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Intraoperative frozen section (FS) margin evaluation is not common practice for patients undergoing breast conservation therapy (BCT), but offers a significant reduction in reoperation. In this study, a technique to allow for more effective freezing of breast tissue was developed to perform FS evaluation of lumpectomy margins (FSM) for all patients undergoing BCT at an ambulatory surgery center. FS evaluation of sentinel lymph node biopsy specimens was performed concurrently. One hundred eighty-one study and 188 control patients, with and without FS evaluation, were compared. Reexcision was reduced 34% (from 48.9% to 14.9%) and reoperation was reduced 36% (from 55.3% to 19.3%) with FS evaluation. Most of the decrease in reoperative rate was because of a decrease in the need for margin reexcision. The number of patients requiring 1, 2, or 3 operations to complete therapy was 84, 92, and 12, respectively, in the control group, and 146, 33, and 2, respectively, in the study group. Lobular subtype, multifocal disease, and larger tumor size (≥2 cm) were significantly associated with failure of FSM to prevent reoperation, but reoperation rates were still significantly decreased in this subgroup of patients (from 75.5% to 43.8%) with FSM. This study highlights an innovative yet simple and adaptable FS approach that resulted in a nearly 3-fold reduction in reoperation for patients undergoing BCT. [ABSTRACT FROM AUTHOR]

Distinction of metastasis to the breast from a breast primary, particularly high-grade triple-negative breast cancer (TNBC), can be challenging due to nonspecific morphology and immunohistochemical (IHC) profiles. Among metastases to the breast, high-grade serous carcinoma (HGSC) of müllerian origin is most likely to be misdiagnosed as TNBC. We assessed breast and müllerian markers on TNBC and HGSC, including keratin 7, keratin 20, GATA3, GCDFP15, mammaglobin, p53, PAX8 (MRQ50 and BC12 clones), TRPS1, SOX10, and WT1. Of 151 TNBC cases, TRPS1 had the highest sensitivity, showing expression in 149 (98.7%) cases, followed by SOX10 (110/151; 72.8%), GATA3 (102/151; 67.5%), GCDFP15 (29/151; 19.2%), and mammaglobin (27/151; 17.9%). PAX8 positivity was seen in 40.4% (61/151) of TNBC via the MRQ50 clone but was negative in all via the BC12 clone. Of 185 HGSC cases, PAX8 via the MRQ50 clone was the most sensitive (179/185; 96.8%), followed by WT1 (171/185; 92.4%) and PAX8 via the BC12 clone (164/185; 88.6%). In addition, TRPS1 positivity was seen in 75 HGSC cases (40.5%). Aberrant p53 patterns were seen in 64.9% (98/151) of TNBC and 94.1% (174/185) of HGSC. TRPS1 positivity in HGSC and PAX8 positivity via the MRQ50 clone in TNBC represent potential pitfalls in assessing high-grade carcinoma for which the differential diagnosis includes TNBC and HGSC. However, with this knowledge, utilization of a panel of breast and müllerian markers, including preferential use of the PAX8 BC12 clone, can facilitate accurate diagnosis., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Axillary assessment in breast cancer is key to determining an upfront surgery or neoadjuvant chemotherapy (NAC) approach. We investigated the false-negative rate (FNR) of axillary-node ultrasound-guided core-needle biopsy (US-CNBx) and the surgical management of pN ​+ ​patients., Methods: This single-institution study from 2010 to 2020 included patients with benign findings on US-CNBx and upfront surgery. Statistical analyses were performed via t-tests and chi-squared tests., Results: 95 axillae met inclusion, 23 were pN+, resulting in a US-CNBx FNR of 24.2 ​%. pN ​+ ​patients more frequently had cT2-T3 tumors vs pN0 patients (43.5 ​% vs 27.8 ​%, p ​= ​0.03). Of the 23 ​pN ​+ ​patients, 9 underwent breast-conserving surgery (BCS) and 14 underwent mastectomy. In those with BCS, 7 had 1-2 positive nodes, 2 had ≥3 nodes; 3 received an ALND. In those with mastectomies, 12 had 1-2 positive nodes, 2 had ≥3 positive nodes; 6 received an ALND., Conclusion: In this cohort, US-CNBx had a FNR of 24.2 ​%. pN ​+ ​patients had a greater frequency of cT2-cT3 tumors, therefore clinicians should be cognizant of potential occult nodal disease despite negative CNBx when deciding management., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: To evaluate the utilization of hematopathology resources within our enterprise on axillary lymph node core biopsy (AxLNCB) specimens, particularly those obtained in the context of breast cancer screening., Methods: The utilization of hematopathology resources was determined for all AxLNCB specimens over a 30-month period from across our enterprise, and chart review was performed for select patient demographics and radiographic features. The AxLNCB cases with benign histology were reviewed for subtyping of histologic patterns., Results: Of the total 594 AxLNCB specimens, 61.6% were benign and 38.6% malignant. Of malignant cases, only 9.3% contained any hematologic malignancy, yet 94% of all cases received tissue triage for lymphoma, and 81% were reviewed at least in part by a hematopathologist. Six clinical parameters were found to independently predict risk of hematologic malignancy: male sex (P = .041), bilateral lymphadenopathy (P = .004), diffuse cortical thickening (P = .005), lack of breast cancer (P = .001), older age (P < .001), and history of hematologic malignancy (P < .001)., Conclusions: Our enterprise overused hematopathology resources in the evaluation of AxLNCB performed in the study period. Our process could improve from the application of a simple tool generated from this cohort to predict percent risk of the specimen containing hematologic malignancy using patient characteristics easily found via routine chart review., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

PD-L1 immunohistochemistry (IHC) has become an established method for predicting cancer response to targeted anti-PD1 immunotherapies, including breast cancer (BC). The alternative PD-1 ligand, PD-L2, remains understudied but may be a complementary predictive marker. Prospective analysis of 32 breast cancers revealed divergent expression patterns of PD-L1 and PD-L2. PD-L1-positivity was higher in immune cells than in cancer cells (median = 5.0% vs. 0.0%; p = 0.001), whereas PD-L2-positivity was higher in cancer cells than immune cells (median = 30% vs. 5.0%; p = 0.001). Percent positivity of PD-L1 and PD-L2 were not correlated, neither in cancer cells nor immune cells. Based on a cut-point of ≥1% positivity, ER+ tumors (n = 23) were frequently PD-L2-positive (73.9%), whereas only 40.9% were PD-L1-positive. These data suggest differential control of cellular PD-L1 and PD-L2 expression in BC and a potential role for PD-L2 IHC as a complementary marker to PD-L1 to improve selection of aggressive ER+ BC that may benefit from anti-PD-1 therapy.

