Low-grade Ductal Carcinoma Research Articles

Metastatic Carcinoid Tumor to Bilateral Breasts Mimicking Primary Low-Grade Invasive Ductal Carcinoma: An Impact on Patient Care

Metastatic Carcinoid Tumor to Bilateral Breasts Mimicking Primary Low-Grade Invasive Ductal Carcinoma: An Impact on Patient Care

Survival Benefit of Breast Surgery for Low-Grade Ductal Carcinoma In Situ: A Population-Based Cohort Study.

While the prevalence of ductal carcinoma in situ (DCIS) of the breast has increased substantially following the introduction of breast-screening methods, the clinical significance of early detection and treatment for DCIS remains unclear. To investigate the survival benefit of breast surgery for low-grade DCIS. A retrospective longitudinal cohort study using the Surveillance, Epidemiology, and End Results (SEER) database from October 9, 2014, to January 15, 2015, at the Dana-Farber/Brigham Women's Cancer Center. Between 1988 and 2011, 57,222 eligible cases of DCIS with known nuclear grade and surgery status were identified. Patients were divided into surgery and nonsurgery groups. Propensity score weighting was used to balance patient backgrounds between groups. A log-rank test and multivariable Cox proportional hazards model was used to assess factors related to overall and breast cancer-specific survival. Of 57,222 cases of DCIS identified in this study, 1169 cases (2.0%) were managed without surgery and 56,053 cases (98.0%) were managed with surgery. With a median follow-up of 72 months from diagnosis, there were 576 breast cancer-specific deaths (1.0%). The weighted 10-year breast cancer-specific survival was 93.4% for the nonsurgery group and 98.5% for the surgery group (log-rank test, P < .001). The degree of survival benefit among those managed surgically differed according to nuclear grade (P = .003). For low-grade DCIS, the weighted 10-year breast cancer-specific survival of the nonsurgery group was 98.8% and that of the surgery group was 98.6% (P = .95). Multivariable analysis showed there was no significant difference in the weighted hazard ratios of breast cancer-specific survival between the surgery and nonsurgery groups for low-grade DCIS. The weighted hazard ratios of intermediate- and high-grade DCIS were significantly different (low grade: hazard ratio, 0.85; 95% CI, 0.21-3.52; intermediate grade: hazard ratio, 0.23; 95% CI, 0.14-0.42; and high grade: hazard ratio, 0.15; 95% CI, 0.11-0.23) and similar results were seen for overall survival. The survival benefit of performing breast surgery for low-grade DCIS was lower than that for intermediate- or high-grade DCIS. A prospective clinical trial is warranted to investigate the feasibility of active surveillance for the management of low-grade DCIS.

Tubular carcinoma of the breast: institutional and SEER database analysis supporting a unique classification.

Tubular carcinoma (TC) of the breast is an uncommon, well-differentiated subtype of breast cancer with an excellent prognosis, but ambiguity in how it should be defined and treated. To determine the clinicopathologic characteristics and survival outcomes of patients with TC. The University of Virginia (UVA) Breast Cancer Database and the Surveillance, Epidemiology and End Results (SEER) databases were queried for patients with either grade 1 TC or grade 1 ductal (G1D) breast cancer. Nineteen institutional TC cases were identified and compared to 54 G1D cases. Flat epithelial atypia frequently was found with TC and not with G1D. There was no difference in overall or progression free survival. In SEER 18, 9,565 cases of TC were found. Most cases were stage I and patient characteristics were nearly identical. Both cause specific survival and overall survival were significantly longer for TC when compared to G1D. This review shows TC to have favorable behavior, with similar features to, but superior survival compared to low-grade ductal carcinoma of the breast. This suggests the adequacy of histopathologic review while reinforcing the designation of TC as a unique subtype.

The survival benefit offered by the surgical management of low-grade ductal carcinoma in situ of the breast.

1006 Background: The current management of ductal carcinoma in situ (DCIS) of the breast includes lumpectomy with/without whole breast radiation or mastectomy, however the magnitude of benefit for ...

