Pub Date : 2026-02-01Epub Date: 2025-12-17DOI: 10.1016/j.prp.2025.156337
Xiaoxi Wang , Xiaochen Shen , Moxuan Yang , Ling Yang , Ying He , Yanni Ren , Shuhao Wang , Dayi Wu , Yuanyuan Guo , Yiru Niu , Kaiyue Peng , Zhihui Wang , Jingpeng Wu , Jiacheng Li , Wei Wang , Feng Wang , Lijuan Cui , Wei Wang , Congrong Liu , Dingrong Zhong
Uterine smooth muscle tumors (USMTs) are the most common tumors of the female reproductive system, but remain diagnostically challenging due to morphological overlap among leiomyosarcoma (LMS), various leiomyoma (LM) subtypes, and smooth muscle tumors of uncertain malignant potential (STUMP). This study aimed to develop a weakly supervised artificial intelligence (AI) model for classifying USMTs as benign or malignant using only slide-level labels. A multi-center dataset comprising 94 LMS cases (408 whole-slide images, WSIs) and 634 benign cases (1389 WSIs) was used for model training and internal testing, with an independent external test set including 27 LMS cases (54 WSIs) and 90 benign cases (248 WSIs). The CAMEL2-based model achieved excellent diagnostic performance, with AUCs of 0.9976 and 0.9889 on the internal and external test sets, respectively, and accuracies exceeding 0.97. Heatmaps frequently highlighted regions enriched for key pathological features of LMS, while benign tissues were consistently assigned low-suspicion regions. In STUMP cases, heatmaps emphasized morphologically suspicious regions that often overlapped with areas identified by pathologists, supporting their potential as decision-support visualizations. In the AI–human collaboration study, model assistance was associated with improved diagnostic accuracy and reduced diagnostic time. This represents the first weakly supervised learning model for USMT diagnosis, achieving high accuracy and interpretability with minimal annotation requirements.
{"title":"An interpretable model based on weakly supervised learning for uterine smooth muscle tumor diagnosis: A multi-center study","authors":"Xiaoxi Wang , Xiaochen Shen , Moxuan Yang , Ling Yang , Ying He , Yanni Ren , Shuhao Wang , Dayi Wu , Yuanyuan Guo , Yiru Niu , Kaiyue Peng , Zhihui Wang , Jingpeng Wu , Jiacheng Li , Wei Wang , Feng Wang , Lijuan Cui , Wei Wang , Congrong Liu , Dingrong Zhong","doi":"10.1016/j.prp.2025.156337","DOIUrl":"10.1016/j.prp.2025.156337","url":null,"abstract":"<div><div>Uterine smooth muscle tumors (USMTs) are the most common tumors of the female reproductive system, but remain diagnostically challenging due to morphological overlap among leiomyosarcoma (LMS), various leiomyoma (LM) subtypes, and smooth muscle tumors of uncertain malignant potential (STUMP). This study aimed to develop a weakly supervised artificial intelligence (AI) model for classifying USMTs as benign or malignant using only slide-level labels. A multi-center dataset comprising 94 LMS cases (408 whole-slide images, WSIs) and 634 benign cases (1389 WSIs) was used for model training and internal testing, with an independent external test set including 27 LMS cases (54 WSIs) and 90 benign cases (248 WSIs). The CAMEL2-based model achieved excellent diagnostic performance, with AUCs of 0.9976 and 0.9889 on the internal and external test sets, respectively, and accuracies exceeding 0.97. Heatmaps frequently highlighted regions enriched for key pathological features of LMS, while benign tissues were consistently assigned low-suspicion regions. In STUMP cases, heatmaps emphasized morphologically suspicious regions that often overlapped with areas identified by pathologists, supporting their potential as decision-support visualizations. In the AI–human collaboration study, model assistance was associated with improved diagnostic accuracy and reduced diagnostic time. This represents the first weakly supervised learning model for USMT diagnosis, achieving high accuracy and interpretability with minimal annotation requirements.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156337"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145798004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-12-29DOI: 10.1016/j.prp.2025.156348
Tingting Liu , Lanyue Zhang , Yang Li, Wenxin Liao, Juexiao Deng, Hua Liang, Fujin Shen
Background
Tumour-associated macrophages (TAMs) within the tumour microenvironment play crucial roles in tumour initiation, invasion, and metastasis. While glutamine synthetase (GS) is expressed predominantly in the tumour stroma, particularly in TAMs, the role of glutamine metabolism in regulating TAM polarization and function in cervical cancer (CC) remains poorly understood. This study aims to clarify this role and its implications for cancer progression.
Methods
CD68 and GS expression in cervical tissues was detected using immunofluorescence staining. The effects of glutamine metabolism on TAM polarization were investigated via RTqPCR, flow cytometry, Western blotting and NAA treatment analyses. CCK8, colony formation, and Transwell assays were conducted to determine the effects of MSO-treated macrophages on tumour cell proliferation, migration, and invasion.
