摘要
背景
乳腺癌是一组恶性上皮性肿瘤,具有明显的局部侵袭能力和远处转移倾向。由于乳腺癌干细胞具备多向分化的潜能且不同个体微环境存在差异,乳腺癌的形态学表现呈多样性,某些组织学类型具有其独特的临床特点和预后意义。乳腺癌已成为全球范围内备受关注的影响女性健康的疾病,其发病率有较大地区差异,一般发达地区较高。近20年来,乳腺癌发病率在全球范围内呈上升趋势,且发病年龄倾向于年轻化,但总生存期及无病生存期均有所延长。
钼靶X线摄影技术是一种软X线摄影,其广泛应用使越来越多的乳腺癌患者受益于早期诊断及治疗,明显提高了不可触及乳腺癌的检出率,使其在发生局部进展或远处转移之前得到及时治疗,从而改善了患者的预后。乳腺癌的组织形态学表现多种多样,在钼靶X线摄影上的表现也不尽相同。乳腺癌的钼靶X线特点与其临床病理表现均决定于原发肿瘤的基因学基础,他们之间必然有某种程度的相关性,关于这一点已有部分相关报道。浸润性导管癌作为乳腺癌最常见的一种组织学分类,其临床表现、大体病理特点、组织形态学表现、分子生物学特点及预后仍存在极大的差异。关于乳腺浸润性导管癌的钼靶X线表现与临床、病理特征的相关性及其对治疗、预后的预测价值方面的研究尚未见报道。
钼靶X线摄影的应用使无症状乳腺癌的检出率有所增加,但由于国内乳腺癌筛查尚未大面积普及,临床所见乳腺癌多有症状,虽以乳房肿块居多,仍有约7～9%的患者表现为乳头异常,如乳头溢液、乳头湿疹样改变或乳头内陷等。病理性乳头溢液是指自发性的单侧、单孔乳头溢液,且一般呈持续性,通常认为导管内增生性病变、导管内乳头状肿瘤及部分浸润性乳腺癌是病理性乳头溢液的常见病因。大多数病理性乳头溢液是由良性疾病引起的,由浸润性乳腺癌及其前驱病变导致的乳头溢液约占8-15%,且该组乳腺癌在单纯钼靶X线照片上多无阳性征象,需借助乳管造影。钼靶X线乳管造影、乳头溢液脱落细胞学检查及超声检查对乳头溢液疾病的诊断均有一定的价值,但是均不够可靠。已有文献报道不同的乳管造影表现对组织病理学类型具有一定程度的阳性预测价值,但尚未发现特异性较强的征象。伴有乳头溢液的乳腺癌是否具有独特的临床病理特征,与钼靶X线乳管造影表现是否具有相关性亦少见报道。
第一部分浸润性导管癌的钼靶X线表现与其临床病理特征相关性的分析
目的
探讨乳腺浸润性导管癌的铝靶X线表现与其临床病理特征的相关性。探讨特定的钼靶X线表现对乳腺癌的治疗及预后是否具有预测价值。
方法
对2008年6月至2010年3月间于我科行手术治疗的108例乳腺癌患者的临床特点、病理特征及钼靶X线表现进行评价,并作相关性分析。
1.乳腺浸润性导管癌患者临床、病理信息收集
组织学类型为浸润性导管癌、伴或不伴有导管内癌成分、无其他浸润性癌特征的108例患者的临床信息,包括：年龄、绝经状态、肿瘤长径、组织学分级、腋窝淋巴结状态及临床TNM分期等。
2.乳腺浸润性导管癌标本石蜡组织切片的免疫组织化学分析
用PV-9000试剂盒(GBI, USA)采用二步法免疫组织化学染色检测乳腺癌石蜡组织切片中雌激素受体(estrogen receptor, ER)、孕激素受体(progesterone receptor, PR)、人表皮生长因子受体-2(human epidermal growth factor receptor2, Her2)及细胞周期相关蛋白Ki67的表达。ER、PR染色细胞数≥10%认为是阳性,Ki67着色细胞数>30%认为是阳性,Her2表达按照HercepTestTM评分指南,2+或者3+认为是阳性。
3.乳腺浸润性导管癌患者钼靶X线表现的评价
每位患者术前均接受了双侧乳房铝靶X线摄影检查,常规采用CC位和ML位。所有钼靶X线照片均参照BI-RADS对乳腺实质组成类型及主要阳性征象包括肿块、钙化、结构扭曲及不对称密度等进行评价。
4.统计学分析
所有数据均用IBM SPSS Statistics19软件进行x2检验,p<0.05视为有统计学意义。
结果
1.共19例标本伴有导管内癌成分,ER、PR阳性率分别为76%、67%；Ki67阳性率为56%；Her2阳性率为27%；63例患者钼靶X线可见肿块,48例可见钙化,25例表现为肿块合并钙化,钼靶X线摄影可见肿块的63例中,边缘呈星芒状的有27例。
2.钼靶X线肿块与组织学类型为纯粹浸润性导管癌显著相关,而钙化与伴有导管内癌成分相关(p<0.01)。
3.钼靶X线表现为肿块合并钙化与腋窝淋巴结转移相关(p<0.05)且肿瘤长径通常大于2cm(p<0.01)。
4.钼靶X线肿块边缘呈星芒状的患者ER、PR阳性率明显高于肿块边缘呈非星芒状的患者(p<0.01)；而Her2阳性率及肿瘤增殖活性显著低于肿块边缘呈非星芒状的患者(p<0.05,p<0.01)。
第二部分伴有乳头溢液乳腺癌的钼靶X线乳管造影表现与其临床病理特征的相关性
目的
探讨钼靶x线乳管造影表现对乳腺肿瘤组织学类型的阳性预测价值及与乳腺癌临床病理特征的相关性；分析伴有乳头溢液乳腺癌的组织病理学及分子生物学特点。
方法
1.乳头溢液患者临床、病理信息收集
