脑肿瘤CT灌注成像的实验与临床研究
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摘要
前言
脑胶质瘤发病率高,约占全部颅内肿瘤的40%,其影像学研究是神经放射学中最富有挑战性的领域之一。脑胶质瘤的恶性程度不同,其治疗方法及预后亦不同,术前正确判断肿瘤的病理学级别及其预后有重要的临床意义。胶质瘤最大的特性就是其浸润性的生长方式,且其浸润的程度不与胶质瘤的等级严格一致,低级星形细胞瘤可以显示出邻近组织的广泛浸润。因此不管其分化程度如何,现有的各种治疗方法均难以达到根治程度,几乎毫无例外地迟早都要复发。手术仍是目前胶质瘤治疗的首选方法,但由于脑手术的特殊性,邻近脑功能区的肿瘤不能做到全切,故术后肿瘤残余是临床常常要面对的问题。术后辅以放疗是临床常采用的手段,充分了解术后肿瘤是否有复发,手术区是否有肿瘤残余或是手术造成的残腔对于放疗方案的制定有重要临床意义。肿瘤发生、生长、浸润及转移均与肿瘤血管生成密切相关,在肿瘤的化疗和放疗等治疗过程中,肿瘤微血管的功能状况决定肿瘤的疗效及预后。常规CT及MRI检查方法虽然在显示颅内肿瘤的形态学信息方面有着无可争议的价值,然而却难以获得肿瘤的病理学分级及肿瘤微血管生成等功能性信息,因此寻找一种便捷、无创且能在活体上重复使用,反映肿瘤微血管功能状况的影像检查方法对于肿瘤的治疗具有重要意义。CT灌注成像(CT perfusion imaging)是一种功能成像,经静脉注射对比剂,同时对某一感兴趣层面进行动态扫描,获得该层面的时间-密度曲线,所用对比剂作为一种生理示踪剂,可准确反映局部微血管的功能状况,从而获得组织的功能方面的信息。
本研究应用CT灌注成像这一新的影像学手段,将最前沿的肿瘤发生机制的研究理念和方法引入现有的影像研究领域,突破传统的影像学研究理念,从研究活体脑内微循环着手,采用动物实验与临床并用的研究手段,并与组织病理学建立起相关性,探讨CT灌注成像在监测脑肿瘤放疗效应及在脑胶质瘤病理分级及术后随访中的价值及作用。
目的
本研究通过对兔脑VX2种植瘤放疗前后CT灌注参数的改变及程度与肿瘤微血管密度的相关性研究,旨在建立活体影像学研究与组织学的相关性,为探讨CT灌注成像能否成为活体检测肿瘤血管生成技术、成为放疗疗效评估及制定治疗方案新的影像学标准提供实验依据。
通过对临床胶质瘤病人的CT灌注成像与胶质瘤病理分级及肿瘤微血管密度的相关性研究,探讨CT灌注成像在术前预测脑胶质瘤恶性程度、评估预后的临床实用价值及探讨CT灌注成像是否能成为活体检测肿瘤微血管密度的影像学手段。
通过对胶质瘤术后病人的CT灌注成像的随访研究,探讨CT灌注成像在鉴别胶质瘤术后复发、残余或手术残腔方面的作用,在胶质瘤术后随访中的意义及价值。
材料与方法
选择9只新西兰白兔作为实验研究对象,采用颅骨钻孔法及颅骨开窗法,在右侧顶叶脑白质区接种VX2瘤组织块制成兔脑VX2肿瘤模型,一周后开始CT增强及CT灌注成像扫描观察肿瘤生长情况,至肿瘤生长至大小4mm以上开始实验研究。将实验兔分成治疗组(4只)及非治疗组(5只),在治疗前一天两组均做CT平扫、增强及CT灌注成像扫描,之后,治疗组做颅脑肿瘤定向放疗,放疗设备为西门子PRIMUS-H型医用电子直线加速器。射线质:6MEV-E电子线。总剂量:100Gy。非治疗组不做处理。放疗一周后,两组实验兔均再次做CT灌注成像扫描。影像资料采集完成后,将实验兔处死取脑。脑组织常规福尔马林固定、石蜡包埋、切片、HE染色,高倍镜下观察瘤细胞并做病理摄片。应用SP法单抗CD34免疫组化染色,采用Weidner法做微血管密度(MVD)计数。CT机为GE Light Speed 16层螺旋CT,应用工作站(AW 4.1)Perfusion 3软件处理获得8个扫描层面的反映、肿瘤灌注功能状态的脑血流量(cerebral blood flow,CBF)、脑血容量(cere-bral blood volume,CBV)、及脑血管表面通透性(permeability surface,PS)伪彩功能图。分别测量瘤区、瘤周区及正常脑组织的各CT灌注参数值(CBF值、CBV值及PS值),采用SPSS11.0统计软件包分析数据,独立样本t检验分别对兔脑VX2种植瘤的肿瘤区与肿瘤周边区、肿瘤区与正常脑组织区、肿瘤周边区与正常脑组织区的CT灌注各参数值(包括rCBF、rCBV、rPS)进行显著性分析,并分别对治疗组与非治疗组放疗前后的CT灌注参数进行显著性分析,取显著性水平α=0.05,P＜0.05被认为差异有统计学意义。所有灌注数值结果以均数±标准差((?)±s)表示。并将治疗组肿瘤放疗后与非治疗组肿瘤区的CT灌注参数值CBV值与肿瘤MVD作Pearson相关性分析,P＜0.05被认为有统计学意义。
经手术病理证实且在术前一个月内在本院做CT灌注成像的胶质瘤病人27例,男:17例,女:10例。年龄:23～73岁,平均38岁。其中低级星形细胞瘤【世界卫生组织(WHO)分级Ⅰ～Ⅱ级】13例:Ⅰ级2例,Ⅱ级11例;高级星形细胞瘤(WHO分级Ⅲ～Ⅳ级)14例:间变型星形细胞瘤8例,多形胶质母细胞瘤6例。测量病变区的CT灌注参数值(CBF值、CBV值及PS值),分别对低级星形细胞瘤、高级星形细胞瘤的CT灌注各参数值进行显著性分析,并将病变区的CT灌注参数值CBF值与CBV值、CBF值与PS值、CBV值与PS值分别做Pearson相关性分析,同时做低级星形细胞瘤与高级星形细胞瘤组的CT灌注CBV值与肿瘤MVD的相关性分析,P＜0.05被认为有统计学意义。
在本院神经外科手术并经病理证实的胶质瘤术后病人36例进行CT灌注成像及MR增强检查影像随访。男17例,女19例。年龄32～73岁,平均43.5岁。其中低级星形细胞瘤【世界卫生组织(WHO)分级Ⅰ～Ⅱ级】19例:Ⅰ级5例,Ⅱ级14例;高级星形细胞瘤(WHO分级Ⅲ～Ⅳ级)16例:间变型星形细胞瘤10例,多形胶质母细胞瘤6例。原始神经外胚层来源恶性瘤1例。CT灌注检查时间为术后17d至4年。分别对肿瘤术后复发残余病例与术后未复发病例、残腔病例、脑组织正常区域;未复发病例与术后残腔病例、脑组织正常区域的CT灌注各参数值(包括CBF、CBV、PS、rCBF、rCBV、rPS)进行显著性分析,取显著性水平α=0.05,P＜0.05被认为差异有统计学意义。
结果
1.兔脑VX2肿瘤治疗组与非治疗组放疗前后CT灌注参数的比较及与肿瘤微血管密度(MVD)的相关性
兔脑VX2肿瘤模型瘤区CBF值、CBV值及PS值均较正常脑组织明显升高,各组瘤区、瘤周区、正常脑组织CT灌注各参数值之间均有明显统计学差异,治疗组放疗后瘤区及瘤周区的CT灌注各参数值较放疗前均有明显下降,与放疗前及非治疗组CT灌注参数有明显统计学差异,治疗组放疗后与非治疗组的CT灌注参数CBV值与肿瘤MVD之间呈明显的正相关(r=0.896,P＜0.01)。
2.低级星形细胞瘤与高级星形细胞瘤的CT灌注参数值比较及CBV值与胶质瘤MVD之间的相关性
2例Ⅰ级星形细胞瘤中1例CT灌注参数值CBF值、CBV值及PS值均表现为正常,另1例CBF值及CBV值升高,分别为67.80±29.05ml.min~(-1).100g~(-1),2.46±0.66ml.100g~(-1),病变区PS值大部为正常,只有1点PS值略升高,为2.67±2.55ml.min~(-1).100g~(-1)。Ⅱ级星形细胞瘤组病变区的CBF值、CBV值及PS值均较正常组织升高,分别为脑正常组织的1.41倍(rCBF 1.41±0.16)、2.31倍(rCBV 2.31±0.28)及6.67倍(rPS 6.67±2.88)。高级星形细胞瘤病变区的CBF值、CBV值及PS值较正常脑组织有明显升高,分别为4.96倍(rCBF4.96±2.17)、4.69倍(rCBV4.69±1.98)及19.19倍(rPS19.19±9.19),二者CT灌注参数值差异均有明显统计学意义,CBV值P＜0.05,CBF值及PS值P＜0.01。低级星形细胞瘤与高级星形细胞瘤的CBV值与肿瘤的MVD之间呈明显的正相关(r=0.809,P＜0.001)。
