Virchows Archiv最新文献

{"title":"Uncertainty-aware and interpretable deep learning in cytopathology: toward trustworthy AI-powered diagnostics.","authors":"Shahid Mehmood, Muzammil Hussain, Muhammad Adnan Khan","doi":"10.1007/s00428-026-04727-4","DOIUrl":"https://doi.org/10.1007/s00428-026-04727-4","url":null,"abstract":"<p><p>Deep learning has shown remarkable success in cytopathology, particularly in cervical cancer screening and thyroid nodule classification. Yet, most models remain \"black boxes,\" offering deterministic predictions without indicating uncertainty or explaining their reasoning, limiting clinical adoption. This review systematically examines uncertainty quantification (UQ) and explainable AI (XAI) techniques for trustworthy deep learning in cytology-the first to do so in this domain. We review state-of-the-art methods such as Bayesian neural networks, Monte Carlo dropout, and deep ensembles for uncertainty estimation, alongside Grad-CAM, attention mechanisms, and surrogate models for interpretability. Applications span cervical, thyroid, urinary, and hematological cytopathology. UQ methods help identify model limitations, flagging cases that need human review, while studies show improved accuracy for high-confidence predictions and better detection of misclassified cases. Visual explanation tools, especially Grad-CAM, highlight diagnostically relevant cellular features that align with pathologists' reasoning. Integrating UQ and XAI fosters effective human-AI collaboration, enabling systems to communicate both confidence levels and diagnostic rationale. This addresses the clinical trust gap, positioning AI as an assistive colleague rather than a black box, ultimately enhancing diagnostic accuracy and efficiency in cytopathology workflows.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149076100","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":"OGT-rearranged mesenchymal neoplasm of the palm with a novel C3orf62/MAPS partner gene: expanding the molecular spectrum of this rare entity.","authors":"Federico Repetto, Klaus J Busam, Arivarasan Karunamurthy, Mohamed Yakoub, Konstantinos Linos","doi":"10.1007/s00428-026-04717-6","DOIUrl":"https://doi.org/10.1007/s00428-026-04717-6","url":null,"abstract":"<p><p>OGT-rearranged mesenchymal neoplasm is a rare, molecularly defined soft tissue tumor with an acral predilection and recurrent fusions involving FOXO1, FOXO3, FOXO4, or CITED1. We report a tumor of the left ulnar palm in a 72-year-old woman presenting as a scaly papule. Shave biopsy demonstrated a bland dermal mesenchymal neoplasm composed of epithelioid to spindled cells arranged in cords and small nests within a hyalinized to fibromyxoid stroma. The lesional cells expressed CD34 diffusely and EMA focally, whereas SOX10 and SMA were negative. Targeted RNA sequencing identified a novel in-frame OGT::C3orf62/MAPS fusion joining OGT exon 22 to MAPS exon 3 and predicted to preserve the OGT enzymatic architecture. MAPS is implicated in phase separation and chromatin organization. This case expands the molecular and clinical spectrum of OGT-rearranged mesenchymal neoplasm, documents C3orf62/MAPS as a novel fusion partner, and highlights its dermal papular presentation as a potential diagnostic pitfall in routine dermatopathology.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148971534","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":"HER2-low metastatic breast cancers: clinic-pathological characteristics, metastatic sites, and survival impact on biomarker discordance.","authors":"Ka Long Leung, Ronald Chan, Howard Leung, Joshua Li, Chaiwat Aphivatanasiri, Yun-Bi Ni, Julia Y Tsang, Man-Chi Eric Fu, Dajiang Guo, Gary M Tse","doi":"10.1007/s00428-026-04710-z","DOIUrl":"https://doi.org/10.1007/s00428-026-04710-z","url":null,"abstract":"<p><p>Trastuzumab Deruxtecan has shown promising results in patients with HER2-low and -ultralow (UL) metastatic breast cancers, attracting extensive research on these tumors. While most studies focus on primary tumors, there is limited data on metastatic disease. Here, we aimed to evaluate the clinicopathological features, metastatic patterns and biomarker discordance in HER2-low/UL metastatic breast cancers. The HER2 status in a large cohort of metastatic breast cancer cases was correlated with different pathological and survival parameters. Data from matched primary tumours were also retrieved for further comparisons. HER2-low metastatic breast cancer is significantly associated with ER positivity (p = 0.033), PR positivity (p = 0.037) and Luminal status (p = 0.047), but no distinct overall survival. These tumors were preferentially found in liver metastases (42.9%), differing significantly from HER2-zero cancers (p < 0.001). Downregulation of HER2-positive primaries to HER2-negative metastasis was found to be the highest in liver (50.0%), and the least in lung (0%). Downregulation of HER2 is associated with poorer OS (Chi-sq = 9.248, p = 0.002). In metastatic settings, features and survival outcomes of HER2-UL are not significantly distinct from HER2-null tumors. HER2-low metastatic cancers largely retain clinicopathological characteristics of their primary origins. Liver is the predominant site of HER2-low metastasis and shows a notable risk of HER2 discordance. Given that discordance, particularly the link of worse outcome to HER2 downregulation, re-evaluation of biomarker status in high-risk sites should be considered to optimise therapeutic strategies.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148956648","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":"Invasive carcinoma ex intraductal carcinoma of the salivary gland showing extensive infiltrative growth despite deceptively low-grade cribriform morphology.","authors":"Meejeong Kim, Jun-Ook Park, Dong-Il Sun, Youn Soo Lee","doi":"10.1007/s00428-026-04715-8","DOIUrl":"https://doi.org/10.1007/s00428-026-04715-8","url":null,"abstract":"<p><p>Intraductal carcinoma (IDC) of the salivary gland is an uncommon neoplasm frequently associated with RET rearrangements, particularly in the intercalated duct subtype. Although invasive carcinoma ex IDC has increasingly been recognized, most reported cases have demonstrated overtly invasive or high-grade morphology distinct from the associated intraductal component. Herein, we report a case of NCOA4::RET fusion-positive IDC of the parotid gland showing extensive infiltrative growth into adjacent soft tissue despite deceptively low-grade cribriform histomorphology. Tumor cells showed diffuse SOX10 and S100 expression, supporting intercalated duct differentiation, while cribriform nests demonstrated heterogeneous myoepithelial cell preservation, ranging from an intact peripheral layer to its complete absence. Targeted next-generation sequencing identified an in-frame NCOA4::RET fusion. This case expands the morphologic spectrum of invasive carcinoma ex IDC and highlights that unequivocal infiltrative growth may occur despite retention of a deceptively low-grade feature.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148956643","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":"Current quality challenges in H&E preparation: The critical foundation for increased use of digital pathology and AI emergence.","authors":"Clément Tondon, Gilles Erb, Caroline Egele, Jean-Philippe Michot, Dominique Fetique, Marie-Pierre Chenard, Jean-Pierre Bellocq","doi":"10.1007/s00428-026-04714-9","DOIUrl":"https://doi.org/10.1007/s00428-026-04714-9","url":null,"abstract":"<p><p>Hematoxylin and Eosin (H&E) glass slide preparation is fundamental to histopathology. Pathologists' expertise routinely mitigates potential issues due to quality variability into or across laboratories, ensuring diagnostic accuracy. However, as artificial intelligence (AI) induced by whole slide imaging (WSI) emerges as a future advancement in pathology, a shift toward greater technical standardisation of the preparations or adaptive algorithms deserves consideration. This study examined longitudinal data (2019-2024) from the French national external quality assessment (EQA) programme integrated with a national survey conducted in 2024. We report that up to 25,5% of H&E slides, varying by tissue type and assessment year, exhibited technical preparation imperfection from multiple stages, including microtomic sectioning, excessive thickness, and tissue stretching. Separately, 8,3% to 23,8% of slides showed suboptimal staining, characterised mainly by insufficient nucleo-cytoplasmic contrast or intensity fluctuations. Advocating sustained quality improvement to prepare for future diagnostic pathology, we emphasise that optimising pre-analytical H&E preparation quality before AI deployment is critical: robust AI performance requires consistent, high-quality inputs rather than reliance on hypothetical post-hoc algorithmic compensation. Prioritising quality at the source reduces computational burden, environmental impact, and deployment costs while enhancing ethical transparency. Our findings provide technical areas for improvement to enhance H&E testing while anticipating AI integration at scale.