垂體腺瘤侵襲及復(fù)發(fā)相關(guān)因素研究進(jìn)展

閻曉玲 張學(xué)斌

.綜述.

垂體腺瘤侵襲及復(fù)發(fā)相關(guān)因素研究進(jìn)展

閻曉玲 張學(xué)斌

垂體腺瘤作為臨床常見的中樞神經(jīng)系統(tǒng)內(nèi)分泌腫瘤,多呈良性,部分具有侵襲性、易復(fù)發(fā),是神經(jīng)外科亟待解決的難題.其臨床預(yù)后主要受生物學(xué)因素和臨床因素的影響,生物學(xué)因素方面,隨著陣列技術(shù)等分子病理學(xué)的應(yīng)用,以及對垂體腺瘤病因?qū)W與腫瘤進(jìn)展,不同亞型垂體腺瘤基因表達(dá)調(diào)控研究的深入,篩選出多種預(yù)測性、診斷分型和治療相關(guān)預(yù)測因子和基因;臨床因素方面,規(guī)范的診斷與治療流程以及新技術(shù)的應(yīng)用明顯改善垂體腺瘤預(yù)后.本文擬就生物學(xué)因素和臨床因素與垂體腺瘤侵襲和復(fù)發(fā)的研究進(jìn)展進(jìn)行簡要綜述.

垂體腫瘤; 腺瘤; 腫瘤侵潤; 腫瘤復(fù)發(fā),局部; 綜述Corresponding author:YAN Xiao?ling(Email:ll934065@126.com)

垂體腺瘤是臨床最為常見的垂體腫瘤,尸檢發(fā)現(xiàn)率約為15%[1?2].有1/3的垂體腺瘤侵犯海綿竇和蝶竇且具有復(fù)發(fā)傾向.確定腫瘤復(fù)發(fā)及復(fù)發(fā)程度,是制定治療策略的關(guān)鍵環(huán)節(jié).垂體腺瘤的臨床預(yù)后主要受生物學(xué)因素和臨床因素的影響,垂體腺瘤亞型是了解其生物學(xué)行為和制定治療策略的基礎(chǔ).激素水平以及腫瘤組織學(xué)形態(tài)和(或)免疫組織化學(xué)特征有助于垂體腺瘤分型,在此基礎(chǔ)上的其他生物學(xué)標(biāo)志物方有指導(dǎo)意義.研究顯示,多種因素可以影響不同亞型垂體腺瘤的增生,如血管生成和(或)重建[3?4]、細(xì)胞凋亡[5]、生長因子、癌基因[6]、抑癌基因[7]和激素受體[8]等.生物學(xué)因素中核分裂象、Ki?67抗原標(biāo)記指數(shù)和P53免疫反應(yīng)性(IR)是常用的預(yù)測腫瘤復(fù)發(fā)和預(yù)后的指標(biāo);臨床因素中術(shù)前腫瘤最大徑、侵犯海綿竇、術(shù)中未完整切除腫瘤是術(shù)后腫瘤復(fù)發(fā)和不良預(yù)后的指標(biāo).

