Modern Pathology最新文献_第6页

Diagnostic Discordance and Error in Breast Pathology: Causes, Classifications, and Medicolegal Implications 乳腺病理诊断的不一致和错误：原因、分类和医学法律意义。

IF 5.5 1区医学 Q1 PATHOLOGY

Modern Pathology

Pub Date : 2026-01-01 Epub Date: 2025-11-22 DOI: 10.1016/j.modpat.2025.100942

Emad A. Rakha , Cecily M. Quinn , Elena Provenzano , Sarah E. Pinder , Ian O. Ellis

Diagnostic pathology is inherently interpretative and subject to interobserver variability. Although diagnostic concordance is a critical quality metric, distinguishing between acceptable variation, diagnostic error, and professional negligence is essential for both clinical care and medicolegal clarity. This review highlights the difference between interobserver variability (diagnostic disagreement/discordance) that remains within acceptable professional limits, diagnostic error (a deviation from expected standards due to cognitive, technical, or systemic factors), and negligence (a repeated, reckless, or unjustified deviation from established standards). Errors in pathology often reflect systemic vulnerabilities, such as workflow inefficiencies, inadequate quality control, or limited biopsy sampling, rather than individual performance alone. They may occur at any stage of the diagnostic pathway (preanalytical, analytical, or postanalytical) and arise from specimen misidentification, contamination or loss, inadequate sampling, or incomplete documentation. Pathologist-related errors encompass failure to recognize significant pathology, misinterpretation, omission of appropriate ancillary studies, insufficient workup of complex cases, including failure to seek a second opinion, or substandard reporting. Medicolegal implications are heightened when such errors result in delayed diagnosis or major misclassification, leading to patient harm. In breast pathology, interobserver variation in the classification of borderline lesions (eg, grading of phyllodes tumors) and in the interpretation of overlapping entities (eg, atypical apocrine lesions) is well recognized. Although such differences may influence management, they should be regarded as acceptable professional variability, rather than error or negligence. To minimize diagnostic risk and uphold standards, structured reporting, vigilance in complex cases, participation in quality assurance, explicit documentation of uncertainty, active multidisciplinary team engagement, and laboratory accreditation are strongly recommended. Supporting pathologists as diagnosticians and patient safety advocates, within a culture of openness, shared learning, and institutional support, remains central to diagnostic accuracy, transparency, and medicolegal defensibility.

诊断病理学本质上是解释性的，并受制于观察者之间的差异。虽然诊断一致性是一个关键的质量指标，区分可接受的变异、诊断错误和专业疏忽对于临床护理和医学法律清晰度都是至关重要的。本综述强调了在可接受的专业范围内的观察者间可变性（诊断分歧/不一致）、诊断错误（由于认知、技术或系统因素而偏离预期标准）和疏忽（重复、鲁莽或不合理地偏离既定标准）之间的区别。病理错误通常反映的是系统脆弱性，如工作流程效率低下、质量控制不足或活检样本有限，而不仅仅是个人表现。它们可能发生在诊断途径的任何阶段（分析前、分析后或分析后），由标本错误鉴定、污染或丢失、取样不充分或文件不完整引起。病理学相关的错误包括未能认识到重要的病理，误解，遗漏适当的辅助研究，对复杂病例的检查不足，包括未能寻求第二意见，或报告不合格。当此类错误导致延误诊断或严重错误分类，从而导致患者受到伤害时，医学法律影响就会加剧。在乳腺病理学中，在边缘病变的分类（如分叶状肿瘤的分级）和重叠实体（如非典型大汗腺病变）的解释中，观察者之间的差异是公认的。虽然这些差异可能影响管理，但它们应被视为可接受的专业变异性，而不是错误或疏忽。为了最大限度地降低诊断风险和维护标准，强烈建议进行结构化报告、对复杂病例保持警惕、参与质量保证、明确记录不确定性、积极的多学科团队参与和实验室认证。在开放、共享学习和机构支持的文化中，支持病理学家作为诊断医生和患者安全倡导者，仍然是诊断准确性、透明度和医学法律可辩护性的核心。

