术中超声引导脑胶质瘤切除及其超声造影与微血管密度关系的研究
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摘要
目的通过应用二维及多普勒超声及其声学造影对脑胶质瘤患者手术进行术中引导，对病灶准确定位，明确病灶范围和与周围结构的关系，实时监测切除的范围和程度；定量分析术中肿瘤的超声造影血流灌注指标，对比分析不同分化程度脑胶质瘤造影定量指标与微血管密度的关系，并对患者进行定期术后生存时间随访，探讨超声影像在指导脑胶质瘤手术入路，评价病理分级，提高手术全切除率和患者生存时间等方面的应用价值。
材料与方法(1)我院2004年10月至2009年2月间经CT或MRI疑为脑胶质瘤(均在术后病理检查证实)的患者113例，术中超声探查使用经无菌处理后的术中探头直接置于硬脑膜或脑表面，完整显示病灶特征及与周围组织和血管的关系，并在手术进行过程中实时扫描，监测病灶的切除情况，手术结束前再次探查有无病灶和血肿残留。术后结合病理诊断，对比不同病理级别脑胶质瘤患者的超声图像特点，对各级别的病灶超声图像进行分析总结。(2)对超声显像提示边界不清的33例患者行超声造影检查，确定病灶位置后，启动超声造影功能，经大隐静脉下段以团注方式注入六氟化硫微泡悬液2．4ml，在注射造影剂同时打开超声计时器，实时观察肿瘤血流灌注情况及增强特点，将原始资料存于仪器硬盘中，造影完成后，启动声学定量分析软件分析图像，根据病灶大小确定感兴趣区，自动绘制时间强度曲线，分析曲线形态，获取定量指标。术后对切除的病灶行常规病理检查，应用免疫组织化学法检测CD34表达状态，参照Weidner计数法，记录肿瘤的微血管密度，并对脑胶质瘤进行病理分级，定量分析造影后不同级别脑胶质瘤血液灌注指标与术后病理微血管密度的相关性。(3)对经术中超声引导切除的脑胶质瘤患者术后建立详细的随访资料，采用电话或门诊或住院随访相结合的方法，对患者生存时间定期随访，随访时间为3个月～50个月，患者临床资料和随访结果在计算机上建立数据库。此外随机选取未经术中超声引导的30例高级别脑胶质瘤患者，随访其生存时间并统计分析与本组研究对象的生存率差异。
结果(1)术中探查病灶显示率100％，所有病灶均可准确定位，在超声引导下对113例脑胶质瘤患者中行全切除80例(71％)，次全切除33例(29％)。脑胶质瘤在超声上表现为不同于正常脑组织和水肿组织的高回声，不同病理分级的脑胶质瘤超声图像表现有其不同的特点，低级别脑胶质瘤与高级别脑胶质瘤在病灶形态、边界、内部回声、周围水肿带、内部血流情况等方面有不同的超声表现。(2)术中超声造影后肿瘤组织回声明显增强，边界显示更加清晰，可以准确实时显示肿瘤的位置、肿瘤内部血管、与邻近血管的关系及肿瘤血流灌注特点，造影前、后病灶内彩色多普勒血流分级差异有统计学意义(P＜0．05)。通过超声造影时间-强度曲线和肿瘤微血管密度分析显示，低级别和高级别脑胶质瘤的造影达峰时间分别为(40．9±6．2)s和(29．8±7．5)s，两组间比较有统计学差异(P＜0．05)；微血管密度值分别46．1±5．5和63．5±6．6，两组间差异有统计学意义(P＜0．05)；不同分化程度的脑胶质瘤超声造影达峰时间与微血管密度之间呈负相关关系(r=-0．79P＜0．05)。(3)113例病人中92例病人随访资料完整，随访率81．4％，随访时间为3个月～50个月。根据术后早期复查的影像学结果判断63例病灶完全切除(69％)，次全切除29例(31％)。病例随访中49例出现局部复发，复发率53．3％，其中45例患者在随访过程中因肿瘤复发死亡。全切除患者的术后生存时间明显长于次全切除患者；低分级胶质瘤患者生存率明显高于高分级胶质瘤患者。对照组30例中28例患者在随访过程中死亡，其生存时间为3～24个月，术后6个月、1年、2年生存率分别为83．3％、43．3％、13．3％；与研究组高级别脑胶质瘤术后6个月、1年、2年生存率94．0％、62．0％、38．0％比较，两组1年及2年生存率有显著性差异(P＜0．05)。
结论(1)术中实时超声引导对脑胶质瘤病灶定位准确、可靠，可指导术者准确入路；同时术中实时监测病灶切除的范围、程度，及时发现残留组织和血肿，有助于保护神经功能和降低手术并发症的发生；且不同级别的脑胶质瘤有不同的超声影像特点，根据此特点再结合患者的术前影像资料，超声可以帮助神经外科医师在术中对脑胶质瘤的病理情况有完整的认识，有利于病理检查的准确性。(2)术中超声造影可以使脑胶质瘤肿瘤组织回声明显增强，边界显示更加清晰，可以准确显示肿瘤的位置，判断手术的切除程度，实时动态地观察微血管的灌注情况，在检测脑胶质瘤血管生成方面具有很大潜力。根据不同分化程度脑胶质瘤超声造影达峰时间与微血管密度的负相关关系，超声造影血液灌注定量指标可以对肿瘤组织的微血管生成情况进行判断，间接反映脑胶质瘤血管生成情况，提示肿瘤内微血管密度，有助于术者准确判定脑胶质病理分级，指导手术切除及术后治疗。(3)脑胶质瘤手术术中借助超声引导，可帮助术者明确肿瘤和周围重要结构的关系，达到最大限度切除肿瘤和保护正常脑组织的目的，增加手术的安全性，减少肿瘤的残留，提高肿瘤的全切率和患者的生存时间。
