Revisiting KIR restriction and CD94 expression in diagnostic criteria for NK–large granular lymphocytic leukemia

Recent diagnostic criteria for natural killer (NK)-large granular lymphocytic leukemia (NK-LGLL) proposed by Pastoret et al 1 incorporate immunophenotypic and molecular features, including killer cell immunoglobulin-like receptor (KIR) restriction and CD94/NKG2A overexpression by flow cytometry, as major diagnostic criteria.The authors describe a weighted scoring system combining 4 major criteria (NK-cell lymphocytosis ≥1.0 × 10 9 /L, KIR restriction, CD94 or NKG2A overexpression, and STAT3/5B, CCL22, or TET2 mutations without other myelodysplastic syndrome-defining alterations) and 4 minor clinicopathologic features, with diagnosis requiring either 3 major criteria or 2 major and 2 minor criteria.1 Although this framework represents an important step toward standardizing diagnosis, the performance of these parameters depends critically on how they are defined and measured.Based on our experience evaluating NK-cell clonality by flow cytometry, we identified important limitations in the current definitions of KIR restriction and CD94 overexpression that may reduce the sensitivity and specificity of the proposed scoring system.First, although KIR restriction is an important surrogate marker of NK-cell clonality, the operational definition proposed by Pastoret et al, 1,2 that is, reduced expression of at least 2 KIR markers (CD158a