Genetic and epigenetic aberrations occurring in colorectal tumors associated with serrated pathway

To clarify molecular alterations in serrated pathway of colorectal cancer (CRC), we performed epigenetic and genetic analyses in sessile serrated adenoma/polyps (SSA/P), traditional serrated adenomas (TSAs) and high‐methylation CRC. The methylation levels of six Group‐1 and 14 Group‐2 markers, established in our previous studies, were analyzed quantitatively using pyrosequencing. Subsequently, we performed targeted exon sequencing analyses of 126 candidate driver genes and examined molecular alterations that are associated with cancer development. SSA/P showed high methylation levels of both Group‐1 and Group‐2 markers, frequent BRAF mutation and occurrence in proximal colon, which were features of high‐methylation CRC. But TSA showed low‐methylation levels of Group‐1 markers, less frequent BRAF mutation and occurrence at distal colon. SSA/P, but not TSA, is thus considered to be precursor of high‐methylation CRC. High‐methylation CRC had even higher methylation levels of some genes, e.g., MLH1, than SSA/P, and significant frequency of somatic mutations in nonsynonymous mutations (p < 0.0001) and insertion/deletions (p = 0.002). MLH1‐methylated SSA/P showed lower methylation level of MLH1 compared with high‐methylation CRC, and rarely accompanied silencing of MLH1 expression. The mutation frequencies were not different between MLH1‐methylated and MLH1‐unmethylated SSA/P, suggesting that MLH1 methylation might be insufficient in SSA/P to acquire a hypermutation phenotype. Mutations of mismatch repair genes, e.g., MSH3 and MSH6, and genes in PI3K, WNT, TGF‐β and BMP signaling (but not in TP53 signaling) were significantly involved in high‐methylation CRC compared with adenoma, suggesting importance of abrogation of these genes in serrated pathway.     

Histology subtypes and polyp size are associated with synchronous colorectal carcinoma of colorectal serrated polyps: a study of 499 serrated polyps

Sessile serrated adenomas (SSA) and traditional serrated adenomas (TSA) are considered as precursors of colorectal cancer, and are often diagnostic challenges. Their true prevalence is masked by significant inter-observer variations. To investigate the true prevalence and synchronous colorectal carcinoma (sCRC) of colorectal serrated polyps (CSP) and their associated factors, we first retrospectively identified all colorectal polyps collected at our institution between June 1995 and May 2013. After centrally reclassifying all CSP to reduce inter-observer variations, Chi-square tests and logistic regression analyses were used to analyze the potential factors. Among the included 5501 colorectal polyps, 499 CSP of 428 patients were identified and studied, including 353 hyperplastic polyps (HP, 70.7%), 80 SSA (16.0%), 61 TSA (12.2%) and 5 mixed polyp (1.0%). Diagnostic disagreements were found in 68 CSP (13.63% of CSP). SSA and TSA were more often larger than 5 mm and in proximal colon than HP. SSA were also more likely associated with older age (p=0.005), size ≥5 mm (p<0.001) and ≥3 polyps (p=0.004) than HP in distal colon, but only more likely associated with older age (p=0.006) in proximal colon. Multivariate regression analysis demonstrated that CSP with sCRC, compared with CSP without sCRC, were linked to CSP size ≥1 cm (vs <1 cm, odds ratio [OR] 4.412, 95% confidence interval [CI] 1.684-11.556, P=0.003) and a diagnosis of SSA or TSA (vs HP, OR 6.194, 95% CI 1.870-20.513, P=0.003 and OR 6.754, 95% CI 1.981-23.028, P=0.002, respectively), but not age, gender, polyp number and polyp shape. SSA and TSA are similarly often associated with sCRC (P=0.460). In conclusion, histology subtypes and polyp size may serve as markers for sCRC of CSP. SSA and TSA may warrant careful endoscopic examinations and similar follow-up intervals.     

