《中南大学学报(医学版)》：胃癌Lauren分型研究进展（兰州大学第二医院：杨洁、武赞凯、李连顺、李龙、周辉年、焦作义）

胃癌是常见恶性肿瘤之一,是一种高度异质性肿瘤,根据Lauren分型将胃癌分为肠型和弥漫型。随着临床诊疗观念和技术的不断更新与进步,对胃癌进行规范化及个体化综合治疗已成为主要发展趋势,但不同的胃癌分型及分期,其临床病理特征、治疗方法及预后可能存在差异。

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中南大学学报(医学版) J Cent South Univ(Med Sci) 2015,40(8)http://www.csumedorg REVIEW 综述 Do:101817/ ISsn.16727347.201508018 www.csumed.org/xbwk/fileup/pdf/201508934-pdf 胃癌 Lauren分型研究进展杨洁,武赞凯,李连顺,李龙,周辉年,焦作义 (兰州大学第二医院普外一科,兰州730030) 摘要]胃癌是常见恶性肿瘤之一,是一种高度异质性肿瘤,根据 Lauren分型将胃癌分为肠型和弥漫型。随着临床诊疗观念和技术的不断更新与进步,对胃癌进行规范化及个体化综合治疗已成为主要发展趋势,但不同的胃癌分型及分期,其临床病理特征、治疗方法及预后可能存在差异。 [关键词]胃癌; Lauren分型;病理;预后 Research progress of Lauren classification for gastric cancer YANG Jie, WU Zankai, LI Lianshun, LI Long, ZHOU Huinian, JIAO Zuoyi First Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou 730030, China ABSTRACT Gastric cancer(GC) is one of the most common malignant tumors with high heterogeneity. According to Lauren classification, GC is divided into intestinal type and diffuse type. with rapid progress in technologies and ideas in the clinical diagnosis for GC, the normalized and individualized comprehensive treatment has become the main trend. However, the clinicopathological characteristics, remedy and prognosis for GC may be different because of the different classifications and stages KEY WORDs gastric cancer; Lauren classification; pathology; prognosis WHo数据显示,在世界范围胃癌( gastric世界平均水平的2倍,分别位居我国恶性肿瘤第2 cer,GC)发病率居肿瘤第5位,病死率居第3位和第3位。目前GC的诊断主要依据影像学和病理位,中国是GC高发区,其发病率和病死率均超过学,而GC在国内外有多种病理分型,比较常用的收稿日期( Date of reception):2015-0304 第一作者( First author):杨洁,Ema: iclcyj@l63com 通信作者( Corresponding author):焦作义,Emal: jiaozx@lzueduc 基金项目( Foundation item):中央高校基本科研业务费专项资金(zuby-2013-m04) This work was supported by the Fundamental Research Funds

中南大学学报（医学版） J Cent South Univ (Med Sci) 2015, 40(8) htt p://www.csumed.org 934 胃癌 Lauren 分型研究进展杨洁，武赞凯，李连顺，李龙，周辉年，焦作义 ( 兰州大学第二医院普外一科，兰州 730030 ) [摘要] 胃癌是常见恶性肿瘤之一，是一种高度异质性肿瘤，根据Lauren分型将胃癌分为肠型和弥漫型。随着临床诊疗观念和技术的不断更新与进步，对胃癌进行规范化及个体化综合治疗已成为主要发展趋势，但不同的胃癌分型及分期，其临床病理特征、治疗方法及预后可能存在差异。 [关键词] 胃癌；Lauren分型；病理；预后 Research progress of Lauren classification for gastric cancer YANG Jie, WU Zankai, LI Lianshun, LI Long, ZHOU Huinian, JIAO Zuoyi ( First Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou 730030, China ) ABSTRACT Gastric cancer (GC) is one of the most common malignant tumors with high heterogeneity. According to Lauren classification, GC is divided into intestinal type and diffuse type. With rapid progress in technologies and ideas in the clinical diagnosis for GC, the normalized and individualized comprehensive treatment has become the main trend. However, the clinicopathological characteristics, remedy and prognosis for GC may be diff erent because of the diff erent classifi cations and stages. KEY WORDS gastric cancer; Lauren classifi cation; pathology; prognosis 收稿日期(Date of reception)：2015-03-04 第一作者(First author)：杨洁，Email: jclcyj@163.com 通信作者(Corresponding author)：焦作义，Email: jiaozx@lzu.edu.cn 基金项目(Foundation item)：中央高校基本科研业务费专项资金(lzujbky-2013-m04)。 is work was supported by the Fundamental Research Funds for the Central Universities, P. R. China (lzujbky-2013-m04). DOI:10.11817/j.issn.1672-7347.2015.08.018 www.csumed.org/xbwk/fi leup/PDF/201508934.pdf ·REVIEW· ·综述· WHO数据[1]显示，在世界范围胃癌(gastric cancer，GC)发病率居肿瘤第5位，病死率居第3 位，中国是GC高发区，其发病率和病死率均超过世界平均水平的2倍，分别位居我国恶性肿瘤第2 位和第3位。目前GC的诊断主要依据影像学和病理学，而GC在国内外有多种病理分型，比较常用的

胃癌 Lauren分型研究进展杨洁,等有WHO和 Lauren分型。WHO分型比较详细,并考2.2人类表皮生长因子受体2与肠型GC 虑肿瘤的分化程度,但受限于GC不同的形态学表人类表皮生长因子受体2( human epidermal 现和病理学家主观因素的影响,导致其可重复性 growth factor receptor2,HER2)近年在进展期、晚不高。 Lauren分型相对简单易行,多年来一直受到期或复发性GC的治疗中已成为研究热点,是目前研究者的青睐。 GC分子表型研究中最接近临床转化的代表。多项研究113显示HER2高表达率为9%-25%,中国GC 1定义的HER2高表达率为9.5%-11.9%41。研究[17 发现HER2的阳性率与GC解剖位置相关,肿瘤多 1965年 Lauren根据GC的组织结构和生物行位于近端胃、贲门或食管胃结合部,而肠型GC也为,将GC分为肠型和弥漫型,即 Lauren分型。肠好发于近端胃1.3,提示HER2可能与肠型GC相型GC一般具有明显的腺管结构,瘤细胞呈柱状或关。多项研究11也证实HER2常见于肠型GC。立方形,以高、中分化腺体为主,有时在其浸润但也有研究114显示HER2阳性的GC患者预后欠前沿可见低分化腺体成分。肠型GC常发生于肠化佳,而肠型GC患者预后较好6s1。整理分析上生的背景下,多呈局限性生长。弥漫型GC多呈弥述研究数据,将HER2阳性和肠型GC患者作比较发漫性生长,缺乏细胞连接,一般不形成腺管,以现,两者在性别、年龄、组织学分化程度及肿瘤低分化腺癌或印戒细胞癌为主,有时伴有明显间位置等方面具有相似的比例,明显不同之处在于质纤维结缔组织增生。有10%-15%的GC同时兼有前者多为I-V期患者,而后者1~I期患者居多肠型和弥漫型的特征,称为混合型。 Lauren分型相推测HER2高表达常见于进展期肠型GC,提示预后对简单易行,在不同观察者之间一致性较高,是不良。Qiu等1S研究证实了上述推测,指出HER2 GC最常用的组织学分型标准。阳性是肠型GC预后不良的独立影响因素,而与弥漫型GC预后无相关性,同时提出将 Lauren分型和 2分子表型研究 HER2表达状态的联合检测作为评估GC预后的一项新指标。