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INTRODUCTION
Multiple myeloma (MM) is a plasma cell neoplasia characterized by diffuse tumor infiltration of the bone
marrow. Occasionally, neoplastic plasma cells acquire a different growth pattern generating tumor masses
that are referred to as extramedullary disease (EMD). EMD can arise from skeletal focal lesions, which
disrupt the cortical bone and spread to adjacent tissue forming smaller or larger masses outside the bone,
even though they are in continuity with it. They are called paraskeletal or paraosseous plasmocytoma (PP)
or bone-associated EMD with MM. Furthermore, EMD can appear as extramedullary plasmacytoma (EMP)
[1]
that derives from hematogenous spread forming tumor masses in soft tissues and different organs .
Although PP has a better prognosis than true EMP , in principles EMD has a poorer prognosis and
[2,3]
different biological behavior than classical MM. The pathogenetic mechanisms that distinguish classical
MM, PP, and EMP are still insufficiently known, as are the therapies that would be effective in EMD.
Therefore, additional efforts and research are needed to better understand the pathogenesis of PP and EMP
as the most important prerequisite for better treatment.

Angiogenesis is an important component of the pathogenesis of MM, and there is much evidence that
higher angiogenesis is associated with poorer treatment outcomes and prognosis . Thus far, the influences
[4]
of several proangiogenic factors on neovascularization itself, as well as their association with the response to
[5]
therapy, survival, and prognosis, have been studied in MM .

Osteopontin (OPN) is a chemokine-like protein involved in different aspects of tumor biology, including
enhanced mobility and adhesion of tumor cells, improvement of tumor growth, survival, and promotion of
neoangiogenesis in various hematological malignancies . Some earlier studies showed an association
[6,7]
among OPN production/expression, tumor burden, bone disease, and angiogenesis in MM .
[8,9]
We report two cases of PP with plasmablastic morphology in myeloma patients and an aggressive course of
disease. Our aim was to evaluate the extent of angiogenesis (microvessel density) in paraskeletal masses and
the expression of OPN in myeloma cells, since both factors may be potential therapeutic targets in EMD.

CASE REPORTS
Immunohistochemical staining
To estimate the angiogenesis and OPN expression in our patients, immunohistochemical staining with anti-
CD34 class II (m7165 clone QBEnd10, DAKO, Glostrup, Denmark, dilution 1:500, incubation 30 min at
room temperature) and anti-OPN (OP3 N, Novocastra, Newcastele upon Tyne, UK, dilution 1:100,
incubation 60 min at room temperature) was performed on sections from formalin-fixed and paraffin-
embedded tissue blocks of paraosseous plasmacytoma by using EnVision FLEX, High pH (Link) Code
K8000 (Glostrup, Denmark). For negative control, the slides were stained by substituting the primary
antibody with buffer solution (DAKO).

To determine the angiogenesis, slides were scanned under low power to identify the three areas with the
greatest number of microvessels. These areas were then evaluated at 400 × magnification. The number of
vessels in the entire field was determined for each, and the average was expressed as microvessel density
(MVD). The immunoreactivity of OPN was evaluated on the basis of the percentage of positive plasma cells.

Case 1
Our first patient, a 67-year-old female with a previous history of ischemic heart disease, heart attack and
percutaneous coronary intervention, arterial hypertension, and type II diabetes, was diagnosed as MM, IgG
lambda, ISS II, with symptomatic anemia and extensive osteolytic lesions at presentation. The serum