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Valković et al. J Cancer Metastasis Treat 2022;8:16 https://dx.doi.org/10.20517/2394-4722.2021.208 Page 5 of 7

(pomalidomide, bortezomib and dexamethasone) is in progress.

In this case, maxillar sinus paraosseous plasmacytoma was analyzed, and MVD was 23, while expression of
OPN was assessed as 100% [Figure 2E and F].

DISCUSSION
One of the largest European myeloma registries showed that 14.5% of myeloma patients had PP and 3.7%
[10]
had EMP at diagnosis . At relapse, the incidence of PP rises up to 34% and EMP up to 10% [11,12] . In the final
stage of the disease, an extraskeletal involvement is observed in approximately 70% of cases studied with
[13]
autopsy, with a peculiar involvement of visceral sites . For now, there is no firm evidence that could
establish an association between EMD and any of the drugs for the treatment of MM, nor can it be
concluded that the use of novel drugs is associated with a more frequent occurrence of EMD. The biological
mechanisms behind the acquisition of the EMD-forming phenotype have not yet been fully elucidated. It
seems that TP53 deletions/mutations and RAS mutations are more frequent in EMD than in standard
myeloma [14,15] . However, these cytogenetic changes are also characteristic of the later stages of relapsing and
refractory disease without EMD. Diversely, the cyclin D1 pathway seems to favor the bone marrow homing,
[16]
protecting from extramedullary localizations, as t(11;14) is not observed in MM patients with EMD . All
this suggests that different microenvironmental factors are the main drivers in pathogenesis of EMD.
Therefore, an increased expression of CXCR4 and CXCL12 plays a major role in promoting a bone marrow-
independent behavior, favoring dissemination and homing to distant and unusual sites . Other
[17]
mechanisms are represented by increased expression of CD44 and reduced expression of several adhesion
molecules, in particular VLA-4 and CD56, and chemokine receptors, such as CCR1 and CCR2 [18,19] .

The role of angiogenesis in the pathogenesis of EMD in contrast to MM has not been very clearly
elucidated. Hedvat et al. demonstrated that different genes involved in angiogenesis and adhesion, such as
[20]
angiopoietin-1, Notch3, and fibronectin-1, were upregulated in EMP compared with MM. The same
authors reported that plasma cells in EMD are positive by immunohistochemical staining for CD31 and
endoglin, both angiogenic factors . These data suggest that angiogenesis may play a role in the
[20]
pathogenesis of EMD. In general, EMD is associated with aggressive disease and shorter progression-free
survival and overall survival (OS), albeit treated with new drugs . Pour et al. showed a significantly
[12]
[21]
longer OS for myeloma patients without EMD in comparison with those who had EMD (109 months vs. 38
months). Similarly, Mangiacavalli et al. found that patients without EMD showed a significantly longer
[22]
OS compared to EMD patients (median OS 11 years vs. 2 years). The outcome was significantly worse for
EMP patients compared to PP patients (median OS 1.6 years vs. 2.4 years) .
[22]
Our previous results show an association between serum OPN concentration and bone disease intensity in
[8]
patients with MM . Therefore, we believe that OPN is an important factor in the progression of MM that
also affects bone metabolism and promotes angiogenesis, which is indicated by the works of some other
researchers . We did not find in the literature a description of OPN expression in EMD. In this short
[23]
description of two patients, we decided to determine angiogenesis (MVD) and expression of OPN in PP
with extensive extramedullary mass showing plasmablastic morphology that is otherwise a characteristic of
aggressive EMP . In both cases, the MVD was more than 20; thus, the angiogenesis could be established as
[24]
high grade . Therefore, high MVD in the tumor micro-ecosystem and OPN expression in plasma cells
[25]
were found to be supporting our hypothesis that angiogenesis and OPN could play a biological role in
EMD, both in EMP and in PP with plasmablastic morphology and an aggressive course of disease.
Unfortunately, at the time of taking tumor tissue samples for immunohistochemical analysis, no serum
samples were taken to determine the serum concentration of OPN. Additional interesting information