Mixed Polyps Research Articles

Abstract LB-15: Oncogenic BRAF mutation, IGFBP7 silencing and evasion of senescence in colorectal tumorigenesis

Abstract Serrated polyps are now recognized as the precursor lesion from which sporadic BRAF (V600E) mutant/CIMP-H colorectal cancers (CRC) develop, but it appears likely BRAF mutation alone is not enough to drive progression to carcinoma. CIMP is generally localized to the proximal colon and may cause the epigenetic silencing of key genes such as IGFBP7 that may act in concert with BRAF mutation to promote neoplasia. We are conducting a detailed molecular analysis of the mechanism of serrated neoplasia involving IGFBP7 and evasion of oncogene-induced senescence (OIS). Normally senescence functions as a defense mechanism against tumorigenesis in precursor lesions. We have analysed 44 CRCs and 217 colorectal polyps including 45 advanced serrated polyps (sessile serrated adenomas, serrated adenomas and mixed polyps) and 109 simple serrated polyps (goblet cell rich hyperplastic polyps and microvesicular hyperplastic polyps) for BRAF, K-ras and CIMP relative to clinicopathologic variables. In addition a MethyLight assay was developed to determine IGFBP7 methylation patterns in serrated polyps and cancers. For serrated polyps, both BRAF mutation (75.5%) and CIMP (46.6%) was most frequent in advanced serrated polyps (ASPs). Overall the frequency of CIMP was significantly associated with proximal location (P<0.0001) and larger size (P<0.005). When serrated polyps were analyzed separately, histological type and location showed strong associations, with CIMP frequency differing significantly in proximal vs distal BRAF mutant ASPs and GC/MV-HPs. We find that BRAF mutation is highly associated with both SSAs and MV-HPs throughout the colorectum, but only in proximal SSAs is CIMP highly associated with BRAF mutation (70.8%). For CRCs we found IGFBP7 methylation frequently associated with CIMP and BRAF mutation (87%). For serrated polyps, IGFBP7 methylation was significantly associated with ASPs (P<0.0002), larger size (P<0.0002) and proximal location (P<0.0004). In advanced serrated polyps, which harbour both BRAF mutation and exhibit CIMP, methylation of IGFBP7 was observed 65% of cases. We are currently determining p53 expression levels, Ki67 and the senescence markers p19ARF and Dec1 in different serrated polyp types. This investigation will provide evidence for the involvement of IGFBP7 loss, by DNA hypermethylation, in the evasion of senescence and resulting in the progression of BRAF mutant/CIMP-H carcinoma of the colon. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-15.

Germline Bone Morphogenesis Protein Receptor 1A Mutation Causes Colorectal Tumorigenesis in Hereditary Mixed Polyposis Syndrome

Hereditary mixed polyposis syndrome (HMPS) is characterized by polyps of mixed adenomatous/hyperplastic/atypical juvenile histology that are autosomal dominantly inherited and that eventually lead to colorectal cancer (CRC). Although CRC with adenomatous polyps is initiated by inactivating adenomatous polyposis coli (APC), the initiating event of CRC with mixed polyps remains unclear. We aimed to identify the underlying germline defect in HMPS. We screened for bone morphogenesis protein receptor 1A (BMPR1A) mutation by exonic sequencing, reverse-transcriptase polymerase chain reaction (PCR) followed by cDNA sequencing, and multiplex ligation-dependent probe amplification (MLPA) analysis in eight Singapore Chinese HMPS families. Germline BMPR1A defects were found in four (50%) families. In two families, it is shown to co-segregate with the disease phenotype in all affected members over three generations, indicating that it is the disease-causing mutation. CRC incidence is 75%. The most defining characteristic is the presence of mixed hyperplastic-adenomatous polyps. Juvenile polyps are rarely reported, and if present, are usually of mixed components. Detailed histology of the polyps from one patient over 11 years distinguishes HMPS from juvenile polyposis syndrome (JPS). We report further the first cases of Wilms' tumor and papillary thyroid carcinoma associated with BMPR1A germline defect. Germline BMPR1A defect is the disease-causing mutation in 50% of the HMPS families. If patients present with mixed morphology polyps in the large bowel that are autosomal dominantly inherited and corresponding absence of upper gastrointestinal abnormalities, the gene to begin mutation screening should be BMPR1A rather than APC.

