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The quick diagnosis of Burkitt lymphoma (BL) and its clear-cut differentiation from diffuse large B-cell lymphoma (DLBCL) is of great clinical importance because treatment strategies for these two disease entities differ markedly. As these two lymphomas are difficult to distinguish using the current World Health Organization classification, we studied 39 cases of highly proliferative peripheral blastic B-cell lymphoma (HPBCL) to establish a practical differential-diagnostic algorithm. Characteristics set for BL were a typical morphology, a mature B-cell phenotype of CD10+, Bcl-6+ and Bcl-2- tumour cells, a proliferation rate of >95%, and the presence of C-MYC rearrangements in the absence of t(14;18)(q32;q21). Altogether, these characteristics were found in only five of 39 cases, whereas the majority of tumours revealed mosaic features. We then followed a pragmatic stepwise approach for a classification algorithm that included the assessment of C-MYC status to stratify HPBCL into four predefined diagnostic categories (DC), namely DC I (5/39, 12.8%): 'classical BL', DC II (11/39, 28.2%): 'atypical BL', DC III (9/39, 23.1%): 'C-MYC+ DLBCL' and DC IV (14/39, 35.9%): 'C-MYC- HPBCL'. This proposal may serve as a robust and objective operational basis for therapeutic decisions for HPBCL within 1 week and is applicable to be evaluated for its prognostic relevance in clinical trials with uniformly treated patients.