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Higher levels of progranulin in cerebrospinal fluid of patients with lymphoma and carcinoma with CNS metastasis

  • Laboratory Investigation
  • Published:
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Abstract

Assessing central nervous system (CNS) involvement in patients with lymphoma or carcinoma is important in determining therapy and prognosis. Progranulin (PGRN) is a secreted glycosylated protein with roles in cancer growth and survival; it is highly expressed in aggressive cancer cell lines and specimens from many cancer types. We examined PRGN levels by Enzyme Immuno-Assay (EIA) in cerebrospinal fluid (CSF) samples from 230 patients, including 18 with lymphoma [12 with CNS metastasis (CNS+); 6 without CNS metastasis (CNS−)], 21 with carcinomas (10 CNS+; 11 CNS−), and 191 control patients with non-cancer neurological diseases, and compared PRGN levels among these disease groups. Median CSF PGRN levels in the CNS+ lymphoma group were significantly higher than in the CNS− lymphoma and control non-cancer groups; and were also significantly higher in the CNS+ carcinoma group than in the CNS− carcinoma and control groups, except for patients with infectious neurological disorders. Receiver operating characteristic curve analyses revealed that CSF PGRN levels distinguished CNS+ lymphoma from CNS− lymphoma and non-cancer neurological diseases [area under curve (AUC): 0.969]; and distinguished CNS+ carcinomas from CNS− carcinomas and non-cancer neurological diseases (AUC: 0.918). We report here, for the first time, that CSF PGRN levels are higher in patients with CNS+ lymphoma and carcinomas compared to corresponding CNS− diseases. This would imply that measuring CSF PGRN levels could be used to monitor CNS+ lymphoma and metastasis.

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Acknowledgements

The authors would like to thank Dr. T. Kudo, Dr. M. Yasunishi, Dr. A. Takekoshi, Dr. N. Harada, Dr. A. Koumura and Dr. M. Yamada (Departments of Neurology and Geriatrics, Gifu University Graduate School of Medicine) for providing patients’ clinical information. We also thank Marla Brunker, from Edanz Group (http://www.edanzediting.com/ac) for editing a draft of this manuscript.

Funding

This research was partially supported by a Grant-in-Aid for Scientific Research (C) (26461290) from the Japan Society for the Promotion of Science.

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Authors and Affiliations

  1. Department of Neurology and Geriatrics, Gifu University Graduate School of Medicine, 1-1 Gifu, Yanagido, Gifu, 501-1194, Japan

    Akio Kimura, Nobuaki Yoshikura, Yuichi Hayashi & Takashi Inuzuka

  2. Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu, Japan

    Masao Takemura

  3. Advanced Diagnostic System Research Laboratory, Fujita Health University Graduate School of Health Sciences, Toyoake, Aichi, Japan

    Masao Takemura

  4. R&D and Precision Antibody Divisions, A&G Pharmaceutical Inc, Columbia, MD, USA

    Ginette Serrero

  5. Department of Disease Control and Prevention, Fujita Health University Graduate School of Health Sciences, Toyoake, Aichi, Japan

    Kuniaki Saito

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  1. Akio Kimura
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Correspondence to Akio Kimura.

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11060_2017_2742_MOESM1_ESM.tif

Supplementary Figure 1—Brain MRI of a patient with CNS+ lymphoma, whose CSF PGRN value exceeds the cutoff level, despite having normal brain MRI and CSF findings. FLAIR (A) and enhanced T1-weighted (B) images after one month of confirming increased CSF PGRN level (5.33 ng/mL) show no abnormal findings. FLAIR (C) and enhanced T1-weighted (D) images two months later show extended white matter hyperintensities and multiple parenchymal and leptomeningeal enhancement lesions. CNS: central nervous system, CSF: cerebrospinal fluid, FLAIR: fluid attenuated inversion recovery, MRI: magnetic resonance imaging, PGRN: progranulin (TIF 7076 KB)

11060_2017_2742_MOESM2_ESM.tif

Supplementary Figure 2—FLAIR images of a patient with CNS+ lymphoma, whose CSF PGRN levels increased with getting worse of brain MRI findings. (A, B) FLAIR images when CSF PGRN level was 3.18 ng/mL Slight hyperintensity lesions were observed in bilateral internal capsule and pontine tegmentum. (C, D) FLAIR images in the same patient four months later, when CSF PGRN level was 24.65 ng/mL Extended hyperintensity lesions were observed in cerebral white matter, brain stem, and cerebellum. CNS: central nervous system, CSF: cerebrospinal fluid, FLAIR: fluid attenuated inversion recovery, MRI: magnetic resonance imaging, PGRN: progranulin (TIF 7522 KB)

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Kimura, A., Takemura, M., Serrero, G. et al. Higher levels of progranulin in cerebrospinal fluid of patients with lymphoma and carcinoma with CNS metastasis. J Neurooncol 137, 455–462 (2018). https://doi.org/10.1007/s11060-017-2742-z

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  • DOI: https://doi.org/10.1007/s11060-017-2742-z

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