內(nèi)鏡超聲引導(dǎo)下細(xì)針穿刺活檢對(duì)消化系統(tǒng)腫瘤的診斷價(jià)值

陳素敏 李百文 任迎春 趙秋艷

上海交通大學(xué)附屬第一人民醫(yī)院消化科(201620)

·綜 述·

內(nèi)鏡超聲引導(dǎo)下細(xì)針穿刺活檢對(duì)消化系統(tǒng)腫瘤的診斷價(jià)值

陳素敏 李百文*任迎春 趙秋艷

上海交通大學(xué)附屬第一人民醫(yī)院消化科(201620)

影像學(xué)檢查如CT、MRI、超聲等對(duì)消化系統(tǒng)腫瘤的診斷具有重要意義，但部分消化系統(tǒng)腫瘤因其自身獨(dú)特的臨床特點(diǎn)，常規(guī)影像學(xué)檢查不易早期發(fā)現(xiàn)并作出定性診斷。內(nèi)鏡超聲引導(dǎo)下細(xì)針穿刺活檢(EUS-FNA)不僅可發(fā)現(xiàn)早期病變，還能對(duì)病變作出準(zhǔn)確的定性診斷，該技術(shù)的發(fā)展和完善極大地提高了消化系統(tǒng)腫瘤的診斷水平。本文就EUS-FNA對(duì)消化系統(tǒng)腫瘤的診斷價(jià)值作一綜述。

EUS-FNA； 活組織檢查，針吸； 消化系統(tǒng)腫瘤； 診斷

自從Vilmann和Grimm于1992年先后報(bào)道在內(nèi)鏡超聲(endoscopic ultrasonography, EUS)引導(dǎo)下成功對(duì)胰腺組織進(jìn)行 細(xì)針穿刺活檢以來[1-2]，內(nèi)鏡超聲引導(dǎo)下細(xì)針穿刺活檢(endoscopic ultrasonography-guided fine needle aspiration, EUS-FNA)逐漸成為獲取消化系統(tǒng)組織標(biāo)本的常規(guī)方法。與傳統(tǒng)超聲引導(dǎo)下細(xì)針穿刺活檢(ultrasonography-guided fine needle aspiration, US-FNA)和CT引導(dǎo)下細(xì)針穿刺活檢(CT-guided fine needle aspiration, CT-FNA)相比，EUS-FNA具有下述明顯優(yōu)勢(shì)：操作過程中可直接將超聲探頭置于距病變部位較近的胃或十二指腸壁，從而避免腹壁脂肪和腸道氣體干擾檢測(cè)；可利用多普勒功能實(shí)時(shí)顯示血流和血管聲像圖，以避開血管對(duì)病變部位直接進(jìn)行穿刺，從而降低并發(fā)癥發(fā)生率。EUS-FNA顯著提高了消化系統(tǒng)病變的診斷水平，尤其是對(duì)于某些消化系統(tǒng)腫瘤的早期診斷具有重要臨床意義。本文就EUS-FNA對(duì)消化系統(tǒng)腫瘤的診斷價(jià)值及其應(yīng)用現(xiàn)狀作一綜述。

一、EUS-FNA對(duì)消化系統(tǒng)腫瘤的診斷價(jià)值

1. EUS-FNA對(duì)胰腺癌的診斷價(jià)值：胰腺癌是胰腺外分泌腺惡性程度較高的腫瘤，預(yù)后極差，5年生存率低于5%。胰腺癌起病隱匿，早期通常無特殊癥狀，多數(shù)患者在確診時(shí)已 處于疾病晚期，符合外科手術(shù)切除指征的患者不足20%[3]。因此，胰腺癌的早期診斷是提高患者生存率、改善預(yù)后的關(guān)鍵。

