The Journal of Pathology最新文献

Male meningiomas, comprising approximately 30% of all meningiomas, are more frequently high-grade and associated with poorer clinical outcomes compared to their female counterparts. Although Y chromosome alterations have been studied in various male-predominant tumors, a limited number of studies have evaluated their role in meningiomas. To evaluate the clinicopathological significance of Y chromosome loss in male meningiomas, we assessed the frequency of loss of the Y chromosome (LOY) using droplet digital polymerase chain reaction in combination with multiplex ligation-dependent probe amplification on tumor DNA from 93 male meningioma samples. LOY, detected in nine cases (9.7%), was significantly associated with a higher World Health Organization tumor grade (grade 2: 55.6% versus 14.3%; grade 1: 44.4% versus 85.7%; p = 0.009) and loss of the NF2 gene-encoded protein, moesin-ezrin-radixin-like protein (merlin) (loss: 88.9% versus 50.0%; retained: 11.1% versus 50.0%; p = 0.035). RNA in situ hybridization targeting KDM5D on formalin-fixed paraffin-embedded tissue sections demonstrated a sensitivity of 100% (9/9) and a specificity of 76.2% (64/84) for LOY detection, supporting its utility as a screening modality. Moreover, spatial transcriptomic analysis revealed significant differences in the expression of genes associated with epithelial-mesenchymal transition and extracellular matrix organization between LOY and non-LOY meningioma tumor cells. Our findings emphasize the presence of atypical pathological features and distinct transcriptional profiles in LOY-associated meningiomas. © 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.

One of the most striking features of the adipose depot surrounding the prostate [periprostatic adipose tissue (PPAT)] is that its accumulation is independent of body mass index. Its volume varies considerably between individuals, with some patients exhibiting abundant PPATs, which have been correlated to the occurrence of aggressive prostate cancer (PCa). However, abundant PPAT is not well defined at the biological level. We used a new statistical approach to define abundant PPAT by normalizing PPAT volume to prostate volume in a cohort of 351 patients using a linear regression model. Applying this definition, we confirmed the link between abundant PPAT and PCa aggressiveness, thereby validating our approach. At the biological level, we showed that abundant PPAT exhibited extensive extracellular matrix remodeling, notably of the collagen network, decreasing the mechanical constraints in hypertrophic adipocytes, leading to inflammation-free expansion. Degradation of the most abundant collagen in adipose tissue (AT), collagen VI, was associated with increased production of endotrophin, a signaling peptide derived from AT that was also elevated in the urine of patients with abundant PPAT confirming the clinical relevance of our results. These results highlight a unique mechanism of expansion of an adipose depot and open new mechanistic avenues to explain its role in prostate-related disorders. © 2026 The Pathological Society of Great Britain and Ireland.

High-grade endometrial stromal sarcoma (HGESS), which was not recognized as a distinct entity in the third edition of the World Health Organization (WHO) classification and was therefore included in the undifferentiated uterine sarcoma (UUS) category, was reestablished as a separate entity in the fourth edition. HGESS shares BCL-6 corepressor (BCOR) alterations with undifferentiated small round-cell sarcoma (USRCS) of the soft tissue and clear cell sarcoma of the kidney (CCSK). This study aims to perform a comparative morphological, immunohistochemical, and molecular analysis of HGESS, UUS, USRCS, and CCSK. Consecutive uterine sarcomas diagnosed as HGESS or UUS were reviewed and compared to BCOR-altered USRCS (n = 28) and CCSK (n = 10) (including both previously published and new cases). Molecular, DNA methylome (DNAm), and copy number variation (CNV) analyses were performed. DNAm data of 93 previously analyzed uterine and round-cell tumors of several different types were used for clustering analysis. Twenty-five uterine sarcomas (six HGESS and 19 UUS) were included; five of six HGESS cases showed fusions associated with BCOR alterations (YWHAE::NUTM2A/B, EPC1::KDM2B, ZC3H7B::BCOR); UUS showed no fusions (n = 15) or fusions unrelated to BCOR alterations (n = 4). All USRCS and CCSK cases showed either BCOR-ITD or BCOR alteration-related fusions. BCOR-altered HGESS showed broad morphological and immunophenotypic overlap with USRCS and CCSK. DNAm analysis showed that BCOR-altered HGESS, USRCS, and CCSK clustered together, separately from all other tumor types. The non-BCOR-altered HGESS showed a JAZF1::SUZ12 fusion and arose from a low-grade endometrial stromal sarcoma component. CNVs were found in 15/16 uterine sarcomas and in 16/36 USRCS/CCSK cases. BCOR-altered HGESS appeared to be closely related to BCOR-altered USRCS and CCSK rather than to other uterine sarcomas. We suggest that HGESS with BCOR alterations may warrant reclassification as 'BCOR-altered uterine sarcomas'. © 2026 The Pathological Society of Great Britain and Ireland.

