结直肠浅表锯齿状腺瘤的研究现状

浅表锯齿状腺瘤是2018年提出的一种新型锯齿状病变,具有独特临床病理和分子特征,表现出典型的混合性腺瘤和锯齿状特征。分子机制上,浅表锯齿状腺瘤病变表现为β‑连环蛋白的核积累和MYC过表达,提示WNT信号通路激活,同时浅表锯齿状腺瘤显示出与相关传统锯齿状腺瘤一致的KRAS突变和RSPO融合或过表达,提示浅表锯齿状腺瘤可能是KRAS突变的传统锯齿状腺瘤重要前体。本文重点讲述浅表锯齿状腺瘤的特点以引起内镜医师对该病变的重视。     

结直肠无蒂锯齿状腺瘤的研究进展

结直肠癌(colorectal cancer,CRC)是世界上第3大常见的恶性肿瘤和第4大癌症死亡原因。根据世界卫生组织(WHO)对消化系统肿瘤的分类,锯齿状息肉(serrated polyposis,SPs)分为无蒂锯齿状腺瘤/息肉(sessile serrated adenoma/polyps,SSA/P)、增生性...     

Cyclooxygenase-2 is overexpressed in chronic pancreatitis

INTRODUCTION: Cyclooxygenase enzymes catalyze a critical step in the conversion of arachidonic acid to prostaglandins, which are important mediators of acute and chronic inflammation. The constitutively expressed cyclooxygenase-1 (COX-1) appears to regulate many normal physiologic functions in several cell types, whereas the inducible cyclooxygenase-2 (COX-2) enzyme mediates the inflammatory response. AIMS AND METHODOLOGY: We investigated the expression of COX-2 in tissues of 35 patients with chronic pancreatitis, 6 patients with pancreatic cancer, and 5 control patients by immunohistochemical analysis and correlations to clinicopathologic features. RESULTS: We found an overexpression of COX-2 in the atrophic acinar cells (80% of patients), hyperplastic ductal cells (86% of patients), and islets cells (97% of patients) but not in normal pancreatic tissues. The COX-2 overexpression in the tissue of patients with chronic pancreatitis was significantly correlated with the frequency of acute attacks of pancreatitis. Tissue from patients who had more than five acute attacks of pancreatitis (n = 10) exhibited COX-2 immunoreactivity of a significantly higher score in atrophic acinar cells (p = 0.004). No correlation could be found with other examined clinical features such as duration of the disease, diabetes, alcohol consumption, smoking, or pain. CONCLUSION: Our results support the hypothesis that COX-2 may be involved in inflammatory responses in chronic pancreatitis and in the progression of this chronic inflammatory disease.     

Hyperplastic and serrated polyps of the colorectum

The serrated polyp pathway is a histopathological sequence that begins in a hyperplastic polyp, or precursor serrated aberrant crypt focus, and has the potential to end in a colonic adenocarcinoma that is CIMP-high and, in most cases, also MSI. An activating mutation of the BRAF oncogene is a marker for this pathway. There is evidence that aberrant CpG-island methylation is the molecular engine that drives the progression through sequential steps of the pathway, from hyperplastic polyp to a form of atypical hyperplastic polyp (termed sessile serrated adenoma) to dysplastic serrated polyp and, ultimately to serrated carcinoma. A second serrated pathway, identified by mutations of KRAS in serrated adenoma, is delineated less completely. Its endpoint is a colorectal carcinoma that is CIMP-low and MSS, and both the advanced serrated adenoma and carcinoma stages of this pathway show molecular genetic and morphologic features that overlap with those of the conventional APC carcinogenic pathway. Clinical studies are needed to elucidate the natural history of serrated neoplasia, and provide evidence-based guidance for risk assessment and surveillance of individuals discovered to harbor its various serrated polyp precursors.     

Clinicopathological features of serrated lesions of the colorectum

We reviewed 428 subjects with colorectal serrated lesions resected endoscopically or surgically at our institution. Colorectal serrated lesions were pathologically divided into 3 groups: hyperplastic polyp (HP), sessile serrated adenoma/polyp (SSA/P), and traditional serrated adenoma (TSA). SSA/P was detected frequently in the right colon and SSA/P was mainly flat-elevated. Cancers occurring in SSA/P were found more frequently than HP or TSA. The incidence of cancer in SSA/P was equivalent to that of cancer in traditional adenoma. Further studies are warranted to clarify clinicopathological features of serrated lesions of the colorectum.     

