Modern Pathology最新文献

{"title":"Expression of Programmed Death-Ligand 1 and Programmed Cell Death-1 Across the Anal Neoplasia Disease Continuum and Association With Survival in Anal Cancer","authors":"Sona Chowdhury ,&nbsp;Cynthia Gasper ,&nbsp;Ann A. Lazar ,&nbsp;Kathryn Allaire ,&nbsp;Teresa M. Darragh ,&nbsp;Lawrence Fong ,&nbsp;Joel M. Palefsky","doi":"10.1016/j.modpat.2025.100918","DOIUrl":"10.1016/j.modpat.2025.100918","url":null,"abstract":"<div><div>High-risk human papillomavirus (HPV) is associated with anal high-grade intraepithelial lesion (aHSIL) and anal squamous cell carcinoma (aSCC). The prognostic significance of programmed death-ligand 1 (PD-L1)- expression in aSCC and its impact on overall survival is controversial. ASCC can evade immune surveillance by coopting the PD-L1/programmed cell death-1 (PD-1) immune checkpoint pathway, enhancing tumorigenesis. To assess the potential role of the PD-L1/PD-1 axis on tumor progression, we assessed PD-L1 and PD-1 expression on epithelial cells and immune cells by immunohistochemistry in nonlesional anal tissue (n = 22), aHSIL (n = 22), and aSCC (n = 52) from HIV-negative participants and people living with HIV. PD-L1 expression on epithelial cells was restricted to tumor cells with no expression in nonlesional and HSIL tissues, whereas PD-L1-positive immune cells were present across all 3 diagnostic stages. PD-1 expression was absent on epithelial cells, whereas PD-1-positive immune cells increased along the disease continuum from nonlesional to aSCC. The overall PD-L1 expression on epithelial cells and immune cells measured by the combined positive score (CPS) in aSCC and the aggregate PD-L1 score in nonlesional and HSIL showed a substantial increase from nonlesional to aHSIL to aSCC. In aSCC, PD-L1 expression on immune cells was more prominent than in tumor cells and correlated with increased immune cell infiltration and interferon gamma secretion. Ninety-two percent of aSCC exhibited an adaptive PD-L1 expression pattern characterized by PD-L1 expression on tumor cells, immune cells, or both. HIV status did not affect PD-L1/PD-1 expression in nonlesional, aHSIL, or aSCC. PD-L1 expression in treatment-naive aSCC was associated with improved overall survival. Those with CPS of 0 had a higher risk of death (hazard ratio, 15.2 [95% CI, 3.3-69; <em>P</em> = .0004; log-rank <em>P</em> &lt; .0001]) compared with those with CPS &gt;0. CPS may indicate the presence of immune activation and serve as a potential prognostic marker.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100918"},"PeriodicalIF":5.5,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145313249","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":"2025-10-15","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":"CD180 as a Robust Immunophenotypic Marker for Differentiating Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia From Marginal Zone Lymphoma","authors":"Zhen Guo ,&nbsp;Jing Su ,&nbsp;Lu Liu ,&nbsp;Ninghan Zhang ,&nbsp;Xiao Chen ,&nbsp;Qing Zhong ,&nbsp;Chun Qiao ,&nbsp;Huimin Jin ,&nbsp;Jianyong Li ,&nbsp;Lei Fan ,&nbsp;Yujie Wu","doi":"10.1016/j.modpat.2025.100919","DOIUrl":"10.1016/j.modpat.2025.100919","url":null,"abstract":"<div><div>Precise differential diagnosis between lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) and marginal zone lymphoma (MZL) remains a challenging issue because of overlapping clinicopathological and immunophenotypic features. In the present study, the differential diagnostic potential of CD180 was assessed by determining its expression patterns in patients with MZL and LPL/WM through flow cytometry. The results indicated that LPL/WM cases exhibited a complete absence of CD180 expression on malignant B cells, whereas MZL cases showed robust CD180 expression (<em>P</em> &lt; .001). Receiver operating characteristic analysis demonstrated that CD180 expression percentage showed optimal diagnostic accuracy in LPL/WM and MZL cases (area under the curve = 0.998, sensitivity = 100%, and specificity = 98.0%), with a further improvement in differentiation potential by the CD180 mean fluorescence intensity ratio (lymphocytes/monocytes) of ≤ 0.47 (area under the curve = 0.937). Moreover, although the <em>MYD88</em>^{<em>L265P</em>}/<em>CXCR4</em> mutation was not detected by next-generation sequencing in 2 LPL/WM cases, these cases still showed the absence of CD180 expression. Subsequently, droplet digital PCR revealed low-frequency <em>MYD88</em>^{<em>L265P</em>} mutations (0.95% and 1.6% variant allele frequency) in these CD180-negative cases, which confirmed the superior sensitivity of CD180 in identifying LPL/WM with low tumor burden. Overall, our findings establish CD180 as a novel, rapid, and precise flow cytometry-based biomarker with robust ability for the differential diagnosis of LPL/WM and MZL, particularly relevant in resolving diagnostically challenging cases and providing prompt tumor diagnosis in time-constrained situations.