胃癌高发区高危人群血清HpCagA毒素相关蛋白检测的意义

幽门螺杆菌(Helicobacter pylori,Hp)感染与浅表性胃炎、胃溃疡、萎缩性胃炎乃至胃癌的发生密切相关。近年来研究指出,Hp毒素在Hp致病性中起重要作用,并证明作为Hp的重要致病因素而参与了较严重的胃粘膜病变的发生,并与胃癌的发生有密切关系。目前,根据其CagA~ 蛋白的有无将Hp分为两型:Ⅰ型菌(Hp-CagA~ ):有CagA,表达CagA蛋白,具有毒素活性;Ⅱ型菌(Hp-CagA~-):无CagA,不表达CagA蛋白,无毒素活性。我们通过胃癌高发区高危人群流行病学,血清学及病理学研究,探讨Hp-CagA~ 菌株与有关胃疾病的相关性及其与胃癌发生的可能的病因学联系。     

HP与胃癌

１．ＨＰ与胃癌流行病学ＨＰ感染呈世界性分布，但各地的ＨＰ感染率、胃癌发生率及死亡率差异很大。Ｆｏｒｍａｎ等通过３１９４例人群调查发现，ＨＰ感染高发区胃癌发生率是ＨＰ感染低发区的１１倍，统计学处理有显著意义。在哥伦比亚、秘鲁、墨西哥、中国等发展中国家，...     

胃癌76例临床分析

目的了解胃癌的临床特点及发病情况。方法对我院诊断的76例胃癌患者的资料进行回顾分析。结果胃癌好发于中年男性，既往有慢性萎缩性胃炎，常食腌制、烟熏食品者。胃癌患者中Hp感染者占80．3％。结论对胃癌高危人群应定期进行胃镜检查，以便早诊断、早治疗。并应加强健康饮食习惯的宣教，以利预防。     

新型胃癌筛查评分系统在福建海岛胃癌风险人群的应用

目的　探讨新型胃癌筛查评分系统在福建海岛胃癌风险人群的应用价值。方法　2019年4—6月，对福建省莆田市南日岛人群进行胃癌筛查，前瞻性收集了研究对象的流行病学数据。采用新型胃癌筛查评分系统进行胃癌风险分级后，对所有受试者进行胃镜检查，随后对疑似阳性病例进行放大内镜检查和活检。后续针对阳性人群进行手术治疗（包括内镜及外科手术）。比较胃癌风险分级的各组人群中胃癌及癌前病变的检出率，采用卡方检验等统计学分析。结果　共纳入研究对象1 423例，检出胃癌19例（1.34%）。胃癌风险分级的低危组、中危组和高危组胃癌检出率分别为0.88%（9/1 025）、1.76%（6/341）和7.02%（4/57）。对胃癌检出率进行配对比较显示，低危组和高危组差异有统计学意义（χ2=12.364，P=0.003）。低危组与中危组、中危组与高危组之间差异无统计学意义（P>0.05）。所有患者共检出胃癌前病变87例（6.11%）。对胃癌前病变检出率进行配对比较显示，低危组、中危组和高危组的检出率分别为6.24%（64/1 025）、5.87%（20/341）和5.26%（3/57），3组间差异无统计学意义（P>0.05）。结论　在胃癌筛查过程中，新型胃癌筛查评分系统有助于对福建海岛胃癌风险人群进一步风险分层，为内镜精查提供依据。     

胃癌预防亚太地区共识指南

背景与目的：胃癌是亚太地区的主要健康负担之一，但对其预防策略尚缺乏共识。本共识会议旨在评价预防胃癌的策略。方法：多学科专家组应用德尔菲（Delphi）法制订共识条文，提呈相关数据，对证据等级、推荐强度以及共识水平予以分级。结果：幽门螺杆菌（H.pylori）感染是非贲门胃腺癌必要但非充分的致病因子。盐的高摄人与胃癌强烈相关。新鲜果蔬对胃癌具有预防作用，但维生素和其他饮食补充并不能预防胃癌。Hprtori感染中的宿主-细菌相互作用导致不同类型的胃炎和胃酸分泌，从而决定疾病结局。胃癌阳性家族史是一个重要的危险因素。低血清胃蛋白酶原反映胃萎缩程度，可作为检出胃癌高危人群的标志物。H．prlori筛查和治疗被推荐作为减少高危人群胃癌危险性的一种策略．该策略在萎缩性胃炎发生前实施最为有效，但并不排除对胃癌高危人群的内镜监测。对胃癌低危人群不推荐行H．pylori筛查。H．pylori感染的一线治疗应遵循国家治疗指南。结论：高危人群中H．pylori筛查和根除策略可能会减少胃癌的发生率，本共识根据现有证据予以推荐。     

