The Journal Of Pathology[JOURNAL]
Sun
200 papers
ATM immunohistochemistry as an effective screening method for POLE variants among endometrial carcinomas lacking mismatch repair deficiency and p53 abnormalities.
Huang X, Wang Y, Ni W … +7 more , Zhong L, Qin Y, Zeng S, Xu H, Qu Y, Hu P, Zhang J
J Pathol Clin Res · 2026 Mar · PMID 41891942 · Full text
The molecular classification of endometrial carcinomas (ECs) is now integrated into clinical practice. However, identification of polymerase-ε (POLE) variants remains reliant on DNA sequencing, which limits broader imple...
The molecular classification of endometrial carcinomas (ECs) is now integrated into clinical practice. However, identification of polymerase-ε (POLE) variants remains reliant on DNA sequencing, which limits broader implementation. Given the strong prognostic value of pathogenic POLE mutations and the established efficacy of immunohistochemistry (IHC) for detecting mismatch repair (MMR) deficiency and p53 abnormalities, there is a clear need for IHC-based screening strategies to identify patients likely to carry POLE variants and prioritize them for confirmatory sequencing. In this study, we analyzed 24 cases with POLE pathogenic mutations (POLEmut ECs), 3 with benign POLE variants, and 32 matched cases with no specific molecular profile (NSMP) from a cohort of 378 ECs. IHC evaluation of the ataxia telangiectasia mutated (ATM) protein revealed that POLE-mutated ECs (with pathogenic or benign POLE variants) exhibited significantly higher frequencies of non-diffuse positive staining patterns, including null, heterogeneous positive, and subclonal loss, compared with NSMP cases. Targeted next-generation sequencing of all exons across 474 cancer-related genes in the 27 POLE-mutated ECs and 20 NSMP cases with ATM non-diffuse positive staining patterns confirmed that POLE-mutated ECs typically had high tumor mutational burden and were enriched for ATM truncating variants. ATM molecular alterations, including various variant subtypes and multisite mutations, also closely correlated with these staining patterns. Based on these findings, we refined the ATM IHC interpretation framework to integrate staining patterns with sequencing data for improved molecular correlation. Specifically, the null and subclonal loss patterns showed high specificity (96.9%), positive predictive value (94.1%), and accuracy (79.7%) for identifying POLE variants. Notably, the null pattern appeared exclusively in ECs with pathogenic POLE mutations. These results suggest that ATM IHC staining is an effective screening tool for identifying patients who may benefit from confirmatory POLE sequencing among those lacking MMR deficiency or p53 abnormalities.
Distantly metastatic differentiated thyroid carcinoma is kinase-driven and enriched for DNA repair and DNA methylation gene alterations.
Kong W, Bao L, Hu J … +17 more , Li G, Liu Y, Ran W, Zhang T, Gu H, Zhang X, Wang M, Ji H, Zong X, Zhang Y, Dang S, Li D, Fa L, Yu X, Pan X, Li X, Wang J
J Pathol · 2026 Jul · PMID 41881819 · Publisher ↗
Although distant metastasis is uncommon in differentiated thyroid carcinoma (DTC), it remains the leading cause of thyroid cancer-related mortality. The genetic landscape of distantly metastatic DTC (DMDTC) has not been...
Although distant metastasis is uncommon in differentiated thyroid carcinoma (DTC), it remains the leading cause of thyroid cancer-related mortality. The genetic landscape of distantly metastatic DTC (DMDTC) has not been well characterized in large cohorts. This study aimed to identify functional genetic alterations in DMDTC and validate their biological significance. We included 78 patients with DMDTC and performed DNA-based next-generation sequencing (NGS) in all cases, followed by RNA-based NGS for fusion gene detection, along with a review of previously reported isolated cases. Plasmids harbouring novel variants, including SPON1::ALK and RFTN1::BRAF fusions, and mutations in PTEN (c.322_345del, c.740del, c.968dup), STK11 (c.842C>T, c.1225C>T), and DNMT3A (c.891G>A, c.2312G>A, c.2595A>T, c.2606G>A) were constructed and transfected into TPC-1 and HEK293T cells to investigate downstream signalling. The methylation status of differentially methylated genes (DMGs) associated with DNMT3A mutations was analysed using the Infinium MethylationEPIC v2.0 BeadChip, with several DMGs validated by real-time quantitative PCR. The cohort consisted of 25 males and 53 females, with a mean age of 60.3 years at the diagnosis of metastasis. Histological types included papillary carcinoma (31 cases), follicular carcinoma (44 cases), and oncocytic carcinoma (3 cases). The lung and bone were the most common metastatic sites. Multiple metastases and older age were associated with metastasis-free and overall survival. Genetic alterations involving phosphorylation signalling pathways were identified in 61 cases, among which pathological alterations of DNA damage repair (DDR)-related genes were detected in ten cases. Novel RFTN1::BRAF and SPON1::ALK fusions, along with PTEN (c.740del, c.968dup) and STK11 (c.842C>T) mutations, could enhance downstream phosphorylation levels. DNMT3A mutations (c.891G>A, c.2312G>A, c.2595A>T, c.2606G>A) induced genome-wide methylation dysregulation, with altered expression of SLC12A7, FLNC, HMGB2, BNC2, and DAPK1. This study shows that DMDTCs are characterized by dysregulated phosphorylation signalling, accompanied by chromosomal instability and aberrant methylation, thus underscoring DDR gene-targeted therapy as a promising strategy. © 2026 The Pathological Society of Great Britain and Ireland.
Multinodular and vacuolating neuronal tumor: molecular genetics and DNA methylation analysis of 12 cases.
