Modern Pathology最新文献_第9页

An Integrated Clinical Genomic and Transcriptomic Subgrouping of Central Chondrosarcoma 中枢性软骨肉瘤的综合临床基因组和转录组亚组。

IF 5.5 1区医学 Q1 PATHOLOGY

Modern Pathology

Pub Date : 2025-12-01 Epub Date: 2025-09-19 DOI: 10.1016/j.modpat.2025.100894

Debora M. Meijer , Sanne Venneker , Baptiste Ameline , Zeynep Erdem , Sara Cardoso , Dina Ruano , Inge H. Briaire-de Bruijn , Brendy E. van den Akker , Pauline M. Wijers-Koster , Claire H.J. Scholte , Veroniek M. van Praag , Michiel A.J. van de Sande , Marieke L. Kuijjer , Daniel Baumhoer , Noel F.C.C. de Miranda , Judith V.M.G. Bovée

Central conventional chondrosarcoma, a malignant cartilage-producing bone tumor, is the second most common bone sarcoma. Chondrosarcomas are histologically graded, which is so far the best predictor of survival. Early mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 genes are frequent, leading to the production of the oncometabolite D-2-hydroxyglutarate, which affects DNA methylation, resulting in a preferred chondrogenic differentiation over osteogenic differentiation of mesenchymal stem cells, which are currently considered the precursor cells of chondrosarcoma. DNA methylation profiling has previously revealed distinct profiles between IDH-mutant and IDH–wild-type chondrosarcomas, but the presence of further DNA methylation subgroups indicates that classification based solely on IDH status is too simplistic. In this study, we aim to identify biological subgroups in a total of 116 chondrosarcomas by integrating clinical data, IDH mutation status, gene expression, and genome-wide loss of heterozygosity (LOH). Clinical associations were observed between several factors, including sex and histological grade, as well as tumor site and IDH mutation status. RNA sequencing and genome-wide LOH confirmed the distinction between IDH–wild-type and IDH-mutant chondrosarcomas, where the number of chromosome arms affected by LOH was significantly higher in IDH–wild-type tumors than in IDH-mutant tumors. However, no clear subgroups emerged within each IDH group. Further clustering on RNA expression of differentiation markers identified subgroups characterized by chondrogenic, osteogenic, resting chondrocyte, or dedifferentiated profiles. These different subgroups showed a specific clinical presentation and suggest different precursor cells. Instead of a simple dichotomy between IDH-mutant and IDH–wild-type, our integrated approach highlights interconnected clinical, genomic, and transcriptomic patterns that offer a more nuanced view of chondrosarcoma biology and might potentially guide treatment stratification.

中央常规软骨肉瘤是一种产生软骨的恶性骨肿瘤，是第二常见的骨肉瘤。软骨肉瘤在组织学上是分级的，这是迄今为止最好的生存率预测指标。异柠檬酸脱氢酶(IDH)-1和-2基因的早期突变是常见的，导致肿瘤代谢物d -2-羟基戊二酸的产生，从而影响DNA甲基化，导致间充质干细胞的软骨分化优先于成骨分化，而间充质干细胞目前被认为是软骨肉瘤的前体细胞。DNA甲基化分析先前揭示了IDH突变型和野生型软骨肉瘤之间的不同特征，但进一步的DNA甲基化亚群的存在表明，仅基于IDH状态的分类过于简单。在这项研究中，我们的目标是通过整合临床数据、IDH突变状态、基因表达和基因组广泛杂合性损失（gwLOH）来鉴定总共116例软骨肉瘤的生物学亚群。临床观察到几个因素之间的关联，包括性别和组织学分级，以及肿瘤部位和IDH突变状态。RNAseq和gwLOH证实了IDH野生型和IDH突变型软骨肉瘤的区别，其中IDH野生型肿瘤中受LOH影响的染色体臂数明显高于IDH突变型肿瘤。然而，在每个IDH组中没有出现明确的亚群。分化标记物的RNA表达进一步聚类，确定了以成软骨、成骨、静息软骨细胞或去分化谱为特征的亚群。这些不同的亚群表现出特定的临床表现，表明不同的前体细胞。与IDH突变型和IDH野生型之间的简单二分法不同，我们的综合方法强调了相互关联的临床、基因组和转录组模式，这些模式提供了更细致的软骨肉瘤生物学观点，并可能潜在地指导治疗分层。

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引用次数: 0

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

Modern Pathology

Pub Date : 2025-12-01 Epub 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

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

Modern Pathology

Pub Date : 2025-12-01 Epub 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。

