王 源，孟 剛

伴有轉(zhuǎn)移的胃腸道間質(zhì)瘤臨床病理特征

王 源，孟 剛

目的探討伴有轉(zhuǎn)移的胃腸道間質(zhì)瘤(gastrointestinal stromal tumors, GIST)臨床病理特征及其淋巴結(jié)轉(zhuǎn)移的機(jī)制。方法收集45例伴有轉(zhuǎn)移的GIST并選取同期50例原發(fā)GIST作對(duì)比分析。采用免疫組化EnVision法染色標(biāo)記Ki-67、CD31、D2-40，計(jì)數(shù)微血管密度(micro vessel density, MVD)和微淋巴管密度(lymphatic microvessel density, LMVD)。結(jié)果GIST總轉(zhuǎn)移率為5.45%，血道轉(zhuǎn)移率為1.33%，淋巴結(jié)轉(zhuǎn)移率為1.09%。轉(zhuǎn)移性GIST實(shí)質(zhì)內(nèi)的MVD為每平方毫米398.39±68.20 個(gè)，非轉(zhuǎn)移性GIST實(shí)質(zhì)內(nèi)的MVD為每平方毫米192.07±56.85個(gè)，兩者差異有統(tǒng)計(jì)學(xué)意義。轉(zhuǎn)移性及非轉(zhuǎn)移性GIST實(shí)質(zhì)內(nèi)均無(wú)淋巴管，轉(zhuǎn)移性GIST邊緣區(qū)LMVD為每平方毫米13.28±2.40個(gè)、周圍正常組織LMVD為每平方毫米25.36±6.71個(gè)；非轉(zhuǎn)移性GIST邊緣區(qū)LMVD為每平方毫米12.21±1.83 個(gè)、周圍正常組織LMVD為每平方毫米24.23±8.64個(gè)；兩組GIST邊緣區(qū)及周圍正常組織內(nèi)LMVD差異無(wú)統(tǒng)計(jì)學(xué)意義。GIST形態(tài)學(xué)觀察可見淋巴結(jié)轉(zhuǎn)移組9例均呈浸潤(rùn)性生長(zhǎng)，而非淋巴結(jié)轉(zhuǎn)移組僅12例(12/86)呈浸潤(rùn)性生長(zhǎng)。結(jié)論轉(zhuǎn)移性GIST的MVD高于非轉(zhuǎn)移性GIST，GIST腫瘤實(shí)質(zhì)內(nèi)無(wú)淋巴管，腫瘤呈浸潤(rùn)性生長(zhǎng)可能是淋巴結(jié)轉(zhuǎn)移的原因。

胃腸道腫瘤；胃腸道間質(zhì)瘤；淋巴結(jié)轉(zhuǎn)移；病理

胃腸道間質(zhì)瘤(gastrointestinal stromal tumors, GIST)是胃腸道最為常見的間葉源性腫瘤，發(fā)病率占胃腸道惡性腫瘤的0.1%～3%[1]。肝臟轉(zhuǎn)移和腹腔種植性轉(zhuǎn)移是GIST最常見的轉(zhuǎn)移途徑，淋巴結(jié)轉(zhuǎn)移少見[2]，外科手術(shù)治療亦不考慮淋巴結(jié)清掃。美國(guó)國(guó)立綜合癌癥網(wǎng)絡(luò)(NCCN)軟組織肉瘤臨床實(shí)踐指南(2016)中，新增“對(duì)于SDH缺乏的GIST患者，需考慮切除病理性腫大的淋巴結(jié)”[3]。目前文獻(xiàn)報(bào)道GIST淋巴結(jié)轉(zhuǎn)移病例多為個(gè)案，大宗病例的系統(tǒng)分析罕見，對(duì)其臨床病理特征尚缺乏充分認(rèn)識(shí)。本組收集825例GIST并結(jié)合檢索GIST淋巴結(jié)轉(zhuǎn)移的報(bào)道，對(duì)伴有轉(zhuǎn)移尤其是淋巴結(jié)轉(zhuǎn)移的GIST進(jìn)行分析，探討其獨(dú)特的臨床病理特征及與淋巴結(jié)轉(zhuǎn)移的相關(guān)性分析[4]。

