噬血细胞性淋巴组织细胞增生症六例

 目的　提高对噬血细胞性淋巴组织细胞增生症（HLH）诊断及治疗的认识。方法　总结6例HLH患者的临床特征、诊断依据、治疗方案及疗效,并进行分析讨论。结果　HLH常见的临床表现包括发热、肝脾大及血细胞减少,实验室检查异常包括高三酰甘油血症、低纤维蛋白原血症、肝功能异常、黄疸、转铁蛋白升高、低钠血症,骨髓涂片可见噬血细胞。接受包含依托泊苷的化疗方案在疗程的早期有效,但疗效短暂。结论　HLH病情凶险,预后差,提高对HLH的临床表现及实验室特征的认识,有利于加强HLH的早期诊断和治疗,依据HLH-2004治疗指南可以提高患者生存率,但造血干细胞移植仍是目前唯一能使患者获得长期缓解及治愈的有效措施。     

免疫治疗相关噬血细胞综合征诊疗进展

噬血细胞综合征又称噬血细胞性淋巴组织细胞增多症（hemophagocytic lymphohistiocytosis,HLH），是一种罕见的、危及生命的临床综合征。由于淋巴细胞及巨噬细胞失控性增殖并分泌大量细胞因子，导致多器官、多系统受累。免疫治疗是肿瘤和自身免疫性疾病治疗的重要组成部分，改变了传统治疗模式，提高了患者的生存率。随着免疫治疗的广泛应用，免疫治疗相关HLH因其病情凶险、进展迅速引起研究者关注。目前，这一类HLH多以病例报告形式出现，缺乏统一的诊疗标准。本文将从免疫治疗相关HLH的发病机制、诊断及治疗进展展开综述，以提高医务工作者对此类疾病的认知。     

成年人原发性噬血细胞综合征1例并文献复习

目的探讨成年人原发性噬血细胞综合征(HPS)的临床特征及治疗效果。方法回顾性分析南方医科大学第三附属医院2017年7月收治的1例成年原发性HPS患者的资料, 并复习相关文献。结果患者为53岁女性, 既往无基础病史, 以反复高热为主要表现, STXBP2(FHL5)突变阳性, 根据噬血性淋巴组织细胞增多症(HLH)-2004标准诊断为HPS。给予HLH-2004方案治疗, 效果良好, 随访至2021年5月, 总生存时间45个月。结论非典型原发性HPS及迟发性原发性HPS较罕见, 临床症状较轻, 仅以反复高热为表现, 需尽快完善HPS基因突变检测以明确诊断、及早治疗。     

成年人Still病误诊为恶性淋巴瘤一例

 目的 分析成年人Still病的诊断方法。方法 报道1例成年人Still病患者误诊为恶性淋巴瘤的经过,结合文献分析。结果 患者初诊为恶性淋巴瘤,经化疗后效不佳,遂复查病理排除淋巴瘤,诊断为成年人Still病。经激素治疗后病情控制良好。结论 成年人Still病临床表现复杂,无特异性诊断标准易误诊。     

儿童胸腔内原始神经外胚层肿瘤致库欣综合征

库欣综合征在儿童及青少年很少发生，与单纯性肥胖鉴别的主要特征之一是身高生长受到抑制。一旦临床诊断库欣综合征，应重点明确病因。儿童库欣综合征分为ACTH依赖和非ACTH依赖两种类型，在不同年龄阶段，其病因谱不同。成年人异位ACTH综合征（EAS）占ACTH-依赖性库欣综合征约15％。儿童EAS的病因主要为类癌，     

成年人急性淋巴细胞白血病方案优化与分层治疗

 儿童急性淋巴细胞白血病（AML）疗效在不断改善,而成年人ALL疗效一直没有大的改观。临床上很多危险因素影响其预后,其中最重要的是早期对治疗的反应。儿童ALL的方案与成年人方案相比采用了更大剂量的左旋门冬酰胺酶、激素和长春碱,采用儿童方案可以改善成年人ALL的预后。对于Ph+ ALL、CD+20 ALL联合靶向治疗有助于提高患者长期生存。异基因造血干细胞移植仅适用于高危、复发难治性ALL。     

纵隔非精原细胞瘤合并噬血细胞综合征1例

噬血细胞综合征( hemophagocytic syndrome,HPS)又名噬血细胞性淋巴组织细胞增生症(hemophagocytic lymphohistiocytosis,HLH),是病因及发病机制复杂、组织病理学表现为噬血活性而临床表现相类似的一组症候群.HPS多见于儿童,大多发生于血液系统肿瘤;成人患者极为罕见,发生于非血液系统肿瘤者也较为罕见[1].本文报道1例继发于纵隔非精原细胞瘤的HPS,并结合文献讨论其临床诊断特点,以加强对本病的认识.     

