Comedo Ductal Carcinoma In Situ Research Articles

Abstract 2709: CD44 inhibits DCIS progression to invasive carcinoma

Abstract Ductal carcinoma in situ (DCIS) transition to invasive tumor is an important issue for breast cancer. The human MCF10DCIS.com cell line (abbreviated as MCF10DCIS) is derived from the spontaneously immortalized human MCF10A breast epithelial cell line. The MCF10DCIS xenografts are similar to human high grade comedo DCIS. In the xenograft assay, MCF10DCIS cells form DCIS-like lesion, remain as DCIS-like lesion in the first several weeks, and then progress into invasive carcinoma. Thus, it is an excellent model to study human breast cancer transition from DCIS to invasive carcinoma. To the best of our knowledge, it is the most commonly used model for DCIS transition to invasive carcinoma. We investigated the role of CD44 in breast cancer transition from DCIS to invasive carcinoma by knockdown the expression of CD44 in the MCF10DCIS xenograft model. Our results show that knockdown of CD44 expression in the MCF10DCIS cells enhances DCIS transition to invasive carcinoma. Our finding is supported by a previous study which showed that CD44 expression was lower in invasive human breast carcinomas than in DCIS, especially in the luminal A subtype. Our study uncovered an unexpected role of CD44 in the inhibition of DCIS transition to invasive carcinoma. We will also present a model for the underlying mechanisms for the protective role of CD44 in the inhibition of transition from DCIS to invasive carcinoma. Our findings have important implications for breast cancer. Citation Format: Fang Liu, Jun Zhou, Tanima Kundu-Roy, Joseph Wahler, Jae Young So, Yong Lin, You-Rong Lou, Nicola J. Barnard, Isao Matsuura, Nanjoo Suh. CD44 inhibits DCIS progression to invasive carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2709.

Machine learning-based image analysis for accelerating the diagnosis of complicated preneoplastic and neoplastic ductal lesions in breast biopsy tissues.

Diagnosis of breast preneoplastic and neoplastic lesions is difficult due to their similar morphology in breast biopsy specimens. To diagnose these lesions, pathologists perform immunohistochemical analysis and consult with expert breast pathologists. These additional examinations are time-consuming and expensive. Artificial intelligence (AI)-based image analysis has recently improved, and may help in ordinal pathological diagnosis. Here, we showed the significance of machine learning-based image analysis of breast preneoplastic and neoplastic lesions for facilitating high-throughput diagnosis. Images were obtained from normal mammary glands, hyperplastic lesions, preneoplastic lesions and neoplastic lesions, such as usual ductal hyperplasia (UDH), columnar cell lesion (CCL), ductal carcinoma in situ (DCIS), and DCIS with comedo necrosis (comedo DCIS) in breast biopsy specimens. The original enhanced convoluted neural network (CNN) system was used for analyzing the pathological images. The AI-based image analysis provided the following area under the curve values (AUC): normal lesion versus DCIS, 0.9902; DCIS versus comedo DCIS, 0.9942; normal lesion versus CCL, 0.9786; and UDH versus DCIS, 1.000. Multiple comparison analysis showed precision and recall scores similar to those of single comparison analysis. Based on the gradient-weighted class activation mapping (Grad-CAM) used to visualize the important regions reflecting the result of CNN analysis, the ratio of stromal tissue in the whole weighted area was significantly higher in UDH and CCL than that in DCIS. These analyses may provide a more accurate and rapid pathological diagnosis of patients. Moreover, Grad-CAM identifies uncharted important histological characteristics for newer pathological findings and targets of research for understanding diseases.

Abstract 5052: CD44 inhibits the transition of ductal carcinoma in situ to invasive breast carcinoma

Abstract Ductal carcinoma in situ (DCIS) transition to invasive tumor is a big problem for breast cancer. The human MCF10DCIS.com cell line (abbreviated as MCF10DCIS) is derived from the human MCF10A breast epithelial cell line. The MCF10DCIS xenografts are similar to human high grade comedo DCIS. In the xenograft assay, MCF10DCIS cells form DCIS-like lesion, remain as DCIS-like lesion in the first several weeks, and then progress into invasive carcinoma. Thus, it is an excellent model to study human breast cancer transition from DCIS to invasive carcinoma. We investigated the role of CD44 in breast cancer transition from DCIS to invasive carcinoma by knockdown the expression of CD44 in the MCF10DCIS xenograft model. Our results show that knockdown of CD44 expression in the MCF10DCIS cells promotes DCIS transition to invasive carcinoma. Our finding is supported by a previous study that showed CD44 expression is higher in DCIS than in invasive breast carcinomas for human patients. Furthermore, we will present our ongoing studies for the underlying mechanisms. Our findings have important implications for breast cancer. Citation Format: Fang Liu, Jun Zhou, Tanima Kundu-Roy, Joseph Wahler, Jae Young So, Yong Lin, You-Rong Lou, Nicola J. Barnard, Isao Matsuura, Nanjoo Suh. CD44 inhibits the transition of ductal carcinoma in situ to invasive breast carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5052.

