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WGO Practice Guideline Pancreatic Cystic Lesions (Mandarin)

世界胃肠病学组织全球指南

胰腺囊性病变

 

2019.03

杜丽君 译  戴宁 审校
浙江大学医学院附属邵逸夫医院

 

WGO 审查小组

Juan Malagelada (主席, 西班牙)
Nalini Guda (联合主席, 美国)

Khean-Lee Goh (马来西亚)
Thilo Hackert (德国)
Peter Layer (德国)
Xavier Molero (西班牙)
Stephen Pandol (美国)
Masao Tanaka (日本)
Muhammed Umar (巴基斯坦)
Anton LeMair (新西兰)

 


内容

(点击展开区段)

1. 诊断和治疗中的分级管理和关键点

1.1 关键点和主要实践声明

  • 仔细的病史询问和查体是必要的。
  • 初始囊肿液体抽吸:进行癌胚抗原(CEA)、淀粉酶和细胞学检查。
  • 评估囊肿恶性肿瘤的可能性或并发症的风险。
    有症状的囊肿患者,囊肿大于3cm,有实体成分,或导管扩张:
    —进行超声内镜检查(EUS),包括或不包括细针抽吸(FNA)*,行手术评估。
    对于具有低风险特征的囊肿患者:
    —根据某些指南,继续无创性监测至少5年,尽管长期发展为恶性肿瘤的风险还不明确。  
    —考虑患者的年龄和合并症,并继续进行适当的监测,直到有更好的证据可明确停止监测和风险分层。
    —应考虑患者的意愿和对风险的理解。
    对于性质不确定的囊肿患者:
    —囊液分析和/或影像学特征的监测。
  • 由于有限的数据和高昂的费用,分子检测并不常规进行,但在未来有希望实现。
  • 在开始任何监测策略之前,应与患者就诊断、当前在诊断和治疗中的困境以及诊治过程中经济和心理负担进行充分讨论。

* 当病变位于胰腺体尾部,如果怀疑恶性肿瘤,则可能无法进行FNA,这是由于沿FNA路径传播的风险可能无法通过后续手术解决。在体尾部病变的患者中,胃不能被切除,而在胰头有病变的患者中,十二指肠可在手术时被切除。

1.2 胰腺囊性病变的WGO分级管理

WGO分级管理:根据可用资源的等级处理风险和疾病的一系列诊断、治疗和管理选择。

WGO指南和分级管理旨在强调适用于所有地区的恰当的、与当地环境和资源相适应的治疗方案,无论这些地区是“发展中的”、“半发达的”还是“发达的”。 WGO分级管理提供的方案不仅仅包括资源优先的考量,可能还包括成本效益因素,患者意愿以及设备,技能和专业知识的可用性。

大多数无症状的偶发囊肿,是在资源丰富的国家因评估与胰腺疾病不一定相关的症状而行影像学检查后诊断出来的。以亚太地区为例,最近来自韩国和日本的两篇论文都报道了无症状囊肿的患病率分别为2.2%和3.5%[1,2]。在资源匮乏的国家,大多数诊断都是通过手术或尸检来确定的。

因此,本指南的作者不使用传统的“分级管理”模式,而是根据当前的证据提出建议。我们了解到并非所有的资源都可以在任何地方使用,并且,应该在与患者讨论恶性肿瘤风险、可用资源和成本后再作出明智的决定。

2. 引言

2.1 范围和目标

本指南旨在为全世界的医生提供一种合理的、最新的胰腺囊性病变治疗方法。由于相关的诊断和治疗资源在世界不同地区分布并不均一,因此,这些指南应根据当地的资源和患者的意愿合理使用。                                                        

