摘要
高强度聚焦超声（High intensity focused ultrasound, HIFU）消融技术作为一种安全有效、不开刀、创伤小、恢复快、保留患者器官的治疗手段，其在治疗子宫肌瘤上的应用日益广泛。HIFU消融子宫肌瘤的原理主要是将体外低能量超声波聚焦在肌瘤病灶处，通过焦点区超声波产生的热效应致使靶区内组织发生凝固性坏死，而不损伤靶区外组织。
随着临床治疗病例数的增多，研究者在MRI-T2WI高信号子宫肌瘤是否适合HIFU消融治疗的问题上出现了分歧。有学者认为T2WI高信号者消融常困难，甚至无效，不适合HIFU消融治疗；也有学者认为T2WI高信号肌瘤仅比等低信号者需要较多的辐照能量，消融效果并无明显差异。
本研究旨在通过大样本的研究，对T2WI高信号子宫肌瘤细化分类，从技术成功性的角度评价HIFU消融T2WI高信号子宫肌瘤的安全有效性。通过研究不同亚型T2WI高信号子宫肌瘤及其动态增强MRI上不同的强化程度与消融结果的关系，评价MRI-T2WI和动态增强MRI对HIFU消融T2WI高信号子宫肌瘤疗效的预测作用；通过分析影响HIFU消融基金资助：国家科技支撑计划项目（编号：2011BAI14B01）T2WI高信号子宫肌瘤剂量投放的因素，建立以能效因子（EEF）为基础的HIFU消融T2WI高信号子宫肌瘤的剂量学模型；通过研究HIFU消融复发的T2WI高信号子宫肌瘤，评价二次HIFU消融的疗效；通过对子宫肌瘤标本的研究，分析T2WI高信号子宫肌瘤的生物学特性及其对HIFU消融结果的影响。为HIFU消融治疗子宫肌瘤适应症的选择、治疗方案的优化和规范提供决策依据。
目的
1.评价HIFU消融T2WI高信号子宫肌瘤的技术安全有效性；
2.评价MRI-T2WI和动态增强MRI对HIFU消融T2WI高信号子宫肌瘤消融效果的预测作用；
3.分析影响HIFU消融T2WI高信号子宫肌瘤剂量投放的因素，建立HIFU消融T2WI高信号子宫肌瘤的剂量学模型；
4.评价二次HIFU消融治疗复发T2WI高信号子宫肌瘤的疗效；
5.分析T2WI高信号子宫肌瘤的生物学特性及其对HIFU消融的影响。材料和方法
第一部分
1.研究对象
2010年10月-2013年1月在重庆医科大学附属第一医院接受HIFU消融治疗的子宫肌瘤患者491例，其中符合纳入标准的402例纳入本研究；131例为T2WI高信号子宫肌瘤患者。
2.研究设备
JC型聚焦超声肿瘤治疗系统，由重庆海扶（HIFU）科技股份有限公司生产；核磁共振成像系统，由德国Siemens公司生产。
3.研究方法
（1）术前MRI评估：纳入研究的患者术前行平扫+增强MRI检查，评估子宫位置、大小，肌瘤的数量、大小、位置和T2WI信号强度。所有MRI影像资料均经三位有经验的医师进行评价和测量。
根据T2WI信号强度将子宫肌瘤分为三类：1）低信号：信号强度与骨骼肌大致相当；2）等信号：信号强度高于骨骼肌，但低于子宫肌壁；3）高信号：信号强度等于或大于子宫肌壁。
根据T2WI信号强度和分布情况，将T2WI高信号子宫肌瘤细分为三类：3.1）均匀显著高信号：信号分布均匀，强度明显高于子宫肌壁，接近或等于子宫内膜；3.2）均匀轻度高信号：信号分布均匀，信号强度等于或稍高于子宫肌壁，明显低于子宫内膜；3.3）不均匀高信号：肌瘤内存在片状或条带状（宽度>5mm）接近于子宫内膜信号或骨骼肌信号强度的高低信号影。
根据造影剂注射60秒内增强MRI影像上子宫肌瘤相对于子宫肌层的强化程度，将T2WI高信号子宫肌瘤分为三类：1)轻度强化，肌瘤的强化程度低于子宫肌层，无论均匀与否；2)均匀强化，肌瘤内的强化信号分布均匀，且信号强化程度等于或高于子宫肌层；3)不均匀强化，强化信号分布不均，强化信号和轻度或点片状无强化信号交替分布。
