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Human epidermal growth factor receptor 2 (HER2)-positive breast carcinoma (BC) encompasses a spectrum of molecular subtypes, characterized by varying HER2/CEP17 ratios and HER2 copy numbers, influencing responses to anti-HER2 therapy. This study stratified HER2 fluorescence in situ hybridization (FISH)-positive patients into 3 distinct groups-group 1 with high copy number (G1-HC: ratio ≥2, copy number ≥6), group 1 with low copy number (G1-LC: ratio ≥2, copy number ≥4 and <6), and group 3 (G3: ratio <2.0, copy number ≥6.0)-and evaluated their clinicopathologic features, response to anti-HER2 therapy, and outcomes. In a cohort of 2702 continuous primary BCs, G1-HC BCs accounted for 304 cases (11.3%), G1-LC for 37 cases (1.4%), and G3 for 75 cases (2.8%). G1-HC BCs were associated with younger age, higher tumor grade, and estrogen receptor negativity compared with G1-LC BCs. Furthermore, G1-HC BCs exhibited increased progesterone receptor negativity and HER2 immunohistochemistry 3+ compared with G1-LC and G3 BCs. Analysis of the subgroup of HER2 immunohistochemistry 2+-only cases (n = 166) showed similar results. Notably, G1-HC patients exhibited significantly enhanced responses to anti-HER2 neoadjuvant chemotherapy compared with G1-LC and G3 patients. Conversely, G1-LC patients displayed a lower likelihood of disease-free status compared with G1-HC and G3 patients, albeit with no significant differences in overall survival, distant metastasis, or local recurrence among the groups. These findings offer valuable clinicopathologic insights into different HER2 FISH positive subgroups, potentially informing future criteria for interpreting HER2 FISH results., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Accurate recurrence risk stratification is crucial for optimizing treatment plans for breast cancer patients. Current prognostic tools like Oncotype DX (ODX) offer valuable genomic insights for HR+/HER2- patients but are limited by cost and accessibility, particularly in underserved populations. In this study, we present Deep-BCR-Auto, a deep learning-based computational pathology approach that predicts breast cancer recurrence risk from routine H&E-stained whole slide images (WSIs). Our methodology was validated on two independent cohorts: the TCGA-BRCA dataset and an in-house dataset from The Ohio State University (OSU). Deep-BCR-Auto demonstrated robust performance in stratifying patients into low- and high-recurrence risk categories. On the TCGA-BRCA dataset, the model achieved an area under the receiver operating characteristic curve (AUROC) of 0.827, significantly outperforming existing weakly supervised models (p=0.041). In the independent OSU dataset, Deep-BCR-Auto maintained strong generalizability, achieving an AUROC of 0.832, along with 82.0% accuracy, 85.0% specificity, and 67.7% sensitivity. These findings highlight the potential of computational pathology as a cost-effective alternative for recurrence risk assessment, broadening access to personalized treatment strategies. This study underscores the clinical utility of integrating deep learning-based computational pathology into routine pathological assessment for breast cancer prognosis across diverse clinical settings.

Aims: Human epidermal growth factor receptor 2 (HER2) expression is an important biomarker in breast cancer (BC). Most BC cases categorised as HER2-negative (HER2-) express low levels of HER2 [immunohistochemistry (IHC) 1+ or IHC 2+/in-situ hybridisation not amplified (ISH-)] and represent a clinically relevant therapeutic category that is amenable to targeted therapy using a recently approved HER2-directed antibody-drug conjugate. A group of practising pathologists, with expertise in breast pathology and BC biomarker testing, outline best practices and guidance for achieving consensus in HER2 IHC scoring for BC., Methods and Results: The authors describe current knowledge and challenges of IHC testing and scoring of HER2-low expressing BC and provide best practices and guidance for accurate identification of BCs expressing low levels of HER2. These expert pathologists propose an algorithm for assessing HER2 expression with validated IHC assays and incorporate the 2023 American Society of Clinical Oncology and College of American Pathologist guideline update. The authors also provide guidance on when to seek consensus for HER2 IHC scoring, how to incorporate HER2-low into IHC reporting and present examples of HER2 IHC staining, including challenging cases., Conclusions: Awareness of BC cases that are negative for HER protein overexpression/gene amplification and the related clinical relevance for targeted therapy highlight the importance of accurate HER2 IHC scoring for optimal treatment selection., (© 2024 The Author(s). Histopathology published by John Wiley & Sons Ltd.)

