NET的病理诊断2012天津

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,胃肠,神,经内分泌肿,瘤,病理共识,天津医科大学肿瘤医院病理科,孙保存,NET,的流行病学,NET,命名与分类,NET,的分级、分期与预后,中国,NET,病理共识,-,规范病理诊断,2,内 容,NET,的总体发病率呈上升趋势,6.00,600,2.00,0,1.00,3.00,4.00,5.00,0,100,200,300,400,500,5.25,年,74,76,78,80,82,84,86,88,90,92,94,96,98,00,02,04,所有恶性肿瘤的发病人数,神经内分泌肿瘤的发病人数,每十万人中,NET,的发病人数,每十万人中恶性肿瘤的发病人数,.,Yao JC, et al. J Clin Oncol. 2008:26:3063-3072.,NET,发病率增加的可能原因,来自挪威登记项目的数据与,SEER,一致,可能的原因：,诊断技术进步,对疾病的认识,肿瘤筛查的增加,环境因素,饮食习惯的改变,Yao JC, et al. J Clin Oncol. 2008;26:30633072.,Hauso O, et al. Cancer. 2008;113:26552664.,不同种族间原发,NET,的分布,（,SEER,USA),分布,白种,非洲裔,亚裔,/,太平洋岛国,印地安,肺,*,29.47%,17.16%,15.67%,22.80%,胸腺,0.41%,0.15%,1.25%,0.00%,胃,5.89%,5.72%,7.21%,11.40%,十二指肠,3.05%,9.38%,5.64%,0.98%,空肠,/,回肠,*,14.43%,12.90%,2.82%,2.93%,盲肠,3.46%,3.08%,1.25%,2.93%,阑尾,3.25%,2.05%,0.94%,0.65%,结肠,3.66%,5.57%,3.76%,7.17%,直肠,*,13.41%,26.39%,39.18%,32.57%,胰腺,6.50%,5.28%,7.84%,6.51%,肝,0.81%,0.73%,0.31%,2.28%,其他,15.65%,11.58%,14.11%,9.77%,*,有统计学差异（,P 360, 360,27,胸腺,110,68,40,盲肠,135,107,41,小肠,111,105,56,十二指肠,107,101,57,NET确诊时的情况,远处转移,局部扩散,Yao JC, et al. J Clin Oncol. 2008;26:3063-3072,.,局限性,扩散性,50%,27%,23%,转移性NET的生存,转移性,NET,的五年生存率与其它转移性肿瘤相似,低分化,NET,：,4%,1,高、中度分化,NET,：,35%,1,肺：,4%,2,结直肠,乳腺和前列腺：分别是,11%, 23%,和,31%,2,65%,的转移性,NET,患者的生存期低于,5,年,Yao J, et al. J Clin Oncol. 2008;26:3063-3072;,Jemal A, et al. CA Cancer J Clin. 2010;60:277-300.,时间,(,月,),生存概率,0,0.2,0.4,0.6,0.8,1.0,0,12,24,36,48,60,72,84,96,108,120,中位生存时间,分期,月,95% CI,局部,223,208238,区域侵犯,111,104,118,远处转移,33,31,35,NET,流行病学,NET,命名与分类,NET,分化、分级、分期与预后相关,中国,NET,病理共识,-,规范病理诊断,11,内 容,NET,诊断术语的演变,Neuroendocrine,tumours,APUdoma,Carcinoid tumours,Karzinoide,1907,1969,1928,2000,Oberndorfer,Pearse,Masson,(WHO 2000),2010,Neuroendocrine neoplasm?,(WHO 