M1939 COX-2 Polymorphisms in Colorectal Carcinogenesis: A Strategy for Individualized Chemoprevention

development of multiple serrated polyps and lesser numbers of adenomas. Nine cancers and ninety-three polyps (39 common hyperplastic polyps (HP), 35 advanced serrated polyps comprising 27 SSA, 1 serrated adenoma (SA) and 7 mixed polyps (MP), and 19 traditional adenomas (TA)) from 31 patients were stained for MUC6. Staining was positive in 69% of SSA, 86% of MP, and negative in a single SA. Overall, staining was positive in 70% of advanced serrated polyps which was significantly greater than the level seen in common HP (70% vs 38%; P=0.0065). MUC6 staining, where present, was confined to the crypt bases. All TA and normal mucosa were negative. Four of nine CRC (44%) stained positive for MUC6 and 75% of these were proximal contrasting with 20% of distal CRC. There was no association between MUC6 expression by CRC and mismatch repair deficiency. More proximal serrated polyps stained positively for MUC6 than distal serrated polyps, 66% and 30% respectively (P=0.008). This study suggests that MUC6 lacks the specificity originally observed by Owens et al, with staining present in 38% of HP. Though our findings were obtained in Caucasian patients with HPS, they are consistent with those of Mochizuka and colleagues (Histochem Cell Biol 2007; 128:445-55) who found MUC6 expression was expressed in common HP and SSA but not in traditional SA or normal mucosa in a series of Japanese patients where HPS was not targeted. Our findings further demonstrate that the expression of MUC6 is significantly more frequent in lesions arising in the proximal colon, whether or not advanced morphology was observed. MUC6 is frequently expressed in SSAs and to a lesser extent in HP and therefore does not provide a surrogate marker for advanced morphology in serrated polyps. The correlation of MUC6 expression with proximal location may suggest that a subset of common serrated polyps in the proximal colon may be developmentally related to their more advanced counterparts.

Paneth cell differentiation in colonic epithelial neoplasms: evidence for the role of the Apc/ β-catenin/Tcf pathway

Paneth cell differentiation may occur in colonic epithelial neoplasms. However, its significance and mechanism of development remains unclear. Human defensin 5 is a specific marker of Paneth cells and has been shown to represent one of the target genes of the Apc/beta-catenin/Tcf pathway. The aim of this study was to evaluate the frequency of Paneth cell differentiation in a variety of colonic neoplasms, and to investigate the role of human defensin 5 and beta-catenin in this process. The clinical and pathologic findings, including histologic evidence of Paneth cell differentiation and immunostaining for human defensin 5 and beta-catenin, were evaluated in 29 samples of nonneoplastic colonic mucosa, 18 hyperplastic polyps, 10 sessile serrated adenomas, 12 traditional serrated adenomas, 21 mixed polyps, 39 conventional adenomas, and 40 adenocarcinomas. Human defensin-5 and beta-catenin expression were evaluated for the location and degree of staining in all cell types (dysplastic and nondysplastic) and correlated with histologic areas of Paneth cell differentiation in all types of polyps. Histologic evidence of Paneth cell differentiation was observed in 15 conventional adenomas (38.5%) and 1 adenocarcinoma (2.5%) but not in other types of polyps. Human defensin-5 immunostaining was positive in the cytoplasm of all nonneoplastic Paneth cells and all neoplastic cells with Paneth cell differentiation. Human defensin-5 expression was noted in 0% of hyperplastic polyps, 10% of sessile serrated adenomas, 25% of traditional serrated adenomas, 33.3% of mixed polyps, 82.1% of conventional adenomas, and 17.5% of adenocarcinomas: human defensin 5 expression was significantly higher in conventional adenomas compared to all other groups (P < .01). Seventeen (53.1%) of 32 human defensin 5 positive conventional adenomas, 6 (86%) of 7 of human defensin 5 positive adenocarcinomas, and all human defensin 5-positive sessile serrated adenomas, traditional serrated adenomas, and mixed polyps did not show histologic evidence of Paneth cell differentiation. All mixed polyps (100%) that revealed human defensin 5 expression (7; 33.3%) revealed conventional dysplasia. In the positive mixed polyp cases, human defensin 5 was only positive in areas of conventional dysplasia. Of the 31 conventional adenomas with nuclear beta-catenin staining, 15 (48.4%) revealed histologic evidence of Paneth cell differentiation, and all of the neoplastic cells with Paneth cell differentiation showed nuclear beta-catenin staining, whereas nonneoplastic Paneth cells consistently showed a normal pattern of membranous beta-catenin staining. A strong topographical correlation was noted between human defensin 5 expression and nuclear beta-catenin expression in conventional adenomas and in conventional dysplastic epithelium of mixed polyps. Paneth cell differentiation is common in early colonic neoplasms that develop via the conventional adenoma-carcinoma carcinogenic pathway. Activation of Apc/beta-catenin/Tcf pathway may play a role in Paneth cell differentiation in human colonic neoplasms.

