Changing digital and telecytology practices post COVID-19 comparing ASC survey results from 2016 to 2023.

INTRODUCTION: During the COVID-19 pandemic, the need for digital pathology tools became more urgent. However, there needs to be more knowledge of the use in cytology. We aimed to evaluate current digital cytology practices and attitudes and compare the results with a pre-COVID-19 American Society of Cytopathology (ASC) survey. MATERIALS AND METHODS: Fourteen survey questions assessing current attitudes toward digital cytology were developed from a 2016 ASC Digital Pathology Survey. Ten new survey questions were also created to evaluate telecytology use. The survey was e-mailed to ASC members over 6 weeks in 2023. RESULTS: A total of 123 individuals responded (116 in 2016). Attitudes toward digital cytology were unchanged; most participants stated digital cytology is beneficial (87% 2023 versus 90% 2016). The percentage of individuals using digital cytology was unchanged (56% in 2016 and 2023). However, telecytology for rapid onsite assessment (ROSE) is now considered the best application (55% 2023 versus 31% 2016). Forty-three institutions reported using digital and telecytology tools; 40% made implementations after 2020; most did not feel that COVID-19 affected digital cytology (56%). Telecytology for ROSE is the most common application now (78%) compared with education (30%) in 2016. Limitations for implementing digital imaging in cytology included inability to focus (38%) and expense (33%). CONCLUSIONS: General attitudes toward digital tools by the cytology community have essentially remained the same between 2016 and now. However, telecytology for ROSE is increasingly being used, which supports a need for validation and competency guidelines.

Does ROSE matter? Evaluation of final diagnostic, PD-L1 immunohistochemistry, and molecular testing yields of CT-guided lung biopsies performed before and after the onset of the COVID-19 pandemic.

INTRODUCTION: The onset of the COVID-19 pandemic, with urgent implementation of safety protocols limiting the number of on-site personnel, essentially terminated the use of rapid on-site evaluation (ROSE) for computed tomography (CT)--guided lung biopsies at our institution. The diminished use of ROSE during the pandemic prompted us to reevaluate the potential value of ROSE for CT-guided lung biopsies. MATERIALS AND METHODS: We retrospectively identified all CT-guided lung biopsies from 2017 to 2022. Associations between the use of ROSE, adequate diagnostic and ancillary testing (programmed death-ligand 1 immunohistochemistry and next-generation sequencing) outcomes, and other factors such as the number of passes performed and lesion size, were evaluated. RESULTS: Nine hundred twelve CT-guided lung biopsies were performed from 2017 to 2022; 171 (19%) utilized ROSE. The use of ROSE had been steadily decreasing prior to the pandemic but was essentially eliminated with the onset of the pandemic. By univariable analysis, the employment of ROSE was more likely to be associated with an adequate final diagnosis (odds ratio = 2.14, 95% confidence interval: [1.24-3.70], P = 0.006) and successful molecular testing (odds ratio = 2.16, 95% confidence interval: [1.11-4.21], P = 0.024). However, those associations were not present in multivariable analyses that incorporated the number of passes performed or lesion size. There were no differences in diagnostic adequacy or ancillary testing yields when comparing the periods 2017-2019 and 2020-2022, despite declining use of ROSE. CONCLUSIONS: If ROSE is not requested for CT-guided lung biopsies, proceduralists should err on the side of performing more, rather than fewer, passes, particularly for smaller lesions.

Integrative Co-Registration of Elemental Imaging and Histopathology for Enhanced Spatial Multimodal Analysis of Tissue Sections through TRACE.

Summary: Elemental imaging provides detailed profiling of metal bioaccumulation, offering more precision than bulk analysis by targeting specific tissue areas. However, accurately identifying comparable tissue regions from elemental maps is challenging, requiring the integration of hematoxylin and eosin (H&E) slides for effective comparison. Facilitating the streamlined co-registration of Whole Slide Images (WSI) and elemental maps, TRACE enhances the analysis of tissue regions and elemental abundance in various pathological conditions. Through an interactive containerized web application, TRACE features real-time annotation editing, advanced statistical tools, and data export, supporting comprehensive spatial analysis. Notably, it allows for comparison of elemental abundances across annotated tissue structures and enables integration with other spatial data types through WSI co-registration. Availability and Implementation: Available on the following platforms- GitHub: jlevy44/trace_app , PyPI: trace_app , Docker: joshualevy44/trace_app , Singularity: joshualevy44/trace_app . Contact: joshua.levy@cshs.org. Supplementary information: Supplementary data are available.

