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Non–neoplastic Orthopedic Pathology Updates: Common Problems and Pitfalls and How to Avoid Them 非肿瘤性骨科病理学更新:常见问题和陷阱以及如何避免它们。
IF 5.5 1区 医学 Q1 PATHOLOGY Pub Date : 2025-10-13 DOI: 10.1016/j.modpat.2025.100911
Scott E. Kilpatrick
Despite representing <1% of all musculoskeletal surgical pathology cases, primary musculoskeletal neoplasms are disproportionately emphasized in the surgical pathology literature, compared with non–neoplastic orthopedic pathology. Yet, there remains significant interest among practicing pathologists and their clinical colleagues to maintain expertise in the non–neoplastic arena, as evidenced by increasing volumes of non–neoplastic orthopedic diseases, often reflected in consult cases. Recent literature has renewed the discussion of arthroplasty, emphasized the clinical importance of pathologic examination, and provided updated diagnostic clarification for separating avascular necrosis from degenerative joint disease (DJD)/osteoarthritis (OA) with secondary osteonecrosis, acute infectious osteomyelitis from pseudoabscesses of DJD/OA, and revisited the diagnoses of subchondral insufficiency fracture and rapidly destructive arthropathy. Providing accurate neutrophil counts to help determine periprosthetic joint infection has rapidly become one of the most common sources of frozen section evaluation in the United States. Distinguishing periprosthetic joint infection from aseptic loosening has significant intraoperative implications. In addition to acute arthritis and mass effect, calcium pyrophosphate dihydrate (CPPD) deposition disease may lead to DJD/OA. However, most histologically confirmed examples of CPPD, involving the large extremity joints, are not identified preoperatively or radiologically, requiring pathologic evaluation to reliably establish the diagnosis. The incidence of CPPD deposits appears highest in the humeral head/shoulder, followed by the knees and hips/femoral head. Recent evidence has documented infrequent examples of combined gout and CPPD/pseudogout within the same tophi, associated with unique clinicopathologic features compared with those with gout alone. Carpal tunnel syndrome, trigger finger, and lumbar stenosis represent potential early red flags for the development of transthyretin (TR) cardiac amyloidosis. Although previously discarded at many institutions, excised tissue removed from such specimens, particularly tenosynovium from the carpal tunnel flexor retinaculum, are now routinely evaluated histologically with Congo red staining and, when positive, followed by mass spectrometry for confirmatory amyloid subtyping. With the use of a recently developed TR stabilizer, such as tafamidis, early histologic detection and treatment of TR cardiac amyloidosis has improved clinical outcomes. Herein is a summary of recent relevant developments in non–neoplastic orthopedic surgical pathology, updated diagnostic criteria and pitfalls, and the resulting clinical impact, where applicable.
尽管占所有肌肉骨骼手术病理病例的比例不到1%,但与非肿瘤性骨科病理相比,原发性肌肉骨骼肿瘤在外科病理文献中被不成比例地强调。然而,执业病理学家和他们的临床同事仍然对保持非肿瘤领域的专业知识非常感兴趣,非肿瘤骨科疾病数量的增加证明了这一点,通常反映在会诊病例中。最近的文献更新了对关节置换术的讨论,强调了病理检查的临床重要性,并对区分缺血性坏死与退行性关节疾病(DJD)/继发性骨坏死的骨关节炎(OA)、急性感染性骨髓炎与DJD/OA的假性脓肿提供了更新的诊断澄清,并重新审视了软骨下功能不全骨折和快速破坏性关节病变的诊断。提供准确的中性粒细胞计数以帮助确定假体周围关节感染(PJI)已迅速成为美国冷冻切片评估最常见的来源之一。区分PJI与无菌性松动具有重要的术中意义。除了急性关节炎和团块效应外,焦磷酸钙二水合物(CPPD)沉积病也可能导致DJD/OA。然而,大多数经组织学证实的CPPD病例,包括四肢大关节,在术前或影像学上都没有被发现,需要病理评估来可靠地建立诊断。CPPD沉积的发生率在肱骨头/肩部最高,其次是膝关节和髋关节/股骨头。最近的证据表明,在同一痛风中合并痛风和CPPD/假性痛风的例子并不多见,与单独的痛风相比,它们具有独特的临床病理特征。腕管综合征、扳机指和腰椎管狭窄是甲状腺素型心脏淀粉样变发展的潜在早期危险信号。虽然以前在许多机构被丢弃,但从这些标本中切除的组织,特别是腕管屈肌视网膜带的腱鞘,现在常规用刚果红染色进行组织学评估,阳性时,随后用质谱法进行确认淀粉样蛋白亚型分型。使用最近开发的经甲状腺蛋白稳定剂,如他法底斯,经甲状腺蛋白心脏淀粉样变性的早期组织学检测和治疗改善了临床结果。本文总结了非肿瘤性骨科手术病理学的最新相关进展,更新的诊断标准和缺陷,以及由此产生的临床影响。
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引用次数: 0
Methylation Profiles in Bone and Soft Tissue Tumors: Do They Help Classify the Unclassifiable? 骨和软组织肿瘤的甲基化谱:它们有助于分类不可分类吗?