Molecular characteristics of serrated adenomas of the colorectum

BACKGROUND: Serrated adenomas (SAs) of the colorectum combine architectural features of hyperplastic polyps and cytological features of classical adenomas. Molecular studies comparing SAs and classical adenomas suggest that each may be a distinct entity; in particular, it has been proposed that microsatellite instability (MSI) distinguishes SAs from classical adenomas and that SAs and the colorectal cancers arising from them develop along a pathway driven by low level microsatellite instability (MSI-L). AIMS: To define the molecular characteristics of SAs of the colorectum. MATERIALS AND METHODS: We analysed 39 SAs from 27 patients, including eight SAs from patients with familial adenomatous polyposis (FAP). We screened these polyps for selected molecular changes, including loss of heterozygosity (LOH) close to APC (5q21) and CRAC1 (15q13-q22), MSI, and mutations of K-ras, APC, p53, and beta-catenin. Expression patterns of beta-catenin, p53, MLH1, MSH2, E-cadherin, and O(6)-methylguanine DNA methyltransferase (MGMT) were assessed by immunohistochemistry. Comparative genomic hybridisation was performed on several polyps. RESULTS: MSI was rare (<5% cases) and there was no loss of expression of mismatch repair proteins. Wnt pathway abnormalities (APC mutation/LOH, beta-catenin mutation/nuclear expression) occurred in 11 SAs, including 6/31 (19%) non-FAP tumours. CRAC1 LOH occurred in 23% of tumours. K-ras mutations and p53 mutations/overexpression were found in 15% and 8% of SAs, respectively. Loss of MGMT expression occurred in 18% of polyps and showed a borderline association with K-ras mutations. Aberrant E-cadherin expression was found in seven polyps. Comparative genomic hybridisation detected no gains or deletions of chromosomal material. CONCLUSIONS: The serrated pathway of colorectal tumorigenesis appears to be heterogeneous. In common with classical adenomas, some SAs develop along pathways involving changes in APC/beta-catenin. SAs rarely show MSI or any evidence of chromosomal-scale genetic instability. K-ras mutations may however be less common in SAs than in classical adenomas. Some SAs may harbour changes in the CRAC1 gene. Changes in known genes do not account for the growth of the majority of SAs.     

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.     

Clinicopathologic differences among subtypes of serrated adenomas of the colorectum

BACKGROUND/AIMS: Serrated adenomas (SAs) of the colorectum can be broadly divided into two subtypes: type I more closely mimicking hyperplastic polyps, and type II unequivocal traditional adenomas. The aim of this study was to clarify their differential clinicopathologic and colonoscopic features. METHODOLOGY: A total of 127 SAs (53 type I, 52 type II and 22 admixed type I+II) were investigated and colonoscopic surface patterns were divided into three categories: speckled, granular and cerebriform. RESULTS: The cerebriform pattern was most frequently observed in all SA types. Types I+II (median size, 7.5 mm) or type II SAs (median size, 10 mm) were generally sessile or pedunculated polyps in the rectosigmoid colon whereas some type I lesions (median size, 5 mm) demonstrated a flat-elevated morphology and were found in the ascending colon and cecum. Co-existing (2/127: 1.6%) invasive carcinomas were only detected with type II SAs. In contrast, synchronous invasive carcinomas distant from SAs were more frequently observed with type I (31%) than types I+II (5%) or II (12%). CONCLUSIONS: Clinicopathologic differences are apparent among the types of SAs. A type II SA-invasive carcinoma sequence might exist. We stress recognition of type I SA as a neoplastic, rather than a hyperplastic lesion, often accompanying invasive carcinomas at a distance from the SA.     

Frequent somatic mutations of mitochondrial DNA in traditional serrated adenomas but not in sessile serrated adenomas of the colorectum

