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Objectives: We evaluated the prevalence and characteristics of adenomas in a young population not genetically predisposed for the development of colorectal cancer (CRC)., Methods: The databases of the Dutch Hereditary Colorectal Cancer Registry were used. The study population included patients (n = 444) who had regular endoscopy until mutation analysis revealed they did not carry the (Adenomatous Polyposis Coli (APC)/Mismatch Repair) gene defect identified in their family., Results: At first colonoscopy (n = 342; 50% males, mean age 37 yr) a total of 19 adenomas (10 males, mean age 50 yr, range 24-91 yr) and two CRCs (2 males, age 49 and 72 yr) were identified, and at first sigmoidoscopy (n = 102; 53% males, mean age 29 yr) three adenomas (2 males, age 8, 40, and 41 yr) were found. A second colonoscopy was performed in 14 patients with, and in 162 patients without an adenoma. Three of 14 patients (21%) developed a new adenoma (all >50 yr) and 8 of 162 (5%) patients developed their first adenoma during follow-up. In the colonoscopy group, the cumulative proportion of patients free of adenomas at age 50 yr was 86%. Of all adenomas diagnosed during colonoscopy (n = 49), 65% were located distal from the flexura lienalis. Of the adenomas detected during all endoscopies (n = 53), 9.8% were > or =7 mm, 7.5% showed high-grade dysplasia, and 7.5% showed tubulovillous features., Conclusions: On the basis of our findings during colonoscopy we conclude that the risk of developing adenomas/CRC in young individuals without genetic risk factors is low. Adenoma surveillance programs should focus on young individuals with a positive family (or personal) history for adenomas/CRC, or on individuals >50 yr.

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: The lifetime risk of developing duodenal cancer in familial adenomatous polyposis (FAP) is about 5 per cent. When and to what extent surgical intervention should be undertaken to prevent death from invasive carcinoma is controversial. The aim of this study was to determine the effectiveness of various surgical treatments for cancer and severe duodenal adenomatosis., Methods: A questionnaire was mailed to the members of the Leeds Castle Polyposis Group to obtain data on patients with FAP, treated for duodenal cancer or severe duodenal adenomatosis after 1990., Results: Sixty-nine patients were included. The indication for surgery was invasive cancer in 13 patients, of whom six died from metastatic disease. Fifty-six patients were initially treated for severe duodenal adenomatosis, five (9 per cent) of whom died from metastatic disease (P = 0.002). In surviving patients, adenomas recurred after ampullectomy (six of eight, at mean follow-up of 11 months), after duodenotomy with polypectomy (17 of 21, at mean 29 months) and after pancreatoduodenectomy (six of 25, at mean 47 months). None of six patients who underwent a pancreas-sparing duodenectomy had recurrence of adenoma (mean follow-up 11 months)., Conclusion: Surgery for duodenal adenomatosis should take place before endoscopic biopsy reveals invasive cancer. Even after extensive surgical procedures, small bowel adenomas may occur, emphasizing the need for chemoprevention., (Copyright 2003 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

It is well known that patients with familial adenomatous polyposis (FAP) are at considerable risk of developing extracolonic manifestations of the disease. Particularly, desmoid tumours of the abdominal cavity, and duodenal adenomas and carcinomas are the most serious ones. It is estimated that some 10% of the FAP patients will develop desmoids, whereas 50-90% of the FAP patients will get duodenal adenomas predominantly concentrated on or around the major papilla. Desmoid tumours and duodenal carcinomas are major causes of death in those patients in whom a prophylactic (procto)colectomy has been performed. Desmoids are histologically benign tumours, composed of mature fibroblasts. They usually grow slowly but they can become quite large and may compress or infiltrate surrounding viscera, which might cause significant morbidity as well as mortality. Successful treatment of these tumours is extremely difficult as surgical therapy often requires the removal of considerable lengths of small bowel. Moreover, surgical therapy may lead to uncontrollable bleeding and is seldom radical. Chemotherapy with cytoxic agents seems promising but so far the data are too few for firm conclusions to be drawn. The same holds true for drug regimens which interfere with the metabolic and hormonal metabolism of the tumour. Although various lines of evidence suggest that the adenoma-carcinoma sequence, which is generally accepted for colorectal adenomas, also applies for the duodenal adenomas in FAP patients, it is not clear whether we should screen these patients for upper gastrointestinal adenomas or not. As these polyps are usually small, sessile, multiple and difficult to remove, the benefit of endoscopic surveillance would be the early detection of cancer rather than eradication of the polyps. In addition, evidence that screening and early treatment leads to improvement of the prognosis is not available. Although the role of (procto)colectomy in the treatment of large-bowel polyps is well established in FAP patients, the treatment of their duodenal counterparts is still open for debate. The risk of the development of periampullary cancer is not high enough to warrant an aggressive prophylactic surgical approach, i.e. a Whipple's procedure, immediately after the discovery of duodenal adenomas. The considerable morbidity and mortality rates of this procedure must be weighted against a putative benefit of screening.

