Background & Aims:
MYH-associated polyposis is a recently described disease that is characterized by multiple colorectal adenomas and a recessive pattern of inheritance. Individuals with
...MYH-associated polyposis have biallelic mutations in
MYH, a base excision repair gene, and are negative for germline mutations in the
APC gene. In this study, the 2 most prevalent
MYH mutations in white persons, Y165C and G382D, were analyzed for their presence in 984 subjects selected from 3 groups: 400 undergoing screening colonoscopy and found to have 0–3 polyps, 444 with colorectal cancer (CRC), and 140 referred for
APC mutation analysis in which a germline mutation was not identified.
Methods:
Genotyping for Y165C and G382D was performed by Pyrosequencing.
Results:
Biallelic mutations for Y165C and/or G382D were not found in any of those undergoing screening colonoscopy with 0–3 polyps (n = 400), in those APC-negative patients with <20 adenomatous polyps (n = 26), or in those with CRC who were older than 50 years (n = 328). Furthermore, these 2
MYH mutations were not found among patients whose tumors showed the presence of defective DNA mismatch repair (n = 62). However, the presence of biallelic germline
MYH mutations correlated with the presence of ≥20 adenomatous polyps. Interestingly, 2 of the 116 individuals with CRC diagnosed at 50 years of age or younger also presented with biallelic germline mutations in
MYH.
Conclusions:
These data suggest that screening of
MYH should be considered not only in patients with multiple polyps but also in patients with early-onset CRC.
Several recent reports of high local recurrence and lymph node metastasis in T1 carcinoma of the rectum prompted us to study the risk factors for lymph node metastasis in these lesions.
We reviewed ...the clinical records of 7,543 patients who underwent operative treatment for carcinoma of the colon and rectum from 1979 to 1995. Only patients with sessile T1 lesions who underwent colorectal resection were included in the study, yielding an analysis cohort of 353 patients. The following carcinoma-related variables were assessed: size, mucinous subtype, carcinomatous component, grade, site in colon and rectum, lymphovascular invasion, and depth of submucosal invasion. For the depth, the submucosa was divided into upper third (sm1), middle third (sm2), and lower third (sm3). Chi-squared tests and logistic regression were used to evaluate the variables as potential risk factors for lymph node metastasis.
The incidence of T1 lesions was 8.6 percent. In the analysis cohort, the lymph node metastasis rate was 13 percent. Significant predictors of lymph node metastasis both univariately and multivariately were sm3 (P = 0.001), lymphovascular invasion (P = 0.005), and lesions in the lower third of the rectum (P = 0.007). Poorly differentiated carcinoma was significant univariately (P = 0.001) but not in the multivariate model. No other parameter was associated with a significant risk.
T1 colorectal carcinomas with lymphovascular invasion, sm3 depth of invasion, and location in the lower third of the rectum have a high risk of lymph node metastasis. These lesions should have an oncologic resection. In a case of the lesion in the lower third of the rectum, local excision plus adjuvant chemoradiation may be an alternative.
Colorectal carcinoma with microsatellite instability (MSI-H) has a characteristic clinicopathologic profile, typically forming right-sided, lymphocyte-rich tumors that are often mucinous. Mucinous ...histology in general has been linked to adverse prognosis in some studies, but not in others. MSI-H carcinoma, in contrast, has a better prognosis than microsatellite stable carcinoma in most studies. We assessed the relationship between MSI status, clinicopathologic features and outcome for 248 consecutive patients with resected mucinous carcinoma. All cases were reviewed to confirm mucinous histology. Immunohistochemical stains for DNA mismatch repair enzymes hMLH1, hMSH2 and hMSH6 were performed on a representative block from each case. Tumors lacking expression of a mismatch repair enzyme were designated MSI-H; all others were classified as microsatellite stable. Age, sex, tumor size, site, grade, stage, growth pattern, Crohn's-like reaction, vascular invasion and number of tumor-infiltrating lymphocytes were evaluated without knowledge of MSI status or patient outcome. 72 (29.3%) mucinous carcinomas were MSI-H. Compared to microsatellite stable mucinous cancers, they were more likely to be right-sided (83.3 vs 48.6%, P<0.001), have a Crohn's -like reaction (65.7 vs 29.8%, P<0.001) and have many tumor infiltrating lymphocytes (72.2 vs 20.8%, P<0.001). MSI-H mucinous cancers presented more often as localized disease (66.7 vs 38.1%, P<0.001) and less often with lymph node (26.4 vs 44.9%) or distant (4.2 vs 16.5%) metastases. In univariate analysis, MSI had a favorable effect on age-adjusted survival (hazard ratio 0.597, P=0.02). In multivariate analysis, age, grade, Crohn's-like reaction and stage were independent predictors of survival, but MSI status was not. In conclusion, MSI-H mucinous carcinomas are right-sided, low-stage tumors with Crohn's-like reaction and tumor-infiltrating lymphocytes. The outcome for MSI-H mucinous carcinoma is better than that of microsatellite-stable mucinous carcinoma, but MSI status is not an independent predictor of survival.
