EBV-negative aggressive NK-cell leukemia/lymphoma: a clinical and pathological study from a single institution

Abstract

Aggressive natural killer (NK)-cell leukemia/lymphoma is a systemic NK-cell neoplasm that preferentially affects Asians with a fulminant clinical course and is almost always associated with Epstein-Barr virus (EBV). The data on EBV-negative aggressive NK-cell leukemia/lymphoma are limited. Here we report a series of three patients (two Caucasians, one African-American) with EBV-negative aggressive NK-cell leukemia/lymphoma from a single institution, including a case diagnosed on post-mortem examination. Similar to EBV-positive aggressive NK-cell leukemia/lymphoma, our patients presented with constitutional symptoms and hepatosplenomegaly, and followed a highly aggressive clinical course. The disease involved peripheral blood, bone marrow, liver, spleen, and lymph node, and the neoplastic cells were pleomorphic with prominent azurophilic granules and demonstrated an atypical NK-cell phenotype. Lack of blood lymphocytosis (3 of 3), bone marrow interstitial infiltration (2 of 3), EBER negativity (3 of 3), and atypical phenotype including CD3 negativity by immunohistochemistry make an early recognition of the disease difficult. Ancillary studies revealed a complex karyotype (1 of 2), overexpression (3 of 3), and amplification (1 of 1) of c-MYC. The polycomb repressive complex 2 pathway-associated proteins EZH2 and H3K27me3 and immune checkpoint protein PD-L1 were overexpressed in three of three and two of three cases, respectively. Our findings indicate that the EBV-negative aggressive NK-cell leukemia/lymphoma shares similar clinicopathological features to the EBV-positive counterpart except for the high prevalence of Asian seen in EBV-positive cases. Overexpression of polycomb repressive complex 2 pathway-associated proteins and PD-L1 suggest potential therapeutic targets for this aggressive disease. Next-generation sequencing on two of three cases identified multiple genetic alterations but were negative for JAK-STAT pathway-associated gene mutations previously reported in EBV-positive NK/T-cell lymphoma, suggesting alternative molecular pathogenic mechanisms for EBV-negative aggressive NK-cell leukemia/lymphoma.

CD56-Negative Aggressive NK Cell Leukemia Relapsing as Multiple Cranial Nerve Palsies: Case Report and Literature Review

“…To date, only around one hundred cases have been reported all over the world and the main disease manifestations are in concordance with the patient presented herein. Comparable clinical and pathological features were observed in 3 cases of EBV-negative ANKL that were recently reported [ 12 ].…”

Aggressive natural killer (NK)‐cell leukaemia and extranodal NK/T‐cell lymphoma are two distinct diseases that differ in their clinical presentation and cytogenetic findings

“…The term 'aggressive NK-cell leukaemia/lymphoma' has therefore been used in the literature. 6,20,21 In this study, we intended to evaluate the differences between bone marrow NK/T-cell neoplasms with no extramedullary mass (group 1) and those with extramedullary mass (group 2). Group 1 cases were of the leukaemic form without extramedullary mass, fulfilling the WHO 2017 diagnostic criteria for ANKCL, and commonly had chromosome 7 abnormalities.…”

“…The patients with cytogenetic abnormalities (median 1 month; range 0.4-2 months) had worse survival than those with normal karyotypes (median 3 months; range 0.3-12 months) (P = 0.026; Figure 4B). Group 1 patients with or without cytogenetic abnormalities and group 2 patients with cytogenetic abnormalities had significantly more hazards than group 2 patients with [20],+idic(7)(p14)del (7) (q31q32) [20],-9 [3],-16 [3],der(18)t(18;?)(p11.2;?) [20],-20 [3][cp20] 2 47,X,-X,t(4;6)(q31;p23),+i (7) normal karyotypes in the Cox model with age adjustment (Table S4).…”

EBV-Positive Lymphoproliferations of B- T- and NK-Cell Derivation in Non-Immunocompromised Hosts

“…The aetiology is unknown but the strong association with EBV suggests a pathogenetic role of the virus [ 201 ]. Nevertheless, in the last years, cases of EBV-negative ANKL have been reported [ 210 , 211 ]. EBV-negative ANKL seems to be indistinguishable clinically and pathologically from the EBV-positive cases.…”

“…Little is known about the molecular pathogenesis of ANKL. However, recent studies have identified frequent mutations leading to activation of the JAK/STAT pathway including STAT5B and STAT3 gene mutations [ 211 , 216 ], TP53 mutations have also been reported [ 210 ].…”