Chondrolipoma of the Breast: A Myofibroblastoma Variant or a Distinct Lesion?

The entity commonly referred to as chondrolipoma is a rare and enigmatic breast lesion with unclear histogenesis and a complete lack of molecular characterization. It is uncertain whether it represents a hamartoma, choristoma, or a distinct neoplasm, including possibly a variant of mammary-type myofibroblastoma. We report two additional chondrolipomatous lesions of the breast. The lesions had varying histologic and immunohistochemical features similar to myofibroblastoma, including the loss of retinoblastoma (Rb) protein expression in one lesion. Molecular analysis by chromosomal microarray analysis performed on a second lesion did not demonstrate a loss of 13q14 or 16q typical of myofibroblastoma. Our findings further support the concept that at least a subset of breast lesions that historically have been classified as chondrolipoma are related to myofibroblastoma. However, the lack of myofibroblastoma-specific molecular alterations in one lesion suggests chondrolipomas may also have varying origins.

Sixteen-Year Institutional Review of Magnetic Resonance Imaging-Guided Breast Biopsies: Trends in Histologic Diagnoses With Radiologic Correlation.

Background: Breast magnetic resonance imaging (MRI) is an important imaging tool for the management of breast cancer patients and for screening women at high risk for breast cancer. Objectives: To examine long-term trends in the distribution of histologic diagnoses obtained from MRI-guided breast biopsies. Design: Retrospective analysis. Methods: We retrospectively reviewed the distribution of histologic diagnoses of MRI-guided breast biopsies from 2004 to 2019. All cases underwent central pathology review and lesions were classified based on the most prominent histologic finding present. Magnetic resonance imaging features were extracted from radiology reports when available and correlated with pathology diagnoses. Results: Four hundred ninety-four MRI-guided biopsies were performed on 440 patients; overall, 73% of biopsies were benign and 27% were malignant. The annual percentages of benign and malignant diagnoses remained similar throughout the 16-year period. Of the benign entities commonly identified, the percentage of benign papillary and sclerosing lesions detected in the benign biopsies increased significantly (13% in 2004-2011 vs 31% in 2012-2019, P = .03). The mean size of malignant lesions was larger than benign lesions (30.1 mm compared with 14.2 mm, P = .045); otherwise, there were no distinguishing radiologic features between benign and malignant lesions. Conclusion: The specificity of breast MRI remained constant over a 16-year period; however, there was a shift in the distribution of benign diagnoses with increased detection and biopsy of benign papillary and sclerosing lesions. Monitoring the distribution of breast MRI biopsy diagnoses over time with radiology-pathology correlation might improve the suboptimal specificity of breast MRI.

Use of molecular testing results to analyze the overuse of atypia of undetermined significance in thyroid cytology.