Carcinogenesis in Barrett's esophagus (BE) is associated with an increased expression of cyclooxygenase (COX) 2. However, there has been no direct evidence that inhibition of COX-2 prevents cancer in ...BE. We studied the effect of MF-Tricyclic, a selective COX-2 inhibitor, on the development of BE and adenocarcinoma in a rat model.
Four weeks after esophagojejunostomy, 105 Sprague-Dawley rats were randomized to a chow containing MF-Tricyclic or Sulindac, or a placebo. Ninety-six (92%) rats completed the study and were sacrificed at 28 ± 2 weeks. The animals were assessed for the presence of cancer, tumor volume, BE, degree of inflammation, and COX-2 expression and activity.
MF-Tricyclic and Sulindac reduced the relative risk of development of esophageal cancer by 55% (95% confidence interval Cl = 43%-66%, P < 0.008) and by 79% (95% CI = 68%–87%, P < 0.001), respectively, compared with controls. No significant differences were noted in the risk of esophageal cancer between the MF-Tricyclic and the Sulindac group (P = 0.34). The median tumor volume was not significantly different among the 3 groups (P = 0.081). Moderate to severe degree of inflammation was significantly more common (P = 0.005) in the control compared with the MF-Tricyclic and the Sulindac group; however, the prevalence of BE was not significantly different between groups (P = 0.98). Rats in the control group had higher tissue PGE2 level compared with the MF-Tricyclic and Sulindac groups (P = 0.038).
Selective and nonselective COX-2 inhibitors can inhibit inflammation, COX-2 activity, and development of adenocarcinoma induced by reflux. This provides direct evidence that COX-2 inhibitors may have chemopreventive potential in BE.
Fibrolamellar carcinoma arises in noncirrhotic livers of young individuals and has been considered to be less aggressive than conventional hepatocellular carcinoma. This study compares survival and ...clinicopathologic features of fibrolamellar carcinoma with hepatocellular carcinoma arising in noncirrhotic and cirrhotic livers. Clinical and pathologic features including age, gender, tumor size, stage and survival were recorded in 20 resected cases of fibrolamellar carcinoma. Survival was compared with resected hepatocellular carcinoma without (n=32) and with cirrhosis (n=30). Proliferative activity was determined by immunohistochemistry for Ki-67. In all, 12 (60%) patients with fibrolamellar carcinoma died during follow-up; the 5-year survival was 45%. Mortality in fibrolamellar carcinoma was higher with metastatic disease at presentation (6/7, 86% vs 5/13, 39%, P=0.06). Age, gender and tumor size did not correlate with survival. The 5-year (45 vs 56%, P=0.4) as well as overall survival (40 vs 56.3%, P=0.3) was similar in fibrolamellar carcinoma and hepatocellular carcinoma without cirrhosis. The 5-year and overall survival in hepatocellular carcinoma with cirrhosis was 27 and 23.3%, respectively, which was not significantly different compared to fibrolamellar carcinoma (P=0.2). Among the cases without metastases at presentation, 5-year survival in fibrolamellar carcinoma (62%) and hepatocellular carcinoma without cirrhosis (57%) was significantly better (P=0.03) than hepatocellular carcinoma with cirrhosis (27%). The mean Ki-67 index was similar in all three groups (P=0.1). In conclusion, fibrolamellar carcinoma is an aggressive neoplasm with 45% 5-year survival and overall mortality of 60%. Nearly half the patients develop lymph node or distant metastasis. The prognosis of fibrolamellar carcinoma is similar to conventional hepatocellular carcinoma. Among nonmetastatic cases, the prognosis is better in fibrolamellar carcinoma and hepatocellular carcinoma without cirrhosis compared to hepatocellular carcinoma with cirrhosis. The better outcome in fibrolamellar carcinoma appears to be due to the absence of cirrhosis rather than its distinct clinicopathologic features.
