1、来 茂 德,结直肠肿瘤病理诊断和治疗中的 几个新概念,一 .恶性息肉,NCCN对定义原先是良性腺瘤(息肉),恶变后癌组织浸润超过黏膜肌层到达黏膜下层(pT1),癌组织浸润不超过黏膜肌层不会发生转移这个概念病理医生和临床医生都接受,理解是一致的。病理的高级别上皮内瘤变(重度异型增生和原位癌)和黏膜内瘤变(黏膜内癌)都归入pTNM分期的pTis。,Company Logo,如是单一息肉内镜下切除干净,病理组织学检查为良好的组织学特征,切缘阴性,可以观察,不做进一步处理,无蒂息肉情况同前也可以观察,也可以作进一步的外科手术(局部结肠和区域淋巴结的整块切除),良好的组织学特征:分级1-2级, 无脉管浸
2、润,切缘阴性;不良组织学:分级3-4级,有脉管累犯,切缘阳性,二 .关于淋巴结的取材问题,TNM II期(pN0)的确定至少要取12 枚 定义:pNx不能确定,pN0没有转移,pN1a1个有转移,pN1b2-3个有转移 pN1c结肠的浆膜下有肿瘤细胞浸润或者结肠没有腹膜覆盖的部分的结肠或直肠周围组织有癌细胞的浸润,但没有区域淋巴结的转移pN2a4-6个转移pN2b有7个或7个以上的转移,Organ Number of Cancer centerlymph nodes Leipzig (2003) - Oesophagus 6 100%Stomach 15 80%Colon 12 84%Rect
3、um 12 90%Pancreas 10 64%Lung 6 96%Breast 6 98% -,分类 pN0所需检查的淋巴结数量,病人阳性淋巴结数随着所检淋巴结数的增加而增加,Scott, 1989,Swanson, 2003,前哨淋巴结The sentinel lymph node is the first lymph nodeto receive lymphatic drainage from a primarytumour. 从原发瘤引流淋巴液的第一个淋巴结意义:If it contains metastatic tumour this indicates thatother lymp
4、h nodes may contain tumour. If it does not contain metastatic tumour, otherlymph nodes are not likely to contain tumour.Occasionally there is more than one sentinel lymph node.,UICC Definition2002,有关前哨淋巴结出现癌细胞是否确定为转移还没有大家都接受的定义。一般认为淋巴结内肿瘤细胞灶大于 0.2mm,而小于2mm者称为微转移如小于0.2mm则称为孤立性肿瘤细胞(isolated tumor cell
5、s,ITC)。,TNM Classification of isolated tumour cells Isolated tumour cells (ITC) are single tumour cellsor small clusters of cells not more than 0.2mm ingreatest dimension that are usually detected byimmunhistochemistry or molecular methods.ITCs do not typically show evidence of metastaticactivity (e
6、.g., proliferation or stromal reaction) orpenetration of vascular or lymphatic sinus walls.,前哨淋巴结状态的表述pNX(sn) Sentinel lymph node could not be assessedpN0(sn) No sentinel lymph node metastasispN1(sn) Sentinel lymph node metastasis,UICC Definition2002,三 .微乳头癌,微乳头结构是指排列紧密的肿瘤细胞团,周围包绕以裂隙,无中心纤维脉管束。其内的肿瘤细
7、胞往往具有嗜酸性胞浆和多形性核。 微乳头结构很少独立存在,往往和其它组织学类型并存,当微乳头结构占肿瘤实质的5%以上时,可称之为微乳头癌。,a:100x; b:400x; c:200x; d:400x,M.-J. Kim et al. Human Pathology (2006) 37, 809 815,M.-J. Kim et al. Human Pathology (2006) 37, 809 815,一般而言,微乳头结构所占比例的多少和结直肠癌的发展和预后并无关系。微乳头结构存在时, T1-2期结直肠癌患者中淋巴结转移发生率更高,TNMI-II期患者的预后更差 微乳头结构的判断对于早期结
8、直肠癌患者的诊断和后续治疗选择很有意义。,univariate survival analysis in 119 colorectal cancers with TNM stage I-II,multivariate survival analysis in 119 colorectal cancers with TNM stage I-II,lower differentiation statusincreased tumor buddingmore frequent lymphovascular and perineural invasionmore frequent lymph node
9、 metastasishigher TNM stageless nuclear -catenin staining,Am J Surg Pathol 2009,33(9):1287-92,微乳头与淋巴结转移的关系,四.微卫星不稳定检测,如是高频MSI则很可能是HNPCC,应该对其家属进行筛查,有利于早期发现病人或突变基因携带者。 高频MSI肿瘤病人预后较好,而且对基于5-Fu为基础的化疗较低频或稳定的肿瘤更为有效。,50岁以前发生的结直肠癌或者结直肠癌伴发有HNPCC相关癌如胃癌,宫内膜癌,肾盂肾盏癌应该检测MSI,一般使用1998年NCI推荐的5个位点的检测方法。没有条件的单位可以用免疫组织
