共聚焦激光显微内镜对胃粘膜肠上皮化生的诊断价值
|
摘要
研究背景和目的
胃癌是世界范围内死亡率高居第二位的肿瘤性疾病。胃粘膜的肠上皮化生(gastric intestinal metaplasia,GIM)是肠型胃癌的危险因素,被认为是肠型胃癌的癌前期病变。若能及早通过内镜下识别和治疗使其病变逆转,不失为防治胃癌的有效途径。由于GIM的多灶性分布,在普通内镜及其他内镜下表现缺乏特异性,胃镜下诊断与组织学诊断的一致性较差,目前尚无明确定义的内镜下诊断标准,仍需依靠活组织病理学诊断才能最终确诊。
共聚焦激光显微内镜(confocal laser endomicroscopy,CLE)是最新开发出来的内镜,是在传统的可视内镜的顶端安装了共聚焦激光显微镜,是共聚焦激光显微镜和传统电子内镜的有机结合体,除作标准电子内镜检查外,还能进行共聚焦显微镜检查,模拟体内表面下结构的组织学图像,在内镜检查的同时获得消化道上皮及上皮下高度放大的横切面的图像,对粘膜和粘膜下层做即时的高分辨率的组织学诊断,达到光学活检的目的。与其他光学技术相比,CLE的优势在于它不仅使上皮表面成像,而且可使上皮下成像。这种放大1000倍的图像可清晰辨认组织结构、细胞及亚细胞结构,做即时的高分辨率的组织学诊断。
本研究拟在应用CLE识别正常胃粘膜及GIM时的各种细胞及亚细胞结构,制定GIM共聚焦图像下的诊断、分型和分级标准,并以病理诊断作为金标准评价其诊断效率,最后应用CLE诊断GIM的范围和分布,全面评估CLE对GIM的诊断价值。
材料和方法
1共聚焦激光显微内镜对肠上皮化生细胞及亚细胞结构的识别
采用日本Pentax EC3870KCLE,荧光素钠和吖啶黄素为对比剂。选取28位已知GIM的患者,分别对患者食道、胃及十二指肠粘膜进行共聚焦激光扫描。在正常食道可见食管鳞状上皮细胞,应用吖啶黄素后可见清晰的细胞核。为确认鳞状上皮细胞及细胞核,同时进行了食管鳞状上皮细胞体外培养,吖啶黄素染色,再用CLE观察确定。正常胃粘膜可见正常的胃粘膜柱状上皮,肠化部位可见除可见杯状细胞外,可见细长而色泽明亮的柱状上皮细胞,并在柱状上皮细胞表面可见一条清晰而黑色的线。十二指肠粘膜可见细长而明亮的柱状上皮细胞及杯状细胞。观察后分别进行活检,进行常规病理组织学检查、HID/AB和AB/PAS组织化学染色、CD10免疫组化检查、透射电镜和扫描电镜检查。
2共聚焦激光显微内镜下胃粘膜肠上皮化生诊断标准的制定及评价
第一阶段选取已知GIM的病人用CLE检查,确定在CLE下GIM的诊断标准。第二阶段再选取慢性胃炎或怀疑有GIM的患者进行CLE检查,首先普通内镜观察,判断是否存在GIM,然后用CLE扫描观察,根据CLE标准进行诊断,病理诊断作为金标准评估其诊断效率。
3共聚焦激光显微内镜对胃粘膜肠上皮化生分级和分型的诊断
第一阶段选取已知GIM的病人用CLE检查,确定在CLE下GIM的分型和分级诊断标准。第二阶段再选取怀疑有GIM患者进行CLE检查,根据CLE诊断标准诊断其分型和分级,组织病理诊断为金标准,评估其诊断效率,并对几种胃癌相关基因进行了检测。
4共聚焦激光显微内镜对胃粘膜肠上皮化生范围和程度的诊断
选取慢性胃炎和可疑胃癌伴有GIM患者,应用CLE扫描观察每位患者胃粘膜的11个部位,即时诊断是否有GIM,并对阳性部位活检。根据GIM的阳性部位数,分为局灶性、多灶性和广泛性GIM;根据GIM的分布分为局灶型、胃窦型、小弯型和弥漫型。评价不同范围和分布方式的GIM与胃癌及其他癌前病变的关系。
结果
1分别对28位已知GIM的患者的124个部位进行共聚焦扫描,获得5750幅图像。共聚焦显微内镜可以容易识别在体的食管正常鳞状上皮细胞及其细胞核,与体外培养鳞状上皮细胞吖啶黄素染色后观察一致,与病理检查一致。胃内正常的胃粘膜柱状上皮在共聚焦激光显微内镜图像上为典型的铺路石样改变。杯状细胞表现为大而黑色的细胞,散布于柱状排列的上皮细胞之间,有特异的形态学特征,易于识别。肠化部位及十二指肠出现的细长色泽明亮的细胞为吸收上皮细胞,HID-AB和AB-PAS粘液染色中不着色,与杯状细胞和正常胃柱状吸收上皮细胞明显不同,细胞表面清晰而黑色线CD10免疫组化染色为阳性,在扫描电镜及透射电镜可证实为吸收上皮细胞及刷状缘。
2 GIM在CLE下的诊断标准是,如果在共聚焦图像下出现以下三个特征之一即可诊断为该部位存在GIM:1)存在杯状细胞,表现为大而黑色的细胞;2)存在柱状吸收细胞和刷状缘,特征是比胃粘膜柱状上皮细胞细长而色泽明亮的细胞,刷状缘表现为上皮细胞的表面一条清晰而黑色的线;3)胃小凹呈绒毛状改变。在第二阶段的研究中,共有53位病人接受CLE检查,扫描了267个部位。其中36位病人的160个部位被组织病理诊断为GIM,普通内镜及CLE对GIM的诊断敏感性分别是36.88%和98.13%,特异性分别是91.59%和95.33%,阳性预测值分别是86.76%和96.91%,隐性预测值分别是49.25%和97.14%,普通内镜及CLE与病理诊断的一致性检验中,K值分别是0.25和0.94。
3 GIM在CLE下,根据杯状细胞的形态、是否存在吸收上皮细胞或刷状缘、胃小凹和固有层血管形态进一步被分为完全型和不完全型。根据肠化面积的多少分为轻中重度GIM。共有53位病人接受CLE检查,扫描了267个部位。在CLE诊断的98处完全型GIM中,有83处得到组织学的证实,CLE对完全型GIM诊断的敏感性、特异性、阳性预测值和阴性预测值分别是68.03%、89.66%、84.69%和76.92%;在在CLE诊断的64处不完全型GIM中,有26处得到组织学的证实,CLE对不完全型GIM诊断的敏感性、特异性、阳性预测值和阴性预测值分别是68.42%、83.41%、40.63%和94.09%。CLE与病理分型诊断的κ值是0.67。在可以进行GIM分级诊断的146个部位中,88个部位诊断为轻度GIM,其中的74个部位得到病理的证实;33个部位被CLE诊断为中度,其中的25个与病理诊断一致;25个被CLE诊断为重度的部位中,20个也得到病理诊断的证实。共聚焦激光显微内镜对轻度GIM诊断的敏感性和特异性分别是90.2%和78.1%,对中度GIM诊断的敏感性和特异性分别是69.4%和92.7%,对重度GIM诊断的敏感性和特异性分别是71.4%和95.8%。CLE与病理进行GIM轻、中、重度分级诊断的K值分别是0.69、0.64和0.70,具有较好的一致性。胃癌相关基因CDX2、Ki67及APC在不同亚型及不同严重程度GIM中有不同的表达。
4共70位确诊为慢性胃炎和胃癌伴有GIM患者入选本研究,47.1%的患者GIM范围为局灶性,41.4%为多灶性,11.4%为广泛性。GIM的范围与胃癌及癌前病变有密切关系,多发性和广泛性GIM伴有更多的胃粘膜萎缩,广泛性GIM更多提示了不典型增生和胃癌。37.1%患者GIM为局灶型分布,21.4%为胃窦型,31.4%为小弯型,10.0%为弥漫型分布。GIM的分布与胃癌及癌前病变有密切关系,小弯型和弥漫型分布伴有更多的不典型增生和胃癌。
结论
CLE是一种新开发的诊断工具,可以在内镜检查的同时提供即时可靠的组织学诊断。它可以准确识别正常及GIM时的多种细胞及亚细胞结构,可以非常准确地诊断GIM,并可进行分型、分级诊断,也可以判断GIM的范围和分布方式。
意义
CLE是一种新开发的诊断工具,可以在内镜检查的同时提供即时可靠的组织学诊断,CLE可以非常准确地诊断GIM及分型、分级,判断其范围和分布。GIM是肠型胃癌的危险因素,但多数GIM是癌前状态,而非癌前病变。本研究评价了CLE在筛选和检测GIM这一癌前病变中的作用,可以为患者提供这一病变发展成为胃癌的危险性和随防计划。CLE是光学活检领域内革命性的创新技术,这种全新的诊断工具,观察到的图像毫无疑问使内镜检查进入了一个新的时代,标志着内镜检查从表层走向深层,从形态学迈向组织学的质变。可以预测,CLE将在胃肠内镜方面发挥非常重要的诊断作用。
Background and aims
Gastric cancer is the second leading cause of cancer related mortality worldwide. Gastric intestinal metaplasia(GIM)is a risk factor that leads to the development of intestinal-type gastric cancer and is generally regarded as a precancerous condition.If
GIM was identified under endoscope earlier,effective strategies could be developed to detect the early,curable phase of gastric cancer and prevent its progression.GIM is multifocal and is mostly indistinguishable by the conventional endoscopy or even by other new endoscopic techniques.Conventional endoscopic identification of intestinal metaplasia has a high rate of interobserver variability and correlates poorly with the histological finding.None of them can distinguish the structure of individual cells,or allow the endoscopic criteria of GIM to be defined. Histologic analysis of biopsy material remains the gold standard for the final diagnosis of GIM.
Recently,confocal laser endomicroscopy(CLE)has been developed which is integration of a confocal laser microscope in the distal tip of a conventional videoendoscope.The components enable confocal microscopy in addition to standard videoendoscopy.The new device can provide real-time,high magnification, cross-sectional images of the gastrointestinal epithelium during routine endoscopy without the need for biopsy and thus histopathology has been termed optical biopsy. Compared with other new optics techniques,the greatest advantage of the CLE is that it can enables surface and subsurface imaging of living cells in the mucosa during ongoing colonoscopy.The confocal images that approximately 1000-fold magnification readily permits single cells in the gastrointestinal tract to be resolved.
The aim of this study were to determine if CLE could identify cells and subcellular structures of normal and intestinal metaplasia mucosa,definite the confocal criteria of GIM,definite the criteria of its grading and subtype,and evaluate the efficacy of CLE for the extent and topographic patterns of GIM assessment in vivo.
Methods
1 Identification of cells and subcellular structures in gastric intestinal metaplasia by confocal laser endomicroscopy
Patients with known GIM underwent CLE(Pentax EC-3870K;Pentax,Tokyo, Japan).Fluorescein sodium and acriflavine hydrochloride was used as contrast agent. Esophagus,stomach and duodenum were examined with the CLE system.In normal esophagus,squamous epithelial cell showed rhombus single cells at high resolution with clear visible borders.The nucleus can be stained clearly with acriflavine hydrochloride.Furthermore,squamous epithelial cells were cultured and observed with CLE in vitro for identification.Gastric type columnar epithelial cells and mucin-containing goblet cells can easily recognized in stomach under CLE images.In some areas,a more slender,and brighter than columnar epithelial cells of normal gastric mucosa can be seen with a clear dark line at the surface of the epithelium. These cells and structures also are seen in duodenum.The histologic specimens from each site were compared with the targeted confocal images.All of the biopsy specimens were sectioned vertically and transversely to facilitate the comparison between histology and confocal images.All the biopsy specimens were stained with hematoxylin and eosin.Biopsy specimens diagnosed as GIM and duodenum were further stained by AB-PAS mucin staining,HID-AB mucin staining and CD10 immunohistochemistry.These slender and brighter cells and the clear dark line at the surface of the epithelium were identified with scanning electron microscope(SEM) and transmission electron microscope(TEM).
2 Definition and evaluation of gastric intestinal metaplasia with confocal laser endomicroscopy in Vivo
In first phase,28 patients with known GIM underwent CLE,and CLE criteria for diagnosis of GIM were developed.In addition,53 consecutive patients with known or suspected GIM were prospectively evaluated in second phase.Standard and abnormal appearance areas were examined with the CLE system.Fluorescein was used as contrast agent.Afterwards,a targeted biopsy was done at the same sites.The results of histoathological biopsy specimens taken from the corresponding sites of gastric mucosa under CLE were regarded as gold standard.
3 Diagnostic value of confocal laser endomicroscopy for the prediction of the subtype and grading of gastric intestinal metaplasia
In first phase,28 patients with known GIM underwent CLE,and CLE criteria for classifying and grading GIM were developed.In addition,53 consecutive patients with known or suspected GIM were prospectively evaluated in second phase. Standard and abnormal appearance areas were examined with the CLE system. Fluorescein was used as contrast agent.Afterwards,a targeted biopsy was done at the same sites.The results of histoathological biopsy specimens taken from the corresponding sites of gastric mucosa under CLE were regarded as gold standard.The expression of three gastric carcinoma related gene were detected in different subtype and severity GIM.
4 Diagnostic value of confocal laser endomicroscopy for the prediction of the extent and topographic patterns of gastric intestinal metaplasia
Seventy patients with known GIM underwent CLE.Fluorescein was used as contrast agent.Endoscopic gastric biopsy specimens were obtained using a jumbo forceps from the 11 gastric sites.Five specimens were from the antrum,six from the corpus and one from the incisura angularis.The presence of GIM was made immediately by the endoscopist at the time of the procedure.The extent of GIM was categoried focal,multifocal and extensive GIM.Four topographical patterns of intestinalization emerged:"Focal,","Antrum-predominant,Magenstraβe" and "Diffuse,".The histological evaluation remains the gold standard for the final diagnosis of intestinal metaplasia.
Results
1 All of 28 patients under went CLE with known GIM.A total of 5750 CLE images were obtained from 124 areas under CLE images.The confocal images showed the normal squamous epithelial cells their nucleus on the surface of the esophagus at high resolution in vivo.These patterns can be directly compared with cultured cells in vitro and H&E-stained sections of biopsy specimens cut parallel to the tissue surface.At the surface of the stomach,epithelium a typical cobblestone structure.The mucin-containing goblet cells showed very dark and big within the columnar-lined epithelium.Goblet cells had specific appearance and easily recognized.The more slender and brighter than columnar epithelial cells of normal gastric mucosa were identified as absorptive columnar epithelial cells.These cells were colorless by AB/PAS and HID/AB mucin staining,difference from goblet cells (blue)and gastric epithilum(purple).The clear dark line at the surface of the epithelium were identified as brush border by CD 10 immunohistochemistry,SEM and TEM.
2 GIM was identified if any of the following three features were present in an image field:goblet cells,columnar absorptive cells and brush border,and villiform foveolar epithelium.In a prospective study,a total 267 sites from 53 patients were obtained.160 from 36 patients were diagnosed histopathologically as GIM.The sensitivities of conventional endoscopy and CLE for GIM were 36.88%vs.98.13%, the specificities were 91.59%vs.95.33%,the positive predictive value were 86.76% vs.96.91%,and the negative predictive value were 49.25%vs.97.14%,respectively. The kappa value for the correlation with histological findings was 0.25 for conventional endoscopy vs.0.94 for CLE.
