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Diffuse large B-cell lymphoma in and of the bone. Forms and potential precursors

Primary diffuse large B-cell lymphoma of the bone (PB-DLBCL) is a rare event and is a diagnosis by exclusion of secondary bone involvement. Here we review the literature regarding PB-DLBCL and give essentials for this diagnosis. Furthermore, we give an overview of potential precursors and discuss chronic recurrent multifocal osteomyelitis (CRMO) as a potential risk factor for PB-DLBCL development in the young. Primary Bone Diffuse Large B-cell Lymphoma (PB-DLBCL) Primary bone non-Hodgkin lymphoma, other than plasmocytic myeloma and solitary plasmacytoma of bone, is defined by the World Health Organization (WHO) as a neoplasm composed of malignant lymphoid cells, with one or more bone lesions; by definition, lymph node or other extranodal lesions are not involved [1]. Primary lymphoma of bone is rare and accounts for less than 2% of adult lymphomas [2] and approximatively for 7 % of malignant bone tumors. Between 70 and 80% of primary bone lymphomas are classified as diffuse large B-cell lymphoma (DLBCL), the rest are anaplastic large, mostly ALK-positive T-cell lymphomas [3–5]. These aggressive lymphomas have preference for the axial skeleton and long tubular bones. The most commonly affected bones are femur, ilium, vertebrae, and humerus. PB-DLBCL is exceedingly rare in the young and tends to occur at the age of 45 while the peak incidence is in the range of 75 to 79 years [6]. Main symptoms are pain, local tenderness, redness, swelling, and nerve compression (related to the tumor location). Pathological fractures occur in 10–20% of PB-DLBCL, and, therefore, this is the most frequent complication at presentation of primary bone lymphoma [7]. The standard treatment for all kinds of DLBCL is the R-CHOP (Rituximab immunotherapy, i.e., an anti CD20 monoclonal antibody), combined with cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone), the total number of cycles and addition of radiation therapy depending on tumor bulk [8]. DLBCL is a neoplasm of diffusely arranged medium or large lymphoid B-cells with nuclei more than twice the size of normal lymphocytes nuclei featuring open chromatin [9]. These lymphomas are CD20 + (▶Figure 1 A–D), CD3-, CyclinD1-, CD138and have a high proliferation (KI-67) index generally above 50%. Traditionally, DLBCLs were further characterized by cytomorphology as centroblastic, immunoblastic, plasmoblastic, and anaplastic. The current WHO classification still lists these variants, however, has promoted the transciptomebased molecular subgrouping with the two major subtypes activated B-cell-like (ABC) and germinal-center B-cell-like (GCB); by immunohistochemistry, this subdivision can be approximately done using an algorithm proposed by Hans following the expression of CD10, Bcl-6, and MUM-1 [10]. More recently, multiplatform genetic analysis allowed the identification of five subtypes of DLBCL making a further step in the direction of precision medicine [11, 12]. PB-DLBCL has been found to be predominantly of the ABC type [13]. Regarding bone as primary DLBCL location, the clinical significance of multifocal bone involvement has been investigated, in comparison with unifocal primary and secondary bone lymphoma. Multifocal primary bone DLBCL is very rare and constitutes around 3–10% of cases in the largest reported series of primary bone lymphomas [14]. Findings of Wu et al. (2014) suggest a major similarity between multifocal primary bone and secondary involvement rather than with unifocal DLBCL of the bone [15]. On the other hand, in the study of Messina et al. (2014) prognosis of multifocal primary bone DLBCL is significantly better than bone involvement at advanced stages of systemic DLBCL [14]. The relationship between chronic inflammation and lymphoma development is well established for marginal B-cell lymphoma of the salivary gland and Sjögrens’ disease, of lacrimal gland and chlamydial dacryoadenitis, of gastric marginal B-cell lymphoma and chronic gastritis, e.g., due to H. pylori infection, and for gluten-sensitive enteropathy-associated intestinal T-cell lymphoma [9]. The relationship is far less clear, if at all existing for chronic inflammation of the bone and subsequent lymphoma development. We here list anecdotal observations suggesting such a relationship. ▪ Rheumatoid arthritis: Patients with rheumatoid arthritis (RA) are at a double risk of developing malignant lymphoma and studies and case series of RA-associated lymphomas indicate an increased proportion of diffuse large Bcell lymphomas (DLBCLs) in RA patients [16]. ▪ Implantation of cobalt-chromiummolybdenum alloy joint prosthesis: The coincidence of PB-DLBCL was described in a patient during a surgical revision of the loosened prosthesis. Debris in the periprosthetic membrane are antigenic and lead to chronic inflammation through macrophage activation [17]. The pathogenesis has also been correlated with the release of chromium and cobalt ions from the