Lian F, Wang DD, Gong J … +6 more , Luo T, Guo LA, Wang WM, Chen N, Yao XH, Piao YS
J Pathol · 2026 Jul · PMID 41879092 · Publisher ↗
Multinodular and vacuolating neuronal tumor (MVNT) was recognized as a distinct neuronal tumor entity in the revision of the 2021 World Health Organization (WHO) Classification of Tumors of the CNS. In this study, we ret...
Multinodular and vacuolating neuronal tumor (MVNT) was recognized as a distinct neuronal tumor entity in the revision of the 2021 World Health Organization (WHO) Classification of Tumors of the CNS. In this study, we retrospectively analyzed 12 surgical cases, two of which exhibited ganglioglioma (GG)-like components. The cohort consisted of eight male and four female patients, with a median age of 31 years (age range: 18-53 years). Seizures were the most common clinical presentation, followed by headache and dizziness. Three patients were incidentally identified during physical examination. Ten tumors were located in the cerebral hemisphere, and the remaining two were found in the cerebellum and thalamus, respectively. Histopathological examination revealed clusters of neuroepithelial cells with large amphophilic vacuolated cytoplasm and eccentrically placed round nuclei containing prominent nucleoli. Immunohistochemically, these vacuolated cells were positive for OLIG2, MAP2, SYN and SOX10, and negative for GFAP and NEUN. DNA sequencing analysis identified no mutations in IDH1, IDH2, BRAF V600E, TERT promoter, or EGFR genes. Among the cohort, three cases harbored FGFR2 mutations, and FGFR2::INA gene fusion was detected in both MVNT and GG-like components. Two cases carried BRAF mutation, and one case exhibited MAP2K1 mutation. A novel BCAN::NTRK1 (exon 12-exon 9) gene fusion was identified in one case. DNA methylation profiling of eight cases revealed that none matched with a known CNS tumor type. Six cases formed a separate methylation cluster, suggesting a potential novel molecular subtype, while the remaining two cases exhibited transcriptional similarities to supratentorial pilocytic astrocytoma and rosette-forming glioneuronal tumor (RGNT), respectively. Postoperatively, all patients remained seizure free with no evidence of tumor progression. Only one patient died 16 months after surgery due to an unrelated traffic accident. © 2026 The Pathological Society of Great Britain and Ireland.
Acid ceramidase overactivity drives ceramide loss, leading to atopic dry skin and Th2-skewed immune polarization.
Takada M, Sashikawa-Kimura M, Ohno Y … +6 more , Hossain MR, Xie X, Iwabuchi K, Komine M, Ohtsuki M, Imokawa G
J Pathol · 2026 Jun · PMID 41873507 · Full text
Ceramide deficiency in the stratum corneum (SC) is a key etiological factor in atopic dermatitis (AD). To clarify the direct role of SC ceramide depletion in impairing SC barrier and water-holding functions and in initia...
Ceramide deficiency in the stratum corneum (SC) is a key etiological factor in atopic dermatitis (AD). To clarify the direct role of SC ceramide depletion in impairing SC barrier and water-holding functions and in initiating AD-like skin symptoms and disease-specific molecular alterations, we generated Tg mice overexpressing a mutant form of acid ceramidase (aCDase) under the control of the involucrin promoter, resulting in targeted expression in the upper epidermis. By 3 weeks of age, Tg mice developed noninflammatory, scaly skin characterized by severely compromised barrier integrity and water-holding capacity, along with significantly elevated epidermal aCDase activity and markedly reduced ceramide levels in the SC. Compared to WT controls, Tg mice also exhibited increased epidermal innervation and reduced intraepidermal semaphorin 3a protein levels. Additionally, Tg skin showed substantial changes in the expression of AD-associated biomarkers involved in barrier impairment, pruritus, and Th2 polarization. These included increased levels of Il10, Il17a, S100a7, S100a8, and S100a9 and decreased levels of Cxcl10, Ifng, Il2, Il13, Il33, Sema3a, and Tlr9. Repeated topical application of mite antigens induced allergic responses in Tg mice, but not in WT mice. These responses were characterized by prominent eosinophil infiltration in the dermis and significantly elevated serum IgE levels. Allergen-challenged ear skin from Tg mice also demonstrated significantly increased expression of inflammatory mediators related to AD, including Ccl17, Ccl22, Ccl26, Ccl27, Il3, Il13, Il22, and Il33. These findings establish Tg mice as a pathophysiologically relevant model of AD, presenting key features such as xerotic, pruritic skin, impaired barrier and water-retention functions, and Th2-dominant allergic inflammation. This model provides important insights into ceramide-dependent mechanisms in AD pathogenesis and offers a useful platform for therapeutic development. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Folate receptor alpha (FRα) expression in tubo-ovarian and endometrial tumors: a study of 923 cases.
Töltési I, Němejcová K, Kendall Bártů M … +11 more , Vránková R, Cibula D, Fabian P, Frühauf F, Hausnerová J, Laco J, Méhes G, Špůrková Z, Švajdler M, Matěj R, Dundr P
J Pathol Clin Res · 2026 Mar · PMID 41870959 · Full text
Folate receptor alpha (FRα) is a promising therapeutic target due to its high expression in several tumor types and its rare expression in healthy tissue. Recently, the antibody-drug conjugate mirvetuximab soravtansine h...