3 In the CLE images,GIM was classified as complete or incomplete,according to the shape of goblet cells,the presence of absorptive cells or brush border,and the architecture of vessels and crypts.In a prospective study,a total 267 sites from 53 patients were obtained.Among the 98 sites with complete GIM according to CLE, this was confirmed in 83 by histopathology.The sensitivity,specificity,positive predictive value and negative predictive value of CLE for the diagnosis of complete GIM were 68.03%,89.66%,84.69%and 76.92%,respectively.Among the 64 sites with incomplete GIM according to CLE,this was confirmed histologically in 26.The sensitivity,specificity,positive predictive value and negative predictive value of CLE for the diagnosis of incomplete GIM were 68.42%,83.41%,40.63%and 94.09%, respectively.The kappa score for the agreement between CLE and histopathology was 0.67.Among 146 GIM positive areas,88 were identified as mild GIM by CLE,in which 74 confirmed by histopathology.Thirty-thee areas were diagnosed as moderate GIM by CLE,25 of them were confirmed by histopathology.Twenty-eight areas were diagnosed as marked GIM by CLE,20 of them were confirmed by histopathology. The sensitivity and specificity of CLE were 90.2%and 78.1%for the diagnosis of mild GIM,69.4%and 92.2%for morderate GIM,71.4%and 95.8%for marked GIM,respectively.The kappa coefficient of CLE criteria and the histopathological grading for mild,moderate and marked IM were 0.69,0.64 and 0.70,respectively. There were differences for the expression of CDX2,Ki67 and APC among different subtype and severity GIM.
4 A total of 70 gastric carcinoma and chronic atrophy gastritis patients with GIM were recruited.47.1%of them were focal GIM,41.4%were multifocal GIM and 11.4%were extensive GIM.The extent of GIM is associated with the gastric cancer and associated with lesion precancerous.Multifocal GIM and ententive GIM was significantly associated with the presence of cancer and gastric atrophy.Extensive GIM was significantly associated with the presence of cancer and dysplasia.Of the entire study population of 70 subjects,37.1%of them were focal pattern,21.4% were antrum-predominant pattern,31.4%of them were Magenstraβe pattern,10.0% of them were diffuse pattern.The topographic patterns of GIM is associated with gastric cancer and lesion precancerous.MagenstraBe and diffuse topographic patterns was significantly associated with the presence of cancer and dysplasia.
Conclusion:
Confocal laser endomicroscopy is a newly developed diagnostic tool and may offer an instant and reliable diagnostic tool for in vivo histology.CLE can identify cells and subcellular structures in normal gastric mucosa and GIM at high resolution in vivo,enable classification,grading,extent and topographic patterns of GIM with high accuracy during ongoing endoscopy.
Significance
Confocal laser endomicroscopy is a newly developed diagnostic tool and may offer an instant and reliable diagnostic tool for in vivo histology.CLE can diagnose GIM with high accuracy during ongoing endoscopy,as well as its grading and subtype. The extent and topographic patterns of GIM also be evaluated.GIM is a risk factor that leads to the development of intestinal-type gastric cancer and is generally regarded as a precancerous condition.Most GIMs are only "precancerous conditions" rather than "precancerous lesions".This present study will help determine the role of CLE in screening and surveillance of premalignant conditions.It could serve as a reasonably good predictor of cancer risk and provide appropriate follow-up in an individual patient.Endoscopic confocal imaging systems are revolutionary instruments in the emerging realm of optical biopsy techniques.The new detailed images seen with CLE unequivocally are the beginning of a new era.It is tempting to speculate that CLE will play an important diagnostic role in the future during gastrointestinal endoscopy.
胃癌是世界范围内死亡率高居第二位的肿瘤性疾病。胃粘膜的肠上皮化生(gastric intestinal metaplasia,GIM)是肠型胃癌的危险因素,被认为是肠型胃癌的癌前期病变。若能及早通过内镜下识别和治疗使其病变逆转,不失为防治胃癌的有效途径。由于GIM的多灶性分布,在普通内镜及其他内镜下表现缺乏特异性,胃镜下诊断与组织学诊断的一致性较差,目前尚无明确定义的内镜下诊断标准,仍需依靠活组织病理学诊断才能最终确诊。
共聚焦激光显微内镜(confocal laser endomicroscopy,CLE)是最新开发出来的内镜,是在传统的可视内镜的顶端安装了共聚焦激光显微镜,是共聚焦激光显微镜和传统电子内镜的有机结合体,除作标准电子内镜检查外,还能进行共聚焦显微镜检查,模拟体内表面下结构的组织学图像,在内镜检查的同时获得消化道上皮及上皮下高度放大的横切面的图像,对粘膜和粘膜下层做即时的高分辨率的组织学诊断,达到光学活检的目的。与其他光学技术相比,CLE的优势在于它不仅使上皮表面成像,而且可使上皮下成像。这种放大1000倍的图像可清晰辨认组织结构、细胞及亚细胞结构,做即时的高分辨率的组织学诊断。
本研究拟在应用CLE识别正常胃粘膜及GIM时的各种细胞及亚细胞结构,制定GIM共聚焦图像下的诊断、分型和分级标准,并以病理诊断作为金标准评价其诊断效率,最后应用CLE诊断GIM的范围和分布,全面评估CLE对GIM的诊断价值。
材料和方法
1共聚焦激光显微内镜对肠上皮化生细胞及亚细胞结构的识别
采用日本Pentax EC3870KCLE,荧光素钠和吖啶黄素为对比剂。选取28位已知GIM的患者,分别对患者食道、胃及十二指肠粘膜进行共聚焦激光扫描。在正常食道可见食管鳞状上皮细胞,应用吖啶黄素后可见清晰的细胞核。为确认鳞状上皮细胞及细胞核,同时进行了食管鳞状上皮细胞体外培养,吖啶黄素染色,再用CLE观察确定。正常胃粘膜可见正常的胃粘膜柱状上皮,肠化部位可见除可见杯状细胞外,可见细长而色泽明亮的柱状上皮细胞,并在柱状上皮细胞表面可见一条清晰而黑色的线。十二指肠粘膜可见细长而明亮的柱状上皮细胞及杯状细胞。观察后分别进行活检,进行常规病理组织学检查、HID/AB和AB/PAS组织化学染色、CD10免疫组化检查、透射电镜和扫描电镜检查。
2共聚焦激光显微内镜下胃粘膜肠上皮化生诊断标准的制定及评价
第一阶段选取已知GIM的病人用CLE检查,确定在CLE下GIM的诊断标准。第二阶段再选取慢性胃炎或怀疑有GIM的患者进行CLE检查,首先普通内镜观察,判断是否存在GIM,然后用CLE扫描观察,根据CLE标准进行诊断,病理诊断作为金标准评估其诊断效率。
3共聚焦激光显微内镜对胃粘膜肠上皮化生分级和分型的诊断
第一阶段选取已知GIM的病人用CLE检查,确定在CLE下GIM的分型和分级诊断标准。第二阶段再选取怀疑有GIM患者进行CLE检查,根据CLE诊断标准诊断其分型和分级,组织病理诊断为金标准,评估其诊断效率,并对几种胃癌相关基因进行了检测。
4共聚焦激光显微内镜对胃粘膜肠上皮化生范围和程度的诊断
选取慢性胃炎和可疑胃癌伴有GIM患者,应用CLE扫描观察每位患者胃粘膜的11个部位,即时诊断是否有GIM,并对阳性部位活检。根据GIM的阳性部位数,分为局灶性、多灶性和广泛性GIM;根据GIM的分布分为局灶型、胃窦型、小弯型和弥漫型。评价不同范围和分布方式的GIM与胃癌及其他癌前病变的关系。
结果
1分别对28位已知GIM的患者的124个部位进行共聚焦扫描,获得5750幅图像。共聚焦显微内镜可以容易识别在体的食管正常鳞状上皮细胞及其细胞核,与体外培养鳞状上皮细胞吖啶黄素染色后观察一致,与病理检查一致。胃内正常的胃粘膜柱状上皮在共聚焦激光显微内镜图像上为典型的铺路石样改变。杯状细胞表现为大而黑色的细胞,散布于柱状排列的上皮细胞之间,有特异的形态学特征,易于识别。肠化部位及十二指肠出现的细长色泽明亮的细胞为吸收上皮细胞,HID-AB和AB-PAS粘液染色中不着色,与杯状细胞和正常胃柱状吸收上皮细胞明显不同,细胞表面清晰而黑色线CD10免疫组化染色为阳性,在扫描电镜及透射电镜可证实为吸收上皮细胞及刷状缘。
2 GIM在CLE下的诊断标准是,如果在共聚焦图像下出现以下三个特征之一即可诊断为该部位存在GIM:1)存在杯状细胞,表现为大而黑色的细胞;2)存在柱状吸收细胞和刷状缘,特征是比胃粘膜柱状上皮细胞细长而色泽明亮的细胞,刷状缘表现为上皮细胞的表面一条清晰而黑色的线;3)胃小凹呈绒毛状改变。在第二阶段的研究中,共有53位病人接受CLE检查,扫描了267个部位。其中36位病人的160个部位被组织病理诊断为GIM,普通内镜及CLE对GIM的诊断敏感性分别是36.88%和98.13%,特异性分别是91.59%和95.33%,阳性预测值分别是86.76%和96.91%,隐性预测值分别是49.25%和97.14%,普通内镜及CLE与病理诊断的一致性检验中,K值分别是0.25和0.94。
3 GIM在CLE下,根据杯状细胞的形态、是否存在吸收上皮细胞或刷状缘、胃小凹和固有层血管形态进一步被分为完全型和不完全型。根据肠化面积的多少分为轻中重度GIM。共有53位病人接受CLE检查,扫描了267个部位。在CLE诊断的98处完全型GIM中,有83处得到组织学的证实,CLE对完全型GIM诊断的敏感性、特异性、阳性预测值和阴性预测值分别是68.03%、89.66%、84.69%和76.92%;在在CLE诊断的64处不完全型GIM中,有26处得到组织学的证实,CLE对不完全型GIM诊断的敏感性、特异性、阳性预测值和阴性预测值分别是68.42%、83.41%、40.63%和94.09%。CLE与病理分型诊断的κ值是0.67。在可以进行GIM分级诊断的146个部位中,88个部位诊断为轻度GIM,其中的74个部位得到病理的证实;33个部位被CLE诊断为中度,其中的25个与病理诊断一致;25个被CLE诊断为重度的部位中,20个也得到病理诊断的证实。共聚焦激光显微内镜对轻度GIM诊断的敏感性和特异性分别是90.2%和78.1%,对中度GIM诊断的敏感性和特异性分别是69.4%和92.7%,对重度GIM诊断的敏感性和特异性分别是71.4%和95.8%。CLE与病理进行GIM轻、中、重度分级诊断的K值分别是0.69、0.64和0.70,具有较好的一致性。胃癌相关基因CDX2、Ki67及APC在不同亚型及不同严重程度GIM中有不同的表达。
4共70位确诊为慢性胃炎和胃癌伴有GIM患者入选本研究,47.1%的患者GIM范围为局灶性,41.4%为多灶性,11.4%为广泛性。GIM的范围与胃癌及癌前病变有密切关系,多发性和广泛性GIM伴有更多的胃粘膜萎缩,广泛性GIM更多提示了不典型增生和胃癌。37.1%患者GIM为局灶型分布,21.4%为胃窦型,31.4%为小弯型,10.0%为弥漫型分布。GIM的分布与胃癌及癌前病变有密切关系,小弯型和弥漫型分布伴有更多的不典型增生和胃癌。
结论
CLE是一种新开发的诊断工具,可以在内镜检查的同时提供即时可靠的组织学诊断。它可以准确识别正常及GIM时的多种细胞及亚细胞结构,可以非常准确地诊断GIM,并可进行分型、分级诊断,也可以判断GIM的范围和分布方式。
意义
CLE是一种新开发的诊断工具,可以在内镜检查的同时提供即时可靠的组织学诊断,CLE可以非常准确地诊断GIM及分型、分级,判断其范围和分布。GIM是肠型胃癌的危险因素,但多数GIM是癌前状态,而非癌前病变。本研究评价了CLE在筛选和检测GIM这一癌前病变中的作用,可以为患者提供这一病变发展成为胃癌的危险性和随防计划。CLE是光学活检领域内革命性的创新技术,这种全新的诊断工具,观察到的图像毫无疑问使内镜检查进入了一个新的时代,标志着内镜检查从表层走向深层,从形态学迈向组织学的质变。可以预测,CLE将在胃肠内镜方面发挥非常重要的诊断作用。
Background and aims
Gastric cancer is the second leading cause of cancer related mortality worldwide. Gastric intestinal metaplasia(GIM)is a risk factor that leads to the development of intestinal-type gastric cancer and is generally regarded as a precancerous condition.If
GIM was identified under endoscope earlier,effective strategies could be developed to detect the early,curable phase of gastric cancer and prevent its progression.GIM is multifocal and is mostly indistinguishable by the conventional endoscopy or even by other new endoscopic techniques.Conventional endoscopic identification of intestinal metaplasia has a high rate of interobserver variability and correlates poorly with the histological finding.None of them can distinguish the structure of individual cells,or allow the endoscopic criteria of GIM to be defined. Histologic analysis of biopsy material remains the gold standard for the final diagnosis of GIM.
Recently,confocal laser endomicroscopy(CLE)has been developed which is integration of a confocal laser microscope in the distal tip of a conventional videoendoscope.The components enable confocal microscopy in addition to standard videoendoscopy.The new device can provide real-time,high magnification, cross-sectional images of the gastrointestinal epithelium during routine endoscopy without the need for biopsy and thus histopathology has been termed optical biopsy. Compared with other new optics techniques,the greatest advantage of the CLE is that it can enables surface and subsurface imaging of living cells in the mucosa during ongoing colonoscopy.The confocal images that approximately 1000-fold magnification readily permits single cells in the gastrointestinal tract to be resolved.
The aim of this study were to determine if CLE could identify cells and subcellular structures of normal and intestinal metaplasia mucosa,definite the confocal criteria of GIM,definite the criteria of its grading and subtype,and evaluate the efficacy of CLE for the extent and topographic patterns of GIM assessment in vivo.
Methods
1 Identification of cells and subcellular structures in gastric intestinal metaplasia by confocal laser endomicroscopy
Patients with known GIM underwent CLE(Pentax EC-3870K;Pentax,Tokyo, Japan).Fluorescein sodium and acriflavine hydrochloride was used as contrast agent. Esophagus,stomach and duodenum were examined with the CLE system.In normal esophagus,squamous epithelial cell showed rhombus single cells at high resolution with clear visible borders.The nucleus can be stained clearly with acriflavine hydrochloride.Furthermore,squamous epithelial cells were cultured and observed with CLE in vitro for identification.Gastric type columnar epithelial cells and mucin-containing goblet cells can easily recognized in stomach under CLE images.In some areas,a more slender,and brighter than columnar epithelial cells of normal gastric mucosa can be seen with a clear dark line at the surface of the epithelium. These cells and structures also are seen in duodenum.The histologic specimens from each site were compared with the targeted confocal images.All of the biopsy specimens were sectioned vertically and transversely to facilitate the comparison between histology and confocal images.All the biopsy specimens were stained with hematoxylin and eosin.Biopsy specimens diagnosed as GIM and duodenum were further stained by AB-PAS mucin staining,HID-AB mucin staining and CD10 immunohistochemistry.These slender and brighter cells and the clear dark line at the surface of the epithelium were identified with scanning electron microscope(SEM) and transmission electron microscope(TEM).
