Ectopic ACTH syndrome in the course of ACTH-secreting pancreatic neuroendocrine tumour in a patient with a pituitary lesion - diagnostic challenges and individual approach.

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Two cases of pancreatic neuroendocrine tumors with ectopic ACTH syndrome during their disease course.

Pancreatic neuroendocrine tumors (PanNETs) are rare malignant tumors that occur in the pancreas. They are divided into functioning and non-functioning tumors based on the presence or absence of their specific hormonal hyper-expression symptoms. Adrenocorticotropic hormone (ACTH)-producing PanNETs are rare, functional tumors, and their clinical characteristics and outcomes have not been well reported.Here, we report the cases of two patients with PanNETs who presented with ectopic ACTH syndrome (EAS) during the course of their disease. Case 1 involved a non-functioning PanNET at the time of surgery. During treatment for recurrent liver metastases, the patient presented with EAS and tumor-associated hypercalcemia, probably due to ACTH and parathyroid hormone-related peptide (PTHrP) production from the liver tumor. Case 2 was a gastrinoma, and similar to Case 1, this patient presented with EAS during the treatment of recurrent liver metastases.It is not uncommon for patients with PanNETs to have multiple hormones and develop secondary hormone secretion during their disease course, although tumor phenotypes differ between primary and metastatic sites. In patients with functioning PanNETs, symptom control with anti-hormonal therapy is essential, in addition to anti-tumor therapy, especially for EAS, which is an endocrine emergency disease that requires prompt diagnosis and treatment.

An Overlooked Manifestation of Hypercortisolism: Cerebral Cortical Atrophy and Challenges in Identifying the Etiology of Hypercortisolism - A Report of 2 Pediatric Cases.

INTRODUCTION: Endogenous Cushing's syndrome (CS) is a rare, severe disease that can cause multiple systemic involvements and behavioral problems due to excessive cortisol production. Structural changes can be noted in the brain magnetic resonance imaging (MRI) scans of these cases. CASES: A 9-year-old girl and a 13-year-old boy were admitted with hypercortisolism. In the female patient, altered consciousness was prominent along with cerebral and cerebellar brain atrophy, and findings indicating posterior reversible encephalopathy syndrome were detected in the brain MRI. Although the male patient's neurological examination was normal, significant cerebral atrophy was seen in the brain MRI. Case 1 was diagnosed as having ectopic ACTH syndrome (EAS) due to a thymic carcinoid tumor. Case 2 underwent a pulmonary lobectomy upon detection of a bronchial lesion in the Ga-68 DOTATATE PET/CT scan while being examined for EAS due to a lack of suppression in the high-dose dexamethasone suppression test. However, hypercortisolism persisted despite the removal of the bronchial lesion, and subsequently, a diagnosis of Cushing's disease was established following bilateral inferior petrosal sinus sampling. DISCUSSION: Endogenous hypercortisolism may cause brain atrophy of varying severity. The central nervous system findings can be overlooked in children with CS. More comprehensive studies are needed to better understand the behavioral changes caused by the effects on the brain and to evaluate whether these changes are reversible. In addition, identifying the source of hypercortisolism can be difficult due to a lack of experience related to the rarity of the disease in children.

Atypical thymic carcinoid tumor with ectopic ACTH syndrome in a 33-year-old male patient: A rare case report and literature review.

