Jimenez R E, Warshaw A L, Z'graggen K, Hartwig W, Taylor D Z, Compton C C, Fernández-del Castillo C
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.
Ann Surg. 1999 Oct;230(4):501-9; discussion 509-11. doi: 10.1097/00000658-199910000-00006.
Pancreatic mucinous cystic neoplasms (MCNs) provide a spectrum of neoplastic changes ranging from benign to malignant. The authors have correlated K-ras mutations and p53 overexpression with the evolution of these tumors.
Areas of mild, moderate, or severe dysplasia were microdissected from paraffin-embedded tissue sections of 28 different MCNs (10 benign, 9 borderline, 9 malignant). Nonneoplastic pancreatic ducts were also microdissected from tissues adjacent to the tumors. Ten serous cystadenomas served as negative controls. K-ras codon 12 mutations were identified by a mutant-enriched nested polymerase chain reaction-restriction fragment length polymorphism assay and confirmed by sequencing. p53 overexpression was demonstrated by immunohistochemistry.
K-ras mutations were detected in 20% of benign, 33% of borderline, and 89% of malignant MCNs. Histologically, mutations were found in 26% (7/27) of MCN epithelia with mild dysplasia, 38% (5/13) of MCN epithelia with moderate dysplasia, and 89% (8/9) of MCN epithelia with severe dysplasia or carcinoma. Ten percent (4/39) of nonneoplastic pancreatic ducts at the margins of MCN harbored mutations, all associated with borderline or malignant tumors. Overexpression of p53 occurred in none of the benign or borderline MCNs but in 44% (4/9) of the malignant tumors (p = 0.006 benign/borderline vs. malignant). p53 immunoreactivity was concentrated in areas of severe dysplasia/carcinoma or invasion, where K-ras mutation had been detected.
These findings demonstrate a sequential accumulation of genetic changes in the carcinogenesis of MCN. K-ras mutations appear early and increase in proportion with increasing dysplasia. Overexpression of p53 is a late finding observed only in carcinomas, and in combination with mutated K-ras genes. The presence of K-ras mutations in nonneoplastic ducts supports formal pancreatic resection over enucleation for treatment. Mucinous cystic neoplasms may be a useful model to study the evolution of pancreatic ductal adenocarcinomas, in which precursor lesions remain unknown.
胰腺黏液性囊性肿瘤（MCNs）呈现出从良性到恶性的一系列肿瘤性变化。作者将K-ras突变和p53过表达与这些肿瘤的进展相关联。
从28个不同的MCNs（10个良性、9个交界性、9个恶性）的石蜡包埋组织切片中显微切割出轻度、中度或重度发育异常区域。还从肿瘤邻近组织中显微切割出非肿瘤性胰腺导管。10个浆液性囊腺瘤用作阴性对照。通过突变富集巢式聚合酶链反应-限制性片段长度多态性分析鉴定K-ras密码子12突变，并通过测序进行确认。通过免疫组织化学证明p53过表达。
在20%的良性、33%的交界性和89%的恶性MCNs中检测到K-ras突变。组织学上，在轻度发育异常的MCN上皮中26%（7/27）发现突变，中度发育异常的MCN上皮中38%（5/13）发现突变，重度发育异常或癌的MCN上皮中89%（8/9）发现突变。MCN边缘的非肿瘤性胰腺导管中有10%（4/39）存在突变，均与交界性或恶性肿瘤相关。p53过表达在良性或交界性MCNs中均未出现，但在44%（4/9）的恶性肿瘤中出现（良性/交界性与恶性相比，p = 0.006）。p53免疫反应性集中在重度发育异常/癌或浸润区域，这些区域已检测到K-ras突变。
这些发现表明MCN致癌过程中基因变化的顺序积累。K-ras突变出现较早，且随着发育异常程度增加比例上升。p53过表达是仅在癌中观察到的晚期现象，且与突变的K-ras基因同时出现。非肿瘤性导管中存在K-ras突变支持采用正规胰腺切除术而非剜除术进行治疗。黏液性囊性肿瘤可能是研究胰腺导管腺癌进展的有用模型，其中前体病变尚不清楚。
