IgG4-related illness (IgG4-RD) is a perfect mimic of many disorders due to its proclivity to develop pseudotumors and multisystemic nature. Furthermore, some clinical, serological, radiological, or histological characteristics of the illness may be shared by some mimickers. Recently, four clinical phenotypes were established, and patients in each phenotype have distinct demographic, clinical, and serological characteristics and outcomes. As predicted, a set of differential diagnoses should be explored for each phenotype.

Pancreatic adenocarcinoma and cholangiocarcinoma are the most common differential diagnosis for the pancreatic-hepato-biliary phenotype. Type 2 autoimmune pancreatitis and primary sclerosing cholangitis were two more possibilities. In individuals with a retroperitoneal/aortic phenotype, inflammatory diseases such as idiopathic retroperitoneal fibrosis and large vessel vasculitides should be excluded, and a biopsy is usually required to rule out malignancies. Autoimmune conditions (e.g., granulomatosis with polyangiitis, Graves orbitopathy, sarcoidosis), malignancies, and histiocytosis should be ruled out in the head and neck limited phenotype, whereas Sjögren syndrome, granulomatosis with polyangiitis, and multicentric Castleman disease are the main differential diagnoses in the Mikulicz/systemic phenotype.

Approaching a patient with possible IgG4-RD through a clinical phenotype framework would simplify the diagnostic process and expedite illness diagnosis. Each clinical phenotype had clinical, serological, radiological, and histological markers that, if present, enhanced the chance that a patient had IgG4-RD rather than the mimicker disease. In the course of a patient’s workup, those indicators that indicated IgG4-RD diagnosis should be carefully pursued.