The Journal Of Pathology[JOURNAL]
Sun
200 papers
Cell state dynamics during early stages of serous endometrial carcinoma.
Flesken-Nikitin A, Pirtz MG, Ashe CS … +4 more , Ellenson LH, Yemelyanova A, Cosgrove BD, Nikitin AY
J Pathol · 2025 Nov · PMID 40923619 · Full text
Serous endometrial carcinoma (SEC) is one of the most lethal types of uterine cancer, responsible for about 40% of all endometrial cancer-related deaths. Cell state dynamics during the early stages of SEC remain largely...
Serous endometrial carcinoma (SEC) is one of the most lethal types of uterine cancer, responsible for about 40% of all endometrial cancer-related deaths. Cell state dynamics during the early stages of SEC remain largely unknown, thereby hindering early detection and treatment of this disease. Here, we provide a comprehensive census of cell types and their states for normal, predysplastic, and dysplastic endometrium in a genetic mouse model of SEC. We report that predysplastic changes are characterized by increasingly diverse immature luminal epithelial cell populations. The decrease in differentiated cell states is accompanied by the emergence of a 'single-cell and spatial transcriptome dysregulation' gene signature. This signature contains seven genes that predict poor patient prognosis and are promising diagnostic markers and therapeutic targets. In summary, our results suggest an important role of the luminal epithelial cell state in SEC pathogenesis and validate our mouse SEC model as a capable comparative platform for preclinical studies. © 2025 The Pathological Society of Great Britain and Ireland.
Myeloid sarcoma shows a high frequency of mutations activating the MAPK/ERK pathway and association with clonal hematopoiesis.
Nann D, Schade TC, Overkamp M … +9 more , Mahmutovic L, Bag E, Forchhammer S, Slotta-Huspenina J, Boudova L, Sotlar K, Quintanilla-Martinez L, Bonzheim I, Fend F
J Pathol Clin Res · 2025 Sep · PMID 40906433 · Full text
Myeloid sarcoma (MS) is a mass-forming extramedullary manifestation of myeloid blasts, either in relation to an underlying acute myeloid leukemia (AML), another myeloid neoplasm (MN) or as a de novo occurrence. Data on t...
Myeloid sarcoma (MS) is a mass-forming extramedullary manifestation of myeloid blasts, either in relation to an underlying acute myeloid leukemia (AML), another myeloid neoplasm (MN) or as a de novo occurrence. Data on the genetic profile of MS are sparse. In this study, 41 MS of 34 patients, including 7 de novo cases and 24 patients with antecedent or synchronous MN, were analyzed with targeted next-generation sequencing (NGS), RNA-based fusion detection, and gene expression profiling (GEP). In 10 patients, a MS developed after stem cell transplantation for MN. Additionally, 21 available pre-transplant bone marrow biopsies (BMB) from 20 patients and 6 post-transplant BMB from 6 patients were investigated. The most frequently mutated gene was TET2 (41%), followed by NPM1 (38%) and NRAS (35%). Overall, 74% of the cases exhibited mutations affecting the MAPK/ERK pathway. AML-type fusions were detected in seven MS patients, who were younger than those without fusions (median 49 versus 67 years). Nine of 13 patients with a MN and available pre-transplant BMB showed additional mutations restricted to the MS, including an additional NRAS mutation in 3/5 cases with AML. Five of seven of patients with pre-transplant BMB without evidence of a MN revealed clonal hematopoiesis (CH), mostly shared TET2 mutations. Comparative GEP between BM and MS revealed upregulation of the MAPK/ERK pathway in MS and of gene sets relevant for interaction with the microenvironment. In conclusion, MS is characterized by a high incidence of MAPK/ERK pathway mutations and activation, frequent clonal evolution, and association with CH in elderly patients without recurrent AML-type fusions.
High-fat diets influence breast cancer progression by modulating CAF-immune cell interactions through PLAT signaling.
Li W, He J, Li J … +2 more , Xie X, Zhou P
J Pathol · 2025 Nov · PMID 40899255 · Publisher ↗
Breast cancer progression is profoundly influenced by interactions within the tumor microenvironment, particularly between cancer-associated fibroblasts and immune cells. This study investigated how cancer-associated fib...
Breast cancer progression is profoundly influenced by interactions within the tumor microenvironment, particularly between cancer-associated fibroblasts and immune cells. This study investigated how cancer-associated fibroblasts impact immune cells in the context of high-fat diets, focusing on key genes involved in these interactions. By analyzing breast cancer-related single-cell and bulk RNA sequencing data, we identified candidate genes in cancer-associated fibroblasts that influence immune cell behavior. Using the TCGA-BRCA dataset, we assessed the correlation between these genes and patient survival, as well as their role in immune cell infiltration and their association with clinical and immunological features. Our findings revealed significant cellular communication under high-fat diet conditions, with the cancer-associated fibroblast marker gene PLAT emerging as a key player linked to immune cell infiltration. Analysis of patient data from the GEO and TCGA-BRCA datasets revealed that in high-fat diet-induced breast cancer, patients exhibited reduced stromal scores, and stromal, immune, and ESTIMATE scores were significantly associated with clinical outcomes. In vivo murine experiments indicated that high-fat diets promoted tumor-associated macrophage infiltration while inhibiting CD4 T-cell activation. In vitro experiments confirmed that reduced PLAT expression facilitated M2 macrophage polarization and promoted cancer cell invasion and migration. Overall, our results highlight that high-fat diets can reshape the tumor microenvironment and accelerate breast cancer progression by modulating cancer-associated fibroblast-immune cell interactions, specifically via PLAT signaling. © 2025 The Pathological Society of Great Britain and Ireland.
