Modern Pathology最新文献

{"title":"Diagnostic Discordance and Error in Breast Pathology: Causes, Classifications, and Medicolegal Implications","authors":"Emad A. Rakha ,&nbsp;Cecily M. Quinn ,&nbsp;Elena Provenzano ,&nbsp;Sarah E. Pinder ,&nbsp;Ian O. Ellis","doi":"10.1016/j.modpat.2025.100942","DOIUrl":"10.1016/j.modpat.2025.100942","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100942"},"PeriodicalIF":5.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145596760","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}

{"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":"2026-01-01","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}

{"title":"Expanding the Molecular Characterization of Adenoid Ameloblastoma by Assessing a Panel of Oncogenes and Tumor Suppressor Genes","authors":"Ygor G. Fonseca ,&nbsp;Victor C. Bastos ,&nbsp;Rennan G. Moreira ,&nbsp;Felipe P. Fonseca ,&nbsp;Pablo A. Vargas ,&nbsp;John M. Wright ,&nbsp;Renato S. Aguiar ,&nbsp;Edward W. Odell ,&nbsp;Ricardo S. Gomez ,&nbsp;Letícia M. Guimarães ,&nbsp;Carolina C. Gomes","doi":"10.1016/j.modpat.2025.100920","DOIUrl":"10.1016/j.modpat.2025.100920","url":null,"abstract":"<div><div>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 <em>CTNNB1</em> mutations, is thought to characterize AA, which are <em>BRAF</em> and <em>KRAS</em> 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 <em>AKT1, ALK, BRAF, CTNNB1, EGFR, ERBB2, ERBB3, ESR1, FOXL2, GNA11, GNAQ, IDH1, IDH2, KRAS, KIT, MET, NRAS, PDGFRA, PIK3CA, RAF1, RET</em>, and <em>TP53.</em> Reinforcing the distinct molecular identity of AA, absence of <em>BRAF</em> p.Val600Glu and <em>KRAS</em> p.Gly12Val/Arg mutations was observed. <em>CTNNB1</em> 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, <em>CTNNB1</em> variants co-occurred with either <em>TP53</em> or <em>ERBB2</em> and <em>PIK3CA</em> 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 <em>CTNNB1</em> 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.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100920"},"PeriodicalIF":5.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318589","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}

{"title":"CD38 Expression and 6q/9q Codeletion: Diagnostic Markers for Primary Cutaneous Cribriform Tumor","authors":"Paul W. Harms","doi":"10.1016/j.modpat.2025.100927","DOIUrl":"10.1016/j.modpat.2025.100927","url":null,"abstract":"","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100927"},"PeriodicalIF":5.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145621472","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}

{"title":"Expanding the Clinicopathologic Spectrum of EWSR1::SSX-Rearranged Sarcomas: Series of 11 Cases Including Osteosarcomas and a Novel EWSR1::SSX4 Fusion","authors":"John M. Gross ,&nbsp;David I. Suster ,&nbsp;Ying Zou ,&nbsp;Douglas A. Mata ,&nbsp;Fernanda Amary ,&nbsp;Solange De Noon ,&nbsp;Adrienne M. Flanagan ,&nbsp;Kristina M. Wakeman ,&nbsp;Sintawat Wangsiricharoen ,&nbsp;Fei Dong ,&nbsp;Suk Wai Lam ,&nbsp;Judith V.M.G. Bovée ,&nbsp;Aline Baltres ,&nbsp;Daniel Pissaloux ,&nbsp;Eric Pasmant ,&nbsp;Frédérique Larousserie ,&nbsp;Markku Miettinen ,&nbsp;Meera Hameed ,&nbsp;Gregory W. Charville","doi":"10.1016/j.modpat.2025.100922","DOIUrl":"10.1016/j.modpat.2025.100922","url":null,"abstract":"<div><div>Gene rearrangements involving <em>EWSR1</em> or <em>SSX</em> genes are known to play a role in sarcomagenesis; however, sarcomas harboring <em>EWSR1</em>::<em>SSX</em> fusions are rare. To better understand tumors associated with this distinctive genetic event, we studied 11 additional <em>EWSR1::SSX</em> 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 <em>EWSR1</em>::<em>SSX</em> fusions in all cases, involving <em>SSX1</em> (n = 7), <em>SSX2</em> (n = 2), and <em>SSX3</em> (n = 1), along with a novel <em>EWSR1</em>::<em>SSX4</em> 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 <em>EWSR1::SSX</em> 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.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100922"},"PeriodicalIF":5.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145370371","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}

{"title":"Perianal Intestinal-Type Paget Disease With and Without Invasion, Unassociated With Internal Malignancy: A Distinct Form of Primary Perianal Adenocarcinoma","authors":"Dorukhan Bahceci ,&nbsp;Carla Saoud ,&nbsp;Raymond A. Isidro ,&nbsp;Diogo Caires ,&nbsp;Conrad James Moher ,&nbsp;Nil Urganci ,&nbsp;Melissa Pulitzer ,&nbsp;Julio Garcia-Aguilar ,&nbsp;Martin R. Weiser ,&nbsp;Efsevia Vakiani ,&nbsp;Amitabh Srivastava ,&nbsp;Jinru Shia","doi":"10.1016/j.modpat.2025.100917","DOIUrl":"10.1016/j.modpat.2025.100917","url":null,"abstract":"<div><div>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 <em>TP53</em> mutations (86%, 12/14), <em>ERBB2</em> alterations (57%, 8/14), and <em>MYC</em> amplification (36%, 5/14), with absence of genetic alterations typically seen in rectal adenocarcinomas, such as <em>APC, KRAS,</em> and <em>BRAF</em>. In contrast, a control group of primary extramammary Paget disease cases displayed distinct genomic features, including recurrent <em>PIKC3A</em> and <em>KMT2C</em> 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.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100917"},"PeriodicalIF":5.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145313243","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}

