High-level microsatellite instability (MSI-H) is demonstrated in 10 to 15% of sporadic colorectal cancers and in most cancers presenting in the inherited condition hereditary nonpolyposis colorectal cancer (HNPCC). Distinction between these categories of MSI-H cancer is of clinical importance and the aim of this study was to assess clinical, pathological, and molecular features that might be discriminatory. One hundred and twelve MSI-H colorectal cancers from families fulfilling the Bethesda criteria were compared with 57 sporadic MSI-H colorectal cancers. HNPCC cancers presented at a lower age (P < 0.001) with no sporadic MSI-H cancer being diagnosed before the age of 57 years. MSI was less extensive in HNPCC cancers with 72% microsatellite markers showing band shifts compared with 87% in sporadic tumors (P < 0.001). Absent immunostaining for hMSH2 was only found in HNPCC tumors. Methylation of hMLH1 was observed in 87% of sporadic cancers but also in 55% of HNPCC tumors that showed loss of expression of hMLH1 (P = 0.02). HNPCC cancers were more frequently characterized by aberrant beta-catenin immunostaining as evidenced by nuclear positivity (P < 0.001). Aberrant p53 immunostaining was infrequent in both groups. There were no differences with respect to 5q loss of heterozygosity or codon 12 K-ras mutation, which were infrequent in both groups. Sporadic MSI-H cancers were more frequently heterogeneous (P < 0.001), poorly differentiated (P = 0.02), mucinous (P = 0.02), and proximally located (P = 0.04) than HNPCC tumors. In sporadic MSI-H cancers, contiguous adenomas were likely to be serrated whereas traditional adenomas were dominant in HNPCC. Lymphocytic infiltration was more pronounced in HNPCC but the results did not reach statistical significance. Overall, HNPCC cancers were more like common colorectal cancer in terms of morphology and expression of beta-catenin whereas sporadic MSI-H cancers displayed features consistent with a different morphogenesis. No individual feature was discriminatory for all HNPCC cancers. However, a model based on four features was able to classify 94.5% of tumors as sporadic or HNPCC. The finding of multiple differences between sporadic and familial MSI-H colorectal cancer with respect to both genotype and phenotype is consistent with tumorigenesis through parallel evolutionary pathways and emphasizes the importance of studying the two groups separately.

Summary Ovarian adenocarcinomas develop as the result of multiple genetic and epigenetic changes in the precursor ovarian surface epithelial (OSE) cells which result in a malignant phenotype. We investigated changes in gene expression in ovarian adenocarcinoma using a cDNA array containing 588 known human genes. We found that intercellular adhesion molecule-1 (ICAM-1) was expressed at lower levels in the ovarian tumour cell lines OAW42, PEO1 and JAM than in the immortalised human ovarian surface epithelial cell line HOSE 17.1. Further investigation revealed ICAM-1 was expressed in the surface epithelium of normal ovaries and both mRNA and protein expression levels were reduced in the majority of ovarian adenocarcinoma cell lines and primary tumours. ICAM-1 expression was increased in 8/8 cell lines treated with the de novo methyltransferase inhibitor 5-aza-2′-deoxycytidine, indicating that methylation of CpG islands may play a role in the down-regulation of its expression in primary tumours. There was a significant association between patients whose tumours expressed ICAM-1 and survival (P = 0. 1351-1358© 2001 Cancer Research Campaign doi: 10.1054/ bjoc.2001.2075, available online at http://www.idealibrary.com on http://www.bjcancer.com 1987), SKOV3 (Fogh and Trempe, 1975), COLO316 (Woods et al, 1979), CAOV3 (Wong et al, 1999), OVCAR-3 (Hamilton et al, 1983) and 27/87 (derived by T Hurst) -were all maintained in RPMI 1640 with 10% FCS. Cells were harvested for RNA isolation at about 80% confluence. The cell lines OAW 42, PEO1, PEO14, JAM, SKOV3 and COLO316 were derived from serous tumours, and 27/87 was from an endometrioid tumour. The histological types of the tumours from which the cell lines HEY, CAOV3 and OVCAR3 were derived are unknown.Primary cultures of human ovarian surface epithelial (OSE) cells were prepared according to the method of Kruk et al (1990). Epithelial cells were obtained by scraping contaminating stromal cells away from proliferating epithelial sheets and were cultured in 1:1 MCDB105: Medium 199 with Earles' salts, supplemented with 20 ng ml -1 epidermal growth factor, 400 ng ml -1 hydrocortisone and 15% fetal calf serum. Their distinctive cellular morphology was used to confirm that the cultures were epithelial cells. In one case, RNA was extracted directly from the peeled epithelial cells without culturing.Ovarian adenocarcinomas were obtained from 44 patients undergoing surgery. There were 35 serous, 6 endometrioid, one mucinous and 2 clear-cell tumours. There were 43 malignant tumours and the other was of low malignant potential (LMP). All patients were staged at laparotomy, in accordance with the recommendations of the International Federation of Gynaecology and Obstetrics (FIGO). Of the malignant tumours, one was FIGO stage 1, 4 stage 2, 33 stage 3 and 5 stage 4. There were two grade 1-2, 11 grade 2, 10 grade 2/3, 17 grade 3, one grade 3-4, and 2 that were not graded. Clinicopathological data for these tumours are summarised in Table 2. Constitutional DNA was available in all ca...