Abstract 1073: Role of CD44 in the transition of ductal carcinoma in situ to invasive breast carcinoma

Abstract Ductal carcinoma in situ (DCIS) transition to invasive tumor is an important issue for breast cancer. The human MCF10DCIS.com cell line (abbreviated as MCF10DCIS) is derived from the human MCF10A breast epithelial cell line. The MCF10DCIS xenografts are similar to human high grade comedo DCIS. In the xenograft assay, MCF10DCIS cells form DCIS-like lesion, remain as DCIS-like lesion in the first few weeks, and then progress into invasive carcinoma. Thus, it is an excellent model to study human breast cancer transition from DCIS to invasive carcinoma. To the best of our knowledge, it is also the only cell model for DCIS transition to invasive carcinoma. We investigated the role of CD44 in breast cancer transition from DCIS to invasive carcinoma by knockdown the expression of CD44 in the MCF10DCIS xenograft model. Our results show that knockdown of CD44 expression in the MCF10DCIS cells enhances DCIS transition to invasive carcinoma. Accordingly, a previous study has shown that CD44 expression is lower in invasive human breast tumors compared with DCIS, especially in luminal A subtype. We have also observed that CD44 expression is lower in the invasive carcinomas compared with DCIS. Furthermore, we provide evidence that CD44 plays a role in maintaining the integrity of the myoepithelial layer. Our study uncovered an unexpected role of CD44 in the prevention of DCIS transition to invasive carcinoma. Our findings have important implications for breast cancer. Note: This abstract was not presented at the meeting. Citation Format: Fang Liu, Jun Zhou, Tanima Kundu-Roy, Joseph Wahler, Jae Young So, Yong Lin, You-Rong Lou, Nicola J. Barnard, Isao Matsuura, Nanjoo Suh. Role of CD44 in the transition of ductal carcinoma in situ to invasive breast carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1073.

Cytochrome c1 in ductal carcinoma in situ of breast associated with proliferation and comedo necrosis.

It is well known that comedo necrosis is closely associated with an aggressive phenotype of ductal carcinoma in situ (DCIS) of human breast, but its molecular mechanisms remain largely unclear. Therefore, in this study, we first examined the gene expression profile of comedo DCIS based on microarray data and identified CYC1 as a gene associated with comedo necrosis. Cytochrome c1 (CYC1) is a subunit of complex III in the mitochondrial oxidative phosphorylation that is involved in energy production. However, the significance of CYC1 has not yet been examined in DCIS. We therefore immunolocalized CYC1 in 47 DCIS cases. CYC1 immunoreactivity was detected in 40% of DCIS cases, and the immunohistochemical CYC1 status was significantly associated with tumor size, nuclear grade, comedo necrosis, van Nuys classification, and Ki‐67 labeling index. Subsequent in vitro studies indicated that CYC1 was significantly associated with mitochondrial membrane potential in MCF10DCIS.com DCIS cells. Moreover, CYC1 significantly promoted proliferation activity of MCF10DCIS.com cells and the cells transfected with CYC1 siRNA decreased pro‐apoptotic caspase 3 activity under hypoxic or anoxic conditions. Considering that the center of DCIS is poorly oxygenated, these results indicate that CYC1 plays important roles in cell proliferation and comedo necrosis through the elevated oxidative phosphorylation activity in human DCIS.

Abstract C46: Racial disparities in risk of second breast tumors after ductal carcinoma in situ: A population-based analysis