一、生物學(xué)因素

1.血管生成與垂體腺瘤侵襲及復(fù)發(fā)相關(guān)研究

正常垂體與垂體腺瘤的血管網(wǎng)絡(luò)不同,正常垂體腺泡由富有孔窗的毛細(xì)血管網(wǎng)供血;大多數(shù)垂體腺瘤血供不豐富,電子顯微鏡觀察,腫瘤血管內(nèi)皮細(xì)胞孔窗較少,基底膜增厚且不連續(xù),表明血管生成和(或)重建是垂體腺瘤發(fā)生的關(guān)鍵因素,可以作為腫瘤侵襲及復(fù)發(fā)的預(yù)測因素.血管生成和(或)重建是腫瘤生長和轉(zhuǎn)移的基礎(chǔ),腫瘤血管網(wǎng)絡(luò)一方面可以保證腫瘤細(xì)胞的氧供、營養(yǎng)支持和代謝產(chǎn)物排泄,促進(jìn)腫瘤生長;另一方面血管壁結(jié)構(gòu)不完整,基底膜厚度不勻,有利于腫瘤細(xì)胞的血行轉(zhuǎn)移.早在20世紀(jì)90年代,Folkman[9]即提出經(jīng)典的腫瘤血管生成理論:腫瘤生長首先經(jīng)歷無血管期,當(dāng)腫瘤體積達(dá)1～2 mm3時(shí),不能單純依靠彌漫性氧供,呈現(xiàn)出血管生成表型,腫瘤細(xì)胞釋放多種血管生成因子,引起血管內(nèi)皮細(xì)胞形態(tài)改變,降解宿主毛細(xì)血管靜脈端基底膜,刺激血管內(nèi)皮細(xì)胞迅速增殖并向腫瘤遷徙,逐步發(fā)育為有功能的毛細(xì)血管袢,并與宿主血管相互吻合,構(gòu)成腫瘤血管網(wǎng)絡(luò).絕大多數(shù)腫瘤惡性程度與腫瘤血管豐富程度呈正相關(guān),高侵襲性腫瘤以豐富的血管生成為標(biāo)記[10].血管生成受血管生成因子和抑制因子的共同調(diào)節(jié),其中,生長因子有30余種,最主要的是血管內(nèi)皮生長因子(VEGF),其他如表皮生長因子(EGF)、血小板源性生長因子(PDGF)、堿性纖維母細(xì)胞生長因子(bFGF)、P53、白細(xì)胞介素?1(IL?1)、肝素等均通過血管內(nèi)皮生長因子而發(fā)揮作用[11].研究顯示,與非侵襲性垂體腺瘤相比,侵襲性垂體腺瘤血管內(nèi)皮生長因子水平明顯升高[12].目前評價(jià)腫瘤血管生成的最常用指標(biāo)是平均血管密度,研究顯示,乳腺癌和膠質(zhì)瘤等惡性腫瘤平均血管密度增加,且與腫瘤分級(jí)、轉(zhuǎn)移和復(fù)發(fā)密切相關(guān).

2.內(nèi)皮細(xì)胞特異性分子?1表達(dá)變化與垂體腺瘤侵襲及復(fù)發(fā)相關(guān)研究 內(nèi)皮細(xì)胞特異性分子?1(ESM?1)又稱Endocan,是近年發(fā)現(xiàn)的一種新型內(nèi)皮細(xì)胞特異性分子,于1996年由法國科學(xué)家Lassalle等[13]自人臍靜脈內(nèi)皮細(xì)胞cDNA基因庫克隆,長度為2X103bp,相對分子質(zhì)量20X103,在多種組織中均有表達(dá).生物學(xué)功能尚不明確,有研究證實(shí)其在細(xì)胞黏附、膿毒癥和腫瘤發(fā)生中發(fā)揮重要作用.嚴(yán)重創(chuàng)傷后內(nèi)皮細(xì)胞產(chǎn)生大量細(xì)胞因子如IL?1,IL?6、腫瘤壞死因子?α(TNF?α)、原降鈣素等,這些細(xì)胞因子進(jìn)一步作用于內(nèi)皮細(xì)胞,促進(jìn)其分泌內(nèi)皮細(xì)胞特異性分子?1[14].內(nèi)皮細(xì)胞特異性分子?1主要由內(nèi)皮細(xì)胞分泌,故在血供豐富的腫瘤組織中呈高表達(dá),亦可在血管豐富的正常組織中不表達(dá),如心臟、胎盤、胰腺和腦組織等,尤其是腦組織,而在其他正常組織如肺、腎臟、脂肪、結(jié)腸和直腸黏膜中呈高表達(dá).Abid等[15]發(fā)現(xiàn),內(nèi)皮細(xì)胞特異性分子?1在不同部位的血管內(nèi)皮細(xì)胞中表達(dá)水平不同,且這種部位相關(guān)表達(dá)模式受微環(huán)境的影響,其中最主要的是腫瘤微環(huán)境,故可以解釋為何胚胎等正常組織血管增生明顯而內(nèi)皮細(xì)胞特異性分子?1水平并未升高.內(nèi)皮細(xì)胞特異性分子?1僅在腫瘤組織高表達(dá)的特性使其較其他指標(biāo)更適合檢測腫瘤體積的縮小,尤其在抗血管治療和抗淋巴管治療方面.內(nèi)皮細(xì)胞特異性分子?1在創(chuàng)傷后內(nèi)皮細(xì)胞病理生理變化過程中發(fā)揮重要作用,在體內(nèi)外均有促生長作用,且在血管生成過程中與血管內(nèi)皮生長因子有明顯關(guān)聯(lián)性,在炎癥反應(yīng)和腫瘤發(fā)生中發(fā)揮一定作用[14].業(yè)已證實(shí)內(nèi)皮細(xì)胞特異性分子?1在肺癌、腎細(xì)胞癌、子宮內(nèi)膜癌、胃癌、直腸癌等腫瘤組織中呈高表達(dá)[16],提示其對腫瘤發(fā)生、發(fā)展和預(yù)后具有重要意義.有學(xué)者將內(nèi)皮細(xì)胞特異性分子?1視為"tip cell"的生物學(xué)標(biāo)志物[17]."Tip cell"指活躍的內(nèi)皮細(xì)胞,可以調(diào)控腫瘤血管生成和(或)重建過程中的出芽,對血管內(nèi)皮生長因子有應(yīng)答,且含有豐富的內(nèi)皮細(xì)胞特異性分子?1、基質(zhì)細(xì)胞衍生因子?1(SDF?1,亦稱CXCR4)及其受體(亦稱CXCL12趨化因子),是腫瘤血管生成和(或)重建的標(biāo)記.因此推測,垂體腺瘤內(nèi)皮細(xì)胞特異性分子?1的作用主要針對"tip cell",影響血管出芽,導(dǎo)致血管面積增大,與腫瘤進(jìn)展和轉(zhuǎn)移相關(guān),故成為腫瘤血管生成和腫瘤生長的新型生物學(xué)標(biāo)志物.研究顯示,體外培養(yǎng)的腫瘤細(xì)胞經(jīng)血管內(nèi)皮生長因子誘導(dǎo)分泌的內(nèi)皮細(xì)胞特異性分子?1可以被舒尼替尼阻斷,提示內(nèi)皮細(xì)胞特異性分子?1可能成為血管內(nèi)皮生長因子相關(guān)抗血管治療的生物學(xué)標(biāo)志物,但尚待進(jìn)一步研究.