Continued observation of the natural history of low-grade ductal carcinoma in situ reaffirms proclivity for local recurrence even after more than 30 years of follow-up

Opportunities to study the natural history of ductal carcinoma in situ are rare. A few studies of incompletely excised lesions in the premammographic era, retrospectively recognized as ductal carcinoma in situ, have demonstrated a proclivity for local recurrence in the original site. The authors report a follow-up study of 45 women with low-grade ductal carcinoma in situ treated by biopsy only, recognized retrospectively during a larger review of surgical pathology diagnoses and original histological slides for 26 539 consecutive breast biopsies performed at Vanderbilt, Baptist and St Thomas Hospitals in Nashville, TN from 1950 to 1989. Long-term follow-up was previously reported on 28 of these women. Sixteen women (36%) developed invasive breast carcinoma, all in the same breast and quadrant as their incident ductal carcinoma in situ. Eleven invasive breast carcinomas were diagnosed within 10 years of the ductal carcinoma in situ biopsy. Subsequent cases were diagnosed at 12, 23, 25, 29 and 42 years. Seven women, including one who developed invasive breast cancer 29 years after her ductal carcinoma in situ biopsy, developed distant metastasis, resulting in death 1–7 years postdiagnosis of invasive breast carcinoma. The natural history of low-grade ductal carcinoma in situ may extend more than four decades, with invasive breast cancer developing at the same site as the index lesion. This protracted natural history differs markedly from that of patients with high-grade ductal carcinoma in situ or any completely delimited ductal carcinoma in situ excised to negative margins. This study reaffirms the importance of complete margin evaluation in women treated with breast conservation for ductal carcinoma in situ as well as balancing recurrence risk with possible treatment-related morbidity for older women.

57.: Anti-glutamic acid decarboxylase antibody associated cerebellar ataxia and breast carcinoma

This study aims to highlight the importance of screening for rare causes of acquired ataxia, and present a patient with paraneoplastic anti-Gad antibody cerebellar ataxia. A 79-year-old lady with a past history of Hashimoto’s thyroiditis, spinal ependymoma and noninsulin-dependent diabetes mellitus presented with a 1 month history of gait ataxia. There had been 5 kg unintentional weight loss over several months. Examination revealed gait ataxia without appendicular ataxia, dysarthria, or saccadic eye movement abnormalities. Gaze-evoked nystagmus was intermittently observed. Antineuronal antibodies, tumour markers, vasculitis/antiphospholipid antibody screens, coeliac serology, B12, folate, venereal disease research laboratory, and vitamin E tests were normal or negative. Thyroid-stimulating hormone was mildly elevated with normal T3 and T4 levels. Serum anti-GAD antibody levels were strikingly elevated (>2000 international units/ml). Cerebrospinal fluid (CSF) revealed 4 mononuclear cells. CSF oligoclonal bands were present. Nerve conduction studies did not reveal electrophysiological evidence of peripheral neuropathy. MRI/MR angiography of the brain revealed moderately severe microvascular ischaemic gliosis. MRI of the spine was unremarkable. CT scan of the chest, abdomen and pelvis did not reveal evidence of malignancy. Positron emission tomography scan revealed irregular fluorodeoxyglucose uptake in the thyroid gland and tissues of the right breast. Mammogram revealed three suspicious lesions in the right breast. Biopsy followed by wide local excision revealed invasive tubular carcinoma and low grade ductal carcinoma in situ. Intravenous immunoglobulin G was commenced 4 weeks prior to starting chemotherapy with letrozole. There was a significant improvement in gait ataxia 2 weeks after the second course of Intravenous immunoglobulin G. Anti-GAD antibody associated ataxia is well described, and cases usually respond to immunotherapy. An association with breast cancer has rarely been reported. This case suggests the importance of screening for an underlying malignancy in patients with anti-GAD antibody associated cerebellar ataxia.

Molecular classification of infiltrating breast cancer: toward personalized therapy.

