Assessment of Ki-67 proliferation index with deep learning in DCIS (ductal carcinoma in situ).

The proliferation index (PI) is crucial in histopathologic diagnostics, in particular tumors. It is calculated based on Ki-67 protein expression by immunohistochemistry. PI is routinely evaluated by a visual assessment of the sample by a pathologist. However, this approach is far from ideal due to its poor intra- and interobserver variability and time-consuming. These factors force the community to seek out more precise solutions. Virtual pathology as being increasingly popular in diagnostics, armed with artificial intelligence, may potentially address this issue. The proposed solution calculates the Ki-67 proliferation index by utilizing a deep learning model and fuzzy-set interpretations for hot-spots detection. The obtained region-of-interest is then used to segment relevant cells via classical methods of image processing. The index value is approximated by relating the total surface area occupied by immunopositive cells to the total surface area of relevant cells. The achieved results are compared to the manual calculation of the Ki-67 index made by a domain expert. To increase results reliability, we trained several models in a threefold manner and compared the impact of different hyper-parameters. Our best-proposed method estimates PI with 0.024 mean absolute error, which gives a significant advantage over the current state-of-the-art solution.

Self-Organizing Maps for Cellular In Silico Staining and Cell Substate Classification.

Cellular composition and structural organization of cells in the tissue determine effective antitumor response and can predict patient outcome and therapy response. Here we present Seg-SOM, a method for dimensionality reduction of cell morphology in H&E-stained tissue images. Seg-SOM resolves cellular tissue heterogeneity and reveals complex tissue architecture. We leverage a self-organizing map (SOM) artificial neural network to group cells based on morphological features like shape and size. Seg-SOM allows for cell segmentation, systematic classification, and in silico cell labeling. We apply the Seg-SOM to a dataset of breast cancer progression images and find that clustering of SOM classes reveals groups of cells corresponding to fibroblasts, epithelial cells, and lymphocytes. We show that labeling the Lymphocyte SOM class on the breast tissue images accurately estimates lymphocytic infiltration. We further demonstrate how to use Seq-SOM in combination with non-negative matrix factorization to statistically describe the interaction of cell subtypes and use the interaction information as highly interpretable features for a histological classifier. Our work provides a framework for use of SOM in human pathology to resolve cellular composition of complex human tissues. We provide a python implementation and an easy-to-use docker deployment, enabling researchers to effortlessly featurize digitalized H&E-stained tissue.

Intraductal Carcinomas of the Salivary Gland.

Intraductal carcinoma of the salivary gland is a rare tumor characterized by intracystic proliferations of papillary, cribriform, and solid architecture of small uniform epithelial cells, reminiscent of ductal carcinoma in situ of the breast. Recent literature has identified 4 distinctive subtypes: the intercalated duct type, apocrine type, mixed/hybrid type, and oncocytic type, all with corresponding immunohistochemical and molecular findings. Although these tumors are typically in situ, as evidenced by a retained myoepithelial layer, they can demonstrate minimal invasion or, rarely, widespread invasive growth. Their overall prognosis is favorable, with few reported cases of recurrences and nodal metastases but no evidence of distant metastases.

In Situ DESI-MSI Lipidomic Profiles of Breast Cancer Molecular Subtypes and Precursor Lesions.

