Precursor Adenomas Research Articles

Secondary tumors of the gastrointestinal tract

Metastatic involvement of the gastrointestinal tract is rare and may cause considerable difficulties with respect to differential diagnosis. The gastrointestinal tract may either be affected by direct invasion, intraperitoneal dissemination or hematogenous cancer spread, the latter most often originating from malignant melanoma, breast and lung carcinomas. Metastatic deposits primarily develop within the submucosa. Secondary involvement of the mucosa typically leads to centrally depressed and/or ulcerated (volcano-like) nodular lesions. In histology, lack of a mucosal in situ component favors diagnosis of metastasis, whereas presence of an adenomatous precursor lesion is regarded to be characteristic of primary tumors. This concept, however, has recently been challenged by demonstrating metastatic cancer growth along intact basement membranes within the mucosal layer, i.e. mucosal colonization. The histopathological, immunohistochemical and clinical features of secondary gastrointestinal tumors are discussed in detail, focusing on criteria for differential diagnosis. The prognosis of affected patients is generally poor.

Endoscopy in screening for digestive cancer.

The aim of this study is to describe the role of endoscopy in detection and treatment of neoplastic lesions of the digestive mucosa in asymptomatic persons. Esophageal squamous cell cancer occurs in relation to nutritional deficiency and alcohol or tobacco consumption. Esophageal adenocarcinoma develops in Barrett's esophagus, and stomach cancer in chronic gastric atrophy with Helicobacter pylori infection. Colorectal cancer is favoured by a high intake in calories, excess weight, low physical activity. In opportunistic or individual screening endoscopy is the primary detection procedure offered to an asymptomatic individual. In organized or mass screening proposed by National Health Authorities to a population, endoscopy is performed only in persons found positive to a filter selection test. The indications of primary upper gastrointestinal endoscopy and colonoscopy in opportunistic screening are increasingly developing over the world. Organized screening trials are proposed in some regions of China at high risk for esophageal cancer; the selection test is cytology of a balloon or sponge scrapping; they are proposed in Japan for stomach cancer with photofluorography as a selection test; and in Europe, America and Japan; for colorectal cancer with the fecal occult blood test as a selection test. Organized screening trials in a country require an evaluation: the benefit of the intervention assessed by its impact on incidence and on the 5 year survival for the concerned tumor site; in addition a number of bias interfering with the evaluation have to be controlled. Drawbacks of screening are in the morbidity of the diagnostic and treatment procedures and in overdetection of none clinically relevant lesions. The strategy of endoscopic screening applies to early cancer and to benign adenomatous precursors of adenocarcinoma. Diagnostic endoscopy is conducted in 2 steps: at first detection of an abnormal area through changes in relief, in color or in the course of superficial capillaries; then characterization of the morphology of the lesion according to the Paris classification and prediction of the risk of malignancy and depth of invasion, with the help of chromoscopy, magnification and image processing with neutrophil bactericidal index or FICE. Then treatment decision offers 3 options according to histologic prediction: abstention, endoscopic resection, surgery. The rigorous quality control of endoscopy will reduce the miss rate of lesions and the occurrence of interval cancer.

Complex patterns of altered MicroRNA expression during the adenoma-adenocarcinoma sequence for microsatellite-stable colorectal cancer.

MicroRNAs are short noncoding RNAs that regulate gene expression and are over- or underexpressed in most tumors, including colorectal adenocarcinoma. MicroRNAs are potential biomarkers and therapeutic targets and agents, but limited information on microRNAome alterations during progression in the well-known adenoma-adenocarcinoma sequence is available to guide their usage. We profiled 866 human microRNAs by microarray analysis in 69 matched specimens of microsatellite-stable adenocarcinomas, adjoining precursor adenomas including areas of high- and low-grade dysplasia, and nonneoplastic mucosa. We found 230 microRNAs that were significantly differentially expressed during progression, including 19 not reported previously. Altered microRNAs clustered into two major patterns of early (type I) and late (type II) differential expression. The largest number (n = 108) was altered at the earliest step from mucosa to low-grade dysplasia (subtype IA) prior to major nuclear localization of β-catenin, including 36 microRNAs that had persistent differential expression throughout the entire sequence to adenocarcinoma. Twenty microRNAs were intermittently altered (subtype IB), and six were transiently altered (subtype IC). In contrast, 33 microRNAs were altered late in high-grade dysplasia and adenocarcinoma (subtype IIA), and 63 in adenocarcinoma only (subtype IIB). Predicted targets in 12 molecular pathways were identified for highly altered microRNAs, including the Wnt signaling pathway leading to low-grade dysplasia. β-catenin expression correlated with downregulated microRNAs. Our findings suggest that numerous microRNAs play roles in the sequence of molecular events, especially early events, resulting in colorectal adenocarcinoma. The temporal patterns and complexity of microRNAome alterations during progression will influence the efficacy of microRNAs for clinical purposes.