1 材料與方法

1.1材料收集安徽醫(yī)科大學(xué)第一附屬醫(yī)院病理科2011年11月～2016年10月確診為GIST的825例組織標(biāo)本，選取45例伴有轉(zhuǎn)移的手術(shù)標(biāo)本作為分析對(duì)象，并選取50例同期非轉(zhuǎn)移性GIST作為對(duì)照。

1.2方法所有病例重新切片，行HE及免疫組化EnVision法染色?？贵wCD34、Ki-67、CD31、D2-40及免疫組化試劑，均購(gòu)自福州邁新公司。

1.3結(jié)果判斷免疫組化切片中細(xì)胞陽(yáng)性信號(hào)呈棕黃色細(xì)顆粒狀。計(jì)數(shù)微血管密度(micro vessel density, MVD)和微淋巴管密度(lymphatic microvessel density, LMVD)：觀察用CD31(CD34)/D2-40標(biāo)記的免疫組化切片，在100倍鏡下尋找血管/淋巴管密集的熱點(diǎn)區(qū)域，分別計(jì)數(shù)3個(gè)熱點(diǎn)區(qū)域200倍鏡下的微血管/微淋巴管計(jì)數(shù)，根據(jù)高倍鏡視野直徑計(jì)算每平方毫米的微血管/微淋巴管數(shù)量計(jì)為 MVD/LMVD[5-6]。

1.4統(tǒng)計(jì)學(xué)方法MVD和LMVD結(jié)果運(yùn)用SPSS 13.0軟件進(jìn)行統(tǒng)計(jì)學(xué)方差分析，P<0.05為差異有統(tǒng)計(jì)學(xué)意義。

2 結(jié)果

2.1轉(zhuǎn)移性GIST臨床病理特征825例GIST患者中，45例(5.45%)發(fā)生轉(zhuǎn)移，其中發(fā)生淋巴結(jié)轉(zhuǎn)移者9例(1.09%)、發(fā)生肝臟轉(zhuǎn)移者11例(1.33%)、發(fā)生腹腔轉(zhuǎn)移者25例(2.91%)。轉(zhuǎn)移性患者發(fā)病年齡最小為23歲，最大為82歲，多發(fā)于50～60歲。最常見的原發(fā)部位是胃(24例，53%)，其次為小腸(15例，30%)，結(jié)腸(4例，8.8%)，胃腸道外(2例，4.4%)。HE鏡下細(xì)胞形態(tài)特點(diǎn)：35例為梭形細(xì)胞型，5例為上皮細(xì)胞型，5例為混合細(xì)胞型。淋巴結(jié)轉(zhuǎn)移組GIST中9例均呈浸潤(rùn)性生長(zhǎng)，而非淋巴結(jié)轉(zhuǎn)移組僅12例(12/86)呈浸潤(rùn)性生長(zhǎng)。GIST浸潤(rùn)性生長(zhǎng)的形態(tài)學(xué)特點(diǎn)：當(dāng)腫瘤邊緣位于胃腸道肌層時(shí)，腫瘤組織呈舌狀伸入肌層并包饒肌層細(xì)胞逐漸浸潤(rùn)；當(dāng)腫瘤邊緣位于胃腸道黏膜層、肝臟組織、淋巴結(jié)時(shí)，腫瘤組織呈侵襲性浸潤(rùn)生長(zhǎng)；腫瘤呈浸潤(rùn)性生長(zhǎng)局部MVD明顯高于腫瘤實(shí)質(zhì)中的MVD。