Clinically meaningful molecular subtypes for classification of breast cancers have been established, however, initiation and progression of these subtypes remain poorly understood. The recent development of desorption electrospray ionization-mass spectrometry imaging (DESI-MSI) facilitates the convergence of analytical chemistry and traditional pathology, allowing chemical profiling with minimal tissue pretreatment in frozen samples. Here, we characterized the chemical composition of molecular subtypes of breast cancer with DESI-MSI. Regions of interest were identified, including invasive breast cancer (IBC), ductal carcinoma in situ (DCIS), and adjacent benign tissue (ABT), and metabolomic profiles at 200 µm elaborated using Biomap software and the Lasso method. Top ions identified in IBC regions included polyunsaturated fatty acids, deprotonated glycerophospholipids, and sphingolipids. Highly saturated lipids, as well as antioxidant molecules [taurine (m/z 124.0068), uric acid (m/z 167.0210), ascorbic acid (m/z 175.0241), and glutathione (m/z 306.0765)], were able to distinguish IBC from ABT. Moreover, luminal B and triple-negative subtypes showed more complex lipid profiles compared with luminal A and HER2 subtypes. DCIS and IBC were distinguished on the basis of cell signaling and apoptosis-related ions [fatty acids (341.2100 and 382.3736 m/z) and glycerophospholipids (PE (P-16:0/22:6, m/z 746.5099, and PS (38:3), m/z 812.5440)]. In summary, DESI-MSI identified distinct lipid composition between DCIS and IBC and across molecular subtypes of breast cancer, with potential implications for breast cancer pathogenesis. SIGNIFICANCE: These findings present the first in situ metabolomic findings of the four molecular subtypes of breast cancer, DCIS, and normal tissue, and add to the understanding of their pathogenesis.

Atypical Ductal Hyperplasia and Those Bordering on Ductal Carcinoma In Situ Should Be Included in the Active Surveillance Clinical Trials.

OBJECTIVES: Women with atypical ductal hyperplasia (ADH), unlike those with ductal carcinoma in situ (DCIS), are denied eligibility for active surveillance clinical trials. METHODS: We applied the inclusion criteria of the Comparison of Operative to Monitoring and Endocrine Therapy (COMET) trial to the cases of women (n = 165) at the Roswell Park Cancer Institute who had a diagnosis of ADH, ADH bordering on DCIS, or low- to intermediate-grade DCIS on core biopsy taken during screening mammography. Upgrade of lesions to high risk was based on invasive carcinoma, high-grade DCIS, or DCIS with comedo necrosis. RESULTS: In total, nine (5.5%) lesions were upgraded: two (1.7%) reported ADH, one (5.9%) reported ADH bordering on DCIS, and six (19.4%) reported DCIS (P = .002); and two (1.6%) reclassified ADH vs seven (17.1%) reclassified DCIS (P < .001). In multivariate analysis, only increased number of foci had the potential to predict high risk (odds ratio: 1.39; P = .06). CONCLUSIONS: We conclude that ADH and ADH bordering on DCIS have lower upgrade rates than DCIS. We recommend opening an active surveillance clinical trial for women with these diagnoses.

NCOA4-RET and TRIM27-RET Are Characteristic Gene Fusions in Salivary Intraductal Carcinoma, Including Invasive and Metastatic Tumors: Is "Intraductal" Correct?