目前已有多種影像學(xué)手段可用于診斷胰腺癌，如CT、MRI、ERCP、超聲等，然而這些方法均存在一定的局限性：因腸道氣體干擾以及胰腺位置較深，超聲檢查診斷率較低；CT和MRI難以發(fā)現(xiàn)直徑較小的腫瘤，且無法取活檢作出病理診斷，易發(fā)生漏診[4]。EUS-FNA可通過近距離觀察早期發(fā)現(xiàn)直徑較小尤其是直徑<1 cm的腫瘤，用于診斷胰腺癌時(shí)特異性和準(zhǔn)確性均較高，且并發(fā)癥較少[5]。Eloubeidi等[6]報(bào)道EUS-FNA對(duì)胰腺癌的診斷敏感性超過80%，特異性可達(dá)100%。關(guān)于EUS-FNA對(duì)胰腺實(shí)體腫瘤診斷價(jià)值的meta分析顯示，細(xì)胞學(xué)檢查診斷胰腺癌的特異性和準(zhǔn)確性分別為85%和98%，表明其為診斷胰腺實(shí)體腫瘤的有效手段[7]。Will等[8]的研究中，139例胰腺實(shí)體或囊性腫瘤性病變患者行EUS-FNA細(xì)胞學(xué)檢查，其診斷敏感性、特異性和準(zhǔn)確性分別為83.0%、93.3%和86.3%。以上研究結(jié)果提示EUS-FNA對(duì)于胰腺癌的早期發(fā)現(xiàn)和早期診斷具有重要價(jià)值。

近年隨著研究的深入，越來越多的學(xué)者發(fā)現(xiàn)在細(xì)胞學(xué)或組織學(xué)檢查的同時(shí)行分子生物學(xué)檢測(cè)可進(jìn)一步提高胰腺癌診斷率，為胰腺癌的早期診斷提供了新思路。Jahng等[9]的回顧性研究納入61例胰腺癌或胰腺炎相關(guān)良性病變患者，所有EUS-FNA標(biāo)本均行細(xì)胞學(xué)檢查和腫瘤標(biāo)記物p53、Ki-67檢測(cè)，結(jié)果顯示聯(lián)合檢測(cè)p53或Ki-67可提高細(xì)胞學(xué)檢查診斷胰腺癌的敏感性，單獨(dú)細(xì)胞學(xué)檢查的敏感性和特異性分別為41%和100%，聯(lián)合檢測(cè)p53或Ki-67可分別將敏感性提高至51%和53%，特異性均達(dá)到100%；三項(xiàng)檢測(cè)聯(lián)合的敏感性可達(dá)57%。Mishra等[10]應(yīng)用半定量PCR檢測(cè)胰腺實(shí)體病變EUS-FNA標(biāo)本的端粒酶活性，發(fā)現(xiàn)其對(duì)胰腺癌的診斷敏感性和特異性分別為79%和100%；聯(lián)合細(xì)胞學(xué)檢查可將其敏感性從85%提高至98%，特異性始終為100%。上述發(fā)現(xiàn)表明EUS-FNA病理學(xué)檢查聯(lián)合分子生物學(xué)檢測(cè)可明顯提高胰腺癌診斷率。

2. EUS-FNA對(duì)胰腺神經(jīng)內(nèi)分泌腫瘤(pancreatic neuro-endocrine neoplasm, pNEN)的診斷價(jià)值：pNEN約占所有胰腺腫瘤的1%～2%，根據(jù)腫瘤是否具有激素分泌功能可分為功能性和非功能性兩類，后者因無激素分泌過多的癥狀而不易早期發(fā)現(xiàn)，導(dǎo)致患者失去最佳治療時(shí)機(jī)。因此，早期發(fā)現(xiàn)和早期診斷是改善pNEN患者預(yù)后的關(guān)鍵。

