乳腺导管原位癌伴微浸润与浸润癌患者的临床特征对比分析

目的:分析乳腺导管原位癌伴微浸润（ductal carcinoma in situ with microinvasion,DCIS-MI）与乳腺浸润性导管癌（invasive ductal carcinoma,IDC）患者的临床特征、治疗方式等。方法:回顾性分析55例乳腺导管原位癌伴微浸润及508例乳腺浸润性导管癌患者的临床资料,包括两组患者的年龄、月经情况、雌激素受体（estrogen receptor,ER）、孕激素受体（progestrone receptor,PR）、人表皮生长因子受体（human epidermal growth factor,HER-2）、肿瘤细胞增殖活性标志物（Ki67）的表达情况、分子分型、治疗方式及预后。结果:DCIS-MI组和IDC组患者在年龄上的差异不具有统计学意义（P＞0.05）,DCIS-MI组在已绝经及淋巴结转移阳性比例均低于IDC组（P＜0.05）;DCIS-MI组Ki67阳性表达率显著低于IDC组（P＜0.05）,ER、PR及HER-2阳性表达率与IDC组比较差异无统计学意义（P＞0.05）。DCIS-MI组Luminal A型比例高于IDC组,而Luminal B(HER-2-)型比例低于IDC组,且差异均具有统计学意义（P＜0.05）。其余分子分型差异不具有统计学意义。DCIS-MI组患者单纯乳房切除术比例（10.9%）显著高于IDC组（0.8%）（P＜0.05）。DCIS-MI患者主要采用的手术方式为乳腺癌改良根治术和全乳切除+腋窝淋巴结清扫,其比例分别为60.0%、16.4%,与IDC组患者采用相同手术方式的比例（67.3%、19.9%）无显著差异。DCIS-MI组化疗比例、放疗比例均低于IDC组（P＜0.05）,而两组患者在内分泌治疗、靶向治疗及中药治疗方面差异不具有统计学意义（P＞0.05）。DCIS-MI组和IDC组患者的5年无病生存（disease-free survival,DFS）率分别为97.0%和81.0%,差异具有统计学意义（Log-rank,χ2=4.962,P=0.026）。结论:与IDC患者相比,DCIS-MI组患者绝经前状态比例高、淋巴结转移阳性率及Ki67阳性率更低,Luminal A型比例更高而Luminal B(HER-2-)型比例更低;DCIS-MI组患者行单纯乳房切除术比例更高,放疗及化疗比例更低,其预后更好。     

MFG-E8在乳腺浸润性导管癌中的表达及其相关性

目的：探讨MFG-E8蛋白在乳腺浸润性导管癌组织中的表达及其相关性。方法：应用免疫组织化学法（ SP法）检测54例乳腺浸润性导管癌组织中MFG-E8蛋白的表达,并结合患者的临床病理资料分析与其相关性。结果：乳腺浸润性导管癌组织中的MFG-E8阳性表达率为81.5％（44/54）,高于癌旁正常乳腺组织（P＜0.01）,统计分析结果发现MFG-E8的阳性表达与乳腺癌的组织学分级密切相关（P＜0.01）,而与肿瘤大小、淋巴结转移及临床分期无显著相关（ P＞0.05）。结论：乳腺浸润性导管癌组织中存在MFG-E8的高表达。MFG-E8的高表达是促进乳腺癌侵袭的途径之一。     

Genomic differences between pure ductal carcinoma in situ and synchronous ductal carcinoma in situ with invasive breast cancer

Although ductal carcinoma in situ (DCIS) precedes invasive ductal carcinoma (IDC), the related genomic alterations remain unknown. To identify the genomic landscape of DCIS and better understand the mechanisms behind progression to IDC, we performed whole-exome sequencing and copy number profiling for six cases of pure DCIS and five pairs of synchronous DCIS and IDC. Pure DCIS harbored well-known mutations (e.g., TP53, PIK3CA and AKT1), copy number alterations (CNAs) and chromothripses, but had significantly fewer driver genes and co-occurrence of mutation/CNAs than synchronous DCIS-IDC. We found neither recurrent nor significantly mutated genes with synchronous DCIS-IDC compared to pure DCIS, indicating that there may not be a single determinant for pure DCIS progression to IDC. Of note, synchronous DCIS genomes were closer to IDC than pure DCIS. Among the clinicopathologic parameters, progesterone receptor (PR)-negative status was associated with increased mutations, CNAs, co-occurrence of mutations/CNAs and driver mutations. Our results indicate that although pure DCIS has already acquired some drivers, more changes are needed to progress to IDC. In addition, IDC-associated DCIS is more aggressive than pure DCIS at genomic level and should really be considered IDC. Finally, the data suggest that PR-negativity could be used to predict aggressive breast cancer genotypes.     