（2）超声消融治疗：由具有超声消融资质的专业医生完成。如果为多发肌瘤，仅仅治疗引起患者症状的单个主要肌瘤，而其它肌瘤暂不做消融治疗。
（3）观察指标：治疗时间、辐照功率、辐照时间、辐照能量，治疗强度,消融效率，能效因子，疼痛发生情况及评分。
（4）术后评估：术后一月内行平扫+增强MRI检查，评估术后的消融率、子宫和肌瘤大小，增强MRI上测量无灌注体积（NPV）。
4.统计方法
统计分析由SPSS17.0统计软件完成。
第二部分
1.研究对象
2010年10月-2013年1月在重庆医科大学附属第一医院接受HIFU治疗的MRI-T2WI高信号子宫肌瘤患者128例。
2.研究设备
同第一部分。
3.研究方法
（1）术前MRI评估：记录肌瘤的位置，肌瘤的类型，子宫的位置，肌瘤大小，肌瘤最大层面腹侧面距离皮肤的距离（即声通道组织厚度），肌瘤最大层面背侧面距离骶尾骨的距离，腹壁厚度,肌瘤T2WI信号类型，肌瘤增强MRI上强化类型等。
根据MRI-T2WI信号强度和分布情况，将子T2WI高信号子宫肌瘤分为不均匀高信号、均匀轻度高信号和均匀显著高信号三类，分类标准同第一部分。
根据增强MRI影像上子宫肌瘤相对于子宫肌层的强化程度，将T2WI高信号子宫肌瘤分为轻度强化、不均匀强化和均匀强化三类，分类标准同第一部分。
（2）超声消融治疗：同第一部分。
（3）观察指标：同第一部分。
（4）术后评估：同第一部分。
4.统计方法
统计分析由SPSS17.0统计软件完成。
第三部分
1.研究对象
2010年10月-2013年1月在重庆医科大学附属第一医院接受两次单纯HIFU治疗的15例MRI-T2WI高信号子宫肌瘤患者。
2.研究设备
同第一部分。
3.研究方法
（1）术前MRI评估：两次HIFU消融治疗前均行平扫+增强MRI，评价肌瘤大小、消融情况、肌瘤变化情况。
（2）超声消融治疗：同第一部分。
（3）观察指标：同第一部分。
（4）术后评估：同第一部分。
4.统计方法
统计分析由SPSS17.0统计软件完成。
第四部分
1.研究对象
2012年4月-2012年12月在重庆医科大学附属第一医院接受“子宫肌瘤剔除术”或“子宫切除术”治疗的子宫肌瘤患者35例，术后取其39个新鲜离体肌瘤标本作为研究对象。
2.研究设备
JC200型聚焦超声肿瘤治疗系统，由重庆海扶科技股份有限公司生产；核磁共振成像系统，由德国Siemens公司生产；石蜡切片机，由北京长源实验设备厂生产；OYLMPUS光学显微镜，由日本Olympus公司生产。
3.研究方法
（1）术前MRI评估：根据MRI-T2WI信号强度和分布情况，将子T2WI高信号子宫肌瘤分为不均匀高信号、均匀轻度高信号和均匀显著高信号三类，分类标准同第一部分。
（2）观察指标：根据质量体积法测量子宫肌瘤标本密度；直接干燥法测量子宫肌瘤水分含量；HE染色及苦味酸天狼猩红染色观察子宫肌瘤标本组织结构；免疫组织化学检测雌孕激素受体表达情况。
（3）HIFU辐照离体标本，用消融设备自带软件测量术中灰度范围，用TTC法测量标本辐照后坏死范围。
4.统计方法
统计分析由SPSS17.0统计软件完成。
结果
第一部分
1.消融结果：T2WI高信号肌瘤的消融率、消融效率明显低于等低信号肌瘤，EEF明显高于后者。T2WI高信号肌瘤中，均匀轻度高信号肌瘤的消融率和消融效率最低，EEF最高；不均高信号和均匀显著高信号肌瘤的消融率、消融效率、EEF与等信号肌瘤无明显差异。
患者耐受性：T2WI均匀轻度高信号肌瘤组患者的疼痛发生率和疼痛评分明显高于低信号组。
