Hyperplastic polyps in hereditary nonpolyposis colorectal cancer

OBJECTIVES: Hereditary nonpolyposis colorectal cancer (HNPCC) is a genetic syndrome caused by germline mutations in DNA mismatch repair (MMR) genes, in particular hMLH1, hMSH2, and hMSH6. Dysfunction of MMR genes leads to loss of MMR protein expression and to microsatellite instability (MSI). MSI is also detected in 10-20% of sporadic colorectal cancers. Hyperplastic polyps (HP) may serve as precursor for these MSI+ sporadic colorectal cancers. The aim of this study was to examine whether hyperplastic polyps are also possible premalignant lesions in HNPCC. METHODS: All HPs resected from (suspected) mismatch repair gene mutation carriers were retrieved from a screening program database. Clinical information on patient age at colonoscopy and location of the HP was collected. MLH1, MSH2, and MLH6 protein expression was evaluated using immunohistochemistry. RESULTS: A total of 90 HPs were resected from 21 men and 19 women. The mean patient age at resection was 45.7 yr (44.7 yr in men and 46.6 yr in women). In all patients, 19 (21%) HPs were resected from the proximal colon, 23 (26%) from the distal colon, and 48 (53%) from the rectum. None of the HPs demonstrated loss of MMR protein expression. CONCLUSIONS: Mismatch repair dysfunction in HPs of HNPCC patients is apparently very rare. It seems unlikely that HPs in HNPCC patients are precursors for (MSI+) cancers in these patients

Gynecologic screening in hereditary nonpolyposis colorectal cancer

Objective. In hereditary nonpolyposis colorectal cancer (HNPCC), women with a mismatch repair (MMR) gene mutation have a cumulative lifetime risk of 25-50% for endometrial cancer and 8-12% for ovarian cancer. Therefore, female members of HNPCC families are offered an annual gynecologic and transvaginal ultrasound (TVU) examination and serum level CA 125 analysis. The aim of the present study was to evaluate our 10-year experience with this screening program. Methods. Women who are MMR gene mutation carriers or who fulfil the Amsterdam criteria were identified from our HNPCC database. Information concerning the screening program was retrospectively collected from patient files. Results. Forty-one women, 35 premenopausal and 6 postmenopausal, were enrolled in the program with a median follow-up of 5 years (range 5 months-11 years). In 197 patient years at risk, 17 of 179 TVUs gave reason for endometrial sampling. Three premalignant lesions, with complex atypical hyperplasia, were discovered. One interval endometrial cancer was detected as a result of clinical symptoms. No abnormal CA 125 levels were measured and no ovarian cancers were detected. Conclusion. These results demonstrate that gynecologic screening allows the detection of premalignant lesions of the endometrium but also illustrate that recognition and reporting of clinical symptoms by the women themselves is of utmost importance. (C) 2003 Elsevier Inc. All rights reserved

Assessment of apoptosis by M30 immunoreactivity and the correlation with morphological criteria in normal colorectal mucosa, adenomas and carcinomas

Aims: To investigate the monoclonal antibody M30 for the assessment of apoptosis in colorectal tissues. Although Terminal deoxyribonucleotidyl transferase mediated nick end labelling (TUNEL) and in-situ end labelling (ISEL) are the methods most often used to demonstrate and quantify apoptosis in histological tissue sections, the interpretation and specificity of these techniques have been controversial. Immunohistochemistry using the monoclonal antibody M30 that recognizes caspase-cleaved cytokeratin 18 is considered to be a promising alternative but has yet to be validated against a generally accepted standard. Methods and results: Paraffin sections of normal colonic mucosa (n = 30), normal mucosa obtained from resection margins from carcinomas (n = 30), colorectal adenomas (n = 84) and carcinomas (n = 40) were studied. Apoptosis of epithelial cells was assessed by M30 immunoreactivity and morphological criteria and expressed as a proportion of the total number of cells counted (apoptotic index). Mean apoptotic indices using M30 were 0.18 +/- 0.04% in normal mucosa, 0.42 +/- 0.04% in adenomas and 1.97 +/- 0.24% in carcinomas. Using morphological criteria, these indices were 0.23 +/- 0.03%, 0.62 +/- 0.06% and 1.78 +/- 0.19%, respectively. Apoptotic counts were higher in normal mucosa obtained from resection margins than in genuinely normal mucosa using the M30 antibody. Apoptotic indices obtained by M30 immunoreactivity and morphological criteria were positively correlated (r = 0.71, P <0.01). Conclusion: Assessment of apoptotic cells by M30 immunoreactivity correlates well with morphological criteria. Apoptotic indices increase in the course of the adenoma-carcinoma sequence. Apoptosis in normal mucosa obtained from resection margins differs from genuinely normal mucosa necessitating caution when interpreting studies of apoptosis in normal colonic mucosa. Our findings support the use of the M30 method in the study of apoptosis in colorectal tissues

Expression of TRAIL (TNF-related apoptosis-inducing ligand) and its receptors in normal colonic mucosa, adenomas, and carcinomas

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis intumour cell lines. Four membrane-bound receptors for TRAIL have been identified, two apoptosis-mediating receptors, DR4 and DR5, and two apoptosis-inhibiting receptors, DcR1 and DcR2. The aim of this study was to examine the role of TRAIL and its receptors in colorectal cancer development. The immunohistochemical expression and localization of TRAIL and its receptors were investigated in normal mucosa (n = 10), adenomas (n = 19), and carcinomas (n = 21). Correlations between the expression of TRAIL and its receptors and the degree of apoptosis (assessed by M30 expression) and histopathological characteristics were explored. TRAIL and its receptors were expressed in normal mucosal epithelium. Expression of the receptors was seen in adenomas and carcinomas. TRAIL expression was lost in a subset of colorectal tumours, more frequently in carcinomas than in adenomas (p <0.05). DR4 and DR5 staining was stronger in neoplastic cells than in normal cells and was accompanied by a higher degree of apoptosis. No differences were found between tumour and normal cells regarding DcR1 and DcR2 expression. No correlations were found between TRAIL or TRAIL receptor expression and histopathological characteristics. In conclusion, marked changes were seen in the course of the adenoma-carcinoma sequence with respect to the expression of TRAIL and TRAIL receptors DR4 and DR5. The stronger expression of DR4 and DR5 in neoplastic cells than in normal cells, together with a higher degree of apoptosis, suggests a possible functional role for these receptors in apoptosis induction in neoplastic colorectal cells. Copyright (C) 2003 John Wiley Sons, Ltd