In DESTINY-Breast04 (DB-04), safety and efficacy of HER2-targeted antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) in previously treated HER2-low unresectable/metastatic breast cancer were established. This manuscript describes the analytical validation of PATHWAY Anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody (PATHWAY HER2 (4B5)) to assess HER2-low status and its clinical performance in DB-04. Preanalytical processing and tissue staining parameters were evaluated to determine their impact on HER2 scoring. The recommended antibody staining procedure provided the optimal tumor staining, and deviations in cell conditioning and/or antibody incubation times resulted in unacceptable negative control staining and/or HER2-low status changes. Comparisons between antibody lots, kit lots, instruments, and day-to-day runs showed overall percent agreements (OPAs) exceeding 97.9%. Inter-laboratory reproducibility showed OPAs of ≥97.4% for all study endpoints. PATHWAY HER2 (4B5) was utilized in DB-04 for patient selection using 1340 tumor samples (59.0% metastatic, 40.7% primary, (0.3% missing data); 74.3% biopsy, 25.7% resection/excisions). Overall, 77.6% (823/1060) of samples were HER2-low by both central and local testing, with the level of concordance differing by sample region of origin and collection date. In DB-04, the efficacy of T-DXd over chemotherapy of physician's choice was consistent, regardless of the characteristics of the sample used (primary or metastatic, archival, or newly collected, biopsy or excision/resection). These results demonstrate that PATHWAY HER2 (4B5) is precise and reproducible for scoring HER2-low status and can be used with multiple breast cancer sample types for reliably identifying patients whose tumors have HER2-low expression and are likely to derive clinical benefit from T-DXd., (© 2023. The Author(s).)

Context.—: Human epidermal growth factor receptor 2 (HER2) status in breast cancer is currently classified as negative or positive for selecting patients for anti-HER2 targeted therapy. The evolution of the HER2 status has included a new HER2-low category defined as an HER2 immunohistochemistry score of 1+ or 2+ without gene amplification. This new category opens the door to a targetable HER2-low breast cancer population for which new treatments may be effective., Objective.—: To review the current literature on the emerging category of breast cancers with low HER2 protein expression, including the clinical, histopathologic, and molecular features, and outline the clinical trials and best practice recommendations for identifying HER2-low-expressing breast cancers by immunohistochemistry., Data Sources.—: We conducted a literature review based on peer-reviewed original articles, review articles, regulatory communications, ongoing and past clinical trials identified through ClinicalTrials.gov, and the authors' practice experience., Conclusions.—: The availability of new targeted therapy potentially effective for patients with breast cancers with low HER2 protein expression requires multidisciplinary recognition. In particular, pathologists need to recognize and identify this category to allow the optimal selection of patients for targeted therapy., (© 2024 College of American Pathologists.)

Inflammatory breast cancer (IBC) poses an ongoing challenge as rates of disease recurrence and mortality remain high compared to stage-matched controls. However, frontline therapy has evolved through the years, including the widespread use of neoadjuvant chemotherapy (NAC) given the prognostic importance of pathologic complete response (pCR). Due to these sweeping changes, we need new data to assess current recurrence and survival outcomes for locally advanced IBC in the context of matched non-inflammatory controls. We conducted a retrospective analysis of institutional IBC data from 2010 to 2016 with the primary objective of comparing overall survival (OS), relapse-free survival (RFS), and distant relapse-free survival (DRFS). We matched IBC patients to non-inflammatory controls based on age, receptor status, tumor grade, clinical stage, and receipt of prior NAC. Secondary objectives included assessing pCR rates and identifying prognostic factors. Among NAC recipients, we observed similar pCR rates (47.6 % vs. 49.4 %, p = 0.88) between IBC (n = 84) and matched non-IBC (n = 81) cohorts. However, we noted a significant worsening of OS (p = 0.0001), RFS (p = 0.0001), and DRFS (p = 0.001) in the IBC group. Specifically, 5-year OS in the IBC cohort was 58.9 % vs. 86.7 % for matched controls (p = 0.0003). Older age was a weak negative predictor for OS (HR 1.03, p = 0.001) and RFS (HR 1.02, p = 0.01). For DRFS, older age was also a weak negative predictor (HR 1.02, p = 0.02), whereas the use of NAC was a positive predictor (HR 0.47, p = 0.02). Despite no clear difference in pCR, survival outcomes remain poor for IBC compared to matched non-inflammatory controls., Competing Interests: Declaration of competing interest Dr. Ko Un Park is a consultant with Bayer LLC. All remaining authors have no financial or non-financial relationships or activities to declare in relation to this article., (Copyright © 2023. Published by Elsevier Ltd.)