Dynamic Shift in the Distribution of Colorectal Cancer

Purpose: Colorectal cancer (CRC) is the second leading cause of cancer death overall for both men and women in the U.S. Knowledge of CRC distribution is important as it can guide CRC screening, surveillance, and management. The purpose of this study was to elucidate the CRC distribution patterns in a population of U.S. patients. Methods: This retrospective study was conducted at Caris Life Sciences, a national specialized gastrointestinal pathology laboratory which receives specimens from ambulatory endoscopy centers across the U.S. Electronic data from the Caris database were analyzed, including demographics, clinical information, endoscopic findings, biopsy sites, and histopathologic findings. We extracted the records of all patients who had a diagnosis of CRC by Caris pathologists or a diagnosis of adenomatous polyps (AP) by a single Caris pathologist between 01/01/09 and 12/31/09. Patients were stratified by age into: >90, 80-89, 70-79, 60-69, 50-59, and <49 years old, and by CRC anatomic sites into right, left-sided colon, transverse colon, as well as non otherwise specific. Results: A total of 1,757 patients (age 66+13.3, range 21-96; 53.7% males) had CRC and 1,341 patients (age 60+10.7, 21-89; 59.3% males) had AP. The distributions of CRC and AP had a similar pattern with predominance in left colon, especially the rectosigmoid. Of CRC patients, the age group 60-69 had the highest frequency of CRC (25.8%). Women had more right-sided CRC than men (p=0.037). CRC was consistently less common in hepatic and splenic flexure and descending colon than in other locations. The trend of left-side CRC predominance was significantly correlated with the patient's age and was strongest (84.31%, p<0.001) in patients <49 years old. However, this pattern became progressively less defined with advancing age, and in patients older than 89 there was no difference between right and left colon distribution of CRC. Conclusion: Although the CRC distribution followed similar patterns with its adenomatous precursor, the strength of these correlations gradually diminished with advancing age and was weaker in women. Left-side predominance was strongly associated with younger age. The reason for the lower frequency of CRC in the hepatic and splenic flexure and the descending colon is unclear, but it could be related to a shorter stool transit or stasis time within the colon. Disclosure: One author is employed by Caris Life Sciences.

Abstract 3762: CIMP is common for right-sided colon sessile serrated polyps but not for colorectal adenomas

Abstract Background: Several pathways for colorectal cancer (CRC) have been described. The well-known adenoma-to-carcinoma pathway usually results in microsatellite stable tumors and accounts for about 75% of CRC. Less is established about the origins of microsatellite unstable (MSI) CRC. These tumors are more often in the right colon and commonly characterized as having a CpG Island Methylator Phenotype (CIMP). Objective: We aimed to better understand precursors for MSI colorectal tumors by determining the correlation between CIMP-status and polyp type. Methods: We conducted a case-case comparison of CIMP status among participants aged 24-79 of a colonoscopy-based study, who were diagnosed with colorectal adenomas or hyperplastic polyps (HPs). During colonoscopy, polyps were biopsied, fixed in paraffin, and H&amp;E slides prepared. All participants underwent a standard pathology review to confirm the diagnosis, determine the percent of lesional tissue in the block, and classify each polyp as tubular adenoma, tubulovillous adenoma, HP (both goblet cell and microvesicular), sessile serrated polyp, or serrated adenoma. Medical records were abstracted to ascertain polyp location and size; tissue blocks from polyps at least 3 mm in diameter and containing at least 80% lesional tissue were selected for CIMP analyses. DNA methylation was quantified in 905 polyps by real-time PCR (MethyLight) using a validated CIMP marker panel (CACNA1G, IGF2, NEUROG1, RUNX3, SOCS1). ALU was used to monitor DNA quality. Of the 905 polyps tested, 752 (83%) had an ALU cycle threshold &amp;lt;23, and thus appropriate for CIMP analyses. Results: Of 434 adenomatous polyps, including 113 tubulovillous adenomas, only 2 (&amp;lt;0.5%) were CIMP-positive, both tubulovillous adenomas. For HPs and other serrated polyps, 87 out of 318 (27%) were CIMP-positive. Among these, sessile serrated polyps had the highest proportion of CIMP positivity: 59 of 108 (55%), followed by serrated adenomas: 4 of 11 (37%), and hyperplastic polyps: 24 of 199 (12%). Polyp location was also associated with CIMP status. For HPs/other serrated polyps, 2 of 87 (2%) rectal polyps were CIMP positive, 10 of 75 (13%) left colon polyps were positive, and 75 of 155 (48%) right were positive. Discussion: Until recently, sessile serrated polyps were classified as hyperplastic polyps and therefore, were thought to have little clinical significance. However, our investigation suggests that these polyps, like MSI CRC tumors, are commonly CIMP-positive. Adenomatous polyps, in contrast, were largely CIMP-negative. This finding supports other investigations suggesting MSI CRC is not likely to have an adenomatous precursor, and probably arises from serrated polyps. If confirmed by longitudinal studies, this will have important implications for CRC surveillance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3762. doi:10.1158/1538-7445.AM2011-3762

