Ai D, Zhang Y, Viswanathan K
… +5 more, Zhang J, Magliocca KR, Steward-Tharp S, Hsiao WY, Shi Q
Cancer Cytopathol
· 2026 Mar · PMID 41748276
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BACKGROUND: Thyroid adenoma-associated (THADA) gene fusions are recurrent alterations in thyroid nodules that lead to the overexpression of insulin-like growth factor messenger RNA-binding protein 3 (IMP3). Although IMP3...BACKGROUND: Thyroid adenoma-associated (THADA) gene fusions are recurrent alterations in thyroid nodules that lead to the overexpression of insulin-like growth factor messenger RNA-binding protein 3 (IMP3). Although IMP3 immunohistochemistry has been studied in thyroid tumors, its utility for detecting THADA fusion-positive thyroid specimens remain unassessed. METHODS: The authors evaluated IMP3 expression in cytologic and surgical specimens from 20 indeterminate thyroid nodules. Eleven cases harbored THADA fusions, including THADA::IGF2BP3 (n = 9) and THADA::TRA2A (n = 2), whereas nine control cases lacked detectable THADA fusions. Hematoxylin-and-eosin staining and immunohistochemistry for IMP3 and NRAS Q61R were performed on available cell blocks and surgical specimens. Staining was scored based on extent and intensity, with a composite score >2 considered positive. RESULTS: All nodules with THADA fusions exhibited strong, diffuse, cytoplasmic IMP3 staining in lesional follicular cells, with no staining in adjacent normal thyroid tissue. All control cases were negative for IMP3. NRAS Q61R immunostaining was negative across all cases. CONCLUSIONS: The current findings in a limited cohort demonstrate that IMP3 is a promising surrogate marker for indeterminate thyroid nodules with THADA fusions in both cytologic and surgical specimens. In addition, IMP3 staining may aid in detecting subtle capsular or vascular invasion.
Lichtenberg RS, Mon KS, Mehrotra S
… +5 more, Trabzonlu L, Aragao A, Gordezky R, Akdas Y, Barkan GA
Cancer Cytopathol
· 2026 Mar · PMID 41663331
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BACKGROUND: The 21st Century Cures Act allows patients to have immediate access to their medical records. However, it is documented that health literacy levels in patient portal users vary, and results shared with patien...BACKGROUND: The 21st Century Cures Act allows patients to have immediate access to their medical records. However, it is documented that health literacy levels in patient portal users vary, and results shared with patients may require further explanation. The objective of this exploratory study was to evaluate if an artificial intelligence (AI) chatbot assistant (ChatGPT; Open AI, Inc.) may be used to simplify gynecologic cytopathology reports for patients. The authors also assessed pathologists' opinions on the quality of simplified pathology reports generated with ChatGPT. METHODS: An experienced cytopathologist created 15 unique gynecologic cytopathology reports based on The Bethesda System for Reporting Cervical Cytology. Two cytopathologists evaluated multiple possible prompts to ask ChatGPT for simplified, summarized explanations of cytopathology reports. The two prompts selected for this study were prompt 1 ("Explain this medical report to a child using simple language") and prompt 2 ("What are the most important things I should know from my pathology report?"). Six pathologists received a questionnaire to evaluate factual accuracy, the inclusion of relevant medical information, and potential harm to the patient. They were asked to score each simplified explanation using a five-point Likert scale. Pathologists were also asked to list any missing information and potential physical and/or psychological harm. The scores were tabulated and analyzed. RESULTS: Six board-certified pathologists provided 180 evaluations of ChatGPT's explanations. The vast majority were scored as accurate, factually complete, and not perceived as a possible cause of harm for the patients, especially when using prompt 2. Explanations from ChatGPT for prompt 1 were scored less favorably. CONCLUSIONS: This study provides insight into the field of automated simplification of pathology reports using ChatGPT. With proper prompting, AI chatbots have potential to serve as powerful assistants to patients desiring accurate, simple summaries of their gynecologic cytopathology reports, with minimal or no harm. These findings are based on pathologists' opinions-an indirect measure of patient understanding. Future studies should directly measure patient comprehension and intended follow-up actions to ensure that AI-simplified reports are not only medically accurate but truly patient-centered.