Breast cancer is a heterogeneous disease, which comprises several molecular and genetic subtypes, each with characteristic clinicobiologic behavior and imaging patterns. Traditional classification of breast cancer is based on the histopathologic features but offers limited prognostic value. Novel molecular characterization of breast cancer with cellular markers has allowed a new classification that offers prognostic value, with predictive categories of disease aggressiveness. These molecular signatures also open the door to personalized therapeutic options, with new receptor-targeted therapies. For example, invasive cancer subtypes such as the luminal A and B subtypes show better prognosis and response to hormone receptor-targeted therapies compared with the triple-negative subtypes; on the other hand, triple-negative tumors respond better than luminal tumors to chemotherapy. Tumors that display amplification of the oncogene ERBB2 (also known as the HER2/neu oncogene) respond to drugs directed against this oncogene, such as trastuzumab. The imaging aspects of tumors correlate with molecular subgroups, as well as other pathologic features such as nuclear grade. Smooth tumor margins at mammography may be suggestive of a triple-negative breast cancer, and a human epidermal growth factor receptor 2 (HER2)-positive tumor is characteristically a spiculated mass with calcifications. Low-grade ductal carcinoma in situ (DCIS) is better detected with mammography, although magnetic resonance (MR) imaging may allow better characterization of high-grade DCIS. MR imaging diffusion sequences show higher values for the apparent diffusion coefficient for triple-negative and HER2-positive subtypes, compared with luminal A and B tumors. MR imaging is also a useful tool in the prediction of tumor response after chemotherapy, especially for triple-negative and HER2-positive subtypes.

Low grade Ductal Carcinoma in situ (DCIS): How best to describe it?

BackgroundIn the absence of definitive data about the natural history of DCIS the appropriateness of describing DCIS as cancer is controversial. MethodsWe conducted a survey amongst British Breast Group (BBG) members, to determine which descriptions of DCIS were deemed most accurate and appropriate. Results54/73 (74%) attendees completed the survey: A majority (34/54; 63%) said they would be comfortable using the description that explained DCIS as abnormal cells in the milk ducts that had not spread into other breast tissue and which did not need urgent treatment as if it was breast cancer and this description was overall the most preferred (24/54; 44%). ConclusionsLittle consensus exists regarding how best to explain low grade DCIS to patients.

Intranodal Papillary Epithelial Proliferations

Lymph nodes, particularly those draining in major anatomic sites like axilla, pelvis, and neck are potential sites for the occasional presence of ectopic tissue, usually representative of the organ being drained. Owing to the uncertainty surrounding the processes causing such findings, and particularly in the setting of lymph node dissection and sampling for cancer staging, intranodal epithelial inclusions, rare as they may be, might be fertile soil for overdiagnosis of metastatic disease. Intranodal papillary inclusions are particularly problematic and challenging because of their complex architecture that may easily mimic a metastasis. From the files of the Breast Consultation Service, Department of Pathology at the Vanderbilt University Medical Center in Nashville, we identified 6 cases in which histopathologic examination of axillary lymph nodes revealed intranodal papillary inclusions (papillary epithelial proliferations). One case showed atypical ductal hyperplasia, 1 showed low-grade ductal carcinoma in situ, and 1 showed usual ductal hyperplasia. The corresponding breast lesions were papillomas in 5 of 6 cases, 2 of which displayed atypical ductal hyperplasia, whereas 3 showed low-grade ductal carcinoma in situ. One case showed intermediate-grade invasive ductal carcinoma, and the associated intranodal papilloma lacked atypia. Our findings suggest that intranodal papillary proliferations are often, although not exclusively, associated with papillary and noninvasive breast neoplasms, hence highlighting the origin of these intranodal lesions as independent de novo nodal processes rather than metastatic deposits.

43. Low grade cribriform cystadenocarcinoma: the cytology and histology of a rare salivary gland tumour

Low grade cribriform cystadenocarcinoma (LGCCC) is a rare low grade malignant neoplasm which occurs almost exclusively in the parotid gland. The lesion is also known as low grade intraductal carcinoma of the salivary gland, coined by Delgado et al. in 1996, due to its resemblance to atypical ductal hyperplasia or low grade ductal carcinoma in situ of the breast. The majority of patients are elderly and have a female predominance of 2:1. While there have been several case series and case reports in the literature about its histological and immunohistochemical features, only two studies in the English language literature have given any cytolomorpho-logical description. We present a case of a 62-year-old female with a right parotid mass. A fine needle aspiration showed a hypercelllular smear, with sheet-like and branching architecture, composed of fairly uniform cells with atypical features, in a mucoid/myxoid background. A diagnosis suggestive of a pleomorphic adenoma was given. Five months later, an excision of a 1.5 cm, solid-cystic mass was performed. Histological examination showed an intraductal proliferation of tumour cells akin to a breast low grade ductal carcinoma in situ with papillary and cribriform pattern. A focal area of microinvasion was present. Immunohistochemically, the luminal cells showed strong and diffuse positive cytokeratin and S-100 staining. The myoepithelial marker, calponin, highlighted the basal cells. Hence, a diagnosis of low grade cribriform cystadenocarcinoma was favoured. The characteristic features of this lesion are discussed, with focus given to the cytological findings and the diagnostic difficulties in fine needle aspirates, particularly due to lack in the current literature of definitive diagnostic criteria.

