IPMN tumour cells are usually tall columnar mucin-containing epithelial cells that line dilated ducts or cystic spaces arising from dilated branch ducts. The epithelium typically forms papillary or pseudopapillary structures, but portions of the neoplasm may be lined by non-papillary epithelium or be denuded of epithelium. The amount of mucin production varies widely, as does the degree of duct dilatation {97, 872}. Goblet or Paneth cells may be present as a manifestation of intestinal metaplasia in the neoplastic epithelium, and neuroendocrine cells have also been demonstrated.

The recently described intraductal onco-cytic papillary neoplasm probably represents a rare related phenotype that is similar macroscopically {1244, 1860}. Oncocytic IPMNs are composed of stratified oncocytic cells with pale pink cyto-plasmic granules that are much finer than those seen in Paneth cells. Goblet cells may be interspersed among the oncocytic cells. A characteristic feature of the oncocytic papillary neoplasms is the formation of 'intraepithelial lumina', which are spaces in the epithelium about one quarter the size of the cells.

Fig. 10.24 Intraductal papillary-mucinous neoplasm within the dilated main pancreatic duct and branch ducts.

Histochemistry and immunohistochemistry

A variety of abnormalities have been demonstrated in IPMNs using mucin and immunohistochemical stains. Most IPMNs express epithelial membrane antigen (EMA) as well as several cytokeratins {1917}. A variety of endocrine cell types occur in most tumours but account for fewer than 5 per cent of the tumour cells {1676}. A change in type of mucin has been suggested as a marker of progression since normal duct cells characteristically secrete sulfated mucin, intraductal papil-lary-mucinous adenomas characteristically secrete neutral mucin, and dysplas-tic epithelium secretes predominantly sialomucin {1138, 1916, 1186}. Nearly all IPMNs express MUC2 {2179}. Overexpression of c-erbB-2 protein occurs in a high fraction of IPMNs {1939, 1675, 1877, 380}.

A study of cell proliferation, as shown by PCNA and Ki67 labelling indices, demonstrated a progressive increase in cell proliferation from normal duct epithelium, to adenomas, to borderline tumours, to carcinomas {1917}. The labeling index in IPM carcinomas was lower than in ductal adenocarcinomas. Although immunostaining of p53 protein was detected in a lower fraction of IPMN (31%) than is usually seen in solid ductal adenocarcinomas, it was found only in borderline and malignant IPMN and therefore may be a marker of progression {1939}.

Failure of IPMN to elicit the production of a collagenase that mediates invasion was reported {2193}.

Classification and grading of IPMNs IPMNs have been the source of great confusion that is reflected in a diverse nomenclature found in case and series reports and in standard references {1781}. Because of the variability within a tumour, it is important to sample IPMNs well, giving special emphasis to papillary areas because this is where the highest degree of intraepithelial neoplasia (dysplasia) is likely to occur, and to sclerotic areas that may reflect invasion. IPMNs are classified as benign, borderline, or malignant on the basis of the greatest degree of dysplasia present. In accordance with the previous WHO classification, lesions are specifically designated as intraductal papillary-mucinous adenoma, borderline intraductal papil-lary-mucinous neoplasm, and intraductal papillary-mucinous carcinoma, with or without invasion {947, 1781}. A slightly different histopathological classification has been proposed by the Japan Pancreas Society (JPS) {65}, intraductal tumours are designated as intra-ductal papillary adenoma or adenocarci-noma. The degree of cellular atypia in adenomas is designated as slight, moderate, or severe. The JPS category of adenoma with severe atypia corresponds to the WHO borderline lesion, although some authors also utilize a borderline category {2148}

Intraductal papillary-mucinous adenoma

The epithelium is comprised of tall columnar mucin-containing cells that show slight or no dysplasia, i.e. the epithelium maintains a high degree of differentiation in adenomas.

Borderline intraductal papillary-mucinous neoplasm

IPMNs with moderate dysplasia are placed in the borderline category. The epithelium shows no more than moderate loss of polarity, nuclear crowding, nuclear enlargement, pseudostratification, and nuclear hyperchromatism. Papillary areas maintain identifiable stro-mal cores, but pseudopapillary structures may be present.

Intraductal papillary-mucinous carcinoma IPMNs with severe dysplastic epithelial change are designated as carcinoma even in the absence of invasion. Carcinomas are papillary or micropapil-lary. Cribriform growth and budding of small clusters of epithelial cells into the lumen support the diagnosis of carcinoma. Severe dysplasia is manifest cyto-logically as loss of polarity, loss of differentiated cytoplasmic features including diminished mucin content, cellular and nuclear pleomorphism, nuclear enlargement, and the presence of mitoses (especially if suprabasal or luminal in location). Severely dysplastic cells may lack mucin. Non-invasive lesions are termed non-invasive intraductal papil-lary-mucinous carcinoma. When invasive, an IPMN may be called a papillary-mucinous carcinoma since it is no longer only intraductal. When IPMNs become invasive, the invasive component may assume the appearance of a tubular ductal adenocarcinoma or a mucinous noncystic carcinoma {17}. If the invasive component is dominant, and is a ductal

Fig. 10.26 Intraductal papillary-mucinous carcinoma. This tumour shows moderately differentiated (left) and well differentiated (right) areas.

or mucinous noncystic carcinoma, then that diagnosis may be used, descriptively noting the association with an IPMN component.

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