Results
We observed a significant increase in GS expression in TAMs within cervical cancer (CC) tissues, particularly in M2-like TAMs. Glutamine synthesized by TAMs with high GS expression was found to increase the proliferation, migration, and invasion of CC cells. Inhibition of GS in TAMs notably reduced their tumour-promoting effects. Additionally, the byproducts of glutamine metabolism in CC cells contributed to the polarization of TAMs towards the M2 phenotype. This polarization was completely abrogated when SNAT1, a key glutamine transporter, was inhibited in CC cells.
Conclusions
Our findings demonstrate that glutamine synthesized by TAMs with high GS expression promotes tumour progression in CC. Furthermore, glutamine byproducts produced by CC cells induce TAM polarization towards the M2 phenotype, suggesting crucial metabolic crosstalk between tumour cells and macrophages that supports tumour progression. These results highlight the potential of targeting glutamine metabolism to modulate TAM function and inhibit tumour growth.
{"title":"Glutamine metabolites promote the progression of cervical cancer by inducing M2 macrophage polarization","authors":"Tingting Liu , Lanyue Zhang , Yang Li, Wenxin Liao, Juexiao Deng, Hua Liang, Fujin Shen","doi":"10.1016/j.prp.2025.156348","DOIUrl":"10.1016/j.prp.2025.156348","url":null,"abstract":"<div><h3>Background</h3><div>Tumour-associated macrophages (TAMs) within the tumour microenvironment play crucial roles in tumour initiation, invasion, and metastasis. While glutamine synthetase (GS) is expressed predominantly in the tumour stroma, particularly in TAMs, the role of glutamine metabolism in regulating TAM polarization and function in cervical cancer (CC) remains poorly understood. This study aims to clarify this role and its implications for cancer progression.</div></div><div><h3>Methods</h3><div>CD68 and GS expression in cervical tissues was detected using immunofluorescence staining. The effects of glutamine metabolism on TAM polarization were investigated via RT<img>qPCR, flow cytometry, Western blotting and NAA treatment analyses. CCK8, colony formation, and Transwell assays were conducted to determine the effects of MSO-treated macrophages on tumour cell proliferation, migration, and invasion.</div></div><div><h3>Results</h3><div>We observed a significant increase in GS expression in TAMs within cervical cancer (CC) tissues, particularly in M2-like TAMs. Glutamine synthesized by TAMs with high GS expression was found to increase the proliferation, migration, and invasion of CC cells. Inhibition of GS in TAMs notably reduced their tumour-promoting effects. Additionally, the byproducts of glutamine metabolism in CC cells contributed to the polarization of TAMs towards the M2 phenotype. This polarization was completely abrogated when SNAT1, a key glutamine transporter, was inhibited in CC cells.</div></div><div><h3>Conclusions</h3><div>Our findings demonstrate that glutamine synthesized by TAMs with high GS expression promotes tumour progression in CC. Furthermore, glutamine byproducts produced by CC cells induce TAM polarization towards the M2 phenotype, suggesting crucial metabolic crosstalk between tumour cells and macrophages that supports tumour progression. These results highlight the potential of targeting glutamine metabolism to modulate TAM function and inhibit tumour growth.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156348"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145884322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-12-07DOI: 10.1016/j.prp.2025.156327
Linlin Huang , Jing Li , Huawen Wang , Mei Tang , Min Jing , Xinyi Shi , Yongkun Xiao , Lu Bai , Ling Wang , Dong Liu , Tao Wu , Chao Ding , Jinglong Lv , Huami Ye , Jing Li , Jiamei Fan , Pengchun Wu , Wenbo Zhou , Xiaohui Wu , Hongwei Wang
Background
Angioimmunoblastic T-cell lymphoma (AITL), a subtype of nodal T-follicullar helper (TFH) cell lymphoma, may pccasionally contain Hodgkin/Reed-Sternberg (HRS)-like cells, which poses significant diagnostic challenges. These large atypical cells ofthen express CD30 and weak PAX5, making classical Hodgkin lymphoma (CHL) and increasing the risk of misdiagnosis. Accurate recognition requires integration of histological, immunophenotypic, viral, and molecular features.
Method
We retrospectively analyzed 11 patients diagnosed with AITL containing HRS-like cells between January 2020 and January 2025. All cases were consultation cases from a regional lymphoma diagnostic center, with available formalin-fixed, paraffin-embedded lymph node tissue. A comprehensive review included histomorphology, immunohistochemistry, Epstein-Barr virus-encoded RNA (EBER) in situ hybridization, T-cell receptor (TCR) and immunoglobulin (IG) gene rearrangement studies, and targeted next-generation sequencing (NGS) of lymphoma-associated genes.