Published data on combined breast and gynecologic [breast/gyn] surgical pathology fellowship training programs are limited. Our study aimed to survey the landscape of such fellowships in the United States (US), including specific information about their characteristics and the educational activities therein. Using web searches, we identified programs offering combined breast/gyn surgical pathology fellowship training. We developed a 26-item questionnaire asking program directors to report on the characteristics of their fellowship training structure. The search revealed 25 academic based programs offering one-year combined breast/gyn fellowship training, predominantly located (40 %) in the Northeast area. The following data was obtained: 44 % of the programs were accredited by the ACGME, 82 % required >19 weeks of breast and gyn service, and 69.6 % accepted the common application, 54.5 % of programs require completion of a research project for graduation. An annual average of 3000 breast and 3000 gyn cases appears to be the usual volume of cases. Interestingly, only 36 % of the program directors are graduates of a combined breast/gyn fellowship program. In conclusion, we present the most comprehensive and up-to-date census of combined breast/gyn pathology fellowships in the US. Our study provides valuable information on the current state of combined breast/gyn pathology fellowship training. The information will be helpful to current and prospective trainees, as well as program leaders., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Purpose: The purpose of this study was to evaluate various morphologic features of axillary nodes on ultrasound (US) in predicting malignancy and estimate the incidence of malignancy in axillary nodes based on their imaging mode of detection., Methods and Materials: A retrospective review of all percutaneous US-guided biopsies on axillary nodes performed at our institution between 1/1/2019-09/30/2021 was performed. Sonographic morphologic features of the biopsied node, imaging mode of detection and size of primary breast malignancy were correlated with malignancy., Results: There were 224 malignancies detected in a total of 594 patients who underwent an axillary node biopsy. The positive predictive value (PPV) was significantly associated with the extent of nodal cortical thickening (p < 0.0001). The PPV of malignancy was significantly higher in nodes which lacked a normal hilum (0.61 vs 0.23). The PPV of malignancy in nodes detected on screening mammography (18.8%) or MRI (15.8%) was much lower than those detected on diagnostic imaging, by palpation or on CT/PET (48.4%, 43.8% and 65.3% respectively). Of all screening detected nodes in patients with no history of malignancy and mild cortical thickening, only 2 (4.3%) demonstrated malignancy., Conclusions: Morphology of axillary nodes on sonography is vital in predicting nodal metastasis. Cortical thickness > 5 mm and/or absence of a normal hilum had the highest PPV for metastatic disease. Using clinical history in conjunction with imaging findings will help improve accuracy of axillary nodal biopsies, especially for incidental nodes detected on screening., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Endocrine resistant metastatic disease develops in ~ 20-25% of hormone-receptor-positive (HR+) breast cancer (BC) patients despite endocrine therapy (ET) use. Upregulation of HER family receptor tyrosine kinases (RTKs) represent escape mechanisms in response to ET in some HR+ tumors. Short-term neoadjuvant ET (NET) offers the opportunity to identify early endocrine escape mechanisms initiated in individual tumors., Methods: This was a single arm, interventional phase II clinical trial evaluating 4 weeks (± 1 week) of NET in patients with early-stage HR+/HER2-negative (HER2-) BC. The primary objective was to assess NET-induced changes in HER1-4 proteins by immunohistochemistry (IHC) score. Protein upregulation was defined as an increase of ≥ 1 in IHC score following NET., Results: Thirty-seven patients with cT1-T3, cN0, HR+/HER2- BC were enrolled. In 35 patients with evaluable tumor HER protein after NET, HER2 was upregulated in 48.6% (17/35; p = 0.025), with HER2-positive status (IHC 3+ or FISH-amplified) detected in three patients at surgery, who were recommended adjuvant trastuzumab-based therapy. Downregulation of HER3 and/or HER4 protein was detected in 54.2% of tumors, whereas HER1 protein remained low and unchanged in all cases. While no significant volumetric reduction was detected radiographically after short-term NET, significant reduction in tumor proliferation rates were observed. No significant associations were identified between any clinicopathologic covariates and changes in HER1-4 protein expression on multivariable analysis., Conclusion: Short-term NET frequently and preferentially upregulates HER2 over other HER family RTKs in early-stage HR+/HER2- BC and may be a promising strategy to identify tumors that utilize HER2 as an early endocrine escape pathway., Clinical Trial Registry: Trial registration number: NCT03219476., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aims: Juvenile fibroadenomas (JFA) are biphasic fibroepithelial lesions (FEL) usually occurring in adolescent female patients. Giant (G) JFA, like other FEL, may exhibit prominent pseudoangiomatous stromal hyperplasia (PASH)-like change. We sought to determine clinicopathological and molecular characteristics of GJFA with and without PASH., Methods and Results: Archives were searched for cases of GJFA (1985-2020). All were stained for androgen receptor (AR), beta-catenin, CD34 and progesterone receptor (PR). Cases were sequenced using a custom 16-gene panel - MED12 (exons 1 and 2), TERT promoter (-124C>T and -146Ctable>T), SETD2, KMT2D, RARA (exons 5-9), FLNA, NF1, PIK3CA (exons 10, 11 and 21), EGFR, RB1, BCOR, TP53, PTEN, ERBB4, IGF1R and MAP3K1. Twenty-seven GJFA from 21 female patients aged 10.1-25.2 years were identified. Size ranged from 5.2 to 21 cm. Two patients had multiple, bilateral and later recurrent GJFA. Thirteen (48%) cases showed prominent PASH-like stroma. All were positive for stromal CD34, negative for AR and beta-catenin and one case showed focal PR expression. Sequencing showed MAP3K1 and SETD2 mutations in 17 samples, with KMT2D, TP53 and BCOR aberrations in 10 (45%), 10 (45%) and seven (32%) cases, respectively. Tumours with a PASH-like pattern had higher prevalence of SETD2 (P = 0.004) and TP53 (P = 0.029) mutations, while those without PASH had more RB1 mutations (P = 0.043). MED12 mutation was identified in one case. TERT promoter mutation was observed in four (18%), including two recurrences., Conclusions: Gene mutations along more advanced phases of the proposed FEL pathogenetic pathway in GJFA are unusual, and suggest a mechanism for more aggressive growth in these tumours., (© 2023 John Wiley & Sons Ltd.)