The serrated neoplasia pathway of colorectal tumors: Identification of MUC5AC hypomethylation as an early marker of polyps with malignant potential

The serrated neoplasia pathway accounts for 20–30% of colorectal cancers (CRC), which are characterized by extensive methylation (CpG island methylation phenotype, CIMP), frequent BRAF mutation and high microsatellite instability (MSI). We recently identified MUC5AC mucin gene hypomethylation as a specific marker of MSI CRC. The early identification of preneoplastic lesions among serrated polyps is currently challenging. Here, we performed a detailed pathological and molecular analysis of a large series of colorectal serrated polyps and evaluated the usefulness of mucin genes MUC2 and MUC5AC to differentiate serrated polyps and to identify lesions with malignant potential. A series of 330 colorectal polyps including 218 serrated polyps [42 goblet cell‐rich hyperplastic polyps (GCHP), 68 microvesicular hyperplastic polyps (MVHP), 100 sessile serrated adenoma (SSA) and eight traditional serrated adenoma (TSA)] and 112 conventional adenomas was analyzed for BRAF/KRAS mutations, MSI, CIMP, MLH1 and MGMT methylation, and MUC2 and MUC5AC expression and methylation. We show that MUC5AC hypomethylation is an early event in the serrated neoplasia pathway, and specifically detects MVHP and SSA, arguing for a filiation between MVHP, SSA and CIMP‐H/MSI CRC, whereas GCHP and TSA arise from a distinct pathway. Moreover, MUC5AC hypomethylation specifically identified serrated lesions with BRAF mutation, CIMP‐H or MSI, suggesting that it may be useful to identify serrated neoplasia pathway‐related precursor lesions. Our data suggest that MVHP should be recognized among HP and require particular attention.     

结直肠纤维绒毛锯齿状腺瘤临床病理学及免疫组织化学的观察

目的:探讨纤维绒毛锯齿状腺瘤(FSA)的临床病理学特征以及免疫组织化学特征的意义。方法:收集病理诊断为结直肠各类息肉和腺瘤切片5347例,从中筛选出FSA共18例,同时收集临床相关资料并观察病理学特征。对FSA11例、非纤维绒毛锯齿状腺瘤(NFSA)20例〔其中传统锯齿状腺瘤(TSA)15例、广基锯齿状腺瘤/息肉(SSA/P)5例〕、增生性息肉(HP)20例及绒毛管状腺瘤(VTA)20例分别进行免疫组化Ki-67、p53、-βCatenin、CK7、CK20及CDX-2染色。结果:FSA多发于左半结肠,组织学显示肿物表面可见许多细长丝状或绒毛状的突起,隐窝被覆异型增生的上皮细胞,伴有典型锯齿状改变,该类突起形似绒毛管状腺瘤,但其长度比绒毛管状腺瘤长。多数病例突起末端间质水肿明显(12/18),严重者可膨大呈"球茎"状改变(7/18)。FSA异型增生程度较NFSA和VTA要高,差异有统计学意义,P<0.05。在FSA中p53和Ki-67的表达与其他各组比较差异有统计学意义,P<0.05。结论:FSA是一种较少见的特殊类型锯齿状腺瘤,以其"长绒毛"的典型特征区别于其他锯齿状病变,异型增生程度重,可能具有更高的恶变潜能。     

Sessile serrated polyps of the colorectum are rare in patients with Lynch syndrome and in familial colorectal cancer families

Whereas the generally accepted carcinogenesis pathway of the microsatellite instabile high (MSI-H) colorectal carcinoma (CRC) involves the traditional adenoma in patients with Lynch syndrome, a serrate pathway involving serrate adenomas (SA) and sessile serrate polyps (SSP) characterize the sporadic MSI-H counterpart. Recent studies have, however, challenged such simple one-pathway models, inviting the consideration of alternative, unexpected pathways. Here, the issue as to the possible role of SSP, primarily in the context of Lynch syndrome, but also in subjects from familial CRC families (FCF) is addressed. Polyps coded as hyperplastic polyps (HP) from subjects with Lynch syndrome and FCF enrolled in the HNPCC-register at the Hvidovre University Hospital as well as adenomas from this population were retrieved and reviewed for features of SSP. Ninety-eight polyps coded as HP and 41 polyps coded as adenoma from 14 individuals with Lynch syndrome as well as 17 individuals from FCF constituted the study material. Seven of the 98 polyps coded as HP displayed histological features that, to varying extent, deviated from the traditional HP (THP), yet, merely two of these, both from the FCF, were considered examples of probable SSP. None of the 41 cases coded as adenoma possessed a morphology that qualified as SSP. The prevalence of SSP was not increased as compared to the background population and thus, this serrated lesion does not appear to play a tumorigenic role in Lynch syndrome, nor in FCF.     