3.胶质瘤术后复发残余病例、未复发病例及手术残腔病例CT灌注参数比较
36例胶质瘤患者术后经综合影像学检查随访证实复发病例10例,术后残余病例5例,未复发病例17例,术后残腔病例4例。复发残余组CT灌注参数CBF值、CBV值及PS值均升高,rCBF1.99±0.72;rCBV 2.57±0.79;rPS 10.79±5.85,未复发组CBF值及CBV值均降低,多数病例PS值接近正常值,在术后早期复查病例中PS值有增高。术后复发残余组与术后未复发组间的CT灌注参数值差异均有统计学意义(P≤0.001)。4例术后残腔病例病变处CBF值较正常略降低,与复发残余组差异有统计学意义(P＜0.05);CBV值略有增高,与复发组差异无统计学意义(P＞0.05);PS值有较明显升高,与复发残余组差异无统计学意义,与正常脑组织差异有统计学意义。未复发病例组与术后残腔组CBF值差异无统计学意义,P＞0.05,CBV值及PS值二者均有显著性差异,P＜0.01。
结论
1.CT灌注成像能反映脑肿瘤放疗前后的血流动力学改变及程度,CT灌注脑血容量(CBV)值可以作为活体观测肿瘤微血管密度(MVD)的指标。
2.CT灌注图像能很好地反映胶质瘤血流动力学改变,CT灌注图像中CBV及PS图最能反映胶质瘤的血液动力学特点,CBV图能较准确地量化反映胶质瘤病变区的血管生成程度,PS图能较准确地量化反映血脑屏障破坏情况。
3.CBF值、CBV值及PS值与胶质瘤病理级别相关,CT灌注成像对胶质瘤术前分级有较高的临床应用价值。
4.CT灌注成像的CBF、CBV图在确定肿瘤术后是复发残余还是未复发上有肯定性价值。
5.PS值大小能较准确定量反映血脑屏障的破坏程度,但在鉴别肿瘤术后为复发残余还是残腔上PS图无肯定性价值。
Introduction
Counting for about 40%of the total number of intracranial tumors,cerebral glioma remains to be one of the most challenging issues in the field of neuro-ra-diology.Treatment of glioma varies a lot among different degrees of its malignan-cy.Therefore accurate pathological classification and prognosis estimation of the tumor before operation has become critically important for clinical practice.Gli-oma features most with its infiltrative growth pattern,while the infiltrative degree may not be consistently correlated with its pathological classification.A case in point is that low grade astrocytoma may show spread infiltration in the peripheral region.So none of the current therapeutic modalities can promise a radical cure for glioma,no matter how well the tumor differentiates.The recurrence of the tumor seems to be inevitably coming sooner or later.Although surgical operation remains the first choice for glioma by far,operational range of tumor focus is quite limited by important functional cerebral area.As post -operational rem-nant becomes relatively common,sequential radiation therapy is often taken. Whether there is post-operational recurrence,remnant or just residual cavity is vital for planning of further radiation therapy.Since occurrence,development, infiltration,and metastasis of tumor are all closely related to its angiogenesis state,tumor micro-vascular function may determine the final effect and progno-sis of chemical and radiation therapy.True that routine CT and MRI exams are undoubtedly helpful for morphological description of intracranial tumor,it is still unfortunately hard to tell the pathological classification and micro-angiogenesis state with these methods.Thus better treatment of tumor calls for an alternatively easy,non-invasive and safe imaging method to show the tumor micro-vascu- lar function.And CT perfusion imaging seems to be a possible candidate.Being a member of functional imaging family,CT perfusion imaging can provide time -density curve of certain slice of interest after intravenous administration of contrast and dynamic scan of this slice.The contrast applied is a physiological tracer,which accurately shows the local micro-vascular function and also the histological function.
