【作者】 董印；

【导师】 刘庆伟；

【作者基本信息】 山东大学 ， 影像医学与核医学（专业学位）， 2013， 博士

【摘要】 目的嗜铬细胞瘤(pheochromocytoma)是起源于肾上腺髓质、交感神经节或其它部位嗜铬组织的一种少见肿瘤,具有合成、储存、代谢儿茶酚胺(catecholamine)的功能,部分肿瘤可以释放儿茶酚胺,引起阵发性或持续性高血压和代射紊乱症候群。据报道,尸检发生率约0.005-0.1%。嗜铬细胞瘤大部分为良性,可通过手术切除而治愈,但仍有少部分为恶性,通常认为嗜铬细胞瘤恶性率约10%,但由于人群差异及对恶性嗜铬细胞瘤的诊断标准差别,不同研究报道的恶性率在5-26%之间。恶性嗜铬细胞瘤的临床表现及常规影像学检查均缺乏特异性,在没有明确包膜和血管侵犯的情况下,甚至病理学检查也难以做出恶性嗜铬细胞瘤的诊断,确诊恶性嗜铬细胞瘤的可靠依据是在没有嗜铬细胞的区域发现转移灶,如淋巴结、肝、肺、脊柱等,因此恶性嗜铬细胞瘤诊断的确立常常由影像学家而非病理学家得出。目前常规CT、MR等技术均以发现转移灶作为诊断恶性嗜铬细胞瘤的标准,但此时肿瘤多己进展到晚期,临床治疗极为困难。更为重要的是,并非所有恶性嗜铬细胞瘤在首次就诊时就已经发生转移,因此以转移灶的有无判断嗜铬细胞瘤的良恶性远不能满足临床工作的需要。手术前如果能较为准确地判断嗜铬细胞瘤的性质,对治疗方案的制定、充分的术前检查、手术准备、手术方式和入路选择、术后随访、预后评估具有重要意义,文献报道,准确的术前评估、充分的手术准备可明显降低嗜铬细胞瘤患者的死亡率。磁共振(MR)弥散加权成像(DWI)是一种基于水分子弥散运动的MR成像新技术,表观分布系数(ADC)值的测量可定量反映组织的微观结构信息,间接反映细胞结构和功能信息。尽管结论不一,其在肾上腺原发肿瘤良恶性鉴别上的应用备受国内外学者所关注[9-11]。动态增强扫描(dynamic enhanced imaging)是在三维容积内插体部成像序列(VIBE)基础上通过团注对比剂进行多期增强扫描的一种新技术,由于具有扫描时间短、范围大、容积采集的优势,可间接反映组织灌注情况。本研究尝试通过对嗜铬细胞瘤的磁共振检查资料,尤其DWI、动态增强扫描序列的定量和半定量分析,探讨磁共振动态增强扫描及弥散加权成像对区分肿瘤良、恶性的价值,以期为临床上鉴别良、恶性嗜铬细胞瘤探索诊断线索。方法收集我院2008年9月至2012年1月间因疑诊嗜铬细胞瘤接受MR检查者59例,共63个肿瘤。其中7例患者因扫描参数或检查序列不当(4例)、图像质量不合格(3例)未纳入该研究,另外12例因无病理结果(6例)、诊断错误(3例为乏脂腺瘤)或失访(3例)被排除。共40例患者42个经病理学检查及半年以上术后随访证实的嗜铬细胞瘤纳入本研究。其中男26例,女14例,年龄13-61岁,平均(42.3±2.6)岁。临床症状或体征：具有典型头痛、心悸、多汗“三联征”者6例(3例伴高血压),高血压11例,无症状者23例。化验检查：17例患者血、尿儿茶酚胺升高,其中16例患者24小时尿香草扁桃酸(VMA)含量升高。采用Siemens3.OT Verio磁共振成像仪,以体线圈为射频发射线圈,以腹部相控阵表面线圈为接收线圈。患者取仰卧位,检查范围从膈顶水平至’肾门部,对疑有异位嗜铬细胞瘤者,扫描范围从剑突到盆腔。对可疑嗜铬细胞瘤患者的MR检查,除常规T2WI (TR:3000-4000ms, TE:70-90ms,层厚：5mm,层间隔：0.5mm),化学位移成像外(FA：70。,TR：130ms,TE：2.3(同相位)/3.7(反相位)ms,层厚：5mm,层间隔：0.5mm),均进行DWI及动态增强扫描。每位患者的DWI成像均在动态增强扫描前进行,采用自旋回波单激发平面回波序列(EPI)(TR：2500ms,TE：35ms,层厚：5mm,层间隔：0.5mm),b值为0和800seconds/mm2,动态增强扫描采用三维容积内插的动态增强扫描序列(VIBEXTR:4.1ms, TE:2ms, NEX:0.75,层厚：3mm,层间隔：0),采集对比剂注射前、动脉期及对比剂注射后1、2、3、5分钟共六期图像。最终诊断由手术病理及半年以上随访证实。所有图像均经两名放射科医师(从事体部磁共振诊断5年以上)分别阅片,定性诊断意见不一致时请高一级医师阅片,得出最后结论：定量诊断取其平均值。分析的内容包括：病灶的位置、大小、信号特点、强化特征。所有扫描获得图像传至Siemens Syngo工作站进行图像重建等后处理及测量。通过DWI图像重建ADC图(ADC map),在肿瘤实性部分选取ADC值最低的区域绘制ROI,ROI为圆形或椭圆形,ROI的绘制参考平扫及多期增强扫描MR图像,尽量避开病灶边缘及囊变、坏死部分,以避免部分容积效应及伪影干扰。在ADC图中用圆形兴趣区(ROI)测量病灶实性部分的ADC值,并测量同序列中脾、肾实质的ADC值作对比。对动态增强扫描图像,在动态增强扫描早期图像上选择与ADC值测量区域相近的均匀强化的实性部分,绘制ROI,然后将其复制到其它时相的相应层面和位置,测量病灶实性部分同一部位各期的信号强度,测量结果绘制动态强化信号强度(SI)-时间曲线。手术切除标本进行组织病理及免疫组化分析,肯定恶性诊断的依据是局部或远隔部位淋巴结或其它组织内发现嗜铬细胞瘤；预测嗜铬细胞瘤恶性潜能的依据包括细胞学类型、核分裂像增多、高核／浆比例、肿瘤坏死、包膜侵犯、血管侵犯等。所有确定诊断的嗜铬细胞瘤均进行追踪随访,对病理学检查未发现恶性潜能表现并随访半年以上未见复发或转移者,可确定为良性嗜铬细胞瘤；若随访过程中发现转移灶,不管病理学检查结果如何,均将其确定为恶性。利用SPSS13.0统计软件通过Pearson x2分析肿瘤部位与良恶性的关系,对良、恶性嗜铬细胞瘤患者肿瘤大小、ADC值进行独立样本的t检验,P值<0.05认为有统计学意义。通过绘制ROC曲线、计算曲线下面积分析ADC值在区分良恶性嗜铬细胞瘤中的应用价值,并通过灵敏度、特异度及Youden(?)