AIMS: To provide a practical, pathology-centred overview of Claudin 18.2 as a biomarker and therapeutic target, covering biology, assay methods and interpretation, pre-analytical factors, clinicopathological associations...AIMS: To provide a practical, pathology-centred overview of Claudin 18.2 as a biomarker and therapeutic target, covering biology, assay methods and interpretation, pre-analytical factors, clinicopathological associations and implications for treatment selection. METHODS: We performed a narrative review of the biomedical and pathology literature on /Claudin 18.2, including basic science, translational studies, immunohistochemistry (IHC) and in situ assays, and clinical trials of Claudin 18.2-directed therapies. Reference lists were hand-searched to capture additional relevant reports. Emphasis was placed on data informing routine diagnostic practice (expression patterns, scoring, fixation variables, pitfalls). RESULTS: Claudin 18.2 localises to tight junctions of differentiated gastric epithelium and is aberrantly expressed in gastric and gastro-oesophageal junction adenocarcinomas, with variable expression reported in pancreatic, biliary and other tumours. Loss or dysregulation of Claudin 18.2 contributes to tumour progression via disruption of epithelial integrity and activation of oncogenic pathways; infection-related and inflammation-related downregulation is described in gastric mucosa. For IHC, clone selection, tissue handling, fixation time and membrane-dominant scoring critically affect results; common pitfalls include cytoplasmic staining and heterogeneity. Claudin 18.2 expression shows predictive value for targeted agents under clinical use/evaluation, supporting its role as a companion biomarker. Reporting recommendations include membrane intensity/percentage thresholds and clear documentation of pre-analytical conditions. CONCLUSIONS: Claudin 18.2 is a biologically plausible and clinically actionable biomarker. Robust pre-analytical handling, validated IHC protocols and standardised scoring are essential for reliable patient selection. Wider adoption of harmonised methods and further disease-specific studies will refine cut-offs, clarify prognostic value and optimise integration of Claudin 18.2-directed therapies into routine care.
Accelerated chronic lymphocytic leukaemia (A-CLL) is an aggressive variant of chronic lymphocytic leukaemia (CLL) characterised by distinct histologic features and a higher risk pathogenetic profile compared with convent...Accelerated chronic lymphocytic leukaemia (A-CLL) is an aggressive variant of chronic lymphocytic leukaemia (CLL) characterised by distinct histologic features and a higher risk pathogenetic profile compared with conventional CLL (C-CLL). Although well recognised histologically, peripheral blood (PB) morphology of A-CLL is not well studied. In this study, we compared the PB lymphocyte morphology between 22 cases of biopsy-confirmed A-CLL and 60 cases of biopsy-confirmed C-CLL. PBs in A-CLL had a significantly lower percentage of typical CLL cells (mean: 51.28% vs 86.73%; p<0.001) and a higher percentage of classical prolymphocytes (12.11% vs 3.69%; p=0.021), non-classical prolymphocytes (17.48% vs 5.59%; p<0.001) and other atypical forms (cleaved, Downey-like and flower-shaped cells). Our data ties this distinct PB lymphocyte morphology in A-CLL with aggressive histology and a high-risk pathogenetic profile. Recognising the morphologic spectrum of PB lymphocytosis in A-CLL can facilitate earlier identification of this aggressive variant and help avoid misdiagnosis as other types of lymphoma/leukaemias.
Cuschieri K, Latsuzbaia A, McMahon H
… +11 more, Giubbi C, Martinelli M, Iacobone AD, Bottari F, Piana AF, Pietri R, Salinaro F, Odicino F, Cocuzza C, Arbyn M, European VALHUDES working group
AIMS: Given the increasing adoption of self-sampling in cervical cancer screening, it is essential to evaluate the performance of human papillomavirus (HPV) tests in this context. The aim of the present work was to asses...AIMS: Given the increasing adoption of self-sampling in cervical cancer screening, it is essential to evaluate the performance of human papillomavirus (HPV) tests in this context. The aim of the present work was to assess the accuracy of the Papilloplex high-risk (HR)-HPV test on self-taken samples. METHODS: Women provided a clinician-taken cervical sample (CS), a urine sample and a vaginal swab according to the VALidation of HUman papillomavirus assays and collection Devices for Self-samples and urine samples protocol. Relative sensitivity and specificity for the detection of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) of the Papilloplex HR-HPV assay on self-taken samples versus CS were assessed. Additionally, type-specific concordance and viral load signals (expressed in Ct (crossing thershold) values) between the two self-taken sample types and the CS were evaluated. RESULTS: At the manufacturers' cut-off, the assay showed a relative clinical sensitivity and specificity for CIN2+of 0.95 (95% CI 0.88 to 1.03) and 0.95 (95% CI 0.88 to 1.03) for urine versus CS. Corresponding values for vaginal samples versus CS were 1.05 (95% CI 1.01 to 1.09) and 0.81 (95% CI 0.74 to 0.89). Cut-off optimisation led to relative sensitivity and specificity that included unity for vaginal swabs. Median Ct values were lower in vaginal swabs versus CS, although higher in urine versus CS samples. No relationship between mean Ct values and disease outcome was observed. CONCLUSIONS: The clinical sensitivity of the Papilloplex HR-HPV test was similar on self-collected vaginal swabs and urine compared with CS; clinical specificity on urine was similar to CS yet lower on vaginal samples. Cut-off optimisation resulted in a similar assay specificity on vaginal swabs and CS with no significant detriment to sensitivity.
