There have only been a few studies conducted investigating the morphological picture of plasmacytoma biopsies. Some studies have shown that cells in the bone plasmacytoma are more often characterized by a mature morphology, while cells in the 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 the extramedullary MM relapses, and the morphological features of the tumor substrate cells in newly diagnosed MM and the relapse of the disease may differ.
We investigated the morphological features of the plasmacytoma substrate in 14 patients with bone plasmacytoma and 7 patients with extramedullary plasmacytoma in newly diagnosed MM patients. When comparing the morphological picture of the bone and the extramedullary plasmacytoma, no significant differences were revealed; however, the substrate of the extramedullary plasmacytoma compared to the bone plasmacytoma substrate was more often represented by tumor cells with an immature morphology (57.1% vs. 28.6%).
A possible mechanism for the tumor plasma cell expansion beyond the bone marrow is the downregulation of the adhesion molecules expression (for example, CD56), as a result of which the cell loses its connection with the stromal microenvironment. 18,19The role of the expression of another cell adhesion molecule, CD166, is now actively being investigated in MM. A study on mouse models has shown that CD166 blocks osteoblastogenesis by inhibiting the RUNX2 expression, which is an important transcription factor influencing the differentiation of osteoblasts. In addition, CD166 activates osteoclastogenesis, shifting the balance between RANKL and osteoprotegerin. The CD166 blockage in mouse myeloma cells results in a longer survival, lower total tumor mass, and less pronounced osteolysis compared to individuals with CD166-positive cells .20 Thus, it is assumed that CD166 is a predictor for lytic bone lesions, as it participates in osteogenesis modulation.
In our study, a statistically significant difference in the expression of CD166 was revealed after comparing the expression of this marker in cells of the bone and extramedullary plasmacytoma. It was shown that the mean values of the CD166 expression in the bone plasmacytoma cells were significantly higher (p = 0.033) and amounted to 36.29 ± 7.61% versus 9.57 ± 8.46% in the extramedullary plasmacytoma cells. This may indicate the involvement of CD166 in the mechanisms in bone destruction . In addition, it was demonstrated that the mean expression values of CD166 in plasmacytoma cells with a mature morphology were significantly higher (p = 0.012) and amounted to 38.23 ± 8.37% versus 9.75 ± 5.87% in the plasmacytoma cells with an immature morphology.
SDF-1α and a chemokine receptor, CXCR4, are involved in the processes of cell homing and cell migration. It has been proven that myeloma cells can express these markers on their surface.21,22 Downregulation of the chemokine receptors is considered to be a possible mechanism leading to a weakening of the connection between the myeloma cells and the bone marrow stroma, thus promoting their dissemination. The absence of CXCR4 on the tumor 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 few studies on the role of chemokine receptors in the MM pathogenesis, and the data presented in the literature is contradictory. We have demonstrated a high frequency of CXCR4 expression in the plasmacytoma cells. These results are comparable with the data from a study by M. Weinstock et al., where 38.5% of patients showed CXCR4 expression in the tumor substrate.23
According to the data presented in the literature, the proliferative activity of the tumor 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 from 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 the cells of extramedullary plasmacytoma, there were higher values of the Ki-67 index observed in comparison to cells in the bone plasmacytoma. This data is comparable with the results of a single-center study from Germany, which demonstrated a high proliferative activity in the extramedullary plasmacytoma biopsy specimens from 24 patients with extramedullary MM relapce. 25
Interestingly, our study shows that Ki67 is higher in extramedullary plasmacytomas, and that there is no difference in the mature or the immature morphology of a tumor.There has been an insufficient amount of studies devoted to the investigation of c-MYC in the tumor substrate of plasmacytoma. In the study by L. Billecke et al. it was noted that the overexpression of the c-MYC gene in the plasmacytoma substrate was seen in 18% of patients with bone plasmacytoma and in 28% of patients with extramedullary plasmacytoma.26
Given the low frequency of extramedullary lesions in MM, as well as the fact that it is not always possible to perform a plasmacytoma biopsy due to its inaccessible localization, there have been no studies of the plasmacytoma substrates in large patient populations.