Serrated and non-serrated polyps of the colorectum: their prevalence in an unselected case series and correlation of BRAF mutation analysis with the diagnosis of sessile serrated adenoma

Aims:To determine the prevalence of colorectal polyps of different types in an unselected population, and to correlate the morphological diagnoses with BRAF mutation analysis.Methods:Cases of colorectal polyps diagnosed at endoscopy...

Serrated and non-serrated polyps of the colorectum: their prevalence in an unselected case series and correlation of BRAF mutation analysis with the diagnosis of sessile serrated adenoma

<h3>Aims</h3> To determine the prevalence of colorectal polyps of different types in an unselected population, and to correlate the diagnosis of dysplastic serrated polyps and sessile serrated adenomas with <i>BRAF</i> mutation analysis. <h3>Methods</h3> Cases of colorectal polyps diagnosed at endoscopy were retrieved from the files of Southern.IML Pathology. All slides were reviewed and the lesions classified histologically. A diagnosis of sessile serrated adenoma was made even if the characteristic features were present focally. If there was more than one polyp of a particular type in any patient, one lesion was chosen at random so that the results represented the number of patients with each type of polyp rather than the total number of polyps. A proportion of the polyps were subjected to <i>BRAF</i> mutation analysis. <h3>Results</h3> We identified 1478 patients. Non-serrated (‘conventional') adenomas were found in 65% of patients, hyperplastic polyps in 30%, sessile serrated adenomas in 3.9%, traditional serrated adenomas in 0.7% and mixed hyperplastic adenomatous polyps in 0.7%. <i>BRAF</i> mutations were found in 90% of lesions diagnosed as sessile serrated adenoma, 29% of hyperplastic polyps of microvesicular type, 36% of traditional serrated adenomas, 100% of mixed hyperplastic adenomatous polyps, and 5% of ‘conventional' adenomas. <h3>Conclusions</h3> Sessile serrated adenomas are encountered commonly in routine endoscopy practice. The histological diagnosis correlates strongly with the presence of <i>BRAF</i> mutation.