Abstract Importance: The impact of race and ethnicity on second breast tumors among women with ductal carcinoma in situ (DCIS) has not been well defined. Objective: To examine racial disparity in DCIS outcomes according to clinical characteristics of tumors. Design, Setting, and Patients: Data from 18 US Surveillance, Epidemiology and End Results registries included 102,489 women diagnosed with primary unilateral DCIS from 1988 through 2009 (white 73.6%, black 9.7%, Asian 9.0%, and Hispanic 7.7%). Patients undergoing mastectomy (n=31,899) were excluded from the analysis of ipsilateral breast recurrence. Main Outcomes and Measures: Relative risks (RRs) and their 95% confidence intervals (CI) of ipsilateral breast recurrence and contralateral breast tumors adjusted for pathologic factors, treatment, age at the diagnosis of DCIS, year of diagnosis, and registry. Results: Among 74,809 women treated with breast conserving surgery or with no surgical treatment, 2,925 (3.9%) developed ipsilateral breast recurrence during a median follow-up of 66 months. Compared with white women, black (RR=1.46; 95% CI, 1.29-1.65) and Hispanic (RR=1.18; 95% CI, 1.03-1.36) women experienced elevated risk of ipsilateral recurrence, which was similar for invasive cancer vs DCIS. A significant increase in risk of ipsilateral recurrence among black women persisted, regardless of age at the diagnosis of DCIS, treatment, tumor grade, tumor size, and histology. Overall, 3,723 (3.6%) of 102,489 women with DCIS developed contralateral breast tumors during a median follow-up of 70 months. The risk for contralateral breast tumors was significantly increased among black (RR=1.21; 95% CI, 1.08-1.36) and Asian (RR=1.16; 95% CI, 1.02-1.31) women compared with white women. Such association depended on type of events (Pheterogeneity<.0001); it was stronger for invasive cancer vs DCIS among black women and for DCIS vs invasive cancer among Asian women. The elevated risk of contralateral breast tumors associated with black race was more obvious among women ≥50 years at the diagnosis of DCIS and those with comedo DCIS; in contrast, a significant increase in risk among Asian women was restricted to those<50 years at the diagnosis of DCIS and those with noncomedo DCIS. Conclusions and Relevance: Black women with DCIS had disproportionately excess risks of second breast tumors in the ipsilateral and contralateral breasts, which could not be explained by pathologic features and treatment. The elevated risk of ipsilateral recurrence among black and Hispanic women suggests their need for more intensive follow-up and surveillance. Citation Format: Ying Liu, Graham Colditz. Racial disparities in risk of second breast tumors after ductal carcinoma in situ: A population-based analysis. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr C46. doi:10.1158/1538-7755.DISP13-C46

Racial disparities in risk of second breast tumors after ductal carcinoma in situ.

The purpose of the study was to examine the impact of race/ethnicity on second breast tumors among women with ductal carcinoma in situ (DCIS). We identified 102,489 women diagnosed with primary DCIS between 1988 and 2009 from the 18 NCI-SEER Registries. Cox proportional hazard regression was used to estimate race/ethnicity-associated relative risks (RRs) and their 95% confidence intervals (CI) of ipsilateral breast tumors (IBT; defined as DCIS or invasive carcinoma in the ipsilateral breast) and contralateral breast tumors (CBT; defined as DCIS or invasive carcinoma in the contralateral breast). Overall, 2,925 women had IBT and 3,723 had CBT. Compared with white women, black (RR 1.46; 95% CI 1.29-1.65), and Hispanic (RR 1.18; 95% CI 1.03-1.36) women had higher IBT risk, which was similar for invasive IBT and ipsilateral DCIS. A significant increase in IBT risk among black women persisted, regardless of age at diagnosis, treatment, tumor grade, tumor size, and histology. The CBT risk was significantly increased among black (RR 1.21; 95% CI 1.08-1.36) and Asian/PI (RR 1.16; 95% CI 1.02-1.31) women compared with white women. The association was stronger for invasive CBT among black women and for contralateral DCIS among Asian/PI women (P heterogeneity<0.0001). The black race-associated CBT risk was more pronounced among women ≥50years at diagnosis and those with comedo DCIS; in contrast, a significant increase in risk among Asian/PI women was restricted to those <50years and those with noncomedo DCIS. Racial/ethnic differences in risks of second breast tumors after DCIS could not be explained by pathologic features and treatment.

Abstract B117: Risk factors of second breast cancer among patients with ductal carcinoma in situ

Abstract Background: Women with ductal carcinoma in situ (DCIS) are at increased risk of breast cancer in either ipsilateral or contralateral breasts. However, it is inconclusive about the factors predicting the risk of second breast cancer after DCIS. Methods: We used US Surveillance, Epidemiology, and End Results data on women with first unilateral DCIS diagnosed between 1988 and 2009. Relative risks (RRs) were estimated using cox regression models to identify the factors associated with the risks of second DCIS and second invasive breast cancer (IBC). Results: Of the 74,285 eligible DCIS patients, 6,140 (8.3%) had subsequent breast cancer during 8.5 years of follow-up (714 ipsilateral DCIS, 2,003 ipsilateral IBC, 997 contralateral DCIS, and 2,426 contralateral IBC). Patients &amp;lt;50 years (RR=1.45; 95% confidence interval (CI), 1.29-1.64), black patients (RR=1.60; 95% CI, 1.39-1.83), patients with comedo DCIS (RR=1.19; 95% CI, 1.07-1.32), and patients with poorly differentiated DCIS (RR=1.45; 95% CI, 1.15-1.82) were more likely to develop ipsilateral breast cancer. Solid histologic type was more strongly associated with increased risk of ipsilateral IBC (RR=1.49; 95% CI, 1.12-1.99). The risk of contralateral breast cancer was increased among black women (RR=1.33; 95% CI, 1.16-1.52) and was decreased among young women and women with comedo DCIS, which was more obvious for contralateral IBC. Conclusion: The risk factors were different for second breast cancer in the ipsilateral breast and in the contralateral breast. Improved follow-up of young patients, black patients, patients with poorly differentiated DCIS, and patients with comedo or solid DCIS may reduce the risk of second IBC. Further investigations are needed to identify molecular features of DCIS that predict risk of second breast cancer and/or mediate racial and age differences in second cancer risk. Citation Format: Ying Liu, Graham Colditz. Risk factors of second breast cancer among patients with ductal carcinoma in situ. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B117.

