修回日期: 2012-07-10
接受日期: 2012-07-20
在线出版日期: 2012-08-08
胃肠道间质瘤(gastrointestinal stromal tumor, GIST)是胃肠道最常见的间叶性肿瘤, 近年来随着分子生物学、组织病理学和临床医学的研究进展, 对其认识不断加深. 传统手术与分子靶向药物相结合对GIST的治疗显得尤为重要, 以伊马替尼和舒尼替尼等药物为代表的多靶点和多激酶抑制剂在治疗不可切除及复发性GIST中更是受到高度关注. 本文主要对该病的基因分析、病理组化特点、手术及辅助治疗相关进展作一综述.
引文著录: 胡其欣, 高青. 胃肠道间质瘤的临床特征及治疗进展. 世界华人消化杂志 2012; 20(22): 2050-2057
Revised: July 10, 2012
Accepted: July 20, 2012
Published online: August 8, 2012
Gastrointestinal stromal tumors (GISTs) are the most common gastrointestinal mesenchymal tumors. The development of molecular biology, pathology and clinical medicine in recent years has deepened our understanding of GISTs. The combination of traditional surgery and molecular targeted drugs is particularly important for the treatment of GISTs. Multi-target and multi-kinase inhibitors such as imatinib and sunitinib have been used for the treatment of unresectable and recurrent GISTs. This paper provides a brief review of gene analysis, pathological characteristics, operational and adjuvant therapy of GISTs.
- Citation: Hu QX, Gao Q. Clinical features and treatment of gastrointestinal stromal tumors: Recent advances. Shijie Huaren Xiaohua Zazhi 2012; 20(22): 2050-2057
- URL: https://www.wjgnet.com/1009-3079/full/v20/i22/2050.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v20.i22.2050
胃肠道间质瘤(gastrointestinal stromal tumor, GIST)是最常见的胃肠道间叶源性肿瘤. 20世纪90年代以前, 由于病理技术的限制, 曾被认为是一种平滑肌源性或神经源性肿瘤, 归类为平滑肌瘤或平滑肌母细胞瘤[1]. 90年代后的一系列相关研究显示, 其发育依赖于KIT激酶调控的干细胞因子, 并表达Kit蛋白(CD-117)及CD34, 此类肿瘤可通过免疫组化的方法作出诊断. 近年来, 酪氨酸激酶抑制剂成为治疗GIST的有力手段, 与其相关的基因型分析也为临床实践及药物研究领域带来了新的突破方向. 本文主要对胃肠道间质瘤的病理组织学标志物及辅助治疗相关进展作一综述.
病理学超微结构和免疫组织化学(免疫组化)研究显示: GIST起源于胃肠道间质干细胞-Cajal细胞(intestinal cell of Cajal, ICC)可能性大或向Cajal细胞分化, 大多数GIST表达干细胞因子受体KIT蛋白(CD117)或PDGFRα(胎盘源性生长因子α)[2]. 约有85%的GIST具有酪氨酸激酶基因c-kit或PDGFRA突变[3,4]. 通常, GIST被看做是KIT表达阳性, 并具有c-kit或PDGFR基因突变的间质肿瘤.
1.1.1 c-kit基因突变型:c-kit是一种原癌基因, 编码具有酪氨酸激酶活性的跨膜蛋白, 该蛋白受体受干细胞因子(stemcell factor, SCF)调节, SCF/KIT通过多种信号因子将细胞外信号传至细胞内, 启动正常细胞增殖分化或其他基因表达. c-kit基因发生突变时, 不能精确地调节细胞分化、增殖和凋亡, 使更多的细胞由静止期进入增生期, 可能是引起GIST恶性转化的关键机制之一. GIST中, KIT基因突变约占80%-85%, 这也解释了大多数GIST高度表达CD117(KIT蛋白)的原因. 其基因突变的主要形式包括缺失、插入和点突变, 在恶性GIST病例中是发病的起始机制[5]. 最常见的为11号外显子突变, 突变率为50%-60%[6], 其次为9号外显子突变, 另有少部分突变位于13和17号外显子[7,8].