IF 5.5 1区 医学 Q1 PATHOLOGY Pub Date : 2025-10-13 DOI: 10.1016/j.modpat.2025.100910
Josephine K. Dermawan
Methylation profiling offers a promising avenue for improving the diagnosis and classification of bone and soft tissue tumors, particularly in cases where traditional methods fall short. Through examining tissue- and lineage-specific DNA methylation patterns, this approach can augment the classification of morphologically similar tumors with different genetics (genetic heterogeneity) or tumors that share genetic drivers but diverge phenotypically (phenotypic heterogeneity). This tool can also help clarify previously unclassifiable, poorly differentiated or transdifferentiated nonmesenchymal tumors that mimic sarcomas. By adopting an unbiased approach to grouping and subtyping using unsupervised clustering on methylomes, methylation profiling could potentially revise how we classify sarcomas. There is a need clinically to develop a methylation classifier that accurately predicts sarcoma class based on methylation profile, specifically in sarcomas that are challenging to differentiate due to overlapping morphologic or molecular features. However, current classifiers are limited by the diversity and size of their reference cohorts, dilution of signal by nonneoplastic tissue, and alteration of the methylomic landscape by histone modifications and oncometabolite-related mutations. Key considerations include the importance of quality control for tissue-based methylation profiling, transparent and reproducible pipelines, and open data sharing. Future advancements include continued refinement of methylation-based classifiers with a broader spectrum of rare and ultrarare tumor types and adopting new biological insights from methylome-driven analyses and integration of multiomic approaches. Although methylation profiling emerges as a valuable adjunct to existing diagnostic modalities, clinicopathologic considerations should always be incorporated for a more nuanced, management-based tumor classification system.
甲基化谱为改善骨和软组织肿瘤的诊断和分类提供了一条有希望的途径,特别是在传统方法不足的情况下。通过检查组织和谱系特异性DNA甲基化模式,该方法可以增强具有不同遗传学(遗传异质性)的形态相似肿瘤的分类,或具有共享遗传驱动但表型差异(表型异质性)的肿瘤。该工具还可以帮助澄清以前无法分类,低分化或转分化的非间质肿瘤,类似肉瘤。通过对甲基组采用无监督聚类的无偏分组和分型方法,甲基化分析可能会潜在地改变我们对肉瘤的分类方式。临床需要开发一种基于甲基化谱准确预测肉瘤类型的甲基化分类器,特别是在由于重叠的形态或分子特征而难以区分的肉瘤中。然而,目前的分类器受到参考队列的多样性和规模、非肿瘤组织对信号的稀释、组蛋白修饰和肿瘤代谢物相关突变对甲基化格局的改变等因素的限制。关键考虑因素包括对基于组织的甲基化分析的质量控制的重要性,透明和可重复的管道,以及开放的数据共享。未来的进展包括继续改进基于甲基化的分类器,以更广泛的罕见和超罕见肿瘤类型,采用甲基化驱动分析和多组学方法的整合的新生物学见解。虽然甲基化分析作为一种有价值的辅助手段出现在现有的诊断模式中,但临床病理方面的考虑应该始终被纳入一个更细微的、基于管理的肿瘤分类系统。
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引用次数: 0
Tumors of the Synovium 滑膜肿瘤。
IF 5.5 1区 医学 Q1 PATHOLOGY Pub Date : 2025-10-13 DOI: 10.1016/j.modpat.2025.100913
Yee Lin Tang , Jad Husseini , G. Petur Nielsen
The synovium is an integral component of synovial joints, as well as extra-articular structures such as the tenosynovium and bursae. This article reviews normal histology and the immunohistochemical profile of the synovium. It also discusses several common and distinctive intra-articular and extra-articular tumors arising in synovium-lined structures, such as tenosynovial giant cell tumor, synovial chondromatosis, and the recently described chondroid synoviocytic neoplasm. Among these, tenosynovial giant cell tumor and chondroid synoviocytic neoplasm are the only true neoplasms of synoviocytes. An emerging entity, calcified chondroid mesenchymal neoplasm, will also be mentioned. The clinical, radiologic, morphologic, and molecular genetics features of these tumors are discussed, along with their differential diagnoses. In addition, the article addresses other rare lesions, such as lipoma arborescens, a nonneoplastic condition, and synovial hemangioma, which often present as an intra-articular mass. Finally, a brief overview of selected primary intra-articular sarcomas is provided.
滑膜是滑膜关节以及关节外结构(如腱鞘和滑囊)的组成部分。本文综述了滑膜的正常组织学和免疫组织化学特征。它还讨论了几种常见的和独特的关节内和关节外肿瘤,如腱鞘巨细胞瘤、滑膜软骨瘤病和最近描述的软骨样滑膜细胞肿瘤。其中,滑膜巨细胞瘤和软骨样滑膜细胞瘤是仅有的滑膜细胞肿瘤。一个新兴的实体,钙化软骨样间充质肿瘤,也将被提及。本文讨论了这些肿瘤的临床、放射学、形态学和分子遗传学特征,以及它们的鉴别诊断。此外,本文还讨论了其他罕见病变,如树状脂肪瘤,一种非肿瘤性疾病,以及滑膜血管瘤,通常表现为关节内肿块。最后,简要概述所选择的原发性关节内肉瘤。
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引用次数: 0
Unraveling Round Cell Sarcomas: A Contemporary Diagnostic Guide Beyond Ewing Sarcoma 解开圆细胞肉瘤:超越尤因肉瘤的当代诊断指南。
IF 5.5 1区 医学 Q1 PATHOLOGY Pub Date : 2025-10-13 DOI: 10.1016/j.modpat.2025.100914
Raul Ezequiel Perret
Round cell sarcomas represent a continuously evolving category of malignant mesenchymal tumors, currently encompassing 5 main tumor subtypes: Ewing sarcoma, Capicua Transcriptional Repressor (CIC)rearranged sarcoma, sarcomas with BCL6-corepressor (BCOR)-genetic abnormalities, POZ/BTB and AT hook containing zinc finger 1 (PATZ1)-rearranged sarcoma, and nuclear factor of activated T cells 2 (NFATC2)-rearranged sarcoma. These tumors show some degree of histomorphologic overlap, which, coupled with their infrequency, may render their diagnosis challenging for the pathologist. Furthermore, although ancillary techniques like immunohistochemistry and molecular tests can be of diagnostic aid, they are still limited by inherent sensitivity and specificity issues and cannot replace meticulous integration of clinical and radiologic findings. This review is focused on (1) providing a guide for tackling the diagnosis of round cell sarcomas and their mimics using an integrative approach combining demographics, clinicoradiologic data, histomorphology, and ancillary techniques and (2) detailing the most recent information on round cell sarcomas from the latest World Health Organization classification of Bone and Soft Tissue Tumors (fifth edition).