A Hybrid Model of Tumor–Stromal Interactions in Breast Cancer

Ductal carcinoma in situ (DCIS) is an early stage noninvasive breast cancer that originates in the epithelial lining of the milk ducts, but it can evolve into comedo DCIS and ultimately, into the most common type of breast cancer, invasive ductal carcinoma. Understanding the progression and how to effectively intervene in it presents a major scientific challenge. The extracellular matrix (ECM) surrounding a duct contains several types of cells and several types of growth factors that are known to individually affect tumor growth, but at present the complex biochemical and mechanical interactions of these stromal cells and growth factors with tumor cells is poorly understood. Here we develop a mathematical model that incorporates the cross-talk between stromal and tumor cells, which can predict how perturbations of the local biochemical and mechanical state influence tumor evolution. We focus on the EGF and TGF-β signaling pathways and show how up- or down-regulation of components in these pathways affects cell growth and proliferation. We then study a hybrid model for the interaction of cells with the tumor microenvironment (TME), in which epithelial cells (ECs) are modeled individually while the ECM is treated as a continuum, and show how these interactions affect the early development of tumors. Finally, we incorporate breakdown of the epithelium into the model and predict the early stages of tumor invasion into the stroma. Our results shed light on the interactions between growth factors, mechanical properties of the ECM, and feedback signaling loops between stromal and tumor cells, and suggest how epigenetic changes in transformed cells affect tumor progression.

Abstract LB-18: Expression of discoidin domain receptor tyrosine kinases in breast cancer

Abstract A key step in breast cancer progression is the transition from in situ to invasive carcinoma. This process is partly mediated by defective interactions between the epithelial cells and the extracellular matrix, leading to loss of cell-cell contacts and polarity, increased proliferation, and acquisition of invasive activity. Here we report that a unique set of receptor tyrosine kinases (RTKs) known as the discoidin domain receptors (DDRs) may play a key role during the transition of in situ to invasive breast carcinoma. DDRs are the only RTKs that recognize collagen as their ligands and thus mediate collagen-initiated signaling in both physiological and pathological conditions. The expression of DDRs at various stages of breast cancer progression is unknown. We used a high-density tissue microarray containing samples of normal breast, ductal carcinoma in situ (DCIS), and invasive carcinomas of different clinico-pathological characteristics to examine the expression of DDR1 by immunohistochemistry using an antibody to the C-terminus of DDR1. Expression of DDR1 was evaluated taking into consideration the percentage and intensity of staining, and categorized as low or high. DDR1 was highly expressed in the cytoplasm and membrane of normal epithelial cells in ducts and acini, and in DCIS. In contrast, 88 of 134 (66%) invasive carcinomas displayed low or absent DDR1 expression, while 44% exhibited high levels. DDR1 expression was not associated with histologic type, grade, hormonal receptor or HER2-neu status. Interestingly, 15 of 40 (37.5%) patients with high DDR1 expression developed tumor recurrence compared to 9 of 46 (19.6%) patients with low DDR1 (Kaplan Meier log-rank p=0.05). The expression of DDR1 was also evaluated in a mouse model of breast cancer progression using pre-neoplastic and malignant human MCF10A cell variants. DDR1 was highly expressed in the benign hyperplastic lesions generated by MCF10AT1 cells, and in the comedo DCIS tumors generated by MCF10DCIS.COM cells. In contrast, low or no DDR1 expression was observed in tumors generated by the highly malignant MCF10CA1 variant. Expression analyses of DDR1 isoforms in cultured cells by real-time PCR demonstrated that non-malignant MCF10A cells expressed higher levels of DDR1b mRNA while malignant MCF10CA1 cells showed higher levels of DDR1a suggesting that malignant progression is associated with a DDR1 isoform switch. At present the functional roles of the DDR1 isoforms in breast cancer progression remain unknown. Our analyses suggest that loss of or reduced DDR1 expression is associated with the transition from in situ to invasive carcinomas while patients with invasive carcinomas displaying high DDR1 expression have worse disease free survival. These novel studies highlight a complex role of DDR1 in breast cancer progression that deserves further exploration. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-18. doi:1538-7445.AM2012-LB-18

Metastatic Mammary Carcinoma With DCIS-Like Morphology

Two cases of breast carcinoma with lymph node metastases are presented. In each case the metastases demonstrated the unusual phenomenon of resembling either cribriform or comedo DCIS. Furthermore both cases had the additional rare feature of demonstrable lymphatic involvement by DCIS-like carcinoma.

