Virchows Archiv最新文献

{"title":"FOS gene fusions in osteosarcoma raise the hypothesis of malignant transformation of osteoblastoma.","authors":"Christophe Bontoux, Marie Csanyi-Bastien, Corinne Bouvier, Frédérique Larousserie, Hervé Sartelet, Marie-Paule Algros, Frédéric Bibeau, Sébastien Aubert, Gonzague de Pinieux, Marie Faruch-Bilfeld, Natacha Roussel, Sofia Galanou, Nathalie Van Acker, David Grand, Mélanie Larquier, Sophie Peries, Pierre Brousset, Solène Evrard, Anne Gomez-Mascard","doi":"10.1007/s00428-025-04202-6","DOIUrl":"https://doi.org/10.1007/s00428-025-04202-6","url":null,"abstract":"<p><p>Osteosarcoma is the most common malignant bone tumor among children and young adults. Distinguishing between osteoblastoma and osteosarcoma can be particularly challenging, especially in small tissue samples and for the osteoblastoma-like osteosarcoma subtype. Recent studies with conflicting results have suggested a potential malignant transformation process from osteoblastoma to osteosarcoma. This study aims to investigate the hypothesis of osteoblastoma evolving into osteosarcoma and to discuss its clinical implications. We conducted a retrospective multicentric case-series study, collecting clinical, radiological, histological, and follow-up data from osteosarcoma cases suspected to have originated from malignant transformation of osteoblastoma within the French ResOs network. Molecular analyses (fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS)) were performed. We included two cases (one female and one male), with a median age at osteosarcoma diagnosis of 42 and 73 years old, respectively. One patient had tumor located in the axial skeleton, and both cases exhibited features of osteoblastoma-like osteosarcoma. Notably, one of the patients had a documented history of osteoblastoma diagnosed sixteen years earlier. FISH analysis revealed FOS rearrangements in both osteosarcoma cases, with tumors presenting uncommon fusion transcripts (FOS::VGLL4 and FOS::COL5A2) identified through NGS. Both patients were alive at last follow-up. Our findings suggest that osteosarcoma can rarely present with FOS gene fusions and be associated with an indolent progression, challenging the specificity of such signatures for osteoblastoma diagnosis. This discovery also raises the hypothesis of malignant transformation from osteoblastoma to osteosarcoma and underscores the necessity for diligent monitoring of FOS-rearranged bone-forming tumors for optimal therapeutic management.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145281159","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":"Discovery metabolomics and genetic analysis reveal lipid pathway alterations associated with malignant phenotype acquisition in pleomorphic adenoma and a novel NTF3::ITPR2 fusion in carcinoma ex pleomorphic adenoma.","authors":"Reydson Alcides de Lima-Souza, Talita de Carvalho Kimura, João Figueira Scarini, Luccas Lavareze, Tayná Figueiredo Maciel, Ingrid Iara Damas, Laura Wachter Hara, Alessandra de Sousa Mesquita, Ana Valéria Colnaghi Simionato, Petr Martínek, Michal Michal, Luiz Paulo Kowalski, Erika Said Abu Egal, Albina Altemani, Alena Skálová, Fernanda Viviane Mariano","doi":"10.1007/s00428-025-04242-y","DOIUrl":"https://doi.org/10.1007/s00428-025-04242-y","url":null,"abstract":"<p><p>Pleomorphic adenoma (PA) is the most common salivary gland tumor. Although it is benign, PA may recur, metastasize, and undergo malignant transformation into carcinoma ex pleomorphic adenoma (CXPA). The mechanisms underlying this transformation are unclear, but it is believed that they involve the accumulation of molecular alterations. This study aimed to analyze the metabolomic profile associated with the acquisition of the malignant phenotype in PA and to identify the metabolic pathways involved in this process. A retrospective analysis was conducted using our institutional Salivary Gland Tumor Registry, which comprises 15 cases each of normal salivary gland (NSG), PA, recurrent PA (RPA), and CXPA. Metabolomic profiling was performed on formalin-fixed, paraffin-embedded tissue samples. Selected CXPA cases underwent genetic sequencing to investigate potential molecular alterations. The analysis revealed changes in carbohydrate, amino acid, and lipid metabolism. Notably, alterations in lipid-related