1.1.2 PDGFRA基因突变型: 约有20%的GIST缺少KIT基因突变, 而这些病例的30%(即所有GIST的6%)存在血小板源性生长因子受体A(PDGFRA)基因的突变, PDGFRA与c-kit同属于III型酪氨酸激酶家族, 且结构相似, 其最常见的突变位于18号外显子上, 其他的变异包括外显子12和14[9]. c-kit与PDGFRA变异是互斥的, 同时存在变异的十分罕见[10]. PDGFRA基因突变率较c-kit基因低, 多见于CD117阴性的GIST[11], 且几乎总是发生于胃GIST.
1.1.3 野生型及其他基因突变: 除KIT与PDGFRA基因突变以外, 另有一小部分GIST已发现有BRAF基因突变(约占1%)[12]. Nakajima等[13]采用显微切割技术获得了GIST肿瘤旁的Cajal细胞, 却没有发现有c-kit或PDGFRA-α的突变, 这类GIST被称为野生型(wild type, WT)[14]. 儿童野生型GIST与成人不同, 有研究发现其存在琥珀酸脱氢酶B亚单位(SDHB)相关基因突变[15], 目前WT型GIST的发病机制尚不明确, 这提示GIST的发生可能是肿瘤细胞获得性多基因突变及多个事件共同参与的结果[16].
众多突变基因的发现, 不仅在病理组织学上为GIST的准确诊断提供了可能, 而且在许多病例中, 基因分析也是指导GIST治疗的重要依据.
肿瘤最大直径可达35 cm, 中位大小5 cm, 肉眼观: 呈肉红色或黄白色, 多为局限性生长, 边界清楚, 有假包膜形成, 其血供丰富, 常发生中心缺血性坏死或囊样变性. 镜下: 根据细胞学形态, 可将GIST分为3种主要亚型: 梭状细胞型(70%)、上皮细胞型(20%)和混合细胞型(10%). 3种亚型均见细胞有异型性, 间质可有硬化、纤维化和黏液淀粉样变. 胃的GIST多为梭形细胞为主型及上皮样细胞为主型. 小肠的GIST则大多数为梭形细胞型, 多包含有特征性的圆形、椭圆形或长形的嗜酸性的细胞和PAS染色阳性的沉积在细胞外的胶原纤维[17].
GIST的标志物中, CD117是诊断GIST的最重要指标, GIST中CD117阳性率高达90%-95%[18], 并与GIST的预后有关. 组织学符合典型GIST, CD117阳性的病例可做出GIST的诊断, CD117在GIST肿瘤细胞的阳性表达应定位在胞膜和(或)胞质, 在接受伊马替尼治疗的GIST患者中, CD117的表达下降和丢失则可能与GIST的复发有关[19].
DOG1是一种C蛋白激酶, 也称为TMEM16A. Espinosa等[20]研究发现, DOG1有DOG1.1与DOG1.3两种亚型. DOG1在GIST中普遍呈阳性表达, 尤其是PDGFRA突变的GIST中, 其表达率明显高于CD117与CD34. 其与c-kit在GIST中的灵敏度几乎相同(94.7%和94.7%), 在胃梭形细胞GIST中, 两者均一致呈阳性表达. 但在胃上皮样GIST中, 前者表达稍高于后者, 在小肠GIST中, c-kit灵敏度稍高于DOG1. DOG1在PDGFR-α突变间质瘤、胃肠道外GIST和转移性GIST中也普遍呈阳性表达, 发生于胃肠道的GIST中只有2.6%的病例DOG1和c-kit均呈阴性表达[21], 最近DOG1单抗的应用更加确定了DOG1诊断的准确性和特异性. 约36%CD117阴性的GIST中DOG1呈阳性表达[18].
其他敏感性及特异度稍差的标志物有平滑肌肌动蛋白抗体(SMA)、波形纤维蛋白(Vimentin)、神经元特异性烯醇化酶(NSE)和S-100蛋白、结蛋白(Desmin)、Actin、h-钙调素结合蛋白(h-caldesmon). 一般而言, GIST的CD117阳性率为95%-100%, Vimentin阳性率为80%-90%, CD34为60%-70%, SMA为40%, S-100<5%, Desmin<2%[22,23]. 另外, 部分GIST中PKC-θ阳性表达率为70%, 可与DOG1联合进行检测以提高CD117阴性的GIST诊断率[24].