收集2010年4月至2012年2月于我科行手术治疗、以病理性乳头溢液为主要表现的24例乳腺癌患者及38例良性乳腺疾病患者的临床、病理信息,包括：年龄、绝经状态、肿瘤长径、乳头溢液的颜色、组织病理学类型、浸润性导管癌组织学分级、腋窝淋巴结状态及临床TNM分期等。
2.乳腺癌标本石蜡切片免疫组织化学分析
用PV-9000试剂盒(GBI, USA)采用二步法免疫组织化学染色检测乳腺癌石蜡切片中雌激素受体(estrogen receptor, ER)、孕激素受体(progesterone receptor, PR)、人表皮生长因子受体-2(human epidermal growth factor receptor2, Her2)及细胞周期相关蛋白Ki67的表达。ER、PR染色细胞数≥10%认为是阳性,Ki67着色细胞数>30%认为是阳性,Her2表达按照HercepTestTM评分指南,2+或者3+认为是阳性。
3.钼靶X线乳管造影的实施
自溢液乳管开口缓慢注入76%复方泛影葡胺注射液或优维显300约0.2至0.5ml,术者感到有阻力或病人感到明显疼痛时停止注入,移除针头,立即进行CC位及ML位钼靶X线摄影。
4.钼靶X线乳管造影的评价
所有钼靶X线照片均参照BI-RADS对乳腺实质组成类型及主要阳性征象包括肿块、钙化、结构扭曲及不对称密度等进行评价。溢液乳管系统显影情况的评价：溢液乳管系统的定位,乳管完全中断、管腔内充盈缺损、乳管壁不规则、乳管扩张、乳管周围造影剂溢出及树干征等阳性征象。
5.统计学分析
所有数据均用IBM SPSS Statistics19软件进行x2检验,p<0.05视为有统计学意义。
结果
1.该组乳腺癌患者24例均为导管癌,其中11例为导管内癌,9例为伴有导管内癌成分的浸润性导管癌,2例为浸润性导管癌,2例为导管内乳头状癌。
2.造影成功者均能大概确定溢液乳管系统的位置,并能清晰显示溢液乳管系统管壁、管腔及乳管树分支的改变。
3.较常见其易于判定的钼靶X线乳管造影征象有乳管完全中断、管腔内充盈缺损、乳管扩张、乳管壁不规则、乳管周围造影剂溢出及乳管树分支稀少等。
4.乳管壁不规则对乳腺癌的阳性预测值较高,且与乳腺癌显著相关(p=0.008)；其他征象对肿瘤的良恶性鉴别未见明显意义,但乳管完全中断及管腔内充盈缺损对乳管内占位性病变有较高的提示价值。
5.伴有乳头溢液的导管内癌较少表现为钼靶X线微钙化、几乎无Her2扩增或过表达、ER及PR阳性率更高。
结论
1.乳腺浸润性导管癌常见的钼靶X线表现有肿块、钙化、结构扭曲及肿块合并钙化等,某些浸润性导管癌在钼靶X线摄影上并无阳性征象。乳腺浸润性导管癌的影像学表现与其临床、病理特征相关。
2.钼靶X线钙化合并肿块与腋窝淋巴结转移呈显著正相关；钼靶X线肿块边缘呈星芒状与肿瘤ER、PR阳性及低增殖活性(Ki67阴性)、Her2无扩增呈显著正相关。
3.钼靶X线乳管造影常见并易于判定的征象诸如乳管完全中断、管腔内充盈缺损、乳管扩张及乳管周围造影剂溢出等对于疾病性质的鉴别诊断并无明确意义,且与乳腺癌无显著相关性。乳管完全中断及管腔内充盈缺损对管腔内存在占位性病变具有明确的提示价值。
4.乳管壁不规则这一重新定义的钼靶X线乳管造影征象与乳腺癌显著相关。
意义
1.乳腺浸润性导管癌的钼靶X线表现与其临床、病理特征相关。钙化合并肿块可作为可能存在腋窝淋巴结转移的一个提示因子,并提示预后较差,可作为一个预后因子。
2.钼靶X线肿块边缘呈星芒状的乳腺癌增殖活性低,多无Her2扩增,且ER、PR阳性率高,提示肿块边缘呈星芒状可以作为一个预后良好的因子,或提示可能对内分泌治疗有效。在无法获取肿瘤激素受体状态的情况下可作为内分泌治疗的一个候选指证。反之,当钼靶X线表现为具有星芒状边缘的肿块而免疫组织化学检测ER、PR呈阴性时,可以考虑复检ER、PR,以免患者错失内分泌治疗的机会。
3.钼靶X线乳管造影的评价缺乏统一的标准。我们重新定义了征象“乳管壁不规则”,指乳管壁失去其平滑性、舒展性,节段性狭窄、僵硬与扩张交替出现,可有迂曲延长。典型表现为乳管呈“串珠样”或“腊肠样”改变。该征象与乳腺癌显著相关,阳性预测值高,特异性好,但敏感性过低。因本文中病例数量相对较少,需增大样本继续验证此结论。
4.钼靶X线乳管造影最重要的价值在于其对溢液乳管系统的定位及对手术切除范围的预测,而不是对疾病良恶性的鉴别。钼靶X线乳管造影在乳头溢液疾病的诊治中已占据了不可替代的重要位置,术前进行该项检查是尤为必要的。
BACKGROUND
Worldwide, it is estimated that more than one million women are diagnosed with breast cancer every year, and it accounts for about410,000deaths per year. Breast cancer is already the leading cause of cancer in Southeast Asian women, and is second only to gastric cancer in East Asian women. In some areas of China, the incidence of breast cancer was recorded to be increasing by5%per year, an increase greater than that worldwide.
