Sessile serrated adenoma/polyp showed rapid malignant transformation in the final 13 months

Based on the concept of the adenoma-carcinoma sequence, most colorectal cancers are considered to arise from conventional adenomas. However, recent studies suggested that a subset of colorectal cancers develop through the serrated neoplastic pathway. It has also been documented that serrated polyps can rapidly transform into invasive cancers even when they are small in size. We now describe a case of a sessile serrated adenoma/polyp which had been followed up for 4 years but eventually showed rapid transformation into an advanced cancer accompanied by a remarkable morphological change within only 13 months. Retrospective genetic and epigenetic analyses showed microsatellite instability, CpG island methylator phenotype-positive, and BRAF mutation in the lesion, suggesting the tumor had developed through the serrated neoplastic pathway. This case may provide valuable information about the natural history of sessile serrated adenoma/polyps which eventually progress to advanced cancers.     

Expression of Cytokeratins 7 and 20 in Serrated Adenoma and Related Diseases

The entity of serrated adenoma of the colorectum was first proposed in 1990, and it was characterized as epithelial neoplasia combining the architectural features of a hyperplastic polyp with the cytological features of an adenoma. Over the past few years, various clinicopathological studies on serrated adenoma have been reported, but its histogenesis remains unclear. Recently the existence of a “serrated neoplasia pathway” leading to malignancy, which is different from the so-called adenoma–carcinoma sequence, has been discussed. Yao et al. reported that hyperplastic polyps and serrated adenomas share a common cell lineage with gastric differentiation. To clarify the existence of the serrated neoplasia pathway, we performed immunohistochemical staining of cytokeratin 7 (CK7) and cytokeratin 20 (CK20), which are commonly used to determine the primary site of a metastatic lesion, and we examined the pattern of CK7/CK20 expression in various colorectal lesions including 44 serrated adenomas, 25 hyperplastic polyps, 20 traditional adenomas, and 48 carcinomas. An obvious difference existed in the pattern of CK7/CK20 expression between the serrated lesions (hyperplastic polyps and serrated adenomas) and others. The majority of serrated adenomas and hyperplastic polyps presented a CK7+/CK20+ pattern, whereas most conventional adenomas and adenocarcinomas expressed CK7−/CK20+. Adenocarcinoma developing in serrated adenoma also presented a CK7+/CK20+ pattern. There are several reports that CK7 is a possible marker of transient dedifferentiation in the gastric carcinogenesis process. Taken together with the present results, a distinct pathway of colorectal carcinogenesis must exist, which is different from the adenoma–carcinoma sequence. CK7 is a possible marker for the serrated neoplasia pathway of colorectal carcinogenesis.     

Differenzierte Bewertung der Adenom-Karzinom-Sequenz beim kolorektalen Karzinom

Colorectal adenocarcinoma is one of the most frequent malignancies. Efficient and useful screening strategies are available therefore the knowledge of precursor lesions is crucial. These precursor lesions, the so called adenomas can be subdivided into several histological subgroups. These subgroups display a distinct molecular profile as well as distinct clinical characteristics. Today, classical adenomas with tubular, tubulo-villous and villous morphology are distinguished from serrated lesions, encompassing hyperplastic polyps, sessile serrated adenomas and traditional serrated adenomas. Similar to the classical adenoma carcinoma pathway the sessile and traditional serrated lesions can proceed to an invasive carcinoma. These carcinomas display distinct molecular, clinical and phenotypical characteristics similar to their precursor lesions. These differences are important for cancer prevention, adequate therapy and have prognostic implications.     

