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.     

Grade of recurrent in situ and invasive carcinoma following treatment of pure ductal carcinoma in situ of the breast

The grade of recurrent in situ and invasive carcinoma occurring after treatment of pure ductal carcinoma in situ (DCIS) has been compared with the grade of the original DCIS in 122 patients from four different centres (The Royal Marsden Hospitals, London and Sutton, 57 patients; Guy's Hospital, London, 19 patients; Nottingham City Hospital, 31 patients and The Royal Liverpool Hospital, 15 patients). The recurrent carcinoma was pure DCIS in 70 women (57%) and in 52 women (43%) invasive carcinoma was present, which was associated with an in situ element in 43. In all, 19 patients developed a second recurrence (pure DCIS in 11 and invasive with or without an in situ element in eight). The majority of invasive carcinomas followed high-grade DCIS. There was strong agreement between the grade of the original DCIS and that of the recurrent DCIS (kappa=0.679), which was the same in 95 of 113 patients (84%). The grade of the original DCIS showed only fair agreement with the grade of recurrent invasive carcinoma (kappa=0.241), although agreement was stronger with the pleomorphism score of the recurrent carcinoma (kappa=0.396). There was moderate agreement, in recurrent invasive lesions, between the grade of the DCIS and that of the associated invasive element (kappa=0.515). Other features that showed moderate or strong agreement between the original and recurrent DCIS were necrosis and periductal inflammation. The similarity between the histological findings of the original and subsequent DCIS is consistent with the concept that recurrent lesions represent regrowth of residual carcinoma. In addition, although agreement between the grade of the original DCIS and that of any subsequent invasive carcinoma was only fair, there is no suggestion that low-grade DCIS lesions progress to higher grade lesions or to the development of higher grade invasive carcinoma. This is in agreement with immunohistochemical and molecular data indicating that low-grade and high-grade mammary carcinomas are quite different lesions.     

Paget's病伴浸润性导管癌的临床病理特征及预后因素分析:基于SEER的回顾性研究

目的:分析佩吉特氏病伴浸润性导管癌（Paget's disease with invasive ductal carcinoma,PD-IDC）患者的临床病理特征、治疗和预后情况。方法:通过美国 SEER*Stat 软件搜集2010至2014年病理明确诊断为PD-IDC及浸润性乳腺癌（invasive ductal carcinoma,IDC）并接受手术治疗的患者分别550例和207 221例。用SPSS 21.0进行统计学分析和绘制生存曲线。结果:与IDC相比,PD-IDC患者男性乳腺癌比例更大,可能有更大的体积、更多的淋巴结受累、更高级别以及更晚期的肿瘤（P均<0.05）;且更可能是激素受体（HR）阴性［ER阴性（37.3% vs 18.5%）、PR阴性（52.0% vs 28.5%）］和Her-2阳性（53.3% vs 15.4%）;在治疗方案中更有可能接受乳房切除术（85.8% vs 43.9%）和腋窝淋巴结清扫术（45.1% vs 29.5%）（P均<0.05）;但预后更差,死亡率更高,且乳腺癌相关死亡率（BCSM）更高。此外,Cox回归分析显示肿瘤分级和Her-2状态与PD-IDC患者的总生存时间（OS）显著相关（P<0.05）,而患者性别和肿瘤分级与PD-IDC患者的BCSM相关（P<0.05）,且Her-2阳性者相较于阴性者（OS:HR=0.019,P=0.009;BCSM:HR=0.000,P=0.623）与PD-IDC患者的OS显著相关,淋巴结手术方式也与PD-IDC患者的OS有一定的相关性。结论:与IDC相比,PD-IDC患者更可能是HR阴性和Her-2阳性且预后较差。同时,淋巴结的处理在PD-IDC的治疗中有一定的必要性。     

Clinicopathological predictive factors for ipsilateral and contralateral events following initial surgery to treat ductal carcinoma in situ

Background

Ipsilateral breast tumor recurrence (IBTR) after partial breast resection and contralateral breast tumor recurrence (CBTR) have been shown to occur relatively frequently in patients with ductal carcinoma in situ (DCIS). However, there is only limited data from Japanese institutes to support this.

Methods

Of 301 consecutive DCIS patients, 179 patients underwent a mastectomy, and the other 122 underwent partial resection in the National Cancer Center Hospital, Tokyo, with a median follow-up period of 2,106 days. We reviewed clinicopathological parameters including age, menopausal status, body mass index, family history (FH) of breast cancer, tumor size, histological subtype, nuclear grade (NG), hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status, treatment, and the surgical margin status of partially resected specimens. The risk associated with each of these parameters for IBTR in 122 patients who underwent partial resections, and for CBTR in a total of 301 patients were calculated using Cox proportional hazard general linear models.

