Pure Atypical Ductal Hyperplasia Research Articles

MiRNAs as potential biomarkers in early breast cancer detection: a systematic review.

Breast cancer remains a significant global health challenge, with high incidence and mortality rates. While mammography has contributed to declining mortality, its limitations in sensitivity and specificity for early detection, particularly in distinguishing between pure atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC), highlight the need for more precise tools. Even with core needle biopsy (CNB), conclusive diagnoses often require surgical excision. This underscores the urgency for non-invasive biomarkers to improve early detection and differentiation, potentially reducing invasive procedures. Recent research has shifted focus from mRNA to microRNAs (miRNAs) as promising biomarkers for breast cancer screening. These small non-coding RNAs, which exhibit abnormal expression patterns in breast cancer patients' tissue and serum/plasma, play crucial roles in early breast cancer development by modulating proto-oncogenes or tumor suppressor genes at the post-transcriptional level. Notably, miRNAs such as miR-21, miR-155, and miR-200c are key regulators of cell proliferation and apoptosis, with the potential to distinguish between normal tissue and various stages of breast lesions, including ADH, DCIS, and IDC. Additionally, miRNAs in serum and plasma offer a non-invasive method to differentiate breast cancer stages. This review aims to consolidate current knowledge on early breast lesions and explore the potential of miRNAs as biomarkers for early breast cancer detection, which could enhance risk prediction and reduce reliance on invasive diagnostic procedures.

Breast MRI assists in decision-making for surgical excision of atypical ductal hyperplasia

BackgroundAtypical ductal hyperplasia diagnosed on percutaneous breast biopsy typically undergoes surgical excision, upgrading to invasive breast cancer or ductal carcinoma in situ in 10% to 53%. In efforts to limit excision to those with highest upgrade risk, we sought to determine if breast magnetic resonance imaging has value in predicting upgrade. In this study, we will describe magnetic resonance imaging presentation of atypical ductal hyperplasia and assess magnetic resonance imaging accuracy in predicting upgrade. MethodsAll female patients ≥18 years with atypical ductal hyperplasia on percutaneous breast biopsy undergoing magnetic resonance imaging from 2008 to 2020 were included. Patient demographics, imaging presentation, magnetic resonance imaging enhancement kinetic curves, and pathology features were captured. Categorical variables were analyzed using Fisher exact to test for association between variables and upgrade. Continuous variables were analyzed using t tests. ResultsMagnetic resonance imaging was performed for 125 percutaneous breast biopsy with atypical ductal hyperplasia: 67 after and 58 before atypical ductal hyperplasia diagnosis. On magnetic resonance imaging, atypical ductal hyperplasia site had no enhancement in 45 (36%), nonmass enhancement in 50 (40%), and mass enhancement in 30 (24%). In total, 28% had atypical ductal hyperplasia diagnosed by magnetic resonance imaging–guided percutaneous breast biopsy. Surgical excision was performed for 96 (76.8%) and 15 (15.6%) upgraded (11 ductal carcinoma in situ, 4 invasive breast cancer). All 15 upgrades had enhancement. Any kinetic pattern enhancement was significantly associated with upgrade (P = .009) with upgrade most strongly associated with type III washout. The lowest risk for upgrade was pure atypical ductal hyperplasia and no magnetic resonance imaging enhancement (0%, n = 25). ConclusionsActive monitoring may be safely offered to women with pure atypical ductal hyperplasia on percutaneous breast biopsy when magnetic resonance imaging shows no enhancement. Any enhancement at atypical ductal hyperplasia site, particularly type III washout kinetics, should continue to undergo excision.

The effect of delay of excisional biopsy on upstage rate for atypical ductal hyperplasia, flat epithelial atypia, intraductal papilloma, and radial scar.

PurposeWhen Core Needle Biopsy (CNB) demonstrates Atypical Ductal Hyperplasia (ADH), Flat Epithelial Atypia (FEA), Intraductal Papilloma (IDP), or Radial Scar/Complex Sclerosing Lesion (RS), excisional biopsy (EB) is often performed to rule out underlying malignancy with upstage rates (UR) ranging between 1 and 20%. The COVID-19 pandemic led to delayed EB for many patients. We sought to evaluate whether this delay was associated with higher UR.MethodsWe performed a retrospective analysis of women who underwent CNB and then EB for ADH, FEA, IDP, or RS between 2017 and 2021 using an IRB-approved repository. UR was evaluated by days between CNB and EB.Results473 patients met inclusion. 55 were upstaged to cancer (11.6%). 178 patients had pure ADH on CNB and 37 were upstaged (20.8%). 50 patients had pure FEA and 3 were upstaged (6%). 132 had pure IDP and 7 were upstaged (5.3%). 98 had pure RS and 1 was upstaged (1%). 7/15 (46.7%) had a combination of diagnoses or diagnosis with palpable mass and were upstaged.Days between CNB and EB were < 60 for 275 patients (58.1%), 60–90 for 108 (22.8%), 91–120 for 43 (9.1%), and > 120 for 47 (9.9%). There was no significant difference in UR (10.9% for < 60, 14.8% for 60–90, 7% for 90–120, and 12.8% for > 120, p = 0.54). UR for ADH was clinically increased after 60 days (27.8 vs. 17.5%), but this did not reach statistical significance (p = 0.1).ConclusionSurgical delay was not associated with an increased UR.