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148956614","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":"\"Simple Mucinous Cysts\" associated with pancreatic ductal adenocarcinoma: clinicopathologic and radiologic characterization of an enigmatic cyst and additional evidence for its possible pre-cancerous nature.","authors":"Nuray Tezcan, Duygu Atasoy, Burcu Saka, Ayse Armutlu, Cisel Aydin Mericoz, Rohat Esmer, Pelin Bagci, Burcin Pehlivanoglu, Serdar Balci, Takashi Muraki, Jeanette D Cheng, Alyssa M Krasinskas, Michelle D Reid, Olca Basturk, Bengi Gurses, N Volkan Adsay","doi":"10.1007/s00428-026-04705-w","DOIUrl":"https://doi.org/10.1007/s00428-026-04705-w","url":null,"abstract":"<p><p>Simple mucinous cyst (SMC), previously also termed mucinous non-neoplastic cyst, is now recognized as a separate category in the WHO Classification of Pancreatic Tumours. Recent studies have increasingly identified malignancy-associated molecular alterations, high-grade dysplasia (HGD), and even cases of PDAC arising in SMC. We aimed to define the radiologic and pathologic characteristics of this rare entity and to investigate its association with PDAC by analyzing findings from 920 consecutive cases.SMCs were identified in 15 of 920 PDACs (1.6%); together with 7 additional unpublished SMCs, a total of 22 cases were analyzed. Radiologically, SMCs were typically solitary, unilocular, well-circumscribed, round-to-oval cysts with thin, often enhancing walls. They lacked features of IPMNs such as main duct communication (commonly showing a visible separation from the main duct) and cyst-by-cyst architecture. A distinctive feature was their frequent protrusion into the peripancreatic fat. Histologically, SMCs showed a paucicellular fibrous wall lined by mucinous epithelium, often with epithelial denudation. All cases exhibited cytologic atypia. Among the 7 non-PDAC SMCs, four harbored HGD, with a mean cyst size of 2.4 cm. PDAC-associated SMCs were all adjacent to the carcinoma, lacked mural nodules, and had a mean cyst size of 2.7 cm; HGD was identified in 2 of 15.This study further characterizes the pathologic and radiologic phenotype classified as SMC in the 2026 WHO classification and identifies features that aid its distinction from conventional IPMNs, MCNs, secondary cysts, and other mimics. The occurrence of SMCs in 1.6% of PDAC resections, their spatial proximity to PDAC, the presence of HGD, and previously reported cancer-related molecular alterations provide additional evidence that SMC is likely a pre-cancerous lesion, closely related to yet distinct from other pancreatic precursors. Further studies, including clonality analyses, are needed to determine whether associated PDACs develop through sequential progression from SMC, through a branch-off pathway, or independently in the same patient. Until the natural history and molecular relationships of SMC are clarified, management within the broader framework used for mucinous pancreatic cysts appears prudent.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148931251","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":"Expression of tyrosine hydroxylase (TH) in human tumors: a tissue microarray study evaluating 18,666 tumors from 150 different tumor entities.","authors":"Florian Viehweger, Sören Schönig, Natalia Gorbokon, Maximilian Lennartz, Katharina Möller, Anne Menz, Ria Uhlig, Andreas M Luebke, Martina Kluth, Claudia Hube-Magg, Andrea Hinsch, Florian Lutz, Christian Bernreuther, Guido Sauter, David Dum, Andreas H Marx, Ronald Simon, Till Krech, Till S Clauditz, Frank Jacobsen, Eike Burandt, Stefan Steurer, Sarah Minner","doi":"10.1007/s00428-026-04683-z","DOIUrl":"https://doi.org/10.1007/s00428-026-04683-z","url":null,"abstract":"<p><p>TH immunohistochemistry (IHC) has been proposed as a sensitive and specific tool for the distinction of pheochromocytomas or paragangliomas from epithelial neuroendocrine neoplasms and tumors. However, little is known about the prevalence of TH expression in other tumor entities. To comprehensively evaluate TH expression in normal and tumor tissues, a tissue microarray containing 18,666 samples from 150 different tumor types and subtypes and 608 samples of 76 different normal tissue types were analyzed by IHC. TH immunostaining in tumors was always cytoplasmic. It was detectable in 158 (1%) of the 15,630 analyzable tumors, including 23 (0.1%) with weak, 28 (0.2%) with moderate, and 107 (0.7%) with strong positivity Overall, 14 of 150 tumor