Sensitive laboratory techniques have increased detection of T-cell clonality across many clinical scenarios, including evaluation of cytopenias, lymphocytosis, eosinophilia, and suspected lymphoma. These assays often identify clonal T-cell populations in patients without clinical concern for a T-cell neoplasm. The authors characterize these findings, which can be clinically challenging, and propose a practical approach to minimize unnecessary workup while ensuring malignant clones are recognized.
The article defines a T-cell clone of uncertain significance (TCUS) as any T-cell clone detectable by flow cytometry or molecular methods that does not meet diagnostic criteria for a T-cell neoplasm. Detected clonality can arise from neoplastic mechanisms — a T cell acquiring molecular or cytogenetic abnormalities that drive proliferation or survival — or from nonneoplastic mechanisms such as robust antigen-driven clonal or oligoclonal expansion (for example, in infection or autoimmunity) and homeostatic proliferation in the setting of lymphopenia. The authors note that while persistent antigen stimulation may rarely lead to acquisition of pathogenic mutations, the frequency of such progression remains unclear.
Techniques described include flow cytometric staining of the T-cell receptor constant region (for example, TRBC1/TRBC2 assessment) and molecular-based T-cell receptor clonality testing. These sensitive assays permit detection of small or emerging clones but also increase the frequency of incidentally discovered clones in patients without clinical suspicion for T-cell malignancy.
The proposed algorithm highlights clinical features that should raise concern for an underlying T-cell neoplasm: hepatosplenomegaly, lymphadenopathy, diffuse rash, B symptoms, unexplained persistent cytopenias, unexplained eosinophilia, and autoimmune hemolysis. Presence of these features prompts more aggressive evaluation.
The authors present an algorithm for approaching peripheral blood T-cell clonality in patients without an established diagnosis of a T-cell neoplasm. The framework stratifies detected clones into categories such as "low risk" versus "abnormal population" and integrates immunophenotype, clinical context, and quantitative abundance. For low-risk populations the recommendation is conservative management and surveillance; for abnormal populations, the recommendation is to proceed with molecular testing and further staging as indicated.
To avoid precipitating unnecessary diagnostic cascades, the authors recommend that a TCUS not be reported in the top line of a diagnostic report. Instead, a population meeting criteria for TCUS should be documented in a comment or interpretation section for surveillance purposes, with absolute and relative abundance recorded. When multiple small TRBC-monotypic populations are identified, the recommended phrasing is that findings are "compatible with reactive oligoclonal expansion." If these findings occur in the setting of lymphopenia, reporting should indicate consistency with homeostatic proliferation. For populations meeting criteria as "low risk," the authors advise against top-line reporting and again recommend documentation in a comment with surveillance guidance. An "abnormal population" should be reported in the top line with full immunophenotypic description and abundance.
For clones classified as low risk, the suggested management is clinical and laboratory surveillance, typically with repeat complete blood count (CBC) and clinical follow-up at an interval of 3 to 6 months. Repeat flow cytometry is also typically performed at that time to assess for resolution, stability, or progression of the clone. When an abnormal circulating T-cell population is characterized by flow cytometry, molecular testing on peripheral blood is recommended. For clones suspicious for T-cell large granular lymphocytic leukemia (T-LGLL), targeted molecular testing may include STAT3 for CD8+ clones and STAT5B for CD4+ clones. Imaging for staging may be considered where clinically indicated. The authors note that distinguishing CD4+ TCUS from CD4+ LGLL is not critical in many cases because CD4+ LGLL infrequently requires treatment even when pathogenic STAT5B mutations are present.
The article provides three case vignettes of incidental T-cell clones that illustrate application of the algorithm, including clinical histories, laboratory results, flow cytometry immunophenotyping, and longitudinal molecular tracking. These examples demonstrate decision points for surveillance versus further molecular testing and reinforce the principles of integrating clinical context, immunophenotype, and clone abundance.
Figures included in the article depict: (1) pathophysiologic mechanisms leading to detection of T-cell clonality by flow cytometry or molecular methods; (2) an algorithm for approaching peripheral blood T-cell clonality in patients without established T-cell neoplasm, including reporting and workup recommendations; and (3) three clinical cases showing immunophenotypic and molecular data. The algorithm figure explicitly lists clinical features of concern, phenotype characteristics (for example, large granular lymphocyte phenotype details), reporting language for pathologists, and recommended clinician follow-up.
Incidental detection of T-cell clones is increasingly common with sensitive laboratory testing. The authors propose a conservative, structured approach that favors surveillance for low-risk clones, selective molecular testing for abnormal populations, careful wording in laboratory reports to avoid unnecessary workup, and targeted use of molecular assays such as STAT3 and STAT5B when clinically indicated. This framework aims to balance avoidance of unwarranted procedures and anxiety with timely identification of true T-cell malignancy.
(If additional methodological details, prevalence data, or specific case-level outcomes are required, those details were not reported in the provided source text.)