Intraductal carcinoma (IC) is the new WHO designation for tumors previously encompassed by "low-grade cribriform cystadenocarcinoma" and "low-grade salivary duct carcinoma." The relationship of IC to salivary duct carcinoma (SDC) is controversial, even though they are considered to be distinct entities. IC is a rare low-grade malignant salivary gland neoplasm with histopathological features reminiscent of atypical ductal hyperplasia or ductal carcinoma in situ of the breast, showing diffuse S100 protein and mammaglobin positivity, while it is partially defined genetically. Recently, RET rearrangements including NCOA4-RET and TRIM27-RET have been described in IC. Here, we genetically characterize the largest cohort of IC to date (33 cases) including 8 cases with focal or widespread invasive growth and 1 case with lymph node metastasis. Thirty-three cases of IC were analyzed by next-generation sequencing (NGS) using the FusionPlex Solid Tumor kit (ArcherDX). Identified gene fusions were confirmed using fluorescence in situ hybridization break-apart and fusion probes and an reverse transcription polymerase chain reaction designed specifically for the detected breakpoints. Ten cases of SDC were analyzed for comparison using NGS panels that detect mutations and fusion transcripts. NGS analysis detected an NCOA4-RET fusion transcript in 11 cases of intercalated duct-type IC joining exon 7 or 8 of NCOA4 gene and exon 12 of the RET gene. Eight cases of IC had an invasive growth pattern, including one with widespread invasion and lymph node metastasis. Three invasive ICs harbored an NCOA4-RET fusion transcript, while 1 case was negative, and 2 cases were not analyzable. In addition, a novel TRIM27-RET fusion transcript between exon 3 of TRIM27 and exon 12 of RET was identified in 2 cases of IC with apocrine features, and one of them displayed invasive growth. Two IC cases with invasive growth harbored novel fusions TUT1-ETV5 and KIAA1217-RET, respectively. A total of 42.4% of the cases in this series of IC harbored fusions involving RET. Such fusion transcripts were not detected in any of the 10 SDC cases. We have confirmed NCOA4-RET as a predominant fusion in intercalated duct-type IC, including 3 cases with invasive growth pattern. A novel finding in our series was a case of widely invasive intercalated duct-type IC, with a single lymph node metastasis that revealed an NCOA4-RET fusion transcript. We also demonstrated that a subset of apocrine ICs harbored a TRIM27-RET gene fusion, including one case with invasive growth. In contrast, neither NCOA4-RET nor TRIM27-RET fusions were detected in any tested SDCs. Thus, the distinct molecular findings in IC and SDC support that the tumors are separate malignant salivary tumor entities. The presence of tumor-type-specific NCOA4-RET or TRIM27-RET translocations in a subset of widely invasive carcinomas with intercalated duct-like immunoprofiles suggests that a recharacterization of IC including its redesignation as "intercalated duct carcinoma, invasive or noninvasive" may be appropriate.

Invasive ductal carcinoma with coexisting ductal carcinoma in situ (IDC/DCIS) versus pure invasive ductal carcinoma (IDC): a comparison of clinicopathological characteristics, molecular subtypes, and clinical outcomes.

PURPOSE: Ductal carcinoma in situ (DCIS) is widely recognized as the precursor of invasive ductal carcinoma (IDC). We aimed to analyze the clinicopathological characteristics and clinical outcomes of coexisting DCIS component in IDC and its clinical significance according to molecular subtypes. METHODS: Data from 3001 patients with IDC (79.4%) and IDC/DCIS (20.6%) who underwent surgery from January 2009 to June 2016 were retrospectively assessed. The clinical outcomes of IDC with coexistent DCIS in different molecular subtypes were evaluated. RESULTS: IDC/DCIS patients were more likely to be younger (P < 0.001), had low tumor grade (P = 0.001), had less lymph node involvement (P = 0.038) and received more mastectomy (P = 0.002) than IDC patients. In the comparison of molecular subtype prevalence, IDC/DCIS patients were more frequently presented with luminal B/HER2 positive (12.5% vs 11.0%, P < 0.001) and HER2 positive subtypes (20.9% vs 9.8%, P < 0.001). The 5-year disease-free survival (DFS, 90.9% vs 87.5%, P = 0.021) and 5-year overall survival (OS 96.1% vs 94.0%, P = 0.018) were significantly improved in IDC/DCIS patients compared to IDC patients. In multivariate analysis, the presence of coexisting DCIS (P = 0.048), tumor size (P < 0.001), lymph node status (P < 0.001), lymphovascular invasion (P = 0.007) and molecular subtypes (P < 0.001) were independent prognostic factors for DFS. Furthermore, coexistence of DCIS component in IDC significantly improved DFS in HER2 positive (94.8% vs 78.5%, P = 0.003), but had no association in luminal and triple negative subtypes. CONCLUSIONS: IDC with coexisting DCIS was associated with improved prognosis. Patients with IDC/DCIS presented with more HER2 positive expression and might improve DFS in HER2 positive breast cancer.

Apocrine lesions of the breast: part 1 of a two-part review: benign, atypical and in situ apocrine proliferations of the breast.

