世界衛(wèi)生組織中樞神經(jīng)系統(tǒng)腫瘤分類：神經(jīng)腫瘤專業(yè)醫(yī)師堪與之廝守終生的學(xué)問

楊學(xué)軍 吳浩強 Daniel J.Brat

中樞神經(jīng)系統(tǒng)腫瘤領(lǐng)域的知識體系龐大，理論與技術(shù)不斷進(jìn)步。中樞神經(jīng)系統(tǒng)腫瘤的臨床診治更是個大學(xué)問。2019年第11和12期以及2020年第2期，我在《中國現(xiàn)代神經(jīng)疾病雜志》主持了3期“腦膠質(zhì)瘤”專題，內(nèi)容主要涵蓋我國腦膠質(zhì)瘤臨床診斷與治療指南/規(guī)范建設(shè)、中樞神經(jīng)系統(tǒng)腫瘤病理分類進(jìn)展、腦膠質(zhì)瘤臨床試驗創(chuàng)新體系及臨床療效反應(yīng)評價體系、腦膠質(zhì)瘤侵襲遷移及免疫治療研究、腦科學(xué)及腦功能研究等臨床與轉(zhuǎn)化問題。2020年第2期，我與著名神經(jīng)病理學(xué)家Daniel J.Brat教授作為共同通訊作者在Glioma發(fā)表“A contemporary molecular view of diffuse gliomas with implications for diagnosis”。2020年第12期，我在《中華神經(jīng)醫(yī)學(xué)雜志》以“腦膠質(zhì)瘤的臨床診治擷要”為題，評述當(dāng)前惡性腦膠質(zhì)瘤臨床診療的現(xiàn)實問題。以專題組稿形式推動中樞神經(jīng)系統(tǒng)腫瘤熱點問題的討論以及新理論和新技術(shù)的學(xué)習(xí)，尤其是在疫情之下，形式適宜、開卷有益。

2021年WHO中樞神經(jīng)系統(tǒng)腫瘤分類（第五版，以下簡稱新版腫瘤分類）如約而至，以專題組稿的形式進(jìn)行新版腫瘤分類解讀是《中國現(xiàn)代神經(jīng)疾病雜志》2021年的既定報道計劃，也是我們對新版腫瘤分類里程碑意義的預(yù)判。新版腫瘤分類的亮點包括：更多的腫瘤類型/亞型以生物學(xué)和分子特征共同定義，兒童型與成人型彌漫性膠質(zhì)瘤區(qū)分，成人型彌漫性膠質(zhì)瘤類型簡化，兒童型彌漫性膠質(zhì)瘤依據(jù)分子靶標(biāo)實施治療成為可能，室管膜瘤按照部位和分子特征分類，CNS WHO分級靠攏非中樞神經(jīng)系統(tǒng)腫瘤，分子診斷指標(biāo)首次作為腫瘤分級標(biāo)準(zhǔn)。《中國現(xiàn)代神經(jīng)疾病雜志》2021年第9期組織刊出“2021年WHO中樞神經(jīng)系統(tǒng)腫瘤分類（第五版）解讀”專題，回顧1979-2021年WHO中樞神經(jīng)系統(tǒng)腫瘤分類的演變進(jìn)程，重新整理第一版至第四版修訂版分類簡表并附加簡介，對新版腫瘤分類簡表的類型/亞型進(jìn)行精心中譯；邀約國內(nèi)中樞神經(jīng)系統(tǒng)腫瘤領(lǐng)域的臨床專家就新版腫瘤分類的重要內(nèi)容進(jìn)行專題解讀，涉及分子診斷指標(biāo)、整合診斷及分層診斷、新增腫瘤實體、成人型及兒童型彌漫性膠質(zhì)瘤、局限性星形細(xì)胞膠質(zhì)瘤、室管膜腫瘤、胚胎性腫瘤。對本期專題內(nèi)容和質(zhì)量的期待目標(biāo)是，希望能夠讓神經(jīng)腫瘤專業(yè)醫(yī)師將這本?？詹卦跁鴻恢?，未來5～10年都有翻閱參考的價值。本文作為本期專題的導(dǎo)讀，其撰寫角度和內(nèi)容已在我腦海中積淀許久，文題的靈感來自2021年中國醫(yī)學(xué)科學(xué)院北京協(xié)和醫(yī)學(xué)院開學(xué)典禮上王辰院士的演講。我對WHO中樞神經(jīng)系統(tǒng)腫瘤分類的廝守雖尚未至終生，卻也是情愫繾綣。