Results

Of the 122 patients who underwent partial breast resection, IBTR occurred in 7 (5.7 %). The risk of IBTR was higher or tended to be higher in younger patients or those with lower NG tumors, but did not change significantly with respect to margin status or irradiation. Amongst the entire cohort of 301 patients, CBTR occurred in 18 cases (6.0 %). CBTR occurred significantly more frequently in patients with a FH of breast cancer and with HR+/HER2? subtype tumors by univariate analyses, and tumor subtype was an independent risk factor for CBTR by multivariate analysis.

Conclusions

The local recurrence rate was low following partial resection of DCIS. Younger age was a risk factor for IBTR, whereas the HR+/HER2? tumor subtype and a FH of breast cancer were risk factors for CBTR.

     

Upstaging to invasive ductal carcinoma after mastectomy for ductal carcinoma in situ: predictive factors and role of sentinel lymph node biopsy

Background

The aim of this study was to investigate preoperative factors associated with ductal carcinoma in situ (DCIS) upstaged to invasive ductal carcinoma (IDC) and sentinel lymph node (SLN) status in patients who underwent mastectomy for a preoperative diagnosis of DCIS.

Methods

The medical records of 220 patients who underwent mastectomy for a preoperative diagnosis of DCIS were retrospectively reviewed.

Results

Fifty-one (22.6%) of 226 lesions were upgraded to IDC after mastectomy. Preoperative factors associated with upstaging to IDC included patient-reported signs and symptoms, a clinically palpable mass, ultrasound findings classified as category 4 or 5, the ultrasound appearance of a mass or widely distributed non-mass abnormality (NMA), and a high Ki67 index. The prevalence of SLN macrometastasis was 0.9%. IDC was diagnosed for 10.9% of lesions of a preoperative ultrasound category of 0–3, 13.0% of those with no mass or NMA detected by ultrasonography, and 14.1% of lesions preoperatively diagnosed by methods other than core needle biopsy (CNB). Of those lesions, none was associated with SLN metastasis.

Conclusions

Routinely performing SLN biopsy for patients undergoing mastectomy for a preoperative diagnosis of DCIS is overtreatment, because the prevalence of SLN metastasis was low. SLN biopsy can be omitted for most patients. In particular, we suggest omitting SLN biopsy for patients who have lesions of ultrasound category 0–3, who have neither a mass nor NMA detected by ultrasound, or whose initial diagnosis was made based on a specimen obtained by methods other than CNB.

     

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。     

Genomic differences between pure ductal carcinoma in situ of the breast and that associated with invasive disease: a calibrated aCGH study

PURPOSE: In the quest for new targets, genomes of ductal carcinoma in situ (DCIS) and infiltrating duct carcinoma (IDC) have been compared previously; however, genomic alterations associated with cancer progression were difficult to identify. We hypothesized that significant events can be detected by comparing lesions with a broader range of behavior: from pure DCIS to IDC associated with lymph node metastasis. EXPERIMENTAL DESIGN: Array comparative genomic hybridization, calibrated by self-self hybridization tests, was used to study 6 cases of pure DCIS and 17 cases of DCIS paired with IDC where 8 tumors had spread to the local lymph nodes. RESULTS: Pure DCIS exhibited a marginally higher degree of genomic complexity than DCIS and IDC components of invasive tumors. The latter two showed similarity between tumors and between components of the same tumor with several regions detected preferentially compared with pure DCIS. IDC associated with lymph node metastases showed similarity of genomic profiles as a group. Gain on 17q22-24.2 was associated with higher histologic grade, large IDC size, lymphatic/vascular invasion, and lymph node metastasis (P < 0.05). CONCLUSIONS: Our findings suggest that DCIS and IDC are associated with specific genomic events. DCIS associated with IDC is genomically similar to the invasive component and therefore may represent either a clone with high invasive potential or invasive cancer spreading through the ducts. Specifically, gain on 17q22-24.2 is a candidate region for further testing as a predictor of invasion when detected in DCIS and predictor of nodal metastasis when detected in DCIS or IDC.     

