The Journal of Pathology最新文献

Artificial intelligence (AI) methods for digital pathology have tremendous potential to improve cancer diagnostics, biomarkers, and ultimately patient care. These AI methods, if marketed and sold, require authorisation or clearance as in vitro diagnostic (IVD) devices by regulatory bodies like the Food and Drug Administration (FDA) in the USA or Notified Bodies in the European Union (EU). Many AI tools for digital pathology are unlikely to be commercially viable and taken up by commercial entities ready to navigate these complex and costly processes. However, a longstanding quality framework already exists that allows for lab-developed tests, colloquially known as ‘homebrew’ tests, that are locally validated and performed under the responsibility and oversight of the pathologist. Here we argue for advancing homebrew AI systems within this existing framework to enhance patients' access to supportive digital diagnostic tools. We outline how homebrew AI models are currently permitted under regulatory provisions in the USA and the European Union, how a new US FDA rule may effectively regulate them out of existence, and propose steps to facilitate the safe and effective integration of homebrew AI models in pathology practice. © 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.

Squamous cell carcinoma (SCC) of the thyroid is a rare tumor that is classified as an anaplastic thyroid cancer (ATC) due to its similar unresponsiveness to chemoradiotherapy and an outstandingly poor prognosis. Due to its rarity, current knowledge about this tumor is mostly based on single-case reports. The tumor-cell-origin and molecular pathogenesis remain unclear, although the presence of BRAF mutations in some cases suggest it may evolve from papillary thyroid carcinoma (PTC). Here we provide direct evidence of derivation of SCC of the thyroid from PTC, based on a unique combination of likely pathogenic mutations in KEAP1, STK11 (LKB1), and RB1 found in both tumor components, along with loss of one copy of chromosome 11 and additional somatic mutations in the SCC tumor. Transdifferentiation from PTC to SCC was also evident by immunohistochemistry. Out of eight attempted patient-derived xenografts (PDX) from advanced thyroid cancers, only one derived from thyroid SCC successfully engrafted in immunodeficient NOG mice. Untreated PDXs showed high Ki67 indices but did not reproduce the conspicuous stromal invasion of CDH1^low/SNAI2⁺/CDH2⁺ cells that characterized the primary tumor. Based on the mutation profile (NFE2L2, PIK3CA, CDKN2A, and TP53), experiments were designed to evaluate targeted drug therapy using third-passage PDX transplants. The combination of TRK and PI3K inhibitors, cabozantinib and GDC-0326, additively reduced PDX growth by nearly 90%. Remarkably, CB-839 (telaglenastat), a glutaminase inhibitor targeting metabolic rewiring downstream of NRF2 activation, was equally effective. Both combined treatment with cabozantinib + GDC-0326 and CB-839 monotherapy diminished the expression of NQO1, an NRF2 transcriptional target, in tumor cells. Glutaminase inhibition further promoted squamous differentiation in engrafted tumors. Both investigated SCC tumors were negative for BRAFV600E or any other common driver mutation of thyroid cancer. Collectively, these findings indicate that aberrant activation of the KEAP1/NRF2 pathway due to somatic mutations is a previously unrecognized feature of thyroid SCC and suggest that glutaminase inhibition may serve as a potential therapeutic option for this subgroup of ATC patients. © 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.

Jie-Yi Shi, Liu-Xiao Yang, Zhi-Chao Wang, Ling-Yan Wang, Jian Zhou, Xiao-Ying Wang, Guo-Ming Shi, Zhen-Bin Ding, Ai-Wu Ke, Zhi Dai, Shuang-Jian Qiu, Qi-Qun Tang, Qiang Gao* and Jia Fan*. J Pathol 2015; 235: 546–558. https://doi.org/10.1002/path.4450

The authors apologise for any inconvenience this error may have caused.