2.2  定义

“胰腺囊性病变”是一个传统的术语,指胰腺中含有液体的明确病变。大多数小病灶是在进行扫描以评估非胰腺相关的指征或症状时偶然发现的。胰腺囊肿的病因是多种多样的,它们可能是炎症性的或创伤后的,也可能病因未明。虽然大多数小病灶是良性的,但有些病灶可能发展为恶性肿瘤,因此,需要进一步的检查、监测和治疗。因此,有必要获得详细的病史,并根据需要通过适当的检查判断病变的性质,以评估恶变的风险。由于仅根据临床和形态学特征无法可靠地将潜在的恶性病变与良性病变区分开来,因此,可能需要进一步的评估和/或监测。

胰腺癌前囊性病变包括黏液性囊性肿瘤和导管内乳头状黏液瘤。如上所述,一些胰腺囊性病变可能演变为胰腺腺癌[3]。

由于胰腺导管腺癌(PDAC)和假乳头状瘤很少表现为囊性病变,因此,本指南不涉及它们。

胰腺假性囊肿,缺乏明确的囊肿壁,通常发生在有胰腺炎或外伤史的患者。假性囊肿是良性的,除非它们有症状,通常不需要任何干预就能自行消退;它们不是当前指南的主题。然而,重要的是要确保病变实际上是一个假性囊肿,而不是一个真正的胰腺囊肿。虽然良性或明显恶性病变的治疗不那么模糊,但对不确定风险或中等风险病变的治疗尚不清楚,该指南有望为适当的诊断和治疗提供指导。

3.  胰腺囊性病变

胰腺囊肿通常没有症状,并且通常是良性的,但也有恶性潜能。

胰腺囊性病变可分为:

  • 良性囊肿—例如单纯囊肿、假性囊肿和浆液性囊性肿瘤(SCN)
  • 具有恶性潜能的囊肿—如胰腺囊性肿瘤(PCN),如黏液性囊性肿瘤(MCN)和导管内乳头状黏液瘤(IPMNs)
  • 恶性囊肿—肿瘤性囊肿,如伴有囊性变性的胰腺腺癌和囊性胰腺神经内分泌肿瘤

胰腺囊性肿瘤可能具有恶性潜能,包括MCN和IPMN。也可能没有恶性潜能,包括浆液性囊性肿瘤(SCN)。良性囊性病变可保守治疗,而具有恶性潜能的囊肿则需要手术干预[4]。

3.1  胰腺囊性病变的分类

表2列出了世界卫生组织(WHO)胰腺囊肿的组织学分类,其中还包括实性假乳头状肿瘤。

病变来源—与前体病变的治疗有关:

来源于导管内乳头状黏液瘤(IPMN)进展
来源于黏液性囊性肿瘤(MCN)进展

3.2  胰腺上皮内肿瘤(PanIN)

许多人都同意IPMN和PanIN的主要区别在于大小:PanIN病变是小叶内胰管内出现的微小扁平或乳头状病变,通常大小小于5mm,很少形成囊性结构,通常在横截面成像或EUS上无法检测到。Maire等人[14]试图将纳入人群的EUS表现与组织病理学联系起来。当病灶大于10 mm时,IPMN为首选诊断,小于10 mm时,宜用“扩张侧支”。对于0.5-1cm之间病变的组织学特征还有疑惑。分子、遗传或表观遗传标记可能有助于区分PanIN和IPMN[3,14]。

3.3  胰腺囊肿的鉴别诊断

以下特别强调在鉴别诊断中需要考虑的常见且容易混淆的疾病

  • 慢性胰腺炎与导管内乳头状黏液瘤
  • 胰腺炎后假性囊肿、浆液性肿瘤和黏液性囊性肿瘤
  • 浆液性囊性肿瘤、分支导管内乳头状黏液瘤和腺泡细胞囊腺瘤
  • 浆液性囊性肿瘤(SCN)的实变、神经内分泌肿瘤和实性假乳头状肿瘤
  • 任何实体瘤的囊性形式
  • 罕见的胰腺或胰周囊性病变(如上皮性囊肿)

