The undefined three cases showing mantle cell morphology without cyclin D1expression and IGH/CCND1 rearrangement, which required further study including DNA microarray analysis, to define a diagnostic category. The presence of these cases implies that the REAL/WHO classification is not sufficient to classify diverse mature B-cell lymphoid malignancies. Recently, clusters of cases between typical CLL and MCL were reported based on flow cytometry, and they were found to be correlated with prognosis (13
). Thus, an additional study should contribute to our understanding of mature B-cell lymphoid malignancies.
CD5+ cases account for approximately 5-10% of DLBCL, and usually the frequency of infiltration of bone marrow, the most frequent site of extranodal involvement, is reported to be around 25% (4
). In the present study, the frequency of CD5+ DLBCL among the 25 cases of CD5 positive B-cell lymphoid malignancies involving the bone marrow was 24%, which is not an insignificant number. In view of the fact that reports of CD5+ DLBCL are rare in Korea, a serious underestimation of CD5+ DLBCL is suspected.
De novo CD5+ DLBCL has been recognized to have distinct features; a high age at onset, a female preponderance, a frequent association with poor prognostic components, and an aggressive clinical course (5
). Our cases also showed a higher average age of onset than general DLBCL in Korea (2
) and frequent extranodal infiltration of both liver and spleen.
To explain the correlation between CD5 expression and an unfavorable prognosis, genetic aberrations of CD5+ DLBCL have been evaluated in a number of ways. Initially, an investigation targeting D13S25, p16, and p53 was performed, and the deletion at the D13S25 locus and loss of p16 were revealed, which implies an early transforming event resulting in aggressive DLBCL (8
). In addition to the above mentioned genetic aberrations, the expressions of several other markers such as BCL2, cyclin D3, cyclin B, or survivin have been proposed to be associated with poor outcome (10
). Following a DNA microarray analysis, it was reported that the outcome of patients with DLBCL might be influenced by gene expression profiles other than histologic profiles (14
), and that the gene signature is associated with the control of cell kinetics and host immune response (15
). Thus, study of the genetic aberrations of CD5+ DLBCL would help elucidate previously indistinct diagnostic categories.
The aggressive behavior of CD5+ DLBCL has also been attributed to a tendency to spread widely within tissue, and this phenomenon was associated with the CD5 molecule interacting as a ligand with heavy-chain variable framework regions of surface Ig (16
). The latest study on this topic revealed that the aggressiveness of CD5+ DLBCL might be due to the overexpression of integrin β1 and/or CD36 adhesion molecules (17
). Integrin β1, an adhesion molecule, plays an important role in B-cell lymphoma adhesion and chemotaxis on fibronectin (18
). The protein expression of integrin β1 has already been reported to be associated with extranodal involvement in NHL (19
). The CD36 antigen is transcriptionally regulated by Oct-2, which is a regulator of B-cell differentiation, and its expression is reported to be an indicator of tumor metastasis (20
). However, CD36 in CD5+ DLBCL tissues is expressed in the vascular endothelial cells rather than in malignant cells. This finding implies the pathophysiologic role of the vascular endothelium as an integral part of the cancer, and would explain the high frequency of intravascular or intrasinusoidal infiltration observed in de novo CD5+ DLBCL (5
In conclusion, the present study found that de novo CD5+ DLBCL, with its distinct clinicopathologic features, is present in Korea. Moreover, the characteristics of our CD5+ DLBCL cases share many similarities with those previously reported. Since CD5+ DLBCL may form a distinct subgroup of DLBCLs, there is a need to determine the presence or absence of CD5 antigen expression in all DLBCL cases. It is thus essential to study CD5 expression in DLBCL by immunohistochemistry or flow cytometry, as such findings would be helpful for to predict prognosis and determine future therapeutic strategy. In addition, cytogenetic studies and molecular analyses for proto-oncogenes and tumor suppressor genes would provide insights into the pathogenesis of CD5+ DLBCL, and provide information relevant to the establishment of innovative therapeutic strategies. Furthermore, regarding the difficulty in making a diagnosis of heterogeneous mature B-cell lymphomas, comprehensive flow cytometry, cytogenetic and molecular genetic study would aid in the diagnosis of all mature B cell lymphoid malignancies.