MIB-1 and MCM-2 immunohistochemical analysis does not aid in identification of serrated colorectal polyps with abnormal proliferation

We investigated the staining characteristics of serrated polyps with abnormal proliferation (SPAP) using MIB-1 and MCM-2 to determine if they could provide assistance in delineating SPAPs from traditional hyperplastic polyps (HPs). Using published morphologic criteria we reviewed H&E slides of 107 polyps from 80 patients. Thirty-nine (36.4%) polyps met the criteria for SPAP Within a given region, polyps in the transverse colon had the largest percentage of SPAPs (50.0%) followed by the right colon (40.9%). The majority of SPAPs (82.1%) and HPs (72.1%) showed MIB-1 staining confined to the basal third of the crypts. The majority of SPAPs (59.0%) and HPs (52.9%) showed MCM-2 staining extending into the apical third of the crypts. We do not recommend MIB-1 or MCM-2 staining to differentiate SPAPs from conventional HPs, since staining characteristics are not significantly different between the 2 groups, and frequent variable crypt staining within a given polyp is difficult to interpret.     

Serrated polyps of the colorectum: is sessile serrated adenoma distinguishable from hyperplastic polyp in a daily practice?

The distinction between serrated polyps of the colon is complex, particularly between hyperplastic polyps (HP) and sessile serrated adenomas (SSA). Recent data show that SSA might be the precursors of serrated colonic cancers, underlining the necessity of identifying them. We characterized the demographic and pathologic characteristics of 102 serrated lesions among 321 polyps of the colorectum and determined if SSA can be microscopically distinguished from HP in biopsy material of a daily practice. There were 81 HP (79%) and 7 SSA (7%) of which one displayed low-grade dysplasia. Only six serrated polyps (6%) could not be correctly classified. The main architectural criteria for distinguishing SSA from HP is the serrated feature along the crypt axis and the rarity of undifferentiated cells in the lower third of the crypts. SSA was significantly more often located in the right colon and larger (median, 11 vs 4 mm) than HP. SSA are rare serrated polyps that can be distinguished from HP based on their morphology, location in the right colon, and larger size. One SSA of our series showed low-grade dysplasia supporting the concept that this lesion might be a precursor of serrated adenocarcinoma.     

Cell turnover of serrated adenomas

Serrated adenomas of the colon are characterized by epithelial neoplasia combining the architectural features of hyperplastic polyps and the cytological features of adenomas. Cell turnover, which is related to the malignant potential of these polyps, has not been thoroughly investigated. The aim of this study was to investigate epithelial cell proliferation, apoptosis, and oncoprotein expression in serrated adenomas. Twenty-five hyperplastic polyps, 25 serrated adenomas, and 25 tubulovillous adenomas resected from the colons of 75 patients were studied by immunohistochemical staining using monoclonal antibodies against MIB-1, Bcl-2, Bax, p53, and the TUNEL method for the detection of apoptosis. In serrated adenomas, the proliferation rate was significantly lower than in tubulovillous adenomas in both the lower and the upper parts of the crypts, and higher than that of hyperplastic polyps. Apoptosis was also significantly lower in serrated than in tubulovillous adenomas, but higher than in hyperplastic polyps. p53 oncoprotein expression was significantly greater in both serrated and tubulovillous adenomas than in hyperplastic polyps. bcl-2 protein expression was higher only in tubulovillous adenomas. Bax index was significantly different between tubullovillous and serrated adenomas, but the lowest values were observed in hyperplastic polyps. Serrated adenomas are highly proliferative polyps. They should be considered a biologically different entity from hyperplastic polyps. The intermediate features between serrated adenomas, hyperplastic polyps, and tubulovillous adenomas using the antibodies analysed in this study could have implications for the rate or the mechanism of development of malignancy in this type of polyp.     