GIST的流行病学特征尚不清楚, 确切的发病情况难以统计. 据相关文献报道, GIST的发病率为1.4-1.96/100 000[11], 发病年龄通常在50-70岁, 无明显性别倾向. 其中近10%的病例为尸检发现, 20%经内镜活检发现, 其他则通过外科手术病理证实和腹部影像学等途径诊断[25].
GIST的临床表现缺乏特异性. 最多见的症状为不明原因的腹部不适、隐痛或可扪及腹部肿块; 其次是由肿瘤引起的消化道出血或仅表现为贫血. 其他少见症状有食欲不振、体质量下降、恶心、腹泻、便秘和肠梗阻等[26]. 十二指肠的GIST能引起梗阻性黄疸. 有患者以远处转移为首发症状, 约近1/3的患者没有临床症状. 近来, 家族性GIST也见报道, 其多伴有色素沉着及胃肠道功能紊乱, 如吞咽困难和肠易激综合征等[27]. GIST的复发率极高. 通常为局部复发, 少见周围淋巴结转移[28,29].
大约30%的GIST可明确为恶性, 常远处转移至肝脏[30], 也见转移至淋巴结、肺、骨及皮肤的报道[31], 其余属于恶性潜能不能确定或良性. 影响GIST生物学行为或危险指数的因素很多. 较公认的是肿瘤大小和核分裂象计数, 并应参考肿瘤部位, 综合分析决定其生物学行为.
2008年, 美国国立卫生研究院(NIH)重新讨论了原发GIST切除后的风险分级, 并达成共识,与2006年分级标准相比, 加入了原发肿瘤部位和肿瘤破裂两项预后评估指标(表1), 将肿瘤破裂列为高度危险性GIST, 认为不论肿瘤大小和核分裂数, 一旦肿瘤发生了破裂即认为具有高度危险性[32].
| 危险度分级 | 肿瘤大小(cm) | 核分裂(/50 HPF) | 肿瘤复发部位 |
| 极低 | ≤2 | ≤5 | 任何部位 |
| 低 | 2.1-5.0 | ≤5 | 任何部位 |
| 中 | 2.1-5.0 | >5 | 胃 |
| ≤5 | 6-10 | 任何部位 | |
| 5.1-10.0 | ≤5 | 胃 | |
| 高 | 任何大小 | 任意 | 肿瘤破裂 |
| >10 | 任意 | 任何部位 | |
| 任何大小 | >10 | 任何部位 | |
| >5.0 | >5 | 任何部位 | |
| 2.1-5.0 | >5 | 非胃来源 | |
| 5.1-10.0 | ≤5 | 非胃来源 |
近年来, 国内外学者试图借助分子生物学指标的方法来完善GIST危险度评估. Kikuta与Kubota等[33,34]通过对299例GIST病例进行研究发现, Pfetin是与GIST危险度呈负相关的标志之一, Pfetin阳性的GIST患者5年无病生存率明显较阴性者高, 并可能成为指导临床用药及预防GIST患者复发的潜在靶点. 黏着斑激酶(FAK)与多种肿瘤的进展及恶化相关, 伊马替尼耐药(c-kit 17号外显子突变)的GIST中, FAK明显上调, 提示其可能也参与了GIST的发生发展及恶化[35]. 增殖指数Ki-67是预测GIST的侵袭行为和恶性潜能是非常有效的标志物, 可作为GIST的一项独立预测指标[36,37]. 另有研究发现P53和P16表达阳性及抑癌基因Rb的丢失均可能与预后不良相关[36,38].
对于临床上发现的消化系(包括肠系膜、网膜和后腹膜)实体肿瘤, 在排除了其他消化系常见肿瘤后, 可考虑GIST, 一般有以下诊断步骤: (1)CT扫描和内镜检查证实为实体性肿瘤; (2)肿瘤组织具有梭形细胞和上皮样细胞两种基本细胞成分的病理学特征; (3)CD1l7免疫活性的测定为阳性. 对后者的测定可视为诊断GIST的"金标准".
