皮肤T细胞淋巴瘤的免疫治疗进展

皮肤T细胞淋巴瘤(cutaneous Tcell lymphoma,CTCL)是一组异质性的T细胞来源的恶性肿瘤,以皮肤损害为初发和突出表现。近年来,其发生率和病死率呈上升趋势,严重威胁人类的健康。早期CTCL治疗效果一般较好,但对中晚期CTCL目前尚无有效的治疗方法。随着对抗肿瘤免疫机制的深入了解和CTCL生物学特性的深入研究,免疫治疗已逐渐成为CTCL临床上重要而有效的辅助治疗手段。     

皮肤T细胞淋巴瘤外周血免疫表型CD7缺失的临床分析

目的比较不同分期的皮肤T细胞淋巴瘤(cutaneous T cell lymphom a,CTCL)患者外周血淋巴细胞表面抗原CD7的缺失情况。方法回顾性分析2006年1月-2010年7月本科收治的41例CTCL患者及9例炎症性皮肤病患者外周血淋巴细胞免疫表型的流式细胞检测结果,分析外周血CD7表达。结果 41例CTCL患者中,早期(IA~ⅡA)23例和进展期(ⅡB~ⅣB)18例,CD3+CD7-T细胞比例进展期组与炎症性皮肤病组及早期组比较,均明显升高(P<0.05)。进展期18例患者中6例CD7缺失(33.33%),早期23例患者中仅1例CD7缺失(4.35%),提示CD7缺失在进展期显著高于早期(P<0.05)。无外周血累及的25例蕈样肉芽肿(mycosis fungoides,MF)患者中有2例CD7缺失,均为进展期,提示进展期MF较早期MF更易出现CD7缺失(P<0.05);在进展期MF的CD3+CD7-T细胞比例均高于早期MF和炎症性皮肤病组(P<0.05)。结论 进展期CTCL和无外周血累及的进展期MF外周血CD3+CD7-T细胞比例明显高于早期及炎症性皮肤病组,CTCL进展期较早期更容易发生外周血CD7缺失。     

皮肤T细胞淋巴瘤的治疗进展

皮肤T细胞淋巴瘤(CTCL)是一组原发于皮肤的非霍奇金淋巴瘤。蕈样肉芽肿是最常见的CTCL类型,多数患者处于疾病早期,发展缓慢,以局部治疗为主。但进展期(ⅡB期～Ⅳ期)患者可累及淋巴结、血液和内脏器官,尚缺少有效的治疗方法,进展期患者预后不佳,5年生存率仅为47%。近年随着对肿瘤发病机制的认识加深,出现多种新型疗法,如单克隆抗体和抗体偶联药物、表观遗传学修饰药物、免疫检查点抑制剂等。该文对CTCL的发病机制及治疗进展作一综述。     

皮肤T细胞淋巴瘤的电镜定量分析

蕈样肉芽肿(MF)与 Sézary 综合征(SS)均属于皮肤 T 细胞淋巴瘤(CTCL),晚期诊断并不困难,但早期往往与许多慢性良性非特异性炎症性皮肤病不易鉴别,长期     

维甲酸的诱导分化作用及治疗皮肤T细胞淋巴瘤的进展

阐述维甲酸的诱导分化作用与治疗皮肤T细胞淋巴瘤（CTCL），指出维甲酸对CTCL早期有较好的疗效，进展期或晚期则需与其他制剂联合应用。     

皮肤T细胞淋巴瘤皮损与外周血中TCRγ基因重排的检测

目的：了解已确诊为皮肤T细胞淋巴瘤（CTCL）患者的皮损和外周血中T细胞受体γ链基因重排（TCRγGR）情况。方法：利用PCR测定21例CTCL患者皮损及外周血TCRγGR，扩增产物经琼脂糖及变性梯度凝胶电泳检测。结果：CTCL患者皮损中TCRγGR阳性率显著高于外周血（P〈0．05）；病程≥12个月的患者外周血中TCRγGR阳性率显著高于病程〈12个月的患者（P〈0．05）；年龄≥60岁患者皮损和外周血中TCRγGR阳性率显著高于〈60岁患者（P〈0．05）。结论：在CTCL患者中存在TCRγGR，早期出现在皮损中的TCRγGR可作为CTCL辅助诊断，并有益于CTCL的早期诊断，外周血中检测出TCRγGR可作为皮损阳性结果的补充。     

