Kaposis sarcoma 中文

Beijing Da Xue Xue Bao Yi Xue Ban. 2020 Apr 18; 52(2): 373–377.

Language: Chinese | English

Kaposi sarcoma combined with severe ulcerative colitis: A case report and literature review

Abstract

卡波西肉瘤是与人类疱疹病毒-8感染相关的血管增生性疾病,多见于免疫功能低下的人群,服用免疫抑制剂或糖皮质激素可能是导致人类免疫缺陷病毒阴性患者发生卡波西肉瘤的原因之一.本文报告1例接受糖皮质激素治疗的重度溃疡性结肠炎患者发生的皮肤卡波西肉瘤,并进行文献综述.患者男性,64岁,诊断溃疡性结肠炎1年,因重度溃疡性结肠炎发作接受激素治疗,4个多月后患者躯干,四肢出现多发暗紫色丘疹,结节,质地坚硬,下肢为著,经皮肤组织活检病理学检查提示皮肤卡波西肉瘤,免疫组织化学检测显示人类疱疹病毒-8染色阳性,经停用糖皮质激素,并行化疗后病情缓解.分别在万方数据知识服务平台和中国知网以"卡波西肉瘤"和"炎症性肠病"为检索词检索相关文献,未检索到中文文献.在PubMed上以("ulcerative colitis" OR "Crohn's disease" OR "inflammatory bowel disease") AND (Kaposi sarcoma)为检索词检索,共检索到38篇英文文献,另从相关文献中补充,共检索到25例与炎症性肠病相关的卡波西肉瘤,连同本例的26例患者中,男性占绝大多数(80.8%,21/26).平均年龄(51.1±16.4)岁,溃疡性结肠炎20例,克罗恩病6例.22例患者报告了人类免疫缺陷病毒检测结果,均为阴性.所有患者均使用过至少一种免疫功能调节剂,包括糖皮质激素,硫唑嘌呤/6-巯基嘌呤,氨甲喋呤,环孢菌素,抗肿瘤坏死因子α单克隆抗体.14例报告人疱疹病毒-8结果的患者中,13例阳性,1例阴性.病变单纯累及肠道者18例,单纯累及皮肤者3例,5例患者同时累及皮肤和肠道.25例报告了治疗方案,其中3例患者仅停用免疫调节剂,1例患者停药后接受放疗,1例患者停药后接受化疗,20例患者接受手术治疗,总体而言预后良好.炎症性肠病相关的卡波西肉瘤往往与使用激素,免疫抑制剂和生物制剂有关.鉴别卡波西肉瘤,炎症性肠病相关和药物相关的皮肤表现至关重要.此外,在诊疗过程中重视多学科团队的协同作用,能够更早,更准确地对少见病例做出诊断和治疗.