Translational milestones in urologic pathology: integrating molecular diagnostics across cancer types.
Matoso A, Acosta AM
J Pathol Clin Res · 2025 Sep · PMID 40891689 · Full text
In its first decade, The Journal of Pathology: Clinical Research has become a leading source of translational studies advancing molecular diagnostics in cancer, particularly in urologic pathology. This commentary highlig...
In its first decade, The Journal of Pathology: Clinical Research has become a leading source of translational studies advancing molecular diagnostics in cancer, particularly in urologic pathology. This commentary highlights recent contributions that collectively place precision oncology at the forefront of pathology research. One review examines cancer stem cells in renal cell carcinoma, emphasizing the complexity of cellular plasticity and the tumor microenvironment in driving resistance and recurrence. In prostate cancer, epithelial-to-mesenchymal transition (EMT) regulators, including Twist, Slug, and Snail, are identified as synergistic markers of poor prognosis, linked to hypoxia and invasiveness. Another review details the integration of homologous recombination repair gene testing into clinical workflows, supporting targeted treatment strategies with poly (ADP-ribose) polymerase inhibitors. In pediatric oncology, TP53 alterations in Wilms tumor are shown to occur beyond anaplastic cases, expanding their prognostic significance. Advances in molecular subtyping are also demonstrated in bladder cancer, where transcriptomic profiling could enable tailored neoadjuvant therapy. In clear cell renal cell carcinoma, re-evaluation of a prognostic model revealed that while necrosis or sarcomatoid differentiation correlated with poor outcomes, only DNA methylation markers improved prognostic accuracy, underscoring their utility for biopsy-based risk stratification. Finally, digital spatial profiling of sarcomatoid urothelial carcinoma reveals an immunosuppressive microenvironment with CD163-positive cells, implicating them in EMT and aggressive phenotype. Together, these studies highlight the transformative role of integrated molecular diagnostics in guiding individualized therapies and improving outcomes in urologic cancers.
Overexpression of mG writers METTL1 and BUD23 confers oncogenicity in kidney renal clear cell carcinoma.
Su A, Tieng J, Xu XS … +3 more , Tan RP, Feng Y, Wong JJ
J Pathol · 2025 Sep · PMID 40879514 · Full text
Emerging evidence shows that N7-methylguanosine (mG) modification and its writers contribute to the development of diverse cancers. However, the role of mG writers in kidney renal clear cell carcinoma (KIRC) remains uncl...
Emerging evidence shows that N7-methylguanosine (mG) modification and its writers contribute to the development of diverse cancers. However, the role of mG writers in kidney renal clear cell carcinoma (KIRC) remains unclear. In this study we show that the catalytic components of mG writers, METTL1 and BUD23, are overexpressed in advanced KIRC and are associated with worse overall survival. Knockdown of METTL1 or BUD23 inhibited cell proliferation, colony formation, and migration in KIRC cell lines, indicating their oncogenic role in KIRC. Furthermore, we observed that METTL1 and BUD23 expression was negatively correlated with the expression of key tumor suppressor genes commonly dysregulated in KIRC. We observed METTL1-mediated mG methylation in mRNAs expressed by these tumor suppressor genes, indicating that METTL1 may regulate these genes via mG modification. Overall, our study highlights the oncogenic role of METTL1 and BUD23 in KIRC and their potential as prognostic biomarkers and therapeutic targets in KIRC. © 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.
APC-related multiple salivary gland lesions: spatial transcriptomic analysis reveals progressive WNT activation.
Chan-Pak-Choon F, Beaumont C, Camacho Valenzuela J … +10 more , Leblanc J, Dahlum S, Siebert R, Thuot F, Pusztaszeri M, Chênevert J, Polak P, Cruz Marino T, Rivera B, Foulkes WD
J Pathol · 2025 Nov · PMID 40879644 · Full text
Attenuated familial adenomatous polyposis (AFAP) is a disorder caused by germline pathogenic variants in APC and is characterized by the presence of <100 colonic polyps and a high lifetime risk of developing colorectal c...