Results
The cohort included 7 men and 4 women, with a median age of 63 years. Histologically, all cases showed partial to complete effacement of nodal architecture, proliferation of high endothelial venules, expansion of follicular dendritic cell (FDC) meshworks, and scattered HRS-like cells. Immunophenotypically, HRS-like cells were consistently CD30-positive, weak PAX5-positive (9/11), and variably CD15-positive. Background T cells expressed TFH markers including CD4, PD-1, CD10, BCL-6, CXCL13, and ICOS. EBER was positive in 10 cases. TCR gene clonality was detected in 9 patients, while 2 also showed B-cell clonality. NGS identified frequent mutations in TET2 (11/11) and RHOA (8/11), with additional alterations in DNMT3A, KMT2D, CREBBP, BRD4, and PLCG1.
Conclusions
AITL with HRS-like cells is prone to misdiagnosis as CHL due to overlapping morphological and immunophenotypic features. Integration of EBER, TCR/IG clonality assessment, and molecular profiling, particularly the identification of TET2 and RHOA mutations is essential for accurate classification. Recognizing this entity is critical for avoiding diagnostic pitfalls and guiding appropriate therapeutic strategies.
{"title":"Nodal T-follicular helper cell lymphoma with hodgkin/reed-sternberg-like cells: Clinicopathologic and molecular characterization of 11 cases","authors":"Linlin Huang , Jing Li , Huawen Wang , Mei Tang , Min Jing , Xinyi Shi , Yongkun Xiao , Lu Bai , Ling Wang , Dong Liu , Tao Wu , Chao Ding , Jinglong Lv , Huami Ye , Jing Li , Jiamei Fan , Pengchun Wu , Wenbo Zhou , Xiaohui Wu , Hongwei Wang","doi":"10.1016/j.prp.2025.156327","DOIUrl":"10.1016/j.prp.2025.156327","url":null,"abstract":"<div><h3>Background</h3><div>Angioimmunoblastic T-cell lymphoma (AITL), a subtype of nodal T-follicullar helper (TFH) cell lymphoma, may pccasionally contain Hodgkin/Reed-Sternberg (HRS)-like cells, which poses significant diagnostic challenges. These large atypical cells ofthen express CD30 and weak PAX5, making classical Hodgkin lymphoma (CHL) and increasing the risk of misdiagnosis. Accurate recognition requires integration of histological, immunophenotypic, viral, and molecular features.</div></div><div><h3>Method</h3><div>We retrospectively analyzed 11 patients diagnosed with AITL containing HRS-like cells between January 2020 and January 2025. All cases were consultation cases from a regional lymphoma diagnostic center, with available formalin-fixed, paraffin-embedded lymph node tissue. A comprehensive review included histomorphology, immunohistochemistry, Epstein-Barr virus-encoded RNA (EBER) in situ hybridization, T-cell receptor (TCR) and immunoglobulin (IG) gene rearrangement studies, and targeted next-generation sequencing (NGS) of lymphoma-associated genes.</div></div><div><h3>Results</h3><div>The cohort included 7 men and 4 women, with a median age of 63 years. Histologically, all cases showed partial to complete effacement of nodal architecture, proliferation of high endothelial venules, expansion of follicular dendritic cell (FDC) meshworks, and scattered HRS-like cells. Immunophenotypically, HRS-like cells were consistently CD30-positive, weak PAX5-positive (9/11), and variably CD15-positive. Background T cells expressed TFH markers including CD4, PD-1, CD10, BCL-6, CXCL13, and ICOS. EBER was positive in 10 cases. TCR gene clonality was detected in 9 patients, while 2 also showed B-cell clonality. NGS identified frequent mutations in <em>TET2</em> (11/11) and <em>RHOA</em> (8/11), with additional alterations in <em>DNMT3A, KMT2D, CREBBP, BRD4</em>, and <em>PLCG1</em>.</div></div><div><h3>Conclusions</h3><div>AITL with HRS-like cells is prone to misdiagnosis as CHL due to overlapping morphological and immunophenotypic features. Integration of EBER, TCR/IG clonality assessment, and molecular profiling, particularly the identification of <em>TET2</em> and <em>RHOA</em> mutations is essential for accurate classification. Recognizing this entity is critical for avoiding diagnostic pitfalls and guiding appropriate therapeutic strategies.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156327"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lysine demethylase 2A (KDM2A), a crucial member of the histone demethylase family, plays a vital role in epigenetic regulation by modifying histone methylation and the chromatin structure. It regulates key cellular activities, including development, differentiation, and metabolism, by controlling gene expression and transcriptional silencing, and maintaining genomic stability through the demethylation of histone H3 at lysine 36 (H3K36). In addition to its canonical enzymatic role, KDM2A is involved in diverse biological processes, together with embryonic development, stem cell maintenance, DNA damage response, and metabolic homeostasis. Throughout development, it facilitates gene silencing and activation by engaging DNA regions rich in cytosine-guanine (CpG) dinucleotides and attracting polycomb repressive complexes (PRC), which affect lineage specification and organogenesis. Here, we outline the disease-related effects of KDM2A dysregulation related to developmental disorders, cancers, and metastasis. KDM2A aids in tumor development by influencing cell cycle regulators, oncogenes, and chromatin accessibility while also being involved in preserving cancer stem cell characteristics and facilitating epithelial-mesenchymal transition (EMT), metabolic reprogramming, and interactions with cancer-associated fibroblasts (CAFs). Its dual function as an oncogene and tumor suppressor, which varies with the cellular context, highlights its drug complexity and resistance. This review discusses the multifaceted epigenetic functions of KDM2A under both normal and diseased conditions, emphasizing its increasing importance as a potential epigenetic target. It also summarizes the progress in KDM2A-targeted therapies, including inhibitors, RNA interference, CRISPR-Cas9, and immunoepigenetic strategies, with a focus on future applications of KDM2A modulation in clinical treatments for cancer and other epigenetic-associated diseases.