圆细胞肉瘤是一种不断进化的恶性间质肿瘤,目前主要包括5种肿瘤亚型:Ewing肉瘤、cic重排肉瘤、bco基因异常肉瘤、patz1重排肉瘤和nfatc2重排肉瘤。这些肿瘤表现出一定程度的组织形态重叠,再加上它们的罕见性,可能使病理学家的诊断具有挑战性。此外,虽然免疫组织化学和分子测试等辅助技术可以作为诊断辅助,但它们仍然受到固有敏感性和特异性问题的限制,不能取代临床和放射检查结果的细致整合。这篇综述的重点是:1)使用结合人口统计学、临床放射学数据、组织形态学和辅助技术的综合方法为解决圆细胞肉瘤及其模拟物的诊断提供指南,以及2)详细介绍最新的WHO骨和软组织肿瘤分类(第5版)中关于圆细胞肉瘤的最新信息。
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引用次数: 0
Replacing Molecular Testing With Next-Generation Immunohistochemistry: I Can Diagnose That Soft Tissue Tumor With a Single Antibody! 用新一代免疫组织化学取代分子检测:我可以用一种抗体诊断软组织肿瘤!
IF 5.5 1区 医学 Q1 PATHOLOGY Pub Date : 2025-10-12 DOI: 10.1016/j.modpat.2025.100912
Jason L. Hornick
Immunohistochemistry plays a central role in the diagnosis of soft tissue tumors. Conventional immunohistochemistry uses antibodies directed against lineage-restricted antigens, in an attempt to identify a line of differentiation and narrow down the differential diagnosis. However, in most cases, such markers are inadequate to reach a specific diagnosis. Many soft tissue tumors harbor recurrent, often disease-defining molecular genetic alterations. Increasingly, fluorescence in situ hybridization analysis or next-generation sequencing is employed for identification of such alterations as a diagnostic adjunct. In recent years, immunohistochemistry has been used as a surrogate for such molecular genetic or cytogenetic analysis; this approach can identify the protein correlates of genetic alterations. Numerous next-generation antibodies directed against the protein products of a wide range of genetic alterations (such as gene fusions, amplifications, deletions, and point mutations) have entered our diagnostic armamentarium. In addition, gene expression profiling has uncovered diagnostically useful markers for immunohistochemistry. Finally, epigenetic alterations (eg, methylation) can also be assessed by immunohistochemistry. This review will provide examples of the application of contemporary molecular immunohistochemistry for soft tissue tumor diagnosis.
免疫组织化学在软组织肿瘤的诊断中起着核心作用。传统的免疫组织化学使用针对谱系限制抗原的抗体,试图确定一条分化线并缩小鉴别诊断范围。然而,在大多数情况下,这些标记不足以达到特定的诊断。许多软组织肿瘤具有复发性,通常是疾病定义的分子遗传改变。越来越多地,荧光原位杂交分析或下一代测序被用于识别这种改变作为诊断辅助。近年来,免疫组织化学已被用作此类分子遗传学或细胞遗传学分析的替代方法;这种方法可以识别与基因改变相关的蛋白质。许多“下一代”抗体针对广泛的基因改变(如基因融合、扩增、缺失和点突变)的蛋白质产物,已经进入我们的诊断设备。此外,基因表达谱揭示了免疫组织化学诊断有用的标志物。最后,表观遗传改变(如甲基化)也可以通过免疫组织化学来评估。本文将提供当代分子免疫组织化学在软组织肿瘤诊断中的应用实例。
{"title":"Replacing Molecular Testing With Next-Generation Immunohistochemistry: I Can Diagnose That Soft Tissue Tumor With a Single Antibody!","authors":"Jason L. Hornick","doi":"10.1016/j.modpat.2025.100912","DOIUrl":"10.1016/j.modpat.2025.100912","url":null,"abstract":"<div><div>Immunohistochemistry plays a central role in the diagnosis of soft tissue tumors. Conventional immunohistochemistry uses antibodies directed against lineage-restricted antigens, in an attempt to identify a line of differentiation and narrow down the differential diagnosis. However, in most cases, such markers are inadequate to reach a specific diagnosis. Many soft tissue tumors harbor recurrent, often disease-defining molecular genetic alterations. Increasingly, fluorescence in situ hybridization analysis or next-generation sequencing is employed for identification of such alterations as a diagnostic adjunct. In recent years, immunohistochemistry has been used as a surrogate for such molecular genetic or cytogenetic analysis; this approach can identify the protein correlates of genetic alterations. Numerous next-generation antibodies directed against the protein products of a wide range of genetic alterations (such as gene fusions, amplifications, deletions, and point mutations) have entered our diagnostic armamentarium. In addition, gene expression profiling has uncovered diagnostically useful markers for immunohistochemistry. Finally, epigenetic alterations (eg, methylation) can also be assessed by immunohistochemistry. This review will provide examples of the application of contemporary molecular immunohistochemistry for soft tissue tumor diagnosis.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100912"},"PeriodicalIF":5.5,"publicationDate":"2025-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145292980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Giant Cell-Rich Tumors of Bone and Soft Tissue 富巨细胞骨和软组织肿瘤。
IF 5.5 1区 医学 Q1 PATHOLOGY Pub Date : 2025-10-11 DOI: 10.1016/j.modpat.2025.100915
Robert M. van der Linde , David G.P. van IJzendoorn , Matt van de Rijn , Judith V.M.G. Bovée