Attenuated familial adenomatous polyposis (AFAP) is a disorder caused by germline pathogenic variants in APC and is characterized by the presence of <100 colonic polyps and a high lifetime risk of developing colorectal cancer. Salivary gland basal cell tumours are uncommon and have not previously been reported in AFAP. We present a family with AFAP and multiple salivary gland tumours, including basal cell adenoma (BCA) and basal cell adenocarcinoma (BCAC). The colon and salivary gland tumours showed abnormal nuclear β-catenin staining. Genomic analysis of both parotid BCACs showed copy-number-neutral loss of heterozygosity (CNN-LOH) at the APC locus, implicating loss of full-length APC in the aetiology of parotid BCACs. In contrast, the submandibular BCAC showed a p.(Ile35Thr) CTNNB1 mutation. Spatial transcriptomic analysis revealed a stepwise increase in the expression of WNT pathway genes across the proband's salivary lesions, from benign (intercalated duct hyperplasia and BCAs) to malignant (BCACs). Our results showcase BCA and BCAC as potential new phenotypes of AFAP. © 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.
MYCN amplification defines an aggressive phenotype in IDH-mutant gliomas.
Xie X, Yan Q, Wang F … +3 more , Lu J, Zhang Y, Xi S
J Pathol Clin Res · 2025 Sep · PMID 40857163 · Full text
In alignment with the latest WHO classification system, which underscores the integration of molecular alterations in glioma diagnosis and grading, this study investigates the prognostic significance of MYCN amplificatio...
In alignment with the latest WHO classification system, which underscores the integration of molecular alterations in glioma diagnosis and grading, this study investigates the prognostic significance of MYCN amplification in IDH-mutant gliomas, a relationship that remains poorly characterized despite its established association with adverse outcomes in various malignancies. A cohort of 190 patients with IDH-mutant gliomas was analyzed for clinical and pathological characteristics. MYCN amplification status was determined using fluorescence in situ hybridization (FISH) with an MYCN-specific probe. Survival outcomes were assessed via Kaplan-Meier analysis, while independent prognostic factors were identified through multivariable Cox proportional hazards regression models. Tumor morphology was systematically evaluated in cases with MYCN amplification. MYCN amplification was identified in 28 of 190 cases (14.7%), demonstrating a significant correlation with advanced tumor grade and elevated Ki-67 proliferation indices (p < 0.05). Patients harboring MYCN amplification exhibited markedly reduced overall survival compared to non-amplified cases (112.13 ± 6.58 versus 91.14 ± 14.96 months, p = 0.001), with this association being particularly pronounced in lower-grade (WHO grades 2 and 3) IDH-mutant gliomas (122.12 ± 6.81 versus 47.76 ± 6.58 months, p < 0.001). To address limitations in current grading systems, we propose a refined classification approach that upgrades lower-grade IDH-mutant astrocytomas with MYCN amplification to high-grade status. This MYCN-based grading system demonstrated significant prognostic stratification (112.84 ± 10.40 versus 77.65 ± 11.15 months, p < 0.001). Morphological analysis revealed that 50% of MYCN-amplified cases (14/28) exhibited distinct epithelioid features, characterized by abundant eosinophilic cytoplasm and nuclear displacement. In conclusion, MYCN amplification emerges as a critical prognostic indicator in IDH-mutant gliomas, particularly in lower-grade tumors, and is frequently associated with unique epithelioid histological features. These findings highlight the necessity of incorporating MYCN amplification status into grading paradigms for IDH-mutant gliomas to enhance prognostic accuracy and inform clinical decision-making.
Assessing PD-L1 expression in non-small cell lung carcinoma: a prospective study of matched fine-needle aspirates, core biopsies, and resection specimens using alcohol and forming fixatives.
Haragan A, Kipling N, Shackcloth M … +3 more , Gosney JR, Davies MP, Field JK
J Pathol Clin Res · 2025 Sep · PMID 40853762 · Full text
PD-L1 expression for the prediction of response to immune-checkpoint blockade remains the most broadly utilised clinically validated biomarker in a range of tumour types. In this study, we aimed to assess, in a prospecti...
PD-L1 expression for the prediction of response to immune-checkpoint blockade remains the most broadly utilised clinically validated biomarker in a range of tumour types. In this study, we aimed to assess, in a prospectively collected matched cohort, the impact of sampling technique and both formalin and alcohol fixation on PD-L1 expression and heterogeneity in non-small cell lung carcinoma (NSCLC). Patients undergoing surgical resection for NSCLC were consented. Surgical specimens were received directly from theatre and sampled fresh to produce two sets of core biopsies, two fine-needle aspirates (FNAs) and two whole-block tissue sections from each specimen. A matched biopsy, FNA, and whole-block were placed into formalin or an alcohol-based fixative (Cytolyt™) prior to PD-L1 immunohistochemistry assessment. A total of 114 specimens from 57 patients were included. All whole-block cases (100%), 92% of core biopsies, and 88% of FNAs were adequate for PD-L1 expression analysis. Fixation had no significant impact on adequacy, but cytology specimens fixed in alcohol showed a significant reduction in PD-L1 expression, with 25% of cases placed into different clinically relevant categories of PD-L1 expression. PD-L1 expression by immunochemistry is an exemplar of the challenges of utilising a heterogeneously expressed protein-based predictive biomarker. Regardless of sampling technique, a good quality biopsy or FNA is likely to give a statistically representative PD-L1 expression, although expression ranges close to clinically relevant cut-offs of 1% and 50% remain a source of potential discordance.
