IgG4-Positive Plasma Cell Myeloma: New Insights into the Pathogenesis of IgG4-Related Disease
Julia T Geyer, David S Jayabalan, Roger N Pearse, Ruben Niesvizky, Scott A Ely. Weill Cornell Medical College, New York, NY
Background: IgG4-related disease is a newly described fibroinflammatory process, characterized by tumor formation in various organ systems with a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, storiform fibrosis, and elevated serum IgG4 concentration. IgG4 is a bispecific antibody with reduced ability to activate complement, cross-link antigens or form immune complexes. IgG4 appears to have a predominantly anti-inflammatory activity. Thus, the pathogenesis of IgG4-related disease remains poorly understood. We sought to identify and characterize a subset of IgG4-secreting plasma cell myeloma (PCM), as it may provide a biological model of disease with high serum levels of IgG4.
Design: 98 bone marrow biopsies from patients with IgG PCM were selected. Immunohistochemical staining for IgG4 was performed. These results were correlated with clinical and laboratory findings.
Results: Five out of 98 patients with IgG PCM had extensive expression of IgG4 by the neoplastic plasma cells. Three patients were men and 2 were women, with a mean age of 66 (range 56-87) years. Two patients were asymptomatic at diagnosis. Three had bone pain secondary to plasmacytomas. PET/CT imaging showed fullness of pancreatic head (1), small nonmetabolic lymphadenopathy (1) and bone lytic lesions in all patients. All five patients had elevated serum M-protein (mean 3.1, range 1.2-4.9 g/dL). Four patients were treated with multiple courses of chemotherapy and stem cell transplant. Four patients died after a median follow-up of 4.5 years (range, 1 month to 6 years). Two patients died due to necrotizing fasciitis. One patient is alive 4 years after the diagnosis. All patients had plasmablastic PCM. 2/5 patients had bone marrow fibrosis (2+). Three had kappa and 2 had lambda light chain expression. Three patients expressed CD56. Two patients had a complex karyotype and 3 had a normal karyotype. None had signs or symptoms of IgG4-related disease.
Conclusions: The frequency of IgG4 PCM correlates with the normal distribution of IgG4 isoform (3-6% of IgG). The patients with IgG4 PCM had typical clinical, laboratory and morphologic features of IgG PCM. Despite high serum levels of IgG4, none had evidence of IgG4-related systemic disease. These findings suggest that increased number of IgG4-positive plasma cells is not the primary pathologic culprit in IgG4-related disease, but rather, is part of secondary inflammatory response to an unidentified agent. Elevated serum level of IgG4 is not sufficient to produce the typical disease presentation and should not be considered diagnostic of IgG4-related disease.
Monday, March 4, 2013 11:00 AM
Proffered Papers: Section C, Monday Morning