Pub Date : 2026-01-01Epub Date: 2025-12-09DOI: 10.1016/j.modpat.2025.100948
Ji Hye Moon , Jiyun Hong , Seoung Wan Chae , Inwoong Choi , Chaejoo Kim , Jeong Mo Bae , Gyeong Hoon Kang , Sangwoo Kim , Minsun Jung , Jung Ho Kim
Regional lymph node metastasis is one of the main factors affecting cancer staging. However, the clinical and immunologic implications of nonmetastatic regional lymph nodes (nrLNs) remain poorly understood. Here, we investigated the prognostic significance of the morphologic features of nrLNs in colorectal cancer (CRC) with microsatellite instability-high (MSI-H). Artificial intelligence–aided digital pathology-based quantification of 37 histologic parameters in 873 whole-slide images comprising 5785 nrLNs was performed in 2 independent cohorts of curatively resected MSI-H CRCs (discovery, n = 103; validation, n = 90). The prognostic value of each histologic parameter was evaluated by univariate and multivariate disease-free survival analyses. Quantitative immunohistochemical analysis of tumor-infiltrating immune cells and whole-exome and transcriptome sequencing using tumor tissues were performed to assess associations between prognostic nrLN histologic features and various tumor immuno-molecular factors. As a result, germinal center (GC)–related histologic parameters, including the maximum area, mean area, sum area, and maximum diameter of GCs in the nrLNs, were identified as independent prognostic factors in both cohorts. The prognostic GC-related factors of nrLNs were significantly associated with tertiary lymphoid structures and B cell pathways activation but were not or inversely correlated with the densities of tumor-infiltrating T cells and macrophages. No significant associations were found between prognostic nrLN GC features and major tumor molecular factors such as tumor mutational burden, driver mutations, consensus molecular subtype, or CpG island methylator phenotype. In conclusion, quantitative GC-related histology of nrLNs can serve as a prognostic indicator for MSI-H CRC. Our findings suggest that GC-activated nrLNs may represent B cell–mediated antitumor immunity, independent of tumor-infiltrating T cells and tumor-intrinsic molecular characteristics.
{"title":"Quantitative Histology of Nonmetastatic Regional Lymph Nodes as a Novel Prognostic Indicator in Microsatellite Instability–High Colorectal Cancer","authors":"Ji Hye Moon , Jiyun Hong , Seoung Wan Chae , Inwoong Choi , Chaejoo Kim , Jeong Mo Bae , Gyeong Hoon Kang , Sangwoo Kim , Minsun Jung , Jung Ho Kim","doi":"10.1016/j.modpat.2025.100948","DOIUrl":"10.1016/j.modpat.2025.100948","url":null,"abstract":"<div><div>Regional lymph node metastasis is one of the main factors affecting cancer staging. However, the clinical and immunologic implications of nonmetastatic regional lymph nodes (nrLNs) remain poorly understood. Here, we investigated the prognostic significance of the morphologic features of nrLNs in colorectal cancer (CRC) with microsatellite instability-high (MSI-H). Artificial intelligence–aided digital pathology-based quantification of 37 histologic parameters in 873 whole-slide images comprising 5785 nrLNs was performed in 2 independent cohorts of curatively resected MSI-H CRCs (discovery, <em>n</em> = 103; validation, <em>n</em> = 90). The prognostic value of each histologic parameter was evaluated by univariate and multivariate disease-free survival analyses. Quantitative immunohistochemical analysis of tumor-infiltrating immune cells and whole-exome and transcriptome sequencing using tumor tissues were performed to assess associations between prognostic nrLN histologic features and various tumor immuno-molecular factors. As a result, germinal center (GC)–related histologic parameters, including the maximum area, mean area, sum area, and maximum diameter of GCs in the nrLNs, were identified as independent prognostic factors in both cohorts. The prognostic GC-related factors of nrLNs were significantly associated with tertiary lymphoid structures and B cell pathways activation but were not or inversely correlated with the densities of tumor-infiltrating T cells and macrophages. No significant associations were found between prognostic nrLN GC features and major tumor molecular factors such as tumor mutational burden, driver mutations, consensus molecular subtype, or CpG island methylator phenotype. In conclusion, quantitative GC-related histology of nrLNs can serve as a prognostic indicator for MSI-H CRC. Our findings suggest that GC-activated nrLNs may represent B cell–mediated antitumor immunity, independent of tumor-infiltrating T cells and tumor-intrinsic molecular characteristics.