While considering the request to make a correction, the editors realised that two of the seven cell lines used in the article are listed as problematic in Cellosaurus (https://www.cellosaurus.org/). When the studies were performed, the cell line SMMC-7721 was considered to be an hepatocellular carcinoma cell line, and HL-7702/L02 was considered to originate from normal foetal liver; both are listed in Cellosaurus as derivatives of HeLa (a human papillomavirus-related endocervical adenocarcinoma cell line). Limited use was made of these two cell lines in the article, but readers should consider the possibility that they were contaminated.

The origin of mucinous cystic neoplasms (MCNs) remains a major challenge in hepato-pancreato-biliary pathology. These cystic tumors are defined by their mucinous epithelium and ovarian-like stroma, with an estimated 10% risk of progression to invasive carcinoma. The origin of the ovarian-like stroma remains a subject of debate. In this study, we conducted immunohistochemical profiling, targeted DNA sequencing, and genome-wide DNA methylation analysis on a cohort of 15 pancreatic MCNs (MCN-P) and six hepatic MCNs (MCN-L). Using immunohistochemistry and targeted DNA sequencing, we unequivocally established the diagnosis of MCN. Unsupervised DNA methylation profile analysis of reference classes of pancreatic neoplasms (11 entities and normal pancreatic tissue from 224 unique samples) revealed that MCN-P predominantly forms a distinct group. In the DNA methylation landscape of liver tumors, encompassing five tumor types and normal bile duct tissue from 136 unique samples, MCN-L demonstrated a specific methylation profile when compared with all other entities. Furthermore, within the DNA methylation landscape of ovarian tumors – featuring five tumor types, normal Fallopian tube, and normal ovarian tissue from 90 unique samples – we found that both MCN-P and MCN-L grouped with mucinous ovarian carcinoma and mucinous borderline ovarian tumors (mBOTs). Notably, low-grade MCNs exhibited greater DNA methylation similarities to mBOTs, while high-grade or invasive MCNs were primarily associated with mucinous ovarian carcinomas. When analyzing all samples together (19 tumor types and four normal tissue types, n = 430), MCNs similarly grouped with mucinous ovarian tumors and normal ovarian tissue. Additionally, in a network analysis of differentially methylated probes, MCN-P and MCN-L share significant methylation traits, closely resembling mucinous ovarian tumors. In conclusion, our findings highlight that MCN-P and MCN-L are distinct entities in the landscape of pancreatic and hepatic tumors and show DNA methylation profile similarities with mucinous ovarian tumors, suggesting a potential common origin. © 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 CpG island methylator phenotype (CIMP) occurs in many colorectal cancers (CRCs). CIMP is closely associated with global hypermethylation and tends to occur in proximal tumours with microsatellite instability (MSI), but its origins have been obscure. A few CRCs carry oncogenic (gain-of-function) mutations in isocitrate dehydrogenase IDH1. Whilst IDH1 is an established CRC driver gene, the low frequency of IDH1-mutant CRCs (about 0.5%) has meant that the effects and molecular covariates of those mutations have not been established. We first showed computationally that IDH2 is also a CRC driver. Using multiple public and in-house CRC datasets, we then identified IDH mutations at the hotspots (IDH1 codons 132 and IDH2 codons 140 and 172) frequently mutated in other tumour types. Somatic IDH mutations were associated with BRAF mutations and expression of mucinous/goblet cell markers, but not with KRAS mutations or MSI. All IDH-mutant CRCs were CIMP-positive, mostly at a high level. Cell and mouse models showed that IDH mutation was plausibly causal for DNA hypermethylation. Whilst the aetiology of hypermethylation generally remains unexplained, IDH-mutant tumours did not form a discrete methylation subcluster, suggesting that different underlying mechanisms can converge on similar final methylation phenotypes. Although further analysis is required, IDH mutations may be the first cause of hypermethylation to be identified in a common cancer type, providing evidence that CIMP and DNA methylation represent more than aging-related epiphenomena. Cautious exploration of mutant IDH inhibitors and DNA demethylating agents is suggested in managing IDH-mutant CRCs. © 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.