Invasive Fusobacterium nucleatum may play a role in the carcinogenesis of proximal colon cancer through the serrated neoplasia pathway

The prevalence of invasive Fusobacterium nucleatum (Fn) within the serrated neoplasia pathway of the proximal colon has seldom been investigated. We examined the invasive Fn and bacterial biofilms in 35 proximal hyperplastic polyps (HPs), 33 sessile serrated adenomas (SSAs), 48 proximal colorectal cancers (CRCs) and 10 matched metastatic lymph nodes using 16S rRNA fluorescence in situ hybridization (FISH). Samples of normal mucosa, traditional adenomas (TAs), distal HPs, distal CRCs and matched lymph nodes with or without metastases were used as controls. The prevalence of invasive Fn within proximal HPs (65.7%) and SSAs (78.8%) were significantly higher than that of proximal TAs (28.9%) and distal TAs (24.4%; p < 0.05). Invasive Fn was detected in markedly more proximal CRCs (89.6%) than in distal CRCs (42.2%; p < 0.05). Moreover, invasive Fn was detected in a significantly higher proportion of matched metastatic lymph nodes (100%) than that within nonmetastatic lymph nodes (40.0%; p < 0.001). Bacterial biofilms were found on 52.1% of proximal CRCs, 55.6% of distal CRCs and 48.5% of SSAs. Biofilms were positive for Fn in 47.9% of proximal CRCs, 48.9% of distal CRCs and 27.3% of SSAs. However, the presence of Fn in biofilms was not related to invasive Fn within colorectal tissues (p = 0.415). Invasive Fn may play a role in the carcinogenesis of proximal colon developing via the serrated neoplasia pathway, but might have a less important role in the TA‐carcinoma sequence. Bacterial biofilms may not contribute to the invasion of Fn into tumor tissues.     

BRAF和EphB2在人结直肠锯齿状腺瘤中的表达及意义

目的:探讨鼠类肉瘤滤过性病毒致癌基因同源体B1(v-raf murine sarcoma viral oncogene homolog B1,BRAF)和生促红素人肝细胞蛋白(erythropoietin-producing hepatoma cell line B2,EphB2)在人结直肠锯齿状腺瘤中的表达及其意义。方法:收集滨州医学院附属医院1996年1月至2008年5月10例正常结直肠肠黏膜、21例增生性息肉、22例锯齿状腺瘤、55例腺瘤性息肉(18例管状腺瘤、16例管状绒毛状腺瘤、21例绒毛状腺瘤)石蜡标本。免疫组织化学法检测BRAF和EphB2蛋白的表达量,同时观察蛋白的表达部位。结果:增生性息肉中BRAF蛋白阳性细胞多位于隐窝中下区域,腺瘤性息肉的阳性细胞多表达位于隐窝上部区域,而锯齿状腺瘤阳性细胞多表达于隐窝全层。锯齿状腺瘤与腺瘤性息肉的BRAF蛋白表达量相近[(0.129±0.030)vs(0.130±0.026),P>0.05],但远高于增生性息肉[(0.129±0.030)vs(0.102±0.014),P<0.01];锯齿状腺瘤、管状腺瘤、管状绒毛状腺瘤、绒毛状腺瘤之间BRAF蛋白表达量差异无统计学意义[(0.129±0.030)vs(0.116±0.019),(0.119±0.037),(0.122±0.008),P>0.05]。增生性息肉中EphB2蛋白阳性细胞多位于隐窝中下区域细胞膜上,腺瘤性息肉EphB2蛋白阳性细胞位于隐窝上部,而锯齿状腺瘤EphB2蛋白阳性细胞表达于隐窝全层。锯齿状腺瘤与腺瘤性息肉的EphB2蛋白表达量相近[(0.138±0.024)vs(0.139±0.025),P>0.05],而远高于增生性息肉[(0.138±0.024)vs(0.169±0.018),P<0.01];锯齿状腺瘤与管状腺瘤、管状绒毛状腺瘤、绒毛状腺瘤间EphB2蛋白表达量无区别[(0.138±0.024)vs(0.143±0.027),(0.139±0.028),(0.133±0.021),P>0.05]。结论:BRAF和EphB2蛋白在增生性息肉、腺瘤性息肉中隐窝部分区域表达,而在锯齿状腺瘤中隐窝全层表达,提示锯齿状腺瘤是一类独立的不同于腺瘤性息肉的结直肠肿瘤。     

