Malignant upgrade in lesions of uncertain malignant potential in the breast (B3 lesions) – is open excision always necessary?

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Felix Heindl, Janina Schiel, Carolin C. Hack, Niklas Amann, Sebastian M. Jud, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5429534/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 17 Feb, 2025 Read the published version in Breast Cancer Research and Treatment → Version 1 posted 8 You are reading this latest preprint version Abstract Purpose Unclear or suspicious breast findings are typically clarified by interventional breast biopsy. Lesions with uncertain malignant potential are grouped as B3 lesions in histopathology. The B3 group according to the European Working Group for Breast Screening Pathology (EWGBSP) comprises various breast lesions with different upgrade rates to invasive breast cancer (BC) or ductal carcinoma in situ (DCIS) if surgical removal is performed. The objective of this study was to investigate malignant upgrade rates to DCIS and/or invasive breast cancer (BC) after open surgical excision for the different B3 lesions. Methods A total of 192 patients with histologically verified B3 lesions were followed up retrospectively for this analysis. Patients with the B3 lesions atypical ductal hyperplasia (ADH), flat epithelial atypia (FEA), and classical lobular neoplasia (LN1-2) were combined into one group, while cellular fibroepithelial lesions (CFL) and phyllodes tumors without suspicion of malignancy, as well as papillomas and radial scars/complex sclerosing lesions (RS/CSL) were summarized in two other groups. We investigated the association of the different B3 lesions with invasive BC or DCIS after open surgical excision. Results Histopathological investigation revealed in 21 (10.9%) of the 192 patients invasive BC or DCIS after open surgical excision. The rate of patients with BC and/or DCIS significantly differed between the patient groups (p < 0.01, Fisher’s exact test): The highest rate was 17.5% (95% confidence interval (CI), 10.7–26.2) in patients within the group of ADH, FEA, and LN1-2. In the other two groups, fewer malignant lesions occurred. In the group with papillomas and RS/CSL the malignant upgrade rate was 4.3% (95% CI, 0.9–12.2), while within the group with CFL and phyllodes tumors without suspicion of malignancy no malignant upgrade was observed (0.0%, 95% CI, 0.0-16.9). Conclusions B3 lesions harbor the risk of malignant upgrade after surgical excision. In our collective ADH, FEA, and LN1-2 had significant higher upgrade rates than other B3 lesions. B3 lesions breast cancer DCIS surgery Figures Figure 1 Figure 2 Figure 3 Introduction Core needle biopsies (CNB) and vacuum-assisted biopsies (VAB) are performed as standard of care to clarify unclear or suspected malignant breast lesions. Following histopathological examination of these diagnostic biopsies, they are categorized according to the B-classification system [1, 2]. For biopsies containing lesions of uncertain malignant potential, the category B3 is used. B3 lesions are diagnosed in approximately 5 - 10 % of CNBs [3, 4]. Also due to the increasing use of mammography screening, an increasing detection rate of B3 lesions could be demonstrated [5-7]. B3 lesions represent a heterogeneous group of breast lesions with an increased risk of associated malignancy and show heterogeneity with the risk of an incomplete sampling [8, 9]. When B3 lesions detected via CNB or VAB undergo open excision, they are upgraded to malignancy, namely breast cancer (BC) or ductal carcinoma in situ (DCIS), in 9.9 - 35.1 % of patients. The most common representatives of B3 lesions are atypical ductal hyperplasia (ADH), classical lobular neoplasia (LN1-2), flat epithelial atypia (FEA), cellular fibroepithelial lesions (CFL) or phyllodes tumor without suspicion of malignancy, papilloma and other papillary lesions, and radial scar/complex sclerosing lesion (RS/CSL) [8-10]. LN1 and LN2 are former terms that now correspond to atypical lobular hyperplasia (ALH) and classic lobular carcinoma in situ (LCIS), respectively, in the 5th edition of the WHO tumor classification. Considering the fact that not every B3 lesion carries the same malignancy risk, there is a tendency to further subdivide B3 lesions, enabling the derivation of clinical implications. ADH, FEA, and LN are considered lesions with the risk of associated DCIS or invasive BC. Lesions at risk of incomplete sampling include CFL or phyllodes tumors without suspicion of malignancy, intraductal papillomas, RS/CSL, hemangiomas, and atypical vascular lesions. Additionally, there are rare lesions within the B3 group, such as adenomyoepitheliomas, nipple adenomas, syringomatous tumors, microglandular adenosis, mucocele-like lesions, nodular fasciitis, desmoid-type fibromatosis, and uncertain spindle cell lesions, which, due to their rarity, are not further addressed in this work [10-14]. The clinical management of B3 lesions has undergone substantial evolution over time. Traditionally, every B3 lesion has been subject to open excision. However, recognizing that malignancy is not uniformly associated within B3 lesions, there has been a growing call to de-escalate treatment. To mitigate over-treatment in patients with B3 lesions, there is a noticeable shift away from open excision towards more interventional therapies, such as large volume VABs combined with regular monitoring or simply a follow-up examination [8, 9, 15]. Nevertheless, open excision is still suggested for certain types of B3 lesions due to the increased risk of DCIS or even invasive BC. Yet, it remains unclear which B3 lesions can safely forego open excision, and which should be recommended for it, considering the elevated risk of BC or DCIS. Hence, the objective of this study is to evaluate the incidence of BC or DCIS following open excision of B3 lesions in a German population. Methods Study population The cases included in this study were retrospectively selected from the database of the Institute of Pathology, Erlangen University Hospital, Erlangen, Germany. Every B3 lesion was counted as an individual lesion. For the period March 2013 until June 2019, a total of 277 histologically verified B3 lesions were identified in 251 patients who had undergone a CNB or VAB. Of these 277 B3 lesions, 70 lesions were not followed up by open excision. This resulted in 207 lesions in 194 patients. Additionally, multiple lesions of a patient were randomly removed (i.e, one randomly selected lesion of a patient with multiple lesions remained in the dataset). Two patients younger than 18 years of age were also excluded. The final dataset for this study consisted of 192 patients – see also Figure 1 for lesion selection. Histopathological workup of the B3 lesions Prior to our retrospective study, the corresponding VAB or CNB tissue of each case was processed and evaluated according to the accredited diagnostics protocol of the Institute of Pathology, Erlangen University Hospital, Erlangen, Germany. This comprised formalin fixation, embedding into paraffin, at least six cutting levels and hematoxylin and eosin (H&E) staining. Slide evaluation was performed by board-certified pathologists experienced in breast pathology. Where appropriate, immunohistochemical stainings were used to confirm the H&E diagnosis. The report contained the B-classification according to current guidelines. Based on the biological relevance of the different B3 lesions, we have formed the following distinct groups for further analysis: ADH, FEA, and lobular carcinoma in situ, classical type and atypical lobular hyperplasia (LN1-2) are summarized in the group "Risk of associated invasive BC and DCIS”. The group “Fibroepithelial lesions” contained CFL lesions including phyllodes tumors without suspicion of malignancy. Potentially heterogeneous lesions with risk of incomplete sampling other than fibroepithelial lesion as Papillomas and RS/CSL were combined in the group “Papillomas/RS”. All lesions containing larger cellular atypia were grouped into “Risk of associated invasive BC and DCIS”. According to the current 5th edition of the WHO tumor classification, non-invasive LN are divided into atypical lobular hyperplasia (ALH), classic lobular carcinoma in situ (LCIS), pleomorphic LCIS and florid LCIS. ALH and classic LCIS are synonymous with the former terms LN1 and LN2. Since the diagnoses were made before the current WHO classification of tumors, we used the terms LN1 and LN2 in this study. Surgery All the open surgical excisions took place at the Department of Gynecology and Obstetrics, Erlangen University Hospital, Erlangen, Germany. Preoperatively, non-palpable lesions were marked by wire and palpable lesions by skin marking, respectively. If several lesions were present in one patient, these were removed simultaneously with unambiguous assignment. Open surgical excision was performed under general anesthesia. After open excision of the marked breast tissue, specimens were labeled for orientation. Consecutively, a specimen radiogram was obtained to confirm successful removal of the target lesion. Histopathological workup of the surgical specimens After fixation of the specimens in formalin for at least 16 hours, pathologic processing and reporting was performed according to current guidelines and the accredited in-house protocol, by board-certified pathologists of the Institute of Pathology, Erlangen University Hospital, Erlangen, Germany. In brief, margins were inked and the entire specimen was investigated. Clinical data Individual histological results from the open surgical excision were obtained for every B3 lesion from the database of the Institute of Pathology, Erlangen University Hospital, Erlangen, Germany. Basic epidemiological data were extracted from the patients’ records