胃肠道间质瘤的诊治进展

1983年Mazur和Clark首先提出了胃肠道间质瘤(gastrointestinal stromal tumor ,GIST)这一概念。直到1998年Hirata发现特定的标志物-Kit蛋白(CD117)后与胃肠道平滑肌肿瘤及神经瘤明确区分,GIST才成为胃肠道常见的肿瘤,临床上逐渐有所报道。它常发生在胃肠道并且过度表达Kit蛋白,是一种胃肠道肌层的少见的非上皮性为主的肿瘤,主要是由c-kit原癌基因等发生变异而引起,约占胃肠道肿瘤的1%~3%,遗传学上存在频发性c-kit基因以及血小板源生长因子受体α基因突变,具有广谱生物学行为。现就其诊断和治疗作一综述。

1临床表现

GIST多见于中老年人,发病的中位年龄为50~60岁,男女比例接近。最常见症状是腹部隐痛不适。肿瘤浸润到消化腔内表现为溃疡或出血[1],大约1/3患者有胃肠道出血伴黑便,70%的患者腹部可触及包块。其他少见症状有食欲不振、体重下降、恶心、低血糖、肠梗阻及阻塞性黄疸等。部分GIST临床症状不明显,常在体检或术前检查中被发现。因GIST极少发生淋巴转移,故常无淋巴结肿大,但有报道食管、胃原发GIST发生多处淋巴结转移者[2]。

2诊断

GIST的临床诊断比较困难,术前较难确诊。国内报道的35例,除3例通过内镜活检明确诊断外,其余32例术前均未能确诊,别考虑为平滑肌肿瘤、腹部肿块、上消化道出血、急性阑尾炎而剖腹探查[3]。Sandrasegaran等[4]认为GIST有某些特异性影像学表现,能与其他消化道肿瘤相鉴别;另外,对于发生肝脏转移者MRI比单相CT的评价更有意义,但CT对诊断发生肠系膜转移者更敏感。而且放射科医生可以通过较大且有出血、坏死的外生性肠道包块对该病做出初步诊断,当发现血供丰富的肝脏转移病灶及低密度的小肠占位病变提示极有可能发生了转移,而且CT、MRI、PET(正电子发射断层扫描)还可用于对疗效的客观评估。而采用超声内镜下穿刺活检及免疫组化检查可获确诊。目前要获得明确诊断仍依靠组织学检查和免疫化检查[5]。关于GIST的良恶性目前没有统一的诊断标准,参照恶性肿瘤的生物学特点,如果肿瘤出现浸性生长、远处转移,即诊断其为恶性,但即使没有明确的恶性证据,也不能认为是良性。Miettnen等[6]通过对没有恶性证据病例进行长期随访后发现所有病例都存在复发,故提出没有良性的GIST。2002年Fletcher[7]等推荐依据肿瘤大小和核分裂数来确定其侵袭行为危险程度,将GIST分为极低危组(肿瘤直径

3治疗

手术切除是目前治疗GIST的最佳方法。最佳手术方式是肿块连同周围包绕的正常组织整块切除,如有周围组织及脏器受累应一并切除,5年生存率可达65.2%[10]。也有人采用腹腔镜下切除肿瘤,但术前需要正确评估肿瘤位置、范围及技术复杂度[11]。只要完整切除肿瘤才能获得治愈。对于瘤体较大且浸润多个器官的恶性GIST常不能用手术根除。有报道尽管已作根治性手术,肿瘤复发或腹腔脏器转移及机率仍然很高。GIST的化疗,当前尚无确切的方案,且疗效也不确切,对传统化疗药物高度耐药,以DAM为主的化疗方案化疗,有效率小于10%[12]。放疗在GIST收效甚微,其疗效都未有被充分证明的报道。GIST是KIT普遍强表达的肿瘤,突变活化的KIT基因是GIST形成和发展的关键。甲磺酸伊马替尼(imatinibmesyzate,sTI571)能够有效的选择性抑制某些III型酪氨酸激酶,包括KIT、PDGFR和ABL激酶。其能竞争性地与ATP结合,阻断KIT将基质蛋白磷酸盐从ATP转化成酪氨酸残基,进而阻断KIT介导的信号转换。甲磺酸伊马替尼除可抑制GIST细胞的增长外,还可促进GIST细胞凋亡,抑制有丝分裂原激活的蛋白激酶以及PI3K信号转导通路[13]。2001年,Joensuu等首先报道了一名常规治疗无效的进展期GIST用甲磺酸伊马替尼治疗获得了令人惊讶的疗效。随后进行的临床I期II期试验显示对转移或无法手术切除GIST应用甲磺酸伊马替尼400 mg/d,疗效满意。GIST患者对400 mg/d,600 mg/d不同剂量的疗效并没有差异但副反应明显增多,故推荐应用400 mg/d治疗[14]。对连续服用甲磺酸伊马替尼(400 mg/d)1年的所有获益患者随机分为2组,一组继续原剂量服用;另一组停药观察,待病情进展(PD)时再次服用甲磺酸伊马替尼(400 mg/d)1年即获得完全缓解(CR).PR和SD的GIST患者相比,无进展生存期(PFS)差异有统计学意义(P

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