Independent and joint associations of general and abdominal obesity with the risk of conventional adenomas and serrated polyps: A large population-based study in East Asia

Evidence regarding associations of general and abdominal obesity with the risk of conventional adenomas (ADs) and serrated polyps (SPs) from Asian population is scarce. Our study aimed to investigate the independent and joint associations of general obesity assessed by body mass index (BMI) and abdominal obesity assessed by waist circumference (WC) or waist-to-hip ratio (WHR) with the risk of ADs and SPs among 25 222 participants recruited by a population-based screening program. Compared to participants with normal BMI, those with a BMI ≥28 kg/m² had increased risk of ADs (odds ratio [OR] 1.52, 95% confidence interval [CI]: 1.36-1.70) and SPs (OR 1.69, 95% CI: 1.38-2.07). For participants with a WC ≥102 cm (≥88 cm for females), the risk of ADs (OR 1.37, 95% CI: 1.25-1.51) and SPs (OR 1.81, 95% CI: 1.52-2.16) was higher than that of the reference group. For participants with a WHR ≥0.95 (≥0.90 for females), the risk of ADs (OR 1.26, 95% CI: 1.16-1.36) and SPs (OR 1.46, 95% CI: 1.26-1.69) was higher than that of the reference group. Moreover, participants with both BMI ≥28 kg/m² and WC ≥102 cm (≥88 cm for females) had 61% and 119% higher risk of ADs (OR 1.61, 95% CI: 1.39-1.85) and SPs (OR 2.19, 95% CI: 1.70-2.82) compared to those with both normal BMI and WC. These findings indicate that both general and abdominal obesity are associated with SPs and ADs, presenting stronger association with SPs than ADs. Moreover, the association is more evident when both obesities exist.     

