Sunday, August 05, 2012
paywalled: Patients with Lynch Syndrome Mismatch Repair Gene Mutations Are at Higher Risk for Not Only Upper Tract Urothelial Cancer but Also Bladder Cancer
Patients with Lynch Syndrome Mismatch Repair Gene Mutations Are at Higher Risk for Not Only Upper Tract Urothelial Cancer but Also Bladder Cancer
Abstract
Background
Lynch
syndrome (LS), or hereditary nonpolyposis colorectal cancer, is caused
by mutations in mismatch repair (MMR) genes. An increased risk for upper
tract urothelial carcinoma (UTUC) has been described in this
population; however, data regarding the risk for bladder cancer (BCa)
are sparse.
Objective
To assess the risk of BCa in MMR mutation carriers and suggest screening and management recommendations.
Design, setting, and participants
Cancer
data from 1980 to 2007 were obtained from the Familial Gastrointestinal
Cancer Registry in Toronto for 321 persons with known MMR mutations:
mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli) (MLH1); mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli) (MSH2); mutS homolog 6 (E. coli) (MSH6); and PMS2 postmeiotic segregation increased 2 (S. cerevisiae) (PMS2).
Outcome measurements and statistical analysis
Standardized
incidence ratios from the Ontario Cancer Registry, using the
Surveillance Epidemiology and End Results public database, were used to
compare cancer risk in patients with MMR mutations with the Canadian
population. Microsatellite instability analysis and immunohistochemistry
(IHC) of the MMR proteins were also performed and the results compared
with matched sporadic bladder tumors.
Results and limitations
Eleven of 177 patients with MSH2 mutations (6.21%, p < 0.001 compared with the Canadian population) were found to have BCa, compared with 3 of 129 patients with MLH1 mutations (2.32%, p > 0.05).
Of these 11 tumors, 81.8% lacked expression of MSH2 on IHC, compared
with the matched sporadic cases, which all displayed normal expression
of MSH2 and MLH1. The incidence of UTUC among MSH2 carriers was 3.95% (p < 0.001),
and all tumors were found to be deficient in MSH2 expression on IHC.
Mutations in the intron 5 splice site and exon 7 of the MSH2 gene increased the risk of urothelial cancer. Limitations include possible inflated risk estimates due to ascertainment bias.
Conclusions
LS patients with MSH2 mutations are at an increased risk for not only UTUC but also BCa and could be offered appropriate screening.
Figures and tables from this article:
- Fig. 1. Tumor sections at ×200 magnification: (A) abnormal MSH2 expression—nuclear expression is lost in the tumor, with normal nuclear staining in the adjacent tissue; (B) normal MLH1 expression—normal strong nuclear expression in the tumor and normal tissue.
- View Within Article
- Table 1. Distribution of patients with mismatch repair mutations
- M:F = male-to-female; MLH1 = mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli); MSH2 = mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli); MSH6 = mutS homolog 6 (E. coli); PMS2 = PSM2 postmeiotic segregation increased 2 (S. cerevisiae).
- View Within Article
- Table 2. Total incidence of urothelial cancers due to MLH1 and MSH2
- MLH1 = mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli); MSH2 = mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli); NS = not significant.
- View Within Article
- Table 3. Urothelial cancers in patients with confirmed MSH2 mutations and comparison with matched sporadic bladder cancer patients
- − = absent expression; + = normal expression; CR = colorectal; Dx = diagnosis; EM = endometrial; F = female; GA = gastric; HG = high grade; IHC = immunohistochemistry; LG = low grade; LS = Lynch syndrome; M = male; MSH2 = mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli); MSI = microsatellite instability; MSI-H = high microsatellite instability; MSS = microsatellite stable; OR = occupational risk; OV = ovarian; RP = renal pelvis; U = ureter.Patients H1 and H2 are related.
- View Within Article
- Table 4. Urothelial cancers in patients with confirmed MLH1 mutations
- − = absent expression; + = normal expression; CR = colorectal; HG = high grade; IHC = immunohistochemistry; LG = low grade; LS = Lynch syndrome; M = male; MLH1 = mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli); MSI = microsatellite instability; MSI-H = high microsatellite instability; OR = occupational risk; RP = renal pelvis.
How to generalize efficacy results of randomized trials: recommendations based on a systematic review of possible approaches
How to generalize efficacy results of randomized trials: recommendations based on a systematic review of possible approaches:
Abstract
Rationale, aims and objectives
Randomized controlled trials (RCTs) are the preferred source for evidence for the effect of treatment. However, patients participating in RCTs often manifest important differences from patients seen in practice. Therefore, guideline developers have to decide whether the results are generalizable to the target population not represented in RCTs.
Method
A systematic review of the literature was undertaken to identify methods to decide whether to generalize the results from RCTs to patients who were not represented in these trials.
Results
One approach is to examine the in- and exclusion criteria of trials and infer from these whether the trial population was sufficiently representative. Other authors suggest, because of the inclusion of a broader range of patients, reliance on observational studies if no direct evidence for the target population is available.
Another approach is to apply the relative effect of treatment found in trials to patients in practice unless there is a compelling reason to believe the results would differ substantially as a function of particular characteristics of those patients. Although there are exceptions, this approach is supported by empirical evidence that, in general, relative effect of treatment on benefit outcomes seldom differs to an important extent across subgroups of patients.
Conclusion
We propose this last approach: focusing on RCTs unless there is a compelling reason not to do so. Compelling reasons will most often be found with respect to issues of rare adverse effects, for which observational studies are likely to provide the best estimates.
Medscape: Long-term Risk of Colorectal Cancer After Adenoma Removal
Long-term Risk of Colorectal Cancer After Adenoma Removal
Sessile serrated adenomas: high-risk lesions?
Sessile serrated adenomas: high-risk lesions?
Abstract
Sessile serrated adenomas (SSAs) were unrecognized in pathology and gastroenterology practice until about 2005; we have diagnosed them since 2001, allowing up to 10 years of follow-up. We evaluated follow-up of patients with sessile serrated adenoma diagnosed between 2002 and 2004 in our teaching institution and compared it to follow-up of randomly selected tubular adenomas. Materials from patients diagnosed with sessile serrated adenoma from January 2002 to December 2004 were reviewed. A control group of patients with sporadic tubular adenomas was selected. Ninety-nine sessile serrated adenomas from 93 patients were diagnosed between January 2002 and December 2004. Forty three patients (46.2%) had follow-up colonoscopy. One or more lesions were found in 42 (97.6%) of 43 patients. Mucinous adenocarcinoma was diagnosed in 1 (2.3%) of 43 patients, and 1 (2.3%) of 43 patients had high-grade dysplasia in an sessile serrated adenoma. Sessile serrated adenomas were found in 22 (51.2%) of 43 patients, 16 (37.2%) of 43 patients had tubular adenomas, and hyperplastic polyps were diagnosed in 18 (41.9%) of 43. Ninety-two patients with tubular adenomas between January 2002 and December 2004 formed the control group. Sixty-six patients (71.7%) received follow-up colonoscopy. Most (53/66, 80.3%) patients had tubular adenomas on follow-up, 12 (18.2%) of 66 patients had hyperplastic polyps, and 2 (3.0%) of 66 patients had a sessile serrated adenoma. The follow-up of sessile serrated adenomas from the study period (2002 to 2004) was more rigorous than proposed for sporadic tubular adenomas (patients with sporadic tubular adenomas were also followed up more aggressively than suggested by guidelines). Those with follow-up were managed as per advanced adenomas; their clinical outcomes supported this. These results suggest that guidelines for following up patients with sessile serrated adenomas as per advanced adenomas are warranted.
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