Imaging and Management of Radial Scars and Complex Sclerosing Lesions.

Radial scars and complex sclerosing lesions, often collectively referred to as radial sclerosing lesions (RSLs), are breast lesions characterized by sclerotic stroma with entrapped epithelial elements. RSLs have imaging features that overlap with those of breast malignancy and often become the target of imaging-guided biopsy given their suspicious imaging appearance. These can be identified in isolation or can also be associated with atypia or other high-risk lesions that have intrinsic malignant potential, increasing the risk of carcinoma and affecting prognosis and management of RSLs. Because of this, management of these lesions remains controversial. Traditional management has been surgical excisional biopsy. However, as more RSLs are identified (because digital breast tomosynthesis allows identification of more architectural distortions), optimal management is evolving. Physicians in some practices are using a multidisciplinary approach to the management of RSLs when deciding on surgical excision of these lesions versus imaging follow-up. These discussions also incorporate individual patient risk factors and greater patient informed medical decision making. Reported upgrade rates of RSLs at core needle biopsy vary and can depend on the sampling method, number of samples, gauge of the needle, target being sampled, and radiologic-pathologic concordance or discordance. A precise sampling technique also allows greater accuracy of diagnosis and lower upgrade rates for these lesions, with radiologic-pathologic correlation as an integral component for further management decisions. The authors review the overall histopathologic, clinical, and imaging features of RSLs and discuss appropriate management based on currently available data regarding upgrade rates. ©RSNA, 2023 Quiz questions for this article are available through the Online Learning Center.

Diagnostic Pitfalls in Breast Cancer Pathology With an Emphasis on Core Needle Biopsy Specimens.

CONTEXT.­: Breast pathology has many mimics and diagnostic pitfalls. Evaluation of malignant breast lesions, particularly in the biopsy setting, can be especially challenging, with diagnostic errors having significant management implications. OBJECTIVE.­: To discuss the pitfalls encountered when evaluating ductal carcinoma in situ and invasive breast carcinomas, providing histologic clues and guidance for appropriate use and interpretation of immunohistochemistry to aid in the correct diagnosis. DATA SOURCES.­: Data were obtained from review of pertinent literature of ductal carcinoma in situ and invasive breast carcinomas and from the experience of the authors as practicing breast pathologists. CONCLUSIONS.­: Awareness of the pitfalls in diagnosing breast cancers is important when creating a differential diagnosis for each breast lesion evaluated. This review will cover some of these scenarios to aid in the diagnostic process.

Loss of PTEN Expression, PIK3CA Mutations, and Breast Cancer Survival in the Nurses' Health Studies.

BACKGROUND: The relationships between PTEN loss and/or PIK3CA mutation and breast cancer prognosis remain controversial. We aim to examine the associations in large epidemiologic cohorts. METHODS: We followed women with invasive breast cancer from the Nurses' Health Studies with available data on tumor PTEN expression (n = 4,111) and PIK3CA mutation (n = 2,930). PTEN expression was evaluated by IHC and digitally scored (0%-100%). Pyrosequencing of six hotspot mutations of PIK3CA was performed. RESULTS: We found loss of PTEN expression (≤10%) occurred in 17% of cases, and PIK3CA mutations were detected in 11% of cases. After adjusting for clinical and lifestyle factors, PTEN loss was not associated with worse breast cancer-specific mortality among all samples [HR, 0.85; 95% confidence intervals (CI), 0.71-1.03] or among estrogen receptor (ER)-positive tumors (HR, 0.99; 95% CI, 0.79-1.24). However, among ER-negative tumors, PTEN loss was associated with lower breast cancer-specific mortality (HR, 0.68; 95% CI, 0.48-0.95). PIK3CA mutation was not strongly associated with breast cancer-specific mortality (HR, 0.89; 95% CI, 0.67-1.17). Compared with tumors without PTEN loss and without PIK3CA mutation, those with alterations (n = 540) were not at higher risk (HR, 1.07; 95% CI, 0.86-1.34). However, women with both PTEN loss and PIK3CA mutation (n = 38) were at an increased risk of breast cancer-specific mortality (HR, 1.65; 95% CI, 0.83-3.26). CONCLUSIONS: In this large epidemiologic study, the PTEN-mortality association was more pronounced for ER-negative tumors, and the joint PTEN loss and PIK3CA mutation may be associated with worse prognosis. IMPACT: Further studies with a larger sample of ER-negative tumors are needed to replicate our findings and elucidate underlying mechanisms.