pNEN的形態(tài)學(xué)和生物學(xué)特點(diǎn)異質(zhì)性高，臨床診斷較為困難，僅依靠病史、體格檢查、實(shí)驗(yàn)室和影像學(xué)檢查等常不能明確診斷，確診需組織學(xué)證據(jù)。EUS-FNA是診斷pNEN的新手段，可通過對(duì)病變進(jìn)行穿刺獲取組織標(biāo)本，結(jié)合現(xiàn)場(chǎng)快速評(píng)估 方法和免疫組化染色技術(shù)，可早期發(fā)現(xiàn)和早期診斷pNEN[11]。Larghi等[12]對(duì)30例影像學(xué)檢查疑為非功能性pNEN的患者行EUS-FNA，其中28例獲得足夠的組織學(xué)標(biāo)本并確診，準(zhǔn)確性達(dá)93.3%。

pNEN的準(zhǔn)確分級(jí)對(duì)于腫瘤生物學(xué)行為的預(yù)測(cè)、預(yù)后評(píng)估以及臨床治療方案的選擇具有重要意義，采用世界衛(wèi)生組織(WHO)2010年標(biāo)準(zhǔn)，根據(jù)Ki-67指數(shù)對(duì)標(biāo)本進(jìn)行分級(jí)，EUS-FNA細(xì)胞學(xué)標(biāo)本與手術(shù)標(biāo)本分級(jí)結(jié)果具有較高的一致性[13]。Larghi等[12]的研究納入12例行外科切除術(shù)的非功能性pNEN患者，其中10例(83.3%)術(shù)后標(biāo)本Ki-67指數(shù)分級(jí)與術(shù)前標(biāo)本EUS-FNA分級(jí)結(jié)果一致。Hasegawa等[14]根據(jù)EUS-FNA標(biāo)本的最高Ki-67指數(shù)對(duì)pNEN進(jìn)行分級(jí)，與外科切除標(biāo)本分級(jí)的一致性為77.8%，如剔除腫瘤細(xì)胞數(shù)少于2 000 個(gè)的EUS-FNA標(biāo)本，一致性可提高至90%。Unno等[15]的研究亦顯示EUS-FNA與外科切除標(biāo)本對(duì)pNEN分級(jí)的一致性達(dá)到89.5%。

3. EUS-FNA對(duì)胰腺囊性病變的診斷價(jià)值：胰腺囊性病變是一類呈囊性或囊實(shí)性的占位性病變。近年隨著影像學(xué)技術(shù)的發(fā)展，其在檢查中被偶然發(fā)現(xiàn)的概率呈增高趨勢(shì)[16]。該類病變種類繁多，臨床病理特點(diǎn)各異，準(zhǔn)確的定性診斷是制訂正確治療方案的關(guān)鍵。

常規(guī)影像學(xué)檢查如B超、CT、MRI等是定位診斷胰腺囊性病變的主要手段，但在定性診斷方面均存在一定缺陷。EUS-FNA可抽取囊液進(jìn)行腫瘤標(biāo)記物分析和細(xì)胞學(xué)檢查，進(jìn)而作出定性診斷。研究發(fā)現(xiàn)EUS-FNA抽取囊液行腫瘤標(biāo)記物(CEA、CA19-9)、淀粉酶檢測(cè)和細(xì)胞學(xué)檢查(包括黏液染色)，可鑒別良惡性胰腺囊性病變，提高診斷準(zhǔn)確性[17-18]。囊液CEA聯(lián)合K-ras基因突變檢測(cè)對(duì)惡性胰腺囊性病變的診斷準(zhǔn)確性高達(dá)94.1%[19]。此外，研究還發(fā)現(xiàn)EUS-FNA細(xì)胞學(xué)檢查對(duì)伴有實(shí)性成分的胰腺囊性病變?cè)\斷價(jià)值更高[20-21]。

4. EUS-FNA對(duì)胃腸道間質(zhì)瘤(gastrointestinal stromal tumor, GIST)的診斷價(jià)值：GIST是最常見的胃腸道黏膜下腫瘤，約60%發(fā)生于胃，25%見于小腸，10%見于結(jié)直腸[22]。該病起病隱匿，常以消化道出血或腹部脹痛為首發(fā)癥狀。

