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 Catecholamine excess and mutations in the genes encoding succinate dehydrogenase subunits (SDHx) are frequently found in patients with PHEOs/PGLs. The genetic screening for PHEO/PGL is rarely done because of time and financial constraints. Therefore, we investigated whether SDHB immunohistochemistry could effectively discriminate between SDHx-related and non-SDHx-related PHEOs/PGLs in large prospective and retrospective tumor series. Immunohistochemistry for SDHB was done on 220 tumors. Two retrospective series of 175 PHEOs/PGLs with known germline mutation status for PHEO/PGL susceptibility genes were investigated. Additionally, a prospective series of 45 PHEOs/PGLs was investigated for SDHB immunostaining followed by SDHB, SDHC, and SDHD mutation testing. SDHB protein expression was absent in all 102 PHEOs/PGLs with an SDHB, SDHC, or SDHD mutation, but was present in all 65 PHEOs/PGLs related to multiple endocrine neoplasia type 2, von Hippel-Lindau (VHL) syndrome, and neurofibromatosis type 1 (NF1). There were 47 out of 53 PHEOs/PGLs with no syndromic germline mutation showed SDHB expression. The sensitivity and specificity of the SDHB immunohistochemistry to detect the presence of an SDHx mutation in the prospective series were 100% and 84%, respectively. In another study we assessed genetic background and clinical characteristics of metastatic PHEO and PGL when/from primary tumor found in childhood and adolescence. Forty-five cases of PHEO/PGL in children and adolescents in the age range from 3 to 19 were included. Overall, SDHB mutations including deletions were present in 23 patients (51.1%), VHL in 6 (13.3%), SDHD in 4 (8.9%), NF1 in 2 (4.4%), while 10 patients (22.2%) had sporadic PHEO or PGL. There were 22 out of 23 (86.9%) patients with SDHB mutations developed metastatic disease. Overall, SDHB mutations were found in 20 out of 28 (71.4%) patients with metastatic disease. Metastatic PHEO or PGL developed from the primary tumor in childhood and adolescence is most commonly associated commonly associated with SDHB gene mutations. The presence of SDHB mutation is often seen in patients with negative family history. SDHB gene mutation must be considered as the first genetic test to be performed in this patients'population Imaging of PHEO and PGL Although I-123-MIBG has been in clinical use for imaging of PHEOs/PGLs for many years, a large multicenter evaluation of this agent has never been performed. The present study was designed to provide prospective confirmation of the performance of I-123-MIBG scintigraphy for the evaluation of patients with known or suspected primary or metastatic PHEO/PGL. Eighty-one patients with history of primary or metastatic PHEO/PGL and 69 with suspicion based upon symptoms of catecholamine excess, CT/MRI findings, and/or elevated catecholamines or metanephrines underwent whole-body planar and selected SPECT imaging 24 hours following administration of I-123-MIBG. Images were independently interpreted by three blinded readers, with consensus requiring agreement of at least two readers. Final diagnoses were based upon histopathology, correlative imaging, catecholamine or metanephrine measurements, and close clinical follow-up. Among 140 patients with definitive biochemical proof or exclusions of the presence of a tumor (91 positive, 49 negative), 123I-MIBG planar 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) tumors, sensitivities were 88% and 67%, respectively. This prospective study demonstrated sensitivity of 82-88% and specificity of 82-84% for I-123-MIBG imaging used in the diagnostic assessment of primary or metastatic PHEO/PGL. In another study patients with negative and borderline abnormal I-123-MIBG scans were identified and included in the study if they were diagnosed with PHEO/PGL based on histopathological confirmation of resected tumor or compatible clinical, biochemical, and imaging studies (anatomical and nuclear imaging studies other than I-123-MIBG). A false-negative I-123-MIBG scan was defined as absence of uptake corresponding to a lesion proven to be PHEO/PGL by pathology or, when pathologic examination was not available such as in the presence of multiple metastatic lesions, a normal I-123-MIBG scintigraphy with clinical, biochemical, and imaging findings consistent with PHEO/PGL. We subsequently included 21 patients (6 males, 15 females), seven of which were referred for evaluation and management of primary tumors preoperatively while 14 other cases were referred due to the development of metastases (n=12), recurrence (n=1), and another primary tumor (n=1) after previous surgery for PHEO/PGL. Eleven cases were due to underlying gene mutation in SDHB and 1 other case was part of MEN 2 syndrome;9 had benign disease while 12 others had metastatic disease. Other findings Expression of carboxypeptidase E, a prohormone processing enzyme in different cancer types was analyzed from data in the GEO profile database, and experimentally in PHEO/PGL. Microarray data from the GEO profile database indicated that significantly elevated levels of CPE mRNA was found in many non-endocrine cancers: cervical, colon rectal, renal cancers , Ewing sarcomas (bone cancer) and various types of astrocytomas and oligodendrogliomas, but expression of CPE mRNA was virtually absent in their respective counterpart normal tissues. Moreover there was a good correlation of high CPE mRNA expression with metastasis in cervical cancer and anaplastic oligodendrogliomas and neoplastic astrocytomas. Elevated CPE mRNA expression was found in neuroendocrine tumors in lung and pituitary adenomas, although the significance is unclear since endocrine and neuroendocrine cells normally express CPE. Our studies on PHEOs or PGLs revealed expression of not only wild type CPE, but a variant which was correlated with tumor behavior. Extremely high CPE mRNA copy numbers of the variant were found in very large or invasive tumors, both of which usually indicate poor prognosis. Thus, all the data suggest that CPE is involved in tumorogenesis and that it may play a role in promoting tumor growth and invasion. CPE could potentially serve as a diagnostic and prognostic biomarker for different cancer types including PHEIO/PGL.
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