at the Department of Gynecology Erlangen. In cases of verified BC or DCIS during open excision, additional data, including tumor stage, grading, hormone receptor status, and HER2/neu status, were extracted from the patients' records. Statistical analysis Patient and lesion characteristics are described using appropriate summary statistics. Mean and standard deviation are used calculated for continuous characteristics, frequency and percentage for categorical characteristics. Primary study aim was to investigate whether the assessment of the lesion was associated with actual invasive BC or DCIS. For this purpose, the study population was divided into three groups according to the assessment of the lesion (i.e. "Risk of associated invasive BC and DCIS”, “Fibroepithelial lesions”, and “Papillomas/RS”), and for each group the rate of patients with resected tissue containing invasive BC or DCIS was calculated. These rates were compared using the χ2 test or Fisher’s exact test. The χ2 test was used if the expected number in each cell was greater than 5, Fisher’s exact test was used otherwise. All of the tests were two-sided, and a P value of < 0.05 was regarded as statistically significant. Calculations were carried out using the R system for statistical computing, version 4.3.0, 2023. Results Patient characteristics Between March 2013 and June 2019, a total of 192 patients received the diagnosis of a B3 lesion and underwent open excision of the lesion. In cases where a patient presented with multiple lesions, one lesion was randomly selected, resulting in the inclusion of only one lesion per patient in the final dataset. Patients and lesion characteristics are shown in Table 1 . Mean patient age was 50.0 years (standard deviation (SD) 13.6), with most patients having palpation findings (33.7 %) prior to interventional biopsy. 12.0 % of the 192 patients met the inclusion criteria for genetic testing according to the German Consortium for Hereditary Breast and Ovarian Cancer [16, 17]. The most often used method for interventional breast biopsy was CNB, accounting for 124 cases (64.6 %). With 52.1 %, the majority of interventional biopsies, and thus the diagnosis of B3 lesion, were conducted in the right breast. In complementary mammographic diagnostics prior to breast biopsy, a BI-RADS 4 was most frequently observed, accounting for 92.0 % of cases. Lesion characteristics After interventional breast biopsy microcalcifications were detectable on specimen radiograms in 39.6 %. In our dataset, the most frequently detected B3 lesion types were FEA (38.5 %), and papillomas (35.9 %), whereas lobular neoplasia were less common, comprising LN1 (4.2 %) and LN2 (2.6 %), respectively. The different B3 lesion types including frequencies are shown in Table 1 . The largest B3 subgroup was the “Risk of associated invasive BC and DCIS” group, comprising 103 cases of ADH, FEA, or LN1-2 (53.6 %). In contrast, there were 20 cases (10.4 %) in the “Fibroepithelial lesions” group and 69 patients (35.9 %) in the “Papillomas/RS” group. Histological results from open surgical excision Overall, the resected tissue from 171 (89.1 %) of the 192 patients contained benign tissue, whereas in 15 cases (7.8 %) DCIS, in 5 cases (2.6 %) BC and associated DCIS, and in one case (0.5 %) BC were detected, respectively. Figure 2 provides examples for a malignant upgrade from B3 to DCIS, while Figure 3 shows an example for malignant upgrade from a B3 lesion to invasive BC and DCIS. In total we observed an upgrade rate of 10.9 % (21 out of 192 cases) ( Table 2 ). The rate of patients with diagnosis of breast carcinoma or DCIS significantly differed between the patient groups (P < 0.01, Fisher’s exact test): The highest rate was 17.5 % (95 % confidence interval (CI), 10.7-26.2) in patients within the group “Risk of associated invasive BC and DCIS”. In the other two groups, fewer malignant lesions occurred. Among the 69 cases in the “Papillomas/RS” group, 3 DCIS were identified (4.3 %, 95 % CI, 0.9-12.2). In the "Fibroepithelial lesions" group, not a single invasive BC or DCIS was found (0.0 %, 95 % CI, 0.0-16.9) ( Table 2 ). Discussion B3 lesions represent a heterogeneous group of breast lesions diagnosed by interventional biopsy as CNB or VAB. Due to their uncertain malignant potential, there is a lack of conclusive recommendations after diagnosis of B3 lesions. Since different B3 lesions can be present in one interventional biopsy, we decided to group the different lesions. Therefore, we subsumed biopsies that had various B3 lesions containing cellular atypia as ADH, FEA, and LN1-2 were named as “Risk of associated invasive BC and DCIS”. CFL lesions were grouped as “Fibroepithelial lesions”, while papillomas and RS/CSL were combined as “Papillomas/RS”. We hypothesized, that the group “Risk of associated invasive BC and DCIS” had the highest malignant upgrade rate. This study of 192 patients investigated the malignant upgrade rate of B3 lesions after open surgical excision in a German population. The highest rate of invasive BC and/or DCIS was observed in the group “Risk of associated invasive BC and DCIS” containing the B3 lesions FEA, ADH, and LN1-2, respectively, with 17.5 %. By contrast, the upgrade rates in the "Fibroepithelial lesions" group were 0 %, and for "Papillomas/RS", it was 4.3 %. Overall, we found an upgrade rate of 10.9 %. The group “Risk of associated invasive BC and DCIS” - containing ADH, FEA, and LN1-2 - with 103 lesions represented the largest subgroup (53.6 %) in our database. Compared to the two groups “Fibroepithelial lesions” and “Papillomas/RS”, we found a significant higher malignant upgrade rate of 17.5 % (95 % CI 10.7-26.2 %). For the B3 lesions ADH, FEA, and LN1-2, malignant upgrade rates of 28 %, 11 %, and 17 %, respectively, were reported in a recent meta-analysis [18]. However, for the different lesions a large range of upgrade rates are published. In another review and meta-analysis of 93 studies, a comparable upgrade rate of 29 % (95 % CI 26-32 %) for ADH alone after surgical excision is reported. However, upgrade rates differed also for the distinct biopsy methods, with pooled upgrade rates of 42 % (95 % CI 31-53 %), 23 % (95 % CI 19-27 %), 32 % (95 % CI 22-43 %) for ultrasound guidance, stereotactic guidance, or MRI guidance, respectively [19]. FEA shows a malignant upgrade rate in other meta-analyses between 5 % (95 % CI 3-6 %), 8.8 %, and 11.1 %, respectively [20-22]. Identically, malignant upgrade in LN1-2 is published between 17 % (95 % CI 13-21 %) in a recent meta-analysis and 14 - 28 % in smaller study populations [18, 23, 24]. Our combined malignant upgrade rate of 17.5 % (95 % CI 10.7-26.2 %) for ADH, FEA, and LN fits into the wide range of different upgrade rates with various different study populations, types of breast biopsies, and other numerous preconditions. The second largest group in our data are papillomas and RS/CSL with 69 out of 192 lesions (35.9 %). For this group, we report 4.3 % malignant upgrade. A limitation of our work is that our data lack information regarding the presence or absence of cellular atypia in papillary lesions. Atypical papillary lesions having the highest risk of upgrading to malignant after surgical excision in a meta-analysis [25]. In another systematic review and meta-analysis, an upgrade rate of 12 % (95 % CI 10-15) for papillomas, while for RS/CSL, an upgrade rate of 8 % (95 % CI 6-11) was reported [18]. In contrast, we report an upgrade rate of merely 4.3 % (95 % CI 0.9-12.2). One explanation for our relatively low upgrade rate could be, that we excluded papillary lesions or RS/CSL containing larger cellular atypia from the group “Papillomas/RS” and put them into the group with ADH, FEA, and LN1-2, since cellular atypia is the clinically dominant lesion. Only including papillary lesions without atypia the prementioned meta-analysis presents a upgrade rate of 7 % (95 % CI 4-10)[18]. In line with our results, others found also a lower proportion of malignancies of 3.4 % in non-atypical papillary lesions after surgical excision [26]. B3 lesions with fibroepithelial lesions represent the smallest group in our dataset comprising 20 lesions (10.4 %). In line with other studies, we found no upgrade of fibroepithelial lesions to invasive BC and DCIS [8]. However, the focus in B3 lesions containing fibroepithelial lesions is not to rule out primary BC but malignant phyllodes tumors. In a retrospective analysis of 51 B3 lesions diagnosed as phyllodes tumors, only five were malignant phyllodes tumors after open excision [27]. In our data set, we could not observe an upgrade to malignant phyllodes tumors in the 20 fibroepithelial lesions. Another review found an upgrade rate of less than 2 % for fibroepithelial lesions [28]. In a cohort of 215 patients with fibroepithelial B3 lesions, the upgrade rate to borderline or malignant phyllodes tumors was 2 %, while LCIS was found in 1 % [29]. Therefore, guidelines do not generally recommend the excision of fibroepithelial lesions [2]. A more refined approach for deciding whether to proceed with open excision is to consider the growth rate of the fibroepithelial lesion and suspicion for phyllodes tumor [30, 31]. Missing data on previous breast biopsies or previous diagnosis of invasive BC or DCIS are possible limitations of our work. Since earlier breast malignancy and breast biopsies are risk factors for BC and DCIS, an impact on the previous work cannot be excluded [32, 33]. Furthermore, our data lack information on symptoms prior to interventional breast biopsy. The presented retrospective data originate from a tertiary referral center in a university hospital maybe influencing patient acquisition. Since our work includes data until June 2019, our data lack information regarding the latest classification update on the WHO Classification