Emad A. Rakha

Flower-Win/Lose signaling underlies a tumor–host fitness conflict in ovarian cancer, in which tumor-derived exosomal Tu-stroma reduces the fitness of surrounding host cells, favoring tumor expansion within host tissues. High-grade serous carcinoma (HGSC), the most prevalent histotype of epithelial ovarian cancer and leading cause of ovarian-cancer-related mortality, arises from serous tubal intraepithelial carcinoma (STIC), a noninvasive precursor typically identifiable only by histopathologic examination of excised fallopian tube tissue. Here we evaluated Tu-stroma, a tumor-associated long noncoding RNA enriched in serum extracellular vesicles (EVs), as a circulating biomarker in STIC and early-stage HGSC, representing the earliest histopathologically defined phases of disease. Tu-stroma was quantified in serum EVs from 506 individuals with histologically normal adnexa, benign-adnexal lesions, isolated STIC and HGSC across International Federation of Gynecology and Obstetrics (FIGO) stages I–IV. Normalized EV Tu-stroma ΔC_T values were elevated in STIC (n = 43) and HGSC (n = 232) versus controls (n = 143) and benign-adnexal lesions (n = 88), including premenopausal women (controls = 57, benign = 34, STIC = 32, HGSC = 88). In paired receiver operating characteristic analyses, Tu-stroma showed higher discrimination than cancer antigen 125 (CA125) for STIC versus controls (area under the curve (AUC) = 0.99 versus 0.59, P < 0.001) and benign-adnexal masses (0.99 versus 0.31, P < 0.001), and for HGSC versus controls (AUC = 0.99 versus 0.96, P = 0.001) and benign-adnexal masses (0.98 versus 0.84, P < 0.001). Tu-stroma showed no systematic elevation across inflammatory or physiologic comparators (n = 116) or nonovarian malignancies (n = 160), each assessed against healthy controls (n = 100), supporting disease-context specificity. Modeled risk-enriched contexts yielded predictive values compatible with intended-use populations. These findings identify Tu-stroma as a candidate EV-RNA marker associated with pre-invasive and early HGSC biology. Prospective evaluation in consecutively enrolled real-world cohorts is required to validate diagnostic performance, predictive value and clinical utility.

Papillary breast neoplasms comprise a heterogeneous spectrum ranging from benign intraductal papillomas to invasive carcinomas and remain among the most diagnostically challenging breast lesions because of overlapping morphology, variable myoepithelial cell (MEC) distribution, sampling limitations, the mismatch between conventional histological criteria and clinical behaviour, and evolving concepts of stromal invasion. Recent advances, including the sixth edition of the WHO Classification of Breast Tumours, have refined the classification of papillary neoplasms, particularly encapsulated papillary carcinoma (EPC), and solid papillary carcinoma (SPC). However, important diagnostic and management challenges remain, particularly in distinguishing overlapping papillary neoplasms from one another and from their numerous morphological mimics. This narrative review provides a practical, evidence-based diagnostic framework that integrates morphology, immunohistochemistry, radiological-pathological correlation, and emerging biological concepts. Particular emphasis is placed on contemporary concepts of invasion, recognising papillary neoplasia as a biological continuum rather than discrete entities, and on the limitations of applying conventional histological criteria beyond the biological context in which they were originally established. Recent developments in the classification of invasive papillary neoplasms, mixed papillary lesions, staging challenges, papillary lesion mimics, and interpretation of core needle biopsies are reviewed. Throughout, an integrated, context-dependent approach is advocated, emphasising the interpretation of morphology within its biological and clinicopathological context rather than reliance on isolated diagnostic criteria. This review provides a practical, biologically informed framework for the contemporary classification, diagnosis, and management of papillary breast neoplasms.

Background: Breast phyllodes tumours (PTs) are rare biphasic fibroepithelial neoplasms, classified into benign, borderline and malignant categories. Stromal mitotic activity is a key criterion in grading PT, but the methodology for mitotic assessment has not been clearly articulated. Materials and methods: We discuss the approach to determining stromal mitotic activity in PTs. Whether the most mitotically active area (hotspot) or an average count across several tumour regions should be adopted is reviewed. We also outline the operational protocol for mitotic hotspot evaluation, accounting for different microscope models with varying field diameters. Results: A standardized method of determining stromal mitoses in PTs is recommended in order to improve interobserver reproducibility and accuracy in grading PTs. The application of digital tools in stromal mitotic counting is also addressed. Conclusion: We advocate using the hotspot method of obtaining the highest stromal mitotic count, together with other histological parameters, to classify PTs.