非化疗和化疗治疗皮肤T细胞淋巴瘤的临床疗效比较

目的:比较非化疗与系统性联合化疗治疗皮肤T细胞淋巴瘤(cutaneous T-cell lymphoma,CTCL)的疗效.方法:收集1986年7月-2006年2月在上海瑞金医院住院且分别接受非化疗或系统性联合化疗的32例CTCL患者的临床资料进行回顾性分析,比较两组患者的治疗效果.结果:两组患者的缓解率差异无统计学意义(P＞0.05);化疗组患者获得缓解的时间较短(P＜0.05);非化疗组患者的缓解期(中位数39个月)长于化疗组(中位数3.7个月)(P＜0.01);非化疗组患者的总生存率(52.94%)高于化疗组(8.33%)(P＜0.05);非化疗组患者的总生存期(中位数106.83个月)长于化疗组(中位数10.7个月)(P＜0.01).结论:系统性联合化疗治疗CTCL病情缓解较快;但非化疗方法能获得较长的缓解期、较高的生存率以及较长的总生存期.     

皮肤T细胞淋巴瘤的免疫治疗相关进展

皮肤T细胞淋巴瘤(CTCL)是一组异质性明显的非霍奇金淋巴瘤,最常见的是蕈样肉芽肿(MF)和Sézary综合征。CTCL早期病变进展缓慢,晚期则可累及多系统,预后较差,目前尚无有效的治疗方案。肿瘤的免疫疗法是指通过修复、增强宿主的免疫功能从而控制、清除肿瘤的一种治疗方法,治疗反应比传统疗法更为持久,目前已经在多种实体肿瘤中得到验证。本文就免疫治疗在CTCL中的研究进展作一综述。     

皮肤T细胞淋巴瘤的治疗选择

皮肤T细胞淋巴瘤是一种少见的淋巴细胞增生性疾病,依据疾病的分类及分期不同,治疗选择有很大差异性。多数的皮肤T细胞淋巴瘤病程进展缓慢,诸如早期的蕈样肉芽肿和淋巴瘤样丘疹病,只需要选择皮肤局部治疗的方案。侵袭性或顽固性如Sézary综合征、复发性CTCL等,则需系统治疗,包括化疗。本文对国内现有药物及最新治疗方法进行综述。     

原发性皮肤B细胞性淋巴瘤3例报告

原发性皮肤淋巴瘤(primary cutaneouslymphoma,PCLs)是指临床上起源于皮肤的非霍奇金淋巴瘤(Non-HodgkinLymphoma,NHL),它原发并主要局限于皮肤,并在诊断后6个月内未发现皮肤以外肿瘤病变[1].皮肤淋巴瘤中,以T细胞性淋巴瘤(cutaneous Tlymphocyte lymphoma,CTCL)较多见,并易于辨认和诊断[2],但皮肤B细胞淋巴瘤(cutaneous B lym-phoctyelymphoma,CBCL)的发病率比人们认为的高[3].     