This study used the new radiological method of CT perfusion imaging,in-volving cutting edge research rationale and methods on tumor pathogenesis. Starting with exploration of in-vivo intracranial micro-circulation,this study combined animal experiment and clinical assessment,correlated data with histo-logical and pathological results,and was finally supposed to evaluate CT perfu-sion imaging in effect monitoring of radiation therapy,pathological classifica-tion,and post-operational follow-up of cerebral glioma.
Purpose
With correlative study of CT perfusion parameter change and tumor micro-vascular density change of rat VX2 implanted cerebral tumor after radiation ther-apy,this study was intended to discuss the correlation of in-vivo radiological data and histological results.And this study was also supposed to provide exper-imental basis for evaluation of CT perfusion imaging in measurement of tumor an-giogenesis,effect assessment of radiation therapy,and treatment planning of tumor in-vivo.
With correlative study of CT perfusion imaging,pathological classification, and micro-vascular density of glioma in patients,this study also tried to evalu-ate CT perfusion imaging in pre-operational estimation of malignancy grade of glioma,prognosis expectation of operation,and in-vivo measurement of micro -vascular density.
With post-operational CT perfusion imaging follow-up of patients with glioma,this study finally tried to evaluate CT perfusion imaging in distinguishing of post-operational recurrence,remnant,and residual cavity.
Materials and Methods
Nine New Zealand white rats were involved in this study.Skull perforation and window-open methods were taken.VX2 tumor tissue was planted into right parietal white matter of the rat brain,and CT enhanced and perfusion scans were taken one week later to observe tumor growth state.After the implanted tumors grew to diameter greater than 4mm,all rats were divided into treatment group(n =4)and non-treatment group(n=5).CT plain,enhanced,and perfusion scans were again performed one to two days prior to the treatment.Then rats in treatment group underwent brain directional radiation therapy.Siemens PRIMUS -H medical linear electron accelerator was used and 6MEV-E electron beam as well as 100Gy dose was applied.No intervention was taken in the non-treat-ment group.Another week later,CT perfusion scans were taken once more for both groups and all rats were sacrificed to death thereafter.Brain tissue was then collected and routinely fixed with formalin,berried with paraffin,sliced,HE stained,and observed with microscopy under high magnification,and pathologi-cal photograph was also taken.SP monoclonal CD34 immuno-histo-chemical stain was applied,and Weidner method was used for micro-vascular density (MVD)counting.GE Light Speed 16 spiral CT scanner,AW 4.1 workstation, and Perfusion 3 software were used.From totally 8 slices,three index to cere-bral perfusion function,cerebral blood flow(CBF)map,cerebral blood volume (CBV)map,permeability surface(PS)artificial color map were acquired. CBF,CBV,and PS values were measured within the tumor focus,peripheral to the tumor,and also in the corresponding contralateral normal cerebral area. SPSS11.0 software was applied for independent t tests on 3 pairs of CT perfusion parameters(rCBF,rCBV,rPS included):all parameters within the tumor re-gion and those in peripheral region peripheral to the tumor;parameters within the tumor region and those in the normal cerebral region;parameters in periph-eral region to the tumor and those in the normal cerebral region.Comparisons were also made between CT perfusion parameters before and after the radiation therapy of either treatment or non-treatment group.Criterion ofα=0.05,P＜ 0.05 was taken as statistically significant.All perfusion parameters were shown as mean±standard deviation((?)±s).Pearson correlation study was also made between CBV value and MVD value in treatment group after radiation therapy and in the non-treatment group as well.P＜0.05 was taken as statistically sig-nificant.
Twenty-seven patients with glioma(17 male,10 female,with age ranging from 23 to 73 yrs,and averaged 38 yrs)were involved,and all of them had both pathological results from operation and CT perfusion imaging in our hospital within one month prior to the operation.Among them,there were 13 cases of low- grade astrocytoma(WHO gradeⅠ～Ⅱ,2 inⅠand 11 inⅡ),14 cases of high- grade astrocytoma(WHO gradeⅢ～Ⅳ,8 of intermediate astrocytoma, and 6 of multiform glioblastoma).CT perfusion parameters(CBF,CBV,and PS values)were measured in the focus region.Comparisons were made on all corresponding parameters between low- grade astrocytoma and high- grade as-trocytoma,and Pearson correlation analysis was made for 3 value pairs of CBF and CBV,CBF and PS,CBV and PS,all in the tumor region.Additional corre-lation study was made between CBV and MVD values for both low-grade and high-grade astrocytoma,and P＜0.05 was again chosen as statistically signifi-cant..
Thirty-six post-operational glioma patients(17 male,19 female,with age ranging from 32 to 73 yrs,and averaged 43.5 yrs),and all of them had op-eration in our neuro-surgical department and got pathological results as well as CT perfusion and MR enhanced imaging follow-up of their tumors.Among them,there were 19 cases of low-grade astrocytoma(WHO gradeⅠ～Ⅱ,5 inⅠand 14 inⅡ),16 cases of high-grade astrocytoma(WHO gradeⅢ～Ⅳ,10 of intermediate astrocytoma,and 6 of multiform glioblastoma),and 1 case of ma-lignant tumor generated from primordial neural ectoderm.CT perfusion imaging exams were taken within the 17th day to the 4th year after operation.Independent t-tests were made to compare CT perfusion parameters(CBF,CBV,PS, rCBF,rCBV,rPS)of post-operational recurrent and remnant group with those of non-recurrent group,residual cavity group,and normal cerebral areas.T-tests were also made to compare parameters of non-recurrent group with those of residual cavity group and normal cerebral areas.Criteria ofα=0.05 and P＜0.05 were taken as statistically significant.