2 Definition and evaluation of gastric intestinal metaplasia with confocal laser endomicroscopy in Vivo
In first phase,28 patients with known GIM underwent CLE,and CLE criteria for diagnosis of GIM were developed.In addition,53 consecutive patients with known or suspected GIM were prospectively evaluated in second phase.Standard and abnormal appearance areas were examined with the CLE system.Fluorescein was used as contrast agent.Afterwards,a targeted biopsy was done at the same sites.The results of histoathological biopsy specimens taken from the corresponding sites of gastric mucosa under CLE were regarded as gold standard.
3 Diagnostic value of confocal laser endomicroscopy for the prediction of the subtype and grading of gastric intestinal metaplasia
In first phase,28 patients with known GIM underwent CLE,and CLE criteria for classifying and grading GIM were developed.In addition,53 consecutive patients with known or suspected GIM were prospectively evaluated in second phase. Standard and abnormal appearance areas were examined with the CLE system. Fluorescein was used as contrast agent.Afterwards,a targeted biopsy was done at the same sites.The results of histoathological biopsy specimens taken from the corresponding sites of gastric mucosa under CLE were regarded as gold standard.The expression of three gastric carcinoma related gene were detected in different subtype and severity GIM.
4 Diagnostic value of confocal laser endomicroscopy for the prediction of the extent and topographic patterns of gastric intestinal metaplasia
Seventy patients with known GIM underwent CLE.Fluorescein was used as contrast agent.Endoscopic gastric biopsy specimens were obtained using a jumbo forceps from the 11 gastric sites.Five specimens were from the antrum,six from the corpus and one from the incisura angularis.The presence of GIM was made immediately by the endoscopist at the time of the procedure.The extent of GIM was categoried focal,multifocal and extensive GIM.Four topographical patterns of intestinalization emerged:"Focal,","Antrum-predominant,Magenstraβe" and "Diffuse,".The histological evaluation remains the gold standard for the final diagnosis of intestinal metaplasia.
Results
1 All of 28 patients under went CLE with known GIM.A total of 5750 CLE images were obtained from 124 areas under CLE images.The confocal images showed the normal squamous epithelial cells their nucleus on the surface of the esophagus at high resolution in vivo.These patterns can be directly compared with cultured cells in vitro and H&E-stained sections of biopsy specimens cut parallel to the tissue surface.At the surface of the stomach,epithelium a typical cobblestone structure.The mucin-containing goblet cells showed very dark and big within the columnar-lined epithelium.Goblet cells had specific appearance and easily recognized.The more slender and brighter than columnar epithelial cells of normal gastric mucosa were identified as absorptive columnar epithelial cells.These cells were colorless by AB/PAS and HID/AB mucin staining,difference from goblet cells (blue)and gastric epithilum(purple).The clear dark line at the surface of the epithelium were identified as brush border by CD 10 immunohistochemistry,SEM and TEM.
2 GIM was identified if any of the following three features were present in an image field:goblet cells,columnar absorptive cells and brush border,and villiform foveolar epithelium.In a prospective study,a total 267 sites from 53 patients were obtained.160 from 36 patients were diagnosed histopathologically as GIM.The sensitivities of conventional endoscopy and CLE for GIM were 36.88%vs.98.13%, the specificities were 91.59%vs.95.33%,the positive predictive value were 86.76% vs.96.91%,and the negative predictive value were 49.25%vs.97.14%,respectively. The kappa value for the correlation with histological findings was 0.25 for conventional endoscopy vs.0.94 for CLE.
3 In the CLE images,GIM was classified as complete or incomplete,according to the shape of goblet cells,the presence of absorptive cells or brush border,and the architecture of vessels and crypts.In a prospective study,a total 267 sites from 53 patients were obtained.Among the 98 sites with complete GIM according to CLE, this was confirmed in 83 by histopathology.The sensitivity,specificity,positive predictive value and negative predictive value of CLE for the diagnosis of complete GIM were 68.03%,89.66%,84.69%and 76.92%,respectively.Among the 64 sites with incomplete GIM according to CLE,this was confirmed histologically in 26.The sensitivity,specificity,positive predictive value and negative predictive value of CLE for the diagnosis of incomplete GIM were 68.42%,83.41%,40.63%and 94.09%, respectively.The kappa score for the agreement between CLE and histopathology was 0.67.Among 146 GIM positive areas,88 were identified as mild GIM by CLE,in which 74 confirmed by histopathology.Thirty-thee areas were diagnosed as moderate GIM by CLE,25 of them were confirmed by histopathology.Twenty-eight areas were diagnosed as marked GIM by CLE,20 of them were confirmed by histopathology. The sensitivity and specificity of CLE were 90.2%and 78.1%for the diagnosis of mild GIM,69.4%and 92.2%for morderate GIM,71.4%and 95.8%for marked GIM,respectively.The kappa coefficient of CLE criteria and the histopathological grading for mild,moderate and marked IM were 0.69,0.64 and 0.70,respectively. There were differences for the expression of CDX2,Ki67 and APC among different subtype and severity GIM.
4 A total of 70 gastric carcinoma and chronic atrophy gastritis patients with GIM were recruited.47.1%of them were focal GIM,41.4%were multifocal GIM and 11.4%were extensive GIM.The extent of GIM is associated with the gastric cancer and associated with lesion precancerous.Multifocal GIM and ententive GIM was significantly associated with the presence of cancer and gastric atrophy.Extensive GIM was significantly associated with the presence of cancer and dysplasia.Of the entire study population of 70 subjects,37.1%of them were focal pattern,21.4% were antrum-predominant pattern,31.4%of them were Magenstraβe pattern,10.0% of them were diffuse pattern.The topographic patterns of GIM is associated with gastric cancer and lesion precancerous.MagenstraBe and diffuse topographic patterns was significantly associated with the presence of cancer and dysplasia.
Conclusion:
Confocal laser endomicroscopy is a newly developed diagnostic tool and may offer an instant and reliable diagnostic tool for in vivo histology.CLE can identify cells and subcellular structures in normal gastric mucosa and GIM at high resolution in vivo,enable classification,grading,extent and topographic patterns of GIM with high accuracy during ongoing endoscopy.
Significance
Confocal laser endomicroscopy is a newly developed diagnostic tool and may offer an instant and reliable diagnostic tool for in vivo histology.CLE can diagnose GIM with high accuracy during ongoing endoscopy,as well as its grading and subtype. The extent and topographic patterns of GIM also be evaluated.GIM is a risk factor that leads to the development of intestinal-type gastric cancer and is generally regarded as a precancerous condition.Most GIMs are only "precancerous conditions" rather than "precancerous lesions".This present study will help determine the role of CLE in screening and surveillance of premalignant conditions.It could serve as a reasonably good predictor of cancer risk and provide appropriate follow-up in an individual patient.Endoscopic confocal imaging systems are revolutionary instruments in the emerging realm of optical biopsy techniques.The new detailed images seen with CLE unequivocally are the beginning of a new era.It is tempting to speculate that CLE will play an important diagnostic role in the future during gastrointestinal endoscopy.
引文
1 DaCosta RS, Wilson BC, Marcon NE. Optical techniques for the endoscopic detection of dysplastic colonic lesions. Curr Opin Gastroenterol, 2005; 21(1):70-9.
2 Canto MI, Setrakian S, Willis JE, et al. Methylene blue staining of dysplastic and nondysplastic Barrett' s esophagus: an in vivo and ex vivo study. Endoscopy, 2001; 33:391-400.
3 Pfefer TJ, Paithankar DY, Poneros JM, et al. Temporally and spectrally resolved fluorescence spectroscopy for the detection of high grade dysplasia in Barrett' s esophagus. Lasers Surg Med, 2003, 32:10-16.
4 Poneros JM, Brond S, Baums BE, et al. Diagnosis of specialized intestinal metaplasia by optical coherence tomography. Gastroenterology, 2001, 120:7-12.
5 Shibuya K, Hoshino H, Chiyo M, et al. High magnification bronchovideoscopy combined with narrow band GIMaging could detect capillary loops of angiogenic squamous dysplasia in heavy smokers at high risk for lung cancer. Thorax, 2003; 58:989-995.
6 Gono K, Obi T, Yamaguchi M, et al. Appearance of enhanced tissue features in narrow-band endoscopic GIMaging. J Biomed Opt, 2004; 9:568-577.
7 Wang TD, Van Dam J. Optical biopsy: a new frontier in endoscopic detection and diagnosis. Clin Gastroenterol Hepatol, 2004; 2:744-753.
8 Genta RM, Rugge M. Gastric precancerous lesions:heading for an international consensus.Gut,1999; 45(Suppl 1):15-18.
9 Sipponen P. Gartric Cancer:pathogenesia,risks,and prevention.J Gastroenterol,2002; 37(Suppl 13):39-44.
10 Ito M, Haruma K, Kamada T, et al. Helicobacter pylori eradication therapy GIMproves atrophic gastritis and intestinal metaplasia: a 5-year propective study on patients with atrophic gastritia.AlGIMent Pharmacol Ther 2002; 16:1449-1456.
11 Sung JJ, Lin SR, Ching JY, et al. Atrophy and intestinal metaplasia one year cure of H.pylori infection: a prospective randomized study. Gastroenterology 2000; 119:7-14.
12 Cassaro M,Rugge M,Gutierrez O,et al.Topographic patterns of intestinal metaplasia and gastric cancer.Am J Gastroenterol 2000;95:1431-1438.
13 中华医学会消化病学分会.全国慢性胃炎研讨会共识意见.中华消化杂志,2000:20:199-201.
14 周丽雅,李建辉,林三仁,等.胃粘膜肠上皮化生的内镜分析.中华消化内镜杂志,2001:18:84-86.
15 Kiesslich R,Burg J,Vieth M.Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo.Gastroenteorlogy,2004;127:706-713.
16 Nathanson MH.Confocal colonoscopy,more than skin deep.Gastorenterology,2004;127(3):987-989.
17 DaCostaR S,WilsonB C,MarconN E.Opticalte chniques for the endoscopic detection of dysplastic colonicl esions.Curr Opin Gastroenteod,2005;21:70 -79.
18 Sakashita M,Inoue H,Kashida H.Virtual histology of colorectal lesions using laser-scanning confocal microscopy.Endoscopy,2003;35;1033-1038.
19 Koenig F,Knittel J,Stepp H.Diagnosing cancer in vivo.Science,2001;292;1401-1403
20 Dixon MF,Genta RM,Yardley JH et al.Classification and grading of gastritis.The updated Sydney System.International Workshop on the Histopathology of Gastritis,Houston 1994.Am J Surg Pathol 1996;20:1161-1181
21 刘昊,陈美兰,郭仁舆.激光荧光检查法在肿瘤定位诊断中的应用西安交通大学学报(医学版)2007:28(4):455-457
22 GreavesMF,Hariri G,Newman RA,et al.Selective expression of the common acute lymphoblastic leukemia(gp 100)antigen on GIMmature lymphoid cells and their malignant counterparts.Blood,1983;61:628-39.
23 Tsukamoto T,Mizoshita T,Tatematsu.Gastric-and-intestinal mixed-type intestinal metaplasia:aberrant expression of transcription factors and stem cell intestinalization.Gastric Cancer.2006;9(3):156-66.
1 Walker MM. Is intestinal metaplasia of the stomach reversible? Gut 2003; 52: 1-4.
2 Zhou L, Sung JJ, Lin S, Jin Z, Ding S, Huang X, et al. A five-year follow-up study on the pathological changes of gastric mucosa after H. pylori eradication. Chin Med J (Engl)2003;116: 11-14.
3 Kato I, Vivas J, Plummer M, Lopez G, Peraza S, Castro D,et al. Environmental factors in Helicobacter pylori-related gastric precancerous lesions in Venezuela. Cancer Epidemiol Biomarkers Prev 2004; 13: 468-476.
4 You WC, Zhang L, Gail MH, Li JY, Chang YS, Blot WJ, et al. Precancerous lesions in two counties of China with contrasting gastric cancer risk. Int J Epidemiol 1998; 27: 945-948.
5 Sauerbruch T, Schreiber MA, Schussler P, Permanetter W. Endoscopy in the diagnosis of gastritis: diagnostic value of endoscopic criteria in relation to histological diagnosis. Endoscopy 1984; 16: 101-104
6 Kaminishi M, Yamaguchi H, Nomura S et al. Endoscopic classification of chronic gastritis based on a pilot study by the Research Society for Gastritis. Dig Endosc 2002;14:138-151
7 Uedo N, Ishihara R, Iishi H et al. A new method of diagnosing gastric intestinal metaplasia: narrow-band GIMaging with magnifying endoscopy. Endoscopy 2006; 38: 819-824
8 Dinis-Ribeiro DM, da Costa-Pereira C, Lopes C et al. Magnification chromoendoscopy for the diagnosis of gastric intestinal metaplasia and dysplasia. Gastrointest Endosc 2003;57: 498-504
9 KGIM S, Harum K, Ito M et al. Magnifying gastroendoscopy for diagnosis of histologic gastritis in the gastric antrum. Dig Liver Dis 2004; 36: 286-291
10 Gheorgh C. Narrow-band GIMaging endoscopy for diagnosis of malignant and premalignant gastrointestinal lesions. J Gastrointestin Liver Dis 2006; 15: 77-82
11 Nakayoshi T, Tajiri H, Matsuda K et al. Magnifying endoscopy combined with narrow band GIMaging system for early gastric cancer: correlation of vascular pattern with histopathology [including video]. Endoscopy 2004; 36: 1080-1084
12 Kara MA, Ennahachi M, Fockens P et al. Detection and classification of the mucosal and vascular patterns (mucosal morphology) in Barrett's esophagus by using narrow band GIMaging. Gastrointest Endosc 2006; 64: 155-166
13 Ydgi K, Honda H, Yang JM,et al. Magnifying endoscopy in gastritis of the corpus. Endoscopy 2005; 37: 660-666
14 Dixon MF, Genta RM, Yardley JH et al. Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994. Am J Surg Pathol 1996; 20: 1161-1181
15 Lin BR, Shun CT, Wang TH et al. Endoscopic diagnosis of intestinal metaplasia of stomach-accuracy judged by histology. Hepatogastroenterology 1999; 46:162-166
16 Kiesslich R, Gossner L, Goetz M et al. In vivo histology of Barrett's esophagus and associated neoplasia by Confocal laser endomicroscopy. Clin Gastroenterol Hepatol 2006; 4: 979-987
17 You WC, Zhang L, Gail MH, et al. Precancerous lesions in two counties of China with contrasting gastric cancer risk. Int J Epidemiol. 1998; 27(6):945-8.
18 Morson BC. Intestinal metaplasia of the gastric mucosa. Br J Cancer. 1955; 9:365-367
19 Correa PA. Human model of gastric carcinogenesis. Cancer Res,1988; 48:3554-3560;
20 Lauren P. The two histological main type of gastric carcinoma: diffuse and so-called intestinal type carcinoma. Acta Path Microbiol Scand, 1965,64:31-49,
21 Matsukura N, Shirota A, Maruyama K. Recent advances in research on the intestinal metaplasia of the stomaeh. Gan To Kagaku Ryoho.1983 ; 10(2PtZ):471-81.