Safety of de-escalation of surgical intervention for atypical ductal hyperplasia on percutaneous biopsy: One size does not fit all

BackgroundOncologic safety of active monitoring (AM) for atypical ductal hyperplasia (ADH) on core-needle biopsy (CNB) is not well defined. We sought to define oncologic outcomes for AM to manage ADH meeting institutional predefined low-risk criteria (LOW). MethodsADH was diagnosed on CNB from 10/2015-03/2020. LOW (pure ADH, size <1 cm, >50% removed by CNB, <3 foci, and no necrosis) patients were offered AM; all others were recommended for surgical excision. Oncologic outcomes were compared for AM and surgery. Results111 were included, 21 (19%) meeting LOW. AM occurred in 18 (86%) while 3 elected for excision (with 0% upgrade). Of the 18 LOW in AM, 2 required additional CNB (none at ADH site): 0% were diagnosed with cancer over median 23 month follow-up. ConclusionsThere were no missed cancers at ADH site during AM for LOW, confirming the oncologic safety of AM in this select group.

Abstract 2498: miFISH single cell analysis as a potential tool to stratify the progression risk in patients with Atypical Ductal Hyperplasia (ADH)

Abstract We previously studied synchronous ductal carcinomas in situ (DCIS) and invasive ductal carcinomas (IDC) using our novel approach of multiplex interphase Fluorescence in situ Hybridization (miFISH) that allows simultaneous enumeration of copy numbers of up to 20 gene loci per single cell, providing new insights into tumor clonality and intratumor heterogeneity (ITH). A high degree of chromosomal instability was present in DCIS, and we frequently observed a direct clonal evolution from DCIS to IDC. We now ask whether this degree of instability is also present in even earlier potential precursor lesions like atypical ductal hyperplasias (ADH). We are therefore conducting a retrospective study analyzing ADH lesions from patients without synchronous DCIS or IDC (pure ADH) and from patients with ADH adjacent to higher-grade lesions. Using our miFISH assay, we simultaneously assess copy number changes of six oncogenes (COX2 (1q), PIK3CA (3q), MET (7q), MYC (8q), CCND1 (11q), HER2 (17q), ZNF217 (20q)) and six tumor suppressor genes (FHIT (3p), DBC2 (8p), RB1 (13q), CDH1 (16q), TP53 (17q), NF2 (22q), typical for breast tumorigenesis. So far, we have analyzed fifteen pure ADH and five ADH with synchronous DCIS or IDC. The miFISH analysis showed that the majority of all pure ADH displayed a stable diploid genome without any copy number changes observed for the genes tested while only 3/15 (20%) showed changes, namely (i) a COX2 and HER2 gain in a diploid genome, (ii) a CDH1and MET loss in a tetraploid genome and (iii) a COX2 gain in a diploid genome. In the group of ADH with adjacent higher-grade lesions (n=5), all DCIS and IDC lesions analyzed displayed breast cancer specific copy number changes corroborating our previous results. Of note, two of the ADH lesions adjacent to these aberrant DCIS or IDC lesions had normal diploid genomes. Of the remaining three synchronous ADH lesions, one showed a complex gain and loss pattern similar to its adjacent DCIS, the second one was characterized by a simple COX2 gain which was maintained in the adjacent DCIS in addition to a DBC2 loss and MYC gain. The third ADH displayed a tetraploid clone without any gains or losses, while the adjacent IDC revealed a complex gain and loss pattern in its tetraploid genome. Our preliminary data indicate that the majority of pure ADH does not harbor copy number changes. However, there is a small subset of pure ADH revealing gain and loss patterns typical for DCIS and IDC often involving COX2 gain indicating it as an early event. Of note, ADH lesions adjacent to DCIS or IDC tend to display similar changes as their adjacent higher-grade lesions suggesting them as direct precursor lesions. We are currently analyzing more ADH samples and plan to add material from an ADH patient cohort with long-term follow-up to explore whether miFISH can stratify ADH patients into different risk groups. Citation Format: Kiara Whitaker, Jausheng Tzeng, Daniela Hirsch, Irianna Torres, Steven Brower, Gert Auer, Miguel Sanchez, Thomas Ried, Kerstin Heselmeyer-Haddad. miFISH single cell analysis as a potential tool to stratify the progression risk in patients with Atypical Ductal Hyperplasia (ADH) [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 2498.

