NSAID-induced polyp regression in familial adenomatous polyposis patients

NSAIDs inhibit prostaglandin synthesis. In 1983, Waddell et al first reported that sulindac, a NSAID (Clinoril), caused regression of rectal adenomatous polyps in several patients with familial adenomatous polyposis, an inherited form of colorectal cancer. Subsequently, NSAIDs have been used as chemopreventive agents in animal carcinogenesis models and adenoma regression had been confirmed in human trials with sulindac. This article summarizes these developments and describes possible mechanisms of colorectal neoplasia chemoprevention.     

Colorectal adenoma in patients with a history of breast cancer: a prospective study in Taiwan

The increased incidence of colorectal cancer in women with a history of breast cancer is well established. However, the relationship between the prevalence of adenomatous polyps and breast cancer is still controversial. We conducted a prospective study of the incidence of colorectal polyps in patients with a history of breast cancer in Taiwan. Eighty-nine patients (86 women and 3 men) received colonoscopy to test for precancerous lesions. Mean age was 49.4 +/- 10.4 years. Twelve polyps (9 adenomatous, 2 hyperplastic, 1 inflammatory) (13.5%) and one cancer (1.1%) were found. The mean age of patients with and without colorectal neoplasia was 56.3 +/- 9.4 and 48.2 +/- 10.2 years respectively, (p < 0.005); 10 out of 13 patients (77%) with colorectal neoplasia were over 50 (p < 0.1). Compared with a study of Chinese people in Hong Kong, our population had a lower incidence of colorectal adenomatous polyps, but breast cancer patients have a greater risk of developing colorectal cancer than the general population in Taiwan.     

Reducing the subconscious frown by endoscopic resection of the corrugator muscles

A prospective study concerning colorectal polyps in symptomatic patients was held at Lima, Perú, an area considered of low incidence for colorectal neoplasia. In 137 patients, 272 polyps were resected by colonoscopic polypectomy or surgery. 55.9% were adenomas, 40.4% non neoplastic polyps and 3.7% polypoid carcinomas. The distribution of polyps, and the incidence of dysplasia and malignant changes in the adenomas, were similar of that reported in areas with high incidence of colorectal cancer. A high proportion of patients with adenomas (21.4% had a synchronous advanced carcinoma, specially if there were multiple adenomas. The figure was lower in patients with only non neoplastic polyps (7.5%). There were no cases of "de novo" carcinoma. This evidence suggest that adenomas play an essential role in colorectal cancer histogenesis, even in areas of low incidence of this neoplasia.     

Does colonoscopic polypectomy reduce the incidence of colorectal carcinoma?

The study's objective was to examine whether there is evidence that colonoscopic polypectomy reduces the incidence of colorectal cancer. The records of all patients who underwent colonoscopic polypectomy by a single surgeon between 1974 and 1991 were reviewed. Patients with colorectal cancer diagnosed at the initial colonoscopy, with a history of colorectal cancer, inflammatory bowel disease or familial adenomatous polyposis or with only hyperplastic polyps were excluded. There were 1008 remaining patients, of whom 645 have attended at least one follow-up colonoscopic examination, and these 645 patients from the basis of the study, because the incidence of cancer is known exactly in this group. The mean period of follow up was 4.4 years and the mean number of follow-up colonoscopic examinations was 2.2. There was a total of 2847 person-years of colonoscopic follow up. The expected incidence of cancer, age and sex adjusted, is calculated using Australian epidemiological figures. The observed incidence of cancer was 3 cases (all asymptomatic) per 2847 person-years, which is indistinguishable from the general population's risk of 3.75 cases per 2847 person-years. Analysis of previous publications suggests that patients with adenomas are at an increased risk of developing colorectal cancer of about 2.5 times the general population's risk. If correct, then the observed incidence of 3 cases per 2847 person-years is less than the expected incidence of 9.4 cases per 2847 person-years. This analysis suggests colonoscopic polypectomy does reduce the incidence of colorectal cancer.     