A surveillance programme comprising either colonoscopy of sigmoidoscopy plus barium enema every 2-3 years was instituted in 50 hereditary nonpolyposis colorectal cancer (HNPCC) families. The families included 238 patients with colorectal cancer (CRC) (mean age at diagnosis: 43.7 years; range: 16-86 years). These patients had 597 first-degree relatives of whom 493 could be traced and 388 (79%) accepted the invitation for screening. The control group were relatives (index patients) with symptomatic CRC. The average follow-up duration was 5 years (1-20 years). Screening led to the detection of adenomas in 33 patients and CRC in 11 patients. Pathological examination revealed 1 Dukes' A, 7 Dukes' B and 3 Dukes' C cancers. In contrast, among the control group 47% had advanced CRC (Dukes' C or distant metastases). The 5-year survival of the screen-detected cases was 87% versus 63% in the control group. Of the 11 CRC cases in the screening group, 4 were detected within 1-4 years after a negative colonic examination. A large proportion of the polyps found in the screening and control groups showed a villous growth pattern and/or a high degree of dysplasia. We conclude that periodic examination of HNPCC families allows the detection of cancer at an earlier stage than in patients not under surveillance. Because of the possibly more aggressive nature of polyps associated with HNPCC, we recommend a screening interval of 1-2 years.

The expression of tetranectin in colonic neoplasia was evaluated by determining the tissue distribution by immunohistological analysis of tissue sections and the antigen levels in tissue homogenates and plasma. In normal colonic mucosa tetranectin staining was predominantly found in the goblet cells whereas in adenocarcinomas this staining was confined to the tumour stroma. Colonic adenomas, benign precursors of adenocarcinomas, showed fewer tetranectin positive goblet cells and in some cases showed tetranectin expression in the stroma. Within the tissue homogenates no differences were found in the tetranectin levels between normal mucosa, adenomas and carcinomas. Patients with colonic cancer were found to have significantly decreased plasma tetranectin levels compared to healthy controls. Thus, colonic neoplasia is associated with a change in the tissue distribution of tetranectin, without an obvious change in the tissue level, and a low plasma tetranectin level.

Forty-nine acromegalics and 57 controls matched for age and sex underwent colonoscopy. The control group consisted of patients investigated because of atypical abdominal complaints compatible with irritable bowel syndrome or constipation. The exclusion criteria for both groups included: age over 75 years, previous colonic polyps or cancer, previous colonic surgery, rectal blood loss, anemia, previous abdominal radiation, sigmoidoscopy, colonoscopy or barium enema performed for any indication within 3 years prior to the present study. Colonoscopy was successful in reaching the cecum in 72 and 77% of the controls and acromegalics, respectively (p = NS). Eleven (22%) of 49 acromegalics had biopsy-proven colonic adenomas versus only five (9%) of the control group (p < or = 0.05). Multiple adenomas were found in three of the 11 acromegalics and in none of the controls. In five of these 11 patients and in only one of the controls, at least one adenoma was located in the right colon. In addition, acromegalics tended to have larger adenomas. The group of acromegalics with and without adenomas did not differ significantly in age or duration of active disease. In conclusion, the present study shows that acromegalic patients have an increased risk of developing colonic adenomas.

Until 1992, 192 patients with a villous tumour of the duodenum have been reported. The symptoms and signs of this tumour are mostly related to obstruction of the duodenal lumen or bile ducts. Radiological examination (e.g., hypotonic duodenography) may be of some help in diagnosing a villous tumour of the duodenum. In histological specimens, superficial parts of the tumour may appear benign while deeper parts may contain adenocarcinoma. Therefore, endoscopy with multiple biopsies or the use of electrocautery for removal of large fragments of the tumour should play a major role in obtaining an accurate preoperative diagnosis. Forty-two per cent of all reported villous tumours showed malignant changes at the time of presentation. Because of this great risk of malignant transformation, these tumours should always be resected. Unlike large bowel mucosa, small bowel mucosa contains lymphatics that course through the villi extending near the luminal surface, suggesting the possibility of early lymphatic spread before invading the muscularis mucosae. In 24 patients with intramucosal carcinoma, however, no metastases were found. For this reason, a mucosal resection of these tumours would appear to be an effective and safe treatment. Invasive carcinomas or recurrent villous tumours require more radical surgery. Depending on histological evaluation, location in the duodenum and intraoperative findings, segmental resection of the villous tumour or pancreaticoduodenectomy would seem to be an appropriate surgical procedure. A pedunculated villous tumour may be removed endoscopically. It is recommended that all patients who had their tumour resected locally, should be surveyed endoscopically.