Mucosal Colonization by Metastatic Carcinoma in the Gastrointestinal Tract

The gastrointestinal (GI) tract is a common site for both primary and metastatic carcinomas. Distinguishing the two can occasionally be difficult, particularly when metastatic tumor reaches the mucosal surface. Features that are typically used to make this distinction include the presence of an adenomatous precursor lesion, regional lymph node involvement, and gross configuration of the tumor. However, we recently encountered 2 index cases of metastatic carcinoma in the small intestine (1 from the colorectum and 1 of endocervical origin) that were initially misinterpreted as primary small bowel carcinomas because of apparent in situ growth in the mucosal surface resembling polypoid, adenomatous precursor lesions. We, therefore, studied 100 GI resections from 1987 to 2009 that were reported to show mucosal involvement by metastatic carcinoma, and compared the histologic features with a control group of 29 primary small bowel adenocarcinomas. Gross descriptions and histologic sections were evaluated for the following: (1) tumor spread along an intact basement membrane of villi/crypts (mucosal colonization), (2) resemblance to an adenoma/precursor lesion, (3) gross configuration of the tumor, (4) lymphovascular invasion, and (5) regional lymph node involvement in the metastatic site. Metastatic sites included the small intestine (n=74), colorectum (n=16), or both (n=10). Primary tumors were GI (n=55, with 47 from colorectum), gynecologic (n=28), pulmonary (n=8), genitourinary (n=6), head and neck (n=2), and breast (n=1). Overall, 42 (42%) of the metastases that reached the mucosal surface of the bowel showed at least focal mucosal colonization, 26% resembled a precursor adenoma, 62% had regional lymph node positivity, and only 24% cases showed a classic serosal-based configuration. In 4 cases (2 of GI origin and 2 of gynecologic origin), metastatic tumors were initially interpreted as new primaries by the pathologist (n=2) or clinicians (n=2). Metastatic carcinomas originating from the GI tract were significantly more likely to show mucosal colonization (60% vs. 20%, P<0.0001) and resemblance to a precursor lesion (45% vs. 2%, P<0.0001) than other primary tumors. In a comparison between 29 primary small bowel carcinomas and 41 metastatic colorectal carcinomas in the small bowel, metastatic tumors were distinguished by a higher prevalence of multiple lesions (0% vs. 39%, P<0.0001), whereas small bowel primaries were more likely to show high tumor grade (41% vs. 17%, P=0.03). There were no significant differences in the mean age (61.4 y vs. 60.9 y), number of male participants (69% vs. 56%), growth along basement membranes (62% vs. 63%), apparent precursor lesion (55% vs. 46%), lymphovascular invasion (69% vs. 73%), or lymph node positivity (68% vs. 37.5%, P=0.065). These results confirm that metastatic carcinomas involving the mucosal surface of the intestines frequently exhibit gross and histologic features, which mimic second primaries, especially when they originate from the GI tract. In situ growth and presence of an apparent adenoma cannot be taken as prima facie evidence of a primary neoplasm.