结直肠锯齿状病变104例形态学及细胞增殖活性的观察

目的 探讨结直肠锯齿状病变增生性息肉(HP)、广基锯齿状腺瘤(SSA)、传统锯齿状腺瘤(TSA)的临床特征,组织病理学诊断,鉴别诊断及细胞增殖状况.方法 复习北京军区总医院2002年11月至2007年12月2628例病理诊断为结直肠息肉/腺瘤的病理切片,从中收集104例结直肠锯齿状病变,综合文献标准进行分类,观察各类型病变临床病理学特征,以及细胞增殖指数Ki-67的表达特点.结果 104例锯齿状病变中包括HP 60例,TSA 20例,SSA 11例,混合性锯齿状息肉/腺瘤7例,混合件锯齿状息肉/腺瘤+普通腺瘤6例.对各型组织学特征进行总结归纳.免疫组织化学显示正常结肠黏膜Ki-67阳性细胞位于基底(隐窝下1/3),呈间隔分布;51例HP中阴性或阳性细胞数最<25%的40例(78%),大多数阳性位于隐窝下1/3(基底);15例TSA中11例阳性细胞数量在25%～50%或>50%,其中大多数位于隐窝中1/3,少数(2例)隐窝弥漫分布;SSA的数量与分布和TSA相似;相比之下低级别管状腺瘤26例中24例(92%)阳性数量>50%,18例(69%)分布于隐窝表面,6例(23%)弥漫分布;高分化管状腺癌10例全部呈弥漫分布,7例Ki-67阳性指数在70%左右.阳性细胞多少与分布部位差异有统计学意义,阳性细胞)χ2=34.601,P=0.000,阳性分布χ2=63.077,P=0.000.结论 HP、SSA、TSA组织学鉴别诊断的主要难点是在HP与SSA两者之间,SSA锯齿状隐窝基底扩张结构特征是诊断的关键,比细胞学改变更重要.TSA与SSA的主要形态鉴别在于TSA锯齿状腺体有明显异型增生(普通腺瘤样增生)以及几乎所有TSA异型增生的腺体都不与黏膜肌相邻(ECF现象).细胞增殖指数Ki-67数量及分布的表达可为HP、SSA及TSA鉴别诊断提供一定帮助.锯齿状腺瘤中TSA和SSA的Ki-67表达指数都比普通腺瘤要低.     

Expression of Ki-67 and cytokeratin 20 in hyperplastic polyps of the colorectum

AIMS: To study the expression of Ki-67 and cytokeratin 20 (CK20) in a group of hyperplastic polyps (including a group with "atypical" features) with the aim of determining whether upper crypt Ki-67 staining and lower crypt CK20 staining correlated with these atypical features, as assessed by light microscopy. METHODS: Fifty seven formalin fixed, paraffin wax embedded hyperplastic colorectal polyps from 53 patients were selected on histological grounds; these comprised 26 typical polyps and 31 with atypical features, which included nuclear hyperchromatism, basal crowding, and increased mitotic activity. These polyps were examined using a standard immunohistochemical method with antibodies against CK20 and Ki-67. Comparisons were made with normal mucosa, adenomatous polyps, and carcinomas. RESULTS: Of the 26 typical polyps, 17 showed the usual pattern of lower crypt Ki-67 and upper crypt CK20 staining; one with upper crypt Ki-67 staining but normal surface CK20 staining; seven with Ki-67 confined to the lower half of crypts but with scattered lower crypt CK20; and one with both upper crypt Ki-67 staining, together with scattered CK20 basal staining. Of the 31 polyps with atypical features, 11 showed the usual staining pattern of lower crypt Ki-67 staining and surface staining with CK20; two showed Ki-67 staining extending into the upper half of crypts, but with a normal surface staining with CK20; 14 showed Ki-67 confined to the lower half of crypts, but scattered lower crypt staining with CK20; and four showed upper crypt Ki-67 staining together with scattered CK20 lower crypt staining. CONCLUSIONS: The normal pattern of lower crypt Ki-67 and upper crypt CK20 was seen in 28 of the 57 hyperplastic polyps and, in general, this corresponded with standard light microscopic appearances. Twenty one of the 57 polyps showed lower crypt mosaic CK20 staining, which in general corresponded with basal abnormalities on light microscopy, although seven specimens had normal appearances. Two smaller subsets emerged, one showing upper crypt Ki-67 staining in the presence of normal CK20 expression (three cases) and another in which a combination of lower crypt CK20 and upper crypt Ki-67 expression was seen (five cases). This last pattern was similar to that of neoplastic polyps and raises the possibility that a subgroup of hyperplastic polyps exists that may be a variant with malignant potential. Further studies with markers of mismatch repair genes and K-ras mutations may help to clarify this issue.     

