MiT家族易位性腎細(xì)胞癌:15例患者影像學(xué)特征

劉 偉 陸亞文 劉曉航 高洪波 湯 偉 周良平△

(1復(fù)旦大學(xué)附屬腫瘤醫(yī)院放射診斷科,3病理科 上海 200032; 2上海市影像醫(yī)學(xué)研究所 上海 200032; 4復(fù)旦大學(xué)上海醫(yī)學(xué)院腫瘤學(xué)系 上海 200032)

2016版WHO腎臟腫瘤分類將Xp11.2/TFE3基因易位性腎癌(renal cell carcinoma with Xp11.2 translocations/TFE3 gene fusion,Xp11.2 RCC)與t(6;11) (p21;q12)基因易位性RCC[renal cell carcinoma with t(6;11) (p21;q12),t(6;11)RCC]一起歸入MiT家族易位性腎細(xì)胞癌(renal cell carcinoma,RCC)[1]。Xp11.2 RCC少見,好發(fā)于兒童,占兒童RCC的20%～40%,僅占成人RCC的1%～1.6%[2]。t(6;11)RCC更為罕見,截至2016年報(bào)道僅50余例,預(yù)后較Xp11.2 RCC好[3]。雖然對(duì)Xp11.2 RCC的影像學(xué)特征已有一些總結(jié)[4-6],但仍不足以建立一個(gè)清晰的影像診斷系統(tǒng),而對(duì)t(6;11)RCC描述較為詳細(xì)的影像學(xué)研究?jī)H檢索到1篇[7]。本研究旨在對(duì)MiT家族易位性RCC的影像征象進(jìn)行探究,以期為其術(shù)前診斷提供一定的提示價(jià)值。

資 料 和 方 法

病例來源篩選2013年1月至2017年1月于復(fù)旦大學(xué)附屬腫瘤醫(yī)院術(shù)前行CT和/或MRI檢查并經(jīng)手術(shù)病理證實(shí)的15例MiT家族易位性RCC患者,包括14例Xp11.2 RCC和1例t(6;11)RCC。其中3例行CT和MRI檢查,5例行CT檢查,7例行MRI檢查。

影像學(xué)檢查CT為西門子64排MDCT(電壓120 kV、電流200 mA)。均行平掃及動(dòng)態(tài)增強(qiáng)掃描,采用碘造影劑歐乃派克300,經(jīng)肘靜脈以3.0 mL/s的速率注射90 mL,注射30～35 s后行皮質(zhì)期掃描,65～70s后行實(shí)質(zhì)期掃描。MRI采用3.0T Signa MR掃描儀。掃描參數(shù):層厚5～8 mm,層間距0.5～2.0 mm,掃描序列包括擾相梯度回波(spoiled gradient echo,SPRG)正相位(in-phase) (TR:150～230 ms,TE:1.4～2.4 ms)和反相位(out-phase) (TR:150～230 ms,TE:3.2～4.6 ms)T1WI序列和脂肪抑制快速自旋回波(TR:3 200～4 000 ms,TE:78～92 ms)T2WI序列。動(dòng)態(tài)增強(qiáng)掃描采用屏氣脂肪抑制的肝臟快速三維容積采集(3D gradient recalled echo,3D-LAVA)序列(TR:2.6～3.2 ms,TE:1.2～1.5 ms),造影劑為馬根維顯(Gd-DTPA,德國(guó)拜爾先靈公司),經(jīng)靜脈以2 mL/s的速率注射15 mL,注射20 s后行皮質(zhì)期掃描,70 s后行實(shí)質(zhì)期掃描。

影像及數(shù)據(jù)分析2位具有5～10年臨床診斷經(jīng)驗(yàn)的放射科醫(yī)師來分析影像學(xué)特征,包括腫瘤的位置、大小、壞死、出血、鈣化、形狀、邊緣、脂肪、均質(zhì)性、轉(zhuǎn)移、密度特征(平掃CT:CTtumour-CTrenal≥10 Hu為稍高密度,≥20 Hu為高密度,<10 Hu為等密度[4])、信號(hào)特征等。ROI的選取均在腫瘤的實(shí)性部位,避開鈣化,以避免局部容積效應(yīng)。在面積為40 mm2的ROI內(nèi)取3次平均值,獲取CT值。