2010),1980 2000 2010,I,类癌,1.,高分化神经内分泌瘤（,WDET,）,a,1.NET G1,（类癌）,b,2.,高分化神经内分泌癌（,WDEC,）,a,2.NET G2,a,3.,低分化神经内分泌癌,/,小细胞癌（,PDEC,）,3.NEC,（大细胞或小细胞癌）,b,c,II,粘液类癌,4.,混合性外分泌,-,内分泌癌（,MEEC,）,4.,混合性腺内分泌癌（,MANEC,）,III,混合性类癌,-,腺癌,IV,假瘤性病变,5.,瘤样病变（,TLL,）,5.,增生性和肿瘤前病变,G,，分级,; NEC,，神经内分泌癌,; NET,，神经内分泌瘤,a.WDET,和,WDEC,之间的区别按,WHO2000,分类分期特点下定义。,G2 NET,不能完全转为,WHO2000,分类的,WDEC,。,b.,括号内的定义按肿瘤疾病国际分类（,ICD-0,）编码。,c.“NET G3”,不推荐使用，因为,NET,被定义为高分化。,消化系统,NET,分类,WHO,标准的演变,WHO(2010),列举的可用的疾病名称,食管,/,肛管,胃,壶腹部,小肠,阑尾,结直肠,肝外胆管,/,胆囊,胰腺,神经内分泌肿瘤,G1,神经内分泌肿瘤,G2,神经内分泌癌,大细胞类型,小细胞类型,混合型腺,-,神经内分泌癌,EC,细胞、产生,5-,羟色胺的神经内分泌肿瘤,产生胃泌素的神经内分泌肿瘤（胃泌素瘤）,产生生长抑素的神经内分泌肿瘤,节细胞副神经节瘤,L,细胞、产生胰高血糖素样肽和,PP/YPP,的神经内分泌肿瘤,杯状细胞类癌,小管状类癌,胰高血糖素瘤,胰岛素瘤,血管活性肠肽瘤,第一诊断,第二诊断,NET,流行病学,NET,命名与分类,NET,分化、分级、分期与预后,中国,NET,病理共识,-,规范病理诊断,15,内 容,判定,NET,恶性潜能的主要标准,组织病理学,分化好,分化差,增殖活性,G1,G2,G3,肿瘤部位、大小、浸润,/,侵犯、转移（,TNM,分期）,食管、胃、十二指肠、空回肠、阑尾、结直肠,Histopathology:,well differentiated,Histopathology:,poorly differentiated,组织病理学,NET,分化程度与生存期,Yao JC, et al.,J Clin Oncol.,2008; 26:30633072.,0,0.2,0.4,0.6,0.8,1.0,0,12,24,36,48,60,72,84,96,108,120,时间,(,月,),高分化,中度分化,低分化,世界卫生组织没有定义中度分化，只有美国定义,WHO,胃肠胰腺,NET,的分级,(2010),19,NET G1,NET G2 NEC,Ki-67 (%),2 3,20 20,核分裂,/10 HPF,20,*,10 HPF:,高倍视野,= 2 mm,2,在有丝分裂密度最高的区域，至少评价,40,个视野,(,放大倍数：,40,倍,).,* MIB1,抗体,;,核标记最高的区域，,2000,个肿瘤细胞中阳性所占的百分比,.,Ki67计数,量化的几种手段,系统性的规定,人工,观察一定数量的肿瘤细胞（例如500-2000），最密集处，然后计算阳性比例。,使用电脑,数字图像,分析系统，计算阳性细胞的比例,仅仅以,“目测”,的方式大致评估阳性细胞比例。,Ki67 计数,结果必须是一个,明确的,百分比值，从而反映所选计数区域的平均情况，而不是给出一个范围值。,根据分级评估分类,最简单的评估增殖系数的方法即是计算,核分裂像,，这一方法也被一致的认为在NET完整病理学报告中是必须的。,核分裂像,应该计算,50,个视野下的核分裂数,而核分裂像的报告则是,10,个高倍视野下的核分裂像值 (2 mm,2,)。