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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

Modern Pathology

Pub Date : 2026-01-01 Epub 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。

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引用次数: 0

Expanding the Molecular Characterization of Adenoid Ameloblastoma by Assessing a Panel of Oncogenes and Tumor Suppressor Genes 通过评估一组癌基因和肿瘤抑制基因，扩大腺样成釉细胞瘤的分子特征。

IF 5.5 1区医学 Q1 PATHOLOGY

Modern Pathology

Pub Date : 2026-01-01 Epub Date: 2025-10-16 DOI: 10.1016/j.modpat.2025.100920

Ygor G. Fonseca , Victor C. Bastos , Rennan G. Moreira , Felipe P. Fonseca , Pablo A. Vargas , John M. Wright , Renato S. Aguiar , Edward W. Odell , Ricardo S. Gomez , Letícia M. Guimarães , Carolina C. Gomes

Adenoid ameloblastoma (AA) is a rare epithelial odontogenic tumor microscopically characterized by ameloblastoma-like epithelium, duct-like structures, epithelial whorls, cribriform architecture, and dentinoid matrix. Wnt/β-catenin activation, usually by CTNNB1 mutations, is thought to characterize AA, which are BRAF and KRAS wild type. The present study aimed to expand the genetic characterization of AA by interrogating variants at several sites known to be linked to solid tumor pathogenesis. Six AA samples were sequenced at an unprecedented sequencing depth using a 22-gene panel including oncogenes and tumor suppressor genes commonly mutated in solid human tumors, namely AKT1, ALK, BRAF, CTNNB1, EGFR, ERBB2, ERBB3, ESR1, FOXL2, GNA11, GNAQ, IDH1, IDH2, KRAS, KIT, MET, NRAS, PDGFRA, PIK3CA, RAF1, RET, and TP53. Reinforcing the distinct molecular identity of AA, absence of BRAF p.Val600Glu and KRAS p.Gly12Val/Arg mutations was observed. CTNNB1 mutations were identified in 4 of 6 cases (67%), including previously reported variants (p.Ser33Cys and p.Gly34Arg) as well as novel ones (p.Leu31Leu and p.Gln68∗), supporting the involvement of the Wnt/β-catenin signaling pathway in AA pathogenesis. In 2 cases, CTNNB1 variants co-occurred with either TP53 or ERBB2 and PIK3CA variants, suggesting potential secondary oncogenic events. Notably, in 2 cases, no variants were detected. Our findings provide further evidence for AA classification as a separate tumor entity. The identification of previously reported CTNNB1 and novel genetic variants contributes to better characterization of the molecular profile of AA. Future studies are required to interrogate variants in other genes in wild-type cases.

腺样成釉细胞瘤（Adenoid ameloblastoma， AA）是一种罕见的上皮性牙源性肿瘤，其显微特征为成釉细胞瘤样上皮、管状结构、上皮螺旋、筛状结构和牙本质样基质。Wnt/β-连环蛋白激活通常由CTNNB1突变引起，被认为是AA的特征，即BRAF和KRAS野生型。本研究旨在通过询问与实体瘤发病机制相关的几个位点的变异来扩大AA的遗传特征。对6份AA样品进行了前所未有的测序深度，使用了22个基因面板，包括人类实体肿瘤中常见突变的致癌基因和肿瘤抑制基因，即AKT1、ALK、BRAF、CTNNB1、EGFR、ERBB2、ERBB3、ESR1、FOXL2、GNA11、GNAQ、IDH1、IDH2、KRAS、KIT、MET、NRAS、PDGFRA、PIK3CA、RAF1、RET和TP53。我们观察到BRAF p.Val600Glu和KRAS p.v al12val /Arg突变的缺失，从而增强了AA的分子特性。在4/6（67%）的病例中发现CTNNB1突变，包括先前报道的变异（p.Ser33Cys和p.Gly34Arg）以及新变异（p.Leu31Leu和p.Gln68*），支持Wnt/β-catenin信号通路参与AA发病机制。在2例中，CTNNB1变异体与TP53或ERBB2和PIK3CA变异体同时发生，提示潜在的继发性致癌事件。值得注意的是，有2例未检测到变异。我们的发现为AA分类作为一个单独的肿瘤实体提供了进一步的证据。先前报道的CTNNB1和新的遗传变异的鉴定有助于更好地表征AA的分子谱。未来的研究需要询问野生型病例中其他基因的变异。

