The Journal Of Pathology[JOURNAL]
Sun
200 papers
Hypoxia-induced regional heterogeneity in proliferative vitreoretinopathy: implications for targeted therapies.
Yin W, Xu M, Gao Y … +6 more , Niu Z, Wu X, Song Y, Liu Q, Mao X, Yuan S
J Pathol · 2026 Jan · PMID 41215615 · Publisher ↗
Proliferative vitreoretinopathy (PVR) represents a common and challenging complication leading to blindness following ocular injury. The prevailing view, which guides current drug development efforts, posits that the mes...
Proliferative vitreoretinopathy (PVR) represents a common and challenging complication leading to blindness following ocular injury. The prevailing view, which guides current drug development efforts, posits that the mesenchymal transition of retinal pigment epithelium (RPE) underlies the pathogenesis of PVR. However, in our study, by employing single-cell sequencing and immunofluorescence staining on surgically excised PVR membranes, we demonstrate that PVR exhibits distinct cytopathological characteristics depending on their retinal location. Specifically, epiretinal PVR predominantly comprises macrophages, whereas subretinal PVR is primarily constituted of PMEL RPE-derived cells. Both molecular pathological phenotypes are unified by retinal hypoxia following injury, yet they diverge in their downstream hypoxic pathway selection. Targeting HIF1α-regulated glycolysis selectively reduced epiretinal PVR formation, while inhibiting reactive oxygen species production specifically abrogated subretinal PVR. Furthermore, the application of hyperoxia chamber in a mouse model of dispase-induced retinal injury effectively eradicated PVR across all retinal regions and restored retinal morphology. Our findings establish hypoxia-induced regional heterogeneity as a pathological mechanism in PVR progression and advocate for anatomically targeted therapeutic strategies. © 2025 The Pathological Society of Great Britain and Ireland.
Molecular evidence of a clonal relationship of synchronous/multifocal gastric-type lesions of the female genital tract.
Shi M, Yang H, Zhang F … +12 more , Hou T, Huang H, Lu Y, Zhou Y, Lan T, Ji J, Hou J, Zhou C, Zhang Z, Qin S, Huang Z, Liu Y
J Pathol · 2026 Jan · PMID 41208479 · Publisher ↗
Synchronous/multifocal gastric-type lesions (SMGLs) of the female genital tract are heterogeneous diseases that are rare and challenging to diagnose. The core issue is distinguishing between multiple primaries and multif...
Synchronous/multifocal gastric-type lesions (SMGLs) of the female genital tract are heterogeneous diseases that are rare and challenging to diagnose. The core issue is distinguishing between multiple primaries and multifocal metastases from a single lesion. This is vital for staging, prognosis, and treatment decisions, especially when metastases mimic primary and early lesions at the relevant sites. Traditional morphological diagnosis often faces a paradoxical situation on this key issue and cannot quantitatively evaluate the correlations among multiple foci. Here, six cases of SMGL were collected, two of which exhibited pagetoid dissemination within the genital tract, with all lesions being noninvasive. A total of 24 samples were subjected to whole-exome sequencing. By inference based on overlapping genetic variations, base substitution mutation patterns, composition and similarity of COSMIC signatures, clonality indices, and the construction of evolutionary trees, it was inferred that the multiple foci in each patient were clonally related, indicating that all cases were metastatic. The follow-up duration ranged from 7 to 62 months (median: 24.5 months). Four patients died of disease (median survival time: 24.5 months, range: 8-47 months), including one patient who had no invasive lesions at initial diagnosis; two patients experienced recurrences at 17 and 40 months, respectively. These results imply that even if all foci exhibit the appearance of in situ or premalignant changes histologically, they may actually be aggressive. Hence, for SMGLs, before opting for conservative treatment, comprehensive clinical assessment, appropriate surgical extent, adequate sampling, and careful microscopic examination are crucial. Clonal analysis should also be conducted where necessary to avoid undertreatment due to understaging. The study further explored the genomic traits of SMGLs involving more than two sites. © 2025 The Pathological Society of Great Britain and Ireland.
Transcriptomic profiling reveals the role of Hedgehog signaling as a biomarker and in the pathogenesis of Ménétrier's disease.
Shin M, Gabriel TT, Ofosu FK … +5 more , Zhang J, Wang TT, Bechard ME, Coffey RJ, Huh WJ
J Pathol · 2026 Jan · PMID 41199529 · Full text
Both Ménétrier's disease (MD) and juvenile polyposis syndrome (JPS) are rare premalignant conditions that can lead to gastric cancer. MD is an acquired disease without known causative mutations that is characterized by i...