Many benign and malignant bone and soft tissue tumors can contain giant cells in variable amounts. In some tumors, such as tenosynovial giant cell tumor and giant cell tumor of bone, these osteoclast-like giant cells are so prominent and characteristic that their presence has defined the entity. Other examples of bone tumors in which the presence of osteoclast-like giant cells is characteristic include chondroblastoma, aneurysmal bone cyst, nonossifying fibroma, and central giant cell granuloma. These tumors have a distinct pathogenesis, although some parallels can be identified. The osteoclast-like giant cells within these tumors are not the neoplastic component but are nonneoplastic bystanders and part of the tumor microenvironment. Notably, the activation of the colony-stimulating factor 1 (CSF1)-CSF1 receptor (CSF1R) and/or the receptor activator of NFκB ligand-receptor activator of NFκB signaling pathways, best studied in tenosynovial giant cell tumor and giant cell tumor of bone, respectively, appears to be key in attracting macrophages and the formation of osteoclast-like giant cells within the tumor. Among soft tissue tumors, a plethora of tumors have been described to contain variable amounts of giant cells, and the underlying mechanisms are so far less well understood. One exception is the recently described keratin-positive giant cell-rich tumor of soft tissue, which also seems to rely on CSF1-CSF1R signaling to attract giant cells. The CSF1-CSF1R and receptor activator of NFκB ligand-receptor activator of NFκB pathways are suitable targets for nonsurgical interventions, and inhibitors of these pathways are already being used for some entities in clinical practice. These inhibitors inhibit tumor growth and may induce bone formation, although pathologists should be aware when evaluating posttreatment specimens that the neoplastic cells remain unaffected.
许多良性和恶性骨和软组织肿瘤可含有巨细胞,其数量不等。在一些肿瘤中,如腱鞘巨细胞瘤(TGCT)和骨巨细胞瘤(GCTB),这些破骨细胞样巨细胞是如此突出和特征性,以至于它们的存在定义了实体。其他以破骨细胞样巨细胞为特征的骨肿瘤包括成软骨细胞瘤、动脉瘤性骨囊肿、非骨化纤维瘤和中央巨细胞肉芽肿。这些肿瘤有不同的发病机制,尽管可以确定一些相似之处。这些肿瘤内的破骨细胞样巨细胞不是肿瘤的组成部分,而是非肿瘤的旁观者和肿瘤微环境的一部分。值得注意的是,分别在TGCT和GCTB中研究最好的CSF1-CSF1R和/或RANKL-RANK信号通路的激活似乎是肿瘤内吸引巨噬细胞和形成破骨细胞样巨细胞的关键。在软组织肿瘤中,大量的肿瘤被描述为含有不同数量的巨细胞,其潜在的机制到目前为止还不太清楚。一个例外是最近描述的富含角蛋白阳性巨细胞的软组织肿瘤,它似乎也依赖于CSF1-CSF1R信号来吸引巨细胞。CSF1-CSF1R和RANKL-RANK通路是非手术干预的合适靶点,这些通路的抑制剂已经在临床实践中用于一些实体。这些抑制剂抑制肿瘤生长并可能诱导骨形成,尽管病理学家在评估治疗后标本时应注意肿瘤细胞不受影响。
{"title":"Giant Cell-Rich Tumors of Bone and Soft Tissue","authors":"Robert M. van der Linde ,&nbsp;David G.P. van IJzendoorn ,&nbsp;Matt van de Rijn ,&nbsp;Judith V.M.G. Bovée","doi":"10.1016/j.modpat.2025.100915","DOIUrl":"10.1016/j.modpat.2025.100915","url":null,"abstract":"<div><div>Many benign and malignant bone and soft tissue tumors can contain giant cells in variable amounts. In some tumors, such as tenosynovial giant cell tumor and giant cell tumor of bone, these osteoclast-like giant cells are so prominent and characteristic that their presence has defined the entity. Other examples of bone tumors in which the presence of osteoclast-like giant cells is characteristic include chondroblastoma, aneurysmal bone cyst, nonossifying fibroma, and central giant cell granuloma. These tumors have a distinct pathogenesis, although some parallels can be identified. The osteoclast-like giant cells within these tumors are not the neoplastic component but are nonneoplastic bystanders and part of the tumor microenvironment. Notably, the activation of the colony-stimulating factor 1 (CSF1)-CSF1 receptor (CSF1R) and/or the receptor activator of NFκB ligand-receptor activator of NFκB signaling pathways, best studied in tenosynovial giant cell tumor and giant cell tumor of bone, respectively, appears to be key in attracting macrophages and the formation of osteoclast-like giant cells within the tumor. Among soft tissue tumors, a plethora of tumors have been described to contain variable amounts of giant cells, and the underlying mechanisms are so far less well understood. One exception is the recently described keratin-positive giant cell-rich tumor of soft tissue, which also seems to rely on CSF1-CSF1R signaling to attract giant cells. The CSF1-CSF1R and receptor activator of NFκB ligand-receptor activator of NFκB pathways are suitable targets for nonsurgical interventions, and inhibitors of these pathways are already being used for some entities in clinical practice. These inhibitors inhibit tumor growth and may induce bone formation, although pathologists should be aware when evaluating posttreatment specimens that the neoplastic cells remain unaffected.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100915"},"PeriodicalIF":5.5,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145286598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Comparative Analysis Reveals Recurrent Molecular Alterations in Low-Risk Human Papillomavirus 6 and Human Papillomavirus 11-Associated Squamous Cell Carcinoma of the Uterine Cervix and Vulva 比较分析揭示低危HPV6和hpv11相关的宫颈和外阴鳞状细胞癌复发性分子改变。