Results
1.Comparisons of CT perfusion parameters of rat brain VX2 implanted tumor between measurements before and after radiation therapy in either the treatment group or the non-treatment group;Correlation of CBV and MVD val-ues of tumor
Values of CBF,CBV,and PS within tumor region of rat brain VX2 tumor model were significantly higher than those of normal cerebral region.Statistically significant differences were found among CT perfusion parameters measured within the tumor region,in the peripheral region,and in the normal cerebral re-gion.All CT perfusion parameter values in both the tumor and peripheral regions of the treatment group after radiation therapy,decreased significantly compared with those values prior to the radiation therapy in the same regions of the same group,and parallel values in the non-treatment group as well(P＜0.01). CBV and MVD values were significantly positively correlated with each other in both the treatment group after radiation therapy and the non-treatment group(r =0.896).
2.Comparisons of CT perfusion parameters between low-grade and high-grade astrocytoma;Correlation of CBV and MVD values of the two types of glio-ma
One of the two patients with gradeⅠastrocytoma showed normal CBF, CBV,and PS values.While the other had elevated CBF and CBV values, 67.80±29.05 ml.min~(-1).100g~(-1),2.46±0.66ml.100g~(-1)respectively,and normal PS value in almost the whole tumor region except for a single voxel with PS of 2.67±2.55 ml.min~(-1).100g~(-1).CBF,CBV,and PS values in tumor re-gion of gradeⅡastrocytoma were significantly higher than those in the normal cerebral region,with rCBF of 1.41±0.16,rCBV of 2.31±0.28,and rPS of 6.67±2.88.CBF,CBV,and PS values in tumor region of high-grade astro-cytoma were significantly higher than those in the normal cerebral region,with rCBF of 4.96±2.17,rCBV of 4.69±1.98,rPS of 19.19±9.19.All parame-ters in tumor region of these two grades were also significantly different,and P＜0.05 for CBV value,P＜0.01 for CBF and PS values.CBV and MVD values in tumor region were significantly positively correlated with each other for both low and high grades of astrocytoma(r=0.809).
3.Comparisons of post-operational CT perfusion parameters of glioma ca-ses of recurrent or remnant groups,and those of non-recurrent,residual cavity Ten out of all 36 glioma patients were found with recurrent tumor proved by pathology result from their second operation or by multi-modality radiological follow-up;5 of them were found with remnant tumor;17 were non-recurrent cases;the other 4 were residual cavity.Values of CBF,CBV,and PS of recur-rent and remnant group were significantly higher than those of non-recurrent group(P≤0.001):rCBF1.99±0.72;rCBV 2.57±0.79;rPS 10.79±5.85. For non-recurrent group,CBF and CBV values were significantly lower than those of corresponding normal cerebral area;Most of them showed almost normal PS values;6 of them showed elevated PS values during early post-operational period.For 4 residual cavity cases,CBF values were slightly lower than that of normal,and were significantly different from that of recurrent and remnant group (P＜0.05);CBV values were slightly elevated,and showed no significant difference from that of recurrent and remnant group(P＞0.05);PS values ele-vated significantly than that of normal,but showed no significant difference from that of recurrent and remnant group.No significant difference was found between CBF value of non-recurrent group and that of residual cavity group(P＞0.05),while CBV and PS values were significantly different between the two groups(P＜0.01).
Conclusion
1.CT perfusion imaging is able to reflect hemodynamic changes of brain tumors after radiation therapy.CT perfusion cerebral blood flow(CBV)value can be taken as an index to the mean vascular density(MVD)of tumor in-vi-vo.
2.CT perfusion images can well reflect hemodynamic changes of glioma. And CBV and PS maps are especially good at characterizing hemodynamic status of glioma.CBV map provides quite accurate quantified information of angiogene-sis of glioma focus,while PS map contributes more to the quantified information of damage to the blood-brain barrier.
