Biochemically silent abdominal paragangliomas in patients with mutations in the succinate dehydrogenase subunit B gene

Abstract

Context: Patients with adrenal and extra-adrenal abdominal paraganglioma (PGL) almost invariably have increased plasma and urine concentrations of metanephrines, the O-methylated metabolites of catecholamines. We report four cases of biochemically silent abdominal PGL, in which metanephrines were normal despite extensive disease.

Objective: Our objective was to identify the mechanism underlying the lack of catecholamine hypersecretion and metabolism to metanephrines in biochemically silent PGL.

Design: This is a descriptive study.

Setting: The study was performed at a referral center.

Patients: One index case and three additional patients with large abdominal PGL and metastases but with the lack of evidence of catecholamine production, six patients with metastatic catecholamine-producing PGL and a mutation of the succinate dehydrogenase subunit B (SDHB) gene, and 136 random patients with catecholamine-producing PGL were included in the study.

Main outcome measures: Plasma, urine, and tumor tissue concentrations of catecholamines and metabolites were calculated with electron microscopy and tyrosine hydroxylase immunohistochemistry.

Results: All four patients with biochemically silent PGL had an underlying SDHB mutation. In the index case, the tumor tissue concentration of catecholamines (1.8 nmol/g) was less than 0.01% that of the median (20,410 nmol/g) for the 136 patients with catecholamine-producing tumors. Electron microscopy showed the presence of normal secretory granules in all four biochemically silent PGLs. Tyrosine hydroxylase immunoreactivity was negligible in the four biochemically silent PGLs but abundant in catecholamine-producing PGLs.

Conclusions: Patients with SDHB mutations may present with biochemically silent abdominal PGLs due to defective catecholamine synthesis resulting from the absence of tyrosine hydroxylase. Screening for tumors in patients with SDHB mutations should not be limited to biochemical tests of catecholamine excess.

Figure 1

Relationship between tumor volume and plasma free metanephrines (MN) (upper panel), and between tumor catecholamine content and plasma free metanephrines (lower panel) in catecholamine-secreting PGLs. The arrows mark the data points for the biochemically silent tumor in patient no. S1. E, Epinephrine; NE, norepinephrine; NMN, normetanephrine.

Figure 2

Electron microscopy of a catecholamine-secreting PGL (patient no. C4, left panel) and a biochemically silent PGL (patient no. S1, right panels). Red arrows indicate examples of secretory granules. Secretory granules are present in both the secreting and silent tumor.

Figure 3

Tyrosine hydroxylase immunohistochemistry in two catecholamine-secreting PGLs (patient nos. C2 and C4, upper panels) in a biochemically silent PGL (patient no. S1, left-lower panel) and in rat adrenal medulla (right-lower panel). Tyrosine hydroxylase activity is abundant in the human and rat controls but absent in the silent tumor.