Head and Neck Malignancies in Autoimmune Polyendocrine Syndrome Type 1 (APS-1/APECED): A Scoping Review of Molecular Pathogenesis, Clinical Features, and Outcomes.

Autoimmune polyendocrine syndrome type 1 (APS-1, APECED) is a rare monogenic disorder caused by biallelic AIRE mutations and is classically associated with chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and adrenal insufficiency. Apart from the autoimmune manifestations, APS-1 is associated with an increased risk of squamous cell carcinoma (SCC), particularly in the oral cavity and esophagus. However, the evidence is patchy and has not yet been systematically reviewed. We conducted a scoping review according to the PRISMA-ScR guidelines. Pub-Med, Scopus, and Web of Science were searched using the terms APS-1/APECED and malignancy until July 2025. Eligible studies reported on APS-1 patients with histologically confirmed head, neck or esophageal cancer. Clinical, pathological, genetic and outcome data were summarized narratively. Nine publications described 19 APS-1 patients with 26 tumors. The mean age at cancer diagnosis was 35 years, with a latency period of ~24 years from the onset of APS-1. Tumors occurred most frequently in the oral cavity (65%), followed by the lip (19%) and esophagus (15%). In 96% of cases, the tumors were SCC. The grade of the tumor varied, and almost half of the cases were diagnosed at an advanced stage. As far as reported, the usual risk factors were not particularly pronounced; many patients did not smoke or drink alcohol. The main treatment consisted of surgery, often in combination with radiotherapy or chemoradiotherapy, alongside long-term antifungal therapy. Despite the multimodal treatment, outcomes were poor: the overall survival rate was ~50%, with recurrence occurring in 38% of cases and a second primary tumor in 26%. A further 14 cases were reported from another Italian cohort, which together with the national cohort dana suggest a risk of approximately ~10% with APS-1; however, the true lifetime risk remains uncertain. Head and neck malignancies in APS-1 occur early, often without classic risk factors, and have a high recurrence and mortality rate. Lifelong surveillance, antifungal stewardship and increased clinical awareness, ideally as part of multidisciplinary treatment pathways, are critical to improving outcomes in this rare but high-risk population.