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引用次数: 0

Corrigendum to “Spatial Evaluation and Prognostic Significance of V-Domain Immunoglobulin Suppressor of T-Cell Activation (VISTA) in Human Resectable Cervical Carcinoma: Implications for Immune Activation and Suppression” [Modern Pathology 2025;38(12):100851] “t细胞活化的v域免疫球蛋白抑制因子（VISTA）在人类可切除宫颈癌中的空间评价和预后意义：免疫激活和抑制的含义”的更正[现代病理学2025；38(12):100851]。

IF 5.5 1区医学 Q1 PATHOLOGY

Modern Pathology

Pub Date : 2025-12-01 Epub Date: 2025-10-07 DOI: 10.1016/j.modpat.2025.100892

Qingsheng Xie , Jinqing Li , Jieyao Li , Chaoqun Liu , Yangyang Li , Hong Zeng , Jingwei Yu , Yingchen Wu , Kaiqian Chen , Zhaonan Zhang , Bo Wang

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

Modern Pathology

Pub Date : 2025-12-01 Epub 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

A Rational Approach to the Diagnosis of Liver Metastases 一种合理的肝转移诊断方法。

IF 5.5 1区医学 Q1 PATHOLOGY

Modern Pathology

Pub Date : 2025-12-01 Epub Date: 2025-10-02 DOI: 10.1016/j.modpat.2025.100903

Shaomin Hu, Daniela S. Allende

The diagnosis of liver metastases encompasses a broad spectrum of entities and relies on clinicopathological correlation, with some cases being diagnosable using hematoxylin and eosin staining alone. For more challenging cases, ancillary testing is often required, with a focus on maximizing diagnostic yield while preserving tissue. This review draws on years of experience at a high-volume, tertiary referral center and incorporates an in-depth analysis of the existing literature in the field. When evaluating a liver lesion, the first step is to determine whether it represents a primary hepatic tumor or a metastasis. This review discusses a practical panel of immunohistochemical stains valuable in making this distinction. Next, it outlines a morphologic pattern-based approach to metastatic liver tumors, categorized by epithelioid, spindle, undifferentiated, and small round blue cell morphology. For each category, readers will find a proposed list of differentials based on the morphologic pattern, a suggested screening immunohistochemical panel, a focused discussion of potential pitfalls and practical tips for ancillary testing (“important aspects of ancillary testing”), and additional insights on specific entities within each group (“special diagnostic considerations”). This review provides a comprehensive overview of the diagnosis of liver metastases, along with a current guide to immunohistochemical and molecular testing for the classification of these tumors. It underscores the importance of careful consideration and prioritizing site-agnostic biomarkers and tumor lineage classification (eg, carcinoma, sarcoma, lymphoma, or melanoma) when choosing ancillary stains in challenging cases with limited material.

肝转移的诊断包括广泛的实体，依赖于临床病理相关性，有些病例仅使用苏木精和伊红染色即可诊断。对于更具挑战性的病例，通常需要辅助检测，重点是在保留组织的同时最大限度地提高诊断率。这篇综述借鉴了多年来在一个高容量的三级转诊中心的经验，并结合了对该领域现有文献的深入分析。当评估肝脏病变时，第一步是确定它是否代表原发性肝脏肿瘤或转移。这篇综述讨论了一组实用的免疫组织化学染色，对进行这种区分很有价值。接下来，它概述了一种基于形态学模式的转移性肝肿瘤的方法，根据上皮样、纺锤形、未分化和小圆蓝色细胞形态进行分类。对于每个类别，读者将发现基于形态学模式的建议差异列表，建议筛选免疫组织化学小组，集中讨论潜在的陷阱和辅助测试的实用技巧（“辅助测试的重要方面”），以及对每组中特定实体的额外见解（“特殊诊断考虑”）。这篇综述提供了肝转移的诊断的一个全面的概述，以及当前的指南免疫组织化学和分子检测的分类这些肿瘤。它强调了在材料有限的挑战性病例中选择辅助染色时，仔细考虑和优先考虑与部位无关的生物标志物和肿瘤谱系分类（例如，癌、肉瘤、淋巴瘤或黑色素瘤）的重要性。

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引用次数: 0

Comparative Analysis of Somatic and Germline Polymerase Proofreading Deficiencies in Cancer: Molecular and Clinical Implications 肿瘤中体细胞和种系聚合酶校对缺陷的比较分析：分子和临床意义。