WHO中樞神經(jīng)系統(tǒng)腫瘤分類——我的專業(yè)啟迪。1990年，薛慶澄教授主編，王忠誠、史玉泉教授副主編的《神經(jīng)外科學(xué)》出版，這是我神經(jīng)外科學(xué)啟蒙的首部專著，教我知曉了第一版（1979年）WHO中樞神經(jīng)系統(tǒng)腫瘤分類。20世紀(jì)90年代，惡性腦膠質(zhì)瘤的分子生物學(xué)研究和基因治療方興未艾，第二版（1993年）和第三版（2000年）WHO中樞神經(jīng)系統(tǒng)腫瘤分類相繼出版。當(dāng)時，我的導(dǎo)師天津醫(yī)科大學(xué)總醫(yī)院楊樹源教授和浦佩玉教授給我們的考試題目中就有默寫WHO神經(jīng)上皮組織腫瘤分類。1994-1997年，在浦佩玉教授的悉心指導(dǎo)下，我完成博士學(xué)位課題“惡性腦膠質(zhì)瘤自殺基因治療研究”，并在中南大學(xué)腫瘤研究所姚開泰院士、曹亞教授實驗室完成攜帶HSV-TK基因的逆轉(zhuǎn)錄病毒載體重組、病毒載體的轉(zhuǎn)導(dǎo)包裝等重要分子生物學(xué)實驗。如果說我在中樞神經(jīng)系統(tǒng)腫瘤手術(shù)治療、基礎(chǔ)與轉(zhuǎn)化研究、教學(xué)方面略具綜合實力的話，則是那個時期奠定的基礎(chǔ)，WHO中樞神經(jīng)系統(tǒng)腫瘤分類的引領(lǐng)功不可沒。

WHO中樞神經(jīng)系統(tǒng)腫瘤分類——我的專業(yè)閱讀。各版WHO中樞神經(jīng)系統(tǒng)腫瘤分類均首先在專業(yè)雜志上以評述的形式介紹框架及內(nèi)容的主要變化，隨后再正式發(fā)行出版“藍(lán)皮書”。2001年，我到日本久留米大學(xué)醫(yī)院神經(jīng)外科學(xué)習(xí)，在科室的閱覽室中第一次見到2000年版“藍(lán)皮書”，那時直接購買原版書在經(jīng)濟上還是有困難的，于是我將整本書復(fù)印下來，保存至今。1993年版“藍(lán)皮書”由柏林Springer-Verlag出版社發(fā)行，我在德國學(xué)習(xí)時惜得此書。2007年版“藍(lán)皮書”我保存的是電子版的彩色打印本。2016年版“藍(lán)皮書”是我參加國際會議時在國外購得原版書。目前僅1979年版“藍(lán)皮書”我還未能搜集到。自2000年版開始，“藍(lán)皮書”由前兩版的“小冊子”擴充為數(shù)百頁的“書”，對中樞神經(jīng)系統(tǒng)腫瘤的組織病理學(xué)特征進(jìn)行精確注釋，豐富分子生物學(xué)和分子遺傳學(xué)信息，并描述腫瘤的流行病學(xué)、臨床癥狀與體征、影像學(xué)、結(jié)局和預(yù)測因素。閱讀“藍(lán)皮書”，讓我知歷史，懂演變，長學(xué)問。書櫥里的系列“藍(lán)皮書”也記錄了我學(xué)術(shù)成長的過程。

WHO中樞神經(jīng)系統(tǒng)腫瘤分類——我的駐足之旅。2003年末至2006年初，我到德國海德堡大學(xué)學(xué)習(xí)，期間為學(xué)習(xí)高流量顱內(nèi)外血管搭橋術(shù)，曾在荷蘭烏特勒支大學(xué)醫(yī)學(xué)中心接受Tulleken教授的訓(xùn)練。巧合的是，2007年版（海德堡）、2016年修訂版（海德堡）和2021年版（烏特勒支）WHO中樞神經(jīng)系統(tǒng)腫瘤分類最后的共識會議即在海德堡大學(xué)和烏特勒支大學(xué)召開。2004年，德國波恩大學(xué)神經(jīng)病理研究所原所長Wiestler教授任職德國癌癥研究中心（DKFZ）主席和科研主任，德國癌癥研究中心就設(shè)在海德堡大學(xué)校園內(nèi)，我有幸聽到Wiestler教授關(guān)于髓母細(xì)胞瘤分子生物學(xué)研究的講座，而Wiestler教授是2007年版和2016年修訂版“藍(lán)皮書”的署名作者。我在德國癌癥研究中心和荷蘭烏特勒支大學(xué)醫(yī)學(xué)中心留照，記錄了我在近3版WHO中樞神經(jīng)系統(tǒng)腫瘤分類“誕生地”的駐足之旅。