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100948"},"PeriodicalIF":5.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743406","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}
Pub Date : 2026-01-01Epub Date: 2025-11-07DOI: 10.1016/j.modpat.2025.100932
Elias Baumann , Luca E.M. Schäfer , Frédérique Meeuwsen , Richard Kirsch , Iris D. Nagtegaal , Martin D. Berger , Heather Dawson , Inti Zlobec
Microsatellite instability (MSI) is an important biomarker in colorectal cancer, influencing both patient prognosis and treatment decisions. Current approaches for MSI prediction from hematoxylin and eosin--stained whole-slide images (WSI) rely on end-to-end deep learning (“black-box”) models with limited interpretability, often relying on heatmaps for visualization. However, experienced pathologists can intuitively identify MSI through specific histologic features and have developed manual classification systems such as MS-Path for Lynch syndrome screening. We present a novel hybrid approach that combines computational and pathologist expertise to create an explainable and verifiable method for MSI prediction in colorectal cancer, applicable to resection and biopsy WSI. Our proposed method uses nuclei and tissue segmentation models to automatically quantify MSI-associated histologic features outlined in the Bethesda guidelines, including intraepithelial lymphocytes, grade of differentiation, mucinous components, and tertiary lymphoid structures. After validation on annotated data sets, these features are integrated with clinical data and used in logistic regression and random forest models to predict MSI status. We validated our approach using 3256 WSI from 2267 patients across 7 cohorts from 5 centers. The method achieved an area under the curve of up to 0.88 across all resection cohorts, and 0.90 on biopsies, performing on par with published black-box deep learning models. Importantly, the learned variable importances strongly correlated with manual scoring systems and aligned with manual pathologist assessments. We observed significant intrapatient heterogeneity in predicted scores, emphasizing the importance of whole-case analysis. Our approach also shows potential as a screening tool that could exclude 41% of patients from gold-standard MSI testing while maintaining 95% sensitivity. This study demonstrates that classifiers based on clinical and validated histologic information can predict MSI status as effectively as black-box models while providing complete interpretability. Our method offers an alternative pathway for understandable, explainable, and trustworthy biomarker prediction in computational pathology.
{"title":"MSAI-Path: Predicting Microsatellite Instability From Routine Histology Slides Without Reinventing the Wheel","authors":"Elias Baumann , Luca E.M. Schäfer , Frédérique Meeuwsen , Richard Kirsch , Iris D. Nagtegaal , Martin D. Berger , Heather Dawson , Inti Zlobec","doi":"10.1016/j.modpat.2025.100932","DOIUrl":"10.1016/j.modpat.2025.100932","url":null,"abstract":"<div><div>Microsatellite instability (MSI) is an important biomarker in colorectal cancer, influencing both patient prognosis and treatment decisions. Current approaches for MSI prediction from hematoxylin and eosin--stained whole-slide images (WSI) rely on end-to-end deep learning (“black-box”) models with limited interpretability, often relying on heatmaps for visualization. However, experienced pathologists can intuitively identify MSI through specific histologic features and have developed manual classification