Clinicopathological characteristics of serrated polyps as precursors to colorectal cancer: Current status and management

Serrated polyps have long been thought to lack malignant potential in the human colorectum. However, identification of the serrated pathway to colorectal cancer based on molecular biology has improved our understanding of the pathogenesis of colorectal cancers. Accordingly, serrated polyps such as traditional serrated adenoma and sessile serrated adenoma/polyps (SSA/P) are now considered to be precursor lesions of the serrated pathway. Recently, serrated polyps were classified into three subtypes, consisting of hyperplastic polyp, SSA/P, and traditional serrated adenoma, according to the World Health Organization classification. It has been suggested that SSA/P in the proximal colon are a precursor lesion of pathogenesis of colorectal cancer and are characterized by BRAF mutation and a CpG island methylator phenotype with or without microsatellite instability. However, SSA/P is more challenging to detect by colonoscopy and is likely to account for some interval cancers, particularly in the proximal colon because it presents flat or sessile, isochroous appearance, and occasionally has a mucous cap. Furthermore, the possibility has been raised that pathologists misclassify SSA/P as hyperplastic polyp. It is important for gastroenterologists to recognize the endoscopic features of serrated polyps to facilitate their detection and removal and also to establish postpolypectomy surveillance guidelines. In this review, we discuss the recent classification of serrated polyps; the molecular characteristics of the serrated pathway; appropriate diagnostic methods using endoscopy, including a new image‐enhanced endoscopic technique; and management of these lesions.     

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.     

Sessile serrated adenoma/polyps: Where are we at in 2016?

It is currently known that colorectal cancers(CRC) arise from 3 different pathways: the adenoma to carcinoma chromosomal instability pathway(50%-70%); the mutator "Lynch syndrome" route(3%-5%); and the serrated pathway(30%-35%). The World Health Organization has classified serrated polyps into three types of lesions: hyperplastic polyps(HP),sessile serrated adenomas/polyps(SSA/P) and traditional serrated adenomas(TSA),the latter two strongly associated with development of CRCs. HPs do not cause cancer and TSAs are rare. SSA/P appear to be the responsible precursor lesion for the development of cancers through the serrated pathway. Both HPs and SSA/Ps appear morphologically similar. SSA/P are difficult to detect. The margins are normally inconspicuous. En bloc resection of these polyps can hence be troublesome. A careful examination of borders,submucosal injection of a dye solution(for larger lesions) and resection of a rim of normal tissue around the lesion may ensure total eradication of these lesions.     

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.     

Editorial: sessile serrated adenomas and their pit patterns: we must first see the forest through the trees

Serrated lesions of the colorectum include hyperplastic polyps, which are non-neoplastic, and sessile serrated adenomas (SSAs, also known as sessile serrated polyps) and traditional serrated adenomas, which are premalignant. It is believed that up to 30% of colon cancers and many post-colonoscopy cancers arise from serrated neoplasms. Post-colonoscopy cancers have been found to have a molecular signature similar to SSAs, including CpG island methylation, BRAF mutations, and microsatellite instability. A novel pit pattern, Type II-O, has been demonstrated to have a high specificity for SSAs. Unfortunately, the sensitivity is too low to utilize a Type II-O pit pattern to determine which serrated lesion is neoplastic and needs resection. Moreover, there is significant endoscopist-related variability in the detection of serrated lesions of the colon. Efforts to improve the detection of serrated neoplasms are warranted.     

MicroRNA-31 expression in colorectal serrated pathway progression

MicroRNAs have been increasingly recognized as useful biomarkers for colorectal cancers (CRC). We have recently observed that microRNA-31 (miR-31) expression is associated with BRAF mutation and prognosis in CRC. Moreover, high miR-31 expression is frequently detected in sessile serrated adenomas compared with hyperplastic polyps (HPs). These results suggest that miR-31 may contribute to the progression of serrated lesions. At a follow-up colonoscopy, we observed the case of a 75-year-old man with a 7-mm flat-elevated lesion in the cecum and diagnosed the lesion as an early invasive carcinoma with serrated features. Tissue specimens were obtained from the representative areas to compare the molecular alterations in the carcinoma component with those in the HP component. Higher miR-31 expression was observed in the carcinoma component (57-fold increase) and the HP component (8-fold increase) compared with the paired normal mucosa, suggesting that miR-31 may be one of the key molecules in serrated pathway progression.     