Objective To observe the scope of the lesion and the relationship with thesurrounding structures,real-time monitoring of resection by using intraoperativeultrasonography and contrast-enhanced ultrasound in patients with cerebral glioma to locatethe lesion;to analyze quantitatively the correlation between the contrast-enhancedultrasound parameters and tumor microvessel density (MVD) of different pathologic gradesof cerebral gliomas,and to follow-up patients regularly postoperative survival time.Theapplication value of intraoperative ultrasonography and contrast-enhanced ultrasound in realtimeguidance and pathological grade analysis was investigated.
Methods (1) 113 patients who were doubted cerebral gliomas by computedtomography (CT) or magnetic resonance (MR) were involved in the study.The ultrasonicprobe was sterilized and placed lightly on the surface of the brain during the operation.Thelocation,extent,characteristics and adjacent tissue of the lesion were observed.Residuals oftumor or hematoma were identified before the operation ending.Combination of pathologicaldiagnosis compared with ultrasound echo characteristic of different pathologic grades ofcerebral gliomas after operation.(2) 33 cases were examined by contrast-enhancedultrasound after the lower segment of great saphenous vein injection of 2.4ml SonoVue,realtimeobservation of tumor blood perfusion and enhance characteristics.The results were recorded and compared with baseline ultrasound.Imaging is completed,start the acousticanalysis software,according to lesion size determine the sense of interest areas,automaticallydraw the time-intensity curves,analysis of curve patterns.The microvessels were counted byimmunostaining with anti-CD34,and the differences of these parameters in cerebral gliomaswere compared and the correlation between contrast-enhanced ultrasound time of maximum(Tmax) and tumor MVD was analyzed.(3) The patients of cerebral gliomas who hadundergone intraoperative ultrasound-guided were regularly followed-up postoperativesurvival time using the telephone or out-patient or in hospital way,following-up time 3months to 50 months.In addition,randomly selected 30 patients of high grade cerebralgliomas that without intraoperative ultrasound-guided,follow-up their survival time andstatistical analysis the differences in the survival time.
