Serrated route to colorectal cancer: back street or super highway?

Morphological and molecular studies are beginning to distinguish separate evolutionary pathways for colorectal cancer, The serrated pathway encompassing hyperplastic aberrant crypt foci, hyperplastic polyps. mixed polyps, and serrated adenoma is increasingly being linked with genetic alterations, including DNA methylation, DNA microsatellite instability, Ii-ras mutation, and loss of chromosome Ip, The importance of the serrated pathway has been underestimated in terms of its frequency and potential for rapid progression, Copyright (C) 2001 John Wiley & Sons, Ltd.

Hyperplastic polyposis - Association with colorectal cancer

Hyperplastic polyposis is a loosely defined syndrome initially thought not to confer a clinically important predisposition to colorectal cancer. The aim of the current study was to examine the clinical, histologic, and molecular features of a prospective series of cases meeting a strict definition of the condition. Twelve patients were identified, seven of whom had developed colorectal cancer. Most polyps were hyperplastic, but 11 patients also had polyps containing dysplasia as either serrated adenomas. mixed polyps, or traditional adenomas. The mean percentage of dysplastic polyps in patients with cancer was 35%, and in patients without cancer, 11%(p < 0.05). Microsatellite instability (MSI) was present in 3 of 47 hyperplastic polyps and two of right serrated adenomas. Kras was mutated in 8 of 47 hyperplastic polyps and two of eight serrated adenomas. No polyps showed loss of heterozygosity of chromosomes 5q, 1p, or 18q. Two of seven cancers showed a high level of MSI. It is concluded that hyperplastic polyposis is associated with a high risk of colorectal cancer. Hyperplastic polyps are the dominant type of polyp, but most cases have some dysplastic epithelium. A higher proportion of dysplastic polyps is associated with increased cancer risk. Clonal generic changes are observed in some hyperplastic polyps and serrated adenomas.

Ki-67 expression in non-tumour epithelium adjacent to oral cancer as risk marker for multiple oral tumours

Objective: The aim of this study was to determine whether the differential assessment of epithelial proliferation is useful to diagnose premalignant fields and assess the risk of multiple tumours. Material and methods: We analysed 83 oral carcinomas with associated non-tumour epithelium classified as distant or close according to its distance (> or < 1 cm) from the invasion point, and as squamous hyperplasia, mild, moderate, severe dysplasia or carcinoma in situ. Twenty-five healthy oral mucosa samples were used as controls. An immunohistochemical technique was applied using Mib-1. Ki-67 in premalignant epithelium was assessed in basal layer, parabasal layer, medium and upper third. Results: Parabasal expression was significantly higher or showed a tendency to be higher in close and distant epithelia with any histological grade than in the controls. Parabasal Ki-67 significantly differed between distant epithelia associated with multiple vs single tumours (P < 0.001) and between distant epithelia associated with multiple tumours vs controls (P < 0.001). This difference was not observed between distant epithelia associated with single tumours and controls (P = 0.175). The cut-off point that differentiated epithelia associated with multiple tumours was > 50% of Ki-67 + parabasal cells in distant epithelia, which yielded 0.88 sensitivity and 0.79 specificity. Conclusions: The concept of a precancerous field may be linked to an increase in the proliferative activity of parabasal cells.

Tissue Eosinophilia and Its Association With Tumoral Invasion of Oral Cancer

This study investigated if tumor-associated tissue eosinophilia (TATE) could be associated with the process of tissue invasion in oral squamous cell carcinomas (OSCCs) and its influence on patient`s prognosis. Forty-three patients treated for OSCCs with or without lymph nodes involvement, at A. C. Camargo Cancer Hospital, Brazil, were selected for TATE analysis. Two degrees of tissue eosinophilia were established in OSCC: absent/mild and intense. The TATE was evaluated in relation to the clinicopathological features and prognostic value using chi(2) test and the Kaplan-Meier method. Most of the patients with OSCC in advanced clinical stage presented Muscular infiltration and significantly intense TATE whereas those with tumors in early stage frequently showed absent/mild eosinophilia (P = .009). The TATE showed no prognostic value for 5-year and 10-year survival rates of the OSCC. These findings suggest that intense TATE seems to reflect the stromal invasion of the OSCCs that occur in advanced clinical stage.

