Early genetic instability of both epithelial and stromal cells in esophageal squamous cell carcinomas, contrasted with Barrett's adenocarcinomas

Background We have shown previously that stromal genetic alteration may make a greater contribution to early genesis of ulcerative colitis-associated tumors than sporadic colon cancers. We assessed whether similar differences in genetic alteration might exist between squamous cell carcinomas (SCCs) and Barrett's adenocarcinomas (BACs) of the esophagus. Methods We investigated epithelial and stromal genetic instability with five National Cancer Institute standard (NCI), four chromosome 17 (Chr. 17), and six tumor suppressor gene (TSG) microsatellite markers in 26 SCC and 12 BAC cases and in 11 normal controls, using a novel combination of microdissection, polymerase chain reaction, and GeneScan. Results Frequency of epithelial loss of heterozygosity (LOH) increased in the order background mucosa, to precursor lesions, to tumors with both types of carcinoma, especially for the Chr. 17 and TSG markers, while stromal LOH was relatively high but consistent from background mucosa to carcinoma. Epithelial LOH of D17S796 demonstrated a significantly higher frequency in SCCs than in BACs, without significant variation in p53 overexpression. The frequency of microsatellite instability (MSI) showed constant high levels in both epithelium and stroma of background, dysplasia, and carcinomas in the SCC series, and rather low frequencies in the BAC series. Although epithelial hMLH1 and hMSH2 expression decreased with tumor progression, no correlation was found with the individual MSI status. Conclusions Although epithelial LOH exists similarly in both lesion types, whereas epithelial and stromal MSI may occur in a relatively early phase of SCC development, stromal MSI is rare in BACs, strongly suggesting differences in tumorigenesis between the two types.     

DNA microsatellite instability and mismatch repair protein loss in adenomas presenting in hereditary non-polyposis colorectal cancer

BACKGROUND AND AIM: Hereditary non-polyposis colorectal cancer (HNPCC), as its name implies, is associated with few adenomas, and the early evolution of colorectal neoplasia is poorly understood. In this study our aim was to clarify the genetic profiles of benign polyps in subjects with HNPCC using a combined molecular and immunohistochemical approach. METHODS: Thirty adenomas and 17 hyperplastic polyps were obtained from 24 affected HNPCC subjects. DNA was extracted from paraffin embedded tissue by microdissection and analysed for the presence of microsatellite instability (MSI) and mutations in five genes known to be targets in mismatch repair deficiency (TGFbetaRII, IGF2R, BAX, hMSH3, and hMSH6). Serial sections were stained by immunohistochemistry for hMLH1 and hMSH2. RESULTS: Twenty four (80%) of 30 adenomas showed MSI. Of MSI positive adenomas, 66.7% showed MSI at more than 40% of markers (high level of MSI (MSI-H)). Two of 17 hyperplastic polyps revealed MSI at one marker (low level of MSI (MSI-L)). A significant association was found between MSI-H and high grade dysplasia in adenomas (p=0.004). Eight of nine adenomas with mutations of coding sequences revealed high grade dysplasia and all nine were MSI-H. Four of the nine ranged in size from 2 to 5 mm. The presence of the hMSH6 mutation was significantly correlated with high levels of MSI (80% of markers) (p<0.02). Twenty four adenomas gave evaluable results with immunohistochemistry. One of six (17%) microsatellite stable, six of seven (86%) MSI-L, and 11 of 11 (100%) MSI-H adenomas showed loss of either hMLH1 or hMSH2. CONCLUSIONS: Most adenomas in subjects with a definite diagnosis of HNPCC show MSI (80%). The finding of MSI-L is usually associated with loss of expression of hMLH1 or hMSH2, unlike the situation in MSI-L sporadic colorectal cancer. The transition from MSI-L to MSI-H correlated with the finding of high grade dysplasia and mutation of coding sequences and may be driven by mutation of secondary mutators such as hMSH3 and hMSH6. Advanced genetic changes may be present in adenomas of minute size.     

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.     

