Virchows Archiv最新文献

{"title":"Myeloperoxidase-positive mononuclear cells predominate over CD3-positive T-lymphocytes in the epidermis of Stevens-Johnson syndrome and toxic epidermal necrolysis.","authors":"Masakazu Fujimoto, Yuki Teramoto, Kai Mizoguchi, Kodai Furuta, Hiroyuki Irie, Yo Kaku, Masahiro Hirata, Kenji Kabashima, Hironori Haga","doi":"10.1007/s00428-025-04279-z","DOIUrl":"https://doi.org/10.1007/s00428-025-04279-z","url":null,"abstract":"<p><p>Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are life-threatening mucocutaneous conditions traditionally regarded as severe T cell-mediated hypersensitivity reactions. However, recent evidence has highlighted the potential role of myeloperoxidase (MPO), primarily produced by neutrophils, in the pathogenesis of SJS/TEN. Here, we examined the expression of MPO in skin biopsy specimens from patients with SJS/TEN (n = 15) to evaluate its diagnostic utility, comparing the findings with those from patients with erythema multiforme (EM) (n = 8) and graft-versus-host disease (GVHD) (n = 10). MPO-positive mononuclear cells were present in all SJS/TEN cases, often outnumbering CD3-positive T cells (86.7%). A significantly higher number of cases with an MPO/CD3 ratio greater than 1 was observed in patients with SJS/TEN compared with that in patients with GVHD (p < 0.01). However, no such difference was observed between SJS/TEN and EM. These findings suggest that an MPO/CD3 > 1 is a pathologic feature of SJS/TEN; however, its specificity may be limited.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145245462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diffuse hemispheric glioma, H3 G34-mutant, a single centre experience and histopathological analysis.","authors":"Faizan Amer, Usman Hassan, Sajid Mushtaq, Asif Loya, Mudassar Hussain, Hina Maqbool","doi":"10.1007/s00428-025-04280-6","DOIUrl":"https://doi.org/10.1007/s00428-025-04280-6","url":null,"abstract":"<p><p>Diffuse hemispheric glioma, H3 G34-mutant, is a rare, recently categorized, high-grade, infiltrative glioma. It usually occurs in the cerebral hemispheres of adolescents and young adults. Mutations in the H3-3A gene play a key oncogenic role in the pathogenesis of this entity, with missense mutations caused by amino acid substitutions at p.G35 (G34) position being the most common. The tumor has a broad histological spectrum, a distinct immunoprofile, and a dismal prognosis. Only a few studies have provided a detailed histopathological analysis of this tumor, and to the best of our knowledge, no study has been published on this tumor within the Pakistani population. The aim of this study is to provide an account of our experience with this tumor within the Pakistani population. Here, we provide a retrospective analysis of 13 cases diagnosed at our hospital, highlighting the extremely varied morphology we encountered, along with their complete immunohistochemical workup.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145245477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Utility of quantitative pathologic analysis of pT1 colorectal carcinomas to improve prediction of lymph node metastasis.","authors":"Priya Nayak, Heidi Kosiorek, Reetesh K Pai, Sameer Shivji, Catherine E Hagen, Rondell P Graham, Daniel D Buchanan, Mark A Jenkins, Amanda I Phipps, Loic Le Marchand, Christina Wu, Niloy J Samadder, Carol J Swallow, Steven J Gallinger, Robert C Grant, Thomas Westerling-Bui, James Conner, David P Cyr, Richard Kirsch, Rish K Pai","doi":"10.1007/s00428-025-04284-2","DOIUrl":"https://doi.org/10.1007/s00428-025-04284-2","url":null,"abstract":"<p><p>According to the National Comprehensive Cancer Network (NCCN), submucosally invasive (pT1) colorectal carcinomas (CRCs) should be evaluated for tumor grade, lymphatic invasion, and tumor budding to determine the risk of lymph node metastasis. The presence of any one of these high-risk features is an indication for surgery in endoscopically removed pT1 CRCs. In this study, we determined if quantitative pathologic analysis with the QuantCRC algorithm can augment NCCN risk