Results (1) Lesions were indentified and located with 100% accuracy byintraoperative ultrasonography,enable the neurosurgeon to procure appropriate treatmentadvice.Total removal of the lesion was achieved in 80 cases (71%) and subtotal removal in33 cases (29%).All lesions showed hyperecho compared with normal brain tissue,differentpathologic grades of cerebral gliomas present different ultrasonic appearances.(2) Aftercontrast-enhanced ultrasound,the tumor tissue echo significantly increased,the bordershowed more clear,can real-time display of the tumor location,blood vessels and bloodperfusion characteristics,the lesions in blood classification have statistic significance(P＜0.05)before and after contrast-enhanced ultrasound.The mean of Tmax in the low and high gradecerebral gliomas was (40.9±6.2) s and (29.8±7.5) s,The mean of MVD in the group of thelow and high grade cerebral gliomas was 46.1±5.5 and 63.5±6.6,Tmax with differentiationswas found to have statistic significance,and the MVD in the low and high grade cerebralgliomas was statistically significant.Tmax was negative correlation with MVD (r=-0.79P＜0.05 ).(3) 92 cases of patients in 113 cases with complete follow-up data,follow-up ratewas 81.4 percent,following-up time 3 months to 50 months.Total removal of the lesion was63 cases(69%) and subtotal removal in 29 cases(31%).49 cases appear partial recurrence,recurrence rate 53.3%,45 patients death due to tumor recurrence.Patients with total tumorresection experienced a longer survival time than those patients who had subtotal resection.Survival rate in patients with low grade gliomas was significantly higher than that in patientswith high grade glioma.28 patients died in 30 cases of control group in follow-up process, the survival time of 3～24 months,The postoperative 6 months,1 year and 2 year survivalrates for these patients were 83.3%,43.3% and 13.3%;and research group after 6 months,1year and 2 year survival rates of 94.0%,62.0% and 38.0%,1 year and 2 year survival rateshave statistic significance(P＜0.05).
Conclusion (1) Intraoperative ultrasonography can be helpful to the reliable andaccurate location of the lesions,real-time monitoring of resection and residuals detection oftumor or hematoma.Therefore it can be used to protect neurological function and reducecomplications in cerebral gliomas operation.The intraoperative ultrasonic imaging correlatedto pathologic grades of cerebral gliomas,so intraoperative ultrasonography is valuable ingrading cerebral gliomas.(2) Intraoperative contrast-enhanced ultrasound can enhance theimaging of cerebral gliomas significantly and make the border display more clearly.Thistechniche can accurately show the tumor position,determine the extent of surgical resection,and observe microvascular perfusion in real-time.According to Tmax and MVD negativecorrelation,contrast-enhanced ultrasound parameters can indirectly reflect the information ofMVD in cerebral gliomas,which is help to grade cerebral gliomas,guide surgical resectionand postoperative treatment.(3) Cerebral gliomas operation with intraoperativeultrasonography guidance is helpful for operator to understand the relationship between thelesion and essential surrounding structure,increase the safety of surgery and reduce theresidual tumor.It is of great value in improving total resection rate of the tumor and thesurvival time of patients.