In response to recent clinical trials that demonstrate the clinical benefit of antibody-drug conjugate drug therapy in breast cancer (BC) with human epidermal growth factor 2 (HER2) immunohistochemical scores of 1+ or 2+ and negative in situ hybridization results, a new concept of "HER2-low BC" has emerged to describe this newly relevant therapeutic category of BC. Clinical recognition of HER2-low BC has caused a paradigm shift in the therapeutic landscape and management of patients with BC and resulted in rapid changes in clinical practice guidelines. In addition the American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) recently updated their HER2 Guidelines Recommendations to specifically address HER2-low BC. A literature search in PubMed of peer-reviewed articles, regulatory communications, and relevant practice guidelines pertaining to HER2-low BC was conducted. In this review, we have summarized current published knowledge regarding the clinicopathologic and molecular features, diagnostic criteria, and most current guideline recommendations regarding HER2-low BC, and also highlight ongoing practical and diagnostic challenges when identifying HER2-low BC in routine clinical practice., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: The immunomodulatory impact of corticosteroids and concurrent chemotherapy is poorly understood within triple-negative breast cancer (TNBC). On a biochemical level, steroids have been linked to the signaling of chemotherapy-resistant pathways. However, on a clinical level, steroids play an essential role in chemotherapy tolerance through the prevention of chemotherapy-induced nausea and vomiting (CINV) and hypersensitivity reactions. Given these conflicting roles, we wanted to evaluate this interplay more rigorously in the context of early-stage TNBC., Methods: We performed a retrospective analysis of patients with operable TNBC who received neoadjuvant chemotherapy (NAC) between January 2012 and November 2018, with the primary goal of examining the dose-dependent relationship between pathological complete response (pCR) rates and corticosteroid use. Secondary endpoints included the impact of steroid dosing on overall survival (OS) and recurrence-free survival (RFS), along with a breakdown in pCR rates based on steroid doses provided during each chemotherapy phase. Further adjusted analyses were performed based on patient age, diabetic status, and anatomical stage. Finally, we explored the relationship between tumor-infiltrating lymphocytes (TILs) seen on tissue samples at baseline and dexamethasone doses in terms of pCR rates., Results: In total, of the 174 patients screened within this study period, 116 met full eligibility criteria. Of these eligible patients, all were female, with a median age of 51.5 years (27.0 to 74.0) and a mean body mass index (BMI) of 29.7 [standard deviation (SD) 7.04]. The majority were nondiabetic (80.2%). For cancer stage, 69.8% (n = 81) had stage 2 breast cancer. We found no statistically significant association between pCR rates and dexamethasone use, both in terms of the total dose (p = 0.55) and mean dose per NAC cycle (p = 0.74). Similarly, no difference was noted when adjusting for diabetic status, metformin use, or age at diagnosis, regardless of the total steroid dose provided (p = 0.72) or mean dose per cycle (p = 0.49). No meaningful changes to pCR rate were seen with higher mean or higher total steroid doses during the paclitaxel (T) phase (adjusted p = 0.16 and p = 0.76, respectively) or doxorubicin and cyclophosphamide (AC) phase (adjusted p = 0.83 and p = 0.77, respectively). Furthermore, we found no clinically significant association between dexamethasone dose and either RFS (p = 0.45) or OS (p = 0.89). Of the 56 patients who had available pre-treatment biopsy tissue samples, 27 achieved pCR, with higher TILs at baseline being associated with higher pCR rates, regardless of the mean dexamethasone dose used., Conclusion: Our findings demonstrate that dexamethasone has no clinically significant impact on pCR, RFS, or OS when given concurrently with NAC in patients with curative TNBC, regardless of diabetic status., (© 2023. The Author(s).)

Human epidermal growth factor receptor 2 (HER2)-low breast cancer, defined by an immunohistochemical (IHC) score of 1+ or 2+ with negative in situ hybridization, is emerging as a predictive marker for the use of the antibody-drug conjugate. To understand how this category differs from HER2-zero cases, we investigated clinicopathological characteristics and HER2 fluorescence in situ hybridization results in a large cohort of 1309 continuous HER2-negative invasive breast carcinomas from 2018 to 2021 evaluated by the Food and Drug Administration-approved HER2 IHC test. Additionally, we compared Oncotype DX recurrence scores and HER2 mRNA expression between HER-low and HER2-zero cases in a separate cohort of 438 estrogen receptor-positive (ER+) early-stage breast carcinoma cases from 2014 to 2016. Based on the cohort from 2018 to 2021, the incidence of HER2-low breast cancers was approximately 54%. HER2-low cases had less frequent grade 3 morphology, less frequent triple-negative results, ER and progesterone receptor negativity, and a higher mean HER2 copy number and HER2/CEP17 ratio than HER2-zero cases (P < .0001). Among ER+ cases, HER2-low cases showed significantly less frequent Nottingham grade 3 tumors. In the cohort from 2014 to 2016, HER2-low cases showed significantly higher ER+ percentages, fewer progesterone receptor-negative cases, lower Oncotype DX recurrence scores, and higher HER2 mRNA expression scores than HER2-zero cases. In summary, this is the first study, to our knowledge, using a large cohort of continuous cases evaluated by the Food and Drug Administration-approved HER2 IHC companion diagnostic test for HER2-low expression and HER2 fluorescence in situ hybridization profile in a real-world setting. Although HER2-low cases showed a higher HER2 copy number, ratio, and mRNA level than HER2-zero cases statistically, such small differences are unlikely to be biologically or clinically meaningful. However, our study suggests that HER2-low/ER+ early-stage breast carcinoma may represent a less aggressive group of breast carcinoma, given its association with a lower Nottingham grade and Oncotype DX recurrence score., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Intravascular papillary endothelial hyperplasia (Masson's Tumor) is a rare benign endothelial vascular lesion that can mimic angiosarcoma if not properly recognized. It represents less than 2% of all vascular tumors, but has been seen in the postradiation setting, which also makes differentiating it from angiosarcoma crucial. It is classically characterized as a circumscribed, intravascular mass that is hypoechoic on ultrasound, and T1 isointense and T2 heterogenous on MRI with variable enhancement. Histologically, it demonstrates papillary architecture without significant atypia, and associated vascular thrombus. Although it typically occurs in the soft tissues of the trunk and neck, a very small percentage of cases have been found in the breast. The following case will involve a 64-year-old female with a Masson's tumor involving the capsule of her left breast implant, in the setting of previously treated ductal carcinoma in situ, which was surgically excised and irradiated over 20 years prior., (© 2023 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)

