Prevalence, risk factors, and BRAF mutation of colorectal sessile serrated lesions among Vietnamese patients

BACKGROUND Sessile serrated lesions(SSLs)are considered precancerous colorectal lesions that should be detected and removed to prevent colorectal cancer.Previous studies in Vietnam mainly investigated the adenoma pathway,with limited data on the serrated pathway.AIM To evaluate the prevalence,risk factors,and BRAF mutations of SSLs in the Vietnamese population.METHODS This is a cross-sectional study conducted on patients with lower gastrointestinal symptoms who underwent colonoscopy at a tertiary hospital in Vietnam.SSLs were diagnosed on histopathology according to the 2019 World Health Organi-zation classification.BRAF mutation analysis was performed using the Sanger DNA sequencing method.The multivariate logistic regression model was used to determine SSL-associated factors.RESULTS There were 2489 patients,with a mean age of 52.1±13.1 and a female-to-male ratio of 1:1.1.The prevalence of SSLs was 4.2%[95%confidence interval(CI):3.5-5.1].In the multivariate analysis,factors significantly associated with SSLs were age≥40[odds ratio(OR):3.303;95%CI:1.607-6.790],male sex(OR:2.032;95%CI:1.204-3.429),diabetes mellitus(OR:2.721;95%CI:1.551-4.772),and hypertension(OR:1.650,95%CI:1.045-2.605).The rate of BRAF mutations in SSLs was 35.5%.CONCLUSION The prevalence of SSLs was 4.2%.BRAF mutations were present in one-third of SSLs.Significant risk factors for SSLs included age≥40,male sex,diabetes mellitus,and hypertension.

Superficial Serrated Adenoma (SuSA): A New Subtype of Serrated Lesions

Superficial serrated adenoma (SuSA) is a new subtype of serrated lesions proposed in recent years, most of which are located in the sigmoid colon or rectum, with typical mixed adenoma and serrated pathological features, and its molecular features are high frequency of KRAS mutation and RSPO fusion or overexpression. At present, it is believed that SuSA has two subtypes: traditional serrated adenoma (TSA)-associated SuSA and isolated SuSA. Solitary SuSA showed faded pedicle-free protuberant lesions under endoscope and lobulated, pp (pit pattern) classification was type II and type IIIH, TSA-associated SuSA showed double-layer eminence, SuSA part showed white flat eminence, pp classification showed type II and IIIH, TSA part showed red tone high eminence, pp was IVH type. SuSA can develop into colorectal cancer through the evolution of TSA, and it can also directly develop into MSS colorectal cancer. In view of the superficial understanding of SuSA and the lack of a complete description of SuSA, this paper review the research progress of SuSA at home and abroad from the origin, endoscope features, histopathological features, molecular biology, differential diagnosis and treatment of SuSA, in order to better promote the understanding and clinical diagnosis of lesions.

How to"pick up"colorectal serrated lesions and polyps in daily histopathology practice:From terminologies to diagnostic pitfalls

Over the last decade,our knowledge of colorectal serrated polyps and lesions has significantly improved due to numerous studies on this group of precursor lesions.Serrated lesions were misleading as benign before 2010,but they are currently reclassified as precancerous lesions that contribute to 30%of colorectal cancer through the serrated neoplasia pathway.The World Health Organization updated the classification for serrated lesions and polyps of the colon and rectum in 2019,which is more concise and applicable in daily practice.The responsible authors prescribe that“colorectal serrated lesions and polyps are characterized by a serrated(sawtooth or stellate)architecture of the epithelium.”From a clinical standpoint,sessile serrated lesion(SSL)and SSL with dysplasia(SSLD)are the two most significant entities.Despite these advancements,the precise diagnosis of SSL and SSLD based mainly on histopathology remains challenging due to various difficulties.This review describes the nomenclature and the terminology of colorectal serrated polyps and lesions and highlights the diagnostic criteria and obstacles encountered in the histopathological diagnosis of SSL and SSLD.