stratification in a multi-institutional cohort of 512 surgically resected pT1 CRC. LASSO regression identified %high-grade, %inflammatory stroma (stromal area), and %tumor budding/poorly differentiated clusters (%TB/PDC) as important QuantCRC features and were used in subsequent logistic regression analysis. Five logistic regression models were built using NCCN and QuantCRC variables, with the combined NCCN + QuantCRC model providing the highest Area Under the Curve (AUC) of 0.74 (95% CI 0.68-0.81). A predicted probability cutoff of 0.092 provided a sensitivity of 78.3% and specificity of 62.1% in the NCCN + QuantCRC model with a 24.3% rate of lymph node positivity for high-risk (HR) tumors compared to 5.2% for low-risk (LR) CRCs. Fifteen pT1 CRCs were reclassified from NCCN LR to NCCN + QuantCRC HR and 3/15 (20%) demonstrated lymph node positivity. The median predicted probability of lymph node metastasis in the NCCN + QuantCRC model was used to define two HR groups (HR1: 0.092-0.218 and HR2: > 0.218). HR2 CRCs had a rate of lymph node positivity of 31.5% compared to 17.1% for HR1 CRCs (P = 0.02). Lastly, the NCCN + QuantCRC model was validated in a cohort of 29 endoscopically resected pT1 CRCs followed by surgical resection. In the NCCN + QuantCRC model, the 8 pN + CRCs in this cohort had a higher median predicted probability of lymph node metastasis compared to 21 pN0 CRCs (0.219 vs. 0.080, P = 0.04). In summary, the addition of variables from QuantCRC can improve risk stratification of pT1 CRCs over NCCN criteria alone.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AI assessment of tumor-infiltrating lymphocytes on routine H&E-slides as a predictor of response to neoadjuvant therapy in breast cancer-a real-world study.","authors":"Dusan Rasic, Elisabeth Ida Specht Stovgaard, Anne Marie Bak Jylling, Roberto Salgado, Johan Hartman, Mattias Rantalainen, Anne-Vibeke Lænkholm","doi":"10.1007/s00428-025-04283-3","DOIUrl":"https://doi.org/10.1007/s00428-025-04283-3","url":null,"abstract":"<p><p>Tumor-infiltrating lymphocytes (TILs) are a predictive and prognostic biomarker in triple-negative (TNBC) and HER2 + breast cancer (BC). This study applies artificial intelligence (AI) to evaluate their value in a multi-institutional cohort of TNBC and HER2 + BC patients treated with neoadjuvant chemotherapy (NACT). A supervised deep learning pipeline was developed to analyze hematoxylin and eosin-stained whole-slide images from a discovery cohort of 273 patients and a validation cohort of 245 BC patients. AI quantified stromal TILs percentage, stromal TILs density, and intraepithelial TILs density. Associations between AI-derived TILs metrics, clinicopathological characteristics, and patient outcomes were assessed. AI-based scores were highly correlated with pathologists' scores (Spearman R = 0.61-0.77, p-val < .001). Higher AI-assessed TILs levels were significantly associated with better NACT response, and both stromal and intraepithelial TILs were strong and independent predictors of pathological complete response in TNBC and HER2 + subtypes. Furthermore, patients with higher TILs had longer disease-free survival and overall survival in the discovery cohort and TNBC subtype, but not in HER2 + BC. This study supports AI-driven TILs quantification as a predictive and prognostic tool in BC patients receiving NACT. AI-derived stromal and intraepithelial TILs densities are independent predictors of response, highlighting their potential for integration into digital pathology workflows for risk stratification.