Background: Very few studies have investigated mismatch repair (MMR) deficiency in breast carcinoma (BC) in clinical setting. Given the recent approval of Pembrolizumab for solid tumors with MMR deficiency, we screened clinically advanced breast carcinoma patients for immunotherapy by examining their MMR status., Patients and Methods: The cohort consisted of 163 clinical advanced BCs, including 5 primary, 14 locally recurrent, and 144 metastatic BCs. Immunohistochemistry (IHC) with anti-MMR proteins or next generation sequencing (NGS) to detect microsatellite instability was performed to evaluate MMR status. The relationship between MMR status and clinicopathologic characteristics was evaluated., Results: Among 163 advanced BCs, 19 were hormone receptor (HR)-positive (≥ 10%)/HER2-negative, 17 were HER2+, and 127 were TNBCs/low HR-positive (< 10%). MMR status was evaluated by IHC in 131 cases and by NGS in 32 cases. Among all cases, only 1 case (0.6%) showed MMR deficiency. The case with MMR deficiency showed loss of MLH1 and PMS2 proteins, but no hypermethylation of MLH1 promoter. Sequencing analysis revealed MLH1 genetic alteration with a splice site mutation (208-1G > A), which results in disruption of the N-terminal ATPase-containing domain (amino acids 25-336). All 127 TNBCs/low HR-positive BCs showed preserved MMR. PD-L1 (SP142) testing was performed in 66 cases with 18 (27%) as positive and 48 (73%) as negative, and its expression showed no correlation with MMR status., Conclusion: MMR deficiency exists in an extremely low percentage of breast carcinomas, including TNBCs, suggesting a routine MMR testing to screen BC patients for immunotherapy may not be cost effective., (Copyright © 2022. Published by Elsevier Inc.)

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.

Anastomosing hemangioma (AH), a rare benign genitourinary tract hemangioma is subject to frequent misdiagnosis due to its rarity and clinical, histological, and immunohistochemical similarities it shares with several diagnoses, including well-differentiated angiosarcoma (AS). This is particularly true of angiosarcoma, nearly identical to AH when presented in tissue samples of limited size. Lack of specific clinical and radiologic manifestations on initial preoperative assessment, coupled with limited diagnostic experience or awareness, can lead to misinterpretation of this entity, potentially leading to unnecessary clinical management. We present an initial misdiagnosis of AS which, upon review of the entire lesion, was identified as AH., (© 2022 Published by Elsevier Inc.)

Invasive lobular carcinoma (ILC) accounts for 10% to 15% of breast cancers in the United States, 80% of which are estrogen receptor (ER)-positive, with an unusual metastatic pattern of spread to sites such as the serosa, meninges, and ovaries, among others. Lobular cancer presents significant challenges in detection and clinical management given its multifocality and multicentricity at presentation. Despite the unique features of ILC, it is often lumped with hormone receptor-positive invasive ductal cancers (IDC); consequently, ILC screening, treatment, and follow-up strategies are largely based on data from IDC. Despite both being treated as ER-positive breast cancer, querying the Cancer Genome Atlas database shows distinctive molecular aberrations in ILC compared with IDC, such as E-cadherin loss (66% vs. 3%), FOXA1 mutations (7% vs. 2%), and GATA3 mutations (5% vs. 20%). Moreover, compared with patients with IDC, patients with ILC are less likely to undergo breast-conserving surgery, with lower rates of complete response following therapy as these tumors are less chemosensitive. Taken together, this suggests that ILC is biologically distinct, which may influence tumorigenesis and therapeutic strategies. Long-term survival and clinical outcomes in patients with ILC are worse than in stage- and grade-matched patients with IDC; therefore, nuanced criteria are needed to better define treatment goals and protocols tailored to ILC's unique biology. This comprehensive review highlights the histologic and clinicopathologic features that distinguish ILC from IDC, with an in-depth discussion of ILC's molecular alterations and biomarkers, clinical trials and treatment strategies, and future targets for therapy. IMPLICATIONS FOR PRACTICE: The majority of invasive lobular breast cancers (ILCs) are hormone receptor (HR)-positive and low grade. Clinically, ILC is treated similar to HR-positive invasive ductal cancer (IDC). However, ILC differs distinctly from IDC in its clinicopathologic characteristics and molecular alterations. ILC also differs in response to systemic therapy, with studies showing ILC as less sensitive to chemotherapy. Patients with ILC have worse clinical outcomes with late recurrences. Despite these differences, clinical trials treat HR-positive breast cancers as a single disease, and there is an unmet need for studies addressing the unique challenges faced by patients diagnosed with ILC., (© 2021 AlphaMed Press.)