WHO中樞神經(jīng)系統(tǒng)腫瘤分類——助我授人以漁。WHO中樞神經(jīng)系統(tǒng)腫瘤分類的知識是需要“厚積”的，因為每一版本均是前一版的延伸，真正是溫故方知新；中樞神經(jīng)系統(tǒng)腫瘤分類的變化即是對神經(jīng)腫瘤認(rèn)識的深化，也為神經(jīng)腫瘤的診療設(shè)定了新標(biāo)準(zhǔn)。2007年版和2016年修訂版發(fā)表以后，我均在1個月內(nèi)快速完成解讀的撰寫，并在《中國神經(jīng)精神疾病雜志》述評發(fā)表?！帮B內(nèi)腫瘤總論”是神經(jīng)外科學(xué)的重要章節(jié)，在流行病學(xué)、病因?qū)W、病理學(xué)及分子病理學(xué)、診斷方法、治療方面有諸多知識需要更新。我非常有幸參編多部《神經(jīng)外科學(xué)》并主筆“顱內(nèi)腫瘤總論”章節(jié)，其內(nèi)容涉及1993年以后的各版WHO中樞神經(jīng)系統(tǒng)腫瘤分類，包括楊國瑞教授主編的《臨床神經(jīng)外科學(xué)》（人民軍醫(yī)出版社）、趙繼宗教授主編的《神經(jīng)外科學(xué)》第一版至第三版（人民衛(wèi)生出版社）、楊樹源教授主編的《神經(jīng)外科學(xué)》第一版和第二版（人民衛(wèi)生出版社）、王忠誠教授主編的《王忠誠神經(jīng)外科學(xué)》第二版（湖北科學(xué)技術(shù)出版社）。如果新一代神經(jīng)外科醫(yī)師受益于我在“顱內(nèi)腫瘤總論”中撰寫的知識，應(yīng)共同感恩WHO中樞神經(jīng)系統(tǒng)腫瘤分類帶給我們的學(xué)問。

WHO中樞神經(jīng)系統(tǒng)腫瘤分類——讓我感悟研究的真諦。WHO中樞神經(jīng)系統(tǒng)腫瘤分類走進(jìn)組織學(xué)形態(tài)結(jié)合分子特征以確定分類的時代，我們應(yīng)歸功于醫(yī)學(xué)轉(zhuǎn)化的推動。如果我來回答中樞神經(jīng)系統(tǒng)腫瘤分子分型最重要的推手為何？閻海教授關(guān)于彌漫性膠質(zhì)瘤IDH突變的發(fā)現(xiàn)當(dāng)之無愧。Gertrud Reemtsma基金會把“2021年轉(zhuǎn)化神經(jīng)科學(xué)國際獎”頒發(fā)給美國杜克大學(xué)醫(yī)學(xué)院閻海教授和德國海德堡大學(xué)醫(yī)學(xué)院Andreas von Deimling教授，以表彰其對IDH1和IDH2突變作為星形細(xì)胞瘤和少突膠質(zhì)細(xì)胞瘤的分子生物學(xué)標(biāo)志物并影響腫瘤代謝和永生化的研究，以及建立IDH1突變蛋白免疫組化檢測方法的杰出貢獻(xiàn)。閻海教授是我的好朋友，感謝他最近對我的一段評價，“Dr.Yang is an academic leader focusing on both clinical practice and basic sciences.His research covering brain function & neuroplasticity as well as biological behaviors and molecular genetics of glioma.It is rare to have a physician with both kinds of skill sets in this field,not only in China,but internationally”。他才是腦膠質(zhì)瘤研究與轉(zhuǎn)化的典范。國際上還有很多與我們交流密切、到訪過中國的神經(jīng)腫瘤研究與轉(zhuǎn)化的著名專家，他們都在各自的領(lǐng)域推動惡性腦膠質(zhì)瘤的臨床研究與轉(zhuǎn)化，例如美國德州大學(xué)MD安德森癌癥中心W.K.Alfre Yung教授、美國哈佛大學(xué)醫(yī)學(xué)院Patrick Y.Wen教授、美國西北大學(xué)Daniel J.Brat和Roger Stupp教授、德國海德堡大學(xué)醫(yī)學(xué)院Wolfgang Wick和Andreas von Deimling教授、美國斯坦福大學(xué)醫(yī)學(xué)院Micheal Lim教授、瑞士蘇黎世大學(xué)醫(yī)學(xué)院Michael Weller教授、美國加州大學(xué)圣地亞哥分校Webster K.Cavenee教授等。我想與國內(nèi)學(xué)者共勉的是，科學(xué)研究的價值在于產(chǎn)出有用的知識。