{"title":"KDM2A demethylase: A versatile epigenetic regulator in development, cancer, and therapeutic horizons","authors":"Tajrin Sultana , Md Sadikul Islam , S.M. Abdus Salam , Eshrat Jahan , Md Khalesur Rahman , Md Shiblee Sadik Sabuj , Byung-Yong Park , Tanvir Ahmed , Md Jamilur Rahman , Md Rashedunnabi Akanda","doi":"10.1016/j.prp.2025.156336","DOIUrl":"10.1016/j.prp.2025.156336","url":null,"abstract":"<div><div>Lysine demethylase 2A (KDM2A), a crucial member of the histone demethylase family, plays a vital role in epigenetic regulation by modifying histone methylation and the chromatin structure. It regulates key cellular activities, including development, differentiation, and metabolism, by controlling gene expression and transcriptional silencing, and maintaining genomic stability through the demethylation of histone H3 at lysine 36 (H3K36). In addition to its canonical enzymatic role, KDM2A is involved in diverse biological processes, together with embryonic development, stem cell maintenance, DNA damage response, and metabolic homeostasis. Throughout development, it facilitates gene silencing and activation by engaging DNA regions rich in cytosine-guanine (CpG) dinucleotides and attracting polycomb repressive complexes (PRC), which affect lineage specification and organogenesis. Here, we outline the disease-related effects of KDM2A dysregulation related to developmental disorders, cancers, and metastasis. KDM2A aids in tumor development by influencing cell cycle regulators, oncogenes, and chromatin accessibility while also being involved in preserving cancer stem cell characteristics and facilitating epithelial-mesenchymal transition (EMT), metabolic reprogramming, and interactions with cancer-associated fibroblasts (CAFs). Its dual function as an oncogene and tumor suppressor, which varies with the cellular context, highlights its drug complexity and resistance. This review discusses the multifaceted epigenetic functions of KDM2A under both normal and diseased conditions, emphasizing its increasing importance as a potential epigenetic target. It also summarizes the progress in KDM2A-targeted therapies, including inhibitors, RNA interference, CRISPR-Cas9, and immunoepigenetic strategies, with a focus on future applications of KDM2A modulation in clinical treatments for cancer and other epigenetic-associated diseases.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156336"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145782388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2026-01-03DOI: 10.1016/j.prp.2026.156350
Amber Louw, Jacqueline Bentel, Andrew Laycock
Background
Following diagnosis of resectable non-small cell lung cancer (NSCLC), delays in surgery can lead to poorer outcomes, including interval progression of disease. In this study, we investigated the accuracy of a biopsy diagnosis of adenocarcinoma with high-grade features and its potential use to expedite surgery for patients with these poor prognosis tumors.
Methods
Hematoxylin and eosin (H&E) stained slides from lung biopsies of 144 patients who proceeded to resection were reviewed. The histologic subtype, presence and percentage of architectural patterns in tumor biopsies were recorded. Results were compared to the diagnosis and grading of the excision specimens.
Results
High-grade architectural features, including solid, micropapillary, complex glandular or cribriform histology were identified in 29 of 89 biopsies from adenocarcinomas. Following resection, 22 of these tumors were diagnosed as high-grade, while 55 of 62 biopsies with low/intermediate-grade histologies were found to be low/intermediate-grade on resection. Use of biopsy specimens to predict final grade was associated with a positive predictive value of 75.9 % and a negative predictive value of 91.7 %. Overall, the sensitivity was 81.5 % and specificity was 88.7 %.
Conclusions
Identification of high-grade histologic patterns in lung adenocarcinoma biopsies is strongly indicative of high-grade tumors. In combination with imaging and clinical information, provisional diagnosis of high-grade adenocarcinomas can help to prioritize surgery for patients with these poor prognosis tumors.
