Experimental And Clinical Studies On CT Perfusion Imaging Of Brain Tumor

IntroductionCounting 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.PurposeWith 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 MethodsNine 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.Results1.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 tumorValues 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-maOne 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^-1respectively,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).Conclusion1.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.