RATIONALE: Atypical thymic carcinoid tumor is an exceedingly rare thymic neuroendocrine tumor derived from the cells of neuroendocrine system. Misdiagnosis or delayed diagnosis may result in disease progression to advanced stages and eventually leads to a poor prognosis. It is therefore necessary to make a correct diagnosis and provide an adequate treatment. PATIENT CONCERNS: A 33-year-old Chinese male presented with numbness in bilateral lower extremities and general fatigue for a month. Chest computed tomography revealed a superior anterior mediastinal mass. Thymoma was initially considered, given the location of the mass and radiographic presentation. DIAGNOSIS: Microscopic findings showed that the tumor cells are arranged in pseudoepitheliomatous growth or irregular nested growth pattern in a background of fibroconnective tissue, with focal infiltration into adipose tissue. The chrysanthemum-like structure or beam-like structure seen often in typical carcinoid tumor was not identified in this case. The tumor cells are spindled or oval, with focal active mitosis. The immunohistochemical staining showed strong positivity for CD56, CgA and Syn, positivity for CK, ACTH, and TTF-1, negativity for Vimentin, and ki67 labeled proliferation index was up to 10% in focal areas. According to the radiological and pathological findings, the diagnosis of atypical thymic carcinoid was made. INTERVENTIONS: The patient underwent surgical resection of the mass. OUTCOME: No recurrence or metastasis was identified during the follow up. LESSONS: Because of its low incidencen, onspecific clinical symptoms, tissue location, and radiological findings, atypical thymic carcinoid tumor may sometimes be misdiagnosed as thymoma. Attention should be paid to avoid misdiagnosis.

Ectopic sphenoidal ACTH-secreting adenoma revealed by 11C Methionine PET scan: case report.

BACKGROUND: Ectopic ACTH pituitary adenomas (EAPA), located outside the sella turcica and deriving from cellular remnants of Rathke's pouch are a very rare cause of Cushing's syndrome (CS). The diagnosis is often difficult and delayed, even after comprehensive work-up. To our knowledge, we report for the first time an ectopic corticotroph tumor of the posterior wall of the sphenoid sinus, leading to false positive results of bilateral inferior petrosal sinus sampling (BIPPS) and which was finally localized by a co-registered11 C Methionine PET/MR imaging. CASE PRESENTATION: A 48-year-old woman was referred for a high clinical suspicion of ACTH-dependent CS. Biological testing comprising low dose dexamethasone suppression and CRH stimulation tests were indicative of pituitary Cushing's disease, but comprehensive pituitary MRI did not reveal any pituitary adenoma. BIPSS confirmed however a central origin of ACTH secretion (central-to-peripheral ACTH ratio > 100) and revealed a significant right-to-left gradient (6.2), leading to a first right-sided exploratory hypophysectomy, that did not cure the patient. BIPSS images were reviewed and revealed preferential drainage of the left pituitary to the right petrosal sinus, leading us to a left sided exploratory hypophysectomy, which was again unsuccessful. A11 C Methionine PET/MRI was performed and revealed a hypermetabolic lesion adjacent to the posterior wall of the sphenoidal sinus. After surgical resection, this polypoid mass was identified as an ectopic ATCH-secreting pituitary adenoma expressing ACTH and T-Pit and complete remission of hypercortisolism was observed. CONCLUSIONS: In conclusion, we report a case of ACTH-dependent Cushing's syndrome, caused by an ectopic corticotroph adenoma located in the sphenoidal sinus, which perfectly mimicked the biological features of a classical pituitary ACTH adenoma on a comprehensive hormonal evaluation including BIPPS, and the features of a benign naso-sinusal polyp at MRI. We report for the first time a key role of11 C Methionine PET co-registered to high resolution MRI for localizing ectopic adenomas, efficiently guiding surgical removal and leading to complete remission of hypercortisolism.

Clinical profile and treatment outcomes of patients with ectopic ACTH syndrome compared to Cushing disease: a single-center experience.