Both Ménétrier's disease (MD) and juvenile polyposis syndrome (JPS) are rare premalignant conditions that can lead to gastric cancer. MD is an acquired disease without known causative mutations that is characterized by increased expression of an EGF receptor (EGFR) ligand, transforming growth factor-alpha (TGFα), in the stomach. JPS is inherited in an autosomal dominant pattern and is caused by BMPR1A or SMAD4 mutations. Although there are distinct clinico-pathological features that differ between the two diseases, they also share similar features that often lead to misdiagnosis. To identify diagnostic markers for MD and to better understand the pathogenesis of the disease, we performed transcriptomic profiling of stomach tissues from normal (NL), MD, and JPS patients. Comparative analysis between MD and JPS revealed both common and differential gene signatures. Common gene signatures included estrogen receptor signaling, integrin signaling, mTOR signaling, and others, which may be responsible for histopathological similarities. Among differential gene signatures, we found that Hedgehog (Hh) signaling is upregulated in MD and confirmed that protein expression of Hh signaling downstream targets, GLI1 (glioma-associated oncogene homolog 1) and HHIP (Hedgehog-interacting protein), is higher in MD than in JPS, particularly in foveolar cells by immunohistochemistry. We also demonstrated that treatment with an Hh pathway inhibitor partially rescued the histopathological phenotypes in an MD mouse model. This study provides valuable insights into the potential mechanisms underlying the similar clinico-pathological features observed in MD and JPS. We also identified GLI1 and HHIP as diagnostic markers that can help to distinguish MD from JPS. Furthermore, Hh signaling was shown to play an important role in the pathogenesis of MD and may serve as a potential therapeutic target. © 2025 The Pathological Society of Great Britain and Ireland.
Secretory breast carcinoma: morphologic and molecular heterogeneity with indicators of aggressive potential in a cohort of 29 cases.
Ren H, Tong W, Ma J … +7 more , Chen X, Huang H, Wei N, Liu Y, Yang M, Zhang L, Li H
J Pathol Clin Res · 2025 Nov · PMID 41195654 · Full text
Secretory breast carcinoma (SBC) is a rare tumour defined by ETV6-NTRK3 rearrangement, but its clinicopathological spectrum and potential for aggressive behaviour remain incompletely characterised. We retrospectively rev...
Secretory breast carcinoma (SBC) is a rare tumour defined by ETV6-NTRK3 rearrangement, but its clinicopathological spectrum and potential for aggressive behaviour remain incompletely characterised. We retrospectively reviewed 29 SBCs diagnosed between 2014 and 2024, including 28 females and one male aged 12-63 years (median 44). Twenty-eight tumours arose in the breast parenchyma and one in axillary accessory breast tissue. Histologically, microcystic and tubular patterns predominated and carcinoma in situ was common. Most tumours were nuclear grade 1 with rare mitoses (0-1/10 high-power fields, HPF). A single patient with distant metastasis harboured a solid-predominant tumour showing nuclear grade 2-3, brisk mitoses (6/10 HPF), and multifocal necrosis. All tumours demonstrated diffuse S100 and pan-TRK expression. Oestrogen and/or progesterone receptor staining was observed in 16 of 29 cases (2-30% of tumour cells), and all were HER2 negative or low (0-1+). Ki-67 ranged from 3% to 20% (mean 7%). Fluorescence in situ hybridisation (FISH) was positive in 17 of 17 tested tumours (14 ETV6-NTRK3 dual-fusion; 3 NTRK3 break-apart). In the metastatic case, RNA sequencing confirmed canonical ETV6-NTRK3 fusion, while targeted DNA sequencing identified additional variants of uncertain significance (VUS) - RANBP2 p.S1843R, NUP107 p.K382Q, NCOR1 p.A1947V (missense), and PREX2 p.G606G (synonymous). All patients underwent surgery, and 14 received adjuvant chemotherapy. During follow-up ranging from 6 to 135 months (median 76), one patient developed lung metastasis and was alive with disease at 88 months; the remaining 28 patients were alive without recurrence or metastasis. In summary, SBC is typically indolent and characterised by ETV6-NTRK3 rearrangement with diffuse pan-TRK/S100 positivity. A solid-predominant pattern with increased cytological atypia, mitotic activity, and necrosis may indicate aggressive potential. Routine NTRK testing supports diagnosis and may help identify patients who could benefit from TRK-inhibitor therapy in advanced disease.
Contrastive virtual staining enhances deep learning-based PDAC subtyping from H&E-stained tissue cores.
Fischer M, Muckenhuber A, Peretzke R … +17 more , Farah L, Ulrich C, Ziegler S, Schader P, Feineis L, Gao H, Xiao S, Götz M, Nolden M, Steiger K, Sieveke JT, Endrös L, Braren R, Kleesiek J, Schüffler P, Neher P, Maier-Hein K
J Pathol · 2026 Jan · PMID 41188199 · Full text
Pancreatic ductal adenocarcinoma (PDAC) subtyping typically relies on immunohistochemistry (IHC) staining for critical markers like HNF1A and KRT81, a labor-intensive manual staining process that introduces variability....
