The histological diagnosis of IgG4-related disease on small biopsies: challenges and pitfalls

The pathological diagnosis of IgG4-related disease (IgG4-RD) relies on histology, IgG4-positive cells, and an increased IgG4/IgG ratio. Small biopsies from patients with a presumptive diagnosis of IgG4-RD often fail to meet consensus histological criteria. The aims of this study were to evaluate consecutive small biopsies from patients with a presumptive diagnosis of IgG4-RD, and to assess the significance of the pathological findings.

We evaluated 55 small biopsies from patients with a presumptive diagnosis of IgG4-RD. The retrospective cohort comprised 71 patients with IgG4-RD and 57 mimics. We performed immunohistochemistry (IHC) and in-situ hybridisation (ISH) for IgG4 and IgG. Twenty-six patients from the prospective cohort met the histological criteria for IgG4-RD (definite); 29 patients lacked one or more pathological features (borderline). Twenty biopsies (36%) lacked both storiform fibrosis and obliterative phlebitis, and nine (16%) lacked an increase in the number of IgG4-positive plasma cells. Ninety-three per cent of patients showed an IgG4/total IgG ratio of >40% (>30% by ISH). There were no differences in the incidence of multiorgan disease (P = 0.9), serum IgG4 levels (P = 0.6) and response to therapy between the definite and borderline groups. A strong correlation (Pearson 0.77) between the IHC and ISH platforms was noted with regard to the IgG4/total IgG ratio.

Patients with a presumptive diagnosis of IgG4-RD but lacking the characteristic pathological features of this disease appear to be clinically similar to those who meet the current pathological criteria. An elevated IgG4/total IgG ratio is the most sensitive pathological feature, and ISH provides a robust quantification platform. We recommend evaluating tumefactive lymphoplasmacytic infiltrates with an increased IgG4/IgG ratio, regardless of histological features, for IgG4-RD.