There have only been a few studies conducted to investigate the morphological features of plasmacytoma biopsies. Some studies have shown that cells in bone plasmacytoma are more often characterized by a mature morphology, while cells in extramedullary plasmacytoma are represented by young, immature cell types. 9–11 It should be noted that most of these works are devoted to the study of extramedullary MM relapses. However, importantly, the morphological features of tumour substrate cells in newly diagnosed MM and relapsed disease may differ.
We investigated the morphological features of the plasmacytoma substrate in 14 patients with bone plasmacytoma and 7 patients with extramedullary plasmacytoma among newly diagnosed MM patients. The small sample size was due to the rare rate of plasmacytoma, especially extramedullary foci. Moreover, biopsying for plasmacytoma is not a compulsory method for MM diagnosis. If we have irrefutable proof of diagnosis (CRAB syndrome or infiltration of plasma cells into the bone marrow), we need to start treatment without biopsying for plasmacytoma. However, sometimes the diagnosis of MM is established after tumour biopsy. This group of patients is presented in our study. When comparing the morphological features of bone and extramedullary plasmacytoma, no significant differences were revealed; however, the substrate of extramedullary plasmacytoma was more often represented by tumour cells with an immature morphology than was the bone plasmacytoma substrate (57.1% vs. 28.6%, respectively).
A possible mechanism for tumour plasma cell expansion beyond the bone marrow is the downregulation of adhesion molecule expression (for example, CD56), which results in cells losing their connection with the stromal microenvironment. 18,19 The role of the expression of another cell adhesion molecule, CD166, is now being actively investigated in MM. A study on mouse models showed that CD166 blocked osteoblastogenesis by inhibiting RUNX2 expression, which is an important transcription factor influencing the differentiation of osteoblasts. In addition, CD166 activated osteoclastogenesis, shifting the balance between RANKL and osteoprotegerin. CD166 blockade in mouse myeloma cells resulted in longer survival, a lower total tumour mass, and less pronounced osteolysis than in mouse with CD166-positive cells.20 Thus, it is assumed that CD166 is a predictor for lytic bone lesions, as it participates in osteogenic modulation.
In our study, a statistically significant difference in the expression of CD166 was revealed after comparing the expression of this marker in bone and extramedullary plasmacytoma cells. The mean values of CD166 expression in bone plasmacytoma cells were significantly higher than those in the extramedullary plasmacytoma cells (p = 0.033) and amounted to 36.29 ± 7.61% versus 9.57 ± 8.46%, respectively. This may indicate the involvement of CD166 in the mechanisms of bone destruction. In addition, it was demonstrated that the mean expression values of CD166 in plasmacytoma cells with a mature morphology were significantly higher than those in plasmacytoma cells with an immature morphology (p = 0.012) and amounted to 38.23 ± 8.37% versus 9.75 ± 5.87%, respectively.
SDF-1α and a chemokine receptor, CXCR4, are involved in the processes of cell homing and cell migration. It has been indicated that myeloma cells can express these markers on their surface.21,22 Downregulation of chemokine receptor expression is considered to be a possible mechanism leading to a weakening of the connection between myeloma cells and the bone marrow stroma, thus promoting myeloma cell dissemination. The absence of CXCR4 on the tumour plasma cell surface, while not being a strict predictive factor of extramedullary lesions, probably plays a role in the formation of extraosseous foci.
There have been only a few studies on the roles of chemokine receptors in MM pathogenesis, and the data presented in the literature are contradictory. We demonstrated a high frequency of CXCR4 expression in plasmacytoma cells. These results are comparable with data from a study by M. Weinstock et al., where 38.5% of patients showed CXCR4 expression in the tumour substrate.23
According to the data presented in the literature, the proliferative activity of tumour cells in MM is low. An increased Ki-67 index is a marker of active cell growth and correlates with the progression of the disease. Researchers at the Mayo Clinic showed that a high level of proliferative activity, even with a minimum number of plasma cells in the bone marrow, is a risk factor for early relapse and high mortality.24
We noticed that in extramedullary plasmacytoma cells, there were higher values for the Ki-67 index observed in comparison with bone plasmacytoma cells. These data are comparable with the results of a single-centre study from Germany, which demonstrated high proliferative activity in extramedullary plasmacytoma biopsy specimens from 24 patients with extramedullary MM relapse.25 Interestingly, our study shows that Ki67 expression is higher in extramedullary plasmacytoma than in bone plasmacytoma regardless of cell morphology. There has been an insufficient number of studies devoted to the investigation of c-MYC in the tumour substrate of plasmacytoma. In a study by L. Billecke et al., overexpression of the c-MYC gene in the plasmacytoma substrate was observed in 18% of patients with bone plasmacytoma and 28% of patients with extramedullary plasmacytoma.26
There have been no studies of plasmacytoma substrates in large patient populations.
This is partly because extramedullary lesions in MM are rare and it is not always possible to perform a plasmacytoma biopsy due to its inaccessible localization.