IgG4-positive plasma cells in nonspecific sialadenitis and sialolithiasis

Abstract

Chronic sclerosing sialadenitis is commonly regarded as a manifestation of IgG4-related disease. We previously found that a high IgG4 expression or IgG4-related disease could accompany nonspecific sialadenitis, whereas chronic sclerosing sialadenitis was not directly associated with IgG4-related disease. Our previous findings lead us to hypothesize that these inflammatory conditions of the submandibular gland signify a continuous progression of disease rather than different disease entities. We, therefore, aimed to determine the presence of IgG4-positivity and genuine IgG4-related disease in a cohort of 165 submandibular gland specimens from patients who underwent surgery due to chronic nonspecific sialadenitis or sialolithiasis. To do so, we re-evaluated histopathological features and divided samples into three groups: (A) nonspecific sialadenitis without known sialolithiasis, (B) sialadenitis with sialolithiasis, and (C) sialolithiasis without sialadenitis. We performed immunohistochemical staining for IgG4, IgG, and CD31, and assessed the Boston consensus statement criteria for IgG4-related disease in IgG4-positive samples. We also reviewed patient records and supplemented follow-up data with a questionnaire among patients with IgG4-positive samples. IgG4-positive plasma cells (range 1–344) were found in 131 samples. Among these, 19 samples were classified as IgG4-positive (≥70 IgG4-positive plasma cells/high-power field). Two IgG4-positive samples were histologically highly suggestive of IgG4-related disease, but only one had a clinically confirmed diagnosis of IgG4-related disease. Our results indicate that patients with sialadenitis and sialolithiasis often present with IgG4-positive lymphoplasmacytic infiltrates, but exceedingly rarely present with genuine IgG4-related disease. In sialolithiasis without sialadenitis, IgG4-positive plasma cells are often absent or appear in small numbers. These results support our hypothesis of a continuum of disease, and indicate that progressive inflammation of the submandibular gland leads to the development of more specific pathological features over time.

Chronic sclerosing sialadenitis of the bilateral submandibular glands in childhood – a diagnostic dilemma

“…Association with sialoliths can occasionally occur in CSS, most likely due to local impairment of saliva flow; after the sialolith formation, the inflammatory phenomena may flare up but the sialolith itself is not the cause of the salivary tissue affliction but merely a consequence of the disease. Moreover, the association between CSS, sialolithiasis and IgG4-RD depends on population; Japanese patients develop quite frequent IgG4-RD, in quite numerous cases with associated salivary affliction CSS type [ 16 , 18 ], while Finish patients did not associate CSS with IgG4-RD despite the high IgG4(+) plasma cells count within the salivary tissue [ 28 , 29 , 30 ]. Further studies are necessary to identify supplementary criteria for IgG4-RD CSS; CD4+/CD8+ T-cells ratio may be one of them, based on accumulating evidence of the role played by T-cells in IgG4-RD pathogenicity.…”

Viral DNA in submandibular gland tissue with an inflammatory disorder

“…The patients in this study were selected from cohorts formed in two earlier retrospective studies, which examined the association of IgG4-RD and IgG4-positive plasma cell infiltrates in a cohort of patients diagnosed with CSS and a cohort of patients diagnosed with CS and sialolithiasis [ 10 , 12 ]. From this patient series we formed two study groups: an IgG4-positive group and an IgG4-negative group.…”

“…From this patient series we formed two study groups: an IgG4-positive group and an IgG4-negative group. IgG4-positivity in a tissue sample was defined as a finding of ≥ 70 IgG4-positive plasma cells in a high-power field of x40 magnification [ 10 , 12 ]. In the IgG4-positive group, we included all the samples that were confirmed as IgG4 positive or as true IgG4-RD in the two previous studies.…”

“…These conflicting findings have led to a hypothesis of a specific form of submandibular sialadenitis, separate from true IgG4-RD, where chronic inflammatory infiltrates produce overexpression of IgG4-positive plasma cells in the affected salivary gland. However, the trigger behind the overexpression of IgG4 in some forms of sialadenitis is unknown [ 9 , 10 , 12 ].…”

Toll-like receptors 2 and 4, and bacterial proteins in IgG4-related sialadenitis, other types of chronic sialadenitis and sialolithiasis

“…Our results led us to hypothesise that an inflammatory entity histologically overlapping with, but likely aetiologically differing from genuine IgG4-RD exists. In this inflammatory continuum, numerous IgG4-positive plasma cells appear in the affected submandibular gland resulting from a prolonged inflammation stemming from an unidentified antigen [ 11 , 12 ]. Thus far, the significance of IgG4 overexpression in submandibular sialadenitis remains unclear.…”