The Clinical Features and Molecular Mechanisms of ACTH-Secreting Pancreatic Neuroendocrine Tumors

Cui Zhang; Jiabin Jin; Jing Xie; Lei Ye; Tingwei Su; Lei Jiang; Weiwei Zhou; Yiran Jiang; Luming Wu; Ting Wang; Xu Zhong; Guang Ning; Baiyong Shen; Weiqing Wang


J Clin Endocrinol Metab. 2020;105(11) 

In This Article

Abstract and Introduction


Objective: Pancreatic neuroendocrine tumors (pNETs) causing ectopic adrenal corticotropic hormone (ACTH) syndrome (EAS) are rare and aggressive with little known information. We aimed to elucidate the clinical features and molecular mechanisms of pNETs with EAS by methylation analysis.

Methods: Seven patients with ectopic ACTH-secreting pNETs who were diagnosed at Shanghai Clinical Endocrine and Metabolic Diseases Center and Pancreatic Disease Center in Ruijin Hospital between 2001 and 2019 were enrolled. Twenty patients with ectopic ACTH-secreting thymic neuroendocrine tumors (TNETs) and 7 with nonfunctional pNETs (nf-pNETs) were also enrolled as controls. We collected clinical data and measured POMC promoter CpG methylation.

Results: All 7 patients had elevated ACTH and urinary free cortisol (UFC) levels with positive ACTH staining in the pancreas and were diagnosed with ectopic ACTH-secreting pNET. Of the 7 patients, 6 underwent surgery and 1 underwent transarterial embolization (TAE). Two patients were free of disease after surgery; 2 died within 90 days after surgery; and 3 had metastases and died within 1 year. Compared with ACTH-secreting TNETs, ACTH-secreting pNETs had similar clinical and biochemical features but a significantly poorer prognosis. POMC promoter CpG methylation was significantly lower in ACTH-secreting pNETs than in nf-pNETs and normal pancreas.

Conclusions: ACTH-secreting pNETs are aggressive and fatal. Surgery is definitively curative for patients with resectable primary tumors without metastasis. Pro-opiomelanocortin (POMC) promoter hypomethylation caused pNETs to produce ACTH. This study further supplements the genetic features of ACTH-secreting NETs.


Ectopic adrenal corticotropic hormone (ACTH) syndrome (EAS), accounting for 10% of Cushing syndrome (CS),[1] results in cardiovascular, metabolic, infectious, and skeletal complications, regardless of etiology.[2–4] A total of 4% to 16% of EAS originates in the pancreas, mainly caused by pancreatic neuroendocrine tumor (pNET), which is rarely seen and has only been reported in a single case.[5] The prognosis is poorly understood.

With the development of imaging techniques, especially 68Ga-DOTATATE positron emission tomography (PET)/computed tomography (CT), the localization of pNETs has been clarified.[6,7] There are 2 issues regarding ACTH-secreting pNETs: How to manage them and why they secrete ACTH. Treatments include excision of the primary tumor, bilateral adrenalectomy, transarterial embolization (TAE) of the hepatic metastasis,[8] and medical control of the hypercortisolemia.[9] However, radical surgery has been elusive, as most patients are diagnosed in locally advanced or metastatic stages. In patients with neuroendocrine tumors (NETs), the 5-year survival of EAS patients was significantly shorter than that of non-EAS patients.[10] Therefore, it is meaningful to explore how ACTH is produced in this kind of NET. By comprehending the molecular mechanism, targeted treatment could be possible.[11] The hypomethylation of the POMC promoter has been reported in small cell lung cancer (SCLC),[12] thymic neuroendocrine tumors (TNETs),[13] and pancreatic solitary fibrous tumors,[14] but it has never been studied in pNETs.

In this single-institution study, we analyzed a continuous series of 7 patients with ACTH-secreting pNETs. The clinical characteristics, treatments and prognosis of these patients will be described, and one group of ACTHsecreting TNETs and 1 group of nonfunctional pNETs (nf-pNETs) simultaneously treated will be compared and discussed.