Endoscopic diagnosis of sessile serrated adenoma/polyp with and without dysplasia/carcinoma

Sessile serrated adenoma/polyps(SSA/Ps) are early precursor lesions in the serrated neoplasia pathway, which results in colorectal carcinomas with BRAF mutations, methylation for DNA repair genes, a Cp G island methylator phenotype, and high levels of microsatellite instability. Some of these lesions can rapidly become dysplastic or invasive carcinomas that exhibit high lymphatic invasion and lymph node metastasis potentials. Detecting serrated lesions, including SSA/Ps with and without dysplasia/carcinoma, is critical, but SSA/Ps can be difficult to detect, are inconsistently identified by endoscopists and pathologists, and are often incompletely resected. Therefore, SSA/Ps are considered to be major contributors to "interval cancers". If colonoscopists can identify the specific endoscopic characteristics of SSA/Ps, their detection and the effectiveness of colonoscopy may improve. Here, the endoscopic features of SSA/Ps with and without dysplasia/carcinoma, including the characteristics determined using magnifying endoscopy, are reviewed in the context of previous reports. Endoscopically, these subtle polyps are like hyperplastic polyps, because they are slightly elevated and pale. Unlike hyperplastic polyps, SSA/Ps are usually larger than 5 mm, frequently covered by a thin layer called the ‘‘mucus cap'', and are more commonly located in the proximal colon. Magnifying narrow-band imaging findings, which include dark spots inside the crypts and varicose microvascular vessels, in addition to the type II-open pit patterns detected using magnifying chromoendoscopy, effectively differentiate SSA/Ps from hyperplastic polyps. The lesions' endoscopic characteristics, which include their(semi)pedunculated morphologies, double elevations, central depressions, and reddishness, and the use of magnifying endoscopy, might help to detect dysplasia/carcinoma within SSA/Ps. Greater awareness may promote further research into improving the detection, identification, and complete resection rates of SSA/Ps with and without dysplasia/carcinoma and reduce the interval cancer rates.

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 colorectal cancer: Molecular classification, prognosis, and response to chemotherapy

Molecular advances support the existence of an alternative pathway of colorectal carcinogenesis that is based on the hypermethylation of specific DNA regions that silences tumor suppressor genes. This alternative pathway has been called the serrated pathway due to the serrated appearance of tumors in histological analysis. New classifications for colorectal cancer(CRC) were proposed recently based on genetic profiles that show four types of molecular alterations: BRAF gene mutations, KRAS gene mutations, microsatellite instability, and hypermethylation of Cp G islands. This review summarizes what is known about the serrated pathway of CRC, including CRC molecular and clinical features, prognosis, and response to chemotherapy.

Endoscopic and histologic characteristics of serrated lesions

In recent years , a second pathway for colonic carcinogenesis , distinct from the adenomatous pathway, has been explored. This is referred to as serrated pathway and includes three types of polyp,characterised by a serrated appearance of the crypts:hyperplastic polyps(HP),sessile serrated adenomas(SSA)or lesions,and traditional serrated adenomas.Each lesion has its own genetic,as well as macroscopic and microscopic morphological features.Because of their flat aspect,their detection is easier with chromoendoscopy(carmin indigo or narrow-band imaging).However,as we show in this review,the distinction between SSA and HP is quite difficult.It is now recommended to resect in one piece as it is possible the serrated polyps with a control in a delay depending on the presence or not of dysplasia.These different types of lesion are described in detail in the present review in general population,in polyposis and in inflammatory bowel diseases patients.This review highlights the need to improve characterization and understanding of this way of colorectal cancerogenesis.

Serrated pathway:Alternative route to colorectal cancer

Serrated polyps have been an area of intense focus for gastroenterologists over the past several years. Contrary to what was thought before,a growing body of literature indicates that these polyps can be precursors of colorectal cancer(CRC).Most of these lesions, particularly those in the proximal colon,have so far been under-recognized and missed during colonoscopy,qualifying these lesions to be the main cause of interval cancers.It is estimated that 10%-20%of CRCs evolve through this alternative,serrated pathway, with a distinct genetic and epigenetic profile.Aberrant DNA methylation plays a central role in the development of this CRC subtype.This characteristic molecular background is reflected in a unique pathological and clinical manifestation different from cancers arising via the traditional pathway.In this review we would like to highlight morphological,molecular and clinical features of this emerging pathway that are essential for gastroenterologists and may influence their everyday practice.