Abstract P1-15-09: Ductal Carcinoma In Situ of the Breast: Clinico-Pathological Features Predicting Residual Disease in Postlumpectomy Re-Excision Specimens

Abstract INTRODUCTION: Ductal carcinoma in situ (DCIS) is a non-invasive breast cancer, which often grows discontinuously within the breast tissue. Younger age, residual mammographic microcalcifications, positive surgical margins, tumor size, nuclear grade and architectural type are consistently related to ipsilateral breast tumor recurrence in DCIS. To re-excise or not when a lumpectomy margin is close is a controversial issue for breast pathologists, surgeons and oncologists, and often no residual disease is found when a re-excision is performed. The aim of this study is to investigate the clinico-pathological features of DCIS that might predict residual disease in the re-excision specimen in patients treated by lumpectomy with either positive or close margins. METHODS: Consecutive patients with DCIS who required postlumpectomy re-excision either for positive or for close margins were selected in this retrospective analysis. Close margin was defined as less than 0.1 cm. The initial lumpectomy specimens were examined for tumor size, architectural type, nuclear grade and margin status, and patient age was considered. The subsequent re-excision specimens were analyzed for residual disease. The clinico-pathological features of original lumpectomy specimens were correlated with the presence or absence of residual DCIS in the re-excision specimens. Logistic regression statistical test was used to determine if any of these clinico-pathological features predicted the presence or absence of DCIS in the subsequent re-excision specimens. RESULTS: There were 37 cases of DCIS without accompanying invasive carcinoma that had positive or close resection margins (positive margin n=8; 21.6%, close margin n=29; 78.4%). Age of the patients ranged from 30 to 93 years. DCIS present in the original lumpectomy specimen was comedo type with necrosis n=8; 21.6% and non-comedo type n-29; 78.4%. Twenty-one lumpectomy specimens (57%) exhibited more than one type of DCIS. Four tumors were nuclear grade 1 (10.8%). 17 were nuclear grade 2 (45.9%), and 16 were nuclear grade 3 (43.2%). Residual DCIS was present in 20 out of 37 (54.1%) re-excision specimens. Six out of 8 (75%) comedo DCIS had residual disease, compared to 14 out of 29 (48.3%) non-comedo DCIS. Eleven out of 20 patients (55%) with residual disease were younger than 60 years. The correlation of patient age and type of DCIS to residual disease in the re-excision specimens was short of statistical significance due to small size of study sample (p value = 0.178 and 0.175 respectively). There was no statistically significant association between nuclear grade and distance to margin with residual disease in re-excision specimens (p value = 0.757 and 0.734 respectively). CONCLUSION: Younger age and comedo type DCIS may be important factors in predicting residual disease in the re-excision specimens. If this can be confirmed in a larger, multi-institutional data set, there could be a more tailored selection of who needs a re-excision. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-15-09.

The Use of Oncoplastic Reduction Techniques to Reconstruct Partial Mastectomy Defects in Women with Ductal Carcinoma In Situ

The application of oncoplastic techniques to breast conservation therapy (BCT) is thought to improve cosmetic results with some documented oncologic advantages in certain patients. Although present data highlight the oncologic safety of this approach, the role of oncoplastic surgery specific to ductal carcinoma in situ (DCIS) has not been elucidated. In this study, all women in the Emory Healthcare system between January 1991 and June 2006 with biopsy-proven DCIS who underwent lumpectomies combined with simultaneous reduction mammaplasties or mastopexies were identified. Medical records, including office notes, operative and pathology reports were analyzed. Parameters included age, BMI, histologic grade (low, intermediate, high) and type (comedo versus non-comedo) of DCIS, margin status, locoregional recurrence, specimen weight, postoperative complications, and overall outcomes. Pedicle design and contralateral breast pathology were also analyzed. Twenty-eight women were included in the study with an average age of 47. Therapeutic mammaplasty was the definitive procedure for 18 (64%) of these patients. Ten patients (36%) required reoperations: nine for positive margins and one for residual microcalcifications (stereo biopsy DCIS). Overall, seven patients (25%) required completion mastectomy with reconstruction (transverse rectus abdominus myocutaneous flap: n = 3, latissimus flap: n = 4), whereas three patients (11%) underwent re-excisions with confirmation of negative margins. All ten women who required completion mastectomy or re-excisions exhibited either intermediate or high-grade, comedo DCIS. Overall, 50% (6/12) of women diagnosed with high-grade comedo DCIS required completion mastectomy with reconstruction after initial therapeutic mammaplasty. The final positive-margin rate for women diagnosed with intermediate-grade, comedo necrosis was 43% (3/7). The women in this failed group that required reoperations were overall younger (mean: 45.6; median: 43) than those in which oncoplastic surgery was the definitive procedure (mean: 57.8; median: 57). There were no significant differences between the failed and successful groups in terms of biopsy weight (failed: 253 g, successful: 237 g), type of excision (e.g., wire-localized), location of tumor, reduction type (e.g., superior medial), or postoperative complications. There was one case of locoregional recurrence of DCIS 7 months after the initial operation. All 28 patients had no evidence of disease at an average follow-up of 2.7 years. This study suggests that although oncoplastic reduction techniques are a reasonable approach for women with DCIS, stricter patient selection and improved confirmation of negative margins will minimize the need for either re-excisions or completion mastectomy and reconstruction.