INTRODUCTION: The suggested atypia of undetermined significance (AUS) rate for thyroid fine-needle aspiration biopsies is 10% or less. Prompted by a high institutional AUS rate, we examined using molecular testing results (MTR) as a potential quality metric tool to reduce the AUS rate. We correlated MTR with AUS cytologic findings, surgical pathology follow-up, and individual pathologist AUS rates. MATERIALS AND METHODS: Demographic data, cytologic diagnoses, MTR, and surgical pathology diagnoses were retrospectively obtained. MTR were classified as either positive or negative. AUS rates and MTR proportions were compared among pathologists. The cytomorphologic features of 143 AUS cases were assessed and correlated with MTR. RESULTS: Between 2017 and 2022, 710 of 3247 thyroid fine-needle aspirations were classified as AUS, with a yearly average rate of 22% (range = 19%-26%). AUS cases included: 331 (47%) with architectural atypia; 204 (29%) with oncocytic (Hürthle cell) atypia; 99 (14%) with combined architectural and cytologic atypia; and 76 (10%) with isolated cytologic atypia. Most AUS cases with molecular testing had negative MTR (360/492, 73%). AUS with cytologic atypia had higher positive MTR risk (logarithm of odds ratio = 1.27, 95% credible interval [0.5-2.04], P = 0.001). The average positive MTR rate by pathologist was 21.5% (range 0%-35%); higher positive MTR rates had better correlation with subsequent neoplastic/malignant histologic diagnoses. The MTR sensitivity for malignant disease was 89% and the negative predictive value was 91%. CONCLUSIONS: MTR analysis reveals the importance of cytologic atypia as a determinant of malignancy risk in AUS cases. Periodic analysis of MTR data alongside individual pathologist AUS rates can help refine diagnostic criteria and potentially reduce AUS overuse.

Estrogen Therapy Induces Receptor-Dependent DNA Damage Enhanced by PARP Inhibition in ER+ Breast Cancer.

PURPOSE: Clinical evidence indicates that treatment with estrogens elicits anticancer effects in ∼30% of patients with advanced endocrine-resistant estrogen receptor α (ER)-positive breast cancer. Despite the proven efficacy of estrogen therapy, its mechanism of action is unclear and this treatment remains underused. Mechanistic understanding may offer strategies to enhance therapeutic efficacy. EXPERIMENTAL DESIGN: We performed genome-wide CRISPR/Cas9 screening and transcriptomic profiling in long-term estrogen-deprived ER+ breast cancer cells to identify pathways required for therapeutic response to the estrogen 17ß-estradiol (E2). We validated findings in cell lines, patient-derived xenografts (PDX), and patient samples, and developed a novel combination treatment through testing in cell lines and PDX models. RESULTS: Cells treated with E2 exhibited replication-dependent markers of DNA damage and the DNA damage response prior to apoptosis. Such DNA damage was partially driven by the formation of DNA:RNA hybrids (R-loops). Pharmacologic suppression of the DNA damage response via PARP inhibition with olaparib enhanced E2-induced DNA damage. PARP inhibition synergized with E2 to suppress growth and prevent tumor recurrence in BRCA1/2-mutant and BRCA1/2-wild-type cell line and PDX models. CONCLUSIONS: E2-induced ER activity drives DNA damage and growth inhibition in endocrine-resistant breast cancer cells. Inhibition of the DNA damage response using drugs such as PARP inhibitors can enhance therapeutic response to E2. These findings warrant clinical exploration of the combination of E2 with DNA damage response inhibitors in advanced ER+ breast cancer, and suggest that PARP inhibitors may synergize with therapeutics that exacerbate transcriptional stress.

Alternating 17ß-Estradiol and Aromatase Inhibitor Therapies Is Efficacious in Postmenopausal Women with Advanced Endocrine-Resistant ER+ Breast Cancer.

PURPOSE: Strategies to implement estrogen therapy for advanced estrogen receptor-positive (ER+) breast cancer are underdeveloped. Preclinical data suggest that cycling treatment with 17ß-estradiol followed by estrogen deprivation can control tumor growth long-term. PATIENTS AND METHODS: Postmenopausal women with advanced ER+/HER2- breast cancer with recurrence or progression on ≥ 1 antiestrogen or aromatase inhibitor (AI)-based therapy were eligible. Patients received 17ß-estradiol (2 mg orally, three times a day) for 8 weeks followed by AI (physician's choice) for 16 weeks, alternating treatments on an 8-week/16-week schedule until disease progression. Patients then optionally received continuous single-agent treatment until a second instance of disease progression. Endpoints included 24-week clinical benefit and objective response per RECIST, and tumor genetic alterations. RESULTS: Of 19 evaluable patients, clinical benefit rate was 42.1% [95% confidence interval (CI), 23.1%-63.9%] and objective response rate (ORR) was 15.8% (95% CI, 5.7%-37.9%). One patient experienced a grade 3 adverse event related to 17ß-estradiol. Among patients who received continuous single-agent treatment until a second instance of disease progression, clinical benefit was observed in 5 of 12 (41.7%) cases. Tumor ER (ESR1) mutations were found by whole-exome profiling in 4 of 7 (57.1%) versus 2 of 9 (22.2%) patients who did versus did not experience clinical benefit from alternating 17ß-estradiol/AI therapy. The only two patients to experience objective responses to initial 17ß-estradiol had tumor ESR1 mutations. CONCLUSIONS: Alternating 17ß-estradiol/AI therapy may be a promising treatment for endocrine-refractory ER+ breast cancer, including following progression on CDK4/6 inhibitors or everolimus. Further study is warranted to determine whether the antitumor activity of 17ß-estradiol differs according to ESR1 mutation status.

