胃腸道間質(zhì)瘤課件

1、胃腸道間質(zhì)瘤,胃腸道間質(zhì)瘤 Gastrointestinal stromal tumors,胃腸道間質(zhì)瘤,胃腸間質(zhì)瘤（GIST）身世之謎,Cajal細(xì)胞胞,胃腸道間質(zhì)瘤,胃腸道間質(zhì)瘤定義 Gastrointestinal stromal tumors（GIST）,是胃腸道最常見的間葉性腫瘤； 由突變的c-kit或血小板源性生長(zhǎng)因子受體-（PDGFRA）基因驅(qū)動(dòng)； 組織學(xué)上由梭形細(xì)胞、上皮樣細(xì)胞、偶或多形性細(xì)胞，排列成束狀或彌漫狀圖像； 免疫組化檢測(cè)通常為CD117或DOG-1表達(dá)陽性,胃腸道間質(zhì)瘤,治 療,發(fā)病機(jī)制,病理特點(diǎn),臨床特征,診 斷,內(nèi)容,胃腸道間質(zhì)瘤,P,P,P,P,P,ATP,激

2、酶結(jié)構(gòu)域,有關(guān),c-kit激酶區(qū)通過磷酸化激活底物蛋白，如磷酸肌醇-3激酶（ PI3 -K）,激活的底物促發(fā)信號(hào)傳導(dǎo)的級(jí)聯(lián)反應(yīng)，而調(diào)節(jié)基因表達(dá)、控制細(xì)胞生長(zhǎng)、增殖和分化。,c-kit基因突變導(dǎo)致酪氨酸激酶持續(xù)活化致使突變細(xì)胞增殖失控,底物蛋白,發(fā)病機(jī)制,Go,胃腸道間質(zhì)瘤,Heinrich et al. Hum Pathol. 2002;33:484. Corless et al. Proc Am Assoc Cancer Res. 2003;44. Abstract R4447.,GIST中c-kit和 PDGFRA 突變,細(xì)胞膜,細(xì)胞質(zhì),外顯子 11 (67.1%),外顯子 9 (11%)

3、,外顯子 13 (0.9%),外顯子 17 (0.5%),外顯子 12 (0.9%),外顯子 18 (6.3%),c-kit,PDGFRA,突變率: 5-10%,外顯子 14 (0.3%),突變率: 80%,胃腸道間質(zhì)瘤,c-kit基因突變,1998年Hirota發(fā)現(xiàn)80-88的GIST存在 c-kit突變 表達(dá)c-kit蛋白產(chǎn)物CDll7,PDGFRA -突變,野生型,2004年 Heinrich等在c-kit突變陰性的GIST 中發(fā)現(xiàn)了血小板生長(zhǎng)因子受體,c-kit和PDGFRA -突變基因均無突變,發(fā)病機(jī)制,胃腸道間質(zhì)瘤,病理特征,一般與周圍組織界限清楚，可有或無包膜，切面灰紅或灰白色。

4、較大的腫瘤可發(fā)生出血壞死或黏液樣變性; 可向腔內(nèi)、腔外生長(zhǎng)、壁內(nèi)生長(zhǎng)或同時(shí)生長(zhǎng),大體病理特征,胃腸道間質(zhì)瘤,病理特征,大體病理特征,胃腸道間質(zhì)瘤,病理特征,大體病理特征,胃腸道間質(zhì)瘤,病理特征,組織學(xué)病理特征,混合型,上皮樣細(xì)胞,梭形細(xì)胞,0% 20% 40% 60% 80% 100%,10%,20%,70%,依據(jù)細(xì)胞形態(tài)可將GIST分為3大類:梭形細(xì)胞型、上皮樣細(xì)胞型和梭形細(xì)胞(或上皮樣細(xì)胞)混合型,胃腸道間質(zhì)瘤,梭形細(xì)胞,上皮樣細(xì)胞,病理特征,組織學(xué)病理特征,胃腸道間質(zhì)瘤,臨床特征,年齡,發(fā)病人群在40-70歲 中位年齡60歲 男性多于女性,部位,胃腸道間質(zhì)瘤,臨床表現(xiàn),消化道出血,腹部隱