The molecular events that give rise to ovarian epithelial neoplasms are not well understood. In particular, it is not known whether adenocarcinomas arise from benign or low malignant potential (LMP) precursors. We have examined a large series of benign (25) and LMP (31) ovarian tumors for loss of heterozygosity (LOH) at multiple loci on 17 chromosomes. LOH was observed in benign tumors on chromosomes 6 (14%) and 9 (5%) and on the X chromosome (33%) only. LOH on these chromosomes was also detected in a small number of LMP neoplasms, suggesting that these may derive sometimes from benign precursors. In addition, we examined LOH in 93 adenocarcinomas. Analysis of associations between LOH events showed that LOH on chromosomes 5 and 17 (P = 0.0002) and on chromosomes 17 and 18 (P = 0.00007) were associated significantly with each other, which suggests that these may represent cooperative, progressive events. No novel significant associations were identified between LOH events and stage, grade, or histology, which would indicate the existence of genetic heterogeneity in ovarian neoplasms. KRAS2 mutations were detected more often in LMP neoplasms than in malignant tumors (P = 0.004) and were detected more often in Stage I/II malignant tumors than in Stage III/IV malignant tumors (P = 0.033), suggesting that LMP tumors with KRAS2 mutations are unlikely to progress to frank malignancy. Univariate (but not multivariate) survival analysis showed that LOH of chromosomes 11 (P = 0.039) and 17 (P = 0.04) was associated with a significantly worse prognosis. Replication of these novel findings is necessary, and the identification, isolation, and characterization of the critical genes affected by LOH will determine their importance in the pathogenesis of ovarian malignancies. Genes Chromosom. Cancer 18:75–83, 1997. © 1997 Wiley‐Liss, Inc.

We evaluated the types, frequency, and significance of stromal reaction patterns in urothelial carcinoma (UC) of the bladder in 60 transurethrally resected pT1 specimens (low-grade UC, 12; high-grade UC, 48). We observed 5 reaction patterns with 1 pattern in 37 cases (62%) and 2 or more patterns in the remainder. Dominant and secondary patterns, respectively, were as follows: stromal retraction, 30 (50%) and 4 (7%); edema, 18 (30%) and 1 (2%); inflammation, 8 (13%) and 14 (23%); fibroblastic proliferation, 3 (5%) and 5 (8%); fibrosis, 1 (2%) and 4 (7%). Progression occurred in 21 cases, including 9 (30%) of 30 with stromal retraction, 8 (45%) of 18 with edema, 2 (25%) of 8 with inflammation, 1 (33%) of 3 with fibroblastic proliferation, and 1 (100%) of 1 with fibrosis. Differences in progression rates and mean progression-free survival times were not statistically significant. We found that the most common stromal reaction in UC of the bladder is stromal retraction. Stromal reaction patterns seem to have some prognostic usefulness. Cases with stromal edema might benefit from closer follow-up. Awareness of the different types of stromal reactions also is useful for diagnosing invasion.

We evaluated the types, frequency, and significance of stromal reaction patterns in urothelial carcinoma (UC) of the bladder in 60 transurethrally resected pT1 specimens (low-grade UC, 12; high-grade UC, 48). We observed 5 reaction patterns with 1 pattern in 37 cases (62%) and 2 or more patterns in the remainder. Dominant and secondary patterns, respectively, were as follows: stromal retraction, 30 (50%) and 4 (7%); edema, 18 (30%) and 1 (2%); inflammation, 8 (13%) and 14 (23%); fibroblastic proliferation, 3 (5%) and 5 (8%); fibrosis, 1 (2%) and 4 (7%). Progression occurred in 21 cases, including 9 (30%) of 30 with stromal retraction, 8 (45%) of 18 with edema, 2 (25%) of 8 with inflammation, 1 (33%) of 3 with fibroblastic proliferation, and 1 (100%) of 1 with fibrosis. Differences in progression rates and mean progression-free survival times were not statistically significant. We found that the most common stromal reaction in UC of the bladder is stromal retraction. Stromal reaction patterns seem to have some prognostic usefulness. Cases with stromal edema might benefit from closer follow-up. Awareness of the different types of stromal reactions also is useful for diagnosing invasion.