Large-scale validation study of an improved semiautonomous urine cytology assessment tool: AutoParis-X.

BACKGROUND: Adopting a computational approach for the assessment of urine cytology specimens has the potential to improve the efficiency, accuracy, and reliability of bladder cancer screening, which has heretofore relied on semisubjective manual assessment methods. As rigorous, quantitative criteria and guidelines have been introduced for improving screening practices (e.g., The Paris System for Reporting Urinary Cytology), algorithms to emulate semiautonomous diagnostic decision-making have lagged behind, in part because of the complex and nuanced nature of urine cytology reporting. METHODS: In this study, the authors report on the development and large-scale validation of a deep-learning tool, AutoParis-X, which can facilitate rapid, semiautonomous examination of urine cytology specimens. RESULTS: The results of this large-scale, retrospective validation study indicate that AutoParis-X can accurately determine urothelial cell atypia and aggregate a wide variety of cell-related and cluster-related information across a slide to yield an atypia burden score, which correlates closely with overall specimen atypia and is predictive of Paris system diagnostic categories. Importantly, this approach accounts for challenges associated with the assessment of overlapping cell cluster borders, which improve the ability to predict specimen atypia and accurately estimate the nuclear-to-cytoplasm ratio for cells in these clusters. CONCLUSIONS: The authors developed a publicly available, open-source, interactive web application that features a simple, easy-to-use display for examining urine cytology whole-slide images and determining the level of atypia in specific cells, flagging the most abnormal cells for pathologist review. The accuracy of AutoParis-X (and other semiautomated digital pathology systems) indicates that these technologies are approaching clinical readiness and necessitates full evaluation of these algorithms in head-to-head clinical trials.

Examining longitudinal markers of bladder cancer recurrence through a semiautonomous machine learning system for quantifying specimen atypia from urine cytology.

BACKGROUND: Urine cytology is generally considered the primary approach for screening for recurrence of bladder cancer. However, it is currently unclear how best to use cytological examinations for assessment and early detection of recurrence, beyond identifying a positive finding that requires more invasive methods to confirm recurrence and decide on therapeutic options. Because screening programs are frequent, and can be burdensome, finding quantitative means to reduce this burden for patients, cytopathologists, and urologists is an important endeavor and can improve both the efficiency and reliability of findings. Additionally, identifying ways to risk-stratify patients is crucial for improving quality of life while reducing the risk of future recurrence or progression of the cancer. METHODS: In this study, a computational machine learning tool, AutoParis-X, was leveraged to extract imaging features from urine cytology examinations longitudinally to study the predictive potential of urine cytology for assessing recurrence risk. This study examined how the significance of imaging predictors changes over time before and after surgery to determine which predictors and time periods are most relevant for assessing recurrence risk. RESULTS: Results indicate that imaging predictors extracted using AutoParis-X can predict recurrence as well or better than traditional cytological/histological assessments alone and that the predictiveness of these features is variable across time, with key differences in overall specimen atypia identified immediately before tumor recurrence. CONCLUSIONS: Further research will clarify how computational methods can be effectively used in high-volume screening programs to improve recurrence detection and complement traditional modes of assessment.

Periductal Stromal Tumor of the Breast with a TERT Promoter Mutation: First Case Report with Comprehensive Molecular Analysis.