Targeting the cancer glycocalyx in salivary duct carcinoma: tumor-associated mucin 1 (Tn-MUC1) as a novel cell surface marker.
Kuroki M, Kawaura R, Tomita H … +6 more , Shibata H, Ohashi T, Ishikawa T, Okada H, Hara A, Ogawa T
J Pathol Clin Res · 2025 Sep · PMID 40844495 · Full text
Despite the use of targeted drugs for human epidermal growth factor receptor type 2 (HER2)-positive salivary duct carcinoma (SDC) treatment, the overall prognosis for SDC remains poor. In this study, we aimed to investig...
Despite the use of targeted drugs for human epidermal growth factor receptor type 2 (HER2)-positive salivary duct carcinoma (SDC) treatment, the overall prognosis for SDC remains poor. In this study, we aimed to investigate whether the glycocalyx of SDC cells serves as a potential cell surface marker. To understand the complex structure of the glycocalyx of salivary gland tumors, we used a lectin with glycan-specific binding properties. Lectin staining was performed for five types of common salivary gland tumors. We determined the expression of the transmembrane glycoprotein mucin 1 with Tn antigen (GalNAc), Tn-MUC1, using 20 clinical SDC specimens. Vicia villosa lectin (VVL) was not stained in the vascular endothelium but specifically stained in the SDC tumor cells. GalNAc, to which VVL binds, formed Tn-MUC1 via glycosylation with N-acetylgalactosaminyltransferases (GALNTs). GALNT7 was highly expressed in SDC. Analysis of clinical SDC specimens revealed that Tn-MUC1 was also positive in the SDC tumor cells, suggesting its potential as a cell surface target for SDC.
Characteristic miRNA profiles represent clinicopathological diversity of small cell lung cancer.
Horie M, Takumida H, Koba H … +11 more , Ueda T, Tanaka H, Suzuki M, Ito Y, Ito A, Kondo M, Suzuki HI, Matsumoto I, Yano S, Saito A, Maeda D
J Pathol · 2025 Oct · PMID 40842416 · Full text
Small cell lung cancer (SCLC) is classified into distinct molecular subtypes based on the expression patterns of four transcription regulators: achaete-scute homolog 1 (ASCL1), neuronal differentiation 1 (NEUROD1), POU c...
Small cell lung cancer (SCLC) is classified into distinct molecular subtypes based on the expression patterns of four transcription regulators: achaete-scute homolog 1 (ASCL1), neuronal differentiation 1 (NEUROD1), POU class 2 homeobox 3 (POU2F3), and yes-associated protein 1 (YAP1). MicroRNAs (miRNAs) play critical roles in cancer cellular processes but their subtype-specific implications in SCLC remain underexplored. Out of 46 surgically resected SCLC samples, miRNA visualization through in situ hybridization identified high expression of miR-375 in the ASCL1, NEUROD1, and ASCL1/NEUROD1 subtypes, and miR-9-5p in the POU2F3 subtype. Comprehensive enhancer profiling using SCLC cell lines indicated that miR-375 and miR-9-5p were regulated by super-enhancers in a subtype-specific manner. Multiplex immunohistochemistry by imaging mass cytometry found that the miR-9-5p-high SCLC was characterized by a higher stromal area ratio, increased numbers of CD8 T cells and CD163 macrophages in the intra-tumoral area, and an increased number of plasma cells in the stromal area, as compared with the miR-9-5p-low SCLC. Finally, clinicopathological analysis revealed that the miR-375-high SCLC was associated with YAP1 downregulation, increased serum pro-gastrin-releasing peptide levels, and poor prognosis. These findings highlight the critical role of super-enhancer-related miRNAs in the diversity of SCLC, and underscore the potential for novel diagnostic and prognostic biomarkers based on these subtype-specific miRNAs. © 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.
Development of a prognostic risk model for clear cell renal cell carcinoma by systematic evaluation of DNA methylation markers: an update after ISUP/WHO 2022 classification.
Odeh S, Samarska I, Matoso A … +6 more , Baldewijns MM, Hulsbergen-van de Kaa CA, Zur Hausen A, van Engeland M, Schouten LJ, Smits KM
J Pathol Clin Res · 2025 Sep · PMID 40820938 · Full text
Although several prognostic models have been developed for clear cell renal cell carcinoma (ccRCC), these are still suboptimal and there is a need to identify additional prognostic biomarkers. Previously, we developed a...
