An Uncommon Case of Ectopic Adrenocorticotropic Hormone Syndrome from a Pancreatic Neuroendocrine Tumor

Ectopic adrenocorticotropic hormone (ACTH) syndrome is a rare form of Cushing disease (CD) with over-secretion of ACTH from nonpituitary tumor outside the adrenal or pituitary glands. Its diagnosis relies on both biochemical tests (high-dose dexamethasone suppression test, ACTH level, corticotropin-releasing hormone test) to confirm ACTH-dependent CD and image studies (CT or MRI of chest, abdomen, and/or pelvis) for source localization. We present a rare case of ectopic ACTH syndrome from a pancreatic neuroendocrine tumor (NET).


Introduction
Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is one type of Cushing disease (CD) where the source of ACTH is outside the pituitary gland. It is associated with a variety of benign or malignant tumor types, predominantly pulmonary, thymic, and pancreatic carcinoids, small cell lung carcinoma, pheochromocytoma, medullary thyroid carcinoma, and prostate carcinoma [1][2][3][4][5]. EAS rarely can be associated with nonendocrine, nonpulmonary tumors. Here we report a rare case of ectopic ACTH syndrome from a pancreatic neuroendocrine tumor (NET).

Case Presentation
A sixty-four-year-old female with a past medical history of newly diagnosed hypertension (HTN), type two diabetes mellitus, and hyperlipidemia presented with worsening generalized weakness and bilateral lower extremity swelling for two to three months. She also reported occasional flushing and easy bruising. She gained 20 pounds over six months with centrally distributed fat.
She was recently diagnosed with HTN and diabetes type two by her primary care physician. Routine lab work also showed hypokalemia. Examination revealed high blood pressure and tachycardia with two plus pretibial pitting edema bilaterally.
Due to the combination of recently diagnosed HTN and diabetes type two with hypokalemia, the patient underwent a workup for Cushing syndrome. Cortisol level in the early morning was 45 ug/dL (normal range: 7-28 μg/dL), and ACTH was 444 pg/mL (normal range: 10--60 pg/mL). High-dose dexamethasone suppression test was positive. Prolactin, insulin-like growth factor 1 (IGF-1), and thyroid-stimulating hormone (TSH) were all within normal limits. Subsequently, the patient had an MRI of brain which was negative for any mass. However, the CT scan of abdomen/pelvis with contrast revealed a mass in the pancreas with multiple liver lesions and lymphadenopathy ( Figure 1). Pathology of the pancreatic mass which was obtained via endoscopic ultrasound (EUS) confirmed a well-differentiated intermediate-grade NET. Subsequently tumor markers were checked. Carbohydrate antigen (CA) 19-9 was 41.1 U/mL (normal range: 0-35 U/mL). Carcinoembryonic antigen (CEA) was 4.7 ng/mL (normal range: 0-5 ng/mL). Chromogranin A was 210 ng/mL (normal range: 0-95 ng/mL). The patient was evaluated for possible Whipple procedure. However, she was deemed not a candidate due to significant liver tumor burden. Her clinical course deteriorated rapidly despite medical management. She passed away two months after the diagnosis of the pancreatic NET.

FIGURE 1: CT scan of abdomen with intravenous contrast.
There is an ill-defined hypo-enhancing mass in the superior aspect of the pancreatic head which measures approximately 3.2 cm x 2.9 cm.
Ectopic adrenocorticotropic hormone syndrome may cause significant comorbidity in patients with underlying malignancy and severe hypercortisolism [3,8]. Surgical removal of the tumor can result in full recovery in some cases; however, it may recur later on. If surgery is not an option due to severe metastatic disease, a multidisciplinary approach should be adopted to control tumor growth and associated symptoms. These approaches may include somatostatin analog therapy, peptide receptor radionuclide therapy, chemotherapy, radiotherapy, and/or targeted therapies [3]. In such cases, control of the hypercortisolemia can be achieved with long-term adrenolytic medication, such as methyrapone, ketoconazole, mitotane, or even etomidate [8,12].

Conclusions
Pancreatic NET is a rare cause of ACTH-dependent Cushing syndrome. Suspicion for this condition should be raised in patients without primary pituitary lesion and other apparent sources. Diagnosis is based on biochemical tests to confirm EAS and imaging studies for tumor localization. Treatment should focus on resection, chemo-radiation, and hormone analogs. Close follow-up is very important in this rare yet aggressive tumor.

Additional Information Disclosures
Human subjects: Consent was obtained by all participants in this study.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.