IF 5.5 1区医学 Q1 PATHOLOGY

Modern Pathology

Pub Date : 2025-12-01 Epub Date: 2025-07-16 DOI: 10.1016/j.modpat.2025.100843

Julen Viana-Errasti , Raúl Marín , Sandra García-Mulero , Tirso Pons , Mariona Terradas , Gabriel Capellá , Victor Moreno , Pilar Mur , Laura Valle

Polymerases ε and δ maintain genome integrity through exonuclease proofreading. Germline and somatic pathogenic variants (PVs) in the exonuclease domain (ED) of POLE and POLD1 impair proofreading, causing hypermutated tumors. Despite shared mutational features that make these tumors highly immunogenic, molecular and clinical distinctions between POLE and POLD1 mutations and between somatic and germline variants remain incompletely understood. We compared the molecular and clinical characteristics of POLE and POLD1 ED PVs (n = 31), assessing their location, pathogenicity, clinical phenotypes, mismatch repair (MMR) status, tumor mutational burden, and signatures. We analyzed 360 proofreading-deficient tumors (source: The Cancer Genome Atlas [TCGA] and Catalogue Of Somatic Mutations In Cancer [COSMIC]) and 70 families (249 individuals) with polymerase proofreading-associated polyposis. All germline and somatic PVs had high AlphaMissense scores (0.87-1) and clustered within or near Exo motifs. Recurrent, nonfounder germline PVs, POLE L424V and POLD1 S478N, showed low/modest REVEL scores. Somatic variants occurred mainly in endometrial cancers (75% of proofreading-deficient TCGA cancers), whereas colorectal cancer predominated in polymerase proofreading-associated polyposis (56% of carriers). Cancer risks and tumor spectra differed between POLE and POLD1 PV carriers. Aggressive hereditary phenotypes were linked to either specific POLE PVs (eg, S297F, V411L, P436R, M444K, A456P, and S461T) or the co-occurrence of germline ED PVs with germline MMR gene PVs. Distinct hypermutator profiles were confirmed for polymerase ε and polymerase δ proofreading deficiencies via unique mutational signatures (Polymerase ε: SBS10a/b, SBS28; Polymerase δ: SBS10c/d). Tumors with combined proofreading and MMR deficiencies had significantly higher tumor mutational burden and a shift in the associated mutational spectra. Unlike POLE, POLD1 ED PVs exhibited haplosufficiency, typically requiring a somatic second hit (eg, loss of heterozygosity) or MMR deficiency to drive hypermutation. In conclusion, differences between POLE and POLD1 and between somatic and germline mutations influence clinical presentation, mutagenic potential, and reliance on cooperating defects in tumorigenesis. These insights advance the understanding of proofreading-deficient cancers, with implications for diagnostics, genetic counseling, and precision oncology.

聚合酶ε和δ通过核酸外切酶校对维持基因组完整性。POLE和POLD1的外切酶结构域（ED）中的种系和体细胞致病变异（pv）损害了校对，导致肿瘤的超突变。尽管共同的突变特征使这些肿瘤具有高度的免疫原性，但POLE和POLD1突变之间以及体细胞和种系变异之间的分子和临床区别仍然不完全清楚。我们比较了pol和POLD1 ED pv （n=31）的分子和临床特征，评估了它们的定位、致病性、临床表型、错配修复（MMR）状态、肿瘤突变负担（TMB）和特征。我们分析了360例校对缺陷肿瘤（TCGA/COSMIC）和70个家族（249个个体）的聚合酶校对相关息肉病（PPAP）。所有种系和体细胞pv都具有较高的AlphaMissense得分（0.87-1），并且聚集在Exo基序内或附近。复发性非始祖生殖系pv， POLD1 L424V和POLD1 S478N显示低/中等水平的REVEL得分。体细胞变异主要发生在子宫内膜癌（75%的校对缺陷TCGA癌症），而结直肠癌主要发生在PPAP（56%的携带者）中。pol和POLD1 PV携带者之间的肿瘤风险和肿瘤谱存在差异。侵略性遗传表型与特定的POLE pv（例如，S297F, V411L, P436R, M444K, A456P, S4611T）或种系ED pv与种系MMR基因pv共同出现有关。通过独特的突变特征，证实了聚合酶ε和聚合酶δ校对缺陷的不同超突变子谱(聚合酶ε: SBS10a/b， SBS28；聚合酶δ: SBS10c/d)。合并校对和MMR缺陷的肿瘤有明显更高的TMB和相关突变谱的转移。与POLE不同，POLD1 ED pv表现出单倍性，通常需要体细胞二次命中（例如，杂合性的丧失）或MMR缺陷来驱动超突变。总之，POLE和POLD1之间的差异，以及体细胞和种系突变之间的差异，影响了临床表现、致突变潜力以及肿瘤发生中对合作缺陷的依赖。这些见解促进了对校对缺陷癌症的理解，对诊断、遗传咨询和精确肿瘤学具有指导意义。