材料与方法(1)我院2004年10月至2009年2月间经CT或MRI疑为脑胶质瘤(均在术后病理检查证实)的患者113例，术中超声探查使用经无菌处理后的术中探头直接置于硬脑膜或脑表面，完整显示病灶特征及与周围组织和血管的关系，并在手术进行过程中实时扫描，监测病灶的切除情况，手术结束前再次探查有无病灶和血肿残留。术后结合病理诊断，对比不同病理级别脑胶质瘤患者的超声图像特点，对各级别的病灶超声图像进行分析总结。(2)对超声显像提示边界不清的33例患者行超声造影检查，确定病灶位置后，启动超声造影功能，经大隐静脉下段以团注方式注入六氟化硫微泡悬液2．4ml，在注射造影剂同时打开超声计时器，实时观察肿瘤血流灌注情况及增强特点，将原始资料存于仪器硬盘中，造影完成后，启动声学定量分析软件分析图像，根据病灶大小确定感兴趣区，自动绘制时间强度曲线，分析曲线形态，获取定量指标。术后对切除的病灶行常规病理检查，应用免疫组织化学法检测CD34表达状态，参照Weidner计数法，记录肿瘤的微血管密度，并对脑胶质瘤进行病理分级，定量分析造影后不同级别脑胶质瘤血液灌注指标与术后病理微血管密度的相关性。(3)对经术中超声引导切除的脑胶质瘤患者术后建立详细的随访资料，采用电话或门诊或住院随访相结合的方法，对患者生存时间定期随访，随访时间为3个月～50个月，患者临床资料和随访结果在计算机上建立数据库。此外随机选取未经术中超声引导的30例高级别脑胶质瘤患者，随访其生存时间并统计分析与本组研究对象的生存率差异。
结果(1)术中探查病灶显示率100％，所有病灶均可准确定位，在超声引导下对113例脑胶质瘤患者中行全切除80例(71％)，次全切除33例(29％)。脑胶质瘤在超声上表现为不同于正常脑组织和水肿组织的高回声，不同病理分级的脑胶质瘤超声图像表现有其不同的特点，低级别脑胶质瘤与高级别脑胶质瘤在病灶形态、边界、内部回声、周围水肿带、内部血流情况等方面有不同的超声表现。(2)术中超声造影后肿瘤组织回声明显增强，边界显示更加清晰，可以准确实时显示肿瘤的位置、肿瘤内部血管、与邻近血管的关系及肿瘤血流灌注特点，造影前、后病灶内彩色多普勒血流分级差异有统计学意义(P＜0．05)。通过超声造影时间-强度曲线和肿瘤微血管密度分析显示，低级别和高级别脑胶质瘤的造影达峰时间分别为(40．9±6．2)s和(29．8±7．5)s，两组间比较有统计学差异(P＜0．05)；微血管密度值分别46．1±5．5和63．5±6．6，两组间差异有统计学意义(P＜0．05)；不同分化程度的脑胶质瘤超声造影达峰时间与微血管密度之间呈负相关关系(r=-0．79P＜0．05)。(3)113例病人中92例病人随访资料完整，随访率81．4％，随访时间为3个月～50个月。根据术后早期复查的影像学结果判断63例病灶完全切除(69％)，次全切除29例(31％)。病例随访中49例出现局部复发，复发率53．3％，其中45例患者在随访过程中因肿瘤复发死亡。全切除患者的术后生存时间明显长于次全切除患者；低分级胶质瘤患者生存率明显高于高分级胶质瘤患者。对照组30例中28例患者在随访过程中死亡，其生存时间为3～24个月，术后6个月、1年、2年生存率分别为83．3％、43．3％、13．3％；与研究组高级别脑胶质瘤术后6个月、1年、2年生存率94．0％、62．0％、38．0％比较，两组1年及2年生存率有显著性差异(P＜0．05)。
结论(1)术中实时超声引导对脑胶质瘤病灶定位准确、可靠，可指导术者准确入路；同时术中实时监测病灶切除的范围、程度，及时发现残留组织和血肿，有助于保护神经功能和降低手术并发症的发生；且不同级别的脑胶质瘤有不同的超声影像特点，根据此特点再结合患者的术前影像资料，超声可以帮助神经外科医师在术中对脑胶质瘤的病理情况有完整的认识，有利于病理检查的准确性。(2)术中超声造影可以使脑胶质瘤肿瘤组织回声明显增强，边界显示更加清晰，可以准确显示肿瘤的位置，判断手术的切除程度，实时动态地观察微血管的灌注情况，在检测脑胶质瘤血管生成方面具有很大潜力。根据不同分化程度脑胶质瘤超声造影达峰时间与微血管密度的负相关关系，超声造影血液灌注定量指标可以对肿瘤组织的微血管生成情况进行判断，间接反映脑胶质瘤血管生成情况，提示肿瘤内微血管密度，有助于术者准确判定脑胶质病理分级，指导手术切除及术后治疗。(3)脑胶质瘤手术术中借助超声引导，可帮助术者明确肿瘤和周围重要结构的关系，达到最大限度切除肿瘤和保护正常脑组织的目的，增加手术的安全性，减少肿瘤的残留，提高肿瘤的全切率和患者的生存时间。
Objective To observe the scope of the lesion and the relationship with thesurrounding structures,real-time monitoring of resection by using intraoperativeultrasonography and contrast-enhanced ultrasound in patients with cerebral glioma to locatethe lesion;to analyze quantitatively the correlation between the contrast-enhancedultrasound parameters and tumor microvessel density (MVD) of different pathologic gradesof cerebral gliomas,and to follow-up patients regularly postoperative survival time.Theapplication value of intraoperative ultrasonography and contrast-enhanced ultrasound in realtimeguidance and pathological grade analysis was investigated.