Although several prognostic models have been developed for clear cell renal cell carcinoma (ccRCC), these are still suboptimal and there is a need to identify additional prognostic biomarkers. Previously, we developed a prognostic model containing five DNA methylation markers (NEFH, NEURL, GATA5, GREM1, and LAD1) and clinicopathological characteristics based on the TNM 3rd edition and Fuhrman grading system. Here, we evaluated the effect of the recent ISUP/ 2022 WHO revisions on our previous prognostic model by incorporating the new ISUP/WHO standards, TNM 8th edition, and several novel prognostic factors (necrosis, lymphovascular invasion, sarcomatoid and rhabdoid features). Data from 308 ccRCC cases from the Netherlands Cohort Study were included for this study. Clinicopathological factors, novel prognostic factors, and the five methylation markers were analyzed for their individual and combined prognostic value using Kaplan-Meier analyses and Cox proportional hazard models. To compare models, the Akaike information criterion (AIC) and c-statistic were used. All evaluated factors were statistically significantly associated with cause-specific survival. The clinical model using the ISUP and TNM 8th edition performed similarly when compared to the Fuhrman/TNM 3rd edition model (AIC 592, c-statistic 0.63 and AIC 595, c-statistic 0.62, respectively). After addition of the five DNA methylation markers to the ISUP/TNM 8th model, this model was slightly improved (AIC 584, c-statistic 0.70). The addition of necrosis and lymphovascular invasion (LVI) did not further improve these results (AIC 586, c-statistic 0.71 and AIC 588, c-statistic 0.71, respectively). Despite the individual prognostic significance of necrosis, LVI, the presence of sarcomatoid and/or rhabdoid differentiation, ISUP, and TNM 8th edition, these factors did not influence the performance of our prognostic model. The model including the five DNA methylation markers, age at diagnosis, sex, TNM stage (8th edition), ISUP grading, and tumor size was the best performing model, thereby highlighting the potential importance of molecular markers.
STING inhibition alleviates experimental peritoneal damage: potential therapeutic relevance for peritoneal dialysis.
Marchant V, García-Giménez J, González-Mateo GT … +10 more , Sandoval P, Tejedor-Santamaria L, Rayego-Mateos S, Ramos R, Jiménez-Heffernan JA, Ortiz A, Raby AC, López-Cabrera M, Ramos AM, Ruiz-Ortega M
J Pathol · 2025 Oct · PMID 40810380 · Full text
Peritoneal dialysis (PD) is a widely used kidney replacement therapy for patients with end-stage kidney disease. Nevertheless, long-term exposure to PD fluid can damage the peritoneal membrane, leading to ultrafiltration...
Peritoneal dialysis (PD) is a widely used kidney replacement therapy for patients with end-stage kidney disease. Nevertheless, long-term exposure to PD fluid can damage the peritoneal membrane, leading to ultrafiltration failure and, ultimately, discontinuation of PD. Investigation of the molecular mechanisms underlying this damage is essential for identifying new therapeutic targets to mitigate peritoneal deterioration in PD patients. To this end, we employed RNA sequencing in a preclinical model of peritoneal injury, induced by prolonged chlorhexidine (CHX) exposure, which revealed cytosolic DNA-sensing signaling as a novel pathway. Next, we demonstrated that key players in this pathway, such as the stimulator of interferon genes (STING) and its downstream signaling effectors (interferon regulatory factor 3, interferon-stimulated genes, and nuclear factor-κB signaling), were upregulated in experimental peritoneal damage. Moreover, increased STING expression was observed in human peritoneal biopsies from patients with PD. Subsequent studies in STING-deficient mice showed reduced proinflammatory gene expression and immune cell infiltration, together with inhibited nuclear factor-κB pathway activation at both early (10 days) and late (30 days) stages of CHX-induced peritoneal injury. STING deficiency also reduced peritoneal membrane thickening, fibrosis, and mesothelial-to-mesenchymal transition (MMT)-related changes in advanced CHX-induced damage. Furthermore, pharmacological inhibition of STING with C-176 attenuated CHX-induced peritoneal inflammation. Macrophages were identified as one of the STING-expressing cell types in the injured peritoneum. Hence, in vitro STING blockade in activated macrophages inhibited MMT in cultured mesothelial cells, suggesting that STING activation in this population may drive peritoneal fibrosis. Additionally, STING deficiency reduced peritoneal inflammation in S. epidermidis-induced peritonitis and decreased adhesion scores in a postsurgical intra-abdominal adhesion model. These findings identify STING as a pivotal mediator of peritoneal injury and support its potential as a novel therapeutic target to prevent PD-associated ultrafiltration failure. © 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.
Activation of PI3K and deletion of p53 in keratin 15-expressing mouse mammary cells induces tumor heterogeneity and plasticity modeling metaplastic breast cancer.
Nguyen KA, McLemore LE, Ke Y … +9 more , DePledge LN, Smith LP, Bian L, Aleman JD, Debretsion D, Wong E, Manning N, Wang XJ, Young CD
J Pathol · 2025 Oct · PMID 40804766 · Full text
Although relatively rare, metaplastic breast cancer responds poorly to traditional therapies compared to other subtypes. Accordingly, there is a need for novel animal models to understand its pathogenesis and plasticity....
