第二军医大学学报  2018, Vol. 39 Issue (5): 525-530   PDF    
胰腺囊性肿瘤诊治进展
盛彧, 边云, 王莉     
海军军医大学(第二军医大学) 长海医院影像医学科, 上海 200433
摘要: 胰腺囊性肿瘤组织学分类广泛,随着影像学技术如CT、MRI等的不断发展,其检出率增加,因此规范化诊治成为临床面临的挑战。目前临床对胰腺囊性肿瘤的影像学特征及肿瘤标志物认识不足,未能制定合理的诊疗方案。影响力较高的胰腺囊性肿瘤诊治规范有国际共识指南、欧洲专家共识声明、美国胃肠病学会指南,本文围绕上述指南/专家共识声明对比分析其提出的诊治策略及建议,并结合超声内镜相关检查技术,为临床处理该类疾病提供参考意见。
关键词: 胰腺囊肿     导管内乳头状黏液瘤     国际共识指南     欧洲专家共识声明     美国胃肠病学会指南    
Recent advances on management of pancreatic cysts
SHENG Yu, BIAN Yun, WANG Li     
Department of Medical Imaging, Changhai Hospital, Navy Medical University (Second Military Medical University), Shanghai 200433, China
Abstract: Pancreatic cysts have many histological subtypes. With development of imaging techniques such as computed tomography and magnetic resonance imaging, detection rate of pancreatic cysts has been increasing. And standardized diagnosis and treatment of pancreatic cysts remains a clinical challenge. Due to insufficient understanding of imaging features and tumor markers of pancreatic cysts, a reasonable procedure of diagnosis and treatment has not been published so far. Several guidelines for the diagnosis and treatment of pancreatic cysts with high impact have been published, including international consensus guidelines, European experts consensus statement and American Gastroenterological Association guidelines. This review focused on the diagnosis and treatment strategies and suggestions proposed by the above guidelines, and application of endoscopic ultrasonography, so as to provid references for treatment of pancreatic cysts.
Key words: pancreatic cyst     intraductal papillary mucinous neoplasm     international consensus guidelines     European experts consensus statement     American Gastroenterological Association guidelines    

随着腹部影像学技术的不断发展,越来越多的胰腺囊性肿瘤被发现,其中大部分患者无明显临床症状[1]。文献报道,CT和MRI检出的胰腺囊性肿瘤分别占所有检查患者的3%和20%,且发现时囊肿体积都不大[2]。胰腺囊性肿瘤组织学分类有良性病变[如假性囊肿、浆液性囊腺瘤(serous cystic neoplasm,SCN)]、潜在恶性病变[如黏液性囊腺瘤(mucinous cystic neoplasm,MCN)、导管内乳头状黏液瘤(intraductal papillary mucinous neoplasm,IPMN)]与恶性病变[如导管腺癌、胰腺内分泌肿瘤、实性假乳头状瘤(solid pseudo-papillary tumor,SPT)][3]。不同病理类型的胰腺囊性肿瘤临床处理方式不同,临床面临的最新挑战是术前对病变的诊断及对其良恶性的准确评估。目前尚存在的不足是临床对胰腺囊性肿瘤的影像学特征和肿瘤标志物等认识不足,以及做不到依据指南制定合理的诊疗方案。本文围绕国际重要指南深入分析胰腺囊性肿瘤的诊治策略,以期为临床处理胰腺囊性肿瘤提供参考。

1 临床对胰腺囊性肿瘤诊治现状

胰腺囊性肿瘤男女患病比例为1.0:2.4,获得诊断时平均年龄为47.5(8~89)岁,其中SPT最常见,约占32.0%,其次是SCN及IPMN,MCN占比最少;IPMN恶变率最高,约为32.0%,SCN恶变率最低,仅0.6%;胰腺囊性肿瘤术前模糊诊断常见、错误诊断率高,术前精确到亚型的正确诊断率仅为33.0%,尤以SCN最低(13.7%)[4]。CT、MRI检查是目前临床检出胰腺囊性肿瘤及明确分类的主要手段,其可显示病变形态学特征如囊壁钙化、附壁结节、纤维分隔、炎性改变等。高分辨率CT增强扫描及其多种后处理技术可显示病变全貌,薄层图像对微小附壁结节、钙化显示清晰,但鉴于放射损伤及碘造影剂的肾毒性,仍不推荐作为首选。MRI的组织分辨率高,能更好地显示囊腔内容物的特征,且在T2加权像上较CT更易发现微小囊肿[5]。磁共振胆胰管造影(magnetic resonance cholangiopancreatography,MRCP)可直观地显示扩张主胰管的全程以及囊性病灶与主胰管的沟通情况。MRCP对IPMN胰管交通的检出率为73%,高于CT检出率的18%;且与MRCP比较,CT检查过高地估计了主胰管受累[6]。MRI对多灶性病变检出率也高于CT,因此学者认为胰腺囊性肿瘤的最佳影像学检查手段为MRI联合MRCP。当CT或MRI对部分囊性病变无法定性时应建议患者行超声内镜(endoscopic ultrasonography,EUS)进一步检查。

