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Large duct pattern of pancreatic ductal adenocarcinomas (PDACs) comprises occasional large cancer glands (0.5 mm in size), along with conventional smaller cancer glands. They histologically mimic intraductal papillary mucinous neoplasms. However, the clinicopathologic significance of PDACs with predominant large duct pattern (PLDP) has not been systematically evaluated. A total of 41 cases of PDACs with PLDP, which were defined as irregularly-shaped cancer glands0.5 mm in size occupied50% of tumor volume, were enrolled and their clinicopathological, immunohistochemical, and targeted exome-wise mutational characteristics were compared with 298 conventional PDACs. PDACs with PLDP had cancers with larger tumor sizes (P = 0.025), which were more frequently well to moderately differentiation (P 0.001), with less lymphovascular invasion (P = 0.013) and had a higher T category (P = 0.023) than conventional PDACs. Immunohistochemically, PDACs with PLDP showed similar abnormal p53 (61%) and SMAD4 (59%) expression patterns as conventional PDACs. In addition, PDACs with PLDP showed diffuse MUC1 (88%), MUC5AC (100%), MUC6 (66%), and focal MUC2 (20%) expressions. More frequent ROS1 mutations were observed in PDACs with PLDP. PDAC patients with PLDP had a better overall and recurrence-free survival (OS and RFS; median, 42 and 34 months) than that of patients with conventional PDACs (34 and 16 months) as per univariate (P = 0.037 and P = 0.001) and multivariate (P = 0.031 and P = 0.034) analyses. PDACs with PLDP showed mutational patterns similar to those of conventional PDACs. They had unique histologic features and longer OS and RFS compared to those of conventional PDACs. Therefore, PDACs with PLDP could be considered a histologic subtype of PDACs.

Summary Tumor budding (TB) in colorectal carcinoma (CRC) is related to epithelial-mesenchymal transition and has been recently characterized as an indicator of poor prognosis along with lymphovascular tumor emboli, perineural invasion, and an infiltrative growth pattern. Mutations in the genes of the Ras–mitogen-activated protein kinase and phosphatidylinositol-4,5-bisphosphate 3-kinase pathways are associated with epithelial-mesenchymal transition and an aggressive CRC phenotype and have been used in patient stratification for anti–epidermal growth factor receptor therapies; however, the impact of these mutations on CRC morphology and behavior remains unclear. In this study, using a multigene panel, we detected KRAS , NRAS , BRAF , PIK3CA , TP53 , and POLE mutations in 90 CRCs and investigated their associations with clinicopathological parameters, including TB. Our results showed that 21 of 34 tumors with high-grade TB had KRAS mutations ( P =.001) and KRAS G12D and PIK3CA exon 9 variants were significantly associated with high-grade TB ( P =.002 and .006, respectively); furthermore, tumors with KRAS mutations in exons 3 and 4 tended to have lymphovascular tumor emboli and perineural invasion ( P =.044 and .049, respectively). PIK3CA exon 9 mutations indicated a tendency for shorter disease-free survival ( P =.030), whereas BRAF mutations were associated with extracellular mucin deposition ( P =.016). Our study revealed a correlation of KRAS mutations with high-grade TB, an association of certain KRAS and PIK3CA variants with aggressive clinicopathological features, as well as a possible relationship between BRAF mutations and mucin production in CRC.

The present study aimed to elucidate whether the stemness molecule, CD133, is expressed in well-differentiated pancreatic neuroendocrine tumors (PanNETs; World Health Organization grades 1 and 2) and establish its clinical relevance using 2 separate cohorts. In the first series (n = 178) in which tissue microarrays were available, immunohistochemistry revealed that CD133 was expressed in 14 cases (8%). CD133+ PanNETs had higher TNM stages (P < .01), more frequent lymphovascular invasion (P = .01), and higher recurrence rates (P = .01). In the second cohort (n = 56), the expression of CD133 and CK19 was examined in whole tissue sections. CD133 and CK19 were positive in 10 (18%) and 36 (64%) cases, respectively. CD133 expression correlated with higher pT scores (P < .01), the presence of microscopic venous infiltration (P = .03), and shorter disease-free periods (P < .01). When cases were divided into grade 1 and 2 neoplasms, patients with CD133+ PanNET continued to have shorter disease-free periods than did those with CD133- tumors in both groups (P < .01 and P = .02, respectively). Although CK19+ cases had shorter disease-free periods than did CK19- cases in the whole cohort (P = .02), this difference was less apparent in subanalyses of grade 1 and 2 cases. CD133 expression also appeared to be an independent predictive factor for tumor recurrence in a multivariate analysis (P = .018). The CD133 phenotype was identical between primary and metastatic foci in 17 of 18 cases from which tissues of metastatic deposits were available. In conclusion, the combination of CD133 phenotyping and World Health Organization grading may assist in stratifying patients in terms of the risk of progressive clinical courses.