22 Oohara T, Aono G, Ukawa S, Takezoe K, JohjGIMa Y, Kurosaka H, Asakura R, Tohma H.Clinical diagnosis of minute gastric cancer less than 5 mm in diameter.Cancer. 1984; 53(1): 162-5.
23 Rubio CA, Kato Y, Sugano H, etal.Intestinal metaplasia of the stomach in Smedish and Japanese Patients without ulcers or careinoma. Jpn J Caneer Res. 1987; 78:467-472.
24 Mutoh H,Sakurai S,Satoh K,etal.Development of gastric careinoma from intestinal metaplasia in CDX2-transgenic mice.Caneer Res.2004;64(21):7740-7.
25周丽雅,李建辉,林三仁,等.胃粘膜肠上皮化生的内镜分析.中华消化内镜杂志,2001:18:84-86.
26 Fennerty MB,Emerson JC,Smapliner RE,etal.Gastric intestinal metaplasia in ethnic groups in the Southwestern United States.Cancer Epidemiol Biomarkers Prev.1992:1:293-296.
27 Kaminishi M,Yamaguchi H,Nomura S et al.Endoscopic classification of chronic gastritis based on a pilot study by the Research Society for Gastritis.Dig Endosc 2002;14:138-151
28 Sirigu F Dessi A Toeeo G etal.Intestinal metaplasia of the gastric mucosa:a study of its incidence in various disease states.Riv Eur Sci Med Farmaeol.1991;13(1-2):25-8
29 SuzukiS,MurakamiH,SuzukiH,etal.An endoscopic staining method for detection and operation of early gastric caneer.Int Adv Surgoneol.1979:2:223-41.
30 KohliY,HattoriS,KodamaT,etal.Endoseopic diagnosis of intestinal metaplasia in asymptomatic(control)volunteers.Gastroenterol Jpn.1979:14(1):14-18
31 HashGIMotoT,SuzukuS,Haseg T,et al.Application of the methylene blue staining method to the study of experGIMentally PNNG-induced intestinal metaplasia of the canine stomaeh.Endoseopy.1980;12(5):205-10.
32 Wo JM,Ray MB,Mayfield-Stokes S,et al.Comparison of methylene blue-directed biopsies and conventional biopsies in the detection of intestinal metaplasia and dysplasia in Barrett's esophagus:a prelGIMinary study.Gastrointest Endosc.2001;54(3):294-301.
33 Yang JM,Chen L,Fan YL,et al.Endoseopic patterns of gastric mucosa and its clinico pathological significance.World J Gastroenterol.2003;9(11):2552-6.
34 黄永辉,周丽雅,林三仁,等.放大内镜下胃小凹形态学分类及其临床病理意义.中国内镜杂志.200:410(3):14-16
35 郭玉婷,李延青,赵幼安,等.共聚焦激光内镜对胃粘膜肠上皮化生的诊断价值.中华消化内镜杂志,2007:24(1):8-13
36 刘昊,陈美兰,郭仁舆.激光荧光检查法在肿瘤定位诊断中的应用西安交通大学学报(医学版).2007:28(4):455-457
37 Amano Y,Kushiyama Y,Ishihara S,et al.Crystal violet chromoendoscopy with mucosal pit pattern diagnosis is useful for surveillance of short-segment Barrett's esophagus.Am J Gastroenterol.2005;100(1):21-6.
38 Tajiri H,Doi T,Endo H,et al.Routine endoscopy using a magnifying endoscope for gastric cancer diagnosis.Endoscopy.2002;34(10):772-7.
39 Endo T,Awakawa T,Takahashi H,et al.Classification of Barrett's epithelium by magnifying endoscopy.Gastrointest Endosc.2002;55(6):641-7.
40 Pohl J,May A,Rabenstein T,et al.Computed virtual chromoendoscopy:a new tool for enhancing tissue surface structures.Endoscopy.2007;39(1):80-3.
41 Mayinger B,Oezturk Y,Stolte M,et al.Evaluation of sensitivity and inter- and intra-observer variability in the detection of intestinal metaplasia and dysplasia in Barrett's esophagus with enhanced magnification endoscopy.Scand J Gastroenterol.2006;41(3):349-56.
1 Neugut AI, Hayek M, Howe G. Epidemiology of gastric cancer. Semin Oncol, 996;23:281-91.
2 Correa P . Human gastric carcinogenesis: a multistep and multifactorial process. First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res 1992; 52:6735-40.
3 Correa P, Cuello C, Duque E, et al. Gastric cancer in Colombia. III. Natural history of precursor lesions. J Natl Cancer Inst 1976; 57:1027-35.
4 Correa P, Cuello C, Haenszel W. The pathogenesis of gastric carinoma-epidemiologic pathology of precursor lesions. Leber Magen Darm 1976; 6:72-9.
5 ShGIMoyama T, Fukuda S, Tanaka M, Nakaji S, Munakata A. Evaluation of the applicability of the gastric carcinoma risk index for intestinal type cancer in Japanese patients infected with Helicobacter pylori.Virchows Arch. 2000; 436(6):585-7.
6 Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M, Taniyama K, Sasaki N, Schlemper RJ.Helicobacter pylori infection and the development of gastric cancer.N Engl J Med. 2001 13;345(11):784-9.
7 Genta RM. Review article: Gastric atrophy and atrophic gastritis-nebulous concepts in search of a definition. AlGIMent Pharmacol Ther 1998; 12 Suppl 1:17 - 23.
8 Leung WK, Sung JJ. Review article: intestinal metaplasia and gastric carcinogenesis. AlGIMent Pharmacol Ther 2002; 16:1209 - 16.
9 Correa P, Fontham ET, Bravo JC, et al. Chemoprevention of gastric dysplasia: randomized trial of antioxidant supplements and anti-Helicobacter therapy. J Natl Cancer Inst 2000; 92:1881 - 8.
10 Sung JJ, Lin SR, Ching JY, et al. Atrophy and intestinal metaplasia one year after cure of H. pylori infection: a prospective, randomized study. Gastroenterology 2000; 119:7 -14.
11 Leung WK, Lin SR, Ching JY, et al. Factors predicting progression of gastric intestinal metaplasia: results of a randomised trial on Helicobacter pylori eradication. Gut 2004; 53:1244-9.
12 You WC, Zhang L, Gail MH, Li JY, Chang YS, Blot WJ, et al. Precancerous lesions in two counties of China with contrasting gastric cancer risk. Int J Epidemiol 1998; 27: 945-948.
13 Rokkas T, Filipe MI, Sladen GE. Detection of an increased incidence of early gastric cancer in patients with intestinal metaplasia type III who are closely followed up. Gut 1991; 32: 1110-1113
14 Dixon MF, Genta RM, Yardley JH et al. Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994. Am J Surg Pathol 1996; 20: 1161-1181
15 Leung WK, Ng EK, Chan WY, et al. Risk factors associated with the development of intestinal metaplasia in first-degree relatives of gastric cancer patients.Cancer Epidemiol Biomarkers Prev. 2005; 14(12):2982-6.
16 You WC, Li JY, Blot WJ,et al. Evolution of precancerous lesions in a rural Chinese population at high risk of gastric cancer.
17 Sipponen P, Kosunen TU, Valle J, et al. Helicobacter pylori infection and chronic gastritis in gastric cancer. J Clin Pathol 1992; 45:319-323.
18 Filipe MI, Munoz N, Matko I, et al. Intestinal metaplasia types and the risk of gastric cancer and the risk of gastric cancer: a cohort study in Slovenia. Int J Cancer 1994; 57: 324-9.
19 Meining A, Morgner A, Miehlke S, et al. Atrophy-metaplasia-dysplasia-carcinoma sequence in the stomach: a reality or merely an hypothesis? Best Pract Res Clin Gastroenterol 2001; 15: 983-998
20 Rokkas T, Filipe MI, Sladen GE. Detection of an increased incidence of early gastric cancer in patients with intestinal metaplasia type III who are closely followed up. Gut 1991;32: 1110-1113.
21 Dinis-Ribeiro M, Lopes C, da Costa-Pereira A, et al. A follow up model for patients with atrophic chronic gastritis and intestinal metaplasia. J Clin Pathol 2004; 57 : 177-182
22 Lin BR, Shun CT, Wang TH et al. Endoscopic diagnosis of intestinal metaplasia of stomach - accuracy judged by histology. Hepatogastroenterology 1999; 46:162-166
23周丽雅,李建辉,林三仁等.胃粘膜肠上皮化生的内镜分析.中华消化内镜杂志.2001:18(2):84-86.
24 Rokkas T,Filipe Ml,Sladen GE.Detection of an increased incidence of early gastric cancer inpatients with intestinal metaplasia type Ⅲ who are closely followed up.Gut.1991;32:1110-1113;
25 Jass JR,Filipe MI.Sulphomucins and precancerous lesions of the human stomach.Histopathology 1980;4:271-9.
26 Tosi P,Filipe MI,Baak JP et al.Morphometric definition and grading of gastric intestinal metaplasia.J Pathol 1990;161:201-208
27 Kiesslich R,Gossner L,Goetz M et al.In vivo histology of Barrett's esophagus and associated neoplasia by confocal laser endomicroscopy.Clin Gastroenterol Hepatol 2006;4:979-987
28 Kiesslich R,Burg J,Vieth M et al.Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo.Gastroenterology 2004;127:706-713
29 Aydin O,Egilmez R,Karabacak T,Kanik A.Interobserver variation in histopathological assessment of Helicobacter pylori gastritis.World J Gastroenterol.2003;9(10):2232-5.
30 Uedo N,Ishihara R,Iishi H et al.A new method of diagnosing gastric intestinal metaplasia:narrow-band imaging with magnifying endoscopy.Endoscopy 2006;38:819-824
31 游伟程,李吉友,昌云生等.胃癌高发区人群胃粘膜不同病变的转化与暴露时间关系的分析.中华肿瘤杂志,1991:13(2):100-102
32 Parkin DM,Bray FI,Devesa SS.Cancer burden in the year 2000.The global picture.Eur J Cancer 2001;37(Supp18):S4-66.
33 Rugge M,Genta RM.Staging and grading of chronic gastritis.Hum Pathol 2005;36:228-233.
34 Testino G.Gastric preneoplastic changes.Recenti Prog Med 2004;95:239-244.
35 Segura DI,Montero C.Histochemical characterization of different types of intestinal metaplasia in gastric mucosa.Cancer.1983:52(2):498-500.
36 Fang DC,Liu W.Different types of intestinal metaplasia and Gastric cancer:a clinico-endoseopic follow-up of 112 cases.Zhonghua Nei Ke Za Zhi 1990;29(8):465-8,509-10.
37 Sirigu F,Dessi A,Toeeo G,et al.Intestinal metaplasia of the gastric mucosa:a study of its incidence in various disease states.Riv Eur Sci Med Farmacol 1991;13(1-2):25-8.
38 Turani H,Lurie B,ChaGIMoff C,etal.The diagnostic significance of sulphated acid mucin content in gastric intestinal metaplasia with early gastric caneer.Anl J Gastroenterol.1986:81(2):343-345.
39 Filipe MI,Potet F,Bogomoletz WV,et al.Incomplete sulphomucin secreting intestinal metaplasia for gastric caneer.PrelGIMinary data from a prospective study from three centres.Gut.1985;26(4):1319-1321.
40 李宁,祝庆孚,李维华.胃粘膜肠上皮化生中凝集素受体的分布和分型与胃癌发生的关系.中华病理学杂志1992:21(4):373-375
41 Dinis-Ribeiro M,daCosta-Pereira A,Lopes C,et al.Magnification Chromoendoscopy for the diagnosis of gastricintestinal metaplasia and dysplasia.Gastrointest Endosc 2003;57(4):498-504.
42 Yang JM,Chen L,Fan YL,et al.Endoseopic patterns of gastric mucosa and its clinic pathological significance.World J Gastroenterol 2003;9(11):2552-6.
43 黄永辉,周丽雅,林三仁,等.放大内镜下胃小凹形态学分类及其临床病理意义.中国内镜杂志.2004;10(3):14-16
44 郑京华,魏虹,杨海燕,等.胃粘膜萎缩及伴肠上皮化生的可视性诊断.潍坊医学院学报2001:23(2):116-117.
45 Tsukamoto T,Mizoshita T,Tatematsu M et al.Gastric-and-intestinal mixed-type intestinal metaplasia:aberrant expression of transcription factors and stem cell intestinalization.Gastric Cancer 2006;9:156-166
46 Inada K,Tanaka H,Nakanishi H,et al.Identification of Paneth cells in pyloric glands associated with gastric and intestinal mixed-type intestinal metaplasia of the human stomach.Virchows Arch 2001;439:14-20.
47 Kakeji Y,Yamaguchi S,Yoshida D,et al.Development and assessment of morphologic criteria for diagnosing gastric cancer using Confocal endomicroscopy: an ex vivo and in vivo study. Endoscopy 2006; 38: 886-890.
48 Rugge M, Correa P, Dixon MF, et al. Gastric mucosal atrophy: interobserver consistency using new criteria for classification and grading. AlGIMent Pharmacol Ther, 2002; 16: 1249-1259.
49 Lauwers GY, Riddell RH. Gastric epithelial dysplasia. Gut 1999; 45 : 784-790.
50 Rugge M, Correa P , Dixon MF ,et al . Gastric Dysplasia . The Padova international classification. Am J Surg Pathol, 2000; 124 :167-176.
51 Tosi P, Filipe MI, Luzi P, et al. Gastric intestinal metaplasia type III cases are classified as low-grade dysplasia on the basis of morphometry. J Pathol 1993; 169:73-8.
52 Dixon MF.Prospcets for intervention in gastric carcinogenesis: reversibility of gastric atrophy and intestinal metaplasia.Gut. 2001; 49:2-4.
53 宋艳,李凌．肠道上皮特异性基因CDX2．世界华人消化杂志 2004：12(2)：443—445．
54 Mutoh H,Satoh K, Kita H, et al.CDX2 specifies the differentiation of morphological as well as functional absorptive enterocytes of the small intestine. Int J Dev Biol,2005;49(7):867-71.
55 Hinoi T, Gesina G, Akyol A, et al.CDX2-regulated expression of iron transport protein hephaestin in intestinal and colonic epithelium.Gastroenterology,2005;128(4):946-61.
56 Mizoshita T, Inada K, Tsukmaoto T, et al. Expression of cdx1 and CDX2 mRNAs and relevance of this expression to differentiation in human gastrointestinal mucosa-with special emphasis on participation in intestinal metaplasia of the human stomach. Gastric Cancer. 2001; 4(4): 185-91.
57 Silberg DG, Sullivan J, Kang E, et al. CDX2 ectopic expression induces gastricintestinal metaplasia in transgenic mice. Gastroenterology.2002; 122(3):689-96.
58 Suh E, Traber PG. Aninte stine-spceific homeoboxgene regulates proliferation and differentiation. Mol Cell Biol. 1996 ;16(2):619-25.
59 Eda A, Oswaa H, Yanaka I, et al. Expression of homeobox gene CDX2 procedes that of CDX1 during the progression of intestina lmetaplasia. J Gastroenterol. 2002; 37(2):94-100.
60 Bai YQ, Ymaamoto H, Akiyama Y, et al. Eetopic expression of homeodomain protein CDX2 in intestinal metaplasia and carcinomas of the stomach. Cancer Lett. 2002 ;176(1):47-55.
