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腹膜假黏液瘤(摘自2018年3月UpToDate)
来源: | 作者: 三人形 | 发布时间: 2019-07-18 | 817 次浏览 | 分享到:


摘自2018年3月UpToDate平台发布的文献

UpToDate是基于循证医学原则的临床决策支持系统,成为医生在诊疗时获取医学知识的主要资源,为他们提供基于循证医学原则、且不断更新的信息。UpToDate整合了研究证据并给出分级的推荐意见,这些意见都能够运用于临床实践。UpToDate的专题都由医生撰写和编辑,他们恪守严谨的编辑流程并利用先进的专题发布平台,根据研究进展随时对专题内容进行更新,帮助UpToDate的用户及时掌握最新的循证临床信息。UpToDate遍布全球170多个国家,3万余家医院,使用医生超过100万。挪威、西班牙、沙特阿拉伯、等国卫生部门还通过政府采购的方式,将UpToDate提供给全国的医院使用。国内已有近百家医院使用过或正在使用UpToDate。临床顾问:如中国人民解放军总医院、四川大学华西医院、香港大学深圳医院、复旦大学附属妇产科医院、中日友好医院、中国医科大学等。)

 

腹膜假黏液瘤 — PMP是一种独特的疾病,以腹腔和盆腔弥漫性的胶冻状物质积聚及腹膜表面黏液性种植物为特点。PMP一词最初用来指阑尾囊腺瘤引起的腹腔内黏液性播散。随着肿瘤的生长并堵塞阑尾管腔,黏液积聚,阑尾破裂。随后,产黏液的细胞在腹膜上种植,继续增殖和产生黏液。大量黏液性液体不断积聚,逐渐填满腹膜腔,从而形成特征性的“果冻腹(jelly belly)”[24]。这种疾病不可避免地进展至肠梗阻,如不治疗,将危及生命。

多年来,PMP一词开始被一些学者和临床医生更为广泛地应用,不仅仅用于指良性囊腺瘤破裂所致腹腔内黏液性播散,还用于指阑尾、大肠、小肠、肺、乳腺、胰腺、胃、胆管、胆囊和输卵管/卵巢产黏液性腺癌的腹膜播散[25,26]

然而,PMP一词应当限用于“组织学上以良性腹膜肿瘤(往往与阑尾黏液性腺瘤相关)为特点且病理学和预后同质的一组病例”[24,25]。最近将这些病例归类为播散性腹膜腺黏液蛋白病(disseminated peritoneal adenomucinosis, DPAM)[27]

为评估治疗效果,这种缩窄的定义界定了一组更为同质的疾病,但由于该定义未被广泛接受,使得难以对已发表的结果进行比较。虽然有人认为播散性产黏蛋白性阑尾腺癌(称腹膜黏液性转移癌)应归入PMP分类,但是这种变型属于腹膜黏液性肿瘤中的侵袭性亚组,其行为与较为惰性的DPAM不同[28,29]。下述报道阐述了组织学亚组间的预后差异:

●在一项病例系列研究中,DPAM患者的年龄校正5年生存率为84%,而腹膜黏液性转移癌患者为7%,具有中间特征的患者为38%[27]

●另一项回顾性多中心病例系列研究中,2298例表现为PMP的患者接受了减瘤性手术和腹腔内化疗,其中DPAM患者的5年生存率为81%,而腹膜黏液性转移癌患者为59%,具有中间特征的患者为78%[30]。 (参见下文‘积极的减瘤和腹腔内化疗’)

临床表现 — PMP更多见于女性,每10,000例剖腹手术中约意外发现2例[25]。男性和女性患者最常见的主诉症状均为腹围渐增;男性第二常见的症状为腹股沟疝(占25%的病例),而女性第二常见的症状为常规妇科检查时触及卵巢肿块[24]。如果在疝修补时发现黏液性液体,采集此液体和疝囊行组织学检查很重要[31]。 (参见“成人腹股沟疝和股疝的分类、临床特征及诊断”)

 

PMP的放射影像学表现具有特征性。在CT扫描上,黏液性物质的密度与水相近,并表现出异质性。肝、脾和肠系膜的扇贝状压迹易于显示,钙化常见(影像 1)。横膈下表面可能因黏液肿瘤的大型囊性肿块而大为增厚(影像 2)。早期突出的表现是肿瘤在腹腔和盆腔内呈特征性的周边分布,小肠和肠系膜相对不受累,并向中心移位(称为“再分布现象”)[24,32]

