付義林,佟 倜
(吉林大學(xué)第二醫(yī)院 胸外科,吉林 長(zhǎng)春130041)
*通訊作者
肺大細(xì)胞神經(jīng)內(nèi)分泌癌的診療進(jìn)展
付義林,佟 倜*
(吉林大學(xué)第二醫(yī)院 胸外科,吉林 長(zhǎng)春130041)
最新版的世界衛(wèi)生組織 (World Health Organization,WHO) 2015年肺癌病理分類(lèi)將小細(xì)胞肺癌(SCLC)、類(lèi)癌(typical carcinoid,TC)及肺大細(xì)胞神經(jīng)內(nèi)分泌癌(LCNEC)共同歸類(lèi)于神經(jīng)內(nèi)分泌腫瘤[1],這也為今后肺LCNEC的診療指明了新的道路。肺大細(xì)胞神經(jīng)內(nèi)分泌癌(LCNEC)約占肺癌病例的2.1%-3.5%[2],然而隨著組織學(xué)診斷技術(shù)的進(jìn)步,尤其是免疫組化神經(jīng)內(nèi)分泌標(biāo)志物的發(fā)展,越來(lái)越多的肺部神經(jīng)內(nèi)分泌腫瘤得以診斷并分型,這也是近年來(lái)肺部神經(jīng)內(nèi)分泌腫瘤發(fā)病率不斷增高的原因之一[4],其真實(shí)發(fā)病率通常高于預(yù)計(jì)值。肺LCNEC的高危因素通常包括:男性,高齡(中位年齡為65周歲),吸煙史[5]。
肺LCNEC與惡性腫瘤一樣通常都表現(xiàn)出侵襲性的生物學(xué)行為[6]。肺LCNEC初期的患者一般無(wú)明顯癥狀,咳嗽、咳痰、咯血、阻塞性肺炎較少見(jiàn)[7],部分患者可有無(wú)痛性淋巴結(jié)腫大及胸痛,無(wú)特異性的流感樣癥狀、呼吸困難、盜汗,副癌綜合征較少見(jiàn)[8]。因此在確診時(shí),肺LCENC的患者淋巴結(jié)轉(zhuǎn)移率高((60%-80%)、遠(yuǎn)處轉(zhuǎn)移率高(40%)[9,10],與小細(xì)胞肺癌相似(表1)。
胸部CT(computed tomography,CT)通常作為首選檢查,肺LCNEC在CT上通常呈周?chē)蛿U(kuò)張性生長(zhǎng)、邊緣不規(guī)則的肺部腫塊,有分葉征、毛刺征及胸膜牽拉征[11],與擴(kuò)張性生長(zhǎng)的周?chē)蚐CLC、低分化腺癌、鱗癌等類(lèi)似,極少數(shù)為縱膈型[12]。約有10%的病例伴有部分鈣化[13],大量淋巴結(jié)腫大的情況較少見(jiàn)。因此術(shù)前單純從胸部CT區(qū)分LCNEC與其他肺部惡性腫瘤的難度較大。
痰液脫落細(xì)胞學(xué)檢查陽(yáng)性率通常較低[14]。若病灶位置適宜,支氣管鏡檢查及病變組織活檢可作為確診的進(jìn)一步檢查[15],但應(yīng)同時(shí)考慮到纖維支氣管鏡活檢受標(biāo)本大小、組織形態(tài)等因素的影響較大,使得LCNEC 術(shù)前的診斷率低。
神經(jīng)內(nèi)分泌腫瘤中生長(zhǎng)激素抑制素受體(SSTR)表達(dá)率高[16],近年來(lái)SSTR顯像診斷技術(shù)已被用于術(shù)前診斷。肺LCNEC的診斷通常需要免疫組織化學(xué)染色及超微顯微鏡下確定神經(jīng)內(nèi)分泌分化的明顯標(biāo)志,在沒(méi)有大量活體組織標(biāo)本時(shí)或術(shù)前診斷LCNEC相當(dāng)困難。