Background and Aim: Serrated adenomas (SAs), recently subdivided into traditional SAs (TSAs) and sessile SAs (SSAs), are recognized as a distinct form of neoplasia of the colorectum. One of the characteristics of SAs is hypermaturation of the gland epithelium due to the low extent of cell loss by apoptosis. Mutations of mitochondrial DNA (mtDNA) are closely associated with abnormality in apoptosis. We therefore examined mtDNA mutations in colorectal lesions including hyperplastic polyps (HPs), SSAs, TSAs, and carcinomas. Methods: Examined were 25 HPs, 32 SSAs, 19 TSAs, and 138 carcinomas. The D310 region of the mtDNAs was examined by microsatellite assay. Results: mtDNA mutations were detected in none of 25 (0%) HPs, one of 32 (3%) SSAs, six of 19 (32%) TSAs, and eleven of 133 (8%) carcinomas (five of the 138 carcinomas were not informative). The frequency of mtDNA mutations in the TSAs was significantly higher than that in the HPs, SSAs, and carcinomas (P = 0.004, P = 0.008, and P = 0.009, respectively). The frequency of mtDNA mutations in carcinomas was not significantly higher than that in HPs and SSAs (P = 0.14 and P = 0.28, respectively). Conclusion: Our data suggest that mtDNA mutations may play an important role in the development of TSAs and could be used as a genetic marker to aid in the diagnosis of colorectal lesions.     

Infrequent K-ras codon 12 mutation in serrated adenomas of human colorectum

Background—Serrated adenoma is a new morphologicalsubtype of colorectal adenoma. The lesion provides a distinctmorphological route to carcinoma, but the underlying genetic changeshave not yet been investigated.
Aims—To determine the frequency ofK-ras mutation in serrated adenoma.
Methods—The frequency of K-ras codon12 point mutation in 20 serrated adenomas, five atypical hyperplasticpolyps, and 58sporadic polypoid adenomas was investigated by nestedpolymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) methods.
Results—Although most of the serrated adenomaswere large (average size 11.4 mm) and polypoid, K-rascodon 12 point mutation was detected in only one of the 20 (5%), whichis a significantly lower frequency than that in sporadic polypoidadenomas (18/60; 30%) (p = 0.017). No mutation was detected in theatypical hyperplastic polyps. Three of 20 (15%) serrated adenomascontained a focus of carcinoma in situ, indicating their malignantpotential and the existence of a serrated adenoma-carcinoma sequence,but no mutation was detected in the foci of carcinoma in situ.
Conclusions—K-ras mutation isuncommon in serrated adenomas, indicating a different spectrum ofgenetic alterations in these lesions from those in typical polypoidsporadic adenomas. This subtype of colorectal adenoma represents a newgenetic pathway in the histogenesis of colorectal carcinoma.

Keywords:serrated adenoma; colorectal adenoma; K-ras mutation; PCR-RFLP

     

Serrated adenoma of the colorectum: colonoscopic and histologic features

BACKGROUND: Serrated adenoma is a recently recognized epithelial neoplasm of the colorectum. The aim of this study is to clarify the colonoscopic features of serrated adenomas. METHODS: The endoscopic findings for 52 serrated adenomas of the colorectum were investigated; these were then divided into three groups according to surface features. The histologic type (tubular, tubulovillous or villous) and the incidence of high-grade dysplasia were compared among the three groups. RESULTS: The surface under chromoscopy showed a hyperplastic pattern in 17 lesions, a cerebriform pattern in 18 lesions and a combined pattern in 17 lesions. The tubular type of serrated adenoma was predominant in the hyperplastic pattern group (94%), whereas the tubulovillous or villous histologic types were frequent in the cerebriform pattern (89%) and combined pattern (82%) groups. High-grade dysplasia was found in 18% of the combined pattern adenomas; the incidence was lower in hyperplastic (6%) or cerebriform pattern (0%) adenomas. CONCLUSIONS: Surface features of serrated adenomas have a close correlation with their histologic type. A combined hyperplastic-cerebriform surface pattern under chromoscopy was seen only in serrated adenomas.     

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.     

Correlations of morphology and molecular alterations in traditional serrated adenoma

Traditional serrated adenoma was first reported by Longacre and Fenoglio-Presier in 1990. Their initial study described main features of this lesion, but the consensus diagnostic criteria were not widely adopted until recently. Traditional serrated adenoma presents with grossly protuberant configuration and pinecone-like appearance upon endoscopy. Histologically, it is characterized by ectopic crypt formation, slit-like serration, eosinophilic cytoplasm and pencillate nuclei. Although much is now known about the morphology and molecular changes, the mechanisms underlying the morphological alterations are still not fully understood. Furthermore, the origin of traditional serrated adenoma is not completely known. We review recent studies of the traditional serrated adenoma and provide an overview on current understanding of this rare entity.     