Apocrine morphology is a common phenomenon encountered in everyday breast pathology practice, and is defined as cuboidal or columnar cells exhibiting abundant eosinophilic granular cytoplasm, prominent apical granules, a low nuclear-cytoplasmic ratio, and round nuclei with pale chromatin and prominent nucleoli. Apocrine morphology is recognised in benign, atypical and malignant lesions of the breast. The morphology of apocrine atypia and non-high-grade apocrine ductal carcinoma in situ (DCIS) is less well defined due to the relative rarity of these lesions. In part 1 of this two-part review, we focus on the morphological characteristics of benign, atypical and in situ apocrine lesions of the breast, summarise the available data to date regarding distinction of atypical apocrine proliferations from non-high-grade apocrine DCIS and the biological significance of apocrine atypia, and provide practical guidance on handling these difficult lesions. Part 2 of this review will focus on the concept of pure apocrine carcinoma with emphasis on its definition and molecular data, including the current understanding of the molecular apocrine signature in breast carcinoma. We complete the review with a synopsis on the utility of immunohistochemistry in the diagnosis of apocrine lesions of the breast.

Differences and Relationships Between Normal and Atypical Ductal Hyperplasia, Ductal Carcinoma In Situ, and Invasive Ductal Carcinoma Tissues in the Breast Based on Raman Spectroscopy.

The aim of this study was to find the differences and relationships between normal, atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC) lesions of the breast based on biochemical characteristics determined by Raman spectroscopy (RS). After collecting 39 frozen sections from patients who underwent surgical resection or mammotome biopsy, nine normal tissues, seven ADH, eight DCIS, and 15 IDC lesions were detected using confocal RS. We then used leave-one-out cross-validation (LOOCV) and radial basis function (RBF) to build a support vector machine (SVM) diagnosis model. Pronounced mean Raman spectra differences were observed between normal tissues, ADH, DCIS, and IDC tissues. Most noticeable was the increased protein and reduced lipid levels of ADH tissues compared to normal tissues. The major spectra differences in ADH, DCIS, and IDC spectrograms were evidenced by a red shift with a broad peak of CH2 (1301 cm-1), the intensity of the stretching vibration peak of carotenoids (1526 cm-1), a relatively strong band of amide-I (1656 cm-1), and the nuclear (882 cm-1) acid peak. Atypical ductal hyperplasia tissues had the largest constituent variations between subjects. During the disease progression, IDC tissues have smaller inter-subject constituent variations than DCIS and ADH tissues. The overall accuracy of SVM model is 74.39%. The sensitivities of normal tissue, ADH, DCIS, and IDC are 62.5%, 50%, 90%, and 66.7%, respectively. The specificities of normal tissue, ADH, DCIS, and IDC are 100%, 100%, 66.7%, and 89.06%, respectively. Atypical ductal hyperplasia shows significant differences and the relationship between normal tissue and malignant disease. Further study to explain the biochemical relationships between these differences will shed more light into a better understanding of the mechanism by which ADH converts to DCIS and to IDC.

Radiopathological features predictive of involved margins in ductal carcinoma in situ.

INTRODUCTION Ductal carcinoma in situ (DCIS) usually manifests as microcalcification on mammography but may be uncalcified. Consequently, a quarter of patients undergoing excision of a presumed pure DCIS require further surgery to re-excise margins. Patients at highest risk of margin involvement may benefit from additional preoperative assessment. METHODS A retrospective review was carried out of patients treated for screen detected, biopsy proven DCIS in a single centre over a ten-year period (1999-2009). Logistic regression analysis identified factors predictive of need for further surgery to clear margins. RESULTS Overall, 248 patients underwent surgery for DCIS (low/intermediate grade: 82, high grade: 155) and 49 (19.8%) required further surgery. High grade disease was associated with greater mammographic extent (mean: 32mm [range: 5-120mm] vs 25mm [range: 2-100mm]), p=0.009) and higher incidence of mastectomy (38% vs 24%, p=0.034). Factors predictive of involvement of surgical margins necessitating further surgery included negative oestrogen receptor status (OR: 5.2, 95% CI: 2.1-12.8, p<0.001) and mammographic extent (odds ratio [OR]: 1.6, 95% confidence interval [CI]: 1.2-2.1, p=0.004). Once size exceeded 30mm, more than 50% of patients required secondary breast surgery for margins. CONCLUSIONS Reoperation rates for DCIS increase with preoperative size on mammography and negative oestrogen receptor status on core biopsy. Patients with these risk features should be counselled accordingly and consideration should be given to the role of additional preoperative imaging.

