Search

Context.-The Nottingham Grading System (NGS) developed by Elston and Ellis is used to grade invasive breast cancer (IBC). Glandular (acinar)/tubule formation is a component of NGS. Objective.-To investigate the ability of pathologists to identify individual structures that should be classified as glandular (acinar)/tubule formation. Design.-A total of 58 hematoxylin-eosin photographic images of IBC with 1 structure circled were classified as tubules (41 cases) or nontubules (17 cases) by Professor Ellis. Images were sent as a PowerPoint (Microsoft) file to breast pathologists, who were provided with the World Health Organization definition of a tubule and asked to determine if a circled structure represented a tubule. Results.-Among 35 pathologists, the [kappa] statistic for assessing agreement in evaluating the 58 images was 0.324 (95% CI, 0.314-0.335). The median concordance rate between a participating pathologist and Professor Ellis was 94.1% for evaluating 17 nontubule cases and 53.7% for 41 tubule cases. A total of 41% of the tubule cases were classified correctly by less than 50% of pathologists. Structures classified as tubules by Professor Ellis but often not recognized as tubules by pathologists included glands with complex architecture, mucinous carcinoma, and the "inverted tubule" pattern of micropapillary carcinoma. A total of 80% of participants reported that they did not have clarity on what represented a tubule. Conclusions.-We identified structures that should be included as tubules but that were not readily identified by pathologists. Greater concordance for identification of tubules might be obtained by providing more detailed images and descriptions of the types of structures included as tubules. (Arch Pathol Lab Med. 2024;148:1119-1125; doi: 10.5858/arpa.2023-0163-OA), Histologic grading of invasive breast carcinoma (IBC) represents a morphologic assessment of the degree of tumor differentiation and is routinely reported in the pathologic assessment of IBC. Histologic grade is [...]

PurposeLynch syndrome is defined by germline pathogenic mutations involving DNA mismatch repair (MMR) genes and linked with the development of MMR-deficient colon and endometrial cancers. Whether breast cancers developing in the context of Lynch syndrome are causally related to MMR deficiency (MMRd), remains controversial. Thus, we explored the morphologic and genomic characteristics of breast cancers occurring in Lynch syndrome individuals.Experimental designA retrospective analysis of 20,110 patients with cancer who underwent multigene panel genetic testing was performed to identify individuals with a likely pathogenic/pathogenic germline variant in MLH1, MSH2, MSH6, or PMS2 who developed breast cancers. The histologic characteristics and IHC assessment of breast cancers for MMR proteins and programmed death-ligand 1 (PD-L1) expression were assessed on cases with available materials. DNA samples from paired tumors and blood were sequenced with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (≥468 key cancer genes). Microsatellite instability (MSI) status was assessed utilizing MSISensor. Mutational signatures were defined using SigMA.ResultsA total of 272 individuals with Lynch syndrome were identified, 13 (5%) of whom had primary breast cancers. The majority of breast cancers (92%) were hormone receptor-positive tumors. Five (42%) of 12 breast cancers displayed loss of MMR proteins by IHC. Four (36%) of 11 breast cancers subjected to tumor-normal sequencing showed dominant MSI mutational signatures, high tumor mutational burden, and indeterminate (27%) or high MSISensor scores (9%). One patient with metastatic MMRd breast cancer received anti-PD1 therapy and achieved a robust and durable response.ConclusionsA subset of breast cancers developing in individuals with Lynch syndrome are etiologically linked to MMRd and may benefit from anti-PD1/PD-L1 immunotherapy.

