胃癌及其癌前变化的临床问题

胃癌及其癌前变化的临床问题目录CONTENTS1.癌前病变的监测2.随访和管理3.胃癌的预防：成熟和研究中的1. 癌前病变的监测有关癌前病变的概念●WHO胃癌的癌前变化分为癌前疾病（癌前状态）和癌前病变，前者是指与胃癌相关的胃良性疾病，有发生胃癌的危险性；后者是指较易转变为癌组织的病理学变化，主要系指异性增生。

●国外学者将上述的癌前疾病和癌前病变统归为广义的癌前病变（precancerous lesion, precursor lesion），萎缩，肠化和异型增生均属于此。

●国内消化病理学术界尚未应用此广义的癌前病变概念。

Ma JL, et al. Fifteen-year effects of Helicobacter pylori, garlic, and vitamin treatments on gastric cancer incidence and mortality. J Natl Cancer Inst. 2012 Mar 21;104(6):488-92.Wong BC, et al. Effects of selective COX-2 inhibitor and Helicobacter pylori eradication on precancerous gastric lesions. Gut. 2012 Jun;61(6):812-8.Pimentel-Nunes P, et al. A multicenter validation of an endoscopic classification with narrow band imaging for gastric precancerous and cancerous lesions. Endoscopy. 2012 Mar;44(3):236-46.Chronic atrophic gastritis is a progressive disease: analysis of medical reports from Shanghai (1985-2009)Chooi EY, et al. Chronic atrophic gastritis is a progressive disease: analysis of medical reports from Shanghai (1985-2009). Singapore Med J. 2012 May;53(5):318-24.预测CAG数学模型及其多因素回归分析All the participants received endoscopy and histological examination as well as a standard questionnaire. Multivariate analysis was performed by logistic regression to build the CAG risk model. 63 subjects received another endoscopy after 1-year follow-up and divided into three groups according to the comparison of the histological results (improved, no change andworse).The model showed relatively good discrimination, with an AUROC of 0.888 (95% CI 0.852-0.925). A final probability cut-off score of 0.73 was used to predict the presence (>0.73) or absence of CAG (≤0.73). Sensitivity, specificity, PPV and NPV were 82.8%, 74.7%, 91.8% and 56%, respectively.扩大样本前瞻性研究The predicted results of 1418 subjects compared with the histological results were quite similar. There was a significant difference of the scores between three groups who were followed-up for 1 year (F = 3.248, p = 0.046).模型：CAG发生危险度= Y / (1+Y), 其中Y = exp (0.9829 –0.7103 * X1 + 0.8342 * X2 + 1.3059 * X3 - 1.1250 * X4 - 1.1254 * X5 - 1.4227 * X6 + 1.7224 * X7)参数X1 性别（女1，男2）X2 一般健康情况（健康1，普通2，差3，很差4）X3 胃癌家族史（有1，无0）X4 除胃癌之外的其他肿瘤家族史（有1，无0）X5 进餐时饮用汤、水（是1，否0）X6 喜好口味比较清淡（是1，否0）X7 饮酒（是1，否0）Gao QY, Fang JY, et al. A novel model might predict the risk of chronic atrophic gastritis: a multicenter prospective study in China. Scand J Gastroenterol. 2012 May;47(5):509-17.胃龄Stomach Age●胃的生物学年龄●真实反映胃衰老程度●同一年龄者可有不同的胃龄●胃龄的大小将依据端粒的长度进行测定，计算精确胃龄数学模型X (years) = (11.719 - Y) / 0.174Y 为FISH实验测定的荧光强度值X 则为精确胃龄胃龄简易数字模型胃龄（岁）= 实际年龄+ Δ年龄Stomach Age （years）= real age + ΔageΔage = 1.87 –0.45 * X1 –3.39 * X2 + 1.72 * X3 + 3.15 * X4 + 13.99 * X5 + 18.62 * X6 –16.96 * X7 + 18.16 * X8;X1 -X4 均来自胃镜病理诊断（无0，轻度1，中度2，重度3）X1 炎症，X2 活动性，X3 萎缩，X4 肠化X5 胃癌家族史（有1，无0）X6 有无合并心血管系统疾病（有1，无0）X7 有无合并胃食管反流性疾病（有1，无0）X8 每周进食垃圾食品/饮料的次数（有1，无0）不同Δage值的推荐使用范围胃癌高发地区患者：Δage>0标准，随访人群范围扩大，减少漏诊率胃癌一般发病率地区：Δage>3.11标准，随访人群相对减少，节约医疗费用Gao QY, Fang JY, et al. Evaluation and clinical significance of the stomach age model for evaluating aging of the stomach-a multicenter study in China. BMC Clin Pathol, 2014; 28:14-29.