Possibility of different cancer development between the proximal and distal colon: comparison of the distribution between adenomatous polyps and cancer

BACKGROUND/AIM: The aim of this study was to compare the distribution of adenomatous polyps with that of cancer in the colon by using adenomatous polyps removed by colonoscopy. METHODOLOGY: 1223 adenomatous polyps removed by an endoscopic polypectomy were compared with 226 colon cancers with regard to their distribution, size and age. RESULTS: With patients over 65 years of age, the incidence of adenomatous polyps was lower in the proximal colon than in the distal colon, however, the incidence of cancer was higher in the proximal colon than in the distal colon (p<0.05). The distribution of adenomatous polyps according to size was also significantly different between the proximal and distal colon (p<0.05). CONCLUSION: These results thus suggest that some difference may exist in cancer development between the proximal and distal colon.     

Pneumocephalus and respiratory depression after accidental dural puncture during epidural analgesia--a case report

BACKGROUND: Adenomatous colonic polyps are accepted as premalignant lesions. There is controversy regarding the significance of the hyperplastic polyp. The aim of this study was to determine the incidence of further polyps in patients with only hyperplastic polyps on a first colonoscopy in comparison with patients without polyps and with adenomatous polyps. METHODS: Ninety patients had only hyperplastic polyps (group I). These patients were paired according to age and sex with subjects having no polyps (group II) and with patients having adenomas (group III). RESULTS: Fifty-six patients in group I had at least one follow-up examination. New polyps were found in 46.4% in group I versus 15.5% in group II (p < 0.001) and 50% in group III (NS). In group I, 30.7% of new polyps were hyperplastic and 69.3% were adenomas. In fact, 32.2% of group I patients developed further adenomas (mean 1.5 +/- 0.8 adenomas). These adenomas occurred 1 to 4 years after the first polypectomy (mean 2.4 +/- 0.8 years). Most of these adenomas were small and tubular, but 16.6% were villous or had severe dysplasia. CONCLUSION: Patients with hyperplastic polyps were 2.4 times more likely to have further adenomas than were those without polyps.     

Evaluation of various screening and surveillance methods in colorectal carcinoma

Colorectal cancer is a common disease which is almost wholly preventable by early removal of adenomatous polyps. Screening should be offered to all persons without risk factors from the age of 50. Selection of the appropriate screening programme should take into account personal preference, local expertise and insurance coverage. Endoscopic screening and surveillance investigations should be strongly encouraged in all persons wit risk factors such as (1) previous treatment of colorectal adenomatous polyps or cancers, (2) ulcerative colitis, (3) patients with hereditary colorectal cancer syndromes and (4) first degree relatives of patients with colorectal cancer. The following four strategies are available for candidates > 50 years without risk factors: (1) faecal occult blood testing (annually), (2) flexible sigmoidoscopy (every 5 years), (3) a combination of both (1 + 2) strategies and (4) coloscopy (every 10 years). Coloscopy should be performed after a positive test result in strategy programs 1-3. Results from prospective randomized trials are available only for faecal occult blood testing, showing an approximately 15% reduction of mortality in the screening group. The potential for reduction of colorectal cancer mortality has been estimated at 30-70% and 60-90% for flexible sigmoidoscopy and coloscopy respectively. However, no results from prospective randomized trials are presently available. Cost-effectiveness analysis has not shown relevant differences between the four different screening strategies.     