Lessons From Lynch Syndrome: A Tumor Biology-Based Approach to Familial Colorectal Cancer

Colorectal cancer (CRC) develops within precursor lesions in the single-celled epithelial lining of the gut. The two most common epithelial lesions are the adenoma and the serrated polyp. CRC is also one of the most familial of the common cancers, and just as there are syndromes associated with increased risk of CRC arising in adenomas, there are also syndromes with increased CRC risk associated with serrated polyps. In this article, we describe the features of such a syndrome, familial serrated neoplasia, which distinguish it from the well-characterized condition Lynch syndrome (or hereditary nonpolyposis CRC), and show that the molecular pathology of tumors forms the basis for this distinction. Lynch syndrome CRC arises almost exclusively within adenomatous precursor lesions, in contrast with familial serrated neoplasia where at least half of the cancers develop in serrated polyps. Finally, rare families exist in which both conditions segregate independently, producing a difficult diagnostic picture.

Prevalence and risk of colorectal adenoma in asymptomatic Koreans aged 40–49 years undergoing screening colonoscopy

Colorectal cancer screening is recommended for average-risk persons beginning at age 50. However, information about the incidence and risk factors of precursor adenoma in preceding decades is limited. The aim of this study was to determine the prevalence and risk factors of colorectal adenoma in persons aged 40-49 years and to compare the data with those aged 30-39 years and 50-59 years. A cross-sectional study of 5254 asymptomatic subjects who underwent screening colonoscopy was conducted. Data were stratified by age into three groups: 608 aged 30-39 years, 1930 aged 40-49 years, and 2716 aged 50-59 years. Prevalence of overall adenomas was 10.4% in the 30-39 years age group, 22.2% in the 40-49 years age group, and 32.8% in the 50-59 years age group. Advanced adenoma was found in 0.7% of the 30-39 years age group, 2.7% of the 40-49 years age group, and 4.1% of the 50-59 years age group. In the 40-49 years age group, male sex and current smoking habits showed associations with low-risk adenoma after multiple adjustments. Moreover, male sex (odds ratio [OR] = 1.55, 95% confidence interval [CI]: 1.02-3.23), current smoking (OR = 1.58, 95%CI: 1.06-3.50), and family history of colorectal cancer (OR = 2.54, 95%CI: 1.16-5.56) were independent predictors of advanced adenoma in this age group. Prevalence of adenoma in subjects aged 40-49 years was higher than in previous studies. Male sex and current smoking habits along with a family history of colorectal cancer were associated with advanced adenoma in this age group.

Chromocolonoscopy detects more adenomas than white light colonoscopy or narrow band imaging colonoscopy in hereditary nonpolyposis colorectal cancer screening

Individuals carrying germline mutations in one of the genes responsible for hereditary nonpolyposis colon cancer (HNPCC) have a lifetime risk of up to 80 % of developing colorectal cancer. As there is evidence for a higher incidence of flat adenomatous precursors and because an accelerated adenoma-carcinoma sequence has been postulated for these patients, early detection of these lesions is essential. It was the aim of the present study to assess the detection rate of polypoid lesions by comparing chromocolonoscopy with standard white light colonoscopy and narrow-band imaging (NBI) colonoscopy. 109 patients were included (98 with a functionally relevant mutation in a mismatch repair gene, 11 fulfilling the strict Amsterdam criteria). In 47 patients, standard colonoscopy was followed by chromocolonoscopy with indigo carmine. In 62 patients, NBI was performed first followed by chromocolonoscopy. A total of 128 hyperplastic and 52 adenomatous lesions were detected. In the first series, 0.5 lesions/patient were identified by standard colonoscopy and 1.5 lesions/patient by chromocolonoscopy ( P < 0.001). In the second series, 0.7 lesions/patient were detected by NBI colonoscopy and 1.8 lesions/patient by chromocolonoscopy ( P = 0.01). At least one adenoma was detected in 15 % of patients by both standard and NBI colonoscopy compared with 28 % of patients by chromocolonoscopy. According to this study, chromocolonoscopy detects significantly more hyperplastic and, in particular, adenomatous lesions than standard white light colonoscopy or NBI.

