Department of Diabetes, Metabolism and Endocrinology, Kumamoto University Hospital, 1-1-1 Honjo, Chuo-Ward, Kumamoto, 860-8556, Japan.
Department of Diagnostic Pathology, Department of Clinical Research, National Hospital Organization, Hakodate Hospital, 16-18 Kawahara, Hakodate, Hokkaido, 041-8512, Japan.
BMC Endocr Disord. 2022 Jul 19;22(1):184. doi: 10.1186/s12902-022-01090-8.
Ectopic ACTH-dependent Cushing syndrome is rarely caused by pheochromocytoma (PCC). Glucocorticoid-regulated positive feedback loops in ACTH and catecholamines were proposed in some similar cases.
We present here an 80-year-old man who had previously undergone surgery for a left adrenal PCC and newly developed severe hypertension, hypokalemia, and typical Cushingoid manifestations. Investigations revealed hyperglycemia, hypokalemia, and extremely high catecholamines and their metabolites, ACTH and cortisol. Imaging modalities showed a recurrent large left adrenal mass positively visualized with I-metaiodobenzylguanidine as well as somatostatin receptor scintigraphy. Surgical interventions were not indicated; thus, metyrapone, phentolamine, and doxazocin were initiated, which successfully controlled his symptoms and biochemical conditions. With the evidence that metyrapone administration decreased ACTH and catecholamine levels, the existence of positive feedback loops was speculated. During the terminal stages of the disease, additional metyrosine treatment successfully stabilized his physiological and biochemical conditions. Upon the patient's death, pathological autopsy was performed. Immunohistochemical analysis indicated that the tumor appeared to be co-positive with tyrosine hydroxylase (TH) as well as ACTH in most tumor cells in both PCC and liver metastasis. Most cells were clearly positive for somatostatin receptor 2 staining in the membrane compartment. The dense immunostaining of ACTH, TH, dopamine-β-hydroxylase and the large tumor size with positive feedback loops may be correlated with high levels of ACTH and catecholamines in the circulation.
We experienced a case of severe ectopic ACTH producing the largest reported recurrent malignant left PCC with liver metastases that presented positive feedback loops in the ACTH/cortisol and catecholamine/cortisol axes. Clinicians should be aware of the paradoxical response of ACTH on metyrapone treatment and possible steroid-induced catecholamine crisis.
异位 ACTH 依赖性库欣综合征很少由嗜铬细胞瘤（PCC）引起。在一些类似病例中，提出了 ACTH 和儿茶酚胺的糖皮质激素调节正反馈环。
我们在此介绍一位 80 岁男性，此前因左侧肾上腺 PCC 接受了手术治疗，新出现严重高血压、低血钾和典型库欣表现。检查发现血糖升高、低血钾和儿茶酚胺及其代谢物、ACTH 和皮质醇极高。影像学检查显示左侧肾上腺复发性大肿块，I-间碘苄胍正位显影，生长抑素受体闪烁显像也显影。手术干预不适用；因此，开始使用美替拉酮、酚妥拉明和多沙唑嗪，成功控制了他的症状和生化状况。由于美替拉酮给药降低了 ACTH 和儿茶酚胺水平的证据，推测存在正反馈环。在疾病的终末期，额外的间酪氨酸治疗成功稳定了他的生理和生化状况。在患者死亡后进行了尸检。免疫组织化学分析表明，肿瘤在大多数 PCC 和肝转移瘤细胞中似乎与酪氨酸羟化酶（TH）以及 ACTH 共阳性。大多数细胞在膜区明显对生长抑素受体 2 染色呈阳性。ACTH、TH、多巴胺-β-羟化酶的密集免疫染色和大肿瘤尺寸与循环中 ACTH 和儿茶酚胺水平升高相关，可能与 ACTH 产生的异位产生相关。
我们遇到了一例严重的异位 ACTH 产生的最大报道的复发性恶性左侧 PCC 伴肝转移，其在 ACTH/皮质醇和儿茶酚胺/皮质醇轴中存在正反馈环。临床医生应注意美替拉酮治疗时 ACTH 的矛盾反应和可能的类固醇诱导的儿茶酚胺危象。
