Momin T. Siddiqui

Objective: Fine‐needle aspiration (FNA) is central to evaluation of thyroid nodules, yet risk stratification for follicular neoplasm categorized as Bethesda IV (FN/SFN) remains challenging due to substantial cytologic overlap and evolving diagnostic criteria. This study assesses whether subclassifying FN/SFN cases by nuclear atypia, oncocytic features, together with molecular testing, improves risk of malignancy (ROM) estimation and clinical decision‐making. Methods: This was a retrospective review of thyroid FNAs classified as Bethesda Category IV at our institution from January 2015 to December 2024. FN/SFN cases were subcategorized as FN/SFN, FN/SFN with PTC‐like nuclear features (FN/SFN‐PTC) and oncocytic follicular neoplasm (FN/SFN‐O). Risk of malignancy (ROM) was calculated for each subcategory and correlated with surgical resections when available. Molecular testing results, including mutational analysis and molecular risk, were extracted from Afirma and ThyGeNEXT/ThyraMIR. Chi‐squared analysis was used for statistical analysis with p < 0.05 being significant. Results: Of 13,865 thyroid FNAs, 449 (3.2%) were classified as Bethesda Category IV; 146 had surgical follow‐up (1.1%). FN/SFN‐PTC demonstrated the highest ROM (50.3%) and neoplastic rate (78.1%; p = 0.03). RAS‐like mutations were the most common molecular alteration (27.4%), but were not significantly predictive of malignancy. BRAF‐like alterations were exclusive to FN/SFN‐PTC and all BRAF‐like cases were malignant. FN/SFN‐O showed elevated ROM and neoplastic rate compared with conventional FN. FN/SFN‐O had the highest proportion of mutation‐negative cases (89.4%; p < 0.05); however, 40% of mutation‐negative FN/SFN‐O cases were malignant on surgical resection. Conclusions: Cytologic subcategorization of Bethesda Category IV thyroid FNA specimens provides clinically meaningful and statistically significant risk stratification. PTC‐like nuclear atypia is associated with higher ROMs and neoplastic rates. Oncocytic features show distinct molecular characteristics in which mutation‐negative status does not reliably exclude malignancy, highlighting a diagnostic challenge. Molecular testing complements cytologic subcategorization.

We developed a pan-cancer patient-derived organoid (PDO) platform comprising 220 PDOs from 191 patients across 15 cancer types to advance functional precision oncology. Comprehensive characterization demonstrated high fidelity to parent tumors, with 93% histopathology concordance, 80% median genomic concordance for driver mutations, and a 0.85 median gene expression correlation. Expression profiles remained largely stable over 10 passages, ensuring reproducibility for long-term screening. Clonality analysis showed that 85% of dominant tumor clones were preserved, with genomic concordance directly reflecting clonal similarity. Even PDOs with lower concordance retained key oncogenic drivers, validating their utility as disease models. Functional assays revealed that 58% of PDOs from patients ineligible for US Food and Drug Administration–approved poly(adenosine 5′-diphosphate–ribose) polymerase inhibitors were sensitive to talazoparib, linked to DNA damage repair alterations. Furthermore, combination screens identified agents that overcome resistance, particularly in TP53 -mutant models. Our platform enables the investigation of targeted therapies and molecular drivers of drug sensitivity, providing translational insights for personalized treatment beyond current biomarker guidelines.

Introduction: The aim of this project is to assess interobserver agreement for programmed death‐ligand 1 (PD‐L1) scoring on of non–small cell lung cancer (NSCLC) on cytological specimens in a large‐scale multicenter study, by exploiting the cell block‐derived tissue microarray (cbTMA) approach.Methods: A total of 65 cell blocks (CB) diagnosed as NSCLC were retrospectively collected and selected for TMA preparation. Hematoxylin–eosin and PD‐L1 stained slides were digitized and uploaded on a free web sharing platform. Participants were asked to provide PD‐L1 assessment by using the clinically relevant cutoff of tumor proportion score (TPS) (50%). Interobserver agreement was calculated using Fleiss’s κ.Results: Of 65 CBs, 11 were deemed not suitable; therefore, an overall number of 54 cores were used for the preparation of four TMAs. A total of 1674 evaluations were provided by 31 cytopathologists from 21 different institutions in nine countries. The statistical analysis showed a moderate overall agreement (κ = 0.49). The highest agreement was achieved in the TPS >50% category (κ = 0.57); moderate agreement was observed in TPS <1% category (κ = 0.51) and the lowest κ value was obtained for TPS 1%–49% category (k = 0.32).Conclusions: The overall moderate agreement observed showed that there is still room for improvement in inter‐pathologist agreement for PD‐L1 evaluation on cytological samples, highlighting the need for standardization in sample preparation, focused training in PD‐L1 evaluation on cytological material, and the integration of machine learning tools to improve interobserver consistency.

