Are there atypical sites of IgG4 related disease in head and neck region? Personal experience and literature review.

Purpose: Immunoglobulin G4-related disease (IgG4-RD) is a complex systemic fibroinflammatory condition with different clinical manifestations affecting multiple organ systems. Despite its rarity, the disease presents diagnostic and therapeutic challenges due to its mimicry of malignancies and other immune-mediated disorders. The 2019 American College of Rheumatology/European League Against Rheumatism Classification Criteria for IgG4-Related Disease is the current state of art to confirm the diagnosis of IgG4-RD even in the absence of histological analysis. However, this classification excludes atypical sites, focusing on the more typical ones, even in case of histological confirmation. In the ENT field, several localizations of this disease have been described.

Methods: We report two clinical cases at the Otolaryngology Unit of IRCCS San Martino Hospital, Genoa affected by IgG4-RD arising in atypical sides of the head and neck region. Additionally, we perform a clinical review of the current literature.

Discussion: The review provides an extensive overview of IgG4-RD, encompassing epidemiology, clinical manifestations, diagnostic approaches, and therapeutic strategies. We discuss the evolution of diagnostic criteria, emphasizing the necessity of interdisciplinary collaboration among clinicians, radiologists, and pathologists for accurate diagnosis. Diagnostic imaging plays a crucial role, with characteristic radiological patterns aiding in the identification of affected organs. However, definitive diagnosis often requires histopathological confirmation, highlighting the importance of biopsy in challenging cases. We also focus on the treatment of IgG4-RD which poses significant challenges, with glucocorticoids remaining the cornerstone of therapy. Emerging steroid-sparing agents such as rituximab and Dupilumab, show promising results in refractory or recurrent disease.

Conclusions: IgG4-RD is a multisystemic fibroinflammatory disease that can potentially affect any part of the body. The 2019 ACR/EULAR 3-stage classification criteria for IgG4-RD considers only a few head and neck sites. Therefore, it is of paramount importance that neurosurgeons, head and neck surgeons, and oral and maxillofacial pathologists are familiar with the clinicopathological manifestations of IgG4-RD in these sites to avoid misdiagnosis and inappropriate treatment, which can lead to a decrease in patients' quality of life. To our knowledge, there are no risk factors or genetic predispositions. Further studies are needed to elucidate the pathophysiology of IgG4-RD with the aim of providing a targeted therapy that could spare steroid-related effects and reduce relapses.