Although general characteristics of intraductal papillary mucinous neoplasms (IPMNs) and their delineation from other pancreatic tumors have been well established, several issues regarding their biology and management remain unresolved. It has been noted briefly by us and other authors that there are different types of papillae in IPMNs; however, their frequency, biologic significance, and clinical relevance are unknown. In this study, the association of different papillary patterns with clinical, pathologic, and biologic parameters was studied in 74 IPMNs, and the expression profile of CDX2 (a specific marker and one of the key determinants of intestinal "programming," and a tumor suppressor) was determined immunohistochemically in addition to MUC1 (a marker of an "aggressive" phenotype in pancreatic neoplasia) and MUC2 ("intestinal type mucin," a marker of the "indolent" phenotype, and a tumor suppressor). The patterns of papillae identified and their association with these parameters were as follows: 1) The intestinal-type (Yonezawa's dark-cell type), similar to villous adenomas, was seen in 26 of 74 (35%) cases. The majority harbored carcinoma in situ (85%) or borderline atypia (15%). They tended to be large (mean, 5.5 cm). Most expressed CDX2 (95%) and MUC2 (92%) but not MUC1 (8%). This type was more commonly associated with colloid-type invasion (14 of 16 invasive carcinomas were of colloid type). 2) The pancreatobiliary type, characterized by arborizing papillae lined by cuboidal cells resembling papillary neoplasms of the biliary tract, was present in 22% of the cases. These were mostly graded as carcinoma in situ (94%); they rarely expressed CDX2 (6%) or MUC2 (19%) but often showed MUC1 labeling (44%). This pattern was more commonly associated with the tubular type of invasive carcinoma and had a slight tendency for a more aggressive clinical course. 3) The null type was characterized by abundant apical mucin and basally located nuclei, similar to the gastric foveolar epithelium. Thirty-one percent of IPMNs had this type of papillae, but this pattern was also present in the background of other IPMNs and in the cystic components of most cases as well. Most pure null-type IPMNs were devoid of complexity and consequently classified as adenoma (48%). They tended to be small (mean, 2.6 cm), were often negative for CDX2, MUC1, and MUC2, and were rarely associated with invasive carcinoma. 4) Some IPMNs (12%) exhibited features that were difficult to classify, and 2 cases had a mixture of pancreatobiliary and intestinal types of papillae. In conclusion, IPMNs include pathologically and biologically distinct epithelial patterns. CDX2 and MUC2 expression is relatively specific for the intestinal type papillae, confirming that these IPMNs indeed exhibit intestinal differentiation. Their close association with colloid carcinoma, which also shows consistent MUC2 and CDX2 expression, supports the existence of an intestinal pathway of carcinogenesis. This "metaplastic" pathway may reflect different genetic events in th...

Emerging evidence suggests a dichotomy in the dysplasia-CIS-invasive carcinoma sequence in the pancreas. Pancreatic intraepithelial neoplasms (PanINs; small, incidental duct lesions) progress to invasive ductal adenocarcinomas (5-y survival of <15%), whereas intraductal papillary mucinous neoplasms (large, intraductal tumors with ductal dilatation) are often associated with colloid carcinoma (5-y survival of >55%). We explored the relationship of these lesions by examining the expression of MUC1 and MUC2, glycoproteins reportedly reflecting "aggressive" and "indolent" phenotypes in pancreas cancer, respectively. Immunohistochemical labeling with MUC1 (clone Ma695) and MUC2 (clone Ccp58) antibodies was performed on PanINs (n ‫؍‬ 43), intraductal papillary mucinous neoplasms (n ‫؍‬ 74), ductal adenocarcinomas (n ‫؍‬ 136), and colloid carcinomas (n ‫؍‬ 15). Fifty-four percent of the intraductal papillary mucinous neoplasms expressed MUC2, whereas none of the PanINs did. In contrast, PanINs, especially higher grade lesions, were often positive for MUC1 (61% of PanIN 3), whereas the expression of this glycoprotein was infrequent in intraductal papillary mucinous neoplasms (20%). This dichotomy was further accentuated in the invasive carcinomas with which these two preinvasive pathways are respectively associated: all colloid carcinomas were MUC2؉ (100%) and MUC1؊ (0%), whereas the labeling pattern was the reverse for ductal adenocarcinomas: 63% were MUC1؉ and only 1% were MUC2؉. These results support a dichotomy in the dysplasia-CIS sequence in the pancreas. Because these two pathways often lead to different types of invasive carcinomas, this is an invaluable model for the study of carcinogenesis. The findings here also support the previous impression that MUC2 (the mucin associated with gel formation) is a marker of the "indolent" pathway (intraductal papillary mucinous neoplasm and colloid carcinoma), whereas MUC1 (the glycoprotein known to have an inhibitory role in cell-cell and cell-stroma interactions as well as in immunoresistance of tumor cells) is a marker of the "aggressive" pathway (PanIN to ductal adenocarcinoma). The vast majority of pancreatic neoplasms are ductal adenocarcinomas, characterized morphologically by invasive tubular units that are often associated with a dense desmoplastic stroma. Ductal adenocarcinomas are among the most lethal cancers, with an overall 5-year patient survival rate of Ͻ5% (1-3). As is true for other epithelial malignancies, ductal adenocarcinomas are believed to arise from morphologically distinct precursor lesions (4 -12). A uniform nomenclature and standardized diagnostic criteria for these precursor lesions have recently been adopted, and the accepted terminology is now pancreatic intraepithelial neoplasia (PanIN; 13). KEY WORDS: Carcinogenesis