Cellular differentiation status of epithelial polyps of the colorectum: the gastric foveolar cell-type in hyperplastic polyps

AIMS: The 'metaplastic' polyp of the colorectum, a synonym for the hyperplastic polyp, was named based only on features of the crypt epithelium. It is considered non-neoplastic, but the precise cellular differentiation status remains to be proven. METHODS AND RESULTS: Forty-eight hyperplastic polyps, 12 serrated adenomas, 45 tubular adenomas and five juvenile polyps were studied for their phenotypic expression using gastric (foveolar or pyloric gland cell), small intestinal (goblet cell), and colonic (goblet cell) cellular markers by immunohistochemical and mucin histochemical techniques. Gastric foveolar cell-type differentiation was significantly expressed in hyperplastic polyps, while colonic differentiation was also consistently preserved. Neither gastric pyloric-type nor small intestinal differentiation was observed. The same cell differentiation status as hyperplastic polyps was observed in serrated adenomas but not in tubular adenomas or juvenile polyps. CONCLUSIONS: A large proportion of hyperplastic polyps are composed of hybrid epithelium, with bidirectional differentiation to both gastric foveolar and colonic epithelial cells in the same crypt. Therefore hyperplastic polyps might be interpreted as the outcome of abnormal cell differentiation of stem cells. The same phenotypic expression suggests that hyperplastic polyps and serrated adenomas share the same cell lineage.     

Serrated colorectal polyps: emerging evidence suggests the need for a reappraisal

A set of polyps that superficially resemble ordinary hyperplastic polyps of the left colon but with divergent morphology and probably divergent biology has become apparent. Such polyps differ from typical small left-sided hyperplasic polyps by the large sizes they may attain, their tendency to be right-sided, and subtle morphologic differences. It is important to separate these polyps, which some have called "sessile serrated polyps" from hyperplastic polyps as they are associated with progression to carcinoma probably through mismatch repair defects.     

Serrated neoplasia of the gastro-intestinal tract

Serrated neoplasia of the gastro-intestinal tract have peculiar microscopic and molecular features that are still incompletely described. Some serrated polyps seem to be involved in a new carcinogenic pathway in the colon: the serrated neoplasia pathway, with hypermethylation of the cytosine-guanine dinucleotides, located in the promoter of some genes such as h-MLH1, BRAF and MGMT. The natural history of the serrated polyps and their risk for progression to malignancy are still unclear. There is no official guideline for the management of serrated polyps. The aim of this article is to describe the epidemiological, morphological, immunohistochemical and molecular characteristics of the serrated neoplasia of the gastrointestinal tract: hyperplastic polyps, "traditional" serrated adenomas, mixed hyperplastic and adenomatous polyps, sessile serrated adenomas, hyperplastic polyposis and serrated adenocarcinomas.     

Survivin and hedgehog protein expression in serrated colorectal polyps: an immunohistochemical study

Sessile serrated adenomas and traditional serrated adenomas are pathogenetically related to inhibition of apoptosis. Survivin and hedgehog proteins, including sonic hedgehog, patched, and smoothened, inhibit apoptosis, with hedgehog proteins forming a signal transduction cascade implicated in digestive cancers. This study compares survivin and hedgehog protein expression in serrated polyps and tubulovillous adenomas. Biopsies of sessile serrated adenomas (48) and traditional serrated adenomas (10) diagnosed during 2005 were retrieved from our files. Biopsies of normal mucosa (10), hyperplastic polyps (14), and tubulovillous adenomas (22) were used for comparison. Immunohistochemistry for survivin, sonic hedgehog, patched, and smoothened was graded as high or low grade. chi(2) tests were used to evaluate correlation between polyp type and survivin and hedgehog expression. Traditional serrated adenomas were also compared to sessile serrated adenomas with foci of cytological dysplasia (11 cases) with respect to MLH1 and p53 expression. Sessile serrated adenomas showed high-grade nuclear and cytoplasmic expression of survivin at the bottom of crypts more frequently than tubulovillous adenomas (60% versus 18%, P = .001 [nuclear]; 54% versus 18%, P = .005 [cytoplasm]), the latter showing a top-heavy pattern of staining. Survivin expression in hyperplastic polyps was similar to sessile serrated adenomas, being bottom-heavy, whereas traditional serrated adenomas showed diffuse staining throughout crypts. Although traditional serrated adenomas showed high-grade expression of sonic hedgehog more frequently than tubulovillous adenomas (90% versus 18%; P < .001), sonic hedgehog, patched, and smoothened expression was low grade among normal mucosa, hyperplastic polyps, and sessile serrated adenomas. All cytological dysplasias showed increased p53 expression within dysplastic foci, and MLH1 was also lost within dysplastic foci in 4 cases; traditional serrated adenomas showed intact MLH1 expression and minimal p53 expression throughout. Survivin expression is localized to the bottom of crypts in sessile serrated adenomas and hyperplastic polyps, whereas tubulovillous adenomas show top-heavy expression. Traditional serrated adenomas express survivin throughout crypts, suggesting intersection between the serrated and conventional adenoma-cancer pathways. Sonic hedgehog up-regulation is characteristic of traditional serrated adenomas, distinguishing this entity from other colorectal polyps.     