{"title":"Large Language Models Can Generate High-Quality Pathology Multiple-Choice Questions Comparable With Questions Written by a Human Expert","authors":"Michael J. Borowitz ,&nbsp;Amanda L. Blackford ,&nbsp;Suman Nagelia ,&nbsp;Ralph H. Hruban","doi":"10.1016/j.modpat.2025.100940","DOIUrl":"10.1016/j.modpat.2025.100940","url":null,"abstract":"<div><div>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; <em>P</em> = .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; <em>P</em> = .56). As LLMs improve, they will form a useful tool for the efficient generation of large numbers of high-quality pathology test questions.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100940"},"PeriodicalIF":5.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145588292","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}

{"title":"ZFTA::NCOA1/2-Rearranged Epithelioid Mesenchymal Tumor—A Phenotypically Distinct Myoepithelial-Like Neoplasm Epigenetically Overlapping With Chondroid Lipoma","authors":"Raheel Rizwan ,&nbsp;Vivek Venkataramani ,&nbsp;Lukas Haug ,&nbsp;Travis Hattery ,&nbsp;Mark Chen ,&nbsp;Joy Nakitandwe ,&nbsp;Sheila Shurtleff ,&nbsp;Elizabeth M. Azzato ,&nbsp;Maria-Veronica Teleanu ,&nbsp;Jennifer Hüllein ,&nbsp;Stefan Fröhling ,&nbsp;Robert Stoehr ,&nbsp;Steven D. Billings ,&nbsp;Michael Michal ,&nbsp;Karen J. Fritchie ,&nbsp;Abbas Agaimy ,&nbsp;Josephine K. Dermawan","doi":"10.1016/j.modpat.2025.100939","DOIUrl":"10.1016/j.modpat.2025.100939","url":null,"abstract":"<div><div><em>ZFTA</em> (formerly <em>C11orf95</em>) gene rearrangements are recurrent in rare tumors of the central nervous system, such as ependymomas (mostly <em>ZFTA::RELA</em>) and soft tissue tumors, such as chondroid lipomas (<em>ZFTA::MRTFB</em>). To date, among mesenchymal tumors, the <em>ZFTA::NCOA1</em> fusion has only been reported in a single case of chondroid lipoma. We describe 5 distinct soft tissue tumors harboring <em>ZFTA::NCOA1</em>/<em>2</em> 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 <em>ZFTA::NCOA1</em> fusions in 3 and <em>ZFTA::NCOA2</em> 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, <em>ZFTA::NCOA1/2</em>-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.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100939"},"PeriodicalIF":5.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145573856","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}

{"title":"Defining NECTIN4 Amplification and Protein Expression in Urothelial Carcinoma and Histologic Subtypes","authors":"John C. Cheville ,&nbsp;Jacob J. Orme ,&nbsp;Sounak Gupta ,&nbsp;Fabrice Lucien-Matteoni ,&nbsp;Robert J. Karnes ,&nbsp;Prabin Thapa ,&nbsp;Abhinav Khanna ,&nbsp;Shruthi Naik ,&nbsp;Vidit Sharma ,&nbsp;Igor Frank ,&nbsp;Lance Pagliaro ,&nbsp;Fernando Quevedo ,&nbsp;Burak Tekin ,&nbsp;Ryan Knudson ,&nbsp;Patricia Greipp ,&nbsp;Carrie Brandt ,&nbsp;Justin Koepplin ,&nbsp;Brian Costello ,&nbsp;Elisabeth Heath ,&nbsp;George Vasmatzis ,&nbsp;Paras H. Shah","doi":"10.1016/j.modpat.2025.100928","DOIUrl":"10.1016/j.modpat.2025.100928","url":null,"abstract":"<div><div>Chromosome 1q23.3 is commonly amplified in metastatic urothelial carcinoma (UC). This region contains <em>NECTIN4</em> 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 <em>NECTIN4</em> 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. <em>NECTIN4</em> 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 <em>NECTIN4</em> amplification had significantly higher H scores compared with nonamplified tumors (<em>P</em> &lt; .0001), and H scores increased with increasing copy number in amplified tumors. <em>NECTIN4</em> amplification was identified in 17% of lymph node metastases, and 70% of amplified primary tumors had an amplified metastasis, which increased to &gt;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). <em>NECTIN4</em> amplifications vary in frequency among UC and subtypes, and amplifications result in higher protein expression. Bladder cancer with <em>NECTIN4</em> amplification may have limited protein expression, whereas nonamplified tumors may show high expression. There was concordance of <em>NECTIN4</em> 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.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100928"},"PeriodicalIF":5.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145422125","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}

{"title":"Tumors of the Synovium","authors":"Yee Lin Tang ,&nbsp;Jad Husseini ,&nbsp;G. Petur Nielsen","doi":"10.1016/j.modpat.2025.100913","DOIUrl":"10.1016/j.modpat.2025.100913","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100913"},"PeriodicalIF":5.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145301875","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}