Abstract P2-03-03: Feasibility of evaluation of breast tissue using confocal microscopy with strip mosaicing

Abstract Background: Confocal microscopic strip mosaicing (CSM) provides noninvasive optical sectioning and high resolution, which allows for imaging of nuclear and morphological detail in freshly excised tissue. CSM can image large areas of tissue at micron-level resolution in minutes, which may offer an advantage over standard histology that requires days. We have conducted a preliminary investigation of the feasibility of this technology for the evaluation of breast tissue from surgical excision specimens. Design: In a prospective study, 80 fresh human breast tissue samples from surgical excision specimens of 24 patients were imaged using a prototype confocal strip scanner. Fresh tissue specimens were immersed in Acridine Orange (AO) for 45 seconds to stain the nuclei, then pressed against the glass imaging window and imaged with a 30X, 0.75 numerical aperture (measured) objective lens and a 488 nm laser. Images were acquired in two modes of contrast: in fluorescence (with AO), showing nuclear morphology, and in reflectance (endogenous), showing stroma. The use of fluorescence for nuclear staining mimics the use of hematoxylin in pathology, and the use of reflectance eosin. Use of two contrast modes allows the fluorescence image to be colorized purple and the reflectance image pink, producing confocal strip mosaics that mimic H&amp;E histology in appearance. Specimens were subsequently fixed in formalin and routinely processed to obtain H&amp;E stained sections. H&amp;E and confocal images were compared by the study pathologist (M.M.) Results: Freshly excised breast tissue samples as large as 2 cm x 2 cm were imaged in less than five minutes, with 1-micron resolution and measured optical sectioning of 6 microns. We compared the CSM images against standard histopathology images. In our series we evaluated the following histologies: 12 invasive carcinoma (11 ductal, 1 lobular), 3 ductal carcinoma in-situ, 3 lobular carcinoma in situ, 1 atypical lobular hyperplasia, 1 atypical ductal hyperplasia and various benign lesions such as fat necrosis, fibrocystic changes, and ductal hyperplasia. In confocal images invasive and in situ carcinoma as well as benign ducts and lobules were distinguished from surrounding stromal tissue. Limitations that are typically encountered in standard histology, such as distinguishing low grade ductal carcinoma in situ (DCIS) from lobular carcinoma in situ (LCIS) or atypical proliferations were encountered in the grayscale confocal images as well. Conclusion: In this initial feasibility study, CSM produced images that could be diagnosed as benign or neoplastic by the study pathologist. Further study is needed to build an image library of breast histology and compare reproducibility of histologic diagnoses between CSM (grayscale and colorized images) and traditional optical microscopy, and assess interobserver reproducibility in diagnosis. CSM potentially provides rapid and noninvasive evaluation of breast parenchyma, and has a potential application for intraoperative margin assessment of resected breast specimens. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-03-03.

Pseudo-micropapillary structures associated with columnar cell lesions of the breast are an artifact due to traumatic epithelial detachment: a potential pitfall which can lead to overtreatment