* Context.--Breast carcinoma grade, as determined by the Nottingham Grading System (NGS), is an important criterion for determining prognosis. The NGS is based on 3 parameters: tubule formation (TF), nuclear pleomorphism (NP), and mitotic count (MC). The advent of digital pathology and artificial intelligence (AI) have increased interest in virtual microscopy using digital whole slide imaging (WSI) more broadly. Objective.--To compare concordance in breast carcinoma grading between AI and a multi-institutional group of breast pathologists using digital WSI. Design.--We have developed an automated NGS framework using deep learning. Six pathologists and AI independently reviewed a digitally scanned slide from 137 invasive carcinomas and assigned a grade based on scoring of the TF, NP, and MC. Results.--Interobserver agreement for the pathologists and AI for overall grade was moderate ([kappa] = 0.471). Agreement was good ([kappa] = 0.681), moderate ([kappa] = 0.442), and fair ([kappa] = 0.368) for grades 1, 3, and 2, respectively. Observer pair concordance for AI and individual pathologists ranged from fair to good ([kappa] = 0.313-0.606). Perfect agreement was observed in 25 cases (27.4%). Interobserver agreement for the individual components was best for TF ([kappa] = 0.471 each) followed by NP ([kappa] = 0.342) and was worst for MC ([kappa] = 0.233). There were no observed differences in concordance amongst pathologists alone versus pathologists + AI. Conclusions.--Ours is the first study comparing concordance in breast carcinoma grading between a multi-institutional group of pathologists using virtual microscopy to a newly developed WSI AI methodology. Using explainable methods, AI demonstrated similar concordance to pathologists alone. doi: 10.5858/arpa.2021-0299-OA, Over the years, microscopic evaluation of hematoxylin-eosin-stained slides from patient samples has been the gold standard for cancer diagnosis and grading of malignancy. The Nottingham Grading System (NGS) is widely [...]

Aims Methods Results Conclusion Breast cancer with human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) 1+ or 2+ with negative in‐situ hybridisation (ISH) (HER2‐low) can now be targeted by HER2 antibody drug conjugates. We set out to compare HER2 status between matched primary invasive breast carcinoma (IBC) and distant metastases (DM) with clinical–pathological correlation, with specific interest in HER2‐low.Biomarker studies and clinical–pathological features of primary IBC with matched DM diagnosed between 2021 and 2022 were retrospectively analysed. HER2 status was assessed per 2023 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines for IHC (4B5) and ISH (IQFISH pharmDX). Bilateral breast primaries were excluded. HER2 IHC 0 to 1+ were reassessed.One hundred and forty‐seven cases of primary IBC with matched DM were identified. Biomarkers were performed on core biopsy (n = 74) and resection (n = 73). One hundred and twenty‐six (86%) were initially classified as ‘HER2‐negative’; of these, 67 (46%) were reclassified as HER2‐low. Patients with HER2‐positive primaries were younger (P = 0.01) and had an increased incidence of micropapillary carcinoma (P = 0.02). HER2‐low primaries also had an increased incidence of micropapillary carcinoma (P = 0.02) and oestrogen receptor (ER) positivity (P = 0.02) compared to HER2 0. One hundred and sixty‐nine matched DM cases excluding bone metastasis were identified (range = one to seven metastases per IBC). The most common sites of metastases were liver (50 of 169, 30%), lung (36 of 169; 21%), distant lymph node (26 of 169, 15%); 138 DM cases (82%) were previously classified as ‘HER2‐negative’, and 62 (37%) were reclassified as HER2‐low. Like HER2‐low primaries, HER2‐low metastases were frequently ER‐positive (52 of 62; 84%) (P = 0.02). Brain metastases were more frequently HER2‐positive (five of 32; 16%) (P = 0.04). Comparing HER2 status in matched primaries and DM, HER2 status was discordant in 62 cases (37%). Most changes occurred from HER2‐low to HER2 0 (33 of 169, 20%), HER2 0 to HER2‐low (17 of 169, 10%) and HER2‐low to positive (10 of 169, 6%). All HER2‐low to HER2 0 changes were HER2 1+ to 0. In 30 patients with multiple DM sites (47 cases), HER2 status among different DM samples was discordant in 16 patients (53%), mainly from HER2‐low to HER2 0 (16 of 47, 34%).A significant proportion of previous ‘HER2‐negative’ primaries and DM cases were reclassified as HER2‐low. Discordant HER2 status between IBC primary and metastasis and between different DM sites demonstrated tumour heterogeneity and highlights the need for HER2 retesting in distant metastasis. [ABSTRACT FROM AUTHOR]