Pancreatic ductal adenocarcinoma (PDAC) subtyping typically relies on immunohistochemistry (IHC) staining for critical markers like HNF1A and KRT81, a labor-intensive manual staining process that introduces variability. Virtual staining methods offer promising alternatives by generating synthetic IHC images from routine hematoxylin and eosin (H&E) slides. However, most current approaches evaluate success by image quality measures rather than assessing diagnostically relevant features. Here, we introduce a novel cycleGAN framework utilizing a contrastive-inspired approach trained on semipaired datasets derived from consecutive tissue sections. Our method significantly enhances PDAC subtyping accuracy based on synthetic IHC images generated from standard H&E inputs, improving the classification F1-score from 0.66 to 0.77 for KRT81 and from 0.61 to 0.73 for HNF1A, compared with classification directly on H&E images. This approach also substantially outperforms baseline CycleGAN models. These results underscore the clinical potential of contrastive virtual staining to streamline PDAC diagnostics and improve their robustness. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
mTOR-mediated upregulation of B7-H3 in MiT/TFE translocation renal cell carcinoma.
Li H, Amaral A, Vidotto T … +11 more , Woo J, Liu HB, Oliveira LD, Dairo O, Feng K, Shenderov E, Argani P, Schmidt LS, Linehan WM, Lotan TL, Asrani K
J Pathol · 2026 Jan · PMID 41178060 · Publisher ↗
Clinical trials targeting B7-H3 (CD276), a membranous immunomodulatory molecule in the B7 superfamily, have shown promise in prostate cancer and may be expanded to additional tumor types with high expression, such as tho...
Clinical trials targeting B7-H3 (CD276), a membranous immunomodulatory molecule in the B7 superfamily, have shown promise in prostate cancer and may be expanded to additional tumor types with high expression, such as those with mTOR signaling activation. MiT/TFE-rearranged translocation renal cell carcinoma (tRCC) is a rare, aggressive subtype that is relatively immune-depleted, with high levels of mTOR activity. Thus, we assessed B7-H3 expression in preclinical tRCC models and human tRCC samples. As hypothesized, we found that induction of TFE3 fusion proteins, including SFPQ-TFE3, PRCC-TFE3, ASPSCR1-TFE3, and NONO-TFE3, is associated with upregulation of B7-H3 in multiple human preclinical tRCC cell line systems and transgenic mouse models. Pharmacologic or genetic inhibition of mTOR signaling is sufficient to downregulate B7-H3 expression in inducible and patient-derived, human cell line models of tRCC. In keeping with these preclinical results, human tRCC demonstrated significantly higher gene expression of CD276 than normal kidney, across five of the six fusions studied. At the protein level, tRCC had higher tumor cell B7-H3 intensity and proportion scores than normal kidney or clear cell RCC (ccRCC). B7-H3 expression in tumor vasculature was similar in tRCC and ccRCC, both of which showed significantly higher expression than normal kidney. Within tRCC cases, higher CD276 expression was observed in metastatic compared to localized tumors and was associated with lower tumoral CD4 T-cell content by bulk RNAseq deconvolution. Taken together, tRCC fusion proteins upregulate B7-H3 expression via increased mTOR signaling, resulting in a higher tumoral B7-H3 expression compared to normal kidney or conventional RCC, suggesting that B7-H3 may be a promising therapeutic target in tRCC. © 2025 The Pathological Society of Great Britain and Ireland.
Phylogenetic analysis of paired breast carcinomas identifies genetic events associated with clonal recurrence and invasive progression.
Kader T, Zethoven M, Mahale S … +30 more , Saunders H, Tjoeka L, Lehmann R, Jayawardana MW, Pang JM, Lesche D, Rajan N, Semple T, Lee JEA, Lupat R, Byrne DJ, Hughes S, Nguyen H, Lai S, Pechlivanis M, Craig O, Devereux L, House E, Jayasinghe SI, Kaufmann TL, Schwarz RF, Green AR, Miligy IM, Cummings M, Lakhani S, Campbell IG, Rakha E, Fox SB, Mann GB, Gorringe KL
J Pathol · 2026 Jan · PMID 41165701 · Full text
Development of ipsilateral breast carcinoma following a diagnosis of breast ductal carcinoma in situ (DCIS) has been assumed to represent recurrence of the primary tumour. However, this may not always be the case, and it...