61 Bai Y, AkiyamaY, Nagasaki H, et al. Distinct expression of CDX2 and GATA4/5. development-related genes, in human gastric cancer cell lines. Mol Carcinog. 2000 ; 28(3): 184-8.
62 Mutoh H, Sakurai S, Satoh K, et al. Development of gastric carcinoma from intestinal metaplasia in CDX2-transgenic mice.Cancer Res.2004; 64(21):7740-7.
63 Hamilton SR. Molecular genetics of colorectal carcinoma . Cancer , 1992 ;70 (5 Suppl) :121621221.
1. Neugut AI, Hayek M, Howe G. Epidemiology of gastric cancer. Semin Oncol 1996; 23:281-91.
2. Correa P, Cuello C, Duque E, et al. Gastric cancer in Colombia. III. Natural history of precursor lesions. J Natl Cancer Inst 1976; 57:1027-35.
3. Correa P, Cuello C, Haenszel W. The pathogenesis of gastric carcinoma—Epidemiologic pathology of precursor lesions. Leber Magen Darm 1976; 6:72-9.
4. Correa P. Human gastric carcinogenesis: A multistep and multifactorial process-First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res 1992; 52:6735-40.
5. Nomura A, Stemmermann GN. Helicobacter pylori and gastric cancer. J Gastroenterol Hepatol 1993; 8:294 -303.
6. Rugge M, Leandro G, Farinati F, et al. Gastric epithelial dysplasia. How clinicopathologic background relates to management. Cancer 1995; 76:376-82.
7. Rugge M, Cassaro M, Leandro G, et al. Helicobacter pylori in promotion of gastric carcinogenesis. Dig Dis Sci 1996; 41: 950-5.
8. Infection with Helicobacter pylori. IARC Monogr Eval Carcinog Risks Hum 1994; 61:177-240.
9 .Correa P, Haenszel W, Cuello C, et al. Gastric precancerous process in a high risk population: Cross-sectional studies. Cancer Res 1990; 50:4731-6.
10. Ihamaki T, Sipponen P, Varis K, et al. Characteristics of gastric mucosa which precede occurrence of gastric malignancy: Results of long-term follow-up of three family samples. Scand J Gastroenterol 1991; 186(suppl):16-23.
11 Kokkola A, Haapiainen R, Laxen F, et al. Risk of gastric carcinoma in patients with mucosal dysplasia associated with atrophic gastritis: A follow up study. J Clin Pathol 1996; 49: 979-84.
12. Dixon MF. Histological responses to Helicobacter pylori infection: Gastritis, atrophy and preneoplasia. Baillieres Clin Gastroenterol 1995; 9:467- 86.
13. Dixon MF, Genta RM, Yardley JH, Correa P. Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994. Am J Surg Pathol 1996; 20:1161- 81.
14 Rugge M, Cassaro M, Farinati F, et al. Helicobacter pylori and atrophic gastritis: GIMportance of the cagA status. J Natl Cancer Inst 1996; 88:762-3.
15. Jass JR, Filipe ML Sulphomucins and precancerous lesions of the human stomach. Histopathology 1980; 4:271-9.
16. Yu-ting Guo, Yan-qing Li, Tao Yu, et al. Diagnosis and Classification of gastric intestinal metaplasia with Confocal laser endoscopy in vivo: a prospective study. Endoscopy 40: 1-7
17．中华医学会消化病学分会．全国慢性胃炎研讨会共识意见．中华消化杂志2000；20(3)：199—201
18. Cassaro M, Rugge M, Gutierrez O, et al.Topographic patterns of intestinal metaplasia and gastric cancer. Am J Gastroenterol. 2000 ; 95(6): 1431-8.
19. Genta RM, Lew GM, Graham DY. Changes in the gastric mucosa following eradication of Helicobacter pylori. Mod Pathol 1993; 6:281-9.
20. Wyatt JI. Histopathology of gastroduodenal inflammation: The GIMpact of Helicobacter pylori. Histopathology 1995; 26: 1-15.
21. Stemmermann GN, Hayashi T. Intestinal metaplasia of the gastric mucosa: A gross and microscopic study of its distribution in various disease states. J Natl Cancer Inst 1968;41:627-34.
22. Nakahara K. Special features of intestinal metaplasia and its relation to early gastric carcinoma in man: Observation by a method in which leucine aminopeptidase activity is used. J Natl Cancer Inst 1978; 61:693-701.
23. KGIMura K. Chronological transition of the fundic-pyloric border determined by stepwise biopsy of the lesser and greater curvatures of the stomach. Gastroenterology 1972; 63:584-92.
24. KGIMura K, Satoh K, Ido K, et al. Gastritis in the Japanese stomach. Scand J Gastroenterol 1996; 214(suppl):17-20.
25 Stemmermann GN. Intestinal metaplasia of the stomach. A status report. Cancer 1994; 74:556-64.
26 Guelrud M, Herrera I, Essenfeld H, et al. Intestinal metaplasia of the gastric cardia: A prospective study with enhanced magnification endoscopy. Am J Gastroenterol. 2002; 97(3):584-9
27 Sharma P, McElhinney C, Topalovski M, et al. Detection of cardia intestinal metaplasia: do the biopsy number and location matter? Am J Gastroenterol. 2004; 99(12):2424-8.
28. Soren A. Joint inflammations as complications in intestinal inflammations. Z Rheumatol 1981;40:1-5.
29. Utriainen M, Hanninen ML. Detection of Helicobacter-like bacteria in porcine gastric biopsy samples by amplification of 16S rRNA, ureB, vacA and cagA genes by PCR. Vet Res Commun 1998; 22:373- 83
30 .Savalgi RS, Corbishley CM, Caygill C,et al. Relation between severity and extent of precancerous lesions in the postoperative stomach. Lancet. 1990 Aug 18;336 (8712):413-6.
31 .Fraser AG, Peng SL, Jass JR. Intestinal metaplasia subtypes and Helicobacter pylori infection: a comparison of ethnic groups in New Zealand. J Gastroenterol Hepatol. 1998; 13(6):560-5.
32 .Kapadia CR. Gastric atrophy, metaplasia, and dysplasia: a clinical perspective. J Clin Gastroenterol. 2003; 36(5 Suppl):S29-36; discussion S61-2.
33 .Testino G. Gastric precancerous changes: carcinogenesis, clinical behaviour GIMmunophenotype study and surveillance. Panminerva Med. 2006; 48(2): 109-18.
34 .Stemmermann GN. Intestinal metaplasia of the stomach. A status report. Cancer. 1994 Jul 15;74(2):556-64.
35 .Mastracci L, Bruno S, Spaggiari P, et al. The GIMpact of biopsy number and site on the accuracy of intestinal metaplasia detection in the stomach A morphometric study based on virtual biopsies. Dig Liver Dis. 2008 Apr 9 [Epub ahead of print]
36 .El-ZGIMaity HM, Ota H, Graham DY, et al. Patterns of gastric atrophy in intestinal type gastric carcinoma.Cancer. 2002; 94(5): 1428-36
1 Walker MM. Is intestinal metaplasia of the stomach reversible? Gut 2003; 52: 1-4
2 Zhou L, Sung JJ, Lin S et al. A five-year follow-up study on the pathological changes of gastric mucosa after H. pylori eradication. Chin Med J (Engl) 2003; 116:11-14
3 Kato I, Vivas J, Plummer M et al. Environmental factors in Helicobacter pylori-related gastric precancerous lesions in Venezuela. Cancer Epidemiol Biomarkers Prev 2004; 13: 468-476
4 Sauerbruch T, Schreiber MA, Schussler P et al. Endoscopy in the diagnosis of gastritis: diagnostic value of endoscopic criteria in relation to histological diagnosis. Endoscopy 1984; 16: 101-104
5 Kaminishi M, Yamaguchi H, Nomura S et al. Endoscopic classification of chronic gastritis based on a pilot study by the Research Society for Gastritis. Dig Endosc 2002;14: 138-151
6 Uedo N, Ishihara R, Iishi H et al. A new method of diagnosing gastric intestinal metaplasia: narrow-band imaging with magnifying endoscopy. Endoscopy 2006; 38: 819-824
7 Dinis-Ribeiro DM, da Costa-Pereira C, Lopes C et al. Magnification chromoendoscopy for the diagnosis of gastric intestinal metaplasia and dysplasia. Gastrointest Endosc 2003; 57: 498-504
8 Kim S, Harum K, Ito M et al. Magnifying gastroendoscopy for diagnosis of histologic gastritis in the gastric antrum. Dig Liver Dis 2004; 36: 286-291
9 Gheorgh C. Narrow-band imaging endoscopy for diagnosis of malignant and premalignant gastrointestinal lesions. J Gastrointestin Liver Dis 2006; 15: 77-82
10 Nakayoshi T, Tajiri H, Matsuda K et al. Magnifying endoscopy combined with narrow band imaging system for early gastric cancer: correlation of vascular pattern with histopathology [including video]. Endoscopy 2004; 36: 1080-1084
11 Kara MA, Ennahachi M, Fockens P et al. Detection and classification of the mucosal and vascular patterns (mucosal morphology) in Barrett's esophagus by using narrow band imaging. Gastrointest Endosc 2006; 64: 155-166
12 Ydgi K, Honda H, Yang JM,et al. Magnifying endoscopy in gastritis of the corpus. Endoscopy 2005; 37: 660-666
13 Kiesslich R, Gossner L, Goetz M et al. In vivo histology of Barrett's esophagus and associated neoplasia by Confocal laser endomicroscopy. Clin Gastroenterol Hepatol 2006; 4: 979-987
14 Kiesslich R,Burg J,Vieth M et al. Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo. Gastroenterology 2004; 127:706-713
15 Kiesslich R, Goetz M,Burg J, Stolte M et al. Dignosing Helicobacter pylori in vivo by Confocal laser endoscopy. Gastroenterology 2005; 128: 2119-2123
16 Kakeji Y, Yamaguchi S, Yoshida D et al. Development and assessment of morphologic criteria for diagnosing gastric cancer using Confocal endomicroscopy: an ex vivo and in vivo study. Endoscopy 2006; 38: 886-890
17 Kitabatake S, Niwa Y, Miyahara R et al. Confocal endomicroscopy for the diagnosis of gastric cancer in vivo. Endoscopy 2006; 38: 1110-1114
18 Dixon MF, Genta RM, Yardley JH et al. Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994. Am J Surg Pathol 1996; 20: 1161-1181
19 Lin BR, Shun CT, Wang TH et al. Endoscopic diagnosis of intestinal metaplasia of stomach - accuracy judged by histology. Hepatogastroenterology 1999; 46:162-166
20 Sipponen P, Kosunen TU, Valle J et al. Helicobacter pylori infection and chronic gastritis in gastric cancer. J Clin Pathol 1992; 45:319-323
21 Filipe MI, Munoz N, Matko I et al. GIM types and the risk of gastric cancer: a cohort study in Slovenia. Int J Cancer 1994; 57: 324-329
22 Tosi P, Filipe MI, Baak JP et al. Morphometric definition and grading of gastric intestinal metaplasia. J Pathol 1990; 161: 201-208
23 You WC, Zhang L, Gail MH et al. Precancerous lesions in two counties of China with contrasting gastric cancer risk. Int J Epidemiol 1998; 27: 945-948
24 Tosi P, Filipe MI, Luzi P et al. Gastric intestinal metaplasia type III cases are classified as low-grade dysplasia on the basis of morphometry. J Pathol 1993; 169: 73-78
25 Meining A, Morgner A, Miehlke S et al. Atrophy-metaplasia-dysplasia-carcinoma sequence in the stomach: a reality or merely a hypothesis? Best Pract Res Clin Gastroenterol 200; 15: 983-998
26 Rokkas T, Filipe MI, Sladen GE. Detection of an increased incidence of early gastric cancer in patients with intestinal metaplasia type III who are closely followed up. Gut 1991; 32: 1110-1113
27 Dinis-Ribeiro M, Lopes C, da Costa-Pereira A et al. A follow up model for patients with atrophic chronic gastritis and intestinal metaplasia. J Clin Pathol 2004; 57: 177-182
1. Neugut AI, Hayek M, Howe G. Epidemiology of gastric cancer. Semin Oncol 1996; 23:281-91.
2. Correa P, Cuello C, Duque E, et al. Gastric cancer in Colombia. III. Natural history of precursor lesions. J Natl Cancer Inst 1976; 57:1027-35.
3. Correa P, Cuello C, Haenszel W. The pathogenesis of gastric carcinoma-Epidemiologic pathology of precursor lesions. Leber Magen Darm 1976; 6:72-9.
4. Correa P. Human gastric carcinogenesis: A multistep and multifactorial process-First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res 1992; 52:6735-40.
5. Nomura A, Stemmermann GN. Helicobacter pylori and gastric cancer. J Gastroenterol Hepatol 1993; 8:294-303.
6. Rugge M, Leandro G, Farinati F, et al. Gastric epithelial dysplasia. How clinicopathologic background relates to management. Cancer 1995; 76:376-82.
7. Rugge M, Cassaro M, Leandro G, et al. Helicobacter pylori in promotion of gastric carcinogenesis. Dig Dis Sci 1996; 41: 950-5.
8. Infection with Helicobacter pylori. IARC Monogr Eval Carcinog Risks Hum 1994; 61:177-240.
9 Correa P, Haenszel W, Cuello C, et al. Gastric precancerous process in a high risk population: Cross-sectional studies. Cancer Res 1990; 50:4731- 6.
10. Ihamaki T, Sipponen P, Varis K, et al. Characteristics of gastric mucosa which precede occurrence of gastric malignancy: Results of long-term follow-up of three family samples. Scand J Gastroenterol 1991; 186(suppl):16-23.
11 Kokkola A, Haapiainen R, Laxen F, et al. Risk of gastric carcinoma in patients with mucosal dysplasia associated with atrophic gastritis: A follow up study. J Clin Pathol 1996; 49: 979-84.
12. Dixon MF. Histological responses to Helicobacter pylori infection: Gastritis, atrophy and preneoplasia. Baillieres Clin Gastroenterol 1995; 9:467- 86.
13. Genta RM. Review article: Gastric atrophy and atrophic gastritis-nebulous concepts in search of a definition. Aliment Pharmacol Ther 1998; 12 Suppl 1:17-23.
14. Leung WK, Sung JJ. Review article: intestinal metaplasia and gastric carcinogenesis. Aliment Pharmacol Ther 2002; 16:1209 - 16.
15. Correa P, Fontham ET, Bravo JC, et al. Chemoprevention of gastric dysplasia: randomized trial of antioxidant supplements and anti-Helicobacter therapy. J Natl Cancer Inst 2000;92:1881 - 8.
16. Sung JJ, Lin SR, Ching JY, et al. Atrophy and intestinal metaplasia one year after cure of H. pylori infection: a prospective, randomized study. Gastroenterology 2000;119:7- 14.
17. Leung WK, Lin SR, Ching JY, et al. Factors predicting progression of gastric intestinal metaplasia: results of a randomised trial on Helicobacter pylori eradication. Gut 2004;53:1244-9.
18. Jass JR, Filipe MI. Sulphomucins and precancerous lesions of the human stomach. Histopathology 1980; 4:271-9.
19. Dixon MF, Genta RM, Yardley JH, Correa P. Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994. Am J Surg Pathol 1996; 20:1161- 81.
