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18F-fluorodihydroxyphenylalanine PET/CT in pheochromocytoma and paraganglioma: relation to genotype and amino acid transport system L

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Abstract

Purpose

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 and 18F-FDOPA PET imaging results in PPGL.

Methods

From 2007 to 2015, 175 patients with non-metastatic PPGL were evaluated by 18F-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 the 18F-FDOPA positivity. LAT1 and CD98hc were co-expressed in 6/8 18F-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 reduce 18F-FDOPA uptake.

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Authors and Affiliations

  1. INSERM U1081, Institute for Research on Cancer and Aging of Nice (IRCAN), Nice, France

    Chloé C. Feral, Floriane S. Tissot & Lionel Tosello

  2. Department of Otorhinolaryngology-Head and Neck Surgery, Conception Hospital, Aix-Marseille University, Marseille, France

    Nicolas Fakhry

  3. Department of Endocrine Surgery, Conception Hospital, Aix-Marseille University, Marseille, France

    Fréderic Sebag

  4. Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health, Bethesda, MD, 20892, USA

    Karel Pacak

  5. Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Aix-Marseille University, Marseille, France

    David Taïeb

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  1. Chloé C. Feral
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  3. Lionel Tosello
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Correspondence to David Taïeb.

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The review did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Feral, C.C., Tissot, F.S., Tosello, L. et al. 18F-fluorodihydroxyphenylalanine PET/CT in pheochromocytoma and paraganglioma: relation to genotype and amino acid transport system L. Eur J Nucl Med Mol Imaging 44, 812–821 (2017). https://doi.org/10.1007/s00259-016-3586-z

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  • DOI: https://doi.org/10.1007/s00259-016-3586-z

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