of Tumours - Breast Tumours - in particular the new classification of lobular neoplasia [34]. In brief, the advantage of this study is the large number of patients included. The case only study design with the absence of specific inclusion criteria (e.g. type of biopsy or lesion type), the large study population of 192 patients, and grouping of B3 lesions separates this study from others. Since we identify statistically significant differences between the three B3 lesion groups, our results suggest distinct therapeutic implications. As proposed by other research groups, a surgical excision can be avoided for lesions with an upgrade rate of less than 2 %. This is extrapolated analogously to the BI-RADS category 3, where a possible diagnostic delay is not associated with a worse prognosis [35]. Therefore, we suggest open surgical excision should be recommended for ADH, FEA, LN1-2, papillomas, and RS/CSL. Fibroepithelial lesions without growth tendency and without diagnostic uncertainties do not need to be excised. Conclusion Lesions of uncertain malignant potential in the breast (B3 lesions) comprise different histopathologic distinct breast lesions with a heterogenous risk of ductal carcinoma in situ (DCIS) or invasive breast cancer (BC). In our study, we found the highest malignant upgrade rates for B3 lesions containing ADH, FEA, and LN1-2 after open surgical excision of 17.5 %. Other B3 lesions in our data set had an upgrade rate of less than 5 %. Based on our data, we recommend open surgical of the B3 lesions ADH, FEA, and LN1-2. For the other investigated B3 lesions at least follow-up examinations should be recommended. Abbreviations ACR American College of Radiology ADH Atypical ductal hyperplasia ALH Atypical lobular hyperplasia B3 Lesions of uncertain malignant potential in the breast BC Breast cancer BI-RADS Breast Imaging Reporting and Data System CFL Cellular fibroepithelial lesions CI Confidence interval CNB Core needle biopsy CSL Complex sclerosing lesion DCIS Ductal carcinoma in situ EWGBSP European Working Group for Breast Screening Pathology FEA Flat epithelial atypia H&E Hematoxylin and eosin LCIS Classic lobular carcinoma in situ LN Classical lobular neoplasia VAB Vacuum-assisted biopsy RS Radial scar SD Standard deviation Declarations Author Contributions: Conceptualization: F.H., S.M.J., C.I.P., R.E.; data curation: F.H.; formal analysis: L.H.; investigation: F.H., J.S., S.M.J., C.I.P., R.E.; project administration: F.H., S.M.J., C.I.P., R.E.; resources: A.H., M.W.B.; supervision: F.H., R.E..; visualization: F.H., L.H., R.E.; writing - original draft: F.H., L.H., R.E.; writing-review & editing: all authors. All the authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Data availability: Data that support the findings of this study are available from the corresponding author upon reasonable request. Ethics approval and consent to participate: This study was approved by the ethics committee of the Faculty of Medicine at Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) (ref. number 24-41-Br). All procedures were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Written informed consent for interventional breast biopsy and open surgical excision was obtained for all patients. Supplemental agreement to the study was waived due to the retrospective study design including only anonymized data analysis. There was no use of animal research within this project. Acknowledgments The present work was performed in partial fulfillment of the requirements for obtaining the degree „Dr. med.“ of J.S. Compliance with ethical standards Disclosure of potential conflicts of interest Arndt Hartmann had an advisory role and received honoraria for lectures or consulting/advisory boards from Abbvie, Agilent, AstraZeneca, Biocartis, BMS, Boehringer Ingelheim, Cepheid, Diaceutics, Gilead, Illumina, Ipsen, Janssen-Cilag, Lilly, Merck, MSD, Nanostring, Novartis, Pfizer, Qiagen, QuIP GmbH, Roche, Sanofi, and 3DHistotech. Ramona Erber has received honoraria from Roche, Eisai, Pfizer, BioNTech, Veracyte (PROCURE), Diaceutics, Mindpeak, AstraZeneca, MEDAC, Lilly and Novartis. The institution of Arndt Hartmann and Ramona Erber conducts research for, AstraZeneca, Biocartis, Biontech, Cepheid, Gilead, Illumina, Janssen-Cilag, Nanostring Technologies, Mindpeak, MSD, Novartis, Owkin, palleos healthcare, Owkin, Qiagen, QuIP GmbH, Roche, Sanofi, Stratifyer and Zytovision. 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Tables Table 1 Patient and lesion characteristics Characteristic Age (years) 50.0 (13.6) BMI (kg/m 2 ) 25.1 (5.6) Patient from the mammography screening program No 119 (62.0) Yes 54 (28.1) Unknown 19 (9.9) Clinical findings leading to CNB or VAB Palpation findings 64 (33.7) Microcalcifications 31 (16.3) Nipple secretion 8 (4.2) Abnormal findings on mammography 46 (24.2) Abnormal findings on breast ultrasound 20 (10.5) Mastodynia 14 (7.4) Miscellaneous 7 (3.7) Inclusion criteria for genetic testing according to the German Consortium for Hereditary Breast and Ovarian Cancer Not available 6 (3.1) Negative 163 (84.9) Positive 23 (12.0) Side of the breast biopsy Left 92 (47.9) Right 100 (52.1) Type of breast biopsy CNB 124 (64.6) VAB 68 (35.4) Mammographic density ACR a 4 (2.8) ACR b 82 (56.9) ACR c 40 (27.8) ACR d 18 (12.5) BI-RADS BI-RADS 0 2 (1.1) BI-RADS 2 3 (1.6) BI-RADS 3 2 (1.1) BI-RADS 4 172 (92.0) BI-RADS 5 8 (4.3) ADH in breast biopsy No 156 (81.2) Yes 36 (18.8) FEA in breast biopsy No 118 (61.5) Yes 74 (38.5) LN1-2 in breast biopsy no LN 179 (93.2) LN1 8 (4.2) LN2 5 (2.6) Cellular fibroepithelial lesions in breast biopsy No 159 (82.8) Yes 33 (17.2) Phyllodes tumour without suspicion of malignancy in breast biopsy No 177 (92.2) Yes 15 (7.8) Papilloma in breast biopsy No 123 (64.1) Yes 69 (35.9) RS/CSL in breast biopsy No 174 (90.6) Yes 18 (9.4) Microcalcifications in breast biopsy No 116 (60.4) Yes 76 (39.6) Biopsy group: "Risk of associated invasive BC and DCIS” No 89 (46.4) Yes 103 (53.6) Biopsy group: “Fibroepithelial lesions” No 172 (89.6) Yes 20 (10.4) Biopsy group: “Papillomas/RS” No 123 (64.1) Yes 69 (35.9) Histological result from open surgical excision Invasive BC only 1 (0.5) DCIS only 15 (7.8) Invasive BC and DCIS 5 (2.6) Benign 171 (89.1) Patient and tumor characteristics, showing mean and standard deviation or frequency and percentage ACR: American College of Radiology, BI-RADS: Breast Imaging Reporting and Data System. Table 2 Histopathological results of the open excision Assessment of the lesion All patients (N = 192) Patients with resected tissue containing invasive BC and/or DCIS (N = 21) N N Rate with 95 % CI in % “Risk of associated invasive BC and DCIS” 103 18 17.5 (10.7, 26.2) “Fibroepithelial lesions” 20 0 0.0 (0.0, 16.8) “Papillomas/RS” 69 3 4.3 (0.9, 12.2) CI: Confidence interval Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 17 Feb, 2025 Read the published version in Breast Cancer Research and Treatment → Version 1 posted Editorial decision: Revision requested 30 Dec, 2024 Reviews received at journal 27 Dec, 2024 Reviewers agreed at journal 26 Dec, 2024 Reviewers agreed at journal 26 Dec, 2024 Reviewers invited by journal 26 Dec, 2024 Editor assigned by journal 11 Nov, 2024 Submission checks completed at journal 11 Nov, 2024 First submitted to journal 11 Nov, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5429534","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":376705046,"identity":"6d96d6a8-4c82-4ca7-ac03-862051b16792","order_by":0,"name":"Felix Heindl","email":"data:image/png;base64,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","orcid":"","institution":"Department of Gynecology and Obstetrics, Universitätsklinikum Erlangen, Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)","correspondingAuthor":true,"prefix":"","firstName":"Felix","middleName":"","lastName":"Heindl","suffix":""},{"id":376705048,"identity":"171d98d0-444a-4e53-af06-7706cbcdcc38","order_by":1,"name":"Janina Schiel","email":"","orcid":"","institution":"Department of Gynecology and Obstetrics, Universitätsklinikum Erlangen, Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)","correspondingAuthor":false,"prefix":"","firstName":"Janina","middleName":"","lastName":"Schiel","suffix":""},{"id":376705050,"identity":"53040895-d8b5-4dfb-9477-6085c553a7d5","order_by":2,"name":"Carolin C. Hack","email":"","orcid":"","institution":"Department of Gynecology and Obstetrics, Universitätsklinikum Erlangen, Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)","correspondingAuthor":false,"prefix":"","firstName":"Carolin","middleName":"C.","lastName":"Hack","suffix":""},{"id":376705052,"identity":"e114a94a-c3b1-4510-86af-89216ae5ce11","order_by":3,"name":"Niklas Amann","email":"","orcid":"","institution":"Department of Gynecology and Obstetrics, Universitätsklinikum Erlangen, Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)","correspondingAuthor":false,"prefix":"","firstName":"Niklas","middleName":"","lastName":"Amann","suffix":""},{"id":376705053,"identity":"1e919e6e-37e4-4958-bab9-6ca63794af9f","order_by":4,"name":"Sebastian M. Jud","email":"","orcid":"","institution":"Department of Gynecology and Obstetrics, Universitätsklinikum Erlangen, Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)","correspondingAuthor":false,"prefix":"","firstName":"Sebastian","middleName":"M.","lastName":"Jud","suffix":""},{"id":376705054,"identity":"4cc77184-d453-4066-bc92-161dd0b570a2","order_by":5,"name":"Caroline I. Preuss","email":"","orcid":"","institution":"Department of Gynecology and Obstetrics, Universitätsklinikum Erlangen, Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)","correspondingAuthor":false,"prefix":"","firstName":"Caroline","middleName":"I.","lastName":"Preuss","suffix":""},{"id":376705055,"identity":"8535720a-c9bb-428c-888e-34fcfcfb627c","order_by":6,"name":"Lothar