肿瘤细胞治疗研究
英文原题：Clinicopathological findings, prognosis, and Epstein-Barr virus infection in rheumatoid arthritis patients with other iatrogenic immunodeficiency-associated T- and NK-cell lymphoproliferative disorders.
与OIIA B-LPDs相比，OIIA TNK-LPDs发生在RA早期，并偶可表现为致死性进展性临床病程。识别具有不良预后因素的OIIA TNK-LPD患者是必要的。持续RA、MTX和生物制剂导致免疫抑制患者中的EBV感染，可能在TNK-LPDs的肿瘤微环境形成和淋巴瘤发生中发挥作用。
其他医源性免疫缺陷相关（OIIA）T细胞和自然杀伤（NK）细胞淋巴增殖性疾病（TNK-LPDs）在类风湿关节炎（RA）患者中罕见。
我们研究了21例伴有OIIA TNK-LPDs的RA患者的临床病理特征、EBV感染情况、遗传学发现、治疗反应及预后因素，并将其与39例OIIA B细胞LPDs（B-LPDs）和22例非OIIA B-LPDs患者进行了比较。
免疫组织学上，11例患者（52%）表现为CD4+ T-LPDs，其中7例具有T滤泡辅助（TFH）表型。其余9例患者（43%）表现为CD8+ T-LPDs，剩余1例（5%）具有CD3+ CD4- CD8-鼻型TNK细胞淋巴瘤特征。CD30+、p53+和CMYC+非典型淋巴细胞分别在7例（33%）、8例（38%）和5例（24%）患者中检出。原位杂交检测到EBV编码RNA（EBER）+大非典型淋巴细胞在5例患者（24%）中。17例患者中9例（53%）通过聚合酶链反应显示TCRγ克隆峰。停用MTX和生物制剂对12例患者（57%）有效，8例（38%）接受了化疗。2例TFH+或EBV+ CD4+ CD30+大细胞外周T细胞淋巴瘤患者、1例CD8+系统性间变性大细胞淋巴瘤患者和2例儿童系统性EBV+ CD8+ T细胞淋巴瘤患者表现出致死性进展性临床病程，在13个月内死亡。此外，> 500 U/L LDH、大非典型淋巴细胞、CD30、p53和CMYC表达以及EBER+非典型淋巴细胞是总体生存的显著不良预后因素（p < 0.05）。从RA发病到OIIA TNK-LPDs的中位间隔为72个月，短于OIIA B-LPDs的166个月（p = 0.003）。EBV+非典型和反应性淋巴细胞在15例OIIA TNK-LPDs患者（71%）、27例OIIA B-LPDs患者（69%）中频繁发现，而仅在3例非OIIA B-LPDs患者（14%）中发现。
BACKGROUND: Other iatrogenic immunodeficiency-associated (OIIA) T- and natural killer (NK)-cell lymphoproliferative disorders (TNK-LPDs) are rare in patients with rheumatoid arthritis (RA). METHODS: We investigated the clinicopathological characteristics, Epstein-Barr virus (EBV) infection, genetic findings, therapeutic response, and prognostic factors in 21 RA patients with OIIA TNK-LPDs and compared these with those of 39 with OIIA B-cell LPDs (B-LPDs) and 22 with non-OIIA B-LPDs. RESULTS: Immunohistologically, 11 patients (52%) showed CD4+ T-LPDs, and 7 had a T follicular helper (TFH) phenotype. The other nine patients (43%) showed CD8+ T-LPDs, and the remaining one (5%) had features of CD3+ CD4- CD8- nasal type TNK-cell lymphoma. CD30+, p53+, and CMYC+ atypical lymphocytes were identified in seven (33%), eight (38%), and five (24%) patients, respectively. In situ hybridisation detected EBV-encoded RNA (EBER) + large atypical lymphocytes in five patients (24%). Nine of 17 patients (53%) showed clonal peaks of TCRγ by polymerase chain reaction. Withdrawal of MTX and biologic drugs was effective in 12 patients (57%), and 8 (38%) received chemotherapies. Two patients with TFH+ or EBV+ CD4+ CD30+ large cell peripheral T-cell lymphoma, one with CD8+ systemic anaplastic large cell lymphoma, and two with systemic EBV+ CD8+ T-cell lymphoma of childhood showed a lethal progressive clinical course within 13 months. Moreover, > 500 U/L LDH, large atypical lymphocytes, expression of CD30, p53, and CMYC, and EBER+ atypical lymphocytes were significantly poor prognostic factors for overall survival (p < 0.05). Median interval from RA onset to OIIA TNK-LPDs was 72 months, which was shorter than 166 months in OIIA B-LPDs (p = 0.003). EBV+ atypical and reactive lymphocytes were frequently found in 15 patients with OIIA TNK-LPDs (71%), in 27 with OIIA B-LPDs (69%), and only in 3 with non-OIIA B-LPDs (14%). CONCLUSIONS: OIIA TNK-LPDs occurred in early phase of RA, compared with OIIA B-LPDs, and occasionally showed a lethal progressive clinical course. Detection of OIIA TNK-LPD patients with poor prognostic factors is necessary. EBV infection in immunosuppressed patients due to persistent RA, MTX, and biologic drugs may play a role in forming the tumour microenvironment and lymphomagenesis of TNK-LPDs.
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