Identifying the accurate origin of periampullary cancers is important because different origins may trigger different clinicopathological behaviors. The presence of intraepithelial precursor lesions, including high-grade pancreatic intraepithelial neoplasias (PanINs) and/or high-grade biliary intraepithelial neoplasias (BilINs), may be suggestive of the origin of the periampullary carcinoma in challenging cases. To prove the usefulness of high-grade intraepithelial precursor lesions in identifying the origin of ambiguous periampullary cancers, the status and grades of PanINs and BilINs were evaluated in 256 periampullary carcinomas with a well-defined cancer origin as a test set, including 114 pancreatic cancers, 82 distal bile duct cancers, 54 ampullary cancers, and 6 duodenal cancers. One hundred twelve periampullary carcinomas with clinically equivocal epicenter either by radiologic imaging or by endoscopic finding used as a validation set. High-grade PanINs were found more commonly in pancreatic cancers than in distal bile duct, ampullary, and duodenal cancers both in test (P = .002) and validation sets (P < .001). Similarly, high-grade BilINs were identified more frequently in distal bile duct cancers than in ampullary, pancreatic, and duodenal cancers both in test (P < .001) and validation sets (P = .039). High-grade PanINs were found most commonly in pancreatic cancers, whereas high-grade BilINs were seen most frequently in distal bile duct cancers. In addition, both high-grade PanINs and high-grade BilINs are uncommonly noted in ampullary or duodenal cancers. The recognition of high-grade intraepithelial lesions can help identify the primary origin of periampullary cancers, especially when the epicenter of the periampullary cancer is ambiguous.

Granular cell tumors (GCTs) are uncommon benign neoplasms in the gastrointestinal (GI) tract, and our current understanding of GCT in GI tract is limited. A total of 98 GCTs were retrieved from 95 patients, and the clinicopathological and immunohistochemical features were compared. The male-to-female ratio was 2.2:1 and with a mean age of 49 years. The mean tumor size was 0.37 cm. Seventy-three esophageal (75%), 21 colorectal (21%), and 4 gastric (4%) GCTs were included. Gastric (mean, 0.75 cm) and colorectal (0.6 cm) GCTs were significantly larger than esophageal tumors (0.27 cm; P

A better molecular characterization of intraductal papillary mucinous neoplasm (IPMN), the most frequent cystic precursor lesion of pancreatic adenocarcinoma, may have a pivotal role in its early detection and in the development of effective therapeutic strategies. BRG1, a central component of the chromatin remodeling complex SWI/SNF regulating transcription, is inactive in several malignancies. In this study, we evaluate the Brg1 expression in intraductal papillary mucinous neoplasm to better understand its role in the pancreatic carcinogenesis. Tissue microarrays of 66 surgically resected IPMNs were immunolabeled for the Brg1 protein. Expression patterns were then correlated with clinicopathologic parameters. Normal pancreatic epithelium strongly immunolabeled for Brg1. Reduced Brg1 expression was observed in 32 (53.3%) of the 60 evaluable IPMN lesions and occurred more frequently in high-grade IPMNs (13 of 17 showed loss; 76%) compared to intermediate-grade (15 of 29 showed loss; 52%) and low-grade IPMNs (4 of 14 showed loss; 28%) (P = .03). A complete loss of Brg1 expression was observed in 5 (8.3%) of the 60 lesions. Finally, a decrease in Brg1 protein expression was furthermore found in a low-passage noninvasive IPMN cell line by Western blot analysis. We did not observe correlation between Brg1 expression and IPMN subtype or with location of the cyst. We provide first evidence that Brg1 expression is lost in noninvasive cystic precursor lesions of pancreatic adenocarcinoma.