categories showed detectable TH expression and only 5 tumor categories included at least one case with strong TH positivity. TH staining was most frequent in pheochromocytomas (100%, including 74.0% with strong positivity), ganglioneuroma (25.0%; including 16.7% with strong positivity), paragangliomas \"probably sympathetic\" (50.0%; including 43.8% with strong positivity), and paragangliomas \"probably parasympathetic\" (13.6%; of which all showed strong positivity). Other tumor types showing TH positivity less commonly and at a lower level included medullary thyroid carcinoma (5.9%), squamous cell carcinomas of several organs of origin (up to 4.5%), neuroendocrine neoplasms from several organs (up to 4.3%) and colorectal adenocarcinoma (0.2%). In \"non-neural crest\" derived tumors, TH staining was often limited to few interspersed cells. In conclusion, a strong positive TH immunostaining is highly specific for pheochromocytomas, ganglioneuroma, and paragangliomas although sensitivity is < 30% for paragangliomas.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148945839","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 in CNS tumor diagnostics: a single-centre real-world experience from Central Europe.","authors":"Marián Švajdler, Tomáš Vaněček, Petr Martínek, Veronika Hájková, Jiří Soukup, Tomáš Jirásek, Michal Hendrych, Martin Syrůček, Dagmar Dolinská, Jozef Bocko, Kristýna Pivovarčíková, Richard Koleják, Jan Mraček, Vladimír Přibáň, Peter Švajdler, Miha Jerala, Matic Bošnjak, Marián Grendár, Roman Mezencev","doi":"10.1007/s00428-026-04712-x","DOIUrl":"https://doi.org/10.1007/s00428-026-04712-x","url":null,"abstract":"<p><p>Genome-wide DNA methylation profiling has transformed neuro-oncology by providing an objective, machine learning-based taxonomy that mitigates interobserver variability and refines the histo-molecular criteria of the current WHO classification. We evaluate the real-world diagnostic performance and clinical utility of this modality in a prospective, consecutively accrued three-year cohort of 291 central nervous system (CNS) tumors across a mixed adult-pediatric population. Successful profiling was completed in 95.9% of cases. Using the Epignostix classifier, a high-confidence diagnostic match (calibrated score [CS] ≥ 0.84) was achieved in 70.3% of analyzable samples, while 26.5% returned lower-confidence scores (≥ 0.3 to < 0.84) and only 3.2% remained completely unclassifiable (CS < 0.3). When integrated into a comprehensive diagnostic framework, methylation profiling provided clinically useful results in 81.1% of cases, establishing diagnoses in 70 cases submitted for molecular subclassification and resolving diagnostic uncertainty or prompting major revisions in 149 histologically challenging tumors. Within truly ambiguous lesions, integration of methylome data dictated tumor grade modifications in 38.8% of cases (upgrading in 29.4% and downgrading in 9.4%), shifting patient risk stratification. Crucially, over half (52.7%) of the lower-confidence cases yielded meaningful clinical integration when supported by histomorphology and ancillary genetic or immunohistochemical markers, demonstrating that rigid score cutoffs should not dictate assay failure. Discrepant or misleading classifications occurred in 1.9%. Updating bioinformatic pipelines from version 11b4 to 12.8 rescued multiple ambiguous entries, increasing overall clinical utility to 84.1%. These findings demonstrate that integrating computational epigenomics with classical neuropathology enhances diagnostic precision, while highlighting the ongoing need for careful clinical-pathological correlation.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148913327","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":"Gastric carcinoma classification in the WHO 6th edition (2026): Updated framework and emerging entities.","authors":"Ryoji Kushima","doi":"10.1007/s00428-026-04697-7","DOIUrl":"https://doi.org/10.1007/s00428-026-04697-7","url":null,"abstract":"<p><p>The sixth edition of the WHO Classification of Digestive System Tumours (2026) represents an important step in the continuing evolution of gastric carcinoma classification. While preserving morphology as the foundation of diagnosis, it incorporates advances in molecular pathology, genotype-phenotype correlations, tumour evolution, and predictive biomarker assessment. This review summarizes the development of the WHO classification from the third edition (2000) to the sixth edition (2026) and highlights its relationship with other major