关于萎缩----假性萎缩的情况小凹上皮肠化淋巴滤泡占位溃疡/糜烂边缘粘膜不算萎缩性胃炎萎缩是否可逆转的可能预测可逆难或不可逆施尧.慢性胃炎的萎缩诊断标准和分期分级[J].胃肠病学,2006,11(4):195-197.AB-HID染色：1、AB阳性为小肠型肠化2、HID阳性为大肠型肠化3、均阳性为混合型肠化完全型肠化HE染色与小肠粘膜吸收细胞相似，有刷状缘，不分泌粘液，具有潘氏细胞、杯状细胞和吸收细胞AB-PAS染色：AB+PAS-不完全型肠化HE染色无刷状缘，刷状缘不明显，微绒毛发育不全，胞浆内有粘液分泌颗粒AB-PAS染色：AB+PAS+Fig.2. Morphologic changes in gastric mucosa during gastric carcinogenesis. c,d Moderate atrophy of deep antral glands (gland loss between 30% and 60%), without intestinal metaplasia: (c) H&E staining, ×40; (d) Periodic acid–Schiff (PAS) – alcian blue staining, ×40, highlighting gland loss and a single focus of intestinal metaplasia in the superficial part of the gastric mucosa. e,f Severe atrophy of antral mucosa, with loss of more than 60% of original mucous-secreting glands, replaced by intestinal metaplasia: (e) H&E, ×40; (f) PAS– alcian blue, ×40.A review of the evidence●对所有评估IM不同类型主体罹患胃癌的风险的横断面（n = 14）研究和随访（n =10）研究进行了检索●在14项横断面研究中，有13项研究表明：相较于其他胃部病变，广泛的不完整型肠化生在胃癌中有统计意义的显著增高●在10项随访研究中，6项研究发现不完全型肠化生与罹患胃癌的风险在统计学上有显著关联●在报道风险高低的研究中，存在不完全型肠化生与完整型或不存在不完整型相比，罹患胃癌的风险升高4-11倍●根据这一全面的综述，大部分科学证据支持IM分型对预测GC风险的价值Gonzalez CA, et al. Utility of subtyping intestinal metaplasia as marker of gastric cancer risk. A review of the evidence. Int J Cancer, 2013 Sep 1;133(5):1023-32.2. 随访与管理胃癌的早期筛查和检测：常用标志物灵敏度临床应用标志物截断值早期进展期筛查进展判断监测复发肿瘤抗原CEA 5.0ng/ml <20% 40-50% 可以可以CA19-9 37.0U/ml <20% 20-50% 可以可以CA72-4 6.0U/ml <20% 30-50% 可以可以AFP 5.0ng/ml 可以可以激素B-HCG 4pmol/l 20-53% 30-50% 可以蛋白酶Wu HH, et al. Advances in molecular biomarkers for gastric cancer: miRNAs as emerging novel cancer markers.Expert Review in Mol Med, 2014; 16: e1.癌前疾病的管理程序González C, Agudo A. Carcinogenesis, prevention and early detection of gastric cancer: where we are and where we should go. Int J Cancer. 2012 Feb 15;130(4):745-53.欧洲胃肠内镜学会等胃癌癌前状态处理共识意见Dinis-Ribeiro M, et al. Management of precancerous conditions and lesions in the stomach (MAPS): guideline from the European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter Study Group (EHSG), European Society of Pathology (ESP), and the Sociedade Portuguesa de Endoscopia Digestiva (SPED). Endoscopy 2012; 44: 74-94.3. 胃癌的预防：成熟的和研究中的Environmental, dietary and lifestyle factors associated with gastriccancer riskGonzález C, Agudo A. Int J Cancer. 2012 Feb 15;130(4):745-53.