2.消融结果：均匀强化组肌瘤的消融率、消融效率明显低于轻度强化和不均匀强化组，而EEF明显高于两者。
患者耐受性：各组间各种疼痛的发生率及总的疼痛发生率无明显差异，均匀强化组患者的疼痛评分明显高于不均匀强化和轻度强化组。
3.消融结果：T2WI均匀轻度高信号组中的均匀强化亚组的消融率和消融效率最低，EEF最高。
患者耐受性：各组间疼痛发生率无明显差异，但是T2WI均匀轻度高信号组中的均匀强化亚组的疼痛评分较高。
三种方法的特异性：T2WI联合动态增强MRI对预测消融困难肌瘤的特异性最高。
第二部分
1.HIFU消融T2WI高信号子宫肌瘤剂量的投放与肌瘤腹侧面到皮肤的距离、肌瘤最大径、肌瘤强化类型、肌瘤T2WI高信号类型有关。
2.HIFU消融T2WI高信号子宫肌瘤的剂量学模型为：y=0.474*X1-0.427*X2+6.212*X3+4.914*X4[y=EEF；X1=肌瘤腹侧面到皮肤的距离；X2=肌瘤最大径；X3=肌瘤强化类型（轻度强化=1、不均匀强化=2、均匀强化=3）；X4=肌瘤T2WI高信号类型（T2WI不均匀高信号=1、均匀显著高信号=2、均匀轻度高信号=3）]
第三部分
1.消融结果：二次HIFU消融复发的T2WI高信号子宫肌瘤，与首次HIFU相比，在消融效率、消融效率和EEF上无明显差异。
患者耐受性：首次HIFU治疗和二次治疗过程疼痛的发生率和疼痛评分无明显差异。
第四部分
1.T2WI均匀轻度高信号肌瘤的组织密度明显低于不均匀高信号和低信号肌瘤，水分含量明显高于低信号肌瘤；T2WI均匀轻度高信号肌瘤的细胞成分丰富，胶原纤维较少，肌瘤组织的ER、PR受体表达水平明显高于不均匀高信号及等低信号肌瘤。
2.HIFU辐照离体肌瘤组织时，T2WI均匀轻度高信号肌瘤术中灰度变化范围和术后坏死范围均小于低信号肌瘤。
结论
1.从技术成功的角度，T2WI不均匀高信号和均匀显著高信号肌瘤容易消融，均匀轻度高信号子宫肌瘤消融困难；动态增强MRI上动脉灌注期呈轻度和不均匀强化的子宫肌瘤容易消融治疗，均匀强化的子宫肌瘤消融困难；动态增强MRI上呈均匀强化的T2WI均匀轻度高信号子宫肌瘤消融最困难。T2WI联合动态增强MRI对预测HIFU消融困难的T2WI高信号子宫肌瘤有较高的特异性。
2.肌瘤腹侧面到皮肤的距离、肌瘤最大径、肌瘤的强化类型、肌瘤的T2WI高信号类型可作为指导HIFU消融T2WI高信号子宫肌瘤临床剂量投放的变量。
3.首次HIFU消融困难的T2WI均匀轻度高信号肌瘤，术后复发行二次单纯HIFU消融治疗仍旧困难。
4. T2WI均匀轻度高信号子宫肌瘤组织密度低、水分含量高、细胞成分丰富、雌孕激素受体表达高，是HIFU消融治疗困难、术后易复发的生物学基础。
High intensity focused ultrasound（HIFU）ablation is safe and feasible,non-surgical, small wound, early recovery, organ-preserving techniques forthe treatment of uterine fibroids.It is widely used for treatment of uterinefibroids. HIFU can create a coagulative necrosis region by hightemperature effect produced by a tightly and precisely focused,high-intensity ultrasound beam, without harming tissues outside of thefocus.