Although relatively rare, metaplastic breast cancer responds poorly to traditional therapies compared to other subtypes. Accordingly, there is a need for novel animal models to understand its pathogenesis and plasticity. Since alterations in PIK3CA and TP53 genes are common in metaplastic breast cancer, we generated a mouse model of metaplastic breast cancer by driving Pik3ca activation and Trp53 loss in keratin 15-expressing mammary cells. In this model, male and female mice developed spontaneous mammary lesions, with malignancy reliant on loss of both Trp53 alleles. Importantly, tumors of this model are heterogeneous and resemble the mixed histology of metaplastic breast cancer by exhibiting squamous cell carcinoma, carcinosarcoma, and sarcoma features. We developed mammary cell lines from mouse tumors representing these different histological subtypes. These Pik3ca-activated tumor cells were more sensitive to alpelisib, a p110α-selective inhibitor approved by the FDA for the treatment of some PIK3CA mutant cancers, compared to Pik3ca WT cells. Additionally, some of these cell lines expressed the androgen receptor, a hormone receptor targeted in prostate cancer and currently under investigation as a therapeutic target in breast cancer. Transplantation of these cell lines into recipient mice maintained histological heterogeneity. Additionally, transplantation of either Epcam+ or Epcam- sorted cells, representing epithelial cell-like and nonepithelial cell-like, respectively, from a carcinosarcoma cell line, initiated tumor formation. Both sorted populations formed tumors with mixed histologic features, demonstrating plasticity arising from different tumor-initiating components. These new models of metaplastic breast cancer from relevant genetic drivers serve as a platform for identifying mechanisms driving plasticity that could inform therapeutic strategies based on histology and reveal how plasticity alters treatment efficacy. © 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.
MS4A4A-positive tumor-associated macrophages associate with poor prognosis and T-cell exhaustion in patients with urothelial carcinoma of the bladder.
Yang T, Sun X, Chen J … +8 more , Li J, Liu C, Yu J, Meng W, Wang Y, Yu H, Huang J, Wang B
J Pathol · 2025 Oct · PMID 40804697 · Publisher ↗
Tumor-associated macrophages (TAMs) have multiple potent functions in cancer representing important therapeutic targets. MS4A4A is a functional TAM marker with controversial implications for prognosis. This study aimed t...
Tumor-associated macrophages (TAMs) have multiple potent functions in cancer representing important therapeutic targets. MS4A4A is a functional TAM marker with controversial implications for prognosis. This study aimed to evaluate the association between MS4A4A TAM infiltration and clinical outcomes in urothelial carcinoma of the bladder (UCB), as well as their impact on the immune landscape. A total of 400 UCB patients from cohorts at Sun Yat-sen Memorial Hospital were analyzed. Immunohistochemistry was used to quantify MS4A4A TAMs and assess their spatial distribution alongside various immune components, evaluate the benefit of Bacillus Calmette-Guérin (BCG) immunotherapy, and analyze survival outcomes. Additionally, matched UCB tissues were examined before and after recurrence or progression. We observed that MS4A4A TAMs were present at higher levels in the stromal region compared to the intratumoral region, and correlated with advanced tumor stage and poor prognosis in both regions. No significant difference was observed in the number of MS4A4A TAMs before and after recurrence/progression in the same patient. Stromal MS4A4A TAMs were negatively correlated with BCG efficacy and recurrence-free survival. These TAMs were positively associated with CD8 T cells, Foxp3 regulatory T cells, immune checkpoints (PD-1, LAG-3, HAVcr-2, TIGIT), and anti-inflammatory molecules (TGF-β1, IL-4) in the same respective regions. Additionally, MS4A4A TAMs expressed high levels of TGF-β1 and HAVcr-2 in UCB tissues. In vitro, IL-4 induced MS4A4A expression in mouse bone marrow-derived macrophages, while Ms4a4a knockdown reduced the anti-inflammatory molecule Arg1 and increased pro-inflammatory molecule Nos2 expression. These findings demonstrate that MS4A4A is a reliable prognostic marker and predictor of BCG response in UCB, highlighting its role in shaping the immune landscape and immunotherapy outcomes. © 2025 The Pathological Society of Great Britain and Ireland.
Spatial transcriptomics exploration of the primary neuroblastoma microenvironment in archived FFPE samples unveils novel paracrine interactions.
Siaw JT, Merseburger P, Borenäs M … +8 more , Jansson C, Karlsson J, Claeys A, Jennische E, Lind DE, Gisselsson Nord D, Palmer RH, Van den Eynden J
J Pathol · 2025 Oct · PMID 40778592 · Full text
High-risk neuroblastomas exhibit a high degree of intratumoral heterogeneity. Single-cell RNA sequencing has greatly improved our understanding of these tumors, but the method lacks cellular tissue context and spatial in...
