Immune Checkpoint Inhibitor-Induced Hypophysitis in Renal Cell Carcinoma: Two Contrasting Case Presentations

Abstract

Background: Increasing use of immune checkpoint inhibitor (ICI) therapy for malignancy has led to rising incidence of ICI-mediated endocrinopathies. We describe two varying cases of patients with renal cell carcinoma (RCC) who presented with ICI-mediated hypophysitis. Cases: Patient A: A 72 year old female with RCC (T1bN0M0) diagnosed after an incidental renal mass was found on CT scan following a motor vehicle accident. After nephrectomy, she received 5 cycles of nivolumab (6/2019 to 10/2019). One month later, she presented in severe DKA and was diagnosed with ICI-mediated diabetes (low c-peptide, negative autoantibodies). ICI therapy was stopped. In 4/2020, she experienced a drastic reduction in her insulin requirement (~30 units/day of basal/bolus insulin to ~6 units/day of basal insulin only). She had a primary care visit for fatigue, nausea, and anorexia. Biochemical evaluation showed hyponatremia, normokalemia, normoglycemia, and no acid-base disorder. One week later, she presented to the emergency department (ED) with worsening symptoms. She was hypotensive (94/56 mmHg), hyponatremic (129 mmol/L), normokalemic, and azotemic. Cosyntropin stimulation test (CST) showed an inappropriate response [ACTH <5 pg/ml; cortisol response of 0.4 to 8.1 µg/dl]. Brain MRI showed a partially empty sella. She was diagnosed with secondary adrenal insufficiency (AI) due to hypophysitis and started on steroid replacement. A repeat CST after 3 months did not show HPA axis recovery. Her presentation is unique because she developed secondary AI six months after nivolumab therapy. Patient B: A 43 year old female with RCC (T4N1M1) who received 4-cycles of ipilimumab and nivolumab (11/2019 to 1/2020). One month later, she presented to the ED with hypotension, anorexia, and fatigue. Biochemical evaluation showed severe DKA. She was diagnosed with ICI-mediated diabetes (low c-peptide, negative autoantibodies) and started on basal/bolus insulin. Her ICI-therapy was stopped. One month later, she was readmitted for hypotension and severe headaches and found to have hyponatremia (131 mmol/L), normokalemia, hyperprolactinemia (29 ng/ml), cortisol 4.5 µg/dl (previous random cortisol a month earlier was 33 µg/dl). Pituitary gland was normal on MRI. She was presumed to have secondary AI due to hypophysitis and started on steroid replacement. A CST performed after 3 months showed ACTH <5 pg/ml and cortisol response of 3.5 to 4.5 µg/dl. Her case was a usual presentation of ICI-mediated secondary AI as it occurred within 1-2 months of stopping ICI therapy. Conclusion: As we continue to learn about ICI-mediated endocrinopathies, it is imperative to document the variation in timing of presentation. ICI-mediated hypophysitis can present at any time after the initiation of therapy. Given this variation, there is need for routine screening and early treatment of hypophysitis to reduce ED visits and readmission rates.