Challenges in diagnosing paraneoplastic isolated adrenocorticotropic hormone deficiency: Insights from cancer histology and human leukocyte antigen analysis

The specific human leukocyte antigen (HLA) alleles in individuals with tumors that ectopically express adrenocorticotropic hormone (ACTH), resulting in paraneoplastic isolated ACTH deficiency (IAD), remain elusive, primarily because of the scarcity of reported cases. In this study, we endeavored to elucidate the pathogenic mechanisms underlying paraneoplastic IAD, a novel subtype of autoimmune hypophysitis. We specifically examined the histological characteristics of ACTH-expressing cells in cancer tissues of one patient and investigated the prevalence of shared HLA alleles across three patients diagnosed with paraneoplastic IAD. We analyzed the histological features of prostate-cancer tissues, including ectopic ACTH expression, in a patient with paraneoplastic IAD. In addition, we investigated common HLA alleles and estimated haplotypes among this patient and two others with paraneoplastic IAD on which we previously reported. Immunohistochemical analyses revealed ACTH-positive cells in only one of four tissue samples. Ectopic ACTH expression was limited to areas of relatively high-grade prostate cancer, with cellular cords and cribriform glands that exhibited nuclear hyperchromatism. HLA typing revealed shared class II alleles and haplotypes, including DRB4*01:03, among the three cases. This study provides novel histological insights and highlights the commonality of HLA class II alleles in the diagnosis and pathogenesis of paraneoplastic IAD, potentially aiding the identification of new cases and our understanding of the underlying mechanisms of the disease.