Prognostic implications of BAX protein expression and microsatellite instability in all non-metastatic stages of primary colon cancer treated by surgery alone.

PURPOSE: This study examined whether the apoptosis-related protein, BAX, or the microsatellite-instability phenotype provide prognostic information in patients with resected colon cancer. METHODS: A total of 371 stage I-III patients that previously underwent radical surgery were included (mean follow-up 51.8 months). BAX expression was examined by immunohistochemical staining; high-frequency microsatellite instability (MSI+) was determined by assessing the specific marker, BAT26, using single-strand conformation polymorphism (SSCP)-based analysis. RESULTS: High BAX expression was found in 66.4% of patients. MSI+ tumors were observed in 14.8% of 344 patients. Univariate analysis showed that unlike MSI, low BAX expression was significantly correlated with poor disease-specific overall survival (OS) in stages I-III (p = 0.04). Multivariate subgroup analyses revealed that unlike MSI, low BAX was an independent predictor for OS in stage II (p = 0.009); however, in stages I or III, BAX or MSI were not independent predictors of OS. CONCLUSIONS: In stage II colon cancer treated with surgery alone, BAX protein expression may be a predictor for prognosis.

Cytokeratin 7/20 and mucin core protein expression in ulcerative colitis-associated colorectal neoplasms.

Different histogenetic pathways have been suggested between ulcerative colitis (UC)-associated neoplasia and sporadic colorectal neoplasia. Little is known about the cytokeratin (CK) and mucin expression in UC-associated neoplasms. To clarify the characteristics of UC-associated colorectal carcinogenesis, we examined the immunohistochemical expression of CK7, CK20, MUC2, MUC5AC and MUC6 in 90 colorectal neoplasms, including 22 UC-associated adenocarcinomas (colitic cancer; CC), ten high-grade dysplasias (HGD) in UC, nine low-grade dysplasias (LGD) in UC, 24 sporadic tubular adenomas (TA) and 25 adenocarcinomas (AC). CK7 was positive in most of UC-associated neoplasms: 59% of CC cases, 80% of HGD and 89% of LGD, respectively, whereas, in non-UC associated neoplasia, 21% of TA and 12% of AC. The frequency of MUC6 expression in UC-associated neoplasia was 32% in CC, 30% in HGD and 44% in LGD, respectively, whereas, in non-UC associated neoplasia, 4.2% in TA and 0% in AC. MUC5AC expression in UC-associated neoplasia was detectable in 73% of CC, 90% of HGD and 89% of LGD, respectively; in non-UC associated neoplasia 67% in AC and 20% in TA. There were obvious differences in the expression of CK7 and MUC6 between UC-associated neoplasms and sporadic tumors. The incidence of MUC5AC expression in UC-associated neoplasms was also higher than sporadic tumors. These results suggest that gastric-type mucins play an important role in the initial step of CC-tumorigenesis, and CK7 and gastric-type mucins may be useful in the differential diagnosis between UC-associated neoplasms and sporadic ones.

Low BAX protein expression correlates with disease recurrence in preoperatively irradiated rectal carcinoma.

PURPOSE: To determine the prognostic impact of BAX in correlation to its upstream effector p53 as well as clinicopathologic variables and patient outcome in preoperatively irradiated rectal carcinoma. METHODS AND MATERIALS: We investigated 92 rectal carcinoma patients treated by preoperative radiotherapy to a total dose of 30 Gy followed by surgery. Median follow-up was 71 months. Immunohistochemistry was performed on paraffin sections of pretreatment biopsy samples for BAX protein. Also, we considered the previously determined p53 expression data from this cohort. RESULTS: BAX protein expression was classified as high and low in 63 (68.5%) and 29 (31.5%) tumors, respectively. Unlike clinicopathologic variables, high BAX expression was significantly associated with improved disease-free survival by univariate analysis (p = 0.048). Moreover, in multivariate analyses, high BAX expression was an independent prognostic indicator for both improved local recurrence-free interval and improved disease-free survival (p = 0.03 and 0.047, respectively). Concerning the p53/BAX pathway, subgroup analysis yielded no association between p53 immunonegative/BAX high vs. p53 immunopositive/BAX low expressing tumors with regard to overall, disease-free, or local recurrence-free survival in either univariate (p = 0.88, 0.54, and 0.16, respectively) or multivariate analysis. CONCLUSIONS: This study demonstrates that BAX protein expression might help to predict disease recurrence in preoperatively irradiated rectal carcinoma, whereas determination of p53, the proposed upstream regulator of BAX-induced apoptosis, did not provide additional prognostic information.