病理檢查2名具有5～10年經(jīng)驗(yàn)的病理科醫(yī)師進(jìn)行病理診斷。在標(biāo)本上常規(guī)取材、脫水、HE染色,13例行免疫組化檢測(cè),15例采用熒光原位雜交技術(shù)(fluorescencein-situhybri dization,FISH)檢測(cè)TFE-3和TFE-B基因。

結(jié) 果

臨床特征14例Xp11.2 RCC患者平均年齡(26±7)歲(14～42歲),臨床特征見表1。1例t(6;11)RCC患者,29歲,男性,因肉眼血尿入院,觸及包塊,未見其他癥狀。

表1 14例Xp11.2 RCC的臨床資料Tab 1 Clinic date of 14 cases with Xp11.2 RCC

影像學(xué)征象14例Xp11.2 RCC中,腫塊主體位于腎髓質(zhì)12例,最大徑為 (5.6±1.5)cm(3.2～8.0 cm),形態(tài)規(guī)則12例,邊緣清晰11例,周圍脂肪浸潤(rùn)1例,腹膜后淋巴結(jié)轉(zhuǎn)移3例,遠(yuǎn)處轉(zhuǎn)移(肺)1例,下腔靜脈有癌栓1例。8例CT征象見表2,9例MRI征象見表3。

1例t(6;11) RCC在MRI上表現(xiàn)為類圓形不均勻信號(hào)腫塊,最大徑約16 cm,邊緣清晰,內(nèi)見出血,主體位于腎實(shí)質(zhì)內(nèi)。信號(hào)混雜,主體信號(hào)在T1WI上稍高,在T2WI上稍低,呈不均勻持續(xù)性中度強(qiáng)化。

病理結(jié)果Xp11.2 RCC鏡下細(xì)胞排列可呈巢狀、腺泡狀、腺管狀,內(nèi)可見透明細(xì)胞或嗜鉻細(xì)胞乳 頭狀形態(tài),伴有大量砂粒體。t(6;11)RCC鏡下癌細(xì)胞呈巢狀排列,由兩種上皮細(xì)胞組成,其中形態(tài)較小的上皮細(xì)胞圍繞著玻璃樣變的基底膜樣物質(zhì)形成菊形團(tuán)樣結(jié)構(gòu),腫瘤周邊常見內(nèi)陷的腎小管。13例免疫組化病例檢查發(fā)現(xiàn)特異性標(biāo)記物TFE-3 (2例弱陽(yáng)性、9例陽(yáng)性)和TFEB(1例陽(yáng)性),另外可見一些指標(biāo)呈陽(yáng)性表現(xiàn):Vimentin(7例)、CD10(7例)、Ki67(9例)、PTEN(8例)、EGFR(10例)、VEGF(10例)等。FISH法檢測(cè)t(Xp11.2)(TFE-3),14例腫瘤細(xì)胞(≥5%)內(nèi)有紅綠分離信號(hào),即有TFE-3基因相關(guān)易位;FISH法檢測(cè)t(6;11)(TFEB),1例腫瘤細(xì)胞(20%)內(nèi)有紅綠分離信號(hào),即有TFEB基因相關(guān)易位。

表2 8例Xp11.2 RCC的CT征象Tab 2 CT imaging findings of 8 cases with Xp11.2 RCC

aUnenhanced tumor Hu was classified as slightly high if greater than 10 HU and high greater than 20 Hu compared to normal renal cortex.