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引用次数: 0

GLI1-Altered Tumors of the Ovary: A Report of 4 Cases of an Underrecognized Neoplasm That May Mimic Sex Cord–Stromal Tumors 卵巢gli1改变肿瘤——四例未被充分认识的可能类似性索间质肿瘤的肿瘤报告。

IF 5.5 1区医学 Q1 PATHOLOGY

Modern Pathology

Pub Date : 2025-12-01 Epub Date: 2025-07-16 DOI: 10.1016/j.modpat.2025.100848

Kyle M. Devins, Adam S. Fisch, Robert H. Young, Dora Dias-Santagata, Esther Oliva

GLI1 (glioma-associated oncogene homologue 1) altered neoplasms are an emerging group of tumors of presumed mesenchymal derivation, which occur mostly in the head and neck or soft tissues of the trunk and extremities. We have recently identified 4 ovarian neoplasms with GLI1 gene fusions; all were initially diagnosed as unusual sex cord–stromal tumors (n = 3) or endometrioid adenocarcinoma with sex cord-like morphology (n = 1). Patients’ age ranged from 11 to 70 years and tumor size from 3 to 15 cm; all were confined to the ovary. Three tumors displayed dominant patterns of large irregular aggregates and smaller well-delineated nests of round cells with minimal to moderate amounts of clear to eosinophilic cytoplasm and monotonous round to ovoid nuclei divided by collagenous septae and focal myxoid areas. The final tumor showed alternating hypocellular and cellular areas composed of a loose, haphazard arrangement of spindled cells associated with myxoid stroma, imparting a “lace-like” reticular appearance, with only focal nested round cell morphology (20%). Additional minor patterns included tubules (n = 3), trabeculae (n = 2), follicle-like macrocysts (n = 2), cords (n = 1), microcysts (n = 1), and rosette-like formations (n = 1). Mitotic activity was minimal (<1 to 2/10 high-power fields). All tumors had a network of numerous capillary-sized vessels. Two tumors had some positivity for markers of sex cord–stromal differentiation, with focal, strong calretinin expression in one and diffuse, weak SF1 in another. RNA-based next-generation sequencing revealed PTCH1::GLI1 fusions in all 3 tumors with round cells and an ACTB::GLI1 fusion in the predominantly spindled tumor. Our experience with these tumors, particularly the discovery of 3 of the cases in a relatively short time frame, suggests that they are underrecognized in the ovary, where their morphologic features often mimic those of sex cord–stromal neoplasms. Awareness of their morphologic features and appropriate use of genetic testing will ensure accurate diagnosis and lead to a greater understanding of these rare neoplasms.

gli1改变肿瘤是一种新兴的间质来源肿瘤，主要发生在头颈部或躯干和四肢的软组织。我们最近发现了四例GLI1基因融合的卵巢肿瘤；所有患者最初均被诊断为异常性索间质瘤（n=3）或子宫内膜样腺癌（n=1）。患者年龄11-70岁，肿瘤3-15厘米；所有病例均局限于卵巢。其中三种表现为大的不规则聚集体和较小的圆形细胞巢，有少量到适量的透明到嗜酸性细胞质和单调的圆形到卵形细胞核，由胶原隔和局灶黏液区分隔。最终肿瘤显示细胞下区和细胞区交替，由松散、随意排列的纺锤状细胞与黏液样间质组成，呈“蕾丝样”网状外观，仅有局灶嵌套圆形细胞形态（20%）。其他次要类型包括小管（n=3）、小梁（n=2）、卵泡样大囊肿（n=2）、索状囊肿（n=1）、微囊肿（n=1）和莲座样形成（n=1）。有丝分裂活性极低(

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引用次数: 0

Apolipoprotein E Immunostaining Has Diagnostic Utility in Differentiating Dense Deposit Disease and C3 Glomerulonephritis: Clone-Based Evaluation of D719N, EP1373Y, and 1B2C9 ApoE免疫染色在鉴别致密沉积病和C3肾小球肾炎方面具有诊断价值：D719N、EP1373Y和1B2C9的克隆评价