Cancer metabolic remodeling impacts the entire network of metabolic pathways, and strategies that target various points within this system could contribute to successfully abrogating cancer cell survival. Fatty acids (FAs) are essential to cancer cells because they support membrane biosynthesis during proliferation and provide energy during metabolic stress. Fatty acid transport protein 1 (FATP1)has been shown to mediate FA uptake in breast carcinoma (BC). The light chain of cysteine/glutamate amino acid exchange transporter system Xc (xCT)is crucial for the uptake of cysteine serving as a carbon and sulfur source that contributes to redox control, bioenergetics, and biosynthesis. In this study, targeting of FA and cysteine metabolic pathways was shown to be a potential strategy for managing BC by inhibiting FATP1 and xCT with arylpiperazine 5k and selenium-chrysin (SeChry), respectively. In BC cell lines, FATP1 expression is controlled by estrogen receptor β (ER-β) and promotes the accumulation of lipid droplets (LDs), which is associated with triple-negative breast carcinoma (TNBC) cells showing increased rates of cell proliferation, two-dimensional directional cell migration, and higher chemoresistance. Expression of xCT was also associated with the TNBC molecular BC subtype. In BC specimens, an association between FATP1 and xCT expression was observed. In vitro, SeChry induced ferroptosis in BC cells by targeting xCT and cysteine reliance and ultimately inducing cell death. In xenograft BC tumors, arylpiperazine 5k abrogated the effects of SeChry encapsulated in polyurea dendrimers functionalized with folate (SeChry@PURE_G4-FA₂) by reducing intracellular FA and rescuing ferroptosis. In vitro, SeChry sensitized BC cells to cisplatin and may therefore serve as an alternative in combination therapy. Overall, our study confirmed FATP1 as a marker and xCT as both a marker and a target in BC, particularly in TNBC. Induction of ferroptosis by interfering with xCT function may provide an opportunity to improve BC treatment, and a therapeutic approach using SeChry@PURE_G4-FA₂ is a promising strategy. © 2026 The Pathological Society of Great Britain and Ireland.

The conceptualization of mitochondria, previously restricted to their function as cellular 'powerhouses', has evolved to recognize their function as central coordinating hubs for the orchestration of cancer cell metabolism, signaling, and fate determination. Within the context of lung cancer, encompassing both non-small cell lung cancer and small cell lung cancer, these organelles undergo profound functional and structural dysregulation integral to tumor initiation, progression, and most critically, therapeutic resistance. This review presents a synthesis of the burgeoning field of mitochondrial inhibitors as a strategic approach for lung cancer treatment, achieved by synthesizing detailed mechanistic and preclinical data into an evidence-graded framework. This document first provides a delineation of the fundamental dysregulation of mitochondrial functions in lung cancer, inclusive of metabolic reprogramming toward oxidative phosphorylation dependency, particularly in distinct genetic contexts (e.g., LKB1, SWI/SNF-mutant). Subsequent sections systematically categorize and analyze the major classes of mitochondrial inhibitors predicated upon their mechanisms of action, including electron transport chain inhibitors, pro-apoptotic agents (e.g., B-cell lymphoma 2/B-cell lymphoma xL inhibitors), and modulators of metabolism and dynamics. A critical focus is applied to the role of these agents in the supersession of acquired resistance to established therapies, such as epidermal growth factor receptor-tyrosine kinase inhibitors, chemotherapy, and immunotherapy. The translational landscape is consolidated herein by summarizing key clinical trials (including terminations precipitated by toxicity) and distinguishing small cell lung cancer specific vulnerabilities. Finally, the significant challenges of on-target, off-tumor toxicity and the crucial necessity for predictive biomarkers are addressed. Through the synthesis of these disparate fields into a unified, clinically oriented framework, it is posited that targeting mitochondrial vulnerabilities possesses the potential to overcome longstanding therapeutic hurdles in lung cancer. © 2026 The Pathological Society of Great Britain and Ireland.