Establishment of a colonic polyp registry in Rhode Island

A colonic adenomatous polyp registry (PR) has been organized at the Roger Williams Medical Center whose main functions are to prevent the occurrence of colorectal cancer (CRC) in the enrollees, to provide a population of subjects for epidemiological and interventional studies, and to provide educational, including dietary, information to subjects and physicians. One hundred four and 202 patients with polyps, originally retrieved from the hospital pathology files, were enrolled in the 1984 and 1987 cohorts, respectively, of whom about 90% were followed for at least three years after polypectomy. Three carcinomas, all Dukes A, were found in the right colon in the follow-up period. New polyps identified in the first three years after polypectomy were generally small tubular adenomas with a greater predilection for the right colon than was found for the index polyps. Risk factors for new polyps included history of previous polyps and, probably, multiple index polyps. The use of colonoscopy for postpolypectomy surveillance increased between 1984 and 1987. About 25% of the subjects in each cohort were either lost to follow-up or received no endoscopic surveillance. On the other hand, some of those who were followed were probably subjected to excessive numbers of procedures. Defects in the PR include inadequacy of personal and family history data, and steady loss of patients during the three to six years after polypectomy. Despite the small size and limited resources of our hospital, its colonic polyp registry has already provided information that may help in the management of patients with this premalignant condition. The more widespread use of securely funded polyp registries would probably reduce the incidence of metachronous CRC in that population and would have significant epidemiological and educational functions.     

Pathologic features of initial adenomas as predictors for metachronous adenomas of the rectum

BACKGROUND: Colorectal cancer is the third most common cancer in the world, arising mostly from pre-existing adenomatous polyps (adenomas) of the large bowel. Patients with colorectal adenomas are at increased risk of colorectal cancer because of a high recurrence rate for adenomas. We followed a cohort of 1490 patients with rectal adenomas to determine whether recurrence might be related to pathologic characteristics of the initial adenomas. METHODS: The patients were identified in Haining County, China, from 1977 through 1978 by means of examination with a 15-cm rigid sigmoidoscope. They were followed by endoscopic examination at years 2, 4, 6, 11, and 16 after their initial polypectomy. New adenomas in the rectum were identified in 280 patients in these follow-up examinations. RESULTS: Statistically significant twofold to threefold elevated risks of metachronous (recurrent) adenomas were observed for patients who had more than two initial adenomas or whose most advanced initial adenoma was more than 1.0 cm in size, was of villous/tubulovillous type, or showed moderate to severe dysplasia. Much stronger associations were observed for advanced metachronous neoplasms, which are defined as cancers or adenomas with severe dysplasia, with multivariate adjusted relative risks (95% confidence interval) of 4.2 (1.8-9.9) for a large initial adenoma (>1.0 cm), 8.1 (4.2-15.6) for villous/tubulovillous architecture, and 14.4 (5.0-41.3) for severe dysplasia. In particular, patients who had a large (>1.0 cm) adenoma with severe dysplasia at baseline had a relative risk of 37 (7.8-174.7) of developing advanced metachronous neoplasms compared with patients who had small adenoma(s) with mild dysplasia. CONCLUSIONS: The risk of metachronous adenomas is closely related to the pathology of initial adenomas, thus allowing identification of a high-risk group of adenoma patients for close surveillance after their initial polypectomy.     

Complications in the endoscopic polypectomy of colonic adenomas

Endoscopic polypectomy is associated with a small but definite risk of bleeding and perforation. Patients with large adenomas are thus usually hospitalized for endoscopic resection. In order to evaluate whether these procedures can be performed in the setting of one day surgery, we retrospectively analyzed the complications and results of polypectomy done in the period from 1.1.1990 through 31.12.1994. Of 1399 colorectal adenomas respected in 680 patients, 385 (28%) were larger than 1 cm. Altogether we observed only 3 (0.2%) clinically significant complications: bleeding was seen in 2 patients, of whom only one required transfusion of one unit. One patient required surgery because of perforation after removal of a sessile cecal adenoma with uneventful outcome. These results show that endoscopic resection of colorectal adenomas is safe even if the polyps are large.     

Flat adenoma as a precursor of colorectal carcinoma in hereditary nonpolyposis colorectal carcinoma