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引用次数: 0

CD38 Expression and 6q/9q Codeletion: Diagnostic Markers for Primary Cutaneous Cribriform Tumor CD38表达和6q/9q编码：原发性皮肤筛网瘤的诊断标记

IF 5.5 1区医学 Q1 PATHOLOGY

Modern Pathology

Pub Date : 2026-01-01 Epub Date: 2025-11-25 DOI: 10.1016/j.modpat.2025.100927

Paul W. Harms

引用次数: 0

Expanding the Clinicopathologic Spectrum of EWSR1::SSX-Rearranged Sarcomas: Series of 11 Cases Including Osteosarcomas and a Novel EWSR1::SSX4 Fusion 扩大EWSR1:: ssx重排肉瘤的临床病理谱：11例包括骨肉瘤和一种新的EWSR1::SSX4融合

IF 5.5 1区医学 Q1 PATHOLOGY

Modern Pathology

Pub Date : 2026-01-01 Epub Date: 2025-10-24 DOI: 10.1016/j.modpat.2025.100922

John M. Gross , David I. Suster , Ying Zou , Douglas A. Mata , Fernanda Amary , Solange De Noon , Adrienne M. Flanagan , Kristina M. Wakeman , Sintawat Wangsiricharoen , Fei Dong , Suk Wai Lam , Judith V.M.G. Bovée , Aline Baltres , Daniel Pissaloux , Eric Pasmant , Frédérique Larousserie , Markku Miettinen , Meera Hameed , Gregory W. Charville

Gene rearrangements involving EWSR1 or SSX genes are known to play a role in sarcomagenesis; however, sarcomas harboring EWSR1::SSX fusions are rare. To better understand tumors associated with this distinctive genetic event, we studied 11 additional EWSR1::SSX sarcomas, affecting 10 women and 1 man with an average age of 46 years (range, 22-72 years). Eight tumors arose in the bone (rib, femur, pelvis, or vertebra with multifocal bone involvement at presentation in 3 cases); 2 tumors arose in soft tissue (deep thigh or groin); and 1 patient presented with a visceral (lung) mass. The tumors were bulky, averaging 12.1 cm (range, 4-20 cm). Histologically, in keeping with a translocation-driven sarcoma, all tumors were cytologically monotonous. Seven tumors were osteosarcomas, 6 of which were classified as sclerosing osteosarcomas with extensive bone matrix production. Three tumors were composed of uniform fascicles of spindle cells, punctuated in 2 cases by a biphasic glandular or nested epithelioid component, reminiscent of synovial sarcoma. One tumor was an undifferentiated sarcoma with round to spindle cell cytomorphology and focal osteogenic differentiation. By immunohistochemistry, 5 of 5 cases tested were positive for SSX C-terminus; 1 of 5 showed patchy weak staining with SS18::SSX fusion-specific antibody. All tested tumors were positive for CD99 (4/4) and TLE1 (3/3). Next-generation sequencing identified EWSR1::SSX fusions in all cases, involving SSX1 (n = 7), SSX2 (n = 2), and SSX3 (n = 1), along with a novel EWSR1::SSX4 fusion. Follow-up was available for 9 patients; 5 patients died of disease 1.5 to 14 years (average, 6 years) after diagnosis, 2 patients were alive with metastatic disease, 1 patient was alive without disease at 25 months, and 1 patient presented recently. Sarcomas with EWSR1::SSX fusions are rare and clinically aggressive; the histologic patterns in this series and in prior reports are heterogeneous, consisting of essentially 3 phenotypes: (1) primitive round or epithelioid cells, (2) osteoblasts that produce bone, or (3) uniform small spindle cells arranged in tight fascicles, sometimes with a biphasic epithelioid component, as seen in synovial sarcoma. By studying 11 additional examples of these rare sarcomas, we provide an expanded view of their clinicopathologic and molecular genetic spectrum.

