Intracellular and extracellular immunoglobulin crystals assuming a multitude of geometric shapes in an IgG‐λ plasma cell neoplasm

Abstract

Intracytoplasmic immunoglobulin deposition is frequently associated with plasma cell neoplasms but generally takes on a globular form (Russell bodies). The presence of crystalline immunoglobulin structures within malignant plasma cells occurs rarely 1-7. Here we show images of a post-treatment bone marrow biopsy from a 47-year-old woman diagnosed with a plasma cell neoplasm based on the presence of a serum monoclonal IgG-λ paraprotein (0.5 g/dL) and 30% plasma cells with cytoplasmic λ light chain restriction demonstrated by flow cytometry 8. Although she initially achieved a complete remission with intensive therapy, this bone marrow biopsy shows early progression of disease with 10–15% monoclonal λ light chain-restricted plasma cells. Additionally, focal areas containing large, rhomboidal-, hexagonal-, rectangular-, and square-shaped crystalline structures were noted in both the bone marrow aspirate (Image 1A, Wright-Geimsa stain, arrowheads) and trephine biopsy specimens [Image 1B, hematoxylin & eosin (H&E) stain]. Scattered lymphohistiocytic aggregates infiltrated by eosinophils and occasional multinucleated giant cells were present (Image 1C and inset, H&E). Some of the crystals are clearly extracellular (Image 1C, arrows) while others appear to be intracytoplasmic as suggested by flattening of the nuclei in cells juxtaposed to crystals (Image 1C, arrowheads). An immunohistochemical stain for CD138 highlights plasma cells (Image 1D) and outlines the intracellular subset of crystals. Stains for κ and λ light chains show λ light chain restriction, and the crystals are similarly outlined by the λ (Image 1E), but not the κ, stain (Image 1F). Immunostaining for CD68 delineated macrophages and giant cells but did not outline the crystalloid structures, thus supporting the plasma cell localization of the crystals. Staining for acid-fast bacteria and fungus was negative throughout, and a congo red stain did not highlight any amyloid deposits nor did it mark the crystals. Of note, the patient's CBC showed no cytopenias at this time, though there was recurrence of the serum monoclonal paraprotein (0.86 g/dL IgG-λ). She remains alive with a normal CBC and stable marrow disease 18 months after high-dose therapy. Although crystal deposition within plasma cells has been reported in reactive conditions, including rheumatologic disorders and helicobacter-associated gastritis, the monoclonal nature of the immunoglobulin in this case as demonstrated by both flow cytometry and immunohistochemical analysis argues against a reactive process. Crystal storing histiocytosis (CSH), in which immunoglobulin crystals are deposited in macrophages is an unusual variant of this phenomenon and is also associated with plasma cell and other lymphoproliferative neoplasms 9. The κ light chains predominate in CSH, as they appear to be more resistant to degradation by macrophage lysosomal enzymes than λ light chains. The mechanism underlying the accumulation of immunoglobulin crystals within neoplastic plasma cells as presented here is not certain but does not appear to favor either κ or λ light chains and may involve abnormalities in protein synthetic and transport pathways. The significance of immunoglobulin crystals in plasma cell myeloma is unknown, but it has been hypothesized that their presence may portend a nonprogressive clinical course and therefore a favorable prognosis 10.