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. Hereditary PHEO and PGL Extra-adrenal PHEOs, otherwise known as PGLs, account for about 20% of catecholamine-producing tumors. Catecholamine excess and mutations in the genes encoding succinate dehydrogenase subunits (SDHx) are frequently found in patients with PGLs. Only 2% of PGLs are found in the mediastinum, and little is known about genetic alterations in patients with mediastinal PGLs, catecholamine production by these tumors, or their clinical behavior. We hypothesized that most mediastinal PGLs are associated with SDHx mutations, norepinephrine and/or dopamine excess, and aggressive behavior. The objective of this study was to characterize genetic, biochemical, and clinical data on a series of 10 patients with mediastinal PGLs. All 10 primary mediastinal PGL patients had germline SDHx mutations, 6 in SDHB and 4 in SDHD genes. Chest or back pain was the most common presenting symptom (5 patients), and catecholamines and/or their metabolites were elevated in 7 patients. Additional tumors included head and neck PGLs in 4 patients, PHEO in 1 patient, and bladder PGL in another. Metastatic disease was documented in 6 patients (60%), and a concurrent abdominal mass was found in one patient. We concluded that mediastinal PGLs were strongly associated with SDHB and SDHD gene mutations, noradrenergic phenotype, and aggressive behavior. The present data suggests that all patients with mediastinal PGLs should be screened for SDHx gene mutations, regardless of age. We also found that SDHx mutations are prevalent in pediatric and adult PGLs of the organ of Zuckerkandl. In addition, PGLs of the organ of Zuckerkandl are strongly associated with noradrenergic phenotype and aggressive behavior. The identification of SDHx mutations in patients with organ of Zuckerkandl PGLs has important implications for patient care and screening of family members. Patients with PGLs of the organ of Zuckerkandl should be screened for SDHx mutations;in addition asymptomatic carriers of an SDHx mutation among the relatives of affected patients may benefit from tumor screening for early PGL detection. In another study of about 21 children entered into the protocol study over more than 10 years, we found that familial PHEO/PGL is presented in more than 50% of these patients. We now recommend the screening for these patients start at age 5. We also describes the phenotype of 41 relatives of Spanish-Mexican descent found to have the same founder exon 1 SDHB heterozygous deletion previously reported in the literature for patients from the Iberian Peninsula. Family history or clinical information was obtained on 114 relatives and a total of 70 patients were screened for a large exon 1 SDHB deletion. The clinical and biochemical presentation of 41 mutation carriers is summarized. Variable expressivity of the phenotype associated with a large exon 1 SDHB deletion in this kindred was observed, including diverse primary PGL tumor locations, biochemistry, malignant potential, and age of onset. An inheritance pattern suggestive of genetic anticipation was observed with subsequent generations presenting at an earlier age and associated with more aggressive tumor behavior. Imaging of PHEO and PGL We compared functional imaging modalities including positron emission tomography (PET) with 6-18F-fluorodopamine (18F-DA) against 123I-metaiodobenzylguanidine (123I-MIBG) and somatostatin receptor scintigraphy (SRS) with 111In-pentetreotide (Octreoscan) in non-metastatic and metastatic PHEO/PGL. We studied 25 men and 28 women (mean ageSD: 44.214.2 years) with biochemically-proven non-metastatic (n: 17) or metastatic (n: 36) PHEO/PGL. Evaluation included anatomical imaging with computed tomography (CT) and/or magnetic resonance imaging (MRI) and functional imaging that included at least two nuclear medicine modalities: 18F-DA PET, 123I-MIBG scintigraphy, or SRS. Sensitivity of functional imaging vs. anatomical imaging was assessed on a per-patient and on a per-region basis. For this available cohort, on a per patient basis, overall sensitivity (combined for non-metastatic and metastatic PHEO) was 90.2% for 18F-DA PET, 76.0% for 123I-MIBG scintigraphy, and 22.0% for SRS. On a per-region basis, overall sensitivity was 75.4% for 18F-DA PET, 63.4% for 123I-MIBG scintigraphy, and 64.0% for SRS. If available, 18F-DA PET should be used in the evaluation of PHEO/PGL, since it is more sensitive than 123I-MIBG scintigraphy or SRS. If 18F-DA PET is not available, 123I-MIBG scintigraphy (for non-metastatic/adrenal PHEO) and SRS (for metastatic PHEO) should be the first alternative imaging methods to be used. In another study, we found that among 140 patients with definitive biochemical proof or exclusions of the presence of PHEO/PGL (91 positive, 49 negative), 123I-MIBG scintigraphy had sensitivity and specificity of 82%. For patients evaluated for suspected disease, sensitivity and specificity were 88% and 84%, respectively. For the subpopulations of adrenal PHEO and extraadrenal PGL, sensitivities were 88% and 67% respectively. Addition of SPECT increased reader confidence but had minimal effect on sensitivity and specificity. This prospective study demonstrated sensitivity of 82-88% and specificity of 82-84% for 123I-MIBG scintigraphy used in the diagnostic assessment of primary or metastatic PHEO or PGL. We also found that intravenous low osmolar contrast enhanced CT can safely be used in PHEO/PGL patients without alpha or beta-adrenergic blockade. Other findings To establish if classification of patients with SDHB-related metastatic PHEO/PGL, based on a characteristic urinary peptide pattern, is possible, the urine of patients with SDHB derived metastatic PHEO/PGL (SDHB-met, n=11) was compared to samples of SDHB derived non-metastatic PHEO/PGL (SDHB-nm, n=7) and healthy SDHB mutation carriers (SDHB-hlty, n=12). Differential urine peptide analysis was performed by capillary electrophoreses (CE) coupled electrospray ionization time-of-flight mass spectrometry (TOF-MS). Peptides of interest were identified by matching of retention time and molecular weight to a urine peptide database as well as by different MS/MS approaches;this study is ongoing. Two peptides, amongst the best 5 peptides to distinguish SDHB-met and SDHB-hlty, were identified as fragments of collagen alpha-1 (III) chain. A closer look at these fragments revealed that absence of peptide 76415 correlates particularly well with metastatic disease. Only 1 out of 12 patients with metastatic disease showed this peptide, however, the peptide was found in 16 out of 18 patients without metastases (SDHB-nm &SDHB-hlty).
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