已知涉及EWSR1或SSX基因的基因重排在肉瘤形成中起作用；然而，含有EWSR1::SSX融合的肉瘤是罕见的。为了更好地了解与这种独特遗传事件相关的肿瘤，我们研究了另外11例EWSR1::SSX肉瘤，影响10名女性和1名男性，平均年龄为46岁（范围：22至72岁）。8例肿瘤出现在骨（肋骨、股骨、骨盆或椎体，3例出现时伴有多灶性骨受累），2例肿瘤出现在软组织（大腿深或腹股沟），1例出现内脏（肺）肿块。肿瘤体积大，平均12.1厘米（范围：4 ~ 20厘米）。组织学上，与易位驱动型肉瘤一致，所有肿瘤在细胞学上都是单调的。7例为骨肉瘤，其中6例为广泛骨基质生成的硬化性骨肉瘤。三个肿瘤由均匀的梭形细胞束组成，其中两个病例被双相腺状或巢状上皮样成分打断，使人联想到滑膜肉瘤。一例肿瘤为未分化肉瘤，细胞形态为圆形到梭形细胞，局灶性成骨分化。免疫组化检测，5/5的患者SSX c -末端阳性；SS18::SSX融合特异性抗体染色1/5呈斑片状弱染色。所有肿瘤CD99（4/4）和TLE1（3/3）阳性。下一代测序在所有病例中发现了EWSR1::SSX融合，包括SSX1 （n=7）、SSX2 （n=2）和SSX3 (n=1)，以及一种新的EWSR1::SSX4融合。9例患者随访；5例患者在诊断后1.5至14年（平均6年）死于疾病，2例患者存在转移性疾病，1例患者在25个月时无疾病存活，1例患者最近就诊。伴有EWSR1::SSX融合的肉瘤是罕见且具有临床侵袭性的；本系列和先前报道的组织学模式是异质性的，主要由三种表型组成：1)原始圆形或上皮样细胞，2)产生骨的成骨细胞，或3)排列成紧密束状的均匀小梭形细胞，有时具有双相上皮样成分，如滑膜肉瘤。通过研究这些罕见肉瘤的11个额外的例子，我们提供了他们的临床病理和分子遗传谱的扩展视图。

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引用次数: 0

Perianal Intestinal-Type Paget Disease With and Without Invasion, Unassociated With Internal Malignancy: A Distinct Form of Primary Perianal Adenocarcinoma 伴有或不伴有侵犯、与内部恶性肿瘤无关的肛周肠型佩吉特病：原发性肛周腺癌的一种独特形式。

IF 5.5 1区医学 Q1 PATHOLOGY

Modern Pathology

Pub Date : 2026-01-01 Epub Date: 2025-10-15 DOI: 10.1016/j.modpat.2025.100917

Dorukhan Bahceci , Carla Saoud , Raymond A. Isidro , Diogo Caires , Conrad James Moher , Nil Urganci , Melissa Pulitzer , Julio Garcia-Aguilar , Martin R. Weiser , Efsevia Vakiani , Amitabh Srivastava , Jinru Shia