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145239747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Superficially located CIC::DUX4-rearranged sarcomas in children: insights from a long-term survival case series.","authors":"Gina Del Vecchio, Rita Alaggio, Alessandra Stracuzzi, Gabriele Gaggero, Isabella Giovannoni, Sabina Barresi, Sabrina Rossi, Francesca Arienzo, Giuseppe Maria Milano, Ida Russo, Monia Di Prete, Carlo Cota, Maja Cesen, Jessica L Davis, Daniel Orbach, Damiano Arciuolo","doi":"10.1007/s00428-025-04231-1","DOIUrl":"https://doi.org/10.1007/s00428-025-04231-1","url":null,"abstract":"<p><p>Soft tissue sarcomas account for approximately 10% of all cancers in the pediatric population, with undifferentiated round cell sarcomas-historically referred to as Ewing-like sarcomas-forming a notable subset. Recent molecular profiling has reclassified these tumors into distinct subtypes, including CIC::DUX4-rearranged sarcomas. While CIC::DUX4 sarcomas are more commonly found in adults, they are rarer in children and are typically located in deep soft tissues. The current study focuses on pediatric cases of superficially located CIC::DUX4 sarcomas, aiming to describe their clinical, morphological, and molecular features. This retrospective study includes pediatric patients diagnosed with superficial CIC::DUX4-rearranged sarcoma from January 2018 to December 2024. Relevant clinical data, including patient demographics, tumor location, and follow-up outcomes, were extracted from medical records. Tumor samples were examined histologically, and RNA sequencing was performed to confirm the presence of the CIC::DUX4 fusion. For survival analysis, we compared our series with 27 pediatric deep-seated CIC::DUX4 sarcomas. Five cases of superficial CIC::DUX4 sarcoma were identified. The patients ranged from 4 to 18 years old, with a mean age of 10.6 years. Only one patient presented with pulmonary metastases at diagnosis. All patients underwent excisional biopsies. Follow-up revealed complete remission in all cases and a statistically significant difference in OS (p = 0.00256) and DFS (p = 0.0239) compared to deep-seated CIC::DUX4 sarcoma. This study presents the first pediatric case series of superficial CIC::DUX4 sarcomas. While CIC::DUX4 sarcomas in adults are known for their aggressive behavior, our findings suggest that superficial tumors with well-defined margins in children may have a more favorable prognosis. These results highlight the need for further research into the biological behavior and long-term outcomes of these rare pediatric tumors.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145239733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Perivascular epithelioid cell tumors of the urinary bladder: a multi-institutional clinicopathologic and molecular analysis of 21 cases.","authors":"Ankur R Sangoi, Anandi Lobo, Ankit Tiwari, Mahmut Akgul, Shivani Kandukuri, Andres M Acosta, Khaleel I Al-Obaidy, Shilpy Jha, Seema Kaushal, Swati Satturwar, Jasreman Dhillon, Adeboye O Osunkoya, Sean R Williamson, Dinesh Pradhan, Rajal B Shah, Anil V Parwani, Liang Cheng, Arndt Hartmann, Sambit K Mohanty, Abbas Agaimy","doi":"10.1007/s00428-025-04250-y","DOIUrl":"https://doi.org/10.1007/s00428-025-04250-y","url":null,"abstract":"<p><p>While perivascular epithelioid cell tumor (PEComas) have been described in most organ systems, only a few bladder PEComas have been reported. Although most behave in an indolent fashion, a subset may develop metastasis. Herein, we describe the clinicopathologic and molecular characteristics of 21 bladder PEComas, including biomarker analysis and comprehensive sequencing. Patients included 13 females and 8 males, with age ranging from 17-81 years (mean = 47.6 years). Clinical follow-up data was available for 17 patients (ranging 5-60 months; mean = 19.4 months). The morphologic features significantly associated with metastatic disease included ≥ 2 mitoses/10 high-power fields (p = 0.0023), atypical mitoses (p = 0.0152), and necrosis (p = 0.0023); the presence of ≥ 70% atypical epithelioid cells and vascular invasion did not meet statistical significance. The Biomarker profile (p16, p53, TRIM63 ISH, ATRX, RB1) found no statistical significance with metastasis. TRIM63 ISH showed high sensitivity (86%) with poor specificity (11%) for TFE3 rearrangements. NGS revealed TFE3 fusions in 8/17 cases (47%): 7 with SFPQ::TFE3 fusions and 1 with NONO::TFE3 fusion). Overall, mTOR pathway mutations were detected in 9 cases (53%): TSC1/2 mutations in 6 (35%), MTOR mutation in 1 (6%), and co-mutations of TSC/MTOR in 2 (12%) cases. Additionally, co-mutations involving p53 were noted in 2 tumors (1 SFPQ::TFE3/p53; 1 MTOR/p53). Metastasis was identified in 5 TFE3-rearranged PEComas (OR = 8.7509) and 2 TSC/MTOR- mutated tumors (OR = 0.1143). TFE3-rearranged bladder PEComas show a higher propensity towards aggressive behavior compared to TSC/MTOR- mutated tumors. Awareness of the molecular signature may be important for prognostic stratification and targeted therapeutic approaches.