Development of ipsilateral breast carcinoma following a diagnosis of breast ductal carcinoma in situ (DCIS) has been assumed to represent recurrence of the primary tumour. However, this may not always be the case, and it is important to determine how often such recurrences represent new tumours. Ipsilateral primary-recurrence pairs (n = 78) were sequenced to test their clonal relatedness. Shared genetic events were identified from whole exome sequencing (n = 54 pairs) using haplotype-specific copy number and phylogenetic analysis. The remaining pairs were sequenced using a targeted panel or low-coverage whole genome sequencing. We included 32 non-recurrent DCIS to compare recurrent and non-recurrent disease. We found that 7% of DCIS recurrences were non-clonal by whole exome sequencing, indicative of a new breast carcinoma. Lower resolution methods detected a higher non-clonality rate (29%). By comparing primary DCIS with their recurrence, we found that the evolution of DCIS to invasive disease was associated with increased ploidy and copy number events. TP53 mutations were enriched in DCIS with clonal recurrence compared with non-recurrent DCIS. Our results verify that de novo 'recurrent tumours' of independent origin occur in patients who may be at high risk. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Context is key: how diagnostic and prognostic markers are reshaping gynecologic pathology.
Köbel M, Karnezis AN
J Pathol Clin Res · 2025 Nov · PMID 41165400 · Full text
The field of gynecologic pathology is undergoing a transformative change. The translation of molecular findings from large-scale genomic studies into clinical practice has been facilitated by robust surrogate assays, par...
The field of gynecologic pathology is undergoing a transformative change. The translation of molecular findings from large-scale genomic studies into clinical practice has been facilitated by robust surrogate assays, particularly immunohistochemistry (IHC). These tools provide scalable molecular proxies with short turnaround times, enabling molecular subclassification and conclusive prognostic biomarker studies. This commentary highlights how prognostic markers now refine diagnoses in challenging borderline areas, where an abnormal result can help exclude benign or precursor entities. However, the utility of these markers is highly context-dependent, modified by histotype and molecular subtype. Furthermore, the confident diagnosis of rare entities and the study of their precursors have been advanced by defining specific molecular and IHC profiles, opening new avenues for research and therapy. The integration of morphology with molecular features is increasing the robustness of diagnoses and dictating oncology management as never before.
Diffuse glioma with FGFR3-TACC3 fusion in adults is not a homogenous clinicopathological and molecular entity.
Su X, Wu J, Wang P … +8 more , Hu L, Chen Y, Ren C, Song F, Lin H, Ji C, Xie Y, Wang X
J Pathol Clin Res · 2025 Nov · PMID 41165398 · Full text
Adult diffuse gliomas with FGFR3-TACC3 (F3T3) fusion are rare and highly heterogeneous central nervous system (CNS) tumors. Current research on the biological behavior of these tumors is limited, especially regarding whe...
Adult diffuse gliomas with FGFR3-TACC3 (F3T3) fusion are rare and highly heterogeneous central nervous system (CNS) tumors. Current research on the biological behavior of these tumors is limited, especially regarding whether histopathologically low-grade tumors are indolent or represent early-stage high-grade tumors, thereby posing challenges for grading. In this single-center study of 17 patients with adult F3T3 fusion diffuse gliomas (F3T3 gliomas), both low- and high-grade F3T3 gliomas presented distinctive recurrent histopathological features, such as oligodendrocyte-like cells, branched vessels and frequent calcifications. Molecularly, TERT promoter mutations and 7+/10- chromosomal alterations were common; one patient with recurrent glioma with histopathological features of polymorphous low-grade neuroepithelial tumor of the young (PLNTY) had additional CDK4 and MDM2 amplifications. Methylation profiling of 3 samples revealed varied results. A patient whose tumor had histopathological features consistent with PLNTY and a methylation subtype classified as the mesenchymal subtype of glioblastoma (GBM) experienced tumor recurrence 8 months after surgery. After 5-62 months of follow-up, seven patients relapsed, and six died; the primary tumors of the three patients with recurrence presented histopathological characteristics of low-grade glioma (LGG). GBM patients had worse overall survival than LGG patients (p = 0.035) but similar progression-free survival (p = 0.47), indicating that LGG patients may experience recurrence. For adults with tumors with histopathological features of PLNTY, further molecular and methylation analyses are needed for grading. If TERT promoter mutations are present, even with a PLNTY methylation profile, these tumors can still exhibit the biological behavior of high-grade gliomas.
MicroRNA profiling of testicular Leydig cell tumors identifies a microRNA signature associated with malignancy and miR-196b-5p as a potentially useful biomarker.
Lobo J, Tavares NT, Fernandes-Pontes F … +20 more , Constâncio V, Marques AT, Oliveira-Lopes B, Fonseca D, Jerónimo C, Henrique R, Michalova K, Cornejo KM, Colecchia M, Ricci C, Idrees MT, Contreras F, Gonzalez IMF, Anderson WJ, MacLean F, Osunkoya AO, Kao CS, Sangoi AR, Ulbright TM, Acosta AM
J Pathol · 2026 Jan · PMID 41152570 · Full text
Approximately 10% of testicular Leydig cell tumors (LCTs) are clinically malignant and unresponsive to systemic treatment. Predicting their clinical behavior can be problematic because there are no biomarkers that can co...