Comparison of magnetic resonance imaging, multidetector row computed tomography, ultrasonography, and mammography for tumor extension of breast cancer

Breast imaging modalities can assess the tumor extent and adequacy of excision, but there have been no reports comparing magnetic resonance (MR) imaging, multidetector row computed tomography (MDCT), ultrasonography (US) and mammography (MMG) for the tumor extent of breast cancer. We prospectively assessed the accuracy of MR imaging, MDCT, US and MMG for preoperative assessment of the tumor extent of breast cancer. Preoperative MR imaging, MDCT, US and MMG were performed for 210 breasts with breast cancer. The MR and MDCT images were independently interpreted by one of two radiologists with knowledge of the clinical and MMG findings. The US was performed with knowledge of the clinical and MMG findings by one of five US technologists. The correlation of the results of these examinations with histological findings was examined. Of the 210 index breast tumors, 210 (100%) could be detected on MR, 208 (99%) were detected on MDCT, 209 (99.5%) were detected on US, and 195 (93%) were detected on MMG. For evaluating local tumor extent, the accuracy of MR imaging (76%) was significantly higher than those of MDCT, US, and MMG (71%, 56%, and 52%, respectively) (P = 0.001, P < 0.0001, and P < 0.0001). MDCT was significantly more accurate than US (P < .0001) or MMG (P < .0001), and US was significantly more accurate than MMG (P = 0.004). MR imaging and US had substantial risk (11% and 17%) of overestimation of the tumor extent. Regarding ductal carcinoma in situ (DCIS), for non-comedo DCIS, the accuracies of MR imaging (89%), MDCT (72%), and US (61%) were significantly higher than the 22% accuracy of MMG (P < 0.0001, P = 0.012, and P = 0.016), but for comedo DCIS, there were no significant differences among the four breast imaging modalities. MR imaging was the most accurate breast imaging modality for the tumor exten of breast cancer, although MR imaging had a substantial of risk of overestimation. MR imaging, MDCT and US can complement MMG for the preoperative evaluation of patients who are candidates for breast-conserving surgery.

The value of sentinel lymph node biopsy in ductal carcinoma in situ (DCIS) and DCIS with microinvasion of the breast

Aim Ductal carcinoma in situ (DCIS) refers to the preinvasive stage of breast carcinoma and should not give axillary metastases. Its diagnosis, however, is subject to sampling errors. The role of sentinel lymph node biopsy (SLNB) in management of DCIS or DCISM (with microinvasion) remains unclear. The purpose of this study was to review our experience with SLNB in DCIS and DCISM. Methods A review of 51 patients with a diagnosis of DCIS ( n = 45) or DCISM ( n = 6), who underwent SLNB and a definitive breast operation between January 1999 and December 2006, was performed. Results In 10 patients (19.6%) definitive histology revealed an invasive carcinoma. SLN (micro)metastases were detected in 5 out of 51 patients, of whom 2 had a preoperative diagnosis of grade III DCIS and 3 of DCISM. Three patients (75%) had micrometastases (<2 mm) only. In 2 patients, histopathology demonstrated a macrometastasis (>2 mm). All 5 patients underwent axillary dissection. No additional positive axillary lymph nodes were found. Conclusions In case of a preoperative diagnosis of grade III DCIS or a grade II DCIS with comedo necrosis and DCIS with microinvasion, an SLNB procedure has to be considered because in almost 20% of the patients an invasive carcinoma is found after surgery. In this case the SLNB procedure becomes less reliable after a lumpectomy or ablation has been performed. SLN (micro)metastases were detected in nearly 10% of the patients. The prognostic significance of individual tumour cells remains unclear.