Methods (1) 113 patients who were doubted cerebral gliomas by computedtomography (CT) or magnetic resonance (MR) were involved in the study.The ultrasonicprobe was sterilized and placed lightly on the surface of the brain during the operation.Thelocation,extent,characteristics and adjacent tissue of the lesion were observed.Residuals oftumor or hematoma were identified before the operation ending.Combination of pathologicaldiagnosis compared with ultrasound echo characteristic of different pathologic grades ofcerebral gliomas after operation.(2) 33 cases were examined by contrast-enhancedultrasound after the lower segment of great saphenous vein injection of 2.4ml SonoVue,realtimeobservation of tumor blood perfusion and enhance characteristics.The results were recorded and compared with baseline ultrasound.Imaging is completed,start the acousticanalysis software,according to lesion size determine the sense of interest areas,automaticallydraw the time-intensity curves,analysis of curve patterns.The microvessels were counted byimmunostaining with anti-CD34,and the differences of these parameters in cerebral gliomaswere compared and the correlation between contrast-enhanced ultrasound time of maximum(Tmax) and tumor MVD was analyzed.(3) The patients of cerebral gliomas who hadundergone intraoperative ultrasound-guided were regularly followed-up postoperativesurvival time using the telephone or out-patient or in hospital way,following-up time 3months to 50 months.In addition,randomly selected 30 patients of high grade cerebralgliomas that without intraoperative ultrasound-guided,follow-up their survival time andstatistical analysis the differences in the survival time.
Results (1) Lesions were indentified and located with 100% accuracy byintraoperative ultrasonography,enable the neurosurgeon to procure appropriate treatmentadvice.Total removal of the lesion was achieved in 80 cases (71%) and subtotal removal in33 cases (29%).All lesions showed hyperecho compared with normal brain tissue,differentpathologic grades of cerebral gliomas present different ultrasonic appearances.(2) Aftercontrast-enhanced ultrasound,the tumor tissue echo significantly increased,the bordershowed more clear,can real-time display of the tumor location,blood vessels and bloodperfusion characteristics,the lesions in blood classification have statistic significance(P＜0.05)before and after contrast-enhanced ultrasound.The mean of Tmax in the low and high gradecerebral gliomas was (40.9±6.2) s and (29.8±7.5) s,The mean of MVD in the group of thelow and high grade cerebral gliomas was 46.1±5.5 and 63.5±6.6,Tmax with differentiationswas found to have statistic significance,and the MVD in the low and high grade cerebralgliomas was statistically significant.Tmax was negative correlation with MVD (r=-0.79P＜0.05 ).(3) 92 cases of patients in 113 cases with complete follow-up data,follow-up ratewas 81.4 percent,following-up time 3 months to 50 months.Total removal of the lesion was63 cases(69%) and subtotal removal in 29 cases(31%).49 cases appear partial recurrence,recurrence rate 53.3%,45 patients death due to tumor recurrence.Patients with total tumorresection experienced a longer survival time than those patients who had subtotal resection.Survival rate in patients with low grade gliomas was significantly higher than that in patientswith high grade glioma.28 patients died in 30 cases of control group in follow-up process, the survival time of 3～24 months,The postoperative 6 months,1 year and 2 year survivalrates for these patients were 83.3%,43.3% and 13.3%;and research group after 6 months,1year and 2 year survival rates of 94.0%,62.0% and 38.0%,1 year and 2 year survival rateshave statistic significance(P＜0.05).
Conclusion (1) Intraoperative ultrasonography can be helpful to the reliable andaccurate location of the lesions,real-time monitoring of resection and residuals detection oftumor or hematoma.Therefore it can be used to protect neurological function and reducecomplications in cerebral gliomas operation.The intraoperative ultrasonic imaging correlatedto pathologic grades of cerebral gliomas,so intraoperative ultrasonography is valuable ingrading cerebral gliomas.(2) Intraoperative contrast-enhanced ultrasound can enhance theimaging of cerebral gliomas significantly and make the border display more clearly.Thistechniche can accurately show the tumor position,determine the extent of surgical resection,and observe microvascular perfusion in real-time.According to Tmax and MVD negativecorrelation,contrast-enhanced ultrasound parameters can indirectly reflect the information ofMVD in cerebral gliomas,which is help to grade cerebral gliomas,guide surgical resectionand postoperative treatment.(3) Cerebral gliomas operation with intraoperativeultrasonography guidance is helpful for operator to understand the relationship between thelesion and essential surrounding structure,increase the safety of surgery and reduce theresidual tumor.It is of great value in improving total resection rate of the tumor and thesurvival time of patients.
引文
1周良辅．现代神经外科学．上海：上海医科大学出版社，2001，375-376
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