Endoscopic polypectomy: outcomes of 467 cases in 20 years

Aim: Endoscopic polypectomy has an important place in the treatment of polyps—the preliminary lesions of colorectal cancers. This study aimed to discuss the outcomes of endoscopic polypectomy in 467 patients for 692 polyps over the course of 20 years. Materials and methods: The records of 692 endoscopic polypectomies performed in 467 patients between July 1988 and July 2008 were retrospectively evaluated. Results: Patient age ranged from 3 to 85 years (mean: 50.6 years), and 302 of the 467 (64.7%) patients were male. Polypectomy was performed for 692 polyps (mean: 1.5; range: 1-12). The most common polyp location was the rectum (41.5%), polyp diameter ranged between 1 and 40 mm (mean: 6.1 mm), and 451 of the polyps (65.2%) were pedunculated. In 2 (0.4%) patients, major complications developed, but there was no mortality. Histopathologically, 43.8% of the polyps were hyperplastic, 22.8% were adenomatous, 17.1% were mixed, 9.4% were hamartomas, 6.2% were serrated adenomas, and 0.7% were inflammatory polyps. The risk of malignant degeneration was significantly higher in patients with multiple polyps (P < 0.01), right colon polyps (P < 0.01), polyps larger than 10 mm (P < 0.01), sessile polyps (P < 0.01), and adenomatous polyps, mixed polyps, and serrated adenomas (P < 0.05). Of the 26 (5.6%) patients with malignant polyps, 6 in whom in situ and early carcinomas were detected were treated with polypectomy and followed-up with regular examinations. Another 20 patients with invasive carcinomas or familial polyposis were treated with surgery. Conclusion: Flexible endoscopic polypectomy is a simple and reliable method for removing colorectal polyps, and for treating in situ and early colorectal polypoid cancers.

Management of Serrated Adenomas and Hyperplastic Polyps

The benign serrated architecture of the hyperplastic polyp has now been recognized in morphologically similar lesions with potential for transformation to colorectal carcinoma: the sessile serrated adenoma (SSA), traditional serrated adenoma (TSA), and mixed polyp. These represent a group of serrated polyps with potential to evolve into colorectal cancer through a different molecular pathway than the traditional adenoma-carcinoma sequence, called the serrated pathway. Genetic characteristics involve a defect in apoptosis caused by BRAF and K-ras mutations that create distinct histologic characteristics of atypia in serrated architectural distortion of the crypts. An evidence-based algorithm for the clinical management of this polyp has yet to be determined. Current recommendations suggest these lesions be managed similar to conventional adenomas. The histology of serrated polyps is reviewed, as well as the common characteristics, and implications for treatment and surveillance.

Significance of serrated polyps of the colon

The fundamental view that colon adenocarcinomas arise only from conventional adenomas has been challenged by the now recognized hyperplastic polyp-serrated adenoma-adenocarcinoma pathway. This article describes the history of the serrated adenoma (both the traditional serrated adenoma and the sessile serrated adenoma) as well as the histology and endoscopic appearance of these lesions in comparison with hyperplastic polyps and mixed polyps. Although the exact pathway is the subject of ongoing research, compelling histologic associations and molecular phenotypes that define the model of the serrated polyp-carcinoma sequence, including microsatellite instability, BRAF/KRAS mutations, and CpG island methylator phenotype, provide strong evidence that this is a genuine pathway. Management of serrated neoplasia of the colon includes careful colonoscopy, complete removal of colonic polyps, sampling fields of diminutive polyps of the rectosigmoid, and basing surveillance on histology of removed polyps.

Colorectal polyposes: From phenotype to diagnosis

The colorectal polyposes are uncommon and frequently present diagnostic difficulties. Although the final diagnostic arbiter is the demonstration of a germline mutation, this may not always be demonstrable, and some forms of colorectal polyposis have no known genetic basis. Therefore, an accurate description of the phenotype by the pathologist is central to the establishment of a working diagnosis. This can direct the search for the underlying genetic cause (if any) and is also essential for establishing the magnitude of risk of colorectal malignancy for the patient and the patient's relatives. The pathologist may be provided with only a small and selected sample of endoscopically resected polyps or with prodigious numbers of polyps (too many to sample) when receiving a surgical specimen. Each type of polyposis presents its own particular diagnostic problems that may relate to polyp numbers, gross recognition of small or flat polyps, incomplete development of the full phenotype at the stage of investigation, and the histological classification of unusual or mixed polyps. The aim of this review is to highlight the principles and pitfalls in achieving a comprehensive description of the various types of colorectal polyposis, including classical FAP, attenuated FAP, MUTYH- (formerly MYH-) associated polyposis (MAP), other presentations of multiple adenomas, Peutz-Jeghers syndrome (P-JS), juvenile polyposis syndrome (JPS), Cowden syndrome (CS), hereditary mixed polyposis syndrome (HMPS), and hyperplastic polyposis syndrome (HPS).