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 12","pages":"Article 100919"},"PeriodicalIF":5.5,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145313262","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":"Cribriform Tumor of the Skin: Identification of 6q and 9q Loss as a Recurrent Cytogenomic Alteration","authors":"Shira Ronen ,&nbsp;David G. Grand ,&nbsp;Wahab A. Khan ,&nbsp;Michael Michal ,&nbsp;Donald C. Green ,&nbsp;Jennifer S. Ko ,&nbsp;Robert E. LeBlanc ,&nbsp;Jeffrey M. Cloutier","doi":"10.1016/j.modpat.2025.100916","DOIUrl":"10.1016/j.modpat.2025.100916","url":null,"abstract":"<div><div>Cribriform tumor is a rare sweat-gland neoplasm of uncertain malignant potential. Although its histopathologic features are well described, the molecular underpinnings of cribriform tumor remain incompletely characterized. We performed comprehensive molecular profiling of 6 cribriform tumors from 3 institutions using whole-exome sequencing, transcriptome sequencing, and single-nucletide polymorphism array copy number analysis. The cohort included 3 women and 3 men (median age, 54 years; range, 40-66 years), with tumors measuring 0.3 to 2.0 cm. Most arose on the extremities, with one located on the back. The most consistent genomic alteration was arm-level losses of chromosomes 6q and 9q, detected in 5 out of 6 cases. These alterations were validated across independent sequencing and single-nucletide polymorphism array platforms. Whole-exome sequencing identified likely pathogenic variants in 2 tumors (<em>CHEK2</em> p.R145W and <em>NF1</em> p.R1830H). No gene fusions were detected. Taken together, these findings provide independent confirmation that 6q/9q loss represents a consistent cytogenomic alteration in cribriform tumor, supporting its use as a molecular hallmark of this tumor.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100916"},"PeriodicalIF":5.5,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145308501","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":"Non–neoplastic Orthopedic Pathology Updates: Common Problems and Pitfalls and How to Avoid Them","authors":"Scott E. Kilpatrick","doi":"10.1016/j.modpat.2025.100911","DOIUrl":"10.1016/j.modpat.2025.100911","url":null,"abstract":"<div><div>Despite representing &lt;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.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 12","pages":"Article 100911"},"PeriodicalIF":5.5,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145301910","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":"Methylation Profiles in Bone and Soft Tissue Tumors: Do They Help Classify the Unclassifiable?","authors":"Josephine K. Dermawan","doi":"10.1016/j.modpat.2025.100910","DOIUrl":"10.1016/j.modpat.2025.100910","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 12","pages":"Article 100910"},"PeriodicalIF":5.5,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145301951","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":"2025-10-13","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}

{"title":"Unraveling Round Cell Sarcomas: A Contemporary Diagnostic Guide Beyond Ewing Sarcoma","authors":"Raul Ezequiel Perret","doi":"10.1016/j.modpat.2025.100914","DOIUrl":"10.1016/j.modpat.2025.100914","url":null,"abstract":"<div><div>Round cell sarcomas represent a continuously evolving category of malignant mesenchymal tumors, currently encompassing 5 main tumor subtypes: Ewing sarcoma, <em>Capicua Transcriptional Repressor</em> (CIC)<em>–</em>rearranged sarcoma, sarcomas with <em>BCL6-corepresso</em>r (<em>BCOR</em><em>)</em>-genetic abnormalities, <em>POZ/BTB and AT hook containing zinc finger 1</em> (<em>PATZ1</em><em>)</em>-rearranged sarcoma, and <em>nuclear factor of activated T cells 2</em> (<em>NFATC2</em><em>)</em>-rearranged sarcoma. These tumors show some degree of histomorphologic overlap, which, coupled with their infrequency, may render their diagnosis challenging for the pathologist. Furthermore, although ancillary techniques like immunohistochemistry and molecular tests can be of diagnostic aid, they are still limited by inherent sensitivity and specificity issues and cannot replace meticulous integration of clinical and radiologic findings. This review is focused on (1) providing a guide for tackling the diagnosis of round cell sarcomas and their mimics using an integrative approach combining demographics, clinicoradiologic data, histomorphology, and ancillary techniques and (2) detailing the most recent information on round cell sarcomas from the latest World Health Organization classification of Bone and Soft Tissue Tumors (fifth edition).