Unveiling Idiopathic Multicentric Castleman’s Disease Disguised as IgG4-Related Disease: A Systematic Review

Introduction Idiopathic multicentric Castleman’s disease of the idiopathic plasmacytic lymphadenopathy variant (iMCD-IPL) and IgG4-related disease (IgG4-RD) are challenging differential diagnoses to delineate for non-malignant lymphadenopathy with systemic symptoms. Histological overlap complicates the distinction: iMCD-IPL biopsies often show plasma cell infiltrates with >40% IgG4:IgG surface expression, fulfilling histological criteria for IgG4-RD. However, accurate differentiation is critical given distinct pathogenesis and treatments. This systematic review aimed to consolidate published data into a practical list of distinguishing features between iMCD and IgG4-RD. Method Embase and MEDLINE were searched using the title terms ‘Castleman’ AND ‘IgG4’. Of 67 articles identified, 23 remained after exclusion of duplicates and irrelevant studies. One was excluded for not applying the 2017 consensus criteria for iMCD, two for pre-dating the definition of iMCD-IPL, and one for conflating the features of the two diseases, leaving 19 articles: 11 retrospective case-control studies and 8 case reports, including 277 patients with iMCD-IPL and 172 with IgG4-RD. Statistically significant (P<0.05) clinical, radiological, histopathological, and laboratory features from case-control studies were compiled, supplemented by case report observations, to generate a ranked list of markers distinguishing iMCD-IPL from IgG4-RD. Results The most consistently useful features for identifying iMCD-IPL cases were: clinical—no/incomplete response to corticosteroids (42.1% of studies), radiological—fluorodeoxyglucose positron emission tomography showing atypical organ involvement for IgG4-RD (21.1%), peripheral blood—elevated C-reactive protein (68.4%), anaemia (63.2%), raised IL-6 (52.6%), raised IgA (47.4%), and heterogenous IgG elevation (47.4%), and histopathology—sheet-like mature plasma cell infiltration (57.9%), low/no eosinophils (36.8%), lower IgG4/IgG ratio than IgG4-RD (31.2%), and absence of storiform fibrosis and obliterative phlebitis (26.3%). Conclusion iMCD can masquerade as steroid-refractory IgG4-RD. Awareness of these distinguishing features can guide diagnosis and treatment and could form the foundation of future diagnostic scoring tools.