IF 5.5 1区 医学 Q1 PATHOLOGY Pub Date : 2025-10-10 DOI: 10.1016/j.modpat.2025.100909
Ying Sun , Colton Smith , Jason Murray , Jing Zhu , Aparna Pallavajjala , Sichen Liang , Melanie Klausner , Ya-Chea Tsai , Chien-Fu Hung , Tzyy-Choou Wu , Ying S. Zou , Deyin Xing
Although the association between human papillomavirus (HPV) 6 and HPV11 and squamous cell carcinomas (SCCs) has been well documented, the molecular alterations and mechanisms by which these low-risk HPVs contribute to carcinogenesis remain largely unknown. In this study, we comparatively elucidated the molecular landscape of HPV6/11-associated condylomas (9 cases) and SCCs (8 cases) of the uterine cervix and vulva. Sixteen of 17 cases were successfully analyzed using deep next-generation sequencing. Recurrent molecular alterations in the SCCs included mutations in the TERT promoter (pTERT, 71%), NOTCH1 (57%), NFE2L2 (57%), NOTCH3 (29%), and CDKN2A (29%). Mutations in NOTCH1 and NFE2L2 tended to be mutually exclusive. Less common somatic mutations were each detected in the following genes: AR, ARID1A, ASXL1, BCORL1, DAZAP1, FNDC1, HRAS, KMT2B, NOTCH2, NRAS, PIK3R1, and TP53. Etiologically similar to the SCCs, the vast majority of vulvar and cervical condylomas (7/9, 78%) were infected with HPV6 rather than HPV11. Unlike the SCCs, condylomas rarely harbored recurrent pathogenic somatic mutations. NOTCH1 and NOTCH2 were the only mutant genes detected in both SCCs and condylomas in this series, suggesting a critical role for the NOTCH pathway in the initiation and maintenance of HPV6/11-related early squamous lesions. Although pathogenic mutations in NOTCH1, NOTCH2, ERBB3, ATRX, FGFR2, EPHA5, CARD11, STAG2, and TSC2 were detected in condylomas, none were recurrent, indicating diverse genetic alterations involved in the development of these lesions. Case 8 illustrated a stepwise progression from condyloma to invasive SCC, in which pathogenic mutations in pTERT and NOTCH1 were detected in the SCC (age 58) and the condyloma at age 55, but not in the condyloma at age 44. Our study presents the first report on the molecular landscape of HPV6/11-associated SCCs of the uterine cervix and vulva. We provide evidence that SCCs associated with low-risk HPV are distinct entities, differing from those related to high-risk HPV and more closely resembling HPV-independent neoplasms. Given that low-risk HPV-associated SCCs of the cervix and vulva exhibit unique morphological and molecular features, they should either be described separately within existing classification systems or classified as a distinct new entity.
虽然HPV6和HPV11与鳞状细胞癌(SCCs)的关系已经有了很好的文献记载,但这些低风险hpv导致癌变的分子改变和机制在很大程度上仍然未知。在本研究中,我们比较阐明了hpv6 /11相关尖锐湿疣(9例)和宫颈及外阴SCCs(8例)的分子图谱。17例中有16例使用深度下一代测序成功分析。SCCs中复发性分子改变包括TERT启动子(pTERT, 71%)、NOTCH1(57%)、NFE2L2(57%)、NOTCH3(29%)和CDKN2A(29%)的突变。NOTCH1和NFE2L2的突变倾向于互斥。在以下基因中分别检测到不太常见的体细胞突变:AR、ARID1A、ASXL1、BCORL1、DAZAP1、FNDC1、HRAS、KMT2B、NOTCH2、NRAS、PIK3R1和TP53。病因学上与SCCs相似,绝大多数外阴和宫颈尖锐湿疣(97.78%)感染HPV6而不是HPV11。与SCCs不同,尖锐湿疣很少有复发性致病性体细胞突变。NOTCH1和NOTCH2是该系列中仅有的在SCCs和尖锐湿疣中检测到的突变基因,这表明NOTCH通路在hpv6 /11相关的早期鳞状病变的启动和维持中起关键作用。尽管在尖锐湿疣中检测到NOTCH1、NOTCH2、ERBB3、ATRX、FGFR2、EPHA5、CARD11、STAG2和TSC2的致病突变,但没有一个复发,表明这些病变的发展涉及多种遗传改变。病例8显示了从尖锐湿疣到侵袭性鳞状细胞癌的逐步进展,其中在58岁的鳞状细胞癌和55岁的尖锐湿疣中检测到pTERT和NOTCH1的致病突变,但在44岁的尖锐湿疣中未检测到。我们的研究首次报道了宫颈和外阴hpv6 /11相关SCCs的分子景观。我们提供的证据表明,与低风险HPV相关的SCCs是不同的实体,不同于与高危HPV相关的SCCs,更接近于与HPV无关的肿瘤。鉴于宫颈和外阴的低风险hpv相关SCCs表现出独特的形态学和分子特征,它们应该在现有的分类系统中单独描述或归类为一个独特的新实体。
{"title":"Comparative Analysis Reveals Recurrent Molecular Alterations in Low-Risk Human Papillomavirus 6 and Human Papillomavirus 11-Associated Squamous Cell Carcinoma of the Uterine Cervix and Vulva","authors":"Ying Sun ,&nbsp;Colton Smith ,&nbsp;Jason Murray ,&nbsp;Jing Zhu ,&nbsp;Aparna Pallavajjala ,&nbsp;Sichen Liang ,&nbsp;Melanie Klausner ,&nbsp;Ya-Chea Tsai ,&nbsp;Chien-Fu Hung ,&nbsp;Tzyy-Choou Wu ,&nbsp;Ying S. Zou ,&nbsp;Deyin Xing","doi":"10.1016/j.modpat.2025.100909","DOIUrl":"10.1016/j.modpat.2025.100909","url":null,"abstract":"<div><div>Although the association between human papillomavirus (HPV) 6 and HPV11 and squamous cell carcinomas (SCCs) has been well documented, the molecular alterations and mechanisms by which these low-risk HPVs contribute to carcinogenesis remain largely unknown. In this study, we comparatively elucidated the molecular landscape of HPV6/11-associated condylomas (9 cases) and SCCs (8 cases) of the uterine cervix and vulva. Sixteen of 17 cases were successfully analyzed using deep next-generation sequencing. Recurrent