Division of Hematopathology, Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Division of Hematology-Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Mod Pathol. 2017 Aug;30(8):1100-1115. doi: 10.1038/modpathol.2017.37. Epub 2017 May 26.
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.
侵袭性自然杀伤（NK）细胞白血病/淋巴瘤是一种系统性 NK 细胞肿瘤，主要影响亚洲人，临床病程迅猛，几乎总是与 EBV 相关。关于 EBV 阴性侵袭性 NK 细胞白血病/淋巴瘤的数据有限。在此，我们报告了来自单一机构的三例 EBV 阴性侵袭性 NK 细胞白血病/淋巴瘤患者（两例白人，一例非裔美国人），包括一例尸检诊断病例。与 EBV 阳性侵袭性 NK 细胞白血病/淋巴瘤相似，我们的患者表现出全身症状和肝脾肿大，并呈现出高度侵袭性的临床病程。疾病累及外周血、骨髓、肝脏、脾脏和淋巴结，肿瘤细胞形态多样，具有明显的嗜天青颗粒，并表现出非典型 NK 细胞表型。缺乏血液淋巴细胞增多症（3 例中有 3 例）、骨髓间质浸润（3 例中有 2 例）、EBER 阴性（3 例中有 3 例）以及免疫组化 CD3 阴性等不典型表型，使得早期识别该疾病变得困难。辅助研究显示复杂的核型（2 例中有 1 例）、c-MYC 的过表达（3 例中有 3 例）和扩增（1 例中有 1 例）。多梳抑制复合物 2 通路相关蛋白 EZH2 和 H3K27me3 以及免疫检查点蛋白 PD-L1 在 3 例中有 3 例和 2 例中有 3 例中过表达。我们的研究结果表明，除了 EBV 阳性病例中常见的亚洲人高患病率外，EBV 阴性侵袭性 NK 细胞白血病/淋巴瘤与 EBV 阳性病例具有相似的临床病理特征。多梳抑制复合物 2 通路相关蛋白和 PD-L1 的过表达表明，针对这种侵袭性疾病可能存在潜在的治疗靶点。对 2 例中的 2 例进行下一代测序发现了多种基因改变，但未发现 EBV 阳性 NK/T 细胞淋巴瘤中先前报道的 JAK-STAT 通路相关基因突变，提示 EBV 阴性侵袭性 NK 细胞白血病/淋巴瘤存在替代的分子发病机制。