Mansour MSI, Pettersson L, Pedersen R
… +7 more, Mager U, Hejny K, Kronqvist F, Aronsson A, Seidal T, Akyürek LM, Kholová I
Cancer Cytopathol
· 2026 Mar · PMID 41663326
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BACKGROUND: Programmed death-ligand 1 (PD-L1) immunocytochemical (ICC) analysis of cell blocks (CBs) has recently emerged in clinical practice. Unlike standardized immunohistochemistry on formalin-fixed, paraffin-embedde...BACKGROUND: Programmed death-ligand 1 (PD-L1) immunocytochemical (ICC) analysis of cell blocks (CBs) has recently emerged in clinical practice. Unlike standardized immunohistochemistry on formalin-fixed, paraffin-embedded tissues, cytology involves various preparation methods and fixatives. This study investigated how various fixatives influence PD-L1 immunoreactivity in CBs from malignant pleural effusions (MPEs) with metastatic pulmonary adenocarcinoma (AC). METHODS: Thirty-three MPEs from patients with pulmonary AC were prospectively included. Four matched CBs per case were fixed in four different fixatives and immunostained with three PD-L1 antibodies. Tumor proportion score and staining intensity were evaluated at multiple cutoffs. RESULTS: The cytology-cytology correlation of PD-L1 expression with the antibodies 28-8, 22C3, and SP263 was assessed in matched CBs fixed in either formalin, PreservCyt, CytoLyt, or CytoRich Red (the latter only in 26 cases). Compared to formalin, PreservCyt and CytoLyt showed moderate concordance at the ≥1% cutoff (Cohen kappa [κ], 0.463-0.535 and 0.57-0.586, respectively), except SP263 with CytoLyt, which demonstrated only fair concordance (κ, 0.382). The corresponding figures for CytoRich Red indicated substantial concordance for 28-8 and SP263 (κ, 0.601 and 0.669) and very good concordance for 22C3 (κ, 0.806). At the ≥50% cutoff, concordance improved for 28-8 and 22C3 but remained largely unchanged for SP263. All alcohol-based fixatives produced significantly weaker PD-L1 staining intensity than formalin across all antibodies (p < .001-.007). CONCLUSIONS: PD-L1 ICC expression in CBs depends on the fixative and antibody used. Alcohol-based fixatives, particularly with low cutoffs, risk underestimating PD-L1 positivity, and may contribute to false-negative results. ICC protocol optimization is essential before diagnostic use.
Elsheikh TM, Sheen C, Bell T
… +6 more, Booth C, Doxtader EE, Hamadeh F, Underwood D, Yang L, Chaari R
Cancer Cytopathol
· 2026 Feb · PMID 41609234
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BACKGROUND: Atypia of undetermined significance (AUS) is a subjective diagnosis with reported interinstitutional rates ranging from 1% to 20%. The Bethesda System for Reporting Thyroid Cytology (TBS) endorsed ≤10% as an...BACKGROUND: Atypia of undetermined significance (AUS) is a subjective diagnosis with reported interinstitutional rates ranging from 1% to 20%. The Bethesda System for Reporting Thyroid Cytology (TBS) endorsed ≤10% as an achievable target; however, lowering AUS rates without informed, adjusted diagnostic thresholds can compromise the sensitivity of thyroid cytology. The authors conducted this study to identify quality-assurance measures that can assess individual pathologist's metrics compared with laboratory averages and published benchmarks and can provide feedback to pathologists on the causes of discrepancy. METHODS: AUS rates of 15 cytopathology-boarded pathologists were correlated with AUS:malignant ratios (AUS:M), histologic risks of malignancy (ROMs), and Afirma molecular-positive call rates (PCRs), and scatterplots were constructed. The distribution of pathologist TBS diagnostic categories was compared with laboratory averages and correlated with the above metrics. RESULTS: Pathologist AUS rates ranged from 7% to 44% (mean, 19%; 926 of 4801 cases). Average AUS:M and ROM rates were 7.0% and 68% (range, 3%-35% and 25%-87%), respectively. Regression analysis highlighted pathologists' metrics that were outliers. Evaluation of the distribution of individual pathologist's TBS diagnostic categories identified patterns/trends that explained deviations from laboratory averages, including patterns of significant overcalling of benign as AUS and downgrading diagnoses across multiple TBS categories. CONCLUSIONS: Correlation of AUS, AUS:M, and ROM with molecular results, in addition to the distribution of pathologist TBS categories, offer a robust framework for quality assurance that illustrates deviations from target benchmarks, including shifts in interpretations from one TBS category to another. Giving feedback to pathologists regarding their practice patterns can help standardize diagnostic thresholds and meet designated target metrics.