3.TP53基因表達(dá)變化與垂體腺瘤侵襲及復(fù)發(fā)相關(guān)研究 TP53基因是目前研究最多的抑癌基因之一,與端粒酶相關(guān)蛋白1結(jié)合后對其功能進(jìn)行抑制,誘發(fā)端粒酶表達(dá),故TP53基因突變和端粒酶表達(dá)在腫瘤發(fā)生中發(fā)揮重要作用.正常TP53基因編碼野生型P53蛋白,突變型TP53基因編碼突變型P53蛋白.野生型P53蛋白具有抑制腫瘤發(fā)生的作用,約50%的腫瘤組織可以檢出突變型P53蛋白,突變型P53蛋白水平高于野生型100～1000倍,且半衰期延長至20～40小時(shí).TP53基因突變多為點(diǎn)突變,常發(fā)生于長度為600 bp的區(qū)域內(nèi),包含5～8個(gè)外顯子,該區(qū)域內(nèi)有4個(gè)突變位點(diǎn),其中3個(gè)與中樞神經(jīng)系統(tǒng)腫瘤的發(fā)生密切相關(guān).TP53基因突變后失去對正常細(xì)胞生長和血管生成的抑制作用,從而刺激細(xì)胞增殖[18].Yagnik等[19]在無功能性垂體腺瘤TP53基因第4外顯子第72號(hào)密碼子發(fā)現(xiàn)rs1042522位點(diǎn)(G>C)單核苷酸多態(tài)性(SNP)對腫瘤的影響,即攜帶G等位基因(變異體)的垂體腺瘤進(jìn)展較迅速、細(xì)胞增殖較明顯,表明TP53基因多態(tài)性與垂體腺瘤生長相關(guān).TP53基因突變與端粒酶表達(dá)密切相關(guān),端粒酶提示具有無限增殖能力腫瘤細(xì)胞的存在,近年對垂體腺瘤中端粒酶表達(dá)變化的研究結(jié)果不盡一致,Miermeister等[20]的研究顯示,端粒酶是評價(jià)垂體腺瘤生長和預(yù)后的重要指標(biāo),證實(shí)P53蛋白在典型和非典型垂體腺瘤及垂體癌中的表達(dá)不同[21],以核分裂象≥2個(gè)/10高倍視野和P53陽性檢出率≥2%作為診斷非典型垂體腺瘤的重要指標(biāo).此外,野生型P53蛋白還可以刺激內(nèi)源性TSP21基因以抑制血管生成,通過堿性纖維母細(xì)胞生長因子參與腫瘤血管生成.Mukhopadhyay等[22]報(bào)告野生型P53蛋白以劑量和時(shí)間依賴性方式抑制血管內(nèi)皮生長因子啟動(dòng)子活性上調(diào),并抑制突變型v?Sre酪氨酸激酶對血管內(nèi)皮生長因子的正性誘導(dǎo)作用;野生型P53蛋白缺失后,血管內(nèi)皮生長因子水平升高.

