NKG2C Improves Diagnostic Specificity of NK Cell Receptor Restriction by Identifying Non-Neoplastic Adaptive NK Cell Clones

Natural killer (NK) cell neoplasms are a diverse group of entities with often nonspecific clinical presentations, making immunophenotyping essential for diagnosis. Immunophenotyping by flow cytometry can identify clonal NK cell populations by detecting restricted expression patterns of NK cell receptors such as killer cell immunoglobulin-like receptors (KIRs). However, reactive NK cells may also demonstrate KIR restriction through expansion of self-KIR–expressing NK cells, leading to identification of NK clones of uncertain significance (NK-CUS). A well-described reactive NK subset, termed “adaptive” NK cells, arises in response to cytomegalovirus (CMV) infection or reactivation, often appears KIR-restricted, and is defined by coexpression of CD57 and the activating receptor NKG2C. Because CMV reactivation is common among patients undergoing evaluation for hematolymphoid malignancy, we hypothesized that NK-CUS may frequently correspond to this non-neoplastic adaptive NK cell subset. Here, we describe a flow cytometry panel for immunophenotypic characterization of cytotoxic lymphocytes that includes NKG2C, enabling detection of non-neoplastic adaptive NK cells. We show that NK-CUS frequently represent reactive NKG2C ⁺ adaptive NK cells. We describe several cases that meet diagnostic criteria for NK-large granular lymphocytic leukemia (NK-LGLL) and demonstrate that the NK cell clones are non-neoplastic NKG2C ⁺ adaptive NK cells arising in the setting of CMV viremia. Further, we show that NKG2C expression is uncommon by cytotoxic lymphocyte malignancies with recurrent molecular or cytogenetic abnormalities. Collectively, we demonstrate that NKG2C has a high specificity for reactive NK cell populations, and its inclusion in NK cell immunophenotyping panels is a useful strategy to more reliably distinguish between neoplastic and reactive NK cell populations.