Cyclooxygenase-2 is instrumental in Parkinson's disease neurodegeneration

Parkinson's disease (PD) is a neurodegenerative disorder of uncertain pathogenesis characterized by the loss of the nigrostriatal dopaminergic neurons, which can be modeled by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Increased expression of cyclooxygenase type 2 (COX-2) and production of prostaglandin E(2) have been implicated in neurodegeneration in several pathological settings. Here we show that COX-2, the rate-limiting enzyme in prostaglandin E(2) synthesis, is up-regulated in brain dopaminergic neurons of both PD and MPTP mice. COX-2 induction occurs through a JNKc-Jun-dependent mechanism after MPTP administration. We demonstrate that targeting COX-2 does not protect against MPTP-induced dopaminergic neurodegeneration by mitigating inflammation. Instead, we provide evidence that COX-2 inhibition prevents the formation of the oxidant species dopamine-quinone, which has been implicated in the pathogenesis of PD. This study supports a critical role for COX-2 in both the pathogenesis and selectivity of the PD neurodegenerative process. Because of the safety record of the COX-2 inhibitors, and their ability to penetrate the blood-brain barrier, these drugs may be therapies for PD.     

Significance of small distal adenoma for detection of proximal neoplasms in the colorectum

BACKGROUND: The significance of the small distal tubular adenoma detected by sigmoidoscopy as a predictor of proximal neoplasm remains controversial. The aim of this study was to examine the prevalence of proximal neoplasms in patients with and without distal neoplasms. METHODS: This is a retrospective study of 3131 asymptomatic middle-aged men who underwent total colonoscopy. For 812 men with colorectal neoplasms characteristics of the identified neoplasms were determined. RESULTS: The prevalence of proximal neoplasms in patients with small distal tubular adenoma was 20% (92 of 461), whereas the prevalence of proximal neoplasms in patients without distal neoplasms was 11.5% (301 of 2620). The prevalence of advanced proximal neoplasms in patients with small distal tubular adenoma and without distal neoplasm was 1.3% and 0.8%, respectively. In the 29 patients with advanced proximal neoplasms, only 6 (21%) had a small distal tubular adenoma. CONCLUSIONS: The presence of small distal tubular adenomas may provide a clue to the presence of small proximal tubular adenomas. However, the majority of advanced proximal neoplasms (79%) do not have a synchronous small distal tubular adenoma. (Gastrointest Endosc 2000;52:358-61).     

大肠锯齿状腺瘤基础与临床研究进展

由于中国人生活方式和饮食习惯的改变等原因，大肠癌的发病率也呈逐年上升趋势。目前普遍认同大肠腺瘤是大肠上皮从良性向恶性演变的重要环节，也是最具恶变潜能的癌前状态。国内外学者对大肠腺瘤进行着广泛而深入地研究。近年来大肠锯齿状腺瘤（serrated adenoma，简称锯齿状腺瘤）正日益受到关注。大肠锯齿状腺瘤独特的结构特征和细胞学特点由Goldman等于1970年最先报道，1990年Longacre等报道了110例，并首次将这类病例命名为大肠锯齿状腺瘤。据报道大约5％～10％的锯齿状腺瘤病灶内发生黏膜内癌。2000年世界卫生组织（WHO）正式将大肠锯齿状腺瘤定为大肠的第四种腺瘤病理形态（前三种是管状腺瘤、     

The human MDM-2 oncogene is overexpressed in leukemias

The human homologue of the mouse double minute 2 (MDM-2) gene codes for a cellular protein that forms a complex with the mutant and wild-type p53 protein and modulates its trans-activation activity. Overexpression of the MDM-2 gene in cells increases their tumorigenic potential and overcomes the growth-suppressive activity of p53. Previous reports have shown that the MDM-2 gene is amplified in approximately one third of human sarcomas. To examine the role of MDM-2 in leukemia, we analyzed MDM-2 gene amplification and mRNA expression in various types of leukemias. We did not detect gene amplification in any of the 48 cases of leukemia that we examined. In contrast, we observed significant MDM- 2 mRNA overexpression in 34 of 64 cases (53%). The level of mRNA overexpression in some cases of leukemias was comparable to that observed in some cases of sarcomas, which demonstrate more than 50-fold MDM-2 gene amplification. Furthermore, we divided these cases into different prognostic groups according to their karyotypic abnormalities. MDM-2 overexpression seemed to be associated with unfavorable chromosomal abnormalities. These findings suggest that the expression of the MDM-2 gene is altered in a significant fraction of human leukemias and MDM-2 may play a significant role in leukemogenesis. In addition, these results suggest that mechanisms other than gene amplification may play a significant role in deregulating the MDM-2 expression.