{"title":"Prediction of high-grade lung adenocarcinomas in small biopsies: A triaging tool for patients with resectable tumors","authors":"Amber Louw, Jacqueline Bentel, Andrew Laycock","doi":"10.1016/j.prp.2026.156350","DOIUrl":"10.1016/j.prp.2026.156350","url":null,"abstract":"<div><h3>Background</h3><div>Following diagnosis of resectable non-small cell lung cancer (NSCLC), delays in surgery can lead to poorer outcomes, including interval progression of disease. In this study, we investigated the accuracy of a biopsy diagnosis of adenocarcinoma with high-grade features and its potential use to expedite surgery for patients with these poor prognosis tumors.</div></div><div><h3>Methods</h3><div>Hematoxylin and eosin (H&E) stained slides from lung biopsies of 144 patients who proceeded to resection were reviewed. The histologic subtype, presence and percentage of architectural patterns in tumor biopsies were recorded. Results were compared to the diagnosis and grading of the excision specimens.</div></div><div><h3>Results</h3><div>High-grade architectural features, including solid, micropapillary, complex glandular or cribriform histology were identified in 29 of 89 biopsies from adenocarcinomas. Following resection, 22 of these tumors were diagnosed as high-grade, while 55 of 62 biopsies with low/intermediate-grade histologies were found to be low/intermediate-grade on resection. Use of biopsy specimens to predict final grade was associated with a positive predictive value of 75.9 % and a negative predictive value of 91.7 %. Overall, the sensitivity was 81.5 % and specificity was 88.7 %.</div></div><div><h3>Conclusions</h3><div>Identification of high-grade histologic patterns in lung adenocarcinoma biopsies is strongly indicative of high-grade tumors. In combination with imaging and clinical information, provisional diagnosis of high-grade adenocarcinomas can help to prioritize surgery for patients with these poor prognosis tumors.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156350"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145912602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-12-16DOI: 10.1016/j.prp.2025.156335
Han Wang , You-Wen Qian , Xia Sheng , Chun-Yan Xia , Hong-Zhen Chen , Zhen-Yu Cao , Hua Yu , Ying-Ying Zhou , Wen-Ming Cong , Miao-Xia He , Hui Dong
Background
Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) lacks standardized pathological diagnostic paradigm. The significance of tumor necrosis in cHCC-CCA remains undefined. This study aimed to decipher its role and develop a practical grading system.
Methods
A multicenter analysis was conducted on 307 cHCC-CCA patients. Tumor necrosis was pathologically graded as: TN1 (no necrosis, N = 35), TN2 (focal necrosis; maximum diameter of a single focus ≤0.55 cm/one low-power field, N = 129), and TN3 (extensive necrosis; >0.55 cm, N = 143). Associations between tumor necrosis and clinicopathological features, recurrence-free survival (RFS), overall survival (OS), early RFS (≤2 years), and late RFS (>2 years) were assessed. The impact of postoperative adjuvant transarterial chemoembolization (PA-TACE) was also evaluated.
Results
Higher necrosis grades (TN2/TN3) were significantly associated with aggressive tumor characteristics, including larger tumor size, vascular invasion, and lymph node metastasis. TN3 patients had the worst median RFS (0.28 years) and OS (1.36 years), compared to TN2 (RFS: 0.68 years; OS: 2.64 years) and TN1 (RFS: 1.46 years; OS: not reached). The grading system was an independent prognostic factor for RFS, OS, and early RFS in multivariate analysis. PA-TACE significantly improved early RFS in the TN2/TN3 groups and RFS in the TN3 group specifically, but not in the TN1 group.
Conclusions
Tumor necrosis in cHCC-CCA indicates aggressive tumor biology and poorer outcomes. The proposed three-tier grading system provides robust prognostic stratification. PA-TACE benefits patients with significant necrosis (TN2/TN3), particularly in preventing early recurrence. Standardized assessment of tumor necrosis is recommended to optimize risk stratification and guide adjuvant therapy decisions for cHCC-CCA patients.