Low rate of microsatellite instability in young patients with adenomas: reassessing the Bethesda guidelines

BACKGROUND AND AIM: Screening adenomas for microsatellite instability (MSI) in patients younger than 40 yr of age has been recommended by the Bethesda Guidelines as a means of identifying patients at risk for hereditary nonpolyposis colorectal cancer (HNPCC). We sought to determine the rate of MSI in adenomas removed from individuals under 40 yr of age over a 5-yr period in a university general gastroenterology practice. METHODS: We identified patients between 18 and 39 yr of age with endoscopically removed adenomatous colorectal polyps. Patients with polyposis syndromes, inflammatory bowel disease, or colorectal carcinoma were excluded. A three-generation family history was obtained via telephone interview. Endoscopic and histology reports were reviewed. Adenomas were tested for MSI using the BAT26 and BAT40 microsatellite markers, and expression of the MSH2 and MLH1 proteins was assessed by immunostaining. RESULTS: A total of 34 patients had 46 adenomas removed endoscopically. Out of 34 patients, 14 (41%) had a family history of colorectal cancer and 3 were from Amsterdam criteria positive families. A total of 28 of 46 adenomas (61%) were distal to the splenic flexure. Polyps ranged in size from 2 to 20 mm and averaged 6.6 mm. Five polyps (11%) were tubulovillous adenomas, and the remainder were tubular adenomas. None of the polyps were serrated adenomas and none demonstrated high-grade dysplasia. Among the 40 adenomas available for testing, none demonstrated MSI using either BAT26 (0/40) or BAT40 (0/21), nor did any of the polyps tested demonstrate loss of either MSH2 or MLH1 expression (0/16). CONCLUSION: Screening adenomas from patients younger than 40 yr of age for MSI was ineffective in identifying potentially new cases of HNPCC. New strategies that improve on the current clinical and molecular screening methods should be developed so that at-risk individuals can be identified and referred for germline testing before developing their first cancer.     

Stromal eosinophilia in colonic epithelial neoplasms

OBJECTIVE: The purpose of this retrospective study was to determine the frequency and intensity of eosinophilic infiltration (or tissue eosinophilia) in the stroma of colonic adenomas, hyperplastic polyps, and colorectal adenocarcinomas. Eosinophilic infiltration in various malignancies has been reported but has not been evaluated in benign colorectal adenomas and hyperplastic polyps. METHODS: We analyzed 488 colonic neoplasms: 176 tubular adenomas, 55 tubulovillous adenomas, 82 villous adenomas, 15 early carcinomas in polyps, 95 invasive adenocarcinomas, and 65 hyperplastic polyps for the presence of eosinophilic infiltration. The eosinophilic infiltration was graded as negative (< or =5%), mild to moderate (>5-40%), or marked (>40%), depending on the percentage of eosinophils relative to total inflammatory cells in the stroma. RESULTS: Mild to moderate eosinophilia was noted in 75% of all adenomas. The transitional zone in all cases of invasive adenocarcinoma (zone between normal tissue and adenocarcinoma) revealed a high percentage of tissue eosinophilia. There was a striking absence of TE in the stroma of invasive adenocarcinomas. Only 5% of hyperplastic polyps had any eosinophilic infiltration. CONCLUSIONS: These data suggest that, in the spectrum of colonic neoplasms, stromal eosinophilia is most prominent in adenomas and seems to decrease with progression through the adenoma-carcinoma sequence. The ramifications of this study may alter management plans and provide some prognostic information for clinical evaluation.     

p53 overexpression in flat serrated adenomas and flat tubular adenomas of the colorectal mucosa