因此精準(zhǔn)的病理學(xué)診斷在肺LCNEC的診療過(guò)程中是必不可少的一個(gè)環(huán)節(jié),是下一步的診療計(jì)劃的基礎(chǔ)。國(guó)際肺癌研究聯(lián)合會(huì)(International Association for the Study of Lung Cancer)建議應(yīng)用TNM(tumor,node,metastasis)分期預(yù)測(cè)神經(jīng)內(nèi)分泌腫瘤的預(yù)后[17]。
表1 肺LCNEC的主要臨床病理學(xué)特征
肺LCNEC呈浸潤(rùn)性生長(zhǎng),細(xì)胞病理學(xué)特征包括:細(xì)胞體積大;有豐富的壞死組織;低核/質(zhì)比(細(xì)胞核大,核仁明顯);細(xì)胞呈巢狀排列;神經(jīng)內(nèi)分泌腫瘤常見(jiàn)的形態(tài)學(xué)特征如器官樣,柵樣,花瓣樣或小梁狀的細(xì)胞生長(zhǎng)排列方式[18];超微結(jié)構(gòu)上常見(jiàn)少量腺樣或鱗狀的分化。(表1)。
腺癌細(xì)胞或鱗癌細(xì)胞有時(shí)共同存在于這些腫瘤中,我們將這些肺LCNEC命名為“混合神經(jīng)內(nèi)分泌癌[19](mixed LCNEC)”。盡管前瞻性的數(shù)據(jù)具有不確定性,但現(xiàn)有數(shù)據(jù)表明混合肺LCNEC患者5年生存率(overall survival ,OS)約為30%[20],與單純肺LCNEC患者5年生存率類(lèi)似。
LCNEC與AC(非典型類(lèi)癌,atypical carcinoids ,AC)具備某些共同的病理學(xué)特征,如生長(zhǎng)模式及細(xì)胞壞死,因此鑒別診斷對(duì)病理科醫(yī)生是一項(xiàng)挑戰(zhàn)。例如,AC有絲分裂少見(jiàn),LCNEC壞死細(xì)胞更為常見(jiàn),>11/10高倍鏡(HP)的有絲分裂率(表2)是LCNEC和SCLC不同于AC的關(guān)鍵。
在診斷非小細(xì)胞肺癌時(shí),通常使用免疫組織化學(xué)標(biāo)記。鱗狀標(biāo)記包括細(xì)胞角蛋白(CK)5/6,蛋白(p)63,和p40[21]。腺癌標(biāo)記包括甲狀腺轉(zhuǎn)錄因子-1,napsin A,和CK7[22]。而神經(jīng)內(nèi)分泌癌標(biāo)記物包括嗜鉻素A(chromogranin A)、突觸素(synaptophysin)、CD56[23],其中至少有 1 種以上表達(dá)陽(yáng)性。最新數(shù)據(jù)顯示,相對(duì)于非神經(jīng)內(nèi)分泌腫瘤(non—LCNECs)和小細(xì)胞肺癌(SCLC),LCNEC在免疫組化中表達(dá)更高水平的原肌球相關(guān)激酶B(tropomyosin-related kinase B)和腦源性神經(jīng)因子[24](brain-derived neurotrophic factor),這為進(jìn)一步區(qū)分LCNEC與其他肺臟內(nèi)分泌源性腫瘤提供了良好的依據(jù)。
SCLC與肺LCNEC的共同點(diǎn)表現(xiàn)在:男性吸煙者高發(fā),細(xì)胞高有絲分裂率,表達(dá)多種神經(jīng)內(nèi)分泌細(xì)胞標(biāo)記物,惡性度高,預(yù)后差,存在基因突變[25](如MEN1基因突變)。這也使得這兩種組織分型均歸屬到 “高度惡性神經(jīng)內(nèi)分泌腫瘤(high-grade neuroendocrine carcinoma ,HGNEC)”中。
精確的病理學(xué)細(xì)胞形態(tài)區(qū)分可以很好的為兩者劃清界限[26]:(表 2)
表2 SCLC與肺LCNEC鑒別診斷要點(diǎn)
