{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T18:48:35Z","timestamp":1793213315132,"version":"4.5.0"},"reference-count":26,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,4,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>The differences between EBV-positive and EBV-negative aggressive NK-cell leukemia (ANKL) remain po orly understood. Herein, we sought to investigate the clinicopathologic and molecular differences between EBV-positive and EBV-negative ANKL.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We retrospectively analyzed 14 ANKL cases (9 EBV-positive, 5 EBV-negative), assessing clinicopathologic, cytogenetic, and mutational features. In addition, we searched the published literature to further analyze the distribution of genetic variation between EBV-positive (n=116) and EBV-negative-ANKL (n=14). Lastly, we assessed the utility of p53 immunohistochemistry to screen for EBV-negative-ANKL.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Demographically, EBV-negative-ANKL patients were older (median age 64 vs. 37 years) and showed longer survival (median 13 vs. 1 month) than EBV-positive counterparts. Morphologic and immunophenotypic features were similar between groups. All EBV-negative cases assessed in our cohort harbored TP53 mutations (3\/3). Combining our data with all reported ANKL cases with comprehensive mutational assessment of TP53, JAK\/STAT and epigenetic modifier genes in the literature we find TP53 mutations or copy number alterations present in 82% of EBV-negative-ANKL (14\/17) but in only 25% (29\/116) of EBV-positive cases. In contrast, EBV-negative-ANKL showed less JAK\/STAT and epigenetic modifier gene mutations compared to EBV-positive ANKL. Given the high frequency of TP53 genetic alteration, we show that p53 immunohistochemistry overexpression is present in all but one EBV-negative-ANKL case assessed thus far.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings suggest that EBV-negative-ANKL is a distinct subtype of ANKL, highly enriched for TP53 genetic alterations and showing different epidemiologic and prognostic features compared to EBV-positive-ANKL. In addition, p53 immunohistochemistry may serve as a screening tool for EBV-negative-ANKL.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/ajcp\/aqag027","type":"journal-article","created":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T12:50:10Z","timestamp":1772283010000},"source":"Crossref","is-referenced-by-count":1,"title":["<i>TP53<\/i>\n                    genetic alterations are highly recurrent in Epstein-Barr virus\u2013negative aggressive NK-cell leukemia: insights from an institutional experience and comprehensive literature review"],"prefix":"10.1093","volume":"165","author":[{"given":"Miguel","family":"Gonzalez Mancera","sequence":"first","affiliation":[{"name":"Department of Pathology, Stanford University , Stanford, CA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron J","family":"Wilk","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stanford University , Stanford, CA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean","family":"Oak","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stanford University , Stanford, CA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9816-1018","authenticated-orcid":false,"given":"Yasodha","family":"Natkunam","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stanford University , Stanford, CA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0808-2592","authenticated-orcid":false,"given":"Oscar","family":"Silva","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stanford University , Stanford, CA,","place":["United 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