Characterization of True and False Positive Findings on Contrast-Enhanced Mammography.

RATIONALE AND OBJECTIVES: The purpose of this paper is to characterize true and false positive findings on contrast-enhanced mammography (CEM) and correlate enhancement pattern and method of detection with pathology outcomes. MATERIALS AND METHODS: This was an IRB-approved retrospective review of diagnostic CEM performed from December 2015 through December 2019 for which biopsy was recommended. Background parenchymal enhancement, tissue density, finding features, pathologic/clinical outcomes, and method of detection were captured. CEM includes low-energy images (LE), similar to standard 2D mammography, and recombined images (RI) that show enhancement. 'MG-detected' findings were identified on mammography or LE. 'RI-detected' findings were identified due to enhancement on RI. The positive predictive value (PPV2) was calculated on a per-case and a per-finding level. Comparisons were performed using Pearson chi-square and Fisher exact tests. RESULTS: One hundred sixty CEM cases with 220 findings were evaluated with a case PPV2 of 58.1%. 32.3% (71/220) of lesions were RI-detected.  The PPV2 of RI-detected enhancement was 40.8% with subanalysis revealing PPV2 of 22.2%, 32%, and 51.4% for foci, NME, and masses, respectively. The PPV2 of MG-detected enhancement was 73.5% with subanalysis revealing PPV2 of 50%, 54.1%, and 83.8% for foci, NME, and masses, respectively. There were 100 false positives findings, 42 of which were RI-detected. CONCLUSION: PPV2 of diagnostic CEM is within the range of other diagnostic breast imaging exams. However false positives remain a challenge, especially for RI-detected findings. Additional efforts to improve specificity of RI-detected findings are worthwhile.

Limited Reporting of Histopathologic Details in a Multi-Institutional Academic Cohort of Phyllodes Tumors: Time for Standardization.

BACKGROUND: Phyllodes tumors are rare fibroepithelial neoplasms that are classified by tiered histopathologic features. While there are protocols for the reporting of cancer specimens, no standardized reporting protocol exists for phyllodes. METHODS: We performed an 11-institution contemporary review of phyllodes tumors. Granular histopathologic details were recorded, including the features specifically considered for phyllodes grade classification. RESULTS: Of 550 patients, median tumor size was 3.0 cm, 68.9% (n = 379) of tumors were benign, 19.6% (n = 108) were borderline, and 10.5% (n = 58) were malignant. All cases reported the final tumor size and grade classification. Complete pathologic reporting of all histopathologic features was present in 15.3% (n = 84) of cases, while an additional 35.6% (n = 196) were missing only one or two features in the report. Individual details regarding the degree of stromal cellularity was not reported in 53.5% (n = 294) of cases, degree of stromal atypia in 58.0% (n = 319) of cases, presence of stromal overgrowth in 56.2% (n = 309) of cases, stromal cell mitoses in 37.5% (n = 206) of cases, and tumor border in 54.2% (n = 298) of cases. The final margin status (negative vs. positive) was omitted in only 0.9% of cases, and the final negative margin width was specifically reported in 73.8% of cases. Reporting of details was similar across all sites. CONCLUSION: In this academic cohort of phyllodes tumors, one or more histopathologic features were frequently omitted from the pathology report. While all features were considered by the pathologist for grading, this limited reporting reflects a lack of reporting consensus. We recommend that standardized reporting in the form of a synoptic-style cancer protocol be implemented for phyllodes tumors, similar to other rare tumors.