WHO中樞神經(jīng)系統(tǒng)腫瘤分類——讓我對神經(jīng)病理學(xué)家充滿敬意。我國老一輩神經(jīng)病理學(xué)家黃克維、張福林、黃文清、吳在東教授等，數(shù)十年前即在神經(jīng)腫瘤分類方面有過探索。如今，在卞修武院士、盧德宏和于士柱教授的帶領(lǐng)下，神經(jīng)病理學(xué)獲得新的發(fā)展及國際認(rèn)可。汪寅、李青、李桂林、李智、樸月善、王行富教授等經(jīng)?；钴S在各種神經(jīng)腫瘤學(xué)術(shù)場合。神經(jīng)病理科醫(yī)師是我們在神經(jīng)腫瘤臨床實踐中的好老師、好同事。本期專題立足于臨床醫(yī)師對WHO中樞神經(jīng)系統(tǒng)腫瘤分類原則及變化的學(xué)習(xí)，不涉及病理學(xué)診斷程序和標(biāo)準(zhǔn)等復(fù)雜的病理學(xué)專業(yè)內(nèi)容，故未煩邀各位病理學(xué)大家，但仍在數(shù)篇文章中請求了支援。本期專題當(dāng)是我們向病理學(xué)家寫出的一份學(xué)習(xí)心得，這里寫不清、搞不懂甚至錯誤的地方，剛好是隨后神經(jīng)病理學(xué)領(lǐng)域?qū)π掳婺[瘤分類進(jìn)行解讀時，幫助指正和回答的問題。本期專題中，除我親自撰寫及署名的稿件外，其他稿件我也審讀2～4遍不等，可以肯定的是，仍會有疏漏或失嚴(yán)謹(jǐn)，文責(zé)有我，當(dāng)致歉意。在此，我還要感謝兩位世界著名神經(jīng)病理學(xué)家、WHO中樞神經(jīng)系統(tǒng)腫瘤分類的重要編者——香港中文大學(xué)吳浩強教授和美國西北大學(xué)Daniel J.Brat教授。他們應(yīng)邀為本期專題撰寫新版腫瘤分類的編寫信息，以此鞭策我們臨床醫(yī)師對新版腫瘤分類的學(xué)習(xí)。

WHO中樞神經(jīng)系統(tǒng)腫瘤分類——堪與之廝守終生的學(xué)問。提到做學(xué)問，我所熟知的神經(jīng)外科學(xué)界有眾多楷模值得我們學(xué)習(xí)。我的導(dǎo)師楊樹源和浦佩玉教授，一生樸素做人，扎實學(xué)問，不求虛名，80多歲高齡仍追蹤最新學(xué)術(shù)進(jìn)展，現(xiàn)今仍思路清晰、記憶過人，我想這是學(xué)問對他們的回報。趙繼宗和周良輔院士為我和馬文斌教授主編的《腦膠質(zhì)瘤診療規(guī)范臨床解讀》（人民衛(wèi)生出版社，即將出版）作序，他們通覽全書、細(xì)閱章節(jié)，治學(xué)之嚴(yán)謹(jǐn)，讓吾輩仰視。周定標(biāo)教授的“最優(yōu)秀的神經(jīng)外科醫(yī)生應(yīng)該做腫瘤”的激勵話語，吹響青年神經(jīng)外科醫(yī)師學(xué)習(xí)“最難的”學(xué)問的集結(jié)號。睹物、思人、辨是，在國內(nèi)神經(jīng)外科領(lǐng)域和神經(jīng)腫瘤領(lǐng)域仍有許多醫(yī)學(xué)大家在真正做學(xué)問，他們都是值得我們尊敬的人。WHO中樞神經(jīng)系統(tǒng)腫瘤分類恰好就是這樣一門考驗我們的學(xué)問，寧靜致遠(yuǎn)，值得我們廝守終生。

（清華大學(xué)附屬北京清華長庚醫(yī)院神經(jīng)外科 楊學(xué)軍）

At the time of writing,due to delays arising from Covid and Delta viruses,the new WHO Classification of Tumors has not yet been published but the basic framework of the classification has been extensively disseminated by many international conferences and by a joint paper by the Expert Panel(PMID 34185076). Moreover,the current WHO Classification is based on a series of consensus papers(total:seven)called c IMPACT-NOW；these were meant to be periodic updates of the last WHO(2016)Classification so a lot of the recommendations of the new classification was already known.In fact,a group of leading neuropathologists and neurooncologists had also met at Utretch,the Netherlands in 2019 and the consensus paper published afterwards(PMID 32307792)can almost be regarded as a forerunner of the 2021 Classification.

