A Case of Aldosterone Producing Adrenocortical Carcinoma

Introduction: Adrenocortical carcinomas (ACCs) are rare and aggressive cancers. Approximately 60% of ACCs are functional, presenting with Cushing syndrome and/or virilization. Aldosterone producing ACCs account for about 1-3% of hormonally active ACCs. Despite aldosterone production, their mutational landscape is not different from other functional ACCs - they do not harbor mutations of known aldosterone-producing adenoma (APA) associated genes. They present with uncontrolled hypertension and hypokalemia, as seen in this case. Case: 63 year old Asian female with previously well controlled hypertension experienced resistant hypertension and hypokalemia for over a year. Since the onset of hypokalemia, patient noticed worsening hypertension despite addition of multiple medications. CT abdomen during an episode of severe gastroenteritis revealed a 3.7 cm heterogenous multilobulated left adrenal mass. Hormonal workup showed elevated aldosterone of 35 ng/dl with suppressed plasma renin activity of 0.41 ng/ml/h and serum potassium of 3.4 while patient was on 50 mg of spironolactone. Plasma and urine metanephrine levels were unremarkable. Plasma ACTH was <5 ng/L, cortisol was 12 ug/dl and DHEA-S was 149 ng/dl. 24 hour urine free cortisol result was not available. Repeated CT abdomen revealed a 5.2 cm left adrenal mass (Non-contrast HU of 38, 50% absolute wash out), increasing in size from 3.7 cm in 6 months. The mass was FDG avid with SUV of 13.2. Patient underwent laparoscopic left adrenalectomy and surgical pathology revealed a 4.2 cm, high grade ACC with vascular invasion, Ki67 index of 35% and modified Weiss score of 6. Hypertension and hypokalemia resolved after tumor removal, no longer requiring antihypertensive medications. Plasma aldosterone level also remains normal after surgery. However, postoperative CT (6 weeks after surgery) revealed numerous pulmonary metastases. Germline genetic testing is pending. Genomic interrogation of the primary tumor identified CDKN2A and CDKN2B deletions, along with pathogenic mutations in CTNNB1 and DNMT3A. Copy number analysis revealed numerous large scale chromosomal alterations including many arm level and whole chromosome gains and losses. These somatic mutations affect p53/Rb1 signaling (CDKNs), chromatic remodeling (DNMT3A) and wnt signaling pathway (CTNNB1). Together with noisy pattern of copy number alterations, these genomic alterations likely account for the aggressive nature of this tumor. Clinical Lessons: (1) Clinicians should raise the suspicion of ACC during the workup for primary hyperaldosteronism, especially if an adrenal mass does not have the reassuring radiographic features suggestive of a benign adrenal mass. (2) Metastatic lesions may not necessarily produce aldosterone as the primary tumor does. (3) Mutational analysis of the tumor informs molecular subtypes of ACC, prognosis, and treatment decisions.