Häberle","email":"","orcid":"","institution":"Department of Gynecology and Obstetrics, Universitätsklinikum Erlangen, Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)","correspondingAuthor":false,"prefix":"","firstName":"Lothar","middleName":"","lastName":"Häberle","suffix":""},{"id":376705056,"identity":"b8482c12-63ae-4c66-a462-28b354464b64","order_by":7,"name":"Arndt Hartmann","email":"","orcid":"","institution":"Institute of Pathology, Universitätsklinikum Erlangen, Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)","correspondingAuthor":false,"prefix":"","firstName":"Arndt","middleName":"","lastName":"Hartmann","suffix":""},{"id":376705057,"identity":"9d320349-b448-4a34-bd45-6628f303414d","order_by":8,"name":"Rüdiger Schulz-Wendtland","email":"","orcid":"","institution":"Institute of Radiology, Universitätsklinikum Erlangen","correspondingAuthor":false,"prefix":"","firstName":"Rüdiger","middleName":"","lastName":"Schulz-Wendtland","suffix":""},{"id":376705058,"identity":"2c1fb61a-506a-4724-92de-0a8b954b957b","order_by":9,"name":"Matthias Wetzl","email":"","orcid":"","institution":"Institute of Radiology, Universitätsklinikum Erlangen","correspondingAuthor":false,"prefix":"","firstName":"Matthias","middleName":"","lastName":"Wetzl","suffix":""},{"id":376705059,"identity":"90efc5eb-c572-42de-a3a6-c7415e208f53","order_by":10,"name":"Matthias W. Beckmann","email":"","orcid":"","institution":"Department of Gynecology and Obstetrics, Universitätsklinikum Erlangen, Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)","correspondingAuthor":false,"prefix":"","firstName":"Matthias","middleName":"W.","lastName":"Beckmann","suffix":""},{"id":376705062,"identity":"69eb5d6f-90e7-447e-8e11-f83a405bc39d","order_by":11,"name":"Ramona Erber","email":"","orcid":"","institution":"Institute of Pathology, Universitätsklinikum Erlangen, Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)","correspondingAuthor":false,"prefix":"","firstName":"Ramona","middleName":"","lastName":"Erber","suffix":""}],"badges":[],"createdAt":"2024-11-11 07:08:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5429534/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5429534/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10549-025-07632-7","type":"published","date":"2025-02-17T15:57:23+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":71554882,"identity":"9efc573f-0256-4f1f-88e7-0fb9f947ed51","added_by":"auto","created_at":"2024-12-16 16:19:05","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":56128,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of lesion selection\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5429534/v1/74f5512a0688d78b967736b6.png"},{"id":71554884,"identity":"94dc874c-12c9-4262-8842-95e2648b295b","added_by":"auto","created_at":"2024-12-16 16:19:05","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":2735243,"visible":true,"origin":"","legend":"\u003cp\u003eExamples for malignant upgrade from B3 to DCIS. Case 1 presented with A) flat epithelial atypia (FEA) in the initial vacuum biopsy (H\u0026amp;E, 200x) but with B) DCIS in the surgical specimen (H\u0026amp;E, 100x). Case 2 showed A) atypical ductal hyperplasia (ADH) in the initial vacuum biopsy (H\u0026amp;E, 200x) but with B) DCIS in the surgical specimen (H\u0026amp;E, 100x).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5429534/v1/8df23054d915618fcca22c14.png"},{"id":71554885,"identity":"742fa50d-a21c-4dfa-82ef-db9349aafbdb","added_by":"auto","created_at":"2024-12-16 16:19:05","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":2392535,"visible":true,"origin":"","legend":"\u003cp\u003eExample for malignant upgrade from B3 to invasive breast cancer and DCIS. In this case, the initial vacuum biopsy showed A) flat epithelial atypia (FEA) (H\u0026amp;E, 200x) and B) atypical ductal hyperplasia (ADH) (H\u0026amp;E, 400x). However, invasive breast cancer NST with associated DCIS was diagnosed in the surgical specimen (each H\u0026amp;E, C) 100x, D) 400x).\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5429534/v1/2cda2e3239d121708aa76d68.png"},{"id":77052561,"identity":"d52ab12e-3c73-4fea-9a9c-5c527539f70d","added_by":"auto","created_at":"2025-02-24 16:15:00","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5332914,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5429534/v1/e37a364f-5987-4442-93d2-9c909ae36bc2.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Malignant upgrade in lesions of uncertain malignant potential in the breast (B3 lesions) – is open excision always necessary?","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCore needle biopsies (CNB) and vacuum-assisted biopsies (VAB) are performed as standard of care to clarify unclear or suspected malignant breast lesions. Following histopathological examination of these diagnostic biopsies, they are categorized according to the B-classification system [1, 2]. For biopsies containing lesions of uncertain malignant potential, the category B3 is used. B3 lesions are diagnosed in approximately 5 - 10 % of CNBs [3, 4]. Also due to the increasing use of mammography screening, an increasing detection rate of B3 lesions could be demonstrated [5-7].\u003c/p\u003e\n\u003cp\u003eB3 lesions represent a heterogeneous group of breast lesions with an increased risk of associated malignancy and show heterogeneity with the risk of an incomplete sampling [8, 9]. When B3 lesions detected via CNB or VAB undergo open excision, they are upgraded to malignancy, namely breast cancer (BC) or ductal carcinoma in situ (DCIS), in 9.9 - 35.1 % of patients.\u003c/p\u003e\n\u003cp\u003eThe most common representatives of B3 lesions are atypical ductal hyperplasia (ADH), classical lobular neoplasia (LN1-2), flat epithelial atypia (FEA), cellular fibroepithelial lesions (CFL) or phyllodes tumor without suspicion of malignancy, papilloma and other papillary lesions, and radial scar/complex sclerosing lesion (RS/CSL) [8-10]. LN1 and LN2 are former terms that now correspond to atypical lobular hyperplasia (ALH) and classic lobular carcinoma in situ (LCIS), respectively, in the 5th edition of the WHO tumor classification.\u003c/p\u003e\n\u003cp\u003eConsidering the fact that not every B3 lesion carries the same malignancy risk, there is a tendency to further subdivide B3 lesions, enabling the derivation of clinical implications. ADH, FEA, and LN are considered lesions with the risk of associated DCIS or invasive BC. Lesions at risk of incomplete sampling include CFL or phyllodes tumors without suspicion of malignancy, intraductal papillomas, RS/CSL, hemangiomas, and atypical vascular lesions. Additionally, there are rare lesions within the B3 group, such as adenomyoepitheliomas, nipple adenomas, syringomatous tumors, microglandular adenosis, mucocele-like lesions, nodular fasciitis, desmoid-type fibromatosis, and uncertain spindle cell lesions, which, due to their rarity, are not further addressed in this work [10-14].\u003c/p\u003e\n\u003cp\u003eThe clinical management of B3 lesions has undergone substantial evolution over time. Traditionally, every B3 lesion has been subject to open excision. However, recognizing that malignancy is not uniformly associated within B3 lesions, there has been a growing call to de-escalate treatment. To mitigate over-treatment in patients with B3 lesions, there is a noticeable shift away from open excision towards more interventional therapies, such as large volume VABs combined with regular monitoring or simply a follow-up examination [8, 9, 15].\u003c/p\u003e\n\u003cp\u003eNevertheless, open excision is still suggested for certain types of B3 lesions due to the increased risk of DCIS or even invasive BC. Yet, it remains unclear which B3 lesions can safely forego open excision, and which should be recommended for it, considering the elevated risk of BC or DCIS. Hence, the objective of this study is to evaluate the incidence of BC or DCIS following open excision of B3 lesions in a German population.\u003c/p\u003e"},{"header":"Methods","content":"\u003ch2\u003eStudy population\u003c/h2\u003e\n\u003cp\u003eThe cases included in this study were retrospectively selected from the database of the Institute of Pathology, Erlangen University Hospital, Erlangen, Germany. Every B3 lesion was counted as an individual lesion. For the period March 2013 until June 2019, a total of 277 histologically verified B3 lesions were identified in 251 patients who had undergone a CNB or VAB. Of these 277 B3 lesions, 70 lesions were not followed up by open excision. This resulted in 207 lesions in 194 patients. Additionally, multiple lesions of a patient were randomly removed (i.e, one randomly selected lesion of a patient with multiple lesions remained in the dataset). Two patients younger than 18 years of age were also excluded. The final dataset for this study consisted of 192 patients \u0026ndash; see also Figure 1 for lesion selection.\u003c/p\u003e\n\u003ch2\u003eHistopathological workup of the B3 lesions\u003c/h2\u003e\n\u003cp\u003ePrior to our retrospective study, the corresponding VAB or CNB tissue of each case was processed and evaluated according to the accredited diagnostics protocol of the Institute of Pathology, Erlangen University Hospital, Erlangen, Germany. This comprised formalin fixation, embedding into paraffin, at least six cutting levels and hematoxylin and eosin (H\u0026amp;E) staining. Slide evaluation was performed by board-certified pathologists experienced in breast pathology. Where appropriate, immunohistochemical stainings were used to confirm the H\u0026amp;E diagnosis. The report contained the B-classification according to current guidelines. Based on the biological relevance of the different B3 lesions, we have formed the following distinct groups for further analysis: ADH, FEA, and lobular carcinoma in situ, classical type and atypical lobular hyperplasia (LN1-2) are summarized in the group \u0026quot;Risk of associated invasive BC and DCIS\u0026rdquo;. The group \u0026ldquo;Fibroepithelial lesions\u0026rdquo; contained CFL lesions including phyllodes tumors without suspicion of malignancy. Potentially heterogeneous lesions with risk of incomplete sampling other than fibroepithelial lesion as Papillomas and RS/CSL were combined in the group \u0026ldquo;Papillomas/RS\u0026rdquo;. All lesions containing larger cellular atypia were grouped into \u0026ldquo;Risk of associated invasive BC and DCIS\u0026rdquo;.