胰腺导管内乳头状黏液瘤的研究进展

摘要

胰腺导管内乳头状黏液瘤(intraductal papillary mucinous neoplasm, IPMNs)为来源于胰腺导管上皮的分化程度多样的胰腺肿瘤, 位于主胰管或其分支内, 可分泌黏液, 为胰腺癌的癌前病变. 区分IPMNs的良恶性对制定治疗方案, 预估患者预后意义重大. 随影像学和内镜的发展, IPMNs发现率逐年提高, 但目前仍无敏感度和特异度均高的术前IPMNs良恶性评估标准. 超声内镜引导下细针穿刺活检(endoscopic ultrasonography guided fine-needle aspiration, EUS-FNA)及内镜逆行胰胆管造影(endoscopic retrograde cholangio-pancreatography, ERCP)在IPMNs诊断中的应用逐渐增多, 但必要性尚存在争议. 本文对IPMN研究进展进行综述, 并总结文献中良恶性IPMNs可能存在的差异.

关键词: 胰腺导管内乳头状黏液瘤; 诊断; 治疗

Progress in research of intraductal papillary mucinous neoplasms

Zi-Hao Guo, Jie Zhang, Jian-Yu Hao

Zi-Hao Guo, Jie Zhang, Jian-Yu Hao, Department of Gastroenterology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China

Correspondence to: Professor Jian-Yu Hao, Department of Gastroenterology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China. haojianyu@medmail.com.cn

Received: May 19, 2011
Revised: June 23, 2011
Accepted: July 5, 2011
Published online: August 8, 2011

Abstract

Intraductal papillary mucinous neoplasms (IPMNs) represent a spectrum of neoplasms arising from the main pancreatic duct or branch ducts and producing mucin and can be regarded as a type of precancerous lesions. Thanks to improvements in endoscopy and imaging techniques, IPMNs are being diagnosed with increasing frequency. However, there are currently no highly sensitive and specific preoperative criteria available to distinguish benign IPMNs from malignant ones. What's more, the necessity for EUS and ERCP in the diagnosis of IPMNs is still under debate. Here, we review recent advances in research of IPMNs and summarize potential differences between benign and malignant IPMNs.

Key Words: Intraductal papillary mucinous neoplasms; Diagnosis; Treatment

0 引言

胰腺导管内乳头状黏液瘤(intraductal papillary-mucinous neoplasms, IPMNs)是临床较少见的一种胰腺囊性肿瘤, 约占胰腺外分泌肿瘤的1%[1], 近年来随着影像技术的发展, IPMNs的发现率逐年增高, 50%的IPMN为临床偶然发现的胰腺囊性肿物[2,3]. IPMNs的病理类型多样, 包括良性、交界性、原位癌、侵袭性癌等不同分化阶段, 并且可伴发胰腺导管内瘤变(pancreatic intraepithelial neoplasia, PanIN)、胰腺导管细胞癌, 为胰腺癌的癌前病变类型之一[4,5]. 因而早期诊断IPMNs并鉴别其良恶性, 有助于治疗方案的选择, 提高患者生存率. 近年来IPMNs在诊断学上的进展很快, 尤其是影像及内镜学方面, 本文对IPMNs进展综述如下.

1 概述

对IPMNs的认识经历了约20年, 1982年由Ohhashi首次报道, 后曾有乳头状癌、绒毛样腺瘤、高分泌黏液癌、黏液性导管扩张症等多种命名, 直至2000年世界卫生组织(WHO)将此类肿瘤正式命名为IPMNs[6-8]. 2003年在约翰霍普金斯医院举行的全球胰腺会议中将IPMNs定义为: 起源于主胰管或分支胰管的乳头状(多见)或扁平(少见)状的大体上可见的胰腺肿瘤, 非侵袭性, 可产黏液, 并伴有不同程度的胰管扩张, 病变直径多>1 cm, 细胞及组织异型性多样[9].

2 临床表现

IPMNs的发病率男女均等, 最常见于60-70岁的老年人, 平均发病年龄为65岁, 恶性IPMNs患者的平均发病年龄较良性患者大6.4岁[10-12]. 临床表现多样, 无特异性的症状, 最常见的症状为腹痛、体质量下降、急慢性胰腺炎反复发作、黄疸, 可伴发糖尿病的发生或加重, 另约有1/3的患者可无任何表现[13,14]. 黄疸和糖尿病同恶性IPMN高度相关[15].

3 病理学表现

IPMNs具有多种病理类型[16-18]. 根据上皮的异型性和分为非浸润癌和浸润癌, 非浸润癌又可分为低、中、高度异型性, 浸润癌可分为胶样癌、导管腺癌及其他类型, 如未分化癌等. 根据被覆上皮的形态及免疫组织化学, 可分为胃型、肠型、胰胆管细胞型和嗜酸性细胞型, 各类型可同时出现, 都有MUC5AC(+). 胃型IPMNs具有类似胃小凹的上皮细胞, 细胞异型性小, 常为良性小囊性肿物; 肠型IPMNs细胞高柱状假复层排列, 类似肠乳头状腺瘤, 伴中-重度不典型增生, 多为位于主胰管或分支胰管的大的囊性肿物, 特异性的表达MUC2(+); 胰胆管型IPMNs类似胆管乳头状腺瘤, 常为重度不典型增生, 多为原位癌, MUC1(+); 嗜酸细胞型含有丰富的嗜酸性胞质和圆形核, 重度不典型增生, MUC1(+)[19-23].