Dear Editor, Columnar cell lesions (CCLs) of the breast including flat epithelial atypia (FEA) are believed to be nonobligatory precursors of a low-nuclear-grade breast neoplasia family [1]. They are detected increasingly in needle core biopsies because of the presence of microcalcifications observed on screening mammography. Here, we report a hitherto undescribed artifact associated with CCLs of the breast, which superficially resembles micropapillary atypical ductal hyperplasia (ADH) or low-grade ductal carcinoma in situ (DCIS). The complexity of this artifact varies widely from a simple fold to a complex labyrinthine-like structure. If the latter is confused with genuine micropapillary structures or Roman bridges, overtreatment can occur because management of patients differs between pure CCLs and those associated with ADH/low-grade DCIS, especially when found in needle core biopsies. We have recently observed two cases of CCL of the breast that showed complex pseudo-micropapillary structures protruding into the duct lumen. Based on histopathological and immunohistochemical findings, we infer that these structures are not a true micropapillary overgrowth but an artifact, which originates from folding and adhesion of epithelial sheets detached from CCLs. The first case concerns a 49-year-old Japanese woman whose screening mammography revealed microcalcifications in the left breast. Vacuum-assisted needle core biopsy (VAB) was performed because the microcalcifications varied in size and shape and were localized to the upper half of the breast in a segmental fashion. The VAB was composed of 12 fragments of breast tissue. Four fragments contained CCLs; variably distended ductules were lined by columnar epithelial cells with apical cytoplasmic snouts (Fig. 1a–c). In the lumina of some dilated ductules, racetracks were seen or ribbon-like bridges continuous with the epithelial lining of CCL. These pseudo-micropapillary structures lacked fibrovascular cores and contained two epithelial layers. The cells were similar to luminal cells of CCL (Fig. 1c). Immunohistochemical staining with cytokeratin 5/6 demonstrated a few myoepithelial cells attached to the basal S. Ichihara (*) : S. Moritani :M. Hasegawa Department of Pathology, Nagoya Medical Center, 4-1-1 Sannomaru Naka-ku Nagoya, 460-0001 Aichi, Japan e-mail: shu-kkr@umin.ac.jp

Tubular carcinomas of the breast: A comparison of features and survival outcomes versus low grade ductal and lobular carcinomas in the SEER database.

e11596 Background: Tubular carcinoma of the breast (TC) is a rare histologic subtype of breast cancer considered to have a favorable prognosis relative to other histologies. TC is by definition low grade. TC is described to have clinical behavior similar to low grade ductal and lobular breast cancers, but due to its infrequent presentation, long-term follow-up studies of TC are lacking. Methods: The Surveillance, Epidemiology and End Results database was queried to include the years 1988-2009, selecting for patients with either grade 1 TC or grade 1 ductal and lobular breast cancer (G1BC). Data collected included age at diagnosis, race, stage, receptor status, overall survival, and surgery type. Two Cox proportional hazard models were assessed for differences between TC and G1BC, adjusting for age at diagnosis. Results: In SEER 18, 115,945 cases of TC+G1BC breast cancer are found, with 6.1% classified as TC. Of TC cases, 91% are stage 1, while 71% of GIBC are stage 1. Presenting stage 3 or 4 disease occurred in only 4.7% of G1BC versus 0.68% of TC cases. Due to the rarity of advanced disease, we analyzed early stage disease. For early Stage (1-2) breast cancer, mean age was 61.5 years for TC and 63.5 years for G1BC. The TC cases were 92% white, 4% black, 97% Estrogen Receptor (ER) positive, 82% Progesterone Receptor (PR) positive. Of G1BC cases, 88% were white, 5% black, 96% ER positive, 84% PR positive. Treatment differed with 76% of TC patients receiving lumpectomy versus G1BC where 65% received lumpectomy (p&lt;0.001). There was no significant difference in overall survival between Stage I TC and G1BC (p=0.98), or between Stage II TC and G1BC (p=0.075), with the survival estimate higher for TC. Conclusions: In this large-scale analysis, TC was limited to early stage disease and there was no difference in overall survival between patients with early stage TC and early stage GIBC. There were similar receptor statuses and baseline characteristics, but more conservative surgical treatment in TC. Because no survival difference exists for early stage disease, the finding of tubular histology to guide treatment decisions may not be warranted.