Pathogenesis and Management of Serrated Polyps: Current Status and Future Directions

Hyperplastic or serrated polyps were once believed to have little to no clinical significance. A subset of these polyps are now considered to be precursors to colorectal cancers (CRC) in the serrated pathway that may account for at least 15% of all tumors. The serrated pathway is distinct from the two other CRC pathways and involves an epigenetic hypermethylation mechanism of CpG islands within promoter regions of tumor suppressor genes. This process results in the formation of CpG island methylator phenotype tumors. Serrated polyps are divided into hyperplastic polyps, sessile serrated adenomas/polyps (SSA/Ps), and traditional serrated adenomas (TSAs). The SSA/P and the TSA have the potential for dysplasia and subsequent malignant transformation. The SSA/Ps are more common and are more likely to be flat than TSAs. Their flat morphology may make them difficult to detect and thus explain the variation in detection rates among endoscopists. Challenges for endoscopists also include the difficulty in pathological interpretation as well surveillance of these lesions. Furthermore, serrated polyps may be inadequately resected by endoscopists. Thus, it is not surprising that the serrated pathway has been linked with interval cancers. This review will provide the physician or clinician with the knowledge to manage patients with serrated polyps.     

结直肠锯齿状癌变途径的分子基础

锯齿状癌变途径是近年提出的概念．用来解释一部分缺乏染色体不稳定性结直肠癌的发生，包括部分增生性息肉、无蒂锯齿状息肉、锯齿状腺瘤和混合性息肉。早期发生BRAF突变、DNA高甲基化以及微卫星不稳定是大部分这类息肉的分子特征．经典的Wnt信号通路在这条途径中可能不起主要作用。     

Hyperplastic polyposis associated with two asynchronous colon cancers

We report a patient with hyperplastic polyposis who had two asynchronous colon cancers, a combined adenoma-hyperplastic polyp, a serrated adenoma, and tubular adenomas. Hyperplastic polyposis is thought to be a precancerous lesion; and adenocarcinoma arises from hyperplastic polyposis through the hyperplastic polyp-adenoma-carcinoma sequence. Most polyps in patients with hyperplastic polyposis present as bland- looking hyperplastic polyps, which are regarded as non- neoplastic lesions; however, the risk of malignancy should not be underestimated. In patients with multiple hyperplastic polyps, hyperplastic polyposis should be identified and followed up carefully in order to detect malignant transformation in the early stage.     

Emerging concepts in colorectal serrated polyps

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.     

Differential expression of p53 and p504s in hyperplastic polyp, sessile serrated adenoma and traditional serrated adenoma

Aims  

Known collectively as serrated polyps, hyperplastic polyps (HP), sessile serrated adenomas (SSA/SSP) and traditional serrated adenoma (TSA) may represent a spectrum of increasing malignant potential with characteristic immunological markers. There is increasing evidence that HP, SSA/SSP and TSA are biologically different and are likely to represent a spectrum along the serrated polyp pathway. Although there is general consensus about the diagnostic features of serrated polyps, the morphological differences between the categories are often subtle. This study compares the expression of p53 and P504S among serrated polyps. Sixty seven randomly selected biopsies (n = 59) and resection specimens (n = 8) histologically diagnosed for SSA/SSP, TSA and HP (19, 30 and 18 specimens, respectively) were obtained.     

High prevalence of sessile serrated adenomas with BRAF mutations: a prospective study of patients undergoing colonoscopy

BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.     

Colorectal proliferation and apoptosis in serrated versus conventional adenoma‐carcinoma pathway: growth,progression and survival

Background: Hyperplastic polyp, serrated adenoma and serrated adenocarcinoma form a morphological continuum, and are likely to be biologically related. The growth rate and malignant conversion rate of serrated adenoma are postulated to be higher than those of conventional adenoma. Methods: Immunohistochemistry for M30 and Ki67 was used to compare apoptosis and proliferation in colorectal hyperplastic polyps, serrated adenomas and serrated adenocarcinomas, and in relation to conventional adenomas and adenocarcinomas. Results: There was an abrupt increase in the apoptosis in carcinomas of serrated adenoma–serrated adenocarcinoma pathway, indicating that inhibition of apoptosis is not maintained in serrated adenocarcinomas. Proliferation was significantly lower at the invasive margin than in the central part in adenocarcinomas, particularly in serrated adenocarcinomas (P?Conclusions: Disordered regulation of apoptosis occurs later in serrated pathway than in conventional adenoma‐carcinoma pathway during malignant conversion. Serrated adenoma growth is not likely to be slower than adenoma growth, as judged by the proliferation and apoptosis rates in serrated adenomas and adenomas. In cancer, the decrease of proliferation and apoptosis in the invasive margin is likely to influence the behaviour of the tumour.     