由于GIST的临床表现繁多, 缺乏特异性, 临床诊断具有一定难度, 故联合多种影像学检查(X线造影、CT、MRI、PET和超声内镜引导下的经皮穿刺活检)及内镜活检可明显提高诊断的阳性率[39,40].
超声可描述原发和转移肿瘤的内部特征, 通常表现为胃肠道紧密相连的均匀低回声团块, 但由于GIST肿瘤往往较大, 超声视野中不能观其全貌, 无法获知肿瘤与周围组织的关系. 单纯X线对GIST检测作用不大, 胃肠道钡餐造影检测可显示GIST累及黏膜面和管腔改变. CT能直接观察肿瘤的大小、形态、密度、周围侵犯情况及其他部位的转移灶, 并可作为判断药物疗效的手段[41]. GIST的MRI信号表现复杂, 可提供更佳的软组织对比分辨率和直接多平面影像, 有助于肿瘤的定位. PET检测可运用造影剂观测肿瘤的功能活动, 从而可分辨良恶性,其对小肠肿瘤的敏感性较高, 可提高对治疗反应的判断率[42], 并为临床随访和治疗措施提供依据. 血管造影主要用于明确GIST合并消化道出血的原因和部位, 并协助栓塞止血或栓塞化疗的定位[43]. 超声内镜引导下经皮穿刺活检(EUS-FNA)是一种安全有效的诊断方法, 其准确性为91%[29,44], 多于进行新辅助治疗或姑息治疗需病理结果支持时采用, 初发疑似GIST(如排除淋巴瘤)及术前需明确性质的, 也首选(EUS-FNA)[45].
外科手术是原发未转移GIST的首要治疗手段, 对于肿瘤病变局限和最大径线大于或等于2 cm者, 原则上应手术行完整切除. 孤立性复发或转移病变, 估计手术能完整切除且不严重影响相关脏器功能者, 可以直接手术. 原难以完全切除的GIST, 可经新辅助靶向治疗, 待肿瘤缩小后切除. 因GIST极少有淋巴结转移, 故通常手术切缘距肿瘤边缘2 cm已足够, 除非有明确淋巴结转移迹象, 一般不进行淋巴结的清扫. 而对于大部分的原发性GIST均不推荐术前活检或术中冷冻活检[45]. 腹腔镜手术治疗GIST以<5 cm的肿瘤为宜. 但亦有学者认为, 腹腔镜手术发生肿瘤破裂和腹腔种植的风险高于开腹手术, 一般不建议选择, 可在腔内肿瘤较小(≤2 cm)考虑使用腹腔镜手术[46]. DeMatteo等[47]分析了200例恶性GIST患者的术后生存情况, 结果显示无转移的原发肿瘤患者根治性手术后中位生存期约为60 mo, 5年生存率为54%. Gold等[48]对靶向治疗应用之前的119例复发转移的GIST病例进行分析, 发现手术是改善患者预后的独立因素.
GIST术前辅助治疗的应用能够降低手术风险, 减小肿瘤体积, 最大限度地保留重要脏器功能[49]. McAuliffe等[50]报道的一项Ⅱ期临床试验结果显示, 术前短期应用伊马替尼可使约70%的患者在影像学上表现为肿瘤代谢水平降低(≥40%)和肿瘤血流减少(>10%), 肿瘤细胞凋亡率平均增加12%(0%-33%), 并与术前伊马替尼应用时间呈正相关. Eisenberg等[51]的研究也提示术前辅助化疗有助于改善原发性GIST的预后.
对复发的GIST术前进行辅助治疗, 能改善复发转移患者的预后, 增加再次手术的机会, 而再次手术不仅能提高其无进展生存期, 也能降低肿瘤耐药的危险[52,53]. Schurr等[54]对41例复发转移患者进行分析, 发现手术联合靶向治疗患者的预后优于单独行手术或靶向治疗者. 随着术后辅助治疗地位的确立, 新辅助治疗也将有助于在术前筛选出对分子靶向治疗敏感的病例.
