Modern Pathology最新文献

{"title":"An Exploratory Application of a Central Nervous System (CNS) Tumor Methylation Classifier in Ovarian Neuroectodermal Tumors","authors":"Jie Yang ,&nbsp;Tianyu Zhang ,&nbsp;Ying Zhang ,&nbsp;Xinyue Zhang ,&nbsp;Yang Xiang ,&nbsp;Huanwen Wu ,&nbsp;Leiming Wang ,&nbsp;Xiaohua Shi ,&nbsp;Jiaxin Yang","doi":"10.1016/j.modpat.2025.100930","DOIUrl":"10.1016/j.modpat.2025.100930","url":null,"abstract":"<div><div>Ovarian neuroectodermal tumors (NETs) are rare malignancies with unclear diagnostic criteria and challenging treatment. We aimed to assess the utility of DNA methylation in the diagnostic classification and prognostic stratification of ovarian NETs. This retrospective study included 15 patients diagnosed with ovarian NETs at Peking Union Medical College Hospital between 2010 and 2024. Paraffin-embedded tumor tissues from all patients underwent clinicopathologic review, DNA methylation microarray assay, EWSR1 fluorescence in situ hybridization, and immunohistochemistry. The median age at diagnosis of ovarian NETs was 19 years (range, 9-73 years). These tumors often displayed nonspecific clinical manifestations and were frequently diagnosed at an advanced stage. Morphologic diagnosis included 3 medulloblastoma, 1 neuroblastoma, 3 embryonal tumors with multilayered rosettes (ETMRs), 3 ependymomas, 1 high-grade glioma, 1 gliosarcoma, 1 low-grade neuronal-glial tumor, and 2 tumors that cannot be specified. A teratoma background was present in 73.3% (11/15) of the cases. None of the tumors exhibited <em>EWSR1</em> gene rearrangement. Methylation classification was consistent with morphologic diagnosis in 30% of patients (5/15). A novel ETMR, non-<em>C19MC</em>-altered type ovarian tumor was identified in 3 patients. The median follow-up period of all patients was 14.9 months (range, 2.1-216.4 months), during which 60.0% of patients experienced recurrence or disease progression, and the mortality rate was 33.3%. Patients with ETMR non-<em>C19MC</em>-altered subtype and unmatched tumors exhibited extremely poor outcomes, with 80% (4/5) mortality within 12 months. DNA methylation profiling classified a subset of ovarian NETs into molecular subtypes resembling those of central nervous system (CNS) tumor counterparts, with corresponding prognostic similarities. Leveraging the CNS tumor methylation classifier to diagnose peripheral neuroectodermal tumors may offer critical clinical insights for these rare malignancies, enabling molecular subtyping, prognostication, and alignment with CNS-targeted therapeutic strategies.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100930"},"PeriodicalIF":5.5,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145471480","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":"Low-Grade Fibro-Osseous Lesions With Isolated Chromosome 12 Chromothripsis: A Distinct Entity Or a Low-Grade Central Osteosarcoma With a Novel Driver?","authors":"Carla Saoud ,&nbsp;Yanming Zhang ,&nbsp;Jamal Benhamida ,&nbsp;Liliana Villafania ,&nbsp;Gunes Gundem ,&nbsp;Robert Cimera ,&nbsp;Sinchun Hwang ,&nbsp;Neerav N. Shukla ,&nbsp;Damon Reed ,&nbsp;Elli Papaemmanouil ,&nbsp;Narasimhan P. Agaram ,&nbsp;Konstantinos Linos ,&nbsp;Marc Ladanyi ,&nbsp;Carol D. Morris ,&nbsp;Meera R. Hameed","doi":"10.1016/j.modpat.2025.100931","DOIUrl":"10.1016/j.modpat.2025.100931","url":null,"abstract":"<div><div>Chromothripsis, a catastrophic genomic event causing extensive chromosomal fragmentation and rearrangement, has been identified in conventional osteosarcoma, contributing to karyotypic heterogeneity. Chromothripsis was also detected in a subset of parosteal osteosarcomas, primarily involving chromosome 12, but not well documented in low-grade central osteosarcoma (LGCOS). Here, we report 2 cases of low-grade fibro-osseous lesions with isolated chromosome 12 chromothripsis, aiming to characterize them by comparing their genomic and epigenetic profiles to those of other bone neoplasms. Case 1 was a 12-year-old male with a destructive lesion involving the proximal left tibia, and case 2 was a 13-year-old female with an expansile lucent bone lesion involving the distal tibia with cortical breakthrough. Both cases consisted of hypocellular bland fibroblastic proliferation. Areas of thin trabeculae