儿童肿瘤早发现

提到肿瘤,人们觉得往往是老年人容易得肿瘤,但实际上儿童也会得恶性肿瘤,今天我们邀请到的是北京儿童医院儿童肿瘤外科的副主任医师韩炜老师,来给大家讲一讲关于儿童肿瘤的防治知识。儿童肿瘤发病有什么特点?儿童不等同于缩小的成年人,儿童肿瘤跟成年人肿瘤的最大区别就是病种不同。比如成年男性发病最高的是肺癌。     

成年人急性淋巴细胞白血病方案优化与分层治疗

儿童急性淋巴细胞白血病(AML)疗效在不断改善,而成年人ALL疗效一直没有大的改观.临床上很多危险因素影响其预后,其中最重要的是早期对治疗的反应.儿童ALL的方案与成年人方案相比采用了更大剂量的左旋门冬酰胺酶、激素和长春碱,采用儿童方案可以改善成年人ALL的预后.对于Ph+ALL、CD+20ALL联合靶向治疗有助于提高患者长期生存.异基因造血干细胞移植仅适用于高危、复发难治性ALL.     

伴噬血细胞综合征EB病毒阳性T细胞淋巴瘤患者临床特征及疗效分析

目的:探讨噬血细胞综合征[又称噬血细胞性淋巴组织细胞增多症（HLH）]对EB病毒（EBV）阳性T细胞淋巴瘤（TCL）患者临床特征及治疗效果的影响。方法:回顾性分析2015年11月至2020年8月于广州医科大学附属第一医院经病理检查确诊的23例EBV-TCL患者临床资料。按发病时是否伴HLH分为HLH组（10例）和非HLH组（13例）,比较两组患者临床特征及预后。比较不同治疗方式、血浆EBV-DNA定量患者的疗效。结果:23例患者中,Ann Arbor分期Ⅰ~Ⅱ期3例（13.0%）,Ⅲ~Ⅳ期20例（87.0%）;国际预后指数（IPI）评分1分3例（13.0%）,2分4例（17.4%）,3分8例（34.8%）,4分8例（34.8%）。HLH组中侵袭性NK细胞白血病2例,儿童系统性EBV-TCL 3例,非HLH组无这两种病理类型患者。HLH组中发热、骨髓侵犯、IPI评分>2分、EBV-DNA>10 4拷贝/ml患者均多于非HLH组（均 P<0.05）。所有患者化疗后客观缓解（完全缓解+部分缓解）率为47.8%（11/23）;HLH组和非HLH组均有3例行造血干细胞移植,且均获得客观缓解;HLH组和非HLH组未行造血干细胞移植的7例和10例患者经过淋巴瘤方案化疗后,客观缓解分别为0例和5例,差异有统计学意义（ P＝0.044）。单纯化疗组17例患者中客观缓解5例,化疗+移植组6例患者均客观缓解,差异有统计学意义（ P＝0.039）。血浆EBV-DNA定量转阴的16例患者中客观缓解11例,持续阳性的7例患者均未客观缓解,差异有统计学意义（ P＝0.001）。所有患者1年总生存率为69.3%,2年总生存率为52.0%。HLH组中7例单纯化疗患者和3例化疗+移植患者的1、2年总生存率均分别为42.9%和66.7%。非HLH组中10例单纯化疗患者和3例化疗+移植患者的1年总生存率分别为80.0%和100.0%,2年总生存率分别为26.7%和100.0%。两组中化疗+移植患者的总生存均优于单纯化疗患者,差异均有统计学意义（均 P<0.05）。 结论:EBV-TCL患者总体临床分期较晚,伴HLH的患者预后更差,治疗效果可能与血浆EBV-DNA定量相关。造血干细胞移植能提高缓解率。     

A consensus review on malignancy‐associated hemophagocytic lymphohistiocytosis in adults

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of severe immune activation and dysregulation resulting in extreme and often life‐threatening inflammation. HLH has been well recognized in pediatric populations, and most current diagnostic and therapeutic guidelines are based on pediatric HLH. Recently there has been recognition of HLH in adults, especially secondary to immune deregulation by an underlying rheumatologic, infectious, or malignant condition. This review is focused on malignancy‐associated HLH (M‐HLH), in which possible mechanisms of pathogenesis include severe inflammation, persistent antigen stimulation by the tumor cells, and loss of immune homeostasis because of chemotherapy, hematopoietic stem cell transplantation, or infection. Previously considered rare, M‐HLH may occur in up to 1% of patients with hematologic malignancies. M‐HLH is often missed or diagnosed late in most published studies, and it has been associated with a poor median survival of less than 2 months. Identification of the clinical and laboratory features specific to M‐HLH in adults may allow early detection, consultation with HLH experts, and intervention. Improved management of adult M‐HLH with optimal combinations of T‐lympholytic and immunosuppressive agents and the incorporation of novel agents based on the pediatric experience hopefully will improve outcomes in adults with M‐HLH. Cancer 2017;123:3229‐40. © 2017 American Cancer Society.     