Roque RR, Srebotnik Kirbiš I, Pinheiro CSC
… +4 more, Martins RSF, Tavares VS, André S, Félix A
Cancer Cytopathol
· 2026 Feb · PMID 41504087
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BACKGROUND: On-slide controls are essential for quality assurance in immunocytochemistry, yet their use in non-cell block cytology preparations remains a significant challenge. This study presents and evaluates a novel m...BACKGROUND: On-slide controls are essential for quality assurance in immunocytochemistry, yet their use in non-cell block cytology preparations remains a significant challenge. This study presents and evaluates a novel method for preparing on-slide controls from long-term prefixed cell suspensions, applicable to all types of cytology preparations. METHODS: A methodology for preparing on-slide controls is described in detail and comprehensively validated via three key evaluations: assessing antigen and cellular morphology stability in 17 suspensions over 29 months; conducting a retrospective review of immunocytochemistry records (2019-2024) to determine feasibility; and performing a tracer study to evaluate cell carryover risk. RESULTS: In the stability assessment, all 20 evaluated antigens and cellular morphologies remained well preserved in the stored control samples, with only transient partial loss of antigenicity observed on three of 149 slides. The method was successfully and reliably applied in 1904 immunocytochemistry tests (n = 48 primary antibodies), with a failure rate of 0.3% (95% CI, 0.1%-0.7%). The dedicated tracer study confirmed the complete absence of cell carryover or cross-contamination. CONCLUSIONS: The described method offers a robust, practical, and adaptable solution for preparing on-slide controls applicable to all cytology preparations, including previously stained and mounted slides. Implementing this approach strengthens quality control for non-cell block cytology slides, enhances diagnostic reliability, and brings cytology practice closer to the quality standards established in immunohistochemistry.
Jeong JS, Choi YJ, Lee JH
… +4 more, Baek JH, Lee YM, Sung TY, Song DE
Cancer Cytopathol
· 2026 Jan · PMID 41432102
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BACKGROUND: Ultrasound-guided fine-needle aspiration (FNA) of various thyroid nodules often yields nondiagnostic results, which reveal a wide range of the risk of malignancy (ROM) and complicate patient management decisi...BACKGROUND: Ultrasound-guided fine-needle aspiration (FNA) of various thyroid nodules often yields nondiagnostic results, which reveal a wide range of the risk of malignancy (ROM) and complicate patient management decisions. This ROM variability likely reflects selection bias, given that previous studies frequently excluded patients without histologic follow-up. METHODS: This retrospective cohort study included 1269 patients with nondiagnostic thyroid nodules from a total of 10,337 patients who underwent FNA at Asan Medical Center. The ROM was determined on the basis of pathologic findings after core needle biopsy (CNB) or resection. RESULTS: The median follow-up period after the initial FNA was 14.14 months (range, 0.03-145.81 months). Histologic follow-up was available for 361 patients (28.4%), with 49 patients (13.6%) having only surgical resection specimens, 252 patients (69.8%) having only CNB specimens, and 60 patients (16.6%) having both resection and CNB specimens. Sixty-four patients were diagnosed with malignancy on the basis of CNB or surgical resection. The ROM in this cohort ranged from 5.0% to 17.7%. The upper limit of the ROM (13.2%) at the 12-month follow-up in this study was the same as the mean ROM (13%) suggested in The Bethesda System for Reporting Thyroid Cytopathology as updated in 2023. Multivariate logistic regression revealed that younger age (p = .013), spiculated margins (p = .010), and hypoechogenicity (p = .001) were independently associated with malignancy. CONCLUSIONS: This study aimed to reduce the overestimated upper limit of the ROM in nondiagnostic thyroid nodules, which was previously based solely on rare surgical follow-up results. Using CNB as an ancillary diagnostic tool can help to rapidly characterize initially nondiagnostic thyroid nodules and guide appropriate management.
Cancer Cytopathol
· 2026 Jan · PMID 41432097
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Generative artificial intelligence represents a fascinating, disruptive force in cytopathology. Anecdotal experience with the commercially available ChatGPT confirms both its appeal and limitations.Generative artificial intelligence represents a fascinating, disruptive force in cytopathology. Anecdotal experience with the commercially available ChatGPT confirms both its appeal and limitations.