#EBUSTwitter: Novel Use of Social Media for Conception, Coordination, and Completion of an International, Multicenter Pathology Study.

CONTEXT.­: Social media sites are increasingly used for education, networking, and rapid dissemination of medical information, but their utility for facilitating research has remained largely untapped. OBJECTIVE.­: To describe in detail our experience using a social media platform (Twitter) for the successful initiation, coordination, and completion of an international, multi-institution pathology research study. DESIGN.­: Following a tweet describing a hitherto-unreported biopsy-related histologic finding in a mediastinal lymph node following endobronchial ultrasound-guided transbronchial needle aspiration, a tweet was posted to invite pathologists to participate in a validation study. Twitter's direct messaging feature was used to create a group to facilitate communication among participating pathologists. Contributing pathologists reviewed consecutive cases of mediastinal lymph node resection following endobronchial ultrasound-guided transbronchial needle aspiration and examined them specifically for biopsy site changes. Data spreadsheets containing deidentified data and digital photomicrographs of suspected biopsy site changes were submitted via an online file hosting service for central review by 5 pathologists from different institutions. RESULTS.­: A total of 24 pathologists from 14 institutions in 5 countries participated in the study within 143 days of study conception, and a total of 297 cases were collected and analyzed. The time interval between study conception and acceptance of the manuscript for publication was 346 days. CONCLUSIONS.­: To our knowledge, this is the first time that a social media platform has been used to generate a research idea based on a tweet, recruit coinvestigators publicly, communicate with collaborating pathologists, and successfully complete a pathology study.

Displaced Cartilage Within Lymph Node Parenchyma Is a Novel Biopsy Site Change in Resected Mediastinal Lymph Nodes Following EBUS-TBNA.

Biopsy site changes in mediastinal lymph nodes (LNs) attributable to prior endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) have not been studied in a systematic manner. Twenty-four contributors from 14 institutions in 5 countries collaborated via social media (Twitter) to retrospectively review consecutive cases of resected mediastinal LNs from patients with prior EBUS-TBNA. Resected LNs were reexamined by submitting pathologists for changes attributable to EBUS-TBNA. Patients who received neoadjuvant therapy were excluded. Cases with suspected biopsy site changes underwent central review by 5 pathologists. A total of 297 mediastinal LN resection specimens from 297 patients (183 male/114 female, mean age: 65 y, range: 23 to 87) were reviewed. Biopsy site changes were most common in station 7 (10 cases) followed by 11R, 4R, and 10R, and were found in 34/297 (11.4%) cases, including displacement of tiny cartilage fragments into LN parenchyma in 26, intranodal or perinodal scars in 7, and hemosiderin in 1. Cartilage fragments ranged from 0.26 to 1.03 mm in length and 0.18 to 0.62 mm in width. The mean interval between EBUS-TBNA and LN resection was 38 days (range: 10 to 112) in cases with biopsy site changes. A control group of 40 cases without prior EBUS-TBNA, including 193 mediastinal LN stations, showed no evidence of biopsy site changes. Biopsy site changes are identified in a subset of resected mediastinal LNs previously sampled by EBUS-TBNA. The location of the abnormalities, temporal association with prior EBUS-TBNA, and the absence of such findings in cases without prior EBUS-TBNA support the contention that they are caused by EBUS-TBNA.

Management of BIRADS 3, 4A, and 4B Lesions Diagnosed as Pure Papilloma by Ultrasound-Guided Core Needle Biopsy: Is Surgical Excision Necessary?