4. 临床表现

大多数胰腺囊肿是无症状的,是在因不相关的症状或原因而进行的影像学检查中偶然发现的。在少数病例中,最初可能是由于症状性囊肿而表现为急性胰腺炎、出血、黄疸或可触及的肿块。在世界上没有先进的诊断成像技术或采用更严格诊断标准的地区,胰腺囊性病变可能在晚期才被发现,但这通常意味着更大的囊性肿块或已进展为肿瘤。

在有症状的囊肿患者中,疼痛是最常见的表现。除外胰腺炎后假性囊肿,疼痛可能提醒医生恶性肿瘤的可能性更大,恶性肿瘤的风险可能与症状的持续时间有关[15,16]。其它症状包括黄疸、恶心和继发于胃压迫的呕吐,或继发于十二指肠腔外源性压迫的胃出口梗阻。

MCN患者也可能出现疼痛、腹部肿块或体重减轻,这些症状可能在诊断前已经存在多年[17]。然而,大多数MCN是在其它无症状患者的横断面影像上发现的。

患者访谈:病史和背景

  • 就诊原因
  • 人口学特征
  • 家族和个人病史,包括胰腺疾病(如胰腺癌、胰腺炎、糖尿病)
  • 酗酒、吸烟、吸毒、药物史
  • 体重指数

与特定类型囊肿相关的可能的临床表现:值得注意的是,大多数胰腺囊肿患者无症状。

5. 囊性病变的评估

5.1  引言

世界各地偶然发现囊肿的患者越来越多,这就需要进一步完善影像学检查的建议[6,8]。

由于缺乏良好的自然病史数据,很少有发表的长期随访数据的研究,并且可能存在偏倚,因大多数报告来自专门治疗胰胆疾病的中心,因此,胰腺囊肿的治疗仍然存在问题。

  •  一般来说,病变较小(<2cm)的患者不太可能有症状,而且病变通常是偶然发现的。
  • 一般来说,较小的囊性病变比较大的囊肿(>3cm)更少出现恶性肿瘤的影像学特征(例如,实性成分或导管扩张)。
  • 胰腺囊肿的患病率随着年龄的增长而增加,可能的原因是老年患者更可能有合并症(如个人恶性肿瘤病史),因此增加影像学检查。大多数情况下,由于其它原因在行计算机断层扫描(CT)和磁共振成像(MRI)时偶然发现了囊性病变。
  • 95%的病例中,囊性肿瘤包括导管内乳头状黏液瘤(IPMN)、黏液性囊性肿瘤(MCN)、浆液性囊性肿瘤和实性假乳头状瘤(SPN)。
  • 恶性肿瘤的风险从0%到60%以上。因此,诊断过程旨在区分肿瘤性囊性病变和非肿瘤性囊性病变,以及浆液性和黏液性病变,因为它们具有不同的恶性潜能。
  • 需要精确诊断,以便相应地调整监测或治疗策略。这可以通过对影像学数据,结合囊液的生化检测和临床特征的分析来提供。
  • 对于恶性肿瘤或转化为恶性肿瘤的可能性较低的患者,应避免胰腺切除[6,18,19]。

不断发展的技术,如分子分析(分子标记、基因检测)和一线检测结果(细胞学、影像学和囊液生化学),可能比目前的诊断检测方法更准确地确定胰腺囊肿的恶性潜能[20]。然而,到目前为止,并不是所有可用的技术都常规地包含在临床实践中。

5.2  诊断方法选择

胰腺囊性病变患者必须评估其敏感性:

  • 误诊对患者的潜在风险
  • 侵入性操作和手术对患者的潜在风险
  • 累计成本
  • 频繁检测、诊断不确定性、恶变风险和财务影响对生活质量的未知影响

通常,具有简单特征的小病变(<2 cm)仅需相对有限的诊断评估,并且可以通过观察和随访进行处理。而在疾病谱的另一端,具有明显实性成分或导管扩张特征的大病变应进行及时手术,以避免迂回和昂贵的检查。

疾病谱中间部分是那些最可能需要仔细,深入评估的病变,因为手术会带来很高的发病率和死亡风险。

5.2.1  实验室检查

目前尚无用于评估胰腺囊性病变的血清学检测方法。在恶性囊性病变中血清CA-19-9可能升高,而在伴发胰腺炎的症状性囊肿中观察到淀粉酶和脂肪酶水平升高。 请参阅表4和表5。

5.2.2  影像学检查

影像学检查是为了更好地获得囊肿的特征。因此,所使用的方法取决于检测所述病变的初始影像学方法。.