Breast cancer classification and prognostication through diverse systems along with recent emerging findings in this respect; the dawn of new perspectives in the clinical applications.

Breast cancer is the most common malignancy among women and the second leading cause of mortality due to cancer worldwide. The complexity of breast cancer resembles an intricate ecosystem comprising various cleverly designed interaction levels of internal and external factors to generate a pliable context in the clonal evolution of breast cancer cells. Principally, the complex entity can become evident toward delineating a number of significant variations in the specific fields of breast cancer analyses, including the molecular, physiological, and morphological characteristics, clinical presentations, risk factors, the histopathological conditions, and response to systemic therapy regarding the maintenance of tumor as a whole. In hindsight, various classification systems developing based on specific inclusion criteria have indisputably changed both our appreciation of the biological demeanor of breast cancer and the main strategies for designing tailored therapy regimens through the proper evaluation of diagnosis and prognostication of given specimens. Here, we endeavor to provide a general overview of different types of breast cancer classification as well as the clinical acceptance of their applications along with the latest findings in this area. Taken together, the major significance of breast cancer management that can be ascertained by operational convergent points of its stratification areas is owing to the fact that the achievement of individualized and targeted therapy may denounce new horizons of surveillance and treatment strategies in which they may function as a rheostat of specific therapy regimens toward reducing the detected distances between experimental data and operating options in clinical practice.

Papillary carcinoma of the breast: diagnostic agreement and management implications.

AIMS: Papillary carcinoma (PC), which is a rare type of breast cancer, comprises a heterogeneous group of tumours. The diagnostic categorization of PC as in-situ and invasive disease remains a matter of debate with respect to interpretation of its overlapping histological features, and with respect to the uncertainty in clinical behaviour that this dilemma raises. The aim of this study was to assess the diagnostic agreement regarding PC among reporting breast pathologists. METHODS AND RESULTS: Six cases of PC included in the UK National Health Service Breast Screening Programme breast pathology interpretive external quality assurance scheme in the last 10 years were reviewed. In this scheme, one representative haematoxylin and eosin-stained slide from each case is circulated to an average of 600 participants. Data on diagnostic categories were collected and slides were reviewed according to the World Health Organization (WHO) diagnostic criteria. The number of final diagnoses of malignancy (in situ or invasive) was highest for invasive PC (99% of the participants diagnosed it as malignant), followed by solid PC (94% and 95%, respectively), encapsulated PC (92% and 92%, respectively), and papillary ductal carcinoma in situ (DCIS) (88%). Most cases of papillary DCIS were correctly classified as in-situ disease (77%), but 28% of the participants classified invasive PC cases as in-situ disease. Of the participants, 24% reported encapsulated PC as invasive disease. Of the two solid PC cases, one showed some features consistent with the WHO description of invasive solid PC, whereas the other showed features of classic (non-invasive) solid PC. Both cases were reported as invasive by 75% and 77% of participants, respectively. Breast specialists more frequently classified PC as an in-situ carcinoma than did non-specialist participants, and the difference was significant (P = 0.013). CONCLUSIONS: Recognition of PC as a malignant entity (in situ or invasive) is high, but concordance of its classification into in-situ and invasive disease is low. Histological features that can define invasion in PC should be better defined. These rare lesions require additional diagnostic work-up, and difficult cases should trigger consensus opinion or expert referral.

Identification of lesion subtypes in biopsies of ductal carcinoma in situ of the breast using biomarker ratio imaging microscopy.

