NKG2C Improves Diagnostic Specificity of Natural Killer (NK) Cell Receptor Restriction by Identifying Nonneoplastic...

Natural killer (NK) cell neoplasms are a diverse group of entities with often nonspecific clinical presentations, making immunophenotyping essential for diagnosis. Immunophenotyping using 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, is often KIR-restricted, and is defined by coexpression of CD57 and the activating receptor NK group 2, member C (NKG2C). Because CMV reactivation is common among patients undergoing evaluation for hematolymphoid malignancy, we hypothesized that NK-CUS may frequently correspond to this nonneoplastic adaptive NK cell subset. Here, we described a flow cytometry panel for immunophenotypic characterization of cytotoxic lymphocytes that includes NKG2C, enabling detection of nonneoplastic adaptive NK cells. We showed that NK-CUS frequently represent reactive NKG2C⁺ adaptive NK cells. We described several cases that meet diagnostic criteria for NK-large granular lymphocytic leukemia and demonstrated that the NK cell clones are nonneoplastic NKG2C⁺ adaptive NK cells arising in the setting of CMV viremia. Further, we showed that NKG2C expression is uncommon in neoplastic NK cell proliferations with recurrent molecular or cytogenetic abnormalities. Collectively, we demonstrated 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.