Approximately 10% of testicular Leydig cell tumors (LCTs) are clinically malignant and unresponsive to systemic treatment. Predicting their clinical behavior can be problematic because there are no biomarkers that can consistently discriminate between benign and malignant LCTs. We assessed microRNA expression profiles of LCTs to identify differentially expressed microRNAs that could potentially distinguish benign from malignant neoplasms. The study consisted of two phases. In the first (discovery) phase, we interrogated 768 microRNAs in a series of 11 LCTs (six malignant and five benign) using Taqman Low-Density Array (TLDA) microRNA profiling. In the second phase, we validated the top differentially expressed microRNA targets with real-time quantitative PCR on a series of 35 LCTs (17 malignant and 18 benign), assessing their clinical performance for distinguishing malignant from benign LCTs. Target biologic pathways were analyzed using the miRTargetLink 2.0 tool. A total of 50 microRNAs were differentially regulated in malignant LCTs (27 upregulated, 23 downregulated). The top six microRNA candidates (top three upregulated and top three downregulated) were validated, showing good performance for discriminating between malignant and benign LCTs, with an area under the curve (AUC) ranging between 0.69 and 0.87. MiR-196b-5p showed the best performance, with sensitivity, specificity, negative predictive value, positive predictive value, and accuracy of 82%, 83%, 83%, 82%, and 83%, respectively. A panel (i.e. combined) analysis reached 100% sensitivity and 83% specificity. Pathway analysis revealed significant overlap in the biological process targeted by the upregulated microRNAs in malignant LCTs, including proliferation, development, metabolism, hormone synthesis, and cell death. Our results support the idea that malignant LCTs are associated with a distinct microRNA signature. MiR-196b-5p was identified as a potentially useful biomarker to distinguish benign from malignant tumors. The shared downstream targets of the top upregulated microRNAs suggest that dysregulation of cell proliferation and apoptosis underlie aggressive biologic behavior in LCTs and may offer opportunities for targeted therapies. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Identification of actionable targets using DEPArray-based sorting of pure carcinoma and stromal populations from formalin-fixed paraffin-embedded tissues followed by shallow whole-genome sequencing.
Nteliopoulos G, Wren E, Rushton A … +18 more , Wadsley MK, Fernandez-Garcia D, Manodoro F, Agbaimoni O, Chauhan R, Cheng Z, Ennis DP, Page K, Allsopp RC, Bautista J, Puccio I, Matthews N, Gleason KL, Farah R, Kenny L, McNeish IA, Shaw JA, Coombes RC
J Pathol · 2026 Jan · PMID 41144934 · Full text
Formalin-fixed paraffin-embedded (FFPE) tissue specimens represent precious resources for clinical genomic profiling studies, especially when coupled with comprehensive medical records. Even though next-generation sequen...
Formalin-fixed paraffin-embedded (FFPE) tissue specimens represent precious resources for clinical genomic profiling studies, especially when coupled with comprehensive medical records. Even though next-generation sequencing (NGS) is an effective tool to detect somatic mutations and somatic copy number alterations (sCNA), the biggest challenges in unlocking clinically translatable genomic information from FFPE tissue are low DNA yields and degraded DNA, affected by variable formalin fixation. Another issue is that the proportion of carcinoma and other noncarcinoma cells is variable and can be confounded by intratumoral heterogeneity. To explore these challenges, we isolated pure carcinoma and stromal cells using the DEPArray™ NxT system, a microchip-based digital sorter that allows isolation of pure, homogeneous subpopulations of cells from FFPE samples. We isolated pure carcinoma and stromal cell populations from 12 FFPE tissues, including tissues from nine primary and metastatic breast cancer and three primary ovarian high-grade serous carcinomas. This was followed by downstream shallow whole-genome sequencing (WGS) for copy number landscape profiling (10 samples) and/or a targeted panel for somatic mutation and sCNA analysis (seven samples), subject to cell availability. Seven out of 10 samples (even some with low tumour content or of old age) produced good-quality genomic data, detecting sCNA in all carcinoma population samples but not in the stromal populations. Mutation analysis was performed successfully in 6/7 samples and somatic mutations were detected in all of them. Our workflow enabled the identification of clinically actionable targets, including PIK3CA, ERBB2, FGFR1/2, CDK6, CCNE1, KRAS amplifications and RB, BRCA1/2 losses in patients that would direct therapy. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Issues and missed opportunities in lymph node assessment after neoadjuvant chemotherapy.
Ryan L, Provenzano E, Grigoriadis A … +1 more , Pinder SE
J Pathol · 2025 Dec · PMID 41132035 · Full text
Assessment of axillary lymph nodes in breast cancer patients following neoadjuvant chemotherapy (NACT) is a crucial part of the clinical and pathological assessment of the disease and has prognostic and management implic...