Although epidemiological studies propose aggressive and non-aggressive forms of ductal carcinoma in situ (DCIS), they cannot be identified with conventional histopathology. We now report a retrospective study of human biopsy samples using biomarker ratio imaging microscopy (BRIM). Using BRIM, micrographs of biomarkers whose expression correlates with breast cancer aggressiveness are divided by micrographs of biomarkers whose expression negatively correlates with aggressiveness to create computed micrographs reflecting aggressiveness. The biomarker pairs CD44/CD24, N-cadherin/E-cadherin, and CD74/CD59 stratified DCIS samples. BRIM identified subpopulations of DCIS lesions with ratiometric properties resembling either benign fibroadenoma or invasive carcinoma samples. Our work confirms the existence of distinct subpopulations of DCIS lesions, which will likely have utility in breast cancer research and clinical practice.

Premalignancy in Prostate Cancer: Rethinking What we Know.

High-grade prostatic intraepithelial neoplasia (PIN) has been accepted as the main precursor lesion to invasive adenocarcinoma of the prostate, and this is likely to be the case. However, in an unknown number of cases, lesions fulfilling the diagnostic criteria for high-grade PIN may actually represent intra-acinar or intraductal spread of invasive carcinoma. Intriguingly, this possibility would not contradict many of the findings of previous epidemiologic studies linking high-grade PIN to carcinoma or molecular pathologic studies showing similar genomic (e.g., TMPRSS2-ERG gene fusion) as well as epigenomic and molecular phenotypic alterations between high-grade PIN and carcinoma. Also, this possibility would be consistent with previous anatomic studies in prostate specimens linking high-grade PIN and carcinoma in autopsy and other whole prostate specimens. In addition, if some cases meeting morphologic criteria for PIN actually represent intra-acinar spread of invasive carcinoma, this could be an important potential confounder of the interpretation of past clinical trials enrolling patients presumed to be without carcinoma, who are at high risk of invasive carcinoma. Thus, in order to reduce possible bias in future study/trial designs, novel molecular pathology approaches are needed to decipher when an apparent PIN lesion may be intra-acinar/intra-ductal spread of an invasive cancer and when it truly represents a precursor state. Similar approaches are needed for lesions known as intraductal carcinoma to facilitate better classification of them as true intra-ductal/acinar spread on one hand or as precursor high-grade PIN (cribriform type) on the other hand; a number of such molecular approaches (e.g., coevaluating TMPRSS-ERG fusion and PTEN loss) are already showing excellent promise. Cancer Prev Res; 9(8); 648-56. ©2016 AACR.

Molecular classification of non-invasive breast lesions for personalised therapy and chemoprevention.

Breast cancer screening has led to a dramatic increase in the detection of pre-invasive breast lesions. While mastectomy is almost guaranteed to treat the disease, more conservative approaches could be as effective if patients can be stratified based on risk of co-existing or recurrent invasive disease.Here we use a range of biomarkers to interrogate and classify purely non-invasive lesions (PNL) and those with co-existing invasive breast cancer (CEIN). Apart from Ductal Carcinoma In Situ (DCIS), relative homogeneity is observed. DCIS contained a greater spread of molecular subtypes. Interestingly, high expression of p-mTOR was observed in all PNL with lower expression in DCIS and invasive carcinoma while the opposite expression pattern was observed for TOP2A.Comparing PNL with CEIN, we have identified p53 and Ki67 as predictors of CEIN with a combined PPV and NPV of 90.48% and 43.3% respectively. Furthermore, HER2 expression showed the best concordance between DCIS and its invasive counterpart.We propose that these biomarkers can be used to improve the management of patients with pre-invasive breast lesions following further validation and clinical trials. p53 and Ki67 could be used to stratify patients into low and high-risk groups for co-existing disease. Knowledge of expression of more actionable targets such as HER2 or TOP2A can be used to design chemoprevention or neo-adjuvant strategies. Increased knowledge of the molecular profile of pre-invasive lesions can only serve to enhance our understanding of the disease and, in the era of personalised medicine, bring us closer to improving breast cancer care.