5、痛不適、腹痛、急腹癥,腹部包塊,非特異性癥狀：乏力、惡心、嘔吐、早飽等,常見的轉(zhuǎn)移部位是肝臟和腹腔,無意義,胃腸道間質(zhì)瘤,實(shí)驗(yàn)室檢查：無； 影像學(xué)檢查：CT、MRI、PET-CT； 內(nèi)鏡：要特征為黏膜下半球形隆起，黏膜 光整，可伴有糜爛和潰瘍； 病理診斷:診斷GIST的根本,診 斷,胃腸道間質(zhì)瘤,胃,影像學(xué)輔助檢查,胃腸道間質(zhì)瘤,小腸,影像學(xué)檢查：,胃腸道間質(zhì)瘤,內(nèi)鏡檢查,回,胃腸道間質(zhì)瘤,病理診斷,組織學(xué)：由梭形細(xì)胞、上皮樣細(xì)胞組成 免疫組化檢測(cè)： CD117陽性率約95%,DOG- 1陽性率98%,CD34陽性率70%,-SMA陽性率40%；,c-kit基因的第11913和17號(hào)外顯子 P

6、DGFRA基因的第12和18號(hào)外顯子,包括原發(fā)腫瘤的部位腫瘤的大小核分裂像以及是否發(fā)生破裂等.,基本診斷,基因檢測(cè),危險(xiǎn)度評(píng)估,GIST,診斷,胃腸道間質(zhì)瘤,病理診斷思路,DOG-1 檢測(cè),CD117免疫組化檢測(cè),野生型GIST或其他,PDGFRA基因檢測(cè),有可能GIST,c-kit基因檢測(cè),GIST,GIST,GIST,（+）是,（+）是,（-）否,（-）否,有突變,有突變,無突變,無突變,回,胃腸道間質(zhì)瘤,20.Joensuu H. Hum Path. 2008;39:1411-1419.,NIH原發(fā)GIST切除術(shù)后的風(fēng)險(xiǎn)分級(jí)（2008）,幣,胃腸道間質(zhì)瘤,惡,黏膜浸潤(rùn),瘤細(xì)胞顯著異性,神

7、經(jīng)浸潤(rùn),脂肪浸潤(rùn),淋巴結(jié)轉(zhuǎn)移,腫瘤性壞死,肌層浸潤(rùn),核分裂像大于或等于10個(gè)/50 HPF,圍繞血管呈古錢幣樣生長(zhǎng),血管浸潤(rùn),惡性GIST診斷標(biāo)準(zhǔn),胃腸道間質(zhì)瘤,外科治療,分子靶向治療,1,2,治 療,GIST對(duì)于放療、化療幾乎不敏感,Go,Go,胃腸道間質(zhì)瘤,Go,應(yīng)該注意不適當(dāng)?shù)幕顧z可能引起腫瘤的破潰出血和增加腫瘤播散的危險(xiǎn)性;尤其對(duì)于部位較深的,如腫瘤位于十二指腸,進(jìn)行活檢需慎重,.,活檢原則,手術(shù)適應(yīng)證,手術(shù)原則,外科治療,外科治療原則,根據(jù)腫瘤的大小、位置 復(fù)發(fā)或轉(zhuǎn)移 急診手術(shù),Go,手術(shù)基本原則 腹腔鏡、胃、小腸等,回,胃腸道間質(zhì)瘤,初發(fā)且疑似GIST者,術(shù)前需明確性質(zhì),首選超聲內(nèi)

8、鏡引導(dǎo)下穿刺活檢,需要聯(lián)合多臟器切除者,或手術(shù)后影響相關(guān)臟器功能者, 考慮活檢,無法切除或估計(jì)難以獲得R0切除的病變,擬采用術(shù)前藥物治療者,經(jīng)皮穿刺,適用于腫瘤已經(jīng)播散或復(fù)發(fā)的患者,活檢原則,對(duì)于大多數(shù)可以完整切除的GIST,手術(shù)前不推薦常規(guī)活檢或穿刺,對(duì)于直腸和盆腔腫物,如需術(shù)前活檢,推薦經(jīng)直腸前壁穿刺活檢,活檢原則,返回,胃腸道間質(zhì)瘤,手術(shù)適應(yīng)癥,回,胃腸道間質(zhì)瘤,手術(shù)中觸摸腫瘤不當(dāng)造成破潰出血、術(shù)中播散,初次手術(shù)僅為R1切除,預(yù)計(jì)再次手術(shù)難度低且風(fēng)險(xiǎn)可控制, 考慮二次手術(shù),GIST很少發(fā)生淋巴結(jié)轉(zhuǎn)移,除非有明確淋巴結(jié)轉(zhuǎn)移,一般不必常規(guī)清掃,對(duì)于術(shù)后切緣陽性,目前國(guó)內(nèi)外學(xué)者傾向于采用分子靶