3.CBF,CBV,and PS values are correlated with pathological grade of glio-ma.And CT perfusion imaging is quite valuable for pre -operational classifica-tion of glioma.
4.CBF,CBV maps in CT perfusion imaging are definitely valuable for dis-tinguishing recurrent from non -recurrent cases after operation.
5.PS value may accurately reflect degree of damage to the blood- brain barrier,but it shows no significant value for differentiation between post-opera-tional recurrence or remnant and residual cavity of glioma.
脑胶质瘤发病率高,约占全部颅内肿瘤的40%,其影像学研究是神经放射学中最富有挑战性的领域之一。脑胶质瘤的恶性程度不同,其治疗方法及预后亦不同,术前正确判断肿瘤的病理学级别及其预后有重要的临床意义。胶质瘤最大的特性就是其浸润性的生长方式,且其浸润的程度不与胶质瘤的等级严格一致,低级星形细胞瘤可以显示出邻近组织的广泛浸润。因此不管其分化程度如何,现有的各种治疗方法均难以达到根治程度,几乎毫无例外地迟早都要复发。手术仍是目前胶质瘤治疗的首选方法,但由于脑手术的特殊性,邻近脑功能区的肿瘤不能做到全切,故术后肿瘤残余是临床常常要面对的问题。术后辅以放疗是临床常采用的手段,充分了解术后肿瘤是否有复发,手术区是否有肿瘤残余或是手术造成的残腔对于放疗方案的制定有重要临床意义。肿瘤发生、生长、浸润及转移均与肿瘤血管生成密切相关,在肿瘤的化疗和放疗等治疗过程中,肿瘤微血管的功能状况决定肿瘤的疗效及预后。常规CT及MRI检查方法虽然在显示颅内肿瘤的形态学信息方面有着无可争议的价值,然而却难以获得肿瘤的病理学分级及肿瘤微血管生成等功能性信息,因此寻找一种便捷、无创且能在活体上重复使用,反映肿瘤微血管功能状况的影像检查方法对于肿瘤的治疗具有重要意义。CT灌注成像(CT perfusion imaging)是一种功能成像,经静脉注射对比剂,同时对某一感兴趣层面进行动态扫描,获得该层面的时间-密度曲线,所用对比剂作为一种生理示踪剂,可准确反映局部微血管的功能状况,从而获得组织的功能方面的信息。
本研究应用CT灌注成像这一新的影像学手段,将最前沿的肿瘤发生机制的研究理念和方法引入现有的影像研究领域,突破传统的影像学研究理念,从研究活体脑内微循环着手,采用动物实验与临床并用的研究手段,并与组织病理学建立起相关性,探讨CT灌注成像在监测脑肿瘤放疗效应及在脑胶质瘤病理分级及术后随访中的价值及作用。
目的
本研究通过对兔脑VX2种植瘤放疗前后CT灌注参数的改变及程度与肿瘤微血管密度的相关性研究,旨在建立活体影像学研究与组织学的相关性,为探讨CT灌注成像能否成为活体检测肿瘤血管生成技术、成为放疗疗效评估及制定治疗方案新的影像学标准提供实验依据。
通过对临床胶质瘤病人的CT灌注成像与胶质瘤病理分级及肿瘤微血管密度的相关性研究,探讨CT灌注成像在术前预测脑胶质瘤恶性程度、评估预后的临床实用价值及探讨CT灌注成像是否能成为活体检测肿瘤微血管密度的影像学手段。
通过对胶质瘤术后病人的CT灌注成像的随访研究,探讨CT灌注成像在鉴别胶质瘤术后复发、残余或手术残腔方面的作用,在胶质瘤术后随访中的意义及价值。
材料与方法
选择9只新西兰白兔作为实验研究对象,采用颅骨钻孔法及颅骨开窗法,在右侧顶叶脑白质区接种VX2瘤组织块制成兔脑VX2肿瘤模型,一周后开始CT增强及CT灌注成像扫描观察肿瘤生长情况,至肿瘤生长至大小4mm以上开始实验研究。将实验兔分成治疗组(4只)及非治疗组(5只),在治疗前一天两组均做CT平扫、增强及CT灌注成像扫描,之后,治疗组做颅脑肿瘤定向放疗,放疗设备为西门子PRIMUS-H型医用电子直线加速器。射线质:6MEV-E电子线。总剂量:100Gy。非治疗组不做处理。放疗一周后,两组实验兔均再次做CT灌注成像扫描。影像资料采集完成后,将实验兔处死取脑。脑组织常规福尔马林固定、石蜡包埋、切片、HE染色,高倍镜下观察瘤细胞并做病理摄片。应用SP法单抗CD34免疫组化染色,采用Weidner法做微血管密度(MVD)计数。CT机为GE Light Speed 16层螺旋CT,应用工作站(AW 4.1)Perfusion 3软件处理获得8个扫描层面的反映、肿瘤灌注功能状态的脑血流量(cerebral blood flow,CBF)、脑血容量(cere-bral blood volume,CBV)、及脑血管表面通透性(permeability surface,PS)伪彩功能图。分别测量瘤区、瘤周区及正常脑组织的各CT灌注参数值(CBF值、CBV值及PS值),采用SPSS11.0统计软件包分析数据,独立样本t检验分别对兔脑VX2种植瘤的肿瘤区与肿瘤周边区、肿瘤区与正常脑组织区、肿瘤周边区与正常脑组织区的CT灌注各参数值(包括rCBF、rCBV、rPS)进行显著性分析,并分别对治疗组与非治疗组放疗前后的CT灌注参数进行显著性分析,取显著性水平α=0.05,P＜0.05被认为差异有统计学意义。所有灌注数值结果以均数±标准差((?)±s)表示。并将治疗组肿瘤放疗后与非治疗组肿瘤区的CT灌注参数值CBV值与肿瘤MVD作Pearson相关性分析,P＜0.05被认为有统计学意义。
经手术病理证实且在术前一个月内在本院做CT灌注成像的胶质瘤病人27例,男:17例,女:10例。年龄:23～73岁,平均38岁。其中低级星形细胞瘤【世界卫生组织(WHO)分级Ⅰ～Ⅱ级】13例:Ⅰ级2例,Ⅱ级11例;高级星形细胞瘤(WHO分级Ⅲ～Ⅳ级)14例:间变型星形细胞瘤8例,多形胶质母细胞瘤6例。测量病变区的CT灌注参数值(CBF值、CBV值及PS值),分别对低级星形细胞瘤、高级星形细胞瘤的CT灌注各参数值进行显著性分析,并将病变区的CT灌注参数值CBF值与CBV值、CBF值与PS值、CBV值与PS值分别做Pearson相关性分析,同时做低级星形细胞瘤与高级星形细胞瘤组的CT灌注CBV值与肿瘤MVD的相关性分析,P＜0.05被认为有统计学意义。
在本院神经外科手术并经病理证实的胶质瘤术后病人36例进行CT灌注成像及MR增强检查影像随访。男17例,女19例。年龄32～73岁,平均43.5岁。其中低级星形细胞瘤【世界卫生组织(WHO)分级Ⅰ～Ⅱ级】19例:Ⅰ级5例,Ⅱ级14例;高级星形细胞瘤(WHO分级Ⅲ～Ⅳ级)16例:间变型星形细胞瘤10例,多形胶质母细胞瘤6例。原始神经外胚层来源恶性瘤1例。CT灌注检查时间为术后17d至4年。分别对肿瘤术后复发残余病例与术后未复发病例、残腔病例、脑组织正常区域;未复发病例与术后残腔病例、脑组织正常区域的CT灌注各参数值(包括CBF、CBV、PS、rCBF、rCBV、rPS)进行显著性分析,取显著性水平α=0.05,P＜0.05被认为差异有统计学意义。
结果
1.兔脑VX2肿瘤治疗组与非治疗组放疗前后CT灌注参数的比较及与肿瘤微血管密度(MVD)的相关性
兔脑VX2肿瘤模型瘤区CBF值、CBV值及PS值均较正常脑组织明显升高,各组瘤区、瘤周区、正常脑组织CT灌注各参数值之间均有明显统计学差异,治疗组放疗后瘤区及瘤周区的CT灌注各参数值较放疗前均有明显下降,与放疗前及非治疗组CT灌注参数有明显统计学差异,治疗组放疗后与非治疗组的CT灌注参数CBV值与肿瘤MVD之间呈明显的正相关(r=0.896,P＜0.01)。
2.低级星形细胞瘤与高级星形细胞瘤的CT灌注参数值比较及CBV值与胶质瘤MVD之间的相关性
2例Ⅰ级星形细胞瘤中1例CT灌注参数值CBF值、CBV值及PS值均表现为正常,另1例CBF值及CBV值升高,分别为67.80±29.05ml.min~(-1).100g~(-1),2.46±0.66ml.100g~(-1),病变区PS值大部为正常,只有1点PS值略升高,为2.67±2.55ml.min~(-1).100g~(-1)。Ⅱ级星形细胞瘤组病变区的CBF值、CBV值及PS值均较正常组织升高,分别为脑正常组织的1.41倍(rCBF 1.41±0.16)、2.31倍(rCBV 2.31±0.28)及6.67倍(rPS 6.67±2.88)。高级星形细胞瘤病变区的CBF值、CBV值及PS值较正常脑组织有明显升高,分别为4.96倍(rCBF4.96±2.17)、4.69倍(rCBV4.69±1.98)及19.19倍(rPS19.19±9.19),二者CT灌注参数值差异均有明显统计学意义,CBV值P＜0.05,CBF值及PS值P＜0.01。低级星形细胞瘤与高级星形细胞瘤的CBV值与肿瘤的MVD之间呈明显的正相关(r=0.809,P＜0.001)。
3.胶质瘤术后复发残余病例、未复发病例及手术残腔病例CT灌注参数比较
36例胶质瘤患者术后经综合影像学检查随访证实复发病例10例,术后残余病例5例,未复发病例17例,术后残腔病例4例。复发残余组CT灌注参数CBF值、CBV值及PS值均升高,rCBF1.99±0.72;rCBV 2.57±0.79;rPS 10.79±5.85,未复发组CBF值及CBV值均降低,多数病例PS值接近正常值,在术后早期复查病例中PS值有增高。术后复发残余组与术后未复发组间的CT灌注参数值差异均有统计学意义(P≤0.001)。4例术后残腔病例病变处CBF值较正常略降低,与复发残余组差异有统计学意义(P＜0.05);CBV值略有增高,与复发组差异无统计学意义(P＞0.05);PS值有较明显升高,与复发残余组差异无统计学意义,与正常脑组织差异有统计学意义。未复发病例组与术后残腔组CBF值差异无统计学意义,P＞0.05,CBV值及PS值二者均有显著性差异,P＜0.01。