目前普遍共识推荐在GC患者初期诊断时 2.1环氧化酶-2与肠型GC 即常规检测HER2的表达状态,认为曲妥珠单抗联环氧化酶2( cyclooxygenase-2,COx2)是合化疗可作为HER2阳性晚期或复发性GC患者的前列腺素环氧化物水化酶的同工酶,是前列腺种选择方案,但HER2及其靶向治疗与肠型GC的相素的限速酶。刘贵生等应用组织芯片技术检关性仍需进一步研究。测Coⅹ-2阳性率在慢性萎缩性胃炎伴胃黏膜肠化生灶、癌旁胃黏膜肠化生灶和肠型GC中分2.3CDH1与弥漫型GC 别为45.7%,59.4%和77.3%,明显高于弥漫型 E-钙黏蛋白是钙黏蛋白家族的重要成员之 GC(16.8%),且三者呈逐渐升高趋势。而流行病 CDH1基因失活或表达下降可导致细胞黏附学调查显示,肠型GC患者多呈现慢性萎缩性胃结构失调,细胞极性丧失,与多种癌症的发生发炎、肠上皮化生、癌前病变及肠型GC的发病过展密切相关。多项研究102证实CDH1基因突变程,这恰好与上述研究中Coⅹ-2阳性率呈递增表与弥漫型GC相关,其胃黏膜早期可出现少量印达的趋势相一致,提示COX-2可能作为肠化生的戒细胞癌病灶,部分癌灶逐渐向下浸润成为进恶变指标,与肠型GC的发生发展密切相关。De展期弥漫型GC。有报道23称CDH1基因突变携等也发现肠型GC的COⅹ-2阳性率明显高于正带者有超过80%的概率罹患弥漫型GC,建议对常胃黏膜组织,认为COⅹ-2低甲基化与肠型GC此类人群实施预防性胃切除术。部分弥漫型GC 相关。研究□表明:Coⅹ-2与调控细胞周期、免有家族聚集和遗传性,称为遗传性弥漫型胃癌疫抑制、细胞凋亡、前致癌物活化、促进肿瘤新( hereditary diffuse gastric cancer,HDGC),占GC 生血管生成及肿瘤浸润转移等方面有高度相关的1%-3%24。 Guilford等23通过遗传连锁分析发性。美国食品与药品监督管理局已批准选择性现毛利人HDGC为常染色体显性遗传,并首次确 OX-2抑制剂为家族性结肠腺瘤病的治疗药物, 定CDH基因外显子胚系突变是HDGC遗传的主要预防结肠癌的发生。COX-2的研究将对GC尤其病因。多项研究表明2:HDGC患者CDH1基因是肠型GC的预防、早期发现和针对性治疗有重外显子突变是导致基因失活、肿瘤发生的最重要要意义。原因。但同时也有研究1认为存在影响HDGC发

胃癌 Lauren 分型研究进展杨洁，等 935 有WHO和Lauren分型。WHO分型比较详细，并考虑肿瘤的分化程度，但受限于GC不同的形态学表现和病理学家主观因素的影响，导致其可重复性不高。Lauren分型相对简单易行，多年来一直受到研究者的青睐[2]。 1 定义 1965年Lauren[3]根据GC的组织结构和生物行为，将GC分为肠型和弥漫型，即Lauren分型。肠型GC一般具有明显的腺管结构，瘤细胞呈柱状或立方形，以高、中分化腺体为主，有时在其浸润前沿可见低分化腺体成分。肠型GC常发生于肠化生的背景下，多呈局限性生长。弥漫型GC多呈弥漫性生长，缺乏细胞连接，一般不形成腺管，以低分化腺癌或印戒细胞癌为主，有时伴有明显间质纤维结缔组织增生。有10%~15%的GC同时兼有肠型和弥漫型的特征，称为混合型。Lauren分型相对简单易行，在不同观察者之间一致性较高，是 GC最常用的组织学分型标准[4]。 2 分子表型研究 2.1 环氧化酶 -2 与肠型 GC 环氧化酶-2(cyclooxygenase-2，COX-2)是前列腺素环氧化物水化酶的同工酶，是前列腺素的限速酶。刘贵生等[5]应用组织芯片技术检测COX-2阳性率在慢性萎缩性胃炎伴胃黏膜肠化生灶、癌旁胃黏膜肠化生灶和肠型 G C 中分别为45.7%，59.4%和77.3%，明显高于弥漫型 GC(16.8%)，且三者呈逐渐升高趋势。而流行病学调查显示，肠型G C患者多呈现慢性萎缩性胃炎、肠上皮化生、癌前病变及肠型G C的发病过程，这恰好与上述研究中COX-2阳性率呈递增表达的趋势相一致，提示COX-2可能作为肠化生的恶变指标，与肠型G C的发生发展密切相关。D e 等[6]也发现肠型G C的COX-2阳性率明显高于正常胃黏膜组织，认为COX-2低甲基化与肠型G C 相关。研究[7]表明：COX-2与调控细胞周期、免疫抑制、细胞凋亡、前致癌物活化、促进肿瘤新生血管生成及肿瘤浸润转移等方面有高度相关性。美国食品与药品监督管理局已批准选择性 COX-2抑制剂为家族性结肠腺瘤病的治疗药物，预防结肠癌的发生。COX-2的研究将对G C尤其是肠型G C的预防、早期发现和针对性治疗有重要意义。 2.2 人类表皮生长因子受体 2 与肠型 GC 人类表皮生长因子受体2(human epidermalgrowth factor receptor 2，HER2)近年在进展期、晚期或复发性GC的治疗中已成为研究热点，是目前 GC分子表型研究中最接近临床转化的代表。多项研究[8-13]显示HER2高表达率为9%~25%，中国G C 的HER2高表达率为9.5%~11.9%[14-16]。研究[11,14-17] 发现HER2的阳性率与G C解剖位置相关，肿瘤多位于近端胃、贲门或食管胃结合部，而肠型GC也好发于近端胃[15,18]，提示HER2可能与肠型G C相关。多项研究[8,11-17]也证实HER2常见于肠型GC。