Serrated polyps of the colon and rectum: Endoscopic features including image enhanced endoscopy

In this review, I outline the characteristic endoscopic findings of serrated lesions of the colorectum based on image enhanced endoscopy(IEE). Histopathologically, lesions with serrated structures are typically classified into the following three types based: hyperplastic polyps(HPs), traditional serrated adenomas(TSAs), and sessile serrated adenoma/polyps(SSA/Ps). Both HP and SSA/P often present as dark-green colors on auto fluorescence imaging(AFI) colonoscopy that are similar to the normal surrounding mucosa. In contrast, TSAs often have elevated shapes and present as magenta colors that are similar to the tubular adenomas. The superficial type of TSA also includes many lesions that present as magenta colors. When SSA/Ps are associated with cytological dysplasia, many lesions present with magenta colors, whereas lesions that are not associated with cytological dysplasia present with dark-green colors. When observed via narrow band imaging(NBI), many SSA/P include lesions with strong mucous adhesions. Because these lesions are observed with reddish mucous adhesions, we refer to them as "red cap sign" and place such signs among the typical findings of SSA/P. Because the dilatation of the pit in SSA/P is observed as a round/oval black dot on magnified observations, we refer to this finding as Ⅱ-dilatation pit(Ⅱ-D pit) and also positioned it as a characteristic finding of SSA/P. In contrast, dilatations of the capillary vessels surrounding the glands, such as those that occur in tubular adenoma, are not considered to be useful for differentiating HPs from SSA/Ps. However, in cases in which SSA/P is associated with cytological dysplasia, the dilatation of capillary vessels is observed in the same area. When submucosal layer invasion occurs in the same area, the blood flow presents with irregularities that are similar to those of common colorectal cancer at an early stage and disappears as the invasion proceeds deeply. The surface pattern of invasive cancer that is observed at the tumor surface is also likely to disappear. Based on the above results, we considered that the differentiations between HP and TSA, between TSA and SSA/P, and between HP and SSA/P might become easier due to the concomitant use of white light observation and IEE. We also concluded that AFI and NBI can be useful modalities for SSA/P lesions associated with cytological dysplasia.

Sessile serrated adenomas:Demographic,endoscopic and pathological characteristics

AIM:To study the demographic and endoscopic characteristics of patients with sessile serrated adenoma(SSA) in a single center.METHODS:Patients with SSA were identified by review of the pathology database of Mayo Clinic Arizona from 2005 to 2007.A retrospective chart review was performed to extract data on demographics,polyp characteristics,presence of synchronous adenomatous polyps or cancer,polypectomy methods,and related complications.RESULTS:One hundred and seventy-one(2.9%) of all patients undergoing colonoscopy had a total of 226 SSAs.The mean(SE) size of the SSAs was 8.1(0.4) mm;42% of SSAs were ≤ 5 mm,and 69% were ≤ 9 mm.Fifty-one per cent of SSAs were located in the cecum or ascending colon.Approximately half of the patients had synchronous polyps of other histological types,including hyperplastic and adenomatous polyps.Synchronous adenocarcinoma was present in seven(4%) cases.Ninety-seven percent of polyps were removed by colonoscopy.CONCLUSION:Among patients with colon polyps,2.9% were found to have SSAs.Most of the SSAs were located in the right side and were safely managed by colonoscopy.

Serrated pathway in colorectal carcinogenesis

Serrated adenocarcinoma is a recently described subset of colorectal cancer(CRC),which account for about10%of all CRCs and follows an alternative pathway in which serrated polyps replace the traditional adenoma as the precursor lesion to CRC.Serrated polyps form a heterogeneous group of colorectal lesions that includes hyperplastic polyps(HPs),sessile serrated adenoma(SSA),traditional serrated adenoma(TSA)and mixed polyps.HPs are the most common serrated polyp followed by SSA and TSA.This distinct histogenesis is believed to have a major influence in prevention strategies,patient prognosis and therapeutic impact.Genetically,serrated polyps exhibited also a distinct pattern,with KRAS and BRAF having an important contribution to its development.Two other molecular changes that have been implicated in the serrated pathway include microsatellite instability and the CpG island methylator phenotype.In the present review we will address the current knowledge of serrated polyps,clinical pathological features and will update the most recent findings of its molecular pathways.The understanding of their biology and malignancy potential is imperative to implement a surveillance approach in order to prevent colorectal cancer development.

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.

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.