Assessment of axillary lymph nodes in breast cancer patients following neoadjuvant chemotherapy (NACT) is a crucial part of the clinical and pathological assessment of the disease and has prognostic and management implications. This, however, currently lacks standardisation and focuses only on the number of lymph nodes with metastases still present, the largest metastasis, and the presence of pathological complete response. Potential changes in any residual disease or within the lymph node parenchyma are not examined. Novel methods of more nuanced approaches are rare in the literature, even when considering multiple cancer types, but can offer an insight into the potential additional information to be gained and improvement in patient stratification. Given how common NACT is as the backbone of cancer therapy, there is a surprising lack of research into the lymph node response and determination of the biological factors driving what is seen histologically. Furthermore, with NACT now being administered alongside immunotherapy, there is an increasing need to understand the functional and architectural changes induced in the lymph nodes by metastatic tumour and systemic therapies. This review summarises current approaches, with breast cancer as an exemplar, and discusses the literature investigating a possible more granular approach to lymph node assessment after NACT. Translating these multiple carcinoma studies to breast cancer patients may prompt tissue-based research and, with clinical validation studies, changes to the reporting of lymph node response, for example percentage of viable tumour and immunological architectural features such as germinal centres. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Genetic landscape of non-UV-induced cutaneous squamous cell carcinomas.
Al Youssef C, Alkobtawi M, Safi R … +18 more , Chanal J, Sohier P, Leclerc-Mercier S, Zehou O, Ortonne N, Moguelet P, Senet P, Adoux L, Letourneur F, Bergqvist C, Abbas O, Kibbi AG, Bodemer C, Ferré VM, Guégan S, Oulès B, Aractingi S, Nassar D
J Pathol · 2025 Dec · PMID 41132030 · Publisher ↗
Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer and is most often caused by cumulative UV exposure. However, cSCC may also arise independently of UV exposure, on sites of sustained skin dam...
Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer and is most often caused by cumulative UV exposure. However, cSCC may also arise independently of UV exposure, on sites of sustained skin damage like chronic ulcers, scars, Recessive Dystrophic Epidermolysis Bullosa (RDEB), and inflammatory skin diseases such as hidradenitis suppurativa (HS). Little is known about non-UV-induced skin carcinomas. We aimed to describe the clinical, pathological, and genetic features, of non-UV-induced cSCC. We collected clinical and pathologic data corresponding to 31 patients with non-UV-induced cSCC, including 5 cSCC on HS, 4 on chronic leg ulcers and 8 on RDEB. DNA was extracted from FFPE samples and analysed using a NGS assay targeting 523 cancer genes. A comparison was performed with published genetic data obtained in non-UV-induced and UV-induced cSCC. We found that the Tumour Mutational Burden (TMB) of non-UV-induced cSCC was 6-times lower than the published TMB of UV-induced cSCC. The predominant mutational signature was a clock-wise signature. By comparing the frequency of driver mutations, we found TP53 and NOTCH1 to be significantly less frequently mutated than in UV-mutated cSCC. Interestingly, KMT2B (a histone methyl transferase) was mutated in 11/31 non-UV-induced cSCC and this proportion was significantly higher than in UV-mutated cSCC. These mutations were high impact loss-of-function mutations. We found that knocking down KMT2B expression using siRNA did not affect cell proliferation of SCC-13 and A-431 cell lines, however, it significantly increased cell migration in vitro. Taken together, this study provides a comprehensive description of non-UV-induced cSCC and identifies that KMT2B is mutated and involved in non-UV-induced cSCC carcinogenesis. © 2025 The Pathological Society of Great Britain and Ireland.
Fibroblast-specific palladin drives kidney fibrosis via MRTF-SRF signaling.
Yamamoto N, Sakai N, Yamamura Y … +25 more , Kaikoi D, Hayashi D, Matsuno T, Koshino A, Sako K, Horikoshi K, Yuasa T, Tamai A, Minami T, Oshima M, Nakagawa S, Kitajima S, Hara A, Shimizu M, Terakawa J, Horike SI, Daikoku T, Mizokami A, Ikeda H, Kadoguchi M, Arakawa H, Ohtsuki S, Lagares D, Wada T, Iwata Y
J Pathol · 2026 Jan · PMID 41131992 · Full text
Fibrosis is a common end-stage pathway of progressive chronic kidney diseases. Previously we demonstrated that myocardin-related transcription factor (MRTF)-serum response factor (SRF) signaling drives the expression of...