淋巴結(jié)轉(zhuǎn)移灶腫瘤邊緣界限不清(圖1)，CD117免疫組化染色陽(yáng)性(圖2)。淋巴結(jié)轉(zhuǎn)移性GIST中男性6例，女性3例；6例原發(fā)于胃，3例原發(fā)于小腸；2例原發(fā)于胃者腫瘤直徑<5 cm，7例腫瘤直徑≥5 cm。組織學(xué)類型：7例呈梭形細(xì)胞型，1例為上皮樣細(xì)胞型，1例為混合細(xì)胞型。危險(xiǎn)度分級(jí)：8例為高度危險(xiǎn)，1例呈中度危險(xiǎn)。淋巴結(jié)轉(zhuǎn)移性GIST的Ki-67增殖指數(shù)、核分裂象、MVD均一致偏高，且明顯高于非淋巴結(jié)轉(zhuǎn)移性GIST(P<0.05)；9例淋巴結(jié)轉(zhuǎn)移性GIST顯微鏡下均呈浸潤(rùn)性生長(zhǎng)(表1)。

2.2轉(zhuǎn)移性GIST與風(fēng)險(xiǎn)度評(píng)價(jià)根據(jù)2008年美國(guó)國(guó)立衛(wèi)生研究院(NIH)關(guān)于GIST風(fēng)險(xiǎn)度評(píng)價(jià)，本組轉(zhuǎn)移性GIST患者中，32例為高度風(fēng)險(xiǎn)，9例為中度風(fēng)險(xiǎn)，3例為低度風(fēng)險(xiǎn)，1例為極低風(fēng)險(xiǎn)。8例(8/9)淋巴結(jié)轉(zhuǎn)移、7例(7/11)肝臟轉(zhuǎn)移病例和17例(17/25)腹腔轉(zhuǎn)移病例屬于高度風(fēng)險(xiǎn)。轉(zhuǎn)移性GIST中，1例淋巴結(jié)轉(zhuǎn)移和1例肝臟轉(zhuǎn)移腫塊最大徑為1 cm(<2 cm)，其余44例轉(zhuǎn)移性間質(zhì)瘤腫瘤最大徑均>2 cm，其中有39例(87%)患者的腫瘤最大徑≥5 cm。

2.3轉(zhuǎn)移性GIST的MVD轉(zhuǎn)移性GIST的MVD明顯高于非轉(zhuǎn)移性GIST(圖3、4)，兩者差異有統(tǒng)計(jì)學(xué)意義(P<0.05)。其中發(fā)生于淋巴結(jié)轉(zhuǎn)移性GIST的MVD(實(shí)質(zhì))為每平方毫米511.11±72.20 個(gè)，發(fā)生于肝臟的轉(zhuǎn)移性GIST的MVD(實(shí)質(zhì))為每平方毫米(345.00±52.50 個(gè)，淋巴結(jié)轉(zhuǎn)移性GIST的MVD高于肝臟轉(zhuǎn)移性GIST的MVD，差異有統(tǒng)計(jì)學(xué)意義(P=0.041)。在腫瘤邊緣發(fā)生浸潤(rùn)性生長(zhǎng)區(qū)域觀察微血管分布發(fā)現(xiàn)：這些區(qū)域的MVD很高，平均每平方毫米633.78±125.64個(gè)，且血管排列紊亂扭曲(圖5、6)。

2.4轉(zhuǎn)移性GIST的LMVD所有轉(zhuǎn)移性GIST及非轉(zhuǎn)移性GIST的腫瘤實(shí)質(zhì)中均無(wú)淋巴管分布。轉(zhuǎn)移性GIST的邊緣區(qū)LMVD為每平方毫米13.28±2.40個(gè)，非轉(zhuǎn)移性GIST邊緣區(qū)的LMVD為每平方毫米12.21±1.83個(gè)；轉(zhuǎn)移性GIST腫瘤周圍正常組織的LMVD為每平方毫米25.36±6.71個(gè)，非轉(zhuǎn)移性GIST腫瘤周圍正常組織LMVD為每平方毫米24.23±8.64個(gè)。經(jīng)統(tǒng)計(jì)學(xué)分析，差異均無(wú)統(tǒng)計(jì)學(xué)意義(P<0.05)。

①②③④⑤⑥

圖1淋巴結(jié)轉(zhuǎn)移灶，腫瘤邊界不清圖2CD117呈陽(yáng)性，EnVision法圖3轉(zhuǎn)移性GIST的微血管分布，EnVision法圖4非轉(zhuǎn)移性GIST的微血管分布，EnVision法圖5轉(zhuǎn)移性GIST浸潤(rùn)性生長(zhǎng)區(qū)域圖6CD31標(biāo)記的MVD，EnVision法