Metabolic reprogramming is pivotal in the initiation and progression of lung adenocarcinoma (LUAD). However, a substantial gap remains in the understanding of the primary drivers of metabolic reprogramming and alterations in early-stage LUAD. Using an unbiased, large-scale metabolomics analysis of 2,531 plasma and serum samples from three independent clinical centers, we identified significant perturbations in purine metabolism that characterized reprogrammed metabolism in early-stage LUAD. Additionally, hypoxanthine (p < 0.001) and xanthine (p < 0.05) were identified as two typical early risk indicators, with odd ratios (ORs) more than 2.8 and 1.45, respectively. Guanosine monophosphate synthetase (GMPS) was identified as a pivotal factor in the early development and malignant progression of LUAD. Progression of LUAD was significantly attenuated by GMPS knockdown and markedly exacerbated by its overexpression. Further data indicated that GMPS primarily contributed to the reprogrammed metabolic phenotypes of LUAD through its enzymatic activity and subsequent production of purine nucleotides, based on the relative abundance of the labeled isotope metabolites. Collectively, dysregulated purine metabolism emerged as a key characteristic of early-stage LUAD, and targeting GMPS activity may offer a promising therapeutic potential for LUAD treatment. © 2025 The Pathological Society of Great Britain and Ireland.

Peritoneal fibrosis (PF) is a serious complication contributing to ultrafiltration failure in patients undergoing peritoneal dialysis that currently lacks effective treatment strategies. Our recent studies highlighted the key role of histone deacetylase 6 (HDAC6) in the development of PF. To better understand the mechanisms underlying the involvement of HDAC6 in PF, we conducted in vivo experiments using Hdac6 KO mice and in vitro studies using human peritoneal mesothelial cells (HPMCs). Our results demonstrated that HDAC6 gene silencing improved PF and angiogenesis in vivo and altered pathological phenotypes in vitro. In Hdac6 KO mice, the key pathways regulating extracellular matrix accumulation, angiogenesis, and secretion of inflammatory cytokines (including TGFB1/SMAD3, HIF-1α/VEGFR-2/MAPK3/MAPK1, and TLR4/NF-κB pathways) were inhibited. We also identified heat shock protein 90 (HSP90) as the substrate of HDAC6 in both PF mice and HPMCs and demonstrated that HDAC6 exerted its regulatory function in PF through the deacetylation of HSP90. Overall, our study provides novel insights into the critical role of the HDAC6-HSP90 interplay in PF using Hdac6 KO mice. We identify HSP90 as an essential substrate through which HDAC6 exerts its function in PF, providing an experimental basis for the development of novel therapeutic strategies. © 2025 The Pathological Society of Great Britain and Ireland.

Lung cancer is the leading cause of cancer-related death globally. To better understand the biology of lung cancer, mouse models have been developed using either tail vein-injected tumour cell lines or genetically modified mice. The current gold-standard models typically present with multiple lung foci. However, although these models are widely used, their correlation with human disease are limited, as early-stage human lung cancer usually presents as a single lesion rather than multiple foci. Additionally, a major challenge of using multifocal lung tumour models is the difficulty in distinguishing primary lung tumours from intrathoracic metastasis and lethal levels of lung congestion before distant metastases develop. Here, we present a refined and detailed surgical method in which murine tumour cells [Lewis lung carcinoma (LLC), alveogenic lung carcinoma (CMT), or Kras/Trp53-KP mutant cells] were injected directly into the left lung lobe of C57BL/6 mice, or, alternatively, adenoviral-Cre or adenoviral-FlpO was administered directly into the left lung lobe of Kras^LSL-G12D;Trp53^fl/fl or Kras^FSF-G12D;Trp53^frt/frt (KP) mice, respectively. This method generated unifocal primary left lung lobe tumours with traceable spread to local and distant sites. A cross-comparison of the unifocal models described commonalties and differences between LLC, CMT, KP cells, and adenoviral-Cre or -FlpO methods in terms of timings for primary lung tumour growth and traceable spread to local and distant sites, histological analysis of CD3 and CD11b immune cell infiltration, and Picrosirius Red analysis of extracellular matrix complexity. Lastly, the frequency of clinical histopathological features typical of human lung cancer were assessed across the unifocal mouse models to provide a direct comparison with human lung cancer. Overall, this study details a refined and reproducible protocol for intralobular lung injection to generate unifocal lung cancer models that resemble key features of human lung cancer. This approach can be applied to other lung cancer initiation strategies. The cross-comparative histological analysis across the models tested here offers a valuable resource to aid researchers in selecting the most appropriate next-generation unifocal lung cancer models for their specific research needs. © 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.