9、向藥物治療,手術(shù)適應(yīng)癥,手術(shù)目標(biāo)是盡量爭(zhēng)取達(dá)到R0切除,腹腔鏡手術(shù)容易引起腫瘤破裂和導(dǎo)致腹腔種植,所以不推薦常規(guī)應(yīng)用,手術(shù)原則,胃腸道間質(zhì)瘤,胃外GIST手術(shù),GIST內(nèi)鏡下治療,腹腔鏡GIST手術(shù),小腸GIST手術(shù),胃GIST手術(shù),十二指腸與結(jié)腸,手術(shù)原則,返回,胃腸道間質(zhì)瘤,29,何謂腫瘤分子靶向治療？,腫瘤分子靶向治療是針對(duì)可能導(dǎo)致細(xì)胞癌變的環(huán)節(jié)，如細(xì)胞信號(hào)傳導(dǎo)通路、原癌基因和抑癌基因、細(xì)胞因子及受體、抗腫瘤血管形成、自殺基因等，從分子水平來逆轉(zhuǎn)這種惡性生物學(xué)行為，從而抑制腫瘤細(xì)胞生長(zhǎng)，甚至使其完全消退的一種全新的生物治療模式。,胃腸道間質(zhì)瘤,傳統(tǒng)治療模式,個(gè)體化治療,特異性地作用于腫瘤

10、細(xì)胞,腫瘤分子靶向治療,胃腸道間質(zhì)瘤,伊馬替尼,激酶區(qū),伊馬替尼占據(jù)了ATP在KIT激酶區(qū)的結(jié)合位點(diǎn) 從而阻止了底物磷酸化及信號(hào)轉(zhuǎn)導(dǎo) 信號(hào)缺失抑制了細(xì)胞的增殖和存活,Savage and Antman. N Engl J Med. 2002;346:683. Scheijen and Griffin. Oncogene. 2002;21:3314.,伊馬替尼的作用機(jī)制,回,胃腸道間質(zhì)瘤,通用名：甲磺酸伊馬替尼 商品名：格列衛(wèi) 劑量/劑型：100mg x 60片/盒 價(jià)格：12000/60片/盒 英文商用名： Imatinib Mesylate Capsules,伊馬替尼（格列衛(wèi)）,伊馬替尼（i

11、matinib）：一種選擇性抑制bcr-abl酪氨酸激酶，同時(shí)還是PDGFR和干細(xì)胞因子受體c-kit的強(qiáng)抑制劑。,胃腸道間質(zhì)瘤,Joensuu et al. N Engl J Med. 2001;344:1052-1056.,治療4周后,2000年2月伊馬替尼治療的第一例GIST,胃腸道間質(zhì)瘤,減小腫瘤體積,降低臨床分期;縮小手術(shù)范圍,避免不必要的聯(lián)合臟器切除,降低手術(shù)風(fēng)險(xiǎn),同時(shí)增加根治性切除機(jī)會(huì),.,術(shù)前治療,術(shù)后輔助治療,轉(zhuǎn)移或復(fù)發(fā),靶向治療,分子靶向治療,Go,Go,Go,適應(yīng)癥 時(shí)限 劑量,胃腸道間質(zhì)瘤,估計(jì)需要進(jìn)行多臟器聯(lián)合切除手術(shù),術(shù)前估計(jì)難以達(dá)到R0切除,腫瘤體積巨大(大于10