20. Groves FD, Perez-Perez G, Zhang L, et al. Serum antibodies to Helicobacter pylori and the CagA antigen do not explain differences in the prevalence of precancerous gastric lesions in two Chinese populations with contrasting gastric cancer rates. Cancer Epidemiol Biomarkers Prev 2002; 11:1091 - 4.
21 Rugge M, Cassaro M, Farinati F, et al. Helicobacter pylori and atrophic gastritis: GIMportance of the cagA status. J Natl Cancer Inst 1996; 88:762-3.
22 Guarner J, Herrera-Goepfert R, Mohar A, et al. Gastric atrophy and extent of intestinal metaplasia in a cohort of Helicobacter pylori-infected patients. Hum Pathol. 2001;32 (1):31-5.
23 Cassaro M, Rugge M, Gutierrez O, et al.Topographic patterns of intestinal metaplasia and gastric cancer. Am J Gastroenterol. 2000 ; 95(6): 1431-8.
24 Genta RM, Lew GM, Graham DY. Changes in the gastric mucosa following eradication of Helicobacter pylori. Mod Pathol 1993; 6:281-9.
25. Wyatt JI. Histopathology of gastroduodenal inflammation: The GIMpact of Helicobacter pylori. Histopathology 1995; 26: 1-15.
26. Stemmermann GN, Hayashi T. Intestinal metaplasia of the gastric mucosa: A gross and microscopic study of its distribution in various disease states. J Natl Cancer Inst 1968;41:627-34.
27. Nakahara K. Special features of intestinal metaplasia and its relation to early gastric carcinoma in man: Observation by a method in which leucine aminopeptidase activity is used. J Natl Cancer Inst 1978; 61:693-701.
28. KGIMura K. Chronological transition of the fundic-pyloric border determined by stepwise biopsy of the lesser and greater curvatures of the stomach. Gastroenterology 1972; 63:584-92.
29. KGIMura K, Satoh K, Ido K, et al. Gastritis in the Japanese stomach. Scand J Gastroenterol 1996; 214(suppl):17-20.
30 Stemmermann GN. Intestinal metaplasia of the stomach. A status report. Cancer 1994; 74:556-64.
31 Guelrud M, Herrera I, Essenfeld H, et al. Intestinal metaplasia of the gastric cardia: A prospective study with enhanced magnification endoscopy. Am J Gastroenterol. 2002; 97(3):584-9
32 Sharma P, McElhinney C, Topalovski M, et al. Detection of cardia intestinal metaplasia: do the biopsy number and location matter? Am J Gastroenterol. 2004; 99(12):2424-8.
33. Soren A. Joint inflammations as complications in intestinal inflammations. Z Rheumatol 1981;40:l-5.
34. Utriainen M, Hanninen ML. Detection of Helicobacter-like bacteria in porcine gastric biopsy samples by amplification of 16S rRNA, ureB, vacA and cagA genes by PCR. Vet Res Commun 1998; 22:373- 83
35 Savalgi RS, Corbishley CM, Caygill C,et al. Relation between severity and extent of precancerous lesions in the postoperative stomach. Lancet. 1990 Aug 18;336 (8712):413-6.
36 Fraser AG, Peng SL, Jass JR. Intestinal metaplasia subtypes and Helicobacter pylori infection: a comparison of ethnic groups in New Zealand. J Gastroenterol Hepatol. 1998; 13(6):560-5.
37 Kapadia CR. Gastric atrophy, metaplasia, and dysplasia: a clinical perspective. J Clin Gastroenterol. 2003; 36(5 Suppl):S29-36; discussion S61-2.
38 Testino G. Gastric precancerous changes: carcinogenesis, clinical behaviour GIMmunophenotype study and surveillance. Panminerva Med. 2006; 48(2): 109-18.
39 Stemmermann GN. Intestinal metaplasia of the stomach. A status report. Cancer. 1994 Jul 15;74(2):556-64.
2 Canto MI, Setrakian S, Willis JE, et al. Methylene blue staining of dysplastic and nondysplastic Barrett' s esophagus: an in vivo and ex vivo study. Endoscopy, 2001; 33:391-400.
3 Pfefer TJ, Paithankar DY, Poneros JM, et al. Temporally and spectrally resolved fluorescence spectroscopy for the detection of high grade dysplasia in Barrett' s esophagus. Lasers Surg Med, 2003, 32:10-16.
4 Poneros JM, Brond S, Baums BE, et al. Diagnosis of specialized intestinal metaplasia by optical coherence tomography. Gastroenterology, 2001, 120:7-12.
5 Shibuya K, Hoshino H, Chiyo M, et al. High magnification bronchovideoscopy combined with narrow band GIMaging could detect capillary loops of angiogenic squamous dysplasia in heavy smokers at high risk for lung cancer. Thorax, 2003; 58:989-995.
6 Gono K, Obi T, Yamaguchi M, et al. Appearance of enhanced tissue features in narrow-band endoscopic GIMaging. J Biomed Opt, 2004; 9:568-577.
7 Wang TD, Van Dam J. Optical biopsy: a new frontier in endoscopic detection and diagnosis. Clin Gastroenterol Hepatol, 2004; 2:744-753.
8 Genta RM, Rugge M. Gastric precancerous lesions:heading for an international consensus.Gut,1999; 45(Suppl 1):15-18.
9 Sipponen P. Gartric Cancer:pathogenesia,risks,and prevention.J Gastroenterol,2002; 37(Suppl 13):39-44.
10 Ito M, Haruma K, Kamada T, et al. Helicobacter pylori eradication therapy GIMproves atrophic gastritis and intestinal metaplasia: a 5-year propective study on patients with atrophic gastritia.AlGIMent Pharmacol Ther 2002; 16:1449-1456.
11 Sung JJ, Lin SR, Ching JY, et al. Atrophy and intestinal metaplasia one year cure of H.pylori infection: a prospective randomized study. Gastroenterology 2000; 119:7-14.
12 Cassaro M,Rugge M,Gutierrez O,et al.Topographic patterns of intestinal metaplasia and gastric cancer.Am J Gastroenterol 2000;95:1431-1438.
13 中华医学会消化病学分会.全国慢性胃炎研讨会共识意见.中华消化杂志,2000:20:199-201.
14 周丽雅,李建辉,林三仁,等.胃粘膜肠上皮化生的内镜分析.中华消化内镜杂志,2001:18:84-86.
15 Kiesslich R,Burg J,Vieth M.Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo.Gastroenteorlogy,2004;127:706-713.
16 Nathanson MH.Confocal colonoscopy,more than skin deep.Gastorenterology,2004;127(3):987-989.
17 DaCostaR S,WilsonB C,MarconN E.Opticalte chniques for the endoscopic detection of dysplastic colonicl esions.Curr Opin Gastroenteod,2005;21:70 -79.
18 Sakashita M,Inoue H,Kashida H.Virtual histology of colorectal lesions using laser-scanning confocal microscopy.Endoscopy,2003;35;1033-1038.
19 Koenig F,Knittel J,Stepp H.Diagnosing cancer in vivo.Science,2001;292;1401-1403
20 Dixon MF,Genta RM,Yardley JH et al.Classification and grading of gastritis.The updated Sydney System.International Workshop on the Histopathology of Gastritis,Houston 1994.Am J Surg Pathol 1996;20:1161-1181
21 刘昊,陈美兰,郭仁舆.激光荧光检查法在肿瘤定位诊断中的应用西安交通大学学报(医学版)2007:28(4):455-457
22 GreavesMF,Hariri G,Newman RA,et al.Selective expression of the common acute lymphoblastic leukemia(gp 100)antigen on GIMmature lymphoid cells and their malignant counterparts.Blood,1983;61:628-39.
23 Tsukamoto T,Mizoshita T,Tatematsu.Gastric-and-intestinal mixed-type intestinal metaplasia:aberrant expression of transcription factors and stem cell intestinalization.Gastric Cancer.2006;9(3):156-66.
1 Walker MM. Is intestinal metaplasia of the stomach reversible? Gut 2003; 52: 1-4.
2 Zhou L, Sung JJ, Lin S, Jin Z, Ding S, Huang X, et al. A five-year follow-up study on the pathological changes of gastric mucosa after H. pylori eradication. Chin Med J (Engl)2003;116: 11-14.
3 Kato I, Vivas J, Plummer M, Lopez G, Peraza S, Castro D,et al. Environmental factors in Helicobacter pylori-related gastric precancerous lesions in Venezuela. Cancer Epidemiol Biomarkers Prev 2004; 13: 468-476.
4 You WC, Zhang L, Gail MH, Li JY, Chang YS, Blot WJ, et al. Precancerous lesions in two counties of China with contrasting gastric cancer risk. Int J Epidemiol 1998; 27: 945-948.
5 Sauerbruch T, Schreiber MA, Schussler P, Permanetter W. Endoscopy in the diagnosis of gastritis: diagnostic value of endoscopic criteria in relation to histological diagnosis. Endoscopy 1984; 16: 101-104
6 Kaminishi M, Yamaguchi H, Nomura S et al. Endoscopic classification of chronic gastritis based on a pilot study by the Research Society for Gastritis. Dig Endosc 2002;14:138-151
7 Uedo N, Ishihara R, Iishi H et al. A new method of diagnosing gastric intestinal metaplasia: narrow-band GIMaging with magnifying endoscopy. Endoscopy 2006; 38: 819-824
8 Dinis-Ribeiro DM, da Costa-Pereira C, Lopes C et al. Magnification chromoendoscopy for the diagnosis of gastric intestinal metaplasia and dysplasia. Gastrointest Endosc 2003;57: 498-504
9 KGIM S, Harum K, Ito M et al. Magnifying gastroendoscopy for diagnosis of histologic gastritis in the gastric antrum. Dig Liver Dis 2004; 36: 286-291
10 Gheorgh C. Narrow-band GIMaging endoscopy for diagnosis of malignant and premalignant gastrointestinal lesions. J Gastrointestin Liver Dis 2006; 15: 77-82
11 Nakayoshi T, Tajiri H, Matsuda K et al. Magnifying endoscopy combined with narrow band GIMaging system for early gastric cancer: correlation of vascular pattern with histopathology [including video]. Endoscopy 2004; 36: 1080-1084
12 Kara MA, Ennahachi M, Fockens P et al. Detection and classification of the mucosal and vascular patterns (mucosal morphology) in Barrett's esophagus by using narrow band GIMaging. Gastrointest Endosc 2006; 64: 155-166
13 Ydgi K, Honda H, Yang JM,et al. Magnifying endoscopy in gastritis of the corpus. Endoscopy 2005; 37: 660-666
14 Dixon MF, Genta RM, Yardley JH et al. Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994. Am J Surg Pathol 1996; 20: 1161-1181
15 Lin BR, Shun CT, Wang TH et al. Endoscopic diagnosis of intestinal metaplasia of stomach-accuracy judged by histology. Hepatogastroenterology 1999; 46:162-166
16 Kiesslich R, Gossner L, Goetz M et al. In vivo histology of Barrett's esophagus and associated neoplasia by Confocal laser endomicroscopy. Clin Gastroenterol Hepatol 2006; 4: 979-987
17 You WC, Zhang L, Gail MH, et al. Precancerous lesions in two counties of China with contrasting gastric cancer risk. Int J Epidemiol. 1998; 27(6):945-8.
18 Morson BC. Intestinal metaplasia of the gastric mucosa. Br J Cancer. 1955; 9:365-367
19 Correa PA. Human model of gastric carcinogenesis. Cancer Res,1988; 48:3554-3560;
20 Lauren P. The two histological main type of gastric carcinoma: diffuse and so-called intestinal type carcinoma. Acta Path Microbiol Scand, 1965,64:31-49,
21 Matsukura N, Shirota A, Maruyama K. Recent advances in research on the intestinal metaplasia of the stomaeh. Gan To Kagaku Ryoho.1983 ; 10(2PtZ):471-81.
22 Oohara T, Aono G, Ukawa S, Takezoe K, JohjGIMa Y, Kurosaka H, Asakura R, Tohma H.Clinical diagnosis of minute gastric cancer less than 5 mm in diameter.Cancer. 1984; 53(1): 162-5.
23 Rubio CA, Kato Y, Sugano H, etal.Intestinal metaplasia of the stomach in Smedish and Japanese Patients without ulcers or careinoma. Jpn J Caneer Res. 1987; 78:467-472.
24 Mutoh H,Sakurai S,Satoh K,etal.Development of gastric careinoma from intestinal metaplasia in CDX2-transgenic mice.Caneer Res.2004;64(21):7740-7.
25周丽雅,李建辉,林三仁,等.胃粘膜肠上皮化生的内镜分析.中华消化内镜杂志,2001:18:84-86.
26 Fennerty MB,Emerson JC,Smapliner RE,etal.Gastric intestinal metaplasia in ethnic groups in the Southwestern United States.Cancer Epidemiol Biomarkers Prev.1992:1:293-296.
27 Kaminishi M,Yamaguchi H,Nomura S et al.Endoscopic classification of chronic gastritis based on a pilot study by the Research Society for Gastritis.Dig Endosc 2002;14:138-151
28 Sirigu F Dessi A Toeeo G etal.Intestinal metaplasia of the gastric mucosa:a study of its incidence in various disease states.Riv Eur Sci Med Farmaeol.1991;13(1-2):25-8
29 SuzukiS,MurakamiH,SuzukiH,etal.An endoscopic staining method for detection and operation of early gastric caneer.Int Adv Surgoneol.1979:2:223-41.
30 KohliY,HattoriS,KodamaT,etal.Endoseopic diagnosis of intestinal metaplasia in asymptomatic(control)volunteers.Gastroenterol Jpn.1979:14(1):14-18
31 HashGIMotoT,SuzukuS,Haseg T,et al.Application of the methylene blue staining method to the study of experGIMentally PNNG-induced intestinal metaplasia of the canine stomaeh.Endoseopy.1980;12(5):205-10.
32 Wo JM,Ray MB,Mayfield-Stokes S,et al.Comparison of methylene blue-directed biopsies and conventional biopsies in the detection of intestinal metaplasia and dysplasia in Barrett's esophagus:a prelGIMinary study.Gastrointest Endosc.2001;54(3):294-301.
33 Yang JM,Chen L,Fan YL,et al.Endoseopic patterns of gastric mucosa and its clinico pathological significance.World J Gastroenterol.2003;9(11):2552-6.
34 黄永辉,周丽雅,林三仁,等.放大内镜下胃小凹形态学分类及其临床病理意义.中国内镜杂志.200:410(3):14-16
35 郭玉婷,李延青,赵幼安,等.共聚焦激光内镜对胃粘膜肠上皮化生的诊断价值.中华消化内镜杂志,2007:24(1):8-13
36 刘昊,陈美兰,郭仁舆.激光荧光检查法在肿瘤定位诊断中的应用西安交通大学学报(医学版).2007:28(4):455-457
37 Amano Y,Kushiyama Y,Ishihara S,et al.Crystal violet chromoendoscopy with mucosal pit pattern diagnosis is useful for surveillance of short-segment Barrett's esophagus.Am J Gastroenterol.2005;100(1):21-6.
38 Tajiri H,Doi T,Endo H,et al.Routine endoscopy using a magnifying endoscope for gastric cancer diagnosis.Endoscopy.2002;34(10):772-7.
39 Endo T,Awakawa T,Takahashi H,et al.Classification of Barrett's epithelium by magnifying endoscopy.Gastrointest Endosc.2002;55(6):641-7.