How different terminology for ductal carcinoma in situ impacts women's concern and treatment preferences: a randomised comparison within a national community survey.

OBJECTIVE: There have been calls to remove 'carcinoma' from terminology for in situ cancers such as ductal carcinoma in situ (DCIS), to reduce overdiagnosis and overtreatment. We investigated the effect of describing DCIS as 'abnormal cells' versus 'pre-invasive breast cancer cells' on women's concern and treatment preferences. SETTING AND PARTICIPANTS: Community sample of Australian women (n=269) who spoke English as their main language at home. DESIGN: Randomised comparison within a community survey. Women considered a hypothetical scenario involving a diagnosis of DCIS described as either 'abnormal cells' (arm A) or 'pre-invasive breast cancer cells' (arm B). Within each arm, the initial description was followed by the alternative term and outcomes reassessed. RESULTS: Women in both arms indicated high concern, but still indicated strong initial preferences for watchful waiting (64%). There were no differences in initial concern or preferences by trial arm. However, more women in arm A ('abnormal cells' first term) indicated they would feel more concerned if given the alternative term ('pre-invasive breast cancer cells') compared to women in arm B who received the terms in the opposite order (67% arm A vs 52% arm B would feel more concerned, p=0.001). More women in arm A also changed their preference towards treatment when the terminology was switched from 'abnormal cells' to 'pre-invasive breast cancer cells' compared to arm B. In arm A, 18% of women changed their preference to treatment while only 6% changed to watchful waiting (p=0.008). In contrast, there were no significant changes in treatment preference in arm B when the terminology was switched (9% vs 8% changed their stated preference). CONCLUSIONS: In a hypothetical scenario, interest in watchful waiting for DCIS was high, and changing terminology impacted women's concern and treatment preferences. Removal of the cancer term from DCIS may assist in efforts towards reducing overtreatment.

A Molecular Portrait of High-Grade Ductal Carcinoma In Situ.

Ductal carcinoma in situ (DCIS) is a noninvasive precursor lesion to invasive breast carcinoma. We still have no understanding on why only some DCIS lesions evolve to invasive cancer whereas others appear not to do so during the life span of the patient. Here, we performed full exome (tumor vs. matching normal), transcriptome, and methylome analysis of 30 pure high-grade DCIS (HG-DCIS) and 10 normal breast epithelial samples. Sixty-two percent of HG-DCIS cases displayed mutations affecting cancer driver genes or potential drivers. Mutations were observed affecting PIK3CA (21% of cases), TP53 (17%), GATA3 (7%), MLL3 (7%) and single cases of mutations affecting CDH1, MAP2K4, TBX3, NF1, ATM, and ARID1A. Significantly, 83% of lesions displayed numerous large chromosomal copy number alterations, suggesting they might precede selection of cancer driver mutations. Integrated pathway-based modeling analysis of RNA-seq data allowed us to identify two DCIS subgroups (DCIS-C1 and DCIS-C2) based on their tumor-intrinsic subtypes, proliferative, immune scores, and in the activity of specific signaling pathways. The more aggressive DCIS-C1 (highly proliferative, basal-like, or ERBB2(+)) displayed signatures characteristic of activated Treg cells (CD4(+)/CD25(+)/FOXP3(+)) and CTLA4(+)/CD86(+) complexes indicative of a tumor-associated immunosuppressive phenotype. Strikingly, all lesions showed evidence of TP53 pathway inactivation. Similarly, ncRNA and methylation profiles reproduce changes observed postinvasion. Among the most significant findings, we observed upregulation of lncRNA HOTAIR in DCIS-C1 lesions and hypermethylation of HOXA5 and SOX genes. We conclude that most HG-DCIS lesions, in spite of representing a preinvasive stage of tumor progression, displayed molecular profiles indistinguishable from invasive breast cancer.

Intraductal papillomas on core biopsy can be upgraded to malignancy on subsequent excisional biopsy regardless of the presence of atypical features.