4 血清学检查

尚未发现特异性改变, 部分胰腺囊性病变患者中可见CA19-9或CEA的升高, 且多发生于恶性者, 有文献报道[24], CA19-9升高的胰腺囊性病变患者因其潜在恶性, 均应行外科手术切除. 此外, 血清Span-1、DUPAN-2、PAM4水平及外周血Foxp3/CD25/CD4 T淋巴细胞数目或可用于鉴别良恶性IPMNs[6].

5 影像表现概述

IPMNs的临床症状不典型, 多由影像学检查偶然发现, 且影像学检查是术前诊断的主要依据[25]. 根据肿瘤起源不同, 在影像学上可分为主胰管型、分支胰管型和混合型, 其中主胰管型和混合胰管型的恶性程度较高[26,27]. 分支型IPMNs较少被关注, 部分可不含壁结节, 生长缓慢, 长期随访可有84.1%的患者无明显进展[28].

主胰管型表现为主胰管呈弥漫性和(或)节段性扩张, 管壁变薄, 胰管壁上可见结节状和(或)扁平状的软组织突起, 管腔内的黏液栓可造成管腔内密度不均匀增高, 常合并胰腺实质的萎缩, 十二指肠乳头增大, 突入肠腔. 分支型表现为单房或多房囊性肿瘤, 肿瘤内部有厚薄不均的分隔及大小不等的壁结节, 囊性肿瘤与主胰管相交通, 当主胰管受累时, 可伴主胰管不同程度的扩张. 是否与主胰管相通是鉴别IPMNs和浆液性囊腺瘤/癌的要点[29,30].

不同影像学手段对IPMNs诊断有不同方面的价值[31,32]. 增强动态MRCP有助于定位、分期及确定外科手术的可能性. 增强CT有助于评估肿瘤与周围脏器和血管的关系, 有无侵犯. ERCP可观察胰管形态, 及可观察十二指肠乳头的扩张("鱼眼征")及黏液溢出, 通过判断囊性肿物是否与主胰管相连, ERCP有助于区分IPMNs和胰腺囊腺癌, 这是非侵入性影像检查不能做到的, 同时ERCP可作为一种治疗手段, 暂时胆道减压, 缓解黄疸[33,34]. EUS不仅可显示病变及扩张胰管, 还可通过细针穿刺活检(fine needle aspiration, FNA)行细胞学及分子学检测[35,36].

6 EUS-FNA在IPMNs诊断中的应用

在EUS下IPMNs可表现为: (1)实性肿物; (2)多囊性病变, 并与扩张的主胰管相通; (3)胰管充盈缺损; (4)低回声囊肿, 内可疑黏液[37]. EUS下尚无明确的良恶性IPMNs区分标准, Kubo等在2001年提出超声内镜下恶性IPMNs诊断标准: (1)主胰管型IPMNs主胰管扩张(≥10 mm); (2)分支型IPMNs肿瘤直径>40 mm并伴不规则厚间隔; (3)主胰管型或分支型IPMN中发现大的腔壁结节(>10 mm). 根据上述标准, 据近期Aso等[38]研究报道据此标准诊断率为79%, 并可发现全部侵袭性胰腺癌. Aso等认为超声内镜下恶性IPMNs的诊断标准可以有效鉴别良恶性IPMNs, 指导外科决策的制定. Maire等[39]对40例IPMNs患者进行了术前EUS, 发现在主胰管型IPMNs中, 主胰管直径<5 mm时IPMNs患病率为8%, 直径5-10 mm时IPMNs患病率为57%, 恶性率为33%, 直径≥10 mm时恶性率为100%, 且管壁结节为恶性IPMN所独有. 分支型IPMNs中, 胰管直径≥10 mm则IPMNs患病率为100%, 有管壁结节者恶性率为62%. 并且78%的IPMNs患者并发PanIN, 恶性IPMNs更易并发PanIN.

在行EUS同时还可进行FNA对囊液进行细胞学、生化及肿瘤标志物的检查, 以区分IPMNs良恶性. 囊液CEA>200 μg/L区分良恶性IPMNs的敏感性为47%; 囊液CA19-9>10 000 kU/L区分良恶性IPMNs的敏感性为80%[6]. Maire等[40]等发现囊液CEA和CA72-4水平可作为良好的恶性IPMNs阴性预测指标: CEA>200 μg/L诊断恶性IPMNs的敏感度为90%、特异性为71%、阳性预测值为50%、阴性预测值为96%; CA72-4>40 kU/L敏感度为87.5%, 特异性为73%, 阳性预测值为47%, 阴性预测值为96%.