表3 9例Xp11.2 RCC的MRI表現(xiàn) Tab 3 MRI features of 9 cases of Xp11.2 RCC

討 論

目前分子遺傳學(xué)檢測(cè)(如FISH法)是診斷MiT易位性RCC的最佳標(biāo)準(zhǔn)[8-11],但耗時(shí)較長(zhǎng)。Xp11.2 RCC好發(fā)于兒童及年輕人,且以女性多見(14例中13例在30歲以下,男∶女=1∶2.5),可能是因?yàn)榕缘腦染色體量更多,基因的易位往往發(fā)生在活躍的X染色體上[10]。臨床上Xp11.2 RCC可表現(xiàn)為側(cè)腹痛、腹部包塊,也可無癥狀,因此無特異性。但血尿出現(xiàn)的概率相對(duì)其他RCC略高。Xp11.2 RCC患者中約1/3出現(xiàn)轉(zhuǎn)移[12],本組研究中有27%的患者出現(xiàn)了轉(zhuǎn)移。

Xp11.2 RCC在影像學(xué)上主要表現(xiàn)為較大[(5.6±1.5)cm]、界清(79%)、規(guī)則(86%)的腫塊,可伴有腹膜后淋巴結(jié)轉(zhuǎn)移(21%),也可伴有遠(yuǎn)處轉(zhuǎn)移及下腔靜脈癌栓,這與多數(shù)既往研究的結(jié)果相符[4-6,13-14]。與病理對(duì)照發(fā)現(xiàn),Xp11.2 RCC有一層不完整的假包膜[15],因而腫塊在CT增強(qiáng)實(shí)質(zhì)期及MRI上表現(xiàn)出清晰的邊緣(圖3),也使其很少累及腎周和腎竇脂肪(14例中僅1例有腎竇脂肪浸潤(rùn))。Chen等[4]及Zhu等[16]等報(bào)道Xp11.2 RCC位于腎髓質(zhì),Liu等[17]報(bào)道5例均位于腎皮質(zhì),而He等[5,13]及Wang 等[6]發(fā)現(xiàn)腫瘤位置多涉及腎皮質(zhì)及實(shí)質(zhì)。我們發(fā)現(xiàn),雖然Xp11.2 RCC的體積較大,但突出腎臟輪廓之外的部分很小,其主體位于腎髓質(zhì)。故我們認(rèn)為,Xp11.2 RCC位于腎髓質(zhì),因其體積較大而向外累及腎皮質(zhì),向內(nèi)與腎集合系統(tǒng)毗鄰。但其他腎臟腫瘤也可位于腎髓質(zhì),如部分腎透明細(xì)胞癌、乳頭狀癌、嫌色細(xì)胞癌、髓樣癌、集合管癌,因此位置的診斷價(jià)值有限。

Xp11.2 RCC在CT上主要表現(xiàn)為混雜密度(75%)(圖1),這與之前的研究相符[4-5,13]。另外,本組研究中有半數(shù)腫瘤出現(xiàn)點(diǎn)片樣鈣化,He等[5,13]認(rèn)為典型者呈環(huán)形分布,本組研究中2例有此表現(xiàn)(圖1、2)。Xp11.2 RCC實(shí)性部分密度較腎皮質(zhì)高,其腫瘤/皮質(zhì)指數(shù)約為1.65,這可能與出血、豐富的蛋白成分、較高的細(xì)胞密度等有關(guān)[15,18]。在MRI上(圖2),Xp11.2 RCC大多為混雜信號(hào)(78%),與腎皮質(zhì)相比,主體信號(hào)在T1WI上稍高(67%),在T2WI上呈低或稍低(89%),且反相位上并無信號(hào)的減低。Liu等[17]的研究與本研究一致,但是Zhong等[19]、Chen等[4]及Wang等[6]研究發(fā)現(xiàn)Xp11.2 RCC在T1WI上為中等或稍低信號(hào),在T2WI上呈稍低信號(hào)。這可能是因?yàn)閄p11.2 RCC內(nèi)部常見出血、囊變壞死、鈣化及含鐵血黃素的沉積[15],因而信號(hào)混雜多變,且不同的設(shè)備、場(chǎng)強(qiáng)、掃描序列對(duì)組織信號(hào)也有影響。MRI因其對(duì)出血檢測(cè)的敏感性,因而其發(fā)現(xiàn)腫瘤內(nèi)部出血(56%)比CT(38%)敏感。Xp11.2 RCC主體位于腎髓質(zhì),易出血,假包膜不完整,且往往較大,這些可能是患者容易出現(xiàn)血尿的原因。

A-B:Unenhanced CT scan showed a heterogeneously slightly hyperdensive mass (45 Hu) compared with renal parenchyma (35 Hu) in the renal medulla and some calcification distributing like a circle.Additionally,patchy hyper-dense part in the neoplasm indicated hemorrhage.C-D:It was less enhancing than the cortex on all phases,while it was more enhancing than the medulla on arterial phase,and less enhancing on nephrographic phase.A clear boundary could be found on enhanced CT scan.