Small intestinal adenocarcinoma is a rare malignant neoplasm, and its clinicopathologic characteristics have not been well elucidated. A total of 197 small intestinal adenocarcinoma cases were collected from 22 institutions in South Korea and were evaluated for clinicopathologic factors that affect the prognosis of small intestinal adenocarcinoma patients using univariate and multivariate analyses. The mean patient age was 59 years, and the male-to-female ratio was 1.7:1. Tumors were located in the duodenum of 108 cases (55%), the jejunum in 59 (30%), and the ileum in 30 (15%). Predisposing conditions were observed in 23 cases (12%), including 17 cases with sporadic adenomas, 3 with Peutz-Jeghers syndrome, 2 with Meckel diverticulum, and 1 with Crohn disease. Synchronous or metachronous malignant tumors were identified in 31 cases (16%), including 13 colorectal and 10 stomach cancers. About 90% of tumors were classified as either pT3 (63 cases) or pT4 (112 cases). The median survival time for all small intestinal adenocarcinoma patients was 39.7 months. Compared with small intestinal adenocarcinomas without accompanying sporadic adenomas, small intestinal adenocarcinomas with accompanying adenomas were more well differentiated (P < .0001), with a more polypoid growth pattern (P < .0001), a lower pT classification (P < .0001), less perineural invasion (P = .01), and less lymphatic invasion (P = .03). Small intestinal adenocarcinoma patients with associated sporadic adenomas (77%) had a significantly better 5-year survival rate than those without sporadic adenomas (38%, P = .02). By univariate analysis, small intestinal adenocarcinoma patients had significantly different survival based on pT classification (P = .003), lymph node metastasis (P < .0001), distal location (jejunal and ileal carcinomas) (P = .003), retroperitoneal tumor seeding (P < .0001), vascular invasion (P = .007), lymphatic invasion (P = .001), peritumoral dysplasia (P = .004), and radiation therapy (P = .006). By multivariate analysis, lymph node metastasis (P = .01) and distal location (P = .003) were independent predictors of a worse prognosis. In conclusion, (1) small intestinal adenocarcinomas are diagnosed at an advanced disease stage; therefore, the development of strategies for detection at an earlier stage is needed. (2) Small intestinal adenocarcinoma patients with an adenomatous component had a better survival than those without an adenomatous component. (3) Lymph node metastasis and distal location (jejunum and ileum) of tumor are the most important independent prognostic factors.

Micropapillary carcinoma (MC) has been well described in other organs, including breast, urinary bladder, lung, ovary, and salivary gland, but has not been described in the large intestine. We compared the clinicopathologic and immunohistochemical findings of MC with those of conventional adenocarcinoma in the large intestine. Fifty-five cases of adenocarcinoma with an MC component were identified among 585 consecutive cases of colorectal cancer at the Asan Medical Center between January 2003 and June 2004 and were compared with 119 cases of conventional adenocarcinoma of colorectum without an MC component. Arrayed tissue blocks were constructed and immunostained for cytokeratin 7 and 20 and CDX2. We also compared the results of MLH-1, MSH-2, p53, and carcinoembryonic antigen immunostainings between the 2 groups. The grade of both MC and conventional adenocarcinoma was mostly moderately differentiated. The proportion of MC ranged from 5% to 80%. The presence but not extent of MC in the primary tumors was associated with more frequent lymphovascular invasion and lymph node (LN) metastases, a greater mean number of positive LNs, and a higher tumor stage with more frequent distant metastases, compared with conventional adenocarcinoma (P < .05). Cytokeratin 7 staining was occasionally observed in both MC (9.1%, 5/55 cases) and conventional adenocarcinoma (13.4%, 16/119 cases). Although MLH-1 and CDX2 expression tended to be lower in conventional adenocarcinoma, none of the immunohistochemical results was significantly different between 2 groups. Recognition of MC component is important as MC appeared to be an aggressive variant of colonic adenocarcinoma and presented at a higher stage, with frequent lymphovascular invasion, LN metastasis, and distant metastasis, compared with conventional adenocarcinoma. The proportion of MC component did not impact the prognosis, and the immunoprofiles of MC were not significantly different from those of conventional adenocarcinoma.