PURPOSE: We aimed to evaluate and compare the clinical, biochemical and radiological profile and outcomes of patients with ectopic ACTH syndrome (EAS) and Cushing disease (CD) treated over a period of 10 years (2013-2022). METHODS: In this ambispective observational study, we collected data for 146 patients with ACTH-dependent CS (EAS, n = 23; CD, n = 94; occult ACTH source, n = 29). Relevant details were filled in a predesigned proforma and outcomes were ascertained at the most recent visit. RESULTS: EAS was more common in males (65.2 vs. 27.6%, p < 0.001). Patients with EAS had a shorter duration of symptoms [12 (6-12) vs. 31.5 (15-48) months, p < 0.001] and were more likely to have hypokalemia (82.6 vs. 21.0%, p = 0.001), pedal edema (65.2 vs. 34.2%, p = 0.015), weight loss (34.8 vs. 4.0%, p < 0.001) and systemic infection (30.4 vs. 6.5%, p = 0.006). They also had significantly higher 8 a.m. serum cortisol, midnight serum and salivary cortisol and 8 a.m. plasma ACTH levels. Bronchial carcinoid (n = 10, 43.5%) was the most common etiology of EAS. Bilateral adrenalectomy was performed in 11 (47.8%) patients with EAS. Eight patients (34.8%) with EAS died at the last follow-up, of whom 7 (87.5%) had metastatic disease. In CD group, overall remission rate was 69.4% (56.1%, early and 13.3%, delayed) and 26.3% of patients with an initial remission had recurrence. CONCLUSIONS: Bronchial carcinoid was the most common cause of EAS in our cohort. Bilateral adrenalectomy was performed in approximately every 1 in 2 patients with EAS and approximately every 1 in 3 patients expired till the last follow-up.

Ectopic adrenocorticotropic hormone-secreting carcinoid with solitary cryptococcosis in the lungs.

BACKGROUND: Carcinoid tumors can on rare occasions ectopically produce adrenocorticotropic hormone (ACTH), causing Cushing's syndrome, and patients could become immunocompromised. Care must therefore be taken regarding infectious complications. In particular, ACTH-producing pulmonary carcinoid is not easy to diagnose by itself, and when combined with pulmonary nodules as infectious foci, each is very difficult to diagnose. CASE: The patient was a 71-year-old woman with refractory diabetes. She showed clinical symptoms of Cushing's syndrome during treatment for diabetes and ectopic ACTH production was suspected based on biochemical and imaging tests. Nodules were identified in the left lung apex and lingual segment. Examination of resected nodules revealed that the nodule in the apex was pulmonary cryptococcosis, while the nodule in the lingual segment represented typical carcinoid. After surgery, clinical symptoms, laboratory findings, and diabetes all improved. CONCLUSION: We present this very instructive case in terms of the difficulty of diagnosing ACTH-producing tumors, the possibility of infection complicating the immunodeficiency caused by ACTH-producing tumors, and the surgical strategy.

ACTH-secreting parotid acinic cell carcinoma unusually reported as a paraneoplastic syndrome.

Paraneoplastic syndromes, induced by an immunological cross-reaction or hormone/peptide secretion, are an atypical presentation of tumors. Some tumors, such as small cell lung cancer and bronchial carcinoid, can be adrenocorticotropic hormone (ACTH) secreting tumors. Less commonly, parotid acinic cell carcinoma can be ACTH-secreting tumor leading to Cushing's syndrome. Few literature cases have described ACTH related paraneoplastic syndrome of parotid adenocarcinoma. Because of the rarity of the condition, little is known about the management and prognosis of this phenomenon. In this report, we highlighted the case of a 59-year-old male with a past medical history of parotid adenocarcinoma treated with surgery, chemotherapy, and radiation therapy presented with clinical and biochemical signs of hyperaldosteronism. Abdominal ultra-sound, computed tomography, and magnetic resonance imaging showed hepatic mass. Liver biopsy with immunohistochemistry confirmed the presence of parotid adenocarcinoma secreting ACTH. He is on paclitaxel and carboplatin medication with good clinical response.

Ectopic ACTH-producing neuroendocrine tumor occurring with large recurrent metastatic pheochromocytoma: a case report.

BACKGROUND: 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. CASE PRESENTATION: 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 123I-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-ß-hydroxylase and the large tumor size with positive feedback loops may be correlated with high levels of ACTH and catecholamines in the circulation. CONCLUSIONS: 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.

Ectopic ACTH syndrome in a patient with Crohn's disease.

