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) 

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This is the largest series of ACTH-secreting NETs in the pancreas and thymus from a single institute (n = 27) reported out of the few studies focusing on the clinical features and prognosis of ACTH-secreting pNETs. In our study, all patients had CS, but hypokalemia and severe fatigue were the first symptoms instead of a moon face or truncal obesity, which suggested that the serum cortisol level increased rapidly, as was reported previously.[1] ACTH-secreting pNETs had similar levels of cortisol and other laboratory indices as ACTH-secreting TNETs, which shared common clinical features with EAS. Three patients were bedridden with severe fatigue or pneumonia and were contraindicated to undergo HDDST, with extremely high cortisol levels. Patients with ACTH-secreting TNETs mainly experienced metastasis to nearby lymph nodes (8 of 20), 2 (2 of 20) had bone metastasis, and 1 had peritoneal metastasis; however, patients with ACTH-secreting pNETs mostly experienced liver metastasis (2/7). One patient (Case 7) even experienced metastasis to both adrenal glands, which is rarely seen.

Furthermore, ACTH-secreting pancreatic tumors may not be neuroendocrine tumors.[14] ACTH-secreting pancreatic acinar cell carcinoma was previously reported with positive trypsin and negative SYN and CgA;[22] mixed neuroendocrine-non neuroendocrine neoplasms producing ACTH were also reported.[23] In our study, Case 7 had positive staining for trypsin at the same time. This patient had a short course from onset with the highest cortisol level and most places of metastasis.

ACTH-secreting pNETs could be isolated (Cases 1, 2, and 3), locally advanced (Case 4) or metastasized (Cases 5, 6, and 7);[22] the clinical and biological behaviors were once poorly understood, and evidence-based or guided treatment is limited.[24,25] For early-stage tumors with controlled CS and infection, surgery showed satisfactory outcomes (Case 1 and Case 3); compared with other patients, their serum cortisol and plasma ACTH levels were relatively lower, and their disease courses were relatively longer, which means that the tumor progressed slowly. Three patients (Cases 2, 4, and 7) had uncontrolled hypercortisolemia and infection preoperatively. They were all complicated with more severe infections postoperatively, which eventually led to death. As immune function is always impaired by increased cortisol secretion, severe infections or even sepsis could happen.[9] In our series, 6 patients underwent surgery. Four patients had tumors in the uncinate process, and 3 of them underwent simple enucleation. Some retrospective studies have demonstrated that pNETs, including smaller tumors, are associated with lymph node metastasis.[5,26] Until now, there has been no high-level trial confirming the superiority of standard pancreatectomy with regular lymphadenectomy compared with single enucleation, especially for ACTH-secreting pNETs.[5] A curative multiorgan resected pancreatectomy plus lymphadenectomy may worsen the patient's condition and may increase surgery-related complications. Some papers also reported that after removal of the primary lesions, hormone secretion could disappear and prolong the progression of metastasis, indicating that metastasis ability might be impaired.[27] Due to this heterogeneous nature, we tried to resect the primary lesion in the body of the pancreas of Case 7; unfortunately, no remission was achieved. However, with the whole primary specimen, we could finally evaluate the pathological grade and might develop a further therapeutic strategy. A further study focusing on the functional location of this kind of tumor might be strongly needed, such as selective arterial calcium stimulation and hepatic venous sampling in locating insulinoma.

Compared with ACTH-secreting TNETs, the metastases of ACTH-secreting pNETs were more frequent with a poorer prognosis, which is in accordance with the findings of the previous study.[2] For TNETs, the prognosis is generally inferior to that of other NETs of similar stages.[28] The literature shows that an increased Ki-67 index and tumor grade are related to a poor prognosis for pNETs;[29] meanwhile, the overall prognosis of EAS patients is mainly determined by the tumor grade and stage at the time of diagnosis.[10] However, Ki-67 indices were similar among 2 groups. In our series, the only 2 survivors were G1, and the average time from onset to treatment was 8 months for ACTH-secreting pNETs, while for ACTH-secreting TNETs, it was 3 months, which means that the formal tumor was actually diagnosed and treated later. For ACTH-secreting TNETs, survival was better for those patients who underwent surgery than those who did not.[30] However, for ACTH-secreting pNETs, surgery does not always seem to be the best option. Patients commonly had severe infections, unresectable primary tumors or functional metastases, so lowering serum cortisol was the first option. In our series, after surgery, the patients mostly died from hypercortisolemia complicated events. Pancreatic surgery was inherently associated with more morbidity and mortality than other surgeries.[31] Thus, a multidisciplinary discussion and a cautious assessment before surgery should be recommended as priority, even in emergency cases.[9,32–34] Only patients with a resectable primary tumor in the pancreas with expected normalized cortisol should be recommended for surgery; otherwise, lowering hypercortisolemia has priority as the treatment.