of woven bone surrounded by osteoblasts were present. In addition, case 1 showed areas of atypical cartilaginous islands and areas reminiscent of LGCOS. By single-nucleotide polymorphism array, both cases showed extremely complex and numerous genomic alterations involving chromosome 12. Whole-genome sequencing and optical genome sequencing confirmed the chromothriptic event involving chromosome 12. Using the Heidelberg Epignostix sarcoma methylation classifier (v12.3), both cases matched to fibrous dysplasia methylation class. Dimensionality reduction using Uniform Manifold Approximation and Projection demonstrated that the 2 index cases clustered primarily with low-grade osteosarcomas lacking <em>MDM2</em> amplification and with fibrous dysplasia, whereas remaining separate from parosteal osteosarcomas and <em>MDM2</em>-amplified low-grade osteosarcomas. Our findings suggest that chromothripsis of chromosome 12 may represent an early and/or an alternate mechanism in fibro-osseous lesions progressing to LGCOS instead of or before the development of the well-recognized <em>CDK4/MDM2</em> amplification. Larger cohorts with long-term follow-ups and integrative molecular studies are needed to clarify the biological significance and clinical implications, including recurrence, dedifferentiation, and survival.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100931"},"PeriodicalIF":5.5,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145471545","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":"Updates in Peripheral Nerve Sheath and Adipocytic Tumors","authors":"Sarah Dry","doi":"10.1016/j.modpat.2025.100929","DOIUrl":"10.1016/j.modpat.2025.100929","url":null,"abstract":"<div><div>Certain areas in peripheral nerve sheath and adipocytic neoplasm diagnosis historically were characterized by a lack of clarity and consensus regarding terminology, diagnostic criteria, and prognosis. Recent work has led to important clarifications in diagnostic criteria and/or outcome data for neurofibromas with atypia and MDM2 amplification–negative adipocytic tumors. However, these clarifications remain incompletely recognized by many pathologists, in part due to the paucity of these neoplasms. This paper reviews the history and recent advances in diagnostic criteria, terminology, and understanding of prognosis for neurofibromas with atypia, malignant peripheral nerve sheath tumor (MPNST), malignant melanotic nerve sheath tumor, and atypical spindle cell/pleomorphic lipomatous tumor. Melanoma may be histologically identical to MPNST, and this paper also provides an overview of helpful clinical and molecular features that allow accurate identification of melanoma, including undifferentiated, dedifferentiated, and transdifferentiated melanoma, and their distinction from MPNST.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100929"},"PeriodicalIF":5.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145438642","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":"2025-10-29","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":"International Expert Consensus Recommendations for HER2 Reporting in Breast Cancer: Focus on HER2-Low and Ultralow Categories","authors":"Emad A. Rakha ,&nbsp;Puay Hoon Tan ,&nbsp;Mieke R. Van Bockstal ,&nbsp;Kimberly H. Allison ,&nbsp;Edi Brogi ,&nbsp;Grace Callagy ,&nbsp;Gábor Cserni ,&nbsp;Shabnam Jaffer ,&nbsp;Maria Pia Foschini ,&nbsp;Helenice Gobbi ,&nbsp;Janina Kulka ,&nbsp;Xiaoxian Li ,&nbsp;Elena Provenzano ,&nbsp;Abeer M. Shaaban ,&nbsp;Gary M. Tse ,&nbsp;Zsuzsanna Varga ,&nbsp;Anne Vincent-Salomon ,&nbsp;Rin Yamaguchi ,&nbsp;Wentao Yang ,&nbsp;Soha ElSheikh ,&nbsp;Cecily Quinn","doi":"10.1016/j.modpat.2025.100925","DOIUrl":"10.1016/j.modpat.2025.100925","url":null,"abstract":"<div><div>The concept of “HER2-negative” breast cancer is evolving, with the recognition of HER2-low and HER2-ultralow subsets. These subsets are clinically relevant regarding treatment with the antibody-drug conjugate trastuzumab deruxtecan (T-DXd), which has shown survival benefit in patients with metastatic carcinoma with minimal HER2 protein expression that lack <em>HER2</em> gene amplification by in situ hybridization. In clinical trials using T-DXd, HER2-low was defined as an immunohistochemistry (IHC) score 1+ or an IHC score 2+ without <em>HER2</em> gene amplification. HER2-ultralow was defined as faint or barely perceptible, incomplete membrane staining in &gt;0% to ≤10% of tumor cells (IHC score 0+/with membrane staining) and HER2-null as the complete absence of staining (IHC score 0/absent membrane staining). These results now necessitate more detailed evaluation and reporting of traditional “HER2-negative” results to identify patients with metastatic breast cancer who may benefit from T-DXd therapy. Both the US Food and Drug Administration and the European Medicines Agency have extended the regulatory approval of T-DXd to patients with metastatic breast cancer showing HER2-low or HER2-ultralow expressions. Updated clinical management guidelines now, therefore, incorporate the spectrum of HER2 results into treatment selection algorithms in the metastatic setting. To align histopathologic practice with these developments, the College of American Pathologists has issued a new biomarker-reporting template that recommends explicit distinction between IHC 0/absent membrane staining and IHC 0+/with membrane staining. Key concerns among pathologists include assay variability, scoring reproducibility, and quality assurance standards for accurately detecting such low levels of HER2 expression. This manuscript provides expert consensus, evidence-based practical recommendations for identifying and reporting tumors with HER2-low and HER2-ultralow expression. We emphasize standardized testing protocols, validated assays, robust internal and external controls, and focused training for pathologists. A universal structured pathology report is proposed to highlight the accurate distinction between IHC 0 (null), IHC 0+ (ultralow), and HER2-low expressions.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100925"},"PeriodicalIF":5.5,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145408978","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":"Tumor Deposits in Colorectal Cancer: Definitions for Ninth Edition of the Tumor Node Metastasis Staging System","authors":"Iris D. Nagtegaal ,&nbsp;Kay Washington ,&nbsp;James D. Brierley ,&nbsp;George J. Chang ,&nbsp;Richard M. Goldberg ,&nbsp;Qian Shi ,&nbsp;Sanjay Kakar ,&nbsp;Heidi Kaur","doi":"10.1016/j.modpat.2025.100924","DOIUrl":"10.1016/j.modpat.2025.100924","url":null,"abstract":"<div><div>Tumor deposits (TDs) have been a contentious element of the tumor node metastasis staging system for colorectal cancer since their introduction in 1997. Classified within the nodal category, their definition has changed repeatedly due to unclear distinctions from lymph node metastases, extramural vascular invasion, and perineural invasion. Despite updates in the tumor node metastasis system eight edition, ambiguity remains, with current criteria relying heavily on pathologist discretion. The fact that TDs are among the most powerful prognostic indicators warrants standardization, based on scientific evidence. A Delphi consensus among expert pathologists confirmed the lack of specificity and reproducibility in the current definition. In response, a new definition was developed, identifying TDs as discrete tumor nodules in pericolic or perirectal fat, distinct from lymph nodes, extramural vascular invasion, or perineural invasion but possibly originating from them. This definition emphasizes the need to report TDs separately when there is unequivocal tumor extension in relation to vessels or nerves. Size and distance from the primary tumor are debated as potential criteria, although they are not part of the proposed definition. The new definition is a first step to incorporate a more robust, biologically relevant definition of TDs into cancer staging.