表1 淋巴結(jié)轉(zhuǎn)移性GIST臨床病理特征(n=9)

表2 文獻(xiàn)報(bào)道淋巴結(jié)轉(zhuǎn)移性GIST的臨床病理特征

NG：結(jié)果未知；LN：淋巴結(jié)

3 討論

本文在基于現(xiàn)有實(shí)驗(yàn)結(jié)果的基礎(chǔ)上結(jié)合目前對(duì)于GIST淋巴結(jié)轉(zhuǎn)移的個(gè)案報(bào)道(表2)探討伴淋巴結(jié)轉(zhuǎn)移GIST的臨床特點(diǎn)。GIST屬于最常見且最具惡性潛能的胃腸道間葉源性腫瘤，占胃腫瘤的1%～3%[20]，文獻(xiàn)報(bào)道20%～25%胃原發(fā)GIST、40%～50%腸原發(fā)GIST為惡性，表現(xiàn)為局部復(fù)發(fā)、腹腔轉(zhuǎn)移及肝臟轉(zhuǎn)移，淋巴結(jié)轉(zhuǎn)移較罕見[21]。目前，文獻(xiàn)報(bào)道20例GIST有淋巴結(jié)轉(zhuǎn)移，均為個(gè)案報(bào)道。2006～2016年NCCN指南中關(guān)于GIST淋巴結(jié)轉(zhuǎn)移的處理意見：由于GIST發(fā)生淋巴結(jié)轉(zhuǎn)移者少見，所以外科手術(shù)不要求做淋巴結(jié)清掃。2016年NCCN(2版)指南中關(guān)于GIST淋巴結(jié)轉(zhuǎn)移處理更改為“對(duì)于SDH缺乏的GIST患者，需考慮切除病理性腫大的淋巴結(jié)”，隨著文獻(xiàn)報(bào)道GIST淋巴結(jié)轉(zhuǎn)移病例的增多，人們對(duì)GIST淋巴結(jié)轉(zhuǎn)移問(wèn)題重新給予較多的關(guān)注，GIST手術(shù)后是否行淋巴結(jié)清掃再次成為大家關(guān)注的焦點(diǎn)。

本組825例GIST患者中，45例發(fā)生轉(zhuǎn)移，淋巴結(jié)轉(zhuǎn)移者9例(1%)，且發(fā)生淋巴結(jié)轉(zhuǎn)移者幾乎均為腫瘤體積大、風(fēng)險(xiǎn)度高、核分裂象及Ki-67增殖指數(shù)高的患者，提示上述指標(biāo)對(duì)GIST生物學(xué)行為預(yù)測(cè)的有效性。但有1例直徑為2 cm的胃原發(fā)GIST也發(fā)生周圍淋巴結(jié)的轉(zhuǎn)移，這提示在臨床工作中腫瘤大小僅具有參考價(jià)值，如活檢提示組織有限時(shí)或形態(tài)學(xué)難以定論時(shí)或冷凍需要確定手術(shù)范圍時(shí)，腫瘤大者可能偏向惡性，腫瘤小者可能偏向良性[22]。目前，對(duì)于淋巴結(jié)轉(zhuǎn)移的GIST術(shù)前尚無(wú)可預(yù)測(cè)的臨床指標(biāo)，但本組伴有淋巴結(jié)轉(zhuǎn)移的病例均表現(xiàn)為浸潤(rùn)性生長(zhǎng)。因此，對(duì)于顯微鏡下呈浸潤(rùn)性生長(zhǎng)的病例，應(yīng)建議臨床密切隨診，同時(shí)浸潤(rùn)性生長(zhǎng)是否可以作為評(píng)價(jià)GIST生物學(xué)行為的新指標(biāo)有待于進(jìn)一步大宗病例分析。