Ductal carcinoma in situ (DCIS) in males is rare, and there are limited data aimed at understanding the adequate workup, imaging, and follow-up for men who present with breast masses. Attention should be given to black men who have a higher cancer risk and worse prognosis than white male counterparts., Competing Interests: None declared., (© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

Objective: The primary objective of this study was to delineate differences in management, overall and distant disease-free survival in males diagnosed with breast cancer and treated at The Ohio State University Comprehensive Cancer Center as compared to comprehensively matched female subjects. Secondary objectives included assessment of clinical and histopathologic features and recurrence score, as measured by Oncotype DX and the modified Magee equation #2., Materials and Methods: This single institution retrospective study compared male and comprehensively matched female patients (1:2) with stage I-III breast cancer between 1994 and 2014. Recurrence risk was estimated using a modified Magee equation. Overall survival and distant disease-free survival were estimated and compared using Kaplan-Meier and Log-rank methods., Results: Forty-five male breast cancer patients were included (stage I: 26.7%; stage II: 53.3%; stage III: 20.0%; hormone receptor positive: 97.8%; human epidermal growth factor receptor 2 negative: 84.4%) with a median age of 63.8 (43.0-79.4) years at diagnosis. Intermediate and low recurrence scores were most common in male and female patients respectively; mean score was similar between groups (20.3 vs. 19.8). The proportion of male breast cancer patients treated with adjuvant chemotherapy and post-mastectomy radiation was lower compared to female patients (42.2% vs. 65.3%, p=0.013; 22.7% vs. 44.4%, p=0.030, respectively). Overall survival and distant disease-free survival between male and female patients were similar., Conclusion: Male breast cancer patient outcomes were similar compared to well-matched female patients suggesting that breast cancer specific factors are more prognostic than gender., Competing Interests: Conflict of Interest: The authors have no conflicts of interest to declare., (Copyright © 2020 Turkish Federation of Breast Diseases Associations.)

Primary small cell carcinoma of the breast (SCCB) is a rare tumor subtype comprising <0.1% of all breast carcinomas. Here we present a case of thyroid transcription factor-1 (TTF-1) positive SCCB that recurred within 3 years of diagnosis in the lung and lymph nodes. Given the small number of cases, no clear guidelines exist on the appropriate management of patients with these aggressive tumors. We present a case study and review the current literature to highlight the knowledge gaps and needs of patients with these rare tumors. A 50-year-old premenopausal woman with no family history, presented with a palpable right breast mass. Biopsy was consistent with primary SCCB that was poorly differentiated, positive for synaptophysin and chromogranin and TTF-1 and presence of ductal carcinoma in situ component showing neuroendocrine differentiation. Imaging with PET, CT, and MRI brain excluded any other sites of primary disease. She underwent a right lumpectomy with axillary lymph node dissection and was treated with adjuvant cisplatin-based chemotherapy and concurrent radiation therapy. Thirty-four months later, routine scans showed a new right lower-lobe lung nodule and an enlarged sub-carinal node that was proven to be poorly differentiated neuroendocrine cancer. This case report sheds light on a rarely described disease and provides a comprehensive approach to diagnosis and management. Primary SCCB is an extremely rare, aggressive form of breast cancer that is molecularly and histologically similar to SCLC. However, a review of the literature highlights recent mutational analyses that show important differences between these two cancer types, including an increase in PIK3CA mutations in primary SCCB. Further studies, including genomic analyses are needed to better define this malignancy and to develop a standard treatment., (Copyright © 2020 Boutrid, Kassem, Tozbikian, Morgan, White, Shah, Vandeusen, Sardesai, Williams, Stover, Lustberg, Wesolowski, Pudavalli, Williams, Konda, Fortier, Carbone, Ramaswamy and Cherian.)

Background: Subjective qualitative descriptors are sometimes used to describe atypical breast lesions diagnosed on core needle biopsy (CNB) which are limited in extent. In clinical practice, this terminology is used to imply a lower expected risk of upgrade on surgical excision (EXC). It is uncertain how subjective terminology impacts clinical management., Methods: We conducted a retrospective review of CNB with atypia and compared the EXC and upgrade rates of atypical ductal hyperplasia (ADH) and flat epithelial atypia (FEA) to lesions described as "focal" atypical ductal hyperplasia (FADH), to determine the impact of this diagnostic phrasing on surgical management and risk of malignancy., Results: FADH and ADH were excised at similar rates (82% vs. 78%). FADH lesions showed a similar upgrade rate (13%) compared to non-focal ADH (10%), and both showed a trend towards higher upgrade and EXC rates compared to FEA. ADH, FADH and FEA all had an upgrade risk that warranted EXC. In non-upgraded EXC, for each diagnostic category we observed similar rates of residual atypia in the EXC., Conclusions: Pathologists should avoid the use of qualitative descriptors when describing ADH on CNB because of the potential of this terminology to influence clinical decision making which is unwarranted.