Neuroendocrine differentiation is known to be one of the prognostic factors in many carcinomas. However, the characteristics of neuroendocrine differentiation are not well elucidated in extrahepatic bile duct (EBD) carcinomas. One hundred ninety-four cases of EBD carcinomas were analyzed using immunohistochemistry with synaptophysin and chromogranin. The tumors were graded as degree 0, 1, and 2 when the positive tumor cells were 5% or less, 6% to 25%, and 26% or more, respectively. Immunohistochemical results were compared with clinicopathologic variables and survival rate. Synaptophysin and chromogranin were positive in 54 (27.8%) and 74 (38.1%) cases, respectively. Thirty-four cases (17.5%) were positive for both synaptophysin and chromogranin, 20 (10.3%) and 40 cases (20.6%) were positive only for synaptophysin and for chromogranin, respectively, and 100 cases (51.6%) were negative for both markers. There was a significant survival difference between overall synaptophysin-positive (median, 27 months) and synaptophysin-negative (38 months) groups (P < .05). However, there was no survival difference between chromogranin-positive and chromogranin-negative groups. There was a significant survival difference between the dual-positive expression to synaptophysin and chromogranin group (median, 21 months) and the dual-negative expression group (median, 35 months; P < .05). In summary, synaptophysin expression was an important prognostic factor because synaptophysin-positive cases showed a worse prognosis than synaptophysin-negative cases. The more tumor cells expressed chromogranin, the poorer the survival. Therefore, immunohistochemical studies for neuroendocrine differentiation may be helpful in routine pathological examinations for evaluating the survival and the prognosis of patients with EBD carcinomas.

The T classification for pancreatic cancer of the American Joint Committee on Cancer may be inaccurate owing to lack of consideration of tumor size in cases of extension beyond the pancreas. To examine the accuracy of American Joint Committee on Cancer staging and to determine the prognostic implication of combined tumor size and extrapancreatic extension, 6145 cases of pancreatic ductal adenocarcinomas from the Surveillance, Epidemiology, and End Results database were categorized according to tumor size and extension as follows: group 1 (G1, ≤2 cm and limited to the pancreas), G2 (>2 cm and limited to the pancreas), G3 (≤2 cm with extrapancreatic extension), and G4 (>2 cm with extrapancreatic extension). The median survival of G1, G2, G3, and G4 were 23, 15, 19, and 14 months, respectively (P < .001), and the survival time in G3 was closer to that of G2 than G4. To test the classification system for accuracy of prognosis, G3 was merged with G2. The survival discrimination of this new grouping was greater (overall comparison, P < .001; G1 versus G2 + G3, P < .001; G2 + G3 versus G4, P < .001; χ(2) = 92.043) than that of the current T-classification scheme (overall comparison, P < .001; G1 versus G2, P < .001; G2 versus G3 + G4, P = .048; χ(2) = 60.424). To better discriminate survival, patients with a tumor less than or equal to 2 cm extending beyond the pancreas should be downstaged from the current class T3 to class T2.

Solid pseudopapillary neoplasms (SPNs) are rare tumors of the pancreas characterized by poorly cohesive uniform cells with solid and pseudopapillary growth patterns. Nuclear pleomorphism is not a well-recognized feature of SPNs and may complicate differentiation from other pancreatic neoplasms. We compared histologic, immunohistochemical, and clinical features of 18 pleomorphic SPNs with 121 conventional SPNs. The prevalence of pleomorphic SPN was 12.9% (18/139). Pleomorphic SPNs arose in older patients (median, 45 years versus 32 years; P < .001), but no differences were found in sex, tumor location, recurrence, and metastasis when compared with conventional SPNs. Except for pleomorphic nuclei, other cytologic and histologic features of pleomorphic SPNs, such as growth pattern, tumor size, infiltrative pattern, tumor extension, mitosis, and Ki-67 labeling index, were not different from those of conventional SPNs. Pleomorphic SPNs showed a significantly higher p53 protein expression (64.7% [11/17 cases]) than that of conventional SPNs (1.8% [2/112 cases], P < .001). However, immunoreactivity for β-catenin and E-cadherin was not different between pleomorphic and conventional SPNs. A TP53 gene mutation was observed in 2 of 3 p53-immunoreactive pleomorphic SPNs. In summary, nuclear pleomorphism occurs in a subset of SPNs. They are more often p53 immunoreactive than SPNs without pleomorphism, and some harbor TP53 gene mutations. However, pleomorphic SPNs do not appear to be more aggressive than conventional SPNs. Low mitotic rate and Ki-67 labeling index may suggest nuclear pleomorphisms as degenerative changes. Recognition of typical poorly cohesive tumor cells and immunohistochemical features could establish the correct diagnosis of SPNs.