Canonical MN1 fusions with either BEND2 or CXXC5 gene partners represent the molecular hallmark of astroblastoma, a stand-alone group among central nervous system (CNS) high-grade neuroepithelial tumors based on their distinct methylation profile. Outside the CNS, MN1 fusions have been rarely reported, mostly with nonrecurrent gene partners. Herein, we present three cases of soft tissue sarcomas harboring MN1 gene rearrangements, two of which had MN1 (exon 1)::CXXC5 (exon 2) gene fusion and the last had MN1 (exon 1)::ZFP64 (exon 2) gene fusion. The tumors occurred in young to middle-aged adults (two females and one male) and involved the preauricular, abdominal, and sacral soft tissue. Patients with MN1::CXXC5 fusion had widespread metastatic disease at presentation. Histologically, tumors with the MN1::CXXC5 fusion showed nests of monomorphic round and focally spindled cells, compatible with round cell sarcoma, while MN1::ZNFP64 fused tumors exhibited monomorphic spindle cells arranged in storiform and short fascicular patterns. Mitotic activity was brisk in all cases; however, tumor necrosis was minimal to absent. MN1::CXXC5 fused tumors exhibited CD99 and S100 expression, an immunophenotype that is not specific for a particular line of differentiation and is distinct from astroblastoma. MN1::ZNFP64 were positive for p63 and androgen receptor (AR) expression. Low tumor mutation burden and low levels of genome alteration were seen in all cases. DNA methylation profiling showed that the three cases could not be classified into any of the current methylation classes using the DKFZ classifier for sarcomas (version 12.2) or CNS tumors (version 12.8). T-distributed Stochastic Neighbor Embedding analysis revealed that the three sarcomas with MN1 gene rearrangement clustered together, forming a distinct group, in close proximity to epithelioid sarcoma, separate from CNS high-grade neuroepithelial tumor with MN1 alterations. In our series, all three cases exhibited aggressive clinical behavior; notably, the two patients with MN1::CXXC5 gene fusion sarcomas succumbed to the disease within 20 to 23 months. © 2025 The Pathological Society of Great Britain and Ireland.

Post-COVID-19 condition (PCC), also known as long COVID, is a complex multiple organ system condition that can develop and persist for months after acute COVID-19. PCC encompasses a wide range of symptoms, resulting in heterogeneous clinical manifestations. These manifestations likely arise from diverse underlying pathophysiological mechanisms, which, in turn, are influenced by risk factors such as age, sex, and comorbidities. To this end, characterising clinical phenotypes of PCC is essential for deepening our understanding of its (potentially) distinct pathophysiological mechanisms and for advancing diagnostic and patient-tailored management strategies. PCC is thought to result from a complex interaction of various pathophysiological mechanisms, leading to functional and structural pathological alterations across multiple organ systems. Investigating these alterations is critical to improving our currently incomplete understanding of PCC's complex pathophysiology. This review provides an overview of the main clinical phenotypes of PCC, characterises these phenotypes by examining symptoms and signs, as well as the associated risk factors. The main hypothesised pathophysiological mechanisms are discussed by outlining the current knowledge on PCC pathology, focussing on the most commonly affected organ systems. Current PCC management includes supportive care such as physiotherapy and the repurposing of existing drugs primarily targeting persistence of SARS-CoV-2 (e.g. antivirals, monoclonal antibodies) and immune dysfunction (e.g. antiinflammatory drugs, immunomodulators). To date, prevention of SARS-CoV-2 infection remains critical, which can be achieved through effective public health measures and vaccination strategies. Finally, this review highlights current knowledge gaps and proposes future research directions to advance the understanding and treatment of PCC. © 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.