李冬冬,陳磊,胡春華,項洪剛
(上海交通大學(xué)醫(yī)學(xué)院附屬新華醫(yī)院 普通外科,上海 200092)
胃癌是消化道系統(tǒng)中常見的具有高度異質(zhì)性的惡性腫瘤,預(yù)后相對較差,其在我國癌癥中的發(fā)病率和病死率均居前列,手術(shù)是其主要治療方法[1-2]。但由于胃癌早期缺乏明顯特異性的臨床表現(xiàn),難以早期發(fā)現(xiàn)和診療,故而臨床上的大多病例初診時已發(fā)展至進展期或者晚期,甚至有相當(dāng)部分的患者出現(xiàn)遠處轉(zhuǎn)移,喪失手術(shù)治療的機會[3-4]。腹膜轉(zhuǎn)移屬于胃癌的遠處轉(zhuǎn)移,常見的診斷方法如內(nèi)鏡檢查和影像學(xué)檢查(B超檢查、腹部CT檢查等)可為胃癌腹膜轉(zhuǎn)移提供輔助診斷,但其存在患者依從性較差、敏感度較低、費用較高等問題[5-8]。因此,尋求一種相對簡單、便捷且可能提前診斷胃癌腹膜轉(zhuǎn)移的方法顯得尤為重要。相關(guān)研究已證實,血清腫瘤標(biāo)志物的表達與胃癌的分化、浸潤和轉(zhuǎn)移相關(guān)。本研究擬通過Logistic回歸及ROC曲線探討聯(lián)合檢測血清腫瘤標(biāo)志物CEA和CA19-9、CA125、CA724、CA211、CA242在胃癌腹膜轉(zhuǎn)移診斷中的應(yīng)用價值。
回顧性隨機抽選2015年12月—2016年12月于我院普外科收治診療的8 9例胃癌患者為研究對象。所有入選患者術(shù)前均已行胃鏡活檢取材并病理證實為胃癌,同時排除并存其他系統(tǒng)腫瘤以及可引起CE A、C A 1 9-9、CA12 5、CA724、CA211、CA242指標(biāo)異常改變的其他疾病。患者術(shù)前均未行化療、放療及免疫治療,且都具有完整的病歷資料。所有研究對象均簽署知情同意書并經(jīng)醫(yī)院倫理委員會審查批準(zhǔn)。根據(jù)術(shù)中探查情況及最終術(shù)后病理報告,將89例胃癌患者有無胃癌腹膜轉(zhuǎn)移分為轉(zhuǎn)移組(1 7例)和無轉(zhuǎn)移組(7 2例)。轉(zhuǎn)移組中,男15例,女2例;年齡39~77歲,平均年齡為(60.5±11.2)歲。無轉(zhuǎn)移組中,男46例,女26例;年齡35~85歲,平均年齡為(62.6±11.7)歲。
所有患者均于入院后次日清晨空腹?fàn)顟B(tài)下完成靜脈血采樣約4 mL,置于真空采集管中混勻,室溫下靜置后進行血清分離,隨后將血樣置于-20 ℃冰箱保存?zhèn)溆?。采用AX-SYM全自動免疫分析儀(雅培,美國)及該公司提供的配套試劑進行檢測。所有檢測均嚴(yán)格按照相關(guān)操作說明進行。CEA正常值上限為10 ng/mL,CA19-9正常值上限為39 U/mL,CA125正常值上限為35 U/mL,CA724正常值上限為6.9 U/mL,CA211正常值上限為3.3 ng/mL,CA242正常值上限為15 IU/mL。上述各項腫瘤標(biāo)志物檢測值超過正常值上限即為陽性。
研究中所涉及到的數(shù)據(jù)均采用SPSS 22.0統(tǒng)計學(xué)軟件進行分析處理,用單樣本K-S檢驗進行數(shù)據(jù)的正態(tài)性檢驗;符合正態(tài)分布計量資料以均數(shù)±標(biāo)準(zhǔn)差()表示,采用t檢驗;計數(shù)資料采用χ2檢驗;運用逐Logistic回歸法(P>0.10剔除)和強制選入Logistic回歸法建立回歸方程式;對新變量Y1、Y2及各單項指標(biāo)進行ROC曲線分析,手工Z檢驗比較曲線下面積差異;P<0.05為差異有統(tǒng)計學(xué)意義。
轉(zhuǎn)移組和無轉(zhuǎn)移組患者在年齡、性別、腫瘤部位、是否有淋巴結(jié)轉(zhuǎn)移方面差異無統(tǒng)計學(xué)意義(均P>0.05);在浸潤深度、分化程度、腫瘤大小、是否有腹水方面差異有統(tǒng)計學(xué)意義(均P<0.05)(表1)。
表1 兩組患者臨床病理資料的比較Table 1 Comparison of the clinicopathologic data between the two groups of patients
轉(zhuǎn)移組和無轉(zhuǎn)移組血清腫瘤標(biāo)志物CEA、CA19-9、CA125、CA724、CA211和CA242檢測值經(jīng)單樣本K-S檢驗均為非正態(tài)分布,故而檢測結(jié)果用中位數(shù)和數(shù)據(jù)范圍[M(范圍)]表示(表2)。
表2 兩組血清腫瘤標(biāo)志物的檢測結(jié)果[M(范圍)]Table 2 Results of the detection of the tumor markers in the two groups [M (range)]
轉(zhuǎn)移組CA125、CA724、CA211的陽性檢出率高于無轉(zhuǎn)移組,組間差異均有統(tǒng)計學(xué)意義(均P<0.05);兩組CEA、CA19-9、CA242陽性檢出率無統(tǒng)計學(xué)差異(均P>0.05)(表3)。
表3 兩組血清腫瘤標(biāo)志物的陽性檢出率比較[n(%)]Table 3 Comparison of the positive detection rates of the tumor markers between the two groups [n (%)]
