【作者】 王廷；

【导师】 窦科峰； 王岭；

【作者基本信息】 第四军医大学 ， 外科学， 2008， 博士

【摘要】 乳腺癌已经成为严重威胁女性生命健康最常见的恶性肿瘤。乳腺癌是否能够早期发现并制定相应合理的治疗策略是影响乳腺癌预后的重要因素,但是,目前临床使用的乳腺癌早期诊断方法仍有这样或那样的不足。乳腺钼靶X线检查是目前临床最广泛应用的乳腺癌早期检查手段,但设备昂贵,检查费用较高,检查时需要挤压乳房,给患者带来痛苦,同时放射线对人体有损害,年轻妇女乳腺组织比较致密而不易检出病灶,故一般认为40岁以下的妇女不适宜行乳腺X线钼靶检查,因而这种检查方法并不广泛适用于临床普查。超声检查对比较小的病灶敏感度不高,同时在很大程度上依赖于操作者水平,所以也不适宜单独用作乳腺普查的手段。CT、磁共振检查因设备昂贵,检查时间长,检查费用高而不适于大规模的人群普查。乳腺红外线扫描的敏感性较低,且假阳性率偏高,图像质量容易受多种因素的影响,因此这种检查手段也不宜用于妇女乳腺的普查。综上所述,目前还没有一种检测方法可以称得上是理想的普查手段。乳腺电阻抗扫描成像(EIS)技术是近年来发展起来的新技术,以其无损害、无创伤、成本低等优势,为乳腺癌的早期检查与辅助诊断开辟了一个新的方向。国外研究表明,乳腺癌与正常组织和良性病变组织在电阻抗特性上存在显著差异,而良性病变与正常组织电阻抗特性非常接近,因此利用乳腺组织的电阻抗特性可以诊断乳腺癌。临床应用研究也证明乳腺EIS成像检测对乳腺癌有较高的敏感性、特异性。乳腺EIS检测具有易于使用,对人体无明显伤害的特点,具有良好的患者接受度。但目前的乳腺电阻抗检测的研究也存在以下一些问题:(1)判断标准:基础研究表明乳腺癌组织的电阻率比其周围正常组织的电阻率低3～6倍,因而乳腺癌在电阻抗成像中应该呈现高电导区域,而我们使用课题组自行研制的乳腺电阻抗扫描成像(EIS)设备进行临床研究时发现,大部分乳腺癌的EIS影像呈现高电导区域,也有一部分呈现低电导区域。国外文献中的诊断标准大多数以高电导区域作为诊断标准,也有少量文献提到类似情况,但未对此给予说明和继续更深入的研究。(2)EIS临床测量的数据量还远远不够,不同乳腺疾病的EIS检测特点还没有足够多的数据来描述和支持。(3)不同人种间的乳腺差别很大,各种乳腺疾病发生率和发病年龄有较大差别,其电特性也应不同。目前的临床研究仅限于在欧美国家进行,其主要研究对象为白种人。(4)以目前的临床检测诊断水平,EIS还远远不能取代已经作为标准早期检测手段的乳腺钼靶X线检查。那么是否能为EIS乳腺检测找到更好的适用人群和用途。为了解决以上问题,我们一方面建立了中国妇女乳腺组织电阻抗频谱测量平台,相对系统地研究了我国妇女乳腺组织电阻抗频谱特性;另一方面我们开展了大量我国女性乳腺电阻抗成像的临床病例检测,同时进行EIS与超声、钼靶等传统检查的对照试验,研究和掌握我国女性乳腺EIS成像的特点。本文的具体工作及结果如下:1.离体乳腺组织阻抗频谱测量系统的设计为了更好的进行离体乳腺组织的阻抗频谱测量,获得稳定一致的结果,我们设计了以阻抗分析仪Solartron SI-1255B为核心的乳腺组织阻抗频谱测量系统。该系统包含可以提供多频率驱动电流和测量电路的阻抗分析仪,自行设计的带有屏蔽网、可以测量固定尺寸组织的阻抗测量盒,4根直径0.5mm的针状银电极。整个测量系统适合用于较宽频率范围的生物阻抗频谱测量并具有较高的测量精度。同时,为了保证实验条件的一致性,我们在测量时对环境的温度、湿度等条件也进行了控制。2.常见乳腺病变组织电特性离体测量研究采用我们自行设计的离体组织阻抗测量系统,对临床上常见的人体乳腺病变组织,(包括浸润性导管癌、浸润性小叶癌、乳腺腺病、乳腺纤维腺瘤、导管内乳头状瘤和乳腺囊性增生)进行离体电阻抗频谱测量。结果表明:不同个体同类型病理组织其电阻抗特性非常接近;而不同病理状态的各种乳腺组织的电阻抗频谱特性的值不尽相同:乳腺癌与乳腺良性病变组织的电阻抗特性存在显著差异,而两种乳腺癌之间,4种良性病变之间电阻抗特性没有显著差异。3.乳腺癌及其周围组织电阻抗频谱测量及其与在体EIS成像上的对照研究本试验采用我们自行设计的离体组织阻抗测量系统对手术切除的乳腺癌及其周围组织电阻抗频谱特性进行离体测量和分析,寻找乳腺癌与周围组织在电阻抗特性上存在的差异。同时,将这种差异与在体EIS成像进行对照研究,分析二者的关系。结果显示:乳腺癌及其周围组织的电阻抗特性也存在显著性差异,乳腺癌电阻率高于正常腺体和皮肤组织而远低于脂肪组织;同时通过与在体的EIS成像结果进行对照,我们发现乳腺癌在EIS大体成像的特点与乳腺癌灶周围组织的性质密切相关,当周围组织以脂肪组织为主时,乳腺癌在EIS成像上多表现为高亮区,当周围组织以腺体组织为主时,其成像多表现为暗区。这个结果一方面再次验证了EIS进行乳腺癌诊断的可行性,另一方面更为重要的是,首次发现乳腺癌周围组织的不同对电阻抗频谱特性的影响,将其与EIS在体成像结果结合,科学合理地解释了我国女性乳腺癌电阻抗扫描成像(EIS)呈现高电导区和低电导区并存的现象,也解决了国外相关资料在这方面的矛盾和模糊问题。在国际上未见报道。4.我国女性正常乳腺电阻抗检测病例的收集和分析使用具有我国自主知识产权的电阻抗乳腺诊断仪Angelplan-EIS1000对191例志愿者进行了正常乳腺的检测,收集了每一例志愿者两侧乳腺各9个部位电阻抗的实部、虚部、幅值和相位参数,对其分析,对比。结果显示:不同个体电阻抗四种参数的离散程度很大,某一个体电阻抗参数的异常改变相对于其他个体的正常波动很难区分;同一个体左右两侧乳腺电阻抗参数较为一致,而且左右两侧的差异要远小于不同个体的差异;被测者的年龄、身高、体质量对电阻抗参数无明显影响。因此,我们得到结论:乳腺电阻抗检测无法通过统一的绝对标准作为乳腺癌诊断依据;但因同一个体电阻抗参数分布均匀,左右一致,所以可以采用相对标准作为乳腺癌诊断依据。5.乳腺EIS检测临床病例的收集为了深入研究EIS在乳腺癌检测方面的临床应用价值,掌握我国女性乳腺癌EIS检测的规律和特点,需要大量临床病例的收集和总结分析。从2005年12月～2007年12月,我们对3124例乳腺门诊病人,在患者自愿的前提下行乳腺EIS检测,同时收集了其病理检查结果,病史,查体等临床资料,对所有资料进行分类、归纳和分析。结果显示:(1)使用我们自主研发的Angelplan-EIS1000电阻抗乳腺诊断仪进行乳腺癌的诊断有较高的敏感性和特异性,在检测能力上与国外商品化的产品TransScan TS 2000相当。(2)乳腺EIS检测有着其他乳腺检查无法替代的诊断特性。(3)乳腺EIS检测不受乳腺大小和年龄的影响。(4)对于不同大小的包块,EIS对乳腺癌的检测能力有较大的差别,对包块小于2cm的乳腺病灶,EIS乳腺检测有更好的表现。(5)月经期后阶段进行乳腺EIS检查有着更高的敏感度和特异度6.