With the increasing use of HIFU in treating uterine fibroids, there aresome differences of opinions in the HIFU ablating uterine fibroids withhyperintense on T2-weighted MR imaging(MRI-T2WI) among researchers.Some people think that it is difficult to ablate and even is invalid, but othersdisagreed with that and they believed hyperintense fibroids only consumedmore sonication energy than isointense fibroids and hypointense fibroids,there are not differences of therapeutic effect.
The objective of this study is to investigate the safety and efficiency of HIFU ablating uterine fibroids with hyperintense on MRI-T2WI by meansof investigating associated cases of large samples, from a technicalstandpoint. The study is to explore the role of MRI-T2WI and dynamiccontrast-enhanced MRI for predicting the difficulties during HIFU ablatinghyperintense fibroids; to analyze affecting factors of sonication energyduring HIFU ablating hyperintense fibroids by building an dosimetrymodel, to evaluate efficacy of the second HIFU by HIFU ablating recurringhyperintense fibroids which are difficult to treat by the first HIFU, toexplore biological characteristics of hyper-intense fibroids and itsinfluence on HIFU ablating by researching the isolated uterine fibroid. Wewant to provide a basis for indications and optimal treatment of HIFUablating hyperintense fibroids.
Purpose
1. To evaluate the safety and efficiency of HIFU ablating uterine fibroidswith hyper-intense on MRI-T2WI from a technical standpoint.
2. To study the role of MRI-T2WI and dynamic contrast-enhanced MRI forpredicting the results of HIFU ablating hyperintense fibroids.
3. To build a dosimetry model of HIFU ablating hyperintense fibroids andanalyze affecting factors of sonication energy.
4. To explore the effect of the second HIFU by HIFU ablating recurringhyperintense fibroids.
5. To explore biological characteristics of hyperintense fibroids and its influence on HIFU ablating.
Materials and methods
Part one
1. Objective
From Octomber2010to January2013,491patients diagnosed withuterine fibroids and scheduled for HIFU were enrolled in the1st AffiliatedHospital of Chongqing Medical University,402patients were inaccordance with the inclusive criteria;131patients with hyperintenseuterine fibroids on MRI-T2WI.
2. Equipments
JC HIFU tumour therapeutic system produced by ChongqingHaifu(HIFU) Tech Co. Ltd; Magnetic resonance imaging system produced byGermany Siemens.
3. Methods
(1) Pretreatment magnetic resonance image evaluation: The plain andenhanced MRI scanning were performed before HIFU ablating in allpatients to evaluate the size, number and position of the uterus and fibroids,and signal intensity of fibroid on MRI-T2WI. All the images were readand measured by three experienced radiologists.
Uterine fibroids were classified as three types on pretreatmentT2-weighted MRI:1) hypointense, signal intensity like skeletal muscle;2)isointense, signal intensity is lower than myometrium but higher than thatof skeletal muscle;3) hyperintense, signal intensity is the same as or higher than myometrium.
Hyperintense fibroids were subjectively classified as three groups:3.1)hetero-geneous hyperintense fibroids were defined as barred (>5mm) orlamellar high signal intensity approximately or equal to endometrium, orbarred (>5mm) or lamellar low signal intensity like skeletal muscle insidethe fibroid;3.2) slightly homogenous hyperintense fibroids were defined asuniformly distributed high signal intensity equal to or slightly higher thanmyometrium;3.3) markedly homogenous hyperintense fibroids were thatof uniformly distributed high signal intensity which was markedly higherthan myometrium and approximately equal to endometrium.
Uterine fibroids were classified as slight enhancement, irregularenhancement and regular enhancement relative to myometrium on the basisof dynamic contrast-enhanced MRI during the60seconds after theinjection of gadolinium:1) Slight enhancement is that the enhancementdegree was lower than that of myometrium;2) Regular enhance-ment isdefined as that of the distribution of enhanced signal is regular and theenhance-ement degree is the same as or higher than that of myometrium;3)Irregular enhance-ment is that the distribution of enhanced signal isirregular and slightly enhanced signal is interspersed among enhancedsignal.
