Differences in Histologic Characteristics and Oncogenic Protein Expression of Intraductal Papillary Mucinous Neoplasm of Pancreas

Abstract

Introduction Intraductal papillary mucinous neoplasm (IPMN) and pancreatic intraepithelial neoplasia (PanIN) are precursors of pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to figure out the histologic characteristics of IPMN, and to document histologic and oncogenic uniqueness of IPMN according to the histologic configuration.

Methods Between January 2001 and December 2009, 98 patients with IPMN satisfying following conditions were analyzed: 1) a cyst of greater than 10mm at preoperative radiologic study, 2) main pancreatic duct dilatation exceeding 5mm at preoperative radiologic study, 3) pathologically diagnosed as IPMN after resection. In order to reassess 98 cases according to the histologic findings excluding the size of cyst, five histologic parameters were evaluated as follows, 1) histologic pattern, 2) glandular type, 3) dysplasia grade of epithelium, 4) transition of normal duct cells to tumor cells, and 5) mucin. With histologic criteria, initial pathologic diagnosis was classified into papillary and mucinous dominant (PM), tubular (T), and flat (F) IPMN. According to the invasiveness, those groups were also classified into noninvasive (NI) and invasive (INV) groups. The expressions of 11 oncogenic proteins (MUC1, MUC2, MUC5ac, SMAD4, S100A4, MSH2, APC, p53, p16, p21, and CD24) in IPMN were analyzed

Results Of the 98 consecutive, mean age was 64.5 years and 66.3% were male. Lesions were commonly found in pancreas head (52.0%) and mean cystic size was 33.0 mm in diameter. Main duct, branch duct, and mixed type of IPMN were found in 15.3%, 61.2%, and 23.5%, respectively. Curative resection was achieved in 94.6%. Of the 46 patients in invasive group, 43.5%, 17.4%, and 39.1% were reclassified as PM-INV, T-INV, and F-INV, respectively. In cellular types, PM-INV showed higher rate of intestinal subtype and T-INV noted pancreatobiliary or oncocytic subtype more frequently (p<0.001). In cystic portion, high rate of MUC1 expression (p=0.009) and APC loss (p=0.003) were noted in T-INV and F-INV. MUC2 was the major differentially expressed protein both in PM-NI and in PM-INV. In invasive portion, MUC2 expression was higher in PM-INV than T-INV and F-INV (p<0.001). MUC1 (p<0.001), SMAD4 loss (p<0.001), S100A4 (p=0.011), and p53 (p=0.029) showed higher expression in F-INV than PM-INV. In invasive group, F-INV showed poorer prognosis than PM-INV in terms of disease-specific survival (p=0.002) and recurrence free survival (p=0.046).

Conclusion We demonstrated that IPMNs with flat configuration were different from other types of IPMN in terms of expression of oncogenic protein and histologic characteristics. Flat IPMN showed unique characteristics sharing that of PanIN, and demonstrated poorer prognosis. Thus, flat IPMN can be regarded as PanIN, and this classification can provide clues to proper management of IPMN.