Artificial intelligence (AI)-powered diagnostic pathology involves combining traditional histological techniques with computer-assisted AI technology. This process comprises several key steps: generating whole slide digi...Artificial intelligence (AI)-powered diagnostic pathology involves combining traditional histological techniques with computer-assisted AI technology. This process comprises several key steps: generating whole slide digital images; annotating and training algorithms; constructing robust datasets; testing and monitoring consistency with clinical expectations; validating results externally and overseeing the output of algorithms. All of these steps must adhere to quality standards and ensure patient safety.Current scientific evidence suggests that, while AI can enhance the accuracy of human diagnostics, it cannot replace humans as autonomous classifiers. Generative intelligence offers new, promising technological advancements. When applying these technologies in clinical practice, international healthcare institutions recommend clearly defining the application domains and implementing and monitoring safety measures.This critical review of current AI applications in diagnostic pathology underscores the paramount significance of patient-centred safety considerations. It also highlights the necessity of collaborative efforts among governments, academic institutions, international healthcare agencies, scientific societies, patient associations and algorithm developers to implement safety-oriented regulatory measures for AI-powered pathology.
Weber TD, Gershman B, Wang L
… +3 more, Rosen S, Fujimoto JG, Sun Y
J Clin Pathol
· 2026 Feb · PMID 41193175
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AIM: Transurethral resection of bladder tumour (TURBT) is the standard approach for diagnosing and staging non-muscle invasive bladder cancer. Accurate staging depends on the presence of muscularis propria (MP) in resect...AIM: Transurethral resection of bladder tumour (TURBT) is the standard approach for diagnosing and staging non-muscle invasive bladder cancer. Accurate staging depends on the presence of muscularis propria (MP) in resected tumour specimens, and inadequate MP sampling may necessitate repeat procedures. Non-linear microscopy (NLM), a laser-scanning, non-destructive imaging technique, enables real-time evaluation of fresh tissue and has the potential to improve staging accuracy intraoperatively. METHODS AND RESULTS: We retrospectively reviewed 94 TURBT pathology reports with high-grade urothelial carcinoma to assess MP sampling rates by tumour stage. MP was present in 55% (52/94) of cases, with variability across stages: 55% (23/42) in high-grade pTa, 39% (9/23) in pTis, 55% (11/20) in pT1 and 100% (9/9) in pT2. NLM was used to evaluate six fresh and 25 archived formalin-fixed, paraffin-embedded (FFPE) TURBT specimens. Fresh tissues were stained and imaged in real time, while thick sections from FFPE specimens were deparaffinised, imaged using NLM and converted to a digital format analogous to whole-slide images. NLM provided high-resolution imaging of MP as distinct, thick smooth muscle bundles in fresh specimens. Furthermore, NLM images of deparaffinised sections closely resembled conventional H&E histology, and a blinded reader achieved a sensitivity of 95% and specificity of 100% for MP detection. CONCLUSION: This proof-of-concept study supports the feasibility of NLM for intraoperative MP assessment during TURBT. By providing rapid, high-resolution and non-destructive tissue evaluation, NLM has the potential to improve staging accuracy, optimise intraoperative surgical decision-making and reduce the need for repeat TURBT.