Background: Breast-conserving surgery is aimed at removing all cancerous cells while minimizing the loss of healthy tissue. To ensure a balance between complete resection of cancer and preservation of healthy tissue, it is necessary to assess themargins of the removed specimen during the operation. Deep ultraviolet (DUV) fluorescence scanning microscopy provides rapid whole-surface imaging (WSI) of resected tissues with significant contrast between malignant and normal/benign tissue. Intra-operative margin assessment with DUV images would benefit from an automated breast cancer classification method., Methods: Deep learning has shown promising results in breast cancer classification, but the limited DUV image dataset presents the challenge of overfitting to train a robust network. To overcome this challenge, the DUV-WSI images are split into small patches, and features are extracted using a pre-trained convolutional neural network-afterward, a gradient-boosting tree trains on these features for patch-level classification. An ensemble learning approach merges patch-level classification results and regional importance to determine the margin status. An explainable artificial intelligence method calculates the regional importance values., Results: The proposed method's ability to determine the DUV WSI was high with 95% accuracy. The 100% sensitivity shows that the method can detect malignant cases efficiently. The method could also accurately localize areas that contain malignant or normal/benign tissue., Conclusion: The proposed method outperforms the standard deep learning classification methods on the DUV breast surgical samples. The results suggest that it can be used to improve classification performance and identify cancerous regions more effectively., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 To, Lu, Jorns, Patton, Schmidt, Yen, Yu and Ye.)

Background: In DCIS, ER status is an important marker. The utility of concomitant PR testing remains unclear., Methods: A single-institution retrospective cohort study was performed with a comparative analysis of the NCDB to assess annual cost-savings with omission of routine PR testing. National Medicare payment standards determined PR staining costs to be $124.92., Results: 150 institutional DCIS cases with receptor data were identified. 104 (69%) were ER+/PR+, 16 (11%) were ER+/PR-, and none were ER-/PR+. Omission of routine PR testing would have resulted in $18,738 saved annually. Within the NCDB, 34,100 DCIS cases had receptor data: 29,277 (85.9%) patients were ER+, and 26,008 (76%) were both ER/PR+. 211 (0.6%) patients were ER-/PR+. Annual national cost-savings with omission of routine PR-testing would have been $4.3 million., Conclusion: PR testing for DCIS should be reserved only for patients with ER- DCIS undergoing breast conservation to determine the utility of adjuvant endocrine therapy., Competing Interests: Declaration of competing interest The authors have no financial or non-financial interests to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: T-cell-mediated cytotoxicity is suppressed when programmed cell death-1 (PD-1) is bound by PD-1 ligand-1 (PD-L1) or PD-L2. Although PD-1 inhibitors have been approved for triple-negative breast cancer, the lower response rates of 25%-30% in estrogen receptor-positive (ER+) breast cancer will require markers to identify likely responders. The focus of this study was to evaluate whether PD-L2, which has higher affinity than PD-L1 for PD-1, is a predictor of early recurrence in ER+ breast cancer., Methods: PD-L2 protein levels in cancer cells and stromal cells of therapy-naive, localized or locoregional ER+ breast cancers were measured retrospectively by quantitative immunofluorescence histocytometry and correlated with progression-free survival (PFS) in the main study cohort (n = 684) and in an independent validation cohort (n = 273). All patients subsequently received standard-of-care adjuvant therapy without immune checkpoint inhibitors., Results: Univariate analysis of the main cohort revealed that high PD-L2 expression in cancer cells was associated with shorter PFS (hazard ratio [HR], 1.8; 95% CI, 1.3 to 2.6; P = .001), which was validated in an independent cohort (HR, 2.3; 95% CI, 1.1 to 4.8; P = .026) and remained independently predictive after multivariable adjustment for common clinicopathological variables (HR, 2.0; 95% CI, 1.4 to 2.9; P < .001). Subanalysis of the ER+ breast cancer patients treated with adjuvant chemotherapy (n = 197) revealed that high PD-L2 levels in cancer cells associated with short PFS in univariate (HR, 2.5; 95% CI, 1.4 to 4.4; P = .003) and multivariable analyses (HR, 3.4; 95% CI, 1.9 to 6.2; P < .001)., Conclusion: Up to one third of treatment-naive ER+ breast tumors expressed high PD-L2 levels, which independently predicted poor clinical outcome, with evidence of further elevated risk of progression in patients who received adjuvant chemotherapy. Collectively, these data warrant studies to gain a deeper understanding of PD-L2 in the progression of ER+ breast cancer and may provide rationale for immune checkpoint blockade for this patient group.

Positive margin status after breast-conserving surgery (BCS) is a predictor of higher rates of local recurrence. Intraoperative margin assessment aims to achieve negative surgical margin status at the first operation, thus reducing the re-excision rates that are usually associated with potential surgical complications, increased medical costs, and mental pressure on patients. Microscopy with ultraviolet surface excitation (MUSE) can rapidly image tissue surfaces with subcellular resolution and sharp contrasts by utilizing the nature of the thin optical sectioning thickness of deep ultraviolet light. We have previously imaged 66 fresh human breast specimens that were topically stained with propidium iodide and eosin Y using a customized MUSE system. To achieve objective and automated assessment of MUSE images, a machine learning model is developed for binary (tumor vs. normal) classification of obtained MUSE images. Features extracted by texture analysis and pre-trained convolutional neural networks (CNN) have been investigated for sample descriptions. A sensitivity, specificity, and accuracy better than 90% have been achieved for detecting tumorous specimens. The result suggests the potential of MUSE with machine learning being utilized for intraoperative margin assessment during BCS.

