title: 18F-fluorodihydroxyphenylalanine PET/CT in pheochromocytoma and paraganglioma: relation to genotype and amino acid transport system L.
abstract: OBJECTIVE
  F-FDOPA is a highly sensitive and specific radiopharmaceutical for pheochromocytoma and paraganglioma (PPGL) imaging. However,18F-FDOPA might be falsely negative in these tumors, especially those related to mutations in succinate dehydrogenase genes (SDHx). The aim of the present study was to evaluate the relationship between expression of L-DOPA transporters and18F-FDOPA PET imaging results in PPGL.
  
  
  METHODS
  From 2007 to 2015, 175 patients with non-metastatic PPGL were evaluated by18F-FDOPA PET/CT for initial diagnosis/staging and follow-up.18F-FDOPA PET/CT was considered as falsely negative for at least one lesion in 10/126 (8%) patients (two sporadic, six SDHD, two SDHB PPGLs). The mRNA and protein expression levels of CD98hc and LATs were evaluated in samples with different genetic backgrounds and imaging phenotypes. The qRT-PCR and immunohistochemical analyses were performed in 14 and 16 tumor samples, respectively.
  
  
  RESULTS
  The SDHx mutated samples exhibited a significant decrease in mRNA expression of LAT3 when compared to sporadic PPGLs (P = 0.042). There was also a statistical trend toward decreased CD98hc (P = 0.147) and LAT4 (P = 0.012) levels in SDHx vs sporadic PPGLs. No difference was observed for LAT1/LAT2 mRNA levels. LAT1 protein was expressed in 15 out of 16 (93.75%) SDHx tumors, regardless of the18F-FDOPA positivity. LAT1 and CD98hc were co-expressed in 6/818F-FDOPA-negative PPGLs. In contrast, in one case with absence of LAT1/CD98hc,18F-FDOPA uptake was positive and attributed to LAT4 expression.
  
  
  CONCLUSIONS
  We conclude that down-regulation of LAT1/CD98hc cannot explain the imaging phenotype of SDHx-related PPGLs. A reduced activity of LAT1 remains the primary hypothesis possibly due to a modification of intracellular amino acid content which may reduce18F-FDOPA uptake.
authors.affiliation: INSERM U1081, Institute for Research on Cancer and Aging of Nice (IRCAN), Nice, France.
authors.forename: Chloé C
authors.initials: CC
authors.lastname: Feral
authors.affiliation: INSERM U1081, Institute for Research on Cancer and Aging of Nice (IRCAN), Nice, France.
authors.forename: Floriane S
authors.initials: FS
authors.lastname: Tissot
authors.affiliation: INSERM U1081, Institute for Research on Cancer and Aging of Nice (IRCAN), Nice, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Tosello
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Conception Hospital, Aix-Marseille University, Marseille, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Fakhry
authors.affiliation: Department of Endocrine Surgery, Conception Hospital, Aix-Marseille University, Marseille, France.
authors.forename: Fréderic
authors.initials: F
authors.lastname: Sebag
authors.affiliation: Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
authors.affiliation: Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Aix-Marseille University, Marseille, France. david.taieb@ap-hm.fr.
authors.forename: David
authors.initials: D
authors.lastname: Taïeb
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000000981:diagnostic imaging* / Q000235:genetics; D000368:Aged; D027062:Amino Acid Transport System L / Q000235:genetics*; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives*; D005188:False Negative Reactions; D005260:Female; D027282:Fusion Regulatory Protein 1, Heavy Chain / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D009154:Mutation; D010235:Paraganglioma / Q000000981:diagnostic imaging* / Q000235:genetics; D010673:Pheochromocytoma / Q000000981:diagnostic imaging* / Q000235:genetics; D000072078:Positron Emission Tomography Computed Tomography; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000235:genetics
chemical_list: D027062:Amino Acid Transport System L; D027282:Fusion Regulatory Protein 1, Heavy Chain; D012333:RNA, Messenger; C043437:fluorodopa F 18; D004295:Dihydroxyphenylalanine; D013385:Succinate Dehydrogenase
keywords: 18F-FDOPA; Amino acid transport system L; Paragangliomas