结论
1.CT灌注成像能反映脑肿瘤放疗前后的血流动力学改变及程度,CT灌注脑血容量(CBV)值可以作为活体观测肿瘤微血管密度(MVD)的指标。
2.CT灌注图像能很好地反映胶质瘤血流动力学改变,CT灌注图像中CBV及PS图最能反映胶质瘤的血液动力学特点,CBV图能较准确地量化反映胶质瘤病变区的血管生成程度,PS图能较准确地量化反映血脑屏障破坏情况。
3.CBF值、CBV值及PS值与胶质瘤病理级别相关,CT灌注成像对胶质瘤术前分级有较高的临床应用价值。
4.CT灌注成像的CBF、CBV图在确定肿瘤术后是复发残余还是未复发上有肯定性价值。
5.PS值大小能较准确定量反映血脑屏障的破坏程度,但在鉴别肿瘤术后为复发残余还是残腔上PS图无肯定性价值。
Introduction
Counting for about 40%of the total number of intracranial tumors,cerebral glioma remains to be one of the most challenging issues in the field of neuro-ra-diology.Treatment of glioma varies a lot among different degrees of its malignan-cy.Therefore accurate pathological classification and prognosis estimation of the tumor before operation has become critically important for clinical practice.Gli-oma features most with its infiltrative growth pattern,while the infiltrative degree may not be consistently correlated with its pathological classification.A case in point is that low grade astrocytoma may show spread infiltration in the peripheral region.So none of the current therapeutic modalities can promise a radical cure for glioma,no matter how well the tumor differentiates.The recurrence of the tumor seems to be inevitably coming sooner or later.Although surgical operation remains the first choice for glioma by far,operational range of tumor focus is quite limited by important functional cerebral area.As post -operational rem-nant becomes relatively common,sequential radiation therapy is often taken. Whether there is post-operational recurrence,remnant or just residual cavity is vital for planning of further radiation therapy.Since occurrence,development, infiltration,and metastasis of tumor are all closely related to its angiogenesis state,tumor micro-vascular function may determine the final effect and progno-sis of chemical and radiation therapy.True that routine CT and MRI exams are undoubtedly helpful for morphological description of intracranial tumor,it is still unfortunately hard to tell the pathological classification and micro-angiogenesis state with these methods.Thus better treatment of tumor calls for an alternatively easy,non-invasive and safe imaging method to show the tumor micro-vascu- lar function.And CT perfusion imaging seems to be a possible candidate.Being a member of functional imaging family,CT perfusion imaging can provide time -density curve of certain slice of interest after intravenous administration of contrast and dynamic scan of this slice.The contrast applied is a physiological tracer,which accurately shows the local micro-vascular function and also the histological function.
This study used the new radiological method of CT perfusion imaging,in-volving cutting edge research rationale and methods on tumor pathogenesis. Starting with exploration of in-vivo intracranial micro-circulation,this study combined animal experiment and clinical assessment,correlated data with histo-logical and pathological results,and was finally supposed to evaluate CT perfu-sion imaging in effect monitoring of radiation therapy,pathological classifica-tion,and post-operational follow-up of cerebral glioma.
Purpose
With correlative study of CT perfusion parameter change and tumor micro-vascular density change of rat VX2 implanted cerebral tumor after radiation ther-apy,this study was intended to discuss the correlation of in-vivo radiological data and histological results.And this study was also supposed to provide exper-imental basis for evaluation of CT perfusion imaging in measurement of tumor an-giogenesis,effect assessment of radiation therapy,and treatment planning of tumor in-vivo.
With correlative study of CT perfusion imaging,pathological classification, and micro-vascular density of glioma in patients,this study also tried to evalu-ate CT perfusion imaging in pre-operational estimation of malignancy grade of glioma,prognosis expectation of operation,and in-vivo measurement of micro -vascular density.
With post-operational CT perfusion imaging follow-up of patients with glioma,this study finally tried to evaluate CT perfusion imaging in distinguishing of post-operational recurrence,remnant,and residual cavity.