胃癌高发区人群幽门螺杆菌感染现状

幽门螺杆菌(Hp)感染在胃癌发病中起重要作用,扬中地区系胃癌高发区,本研究用呼气试验方法调查当地人群Hp感染现状,现就结果报道如下。     

P53Arg72Pro多态性及H pylori感染与胃癌高发区甘肃河西地区胃癌的关系

目的:检测H pylori在甘肃河西地区健康人群与胃癌患者中的感染,并探讨P53Arg72Pro基因多态性以及H pylori感染与胃癌高发区甘肃河西地区胃癌发生的关系.方法:采用PCR-TaqMan探针法检测甘肃河西地区健康人群和胃癌患者P53Arg72Pro的基因多态性,用Warhin-starry染色法检测本研究对象的H pylori感染率.结果:H pylori感染率在胃癌组和对照组分别为68.6%,50.4%,H pylori感染率在两组间具有显著差异(OR=2.147,95%CI:1.302-3.541);P53Arg72Pro分为Arg/Arg,Arg/Pro,Pro/Pro3 种基因型,其频率在胃癌患者中分别为15.7%,60.0%,24.3%;在健康人群中分别为25.6%,54.4%,20.0%.与Arg/Arg基因型相比,Arg/Pro或Pro/Pro单独频率在2组间差异无统计学意义,但P53Pro等位基因(Arg/Pro+Pro/Pro)携带者在胃癌者和对照组间差异有统计学意义(OR=1.846;95%CI:1.006-3.387).分层分析提示H pylori阳性感染者或吸烟人群,若其同时携带有P53Pro等位基因,他们患胃癌的风险明显增加.结论:P53Arg72Pro位点基因多态性与我国胃癌高发区甘肃河西地区胃癌发病的风险相关,P53Pro等位基因与H pylori感染或吸烟因素有一定的协同作用.     

筛查幽门螺杆菌感染预防胃癌的费用效果分析

目的评价在人群中筛选幽门螺杆菌感染以预防胃癌的临床和经济学效果.方法用Markov模型估计在10万名40岁～45岁人群中筛查幽门螺杆菌感染者并对筛查试验阳性者进行治疗的远期效果及费用,并与不进行任何干预的结果相比较,进行卫生经济学评价.对治疗感染者减少胃癌发生危险度的有效率和胃癌发病率进行敏感性分析.结果在有效率为50%时,每筛查10万人可减少291例胃癌的发生,增加2612个生命年.当预防胃癌的有效率从5%到100%变化时,每增加一个生命年的费用从7747元下降到2325元,在胃癌高发区筛查更经济有效.结论筛查幽门螺杆菌感染是一种潜在的能减少胃癌发生的有效措施.     

胃癌及癌前病变组织中细胞凋亡和增殖的原位观察

肿瘤的发生发展是一个较长的、多步骤的过程,细胞凋亡和细胞增殖在其中起到重要作用．目前,对胃癌前各阶段病变及胃癌中细胞凋亡和增殖状态的比较研究未见报道．我们应用ＤＮＡ缺口末端标记（ＤＮＥＬ）技术［１］和增殖细胞核抗原（ＰＣＮＡ）免疫组化染色技术对正常胃粘膜、胃癌前病变及胃癌细胞凋亡和增殖状态进行动态观察和比较研究,以期揭示二者在胃癌发生发展过程中的变化规律和作用．１　材料和方法１．１　材料　辽宁庄河胃癌高发区高危人群接受内镜筛检者１３０例,其中包括基本正常胃粘膜２０例,慢性浅表性胃炎３０例,慢性萎…     

