Case Presentation: An 85 y/o man with non-small cell lung cancer and osseous metastases on pembrolizumab presented with 5 months of progressive weakness, intermittent nausea with non-bloody emesis, and decreased appetite with 20 lb. unintentional weight loss. Interval cancer surveillance with PET CT obtained 1 week prior showed a decrease in disease burden suggestive of a response to immunotherapy. A TSH checked 4 months before was newly decreased at 0.46 mlU/L and the patient was started on levothyroxine. He had an eosinophilia of 5.9% at that time. On admission, his physical exam was notable for severe muscular weakness and inability to ambulate without assistance. Lab data showed a WBC of 9.2K/uL with an eosinophilia of 35%. Creatinine was elevated at 1.6 mg/dL (1.1 mg/dL baseline). Given initial concerns for immune related adverse events (irAE) the patient received 80mg IV methylprednisolone and admission for further evaluation. After 1 day, his eosinophilia resolved at 0.9% with improvement in his symptoms. To clarify suspicion for immune checkpoint inhibitor (ICI)-associated hypophysitis, steroids were held. By day 4, his symptoms and eosinophilia recurred at 28%. A 6 A.M. spot cortisol was <2.0 ug/dL. ACTH and Free T4 were also low at 7pg/mL and 0.5 ng/dl, respectively. The patient was diagnosed with ICI-associated hypophysitis and started on low dose prednisone upon discharge with subsequent improvement in his symptoms.
Discussion: Hypophysitis is a rare complication of ICIs. The onset of symptoms is often insidious with variable timeline, making diagnosis challenging. Hallmark features of weakness, dizziness, and anorexia reflect underlying thyroid dysfunction and adrenal insufficiency (with low ACTH and morning cortisol). Problems with ADH regulation are common, resulting in dehydration and AKI, as seen in this patient. Growth hormone and gonadotrophin deficiencies are less evident, as patients are usually older in age. ICI-associated hypophysitis is typically subacute in nature and rarely presents with features of acute primary hypopituitism, such as hyponatremia, hypoglycemia, or hypotension. Imaging is of low yield in establishing the diagnosis, as MRI brain is often normal. There is increasing evidence that eosinophilia is an early sign of irAE in patients on ICIs. Thus, a persistent, rising eosinophilia should not be ignored. To manage patients with ICI-associated hypophysitis, endocrinology should be involved, and patients should be treated with the lowest tolerated dose of steroids. Patients rarely present with acute adrenal crisis and do not necessitate treatment with high dose steroids. Additionally, studies have demonstrated a survival benefit and an increased length of time until treatment failure in patients treated with low dose steroids rather than high dose steroids.
Conclusions: Immuno-oncology has forever changed the landscape of cancer care. With the increasing use of ICIs, hospitalists must be aware of the potential for irAE and understand how to diagnose and treat irAE without compromising the immunogenic effects of therapy. Establishing the diagnosis of irAE, specifically hypophysitis, can be difficult, but an early and sustained eosinophilia can assist providers in making the diagnosis. Low dose steroids and thyroid replacement therapy should be continued indefinitely.