Folate receptor alpha (FRα) is a promising therapeutic target due to its high expression in several tumor types and its rare expression in healthy tissue. Recently, the antibody-drug conjugate mirvetuximab soravtansine has been approved for treatment of advanced platinum-resistant high-grade serous carcinoma (HGSC). Immunohistochemical expression of FRα has been extensively studied in HGSC, but most studies conducted before the clinical studies targeting FRα used variable antibodies and scoring criteria, which makes comparison of older literature data with recent studies difficult. Moreover, the data regarding its expression in other types of ovarian and other female genital tract tumors are limited or absent. In our study, we focused on immunohistochemical expression in 923 tubo-ovarian and endometrial tumors (assessed on tissue microarrays), using standardized scoring criteria and the VENTANA FOLR1 CDx assay. The results of our study showed the highest FRα expression in serous carcinomas, specifically HGSC (45% positive cases), followed by low-grade serous carcinoma (25%), endometrial serous carcinoma (11%), and serous borderline tumor (10%). Endometrioid and clear cell ovarian carcinomas showed rare positivity (2% and 1%, respectively). All other tumors examined were negative, including mucinous ovarian tumors, sex cord-stromal tumors, endometrial endometrioid carcinomas, undifferentiated and dedifferentiated carcinomas, and endometrial clear cell carcinomas. In conclusion, these results confirm that FRα expression in HGSC and LGSC reaches similar values compared to published data, and is present in a minority of endometrial serous carcinomas. In other ovarian and endometrial tumors examined, FRα expression is absent or rare.
Novel genomic risk stratification model for primary high-grade malignant peripheral nerve sheath tumor (MPNST).
Chang HY, Dermawan JK, Tap W … +3 more , Singer S, Chi P, Antonescu CR
J Pathol · 2026 Jun · PMID 41863012 · Publisher ↗
Risk stratification across the three main clinical subsets of malignant peripheral nerve sheath tumor (MPNST), neurofibromatosis type I (NF1-related), sporadic, and prior radiation therapy (RT), is based mainly on clinic...
Risk stratification across the three main clinical subsets of malignant peripheral nerve sheath tumor (MPNST), neurofibromatosis type I (NF1-related), sporadic, and prior radiation therapy (RT), is based mainly on clinicopathologic parameters, such as size, grade, stage, and NF1 status. Moreover, no prior study investigated the additional impact of genomic alterations in the prognosis of high-grade MPNST using clinically validated DNA targeted next-generation sequencing (NGS) panels. Our goal was to integrate clinicopathologic and genomic parameters using an elastic-net penalized Cox proportional hazards machine learning model using OncoCast for risk prediction. Herein we perform comprehensive mutational and copy number profiling using Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) on 81 primary localized high-grade MPNSTs (51% NF1-related, 38% sporadic, 11% RT-associated). The most common genomic alterations included NF1 (51% germline, 59% somatic), CDKN2A/B (62%), PRC2 components (SUZ12, EED) (53%), and TP53 (25%). Variables selected by OncoCast as significantly associated with survival were used to construct a three-tier risk stratification model for progression-free survival (PFS) and disease-specific survival (DSS). For PFS, patients with chr16 deletion were classified as high-risk, those with concurrent germline and somatic NF1 alterations as low-risk, and the remainder was assigned to the intermediate-risk group. For DSS, cases with fraction genome altered (FGA) > 50% were defined as high-risk, those with PRC2 abnormalities, CDKN2A deletion, TERT promoter mutation, or chr16 deletion as intermediate-risk, and cases lacking all the aforementioned alterations as low-risk. The high-risk group showed significantly inferior survival compared to the low-risk group (both PFS and DSS p < 0.001). Subgroup analysis showed that among NF1-related MPNST, co-occurring somatic NF1 mutation or WT TP53 was associated with superior PFS. Collectively, genomic alterations detected by clinical NGS panels provide potential new biomarkers for risk stratification that can be integrated with conventional parameters to provide improved prognostication and guide therapeutic strategies. © 2026 The Pathological Society of Great Britain and Ireland.
Functional reassessment of extended splice region variants in MYO7A with hearing loss and Usher syndrome.
Shi T, Huang Y, Su X … +3 more , Yu L, Zhao Y, Cheng J
J Pathol · 2026 Jun · PMID 41852313 · Full text
MYO7A is a causal gene, underlying Usher syndrome type 1B (USH1B) and both autosomal recessive (DFNB2) and dominant (DFNA11) non-syndromic hearing loss. Despite the large number of reported MYO7A variants (over 2,200), v...
MYO7A is a causal gene, underlying Usher syndrome type 1B (USH1B) and both autosomal recessive (DFNB2) and dominant (DFNA11) non-syndromic hearing loss. Despite the large number of reported MYO7A variants (over 2,200), variants located in an extended splice region remain difficult to interpret and are often classified as variants of uncertain significance (VUS). We investigated the clinical impact of MYO7A extended splice region variants, located within ±50 bp of exon-intron boundaries, by analyzing a nationwide Chinese cohort of 10,664 undiagnosed individuals with hearing loss. Twelve such variants (in 11 probands, two variants were in cis) were identified for functional analysis. Using minigene splicing assays coupled with in silico splicing predictions, we evaluated each variant's effect on pre-mRNA processing and applied ACMG/AMP guidelines for classification. Six of the tested variants completely disrupted normal splicing, and eight variants in total were reclassified from VUS to pathogenic or likely pathogenic based on aberrant transcript outcomes. Notably, several variants generated multiple distinct abnormal transcripts, and two-thirds of these variants fell within the myosin motor domain (others in the FERM2 domain). Splicing predictions from in silico algorithms were largely concordant with the experimental results, further supporting their utility in variant interpretation. This functional evidence enabled definitive molecular diagnoses in previously unresolved cases spanning DFNA11, DFNB2, and USH1B phenotypes. In summary, our study demonstrated that integrating experimental splicing assays with predictive tools can definitively determine the pathogenicity of extended splice region variants in MYO7A, thereby improving the diagnostic accuracy of genetic testing for both non-syndromic and syndromic hearing loss. This approach could be applied to other genes to enhance genetic diagnosis. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Could the naked mole-rat become the new standard for studying human gut health and probiotics?.
Pearson AC, Barreñada O, Brieño-Enríquez MA
J Pathol · 2026 Jun · PMID 41848207 · Full text
The naked mole-rat (NMR; Heterocephalus glaber) is a subterranean rodent native to the arid regions of the Horn of Africa. The NMR is the longest-lived rodent and is known for its distinctive physiological and social tra...