结直肠锯齿状病变h-MLH1基因甲基化状态和蛋白表达意义研究

目的：通过研究结直肠锯齿状病变组织中h-MLH1基因启动子区CpG岛甲基化及蛋白表达,探讨h-MI．H1启动子甲基化状态与蛋白表达相关性及在锯齿状癌变通路中的作用,并分析hMLH1基因在不同年龄层段甲基化程度。方法：收集北京军区总医院病理科2007-0101-201212-31诊断为锯齿状病变标本225例,其中包括96例增生性息肉（hyperplasticpolyp,HP）、61例广基（无蒂）锯齿状腺瘤/息肉（sessileserratedadenoma／polyp,SSA／P）和68例传统锯齿状腺瘤（traditionalserratedadenoma,TSA）;同时收集同院同期的54例管状腺瘤（tubularadenoma,TA）、69例结直肠癌（colorectaIcancer,CRC）和42例正常结直肠黏膜组织作为对照。应用Taqman探针qPCR（MethyLight）方法检测各组织中h-MLH1基因CpG岛甲基化状态,同时采用免疫组织化学方法检测其蛋白表达水平,其中随机抽取锯齿状病变116例（HP52例、SSA／P41例、TSA23例）、TA20例、CRC24例和正常结直肠黏膜组织24例,并将其甲基化状态与相应的蛋白表达水平及临床病理学资料进行统计学分析。结果：正常、TA、HP、SSA／P、TSA和CRC组织中,MLH1基因启动子CpG岛甲基化阳性表达率分别为9．24％（4／42）、40．74％（22／54）、22．92％（22／96）、45．90％（28／61）、61．76％（42／68）和52．17％（36／69）。HP组与正常、SSA／P、TSA及CRC组之间比较,正常组与SSA／P及TSA组之间比较,差异均有统计学意义,P〈0．05;其余各组之间比较,差异均无统计学意义,P〉0．05。正常、TA、HP、SSA／P、TSA和CRC组织中,h-MLH1蛋白阳性表达率分别为100％（24／24）、80．00％（16／20）、98．08％（51／52）、75．61％（31／41）、69．57％（16／23）和70．83％（17／24）。正常组与HP、SSA／P、TSA、TA、CRC组之间比较,差异均有统计学意义,P％0．05;其余各组之间比较,差异均无统计学意义,P〉0．05。TA、SSA／P和TSA组中,hMLH1基因甲基化与其蛋白表达差异均有统计学意义（P〈o．05）,且呈负相关,相关系数．y分别为-0．553、-0．497、和-0．473。TA、HP、SSA／P和TSA组中,h-MLH1基因甲基化与年龄差异均有统计学意义（P〈0．05）,且呈正相关,相关系数7分别为0．475、0．289、0．450和0．575。结论：结直肠锯齿状病变组织中h-MLH1基因甲基化可能导致其蛋白表达下调,与锯齿状病变的发生和发展密切相关,同时,h-MLH1基因甲基化又可能与年龄相关,随年龄增长,甲基化程度越高。     

Current progress on the endoscopic features of colorectal sessile serrated lesions

Along with the discovery and refinement of serrated pathways, the World Health Organization amended the classification of digestive system tumors in 2019, recommending the renaming of sessile serrated adenomas/polyps to sessile serrated lesions (SSLs). Given the particularity of the endoscopic appearance of SSLs, it could easily be overlooked and missed in colonoscopy screening, which is crucial for the occurrence of interval colorectal cancer. Existing literature has found that adequate bowel preparation, reasonable withdrawal time, and awareness of colorectal SSLs have improved the quality and accuracy of detection. More particularly, with the continuous advancement and development of endoscopy technology, equipment, and accessories, a potent auxiliary tool is provided for accurate observation and immediate diagnosis of SSLs. High-definition white light endoscopy, chromoendoscopy, and magnifying endoscopy have distinct roles in the detection of colorectal SSLs and are valuable in identifying the size, shape, character, risk degree, and potential malignant tendency. This article delves into the relevant factors influencing the detection rate of colorectal SSLs, reviews its characteristics under various endoscopic techniques, and expects to attract the attention of colonoscopists.     

Body fatness over the life course and risk of serrated polyps and conventional adenomas

Serrated polyps (SPs) and conventional adenomas represent 2 distinct groups of colorectal premalignancy. The influence of early life adiposity on risk of these precursors remains unclear. Within the Nurses' Health Study, the Nurses' Health Study 2, and the Health Professionals Follow-up Study, we assessed body fatness during childhood using 9-level somatotype and obtained weight and body mass index (BMI) in adulthood. We used multivariable-adjusted logistic regression to examine the association of SPs and conventional adenomas with body fatness in early childhood (age 5), late childhood (age 10), early adulthood (age 18/21) and middle adulthood (baseline) and weight change during early-to-middle adulthood. During 18–20 years of follow-up, we documented 8,697 SPs and 10,219 conventional adenomas in 132,514 women; 2,403 SPs and 4,495 conventional adenomas in 29,207 men. We found a modest positive association of adiposity in early and late childhood with risk of SPs and conventional adenomas, with odds ratios ranging from 1.12 to 1.18 for comparison of extreme somatotypes groups. The associations were attenuated after adjusting for adulthood BMI but remained significant for conventional adenomas. No association with early life body fatness was found in men. Adulthood body fatness and weight change during early-to-middle adulthood showed positive relationships with SPs and conventional adenomas in both women and men, with stronger associations observed for SPs (p_{heterogeneity} < 0.0001). Our findings indicated a potential role in development of colorectal cancer precursors of childhood body fatness in women, and early-to-middle adulthood weight gain and attained adiposity in both sexes.     