成人噬血细胞性淋巴组织细胞增生症21例临床分析

目的:探讨成人噬血细胞性淋巴组织细胞增生症(HLH)的临床特点。方法:对2005年1月－2015年1月在南京医科大学第二附属医院血液科收治的21例成人HLH患者的临床资料进行回顾性分析。结果:21例患者初治时均表现为高热、肝脾肿大、凝血功能异常、血常规三系或二系受累。病因分析中7例（33.3%）为血液肿瘤相关性;10例（47.6%）为感染,其中3例确诊为发热伴血小板减少综合征（新型布尼亚病毒核酸检测阳性）;1例（4.8%）肿瘤相关性（骨髓活检示转移癌）;3例（14.3%）原因不明。随访中死亡16例,存活3例（最长至今已5年7个月）,2例失访;生存时间为4天～5.7年（中位生存时间183天）。结论:HLH为罕见的致死性疾病,成人更为少见。临床表现复杂,常伴有多脏器受损,病情凶险,进展迅速。预后大多不良。发病机制和治疗手段有待进一步研究。     

Gastric cancer complicated with hemophagocytic lymphohistiocytosis: case report and a brief review

Hemophagocytic lymphohistiocytosis (HLH) comprises a group of severe immune function disorders that can lead to immune-mediated organ damage. There are two subtypes of HLH: primary and secondary. Secondary HLH is associated with infectious, oncologic, chemotherapeutic, and other underlying causes, and studies on HLH triggered by tumors have mainly focused on hematological malignancies. Secondary HLH in patients with solid tumors is rare. Here, we present two cases of gastric cancer complicated with HLH. The patient 1 was diagnosed as gastric cancer at stage I and got intractable fever after a distal subtotal gastrectomy without any evidence of infections or other complications. The patient 2 suffered from unresectable gastric adenocarcinoma and got fever, hemorrhagic rashes, and petechiae in mouth after six cycles of neoadjuvant chemotherapy. After detailed and comprehensive examinations, HLH was diagnosed in the two patients according to 2004 HLH diagnostic criteria, and the patients received treatment including immunosuppressive agents immediately. After therapy, the two patients showed partial remission, but both eventually died due to HLH relapse or progression of the primary tumor. The treatment regimen for HLH is intricate, and only a few relevant studies have focused on the treatment of cancer patients with HLH. The high mortality associated with this disease calls for more attention and additional research to improve the prognosis for these patients.     

B-cell lymphoma-associated hemophagocytic lymphohistiocytosis: A case report

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by an exaggerated but dysregulated immune response resulting in hyperinflammation, with a potential for progression to multiple organ dysfunction and failure. Infectious diseases, inflammatory disorders, malignancies and immunodeficiency syndromes are known triggers of HLH in adults. The present study reported the case of a middle-aged man with HLH triggered by B-cell lymphoma who was successfully treated with dexamethasone; etoposide, prednisone, vincristine, cyclophosphamide, hydroxy-doxorubicin and rituximab chemotherapy; and multiple intrathecal methotrexate with a good outcome.     

Hemophagocytic lymphohistiocytosis after allogeneic bone marrow transplantation during chronic norovirus infection

Hemophagocytic lymphohistiocytosis (HLH) is a macrophage activating syndrome that is known to develop in patients with autoimmune disease, malignancies or infection, for example with Epstein–Barr virus, cytomegalovirus or varicella zoster virus. We describe a 24‐month old boy with acute myelogenous leukaemia relapse and allogeneic bone marrow transplantation, who developed HLH on day +40 during chronic infection with norovirus. Here, we report for the first time the development of HLH in combination with chronic norovirus infection after allogeneic bone marrow transplantation in a hematopoietic malignancy. Copyright © 2013 John Wiley & Sons, Ltd.     