腫瘤的轉(zhuǎn)移是多步驟、多環(huán)節(jié)過(guò)程，包括腫瘤細(xì)胞自發(fā)性脫落、浸潤(rùn)周圍組織進(jìn)入循環(huán)系統(tǒng)，在遠(yuǎn)隔部位突破毛細(xì)血管形成轉(zhuǎn)移灶，其中新生血管的生成是腫瘤侵襲轉(zhuǎn)移的重要環(huán)節(jié)[23]。癌主要經(jīng)淋巴道轉(zhuǎn)移，肉瘤常常血道轉(zhuǎn)移，文獻(xiàn)對(duì)此現(xiàn)象缺少系統(tǒng)研究。本實(shí)驗(yàn)發(fā)現(xiàn)GIST腫瘤實(shí)質(zhì)內(nèi)無(wú)淋巴管，且呈膨脹性生長(zhǎng)的腫瘤邊緣區(qū)淋巴管也由于受壓而萎縮、塌陷呈閉塞狀，有研究認(rèn)為此類淋巴管屬于無(wú)功能狀態(tài)的淋巴管[5]，這可能是GIST罕見淋巴結(jié)轉(zhuǎn)移的原因。對(duì)于伴有淋巴結(jié)轉(zhuǎn)移的GIST，腫瘤邊緣常常界限不清呈浸潤(rùn)性生長(zhǎng)且局部MVD高于腫瘤實(shí)質(zhì)及非浸潤(rùn)性生長(zhǎng)區(qū)域，腫瘤邊緣可見擴(kuò)張的淋巴管，這可能是其發(fā)生淋巴結(jié)轉(zhuǎn)移的原因。

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Clinicopathologicfeaturesofmetastaticgastrointestinalstromaltumors

WANG Yuan, MENG Gang

(DepartmentofPathology,theSchoolofBasicMedicalCollege,AnhuiMedicalUniversity,Hefei230032,China)

PurposeTo explore the clinicopathologic features of metastatic gastrointestinal stromal tumors (GIST) and the mechanism of lymph node metastasis.Methods45 cases of surgical specimens with metastasis were selected as the research object and 50 cases of primary tumors in the same period were compared. All materials were stained with immunohistochemical method that marked Ki-67, CD31, D2-40, and then micro vessel density (MVD) and lymphatic microvessel density (LMVD) in each group were calculated.ResultsThe total metastatic rate was 5.45%, the blood metastatic rate was 1.33% and the lymph node metastatic rate was 1.09%. MVD of metastatic GIST was 398.39±68.20/mm2and MVD of non-metastatic GIST was 192.07±56.85/mm2, and the difference between them was statistically significant. There was no lymphatic vessels distribution in the essence of GIST regardless of metastasis. About metastatic GIST, LMVD of the edge area of the essence was 13.28±2.40 /mm2and LMVD of normal tissue around the essence was 25.36±6.71/mm2. In regard to non-metastatic GIST, LMVD of the edge area of the essence was 12.21±1.83/mm2and LMVD of normal tissue around the essence was 24.23±8.64/mm2. No statistically significant existed between LMVD of the edge area of the essence and LMVD of normal tissue around the essence. All of the 9 cases of lymph node metastatic GIST and 12 from 86 cases of non-metastatic GIST showed invasive growth.ConclusionMVD of metastatic GIST is higher than that of non-metastatic GIST. There is no lymphatic vessel within the essence of GIST. The invasive growth way may be the cause of the lymph node metastasis.

gastrointestinal neoplasm; gastrointestinal stromal tumors; lymph node metastasis; pathology

時(shí)間：2017-9-18 6:23 網(wǎng)絡(luò)出版地址：http://kns.cnki.net/kcms/detail/34.1073.R.20170918.0623.009.html

R 735

A

1001-7399(2017)09-0982-05

10.13315/j.cnki.cjcep.2017.09.009

接受日期：2017-07-11

安徽醫(yī)科大學(xué)基礎(chǔ)醫(yī)學(xué)院病理學(xué)教研室，合肥 230032

王 源，女，碩士，醫(yī)師。E-mail: 1151285373@qq.com

孟 剛，男，博士，教授，通訊作者。E-mail: menggangbl@163.com