Background: Features of index adenomas in the colorectum may be important for the prediction of metachronous adenoma development., Methods: Complete colonoscopic follow-up for a mean period of 10 years was achieved in 70 of 124 patients after endoscopic polypectomy of an adenoma from the colorectum. On the basis of the clinical outcome, the patients were divided into three groups: Group I, patients who had a colorectum free of adenomas and cancer; Group II, patients who had one or more metachronous adenomatous polyps; and Group III, patients who subsequently had a colorectal carcinoma. The clinical characteristics of the patients were collected, and the neoplastic specimens were re-examined with regard to pathologic parameters and flow cytometrically determined nuclear DNA content., Results: Aneuploid stemlines were found in 35% of the index adenomas. Significantly more aneuploid adenomas were found in the index adenomas of Group I patients than in the adenomas of Group II patients (r = -0.20; P = 0.05). However, in the index adenomas of Group II patients, aneuploidy was associated with villous architecture (P < 0.05) and inversely related to cellular atypia (P < 0.05). Such relations were not found in the adenomas from Group I. In addition, in the Group II adenomas, aneuploidy was found frequently in the more proximally localized adenomas in the large intestine. Remarkably, all adenocarcinomas of the Group III patients were localized in the right colon. No significant differences were found in ploidy and mean DNA index between index adenomas and metachronous adenomas of the Group II patients. However, the ploidy class of the index adenomas was found not to be related to that of the metachronous adenomas in the individual patients., Conclusions: These results demonstrate that DNA cytometry in adenomas alone is not helpful in the prediction of the possibility of the development of a metachronous adenoma. However, aneuploidy in a villous adenoma located more proximally in the colon might indicate a higher risk for metachronous neoplasia development. Index and metachronous adenomas are similar in DNA content but show no relation with respect to ploidy class.

Carcinogenesis in the human colon is associated with a marked increase in the tissue content of the urokinase-type plasminogen activator (u-PA). This study was performed to determine the type of cells responsible for the u-PA increase in carcinomas of the colon and in their precursor lesions, the adenomas, by immunohistological evaluation applying monoclonal antibody 3689 directed to the beta-chain of u-PA. Normal intestinal mucosa (n = 17) showed hardly any staining of u-PA, but some lamina propria cells were faintly positive. Carcinomas (n = 17) and adenomas (n = 16) showed a considerable and comparable staining intensity of u-PA in neoplastic columnar epithelial cells, and this staining was found to be diffuse and cytoplasmic. In a majority of the neoplastic tissues the u-PA staining was found to be patchy and not related to known risk markers of malignancy such as dysplasia in the adenomas, or to prognostic determinants such as Dukes' classification or differentiation in the carcinomas. The observation of strong u-PA positive lamina propria cells in adenomas but infrequently observed in normal mucosa and carcinomas was noteworthy. u-PA staining intensity of the tissue sections was found to correlate well with the u-PA antigen level in the tissue extracts determined by ELISA (r = 0.52, P = 0.0001) but poorly with the u-PA activity determined enzymatically (r = 0.28, P = 0.05). In conclusion, the u-PA increase in neoplasia of the human colon can be attributed to an increased diffuse cytoplasmic content of u-PA in neoplastic columnar epithelial cells.

The histological, mucin histochemical and immunohistochemical features were evaluated of 74 solitary and 73 synchronous colorectal adenomas which were endoscopically removed from 124 patients. Of the patients, 60% had a single adenoma, whereas 40% had at least two adenomas in their colorectum. Comparing the incidence of synchronous adenomas in both sexes revealed a statistically significant higher incidence (P less than 0.005) in males. The localization of the solitary and synchronous adenomas in the large bowel was similar. Moreover, parameters of malignant change within the adenomas (size, predominant type of mucosal growth and degree of dysplasia-with the exception of severe dysplasia) as well as signs of dedifferentiation (relative proportions of goblet and columnar cells) were also similar. Mucin staining intensities (periodic acid-Schiff, high iron diamine and alcian blue) and the immunoreactivity patterns of secretory component and carcinoembryonic antigen, both cytoplasmic and on the surface of the epithelial cells, were also identical in both groups of adenomas. Thus, neither the routine histological nor the mucin- and immunohistochemical features differed between the groups, except for severe dysplasia. It is concluded that there is no inherent difference in malignant potential between solitary and synchronous adenomas, with the possible exception of the degree of dysplasia.

