Late-Onset Hypophysitis Induced by Nivolumab in Advanced Esophageal Squamous Cell Carcinoma

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, particularly in advanced esophageal squamous cell carcinoma (ESCC), where nivolumab has demonstrated significant survival benefits. However, these therapies may precipitate immune-related adverse events (irAEs), including endocrine disorders such as hypophysitis. While hypophysitis is more commonly associated with anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) agents, its occurrence following anti-programmed cell death protein 1 (PD-1) inhibitors like nivolumab remains rare and diagnostically challenging due to nonspecific symptoms and frequent absence of radiographic abnormalities. We report a unique case of late-onset hypophysitis in a 68-year-old male with advanced ESCC, emerging after 21 cycles of nivolumab therapy. Initially asymptomatic, the patient presented with progressive fatigue, anorexia, and significant weight loss, necessitating hospitalization. Laboratory investigations identified severe hyponatremia and adrenal insufficiency, confirmed by low cortisol and adrenocorticotropic hormone (ACTH) levels. Notably, pituitary magnetic resonance imaging (MRI) revealed no structural anomalies, highlighting the diagnostic complexity of immune-mediated hypophysitis in this context. Hydrocortisone replacement therapy led to symptomatic improvement; however, nivolumab was permanently discontinued due to unresolved adrenal insufficiency and tumor progression. This case underscores the critical need for sustained clinical vigilance and proactive endocrine monitoring in patients receiving ICIs, even in the absence of overt early symptoms. Timely recognition and intervention are paramount to mitigating life-threatening complications. Furthermore, patient education on long-term adrenal insufficiency management is essential to safeguarding quality of life. Our report emphasizes the dual challenges of optimizing immunotherapy efficacy while managing its unpredictable risks, advocating for a multidisciplinary approach to patient care. By illustrating the unique diagnostic and therapeutic hurdles posed by delayed hypophysitis in anti-PD-1 therapy, this case contributes to the growing evidence on rare irAEs, reinforcing the importance of tailored surveillance strategies in oncology practice.