Basal cytokeratin as a potential marker of low risk of invasion in ductal carcinoma in situ

OBJECTIVES:Biological markers that predict the development of invasive breast cancer are needed to improve personalized therapy for patients diagnosed with ductal carcinoma in situ. We investigated the role of basal cytokeratin 5/6 in the risk of invasion in breast ductal carcinoma in situ.METHODS:We constructed tissue microarrays using 236 ductal carcinoma in situ samples: 90 pure samples (group 1) and 146 samples associated with invasive carcinoma (group 2). Both groups had similar nuclear grades and were obtained from patients of similar ages. The groups were compared in terms of estrogen (ER) and progesterone receptor (PR) status, human epidermal growth factor receptor 2 (HER2) expression, cytokeratin 5/6 immunostaining, human epidermal growth factor receptor 1 (EGFR) membrane staining and molecular subtype, as indicated by their immunohistochemistry profiles.RESULTS:ER/PR-negative status was predictive of invasion, whereas HER2 superexpression and cytokeratin 5/6-positive status were negatively associated with invasion. Among the high-grade ductal carcinoma in situ cases, a triple-positive profile (positive for estrogen receptor, progesterone receptor, and HER2) and cytokeratin 5/6 expression by neoplastic cells were negatively associated with invasion. In the low-grade ductal carcinoma in situ subgroup, only cytokeratin 5/6 expression exhibited a negative association with the probability of invasion.CONCLUSION:The immunohistochemical expression of cytokeratin 5/6 by ductal carcinoma in situ epithelial cells may provide clinically useful information regarding the risk of progression to invasive disease.

Pathological observation on 38 cases with solid papillary carcinoma of the breast

Objective To study the clinicopathologic features immunophenotype and the differential diagnosis of solid papillary carcinoma(SPC) of breast.Methods 38 cases of SPC with or without invasive carcinoma were collected.The clinical data and histopathologic features were analyzed with further investigation of immunohistochemical staining (EnVision method).Selected antibodies included CK,P63,E-cadherin,CD56,Syn,CgA,ER,PR,HER-2,P53,KI-67 etc.Results All the patients were females with mean age of 63.2 years.The presenting symptoms were either a palpable nipple blood discharge.13 cases with metastasis were observed in 28 cases who had undergone sentinel axillary lymph nodes dissection.Histologically,the tumor displayed solid papillary growth pattern with mucin production demonstrated in 12 cases,with invasive carcinoma in 20 cases.Immunohistochemical study showed that the tumor cells were negative for basal cell cytokeratin.Positivity for p63 was demonstrated in the myoepithelial of fibrovascular cores.Most cases showed cytoplasmic positivity for neuroendocrine.The proliferating index,as high lighted by Ki-67 immunostaining was 9.6％.The tumor mainly expressed estrogen receptor and progesterone receptor.The staining for HER-2 oncoprotein was in the most cases.Conclusion SPC represents a subgroup of low-grade ductal carcinoma in situ,SPC is associated with neuroendocrine component.Follow-up data suggest that SPC has a good prognosis. Key words: Breast neoplasms ; Pathology, Clinical

Expression of centrosomal tubulins associated with DNA ploidy in breast premalignant lesions and carcinoma

The centrosome plays an essential role in chromosomal segregation during cell division. Centrosome dysfunction might lead to aneuploidy and chromosomal instability. Invasive breast tumors with centrosome amplification often show aneuploidy.Flow cytometry (FCM) was used to examine the aneuploidy rate in 30 cases of each of the following seven tissue types: normal breast tissue, usual ductal hyperplasia, atypical ductal hyperplasia, low-grade ductal carcinoma in situ, high-grade ductal carcinoma in situ, low-grade invasive ductal carcinoma, and high-grade invasive ductal carcinoma. Centrosomal α, γ-tubulin expression was examined by FCM immunofluorescence and compared between diploid and aneuploid cells.The aneuploidy rate was 0, 6.7%, 26.7%, 30.0%, 46.7%, 56.7%, and 86.7%, respectively, in the seven tissue types. The percentage of cells expressing α- and γ-tubulins was significantly different between the seven groups, and the positive rate of α- and γ-tubulin expression in ADH, DCIS and IDC was higher than that in NBT and UDH. The percentage of cells expressing α- and γ-tubulins in the diploid state was significantly lower than that in the aneuploid state.Expression of centrosomal α- and γ-tubulins seems to be associated with DNA ploidy in breast premalignant lesions and carcinoma during the progression of breast cancer.

