The Section is conducting patient-oriented research about the etiology, pathophysiology, genetics, diagnosis, and treatment of pheochromocytoma (PHEO) and paraganglioma (PGL). Projects include not only translational research-applying basic science knowledge to clinical diagnosis, pathophysiology, and treatment-but also reverse translation research where appreciation of clinical findings leads to new concepts that basic researchers can pursue in the laboratory. In order to achieve our goals, the strategy of the Section is based on the multidisciplinary collaborations among investigators from multiple NIH Institutes and outside medical centers. Our Section links together a patient-oriented component with two bench-level components. The patient-oriented component (Medical Neuroendocrinology) is currently the main driving force for our hypotheses and discoveries. The two bench-level components (Tumor Pathogenesis and Chemistry &Biomarkers) emphasize first, technologies of basic research tailored for pathway and target discovery and second, the development of the discoveries into clinical applications. Clinical aspects of PHEO/PGL Recently, we have presented data on the high rate of SDHB mutations in patients with metastatic PHEO/PGL whose initial tumor presentation was in childhood or adolescence. From 2000 - 2010, 263 PHEO/PGL patients were evaluated through NIH. Of those 263 patients, 125 presented with or were found to have metastatic disease;of these 125 patients, 32 presented with a tumor prior to age 20. An additional 17 patients presented with a tumor prior to age 20 but demonstrated no development of metastatic disease. Genetic testing for mutations in the VHL, RET, and SDHB/C/D genes was performed on patients without previously identified genetic mutations. Of the 32 patients who presented with metastatic disease and had their primary tumor in childhood or adolescence, sequence analysis of germline DNA found SDHB mutations in 23 (71.9%), SDHD mutations in 3 (9.4%), VHL mutations in 2 (6.3%), and absence of a known mutation in 4 (12.5%). The majority (78.1%) of these 32 patients presented with primary tumors in an extra-adrenal location (retroperitoneum and head and neck). We concluded that the majority of patients with metastatic PHEO/PGL who presented with a primary tumor in childhood or adolescence had primary extra-adrenal tumors and harbored SDHB mutations. Except for primary tumors located in the head and neck where SDHD genetic testing is advised, we recommend that patients presenting with metastatic PHEO/PGL with primary tumor development in childhood or adolescence undergo SDHB genetic testing. In another study we identified 41 subjects with metastatic PHEO and 108 subjects with apparently benign PHEO. We assessed the dimensions and biochemical profile of the primary tumor, age at presentation, and time to develop metastases. Subjects with metastatic PHEO presented at a significantly younger age (41.414.7 vs. 50.213.7 years;P<0.001), with larger primary tumors (8.383.27 cm vs. 6.182.75 cm;P<0.001), and more frequently secreted norepinephrine (95.1% vs. 83.3 %;P=0.046) compared to subjects with apparently benign PHEOs. No significant differences were found in the incidence of genetic mutations in both groups of subjects (25.7% in the metastatic group and 14.7% in the benign group;P=0.13). From available histopathologic markers of potential malignancy, only necrosis occurred more frequently in subjects with metastatic PHEO (27.6% vs. 0%;P<0.001). The median time to develop metastases was 3.6 years, with the longest interval 24 years. In conclusion, regardless of a genetic background, the size of a primary PHEO and age of its first presentation are two independent risk factors associated with the development of metastatic disease Hereditary PHEO/PGL MAX has been recently identified as the 10th susceptibility gene for PHEO. However, its clinical relevance was not addressed. An international study, based on an outstanding series of 1694 unrelated patients with PHEO or PGL, has ascertained the prevalence of MAX mutations in PHEO patients, extended the spectrum of MAX‐related tumors to PGL, uncovered contributions of somatic MAX mutations to sporadic disease, and defined an intermediate catecholamine phenotype that may guide testing for the MAX gene in patients with PHEO/PGLs. This study also confirmed a preferential paternal mode of transmission with important consequences for genetic counseling. We established that MAX germline mutations were responsible for the disease in 1.12% of cases, similarly to the genes recently described, such as TMEM127, SDHAF2, or SDHA, and now recommend that MAX be considered in the genetic work‐up of affected patients. Imaging of PHEO/PGL We performed a study aimed to establish the sensitivity and specificity of 18F-FDG PET/CT for tumor localization and staging of PHEO/PGL as compared to conventional imaging by 123I-MIBG SPECT and CT/MRI. 216 patients (106 males, 110 females, meanSD age 45.214.9 years) with (suspected) PHEO/PGL were consecutively studied. There were 60 cases of non-metastatic PHEO/PGL, 95 cases of metastatic PHEO/PGL, and 61 PHEO/PGL-negative patients. Besides CT or MRI, patients underwent 18F-FDG PET/CT and 123I-MIBG SPECT/CT. For non-metastatic tumors, the sensitivity was 95.7% for CT/MRI, 76.8% for 18F-FDG (p<0.001 versus CT/MRI), and 77.0% for 123I-MIBG (p=0.002 versus CT/MRI, not significant versus 18F-FDG). The specificity was 90.2% for 18F-FDG, 91.80% for 123I-MIBG, and 90.2% for CT/MRI. Cut-off values for 18F-FDG uptake to distinguish between PHEO/PGL and normal adrenal glands were 1.1 (100% sensitivity, 73% specificity) and 4.6 (100% specificity, 82% sensitivity). 18F-FDG uptake was higher in SDH- and VHL-related tumors than in MEN2-related tumors. For metastases, sensitivities were 74.4% for CT/MRI, 82.5% for 18F-FDG (p<0.001 versus 123I-MIBG), and 50.0% for 123I-MIBG (p<0.001 versus CT/MRI). For bone metastases, the highest sensitivity was reached by 18F-FDG: 93.7%, versus 76.7% for CT/MRI (p<0.05) and 61.5% for 123I-MIBG (p<0.001). Compared to 123I-MIBG SPECT and CT/MRI, which are all considered the gold standard for PHEO/PGL imaging, metastases were better detected by 18F-FDG PET. 18F-FDG PET is highly specific in cases with a biochemically established diagnosis of PHEO/PGL. Quantification of 18F-FDG uptake distinguishes well between PHEO/PGL and normal adrenal glands and provides important clues for a hereditary syndrome. Treatment of PHEO/PGL Although PHEOs/PGLs are intensively studied, a very effective treatment for metastatic PHEO or PGL has not yet been established. Preclinical evaluations of novel therapies for these tumors are very much required. Therefore, in another study we tested the effect of triptolide (TTL), a potent nuclear factor-kappaB (NF-κB) inhibitor, on NET, considered to be the gatekeeper for 131I-MIBG. We measured changes in the mRNA and protein levels of NET and correlated them with proapoptotic factors and metastasis inhibition. The study was carried out on three different stable pheochromocytoma cell lines. We found that blocking NF-κB with TTL or capsaicin increased both NET mRNA and protein levels. Involvement of NF-κB in the upregulation of NET was verified by mRNA silencing of this site and also by using NF-κB antipeptide. Moreover, MIBG transport was increased in TTL-treated cells and in vivo treatment with TTL significantly reduced metastatic burden in an animal model of metastatic pheochromocytoma. This study showed for the first time how NF-κB inhibitors could be successfully used in the treatment of metastatic PHEO/PGL by a significant upregulation of NET to increase the efficacy of 131I-MIBG and by the induction of apoptosis.
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