Prospective Analysis Using a Novel CNN Algorithm to Distinguish Atypical Ductal Hyperplasia From Ductal Carcinoma in Situ in Breast

IntroductionWe previously developed a convolutional neural networks (CNN)-based algorithm to distinguish atypical ductal hyperplasia (ADH) from ductal carcinoma in situ (DCIS) using a mammographic dataset. The purpose of this study is to further validate our CNN algorithm by prospectively analyzing an unseen new dataset to evaluate the diagnostic performance of our algorithm. Materials and MethodsIn this institutional review board-approved study, a new dataset composed of 280 unique mammographic images from 140 patients was used to test our CNN algorithm. All patients underwent stereotactic-guided biopsy of calcifications and underwent surgical excision with available final pathology. The ADH group consisted of 122 images from 61 patients with the highest pathology diagnosis of ADH. The DCIS group consisted of 158 images from 79 patients with the highest pathology diagnosis of DCIS. Two standard mammographic magnification views (craniocaudal and mediolateral/lateromedial) of the calcifications were used for analysis. Calcifications were segmented using an open source software platform 3D slicer and resized to fit a 128 × 128 pixel bounding box. Our previously developed CNN algorithm was used. Briefly, a 15 hidden layer topology was used. The network architecture contained 5 residual layers and dropout of 0.25 after each convolution. Diagnostic performance metrics were analyzed including sensitivity, specificity, accuracy, and area under the receiver operating characteristic curve. The “positive class” was defined as the pure ADH group in this study and thus specificity represents minimizing the amount of falsely labeled pure ADH cases. ResultsArea under the receiver operating characteristic curve was 0.90 (95% confidence interval, ± 0.04). Diagnostic accuracy, sensitivity, and specificity was 80.7%, 63.9%, and 93.7%, respectively. ConclusionProspectively tested on new unseen data, our CNN algorithm distinguished pure ADH from DCIS using mammographic images with high specificity.

Upgrade Rate of Percutaneously Diagnosed Pure Atypical Ductal Hyperplasia: Systematic Review and Meta-Analysis of 6458 Lesions.

Background Management of percutaneously diagnosed pure atypical ductal hyperplasia (ADH) is an unresolved clinical issue. Purpose To calculate the pooled upgrade rate of percutaneously diagnosed pure ADH. Materials and Methods A search of MEDLINE and EMBASE databases was performed in October 2018. Preferred Reporting Items for Systematic Reviews and Meta-Analyses, or PRISMA, guidelines were followed. A fixed- or random-effects model was used, along with subgroup and meta-regression analyses. The Newcastle-Ottawa scale was used for study quality, and the Egger test was used for publication bias. Results Of 521 articles, 93 were analyzed, providing data for 6458 ADHs (5911 were managed with surgical excision and 547 with follow-up). Twenty-four studies used core-needle biopsy; 44, vacuum-assisted biopsy; 21, both core-needle and vacuum-assisted biopsy; and four, unspecified techniques. Biopsy was performed with stereotactic guidance in 29 studies; with US guidance in nine, with MRI guidance in nine, and with mixed guidance in eight. Overall heterogeneity was high (I2 = 80%). Subgroup analysis according to management yielded a pooled upgrade rate of 29% (95% confidence interval [CI]: 26%, 32%) for surgically excised lesions and 5% (95% CI: 4%, 8%) for lesions managed with follow-up (P < .001). Heterogeneity was entirely associated with surgically excised lesions (I2 = 78%) rather than those managed with follow-up (I2 = 0%). Most variability was explained by guidance and needle caliper (P = .15). At subgroup analysis of surgically excised lesions, the pooled upgrade rate was 42% (95% CI: 31%, 53%) for US guidance, 23% (95% CI: 19%, 27%) for stereotactic biopsy, and 32% (95% CI: 22%, 43%) for MRI guidance, with heterogeneity (52%, 63%, and 56%, respectively) still showing the effect of needle caliper. When the authors considered patients with apparent complete lesion removal after biopsy (subgroups in 14 studies), the pooled upgrade rate was 14% (95% CI: 8%, 23%). Study quality was low to medium; the risk of publication bias was low (P = .10). Conclusion Because of a pooled upgrade rate higher than 2% (independent of biopsy technique, needle size, imaging guidance, and apparent complete lesion removal), atypical ductal hyperplasia diagnosed with percutaneous needle biopsy should be managed with surgical excision. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Brem in this issue.