Objectives: Either immunohistochemistry (IHC) or in situ hybridization (ISH) can be used to determine human epidermal growth factor receptor 2 (HER2) status. Breast cancers (BCs) with HER2 IHC-negative (IHC-) and ISH-amplified (ISH+) results have been rarely reported but not well studied. We investigated the frequency of HER2 IHC-/ISH+ BCs and their response to anti-HER2 neoadjuvant chemotherapy (NAC)., Methods: Seventeen BCs with HER2 IHC-/ISH+ results were identified from 1,107 consecutive invasive BCs (1.5%, 17/1,107)., Results: Gene protein assay confirmed the original HER2 IHC and ISH results. Increased HER2 RNA level was detected in HER2 IHC-/ISH+ cases compared with HER2 IHC-/ISH- cases. Eight patients had anti-HER2 NAC; three had pathologic complete response, and five had residual tumors., Conclusions: A small percentage of patients (1.5%) showed discordant HER2 IHC and ISH results (IHC-/ISH+) and would have lost the opportunity for potentially beneficial anti-HER2-targeted therapy if only HER2 IHC testing had been used.

This unusual case of concurrent eccrine adenocarcinoma, phyllodes tumor, and multinodular goiter serves to alert the oncologic community to the high prevalence of second cancers after childhood radiotherapy. Increased surveillance and index of suspicion are recommended to successfully diagnose and treat second primary cancers in this vulnerable population.

Background: The Ki67 Index has been extensively studied as a prognostic biomarker in breast cancer. However, its clinical adoption is largely hampered by the lack of a standardized method to assess Ki67 that limits inter-laboratory reproducibility. It is important to standardize the computation of the Ki67 Index before it can be effectively used in clincial practice., Method: In this study, we develop a systematic approach towards standardization of the Ki67 Index. We first create the ground truth consisting of tumor positive and tumor negative nuclei by registering adjacent breast tissue sections stained with Ki67 and H&E. The registration is followed by segmentation of positive and negative nuclei within tumor regions from Ki67 images. The true Ki67 Index is then approximated with a linear model of the area of positive to the total area of tumor nuclei., Results: When tested on 75 images of Ki67 stained breast cancer biopsies, the proposed method resulted in an average root mean square error of 3.34. In comparison, an expert pathologist resulted in an average root mean square error of 9.98 and an existing automated approach produced an average root mean square error of 5.64., Conclusions: We show that it is possible to approximate the true Ki67 Index accurately without detecting individual nuclei and also statically demonstrate the weaknesses of commonly adopted approaches that use both tumor and non-tumor regions together while compensating for the latter with higher order approximations.

The importance of the tumor-associated stroma in cancer progression is clear. However, it remains uncertain whether early events in the stroma are capable of initiating breast tumorigenesis. Here, we show that in the mammary glands of non-tumor bearing mice, stromal-specific phosphatase and tensin homolog (Pten) deletion invokes radiation-induced genomic instability in neighboring epithelium. In these animals, a single dose of whole-body radiation causes focal mammary lobuloalveolar hyperplasia through paracrine epidermal growth factor receptor (EGFR) activation, and EGFR inhibition abrogates these cellular changes. By analyzing human tissue, we discover that stromal PTEN is lost in a subset of normal breast samples obtained from reduction mammoplasty, and is predictive of recurrence in breast cancer patients. Combined, these data indicate that diagnostic or therapeutic chest radiation may predispose patients with decreased stromal PTEN expression to secondary breast cancer, and that prophylactic EGFR inhibition may reduce this risk.

In pathology, Immunohistochemical staining (IHC) of tissue sections is regularly used to diagnose and grade malignant tumors. Typically, IHC stain interpretation is rendered by a trained pathologist using a manual method, which consists of counting each positively- and negatively-stained cell under a microscope. The manual enumeration suffers from poor reproducibility even in the hands of expert pathologists. To facilitate this process, we propose a novel method to create artificial datasets with the known ground truth which allows us to analyze the recall, precision, accuracy, and intra- and inter-observer variability in a systematic manner, enabling us to compare different computer analysis approaches. Our method employs a conditional Generative Adversarial Network that uses a database of Ki67 stained tissues of breast cancer patients to generate synthetic digital slides. Our experiments show that synthetic images are indistinguishable from real images. Six readers (three pathologists and three image analysts) tried to differentiate 15 real from 15 synthetic images and the probability that the average reader would be able to correctly classify an image as synthetic or real more than 50% of the time was only 44.7%.

The consequences of patient identification errors due to specimen mislabeling can be deleterious. We describe two near-miss events involving mislabeled breast specimens from two patients who sought treatment at our institution. In both cases, microscopic review of the slides identified inconsistencies between the histologic findings and patient age, unveiling specimen identification errors. By correlating the clinical information with the microscopic findings, we identified mistakes that had occurred at the time of specimen accessioning at the original laboratories. In both cases, thanks to a timely reassignment of the specimens, the patients suffered no harm. These cases highlight the importance of routine clinical and pathologic correlation as a critical component of quality assurance and patient safety. A review of possible specimen identification errors in the anatomic pathology setting is presented., (© 2017 Wiley Periodicals, Inc.)

