Immune checkpoint inhibitor induced hypophysitis: a specific disease of corticotrophs?

Abstract

Introduction: The aim of this study was to define functional and anatomical pituitary disease at the time of presentation following immune checkpoint inhibitor (ICI) therapy and to describe any changes in pituitary function over time.

Methods: We conducted a retrospective observational audit of patients on ICI therapy at our centre between January 2013 and September 2023. We reviewed all patients on ICI therapy under the care of the oncology department at University Hospital Plymouth, a 1000-bedded hospital serving a population of 500,000 people. From this group, we identified all individuals referred to the endocrinology department with a suspected diagnosis of adrenal insufficiency. Patients were established on adrenal steroid replacement and subsequently underwent formal pituitary testing. People were included if they had pituitary disease, as evidenced by low ACTH, other pituitary dysfunction and/or abnormalities on pituitary imaging.

Results: Nine hundred and fifty-four patients received ICI therapy during the study period, and 37 (a prevalence of 3.9%) developed hypothalamic-pituitary-adrenal axis dysfunction. Their mean age was 65 years, and 70% were male. About 86.5% of the total patients affected were treated for metastatic malignancies. Ten of the 37 patients died during follow-up as a direct consequence or complication of their primary cancer diagnosis. The median interval for the onset of symptoms was 4 months. Following repeated testing, there was no recovery in cortisol or ACTH levels for any individual. Other permanent anterior pituitary hormone defects were unusual. Hypophysitis associated with immunotherapy appears to specifically target the corticotrophs, with no evidence of recovery over time. There was a specific abnormality seen in MRI scans of 7 of 27 patients who had scans, which appeared to be a particular feature of immune-mediated hypophysitis. These were confined to the anterior aspect of the pituitary gland, appearing as striations, and were not visible on any of the scans performed more than 3 months after the likely onset of the disease.

Conclusion: These data show that immune-related hypophysitis is a common complication of immune checkpoint inhibitor therapy. This may result in an imaging abnormality within the areas of the pituitary that are richest in corticotrophs. The endocrine consequence of this is a permanent defect in ACTH and, therefore, cortisol production.

Keywords: ACTH; cortisol; hypophysitis; immune checkpoint inhibitor; pituitary.

Figure 1

(A, B) Post-contrast T1 coronal and sagittal slices showing linear abnormalities present in the anterior aspect of the pituitary that were not present on repeat imaging at 6 months. Admitted to the hospital with severe headache, nausea, fatigue and hyponatraemia 12 weeks after starting Ipilimumab and Nivolumab. Pituitary function was normal apart from low cortisol and ACTH.

Figure 2

(A, B) Post contrast T1 coronal and sagittal slices showing linear abnormalities within the anterior part of the pituitary. The patient presented with persistent headache, having had treatment for ocular melanoma, including starting Ipilimumab 8 weeks earlier. Endocrinology showed raised prolactin at 1034 mIU/L, hypogonadotrophic hypogonadism and low ACTH and low cortisol. Imaging and endocrinology were not repeated as she died 5 months later.