Platinum Opinion – Editorial Immunoglobulin G4–related Disease in Genitourinary Organs: An Emerging Fibroinflammatory Entity Often Misdiagnosed Preoperatively as Cancer Rodolfo Montironi a,y, *, Marina Scarpelli a,y , Liang Cheng b , Antonio Lopez-Beltran c , Maurizio Burattini d , Ziya Kirkali e , Francesco Montorsi f a Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, Italy; b Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA; c Department of Surgery, Cordoba University Medical School, Cordoba, Spain; d Unit of Internal Medicine, Carlo Urbani Hospital, Jesi, Italy; e Departments of Urology, School of Medicine, Dokuz Eylu ¨l University, Izmir, Turkey; f Department of Urology, University Vita-Salute, Scientific Institute H San Raffaele, Milan, Italy 1. What is immunoglobulin G4? Immunoglobulin G4 (IgG4) is the least common of the four subclasses of immunoglobulin G (IgG), namely IgG1, IgG2, IgG3, and IgG4, normally constituting only 3% to 6% of the entire IgG fraction. The major differences among the subclasses lie in the composition and structure of the hinge region that has significant effects on the antigen binding and effector functions of the immunoglobulin molecules, result- ing in different functional characteristics of each IgG subclass. For instance, IgG4, in contrast to the other IgG subclasses, does not activate complement and has a low affinity for target antigens. IgG4 is a T-helper 2 (Th2) cell-dependent isotype. Despite uncertainties about its normal function, IgG4 seems to play a significant role in allergic reactions, such as atopic eczema, bronchial asthma, and bullous skin lesions [1]. IgG4 has not attracted the attention of pathologists and clinicians until the recent recognition of the syndrome of IgG4-related disease (IgG4-RD), a fibroinflammatory condi- tion with a marked propensity to present as mass-forming lesions [2]. 2. Pathogenic mechanisms in immunoglobulin G4–related disease Autoimmunity and infectious agents are potential immuno- logic triggers in IgG4-RD. Interleukins 4, 5, 10, and 13 and EUROPEAN UROLOGY 64 (2013) 865–872 available at www.sciencedirect.com journal homepage: www.europeanurology.com [(Fig._1)TD$FIG] Fig. 1 – Imaging features (magnetic resonance) of a bladder lesion originally considered to be neoplastic. y These authors contributed equally to this work. * Corresponding author. Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Via Conca 71, I-60126 Torrette, Ancona, Italy. Tel. +39 071 5964830; Fax: +39 071 889985. E-mail address: r.montironi@univpm.it (R. Montironi). 0302-2838/$ – see back matter # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.eururo.2012.11.056