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145226245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteomic subtyping highlights tumor heterogeneity of human HCC.","authors":"Thomas Ritz, Jovan Tanevski, Jana Baues, Sven H Loosen, Tom Luedde, Ulf Neumann, Peter Boor, Peter Schirmacher, Julio Saez-Rodriguez, Thomas Longerich","doi":"10.1007/s00428-025-04260-w","DOIUrl":"https://doi.org/10.1007/s00428-025-04260-w","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) has a poor prognosis. While molecular profiling has identified subclasses with potentially druggable pathways, implementation in routine diagnostics remains challenging. Although immunohistology may aid HCC classification, multiplexed protein-based approaches have not yet been established. Proteomic heterogeneity in HCC tissue also remains poorly understood. Tissue microarrays from 58 HCC patients were analyzed using a multispectral imaging platform, enabling the detection of multiple protein biomarkers on a single tissue slide. A machine learning-based algorithm facilitated single-cell expression analysis, clustering, and spatial distribution assessment. A 4-plex immunofluorescence marker panel was designed and applied to interrogate altered signaling pathways in HCC. Unsupervised analysis revealed four factors corresponding to three HCC clusters defined by the overexpression patterns of p-S6/CRP (Cluster A), glutamine synthetase (Cluster B), and EpCam (Cluster C). Single-cell resolution uncovered substantial intratumoral heterogeneity. Only one third of HCCs showed a ≥ 0.95 purity of tumor cells in the predominant cluster. Clinically, Cluster C was associated with reduced median overall survival, while the other clinico-pathological features were not significantly different between the clusters. A protein-based subclassification of human HCC was established, characterized by three distinct subclasses (inflammation, beta-catenin/WNT signaling, progenitor-like) that align with known molecular categories. Cases with dominant progenitor features tended to have a shorter survival probability. The intratumoral heterogeneity observed in most cases may promote therapy resistance and underscores the need for precise molecular stratification to improve treatment outcomes.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ERBB2/ERBB3‑mutated S100/SOX10‑positive high‑grade uterine sarcoma-a case report on a rare entity.","authors":"Xingming Huang, Ying He, Wei Wang","doi":"10.1007/s00428-025-04257-5","DOIUrl":"https://doi.org/10.1007/s00428-025-04257-5","url":null,"abstract":"<p><p>ERBB2/ERBB3‑mutated S100/SOX10‑positive uterine sarcoma is a recently described entity with distinct morphological, immunophenotypic, and molecular features, representing a subset of high-grade uterine sarcomas. This tumor is characterized by ERBB2/ERBB3 mutations or ERBB2 amplification, which leads to the overexpression or constitutive activation of HER2. The presence of HER2 amplification represents a potential target for the treatment with HER2 inhibitors. Here we present a case of high-grade uterine cervix sarcoma with ERBB2 amplification and S100/SOX10 expression in a 58-year-old patient. The tumor measured 50 mm at its largest dimension and recurred two years after surgery. Histologically, the tumor was composed of round and spindle cell, showing diffuse nuclear expression of SOX10 and both nuclear and cytoplasm expression of S100. It also demonstrated ERBB2 amplification, as well as mutations in ATRX and BACH1. Accurate recognition of such tumors is crucial due to their propensity for aggressive behavior and the availability of potential targeted therapeutic options.