Metastatic breast carcinoma with appearance resembling micropapillary ductal carcinoma in situ.

AIM--To investigate tumour in an axillary lymph node resembling micropapillary ductal carcinoma in situ. METHODS--Sections of tumour in the breast and axillary lymph node were stained with haematoxylin and eosin, and immunohistochemically with antibodies to basement membrane and myoepithelial cells. RESULTS--Tumour in both the breast and axillary lymph node contained areas resembling micropapillary ductal carcinoma in situ. Surrounding these islands, there was a band of eosinophilic material resembling basement membrane and spindle cells that in places appeared to lie outside the basement membrane. Micropapillary tumour at both sites showed weak and discontinuous staining for collagen IV and laminin. The spindle cells stained for alpha-smooth muscle actin, but not for S100. By contrast, immunohistochemistry showed complete rings of basement membrane and myoepithelial cells around definite ductal carcinoma in situ and normal breast lobules and ducts. CONCLUSIONS--Invasive primary and metastatic carcinoma of the breast can have a growth pattern resembling micropapillary ductal carcinoma in situ.     

乳腺导管内癌分子分型应用研究

目的 采用免疫组织化学检测方法 对乳腺导管内癌进行分子分型.方法 收集50例乳腺导管内癌存档蜡块,用单克隆抗体CK5/6、CK8、CK18、34βE12、p63、S-100、SMA、CD10、CD117、EGFR、ER、PR和HER2进行免疫组织化学EnVision法染色,按照免疫表型分为5种类型:腺腔A型(ER+/PR+/HER2-)、腺腔B型(ER+/PR+/HER2+)、正常乳腺样型(ER-/PR-/HER2-且不表达基底/肌上皮标记及EGFR)、HER2过表达型(ER-/PR-/HER2+)和基底细胞样型(ER-/PR-/HER2-,且至少表达一种基底型角蛋白和(或)肌上皮标记物或EGFR).结果 腺腔A型16例(32%),腺腔B型19例(38%),HER2过表达型13例(26%),基底细胞样型2例(4%),无正常乳腺型.2例基底细胞样型,均表达CK5/6、CD117,例1同时表达SMA,例2表达CK8、CK18、34βE12、S-100,均为高级别导管内癌.结论 乳腺导管内癌可按免疫表型进行分子分型,部分导管内癌具有与基底细胞样癌相同的免疫表型,可能是基底细胞样癌的前驱病变,其诊断依赖于免疫组化检测.     

Mixed apocrine/endocrine ductal carcinoma in situ of the breast coexistent with lobular carcinoma in situ

An unusual mixed form of ductal carcinoma in situ (DCIS) of the breast is described, which exhibits a biphenotypic morphology encompassing a range of differential diagnostic DCIS subtypes. In addition, immunophenotypic and ultrastructural studies demonstrate neuroendocrine and apocrine differentiation, raising questions regarding appropriate classification and biological behaviour. In two cases, coexistence of this mixed form of DCIS with lobular carcinoma in situ (LCIS) in the same duct lobular units is an additional unusual feature that might, at least in some cases, indicate a closer relation between them.     

Atypical ductal hyperplasia and ductal carcinoma in situ of the breast associated with perineural invasion

Perineural invasion is a histologic feature usually diagnostic of invasion in malignancies. In the breast, however, it has been associated with benign lesions such as sclerosing adenosis (SA), complex sclerosing lesion/radial scar (CSL/RS), and ductal carcinoma in situ (DCIS). This article describes perineural invasion associated with atypical ductal hyperplasia (ADH), florid hyperplasia without atypia (FH), and DCIS. All cases with a diagnosis of perineural invasion were selected from a series of 10,000 breast consult cases. Invasive mammary carcinomas were excluded. Fourteen cases of perineural invasion were found and associated with the following diagnoses: ADH (5), DCIS (3), FH (5), and ductal adenoma (1). Nine cases developed in CSL/RS, 4 cases in SA, and 1 case in a previous biopsy site of ductal adenoma; lesions were all less than 3 mm. The glands involving nerves showed cytologic and architectural features of the adjacent ADH, DCIS, and FH. Immunostaining for protein gene product (PGP) 9.5 marked nerves, and smooth muscle actin antibody highlighted the myoepithelial cells around glands. Perineural invasion seen in association with DCIS and ADH, in a background of CSL/RS and SA, may pose difficulty in diagnosis, especially in small biopsy specimens. It should be assessed with care to avoid misinterpretation as invasive mammary carcinoma.     

