Back to basics: the complete blood cell count adds to the ability of immunohistochemistry in diffuse large B-cell lymphoma prognosis

Diffuse large B-cell lymphoma (DLBCL) is clinically heterogeneous, encompassing a variety of diagnostic presentations and responses to therapy. Yet despite, or perhaps because of, its crudity, the international prognostic index (IPI) still remains by far the most widely adopted prognosticator. With increasing numbers of new therapies on the horizon, it is critical that new ways to stratify this disease are validated. Such strategies must take into account the lymphoma's biological characteristics. Gene expression profiling (GEP) of DLBCL has proved most successful, and has been used to define two distinct diseases, based on the putative malignant B-cell's cell of origin (COO). Germinal center B-cell-like (GCB) DLBCL has a superior prognosis following chemo-immunotherapy to that of activated B-cell-like (ABC) DLBCL [1]. As yet, GEP has not had wide applicability outside of the research setting, due to prohibitive costs and the lack of a robust platform that could be applied to paraffin-embedded sections. Attempts have been made to develop more “user-friendly” diagnostic tests, using proteins that are differentially expressed in the two types of DLBCL. Several immunohistochemical algorithms have been proposed to approximate to GEP (with mixed results), including that proposed by Hans and colleagues ,[2].

However, that most basic, reproducible, cheap and widely used of clinical measures, the complete blood cell count (CBC), has until now been largely disregarded. In this issue, the article by Porrata and colleagues [3] at the Mayo Clinic suggests that we should think again. They postulate that the CBC can be used as a surrogate of the interaction between the malignant B-cell and host immune microenvironment previously alluded to in GEP studies [4]. They report on a retrospective cohort of 99 R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) treated patients in whom the absolute monocyte count and absolute lymphocyte count (AMC/ALC) score had prognostic significance in DLBCL. A previous study by the group has already established that the AMC/ALC score predicts progression-free and overall survival independent of the IPI for DLBCL [5]. In this issue they confirm this, and also identify the AMC/ALC score as an independent predictor of outcome in relation to COO (by Hans).

The ALC at diagnosis has already been described as a prognostic factor for survival in DLBCL [6]. Much recent interest has focused on tumor-associated macrophages (TAMs), which have been shown to promote disease progression and support tumor cell survival and expansion. TAMs and the related monocytic myeloid-derived suppressor cells (moMDSCs) also promote tumor angiogenesis and suppress adaptive immune responses. Monocytes from patients with non-Hodgkin lymphoma (NHL) suppress T-cell proliferation, are unresponsive to Toll-like receptor stimulation by CpG and resist maturation into CD83 + dendritic cells [7]. Interestingly, patients with increased ratios of CD14+ HLA-DRlo/neg monocytes have more advanced disease and suppressed immune functions, indicating that CD14+ HLA-DRlo/neg monocytes are a pivotal contributor to systemic immunosuppression in NHL.

Although in the current article the contribution of the monocyte phenotype or function is not specifically addressed, it is likely that the type, in addition to the number of monocytes circulating in the peripheral blood of patients with DLBCL, may impact on outcome. Monocytes/macrophages are versatile and functionally plastic cells that have an extraordinary repertoire of functions and a range of activation states. The extremes of monocyte/ macrophage polarization have been given the terms M1 and M2 [8]. M1 polarized macrophages have high levels of inducible nitric oxide synthase, whereas the arginase pathway predominates in the M2. There are key differences in their cytokine production: M1 cells produce the T-helper type 1 (TH1) cytokines interleukin-12 (IL-12) and tumor necrosis factor, whereas M2 macrophages produce IL-10, IL-1 receptor antagonist and the type II IL-1 decoy receptor. Analysis of the GEP of circulating monocytes in patients with DLBCL would provide crucial insights into the contribution of monocytes to disease progression.

Notably, Porrata et al. [3] could further stratify the COO by using the AMC/ALC score to identify patients at high and low risk. Clearly, large prospective validations are required. Perhaps one day a combined index incorporating IPI, COO and AMC/ALC might even be the universal standard. Alternatively, its importance is not only because it can be used as a prognostic tool, but also because AMC/ALC gives us important insights into the complex, dynamic and interconnected nature of DLBCL.

Potential conflict of interest

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