High-risk neuroblastomas exhibit a high degree of intratumoral heterogeneity. Single-cell RNA sequencing has greatly improved our understanding of these tumors, but the method lacks cellular tissue context and spatial information about local signaling dynamics. To address this, we profiled untreated and chemotherapy-treated high-risk neuroblastomas from archived, formalin-fixed, paraffin-embedded (FFPE) tissues from two patients using spatial transcriptomics. We confirmed the transcriptional and cellular heterogeneous nature of the neuroblastoma microenvironment and identified several unique spatial niches and patterns. In one of the treated tumors, a spatially constrained cluster of undifferentiated and 11p-gained cancer cells was identified, surrounded by a rim of macrophages. A signaling interaction between the chemokine CCL18 and its receptor PITPNM3 was predicted between these cells. In the other tumor, we identified a stromal cluster with high transcriptional similarity to the adrenal cortex. These adrenocortical-like cells expressed several oncogenic ligand-encoding genes (e.g. ALKAL2 and NRTN), which were predicted to communicate with neighboring cancer cells that expressed the corresponding receptors (e.g. ALK, RET). Several of these interactions were further validated experimentally and were shown to be clinically relevant. Collectively, our spatial analysis identifies multiple previously unrecognized signaling axes that may offer novel therapeutic options in neuroblastoma. © 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.
Revisionist history uncovers a simplified molecular-based classification of differentiated thyroid cancer.
Asa SL, Baloch Z, Jung CK … +6 more , Cipriani NA, Gamboa-Domínguez A, Juhlin CC, Riddle ND, Stojanov IJ, Mete O
J Pathol · 2025 Oct · PMID 40762994 · Full text
The diagnostic classification of differentiated thyroid cancer has been a longstanding topic of debate among pathologists, largely due to high interobserver variability. This complexity has increased with the expansion o...
The diagnostic classification of differentiated thyroid cancer has been a longstanding topic of debate among pathologists, largely due to high interobserver variability. This complexity has increased with the expansion of tumor types and subtypes. However, molecular studies have revealed a simpler and less controversial approach, categorizing these lesions into RAS-like and BRAF p.V600E-like neoplasms. In this review, the authors propose a classification that is based on, but does not require, the confirmation of molecular alterations. This approach aligns with and helps inform the pattern-based assessment of tumor growth and cytologic atypia that is already widely used in clinical practice for preoperative patient stratification and tumor diagnosis, and promises a simpler conceptual understanding. © 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.
Synchronous endometrial/cervical and ovarian/fallopian tube carcinoma: a genome-wide mutation analysis.
Li L, Yao M, Li L … +2 more , Shi S, Song Y
J Pathol Clin Res · 2025 Sep · PMID 40760340 · Full text
In this study, we explored the genomic underpinnings of synchronous endometrial and ovarian/fallopian tube carcinoma (SEOC) and synchronous cervical and ovarian/fallopian tube carcinoma (SCOC), focusing on their clonal r...
In this study, we explored the genomic underpinnings of synchronous endometrial and ovarian/fallopian tube carcinoma (SEOC) and synchronous cervical and ovarian/fallopian tube carcinoma (SCOC), focusing on their clonal relationships to discern whether these malignancies represent dual primary tumors (DPTs) or have metastatic origins. We established a cohort comprising 54 SEOC patients and 7 SCOC patients. After selection, 17 patients (12 SEOC and 5 SCOC) underwent comprehensive analysis via whole-exome sequencing. The study encompassed a diverse array of histological subtypes, including high-grade serous carcinoma (HGSC) or uterine serous carcinoma (USC), endometrioid carcinoma exhibiting papillary/mucinous features, dedifferentiated carcinoma (DC), clear cell carcinoma (CCC), HPV-associated cervical squamous cell carcinoma, and HPV-independent cervical adenocarcinoma. Analysis revealed that 58.3% (7 of 12) of SEOC cases and all SCOC cases demonstrated shared mutations. This suggests a clonal relationship and supports a metastatic origin for these tumors. Notably, metastatic SEOC instances included co-occurrences of USC and HGSC in both the endometrium and the ovaries/fallopian tubes, endometrial and ovarian CCC, concurrent endometrioid endometrial carcinoma (EEC) and endometrioid ovarian carcinoma (EOC) with mucinous metaplasia, as well as cases of endometrial DC with ovarian CCC, and both EEC and ovarian DC. Among the SEOC cases classified as metastatic, patients with high-grade tumors and advanced ovarian stage succumbed to their disease, whereas the remainder survived without relapse. In the SCOC cohort, one patient died from the disease. The favorable survival outcomes across varied histotypes suggest that a stage upgrade may not be warranted. Given the favorable clinical outcomes observed, the term 'trans-tubal spread' may be more appropriate than 'metastasis' in this context to prevent potential overtreatment. Directionality analysis revealed a bidirectional pattern of trans-tubal spread between the uterus/cervix and ovary/fallopian tubes. The presence of dedifferentiated carcinoma confirms the manifestation of dedifferentiation during spread. These findings lend support to the trans-tubal implantation hypothesis and contribute novel insights into the molecular mechanisms underlying tumor dissemination in SEOC and SCOC.
Increased expression of the PIEZO2 mechanoreceptor in fibroblasts and endothelial cells within the lymphatic and vascular vessels of keloids.
