弥漫性大B细胞淋巴瘤中YB-1核表达的临床意义

 目的　探讨Y-盒结合蛋白（YB-1）在弥漫性大B细胞淋巴瘤(DLBCL)中表达及其临床意义。方法　采用Envision两步法检测50例DLBCL和10例反应性淋巴结增生（RLH）患者石蜡标本中YB-1与增生细胞核抗原（PCNA）的表达,分析YB-1表达与临床参数及PCNA表达的关系。结果　DLBCL组与RLH组的YB-1胞质阳性表达率差异无统计学意义（P＞0.05）,而DLBCL组的YB-1胞核阳性表达率明显高于RLH组（P＜0.05）;DLBCL临床Ⅲ~Ⅳ期患者的YB-1胞核阳性表达率明显高于Ⅰ~Ⅱ期（P＜0.05）;结外淋巴组织侵犯组的YB-1胞核阳性表达率明显高于结内病变组（P＜0.05）;骨髓浸润组的YB-1胞核阳性表达率显著高于无骨髓浸润组（P＜0.05）;YB-1的胞核阳性表达与PCNA积分呈正相关（P＜0.05）;化疗无效组的YB-1核阳性表达率及PCNA积分均明显高于化疗有效组（P＜0.05）。结论　YB-1的核阳性表达可能参与了肿瘤的发生;YB-1核阳性表达与肿瘤的高侵袭力及肿瘤细胞的高增生能力密切相关,提示患者预后不良。     

MUC1、MUC2及MUC5AC在大肠黏液腺癌组织中的表达及意义

目的探讨黏蛋白MUC1、MUC2和MUC5AC在大肠黏液腺癌组织中的表达及意义。方法采用免疫组织化学法的SP法,检测40例大肠黏液腺癌组织中黏蛋白MUC1、MUC2和MUC5AC的表达。结果大肠黏液腺癌组织中MUC1、MUC2和MUC5AC的阳性表达率分别为55.0%、82.5%和77.5%。大肠黏液腺癌组织中MUC1、MUC2及MUC5AC的表达与肿瘤大小及分化程度无关(P>0.05),MUC1表达与浸润深度、淋巴结转移、Dukes分期呈负相关,而MUC2、MUC5AC表达与浸润深度、淋巴结转移、Dukes分期呈正相关(P<0.05)。结论MUC1、MUC2和MUC5AC的表达可预示大肠黏液腺癌的浸润转移潜能。     

黏蛋白MUC1和Cyclin D1在胰腺癌组织中的表达意义

目的探讨胰腺癌组织中黏蛋白MUC1和周期蛋白Cyclin D1的表达及其意义。方法采用免疫组化方法对47例胰腺癌和15例正常胰腺组织中的MUC1和Cyclin D1进行检测。结果 47例胰腺癌组织中有39例（82.98%）MUC1表达阳性和32例（68.09%）Cyclin D1表达阳性,15例正常胰腺组织中3例（2.00%）MUC1表达阳性和0例（0）Cyclin D1表达阳性;MUC1的表达和Cyclin D1的表达呈正相关;且MUC1的阳性表达在胰腺癌分期较晚和淋巴结转移的组织中明显高于分期较早和无淋巴结转移的组织（P〈0.05）;Cyclin D1在有淋巴结转移的胰腺癌组织中的表达明显高于无淋巴结转移的胰腺癌组织（P〈0.05）。结论 MUC1和Cyclin D1参与胰腺癌的发生发展,MUC1是胰腺癌诊断和治疗靶点的理想标志物。     