Keywords: 卡波西肉瘤, 炎症性肠病, 人类疱疹病毒-8, 免疫调节治疗

Abstract

SUMMARY Kaposi’s sarcoma (KS) is an unusual vascular tumor associated with human herpesvirus-8 (HHV-8) infection, which is common in immunosuppressors. Although extremely rare, iatrogenic (drug-related) KS can occur in human immunodeficiency virus (HIV)-negative patients under immunosuppressive therapy. We report a 64-year-old male diagnosed with ulcerative colitis for 1 year. He was treated with methylprednisolone because of an acute severe disease flare. He presented with several popular violet lesions on the body 4 months after steroid therapy. Histological examination of skin biopsies showed Kaposi’s sarcoma associated with HHV-8. The skin lesions regressed after steroid withdrawal and chemotherapy. Two key words “Kaposi’s sarcoma” and “inflammatory bowel disease” were searched in Wanfang data and CNKI, but no relevant articles were found. Thirty-eight articles in English were retrieved on PubMed with the key words of (“ulcerative colitis” OR “Crohn’s disease” OR “inflammatory bowel disease”) AND (Kaposi sarcoma). Twenty-five cases of Kaposi’s sarcoma related to inflammatory bowel disease (IBD) were reported. Including this case, the majority of 26 Kaposi’s sarcoma related IBD patients were male (80.8%, 21/26). The average age was (51.1 ± 16.4) years. Twenty cases were ulcerative colitis and 6 were Crohn’s disease. All the patients received immunomodulatory therapy, including glucocorticoid, azathioprine/mercaptopurine, methotrexate, cyclosporin and anti tumor necrosis factor α antibody. Thirteen cases were positive for HHV-8. There were 18 cases involving the distal ileum and colorectum only, 3 cases involving skin only, and 5 cases involving both skin and colorectum at the same time. Overall, the prognosis was good. Three patients only stopped immunosuppressive therapy, 1 received radiotherapy, 1 received chemotherapy, and 20 received surgery. Kaposi’s sarcoma could be seen in IBD patients with immunomodulatory therapy. It is very important to distinguish from the skin lesions related to IBD or drug treatment. The adverse reactions of immunomodulatory therapy should not be ignored. In addition, attention should be paid to the cooperation of multi-disciplinary team, which can diagnose and treat rare cases earlier and more accurately.

Keywords: Kaposi's sarcoma, Inflammatory bowel disease, Human herpes virus-8, Immunomodulatory therapy

卡波西肉瘤(Kaposi's sarcoma,KS)是与人类疱疹病毒-8(human herpesvirus-8,HHV-8)感染相关的血管增生性疾病,常见于免疫抑制者.我国卡波西肉瘤比较少见,主要见于人类免疫缺陷病毒(human immunodeficiency virus,HIV)感染者.实际上,除了广为人知的HIV相关性卡波西肉瘤外,卡波西肉瘤还有一个类型,即医源性卡波西肉瘤,主要与使用免疫抑制剂有关,多见于实性器官移植治疗之后数月或数年.国外有炎症性肠病患者长期或间断接受糖皮质激素或免疫调节治疗后发生卡波西肉瘤的个案报道,我国尚未见报告.炎症性肠病的本质是病因不明的肠道炎症性疾病,与免疫功能有密切的关系,本身就可能出现皮肤表现,而且治疗炎症性肠病的药物也可能导致皮肤损伤.由于这几种原因导致的皮肤病变治疗思路截然不同,如何对此进行鉴别,及早明确诊断,是临床面临的实际问题.

本文报告1例接受糖皮质激素治疗的溃疡性结肠炎患者发生皮肤卡波西肉瘤的病例,并对文献进行综述.

1. 病例资料

患者男性,64岁.2014年5月无诱因出现间断腹泻伴有黏液脓血便,当地医院予中药+地塞米松10 mg+庆大霉素80万U灌肠,治疗1个月后症状减轻,偶尔便纸上少量鲜血,患者停药.2018年2月患者症状复发,当地医院经肠镜等检查诊断为"溃疡性结肠炎"(具体不详),予美沙拉嗪治疗后症状缓解,继续以美沙拉嗪维持治疗.2019年1月10日再次出现腹泻,大便10~15次/d,不成形,带有较多黏液脓血,伴里急后重,排便前左下腹痛,发热,体温最高40 ℃,当地医院经肠镜等检查诊断"溃疡性结肠炎复发",于2019年1月18日开始予甲基强的松龙40 mg,每天1次,静脉滴注2周,效果不佳,增至60 mg,每天1次,静脉滴注1周,再次予40 mg,每天1次,静脉滴注10 d,以后改为甲基强的松龙口服40 mg,每天1次,共2周,大便仍8~9次/d,间断有便血,伴腹痛,无发热,为进一步诊治来北京大学第三医院住院治疗.患者住院后完善相关检查,血常规:白细胞4.53×109个/L, 血红蛋白93.0 g/L, 血小板222×1012个/L.红细胞沉降率 66 mm/h,C反应蛋白1.13 g/L,粪便巨细胞核酸检测1.05×104 copy/mL,粪便EB病毒核酸检测4.42×103 copy/mL.其他粪便病原学检查均为阴性,血巨细胞核酸检测,免疫球蛋白M 均为阴性.结肠黏膜活检示巨细胞病毒免疫组织化学检测阳性.患者诊断为:溃疡性结肠炎[慢性复发型,广泛结肠炎型,活动期,重度(Mayo 11分)]合并巨细胞病毒感染.经更昔洛韦抗病毒治疗后患者症状明显缓解,由于患者拒绝使用生物制剂,病情稳定后甲基强的松龙以每10~14天减4 mg/d,16 mg以下每2周减2 mg/d的速度减量,同时给予美沙拉嗪4 g/d口服.

