Hepatosplenic T-cell lymphoma gamma-delta versus alpha-beta: A comparative study of clinicopathologic features and outcomes

Introduction: Hepatosplenic T-cell lymphoma (HSTCL) is an aggressive rare extranodal T-cell lymphoma. It is most commonly derived from gammadelta T cells, though an alphabeta variant has been increasingly recognized. While gammadelta HSTCL is considered the prototypic form and accounts for the majority of cases, the clinical significance, biological behavior, and prognostic impact of alphabeta versus gammadelta T-cell receptor (TCR) expression remain poorly defined due to the scarcity of comparative data. We conducted this study to compare the clinicopathological characteristics of both subtypes. Methods: To study the clinicopathologic characteristics, prognostic factors, and overall survival (OS), we compiled a pooled database of HSTCL cases. Patients were stratified into two groups based on TCR expression: gammadelta-HSTCL and alphabeta-HSTCL. Descriptive statistics were used to summarize baseline characteristics. Continuous variables were compared using t-test, and categorical variables by χ² test. Survival outcomes were analyzed using Kaplan-Meier methodology. Results: A total of 226 patients with HSTCL were identified, 52 alphabeta and 174 gammadelta. The median age at diagnosis was similar between subgroups (30 vs 34 years), with a slight male predominance in both, more pronounced in the gammadelta cohort (59% vs 72%). A history of immune suppression was frequent in both groups (76% alphabeta vs 71% gammadelta), with comparable durations of exposure (median 4.7 vs 5 years) and latency to lymphoma onset (4 vs 5 years). Both cohorts had high rates of hepatosplenomegaly (100% alphabeta vs 99% gammadelta) and marrow infiltration (100% in both). Cytopenias were common and showed no significant differences: anemia (90% vs 95%), leukopenia (66% vs 61%), and thrombocytopenia (86% vs 88%). Median LDH levels were elevated in both subtypes (797.5 vs 968 U/L). Median overall survival was similarly poor-10 months in alphabeta and 11 months in gammadelta HSTCL. Immunophenotypically, the two subtypes shared high expression of CD2, CD3, CD7, CD16, CD38, and CD56. However, CD5 was more frequently expressed in alphabeta cases (39% vs 14%, P = 0.001) as well as CD8 positivity (57% vs 31%, P = 0.005) and CD57 (41% vs 5%, P = 0.01). Trisomy 8 (33% vs 36%) and i/r 7 (72% vs 75%) were prevalent and comparable between groups. Conclusion: In this large comparative cohort, alphabeta and gammadelta HSTCL demonstrated strikingly similar clinical features, patterns of immune suppression, cytopenias, organ involvement, cytogenetic abnormalities, and dismal overall survival. However, significant immunophenotypic differences-most notably higher expression of CD5, CD8, and CD57 in alphabeta HSTCL-suggest underlying biologic divergence between the two TCR-defined subtypes. These findings highlight that while both forms remain clinically indistinguishable at presentation and equally lethal, their distinct immunoprofiles may have diagnostic relevance and could inform future exploration of targeted therapeutic strategies.