目前胰腺囊性肿瘤尚无有效的内镜及药物治疗方法,临床多选择手术治疗或随访观察。存在以下情况之一时倾向于手术治疗:(1)合并有明显临床症状如腹痛、反复发作胰腺炎、黄疸等;(2)影像学检查倾向恶性病变[5]。当患者未达到手术标准但仍有可能发展为恶性时,应根据病情制定随访计划并及时干预,术后亦应对残余胰腺组织随访观察。以上治疗策略的选择需严格依据患者的临床表现和CT、MRI、EUS等影像学表现及囊液分析结果,并且应结合患者实际情况如年龄、并发症等权衡手术治疗或随访观察的利弊。然而目前在临床上尚做不到依据指南制定合理的诊疗方案,而且即使采用最先进的CT或MRI扫描技术并结合EUS及囊液分析,也难以准确鉴别部分病变的良恶性。

2 重要指南对胰腺囊性肿瘤诊治建议 2.1 国际共识指南(international consensus guidelines,ICG 2006)[6]

国际共识指南又称仙台指南,于2006年在仙台胰腺学术会议上发布。该指南主要针对IPMN及MCN,其手术指征为主胰管型和混合型IPMN、MCN;分支胰管型导管内乳头状黏液瘤(branch duct-intraductal papillary mucinous neoplasm,BD-IPMN)直径>3 cm、附壁结节、黄疸或反复发作胰腺炎、细胞学检查阳性亦应予手术治疗。直径<3 cm的BD-IPMN需根据囊肿大小制定随访计划:1~2 cm每半年随访1次,2~3 cm每3~6个月随访1次。

2.2 国际共识指南修订(revised international consensus guidelines,ICG 2012)

仙台指南阳性预测值(positive predictive value, PPV)低(11%~52%)导致很多不必要的手术[7]。因此2012年胰腺专家在仙台指南基础上进行了一次修订,又称福冈指南[8]。该指南同样针对IPMN及MCN。MCN患者均需手术治疗,囊肿直径<4 cm且无附壁结节可行腹腔镜手术切除。IPMN患者出现“报警指征”(黄疸、强化的附壁结节、主胰管扩张至直径≥10 mm)应手术治疗;出现“可疑指征”(囊肿直径>3 cm、囊壁及分隔增厚强化、不强化的附壁结节、主胰管直径为5~9 mm、反复发作胰腺炎)应行EUS及细针穿刺(fine needle aspiration,FNA)检查,并根据其检查结果决定是否行手术治疗。无以上表现的IPMN应随访:囊肿直径为1~2 cm者每2年随访1次;囊肿直径为2~3 cm者每3~6个月行EUS检查,若无恶性指征延长随访时间。见表 1

表 1 3篇胰腺囊性肿瘤指南/专家共识声明中EUS检查指征、手术指征和随访建议 Tab 1 Indications of EUS, and surgery and surveillance for pancreatic cyst in three guidelines/consensus

2.3 欧洲专家共识声明(European experts consensus statement)

2013年欧洲胰腺专家发表了胰腺囊性肿瘤欧洲专家共识声明[9],该指南在方法学和诊治建议方面与ICG 2012十分相似,但其着重讨论了4种常见胰腺囊性肿瘤IPMN、SCN、MCN和SPT的诊治策略,其中MCN、SPN、主胰管型IPMN、混合型IPMN均需手术治疗。该共识将BD-IPMN的手术指征提高,将囊肿直径≥4 cm作为手术的独立指征。若囊肿直径<4 cm且合并有附壁结节、主胰管扩张至直径>6 mm或黄疸、胰腺炎性改变等临床症状亦应手术治疗。无上述表现的患者在确诊后的第1年每6个月行MRI或EUS检查,若病灶无变化可延长随访时间。见表 1

2.4 美国胃肠病协会(American Gastroenterological Association,AGA)指南

2015年AGA指南主要针对无症状胰腺囊性肿瘤患者[10]。存在囊肿直径>3 cm、主胰管扩张、附壁结节中任2个危险因素者行EUS检查,同时存在主胰管扩张和附壁结节或合并细胞学检查阳性行手术治疗。EUS检查阴性或无上述影像学表现的患者应随访观察:确诊后第1年行MRI检查,随后每2年复查1次,5年病灶无明显变化可停止随访。见表 1