40 Pohl J,May A,Rabenstein T,et al.Computed virtual chromoendoscopy:a new tool for enhancing tissue surface structures.Endoscopy.2007;39(1):80-3.
41 Mayinger B,Oezturk Y,Stolte M,et al.Evaluation of sensitivity and inter- and intra-observer variability in the detection of intestinal metaplasia and dysplasia in Barrett's esophagus with enhanced magnification endoscopy.Scand J Gastroenterol.2006;41(3):349-56.
1 Neugut AI, Hayek M, Howe G. Epidemiology of gastric cancer. Semin Oncol, 996;23:281-91.
2 Correa P . Human gastric carcinogenesis: a multistep and multifactorial process. First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res 1992; 52:6735-40.
3 Correa P, Cuello C, Duque E, et al. Gastric cancer in Colombia. III. Natural history of precursor lesions. J Natl Cancer Inst 1976; 57:1027-35.
4 Correa P, Cuello C, Haenszel W. The pathogenesis of gastric carinoma-epidemiologic pathology of precursor lesions. Leber Magen Darm 1976; 6:72-9.
5 ShGIMoyama T, Fukuda S, Tanaka M, Nakaji S, Munakata A. Evaluation of the applicability of the gastric carcinoma risk index for intestinal type cancer in Japanese patients infected with Helicobacter pylori.Virchows Arch. 2000; 436(6):585-7.
6 Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M, Taniyama K, Sasaki N, Schlemper RJ.Helicobacter pylori infection and the development of gastric cancer.N Engl J Med. 2001 13;345(11):784-9.
7 Genta RM. Review article: Gastric atrophy and atrophic gastritis-nebulous concepts in search of a definition. AlGIMent Pharmacol Ther 1998; 12 Suppl 1:17 - 23.
8 Leung WK, Sung JJ. Review article: intestinal metaplasia and gastric carcinogenesis. AlGIMent Pharmacol Ther 2002; 16:1209 - 16.
9 Correa P, Fontham ET, Bravo JC, et al. Chemoprevention of gastric dysplasia: randomized trial of antioxidant supplements and anti-Helicobacter therapy. J Natl Cancer Inst 2000; 92:1881 - 8.
10 Sung JJ, Lin SR, Ching JY, et al. Atrophy and intestinal metaplasia one year after cure of H. pylori infection: a prospective, randomized study. Gastroenterology 2000; 119:7 -14.
11 Leung WK, Lin SR, Ching JY, et al. Factors predicting progression of gastric intestinal metaplasia: results of a randomised trial on Helicobacter pylori eradication. Gut 2004; 53:1244-9.
12 You WC, Zhang L, Gail MH, Li JY, Chang YS, Blot WJ, et al. Precancerous lesions in two counties of China with contrasting gastric cancer risk. Int J Epidemiol 1998; 27: 945-948.
13 Rokkas T, Filipe MI, Sladen GE. Detection of an increased incidence of early gastric cancer in patients with intestinal metaplasia type III who are closely followed up. Gut 1991; 32: 1110-1113
14 Dixon MF, Genta RM, Yardley JH et al. Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994. Am J Surg Pathol 1996; 20: 1161-1181
15 Leung WK, Ng EK, Chan WY, et al. Risk factors associated with the development of intestinal metaplasia in first-degree relatives of gastric cancer patients.Cancer Epidemiol Biomarkers Prev. 2005; 14(12):2982-6.
16 You WC, Li JY, Blot WJ,et al. Evolution of precancerous lesions in a rural Chinese population at high risk of gastric cancer.
17 Sipponen P, Kosunen TU, Valle J, et al. Helicobacter pylori infection and chronic gastritis in gastric cancer. J Clin Pathol 1992; 45:319-323.
18 Filipe MI, Munoz N, Matko I, et al. Intestinal metaplasia types and the risk of gastric cancer and the risk of gastric cancer: a cohort study in Slovenia. Int J Cancer 1994; 57: 324-9.
19 Meining A, Morgner A, Miehlke S, et al. Atrophy-metaplasia-dysplasia-carcinoma sequence in the stomach: a reality or merely an hypothesis? Best Pract Res Clin Gastroenterol 2001; 15: 983-998
20 Rokkas T, Filipe MI, Sladen GE. Detection of an increased incidence of early gastric cancer in patients with intestinal metaplasia type III who are closely followed up. Gut 1991;32: 1110-1113.
21 Dinis-Ribeiro M, Lopes C, da Costa-Pereira A, et al. A follow up model for patients with atrophic chronic gastritis and intestinal metaplasia. J Clin Pathol 2004; 57 : 177-182
22 Lin BR, Shun CT, Wang TH et al. Endoscopic diagnosis of intestinal metaplasia of stomach - accuracy judged by histology. Hepatogastroenterology 1999; 46:162-166
23周丽雅,李建辉,林三仁等.胃粘膜肠上皮化生的内镜分析.中华消化内镜杂志.2001:18(2):84-86.
24 Rokkas T,Filipe Ml,Sladen GE.Detection of an increased incidence of early gastric cancer inpatients with intestinal metaplasia type Ⅲ who are closely followed up.Gut.1991;32:1110-1113;
25 Jass JR,Filipe MI.Sulphomucins and precancerous lesions of the human stomach.Histopathology 1980;4:271-9.
26 Tosi P,Filipe MI,Baak JP et al.Morphometric definition and grading of gastric intestinal metaplasia.J Pathol 1990;161:201-208
27 Kiesslich R,Gossner L,Goetz M et al.In vivo histology of Barrett's esophagus and associated neoplasia by confocal laser endomicroscopy.Clin Gastroenterol Hepatol 2006;4:979-987
28 Kiesslich R,Burg J,Vieth M et al.Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo.Gastroenterology 2004;127:706-713
29 Aydin O,Egilmez R,Karabacak T,Kanik A.Interobserver variation in histopathological assessment of Helicobacter pylori gastritis.World J Gastroenterol.2003;9(10):2232-5.
30 Uedo N,Ishihara R,Iishi H et al.A new method of diagnosing gastric intestinal metaplasia:narrow-band imaging with magnifying endoscopy.Endoscopy 2006;38:819-824
31 游伟程,李吉友,昌云生等.胃癌高发区人群胃粘膜不同病变的转化与暴露时间关系的分析.中华肿瘤杂志,1991:13(2):100-102
32 Parkin DM,Bray FI,Devesa SS.Cancer burden in the year 2000.The global picture.Eur J Cancer 2001;37(Supp18):S4-66.
33 Rugge M,Genta RM.Staging and grading of chronic gastritis.Hum Pathol 2005;36:228-233.
34 Testino G.Gastric preneoplastic changes.Recenti Prog Med 2004;95:239-244.
35 Segura DI,Montero C.Histochemical characterization of different types of intestinal metaplasia in gastric mucosa.Cancer.1983:52(2):498-500.
36 Fang DC,Liu W.Different types of intestinal metaplasia and Gastric cancer:a clinico-endoseopic follow-up of 112 cases.Zhonghua Nei Ke Za Zhi 1990;29(8):465-8,509-10.
37 Sirigu F,Dessi A,Toeeo G,et al.Intestinal metaplasia of the gastric mucosa:a study of its incidence in various disease states.Riv Eur Sci Med Farmacol 1991;13(1-2):25-8.
38 Turani H,Lurie B,ChaGIMoff C,etal.The diagnostic significance of sulphated acid mucin content in gastric intestinal metaplasia with early gastric caneer.Anl J Gastroenterol.1986:81(2):343-345.
39 Filipe MI,Potet F,Bogomoletz WV,et al.Incomplete sulphomucin secreting intestinal metaplasia for gastric caneer.PrelGIMinary data from a prospective study from three centres.Gut.1985;26(4):1319-1321.
40 李宁,祝庆孚,李维华.胃粘膜肠上皮化生中凝集素受体的分布和分型与胃癌发生的关系.中华病理学杂志1992:21(4):373-375
41 Dinis-Ribeiro M,daCosta-Pereira A,Lopes C,et al.Magnification Chromoendoscopy for the diagnosis of gastricintestinal metaplasia and dysplasia.Gastrointest Endosc 2003;57(4):498-504.
42 Yang JM,Chen L,Fan YL,et al.Endoseopic patterns of gastric mucosa and its clinic pathological significance.World J Gastroenterol 2003;9(11):2552-6.
43 黄永辉,周丽雅,林三仁,等.放大内镜下胃小凹形态学分类及其临床病理意义.中国内镜杂志.2004;10(3):14-16
44 郑京华,魏虹,杨海燕,等.胃粘膜萎缩及伴肠上皮化生的可视性诊断.潍坊医学院学报2001:23(2):116-117.
45 Tsukamoto T,Mizoshita T,Tatematsu M et al.Gastric-and-intestinal mixed-type intestinal metaplasia:aberrant expression of transcription factors and stem cell intestinalization.Gastric Cancer 2006;9:156-166
46 Inada K,Tanaka H,Nakanishi H,et al.Identification of Paneth cells in pyloric glands associated with gastric and intestinal mixed-type intestinal metaplasia of the human stomach.Virchows Arch 2001;439:14-20.
47 Kakeji Y,Yamaguchi S,Yoshida D,et al.Development and assessment of morphologic criteria for diagnosing gastric cancer using Confocal endomicroscopy: an ex vivo and in vivo study. Endoscopy 2006; 38: 886-890.
48 Rugge M, Correa P, Dixon MF, et al. Gastric mucosal atrophy: interobserver consistency using new criteria for classification and grading. AlGIMent Pharmacol Ther, 2002; 16: 1249-1259.
49 Lauwers GY, Riddell RH. Gastric epithelial dysplasia. Gut 1999; 45 : 784-790.
50 Rugge M, Correa P , Dixon MF ,et al . Gastric Dysplasia . The Padova international classification. Am J Surg Pathol, 2000; 124 :167-176.
51 Tosi P, Filipe MI, Luzi P, et al. Gastric intestinal metaplasia type III cases are classified as low-grade dysplasia on the basis of morphometry. J Pathol 1993; 169:73-8.
52 Dixon MF.Prospcets for intervention in gastric carcinogenesis: reversibility of gastric atrophy and intestinal metaplasia.Gut. 2001; 49:2-4.
53 宋艳,李凌．肠道上皮特异性基因CDX2．世界华人消化杂志 2004：12(2)：443—445．
54 Mutoh H,Satoh K, Kita H, et al.CDX2 specifies the differentiation of morphological as well as functional absorptive enterocytes of the small intestine. Int J Dev Biol,2005;49(7):867-71.
55 Hinoi T, Gesina G, Akyol A, et al.CDX2-regulated expression of iron transport protein hephaestin in intestinal and colonic epithelium.Gastroenterology,2005;128(4):946-61.
56 Mizoshita T, Inada K, Tsukmaoto T, et al. Expression of cdx1 and CDX2 mRNAs and relevance of this expression to differentiation in human gastrointestinal mucosa-with special emphasis on participation in intestinal metaplasia of the human stomach. Gastric Cancer. 2001; 4(4): 185-91.
57 Silberg DG, Sullivan J, Kang E, et al. CDX2 ectopic expression induces gastricintestinal metaplasia in transgenic mice. Gastroenterology.2002; 122(3):689-96.
58 Suh E, Traber PG. Aninte stine-spceific homeoboxgene regulates proliferation and differentiation. Mol Cell Biol. 1996 ;16(2):619-25.
59 Eda A, Oswaa H, Yanaka I, et al. Expression of homeobox gene CDX2 procedes that of CDX1 during the progression of intestina lmetaplasia. J Gastroenterol. 2002; 37(2):94-100.
60 Bai YQ, Ymaamoto H, Akiyama Y, et al. Eetopic expression of homeodomain protein CDX2 in intestinal metaplasia and carcinomas of the stomach. Cancer Lett. 2002 ;176(1):47-55.
61 Bai Y, AkiyamaY, Nagasaki H, et al. Distinct expression of CDX2 and GATA4/5. development-related genes, in human gastric cancer cell lines. Mol Carcinog. 2000 ; 28(3): 184-8.
62 Mutoh H, Sakurai S, Satoh K, et al. Development of gastric carcinoma from intestinal metaplasia in CDX2-transgenic mice.Cancer Res.2004; 64(21):7740-7.
63 Hamilton SR. Molecular genetics of colorectal carcinoma . Cancer , 1992 ;70 (5 Suppl) :121621221.
1. Neugut AI, Hayek M, Howe G. Epidemiology of gastric cancer. Semin Oncol 1996; 23:281-91.
2. Correa P, Cuello C, Duque E, et al. Gastric cancer in Colombia. III. Natural history of precursor lesions. J Natl Cancer Inst 1976; 57:1027-35.
3. Correa P, Cuello C, Haenszel W. The pathogenesis of gastric carcinoma—Epidemiologic pathology of precursor lesions. Leber Magen Darm 1976; 6:72-9.
4. Correa P. Human gastric carcinogenesis: A multistep and multifactorial process-First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res 1992; 52:6735-40.
5. Nomura A, Stemmermann GN. Helicobacter pylori and gastric cancer. J Gastroenterol Hepatol 1993; 8:294 -303.
6. Rugge M, Leandro G, Farinati F, et al. Gastric epithelial dysplasia. How clinicopathologic background relates to management. Cancer 1995; 76:376-82.
7. Rugge M, Cassaro M, Leandro G, et al. Helicobacter pylori in promotion of gastric carcinogenesis. Dig Dis Sci 1996; 41: 950-5.
8. Infection with Helicobacter pylori. IARC Monogr Eval Carcinog Risks Hum 1994; 61:177-240.
9 .Correa P, Haenszel W, Cuello C, et al. Gastric precancerous process in a high risk population: Cross-sectional studies. Cancer Res 1990; 50:4731-6.
10. Ihamaki T, Sipponen P, Varis K, et al. Characteristics of gastric mucosa which precede occurrence of gastric malignancy: Results of long-term follow-up of three family samples. Scand J Gastroenterol 1991; 186(suppl):16-23.
11 Kokkola A, Haapiainen R, Laxen F, et al. Risk of gastric carcinoma in patients with mucosal dysplasia associated with atrophic gastritis: A follow up study. J Clin Pathol 1996; 49: 979-84.
12. Dixon MF. Histological responses to Helicobacter pylori infection: Gastritis, atrophy and preneoplasia. Baillieres Clin Gastroenterol 1995; 9:467- 86.
13. Dixon MF, Genta RM, Yardley JH, Correa P. Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994. Am J Surg Pathol 1996; 20:1161- 81.
14 Rugge M, Cassaro M, Farinati F, et al. Helicobacter pylori and atrophic gastritis: GIMportance of the cagA status. J Natl Cancer Inst 1996; 88:762-3.
15. Jass JR, Filipe ML Sulphomucins and precancerous lesions of the human stomach. Histopathology 1980; 4:271-9.
16. Yu-ting Guo, Yan-qing Li, Tao Yu, et al. Diagnosis and Classification of gastric intestinal metaplasia with Confocal laser endoscopy in vivo: a prospective study. Endoscopy 40: 1-7
17．中华医学会消化病学分会．全国慢性胃炎研讨会共识意见．中华消化杂志2000；20(3)：199—201
18. Cassaro M, Rugge M, Gutierrez O, et al.Topographic patterns of intestinal metaplasia and gastric cancer. Am J Gastroenterol. 2000 ; 95(6): 1431-8.
19. Genta RM, Lew GM, Graham DY. Changes in the gastric mucosa following eradication of Helicobacter pylori. Mod Pathol 1993; 6:281-9.