Serrated route to colorectal cancer: back street or super highway?

Morphological and molecular studies are beginning to distinguish separate evolutionary pathways for colorectal cancer. The serrated pathway encompassing hyperplastic aberrant crypt foci, hyperplastic polyps, mixed polyps, and serrated adenoma is increasingly being linked with genetic alterations, including DNA methylation, DNA microsatellite instability, K-ras mutation, and loss of chromosome 1p. The importance of the serrated pathway has been underestimated in terms of its frequency and potential for rapid progression.     

Colorectal serrated adenocarcinoma

Colorectal cancer (CRC) ranks among the three most common cancers in terms of both cancer incidence and cancer-related deaths in most Western countries. Serrated adenocarcinoma is a recently described, distinct variant of CRC, accounting for about 7.5% of all CRCs and up to 17.5% of most proximal CRCs. It has been postulated that about 10-15% of sporadic CRCs would have their origin in serrated polyps that harbour a significant malignant potential. These lesions include hyperplastic-type aberrant crypt foci, hyperplastic polyps, sessile serrated adenomas, admixed polyps and serrated adenomas, and constitute the so-called 'serrated pathway', which is distinct from both the conventional adenoma-carcinoma pathway and the mutator pathway of hereditary non-polyposis CRC and is characterized by early involvement of oncogenic BRAF mutations, excess CpG island methylation (CIM) and subsequent low- or high-level DNA microsatellite instability (MSI). Methylation of hMLH1 is likely to explain the increased frequency of high-level MSI (16%) and methylation of MGMT is postulated to explain the low-level MSI (29%) in serrated adenocarcinomas. Reproducible histopathological criteria for serrated adenocarcinoma have recently been established and they have been qualified by DNA expression analysis for 7928 genes, showing clustering of serrated adenocarcinomas into a molecular entity apart from conventional adenocarcinoma, and representing with distinct down-regulation of EPHB2, PTCH and up-regulation of HIF1alpha.     

Small colonic microsatellite unstable adenocarcinomas and high-grade epithelial dysplasias in sessile serrated adenoma polypectomy specimens: a study of eight cases

Eight sessile serrated adenoma (SSA), right colon polypectomies with focal invasive adenocarcinoma or high-grade dysplasia were studied to identify features indicating a high risk of transformation and characterize the morphologic features of serrated dysplasia; 6 cases had invasive adenocarcinoma; 2 were high-grade dysplasia. All 8 were microsatellite unstable-high and had absent hMLH1 nuclear immunoreactivity. The mean patient age at polypectomy was 69.5 years (range, 57.1-83.9 years). Mean polyp maximum dimension was 8.5 mm (range, 6-12 mm). The majority of each polyp was nonmalignant SSA. All 8 cases had an abrupt transition from benign to high-grade in situ or invasive malignancy. In the 6 invasive adenocarcinomas, the neoplasm extended directly down into the submucosa without lateral intramucosal spread. The mean maximum dimension of the invasive adenocarcinoma was 2.9 mm (range, 2-4 mm). All 8 cases had high-grade serrated-type dysplasia. The nonmalignant SSAs had marked expansion of the proliferative zone. Crypts adjacent to malignancy had moderately enlarged nuclei, irregular nuclear membranes, and overly prominent nucleoli. SSA crypts were lined by a variety of gastric-type cells; no cell type predominated. Foci of adjacent crypts had similar cytologic features. Small proximal SSAs can transform into adenocarcinoma without a component of adenomatous dysplasia.     