The molecular pathogenesis of breast fibroepithelial tumors continues to be elucidated. Recently, highly recurrent MED12 mutations arising in exon 2 at codon 44 were discovered in fibroadenomas and phyllodes tumors. In addition, a high prevalence of TERT promoter mutations in two hotspots (124 and 126 bp upstream from the translation start site) was discovered in up to 65% of phyllodes tumors. Breast periductal stromal tumors are a potentially distinct category of fibroepithelial lesions that are exceptionally rare with controversial classification and pathogenesis. Herein, we report the first comprehensive molecular genetic workup of a breast periductal stromal tumor that harbored a TERT promoter -124C > T mutation, supporting a relation to phyllodes tumors.

Uncovering additional predictors of urothelial carcinoma from voided urothelial cell clusters through a deep learning-based image preprocessing technique.

BACKGROUND: Urine cytology is commonly used as a screening test for high-grade urothelial carcinoma for patients with risk factors or hematuria and is an essential step in longitudinal monitoring of patients with previous bladder cancer history. However, the semisubjective nature of current reporting systems for urine cytology (e.g., The Paris System) can hamper reproducibility. For instance, the incorporation of urothelial cell clusters into the classification schema is still an item of debate and perplexity among expert cytopathologists because several previous works have disputed their diagnostic relevance. METHODS: In this work, an automated preprocessing tool for urothelial cell cluster assessment was developed that divides urothelial cell clusters into meaningful components for downstream assessment (ie, population-based studies, workflow automation). RESULTS: In this work, an automated preprocessing tool for urothelial cell cluster assessment was developed that divides urothelial cell clusters into meaningful components for downstream assessment (ie, population-based studies, workflow automation). Results indicate that cell cluster atypia (i.e., defined by whether the cell cluster harbored multiple atypical cells, thresholded by a minimum number of cells), cell border overlap and smoothness, and total number of clusters are important markers of specimen atypia when considering assessment of urothelial cell clusters. CONCLUSIONS: Markers established through techniques to separate cell clusters may have wider applicability for the design and implementation of machine learning approaches for urine cytology assessment.

Large-scale longitudinal comparison of urine cytological classification systems reveals potential early adoption of The Paris System criteria.

INTRODUCTION: Urine cytology is used to screen for urothelial carcinoma in patients with hematuria or risk factors (eg, smoking, industrial dye exposure) and is an essential clinical triage and longitudinal monitoring tool for patients with known bladder cancer. However, urine cytology is semisubjective and thus susceptible to issues including specimen quality, interobserver variability, and "hedging" towards equivocal ("atypical") diagnoses. These factors limit the predictive value of urine cytology and increase reliance on invasive procedures (cystoscopy). The Paris System for Reporting Urine Cytology (TPS) was formulated to provide more quantitative/reproducible endpoints with well-defined criteria for urothelial atypia. TPS is often compared to other assessment techniques to justify its adoption. TPS results in decreased use of the atypical category and better reproducibility. Previous reports comparing diagnoses pre- and post-TPS have not considered temporal differences between diagnoses made under prior systems and TPS. By aggregating across time, studies may underestimate the magnitude of differences between assessment methods. MATERIALS AND METHODS: We conducted a large-scale longitudinal reassessment of urine cytology using TPS criteria from specimens collected from 2008 to 2018, prior to the mid-2018 adoption of TPS at an academic medical center. RESULTS: Findings indicate that differences in atypical assignment were largest at the start of the period and these differences progressively decreased towards insignificance just prior to TPS implementation. CONCLUSIONS: This finding suggests that cytopathologists had begun to utilize the quantitative TPS criteria prior to official adoption, which may more broadly inform adoption strategies, communication, and understanding for evolving classification systems in cytology.

A 43-Year-Old Woman With Fatigue, Pancytopenia, and Mediastinal Adenopathy.

CASE PRESENTATION: A 43-year-old woman without significant medical history was admitted with fatigue for 2 months. Before her current presentation, she had experienced several weeks of heavy menstrual bleeding and easy bruising. She denied night sweats, weight loss, chills, sore throat, neck swelling, rash, joint pain, cough, fever, or shortness of breath. The patient admitted a 20-year half-pack per day smoking habit that she had not been able to quit. She denied significant occupational or environmental exposures, a family history of malignancy, or current use of medications.