The naked mole-rat (NMR; Heterocephalus glaber) is a subterranean rodent native to the arid regions of the Horn of Africa. The NMR is the longest-lived rodent and is known for its distinctive physiological and social traits. This species has become a notable model organism for studying aging, cancer biology, behavioral ecology, and reproduction. Recently, NMRs have gained attention because their gastrointestinal tract features an exceptionally strong intestinal barrier, a large number of goblet cells, a thicker mucin layer, and reduced gut permeability. The NMR gut microbiome, similar to that observed in human centenarians, is highly diverse and characterized by a high microbial load. In fact, Hart et al (2026) demonstrated that spontaneous infection with Citrobacter braakii in the NMR causes clinical symptoms and histopathological changes that are very similar to those observed in human colitis. If left untreated, the disease can progress and become fatal. However, probiotic treatment can reverse the clinical and histopathological phenotypes. These findings indicate that, in addition to serving as a powerful model for aging, cancer, and reproduction, the NMR may also serve as a powerful tool for studying human diseases such as gut dysbiosis, gut barrier dysfunction, and colitis. © 2026 The Pathological Society of Great Britain and Ireland.
Weakly supervised deep learning for cutaneous squamous and basal cell carcinoma in whole-slide histopathology.
Petzold A, Wessely A, Schliep S … +8 more , Jiang H, Tran M, Koch EA, Peng T, Starz H, Berking C, Marr C, Heppt MV
J Pathol Clin Res · 2026 Mar · PMID 41841638 · Full text
Distinguishing infiltrative basal cell carcinoma (BCC) from poorly differentiated cutaneous squamous cell carcinoma (cSCC) remains a significant histopathological challenge. Automated deep learning approaches hold promis...
Distinguishing infiltrative basal cell carcinoma (BCC) from poorly differentiated cutaneous squamous cell carcinoma (cSCC) remains a significant histopathological challenge. Automated deep learning approaches hold promise for improving diagnostic reliability, yet robust external validation is essential. In this study, we developed a weakly supervised deep learning model to classify these diagnostically challenging subtypes and evaluated its generalizability across internal and external cohorts, as well as in comparison to a dermatopathology foundation model (HistoGPT). The model employed a multiple-instance learning framework (CLAM) using the histopathology-specific transformer Phikon for feature extraction from whole-slide images. Slide-level ground-truth diagnoses from the collected images (n = 335, University Hospital Erlangen) were derived from routine clinical practice and re-evaluated by two board-certified dermatopathologists. Performance was assessed on an internal test set of 84 whole-slide images (27 cSCC and 57 BCC) and two external datasets: Queensland cohort (n = 10, curated in-distribution cases) and the COBRA cohort (n = 200, broad, partly out-of-distribution cases). Model discrimination was quantified using ROC curves, while accuracy, sensitivity, and specificity were reported alongside 95% Wilson confidence intervals (CIs). On the internal test set, the model achieved perfect classification [area under the receiver operating characteristic (AUC) = 1.0; 100% accuracy, sensitivity, and specificity]. Similarly, strong performance was observed in the Queensland cohort (AUC = 1.0), although limited by sample size. In the more heterogeneous COBRA cohort, discrimination remained high (AUC = 0.923, 95% CI 0.885-0.961), requiring threshold adjustment to correct for marked calibration shift (balanced accuracy 86.5% at Youden's J). Attention heatmaps highlighted histologically meaningful regions. In zero-shot evaluation on the internal test set, HistoGPT achieved an overall accuracy of 77%, with high class-wise sensitivity for BCC (98%, 95% CI 91-100) but markedly reduced sensitivity for cSCC (33%, 95% CI 19-52). Fine-tuning a task-specific classifier on the HistoGPT backbone substantially improved performance, achieving near-perfect discrimination and 98% balanced accuracy. These findings demonstrate that weakly supervised deep learning enables highly accurate classification of diagnostically challenging BCC and cutaneous squamous cell carcinoma subtypes. However, reliable deployment across institutions necessitates careful calibration and domain adaptation, and even powerful foundation models such as HistoGPT benefit from targeted fine-tuning to ensure robust performance in dermatopathology.
Spatial heterogeneity of antibody-drug conjugate targets in pancreatic ductal adenocarcinoma.
Sabtan D, Eich ML, Loch F … +8 more , Pérez Zuschneid JK, Möbs M, Böhme J, Klauschen F, Horst D, Dragomir MP, Dernbach G, Schallenberg S
J Pathol Clin Res · 2026 Mar · PMID 41837391 · Full text
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease, with limited therapeutic options, few patients showing targetable molecular changes. New therapeutic strategies are necessary. Antibody-drug conjugates (ADCs)...
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease, with limited therapeutic options, few patients showing targetable molecular changes. New therapeutic strategies are necessary. Antibody-drug conjugates (ADCs) have emerged as alternative therapeutic strategies across various cancer types. Herein, we analyze the expression and spatial heterogeneity (six cores per patients) of three ADC targets (c-MET, NECTIN4, and TROP-2) in a cohort of 62 PDAC patients (1,116 tissue cores) and associate their levels with clinicopathological and genomic parameters, and the expression of immune checkpoints. c-MET exhibited significantly higher expression at the tumor front versus tumor center, along with notable intratumoral heterogeneity. In contrast, NECTIN4 and TROP-2 displayed homogeneous expression patterns, with NECTIN4 being absent in approximately two-thirds of cases, while TROP-2 showed consistently strong positivity across tumor regions (98% 3+). By simulating sampling sufficiency for reliable scoring, we observed that, for c-MET, two tumor samples were sufficient to achieve a maximum score of 1+, while for higher scores (2+ and 3+), four samples were required. For NECTIN4, four samples were necessary to detect scores of 1+ and 2+. For TROP-2, for a 3+ score, just two samples were sufficient to reach the maximum score. c-MET or TROP-2 expression scores were not associated with any clinicopathological parameters. In contrast, NECTIN4 expression showed an association with tumor grade. Correlations with immune checkpoints revealed that high TROP-2 expression was inversely correlated with PD-L1 expression. For all three markers no significant differences in expression were found between SMAD4 wild-type and SMAD4-mutated tumors, nor between TP53 wild-type and TP53-mutated tumors. Furthermore, analysis of lymph node and distant (liver and peritoneal) metastases revealed significantly higher c-MET and NECTIN4 expression in the metastatic setting. In conclusion, TROP-2 is highly expressed in most PDACs, independent of clinicopathological and genomic parameters, and inversely correlating with PD-L1, making TROP-2 an ideal ADC target.