Materials and Methods
Nine New Zealand white rats were involved in this study.Skull perforation and window-open methods were taken.VX2 tumor tissue was planted into right parietal white matter of the rat brain,and CT enhanced and perfusion scans were taken one week later to observe tumor growth state.After the implanted tumors grew to diameter greater than 4mm,all rats were divided into treatment group(n =4)and non-treatment group(n=5).CT plain,enhanced,and perfusion scans were again performed one to two days prior to the treatment.Then rats in treatment group underwent brain directional radiation therapy.Siemens PRIMUS -H medical linear electron accelerator was used and 6MEV-E electron beam as well as 100Gy dose was applied.No intervention was taken in the non-treat-ment group.Another week later,CT perfusion scans were taken once more for both groups and all rats were sacrificed to death thereafter.Brain tissue was then collected and routinely fixed with formalin,berried with paraffin,sliced,HE stained,and observed with microscopy under high magnification,and pathologi-cal photograph was also taken.SP monoclonal CD34 immuno-histo-chemical stain was applied,and Weidner method was used for micro-vascular density (MVD)counting.GE Light Speed 16 spiral CT scanner,AW 4.1 workstation, and Perfusion 3 software were used.From totally 8 slices,three index to cere-bral perfusion function,cerebral blood flow(CBF)map,cerebral blood volume (CBV)map,permeability surface(PS)artificial color map were acquired. CBF,CBV,and PS values were measured within the tumor focus,peripheral to the tumor,and also in the corresponding contralateral normal cerebral area. SPSS11.0 software was applied for independent t tests on 3 pairs of CT perfusion parameters(rCBF,rCBV,rPS included):all parameters within the tumor re-gion and those in peripheral region peripheral to the tumor;parameters within the tumor region and those in the normal cerebral region;parameters in periph-eral region to the tumor and those in the normal cerebral region.Comparisons were also made between CT perfusion parameters before and after the radiation therapy of either treatment or non-treatment group.Criterion ofα=0.05,P＜ 0.05 was taken as statistically significant.All perfusion parameters were shown as mean±standard deviation((?)±s).Pearson correlation study was also made between CBV value and MVD value in treatment group after radiation therapy and in the non-treatment group as well.P＜0.05 was taken as statistically sig-nificant.
Twenty-seven patients with glioma(17 male,10 female,with age ranging from 23 to 73 yrs,and averaged 38 yrs)were involved,and all of them had both pathological results from operation and CT perfusion imaging in our hospital within one month prior to the operation.Among them,there were 13 cases of low- grade astrocytoma(WHO gradeⅠ～Ⅱ,2 inⅠand 11 inⅡ),14 cases of high- grade astrocytoma(WHO gradeⅢ～Ⅳ,8 of intermediate astrocytoma, and 6 of multiform glioblastoma).CT perfusion parameters(CBF,CBV,and PS values)were measured in the focus region.Comparisons were made on all corresponding parameters between low- grade astrocytoma and high- grade as-trocytoma,and Pearson correlation analysis was made for 3 value pairs of CBF and CBV,CBF and PS,CBV and PS,all in the tumor region.Additional corre-lation study was made between CBV and MVD values for both low-grade and high-grade astrocytoma,and P＜0.05 was again chosen as statistically signifi-cant..
Thirty-six post-operational glioma patients(17 male,19 female,with age ranging from 32 to 73 yrs,and averaged 43.5 yrs),and all of them had op-eration in our neuro-surgical department and got pathological results as well as CT perfusion and MR enhanced imaging follow-up of their tumors.Among them,there were 19 cases of low-grade astrocytoma(WHO gradeⅠ～Ⅱ,5 inⅠand 14 inⅡ),16 cases of high-grade astrocytoma(WHO gradeⅢ～Ⅳ,10 of intermediate astrocytoma,and 6 of multiform glioblastoma),and 1 case of ma-lignant tumor generated from primordial neural ectoderm.CT perfusion imaging exams were taken within the 17th day to the 4th year after operation.Independent t-tests were made to compare CT perfusion parameters(CBF,CBV,PS, rCBF,rCBV,rPS)of post-operational recurrent and remnant group with those of non-recurrent group,residual cavity group,and normal cerebral areas.T-tests were also made to compare parameters of non-recurrent group with those of residual cavity group and normal cerebral areas.Criteria ofα=0.05 and P＜0.05 were taken as statistically significant.
Results
1.Comparisons of CT perfusion parameters of rat brain VX2 implanted tumor between measurements before and after radiation therapy in either the treatment group or the non-treatment group;Correlation of CBV and MVD val-ues of tumor
Values of CBF,CBV,and PS within tumor region of rat brain VX2 tumor model were significantly higher than those of normal cerebral region.Statistically significant differences were found among CT perfusion parameters measured within the tumor region,in the peripheral region,and in the normal cerebral re-gion.All CT perfusion parameter values in both the tumor and peripheral regions of the treatment group after radiation therapy,decreased significantly compared with those values prior to the radiation therapy in the same regions of the same group,and parallel values in the non-treatment group as well(P＜0.01). CBV and MVD values were significantly positively correlated with each other in both the treatment group after radiation therapy and the non-treatment group(r =0.896).
2.Comparisons of CT perfusion parameters between low-grade and high-grade astrocytoma;Correlation of CBV and MVD values of the two types of glio-ma
One of the two patients with gradeⅠastrocytoma showed normal CBF, CBV,and PS values.While the other had elevated CBF and CBV values, 67.80±29.05 ml.min~(-1).100g~(-1),2.46±0.66ml.100g~(-1)respectively,and normal PS value in almost the whole tumor region except for a single voxel with PS of 2.67±2.55 ml.min~(-1).100g~(-1).CBF,CBV,and PS values in tumor re-gion of gradeⅡastrocytoma were significantly higher than those in the normal cerebral region,with rCBF of 1.41±0.16,rCBV of 2.31±0.28,and rPS of 6.67±2.88.CBF,CBV,and PS values in tumor region of high-grade astro-cytoma were significantly higher than those in the normal cerebral region,with rCBF of 4.96±2.17,rCBV of 4.69±1.98,rPS of 19.19±9.19.All parame-ters in tumor region of these two grades were also significantly different,and P＜0.05 for CBV value,P＜0.01 for CBF and PS values.CBV and MVD values in tumor region were significantly positively correlated with each other for both low and high grades of astrocytoma(r=0.809).