Small-cell carcinoma of the gastrointestinal tract: a retrospective study of 64 cases

Small-cell carcinoma (SmCC) of the gastrointestinal tract is a very rare and aggressive malignancy. To better define its clinicopathological features, the records of all patients with this disease seen at Memorial Sloan Kettering Cancer Center between 1980 and 2002 (n=64) were reviewed. The most common primary tumour locations were in the large bowel and oesophagus. Predisposing medical conditions for non-small-cell cancers, positive family cancer history, and metachronous tumours were common. In all, 37% had mixed tumour histology and 48% presented with extensive disease, according to the Veterans' Administration Lung Study group (VALSG) staging system used for small-cell lung cancer. Treatment outcome in limited disease (LD) suggested a role for surgery and chemotherapy. Platinum-based regimens resulted in a 50% response rate. The 2-year survival was 23% and two prognostic factors were identified, the extent of disease according to the VALSG system (P<0.01) and TNM stage (P=0.03). Anatomic location had no clinical impact. In conclusion, SmCC from various gastrointestinal sites can be viewed as one clinical entity. Mixed tumour histology is common and may affect therapy. Surgery, combined with chemotherapy, should be considered for LD. The value of the VALSG system was implied and possible differences from small-cell lung cancer were noted.     

Intragastric nitrosation and precancerous lesions of the gastrointestinal tract: testing of an etiological hypothesis

The N-nitrosoproline (NPRO) test was used to study whether subjects with precancerous conditions of the stomach have an elevated potential for endogenous nitrosation. The highest yield of NPRO after ingestion of beetroot juice (as a source of nitrate) and proline was seen in subjects whose pH of fasting gastric juice was about 1.5-2. No increased level of NPRO was detected in subjects with more advanced lesions, compared to those with a normal stomach. Counts of total and nitrate-reducing bacteria were positively correlated with the pH of gastric juice but did not correlate with the urinary level of NPRO in the same individuals. Bacteria and intragastric nitrosation are discussed as possible etiological factors in human stomach cancer.     

Relation between normal rectal methylation,smoking status,and the presence or absence of colorectal adenomas

BACKGROUND:

Colorectal cancer (CRC) is 1 of the leading causes of death in the Western world. CRC develops from premalignant lesions, chiefly colorectal adenomas. Currently, the most accurate and recommended screening method for finding colorectal adenomas is colonoscopy performed on all individuals aged >50 years. However, the costs and risks associated with this procedure are relatively high. The objectives of the current study were to correlate epigenetic alterations that occur in normal rectal mucosa, smoking status, and age with the presence or absence of concomitant colorectal adenomas and to assess the potential clinical value of methylation in normal rectal biopsies as a screening assay for the presence of polyps and, hence, the need for a full colonoscopy.

METHODS:

One hundred thirteen normal rectal mucosal biopsies from 113 patients were studied. DNA was extracted, modified with sodium bisulfite, and subjected to real‐time quantitative, methylation‐specific polymerase chain reaction analysis for the following genes: adenomatous polyposis coli (APC); cadherin 1, type 1, E‐cadherin (epithelial) (CDH1); estrogen receptor 1 (ESR1); cytokine high in normal 1 (HIN1); hyperplastic polyposis protein 1 (HPP1); O‐6 methylguanine‐DNA methyltransferase (MGMT); neural epidermal growth factor‐like 1 (NELL1); splicing factor 3B, 14‐kDa subunit (p14); cyclin‐dependent kinase (CDK) inhibitor 2B (inhibits CDK4) (p15); retinoic acid receptor beta (RARβ); somatostatin (SST); tachykinin, precursor 1 (TAC1); and tissue inhibitor of metalloproteinase (TIMP) metallopeptidase inhibitor 3 (TIMP3). Data were then analyzed using several proprietary software programs.