Clinicopathologic and molecular landscape of villitis of unknown etiology: insights from a large-scale case-control study in PR China.
Wang M, Sun X, Ren H … +6 more , Gao F, Sun X, Lu C, Yin Y, Li J, Zhao C
J Pathol Clin Res · 2026 Mar · PMID 41837385 · Full text
Villitis of unknown etiology (VUE) is a chronic placental inflammatory lesion characterized by lymphohistiocytic infiltration and destruction of villous architecture in the absence of infection. Although VUE is well reco...
Villitis of unknown etiology (VUE) is a chronic placental inflammatory lesion characterized by lymphohistiocytic infiltration and destruction of villous architecture in the absence of infection. Although VUE is well recognized for its association with fetal growth restriction and adverse pregnancy outcomes, its clinicopathologic correlates and molecular basis remain poorly understood. VUE cases were identified from the pathology database of Jinan Maternal and Child Health Hospital (2020-2023) and classified as high-grade or low-grade according to the Amsterdam criteria. Clinical data, maternal complications, and neonatal outcomes were collected from electronic medical records. Multivariable logistic regression was used to determine independent risk factors. RNA sequencing was performed on 28 placental samples (24 VUE and 4 controls) to identify differentially expressed genes and pathways. A total of 970 cases (381 high-grade and 589 low-grade) and 980 controls were included. VUE prevalence was 5.8%. Hypertensive disorders of pregnancy (HDP) were independently associated with VUE occurrence (odds ratio 1.67, 95% CI 1.28-2.19, p < 0.001). VUE placentas frequently exhibited chronic intervillositis, chronic deciduitis, and avascular villi, whereas maternal vascular malperfusion showed no significant difference from controls. High-grade VUE was significantly associated with low-birth-weight, small-for-gestational-age infants, and increased neonatal intensive care unit admissions, indicating a severity-dependent impact on neonatal outcomes. Transcriptomic profiling revealed robust upregulation of interferon-inducible, cytotoxic, and chemokine genes - most notably GBP5, CXCL9, and CXCL10 - with enrichment of interferon-γ, IL-6/JAK/STAT3, TNF-α/NF-κB, and antigen presentation pathways. VUE, particularly its high-grade form, is a significant placental lesion associated with HDP, adverse neonatal outcomes, and avascular villi. Its distinct interferon-rich molecular profile, consistent with a maternal anti-fetal T-cell-mediated process, underscores its clinical and biological importance. GBP5 emerges as a potential biomarker of interferon-driven inflammation, providing new mechanistic insight and diagnostic relevance for placental immune injury.
Genomic landscape and homologous recombination deficiency in malignant germ cell tumors reveals sex-specific therapeutic opportunities.
Xu B, Chen J, Peng H … +2 more , Su X, He C
J Pathol · 2026 Jun · PMID 41831125 · Publisher ↗
Malignant germ cell tumors (GCTs) are relatively rare tumors with limited therapeutic options. This study examined the homologous recombination deficiency (HRD) status and genomic characteristics in 14 patients with GCT...
Malignant germ cell tumors (GCTs) are relatively rare tumors with limited therapeutic options. This study examined the homologous recombination deficiency (HRD) status and genomic characteristics in 14 patients with GCT who underwent next-generation sequencing. HRD was evaluated using the genomic instability score (GIS), which incorporates three components: loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale transition (LST). Our findings showed that 57.1% (8/14) of participants were HRD positive. Female patients presented a significantly higher prevalence of HRD positivity (87.5%, 7/8) compared with male patients (16.7%, 1/6). HRD positivity in female cases had a mean GIS of 56 (range 48-76), including one patient harboring a germline BRCA2 p.S2670L (c.8009C>T) likely pathogenic mutation. LST demonstrated the strongest correlation with the integrated GIS (R = 0.945), followed by LOH (R = 0.872). Distinct mutation patterns were observed based on gender. GCTs in male cases predominantly exhibited mutations in TP53 (50% in yolk sac tumors; 50% in teratomas). GCTs in male cases also demonstrated TP53 mutations in one mediastinal yolk sac tumor and one mediastinal teratoma. Male cases showed recurrent alterations in KRAS, PRKDC, and CDKN1B, alongside frequent chromosome 12p amplifications in two cases. One particularly complex mediastinal teratoma in a male patient, featuring rhabdomyosarcomatous transformation, displayed bidirectional intergenic (TWSG1, MANEA-DT)-ROS1fusions, a HRAS-intergenic (RNH1) fusion, and MET focal amplification. These findings suggest a promising therapeutic opportunity with poly (ADP-ribose) polymerase (PARP) inhibitors for female patients with HRD-positive GCTs. Additionally, the complex composition of gene variants found in male patients with GCTs, including ROS1 fusions and MET focal amplification, points toward potential targeted therapeutic strategies. This study underscores the presence of sex-specific therapeutic vulnerabilities in GCTs, which warrant further exploration in larger cohorts. © 2026 The Pathological Society of Great Britain and Ireland.