旨数确定区分嗜铬细胞瘤良恶性ADC阈值。结果本组42个肿瘤均经手术切除,经组织病理(细胞核形态、染色,包膜、血管侵犯情况)及免疫组化分析,结果显示：10例嗜铬细胞瘤患者发现局部淋巴结转移,其中2个病灶累及肾静脉,病理诊断为恶性,另有3例病理学检查为良性、但提示恶性潜能者,在术后随访过程中发现腹膜后淋巴结、肺转移；另29个嗜铬细胞瘤病理学未见明显恶性征象,随访半年以上未见肿瘤复发及转移。经病理检查及半年以上随访证实,27例患者的29个嗜铬细胞瘤(其中1例患者在双侧肾上腺发现三个肿瘤)为良性,13例患者的13个嗜铬细胞瘤为恶性。13个恶性嗜铬细胞瘤中,8个病灶位于肾上腺(均为单发)；5个为异位(肾门3例,腹主动脉旁2例)；异位嗜铬细胞瘤中恶性嗜铬细胞瘤的发生率(5/13)高于肾上腺嗜铬细胞瘤恶性发生率(8/29),但在本研究没有显著性差异(Pearson×2=0.497；P=0.481)。13个恶性嗜铬细胞瘤大小为3.6-12.4cm,平均(6.1±1.7)cm：27个良性嗜铬细胞瘤大小1.7-9.6cm,平均(5.4±1.7)cm。经独立样本t检验,本组病例中良恶性嗜铬细胞瘤大小差别无统计学意义(P=0.062)。本组40例患者42个嗜铬细胞瘤均行常规平扫及弥散加权、动态增强扫描成像,信号均匀者9个(1.7cm-5.1cm),不均匀者18个(2.2-10.6cm),伴有明显囊变、坏死者15个(4.7-12.4cm)。T2WI病变呈均匀或不均匀高信号,双回波序列未见信号衰减,呈均匀或不均匀等或低信号。5个病灶内见斑片状短T1、短T2信号。DWI示病灶均匀或不均匀弥散受限。增强扫描病灶呈均匀或不均匀强化,部分病灶内可见囊变或不规则坏死。在b值为0和800sec/mm-2时,恶性嗜铬细胞瘤的表观分布系数(ADC)明显大于良性嗜铬细胞瘤,分别为(1.175±0.132)×10-3mm2/sec和(0.918±0.124)×10-3mm2/sec,差异具有统计学意义(P<0.001)。ROC曲线分析显示,在b值为0和800sec/mm2时,ADC值测量可以区分嗜铬细胞瘤良恶性(曲线下面积为0.906),阈值取1.016×10-3mm2/sec时,区分良恶性的灵敏度、特异度分别为93.3%和77.8%。40例患者42个肿瘤均进行了动态增强扫描,病变在早期均出现明显强化,在随后的多期扫描中,逐渐廓清。其中9个为均匀一致强化,18个不均匀强化,另外15个表现为伴有中心巨大囊变、坏死的不规则环形强化。通过绘制信号强度(SI)-时间曲线,可以直观的看到：13个单发肿瘤实性部分于动脉早期(20sec)达到峰值,此后迅速廓清,另外29个肿瘤于对比剂注射lmin达到峰值,此后逐渐廓清。与病理结果对照发现：动脉期达到峰值的13个嗜铬细胞瘤均为恶性,另外29个为良性嗜铬细胞瘤。结论在我们的研究中,良、恶性嗜铬细胞瘤弥散加权成像(b值为0和800sec/mm2) ADC值测量有显著性差异,动态增强扫描强化曲线类型亦有所差别。因此,弥散加权成像及动态增强扫描对嗜铬细胞瘤术前良恶性预测及预后评估,尤其对常规检查没有明确转移和血管侵犯的肿瘤,意义更大。更多还原

【Abstract】 Objective; Pheochromocytoma are rare tumors derived from adrenal medulla, sympathetic ganglion and other tissues, some of which can synthesize secrete catecholamine and cause hypertension and dys-metabolism symptoms. Incidence of pheochromocytma was reported to be0.005-0.1%in autopsy. Most of pheochromocytomas are benign which can be cured by operation. However, about10percents (5-26%) of pheochromocytomas are malignant. There was no specific manifestation for malignant pheochromocytomas clinically and routine radiological imaging. It is difficult to make malignancy diagnose even pathologically without evidence of capsular or vascular invasion. Definite diagnosis of malignant pheochromocytomas was based on metastasis to lymph node, liver, lung, spine, et al. So it is usually made by radiologist other than pathologist. However, treatment of malignant pheochromocytoma in such stage is rather difficult, and not all malignant pheochromocytoma metastasize at onset. So it not sufficient for clinical use to made malignancy diagnosis by evidence of metastasis. Full evaluation of pheochromocytoma is very important before operation, especially for prognosis. DWI was appreciated in differentiation of