systems such as MS-Path for Lynch syndrome screening. We present a novel hybrid approach that combines computational and pathologist expertise to create an explainable and verifiable method for MSI prediction in colorectal cancer, applicable to resection and biopsy WSI. Our proposed method uses nuclei and tissue segmentation models to automatically quantify MSI-associated histologic features outlined in the Bethesda guidelines, including intraepithelial lymphocytes, grade of differentiation, mucinous components, and tertiary lymphoid structures. After validation on annotated data sets, these features are integrated with clinical data and used in logistic regression and random forest models to predict MSI status. We validated our approach using 3256 WSI from 2267 patients across 7 cohorts from 5 centers. The method achieved an area under the curve of up to 0.88 across all resection cohorts, and 0.90 on biopsies, performing on par with published black-box deep learning models. Importantly, the learned variable importances strongly correlated with manual scoring systems and aligned with manual pathologist assessments. We observed significant intrapatient heterogeneity in predicted scores, emphasizing the importance of whole-case analysis. Our approach also shows potential as a screening tool that could exclude 41% of patients from gold-standard MSI testing while maintaining 95% sensitivity. This study demonstrates that classifiers based on clinical and validated histologic information can predict MSI status as effectively as black-box models while providing complete interpretability. Our method offers an alternative pathway for understandable, explainable, and trustworthy biomarker prediction in computational pathology.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100932"},"PeriodicalIF":5.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145482511","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}
Pub Date : 2026-01-01Epub Date: 2025-11-07DOI: 10.1016/j.modpat.2025.100933
Josiane Gonçalves , Bruna P. Coura , Vanessa F. Bernardes , Luiz A. De Marco , Manoela D. Martins , Danyel E. da C. Perez , Ricardo S. Gomez , Carolina C. Gomes
The adenomatoid odontogenic tumor (AOT) is a benign, encapsulated odontogenic tumor characterized by slow growth and indolent behavior. AOT shows mitogen-activated protein kinase/ERK pathway activation, and KRAS p.Gly12Val or p.Gly12Arg mutations occur in 70% of cases. The molecular events underlying the pathogenesis of the other 30% of cases remain unclear. The BRAF p.Val600Glu mutation was reported by a single study in 2 AOT cases, 1 of which also harbored KRAS p.Gly12Val. Given that BRAF p.Val600Glu has not been previously detected in AOT and that BRAF and KRAS mutations are mutually exclusive, we aimed to assess BRAF p.Val600Glu irrespective of KRAS mutational status to explore the potential involvement of BRAF mutations in AOT pathogenesis and the co-occurrence of BRAF and KRAS mutations. Whereas KRAS codon 13 and 61 hotspot mutations have not been previously detected in AOT, KRAS codon 146 hotspot mutations have been investigated in a few AOT cases to date. Therefore, we further sequenced KRAS codon 146 in KRAS codon 12 wild-type cases. A total of 29 AOT samples, including 21 KRAS codon 12 mutation-positive cases and 8 wild-type cases, were evaluated for the BRAF p.Val600Glu pathogenic mutation using allele-specific qPCR and/or Sanger sequencing. In addition, KRAS codon 146 was Sanger sequenced in 4 out of 29 samples. BRAF p.Val600Glu was not detected in any of the 29 AOT cases evaluated, either alone or as a comutation with KRAS mutations. All codon 12 wild-type cases were wild-type for KRAS codon 146 mutations. These findings reinforce that KRAS codon 12 mutant alleles predominate in the context of AOT tumorigenesis, whereas BRAF p.Val600Glu does not constitute a molecular feature of this tumor and the presence of the BRAF mutation does not support the diagnosis of AOT in challenging cases. In addition, the results further strengthen the notion that BRAF and KRAS mutations are mutually exclusive events.
