Rosty Christophe, Geradts Joseph, Sato Norihiro, Wilentz Robb E, Roberts Helen, Sohn Taylor, Cameron John L, Yeo Charles J, Hruban Ralph H, Goggins Michael
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.
Am J Surg Pathol. 2003 Dec;27(12):1495-501. doi: 10.1097/00000478-200312000-00001.
Patients with long-standing chronic pancreatitis are thought to be at increased risk of developing pancreatic ductal adenocarcinoma, but the mechanism for this increased risk is unknown. Since increasing evidence supports the notion that infiltrating pancreatic ductal adenocarcinomas arise from pancreatic intraepithelial lesions (PanINs), we sought to determine if patients with chronic pancreatitis harbor PanINs with alterations in tumor suppressor genes that are associated with infiltrating pancreatic ductal adenocarcinoma. We identified 122 patients with a diagnosis of chronic pancreatitis and 29 patients with a well-differentiated pancreatic endocrine tumor that underwent pancreatic surgery at the Johns Hopkins Hospital from 1985 to 1999. PanINs from each resection specimen were identified, graded, counted, and correlated with smoking and alcohol history. The expression patterns of p16 and Smad4 were determined in a subset of PanINs by immunohistochemistry, and the pattern of labeling compared with that seen in PanINs associated with infiltrating adenocarcinoma of the pancreas as identified in prior studies, and to PanINs associated with pancreatic endocrine tumor. Duct lesions were present in 80 of the 122 pancreata with chronic pancreatitis (66%). Of 405 duct lesions identified in the chronic pancreatitis group, 7.6% were reactive changes, 65.5% were PanIN-1A, 18% were PanIN-1B, 7.4% were PanIN-2, and 1.5% were PanIN-3. Within the pancreatic endocrine tumor group, 22 PanINs were identified: 15 PanIN-1A, 4 PanIN-1B, and 3 PanIN-2. There were significantly fewer high-grade PanINs in the pancreata with chronic pancreatitis than in pancreata with pancreatic adenocarcinoma (P < 0.0001). Within the chronic pancreatitis group, the 80 patients with PanINs were significantly older than the 42 patients without PanINs (mean age 57.0 +/- 14.1 years vs. 50.9 +/- 14.7 years, P = 0.01). Smoking history was not associated with PanIN prevalence or grade, but patients who reported a history of excessive alcohol consumption had fewer PanINs (25 of 44 harbored PanINs, 57%) than those who did not (54 of 74, 73%, P = 0.07). In the chronic pancreatitis group, 0% of PanIN-1A, 11% of the PanIN-1B, 16% of the PanIN-2, and 40% of the PanIN-3 lesions showed loss of p16 expression, whereas all of the PanINs from patients with an pancreatic endocrine tumor retained p16 expression. All of the PanINs analyzed from patients with chronic pancreatitis retained normal Smad4 expression. We conclude that a significant minority of PanINs arising in patients with chronic pancreatitis show loss of p16 expression. This alteration, common to pancreatic cancer-associated PanINs, may contribute to the predisposition of patients with chronic pancreatitis to develop pancreatic ductal adenocarcinoma.
长期慢性胰腺炎患者被认为患胰腺导管腺癌的风险增加，但其风险增加的机制尚不清楚。由于越来越多的证据支持浸润性胰腺导管腺癌起源于胰腺上皮内病变（PanINs）这一观点，我们试图确定慢性胰腺炎患者是否存在具有与浸润性胰腺导管腺癌相关的肿瘤抑制基因改变的PanINs。我们确定了1985年至1999年在约翰霍普金斯医院接受胰腺手术的122例慢性胰腺炎患者和29例高分化胰腺内分泌肿瘤患者。从每个切除标本中识别、分级、计数PanINs，并将其与吸烟和饮酒史相关联。通过免疫组织化学在一部分PanINs中确定p16和Smad4的表达模式，并将标记模式与先前研究中确定的与胰腺浸润性腺癌相关的PanINs以及与胰腺内分泌肿瘤相关的PanINs中观察到的模式进行比较。122例慢性胰腺炎胰腺中有80例存在导管病变（66%）。在慢性胰腺炎组中识别出的405个导管病变中，7.6%为反应性改变，65.5%为PanIN-1A，18%为PanIN-1B，7.4%为PanIN-2，1.5%为PanIN-3。在胰腺内分泌肿瘤组中，识别出22个PanINs：15个PanIN-1A，4个PanIN-1B和3个PanIN-2。慢性胰腺炎胰腺中的高级别PanINs明显少于胰腺腺癌胰腺中的高级别PanINs（P < 0.0001）。在慢性胰腺炎组中，有PanINs的80例患者明显比没有PanINs的42例患者年龄大（平均年龄57.0 +/- 14.1岁对50.9 +/- 14.7岁，P = 0.01）。吸烟史与PanINs的患病率或分级无关，但报告有过量饮酒史的患者的PanINs比没有过量饮酒史的患者少（44例中有25例有PanINs，57%对74例中有54例，73%，P = 0.07）。在慢性胰腺炎组中，0%的PanIN-1A、11%的PanIN-1B、16%的PanIN-2和40%的PanIN-3病变显示p16表达缺失，而胰腺内分泌肿瘤患者的所有PanINs均保留p16表达。从慢性胰腺炎患者分析的所有PanINs均保留正常的Smad4表达。我们得出结论，慢性胰腺炎患者中产生的一小部分PanINs显示p16表达缺失。这种改变是胰腺癌相关PanINs所共有的，可能导致慢性胰腺炎患者易患胰腺导管腺癌。