(2) Ultrasound ablation: The operation was completed by qualifiedphysician. When patients had multiple uterine fibroids, only one dominant fibroid was treated.
(3) Main Outcome Measures: treatment time, sonication watt, sonicationtime, sonication energy, therapeutic intensity, ablation efficiency, EEF, painscore.
(4) Posttreatment magnetic resonance image evaluation: The plain andenhanced MRI scanning was performed in a month after HIFU ablating inall patients to evaluate the size of the uterus and fibroids, Non-perfusedvolume (NPV).
4. Statistical methods
Statistical analysis was performed by using SPSS17.0software.Part two
1. Objective
From Octomber2010to January2013,128patients with hyperintenseuterine fibroids on MRI-T2WI who scheduled for HIFU were enrolled inthe1st Affiliated Hospital of Chongqing Medical University.
2. Equipments
Equipment is the same as that of the first part research.
3. Methods
(1) Pretreatment magnetic resonance image evaluation:The size, numberand position of the uterus and fibroids, signal intensity of fibroid onMRI-T2WI and dynamic contrast-enhanced MR imaging，the distance fromfibroid ventral side to skin and fibroid dorsal side to sacral, abdominal wallthickness, hyperintense signal type of fibroids, enhancement type of fibroids are recorded. All the images were read and measured by threeexperienced radiologists.
Uterine fibroids were classified as hypointense, isointense andhyperintense on pretreatment T2-weighted MRI isointense. Classificationcriterias is the same as that of the first part research.
Uterine fibroids were classified as slight enhancement, irregularenhancement and regular enhancement relative to myometrium on the basisof dynamic contrast-enhanced MRI. Classification criterias is the same asthat of the first part research.
(2) Ultrasound ablation: The proceses is the same as that of the first partresearch.
(3) Main Outcome Measures: Main outcome measures are the same asthat of the first part research.
(4) Posttreatment magnetic resonance image evaluation: Parameters arethe same as that of the first part research.
4. Statistical methods
Statistical analysis was performed by using SPSS17.0software.
Part three
1. Objective
From October2010to January2013,15patients with hyperintenseuterine fibroids who undergone double HIFU were enrolled in the1stAffiliated Hospital of Chongqing Medical University.
2. Equipments
Equipment is the same as that of the first part research.
3. Methods
(1) Pretreatment magnetic resonance image evaluation: The size, NPV,NPV ratio of fibroids are recorded by plain and enhanced MRI scanningbefore and after1st HIFU treatment.
(2) Ultrasound ablation: The proceses is the same as that of the first partresearch.
(3) Main Outcome Measures: Main outcome measures are the same as thatof the first part research.
(4) Posttreatment magnetic resonance image evaluation: Parameters are thesame as that of the first part research.
4. Statistical methods
Statistical analysis was performed by using SPSS17.0software.
Part four
1. Objective
From April2012to December2012,35patients who undergonemyomectomy or hysterectomy, a total of39isolated fibroid specimens areenrolled in the1st Affiliated Hospital of Chongqing Medical University.
2. Equipments
Paraffin section machine is produced by Chang yuan experimental setupfactory in Beijing; Light microscope is produced by Japanese OlympusCompany. Other equipment is the same as that of the first part research.
3. Methods
(1) Pretreatment magnetic resonance image evaluation: Measurement isthe same as that of the first part research.
(2) Main Outcome Measures: The density of fibroids is measured bymass and volume method, the moisture content of fibroids is measured bydrying method, the organization structure of fibroids is observed by HE andporosities red staining, the expression of PR and ER is observed byimmunohistochemical staining.
(3) Ultrasound ablation: Isolated fibroid specimen is ablated by HIFU,gray scale of fibroid specimen during procedure is recorded by includedsoftware of HIFU system, coagulation necrosis area of fibroid specimenafter procedure is measured.