Purpose: To investigate nuclear estrogen receptor α (ERα) and progesterone receptor (PR) immunohistochemistry (IHC) patterns in the stroma surrounding invasive carcinoma and assess associations with clinicopathologic features., Methods: A retrospective database search (1/2017-12/2020) identified breast core biopsies with invasive carcinoma. ERα/PR IHC expression in invasive carcinoma and stromal cells was categorized visually as positive (> 10%), low positive (1-10%) or negative (< 1%). Tumors were divided into 4 subtypes by IHC: Luminal, Luminal HER2, HER2 enriched, and triple negative. Clinicopathologic features associated (univariate p-value < 0.15) with ERα/PR stromal expression were investigated further using stepwise multivariable logistic regression., Results: Of 1512 biopsies, 1278 had accessible IHC. 55.6% (711/1278) and 10.4% (133/1274) of cases showed cancer-associated stromal fibroblast expression of ERα and PR, respectively. Stromal ER positivity was significantly associated with use of the Ventana (with SP1 clone) versus Leica (with 6F11 clone) platform and in cases with Luminal cancer subtype. PR stromal expression was significantly associated with Luminal subtype, obesity, and younger age., Conclusions: Expression of ERα and PR in breast cancer-associated stroma showed associations that suggest both biologic and analytic influence. Reproducible expression patterns may inform expansion of ERα/PR guidelines for the assessment of internal controls., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: To determine outcomes following relocation of frozen section services (FSS) and the implementation of a dedicated gastrointestinal frozen service., Methods: We reviewed our FSS 6 months prior to and following FSS relocation. Satisfaction surveys were sent to surgeons and pathologists. Survey feedback resulted in a pilot of gastrointestinal subspecialist frozen section coverage., Results: There were 1,607 and 1,472 specimens from 667 and 602 patients pre- and post-FSS relocation, respectively. There was a decline in median specimen delivery time to pathology (12 vs 10 minutes, P < .001) and an increase in median time from receipt in pathology to intraoperative diagnosis (20 vs 22 minutes, P = .008) in cases with intrapathology consultation but no change without consultation (median, 19 minutes). Intrapathology consultation decreased from 19.7% (317/1,607) to 11.5% (169/1,472) (P < .001). Discordance rates between frozen section and permanent section remained low and similar (2.0% [33/1,607] vs 2.7% [40/1,472], P = .24). There was no significant change in discordance with dedicated gastrointestinal subspecialty frozen section interpretation., Conclusions: Relocation of FSS and dedicated subspecialty interpretation may improve surgeon satisfaction but can also create workflow challenges. Pathology departments need to achieve a balance between satisfaction and adequacy to establish best frozen section coverage models., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Primary breast neuroendocrine tumors (BNETs) represent < 1% of breast cancers. Diagnosing BNETs can be challenging, and a limited amount of cohort data currently exists in literature. We aimed to describe primary BNET characteristics, treatment modalities, and survival outcomes through the National Cancer Database (NCDB)., Methods: A retrospective cohort analysis was performed using the NCDB from 2004 to 2017. BNET cases were compared with patients with invasive ductal carcinoma (IDC). A matched IDC cohort was created by matching patient age, race, and disease stage. Kaplan-Meier analysis was performed, and hazard ratios (HR) were calculated through the bootstrap sampling method., Results: A total of 1389 BNET and 1,967,401 IDC cases were identified. When compared with IDC patients, BNET patients were older, had more comorbidities, and were more often male (p < 0.01). BNETs were larger, higher grade, and more frequently hormone receptor negative (p < 0.01). While BNET patients were treated with surgery and radiotherapy (p < 0.01) less often compared with IDC patients, they presented at later disease stage (p < 0.001) and received systemic treatment more frequently (53.5% vs. 40%, p < 0.01). Patients with BNET had increased mortality compared with the matched IDC cohort: stage 1 HR 1.8, stage 2 HR 2.0, stage 3 HR 1.8, and stage 4 HR 1.5 (p < 0.001 for all)., Conclusion: Patients with BNET tend to present at higher clinical stages, are more frequently hormone receptor negative, and have inferior overall survival compared with patients with IDC. Further treatment strategies and studies are needed to elucidate optimal therapies to maximize patient outcomes., (© 2022. Society of Surgical Oncology.)

While screening has improved early detection of primary breast cancers, it may also identify metastasis to the breast in rare instances. High-grade carcinomas identified on breast screening may have non-specific morphology and immunoprofiles, making distinction from metastasis problematic. High-grade carcinomas frequently lose expression of specific tumor markers. New evidence specifically challenges GATA3/PAX8 exclusivity in the differential diagnosis of high-grade triple-negative breast cancer and high-grade serous carcinoma of müllerian origin. This case series provides a careful and detailed review of immunohistochemistry interpretation, with focus on PAX8, and the potential pitfalls in making a definitive pathological diagnosis, which is essential in determining oncological treatment options.

Microscopy with ultraviolet surface excitation (MUSE) is increasingly studied for intraoperative assessment of tumor margins during breast-conserving surgery to reduce the re-excision rate. Here we report a two-step classification approach using texture analysis of MUSE images to automate the margin detection. A study dataset consisting of MUSE images from 66 human breast tissues was constructed for model training and validation. Features extracted using six texture analysis methods were investigated for tissue characterization, and a support vector machine was trained for binary classification of image patches within a full image based on selected feature subsets. A weighted majority voting strategy classified a sample as tumor or normal. Using the eight most predictive features ranked by the maximum relevance minimum redundancy and Laplacian scores methods has achieved a sample classification accuracy of 92.4% and 93.0%, respectively. Local binary pattern alone has achieved an accuracy of 90.3%., Competing Interests: The authors have no conflicts of interest to claim., (© 2022 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement.)

Background: Androgen receptor (AR) expression has emerged as a potential prognostic and predictive marker in patients with triple negative breast cancer (TNBC). We conducted a retrospective analysis to evaluate pathologic complete response (pCR) rates, disease-free survival (DFS) and overall survival (OS) in patients with AR positive and AR negative TNBC treated with neoadjuvant chemotherapy. Methods: 107 patients with TNBC subtype, treated with neoadjuvant chemotherapy between June 2006 and March 2016 were evaluated for AR expression. Androgen receptors were evaluated by immunohistochemical staining (clone AR441, Dilution 1:50, Dako-Agilent, Santa Clara, CA) using whole tissue sections from archived paraffin-embedded formalin-fixed (FFPE) blocks. AR positive was defined as ≥10% nuclear stained cells. Correlation of AR expression was examined with age, BMI, race, menopausal status, tumor grade, tumor size, and lymph node involvement, and response and outcomes. Univariate and multivariate analyses were performed to determine an association with AR expression and pathologic response and survival outcomes. Results: Fifty-eight patients with available tumor specimens were stained, with twenty (34.5%) being AR-positive and thirty-eight (65.5%) being AR negative. Median age was 49 years and median follow up was 5.7 years. All patients received anthracycline based neoadjuvant chemotherapy with 13 patients (23%) receiving an additional platinum chemotherapy. BRCA mutation positivity was 7% for the entire group. No differences in age, menopausal status, BMI, race, tumor size and lymph node involvement were observed between the two groups. However, there was a statistically significant difference in tumor grade between the two groups (p=0.008). Overall pCR rate was 28% with no difference between the two groups (30% vs 26%, p=0.56). There was no statistically significant difference in median DFS (5.9 years vs 5.2 years ( p =0.94) and median OS (6.2 years vs 5.4 years, p =0.98) between the AR positive and AR negative groups. Conclusions: Our study did not find an association of AR status and the pathologic responses or survival outcomes in patients with TNBC treated with neoadjuvant chemotherapy. Further studies exploring the prognostic and predictive role of AR in patients with TNBC are warranted., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The 5th edition WHO Classification of Breast Tumours (2019) has introduced changes to our practices. Highlights are presented below, with a focus on modifications to morphological subtype categorization. In addition, we summarize important updates to ER and PR testing made in the 2020 ASCO/CAP guidelines, and briefly discuss PD-L1 and Ki-67 testing in breast cancer.