Ehinger M, Calaminici M, Cozzolino I
… +2 more, Zeppa P, Field AS
Cancer Cytopathol
· 2026 Jan · PMID 41432088
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The objective of the recently published World Health Organization Reporting System for Lymph Node, Spleen, and Thymus Cytopathology (WHO system) is to standardize the diagnostic approach to fine-needle aspiration biopsie...The objective of the recently published World Health Organization Reporting System for Lymph Node, Spleen, and Thymus Cytopathology (WHO system) is to standardize the diagnostic approach to fine-needle aspiration biopsies of hematolymphoid tissues. By categorizing specimens into five diagnostic groups-inadequate/insufficient/nondiagnostic, benign, atypical, suspicious for malignancy, and malignant-the system provides a structured framework that enhances diagnostic clarity and facilitates communication between cytopathologists and clinicians. Each category is associated with a defined risk of malignancy, supporting informed clinical decision making regarding further diagnostic workup. Accurate categorization requires the integration of cytomorphologic features and clinical context, and final and specific diagnoses often require ancillary techniques such as flow cytometry, immunocytochemistry, in situ hybridization, and molecular diagnostics. To assist cytopathologists, especially those less familiar with hematolymphoid neoplasms, the WHO system incorporates a pattern-based diagnostic approach. Four cytopathologic patterns-mixed lymphoid cell; predominantly small/intermediate cell; predominantly large/pleomorphic/blastic cell; and single, very large, atypical cell-serve as guides to narrow down differential diagnoses. However, interpretation can be challenging because of overlapping features, variable inflammatory backgrounds, and limited sample material. This review provides a brief overview of the WHO system and its application to hematolymphoid proliferations, emphasizing the importance of clinical correlation and the use of relevant ancillary techniques. It then provides in-depth discussion of the pattern-based approach to diagnosing hematolymphoid neoplasms on cytopathology. It highlights the strengths and limitations of cytopathologic evaluation in hematolymphoid neoplasms and provides practical insights for applying the WHO system in routine practice.
Mayer M, Kourou S, Alfarra M
… +14 more, Laatz C, Hansen K, Esser J, Eckel HNC, Möllenhoff K, Hieggelke L, Engels M, Arolt C, Quaas A, Wolber P, Jansen L, Nachtsheim L, Klussmann JP, Shabli S
Cancer Cytopathol
· 2026 Jan · PMID 41416670
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BACKGROUND: Salivary gland tumors are rare and heterogeneous head and neck neoplasms. Preoperative distinction between benign and malignant lesions is challenging because imaging is often insufficient. Fine-needle aspira...BACKGROUND: Salivary gland tumors are rare and heterogeneous head and neck neoplasms. Preoperative distinction between benign and malignant lesions is challenging because imaging is often insufficient. Fine-needle aspiration cytology (FNAC) combined with the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) provides standardized risk stratification and diagnostic guidance; however, its influence on surgical frequency remains insufficiently characterized. METHODS: This retrospective single-center study included patients with histologically confirmed malignant tumors within the major salivary glands with preoperative FNAC and surgery. The association between MSRSGC category and number of surgeries was evaluated using χ tests and multivariate Poisson regression. RESULTS: Overall, 157 patients were included. Those with high-to-intermediate-risk MSRSGC categories (two surgeries: 22.3% vs. one surgery: 77.7%) required significantly fewer surgeries than those with low-risk/nondiagnostic FNAC (two surgeries: 54.2%/53.3% vs. one surgery: 45.8%/46.7%, p < .001). A high-to-intermediate risk compared to a nondiagnostic FNAC results was an independent predictor for fewer surgeries in multivariate analysis (incidence rate ratio, 0.875; 95% confidence interval, 0.773-0.990; p = .034). True-positive results were most frequent in squamous cell carcinoma, whereas acinic cell and mucoepidermoid carcinomas were often misclassified. CONCLUSIONS: The use of the MSRSGC enables reliable preoperative risk stratification of malignant salivary gland tumors. High-to-intermediate-risk categories (Milan III/IVb/V/VI) were associated with a lower likelihood of multiple surgeries. True-positive FNAC results were most frequent in squamous cell carcinoma and metastatic melanoma, whereas acinic cell, mucoepidermoid, and salivary duct carcinomas were prone to misclassification. Structured FNAC reporting improves diagnostic accuracy and informs personalized surgical planning, reducing interventions and optimizing management.