乳腺EIS检测与超声及钼靶X线检查对T1期乳腺癌诊断能力的对照试验为了进一步研究EIS乳腺检测在乳腺癌诊断方面的能力与优缺点,我们分别设计了其与乳腺超声和钼靶X线检查的对照试验,两项研究均为为双盲前瞻性研究。两项对照试验分别有163例和207例患者入组。结果显示:乳腺EIS检测与乳腺超声检查在T1期肿瘤的诊断能力上无明显差别,但是,两种检测方式有良好的互补性,两者联合可以明显提高检测敏感度和阴性预测值。乳腺EIS检测在T1期乳腺癌的诊断方面比钼靶X线检查还有一定的差距,但在分年龄段进行的亚组研究中,我们发现对年龄较大的患者(≥40岁)钼靶X线对EIS检测的优势较为明显,而在年龄较小患者(＜40岁),两者间的敏感度没有明显差别。7.乳腺EIS与超声联合检测评价年轻女性罹患乳腺癌危险度的前瞻性研究我们从2006年10月至2007年12月对583例年龄在25岁到45岁之间的年轻女性进行了临床观察,所有患者均由其他检查方法(体检,乳腺拍片或磁共振)判定为需要进行乳腺活组织检查。在活检之前分别进行乳腺EIS检测及超声检查。本研究为双盲前瞻性临床观察研究。研究结果提示:乳腺EIS与超声联合检测用来评价年轻女性罹患乳腺癌危险度有良好的互补性,可以很好的预测年轻女性罹患乳腺癌的风险,有可能成为广泛应用的年轻女性乳腺癌的早期筛查方法。更多还原

【Abstract】 Breast cancer is the most common malignant tumor that threatens the health and even lives of women.It is an important factor of prognosis of breast cancer that whether early breast cancer is detected and reasonable therapy strategy is set down.But the currently available clinical examination instruments don’t fit the general breast survey of the woman because of their limitations in clinical application.As the commonly used early detection method,mammography has high cost and brings pain and damage of X-ray to patients,and is not suitable to early detection of all patients.Sonography is also not suitable because of its low sensitivity to small lesions and dependent on the experience of operator.CT,MRI and CDI are also not suitable owing to many shortcomings.Thanks to its freedom from radiation,invasion and high cost,breast Electrical Impedance Imaging(EIS) has opened up a brand-new horizon in the early detection and assistant diagnosis of the breast cancer.Previous researches had proved that there is significant difference in impedance characteristics between the breast cancer and the normal tissues.The feasibility of the application of EIS to breast cancer diagnosis is also confirmed by clinical observation tests.There yet have been many problems in the study of EIS.(1) criteria:The basic studies pointed out that resistivity of the breast cancer is 3～6 times lower than that of either the normal tissue or the benign lesion.So,the breast cancer appears as bright spots with high conductivity on EIS.But we found that some breast cancer appeared as ether bright or dark spots on the EIS equipment developed by ourselves,which phenomenon had been seldom reported abroad and needed further observation.(2) The ability of EIS test to early diagnosis of breast cancer needed more adequate clinical data to support.(3) Based on the differences in components and incidence of breast disease of different races,the characteristic of EIS must be different which has not ever been reported abroad. (4) With present level of diagnosis,EIS test can not replace mammography which has been used as a standard means of early detection of breast cancer.To find a better application area is very important.In order to explore the impedance characteristics of Chinese women and resolve those problems,we build a system for impedance spectroscopy measurement in vitro,with which a relative systemic study is indispensable on the