Surgical Margins in Breast Conservation

Significant progress has been made in the diagnosis and treatment of breast cancer during the past 30 years. The increased availability of screening mammography has resulted in a higher percentage of woman being diagnosed with early stage disease allowing the option of breast conservation therapy to be more widely available. Long-term follow-up studies clearly demonstrate equivalent survival with breast conservation surgery (lumpectomy) and radiotherapy versus total mastectomy [1–3]. The importance of obtaining clear lumpectomy surgical margins has been well established in minimizing the risk of local recurrence [4]. Unfortunately there is a lack of uniform guidelines in terms of what constitutes an adequately clear lumpectomy margin. Substantial debate about bigger margins being better continues [5]. This has led to wide variations in lumpectomy margin reexcision rates from 15 to 47% [6]. These additional surgical procedures cause significant patient distress, utilize health care resources, and can adversely affect cosmesis. From the patient perspective, they may wonder why we did not get it right the first time. They want their cancer gone while maintaining a normal appearance. This special issue highlights the areas of controversy and demonstrates current best practices and emerging novel approaches towards optimal breast conservation approach. The goal is to improve our ability to provide breast-conserving approaches for breast cancer while avoiding multiple surgical procedures, minimizing recurrence risk while obtaining excellent cosmesis. We have chosen 6 of 16 submissions to be published in this special issue. Each paper was evaluated by at least two expert reviewers and revised according to review comments. P. Ananthakrishnan et al. provide an excellent comprehensive review article on all aspects involved in optimizing breast conservation. They include discussion of preoperative breast imaging, lesion localization, impact of tumor biology and systemic therapy, intraoperative lesion identification and margin assessment techniques, the role of margin ablation and oncoplastic techniques. They also discuss the promise of ductal anatomy mapping toward the goal of validating the “Sick lobe hypothesis” [7, 8] which may allow for more accurate identification of breast tissue to be targeted for excision. R. Emmadi and E. L. Wiley provide an excellent review from the pathology perspective of the different approaches to margin assessment. They explore issues of specimen processing, fixation, cutting techniques, and reporting. They well explain the reasons for the reporting variations between institutions and the need for standardization. J. L. Baker et al. present a scholarly review of our current understanding of the issue of atypical ductal hyperplasia (ADH) as it relates to surgical margins. They highlight the large interobserver variability among pathologists in differentiating ADH from low-grade ductal carcinoma in situ (DCIS). The issue of whether ADH is a precursor lesion to DCIS is explored. R. J. Rivera et al. report on a 21-site multicenter clinical trial evaluating the performance of the MarginProbe intraoperative device. This device is based on radiofrequency spectroscopy to assess adequacy of lumpectomy margins. They analyzed volume or resection and reexcision rates in the device group versus usual surgical standard of care (SOC). They demonstrate the reexcision rate of 14.1% in the device group versus 29.9% with SOC. Increased resection volume was 2.6% using the device. M. M. Chang et al. provide a comprehensive overview of oncoplastic breast reduction. This is a complete review of the techniques including indication, patient selection, practical pointers, and their experience including a low (3.3%) rate of margin failure. They stress the importance of a coordinated team approach between breast surgical oncology, plastic surgery, breast imaging, and radiation oncology. Lastly, G. H. T. Au et al. present an exciting research paper on margin assessment using a Quantum-Dot Molecular probe in a mouse model. This employs nanoparticle monoclonal antibodies with molecular imaging. Their concept has a potential advantage over optical imaging and radiofrequency spectroscopy in that it is not affected by tissue heterogeneity. It also can display and differentiate very small (100–200 cells) spots. Timeline of 30 minutes is practical for intraoperative use. This early work is an highly innovative approach to a practical issue. These papers present a great deal of important information and well explore the current state of the art, controversies and future directions towards the important goal of optimizing breast conservation with particular attention to margin issues.

Tubular Carcinoma of the Breast: Clinicopathologic Features and Survival Outcome Compared with Ductal CarcinomaIn Situ