Expression of survivin in normal, hyperplastic, and neoplastic colonic mucosa

The regulation of apoptotic cell death may have a profound effect on the pathogenesis and progression of colon cancer. Survivin, a member of the inhibitor of apoptosis gene family, has been detected in fetal tissue and in a variety of human malignancies. In the current study, we investigated survivin expression by an immunohistochemical approach in benign, hyperplastic, premalignant, and malignant lesions of the colon. Survivin was detected in all cases of normal colonic mucosa (20/20), hyperplastic polyps (20/20), adenomatous polyps (20/20), and in both well differentiated and moderately differentiated colonic adenocarcinomas (20/20). In the normal colonic mucosa, survivin expression was mostly restricted to the base of the colonic crypts. All epithelial cells showed uniformly intense staining for survivin in hyperplastic polyps. By contrast, adenomas and adenocarcinomas showed a heterogeneous staining pattern with cell-to-cell, gland-to-gland, and regional variability in the intensity of survivin staining. In contrast to the basal preponderance of staining in normal colonic mucosa, numerous survivin positive cells were present at the luminal surface of hyperplastic polyps, adenomatous polyps, and adenocarcinomas. In conclusion, the expression of survivin is not a specific marker of adenocarcinoma of the colon but does show characteristic and reproducible patterns of expression in non-neoplastic proliferative lesions and in normal colonic mucosa.     

Fibroblastic polyp of the colon: clinicopathological analysis of 10 cases with emphasis on its common association with serrated crypts

AIMS: To describe the clinical and pathological features of 10 further cases of fibroblastic polyps (FP), a recently described, distinctive type of colorectal mucosal polyp. METHODS AND RESULTS: The patients were seven women and three men with ages ranging from 44 to 63 years. The lesions ranged in size from 2 to 4 mm. Eight of the polyps were located in the sigmoid colon. Five cases were associated with hyperplastic polyps. Histologically, FP displayed bland, plump spindle cells with oval nuclei arranged as bundles parallel to the surface or as haphazardly orientated sheets with a focal periglandular or perivascular concentric arrangement. Eight polyps represented mixed fibroblastic/hyperplastic polyps as they contained serrated (hyperplastic) crypts. Immunohistochemically, all cases were positive for vimentin and negative for desmin, smooth-muscle actin, h-caldesmon, S100 protein, c-Kit, epithelial membrane antigen, cytokeratin AE1/3, CD34, CD68, COX-2, and factor XIIIa. Ultrastructural examination supported the fibroblastic nature of the tumour cells. CONCLUSIONS: FP is a distinctive type of benign mucosal colorectal polyp characterized by its distal location, small size, frequent association with hyperplastic polyps, distinct morphological appearance and typical immunonegativity for markers of specific differentiation. FP with serrated crypts (mixed fibroblastic/hyperplastic polyp) represents a frequent variant of this lesion. Pathologists should recognize FP and discriminate it from other types of colorectal polyps.     

Frequent p53 gene mutations in serrated adenomas of the colorectum

Serrated adenoma has been recently proposed as a distinct histological lesion of the colorectum. This study examined p53 immunoreactivity, mutations of exons 5–8 of the p53 gene, codon 12 of the Ki-ras gene by PCR–SSCP analyses, and microsatellite instability in 19 serrated adenomas, ten adenocarcinomas in/with serrated adenomas, 23 hyperplastic nodules, four hyperplastic polyps and 29 tubular adenomas of the colorectum. Eleven of 11 (100 per cent) serrated adenomas had p53 immunoreactivity and all six (100 per cent) adenocacinomas in/with serrated adenomas exhibited moderate to severe p53 immunoreactivity. It was confirmed that 9 of 19 (47 per cent) serrated adenomas and 5 of 10 (50 per cent) adenocarcinomas in/with serrated adenomas harboured p53 gene mutations. On the other hand, no p53 gene mutation was detected in the other colorectal lesions. Meanwhile, 11 (58 per cent) serrated adenomas and six (60 per cent) adenocarcinomas in/with serrated adenomas had Ki-ras gene mutations, as also did 9 of 23 (39 per cent) hyperplastic nodules, 3 of 4 (75 per cent) hyperplastic polyps, and 12 of 29 (41 per cent) tubular adenomas. Microsatellite instability was detected in one (5 per cent) serrated adenoma and one (10 per cent) adenocarcinoma in a serrated adenoma. The other lesions did not show microsatellite instability. Serrated adenomas had significantly frequent p53 gene mutations compared with hyperplastic lesions or tubular adenomas (p<0·005). On the other hand, they did not exhibit significant differences in mutations of the Ki-ras gene or in microsatellite instability. Genetic changes were then examined in small parts of serrated adenomas, such as the upper or lower parts of crypts, to determine the extent of gene mutations by using a microdissection technique. Exon 15 of the APC gene and the DCC gene, in addition to the p53 and Ki-ras genes and microsatellite instability, were analysed. Identical mutations of the p53 gene were found in both invasive adenocarcinomas and adjacent serrated adenomas by direct sequencing, suggesting single clonal origins for those lesions. Mutations of the APC gene and microsatellite instability were heterogeneous in some lesions. No loss of heterozygosity (LOH) of the DCC gene was found. These findings suggest that mutations of the p53 gene are the most characteristic genetic alterations in serrated adenomas, as a relatively early event in a multistep carcinogenic pathway of this type of colorectal lesion, that might be distinct from the ordinary adenoma–carcinoma sequence or from carcinogenesis via mutations of mismatch repair genes. Copyright © 1998 John Wiley & Sons, Ltd.     