The application of mammography benefits more and more patients by leading to earlier detection and management because the introduction of mammography screening has led to an increased detection of smaller invasive tumors without local or distant metastasis. Breast cancer often exhibits intratumoral heterogeneity, so that mammographic patterns of breast cancer have a wide range of variation. Recently, we reported that mammographically occult breast cancer had a worse prognosis compared with mammographically positive breast cancer. At the same time, the insufficient of mammography is revealed. Mammography may increase the risk of breast cancer if received frequently. The sensitivity of breast cancer in dense breast is low, which needing other iconography examination to avoid missing of diagnosis. Some invasive breast cancer are not visible on mammogram, and the prognosis of them is poorer than that of visible on mammogram. Although an increased detection of ductal carcinoma in situ due to the high mammography sensitivity for calcification is observed, unnecessary stereoscopic core needle biopsy of suspicious calcification increased also。
In addition, it has been reported that some particular histological types of breast carcinomas have certain specific mammographic features. Mucinous carcinoma of the breast usually presents as a mass with a well-defined margin rather than a spiculated one, and is associated with the absence of calcifications, while tubular carcinoma of the breast usually manifests as a small spiculated mass. Both of these types have more favorable prognosis than common invasive ductal carcinoma. To our knowledge, there are few articles reporting the mammographic features of invasive ductal carcinomas (IDC). The aim of the current study was to evaluate the different types of mammographic tumoral appearances for their relationships with clinical, pathological and biological characteristics in a series of patients with IDC.