三种胃癌初筛方法在健康体检人群早期胃癌筛查中的对比研究

目的　比较血清幽门螺杆菌（HP）抗体联合胃蛋白酶原（PG）（即ABC法）、血清PG联合胃泌素‑17（G‑17）（即新ABC法）和新型胃癌筛查评分法,这3种胃癌初筛方法在健康体检人群早期胃癌筛查中的作用和效能。方法　对2019年1月—2021年12月在上海市松江区中心医院体检中心进行健康体检并行胃镜检查者行上述3种胃癌初筛,每种方法均分为低危人群、中危人群和高危人群,以胃镜和活检病理为金标准,计算3种筛查方法各危险分层的比例和胃癌的检出率,评价各筛查方法的优缺点。结果　完成健康体检和胃镜检查纳入研究者共3 199例。胃镜检出食管癌10例（0.31%）,均为早期食管癌;胃癌37例（1.16%）,其中早期胃癌者占86.49%（32/37）。采用3种胃癌初筛方法评估受检者胃癌风险,ABC法评为低危人群1 853例（7.92%）、中危人群1 339例（41.86%）、高危人群7例（0.22%）,胃癌检出率分别为0.97%（18/1 853）、1.42%（19/1 339）、0.00%;新ABC法评为低危人群2 362例（73.84%）、中危人群804例（25.13%）、高危人群33例（1.03%）,胃癌检出率分别1.14%（27/2 362）、1.24%（10/804）、0.00%;新型胃癌筛查评分法评为低危人群1 448例（45.26%）、中危人群1 213例（37.92%）、高危人群538例（16.82%）,胃癌检出率分别为0.28%（4/1 448）、1.32%（16/1 213）、3.16%（17/538）。中、高危人群合计的胃癌检出率明显大于低危人群,差异有统计学意义（χ2=17.935,P<0.001）。观察受试者工作特征（ROC）曲线下面积（AUC）,ABC法为0.546、新ABC法为0.503、新型胃癌筛查评分法为0.760,新型胃癌筛查评分法的AUC明显大于ABC法和新ABC法,差异均有统计学意义（P<0.001）。结论　新型胃癌筛查评分法中、高危人群的胃癌检出率高于低危人群,胃癌漏诊率低于ABC法和新ABC法,在健康体检人群的早期胃癌筛查中具有较高的价值。     

胃癌序贯筛查实施现场胃癌患者术后生存分析—11年随访

探讨胃癌序贯筛查法实施后手术治疗对胃癌患者生存率的影响。方法：参加胃癌序贯筛查的人群及作为对照的非筛查人群中发现胃癌并进行手术治疗的67例患者为研究对象,其中筛查组27例,非筛查组40例,自1987年随访至1997年,详细记录其生存时间等资料并进行生存分析。结果：胃癌筛查组患者术后5年及10年生存率均明显高于非筛查组患者、存在显著统计学差异（5年生存率：73．0％比34．5％,P＜0．05;10年生存率：69．0％比0,P＜0．05）。筛查组早期胃癌患者的比例亦明显高于非筛查组（63％比5％,P＜0．05）。结论：实施胃癌序贯筛查可以探查出更多的早期胃癌,手术治疗可以明显延长患者的生存时间。     

Testing for faecal calprotectin (PhiCal) in the Norwegian Colorectal Cancer Prevention trial on flexible sigmoidoscopy screening: comparison with an immunochemical test for occult blood (FlexSure OBT)

BACKGROUND: Screening for colorectal cancer (CRC) using guaiac based faecal occult blood tests (FOBT) has an estimated programme sensitivity of >60% but <30% for strictly asymptomatic CRC in a single screening round. In search for improved non-invasive tests for screening, we compared a test for faecal calprotectin (PhiCal) with a human haemoglobin immunochemical FOBT (FlexSure OBT). METHODS: In the Norwegian Colorectal Cancer Prevention (NORCCAP) trial, screenees in one screening arm were offered screening with combined flexible sigmoidoscopy (FS) and FlexSure OBT. They were also requested to bring a fresh frozen sample of stool for the PhiCal test which was performed on samples from screenees with CRC (n = 16), high risk adenoma (n = 195), low risk adenoma (n = 592), and no adenoma (n = 1518) (2321 screenees in total). A positive PhiCal test was defined by a calprotectin level > or =50 microg/g. RESULTS: The PhiCal test was positive in 24-27% of screenees whether they had no adenoma, low risk adenoma, or high risk adenoma. Ten (63%) of 16 CRCs gave a positive PhiCal test. The total positivity rate in this population was 25% for the PhiCal test compared with 12% for FlexSure OBT, with a sensitivity for advanced neoplasia of 27% and 35%, respectively. Specificity for "any neoplasia" was 76% for the PhiCal test and 90% for FlexSure OBT. CONCLUSIONS: In colorectal screening, the performance of the PhiCal test on a single spot from one stool sample was poorer than a single screening round with FlexSure OBT and cannot be recommended for population screening purposes. The findings indicate a place for FlexSure OBT in FOBT screening.     