Clinicopathological features of multiple primary gastric carcinoma

The clinicopathological features of multiple primary gastric carcinoma in 107 patients who had undergone gastrectomy between 1972 and 1992 were studied and compared with those of single gastric carcinoma in 1,456 patients. The incidence of occurrence of multiple primary gastric carcinoma was 6.8% of patients who had gastrectomy for gastric cancer. Such carcinoma was detected less often in patients <49 years of age. Dominant findings involved an elevated gross appearance, papillary or well-differentiated adenocarcinoma in the histology, and invasion to the depth of mucosa. When multiple primary gastric carcinoma was classified by main and concomitant lesions based on the stage of the disease, concomitant lesions were detected more often in the lower third of the stomach and at the distal site of main lesions located in the upper or middle third of the stomach. These results indicate that the lower third of the stomach and the distal site of the main lesion must be investigated carefully to ensure that incidental concomitant lesions are not overlooked, especially when a patient has the clinicopathological features described above. © 1996 Wiley-Liss, Inc.     

乳腺导管内癌与乳腺浸润性导管癌的超声特征及病理对照分析

目的探讨乳腺导管内癌与乳腺浸润性导管癌的超声特征及病理情况。方法选取2014年2月至2016年1月间广东省肇庆市第一人民医院收治的45例乳腺导管内癌患者与45例乳腺浸润性导管癌,分析两种乳腺癌患者的超声声像特点与病理情况的差异。结果两种乳腺癌患者的病灶大小、形状、血流信号、病灶周边毛刺与边界情况比较,差异均有统计学意义(均P<0.05)。结论乳腺导管内癌与乳腺浸润性导管癌的超声特征及病理情况上有差异明显,有助于临床疾病的鉴别诊断。     

Pure ductal carcinoma in situ and in situ component of ductal invasive carcinoma of the breast. A preliminary morphometric study

Nuclear pleomorphism is a fundamental feature in evaluating the aggressiveness of ductal carcinoma in situ (DCIS) of the breast. In this study, pure DCIS and the in situ component (IS-comp) of invasive duct carcinoma (IDC) are compared in order to verify if these are two different entities or the same process observed at different times during its evolution. Five cases of pure DCIS and nine of IDC with extensive in situ component were selected. They were moderately and poorly differentiated. 30 nuclei for each DCIS, and 30 nuclei for both the in situ and invasive component of each IDC were studied; thus, a total of 720 nuclei were submitted to the SAM (Shape Analytical Morphometry) analysis, which enables a numerical expression not only of dimensions (area, perimeter, diameter) but also of nuclear contour irregularities and nuclear shape distortions. Univariate statistical comparisons were carried out between the nuclei of: (1) DCIS and in situ component of invasive duct carcinoma, (2) DCIS and the invasive component of infiltrating carcinoma and (3) between the in situ and invasive component of infiltrating carcinoma. Multivariate analysis was utilized to compare nuclei of DCIS with the in situ component of IDC. The in situ features of each tumor were also evaluated with the mitotic index (MI). Nuclei of pure DCIS resulted significantly larger (p < 0.001) and with a more regular shape (p < 0.001) than those of the in situ component of IDC. No differences were observed between the nuclei of the in situ and the invasive component of infiltrating carcinomas. Multivariate statistical analysis discriminated 77% of nuclei of in situ proliferation when both G2 and G3 tumors were considered, and 80% when only G3 tumors were considered. In conclusions morphological differences exist between pure DCIS and the in situ component of IDC, which may be an expression of their biological behavior; moreover, these morphological differences seem to have a better discriminating power within the same histological grade.     

Incidence and prediction of invasive disease and nodal metastasis in preoperatively diagnosed ductal carcinoma in situ

For breast cancer patients with a preoperative diagnosis of ductal carcinoma in situ (DCIS), sentinel lymph node (SN) biopsy has been proposed as an axillary staging procedure in selected patients with a higher likelihood of having occult invasive lesions. With detailed histological examination of primary tumors and molecular whole‐node analysis of SNs, we aimed to validate whether this selective application accurately identifies patients with SN metastasis. The subjects were 336 patients with a preoperative needle‐biopsy diagnosis of DCIS who underwent SN biopsy using the one‐step nucleic acid amplification assay in the period 2009–2011. The incidence and preoperative predictors of upstaging to invasive disease on final pathology and SN metastasis, and their correlation, were investigated. Of the 336 patients, 113 (33.6%) had invasive disease, and 6 (1.8%) and 17 (5.0%) had macro‐ and micrometastasis in axillary nodes respectively. Of the 113 patients with invasive disease, 4 (3.5%) and 9 (8.0%) had macro‐ and micrometastasis. Predictors of invasive disease included palpability, mammographic mass, and calcifications (spread >20 mm), and intraductal solid structure, but no predictor was found for SN metastasis. Therefore, even though occult invasive disease was found at final pathology, most of the patients had no metastasis or only micrometastasis in axillary nodes. Predictors of invasive disease and SN metastasis were not completely consistent, so the selective SN biopsy for patients with a higher risk of invasive disease may not accurately identify those with SN metastasis. More accurate application of SN biopsy is required for patients with a preoperative diagnosis of DCIS.     