pathways, particularly those involving fatty acids, appeared to play a significanat role in the acquisition of the malignant phenotype. Genetic analysis identified a novel NTF3::ITPR2 fusion in one CXPA case. Additionally, variants were detected in ARID1A, NSD1, XPO1, FOXA1, TP53, GATA2, LZTR1, PIK3CA, IRF4, and CHEK1, with allele frequencies ranging from 10% to 84%, indicating substantial genetic heterogeneity among CXPA cases. This study provides the first comprehensive metabolomic snapshot of malignant phenotype acquisition in PA. Identifying lipid metabolic dysregulation and a novel NTF3::ITPR2 gene fusion highlights potential diagnostic biomarkers and unveils actionable pathways that could be translated into targeted and personalized therapies for salivary gland tumors.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145281143","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":"STR genotyping diagnosis of hydatidiform moles: an assessment of 2871 consecutive products of conceptions.","authors":"Razie Amraei, Na Niu, Mitchel Clark, Elena Ratner, Natalia Buza, Pei Hui","doi":"10.1007/s00428-025-04282-4","DOIUrl":"https://doi.org/10.1007/s00428-025-04282-4","url":null,"abstract":"<p><p>This study evaluated the incidence of hydatidiform moles in a tertiary care setting and examined the efficacy of short tandem repeat genotyping (STR) as a primary ancillary diagnostic tool for molar gestations. Consecutive products of conceptions undergoing genotyping were analyzed. A total of 2871 cases were analyzed, comprising 1693 in-house and 1178 consultation specimens. Patient ages ranged from 10 to 57 years (mean 32, median 33). Laser microdissection was performed in 138 specimens. STR genotyping yielded a definitive diagnosis in 99.5% of cases (2857/2871), classifying them as 282 complete moles (241 monospermic, 41 dispermic), 564 partial moles (546 dispermic, 12 monospermic, 6 triandric tetraploid), and 2006 non-molar gestations (including 125 trisomies, 24 digynic triploids, 4 egg donor conceptions, 1 trigynic tetraploid, 3 androgenetic/biparental mosaics, 2 chimeric twin gestations with a molar component of either monospermic complete mole or heterozygous partial mole, and 1 trigynic tetraploid). Among molar gestations, complete and partial moles accounted for 38.6% and 61.4% of in-house cases and 28.2% and 72.0% of consultation cases, respectively. Notably, complete moles occurred exclusively in patients younger than 15 or older than 50. The mean turnaround time for STR genotyping was 5.3 days overall (5.7 days for in-house and 4.8 days for consultation cases). Hydatidiform moles accounted for 29.4% of the study cohort in our tertiary care setting, with partial hydatidiform moles comprising two-thirds of these cases. With an average turnaround time of 5.3 days and a 99.5% success rate, STR genotyping demonstrated high efficiency in the accurate diagnosis and classification of hydatidiform moles.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276033","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":"Uterine mesenchymal tumour with a novel EWSR1::CTBP1 gene fusion.","authors":"Beata Bode-Lesniewska, Frank Illigen, Matthias S Matter","doi":"10.1007/s00428-025-04205-3","DOIUrl":"https://doi.org/10.1007/s00428-025-04205-3","url":null,"abstract":"<p><p>A growing number of mesenchymal uterine tumours are defined by a specific molecular aberration. We present the case of a 65-year-old woman who presented with postmenopausal bleeding and a large intramural uterine tumour. Histopathological analysis of the resected uterus revealed an intramural, mesenchymal neoplasm comprising of spindle and epithelioid cells, with no immunohistochemical expression of lineage-specific markers and low proliferative activity. Molecular testing using next-generation sequencing (NGS) revealed an EWSR1::CTBP1 gene fusion, which was confirmed by the presence of EWSR1 gene rearrangement detected using fluorescence in situ hybridisation (FISH). Staging revealed no further tumour manifestations, and the 3-year follow-up was uneventful. The EWSR1::CTBP1 gene fusion has never previously been reported in uterine tumours, having been reported in the literature only once, in the context of a gastroblastoma. The presented case expands the range of the gene-fusion-associated mesenchymal tumours of the uterus.