Histopathological and clinical evaluation of serrated adenomas of the colon and rectum.

We evaluated the diagnostic utility of the histological characteristics ascribed in the literature to serrated adenomas and developed a practical working model to allow their reliable identification. We also documented the frequency and location of serrated adenomas identified in an unselected series of individuals undergoing colonoscopic evaluation, as well as the clinical characteristics of those individuals. One hundred forty consecutive individuals (prospective polyp data set; 97 male, 43 female; age mean: 63.3 y; age range: 29-98 y) with 255 polyps were identified from 919 individuals undergoing colonoscopy. Further polyps previously removed from these individuals were added for the purpose of histological assessment (extended polyp data set, n = 380). All polyps were assessed by two independent examiners for eight selected architectural and cytological features of serrated adenomas. In the prospective polyp data set, 56 patients had 72 hyperplastic polyps, 7 had 9 serrated adenomas, 3 had 4 admixed polyps, and 98 had 170 conventional adenomas. There was no difference in the age, sex, or cancer association of the seven patients with serrated adenomas when compared with the case of other individuals with polyps. The prevalence of serrated adenomas was 9/919 (1%) in our population, with an average size of 5.8 mm. When assessing serrated adenomas histologically, the combination of nuclear dysplasia and serration of >/=20% of crypts provided the most accurate model for detection of these lesions (sensitivity 100%, specificity 97%). Other criteria provided supportive evidence but did not increase the diagnostic yield. The optimum model for the histological identification of the serrated adenoma includes the presence of a serrated architecture in >/=20% of crypts in association with surface epithelial dysplasia.     

Hyperplastic polyp of the duodenum: a report of 9 cases with immunohistochemical and molecular findings

Benign serrated polyps are commonly found in the colorectum but have rarely been described in other parts of the gastrointestinal tract. We report a series of 9 serrated polyps arising in the duodenum with clinicopathologic features, immunohistochemical expression profile of mucins (MUC2, MUC5AC, MUC6), and molecular analysis for BRAF and KRAS. The polyps were diagnosed as incidental endoscopy findings in 9 different patients, comprising 3 male and 6 female patients, with a mean age of 52.2 years (range, 21-72 years). The second part of the duodenum was the most common site (n = 5), followed by the ampulla (n = 1) and the distal duodenum (n = 1), with the location of the 2 remaining polyps unspecified. Other upper gastrointestinal tract pathology features included Barrett esophagus for 5 patients, Helicobacter gastritis for 1 patient, and mild chronic gastritis for 1 patient. The histologic appearance of the polyps was similar to microvesicular hyperplastic polyp in the colorectum. Immunostaining for mucins showed MUC6 expression in the crypt bases of all polyps, MUC5AC expression in 8 cases (89%), and mucin 2 expression in 6 cases (67%). Molecular testing was successful in 6 polyps, showing BRAF mutation (V600E) in 2 polyps, KRAS mutation in 2 polyps, and no mutation for either gene in 2 polyps. Colonoscopy reports were available for 6 patients, of whom 4 were diagnosed with hyperplastic polyps or sessile serrated polyps in the colorectum. However, no patient met the criteria for serrated polyposis. Although probably rare and of uncertain malignant potential, hyperplastic polyp should be considered in the differential diagnosis of benign duodenal polyp.     

