Prognostic significance of maspin in pancreatic ductal adenocarcinoma: tissue microarray analysis of 223 surgically resected cases

Modern Pathology (2007) 20, 570–578 & 2007 USCAP, Inc All rights reserved 0893-3952/07 $30.00 www.modernpathology.org Prognostic significance of maspin in pancreatic ductal adenocarcinoma: tissue microarray analysis of 223 surgically resected cases Dengfeng Cao1, Qian Zhang2, Lee Shun-Fune Wu3, Safia N Salaria1, Jordan W Winter4, Ralph H Hruban1,5,6, Michael S Goggins1,6, James L Abbruzzese2, Anirban Maitra1,5,6 and Linus Ho2 1 Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA; 2Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA; 3 School of Public Health Department of International Health, The Johns Hopkins Medical Institutions, Baltimore, MD, USA; 4Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, MD, USA; 5 Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA and 6The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD, USA Maspin (SERPINB5), a serine proteinase inhibitor, was first identified as a potential tumor suppressor on the basis of its differential expression between normal mammary epithelial cells and human breast carcinoma cell lines. Recent studies have shown that maspin might be a prognostic tumor marker. Pancreatic ductal adenocarcinoma acquires maspin expression through hypomethylation of the maspin promoter. However, no study has investigated the prognostic significance of maspin expression in pancreatic ductal adenocarcinomas. In this study, we investigated maspin protein expression in a large series of 223 surgically resected pancreatic ductal adenocarcinomas using immunohistochemical staining and high throughput tissue microarrays. Maspin expression was correlated with postoperative survival and other clinicopathologic factors. Maspin was detected in 209 of these 223 (94% cases) pancreatic ductal adenocarcinomas including 39 (18% cases) focal (5–50% tumor cells) and 170 (76% cases) diffuse (450% tumor cells). Fourteen (or 6% cases) pancreatic ductal adenocarcinomas did not show maspin expression by immunohistochemical staining (o5% tumor cells). Normal ductal epithelium is not labeled with maspin. Overexpression of maspin in pancreatic ductal adenocarcinoma is associated with worse postoperative survival especially in patients whose tumors exhibit diffuse expression of maspin. After adjusting other clinicopathologic factors, maspin expression remains to be an independent adverse prognosticator for postoperative survival. Maspin expression is not associated with patient age, gender, tumor size, tumor pathologic stage, lymph node status, and vascular invasion or perineural invasion. Nuclear labeling of maspin is associated with better tumor differentiation although this staining pattern is not associated with a better prognosis. In addition, maspin overexpression is also observed in 48% low-grade (grades 1a and 1b) pancreatic intraepithelial neoplasias (PanINs) and 78% high-grade (grades 2 and 3) PanINs, suggesting that maspin upregulation occurs early during the multi-step progression model of pancreatic ductal adenocarcinoma. Modern Pathology (2007) 20, 570–578. doi:10.1038/modpathol.3800772; published online 30 March 2007 Keywords: maspin; immunohistochemistry; prognosis; survival; pancreatic ductal adenocarcinoma Correspondence: Dr D Cao, MD, PhD, Division of Surgical and Gynecologic Pathology, Department of Pathology, The Johns Hopkins Medical Institutions, Weinberg 2242, 401 North Broadway, Baltimore, MD 21231, USA. E-mail: Received 20 November 2006; revised 22 January 2007; accepted 29 January 2007; published online 30 March 2007 Pancreatic ductal adenocarcinoma is the fourth leading cause of cancer death in the US and about 32 300 patients will die from this disease in 2006.1 The vast majority of patients with pancreatic ductal adenocarcinoma present with advanced non-resectable disease because of the lack of sensitive and specific tools to screen for early disease. Unfortunately non-surgical treatments such as chemo- Novel markers in pancreatic cancer D Cao et al 571 therapy, radiation therapy, and immunotherapy are minimally effective for these patients.2 The development of early detection and novel treatment strategies are the keys to improve prognosis. A better understanding of pathogenesis of this cancer at the molecular level including identification and characterization of novel genes involved in the pathogenesis are essential to achieve these goals. Several recent studies have shown that a novel gene, maspin, is overexpressed in the vast majority of pancreatic ductal adenocarcinomas but not in normal ductal epithelium.3,4 Maspin (SERPINB5), a serine proteinase inhibitor, was first identified as a potential tumor suppressor on the basis of its differential expression between normal mammary epithelial cells and human breast carcinoma cell lines.5 Several studies have demonstrated that maspin might be a prognostic tumor marker. For example, high expression of maspin has been reported to be associated with a better prognosis in oral squamous cell carcinoma,6 thyroid carcinoma,7 colon adenocarcinoma8 and prostate adenocarcinoma,9 whereas in breast carcinoma,10 maspin expression was associated with a poor prognosis. The data on lung carcinomas11–13 and ovarian epithelial carcinomas14–16 have been conflicting. Although it has been demonstrated that human pancreatic ductal adenocarcinoma acquired maspin expression through hypomethylation of the maspin promoter,17,18 little is known about the prognostic significance of maspin protein expression in human pancreatic ductal adenocarcinoma. In this study, we investigated maspin protein expression in a large series of 223 surgically resected pancreatic ductal adenocarcinomas using immunohistochemical staining and high throughput tissue microarrays (TMAs). All these 223 patients underwent resection (pancreatoduodenectomy, distal pancreatectomy, or total pancreatectomy) at The Johns Hopkins Hospital between 1998 and 2003. We correlated maspin expression with postoperative survival as well as other clinicopathologic factors such as patient age, tumor size, tumor differentiation, pathologic stage, lymph node status, vascular invasion, and perineural invasion. Materials and methods Permission to perform this study was obtained from The Johns Hopkins Institutional Review Board. Patient Selection A total of 223 patients who had surgery (Whipple procedure, distal pancreatectomy, or total pancreatectomy) performed at The Johns Hopkins Hospital for primary invasive pancreatic ductal adenocarcinoma between 1998 and 2003 (five cases in 2003) were included in this study. Clinicopathologic factors were obtained from patients’ electronic medical record. The follow-up information was obtained either from the electronic medical record and/or hospital tumor registry. Of the 223 patients, 116 were men and 10 (...truncated)