PurposeTubular carcinoma (TC) of the breast is an uncommon histological subtype of invasive breast cancer with an excellent prognosis compared with standard invasive ductal carcinoma. Recent studies suggested a possible precursor role for low grade ductal carcinoma in situ (DCIS) in the development of TC. The goal of this analysis was to understand the clinicopathologic features and outcomes of TC by comparing TC with DCIS.MethodsA retrospective review identified 70 patients with TC and 1,106 patients with DCIS between 1995 and 2011. Student t-test and Fisher exact test were used to compare the clinicopathologic characteristics of TC patients with those of DCIS patients. The Kaplan-Meier method and Cox regression analysis were used to determine disease-free survival (DFS) rates.ResultsCompared to DCIS, TC exhibited favorable clinicopathologic characteristics such as a lower nuclear grade (92.3%), higher expression of hormonal receptors (estrogen receptor-positive, 92.9%; progesterone receptor-positive, 87.0%), and less frequent overexpression of human epidermal growth receptor 2 (12.9%). DFS did not differ significantly between the TC and DCIS groups (5-year DFS, 100% vs. 96.7%; 10-year DFS, 92.3% vs. 93.3%; p=0.324), and cancer-specific deaths were not noted in either group. However, axillary lymph node involvement was observed in six (8.6%) of the 70 patients with TC. Three of these patients had small tumors (≤1 cm).ConclusionIn our study cohort, TC was associated with an excellent prognosis and a low rate of lymph node metastasis. However, lymph nodes metastases were found even in patients with small tumors (≤1 cm). Axillary staging must be considered for all patients with TC of the breast.

良性病変との鑑別を要する低異型度乳管癌の細胞学的検討

目的 : 小型核を主体とする低異型度の乳管癌に対し, 良性病変との鑑別に有用な細胞所見を検討する.方法 : 悪性の疑いまたは鑑別困難と判定していた症例のうち, 小型核を主体とする乳管癌 37 例, および筋上皮細胞が不明瞭な細胞集塊が出現していた良性病変 13 例の計 50 例に対し, (1)双極裸核, (2)細胞集塊の重積性, (3)細胞間結合性, (4)核小体, (5)クロマチンパターン, (6)核溝の 6 項目の細胞所見についてスコア化を行い, それぞれの出現頻度を比較した. さらに統計学的有意差がみられた細胞所見に対して点数加算を行い, 乳管癌と良性病変の鑑別を試みた.成績 : 6 項目の細胞所見のうち, 双極裸核 (p=0.007), 核溝 (p=0.02) に統計学的有意差がみられた. 双極裸核は対物レンズ 40 倍で 1 視野あたり平均 20 個を超えるものを score 1, 6∼20 個であるものを score 2, 5 個以下であるものを score 3, 核溝は明らかでないものを score 1, 核溝がみられるものを score 2 とし, それらのスコアの合計が 4 点以上であるものを乳管癌とすると, 感度 76%, 特異度 77%, 陽性的中率 90%, 陰性的中率 53%であった.結論 : 低異型度乳管癌と良性病変の鑑別に, 双極裸核の数および核溝に着目し, スコア化を行うことは鑑別困難症例の減少につながると考えられた.

Differential copy number aberrations in novel candidate genes associated with progression from in situ to invasive ductal carcinoma of the breast

Only a minority of intraductal carcinomas of the breast give rise to stromally invasive disease. We microdissected 206 paraffin blocks representing 116 different cases of low-grade ductal carcinoma in situ (DCIS). Fifty-five were pure DCIS (PD) cases without progression to invasive carcinoma. Sixty-one cases had a small invasive component. DNA was extracted from microdissected sections and hybridized to high-density bacterial artificial chromosome arrays. Array comparative genomic hybridization analysis of 118 hybridized DNA samples yielded data on 69 samples that were suitable for further statistical analysis. This cohort included 20 pure DCIS cases, 25 mixed DCIS (MD), and 24 mixed invasive carcinoma samples. PD cases had a higher frequency of DNA copy number changes than MD cases, and the latter had similar DNA profiles compared to paired invasive carcinomas. Copy number changes on 13 chromosomal arms occurred at different rates in PD versus MD lesions. Eight of 19 candidate genes residing at those loci were confirmed to have differential copy number changes by quantitative PCR. NCOR2/SMRT and NR4A1 (both on 12q), DYNLRB2 (16q), CELSR1, UPK3A, and ST13 (all on 22q) were more frequently amplified in PD. Moreover, NCOR2, NR4A1, and DYNLRB2 showed more frequent copy number losses in MD. GRAP2 (22q) was more often amplified in MD, whereas TAF1C (16q) was more commonly deleted in PD. A multigene model comprising these candidate genes discriminated between PD and MD lesions with high accuracy. These findings suggest that the propensity to invade the stroma may be encoded in the genome of intraductal carcinomas.