We present the case of a 62-year-old man with Crohn's disease who consulted for abdominal pain and lower limbs edema. The patient developed Cushing's syndrome due to ectopic secretion of ACTH. Diagnostic imaging tests showed multiple metastatic liver lesions and asymmetric thickening of the ileum, that was suspected as the primary tumor. This tumor produced destabilizing gastrointestinal bleeding and an urgent surgical resection was performed. The histopathological study of the resection specimen confirmed a grade 3 neuroendocrine tumor.

Cushing syndrome due to ectopic ACTH secreting pheochromocytoma.

In this case report, we present a case of a woman in her late 30s who presented with bilateral motor weakness, headache, hyperglycaemia and hypertension. Investigations revealed very high 24-hour urine cortisol of 90 524, ectopic adrenocorticotropic hormone secreting pheochromocytoma, normal metanephrine levels and empty sella, which has never been reported. CT chest and abdomen revealed enlarged left adrenal gland with large necrotic mass 4.7×4.0 cm most likely neoplastic lesion. The patient was cured after surgical removal of the left adrenal mass. Histological examination revealed 3.5×2.5×2 cm mass consistent with pheochromocytoma. After surgery and a short stay in the intensive care unit, the patient started improving and both antihypertensive treatment and insulin injections were withdrawn.

Pancreatic neuroendocrine tumor with ectopic adrenocorticotropic hormone syndrome: a case report and 5-year follow-up.

Pancreatic neuroendocrine tumors (P-NETs) secreting ectopic adrenocorticotropic hormones (ACTH) are rare and often delayed in diagnosis due to their atypical clinical characteristics. Here, we describe a case of P-NET in the pancreatic tail. The tumor had metastasized to the liver and secreted gastrin and ACTH. A 60-year-old female patient was diagnosed with gastrinoma in the pancreatic tail with liver metastases in 2015. After 3 months, the patient presented refractory hypokalemia and thyroid dysfunction. The final diagnosis was P-NET with ectopic ACTH syndrome (EAS). After cytoreductive surgery and the use of long-acting somatostatin analogs, plasma potassium levels and thyroid function were effectively corrected. Although Sandostatin LAR® Depot and proton pump inhibitors (PPIs) were used throughout the follow-up period, the tumor relapsed 4 years later. After aggressive treatment, including right hepatectomy, microwave coagulation of the left liver, and cholecystectomy, the tumor returned 4 months later. Finally, the patient underwent three hepatic artery embolizations and 12 courses of CAPTEM regimen chemotherapy. The markers of disease were almost maintained in the normal ranges until now. We have followed up on this case for more than 5 years. A timely and comprehensive examination of hormones and immunohistochemistry is essential. The prognosis of P-NET is poor. Regular long-term follow-up and the application of combined therapies are helpful to control the disease and improve the prognosis.

Cushing's syndrome due to adrenocorticotropic hormone-secreting metastatic neuroendocrine tumor of unknown primary origin: a case report and literature review.

BACKGROUND: In this article, we present a case of neuroendocrine neoplasm of unknown primary origin (UPO NEN), which is a rare cause of ectopic Cushing's syndrome (ECS) presenting numerous challenges, together with a literature review. CASE REPORT: A 43-year-old male patient presented with clinical features consistent with Cushing's syndrome (CS) and adrenocorticotropic hormone (ACTH)-dependent hypercortisolemia. Despite a suspicious lesion on pituitary MRI, the high-dose dexamethasone suppression test and bilateral inferior petrosal sinus sampling results were not compatible with Cushing's disease. Bilateral non-homogeneous opacities were observed in the thorax CT of the patient, who also had a history of COVID-19 infection, but no tumoral lesion was detected. When 68Ga-SSTR PET/CT and 18FDG-PET/CT were performed, multiple metastatic foci were detected in mediastinal and hilar lymph nodes and the axial skeleton. Paratracheal-subcarinal lymph nodes were excised mediastinoscopically, and the diagnosis of NEN was made. Histopathological findings indicated that the possible origin was an atypical pulmonary carcinoid with a low Ki-67 labeling index. After controlling hypercortisolemia, a regimen of somatostatin analogs and capecitabine plus temozolomide was decided upon as treatment by a multidisciplinary council. CONCLUSION: This is a challenging case of UPO NEN presenting with ECS and confounding factors, such as previous infection and incidental lesions, during the diagnosis process. The case in question highlighted the fact that atypical pulmonary carcinoid with a low proliferation index may cause visible metastases even when radiologically undetectable.

