垂體腺瘤侵襲及復發相關因素研究進展

閻曉玲 張學斌

.綜述.

垂體腺瘤侵襲及復發相關因素研究進展

閻曉玲 張學斌

垂體腺瘤作為臨床常見的中樞神經系統內分泌腫瘤,多呈良性,部分具有侵襲性、易復發,是神經外科亟待解決的難題.其臨床預后主要受生物學因素和臨床因素的影響,生物學因素方面,隨著陣列技術等分子病理學的應用,以及對垂體腺瘤病因學與腫瘤進展,不同亞型垂體腺瘤基因表達調控研究的深入,篩選出多種預測性、診斷分型和治療相關預測因子和基因;臨床因素方面,規范的診斷與治療流程以及新技術的應用明顯改善垂體腺瘤預后.本文擬就生物學因素和臨床因素與垂體腺瘤侵襲和復發的研究進展進行簡要綜述.

垂體腫瘤; 腺瘤; 腫瘤侵潤; 腫瘤復發,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,尸檢發現率約為15%[1?2].有1/3的垂體腺瘤侵犯海綿竇和蝶竇且具有復發傾向.確定腫瘤復發及復發程度,是制定治療策略的關鍵環節.垂體腺瘤的臨床預后主要受生物學因素和臨床因素的影響,垂體腺瘤亞型是了解其生物學行為和制定治療策略的基礎.激素水平以及腫瘤組織學形態和(或)免疫組織化學特征有助于垂體腺瘤分型,在此基礎上的其他生物學標志物方有指導意義.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.生物學因素中核分裂象、Ki?67抗原標記指數和P53免疫反應性(IR)是常用的預測腫瘤復發和預后的指標;臨床因素中術前腫瘤最大徑、侵犯海綿竇、術中未完整切除腫瘤是術后腫瘤復發和不良預后的指標.

一、生物學因素

1.血管生成與垂體腺瘤侵襲及復發相關研究

正常垂體與垂體腺瘤的血管網絡不同,正常垂體腺泡由富有孔窗的毛細血管網供血;大多數垂體腺瘤血供不豐富,電子顯微鏡觀察,腫瘤血管內皮細胞孔窗較少,基底膜增厚且不連續,表明血管生成和(或)重建是垂體腺瘤發生的關鍵因素,可以作為腫瘤侵襲及復發的預測因素.血管生成和(或)重建是腫瘤生長和轉移的基礎,腫瘤血管網絡一方面可以保證腫瘤細胞的氧供、營養支持和代謝產物排泄,促進腫瘤生長;另一方面血管壁結構不完整,基底膜厚度不勻,有利于腫瘤細胞的血行轉移.早在20世紀90年代,Folkman[9]即提出經典的腫瘤血管生成理論:腫瘤生長首先經歷無血管期,當腫瘤體積達1～2 mm3時,不能單純依靠彌漫性氧供,呈現出血管生成表型,腫瘤細胞釋放多種血管生成因子,引起血管內皮細胞形態改變,降解宿主毛細血管靜脈端基底膜,刺激血管內皮細胞迅速增殖并向腫瘤遷徙,逐步發育為有功能的毛細血管袢,并與宿主血管相互吻合,構成腫瘤血管網絡.絕大多數腫瘤惡性程度與腫瘤血管豐富程度呈正相關,高侵襲性腫瘤以豐富的血管生成為標記[10].血管生成受血管生成因子和抑制因子的共同調節,其中,生長因子有30余種,最主要的是血管內皮生長因子(VEGF),其他如表皮生長因子(EGF)、血小板源性生長因子(PDGF)、堿性纖維母細胞生長因子(bFGF)、P53、白細胞介素?1(IL?1)、肝素等均通過血管內皮生長因子而發揮作用[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皮生長因子水平明顯升高[12].目前評價腫瘤血管生成的最常用指標是平均血管密度,研究顯示,乳腺癌和膠質瘤等惡性腫瘤平均血管密度增加,且與腫瘤分級、轉移和復發密切相關.