Primary perianal adenocarcinoma of intestinal type (PPAI) has been described in recent literature and proposed as a subtype of extramucosal anal adenocarcinoma. Whether this represents a unique entity remains to be elucidated. Herein, we analyzed the clinicopathologic and genomic features of 14 cases of PPAI. Fourteen patients, predominantly older adults with a median age of 73 years (range, 50-85), with a slight woman predilection (5 men and 9 women) were identified. All cases presented with pagetoid intraepithelial growth, and 9 were eventually found to have underlying invasive carcinoma at the site of the Paget disease. Clinical and radiographic evaluation failed to detect another primary site, either in the anorectal region or elsewhere, in all patients. By immunohistochemistry, all but 1 case showed an intestinal phenotype with cytokeratin 20 and caudal-related homeobox transcription factor 2 (CDX2) positivity and variable cytokeratin 7. Metastasis developed in 4 of 14 patients, including regional lymph node and distant bone metastasis. Patient survival for localized disease ranged from 29 to 176 months (median, 62 months), whereas for metastatic disease, it ranged from 13 to 75 months (mean, 31 months). Genomic profiling revealed a high frequency of TP53 mutations (86%, 12/14), ERBB2 alterations (57%, 8/14), and MYC amplification (36%, 5/14), with absence of genetic alterations typically seen in rectal adenocarcinomas, such as APC, KRAS, and BRAF. In contrast, a control group of primary extramammary Paget disease cases displayed distinct genomic features, including recurrent PIKC3A and KMT2C mutations. Treatment included surgical excision, radiation therapy, and systemic chemotherapy in metastatic cases, with radiation proving effective in preventing local recurrence among those with localized disease. In metastatic cases, chemotherapeutic regimens including capecitabine/oxaliplatin and folinic acid, fluorouracil, and oxaliplatin were employed. The absence of anorectal or other visceral adenocarcinomas along with distinct genomic findings supports the classification of PPAI as a distinct clinicopathologic entity.

原发性肠型肛周腺癌（PPAI）在最近的文献中被描述并被认为是粘膜外肛门腺癌的一种亚型。这是否代表一个独特的实体还有待阐明。在此，我们分析了14例PPAI的临床病理和基因组特征。14例患者，主要是年龄中位数为73岁的老年人（范围50-85），有轻微的女性偏好（5名男性和9名女性）。所有病例均表现为Paget样上皮内生长，其中9例最终发现在Paget病部位存在潜在的浸润性癌。在所有患者中，无论是在肛肠区还是其他地方，临床和影像学评估都未能发现另一个原发部位。通过免疫组化，除一例外，其余病例均表现为CK20和CDX2阳性，CK7可变。14例患者中有4例发生转移，包括局部淋巴结和远端骨转移。局部疾病的患者生存期为29至176个月（中位：62个月），而转移性疾病的患者生存期为13至75个月（平均：31个月）。基因组分析显示TP53突变（86%,12/14）、ERBB2突变（57%,8/14）和MYC扩增（36%,5/14）的频率较高，而直肠腺癌如APC、KRAS、BRAF中没有常见的遗传改变。相比之下，对照组的原发性乳腺外佩吉特病（EMPD）病例显示出不同的基因组特征，包括复发的PIKC3A和KMT2C突变。治疗包括手术切除、放射治疗和转移病例的全身化疗，放射治疗被证明对局部疾病的局部复发有效。在转移病例中，化疗方案包括卡培他滨/奥沙利铂（CAPOX）和亚叶酸、氟尿嘧啶和奥沙利铂（FOLFOX）。肛门直肠或其他内脏腺癌的缺失以及独特的基因组发现支持PPAI作为一种独特的临床病理实体的分类。

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引用次数: 0

Large Language Models Can Generate High-Quality Pathology Multiple-Choice Questions Comparable With Questions Written by a Human Expert 大型语言模型可以生成与人类专家编写的问题相当的高质量病理选择题。