Colonoscopic Features of Sessile Serrated Polyps

Sessile serrated polyps (SSPs) are one of the precursors for colon cancer, because of a high BRAF mutation rate. However, the colonoscopic appearances of SSP are still unclear. This study aimed to clarify colonoscopic features of SSPs. Methods: One experienced colonoscopist performed chromocolonoscopy for 190 patients in Australia with the aim to remove all polyps. 166 serrated polyps were detected, of which 54 serrated polyps measuring 5 mm or greater were enrolled. Polyp size was assessed based on resected specimens. One independent colonoscopist reviewed printed photographs of the serrated polyps, blinded to histology. Polyp morphology (flat, protruded), polyp surface (smooth, rough), polyp hue (pale, pink), adherent mucus (thin, thick) and pit pattern (asteroid, elliptic, gyrus-like) were evaluated. Histology was assessed by a single pathologist, and serrated polyps were subclassified as goblet cell (GC) type, microvesicular (MV) type, SSP, traditional serrated adenoma (TSA) and mixed polyp. Results: Ten serrated polyps were excluded because of poor quality photographs, leaving 44 serrated polyps which were studied. The mean size ( ± SD) of the 44 serrated polyps was 8.8 ± 4.0 mm, and 61% were located in the proximal colon. The mean size, location and colonoscopic features of each histological type are shown in the table. All 5 mixed polyps included a TSA component on histology, so these types were combined. The mean size of polyps in the TSA/mixed polyp category was significantly larger than those of MV type and SSP (Bonferroni correction), but there was no significant difference between mean size of MV type and SSP. Except for proximal location, SSPs were very similar in endoscopic appearance to the MV type. Both types of serrated polyps were pale, smooth and flat in appearance with an asteroid pit pattern. The majority of GC type located in the proximal colon showed protruded morphology. The TSA and mixed polyps were distributed evenly and there was no specific morphology. Conclusion: At colonoscopy, GC type can be discriminated from MV type and SSP. However, both MV type and SSP were pale, smooth and flat in appearance with an asteroid pit pattern, making differentiation difficult. The only difference was the anatomical distribution.

Cyclooxygenase-2 overexpression is common in serrated and non-serrated colorectal adenoma, but uncommon in hyperplastic polyp and sessile serrated polyp/adenoma

BackgroundCyclooxygenase-2 (COX-2, PTGS2) plays an important role in colorectal carcinogenesis. COX-2 overexpression in colorectal cancer is inversely associated with microsatellite instability (MSI) and the CpG island methylator phenotype (CIMP). Evidence suggests that MSI/CIMP+ colorectal cancer may arise through the serrated tumorigenic pathway through various forms of serrated neoplasias. Therefore, we hypothesized that COX-2 may play a less important role in the serrated pathway.MethodsBy immunohistochemistry, we assessed COX-2 expression in 24 hyperplastic polyps, 7 sessile serrated polyp/adenomas (SSA), 5 mixed polyps with SSA and adenoma, 27 traditional serrated adenomas, 515 non-serrated adenomas (tubular adenoma, tubulovillous adenoma and villous adenoma), 33 adenomas with intramucosal carcinomas, 96 adenocarcinomas with serration (corkscrew gland) and 111 adenocarcinomas without serration.ResultsStrong (2+) COX-2 overexpression was more common in non-serrated adenomas (28% = 143/515) than in hyperplastic polyps (4.2% = 1/24, p = 0.008) and serrated polyps (7 SSAs and 5 mixed polyps) (0% = 0/12, p = 0.04). Furthermore, any (1+/2+) COX-2 overexpression was more frequent in non-serrated adenomas (60% = 307/515) than in hyperplastic polyps (13% = 3/24, p < 0.0001) and serrated polyps (SSAs and mixed polyps) (25% = 3/12, p = 0.03). Traditional serrated adenomas and non-serrated adenomas showed similar frequencies of COX-2 overexpression. Regardless of serration, COX-2 overexpression was frequent (~85%) in colorectal adenocarcinomas. Tumor location was not significantly correlated with COX-2 overexpression, although there was a trend towards higher frequencies of COX-2 overexpression in distal tumors (than proximal tumors) among hyperplastic polyps, SSAs, mixed polyps, traditional serrated adenomas and adenocarcinomas.ConclusionCOX-2 overexpression is infrequent in hyperplastic polyp, SSA and mixed polyp with SSA and adenoma, compared to non-serrated and serrated adenoma. COX-2 overexpression becomes more frequent as tumors progress to higher grade neoplasias. Our observations suggest that COX-2 may play a less significant role in the serrated pathway of tumorigenesis; however, COX-2 may still play a role in later stage of the serrated pathway.