多梳基因家族蛋白在常见皮肤T细胞淋巴瘤及淋巴组织增殖性疾病中的表达

【摘要】 目的 探讨表观遗传抑制因子PcG家族成员果蝇zeste基因增强子的人类同源物1/2（EZH1/EZH2）、胚胎外胚层发育蛋白（EED）及胚胎干细胞抑制蛋白（SUZ12）在常见皮肤T细胞淋巴瘤及淋巴组织增殖性疾病（CTCL/ LPD）中的表达。方法 收集2012—2019年于中国医学科学院皮肤病医院确诊的93例CTCL/LPD及8例扁平苔藓皮损石蜡标本，行免疫组化染色，观察EZH2、EED、SUZ12及EZH1蛋白表达。采用SPSS 25.0软件进行卡方检验及Spearman相关分析。结果 93例中包括44例蕈样肉芽肿（MF）、17例NK/T细胞淋巴瘤（NK/TCL）及原发性皮肤间变大细胞淋巴瘤（PC?ALCL）、淋巴瘤样丘疹病（LyP）、种痘水疱病样淋巴组织增殖性疾病（HV?like LPD）及皮下脂膜炎样T细胞淋巴瘤（SPTCL） 各8例。93例CTCL/LPD中83例（89.2%）EZH2、81例（87.1%）EED、78例（83.9%）SUZ12、37例（39.8%）EZH1阳性；8例扁平苔藓中1例EZH2、8例EZH1阳性，EED、SUZ12全阴性。CTCL/LPD与扁平苔藓4种蛋白的表达分级差异均有统计学意义（χ2分别为41.75、39.74、39.36及32.83，均P < 0.001），且MF、NK/TCL、PC?ALCL、LyP、HV?like LPD及SPTCL与扁平苔藓的表达差异亦均有统计学意义（α = 0.008 3，均P < 0.001）。同时，EZH2与EZH1的表达评分在MF、NK/TCL、PC?ALCL、LyP、HV?like LPD及SPTCL中均呈负相关（rs分别为-0.60、-0.68、-0.89、-0.74、-0.93、-0.80，均P < 0.05）。结论 PcG家族成员EZH2、EED、SUZ12及EZH1在CTCL/LPD中表达异常。     

生存素、Ki67在皮肤结外鼻型NK/T细胞淋巴瘤中的表达及其意义

目的 探讨生存素、Ki67在皮肤结外鼻型NK/T细胞淋巴瘤中的表达及意义。方法 选取确诊的以皮损为首发表现的15例皮肤结外鼻型NK/T细胞淋巴瘤为研究对象,常规SP免疫组化染色法检测生存素、Ki67。每张切片选取5个有代表性的高倍镜视野,每个视野随机计数200个肿瘤细胞,分别计算1000个肿瘤细胞内生存素、Ki67阳性细胞百分比。结果 15例皮肤结外鼻型NK/T细胞淋巴瘤中,9例瘤细胞表达CD56,13例表达CD3ε,15例表达TIA-1,10例表达粒酶B,2例表达CD3。15例均表达1 ～ 2个T细胞抗原（CD2、CD45RO或CD7）,1例表达βF1,3例表达CD30的病例阳性细胞均为大瘤细胞。所有病例均不表达CD4、CD5、CD8、CD20和CD79α。14例中3例被检出TCR-γ基因克隆性重排,15例EBER1/2原位杂交均阳性。15例中,11例（73.3%）表达生存素,阳性细胞表达率为23.97% ± 18.35%;14例（15例中1例掉片）均表达Ki67,阳性细胞表达率41.20% ± 19.52%。核分裂0 ～ 2个/高倍视野的9例Ki67表达阳性细胞率为25.27% ± 12.96%,核分裂 ＞ 2个/高倍视野的6例为58.23% ± 16.02%,两组差异有统计学意义（F = 19.14,P = 0.001）。皮肤结外鼻型NK/T细胞淋巴瘤中生存素、Ki67都有较高的表达,生存素与Ki67表达之间无相关性。结论 生存素、Ki67的高表达可能在皮肤结外鼻型NK/T细胞淋巴瘤发生发展中起着一定作用。     

Cutaneous lymphomas showing prominent granulomatous component: clinicopathological features in a series of 16 cases