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。     

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.     

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.     

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。     

乳腺浸润性导管/小叶混合癌的临床病理特征和预后分析

目的:探讨乳腺浸润性导管/小叶混合癌（IDC-L）与浸润性小叶癌（ILC）及浸润性导管癌（IDC）临床病理特征以及预后的差异。方法:回顾性分析2009年1月至2015年12月上海交通大学乳腺癌数据库中有完整临床病理资料与随访资料的IDC-L、ILC与IDC患者的临床病理特征以及预后的差异。结果:共2 957例乳腺癌患者入组,其中IDC-L、ILC与IDC分别有109、177和2 671例。多因素分析显示,与IDC-L相比,IDC患者多中心病灶和脉管浸润较少,而HER2阳性和Ki-67高表达较多（P<0.05）;ILC患者发病年龄较大、脉管浸润较少（P<0.05）。IDC-L患者的5年无乳腺癌生存率（BCFI）（82.1% vs 90.7%,P=0.040）和总生存率（OS）（91.0% vs 94.4%,P=0.029）比IDC患者差;但与ILC患者（BCFI:84.1%,P=0.803,OS:92.6%,P=0.803）无明显差异。多因素生存分析显示,病理类型、肿瘤大小、淋巴结状态以及分子分型是影响患者BCFI和OS的独立因素（P<0.05）,IDC-L较IDC患者有较差的BCFI（HR=1.67,95%CI:1.02~2.70,P=0.042）及OS（HR=1.89,95%CI:1.04~3.45,P=0.037）。结论:IDC-L临床病理特征与ILC相似,但与IDC有较多不同;IDC-L预后劣于IDC,与ILC无明显差异,有待进一步研究证实。     

乳腺导管原位癌与浸润性导管癌染色体微卫星杂合性缺失的比较

目的:研究乳腺导管原位癌与浸润性导管癌染色体3p区域微卫星杂合性缺失(loss of heterozygosity,LOH)的发生情况.方法:选取本院2005年9月至2009年2月手术切除石蜡包埋的乳腺癌组织切块43例,应用激光显微切割技术留取组织中乳腺浸润性导管癌(invasive ductal type carci...     

Clinicopathological significance of stromal myofibroblasts in invasive ductal carcinoma of the breast.

The purpose of this study was to investigate the distribution of CD34-positive fibroblasts and alpha-smooth muscle actin (alpha-SMA)-reactive myofibroblasts in the stroma of benign and malignant breast lesions and, secondly, to determine whether the presence of stromal myofibroblasts is associated with some of the clinicopathological characteristics of patients with invasive ductal carcinoma. The presence of stromal CD34-positive fibroblasts and myofibroblasts was investigated (as defined immunohistochemically) in 8 normal breast tissue samples, 58 invasive ductal carcinomas, 9 ductal carcinomas in situ and 16 specimens with benign lesions of the breast (fibroadenomas, ductal hyperplasias). We further studied the correlations between the presence of stromal myofibroblasts with 7 clinicopathological parameters in 58 invasive ductal carcinomas. The results indicated that the stroma of normal breast tissues contained CD34-positive fibroblasts. All benign breast lesions exhibited stromal CD34-positive fibroblasts. In contrast, the stroma of ductal carcinomas showed a complete loss of CD34-positive fibroblasts. alpha-SMA expression in stromal fibroblasts (myofibroblasts) was not detected in normal tissue samples or benign lesions except in 1 case of fibroadenoma, whereas positive myofibroblasts were found in 44.4% of ductal carcinomas in situ and 56.9% of invasive breast carcinomas. Comparison of clinicopathological parameters between invasive ductal carcinomas with and without stromal myofibroblasts revealed significant differences in lymph node metastasis, high histological grade and high microvessel density. These results suggest that CD34 loss and the presence of myofibroblasts favor the diagnosis of breast carcinoma. In invasive ductal carcinoma, the presence of stromal myofibroblasts correlated significantly with pathological parameters associated with a poor prognosis.     

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.