Pheochromocytoma and Paraganglioma Patients With Poor Survival Often Show Brown Adipose Tissue Activation

Abstract

Context: Pheochromocytomas/paragangliomas (PPGLs) are neuroendocrine tumors that can secrete norepinephrine (NE). Brown adipose tissue (BAT) activation is mediated through the action of NE on β-adrenoceptors (β-ARs). In some malignancies, BAT activation is associated with higher cancer activity.

Objective: To study the relationship between BAT activation and PPGL clinical outcomes.

Design: A retrospective case-control study that included 342 patients with PPGLs who underwent 18F-fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography (18F-FDG PET/CT) imaging at the National Institutes of Health (NIH). We excluded all patients with parasympathetic tumors and those who underwent 18F-FDG PET/CT after PPGL resection. Scans of 205 patients were reviewed by 2 blinded nuclear medicine physicians; 16 patients had BAT activation on 18F-FDG PET/CT [7.80%; age 27.50 (15.00-45.50) years; 10 female/6 male; body mass index [BMI] 24.90 [19.60-25.35] kg/m2). From the remaining 189 patients, we selected 36 matched controls (age 34.4 [25.4-45.5] years; 21 female/15 male; BMI 25.0 [22.0-26.0] kg/m2).

Primary outcome measure: Overall survival.

Results: The presence of active BAT on 18F-FDG PET/CT was associated with decreased overall survival when compared with the control group (HRz 5.80; 95% CI, 1.05-32.05; P = 0.02). This association remained significant after adjusting for the SDHB mutation. Median plasma NE in the BAT group was higher than the control group [4.65 vs 0.55 times above the upper limit of normal; P < 0.01]. There was a significant association between higher plasma NE levels and mortality in PPGLs in both groups.

Conclusions: Our findings suggest that the detection of BAT activity in PPGL patients is associated with higher mortality. We suggest that BAT activation could either be reflecting or contributing to a state of increased host stress that may predict poor outcome in metastatic PPGL.

Keywords: 18F-FDG; PET/CT; brown adipose tissue; cancer; norepinephrine; paraganglioma; pheochromocytoma; succinate dehydrogenase; survival.

Figure 1.

We evaluated 343 consecutive patients with PPGLs who underwent ¹⁸F-FDG PET/CT studies. We excluded patients with normal biochemical profiles as we wanted to study BAT activation and clinical behavior of PPGLs. After exclusion, we had a study cohort of 205 patients with PPGLs who underwent ¹⁸F-FDG PET/CT, among whom 16 patients had evidence of BAT.

Figure 2.

Bar graph of gene clusters (a) and stratification (b) in BAT group and gene clusters (c) and stratification (d) in the BAT group vs control group. Cluster 1 (germ-line variants of succinate dehydrogenase subunits A, B, C, and D and assembly factor 2 [SDHA/B/C/D/AF2], and von Hippel-Lindau [VHL]). Cluster 2 (variants of neurofibromatosis type 1 [NF1], rearranged during transfection [RET] genes), hypoxia-inducible factor 2α (HIF2A).

Figure 3.

Unadjusted Kaplan-Meier survival curves of the BAT vs control group (a) showing a significantly lower overall survival, with a median survival of 11 years. The hazard ratio of death in the BAT group is 5.80; 95% CI, 1.05–32.05; P = 0.02. Unadjusted Kaplan-Meier survival curves of the combination of BAT and SDHx mutation vs SDHx alone (b) showing that the combination of BAT and SDHx is associated with significantly lower survival compared with SDHx alone with P < 0.001. Comparison of survival curves was made using the log-rank (Mantel-Cox) test. The graph does not plot actual raw-data survival proportions, but estimated proportions.

Figure 4.

The difference in median (IQR) of plasma dopamine (a), epinephrine (b) and norepinephrine (NE) (c) showing significantly higher NE in the BAT group compared with control (c). Mean ± SD of mean arterial pressure in mmHg (d), body temperature (°C) (e), and heart rate (beats/min) (f) in the BAT group compared with control group, respectively. Values are presented as multiples of the ULN, respectively. Paired t-tests were used to analyze data that were normally distributed; for nonparametric data, Wilcoxon matched-pairs tests were used. Abbreviation: ULN, upper limit of normal.