20. Wyatt JI. Histopathology of gastroduodenal inflammation: The GIMpact of Helicobacter pylori. Histopathology 1995; 26: 1-15.
21. Stemmermann GN, Hayashi T. Intestinal metaplasia of the gastric mucosa: A gross and microscopic study of its distribution in various disease states. J Natl Cancer Inst 1968;41:627-34.
22. Nakahara K. Special features of intestinal metaplasia and its relation to early gastric carcinoma in man: Observation by a method in which leucine aminopeptidase activity is used. J Natl Cancer Inst 1978; 61:693-701.
23. KGIMura K. Chronological transition of the fundic-pyloric border determined by stepwise biopsy of the lesser and greater curvatures of the stomach. Gastroenterology 1972; 63:584-92.
24. KGIMura K, Satoh K, Ido K, et al. Gastritis in the Japanese stomach. Scand J Gastroenterol 1996; 214(suppl):17-20.
25 Stemmermann GN. Intestinal metaplasia of the stomach. A status report. Cancer 1994; 74:556-64.
26 Guelrud M, Herrera I, Essenfeld H, et al. Intestinal metaplasia of the gastric cardia: A prospective study with enhanced magnification endoscopy. Am J Gastroenterol. 2002; 97(3):584-9
27 Sharma P, McElhinney C, Topalovski M, et al. Detection of cardia intestinal metaplasia: do the biopsy number and location matter? Am J Gastroenterol. 2004; 99(12):2424-8.
28. Soren A. Joint inflammations as complications in intestinal inflammations. Z Rheumatol 1981;40:1-5.
29. Utriainen M, Hanninen ML. Detection of Helicobacter-like bacteria in porcine gastric biopsy samples by amplification of 16S rRNA, ureB, vacA and cagA genes by PCR. Vet Res Commun 1998; 22:373- 83
30 .Savalgi RS, Corbishley CM, Caygill C,et al. Relation between severity and extent of precancerous lesions in the postoperative stomach. Lancet. 1990 Aug 18;336 (8712):413-6.
31 .Fraser AG, Peng SL, Jass JR. Intestinal metaplasia subtypes and Helicobacter pylori infection: a comparison of ethnic groups in New Zealand. J Gastroenterol Hepatol. 1998; 13(6):560-5.
32 .Kapadia CR. Gastric atrophy, metaplasia, and dysplasia: a clinical perspective. J Clin Gastroenterol. 2003; 36(5 Suppl):S29-36; discussion S61-2.
33 .Testino G. Gastric precancerous changes: carcinogenesis, clinical behaviour GIMmunophenotype study and surveillance. Panminerva Med. 2006; 48(2): 109-18.
34 .Stemmermann GN. Intestinal metaplasia of the stomach. A status report. Cancer. 1994 Jul 15;74(2):556-64.
35 .Mastracci L, Bruno S, Spaggiari P, et al. The GIMpact of biopsy number and site on the accuracy of intestinal metaplasia detection in the stomach A morphometric study based on virtual biopsies. Dig Liver Dis. 2008 Apr 9 [Epub ahead of print]
36 .El-ZGIMaity HM, Ota H, Graham DY, et al. Patterns of gastric atrophy in intestinal type gastric carcinoma.Cancer. 2002; 94(5): 1428-36
1 Walker MM. Is intestinal metaplasia of the stomach reversible? Gut 2003; 52: 1-4
2 Zhou L, Sung JJ, Lin S et al. A five-year follow-up study on the pathological changes of gastric mucosa after H. pylori eradication. Chin Med J (Engl) 2003; 116:11-14
3 Kato I, Vivas J, Plummer M et al. Environmental factors in Helicobacter pylori-related gastric precancerous lesions in Venezuela. Cancer Epidemiol Biomarkers Prev 2004; 13: 468-476
4 Sauerbruch T, Schreiber MA, Schussler P et al. Endoscopy in the diagnosis of gastritis: diagnostic value of endoscopic criteria in relation to histological diagnosis. Endoscopy 1984; 16: 101-104
5 Kaminishi M, Yamaguchi H, Nomura S et al. Endoscopic classification of chronic gastritis based on a pilot study by the Research Society for Gastritis. Dig Endosc 2002;14: 138-151
6 Uedo N, Ishihara R, Iishi H et al. A new method of diagnosing gastric intestinal metaplasia: narrow-band imaging with magnifying endoscopy. Endoscopy 2006; 38: 819-824
7 Dinis-Ribeiro DM, da Costa-Pereira C, Lopes C et al. Magnification chromoendoscopy for the diagnosis of gastric intestinal metaplasia and dysplasia. Gastrointest Endosc 2003; 57: 498-504
8 Kim S, Harum K, Ito M et al. Magnifying gastroendoscopy for diagnosis of histologic gastritis in the gastric antrum. Dig Liver Dis 2004; 36: 286-291
9 Gheorgh C. Narrow-band imaging endoscopy for diagnosis of malignant and premalignant gastrointestinal lesions. J Gastrointestin Liver Dis 2006; 15: 77-82
10 Nakayoshi T, Tajiri H, Matsuda K et al. Magnifying endoscopy combined with narrow band imaging system for early gastric cancer: correlation of vascular pattern with histopathology [including video]. Endoscopy 2004; 36: 1080-1084
11 Kara MA, Ennahachi M, Fockens P et al. Detection and classification of the mucosal and vascular patterns (mucosal morphology) in Barrett's esophagus by using narrow band imaging. Gastrointest Endosc 2006; 64: 155-166
12 Ydgi K, Honda H, Yang JM,et al. Magnifying endoscopy in gastritis of the corpus. Endoscopy 2005; 37: 660-666
13 Kiesslich R, Gossner L, Goetz M et al. In vivo histology of Barrett's esophagus and associated neoplasia by Confocal laser endomicroscopy. Clin Gastroenterol Hepatol 2006; 4: 979-987
14 Kiesslich R,Burg J,Vieth M et al. Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo. Gastroenterology 2004; 127:706-713
15 Kiesslich R, Goetz M,Burg J, Stolte M et al. Dignosing Helicobacter pylori in vivo by Confocal laser endoscopy. Gastroenterology 2005; 128: 2119-2123
16 Kakeji Y, Yamaguchi S, Yoshida D et al. Development and assessment of morphologic criteria for diagnosing gastric cancer using Confocal endomicroscopy: an ex vivo and in vivo study. Endoscopy 2006; 38: 886-890
17 Kitabatake S, Niwa Y, Miyahara R et al. Confocal endomicroscopy for the diagnosis of gastric cancer in vivo. Endoscopy 2006; 38: 1110-1114
18 Dixon MF, Genta RM, Yardley JH et al. Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994. Am J Surg Pathol 1996; 20: 1161-1181
19 Lin BR, Shun CT, Wang TH et al. Endoscopic diagnosis of intestinal metaplasia of stomach - accuracy judged by histology. Hepatogastroenterology 1999; 46:162-166
20 Sipponen P, Kosunen TU, Valle J et al. Helicobacter pylori infection and chronic gastritis in gastric cancer. J Clin Pathol 1992; 45:319-323
21 Filipe MI, Munoz N, Matko I et al. GIM types and the risk of gastric cancer: a cohort study in Slovenia. Int J Cancer 1994; 57: 324-329
22 Tosi P, Filipe MI, Baak JP et al. Morphometric definition and grading of gastric intestinal metaplasia. J Pathol 1990; 161: 201-208
23 You WC, Zhang L, Gail MH et al. Precancerous lesions in two counties of China with contrasting gastric cancer risk. Int J Epidemiol 1998; 27: 945-948
24 Tosi P, Filipe MI, Luzi P et al. Gastric intestinal metaplasia type III cases are classified as low-grade dysplasia on the basis of morphometry. J Pathol 1993; 169: 73-78
25 Meining A, Morgner A, Miehlke S et al. Atrophy-metaplasia-dysplasia-carcinoma sequence in the stomach: a reality or merely a hypothesis? Best Pract Res Clin Gastroenterol 200; 15: 983-998
26 Rokkas T, Filipe MI, Sladen GE. Detection of an increased incidence of early gastric cancer in patients with intestinal metaplasia type III who are closely followed up. Gut 1991; 32: 1110-1113
27 Dinis-Ribeiro M, Lopes C, da Costa-Pereira A et al. A follow up model for patients with atrophic chronic gastritis and intestinal metaplasia. J Clin Pathol 2004; 57: 177-182
1. Neugut AI, Hayek M, Howe G. Epidemiology of gastric cancer. Semin Oncol 1996; 23:281-91.
2. Correa P, Cuello C, Duque E, et al. Gastric cancer in Colombia. III. Natural history of precursor lesions. J Natl Cancer Inst 1976; 57:1027-35.
3. Correa P, Cuello C, Haenszel W. The pathogenesis of gastric carcinoma-Epidemiologic pathology of precursor lesions. Leber Magen Darm 1976; 6:72-9.
4. Correa P. Human gastric carcinogenesis: A multistep and multifactorial process-First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res 1992; 52:6735-40.
5. Nomura A, Stemmermann GN. Helicobacter pylori and gastric cancer. J Gastroenterol Hepatol 1993; 8:294-303.
6. Rugge M, Leandro G, Farinati F, et al. Gastric epithelial dysplasia. How clinicopathologic background relates to management. Cancer 1995; 76:376-82.
7. Rugge M, Cassaro M, Leandro G, et al. Helicobacter pylori in promotion of gastric carcinogenesis. Dig Dis Sci 1996; 41: 950-5.
8. Infection with Helicobacter pylori. IARC Monogr Eval Carcinog Risks Hum 1994; 61:177-240.
9 Correa P, Haenszel W, Cuello C, et al. Gastric precancerous process in a high risk population: Cross-sectional studies. Cancer Res 1990; 50:4731- 6.
10. Ihamaki T, Sipponen P, Varis K, et al. Characteristics of gastric mucosa which precede occurrence of gastric malignancy: Results of long-term follow-up of three family samples. Scand J Gastroenterol 1991; 186(suppl):16-23.
11 Kokkola A, Haapiainen R, Laxen F, et al. Risk of gastric carcinoma in patients with mucosal dysplasia associated with atrophic gastritis: A follow up study. J Clin Pathol 1996; 49: 979-84.
12. Dixon MF. Histological responses to Helicobacter pylori infection: Gastritis, atrophy and preneoplasia. Baillieres Clin Gastroenterol 1995; 9:467- 86.
13. Genta RM. Review article: Gastric atrophy and atrophic gastritis-nebulous concepts in search of a definition. Aliment Pharmacol Ther 1998; 12 Suppl 1:17-23.
14. Leung WK, Sung JJ. Review article: intestinal metaplasia and gastric carcinogenesis. Aliment Pharmacol Ther 2002; 16:1209 - 16.
15. Correa P, Fontham ET, Bravo JC, et al. Chemoprevention of gastric dysplasia: randomized trial of antioxidant supplements and anti-Helicobacter therapy. J Natl Cancer Inst 2000;92:1881 - 8.
16. Sung JJ, Lin SR, Ching JY, et al. Atrophy and intestinal metaplasia one year after cure of H. pylori infection: a prospective, randomized study. Gastroenterology 2000;119:7- 14.
17. Leung WK, Lin SR, Ching JY, et al. Factors predicting progression of gastric intestinal metaplasia: results of a randomised trial on Helicobacter pylori eradication. Gut 2004;53:1244-9.
18. Jass JR, Filipe MI. Sulphomucins and precancerous lesions of the human stomach. Histopathology 1980; 4:271-9.
19. Dixon MF, Genta RM, Yardley JH, Correa P. Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994. Am J Surg Pathol 1996; 20:1161- 81.
20. Groves FD, Perez-Perez G, Zhang L, et al. Serum antibodies to Helicobacter pylori and the CagA antigen do not explain differences in the prevalence of precancerous gastric lesions in two Chinese populations with contrasting gastric cancer rates. Cancer Epidemiol Biomarkers Prev 2002; 11:1091 - 4.
21 Rugge M, Cassaro M, Farinati F, et al. Helicobacter pylori and atrophic gastritis: GIMportance of the cagA status. J Natl Cancer Inst 1996; 88:762-3.
22 Guarner J, Herrera-Goepfert R, Mohar A, et al. Gastric atrophy and extent of intestinal metaplasia in a cohort of Helicobacter pylori-infected patients. Hum Pathol. 2001;32 (1):31-5.
23 Cassaro M, Rugge M, Gutierrez O, et al.Topographic patterns of intestinal metaplasia and gastric cancer. Am J Gastroenterol. 2000 ; 95(6): 1431-8.
24 Genta RM, Lew GM, Graham DY. Changes in the gastric mucosa following eradication of Helicobacter pylori. Mod Pathol 1993; 6:281-9.
25. Wyatt JI. Histopathology of gastroduodenal inflammation: The GIMpact of Helicobacter pylori. Histopathology 1995; 26: 1-15.
26. Stemmermann GN, Hayashi T. Intestinal metaplasia of the gastric mucosa: A gross and microscopic study of its distribution in various disease states. J Natl Cancer Inst 1968;41:627-34.
27. Nakahara K. Special features of intestinal metaplasia and its relation to early gastric carcinoma in man: Observation by a method in which leucine aminopeptidase activity is used. J Natl Cancer Inst 1978; 61:693-701.
28. KGIMura K. Chronological transition of the fundic-pyloric border determined by stepwise biopsy of the lesser and greater curvatures of the stomach. Gastroenterology 1972; 63:584-92.
29. KGIMura K, Satoh K, Ido K, et al. Gastritis in the Japanese stomach. Scand J Gastroenterol 1996; 214(suppl):17-20.
30 Stemmermann GN. Intestinal metaplasia of the stomach. A status report. Cancer 1994; 74:556-64.
31 Guelrud M, Herrera I, Essenfeld H, et al. Intestinal metaplasia of the gastric cardia: A prospective study with enhanced magnification endoscopy. Am J Gastroenterol. 2002; 97(3):584-9
32 Sharma P, McElhinney C, Topalovski M, et al. Detection of cardia intestinal metaplasia: do the biopsy number and location matter? Am J Gastroenterol. 2004; 99(12):2424-8.
33. Soren A. Joint inflammations as complications in intestinal inflammations. Z Rheumatol 1981;40:l-5.
34. Utriainen M, Hanninen ML. Detection of Helicobacter-like bacteria in porcine gastric biopsy samples by amplification of 16S rRNA, ureB, vacA and cagA genes by PCR. Vet Res Commun 1998; 22:373- 83
35 Savalgi RS, Corbishley CM, Caygill C,et al. Relation between severity and extent of precancerous lesions in the postoperative stomach. Lancet. 1990 Aug 18;336 (8712):413-6.
36 Fraser AG, Peng SL, Jass JR. Intestinal metaplasia subtypes and Helicobacter pylori infection: a comparison of ethnic groups in New Zealand. J Gastroenterol Hepatol. 1998; 13(6):560-5.
37 Kapadia CR. Gastric atrophy, metaplasia, and dysplasia: a clinical perspective. J Clin Gastroenterol. 2003; 36(5 Suppl):S29-36; discussion S61-2.
38 Testino G. Gastric precancerous changes: carcinogenesis, clinical behaviour GIMmunophenotype study and surveillance. Panminerva Med. 2006; 48(2): 109-18.
39 Stemmermann GN. Intestinal metaplasia of the stomach. A status report. Cancer. 1994 Jul 15;74(2):556-64.