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.     

Cyclooxygenase-2 is overexpressed in serrated adenoma of the colorectum

PURPOSE: The aim of this study was to clarify whether cyclooxygenase-2 and cyclooxygenase-1 is expressed in hyperplastic polyps and serrated adenomas. METHODS: Forty-nine serrated adenomas and 25 hyperplastic polyps were immunostained using anticyclooxygenase-2 and anticyclooxygenase-1 antibodies. Cyclooxygenase-2 and cyclooxygenase-1 expression was investigated in all specimens. RESULTS: Cyclooxygenase-2 was expressed in dysplastic glands in the majority of serrated adenomas. Thirty-five of 49 (71.4 percent) serrated adenomas exhibited moderate to intense cyclooxygenase-2 immunoreactivity, and 8 of 25 hyperplastic polyps (32 percent) showed weak to moderate cyclooxygenase-2 immunoreactivity. Cyclooxygenase-1 immunoreactivity was very weak in all the hyperplastic polyps and serrated adenomas. CONCLUSIONS: These results suggest that cyclooxygenase-2 is overexpressed in serrated adenoma of the colorectum. Cyclooxygenase-2 inhibitors will reduce the incidence of serrated adenomas.     

The BRAF mutation is associated with the prognosis in colorectal cancer

Background

Two members of the Ras/Raf signaling pathway, KRAS and B-raf, are suspected to be involved in the stepwise progression of colorectal cancer (CRC) tumorigenesis.

Objective

We compared the KRAS and BRAF mutation status of CRC patients with their clinicopathological characteristics and examined the effect of mutation status on survival rates.

Methods

DNA was extracted from 164 samples, and the mutation statuses of KRAS and BRAF were assessed using peptide PNA clamp real-time PCR method. The presences of mutation were compared with clinicopathological factors and 5-year survival rate.

Results

Among the 164 CRC cases, KRAS mutation as detected in 71 cases (43.3 %), respectively, with no relationship with clinicopathological factors of the patients. On Kaplan–Meier survival analysis, KRAS mutation was not significantly associated with survival (p = 0.971). BRAF mutation was detected in 26 cases (15.9 %) and not associated with clinicopathological factors of the patients. However, the 5-year survival rate of BRAF mutations was significantly decreased (p = 0.02).

Conclusions

The presence of KRAS mutation did not correlate with the various clinicopathological factors of CRC patients or the survival rate. However, the survival rate was reduced in BRAF-mutated CRC patients. Therefore, BRAF mutation could be an important prognostic factor in CRC patients.     

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

     

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.     

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.     

Growth plate senescence is associated with loss of DNA methylation

The overall body size of vertebrates is primarily determined by longitudinal bone growth at the growth plate. With age, the growth plate undergoes programmed senescence, causing longitudinal bone growth to slow and eventually cease. Indirect evidence suggests that growth plate senescence occurs because stem-like cells in the growth plate resting zone have a finite proliferative capacity that is gradually exhausted. Similar limits on replication have been observed when many types of animal cells are placed in cell culture, an effect known as the Hayflick phenomenon. However, we found that the number of population doublings of rabbit resting zone chondrocytes in culture did not depend on the age of the animal from which the cells were harvested, suggesting that the mechanisms limiting replicative capacity of growth plate chondrocytes in vivo are distinct from those in vitro. We also observed that the level of DNA methylation in resting zone chondrocytes decreased with age in vivo. This loss of methylation appeared to occur specifically with the slow proliferation of resting zone chondrocytes in vivo and was not observed with the rapid proliferation of proliferative zone chondrocytes in vivo (i.e. the level of DNA methylation did not change from the resting zone to the hypertrophic zone), with proliferation of chondrocytes in vitro, or with growth of the liver in vivo. Thus, the overall level of DNA methylation decreases during growth plate senescence. This finding is consistent with the hypothesis that the mechanism limiting replication of growth plate chondrocytes in vivo involves loss of DNA methylation and, thus, loss of DNA methylation might be a fundamental biological mechanism that limits longitudinal bone growth in mammals, thereby determining the overall adult size of the organism.     

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...     

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.     

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.     

The BRAF mutation is not associated with poor prognostic factors in Korean patients with conventional papillary thyroid microcarcinoma

BACKGROUND: The BRAF(V600E) mutation, the most common genetic alteration reported in papillary thyroid carcinoma, has been associated with poor prognostic factors. AIM: To determine whether the presence of the BRAF(V600E) mutation is associated with poor prognosis in Korean patients with conventional papillary thyroid microcarcinoma (micro-PTC). PATIENTS AND METHODS: DNA was extracted from paraffin-embedded thyroid tumour specimens taken from 60 patients with conventional micro-PTC, as well as from nine patients with follicular variant papillary carcinoma, six with nodular hyperplasia, four with follicular carcinoma (including one with Hürthle cell carcinoma), four with follicular adenoma (including two with Hürthle cell adenoma) and one each with medullary carcinoma, poorly differentiated carcinoma and anaplastic carcinoma. The presence of the BRAF(V600E) mutation was determined by polymerase chain reaction (PCR) amplification of exon 15 followed by direct sequencing. RESULTS: The BRAF(V600E) mutation was detected in tumour samples from 31 of 60 conventional micro-PTC patients (52%), but was not detected in patients with other types of thyroid tumours. The age distribution, tumour size, extrathyroid extension, multifocality and staging did not differ significantly between patients with and without the BRAF(V600E) mutation. CONCLUSION: In Korean patients with conventional micro-PTC, the presence of the BRAF(V600E) mutation was not significantly associated with prognostic factors.