圖126歲女性患者左腎Xp11.2RCC的CT影像
Fig1CTimagingofleftkidneyofa26-year-oldfemalepatientwithXp11.2RCC

CT增強(qiáng)后,Xp11.2 RCC實(shí)性部分強(qiáng)化程度在皮質(zhì)期較腎皮質(zhì)弱而較腎髓質(zhì)高,在實(shí)質(zhì)期較腎皮質(zhì)及髓質(zhì)均低,平掃、皮質(zhì)期、實(shí)質(zhì)期CTtumour/CTcortex分別為1.65、0.51、0.44,CTtumour/CTmedulla分別為1.69、1.30、0.40。MRI T1WI增強(qiáng)上,大多為不均勻持續(xù)性輕中度強(qiáng)化(圖3)。這與之前的研究符合[4-6,14,20]。有研究表明,周圍假包膜呈漸進(jìn)性強(qiáng)化,與腫瘤內(nèi)部實(shí)質(zhì)部分的持續(xù)性強(qiáng)化不同,這種漸進(jìn)性強(qiáng)化的表現(xiàn)也出現(xiàn)在腫瘤壞死囊變區(qū)域的周圍[6]。

A:A circular calcification could be seen on plain CT.B-D:Metastatic Lymph nodes were found in the retroperitoneal area,and inferior vena cava tumor thrombosis was shown on the picture D.E:In the lung some nodes can be seen,which were derived from the left renal tumor confirmed by pathology.F:On this reconstructed 3-dimension image,the tumor was not obviously out of the left renal outline.

圖228歲女性患者左腎Xp11.2RCC且表現(xiàn)為肉眼血尿的MRI影像
Fig2MRIfindingsofgrosshematuriainleftkidneyofa28-year-oldfemalepatientwithXp11.2RCC

A:T1-weighted MR imaging revealed a heterogeneously left renal mass with a large part of slight hyperintensity.B:Reduction of signal intensity could not be found on the out-phase T1WI.C:T2-weighted MRI showed a mass slightly hypointense relative to the renal parenchyma.D-F:T1-weighted enhanced MRI on all phase revealed a heterogeneous mass with persistently slight enhancement,and was less enhancement relative to the renal cortex.A clear boundary was seen on every pictures because of the false capsule sign.

圖313歲男性患者左腎Xp11.2RCC的MRI影像
Fig3MRIfindingsofleftrenalofa13-year-oldmalepatientwithXp11.2RCC

MiT家族易位性RCC需要與其他類型的腎臟腫瘤鑒別。RCC好發(fā)于50～60歲,而 MiT家族易位性RCC好發(fā)于兒童及年輕成人(≤30歲)。腎透明細(xì)胞癌是最常見的RCC,可有壞死囊變、出血及淋巴節(jié)轉(zhuǎn)移[21-22],因而需與Xp11.2 RCC鑒別。但腎透明細(xì)胞癌是富血供腫瘤,其強(qiáng)化廓清較快,外生表現(xiàn)較為常見,且實(shí)性成分較所占比例較大,鈣化少見[13],因而較易鑒別。腎乳頭狀細(xì)胞癌通常表現(xiàn)為邊界清楚的、形狀較規(guī)則的乏血供腫瘤,其密度與腎皮質(zhì)相比呈等或稍高密度[23]。與腎乳頭狀癌相比,Xp11.2 RCC往往較大,囊變壞死改變更加明顯,點(diǎn)片樣鈣化、較高密度的實(shí)性部分及轉(zhuǎn)移的出現(xiàn)也起到一定的提示作用[5,14]。然而2類腎乳頭狀癌往往較大,鈣化出現(xiàn)的概率增加,與Xp11.2 RCC難以鑒別,但Xp11.2 RCC有更清晰的邊緣,更明顯的囊變壞死區(qū)[5],在T2WI上表現(xiàn)為更加混雜的信號(hào)[6]。腎嫌色細(xì)胞癌好發(fā)于腎皮質(zhì),往往呈現(xiàn)較大、界清、均質(zhì)實(shí)性的腫塊,出血及鈣化少見,皮質(zhì)期強(qiáng)化明顯,實(shí)質(zhì)期強(qiáng)化減退,典型者瘤內(nèi)可見延遲強(qiáng)化的輪輻射狀纖維瘢痕[24],因此與Xp11.2 RCC較易鑒別。腎集合管癌多位于中心區(qū)域,大多有腎竇脂肪浸潤(rùn)表現(xiàn),而Xp11.2 RCC很少侵犯腎竇脂肪(1/14例),且多呈浸潤(rùn)性生長(zhǎng),邊緣模糊,因此較易鑒別[16]。乏脂肪血管平滑肌脂肪瘤(angiomyolipoma,AML)血供相對(duì)較多,皮質(zhì)期強(qiáng)化與腎皮質(zhì)接近,實(shí)質(zhì)期減退明顯,鈣化罕見[25-26],有時(shí)在正反相位上能夠發(fā)現(xiàn)微脂肪灶,因而兩者較易鑒別。

