Our patient was a 58 year old male with a history of metastatic melanoma on nivolumab and ipilimumab who was directly admitted from clinic to the medicine service for increased lethargy and flu-like symptoms. The patient described a one week history of fevers/chills, headache, muscle ache, and malaise; as well as nausea, vomiting, and poor oral intake. On presentation, vital signs were stable and physical exam was unremarkable apart from an overall fatigued appearance. Laboratory work-up was significant for a TSH 0.04 (nl 0.30-4.20), fT4 0.40 (nl 0.90-1.70), ACTH 5.0 (nl 7.0-63.0), LH < 1.0, testosterone < 7.0, prolactin 1.4 (nl 3.5-19.4), and morning cortisol 2.4 (nl 3.7-19.4). PET-CT showed widespread metastatic disease and new increased FDG uptake within the pituitary. MRI brain showed an irregularly enhancing sellar/suprasellar lesion that was concerning for a metastatic lesion versus pituitary hemorrhage. Upon further discussion with neuroradiology and endocrinology, the patient’s clinical presentation and imaging findings were felt to be most consistent with hypophysitis (or less likely, a pituitary metastasis). He was started on 5mg prednisone and 150mcg levothyroxine per endocrinology recommendations prior to discharge.
Discussion:
Hypophysitis is a life-threatening complication of immunotherapy that has been associated with nivolumab and ipilimumab combination therapy. Reported incidences vary from as low as 0.7%-1.8% to upwards of 10-15%. Patients typically present with lethargy, weakness, and headache within 2-3 months of initiating therapy. As with this patient, laboratory evaluation often demonstrates pituitary axis abnormalities consistent with panhypopituitarism. The mechanism of pituitary injury is poorly understood but thought to be predominately ipilimumab mediated. Ipilimumab is a monoclonal antibody against cytotoxic T-cell lymphocyte antigen-4 (CTLA-4), a cell surface mediator of T-cell inactivation. CTLA-4 is expressed within the human pituitary and binding of CTLA-4 antibodies is thought to induce toxicity and inflammation through complement activation. Lethargy, nausea, and vomiting are common presenting symptoms managed by hospitalists. However, in caring for oncologic patients it is important to consider that such symptoms may suggest severe adverse drug effects or disease progression.
Conclusions:
Immune checkpoint inhibitor therapy has demonstrated great promise in treatment of advanced malignancies. Along with their tremendous benefits these therapies come with a tremendous side effect burden. As the use of immune checkpoint inhibitors becomes more ubiquitous, the incidence of adverse complications will undoubtedly increase. Given the severity of these complications, hospitalists and other inpatient physicians are more likely to encounter patients with complications of immunotherapy. Hospitalists should maintain a high index of suspicion for hypophysitis and other endocrinopathies when evaluating patients with common symptoms and recent exposure to immune checkpoint inhibitors.