如果资源有限,评估胰腺囊肿的最佳选择是CT。

胰腺CT检查方案:

  • CT有助于确认和定性超声初步诊断的囊性病变。
  • 鉴于涉及的放射线暴露,应谨慎使用CT扫描,尤其是在需要多次/重复影像学检查的情况下。

磁共振胰胆管造影(MRCP)方案:

  • MRCP有助于确定囊性病变与胆胰管之间的关系。
  • MRI的优势在于它不涉及任何辐射暴露,同时可以更好地显示胰管。这对于识别分支IPMN很有帮助。
  • MRI的缺点是:它可能更昂贵;不是普遍可用的;并且无法在体内植入任何金属的患者中进行。如果无法获得MRI,费用昂贵或禁忌使用MRI,则CT是监测的合理选择。

超声内镜(EUS)准确度高,并且:

  • 可进行细针抽吸(FNA)
  • 在监测期间避免辐射暴露。然而,这是一种侵入性操作。
  • 尤其是当囊肿形态改变或患者出现症状时,可以重复进行FNA。

内镜逆行胰胆管造影(ERCP):

  • 很少推荐。
  • 组织取样的诊断率较低(与EUS相比)。
  • 对于IPMN,胰腺内镜检查尚无公认的优势。

5.2.3  活检—囊液分析

EUS引导下的FNA

细针穿刺可在EUS指导下进行,以进行细胞学评估和囊液引流,以区分浆液性和黏液性病变。在条件许可情况下,与CT或超声引导的经皮穿刺相比,EUS引导的FNA是首选方法。

  • 可以检查囊液中的癌胚抗原水平。
  • 可以进行具有高度恶性风险病变的细胞学鉴定。
  • 目前关于囊液中分子标志物评估的数据有限。

细胞学,涂片

囊液分析。抽吸液体时,根据抽吸量,建议按照所述顺序进行以下测试:

  • 细胞学:富含糖原细胞(SCN)或含粘蛋白细胞(MCN和IPMN),但敏感性较低。
  • 肿瘤标记物:CEA水平,一种诊断黏液性PCN的准确肿瘤标记物(准确度和临界值因实验室而异)。
  • 诊断分子标记:KRAS、GNAS、VHL、CTNNB1。
  • 预后分子标记:TP53、PIK3CA、PTEN。
  • 粘蛋白:粘蛋白的评估是对囊肿CEA水平和细胞学的补充[21,22]。
  • 粘度:“拉丝征”概念[22,23]是一种间接,廉价但主观的粘度测量方法,通过在拇指和食指之间放置液体样本并测量破裂前的拉伸长度来进行评估。Leung等人注意到良性囊肿的中位拉丝长度为0mm,黏液性囊肿的拉丝中位长度为3.5mm,每增加1mm,黏液囊肿的风险增加116%。但仍然需要进行验证性研究。
  • 淀粉酶(或脂肪酶)。

6. 评估,治疗,随访

6.1 恶变的危险因素

评估以下风险特征有助于在观察与手术方案之间做出决策。具有这些危险因素中至少两个的患者发生胰腺恶性肿瘤的几率约为15%:

  • 病灶大于3cm:恶性肿瘤风险增加3倍。
  • 存在壁结节:恶性肿瘤风险增加8倍。
  • 主胰管扩张似乎有恶变的风险,尽管该数据仅得到回顾性研究的支持[29,30]。