Importance: Trastuzumab deruxtecan (T-DXd) has shown efficacy in patients with breast cancer with ERBB2 immunohistochemistry (IHC) scores of 1+ or 2+ but not 0 as read in central pathology laboratories. The drug is currently being tested in large randomized clinical trials with registration intent for this patient population., Objective: To determine the suitability of the current standard ERBB2 IHC assays to select patients with low ERBB2 positivity for treatment with T-DXd., Design and Setting: Assessment of data from College of American Pathologists surveys and assessment of analytic data from a Yale University-based study of concordance of 18 pathologists reading 170 breast cancer biopsies., Results: The total survey data set included scores over 2 years from 1391 to 1452 laboratories of 40 ERBB2 cores from each laboratory (20 cores twice a year for a total of 80). College of American Pathologists surveys show that 19% of cases read by the laboratories generate results with less than or equal to 70% concordance for IHC ERBB2 score 0 vs 1+. When 18 pathologists read the scanned slides from a selected set of breast cancer biopsies using a 4-point scale, there was only 26% concordance between 0 and 1+ compared with 58% concordance between 2+ and 3+., Conclusions and Relevance: In this study using a current standard ERBB2 IHC assay, the scoring accuracy for ERBB2 IHC in the low range (0 and 1+) was poor. This inaccuracy in the real world could lead to misassignment of many patients for treatment with T-DXd.

Objectives: There are little data on how changes in the clinical management of axillary lymph nodes in breast cancer have influenced pathologist evaluation of sentinel lymph nodes., Methods: A 14-question survey was sent to Canadian and US breast pathologists at academic institutions (AIs)., Results: Pathologists from 23 AIs responded. Intraoperative evaluation (IOE) is performed for selected cases in 9 AIs, for almost all in 10, and not performed in 4. Thirteen use frozen sections (FSs) alone. During IOE, perinodal fat is completely trimmed in 8, not trimmed in 9, and variable in 2. For FS, in 12 the entire node is submitted at 2-mm intervals. Preferred plane of sectioning is parallel to the long axis in 8 and perpendicular in 12. In 11, a single H&E slide is obtained, whereas 12 opt for multiple levels. In 11, cytokeratin is obtained if necessary, and immunostains are routine in 10. Thirteen consider tumor cells in pericapsular lymphatics as lymphovascular invasion (LVI), and 10 consider it isolated tumor cells (ITCs)., Conclusions: There is dichotomy in practice with near-equal support for routine vs case-by-case multilevel/immunostain evaluation, perpendicular vs parallel sectioning, complete vs incomplete fat removal, and tumor in pericapsular lymphatics as LVI vs ITCs., (© American Society for Clinical Pathology, 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Most breast cancer deaths are caused by estrogen receptor-α–positive (ER + ) disease. Preclinical progress is hampered by a shortage of therapy-naïve ER + tumor models that recapitulate metastatic progression and clinically relevant therapy resistance. Human prolactin (hPRL) is a risk factor for primary and metastatic ER + breast cancer. Because mouse prolactin fails to activate hPRL receptors, we developed a prolactin-humanized Nod-SCID-IL2Rγ (NSG) mouse (NSG-Pro) with physiological hPRL levels. Here, we show that NSG-Pro mice facilitate establishment of therapy-naïve, estrogen-dependent PDX tumors that progress to lethal metastatic disease. Preclinical trials provide first-in-mouse efficacy of pharmacological hPRL suppression on residual ER + human breast cancer metastases and document divergent biology and drug responsiveness of tumors grown in NSG-Pro versus NSG mice. Oncogenomic analyses of PDX lines in NSG-Pro mice revealed clinically relevant therapy-resistance mechanisms and unexpected, potently actionable vulnerabilities such as DNA-repair aberrations. The NSG-Pro mouse unlocks previously inaccessible precision medicine approaches for ER + breast cancers.

Context.—: In recent years, there has been a shift to less aggressive surgical management of the axilla in breast cancer. Consequently, sentinel lymph node evaluation by frozen section (FS) has declined. Additionally, there has been an impetus to decrease efforts in identifying small sentinel lymph node metastases., Objectives.—: To critically evaluate our enterprise performance in evaluating axillary sentinel lymph nodes submitted for FS prior to considering changes in processing., Design.—: A retrospective review (August 1, 2017-July 31, 2019) was conducted to identify sentinel and nonsentinel lymph nodes from 1 academic institution and 2 community sites. Cases were evaluated for grossing technique and discordance between FS and permanent section (PS) due to sampling and/or interpretive error. Clinicopathologic features were assessed., Results.—: Lymph nodes from 426 patients with 432 neoplasms were sent for FS. Serial sectioning at 2-mm intervals was adhered to in 338 of 432 (78.2%). Serial sectioning was significantly lower at the community sites (14 of 60; 23.3%) versus at the academic institution (324 of 372; 87.1%; P < .001). Discordant cases were all false negatives (21 of 432; 4.8%). A total of 7 of 21 false negatives (33.3%) had macrometastatic (>2 mm) disease; of these, 3 were post-neoadjuvant chemotherapy, 3 were neither serially sectioned nor posttherapy, and 1 was a small (0.3-cm) focus. A total of 15 of 16 false negatives due to sampling error were detected on the first permanent section level., Conclusions.—: Standard serial sectioning of sentinel lymph nodes at 2-mm intervals resulted in infrequent false negatives due to macrometastatic disease. A single additional permanent section level is reasonable, given adherence to serial sectioning., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article.