Background  The presence of a prominent granulomatous tissue reaction in skin biopsies from primary cutaneous or systemic malignant lymphomas with secondary cutaneous involvement is a rare but well-known phenomenon.
Objective  This paper aims to characterize and study a series of cutaneous lymphomas showing a prominent granulomatous component.
Patients and methods  The clinical, histopathological and evolutive features of granulomatous variants of mycosis fungoides (5 patients, 2 of them associating 'granulomatous slack skin' features), Sézary syndrome (1 patient), CD30⁺ cutaneous T-cell lymphoma (2 patients), CD4⁺ small/medium pleomorphic cutaneous T-cell lymphoma (1 patient), primary cutaneous B-cell lymphoma (3 patients) and peripheral T-cell lymphoma with secondary epithelioid granulomatous cutaneous involvement (4 patients) were reviewed.
Results  The observed features were clinically non-distinctive. Only those cases presenting with granulomatous slack skin features were clinically suspected (2 patients). Non-necrotizing granulomata (11 patients) and granuloma annulare-like (4 patients) were the most frequently observed histopathological patterns. In five cases, no diagnostic lymphomatous involvement was initially observed. From our series, no definite conclusions regarding prognosis could be established.
Conclusion  The diagnosis of cutaneous lymphoma may be difficult when a prominent cutaneous granulomatous inflammatory infiltrate obscures the true neoplastic nature of the condition. However, the presence of concomitant lymphoid atypia may help to suspect the diagnosis. In doubtful cases, the clinical evolution and the demonstration of a monoclonal lymphoid B- or T-cell population may lead to a definite diagnosis.

Conflicts of interest

None declared.     

Molecular pathogenesis of cutaneous lymphoma–Future directions

The pathogenesis of cutaneous T-cell lymphomas is not clear. In recent years, the genetic changes in CTCL were explored. The detected mutations showed a great deal of heterogeneity between individual patients. The studies documented various copy number variations (CNV) and single nucleotide variations (SNV) in multiple genes involved in multiple signalling pathways. Recurrently mutated signalling pathways include JAK-STAT, MAPK, T-cell receptor, TNF receptor and NFκB signalling. In the period between 2018 and today, additional studies towards the genetic changes in CTCL were carried out. Genetic changes in gamma delta T-cell lymphoma are also shown in genes of the JAK-STAT, MAPK, MYC and chromatin signalling pathways. These studies might indicate a shift away from targeted sequencing approaches towards whole-genome sequencing. This approach demands additional resources in terms of funding but has the advantage of finding mutations in non-coding regions. These mutations were neglected for a long time, but as shown in contemporary research these regions harbour highly recurrent mutations affecting gene expression and regulation. Nevertheless, the detection of specific molecular changes in known pathways enables considerations for targeted therapies.     

Characteristics of cutaneous lymphomas in Osaka, Japan (1988-1999) based on the European Organization for Research and Treatment of Cancer classification

Based on accumulating information, European investigators proposed a new classification for primary cutaneous lymphomas known as the European Organization for Research and Treatment of Cancer (EORTC) classification. The clinical utility of this classification in Japanese cases has not been evaluated. Material from 65 patients with cutaneous lymphomas (48 with primary disease and 17 with secondary disease) who were admitted to Osaka University Hospital during the period 1988 through 1999 was reviewed. Immunohistochemical analysis was performed in all cases. Cutaneous T-cell lymphoma (CTCL) comprised mycosis fungoides (15 cases), Sézary syndrome (1 case), lymphomatoid papulosis (5 cases), large cell CTCL (13 cases), pleomorphic small- or medium-sized CTCL (2 cases), and cutaneous natural killer /T-cell lymphoma (4 cases). B-cell lymphomas comprised 7 cases of follicle center cell lymphoma and 1 case of diffuse large B-cell lymphoma of the leg. Each category of disease in the EORTC scheme showed its characteristic features in our series. Five of 13 large cell CTCL cases were positive for CD30, and 5 were negative. The 5-year survival rate of patients with large cell CTCL CD30+ disease was 100% and that of patients with CD30- disease was 0%. (p > 0.1). Only 1 of 7 CTCL cases expressing CD30 was ALK-1+, and all 7 cases showed a favorable clinical course. The EORTC classification is effective in dealing with Japanese cases of cutaneous lymphomas.     