Objectives: This study aimed to compare a modified Magee equation with Oncotype DX (Genomic Health, Redwood City, CA) recurrence score (RS) and identify patients who are unlikely to benefit from Oncotype DX., Methods: Magee equation RS was calculated in 438 cases and correlated with Oncotype DX RS., Results: The Pearson correlation coefficient ( r ) for the Magee equation and Oncotype DX RS was 0.6645 ( P  < .00001), and the overall agreement was 66.4%. All cases (11.6%) with a Magee equation RS greater than 30 or 11 or less had been correctly predicted to have either high Oncotype DX RS or low Oncotype DX RS, respectively., Conclusions: The modified Magee equation is able to identify up to 12% patients who are unlikely to benefit from Oncotype DX testing. Using the modified Magee equation RS on these patients would be an alternative to Oncotype DX, leading to cost savings., (© American Society for Clinical Pathology, 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Background: The clinical implications of the diagnosis of atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS) are very different. Yet there are "borderline" breast lesions that have characteristics of both ADH and DCIS. We examined interobserver diagnostic variability for such lesions and correlated pathologic features of the lesions with clinical outcomes., Methods: We identified all cases of borderline ADH/DCIS lesions treated at our center from 1997 to 2010. Five specialized breast pathologists blinded to clinical outcomes independently reviewed all available slides from each case and were instructed to classify each as benign, ADH, or DCIS. A majority diagnosis (MajDx) was defined as a diagnosis agreed upon by ≥3 pathologists., Results: A total of 105 women with borderline ADH/DCIS and slides available for review were identified. The MajDx was ADH in 84 (80%), and DCIS in 18 (17%). There were split diagnoses in 3 (3%). MajDx of DCIS correlated significantly with lesion size and nuclear grade. There was diagnostic agreement by all 5 pathologists in 30% of cases, 4 pathologists in 42%, and 3 pathologists in 25%. At a median follow-up of 37 months, 4 (3.8%) patients developed subsequent ipsilateral breast carcinoma (2 invasive, 2 DCIS); all 4 cases had MajDx of ADH., Conclusions: Borderline ADH/DCIS represents an entity for which reproducible categorization as ADH or DCIS cannot be achieved. Furthermore, histologic features of borderline lesions resulting in MajDx of ADH vs. DCIS are not prognostic for risk of subsequent breast carcinoma.

In patients treated with neoadjuvant chemotherapy (NAC), there is no consensus on retesting biomarkers within the excision specimen. Our aim was to investigate the clinical relevance of biomarker changes post-NAC at a large tertiary medical center. A retrospective search was performed to identify cases from 2012 to 2015 with needle biopsy-confirmed invasive breast carcinoma treated with NAC and subsequent excision containing residual invasive tumor. Biomarkers (estrogen receptor [ER], progesterone receptor [PR], and HER2/neu [HER2]) were performed on all pre-NAC biopsies. One hundred fifty-four NAC-treated cases were identified in which 83 (54%) had repeat testing of at least 1 biomarker on the surgical specimen. Twenty-five (30%) of 83 repeated cases demonstrated changes in pre-NAC biopsy versus post-NAC resection biomarker status. There was no impact of age or grade on biomarker status changes. Tumors that were triple negative at biopsy were more likely to remain triple negative. Clinically relevant changes were identified including the following: (1) ER negative to ER positive, 2 (3%) of 75; (2) PR negative to PR positive with ER negative both pre- and post-NAC, 2 (3%) of 73; and (3) HER2 negative to positive, 1 (1%) of 77. Four of 5 of the changes led to modifications of the adjuvant treatment regimen, including the addition of adjuvant tamoxifen, anastrazole, or trastuzumab. In summary, post-NAC biomarker repeat testing in patients with breast cancer impacts therapeutic management in a small subset of patients and therefore, repeat testing may be considered for patients that are hormone receptor and/or HER2 negative before NAC., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Nipple adenoma is a very uncommon, benign proliferative process of lactiferous ducts of the nipple. Clinically, it often presents as a palpable nipple nodule, a visible nipple skin erosive lesion, and/or with discharge from the surface of the nipple skin, and is primarily seen in middle-aged women. Resultantly, nipple adenoma can clinically mimic the presentation of mammary Paget's disease of the nipple. The purpose of our current case report is to present a comprehensive review of the available data on nipple adenoma, as well as provide useful information to health care providers (including dermatologists, breast health specialists, and other health care providers) who evaluate patients with dermatologic conditions of the breast skin for appropriately clinically recognizing, diagnosing, and treating patients with nipple adenoma., Case Presentation: Fifty-three year old Caucasian female presented with a one year history of erythema and induration of the skin of the inferior aspect of the right nipple/areolar region. Skin punch biopsies showed subareolar duct papillomatosis. The patient elected to undergo complete surgical excision with right central breast resection. Final histopathologic evaluation confirmed nipple adenoma. The patient is doing well 31 months after her definitive surgical therapy., Conclusions: Since nipple adenoma represents a benign proliferative process of the nipple, complete surgical excision is curative. However, the coexistence of nipple adenoma and ipsilateral or contralateral breast cancer is well reported in the literature. The potential for a direct causal link or association of nipple adenoma and breast cancer cannot be fully excluded.