10、化学方法检测MLH1,MSH2,MSH6和PMS蛋白的表达来初筛。,MSS: No microsatellite instability MSI-L: 1 instable marker MSI-H: 2 instable markers,基于MSI的分类,CRC,CRC,MSI,MSI-H,Beta-catenin+ Braf+,HNPCC,MSI-L/MSS,Braf- sporadic hMLH1promoter methy,MGMT Methy 64%MSI-L26%MSS,MSI-diagnosis in colorectal cancer Immunohistochemistry:
11、 Loss of hMLH1,MSS,MSI-H 5个位点,MSI-L1个位点,临床意义,MSI-H CRC,Proximal colonic location,Mucinous and undifferentiated histology,Crohns lymphoid reaction,Better prognosis,Usually without liver metastasis And expansile growth pattern,MSI-H colorectal cancer: special histologic types,mucinous,signet ring cell
12、,medullary,六.K-ras突变的检测,K-ras突变的检测在应用抗EGFR抗体靶向治疗时必须要做,盲目用药不仅费用高还有毒副作用,而且以后还会有医疗纠纷。有K-ras突变的结直肠癌不能再用 (cetuximab,panitumumab)。B-raf V600E突变的检测也列入NCCN标准。最近基本肯定B-raf V600E突变的病例也不能用这种靶向治疗。,KRAS status 与靶向治疗,July 2008 the european medicines evaluation agency has extended the approval for cetuximab to any
13、line of treatment and any fluoropyrimidine-based chemotherapy combination in mCRC, but only in patients with a wild-type KRAS tumor.January 2009, American Society of Clinical Oncology published guidelines that strongly support the use of anti-EGFR drugs in mCRC only in patients with wild-type KRAS.,
14、KRAS 是EGFR信号传导下游的重要分子 K-ras 突变病人不适合于EGFR 抑制剂治疗 具有野生型 KRAS 基因的病人对EGFR 抑制剂治疗反应,明显延长生存时间,KRAS 突变检测确定EGFR 抑制剂治疗,K-RAS 突变 和 EGFR 抗体治疗,K-RASwt,MEK,Elk,Raf,EGFR,EGFR,ERK,Normal Colon mucosa: EGFR not activated K-RAS unmutated (K-RASwt),K-RASwt,MEK,Elk,Raf,EGFR,EGFR,ERK,Colon carcinomas: EGFR activated 60%
15、K-RAS unmutated (K-RASwt),K-RAS 突变和 EGFR抗体治疗,K-RASwt,MEK,Elk,Raf,EGFR,EGFR,ERK,Cetuximab/Panitumumab inhibit EGFR/K-RAS signal transduction,K-RAS 突变 和 EGFR 抗体治疗,西妥昔单抗,MEK,Elk,ERK,Raf,aktiv,EGFR,EGFR,40% of colon carcinomas: EGFR activated, but K-RAS mutated (K-RASmut),K-RASmut,K-RASwt,MEK,Elk,Raf,EG
16、FR,EGFR,ERK,K-RAS 突变 和 EGFR 抗体治疗,Cetuximab/Panitumumab inhibit EGFR/K-RAS,K-RASwt,MEK,Elk,Raf,EGFR,EGFR,ERK,MEK,Elk,ERK,Raf,aktiv,EGFR,EGFR,Cetuximab/Panitumumab inefficious,K-RASmut,K-RAS 突变 和 EGFR 抗体治疗,Cetuximab/Panitumumab inhibit EGFR/K-RAS,K-RASwt,MEK,Elk,Raf,EGFR,EGFR,ERK,Cetuximab/Panitumumab
17、 wirkungslos,ca. 40% der Patienten,EGFR,EGFR,MEK,Elk,Rasmut,Karapetis CS et al. NEJM 2008,K-RAS 突变 和 EGFR 抗体治疗,Cetuximab/Panitumumab inhibit EGFR/K-RAS,西妥昔治疗肝转移,治疗前 治疗后,Dr.Gattenloener,Wuetzburg,Dr.Gattenloener,Wuetzburg,KRAS突变的意义,KRAS mutations 与 sex, age, tumor site or Dukes stage 无关 KRAS mutation 增加 recurrence and death危险 Only the glycine to valine mutation in codon 12 was found to retain an independent increased risk of recurrence and death. KRAS mutations 病人较没有突变者 a worse outcome,Laboratory analysis of KRAS mutations,Data source: Nat Rev Clin Oncol. 2009, 6(9):519-27,谢谢,