乳腺浸润性导管癌超声图像特征与分子亚型的关系

背景与目的：乳腺浸润性导管癌(breast invasive ductal carcinoma,IDC)属于乳腺癌中最常见的一种类型,其各分子亚型的超声图像特征具有重要的临床价值。该研究探讨了IDC超声图像特征与其分子亚型的关系。方法：该研究回顾性分析112例具有完整术前超声图像特征及术后病理结果的IDC病例资料。其中以雌激素受体(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 receptor-2,HER-2)及细胞核增值抗原(Ki-67)的免疫组织化学检测结果进行分子分型,即Luminal A型、Luminal B型、ERBB2阳性型和Basal-like型。结果：在112例IDC病例中,Luminal A型14例,占12.5%;Lu-minal B型62例,占55.4%;ERBB2阳性型21例,占18.7%;Basal-like型15例,占13.4%。4个亚型的超声图像特征在肿块长径、淋巴结数量、边界、形态和血流方面差异均有统计学意义(P<0.05);而在内部回声、微钙化、后方回声衰减及弹性成像方面差异无统计学意义(P>0.05)。在所统计的IDC病例中,Luminal A型和Luminal B型转移淋巴结数量相对少,边界多不清,形态不规则;ERBB2阳性型血供丰富,肿块较大,转移淋巴结较多;Basal-like型多边界清,形态规则,肿块大,转移淋巴结多。结论：IDC超声图像特征与其分子亚型存在一定相关性,为IDC的早期诊断、术前、术中及预后评估有重要的临床指导意义。     

超声及钼靶X线对乳腺导管内癌与乳腺浸润性导管癌的诊断价值

目的:探讨乳腺导管内癌（ductal caicinoma in situ,DCIS）与乳腺浸润性导管癌（invasive ductal carcinoma,IDC）的超声及钼靶X线影像特征差异。方法:回顾性分析160例患者（包括62例DCIS患者及98例IDC患者）的超声及钼靶X线资料。结果:161个乳腺病灶中,有62个DCIS病灶（DCIS组）及99个IDC病灶（IDC组）。超声对IDC组病灶的检出率明显高于DCIS组,两组间的检出率有统计学意义（P＜0.05）;两组间病灶超声表现中形状、边界、边缘特征及血流信号差异有统计学意义（P＜0.05）。钼靶X线在两组病灶检出率差异有统计学意义（P＜0.05）;两组间病灶钼靶X线表现形状及边缘特征的例数差异有统计学意义（P＜0.05）。对于DCIS组,超声及钼靶X线病灶的检出率差异有统计学意义（P＜0.05）;在病灶边缘及乳腺腺体内钙化检出率这些方面,两种方法有统计学意义（P＜0.05）。结论:乳腺钼靶X线对DCIS腺体内钙化灶诊断率较高,乳腺超声对DCIS病灶检出、病灶边缘特征显示具有诊断优势。     

乳腺浸润性导管癌的超声特征及其与分子分型的相关性

目的:研究乳腺浸润性导管癌的超声表现特征,分析其与临床病理参数的关系。方法:回顾分析我院2014年1月至2018年12月乳腺外科收治的110例乳腺浸润性导管癌患者临床资料。按照不同分子亚型分为Luminal 型、HER-2 过表达型及TN 型。观察不同亚型乳腺浸润性导管癌患者的超声征象并对比分析。结果:彩色多普勒超声检测显示,乳腺浸润性导管癌病例肿块多呈现为形态不规则、边缘毛刺、垂直生长,以内部回声无变化、无微钙化发生、血流分级2级、淋巴结转移、弹性评分≥3分为主。乳腺浸润性导管癌不同分子分型中超声征象形态、边缘、方位、内部回声、微钙化、血流分级、弹性评分组间差异具有统计学意义（P＜0.05）,淋巴结转移与否差异无统计学意义（P＞0.05）。Luminal 型多见于形态不规则、边缘毛刺、垂直生长;TN型多见于形态规则、边缘光整、平行生长;HER-2过表达型多肿块内部微钙化、弹性评分≥3分。不同分子分型组间两两比较,Luminal型和TN型超声征象边缘、方位组间具有统计学差异（P＜0.012 8）;HER-2型和TN型超声征象边缘组间具有统计学差异（P＜0.012 8）;Luminal型和HER-2型超声征象内部回声、微钙化及弹性评分组间具有统计学差异（P＜0.012 8）。结论:乳腺癌超声特征与其分子分型存在一定关系,超声特征可为其分子分型提供一定参考信息。     