We describe 5 cases (4 males, 14-43 years old; 1 female, 61 years old) of primary cutaneous T-cell lymphoproliferative lesions expressing a CD8/granzyme/CD30-positive phenotype. Four cases were compatible with lymphomatoid papulosis (LyP) based on the clinical course, which was recurrent asymptomatic papular nodular lesions over years responding to methotrexate; granulomatous inflammation and lack of other inflammatory cell elements were characteristic. In 1 case, an initial erroneous diagnosis was made of aggressive epidermotropic CD8+ T-cell lymphoma. The fifth case in this series was first interpreted as representing primary cutaneous anaplastic large cell lymphoma but was later recategorized as primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma owing to the extent of extracutaneous dissemination, including testicular involvement and disease progression despite chemotherapeutic intervention. Although all cases of LyP showed sharp cytoplasmic membrane staining with perinuclear Golgi accentuation with CD30, the recategorized case of aggressive epidermotropic CD8 cytotoxic T-cell lymphoma manifested only a weak cytoplasmic staining pattern. CD8 LyP defines a distinctive entity with characteristic light microscopic and phenotypic findings and has a predilection for young males. CD30 expression can occur in other forms of CD8 lymphoproliferative disease unrelated to primary cutaneous anaplastic large cell lymphoma or LyP.

Despite the exceedingly poor prognosis of pancreatic cancer, it is often histologically well to moderately differentiated. The apparent resistance to conventional therapeutic modalities is poorly understood and may be related to the molecules involved in its progression or its propensity for perineurial invasion. Cyclooxygenase-2 (COX-2) is an inducible enzyme homologous to COX-1 that is responsible for production of prostaglandins at sites of inflammation. It is activated by a variety of growth factors and tumor promoters, and it has been implicated in cancer progression. It may also have a role in the resistance to therapy. Anti-COX-2 agents have been documented to have antitumor activity, and some are now being tested in the therapy for various cancers, including those of the pancreas. Experience regarding the rate of COX-2 expression in pancreatic cancer and its relationship to the clinical and biologic parameters is very limited. In this study, immunohistochemical stains for COX-2 have been performed on 120 cases of pancreatic ductal adenocarcinoma. The stains were scored according to the percentage (0: no staining, 1: < 10%, 2: 10-50%, and 3: >50% of the cells staining) and intensity (0 for no staining, 1 for mild staining, and 2 for dark staining) of staining. Based on the combined score for each case, they were divided into low expressors (percentage and intensity < or =1) and high expressors (percentage or intensity >1). In addition to global scoring for each case, the glandular and solid (poorly differentiated) components, when present, were scored separately. The global scores were correlated with clinical and biologic parameters. Seventy-four percent of the cases exhibited expression of COX-2 and 53% were high expressors. No significant association was observed when comparing the global COX-2 expression to survival, tumor size, stage, and vascular invasion. Increased perineural invasion was found to be significantly associated with COX-2 expression (p < 0.05). Increased expression was also more common in the glandular component as compared with the solid component of the tumors (68% versus 35%, p < 0.05). Of the 34 patients who received radiotherapy, 9 were low expressor (median survival 19.5 months) and 25 were high expressors (median survival 14 months). The difference in survival was not statistically significant.