molecular alterations in the SCCs included mutations in the <em>TERT</em> promoter (<em>pTERT</em>, 71%), <em>NOTCH1</em> (57%), <em>NFE2L2</em> (57%), <em>NOTCH3</em> (29%), and <em>CDKN2A</em> (29%). Mutations in <em>NOTCH1</em> and <em>NFE2L2</em> tended to be mutually exclusive. Less common somatic mutations were each detected in the following genes: <em>AR</em>, <em>ARID1A</em>, <em>ASXL1</em>, <em>BCORL1</em>, <em>DAZAP1</em>, <em>FNDC1</em>, <em>HRAS, KMT2B</em>, <em>NOTCH2</em>, <em>NRAS</em>, <em>PIK3R1</em>, and <em>TP53</em>. Etiologically similar to the SCCs, the vast majority of vulvar and cervical condylomas (7/9, 78%) were infected with HPV6 rather than HPV11. Unlike the SCCs, condylomas rarely harbored recurrent pathogenic somatic mutations. <em>NOTCH1</em> and <em>NOTCH2</em> were the only mutant genes detected in both SCCs and condylomas in this series, suggesting a critical role for the NOTCH pathway in the initiation and maintenance of HPV6/11-related early squamous lesions. Although pathogenic mutations in <em>NOTCH1</em>, <em>NOTCH2</em>, <em>ERBB3</em>, <em>ATRX</em>, <em>FGFR2</em>, <em>EPHA5</em>, <em>CARD11, STAG2,</em> and <em>TSC2</em> were detected in condylomas, none were recurrent, indicating diverse genetic alterations involved in the development of these lesions. Case 8 illustrated a stepwise progression from condyloma to invasive SCC, in which pathogenic mutations in <em>pTERT</em> and <em>NOTCH1</em> were detected in the SCC (age 58) and the condyloma at age 55, but not in the condyloma at age 44. Our study presents the first report on the molecular landscape of HPV6/11-associated SCCs of the uterine cervix and vulva. We provide evidence that SCCs associated with low-risk HPV are distinct entities, differing from those related to high-risk HPV and more closely resembling HPV-independent neoplasms. Given that low-risk HPV-associated SCCs of the cervix and vulva exhibit unique morphological and molecular features, they should either be described separately within existing classification systems or classified as a distinct new entity.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 12","pages":"Article 100909"},"PeriodicalIF":5.5,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Deep Learning–Based Segmentation of Lung Adenocarcinoma Whole-Slide Images for Objective Grading, Tumor Spread Through Air Spaces Identification, and Mutation Prediction 基于深度学习的肺腺癌切片图像分割,用于客观分级、STAS识别和突变预测。
IF 5.5 1区 医学 Q1 PATHOLOGY Pub Date : 2025-10-10 DOI: 10.1016/j.modpat.2025.100907
David Joon Ho , Jason C. Chang , Rania G. Aly , Hai Cao Truong Nguyen , Prasad S. Adusumilli , Thomas J. Fuchs , William D. Travis , Chad M. Vanderbilt
Manual quantification of morphologic patterns in lung adenocarcinoma is subject to reproducibility issues due to interpathologist variability. In this study, we developed a deep learning–based multiclass segmentation model providing a modality for objective and quantitative grading of digitized lung adenocarcinoma images from resected specimens. Additionally, the model can detect tumor spread through air spaces and show enrichment of specific morphologic patterns in tumors with different genomic alterations. The study was based on 766 resected nonmucinous lung adenocarcinomas. Deep Multi-Magnification Network was trained to segment 14 tissue subtypes based on annotations of 108 internal whole-slide images at pixel level by thoracic pathologists (J.C.C. and W.D.T.). The trained model was validated on an external cohort of 130 cases for determining predominant patterns and on the remaining 528 internal cases for the 3 clinical tasks. The model graded nonmucinous lung adenocarcinomas based on the International Association for the Study of Lung Cancer Pathology Committee recommendation and successfully stratified patients into well, moderately, and poorly differentiated morphologies (P < 1 × 10−4). Pixels categorized as spread through air spaces significantly correlated with pathologists’ interpretations. For molecular analysis, solid pattern was enriched with TP53 mutations and depleted of EGFR kinase domain mutations. Lepidic pattern was inversely associated with TP53 mutations. Acinar was enriched with EGFR mutations, whereas papillary was associated with RET fusions. Our study demonstrated that deep learning–based segmentation can accurately quantify histologic patterns in lung adenocarcinoma and identify additional prognostic features. By simultaneously providing an objective assessment of various tasks, our comprehensive methodology in lung adenocarcinoma paves way for deep learning–assisted pathologic diagnosis and treatment guidance.