GIST在常規(guī)內(nèi)鏡下主要依據(jù)黏膜層隆起情況進(jìn)行定位診斷，但因難以獲取病變組織而不能進(jìn)行定性診斷[23]。而EUS-FNA不僅可發(fā)現(xiàn)GIST病變并準(zhǔn)確判斷其大小、深度和來源，還可直接獲取病變組織用于細(xì)胞學(xué)、組織學(xué)檢查和免疫組化染色，從而對(duì)病變作出定性診斷。Mekky等[24]報(bào)道EUS-FNA對(duì)胃黏膜下腫瘤(主要是胃間質(zhì)瘤)的診斷準(zhǔn)確性為95.6%，鑒別良性與潛在惡性病變的敏感性、特異性和準(zhǔn)確性分別為92.4%、100%和94.2%。Akahoshi等[25]的回顧性研究顯示，EUS-FNA標(biāo)本免疫組化染色對(duì)小于2 cm的胃上皮下實(shí)體病變的診斷準(zhǔn)確性為98%，是這類腫瘤早期診斷的有效手段。

5. EUS-FNA對(duì)膽管癌和其他膽管梗阻或狹窄性病變的診斷價(jià)值：膽管癌是一類起源于膽管上皮的惡性腫瘤，常因缺乏特異性表現(xiàn)而難以在疾病早期被發(fā)現(xiàn)，多數(shù)患者確診時(shí)已處于疾病晚期，喪失了根治性治療的機(jī)會(huì)，預(yù)后較差。

較之常規(guī)影像學(xué)檢查，EUS-FNA在膽管癌的早期發(fā)現(xiàn)和早期診斷方面具有一定優(yōu)勢(shì)，其可避免腸道氣體干擾，能更清晰地顯示膽管病變，還可穿刺獲取病變組織進(jìn)行組織學(xué)檢查。研究[26]報(bào)道EUS-FNA對(duì)肝門部膽管癌術(shù)前診斷的敏感性、特異性和準(zhǔn)確性分別為89%、100%和91%，對(duì)于不明原因肝門部狹窄是一種有價(jià)值的微創(chuàng)診斷技術(shù)，約半數(shù)患者因該項(xiàng)檢查而改變預(yù)先計(jì)劃的手術(shù)路徑。Eloubeidi等[27]的研究顯示，EUS-FNA對(duì)膽管癌的診斷敏感性、特異性和準(zhǔn)確性分別為86%、100%和88%，可對(duì)84%患者的臨床治療產(chǎn)生積極引導(dǎo)作用。DeWitt等[28]報(bào)道EUS-FNA對(duì)ERCP刷檢細(xì)胞學(xué)檢查陰性或刷檢失敗的近端膽管狹窄性病變具有較高診斷價(jià)值，敏感性、特異性和準(zhǔn)確性分別為77%、100%和79%，然而鑒于其陰性預(yù)測(cè)值較低，即使結(jié)果陰性亦不能排除惡性腫瘤可能。Weilert等[29]比較了EUS-FNA和ERCP獲取的組織樣本對(duì)可疑惡性膽管梗阻的診斷價(jià)值，發(fā)現(xiàn)EUS-FNA的總體敏感性和準(zhǔn)確性優(yōu)于ERCP(94%對(duì)50%和94%對(duì)53%)，但其優(yōu)勢(shì)在于診斷胰腺腫物所致的梗阻，對(duì)膽道腫物和不明原因梗阻的診斷價(jià)值與ERCP相似。綜上，EUS-FNA對(duì)膽管癌以及惡性膽管梗阻或狹窄性病變的診斷具有重要意義。