Neutrophil extracellular traps aggravate lung injury by inducing pyroptosis of alveolar macrophages.
Lu J, Song R, Yang H … +1 more , Liu C
J Pathol · 2026 Jun · PMID 41823322 · Publisher ↗
Neutrophil extracellular traps (NETs) contribute to chronic obstructive pulmonary disease (COPD) pathogenesis by amplifying airway inflammation. Gasdermin D (GSDMD)-mediated pyroptosis is a critical driver of COPD progre...
Neutrophil extracellular traps (NETs) contribute to chronic obstructive pulmonary disease (COPD) pathogenesis by amplifying airway inflammation. Gasdermin D (GSDMD)-mediated pyroptosis is a critical driver of COPD progression. This study provides insights into COPD pathogenesis and provides a theoretical basis for potential therapeutic targets. Mice were exposed to cigarette smoke (CS) for 16 weeks to establish a COPD model. In vitro, alveolar macrophages (AMs) (MH-S) and alveolar epithelial cells (MLE-12) were treated with cigarette smoke extract (CSE). Subsequently, NETs were isolated from phorbol-12-myristate-13-acetate (PMA)-stimulated neutrophils. Lung histopathology, inflammatory markers, and pyroptosis-related proteins were analyzed. Co-immunoprecipitation analysis was used to verify the binding of GSDMD and ubiquitin molecules in cells. Interventions included DNase1 to degrade NET and GSDMD knockdown. In CS-exposed mice, NETs increased the levels of proinflammatory cells and mediators, and lung structure was further disrupted. Pyroptosis of AMs was increased, while phagocytosis of AMs was inhibited. However, treatment with DNAse1 partially reversed the results caused by CS exposure and NET induction. Consistently, NETs aggravated inflammatory response and pyroptosis in the CSE-induced MH-S cell model. Furthermore, NETs significantly caused an increase in ROS, which promoted the activation of GSDMD deubiquitination and subsequent pyroptosis pathway in AMs. DNase1 treatment or GSDMD silencing attenuated pyroptosis, reduced inflammatory mediators, and improved lung function. NETs aggravated CS-induced lung inflammation and injury by activating GSDMD to promote pyroptosis in AMs. Targeting GSDMD or NETs represents a novel therapeutic strategy for COPD. © 2026 The Pathological Society of Great Britain and Ireland.
Frequent NPM1 mutation, monoblastic/monocytic origin and prognostic significance of organ and system involvement in myeloid sarcoma: a multicenter study.
Jenei A, Kajtár B, László T … +8 more , Juratli HA, Vida L, Szepesi Á, Mózes R, Timár B, Halter J, Dirnhofer S, Tzankov A
J Pathol Clin Res · 2026 Mar · PMID 41781345 · Full text
Myeloid sarcoma (MS) is a tumorous extramedullary proliferation of blast or blast equivalent cells (e.g., promonocytes or promyelocytes). The most frequent cutaneous presentation is often referred to as leukemia cutis (L...
Myeloid sarcoma (MS) is a tumorous extramedullary proliferation of blast or blast equivalent cells (e.g., promonocytes or promyelocytes). The most frequent cutaneous presentation is often referred to as leukemia cutis (LC). These lesions, especially without the clinical context of a known bone marrow disease, pose a differential diagnostic challenge. In this retrospective multicenter clinico-pathological study on 154 patients with MS or LC, 169 samples were analyzed by morphology, immunohistochemistry, and fluorescent in situ hybridization, and a subset by additional sequencing [TP53]. The majority of cases were lysozyme positive (diffuse in 91% and focal in 5%), 51% showed diffuse and 6% focal expression of CD56, and IRF8 was strongly positive in 31% of the lesions. Lack of myeloperoxidase (MPO), CD117, and CD34 expression was observed in 27%, 39%, and 58%, respectively. PU.1 was positive in almost all instances (95%), but BRAF V600E was consistently negative. CD123 was diffusely (13%) or focally (25%) positive, which, in addition to frequent CD4 (73%) and CD56 expression, pointed to a phenotypic overlap with blastic plasmacytoid dendritic cell neoplasms. Survival analysis revealed that MS occurring at sanctuary sites (CNS, orbit, ovary, and testis) was characterized by excellent survival. Similarly to histiocytoses, there was a prognostic difference between isolated and multisystemic involvement by MS. Patients who underwent allogeneic hematopoietic stem cell transplantation showed significantly improved survival. In conclusion, this multicenter study suggests that most MS are of myelomonocytic/monoblastic origin, a high proportion of them are NPM1 mutated, and may lack expression of MPO and CD34. NPM1 mutation-specific antibodies should be integrated into the diagnostic panels for MS or LC, while IRF8 and PU.1 are not recommended as they cannot distinguish MS from histiocytic neoplasms.
AI-derived prognostic biomarkers from melanoma whole slide image segmentation: an initial discovery and assessment.
Clarke EL, Magee D, Newton-Bishop J … +13 more , Saldanha G, Merchant W, Hall M, Insall R, Maher NG, Scolyer RA, Farnworth G, Ali A, Bamford M, Sticova E, Kujal P, O'Shea S, Treanor D
J Pathol Clin Res · 2026 Mar · PMID 41778962 · Full text
The current melanoma staging system predicts 74% of the variance in survival, with prognostic biomarkers subject to high levels of inter-observer variation. This work assesses whether a previously developed convolutional...