IF 5.5 1区医学 Q1 PATHOLOGY

Modern Pathology

Pub Date : 2026-01-01 Epub Date: 2025-11-22 DOI: 10.1016/j.modpat.2025.100940

Michael J. Borowitz , Amanda L. Blackford , Suman Nagelia , Ralph H. Hruban

Multiple-choice questions can be effective tools to assess student and trainee performance, but the creation of these questions can be time consuming and requires expertise. To test the quality of pathology test questions created by large language models (LLMs), 100 questions on pancreas pathology were written by a human expert, and 50 questions were generated by each of 2 LLMs (ChatGPT-4.0 and Gemini 2.5 Flash). After an initial review, 16% of the multiple-choice questions generated by the 2 LLMs had to be revised through additional interactive prompting. The final set of questions was then evaluated by 190 volunteers with a variety of backgrounds and levels of expertise. We found that ChatGPT-generated—but not Gemini-generated—questions were rated as easier than human-authored questions; there were slightly more poor/unacceptable questions compared with adequate/good/excellent questions written by the LLMs than those written by the human expert (11.7% vs 10.1%; odds ratio, 1.64; 95% CI, 1.13-2.37; P = .009), but there was no difference in the proportion of questions rated good or excellent. Qualitatively, human-authored questions were thought to be most clinically realistic but felt to be more inconsistent and sometimes thought to be testing trivial points. There was no difference in the mean point biserial between human-authored and LLM-generated questions (0.31 vs 0.29; P = .56). As LLMs improve, they will form a useful tool for the efficient generation of large numbers of high-quality pathology test questions.

多项选择题（mcq）是评估学生和实习生表现的有效工具，但这些问题的创建既耗时又需要专业知识。为了测试由大型语言模型（llm）创建的病理试题的质量，由一位人类专家编写了100个关于胰腺病理的问题，并由两个大型语言模型（Chat GPT4.0和Gemini 2.5 Flash）各生成50个问题。经过初步审查，两位法学硕士生成的mcq中有16%必须通过额外的交互式提示进行修改。最后一组问题由190名具有不同背景和专业水平的志愿者进行评估。我们发现：聊天GPT（而不是双子座生成的问题）被认为比人工编写的问题更容易；法学硕士编写的问题比人类专家编写的问题略差/不可接受/好/优秀（11.7% vs 10.1%, OR 1.64, 95% CI: 1.13, 2.37, p=0.009）；但被评为优秀或优秀的问题的比例没有差异。从质量上讲，人类撰写的问题被认为是最符合临床实际的，但感觉更不一致，有时被认为是在测试琐碎的点。人类撰写的问题和llm生成的问题的平均点双序列没有差异（0.31 vs 0.29, p=0.56）。随着大型语言模型的改进，它们将成为高效生成大量高质量病理试题的有用工具。

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引用次数: 0

Defining NECTIN4 Amplification and Protein Expression in Urothelial Carcinoma and Histologic Subtypes 尿路上皮癌和组织学亚型中NECTIN4扩增和蛋白表达的定义

IF 5.5 1区医学 Q1 PATHOLOGY

Modern Pathology

Pub Date : 2026-01-01 Epub Date: 2025-10-29 DOI: 10.1016/j.modpat.2025.100928

John C. Cheville , Jacob J. Orme , Sounak Gupta , Fabrice Lucien-Matteoni , Robert J. Karnes , Prabin Thapa , Abhinav Khanna , Shruthi Naik , Vidit Sharma , Igor Frank , Lance Pagliaro , Fernando Quevedo , Burak Tekin , Ryan Knudson , Patricia Greipp , Carrie Brandt , Justin Koepplin , Brian Costello , Elisabeth Heath , George Vasmatzis , Paras H. Shah