其它因素也可能预示恶性肿瘤的高风险[3138]:

  • 胰腺癌家族史(增加IPMN风险)
  • 易患胰腺癌的突变(尤其是BRCA2)
  • CA-19-9的血液水平异常
  • 不明原因急性胰腺炎,尤其是年龄>50岁的患者
  • 新近发病的糖尿病
  • 超重
  • 低水平的血清胰淀粉酶和脂肪酶
  • 粗钙化

此外,由于癌前病变可能是多灶性的,因肿瘤性病变行部分胰腺切除术后残余胰腺仍然可能发生恶性肿瘤。根据Lafemina等人的研究,IPMN患者胰腺其它部位发生浸润性癌的风险为2.8%[39]。

手术的风险可能很大,有2%的死亡风险和高达40%的发病风险,应将这些风险与相对于上述特征评估的恶性肿瘤风险进行权衡。应始终考虑患者的年龄和合并症,因为它们是至关重要的危险因素。

6.1.1  专科医生评估适应证

胰腺囊肿通常是在评估非特异性腹部或非胃肠道症状而进行的横断面影像学检查中偶然发现的。在此初始发现阶段,全科医生,内科医生或外科医生可能承担评估病情的主要责任。

小(<2cm)且无明显恶性征象的单纯囊肿可能不需要专科医生会诊,按先前详述的间隔时间观察是合适的。

6.2  监测

如果诊断可靠,可以通过观察和监测进行评估、管理和随访。

浆液性囊腺瘤均属良性。然而,黏液性病变被认为是癌前病变。在诊断时大于3cm的病变时,恶性肿瘤的风险似乎更高,因此建议手术治疗。较小的病变可监测随访。

不幸的是,术前可靠区分浆液性和黏液性病变的能力有限。在一些研究中,传统的放射学研究,如CT或超声,仅能对10-15%的病变进行准确的分类。此外,囊肿壁常有部分脱落,因此,即使是术中活检也不可靠。表7列出了高风险征象和报警征。

随访时囊肿大小和生长速度可作为手术切除的指标。如果在MRI/MRCP上没有报警征[41], 则首先在1年后复查,再在2年后复查。

  • 放射学指南建议,稳定2年后可暂停监测[42]。美国胃肠病学协会(AGA)指南中也有类似的建议,但需经过5年的稳定期[43]。
  • 尚未为分支胰管IPMN建立有效的监测计划。目前的标准是每6个月交替进行CT扫描和MRCP检查(有些建议在稳定2年后延长筛查间隔)。
  • 在最近一项荟萃分析中,对仙台共识的恶性肿瘤预测标准和分支胰管IPMN的临床治疗进行了准确性分析,结果显示(12项研究的)联合敏感度为56%,特异性为74% [44]。
  • 行手术切除的仙台标准是:临床症状、细胞学检查阳性、有壁结节、主胰管扩张(MPD)>6mm、囊肿大小>3cm[45]。

在胰腺囊性癌前病变患者的监测方式上存在差异。来自Choi等人[46] 的系统回顾和荟萃分析提示,低风险IPMN(无主胰管受累或壁结节)进展为癌症的发病率3年为1.4%,5年为3.1%,10年为7.7%。具有某些风险特征的IPMN发病率增加:3年为5.7%,5年为9.7%,10年为24.7%。作者建议继续对所有类型的IPMN进行长期监测[46]。

6.3  导管内乳头状黏液瘤(IPMN)

手术适应证[5,48]:

7.  附录

7.1 缩略词

7.2  作者的利益冲突说明

7.3  发表的指南

7.3.1  国际指南

       2018 Gut. European evidence-based guidelines on pancreatic cystic neoplasms [29]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5890653/

       2018 Am J Gastroenterol. ACG clinical guideline: diagnosis and management of pancreatic cysts [49].

       2017 J Am Coll Radiol. Management of incidental pancreatic cysts: a white paper of the ACR Incidental Findings Committee [50]. Available from: https://www.jacr.org/article/S1546-1440(17)30318-6/fulltext