The current melanoma staging system predicts 74% of the variance in survival, with prognostic biomarkers subject to high levels of inter-observer variation. This work assesses whether a previously developed convolutional neural network (CNN) for invasive melanoma segmentation in whole slide images (WSIs) may reveal new insights into melanoma morphology and patient prognosis. This paper uses Cox proportional multivariate regression analyses to evaluate the ability of the CNN outputs to predict patient survival across 745 WSIs from 5 data sources. Five objective histomorphological parameters of tumour size and shape that are independently associated with overall and melanoma-specific survival were created from the CNN: tumour area(log) (HR 1.48 CI 1.30-1.68, p < 0.001), tumour perimeter(log) (HR 1.86 CI 1.48-2.32, p < 0.001), major axis length(log) (HR 1.88 CI 1.42-2.48, p < 0.001), Nodularity Index(log) (HR 1.77 CI 1.28-2.43, p < 0.001) and digital Breslow thickness(log) (HR 2.04, CI 1.63-2.54, p < 0.001). These results indicate that melanoma segmentation of the entire lesion within a WSI may be used to predict patient outcome. Moreover, this technology can be used to make new morphological discoveries to provide information not currently contained within our staging system (e.g. Nodularity Index), as well as provide objectivity and automation of current biomarkers (e.g. digital Breslow thickness). Further work is required to validate this initial discovery and evaluation.
Clinicopathological characteristics of patients with inoperable non-small cell lung cancer harboring circulating NRF2 pathway mutations.
Härkönen J, Tiainen S, Kujala J … +12 more , Muhonen L, Mohanasundaram P, Tikkanen T, Pöhner I, Patinen T, Adinolfi S, Väyrynen JP, Auvinen P, Mannermaa A, Pölönen P, Rauramaa T, Levonen AL
J Pathol · 2026 Jun · PMID 41771797 · Full text
Lung cancer is the leading cause of global cancer-related morbidity and mortality, with tobacco smoking as its strongest risk factor. Nuclear factor erythroid 2-related factor 2 (NRF2) is a redox-regulated transcription...
Lung cancer is the leading cause of global cancer-related morbidity and mortality, with tobacco smoking as its strongest risk factor. Nuclear factor erythroid 2-related factor 2 (NRF2) is a redox-regulated transcription factor frequently dysregulated in non-small cell lung cancer (NSCLC), leading to aggressive disease and resistance to therapy. In this study, we analyzed circulating cell-free tumor DNA from a real-world cohort to characterize clinicopathological features and identify risk factors associated with oncogenic NRF2 activation in inoperable NSCLC. Key findings were further validated using retrospective datasets. Our results demonstrate that NRF2 pathway-mutated NSCLC represents a smoking-associated, high-risk molecular subtype frequently accompanied by detrimental SMARCA4 mutations. Importantly, these co-occurring mutations cumulatively worsen clinical outcomes independently of other risk factors. We show that NRF2-mutated tumors generally exhibit lower leukocyte infiltration, while high tumor mutation burden independently correlates with increased cytotoxic T lymphocyte density, regardless of NRF2 status. Furthermore, our data indicate that NRF2 activation can be reliably identified through immunohistochemical detection of protein expression of markers AKR1B10 and AKR1C1, both of which correlate with inferior outcomes. As mutations in NRF2-regulating tumor suppressors KEAP1 and CUL3 are not confined to specific hotspot regions, our findings advocate for a multimodal profiling approach combining somatic mutation assessment with protein or transcriptomic evaluation of NRF2 targets. This comprehensive strategy effectively identifies oncogenic NRF2 hyperactivity, enhancing diagnostic accuracy and clinical decision-making in NSCLC management. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Preservation of cell-free RNA in percutaneous core-needle biopsy specimens' supernatants from non-small cell lung cancer improves genomic testing performance.
Xu S, Ma YD, Bie ZX … +4 more , Huang JY, Li YM, Wang Z, Li XG
J Pathol Clin Res · 2026 Mar · PMID 41748474 · Full text
This prospective single-center study aimed to investigate whether preserving cell-free ribonucleic acid (cfRNA) in specimens' supernatants (SS) obtained from percutaneous core-needle biopsy (CNB) of non-small cell lung c...
This prospective single-center study aimed to investigate whether preserving cell-free ribonucleic acid (cfRNA) in specimens' supernatants (SS) obtained from percutaneous core-needle biopsy (CNB) of non-small cell lung cancer (NSCLC) can improve the performance of genomic testing. Forty-three NSCLC patients who underwent image-guided CNB were enrolled. The SS from each CNB specimen was divided into two parts: one was mixed 1:1 with a cfRNA-protective solution, and the other was left unhandled. For quantitative analysis, 30 patients (regardless of mutation status) were evaluated by comparing cfRNA yield between cfRNA-protected and -unprotected SS. For qualitative analysis, 15 patients with fusion gene alterations were assessed by comparing genotyping results from cfRNA-protected SS to those from paired CNB specimens. Pneumothorax was the most frequent adverse event in CNB procedures, occurring in 20.9% of cases (9/43). No one experienced severe adverse events. In the quantitative analysis, 90.0% (27/30) of cfRNA-protected SS yielded adequate cfRNA, significantly higher than 53.3% (16/30) in cfRNA-unprotected SS (p < 0.01). In the qualitative analysis, despite ineffective cfRNA preservation in three cases, DNA-level mutations were still detected in both the CNB specimens and cfRNA-protected SS. The overall concordance of genotyping results between cfRNA-protected SS and paired CNB specimens was 100%, correctly identifying all ALK fusions, ROS1 rearrangements, and MET-14 skipping alterations. These findings highlight that preserving cfRNA in CNB-SS from NSCLC can improve the performance of genomic testing, particularly for RNA-based assays, without compromising the accuracy of DNA-based assays.
Impact of tissue staining and scanner variation on the performance of pathology foundation models: a study of sarcomas and their mimics.
Chai B, Chen J, Cool P … +5 more , Oumlil F, Tollitt A, Steiner DF, Chakraborti T, Flanagan AM
J Pathol Clin Res · 2026 Mar · PMID 41735241 · Full text
Histopathological analysis is considered the gold standard for the diagnosis and prognostication of cancer. Recent advances in AI, driven by large-scale digitisation and pan-cancer foundation models, are opening new oppo...