Nipple discharge is a common complaint of women. The spontaneous, unilateral, single-duct nipple discharge is defined as pathological nipple discharge. Although most of pathological nipple discharge is caused by benign diseases, such as intraductal papilloma, about5～15%of patients with nipple discharge have cancer. Ultrasonography and exfoliative cytology are useful in the diagnosis of spontaneous pathological nipple discharge but are not reliable enough both. Galactography, also known as ductography, plays an important role in the management of spontaneous pathological nipple discharge. The purpose of this study is to illustrate the role of galactography in the management of nipple discharge and to assess the diagnostic value of preoperative galactography in women with nipple discharge.
PART1Mammography features are correlated with clinicopathological characteristics in breast invasive ductal carcinoma
OBJECT
To assess the correlation between mammographic features and clinicopathologic characteristics of invasive breast carcinoma. To evaluate if mammographic appearance can predict the therapy and prognosis of breast cancer.
METHODS
The mammographic appearance and clinicopathological data of108patients with invasive ductal carcinoma were retrospectively analyzed.
1.The collection of clinicopathological informations of invasive ductal carcinomas
The histological type of all the108patients was invasive ductal carcinoma, no matter companied by component of ductal carcinoma in situ or not, with infiltrative peculiar carcinomas excluded. The clinical information, including age, menopausal status, tumor size, grade, stage, and axillary lymph node status, were collected from our database.
2.Immunohistostaining analysis
The immunohistostaining analysis was performed with PV-9000Polymer Detection System for Immuno-Histological Staining (GBI, USA). Estrogen recptor (ER), progesterone receptor (PR), human epidermal growth factor receptor2(Her2) and Ki67were successfully detected in all the paraffin sections. ER and PR were considered positive if nuclear staining was present in≥10%of the cells, and Ki67expression was considered positive in cases of a substantial percentage of positively stained nuclei(>30%). Her2expression was graded as recommended by the HercepTestTM scoring guidelines. Her2was considered to be positive if the score was2+or3+.
3.Assessment of mammograms according to BI-RADS
Every patient received mammography screening bilaterally before the surgery with the use of a Mammomat Novation DR system (Simmens AG, Germany). Craniocaudal view (CC) and mediolateral view (ML) were performed routinely for all patients, and mediolateral oblique view (MLO) was obtained when necessary. All the mammograms were assessed according to the analytic criteria of Breast Imaging Reporting and Data System (BI-RADS) in which the mammographic features mass, calcification, architectural distortion and asymmetric density were recorded.
4.Statistical analysis
All data were analyzed using Statistical Package for the Social Sciences statistical software (version19.0; SPSS Inc., Chicago, IL, USA). Correlations between mammographic appearance and clinicopathological parameters of IDC were also evaluated by chi-square test. All statistical tests were two-sided. Ap-value of<0.05was considered as being significant.
RESULTS
1.Nineteen samples were invasive ductal carcinoma accompanied by ductal carcinoma in situ. The positive rates of ER and PR were76%and67%respectively, that of Her2was27%, and that of Ki67was56%. Sixty three patients manifested mammographic mass, and48had visible calcification on the mammogram. Twenty five patients showed evident mass accompanied with calcification. Twenty seven masses had a spiculated margin.
2.The mammographically visible mass was frequently observed in histologically pure IDC, while mammographic calcification was significantly associated with IDC accompanied with DCIS (p<0.01).
3.Mammographic calcification accompanied by evident mass was correlated with axillary lymph node metastasis (p<0.05). The tumor size was usually larger than2cm when the mammographic mass was accompanied by calcification (p<0.01).
4.Tumors from patients presenting with spiculated mass had a significantly higher ER-positive and PR-positive rates than those from patients presenting with non-spiculated mass (p<0.01). Tumors from patients presenting with spiculated mass had Her2negativity (p<0.05) and lower proliferative activity as labeled by Ki67compared with those from patients presenting with non-spiculated mass (p<0.01).
PART2Correlation between clinicopathological characteristics and galactographic features of breast cancer with nipple discharge
OBJECT
The purpose of this study was to illustrate the role of galactography in the management of nipple discharge and to assess the diagnostic value of preoperative galactography in women with nipple discharge. The histopathological and molecular biological characteristics of breast cancer manifesting nipple discharge were analyzed also.
METHODS
1.The collection of clinicopathological informations of patients with pathological nipple discharge
Twenty four breast cancer and38benign leisons manifested as pathological nipple discharge were involved in this study. The clinical information, including age, menopausal status, colour of fluid, tumor size, histopathological category, grade, stage, and axillary lymph node status, were collected from our database.