 

空肠、近端回肠或邻近肠系膜上肿瘤种植物大于5cm据称更符合黏液性腺癌伴继发性腹膜转移癌(相比于DPAM)的表现[24,32]。存在小肠的节段性梗阻也应引起对腹膜腺转移癌的怀疑,这两种发现均预示着进行积极减瘤和腹腔内热灌注化疗(heated intraperitoneal chemotherapy, HIPEC;见下文)的结局不太理想[32]。尚不清楚钆增强MRI是否可以在术前对DPAM与腹膜黏液性转移癌进行区分,目前该问题还在研究中[33]

治疗 — PMP(在本专题余下内容中,定义为良性形式,DPAM)的标准治疗是对有症状的疾病重复进行手术减瘤[25]。该治疗不是根治性的,旨在切除肉眼可见病灶,以限制黏液累积和其压力作用。疾病复发需要重复施行手术,并且因为粘连和纤维化,手术难度逐渐增加。

为了改善结局,已尝试加用外照射放疗、腹腔内放射性核素治疗、腹腔内化疗及全身化疗[25]。由于未进行随机临床试验,并且对临床亚群的定义未达成一致意见,所以尚不清楚加用任何这些治疗能否延长生存期。对3家不同中心接受这些方法联合治疗的小群体患者数据进行回顾性分析表明,有适当百分比的患者生存5年(可能反映了该疾病的惰性自然病程),但10年生存率明显下降(表 8)[26,34,35]

积极的减瘤和腹腔内化疗 — 一些临床医生为了达到治愈目的,采取了一种更为积极的方案,包括切除所有腹腔内和盆腔内病灶的根治性手术联合HIPEC。鉴于在PMP或DPAM患者中腹膜外播散较为罕见,从直观上来看,腹腔内化疗(可使腹腔内药物浓度较全身用药时增加数倍)可能控制腹膜病灶的生长。然而,即使存在这一局部优势,药物渗透入肿瘤组织也仅限于距表面最多1-2mm[35-38]

通过对含化疗药物的灌注液加热可能增加药物的渗透性,这一种方案称为HIPEC[24,38]。最适合于外科减瘤术后残留病灶极小(沉积物小于2-2.5mm)的患者。对于大的肿瘤沉积物,即便是加热的化疗药物溶液,也不太可能渗透进去。

关于积极手术减瘤联合HIPEC治疗腹膜表面恶性肿瘤,Sugarbaker及其同事的论著最广泛。他的研究小组采用4种临床评估方法来选择最有可能从联合治疗中获益的患者[32,38]

●组织病理学评估–非侵袭性恶性肿瘤(如PMP或腹膜间皮瘤)更有可能通过腹膜切除实现肉眼无病灶,而相比于其他侵袭性的组织学类型,向区域淋巴结、肝脏或其他全身部位扩散的可能性更小。 (参见“恶性腹膜间皮瘤的治疗”)

●术前胸部、腹部和盆腔的对比剂(口服和静脉应用)增强CT–除了排除肝脏或其他全身转移瘤之外,最有助于预测积极减瘤联合HIPEC治疗后不良结局的2个放射学标准为:小肠节段性梗阻以及小肠表面或者与空肠或上段回肠直接毗邻的小肠系膜处存在直径大于5cm的肿瘤结节。 (参见上文‘临床表现’)

其他报道称,术前CT显示右上腹的广泛病变似乎尤其与更差的生存结局相关[39]

●另外2个临床指标均来源于术中,即腹膜癌指数(peritoneal cancer index, PCI,根据腹膜表面结节的大小和分布定量评估预后的指标)和减瘤完全性程度评分(最大限度减瘤后残存肿瘤结节的大小)。

关于Sugarbaker的术中热灌注(通常为丝裂霉素)和术后早期腹腔热灌注化疗[通常为氟尿嘧啶(fluorouracil, FU)]方案的细节,已有详细的介绍[32,38]

3项最大病例系列研究的结果描述如下:

●Sugarbaker研究组2001年的一项研究纳入了10年间(1983-1993)接受手术减瘤联合术中腹腔内应用丝裂霉素(加热或不加热)治疗的108例PMP患者[28]。化疗方案还包括术后第1-6日腹腔内应用FU以及随后3个疗程的静脉(intravenous, IV)应用丝裂霉素和腹腔内应用FU的辅助治疗。

患者群是异质性的。一组(n=65)患者存在DPAM,以组织学上温和的或低级别腺瘤性黏液样上皮伴大量与纤维化相关的细胞外黏蛋白为特征;第2组(n=29)患者存在腹膜黏液性癌(所有的阑尾黏液腺癌均为印戒细胞变异型,见下文);第3组(n=14)患者具有中间特征。组织学类型与生存情况关系密切,DPAM组患者的生存情况显著好于合并的其他两组患者(表 9)。

●Sugarbaker研究组的一项更早期报道阐述了组织学类型对结局的影响,该研究纳入了1989-1999年间385例有腹膜表面播散的阑尾恶性肿瘤患者,这些患者接受了积极的手术减瘤联合加热或不加热的腹腔内化疗[40,41]。在多变量分析中,生存的预后因素包括:减瘤的完全程度、阑尾恶性肿瘤的组织病理学和既往手术干预的程度。接受完全减瘤治疗腺黏液蛋白病(DPAM)患者的5年生存率为86%;而那些具有“混合”病理特征患者的5年生存率为50%。不完全减瘤(残留灶>2.5mm)患者的结局明显更差(5年和10年生存率分别为20%和0)。

之后一项关于174例行不完全减瘤术患者的报道也证实了这组患者的预后不良,这174例患者来自共计645例接受手术减瘤和HIPEC的阑尾起源的腹膜上皮表面恶性肿瘤患者[42]。这174例患者的1年、3年和5年生存率分别为71%、34%和15%。

其他研究小组也在病例系列研究中报道了实施根治性手术之后再进行HIPEC治疗的结果,这些研究纳入的患者群为异质性的,包括经典的PMP(DPAM)患者以及有腹膜黏液性转移癌的患者[29,43]。对报道的病例系列研究结果(以及报道的围术期并发症发病率和死亡率)进行汇总,如表所示(表 10)[29,40,44-50]。下文将介绍腹膜黏液性转移癌患者人群的结果。 (参见下文‘腹腔内热灌注化疗’)

组织学类型为DPAM的患者结果似乎最好,下述报告可证明这一点(参见上文‘腹膜假黏液瘤’):

●一项系统评价[51]纳入了5项病例系列研究中报告了根治性手术和HIPEC治疗结局的382例组织学类型仅有DPAM的患者,其中3项研究来自Sugarbaker研究组[26,28,43,51,52]。5年生存率为70%-86%,而在10年时,2项不同的病例系列研究中分别有60%和68%的患者依然存活(表 11)。

●一项基于多机构登记处的病例系列研究纳入了接受减瘤性手术和HIPEC治疗PMP的2298例患者,其中包括1419例DPAM、700例腹膜黏液性腺癌以及140例存在混合组织学类型的病例[30]。组织学类型为DPAM患者的5年和10年生存率分别为81%和70%;腹膜黏液性转移癌的患者分别为59%和49%,存在混合组织学类型的患者分别为78%和63%。

这些生存统计数据(尤其是DPAM患者)让人印象深刻。尚不清楚这些结果是归因于积极的治疗、患者选择,还是两者均有。关于生存期延长是归因于治疗还是归因于允许这些患者接受完全减瘤性手术的生物学特点,还缺乏充分的证据来得出结论。

此外,减瘤性手术的质量依赖外科医生的技术和经验水平[53]。这一领域的国际专家所达到的良好结果(特别是治疗相关毒性方面)在常规临床实践中可能无法重现。在Dr. Sugarbaker的网站上可获取国际上腹膜表面恶性肿瘤专业治疗中心列表[54]。面向患者的网站上还有关于美国相关治疗中心的更多信息[55]

随机试验是判定HIPEC和积极减瘤治疗PMP真正获益的唯一办法。然而,这种试验最起码在美国是不大可能开展的。在具有此法专业技术的中心,对于合适的有症状患者,减瘤手术后进行HIPEC是定期减瘤手术(不进行HIPEC)的替代治疗选择。

 

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