RATIONALE AND OBJECTIVES: There is lack of consensus on managing papillomas due to varied upgrade rates in the literature related to variability in the studied populations. We specifically studied upgrade rates of pure papilloma diagnosed with ultrasound core biopsy (UCB) using spring-loaded (SLB) and vacuum-assisted (VAB) biopsy devices in patients with low-to-intermediate pre-test probability for malignancy on imaging. MATERIALS & METHODS: From 01/01/2008 to 06/30/2016, 227 patients with 248 pure papillomas classified as BI-RADS 3, 4a, and 4b were diagnosed by UCB and underwent surgical excision or clinical and/or imaging follow-up. Imaging features, biopsy device, and final pathology were documented. RESULTS: 177 lesions were biopsied with SLB (14-gauge) and 71 lesions with VAB (9-13 gauges). At surgery, upgrade rates to high-risk lesions and malignancy for SLB were 14.3% (22/154) and 1.9% (3/154), and for VAB were 3.5% (2/57) and 0% (0/57), respectively (p < 0.05). The combined surgical upgrade rate to high-risk lesions and malignancy was 11.4% (24/211) and 1.4% (3/211), respectively. The overall upgrade rate (including surgical and clinical and/or imaging follow-up) to high-risk lesions and malignancy was 9.7% (24/248) and 1.2% (3/248), respectively. No ultrasound features were predictive of upgrade. Rates of complete excision were 7.1% (11/154) for SLB and 19.3% (11/57) for VAB (p < 0.05). CONCLUSION: BI-RADS 3, 4a, or 4b masses biopsied with UCB revealed pure papilloma upgrade to malignancy in less than 2% of cases. SLB was associated with greater upgrades compared with VAB. Therefore, follow-up imaging is a reasonable alternative to excision, particular in those sampled by VAB. Excision could be considered if the diagnosis of a high-risk lesion would change clinical management.

Multiscale nonlinear microscopy and widefield white light imaging enables rapid histological imaging of surgical specimen margins.

The ability to histologically assess surgical specimens in real-time is a long-standing challenge in cancer surgery, including applications such as breast conserving therapy (BCT). Up to 40% of women treated with BCT for breast cancer require a repeat surgery due to postoperative histological findings of close or positive surgical margins using conventional formalin fixed paraffin embedded histology. Imaging technologies such as nonlinear microscopy (NLM), combined with exogenous fluorophores can rapidly provide virtual H&E imaging of surgical specimens without requiring microtome sectioning, facilitating intraoperative assessment of margin status. However, the large volume of typical surgical excisions combined with the need for rapid assessment, make comprehensive cellular resolution margin assessment during surgery challenging. To address this limitation, we developed a multiscale, real-time microscope with variable magnification NLM and real-time, co-registered position display using a widefield white light imaging system. Margin assessment can be performed rapidly under operator guidance to image specific regions of interest located using widefield imaging. Using simulated surgical margins dissected from human breast excisions, we demonstrate that multi-centimeter margins can be comprehensively imaged at cellular resolution, enabling intraoperative margin assessment. These methods are consistent with pathology assessment performed using frozen section analysis (FSA), however NLM enables faster and more comprehensive assessment of surgical specimens because imaging can be performed without freezing and cryo-sectioning. Therefore, NLM methods have the potential to be applied to a wide range of intra-operative applications.

Rapid histopathological imaging of skin and breast cancer surgical specimens using immersion microscopy with ultraviolet surface excitation.

Rapid histopathological evaluation of fresh, unfixed human tissue using optical sectioning microscopy would have applications to intraoperative surgical margin assessment. Microscopy with ultraviolet surface excitation (MUSE) is a low-cost optical sectioning technique using ultraviolet illumination which limits fluorescence excitation to the specimen surface. In this paper, we characterize MUSE using high incident angle, water immersion illumination to improve sectioning. Propidium iodide is used as a nuclear stain and eosin yellow as a counterstain. Histologic features of specimens using MUSE, nonlinear microscopy (NLM) and conventional hematoxylin and eosin (H&E) histology were evaluated by pathologists to assess potential application in Mohs surgery for skin cancer and lumpectomy for breast cancer. MUSE images of basal cell carcinoma showed high correspondence with frozen section H&E histology, suggesting that MUSE may be applicable to Mohs surgery. However, correspondence in breast tissue between MUSE and paraffin embedded H&E histology was limited due to the thicker optical sectioning in MUSE, suggesting that further development is needed for breast surgical applications. We further demonstrate that the transverse image resolution of MUSE is limited by the optical sectioning thickness and use co-registered NLM to quantify the improvement in MUSE optical sectioning from high incident angle water immersion illumination.