adrenal tumors for its indirect reflecting cell microstructures and function. MR dynamic enhanced imaging was new sequence indirect reflecting tissues perfusion. Quantity and semi-quantity evaluation of ADCs and dynamic contrast-enhanced imaging of pheochromocytomas were employed to determine whether it is useful for differentiating malignant pheochromocytomas from benign ones.Methods:Sixty-three tumors in59patients were examed, and19patients were excluded for under-quality image, no pathology results and mistake diagnosis. Forty patients (26are male,14are female) were included in this study, ageing from13to61(42.3+2.6). Symptoms are headache, palpitation, and sweating. Serine and urine catecholamine and VMA in some cases was above normal level. Siemens3.0T Verio with phase contrast array was employed. Patients was supine and covered from diaphragm to kidney, and elongated to pelvic if ectopic pheochromocytoma was suspected. DWI in addition to T2-weighted sequences, chemical shift imaging techniques, and dynamic contrast-enhanced MR imaging. In each patient, precontrast single-shot spin-echo echo-planar DWI was performed with b values of0and800seconds/mm’. In each patient,3-dimensional fat-saturated Tl-weighted dynamic contrast enhanced MR imaging (VIBE) was performed at baseline (precontrast), during the arterial phase, and1,2,3, and5minutes after contrast injection. Diagnosis was based on pathologic findings in surgical specimens and more than one years’ followup. Independent samples t test was used to compare ADCs of benign and malignant pheochromocytomas. Receiver operating characteristic curve analysis was used to test the ability of ADCs in differentiating malignant from benign pheochromocytomas. Differences in dynamic contrastenhanced patterns between malignant and benign pheochromocytomas were analyzed. The definite diagnosis was based on pathology and more than half year" follow-up. All images were read by two radiologist without knowing each other, and a high rank radiologist for definite describing diagnosis, and average result was accepted for measurement. Location, size, signal and contrast enhancement was analyzed in Siemens Syngo workstation, ADC map was generated and round or oval ROI was used for measurement of ADC and signal intensity (SI) of enhanced image. SI-time curve w: as drawn with software. Diagnosis was based on pathology and follow up; definite diagnosis of malignancy was based on metastasis at diagnosis or follow up. Pearson×4, independent t test ROC curve was used to do analysis