2019年5月下旬患者发现双小腿远端出现大小不等出血点,左小腿背侧黑褐色皮疹,3 cm×4 cm,质硬,中心破溃,无明显疼痛,瘙痒,当地医院诊断"感染",予消毒包扎.病情逐渐加重,皮疹泛发至躯干,四肢,左小腿背侧皮疹增大,2019年7月中旬于皮肤科就诊,考虑"坏疽性脓皮病?",将甲基强的松龙从14 mg/d增加到24 mg/d,卤米松乳膏外用.治疗14 d后皮疹无明显减少或缩小,仍可见新发皮疹(图1).于2019年7月29日在北京大学第三医院第二次住院.入院查体:躯干,四肢多发大小不等暗紫色丘疹,结节,质地坚硬,压之不褪色,皮温升高,伴轻度压痛,双小腿皮损分布较为密集.左小腿胫后7 cm×8 cm黑紫色斑块,表面结黑色厚痂,基底破溃,坏死,出血,压痛(+),左小腿轻度水肿.辅助检查:血常规:白细胞13.6×109个/L, 血红蛋白129 g/L, 血小板147×1012个/L,红细胞沉降率4 mm/h, C反应蛋白0.34 g/L,免疫球蛋白M 0.38 g/L,抗可溶性抗原(extractable nuclear antigen,ENA)谱(-),便常规:黄色软便, 未见异常,潜血(-).

左下肢皮疹

Skin lesions of left lower extremity

A, several popular violet lesions on the left lower extremtity after 4 months of steroid therapy; B,skin lesions became more elevated 2 weeks later; C, skin lesions regressed after 5 months of steroid withdrawal and chemotherapy.

经多学科团队讨论,考虑患者溃疡性结肠炎病情已经得到控制的情况下皮肤病变仍在加重,坏疽性脓皮病难以解释,决定进行皮肤活检.经患者知情同意后行皮肤活检,病理检查见图2,表皮角化亢进,棘细胞层轻度增生,表皮脚轻度下延,真皮见血管纤维增生性病变,细胞轻度异型,偶见核分裂像,免疫组织化学检测HHV-8(+),符合卡波西肉瘤.再次复习上次住院结肠黏膜活检,符合溃疡性结肠炎活动期表现,未见卡波西肉瘤样改变, HHV-8染色阴性.排除患者肠道炎症表现为卡波西肉瘤和/或HHV-8感染所致.

皮肤活检病理检查证实卡波西肉瘤,免疫组织化学显示HHV-8阳性

Histological examination of skin biopsies showed Kaposi's sarcoma, immunohistochemistry for the detection of HHV-8 proved positive

A, ×20; B, ×100; C, ×100.

患者确诊后将甲基强的松龙快速减停,美沙拉嗪+五味苦参胶囊治疗溃疡性结肠炎,溃疡性结肠炎处于缓解期.同时转到肿瘤专科医院进行化疗,2019年11月底随访已化疗5次.皮肤病变较前明显缓解,无新发病变,原有病变有缩小,双下肢水肿较前好转.

