Ann Surg：胃亚型胰腺导管内乳头状黏液瘤常恶变为胰腺导管腺癌

在2013年3月25日在线出版的《外科学年鉴》(Annals of Surgery)杂志上，发表了美国外科医师学会会员、日本九州大学Masao Tanaka博士等人的一项研究结果，该研究通过组织病理学方法进行亚型确定，旨在鉴定出胰腺导管腺癌(PDAC)的高风险患者组别，PDAC可独立出现于存在胰腺导管内乳头状黏液瘤(IPMN)的胰腺之中。目前在IPMN与PDAC的不同病理特征，包括IPMN组织病理亚型以及PDAC表型方面，尚未得到较为透彻的描述。通过黏液性表达类型以及GNAS和KRAS的突变状态，有助于对这两类病变类型间的关系进行考察。

该研究考察了179例接受手术切除的IPMN患者，和180例接受手术切除但无IPMN的PDAC患者的临床病理数据。在该研究中，IPMN被分为4个级别(低度、中度、高度分化不良以及相关的浸润癌)以及4个亚型(胃亚型、肠亚型、胰胆道亚型及嗜酸细胞亚型)。通过对IPMN及存在或不存在IPMN的PDAC进行免疫组化检测，研究人员考察了MUC1、MUC2、MUC5AC、MUC6以及CDX2的表达情况。并通过对PDAC及病前/共存的IPMN进行循环测序，评价了GNAS及KRAS的突变状态。

研究人员在20例存在IPMN的患者中，鉴定出26处并发或异时性PDAC。观察发现，与肠亚型(1例/49例, 2.0%)、胰胆道亚型(1例/17例, 5.9%)及嗜酸细胞亚型(0例/3例, 0%)相比，胃亚型IPMN更常伴发PDAC(18例/110例, 16.4%，P = 0.047)。经免疫组化分析发现，无论存在或不存在IPMN，PDAC的MUC1、MUC5AC及MUC6表达均常为阳性，但MUC2及CDX2则常为阴性。粘蛋白染色类型与胃亚型IPMN中的浸润性管状腺癌类似。在PDAC及胃亚型IPMN中，未发现201位密码子存在GNAS突变，但多数存在KRAS突变。然而，在1例同时存在IPMN及不同PDAC的胃亚型患者中，发现存在R201HGNAS突变。

研究人员认为，根据黏液表达类型，在未发生GNAS突变的情况下，良性胃亚型IPMN常出现无GNAS突变的侵犯性亚型PDAC。
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Intraductal Papillary Mucinous Neoplasms of the Pancreas With Distinct Pancreatic Ductal Adenocarcinomas Are Frequently of Gastric Subtype.
OBJECTIVE
To identify a high-risk group of patients with pancreatic ductal adenocarcinoma (PDAC), independently arising in the pancreas with intraductal papillary mucinous neoplasm (IPMN), using histopathologic subtypes.
BACKGROUND
Pathologic features of IPMN with distinct PDAC, including histopathologic subtypes of IPMN and PDAC phenotypes, have not been well characterized. Mucin expression patterns and the mutational status of GNAS and KRAS are useful to explore the relationship between these 2 lesion types.
METHODS
Clinicopathologic data of 179 resected IPMNs and 180 resected PDACs without IPMNs as a control group were reviewed. IPMNs were classified into 4 grades (low-grade, intermediate-grade, high-grade dysplasia, and an associated invasive carcinoma) and 4 subtypes (gastric, intestinal, pancreatobiliary, and oncocytic). The expression of MUC1, MUC2, MUC5AC, MUC6, and CDX2 was investigated by immunohistochemistry in IPMNs and PDACs with and without IPMNs. The mutational status of GNAS and KRAS was evaluated by cycle sequencing in PDACs and pre-/coexisting IPMNs.
RESULTS
Twenty-six synchronous or metachronous PDACs were identified in 20 patients (11.2%) with IPMNs. Occurrence of concomitant PDACs was more frequently observed in gastric-type IPMNs (18/110, 16.4%) compared with intestinal (1/49, 2.0%), pancreatobiliary (1/17, 5.9%), or oncocytic-type (0/3, 0%) (P = 0.047). Both PDACs with and without IPMNs were frequently positive for MUC1, MUC5AC, and MUC6 expression, as assessed by immunohistochemistry, but were negative for MUC2 and CDX2. The mucin-staining patterns were similar to those of invasive tubular adenocarcinoma arising from gastric-type IPMNs. Mutation of GNAS within codon 201 was not detected in PDACs and gastric-type IPMNs, whereas most of these exhibited KRAS mutations. However, the R201H GNAS mutation was detected in 1 intestinal-type IPMN with distinct PDAC.
CONCLUSIONS
Mucin expression patterns demonstrate that PDAC without GNAS mutations of an aggressive phenotype frequently arise in the pancreas with benign gastric-type IPMN in the absence of GNAS mutations.