由于病理间的可变性,肺腺癌形态学模式的人工定量受到可重复性问题的影响。在这项研究中,我们开发了一种基于深度学习的多类分割模型,为从切除标本中提取的数字化肺腺癌图像提供了一种客观定量分级的模式。此外,该模型可以检测肿瘤通过空气空间(STAS)扩散,并显示不同基因组改变的肿瘤中特定形态模式的富集。该研究基于766例切除的非粘液肺腺癌。基于胸部病理学家对108张内部整张切片图像的像素级注释,训练深度多重放大网络对14个组织亚型进行分割。经过训练的模型在130例外部队列中进行验证,以确定主要模式,并在其余528例内部病例中进行验证,以完成三个临床任务。该模型根据国际肺癌病理研究协会的建议对非粘液肺腺癌进行分级,并成功地将患者分为良好、中度和低分化形态(p-4)。归类为STAS的像素与病理学家的解释显著相关。对于分子分析,固体模式富含TP53突变和EGFR激酶结构域突变。Lepidic模式与TP53突变呈负相关。腺泡富含EGFR突变,而乳头状细胞则与RET融合有关。我们的研究表明,基于深度学习的分割可以准确地量化肺腺癌的组织学模式,并确定其他预后特征。通过同时提供各种任务的客观评估,我们的肺腺癌综合方法为深度学习辅助病理诊断和治疗指导铺平了道路。
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引用次数: 0
Clinicopathologic and Molecular Genetic Features of Spindle Cell Rhabdomyosarcoma Harboring ZFP64::NCOA2/3 Fusions: A Series of 14 Cases 含有ZFP64::NCOA2/3融合体的梭形细胞横纹肌肉瘤14例临床病理及分子遗传学特征
IF 5.5 1区 医学 Q1 PATHOLOGY Pub Date : 2025-10-10 DOI: 10.1016/j.modpat.2025.100906
Carina A. Dehner , Baptiste Ameline , Fernanda Amary , John M. Gross , Ying Zou , Michael Michal , Zdenek Kinkor , Jorge Torres-Mora , Faizan Malik , Erica Y. Kao , Robert W. Ricciotti , Nasir Ud Din , Ivy John , Brendan C. Dickson , Elizabeth G. Demicco , Abbas Agaimy , Konstantinos Linos , Meera R. Hameed , Andrew L. Folpe , Daniel Baumhoer
Spindle cell rhabdomyosarcomas (SCRMS), recognized by the 2020 World Health Organization Classification of Tumors of Soft Tissue and Bone as a distinct entity, comprise a family of malignant skeletal muscle tumors sharing spindle cell morphology. To date, members of this family include (1) MyoD1-mutated SCRMS/sclerosing rhabdomyosarcomas (RMS), (2) intraosseous SCRMS with FET::TFCP2 or MEIS1::NCOA2 fusions, and (3) infantile/congenital SCRMS harboring NCOA1/2 or VGLL3 rearrangements. A rare, emerging subtype of SCRMS has been reported to harbor recurrent ZFP64::NCOA3 fusions. We studied 14 cases of this rare SCRMS subtype. The tumors presented in 11 men and 3 women (median age, 39.5 years; range, 22-69 years) and involved the thigh (4), lower leg (2), gluteal soft tissues (2), abdominal wall (1), mediastinum (1), subperiosteal surface of third rib (1), glottis (1), prostate (1), and pelvis (1). Morphologically, 11 tumors showed uniform spindle cell morphology with a fascicular architecture, whereas the remaining 3 tumors demonstrated focal or predominant round cell morphology. Extensive chondro-osseous differentiation was seen in 2 cases. By immunohistochemistry, tumors were variably positive for both desmin and MyoD1 (6 tumors), desmin, MyoD1, and myogenin (1 tumor), desmin alone (3 tumors of which only 1 was also tested for MyoD1), or MyoD1 alone (3 tumors). Smooth muscle actin was noted in 6 of 10 tested cases, and 2 of 5 tested cases showed ALK expression. A ZFP64::NCOA3 fusion was detected in 8 tumors, and a ZFP64::NCOA2 fusion was detected in 6 tumors. Methylation studies showed all but 1 tested tumor to form a tight cluster, clearly separate from other RMS subtypes and non-RMS morphologic mimics. Clinical follow-up (10/14 cases; median, 35 months; range, 3-108 months) demonstrated local recurrence in 2 patients and distant metastases in 5 patients (median, 12 months; range, at presentation - 106 months). At the time of last follow-up, 5 patients were alive without evidence of disease, 3 patients were alive with disease, and 2 patients died of disease at 34 and 108 months. We conclude that SCRMS with ZFP64::NCOA2/3 fusions represents a distinct, clinically aggressive sarcoma characterized by fascicular and sometimes round cell morphology, occasional chondro-osseous differentiation, and variable skeletal muscle marker expression. Recognition of this emerging subtype of SCRMS may have prognostic and therapeutic implications.
