variable clinical presentations, including spells with paroxysmal hypertension and palpitations. Untreated PCC/PGL can lead to cardiovascular collapse or death due to excess
Immunohistochemistry
Tissue sections (5-μm thick) were deparaffinized and rehydrated prior to antigen retrieval in citrate buffer (pH 6.0) (Thermo Scientific) for 20 minutes. The sections were incubated with HIF-1α (Sigma-Aldrich), HIF-2α (Novus Biologicals), or tyrosine hydroxylase (Immunostar) primary antibodies for 1 hour at 37°C. After incubation with horseradish peroxidase–labelled polymer secondary antibody (DAKO) for 45 minutes, the tissue sections were incubated with a freshly prepared chromogen/substrate
Case
A 66-year-old man with a 20-year history of hypertension presented for evaluation of primary hyperparathyroidism and parathyroidectomy. Medications that he was taking included amlodipine 10 mg, lisinopril 20 mg, simvastatin 20 mg, ascorbic acid 500 mg, and omega-3 tablets. Several years prior to presentation, he had an intermittent history of atrial fibrillation. A myocardial perfusion scan revealed no inducible ischemia and a minimally dilated left ventricle at rest. The ejection fraction was
DISCUSSION
This is a unique case of an incidentally discovered catecholamine-producing PGL associated with an underlying SDHC mutation as a result of imaging performed for primary hyperparathyroidism. An ectopic parathyroid adenoma was eventually identified as the source of the patient's hyperparathyroidism. The patient had a longstanding history of hypertension that may have been related to catecholamine excess. SDHC-associated PGLs typically have a benign course and are generally nonfunctional or may
CONCLUSION
The present case illustrates that all PCCs/PGLs require a complete biochemical evaluation for catecholamine production. Germline SDHC mutations may still be associated with the production of large amounts of catecholamines and can behave aggressively. By histology, the index patient's tumor shows the presence of HIF-2α, which demonstrates that the tumor was perhaps utilizing the hypoxia signaling pathway like other known aggressive PGLs.
DISCLOSURE
Dr. Brandon Isaacson is a consultant for Styker, Medtronic, Advanced Bionics. Medical Advisory Board – Advanced Bionics. The other authors have no multiplicity of interest to disclose.
ACKNOWLEDGMENT
We would like to acknowledge support for this research from the North American Neuroendocrine Tumor Society (NANETS) to H.K.G.
REFERENCES (18)
- et al.
Genetics, diagnosis, and management of medullary thyroid carcinoma and pheochromocytoma/paraganglioma
Endocr Pract
(2014) On the association of succinate dehydrogenase mutations with hereditary paraganglioma
Trends Endocrinol Metab
(2003)- et al.
Hypoxia-inducible factor signaling in pheochromocytoma: turning the rudder in the right direction
J Natl Cancer Inst
(2013) - et al.
Untuning the tumor metabolic machine: HIF-α: pro- and antitumorigenic?
Nat Med
(2012) - et al.
Decreased expression of cystathionine β-synthase promotes glioma tumorigenesis
Mol Cancer Res
(2014) - et al.
Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia
N Engl J Med
(2012) - et al.
New syndrome of paraganglioma and somatostatinoma associated with polycythemia
J Clin Oncol
(2013) - et al.
Proportion of heritable paraganglioma cases and associated clinical characteristics
Laryngoscope
(2001) - et al.
Clinically guided genetic screening in a large cohort of Italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas
J Clin Endocrinol Metab
(2009)