12、 cm),術(shù)中易出血破裂,可能造成醫(yī)源性播散,腫瘤雖可以切除,但估計(jì)手術(shù)風(fēng)險(xiǎn)較大,術(shù)后復(fù)發(fā)率死亡率較高,術(shù)前治療適應(yīng)癥,特殊部位的腫瘤(如十二指腸低位直腸等),手術(shù)易損害重要臟器的功能,術(shù)前治療的適應(yīng)證,其他,胃腸道間質(zhì)瘤,推薦初始劑量,術(shù)前治療時(shí)間,術(shù)前停藥時(shí)間,伊馬替尼400mg,6個(gè)月,1周,術(shù)前治療,back,胃腸道間質(zhì)瘤,術(shù)后輔助治療,輔助治療適應(yīng)證,輔助治療時(shí)限,輔助治療劑量,推薦有中高危復(fù)發(fā)風(fēng)險(xiǎn)患者作為輔助治療的適合人群.,中危患者,應(yīng)至少給予伊馬替尼輔助治療1年 高?；颊?輔助治療時(shí)間為3年,建議初始劑量為400 mg/d 如果 KIT 外顯子9陽性，則初始劑量為800 mg/

13、d,天,胃腸道間質(zhì)瘤,轉(zhuǎn)移復(fù)發(fā)或不可切除GIST的治療,一線治療,二線治療,三線治療,伊馬替尼是轉(zhuǎn)移復(fù)發(fā)或不可切除GIST的一線治療藥物,初始推薦劑量為400 mg/d.,伊馬替尼標(biāo)準(zhǔn)劑量失敗后的治療選擇； 伊馬替尼增加劑量；舒尼替尼治療,伊馬替尼與舒尼替尼治療失敗后的維持治療 建議參加新藥臨床研究 也可以考慮使用其他分子靶向藥物,如索拉非尼,天,back,胃腸道間質(zhì)瘤,原發(fā)局部疾病,可切除,手術(shù),術(shù)后給予伊馬替尼,無法切除或需要擴(kuò)大手術(shù)方能切除或存在器官功能障礙的危險(xiǎn),伊馬替尼,仍無法切除,伊馬替尼,若有微轉(zhuǎn)移疾病，可考慮切除原發(fā)灶，尤其是有癥狀時(shí),復(fù)發(fā)或轉(zhuǎn)移性疾病,緩解/ 疾病穩(wěn)定,局灶進(jìn)

14、展,彌漫性進(jìn)展,手術(shù) 肝動(dòng)脈栓塞術(shù) 射頻消融術(shù),舒尼替尼 其它新藥,繼續(xù)使用伊馬替尼,GIST的治療規(guī)程,胃腸道間質(zhì)瘤,胃腸道間質(zhì)瘤,GIST:藥物療效的判斷,GIST靶向治療Choi療效評(píng)價(jià)標(biāo)準(zhǔn)32,32.Choi H. Oneologist.2008;13(Suppl 12):4-7.,胃腸道間質(zhì)瘤,Diagram,Text in here,Text in here,Text in here,Title,Title,ThemeGallery is a Design Digital Content 不能切除的局限性GIST,或臨界可切除,但切除風(fēng)險(xiǎn)較大或嚴(yán)重影響臟器功能者,宜先行術(shù)前藥物治療

15、,待腫瘤縮小后再行手術(shù),對(duì)于腫瘤最大徑線小于或等于2 cm的可疑局限性GIST,有癥狀者應(yīng)進(jìn)行手術(shù) 位于胃的無癥狀GIST,一旦確診后,應(yīng)根據(jù)其表現(xiàn)確定超聲內(nèi)鏡風(fēng)險(xiǎn)分級(jí)；如合并不 良因素,應(yīng)考慮切除;如無不良因素,可定期復(fù)查超聲內(nèi)鏡 直腸的GIST, 腫瘤一旦增大,保留肛門功能的手術(shù)難度增大,傾向于及早手術(shù)切除,手術(shù)適應(yīng)癥,急診手術(shù)適應(yīng)證:在GIST引起完全性腸梗阻消化道穿孔保守治療無效的消化道大出血以及腫瘤自發(fā)破裂引起腹腔大出血時(shí),須行急診手術(shù),復(fù)發(fā)或轉(zhuǎn)移,分多種情況區(qū)別對(duì)待（略）,1,2,3,4,返回,返回,胃腸道間質(zhì)瘤,Diagram,- ThemeGallery is a Design

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