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Isolated adrenocorticotropic hormone deficiency as a form of paraneoplastic syndrome

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Abstract

Purpose

In isolated adrenocorticoropic hormone (ACTH) deficiency (IAD), autoimmunity against corticotrophs has been suggested; however, the pathogenesis remains largely unknown. Large cell neuroendocrine carcinoma (LCNEC) of the lung is a pulmonary tumor of high-grade malignant neuroendocrine tumor and it reportedly caused paraneoplastic syndrome by autoimmunity in several cases.

Methods

A 42-year-old woman with isolated adrenocorticotropic (ACTH) hormone deficiency (IAD) was diagnosed with large cell neuroendocrine carcinoma (LCNEC) 3 years after being diagnosed with IAD. We hypothesized that the LCNEC played a causal role in the development of IAD as a paraneoplastic syndrome and analyzed the autoimmunity. We also analyzed another case of ectopic ACTH syndrome to prove this hypothesis.

Results

The LCNEC tissue revealed an ectopic ACTH expression and lymphocyte infiltration. Interestingly, autoantibody against the proopiomelanocortin (POMC) protein was detected in the peripheral blood. Although, patient’s serum did not show any effects on cell viability, proliferation, nor pomc expression in a corticotroph cell line, AtT20 cells, patient’s lymphocytes in the peripheral blood specifically reacted toward POMC protein, indicating a presence of cytotoxic T lymphocytes (CTLs). In addition, the analysis of another case of ectopic ACTH syndrome showed lymphocyte infiltration not only in the metastatic liver tumors but also in the pituitary. Moreover, most CD8-positive cells resided adjacent to corticotrophs.

Conclusions

These data indicate that the ectopic ACTH expression in the tumor evoked the autoimmunity to corticotrophs and caused IAD as a form of paraneoplastic syndrome.

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Acknowledgements

We thank Drs. M Takahashi, M Kanzawa, M Nishio, and T Nakamura for their fruitful suggestions and C Ogata and K Imura for their excellent technical assistance.

Funding

This work was supported by Japan Society for the Promotion of Science (JSPS) (KAKENHI, Grant Numbers 23591354, 23659477, 26670459 [Y Takahashi], 15K09431 [G Iguchi], and 17K16165 [H Bando]), the Japan Agency for Medical Research and Development (AMED) (17bm0804012h0001), the Uehara Memorial Foundation (Y Takahashi), and the Naito Foundation (Y Takahashi).

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Authors and Affiliations

  1. Division of Diabetes and Endocrinology, Kobe University Hospital, Kobe, Japan

    Hironori Bando, Genzo Iguchi, Hitoshi Nishizawa & Hidenori Fukuoka

  2. Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan

    Keitaro Kanie, Ryusaku Matsumoto, Yasunori Fujita, Yukiko Odake, Kenichi Yoshida, Kentaro Suda, Wataru Ogawa & Yutaka Takahashi

  3. Brain Research Institute, Niigata University, Niigata, Japan

    Keiko Tanaka

Authors
  1. Hironori Bando
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  2. Genzo Iguchi
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  3. Keitaro Kanie
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  13. Yutaka Takahashi
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Contributions

HB, GI, and YT conceived and designed the experiments. HB contributed to the development of methodology and acquisition of data. HN, RM, KS, and HF contributed to the technical and material support. KK, YF, YO, KY, KT, and WO interpreted the experiments and analyzed the data. HB and GI wrote the draft. YT contributed to the study supervision and critical revision of the article for important intellectual content.

Corresponding author

Correspondence to Yutaka Takahashi.

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The authors have declared that no conflict of interest exists.

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Bando, H., Iguchi, G., Kanie, K. et al. Isolated adrenocorticotropic hormone deficiency as a form of paraneoplastic syndrome. Pituitary 21, 480–489 (2018). https://doi.org/10.1007/s11102-018-0901-7

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