The expression of the p53 protein was investigated in flat serrated neoplasias as well as in other histological phenotypes of flat or exophytic hyperplasias or neoplasias of the colorectal, mucosa. A total of 104 such lesions were analyzed: 24 were flat serrated neoplasias (22 flat serrated adenomas and 2 flat serrated adenocarcinomas), 26 flat tubular adenomas, 17 flat hyperplastic polyps, 29 exophytic tubular and/or villous neoplasias (23 adenomas and 6 exophytic adenocarcinomas) and the remaining 8, exophytic hyperplastic polyps. Deparaffinized, rehydrated sections were treated immunohistochemically to detect those overexpressing the p53 protein. Lesions having slight (+), moderate (++) or intense (+++) staining were considered immunoreactive. The results showed that 50% of the flat serrated adenomas with low-grade dysplasia (LGD) and 66.7% of those with high-grade dysplasia (HGD) had p53 immunoreactivity. None of the flat tubular or of the exophytic adenomas with LGD expressed p53, but immunoreactivity was present in 61.5% of the flat tubular adenomas with HGD and in 52.3% of the exophytic adenomas with HGD. All adenocarcinomas had an intense p53 reaction. Weak p53 expression was demonstrated by 11.7% of the flat hyperplastic polyps but none of the exophytic polyps reacted. The occurrence of p53 expression in flat serrated adenomas with LGD suggested that, despite its low histological profile, one-half of those lesions could be biologically already committed to independent growth. The occurrence of p53 expression in nearly 12% of the flat hyperplastic polyps was totally unexpected and deserves further investigation. Flat serrated adenoma emerges as a novel, independent histological entity among the various phenotypes of flat neoplasias of the colorectal mucosa.     

遗传性非息肉性结直肠癌患者腺瘤和癌组织微卫星基因型分析

背景：遗传性非息肉性结直肠癌（HNPCC）是一种由错配修复基因种系突变引起的常染色体显性遗传病，高度微卫星不稳定（MSI—H）为其分子生物学特征之一。目的：利用5个微卫星位点建立正常结直肠黏膜、结直肠腺瘤和癌组织的微卫星基因型，探讨HNPCC的MSI发生情况和MSI检测的临床意义。方法：纳入源自33个HNPCC家系的腺瘤28例和腺癌14例，其中4例为同步腺瘤-癌；以32例散发性结直肠腺瘤和24例散发性结直肠癌作为对照。选用BAT25、BAT26、D2S123、D5S346、D17S250五个微卫星位点行荧光标记聚合酶链反应（PCR），以GeneMapper软件分析PCR产物。通过与正常黏膜微卫星序列PCR片段长度进行比较，判定腺瘤和癌组织的MSI情况。结果：HNPCC腺瘤和癌组织MSI-H发生率分别显著高于散发性结直肠腺瘤和结直肠癌（64-3％对3．1％，71.4％对12．5％，P〈0．05）。4例同步腺瘤-癌均表现为MSI—H．其腺瘤和癌组织的MSI类型不同。结论：HNPCC腺瘤和癌组织MSI—H发生率高。同步腺瘤一癌来源于不同克隆。MSI检测可作为HNPCC的临床初筛方法。     

Mixed colorectal polyps. An immunohistologic and mucin-histochemical study

The morphology of mixed colorectal polyps was analysed. Thirteen such polyps were found out of 2700 colorectal polyps (0.5%). Histology showed a spectrum of hyperplastic crypts from almost pure goblet cell population (two polyps) to hypermature serrated epithelium with scanty goblet cells (seven polyps). Tubular adenomas occurred in 12 polyps, and a tubulovillous adenoma was found in the largest polyp. Moderate dysplasia was seen in the five large polyps. The border between neoplastic and hyperplastic cells was usually sharp. Mucin histochemistry showed similarities between the mixed polyps and colorectal carcinomas--namely, the reduction/absence of sialomucin in both mature hyperplastic crypts and adenomatous glands. The expression of carcinoembryonic antigen within the hyperplastic crypts and within the neoplastic crypts showing moderate dysplasia was similar to that seen in colorectal carcinomas, whereas it was normal within the neoplastic crypts with low-grade dysplasia. IgA was reduced or absent in both components. Blood group antigen was found only within the adenomatous component of the largest polyp showing also moderate dysplasia.     

Mucin associated Tn and sialosyl-Tn antigen expression in colorectal polyps.