Loss of heterozygosity analyses of asynchronous lesions of ductal carcinoma in situ and invasive ductal carcinoma of the human breast

BACKGROUND: Ductal carcinoma in situ (DCIS) of the breast is known to possess characteristics of the pre-invasive stage of breast cancer and is the precursor to invasive ductal carcinoma (IDC). However, the natural history of the progression from DCIS to IDC remains unknown at the molecular level. METHODS: We investigated the loss of heterozygosities (LOHs) in tumors of seven patients with a history of breast biopsy. The seven specimens were diagnosed as DCIS on histopathological re-examination. These patients were diagnosed with ipsilateral breast cancer a few years after biopsy. We used thirteen selected microsatellite markers that were mapped to and/or very close to the tumor suppressor genes or regions with frequent LOHs in breast cancer. DNA isolated from microdissected formalin-fixed, paraffin-embedded tissues was subjected to a PCR-LOH analysis for these chromosome loci, and the pattern of LOHs was compared between the two asynchronous lesions for the seven cases. RESULTS: In all patients except one, the LOHs were concordant at 91% as the informative chromosome loci in cases 1 to 6 were 56, and the concordance in LOH pattern between DCIS and IDC was detected at 50 loci. The LOHs had accumulated in accordance with the tumor progression from DCIS to IDC. The recurrent lesion occurred at or near the site of the primary biopsy and had similar or identical histopathologic features. CONCLUSIONS: These recurrences observed were probably residual disease rather than true recurrences. Our results suggest the following: (i) genetic alternations accumulate during cancer progression from DCIS to IDC, (ii) DCIS is a lesion that has a high risk of developing invasive transformation and (iii) after approximately 5 years without treatment, DCIS may develop into IDC.     

The prognostic significance of tumor-associated stroma in invasive breast carcinoma

Fibroblasts in the stromal component of a tumor may influence tumor progression in various organs. The prognostic significance of tumor-infiltrating lymphocytes is also frequently reported. However, the prognostic significance of the stromal component in breast cancers, particularly those of high grade, has not been established. In this study, we analyzed surgically resected specimens from 545 patients with breast carcinoma, including 193 high-grade tumors, for tumor?Cstroma ratio, dominant stroma type [collagen (C), fibroblast (F), or lymphocyte (L) dominant type], and central fibrosis on hematoxylin?Ceosin-stained histological sections. We correlated these features with clinical prognosis. Among the 533 specimens examined, 127 (23.3?%) were of C type, 292 (53.6?%) of F type, and 114 (20.9?%) of L type. Central fibrosis was found in 99 tumors (18?%). The dominant stroma type was a significant prognostic factor on univariate and multivariate analyses, together with T classification, nodal status, and Bloom?CRichardson grade. Tumor?Cstroma ratio and central fibrosis did not predict survival on multivariate analysis. Even in high-grade tumors, relapse-free intervals differed significantly according to dominant stroma type. Thus, conventional hematoxylin?Ceosin-stained tumor slides may contain more prognostic information than previously thought; in particular, the dominant stroma type in invasive breast cancer may potentially be used to predict outcome.     

Protein kinase C alpha expression in normal breast, ductal carcinoma in situ and invasive ductal carcinoma

The purpose of this study was to determine if Protein Kinase C alpha (PKC alpha) is altered in expression or localisation in normal breast, ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC). We obtained 14 mixed cases of invasive ductal carcinoma (IDC) and DCIS, 36 pure DCIS cases and 25 cases of normal breast. The sections were stained immunohistochemically for PKC alpha expression. Staining was cytoplasmic. The results showed a progressive reduction in staining intensity from normal breast to invasive ductal carcinoma. The staining pattern was heterogeneous in the cytoplasm of DCIS and IDC, but homogeneous in the cytoplasm of normal breast ductal epithelium. Interestingly, mitotic cells and cells with aberrant nuclear morphology showed increased cytoplasmic staining in DCIS and IDC. PKC alpha activity is altered in dividing or abnormal cells, but overall expression is reduced in IDC. This raises the possibility of an alteration in the subcellular localisation of PKC alpha which may relate to changes in desmosomal adhesive state.     

