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Peripheral T‐ or natural killer ( NK )‐cell lymphomas are rare and difficult‐to‐recognize diseases. It remains arduous to distinguish between  NK  cell‐ and cytotoxic T‐lymphocyte‐derived lymphomas through routine histological evaluation. To clarify the cells of origin, we focused on  NK ‐cell receptors and examined the expression using immunohistochemistry in 22 cases with T‐ and  NK ‐cell neoplasms comprising angioimmunoblastic T‐cell lymphoma, anaplastic lymphoma kinase ( ALK )‐positive and ‐negative anaplastic large‐cell lymphomas, extranodal  NK /T‐cell lymphoma, nasal type, monomorphic epitheliotropic intestinal T‐cell lymphoma, aggressive  NK ‐cell leukemia, and other peripheral T‐cell lymphomas. Inhibitory receptor leukocyte immunoglobulin‐like receptor subfamily B member 1 ( LILRB 1) was detected in 14 (64%) cases, whereas activating receptors  DNAM 1,  NK p46, and  NKG 2D were expressed in 7 (32%), 9 (41%), and 5 (23%) cases, respectively. Although  LILRB 1 was detected regardless of the disease entity, the activating  NK ‐cell receptors were expressed predominantly in  TIA ‐1‐positive neoplasms ( DNAM 1, 49%;  NK p46, 69%; and  NKG 2D, 38%). In addition,  NK p46 and  NKG 2D were detected only in  NK ‐cell neoplasms and cytotoxic T‐lymphocyte‐derived lymphomas including monomorphic epitheliotropic intestinal T‐cell lymphoma. One Epstein‐Barr virus‐harboring cytotoxic T‐lymphocyte‐derived lymphoma mimicking extranodal  NK /T‐cell lymphoma, nasal type lacked these  NK ‐cell receptors, indicating different cell origin from  NK  and innate‐like T cells. Furthermore,  NKG 2D expression showed a negative impact on survival among the 22 examined cases, which mainly received the standard chemotherapy regimen (log‐rank test,  P  = .024). We propose that the presence of activating  NK ‐cell receptors may provide new insights into understanding peripheral T‐cell lymphomas and characterizing them as innate‐like T‐cell neoplasm.

Expression of activating natural killer‐cell receptors is a hallmark of the innate‐like T‐cell neoplasm in peripheral T‐cell lymphomas