Multiple primary head and neck cancers: a scenario-based framework for diagnosis and modern multidisciplinary management.

Background: Multiple primary tumours (MPT) involving the head and neck represent a growing and insufficiently systematised challenge in contemporary head and neck oncology. Patients with head and neck squamous cell carcinoma (HNSCC) face a cumulative risk of 2-4% per year of developing a second primary malignancy, driven by field cancerisation, persistent exposure to tobacco and alcohol, and improved survival after multimodality treatment. Methods: Observational analysis of patients with ICD-10 C00-C14 and C30-C32 diagnoses treated in a university otolaryngology-head and neck surgery department over a two-year period (2024-2025), with specific focus on cases fulfilling criteria for MPT, was performed. Detailed clinical, pathological and treatment variables for the first and subsequent primaries were extracted and summarised, and illustrative cases were organised into a predefined 2 × 2 clinical matrix: (1) synchronous primaries confined to the head and neck; (2) synchronous HNSCC with an extra head and neck primary; (3) metachronous primaries within the head and neck; and (4) metachronous HNSCC with a non-head and neck malignancy. Results: Among 274 consecutive patients treated for HNSCC, 15 (5.5%) were identified as having MPT. These encompassed all four matrix scenarios and included combinations of laryngeal and oropharyngeal carcinomas, salivary gland tumours, hepatocellular carcinoma, prostate cancer and renal tumours. Across scenarios, optimal care required systematic diagnostic work-up (panendoscopy, high-quality cross-sectional imaging, meticulous histopathology), multidisciplinary discussion, and tailored use of contemporary modalities such as IMRT (including re-irradiation), transoral surgery and immune checkpoint inhibitors. In older, multi-morbid patients, comprehensive geriatric assessment emerged as pivotal for balancing curative intent against toxicity and functional outcome. Conclusions: Multiple primary head and neck cancers constitute a distinct, non-rare workload in tertiary practice and cannot be adequately addressed by isolated case reports or generic HNSCC pathways. A scenario-based framework, operationalised through a 2 × 2 clinical matrix with scenario-specific diagnostic and therapeutic checklists, provides a pragmatic tool to standardise evaluation, structure tumour board deliberations, and align increasingly complex IMRT and immunotherapy-era treatment options with patient prognosis, comorbidity, and values.