MiT家族易位性腎細胞癌:15例患者影像學特征

劉 偉 陸亞文 劉曉航 高洪波 湯 偉 周良平△

(1復旦大學附屬腫瘤醫院放射診斷科,3病理科 上海 200032; 2上海市影像醫學研究所 上海 200032; 4復旦大學上海醫學院腫瘤學系 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家族易位性腎細胞癌(renal cell carcinoma,RCC)[1]。Xp11.2 RCC少見,好發于兒童,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年報道僅50余例,預后較Xp11.2 RCC好[3]。雖然對Xp11.2 RCC的影像學特征已有一些總結[4-6],但仍不足以建立一個清晰的影像診斷系統,而對t(6;11)RCC描述較為詳細的影像學研究僅檢索到1篇[7]。本研究旨在對MiT家族易位性RCC的影像征象進行探究,以期為其術前診斷提供一定的提示價值。

資 料 和 方 法

病例來源篩選2013年1月至2017年1月于復旦大學附屬腫瘤醫院術前行CT和/或MRI檢查并經手術病理證實的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。

影像學檢查CT為西門子64排MDCT(電壓120 kV、電流200 mA)。均行平掃及動態增強掃描,采用碘造影劑歐乃派克300,經肘靜脈以3.0 mL/s的速率注射90 mL,注射30～35 s后行皮質期掃描,65～70s后行實質期掃描。MRI采用3.0T Signa MR掃描儀。掃描參數: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。動態增強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,德國拜爾先靈公司),經靜脈以2 mL/s的速率注射15 mL,注射20 s后行皮質期掃描,70 s后行實質期掃描。

影像及數據分析2位具有5～10年臨床診斷經驗的放射科醫師來分析影像學特征,包括腫瘤的位置、大小、壞死、出血、鈣化、形狀、邊緣、脂肪、均質性、轉移、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])、信號特征等。ROI的選取均在腫瘤的實性部位,避開鈣化,以避免局部容積效應。在面積為40 mm2的ROI內取3次平均值,獲取CT值。

病理檢查2名具有5～10年經驗的病理科醫師進行病理診斷。在標本上常規取材、脫水、HE染色,13例行免疫組化檢測,15例采用熒光原位雜交技術(fluorescencein-situhybri dization,FISH)檢測TFE-3和TFE-B基因。

結 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

影像學征象14例Xp11.2 RCC中,腫塊主體位于腎髓質12例,最大徑為 (5.6±1.5)cm(3.2～8.0 cm),形態規則12例,邊緣清晰11例,周圍脂肪浸潤1例,腹膜后淋巴結轉移3例,遠處轉移(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上表現為類圓形不均勻信號腫塊,最大徑約16 cm,邊緣清晰,內見出血,主體位于腎實質內。信號混雜,主體信號在T1WI上稍高,在T2WI上稍低,呈不均勻持續性中度強化。

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

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 Tab 3 MRI features of 9 cases of Xp11.2 RCC

討 論

目前分子遺傳學檢測(如FISH法)是診斷MiT易位性RCC的最佳標準[8-11],但耗時較長。Xp11.2 RCC好發于兒童及年輕人,且以女性多見(14例中13例在30歲以下,男∶女=1∶2.5),可能是因為女性的X染色體量更多,基因的易位往往發生在活躍的X染色體上[10]。臨床上Xp11.2 RCC可表現為側腹痛、腹部包塊,也可無癥狀,因此無特異性。但血尿出現的概率相對其他RCC略高。Xp11.2 RCC患者中約1/3出現轉移[12],本組研究中有27%的患者出現了轉移。

Xp11.2 RCC在影像學上主要表現為較大[(5.6±1.5)cm]、界清(79%)、規則(86%)的腫塊,可伴有腹膜后淋巴結轉移(21%),也可伴有遠處轉移及下腔靜脈癌栓,這與多數既往研究的結果相符[4-6,13-14]。與病理對照發現,Xp11.2 RCC有一層不完整的假包膜[15],因而腫塊在CT增強實質期及MRI上表現出清晰的邊緣(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)。Chen等[4]及Zhu等[16]等報道Xp11.2 RCC位于腎髓質,Liu等[17]報道5例均位于腎皮質,而He等[5,13]及Wang 等[6]發現腫瘤位置多涉及腎皮質及實質。我們發現,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。故我們認為,Xp11.2 RCC位于腎髓質,因其體積較大而向外累及腎皮質,向內與腎集合系統毗鄰。但其他腎臟腫瘤也可位于腎髓質,如部分腎透明細胞癌、乳頭狀癌、嫌色細胞癌、髓樣癌、集合管癌,因此位置的診斷價值有限。

