Biankin A V, Biankin S A, Kench J G, Morey A L, Lee C-S, Head D R, Eckstein R P, Hugh T B, Henshall S M, Sutherland R L
Cancer Research Program, Garvan Institute of Medical Research, and Division of Surgery, St Vincent's Hospital, Darlinghurst, NSW 2010 Australia.
Gut. 2002 Jun;50(6):861-8. doi: 10.1136/gut.50.6.861.
Intraductal papillary mucinous tumours (IPMT) of the pancreas constitute a unique pathological entity with an overall incidence of associated invasive malignancy of 20%. The malignant potential of an individual IPMT cannot be accurately predicted. Preoperative estimation of the risk of associated invasive malignancy with IPMT would be of significant clinical benefit. As aberrations in cell cycle regulatory genes are associated with the progression of precursor pancreatic ductal lesions to invasive adenocarcinoma, we examined expression of key cell cycle regulatory genes in the cyclin D1/retinoblastoma pathway and the transforming growth factor beta/Smad4 signalling pathway in a cohort of patients with surgically resected IPMT.
Sections of formalin fixed paraffin embedded pancreatic tissue from a cohort of 18 patients with IPMT were examined using immunohistochemistry for protein expression of cell cycle regulatory genes p16(INK4A), p21(CIP1), p27(KIP1), cyclin D1, pRb, and p53, as well as the cell signalling molecule Smad4. A comparison of expression levels was made between adenoma/borderline IPMT (10 patients) and intraductal papillary mucinous carcinoma (IPMC) (eight patients, four of whom harboured invasive carcinoma). Statistical analysis was performed using the chi(2) and Fisher's exact tests.
Aberrant expression of the proteins examined increased in frequency from adenoma/borderline IPMT to IPMC. Specifically, there was a significantly greater incidence of loss of p16(INK4A) expression in IPMC: 8/8 lesions (100%) compared with 1/10 (10%) adenoma/borderline IPMT (p<0.001). Similarly, loss of Smad4 expression was associated with IPMC: 3/8 (38%) versus adenoma/borderline IPMT 0/10 (p<0.03). Loss of Smad4 expression within the IPMT was the best marker for the presence of invasive carcinoma (p<0.001).
These data indicate that loss of p16(INK4A) and Smad4 expression occur more frequently in IPMC alone, or with associated invasive carcinoma, compared with adenoma/borderline IPMT. Aberrant protein expression of these cell cycle regulatory genes in IPMT and pancreatic intraepithelial neoplasia in the current model of pancreatic cancer progression suggest similarities in their development and may also represent the subsequent risk of invasive carcinoma.
胰腺导管内乳头状黏液性肿瘤（IPMT）是一种独特的病理实体，其相关浸润性恶性肿瘤的总体发生率为20%。单个IPMT的恶性潜能无法准确预测。术前评估IPMT相关浸润性恶性肿瘤的风险将具有显著的临床益处。由于细胞周期调节基因的异常与胰腺导管前体病变向浸润性腺癌的进展相关，我们在一组接受手术切除的IPMT患者中检测了细胞周期蛋白D1/视网膜母细胞瘤途径和转化生长因子β/Smad4信号通路中关键细胞周期调节基因的表达。
对18例IPMT患者的福尔马林固定石蜡包埋胰腺组织切片进行免疫组织化学检查，以检测细胞周期调节基因p16（INK4A）、p21（CIP1）、p27（KIP1）、细胞周期蛋白D1、pRb和p53以及细胞信号分子Smad4的蛋白表达。对腺瘤/交界性IPMT（10例患者）和导管内乳头状黏液癌（IPMC）（8例患者，其中4例伴有浸润性癌）的表达水平进行比较。使用卡方检验和Fisher精确检验进行统计分析。
从腺瘤/交界性IPMT到IPMC，所检测蛋白质的异常表达频率增加。具体而言，IPMC中p16（INK4A）表达缺失的发生率显著更高：8/8个病变（100%），而腺瘤/交界性IPMT为1/10（10%）（p<0.001）。同样，Smad4表达缺失与IPMC相关：3/8（38%），而腺瘤/交界性IPMT为0/10（p<0.03）。IPMT内Smad4表达缺失是浸润性癌存在的最佳标志物（p<0.001）。
这些数据表明，与腺瘤/交界性IPMT相比，p16（INK4A）和Smad4表达缺失在单独的IPMC或伴有相关浸润性癌的情况下更频繁发生。在当前胰腺癌进展模型中，IPMT和胰腺上皮内瘤变中这些细胞周期调节基因的异常蛋白表达表明它们在发展过程中有相似之处，也可能代表随后发生浸润性癌的风险。