A family with juvenile polyposis linked to the BMPR1A locus: Cryptic mutation or closely linked gene?

Familial juvenile polyposis syndrome (JPS) is a rare autosomal dominant condition in which patients develop hamartomatous gastrointestinal polyps with malignant potential. Pathogenic germline mutations in both the SMAD4 and BMPR1A genes involved in the transforming growth factor beta pathway account for 40% of cases of JPS. Genetic heterogeneity remains evident, as the balance of cases is not accounted for by mutations in these genes. The aim of this study was to determine the mutation responsible in a family with juvenile polyposis. An Australian Caucasian family with juvenile polyposis have attended and followed surveillance plans through the Familial Bowel Cancer Clinic, The Royal Melbourne Hospital. A pedigree of the family was constructed with attention to the mixed phenotypic expression of polyps in affected members. Genetic testing for SMAD4 and BMPR1A mutations in germline DNA and linkage analysis to SMAD4, BMPR1A and 15q14 (CRAC1 locus) were performed. There were no pathogenic mutations in SMAD4 and BMPR1A. There was no linkage to SMAD4 or 15q14 (CRAC1 locus). Linkage analysis suggested a cryptic BMPR1A mutation or the presence of another gene in close proximity to the BMPR1A locus. Two additional candidate genes in the region of linkage (PTEN and MINPP1) were excluded. Most affected members of this Australian Caucasian family demonstrate a phenotype of mixed polyps: juvenile polyps, adenomas and/or hyperplastic polyps. Cloning of a potentially responsible gene closely linked to the BMPR1A locus or a cryptic mutation in BMPR1A may offer valuable insights into the pathogenesis of JPS.

Serrated colorectal polyps and the serrated neoplastic pathway: Emerging concepts in colorectal carcinogenesis

Several investigators have recently proposed the concept of a ‘serrated neoplastic pathway’ to account for the development of a subset of colonic carcinomas that lack chromosomal instability and loss of heterozygosity. This pathway putatively involves several pathogenetically related polyps, including some hyperplastic polyps, the recently described sessile serrated polyp, serrated adenoma and mixed polyp; and is characterised by early BRAF mutations, DNA hypermethylation and microsatellite instability. Most hyperplastic polyps and sessile serrated polyps harbour mutations in BRAF , one gene involved in the mitogen-activated protein kinase pathway, and abnormal DNA methylation. Presumably, these genetic changes are sufficient to potentiate widespread genomic hypermethylation that ultimately affects the promoter regions of key DNA repair genes, such as hMLH-1 and O 6 -methylguanine methyltransferase , thereby silencing them from transcription and leading to progressive microsatellite instability. The morphological evolution of non-dysplastic serrated lesions (hyperplastic and sessile serrated polyps) to serrated adenomas, mixed polyps and/or colorectal carcinoma is believed to reflect the accumulation of these genetic events. The purpose of this review is to describe the morphological and molecular features of colorectal serrated polyps and to present the available data supporting the concept of a serrated neoplastic pathway of colorectal carcinogenesis.