IF 5.5 1区医学 Q1 PATHOLOGY

Modern Pathology

Pub Date : 2025-12-01 Epub Date: 2025-08-25 DOI: 10.1016/j.modpat.2025.100874

Ozge Hurdogan , Safak Mirioglu , Ahmet Burak Dirim , Muge Doksan , Zeynep Nagehan Yuruk Yildirim , Aydin Turkmen , Isin Kilicaslan , Yasemin Ozluk

Electron microscopy (EM) has been essential for the diagnosis of dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). Recent research showed significantly higher accumulation of apolipoprotein E (ApoE) in DDD compared with C3GN and tested the use of ApoE immunohistochemistry for DDD diagnosis. We aimed to investigate the diagnostic value of ApoE in DDD and C3GN using 3 distinct ApoE clones—D719N, EP1373Y, and 1B2C9. Kidney biopsies of 26 DDD and 18 C3GN, diagnosed based on EM findings, were subjected to immunohistochemical analyses using ApoE clones D719N, EP1373Y, and 1B2C9. Kidney biopsies of 8 immune complex-mediated membranoproliferative glomerulonephritis, 13 acute postinfectious glomerulonephritis, 13 focal segmental glomerulosclerosis, 6 minimal change disease, 13 membranous nephropathy, 11 lupus nephritis, and 9 fibrillary glomerulonephritis constituted the control group. The staining pattern, intensity, and distribution were evaluated in each renal compartment. Linear/predominantly linear staining of score 2 to 3 intensity in a diffuse/global distribution was interpreted as diagnostic for DDD. DDD and C3GN cases were reclassified using each clone individually. D719N confirmed the diagnosis of DDD in 76.9% of the cases, whereas EP1373Y and 1B2C9 in 84.6%. All 3 clones confirmed C3GN diagnosis in 94.4% of the cases. EP1373Y and 1B2C9 demonstrated superior sensitivity (85% vs 77%) and overall diagnostic accuracy compared with D719N (89% vs 85%). Clone 1B2C9 showed significantly more intense background staining compared with D719N and EP1373Y in all cases (P < .001). No cases in the control group showed false-positive staining, except for 66.7% of fibrillary glomerulonephritis. Notably, 2 among 6 D719N-negative DDDs were transplant biopsies, and 2 belonged to the same patient with Barraquer-Simons syndrome. All 3 ApoE clones, D719N, EP1373Y, and 1B2C9, can be used for routine diagnosis in the absence of EM or as an adjunct to EM to increase diagnostic accuracy in differentiating DDD and C3GN.

电子显微镜（EM）已成为诊断致密沉积病（DDD）和C3肾小球肾炎（C3GN）的必要手段。最近的研究表明，与C3GN相比，DDD中载脂蛋白E （ApoE）的积累明显更高，并测试了ApoE免疫组织化学用于DDD诊断的应用。我们的目的是研究ApoE在DDD和C3GN中的诊断价值，使用三个不同的ApoE克隆，D719N， EP1373Y和1B2C9。对26例DDD和18例C3GN进行肾脏活检，根据EM结果诊断，使用ApoE克隆D719N、EP1373Y和1B2C9进行免疫组织化学分析。对照组为免疫复合物介导的膜增生性肾小球肾炎8例、急性感染后肾小球肾炎13例、局灶节段性肾小球硬化13例、微小病变6例、膜性肾病13例、狼疮性肾炎11例、纤原性肾小球肾炎9例。评估各肾间室的染色模式、强度和分布。在弥漫性/全局分布中2-3分强度的线性/主要线性染色被解释为DDD的诊断。DDD和C3GN病例分别使用每个克隆重新分类。D719N诊断为DDD的比例为76.9%，而EP1373Y和1B2C9诊断为84.6%。3个克隆均确诊为C3GN，确诊率为94.4%。与D719N相比，EP1373Y和1B2C9表现出更高的灵敏度（85%对77%）和总体诊断准确性（89%对85%）。与D719N和EP1373Y相比，克隆1B2C9在所有病例中均显示出更强的背景染色(p

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引用次数: 0

Artificial Intelligence (AI)-Driven Screening of Equivocal Prostate Immunohistochemistry (IHC) Cases: Development and Validation of a Screening and Cancer Detection Framework 人工智能对模棱两可的前列腺IHC病例的筛查：筛查和癌症检测框架的开发和验证。