乳腺导管原位癌组织学分级与其他预后因素的关系

目的　探讨乳腺导管原位癌组织学分级与分型以及ｃｅｒｂＢ２ 蛋白、ｐ５３ 蛋白、ＭＩＢ１ 、雌激素受体（ＥＲ） 表达的关系,以期为临床判断潜在恶性程度及预后提供参数。方法　参照Ｖａｎ Ｎｕｙｓ 分类方法,对３２ 例乳腺导管原位癌按核的分级、有无坏死进行组织学分级,并将标本行ｃｅｒｂＢ２ 蛋白、ｐ５３ 蛋白、ＭＩＢ１、ＥＲ的枸橼酸微波ＡＢＣ免疫组化法染色。结果　Ⅰ级（分化好）１２ 例（３７．５％ ） ,Ⅱ级（中度分化）９ 例（２８．１％ ） ,Ⅲ级１１ 例（３４．４％ ）。Ⅲ级患者中,９ 例为粉刺型,１ 例为微乳头状型,１ 例为实体型,Ⅲ级的ｃｅｒｂＢ２、ｐ５３ 和ＭＩＢ１ 蛋白表达的阳性率分别高于Ⅱ级和Ⅰ级,并与Ⅰ级比较差异有显著意义（ Ｐ＜０．０５） ,ＥＲ阳性率低于Ⅱ级和Ⅰ级。结论　乳腺导管原位癌Ｖａｎ Ｎｕｙｓ 组织学分级可能是一个较好的预后指标。     

Microsatellite instability in ductal carcinoma in situ of the breast

Microsatellite instability (MI⁺) is associated with defects in mismatch repair, resulting in a ‘mutator’ phenotype and the development and progression of cancer. MI⁺ has been documented in invasive breast carcinomas. This study was undertaken to determine whether MI⁺ is found in the early non-invasive form of breast cancer, ductal carcinoma in situ(DCIS). We examined microdissected ducts from 23 cases of DCIS with 11 markers comprising mono-, di-, and trinucleotide repeats from six chromosomal regions. Five tumours (22 per cent) displayed MI⁺ at two or more loci, in all ducts examined. A further seven (30 per cent) tumours showed alterations at a single locus (the DM-1 trinucleotide), and for two of these, heterogeneity between ducts was observed. Alterations at microsatellite repeat motifs in the coding regions of four cancer-associated genes (TGFβRII, IGFIIR, BAX, and E2F-4) were not observed. Immunohistochemistry revealed that there was no loss of reactivity for the mismatch repair proteins, MLH1, MSH2, and PMS2, in the DCIS cases. In general, MI⁺ tumours and those with alterations at the DM-1 microsatellite were predominantly of higher nuclear grade and expressing c-erbB-2, suggesting that aberrations in DNA repair functions may lead to the acquisition of a more aggressive phenotype in breast cancer. © 1998 John Wiley & Sons, Ltd.     

Loss of heterozygosity in ductal carcinoma in situ of the breast

Loss of heterozygosity (LOH) at loci reported to show allele loss in invasive breast cancers was examined in ductal in situ carcinomas of the breast using polymorphic short tandem repeats and the polymerase chain reaction (PCR). LOH was detected at all loci examined in at least 11 per cent of the samples examined. The proportion of cases of in situ carcinoma showing LOH at these loci was similar to that previously reported in invasive cancers. Cases of pure in situ cancer without an invasive component exhibited an overall lower frequency of allele loss. LOH at more than one locus was observed in some intraductal cancers. In a small number of cases, LOH was present in the invasive but not in the intraductal component of the tumour, suggesting that mutation at the locus concerned was associated with development of invasive behaviour.     

P-cadherin expression is associated with high-grade ductal carcinoma in situ of the breast

Cadherins are calcium-dependent cell-cell adhesion glycoproteins, separated into several subclasses with distinct adhesive specificities and tissue distribution, which play an important role in many cellular events. We analyse the expression of E-, N- and P-cadherin in a series of ductal carcinoma in situ (DCIS) of the breast, since this disease represents a heterogeneous group, with different risks of progression to invasive breast carcinoma. We also studied the correlation between cadherin expression and DCIS classification systems, namely the Van Nuys and the Holland et al. classification, this latter based on cytonuclear differentiation and cell polarity. Our results showed that, regardless the classification applied, P-cadherin expression is strongly associated with high histological grade of DCIS (P=0.0047) and lack of estrogen receptors (P=0.0008). The use of Holland et al. classification showed a significant correlation between P-cadherin expression and decreased cell polarity (P=0.01). In conclusion, P-cadherin expression seems to be more relevant in DCIS pathogenesis than the altered expression of any other cadherin, including the decrease of E-cadherin expression.     