2.內皮細胞特異性分子?1表達變化與垂體腺瘤侵襲及復發相關研究 內皮細胞特異性分子?1(ESM?1)又稱Endocan,是近年發現的一種新型內皮細胞特異性分子,于1996年由法國科學家Lassalle等[13]自人臍靜脈內皮細胞cDNA基因庫克隆,長度為2X103bp,相對分子質量20X103,在多種組織中均有表達.生物學功能尚不明確,有研究證實其在細胞黏附、膿毒癥和腫瘤發生中發揮重要作用.嚴重創傷后內皮細胞產生大量細胞因子如IL?1,IL?6、腫瘤壞死因子?α(TNF?α)、原降鈣素等,這些細胞因子進一步作用于內皮細胞,促進其分泌內皮細胞特異性分子?1[14].內皮細胞特異性分子?1主要由內皮細胞分泌,故在血供豐富的腫瘤組織中呈高表達,亦可在血管豐富的正常組織中不表達,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、結腸和直腸黏膜中呈高表達.Abid等[15]發現,內皮細胞特異性分子?1在不同部位的血管內皮細胞中表達水平不同,且這種部位相關表達模式受微環境的影響,其中最主要的是腫瘤微環境,故可以解釋為何胚胎等正常組織血管增生明顯而內皮細胞特異性分子?1水平并未升高.內皮細胞特異性分子?1僅在腫瘤組織高表達的特性使其較其他指標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.內皮細胞特異性分子?1在創傷后內皮細胞病理生理變化過程中發揮重要作用,在體內外均有促生長作用,且在血管生成過程中與血管內皮生長因子有明顯關聯性,在炎癥反應和腫瘤發生中發揮一定作用[14].業已證實內皮細胞特異性分子?1在肺癌、腎細胞癌、子宮內膜癌、胃癌、直腸癌等腫瘤組織中呈高表達[16],提示其對腫瘤發生、發展和預后具有重要意義.有學者將內皮細胞特異性分子?1視為"tip cell"的生物學標志物[17]."Tip cell"指活躍的內皮細胞,可以調控腫瘤血管生成和(或)重建過程中的出芽,對血管內皮生長因子有應答,且含有豐富的內皮細胞特異性分子?1、基質細胞衍生因子?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)重建的標記.因此推測,垂體腺瘤內皮細胞特異性分子?1的作用主要針對"tip cell",影響血管出芽,導致血管面積增大,與腫瘤進展和轉移相關,故成為腫瘤血管生成和腫瘤生長的新型生物學標志物.研究顯示,體外培養的腫瘤細胞經血管內皮生長因子誘導分泌的內皮細胞特異性分子?1可以被舒尼替尼阻斷,提示內皮細胞特異性分子?1可能成為血管內皮生長因子相關抗血管治療的生物學標志物,但尚待進一步研究.

3.TP53基因表達變化與垂體腺瘤侵襲及復發相關研究 TP53基因是目前研究最多的抑癌基因之一,與端粒酶相關蛋白1結合后對其功能進行抑制,誘發端粒酶表達,故TP53基因突變和端粒酶表達在腫瘤發生中發揮重要作用.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.TP53基因突變多為點突變,常發生于長度為600 bp的區域內,包含5～8個外顯子,該區域內有4個突變位點,其中3個與中樞神經系統腫瘤的發生密切相關.TP53基因突變后失去對正常細胞生長和血管生成的抑制作用,從而刺激細胞增殖[18].Yagnik等[19]在無功能性垂體腺瘤TP53基因第4外顯子第72號密碼子發現rs1042522位點(G>C)單核苷酸多態性(SNP)對腫瘤的影響,即攜帶G等位基因(變異體)的垂體腺瘤進展較迅速、細胞增殖較明顯,表明TP53基因多態性與垂體腺瘤生長相關.TP53基因突變與端粒酶表達密切相關,端粒酶提示具有無限增殖能力腫瘤細胞的存在,近年對垂體腺瘤中端粒酶表達變化的研究結果不盡一致,Miermeister等[20]的研究顯示,端粒酶是評價垂體腺瘤生長和預后的重要指標,證實P53蛋白在典型和非典型垂體腺瘤及垂體癌中的表達不同[21],以核分裂象≥2個/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.此外,野生型P53蛋白還可以刺激內源性TSP21基因以抑制血管生成,通過堿性纖維母細胞生長因子參與腫瘤血管生成.Mukhopadhyay等[22]報告野生型P53蛋白以劑量和時間依賴性方式抑制血管內皮生長因子啟動子活性上調,并抑制突變型v?Sre酪氨酸激酶對血管內皮生長因子的正性誘導作用;野生型P53蛋白缺失后,血管內皮生長因子水平升高.