Clinicopathological features and BRCA1 and BRCA2 mutation status in a prospective cohort of young women with breast cancer.

BACKGROUND: Breast cancer in young women is more likely to have higher risk features and be associated with germline BRCA1/BRCA2 mutations. We present the clinicopathologic features of breast cancers in a prospective cohort of young women, and associations between surrogate molecular subtype and BRCA1/BRCA2 mutation status. METHODS: Histopathological features, biomarker status, tumour stage and BRCA status were collected. Invasive tumours were categorised as luminal A-like (ER + and/or PR + , HER2-, grade 1/2), luminal B-like (ER + and/or PR + , HER2 + , or ER + and/or PR + , HER2-, and grade 3), HER2-enriched (ER/PR-, HER2 + ) or triple-negative. RESULTS: In all, 57.3% (654/1143) of invasive tumours were high grade. In total, 32.9% were luminal A-like, 42.4% luminal B-like, 8.3% HER2-enriched, and 16.4% triple-negative. Among different age groups, there were no differences in molecular phenotype, stage, grade or histopathology. 11% (131) of tumours were from BRCA mutation carriers; 64.1% BRCA1 (63.1% triple-negative), and 35.9% BRCA2 (55.3% luminal B-like). DISCUSSION: The opportunity to provide comparisons across young age groups, BRCA mutation status, surrogate molecular phenotype, and the identification of more aggressive hormone receptor-positive phenotypes in this population provides direction for future work to further understand and improve disparate outcomes for young women with luminal B-like cancers, particularly BRCA2-associated cancers, with potential implications for tailored prevention and treatment.

Using molecular testing to improve the management of thyroid nodules with indeterminate cytology: an institutional experience with review of molecular alterations.

INTRODUCTION: Molecular testing has helped clinicians and cytopathologists to further categorize indeterminate thyroid fine needle aspiration (FNA) specimens. The purpose of the present study was to evaluate the accuracy of commercially available molecular tests, review their effects on patient treatment, and correlate the molecular alterations with the histologic findings. MATERIALS AND METHODS: A pathology laboratory information system search identified thyroid FNAs performed at our institution between January 1, 2015 and June 30, 2020. The results of surgical follow-up and ancillary molecular testing were collected. We evaluated the accuracy of these tests and whether they could reduce the number of surgeries performed. RESULTS: Our laboratory information system search identified 510 cases reported as atypia of undetermined significance, 94 as suspicious for follicular neoplasm, and 44 as suspicious for follicular neoplasm, Hurthle cell type. Of the specimens, 343 had no ancillary molecular testing, 146 were sent for ThyGenX/ThyraMIR, and 136 were sent for ThyroSeq. Of the patients without molecular testing, 50.4% had undergone follow-up surgery compared with 30.8% after ThyGenX/ThyraMIR and 38.2% after ThyroSeq testing, resulting in 38.9% and 24.2% fewer surgeries and an odds ratio of 0.04 (95% confidence interval, 0.00-0.33) and 0.14 (95% confidence interval, 0.01-0.95), respectively. For ThyGenX/ThyraMIR testing, the risk of malignancy for high and moderate to high risk alterations was 80%, 28.6% for moderate and low to moderate risk alterations, and 23.1% for low risk alterations. For ThyroSeq, the risk of malignancy was 87.5% for high risk alterations, 36.8% for intermediate to high risk alterations, 27.3% for intermediate risk alterations, and 0% for low risk alterations. The areas under the curve for ThyGenX/ThyraMIR and ThyroSeq testing were 0.65 and 0.85, respectively. CONCLUSIONS: These findings suggest that, at our institution, both ThygenX/ThyraMIR and ThyroSeq can be used to effectively stratify cytology specimens based on the risk of malignancy and reduce the number of surgeries performed at our institution.