Sialosyl-Tn antigen and its immediate precursor, Tn antigen, are carbohydrate structures associated with the earliest steps of mucin O-linked glycosylation. Both antigens have been shown previously to be highly sensitive and specific markers of colorectal cancer. One hundred and three colorectal polyps (79 adenomatous; 24 hyperplastic) were examined for expression of Tn antigen using vicia villosa isolectin B4, and for sialosyl-Tn antigen by monoclonal antibody TKH2. Tn antigen was expressed by all of the polyps studied. Sialosyl-Tn, on the other hand was expressed weakly by a few cells in 7 of 24 (29%) hyperplastic polyps. Among the adenomatous polyps, 56% expressed sialosyl-Tn and expression correlated with larger adenoma size, greater villous component, and more severe grades of dysplasia. In individuals with two or more synchronous adenomas, the level of sialosyl-Tn expression within an adenoma was associated with the severity of cytological atypia. All the adenomas that contained a focus of invasive carcinoma expressed sialosyl-Tn. These results indicate that colorectal polyps manifest incomplete glycosylation, exposing antigens in the innermost region of mucin oligosaccharides. In addition, the correlation of sialosyl-Tn antigen expression with the adenoma-carcinoma sequence may make this a useful marker for studying malignant progression in the colon.     

Immunocytochemical Localization of Lymphatic and Venous Vessels in Colonic Polyps and Adenomas

Histopathological localization of lymphatic vessels has been hindered because of a lack of suitable immunocytochemical markers for lymphatic vessels. Using lymphatic vessels endothelial hyaluronan receptor-1 (LYVE-1) immunocytochemical staining, hyperplastic polyps, tubular adenomas to villous adenomas, were investigated for lymphatic vessels compared with immunostained blood vessels using factor-8. Four cases each of hyperplastic polyps, tubular adenomas to villous adenomas, were routinely fixed in formalin and embedded in paraffin and were immunostained using goat anti-LYVE-1 for lymphatic vessels and rabbit anti-factor-8 for blood vessels. In normal colon and hyperplastic polyps, slender lymphatic vessels were noted in muscularis mucosa, which spread into the base of colonic crypt, whereas round venous vessels, they extend into lamina propria. In tubular adenomas, small lymphatic and venous vessels were noted in broad fibrous stalks. In villous adenomas, smaller lymphatic and venous vessels were noted in fine intervillous stroma. In normal colon and hyperplastic polyps, slender, irregularly shaped lymphatic vessels were present in muscularis mucosa, spreading into the base of the colonic crypt. In tubular adenomas, small lymphatic and venous vessels were noted in fibrous stalks. In villous adenomas, smaller lymphatic and venous vessels were noted in intervillous stroma. There are no increased lymphatic and venous vessels in intermucosal stroma and stalks of adenomas compared with normal colon.     

Evolution of colorectal cancer: change of pace and change of direction

This review compiles evidence for an alternative to the classical adenoma-carcinoma sequence in the evolution of colorectal cancer. It is suggested that between 30 and 50 of colorectal cancers are not initiated by mutation of the tumor suppressor gene APC, but through the epigenetic silencing of genes implicated in the control of differentiation, cell cycle control and DNA repair proficiency. The precursor polyps are often characterized by a serrated architecture, and include hyperplastic polyps, admixed polyps and serrated adenomas. The alternative pathway is heterogeneous and may culminate in cancers showing low or high level DNA microsatellite instability (MSI-L and MSI-H, respectively), and in cancers that are microsatellite stable (MSS). Cancers showing DNA MSI may be characterized by an accelerated evolution. Cancers in hereditary non-polyposis colorectal cancer show features of both classical (adenoma and APC mutation) and alternative pathways (rapid evolution, MSI-H and lack of chromosomal instability).     