肺LCNEC與SCLC表現(xiàn)出類(lèi)似的生物學(xué)侵襲性。兩者的生存曲線隨時(shí)間進(jìn)展逐步重疊,其生存率遠(yuǎn)低于其他非小細(xì)胞肺癌[27],即使在術(shù)后Ⅰ期肺LCNEC的患者中,5年生存率仍約為33%。
因其發(fā)病率較低,臨床工作中少見(jiàn),隨機(jī)臨床試驗(yàn)很難進(jìn)行,現(xiàn)階段尚未形成肺LCNEC的治療標(biāo)準(zhǔn)[28]。盡管我們對(duì)確診Ⅰ期的肺LCNEC患者盡早行手術(shù)治療,對(duì)進(jìn)展期的患者采取多種方案聯(lián)合治療,其5年生存率仍然很低。
對(duì)于腫瘤分期處于TNMⅠ—Ⅱ期的患者,手術(shù)治療應(yīng)作為第一首選,同時(shí)這也是肺LCNEC患者確診的主要方法[29]。在縱隔淋巴結(jié)系統(tǒng)采樣中,肺葉切除或者全肺切除的患者可有效減少淋巴結(jié)轉(zhuǎn)移途徑,提高術(shù)后生存率[30],因此推薦肺葉切除或者全肺切除作為手術(shù)患者的第一選擇。(表1)
Grand等人[31]在一項(xiàng)回顧性數(shù)據(jù)分析中比較了肺LCNEC與大細(xì)胞癌(large cell carcinoma,LCC)的診療結(jié)果,就手術(shù)方式(病灶局部切除、肺葉切除、全肺切除)而言,沒(méi)有明顯證據(jù)表明其與術(shù)后整體存活率明顯相關(guān)。
Mazières等人[32]報(bào)道了一宗18個(gè)肺LCENC患者的病例,這些病人先接受了根治性的外科手術(shù)治療,隨后實(shí)驗(yàn)者對(duì)T3和/或 N2的病人進(jìn)行輔助放療。這些病人的一年生存率約為27%,并且與淋巴結(jié)轉(zhuǎn)移與否無(wú)明顯關(guān)聯(lián)。
手術(shù)治療的確使約30%的患者收益[33],因此,完善圍手術(shù)期在提升整體治療效果方面顯得尤為重要[34]。
所有可手術(shù)切除的肺LCNEC患者(TNM Ⅰ—Ⅲ期)均應(yīng)盡早行手術(shù)治療[35]。新輔助化療、輔助化療可作為防止腫瘤復(fù)發(fā)的有效手段[36]。在一項(xiàng)對(duì)144例肺LCNEC患者的回顧性分析中,Ⅰ期患者行術(shù)前或術(shù)后化療獲得了更好的治療效果,表明在LCNEC的早期階段聯(lián)合治療不可忽視[37]。
2006年,Iyoda等人[38]依據(jù)SCLC患者的化療方案,對(duì)肺LCNEC患者進(jìn)行了以“鉑類(lèi)+依托泊苷”為化療方案治療的前瞻性研究。與對(duì)照組同等狀況的患者相比,實(shí)驗(yàn)組明顯受益,5年生存率實(shí)驗(yàn)組vs.對(duì)照組為88.9% vs.47.4%,2年無(wú)病生存率約為86.7% vs.47.8% 。隨著后期臨床試驗(yàn)證明,以“鉑類(lèi)+依托泊苷”為基礎(chǔ)的聯(lián)合化療對(duì)疾病的治療及預(yù)后起到了至關(guān)重要的效果,推薦為一線化療用藥。而以“鉑類(lèi)+氨柔比星”的二線化療方案同樣也在回顧性臨床試驗(yàn)中表明有效[39]。
放療對(duì)肺LCNEC患者的治療效果尚未明確,一些學(xué)者認(rèn)為對(duì)病灶局限、進(jìn)展期或不適宜手術(shù)的患者可試行放療[40]。大量的SCLC患者在化療后得以部分或者完全緩解,而后行預(yù)防性放射治療,這一方法尚不推薦對(duì)肺LCNEC患者進(jìn)行[41]。
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2016-03-26)