Accuracy of CT Colonography for Detection of Large Adenomas and Cancers

Although recognition and curative treatment of both precursor adenomas and localized cancers are possible through early-detection, and regular screening reduces mortality from colorectal cancer, screening is largely underused. Reasons for underuse include performance drawbacks and issues of comfort, availability, and expense. Computed tomographic (CT) colonography is an alternative that provides minimally invasive, structural evaluation of the entire colorectum, and permits rapid imaging of the entire colorectum without sedation, and with few procedure-related complications. Its effectiveness in detecting asymptomatic colorectal lesions in previous studies is controversial, in large part because of differences in patient populations, imaging techniques, and radiologists' qualifications. This large prospective trial compared the accuracy of CT colonography in detecting histologically confirmed, large colorectal adenomas and cancers (≥10 mm in diameter), with findings on screening colonoscopy and histologic review, the reference standard. A total of 2600 asymptomatic patients 50 years of age or older scheduled to undergo routine colonoscopy were recruited at 15 clinical sites between 2005 and 2006. Lesions measuring 5 mm or more in diameter were identified by radiologists trained in CT colonography. The preparation for CT colonography included stool and liquid tagging, laxative purgation, and colonic insufflation. Examinations were performed with multidetector-row CT scanners with a minimum of 16 rows. Complete data were available for 2512 participants examined with CT colonography and colonoscopy on the same day. For adenomas and cancers ≥10 mm, the mean (± SE) per-patient estimates of several measured parameters were as follows: sensitivity (0.90 ±.06); specificity (0.86 ±.05), positive (0.23 ±.04) and negative (0.99 ± <.01) predictive values, and area under the receiver-operating-characteristic curve for CT colonography (0.89 ±.04). The estimated sensitivity of 0.90 for identifying patients with adenomas or cancers ≥10 mm indicates failure of CT colonography to identify large lesion(s) detected by colonoscopy in 10% of patients. The per-patient sensitivity for detecting lesions 6 to 9 mm in diameter was 0.78 ±.07. The per-polyp sensitivity for detecting lesions ≥10 mm was 0.84 ±.04. These data show that CT colonographic screening identified 90% of asymptomatic adults with adenomas and cancers ≥10 mm in diameter that were detected by screening colonoscopy. For smaller lesions (6 to 9 mm), the sensitivity was lower (78%).

Systemic treatment of advanced colorectal cancer: tailoring therapy to the tumor.

Colorectal cancer is a prevalent disease in Western countries. While prevention through screening is the best approach to combat the development of colorectal cancer through the removal of precursor adenomas, many patients present with advanced disease that will require surgery and systemic therapy to improve survival. With reference to systemic therapy, the median survival of patients with metastatic colorectal cancer (those with tumor spread to lymph nodes or distant sites) has improved over the past three decades due to the introduction of 5-fluorouracil (5-FU), its subsequent biomodulation, and the addition other chemotherapeutic agents. There is now evidence that the biology of the colorectal tumor, in addition to the stage of colorectal cancer, may predict response to 5-FU-based therapy. More recently, systemic biological therapies that target signaling processes for tumor growth, such as epidermal growth factor receptor, and vascular endothelial growth factor, are also effective in improving patient survival with metastatic colorectal cancer. The use of a combination of systemic therapies that include chemotherapy and biologic therapy should continue to increase patient survival with metastatic colorectal cancer through appropriately designed clinical trials. Treatments based on the biology of the colorectal tumor also need to be examined through clinical trials.

Screening for Colorectal Lesions with High-Resolution Video Colonoscopes in a German Male Average-Risk Population at 40 to 59 Years of Age