BACKGROUND: Because flat adenoma shows a higher malignancy rate compared with other types of polyps, it is considered to play an important role in the carcinogenesis of colorectal carcinoma. In the present study, we examined flat adenomas in hereditary nonpolyposis colorectal carcinoma (HNPCC) patients. METHODS: Nine HNPCC patients who presented with flat adenomas were examined. All patients underwent either surgery or endoscopic polypectomy for colorectal carcinoma and/or adenoma. In all patients, annual colonoscopy had been performed once a year throughout the follow-up period after the initial treatment. When colorectal polyps were detected during follow-up colonoscopy, all lesions were endoscopically excised. Clinicopathologic features and microsatellite instability of both malignant lesions and adenomas were examined. RESULTS: Thirteen malignant lesions were detected: seven advanced carcinomas and six early carcinomas. Among 4 early carcinomas with submucosal invasion, 3 lesions (75%) were categorized as superficial type, with a configuration similar to flat adenoma. The frequency of flat adenoma was strikingly high in HNPCC patients in the present study. Among 73 polyps detected, 37 (50.7%) were flat adenomas. Both malignant lesions and flat adenomas had proximal predominance, 61.5% and 59.5%, respectively. Eleven of 15 lesions (73.3%) showed replication error. CONCLUSIONS: These results suggest the importance of flat adenoma as a precursor of colorectal carcinoma in some groups of HNPCC patients. Further study is essential to elucidate the natural history of flat adenomas in HNPCC patients.     

Clinical outcome of surgical treatment for invasive early colorectal cancer in Japan

BACKGROUND/AIMS: Despite the high frequency of early colorectal cancer, little is known about the clinicopathologic features of invasive early colorectal cancer for which endoscopic polypectomy is not indicated. We wanted to determine the clinicopathologic features of these early colorectal cancers. MATERIALS AND METHODS: From 1973 to 1994, a total of 728 patients with colorectal cancer were reviewed retrospectively from hospital records. The clinicopathologic features of the 90 invasive early colorectal cancer patients who underwent major surgeries were compared with those of 626 patients with advanced colorectal cancer. RESULTS: The frequency of early colorectal cancer increased significantly from the periods 1973-1979 to 1990-1994: 0% in the former period and 18.3% in the later period. Minimally invasive surgery was chosen more frequently for the treatment of early colorectal cancers than for the treatment of advanced cancers (p < 0.005). Lymph node metastasis, lymph vessel invasion, and vascular invasion were more prevalent in advanced cancer cases than in early cancer cases (p < 0.005). Lymph node metastasis was found in 7 patients with early colorectal cancer (7.8%). There was no difference in histologic type between the early and advanced colorectal cancers. The 5-year survival rates of early colorectal cancer patients were higher than those of advanced cancer patients: 97.5% in early colon cancer patients; 93.5% in early rectal cancer patients; 59.8% in advanced colon cancer patients; 55.4% in advanced rectal cancer patients. Three early colorectal cancer patients died of recurrence. CONCLUSION: Minimally invasive surgery such as laparoscopic colectomy should be performed on patients with invasive early colorectal cancer when it is impossible for the cancer to be removed by endoscopic polypectomy.     

A prospective evaluation of the safety and efficacy of methohexital in the emergency department

OBJECTIVE: Knowledge of a possible correlation between distal polyps found at screening sigmoidoscopy and proximal colonic lesions is important for deciding whether to perform total colonoscopy or not. PATIENTS: A prospective analysis of 2439 consecutive patients with colorectal polyps. Of these, 304 were asymptomatic subjects who underwent complete colonoscopy for screening and were found to have adenomatous or hyperplastic polyps in the distal colorectum. RESULTS: Ten (15%) out of 65 patients with distal hyperplastic polyps only and 86 (36%) out of 239 with distal adenomatous polyps were found to have adenomatous polyps in the proximal colon as well (P < 0.001). The frequency of synchronous proximal adenomas in patients with small (< or = 5 mm) or large distal adenomas (> 5 mm) was comparable (37% and 35%, respectively). However, patients with small distal adenomas had significantly smaller proximal adenomas (P = 0.004) containing less villous component (P = 0.017) than those with large distal adenomas. Neither the patient's age nor the presence of multiple distal adenomas increased the prevalence of proximal adenomas. CONCLUSION: Hyperplastic polyps found on rectosigmoidoscopy do not indicate a need for a complete colorectal examination, as 15% of patients with distal hyperplastic polyps will have proximal adenomatous polyps, a figure that is comparable with that of asymptomatic patients having no distal polyps, either hyperplastic or adenomatous. When only small distal adenomas are found at screening sigmoidoscopy in asymptomatic persons the decision to do a total colonoscopy should be based on individual considerations, as in such cases only small polyps are to be expected in the proximal colon.     