BRAF, K-ras and BAT26 mutations in colorectal polyps and stool

AIM: To assess the feasibility of using BRAF, K-ras and BAT26 genes as stool-based molecular markers for detection of colorectal adenomas and hyperplastic polyps (HPs). METHODS: We applied PCR-SSCP and direct sequencing to detect BRAF mutations of polyps and paired stool samples. Primer-mediated restriction fragment length polymorphism (RFLP) analysis and mutant-enriched PCR were used in detection of K-ras mutations of polyp tissues and paired stool samples respectively. BAT26, a microsatellite instability marker was examined by detection of small unstable alleles in a poly (A) repeat. RESULTS: No genetic alterations were detected in the 36 colonoscopically normal patients in either tissues or stools. BRAF, K-ras and BAT26 mutations were found in 4 (16%), 10 (40%) and 3 (12%) of 25 adenoma tissues and among them, 75%, 80% and 100% of patients were observed to contain the same mutations in their corresponding stool samples. In HPs, mutations of BRAF and K-ras were detected in the tumor DNA of 2 (11.1%) and 8 (33.3%) of 18 patients respectively, all of whom had identical alterations in their stools. Taken together, the three genetic markers detected 15 (60%) of 25 adenomas and 8 (44.4%) of 18 HPs. The sensitivity of stool detection was 80% for adenomas and 100% for HPs with an overall specificity of 92% for adenomas and 100% for HPs. CONCLUSION: BRAF, K-ras and BAT26 genes have the potential to be molecular markers for colorectal adenomas and HPs, and can be used as non-invasive screening markers for colorectal polyps.     

Microsatellite instability in Ewing tumor is not associated with loss of mismatch repair protein expression

Only few clinical factors predict the prognosis of patients with Ewing tumors. Unfavorable outcome is associated with primary metastatic disease, age > 15 years, tumor volume above 200 ml, and the histological response to chemotherapy. The aim of this study was to elucidate the prevalence and clinical impact of microsatellite instability (MSI) together with the relation between MSI and mismatch repair protein expression in Ewing tumors. DNA from 61 primary Ewing tumors and 11 Ewing tumor cell lines was extracted and microsatellite analysis for the detection of instability or loss of heterozygosity was performed for the five markers of the Bethesda panel BAT25, BAT26, D5S346, D2S123, and D17S250, which represents the established marker panel for the analysis of hereditary non-polyposis colorectal carcinoma (HNPCC) patients. In addition, single nucleotide repeat regions of the two tumor genes BAX and transforming growth factor receptor II (TGFBR2) were also included. All of the 61 samples were suitable for LOH analysis and 55 for the determination of MSI-status. LOH of these microsatellite markers was detected in 9 of the 61 patients (14.8%). Over all, genetic instability, i.e. MSI and/or LOH, was detected in 17 tumors (27.9%). One out of the 11 tumor cell lines (STA ET1) was characterized by instability of all the five Bethesda markers, while from primary tumor samples, only one showed MSI in more than one microsatellite marker (D5S346 and D17S250, MSI-high). Eight of the fifty-five patients (14.5%) showed instability of one microsatellite locus (MSI-low). No instability was detected in BAT26, D2S123, BAX and TGFBR2. There was no significant correlation between MSI and loss of expression of mismatch repair proteins MLH1, MSH2, or MSH6. The impairment of the p53 signaling pathway (expression of TP53 and/or MDM2 by immunohistochemistry) was significantly associated with reduced overall survival (15 of 49 patients (30.6%), P = 0.0410, log-rank test). We conclude that MSI is not prevalent in Ewing tumor and that the nature of instability differs from the form observed in colorectal carcinoma, the model tumor of MSI. This is documented by the different pattern of MSI (no BAT26 instability) in Ewing tumors and the lack of a strict correlation between MSI-high and loss of expression of MSH2, MSH6 and MLH1. IA and KLS contributed equally to this study.     