本研究中t(6;11) RCC(圖4)為類圓形不均質(zhì)的巨大腫塊,最大徑約16 cm,邊界清晰,這與Zhao等[7]的研究結(jié)果一致。但增強(qiáng)掃描呈持續(xù)性中度強(qiáng)化,而Zhao等[7]認(rèn)為呈漸進(jìn)性強(qiáng)化。腫瘤呈混雜信號(hào),主體信號(hào)在T1WI上較腎皮質(zhì)稍高,在T2WI上稍低,腫塊內(nèi)有出血信號(hào),反相位上未見信號(hào)減低,故與Xp11.2 RCC無法區(qū)分,但兩者最大徑差異較大。我們查閱文獻(xiàn)獲取62例Xp11.2 RCC[6,15,17,27-28]及38例t(6;11) RCC[3,7,29-32]的腫瘤最大徑,采用SPSS 20進(jìn)行獨(dú)立樣本t檢驗(yàn),提示兩者差異有統(tǒng)計(jì)學(xué)意義(P=0.013),這可能是因?yàn)閠(6;11)RCC的惡性度較低而更易形成巨塊。

A-C:Plain T1WI (A and B,in-phase and out-phase) and Axial T2WI (C) showed a large,well-defined,regular mass with slightly high mixed signal intensity on T1WI and slightly low mixed signal intensity on T2WI relative to renal cortex signal.We could see many necrotic focus in the tumor.D-E:The heterogeneous mass on T1-weighted enhanced MRI showed moderate enhancement on all phases.

圖429歲男性患者右腎t(6;11)RCC且表現(xiàn)有肉眼血尿的MRI影像
Fig4MRIfindingsofgrosshematurisainrightkidneyofa29-year-oldmalepatientwitht(6;11)RCC

本研究存在一些不足:(1)樣本量不夠大,尤其是t(6;11) RCC;(2)文獻(xiàn)中所篩選出的腫瘤最大徑評(píng)估標(biāo)準(zhǔn)可能不一;(3)影像資料齊全(CT和MRI)的病例較少。年輕RCC患者若病灶主體部分位于腎髓質(zhì),界清,相對(duì)較大,呈明顯不均質(zhì)表現(xiàn),與其他類型RCC相比,更易發(fā)生壞死囊變,增強(qiáng)呈持續(xù)輕中度強(qiáng)化,其實(shí)性部分強(qiáng)化程度在動(dòng)脈期較腎皮質(zhì)低,較腎髓質(zhì)高,在實(shí)質(zhì)期較腎皮質(zhì)及腎髓質(zhì)均低,則應(yīng)考慮MiT家族易位性RCC可能,若有環(huán)形分布的點(diǎn)片樣鈣化,則可能性增加。目前尚不能完全從影像上區(qū)分Xp11.2 RCC與t(6;11)RCC,腫瘤大小有一定參考價(jià)值。

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