Title

A sweet enigma: Ectopic Cushing's Syndrome

Authors

1. Likhita Kandimalla, MD, Department of Internal Medicine, University of Tennessee College of Medicine Chattanooga 2. Ty Poston, DO, Department of Internal Medicine, University of Tennessee College of Medicine Chattanooga 3. Maria E. Tudor, DO, Department of Internal Medicine, University of Tennessee College of Medicine Chattanooga 4. Abhinaya Jawahar, MD, Department of Internal Medicine, University of Tennessee College of Medicine Chattanooga

Introduction

Cushing’s syndrome is a state of hypercortisolism that occurs either due to ACTH-dependent or ACTH-independent etiologies. Cushing’s syndrome due to ectopic ACTH secretion (EAS), also called paraneoplastic Cushing’s syndrome is an infrequent form of ACTH-dependent Cushing’s syndrome, that is usually associated with intense hypercortisolism. We present a case of ectopic Cushing’s syndrome due to paraneoplastic ACTH secretion from a neuroendocrine tumor (NET).

Case Presentation

A 67 year old woman with past medical history of poorly controlled type 2 diabetes mellitus, hypertension and morbid obesity presented for evaluation of generalized weakness and dyspnea. She denied any history of exogenous steroid use, new headaches or vision changes. Physical exam revealed moon facies, hirsutism, supraclavicular and dorsal fat pads, violaceous abdominal striae, skin bruises and decubitus ulcers. Lab work up revealed potassium 2.9 mmol/L (range 3.5-5.1), glucose 389 mg/dL, random ACTH 100 pg/mL (range 7.2-63.3) and cortisol 160 ug/dL (range 2.9-17.3). 2 mg dexamethasone suppression test resulted in a non-suppressed 8AM cortisol of 135 ug/dL. 24-hour urine cortisol was 9056 mcg (range 4-50). CT chest and abdomen revealed bilateral adrenal nodules with unclear characteristics and 2 pulmonary nodules in addition to an acute pulmonary embolism (PE) that was treated with anticoagulation. Pituitary MRI showed a 4mm left sided pituitary adenoma which initially raised suspicion for Cushing’s disease due Pituitary ACTH secretion. However, inferior petrosal sinus sampling revealed petrosal sinus to peripheral ACTH ratios <2 pre-cosyntropin administration and <3 post-cosyntropin administration, confirming an ectopic ACTH source. She was started on a steroidogenesis inhibitor (osilodrostat); the dose was gradually increased to 3mg twice a day with significant improvement in 24 hour urinary cortisol to 9mcg and serum cortisol to 25 ug/dL along with overall clinical improvement. Subsequent PET DOTATATE scan revealed uptake in left upper, right lower pulmonary nodules and pancreatic head, suspicious for metastatic pancreatic NET. The left upper lobe pulmonary nodule was biopsied & found to be a carcinoid tumor. Following this, she was started on sandostatin (somatostatin analogue) and is under evaluation for eventual surgical resection of NET.

Discussion

Cushing’s syndrome results in a hypercortisolic state posing a high mortality risk due to adverse cardiovascular events (PE, arrhythmias), increased infection risk, muscular wasting, acute respiratory distress, hyperglycemia, electrolyte imbalances, osteoporosis and decubitus ulcers. This patient had a PE which occurred due to high risk of hypercoagulability and thromboembolism in Cushing’s syndrome and is one of the main causes of mortality in this condition. EAS is a rare, often severe disease. It’s management is complex and requires expertise in two distinct areas: diagnosis and treatment of Cushing's syndrome and treatment of neuroendocrine tumors. Although the ideal treatment is excision of the ACTH-secreting endocrine tumor, it may be impossible to perform initially in patients with occult or metastatic tumors; or when the intensity of hypercortisolism and its associated complications prevent surgery. Hypercortisolism must be controlled without delay and frontline treatment should consist of high-dose, fast-acting steroidogenesis inhibitors or adrenalectomy.

References

1. Jacques Young1, Magalie Haissaguerre2, Oceana Viera-Pinto1, Olivier Chabre3, Eric Baudin4 , Antoine Tabarin2 . Cushing’s syndrome due to ectopic ACTH secretion: an expert operational opinion. European Journal of Endocrinology, Volume 182, Issue 4, Apr 2020, Pages R29–R58, https://doi.org/10.1530/EJE-19-0877 2. John M Uecker 1 , Matthew T Janzow. A case of Cushing syndrome secondary to ectopic adrenocorticotropic hormone producing carcinoid of the duodenum. Am Surg. 2005 May;71(5):445-6. PMID: 15986979 3. Michael T. McDermott. Endocrine secrets, 7th edition