Interpreting MYC and BCL2 in diffuse large B-cell lymphoma

Translocations involving the MYC gene are the cytogenetic hallmark of Burkitt lymphoma (BL) and most commonly involve chromosomes 8 and 14 [1]. This leads to deregulated MYC expression and resultant up-regulation of cell proliferation genes that promote tumor survival [2]. While constitutive MYC overexpression is a classical feature of Burkitt lymphoma, recurrent MYC translocations in other aggressive B-cell lymphomas such as diffuse large B-cell lymphoma (including plasmablastic lymphoma) have recently been described [3–5]. In fact, up to 10% of diffuse large B-cell lymphomas (DLBCLs) harbor a MYC rearrangement. This has clinical relevance in that several studies have now demonstrated that this portends a worse prognosis with standard treatment [4,6]. In DLBCL, there are likely to be different mechanisms of MYC activation and overexpression, other than the presence of a translocation. The prognostic role of high protein expression of MYC in the absence of a translocation has not been well established thus far, and is the subject of many recent clinical trials. In addition, when MYC is highly expressed, the role of high and low expression of other proteins such as BCL2 and BCL6, with or without concomitant translocations, is an area of intense clinical interest.

Herein, Kojima and colleagues retrospectively investigated the prognostic impact of a MYC rearrangement (as well as BCL2 and CD5 expression and postulated cell of origin) in a multicenter study of Japanese patients with DLBCL who received rituximab-containing chemotherapy [7]. Their findings were consistent with other groups in that they showed, at 3 years’ follow-up, a significantly inferior progression-free (30% vs. 57.8%) and overall survival (50% vs. 67.8%) in the MYC-rearranged patients. CD5 and BCL2 expression did not predict outcome, and of three algorithms that were used to predict cell of origin, both the Hans and Muris methods demonstrated an inferior outcome for (predicted) non-germinal center tumors.

While several groups have demonstrated a negative prognostic impact of a MYC rearrangement in patients with DLBCL treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) – with or without the addition of rituximab ^® – the role of high MYC protein expression in the absence of a rearrangement is much less clear. Three recent studies have specifically investigated the association of high MYC expression by immunohistochemistry with clinical outcome [8–10]. In the first two of these, the co-expression of BCL2 with MYC conferred a poor outcome following R-CHOP, and the third (RICOVER) study identified a group of elderly patients with high MYC and BCL2 but low BCL6 who had an inferior outcome after R-CHOP. In these studies, interestingly, the prognostic predictability of immunohistochemistry held up even in the absence of translocations by fluorescence in situ hybridization (FISH).

So how do we interpret the findings of these various studies with respect to the role of immunohistochemistry, and should they influence how we approach newly diagnosed patients with DLBCL? While FISH as a technique for detecting gene-activating breaks in MYC, BCL2 and BCL6 is well established and has high specificity and reproducibility, this is not always the case with immunohistochemistry. Among different centers, the reproducibility of immunohistochemical results may be challenging due to technical and interpretative variability. Techniques such as fixation and processing methods as well as choice of antibody can differ significantly, as can scoring of staining and implementation of cut-offs for positive versus negative interpretation. This does not diminish the importance of these findings, but suggests that these results should be validated in a prospective setting where large cohorts of patients receive identical therapy and standardized immunohistochemical analyses are implemented from the outset.

It is also interesting to consider what underlying tumor biology and critical pathways and mutations are driving expression of these various markers. While many of these studies have interestingly demonstrated the persistence of a negative prognostic impact of high MYC and BCL2 after adjusting for cell of origin, this also warrants further investigation and prospective validation with techniques other than immunohistochemistry algorithms to predict cell of origin. At this point in time, it is unclear what the optimal management of patients who have tumors with MYC-rearrangements (with or without rearranged BCL2) or high MYC/BCL2 protein expression should be. Therefore, these patients should be considered for enrollment in prospective studies that evaluate novel approaches and incorporate investigation and analysis of tumor biology.

Potential conflict of interest

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