Borderland between DLBCL and Burkitt’s lymphoma The pathology of B-cell lymphomas with features intermediate between diffuse large B-cell lymphoma and Burkitt’s lymphoma A. Jack ABSTRACT Haematological Malignancy The diagnosis Burkitt Lymphoma (BL) and its distinction from diffuse large B-cell lymphoma (DLBCL) Diagnostic Service, St James’s is based on the overall pattern of morphological, phenotypic, genetic, clinical, and epidemiological Institute of Oncology, Leeds, UK features. There is variation within each of these parameters and for tumors that deviate from the pro - totypical description of BL, the new category of B-cell lymphoma, unclassifiable with features inter - mediate between BL and DLBCL has been established. This entity is likely to be clinically heteroge - neous, and the borderlines between this group, BL, and DLBCL are open to subjective interpretation Hematology Education: the education program for the and are dependent on the diagnostic techniques used. Patients with these tumors face important annual congress of the European treatment decisions, and the pathological classification needs to be judged by its utility in informing Hematology Association these choices. A combination of immunophenotyping and FISH can be used to define patients who should be considered for intensive chemotherapy and a further group may have poor prognosis 2012;6:187-194 chemorefractory disease. However, data are sparse and many areas of uncertainty remain. New diag - nostic platforms offer the promise of improved clinically effective classification but this will only be achieved if future clinical trials assess new therapies in association with predictive biomarkers. Background However, it is becoming clear that boundaries between BL and DLBCL are blurred, and this Aggressive B-cell lymphomas are a clini - has been formally recognized in the latest edi - cally and pathologically diverse group of tion of the WHO classification through the hematological malignancies that are linked by inclusion of the category B-cell Lymphomas the use of treatment given with curative with features intermediate between DLBCL intent. For many patients, the results of treat - and Burkitt Lymphoma .1 The population inci - ment remain sub-optimal and new options are dence of this group is unknown. While intro - being developed to address the needs of this ducing this new category has merit in that it group. A major challenge in the coming years acknowledges the grey area between the two will be to develop pathological classifications entities rather than attempt to force each case that assist in the targeting therapy to optimize into one or other category, it does little to outcomes, minimize toxicity, and contain address the central clinical question for costs. The relationship between Burkitt patients, which is the choice of therapy. Lymphoma (BL) and diffuse large B-cell lym - phoma (DLBCL) is an excellent example of the difficulties that need to be faced in the Defining Burkitt Lymphoma over the process of aligning pathological classifica - past 50 years tions with treatment options. Ninety percent of patients with aggressive The history of the original description of B-cell lymphoma are currently diagnosed as BL in Uganda is well known and is a land - DLBCL. This group is diverse both clinically mark in oncology. 2 This was catalyst for work and pathologically. Tumors can be classified on cancer genetics, tumor viruses, and the role using gene expression profiling into germinal of the immune system and inflammation in centre, activated B-cell, and type III cate - carcinogenesis. 3 However, the most important gories, although the confidence with which step in the evolution of lymphoma classifica - the assignment is made varies. These pheno - tion was the work of the international consen - typic categories are broadly aligned with sus group that concluded that that BL should molecular and cytogenetic abnormalities, be defined as a tumor consisting of a specific although there is considerable overlap cell type, and that this tumor was not restrict - between the groups and much variation ed to the geographical location, clinical syn - among individual tumors. This complex drome, or population groups described by pathological landscape is matched by diversi - Burkitt in his original publication. 