title: SDHB loss predicts malignancy in pheochromocytomas/sympathethic paragangliomas, but not through hypoxia signalling.
abstract: Prediction of malignant behaviour of pheochromocytomas/sympathetic paragangliomas (PCCs/PGLs) is very difficult if not impossible on a histopathological basis. In a familial setting, it is well known that succinate dehydrogenase subunit B (SDHB)-associated PCC/PGL very often metastasise. Recently, absence of SDHB expression as measured through immunohistochemistry was shown to be an excellent indicator of the presence of an SDH germline mutation in PCC/PGL. SDHB loss is believed to lead to tumour formation by activation of hypoxia signals. To clarify the potential use of SDHB immunohistochemistry as a marker of malignancy in PCC/PGL and its association with classic hypoxia signalling we examined SDHB, hypoxia inducible factor-1α (Hif-1α) and its targets CA-9 and GLUT-1 expression on protein level using immunohistochemistry on a tissue micro array on a series of familial and sporadic tumours of 115 patients. Survival data was available for 66 patients. SDHB protein expression was lost in the tumour tissue of 12 of 99 patients. Of those 12 patients, 5 had an SDHB germline mutation, in 4 patients no germline mutation was detected and mutational status remained unknown in parts in 3 patients. Loss of SDHB expression was not associated with increased classic hypoxia signalling as detected by Hif-1α, CA-9 or GLUT-1 staining. Loss of SDHB expression was associated with an adverse outcome. The lack of correlation of SDHB loss with classic hypoxia signals argues against the current hypoxia hypothesis in malignant PCC/PGL. We suggest SDHB protein loss as a marker of adverse outcome both in sporadic and in familial PCC/PGL.
authors: Institute of Pathology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors: Annika
authors: A
authors: Blank
authors: Anja M
authors: AM
authors: Schmitt
authors: Esther
authors: E
authors: Korpershoek
authors: Francien
authors: F
authors: van Nederveen
authors: Thomas
authors: T
authors: Rudolph
authors: Nicole
authors: N
authors: Weber
authors: Räto Thomas
authors: RT
authors: Strebel
authors: Ronald
authors: R
authors: de Krijger
authors: Paul
authors: P
authors: Komminoth
authors: Aurel
authors: A
authors: Perren
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000201:enzymology* / Q000235:genetics; D015687:Cell Hypoxia / Q000502:physiology; D004247:DNA / Q000737:chemistry / Q000235:genetics; D058645:Denaturing Gradient Gel Electrophoresis; D005260:Female; D018095:Germ-Line Mutation; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D010673:Pheochromocytoma / Q000201:enzymology* / Q000235:genetics; D012189:Retrospective Studies; D013385:Succinate Dehydrogenase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
chemical_list: D051272:Glucose Transporter Type 1; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D004247:DNA; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase