Characterization of morphological and immunophenotypic heterogeneity in adult T‐cell leukemia/lymphoma and development of a peripheral blood tumor load‐based prognostic index

Abstract We evaluated morphologic and immunophenotypic features of adult T‐cell leukemia/lymphoma (ATLL) using morphology and flow cytometry (FCM), compared tumor cell proportions in bone marrow (BM) and peripheral blood (PB), and assessed whether these parameters could improve prognostication beyond existing indices for aggressive ATLL. We retrospectively analyzed PB and BM morphology, FCM, and clinical records of individuals newly diagnosed with ATLL at our institution from 2010 to 2024. Morphologic reevaluation was performed in 47 of 58 enrolled individuals, all with leukemic manifestations. ATLL cells showed heterogeneity. Cytoplasmic vacuoles were present in 61.7% of cases, including a previously undescribed pattern of small peripheral vacuoles (38.3%). Nuclear forms included flower‐like (66.0%), cerebriform (10.6%), and small indented lymphocyte‐like (36.2%) cells. Cells typically expressed CD4, CD25, CD2, and CD5. However, CD25 was negative in 26.3% of cases when assessed with a weakly conjugated fluorochrome. CD8, CD7, and CD56 were consistently absent, CD3 was variable, whereas TRBC1 showed preliminary variability in the limited subset. Both cytology (with more ATLL cells showing abnormal morphology in PB than in BM) and flow cytometry demonstrated a higher tumor burden in PB than in BM. FCM detected BM infiltration more sensitively than conventional BM smears. In this single‐center derivation cohort without validation, the PB tumor load prognostic index (PBTL‐PI), incorporating PB abnormal lymphocyte percentage (PB‐PAL) and corrected calcium, showed excellent apparent discrimination (area under the curve [AUC] = 0.871). PBTL‐PI outperformed the Japan Clinical Oncology Group prognostic index in risk stratification (log‐rank p = 0.0002 vs. 0.0147) and prognostic accuracy (AUC: 0.871 vs. 0.738, DeLong's p = 0.024). However, these findings are exploratory and require independent validation. ATLL shows morphologic and immunophenotypic heterogeneity. Cytology and flow cytometry both confirmed higher tumor burden in PB (vs. BM). FCM improves the detection of BM infiltration. PBTL‐PI may identify high‐risk ATLL and guide risk‐adapted management.