Following lung cancer, breast cancer is the second most common metastatic tumor to the brain, of which triple-negative breast cancer (TNBC) and human epidermal growth factor receptor 2+ (HER2+) breast cancer are the most common subtypes. TNBC does not have standard immunoprofiles and can be difficult to distinguish from other metastases. A tissue microarray was created from 47 patients with breast cancer metastases to the brain and 12 paired breast primaries. Of 47 breast cancer metastases, 24 were HER2+, 14 were TNBC, and 9 were luminal. Forty-five were cytokeratin 7 (CK7) positive, 36 were GATA-binding protein 3 (GATA3) positive, 7 were Sry-related HMg-Box gene 10 (SOX-10) positive, 20 were mammaglobin positive, and 19 were gross cystic disease fluid protein 15 positive. At least one of the CK7, GATA3, or SOX-10 was positive in all TNBC metastases. A panel of CK7, GATA3, and SOX-10 is complementary in the diagnosis of breast cancer brain metastasis. SOX-10 appears to be a specific but not particularly sensitive marker in this context.

Human Epidermal Growth Factor Receptor 2 (HER2), a routinely tested breast cancer marker, is associated with worse prognosis yet increased sensitivity to targeted neoadjuvant therapy (NAT) in breast cancer patients. The presence of HER2 in breast carcinoma can be detected with either immunohistochemistry (IHC) or in situ hybridization (ISH). In this study, we examine the relationship between clinicopathological features, HER2 detection method (IHC vs ISH), and prognostic outcomes in NAT-treated HER2-positive breast cancer patients. We included 99 HER2-positive patients from three academic institutions following 2018 HER2 testing updates and conducted a retrospective correlational study. Seventy-one (72%) were HER2-positive by IHC and 28 (28%) were positive following reflexive ISH. Multivariate analysis showed biomarker status to be significantly associated with pathologic complete response (pCR) (p = 0.003), Residual Cancer Burden (RCB) (p = 0.007), and tumor size downstaging (p = 0.002) and HER2 detection method of IHC to be significantly associated with pCR (p = 0.05), RCB (p = 0.004), and nodal downstaging (p= 0.03). In conclusion, HER2 detection method and biomarker subtype allow for further prognostic stratification of HER2-positive patients when 2018 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline updates are applied., (© 2021 Wiley Periodicals LLC.)

Purpose: Breast magnetic resonance imaging (MRI) has high sensitivity but suffers from low specificity, resulting in many benign breast biopsies for MRI-detected lesions. We sought to compare histologic findings between patients who underwent MRI-guided breast biopsy versus biopsy via other imaging modalities as well as to examine features associated with malignancy in the MRI cohort to help inform MRI-biopsy practice., Methods: A 2-year (2018-2019) retrospective review of breast biopsies at our enterprise was conducted. Biopsies were categorized as stereotactic, ultrasound, MRI, or palpation guided. Pathology was categorized as benign (further divided into nine categories), atypical, or malignant (subdivided into in situ and invasive carcinoma). Pathology was compared between biopsy groups. Clinical, pathologic, and imaging features were compared between pathology groups within the MRI cohort., Results: 5828 biopsies from 4154 patients were reviewed, including 548 MRI-guided biopsies with stratification of MRI-biopsy pathology as follows: 69% benign, 13.8% atypical, and 17.2% malignant. Among benign MRI biopsies, there was higher frequency of "clustered cysts with papillary apocrine metaplasia" (56/548; 10.2%) and lower rate of fibroadenoma/fibroadenomatous change (55/548; 10%) compared to other modalities (158 or 3% and 1144 or 21.7% of 5280 biopsies, respectively). Multivariate analysis revealed indication of breast cancer (p < .0001), ipsilateral cancer (p < .0001) and rapid initial phase kinetics (p = .017) to remain significantly associated with malignant MRI-biopsy pathology., Conclusions: A concurrent or recent breast cancer diagnosis was most predictive of malignancy on MRI-guided breast biopsy. Combined MRI feature evaluation and radiologic-pathologic concordance activities may allow for prognostic refinement and improved risk stratification.

Background: Second opinion review of pathology cases can identify diagnostic errors that impact patient care., Objective: We sought out to determine discrepancy rates and clinical impact of review of pathology cases to reassess our policy of review on all second opinion cases., Methods: All second opinion pathology cases over 1 year (2018) were retrospectively reviewed for discrepancy, multiple pathologist review and clinicopathologic features via chart and slide review. Cases were categorized as no significant discordance, major discordance without management change and major discordance with management change., Results: Among 4239 second opinion cases, 3.7% (156/4239) had major discordance with no change in management and 1% (42/4239) had major discordance with change in management. Discordance was significantly associated with multiple pathologist review at our institution (P < 0.001). Highest rates of discordance were observed for thyroid fine needle aspiration (15.3%, 26/170), tissue biopsy of bone/soft tissue (9.6%), endocrine (8.8%), genitourinary (6.7%), gynecologic (6.2%), hematopathology (4%), gastrointestinal/liver (3.7%) and thoracic (3%) sites., Conclusions: Our study showed a 1% major discordance rate with resulting significant change in clinical management, spread across nearly all subspecialties. Thus, we support recommendations for review of relevant outside pathology material for all patients for which review has the potential to illicit management change such as instituting a major medical or surgical therapy., (© The Author(s) 2021. Published by Oxford University Press on behalf of International Society for Quality in Health Care. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Significance: Re-excision rates for women with invasive breast cancer undergoing breast conserving surgery (or lumpectomy) have decreased in the past decade but remain substantial. This is mainly due to the inability to assess the entire surface of an excised lumpectomy specimen efficiently and accurately during surgery., Aim: The goal of this study was to develop a deep-ultraviolet scanning fluorescence microscope (DUV-FSM) that can be used to accurately and rapidly detect cancer cells on the surface of excised breast tissue., Approach: A DUV-FSM was used to image the surfaces of 47 (31 malignant and 16 normal/benign) fresh breast tissue samples stained in propidium iodide and eosin Y solutions. A set of fluorescence images were obtained from each sample using low magnification (4  ×  ) and fully automated scanning. The images were stitched to form a color image. Three nonmedical evaluators were trained to interpret and assess the fluorescence images. Nuclear-cytoplasm ratio (N/C) was calculated and used for tissue classification., Results: DUV-FSM images a breast sample with subcellular resolution at a speed of 1.0  min  /  cm2. Fluorescence images show excellent visual contrast in color, tissue texture, cell density, and shape between invasive carcinomas and their normal counterparts. Visual interpretation of fluorescence images by nonmedical evaluators was able to distinguish invasive carcinoma from normal samples with high sensitivity (97.62%) and specificity (92.86%). Using N/C alone was able to differentiate patch-level invasive carcinoma from normal breast tissues with reasonable sensitivity (81.5%) and specificity (78.5%)., Conclusions: DUV-FSM achieved a good balance between imaging speed and spatial resolution with excellent contrast, which allows either visual or quantitative detection of invasive cancer cells on the surfaces of a breast surgical specimen.