胆囊良恶性病变组织中MUC1和MUC5AC 表达及其临床病理意义

 目的 研究胆囊良恶性病变组织中黏液蛋白（MUC1和MUC5AC）表达水平及其临床病理意义。 方法 108例胆囊腺癌、46例癌旁组织、15例腺瘤和35例慢性胆囊炎手术切除标本常规制作石蜡包埋切片,MUC1和MUC5AC染色方法为Envision免疫组化法。 结果 胆囊腺癌MUC1阳性表达率明显高于癌旁组织（χ^２=16.49,P<0.01）、腺瘤（χ^２=7.40,P<0.01）和慢性胆囊炎（χ^２=28.57,P<0.01）。胆囊腺癌MUC5AC阳性表达率明显低于癌旁组织（χ２=12.83,P<0.01）、腺瘤（χ^２=4.22,P<0.05）和慢性胆囊炎（χ^２=20.25,P<0.01）。MUC1阳性表达和（或）MUC5AC阴性表达的良性病例的胆囊上皮均呈中至重度不典型增生。肿块最大径<2cm、无淋巴结转移、未侵犯周围组织的病例MUC1阳性表达率明显低于肿块最大径≥2cm、淋巴结转移和侵犯周围组织的病例（P<0.05或P<0.01）;高分化腺癌、肿块最大径<2cm病例MUC5AC阳性表达率明显高于低分化腺癌和肿块最大径≥2cm病例（P<0.05或P<0.01）。 结论 MUC1和MUC5AC的表达与胆囊腺癌的发生、临床生物学行为及预后有密切关系。     

HDAC1和CDK1在结肠癌组织中的表达及其临床意义

目的:研究组蛋白去乙酰化酶1（histone deacetylase 1,HDAC1）和细胞周期蛋白依赖性激酶1（cyclin-dependent kinase 1,CDK1）在结肠癌组织中的表达水平及其与患者临床病理特征及预后的关系。方法:收集2012年2月至2013年6月在本院普外科进行手术切除的51例结肠癌患者的肿瘤组织和癌旁非肿瘤组织,采用qRT-PCR法检测组织中HDAC1和CDK1 mRNA相对表达量,采用免疫组织化学染色法检测HDAC1和CDK1蛋白阳性表达率,分析肿瘤组织中HDAC1和CDK1表达的相关性及其与患者肿瘤直径、淋巴结转移等临床病理特征的关系,采用Kaplan-Meier生存函数分析HDAC1和CDK1不同表达情况与患者5年总生存率的关系。结果:肿瘤组织中HDAC1和CDK1 mRNA表达水平和蛋白阳性表达率均高于癌旁非肿瘤组织（P＜0.05）;肿瘤组织中HDAC1表达水平与CDK1表达水平呈显著正相关（P=0.012）;肿瘤组织中HDAC1表达与患者肿瘤直径和组织分化程度有关（P＜0.05）,CDK1与肿瘤直径、TNM分期、分化程度、淋巴结转移有关（P＜0.05）;HDAC1、CDK1阳性表达患者5年总生存率均低于其相应阴性表达患者（P＜0.05）,HDAC1和CDK1共阳性表达患者5年总生存率低于HDAC1和（或）CDK1阴性患者（P＜0.05）。结论:HDAC1和CDK1在结肠癌组织中高表达,与患者不良预后有关且两者呈正相关,推测两者在促进结肠癌进展中可能存在协同作用。     

牛磺酸上调基因1在弥漫性大B细胞淋巴瘤患者中的表达及其与预后的关系

目的:探讨牛磺酸上调基因1（taurine upregulated gene 1, TUG1）在弥漫性大B 细胞淋巴瘤（diffuse large B-cell Lymphoma,DLBCL）患者组织标本中的表达,分析TUG1 表达与DLBCL患者临床特征及其预后的关系。方法：收集108 例2011 年1 月至2016 年12 月在西南医科大学附属第一医院血液科确诊为DLBCL 的初诊患者和同期47 例反应性淋巴结增生（reactive lymphoid hyperplasia,RLH）患者的组织标本,通过qPCR方法检测DLBCL和RLH患者组织标本中TUG1 的表达,采用Chi-Square 检验、Kaplan-Meier 法和单因素及多因素分析法分别分析TUG1 mRNA表达水平与DLBCL患者临床病理特征的关系和影响DLBCL患者生存时间及预后的因素。结果：TUG1 mRNA在DLBCL患者组织中的表达显著高于RLH患者（6.108±0.332 vs 1.231±0.095,P<0.01）,TUG1 mRNA表达与DLBCL患者的疾病分期、肿瘤大小、B细胞症状、IPI 指数、GCB亚型及化疗敏感性显著相关（均P<0.01）,TUG1 表达量、疾病分期及肿瘤大小是影响DLBCL患者总生存时间（overall survival, OS）的因素。TUG1 mRNA表达、疾病分期、IPI 指数和化疗敏感性是影响DLBCL患者预后的因素。结论：TUG1 mRNA在DLBCL组织中高表达,是影响患者预后的独立因素,TUG1有可能成为DLBCL患者新的预后评估标志物和基因治疗DLBCL的潜在靶点。     