5.3.1 伊马替尼: 传统化疗和放疗对进展期GIST (无法切除或发生转移)几乎无效, 甲磺酸伊马替尼(imatinib)是一种小分子选择性酪氨酸激酶抑制剂, 其作用靶点包括KIT、PDGFR(A和B)和BCR-ABL等, 通过选择性抑制酪氨酸激酶活性, 阻断磷酸基团向酪氨酸残基转移, 进而抑制间质瘤细胞的增殖分化[55]. 一系列多中心临床研究表明, 作为一种分子靶向治疗药物, 伊马替尼对胃肠道间质瘤疗效显著. 其推荐治疗方案为起始剂量400 mg/d, 持续用药12 mo, 这能使无进展生存期达到20-24 mo, 并对高复发风险的GIST同样有效[56]. 美国ACOSOG一项Ⅱ期临床试验表明, 对R0/R1外科手术切除的具有高危因素的胃肠道间质瘤患者给予12 mo的伊马替尼400 mg/d治疗, 经过中位随访时间4年, 结果提示与历史对照组相比, 伊马替尼组能显著提高总生存率和无复发生存率[57]. 另一个Ⅲ期随机对照试验中, 对于外科手术切除的肿瘤直径>3 cm的患者分别给予伊马替尼400 mg/d或者安慰剂治疗12 mo, 结果显示辅助治疗能显著提高无复发生存率[58]. Blanke等[59]分析了147例进展期GIST患者对伊马替尼治疗(73例400 mg/d, 74例600 mg/d)的反应, 中位随访期为63 mo. 患者总体中位生存期为57 mo, 近50%的患者生存期超过5年.
最近研究表明, c-kit基因11号外显子突变的GIST对伊马替尼反应较好, 9号外显子突变者敏感性稍差, 而17号外显子突变及PDGFRA基因18号外显子突变(D842V)者则几乎无效[60]. 虽然提高药物剂量并不能得到更多的益处, 但对于9号外显子突变者, 推荐标准治疗剂量可提高为800 mg/d[61].
随着伊马替尼应用的增加, 其耐药现象已引起临床医师和研究者的高度重视. 长期随访结果显示, 伊马替尼治疗的中位有效时间为29 mo, 大部分接受伊马替尼治疗的患者最终产生耐药. 伊马替尼的最佳疗程仍存在争议, 需要通过进一步的研究确定[62].
关于伊马替尼耐药(包括原发和继发)的机制尚不十分明确, 初步的研究提示有以下几种机制: (1)新的c-kit和PDGFR-a基因位点获得性突变; (2)KIT基因扩增导致KIT受体过表达; (3)其他的受体酪氨酸激酶的激活; (4)近膜热点区域之外的突变导致c-kit和PDGFR-a蛋白的激活.
5.3.2 舒尼替尼: 继伊马替尼后, 另一种多靶点酪氨酸激酶抑制剂-苹果酸舒尼替尼(sunitinib)进入研究者视线, 其可抑制多个与肿瘤的生长和血管生成相关的酪氨酸激酶受体. 一项随机双盲试验中, 对手术无法切除且伊马替尼耐药的患者, 舒尼替尼能明显延长疾病的中位进展时间(6.3 wk vs 27.3 wk, 安慰剂组: 舒尼替尼组)[63]. 2006年, 舒尼替尼被FDA批准成为GIST的二线治疗用药. 2008年ASCO年会上报告舒尼替尼治疗的部分缓解率14%, 疾病稳定率63%, 中位进展时间为37 wk[64]. Demetri与Younus等[63,65]及其他学者研究发现, 其对伊马替尼治疗失败或治疗中断的进展期GIST患者有较好的临床疗效, 且患者耐受性良好. 另有证据显示, 伊马替尼耐药的复发病例经手术切除后, 仍可能对舒尼替尼有较好的敏感性[66]. 有学者提出, 接受舒尼替尼治疗的KIT9号外显子突变者的部分缓解率、无进展生存期及总生存期要显著长于KIT 11号外显子突变者, 而对PDGFRA-18号外显子的D842V突变无效[64,67], 这表明基因型分析在预测分子靶向药物治疗效果及选择合适治疗人群上起着重要作用[68].