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276042","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":"Undifferentiated melanoma: a molecular study of a fatal metastatic \"atypical fibroxanthoma (AFX)\".","authors":"Simon Haefliger, Baptiste Ameline, Veronika Blum, Matthias S Matter, Beata Bode-Lesniewska","doi":"10.1007/s00428-025-04265-5","DOIUrl":"https://doi.org/10.1007/s00428-025-04265-5","url":null,"abstract":"<p><p>Diagnosing undifferentiated spindle cell and pleomorphic tumours of the sun-exposed skin of elderly patients is common and challenging. This paper presents the case of a 64-year-old man with a tumour that was initially diagnosed as an atypical fibroxanthoma, but which metastasised to the bone and lung, resulting in death within two years. Extensive comparative molecular studies were performed using next-generation sequencing (NGS) and methylomic analysis, which demonstrated that the skin tumour and the bone metastases corresponded to the same neoplasms. In addition to other aberrations, NGS analysis of both tumour manifestations revealed NF1 gene mutations, suggesting a diagnosis of undifferentiated melanoma. Interestingly, however, the methylomic analysis grouped the tumours with the \"atypical fibroxanthoma/pleomorphic dermal sarcoma (AFX/PDS)\" class of the reference cases, rather than with conventional or desmoplastic melanomas. Molecular studies may help to reveal the genetic basis of difficult-to-classify undifferentiated skin neoplasms as well as help to estimate their biological potential.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276014","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":"Methylation profiling: a diagnostic tool for the diagnosis of Merkel cell carcinoma of the lymph node without detectable skin primary tumor.","authors":"Paul-Louis Chantreau, Pierre Sohier, Mahtab Samimi, Matthias Tallegas, Anne Tallet, Serge Guyetant, Benjamin Goeppert, Maysa Al-Hussaini, Ferdinand Toberer, Nathalia Giese, Stéphanie Roessler, Andreas von Deimling, Thibault Kervarrec","doi":"10.1007/s00428-025-04271-7","DOIUrl":"https://doi.org/10.1007/s00428-025-04271-7","url":null,"abstract":"<p><p>Merkel cell carcinoma (MCC) is an aggressive tumor mostly related to Merkel cell polyomavirus genomic integration. MCC can present either as a primary cutaneous tumor or as a lymph node metastasis without a primary skin tumor (MCCWOPT). The distinction between MCCWOPT and lymph node metastases of non-cutaneous neuroendocrine carcinomas remains challenging. The present study aims to determine whether the methylation profile can distinguish MCCWOPT from lymph node metastases of extracutaneous neuroendocrine carcinomas. Methylation profiles of twenty MCCWOPT were compared to 23 cutaneous MCC, 37 small-cell lung carcinomas, 17 and 34 well-differentiated neuroendocrine tumors of the ileum and pancreas. Among the controls, cutaneous MCC cases formed a cluster distinct from other extracutaneous neuroendocrine tumors. MCCWOPT clustered together with cutaneous MCC cases. Methylation profiling represents a promising additional tool for the diagnosis of MCCWOPT.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276093","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":"ALK-Rearranged renal neoplasms: update on an institutional cohort.","authors":"Daniel Arizpe, Alexander J Gallan, Adam M Kase, Murli Krishna, Surendra Dasari, Burak Tekin, Rafael E Jimenez, Lori A Erickson, John C Cheville, Sounak Gupta","doi":"10.1007/s00428-025-04292-2","DOIUrl":"https://doi.org/10.1007/s00428-025-04292-2","url":null,"abstract":"<p><p>Anaplastic lymphoma kinase-rearranged renal cell carcinoma (ALK-RCC) is a rare and recently recognized molecular subtype of RCC defined by ALK gene fusions. We describe five ALK-RCC and one likely ALK-rearranged epithelioid mesenchymal neoplasm from both pediatric and adult patients. Tumors exhibited diverse morphologic features, including papillary, mucinous, and cribriform patterns. ALK expression was confirmed in all cases by immunohistochemistry. Molecular profiling revealed several fusion partners including ARNT, EML4, NUMA1, TPM3, and VCL. A single patient with a VCL::ALK gene rearrangement had sickle cell trait. Novel gene rearrangements in RCC include NUMA1::ALK and ARNT::ALK. Metastatic disease was documented in three patients, and two died of disease. This series underscores the morphological heterogeneity of ALK-RCC (including frequent papillary and mucinous features), is informative of novel fusion partners such as NUMA1 and ARNT, further highlights the association of the VCL::ALK fusion with sickle cell trait, and is informative of the natural history of disease in a subset of patients.