Accuracy of Distinguishing Atypical Ductal Hyperplasia From Ductal Carcinoma In Situ With Convolutional Neural Network-Based Machine Learning Approach Using Mammographic Image Data.

OBJECTIVE. The purpose of this study was to test the hypothesis that convolutional neural networks can be used to predict which patients with pure atypical ductal hyperplasia (ADH) may be safely monitored rather than undergo surgery. MATERIALS AND METHODS. A total of 298 unique images from 149 patients were used for our convolutional neural network algorithm. A total of 134 images from 67 patients with ADH that had been diagnosed by stereotactic-guided biopsy of calcifications but had not been upgraded to ductal carcinoma in situ or invasive cancer at the time of surgical excision. A total of 164 images from 82 patients with mammographic calcifications indicated that ductal carcinoma in situ was the final diagnosis. Two standard mammographic magnification views of the calcifications (a craniocaudal view and a mediolateral or lateromedial view) were used for analysis. Calcifications were segmented using an open-source software platform and images were resized to fit a bounding box of 128 × 128 pixels. A topology with 15 hidden layers was used to implement the convolutional neural network. The network architecture contained five residual layers and dropout of 0.25 after each convolution. Patients were randomly separated into a training-and-validation set (80% of patients) and a test set (20% of patients). Code was implemented using open-source software on a workstation with an open-source operating system and a graphics card. RESULTS. The AUC value was 0.86 (95% CI, ± 0.03) for the test set. Aggregate sensitivity and specificity were 84.6% (95% CI, ± 4.0%) and 88.2% (95% CI, ± 3.0%), respectively. Diagnostic accuracy was 86.7% (95% CI, ± 2.9). CONCLUSION. It is feasible to apply convolutional neural networks to distinguish pure atypical ductal hyperplasia from ductal carcinoma in situ with the use of mammographic images. A larger dataset will likely result in further improvement of our prediction model.

Abstract PD1-12: Identification of copy number alterations associated with the progression of high risk premalignant breast lesions to breast carcinoma

Abstract Background: Atypical ductal hyperplasia (ADH) is common finding in the mammographic era, but has wide variation in diagnosis and treatment. ADH is a high risk factor for invasive breast ductal carcinoma (IDC), and is also considered to be a non-obligate precursor to IDC. Although a few studies have revealed some of the common genomic characteristics of ADH, a clear understanding of the molecular changes associated with breast cancer progression has been limited by inadequately powered studies and low resolution methodology (Lopez-Garcia et al., 2010, Histopathology 57: 171-192). Copy number alterations (CNAs), one of the major genetic alterations in cancer, are present in IDC and ductal carcinoma in situ (DCIS) and given a suitable detection method could be used in research and potentially in the clinical setting to predict patient prognosis. Method: We optimised a robust, cost effective low-coverage whole genome sequencing (LCWGS) method for CNA detection, using as little as 5 ng of formalin-fixed paraffin-embedded tissue derived DNA. We applied this novel method to 21 cases of pure ADH (not associated with cancer) as well as 20 ADH with synchronous DCIS and/or IDC. Cases were reviewed independently by two pathologists, followed by micro-dissection and DNA extraction. CNA were analysed using the LCWGS method, using 5-10 ng total DNA input per sample. Results: Highly accurate copy number profiles produced by low input LCWGS are comparable to those obtained from an alternative method, Molecular Inversion Probe arrays, while requiring 10 fold less input DNA (Kader et al., 2016, Genome Medicine 8: 121). Genetic analysis of pure ADH found that 95% had at least one copy number event and the median fraction of the genome altered was 8% (0-19%). Surprisingly, while 29% of pure ADH showed 16q loss and 1q gain (CNAs common in low-grade (LG) breast cancer), 29% of pure ADH showed 8q gain, an event more frequently observed in high grade (HG) cancer. Analysis of ADH with synchronous DCIS and/or IDC showed that 67% of ADH was clonally related with both LG (6/8) and HG carcinoma (4/7). The final analysis of 20 synchronous cases (9 LG, 11 HG) will be presented. Conclusion: Here we report the most detailed molecular taxonomy of this high risk pre-malignant breast lesion with the largest cohort undertaken worldwide. Our observation that 67% of ADH is clonal to breast carcinoma suggests that both LG and HG carcinoma can evolve from a similar ancestor lesion. As ADH has the potential to develop both LG and HG carcinoma, a biomarker signifying breast cancer progression from pre-malignant lesions is highly desirable for the more precise treatment of individual patients diagnosed with ADH. Citation Format: Kader T, Hill P, Opeskin K, Goode DL, Elder K, Pang J-M, Fox SB, Mann GB, Campbell IG, Gorringe KL. Identification of copy number alterations associated with the progression of high risk premalignant breast lesions to breast carcinoma [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD1-12.