Is gastric cancer part of the tumour spectrum of hereditary non-polyposis colorectal cancer? A molecular genetic study

BACKGROUND: Gastric cancer is the second most common extracolonic malignancy in individuals with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome. As gastric cancer is relatively common in the general population as well, it is not clear whether or not gastric cancer is a true HNPCC spectrum malignancy. AIM: To determine whether or not gastric cancer is a true HNPCC spectrum malignancy. Subjects and METHODS: The molecular and clinicopathological profiles of gastric cancers (n = 13) from HNPCC mutation carriers were evaluated and compared with the profiles of sporadic gastric cancers (n = 46) stratified by histology and microsatellite instability (MSI) status. RESULTS: This study on sporadic and HNPCC gastric cancers revealed several important universal associations. Loss of heterozygosity in the adenomatous polyposis coli (APC) region was associated with intestinal histology regardless of the MSI (p = 0.007). KRAS-mutations (p = 0.019) and frameshift mutations in repeat tracts of growth-regulatory genes (p<0.001) were associated with MSI tumours being absent in microsatellite stable (MSS) tumours. The average number of methylated tumour suppressor gene loci among the 24 genes studied (methylation index) was higher in MSI than in MSS tumours regardless of histology (p<0.001). Gastric cancers from HNPCC mutation carriers resembled sporadic intestinal MSI gastric cancers, except that MLH1 promoter methylation was absent (p<0.001) and the general methylation index was lower (p = 0.038), suggesting similar, but not identical, developmental pathways. All these lacked the mismatch repair protein corresponding to the germline mutation and displayed high MSI. CONCLUSION: The present molecular evidence, combined with the previous demonstration of an increased incidence relative to the general population, justify considering gastric cancers as true HNPCC spectrum malignancies.     

Natural history of early gastric cancer: a non-concurrent, long term, follow up study

BACKGROUND: Controversy has arisen on the natural history of early gastric cancer (EGC). While some emphasise the effectiveness of early detection in reducing mortality from gastric cancer, others insist that EGC is a pseudo-cancer. AIMS/PATIENTS/METHODS: To elucidate the natural history of EGC, a non-concurrent, long term, follow up study was conducted in 71 patients who were diagnosed endoscopically as having EGC, which was confirmed as cancer on biopsy, but in whom surgical resection was not conducted or delayed by more than six months. RESULTS: The natural course of EGC was observed in 56 cases. Over a period of 6-137 months, 20 remained in the early stage while 36 progressed to the advanced stage. The proportion remaining in the early stage consistently decreased with time. Median duration of those who remained in the early stage was estimated as 44 months. The cumulative five year risk for progressing to the advanced stage was 63.0%. In 38 cases there was no evidence for undergoing surgical resection for gastric cancer. The cumulative five year corrected survival was estimated as 62.8% among those unresected. Hazard rate ratio for gastric cancer mortality was 0.65 (p=0.34) for screening detected versus non-screening detected. Hazard rate ratio for gastric cancer mortality was 0.51, significantly lower for patients whose operations were delayed compared with those unresected. CONCLUSIONS: Although EGC showed a relatively long natural history in general, it progressed to the advanced stage with time and led to death from gastric cancer for the most part if left untreated.     

Diffuse submucosal cysts of the stomach: report of two cases in association with development of multiple gastric cancers during endoscopic follow up

BACKGROUND: Diffuse submucosal cysts of the stomach have been suggested as a predisposing condition for the development of gastric cancer, especially multiple cancers. We report here two cases of diffuse submucosal cysts of the stomach associated with multiple gastric cancers which were detected during endoscopic follow-up. METHODS AND RESULTS: The first patient was a 75-year-old man and the second patient was a 72-year-old man. In the first case, we performed an endoscopic examination every year and detected an advanced cancer and two early cancers on the fifth year of the follow up. Because one of these cancers was advanced, we examined the second patient endoscopically every six months. In this patient, we detected two early cancers after 1.5 years follow up. CONCLUSIONS: We suggest that patients with this disorder should be examined regularly by endoscopy for the detection of gastric cancer, preferably every six months.     