classification systems, including those of Laurén, Nakamura, and the Japanese Gastric Carcinoma Association (JGCA). Major histological categories remain largely unchanged; however, several important conceptual and diagnostic refinements have been introduced. These include recognition of crawling-type adenocarcinoma as a distinctive variant of tubular adenocarcinoma, subclassification of poorly cohesive carcinoma into signet-ring cell and non-signet-ring cell subtypes, introduction of the concept of pure signet-ring cell carcinoma, and increased emphasis on tumour evolution. The sixth edition also expands and refines the spectrum of uncommon gastric carcinoma subtypes, including gastric carcinoma with lymphoid stroma, AFP-producing carcinoma, micropapillary adenocarcinoma, gastric adenocarcinoma of fundic-gland type, and gastric sarcomatoid carcinoma. Crucially, molecular subgroups originally proposed by The Cancer Genome Atlas (TCGA) and actionable biomarkers-including HER2 (ERBB2), Claudin 18.2, mismatch repair deficiency/microsatellite instability (dMMR/MSI), and programmed death-ligand 1 (PD-L1)-have transitioned from research-based categories into essential tools for precision oncology. Rather than providing exhaustive diagnostic criteria, this review offers a conceptual framework and encourages consultation of the original WHO text for full details. These advances illustrate the transition of gastric carcinoma classification from a predominantly morphology-based system toward an integrated histomolecular framework that more closely links pathological diagnosis with tumour biology, prognostication, and therapeutic stratification.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148913346","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":"Cribriform tumors of the skin: CD38 expression distinguishes from histologic mimics in a multi-institutional series.","authors":"Taylor Kalomeris, Jeffrey M Cloutier, Shira Ronen, Cecilia Lezcano, Melissa P Pulitzer, Andrea P Moy, Joyce M Chen, Yanming Zhang, Carina A Dehner, Eric C Honaker, Alina Bridges, Cynthia M Magro, Klaus J Busam, Konstantinos Linos","doi":"10.1007/s00428-026-04704-x","DOIUrl":"https://doi.org/10.1007/s00428-026-04704-x","url":null,"abstract":"<p><p>Cribriform tumor of the skin (formerly primary cutaneous cribriform carcinoma/primary cutaneous cribriform apocrine carcinoma) is a rare adnexal neoplasm of uncertain malignant potential. Recent studies have identified recurrent co-deletion of the long arm of chromosomes 6 and 9 and CD38 overexpression as potential diagnostic features, but their sensitivity and specificity remain incompletely defined. We identified 11 cribriform tumors with classic morphologic features, including several previously reported molecular characterized cases and additional unpublished cases, from multiple institutions. CD38 immunohistochemistry was performed on all tumors and compared with a panel of morphologic mimics, including adenoid cystic carcinoma (n = 8), digital papillary adenocarcinoma (n = 8), eccrine/apocrine adenomas (n = 7), hidradenoma (n = 2), and endocrine mucin-producing sweat gland carcinoma (n = 3). SNP array analysis was available in nine cases. Patients had a median age of 47 years with a slight female predominance (64%). Tumors commonly involved the extremities and ranged from 0.3 to 2.0 cm. Histologically, all cases demonstrated a well-circumscribed dermal neoplasm of bland epithelial cells arranged in cribriform architecture with characteristic thread-like intraluminal bridging, without high-grade features. CD38 expression was identified in 9/11 cases (82%), typically with moderate-to-strong diffuse cytoplasmic staining. All morphologic mimics (n = 28) were CD38 negative. Recurrent chromosomal deletions involving 6q and/or 9q were identified in 7/8 (88%) successfully tested cases. Two morphologically classic cribriform tumors lacked CD38 expression, including one with confirmed 6q/9q codeletion, while one CD38-positive case lacked detectable genomic copy number alterations. These findings further support cribriform tumors as a molecularly distinct, low-grade adnexal neoplasm characterized by recurrent 6q/9q deletions and frequent CD38 expression. CD38 appears to be a useful adjunctive diagnostic marker with high specificity among the selected mimics tested, although its sensitivity is incomplete, and absence of staining does not exclude the diagnosis.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148901187","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}