此外, 一些针对KIT和PDGFR靶点的其他酪氨酸激酶抑制剂, 如血管生成抑制剂索拉非尼和AMG 706, BCR-ABL激酶抑制剂如达沙替尼和尼洛替尼, 蛋白激酶C抑制剂-PKC412等药物, 通过分别作用于BCR-ABL、PDGFR, VEGFR2及蛋白激酶C、FLT3等靶点, 对伊马替尼、舒尼替尼耐药的GIST有较好的抗肿瘤活性. 另有研究指出, 针对下游信号通路的抑制剂如依维莫司和转录抑制剂夫拉平度等, 与传统酪氨酸激酶抑制剂联用可产生协同作用, 共同抑制伊马替尼/舒尼替尼耐药的GIST细胞株生长, 但均仍待大规模长期临床研究的证明.
对于经外科治疗后的原发性GIST患者, 目前暂无最佳的随访策略. 欧洲及美国的相关指南建议: 对于中-高风险的患者, 每3-4 mo进行一次CT检查, 持续3年, 后每6 mo进行一次持续至第5年, 后每年检查一次. 对于低风险患者, 则每6 mo进行一次CT检查, 持续5年[69,70]. 一些证据表明, 发生GIST的同时, 可能并发其他恶性肿瘤, 这提示其可看做是某个综合征的一部分, 如神经节细胞瘤-胃间质瘤-肺软骨瘤(Carney三联征)[71]. 因此, 尽管非原位复发的GIST与其他恶性肿瘤相比较少见, 但延长随访时间不仅有利于发现复发肿瘤, 而且也能对其他恶性肿瘤进行早期诊断[72].
随着近年来分子生物学、组织病理学和临床医学的发展, GIST的起源、发病机制、病理形态特征和临床特点等已得到较深入的阐述. 手术治疗仍是其常规手段, 对于无法切除或转移性GIST, 酪氨酸激酶抑制剂的成功应用, 使其已成为实体瘤分子靶向治疗的经典模型, GIST的治疗已由原先简单的手术切除发展为针对不同病情采取包括手术、辅助治疗和术前辅助治疗在内的个体化治疗. 在GIST患者的靶向药物治疗中, 明确其基因型并依据其进行治疗, 是以后药物的研发及治疗的重要方向, 并将对GIST的治疗带来重大变化. 对于c-kit/PDGFRA野生型、PDGFRA(D842V)突变及其他少见的对伊马替尼/舒尼替尼耐药的突变型患者, 是否应放弃辅助治疗仅给予密切观察, 还是应尝试给予其他分子靶向药物治疗? 对于高复发风险患者, 伊马替尼/舒尼替尼辅助治疗的时限长短等一系列问题仍有待我们进一步探索.
胃肠道间质瘤是消化系最常见的间叶组织源性肿瘤. 近年来, 由于相关学科的发展,对其发病机制、临床特点都有较深入的认识, 基于基因分析的分子靶向药物在胃肠道间质瘤的治疗中更是受到广泛关注, 并成为研究的热点之一.
王江滨, 教授, 吉林大学中日联谊医院
胃肠道间质瘤的手术治疗是常规手段, 但对于无法切除或转移性GIST, 明确患者基因型, 并选择合适的靶向药物进行个体化治疗显得尤为重要, 对耐药突变的进一步研究, 是以后药物研发及治疗的重要方向.
Demetri等学者长期以来致力于伊马替尼等酪氨酸激酶抑制剂在临床应用中的研究, 如具体用药剂量和疗程长短等, 其提到对于伊马替尼治疗失败或者治疗中断的患者, 苏尼替尼是较好的选择, 联合使用下游信号通路抑制剂也能起到协同作用.
借助分子生物学标志物测定, 可以对胃肠道间质瘤的侵袭行为和恶性潜能进行估计, 同时也能更科学地应用辅助化疗药物, 促进更好的预后.
此文对胃肠道间质瘤的临床病理特点、诊断、治疗及预后等进行了综述, 其中着重于其发病机制及临床分子靶向药物的应用, 对于临床制定辅助治疗方案和随访计划等有较强的指导意义.
本文综述了胃肠道间质瘤的临床特征及诊治进展,综述内容合理、全面, 论述思路清晰, 具有很好的可读性.
编辑:曹丽鸥 电编:闫晋利
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