Detection of decay-accelerating factor in stool specimens of patients with colorectal cancer

BACKGROUND & AIMS: Colorectal cancers have an increased expression of decay-accelerating factor (DAF). The aim of this study was to determine whether stool specimens of patients with colorectal cancer contain increased amounts of DAF. METHODS: DAF was measured using an immunoassay in the stool specimens of 40 persons with colorectal cancer, 18 with colorectal adenomatous polyps, 13 with upper gastrointestinal cancer, and 41 without gastrointestinal disease. RESULTS: Stool DAF concentrations in patients with colorectal cancer (0-9.8 ng/g stool; median, 1.6 ng/g) were significantly higher than those in patients with adenoma (0-6.4 ng/g; median, 0 ng/g) (P < 0.05), patients with upper gastrointestinal cancer (0-3.1 ng/g; median, 0 ng/g) (P < 0.05), and subjects without gastrointestinal disease (0-3.4 ng/g; median, 0 ng/g) (P < 0.01). Resection of colorectal cancers caused a marked decrease in stool DAF concentrations. The stool DAF test was positive in a substantial portion of patients with colorectal cancer whose tumors were small ( < 2 cm), at an early TNM stage, or unassociated with fecal occult blood positivity. The sensitivity of the test for colorectal cancer was 55%, and the specificity was 85%. CONCLUSIONS: The measurement of stood DAF deserves evaluation as a test for detection of colorectal cancer.     

Tissue prostaglandin levels in familial adenomatous polyposis patients treated with sulindac

BACKGROUND: Recent work has demonstrated a correlation between frequency of aspirin ingestion and colorectal cancer prevention. Sulindac, another nonsteroidal anti-inflammatory drug (NSAID), has been shown to cause polyp regression and a fall in cell proliferation in patients with familial adenomatous polyposis, who are destined to develop colorectal cancer unless the colon is removed. However, the mode of action of NSAIDs in colorectal carcinogenesis prevention remains to be determined, although a prostaglandin-mediated mechanism seems likely. METHODS: Rectal or duodenal biopsies from 20 patients with familial adenomatous polyposis, who had been randomized to sulindac or placebo, were analyzed for prostaglandin (PG) E2 and F2 alpha levels before and after treatment. RESULTS: A significant fall in prostaglandin E2 and F2 alpha levels was seen in patients who were on sulindac; this correlated with a visual improvement in number and size of polyps in the same patients (P = 0.0096; PGE2, P = 0.036; PGF2 alpha, Spearman's rank correlation). CONCLUSIONS: Nonsteroidal anti-inflammatory drugs may prevent colorectal cancer by their inhibition of prostaglandin synthesis. Prostaglandins may be implicated in carcinogenesis through an increase in cell proliferation, through immunosuppression, by increasing neovascularization, or via a mutagenic effect.     

Colorectal lesions predisposing to cancer

Precursors of colorectal carcinoma are adenomatous polyps, sporadic or arising in familial adenomatous polyposis and Lynch syndrome and chronic inflammatory lesions related to ulcerative colitis and Crohn's disease. The adenoma-carcinoma sequence is well established and early detection and removal of colorectal adenomas is thought to prevent colorectal cancer in high risk asymptomatic persons, i.e. subjects over 45 years, with personal or familial history of adenomas and colorectal cancers. The precancerous potential of adenomatous polyps varies according to tissue type, with increased risk with the extent of the villous component, high grade of dysplasia, large size greater than 1 cm and multiple adenomas. The development of de novo colorectal cancer from normal mucosa with flat adenomas has been recently emphasized. The risk of colonic cancer in patients with ulcerative colitis and Crohn's disease is controversed.     