结肠直肠癌组织中粘蛋白MUC1和MUC2的表达及临床意义

背景与目的：粘蛋白MUC1的表达上调或MUC2的表达下调可能参与了肿瘤的发生,而MUC1和MUC2的表达中国人结肠直肠癌发生发展的关系未见报道。本研究的目的是探讨结肠直肠癌组织中粘蛋白MUC1和MUC2的表达与不同的临床病理参数间的关系及其临床意义。方法：采用免疫组化方法检测126例结肠直肠癌和20例正常结肠直肠粘膜中粘蛋白MUC1和MUC2的表达。结果：20例正常结肠直肠粘膜中粘蛋白MUC1和MUC2的表达阳性率分别为0和100％,而126例结肠直肠癌中粘蛋白MUC1和MUC2的阳性表达率分别为42．1％和36．5％（P＜0．01）;结肠直肠癌中粘蛋白MUC1的表达与肿瘤的浸润深度、淋巴结转移和Dukes分期呈正相关（P＜0．05）,与肿瘤的分化程度呈负相关（P＜0．01）;粘蛋白MUC2在结肠直肠癌中的表达与肿瘤的浸润浓度、淋巴结转移和Dukes分期密切相关（P＜0．05）,而与肿瘤的分化程度无关（P＞0．05）。结论：粘蛋白MUC1表达上调或MUC2表达下调可能参与了结肠直肠癌的发生发展,检测结肠直肠癌中粘蛋白MUC1和MUC2的表达可间接反映肿瘤的预后。     

MUC1在胰腺肿瘤中的表达及意义

目的探讨MUC1 在胰腺上皮内肿瘤、胰腺导管腺癌组织中的表达及其在胰腺癌早期诊断中的意义.方法应用免疫组化技术检测30例胰腺上皮内肿瘤（PanIN）、52例胰腺导管腺癌和10例正常胰腺组织中MUC1的表达.结果 3例PanIN1-2组织中MUC1阳性表达3/18（16.7%）,7例PanIN-3组织中MUC1阳性表达7/12（58.3%）,PanIN-3与PanIN1-2阳性表达率比较差异有显著意义（P=0.024,P〈0.05）.40例胰腺导管腺癌组织中MUC1阳性表达40/52（76.9%）, MUC1阳性表达与性别、肿块大小无关（P〉0.05）,与侵袭状况、淋巴结转移、肝转移有关（P〈0.05）;结论 MUC1可作为胰腺癌早期辅助诊断指标, 有可能成为胰腺癌免疫治疗的靶抗原.     

MUC1及同种型MUC1/Y基因mRNA在膀胱癌中的表达及临床意义

目的：探讨肿瘤相关抗原MUC1及同种型MUCI／Y粘蛋白基因在膀胱癌中mRNA的表达及其临床意义．方法：22例膀胱癌的组织样本（实验组）和10例正常膀胱组织样本（对照组）中提取总RNA，采用逆转录聚合酶链反应（RT-PCR）技术，检测两组样本中MUC1及同种型MUC1／Y粘蛋白基因mRNA表达水平，结果：膀胱癌组织的MUC1mRNA水平较正常膀胱组织显著增高（P〈0．01）；Ⅲ-Ⅳ期膀胱癌组织的MUC1／YmRNA水平较Ⅰ-Ⅱ期膀胱癌组织显著增高（P〈0．01）。结论：MUC1及同种型MUCI／Y粘蛋白基因mRNA表达水平与膀胱癌有关，对膀胱癌的诊断和治疗有临床意义一，     