Prevalence data for colorectal neoplastic lesions obtained from screening colonoscopies have recently been reported for a U. S. American and a Polish average-risk population. However, prevalence data for a German average-risk population have not been published. From 1998 until 2003 a screening colonoscopy was offered to all male participants of a health assessment program. In a total of 618 volunteers with an average risk for colorectal cancer, polypoid lesions were identified and removed using high-resolution video colonoscopes. The histological features of the lesions were categorised according to those of the most advanced one. An advanced lesion was defined as an adenoma of at least 1 cm in diameter, a polyp with villous histological features or high-grade intraepithelial neoplasms or a cancer. Data were analysed in two groups: age 40 - 49 years (group A) and age 50 - 59 years (group B). In group A (age 40 - 49 years, n = 285), 133 subjects (47 %) had polypoid lesions. Histological findings revealed that 57 subjects (20 %) had non-neoplastic and 76 subjects (27 %) had neoplastic lesions. In nine cases (3.2 %) polyps were classified as advanced lesions with a maximal diameter of 35 mm. In group B (age 50 - 59, n = 333), 183 subjects (55 %) had polypoid lesions. Histological findings revealed that 64 subjects (19 %) had non-neoplastic and 119 subjects (36 %) had neoplastic lesions. Among those, 34 (10.2 %) had advanced lesions with a maximal diameter of 55 mm. In neither group was an invasive cancer detected. The difference in the prevalence of neoplastic lesions between the two age groups was statistically significant (chi (2) = 5.85). An exceptionally high rate of 27 % neoplastic lesions was detected in subjects at 40 to 49 years of age. The rate of detected lesions in the group of older subjects was 36 %. By using high-resolution endoscopes we found an unexpectedly large number of neoplastic lesions in the colon even in a relatively young average-risk population. The question whether screening colonoscopy should therefore not only aim at detecting early colorectal cancer but also at identifying and removing precursor adenomas at younger ages clearly deserves further attention.

A Prospective Study Comparison of Narrow Band Imaging (NBI) Versus Chromoendoscopy with Indigo Carmine (IC) Versus White Light (WL) Colonoscopy in the Detection of Adenomatous Colonic Lesions

Background: Colonic early carcinoma and adenomatous precursor flat lesions may not be diagnosed by conventional colonoscopy in up to 24% of cases. Colonic chromoendoscopy with IC or NBI could potentially increase the detection of such lesions, particularly in the right colon. The aim of this study is to evaluate if a larger number of adenomas can be diagnosed by NBI or chromoendoscopy with IC or white light colonoscopy. Methods: An Olympus HD 180 series has been used by two experienced colonoscopists. Exclusion criteria were a history of Inflammatory Bowel Diseases or right colon resection. Each colonic segment was first examined with white light colonoscopy and then followed by chromoscopy with IC 0,4% or NBI. Study outcome was the number of lesions detected with WL compared with NBI and IC. Results: The study groups were well matched for age and sex. A total of 88 patients were enrolled in the study (43 in the NBI group and 45 in the IC group). Seventy two lesions were detected in 52 patients on white light colonoscopy being 39 adenomas, 32 hyperplastic polyps and 1 adenocarcinoma. Compared with WL, NBI detected 9 more lesions in 6 patients, being all lesions flat adenomas (low grade dysplasia) of the right colon and IC found 15 more lesions in 10 patients being 10 of them low grade dysplasia sessile adenomas and 5 hyperplastic flat polyps, all in the right colon. Mean diameter of the lesions diagnosed with NBI and IC were respectively of 3.7 and 4.2 mm. No statistical differences were seen in examination time between NBI (10.6 ± 1.38 min) and IC (11.1 ± 2.32 min). Conclusion: NBI and IC allow easier detection of small/flat colonic lesions compared to WL colonoscopy. No significant differences were found between NBI and IC in polyp detection rate.

Cancer genetics: colorectal cancer as a model

Cancer is essentially a somatic evolutionary process and is, therefore, effectively defined by the genetic and epigenetic changes underlying this process. An understanding of the function of these changes is fundamental to devising new approaches to prevention and treatment. Colorectal cancer (CRC), apart from its obvious importance as one of the most frequent cancers, provides an excellent model for such studies because of the availability of precursor adenoma lesions and the existence of several clear-cut familial inherited susceptibilities. These include familial adenomatous polyposis (FAP), which led to the identification of the APC gene and the importance of the Wnt pathway, and hereditary non-polyposis CRC (HNPCC), which identified the role of the mismatch repair genes in colorectal and other cancers. The presently known range of genetic and epigenetic changes in CRCs and adenomas is reviewed in this paper and the evidence against a requirement for genomic instability presented, together with a discussion of patterns of gene methylation, including especially our work on the homeobox gene, CDX1. Clearly, familial cancers, such as FAP and HNPCC, cannot account for more than perhaps 5% of the incidence of CRC. There is, however, evidence that approximately a further 25-30% have some inherited susceptibility. Based on the association of APC missense variants with multiple adenomas, we proposed that much of this may be due to the cumulative effects of low frequency, low penetrance variants, and the "rare variant hypothesis". The evidence for this from our work on multiple adenoma cases, and certain other examples, is discussed.

Glycosylated hemoglobin and risk of colorectal cancer and adenoma (United States).