但也有研究[8,11,15]显示HER2阳性的GC患者预后欠佳，而肠型G C患者预后较好[16,18-19]。整理分析上述研究数据，将HER2阳性和肠型GC患者作比较发现，两者在性别、年龄、组织学分化程度及肿瘤位置等方面具有相似的比例，明显不同之处在于前者多为III~IV期患者，而后者I~II期患者居多，推测HER2高表达常见于进展期肠型GC，提示预后不良。Qiu等[15]研究证实了上述推测，指出HER2 阳性是肠型GC预后不良的独立影响因素，而与弥漫型GC预后无相关性，同时提出将Lauren分型和 HER2表达状态的联合检测作为评估GC预后的一项新指标。目前普遍共识推荐在GC患者初期诊断时即常规检测HER2的表达状态，认为曲妥珠单抗联合化疗可作为HER2阳性晚期或复发性GC患者的一种选择方案，但HER2及其靶向治疗与肠型GC的相关性仍需进一步研究。 2.3 CDH1 与弥漫型 GC E -钙黏蛋白是钙黏蛋白家族的重要成员之一，CDH1基因失活或表达下降可导致细胞黏附结构失调，细胞极性丧失，与多种癌症的发生发展密切相关。多项研究[20-22]证实CDH1基因突变与弥漫型G C相关，其胃黏膜早期可出现少量印戒细胞癌病灶，部分癌灶逐渐向下浸润成为进展期弥漫型G C。有报道[23]称CDH1基因突变携带者有超过80%的概率罹患弥漫型G C，建议对此类人群实施预防性胃切除术。部分弥漫型G C 有家族聚集和遗传性，称为遗传性弥漫型胃癌 (hereditary diffuse gastric cancer，HDGC)，占GC 的1%~3%[24]。Guilford等[25]通过遗传连锁分析发现毛利人HDGC为常染色体显性遗传，并首次确定CDHl基因外显子胚系突变是HDGC遗传的主要病因。多项研究表明[26-28]：HDGC患者CDH1基因外显子突变是导致基因失活、肿瘤发生的最重要原因。但同时也有研究[29]认为存在影响HDGC发

中南大学学报(医学版,2015,40(8)htp/www.csumed.org 生的环境因素或其他分子机制,因为部分HDGC分定1。肠型和弥漫型GC在病因、发病机制家族患者并没有发生CDH1基因胚系突变。尽管流行病学、治疗方法及预后等方面存在差异性。如此,当前普遍认为CDH1基因突变可明显提高弥漫型GC的发病率。上述部分研究者232628认3.1临床特征差异为:对于携带CDH1基因胚系突变的高危人群实中国属于GC高发区,有报道称肠型GC好发施预防性胃切除术是预防此类人群肿瘤发生的唯于GC高发区,弥漫型多见于GC低发区叫。但近期根治性疗法,对于不愿接受手术治疗的无症状研究显示5193243 GC患者中肠型占34%-47% 携带者,建议定期行胃镜检查及组织活检。弥漫型占46%~57%。查阅文献发现,亚洲国家(中国、日本、韩国等)以弥漫型GC多见1531,而 24其他分子表型研究西方国家(德国、芬兰、意大利等)则以肠型GC多有研究30报道幽门螺旋杆菌感染所致胃黏见47),也有报道4显示中国以肠型GC多见。膜炎症与胃干细胞和微环境的相互作用,可能提示东西方国家GC的流行病学存在差异性,而且在弥漫型GC的发生过程中扮演重要角色。转录随着时间的推移,肠型和弥漫型GC的发病率也在抑制因子Snai0表达与GC的 Lauren分型有关变化。 snai在肠型GC细胞系中低表达而在弥漫型GC 肠型GC常见于老年、男性,弥漫型多见于细胞系中高表达3。过氧化物酶体增殖物激活年轻、女性11944°研究发现老年GC患者常受体γ通过抑制肿瘤细胞侵袭、迁移及上皮细有慢性萎缩性胃炎病史,易发生肠上皮化生,其胞间质转型使肠型GC患者预后获益32Ueda进一步发展可能多为肠型GC。另有研究2显示慢等国3报道let7g,mR19a,miR-495,miR-433与肠性胃炎及肠上皮化生是肠型GC预后的危险因素, 型GC预后相关,let7b,miR-214与弥漫型GC预后而肠上皮化生也是弥漫型GC预后的危险因素。但相关。而miR-20oa/b/e,miR-141的表达降低常有报道认为弥漫型GC常见于年轻患者,与萎缩见于弥漫型GC3。微卫星不稳性( microsatellite性胃炎及肠上皮化生均无相关性。 Sakitani等研 instability,MsI)在肠型和弥漫型GC中阳性率分究显示:随着年龄的增长,肠上皮化生可从胃底别为7.6%和2.5%,且Kim等13报道肠型GC中向近端贲门移动,故可能导致肠型和弥漫型GC在 MSI高表达的患者预后较好。 Kroepil等发现上肿瘤部位和切除方式上有所差异。Qiu等则报皮细胞黏附分子在弥漫型GC中呈高表达,提示预道肠型GC好发于近端胃,弥漫型好发于远端胃或后欠佳。全胃肠型和弥漫型GC在分子基因水平存在明显差异,体现了不同 Lauren分型组织结构和生物学行为3.2病理特征差异的差异性。胃癌是一个多因素、多基因、多步骤目前,年龄、性别、肿瘤部位、肿瘤大小及发展的疾病,现其治疗方法仍以手术治疗联合多手术切缘作为GC预后的独立影响因素仍存在较大药物化疗为主。对 Lauren分型分子机制的研究可进争议,但浸润深度、淋巴结转移数、TNM分期作一步揭示不同分型胃癌的发生发展过程,而后对为评估预后的独立影响因素已被广泛接受39 其进行有预防性、靶向性的个体化治疗。