Precursor lesions of pancreatic cancer

Abstract

This review article describes morphological aspects, gene abnormalities, and mucin expression profiles in precursor lesions such as pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and mucinous cystic neoplasm (MCN) of the pancreas, as well as their relation to pancreatic ductal adenocarcinoma (PDAC). The gene abnormalities in precursors of PDAC are summarized as follows: (1) KRAS mutation and p16/CDKN2A inactivation are early events whose frequencies increase with the dysplasia grade in both PanIN and IPMN; (2) TP53 mutation and SMAD4/DPC4 inactivation are late events observed in PanIN3 or carcinomatous change of IPMN in both PanIN and IPMN, although the frequency of the TP53 mutation is lower in IPMN than in PDAC; and (3) also in MCN, KRAS mutation is an early event whose frequency increases with the dysplasia grade, whereas TP53 mutation and SMAD4/DPC4 inactivation are evident only in the carcinoma. The mucin expression profiles in precursors of PDAC are summarized as follows: (1) MUC1 expression increases with the PanIN grade, and is high in PDAC; (2) the expression pattern of MUC2 differs markedly between the major subtypes of IPMN with different malignancy potentials (i.e., IPMN-intestinal type with MUC2+ expression and IPMN-gastric type with MUC2- expression); (3) MUC2 is not expressed in any grade of PanINs, which is useful for differentiating PanIN from intestinal-type IPMN; (4) de novo expression of MUC4, which appears to increase with the dysplasia grade; and (5) high de novo expression of MUC5AC in all grades of PanINs, all types of IPMN, MCN, and PDAC.

Keywords: Gene analysis; Intraductal papillary mucinous neoplasm; Mucin expression; Mucinous cystic neoplasm; Pancreatic ductal adenocarcinoma; Pancreatic intraepithelial neoplasia.

Fig. 1

Summary of various gene mutations and mucin expression profiles in precursor lesions (PanIN, IPMN, and MCN) and PDAC. Gene mutations are from various sources as described in the text. Expression profiles of mucins are from our data (references 5, 7, 99 and 102) and also from references 69, 101, 103 and 119. Data of sialyl-Tn in PanIN are from reference 103. Data of CD10 are from our data (reference 102). The rates of gene abnormalities in IPMN are described in categories of IPMN carcinoma and IPMN adenoma, respectively (a and b). The data of mucin expression in IPMN are described in categories of intestinal- and gastric-type IPMNs, and no data of carcinoma cases are included.

Fig. 2

Mechanism of DNA methylation related to gene silencing.

Fig. 3

Mechanism of histone modification related to gene silencing.

Fig. 4

Confirmation of epigenetic silencing of the MUC1 gene by a methylation inhibitor (5-aza-2'-deoxycytidine) and a histone deacetylase inhibitor (trichostatin A).

Fig. 5

Basic structure of mucin, and categories of membrane-associated mucin and secreted mucin.

Fig. 6

Different glycoforms of MUC1 and specific antibodies. MUC1 glycoform (left) is recognized by various antibodies (right). ^*MUC1/DF3 basically react with core peptide, but sialic acid (SA) modification might enhance the affinity [Siddiqui J et al., Proc Natl Acad Sci USA 1988;85:2320-2323].

Fig. 7

Scheme (upper side) and microscopic findings (lower side) of distribution of different glycoforms of MUC1 at acinar to intercalated duct area in normal pancreas. Poorly-glycosylated MUC1 (MUC1/CORE and MUC1/DF3) is expressed in intercalated duct and centroacinar cells (MUC1/CORE usually shows weak staining), whereas glycosylated MUC1 (MUC1/MY1E.12 and MUC1/HMFG-1) is expressed in the wider area including the luminal surface and zymogen granules of acinar cells (Original magnification of the microscopic images: ×70).

Fig. 8

Expression of sialyl-Tn, an aberrant form of the core-region carbohydrate chain, in PDAC (A) and IPMN (B) (Original magnification of microscopy images: A, ×130; B, ×30).

Fig. 9

MUC1 and MUC2 expression differed markedly between PDAC with invasive growth and poor prognosis and IPMN with expansive growth and favorable prognosis. MUC1/DF3 is expressed in PDAC but not in IPMN, whereas MUC2 is expressed in IPMN but not in PDAC) (Original magnification of microscopy images: PDAC, ×80; IPMN, ×30).

Fig. 10

Expression of MUC1 in PDAC was frequently observed at the lateral and/or basal membrane and in the cytoplasm as well as at the cell apices along the luminal side of the tubular structures, particularly in poorly differentiated PDAC (Original magnification of microscopy image: ×250).

Fig. 11

MUC4 is expressed in PDAC (upper side) but not in the nonneoplastic pancreas (lower side) (Original magnification of microscopy images: ×55).

Fig. 12

Malignant transformation of intestinal-type IPMN (A) and gastric-type IPMN (B). In intestinal-type IPMN (A), adenomatous lesion (left side) is changed to carcinoma (right side). In gastric-type IPMN (B), adenomatous lesion (left side) is changed to carcinoma (right side), which was diagnosed as "pancreatobiliary-type IPMN" by US and European experts in pancreas pathology (Original magnification of microscopy images: A and B, ×90). Reprinted from ref. 7 with permition.