RESULTS:

By using several sets of genes, clinical characteristics, and multivariate analyses, the authors developed a prediction model for the presence of concomitant colorectal adenomas at the time of rectal biopsy. They also observed strong correlations between smoking status and rectal methylation pattern and between smoking status and the presence or risk of concomitant adenomas.

CONCLUSIONS:

A prediction model was developed for the presence of colorectal adenomas based on gene methylation patterns in the normal rectum. The results indicated that these genes may be involved in early stages of adenoma formation. The observed epigenetic alterations in these markers may be caused in part by the effects of smoking and/or age. Normal rectal methylation may be useful as a biomarker for narrowing the population in need of screening colonoscopy. Cancer 2010. © 2010 American Cancer Society.     

Serum lipids and left-sided adenomas of the large bowel: an extended study of self-defense officials in Japan

In the on-going study of men retiring from the Self-Defense Forces in Japan, we previously reported that serum total cholesterol was not related to colorectal adenomas but that men with low levels of serum highdensity lipoprotein (HDL) cholesterol had an elevated adenoma risk. We examined whether the previous observation was reproducible in a different set of data accrued subsequently in the study. Serum total cholesterol, HDL-cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides were compared between 138 cases of colorectal adenomas at the depth of 60 cm or less from the anus and 909 controls with normal sigmoidoscopy in the period from October 1988 to December 1990. There was virtually no relation between adenoma risk and any of the serum lipids studied with or without adjustment for smoking, alcohol use, and body mass index. In the analysis combining the earlier and present data, however, men with large adenomas (10 mm, n=25) tended to have lower levels of total cholesterol and LDL-cholesterol compared with controls (n=1,612); adjusted mean differences were –0.21 mmol/l (P=0.24) and –0.26 mmol/l (P=0.13), respectively. These findings are inconclusive, but hypocholesterolemia may be associated with the growth of colorectal adenoma.Dr Kono is with the Department of Public Health, National Defense Medical College, Tokorozawa, Saitama, Japan. Drs Imanishi, Shinchi, and Yanai are with the Self-Defense Forces Fukuoka Hospital, Kasuga-shi, Fukuoka, Japan. Address correspondence to Dr Kono, Department of Public Health, National Defense Medical College, Tokorozawa, Saitama 359, Japan. The work was supported in part by a Grant-in-Aid for Cancer Research (2–3) from the Ministry of Health and Welfare, Japan.     

Alterations of RASSF1A in premalignant cervical lesions: clinical and prognostic significance

This study aimed to understand the importance of RASSF1A and CACNA2D2, located in chromosomal 3p21.31 region, in the development of uterine cervical carcinoma (CACX). To this end, firstly the expression (RNA) profiles of RASSF1A and CACNA2D2 were screened in primary cervical carcinoma (CACX) samples which indicated highly reduced expression for both genes. Thereafter alterations (deletion/methylation) of these genes were analyzed in 23 cervical intraepithelial neoplasia (CIN) and 110 CACX samples. In CIN, deletion was observed only for RASSF1A (26%), whereas methylation was in the following order: RASSF1A (35%) > CACNA2D2 (9%). However, in CACX their deletion frequencies were the same (50%) and methylation frequencies were comparable RASSF1A (33%), CACNA2D2 (27%). The reduced expression and molecular alterations of these genes were concordant. Overall alterations of RASSF1A showed association with CIN lesions and CACNA2D2 with disease progression from CIN → stage I/II. Interestingly, alterations of these genes showed significant association in CACX suggesting possible functional synergism during tumor progression. Alterations of RASSF1A and CACNA2D2 predicted poor prognosis for the patients. Moreover, RASSF1A alterations along with multiparity (≥5 yr) and early sexual debut (<19 yr) were determinants of worse prognosis. Our data suggests the association of RASSF1A and CACNA2D2 in cervical carcinogenesis and its importance in early diagnosis and prognosis of the tumor. © 2011 Wiley Periodicals, Inc.     