4.基因表達(dá)差異性與垂體腺瘤侵襲及復(fù)發(fā)相關(guān)研究 近年來,陣列技術(shù)的應(yīng)用有利于正常垂體和垂體腺瘤的基因研究,這種以雜交為基礎(chǔ)的技術(shù)最早應(yīng)用于大鼠和小鼠模型,可以同時(shí)檢測不同亞型垂體腺瘤的基因表達(dá),還可以識(shí)別微小RNA(miRNA)相關(guān)垂體腺瘤.Bottoni等[23]對32例垂體腺瘤患者和6例正常對照者研究發(fā)現(xiàn),二者之間有30個(gè)miRNAs表達(dá)不同,24個(gè)miRNAs識(shí)別為垂體腺瘤的預(yù)測性標(biāo)志物,29個(gè)miRNAs提示垂體腺瘤亞型.微腺瘤和(或)大腺瘤、治療和(或)未治療的垂體腺瘤miRNA表達(dá)水平亦不同,部分與細(xì)胞增殖和凋亡相關(guān),提示miRNA失調(diào)可能與垂體腺瘤的發(fā)生有關(guān),而預(yù)測性miRNA有望成為診斷指標(biāo),有助于垂體腺瘤分型.Lania等[24]陣列技術(shù)研究業(yè)已發(fā)現(xiàn) PTTG1、GADD45?γ、MEG3、DAPK1等垂體腺瘤相關(guān)基因.垂體腺瘤蛋白質(zhì)組學(xué)和轉(zhuǎn)錄組學(xué)研究顯示,侵襲性與非侵襲性垂體腺瘤之間有1160種基因和283種蛋白表達(dá)不同,差異表達(dá)的分子主要參與分子運(yùn)輸、細(xì)胞遷移和細(xì)胞運(yùn)動(dòng).IL?6是顯著激活的上游調(diào)控因子,而IL?6受體/JAK激酶2(JAK2)/信號(hào)傳導(dǎo)與轉(zhuǎn)錄激活因子3(STAT3)信號(hào)轉(zhuǎn)導(dǎo)通路過度激活在垂體腺瘤的侵襲性中發(fā)揮至關(guān)重要的作用[25].泌乳素腺瘤和促腎上腺皮質(zhì)激素腺瘤可溶性半乳糖苷結(jié)合凝集素3(LGALS3)和hASH?1表達(dá)水平高于生長激素腺瘤、促性腺激素腺瘤和零細(xì)胞腺瘤,且前兩者易進(jìn)展為垂體癌.hASH?1與小細(xì)胞癌生存期縮短有關(guān),且在良性腫瘤中無表達(dá).斷裂轉(zhuǎn)導(dǎo)蛋白樣增強(qiáng)子(TLE)與不同翻譯因子相連接,與特殊DNA區(qū)域結(jié)合后形成多聚復(fù)合體,影響組蛋白乙酰化作用和染色質(zhì)結(jié)構(gòu),進(jìn)而抑制染色質(zhì)翻譯活性.泌乳激素腺瘤斷裂轉(zhuǎn)導(dǎo)蛋白樣增強(qiáng)子?4表達(dá)水平高于促腎上腺皮質(zhì)激素腺瘤.細(xì)胞分化抑制因子2(ID2)在所有垂體腫瘤中均有表達(dá),尤其在垂體癌中呈高表達(dá),由于其與轉(zhuǎn)化因子相關(guān),未來有可能成為垂體腫瘤進(jìn)展和轉(zhuǎn)移的治療靶點(diǎn)[23,26].整合素樣金屬蛋白酶與凝血酶樣6(ADAMTS6)、腦衰蛋白反應(yīng)調(diào)節(jié)蛋白?1(CRMP?1)、垂體腫瘤轉(zhuǎn)化基因(PTTG)、周期蛋白B1(CCNB1)、極光激酶B(AURKB)和著絲粒蛋白E(CENPE)均與垂體腺瘤進(jìn)展和復(fù)發(fā)有關(guān)[27],ADAMTS6、CRMP?1、CCNB1和CENPE與垂體腺瘤分型有關(guān).β?連接素(β?catenin)和原癌基因蛋白(C?myc)在浸潤性腫瘤中呈現(xiàn)過表達(dá)[28],Gruppetta等[29]在無功能性垂體腺瘤中檢測出β?連接素和C?myc,且與腫瘤進(jìn)展呈正相關(guān).其中,β?連接素與腫瘤復(fù)發(fā)相關(guān);C?myc與腫瘤細(xì)胞胞核表達(dá)PTTG相關(guān),且PTTG是垂體腺瘤增殖活性標(biāo)志物,提示PTTG可以誘導(dǎo)C?myc在垂體腺瘤表達(dá),推測C?myc可能作用于早期垂體腺瘤.

