Burkitt lymphoma versus diffuse large B-cell lymphoma

Abstract

Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) represent distinct entities among aggressive B-cell non-Hodgkin lymphomas (B-NHLs) in the WHO classification [1]. According to the clinical setting of the occurrence, endemic, sporadic and immunodeficiency-associated BL can be distinguished as clinical variants. The diagnosis of classical BL rests on the presence of a monotonous infiltrate of mediumsized blastic lymphoid cells that show round nuclei with clumped chromatin and multiple, centrally located nucleoli. The tumor cells have a high proliferation rate and intermingled macrophages containing apoptotic debris lead to the morphological aspect of a ‘starry sky’ [1] pattern. Immunophenotypic features of BL include positivity of tumor cells for CD20 and CD10 (and BCL6), negativity for BCL2 and a proliferation fraction measured by Ki-67 immunohistochemistry of nearly 100%. In addition, a chromosomal rearrangement of MYC, usually in form of the classical translocation t(8;14)(q24;q32) should be demonstrated at the molecular level. In contrast, DLBCL is characterized by the proliferation of large neoplastic B-cells comprising centroblastic, immunoblastic, T-cell/histiocyte-rich and anaplastic morphological variants [1]. While the differential diagnosis between BL and DLBCL may appear clear-cut in theory, daily practice shows that aggressive B-NHLs are encountered that display some (but not all) morphologic, immunophenotypic and genetic features of classical BL. For these cases, the terms ‘atypical BL’ or ‘Burkitt-like lymphomas’ have been coined. According to the criteria of the WHO, the term ‘atypical BL’ denotes true BL with some unusual—for the most part cytological—features, while the term ‘Burkitt-like lymphoma’ is a non-compromising diagnosis. Hence, whether these cases are biologically and clinically closer to BL or DLBCL is currently a matter of debate. For example, are aggressive B-NHLs with morphological features of classical BL, positivity for CD20 and CD10 and a Ki-67 index of 100% ‘true’ BL, when they show coexpression of BCL2? Likewise, do ‘true’ BL exist that lack genetic rearrangements of MYC? Clinically, the diagnosis of the hematopathologist is of major importance, since treatment regimens for BL [2] and DLBCL [3] differ significantly. Specifically, adult BL are frequently treated with high-intensity chemotherapy regimens including central nervous system prophylaxis leading to an overall survival of 50–70% of these patients [2]. Classical BL, i.e. B-NHL that fulfills all of the above mentioned diagnostic criteria, can be highly reproducibly diagnosed among hematopathologists and, therefore, these cases do not represent a problem—neither with respect to their proper classification nor to the therapeutic implication of the diagnosis. However, what does the diagnosis ‘atypical BL’ or ‘Burkitt-like lymphoma’, which has an unacceptably low interand intra-observer reproducibility [4] imply for the treating hematologist and where should pathologists draw the line between the diagnosis of atypical BL and DLBCL? On the genetic level, translocations involving MYC are a hallmark feature of classical BL. Information on the MYC translocation status, however, is insufficient to discriminate between BL and DLBCL, since 5–10% of DLBCLs also carry a MYC translocation [5]. In recent years, several groups have attempted to establish molecular categories within the gray zone between BL and DLBCL. In a study by Haralambieva and colleagues [6], two independent approaches were tested to assign gray zone lymphomas either to the BL or to the DLBCL category. One approach used only information on morphology, immunohistochemistry, age of the patient and site of involvement (without knowledge of any molecular data), whereas in an independent approach immunohistochemical and molecular markers recommended by the WHO classification (positivity for CD10, BCL6, Ki-67 > 90%, negativity for BCL2; presence of aMYC breakpoint, but absence of BCL2 and/or BCL6 breakpoints) were used as a basis for the distinction. In a control group of pediatric BLs, both algorithms were in agreement in 100% of cases. However, only 20% of the investigated gray zone cases fulfilled the criteria of both algorithms suggesting that only a minority of these cases may represent bona fide BL [6]. Nakamura and colleagues [7] investigated 18 cases of B-NHL with proven MYC rearrangement, which were classified as BL or DLBCL based on histological features. Although BLs were characterized by a significantly higher Ki-67 index than DLBCLs and, vice versa, DLBCLs were more frequently positive for BCL2, this study demonstrated a significant overlap between these two groups. A practical approach to the subdivision of highly proliferative BNHL within the spectrum of BL and DLBCL was recently suggested by Cogliatti and coworkers [8]. Based on available information on morphology (categorized as classical BL, atypical BL and DLBCL), immunophenotype (CD20, CD10, The authors report no relationships with companies whose products or services are mentioned in this article.