Serrated adenoma of the stomach:Case report and literature review

Gastric serrated adenomas are histologically characterized by protruding glands with lateral saw tooth-like indentations lined with stratified dysplastic cells containing abundant eosinophilic cytoplasm.Since the first case of gastric serrated adenoma found in 2001,18 additional cases have been reported.Gastric serrated adenomas have a particular proclivity to progress to invasive carcinoma;75% or 15 of the 20 cases now in record-including the present one-exhibited invasive carcinoma.The 20 th case of gastric serrated adenoma reported here differs from the preceding ones in as much as it evolved in a patient with Lynch syndrome,implying that this adenoma phenotype may develop not only sporadically but also in patients with hereditary traits.

Serrated polyposis syndrome:Molecular,pathological and clinical aspects

Hyperplastic polyps have traditionally been considered not to have malignant potential.New pathological classification of serrated polyps and recent discoveries about the serrated pathway of carcinogenesis have revolutionized the concepts and revitalized the research in this area.Until recently,it has been thought that most colorectal cancers arise from conventional adenomas via the traditional tumor suppressor pathway initiated by a mutation of the APC gene,but it has been found thatthis pathway accounts for only approximately 70%-80% of colorectal cancer(CRC)cases.The majority of the remaining colorectal cancer cases follow an alternative pathway leading to CpG island methylator phenotype carcinoma with BRAF mutation and with or without microsatellite instability.The mechanism of carcinomas arising from this alternative pathway seems to begin with an activating mutation of the BRAF oncogene.Serrated polyposis syndrome is a relatively rare condition characterized by multiple and/or large serrated polyps of the colon.Clinical characteristics,etiology and relationship of serrated polyposis syndrome to CRC have not been clarified yet.Patients with this syndrome show a high risk of CRC and both sporadic and hereditary cases have been described.Clinical criteria have been used for diagnosis and frequent colonoscopy surveillance should be performed in order to prevent colorectal cancer.In this review,we try to gather new insights into the molecular pathogenesis of serrated polyps in order to understand their possible clinical implications and to make an approach to the management of this syndrome.

Sessile serrated adenoma detection rate is correlated with adenoma detection rate

AIM To investigated the association between adenoma detection rate(ADR) and sessile serrated ADR(SSADR) and significant predictors for sessile serrated adenomas(SSA) detection.METHODS This study is a retrospective, single-center analysis. Total colonoscopies performed by the gastroenterologists at the University of Tokyo Hospital between January and December 2014 were retrospectively identified. Polyps were classified as low-grade or high-grade adenoma, cancer, SSA, or SSA with cytological dysplasia, and the prevalence of each type of polyp was investigated. Predictors of adenoma and SSA detection were examined using logistic generalized estimating equation models. The association between ADR and SSADR for each gastroenterologist was investigated by calculating a correlation coefficient weighted by the number of each gastroenterologist's examination.RESULTS A total of 3691 colonoscopies performed by 35 gastroenterologists were assessed. Overall, 978 (26.5%) low-and 84 (2.2%) high-grade adenomas, 81 (2.2%) cancers, 66 (1.8%) SSAs, and 2 (0.1%) SSAs with cytological dysplasia were detected. Overall ADR was 29.5%(men 33.2%, women 23.8%) and overall SSADR was 1.8%(men 1.7%, women 2.1%). In addition, 672 low-grade adenomas (68.8% of all the detected lowgrade adenomas), 58 (69.9%) high-grade adenomas, 29 (34.5%) cancers, 52 (78.8%) SSAs, and 2 (100%) SSAs with cytological dysplasia were found in the proximal colon. Adenoma detection was the only significant predictor of SSA detection (adjusted OR: 2.53, 95%CI: 1.53-4.20; P < 0.001). The correlation coefficient between ADR and SSADR weighted by the number of each gastroenterologist's examinations was 0.606(P < 0.001).CONCLUSION Our results demonstrated that ADR is correlated to SSADR. In addition, patients with adenomas had a higher prevalence of SSAs than those without adenomas.

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.

Microstructures,tensile properties and serrated flow of Al_xCrMnFeCoNi high entropy alloys

Microstructures and mechanical properties of dual-phase AlxCrMnFeCoNi (x=0.4, 0.5, 0.6, at.%) alloys were investigated. Thermomechanical processing leads to a microstructural evolution from cast dendritic structures to equiaxed ones, consisting of face-centered cubic (fcc) and body-centered cubic (bcc) phases in the two states. The volume fraction of bcc phase increases and the size of fcc grain decreases with increasing Al content, resulting in remarkably improved tensile strength. Specifically, the serrated flow occurring at the medium temperatures varies from type A+B to B+C or C as the testing temperature increases. The average serration amplitude of these Al-containing alloys is larger than that of CoCrFeNiMn alloy due to the enhanced pinning effect. The early small strain produces low-density of dislocation arrays and bowed dislocations in fcc grains while the dislocation climb and shearing mechanism dominate inside bcc grains. The cross-slip and kinks of dislocations are frequently observed and high-density-tangled dislocations lead to dislocation cells after plastic deformation with a high strain.