Chromosome 1q23.3 is commonly amplified in metastatic urothelial carcinoma (UC). This region contains NECTIN4 that encodes for a membrane protein, and amplification may result in increased NECTIN4 expression. Enfortumab vedotin, an antibody-drug conjugate, targets NECTIN4. The objective of this study was to determine the frequency of NECTIN4 amplification by fluorescence in situ hybridization and protein expression by immunohistochemistry in primary UC and subtypes. Tissue microarrays (TMA) were constructed from 841 patients who underwent cystectomy between 2000 and 2020. In 218 patients, TMA were constructed from a concurrent pelvic lymph node metastasis. NECTIN4 amplification varied by subtype and was present in 18% of UCs, 13% of UCs with squamous differentiation, 25% of micropapillary carcinoma, 19% of plasmacytoid carcinoma, 17% of high-grade neuroendocrine carcinoma, 8% of pure squamous cell carcinoma, 6% of nested carcinoma, and 6% of sarcomatoid carcinoma. Tumors with NECTIN4 amplification had significantly higher H scores compared with nonamplified tumors (P < .0001), and H scores increased with increasing copy number in amplified tumors. NECTIN4 amplification was identified in 17% of lymph node metastases, and 70% of amplified primary tumors had an amplified metastasis, which increased to >90% when whole section fluorescence in situ hybridization was performed in discordant TMA cases. There was a moderate agreement between immunohistochemical staining of primary and lymph node metastases (kappa = 0.41). NECTIN4 amplifications vary in frequency among UC and subtypes, and amplifications result in higher protein expression. Bladder cancer with NECTIN4 amplification may have limited protein expression, whereas nonamplified tumors may show high expression. There was concordance of NECTIN4 amplification and protein expression between primary and lymph node metastases, but there were a small number of cases with amplified primary tumors and unamplified metastases, primary tumors with high protein expression, and metastasis with low expression.

染色体1q23.3通常在转移性尿路上皮癌（UC）中扩增。该区域含有编码膜蛋白的NECTIN4，扩增可导致NECTIN4表达增加。Enfortumab vedotin （EV）是一种靶向NECTIN4的抗体药物偶联物。本研究的目的是通过荧光原位杂交（FISH）和免疫组化（IHC）测定原发性UC及其亚型中NECTIN4扩增的频率。组织微阵列（TMA）是由2000年至2020年间接受膀胱切除术的841例患者构建的。在218例患者中，TMAs是由并发盆腔淋巴结转移构建的。NECTIN4扩增因亚型而异，存在于18%的UCs、13%的鳞状分化UCs、25%的微乳头状癌、19%的浆细胞样癌、17%的高级神经内分泌癌、8%的纯鳞状细胞癌、6%的巢状癌和6%的肉瘤样癌中。与未扩增的肿瘤相比，具有NECTIN4扩增的肿瘤的H评分明显更高(p

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引用次数: 0

ZFTA::NCOA1/2-Rearranged Epithelioid Mesenchymal Tumor—A Phenotypically Distinct Myoepithelial-Like Neoplasm Epigenetically Overlapping With Chondroid Lipoma ncoa1 /2重排上皮样间充质瘤-一种与软骨样脂肪瘤表观遗传重叠的表型不同的肌上皮样肿瘤。

IF 5.5 1区医学 Q1 PATHOLOGY

Modern Pathology

Pub Date : 2026-01-01 Epub Date: 2025-11-19 DOI: 10.1016/j.modpat.2025.100939

Raheel Rizwan , Vivek Venkataramani , Lukas Haug , Travis Hattery , Mark Chen , Joy Nakitandwe , Sheila Shurtleff , Elizabeth M. Azzato , Maria-Veronica Teleanu , Jennifer Hüllein , Stefan Fröhling , Robert Stoehr , Steven D. Billings , Michael Michal , Karen J. Fritchie , Abbas Agaimy , Josephine K. Dermawan