Xp11.2 RCC在CT上主要表現為混雜密度(75%)(圖1),這與之前的研究相符[4-5,13]。另外,本組研究中有半數腫瘤出現點片樣鈣化,He等[5,13]認為典型者呈環形分布,本組研究中2例有此表現(圖1、2)。Xp11.2 RCC實性部分密度較腎皮質高,其腫瘤/皮質指數約為1.65,這可能與出血、豐富的蛋白成分、較高的細胞密度等有關[15,18]。在MRI上(圖2),Xp11.2 RCC大多為混雜信號(78%),與腎皮質相比,主體信號在T1WI上稍高(67%),在T2WI上呈低或稍低(89%),且反相位上并無信號的減低。Liu等[17]的研究與本研究一致,但是Zhong等[19]、Chen等[4]及Wang等[6]研究發現Xp11.2 RCC在T1WI上為中等或稍低信號,在T2WI上呈稍低信號。這可能是因為Xp11.2 RCC內部常見出血、囊變壞死、鈣化及含鐵血黃素的沉積[15],因而信號混雜多變,且不同的設備、場強、掃描序列對組織信號也有影響。MRI因其對出血檢測的敏感性,因而其發現腫瘤內部出血(56%)比CT(38%)敏感。Xp11.2 RCC主體位于腎髓質,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增強后,Xp11.2 RCC實性部分強化程度在皮質期較腎皮質弱而較腎髓質高,在實質期較腎皮質及髓質均低,平掃、皮質期、實質期CTtumour/CTcortex分別為1.65、0.51、0.44,CTtumour/CTmedulla分別為1.69、1.30、0.40。MRI T1WI增強上,大多為不均勻持續性輕中度強化(圖3)。這與之前的研究符合[4-6,14,20]。有研究表明,周圍假包膜呈漸進性強化,與腫瘤內部實質部分的持續性強化不同,這種漸進性強化的表現也出現在腫瘤壞死囊變區域的周圍[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好發于50～60歲,而 MiT家族易位性RCC好發于兒童及年輕成人(≤30歲)。腎透明細胞癌是最常見的RCC,可有壞死囊變、出血及淋巴節轉移[21-22],因而需與Xp11.2 RCC鑒別。但腎透明細胞癌是富血供腫瘤,其強化廓清較快,外生表現較為常見,且實性成分較所占比例較大,鈣化少見[13],因而較易鑒別。腎乳頭狀細胞癌通常表現為邊界清楚的、形狀較規則的乏血供腫瘤,其密度與腎皮質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,點片樣鈣化、較高密度的實性部分及轉移的出現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[5],在T2WI上表現為更加混雜的信號[6]。腎嫌色細胞癌好發于腎皮質,往往呈現較大、界清、均質實性的腫塊,出血及鈣化少見,皮質期強化明顯,實質期強化減退,典型者瘤內可見延遲強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域,大多有腎竇脂肪浸潤表現,而Xp11.2 RCC很少侵犯腎竇脂肪(1/14例),且多呈浸潤性生長,邊緣模糊,因此較易鑒別[16]。乏脂肪血管平滑肌脂肪瘤(angiomyolipoma,AML)血供相對較多,皮質期強化與腎皮質接近,實質期減退明顯,鈣化罕見[25-26],有時在正反相位上能夠發現微脂肪灶,因而兩者較易鑒別。

本研究中t(6;11) RCC(圖4)為類圓形不均質的巨大腫塊,最大徑約16 cm,邊界清晰,這與Zhao等[7]的研究結果一致。但增強掃描呈持續性中度強化,而Zhao等[7]認為呈漸進性強化。腫瘤呈混雜信號,主體信號在T1WI上較腎皮質稍高,在T2WI上稍低,腫塊內有出血信號,反相位上未見信號減低,故與Xp11.2 RCC無法區分,但兩者最大徑差異較大。我們查閱文獻獲取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進行獨立樣本t檢驗,提示兩者差異有統計學意義(P=0.013),這可能是因為t(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)文獻中所篩選出的腫瘤最大徑評估標準可能不一;(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,界清,相對較大,呈明顯不均質表現,與其他類型RCC相比,更易發生壞死囊變,增強呈持續輕中度強化,其實性部分強化程度在動脈期較腎皮質低,較腎髓質高,在實質期較腎皮質及腎髓質均低,則應考慮MiT家族易位性RCC可能,若有環形分布的點片樣鈣化,則可能性增加。目前尚不能完全從影像上區分Xp11.2 RCC與t(6;11)RCC,腫瘤大小有一定參考價值。

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