Early gastric neoplasms are significant risk factor for colorectal adenoma: A prospective case-control study

Although gastric cancer patients have a high incidence and risk of colorectal cancer, evidence is lacking regarding whether early gastric neoplasms (EGNs), such as gastric adenomas and early gastric cancer, are risk factors for colorectal adenoma. This study aimed to investigate the incidence of colorectal adenomas in patients with EGN.This prospective study was conducted between January 2015 and December 2016. Of the 307 patients who underwent gastric endoscopic submucosal dissection for EGN, 110 patients were enrolled in the EGN group, and 110 age- and sex-matched healthy persons from the screening population were included in the control group in a 1:1 ratio. Demographic factors and results of colonoscopy, including quality assessment, were collected, and analyzed.No significant differences in the quality of colonoscopy, including bowel preparation, cecal intubation rate, and withdrawal time between the 2 groups, were observed. The incidence of colorectal adenoma was significantly higher in the EGN group than in the control group (55.5% vs 26.4%, P = .001). Multivariate analysis confirmed that old age (odds ratio: 1.04, 95% confidence interval: 1.01–1.08, P = .005) and a history of EGN (odds ratio: 4.99, 95% confidence interval: 2.60–9.57, P = .001) were independent risk factors for colorectal adenoma.This is the first prospective study to reflect the quality indicator of colonoscopy and confirmed that old age and a history of EGN are significant risk factors for colorectal adenomas. Therefore, more stringent colonoscopy surveillance should be considered in elderly patients with EGN.     

Randomized study on early detection of lung cancer with MSCT in Germany: study design and results of the first screening round

Purpose

Low-dose multislice-CT (MSCT) detects many early-stage lung cancers with good prognosis, but whether it decreases lung cancer mortality and at which costs is yet insufficiently explored. Scope of the present study is to examine within a common European effort whether MSCT screening is capable to reduce the lung cancer mortality by at least 20?% and at which amount of undesired side effects this could be achieved.

Methods

Overall 4,052 heavy smoking men and women were recruited by a population-based approach and randomized into a screening arm with five annual MSCT screens and an initial quit-smoking counseling, and a control arm with initial quit-smoking counseling and five annual questionnaire inquiries.

Results

In the first screening round, 2,029 participants received a MSCT providing 1,488 negative and 540 suspicious screens with early recalls (early recall rate 26.6?%) leading to 31 biopsies (biopsy rate 1.5?%) and 22 confirmed lung cancers (detection rate 1.1?%). Among the lung cancers, 15 were adenocarcinomas, 3 squamous cell carcinomas, one small-cell lung cancer, and 3 others, whereby 18 were in clinical stage I, one in stage II, and 3 in stage III. One interval cancer occurred.

Conclusions

The indicated performance indicators fit into the range observed in comparable trials. The study continues finalizing the second screening round and for the first participants even the last screening round. The unresolved issue of the precise amount of side effects and the high early recall rate precludes currently the recommendation of MSCT as screening tool for lung cancer.     

Occurrence of second primary malignancies in patients with neuroendocrine tumors of the digestive tract and pancreas

An increased association between neuroendocrine tumors of the gastrointestinal tract and pancreas (GEP-NET) and other second primary malignancies has been suggested. We determined whether there is indeed an increased risk for second primary malignancies in GEP-NET patients compared with an age- and sex-matched control group of patients with identical malignancies. The series comprised 243 men and 216 women, diagnosed with a GEP-NET between 2000 and 2009 in a tertiary referral center. The timeline, before-at-after diagnosis, and the type of other malignancies were studied using person-year methodology. Poisson distributions were used for testing statistical significance. All data were cross-checked with the Dutch National Cancer Registry. Out of 459 patients with GEP-NET, 67 (13.7%) had a second primary cancer diagnosis: 25 previous cancers (5.4%), 13 synchronous cancers (2.8%), and 29 metachronous cancers (6.3%). The most common types of second primary cancer were breast cancer (n=10), colorectal cancer (n=8), melanoma (n=6), and prostate cancer (n=5). The number of patients with a cancer history was lower than expected, although not significant (n=25 vs n=34.5). The diagnosis of synchronous cancers, mainly colorectal tumors, was higher than expected (n=13 vs n=6.1, P<0.05). Metachronous tumors occurred as frequent as expected (n=29 vs n=25.2, NS). In conclusion, our results are in contrast to previous studies and demonstrate that only the occurrence of synchronous second primary malignancies, mainly colorectal cancers, is increased in GEP-NET patients compared with the general population.     

