Background/Purpose: Granulomatosis with polyangiitis (GPA) and IgG4-related disease (IgG4-RD) are both immune-mediated conditions that can involve multiple organ systems. In GPA, IgG4-positive plasma cell infiltration has been reported in the kidneys and upper respiratory tract, leading to potential confusion between these two disorders. We sought to determine the degree of IgG4-positive plasma cell infiltration within lung biopsies from patients with ANCA-positive and ANCA-negative GPA, and compared the histopathological and immunohistochemical findings in GPA to biopsies from patients with IgG4-related pulmonary disease. 

Methods: Patients with GPA (n=154) were identified by searching the pathology database of the Massachusetts General Hospital (MGH) for search terms “lung” and “Wegener’s”. Nine ANCA-positive and 4 ANCA-negative patients with wedge biopsy samples of the lung were selected for further analysis. Their clinical, radiologic, and pathologic data were compared to those of 5 patients with IgG4-related pulmonary disease. Hematoxylin and eosin (H&E) stained slides were reviewed in a blinded manner.  Immunohistochemistry was performed using antibodies to IgG4 and IgG and subsequently counted by averaging 3 high-power fields (hpf). The histopathologic features were compared using Fisher’s exact test and IgG4+ plasma cells counts by unpaired t-tests.

Results: The mean number of IgG4+ plasma cells in lung biopsy samples was higher among the IgG4-RD patients compared to those with GPA.  The mean for the IgG4-RD biopsies was 101 IgG4+ plasma cells/hpf (range: 13-240 IgG4+ cells), compared with 25 cells (range: 0-135) for the GPA patients (P=0.035).  IgG4+ plasma cells were numerically higher among GPA patients who were ANCA-positive as opposed to ANCA-negative (40 vs. 11 cells, respectively).  Three of the 9 ANCA-positive GPA patients  had IgG4+ plasma cell infiltrates that exceeded the minimum number considered characteristic of IgG4-RD in the lung (>50 IgG4+ plasma cells/hpf). 

Comparisons of the histopathologic features between GPA and IgG4-RD are shown in Table 1. Two sets of findings were critical in distinguishing the pulmonary pathology of ANCA-positive GPA and IgG4-RD: 1) Obliterative phlebitis, present in 80% of the IgG4-RD biopsies, was not observed in any GPA cases; and, 2) Features of granulomatous inflammation – histiocytes, granulomas, and multi-nucleated giant cells – were absent in IgG4-RD. 

Conclusion: Lung biopsies from both IgG4-RD and GPA patients are characterized by lymphoplasmacytic infiltrates and IgG4+ plasma cells.  Histopathological features, particularly the finding of obliterative phlebitis in IgG4-RD and the absence of granulomatous inflammation, are essential in distinguishing between these conditions.

Table 1: Lung Histopathologic Features: Granulomatosis with polyangiitis (GPA) versus IgG4-related disease (IgG4-RD).