Objectives: To determine diagnostic, workflow, and economic implications of instituting a gross-only policy at our institution., Methods: Retrospective (2017) key word searches were performed to identify "gross-only" cases for which microscopic evaluation could potentially be omitted, but was performed, and those who underwent gross evaluation per surgeon request. Cases were evaluated for type(s), part(s), block volume, turnaround time, demographics, and diagnosis. Laboratory costs and reimbursement were evaluated., Results: In total, 448 potential gross-only cases with 472 specimens consisted of atherosclerotic plaques (33.5%), bariatric stomach/bowel (32.6%), hernia (15.7%), heart valves (12.7%), and other (5.9%). Four (2.6%) bariatric surgery cases had Helicobacter pylori infection; these were the only cases with "significant" histologic findings. Cost analysis revealed that converting all potential gross-only specimens to gross only would result in overall losses based on average reimbursements, most influenced by bariatric specimens (Current Procedural Terminology code 88307), comprising 65.2% of estimated loss., Conclusions: Establishing a gross-only policy should be guided by established recommendations but institutionally individualized and data driven. It was reasonable for us to establish a gross-only policy for most evaluated specimens, while excluding bariatric stomach specimens in which microscopic pathology could be missed, given the lack of H pylori screening at our institution., (© American Society for Clinical Pathology, 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: Neoadjuvant chemotherapy (NAC) is frequently used for the treatment of breast cancer. We sought to analyse the clinical, morphological and immunohistochemical features of tumours from patients who did not achieve pathological complete response following NAC., Methods and Results: We identified stage I-III post-NAC breast cancers from surgical resections (2000-2016) with evaluable residual invasive carcinoma [ypT1a(m) or greater and ≥15% tumour cellularity]. One hundred and forty-three tumours from 142 patients were included. On univariable analysis, a high (score 3) post-NAC mitotic score (as compared with 1 or 2) was significantly associated with invasive ductal carcinoma (IDC) subtype (P = 0.023), high grade, pushing borders with zones of necrosis, hormone receptor and triple-negative status, lack of hormonal therapy, higher cellularity (P < 0.001), and a higher percentage of tumour-infiltrating lymphocytes (P = 0.016). Multivariable analysis showed a high post-NAC mitotic score to be significantly associated with recurrence, distant metastasis, and shortened survival (hazard ratios of 5.73, 4.49, and 3.68, respectively). High post-NAC mitotic score tumours (n = 32) were IDC and had a high Ki67 proliferation index (median, 55%). Of these, 24 (75%) had pushing borders with zones of necrosis; 19 (79.2%) of these had necrosis on preoperative imaging, and 24 (75%), 15 (46.9%) and four (12.5%) lacked androgen receptor, GATA-3 and cytokeratin 18 expression, respectively., Conclusions: High post-NAC mitotic score breast cancers cause high morbidity and mortality, frequently have pushing borders and zones of necrosis, and may show loss of common 'breast cancer markers'. Our findings support that necrosis in pretreatment studies and post-NAC mitotic score should be routinely reported, as they offer significant additional prognostic information to guide management., (© 2019 John Wiley & Sons Ltd.)

Context.—: Microglandular adenosis is a rare borderline neoplastic lesion of the breast composed of haphazardly located small, round tubules with a single cell layer interspersed within breast stroma and/or adipose tissue. Microglandular adenosis is devoid of a myoepithelial cell layer, and has a characteristic immunophenotype, being positive for S100 and negative for estrogen receptor, progesterone receptor, and HER2/ neu . When associated with cancer, microglandular adenosis and associated invasive carcinoma share the same molecular alterations, including TP53 mutation; therefore, microglandular adenosis is considered a nonobligate precursor of triple (HER2/ neu , estrogen and progesterone receptors)-negative breast carcinoma. Microglandular adenosis is an important diagnostic pitfall as it can be easily mistaken for a low-grade invasive carcinoma., Objective.—: To provide a review of the clinicopathologic features of microglandular adenosis and associated invasive carcinoma, with emphasis on key features separating entities in the differential diagnosis., Data Sources.—: Review of current literature on microglandular adenosis and associated invasive carcinoma and personal experience of authors., Conclusions.—: Microglandular adenosis can mimic breast carcinoma; attention to key features, including morphologic-immunophenotypic correlation, is essential in establishing the diagnosis.

Context.—: Evaluation of estrogen receptor (ER), progesterone receptor (PR), and HER2/neu (HER2) biomarkers is standard of care for all cases of newly diagnosed invasive, recurrent, and metastatic breast cancer. Repeat analysis is also performed in select cases per College of American Pathologists/American Society of Clinical Oncology guidelines and other clinical indications. However, in specific scenarios, preanalytic and analytic variables may pose distinct challenges to testing., Objective.—: To provide a review of select challenges in the testing of commonly performed breast cancer biomarkers ER, PR, and HER2 and outline best practices for overcoming these challenges., Data Sources.—: Review of College of American Pathologists/American Society of Clinical Oncology recommendations, current literature, and personal experience of the author., Conclusions.—: Attention must be given to specimen handling to ensure accurate ER, PR, and HER2 biomarker assessment and appropriate management of breast cancer patients.

