A Rare Case of Hypophysitis with Isolated ACTH Deficiency and Thyroiditis Complicating Treatment with Pembrolizumab

Introduction:
Immune checkpoint inhibitors (CPIs) have been shown to be beneficial in the treatment of cancers by enhancing anti-tumor immunity. CPIs block intrinsic down regulators of immunity, such as cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) or its ligand programmed cell death ligand 1 (PD-L1). While useful for targeting malignant tissue, CPIs can have destructive effects on normal tissues, including endocrine organs. Hypophysitis is more common in those receiving anti-CTLA-4 therapy (up to 10% of patients) than those receiving anti-PD1-therapy ( <1% of patients) whereas the opposite stands true for thyroiditis. We present a rare case of a woman with breast cancer treated with the anti-PD-1 therapy pembrolizumab who developed isolated ACTH deficiency from hypophysitis along with thyroiditis.

Case Description:
A 39-year-old female with breast cancer treated with pembrolizumab presented with several weeks of fatigue and confusion. On exam, she was well-appearing and normotensive. Cortisol and TSH were found to be low at <0.1 ug/dL and <0.01 uIU/mol, respectively, raising concern for central adrenal insufficiency and hypothyroidism. Free T4 and free T3 were high indicating the low TSH was from primary thyroid rather than pituitary dysfunction. Cosyntropin stimulation test showed an insufficient rise in cortisol to 1.7 ug/dL, which, along with an inappropriately normal ACTH of 9.9 pg/mL, confirmed the diagnosis of central adrenal insufficiency. Sellar MRI revealed no abnormalities. Adrenal insufficiency was treated with hydrocortisone. Hyperthyroidism quickly transitioned to hypothyroidism, supporting a diagnosis of thyroiditis, which was treated with levothyroxine. Pembrolizumab was stopped and later resumed once clinical symptoms were stabilized while on the hormonal therapy.

Discussion:
CPIs have been associated with a variety of immune mediated adverse endocrine events, including hypophysitis, primary thyroid dysfunction, autoimmune diabetes, and adrenalitis. Although thyroiditis is the most commonly reported adverse endocrine event associated with anti-PD-1 therapy, other adverse events can occur, including hypophysitis rarely. While the diagnosis of hypophysitis can be supported by sellar changes on MRI, it is important for clinicians to be aware that hypophysitis in those on anti-PD1 therapy may lack classic MRI changes. As the endocrine dysfunction can be life-threatening and symptoms often overlap with those of malignancy and related treatments, a high index of suspicion is necessary to ensure prompt diagnosis and treatment. In addition, screening for endocrine dysfunction is recommended in all patients receiving CPIs.