目前临般认为弥漫型GC侵袭性强,常侵犯浆膜,可较早床应用较为成熟的是携带CDH基因突变患者的预出现淋巴结转移,TNM分期较晚。研究叫显示弥防性胃切除术和HER2阳性胃癌患者的靶向治疗漫型GCT4患者明显多于肠型,T1+T2患者明显少其余 Lauren分型分子机制的研究结论尚未得到临床于肠型。Qiu等山报道肠型GC患者约有582%出现工作者的广泛认可,今后仍需大量实验研究进淋巴结转移,弥漫型为71.7%。另有研究发现弥步验证和创新,为胃癌的早期发现、早期诊断及漫型GCI+ⅣV期患者占61.6%,肠型占43.0%,提治疗提供临床依据示弥漫型 GC TNM分期较晚。多项研究1376°报道肿瘤大小是GC患者预后 3临床病理特征及预后的独立影响因素,但Qiu等1对肿瘤直径>5cm GC患者研究发现,肠型所占比例低于弥漫型,差 GC的 Lauren分型自1965年提出一直沿用至异无统计学意义。 Stiekema等1报道弥漫型是GC 今,与其wHO分型(2010)相参照,肠型GC包括患者手术切缘阳性的独立危险因素,肠型和弥漫乳头状腺癌、管状腺癌,弥漫型GC包括印戒细胞型GC患者RI切除率分别为2%和24%,差异有统癌、低分化腺癌,而黏液腺癌根据其主要细胞成计学意义

936 中南大学学报 ( 医学版 ), 2015, 40(8) http://www.csumed.org 生的环境因素或其他分子机制，因为部分HDGC 家族患者并没有发生CDH1基因胚系突变。尽管如此，当前普遍认为CDH1基因突变可明显提高弥漫型G C的发病率。上述部分研究者[23,26,28]认为：对于携带CDH1基因胚系突变的高危人群实施预防性胃切除术是预防此类人群肿瘤发生的唯一根治性疗法，对于不愿接受手术治疗的无症状携带者，建议定期行胃镜检查及组织活检。 2.4 其他分子表型研究有研究[30]报道幽门螺旋杆菌感染所致胃黏膜炎症与胃干细胞和微环境的相互作用，可能在弥漫型G C的发生过程中扮演重要角色。转录抑制因子Snail的表达与G C的Lauren分型有关， Snail在肠型G C细胞系中低表达而在弥漫型G C 细胞系中高表达[31]。过氧化物酶体增殖物激活受体 γ 通过抑制肿瘤细胞侵袭、迁移及上皮细胞间质转型使肠型G C患者预后获益[32]。Ueda 等[33]报道let-7g，miR-19a，miR-495，miR-433与肠型GC预后相关，let-7b，miR-214与弥漫型GC预后相关。而miR-200a/b/c，miR-141的表达降低常见于弥漫型GC[34-35]。微卫星不稳性(microsatellite instability，MSI)在肠型和弥漫型G C中阳性率分别为7.6%和2.5%[36]，且Kim等[37]报道肠型G C中 MSI高表达的患者预后较好。Kroepil等[38]发现上皮细胞黏附分子在弥漫型GC中呈高表达，提示预后欠佳。肠型和弥漫型GC在分子基因水平存在明显差异，体现了不同Lauren分型组织结构和生物学行为的差异性。胃癌是一个多因素、多基因、多步骤发展的疾病，现其治疗方法仍以手术治疗联合多药物化疗为主。对Lauren分型分子机制的研究可进一步揭示不同分型胃癌的发生发展过程，而后对其进行有预防性、靶向性的个体化治疗。目前临床应用较为成熟的是携带CDH1基因突变患者的预防性胃切除术和HER2阳性胃癌患者的靶向治疗，其余Lauren分型分子机制的研究结论尚未得到临床工作者的广泛认可，今后仍需大量实验研究进一步验证和创新，为胃癌的早期发现、早期诊断及治疗提供临床依据。 3 临床病理特征及预后 G C的Lauren分型自1965年提出一直沿用至今，与其WHO分型(2010)[39]相参照，肠型GC包括乳头状腺癌、管状腺癌，弥漫型GC包括印戒细胞癌、低分化腺癌，而黏液腺癌根据其主要细胞成分定[40-41]。肠型和弥漫型GC在病因、发病机制、流行病学、治疗方法及预后等方面存在差异性。 3.1 临床特征差异中国属于G C高发区，有报道称肠型G C好发于GC高发区，弥漫型多见于GC低发区[42]。但近期研究显示[8,15,18-19,32,43]：GC患者中肠型占34%~47%，弥漫型占46%~57%。查阅文献发现，亚洲国家(中国、日本、韩国等)以弥漫型G C多见[8,15,33,44]，而西方国家(德国、芬兰、意大利等)则以肠型GC多见[45-47]，也有报道[16,48-49]显示中国以肠型GC多见。提示东西方国家GC的流行病学存在差异性，而且随着时间的推移，肠型和弥漫型GC的发病率也在变化。肠型G C常见于老年、男性，弥漫型多见于年轻、女性[18-19,44,50]。研究[51]发现老年G C患者常有慢性萎缩性胃炎病史，易发生肠上皮化生，其进一步发展可能多为肠型GC。另有研究[52]显示慢性胃炎及肠上皮化生是肠型GC预后的危险因素，而肠上皮化生也是弥漫型GC预后的危险因素。但有报道[53]认为弥漫型GC常见于年轻患者，与萎缩性胃炎及肠上皮化生均无相关性。Sakitani等[54]研究显示：随着年龄的增长，肠上皮化生可从胃底向近端贲门移动，故可能导致肠型和弥漫型GC在肿瘤部位和切除方式上有所差异。Qiu等[15]则报道肠型GC好发于近端胃，弥漫型好发于远端胃或全胃。 