,高倍视野换算,转移性GEP-NET: 核分裂像计数与 Ki-67指数之间的关系,20,30,40,50,60,70,80,90,100,0,0,10,10,20,30,40,50,60,70,80,90,100,Ki-67,R,2,= 0.813,核分裂像,/10 HPF,Strosberg J, et al.,Human Pathology.,2009;40:1262-1268.,WHO/ENETS/AJCC,分级与生存的关系,Grading proposal for NET*,Grade,Mitotic count (10 HPF),Ki67 index (%),G1,20,20,Rindi G, et al. Virchows Arch. 2006;449:395-401.,Rindi G,et al.,Virchows Arch. 2007;451:757-762.,Pape UF, et al. Cancer. 2008;113:256-265.,0,50,100,150,200,250,Survival Time (mo),0.0,0.2,0.4,0.6,0.8,1.0,Cumulative Survival,G1,G2,G3,G1 vs G2G1 vs G3G2 vs G3,P,= 0.040,P,0.001,P,0.001,* ENETS and AJCC grading system,N=193,27,ENETS,有关,GEP-NEN,的分期标准,WHO,和,NCCN,采用的,AJCC/UICC,标准,中国胃肠胰神经内分泌肿瘤病理学诊断共识意见,建议中国的临床医生可参考使用,WHO 2010,标准,pTNM,分期,RindiG,，,etal.,VirchowsArchiv.2006;449,：,395-401.,RindiG,，,etal. VirchowsArchiv. 2007;451,：,757-762.,Sobin,，,etal.,TNM Classification of Malignant Tumours. Wiley-Blackwell. 7th Edition; 2009.,28,TNM,分类相似：,胃,十二指肠,空肠回肠,结肠直肠,WHO, UICC/AJCC (2009),与,ENETS(2006/2007),TNM,分类的比较,RindiG,，,etal. VirchowsArchiv.2006;449,：,395-401.,RindiG,，,etal. VirchowsArchiv. 2007;451,：,757-762.,Sobin,，,etal. TNM Classification of Malignant Tumours. Wiley-Blackwell. 7th Edition; 2009.,TNM,分类不同,:,阑尾,胰腺,上消化道,NET,的分期与预后,Pape UF, et al.,Cancer.,2008;113:256-265.,29,N = 202,病例,:,胃,(48),十二指肠,(23),胰腺,(131); n = 193.,生存时间,(,月,),I vs II,P,= 0.227,I vs III,P,= 0.048,I vs IV,P, 0.001,II vs III,P,= 0.171,II vs IV,P, 0.001,III vs IV,P,= 0.004,0,50,100,150,200,250,0.0,0.2,0.4,0.6,0.8,1.0,累积生存率,一期,二期,三期,四期,欧洲,NET,学会,肿瘤分期,NET,流行病学,NET,的命名与分类,NET,的分级、分期与预后,中国,NET,病理共识,-,规范病理诊断,30,内 容,2010,中国病理专家共识,2010,年,11,月，在北京召开了中国胃肠胰腺,NET,病理专家共识会，有来自国内的,8,名专家经过讨论而达成了共识。