</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100914"},"PeriodicalIF":5.5,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145301902","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":"Replacing Molecular Testing With Next-Generation Immunohistochemistry: I Can Diagnose That Soft Tissue Tumor With a Single Antibody!","authors":"Jason L. Hornick","doi":"10.1016/j.modpat.2025.100912","DOIUrl":"10.1016/j.modpat.2025.100912","url":null,"abstract":"<div><div>Immunohistochemistry plays a central role in the diagnosis of soft tissue tumors. Conventional immunohistochemistry uses antibodies directed against lineage-restricted antigens, in an attempt to identify a line of differentiation and narrow down the differential diagnosis. However, in most cases, such markers are inadequate to reach a specific diagnosis. Many soft tissue tumors harbor recurrent, often disease-defining molecular genetic alterations. Increasingly, fluorescence in situ hybridization analysis or next-generation sequencing is employed for identification of such alterations as a diagnostic adjunct. In recent years, immunohistochemistry has been used as a surrogate for such molecular genetic or cytogenetic analysis; this approach can identify the protein correlates of genetic alterations. Numerous next-generation antibodies directed against the protein products of a wide range of genetic alterations (such as gene fusions, amplifications, deletions, and point mutations) have entered our diagnostic armamentarium. In addition, gene expression profiling has uncovered diagnostically useful markers for immunohistochemistry. Finally, epigenetic alterations (eg, methylation) can also be assessed by immunohistochemistry. This review will provide examples of the application of contemporary molecular immunohistochemistry for soft tissue tumor diagnosis.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100912"},"PeriodicalIF":5.5,"publicationDate":"2025-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145292980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Giant Cell-Rich Tumors of Bone and Soft Tissue","authors":"Robert M. van der Linde ,&nbsp;David G.P. van IJzendoorn ,&nbsp;Matt van de Rijn ,&nbsp;Judith V.M.G. Bovée","doi":"10.1016/j.modpat.2025.100915","DOIUrl":"10.1016/j.modpat.2025.100915","url":null,"abstract":"<div><div>Many benign and malignant bone and soft tissue tumors can contain giant cells in variable amounts. In some tumors, such as tenosynovial giant cell tumor and giant cell tumor of bone, these osteoclast-like giant cells are so prominent and characteristic that their presence has defined the entity. Other examples of bone tumors in which the presence of osteoclast-like giant cells is characteristic include chondroblastoma, aneurysmal bone cyst, nonossifying fibroma, and central giant cell granuloma. These tumors have a distinct pathogenesis, although some parallels can be identified. The osteoclast-like giant cells within these tumors are not the neoplastic component but are nonneoplastic bystanders and part of the tumor microenvironment. Notably, the activation of the colony-stimulating factor 1 (CSF1)-CSF1 receptor (CSF1R) and/or the receptor activator of NFκB ligand-receptor activator of NFκB signaling pathways, best studied in tenosynovial giant cell tumor and giant cell tumor of bone, respectively, appears to be key in attracting macrophages and the formation of osteoclast-like giant cells within the tumor. Among soft tissue tumors, a plethora of tumors have been described to contain variable amounts of giant cells, and the underlying mechanisms are so far less well understood. One exception is the recently described keratin-positive giant cell-rich tumor of soft tissue, which also seems to rely on CSF1-CSF1R signaling to attract giant cells. The CSF1-CSF1R and receptor activator of NFκB ligand-receptor activator of NFκB pathways are suitable targets for nonsurgical interventions, and inhibitors of these pathways are already being used for some entities in clinical practice. These inhibitors inhibit tumor growth and may induce bone formation, although pathologists should be aware when evaluating posttreatment specimens that the neoplastic cells remain unaffected.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100915"},"PeriodicalIF":5.5,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145286598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}