Efferocytosis is a process that maintains tissue homeostasis by removing apoptotic cells (ACs) by professional or non-professional phagocytes. The intricate process can be categorized into recognition of ACs, engulfment of ACs, and degradation of efferosomes. Aberrations in efferocytosis result in inadequate clearance of ACs, leading to prolonged inflammation that is implicated in the development and progression of various human diseases. Most central nervous system (CNS) diseases are associated with dysregulation of inflammatory homeostasis. Microglia, the resident immune cells of the CNS, play a primary role in efferocytosis in the brain, which is essential for maintaining the homeostasis of the internal environment. In this review, we summarize the current knowledge of the basic processes of efferocytosis and its indispensable role in the developing and aging brain. Additionally, we discuss the regulatory role of immune-metabolism crosstalk and the insights from single-cell sequencing analysis in dissecting microglial heterogeneity during efferocytosis. We also focus on recent discoveries regarding the critical role of efferocytosis in several CNS diseases, including cerebral ischemia, intracerebral hemorrhage, traumatic brain injury, major depressive disorder, glioblastoma multiforme, Alzheimer's disease, and Parkinson's disease. Finally, we outline potential therapeutic strategies and existing challenges, emphasizing the need for context-specific targeting to improve CNS disease outcomes. © 2026 The Pathological Society of Great Britain and Ireland.

Adenoid basal carcinoma (ABC) is a rare cervical tumor that generally carries a favorable prognosis. However, when ABC is mixed with an invasive carcinoma, particularly squamous cell carcinoma (SCC), the prognosis is poor. Moreover, transitional nests (TNs), which are frequently observed in mixed tumors, likely represent an intermediate stage between ABC and SCC. Therefore, elucidating the relationship between these subtypes through histomorphological and molecular biological analysis is essential for guiding effective therapeutic strategies. To this end, we conducted a retrospective study involving 20 cases of ABC, most of which were accompanied by one or more of the three subtypes of SCC, TN, and high-grade squamous intraepithelial lesion (HSIL). Histomorphological analysis revealed that TN were frequently located in the transitional zones between classic ABC and SCC, while maintaining a distinct spatial separation from classic HSIL regions. The central areas of TNs exhibit cytological atypia resembling that of SCC, often surrounded by a cuff-like arrangement of basaloid cells, which express the basal cell marker BCL-2. We performed digital spatial profiling (DSP) analysis on four cases exhibiting concurrent ABC, TN, SCC, and HSIL. We identified the differentially expressed genes CK13 and SCCA2, which distinguish TN from ABC, SCC, and HSIL, and validated these findings by immunohistochemistry. This study investigates the relationship between ABC and SCC and demonstrates the disease spectrum of ABC progressing to SCC through a transitional phase represented by TNs. This finding provides novel insights into the pathogenesis of SCC. In addition, we believe that total hysterectomy may be an appropriate strategy when ABC is accompanied by a TN. However, larger-scale studies will still be needed in the future to guide clinical decisions because of the limited sample size. © 2026 The Pathological Society of Great Britain and Ireland.

