Pheos

Abstract: CONTEXT Modern pheochromocytomas (PHEOs) are often discovered by incidental finding on cross-sectional imaging or mutation-based genetic case detection testing. Little is known about how these PHEOs behave. OBJECTIVE To describe the characteristics and behavior of PHEOs discovered incidentally on imaging or through mutation-based genetic case detection testing. DESIGN Retrospective study. SETTING Referral center. PATIENTS Consecutive patients with pathology-confirmed PHEOs, treated from 2005 to 2016. MAIN OUTCOME MEASURE(S) Tumor size, plasma/urine fractionated metanephrines and catecholamines, and preoperative management. RESULTS Two hundred seventy-one patients (52% women, median age 52.0 years) presented with 296 PHEOs. Discovery method was most often incidental finding on cross-section imaging (61%) rather than PHEO-related symptoms (27%) or mutation-based case detection testing (12%). Patients with incidentally discovered PHEOs were older than symptomatic and mutation-based case detection testing patients (median age 56.6 vs 43 vs 35 years, P < 0.0001). Mutation-based case detection PHEOs were smaller than those discovered due to symptoms (median size 29.0 vs 50.5 mm, P = 0.0027). Patients with PHEOs discovered due to symptoms had the highest median concentration of 24-hour urinary metanephrines and total plasma metanephrines (P < 0.0001). These patients required a higher cumulative phenoxybenzamine dose than patients with incidental or case detection PHEO (median 450 vs 375 vs 270 mg, P = 0.029). CONCLUSIONS PHEOs are primarily discovered due to incidental finding on cross-sectional imaging rather than PHEO-related symptoms. PHEOs discovered through mutation-based genetic case detection testing were smaller and required less α-adrenergic blockade preoperatively compared with PHEOs found due to symptoms, which supports routine case detection testing for patients genetically predisposed for PHEOs.

Abstract: Recent comprehensive molecular analysis allowed the identification of unique molecular signatures in pheochromocytomas (PHEOs) and paragangliomas (PGLs). Here we summarize the main pathway clusters activated by PHEO- and PGL-susceptibility genes: pseudohypoxic, kinase, and Wnt signaling. Molecular characterization and clustering of PHEOs and PGLs may help in the application of principles of personalized medicine and in decision making for targeted therapy of these tumors.

Abstract: Pheochromocytomas (PHEOs) and paragangliomas (PGLs; extra-adrenal tumors) are rare neuroendocrine chromaffin cell tumors with a hereditary background in about 30%-35%. Those caused by succinate dehydrogenase subunit B (SDHB) germline mutations are associated with a high metastatic potential and ultimately higher patient mortality. Succinate dehydrogenase converts succinate to fumarate, uniquely linking the Krebs cycle and oxidative phosphorylation. SDH mutations result in the accumulation of succinate associated with various metabolic disturbances and the shift to aerobic glycolysis in tumor tissue. In the present study, we measured succinate and fumarate levels in mouse pheochromocytoma (MPC) and mouse tumor tissue (MTT) cells and in 10 apparently sporadic, 10 SDHB-, 5 SDHD-, and 2 neurofibromatosis 1-related PHEOs/PGLs and plasma samples using mass spectrometry. We found that the succinate-to-fumarate ratio was significantly higher in the SDHB- and SDHD-related PGLs than in apparently sporadic and neurofibromatosis 1-related PHEOs/PGLs (P = .0376). To further support our data, we silenced SDHB expression in MPC and MTT cells and evaluated the succinate and fumarate levels. Compared with control samples, SDHB-silenced MTT cells also showed an increase in the succinate-to-fumarate ratio (MTT cells: 2.45 vs 7.53), similar to the findings in SDHB-related PGLs. The present findings for the first time demonstrate a significantly increased succinate-to-fumarate ratio in SDHB/D-related PGLs and thus suggest this ratio may be used as a new metabolic marker for the detection of SDHB/D-related PHEOs/PGLs.