ZFTA (formerly C11orf95) gene rearrangements are recurrent in rare tumors of the central nervous system, such as ependymomas (mostly ZFTA::RELA) and soft tissue tumors, such as chondroid lipomas (ZFTA::MRTFB). To date, among mesenchymal tumors, the ZFTA::NCOA1 fusion has only been reported in a single case of chondroid lipoma. We describe 5 distinct soft tissue tumors harboring ZFTA::NCOA1/2 fusions. The tumors arose from 2 females and 3 males with a median age of 31 years (range, 30-72). All tumors were well circumscribed involving the deep (4 cases) or superficial (1 case) soft tissue of the proximal limbs with a median greatest dimension of 4.2 cm (range, 1.7-6.0). Histologically, they displayed lobulated architecture and were composed of monotonous epithelioid-to-plasmacytoid cells arranged in cords, chains, and nests within myxohyaline or sclerosed stroma. Focal loose myxoid reticulate areas and prominent dilated and hyalinized blood vessels were present. One tumor showed focal spindle cells, whereas another demonstrated necrosis and atypical mitotic figures. Definitive adipocytic, lipoblastic, or clear-cell features were absent, except in 1 case. Immunohistochemistry was nonspecific without any consistent lineage-defining marker expression. Targeted RNA sequencing confirmed ZFTA::NCOA1 fusions in 3 and ZFTA::NCOA2 fusion in 2 cases. DNA methylation profiling, available in 4 cases, demonstrated a shared epigenetic profile with chondroid lipoma but not other tumors with histologic or genetic overlap. Copy number variation analysis showed a flat copy number profile in 3 cases and chr9p arm–level copy number loss in the case with necrosis and mitotic activity. All patients underwent complete excision; no recurrences or metastases were observed over a limited follow-up period (available in 4 cases, range, 8-24 months; median, 10.5 months). In conclusion, ZFTA::NCOA1/2-rearranged epithelioid mesenchymal tumors represent a novel, morphologically distinct entity, genetically and epigenetically overlapping with chondroid lipoma. Expanded cohorts and long-term follow-up are necessary to clarify their precise classification and biologic behavior.

ZFTA（原C11orf95）基因重排在罕见的中枢神经系统肿瘤中复发，如室管膜瘤（主要为ZFTA::RELA）和软组织肿瘤如软骨样脂肪瘤（ZFTA::MRTFB）。迄今为止，在间充质肿瘤中，融合ZFTA::NCOA1仅在一例软骨样脂肪瘤中被报道。我们描述了五种不同的软组织肿瘤窝藏ZFTA::NCOA1/2融合。肿瘤发生于2名女性和3名男性，中位年龄31岁（范围30-72岁）。所有肿瘤均边界清楚，累及近端肢体深部软组织（4例）或浅表软组织（1例），最大中位尺寸为4.2 cm（范围1.7 ~ 6.0 cm）。组织学上，它们呈分叶状结构，由单调的上皮样细胞到浆细胞样细胞组成，排列成索状、链状和巢状，分布在粘液透明质或硬化基质中。可见局灶性疏松黏液网状区，血管明显扩张和透明化。一个肿瘤显示局灶梭形细胞，而另一个肿瘤显示坏死和非典型有丝分裂象。除一例外，没有明确的脂肪细胞、脂肪母细胞或透明细胞特征。免疫组织化学是非特异性的，没有任何一致的谱系定义标记表达。靶向RNA测序证实ZFTA::NCOA1融合3例，ZFTA::NCOA2融合2例。4例病例的DNA甲基化谱显示，与软骨样脂肪瘤有共同的表观遗传谱，但与其他肿瘤没有组织学或遗传重叠。拷贝数变异分析显示，3例患者拷贝数分布平坦，坏死和有丝分裂活跃的患者拷贝数丢失chr9p臂水平。所有患者均行完全切除；在有限的随访期内（4例，8-24个月，中位10.5个月）未观察到复发或转移。综上所述，ZFTA:: ncoa1 /2重排上皮样间充质瘤是一种形态独特的新型肿瘤，在遗传和表观遗传上与软骨样脂肪瘤重叠。扩大队列和长期随访是明确其精确分类和生物学行为的必要条件。

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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

Modern Pathology

Pub Date : 2026-01-01 Epub 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。

引用次数: 0