Ectopic ACTH syndrome caused by thymic neuroendocrine tumor: a case report and literature review.

A 36-year-old woman presented with onset of reduced menstrual flow, gradually progressed to typical Cushingoid features with 24-hour urine free cortisol (UFC) increased, low-dose dexamethasone suppression test and high-dose dexamethasone suppression test both not suppressed, adrenocorticotropic hormone (ACTH) increased, and computed tomography (CT) scan of the chest revealed a large mass in the anterior mediastinum. The local hospital administered mediastinal mass resection which afterwards showed type B1 thymoma. The above symptoms were relieved post-operation, and the levels of ACTH and cortisol decreased. Symptoms recurred 5 months after the surgery, with laboratory and imaging suggested possible multiple tumor metastases. The patient was referred to our hospital and was diagnosed with ectopic ACTH syndrome and thymic neuroendocrine tumor with multiple metastases post-operation. After administered mifepristone to antagonize the glucocorticoid receptor, the patient's symptoms improved. The patient also received "etoposide" single-agent chemotherapy, and the symptoms were relieved after 4 months of follow-up. The case showed that complete surgical resection of the primary tumor is the best treatment for ectopic ACTH syndrome, if the primary tumor which cause ectopic ACTH syndrome cannot be completely cured, it is particularly important to control hypercortisolemia and prevent its complications. This article purports to report this case and review the relevant literature.

Case Report: Three Rare Cases of Ectopic ACTH Syndrome Caused by Adrenal Medullary Hyperplasia.

Ectopic ACTH syndrome (EAS) accounts for 10-20% of endogenous Cushing's syndrome (CS). Hardly any cases of adrenal medullary hyperplasia have been reported to ectopically secrete adrenocorticotropic hormone (ACTH). Here we describe a series of three patients with hypercortisolism secondary to ectopic production of ACTH from adrenal medulla. Cushingoid features were absent in case 1 but evident in the other two cases. Marked hypokalemia was found in all three patients, but hyperglycemia and osteoporosis were present only in case 2. All three patients showed significantly elevated serum cortisol and 24-h urinary cortisol levels. The ACTH levels ranged from 19.8 to 103.0pmol/L, favoring ACTH-dependent Cushing's syndrome. Results of bilateral inferior petrosal sinus sampling (BIPSS) for case 1 and case 3 confirmed ectopic origin of ACTH. The extremely high level of ACTH and failure to suppress cortisol with high dose dexamethasone suppression test (HDDST) suggested EAS for patient 2. However, image studies failed to identify the source of ACTH secretion. Bilateral adrenalectomy was performed for rapid control of hypercortisolism. After surgery, cushingoid features gradually disappeared for case 2 and case 3. Blood pressure, blood glucose and potassium levels returned to normal ranges without medication for case 2. The level of serum potassium also normalized without any supplementation for case 1 and case 3. The ACTH levels of all three patients significantly decreased 3-6 months after surgery. Histopathology revealed bilateral adrenal medullary hyperplasia and immunostaining showed positive ACTH staining located in adrenal medulla cells. In summary, our case series reveals the adrenal medulla to be a site of ectopic ACTH secretion. Adrenal medulla-originated EAS makes the differential diagnosis of ACTH-dependent Cushing's syndrome much more difficult. Control of the hypercortisolism is mandatory for such patients.

Ectopic ACTH secretion from a metastatic gastric carcinoma with neuroendocrine component.

