Numerous IgG4-positive plasma cells are ubiquitous in diverse localised non-specific chronic inflammatory conditions and need to be distinguished from IgG4-related systemic disorders

Abstract

Background IgG4-related systemic fibrosclerosis is a recently defined disorder characterised by a diffuse or tumefactive inflammatory reaction rich in IgG4-positive plasma cells associated with sclerosis and obliterative phlebitis. Although characteristic histopathological features are essential for the diagnosis of these disorders, to date there exists no consensus regarding the cut-off values used to define a 'significant IgG4-positive plasma cell count,' and data regarding the distribution of IgG4-positive plasma cells under common (non-specific) inflammatory conditions are lacking. Methods The authors analysed 121 randomly selected histopathological specimens containing prominent lymphoplasmacytic infiltrates (11 obstructive sialadenitis, 27 inflammatory lesions of the oral cavity, 24 inflammatory gastrointestinal lesions, 15 rheumatoid synovitis, 15 non-specific synovitis, eight non-specific dermatitis and 21 primary carcinomas with a peritumoral inflammatory response). For comparison, seven cases of sclerosing sialadenitis (Küttner tumour) were examined. Results High counts of IgG4 plasma cells were found in sclerosing sialadenitis (mean 40/high-power field (hpf)), contrasting sharply with sialadenitis caused by sialolithiasis (mean 3/hpf). Greatly varied but generally high counts of IgG4-positive plasma cells were also seen in several of the other lesions, particularly in rheumatoid synovitis (mean 55/hpf), oral cavity lesions (mean 79/ hpf) and carcinoma-associated inflammatory response (mean 24/hpf). The mean IgG4/IgG ratios for all lesions varied between 0 and 0.4. Conclusions The results demonstrate the ubiquitous occurrence of variably high numbers of IgG4-positive plasma cells under diverse non-specific inflammatory conditions, indicating that high IgG4-positive plasma cell counts and high IgG4/IgG ratios per se do not reliably distinguish IgG4-associated systemic disease from nonspecific conditions, and that the IgG4 counts must be cautiously interpreted in the context of appropriate clinical and histopathological features.

A case of IgG4-related kidney disease complicated by eosinophilic lung disease

“…In hyper IL-6 syndrome, the infiltration of a large number of IgG4-positive cells in the lesion and elevation of the blood IgG4 level are often observed, and some patients histologically fulfill the diagnostic criteria for IgG4-related diseases [7,8]. In the present case, the serum IgG4 level was high.…”

Histopathological findings in 29 lymph node biopsies with increased IgG4 plasma cells

“…5,16 One case in this series did show increased numbers of CD1a/s100-positive Langerhans cells (Case 2), although the typical histological findings of Rosai-Dorfman disease were not evident. The relationship of these entities with increased numbers of IgG4 plasma cells to IgG4-related sclerosing disease has not been clearly demonstrated as yet.…”

“…Ten cases had concurrent flow cytometry results on the lymph node specimens (Cases 2, 5,6,8,11,14,15,16,23,25). In all ten cases, CD4-positive T cells were increased compared with CD8 cells with CD4:CD8 ratios ranging from 3.36 to 11.24.…”

Consensus statement on the pathology of IgG4-related disease

“…39,[44][45][46][47][48] Many IgG4 þ plasma cells can also be present in lymphoproliferative disorders such as multicentric Castleman's disease, or even in non-specific settings such as pulmonary abscess or biliary xanthogranulomatous inflammation. 38,49 However, none of these conditions consistently shows IgG4-rich inflammation and all lack the characteristic histopathological features of IgG4-related disease.…”