The consistently observed epidemiologic associations of obesity and physical activity with colorectal cancer and precursor adenoma risk suggest that insulin and glucose control may be contributory. We evaluated the association of glycosylated hemoglobin (HbA1c), a clinical indicator of average glycemia over the previous 2 months, and possibly, indirectly, a marker of average blood insulin level, with colorectal carcinogenesis. Among women in the Nurses' Health Study, who provided blood in 1989-90 and were diagnosed subsequently in 1989-94, we included 79 colorectal cancer cases and 156 matched controls, and 201 distal colorectal adenoma cases and 201 matched controls. HbA1c concentrations in red blood cells were determined blindly by turbidometric immunoinhibition. Odds ratios (OR) and 95% confidence intervals (CI) were estimated from conditional logistic regression models. HbA1c level did not significantly differ between colorectal cancer cases (median 5.5%) and controls (5.5%, p = 0.5), although a small difference between adenoma cases (5.6%) and controls (5.5%, p = 0.06) was noted. Compared to the lowest tertile of HbA1c (median 5.2%), women in the middle (median 5.5%, OR = 1.2, CI = 0.6-2.5) and upper (5.8%, OR = 1.2, CI = 0.6-2.7) tertiles were not at an increased risk for colorectal cancer. A modestly elevated risk of distal colorectal adenoma in the upper (median 5.8%, OR = 1.4, CI = 0.9-2.3) versus lower (median 5.3%) tertile could not be excluded. These associations were not appreciably altered after adjusting for known and suspected colorectal cancer risk factors. Over the range of levels observed in this relatively small sample of middle-aged women, prediagnostic HbA1c does not clearly predict colorectal cancer and adenoma risk.

Growth patterns in various macroscopic types of noninvasive intramucosal colorectal carcinoma with special reference to apoptosis and cell proliferation.

Apoptotic cell death and cell proliferation play important roles in the histogenesis and development of colorectal carcinoma. The aim of this study was to examine the relationship between apoptosis and cell proliferation in various macroscopic types of intramucosal colorectal carcinoma in relation to the expression of p53 and bcl-2. One hundred forty cases with endoscopically or surgically resected intramucosal colorectal carcinoma were studied. There were 57 cases of polypoid-type carcinomas, 55 cases of superficial-type carcinomas, and 28 cases of granular-type, laterally spreading tumors. Polypoid-type carcinomas were pedunculated, subpedunculated, or sessile polyps. Superficial-type carcinomas were flat lesions with a smooth, even surface. Granular-type, laterally spreading tumors were superficially spreading lesions with aggregates of nodules and a granular surface. Apoptotic cells were identified by the in situ DNA nick end labeling method. Ki-67, p53, and bcl-2 expression were examined immunohistochemically. The superficial-type carcinoma apoptotic index (30.9 percent) was significantly lower than that of polypoid-type carcinoma (54.4 percent) and granular-type, laterally spreading tumor (60.7 percent). The superficial-type carcinoma proliferative index (67.3 percent) was significantly higher than that of polypoid-type carcinoma (42.1 percent) and granular-type, laterally spreading tumor (28.6 percent). In superficial-type carcinomas the proliferative index in p53-positive carcinomas was significantly higher, and the apoptotic index was higher in carcinomas with a lower proliferative index. There was no significant difference in apoptotic index, proliferative index, or p53 protein overexpression between de novo carcinomas and those that had arisen in precursor adenomas. The pattern of cell death and proliferation may vary with different macroscopic types of intramucosal colorectal carcinoma. Superficial-type colorectal carcinomas especially demonstrate diminished apoptosis and increased cell proliferation. This may be useful in understanding their biologic behavior.

Peutz-Jeghers polyps, dysplasia, and K-ras codon 12 mutations

Background—Peutz-Jeghers syndrome (PJS) is a rare, autosomal dominant, polyposis syndrome, associated with an increased risk of gastrointestinal and extragastrointestinal malignancy. Occasionally dysplasia occurs in PJS polyps.Aims—In colorectal carcinomas, mutations in...