原发性胃肠道恶性淋巴瘤的诊断与治疗

目的 :探讨原发性胃肠道恶性淋巴瘤的诊断及治疗。方法 :分析我院近12年来收治的69例原发性胃肠道恶性淋巴瘤的临床资料 ,其生存率由寿命表法计算获得。结果 :本组术前确诊率为27.5 % ,其2年、5年和10年生存率分别是 :Ⅰ期91.7%、83.3%和25 % ,Ⅱ期52 %、32%和20 %。结论 :掌握本病钡餐造影的特点和内镜取材深度 ,可望提高本病的术前诊断率 ,争取手术切除 ,术后辅助化疗、放疗 ,以提高本病生存率。     

Primary gastrointestinal tract lymphoma: diagnosis and management of common neoplasms

Primary gastrointestinal lymphoma represents the most common location of extranodal lymphoma. With the bulk of disease manifesting within the gastrointestinal tract and contiguous lymph nodes, many of the lymphomas occurring in the peripheral lymph nodes can also present with primary gastrointestinal tract involvement. Molecular biology has recently enabled significant progress in the diagnosis and management of primary gastrointestinal lymphoma. Herein, we will discuss the major lymphomas affecting the bowel and highlight their key morphological, immunophenotypical and molecular diagnostic attributes. Similarly, in keeping with recent therapeutic advances, we will briefly discuss some important treatment considerations. Thus, this review is intended to offer clinicians and pathologists an overview of primary gastrointestinal lymphomas.     

The role of endoscopic ultrasonography in the upper gastrointestinal tract: A review with illustrative cases

In this article the current applications of endoscopic ultrasound in the upper gastrointestinal tract and its adnexa, as well as the areas of likely development, are reviewed. Illustrative cases are shown from the author's experience. Pitfalls and limitations of the technique are also discussed.     

The neoplastic impact of tobacco-free betel-quid on the histological type and the anatomical site of aerodigestive tract cancers

Little is known about any consequences of swallowing tobacco-free betel-quid (TF-BQ) juice/remnants following chewing and its carcinogenic impact on the upper aerodigestive tract (UADT) to gastrointestinal tract (GIT). We investigated the neoplastic impact of TF-BQ on different anatomical locations along UADT and GIT, and differences according to their histological categories. We conducted a multicenter case-control study examining patients with 2,163 pathology-proven UADT and GIT cancers, comparing them with 2,250 control subjects. Generalized additive models, piecewise regression and polytomous logistic models were applied to identify possible dose-dependent structures and cancer risks. Contrary to nonsignificant GIT-adenocarcinoma risk (aOR=0.9), TF-BQ users experienced a 1.7- to 16.2-fold higher risk of UADT-squamous cell carcinomas than nonusers, with the peak risk discovered in oral neoplasms. We separately observed a curvilinear and linear TF-BQ dose-risk relationship in oral/pharyngeal/esophageal and laryngeal cancers. Chewers of betel inflorescence were generally at a greater UADT cancer risk. A higher first-piecewise increased risk of esophageal cancer was recognized among areca-fluid swallowers than among nonswallowers (continuous aOR=1.12 vs. 1.03). TF-BQ use accounted for 66.1-78.7% and 17.8-33.2% of the cases of oral/pharyngeal and esophageal/laryngeal cancers, respectively. However, a reduction from heavy TF-BQ consumption to low-to-moderate consumption only reduced 11.3-34.6% of etiologic fraction of oral/pharyngeal cancers. Alcohol supra-additively modified the risk of TF-BQ in determining the development of oral, pharyngeal and esophageal cancers. In conclusion, the interplay of TF-BQ and alcohol/tobacco use, combined with how chewing habit is practiced, influences carcinogenic consequences on anatomically diverse sites of UADT and GIT cancers, and histologically different types.