Acute leukemias with expression of CD56

Recent revisions to acute leukemia classification systems increasingly emphasize genetic drivers of disease; however, critical immunophenotypic features remain essential for accurate diagnosis and risk assessment. CD56, an isoform of the neural cell adhesion molecule, is expressed on natural killer (NK) cells but is aberrantly present across multiple acute leukemias, where it may contribute to diagnostic complexity and adverse clinical outcomes. This review highlights the diagnostic and clinical significance of CD56 expression in acute leukemias.

We review current classification frameworks and relevant literature to examine the role of CD56 immunophenotyping in the evaluation and clinical significance of acute leukemias.

CD56 expression is observed in a heterogeneous group of acute leukemias, including subsets of acute myeloid leukemia (AML), NK lymphoblastic leukemia, acute undifferentiated leukemia, and blastic plasmacytoid dendritic cell neoplasm (BPDCN). In AML, CD56 expression has been associated with extramedullary disease, treatment resistance, and inferior survival in several studies, including high-risk subgroups such as AML with the RAM immunophenotype. In NK lymphoblastic leukemia and BPDCN, CD56 represents a key but nonspecific marker that must be interpreted in conjunction with additional lineage-associated antigens and molecular features to avoid diagnostic misclassification. Acute undifferentiated leukemia frequently demonstrates CD56 expression in the absence of definitive lineage markers, further emphasizing the need for integrated diagnostic approaches.

Acute leukemias with CD56 expression represent a diagnostically challenging and biologically diverse group of neoplasms. While CD56 lacks lineage specificity, its detection by flow cytometry provides valuable information for differential diagnosis, risk stratification, and, in some settings, minimal residual disease assessment. Accurate classification requires careful integration of immunophenotypic, morphologic, and genetic data. As therapeutic strategies become increasingly risk-adapted and targeted, precise recognition of CD56-positive blastoid neoplasms is essential to optimize patient management and outcomes.