4. Statistical methods
Statistical analysis was performed by using SPSS17.0software.Results
Part one
1. Ablation results: Hyperintense fibroids had significantly higher EEFthan that of hypointense/isointense fibroids, but with lower treatmentefficiency and smaller NPV ratio. Among hyperintense fibroids, slightlyhomogeneous hyperintense fibroids had the smallest NPV ratio andtreatment efficiency, but the highest EEF. No difference was observedbetween markedly homogeneous and heterogeneous hyperintense fibroidsand hypointense/isointense fibroids.
Acceptability: The incidence of pain and pain scores were significantlyhigher in patients with slightly homogenous hyperintense fibroids than thatof patients with hypointense/isointense fibroids.
2. Ablation results: The fibroids with regular enhancement on dynamiccontrast-enhanced MRI had the lowest NPV ratio and treatment efficiency,but the highest EEF.
Acceptability: The mean pain scores of regular enhancement are higherthan that of patients with slight and irregular enhancement.
3. Ablation results: Among hyperintense fibroids, the fibroids withslightly homogeneous hyperintense on T2WI and regular enhancement ondynamic contrast-enhanced MRI had the smallest NPV ratio and treatmentefficiency, but the highest EEF.
Acceptability: No difference was observed in the incidence of pain andthe mean pain scores of patients with slightly homogeneous hyperintensefibroids on T2WI and regular enhancement on dynamic contrast-enhancedMRI are higher than other group.Prediction Specificity of three methods: The specificity of T2WIcombining dynamic contrast-enhanced MRI is the highest for predicting theefficacy of HIFU ablating hyperintense fibroids.
Part two
1. The sonication energy of HIFU ablating hyperintense fibroids isrelation to thedistance from fibroid ventral side to skin, maximum diameter of fibroid, enhancement type of fibroids and T2WI hyperintense signal typeof fibroids.
2. Dosimetric models of HIFU ablating hyperintense fibroids:y=0.474*X1-0.427*X2+6.212*X3+4.914*X4[y=EEF, X1=the distance from fibroid ventral side to skin；X2=maximum diameter of fibroid；X3=enhancement type of fibroids（1=slightenhancement，2=irregular enhancement，3=regular enhancement）；X4=hyperintense signal type of fibroids（1=heterogeneous hyperintensefibroids,2=markedly homogeneous fibroids,3=slightly homogenoushyperintense fibroids）]
Part three
Ablation results: The second HIFU ablation of recuring slightlyhomogeneous hyperintense fibroids is no difference with1stHIFU ablationin treatment efficiency, NPV and EEF.
Acceptability: There is no difference between two groups in theincidence of pain and the mean pain scores.
Part four
1. The density and the collagen content of slightly homogeneoushyperintense fibroid are lower than that of hypointense/isointense fibroids,but the moisture content and cell content is richer, the expression of ER andPR is higher.
2. When isolated fibroid specimen is ablated by HIFU, gray scale of slightly homogeneous hyperintense fibroids during procedure is smallerthan hypointense fibroid, and real coagulation necrosis area is also smallerafter procedure.
Conclusions
1. From a perspective of technology success, heterogeneous hyperintensefibroids and markedly hyperintense fibroids on T2-weighted MRI, thefibroids with regular enhancement on dynamic contrast-enhanced MRI canbe considered as an indication of HIFU; the fibroids with slightlyhomogeneous hyperintense on T2WI and regular enhancement on dynamiccontrast-enhanced MRI is the hardest to ablate. MRI-T2WI combiningdynamic contrast-enhanced MRI can predict the efficacy of HIFU ablatinghyperintense fibroids.
2. The distance from fibroid ventral side to skin, maximum diameter offibroid, enhancement type of fibroids and T2WI hyperintense signal type offibroids can be as a predictor of sonication energy of HIFU ablatinghyperintense fibroids.
3. The second HIFU ablation can not improve therapeutic efficacy ofrecuring slightly homogeneous hyperintense fibroid after1stHIFU ablation.
4. Lower density and collagen, richer moisture content and cell content,higher expression of ER and PR are reason for unsatisfactory therapeuticefficacy of HIFU ablating slightly homogeneous hyperintense fibroids.
引文
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