AIMS: ()-mutant renal cell carcinoma (RCC) is a recently recognised entity in the 2022 WHO classification. Due to overlapping features, it is frequently misdiagnosed as clear cell RCC (CCRCC). This study characterises t...AIMS: ()-mutant renal cell carcinoma (RCC) is a recently recognised entity in the 2022 WHO classification. Due to overlapping features, it is frequently misdiagnosed as clear cell RCC (CCRCC). This study characterises the clinicopathological, immunohistochemical and molecular features of six -mutant RCCs to aid in their diagnostic distinction. METHODS: Twenty-eight RCCs initially diagnosed as CCRCC with cytokeratin 7 (CK7) positivity and/or fibromuscular stroma were re-evaluated. Sanger sequencing was performed to detect mutations. The histopathological and immunophenotypic features of the six mutation-positive tumours were compared with those of the remaining 22 cases. RESULTS: The six -mutant tumours occurred in five men and one woman. All specimens showed a multinodular architecture, separated by a thick fibromuscular stroma. Tumour cells exhibited tubular, papillary, nested and tubulocystic patterns, with small branching papillae often present within cysts. The cytoplasm was predominantly clear, and nuclei were low-grade and basally oriented. CK7 expression was moderate to strong, with diffuse membranous staining in papillary areas. Sanger sequencing confirmed point mutations in all cases. In contrast, CCRCCs with fibromuscular stroma were rare, more often exhibited eosinophilic cytoplasm, lacked papillary structures and showed negative or only focal expression of CK7. Sanger sequencing showed the wild-type ELOC genotype. CONCLUSIONS: -mutant RCC exhibits distinctive morphologic and immunohistochemical features; however, a definitive diagnosis requires molecular confirmation. Recognition of its characteristic features, including clustered branching papillae, CK7 positivity in papillary regions and the lack of correlation between cytoplasmic and nuclear grade, can guide appropriate ancillary testing and improve diagnostic accuracy.
Diagnosing and identifying the type of porphyria in a patient requires specialist analysis of porphyrins and/or precursors in blood, urine and faeces. Correct sample storage and handling prior to analysis is essential to...Diagnosing and identifying the type of porphyria in a patient requires specialist analysis of porphyrins and/or precursors in blood, urine and faeces. Correct sample storage and handling prior to analysis is essential to minimise preanalytical error.We evaluated the impact of light exposure, time and temperature on erythrocyte and plasma porphyrins in samples from patients with erythropoietic protoporphyria (EPP) and porphyria cutanea tarda (PCT) stored as whole blood for up to 96 hours, and in addition, the effect of freeze-thaw on plasma porphyrins in EPP, PCT and hereditary coproporphyria patient samples.Plasma porphyrins in the EPP patient samples decreased on average by 19% after 6 hours despite light protection and fridge storage, 36% by 24 hours stored light protected at room temperature, 67% within 1 hour when light exposed and 33% after one freeze-thaw cycle. In contrast, plasma porphyrin in PCT samples demonstrated greater stability compared to the EPP samples when stored light protected or exposed at room temperature and during freeze-thaw. Erythrocyte porphyrins in EPP samples were stable for 96 hours under all three storage conditions examined.Erythrocyte protoporphyrin analysis should be undertaken as an additional first-line investigation alongside plasma porphyrin analysis whenever protoporphyria needs to be excluded, due to the significant instability of plasma protoporphyrin.
Windell D, Magness A, Beyer C
… +12 more, Brears HT, Larkin S, Hobson K, Aljabar P, Fleming K, Fryer E, Kendall TJ, Kainth R, Wakefield P, Langford CR, Bedossa P, Goldin R
J Clin Pathol
· 2026 Feb · PMID 41162156
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AIMS: Annotation of liver biopsies for disease staging is increasingly aided by digital pathology; however, existing systems do not quantify inflammation and steatosis within an anatomical framework. We hypothesise that...AIMS: Annotation of liver biopsies for disease staging is increasingly aided by digital pathology; however, existing systems do not quantify inflammation and steatosis within an anatomical framework. We hypothesise that an artificial intelligence (AI) system that quantifies portal tracts (PT) and the anatomical distribution of steatotic vesicles and inflammatory cells will align with manual pathologist scoring and stratify liver diseases. METHODS: In this observational, cross-sectional study, digitised images of haematoxylin and eosin-stained specimens were pooled from four independent cohorts of metabolic dysfunction-associated steatotic liver disease (MASLD) or steatohepatitis (MASH) or autoimmune hepatitis (AIH) (n=390: 89 MASLD, 238 MASH, 63 AIH). PT, steatosis, and inflammation were quantified using a proprietary AI system and scored by expert pathologists. RESULTS: The percentage of steatosis was higher in MASH (7.5%) than in MASLD (3.2%). Lobular regions had larger steatotic vesicles (260 vs 190 μm). AI-derived steatosis quantification correlated with manual grading (r=0.72). The inflammatory cell number (ICN) was twofold higher in AIH than MASLD/MASH in interface (390 vs 140), portal (4600 vs 1500) and lobular (1500 vs 650) regions. Portal inflammation from manual grading correlated with ICN count at PT (r=0.71) but not lobular regions (r≤0.29). For equivalent grades of portal inflammation, the ICN was up to threefold higher in AIH than in MASLD/MASH (r=0.71). CONCLUSION: A new AI system for anatomical quantification of liver biopsy features measured variation in fat and inflammation across the lobule. It showed that inflammation burden was higher in AIH than MASLD/MASH, despite equivalent portal grades, providing objective support for histological scoring.