impedance characteristics of the breast tissue of Chinese women using our own EIS equipment- Angelplan-EIS 1000.On the other hand,we embarked on EIS of a large number of clinical cases and made the control test with ultrasound and mammography.The present paper covers the following aspects.1.Construction of the breast impedance spectroscopy measurement systemWe constructed an impedance spectroscopy measurement system based on the frequency response analyzer,which provides current injection with different frequencies ranging from 10μHz to 1MHz and voltage measurement circuit with an accurate and stable output signal.The system also consisted of rectangular drawing,which can make the size of tissues fixed and four-terminal silvern configuration.To ensure the consistency of experiment condition,the temperature and humidity were also controlled.2.Measurement of the impedance spectroscopy of pathological breast tissuesBased on our impedance spectroscopy system and technique,the impedance spectroscopy of diseased breast tissues were measured including invasive ductal carcinoma,invasive lobular carcinoma,mastopathy,fibroadenoma,mastoid neoplasm and cysts hyperplasia.The results showed that the impedance of breast carcinoma was higher than that of the benign tissue while there was no difference in impedance between the two carcinomas and between the four benign diseases.3.Impedance spectroscopy measurements of breast carcinoma and its surrounding normal tissues of breast organ with contrast of image produced by EIS in vivo.In this study,we measured the impedance spectroscopy of breast cancer and its surrounding normal tissues,which were obtained from mastectomy surgeries with infiltrating duct carcinoma to find the differences between them.The results were contrasted with the images of EIS test.The results showed there was significant difference in impedance characteristic between the breast carcinoma and its surrounding tissue.This study has indicated that there is an experimental base for Chinese women’s breast survey by means of EIS.The other finding was that with different kind of surrounding tissues,the impedance characteristics were different.If the ingredient is mainly of fatty tissue,the impedance of carcinoma was lower than that of the peripheral tissue and the breast cancer appears as bright spots on EIS image.If the ingredient is mainly of normal gland tissue,the impedance of carcinoma was higher than that of the peripheral tissue and the breast cancer appears as dark spots on EIS image.These results can reasonably explain the reason why some breast cancers shows dark spots on EIS image in some patients and successfully solve the contradiction in abroad articles.4.Analysis of electrical impedance scanning of breasts in normal women.Using our own EIS equipment- Angelplan-EIS 1000,we tested normal breasts of 191 volunteers.The differences between different subjects were analyzed and the similarities between left