621例乳腺浸润性导管癌患者分子分型与临床病理学特征的关系

目的 探讨新疆地区乳腺浸润性导管癌不同分子亚型的分布,并研究分子亚型与各临床病理学特征的关系。方法 收集2013年1月—2014年1月明确诊断为乳腺浸润性导管癌病例621例,根据雌激素受体(ER)、孕激素受体(PR)、表皮生长因子受体-2(HER-2)和Ki-67的表达情况,把所有病例划分为Luminal A型、Luminal B型、HER-2过表达型及Basal-like型,然后结合临床病理特征进行比较统计。结果 621例中Luminal B型占53.1%,Luminal A型、HER-2过表达型和Basal-like型分别占14.5%、15.9%、16.4%。各分子亚型与肿瘤大小、病理组织学分级、肿瘤病理分期、ER状态、PR状态、HER-2状态均有关(P＜0.05),与年龄、淋巴结状态无关(P＞0.05)。结论 浸润性导管癌患者各分子亚型与其临床病理学特征有密切关系,分子分型有利于指导临床个体化治疗方案的制定。     

人类白细胞分化抗原133与乳腺浸润性导管癌临床病理特征的关系

目的 研究肿瘤干细胞标志物人类白细胞分化抗原（CD）133在乳腺浸润性导管癌组织中的表达及其与临床病理因素之间的关系.方法 收集2001年1月至2005年12月间承德市肿瘤医院和承德医学院附属医院肿瘤科的102例乳腺浸润性导管癌组织,采用免疫组织化学方法检测其CD133蛋白表达,并用χ^2验或Fisher确切概率法分析CD133表达与临床病理因素的关系.结果 乳腺浸润性导管癌组织不同程度地表达CD133.不同肿瘤直径组间CD133阳性表达率差异有统计学意义（χ^2=7.476,P=0.024）,其中肿瘤直径〉2～5 cm组CD133阳性表达率明显高于肿瘤直径≤2 cm组[56.72%（38/67）比26.09%（6/23）,χ^26.429,P＆lt;0.012].不同组织学分级间相比,CD133阳性表达率的差异也有统计学意义（χ^26.274,P=0.043）.并且,有淋巴结转移者CD133阳性表达率比无淋巴转移者高[64.71%（22/34）比39.71%（27/68）,χ^25.675,P=0.017）].乳腺浸润性导管癌组织中,CD133阳性表达率在不同年龄、不同临床分期之间差异无统计学意义（χ^20.177,P=0.674;χ^22.874,P=0.242）.结论 CD133有可能作为判断乳腺浸润性导管癌侵袭转移的指标.     

Infiltration of tumor-associated macrophages in human oral squamous cell carcinoma

Tumor-associated macrophages (TAMs) have been shown to display both positive and negative effects on tumor growth of various cancer. In this study, TAMs were immunohistochemically labeled using CD68 antibody in 82 oral cancer. Macrophage index (MI) were analyzed in association with clinical and pathological factors, intratumoral microvessel density (IMVD) and angiogenic factors including VEGF and TP. Significantly higher number of CD68-positive cells was noted in oral cancer. TAM expressions were significantly associated with stages of invasion, IMVD, and angiogenic factors. These findings suggest that TAMs possibly play a role in angiogenesis during oral cancer progression.     

Metallothionein expression and zinc levels in invasive ductal breast carcinoma.

Metallothioneins (MTs) and zinc are both known to promote progression of tumors in human cancers. A close relationship exists between MT and zinc, as synthesis of the former has been reported to be induced by the latter. To assess the relationship between MT and zinc content in breast cancer tissues, we analysed MT expression by immunohistochemistry and tissue zinc levels by atomic absorption spectrometry (AAS) in invasive ductal breast cancers and adjacent benign breast tissues. We observed overexpression of MT in breast cancer tissues and noted that zinc content in breast cancer tissues was twice that of benign breast tissues. The nuclear fraction obtained by subcellular fractionation of breast cancer tissues was found to have a higher zinc content than the plasma membrane and cytosolic fractions. Contrary to expectations, we found a significant inverse correlation of MT expression with zinc levels in breast cancer tissues, suggesting that whilst both synergistically influence growth and survival of tumor cells, they may also have divergent roles in carcinogenesis.     

Comparison of sentinel lymph node biopsy between invasive lobular carcinoma and invasive ductal carcinoma

Background

Recent studies suggested that ALND (axillary lymph node dissection) can be avoided in breast cancer patients with limited SLN (sentinel lymph node) metastasis. However, these trials included only several invasive lobular carcinoma (ILC) cases, and the validity of omitting ALND for ILC remains controversial. Here, we examined whether omitting ALND is feasible in ILC treatment.