二、臨床因素

1.治療規(guī)范 臨床因素對垂體腺瘤預(yù)后的影響越來越受到重視.早期規(guī)范的診斷與治療流程對預(yù)后至關(guān)重要.2015年,Castinetti等[30]提出無功能性垂體腺瘤的臨床診斷與治療規(guī)范:對于癥狀性垂體腺瘤,若出現(xiàn)視力下降、持續(xù)性頭痛,應(yīng)考慮外科手術(shù),但內(nèi)分泌功能障礙不能作為外科手術(shù)的主要指征;對于無癥狀性垂體腺瘤,應(yīng)綜合考慮年齡、病史、視野缺損風(fēng)險(xiǎn)、垂體功能障礙風(fēng)險(xiǎn)、垂體卒中風(fēng)險(xiǎn)等多種因素.2016年,Lucas等[31]建議將內(nèi)分泌功能障礙作為無功能性垂體腺瘤的手術(shù)指征,而現(xiàn)有資料不足以提出無癥狀性垂體腺瘤的治療推薦.同年P(guān)aschou等[32]提出,無手術(shù)指征的垂體腺瘤一經(jīng)明確診斷,即應(yīng)進(jìn)行系統(tǒng)隨訪,包括巨大腺瘤每6個(gè)月、微腺瘤每12個(gè)月復(fù)查頭部MRI,巨大腺瘤每6個(gè)月、微腺瘤每12個(gè)月檢測激素水平.2015年,Nieman等[33]制定Cushing綜合征治療規(guī)范,其中兒童和成年垂體腺瘤致Cushing綜合征,推薦經(jīng)鼻蝶入路垂體腺瘤切除術(shù).