4.基因表達差異性與垂體腺瘤侵襲及復發相關研究 近年來,陣列技術的應用有利于正常垂體和垂體腺瘤的基因研究,這種以雜交為基礎的技術最早應用于大鼠和小鼠模型,可以同時檢測不同亞型垂體腺瘤的基因表達,還可以識別微小RNA(miRNA)相關垂體腺瘤.Bottoni等[23]對32例垂體腺瘤患者和6例正常對照者研究發現,二者之間有30個miRNAs表達不同,24個miRNAs識別為垂體腺瘤的預測性標志物,29個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表達水平亦不同,部分與細胞增殖和凋亡相關,提示miRNA失調可能與垂體腺瘤的發生有關,而預測性miRNA有望成為診斷指標,有助于垂體腺瘤分型.Lania等[24]陣列技術研究業已發現 PTTG1、GADD45?γ、MEG3、DAPK1等垂體腺瘤相關基因.垂體腺瘤蛋白質組學和轉錄組學研究顯示,侵襲性與非侵襲性垂體腺瘤之間有1160種基因和283種蛋白表達不同,差異表達的分子主要參與分子運輸、細胞遷移和細胞運動.IL?6是顯著激活的上游調控因子,而IL?6受體/JAK激酶2(JAK2)/信號傳導與轉錄激活因子3(STAT3)信號轉導通路過度激活在垂體腺瘤的侵襲性中發揮至關重要的作用[25].泌乳素腺瘤和促腎上腺皮質激素腺瘤可溶性半乳糖苷結合凝集素3(LGALS3)和hASH?1表達水平高于生長激素腺瘤、促性腺激素腺瘤和零細胞腺瘤,且前兩者易進展為垂體癌.hASH?1與小細胞癌生存期縮短有關,且在良性腫瘤中無表達.斷裂轉導蛋白樣增強子(TLE)與不同翻譯因子相連接,與特殊DNA區域結合后形成多聚復合體,影響組蛋白乙?；饔煤腿旧|結構,進而抑制染色質翻譯活性.泌乳激素腺瘤斷裂轉導蛋白樣增強子?4表達水平高于促腎上腺皮質激素腺瘤.細胞分化抑制因子2(ID2)在所有垂體腫瘤中均有表達,尤其在垂體癌中呈高表達,由于其與轉化因子相關,未來有可能成為垂體腫瘤進展和轉移的治療靶點[23,26].整合素樣金屬蛋白酶與凝血酶樣6(ADAMTS6)、腦衰蛋白反應調節蛋白?1(CRMP?1)、垂體腫瘤轉化基因(PTTG)、周期蛋白B1(CCNB1)、極光激酶B(AURKB)和著絲粒蛋白E(CENPE)均與垂體腺瘤進展和復發有關[27],ADAMTS6、CRMP?1、CCNB1和CENPE與垂體腺瘤分型有關.β?連接素(β?catenin)和原癌基因蛋白(C?myc)在浸潤性腫瘤中呈現過表達[28],Gruppetta等[29]在無功能性垂體腺瘤中檢測出β?連接素和C?myc,且與腫瘤進展呈正相關.其中,β?連接素與腫瘤復發相關;C?myc與腫瘤細胞胞核表達PTTG相關,且PTTG是垂體腺瘤增殖活性標志物,提示PTTG可以誘導C?myc在垂體腺瘤表達,推測C?myc可能作用于早期垂體腺瘤.