Bile duct tumor thrombus (BDTT), a tumor cluster occupying the luminal space in the large bile duct, is rare in intrahepatic cholangiocarcinoma (iCCA). Most studies on BDTT in iCCA to date are case reports, and the clinicopathological characteristics remain unknown. This study aimed to characterize iCCA with BDTT clinicopathologically and genetically. We analyzed 223 surgically resected iCCA cases, including 102 small duct type (SDT) and 121 large duct type (LDT) cases. BDTT was found in 19.6% (20/102) of SDT cases. Histological and immunohistochemical features of BDTT-positive SDT were comparable with those of conventional SDT (MUC1⁺MUC2^-MUC5AC^-MUC6^+/-CDX-2^-). BDTT-positive SDT showed female predominance and higher T factors compared with conventional SDT. SDT was associated with a significantly longer survival in iCCA. SDT patients with BDTT had significantly shorter survival than those without BDTT and survival rates similar to those of LDT patients; the presence of BDTT in SDT was an independent unfavorable prognostic factor (HR = 2.601, p = 0.006). Whole-exome sequencing analysis revealed recurrent altered gene expression: those more frequent in SDT compared with LDT (BAP1, IDH1/2, ZNF717, FGFR2, NRAS); those more frequent in LDT (KRAS, TP53, SMAD4, MUC6, CACNA1A, MLL2, MDM2, TGFBR1/2); and those found comparably in both SDT and LDT (MUC4, ARID1A, EPHA2, PIK3CA, MUC17, MAP3K4, MUC2, BRAF, NF1). Genetic landscapes were similar in SDT iCCA with and without BDTT; recurrent mutations in MUC2 and MUC17 and FGFR2 fusion genes were more frequent in BDTT-positive SDTs. PTPRK::RSPO3 fusion gene was found in one LDT case. Intraglandular papillary and tubular proliferation is a unique and rare histology of SDT. BDTT was frequently found in SDT with this pattern, and FGFR2 gene rearrangement was frequent. These results highlight the importance of evaluating BDTT in SDT, as it may be the main route of hilar extension in aggressive cases. © 2026 The Pathological Society of Great Britain and Ireland.

By Sara Vázquez-Sánchez, Ana Blasco, Pablo Fernández-Corredoira, Paula Cantolla, Elisa Mercado-García, Elena Rodríguez-Sánchez, Laura González-Lafuente, Jonay Poveda, Daniel González-Moreno, Andrea Matutano, Sonia Peribañez, Inés García-Consuegra, Massimo Volpe, María Fernández-Velasco, Luis M. Ruilope and Gema Ruiz-Hurtado, J Pathol 2025; 265(3): 342–356. https://doi.org/10.1002/path.6388

The corresponding author has informed the editors that some important funding information had not been submitted for this article, first published on 4 February 2025 in Wiley Online Library (wileyonlinelibrary.com).

The following sentence should have been present at the end of the Acknowledgments section and repeated in the online Research Funding side bar for this article online: ‘This study was partially supported by the Italian Ministry of Health (Ricerca Corrente)’.

The authors apologise for the omission and the inconvenience caused.

Every year the editorial team of the Journal of Pathology awards the Jeremy Jass Prize for Research Excellence to the paper published in the prior calendar year that they perceive to be of the highest scientific calibre. Selection is always difficult because the standard of papers published in the Journal is so high.

The paper selected for the Jass Prize for the calendar year 2024 is:

Natálie Klubíčková*,†, Josephine K. Dermawan†, Elaheh Mosaieby, Petr Martínek, Tomáš Vaněček, Veronika Hájková, Nikola Ptáková, Petr Grossmann, Petr Šteiner, Marián Švajdler, Zdeněk Kinkor, Květoslava Michalová, Peter Szepe, Lukáš Plank, Stanislava Hederová, Alexandra Kolenová, Neofit Juriev Spasov, Kemal Kosemehmetoglu, Leo Pažanin, Zuzana Špůrková, Martin Baník, Luděk Baumruk, Anders Meyer, Antonina Kalmykova, Olena Koshyk, Michal Michal, and Michael Michal. Comprehensive clinicopathological, molecular, and methylation analysis of mesenchymal tumors with NTRK and other kinase gene aberrations. J Pathol 2024; 263: 61–73. DOI: 10.1002/path.6260

* Corresponding author. † These authors contributed equally to this study.

We offer our congratulations to the authors, some of whom are shown in Figure 1. The paper is available with Open Access at https://onlinelibrary.wiley.com/doi/full/10.1002/path.6260.