3.2 病理特征差异目前，年龄、性别、肿瘤部位、肿瘤大小及手术切缘作为GC预后的独立影响因素仍存在较大争议，但浸润深度、淋巴结转移数、TNM分期作为评估预后的独立影响因素已被广泛接受[55-57]。一般认为弥漫型GC侵袭性强，常侵犯浆膜，可较早出现淋巴结转移，TNM分期较晚。研究[19]显示弥漫型GC T4患者明显多于肠型，T1+T2患者明显少于肠型。Qiu等[18]报道肠型GC患者约有58.2%出现淋巴结转移，弥漫型为71.7%。另有研究[15]发现弥漫型GC III+IV期患者占61.6%，肠型占43.0%，提示弥漫型GC TNM分期较晚。多项研究[18,57-60]报道肿瘤大小是GC患者预后的独立影响因素，但Qiu等[18]对肿瘤直径>5 cm GC患者研究发现，肠型所占比例低于弥漫型，差异无统计学意义。Stiekema等[19]报道弥漫型是GC 患者手术切缘阳性的独立危险因素，肠型和弥漫型G C患者R 1切除率分别为2 %和24%，差异有统计学意义

胃癌 Lauren分型研究进展杨洁,等 33预后的最佳治疗方法。今后需要多中心、大样本量的弥漫型GC预后较肠型差,常是进展期或晚随机对照研究来分析GC的 Lauren分型与外科治疗期GC。对805例GC患者术后随访研究显示1 策略及预后的相关性,这也是当前肿瘤治疗所强弥漫型是GC患者预后不良因素,肠型和弥漫型调的规范化和个体化治疗目标的体现。 GC患者术后5年生存率分别为527%和44.1%。项长达16年的随访研究发现9:肠型和弥漫型 GC患者中位生存期分别为129月和17月,弥漫型参考文献 GC术后复发率高达73%,即使在行R0切除的114 例患者中,肠型和弥漫型复发率分别为20%和1] nternational Agency for Research on Cancer. GLOBOCAN2012 49%。Ohe等01报道两者仅在根治性全胃切除术 Estimated cancer incidence, mortality and prevalence worldwide in 后复发率差异有统计学意义。一项Meta分析02纳 2012(eb/ol].[2015-03-04]. htTp: //globocan. iarc.fr/pages/fact 入21项研究,共11073例GC病例,结果发现肠型 sheets population.aspx 和弥漫型5年生存率分别为61.7%和41.1%,相对于[2]李忠武曹登峰胃癌病理分型与临床个体化治疗一问题肠型GC,弥漫型GC5年病死率明显增高。zhou 与展望[J中国医学前沿杂志:电子版20124(5):1520. 等报道了相似结果,肠型GC和弥漫型GC5年生 LI Zhongwu, CAO Dengfeng. The problem and outlook of 存率分别为486%和18.4%。 Marrelli等63研究发现 thological type and clinical individualized treatment in gastric 弥漫型和肠型GC总体生存率和无瘤生存率均存在 ncer[J]. Chinese Journal of the Frontiers of Medical Science. 明显差异。Wang等也报道相对于肠型GC,弥漫 Electronic Version, 2012, 4(5):15-20. 型是患者预后的危险因素,可见GC的 Lauren分型[3] Lauren p. The two histological main types of gastric carcinoma 与其预后有直接相关性。 diffuse and so-called intestinal-type carcinoma. An attempt at a histo- 目前GC的 Lauren分型与外科手术治疗相关性 clinical classification [] Acta Pathol Microbiol Scand, 1965, 64:31 的研究极少,但有报道显示其对GC围手术期的放化疗有一定的指导性。一项随机对照研究。显4]HuB, El Hajj n, Sittler S,etal. Gastriccancer: Classification, 示:新辅助放化疗并不能使弥漫型GC患者生存获 histology and application of molecular pathology [J]. JGastrointest 益。 Becker等在以顺铂为基础的新辅助化疗研究 Oncol2012,3(3):25l-26l 中发现:非肠型组织类型是GC肿瘤组织缩小的不]刘贵生,龚均程鹏等用组织芯片技术研究环氧合酶2在利因素。 