A bilateral adrenalectomy by stage or simultaneously could be performed to palliate the symptoms.[33,35–38] Two of our patients (Cases 4 and 7) underwent a 2-stage adrenalectomy (these patients did have another choice) and showed different partial remission responses. Case 7 should have underwent a second removal of the remnant adrenal gland, but she remained in the intensive care unit and was seriously infected after the surgery, being incapable to tolerate a second aggressive surgical approach.[39] Thus, for better measure, a simultaneous bilateral adrenalectomy should be performed during the first surgery. Medical treatment includes cortisol-lowering medicines (ketoconazole, metyrapone, and mitotane are all unavailable in mainland China), chemotherapy,[40] and targeted agents such as everolimus, sunitinib, or even peptide receptor radiotherapy.[41] SSA has been the first choice for the management of clinical symptoms related to functioning pNETs and is often combined with new targeted agents as well as chemotherapy.[42] In our series, the ACTH and UFC levels of Case 4 declined with SSA and everolimus. In Case 7, metyrapone was given after surgery, and the UFC level declined to the normal range.

Hypercortisolemia is the main cause of the high morbidity in patients with ACTH-secreting pNETs.[10] Because of this complexity and the difficulty of treatment, exploring the mechanisms of ACTH production in pNETs is particularly important. The promoter of POMC is embedded within a defined CpG island, and much of this CpG island is methylated in normal nonexpressing tissues. E2F factors binding to the upstream domain IV region of the promoter have been shown to be involved in the expression of POMC in other NETs.[12,13] In our previous study, we found hypomethylation in ACTH-secreting TNETs compared with the normal thymus.[13] In this study of 5 ACTH-secreting pNETs, compared with nf-pNETs, we also found that Domain IV in the POMC promoter showed hypomethylation (significantly on the second site, P < .05). Finally, compared with normal pancreas, hypomethylation in ACTH-secreting pNETs was also significantly lower, even in all 4 sites in the POMC promoter, which might indicate the same mechanism of ectopic ACTH production. However, we did not find that methylation had any correlation with the hormone level, which means that hypomethylation is probably a "switch" for ACTH production but does not reflect clinical or laboratory features. The DNA methylation imprint of a tumor cell is thought to occur at an early time point during tumorigenesis, and our data imply a distinct tumor pathogenesis of ACTH-secreting pNETs.[43] This is the first study illustrating hypomethylation of the POMC promoter contributing to ACTH secretion in pNETs and may reveal the same mechanism for EAS. Both ACTH-secreting pNETS and TNETs had shorter survival time than nf-NETs.[30,44] This result may provide us with a therapeutic target for ACTH-secreting pNETs to prolong the survival of these patients.

For reasons of rarity, this was a retrospective study with limited sample size, and an optimal and individualized approach was created according to the condition of each patient. Prospective studies are expected to provide better treatment strategies. Cortisol-lowering drugs are not available in mainland China, and surgery is the only rapid way to decrease cortisol (tumor resection) or improve CS (adrenalectomy). A different prognosis between ACTH-secreting pNETs and TNETs was found but pancreatic resection was not always promising.

In conclusion, ACTH-secreting pNETs have high metastasis and mortality rates and thus a poor prognosis. Before any treatment, mitigation measures are needed after multidisciplinary discussion. The control of cortisol levels offers the best opportunity for prolonging survival; thus, surgery is reasonable for resectable primary lesions. Compared with nf-pNETs and normal pancreatic tissue, ACTH-secreting pNETs were associated with hypomethylation in the POMC promoter upstream region. This study acts as a supplement to the genetic features of ACTH-secreting pNETs.