3 各指南/专家共识声明对比及最佳手术、随访时机

手术切除不仅可以切除有明确侵袭性的癌变、缓解临床症状,也可早期切除中重度异型增生病变以延长患者寿命,是胰腺囊性肿瘤的主要治疗手段。胰腺手术并发症的发生率高,外科医师应严格把握手术适应证和手术时机,选择最佳手术方案。仙台指南的手术标准对恶性病变有较高的阴性预测值(negative predictive value,NPV),可达到75%~100%,但其PPV较低,仅为11%~52%[7]。学者寄希望于ICG 2012,但仍不尽人意,PPV也仅为27%~62%,NPV为82%~100%[11]。目前检验AGA指南的文献报道较少,Singhi等[12]回顾性分析225例无症状胰腺囊性肿瘤患者的病例资料,其诊断恶性病变的PPV和NPV分别为52%和82%。Ma等[13]研究239例胰腺囊性肿瘤患者的影像及病理资料,认为ICG 2012及AGA指南的PPV、NPV无显著差异。Lekkerkerker等[14]对比分析ICG 2012、AGA指南和欧洲专家共识声明,其手术标准PPV分别为54%、59%、53%,NPV分别为100%、81%、100%。可见这3篇指南/专家共识声明的PPV、NPV相差不大,值得注意的是以上研究都是对术后病理结果的回顾性分析,这部分病例只占胰腺囊性肿瘤病例的小部分,忽视了检查后诊断为良性病变未行手术治疗的病例,因此各指南/专家共识声明的PPV均未达到令人满意的结果。仅凭单一指标评估肿瘤良恶性也是导致结果不准确的原因。Molin等[15]组合了胰腺囊性肿瘤的临床资料和影像学、实验室检查结果,采用生物信息学中MOCA(multivariate organization of combinatorial alterations)分析方法,使术前诊断IPMN的灵敏度、特异度分别提高至94%、90%,鉴别良恶性IPMN的灵敏度、特异度分别提高至81%、61%,且对其他类型胰腺囊性肿瘤的诊断也有帮助。

在随访方面,ICG 2012提出根据囊肿大小制定随访计划,病灶稳定后可延长随访时间;AGA指南认为5年后病灶稳定可停止随访;欧洲专家共识声明推荐终身随访直到出现手术指征。在随访中应优先关注囊肿大小的变化,BD-IPMN囊肿直径平均每年增长0.29 mm,若2年内直径增长超过5 mm则列入恶性的“可疑指征”[7]。患病时间越长恶变风险越高,He等[16]对130例未行手术治疗的良性IPMN患者随访观察,1、5、10年病变发展为恶性的比例分别为0%、7%、38%。术后良性BD-IPMN的复发率为5.4%~9.0%,恶变率为2.3%~5.0%[17]。AGA指南提出术后病理结果若为高级别异型增生或浸润癌应每2年随访1次MRI检查,若为良性病变则不需随访,此建议备受争议。He等[16]对130例手术切除良性IPMN术后患者随访,1、5、10年复发率分别为4%、25%、62%。胰腺癌家族史、手术切缘阳性、病理结果为高级别异型增生或浸润癌患者更易复发,随访时应予以重视[18]。近年来IPMN与胰腺癌关系被密切关注,IPMN发展为胰腺癌的概率为4%,两者先后发病的概率均为11%[7]。Kamata等[19]对102例影像学检查诊断为良性BD-IPMN的患者进行为期6个月的随访,发现7例为胰腺癌,该研究对欧洲专家共识声明中最短随访时间为6个月提出了质疑。手术切除后BD-IPMN也可发生胰腺癌,Ohtsuka等[20]报道了172例术后IPMN患者,其中在随访中发现17例胰腺癌。糖尿病、糖类抗原19-9升高、病理结果为胃型IPMN患者更易发生胰腺癌[21]。综上所述,随访对良性病变及术后患者至关重要,随访频率应根据患者年龄、家族史、临床症状、并发症、预期寿命、术后病理结果行“私人订制”,做到早发现早治疗,并终身随访直至出现手术指征。