牛痘样水疱病样原发性皮肤CD8阳性T细胞淋巴瘤一例

一例13岁女孩面部和四肢为主反复出现红斑、丘疹、水疱样皮损9年,皮疹形态与牛痘水疱病相似(hydroa vacciniforme,HV)。在病情急性进展期,伴高热,体温39℃以上。皮肤科检查:面部水肿,面部和四肢较多的萎缩性圆形和椭网形痘疮样瘢痕,散在红斑、丘疹、坏死和结痂;四肢数个水肿性红色斑块,中心有圆形破溃面。组织学上,在真皮的血管和附属器周围,可见大量表达CD8异形淋巴细胞浸润,诊断CD8⁺皮肤T细胞淋巴瘤。糖皮质激素和免疫抑制剂可使病情缓解,随诊至今,无系统受累情况。     

皮肤T细胞淋巴瘤的光疗进展

光疗可治疗皮肤T细胞淋巴瘤,根据不同分期选用不同光源。宽谱中波紫外线只对斑片期皮损有效,窄谱中波紫外线对斑片期和早期斑块期皮损有效,长波紫外线A1可治疗皮损较厚又不能耐受补骨脂者,单频准分子激光对IA期皮损有效。补骨脂加长波紫外线能清除斑块期皮损,体外光分离置换法对晚期皮肤T细胞淋巴瘤疗效较佳。光动力疗法亦可治疗皮肤T细胞淋巴瘤。     

Primary cutaneous T-cell lymphoma occurring after organ transplantation

Lymphoma occurring after organ transplantation has been well described. The majority of cases are B-cell lymphomas and are usually associated with Epstein-Barr virus. Only a minority of posttransplant lymphomas are of T-cell origin, and primary cutaneous T-cell lymphoma (CTCL) is extremely rare. In this article, we report a case of cutaneous peripheral T-cell lymphoma, pleomorphic CD30+ large-cell type, and review the literature relating to posttransplant primary CTCL. Of the 23 cases of posttransplant primary CTCL, 5 patients had erythrodermic disease, and 8 had primary cutaneous anaplastic large cell lymphoma. In addition, there are two cases of mycosis fungoides, one case of subcutaneous panniculitis-like T-cell lymphoma, one case of CD30+ lymphomatoid papulosis, and 6 cases of peripheral T-cell lymphoma, of which 3 were CD30+ large cell lymphomas. Seventeen cases had renal transplants and the majority received both cyclosporine and azathioprine. No consistent viral association was noted among these cases. The sex ratio was 18:5 (male/female), and the mean age at diagnosis was 53 years. Mean time from transplantation to diagnosis is 6.4 years and mean survival time from diagnosis is 14.5 months. The prognoses normally associated with particular subsets of CTCL do not apply in the posttransplant setting.     

Second Primary Malignancies in CTCL Patients from 1992 to 2011: A SEER-Based,Population-Based Study Evaluating Time from CTCL Diagnosis,Age, Sex,Stage, and CD30+ Subtype

Background

Cutaneous T-cell lymphoma (CTCL) is a diverse group of extranodal non-Hodgkin lymphomas with malignant T lymphocytes localizing in the skin. CTCL can mainly be classified as mycosis fungoides, Sézary syndrome, or primary cutaneous CD30+ lymphoma. Patients with CTCL have an increased risk of developing second primary malignancies.

Objective

Our objective was to analyze the overall incidence of second primary malignancies in patients with CTCL by age, sex, stage, and the primary cutaneous CD30+ lymphoproliferative subtype of CTCL, as this group has usually been excluded from previous analyses.

Methods

We used the Surveillance, Epidemiology, and End Results (SEER) database to evaluate CTCL cases diagnosed between 1992 and 2011. We calculated the multiple primary standardized incidence ratio, comparing the observed incidence of second primary malignant neoplasms in the CTCL patient population versus the general population.

Results

CTCL is associated with an overall increased risk of cancers. This incidence is greatest within the first year of diagnosis. The risk of secondary Hodgkin disease is greatest in patients aged ≥60 years; the risk of secondary non-Hodgkin lymphoma is greatest in patients aged 20–39. Males demonstrated a significantly increased risk of developing Hodgkin lymphoma, while females showed a significantly increased risk of developing bronchopulmonary malignancy. Overall, secondary malignancy incidence was significantly elevated for stage I and IV CTCL. Patients with CD30+ CTCL had a significantly higher incidence of Hodgkin lymphoma, non-Hodgkin lymphoma, and urinary cancers than the general population.

Conclusion

Occult secondary malignancies, particularly lymphomas, should be considered in adult CTCL patients, including those with the CD30+ subtype.