Endogenous interferon α therapy in follicular lymphoma?

Follicular lymphoma (FL) is the second most common B-cell lymphoma in the Western world [1]. The clinical presentation and course of the disease are heterogeneous regarding several aspects. In the majority of cases the disease is clinically well tolerated, and progresses slowly with continuous increase of tissue involvement. In many patients treatment by chemotherapy is not given at diagnosis, but is delayed until the patient suffers from disease-related symptoms. Nevertheless, a subgroup of patients experience an aggressive course and disease-related death within the first years after diagnosis. In addition, the heterogeneity of FL is highlighted by known clinical variants. Some patients present with localized disease at specific sites, such as gastrointestinal or cutaneous FL, without or with a very low tendency to disseminate or transform. Also, age-related differences can be observed, with the example of pediatric FL. Differences in the genetics of these FL variants are well documented, but do not explain the clinical heterogeneity. Reflecting the heterogeneity of the clinical course, the treatment options differ in efficiency and toxicity, ranging from watchful waiting to myeloablative therapy and autologous stem cell transplant [2].

Owing to the heterogeneous outcomes and different treatment options, much effort has been made to identify prognostic markers predicting the clinical course of FL. The clinical follicular lymphoma international prognostic index (FLIPI) includes Ann Arbor stage, number of involved lymph node areas, hemoglobin value, lactate dehydrogenase value, and age [3], and is currently the most powerful tool for prognostication. Additionally, gene expression profiling of FL has drawn attention to non-neoplastic bystander cells admixed within the lymphoma. A gene expression signature predominated by genes expressed by dendritic cells and macrophages seems to be associated with a worse prognosis, compared to a signature of T-cells [4].

However, gene expression analysis is not implemented in routine diagnostics and is not easily applicable to formalin-fixed paraffin-embedded tissue (FFPE). Several attempts have been made to reproduce the prognostic information from gene expression signatures using immunohistochemistry to quantify macrophages, dendritic cells, or T-cell subpopulations in FL. The conflicting results derived from these studies might be due to: (i) the heterogeneity of the analyzed study cohorts in terms of therapy [5], (ii) the inability of immunohistochemistry to detect the complex information of the gene expression signatures, or (iii) the fact that the correct cell type or biomarker has not yet been determined. In fact, gene expression analysis has not indicated an easily defined T-cell population as being associated with outcome [4], and the most promising T-cell populations analyzed by immunohistochemistry (follicular T-helper and regulatory T-cells) are not suggested by gene expression profiling data to be the most relevant.

In this issue of Leukemia and Lymphoma, Butsch et al. report a study in which they analyzed the prognostic role of plasmacytoid dendritic cells (pDC), important effector cells of the innate immunity, assessed by immunohistochemistry in FL. Using a tissue microarray and staining for CD123, the authors indicated a high amount of pDC to be correlated with a favorable prognosis and longer overall survival. This prognostic information was independent of the FLIPI [6]. The study differs from all other previous publications that have correlated outcome in FL with the presence of reactive bystander cells in an important aspect. Although macrophages or cytotoxic, follicular helper, or regulatory T-cells in other studies were associated with survival, it is currently not known whether this association is causative or correlative. Except for follicular T-helper cells [7], there are no convincing hypotheses for how populations of bystander cells functionally affect the FL disease course. This is different in the case of pDC analyzed in the current study by Butsch et al. pDC are known to produce considerable amounts of interferon α [8], an interferon that is well established as having a therapeutic effect on FL, providing a sufficient explanation for the observed association of pDC and favorable disease course.

The authors are clearly aware of the limitations of their study, primarily due to the use of a tissue microarray and the analysis of a heterogeneously treated cohort of patients. However, the results are promising enough to encourage further analysis in cohorts from prospectively treated patients—ideally comparing patients with and without interferon α therapy.

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