The role of molecular biomarkers for predicting adjacent breast cancer of Atypical Ductal Hyperplasia diagnosed on core biopsy.

Atypical Ductal Hyperplasia (ADH) is a disease of the proliferative breast lesion characterized with atypia and when diagnosed on core needle biopsy (CNB), excisional biopsy is the current management to exclude adjacent cancer, which may found 10 to 20%. The purpose of the study is to investigate the role of biomarkers on surgical decision after the diagnosis of ADH on CNB. Patients with pure ADH on core biopsy were retrospectively selected, and categorized according to final pathology after excision into three groups: Group I (n: 39) ADH; Group II (n: 27) ductal carcinoma in situ (DCIS), and Group III (n: 9) invasive cancer (IC). Immunohistochemical analyses were performed using biomarkers MUC1, Ki67, Cyclin B1, and Cyclin D1. Only Cyclin D1 was significant in between group analysis by one-way ANOVA (64.74, 49.44, and 51.11, respectively; p= 0.01). However when appropriate cut-off levels (2%-50%) were used for each biomarkers using X2 test, no statistical significance was found. MUC1, Ki67, Cyclin B, and Cyclin D1have failed to predict adjacent cancer on core biopsy specimens with ADH. Further surgery is warranted for all ADH cases diagnosed on core biopsies until a new predictor is identified.

MiRNAs as potential biomarkers in early breast cancer detection following mammography.

Breast cancer is the most common cancer among American women, except for skin cancers. About 12 % women in the United States will develop invasive breast cancer during their lifetime. Currently one of the most accepted model/theories is that ductal breast cancer (most common type of breast cancer) follows a linear progression: from normal breast epithelial cells to ductal hyperplasia to atypical ductal hyperplasia (ADH) to ductal carcinoma in situ (DCIS), and finally to invasive ductal carcinoma (IDC). Distinguishing pure ADH diagnosis from DCIS and/or IDC on mammography, and even combined with follow-up core needle biopsy (CNB) is still a challenge. Therefore subsequent surgical excision cannot be avoided to make a definitive diagnosis. MicroRNAs (miRNAs) are a highly abundant class of endogenous non-coding RNAs, which contribute to cancer initiation and progression, and are differentially expressed between normal and cancer tissues. They can function as either tumor suppressors or oncogenes. With accumulating evidence of the role of miRNAs in breast cancer progression, including our own studies, we sought to summarize the nature of early breast lesions and the potential use of miRNA molecules as biomarkers in early breast cancer detection. In particular, miRNA biomarkers may potentially serve as a companion tool following mammography screening and CNB. In the long-term, a better understanding of the molecular mechanisms underlying the miRNA signatures associated with breast cancer development could potentially result in the development of novel strategies for disease prevention and therapy.

Flat epithelial atypia with and without atypical ductal hyperplasia: to re-excise or not. Results of a 5-year prospective study

Flat epithelial atypia (FEA) of the breast have a tendency to calcify and, as such, are becoming increasingly detected by mammography. There is no consensus yet on whether to excise these lesions or not after diagnosis on core needle biopsies (CNB). We reviewed 3,948 cases of breast CNB between June 2004 and June 2009 correlating histomorphologic, radiological, and clinical features. There were 3.7 % (145/3,948) pure FEA and 1.5 % (58/3,948) concomitant FEA and atypical ductal hyperplasia (ADH). In the pure FEA population, 46.2 % (67/145) had microcalcifications on mammography with 65.5 % (95/145) of patients undergoing subsequent excisional biopsies with the following findings: benign 20 % (19/95), ADH 37.9 % (36/95), ductal carcinoma in situ (DCIS) 1.1 % (1/95), and DCIS and invasive ductal carcinoma (IDC) 2.1 % (2/95). In the concomitant FEA and ADH group, 86.2 % (50/58) patients had microcalcifications on radiograph with 74.1 % (43/58) of patients undergoing subsequent excisions with: benign 23.3 % (10/43), DCIS 9.3 % (4/43), DCIS and IDC 4.7 % (2/43), DCIS + lobular carcinoma in situ + invasive lobular carcinoma 2.3 % (1/43), and tubular carcinoma 2.3 % (1/43). The incidence of carcinoma in the FEA + ADH group is 18.6 % (8/43) and 3.2 % (3/95) for the pure FEA group. This difference is statistically significant (p = 0.0016). The relative risk of carcinoma in the ADH + FEA group versus the pure FEA group is 6.4773, with 95 % CI of 1.8432 and 22.76 24. Five-year mean follow-up in the unexcised pure FEA did not show any malignancies. These findings suggest that pure FEA has a very low association with carcinoma, and these patients may benefit from close clinical and mammographic follow-up while the combined pure FEA and ADH cases may be re-excised.