4 Emphasis ty in clinical presentation, tumor progression, was placed on the highly characteristic cellu - and response to treatment. BL accounts for lar morphology of a tumor with a monomor - about 6% of aggressive B-cell lymphomas phic population of medium-sized lymphoid and has historically been regarded as a dis - cells with round nuclei and multiple nucleoli tinct and circumscribed pathological entity. and the ‘starry sky’ pattern of reactive Hematology Education: the education programme for the annual congress of the European Hematology Association | 2012; 6(1) | 187 | 17 th Congress of the European Hematology Association macrophages. The conclusions of this paper, published in nucleoli, and vacuolated cytoplasm. There are high rates 1969, effectively set the agenda for subsequent patholog - of cellular proliferation and apoptosis, the latter giving ical and clinical studies. Interestingly, it is clear from this rise to the ‘starry sky’ pattern. These morphological fea - paper that the expert group recognized that the morpho - tures, with minor variations, are part of the core descrip - logical diagnosis of BL by these criteria was difficult and tion of BL but their practical value in differential diagno - was subject to the vagaries of fixation and tissue process - sis needs to be examined. It has always been recognized ing. It is also important to remember that this definition that these morphological features can be altered substan - preceded the effective treatment of aggressive lymphoma tially by sub-optimal fixation and tissue processing. 4,5 using chemotherapy and the modern understanding of This problem is likely to be compounded by the increas - cellular immunology or carcinogenesis. Cytogenetic stud - ing use of small core biopsy with attendant crushing arti - ies subsequently showed a strong linkage between mor - fact. More important is the question of the reproducibility phologically defined BL and balanced translocations of morphological diagnosis based on these criteria by involving the MYC locus at 8q24 and the immunoglobulin both expert hematopathologists and general pathologists. heavy and light chain loci. In one international study of diagnostic reproducibility These morphological and cytogenetic criteria are the among expert pathologists, the distinction between BL direct antecedent of the current definition, used in the and DLBCL was among the poorest categories in terms of WHO classification, of a tumor of highly proliferative diagnostic concordance. 6 In clinical trials of BL, signifi - monomorphic cells with IG-MYC translocations as a char - cant numbers of cases are deemed to be ineligible follow - acteristic but non-specific feature. No single feature is ing review, 7 and the problem has also been further high - regarded as indispensible, and the diagnosis is based on lighted in recent gene expression studies. 8,9 A high prolif - the overall pattern of the disease. Some variation is per - erative rate is a defining feature of BL and this is usually missible across all the characteristics described – epi - demonstrated using Ki67. While this is a sensitive marker demiology, clinical features, morphology, immunopheno - for BL, it is not specific, and less than half of cases of type, and genetics – meaning that the pathologist needs to aggressive B-cell lymphoma with a high Ki67 fraction judge whether a particular case deviates sufficiently from will have MYC rearrangement. 10 the prototypical description to merit inclusion in the inter - All cases of BL have a germinal centre phenotype. mediate category. This decision could have major impli - Whether this reflects the cell of origin or induction of the cations for how the patient is subsequently treated. phenotype by MYC overexpression is an interesting and Understanding how these variables correlate with open question. 11 In formalin fixed paraffin embedded sec - response to particular treatments and clinical outcomes is tions, the core components of this phenotype are expres - critical to the development of a more robust approach to sion of CD20, CD79, CD10, and BCL6 in the absence of classification. CD5 and CD23. The absence of BCL2 expression increases the sensitivity for detecting cases that have a MYC rearrangement as a sole detectable abnormality. 10 Variables that distinguish BL, B-cell lymphoma However, many tumors with this phenotype will lack a intermediate between BL and DLBCL, and detectable rearrangement, and this is of particular impor - DLBCL tance given that this phenotypic group also includes good prognosis germinal centre type DLBCL. 12,13 In many cases Clinical features of BL with a translocation BCL2, immunocytochemistry may be completely negative, some cases show weak Patients with BL and DLBCL present with nodal or staining and can be difficult to report definitively. What extranodal masses. In a group of patients diagnosed as constitutes weak staining is clearly subjective and few sporadic BL, there is a high incidence of abdominal dis - cases with this feature have been systematically studied. 14 ease particularly around the terminal ileum. This interest - A further compounding problem is the lack of reactivity ing feature of BL is unexplained but