       2017 Pancreatology. Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas [40].

       2015 Gastroenterology. AGA guidelines for the management of pancreatic cysts [43].

       2015 World J Gastroenterol. International guidelines for the management of pancreatic intraductal papillary mucinous neoplasms [51]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566378/

       2015 Ann Transl Med [Internet]. International consensus on the management of intraductal papillary mucinous neoplasm of the pancreas [45]. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4671873/

       2013 Dig Liver Dis. European experts consensus statement on cystic tumours of the pancreas [52].

       2012 Pancreatology. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas [8].

       2006 Pancreatology. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas [53].

7.3.2  地区和其它指南

       2015 J Hepatobiliary Pancreat Sci. Revised Japanese guidelines for the management of acute pancreatitis 2015: revised concepts and updated points [54].

       2015 Gastroenterology. American Gastroenterological Association technical review on the diagnosis and management of asymptomatic neoplastic pancreatic cysts [55].

       2015 Gastroenterology. AGA Institute guideline on the diagnosis and management of asymptomatic neoplastic pancreatic cysts [41].

       2015 Gastroenterology. AGA guidelines for the management of pancreatic cysts [43].

       2015 Ann Oncol. Cancer of the pancreas: ESMO clinical practice guidelines for diagnosis, treatment and follow-up [56].

       2015 Am J Gastroenterol. ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes [57].

       2014 Saudi Med J. Saudi Oncology Society clinical management guideline series. Pancreatic cancer [58].

       2014 RöFo. S3 guideline for chronic pancreatitis—diagnosis, classification and therapy for the radiologist [59].

       2014 Pancreas. American Pancreatic Association practice guidelines in chronic pancreatitis: evidence-based report on diagnostic guidelines [60].

       2014 Jpn J Clin Oncol. EBM-based clinical guidelines for pancreatic cancer (2013) issued by the Japan Pancreas Society: a synopsis [61].

       2014 Dig Liver Dis. Italian consensus guidelines for the diagnostic work-up and follow-up of cystic pancreatic neoplasms [62].

       2014 Diagn Cytopathol. Utilization of ancillary studies in the cytologic diagnosis of biliary and pancreatic lesions: the Papanicolaou Society of Cytopathology guidelines for pancreatobiliary cytology [63].

       2014 Diagn Cytopathol. Postbrushing and fine-needle aspiration biopsy follow-up and treatment options for patients with pancreatobiliary lesions: the Papanicolaou Society of Cytopathology guidelines [64].

       2014 Diagn Cytopathol. Standardized terminology and nomenclature for pancreatobiliary cytology: the Papanicolaou Society of Cytopathology guidelines [65].

       2014 Cancer Cytopathol. Guidelines for pancreaticobiliary cytology from the Papanicolaou Society of Cytopathology: a review [66].

       2013 Am J Gastroenterol. American College of Gastroenterology guideline: management of acute pancreatitis [67].

       2012 J Natl Compr Canc Netw. Pancreatic adenocarcinoma, version 2.2012: featured updates to the NCCN Guidelines [68].

       2012 Ann Oncol. Pancreatic adenocarcinoma: ESMO-ESDO clinical practice guidelines for diagnosis, treatment and follow-up [69].

       2008 Ann Oncol. Neuroendocrine gastro-entero-pancreatic tumors: ESMO clinical practice guidelines for diagnosis, treatment and follow-up [70].

       2005 Ann Surg Oncol. Treatment guidelines for branch duct type intraductal papillary mucinous neoplasms of the pancreas: when can we operate or observe? [71].

       2004 Gastrointest Endosc. ASGE guideline: The role of endoscopy in the diagnosis and the management of cystic lesions and inflammatory fluid collections of the pancreas [72].

       Am J Surg Pathol. An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms [73].

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