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276058","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":"Instant confocal histology for the evaluation of kidney transplant procurement biopsies.","authors":"Angela Ernst, Volker Aßfalg, Wolfgang Arns, Luca Cicalese, Avery Koi, Giovanni Gambaro, Albino Eccher, Francesco Pesce, Geoffrey Funk, Matilin Rigsby, Doug Butler, Gavin J Pettigrew, Michael Ströhlein, Alexander Hapfelmeier, Michael Thomas, Dirk Ludger Stippel, Jan U Becker","doi":"10.1007/s00428-025-04270-8","DOIUrl":"https://doi.org/10.1007/s00428-025-04270-8","url":null,"abstract":"<p><p>Prognostic outcome models might help to minimise the discard rates of renal transplants from deceased donors. To this end, we published 2-Step Scores for both delayed graft function and transplant loss with optional histology. With conventional paraffin PAS histology taking at least 3 h excluding transport time, we tested whether fast, mobile confocal histology with portable VivaScope® 2500 systems might offer a viable and more rapid alternative. After omitting 17 biopsies with less than 12 glomeruli and 1 artery, we collected 14 0-h and 16 renal transplant indication (Tx) biopsies for a combined cohort. All biopsies were scanned in less than 10 min with a VivaScope® 2500, rendering pseudo-HE images, and then underwent our regular paraffin work-up. Banff Lesion Scores ct and cv were assessed on the granular ordinal scale and binary as (ct ≤ 1 vs. ct ≥ 2 and cv ≤ 2 vs. cv3) together with the number of glomeruli as used in the previously published 2-Step Scores in a blinded fashion by an expert nephropathologist on the paraffin sections (P) and VivaScope® 2500 scans (V). Additionally, we examined the ratio of globally sclerotic glomeruli. Correlation and mixed effects linear regressions, as well as Fleiss' kappa statistics, comparing P and V on the combined cohort were applied, supplemented with Bland-Altman statistics providing limits of agreement. Between P and V, granular Banff ct correlated with a kappa of 0.513 (p = 8.38e-05) and a Kendall's W of 0.706 (p = 0.0694) on the combined cohort; binary Banff ct correlated with a kappa of 0.869 (p = 1.92e-06). We had to exclude two more biopsies in which no artery was found in the scanning plane in V. Granular Banff cv correlated with a kappa of 0.109 (p = 0.345) and a W of 0.677 (p = 0.103) between P and V on the combined cohort and binary Banff cv with a kappa of 0.24 (p = 0.204). The total number of glomeruli correlated between P and V with an R of 0.75 (p = 2.3e-06), the number of globally sclerotic glomeruli with an R of 0.82 (p = 4.1e-08), and the ratio thereof with an R of 0.86 (p = 8.6e-10). Instant, decentralised VivaScope® 2500 histology might deliver Banff ct and the number of glomeruli with sufficient accuracy for the 2-Step Scores to predict the risk of delayed graft function and 1-year death-censored transplant loss in deceased heart-beating donors. In contrast, VivaScope® 2500 assessment of Banff cv might not be accurate enough for use in 2-Step Scores.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145259371","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":"Calcifying nested stromal-epithelial tumor of the liver: Report of two cases revealing novel WT1 mutation and distinct epigenetic features.","authors":"Andrea Strakova-Peterikova, Franco Fedeli, Boris Rychly, Jiri Soukup, Michael Michal, Petr Martinek, Marian Grendar, Elaheh Mosaieby, Nikola Ptakova, Maryna Slisarenko, Michal Michal, Kvetoslava Michalova","doi":"10.1007/s00428-025-04281-5","DOIUrl":"https://doi.org/10.1007/s00428-025-04281-5","url":null,"abstract":"<p><p>Calcifying nested stromal-epithelial tumor (CNSET) is an extremely rare primary liver tumor of uncertain histogenesis that predominantly occurs in the pediatric age group and young adults. Knowledge regarding the molecular genetic profile of this entity remains limited, with only