Genetic pathways in the evolution of breast ductal carcinoma in situ

The patterns of allelic loss in 28 cases of pure ductal carcinoma in situ (DCIS) and 25 cases of DCIS associated with invasive ductal carcinoma (IDC) were compared, in order to define whether pure DCIS represented an earlier stage than DCIS associated with IDC in the progression of breast carcinoma. To this aim, the polymerase chain reaction (PCR) was performed on microdissected normal and neoplastic breast tissue, formalin-fixed and paraffin-embedded. Fifteen microsatellite markers were examined, on chromosomes 1p, 3p, 7q, 11q, 12p, 13q, 16q and 17q, mostly focused on regions altered in breast cancer. Loss of heterozygosity (LOH) was greater in pure DCIS than in the DCIS component associated with IDC for 11 out of 15 markers. The difference was statistically significant for D13S260 and D17S800 (p=0.008 and p=0.01, respectively). DCIS associated with IDC showed a lesser degree of alteration than the synchronous IDC component for ten out of 15 markers. In contrast, LOH at D11S1816 and D16S318 was lower in pure DCIS than in DCIS associated with IDC and even greater in the IDC component. These results confirm that DCIS is a possible but not an obligate precursor of invasive breast cancer and suggest that pure DCIS and DCIS associated with IDC may be genetically distinct. The evolution from DCIS to IDC may follow multiple pathways and not a linear model.     

Identification of a basal-like subtype of breast ductal carcinoma in situ

Microarray profiling of invasive breast carcinomas has identified subtypes including luminal A, luminal B, HER2-overexpressing, and basal-like. The poor-prognosis, basal-like tumors have been immunohistochemically characterized as estrogen receptor (ER)-negative, HER2/neu-negative, and cytokeratin 5/6-positive and/or epidermal growth factor receptor (EGFR)-positive. The aim of this study was to determine the prevalence of basal-like ductal carcinoma in situ in a population-based series of cases using immunohistochemical surrogates. A total of 245 pure ductal carcinoma in situ cases from a population-based, case-control study were evaluated for histologic characteristics and immunostained for ER, HER2/neu, EGFR, cytokeratin 5/6, p53, and Ki-67. The subtypes were defined as: luminal A (ER+, HER2-), luminal B (ER+, HER2+), HER2 positive (ER-, HER2+), and basal-like (ER-, HER2-, EGFR+, and/or cytokeratin 5/6+). The prevalence of breast cancer subtypes was basal-like (n = 19 [8%]); luminal A, n = 149 (61%); luminal B, n = 23 (9%); and HER2+/ER-, n = 38 (16%). Sixteen tumors (6%) were unclassified (negative for all 4 defining markers). The basal-like subtype was associated with unfavorable prognostic variables including high-grade nuclei (P < .0001), p53 overexpression (P < .0001), and elevated Ki-67 index (P < .0001). These studies demonstrate the presence of a basal-like in situ carcinoma, a potential precursor lesion to invasive basal-like carcinoma.     

Expression of cyclins in ductal hyperplasia, atypical ductal hyperplasia and ductal carcinoma in situ of the breast

Cyclin/cdc complexes are known to function in cell-cycle regulation. Cyclin D1/cdk4 and -6 complexes, which functions as a G1-S checkpoint and cyclin B1/cdc2 complexes, a G2-M checkpoint are essential for DNA synthesis and mitosis, respectively. Thus, dysregulated overexpression of cyclins appears to be involved in uncontrollable cell proliferation and early tumor development. We investigated the expression and proliferative index of cyclin D1 (PIcyclin D1), cyclin B1 (PIcyclin B1) and Ki-67 (PIKi-67) using immunohistochemical staining on 15 cases of ductal hyperplasia (DH), 26 cases of atypical ductal hyperplasia (ADH) and 43 cases of ductal carcinoma in situ (DCIS) of the breast in order to evaluate whether these cyclins are associated with abnormal cell proliferation and play a role in tumor development from ADH to carcinoma. Furthermore, we investigated whether the expression and proliferative index of the cyclins and Ki-67 are correlated with the histologic grade according to the Van Nuys classification and with the histologic subtype according to traditional classification. Finally, we estimated the correlation coefficient among PIcyclin D1, PIcyclin B1, PIKi-67 and estrogen receptor in ADH and DCIS. The expression of cyclin D1 was detected in 39.5% of DCIS and 7.7% of ADH cases. In the DH cases, expression of cyclin D1 was not found. Expression of cyclin B1 was also detected in 69.7% of DCIS, 50.0% of ADH and 93.3% of the DH cases. The PIcyclin D1 was significantly different among these three groups. Moreover, the PIcyclin D1 and PIKi-67 were differed significantly between the low grade DCIS and ADH cases. However, PIcyclin B1 only appeared to be significantly different between the total DCIS and ADH. Results of the correlation coefficient among PIcyclin D1, PIcyclin B1 and PIKi-67 were positively correlated with each other. No significant correlation was found between the expression of ER and cyclin D1 in ADH and DCIS. In summary, our results support the hypothesis that a cyclin D1 and cyclin B1 protein aberration, along with Ki-67, may act as a relatively early event in the tumor development from ADH to carcinoma.     