2. 分析与讨论

卡波西肉瘤是具有局部侵袭性的内皮细胞肿瘤,与HHV-8有关,更常见于男性,据报道男,女比约3 ∶1[1].虽然全球(包括南美洲和亚洲)均已有病例报道,但该病最常见于地中海盆地,中欧,东欧地区的人群及其后代.欧洲发病率最高的地区是地中海地区的两个岛屿撒丁岛和西西里岛[2].我国卡波西肉瘤相对少见.

卡波西肉瘤主要分为4型[3]:(1)经典型:最先由Kaposi描述,见于地中海地区或东欧,常见于中老年人.(2)地方型:在获得性免疫缺陷综合征(acquired immunodeficiency syndrome,AIDS)流行前,在撒哈拉以南非洲地区土著中存在.(3)流行性卡波西肉瘤:与HIV感染和AIDS有关,侵袭性最强.(4)医源性:与免疫抑制药物治疗有关,多见于实体脏器移植患者,糖皮质激素也是相关的药物之一.

国外的报告中,男性有过敏史,患有糖尿病,哮喘,使用糖皮质激素,很少洗澡,不吸烟等与HIV阴性者罹患经典型卡波西肉瘤风险增加有关[4,5].在HIV感染者中,罹患卡波西肉瘤的危险因素包括女性,年龄超过35岁,少数民族,有输血史,肿瘤家族史,不吸烟,不使用蚊帐,CD4细胞计数低,采用当地传统治疗方法等[6,7].总体而言,卡波西肉瘤的发生与患者免疫功能紊乱,卫生条件差有关.

卡波西肉瘤主要见于皮肤,典型病变表现为皮肤多发性斑点状,斑块状或结节状病损,多见于下肢和足部.需要与其他皮肤病变相鉴别,包括周围血管病,细菌性血管瘤病和其他感染,血管肉瘤和良性血管病变(例如血管瘤).

卡波西肉瘤也可累及黏膜,淋巴结和内脏器官,如消化道或呼吸道.消化道受累患者通常症状轻微,但也有便血,腹泻等症状的报告,造成蛋白丢失性肠病,肠套叠,穿孔等[8],需要和炎症性肠病(包括溃疡性结肠炎和克罗恩病),肿瘤,急腹症等疾病进行鉴别.

医源性卡波西肉瘤与服用免疫抑制剂,糖皮质激素有关,多见于实质脏器移植患者,其他疾病长期用药导致免疫功能低下者亦有报道.患者多年纪较大(>50岁), 多见于下肢,病灶可播散,脉管受累多见.医源性卡波西肉瘤在调整治疗后可缓解,也有进展的报告[5].减停免疫抑制剂是首要的治疗策略,病灶可能在免疫抑制剂减量或停用后消退.在美国辛辛那提注册中心的患者中,减少免疫抑制治疗的用量后,黏膜皮肤病变和内脏受累的卡波西肉瘤患者中分别有17%和16%消退,17例肾移植受者用西罗莫司代替环孢素后卡波西肉瘤消退[9].

我国卡波西肉瘤比较少见,主要发生在新疆地区维吾尔族及哈萨克族,汉族和其他少数民族少见,而炎症性肠病发生卡波西肉瘤者更为罕见.在万方数据知识服务平台和中国知网用"卡波西肉瘤"和"炎症性肠病"两个关键词进行检索,并未见到有相关报道.用("ulcerative colitis" OR "Crohn's disease" OR "inflammatory bowel disease")AND (kaposi sarcoma)为检索词在PubMed上检索,共检索出46篇文献,其中38篇英文文献.排除结直肠卡波西肉瘤类似炎症性肠病表现的病例报告外,另从相关文献中补充,共检索到25例与炎症性肠病相关的卡波西肉瘤.