IF 5.5 1区医学 Q1 PATHOLOGY

Modern Pathology

Pub Date : 2025-12-01 Epub Date: 2025-10-01 DOI: 10.1016/j.modpat.2025.100904

Ramin Nateghi , Ruoji Zhou , Madeline Saft , Marina Schnauss , Clayton Neill , Ridwan Alam , Nicole Handa , Mitchell Huang , Eric V. Li , Jeffery A. Goldstein , Hiten D. Patel , Edward M. Schaeffer , Menatalla Nadim , Fattaneh Pourakpour , Bogdan Isaila , Christopher Felicelli , Vikas Mehta , Behtash G. Nezami , Ashley E. Ross , Ximing J. Yang , Lee A.D. Cooper

Artificial intelligence (AI) has been proposed as a solution to meet increasing demand for the diagnostic services of pathologists (B.I., C.F., V.M., B.G.N., X.J.Y.). Prostate biopsies are a significant source of this demand, and a substantial fraction of these biopsies require immunohistochemistry (IHC) staining, which adds work, time, and cost to the diagnostic process. Equivocal cases, which often prompt the use of IHC, not only present the greatest challenge to AI cancer detection tools but also represent the area where properly trained systems could offer the most clinical value by reducing the need for ancillary testing for cancer confirmation. From August 2021 to April 2023, we scanned 25,570 slides from 1641 patients. We investigated the performance of institutionally developed models for prostate cancer detection using digital pathology images, with an aim for reducing work, turnaround time, and costs related to the ordering of IHC equivocal cases. We advanced complementary sensitive and specific models to screen these challenging cases, aiming to identify slides that could be confidently diagnosed without any ancillary IHC tests. Additionally, we compared the performance of a prostate-specific model to a general-purpose foundation model for screening and cancer detection. Our screening models correctly classified 55% of challenging equivocal blocks where IHC was ordered with a 1.4% error rate. We found that the foundation model achieved higher screening rates (ie, percentage of cases where IHC could be avoided), but this came at the cost of uniformly higher error rates and significantly greater computational demands. When trained as a standalone prostate cancer detection system, our model demonstrated high concordance with pathologist ground truth, achieving an area under the curve of 98.5%, sensitivity of 95.0%, and specificity of 97.8%. Computational models can aid in the diagnosis of prostate cancer and can effectively screen challenging prostate biopsy cases, reducing unnecessary IHC utilization and helping to optimize pathology workflows.

Plain language summary

Traditional pathologic diagnosis of prostate cancer can be labor intensive. Equivocal cases in particular often require special testing (immunohistochemistry [IHC]) to establish a diagnosis, which introduces further delay and cost. This study develops an artificial intelligence system specifically designed to screen equivocal cases and reduce the need for IHC. Our model serves as a second-read tool to help optimize pathology workflow and reduce turnaround time and costs by flagging cases where IHC can be safely avoided.

人工智能已被提出作为一种解决方案，以满足病理学家对诊断服务日益增长的需求。前列腺活检是这种需求的重要来源，这些活检的很大一部分需要免疫组织化学染色，这增加了诊断过程的工作量、时间和成本。模棱两可的病例往往促使使用免疫组织化学（IHC），这对人工智能癌症检测工具提出了最大的挑战，但也代表了经过适当训练的系统可以通过减少对癌症确认辅助测试的需求来提供最大临床价值的领域。从2021年8月到2023年4月，我们扫描了1641名患者的25,570张幻灯片。我们研究了使用数字病理图像的机构开发的前列腺癌检测模型的性能，目的是减少与免疫组织化学模糊病例排序相关的工作，周转时间和成本。我们提出了互补的敏感性和特异性模型来筛选这些具有挑战性的病例，旨在确定无需任何辅助免疫组织化学测试即可自信诊断的载玻片。此外，我们比较了前列腺特异性模型与用于筛查和癌症检测的通用基础模型的性能。我们的筛选模型正确分类了55%的具有挑战性的模糊块，其中免疫组织化学排序为1.4%的错误率。我们发现基础模型实现了更高的筛查率（即可以避免IHC的病例百分比），但这是以更高的错误率和更大的计算需求为代价的。当作为一个独立的前列腺癌检测系统进行训练时，我们的模型显示出与病理学家基础事实的高度一致性，曲线下面积为98.5%，灵敏度为95.0%，特异性为97.8%。计算模型可以帮助前列腺癌的诊断，并可以有效地筛选具有挑战性的前列腺活检病例，减少不必要的免疫组织结构利用，并有助于优化病理工作流程。

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引用次数: 0