An elderly gentleman was admitted to hospital with severe hypokalaemia of 1.75mmol/L. A background of a recently diagnosed metastatic gastric carcinoma with a neuroendocrine component pointed towards the diagnosis of ectopic ACTH secretion causing this dangerous electrolyte imbalance. He was treated with aggressive potassium supplementation and the adrenal steroid synthesis blocker metyrapone to acutely control his Cushing's syndrome. Chemotherapy consisting of carboplatin/etoposide combination was initiated but unfortunately the patients' health deteriorated, and he died three months after his initial diagnosis. This case highlights the accelerated presentation of hypercortisolism due to ectopic ACTH secretion. It discusses the classification of neuroendocrine tumours and their varied prognosis depending on the underlying tumour grade. It emphasises the importance of having a multidisciplinary team to be able to care for two underlying pathologies simultaneously: both the severe hypercortisolism and his metastatic gastric tumour.

The Mechanisms Underlying Autonomous Adrenocorticotropic Hormone Secretion in Cushing's Disease.

Cushing's disease caused due to adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (ACTHomas) leads to hypercortisolemia, resulting in increased morbidity and mortality. Autonomous ACTH secretion is attributed to the impaired glucocorticoid negative feedback (glucocorticoid resistance) response. Interestingly, other conditions, such as ectopic ACTH syndrome (EAS) and non-neoplastic hypercortisolemia (NNH, also known as pseudo-Cushing's syndrome) also exhibit glucocorticoid resistance. Therefore, to differentiate between these conditions, several dynamic tests, including those with desmopressin (DDAVP), corticotrophin-releasing hormone (CRH), and Dex/CRH have been developed. In normal pituitary corticotrophs, ACTH synthesis and secretion are regulated mainly by CRH and glucocorticoids, which are the ACTH secretion-stimulating and -suppressing factors, respectively. These factors regulate ACTH synthesis and secretion through genomic and non-genomic mechanisms. Conversely, glucocorticoid negative feedback is impaired in ACTHomas, which could be due to the overexpression of 11ß-HSD2, HSP90, or TR4, or loss of expression of CABLES1 or nuclear BRG1 proteins. Genetic analysis has indicated the involvement of several genes in the etiology of ACTHomas, including USP8, USP48, BRAF, and TP53. However, the association between glucocorticoid resistance and these genes remains unclear. Here, we review the clinical aspects and molecular mechanisms of ACTHomas and compare them to those of other related conditions.

High Molecular Weight ACTH-Precursor Presence in a Metastatic Pancreatic Neuroendocrine Tumor Causing Severe Ectopic Cushing's Syndrome: A Case Report.

Ectopic ACTH-secretion causing Cushing's syndrome is unusual and its diagnosis is frequently challenging. The presence of high-molecular-weight precursors throughout pro-opiomelanocortin (POMC) translation by these tumors is often not reported. We present the case of a 49-year-old woman with a 3-month history of proximal muscular weakness, skin pigmentation, and weight loss. Upon initial evaluation, she had a full moon face, hirsutism, and a buffalo hump. Laboratory workup showed hyperglycemia, hypokalemia and metabolic alkalosis. ACTH, plasma cortisol, and urinary free cortisol levels were quite elevated. Serum cortisol levels were not suppressed on dexamethasone suppression testing. An octreo-SPECT scan showed enhanced nucleotide uptake in the liver and pancreas. Transendoscopic ultrasound-guided biopsy confirmed the diagnosis of a pancreatic ACTH-secreting neuroendocrine tumor (NET). Surgical excision of both pancreatic and liver lesions was carried out. Western blot analysis of the tumor and metastases revealed the presence of a high-molecular-weight precursor possibly POMC (at 30 kDa) but not ACTH (normally 4.5 kDa). ACTH-precursor secretion is more frequent in ectopic ACTH-secreting tumors compared with other causes of Cushing's syndrome. Hence, the measurement of such ACTH precursors warrants further evaluation, especially in the context of ACTH-dependent hypercortisolism.

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

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.