Cu/Zn-containing proteins have recently become of interest with regard to their relation with malignant disorders. Cu Zn-superoxide dismutase (Cu/Zn-SOD) was found increased in chemically induced tumors of the large bowel whereas metallothionein (MT), containing Zn and some Cu, was shown important for the response of tumors to chemotherapy. In the present study, we evaluated the Cu/Zn-SOD and MT content of normal human colonic mucosa and colorectal carcinomas, obtained from 20 resection specimens, and of 47 adenomatous polyps. The Cu/Zn-SOD content of polyps and carcinomas was significantly (p less than 0.01) elevated when compared to normal mucosa. In the adenomatous polyps the Cu/Zn-SOD content increased significantly with increasing grade of epithelial cell dysplasia, diameter, and presence of a villous component. In the carcinomas no relation was noticed between the Cu/Zn-SOD content and the Dukes' stage or the grade of differentiation. The MT content was significantly decreased in both adenomatous polyps and carcinomas when compared to that in normal mucosa. The MT content was not related to the grade of epithelial cell dysplasia of the polyps, and to the Dukes' stage or the differentiation of the carcinomas. In conclusion, neoplasia of the colorectum is accompanied by an increase in Cu/Zn-SOD and a decrease in MT. These findings support the association between changes in Cu/Zn proteins and malignancy.

In a series of 124 consecutive Dutch patients the clinical and morphological features of 166 endoscopically removed colorectal adenomatous polyps were reviewed. The most frequent clinical symptom was manifest blood loss with the stools (51%), but no specific adenoma symptom seemed to exist. Barium enema X-ray examination was done in 108 patients, whereas all patients were colonoscoped. The routinely performed barium examinations detected 71% of the polyps that were found during endoscopy, but not all X-ray examinations were air contrast barium enemas. A good correlation between the localization of the adenomas after both diagnostic modalities was found, indicating that more than 80% were located in the left part of the colon. Nineteen percent of the patients had had a metachronous (pre)neoplastic lesion removed from their large bowel previously, while 40% of the patients had a synchronous polypoid lesion at the moment of polypectomy. Sixty-two percent of the adenomas were tubular, whereas 38% were villous adenomas. There was a strong correlation between size and villous architecture (r = 0.38; p less than 0.001). The epithelial dysplasia was mild in 21%, moderate in 70% and severe in 9% of the adenomas. The degree of dysplasia correlated well with the villous type of mucosal growth (r = 0.24; p less than 0.005). These findings indicate that, 1) there are no colorectal adenoma specific symptoms, 2) to detect colorectal adenomas colonoscopy is the investigation of choice, 3) after the detection of a colorectal adenoma the whole colon should be investigated, 4) colorectal adenoma patients should be kept under surveillance, and 5) determination of the diameter and of the degree of epithelial cell dysplasia may be helpful in assessing the biological behavior of an adenomatous polyp.

Flow cytometry has been used to study the incidence of aneuploidy in a series of 55 colorectal adenomas (29 tubular adenomas, 22 tubulovillous adenomas, and 4 villous adenomas). For comparison, 5 nonadenomatous polyps, 4 normal mucosa samples from colectomy specimens and 16 colorectal cancers were measured. Fifteen (27%) adenomas were aneuploid, 33 (63%) were diploid, and 7 (11%) were peridiploid. The aneuploidy incidence increased with the size of the adenomas (less than 1 cm, 0%; 1 to 2 cm, 30%; greater than 2 cm, 50% aneuploid cases, respectively) but was less dependent on the histological type or degree of dysplasia. However, the degree of aneuploidy [mean DNA index of aneuploid stem lines] was significantly higher in tubulovillous adenomas [1.26 +/- 0.33 (SD)] than in tubular adenomas [1.09 +/- 0.04] and only slightly lower than in carcinomas [1.59 +/- 0.26]. The progressive increase in ploidy abnormality with size and histological type strongly supports the evidence for the adenoma-carcinoma sequence in the development of colorectal cancer.