We in neuro-oncology tend to think only of the WHO Classification of CNS Tumors. In fact,the WHO organizes consensus views and publications of classifications of tumors of all systems of the body.This is the fifth series for all systems and the 2016 Classification for the CNS Tumors was just an update of the Fourth series. Therefore there was only a relatively short interval between 2016 and 2021.In the old days,the WHO classifications for tumors were not very produced and most pathologists and clinicians used the American classifications called Armed Forces Institute of Pathology(AFIP)Fascicles for all cancers. But Professor Paul Kleihues,a neuropathologist from Switzerland,extensively reorganized the WHO classifications for all the systems in the early 21stcentury and they now became the classifications everyone else in the world use. I myself have been involved as a member of the Expert Panel for the 2007, 2016 and 2021 Classifications of CNS Tumors and also Utretch consensus meeting mentioned above.

In the last few years,major administrative changes for the publication of the WHO Classifications took place at the International Agency for Cancer Research(IARC),the branch of WHO which deals with cancers so that the organization of the publication of the classifications of all the tumor systems was made uniform and streamlined.One result of the administrative re-organization was that the Expert Panel for each classification was vastly reduced.In the CNS tumors,it was reduced from about 30 experts from last time to 12 this time,just ten pathologists and two neuro-oncologists. The experts were selected,according to WHO,based on each person's publication matrices and there was no intention for any expert to represent their country or their regions.So in that sense,I am not really a representative of Hong Kong,China or Asia. The reduction of the number of experts in the panel has resulted in some misgivings but in fairness,the actual writing of the chapters of the book actually involved more than 100 experts, including neuropathologists,neuro-oncologists,neurosurgeons and scientists from all over the world,including Asia.

WHO 2021 Classification for CNS Tumors followed the recommendation of molecular diagnostics in the classification.It now clearly separates out a classification for adult and another one for children.For the former,for the astrocytomas which are 1p19q non-deleted,the mutation status of IDH is pivotal to the classification.It laid down molecular diagnostic criteria for IDH mutant and IDH wildtype glioblastoma or Grade 4 astrocytomas.In pediatric gliomas,fine grading beyond low-grade and highgrade is regarded as not clinically useful and further subtyping of high-grade and low-grade pediatric gliomas depends heavily on molecular means.Whole genome methylation profiling is now regarded as a desirable diagnostic criteria for many CNS tumors.For pediatric tumors,there is also extension revision and new additions to embryonal tumors and mesenchymal tumors. Please refer to the excellent summary provided by the Expert Panel in the paper PMID 34185076 and PMID 32307792.

Ho-Keung Ng,MD

Chair Professor

Department of Pathology

Faculty of Medicine

The Chinese University of Hong Kong

Since the early 1900s,and until the 2016 revised 4thedition of the World Health Organization(WHO)Classification of Tumours of the Central Nervous System,brain tumors were classified based upon the morphologic features of neoplastic cells.Molecular testing,if any were performed,played an ancillary role. Over the past decade,numerous investigations have uncovered molecular genetic alterations that can be used to reliably and reproducibly classify brain tumors into clinically meaningful subsets,leading the 2016 WHO 4thEdition update to incorporate diagnostic entities based on the integration of morphologic features with molecular biomarkers.More recent advances in our understanding of the pathogenesis and clinical behavior of specific brain tumor subtypes has led to the inclusion of additional molecular biomarkers into clinical practice.The 2021 WHO 5thEdition relies even more on molecular test results for establishing a diagnosis and now there are also examples of molecular test results impacting the grading of brain tumors. DNA methylome profiling continues to identify brain tumors that display specific methylation patterns that have characteristic genetic alterations and clinical behavior and is becoming a standard for the most definitive classification of challenging cases.The increasing complexity and rapid pace of change in diagnostic criteria,relevant molecular biomarkers,laboratory testing platforms,and clinical practice will require enhanced dependence on laboratory capabilities in molecular pathology and cytogenetics,as well as an integrated clinical approach among neurosurgeons, oncologists radiation oncologists,neuroradiologists, neuropathologists and others involved in the treatment of brain tumors. The tremendous advances now allow us to diagnose disease with much greater certainty,and to guide therapy based on a better understanding of the patient's prognosis.

Daniel J.Brat,MD,PhD

Magerstadt Professor and Chair

Department of Pathology

Northwestern University Feinberg School of Medicine

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