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100924"},"PeriodicalIF":5.5,"publicationDate":"2025-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145527443","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":"Development of an Artificial Intelligence Model to Aid in Measurement of Invasion, Comprehensive Histologic Subtyping, and Grading of Pulmonary Adenocarcinoma","authors":"Jennifer M. Boland ,&nbsp;Lucas Stetzik ,&nbsp;Anja C. Roden ,&nbsp;Joseph J. Maleszewski ,&nbsp;Sarah M. Jenkins ,&nbsp;Trynda N. Kroneman ,&nbsp;Eunhee S. Yi ,&nbsp;Ying-Chun Lo ,&nbsp;Marie Christine Aubry","doi":"10.1016/j.modpat.2025.100923","DOIUrl":"10.1016/j.modpat.2025.100923","url":null,"abstract":"<div><div>The World Health Organization classification of pulmonary adenocarcinoma is complex, posing challenges for pathological reporting. Key difficulties include assessing invasive size in lepidic-predominant tumors and performing comprehensive histologic subtyping. Although these evaluations inform tumor stage, grade, and prognosis, they are time consuming and subjective, leading to interobserver variability. Artificial intelligence (AI) may help streamline these tasks and improve consistency. One representative hematoxylin and eosin slide was selected from each of 100 resected pulmonary adenocarcinomas, which were divided into training (n = 35) and validation (n = 65) sets. Slides were scanned and uploaded to Aiforia for AI model creation. Annotations were completed on the training set by 6 expert pulmonary pathologists and used to train a nested AI model, which was used to evaluate whole slide images of the training and validation sets. Manual assessment of tumor size, invasive size, and comprehensive histologic subtyping was performed by 3 pulmonary pathologists. In both the training and validation sets, the mean and median difference between manual and AI estimations of tumor size was ≤1.3 mm and invasive size was ≤3 mm. The median and mean differences in invasive percentage were ≤15.3% in both the training and validation sets for all patterns except for acinar and lepidic. However, ranges were wide, indicating examples with substantial disagreement. Predominant pattern agreement between AI and each observer ranged from 65.7% to 71.4% in the training set and 45.3% to 54.7% in the validation set. Agreement in grade ranged from 77.1% to 88.6% in the training set and 62.5% to 67.2% in the validation set. There was moderate agreement in grade between the 3 pathologists in the training set and moderate to substantial agreement between AI and each observer. In the validation set, there was substantial agreement in grade between the 3 pathologists and moderate agreement between AI and each observer. Although the AI model shows promise and warrants further refinement, manual pathologist review and potential revision of AI assessments are necessary to ensure the diagnostic accuracy needed for clinical use because disagreement clearly occurs.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100923"},"PeriodicalIF":5.5,"publicationDate":"2025-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145577776","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":"2025-10-24","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":"Mutational Signature in Cancers Following Solid Organ or Allogeneic Stem Cell Transplantation","authors":"Igor Odintsov ,&nbsp;Stephanie E. Siegmund ,&nbsp;Navin R. Mahadevan ,&nbsp;Alanna J. Church ,&nbsp;Lynette M. Sholl ,&nbsp;Jonathan A. Nowak","doi":"10.1016/j.modpat.2025.100921","DOIUrl":"10.1016/j.modpat.2025.100921","url":null,"abstract":"<div><div>Transplant recipients are at a heightened risk of cancer, yet the full spectrum of etiologic factors is poorly understood. In this study, we analysed the mutational patterns in a clinically diverse cohort of 41,874 cancers and identified a mutational signature highly associated with a history of solid organ or allogeneic stem cell transplantation. This signature is characterized by a high tumor mutation burden and a striking predominance of C&gt;A single base substitutions, particularly in the 5′-C[C&gt;A]A-3′ trinucleotide context. We identified 13 transplant recipients whose tumors harbored this signature, which is distinct from previously described mutational processes, including those related to tobacco, defective DNA repair, or polymerase mutations. The discovery of this signature points to a mutagenic force in this vulnerable patient group and provides new insights into the pathogenesis of transplant-associated malignancies.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100921"},"PeriodicalIF":5.5,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145368301","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":"2025-10-16","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}