Abstract
Background: ACTH-independent causes of Cushing Syndrome (CS) have mostly benign etiologies. For the majority of these conditions, surgery is the recommended treatment and is nearly 100% curative. Current guidelines do not specify follow up imaging recommendations in patients with resected adenomas. We present a case of severe CS secondary to an adrenal adenoma that was completely resected, and presented later as a metastatic adrenocortical carcinoma (ACC). Clinical Case: A 34- year-old woman presented with worsening confusion, weight gain and new onset diabetes and hypertension. Her history was significant for a 7 cm left adrenal mass and ACTH- independent CS previously treated with left adrenalectomy 2 years prior to this presentation. She was following with an endocrinologist who weaned her hydrocortisone to 10-5 mg. She completed a successful pregnancy but had worsening depression. Her steroids were stopped on admission and evaluation showed hypokalemia [2.9 mmol/L (n 3.5-5.1)], hypercortisolemia [29.9 mcg/dL (n 6.7-22.6)], and ACTH <12 pg/mL (n<46). This was followed with 1 and 8 mg dexamethasone suppression tests that she failed with cortisol levels of 37.8 and 41.6 mcg/dL respectively, late-night salivary cortisol of 0.974 ug/dL (n <0.181), and extremely elevated 24-hr urinary cortisol of 3,700.2 ug/d (n<45). Of the steroid hormone precursors, 11 deoxycortisol was elevated at 725 ng/dL (n<32) and DHEA-S was 29mcg/dL (n 35-430). A CT scan revealed multiple liver lesions, and no residual nodularity in the left adrenalectomy bed. Liver lesions were PET-avid, and biopsy confirmed metastatic ACC. Due to the extensive hepatic involvement, she was not a candidate for local therapy. She was started on mitotane and metyrapone for CS. She was treated with doxorubicin, cisplatin and etoposide chemotherapy every 4 weeks. Due to insurance issues; metyrapone was replaced by mifepristone. Over 8 weeks, mitotane level became therapeutic at 20 mcg/mL, hepatic masses decreased in size, and she transitioned form CS to adrenal insufficiency (AI) with am cortisol of 3 mcg/dL with accompanying nausea and improved glycemic control without medication. Next generation sequencing studies of the liver biopsy specimen revealed a frameshift loss of function mutation in FH that encodes the protein fumarase (c.912_918del p.F305fs; variant allele fraction - 67.8%). Conclusion: Metastatic ACC presenting with life-threatening CS presents a diagnostic and management challenge. Combination therapy with mitotane and chemotherapy demonstrated benefit in our patient. The transition from severe CS to AI due to mitotane was challenging to monitor biochemically due to mifepristone use. Loss of function FH mutation is associated with cancer progression. Patients with resected large adrenal adenomas require close monitoring to identify malignant behavior.