1966年报道了第1例卡波西肉瘤合并溃疡性结肠炎的病例[10],直到1987年才发表了第2例溃疡性结肠炎患者合并卡波西肉瘤的病例报告,以后陆续报道了23例,连同本例报道,共检索到26例与炎症性肠病相关的卡波西肉瘤[3,10-33],其中男性占绝大多数(21例),女性5例,平均年龄(51.1±16.4)岁,溃疡性结肠炎20例,克罗恩病6例.22例患者报告了HIV检测结果,均为阴性.所有患者在病程中均接受过糖皮质激素治疗,此外,接受硫唑嘌呤/6巯基嘌呤治疗者11例,氨甲喋呤者1例,环孢菌素治疗2例,抗肿瘤坏死因子α单克隆抗体治疗5例.14例报告了HHV-8结果,其中13例为阳性,1例阴性.病变单纯累及肠道者18例,单纯累及皮肤者3例,5例患者同时累及皮肤和肠道.

肠道卡波西肉瘤和炎症性肠病的表现确实十分相近,文献中也有因为肠道卡波西肉瘤的临床表现类似炎症性肠病而误诊为炎症性肠病的报告[34].1985年,Weber等[35]报道了1例37岁男性AIDS患者,出现类溃疡性结肠炎表现,最终诊断为肠道卡波西肉瘤.Biggs等[36]报到了另1例AIDS相关卡波西肉瘤出现类溃疡性结肠炎表现,并发生中毒性巨结肠的病例.二者的鉴别诊断需要病变组织的病理学检查.

炎症性肠病患者的皮肤卡波西肉瘤需要和炎症性肠病相关的皮肤表现相鉴别.炎症性肠病的皮肤表现主要分为以下几类[37]:(1)特异性皮肤表现:包括连续性皮肤表现和皮肤转移性克罗恩病,其皮肤表现的病理特点和炎症性肠病肠道病变相同.(2)反应性皮肤表现:包括坏疽性脓皮病,急性发热性嗜中性皮病(Sweet综合征),增殖性脓皮病,增殖性脓性口炎,阿弗他口炎等.(3)相关性皮肤表现:包括结节性红斑,银屑病,获得性大疱性表皮松解症等,往往和炎症性肠病的活动程度相关.(4)继发性皮肤表现:营养素缺乏或药物诱发所致,治疗炎症性肠病的部分药物可以导致皮肤病变,例如糖皮质激素可导致痤疮样表现,英夫利昔单抗可能诱发银屑病样改变等.皮肤卡波西肉瘤和炎症性肠病的皮肤表现一旦误诊,可能会发生不良后果.如前所述,医源性卡波西肉瘤的治疗需停用免疫抑制剂,而与炎症性肠病活动度相关的皮肤病变多数情况下需加用免疫抑制剂,二者的治疗方向是截然相反的.一旦误诊,治疗方向错误将导致病情加重,因此,确诊需要仔细的询问病史,病变组织的病理学检查在很多病例中也是必需的,对于后续治疗有决定意义.

值得注意的是,不仅传统的免疫抑制剂包括糖皮质激素可能导致卡波西肉瘤,目前在临床广泛用于治疗炎症性肠病的抗肿瘤坏死因子α单克隆抗体也有发生卡波西肉瘤的报告,因此,对于所有影响免疫功能的药物都要提高警惕.

总体而言,炎症性肠病相关的卡波西肉瘤与其他医源性卡波西肉瘤的治疗措施相类似,共有25例患者报告了治疗方案,其中3例患者仅停用免疫抑制剂后病情即得到缓解,1例患者停药后接受放疗,1例患者停药后接受化疗,20例患者接受手术治疗.共有14例患者报告了预后情况,总体而言预后良好.

总之,卡波西肉瘤不仅见于HIV感染者,也可见于炎症性肠病患者.医源性卡波西肉瘤往往与使用激素,免疫抑制剂和生物制剂有关.鉴别卡波西肉瘤,炎症性肠病相关和药物相关的皮肤表现至关重要.此外,在诊疗过程中重视多学科团队的协同作用,能够更早,更准确地对少见病例做出诊断和治疗.

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