Background: The unsatisfactory rate of Pap tests (PT) is an important quality assurance (QA) metric for a cytopathology laboratory. At our institution, an unsatisfactory PT slide is followed by a second ThinPrep (TP) slide. The aim of this study is to evaluate this QA practice.Methods: Our laboratory processes an unsatisfactory TP PT with a follow‐up second TP slide with or without glacial acetic acid. The correlation between the unsatisfactory rate and the second slide rate test was examined.Results: A total of 2739 cases with a second TP slide were prepared for an unsatisfactory initial TP PT. After second slide preparation, 780 cases (28%) remained unsatisfactory. Using Spearman's rank correlation test, there was a notable negative correlation between the unsatisfactory rate and the second slide rate (rho = −0.42). Of those PTs recategorized as satisfactory TP, 1742 were negative for intraepithelial lesion or malignancy (NILM) (89%), 135 as atypical squamous cells of undetermined significance (ASC‐US) (7%), 37 as low‐grade squamous intraepithelial lesion (LSIL) (1.9%), 11 as atypical squamous cells cannot exclude high‐grade squamous intraepithelial lesion (ASC‐H) (0.6%), 8 as high‐grade squamous intraepithelial lesion (HSIL) (0.4%), and 20 as atypical glandular cells (AGC) (1%). The final Bethesda categorization for all cases and the human papilloma virus (HPV) data was tabulated.Conclusions: A second slide preparation significantly reduced the unsatisfactory rate of the PT. This also had a significant impact by detecting clinically significant lesions. HPV testing can also be performed on slides reclassified from unsatisfactory to ASC‐US or higher.

The recently published WHO Reporting System for Pancreaticobiliary Cytopathology (World Health Organization [WHO] System) is an international approach to the standardized reporting of pancreaticobiliary cytopathology, updating the Papanicolaou Society of Cytopathology System for Reporting Pancreaticobiliary Cytology (PSC System). Significant changes were made to the categorization of benign neoplasms, intraductal neoplasms, mucinous cystic neoplasms, and malignant neoplasms considered low grade. Benign neoplasms, such as serous cystadenoma, categorized as Neoplastic: benign in the PSC system, are categorized as Benign/negative for malignancy in the WHO system. Pancreatic neuroendocrine tumor, solid‐pseudopapillary neoplasm, and gastrointestinal stromal tumor, categorized as Neoplastic: other in the PSC system, are categorized as Malignant in the WHO System in accord with their classification in the 5th edition WHO Classification of Digestive System Tumours (2019). The two new categories of Pancreaticobiliary Neoplasm Low‐risk/grade and Pancreaticobiliary Neoplasm High‐risk/grade are mostly limited to intraductal neoplasms and mucinous cystic neoplasms. Low‐risk/grade lesions are mucinous cysts, with or without low‐grade epithelial atypia. High‐risk/grade lesions contain neoplastic epithelium with high‐grade epithelial atypia. Correlation with clinical, imaging, and ancillary studies remains a key tenet. The sections for each entity are written to highlight key cytopathological features and cytopathological differential diagnoses with the pathologist working in low resource setting in mind. Each section also includes the most pertinent ancillary studies useful for the differential diagnosis. Sample reports are provided for each category. Finally, the book provides a separate section with risk of malignancy and management recommendations for each category to facilitate decision‐making for clinicians.

Introduction: The advances of minimally invasive endoscopy-guided procedures that usually yield limited diagnostic material changed pancreaticobiliary cytopathology into one of the most challenging areas of cytopathology given the abundance of differential diagnoses to be considered when dealing with limited specimens. Case Presentation: We describe a few challenging examples of potential pitfalls in pancreatobiliary cytopathology evaluation collected from a busy academic hospital (tertiary) center. Case 1 illustrates the challenges in handling paucicellular specimens from pancreatic solid lesions in which differential diagnoses may include acinar cell carcinoma, neuroendocrine tumors, adenocarcinoma, or even benign pancreatic tissue, among others. Case 2 illustrates the pitfalls in evaluating limited specimens from patients with chronic pancreatitis, specially when distinguishing exuberant reactive atypia from dysplastic changes is mandatory. Case 3 illustrates pitfalls in distinguishing malignancy from reactive changes in biliary brushing specimens from patients with primary sclerosing cholangitis. Finally, cases 4 and 5 highlight the importance of including the possibility of pancreatic metastasis in the differential diagnoses of some pancreatic lesions. Conclusion: Over time, there has been an increasing demand for pathologists to render diagnoses on limited specimens obtained through minimally invasive procedures which can be frequently challenging even for the most experienced professionals. In many difficult cases, salvaging additional material for a cell block can turn out to be extremely helpful given the possibility of utilizing additional ancillary tests for diagnostic confirmation.