ACTH-Dependent Cushing’s Syndrome in an Elderly Woman with Pituitary, Adrenal, and Intrathoracic Lesions

Abstract

A 77-year-old female with rheumatoid arthritis on etanercept, depression on venlafaxine, and treated hypothyroidism presented with easy bruising and muscle weakness. She denied any steroid use. She had normal BP and BMI, but appeared mildly Cushingoid with round facies, and increased dorsocervical and supraclavicular fat.Laboratory evaluation showed: ACTH 70.8 pg/mL (< 63.3), cortisol 24.3 ug/dL, 24 h urine free cortisol 223 ug (< 50), salivary cortisol 0.428 ug/dL, DHEA-S 165.7 ug/dL (< 142.8), LH 0.1 mIU/mL, FSH 2.7 mIU/mL, and hgbA1C 6.1 % (< 5.6 %). All other hormonal testing was normal. MRI of the pituitary showed a 4 x 2 x 3 mm hypoenhancing defect of the anterior pituitary. CT of the chest and abdomen showed a 1.1 cm left adrenal nodule, and a 1 cm non-specific right middle lobe lung nodule. Inferior petrosal sinus sampling (IPSS) with CRH did not show a central ACTH step-up. PET/CT with DOTATATE showed mildly increased tracer uptake in the right middle lobe measuring 1 cm with SUV max 3.7, and a 0.6 cm left apical subpleural nodule with SUV max 1.9.The patient underwent a right middle lobectomy and pathology was positive for typical carcinoid. Post-operatively, she needed hydrocortisone replacement for 9 months. ACTH was 19.7 pg/dL, cortisol 9.5 ug/dL, DHEA-S 31.3 ug/dL, LH 61.8 mIU/mL, and FSH 112.4 mIU/mL. Her Cushingoid features and myopathy resolved.This case highlights several challenges in the diagnosis and source localization in patients with ACTH-dependent Cushing’s Syndrome (CS). In this slim, elderly female, the typical features of CS were subtle. In addition, dynamic biochemical testing with high dose dexamethasone does not reliably distinguish eutopic from ectopic ACTH-dependent CS, as the sensitivity and specificity range from 60–80%. Thus, the diagnosis largely depends on sophisticated imaging and IPSS.The patient had pituitary, adrenal, and lung lesions. The pituitary lesion initially pointed towards a central ACTH source, but IPSS was negative. The prevalence of pituitary incidentalomas is high, at 10.6% based on autopsy data, with an increasing proportion being recognized in the elderly. Adrenal incidentalomas are also often noted in older individuals, but that was clearly not the cause of CS in this patient with a non-suppressed DHEA-S and elevated ACTH. PET/CT with DOTATATE has emerged as a sensitive test for the detection of often small tumors producing ectopic ACTH and was positive in the lung lesion. In spite of newer localization techniques, the source of ectopic ACTH often remains unidentified (12.5% in a large retrospective case-record study). False negatives on PET/CT with DOTATATE imaging may be due to cortisol’s suppressive effect on the somatostatin receptor expression in neuroendocrine tumors. Thus, in cases of ACTH-dependent CS with negative IPSS, ectopic ACTH must remain as a likely source, and be re-explored after medical treatment of the hypercortisolism.