Differential effects of CD20+ B cells and PD-L1+ immune cells on pathologic complete response and outcome: comparison between inflammatory breast cancer and locally advanced breast cancer patients.

PURPOSE: This study evaluated epidemiologic and immune factors associated with pathologic complete response (pCR), breast cancer-specific survival (BCSS) and disease-free survival (DFS) outcomes in inflammatory (IBC) and locally advanced breast cancer (LABC) patients. METHODS: Tumor-infiltrating lymphocytes (TILs) and CD20+ B-cell frequencies (CD20+), and PD-L1 expression on tumor (PD-L1+carcinoma cells) and immune (PD-L1+TILs) cells were analyzed by immunohistochemistry along with clinicopathologic factors as modifiers of pCR and outcomes in 221 IBC and 162 LABC patients. Analysis included Kaplan-Meier curves and Cox proportional hazard models. RESULTS: IBC and LABC display similar levels of TILs, CD20+, and combined CD20+ and PD-L1+TILs (CD20+PD-L1+TILs), while LABC contained more PD-L1+TILs and PD-L1+ carcinoma cells. Absence of lymphovascular involvement, high TILs, PD-L1+ carcinoma cells, and combined CD20+ and PD-L1+ carcinoma cells correlated with pCR in IBC and LABC patients. High PD-L1+TILs correlated with pCR only in LABC; less lymph node involvement at diagnosis, CD20+ and CD20+PD-L1+TILs correlated with pCR only in IBC (P < 0.04, all comparisons). Achievement of pCR in IBC and LABC patients correlated with BCSS and DFS (P < 0.02). In multivariate analyses, pCR remained an independent prognostic factor of improved DFS in IBC and LABC patients, but of BCSS in only LABC. CD20+PD-L1+TILs remained an independent prognostic factor of improved DFS and BCSS only in IBC. CONCLUSION: CD20+PD-L1+TILs are an independent prognostic biomarker of improved outcomes in IBC, but not LABC. Selecting IBC patients by CD20 and PD-L1 status could stratify patients and potentially identify those in whom activating CD20 agents and anti-PD-1/PD-L1 therapy could be explored.

Solitary fibrous tumor of the pancreas clinically mimicking a pancreatic neuroendocrine tumor: Cytologic pitfalls when a transgastric approach is utilized.

Solitary fibrous tumor (SFT) involving the pancreas is a rare entity often diagnosed on surgical specimens rather than cytology samples. Pancreatic SFT frequently mimics pancreatic neuroendocrine tumor radiographically, which presents unique challenges to the cytologist during rapid on-site assessment. We describe a case of pancreatic SFT with a focus on the cytologic pitfalls that might be encountered during transgastric procedures. We also review the available cytologic findings of prior pancreatic SFT cases.

High estrogen receptor alpha activation confers resistance to estrogen deprivation and is required for therapeutic response to estrogen in breast cancer.

Estrogen receptor alpha (ER)-positive breast cancer is commonly treated with endocrine therapies, including antiestrogens that bind and inhibit ER activity, and aromatase inhibitors that suppress estrogen biosynthesis to inhibit estrogen-dependent ER activity. Paradoxically, treatment with estrogens such as 17b-estradiol can also be effective against ER+ breast cancer. Despite the known efficacy of estrogen therapy, the lack of a predictive biomarker of response and understanding of the mechanism of action have contributed to its limited clinical use. Herein, we demonstrate that ER overexpression confers resistance to estrogen deprivation through ER activation in human ER+ breast cancer cells and xenografts grown in mice. However, ER overexpression and the associated high levels of ER transcriptional activation converted 17b-estradiol from a growth-promoter to a growth-suppressor, offering a targetable therapeutic vulnerability and a potential means of identifying patients likely to benefit from estrogen therapy. Since ER+ breast cancer cells and tumors ultimately developed resistance to continuous estrogen deprivation or continuous 17b-estradiol treatment, we tested schedules of alternating treatments. Oscillation of ER activity through cycling of 17b-estradiol and estrogen deprivation provided long-term control of patient-derived xenografts, offering a novel endocrine-only strategy to manage ER+ breast cancer.