Implications of serum pepsinogen I in early endoscopic diagnosis of gastric cancer and dysplasia. Helsinki Gastritis Study Group

BACKGROUND and AIMS: The risk of gastric cancer (GCA) is increased in atrophic gastritis. A low serum pepsinogen group I (SPGI) level is a good serologic indicator of atrophic gastritis of the gastric corpus and fundus, and can be used for diagnosis of subjects with atrophic gastritis and of increased risk for GCA. The present study was undertaken to investigate whether SPGI assay and a diagnostic gastroscopy could enable the diagnosis of GCA at an early stage. MATERIAL and METHODS: The study was carried out as part of the Alpha-Tocopherol, Beta-Carotene Cancer prevention study (ATBC study) in Finland, in which 22,436 male smokers aged 50-69 years were screened by SPGI. Low SPGI levels (< 25 microg/l) were found in 2196 (9.8%) men. Upper GI endoscopy (gastroscopy) was performed in 1344 men (61%) and 78% of these had moderate or severe atrophic corpus gastritis in endoscopic biopsies. A control series of 136 men from the ATBC study cohort with abdominal symptoms, but with SPGI > or = 50 microg/l were similarly endoscopied, and 2.2% of these had corpus atrophy. RESULTS: Neoplastic alterations were found in 63 (4.7%; 95% CI: 3.6%-5.8%) of the 1344 endoscopied men with low SPGI levels. Of these, 42 were definite dysplasias of low grade, 7 dysplasias of high grade, 11 invasive carcinomas, of which 7 were 'early' cancers, and 3 carcinoid tumors. In the control series, 1 man (0.7%) of the 136 men had a definite low-grade dysplasia. Thus, 18 (1.3%; 95% CI 0.7%-2.0%) cases with 'severe' neoplastic lesions (4 advanced cancers, 7 early cancers and 7 dysplasias of high grade) were found in the low SPGI group, but there were none in the control group. All four patients with advanced cancer died from the malignancy within 5 years (mean survival time 2.5 years), whereas surgical treatment in all those with early cancer or high-grade dysplasia was curative. One of the seven patients with early cancer and two of the seven with high-grade dysplasia died within 5 years, but none died from the gastric cancer. Thus, curative treatment was given to 14 of 18 men in whom a malignant lesion was found in gastroscopy. This is about 15% of all gastric cancer cases (92 cases) which were diagnosed within 5 years after SPGI screening in the 22,436 men. Among the gastric cancer cases of the main ATBC study, the 5-year survival rate was 33% (85% of the non-survivors died from gastric cancer). CONCLUSIONS: We conclude that assay of SPGI followed by endoscopy is an approach which can enable the early diagnosis of gastric cancer at a curable stage.     

Clinicopathological study of early cancer-like advanced gastric cancer

We had clinicopathologically studied early cancer-like advanced gastric cancer in relation to peptic ulcer (UI). Early cancer-like advanced cancers with the difficulty to distinguish from early gastric cancer were selected for materials. Result were as followed: 1) Early cancer-like advanced cancers were consisted of 133 lesions, of which 128 lesions (96.2%) had peptic ulcer in cancerous lesion (73 lesions were active stage and 55 lesions were scarring stage). 2) Early cancer-like advanced cancers were 17.0% in all advanced gastric cancers. Proper muscle cancer (in which depth of cancerous invasion is up to proper muscle coat) was more common in early cancer-like advanced cancers than in Borrmann type advanced cancers. 3) Early cancer-like advanced cancers with peptic ulcer showed wide intramucosal cancerous infiltration. Thus, average of maximum diameter was 51.8 mm. 4) Those ulcer were commonly reaching to proper muscle coat or subserosa. Submucosal fibrosis was prominent and scattered proliferation of tumor cells were often seen within fibrosis. 5) Extent of cancerous infiltration in mucosa was more wide than that in submucosa. The above findings have led us to consider that early cancer-like advanced cancers have grown because of high degree submucosal fibrosis by the deep ulcerations due to "malignant cycle".