BackgroundPatients with multiple serrated polyps are at an increased risk for developing colorectal cancer (CRC). Recent reports have linked cigarette smoking with the subset of CRC that develops from serrated polyps. The aim of this work therefore was to investigate the association between smoking and the risk of CRC in high-risk genetics clinic patients presenting with multiple serrated polyps.Methods and FindingsWe identified 151 Caucasian individuals with multiple serrated polyps including at least 5 outside the rectum, and classified patients into non-smokers, current or former smokers at the time of initial diagnosis of polyposis. Cases were individuals with multiple serrated polyps who presented with CRC. Controls were individuals with multiple serrated polyps and no CRC. Multivariate logistic regression was performed to estimate associations between smoking and CRC with adjustment for age at first presentation, sex and co-existing traditional adenomas, a feature that has been consistently linked with CRC risk in patients with multiple serrated polyps. CRC was present in 56 (37%) individuals at presentation. Patients with at least one adenoma were 4 times more likely to present with CRC compared with patients without adenomas (OR = 4.09; 95%CI 1.27 to 13.14; P = 0.02). For females, the odds of CRC decreased by 90% in current smokers as compared to never smokers (OR = 0.10; 95%CI 0.02 to 0.47; P = 0.004) after adjusting for age and adenomas. For males, there was no relationship between current smoking and CRC. There was no statistical evidence of an association between former smoking and CRC for both sexes.ConclusionA decreased odds for CRC was identified in females with multiple serrated polyps who currently smoke, independent of age and the presence of a traditional adenoma. Investigations into the biological basis for these observations could lead to non-smoking-related therapies being developed to decrease the risk of CRC and colectomy in these patients.

ObjectiveHyperplastic polyposis is a colonic polyposis condition of unknown aetiology. The purpose of this study was to examine the spectrum of phenotypic variation in patients with multiple serrated polyps as a basis for gene discovery.MethodsOne hundred and twenty-six patients with multiple (≥5) serrated polyps were recruited to the study. Polyp counts were extracted from histology and colonoscopy reports. Ethnicity was self-reported. Family history of cancer data were derived from pedigrees. Ascertainment status was classified as either index case or identified by screening.ResultsThe average reported polyp count was 39. Patients with highest polyp numbers were more likely to be male (P  = 0.02). Colorectal cancer (CRC) was identified in 49 of 119 patients (41%) and 28% of these patients had multiple CRC. Young onset patients had higher polyp numbers (P  = 0.03) and were more likely to have their CRC in the distal colon (P  = 0.02). CRC was significantly associated with the presence of adenomas (P  = 0.03). Patients were divided into moderate polyposis (5-79 serrated polyps) and dense polyposis (80 or more) categories. The dense polyposis category was associated with a lack of family history for CRC (P  = 0.034) and male gender (P  = 0.014), independent of ascertainment status and recruitment site.ConclusionMultiple serrated polyps were associated with an increased personal risk of CRC. A subset of patients with the highest polyp numbers was more likely to be male and to have no family history of CRC. This result suggests heterogeneous modes of inheritance and has implications for studies investigating the genetic basis of multiple serrated polyps.

The identification of Lynch syndrome has been greatly assisted by the advent of tumour immunohistochemistry (IHC) for mismatch repair (MMR) proteins, and by the recognition of the role of acquired somatic BRAF mutation in sporadic MMR-deficient colorectal cancer (CRC). However, somatic BRAF mutation may also be present in the tumours in families with a predisposition to develop serrated polyps in the colorectum. In a subgroup of affected members in these families, CRCs emerge which demonstrate clear evidence of MMR deficiency with absent MLH1 staining and high-level microsatellite instability (MSI). This may result in these families being erroneously classified as Lynch syndrome or, conversely, an individual is considered "sporadic" due to the presence of a somatic BRAF mutation in a tumour. In this report, we describe two Lynch syndrome families who demonstrated several such inconsistencies. In one family, IHC deficiency of both MSH2 and MLH1 was demonstrated in tumours from different affected family members, presenting a confusing diagnostic picture. In the second family, MLH1 loss was observed in the lesions of both MLH1 mutation carriers and those who showed normal MLH1 germline sequence. Both families had Lynch syndrome complicated by an independently segregating serrated neoplasia phenotype, suggesting that in families such as these, tumour and germline studies of several key members, rather than of a single proband, are indicated to clarify the spectrum of risk.

Duodenal and ampullary carcinoma in familial adenomatosis (FAP) is the third leading cause of FAP related deaths. Management of this condition is a challenging. The aim of this study was to evaluate the role of multiple targeted endoscopic biopsies and macroscopic appearance as the major determinants for surgical intervention. A secondary aim was to assess histological heterogeneity through comparing endoscopic biopsies and describe the clinical outcomes of our cohort after intervention. We reviewed our FAP surveillance database of 67 patients, between January 1999--June 2011 undergoing upper GI surveillance and where indicated, subsequent surgical intervention. Among 67 patients, 11 underwent surgical resection. Pancreas-preserving duodenectomy was performed in four patients (five procedures), and Whipple's operation in seven patients. The average size of polyps was 43 mm (range 17-65 mm), and the average number of targeted endoscopic biopsies per lesion was 7.5 (range 5-10). Two cases of high-grade (severe) dysplasia were diagnosed on endoscopic biopsies each understaged compared with the subsequent surgical specimen. All carcinomas identified have been resectable with no evidence of local spread or distant metastasis. There was one postoperative death, but no cancer related deaths. We identified both cancers at an early stage and there were no missed or late diagnoses. There have been no recurrences of carcinoma in a more than 7 years follow-up. Due to the heterogeneous nature of these lesions, comprehensive macroscopic assessment should be complemented with multiple targeted biopsies to improve the chance of early detection of advanced lesions.