Genetic and epigenetic changes in the <Emphasis Type="Italic">APC</Emphasis> gene in sporadic colorectal carcinoma with synchronous adenoma

BACKGROUND AND AIMS: Somatic APC mutation, frequently associated with colorectal tumors, is implicated in the early stage of tumorigenesis. This study was performed to identify APC-related colorectal tumorigenesis in sporadic colorectal carcinomas with synchronous adenoma. MATERIALS AND METHODS: We screened the entire coding region of APC and also assessed 5q LOH, 5q MSI, and promoter hypermethylation in fresh colorectal tissue and the lymphocytes of 31 patients with synchronous colorectal adenoma and carcinoma. RESULTS: The APC mutation prevalence was greater in carcinomas (70%) than in adenomas (45%). The 5q LOH and MSI were identified in 7 and in 5 of 31 carcinomas and in 6 each of 43 adenomas, respectively. The APC promoter methylation was identified in 3 cases each of both carcinomas and adenomas. Mutations in cases with 5q LOH were identified exclusively from codons 959 to the 3' end of exon 15. Otherwise mutations identified between exons 1 and 14 showed additional mutation on exon 15 and no additional mutation in two cases. All carcinomas with 5q LOH, 5q MSI, or methylation included at least one APC mutation, whereas 5 carcinomas and 6 adenomas showed solely an APC mutation. Both alleles were disrupted in 1 of 31 normal mucosa (3.2%), 12 of 40 adenomas (30%), and 18 of 33 carcinomas (54.5%). CONCLUSION: Genetic and epigenetic events encompassing APC occur variously among patients and tissues in sporadic colorectal cancer patients with synchronous colorectal adenoma. Moreover, these changes sometimes appear to be accumulated in all of the stages of colorectal tumorigenesis.     

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.     

Comparison of cyclo-oxygenase 2 expression in colorectal serrated adenomas to expression in tubular adenomas and hyperplastic polyps

BACKGROUND AND AIMS: Serrated adenoma (SA) is a newly defined category of colorectal neoplasia that contains features of both adenoma and hyperplastic polyp, and has two patterns, hyperplastic and cerebriform patterns. Since cyclooxygenase 2 (COX-2) has been found upregulated in colorectal cancers and adenomas, we examined whether either the hyperplastic or cerebriform pattern of SA has the potential for tumor progression and should be a target for clinical treatment. PATIENTS AND METHODS: An immunohistochemical scoring system was used to compare COX-2 expression in colorectal SAs (n=79), tubular adenomas (n=66), and hyperplastic polyps (n=21). RESULTS: COX-2 scores were significantly higher in SA of the cerebriform pattern (n=44) than in SA of the hyperplastic pattern (n=35). There was no difference in COX-2 scores between SA of the cerebriform pattern and tubular adenoma. In SA accompanied by hyperplastic polyp (n=26) the hyperplastic components expressed little COX-2, the same as traditional hyperplastic polyps. COX-2 expression in the SA component was similar to that in pure SA. CONCLUSION: SA of the cerebriform pattern should be treated similarly as traditional tubular adenomas. COX-2 induction may additionally be involved in progression from hyperplastic polyp to SA.     

Hyperplastic polyps and the risk of adenoma recurrence in the polyp prevention trial

BACKGROUND AND AIMS: Recent studies have suggested that some hyperplastic polyps may be associated with an increased risk of colorectal cancer. Prospective information on the risk of adenoma recurrence associated with hyperplastic polyps is limited. We sought to investigate whether the coexistence of hyperplastic polyps with adenomas increases the risk of adenoma recurrence. METHODS: We used unconditional logistic regression models to examine the association between baseline hyperplastic polyps and subsequent adenoma recurrence during a 3-year follow-up evaluation, among 1637 participants in the Polyp Prevention Trial. RESULTS: A total of 437 participants (26.7%) had hyperplastic polyps coexisting with adenomas at baseline. Of these, 132 (30.2%) had at least one hyperplastic polyp in the proximal colon, whereas 305 (69.8%) had only distal hyperplastic polyps. When compared with subjects without any hyperplastic polyps at baseline, there was no statistically significant association between the presence of baseline hyperplastic polyps and recurrence of any adenoma (odds ratio [OR], 1.19; 95% confidence interval [CI], 0.94-1.51) or advanced adenoma (OR, 1.25; 95% CI, 0.78-2.03). Also, there was no association between hyperplastic polyp location and adenoma recurrence (OR, 1.01; 95% CI, 0.69-1.48) for any proximal hyperplastic polyp (OR, 1.26; 95% CI, 0.96-1.65) and for distal hyperplastic polyps. CONCLUSIONS: The coexistence of hyperplastic polyps with adenomas, irrespective of location, does not confer an increased risk of adenoma recurrence beyond that of adenomas alone within 3 years of follow-up evaluation. Prospective long-term studies on adenoma recurrence risk associated with hyperplastic polyps in screening populations are needed.     

