Final diagnosis:

IgG4 related sclerosing disease

Discussion:

IgG4 related sclerosing disease (IgG4-RD) is a systemic autoimmune disorder characterized by fibroinflammatory pseudotumors with distinct histopathologic features including infiltrates of IgG4 plasma cells.¹ Initially described as a form of sclerosing autoimmune pancreatitis, IgG4-RD has subsequently been described in nearly every organ system. Unlike most autoimmune diseases, IgG4-RD is more prevalent in middle-aged and elderly males.² The most common clinical manifestation is a newly discovered mass with development of site specific symptoms suggestive of malignancy.² The histologic pattern of IgG4-RD is highly characteristic with the major features including (1) a dense lymphoplasmacytic inflammatory infiltrate often containing increased eosinophils with >10 IgG4+ plasma cells/HPF with an IgG4+/IgG+ ratio >40%; (2) storiform fibrosis; and (3) obliterative vasculitis.³ However, a IgG4+rich plasma cell infiltrate may be seen in several benign and malignant processes including lymphoproliferative/histiocytic disorders (Castleman, Rosai-Dorfman), various autoimmune disorders, and spindle cell neoplasms (inflammatory myofibroblastic tumor). ⁴ Serum IgG4 may be used as an additional diagnostic criterion for IgG4-RD; however, only approximately one-half of those with IgG4-RD show increased serum IgG4 with those containing multi-organ involvement more likely to reach the designated cut-off value of >135 mg/dL ^{5, 6} Ultimately, confirmation depends on the combination of histologic features, imaging, serology, other organ involvement and response to trial steroids (HISTORt criteria).⁷

The pathophysiology of IgG4-RD remains controversial and ambiguous. Currently it is postulated that the interplay between regulatory T-cells (Tregs) and TH2 helper T-cells is linked to the development of IgG4-RD. TH2 cells are known to secrete cytokines responsible for IgG4 class switching and eosinophilia while Tregs release cytokines resulting in immunosuppression. Serum from patients with IgG4-RD shows elevated mRNA expression of cytokines from both TH2 and Tregs.² These findings suggest a possible model in which an unknown immunologic trigger induces an exaggerated TH2 response and subsequent robust Treg counter response. IL-10 and TGF-B, cytokines produced by Tregs, induce class switching to IgG4 and stimulate fibroblast activity, respectively.² Thus, repeated antigenic stimulation and cytokine activity produce the histopathologic findings of increased tissue fibrosis and increased IgG4+ cells. However, evidence that TH2 cells drive the inflammatory process has yet to be fully elucidated, and currently no convincing environmental trigger has been identified.²

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List of references:

1. Wallace ZS, Deshpande V, Mattoo H, et al. IgG4-related disease: clinical and laboratory features in one hundred twenty-five patients. Arthritis Rheumatol. 2015;67:2466–2475

2. IgG4-Related Disease A Reminder for Practicing Pathologists Steven C. Weindorf, MD; John Karl Frederiksen, MD, PhD (Arch Pathol Lab Med. 2017;141:1476–1483)

3. Cheuk W, Chan JK. IgG4-related sclerosing disease: a critical appraisal of an evolving clinicopathologic entity. Adv Anat Pathol. 2010;17(5):303–332.

4. Morphologic Overlap Between Inflammatory Myofibroblastic Tumor and IgG4-related Disease Lessons From Next-generation Sequencing Martin S. Taylor, MD, PhD, Abhijit Chougule, MD Allsion R. MacLeay, MS, Pawel Kurzawa, MD, PhD, Ivan Chebib, MD, (Am J Surg Pathol 2019;43:314–324)

5. Umehara H, Okazaki K, Masaki Y, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol. 2012;22(1):21–30.

6. Ebbo M, Grados A, Bernit E, et al. Pathologies associated with serum IgG4 elevation. Int J Rheumatol. 2012;2012:602809.

7. World J Gastrointest Pathophysiol. 2014 May 15; 5(2): 71–81. Review of the diagnosis, classification and management of autoimmune pancreatitis. Derek A O’Reilly, Deep J Malde, Trish Duncan, Madhu Rao, and Rafik Filobbos