背景：肝细胞-胆管合并癌（cHCC-CCA）缺乏标准化的病理诊断模式。肿瘤坏死在cHCC-CCA中的意义尚不明确。本研究旨在解读其作用，并建立一套实用的分级体系。方法：对307例cHCC-CCA患者进行多中心分析。肿瘤坏死病理分级为：TN1（无坏死，N = 35）、TN2（局灶性坏死，单灶最大直径≤0.55 cm/一个低倍视场，N = 129）、TN3（广泛坏死，>0.55 cm, N = 143）。评估肿瘤坏死与临床病理特征、无复发生存期（RFS）、总生存期（OS）、早期RFS（≤2年）和晚期RFS （bb0 ~ 2年）之间的关系。术后辅助经动脉化疗栓塞（PA-TACE）的影响也进行了评估。结果：较高的坏死分级（TN2/TN3）与肿瘤的侵袭性特征显著相关，包括肿瘤大小较大、血管侵犯和淋巴结转移。与TN2 （RFS: 0.68年；OS: 2.64年）和TN1 （RFS: 1.46年；OS：未达到）相比，TN3患者的中位RFS（0.28年）和OS（1.36年）最差。在多变量分析中，分级系统是RFS、OS和早期RFS的独立预后因素。PA-TACE显著改善TN2/TN3组的早期RFS，特别是TN3组的RFS，但TN1组没有。结论：cHCC-CCA肿瘤坏死提示肿瘤生物学侵袭性，预后较差。建议的三层分级系统提供了可靠的预后分层。PA-TACE对显著坏死（TN2/TN3）患者有益，特别是在预防早期复发方面。建议对肿瘤坏死进行标准化评估，以优化风险分层，指导cHCC-CCA患者的辅助治疗决策。
{"title":"Deciphering the significance of tumor necrosis and developing a grading system in combined hepatocellular-cholangiocarcinoma: A multicenter pathological study","authors":"Han Wang , You-Wen Qian , Xia Sheng , Chun-Yan Xia , Hong-Zhen Chen , Zhen-Yu Cao , Hua Yu , Ying-Ying Zhou , Wen-Ming Cong , Miao-Xia He , Hui Dong","doi":"10.1016/j.prp.2025.156335","DOIUrl":"10.1016/j.prp.2025.156335","url":null,"abstract":"<div><h3>Background</h3><div>Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) lacks standardized pathological diagnostic paradigm. The significance of tumor necrosis in cHCC-CCA remains undefined. This study aimed to decipher its role and develop a practical grading system.</div></div><div><h3>Methods</h3><div>A multicenter analysis was conducted on 307 cHCC-CCA patients. Tumor necrosis was pathologically graded as: TN1 (no necrosis, N = 35), TN2 (focal necrosis; maximum diameter of a single focus ≤0.55 cm/one low-power field, N = 129), and TN3 (extensive necrosis; >0.55 cm, N = 143). Associations between tumor necrosis and clinicopathological features, recurrence-free survival (RFS), overall survival (OS), early RFS (≤2 years), and late RFS (>2 years) were assessed. The impact of postoperative adjuvant transarterial chemoembolization (PA-TACE) was also evaluated.</div></div><div><h3>Results</h3><div>Higher necrosis grades (TN2/TN3) were significantly associated with aggressive tumor characteristics, including larger tumor size, vascular invasion, and lymph node metastasis. TN3 patients had the worst median RFS (0.28 years) and OS (1.36 years), compared to TN2 (RFS: 0.68 years; OS: 2.64 years) and TN1 (RFS: 1.46 years; OS: not reached). The grading system was an independent prognostic factor for RFS, OS, and early RFS in multivariate analysis. PA-TACE significantly improved early RFS in the TN2/TN3 groups and RFS in the TN3 group specifically, but not in the TN1 group.</div></div><div><h3>Conclusions</h3><div>Tumor necrosis in cHCC-CCA indicates aggressive tumor biology and poorer outcomes. The proposed three-tier grading system provides robust prognostic stratification. PA-TACE benefits patients with significant necrosis (TN2/TN3), particularly in preventing early recurrence. Standardized assessment of tumor necrosis is recommended to optimize risk stratification and guide adjuvant therapy decisions for cHCC-CCA patients.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156335"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145794214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-12-24DOI: 10.1016/j.prp.2025.156339
Huan Liu , Dong Niu , Tong-Yao Yu , Yu-Hua Wang , Kun-Lin Ran , Yan-Hua Liu , Da-Chuan Yin , Chen-Yan Zhang
Extracellular vesicles (EVs) are key drivers of tumor metastasis and colonization. Their cargo, consisting of proteins, nucleic acids, and other biomolecules, functions as molecular messengers that trigger the epithelial-mesenchymal transition (EMT) process in tumor cells and facilitate immune evasion by releasing immunosuppressive factors to promote immune escape. Additionally, EVs influence intercellular interactions within the tumor microenvironment, facilitating angiogenesis, increasing vascular permeability, and supplying nutrients and oxygen to support tumor growth and metastasis. During metastasis, EVs protect circulating tumor cells (CTCs) from shear forces in the vascular network and attacks from the immune system. Furthermore, tumor-derived EVs facilitate the establishment of pre-metastatic niches (PMNs), thereby facilitating organ-specific metastasis. In this review, we overview the biogenesis and functions of EVs, as well as various factors that regulate their secretion. We systematically review tumor-derived EV functions in tumor progression, and also the effects of their interactions with other cells (such as adipocytes, immune cells, fibroblasts, and mesenchymal stem cells) in the tumor microenvironment was clarified. Additionally, we evaluate the diagnostic and prognostic potential of EVs as biomarkers for early tumor detection. The review also summarizes validated EV-associated biomarkers, offering a valuable foundation for the development of EV-based strategies in cancer diagnosis and therapy.