with SPSS13.0. P<0.05was accepted as significant. Threshold was analyzed with sensitivity, specificity, and Youden index.Results:Pathologic diagnoses revealed that10pheochromocytomas with metastasis in lymph node with2ones invading renal vein, the other3without metastasis and invasion manifested by metastasis to lymph node and lung in follow up. So13cases were considered malignancy in this group. Another27patients (three from both adrenal glands of the same patient) were benign. Eight of13malignant pheochromocytomas were found in adrenal glands and the others are ectopic. Incidence of malignancy ectopic (5/13) was high than that in adrenal gland (8/29), but have no significance (Pearson×2=0.497; P=0.481). Size of13malignant pheochromocytomas arranged from3.6cm to12.4cm (6.1±1.7) while size of benign ones from1.7cm to9.6cm (5.4±1.7), which have no statistic significance (P=0.062) in independent t test. Signals of tumors are homogenous in9cases (1.7cm-5.1cm), non-homogenous in18cases (2.2cm-10.6cm), and cystic or necrotic in15cases(4.7cm-12.4cm). Tumor is homogeneously or non-homogeneously hypertension in T2WI, hypotension in T1WI, non signal cancellation in chemical shift imaging, and hyper T1WI signal intensity in5cases. Diffusion of tumor is homogeneously or non-homogeneously restricted. Tumor was enhanced homogeneously or non-homogeneously after contrast injection。With b values of0and800seconds/mm2,(mean±SD) ADC of malignant pheochromocytomas ([1.175±0.132]×10-3mm2/s) was larger than that of benign ones ([0.918±0.124]×10-3mm2/s), and the difference was significant (P<0.001). Apparent diffusion coefficients obtained with b values of0and800seconds/mm2were effective for distinguishing malignant from benign pheochromocytomas (area under the receiver operating characteristic curve,0.906):A threshold value of1.016×10-3mm2/s permitted distinction with high sensitivity (93.3%) and specificity (77.8%). In contrast-enhanced SI-time curve, malignant pheochromocytomas got peak signal intensity earlier (at arterial phase) than benign ones (1minute after contrast injection), and then wash out gradually. Conclusion:In our study, ADCs in DWimaging with b values of0and800seconds/mm2and dynamic contrast-enhanced pattern of malignant pheochromocytomas were significantly different from that of benign ones, suggesting that DW imaging and dynamic contrastenhanced MR imaging may be useful in preoperative characterization and prognosis of pheochromocytomas, especially for those without obvious metastasis and vascular invasion.更多还原