Interendoscopist variability in proximal colon polyp detection is twice higher for serrated polyps than adenomas

AIM To assess the interendoscopist variability in the detection of colorectal polyps according to their location and histological type.METHODS This study was a retrospective analysis of prospectively collected data from a regional colorectal cancer(CRC) screening program; 2979 complete colonoscopies from 18 endoscopists were included. Variability in performance between endoscopists for detection of at least one adenoma(A), one proximal adenoma(PA), one distal adenoma(DA), and one proximal serrated polyp(PSP) was assessed by using multilevel logistic regression models.RESULTS The observed detection rates among the 18 endoscopists ranged from 24.6% to 47.6%(mean = 35.7%) for A, from 19.1% to 39.0%(mean = 29.4%) for DA, from 6.0% to 22.9%(mean = 12.4%) for PA, and from 1.3% to 19.3%(mean = 6.9%) for PSP.After adjusting for patient-level variables(sex, age), the interendoscopist detection rates variability achieved a significant level for A, PA, and PSP but not for DA(P = 0.03, P = 0.02, P = 0.02 and P = 0.08, respectively). This heterogeneity, as measured by the variance partition coefficient, was approximately threefold higher for PA(6.6%) compared with A(2.1%), and twofold higher for PSP(12.3%) compared with PA.CONCLUSION These results demonstrate significant interendoscopist variability for proximal polyp particularly for serrated p o l y p s, b u t n o t f o r d i s t a l a d e n o m a d e t e c t i o n. These findings contribute to explain the decreased effectiveness of complete colonoscopies at preventing proximal CRCs and the need to carefully assess the proximal colon during scope procedure.

Clinical features of upper gastrointestinal serrated lesions: An endoscopy database analysis of 98746 patients

AIM To analyse the clinical features of patients with the serrated lesions in the upper gastrointestinal tract(UPGI) tract.METHODS Patients who underwent routine esophagogastroduodenoscopy(EGD) at the Digestive Endoscopy Centre of General Hospital, Tianjin Medical University between january 2011 and December 2015 were consecutively recruited. Patients with UPGI serrated lesions were consecutively identified. The patients' demographics and histopathology were recorded. The colorectal findings for patients who underwent colonoscopy simultaneously or within six months were also extracted from the colonoscopy database. In addition, we analyseddifferences in colorectal neoplasia detection between the study patients and randomly selected patients matched for age and gender who did not exhibit serrated lesions and who also underwent colonoscopy in the same period.RESULTS A total of 21 patients out of 98746 patients(0.02%) who underwent EGD were confirmed to have serrated lesions with predominantly crenated, sawtooth-like configurations. The mean age of the 21 patients was(55.3 ± 17.2) years, and 11 patients were male(52.4%). In terms of the locations of the serrated lesions, 17 were found in the stomach(including 3 in the cardia, 9 in the corpus and 5 in the antrum), 3 were found in the duodenum, and 1 was found in the esophagus. Serrated lesions were found in different mucosal lesions, with 14 lesions were detected in polyps(8 hyperplastic polyps and 6 serrated adenomas with low grade dysplasia), 3 detected in Ménétrier gastropathy, 3 detected in an area of inflammation or ulcer, and 1 detected in the intramucosal carcinoma of the duodenum. In addition, colonoscopy data were available for 18 patients, and a significantly higher colorectal adenoma detection rate was observed in the UPGI serrated lesions group than in the randomly selected age- and gender-matched group without serrated lesions who also underwent colonoscopy in the same period(38.9% vs 11.1%, OR = 5.091, 95%CI: 1.534-16.890, P = 0.010). The detection rate of advanced adenoma was also higher in the UPGI serrated lesions group(22.2% vs 4.2%, OR = 6.571, 95%CI: 1.322-32.660, P = 0.028).CONCLUSION Serrated lesions in the UPGI were detected in various mucosal lesions with different pathological morphologies. Moreover colonoscopy is recommended for the detection of concurrent colorectal adenoma for these patients.