and right breasts of the same subject were compared.The results demonstrated that the electrical impedance parameters were quite different between different subjects,but quite similar between the two breasts of the same subject.The characteristics of electrical impedance had no correlation with clinical parameters including age,stature and weight.5.Collection and analysis of EIS test data of patients on a large scale.In this study,a total of 3124 patients were entered into the study between Dec 2005 and Dec 2007.We collected results of EIS,pathological reports,ages, physical sighs,and other clinical information.The data were statically and methodology analyzed.The results demonstrated that:(1) Our self-developed electrical impedance instrument(Angelplan-EIS1000) had high sensitivity and specificity for diagnosis of breast cancer and its ability was not weaker than the foreign mature product TransScan-TS 2000.(2) EIS had some advantages which can’t be replaced by other methods in diagnosis of early breast cancer.(3) The test of EIS rise superior to the size of breast and age.(4) For breast masses with different diameters,EIS has different diagnosis ability.The sensitivity and specificity were higher in groups with masses smaller than 20ram.(5) A higher sensitivity and specificity were observed in patients who received EIS test in delayed menstruation. 6.Contrast test of EIS and ultrasound,mammography.We designed two contrast clinical tests to compare the test ability of EIS and ultrasound,mammography.There were 163 and 207 patients enrolled into the two studies,respectively.The results indicated that there were no differences between the abilities of EIS and ultrasound in diagnosis of T1 breast cancer,but the two kinds of test had complementarity.Combinational detections were obviously able to increase sensitivity and PPV of breast cancer detection. Mammography was prior to EIS in detecting T1 breast cancer,but to patients whose age were younger than 40,the two tests had no differences.7.Prospective study on combinational detection of EIS and ultrasound in estimating risk for development of breast cancer in young women.A prospective,double blind clinical trial was done in young women aged 45 years and under.EIS and ultrasound results were compared with final histopathology results.Study end points included sensitivity and specificity of EIS,ultrasound and both combination,as well as relative probability of breast cancer of positive patients detected by combinational application of EIS and ultrasound.The results show that the combination of EIS and ultrasound could obviously increase sensitivity in detecting breast cancer of young women.The more important results was that the combination could increase the relative possibility of breast cancer of positive young women from 8.67,5.77 to 14.84. The combination of EIS and ultrasound is likely to become a main approach to screen early breast cancer for young women.更多还原