The success of trastuzumab deruxtecan (T-DXd) has expanded the therapeutic relevance of human epidermal growth factor receptor 2 (HER2) expression beyond the traditional HER2-positive population. This has led to evolving concepts such as HER2-low, HER2-ultralow, and HER2-null. Accurately and reproducibly distinguishing HER2 immunohistochemistry (IHC) scores 0, 0+, and 1+ remains challenging because of intratumoral heterogeneity and interobserver variability. This review discusses the challenges in HER2 assessment.

The evolution of HER2 testing and recent guideline updates were reviewed. The implications of HER2-low and HER2-ultralow breast cancers for HER2 testing were discussed.

Challenges in HER2 assessment include interobserver variability and intratumoral heterogeneity. Potential strategies for accurately and reproducibly distinguishing all HER2 IHC categories, especially HER2 IHC 0 from HER2 IHC 0+, are also discussed. Significant discordance has been reported in interpreting low-level HER2 expression. Revisiting HER2 testing guidelines, improving HER2 assessment, and developing sensitive, objective, and reproducible detection methods may reduce variability. No alternative method has been validated as a companion diagnostic for determining eligibility for T-DXd or other HER2-targeted antibody–drug conjugates. Consequently, HER2 immunohistochemistry, supplemented by reflex in situ hybridization testing for equivocal cases, remains the standard despite its limitations at the HER2-low threshold. Digital pathology, quantitative image analysis, artificial intelligence-assisted interpretation, molecular profiling, and other emerging technologies may provide more objective, sensitive, and reproducible approaches to HER2 assessment.

The evolving concepts of HER2-low, HER2-ultralow, and HER2-null emphasize the need to accurately and reproducibly distinguish HER2 IHC categories. Further research and technological advances are needed to better classify HER2 status.

Epithelial-myoepithelial neoplasms of the breast are biphasic tumors composed of both epithelial and myoepithelial cell populations. Their rarity, broad morphologic spectrum, and evolving molecular characterization pose substantial diagnostic challenges, underscoring the need for an integrated review of their diagnostic and molecular features. This review aims to provide a comprehensive overview of epithelial-myoepithelial neoplasms of the breast, emphasizing their morphologic spectrum, diagnostic challenges, and emerging molecular features.

This narrative review is based on a review of the pertinent English-language literature and the author’s firsthand experience as a practicing breast pathologist.

Benign epithelial-myoepithelial tumors include pleomorphic adenoma and classic adenomyoepithelioma. Pleomorphic adenoma of the breast closely resembles its salivary gland counterpart as well as the benign mixed tumor of the skin. In contrast, adenomyoepithelioma is unique to the breast and exhibits a broad spectrum of histomorphologic patterns. Most adenomyoepitheliomas follow a benign clinical course; however, atypical adenomyoepitheliomas may demonstrate more aggressive behavior, including local recurrence, malignant transformation, and, rarely, metastasis. Molecular studies have identified PLAG1/HMGA2 rearrangements in a subset of pleomorphic adenomas and recurrent HRAS Q61 and PI3K-AKT pathway alterations in adenomyoepitheliomas. In malignant adenomyoepithelioma, the malignant component may arise from the ductal epithelial cells, the myoepithelial cells, or both.

The rarity of epithelial-myoepithelial tumors, together with their marked histologic heterogeneity, makes them diagnostically challenging and underscores the potential for diagnostic pitfalls.

Metabolic dysfunction–associated steatotic liver disease (MASLD) and alcohol–associated liver disease (ALD) are leading causes of chronic liver injury with overlapping clinical and histological presentations. This study evaluated a composite histologic pattern, termed the Alcohol Liver Pathology Signature (ALPS), for potential use in the differential diagnosis of ALD and MASLD and to explore potential clinical and demographic correlates.

In this retrospective diagnostic-accuracy study, we reviewed 292 liver biopsies performed between 2021 and 2023. ALPS comprised five histologic features: ductular reaction, bile stasis, neutrophilic satellitosis, portal inflammation, and advanced fibrosis (stage 3–4). Cases were categorized as absent (0–1 features), partial (2–3 features), or full (4–5 features). ALPS performance was then further evaluated in an independent temporal validation cohort of de-identified, mixed, and blindly reviewed liver biopsies collected between 2024 and 2025.

MASLD was the most common diagnosis (25.3%), whereas ALD accounted for 4.8%. Full ALPS was present in 92.8% of clinically diagnosed ALD cases. In MASLD, individual ALPS features were common, but only 20.3% showed full ALPS, corresponding to 79.7% specificity for distinguishing clinically diagnosed ALD from MASLD. The independent temporal validation cohort showed findings consistent with those of the original cohort. Finally, within MASLD, full ALPS was more frequent in African American than non-African American patients (29.2% vs. 3.8%).

ALPS may serve as a histologic prompt for further assessment of potential alcohol exposure but should not be considered etiologically specific. Prospective validation incorporating objective measures of alcohol exposure is warranted.

The International Academy of Cytology Yokohama System for Reporting Breast Fine-Needle Aspiration Biopsy Cytology was developed by a group of expert cytopathologists and clinicians in the breast field. Five categories are defined to stratify breast lesions by their risks of malignancy and managed accordingly. Clinical and radiologic information (triple test) are critical for further management. Ultrasound guidance, and rapid on-site evaluation are valuable for improving the rate of definitive diagnosis. Ancillary studies can be tested on cytologic samples to provide prognostic, predictive information as well as diagnostic clues. Based on many published studies in different institutions worldwide, the implementation of the system appears to have been successful. However, further studies are important for improvements and modifications to the current system.

The Bethesda System for Reporting Thyroid Cytopathology is the first reporting system established in non-gynecologic cytopathology after the Bethesda System for Reporting Cervical Cytopathology. It adopts the same concept of providing a uniform reporting system for all pathologists and clinicians to follow in thyroid cytology. The reporting system is composed of six diagnostic categories. There are defined diagnostic criteria, estimated risk of malignancy, and management recommendations for each category. The reporting system has undergone two revisions upon the emergence of a new entity, updated terminology in histology, and development and refinement of molecular testing. The third edition is soon to be published in 2023. This review will provide an updated summary of the reporting system. Potential diagnostic pitfalls and molecular testing are also discussed.

The Paris System for Reporting Urinary Cytology (TPS 1.0, published in 2016) is the first standardized, evidence-based reporting system established as an international reporting system for urine specimens after the International Congress of Cytology in Paris. Its primary purpose is to reduce the rate of unnecessary indeterminate diagnoses but maintain the excellent performance of urine cytology, in detecting high-grade urothelial carcinoma. The reporting system comprises six diagnostic categories, as well as each category’s diagnostic criteria, estimated risk of malignancy, and management recommendations. After six years, TPS 2.0 was applied in 2022 upon the unfolding of new data. TPS 2.0 clarifies the diagnosis categories and updates the risk of malignancy in each category and developments of molecular tests. This review provides an updated summary of TPS 2.0. Some diagnostic pitfalls and molecular tests were also discussed.