Randomised study of screening for colorectal cancer with faecal-occult-blood test

Case-control studies and a voluntary-based follow-up study have suggested that repeated screening with faecal-occult-blood (FOB) tests can lead to a reduction in mortality from colorectal cancer (CRC). The aim of this randomised study was to compare mortality rates after FOB tests every 2 years during a 10-year period with those of unscreened similar controls. 140,000 people aged 45-75 years lived in Funen, Denmark, in August, 1985, and were considered for inclusion in our study. Before randomisation we excluded individuals who had CRC or precursor adenomas and those who had taken part in a previous pilot study. Randomisation of 137,485 people in blocks of 14 allocated three per 14 to the screening group (30,967), three per 14 to the control group (30,966), and eight not to be enrolled in the study (75,552). Controls were not told about the study and continued to use health-care facilities as normal. Hemoccult-II blood tests (with dietary restrictions but without rehydration) were sent to screening-group participants. Only those participants who completed the first screening round were invited for further screening--five rounds of screening during a 10-year period. Participants with positive tests were asked to attend to full examination and were offered colonoscopy whenever possible. The primary endpoint was death from CRC. Of the 30,967 screening-group participants, 20,672 (67%) completed the first screening round and were invited for further screening; more than 90% accepted repeated screenings. During the 10-year study, 481 people in the screening group had a diagnosis of CRC, compared with 483 unscreened controls. There were 205 deaths attributable to CRC in the screening group, compared with 249 deaths in controls. CRC mortality, including deaths attributable to complications from CRC treatment, was significantly lower in the screening group than in controls (mortality ratio 0.82 [95% CI 0.68-0.99]) p = 0.03). Our findings indicate that biennial screening by FOB tests can reduce CRC mortality. This study is being continued to improve its statistical power and to assess the effect of the removal of more precursor adenomas in the screening-group participants than in controls on CRC incidence.

The Adenoma-carcinoma Sequence in Colorectal Neoplasia

In this article the epidemiologic, pathologic, molecular, and clinical evidence for the adenoma-carcinoma sequence is reviewed. The authors describe the morphologic evolution of the precursor adenomas, from the earliest discernible abnormality of the colon to adenomas with advanced pathologic features, the factors that determine the risk of progression of adenomas to adenocarcinoma, the molecular events that parallel or underlie the morphologic changes, the outcome of clinical interventions that have tested this hypothesis, and the time frame within which this progression is likely to occur.

Diet and risk of colorectal adenomas: macronutrients, cholesterol, and fiber.

Diet is thought to be important in the etiology of colorectal cancer. Studies suggest that a diet high in red meat and saturated fat and low in dietary fiber and vegetables may increase cancer risk. Diet may also be important in the development of colorectal adenomas that are precursors of most colorectal cancers, but this hypothesis has not been well studied. This case-control study was designed to examine the effects of dietary consumption of cholesterol, fiber (vegetables, fruits, beans, and grains), and macronutrients (protein, carbohydrate, and fat) on risk for colorectal adenomas. Analyses were based on data from 236 subjects (105 men and 131 women) with histologically confirmed adenomas (cases) and 409 adenoma-free control subjects (165 men and 244 women), all of whom had had colonoscopy. Case and control subjects were similar with respect to gender, body mass, race, marital status, education, and indications for colonoscopy. Using a validated quantitative food-frequency questionnaire, an experienced graduate nutritionist interviewed each subject by telephone. Sex-specific analyses were conducted because the ranges of nutrient intake were substantially different for men and women. Odds ratios (ORs) were calculated according to quintiles of nutrient intake. Carbohydrate intake was inversely related to adenoma risk in women (P for trend = .002). Compared with women in the lowest quintile of carbohydrate consumption, those in the highest quintile were 60% less likely to develop adenomas (OR = 0.39; 95% confidence interval [CI] = 0.19-0.80). Intake of fruit (P for trend = .028) and intake of fiber derived from vegetables and fruits (P for trend = .012) were also inversely related to adenomas in women. Total fat showed a positive association in women (P for trend = .004), with an OR of 2.69 for the highest versus the lowest quintile (95% CI = 1.31-5.50). Results were comparable for saturated fat (P for trend = .027). The risks in men were generally similar in direction and magnitude but were not statistically significant. These data support the hypothesis that a diet high in fat and low in carbohydrates, fruits, and fruit and vegetable fiber increases risk not only for colorectal cancer but also for precursor colorectal adenomas. These results, which are consistent with findings of other investigators, suggest that environmental factors, influencing risk for colorectal cancer, such as a high-risk diet, may lead to development of the precursor adenomas.