,发表于“中华病理学杂志”（,2011,）,根据共识意见：,规范胃肠胰腺神经内分泌肿瘤的病理诊断,诊断依据主要参考,WHO,（,2010,）分类,参考,WHO,（,2010,）对,NET,功能诊断和,TNM,分期意见,31,规范化的病理报告中应包含的信息,32,1.,标本类型：手术标本 或 穿刺标本,2.,（标本的解剖学）部位,3.,肿瘤大小（至少包含最大直径）*,4.,肿瘤浸润深度、血管脉管累及情况*,5.,与肿瘤的,TNM,分期相关的病理学资料*,6.,肿瘤距切缘的距离*,7.,肿瘤分级（,G1,、,G2,或,G3,）,Ki-67,标记指数（核分裂指数）,8.,嗜铬粒蛋白（,CgA,）染色,9.,突触素（,Syn,）染色,10.,和功能有关的免疫组化染色（在特定情况下，,insulin,、,gastrin,等）,11.,诊断（根据,WHO,分类标准，,2010,）：,部位,+,神经内分泌瘤,1,级,/2,级,/,神经内分泌癌,+,第二诊断,*,在穿刺标本中不必进行,根据是否有症状进行,NET,的分类,既往神经内分泌肿瘤可以根据症状和免疫组化分为：,功能性或非功能性,有症状或无症状,WHO,（,2010,）分类的相关界定：,功能性,NET,的诊断必须根据患者是否有相应症状进行判定,功能性,NET,的诊断诊断必需由临床医生根据患者的临床表现进行诊断，免疫组化染色结果对功能性,NET,诊断不具有意义。,33,病理诊断的变化,病理诊断中无需包括肿瘤的功能状态,对于有特殊临床综合征并过度产生引起相关症状的激素时才可用激素后加“瘤”（“,oma”,）的诊断名称，如胃泌素瘤、生长抑素瘤等,如果只有,IHC,证实瘤细胞存在某种激素而无临床症状时，应诊断为“,NET,，,IHC,染色有胃泌素（生长抑素）产物”,对于多个肿瘤有不同的组织形态和分级，应分别予以诊断,神经内分泌肿瘤的组织病理学,瘤细胞较小，呈多边形、卵圆形，胞质中等量，核圆形，深染，染色质分布较均匀，无明显核仁；,细胞排列方式多样，可呈实心巢状、结节状、菊形团状等,核分裂像少见,小细胞神经内分泌癌的组织病理学,癌细胞小或中等大小，形似淋巴细胞，大小约为成熟淋巴细胞的,2,倍，胞质少；,弥漫性生长或呈巢状构象,核分裂像常见，坏死较常见,约,1/4,的病例可见少量（,30%,）腺癌或鳞癌成分,大细胞神经内分泌癌的组织病理学,肿瘤细胞大，细胞异型性明显，胞质较丰富，核空泡化明显，常见明显核仁,瘤细胞呈巢状、小梁状、菊团形状和栅栏状排列,常见灶性坏死。,须有两个神经内分泌标记（,CgA,，,Syn,，,CD56,）阳性才能诊断,Makino.,A.,et al.Virchows Arch (2006) 448: 644647,混合性腺神经内分泌癌（,MANECs,）,肿瘤由腺癌和神经内分泌癌两种成分组成，每种成分至少占,30%,预后较单一成分的癌要差,Baruch Brenner et al. JCO, 2004, 22(13): 2730-2739,Klppel G,.,et al.,International Collaboration on Neuroendocrine Tumours,. Vienna, Austria.,2011.,突触素,突触小泡,嗜铬粒蛋白,A,神经分泌颗粒的膜蛋白,肽类激素,神经内分泌颗粒,分泌至血浆,生物标记物,NE,N,CgA 在NET病理诊断中的作用,优点:,存在于大多数NET瘤细胞的胞质中,局限性:,多数大肠NET和部分阑尾NET主要分泌CgB，故CgA多为阴性,在分化差的,NET,中可能为阴性,Taupenot L, Harper KL, OConnor DT.,N Engl J Med,. 2003;348:1134-1149,.,40,突触素在NET病理诊断中的作用,优点:,其表达不受分泌颗粒的影响,有助于分泌颗粒较少的NET和低分化NET的诊断,局限性:,不仅在神经内分泌细胞中表达,Chetty R et al. Arch Pathol Lab Med 2008;132:1285-1289.,41,神经内分泌肿瘤的生物标志物,42,必需检测的项目,选择检测的项目,神经内分泌标记,增殖活性标标记,多肽激素,生物活性胺,其它标志物,嗜铬粒素,A,（,CgA,）,突触素,(Syn),Ki-67,5-,羟色胺,胃泌素,高血糖素,胰多肽,生长抑素受体，尤其生长抑素受体,2,（,SSTR2,）,等,44,总结,所有,NEN,都有恶性潜能,过去,30,年间，,NET,发病率急剧升高,消化系统是最常见的,NEN,发病部位,组织标记物检查对,NET,的诊断及预后都是有效工具,了解中国病理共识，规范病理诊断,