Pyloric gland adenoma arising in Barrett's esophagus with mucin immunohistochemical and molecular cytogenetic evaluation.

Pyloric gland adenoma is a recently described and very rare entity. The occurrence of adenoma is very unusual in Barrett's epithelium of the esophagus. We report a case of esophageal polyp showing the features of pyloric gland adenoma, which was surrounded by so-called specialized columnar epithelium. Immunohistochemically, most tumor glands were strongly positive for MUC6, except in the superficial layer. MUC5AC was positive in almost all tumor cells, but MUC2 and CD10 were negative in the tumor. MIB-1-positive proliferating cells were distributed throughout the tumor. Microdissection and comparative genomic hybridization analyses revealed losses on 2p24-25.2, 2q14.1-ter, 5q31.3-32, 6q23-24, 8q23-24.2, 11q22.3-24 and 18q21.1-22. This is the first case of pyloric gland adenoma found to arise in Barrett's epithelium of the esophagus, showing its unstable and precancerous nature.

Gastric-type adenocarcinoma of the duodenal second portion histogenetically associated with hyperplasia and gastric-foveolar metaplasia of Brunner's glands.

We report a case of a pedunculated polyp with a focus of gastric-type adenocarcinoma arising in the opposite side of the papilla Vater of the duodenal second portion. The carcinoma was surrounded by lobules of hyperplastic Brunner's glands. Immunohistochemically the carcinoma tissue showed both gastric foveolar-type mucin ( MUC5AC) and pyloric/Brunner's gland-type mucin ( MUC6), in which proliferating cells positive for MIB-1 (Ki-67) were scattered diffusely. Most of the hyperplastic Brunner's glands were positive for MUC6, while cells toward the lumen in the superficial layer were positive for MUC5AC and MIB-1. This directional pattern of differentiation of Brunner's glands has recently been demonstrated by our group in the histogenetic course of gastric metaplasia originating directly from Brunner's glands. Therefore the present carcinoma is thought to have developed under induction of gastric-foveolar differentiation in a manner very similar to that of gastric metaplasia in hyperplastic Brunner's glands.

Gastric-type well-differentiated adenocarcinoma and pyloric gland adenoma of the stomach.

Since 1985, when gastric-type well-differentiated adenocarcinomas were demonstrated in hyperplastic polyps of the stomach, we have studied phenotypic expression in gastrointestinal epithelial lesions. The recent discovery of MUC genes coding core proteins of mucin has improved research on the phenotypic expression of gastrointestinal neoplasms. The disease entity of gastric-type well-differentiated adenocarcinoma has recently been accepted, especially in Japan and Europe. This entity has often become a clinicopathological subject of discussion, because its biological behavior is possibly highly malignant, in spite of the difficulty in making endoscopic and histopathological diagnoses. Even under these circumstances, the term "gastric adenoma" usually means flat adenoma of the intestinal type. Gastric-type adenomas have been regarded as exceptional until recently. Although gastric-type adenomas could theoretically be classified into foveolar type and pyloric-gland type, foveolar-type adenoma is, in practice, difficult to distinguish from gastric-foveolar-type adenocarcinoma. In 2003, we first reported systematic clinicopathological analyses of pyloric gland adenoma, demonstrating its unstable and precancerous nature. In this article, we review and discuss the clinicopathological and molecular pathological aspects of gastric-type well-differentiated adenocarcinomas and pyloric gland adenomas, mainly based on our published and unpublished data.