\u003c/p\u003e\n\u003cp\u003eAccording to the current 5th edition of the WHO tumor classification, non-invasive LN are divided into atypical lobular hyperplasia (ALH), classic lobular carcinoma in situ (LCIS), pleomorphic LCIS and florid LCIS. ALH and classic LCIS are synonymous with the former terms LN1 and LN2. Since the diagnoses were made before the current WHO classification of tumors, we used the terms LN1 and LN2 in this study.\u003c/p\u003e\n\u003ch2\u003eSurgery\u003c/h2\u003e\n\u003cp\u003eAll the open surgical excisions took place at the Department of Gynecology and Obstetrics, Erlangen University Hospital, Erlangen, Germany. Preoperatively, non-palpable lesions were marked by wire and palpable lesions by skin marking, respectively. If several lesions were present in one patient, these were removed simultaneously with unambiguous assignment. Open surgical excision was performed under general anesthesia. After open excision of the marked breast tissue, specimens were labeled for orientation. Consecutively, a specimen radiogram was obtained to confirm successful removal of the target lesion.\u003c/p\u003e\n\u003ch2\u003eHistopathological workup of the surgical specimens\u003c/h2\u003e\n\u003cp\u003eAfter fixation of the specimens in formalin for at least 16 hours, pathologic processing and reporting was performed according to current guidelines and the accredited in-house protocol, by board-certified pathologists of the Institute of Pathology, Erlangen University Hospital, Erlangen, Germany. In brief, margins were inked and the entire specimen was investigated.\u003c/p\u003e\n\u003ch2\u003eClinical data\u003c/h2\u003e\n\u003cp\u003eIndividual histological results from the open surgical excision were obtained for every B3 lesion from the database of the Institute of Pathology, Erlangen University Hospital, Erlangen, Germany. Basic epidemiological data were extracted from the patients\u0026rsquo; records at the Department of Gynecology Erlangen. In cases of verified BC or DCIS during open excision, additional data, including tumor stage, grading, hormone receptor status, and HER2/neu status, were extracted from the patients\u0026apos; records.\u003c/p\u003e\n\u003ch2\u003eStatistical analysis\u003c/h2\u003e\n\u003cp\u003ePatient and lesion characteristics are described using appropriate summary statistics. Mean and standard deviation are used calculated for continuous characteristics, frequency and percentage for categorical characteristics.\u003c/p\u003e\n\u003cp\u003ePrimary study aim was to investigate whether the assessment of the lesion was associated with actual invasive BC or DCIS. For this purpose, the study population was divided into three groups according to the assessment of the lesion (i.e. \u0026quot;Risk of associated invasive BC and DCIS\u0026rdquo;, \u0026ldquo;Fibroepithelial lesions\u0026rdquo;, and \u0026ldquo;Papillomas/RS\u0026rdquo;), and for each group the rate of patients with resected tissue containing invasive BC or DCIS was calculated. These rates were compared using the \u0026chi;2 test or Fisher\u0026rsquo;s exact test. The \u0026chi;2 test was used if the expected number in each cell was greater than 5, Fisher\u0026rsquo;s exact test was used otherwise.\u003c/p\u003e\n\u003cp\u003eAll of the tests were two-sided, and a P value of \u0026lt; 0.05 was regarded as statistically significant. Calculations were carried out using the R system for statistical computing, version 4.3.0, 2023.\u003c/p\u003e"},{"header":"Results","content":"\u003ch2\u003ePatient characteristics\u003c/h2\u003e\n\u003cp\u003eBetween March 2013 and June 2019, a total of 192 patients received the diagnosis of a B3 lesion and underwent open excision of the lesion. In cases where a patient presented with multiple lesions, one lesion was randomly selected, resulting in the inclusion of only one lesion per patient in the final dataset. Patients and lesion characteristics are shown in \u003cstrong\u003eTable 1\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eMean patient age was 50.0 years (standard deviation (SD) 13.6), with most patients having palpation findings (33.7 %) prior to interventional biopsy. 12.0 % of the 192 patients met the inclusion criteria for genetic testing according to the German Consortium for Hereditary Breast and Ovarian Cancer [16, 17]. The most often used method for interventional breast biopsy was CNB, accounting for 124 cases (64.6 %). With 52.1 %, the majority of interventional biopsies, and thus the diagnosis of B3 lesion, were conducted in the right breast. In complementary mammographic diagnostics prior to breast biopsy, a BI-RADS 4 was most frequently observed, accounting for 92.0 % of cases.\u003c/p\u003e\n\u003ch2\u003eLesion characteristics\u003c/h2\u003e\n\u003cp\u003eAfter interventional breast biopsy microcalcifications were detectable on specimen radiograms in 39.6 %. In our dataset, the most frequently detected B3 lesion types were FEA (38.5 %), and papillomas (35.9 %), whereas lobular neoplasia were less common, comprising LN1 (4.2 %) and LN2 (2.6 %), respectively. The different B3 lesion types including frequencies are shown in \u003cstrong\u003eTable 1\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eThe largest B3 subgroup was the \u0026ldquo;Risk of associated invasive BC and DCIS\u0026rdquo; group, comprising 103 cases of ADH, FEA, or LN1-2 (53.6 %). In contrast, there were 20 cases (10.4 %) in the \u0026ldquo;Fibroepithelial lesions\u0026rdquo; group and 69 patients (35.9 %) in the \u0026ldquo;Papillomas/RS\u0026rdquo; group.\u003c/p\u003e\n\u003ch2\u003eHistological results from open surgical excision\u003c/h2\u003e\n\u003cp\u003eOverall, the resected tissue from 171 (89.1 %) of the 192 patients contained benign tissue, whereas in 15 cases (7.8 %) DCIS, in 5 cases (2.6 %) BC and associated DCIS, and in one case (0.5 %) BC were detected, respectively. \u003cstrong\u003eFigure 2\u003c/strong\u003e provides examples for a malignant upgrade from B3 to DCIS, while \u003cstrong\u003eFigure 3\u003c/strong\u003e shows an example for malignant upgrade from a B3 lesion to invasive BC and DCIS. In total we observed an upgrade rate of 10.9 % (21 out of 192 cases) (\u003cstrong\u003eTable 2\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eThe rate of patients with diagnosis of breast carcinoma or DCIS significantly differed between the patient groups (P \u0026lt; 0.01, Fisher\u0026rsquo;s exact test): The highest rate was 17.5 % (95 % confidence interval (CI), 10.7-26.2) in patients within the group \u0026ldquo;Risk of associated invasive BC and DCIS\u0026rdquo;. In the other two groups, fewer malignant lesions occurred. Among the 69 cases in the \u0026ldquo;Papillomas/RS\u0026rdquo; group, 3 DCIS were identified (4.3 %, 95 % CI, 0.9-12.2). In the \u0026quot;Fibroepithelial lesions\u0026quot; group, not a single invasive BC or DCIS was found (0.0 %, 95 % CI, 0.0-16.9) (\u003cstrong\u003eTable 2\u003c/strong\u003e).\u003cbr\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eB3 lesions represent a heterogeneous group of breast lesions diagnosed by interventional biopsy as CNB or VAB. Due to their uncertain malignant potential, there is a lack of conclusive recommendations after diagnosis of B3 lesions. Since different B3 lesions can be present in one interventional biopsy, we decided to group the different lesions. Therefore, we subsumed biopsies that had various B3 lesions containing cellular atypia as ADH, FEA, and LN1-2 were named as \u0026ldquo;Risk of associated invasive BC and DCIS\u0026rdquo;. CFL lesions were grouped as \u0026ldquo;Fibroepithelial lesions\u0026rdquo;, while papillomas and RS/CSL were combined as \u0026ldquo;Papillomas/RS\u0026rdquo;. We hypothesized, that the group \u0026ldquo;Risk of associated invasive BC and DCIS\u0026rdquo; had the highest malignant upgrade rate.\u003c/p\u003e\n\u003cp\u003eThis study of 192 patients investigated the malignant upgrade rate of B3 lesions after open surgical excision in a German population. The highest rate of invasive BC and/or DCIS was observed in the group \u0026ldquo;Risk of associated invasive BC and DCIS\u0026rdquo; containing the B3 lesions FEA, ADH, and LN1-2, respectively, with 17.5 %. By contrast, the upgrade rates in the \u0026quot;Fibroepithelial lesions\u0026quot; group were 0 %, and for \u0026quot;Papillomas/RS\u0026quot;, it was 4.3 %. Overall, we found an upgrade rate of 10.9 %.\u003c/p\u003e\n\u003cp\u003eThe group \u0026ldquo;Risk of associated invasive BC and DCIS\u0026rdquo; - containing ADH, FEA, and LN1-2 - with 103 lesions represented the largest subgroup (53.6 %) in our database. Compared to the two groups \u0026ldquo;Fibroepithelial lesions\u0026rdquo; and \u0026ldquo;Papillomas/RS\u0026rdquo;, we found a significant higher malignant upgrade rate of 17.5 % (95 % CI 10.7-26.2 %).