Atypical Hyperplasia on Core Biopsy: Is Further Surgery Needed?

IntroductionPercutaneous core needle biopsy (CNB) has been widely performed as a standard technique for initial histological diagnosis of suspicious breast lesions. There have been an increased number of atypical lesions diagnosed on CNB as a consequence of the advances in breast imaging techniques. The authors aim to identify if any of the radiological and histopathological criteria evaluated in this study can predict the presence of malignancy associated with atypical hyperplasia (AH) diagnosed on CNB. MethodsThe authors retrospectively reviewed the medical records of 450 patients diagnosed with AH. Surgical excision was then performed and pathology revealed carcinoma or benign lesions. Patient age, imaging features, number of CNB samples taken, biopsy needle gauge, presence of additional proliferative diseases and calcification on CNB or excision were evaluated in both groups. ResultsFifty-one (11.3%) patients were found to have malignancy on surgical excision; 74.5% had ductal carcinoma in situ only and 25.6% had invasive cancer. In subgroup analysis, pure atypical ductal hyperplasia lesions were upgraded in 11.5%, pure atypical lobular hyperplasia lesions were upgraded in 8.1% and mixed lesions were upgraded in 17.6% (P > 0.05) of patients. The majority of the patients were older than 50 years, and calcification was the main reason for biopsy in both groups. The presence of additional proliferative lesions and needle gauge were not found to be statistically significant (P > 0.05). ConclusionUpgrade rate to cancer after surgical excision was 11.3% of AH patients diagnosed on CNB. However, none of the variables are significant in determining the presence of malignancy associated with AH diagnosed by CNB.

Pure flat epithelial atypia is uncommon in subsequent breast excisions for atypical epithelial proliferation

The management of atypical intraductal lesions of the breast remains controversial. In the present study, the subsequent surgical excision results and follow-up data on 86 (3.65%) atypical intraductal lesions and 78 (3.31%) low-grade ductal carcinoma in situ (DCIS) from a cohort of 2358 needle biopsies were examined. There were 17 cases (0.72%) of pure flat epithelial atypia (FEA), 44 (1.87%) pure atypical ductal hyperplasia (ADH), three (0.13%) pure atypical lobular hyperplasia (ALH), 18 (0.76%) combined ADH + FEA, three (0.13%) combined ALH + FEA and one (0.04%) combined ALH + FEA + ADH. Subsequent surgical excisions were done in 53 cases and revealed the following incidences of malignancy: pure FEA (1/8); pure ADH (17/31); FEA + ADH (7/10); FEA + ALH (2/3); and FEA + ALH + ADH (0/1), with pure FEA showing significantly lower incidence of malignancy. In this cohort, there were 703 carcinomas including 155 DCIS with 78 cases (50.3%) being low-grade. FEA with ADH (and/or ALH) was present in 22 (28.2%) of these 78 cases of low-grade DCISs at surgical excisions. Pure FEA was not detected in any of the subsequently excised surgical materials of the atypical intraductal lesions nor the low-grade DCISs. Thus, pure FEA was very unusual in surgical specimens. When pure FEA is detected at needle biopsy, a wait and see approach can be adopted. However, when the FEA is associated with other concomitant atypical intraductal lesions, especially ADH, further excision should be contemplated.