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145201568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biphasic (squamoid) papillary renal cell carcinoma: a distinct molecular and morphologic subtype within the PRCC spectrum.","authors":"Zhichun Lu, Yan Zhou, Wei Fan, Sanket Choksi, Lila Sultan, Mark H Katz, David S Wang, Qing Zhao, Shi Yang","doi":"10.1007/s00428-025-04248-6","DOIUrl":"https://doi.org/10.1007/s00428-025-04248-6","url":null,"abstract":"<p><p>Biphasic (squamoid) papillary renal cell carcinoma (BPRCC) is a recently recognized and rare variant of renal cell carcinoma, defined by biphasic morphology and distinct immunophenotypic features. Previously considered a subtype of classic papillary RCC, its clinicopathologic and molecular characteristics remain underexplored. We analyzed ten BPRCC cases for histologic, immunophenotypic, molecular, and clinical features. The cohort included seven men and three women (median age = 48 years), with tumors measuring 25-45 mm, all staged as pT1. No disease progression or cancer-related deaths were observed over a median follow-up of 55 months. Histologically, all tumors showed biphasic architecture with variable proportions of large eosinophilic squamoid and smaller basophilic cells. One tumor demonstrated focal rhabdoid-like features. Immunostains were diffusely positive for PAX8, CK7, AMACR, and Claudin4. The two cell populations showed differential expression of Cyclin D1, AMACR, HMWCK (K903), E-cadherin, and Ki-67. All tumors were negative for GATA3, p63, and CAIX (focal in 2 cases), and showed intact p53, RB1, and mismatch repair proteins. FISH confirmed trisomy 7 and 17 in all tumors. Targeted NGS revealed MET amplification (2 cases), MET mutation (1 case), NOTCH1 mutations (9 cases), and alterations in MAP2K2, FGFR4, DDR pathway genes (e.g., PMS2, CDK12R44W, RAD51C/D), and chromatin remodeling genes (EZH2, ARID1A). These findings support BPRCC as a distinct subtype of papillary RCC with consistent biphasic morphology, immunophenotypic divergence, and a unique molecular profile enriched for NOTCH, MAPK, and DDR pathway alterations.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145178838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nodal gamma-delta T-cell lymphoma: expression of TFH-markers causing diagnostic difficulties in a newly described entity.","authors":"Viola Katharina Vetter, Tobias Benoit, Sepehr Rahmani-Khajouei, Daniel Bender, Roman Inauen, Nadia Djerbi, Thorsten Zenz, Marco Matteo Bühler","doi":"10.1007/s00428-025-04268-2","DOIUrl":"https://doi.org/10.1007/s00428-025-04268-2","url":null,"abstract":"<p><p>Gamma-delta T-cell lymphomas are rare, aggressive neoplasms derived from γδ T-cells, typically presenting with extranodal disease. Recently, a distinct lymphonodal subtype, nodal gamma-delta T-cell lymphoma (NGDTCL), has been recognized, which is not well reflected in current lymphoma classifications.We here report a unique case of NGDTCL in a 61-year-old male presenting with cervical lymphadenopathy and refractory disease despite multiple lines of therapy. Histopathological analysis revealed diffuse infiltration of a CD4+ gamma-delta T-cell lymphoma, with loss of CD7 and absence of cytotoxic marker expression. Notably, the lymphoma cells expressed two T follicular helper (TFH) cell markers, PD-1 and ICOS, initially leading to misclassification as a TFH lymphoma. Genomic profiling revealed pathogenic alterations of TP53, CHEK2, and loss of CDKN2A and CDKN2B. Additionally, a rearrangement of the ITK-gene, which is believed to play a role in γδ T-cell development, was identified. To our knowledge, this is the first report of a NGDTCL with co-expression of two TFH markers. This case broadens the phenotypic spectrum of NGDTCL and challenges current diagnostic concepts of T-cell lymphoma classification, particularly the notion that expression of CD4 and two TFH markers are sufficient for diagnosing nodal TFH lymphomas.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145151128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}