E-cadherin abnormalities resulting from CPG methylation promoter in metastatic and nonmetastatic oral cancer

Background. This study aims to compare the alterations in the methylation profiles of E-cadherin in oral cancer, especially in tumors with lowest metatastic potential. Methods. Nine oral verrucous carcinomas (VCs), 20 oral well-differentiated squamous cell carcinomas without lymph node involvement (SCC-pNO), and 17 with lymph node involvement (SCC-pN+) were analyzed using methylation-specific polymerase chain reaction and immunohistochemical expression of E-cadherin gene. Results. The immunohistochemical expression of E-cadherin in VC was significantly higher (p = .016) when compared with SCC-pNO and SCC-pN+ groups. The E-cadherin gene methylation was not correlated with its abnormal immunohistochemical expression in VC and SCC-pNO. All tumors of the SCC-pN+ group with unmethylated E-cadherin gene showed significant loss of E-cadherin immunoexpression (p = .044). Conclusions. The E-cadherin gene methylation presence in tumors with lowest invasive and metastatic potential, such as VC, suggests the early involvement of this epigenetic event in the multistep progression of the oral carcinogenesis. (c) 2007 Wiley Periodicals, Inc.

Methylation of O-6-methylguanine DNA methyltransferase characterizes a subset of colorectal cancer with low-level DNA microsatellite instability

The significance of low-level DNA microsatellite instability (MSI-L) is not well understood. K-ras mutation is associated with MSI-L colorectal cancer and with the silencing of the DNA repair gene O-6-methylguanine DNA methyltransferase (MGMT) by methylation of its promoter region. MGMT methylation was studied in sporadic colorectal cancers stratified as DNA microsatellite instability-high (n = 23), MSI-L (n = 44), and microsatellite-stable (n = 23). Methylation-specific PCR was used to detect MGMT-promoter hypermethylation in 3 of 23 (13%) microsatellite instability-high, in 28 of 44 (64%) MSI-L, and in 6 of 23 (26%) microsatellite-stable cancers (P = 0.0001). K-ras was mutated in 20 of 29 (69%) methylated MSI-L cancers and in 2 of 15 (13%) unmethylated MSI-L cancers (P = 0.001), indicating a relationship between MGMT-methylation and mutation of K-ras. Loss of nuclear expression of MGMT was demonstrated immunohistochemically in 23 of 31 (74%) cancers with methylated MGMT and in 10 of 49 (20%) cancers with nonmethylated MGMT (P < 0.0001). Loss of expression of MGMT was also demonstrated in 9 of 31 serrated polyps. Silencing of MGMT may predispose to mutation by overwhelming the DNA mismatch repair system and occurs with greatest frequency in MSI-L colorectal cancers.

Proliferation, apoptosis, and survival in high-level microsatellite instability sporadic colorectal cancer

Sporadic colorectal cancer (CRC) characterized by high-level DNA microsatellite instability (MSI-H) has a favorable prognosis. The reason for this MSI-H survival advantage is not known. The aim of this study was to correlate proliferation, apoptosis, and prognosis in CRC stratified by MSI status. The proliferative index (PI) was measured by immunohistochemical staining with the Ki-67 antibody in a selected series of 100 sporadic colorectal cancers classified according to the level of MSI as 31 MSI-H, 29 MSI-Low (MSI-L), and 40 microsatellite stable (MISS). The Ki-67 index was significantly higher in MSI-H cancers (P < 0.0001) in which the PI was 90.1 1.2% (mean +/- SE) compared with 69.5 +/- 3.1 % and 69.5 +/- 2.3 % in MSI-L and MSS subgroups, respectively. There was a positive linear correlation between the apoptotic index (AI) and PI (r = 0.51; P < 0.001), with MSI-H cancers demonstrating an increased AI:PI ratio indicative of a lower index of cell production. A high PI showed a trend toward predicting improved survival within MSI-H cancers (P = 0.09) but did not predict survival in MSI-L or MSS cancers. The Al was not associated with survival in any MSI subgroup. In conclusion, this is the first study to show that sporadic MSI-H cancers are characterized by a higher AL:PI ratio and increased proliferative activity compared with MSI-L and MSS cancers, and that an elevated PI may confer a survival advantage within the MSI-H subset.

High frequency of low-level microsatellite instability in early colorectal cancer

Molecular events in early colorectal cancers (CRCs) have not been well elucidated because of the low incidence of early CRCs in clinical practice. Therefore, we studied 104 sporadic early CRCs with invasion limited to submucosa compared with 116 advanced CRCs. Loss of heterozygosity as well as microsatellite instability (MSI) status was examined. A significantly high frequency of low-level MSI (MSI-L) phenotype was detected in early CRCs (51.0%) compared with advanced CRCs (25.9%; P = 0.0001). In early and advanced CRCs, samples with MSI-L phenotype differed from microsatellite stable (MSS) phenotype with respect to loss of heterozygosity at 1p32 and 8p12-22. MSI-L is a frequent genetic event in early CRCs and may be a novel pathway in colorectal carcinogenesis distinct from both MSI-H and MSS.