The use of azathioprine and 6-mercaptopurine for inflammatory bowel disease increased in the early 1990s. We sought to determine the effect of this change in therapy on the risk of lymphoma in ...patients with inflammatory bowel disease. Methods: All patients with inflammatory bowel disease at a single tertiary care medical center who developed lymphoma between 1985–2000 were identified and the pathologic features of the lymphoma including presence of Epstein-Barr virus were determined. The patients were divided into two 8-year periods (1985–1992, 1993–2000) corresponding with the introduction of azathioprine and 6-mercaptopurine in 1993.
Eighteen patients with lymphoma were identified, 6 between 1985–1992 and 12 between 1993–2000. Six of 18 lymphomas occurred in patients treated with azathioprine or 6-mercaptopurine, all between 1993-2000. Seven patients developed Epstein-Barr virus-positive lymphoma (1 from 1985–1992, 6 from 1993–2000). Five of 7 Epstein-Barr virus-positive lymphomas occurred in patients treated with azathioprine or 6-mercaptopurine compared with 1 of 11 Epstein-Barr virus-negative lymphomas (P = 0.01). Approximately 1200 patients with inflammatory bowel disease were treated with these agents between 1993–2000.
Treatment of inflammatory bowel disease with azathioprine or 6-mercaptopurine appears to be associated with a small increased risk of Epstein-Barr virus-positive lymphoma.
Most colorectal cancers that have high levels of microsatellite instability (MSI-H) show loss of immunohistochemical expression of proteins that participate in the DNA mismatch repair process, most ...often involving MLH1 and MSH2. Less commonly, a third DNA mismatch repair protein, MSH6, may also be lost as the primary event. Rarely, tumors with MSI-H show normal expression of these three proteins. The genetic deficiency leading to the MSI-H phenotype in such cases is unknown. PMS2 is another member of the DNA mismatch repair complex. Its expression is generally lost in tumors with MLH1 loss of expression. Rarely, there is selective loss of PMS2 expression. We sought to describe the frequency and clinical correlates of selective loss of expression of PMS2 with the MSI-H tumor phenotype.
Two thousand seven hundred nineteen colorectal cancers from both clinic- and research-based ascertainment were studied. Tumor MSI testing and immunohistochemistry for MLH1, MSH2, MSH6, and PMS2 were conducted. Medical records were abstracted for age at diagnosis, gender, colorectal cancer site, and family history.
Five hundred thirty-five of the 2,719 tumors were MSI-H. Of these, 93% showed loss of expression of MLH1, MSH2, and/or MSH6. Thirty-eight showed normal expression for these proteins. PMS2 immunohistochemical staining was successful in 32 of 38 of these tumors. Of the 32, 23 showed selective loss of expression of PMS2. This was associated with young age of diagnosis and right-sided location but not with a striking family history of cancer.
Overall, 97% of the MSI-H tumors showed loss of expression for one or more of these four mismatch repair proteins. Selective loss of expression of PMS2 was present in 72% of cases in which colorectal cancers had an MSI-H phenotype but no alteration of expression of MLH1, MSH2, and MSH6. The underlying mechanism involved cannot be determined from this study but could involve point mutations in other DNA mismatch repair genes with retention of immunohistochemical expression, somatic inactivation of PMS2, or germ line mutation of PMS2.
Molecular studies of colon cancer have provided insights into pathogenesis, yet it is unclear how important these markers are in predicting prognosis. This study investigated the prognostic ...significance of TUNEL, bcl-2, p53, proliferation marker Ki-67 and DNA mismatch repair (MMR) status in patients with Dukes' stage B2 and C colorectal adenocarcinomas.
Tumor tissue from 366 patients (75% Dukes' C, 25% Dukes' B2) from four randomized North Central Cancer Treatment Group phase III surgical adjuvant trials were used. Eighty-one percent of patients received adjuvant treatment, which was primarily fluorouracil (FU) based (90%). Tumor location was predominantly (87%) the colon. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), Ki-67, p53, bcl-2, and MMR were assayed using immunohistochemistry. Stage, grade, MMR, Ki-67, and previously determined flow cytometry markers (ploidy and S phase) were explored for associations with each other and with overall survival (OS) and disease-free survival (DFS).