Epithelial Displacement in Breast Lesions: A Papillary Phenomenon

Displacement of epithelial cells (DE) in the breast may occur after various types of needling procedures. To determine if specific lesions or entities in the breast are more prone to displacement than others. A review of our computer files from January 1994 to June 2004 yielded 53 cases with DE. Clinical information, including the age of the patient, specific reason for the biopsy, and type of biopsy, was gathered. Histologic review of all hematoxylin-eosin-stained slides (core biopsies and excisions) was performed. Needling procedures included 1 or more of the following: ultrasound-guided core biopsy (24 cases), mammotome core biopsies (16), fine-needle aspiration (8), anesthetic injection (3), suture placement (5), and wire localization (1). Procedures were performed in order to investigate a mass (34 cases), calcifications (15), both (3), or nipple discharge (1). The time from needling to surgical procedure yielding a specimen with DE ranged from minutes to 47 days. Displacement of epithelial cells occurred in the following sites: biopsy tract (42 cases), lymphatic channels (5), both biopsy tract and lymphatic channels (4), and breast stroma (2). The diagnoses included intraductal papilloma (6 cases) and intraductal carcinoma (DCIS) (45; 15 with invasive carcinoma). The remaining 2 cases were invasive carcinoma (colloid and papillary types) devoid of DCIS. Of the DCIS cases, either pure or with invasive carcinoma, the pattern was micropapillary in 23, intraductal papilloma involved by DCIS in 32, and both features in 12. The remaining 2 cases of DCIS included comedo DCIS and cribriform DCIS involving a cyst. With the exception of 3 cases, DE was associated with 1 or more underlying papillary lesions, including pure intraductal papilloma, DCIS involving intraductal papilloma, micropapillary DCIS, and invasive carcinoma. Other etiologies included mucinous carcinoma and cystic lesions, with only 1 case in which a mechanism for DE could not be postulated.

Clinical correlates of HER2 amplification: A multivariable analysis

696 Background: Profiling the status of the HER2 gene has become an increasingly important factor for patients with breast cancer. The purpose of this analysis was to describe clinical correlates for HER2 amplification in patients with infiltrating ductal carcinoma (INDC). Methods: Data were collected prospectively in our institutional review board approved patient registry for patients diagnosed with INDC. Measurement of human epidermal growth factor 2 (HER2) was performed on all tumors using fluorescence in-situ hybridization. Variables analyzed were race; age at diagnosis; hormone receptor status; incidence of bilateral or multifocal tumors; TNM Stage; the presence of angiolymphatic invasion; the type (if any) of ductal carcinoma in-situ (DCIS); Scarff-Bloom-Richardson grade (SBR); and HER2 amplification (HER2+). Logistic regression analysis was used to identify multivariable correlates of HER2+, and model-based probabilities were calculated. Results: Data were available for 1083 patients, including 944 (87%) who were self-described as white and 139 who were black. The median age at diagnosis was 58 years (range 23–94 years). A majority of tumors (74%) were hormone receptor positive, unilateral (95%) and unifocal (90%), TNM Stage I or II (85%), and without associated angiolymphatic invasion (72%). Type DCIS was available for 1023 tumors, including 93 (9%) defined as comedo only; 181 (18%) comedo mixed with any other type; 288 (28%) without DCIS; and 461 (45%) with any non-comedo type. SBR was available for 1045 tumors, including 254 (24%) grade 1; 378 (36%) grade 2; and 413 (40%) grade 3. Of 1083 tumors, 211 (19.5%) were HER2+. The final data model resulted in 3 variables (age, SBR, and type DCIS), and indicated younger patients were more likely to have HER+ tumors; likelihood of HER+ increased as SBR increased, and HER+ was most likely in tumors with comedo DCIS. For example, a 90-year old patient without associated DCIS had a 3.3% chance of HER+ compared to a 55.2% chance for a 30-year old with comedo DCIS. Conclusions: A multivariable analysis indicated that younger patients were more likely to have tumors that were HER2+, and that the likelihood of HER+ increased as SBR increased and in tumors with associated comedo DCIS. No significant financial relationships to disclose.

Age-Specific Incidence Rates of In situ Breast Carcinomas by Histologic Type, 1980 to 2001