3.Comparisons of post-operational CT perfusion parameters of glioma ca-ses of recurrent or remnant groups,and those of non-recurrent,residual cavity Ten out of all 36 glioma patients were found with recurrent tumor proved by pathology result from their second operation or by multi-modality radiological follow-up;5 of them were found with remnant tumor;17 were non-recurrent cases;the other 4 were residual cavity.Values of CBF,CBV,and PS of recur-rent and remnant group were significantly higher than those of non-recurrent group(P≤0.001):rCBF1.99±0.72;rCBV 2.57±0.79;rPS 10.79±5.85. For non-recurrent group,CBF and CBV values were significantly lower than those of corresponding normal cerebral area;Most of them showed almost normal PS values;6 of them showed elevated PS values during early post-operational period.For 4 residual cavity cases,CBF values were slightly lower than that of normal,and were significantly different from that of recurrent and remnant group (P＜0.05);CBV values were slightly elevated,and showed no significant difference from that of recurrent and remnant group(P＞0.05);PS values ele-vated significantly than that of normal,but showed no significant difference from that of recurrent and remnant group.No significant difference was found between CBF value of non-recurrent group and that of residual cavity group(P＞0.05),while CBV and PS values were significantly different between the two groups(P＜0.01).
Conclusion
1.CT perfusion imaging is able to reflect hemodynamic changes of brain tumors after radiation therapy.CT perfusion cerebral blood flow(CBV)value can be taken as an index to the mean vascular density(MVD)of tumor in-vi-vo.
2.CT perfusion images can well reflect hemodynamic changes of glioma. And CBV and PS maps are especially good at characterizing hemodynamic status of glioma.CBV map provides quite accurate quantified information of angiogene-sis of glioma focus,while PS map contributes more to the quantified information of damage to the blood-brain barrier.
3.CBF,CBV,and PS values are correlated with pathological grade of glio-ma.And CT perfusion imaging is quite valuable for pre -operational classifica-tion of glioma.
4.CBF,CBV maps in CT perfusion imaging are definitely valuable for dis-tinguishing recurrent from non -recurrent cases after operation.
5.PS value may accurately reflect degree of damage to the blood- brain barrier,but it shows no significant value for differentiation between post-opera-tional recurrence or remnant and residual cavity of glioma.
引文
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8.涂刚,乔天愚,杨光永,等.VX2兔肾癌模型的制作及传代保存.中华泌尿外科杂志,1999,20(3):167.
9.Cenic A,Nabavi DG,Craen RA,et al.A CT method to measure hemodynamics in brain tumors:validation and application of cerebral blood flow maps.AJNR,2000,21(3):462-470.
10.康立清,张云亭,孙世梅.兔VX2脑瘤的模型建立及病理学、影像学初步研究.中华放射学杂志,2005,39(3):306-309.
11.张洪新,王执民,曹玮,等.兔肝VX2移植模型的病理学和影像学表现.西安:第五届全国介入放射学学术大会论文集,2000,5:165-168.
12.Boehm T,Malich A,Goldberg SN,Reichenbach JR,Hilger I,Hauff P,Reinhardt M,Fleck M,Kaiser WA.Radio-frequency tumor ablation:internally cooled electrode versus saline-enhanced technique in an aggressive rabbit tumor model.Radiology 2002;222:805-813.
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15.Hermans R,Lambin P.Non-invasive tumor perfusion measurement by dynamic CT:Preliminary results.Radiother Oncol.1997,44:159-168
16.Folkerth RD.Descriptive analysis and quantification of angiogenesis in human brain tumors.J Neurooncol,2000,50(1-2):165-172.
17.Johnson PC,Hunt SJ,Drayer BP.Human cerebral gliomas:correlation of postmortem MR imaging and neuropathologic findings.Radiology.1989;170:211-217.
18.Jensen JH,Chandra R.MR Imaging of Microvasculature.Magn reson Med 2000;44:224-230.
19.Law M,Cha S,Knopp EA,High-grade gliomas and solitary metastases:differentiation by using perfusion and proton spectroscopic MR imaging.Radiology 2002;222(3):715-21.
20.Weidner N,Barbarishi M,Gasparini G,et al.Microvascular densty qualification in breast carcinoma.Applied Immunhistochemistry,1995;3(2):75-79.
21.Rojiani AM,Dorovini-Zis K.Glomeruloid vascular structures in glioblastoma multiforme:an immunohistochemical and ultrastructural study.J Neurosurg,1996,85(6):1078-1084.
22.Wesseling P,van der Laak JA,Link M,et al.Quantitative analysis of microvascular changes in diffuse astrocytic neoplasms with increasing grade of malignancy.Hum Pathol,1998,29(4):352-358.
23.Leon SP,Folkerth RD,Black PM.Microvessel density is a Prognostic indicator for Patients with astroglial brain tumors.Cancer,1996,77(2):362-372.
24.Tynninen O,Aronen HJ,Ruhala M,et al.MRI enhancement and microvas- cular density in gliomas correlation with tumor cell proliferation.Invest Radiol,1999,34(6):427-434.
25.Lee SJ,Kim JH,Kim YM,et al.Perfusion MR imaging in gliomas:comparison with histologic tumor grade.Korean J Radiol,2001,2(1):1-7.
26.Lam WW,Chan KW,Wong WL,et al.Pre-operative grading of intracranial gliomas.Acta Radiol,2001,42(6):548-554.
27.郑裴群,余永强,柏亚,等.脑胶质瘤血流容积与肿瘤微血管密度的相关性研究.临床放射学杂志,2003,22(11):905-908.
28.ZHENG Feiqun,YU Yongqiang,BAI Ya,et al.Relationship between cerebral blood volume and tumor micro-vessel density in glioma.Journal of Clinical Radiology,2003,22(11):905-908.
29.龙莉玲,魏新华,黄仲奎,等.MR灌注成像在脑星形细胞瘤术前分级中的应用价值.临床放射学杂志,2004,23(9):748-751.
30.LONG Liling,WEI Xinhua,HUANG Zhongkui,et al.Evaluation of perfusion MR imaging in preoperative grading of astrocytoma.Journal of Clinical Radiology,2004,23(9):748-751.
31.Sugahara T,Korogi Y,Kochi M,et al.Correlation of MRI determined cerebral blood volume maps with histologic and angiography determination of vascularity of gliomas.AJR,1998,171(6):1479-1486.
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