Risk of hemophagocytic lymphohistiocytosis in adults with fevers of unknown origin: the clinical utility of a new scoring system on early detection

The diagnosis of hemophagocytic lymphohistiocytosis (HLH) is delayed by most physicians. This study aimed to identify early parameters and suitable scoring systems for the risk of HLH. Clinical and laboratory data collected ≤3 days after admission were defined as early parameters and used to calculate the number of HLH‐2004 criteria met and bone marrow (BM) score. Between January 2006 and February 2016, 233 immunocompetent adults with naïve fever of unknown origin who underwent a BM study were enrolled to mimic patients at risk of HLH and randomly assigned into the developmental or validation cohort. Hemophagocytic lymphohistiocytosis was finally diagnosed in 47 patients, with non‐Hodgkin lymphoma as the major etiology (51.1%). Upon admission, four‐fifths of patients who developed subsequent HLH fulfilled ≤3 of 8 HLH‐2004 criteria, and 6 early parameters were independent predictors of HLH: anemia (hemoglobin < 10 g/dL), thrombocytopenia (platelet count < 100 × 10³/μL), leukoerythroblastosis, hyperbilirubinemia (total bilirubin > 2 × upper normal limit), hyperferritinemia (ferritin > 1000 ng/mL), and splenomegaly. Compared with the HLH criteria met upon admission, the BM score was an independent predictor (odds ratio = 1.621; 95% confidence interval, 1.355‐1.940) with excellent discrimination (area under the receiver operating characteristic curve = 0.920; 95% confidence interval, 0.883‐0.958). The sensitivity and specificity for a BM score cutoff of 10 points were 95% and 75%, respectively. When approaching immunocompetent adults with a continuously high fever, the BM score at initial admission assists with early identification of patients at risk of HLH.     

Successful treatment of recurrent malignancy-associated hemophagocytic lymphohistiocytosis with a modified HLH-94 immunochemotherapy and allogeneic stem cell transplantation

Acquired hemophagocytic lymphohistiocytosis (HLH) triggered by a known or still to be recognized malignancy is a life-threatening hyperinflammatory syndrome due to massive cytokine release from activated lymphocytes and macrophages. Malignancy-associated HLH (M-HLH) often impedes adequate treatment of malignancy and has the worst outcome compared with any other form of HLH. The incidence of M-HLH is unknown, and there are no published treatment recommendations addressed to this HLH form. Here, we report the case of a young woman with recurrent ALK1-positive anaplastic large T-cell lymphoma and M-HLH successfully treated with a modified HLH-94 protocol, allogeneic stem cell transplantation (alloSCT) and donor lymphocyte infusion (DLI). More than 3 years after DLI, the patient is alive, in complete remission from her malignancy and HLH-free, although suffering from extensive chronic graft-versus-host disease. AlloSCT and, if needed, DLI performed to consolidate remission of malignancy and HLH may have a curative impact on both entities. We propose that when discussing possible treatment options for patients with M-HLH, alloSCT should be considered in eligible individuals.     

Pathogenesis and mechanism of disease progression from hemophagocytic lymphohistiocytosis to Epstein-Barr virus-associated T-cell lymphoma: nuclear factor-kappa B pathway as a potential therapeutic target

Epstein-Barr virus (EBV) can infect T lymphocytes and manifests as hemophagocytic lymphohistiocytosis (HLH), a distinct entity of hemophagocytic syndrome (HPS) characterized by fever, hepatosplenomegaly, cytopenia, hypercytokinemia, and systemic macrophage activation with hemophagocytosis. In a substantial percentage of HLH patients, the disease may relapse or progress to T-cell lymphoma in months to years. In the present review, the authors summarize the previous studies on the pathogenesis of HLH and the potential mechanism for the progression of disease from HLH to T-cell lymphoma. The infection of T cells by EBV could activate T cells to secrete proinflammatory cytokines, particularly tumor necrosis factor-alpha (TNF-alpha), which subsequently activate macrophages. EBV latent membrane protein-1 (LMP-1) is the viral product responsible for the activation of the TNF receptor (TNFR) associated factors/nuclear factor-kappaB (NF-kappaB)/ERK pathway to enhance cytokine secretion mediated through the suppression of the SAP/SH2D1A gene. The activation of NF-kappaB will confer resistance to TNF-alpha-induced apoptosis on EBV-infected T cells through the down-regulation of TNFR-1. Consistent with in vitro observations, EBV-associated T or natural killer/T-cell lymphoma showed constitutive activation of NF-kappaB, explaining its drug resistance, hypercytokinemia, and poor prognosis. Therefore, similar to other inflammation-associated cancers, HLH provides a unique model to study the mechanism of disease progression from a benign virus-infected disorder (HLH) to T-cell lymphoma. Inhibition of the NF-kappaB signal pathway should provide a potential target for the treatment of HLH and EBV-associated T-cell lymphoma.     

Prognostic Factors and Outcomes in Adults With Secondary Hemophagocytic Lymphohistiocytosis: A Single-center Experience

Introduction

Hemophagocytic lymphohistiocytosis (HLH) is a disorder caused by severe immune activation. There are no specific criteria to establish the diagnosis in adults; however, the HLH-04 criteria are among the most commonly used. The HScore is a non-validated tool that can also be useful for HLH diagnosis.