Abstract 6653: Hepatosplenic T-cell lymphoma gamma-delta versus alpha-beta: A comparative study of clinicopathologic features and outcomes.

Abstract Introduction: Hepatosplenic T-cell lymphoma (HSTCL) is an aggressive rare extranodal T-cell lymphoma. It is most commonly derived from γδ T cells, though an αβ variant has been increasingly recognized. While γδ HSTCL is considered the prototypic form and accounts for the majority of cases, the clinical significance, biological behavior, and prognostic impact of αβ versus γδ 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: γδ-HSTCL and αβ-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 αβ and 174 γδ. The median age at diagnosis was similar between subgroups (30 vs 34 years), with a slight male predominance in both, more pronounced in the γδ cohort (59% vs 72%). A history of immune suppression was frequent in both groups (76% αβ vs 71% γδ), 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% αβ vs 99% γδ) 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 αβ and 11 months in γδ HSTCL. Immunophenotypically, the two subtypes shared high expression of CD2, CD3, CD7, CD16, CD38, and CD56. However, CD5 was more frequently expressed in αβ 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, αβ and γδ 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 αβ 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. Citation Format: Philip A. Haddad, Sireesha Vutukuri, Ankita Gupta. Hepatosplenic T-cell lymphoma gamma-delta versus alpha-beta: A comparative study of clinicopathologic features and outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6653.