Over-expression of cathepsin E and trefoil factor 1 in sessile serrated adenomas of the colorectum identified by gene expression analysis

Sessile serrated adenomas are now recognised as precursor lesions of a substantial subset of colorectal cancers arising via a so-called “serrated pathway”. However, their biological markers remain to be defined. The aim of our study was to identify differentially expressed genes in sessile serrated adenomas and conventional adenomas. Gene expression analysis demonstrated molecular differences between polyp types. Further studies using quantitative real-time polymerase chain reaction on cathepsin E (CTSE) demonstrated a significantly (p < 0.05) higher expression in sessile serrated adenomas as compared to hyperplastic polyp and tubular adenomas. Trefoil Factor 1 showed the same trend of expression for sessile serrated adenomas as compared to hyperplastic polyps and was significantly higher in both polyps compared to tubular adenomas. Immunohistochemistry for both proteins demonstrated strong cytoplasmic staining of abnormal crypts in all sessile serrated adenomas, while staining in tubular adenomas and hyperplastic polyps was absent or weak and focal. BRAF and KRAS mutation analysis were employed to further validate polyp discrimination. The findings demonstrated the positive association of the BRAF mutation, V600E, with sessile serrated adenomas and KRAS mutations with tubular adenomas (p < 0.05). This study demonstrates the over-expression in CTSE, in particular, and TFF1 in sessile serrated adenomas compared to both hyperplastic polyps and tubular adenomas.     

Serrated polyps of the colon and rectum (hyperplastic polyps, sessile serrated adenomas, traditional serrated adenomas, and mixed polyps)—proposal for diagnostic criteria

Until recently, two major types of colorectal epithelial polyps were distinguished: the adenoma and the hyperplastic polyp. While adenomas—because of their cytological atypia—were recognized as the precursor lesions for colorectal carcinoma, hyperplastic polyps were perceived as harmless lesions without any potential for malignant progression mainly because hyperplastic polyps are missing cytological atypia. Meanwhile, it is recognized that the lesions, formerly classified as hyperplastic, represent a heterogeneous group of polyps with characteristic serrated morphology some of which exhibit a significant risk of neoplastic progression. These serrated lesions show characteristic epigenetic alterations not commonly seen in colorectal adenomas and progress to colorectal carcinoma via the so-called serrated pathway (CpG-island-methylation-phenotype pathway). This group of polyps is comprised not only of hyperplastic polyps, but also of sessile serrated adenomas, traditional serrated adenomas and mixed polyps, showing serrated and “classical” adenomatous features. Diagnostic criteria and nomenclature for these lesions are not uniform and, therefore, somewhat confusing. In a consensus conference of the Working Group of Gastroenterological Pathology of the German Society of Pathology, standardization of nomenclature and diagnostic criteria as well as recommendations for clinical management of these serrated polyps were formulated and are presented herein.     

Frequent activating GNAS mutations in villous adenoma of the colorectum

To elucidate the role of GNAS mutations in colorectal tumourigenesis, we performed a mutation analysis in a total of 234 colorectal tumours, including adenomas, serrated lesions and adenocarcinomas. Activating GNAS mutations were found in 20 of the 24 villous adenomas (83%) but were absent in all the other tumours, except for one tubulovillous adenoma (3%) and two adenocarcinomas (3%). KRAS and BRAF mutations were always mutually exclusive. KRAS mutations were frequent in villous (67%) and tubulovillous (60%) adenomas but were rare or absent in tubular adenomas (6%) and serrated lesions, including hyperplastic polyps, sessile serrated polyps/sessile serrated lesions and traditional serrated adenomas (0-9%). BRAF mutations were found in four villous adenomas (17%) and in the large majority of serrated lesions (81-92%), but were absent in tubular and tubulovillous adenomas. Seventeen villous adenomas (71%) harboured GNAS mutations concomitantly with KRAS or BRAF mutations. Immunohistochemically, all the villous adenomas retained mismatch repair protein expression, suggesting that they are microsatellite-stable. The current study showed that the presence of activating GNAS mutations, in association with KRAS or BRAF mutations, is a characteristic genetic feature of colorectal villous adenoma.