Original ArticlesIgG4-related Lymphadenopathy A Comparative Study of 41 Cases Reveals Distinctive Histopathologic FeaturesBledsoe, Jacob R. MD*; Ferry, Judith A. MD†; Neyaz, Azfar MD†; Boiocchi, Leonardo MD†; Strock, Cara MS*; Dresser, Karen BS*; Zukerberg, Lawrence MD†; Deshpande, Vikram MD†Author Information *Department of Pathology, UMass Memorial Medical Center, University of Massachusetts, Worcester †The James Homer Wright Pathology Laboratories of the Massachusetts General Hospital, Boston, MA Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Jacob R. Bledsoe, MD, UMass Memorial Health Care, University of Massachusetts, Room 230, Biotech III Building, One Innovation Drive, Worcester, MA 01605 (e-mail: [email protected]). The American Journal of Surgical Pathology: February 2021 - Volume 45 - Issue 2 - p 178-192 doi: 10.1097/PAS.0000000000001579 Buy Metrics Abstract Lymphadenopathy is common in patients with immunoglobulin G4-related disease (IgG4-RD). However, the described histopathologic features of IgG4-related lymphadenopathy have been shown to be largely nonspecific. In an attempt to identify features specific for nodal IgG4-RD we examined the histopathologic features of lymph nodes from 41 patients with established IgG4-RD, with comparison to 60 lymph nodes from patients without known or subsequent development of IgG4-RD. An increase in immunoglobulin (Ig) G4-positive plasma cells >100/HPF and IgG4/IgG ratio >40% was identified in 51% of IgG4-RD cases and 20% of control cases. Localization of increased IgG4-positive plasma cells and IgG4/IgG ratio to extrafollicular zones was highly associated with IgG4-RD, particularly when identified in regions of nodal fibrosis (P<0.0001; specificity: 98.3%), or in the context of marked interfollicular expansion (P=0.022; specificity: 100%). Other features characteristic of IgG4-RD included frequent eosinophils associated with IgG4-positive plasma cells, phlebitis (P=0.06), and perifollicular granulomas (P=0.16). The presence of an isolated increase in intrafollicular IgG4-positive plasma cells and IgG4/IgG ratio was more frequently present in control cases than IgG4-RD (P<0.0001). This study confirms that increased IgG4-positive plasma cells and IgG4/IgG ratio are neither sensitive nor specific for the diagnosis of IgG4-related lymphadenopathy, and most described morphologic patterns are nonspecific. In contrast, nodal involvement by IgG4-rich fibrosis akin to extranodal IgG4-RD or diffuse interfollicular expansion by IgG4-positive plasma cells are highly specific features of true IgG4-related lymphadenopathy. Our findings provide for a clinically meaningful approach to the evaluation of lymph nodes that will assist pathologists in distinguishing IgG4-related lymphadenopathy from its mimics. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.