结直肠肿瘤病理诊断和治疗中的 几个新概念 来 茂 德 二O一0年四月十六日
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。
恶性息肉 有蒂( pedunculated polyp with invasive cancer) 无蒂(sessile polyp with invasive cancer) 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) 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 良好的组织学特征:分级1-2级, 无脉管浸润,切缘阴性; 不良组织学:分级3-4级,有脉管累犯,切缘阳性 Company Logo
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
分类 pN0所需检查的淋巴结数量 Organ Number of Cancer center lymph nodes Leipzig (2003) ---------------------------------------------------------------------------------------------------- Oesophagus 6 100% Stomach 15 80% Colon 12 84% Rectum 12 90% Pancreas 10 64% Lung 6 96% Breast 6 98%
病人阳性淋巴结数随着所检淋巴结数的增加而增加 Swanson, 2003 Scott, 1989
前哨淋巴结 The sentinel lymph node is the first lymph node UICC Definition 2002 前哨淋巴结 The sentinel lymph node is the first lymph node to receive lymphatic drainage from a primary tumour. 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 that other lymph nodes may contain tumour. If it does not contain metastatic tumour, other lymph nodes are not likely to contain tumour. Occasionally there is more than one sentinel lymph node.
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 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 cells,ITC)。
TNM Classification of isolated tumour cells Isolated tumour cells (ITC) are single tumour cells or small clusters of cells not more than 0.2mm in greatest dimension that are usually detected by immunhistochemistry or molecular methods. ITCs do not typically show evidence of metastatic activity (e.g., proliferation or stromal reaction) or penetration of vascular or lymphatic sinus walls.
pNX(sn) Sentinel lymph node could not be assessed UICC Definition 2002 前哨淋巴结状态的表述 pNX(sn) Sentinel lymph node could not be assessed pN0(sn) No sentinel lymph node metastasis pN1(sn) Sentinel lymph node metastasis
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 variable No. of cases No. of died cases P value MP - 108 13 <0.0001 + 11 6 perineural invasion 83 9 0.0159 36 10 tumor budding 50 0.0640 47 ++ 22 7 Bcl 2 86 0.0397 33
multivariate survival analysis in 119 colorectal cancers with TNM stage I-II variable RR (95%CI) P value MP 8.275(3.027-22.619) <0.0001 Bcl2 3.064 (1.217-7.718) 0.0175 lower differentiation status increased tumor budding more frequent lymphovascular and perineural invasion more frequent lymph node metastasis higher TNM stage less nuclear β-catenin staining
Am J Surg Pathol 2009,33(9):1287-92 微乳头与淋巴结转移的关系
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 四.微卫星不稳定检测 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 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。
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 HNPCC MSI-H CRC MSI MSI-L/MSS Beta-catenin+ Braf+ Braf- sporadic hMLH1promoter methy CRC MSI MSI-L/MSS MGMT Methy 64%MSI-L26%MSS
MSI-diagnosis in colorectal cancer Immunohistochemistry: 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 Crohn’s lymphoid reaction Better prognosis Usually without liver metastasis And expansile growth pattern
MSI-H colorectal cancer: special histologic types mucinous signet ring cell 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 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.
KRAS 突变检测确定EGFR 抑制剂治疗 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
K-RAS unmutated (K-RASwt) K-RAS 突变 和 EGFR 抗体治疗 Normal Colon mucosa: EGFR not activated K-RAS unmutated (K-RASwt) K-RASwt EGFR EGFR Raf MEK ERK Elk
60% K-RAS unmutated (K-RASwt) K-RAS 突变和 EGFR抗体治疗 Colon carcinomas: EGFR activated 60% K-RAS unmutated (K-RASwt) K-RASwt EGFR EGFR Raf MEK ERK Elk
Cetuximab/Panitumumab K-RAS 突变 和 EGFR 抗体治疗 西妥昔单抗 Cetuximab/Panitumumab inhibit EGFR/K-RAS signal transduction K-RASwt EGFR EGFR Raf MEK ERK Elk
Cetuximab/Panitumumab K-RAS mutated (K-RASmut) K-RAS 突变 和 EGFR 抗体治疗 Cetuximab/Panitumumab inhibit EGFR/K-RAS 40% of colon carcinomas: EGFR activated, but K-RAS mutated (K-RASmut) K-RASwt K-RASmut EGFR EGFR aktiv EGFR EGFR Raf Raf MEK MEK ERK Elk ERK Elk
Cetuximab/Panitumumab Cetuximab/Panitumumab K-RAS 突变 和 EGFR 抗体治疗 Cetuximab/Panitumumab inhibit EGFR/K-RAS Cetuximab/Panitumumab inefficious K-RASwt K-RASmut EGFR EGFR aktiv EGFR EGFR Raf Raf MEK MEK ERK Elk ERK Elk
Cetuximab/Panitumumab K-RAS 突变 和 EGFR 抗体治疗 Cetuximab/Panitumumab wirkungslos Cetuximab/Panitumumab inhibit EGFR/K-RAS ca. 40% der Patienten K-RASwt EGFR EGFR Rasmut EGFR EGFR Raf MEK MEK ERK Elk Elk Karapetis CS et al. NEJM 2008
Dr.Gattenloener,Wuetzburg 西妥昔治疗肝转移 治疗前 治疗后 Dr.Gattenloener,Wuetzburg
Dr.Gattenloener,Wuetzburg c d 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
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