Lorenzen等4在一项局部进展期GC的新不同亚型胃粘膜肠化生及胃癌中的表达[J中国肿瘤临床, 辅助化疗试验中,分析了 Lauren分型与肿瘤病理组 2005,32(19):1085-10881099 织对化疗反应的相关性,发现肠型肿瘤组织对化 LIU Guisheng, GONG Jun, CHENG Peng, et al. The research on 疗的反应率为32.9%,而弥漫型为17.4%,混合型 expression of the COX-2 in various subtypes of gastric mucous 为18.4%,肠型和弥漫型5年生存率分别为46.9%和 membrane intestinal metaplasia and gastric cancer using tissue 30.6%。 Stessin等6报道了弥漫型GC术后辅助放疗 microarray). Chinese Journal of Clinical Oncology, 2005, 32(19) 和未行辅助放疗患者的预后存在差异,两者中位 1085-1088,1099 生存期分别为30月和18月。 Kucukoner等6研究术6] De Melo CE, Gigek CO, da Silva JN, et al. Association of COX2grne 后放化疗的远期生存结果与病理组织学特征的相 hypomethylation with intestinal type gastric cancer in samples of 关性,其多因素回归分析结果显示 Lauren分型是影 patients from northern Brazil[J]. Tumour BioL, 2014, 35(2):110 响无瘤生存时间的因素之一,且与GC患者术后对辅助放化疗耐受度存在相关性。因此,对于非肠7]于建平刘宏斌韩晓鹏Wt和COx2信号通路在胃癌中的研型或弥漫型GC患者在新辅助化疗或术后辅助放化究现况[]现代肿瘤医学,20142(3):683-687. 疗时需要对其反应率、耐受度和远期生存益处进 YU Jianping, LIU Hongbin, HAN Xiaopeng Research status of Wnt 行综合考虑。 and COX-2 signal pathway in gastric cancer[]. Journal of Moder 4结语 8 Kim JW, Im SA, Kim M, et al. The prognostic significance of HER2 positivity for advanced gastric cancer patients undergoing first-line Lauren分型可认为是GC患者非常重要的独立 modified FOLFOX-6 regimen []. Anticancer Res, 2012, 32(4) 预后因素,相对于肠型GC,弥漫型预后差。尽管 1547-1553. 如此,根治性切除术仍是此类患者获得生存益处[9] Kataoka Y, Okabe F, Yoshizawa A, et al. HER2 expression and its

胃癌 Lauren 分型研究进展杨洁，等 937 3.3 预后弥漫型G C预后较肠型差，常是进展期或晚期GC[50]。对805例GC患者术后随访研究显示[18]：弥漫型是G C患者预后不良因素，肠型和弥漫型 G C患者术后5年生存率分别为52.7%和44.1%。一项长达1 6年的随访研究发现[19]：肠型和弥漫型 G C患者中位生存期分别为129月和1 7月，弥漫型 G C术后复发率高达73%，即使在行R 0切除的114 例患者中，肠型和弥漫型复发率分别为20%和 49%。Ohe等[61]报道两者仅在根治性全胃切除术后复发率差异有统计学意义。一项Meta分析[62]纳入21项研究，共11073例G C病例，结果发现肠型和弥漫型5年生存率分别为61.7%和41.1%，相对于肠型G C，弥漫型GC 5年病死率明显增高。Zhou 等[16]报道了相似结果，肠型GC和弥漫型GC5年生存率分别为48.6%和18.4%。Marrelli等[63]研究发现弥漫型和肠型GC总体生存率和无瘤生存率均存在明显差异。Wang等[48]也报道相对于肠型GC，弥漫型是患者预后的危险因素，可见GC的Lauren分型与其预后有直接相关性。目前GC的Lauren分型与外科手术治疗相关性的研究极少，但有报道显示其对G C围手术期的放化疗有一定的指导性。一项随机对照研究[64]显示：新辅助放化疗并不能使弥漫型GC患者生存获益。Becker等[65]在以顺铂为基础的新辅助化疗研究中发现：非肠型组织类型是GC肿瘤组织缩小的不利因素。Lorenzen等[45]在一项局部进展期GC的新辅助化疗试验中，分析了Lauren分型与肿瘤病理组织对化疗反应的相关性，发现肠型肿瘤组织对化疗的反应率为32.9%，而弥漫型为17.4%，混合型为18.4%，肠型和弥漫型5年生存率分别为46.9%和 30.6%。Stessin等[66]报道了弥漫型GC术后辅助放疗和未行辅助放疗患者的预后存在差异，两者中位生存期分别为30月和18月。Kucukoner等[67]研究术后放化疗的远期生存结果与病理组织学特征的相关性，其多因素回归分析结果显示Lauren分型是影响无瘤生存时间的因素之一，且与GC患者术后对辅助放化疗耐受度存在相关性。因此，对于非肠型或弥漫型GC患者在新辅助化疗或术后辅助放化疗时需要对其反应率、耐受度和远期生存益处进行综合考虑。 