Prevention of gastrointestinal cancer--the potential role of NSAIDs in colorectal cancer

Gastrointestinal cancers are among the leading sites of cancer and leading causes of cancer-related deaths. Gastrointestinal cancers are often at an advanced stage at the time of diagnosis, and are highly resistant to non-surgical therapy. Thus early diagnosis and prevention are approaches that are under active investigation. Screening and surveillance are considered secondary prevention. Primary prevention is the use of dietary or environmental modification or chemopreventive agents. This written review will emphasize the potential role of acetylsalicylic acid and other non-steroidal anti-inflammatory drugs (NSAIDs) in the prevention of gastrointestinal cancer, and specifically colorectal cancer. Cell culture and animal studies have shown that NSAIDs possess anti-proliferative and anti-neoplastic effects. Recent epidemiologic surveys also suggest that individuals who regularly take NSAIDs, particularly acetylsalicylic acid, have about a 50% decrease in colorectal cancer incidence and mortality. However, in the only interventional trial of aspirin (and beta-carotene), a retrospective analysis had inadequate statistical power to demonstrate any protective effect against colorectal cancer. About a dozen small prospective intervention studies have been done in a total of about a hundred patients with familial adenomatous polyposis to test the efficacy of NSAIDs, particularly sulindac. All human trials have shown substantial partial and some complete regression of colorectal and perhaps also duodenal adenomatous polyps. But virtually all patients had regrowth of adenomatous polyps after sulindac was stopped. In addition, sulindac and other NSAIDs result in occasional adverse events such as gastrointestinal bleeding. Thus sulindac cannot be recommended for routine use outside of a study setting. One valid current approach to the prevention of gastrointestinal cancer, and colorectal cancer in particular, is the adoption of a healthy lifestyle and appropriate screening and surveillance. Screening and surveillance guidelines have been developed by several public agencies and their recommendations should be adopted. In addition, we should adopt a healthy lifestyle and diet, which consists of low fat ( < 30% to total calories), and high fiber (> 3 daily servings of fruits/vegetables), with the avoidance of red meats ( < 3 weekly servings) and alcohol ( < 2 drinks daily), and the absolute avoidance of tobacco smoking.     

The inducible prostaglandin biosynthetic enzyme, cyclooxygenase 2, is not mutated in patients with attenuated adenomatous polyposis coli

Germ-line mutations in the APC gene cause adenomatous polyposis coli (APC), a syndrome in which patients develop hundreds to thousands of precancerous adenomatous colorectal polyps. We described previously an attenuated form of APC (AAPC) resulting from very 5' mutations in APC in which affected patients exhibit fewer colorectal polyps and a later age of onset of colorectal cancer. However, because striking variations in colorectal polyp numbers occur among patients carrying identical AAPC mutations, alleles of another gene may modify the expression of the APC disease phenotype. We tested the hypothesis that loss of function of human cyclooxygenase 2 (COX-2), known to modify the APC phenotype in the Apc delta716 mouse, results in a decreased tumor burden in AAPC patients that develop very few colorectal polyps. Genomic DNA sequence analysis of human COX-2 revealed a silent mutation in exon 3 that was evenly distributed between two classes of patients with AAPC, those with small or large numbers of colorectal polyps. We also found no difference in levels of COX-2 mRNA in transformed blood lymphocytes among AAPC patients of either class or patients with classical APC, and no alterations that correlated with a lesser or greater number of colorectal polyps were detectable within approximately the first 1 kb of the promoter sequence. Therefore, mutation of the human COX-2 gene does not appear to be responsible for a low tumor burden among AAPC subjects.     