Cyclooxygenase-2 expression: a potential prognostic and predictive marker for high-grade ductal carcinoma in situ of the breast

AIMS: To study cyclooxygenase-2 (COX-2) expression in ductal carcinoma in situ (DCIS) of the breast and its association with histological features. COX-2, an inducible prostaglandin synthase, has been shown to be important in mammary carcinogenesis, being associated with increased tumour size and unfavourable outcome in breast cancer. Animal studies indicate that COX-2 inhibition is effective in the prevention and treatment of mammary cancers. METHODS AND RESULTS: Fifty-one cases of DCIS diagnosed during 1990-2000 were reviewed. Immunohistochemistry for COX-2 was performed and the COX-2 staining scores were correlated with histological features. The majority of cases [41 of 51 (80%)] had positive COX-2 staining, of which 13 cases (25%) had strong staining. High nuclear grade DCIS was significantly associated with increased COX-2 staining (P = 0.04). CONCLUSIONS: High-grade lesions are known to be associated with a higher recurrence rate following excision and are often oestrogen receptor negative, and as such, may be less responsive to adjuvant tamoxifen therapy. There is a need to examine further the role of COX-2 expression in DCIS, as both a prognostic and predictive factor.     

Comparative features of ductal carcinoma in situ and infiltrating ductal carcinoma of the breast on fine-needle aspiration biopsy

To evaluate the usefulness of fine-needle aspiration biopsy of the breast in separating ductal carcinoma in situ (DCIS) from infiltrating ductal carcinoma, the authors reviewed 16 preoperative fine-needle aspiration biopsies from biopsy-proven exclusive DCIS and 39 fine-needle aspiration biopsies from infiltrating ductal carcinomas with or without an in situ component. Seven (44%) of the DCIS and eight (21%) of the infiltrating ductal carcinomas had inadequate material for diagnosis on the aspiration biopsy. Five (32%) of the DCIS and 29 (74%) of the infiltrating ductal carcinomas caused suspicion or had positive results for malignancy. Four (25%) of the DCIS and two (5%) of the infiltrating ductal carcinomas showed atypical cells. Morphologic features of the atypical or malignant cells in the adequate specimens from these two lesions were similar except that the cells from the infiltrating ductal carcinomas showed more irregular nuclear spacing (94% vs. 44%, P less than 0.01) and more pronounced nuclear overlapping (65% vs. 33%) than those from the DCIS. In addition, the fine-needle aspiration biopsies of the DCIS tended to be hypocellular (less than 10 cells/10X) (44% vs. 6.5%, P less than 0.05) and to contain benign epithelial cells (22% vs. 6.5%) and macrophages (33% vs. 13%). Although the suspicion of DCIS might be raised when hypocellularity, benign epithelial cells, and macrophages are noted in a fine-needle aspiration biopsy of the breast that has positive results or causes suspicion for malignancy, fine-needle aspiration biopsy cannot be relied upon to distinguish DCIS from infiltrating ductal carcinoma.     

CD24 expression in ductal carcinoma in situ and invasive ductal carcinoma of breast: an immunohistochemistry-based pilot study

CD24 is a small, heavily glycosylated cell surface protein, that is expressed in a large variety of solid tumors. It is considered to play an important role in tumor progression and metastasis. We aimed to evaluate CD24 expression in invasive ductal carcinomas (IDCa), ductal carcinoma in situ (DCIS) and non-tumorous breast tissues, and to investigate the relationship between histopathological parameters, estrogen and progesterone receptors, and c-erbB2 expressions. The study included 34 IDCa, 25 DCIS, and 13 non-tumorous breast tissues. All cases were reevaluated histopathologically, and immunohistochemistry was performed with monoclonal CD24 antibody. The results clearly demonstrated that CD24 expression, including membranous and cytoplasmic staining, was significantly higher in DCIS and IDCa than in the non-tumorous breast (p=0.001, p=0.000, and p=0.035, p=0.000, respectively). Cytoplasmic staining was detected predominantly in neoplastic tissues and was significantly increased in high grade DCIS (p=0.013). In invasive carcinomas, although the level of membranous staining was significantly positively correlated with tumor grade (p=0.040), there was no such an association with the cytoplasmic level. However, it showed a trend towards pT (p=0.089). In conclusion, our results suggest that higher CD24 expression may be associated with malignant transformation and progression in breast cancer biology. Furthermore, higher membranous expression and, in particular, cytoplasmic staining seem to predict malignant transformation, and different patterns of CD24 expression may be associated with different pathological features in breast tumors.