two molecular studies conducted to date, which identified pathogenic mutations in the CTNNB1 gene and TERT promoter mutations in all analyzable cases. A more aggressive biological potential than previously reported has been only recently unveiled as well. To further advance the understanding of pathogenic mechanisms of CNSET and to investigate the distinctiveness of this rare entity, we analyzed two cases using immunohistochemistry, next-generation sequencing (NGS), and methylation profiling. The latter was employed to compare the epigenetic landscape of CNSET with that of clinicopathologically similar entities, such as hepatoblastoma and solid pseudopapillary neoplasm (SPN) of the pancreas. Both CNSET cases occurred in women (aged 24 and 23 years) and measured 24 cm and 16 cm in diameter, respectively. Both cases showed similar histological features, being composed of organoid nests of bland spindled to epithelioid cells embedded in myofibroblastic stroma. Both cases were immunohistochemically positive for CD56, WT1, and CAM5.2 and negative for hepatocellular and neuroendocrine markers. Case 2 showed aberrant nuclear expression of β-catenin, while in case 1, there was cytoplasmic positivity only. Using Illumina TruSight Oncology 500 NGS panel, case 1 revealed a pathogenic mutation in the WT1 gene and a TERT promoter mutation, and case 2 had a CTNNB1 mutation. DNA methylation analysis showed that CNSET forms a distinct cluster, separate from other reference entities. Follow-up in case 2 revealed a disease-free status 21 months after partial hepatectomy. This study showed that the molecular landscape of CNSET of the liver is characterized by CTNNB1, TERT promoter, and WT1 gene mutations, with the latter representing a novel alteration. Similarly to CTNNB1, the WT1 gene plays a significant role in the Wnt signaling pathway. Given the metastatic potential and chemotherapy resistance of CNSET, understanding its molecular background is important for potential alternative targeted treatment. Methylation profiling confirms CNSET as a distinct entity, separate from hepatoblastoma and SPN of the pancreas.</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":"145252965","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":"Diagnosis and grading of adrenal cortical carcinoma.","authors":"Giulia Vocino Trucco, Eleonora Duregon, Mauro Papotti, Marco Volante","doi":"10.1007/s00428-025-04278-0","DOIUrl":"https://doi.org/10.1007/s00428-025-04278-0","url":null,"abstract":"<p><p>The 5th edition of the WHO classification of endocrine and neuroendocrine tumors represents a significant advancement in the diagnostic approach to adrenocortical carcinoma (ACC), integrating novel molecular insights with established histopathological criteria to enhance diagnostic accuracy and to refine prognostic assessment. This review outlines key histopathological features and diagnostic strategies for ACC, offering a practical framework for evaluation and grading in daily practice. The updated WHO classification reaffirms the central role of histopathology, employing multiparametric scoring systems that assess invasion, architectural and cytological features, mitotic activity, and necrosis. However, these parameters often pose interpretive challenges, and no single algorithm ensures complete sensitivity, specificity, or reproducibility. Therefore, combining diagnostic approaches is advisable, particularly in morphologically ambiguous cases. For tumor grading, the WHO employs a two-tiered system based on a mitotic count cut of 20 per 10 mm², aiming to improve interinstitutional consistency. Immunohistochemistry remains essential for diagnostic confirmation and prognostic evaluation. Among available markers, SF1 is the most specific for adrenocortical origin, while Ki-67, mismatch repair proteins, p53, and β-catenin are useful for predicting patient outcomes or screening for hereditary predisposition. In this complex diagnostic setting, artificial intelligence holds potential to support ACC diagnostics. However, its application is limited by the rarity of the disease, histological variability, and the scarcity of large, well-annotated datasets necessary for algorithm development.</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":"145245421","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}