付義林，佟 倜

(吉林大學第二醫(yī)院 胸外科,吉林 長春130041)

*通訊作者

肺大細胞神經內分泌癌的診療進展

付義林，佟 倜*

(吉林大學第二醫(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胞肺癌(SCLC)、類癌(typical carcinoid,TC)及肺大細胞神經內分泌癌(LCNEC)共同歸類于神經內分泌腫瘤[1]，這也為今后肺LCNEC的診療指明了新的道路。肺大細胞神經內分泌癌(LCNEC)約占肺癌病例的2.1%-3.5%[2]，然而隨著組織學診斷技術的進步，尤其是免疫組化神經內分泌標志物的發(fā)展，越來越多的肺部神經內分泌腫瘤得以診斷并分型，這也是近年來肺部神經內分泌腫瘤發(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的患者淋巴結轉移率高((60%-80%)、遠處轉移率高(40%)[9，10]，與小細胞肺癌相似(表1)。

2 術前檢查診斷方法

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]，大量淋巴結腫大的情況較少見。因此術前單純從胸部CT區(qū)分LCNEC與其他肺部惡性腫瘤的難度較大。

痰液脫落細胞學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一步檢查[15]，但應同時考慮到纖維支氣管鏡活檢受標本大小、組織形態(tài)等因素的影響較大，使得LCNEC 術前的診斷率低。

神經內分泌腫瘤中生長激素抑制素受體(SSTR)表達率高[16],近年來SSTR顯像診斷技術已被用于術前診斷。肺LCNEC的診斷通常需要免疫組織化學染色及超微顯微鏡下確定神經內分泌分化的明顯標志，在沒有大量活體組織標本時或術前診斷LCNEC相當困難。

因此精準的病理學診斷在肺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。國際肺癌研究聯(lián)合會(International Association for the Study of Lung Cancer)建議應用TNM(tumor,node,metastasis)分期預測神經內分泌腫瘤的預后[17]。

表1 肺LCNEC的主要臨床病理學特征

3 病理學特征

肺LCNEC呈浸潤性生長，細胞病理學特征包括：細胞體積大；有豐富的壞死組織；低核/質比(細胞核大，核仁明顯)；細胞呈巢狀排列；神經內分泌腫瘤常見的形態(tài)學特征如器官樣,柵樣,花瓣樣或小梁狀的細胞生長排列方式[18]；超微結構上常見少量腺樣或鱗狀的分化。(表1)。

腺癌細胞或鱗癌細胞有時共同存在于這些腫瘤中，我們將這些肺LCNEC命名為“混合神經內分泌癌[19](mixed LCNEC)”。盡管前瞻性的數(shù)據具有不確定性，但現(xiàn)有數(shù)據表明混合肺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特征，如生長模式及細胞壞死，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的關鍵。

4 免疫組化及分子標記物

在診斷非小細胞肺癌時，通常使用免疫組織化學標記。鱗狀標記包括細胞角蛋白(CK)5/6,蛋白(p)63,和p40[21]。腺癌標記包括甲狀腺轉錄因子-1,napsin A,和CK7[22]。而神經內分泌癌標記物包括嗜鉻素A(chromogranin A)、突觸素(synaptophysin)、CD56[23]，其中至少有 1 種以上表達陽性。最新數(shù)據顯示，相對于非神經內分泌腫瘤(non—LCNECs)和小細胞肺癌(SCLC)，LCNEC在免疫組化中表達更高水平的原肌球相關激酶B(tropomyosin-related kinase B)和腦源性神經因子[24](brain-derived neurotrophic factor)，這為進一步區(qū)分LCNEC與其他肺臟內分泌源性腫瘤提供了良好的依據。

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)，細胞高有絲分裂率，表達多種神經內分泌細胞標記物，惡性度高，預后差，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 “高度惡性神經內分泌腫瘤(high-grade neuroendocrine carcinoma ，HGNEC)”中。

精確的病理學細胞形態(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 預后及生存率

肺LCNEC與SCLC表現(xiàn)出類似的生物學侵襲性。兩者的生存曲線隨時間進展逐步重疊，其生存率遠低于其他非小細胞肺癌[27]，即使在術后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,隨機臨床試驗很難進行，現(xiàn)階段尚未形成肺LCNEC的治療標準[28]。盡管我們對確診Ⅰ期的肺LCNEC患者盡早行手術治療，對進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，手術治療應作為第一首選，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轉移途徑，提高術后生存率[30]，因此推薦肺葉切除或者全肺切除作為手術患者的第一選擇。(表1)

Grand等人[31]在一項回顧性數(shù)據分析中比較了肺LCNEC與大細胞癌(large cell carcinoma，LCC)的診療結果，就手術方式(病灶局部切除、肺葉切除、全肺切除)而言，沒有明顯證據表明其與術后整體存活率明顯相關。

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治療，隨后實驗者對T3和/或 N2的病人進行輔助放療。這些病人的一年生存率約為27%，并且與淋巴結轉移與否無明顯關聯(lián)。

手術治療的確使約30%的患者收益[33]，因此，完善圍手術期在提升整體治療效果方面顯得尤為重要[34]。

所有可手術切除的肺LCNEC患者(TNM Ⅰ—Ⅲ期)均應盡早行手術治療[35]。新輔助化療、輔助化療可作為防止腫瘤復發(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期患者行術前或術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SCLC患者的化療方案，對肺LCNEC患者進行了以“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”為基礎的聯(lián)合化療對疾病的治療及預后起到了至關重要的效果，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，一些學者認為對病灶局限、進展期或不適宜手術的患者可試行放療[40]。大量的SCLC患者在化療后得以部分或者完全緩解，而后行預防性放射治療，這一方法尚不推薦對肺LCNEC患者進行[41]。

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