Solitary plasmacytoma and multiple myeloma: adhesion molecule and chemokine receptor expression patterns

Abstract

Despite significant differences in terms of both location and clinical behaviour of multiple myeloma (MM) and solitary plasmacytoma (SP), the plasma cells of each are morphologically indistinguishable. As the interaction between the plasma cell and its microenvironment is increasingly recognised to play an important role in the pathogenesis of MM, we performed a screening investigation to examine whether differing cellular adhesion molecule (CAM) or chemokine receptor expression profiles may contribute to the contrasting disease presentations and natural histories of the two conditions. With ethical approval, archival biopsies were obtained from patients with either SP (n = 14) or MM (n = 11). Ten had solitary bone plasmacytoma (two scapular, two rib, three vertebral, fibula, pubic ramus, glenoid), four had solitary extramedullary plasmacytoma (thigh, para-aortic, vallecula, maxillary sinus). Ten biopsies were obtained at the time of diagnosis, two were taken at disease relapse. No patient had circulating plasma cells in peripheral blood. Indirect immunoperoxidase staining, using standard immunohistochemistry methods, was used to examine eleven molecules with a known or suspected role in the pathogenesis of MM (Table I). Slides were examined blind and results were expressed as the percentage of positively stained plasma cells throughout the entire biopsy section. To allow statistical analysis, positive staining was scored in six groups of 0%, 1–10%, 11–30%, 31–50%, 51–70% and 71–100% expression. Statistical analysis was performed using Wilcoxon Rank Sum Test with Bonferroni adjustment; using this method P-values below 0·0045 were considered significant. Only CD49d (α4) showed a statistically significant difference between MM and SP (P = 0·0006). The statistically significant reduction in α4 expression on plasma cells of SP may be an important observation in understanding the differing characteristics of MM and SP. Cell–cell binding of α4, as VLA-4 [very late antigen-4(α4β1)], to its ligands, fibronectin and VCAM-1 (vascular cell adhesion molecule-1), has been shown, in-vitro, to be involved in the promotion of plasma cell colonisation, prevention of cell apoptosis and development of cytotoxin resistance (Okada & Hawley, 1995; Damanio et al, 1999). Such events are inhibited by the use of neutralising antibodies against α4 alone, thus suggesting this is the important functional molecule (Mori et al, 2004). Lower cellular expression of α4 on the plasma cells of SP would help to explain the lower tendency to colonise within the bone marrow and their generally greater susceptibility to therapy. Chemokine (C-X-C motif) receptor 4 (CXCR4) expression levels in MM and SP reached borderline statistical significance by strict Bonferroni analysis. MM cells have been shown to both strongly express CXCR4 and migrate in response to stromal cell-derived factor 1 (SDF-1), constitutively produced by bone marrow stromal cells (Moller et al, 2003). Our study confirmed strong expression of CXCR4 on MM plasma cells but suggested reduced expression by SP plasma cells, which may make them chemotactically less susceptible to SDF-1. Binding of CXCR4 to SDF-1 is also thought to transiently upregulate α4β1 (VLA-4) surface expression (Sanz-Rodriguez et al, 2001; Parmo-Cabanas et al, 2004). The lack of this interaction in SP plasma cells may contribute to the reduced expression of α4 demonstrated here. Much work clearly remains to be done in this field. We have identified two molecules, CD49d and CXCR4, which we feel warrant further investigation. This may lead to a better understanding of the contrasting disease patterns of SP and MM – a prerequisite if future targeted therapy is to be developed.