Context.--It is unclear whether [HER2.sup.+] tumors expressing both estrogen receptor (ER) and progesterone receptor (PR), that is, triple-positive breast carcinomas (TPBCs), show unique morphologic and clinical features and response to neoadjuvant chemotherapy (NAC). Objective.--To study the morphologic and immunohistochemical features of TPBCs from patients who underwent NAC. Design.--We retrospectively reviewed core biopsy and post-NAC slides of 85 TPBCs. H-scores were calculated for ER and PR. HER2 slides and fluorescence in situ hybridization (FISH) reports were reviewed. Residual cancer burden was calculated for post-NAC specimens. Results.--Eighty-one of the 85 tumors (95.3%) showed ductal histology, 3 (3.5%) were invasive lobular carcinomas, and 1 (1.2%) showed mixed ductal and lobular features. A subset showed mucinous (n = 7,8.2%), apocrine (n = 5, 5.9%), and/or micropapillary (n = 4, 4.7%) differentiation. Fifty-four TPBCs (63.5%) showed high ER expression (H-score >200), including 27 (31.8%) with high expression of ER and PR. Fifty-two tumors (61.1%) showed HER2 3+ staining. Mean HER2/CEP17 ratio by FISH was 3.6 (range, 2-12.2) and mean HER2 signals per cell was 8 (range, 3.7-30.4). Pathologic complete response (pCR) rate was 35.3% (30 of 85). HER2 3+ staining was the only significant predictor of pCR on multivariate analysis (odds ratio = 9.215; 95% CI, 2.401-35.371; P < .001). The ER/PR expression did not correlate with response to therapy. Conclusions.--TPBCs are heterogeneous with some showing mucinous, lobular, or micropapillary differentiation. The pCR rate of TPBCs is similar to that reported for ER+/PR/[HER2.sup.+] tumors. HER2 overexpression by IHC was associated with significantly better response to therapy and may help select patients for treatment in the neoadjuvant setting. (Arch Pathol Lab Med. 2021;145:728-735; doi: 10.5858/arpa.2020-0293-OA, HER2 protein overexpression/gene amplification is seen in approximately 15% to 25% of invasive breast carcinomas and has historically been associated with aggressive histopathologic features and poor clinical outcome. (1,2) HER2-targeted [...]

* Context.--The Ventana programmed death ligand-1 (PD-L1) SP142 immunohistochemical assay (IHC) is approved by the US Food and Drug Administration as the companion diagnostic assay to identify patients with locally advanced or metastatic triple-negative breast cancer for immunotherapy with atezolizumab, a monoclonal antibody targeting PD-L1. Objective.--To determine interobserver variability in PD-L1 SP142 IHC interpretation in invasive breast carcinoma. Design.--The pathology database was interrogated for all patients diagnosed with primary invasive, locally recurrent, or metastatic breast carcinoma on which PD-L1 SP142 IHC was performed from November 2018 to June 2019 at our institution. A subset of cases was selected using a computerized random-number generator. PD-L1 IHC was evaluated in stromal tumor-infiltrating immune cells using the IMpassion130 trial criteria, with positive cases defined as immunoreactivity in immune cells in 1% or more of the tumor area. IHC was interpreted on whole slide images by staff pathologists with breast pathology expertise. Interobserver variability was calculated using unweighted k. Results.--A total of 79 cases were assessed by 8 pathologists. Interobserver agreement was substantial (k = 0.727). There was complete agreement among all 8 pathologists in 62% (49 of 79) of cases, 7 pathologists or more in 84% (66 of 79) of cases, and 6 pathologists or more in 92% (73 of 79) of cases. In 4% (3 of 79) of cases, all of which were small biopsies, pathologists' interpretations were evenly split between scores of positive and negative. Conclusions.--The findings show substantial agreement in PD-L1 SP142 IHC assessment of breast carcinoma cases among 8 pathologists at a single institution. Further study is warranted to define the basis for discrepant results. (Arch Pathol Lab Med. 2021;145:1132-1137; doi: 10.5858/arpa.2020-0441-OA, Triple-negative breast carcinomas (TNBCs) lack expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) and are associated with aggressive clinical behavior. Median overall survival for [...]

The cover image is based on the Original Article Radial sclerosing lesions found on core needle biopsy: excision can be safely avoided by Anne Grabenstetter et al., https://doi.org/10.1111/his.15233..By Anne Grabenstetter; Sandra B Brennan; Maxine S Jochelson; Edi Brogi; Monica Morrow; Lee K Tan and Timothy M D'AlfonsoReported by Author; Author; Author; Author; Author; Author; Author [Extracted from the article]