Aberrant circulating CD4+ CD26- T-cells in T-cell rich B-cell lymphomas: Diagnostic pitfall or biomarker? Free

Background:

Morphologically atypical, non-clonal T-cell infiltrates have been demonstrated in a subset of Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) and are associated with younger age and increased risk of relapse, but a corresponding non-invasive peripheral blood (PB) signature has not been defined. Phenotypically abnormal T-cells in PB or tissue biopsy specimens can mimic T-cell non-Hodgkin lymphoma and create diagnostic uncertainty. We describe a cohort of young patients with aggressive B-cell lymphomas who presented with a prominent, phenotypically aberrant yet non-clonal T-cell population in PB.

Methods:

We retrospectively identified six patients with B-cell lymphomas who, during initial diagnostic workup, exhibited a discrete abnormal T-cell population by multiparametric PB flow cytometry. We abstracted clinicopathologic variables (age, sex, stage, cytopenias, LDH), histopathology, and PB flow cytometry results, including T-cell clonality by T-cell receptor (TCR) Vβ repertoire analysis.

Results:

The cohort was young (median age 32.6 years; range 27.7–34.0; 4 male/2 female). Four of six patients had NLPHL (Pattern A, n=1; Pattern E, n=3), one patient had T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL), and one had classic Hodgkin lymphoma (cHL). All presented with advanced disease (stage IIIB, n=1; stage IV, n=5) and cytopenias (pancytopenia, n=2; anemia with thrombocytopenia, n=1; isolated anemia, n=1; isolated thrombocytopenia, n=1; neutropenia, n=1), and LDH was elevated in most (n=5).

PB flow identified a discrete aberrant T-cell population in all cases. A unifying feature in 5/6 was a sizable CD4+ T-cell subset with loss of CD26 (CD4+CD26−), comprising ~15–40% of total PB cellularity. Variable additional aberrancies included partial CD7 loss and CD10 expression. T-cell clonality was tested by TCR Vβ repertoire analysis in 5/6 patients and was negative in all, supporting a reactive, non-neoplastic process. Tissue specimens for these cases consistently showed T-cell-rich backgrounds, including NLPHL pattern E, a variant associated with more aggressive behavior. In the THRLBCL case, the same aberrant non-clonal T-cell population was demonstrated across PB, bone marrow aspirate, and diagnostic lymph node, indicating a systemic reactive infiltrate.

Conclusion:

Our findings highlight the clinical significance of a non-clonal, immunophenotypically aberrant CD4+CD26− T-cell population in young patients with T-cell-rich B-cell lymphomas—predominantly NLPHL and THRLBCL. This systemic reactive population poses a meaningful diagnostic pitfall because its phenotype can mimic T-cell lymphoma, particularly when initial tissue samples are scant or discordant. Beyond avoiding misclassification, the consistent association of this PB signature with T-cell-rich histologies and advanced presentation raises the hypothesis that it may serve as a non-invasive surrogate biomarker of the higher-risk NLPHL variant previously described in tissue studies. Given the enrichment of PD-L1/PD-L2 genetic alterations and sensitivity to PD-1 blockade reported in T-cell-rich microenvironments (e.g., cHL and THRLBCL), correlations between this PB phenotype, 9p24.1 alterations, and response to PD-1-based therapy merit prospective study. Recognition of this reactive immunophenotype should prompt careful clinicopathologic integration and heightened suspicion for an underlying T-cell-rich B-cell lymphoma when early biopsies are inconclusive.

Although our series focuses on NLPHL/THRLBCL, we have also observed a similar T-cell population in a non-GCB DLBCL with a T-cell-rich microenvironment, suggesting this phenomenon may extend to other B-cell malignancies. Larger, prospective cohorts are needed to validate the prevalence of this immunophenotype, define its prognostic significance, and test its utility for risk stratification and response monitoring.