Incidence rates of ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS) have increased rapidly over the past several decades largely due to the increased use of mammography. However, recent data from 1987 to 1999 indicate that invasive ductal carcinoma incidence rates have remained essentially constant, whereas rates of invasive lobular carcinoma have increased 65%, with greater increases observed among postmenopausal women. Data on recent trends in DCIS and LCIS incidence rates, particularly age-specific trends, are lacking. We evaluated trends in the incidence rates of DCIS overall, noncomedo DCIS, comedo DCIS, and LCIS using data from nine Surveillance, Epidemiology, and End Results cancer registries. DCIS incidence rates increased 7.2-fold [95% confidence interval (95% CI), 6.8-7.7] from 1980 to 2001, 1.8-fold (95% CI, 1.7-1.9) over the past 10 years (1992-2001), and 1.1-fold (95% CI, 1.0-1.2) over the past 5 years (1997-2001). The magnitudes of these increases were highest among women ages > or = 50 years. Furthermore, over the past 10- and 5-year periods, rates of noncomedo DCIS have generally increased across all age groups, whereas rates of comedo DCIS held constant or decreased. LCIS incidence rates increased 2.6-fold (95% CI, 2.3-2.9) from 1980 to 2001, 1.3-fold (95% CI, 1.2-1.5) over the past 10 years, and 1.1-fold (95% CI, 1.0-1.3) over the past 5 years. Similar to invasive lobular carcinoma, but unlike invasive ductal carcinoma, incidence rates of both DCIS and LCIS continue to increase in the United States primarily among older women. These trends present important public health and clinical challenges.

The relevance of occult axillary micrometastasis in ductal carcinoma in situ: a clinicopathologic study with long-term follow-up.

Ductal carcinoma in situ (DCIS) represents 20% of newly diagnosed breast carcinoma cases. Historically, the incidence of axillary metastasis in DCIS has been small (1-2%) and its significance has been debated. It is widely known that serial sections of lymph nodes coupled with keratin immunohistochemistry (IHC) increases identification of micrometastasis. The advent of sentinel lymph node evaluation underscores the need to reevaluate the significance of occult micrometastases in DCIS. Patients with DCIS and negative axillary lymph nodes from 1974 to 1992 were selected from the Saint Barnabas Medical Center Tumor Registry. All diagnoses were confirmed, and paraffin blocks were retrieved after acceptance into the study. Seven serial sections were obtained from each block and evaluated with two cytokeratin IHC stains. Clinical follow-up ranged from 10 to 28 years. One hundred two patients were included in the study. Micrometastases were identified in 13 patients (13%), mostly on 1 level and composed of microscopic clusters in the subcapsular sinus. Seven of these lymph node-positive patients (58%) had high-grade comedo DCIS, 4 (33%) had intermediate grades of various types of DCIS, and one had a low-grade micropapillary DCIS. The overall disease recurrence rate was 12%, but micrometasis was not detected in any of the patients who developed disease recurrence. Serial IHC evaluation of lymph nodes dramatically increased the identification of occult micrometastasis. However, IHC detected micrometastasis has no apparent clinical significance in DCIS, based on the current long-term clinicopathologic study. Therefore, the authors questioned the significance of occult micrometastasis, identified by IHC, in DCIS of any type and extent. Further evaluation and follow-up of lymph node micrometastases in patients with invasive tumors of various sizes are needed. The current findings would not support altering the stage of patients with DCIS and micrometastasis detected by IHC only.

Microinvasive ductal carcinoma (T1mic) of the breast. The clinicopathological profile and immunohistochemical features of 28 cases.

Microinvasive ductal carcinoma of the breast, namely ductal carcinoma in situ with microinvasion (T1mic) as defined by the American Joint Committee on Cancer (AJCC) Staging Manual, is a rare disease, although it is increasing because of widespread use of mammography. The aim of the present study was to describe the clinicopathological and immunohistochemical features of this entity. Twenty-eight patients who were diagnosed as T1mic from January 1997 to August 2002 were studied by using 3-5 mm-thick serial sections with hematoxylin-eosin staining. Immunohistochemical staining for the estrogen receptor (ER), progesterone receptor (PR), p53, Ki-67, and HER-2 were performed. All 28 patients were female, with a mean age of 48.8 years. Twenty-six patients (93%) revealed mammographic abnormalities on routine examination. All foci of the invasions were measured using an ocular micrometer. Invasive foci consisted of isolated cells or cell clusters, or appeared as a tongue-like projection of tumor through the basement membrane of the duct of ductal carcinoma in situ (DCIS). The mean number of invasive foci was 3, and the mean size was 0.6 mm. We found that high nuclear grade and predominant comedo subtype of DCIS components were 57.1% and 46.4%, respectively. Twenty-four cases (86%) demonstrated necrosis of DCIS components. Microinvasion was often associated with periductal stromal reaction (71.5%) and/or a lymphocytic infiltration (78.6%). All patients, excluding two, received axillary resection (the mean number of lymph nodes examined per case was 12), and none had lymph node metastasis. The positive expression of ER and PR strongly related to low grade nuclei and non-comedo subtype; however, the positive expression of HER-2 and P53 related to high grade nuclei and comedo subtype (P<0.01). Ki-67 expression was significantly higher in the high grade nuclei group than in the low grade group (P<0.01). Our study suggested that high nuclear grade and comedo DCIS were more aggressive and more common with microinvasion, and that microinvasion is more likely to be multifocal.