MUC1基因在血液系统恶性肿瘤中的表达及临床意义

  目的 探讨MUC1基因在血液系统恶性肿瘤中的作用机制、临床意义及在肿瘤生物治疗中的应用前景。方法 应用半定量RT-PCR检测了55例血液系统恶性肿瘤患者的骨髓及外周血标本中MUC1基因的mRNA表达。其中多发性骨髓瘤（MM）10例、白血病21例、淋巴瘤24例,对照组外周血和骨髓各10例。结果 10例MM患者MUC1mRNA阳性表达率8／10（80 %）和12例急性髓性白血病（AML）阳性表达率7／12（58.3 %）均高于对照组1／10（10 %）（P＜0.05）。24例淋巴瘤患者阳性表达率13／24（54.1 %）,其中非霍奇金淋巴瘤（NHL）阳性表达率11／21（52.4 %）,霍奇金淋巴瘤（HD）阳性表达率2／3（66.7 %）,均高于对照组0／10（0）（P＜0.05）。MUC1高表达与AML患者的髓外浸润呈正相关,与淋巴瘤患者的分期呈正相关。结论 MUC1mRNA在血液系统恶性肿瘤中高表达,其表达与血液系统恶性肿瘤的病情进展及预后相关。为MUC1作为血液系统恶性肿瘤治疗性疫苗的研究从mRNA水平提供有力的证据。     

MUC1, MUC2, MUC5AC, and MUC6 expressions in gastric carcinomas: their roles as prognostic indicators.

BACKGROUND: Although mucin expressions appear to be correlated with prognoses in patients with various cancers, several studies have reported conflicting and inconclusive results on the prognostic significance of mucin expression in gastric carcinomas. METHODS: To clarify the correlations between clinicopathologic profiles and the patients' survival, the expression of MUC1, MUC2, MUC5AC, MUC6 mucins and the p53 protein were evaluated immunohistochemically in 300 consecutive gastric carcinomas using the tissue-array method. In addition, 59 gastric adenomas and 57 adenoma-associated carcinomas were investigated. RESULTS: MUC1 was expressed in 2 (3.4%) cases of gastric adenoma, and MUC2 in 19 (32.2%) cases of gastric adenoma, out of a total of 59 lesions. In consecutive gastric carcinomas, 24.3% of gastric carcinomas expressed MUC1, 27.3% expressed MUC2, 38.0% expressed MUC5AC and 12.7% expressed MUC6. The rate of MUC1 expression in gastric carcinomas was significantly higher than in associated gastric adenomas (P < 0.01). The patients with MUC1-positive carcinomas showed significantly poorer survival than those with MUC1-negative carcinomas. On the other hand, MUC2, MUC5AC and MUC6 expressions were not significantly associated with patient survival. Interestingly, combined evaluation revealed that the group with the MUC1-negative plus p53-negative expression pattern showed a better prognosis than the remaining cases. In contrast, the group with the MUC2-negative plus p53-positive pattern showed a worse prognosis. CONCLUSIONS: Mucin expression is altered in gastric adenoma and carcinoma, and MUC1 mucin expression is significantly associated with poorer outcome in gastric carcinomas. A MUC1-negative plus p53-negative pattern or a MUC2-negative plus p53-positive pattern may predict outcome in patients with gastric carcinomas.     

胃癌及癌前病变组织中MUC5AC基因的异常表达及意义

目的：揭示正常胃粘膜、癌前病变和胃癌组织中ＭＵＣ５ＡＣ基因的表达与其临床病理分型之间的联系。方法：应用免疫组织ＳＰ法检测人正常胃粘膜、癌前病变粘膜以及胃癌组织中ＭＵＣ５ＡＣ核蛋白的表达。结果：人正常胃中的浅表１／３范围内广泛分布ＭＵＣ５ＡＣ基因产物（１００％）,肠化、不典型增生和胃癌组织中的表达阳性率分别是２９．６％、１００％和４０．０％。胃癌组织中ＭＵＣ５ＡＣ核粘蛋白的表达与胃癌患者的性别、肿瘤     

Role of MUC1 and MUC5AC expressions as prognostic indicators in gastric carcinomas

BACKGROUND AND OBJECTIVES: The aim of this study is to clarify the relationship between the expression of MUC1 and MUC5AC mucins and the clinicopathological features in human gastric carcinomas using the mouse monoclonal antibodies VU-4H5 and Clone 45M1, respectively. Furthermore, the possibility of using phenotypes (MUC1+/MUC5AC+, MUC1+/MUC5AC-, MUC1-/MUC5AC-, MUC1-/MUC5AC+) to predict prognosis of the patients is evaluated. METHODS: Formalin-fixed, paraffin wax-embedded tissues from 76 cases of gastric cancer were examined for the expression of MUC1 and MUC5AC mucin antigens immunohistochemically using the avidin-biotin-peroxidase method. RESULTS: Of the 76 cases, MUC1 and MUC5AC immunoreactivities were observed in 49 (64.5%) and in 32 (42.1%) of gastric carcinoma tissues, respectively. MUC1 expression was significantly correlated to the depth of invasion, lymph node metastasis, peritoneal dissemination, and tumor stage. On the other hand, MUC5AC was inversely associated with depth of invasion, lymph node metastasis, liver metastasis, and tumor stage. Multivariate analyses indicated that tumor stage and MUC1 mucin expression were independently correlated with overall survival. The patients with MUC1+/MUC5AC- antigen staining in carcinoma tissues showed the lowest survival rate among four phenotypes. In contrast, the patients with MUC1-/MUC5AC+ antigen staining in carcinoma tissues showed the highest survival rate. CONCLUSIONS: Altogether these data suggest that combined evaluation of MUC1 and MUC5AC mucin staining may be clinically helpful to predict outcome in patients with gastric cancer.     