Complete bone marrow infiltration with profound pancytopenia is very uncommon in breast cancer. Bone marrow metastasis can frequently occur following development of metastatic breast cancer. However, bone marrow failure as the herald of this disease is not typically seen. Very limited data exists as to the safest and most efficacious manner to treat patients with profound pancytopenia due to metastatic solid tumor involvement. In this case, the patient's thrombocytopenia was particularly worrisome, requiring daily platelet transfusions. There was also concern that cytotoxic chemotherapy would exacerbate the patient's thrombocytopenia and increase bleeding risk. The patient's dramatic response to chemotherapy with full platelet recovery is also highly unusual. For our patient, continuous doxorubicin successfully "unpacked" the bone marrow despite a low baseline platelet level, and without increasing the need for more frequent platelet transfusion or risk of catastrophic bleeding. Given the rarity of this presentation, it is currently unknown if the majority of similar patients experience near full recovery of hematopoietic function after initiation of appropriate systemic treatment for metastatic disease.

Mesothelin is a cell surface associated antigen expressed on mesothelial cells and in some malignant neoplasms. Mesothelin-targeted therapies are in phase I/II clinical trials. The clinicopathologic and prognostic significance of mesothelin expression in triple negative breast carcinomas (TNBC) has not been fully assessed. We evaluated the expression of mesothelin and of basal markers in tissue microarrays of 226 TNBC and 88 non-TNBC and assessed the clinicopathologic features of mesothelin-expressing breast carcinomas. Furthermore, we investigated the impact of mesothelin expression on the disease-free and overall survival of patients with TNBC. We found that mesothelin expression is significantly more frequent in TNBC than in non-TNBC (36% vs 16%, respectively; p = 0.0006), and is significantly correlated with immunoreactivity for basal keratins, but not for EGFR. Mesothelin-positive and mesothelin-negative TNBC were not significantly different by patients' race, tumor size, histologic grade, tumor subtype, lymphovascular invasion and lymph node metastases. Patients with mesothelin-positive TNBC were older than patients with mesothelin-negative TNBC, developed more distant metastases with a shorter interval, and had significantly lower overall and disease-free survival. Based on our results, patients with mesothelin-positive TNBC could benefit from mesothelin-targeted therapies.

Breast carcinoma remains one of the most common sources of skin metastases in women. Cutaneous breast carcinoma metastases have variable clinical and histopathologic presentations that can make diagnosis challenging. We report a unique case of metastatic breast carcinoma with prominent clear cell features, thus mimicking a xanthomatous process. Dermatopathologists should be aware of this entity given its resemblance to other clear cell infiltrates and neoplasms., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

An 89-year-old woman was seen for indigestion, light chest pain, and melanotic stools. Endoscopic examination revealed 2 submucosal gastric masses. A subtotal gastrectomy showed 2 submucosal masses in the stomach: one infiltrating through the muscularis propria into the serosa, the second one, a well-circumscribed submucosal nodule. Histologic examination showed large tumor cells infiltrating diffusely through the muscularis propria into the subserosa. On higher magnification, numerous signet ring cells were present against a myxoid stroma, in addition to large vacuolated epithelioid cells. There was no evidence of invasion, necrosis, nuclear pleomorphism, or mitotic activity. Initial diagnostic considerations based on the histology included signet ring cell carcinoma, malignant melanoma, and a myxoid mesenchymal tumor, including gastrointestinal stromal tumor. A panel of immunohistochemical stains showed diffuse strong positivity for S-100 protein and negative reaction for CD117, bcl-2, cytokeratin AE1/AE3, Melan-A, HMB45, smooth muscle antigen, and other differentiation markers. Electron microscopic examination revealed elongated, complex, and interdigitating cell processes covered by a thin layer of continuous basement membrane material characteristic of peripheral nerve sheath differentiation. The presentation of this tumor was significant in that it was multifocal and infiltrative, mimicking a malignant neoplasm. The extensive myxoid/signet ring cell change represents a heretofore-unreported histologic variant of gastric schwannoma.

In this case report, we describe an accessory spleen that presented as a mass in the tail of the pancreas and mimicked a neoplasm. Intrapancreatic accessory spleen have a relatively high prevalence and can be mistaken for tumors. We present a case of intrapancreatic accessory spleen in a 40-year-old man, which was discovered incidentally during a workup for an aortic dissection. Computerized axial tomography and magnetic resonance imaging scans demonstrated a hypervascular mass in the tail of the pancreas. The clinical and radiological differential diagnosis included pancreatic mucinous cystic neoplasm, pancreatic endocrine neoplasm, solid pseudopapillary tumor, ductal adenocarcinoma, and metastasis. After a distal pancreatectomy was completed, microscopic examination revealed heterotopic splenic tissue.