Loss of heterozygosity： An independent prognostic factor of colorectal cancer

AIM: Colorectal cancers result from the accumulation of several distinct genetic alterations. This study was to investigate the frequency and prognostic value of loss of heterozygosity (LOH) and microsatellite instability (MSI) at 14 genetic loci located near or within regions containing important genes implicated in colorectal tumorigenesis. METHODS: We studied colorectal cancers with corresponding normal mucosae in 207 patients (139 males and 68 females, mean age at the time of tumor resection 66.2±12.4 years, range 22-88 years). There were 37 right-sided colonic tumors, 85 left-sided colonic tumors and 85 rectal tumors. The distribution of tumor staging was stage Ⅰ in 25, stage Ⅱ in 73, stage Ⅲ in 68, and stage Ⅳ in 41. We analyzed the LOH and MSI of HPC1, hMSH2, hMLH1, APC, MET, P53, NH23-H1, DCC, BAT25, BAT26, D17S250, MYCL1 and D8S254 with fluorescent polymerase chain reaction and denatured gel electrophoresis. High-frequency LOH was determined to be greater than three, or more than 50% of the informative marker with LOH. High-frequency MSI (MSI-H) was determined as more than four markers with instability (>30%). Correlations of LOH and MSI with clinical outcomes and pathological features were analyzed and compared. RESULTS: The occurrence of MSI-H was 7.25%, located predominantly in the right colons (7/15) and had a higher frequency of poor differentiation (6/15) and mucin production (7/15). LOH in at least one genetic locus occurred in 78.7% of the tumors and was significantly associated with disease progression. Of the 166 potentially cured patients, 45 developed tumor recurrence within 36 mo of follow-up. Clinicopathological factors affecting 3-year disease-free survival (DFS) were TNM staging, grade of differentiation, preoperative CEA level, and high LOH status. Patients with high LOH tumors had a significantly lower DFS (50%) compared with patients with low LOH tumors (84%). Of the patients developing subsequent tumor recurrence, the number and percentage of LOH were 2.97 and 46.8% respectively, similar to the stage IV disease patients. TNM staging had the most significant impact on DFS, followed by high LOH status. CONCLUSION: Clinical manifestations of LOH and MSI are different in colorectal cancer patients. High-frequency LOH is associated with high metastatic potential of colorectal cancers.     

Hyperplastic polyps of the colorectum—Innocent or guilty?

Hyperplastic polyps have traditionally been regarded as nonneoplastic polyps lacking malignant potential. The demonstration of genetic alterations within these lesions indicates an underlying neoplastic cause. There is evidence that hyperplastic polyps are heterogeneous. Most are innocuous, but subsets may have malignant potential. Risk factors for neoplastic progression include multiple, large, and proximally located polyps. Aberrant methylation resulting in the silencing of cancer genes may be an important underlying mechanism, particularly in pathways progessing to tumors with DNA microsatellite instability. Lesions intermediate between hyperplastic polyp and cancer include admixed polyps and serrated adenomas. Currently, pathologists have different thresholds for diagnosing serrated adenomas, including the distinction from large hyperplastic polyps. Reasons for over looking this pathway in the past may include rapid tumor progression and the fact that proximally located hyperplastic polyps may be flat and not especially numerous. Management of the serrated pathway of colorectal neoplasia may require novel approaches to screening, early detection, and prevention.