Objectives: Current College of American Pathologists/American Society of Clinical Oncology guidelines recommend cold ischemic time (CIT) of 1 hour or less for breast specimens to preserve biomarker expression, although some publications support an acceptable CIT of 4 hours or less. We retrospectively evaluated changes in estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) from biopsy to resection specimens that were triaged to optimize CIT., Methods: We identified breast resection specimens collected after institutional implementation of a triage protocol. Clinicopathologic features were assessed., Results: In total, 295 excisions had a prior malignant diagnosis, with CIT of 4 hours or less and repeat ER, PR, and/or HER2; 230 (78%) had CIT of 1 hour or less, and 65 (22%) had CIT of more than 1 hour but 4 hours or less. Categorical change was seen in 10 (17.9%) of 56 with repeated ER/PR and 38 (13.3%) of 285 with repeated HER2 (of which five [1.8%] had meaningful change)., Conclusions: When CIT is optimized, a meaningful change in biomarker expression is infrequent. This study supports that when specimens are appropriately triaged, CIT of 4 hours or less may be acceptable., (© American Society for Clinical Pathology, 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Metastatic outcomes depend on the interactions of metastatic cells with a specific organ microenvironment. Our previous studies have shown that triple-negative breast cancer (TNBC) MDA-MB-231 cells passaged in astrocyte-conditioned medium (ACM) show proclivity to form brain metastases, but the underlying mechanism is unknown. The combination of microarray analysis, qPCR, and ELISA assay were carried out to demonstrate the ACM-induced expression of angiopoietin-like 4 (ANGPTL4) in TNBC cells. A stable ANGPTL4 -knockdown MDA-MB-231 cell line was generated by ANGPTL4 short-hairpin RNA (shRNA) and inoculated into mice via left ventricular injection to evaluate the role of ANGPTL4 in brain metastasis formation. The approaches of siRNA, neutralizing antibodies, inhibitors, and immunoprecipitation were used to demonstrate the involved signaling molecules. We first found that ACM-conditioned TNBC cells upregulated the expression of ANGPTL4, a secreted glycoprotein whose effect on tumor progression is known to be tumor microenvironment- and tumor-type dependent. Knockdown of ANGPTL4 in TNBC MDA-MB-231 cells with shRNA decreased ACM-induced tumor cell metastatic growth in the brain and attributed to survival in a mouse model. Furthermore, we identified that astrocytes produced transforming growth factor-beta 2 (TGF-β2), which in part is responsible for upregulation of ANGPTL4 expression in TNBC through induction of SMAD signaling. Moreover, we identified that tumor cells communicate with astrocytes, where tumor cell-derived interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α) increased the expression of TGF-β2 in astrocytes. Collectively, these findings indicate that the invading TNBC cells interact with astrocytes in the brain microenvironment that facilitates brain metastases of TNBC cells through a TGF-β2/ANGPTL4 axis. This provides groundwork to target ANGPTL4 as a treatment for breast cancer brain metastases., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2019.)

A diagnosis of papilloma with atypia on core biopsy (CB) requires excision, as the risk of associated malignancy is high (average 36.9%). The management of benign intraductal papillomas (IP) diagnosed on CB is controversial due to varying upgradation rates (0-29%, average 7%) reported on excision. Our aim was to study the clinical, radiological, and pathological features associated with benign IP upgradation at our institution. An electronic data base search (keyword papilloma), from Jan. 2000-Aug. 2015 identified 258 CBs. After exclusions, 104 CBs of benign IPs with subsequent excisions from 101 females were reviewed. The clinical, radiological, and pathological features between IPs that had upgrades (defined as malignancy or atypical ductal hyperplasia) and non-upgraded IPs were compared using descriptive statistics. Studies of benign IP on CB with at least 50 follow-up excisions published between 2008 and 2016 were analyzed. Residual IP was present in 83.6% (87/104) of reviewed excisions. There were six upgrades (5.6%) (4 to malignancy (3.8%) and 2 to atypical ductal hyperplasia).Upgrades were associated with mass on imaging with a trend to significance (p = .05). Two cases with malignant upgrade had a history of contralateral cancer. An analysis of 25 published studies showed an average malignant upgrade of 5.7% (182/3164). The majority of benign IP are not upgraded on excision; thus, not all need to be excised. Those that may warrant excision are those with prior history of carcinoma, those with a mass on imaging, and/or suboptimal or imaging-discordant CB sampling.

Invasive papillary carcinoma (IPC) and glycogen-rich clear cell carcinoma (GRCCC) are rare primary breast carcinomas. IPC typically have favorable prognosis, whereas the prognosis of GRCCC is less established. We report a unique case of high-grade invasive mammary carcinoma with mixed IPC and GRCCC features. We review the imaging and pathologic features and discuss prognosis of these unusual breast cancer subtypes.

Objective: Pleomorphic lobular carcinoma in situ (PLCIS) is an aggressive subtype of lobular carcinoma in situ treated similarly to ductal carcinoma in situ. The purpose of this study was to determine the imaging findings, upgrade rate of PLCIS at core needle biopsy (CNB), and the treatment and outcomes of these patients., Materials and Methods: This retrospective single-institution study included women with PLCIS at CNB or excisional biopsy without concomitant DCIS or invasive carcinoma between January 1, 1999, and July 20, 2016. Imaging findings, detection mode, treatment, and outcomes were reviewed. Retrospective review of the images was performed. Upgrade rate to ductal carcinoma in situ or invasive carcinoma at lumpectomy was calculated., Results: Twenty-one patients had a finding of PLCIS at CNB (n = 16) or excisional biopsy (n = 5). Four of 15 (27%; 95% CI, 4-49%) cases of PLCIS at CNB were upgraded to DCIS (two cases) or invasive lobular cancer (two cases) at lumpectomy (one patient declined excision). No unique mammographic features were predictive of need to upgrade or extent of disease. Among the patients with pure PLCIS (not upgraded), 13 of 16 (81%) presented with fine pleomorphic calcifications on screening mammograms, 1 of 16 (6%) with distortion and calcifications, 1 of 16 (6%) with a mass, and 1 of 16 (6%) with nonmass enhancement at MRI. The median imaging size was 11 mm (mean, 14 mm; range, 3-47 mm). Twelve of 16 (75%) patients were treated with lumpectomy and 4 of 16 (25%) with mastectomy. Eight of 16 (50%) patients received adjuvant hormonal therapy, and 2 of 16 (17%) received radiation. There were no local recurrences., Conclusion: PLCIS most commonly presented as fine pleomorphic calcifications on mammograms and had a high upgrade rate after CNB. CNB diagnosis of PLCIS requires surgical excision.