Prognostic value of serum MUC5AC mucin in patients with cholangiocarcinoma

BACKGROUND: The authors recently showed that MUC5AC mucin, which is expressed aberrantly in tumor tissue, is present in significant concentrations in serum from patients with cholangiocarcinoma. Subsequently, determination of serum MUC5AC had high sensitivity and specificity for cholangiocarcinoma. In this study, the possible association between serum MUC5AC mucin and the clinical findings of the patients and their prognostic value were explored. METHODS: The expression of MUC5AC mucin in serum samples from 179 patients with histologically confirmed cholangiocarcinoma were determined using immunoblotting. RESULTS: Detection of serum MUC5AC was associated with patients with blood group Type A, larger-sized tumors (> 5 cm), and advanced-stage disease. Patients who had positive serum MUC5AC status had a significantly poorer prognosis (median survival, 127 days; 95% confidence interval [95% CI], 107-180 days) compared with patients who had negative serum MUC5AC status (median survival, 329 days; 95% CI, 199-458 days; P < 0.001). Multivariate analysis with adjustment for all covariates showed that patients who had positive serum MUC5AC status had a 2.5-fold higher risk of death compared with patients who had negative serum MUC5AC status (P < 0.001). CONCLUSIONS: Serum MUC5AC was associated with tumor burden. The determination of serum MUC5AC may be predictive of poor patient outcome and may be useful in selecting possible treatment options for patients with cholangiocarcinoma. Cancer 2003;98:1438-43.     

Expression and localization of MUC1, MUC2, MUC5AC and small intestinal mucin antigen in pancreatic tumors

Alterations in the expression of mucin family members play an important role as well as alterations in oncogenes and onco-suppressor genes in carcinogenesis and progression of pancreatic cancer. We analyzed the expression and localization of MUC1, MUC2, MUC5AC and small intestinal mucin antigen (SIMA) in pancreatic tumors. MUC1 expression was observed in almost all samples, whereas MUC2 expression was not. MUC5AC expression was observed in 73.9% of the cancerous regions, 48.7% of the dysplastic regions and 72.0% of the hyperplastic regions but not in the normal pancreatic duct. SIMA expression was observed in 45.7% of cancerous regions, 17.9% of the dysplastic regions and 8.0% of the hyperplastic regions. Furthermore, stromal expression of MUC1, MUC5AC and SIMA was observed in 37.0%, 60.9% and 26.1% of the cancerous regions, respectively. Stromal expression of these mucins was not observed in the hyperplastic regions and normal pancreatic duct and was observed in only two dysplastic regions. The survival of pancreatic cancer patients with stromal expression of MUC1 or SIMA was worse than that of other patients (P=0.04). In conclusion, the localization of mucin expression, especially stromal expression of MUC1 or SIMA, might be a prognostic factor for patients with pancreatic cancer.     

结直肠癌组织中黏蛋白MUC2和MUC3的表达及临床意义

目的:探讨散发性结直肠癌组织中MUC2和MUC3的表达与临床病理参数间的关系及其临床意义。方法:采用免疫组化SP法检测90例结直肠癌和30例正常结直肠黏膜组织中MUC2和MUC3的表达。结果:30例正常结直肠黏膜组织中黏蛋白MUC2和MUC3的表达阳性率均为100％,而90例结直肠癌组织中MUC2和MUC3的阳性表达率分别为35．5％和52．2％(P< 0．05);MUC2和MUC3的表达与肿瘤的浸润深度、淋巴结转移和Dukes分期密切相关(P<0．05),黏蛋白MUC3与肿瘤的分化程度呈负相关(P<0．05)。结论:黏蛋白MUC2和MUC3在人结直肠癌组织中表达下调。     