Molecular biology of colorectal cancer

Colorectal cancer is a significant cause of morbidity and mortality in Western populations. This cancer develops as a result of the pathologic transformation of normal colonic epithelium to an adenomatous polyp and ultimately an invasive cancer. The multistep progression requires years and possibly decades and is accompanied by a number of recently characterized genetic alterations. Mutations in two classes of genes, tumor-suppressor genes and proto-oncogenes, are thought to impart a proliferative advantage to cells and contribute to development of the malignant phenotype. Inactivating mutations of both copies (alleles) of the adenomatous polyposis coli (APC) gene--a tumor-suppressor gene on chromosome 5q--mark one of the earliest events in colorectal carcinogenesis. Germline mutation of the APC gene and subsequent somatic mutation of the second APC allele cause the inherited familial adenomatous polyposis syndrome. This syndrome is characterized by the presence of hundreds to thousands of colonic adenomatous polyps. If these polyps are left untreated, colorectal cancer develops. Mutation leading to dysregulation of the K-ras protooncogene is also thought to be an early event in colon cancer formation. Conversely, loss of heterozygosity on the long arm of chromosome 18 (18q) occurs later in the sequence of development from adenoma to carcinoma, and this mutation may predict poor prognosis. Loss of the 18q region is thought to contribute to inactivation of the DCC tumor-suppressor gene. More recent evidence suggests that other tumor-suppressor genes--DPC4 and MADR2 of the transforming growth factor beta (TGF-beta) pathway--also may be inactivated by allelic loss on chromosome 18q. In addition, mutation of the tumor-suppressor gene p53 on chromosome 17p appears to be a late phenomenon in colorectal carcinogenesis. This mutation may allow the growing tumor with multiple genetic alterations to evade cell cycle arrest and apoptosis. Neoplastic progression is probably accompanied by additional, undiscovered genetic events, which are indicated by allelic loss on chromosomes 1q, 4p, 6p, 8p, 9q, and 22q in 25% to 50% of colorectal cancers. Recently, a third class of genes, DNA repair genes, has been implicated in tumorigenesis of colorectal cancer. Study findings suggest that DNA mismatch repair deficiency, due to germline mutation of the hMSH2, hMLH1, hPMS1, or hPMS2 genes, contributes to development of hereditary nonpolyposis colorectal cancer. The majority of tumors in patients with this disease and 10% to 15% of sporadic colon cancers display microsatellite instability, also know as the replication error positive (RER+) phenotype. This molecular marker of DNA mismatch repair deficiency may predict improved patient survival. Mismatch repair deficiency is thought to lead to mutation and inactivation of the genes for type II TGF-beta receptor and insulin-like growth-factor II receptor. Individuals from families at high risk for colorectal cancer (hereditary nonpolyposis colorectal cancer or familial adenomatous polyposis) should be offered genetic counseling, predictive molecular testing, and when indicated, endoscopic surveillance at appropriate intervals. Recent studies have examined colorectal carcinogenesis in the light of other genetic processes. Telomerase activity is present in almost all cancers, including colorectal cancer, but rarely in benign lesions such as adenomatous polyps or normal tissues. Furthermore, genetic alterations that allow transformed colorectal epithelial cells to escape cell cycle arrest or apoptosis also have been recognized. In addition, hypomethylation or hypermethylation of DNA sequences may alter gene expression without nucleic acid mutation.     

Flat cancers do develop in the polyp-free large intestine

PURPOSE AND BACKGROUND: Qualitative and quantitative analysis of many flat early cancers that have been discovered during the last decade led us to recognize that a flat route of cancer development de novo is as important a route as the polypoid one. We aim to prove through a longitudinal study that these flat early cancers indeed develop in flat mucosa and not in an adenomatous polyp. METHODS: From January 1, 1990, to July 31, 1994, 554 patients underwent at least two colonoscopies. These patients consisted of 364 males, and average age was 59 years. We searched for flat early cancers developing in polyp-free colorectal mucosa on or after a second colonoscopy. Polyp-free mucosa here means an intestinal segment proved to possess no adenomatous polyp during the preceding colonoscopies, irrespective of the presence of polyps elsewhere. RESULTS: Four flat early cancers were found developing in polyp-free colonic mucosa in four patients. Average age of the patients was 67 years. Locations of the cancers were the transverse (3) and descending colons (1). The shapes were all depressed, and average size of the lesions was 11 mm. Two lesions were endoscopically resected, and two by surgery. CONCLUSION: These four depressed cancers developing in polyp-free mucosa show that flat early colorectal cancers do arise de novo and not from an adenomatous polyp having collapsed on itself.