{"title":"Extracellular vesicles in tumor microenvironment modulation and clinical diagnosis","authors":"Huan Liu , Dong Niu , Tong-Yao Yu , Yu-Hua Wang , Kun-Lin Ran , Yan-Hua Liu , Da-Chuan Yin , Chen-Yan Zhang","doi":"10.1016/j.prp.2025.156339","DOIUrl":"10.1016/j.prp.2025.156339","url":null,"abstract":"<div><div>Extracellular vesicles (EVs) are key drivers of tumor metastasis and colonization. Their cargo, consisting of proteins, nucleic acids, and other biomolecules, functions as molecular messengers that trigger the epithelial-mesenchymal transition (EMT) process in tumor cells and facilitate immune evasion by releasing immunosuppressive factors to promote immune escape. Additionally, EVs influence intercellular interactions within the tumor microenvironment, facilitating angiogenesis, increasing vascular permeability, and supplying nutrients and oxygen to support tumor growth and metastasis. During metastasis, EVs protect circulating tumor cells (CTCs) from shear forces in the vascular network and attacks from the immune system. Furthermore, tumor-derived EVs facilitate the establishment of pre-metastatic niches (PMNs), thereby facilitating organ-specific metastasis. In this review, we overview the biogenesis and functions of EVs, as well as various factors that regulate their secretion. We systematically review tumor-derived EV functions in tumor progression, and also the effects of their interactions with other cells (such as adipocytes, immune cells, fibroblasts, and mesenchymal stem cells) in the tumor microenvironment was clarified. Additionally, we evaluate the diagnostic and prognostic potential of EVs as biomarkers for early tumor detection. The review also summarizes validated EV-associated biomarkers, offering a valuable foundation for the development of EV-based strategies in cancer diagnosis and therapy.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156339"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145864776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Precision medicine has transformed healthcare by tailoring treatment plans to an individual’s genetic profile, in contrast to standardized therapies. Patient-derived tumoroids facilitate cancer research, while extracellular vesicles (EVs) provide insights into disease states. EVs from tumoroids serve as diagnostic tools for cancer, reflecting gene mutations and enabling minimally invasive tracking of disease progression. Artificial Intelligence (AI) enhances precision medicine by analyzing extensive datasets derived from tumors and EVs, thereby advancing cancer detection and therapy. The tumor microenvironment (TME) plays a pivotal role in tumor development and is studied using patient-derived organoids (PDOs), which accurately recapitulate tissue function and support drug screening and personalized treatment strategies. Integrating precision medicine with AI-driven analysis of tumoroids and EVs holds the potential to improve patient outcomes and quality of life through personalized treatment approaches.
{"title":"Tumoroid-derived extracellular vesicles for prognosis and therapeutics: A valuable tool in precision medicine","authors":"Vijay Murali Ravi Mythili , ArulJothi Kandasamy Nagarajan , Vasanth Kanth Loganathbabu Thasma , Shriya Pattabiram , Kumaran Kasinathan , Ramya Lakshmi Rajendran , Anand Krishnan , Prakash Gangadaran , Byeong-Cheol Ahn","doi":"10.1016/j.prp.2025.156332","DOIUrl":"10.1016/j.prp.2025.156332","url":null,"abstract":"<div><div>Precision medicine has transformed healthcare by tailoring treatment plans to an individual’s genetic profile, in contrast to standardized therapies. Patient-derived tumoroids facilitate cancer research, while extracellular vesicles (EVs) provide insights into disease states. EVs from tumoroids serve as diagnostic tools for cancer, reflecting gene mutations and enabling minimally invasive tracking of disease progression. Artificial Intelligence (AI) enhances precision medicine by analyzing extensive datasets derived from tumors and EVs, thereby advancing cancer detection and therapy. The tumor microenvironment (TME) plays a pivotal role in tumor development and is studied using patient-derived organoids (PDOs), which accurately recapitulate tissue function and support drug screening and personalized treatment strategies. Integrating precision medicine with AI-driven analysis of tumoroids and EVs holds the potential to improve patient outcomes and quality of life through personalized treatment approaches.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156332"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145749027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-12-23DOI: 10.1016/j.prp.2025.156338
Mohammed Kaleem , Purushottam Gangane , Md Ali Mujtaba , Aachal Kanekar , Naiyer Shahzad , Abdullah R. Alzahrani , Ameeduzzafar Zafar , Aftab Ahmad
Breast cancer (BC) is the most common cancer and a major cause of cancer-related deaths in women worldwide. Its significant molecular heterogeneity leads to different response rates, leaving standard therapy approaches comparatively ineffective. Recent evidence highlights the promise of natural compound–based therapies in modulating oncogenic signaling, regulating epigenetic mechanisms, and reshaping the tumor microenvironment. This review systematically explores the anticancer potential of bioactive phytochemicals, including curcumin, resveratrol, thymoquinone, and berberine, in BC. These agents exhibit pleiotropic mechanisms such as promoting apoptosis (e.g., via p53 activation), suppressing angiogenesis (e.g., through VEGF downregulation), and reversing chemoresistance (e.g., by inhibiting the PI3K/AKT/mTOR axis). The role of epigenetic regulation is explored, focusing on DNA methylation, histone modifications, and non-coding RNAs. Compounds like EGCG and ellagic acid have been shown to restore the expression of tumor suppressor genes. Special attention is given to different types of breast cancer, especially triple-negative breast cancer (TNBC), which currently has limited treatment options and poor outcomes. Laboratory studies suggest that plant-based compounds can enhance the sensitivity of TNBC cells to standard chemotherapy, while also impacting immune and metabolic functions. Advances in nanotechnology, such as liposome-encapsulated curcumin, gold nanoparticles containing berberine, and nano-delivery systems for resveratrol, have improved the absorption and effectiveness of these substances. In conclusion, natural compounds represent a valuable source of novel therapeutics for breast cancer management, bridging molecular insights with translational potential.