Aims: Standardised diagnostic criteria in breast pathology primarily guide classification rather than real-world decision-making in borderline or context-dependent scenarios. This study evaluated question-and-answer data from international masterclass cohorts to characterise real-world diagnostic uncertainties, quantify cognitive domain distributions and detail expert decision-making frameworks. Methods: We analysed a structured dataset of 430 attendee questions collected across five international online Breast Pathology Masterclasses (2022–2026), each attended by over 500 participants. Questions were categorised into thematic and cognitive domains by the lead investigator, followed by a collaborative co-author audit to establish classification consensus. Faculty responses were evaluated to assess reasoning patterns, consensus points and areas of diagnostic variation. Results: Diagnostic uncertainty clustered within specific recurring clinical challenges, with borderline and grey-zone lesions constituting a primary focus. Threshold-based queries regarding diagnostic boundaries formed the single largest cognitive domain (40%), rather than queries seeking basic entity definitions. Other major clinical domains included biomarker interpretation, radiology–pathology discordance management and core biopsy sampling limitations. Analysis of faculty responses identified a recurring morphology-first, context-integrated and risk-informed approach to diagnostic decision-making. While consensus on foundational diagnostic principles was high, minor variations occurred in setting specific quantitative thresholds and framing diagnostic uncertainty in pathology reports. Conclusions: These exploratory findings indicate that practical challenges in diagnostic breast pathology frequently arise from boundary determination and contextual ambiguity rather than gaps in established disease classification schemes. Although expert judgement and confidence in managing diagnostic uncertainty develop substantially through experience, educational initiatives may complement experiential learning by making threshold calibration, risk communication and context-dependent reasoning more explicit.

Borderline breast lesions (B3 lesions, also termed lesions of uncertain malignant potential or high-risk lesions) represent a heterogeneous group of entities associated with variable risks of malignancy. While the management of screen-detected B3 lesions has become increasingly standardised, no dedicated international recommendations exist for symptomatic B3 lesions, despite them posing a distinct clinical challenge. Symptomatic lesions differ from screen-detected lesions in their mode of presentation, lesion characteristics, biopsy techniques, and diagnostic objectives; consequently, management strategies derived from screening populations may not be directly applicable. This review summarises the current evidence and proposes a pragmatic management framework for B3 lesions encountered in the symptomatic setting (defined as those presenting with breast symptoms outside population-based screening programmes). This is particularly relevant for patients under 50 years of age, where the primary objective is to exclude malignancy at the index site rather than solely to stratify long-term cancer risk. Clinical-radiological-pathological concordance and multidisciplinary assessment are central to management decisions. Lesions presenting as palpable abnormalities (which are typically larger) or those demonstrating radiological-pathological discordance warrant a lower threshold for additional sampling or excision. Conversely, selected concordant lesions without atypia may be managed conservatively following adequate sampling. The long-term cancer risk associated with epithelial atypia should also be considered with subsequent risk-based surveillance implemented where appropriate. Overall, management requires a risk-adapted, multidisciplinary approach integrating pathological, radiological, and clinical factors alongside patient symptoms and quality-of-life considerations. Given the limited evidence, current recommendations rely on expert consensus and a proposed practical framework. They underscore the need for large-scale, high-quality studies with long-term follow-up to establish formal clinical guidelines.

Background: Encapsulated papillary carcinoma (EPC) of the breast is an uncommon tumour with controversial biological behaviour and staging. Emerging evidence suggests that EPC with adverse pathological features (EPC‐A) may exhibit invasive potential. The absence of uniform staging criteria contributes to management variability. This study evaluates the clinicopathological characteristics and clinical course of high‐grade EPC (HG‐EPC), including EPC‐A. Materials and methods: This retrospective multicentre study (2000–2025) included 25 HG‐EPC cases, irrespectively of ER/PR and HER2 status. Tumours with frank stromal invasion beyond microinvasive foci were excluded. Histopathological re‐evaluation was performed in accordance with 2019 WHO classification criteria. Results: Of 38 cases reviewed, 25 fulfilled the inclusion criteria as EPC (mean age 57.2 years, mean tumour size 2.9 cm). Six cases (24%) demonstrated conventional‐type microinvasive components. A subset of 16 cases fulfilled criteria for EPC‐A, defined by high‐grade morphology in combination with ER/PR‐negative (or ER n = 13) to pT1 ( n = 4) or pT2 ( n = 7), and pT3 ( n = 1). Adjuvant chemotherapy and radiotherapy were administered in 7 and 12 patients respectively. During follow‐up, four local recurrences (three invasive and one in situ ) were observed. One of the locally recurrent patients subsequently developed distant metastasis, and one breast cancer‐related death occurred 200 months after diagnosis. Recurrence or death occurred in 20% (5/25) of patients despite therapy. Microinvasion was seen only in the EPC‐A tumours. Conclusion: HG‐EPC and EPC‐A overlap morphologically and diagnostically with frankly invasive carcinomas and demonstrate a non‐negligible risk of recurrence. Clinical outcomes and more frequent microinvasion in EPC‐A support the view that EPC‐A is more appropriately regarded as an indolent form of invasive carcinoma rather than a purely in situ lesion and demonstrate a non‐negligible risk of recurrence and highlight the need for standardized staging criteria.