Methods

A total of 3771 breast cancer patients underwent surgery for breast cancer at the Aichi Cancer Center Hospital between January 2006 and December 2015. We excluded patients with neoadjuvant therapy or without axillary management, and identified 184 ILC patients and 2402 invasive ductal carcinoma (IDC) patients. We compared SLN and non-SLN metastasis rates and the number of total ALN metastases between the ILC and IDC cohorts, and we examined the factors that influenced non-SLN metastasis in the SLN micrometastasis group.

Results

SLN biopsies were performed in 171 (93%) ILC and 2168 (90%) IDC cases, and 31 (18%) ILC and 457 (21%) IDC cases were SLN micrometastasis and macrometastasis (p?=?0.36). Among SLN macrometastasis patients, 17 (68%) ILC cases and 163 (46%) IDC cases showed non-SLN metastasis (p?=?0.03). The number of non-SLN metastases was greater in ILC cases compared with IDC cases. Multivariate analysis showed that ILC was the influential factor predicting non-SLN metastasis in patients with SLN macrometastasis.

Conclusion

ILC cases had more non-SLN metastasis than IDC cases among SLN-positive cases, and ILC was an important factor for the prediction of non-SLN positivity in SLN macrometastasis cases. Omitting ALND for ILC with positive SLNs requires more consideration.

     

Angiogenesis and invasive recurrence in ductal carcinoma in situ of the breast

The development of an invasive recurrence following treatment for ductal carcinoma in situ (DCIS) converts a non-fatal disease to one associated with mortality. To date, no pathological or molecular features have been found to predict for the type of recurrence. Previous studies have suggested that in DCIS angiogenesis may be an important factor in determining the transformation from in situ to invasive carcinoma. We looked at 355 cases of DCIS and found that 32 had subsequently developed recurrent disease. In these 32 cases and in matched controls, periductal vascular density was determined using morphometry and anti-endothelial antibodies, von Willebrand factor (vWF) and CD34. Vascular density was related to the risk of both invasive and in situ recurrence. Normal lobules at least 2 mm away were used as controls. Differences in the phenotype of individual blood vessels was detected by performing dual staining immunofluorescence on selected cases. The microvessel density (MVD), as detected with the CD34 antibody, was higher around foci of DCIS than around normal breast lobules (P=0.001). Furthermore, it was significantly higher in cases of DCIS that recurred (P<0.0001). The findings with the vWF antibody were less clear cut and suggested a trend in decreasing MVD with increasingly aggressive disease. Dual immunofluorescence staining shows that the increase in MVD seen around DCIS is due to an increase in CD34+/vWF-blood vessels. An increase in CD34+/vWF-of blood vessels may be able to predict cases of DCIS that are at a high risk of developing a recurrence.     

Telomerase activity in ductal carcinoma in situ and invasive breast cancer.

The increasing number of breast carcinoma in situ detected by screening procedures makes it imperative to develop improved markers to stratify the risk of invasive cancer. Telomerase is detectable in invasive cancer, but not in normal tissues. We have microdissected frozen tissue blocks containing both DCIS and invasive cancer to assay the telomerase activity of these two lesions. The 46 available cases of concurrent DCIS and invasive breast cancer resulted in 43 DCIS samples and 38 invasive cancer samples adequate for analysis. Seventy per cent of the DCIS and all invasive cancer samples tested had detectable telomerase activity. In addition, we analysed telomerase activity in ten cases of DCIS that were not associated with invasive cancer, and detected telomerase activity in seven (70%). Mixing experiments showed no evidence of telomerase inhibitors in telomerase negative samples. Furthermore, periductal inflammatory infiltrates were shown to be a potential confounding source of telomerase activity. Since DCIS lesions appear to be heterogeneous with respect to telomerase activity, and telomerase activation appears to precede the development of invasive cancer, telomerase activity may be a useful adjunct in stratifying the risk of developing invasive breast cancer in patients with DCIS.     

乳腺导管原位癌浸润转化及预后的研究进展

乳腺导管原位癌(DCIS)被认为是浸润性导管癌(IDC)的前驱病变,近年来,随着乳腺X线等检查技术的进步及普及,DCIS的检出率逐年升高,占所有新发乳腺癌的20％～25％,而30％～60％的IDC伴有共存性DCIS(DCIS IDC)。DICS浸润转化的机制已成为乳腺癌研究的前沿和热点。目前研究显示,肿瘤基因组等内在因素及肿瘤微环境等外在因素均在DCIS浸润转化过程中发挥重要作用,DCIS IDC亦表现不同于IDC的临床及预后特点。深入了解DICS浸润转化机制及对预后的影响,对乳腺癌患者病情的判断及精准方案的制定具有重要意义。