4 EUS相关技术对胰腺囊性肿瘤诊断意义

EUS较CT及MRI更易观察到附壁结节及分隔。附壁结节根据形态可分为4种:扁平乳头型、息肉型、乳头型及侵袭型,后两种形态诊断恶性的灵敏度为60.0%,特异度为92.9%,准确度为75.9%[22]。在附壁结节大小方面,常认为直径>5mm与恶性病变密切相关[23]。笔者曾对64例存在附壁结节IPMN患者的临床资料进行回顾性分析,认为附壁结节个数、位置、强化程度与病变良恶性无关[24]。有时附壁结节与黏液栓难以在CT或MRI图像上鉴别,增强EUS检查可观察血流信号有利于两者鉴别,其诊断灵敏度为60%、特异度为92.9%,准确度为75.9%[25]。EUS-FNA对囊液行生物化学及分子标志物检测是鉴别胰腺囊性肿瘤及评估良恶性的重要手段。通常癌胚抗原>192 ng/L可诊断为黏液性肿瘤,但其数值大小与良恶性无关[26]。囊液中葡萄糖含量≤5 mg/L诊断黏液性肿瘤的灵敏度为92%、特异度为87%、准确度为90%[27]。生物化学检查需至少1 mL囊液,由于囊液量不足或高度黏稠,仅49%的样本可用于生物化学诊断[5]。分子标志物DNA检测只需0.2 mL囊液,希佩尔-林道肿瘤抑制基因突变可见于SCN,其他囊性肿瘤无此突变;链蛋白β1基因突变见于SPN;鸟苷酸结合蛋白α活性刺激肽(guanine nucleotide-binding protein α-stimulating activity polypeptide,GNAS)基因突变为IPMN特有,其诊断灵敏度为66%;IPMN及MCN囊液内均可发现鼠类肉瘤病毒癌基因(kirsten rat sarcoma viral oncogene,KRAS)及环指蛋白43基因突变[28]。在鉴别良恶性方面,联合KRAS/GNAS和肿瘤蛋白p53/磷脂酰肌醇-3-激酶α亚单位/第10号染色体缺失的磷酸酶张力蛋白同源物基因突变预测恶性的灵敏度为89%、特异度为100%[29]。囊液中性别决定区Y框蛋白17、B细胞淋巴瘤/白血病-2/腺病毒E1B 19 000相互作用蛋白3、叉头框E1、派遣耐药结节细胞分化家族转运蛋白3、神经生长导向因子配体2、无眼基因转录共激活磷酸酶4、分泌型卷曲相关蛋白1基因甲基化异常与病变恶性相关[30]。恶性病灶囊液中9种微RNA(miR18a、miR24、miR30a-3p、miR92a、miR99b、miR106b、miR142-3p、miR342-3p、miR532-3)发生改变,且4种蛋白质基质金属蛋白酶9、糖类抗原72-4、可溶性凋亡相关因子配体、白细胞介素4过度表达[31]

近年来新兴EUS相关技术检查可更直观地显示胰腺囊性病变的影像学特征。共聚焦激光显微内镜(confocal laser endomicroscopy,CLE)技术是在内窥镜头端安装一个共聚焦激光探头,通过激光激发特殊的荧光剂产生组织图像。CLE图像上IPMN表现为指状突起,MCN表现为单层带状上皮组织,SCA形似迂曲走形的网状血管影,假性囊肿内的炎性细胞表现为点状高密度影[32]。此方法鉴别胰腺囊性病变的灵敏度为85.37%、特异度为87.38%、PPV为72.92%、NPV为93.75%、一致性为86.81%[33]。微钳活组织检查(micro-forceps biopsy,MFB)技术是在EUS-FNA基础上使用19号细针,夹取囊壁、分隔、附壁结节等实性组织行病理检查,病变组织获取率可达90%[34]

总之,随着EUS相关技术不断革新和研究不断深入,在诊断胰腺囊性肿瘤并鉴别其良恶性方面展示出良好的应用前景。多种生物化学及分子标志物为临床诊治提供全方位的参考意见,但这些标志物的准确性、可重复性和实用性尚需进一步验证。EUS-FNA对操作者要求极高,操作不当易引发出血、急性胰腺炎等并发症,准确的穿刺取样和标本处理以及经验丰富的病理医师可提高诊断的准确性。

5 展望

诸指南/专家共识声明均很详尽但已无法满足目前对胰腺囊性肿瘤的诊治需求,临床更希望通过CT/MRI/EUS影像学特征及囊液分析结果对病变进行准确的低、中、高级别异型增生及浸润癌的分级诊断,从而指导治疗策略。在CT、MRI、EUS方面,目前比较热门的研究方向为扫描图像与病理切片的对照研究,准确直观地观察影像学中的附壁结节、强化囊壁等特征对应病理切片上哪一种病理类型,从而做到精准的分级诊断。应进一步研发EUS-FNA新技术以增加取样量、提高诊断率。临床决策应联合多个指征,通过特定算法提升胰腺囊性肿瘤良恶性鉴别的灵敏度、特异度,有望对治疗方案的准确制定和预后评估提供重要的参考价值。

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