SUN-506 Geography or Genomics? - A Case of Extra Adrenal Epinephrine Secreting Recurrent Pheochromocytoma

Abstract Disclosure: E. Jalal: None. R.H. Cobin: None. A.C. Levine: None. K.C. Cheesman: None. Background: Glucocorticoids upregulate the enzyme phenylethanolamine N-methyltransferase (PNMT), converting norepinephrine to epinephrine, explaining the exclusive location of epinephrine secreting pheochromocytomas in the adrenal medulla adjacent to the high glucocorticoid concentration of the cortex. This assumption is challenged by the finding of extra-adrenal pheochromocytomas and paragangliomas (PGL) secreting epinephrine. We report a case of an extra-adrenal mass secreting epinephrine many years after surgical removal of the adrenal glands. Case Presentation: A 54-year-old female with MEN2A presented with new headaches, palpitations, and diaphoresis. Bilateral adrenalectomy for pheochromocytoma occurred 29 years prior. Total thyroidectomy for medullary thyroid cancer was done at age 10. Primary hyperparathyroidism is managed conservatively. Serum metanephrines were 310 pg/mL (0-88 pg/mL) compared to 116 pg/mL seven months prior; normetanephrines increased from 144 pg/mL to 236.5 pg/mL (0-244 pg/mL). Fractionated plasma catecholamines were as follows: epinephrine 132 pg/mL (<82 pg/mL), norepinephrine 395 pg/mL (149-564 pg/mL), and normal dopamine and total catecholamine levels. PET/CT dotatate scan showed a 3.2 x 2.4 x 3.7 cm tracer avid soft tissue mass medial to the inferior vena cava. MRI abdomen/pelvis showed a 4.1 cm heterogeneous, diffusion-restricting retrocaval mass. She underwent mass resection with pathology showing a 6 cm pheochromocytoma. A small amount of normal adrenal tissue was seen. Discussion: Our patient developed extra-adrenal recurrence with predominant epinephrine secretion despite her history of bilateral adrenalectomy suggesting that high cortisol concentrations may not be necessary for PMNT upregulation. Typically, PGLs activate hypoxia signaling pathways including HIF2a gene expression, which block glucocorticoid mediated induction of PNMT. In one retrospective study, HRAS and FGFR1 gene mutations were seen in 80% of 29 epinephrine-secreting extra-adrenal PGLs (Jiang et al, 2020). Intra-adrenal HRAS mutated tumors upregulate PNMT expression by phosphorylation of SP1 via the MAPK pathway, do not induce HIF2a, and thus are able to produce PNMT (Li et al, 2023). Therefore, the production of epinephrine in extra-adrenal chromaffin tumors may be explained by their genomic signatures rather than solely by proximity to high cortisol concentrations. Epinephrine secretion alone cannot reliably differential intra from extra-adrenal PPGL. Presentation: Sunday, July 13, 2025