Tumour infiltrating lymphocytes and apoptosis are independent features in colorectal cancer stratified according to microsatellite instability status

Background-The presence of high level DNA microsatellite instability (MSI-H) in colorectal cancer is associated with an improved prognosis, as is the presence of tumour infiltrating lymphocytes (TILs). It is not clear if TILs contribute directly to the survival advantage associated with MSI-H cancers through activation of an antitumour immune response. Aims-To correlate TIL and apoptosis rates in colorectal cancer stratified by MSI status. Methods-The distribution of TILs was characterised and quantified in a selected series of 102 sporadic colorectal cancers classified according to levels of MSI as 32 MSI-H, 30 MSI-low (MSI-L), and 40 microsatellite stable (MSS). Archival blocks were immunostained using the T cell markers CD3 and CD8, and the B cell marker CD20. Apoptosis of malignant epithelial cells was quantified by immunohistochemistry with the M30 CytoDEATH antibody. Results-Positive staining with anti-CD3 and negative staining with anti-CD20 identified virtually all TILs as T cells. The majority of CD3(+) TILs (>75%) also stained with anti-CDS. TILs were most abundant in MSI-H colorectal cancers in which 23/32 (72%) scored as TIL positive. Only 5/40 (12.5%) MSS tumours and 9/30 (30%) MSI-L cancers were TIL positive (p

Timely topic: Premalignant lesions associated with adenocarcinoma of the upper gastrointestinal tract

The changing incidence of adenocarcinomas, particularly in the oesophagus and gastric cardia, has led to the rapid expansion of screening programmes aimed at detecting the precursor lesion of dysplasia before adenocarcinoma develops. The pathologist now has an important role in first diagnosing patients at risk for developing dysplasia, and then correctly classifying dysplasia when it occurs. Barrett's oesophagus has had different diagnostic criteria in previous years but is currently diagnosed by the presence of intestinal metaplasia of any length in the true oesophagus. Intestinal metaplasia confined only to the gastro-oesophageal junction or cardia is of uncertain significance but is probably common, with less risk of progressing to dysplasia or malignancy. In the stomach, patients with autoimmune atrophic gastritis and Helicobacter-associated multifocal atrophic gastritis have an increased risk of adenocarcinoma, but screening protocols are not well-developed compared with those used for Barrett's oesophagus. Dysplasia of glandular epithelium can be classified using well-described criteria. Low grade dysplasia is the most common type and regresses or remains stable in the majority of patients. High grade dysplasia is more ominous clinically, with a propensity to coexist with or progress to adenocarcinoma.

Body size and ovarian cancer: case-control study and systematic review (Australia)

Objective: Although increased body mass is an established risk factor for a variety of cancers, its relation with cancer of the ovary is unclear. We therefore investigated the association between measures of body mass index (BMI) and ovarian cancer risk. Methods: Data from an Australian case-control study of 775 ovarian cancer cases and 846 controls were used to examine the association with BMI. We have also summarized the results from a number of other studies that have examined this association. Results: There was a significant increased risk of ovarian cancer with increasing BMI, with women in the top 15% of the BMI range having an odds ratio (OR) of 1.9 (95% confidence interval (CI), 1.3-2.6) compared with those in the middle 30%. Stratifying by physical activity showed a stronger effect among inactive women (OR = 3.0, 95% CI 1.3-6.9). The overall effect was consistent with the findings of most prior population-based case-control studies, while cohort studies reported positive effects closer to the null. Hospital-based studies gave variable results. Conclusions: Taken together, the evidence is in favor of a small to moderate positive relation between high BMI and occurrence of ovarian cancer.

Cigarette smoking and risk of epithelial ovarian cancer (Australia)

Objectives: We studied the association between cigarette smoking and ovarian cancer in a population-based case-control study. Methods: A total of 794 women with histologically confirmed epithelial ovarian cancer who were aged 18-79 years and resident in one of three Australian states were interviewed, together with 855 controls aged 18-79 years selected at random from the electoral roll from the same states. Information was obtained about cigarette smoking and other factors including age, parity, oral contraceptive use, and reproductive factors. We estimated the relative risk of ovarian cancer associated with cigarette smoking, accounting for histologic type, using multivariable logistic regression to adjust for confounding factors. Results: Women who had ever smoked cigarettes were more likely to develop ovarian cancer than women who had never smoked (adjusted odds ratio (OR) = 1.5; 95% confidence interval (CI) = 1.2-1.9). Risk was greater for ovarian cancers of borderline malignancy (OR = 2.4; 95% CI = 1.4-4.1) than for invasive tumors (OR = 1.7; 95% CI = 1.2-2.4) and the histologic subtype most strongly associated overall was the mucinous subtype among both current smokers (OR = 3.2; 95% CI = 1.8-5.7) and past smokers (OR = 2.3; 95% CI = 1.3-3.9). Conclusions: These data extend recent findings and suggest that cigarette smoking is a risk factor for ovarian cancer, especially mucinous and borderline mucinous types. From a public health viewpoint, this is one of the few reports of a potentially avoidable risk factor for ovarian cancer.