2.新手術(shù)和治療模式 術(shù)前垂體腺瘤最大徑是目前較為公認(rèn)的判斷垂體腺瘤復(fù)發(fā)的指標(biāo).Johnston等[34]采用經(jīng)鼻蝶入路切除Cushing綜合征致垂體腺瘤,結(jié)果顯示,大腺瘤或腫瘤范圍超過垂體和蝶鞍者,提示初始不易緩解和術(shù)后易復(fù)發(fā).Dallapiazza等[35]采用內(nèi)鏡下經(jīng)鼻蝶入路切除垂體大腺瘤,80%全切除患者術(shù)后10年無進(jìn)展,21%部分切除患者術(shù)后10年無進(jìn)展.Oertel等[36]常規(guī)采用0°內(nèi)鏡切除垂體腺瘤,并采用傾斜內(nèi)鏡觀察是否有腫瘤殘留,28%可見腫瘤殘留,腫瘤全切除率達(dá)96%;而單獨(dú)采用0°內(nèi)鏡的患者腫瘤全切除率為80%.Linsler等[37]以手術(shù)方式、手術(shù)范圍、手術(shù)期間并發(fā)癥、術(shù)后內(nèi)分泌和眼科檢查、腫瘤復(fù)發(fā)為指標(biāo)進(jìn)行回顧分析,新手術(shù)策略如經(jīng)鼻蝶入路顯微外科手術(shù)或內(nèi)鏡下經(jīng)鼻蝶入路等微侵襲技術(shù)的應(yīng)用可以顯著降低圍手術(shù)期并發(fā)癥發(fā)生率和病死率、提高遠(yuǎn)期預(yù)后、延長無瘤生存期,以及取得更好的術(shù)后內(nèi)分泌和眼科相關(guān)疾病結(jié)局,宋業(yè)純等[38]也得到類似結(jié)論.某些垂體腺瘤還可采用伽瑪?shù)吨委?也取得進(jìn)一步的進(jìn)展[39].對于侵襲性垂體腺瘤和垂體癌,特別是外科手術(shù)和放射治療均無法控制的患者,替莫唑胺已被證實(shí)是一種有效的治療方法[40].Halevy和Whitelaw[41]研究顯示,約42%患者影像學(xué)可見治療反應(yīng),約27%患者替莫唑胺治療后病情穩(wěn)定;泌乳素腺瘤和促腎上腺皮質(zhì)激素腺瘤均對替莫唑胺治療反應(yīng)良好,反應(yīng)率約為50%,而無功能性垂體腺瘤的反應(yīng)率僅為前兩者的1/2.目前能夠預(yù)測替莫唑胺治療反應(yīng)的生物學(xué)標(biāo)志物包括O6?甲基鳥嘌呤?DNA甲基轉(zhuǎn)移酶(MGMT)和黑色素細(xì)胞刺激素(MSH),但不足以確定治療決策.研究顯示,MGMT表達(dá)變化可能與垂體腺瘤復(fù)發(fā)有關(guān)[42],而與腫瘤侵襲性或其他臨床病理學(xué)指標(biāo)無關(guān)聯(lián)性,提示檢測MGMT可能有助于指導(dǎo)臨床治療和預(yù)測預(yù)后.

縱觀現(xiàn)有的國內(nèi)外文獻(xiàn),垂體腺瘤侵襲及復(fù)發(fā)研究仍是神經(jīng)外科的難點(diǎn)和熱點(diǎn).血管生成和(或)重建、基因表達(dá)調(diào)控及相關(guān)臨床因素的綜合研究提出許多新的有意義的觀點(diǎn),探討規(guī)范治療的最佳方案和預(yù)后影響因素,為垂體腺瘤個(gè)體化治療打下堅(jiān)實(shí)的基礎(chǔ)仍是臨床工作者不斷努力的方向.

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Advances in research of invasion and recurrence of pituitary adenoma

YAN Xiao?ling,ZHANG Xue?bin
Department of Pathology,Tianjin Huanhu Hospital,Tianjin 300350,China

Pituitary adenoma,a common intracranial neuroendocrine tumor is usually a benign tumor,some of which are of invasiveness and high recurrence,making it a problem to be solved in neurosurgery.The clinical prognosis of pituitary adenoma is mainly determined by biological factors and clinical factors.In terms of biological factors,with the application of molecular array technology and others molecular detection progress in etiology and pathology,a lot of prediction,diagnosis,treatment related predictive factors and genes are detected for further screening. As for the other factors,standardized prognosis and treatment procedure and application of new technology are obvious in improving the prognosis of pituitary adenomas.This article reviews the research progress of the factors of pituitary adenoma,and provides the reference for the diagnosis and treatment of pituitary adenoma.

Pituitary neoplasms; Adenoma; Neoplasm invasiveness; Neoplasm recurrence,local; Review

10.3969/j.issn.1672?6731.2017.07.011

300350天津市環(huán)湖醫(yī)院病理科

閻曉玲(Email:ll934065@126.com)

2017?06?19)