●在胃癌高发区的Hp根除治疗组（1130例）和安慰剂组（1128例）随访14.7年●胃癌的发生率分别是3.0%和4.6%；根除Hp可降低胃癌发生率，但对胃癌的死亡率降低无统计学意义大蒜素（提取物或提取油）干预组与维生素干预组短期随访无降低胃癌作用，但长期随访则有降低胃癌发生倾向不同组别和不同周期中胃癌的发生率干预7.3年，停药后又随访7年余Gastric cancer deaths in different interventionsVitmin treatment was associated with statistically significantly fewer deaths from gastric or esophageal cancer, a secondary endpointAbstractIn the Shandong Intervention Trial, 2 weeks of antibiotic treatment for Helicobacter pylori reduced the prevalence of precancerous gastric lesions, whereas 7.3 years of oral supplementation with garlic extract and oil (garlic treatment) or vitamin C, vitamin E, and selenium (vitamin treatment) did not. Here we report 14.7-year follow-up for gastric cancer incidence and cause-specific mortality among 3365 randomly assigned subjects in this masked factorial placebo-controlled trial. Conditional logistic regression was used to estimate the odds of gastric cancer incidence, and the Cox proportional hazards model was used to estimate the relative hazard of cause-specific mortality. All statistical tests were two-sided. Gastric cancer was diagnosed in 3.0% of subjects who received H pylori treatment and in 4.6% of those who received placebo (odds ratio = 0.61, 95% confidence interval = 0.38 to 0.96, P = .032). Gastric cancer deaths occurred among 1.5% of subjects assigned H pylori treatment and among 2.1% of those assigned placebo (hazard ratio [HR] of death = 0.67, 95% CI = 0.36 to 1.28). Garlic and vitamin treatments were associated withnon-statistically significant reductions in gastric cancer incidence and mortality. Vitamin treatment was associated with statistically significantly fewer deaths from gastric or esophageal cancer, a secondary endpoint (HR = 0.51, 95% CI = 0.30 to 0.87; P = .014).Ma JL, et al. Fifteen-year effects of Helicobacter pylori, garlic, and vitamin treatments on gastric cancer incidence and mortality. J Natl Cancer Inst. 2012 Mar 21;104(6):488-92.单一celecoxib 干预（52.8% vs 41.2%）或单独根除（59.3% vs 41.2%）对于胃癌前疾病的好转有利根除Hp 后继之以celecoxib治疗，并无另外益处Wong BC, et al. Gut 2012; 61: 812-8.根除与未根除组4年6个月随访后至少一次组织学积分：萎缩和肠化的进展或逆转情况伊朗德黑兰地区胃癌患者一级亲属人群根除Hp与胃粘膜组织学变化的临床试验Massarrat S, et al. Precancerous conditions after H. pylori eradication: a randomized double blind study in first degree relatives of gastric cancerpatients. Arch Iran Med, 2012; 15: 664-69.荟萃分析显示根除Hp可降低胃癌发生率Fig 2 Forest plot of randomised controlled trials of H pylori eradication therapy: effect on subsequent occurrence of gastric cancer由已发表论文资料分层分析，显示根除Hp时无论有无癌前病变，对于胃癌预防效果均无统计意义Fig 3 Forest plot of randomised controlled trials of H pylori eradication therapy: effect on subsequent occurrence of gastric cancer according to presence or absence of pre-neoplastic lesions at baseline. (You 200632 and Ma 201226 study had missing data concerning presence or absence of pre-neoplastic lesions at baseline for 16 individuals, leading to the loss of one gastric cancer from the analysis)配合应用抗氧化剂或维生素可提高根除Hp预防胃癌的效果Fig 4 Forest plot of randomised controlled trials of H pylori eradication therapy: effect on subsequent occurrence of gastric cancer according to anti-oxidant or vitamin useFord ac, et al. Helicobacter pylori eradication therapy to prevent gastric cancer in healthy asymptomatic infected individuals: systematic review and meta-analysis of randomised controlled trials. BMJ, 2014; 348:g3174.21。