\u003c/p\u003e\n\u003cp\u003eFor the B3 lesions ADH, FEA, and LN1-2, malignant upgrade rates of 28 %, 11 %, and 17 %, respectively, were reported in a recent meta-analysis [18]. However, for the different lesions a large range of upgrade rates are published. In another review and meta-analysis of 93 studies, a comparable upgrade rate of 29 % (95 % CI 26-32 %) for ADH alone after surgical excision is reported. However, upgrade rates differed also for the distinct biopsy methods, with pooled upgrade rates of 42 % (95 % CI 31-53 %), 23 % (95 % CI 19-27 %), 32 % (95 % CI 22-43 %) for ultrasound guidance, stereotactic guidance, or MRI guidance, respectively [19]. FEA shows a malignant upgrade rate in other meta-analyses between 5 % (95 % CI 3-6 %), 8.8 %, and 11.1 %, respectively [20-22]. Identically, malignant upgrade in LN1-2 is published between 17 % (95 % CI 13-21 %) in a recent meta-analysis and 14 - 28 % in smaller study populations [18, 23, 24]. Our combined malignant upgrade rate of 17.5 % (95 % CI 10.7-26.2 %) for ADH, FEA, and LN fits into the wide range of different upgrade rates with various different study populations, types of breast biopsies, and other numerous preconditions.\u003c/p\u003e\n\u003cp\u003eThe second largest group in our data are papillomas and RS/CSL with 69 out of 192 lesions (35.9 %). For this group, we report 4.3 % malignant upgrade. A limitation of our work is that our data lack information regarding the presence or absence of cellular atypia in papillary lesions. Atypical papillary lesions having the highest risk of upgrading to malignant after surgical excision in a meta-analysis [25]. In another systematic review and meta-analysis, an upgrade rate of 12 % (95 % CI 10-15) for papillomas, while for RS/CSL, an upgrade rate of 8 % (95 % CI 6-11) was reported [18]. In contrast, we report an upgrade rate of merely 4.3 % (95 % CI 0.9-12.2). One explanation for our relatively low upgrade rate could be, that we excluded papillary lesions or RS/CSL containing larger cellular atypia from the group \u0026ldquo;Papillomas/RS\u0026rdquo; and put them into the group with ADH, FEA, and LN1-2, since cellular atypia is the clinically dominant lesion.\u003c/p\u003e\n\u003cp\u003eOnly including papillary lesions without atypia the prementioned meta-analysis presents a upgrade rate of 7 % (95 % CI 4-10)[18]. In line with our results, others found also a lower proportion of malignancies of 3.4 % in non-atypical papillary lesions after surgical excision [26].\u003c/p\u003e\n\u003cp\u003eB3 lesions with fibroepithelial lesions represent the smallest group in our dataset comprising 20 lesions (10.4 %). In line with other studies, we found no upgrade of fibroepithelial lesions to invasive BC and DCIS [8]. However, the focus in B3 lesions containing fibroepithelial lesions is not to rule out primary BC but malignant phyllodes tumors. In a retrospective analysis of 51 B3 lesions diagnosed as phyllodes tumors, only five were malignant phyllodes tumors after open excision [27]. In our data set, we could not observe an upgrade to malignant phyllodes tumors in the 20 fibroepithelial lesions. Another review found an upgrade rate of less than 2 % for fibroepithelial lesions [28]. In a cohort of 215 patients with fibroepithelial B3 lesions, the upgrade rate to borderline or malignant phyllodes tumors was 2 %, while LCIS was found in 1 % [29]. Therefore, guidelines do not generally recommend the excision of fibroepithelial lesions [2]. A more refined approach for deciding whether to proceed with open excision is to consider the growth rate of the fibroepithelial lesion and suspicion for phyllodes tumor [30, 31].\u003c/p\u003e\n\u003cp\u003eMissing data on previous breast biopsies or previous diagnosis of invasive BC or DCIS are possible limitations of our work. Since earlier breast malignancy and breast biopsies are risk factors for BC and DCIS, an impact on the previous work cannot be excluded [32, 33]. Furthermore, our data lack information on symptoms prior to interventional breast biopsy. The presented retrospective data originate from a tertiary referral center in a university hospital maybe influencing patient acquisition. Since our work includes data until June 2019, our data lack information regarding the latest classification update on the WHO Classification of Tumours - Breast Tumours - in particular the new classification of lobular neoplasia [34].\u003c/p\u003e\n\u003cp\u003eIn brief, the advantage of this study is the large number of patients included. The case only study design with the absence of specific inclusion criteria (e.g. type of biopsy or lesion type), the large study population of 192 patients, and grouping of B3 lesions separates this study from others. Since we identify statistically significant differences between the three B3 lesion groups, our results suggest distinct therapeutic implications. As proposed by other research groups, a surgical excision can be avoided for lesions with an upgrade rate of less than 2 %. This is extrapolated analogously to the BI-RADS category 3, where a possible diagnostic delay is not associated with a worse prognosis [35]. Therefore, we suggest open surgical excision should be recommended for ADH, FEA, LN1-2, papillomas, and RS/CSL. Fibroepithelial lesions without growth tendency and without diagnostic uncertainties do not need to be excised.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eLesions of uncertain malignant potential in the breast (B3 lesions) comprise different histopathologic distinct breast lesions with a heterogenous risk of ductal carcinoma in situ (DCIS) or invasive breast cancer (BC). In our study, we found the highest malignant upgrade rates for B3 lesions containing ADH, FEA, and LN1-2 after open surgical excision of 17.5 %. Other B3 lesions in our data set had an upgrade rate of less than 5 %. Based on our data, we recommend open surgical of the B3 lesions ADH, FEA, and LN1-2. For the other investigated B3 lesions at least follow-up examinations should be recommended.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eACR American College of Radiology\u003c/p\u003e\n\u003cp\u003eADH Atypical ductal hyperplasia\u003c/p\u003e\n\u003cp\u003eALH Atypical lobular hyperplasia\u003c/p\u003e\n\u003cp\u003eB3 Lesions of uncertain malignant potential in the breast\u003c/p\u003e\n\u003cp\u003eBC Breast cancer\u003c/p\u003e\n\u003cp\u003eBI-RADS Breast Imaging Reporting and Data System\u003c/p\u003e\n\u003cp\u003eCFL Cellular fibroepithelial lesions\u003c/p\u003e\n\u003cp\u003eCI Confidence interval\u003c/p\u003e\n\u003cp\u003eCNB Core needle biopsy\u003c/p\u003e\n\u003cp\u003eCSL Complex sclerosing lesion\u003c/p\u003e\n\u003cp\u003eDCIS Ductal carcinoma in situ\u003c/p\u003e\n\u003cp\u003eEWGBSP European Working Group for Breast Screening Pathology\u003c/p\u003e\n\u003cp\u003eFEA Flat epithelial atypia\u003c/p\u003e\n\u003cp\u003eH\u0026amp;E Hematoxylin and eosin\u003c/p\u003e\n\u003cp\u003eLCIS Classic lobular carcinoma in situ\u003c/p\u003e\n\u003cp\u003eLN Classical lobular neoplasia\u003c/p\u003e\n\u003cp\u003eVAB Vacuum-assisted biopsy\u003c/p\u003e\n\u003cp\u003eRS Radial scar\u003c/p\u003e\n\u003cp\u003eSD Standard deviation\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization: F.H., S.M.J., C.I.P., R.E.; data curation: F.H.; formal analysis: L.H.; investigation: F.H., J.S., S.M.J., C.I.P., R.E.; project administration: F.H., S.M.J., C.I.P., R.E.; resources: A.H., M.W.B.; supervision: F.H., R.E..; visualization: F.H., L.H., R.E.; writing - original draft: F.H., L.H., R.E.; writing-review \u0026amp; editing: all authors. All the authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no external funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the ethics committee of the Faculty of Medicine at Friedrich-Alexander-Universit\u0026auml;t Erlangen-N\u0026uuml;rnberg (FAU) (ref. number 24-41-Br). All procedures were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Written informed consent for interventional breast biopsy and open surgical excision was obtained for all patients. Supplemental agreement to the study was waived due to the retrospective study design including only anonymized data analysis. There was no use of animal research within this project.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u0026emsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe present work was performed in partial fulfillment of the requirements for obtaining the degree \u0026bdquo;Dr. med.\u0026ldquo; of J.S.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompliance with ethical standards\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDisclosure of potential conflicts of interest\u0026emsp;\u003c/p\u003e\n\u003cp\u003eArndt Hartmann had an advisory role and received honoraria for lectures or consulting/advisory boards from Abbvie, Agilent, AstraZeneca, Biocartis, BMS, Boehringer Ingelheim, Cepheid, Diaceutics, Gilead, Illumina, Ipsen, Janssen-Cilag, Lilly, Merck, MSD, Nanostring, Novartis, Pfizer, Qiagen, QuIP GmbH, Roche, Sanofi, and 3DHistotech.\u003c/p\u003e\n\u003cp\u003eRamona Erber has received honoraria from Roche, Eisai, Pfizer, BioNTech, Veracyte (PROCURE), Diaceutics, Mindpeak, AstraZeneca, MEDAC, Lilly and Novartis.\u003c/p\u003e\n\u003cp\u003eThe institution of Arndt Hartmann and Ramona Erber conducts research for, AstraZeneca, Biocartis, Biontech, Cepheid, Gilead, Illumina, Janssen-Cilag, Nanostring Technologies, Mindpeak, MSD, Novartis, Owkin, palleos healthcare, Owkin, Qiagen, QuIP GmbH, Roche, Sanofi, Stratifyer and Zytovision.\u003c/p\u003e\n\u003cp\u003eCaroline I. Preuss has received honoraria and travel expenses from MSD, AstraZeneca and Daiichi-Sankyo.\u003c/p\u003e\n\u003cp\u003eAll the other authors declare that they have no conflicts of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eIbrahim, A.E., et al., \u003cem\u003eThe role and histological classification of needle core biopsy in comparison with fine needle aspiration cytology in the preoperative assessment of impalpable breast lesions.\u003c/em\u003e J Clin Pathol, 2001. \u003cstrong\u003e54\u003c/strong\u003e(2): p. 121-5.