L. Cybulski1, C. Marin1, Z. Lewin2, L. Benavides2, J. Moalem1,4, I. Harbuz-Miller3, A. Moore1,4 1University Of Rochester, Department Of Surgery, Rochester, NY, USA 2University Of Rochester, School Of Medicine And Dentistry, Rochester, NY, USA 3University Of Rochester, Division Of Endocrinology, Rochester, NY, USA 4University Of Rochester, Division Of Endocrine Surgery, Rochester, NY, USA
Introduction: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors with an estimated incidence of 0.5-0.7/100,000 annually in the United States. Most patients present with isolated disease, however 10-20% either present with or develop metastatic disease. Estimated 5-year (5y) survival for metastatic PPGL is up to 85% with treatment and <50% without treatment. Research has shown that histopathologic characteristics (i.e. mitotic activity, cellular atypia, local invasion) are not reliable predictors of metastatic disease. It has been posited that demographic features, tumor characteristics, genetic mutations, and biochemical markers are possible predictors of malignant disease and mortality. Specifically, lower metanephrine levels and higher norepinephrine levels may be associated with metastasis; however, data is conflicting and existing studies are of small sample size. In this study, we aim to further elucidate factors associated with metastasis.
Methods: We created a retrospective database of patients in Rochester, New York diagnosed with PPGL based on either tissue diagnosis or combined imaging and biochemical profile from 2006 to 2024. Demographic data, tumor characteristics, biochemical profiles, and genetic testing information was collected. Data were analyzed using R software.
Results: Metastatic disease was identified in 13% of patients, of which 18% had a germline pathogenic variant. Estimated 5y survival amongst metastatic patients was significantly lower than in non-metastatic patients (70.7% vs 93.7%, p <0.001). Tumor size was not significantly correlated to rate of metastases (p=0.50). Also, patients with metastases had significantly lower levels of urine (p=0.021) and plasma (p<0.001) metanephrines, with no differences in urine or plasma normetanephrine levels. Interestingly, the ratio of metanephrine to normetanephrine was significantly lower in urine (p=0.021) and plasma (p=0.049) in metastatic patients. Tumor size was strongly and significantly correlated to urine normetanephrine level (r=0.823, p<0.001), with moderate correlations to urine metanephrine (r=0.529, p=0.003) and plasma normetanephrine (r=0.353, p=0.003).
Conclusion: Our rate of metastasis and 5y survival are consistent with previously published results in PPGLs. In contrast to prior studies, tumor size alone was not an independent predictor of metastasis nor mortality risk. Metanephrine excess also was not a predictor of metastasis or mortality. However, patients with metastasis did demonstrate relative abundance of normetanephrine production. Tumor size was also most strongly correlated with normetanephrine levels. These results suggest that relative noradrenergic excess may be important to developing advanced disease states in PPGL. In the future, we will examine the cellular biology and tumor microenvironment from PPGL patients with relative noradrenergic excess to determine tumor cell phenotypes more likely to develop metastasis.