二、EUS-FNA技術(shù)的應(yīng)用現(xiàn)狀

EUS-FNA不僅可用于胰腺癌、胃腸道腫瘤、膽管癌等消化系統(tǒng)腫瘤的診斷，還可用于腎臟腫瘤、膀胱癌等的診斷，已逐漸成為腫瘤早期診斷的主要手段之一。EUS-FNA技術(shù)在穿刺前常規(guī)采用彩色多普勒血流成像了解病變內(nèi)部和周圍血流情況，尤其是穿刺路徑上的血管分布情況，可顯著減少并發(fā)癥發(fā)生。EUS-FNA的并發(fā)癥主要包括感染、出血、穿孔、醫(yī)源性胰腺炎、針道腫瘤種植性轉(zhuǎn)移等，但總體發(fā)生率僅為1%～2%，多數(shù)患者可經(jīng)由對(duì)癥治療或外科手術(shù)治療好轉(zhuǎn)或治愈[30]。

EUS-FNA在消化系統(tǒng)腫瘤的早期診斷中起有重要作用，是一項(xiàng)安全、有效的診斷技術(shù)，具有其他影像學(xué)檢查手段無可比擬的優(yōu)越性。然而，該項(xiàng)技術(shù)的整體診斷價(jià)值目前仍未達(dá)到理想水平。對(duì)相關(guān)專業(yè)人員的調(diào)查顯示，臨床實(shí)踐中EUS-FNA的診斷敏感性遠(yuǎn)低于文獻(xiàn)報(bào)道，僅1/3的從業(yè)人員認(rèn)為其診斷實(shí)體腫瘤的敏感性高于80%[31]；此外，盡管EUS-FNA診斷的假陽性率極低，但假陰性率相當(dāng)高[32]。上述現(xiàn)象主要與穿刺獲取樣本量不足、樣本質(zhì)量不高有關(guān)，導(dǎo)致診斷準(zhǔn)確性降低，貽誤治療時(shí)機(jī)。因此，對(duì)于EUS醫(yī)師而言，不斷完善操作技能以提高獲取組織標(biāo)本的數(shù)量和質(zhì)量尤為重要。

近年來，隨著EUS-FNA濕抽技術(shù)(wet suction technique，穿刺針內(nèi)充滿0.9% NaCl溶液后再行FNA)的出現(xiàn)，獲取樣本的數(shù)量和質(zhì)量得到明顯改善，顯著提高了EUS-FNA技術(shù)的診斷水平[33-34]。目前，研究者仍在不斷探索改善EUS-FNA技術(shù)的方法，包括穿刺針規(guī)格、有無針芯、負(fù)壓吸引力大小、穿刺次數(shù)的比較以及有無現(xiàn)場(chǎng)細(xì)胞病理學(xué)評(píng)估等。

三、結(jié)語

綜上所述，EUS-FNA作為一種安全、有效的診斷技術(shù)，現(xiàn)已廣泛應(yīng)用于消化系統(tǒng)腫瘤的早期診斷。隨著EUS-FNA技術(shù)的發(fā)展和日益完善，其在消化系統(tǒng)腫瘤的早期發(fā)現(xiàn)和早期診斷中將發(fā)揮更為重要的作用。

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DiagnosticValueofEndoscopicUltrasonography-guidedFineNeedleAspirationforDigestiveSystemNeoplasms

CHENSumin,LIBaiwen,RENYingchun,ZHAOQiuyan.

DepartmentofGastroenterology,ShanghaiGeneralHospital,ShanghaiJiaoTongUniversity,Shanghai(201620)

LI Baiwen, muzibowen@126.com

Imaging examinations such as CT, MRI and ultrasonography are of great importance for the diagnosis of digestive system neoplasms. However, some digestive system neoplasms are difficult to be detected at early stage and make qualitative diagnosis by conventional imaging techniques because of their unique clinical characteristics. Compared with conventional imaging techniques, endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) can not only detect the early lesions, but also make accurate qualitative diagnosis. The development and improvement of EUS-FNA greatly improve the diagnostic level of digestive system neoplasms. In this paper, the diagnostic value of EUS-FNA in digestive system neoplasms was reviewed.

EUS-FNA; Biopsy, Needle; Digestive System Neoplasms; Diagnosis

10.3969/j.issn.1008-7125.2017.12.009

*本文通信作者，Email: muzibowen@126.com

(2017-05-24收稿；2017-07-06修回)