Fibrosis is a common end-stage pathway of progressive chronic kidney diseases. Previously we demonstrated that myocardin-related transcription factor (MRTF)-serum response factor (SRF) signaling drives the expression of fibrosis-related molecules through actin cytoskeleton dynamics in renal fibroblasts. However, it has not been elucidated whether actin-associated proteins relate to the pathogenesis of fibrosis. Here, we reveal that the actin cytoskeleton-regulating pathway is significantly correlated with estimated glomerular filtration rate (eGFR) and collagen type 1 alpha 1 expression in human proteome analysis. We found that palladin was one of the TGF-β1-dependent actin-associated proteins in renal fibroblasts. Our mechanistic studies demonstrated that palladin activates MRTF-SRF signaling via actin cytoskeleton rearrangement upon TGF-β1 stimulation. In addition, palladin expression itself was enhanced by MRTF-SRF signaling, indicating a positive feedback loop. In vitro, genetic silencing of the palladin-MRTF-SRF axis suppressed extracellular matrix production and myofibroblast differentiation. In preclinical models in vivo, fibroblast-specific palladin-deficient mice (palladin) were protected from kidney dysfunction and fibrosis that developed in adenine-induced nephropathy, which was associated with reduced numbers of myofibroblasts compared to wild type (palladin) mice. In patients with renal disease, palladin was significantly upregulated in the renal interstitium of patients with low eGFR and kidney fibrosis. Moreover, upregulation of the palladin-MRTF-SRF axis correlated with kidney function and fibrosis in patients with various kidney diseases, including IgA nephropathy, diabetic nephropathy, and nephrosclerosis. Taken together, we consider palladin to be a novel regulator of actin cytoskeleton signaling in fibrotic fibroblasts and represents a novel therapeutic target for the treatment of progressive kidney diseases. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Lactate-mediated activation of GPR81 regulates BCR/Abl protein expression in chronic myeloid leukemia cells selected under low oxygen tension.
Menegazzi G, Desideri D, Biagioni A … +3 more , Rovida E, Dello Sbarba P, Peppicelli S
J Pathol · 2025 Dec · PMID 41128634 · Full text
Chronic myeloid leukemia (CML) is a stem cell-driven neoplasia characterized by the expression of the constitutively active tyrosine kinase (TK) BCR/Abl. Under low oxygen, a condition that characterizes stem cell niches...
Chronic myeloid leukemia (CML) is a stem cell-driven neoplasia characterized by the expression of the constitutively active tyrosine kinase (TK) BCR/Abl. Under low oxygen, a condition that characterizes stem cell niches (SCNs) in vivo, the oncogenic BCR/Abl is suppressed. Consequently, leukemia stem cells (LSCs) residing within SCNs show resistance to TK inhibitors (TKIs), the first-line therapy for CML, due to the lack of their molecular target. It is therefore important to deepen understanding of the mechanisms driving BCR/Abl suppression to design new strategies able to repress TKI-resistant LSCs. Our previous studies showed that BCR/Abl suppression occurred when glucose approaches completed exhaustion in culture medium. As lactate is the main byproduct of glucose catabolism in low oxygen, in this study we addressed the role of lactate in regulating BCR/Abl expression. We found that treatment of CML cells with 2-DG, which blocks glycolysis and thereby lactate production, or monocarboxylate transporter (MCT) inhibitors, which reduce lactate excretion, enhanced BCR/Abl expression and promoted maintenance of a BCR/Abl-dependent/TKI-sensitive stem cell phenotype. The effects of MCT inhibition were abolished when exogenous lactate was added to culture medium, resulting in the suppression of BCR/Abl expression. Treatment with 3-hydroxy-butyrate acid, an antagonist of the GPR81 plasma membrane 'lactate' receptor, prevented lactate-driven BCR/Abl suppression, while the selective GPR81 agonist 3-chloro-5-hydroxy-BA counteracted the maintenance of BCR/Abl induced by MCT inhibition. Our results indicate that GPR81 engagement by extracellular lactate determines BCR/Abl suppression in low oxygen environments. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Metamorphoses in pancreatic cancer precursors: the role of simple mucinous cysts.
Camisa PR, Campa D, Esposito I … +1 more , Crippa S
J Pathol · 2026 Mar · PMID 41122920 · Publisher ↗
Pancreatic cystic lesions present a unique opportunity to identify and potentially prevent pancreatic ductal adenocarcinoma (PDAC), one of the deadliest solid tumors. Until now, research has primarily focused on intraduc...
Pancreatic cystic lesions present a unique opportunity to identify and potentially prevent pancreatic ductal adenocarcinoma (PDAC), one of the deadliest solid tumors. Until now, research has primarily focused on intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs), whose potential for malignant transformation is well established. In recent years, however, a new pathological entity has emerged: the simple mucinous cyst (SMC). SMCs are distinct from other cystic lesions, as they lack both communication with the pancreatic ductal system (a hallmark of IPMNs), and the ovarian-like stroma, characteristic of MCNs. The recent work by Pea et al, published in The Journal of Pathology, suggests that these lesions can progress to PDAC, underscoring the need for further characterization. In this commentary, we review the key findings of this study and discuss the potential next steps required to translate these discoveries into actionable clinical practice. © 2025 The Pathological Society of Great Britain and Ireland.
The diagnostic landscape of bone and soft tissue sarcoma: the pan-sarcoma era and AI-driven classification.