细胞学检测敏感度为68%-91%, 于低倍镜下IPMNs的典型表现为可见多少不等的黏液, 且以细胞内的黏液更有诊断意义, 细胞多成乳头状排列, 中有纤维血管束, 并缺乏正常肠上皮的"蜂巢"样结构. 交界性IPMNs或原位癌可表现为微绒毛状排列, 或散在的异性细胞. 坏死性炎症、多形核仅见于恶性IPMNs[37].

EUS在IPMNs的应用渐多[41-43], 但也有文章认为[44]增强CT中胰管直径≥1 cm(P = 0.034)是胰腺高度异型性病变及胰腺癌的显著预测因素, CT上病变直径≥2.5 cm可识别出了71%胰腺癌及高度异型性病变患者, 故增强CT表现为胰腺病变直径≥2.5 cm和/或胰管直径≥1 cm可不需EUS检查.

7 治疗

主胰管型IPMNs恶性率高(57%-92%), 分支型IPMNs恶性率相对较低(6%-46%). 2006年国际胰腺协会(international association of pancreatology, IAP)发表指南, 建议在患者一般情况允许时, 对主胰管型IPMNs均行外科手术治疗; 并且对具有以下特征之一的分支型IPMNs行手术治疗: 有症状的、肿瘤直径大于3 cm、含腔内结节的、主胰管扩张大于6 mm; 对无以上特征的分支型IPMNs可在定期的影像学监测下行保守治疗[45-47]. Tang等[48]及Pelaez-Luna等[49]的临床随访研究均显示依照该指南对恶性IPMNs诊断的敏感性可达100%, 而特异性仅为23%-31%, 提示依照该指南在很好的识别恶性IPMNs的同时, 对于良性IPMNs切除率也较高. Huang等[50]通过TreeAge 2008软件建立模型, 对60岁胰头部分支型IPMNs患者行假设的队列分析, 比较了依据指南切除组、立即手术切除组及根据症状行手术切除组的成本-收获比值, 发现依照现有指南行监测或切除的成本-收获最高, 然而假设队列研究是受年龄、肿瘤部位等因素限制的, 远期而言, 花费仍很大, 需寻找更据特异性的指南.

8 结论

恶性IPMNs可能具有以下特征: 发病年龄偏大, 易伴发黄疸及糖尿病; 主胰管型及混合胰管型的恶性程度较高, 主胰管直径≥6 mm, 病变≥2.5 cm, 含有腔壁结节, 尤其结节直径>10 mm者对恶性有较大的预测意义; 血清CA199或CEA升高; 囊液检测见CEA(>200 μg/L)或CA19-9(>10 000 kU/L)或CA72-4(>40 kU/L)升高; 囊液细胞学检测见微绒毛状排列, 或散在的异性细胞、多形核, 或坏死性炎症; 病理类型多为肠型、胰胆管型、嗜酸细胞型. 虽然2006年的IAP发布的IPMNs指南敏感性高, 但特异度低, 仍需进一步寻找更特异的术前IPMNs良恶性评估标准.

评论

背景资料

胰腺导管内乳头状黏液瘤是临床较少见的一种胰腺囊性肿瘤, 来源于胰腺导管上皮, 分化程度多样, 位于主胰管或其分支内, 可分泌黏液, 是胰腺癌的癌前病变. 随影像技术的进展. 近年其发现率逐年上升, 综合应用各种手段以早期诊断IPMNs并鉴别其良恶性, 有助于治疗方案的选择, 提高患者生存率.

同行评议者

李淑德, 主任医师, 中国人民解放军第二军医大学长海医院消化内科

研发前沿

影像学技术的进步, 应用EUS-FNA技术早期发现IPMNs, 并通过对囊液的细胞学、生化及肿瘤标志物的检查早期鉴别良恶性, 制定更加完善的治疗方案是目前努力的方向.

相关报道

Carrara等对90例胰腺囊性肿瘤患者行EUS-FNA, 收集其囊液进行荧光定量PCR等分子生物学检查, 发现MUC7基因可能为恶性肿瘤的标志基因, 该研究提供了应用EUS-FNA穿刺物行分子生物学检查的新思路.

创新盘点

本文创新性地综述了IPMNs的多种检查手段, 着重介绍了EUS-FNA方面的研究进展, 并总结了恶性IPMNs可能具有的临床特征, 对于指导临床诊断和治疗有指导意义.

应用要点

本文全面系统地阐述了胰腺导管内乳头状黏液瘤的临床表现, 以及病理学、血清学、影像学和EUS-FNA及治疗等方面的研究进展, 并总结了恶性IPMNs可能具有的特征, 对于指导临床诊断和治疗有指导意义.

同行评价

本文从临床表现、病理学、血清学、影像学和EUS-FNA 等方面对胰腺导管内乳头状黏液瘤进行介绍, 对提高临床医生对本病的认识, 以此指导临床诊断和治疗, 有重要指导意义.

备注

编辑:李薇 电编:何基才

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