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年肺癌病理分類將小細(xì)胞肺癌(SCLC)、類癌(typical carcinoid,TC)及肺大細(xì)胞神經(jīng)內(nèi)分泌癌(LCNEC)共同歸類于神經(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]，其真實發(fā)病率通常高于預(yù)計值。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]。

1 臨床表現(xiàn)

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初期的患者一般無明顯癥狀，咳嗽、咳痰、咯血、阻塞性肺炎較少見[7]，部分患者可有無痛性淋巴結(jié)腫大及胸痛，無特異性的流感樣癥狀、呼吸困難、盜汗，副癌綜合征較少見[8]。因此在確診時，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)。

2 術(shù)前檢查診斷方法

胸部CT(computed tomography,CT)通常作為首選檢查，肺LCNEC在CT上通常呈周圍型擴(kuò)張性生長、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)張性生長的周圍型SCLC、低分化腺癌、鱗癌等類似，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。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)分泌腫瘤中生長激素抑制素受體(SSTR)表達(dá)率高[16],近年來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，在沒有大量活體組織標(biāo)本時或術(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的診療過程中是必不可少的一個環(huán)節(jié)，是下一步的診療計劃的基礎(chǔ)。國際肺癌研究聯(lián)合會(International Association for the Study of Lung Cancer)建議應(yīng)用TNM(tumor,node,metastasis)分期預(yù)測神經(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

3 病理學(xué)特征

肺LCNEC呈浸潤性生長，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)胞生長排列方式[18]；超微結(jié)構(gòu)上常見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年生存率類似。

LCNEC與AC(非典型類癌，atypical carcinoids ，AC)具備某些共同的病理學(xué)特征，如生長模式及細(xì)胞壞死，因此鑒別診斷對病理科醫(yī)生是一項挑戰(zhàn)。例如，AC有絲分裂少見，LCNEC壞死細(xì)胞更為常見，>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。

4 免疫組化及分子標(biāo)記物

在診斷非小細(xì)胞肺癌時，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)陽性。最新數(shù)據(jù)顯示，相對于非神經(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)。

5 SCLC與肺LCNEC的鑒別診斷

SCLC與肺LCNEC的共同點表現(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

6 預(yù)后及生存率

肺LCNEC與SCLC表現(xiàn)出類似的生物學(xué)侵襲性。兩者的生存曲線隨時間進(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%。

7 治療及聯(lián)合治療方案

因其發(fā)病率較低，臨床工作中少見,隨機(jī)臨床試驗很難進(jìn)行，現(xiàn)階段尚未形成肺LCNEC的治療標(biāo)準(zhǔn)[28]。盡管我們對確診Ⅰ期的肺LCNEC患者盡早行手術(shù)治療，對進(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]報道了一宗18個肺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，隨后實驗者對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]。在一項對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，對肺LCNEC患者進(jìn)行了以“鉑類+依托泊苷”為化療方案治療的前瞻性研究。與對照組同等狀況的患者相比，實驗組明顯受益，5年生存率實驗組vs.對照組為88.9% vs.47.4%，2年無病生存率約為86.7% vs.47.8% 。隨著后期臨床試驗證明，以“鉑類+依托泊苷”為基礎(chǔ)的聯(lián)合化療對疾病的治療及預(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+氨柔比星”的二線化療方案同樣也在回顧性臨床試驗中表明有效[39]。

放療對肺LCNEC患者的治療效果尚未明確，一些學(xué)者認(rèn)為對病灶局限、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肺LCNEC患者進(jìn)行[41]。

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