纺锤形细胞横纹肌肉瘤(SCRMS)被2020年世界卫生组织软组织和骨骼肿瘤分类认定为一个独特的实体,由一个具有纺锤形细胞形态的恶性骨骼肌肿瘤家族组成。迄今为止,该家族的成员包括1)myod1突变的纺锤体细胞/硬化性RMS (SCRMS/SRMS), 2)伴有FET::TFCP2或MEIS1::NCOA2融合的骨内SCRMS,以及3)含有NCOA1/2或VGLL3重排的婴儿先天性SCRMS。据报道,一种罕见的新兴SCRMS亚型存在复发性ZFP64::NCOA3融合。我们研究了14例这种罕见的SCRMS亚型。11例男性和3例女性(年龄中位数:39.5岁,范围:22-69岁)出现肿瘤,累及大腿(4例)、小腿(2例)、臀软组织(2例)、腹壁(1例)、纵隔(1例)、第三肋骨膜下表面(1例)、声门(1例)、前列腺(1例)和骨盆(1例)。形态学上,11例肿瘤表现为均匀的梭形细胞形态和束状结构,其余3例肿瘤表现为局灶性或主要的圆形细胞形态。2例可见广泛的软骨骨分化。通过免疫组化,肿瘤中desmin和MyoD1(6个肿瘤)、desmin、MyoD1和myogenin(1个肿瘤)、desmin单独(3个肿瘤中只有1个也检测了MyoD1)或MyoD1单独(3个肿瘤)均呈阳性。10例中有6例检测到平滑肌肌动蛋白,5例中有2例检测到ALK表达。ZFP64::NCOA3融合8例,ZFP64::NCOA2融合6例。甲基化研究表明,除了一个被测试的肿瘤外,所有的肿瘤都形成了一个紧密的簇,与其他RMS亚型和非RMS形态模拟明显分开。临床随访(14例中的10例,中位35个月,范围3-108个月)显示2例局部复发,5例远处转移(中位12个月,范围:发病时- 106个月)。末次随访时,5例患者无疾病证据存活,3例患者有疾病存活,2例患者于34个月和108个月死于疾病。我们得出结论,具有ZFP64::NCOA2/3融合的SCRMS代表了一种独特的临床侵袭性肉瘤,其特征是束状细胞形态,有时是圆形细胞形态,偶尔出现软骨骨分化和骨骼肌标志物表达变化。认识到这种新出现的scms亚型可能具有预后和治疗意义。
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引用次数: 0
Head-to-Head Comparison of 2 Artificial Intelligence Tools for Detecting Lymph Node Metastases in Whole-Slide Pathology Images Within and Beyond Their Intended Use 两种人工智能工具在其预期使用范围内和超出其预期用途的全切片病理图像中检测淋巴结转移的正面比较。
IF 5.5 1区 医学 Q1 PATHOLOGY Pub Date : 2025-10-08 DOI: 10.1016/j.modpat.2025.100905
Rachel N. Flach, Milan Samuels, Natalie D. ter Hoeve, Nikolas Stathonikos, Trudy G.N. Jonges, Jan E. Freund, Gerben E. Breimer, Willeke A.M. Blokx, Frans Schutgens, Tri Q. Nguyen, Paul J. van Diest, Carmen van Dooijeweert
The increasing diagnostic workload in pathology, driven by rising cancer incidences, highlights the need for scalable, cost effective solutions. Artificial intelligence (AI) has shown promise in supporting lymph node (LN) metastasis detection, a key prognostic factor in cancer staging. However, the current Conformité Européene In Vitro Diagnostics--certified AI tools are often limited to specific tumor types, reducing their cost efficiency and clinical use. This study evaluates the performance of 2 Conformité Européene In Vitro Diagnostics-certified AI tools—Visiopharm Metastasis Detection App (VMD) and DeepPath LYDIA (DPL)—for multipurpose LN metastasis detection across 6 tumor types, both within and beyond their intended use. We retrospectively analyzed whole-slide images from 455 patients with LN metastases from melanoma, colorectal, head and neck, lung, vulvar, and breast cancer. Both sentinel and nonsentinel LNs were included, with expert pathologists establishing the reference standard, according to clinical practice. Sensitivity was calculated per case and stratified based on metastasis size. False-positive alerts (FPAs) were assessed in 1012 tumor-negative slides. Both applications demonstrated excellent sensitivity for macrometastases across tumor types. DPL showed slightly higher sensitivity for micrometastases and isolated tumor cells compared with VMD, particularly in lung cancer and melanoma. FPA rates were substantial for both tools, with VMD generally producing more alerts, especially in lung and breast cancer. Our findings suggest that a single AI tool may be suitable for LN metastasis detection across multiple tumor types, even beyond its intended use. However, high FPA rates—particularly in lung cancer (inside intended use for DPL)—may limit practical use. Prospective studies are needed to confirm workflow efficiency gains and define optimal implementation strategies. These results support a broader, pragmatic approach to AI validation and regulatory approval, potentially improving the business case for AI adoption in pathology laboratories.
由于癌症发病率的上升,病理诊断工作量不断增加,这突出了对可扩展的、具有成本效益的解决方案的需求。人工智能(AI)在支持淋巴结(LN)转移检测方面显示出希望,这是癌症分期的关键预后因素。然而,目前CE-IVD认证的人工智能工具通常仅限于特定的肿瘤类型,降低了其成本效益和临床实用性。本研究评估了两种CE-IVD认证的人工智能工具——visiopharm Metastasis Detection App (VMD)和DeepPath LYDIA (DPL)——的性能,用于检测六种肿瘤类型的多用途LN转移,无论是在其预期用途内还是超出其预期用途。我们回顾性分析了455例黑色素瘤、结直肠癌、头颈癌、肺癌、外阴癌和乳腺癌淋巴结转移患者的整张幻灯片图像。包括前哨和非前哨淋巴结,由病理学专家根据临床实践建立参考标准。每个病例计算敏感性,并根据转移大小分层。在1012份肿瘤阴性的载玻片中评估假阳性警报(fpa)。这两种应用都显示出对不同肿瘤类型的大转移具有良好的敏感性。与VMD相比,DPL对微转移和分离肿瘤细胞(ITCs)的敏感性略高,特别是在肺癌和黑色素瘤中。两种工具的FPA率都很高,VMD通常产生更多的警报,特别是在肺癌和乳腺癌中。我们的研究结果表明,单一的人工智能工具可能适用于多种肿瘤类型的淋巴结转移检测,甚至超出了其预期用途。然而,高FPA率-特别是肺癌(DPL的预期使用范围内)-可能限制实际可用性。需要前瞻性研究来确认工作流效率的提高和确定最佳的实施策略。这些结果为人工智能验证和监管批准提供了更广泛、更务实的方法,有可能改善病理实验室采用人工智能的商业案例。
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Modern Pathology
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