Akita S, Ikehara S, Kiuchi M … +13 more , Kokubo K, Azuma K, Ohki S, Matsuyama H, Kadarman JT, Hosokawa Y, Akimoto Y, Inaba Y, Hanaoka H, Mitsukawa N, Hirahara K, Nakayama T, Ikehara Y
J Pathol · 2025 Sep · PMID 40742741 · Full text
Keloids are scars that grow abnormally due to excessive extracellular matrix production by fibroblasts and increased angiogenesis. Chronic tension is implicated in their growth, but the exact pathology remains unclear. T...
Keloids are scars that grow abnormally due to excessive extracellular matrix production by fibroblasts and increased angiogenesis. Chronic tension is implicated in their growth, but the exact pathology remains unclear. This study investigated the increased expression of molecules responsible for sensing pressure in keloids compared with lymphedema, which is also a non-tumorous fibroproliferative disease caused by another etiology. Higher expression levels of COL1A2, PIEZO2, and POSTN were observed in the keloid group compared with the lymphedema group. PIEZO2 expression levels showed a strong correlation with both COL1A2 (r = 0.9252, 95% CI 0.8474-0.9641, p < 0.001) and POSTN (r = 0.9118, 95% CI 0.8213-0.9575, p < 0.001). Additionally, PIEZO2 expression levels were significantly higher in recurrent keloids than in non-recurrent keloids (3,032.5 ± 1,090.2 versus 1,241.9 ± 860.7, p = 0.032). Analysis of gene expression at the single-cell level found upregulation of PIEZO2 in vascular and lymphatic endothelial cells, and a subgroup of fibroblasts. Additionally, COL1A1, COL1A2, COL3A1, and POSTN expression was also increased in the fibroblast subgroup. Furthermore, in fibroblasts with high PIEZO2 expression, extracellular matrix collagen production signaling was augmented. Histological analysis confirmed the presence of PIEZO2-positive cells in the perivascular stroma active area of keloid tissue, together with inflammatory cells. Therefore, since PIEZO2-positive cells are highly expressed specifically in keloids and are deeply involved in their recurrence and activity, we propose that the pathogenesis of keloids is constructed by PIEZO2-positive cells. © 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.
Partial-EMT cell state correlates with single cell pattern of invasion in head and neck SCC keratinocytes.
Park PH, Israel LE, Alexander MH … +6 more , Tartaglia G, South HG, Han S, Curry JM, Luginbuhl AJ, South AP
J Pathol · 2025 Sep · PMID 40736379 · Full text
The presence of a single metastatic lesion significantly decreases overall survival in patients with head and neck squamous cell carcinoma (HNSCC), and invasion of malignant keratinocytes is one of the initial steps requ...
The presence of a single metastatic lesion significantly decreases overall survival in patients with head and neck squamous cell carcinoma (HNSCC), and invasion of malignant keratinocytes is one of the initial steps required for HNSCC metastasis. Histological grading of tumor cell invasion predicts outcome in HNSCC, yet the molecular factors that determine the extent of invasion, and subsequent grading are not fully understood. Using a 3D organ culture model and multiple patient-derived HNSCC keratinocytes representing all major anatomical subsites of the disease, we identified a range of cell states that represent a continuum of epithelial-to-mesenchymal (EMT) characteristics. We also demonstrated how these cell states change in response to TGF-beta stimulation and co-culture with cancer-associated fibroblasts in organ cultures. Using 3D culture models that recapitulate the pattern of invasion seen in primary tumors from which the keratinocytes were derived, we identified distinct clusters of partial-EMT marker expression in individual patient HNSCC keratinocyte populations. Partial-EMT transcription factors were correlated with separate invasive characteristics, and we demonstrated that ZEB2 (a known EMT driver) and HIC1 (a novel EMT driver) are central nodes in HNSCC keratinocyte invasion. Collectively, our findings refine the concepts of partial-EMT and tumor cell invasion, and identify potential therapeutic targets for future development. © 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.
The importance of tumor microenvironment modulations in the progression of pancreatic intraductal papillary mucinous neoplasms.
Pea A, Luchini C
J Pathol · 2025 Oct · PMID 40736369 · Full text
Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas have attracted substantial attention since they represent the most prevalent macroscopic precursor of pancreatic cancer. Most lesions show an epithelium wi...
Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas have attracted substantial attention since they represent the most prevalent macroscopic precursor of pancreatic cancer. Most lesions show an epithelium with low-grade dysplasia and will remain indolent and unknown to the patient. Notably, a subgroup of IPMNs will progress to invasive cancer through a stepwise process characterized by the accumulation of specific genomic alterations and concomitant modifications of the tumor microenvironment (TME). The manuscript of Jamouss et al, recently published in The Journal of Pathology, expands the current knowledge on TME dynamics in IPMNs. The neoplastic progression of IPMNs is paralleled by a shift toward an immunosuppressive TME, with depletion of cytotoxic T cells, elevated expression of immune checkpoint molecules, including PD-L1 and VISTA, and increased density of macrophages. Overall, TME modifications are crucial in the progression of pancreatic IPMNs, calling for potential therapeutic strategies focused on TME modulations for cancer interception. © 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.
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