\u003c/li\u003e\n\u003cli\u003eLeitlinienprogramm Onkologie (Deutsche Krebsgesellschaft, D.K., AWMF): S3-Leitlinie Fr\u0026uuml;herkennung, Diagnose, Therapie und Nachsorge des Mammakarzinoms, Version 4.4, 2021, AWMF Registernummer: 032-045OL, http://www.leitlinienprogramm-onkologie.de/leitlinien/mammakarzinom/ . accessed: 11-AUG-2024.\u003c/li\u003e\n\u003cli\u003eAndreu, F.J., et al., \u003cem\u003eBreast core biopsy reporting categories--An internal validation in a series of 3054 consecutive lesions.\u003c/em\u003e Breast, 2007. \u003cstrong\u003e16\u003c/strong\u003e(1): p. 94-101.\u003c/li\u003e\n\u003cli\u003eDeb, R., et al., \u003cem\u003eNational breast screening pathology audit 2015. 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Cheng, \u003cem\u003eNonmalignant breast papillary lesions at core-needle biopsy: a meta-analysis of underestimation and influencing factors.\u003c/em\u003e Ann Surg Oncol, 2013. \u003cstrong\u003e20\u003c/strong\u003e(1): p. 94-101.\u003c/li\u003e\n\u003cli\u003eLiu, C., et al., \u003cem\u003eRisk of malignancy in papillary neoplasms of the breast.\u003c/em\u003e Breast Cancer Res Treat, 2019. \u003cstrong\u003e178\u003c/strong\u003e(1): p. 87-94.\u003c/li\u003e\n\u003cli\u003eAbdulcadir, D., et al., \u003cem\u003ePhyllodes tumours of the breast diagnosed as B3 category on image-guided 14-gauge core biopsy: analysis of 51 cases from a single institution and review of the literature.\u003c/em\u003e Eur J Surg Oncol, 2014. \u003cstrong\u003e40\u003c/strong\u003e(7): p. 859-64.\u003c/li\u003e\n\u003cli\u003ePinder, S.E., et al., \u003cem\u003eNHS Breast Screening multidisciplinary working group guidelines for the diagnosis and management of breast lesions of uncertain malignant potential on core biopsy (B3 lesions).\u003c/em\u003e Clin Radiol, 2018. \u003cstrong\u003e73\u003c/strong\u003e(8): p. 682-692.\u003c/li\u003e\n\u003cli\u003eLimberg, J., et al., \u003cem\u003eFibroepithelial Lesions (FELs) of the Breast: Is Routine Excision Always Necessary?\u003c/em\u003e World J Surg, 2020. \u003cstrong\u003e44\u003c/strong\u003e(5): p. 1552-1558.\u003c/li\u003e\n\u003cli\u003eMousa-Doust, D., et al., \u003cem\u003eExcision of breast fibroepithelial lesions: when is it still necessary?-A 10-year review of a regional centre.\u003c/em\u003e Breast Cancer Res Treat, 2022. \u003cstrong\u003e194\u003c/strong\u003e(2): p. 307-314.\u003c/li\u003e\n\u003cli\u003eRubio, I.T., et al., \u003cem\u003eEuropean guidelines for the diagnosis, treatment and follow-up of breast lesions with uncertain malignant potential (B3 lesions) developed jointly by EUSOMA, EUSOBI, ESP (BWG) and ESSO.\u003c/em\u003e Eur J Surg Oncol, 2024. \u003cstrong\u003e50\u003c/strong\u003e(1): p. 107292.\u003c/li\u003e\n\u003cli\u003eFasching, P.A., et al., \u003cem\u003eBreast Cancer Risk - Genes, Environment and Clinics.\u003c/em\u003e Geburtsh Frauenheilk, 2011. \u003cstrong\u003e71\u003c/strong\u003e(12): p. 1056-1066.\u003c/li\u003e\n\u003cli\u003eHartkopf, A.D., et al., \u003cem\u003eUpdate Breast Cancer 2023 Part 1 - Early Stage Breast Cancer.\u003c/em\u003e Geburtshilfe Frauenheilkd, 2023. \u003cstrong\u003e83\u003c/strong\u003e(6): p. 653-663.\u003c/li\u003e\n\u003cli\u003eTan, P.H., et al., \u003cem\u003eThe 2019 World Health Organization classification of tumours of the breast.\u003c/em\u003e Histopathology, 2020. \u003cstrong\u003e77\u003c/strong\u003e(2): p. 181-185.\u003c/li\u003e\n\u003cli\u003eSickles, E.A. and C. D\u0026rsquo;Orsi, \u003cem\u003eACR BI-RADS Follow-up and Outcome Monitoring. ACR BI-RADS Atlas, Breast Imaging Report Data System. 5th ed. Reston, Va: American College of Radiology.\u003c/em\u003e 2013.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;1\u0026emsp;\u003c/strong\u003ePatient and lesion characteristics\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 35px;\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e50.0 (13.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 35px;\"\u003e\n \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e25.1 (5.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"bottom\" style=\"width: 35px;\"\u003e\n \u003cp\u003ePatient from the mammography screening program\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e119 (62.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e54 (28.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e19 (9.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"7\" valign=\"bottom\" style=\"width: 35px;\"\u003e\n \u003cp\u003eClinical findings leading to CNB or VAB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003ePalpation findings\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e64 (33.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eMicrocalcifications\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e31 (16.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eNipple secretion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e8 (4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eAbnormal findings on mammography\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e46 (24.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eAbnormal findings on breast ultrasound\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e20 (10.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eMastodynia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e14 (7.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eMiscellaneous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e7 (3.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"bottom\" style=\"width: 35px;\"\u003e\n \u003cp\u003eInclusion criteria for genetic testing according to the German Consortium for Hereditary Breast and Ovarian Cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eNot available\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e6 (3.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e163 (84.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e23 (12.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"bottom\" style=\"width: 35px;\"\u003e\n \u003cp\u003eSide of the breast biopsy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eLeft\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e92 (47.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eRight\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e100 (52.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"bottom\" style=\"width: 35px;\"\u003e\n \u003cp\u003eType of breast biopsy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eCNB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e124 (64.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eVAB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e68 (35.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" valign=\"bottom\" style=\"width: 35px;\"\u003e\n \u003cp\u003eMammographic density\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eACR a\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e4 (2.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eACR b\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e82 (56.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eACR c\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e40 (27.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eACR d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e18 (12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"5\" valign=\"bottom\" style=\"width: 35px;\"\u003e\n \u003cp\u003eBI-RADS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eBI-RADS 0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e2 (1.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eBI-RADS 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e3 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eBI-RADS 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e2 (1.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eBI-RADS 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e172 (92.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eBI-RADS 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e8 (4.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"bottom\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"bottom\" style=\"width: 35px;\"\u003e\n \u003cp\u003eADH in breast biopsy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eNo\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e156 (81.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e36 (18.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"bottom\" style=\"width: 35px;\"\u003e\n \u003cp\u003eFEA in breast biopsy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eNo\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e118 (61.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e74 (38.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"bottom\" style=\"width: 35px;\"\u003e\n \u003cp\u003eLN1-2 in breast biopsy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eno LN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e179 (93.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eLN1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e8 (4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eLN2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e5 (2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"bottom\" style=\"width: 35px;\"\u003e\n \u003cp\u003eCellular fibroepithelial lesions in breast biopsy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eNo\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e159 (82.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e33 (17.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"bottom\" style=\"width: 35px;\"\u003e\n \u003cp\u003ePhyllodes tumour without suspicion of malignancy in breast biopsy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eNo\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e177 (92.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e15 (7.