Vacuum-assisted biopsy diagnosis of atypical ductal hyperplasia and patient management

This study sought to evaluate the accuracy of vacuum-assisted biopsy (VAB) in the diagnosis of atypical ductal hyperplasia (ADH) by determining the rate of VAB underestimation compared with definitive histology. In addition, an attempt was made to identify parameters that could help determine the most appropriate patient management. We retrospectively reviewed 1,776 VAB procedures performed between November 1999 and January 2008 for suspicious subclinical breast lesions visible only at mammography. A total of 177 patients with a VAB diagnosis of pure ADH were studied. Patients with a diagnosis of ADH associated with other lesions (lobular intraepithelial neoplasia, papilloma), atypical lobular hyperplasia, lobular carcinoma in situ and any lesions with a microhistological diagnosis other than ADH were excluded. Mammographic appearance of lesions was as follows: 152 mostly clustered microcalcifications (86%); five opacities with microcalcifications (3%); 12 single opacities (3%); and eight parenchymal distortions (4%), of which five were without and three were with microcalcifications. In cases underestimated by VAB, we evaluated the extent of ADH within ducts and lobules. Based on results, patients were subdivided into two groups: ≤2 ADH foci; >2 ADH foci. Patients were subdivided into two groups: one was referred for surgery and the other for follow-up care. The decision to either perform or not perform surgery was based on combined analysis of the following parameters: patient age; risk factors in the patient's history; mammographic extent of microcalcifications; complete excision of microcalcifications at VAB; and final Breast Imaging Reporting and Data System (BI-RADS) assessment. In the first group (n=98), comparison of microhistology with final histology revealed that 19 cases of ADH had been underestimated by VAB. In the second group (n=79), six cases of ADH showed progression of the mammographic abnormality, which was subsequently confirmed by surgical biopsy. The most relevant parameters affecting the decision to proceed to surgical excision were lesion diameter >7 mm on mammography, >2 ADH foci, incomplete removal of the calcifications and a family and/or personal history of breast cancer. Although there are no definite mammographic predictors of malignancy, a radiological assessment of suspicious lesion in the presence of an additional equivocal parameter always warrants surgical management.

P53 nuclear accumulation and ERα expression in ductal hyperplasia of breast in a cohort of 215 Chinese women

IntroductionWomen with ductal hyperplasia including usual ductal hyperplasia (UDH) and atypical ductal hyperplasia (ADH) have an increased risk of developing invasive ductal carcinoma (IDC) of breast. The importance of several molecular markers in breast cancer has been of considerable interest during recent years such as p53 and estrogen receptor alpha (ERα). However, p53 nuclear accumulation and ERα expression have not been assessed in ductal hyperplasia co-existing with ductal carcinoma in situ (DCIS) or IDC versus pure ductal hyperplasia without DCIS or IDC.Materials and methodsWe investigated p53 nuclear accumulation and ERα expression in breast ductal hyperplasia in a cohort of 215 Chinese women by immunohistochemistry (IHC), which included 129 cases of pure ductal hyperplasia, 86 cases of ductal hyperplasia co-existing with DCIS (41 cases) or IDC (45 cases).ResultsNuclear p53 accumulation was identified in 22.8% of ADH (31/136), 41.5% of DCIS (17/41) and 42.2% of IDC (19/45), and no case of UDH (0/79). No difference in nuclear p53 accumulation was observed between pure ADH and ADH co-existing with DCIS (ADH/DCIS) or IDC (ADH/IDC) (P > 0.05). The positive rate of ERα expression was lower in ADH (118/136, 86.8%) than that in UDH (79/79, 100%) (P < 0.001), but higher than that in DCIS (28/41, 68.3%) or IDC (26/45, 57.8%) respectively (P < 0.001). The frequency of ERα expression was lower in ADH/DCIS (23/29, 79.31%) and ADH/IDC (23/30, 76.67%) than that in pure ADH (72/77, 93.51%) respectively (P < 0.05). There was a negative weak correlation between p53 nuclear accumulation and ERα expression as for ADH (coefficient correlation -0.51; P < 0.001).ConclusionsDifferent pathological types of ductal hyperplasia of breast are accompanied by diversity in patterns of nuclear p53 accumulation and ERα expression. At least some pure ADH is molecularly distinct from ADH/CIS or ADH/IDC which indicated the two types of ADH are molecularly distinct entities although they have the same morphological appearance.

Chromosomal Alterations in Pure Nonneoplastic Breast Lesions: Implications for Breast Cancer Progression

