OR29-6 Brown Adipose Tissue Activation in SDHx-Related Pheochromocytoma and Paraganglioma: An Ominous Sign?

Brown adipose tissue (BAT) activation after cold exposure and its subsequent detection via18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is mediated through norepinephrine (NE) induced β3-adrenoceptor activation. Pheochromocytoma/paragangliomas (PPGLs), especially SDH, VHL, and FH germline variants (cluster 1 tumors), predominantly secrete NE and often has higher maximal standardized uptake values of tumors on18F-FDG PET/CT(1). Therefore, 18F-FDG PET/CT scans of these NE-secreting PPGLs should also reveal higher BAT activity. Because BAT activation is also associated with cancer-induced cachexia and thus poor outcomes (2), BAT activation in PPGLs could also indicate aggressive tumor behavior. To study the relationship between BAT activation detected on 18F-FDG PET/CT and the clinical behavior of PPGLs, we performed a retrospective study of 343 patients with genetically characterized and histopathologically confirmed PPGLs who underwent 18F-FDG PET/CT imaging for disease surveillance between 2013 and 2017. After excluding patients with only post-operative PET scans and those with normal serum catecholamines and/or metanephrines, 205 patients were included in the final analysis. BAT activation was observed in 16 patients (7.8%; 28±17y; 10F/6M, 23.4±4.2 kg/m2). Hereditary PPGLs were present in 12/16 patients of which, 10 had cluster 1 variants (SDHx, n=7; HIF2A, n=2; VHL, n=1), 2 had cluster 2 variants (NF1, n=2), and 4 had sporadic PPGL. Elevated plasma biomarkers were as follows: epinephrine (n=0/16); metanephrine (n=2/16); NE (n=11/16); normetanephrine (n=16/16); and dopamine (n=8/16). A matched control group of 36 PPGL patients without detectable BAT activation (34±13y, 21F/15M,23.9±2.5 kg/m2, 12/36 SDHx, p=0.47) revealed a significantly lower mortality rate (n=2/36 vs n=4/16; p=0.043). All deaths in the BAT activation group were found in patients with SDHx variants compared to sporadic PPGL patients in the control group. The development of metastasis was similar in both groups (n=10/16, 62.5% vs. n=27/36, 75%; p=0.36). In conclusion, cluster 1 PPGLs are more likely to be associated with BAT activation. We show for the first time that particularly the combination of an SDHx mutation and BAT activation is associated with a higher mortality. Further investigation is necessary to establish the mechanistic connection between PPGLs, especially those with SDHx mutations, BAT activation, and poorer prognosis. References: 1-Martucci VL, Pacak K. Pheochromocytoma and paraganglioma: diagnosis, genetics, management, and treatment. Current problems in cancer. 2014;38(1):7-41. 2-Petruzzelli M, Schweiger M, Schreiber R, et al. A switch from white to brown fat increases energy expenditure in cancer-associated cachexia. Cell metabolism. 2014;20(3):433-447.