二、臨床因素

1.治療規范 臨床因素對垂體腺瘤預后的影響越來越受到重視.早期規范的診斷與治療流程對預后至關重要.2015年,Castinetti等[30]提出無功能性垂體腺瘤的臨床診斷與治療規范:對于癥狀性垂體腺瘤,若出現視力下降、持續性頭痛,應考慮外科手術,但內分泌功能障礙不能作為外科手術的主要指征;對于無癥狀性垂體腺瘤,應綜合考慮年齡、病史、視野缺損風險、垂體功能障礙風險、垂體卒中風險等多種因素.2016年,Lucas等[31]建議將內分泌功能障礙作為無功能性垂體腺瘤的手術指征,而現有資料不足以提出無癥狀性垂體腺瘤的治療推薦.同年Paschou等[32]提出,無手術指征的垂體腺瘤一經明確診斷,即應進行系統隨訪,包括巨大腺瘤每6個月、微腺瘤每12個月復查頭部MRI,巨大腺瘤每6個月、微腺瘤每12個月檢測激素水平.2015年,Nieman等[33]制定Cushing綜合征治療規范,其中兒童和成年垂體腺瘤致Cushing綜合征,推薦經鼻蝶入路垂體腺瘤切除術.

2.新手術和治療模式 術前垂體腺瘤最大徑是目前較為公認的判斷垂體腺瘤復發的指標.Johnston等[34]采用經鼻蝶入路切除Cushing綜合征致垂體腺瘤,結果顯示,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后易復發.Dallapiazza等[35]采用內鏡下經鼻蝶入路切除垂體大腺瘤,80%全切除患者術后10年無進展,21%部分切除患者術后10年無進展.Oertel等[36]常規采用0°內鏡切除垂體腺瘤,并采用傾斜內鏡觀察是否有腫瘤殘留,28%可見腫瘤殘留,腫瘤全切除率達96%;而單獨采用0°內鏡的患者腫瘤全切除率為80%.Linsler等[37]以手術方式、手術范圍、手術期間并發癥、術后內分泌和眼科檢查、腫瘤復發為指標進行回顧分析,新手術策略如經鼻蝶入路顯微外科手術或內鏡下經鼻蝶入路等微侵襲技術的應用可以顯著降低圍手術期并發癥發生率和病死率、提高遠期預后、延長無瘤生存期,以及取得更好的術后內分泌和眼科相關疾病結局,宋業純等[38]也得到類似結論.某些垂體腺瘤還可采用伽瑪刀治療,也取得進一步的進展[39].對于侵襲性垂體腺瘤和垂體癌,特別是外科手術和放射治療均無法控制的患者,替莫唑胺已被證實是一種有效的治療方法[40].Halevy和Whitelaw[41]研究顯示,約42%患者影像學可見治療反應,約27%患者替莫唑胺治療后病情穩定;泌乳素腺瘤和促腎上腺皮質激素腺瘤均對替莫唑胺治療反應良好,反應率約為50%,而無功能性垂體腺瘤的反應率僅為前兩者的1/2.目前能夠預測替莫唑胺治療反應的生物學標志物包括O6?甲基鳥嘌呤?DNA甲基轉移酶(MGMT)和黑色素細胞刺激素(MSH),但不足以確定治療決策.研究顯示,MGMT表達變化可能與垂體腺瘤復發有關[42],而與腫瘤侵襲性或其他臨床病理學指標無關聯性,提示檢測MGMT可能有助于指導臨床治療和預測預后.

縱觀現有的國內外文獻,垂體腺瘤侵襲及復發研究仍是神經外科的難點和熱點.血管生成和(或)重建、基因表達調控及相關臨床因素的綜合研究提出許多新的有意義的觀點,探討規范治療的最佳方案和預后影響因素,為垂體腺瘤個體化治療打下堅實的基礎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天津市環湖醫院病理科

閻曉玲(Email:ll934065@126.com)

2017?06?19)