Absolute monocyte count identifies high-risk patients with lymphomas: “absolutely” simple and “counts” mean a lot!

An optimal scoring system is a valuable tool for evaluating newly diagnosed patients with follicular lymphoma (FL), as this category of lymphoma has a variable clinical course with a diverse spectrum of outcome and marked biological heterogeneity. Therapeutic approaches range from a “watch and wait” policy to different and more aggressive chemo-immunotherapeutic regimens, including radio-immunotherapy, and there is no agreement as yet on the optimal therapy for patients with FL. Physicians often need a strategy for “who, when and how” to treat FL in daily practice, and the choice of therapy and decision-making for a newly diagnosed patient can sometimes be difficult on an individual basis.

In 2004, an international cooperative study defined the Follicular Lymphoma International Prognostic Index (FLIPI), consisting of five prognostic parameters: age, Ann Arbor stage, hemoglobin level, number of nodal sites and serum lactate dehydrogenase (LDH) level [1,2]. This scoring system, used worldwide, separates patients into three risk categories: low, intermediate and high, and helps to tailor treatment strategy.

In the same year, a significant advance in the understanding of the biology of FL and the role of “non-malignant cells,” including both immune and stromal cells, was reported [3]. Two “gene-expression signatures” influencing survival patterns were identified, and termed: immune response-1 and immune response-2 [3].

Since then, several attempts have been made to translate the above information acquired by gene array analysis, relating basically to the importance of immune tolerance and immune surveillance in FL, into a routine laboratory variable for use as a practical guide in the clinical approach to FL.

Several centers have attempted to use cytokine levels as a surrogate marker for immune-response in patients with FL. In addition, elevated soluble interleukin-2 receptor α (IL-2Rα) levels have also been shown to facilitate immune suppression by T regulatory cells (T-regs), thereby possibly predicting decreased survival [4]. In another study, nine cytokines including interleukin-1 receptor agonist (IL-1Ra), IL-6, IL-7, IL-10, IL-13, tumor necrosis factor α (TNF-α), vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), as well as basic fibroblast growth factor (b-FGF) and transforming growth factor β (TGF-β), were measured. Only two of the above, TGF-β and VEGF, were found to be independent prognostic variables for survival in FL [5]. However, cytokine level analysis by enzyme-linked immunosorbent assay (ELISA) or flow cytometry are time-consuming tests which require local standardization in each laboratory, and therefore are not easily available or readily applicable on a routine basis.

Extended immunohistochemistry (IHC) staining which aims at characterizing the lymphoma cells within not only the lymph node but also the surrounding milieu may well serve as an alternative approach. Recent data reported that expression of multiple myeloma-associated antigen-1/interferon regulatory factor 4 (MUM-1/IRF4) may have clinical significance in FL [6]. However, due to controversial results in a study analyzing the expression of MUM-1, T-regs and lymphoma-associated macrophages, which did not show a correlation between overall survival (OS) and immune cell composition [7], this approach cannot be accepted universally.

In this issue of Leukemia and Lymphoma, Wilcox et al. chose a simple variable, the monocyte count, and examined the prognostic value of the absolute monocyte count (AMC) in 355 patients with FL, diagnosed at the Mayo Clinic between 1998 and 2007 [8]. This report represents one of a triad, reported by the same group, in which they studied the significance of peripheral blood AMC at diagnosis in the most commonly encountered lymphomas: diffuse large B-cell lymphoma (DLBCL) [9], FL [8] and Hodgkin lymphoma [10]. Obviously, among the advantages of this approach are its simplicity, ready availability and economic feasibility, because the peripheral blood count is conveniently available everywhere and easily obtained by standard automated complete blood count (CBC) determination.

After encountering several patients with DLBCL presenting with an absolute monocytosis count at diagnosis in recent years, we had also decided to evaluate its prognostic significance in a cohort of patients with DLBCL seen and treated at our institution. Similarly to the findings described by Wilcox and colleagues [8], we also observed that AMC was associated with inferior OS and was an independent adverse prognostic factor in patients with lymphoma [11].

The underlying biologic mechanism for this observation still remains an open question. However, in this regard, circulating monocytes are recruited to tumor sites by soluble tumor derived chemotactic factors and are identified in the tissues as tumor-associated macrophages (TAMs). When present in increased numbers, TAMs are associated with a poor prognosis [12]. The missing link, regarding their function, could be related to the recognition of a novel heterogeneous cell population: the “myeloid derived suppressor cells” (MDSCs), which are capable of inducing immune tolerance in patients with neoplasia, including hematologic malignancies (reviewed in [13]). These MDSCs are characterized according to their phenotype as either granulocytic or monocytic in type [13]. Understanding the significance and function of monocytic-MDSCs in non-Hodgkin lymphomas (NHLs) remains a challenge, and their anti-lymphoma effect has been investigated recently by several groups [14,15]. Preliminary observations suggest that they may be increased in some cases of NHL [14,15].

The observations reported here and in other studies on lymphoma imply that an AMC may predict survival and identify high-risk patients. Nevertheless, more studies are still needed to determine whether the AMC obtained from a routine blood count will eventually be accepted as a simple and reliable value predictive of prognosis in patients with lymphomas. The initial results appear very promising in this respect.

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