Patient safety and diagnostic quality are central to modern histopathology practice. Current incident investigation approaches often rely on root cause analysis; however, its routine use as a universal method is insufficient to address the highly variable, cognitive, sociotechnical and multifactorial nature of histopathology errors. In practice, incidents range from simple technical failures to complex system-level events requiring distinct investigative strategies. A key limitation of current practice is the lack of proportionality, where similar methods are applied irrespective of case complexity. In addition, corrective actions frequently target the immediate error without adequately considering the broader system context, potentially increasing workload, introducing new risks or degrading long-term service performance and operational sustainability. In this narrative review, we propose a practical five-stage systems framework for incident management in histopathology. This framework integrates proportional incident classification, structured systems investigation, prospective evaluation of corrective actions to minimise unintended consequences, implementation of system-level improvements and continuous performance monitoring. By selectively applying established human factors and quality improvement methodologies according to incident complexity, the framework shifts incident management from retrospective error investigation towards proactive system optimisation and continuous organisational learning. Ultimately, it provides a practical, scalable approach that improves diagnostic reliability, reduces recurrence, enhances efficiency and ensures that corrective actions are effective, sustainable and aligned with real-world laboratory practice.

Ki‐67 is a well‐established marker of tumour proliferation and an important prognostic and predictive biomarker in breast cancer, particularly in hormone receptor–positive (HR‐positive), HER2‐negative disease. Despite its biological relevance, clinical implementation has been limited by the reported interobserver and interlaboratory variability. Recent therapeutic advances have created an increased need for accurate and reproducible Ki‐67 assessment in clinical practice. This review summarizes the biological basis for the use of Ki‐67 as a marker of proliferation, technical requirements for reliable immunohistochemistry and the influence of pre‐analytical and analytical variables on staining performance. We evaluate established and emerging scoring approaches and provide scoring recommendations for practising pathologists. A simplified calibrated global assessment method is presented as an alternative to exhaustive visual quantification that preserves its accuracy while substantially reducing scoring time and avoiding the variability of estimated methods. Image analysis/artificial intelligence (AI) using validated algorithms is recommended where available. We also review the role of Ki‐67 in predicting response to neoadjuvant endocrine and chemotherapy, its integration into prognostic models such as the PEPI score, and its utility in selecting patients for adjuvant CDK4/6 inhibition. The limitations of fixed cut‐off values are discussed, together with the potential advantages of tiered classification and continuous modelling. Finally, we outline the growing role of digital pathology and AI, which have demonstrated improved reproducibility, reduced turnaround time, and prognostic performance superior to manual scoring. Ki‐67 is a clinically meaningful biomarker, the value of which can only be fully realized through rigorous standardization, validated scoring approaches and close communication between pathologists and oncologists. This guidance provides a practical framework for high‐quality Ki‐67 assessment and supports its safe and effective integration into contemporary breast cancer management.

Whole slide imaging (WSI) is increasingly embedded in routine histopathology; however, histological grading of invasive breast carcinoma continues to rely on methodologies developed for conventional light microscopy. This narrative review aims to establish a practical and conceptually refined framework for applying the Nottingham grading system in the digital setting, with emphasis on improving reproducibility, standardisation and biological interpretability. An evidence‐informed, methodological analysis was undertaken, integrating published literature with expert practice to examine the impact of WSI on the assessment of tubule formation, nuclear pleomorphism and mitotic activity. Key technical, perceptual and interpretative challenges specific to digital pathology were identified, and practical, standardised approaches were developed. The three grading components are differentially affected by WSI. Tubule formation remains highly reproducible and is well suited to low‐power digital assessment. Nuclear pleomorphism demonstrates moderate variability, reflecting both intrinsic subjectivity and the influence of display and perceptual factors. Mitotic assessment represents the principal challenge, with variability arising from hotspot identification, area calibration and recognition of mitotic figures in the absence of z‐axis information. Defining counting areas in mm ² (optimally 2–3 mm ² ), prioritizing regions of increased tumour cellularity, and using calibrated high‐power screen fields improve reproducibility. Systematic underestimation of mitotic counts in WSI compared to light microscopy is recognised and is most relevant in cases near grading thresholds. Overall, histological grading can be performed reliably using WSI but requires methodological adaptation rather than direct transfer of glass slide‐based approaches. Standardization of hotspot selection, area calibration, and morphological interpretation is essential. This work provides a practical, evidence‐based framework to support consistent and biologically meaningful grading in contemporary digital pathology practice.