Diagnostic value of mucins (MUC1, MUC2 and MUC5AC) expression profile in endoscopic ultrasound-guided fine-needle aspiration specimens of the pancreas

Mucins are aberrantly expressed in various malignancies. We immunohistochemically tested mucins expression (MUC1, MUC2 and MUC5AC) in EUS-FNA samples from pancreatic occupying lesions for the diagnostic utility. The prevalence of MUC1, MUC2 and MUC5AC expression in pancreatic cancers were 77.5% (31/40), 10.0% (4/40) and 80.0% (32/40), respectively, and in the benign pancreatic diseases 25% (4/16), 31.3% (5/16) and 43.8% (7/16). MUC1 and MUC5AC significantly overexpressed in pancreatic cancer, and MUC1 negatively related with tumor differentiation degree (p < 0.05). The prevalence of MUC1, MUC2 and MUC5AC expression in pancreatic mucinous neoplasms were 66.7% (12/18), 38.9% (7/18) and 88.9% (16/18), respectively, and in the pancreatic non-mucinous neoplasms 60.5% (23/38), 5.3% (2/38) and 57.9% (22/38). MUC2 and MUC5AC significantly overexpressed in pancreatic mucinous neoplasms, especially MUC2 in benign mucinous neoplasms (p < 0.05). Compared with cytology alone, the combination test of MUC1+cytology, and MUC5AC+cytology could achieve higher sensitivity (85 vs. 65%, 100 vs. 65%) and accuracy (89.3% vs. 73.2%, 91.1% vs. 73.2%) for pancreatic cancer diagnosis; the combination test of MUC2 + cytology, and MUC5AC + cytology could achieve higher sensitivity (77.8% vs. 38.9%, 100% vs. 38.9%), and specificity (97.4% vs. 60.5%, 71.1% vs. 60.5%) accuracy (100% vs. 51.8%, 80.4% vs. 51.8%) for mucinous neoplasm diagnosis. The panel MUC1+/MUC2-/MUC5AC+/ was higher specific in pancreatic cancer diagnosis, as well as MUC1-/MUC2+/MUC5AC+/ in pancreatic mucinous neoplasms. Our observations suggest the mucins expression profile in EUS-FNA specimens has higher value for the diagnosis of pancreatic cancer and mucinous neoplasms.     

Intestinal metaplasia of human stomach displays distinct patterns of mucin (MUC1, MUC2, MUC5AC, and MUC6) expression

Intestinal metaplasia is a well-established premalignant condition of the stomach that is characterized by mucin carbohydrate modifications defined by histochemical methods. The purpose of the present study was to see whether the expression of mucin core proteins was modified in the different types of intestinal metaplasia and to evaluate the putative usefulness of mucins as "molecular markers" in this setting. We used a panel of monoclonal antibodies with well-defined specificities to MUC1, MUC2, MUC5AC, and MUC6 to characterize the expression pattern of mucins. In contrast to normal gastric mucosa, the complete form or type I intestinal metaplasia (n = 20) displayed little or no expression of MUC1, MUC5AC, or MUC6 in the metaplastic cells and strong expression of the intestinal mucin MUC2 in the goblet cells of all cases. The incomplete forms of intestinal metaplasia, type II (n = 25) and type III (n = 16), expressed MUC1 and MUC5AC in every case, both in goblet and in columnar cells. MUC6 was also expressed in 16 cases of type II intestinal metaplasia and in 11 cases of type III intestinal metaplasia. The intestinal mucin MUC2 was expressed in every case of incomplete intestinal metaplasia, mostly in goblet cells. The mucin expression profile in the different types of intestinal metaplasia allows the identification of two patterns: one defined by decreased levels of expression of "gastric" mucins (MUC1, MUC5AC, and MUC6) and expression of MUC2 intestinal mucin, which corresponds to type I intestinal metaplasia, and the other defined by coexpression of "gastric mucins" (MUC1, MUC5AC, and MUC6) together with the MUC2 mucin, encompassing types II and III intestinal metaplasia. Our results challenge the classical sequential pathway of intestinal metaplasia (from type I to type III via a type II intermediate step).