T-cell clones of uncertain significance. When is the rogue clone dangerous?

T cell large granular lymphocyte clones that persist over time and that exhibit molecular and immunophenotypic features closely resembling those of T-cell Large Granular Lymphocyte Leukemia (T-LGLL) may be detectable in individuals who lack any clinical or laboratory features supporting a diagnosis of T-cell malignancy. This condition represents a potential precursor state termed T cell clones of uncertain significance (T-CUS). T-CUS represents the even more benign extreme of the wide spectrum of clonal T- large granular lymphocyte proliferations, emphasizing the need for an appropriate multiparametric diagnostic assessment that avoids misdiagnosis of T-cell neoplasia. This approach should overcome the numerical cut-offs as the sole criteria to differentiate the benign condition from the related malignancies. In particular, genomic aberrancies might prospectively identify individuals who are at risk of progression to full blown T-cell malignancy. We herein discuss the significance of these T cell clones in both healthy and disease states suggesting molecular assays for tracking early steps of disease.