2.Immunohistostaining analysis
The immunohistostaining analysis was performed with PV-9000Polymer Detection System for Immuno-Histological Staining (GBI, USA). Estrogen recptor (ER), progesterone receptor (PR), human epidermal growth factor receptor2(Her2) and Ki67were successfully detected in all the paraffin sections. ER and PR were considered positive if nuclear staining was present in≥10%of the cells, and Ki67expression was considered positive in cases of a substantial percentage of positively stained nuclei(>30%). Her2expression was graded as recommended by the HercepTestTM scoring guidelines. Her2was considered to be positive if the score was2+or3+.
3.The implemention of galactography
Gastrografin, a water soluble contrast medium, was injected into the duct system with nipple discharge. Then, mammography was performed with craniocaudal view (CC) and mediolateral view(ML).
4.Assessment of galactograms
All the mammograms were assessed according to the analytic criteria of Breast Imaging Reporting and Data System (BI-RADS) in which the mammographic features mass, calcification, architectural distortion and asymmetric density were recorded. Assessment of duct system developed by gastrografin:the localization of duct system with nipple discharge, the common galactographic findings including complete ductal obstruction, multiple irregular filling defects in the nondilated peripheral ducts, ductal wall irregularities, periductal contrast extravasation.
5.Statistical analysis
All data were analyzed using Statistical Package for the Social Sciences statistical software (version19.0; SPSS Inc., Chicago, IL, USA). Correlations between galactographic appearance and histological category were also evaluated by chi-square test. All statistical tests were two-sided. Ap-value of <0.05was considered as being significant.
RESULTS
I.The twenty four breast cancers were all ductal carcinoma, with11ductal carcinoma in situ,9invasive ductal carcinoma accompanied by DCIS,2invasive ductal carcinoma,2intraductal papillocarcinoma.
2.The source of discharge can be localized approximately by galactography with the injection of contrast medium, and the change of duct wall or lumen can be displayed clearly.
3.Common galactographic findings included completely obstruction of duct, intraductal filling defect, ductal dilatation, ductal wall irregularity, stenosis and periductal contrast extravasation.
4.The positive predictive value of ductal wall irregularity for breast cancer was higher, and ductal wall irregularity was significantly associated with breast cancer.
5.DCIS with pathological nipple discharge usually showed the absence of calcification on the mammogram, and was significantly associated with Her2negativity. The positive rates of ER and PR were usually higher.
CONCLUSION
1.Common mammographic appearances of invasive ductal carcinoma include mass, calcification, architectural distortion and mass accompanied by calcification. Some invasive ductal carcinomas are invisible on mammogram. Mammographic features are correlated with clinicopathological characteristics.
2.If the mass is accompanied by calcifications on the mammogram, the tumor size is frequently larger than2cm. Axillary lymph node metastasis is also significantly related to mammographic mass accompanied by calcification. The spiculated margin of mammographic mass is significantly associated with high positive rate of ER and PR. Spiculated mass is also correlated with low proliferative activity and negative expression of Her2.
3.Some common signs, such as completely obstruction of duct, intraductal filling defect, ductal dilatation and periductal contrast extravasation, have scarcely any of value to differential diagnosis. But completely obstruction of duct and intraductal filling defect were correlated with intraductal space occupying lesion.
4.Ductal wall irregularity is significantly associated with breast cancer.
SIGNIFICANCE
1.Mammographic features are correlated with clinicopathological characteristics in invasive ductal carcinomas. Mammographic mass accompanied by calcification maybe act as a factor that predict the likely presence of axillary lymph node metastasis. And it can be regarded as a bad prognostic factor of breast cancer.
2.Spiculated margin of mammographic mass can act as a good prognosis factor, or may be a predictive factor of endocrine therapy.
3.There is no normative evaluation criteria for galactography. We redefined the appearance "ductal wall irregularity" as the loss of flatness and uniform diameter of the calibre. It can manifest as segmental stenosis, inflexible, or alternative with duct dilatation. This galactographic feature was significantly associated with breast cancer.
4.The major advantage of galactography is the precisely location of the source of discharge, thus enabling the surgeon to adopt an appropriate procedure that removes all diseased tissue and structures as is essential for histological success.
引文
1. Al-Hajj, M., et al., Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A,2003.100(7):p.3983-8.
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