Serrated polyps of the colon and rectum: Remove or not?

In recent years, the serrated neoplasia pathway where serrated polyps arise as a colorectal cancer has gained considerable attention as a new carcinogenic pathway. Colorectal serrated polyps are histopathologically classified into hyperplastic polyps(HPs), sessile serrated lesions, and traditional serrated adenomas; in the serrated neoplasia pathway, the latter two are considered to be premalignant. In western countries, all colorectal polyps, including serrated polyps, apart from diminutive rectosigmoid HPs are removed. However, in Asian countries, the treatment strategy for colorectal serrated polyps has remained unestablished. Therefore, in this review, we described the clinicopathological features of colorectal serrated polyps and proposed to remove HPs and sessile serrated lesions ≥ 6 mm in size, and traditional serrated adenomas of any size.     

BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum

BACKGROUND AND AIMS: Mutations in BRAF have been linked with colorectal cancers (CRC) showing high level microsatellite instability (MSI-H). However, the distribution of BRAF mutations in MSI-H cancers remains to be clarified with respect to precursor lesions and the CpG island methylator phenotype (CIMP). METHODS: Forty three hyperplastic polyps (HP), nine mixed polyps (MP), five serrated adenomas (SA), 28 conventional adenomas (AD), 18 hereditary non-polyposis colorectal cancers (HNPCC), and 127 sporadic CRC (46 MSI-H and 81 non-MSI-H) were collected from patients undergoing colectomy for either CRC or hyperplastic polyposis. Twenty five of 57 serrated lesions were derived from four patients with hyperplastic polyposis. HP were further subdivided according to recently documented morphological criteria into 27 classical HP and 16 variant lesions described as "sessile serrated adenoma" (SSA). All tumours were screened for BRAF activating mutations. RESULTS: The BRAF mutation was more frequent in SSA (75%) and MP (89%) than in classical HP (19%), SA (20%), and AD (0%) (p<0.0001), and also in sporadic MSI-H cancers (76%) compared with HNPCC (0%) and sporadic non-MSI-H cancers (9%) (p<0.0001). The BRAF mutation was identified more often in CIMP-high serrated polyps (72%) and CIMP-high CRC (77%) than in CIMP-low (30%) and CIMP-negative (13%) polyps (p = 0.002) as well as CIMP-low (18%) and CIMP-negative (0%) CRC (p<0.0001). CONCLUSIONS: The BRAF mutation was frequently seen in SSA and in sporadic MSI-H CRC, both of which were associated with DNA methylation. Sporadic MSI-H cancers may originate in SSA and not adenomas, and BRAF mutation and DNA methylation are early events in this "serrated" pathway.     

Case of pediatric traditional serrated adenoma resected via endoscopic submucosal dissection

Traditional serrated adenoma(TSA)is a type of serrated polyp of the colorectum and is thought to be a precancerous lesion.There are three types of serrated polyps,namely,hyperplastic polyps,sessile serrated adenomas/polyps,and TSAs.TSA is the least common of the three types and accounts for about 5% of serrated polyps.Here we report a pediatric case of TSA that was successfully resected by endoscopic submucosal dissection(ESD).This rare case report describes a pediatric patient with no family history of colonic polyp who was admitted to our hospital with hematochezia.On colonoscopy,we found a polypoid lesion measuring 10 mm in diameter in the lower rectum.We selected ESD as a surgical option for en bloc resection,and histopathological examination revealed TSA.The findings in this case suggest that TSA with precancerous potential can occur in children,and that ESD is useful for treating this lesion.