Crowdsourcing scoring of immunohistochemistry images: Evaluating Performance of the Crowd and an Automated Computational Method.

The assessment of protein expression in immunohistochemistry (IHC) images provides important diagnostic, prognostic and predictive information for guiding cancer diagnosis and therapy. Manual scoring of IHC images represents a logistical challenge, as the process is labor intensive and time consuming. Since the last decade, computational methods have been developed to enable the application of quantitative methods for the analysis and interpretation of protein expression in IHC images. These methods have not yet replaced manual scoring for the assessment of IHC in the majority of diagnostic laboratories and in many large-scale research studies. An alternative approach is crowdsourcing the quantification of IHC images to an undefined crowd. The aim of this study is to quantify IHC images for labeling of ER status with two different crowdsourcing approaches, image-labeling and nuclei-labeling, and compare their performance with automated methods. Crowdsourcing- derived scores obtained greater concordance with the pathologist interpretations for both image-labeling and nuclei-labeling tasks (83% and 87%), as compared to the pathologist concordance achieved by the automated method (81%) on 5,338 TMA images from 1,853 breast cancer patients. This analysis shows that crowdsourcing the scoring of protein expression in IHC images is a promising new approach for large scale cancer molecular pathology studies.

Plasma 25-Hydroxyvitamin D and Risk of Breast Cancer in Women Followed over 20 Years.

Experimental evidence supports a protective role of 25-hydroxyvitamin D [25(OH)D] in breast carcinogenesis, but epidemiologic evidence is inconsistent. Whether plasma 25(OH)D interacts with breast tumor expression of vitamin D receptor (VDR) and retinoid X receptor-α (RXR) has not been investigated. We conducted a nested case-control study in the Nurses' Health Study, with 1,506 invasive breast cancer cases diagnosed after blood donation in 1989-1990, 417 of whom donated a second sample in 2000-2002. VDR and RXR expression were assessed by immunohistochemical staining of tumor microarrays (n = 669 cases). Multivariate relative risks (RR) and 95% confidence intervals (CI) were calculated using conditional logistic regression. Plasma 25(OH)D levels were not associated with breast cancer risk overall [top (≥32.7 ng/mL) vs. bottom (<17.2 ng/mL) quintile RR = 0.87; 95% CI, 0.67-1.13; P trend = 0.21]. 25(OH)D measured in summer (May-October) was significantly inversely associated with risk (top vs. bottom quintile RR = 0.66; 95% CI, 0.46-0.94; P trend = 0.01); winter levels (November-April) were not (RR = 1.10; 95% CI, 0.75-1.60; P trend = 0.64; P interaction = 0.03). 25(OH)D levels were inversely associated with risk of tumors with high expression of stromal nuclear VDR [≥30 ng/mL vs. <30 ng/mL RR (95% CI): VDR ≥ median = 0.67 (0.48-0.93); VDR < median = 0.98 (0.72-1.35), P heterogeneity = 0.12] and significantly stronger for summer measures (P heterogeneity = 0.01). Associations were not significantly different by RXR expression. No overall association was observed between plasma 25(OH)D and breast cancer risk. However, our results suggest women with high, compared with low, plasma 25(OH)D levels in the summer have a reduced breast cancer risk, and plasma 25(OH)D may be inversely associated with risk of tumors expressing high levels of VDR. Cancer Res; 76(18); 5423-30. ©2016 AACR.