{"title":"The advancements in targeted therapeutic strategies for breast cancer via intervention of natural molecules: An insight into cellular and molecular mechanisms","authors":"Mohammed Kaleem , Purushottam Gangane , Md Ali Mujtaba , Aachal Kanekar , Naiyer Shahzad , Abdullah R. Alzahrani , Ameeduzzafar Zafar , Aftab Ahmad","doi":"10.1016/j.prp.2025.156338","DOIUrl":"10.1016/j.prp.2025.156338","url":null,"abstract":"<div><div>Breast cancer (BC) is the most common cancer and a major cause of cancer-related deaths in women worldwide. Its significant molecular heterogeneity leads to different response rates, leaving standard therapy approaches comparatively ineffective. Recent evidence highlights the promise of natural compound–based therapies in modulating oncogenic signaling, regulating epigenetic mechanisms, and reshaping the tumor microenvironment. This review systematically explores the anticancer potential of bioactive phytochemicals, including curcumin, resveratrol, thymoquinone, and berberine, in BC. These agents exhibit pleiotropic mechanisms such as promoting apoptosis (e.g., via p53 activation), suppressing angiogenesis (e.g., through VEGF downregulation), and reversing chemoresistance (e.g., by inhibiting the PI3K/AKT/mTOR axis). The role of epigenetic regulation is explored, focusing on DNA methylation, histone modifications, and non-coding RNAs. Compounds like EGCG and ellagic acid have been shown to restore the expression of tumor suppressor genes. Special attention is given to different types of breast cancer, especially triple-negative breast cancer (TNBC), which currently has limited treatment options and poor outcomes. Laboratory studies suggest that plant-based compounds can enhance the sensitivity of TNBC cells to standard chemotherapy, while also impacting immune and metabolic functions. Advances in nanotechnology, such as liposome-encapsulated curcumin, gold nanoparticles containing berberine, and nano-delivery systems for resveratrol, have improved the absorption and effectiveness of these substances. In conclusion, natural compounds represent a valuable source of novel therapeutics for breast cancer management, bridging molecular insights with translational potential.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156338"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-12-22DOI: 10.1016/j.prp.2025.156341
Monica Armanious, Farida K. Gebreel, Reem W. Algendy, Rahma Hefny, Amira M. Ismail, Patrick M. Maximous, Hend M. El Tayebi
Antibody-drug conjugates (ADCs) initiated a pivotal therapeutic strategy in hematologic malignancies, by combining targeted cytotoxicity with high specificity and reduced systemic toxicity. However, despite promising clinical outcomes, resistance to ADCs raises a remarkable challenge, limiting their long-term efficacy. This review explored the multiplex mechanisms underlying ADC resistance emerging in different hematologic cancers, including overexpression of drug efflux pumps, antigen loss or downregulation, impaired intracellular trafficking, and altered apoptotic pathways. The review sheds the light on the role of tumor microenvironment in promoting resistance and hindering the ultimate ADCs efficacy as well as emerging strategies to overcome resistance such as combination therapies, next-generation ADCs, and biomarker-driven patient selection. Understanding the molecular basis of ADC resistance is crucial for optimizing treatment regimens and guiding future therapeutic development in hematologic malignancies.
{"title":"Unraveling ADC resistance in hematologic malignancies: Challenges and new frontiers","authors":"Monica Armanious, Farida K. Gebreel, Reem W. Algendy, Rahma Hefny, Amira M. Ismail, Patrick M. Maximous, Hend M. El Tayebi","doi":"10.1016/j.prp.2025.156341","DOIUrl":"10.1016/j.prp.2025.156341","url":null,"abstract":"<div><div>Antibody-drug conjugates (ADCs) initiated a pivotal therapeutic strategy in hematologic malignancies, by combining targeted cytotoxicity with high specificity and reduced systemic toxicity. However, despite promising clinical outcomes, resistance to ADCs raises a remarkable challenge, limiting their long-term efficacy. This review explored the multiplex mechanisms underlying ADC resistance emerging in different hematologic cancers, including overexpression of drug efflux pumps, antigen loss or downregulation, impaired intracellular trafficking, and altered apoptotic pathways. The review sheds the light on the role of tumor microenvironment in promoting resistance and hindering the ultimate ADCs efficacy as well as emerging strategies to overcome resistance such as combination therapies, next-generation ADCs, and biomarker-driven patient selection. Understanding the molecular basis of ADC resistance is crucial for optimizing treatment regimens and guiding future therapeutic development in hematologic malignancies.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156341"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145878788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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