Columnar cell lesions (CCL) and atypical ductal hyperplasia (ADH) frequently coexist and share molecular changes with in situ and invasive components, suggesting that CCL and ADH may be precursors to breast cancer. These conclusions are largely based on studies examining CCL and/or ADH from patients diagnosed with more advanced disease. We assessed allelic imbalance (AI) in pure CCL or ADH specimens to characterize molecular changes in nonneoplastic breast lesions. DNA samples were obtained from laser-microdissected pure CCL (n = 42) or ADH (n = 31). AI was assessed at 26 chromosomal regions commonly altered in breast cancer. Data were analyzed using Fisher's exact and Student's t-tests using a cutoff of P < 0.05. The average AI frequency was 6.2% in CCL and 6.1% in ADH; approximately 33% of nonneoplastic lesions had no detectable genetic changes. Levels of AI in CCL and ADH were significantly (P < 0.0001) lower than observed in either low- or high-grade ductal carcinoma in situ (DCIS) lesions. Genetic changes characteristic of in situ and invasive disease, especially on chromosomes 16q and 17p, were infrequent in pure nonneoplastic lesions. Pure CCL and ADH lesions demonstrate lower levels of genetic alterations than DCIS, invasive carcinomas or CCL/ADH lesions from cancerous breasts; alterations of chromosomes 16q and 17p were not detected. Pure CCL and ADH lesions are not genetically advanced, and molecular profiles do not support these lesions as obligatory precursors to more advanced disease. Molecular differences between pure and synchronous lesions support re-evaluation of current models of disease initiation, progression, and risk.

Genetic Characterization of Columnar Cellular Lesions and Atypical Ductal Hyperplasia of the Breast.

Abstract Aims: Columnar cell lesions (CCL) and atypical ductal hyperplasia (ADH) frequently coexist and share molecular changes with in situ and invasive components, suggesting that CCL and ADH may be precursors to breast cancer. These conclusions are, however, largely based on studies examining CCL and/or ADH from patients diagnosed with more advanced disease. Thus, we assessed allelic imbalance (AI) in pure CCL or ADH specimens to characterize molecular changes in early breast lesions.Methods and results: DNA samples were obtained from laser microdissected lesions from CCL with (n=42) or with ADH (n=31) without concurrent in situ or invasive disease. AI was assessed at 26 chromosomal regions commonly altered in breast cancer. The average AI frequency was 6.2% (range 0-20%) in CCL and 6.1% (range 0-25%) in ADH with no significant difference in levels of AI between CCL and ADH. The highest levels of AI were on chromosomes 8q24 and 17q21 in ADH (23%) and CCL (15%), respectively.Conclusions: In conjunction with low overall levels of AI, chromosomal alterations that characterize low- and high-grade in situ and invasive disease were not frequent in pure CCL and ADH. Thus, pure lesions are not genetically advanced and are molecularly distinct from synchronous lesions. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5156.

Flat Epithelial Atypia and Atypical Ductal Hyperplasia: Carcinoma Underestimation Rate

This study was carried out to determine the underestimation rate of carcinoma upon surgical biopsy after a diagnosis of flat epithelial atypia and atypical ductal hyperplasia and 11-gauge vacuum-assisted breast biopsy. A retrospective review was conducted of 476 vacuum-assisted breast biopsy performed from May 2005 to January 2007 and a total of 70 cases of atypia were identified. Fifty cases (71%) were categorized as pure atypical ductal hyperplasia, 18 (26%) as pure flat epithelial atypia and two (3%) as concomitant flat epithelial atypia and atypical ductal hyperplasia. Each group were compared with the subsequent open surgical specimens. Surgical biopsy was performed in 44 patients with atypical ductal hyperplasia, 15 patients with flat epithelial atypia, and two patients with flat epithelial atypia and atypical ductal hyperplasia. Five cases of atypical ductal hyperplasia were upgraded to ductal carcinoma in situ, three cases of flat epithelial atypia yielded one ductal carcinoma in situ and two cases of invasive ductal carcinoma, and one case of flat epithelial atypia/atypical ductal hyperplasia had invasive ductal carcinoma. The overall rate of malignancy was 16% for atypical ductal hyperplasia (including flat epithelial atypia/atypical ductal hyperplasia patients) and 20% for flat epithelial atypia. The presence of flat epithelial atypia and atypical ductal hyperplasia at biopsy requires careful consideration, and surgical excision should be suggested.

Clinicopathologic Implications of “Flat Epithelial Atypia” in Core Needle Biopsy Specimens of the Breast

Flat epithelial atypia (FEA) is an emerging entity of uncertain clinical significance, and outcome data are sparse. The aim of this study was to evaluate the clinicopathologic significance of this entity for proper management. All core needle biopsy (CNB) specimens diagnosed as atypical ductal hyperplasia (ADH) from January 2006 to April 2008 were retrieved. H&E-stained slides of 5 levels on each case were reviewed. The differences in upstaging in subsequent excisions in the FEA and ADH group (31/189 [16.4%]) vs the pure FEA group (5/35 [14%]) and pure FEA (5/35 [14%]) vs pure ADH (5/45 [11%]) were not statistically significant. We observed that FEA evolved into ADH at the same site at an average of 3 to 4 levels. Our study concludes that there is an association of FEA with ADH on multiple levels of CNB specimens, and follow-up surgical excision findings for FEA are clinically significant.