Cancer Cytopathol
· 2026 Jan · PMID 41400420
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BACKGROUND: Renal mass biopsy (RMB) cytology is increasingly used for the pretreatment evaluation of renal masses. Cytopathologic classification of RMB specimens facilitates communication with clinicians and provides val...BACKGROUND: Renal mass biopsy (RMB) cytology is increasingly used for the pretreatment evaluation of renal masses. Cytopathologic classification of RMB specimens facilitates communication with clinicians and provides valuable risk stratification to guide management decisions. This study evaluated the risk of malignancy (ROM) associated with RMB cytology in renal oncocytic neoplasms (ONs). DESIGN: The renal neoplasms with oncocytic features were reclassified per the 5th edition of the WHO Classification of Tumors. RMB cases were assigned to six diagnostic categories: 1) nondiagnostic (ND), 2) benign, 3) low risk oncocytic neoplasm (LRON), 4) atypical, 5) suspicious for malignancy (SFM), and 6) malignant. RESULTS: In total, 198 RMB cases with oncocytic features were identified, comprising oncocytoma (111 [56%]), chromophobe renal cell carcinoma (RCC) (55 [28%]), LRON (10 [5%]), hybrid oncocytic neoplasm (8 [4%]), low-grade oncocytic tumor (7 [4%]), papillary RCC (6 [3%]), and eosinophilic vacuolated tumor (1 [1%]). The overall ROM for ONs was 35%. ROMs by category were ND (29%), benign (2%), LRON (30%), atypical (100%), SFM (50%), and malignant (100%). Post-RMB resection was more frequently used for malignant (36 of 57 [63%]), SFM (1 of 2 [50%]), and ND (4 of 7 [57%]), whereas active surveillance was more frequently employed for benign ON (100 of 111 [90%]) and LRON (12 of 20 [60%]). Cryoablation was used in 9% (18 of 198) of ONs. CONCLUSIONS: This study defines ROMs across cytologic categories of ONs to stratify the risks and underscores the valuable role of RMB. These findings provide a framework for clinicians to make informed decisions based on cytologic classification and associated ROM.
Fiorentino V, Giordano W, Pizzimenti C
… +11 more, Zuccalà V, Ieni A, Molinario C, Cannavò S, Campennì A, Tralongo P, Martini M, Giuffrè G, Larocca LM, Fadda G, Rossi ED
Cancer Cytopathol
· 2026 Jan · PMID 41370117
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BACKGROUND: Molecular testing is increasingly used to improve preoperative risk assessment of thyroid nodules, especially those with indeterminate cytology. This study evaluated the performance of the Myriapod next-gener...BACKGROUND: Molecular testing is increasingly used to improve preoperative risk assessment of thyroid nodules, especially those with indeterminate cytology. This study evaluated the performance of the Myriapod next-generation sequencing (NGS) DNA-only cancer panel in fine-needle aspiration cytology thyroid samples, correlating findings with postsurgical diagnoses. METHODS: A retrospective analysis was performed on fine-needle aspiration cytology specimens from 74 thyroid nodules in the TIR3A, TIR3B, TIR4, and TIR5 categories according to the Italian Consensus for the Classification and Reporting of Thyroid Cytology. DNA from these samples, obtained from residual liquid-based cytology material, was analyzed with the Myriapod NGS panel, targeting 16 genes implicated in thyroid cancer. All patients underwent surgery, allowing for histopathologic correlation. RESULTS: The residual liquid-based cytology material yielded adequate DNA for molecular testing in 89.2% of the nodules. All TIR3A (low-risk intermediate) nodules were histologically benign, whereas 50% of TIR3B (high-risk intermediate) nodules were malignant; mutations were identified only in the malignant nodules. In the TIR4 category (suspicious for malignancy), BRAF V600E was the most frequent mutation in malignant nodules. Both TIR5 (malignant) nodules were papillary thyroid carcinomas with a BRAF V600E mutation. The molecular test demonstrated 100% sensitivity, 95.5% specificity, 91.7% positive predictive value, and 100% negative predictive value for samples that were adequate for molecular testing. An intention-to-diagnose analysis that included samples inadequate for molecular testing was also performed, yielding 84.6% sensitivity, 87.5% specificity, 91.7% positive predictive value, and 84% negative predictive value. CONCLUSIONS: The Myriapod NGS panel aids in the preoperative assessment of thyroid nodules. Its high negative predictive value may help avoid unnecessary surgery, whereas the detection of specific mutations strongly correlates with malignancy, thus informing surgical planning.