Histopathological analysis is considered the gold standard for the diagnosis and prognostication of cancer. Recent advances in AI, driven by large-scale digitisation and pan-cancer foundation models, are opening new opportunities for clinical integration. However, it remains unclear how robust these foundation models are to real-world sources of variability, particularly in H&E staining and scanners produced by different manufacturers. In this study, we use soft tissue tumours, a rare and morphologically diverse tumour type, as a challenging test case to systematically investigate the colour-related robustness and generalisability of seven AI models. Controlled staining and scanning experiments were utilised to assess model performance across diverse real-world data sources. Foundation models, particularly UNI-v2, Virchow and TITAN, demonstrated encouraging robustness to staining and scanning variation, particularly when a small number of stain-varied slides were included in the training loop, highlighting their potential as adaptable and data-efficient tools for real-world digital pathology workflows.
Pathological classification of Fuchs endothelial corneal dystrophy into several types and their relationships with CTG18.1 expansion repeats.
Vaitinadapoulé H, Onitiu D, Maurin C … +12 more , Travers G, Crouzet E, Dorado-Cortez O, Poinard S, He Z, Forest F, Ollier E, Touraine R, Gain P, Perone JM, Thuret G, French Fuchs Study Group (FFSG)
J Pathol · 2026 Jun · PMID 41736702 · Full text
Late-onset Fuchs endothelial corneal dystrophy (FECD) is the most common primary disease of the corneal endothelium and the leading indication for corneal transplantation in Western countries. It is characterized by prog...
Late-onset Fuchs endothelial corneal dystrophy (FECD) is the most common primary disease of the corneal endothelium and the leading indication for corneal transplantation in Western countries. It is characterized by progressive accumulation, over two to three decades, of extracellular matrix (ECM) components in Descemet's membrane (DM), leading to the formation of abnormal excrescences, known as guttae, and additional DM layers. Clinical forms and evolutionary profiles vary widely among patients. FECD is strongly associated with intronic CTG trinucleotide repeats (TNRs) in the transcription factor 4 (TCF4) gene. We analysed 500 DMs removed during keratoplasty for FECD across 25 European centres to identify different anatomopathological forms of the disease. Following flat mounting and dehydration, the samples were digitized using transmitted light microscopy and independently assessed by three independent readers. A total of ten parameters - six related to guttae and four on other forms of ECM - were scored. Principal component analysis and an unsupervised clustering method separated three clusters from these parameters. In addition, manual classification was performed by grouping samples with major common features. The number of TNRs in TCF4 was analysed by short tandem repeat (STR)- and triplet repeat primed-polymerase chain reaction (TP-PCR) for 109 patients. We found that (1) five FECD phenotypes exist; (2) guttae and other ECM structures were radially arranged in 95% of samples; (3) 33% of samples exhibited peripheral radial striae that corresponded to a hypertrophied form of similar structures present in healthy corneas; and (4) patients with fewer than 50 TNRs had only two out of five phenotypes and had a significantly higher number of peripheral radial striae (94% versus 49%, p < 0.001). Taken together, these new findings demonstrate the existence of different FECD phenotypes; reveal that lesions affect both the centre and the periphery of the endothelium; and suggest that radial deposits may be produced by pathological cells migrating from the periphery towards the centre. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
What practicing pathologists and oncologists should know about the new computational pathology-based companion diagnostic tools.
Montezuma D, Oliveira SP, Zlobec I … +9 more , Khalili N, Temprana-Salvador J, Leh S, Ameisen D, Șerbănescu MS, Prelaj A, Kather JN, Zerbe N, L'Imperio V
J Pathol · 2026 Jun · PMID 41736658 · Full text
The integration of artificial intelligence into pathology is transforming the assessment of histological and immunohistochemical (IHC) slides, offering opportunities to reduce variability and streamline diagnostics. In p...
The integration of artificial intelligence into pathology is transforming the assessment of histological and immunohistochemical (IHC) slides, offering opportunities to reduce variability and streamline diagnostics. In practical terms, most available tools and research models emulate the diagnostic capabilities of pathologists by detecting, grading, and classifying tumours and other diseases. More recent applications have moved beyond mimicry, aiming to predict established biomarkers, such as microsatellite instability or IHC-based markers, and to tackle even more ambitious tasks, such as directly predicting patient prognosis from H&E whole slide images. Remarkably, novel computational tools are now being designed as companion diagnostic assays, linking the automated evaluation of specific IHC biomarkers to the prediction of response to specific drugs, potentially marking a new chapter in the evolution of digital and computational pathology. The TROPION-PanTumor01 trial recently demonstrated the superiority of a supervised machine learning model (termed the quantitative continuous score [QCS] by the vendor) in assessing TROP2 IHC compared with human scoring, promising better stratification of patients with non-small cell lung cancer for treatment with datopotamab deruxtecan. The same approach has shown promise in refining HER2 (human epidermal growth factor receptor 2) and PD-L1 (programmed death-ligand 1) evaluations, revealing patient subgroups that may benefit from targeted therapies. Moreover, other similar approaches are progressively reaching the market, posing significant opportunities and challenges for clinicians involved in the care of patients with cancer. This Perspective is promoted by the European Society of Digital and Integrative Pathology (ESDIP, founded in 2016, and having long-standing experience in computational pathology, esdipath.org) and the European Interdisciplinary Society of Artificial Intelligence for Cancer Research (ESAC, a recently established initiative, founded in 2024, esac-network.eu), both bringing together clinicians, engineers and other professionals dedicated to the development and clinical translation of computational approaches aimed at improving patient care. It aims to provide an informed overview of novel computational pathology companion diagnostic tools, with a particular focus on the background that practicing pathologists and oncologists need to have with these tools, when transitioning from research to clinical practice, irrespective of their prior familiarity with computational approaches. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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