經(jīng)逐步Logistic回歸分析CEA(P=0.509)、CA19-9(P=0.288)、CA242(P=0.425)被剔除(P>0.10),篩選出有意義的變量為CA125、CA724和CA211(表4)。6種腫瘤標(biāo)志物單獨檢測時,CA125的AUC最大,與其他5項指標(biāo)單獨檢測的差異均有統(tǒng)計學(xué)意義(均P>0.05);聯(lián)合檢測時,逐步Logistic回歸篩選的CA125、CA724、CA211聯(lián)合與強制選入Logistic回歸的CEA、CA19-9、CA125、CA724、CA211、CA242聯(lián)合的AUC均大于各單項檢測的AUC,且差異有統(tǒng)計學(xué)意義(均P<0.05),但兩者間AUC差異無統(tǒng)計學(xué)意義(0.964vs.0.949,P=0.866)(表5)(圖1)。
表4 3種腫瘤標(biāo)志物逐步Logistic回歸分析結(jié)果Table 4 Results of stepwise Logistic regression for the three tumor markers
表5 6種腫瘤標(biāo)志物檢測的AUCTable 5 The AUCs of the detection of the six tumor markers
圖1 6種腫瘤標(biāo)志物檢測的ROC曲線Figure 1 ROC curves of the detection of the six tumor markers
胃癌腹膜轉(zhuǎn)移的確切機制尚不明確,目前較為公認(rèn)的是“種子-土壤”學(xué)說,即胃癌細胞由原發(fā)病灶浸潤出漿膜面形成脫落的“種子”,繼而這些具有高侵襲和轉(zhuǎn)移活力的癌細胞在各種因子的作用下黏附于腹腔臟器或網(wǎng)膜的表面并進一步著床形成轉(zhuǎn)移性癌結(jié)節(jié)[9]。本研究也提示腹膜轉(zhuǎn)移的因素與胃癌原發(fā)腫瘤病灶的大小、浸潤深度及分化程度相關(guān)。
現(xiàn)有相關(guān)研究[10-12]已證實血清腫瘤標(biāo)志物的檢測對消化道系統(tǒng)腫瘤的診斷、預(yù)后有積極意義。CA125是1983年由Bast等[13]從上皮性卵巢癌抗原檢測出可被單克隆抗體OC125結(jié)合的一種糖蛋白,最常見于卵巢腫瘤患者的血清中,主要與卵巢癌的診斷和術(shù)后監(jiān)測復(fù)發(fā)、轉(zhuǎn)移相關(guān);近來有報道[14]提示,胃癌腹膜轉(zhuǎn)移患者中血清CA125水平也可升高,且腹水陽性患者的血清CA125陽性率明顯高于腹水陰性的患者,它可用以評價實體瘤的治療效果及監(jiān)測復(fù)發(fā)或轉(zhuǎn)移。CA724是一種由CC49和B72.3兩株單抗識別的粘蛋白樣的高分子量糖蛋白,在各種消化道腫瘤及卵巢癌均可產(chǎn)生其異常升高,但同時也有相關(guān)報道[15-16]認(rèn)為CA724對于胃癌的檢測特異性較高,在胃癌患者中其異常升高者的比例可將近50%,且CA724水平與胃癌的臨床分期呈正相關(guān);CA211是細胞白蛋白19(CK19)片段,相關(guān)組織病理學(xué)研究[17]表明,其在肺癌組織中表達顯著,但其特異性不高,在其他系統(tǒng)腫瘤中亦可相應(yīng)表達升高。而本研究也同樣證實了在單獨檢測6種腫瘤標(biāo)志物時,CA125的AUC最大為0.889,與其他5項指標(biāo)單獨檢測的差異有統(tǒng)計學(xué)意義(P>0.05),這提示高度懷疑胃惡性腫瘤伴發(fā)腹膜轉(zhuǎn)移的患者術(shù)前檢測血清CA125可提供必要的輔助診斷。國內(nèi)嚴(yán)超等[18]報道了單中心大宗病例關(guān)于術(shù)前檢測血清CA125預(yù)測胃癌腹膜轉(zhuǎn)移;而周鵬等[19]也同樣提出了CA125對胃癌患者發(fā)生腹膜轉(zhuǎn)移及預(yù)后具有預(yù)測價值。同時,本研究也表明在胃癌腹膜轉(zhuǎn)移患者中,聯(lián)合檢測CA125、CA724和CA211的AUC大于任何檢測單一腫瘤標(biāo)志物的AUC,且差異具有統(tǒng)計學(xué)意義(P<0.05),提示聯(lián)合檢測CA125、CA724和CA211可為臨床中胃癌腹膜轉(zhuǎn)移的鑒別診斷提供有效的參考。而相關(guān)研究也認(rèn)為聯(lián)合檢測血清腫瘤標(biāo)志物可提高診斷胃癌發(fā)生腹膜轉(zhuǎn)移的效能[14,20-25]。但與此同時,本研究也發(fā)現(xiàn)行6種腫瘤聯(lián)合檢測對鑒別胃癌腹膜轉(zhuǎn)移的必要性不大,且現(xiàn)實臨床中檢測費時且患者花費較高,因此臨床醫(yī)生應(yīng)注意個體化差異,視具體情況而定。
胃癌是具有高度異質(zhì)性的惡性消化道腫瘤,任何一種術(shù)前單一的輔助檢測手段都難以達到腹膜轉(zhuǎn)移的最確切的鑒別,但嘗試相對無創(chuàng)且靈敏度較高的血清生化檢測可為臨床診斷胃癌腹膜轉(zhuǎn)移提供一種思路和參考。
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