Les polypes festonnés colorectaux : une entité revisitée

Colorectal serrated polyps are heterogeneous epithelial lesions characterized by a serrated architecture. They include the classical hyperplastic polyps and the much rarer serrated adenomas and mixed polyps. Whereas serrated adenomas are composed of an unequivocal adenomatous epithelium with architectural serrated, mixed polyps include two separate hyperplastic and adenomatous components. During the past few years, another type of serrated polyp with only very subtle proliferation abnormalities has been described. These atypical serrated polyps may occur either sporadically or in the context of colorectal polyposis. Despite their close resemblance to traditional hyperplastic polyps, some authors argued that they should be regarded as authentically neoplastic lesions and have proposed to call them "sessile serrated adenomas". Their malignant potential requires their removal when discovered during colonoscopy. This article reviews the histological features, the endoscopic appearance, the natural history and the molecular phenotype of the different categories of serrated polyps and introduces the concept of "serrated neoplastic pathway" in the development of colorectal cancer.

Serrated neoplasia of the colorectum

Serrated polyps of the colorectum form a group of related lesions which include aberrant crypt foci (ACF), conventional hyperplastic polyps, mixed (admixed) polyps, serrated adenomas and sessile serrated adenomas. In recent years the molecular differences between these morphologically similar lesions have been highlighted, and their differing biological potential has been realised. In particular, the sessile serrated adenoma has become recognised as the precursor lesion to a group of sporadic colorectal carcinomas characterised by morphological and molecular features distinct from conventional adenomas. These recent findings have challenged the long held paradigm that all colorectal carcinomas arise via the traditional adenoma-carcinoma sequence. In addition, they present a major challenge for the early detection and management of colorectal cancer, which is no longer regarded as a homogeneous entity.

Singapore Familial Adenomatous Polyposis (FAP) Patients with Classical Adenomatous Polyposis but Undetectable APC Mutations Have Accelerated Cancer Progression

Germline mutation in adenomatous polyposis coli (APC) is detected in up to 80% of familial adenomatous polyposis (FAP) patients worldwide. In this study, we evaluated clinical features and APC mutations of Singapore FAP patients and contrasted genotype-phenotype correlation with Caucasians from other regions of the world and between FAP patients with and without detectable APC mutations. We screened 242 members from 57 unrelated FAP families using a combination of cDNA protein truncation test, multiplex ligation-dependent probe amplification, and differential expression techniques. APC germline mutations were detected in 50 families. In contrast to Caucasians, fundic gland polyposis in Singapore patients was associated with APC mutations throughout the coding region and osteomas were also not confined to codon 767-1573. There was also no FAP-associated hepatoblastoma or medullablastoma. APC mutation-negative patients from four families with mixed (adenomatous/hyperplastic/atypical juvenile) polyps were subsequently reclassified as hereditary mixed polyposis syndrome (HMPS) patients. APC mutation-negative patients with classical adenomatous polyposis were negative for MYH, beta-catenin, and Axin 1 mutations. These patients had a significantly older age at diagnosis (P < 0.001) and more colorectal cancers (P= 0.017) than patients with APC mutations. We achieved a 94% (50/53) APC mutation detection rate via a combination of techniques, suggesting that the current detection rate is probably not exhaustive. Singapore patients have some features similar to and other features distinct from Caucasians. Furthermore, APC mutation-negative patients have accelerated cancer progression that merits closer surveillance.

High Prevalence of Sessile Serrated Adenomas With BRAF Mutations: A Prospective Study of Patients Undergoing Colonoscopy

