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

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 (LILRB1) was detected in 14 (64%) cases, whereas activating receptors DNAM1, NKp46, and NKG2D were expressed in 7 (32%), 9 (41%), and 5 (23%) cases, respectively. Although LILRB1 was detected regardless of the disease entity, the activating NK‐cell receptors were expressed predominantly in TIA‐1‐positive neoplasms (DNAM1, 49%; NKp46, 69%; and NKG2D, 38%). In addition, NKp46 and NKG2D 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, NKG2D 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.