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"bottom\" style=\"width: 35px;\"\u003e\n \u003cp\u003ePapilloma in breast biopsy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eNo\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e123 (64.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e69 (35.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"bottom\" style=\"width: 35px;\"\u003e\n \u003cp\u003eRS/CSL in breast biopsy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eNo\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e174 (90.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e18 (9.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003eMicrocalcifications in breast biopsy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003eNo\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e116 (60.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e76 (39.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"bottom\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"bottom\" style=\"width: 35px;\"\u003e\n \u003cp\u003eBiopsy group: \u0026quot;Risk of associated invasive BC and DCIS\u0026rdquo;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e89 (46.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e103 (53.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"bottom\" style=\"width: 35px;\"\u003e\n \u003cp\u003eBiopsy group: \u0026ldquo;Fibroepithelial lesions\u0026rdquo;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e172 (89.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e20 (10.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"bottom\" style=\"width: 35px;\"\u003e\n \u003cp\u003eBiopsy group: \u0026ldquo;Papillomas/RS\u0026rdquo;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e123 (64.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e69 (35.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"bottom\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" valign=\"bottom\" style=\"width: 35px;\"\u003e\n \u003cp\u003eHistological result from open surgical excision\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eInvasive BC only\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e1 (0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eDCIS only\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e15 (7.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eInvasive BC and DCIS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e5 (2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 45px;\"\u003e\n \u003cp\u003eBenign\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19px;\"\u003e\n \u003cp\u003e171 (89.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;Patient and tumor characteristics, showing mean and standard deviation or frequency and percentage\u003c/p\u003e\n\u003cp\u003eACR: American College of Radiology, BI-RADS: Breast Imaging Reporting and Data System.\u003cbr\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;2\u0026emsp;\u003c/strong\u003eHistopathological results of the open excision\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"576\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAssessment of the lesion\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAll patients\u003cbr\u003e\u0026nbsp;(N = 192)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 255px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatients with resected tissue containing invasive BC and/or DCIS\u003cbr\u003e\u0026nbsp;(N = 21)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eN\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eN\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRate with 95 % CI in %\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u0026ldquo;Risk of associated invasive BC and DCIS\u0026rdquo;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 95px;\"\u003e\n \u003cp\u003e103\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 94px;\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 161px;\"\u003e\n \u003cp\u003e17.5 (10.7, 26.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u0026ldquo;Fibroepithelial lesions\u0026rdquo;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 95px;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 161px;\"\u003e\n \u003cp\u003e0.0 (0.0, 16.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u0026ldquo;Papillomas/RS\u0026rdquo;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 95px;\"\u003e\n \u003cp\u003e69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 94px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 161px;\"\u003e\n \u003cp\u003e4.3 (0.9, 12.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eCI: Confidence interval\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"breast-cancer-research-and-treatment","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"brea","sideBox":"Learn more about [Breast Cancer Research and Treatment](https://www.springer.com/journal/10549)","snPcode":"10549","submissionUrl":"https://submission.nature.com/new-submission/10549/3","title":"Breast Cancer Research and Treatment","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"B3 lesions, breast cancer, DCIS, surgery","lastPublishedDoi":"10.21203/rs.3.rs-5429534/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5429534/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003ePurpose\u003c/b\u003e\u003c/p\u003e \u003cp\u003eUnclear or suspicious breast findings are typically clarified by interventional breast biopsy. Lesions with uncertain malignant potential are grouped as B3 lesions in histopathology. The B3 group according to the European Working Group for Breast Screening Pathology (EWGBSP) comprises various breast lesions with different upgrade rates to invasive breast cancer (BC) or ductal carcinoma in situ (DCIS) if surgical removal is performed. The objective of this study was to investigate malignant upgrade rates to DCIS and/or invasive breast cancer (BC) after open surgical excision for the different B3 lesions.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eA total of 192 patients with histologically verified B3 lesions were followed up retrospectively for this analysis. Patients with the B3 lesions atypical ductal hyperplasia (ADH), flat epithelial atypia (FEA), and classical lobular neoplasia (LN1-2) were combined into one group, while cellular fibroepithelial lesions (CFL) and phyllodes tumors without suspicion of malignancy, as well as papillomas and radial scars/complex sclerosing lesions (RS/CSL) were summarized in two other groups. We investigated the association of the different B3 lesions with invasive BC or DCIS after open surgical excision.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eHistopathological investigation revealed in 21 (10.9%) of the 192 patients invasive BC or DCIS after open surgical excision. The rate of patients with BC and/or DCIS significantly differed between the patient groups (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01, Fisher\u0026rsquo;s exact test): The highest rate was 17.5% (95% confidence interval (CI), 10.7\u0026ndash;26.2) in patients within the group of ADH, FEA, and LN1-2. In the other two groups, fewer malignant lesions occurred. In the group with papillomas and RS/CSL the malignant upgrade rate was 4.3% (95% CI, 0.9\u0026ndash;12.2), while within the group with CFL and phyllodes tumors without suspicion of malignancy no malignant upgrade was observed (0.0%, 95% CI, 0.0-16.9).\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions\u003c/b\u003e\u003c/p\u003e \u003cp\u003eB3 lesions harbor the risk of malignant upgrade after surgical excision. In our collective ADH, FEA, and LN1-2 had significant higher upgrade rates than other B3 lesions.\u003c/p\u003e","manuscriptTitle":"Malignant upgrade in lesions of uncertain malignant potential in the breast (B3 lesions) – is open excision always necessary?","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-16 16:19:00","doi":"10.21203/rs.3.rs-5429534/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-12-30T14:46:33+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-12-27T20:42:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"132030643755157191618613007369360695303","date":"2024-12-26T15:47:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"88647194316296533830088622030048106694","date":"2024-12-26T15:23:53+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-12-26T14:04:03+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-11-11T14:18:57+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-11-11T14:18:18+00:00","index":"","fulltext":""},{"type":"submitted","content":"Breast Cancer Research and Treatment","date":"2024-11-11T06:52:06+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"breast-cancer-research-and-treatment","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"brea","sideBox":"Learn more about [Breast Cancer Research and Treatment](https://www.springer.com/journal/10549)","snPcode":"10549","submissionUrl":"https://submission.nature.com/new-submission/10549/3","title":"Breast Cancer Research and Treatment","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"f73a07cb-4ee7-44f0-88b6-387d2d6fd0fc","owner":[],"postedDate":"December 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-02-24T16:01:07+00:00","versionOfRecord":{"articleIdentity":"rs-5429534","link":"https://doi.org/10.1007/s10549-025-07632-7","journal":{"identity":"breast-cancer-research-and-treatment","isVorOnly":false,"title":"Breast Cancer Research and Treatment"},"publishedOn":"2025-02-17 15:57:23","publishedOnDateReadable":"February 17th, 2025"},"versionCreatedAt":"2024-12-16 16:19:00","video":"","vorDoi":"10.1007/s10549-025-07632-7","vorDoiUrl":"https://doi.org/10.1007/s10549-025-07632-7","workflowStages":[]},"version":"v1","identity":"rs-5429534","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5429534","identity":"rs-5429534","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}