4 结语 Lauren分型可认为是GC患者非常重要的独立预后因素，相对于肠型GC，弥漫型预后差。尽管如此，根治性切除术仍是此类患者获得生存益处的最佳治疗方法。今后需要多中心、大样本量的随机对照研究来分析GC的Lauren分型与外科治疗策略及预后的相关性，这也是当前肿瘤治疗所强调的规范化和个体化治疗目标的体现。参考文献 [1] International Agency for Research on Cancer. GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence worldwide in 2012[EB/OL]. [2015-03-04]. http://globocan.iarc.fr/Pages/fact_ sheets_population.aspx. [2] 李忠武, 曹登峰. 胃癌病理分型与临床个体化治疗——问题与展望[ J]. 中国医学前沿杂志: 电子版, 2012, 4(5): 15-20. LI Zhongwu, CAO Dengfeng. The problem and outlook of pathological type and clinical individualized treatment in gastric cancer[ J]. Chinese Journal of the Frontiers of Medical Science. Electronic Version, 2012, 4(5): 15-20. [3] Lauren P. The two histological main types of gastric carcinoma: diuse and so-called intestinal-type carcinoma. An aempt at a histoclinical classication[ J]. Acta Pathol Microbiol Scand, 1965, 64: 31- 49. [4] Hu B, El Hajj N, Sittler S, et al. Gastric cancer: Classification, histology and application of molecular pathology[ J]. J Gastrointest Oncol, 2012, 3(3): 251-261. [5] 刘贵生, 龚均, 程鹏, 等. 用组织芯片技术研究环氧合酶-2在不同亚型胃粘膜肠化生及胃癌中的表达[ J]. 中国肿瘤临床, 2005, 32(19): 1085-1088, 1099. LIU Guisheng, GONG Jun, CHENG Peng, et al. The research on expression of the COX-2 in various subtypes of gastric mucous membrane intestinal metaplasia and gastric cancer using tissue microarray[ J]. Chinese Journal of Clinical Oncology, 2005, 32(19): 1085-1088, 1099. [6] De Melo CF, Gigek CO, da Silva JN, et al. Association of COX2 gene hypomethylation with intestinal type gastric cancer in samples of patients from northern Brazil[ J]. Tumour Biol, 2014, 35(2): 1107- 1111. [7] 于建平, 刘宏斌, 韩晓鹏. Wnt和COX-2信号通路在胃癌中的研究现况[ J]. 现代肿瘤医学, 2014, 22(3): 683-687. YU Jianping, LIU Hongbin, HAN Xiaopeng. Research status of Wnt and COX-2 signal pathway in gastric cancer[ J]. Journal of Modern Oncology, 2014, 22(3): 683-687. [8] Kim JW, Im SA, Kim M, et al. e prognostic signicance of HER2 positivity for advanced gastric cancer patients undergoing rst-line modified FOLFOX-6 regimen[ J]. Anticancer Res, 2012, 32(4): 1547-1553. [9] Kataoka Y, Okabe H, Yoshizawa A, et al. HER2 expression and its

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