Division of Diabetes and Endocrinology, Kobe University Hospital, Kobe, Japan.
Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan.
Pituitary. 2018 Oct;21(5):480-489. doi: 10.1007/s11102-018-0901-7.
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.
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.
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.
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.
在孤立性促肾上腺皮质激素缺乏症（IAD）中，有人提出针对促皮质细胞的自身免疫；然而，其发病机制在很大程度上仍不清楚。肺大细胞神经内分泌癌（LCNEC）是一种高级别恶性神经内分泌肿瘤的肺部肿瘤，据报道，它在几种情况下通过自身免疫引起副肿瘤综合征。
一名 42 岁女性患有孤立性促肾上腺皮质激素（ACTH）缺乏症（IAD），在被诊断为 IAD 3 年后被诊断为大细胞神经内分泌癌（LCNEC）。我们假设 LCNEC 作为副肿瘤综合征在 IAD 的发展中起因果作用，并分析了自身免疫。我们还分析了另一个异位 ACTH 综合征病例来证明这一假设。
LCNEC 组织显示异位 ACTH 表达和淋巴细胞浸润。有趣的是，在外周血中检测到针对 proopiomelanocortin（POMC）蛋白的自身抗体。尽管患者的血清对促皮质细胞系 AtT20 细胞的细胞活力、增殖或 pomc 表达没有任何影响，但患者外周血中的淋巴细胞特异性地针对 POMC 蛋白反应，表明存在细胞毒性 T 淋巴细胞（CTLs）。此外，对另一个异位 ACTH 综合征病例的分析表明，淋巴细胞浸润不仅存在于转移性肝肿瘤中，也存在于垂体中。此外，大多数 CD8 阳性细胞位于促皮质细胞附近。
这些数据表明肿瘤中的异位 ACTH 表达引发了针对促皮质细胞的自身免疫，并导致 IAD 作为副肿瘤综合征的一种形式。