Univariately, stage B2, low grade, diploid, Ki-67 more than 27%, normal p53, and FU-based adjuvant treatment were significantly associated with improved OS and DFS (P <.05). After adjusting for stage, grade, and ploidy in multivariate analysis, Ki-67 remained significantly related to both OS and DFS (P <.01). Active FU-based adjuvant treatment was significant only for OS in this multivariate model. Neither bcl-2 nor TUNEL were significant.
This retrospective study indicates that Ki-67 and ploidy may have stronger prognostic impact on OS and DFS than other parameters investigated after adjusting for stage and tumor grade. Prospective studies to elucidate the mechanism and prognostic significance of these findings are necessary.
To estimate the prevalence of celiac disease (CD) in pediatric and adult type 1 diabetes mellitus in a defined population and to describe clinical features and HLA class II genotypes predictive of CD ...in screened patients with type 1 diabetes.
All residents of Olmsted County, Minnesota, with type 1 diabetes mellitus on the prevalence date January 1, 2001, were identified with the use of an established medical records linkage system (Rochester Epidemiology Project) and defined clinical criteria. Consenting patients underwent serologic screening with endomysial antibody and tissue transglutaminase antibody testing and intestinal biopsies to confirm the diagnosis of CD. A subset of screened patients also underwent HLA class II genotyping. Quality-of-life screening (Medical Outcomes Study 36-Item Short-Form Health Survey) was completed in a subset of patients at the time of serologic screening.
Overall, 392 Olmsted County residents with type 1 diabetes on January 1, 2001, were identified. A total of 158 patients with type 1 diabetes were tested, representing 40% (158/392) of the enumerated diabetic population, and 11 had biopsy-proven CD for an estimated point prevalence of 7.0% (95% confidence interval, 3.5%-12.1%). Most CD-positive diabetic patients were asymptomatic and expressed an at-risk CD haplotype with at least one of but not both HLA
DQ2 or
DQ8.
Celiac disease is not rare in North American patients with type 1 diabetes, and most CD-positive diabetic patients are asymptomatic irrespective of age at screening.
Determining whether a tumor exhibits microsatellite instability (MSI) is useful in identifying patients with hereditary non-polyposis colorectal cancer and sporadic gastrointestinal cancers with ...defective DNA mismatch repair (MMR). The assessment of MSI status aids in establishing a clinical prognosis and may be predictive of tumor response to chemotherapy. A reference panel of five markers was suggested for MSI analysis by a National Cancer Institute (NCI) workshop in 1997 that has helped to standardize testing. But this panel of markers has limitations resulting from the inclusion of dinucleotide markers, which are less sensitive and specific for detection of tumors with MMR deficiencies compared to other types of markers that are currently available. This study demonstrates that mononucleotides are the most sensitive and specific markers for detection of tumors with defects in MMR and identifies an optimal panel of markers for detection of MSI-H tumors. A set of 266 mono-, di-, tetra- and penta-nucleotide repeat microsatellite markers were used to screen for MSI in colorectal tumors. The best markers for detection of MSI-H tumors were selected for a MSI Multiplex System, which included five mononucleotide markers: BAT-25, BAT-26, NR-21, NR-24 and MONO-27. In addition, two pentanucleotide markers were added to identify sample mix-ups and/or contamination. We classified 153 colorectal tumors using the new MSI Multiplex System and compared the results to those obtained with a panel of 10 microsatellite markers combined with immunohistochemical (IHC) analysis. We observed 99% concordance between the two methods with nearly 100% accuracy in detection of MSI-H tumors. Approximately 5% of the MSI-H tumors had normal levels of four MMR proteins and as a result would have been misclassified based solely on IHC analysis, emphasizing the importance of performing MSI testing. The new MSI Multiplex System offers several distinct advantages over other methods of MSI testing in that it is both extremely sensitive and specific and amenable to high-throughput analysis. The MSI Multiplex System meets the new recommendations proposed at the recent 2002 NCI workshop on HNPCC and MSI testing and overcomes problems inherent to the original five-marker panel. The use of a single multiplex fluorescent MSI assay reduces the time and costs involved in MSI testing with increased reliability and accuracy and thus should facilitate widespread screening for microsatellite instability in tumors of patients with gastrointestinal cancers.
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