Cross WC
J Pathol Clin Res · 2025 Nov · PMID 41122065 · Full text
Bone and soft tissue sarcomas are a diagnostic challenge due to their histological complexity, variety, and mutational heterogeneity. This has led to continued refinements in classification and diagnostic criteria, prese...
Bone and soft tissue sarcomas are a diagnostic challenge due to their histological complexity, variety, and mutational heterogeneity. This has led to continued refinements in classification and diagnostic criteria, presented and soon to be updated by the WHO. This commentary features articles published in this journal and elsewhere that have ultilised pan-sarcoma datasets and artificial intelligence-based classifiers. A notable entry is the DKFZ Sarcoma Classifier, which is based on methylation profiles and available for use via a commercial platform. This work has created hope that one day a comprehensive sarcoma classifier will be available, though it is also a reminder of the many challenges apparent in studying rare cancer types.
Inter-rater agreement of HER2-low scores between expert breast pathologists and the Visiopharm digital image analysis application (HER2 APP, CE2797).
Parry S, Zabaglo L, Shaaban AM … +1 more , Dodson A
J Pathol Clin Res · 2025 Nov · PMID 41103138 · Full text
Inter-observer concordance data for the HER2 category as assessed by a group of 16 specialist breast pathologists on 50 diagnostic core biopsies was compared with that produced by digital image analysis (DIA) using the H...
Inter-observer concordance data for the HER2 category as assessed by a group of 16 specialist breast pathologists on 50 diagnostic core biopsies was compared with that produced by digital image analysis (DIA) using the HER2 APP, CE2797 (VP APP; Visiopharm, Hoersholm, Denmark). Comparing pathologists' consensus scores and DIA scores, 36 cases (73.5%) agreed. Fleiss' kappa statistic was 0.433 (indicative of moderate agreement). Cohen's weighted kappa was used to compare the scores of individual raters to consensus scores; for all 50 cases the kappa scores had a range between 0.412 and 0.854; the VP APP was ranked 12th of 17 raters (kappa score 0.638 indicating substantial agreement). Results for HER2-low cases (N = 44) showed a kappa score range of 0.295 to 0.823; the VP APP ranked 12th of 17 (score 0.535 indicating moderate agreement). For high agreement cases the kappa score range was 0.664 to 1.000 for all HER2 scores (N = 24) and the VP APP scored 0.916 (indicating almost perfect agreement). For the HER2-low scores (N = 20), the kappa score range was 0.506-1.000 and the VP APP scored 0.860 (almost perfect agreement). DIA of the proportions of tumour cells showing expression within each of the HER2 categories demonstrated that the majority of cases showing a low level of agreement between pathologists showed heterogeneity and/or a level of expression close to a cut-point for decision making. This study demonstrates that the VP APP produces results that are extremely well-aligned to those of expert pathologists in cases with good overall agreement, and in difficult cases its reproducibility will outperform that of the visual scorer. The results also suggest that use of the VP APP has the potential to reduce the proportion of cases referred for gene amplification testing by reducing the number of cases incorrectly classified as HER2 2+.
Super resolution of pathology images with hierarchical feature integration and local image patterns.
Xu F, Li L, Wang S … +6 more , Ling R, Zhang X, Deng X, Zhou M, Ling J, Gao C
J Pathol · 2025 Dec · PMID 41081336 · Publisher ↗
Recent advancements in pathological imaging have facilitated single-cell and subcellular-level analysis based on high-resolution images for tumor subtyping, cytomorphological assessment, and infection detection. As high-...
Recent advancements in pathological imaging have facilitated single-cell and subcellular-level analysis based on high-resolution images for tumor subtyping, cytomorphological assessment, and infection detection. As high-resolution imaging is often limited by cost, super-resolution methods provide a practical alternative with only low-resolution data. However, existing methods generally suffer from artifacts, oversmoothing, and slow inference speed. In this study, we developed a hierarchal deep learning framework based on local pathological image patterns, named Hierarchical Local Image Patterns (HLIP), to achieve accurate, high-fidelity, and real-time super resolution with flexible magnifications. HLIP integrates semantic features with both pixel- and morphology-level features and reconstructs super-resolution images by the recognized local pathological image patterns. Benchmark analysis showed HLIP achieved the best performance and robustness on both internal and external test datasets. The generated super-resolution images contain abundant pathological details and maintain high fidelity. HLIP can be used for the enhancement of other models across multiple clinical scenarios, including gland segmentation, cell segmentation, Helicobacter pylori detection, and therapy response prediction. With its superior performance in pathology image super resolution, HLIP offers a versatile tool for image preprocessing in computer-aided systems, thereby supporting accurate diagnosis in clinical practice. © 2025 The Pathological Society of Great Britain and Ireland.
Correction to 'Development and characterization of improved unifocal primary mouse lung cancer models with metastatic potential'.
J Pathol · 2025 Nov · PMID 41077781 · Full text
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