IgG4-related lymphadenopathy is a nodal manifestation of IgG4-related disease (IgG4RD) most frequently affecting the regional lymph nodes draining the extranodal disease sites affected by IgG4RD.1, 2, 3 Since it may occur in patients with prior IgG4RD, patients with concurrent presentation of lymphadenopathy and extranodal disease, or patients who only develop IgG4RD years later,4 IgG4-related lymphadenopathy may present at the time of diagnosis as lymphadenopathy without apparent extranodal IgG4RD.

It is important to recognize IgG4-related lymphadenopathy for several reasons. When lymphadenopathy is generalized, the imaging and clinical impression is often that of lymphoma, multicentric Castleman disease or disseminated malignancy; distinction from these more sinister conditions is important for treatment and prognostication. The clinical differential diagnosis for IgG4-related lymphadenopathy is broad and besides malignancy also includes infection and other immune-related conditions. IgG4-related lymphadenopathy can sometimes produce local effects due to compression on adjacent anatomic structures, such as the ureter or veins; a correct diagnosis facilitates treatment of this steroid-responsive condition.

Similar to extranodal IgG4RD, increased IgG4+ plasma cells (>400 /mm2) and IgG4/IgG ratio (>40 %) are the diagnostic hallmark of IgG4-related lymphadenopathy, in conjunction with compatible clinical and pathologic features. The involved lymph nodes can exhibit diverse patterns of reactive changes, but storiform fibrosis, one of the defining features of IgG4RD, is only uncommonly seen. Thus, most IgG4-related lymphadenopathy morphologic patterns probably only reflect a heightened or dysregulated immune response of the lymph node to IgG4RD, as occasionally also seen in other lymphoid tissue such as the nasopharynx and bone marrow, but does not represent actual involvement by the fibro-inflammatory process of IgG4RD.5, 6, 7 Similar reactive changes in lymph node, sometimes accompanied by raised IgG4 parameters, can also be found in many other reactive or neoplastic conditions unrelated to IgG4RD.3,8, 9, 10 Probably only IgG4-related lymphadenopathy with storiform fibrosis represents the genuine nodal counterpart of IgG4RD.

In patients with established extranodal IgG4RD, the finding of increased IgG4+ plasma cells and IgG4/IgG ratio in a lymph node, particularly within extrafollicular regions, is consistent with IgG4-related lymphadenopathy. In patients without established extranodal IgG4RD, similar findings in lymph nodes may be considered suspicious for IgG4RD, although guidelines including the WHO classification discourage making an initial diagnosis of IgG4RD solely on the basis of lymph node findings . Increased IgG4+ cells and IgG4/IgG ratio may be seen in other non-specific causes of lymphadenopathy, although some morphologic clues in lymph nodes may strongly suggest bona fide IgG4RD. Therefore, to avoid confusion the term “IgG4-related lymphadenopathy” is by convention most appropriately used to refer to characteristic lymphadenopathy in patients with known IgG4RD, rather than as a descriptive term for any lymph node with increased IgG4+ cells.