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Background & Aims: Lynch syndrome family members have a high risk of developing colorectal (CRC), endometrial (EC), and other cancers. A large-scale surveillance program was introduced in The Netherlands in the late 1980s. The aims of the study were to evaluate the effectiveness of this program by assessing mortality because of CRC and EC before and after 1990 and to compare mortality because of all cancers (except CRC/EC) with mortality in the general population., Methods: Family members with at least 50% probability of being a carrier were selected for the study. The standardized mortality ratio (SMR) because of cancer and the absolute excess risk of death (AER) were calculated., Results: In the total cohort (N = 2788), 445 subjects had died because of cancer. The 3 most frequent causes of cancer-related deaths were CRC (50.3%), EC (6.7%), and brain tumors (6.7%). A significant decrease (70%) in SMR for CRC over time was observed (P < .001); the SMR for EC showed no decreasing trend over time. A significantly increased SMR was found for cancer of the small bowel (SMR = 18.3), brain (SMR = 9.1), kidney/ureter (SMR = 5.9), ovarium (SMR = 2.3), pancreas (SMR = 2.2), and stomach (SMR = 2.1). The AER was significantly increased for brain tumors only., Conclusions: Since the introduction of surveillance, the mortality because of CRC has decreased. Except for brain tumors, we did not find a significantly increased AER for tumors other than CRC/EC.

Background and Aims: The adenoma-carcinoma sequence in hereditary nonpolyposis colorectal cancer (HNPCC) is accelerated. It remains unknown whether the mismatch repair (MMR) defect also promotes the development of adenomas. The aim of this study was to compare the risk of developing colorectal adenoma and carcinoma in HNPCC carriers and noncarriers (controls) and to compare the features of adenomas in both groups., Methods: Eighty-six families with a known MMR gene mutation from the Dutch HNPCC Registry were analyzed. Subjects with known mutation status with colonoscopies performed for the purpose of surveillance were selected for this study. Information on the surveillance examinations was obtained from medical reports. The histology of all adenomas was confirmed. Immunohistochemistry was performed in a subgroup of adenomas., Results: We identified 249 carriers and 247 controls. The proportion of subjects free of an adenoma at the age of 60 years was 29.7% for carriers and 70.8% for controls (P < 0.05). The adenomas in carriers were larger, and a higher proportion had villous components and/or high-grade dysplasia (P < 0.05, all analyses). The adenomas and carcinomas of the carriers were located predominantly in the proximal colon. Most adenomas showed absent staining of the MMR proteins., Conclusions: This study indicates that the MMR defect is involved in the early stages of development of adenomas. We recommend immunohistochemical staining of large adenomas with high-grade dysplasia in young patients (younger than 50 years) to identify patients with suspected HNPCC.

Background/aims: Human colorectal carcinogenesis was previously found to be associated with an increased urokinase-type plasminogen activator expression, both in antigen and activity, accompanied by simultaneously enhanced levels of plasminogen activator inhibitors type 1 and type 2. This increased proteolytic activity may contribute to invasive growth and metastasis of the tumors., Methods: In the present study, homogenates of liver metastases, primary colorectal carcinomas, and adjacent normal tissues were evaluated regarding the level and composition of urokinase, tissue-type plasminogen activator, and plasminogen activator inhibitors., Results: Concentrations of urokinase were significantly increased in primary carcinomas and liver metastases compared with normal tissues, whereas tissue-type plasminogen activator levels were significantly decreased. Liver metastases showed, in contrast to the carcinomas, hardly any activity of plasminogen activators, which could be attributed to the enhanced presence of the inactive proenzyme form of urokinase in combination with more complexes of plasminogen activators with inhibitors. Furthermore, liver metastases had an eightfold higher content of inhibitor type 1 compared with the primary carcinomas. The excess of inhibitors was confirmed by addition of plasminogen activators to metastasis homogenates, which resulted in increased complex formation., Conclusions: Colorectal cancer metastasis in the liver is associated with an inactivation of the enhanced urokinase cascade, which might allow tumor cells to settle in the liver.

Neoplastic growth and metastatic spread of adenocarcinomas is characterized by a marked increase of urokinase-type plasminogen activator (u-PA) and a decrease of tissue-type plasminogen activator (t-PA). In this study, the authors determined the activity and antigen levels of u-PA and t-PA, and their inhibitors, plasminogen-activator inhibitors types 1 and 2 (PAI-1 and PAI-2), in normal mucosa, adenomatous polyps, and adenocarcinomas of the human colon. The decrease in t-PA activity in the neoplastic tissues, determined enzymatically and zymographically, was significantly correlated with an increase in PAI-1 and PAI-2, in particular in carcinomas. In spite of significantly higher inhibitor levels in the neoplastic tissues, u-PA was found to be increased as well, both in antigen level and in activity. The authors conclude that PAI-1 and PAI-2 are significantly increased in neoplastic tissue of the human colon and contribute considerably to the decrease of t-PA activity in carcinomas. However, the malignancy-associated increase in u-PA seems not to be affected by the plasminogen activator inhibitors. Thus, it appears that there is an imbalance between plasminogen activators and their inhibitors in colonic neoplasia in favor of u-PA, which may contribute to plasmin-mediated growth, invasiveness, and metastasis. This feature was also noticed in adenomatous polyps, supporting the malignant potency of adenomas.

Of 124 patients who underwent endoscopic polypectomy, 70 were colonoscopically reevaluated during a mean period of 10 years. On the basis of the clinical outcome, the patients were divided into three groups: group 1, 31 patients who had a colon still with no adenomas or cancer; group 2, 35 patients in whom one or more metachronous adenomatous polyps developed; and group 3, 4 patients in whom a carcinoma of the colon subsequently developed. In addition to the clinical and pathological features, the pattern of the immunohistologic staining for carcinoembryonic antigen and secretory component was studied. Moreover, the mucin histochemical staining intensity of neutral mucins, sulfomucins, and sialomucins was evaluated. The features of the 40 index adenomas obtained from patients in group 1 were compared with the features of the 51 index adenomas from patients in group 2. Furthermore, these characteristics of the index adenomas were compared with those in the 69 metachronous adenomas of the group 2 patients. It was found that male sex (P less than 0.005) and a history of colorectal neoplasia (P less than 0.02) are main factors for the development of new adenomas. The neutral mucins were less abundant in the group 2 index adenomas (r = -0.21; P less than 0.05). The expression of the other evaluated markers was not significantly different between both groups, although the group 2 index adenomas were significantly smaller (r = -0.22; P less than 0.05) and showed a trend toward a more pronounced cytoplasmic expression of carcinoembryonic antigen than the index adenomas from group 1 (22% vs. 12.5%). Moreover, it was found that in comparison with the index adenomas, metachronous adenomas were significantly smaller (r = -0.24; P less than 0.01) and more sessile (r = 0.20; P less than 0.002). Significant negative correlations, i.e., decrease, were also found in the expression of carcinoembryonic antigen (surface P less than 0.001; cytoplasmic P less than 0.05) and neutral mucins (P less than 0.005) between the index adenomas and the metachronous adenomas, whereas positive correlations were found for secretory component (P = 0.0001) and sulfomucins (P less than 0.05). These findings suggest that a limited production of neutral mucins in the goblet cells of a small index adenoma from a male patient with a history of colorectal neoplasia is indicative of an increased risk for the development of new colorectal adenomas. Furthermore, the clinical, mucin histochemical, and immunohistochemical findings of the metachronous adenomas show less malignancy-associated features than those of the index adenomas.