IgG4-Related Lymphadenopathy

Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
International Journal of Rheumatology 06/2012; 2012(1):572539. DOI: 10.1155/2012/572539
Source: PubMed


Lymphadenopathy is frequently observed in patients with immunoglobulin G4-related disease (IgG4-RD) and sometimes appears as the first manifestation of the disease. The diagnosis of IgG4-related lymphadenopathy is complicated owing to a great histological diversity, with at least 5 histological subtypes. Indeed, lymph node biopsy may be performed under the suspicion that the lymphadenopathy is a malignant lymphoma or other lymphoproliferative disorder. The diagnosis of IgG4-RD is characterized by both elevated serum IgG4 (>135 mg/dL) and histopathological features, including a dense lymphoplasmacytic infiltrate rich in IgG4(+) plasma cells (IgG4(+)/IgG(+) plasma cell ratio >40%). However, patients with hyper-interleukin (IL-) 6 syndromes such as multicentric Castleman's disease, rheumatoid arthritis, and other immune-mediated conditions frequently show lymph node involvement and often fulfill the diagnostic criteria for IgG4-RD. Owing to these factors, IgG4-RD cannot be differentiated from hyper-IL-6 syndromes on the basis of histological findings alone. Laboratory analyses are crucial to differentiate between the 2 diseases. Hyper-IL-6 syndromes are characterized by elevated serum levels of IgG, IgA, IgM, and C-reactive protein (CRP); thrombocytosis; anemia; hypoalbuminemia; hypocholesterolemia. In contrast, IgG4-RD does not share any of these characteristics. Therefore, the diagnosis of IgG4-RD requires not only pathological findings but also clinical and laboratory analyses.

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    • "The lymph node lesions of IgG4-RD can be subdivided into at least 5 histological subtypes, including the multicentric Castleman’s disease-like, reactive follicular hyperplasia-type, interfollicular expansion and immunoblastosis, progressively transformed germinal center (PTGC)-type, and inflammatory pseudotumor (IPT)-like [1,4]. The PTGC-type usually presents with uniform clinicopathological features of asymptomatic, localized, submandibular lymphadenopathy that persists and/or relapses, and sometimes progresses to extranodal lesions or systemic disease [4,5]. Recently, a few papers have described peripheral nerve involvement in IgG4-RD, especially around the trigeminal nerve and optic nerve branches [6,7]. "
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    ABSTRACT: A 77-year-old man, with a lengthy medical history of chronic dysuria, constipation, hypertension, myocardial infarction, and a submandibular lymphadenopathy that was excised 3 years ago, was hospitalized due to elevated liver enzyme levels. He demonstrated hypergammaglobulinemia, hyperproteinemia, high levels of IgG and IgG4, eosinophilia, sclerosing cholangitis, and retroperitoneal fibrosis. He was diagnosed with IgG4-related disease (IgG4-RD). While hospitalized, he had several episodes of syncope while standing and was diagnosed with autonomic nerve dysfunction. Thirty days after hospitalization, he died of nonocclusive mesenteric ischemia (NOMI). Post-mortem, his submandibular lymphadenopathy lesion was diagnosed with progressively transformed germinal center (PTGC)-type IgG4-related lymphadenopathy. At autopsy, small and large intestines showed mucosal necrosis and the wall muscles of the transverse to sigmoid colon were necrotic. The sigmoid colon was fibrotic and infiltrated with numerous IgG4+ plasma cells and eosinophils; infiltration into Auerbach’s plexus was also observed. The IgG4-RD lesions were also detected in the mesentery of the sigmoid colon, retroperitoneal soft tissue, abdominal aorta, liver, extrahepatic bile duct, bilateral lungs, bilateral kidneys, urinary bladder, prostate, epicardium, bilateral coronary arteries, and lymph nodes. Interestingly, infiltration into the lesions was most notable around the peripheral nerves in every organ. Thus, this case describes an IgG4-RD that progressed from PTGC-type IgG4-related lymphadenopathy to systemic IgG4-RD, suggesting that IgG4-RD may affect many organs through peripheral nerve involvement. Virtual slide The virtual slides for this article can be found here:
    Diagnostic Pathology 02/2014; 9(1):41. DOI:10.1186/1746-1596-9-41 · 2.60 Impact Factor
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    ABSTRACT: Immunoglobulin(Ig)G4-related disease (IgG4-RD) is a fibroinflammatory condition that can affect virtually any organ and usually presents as tumefactive lesions involving multiple sites. Characteristic histopathology of IgG4-RD consists of dense lymphoplasmacytic infiltrate, fibrosis (often in storiform pattern), and obliterative phlebitis, accompanied by tissue infiltration of IgG4-positive plasma cells with or without elevation of serum IgG4 level. Despite a general similarity in the morphologic manifestations of IgG4-RD, site-specific unique morphologic features have been described in some organs including the lung. Compared with other sites, pulmonary involvement by IgG4-RD has been recognized more recently, and lung biopsy interpretation for this condition is often challenging, as both a relative paucity of pathognomonic features and a plethora of overlapping findings with other fibroinflammatory processes of the lung. This review is focused on the morphologic spectrum of IgG4-related lung disease documented in the current literature and on the pertinent issues in the differential diagnoses with other conditions encountered in the lung.
    Seminars in Diagnostic Pathology 11/2012; 29(4):219-25. DOI:10.1053/j.semdp.2012.07.002 · 2.56 Impact Factor
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    ABSTRACT: Lymphadenopathy is a common occurrence in IgG4-related disease; it can appear before, concurrent with, or after the diagnosis of this disease, which is characterized by tumefactive sclerosing inflammatory lesions predominantly affecting extranodal sites, such as the pancreas, salivary gland, and lacrimal gland. Although multiple lymph node groups are commonly involved, constitutional symptoms are absent. The lymph nodes can show a broad morphologic spectrum, including multicentric Castleman disease-like (type I), follicular hyperplasia (type II), interfollicular expansion (type III), progressive transformation of germinal centers (type IV), and inflammatory pseudotumor-like (type V). All are characterized by an increase in IgG4+ plasma cells (>100 per high power field) and IgG4/IgG ratio (>40%). IgG4-related lymphadenopathy is both an underdiagnosed and overdiagnosed entity. The former is because of the fact that this entity has not been characterized until recently, while the latter results from pathologists' enthusiasm in diagnosing "new" entities and the lack of specificity of the morphologic and immunophenotypic features of IgG4-related lymphadenopathy. It is prudent to render this diagnosis only for patients with known IgG4-related disease or in the presence of corroborating clinical and laboratory findings (such as elderly men, systemic lymphadenopathy, elevated serum IgG4, IgG, and IgE but not IgM and IgA, and low titers of autoantibodies). Outside these circumstances, a descriptive diagnosis of "reactive lymphoid hyperplasia with increased IgG4+ cells" accompanied by a recommendation for follow-up will be appropriate because IgG4-related disease will likely ensue only in a minority of such patients.
    Seminars in Diagnostic Pathology 11/2012; 29(4):226-34. DOI:10.1053/j.semdp.2012.07.001 · 2.56 Impact Factor
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