Intraductal papillary lesions of the breast constitute a heterogeneous entity, including benign intraductal papilloma (IDP) with or without atypia and malignant papillary carcinoma. Differentiating between these diagnoses can be challenging. We re-evaluated core biopsy specimens that were diagnosed as IDP and the corresponding surgical excision specimens, and assessed the potential risk for the diagnosis to be modified to malignancy based on excision. By sorting the pathology database of the National Cancer Center Hospital, Tokyo, we identified 146 core biopsy cases that were histologically diagnosed as IDP between 1997 and 2013. The re-evaluated diagnosis was IDP without atypia in 79 (54%) patients, IDP with atypia in 66 (45%), and ductal carcinoma in situ (DCIS) in 1 (1%). Among the 34 patients (23%) who underwent surgical excision subsequent to core biopsy, histological diagnosis was upgraded to carcinoma, excluding lobular carcinoma in situ (LCIS), in 14 (41%) cases, including 4 (33%) of 12 IDPs without atypia and 10 (45%) of 22 IDPs with atypia. Complete surgical excision should be kept in mind for all IDPs diagnosed on core biopsy, not only IDPs with atypia but IDPs without atypia, especially when clinical or imaging diagnosis findings cannot rule out the possibility of malignancy, because papillary lesions comprise a variety of morphological appearances.

Role of second-look ultrasound examinations for MR-detected lesions in patients with breast cancer.

PURPOSE: To assess the clinical value of second-look ultrasound (US) examination for the evaluation of additional enhancing lesions detected on magnetic resonance (MR) imaging. MATERIALS AND METHODS: Between May 2008 and February 2011, 794 consecutive patients with histologically confirmed breast cancer underwent breast MR imaging. We included 101 patients with 132 additional enhancing breast lesions detected on MR imaging who underwent second-look US.  The imaging features and lesion category according to the Breast Imaging and Reporting and Data System (BI-RADS) were assessed with MR and US imaging, respectively. RESULTS: According to the BI-RADS system, 67 lesions (50.8 %) were classified as category 0, 33 lesions (25.0 %) as category 3, and 32 lesions (24.2 %) as category 4. Of the 67 indeterminate lesions on MR imaging, 34 (50.7 %) were demonstrated on second-look US. 11 of these 34 lesions showed suspicious sonographic features, including 1 lesion that showed malignancy (9.1 %, 1/11). Most of the suspicious lesions on MR imaging (26 of 32 BI-RADS category 4 lesions, 81.3 %) were demonstrated on second-look US, and 17 were malignant (65.4 %, 17/26). Of the 6 BI-RADS category 4 lesions without sonographic correlation, 1 was malignant (16.7 %, 1/6). CONCLUSION: Second-look US examination was useful for evaluating MR-detected lesions in patients with breast cancer.

Web based pathology assessment in RTOG 98-04.

AIMS: Radiation Therapy Oncology Group 98-04 sought to identify women with 'good risk' ductal carcinoma in situ (DCIS) who receive no significant benefit from radiation. Enrolment criteria excluded close or positive margins and grade 3 disease. To ensure reproducibility in identifying good risk pathology, an optional web based teaching tool was developed and a random sampling of 10% of submitted slides were reviewed by a central pathologist. METHODS: Submitting pathologists were asked to use the web based teaching tool and submit an assessment of the tool along with the pathology specimen form and DCIS H&E stained slide. Per protocol pathology was centrally reviewed for 10% of the cases. RESULTS: Of the 55 DCIS cases reviewed, three had close or positive margins and three were assessed to include grade 3 DCIS, therefore 95% of DCIS cases reviewed were correctly graded, and 89% reviewed were pathologically appropriate for enrolment. Regarding the teaching tool, 13% of DCIS cases included forms that indicated the website was used. One of these seven who used the website submitted DCIS of grade 3. CONCLUSIONS: Central review demonstrates high pathological concordance with enrolment eligibility, particularly with regard to accurate grading. The teaching tool appeared to be underused.