The primary aims of this best practice article are to provide a laboratory perspective of the merits and pitfalls of different markers currently in use in UK National Health Service (NHS) hospital laboratories, and how b...The primary aims of this best practice article are to provide a laboratory perspective of the merits and pitfalls of different markers currently in use in UK National Health Service (NHS) hospital laboratories, and how best these tests can be used for the detection of heavy (harmful) alcohol consumption. Included are suggested testing algorithms for carbohydrate-deficient transferrin (CDT), ethyl glucuronide (EtG), ethyl sulphate (EtS) and phosphatidylethanol (PEth16:0/18:1), for the purpose of creating suitable bench-to-bedside alcohol services in support of the delivery of hospital alcohol strategy, and the NHS long-term health plan.
AIMS: To assess the impact of adding clinical comments to reports of thyroid function testing in patients treated for hypothyroidism. METHODS: We compared thyroid function test results in primary care patients being trea...AIMS: To assess the impact of adding clinical comments to reports of thyroid function testing in patients treated for hypothyroidism. METHODS: We compared thyroid function test results in primary care patients being treated for hypothyroidism from January 2016 to August 2023 at two NHS Trusts with similar demographics and using the same instruments, but with different interpretative comment policies. One laboratory, Buckinghamshire Health Trust (Bucks), adds interpretative comments, whereas the other, Oxford University Hospitals (Oxford), does not. We used two outcome measures: the percentage of patients with thyroid-stimulating hormone (TSH) within the reference interval on repeat testing and the timing of repeat TSH testing samples, according to the National Institute for Health and Care Excellence guidance (NG145). RESULTS: We identified 18 242 and 31 655 hypothyroid patients (9.0% and 7.7% of the population tested) in Bucks and Oxford, with a total of 121 961 and 247 639 tests over the evaluation period, respectively. The proportion of TSH results within the reference interval (83.4% in Bucks, 83.9% in Oxford) was similar in both Trusts, as was TSH concentration (median TSH concentration 1.60 (IQR 0.78-2.82) mU/L in Bucks, 1.68 (IQR 0.97-2.76) in Oxford). The interval between tests was shorter in Oxford, but differed significantly from NG145 in both Trusts. Differences were statistically significant for both outcome measures, but of questionable clinical significance. CONCLUSIONS: Adding interpretative comments to results of thyroid function tests does not appear to affect the distribution of TSH concentrations in primary care patients on thyroxine replacement or the intervals between tests in a clinically meaningful way.
BACKGROUND: Frozen section (FS) and touch imprint (TI) are common intraoperative evaluation (IOE) techniques for sentinel lymph nodes (SLNs) in breast cancer surgery. Their accuracy in patients receiving neoadjuvant syst...BACKGROUND: Frozen section (FS) and touch imprint (TI) are common intraoperative evaluation (IOE) techniques for sentinel lymph nodes (SLNs) in breast cancer surgery. Their accuracy in patients receiving neoadjuvant systemic therapy (NST) remains variable. OBJECTIVE: To summarise evidence on the diagnostic accuracy of FS and TI in the NST context. METHODS: A systematic search of PubMed, Embase, Scopus and Web of Science was conducted through April 2024 for studies evaluating FS and/or TI in SLNs of breast cancer patients treated with NST. Meta-analysis was performed using the logit function, and Revised Tool for the Quality Assessment of Diagnostic Accuracy Studies-2 and Grading of Recommendation, Assessment, Development and Evaluation were employed to assess risk of bias and evidence certainty. RESULTS: 20 studies were included. At the lymph node level, TI demonstrated pooled sensitivity and specificity of 0.54 and 1.00, respectively, while FS achieved 0.85 and 0.99. At the patient level, TI showed sensitivity and specificity of 0.72 and 1.00, while FS reached 0.82 and 0.98. Combined, FS and TI presented pooled sensitivity and specificity of 0.59 and 1.00 at the patient level. Risk of bias was frequently unclear, and the certainty of evidence for both techniques ranged from low to very low. CONCLUSION: FS exhibits higher sensitivity and specificity than TI at both lymph node and patient levels, but evidence certainty remains limited. Further prospective, blinded studies are needed to validate these findings and optimise IOE methods for NST-treated patients. PROSPERO REGISTRATION NUMBER: CRD42023483079.