Sporadic colorectal cancers with a high degree of microsatellite instability are a clinically distinct subgroup with a high incidence of BRAF mutation and are widely considered to develop from serrated polyps. Previous studies of serrated polyps have been highly selected and largely retrospective. This prospective study examined the prevalence of sessile serrated adenomas and determined the incidence of BRAF and K-ras mutations in different types of polyps. An unselected consecutive series of 190 patients underwent magnifying chromoendoscopy. Polyp location, size, and histologic classification were recorded. All polyps were screened for BRAF V600E and K-ras codon 12 and 13 mutations. Polyps were detected in 72% of patients. Most (60%) were adenomas (tubular adenomas, tubulovillous adenomas), followed by hyperplastic polyps (29%), sessile serrated adenomas (SSAs; 9%), traditional serrated adenomas (0.7%), and mixed polyps (1.7%). Adenomas were more prevalent in the proximal colon (73%), as were SSAs (75%), which tended to be large (64% >5 mm). The presence of at least one SSA was associated with increased polyp burden (5.0 vs 2.5; P < .0001) and female sex (P < .05). BRAF mutation was rare in adenomas (1/248 [0.4%]) but common in SSAs (78%), traditional serrated adenomas (66%), mixed polyps (57%), and microvesicular hyperplastic polyps (70%). K-ras mutations were significantly associated with goblet cell hyperplastic polyps and tubulovillous adenomas (P < .001). The prevalence of SSAs is approximately 9% in patients undergoing colonoscopy. They are associated with BRAF mutation, proximal location, female sex, and presence of multiple polyps. These findings emphasize the importance of identifying and removing these lesions for endoscopic prevention of colorectal cancer.

Hyperplastic Polyposis Coli Syndrome and Colorectal Carcinoma

Patients with hyperplastic polyposis coli syndrome (HPCS) have a propensity to develop colorectal carcinoma (CRC). Details were retrieved from the files of patients attending our hospital between 1988 and 2004 who fulfilled the World Health Organization criteria for HPCS. Over a period of 16 years, 10 cases of HPCS were identified at our hospital (0.625 cases/year or one case every 1.6 years). A mean of 40.3 hyperplastic polyps per patient were found (range 6-159). Other colorectal lesions were found as follows: two patients each had one mixed polyp; there were 15 serrated adenomas in eight patients; and there were 30 tubular, tubulovillous, or villous adenomas in eight patients. Among the 10 patients with HPCS, seven developed a CRC. Of the four villous adenomas, three were associated with a CRC, but only one of the 15 serrated adenomas was associated with a CRC. The pathway of cancer evolution in HPCS patients remains unresolved. Similarly to our results, a review of the literature indicates a high incidence of CRCs in HPCS patients. These patients are at a high risk of developing a CRC and should therefore receive regular colonoscopic surveillance.

Advanced colorectal polyps with the molecular and morphological features of serrated polyps and adenomas: concept of a ‘fusion’ pathway to colorectal cancer

Jass J R, Baker K, Zlobec I, Higuchi T, Barker M, Buchanan D & Young J (2006) Histopathology 49, 121–131Advanced colorectal polyps with the molecular and morphological features of serrated polyps and adenomas: concept of a ‘fusion’ pathway to colorectal cancerAimTo establish and explain the pattern of molecular signatures across colorectal polyps.Methods and resultsThirty-two sessile serrated adenomas (SSA), 10 mixed polyps (MP), 15 traditional serrated adenomas (SA), 49 hyperplastic polyps (HP) and 84 adenomas were assessed for mutation of KRAS and BRAF and aberrant expression of p53. The findings were correlated with loss of expression of O-6-methylguanine DNA methyltransferase (MGMT). KRAS mutation occurred more frequently (26.5%) than BRAF mutation (4.8%) in adenomas (P < 0.001) and particularly in adenomas with villous architecture (50%). Loss of expression of MGMT correlated with KRAS mutation in small tubular adenomas (P < 0.04). BRAF mutation was frequent in HPs (67%) and SSAs (81%), while KRAS mutation was infrequent (4% and 3%, respectively). Of MPs and SAs, 72% had either BRAF or KRAS mutation. Aberrant expression of p53 was uncommon overall, but occurred more frequently in MPs and SAs (12%) than adenomas (1%) (P < 0.04) and there was concordant loss of expression of MGMT.ConclusionsMolecular alterations that are characteristic of the serrated pathway and adenoma–carcinoma sequence can co-occur in a minority of advanced colorectal polyps that then show morphological features of both pathways. These lesions account for only 2% of colorectal polyps, but may be relatively aggressive.