{"title":"BRAF p.Val600Glu Mutations Are Not Detected in Adenomatoid Odontogenic Tumors","authors":"Josiane Gonçalves , Bruna P. Coura , Vanessa F. Bernardes , Luiz A. De Marco , Manoela D. Martins , Danyel E. da C. Perez , Ricardo S. Gomez , Carolina C. Gomes","doi":"10.1016/j.modpat.2025.100933","DOIUrl":"10.1016/j.modpat.2025.100933","url":null,"abstract":"<div><div>The adenomatoid odontogenic tumor (AOT) is a benign, encapsulated odontogenic tumor characterized by slow growth and indolent behavior. AOT shows mitogen-activated protein kinase/ERK pathway activation, and <em>KRAS</em> p.Gly12Val or p.Gly12Arg mutations occur in 70% of cases. The molecular events underlying the pathogenesis of the other 30% of cases remain unclear. The <em>BRAF</em> p.Val600Glu mutation was reported by a single study in 2 AOT cases, 1 of which also harbored <em>KRAS</em> p.Gly12Val. Given that <em>BRAF</em> p.Val600Glu has not been previously detected in AOT and that <em>BRAF</em> and <em>KRAS</em> mutations are mutually exclusive, we aimed to assess <em>BRAF</em> p.Val600Glu irrespective of <em>KRAS</em> mutational status to explore the potential involvement of <em>BRAF</em> mutations in AOT pathogenesis and the co-occurrence of <em>BRAF</em> and <em>KRAS</em> mutations. Whereas <em>KRAS</em> codon 13 and 61 hotspot mutations have not been previously detected in AOT, <em>KRAS</em> codon 146 hotspot mutations have been investigated in a few AOT cases to date. Therefore, we further sequenced <em>KRAS</em> codon 146 in <em>KRAS</em> codon 12 wild-type cases. A total of 29 AOT samples, including 21 <em>KRAS</em> codon 12 mutation-positive cases and 8 wild-type cases, were evaluated for the <em>BRAF</em> p.Val600Glu pathogenic mutation using allele-specific qPCR and/or Sanger sequencing. In addition, <em>KRAS</em> codon 146 was Sanger sequenced in 4 out of 29 samples. <em>BRAF</em> p.Val600Glu was not detected in any of the 29 AOT cases evaluated, either alone or as a comutation with <em>KRAS</em> mutations. All codon 12 wild-type cases were wild-type for <em>KRAS</em> codon 146 mutations. These findings reinforce that <em>KRAS</em> codon 12 mutant alleles predominate in the context of AOT tumorigenesis, whereas <em>BRAF</em> p.Val600Glu does not constitute a molecular feature of this tumor and the presence of the <em>BRAF</em> mutation does not support the diagnosis of AOT in challenging cases. In addition, the results further strengthen the notion that <em>BRAF</em> and <em>KRAS</em> mutations are mutually exclusive events.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100933"},"PeriodicalIF":5.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145482539","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}
Pub Date : 2026-01-01Epub Date: 2025-11-22DOI: 10.1016/j.modpat.2025.100941
Lucy Wang , Varshini Vasudevaraja , Jonathan Serrano , Jennifer Kerkhof , Jessica Rzasa , Stephen Kelly , Esther Oliva , Robert H. Young , Lars-Christian Horn , Kay J. Park , Amir Momeni-Boroujeni , Cristina R. Antonescu , Nadeem R. Abu-Rustum , Yanming Zhang , Lu Wang , Achim Jungbluth , Marc K. Rosenblum , Bekim Sadikovic , Igor Dolgalev , Matija Snuderl , Sarah Chiang
Gynecologic neuroectodermal tumors either exhibit central nervous system (CNS) differentiation (CNS-like) or represent Ewing sarcoma (EWS), which lacks CNS features and harbors FET-ETS gene fusions. DNA methylation profiling reclassified CNS primitive neuroectodermal tumors into common CNS neoplasms or embryonal tumors with specific epigenetic/genetic characteristics. Its utility in classifying gynecologic neuroectodermal tumors is unknown. Whole-genome DNA methylation profiling was performed on 26 gynecologic neuroectodermal tumors (22 CNS-like tumors, 4 EWS) arising in the ovary, paratubal soft tissue, uterus, and vulva, which were classified by using sarcoma and CNS tumor DNA methylation classifiers. Sarcoma-related gene fusions were confirmed by fluorescence in situ hybridization or targeted RNA next-generation sequencing. Tumor-only whole-exome sequencing (WES) was performed in 13 cases. Copy number alterations and zygosity were inferred from DNA methylation array and WES data. Methylation abnormalities associated with imprinting were examined. The sarcoma methylation classifier identified EWS (n = 3) and high-grade endometrial stromal sarcoma (n = 1), confirmed by fluorescence in situ hybridization or next-generation sequencing detection of EWSR1 and YWHAE rearrangements, respectively. The remaining CNS-like tumors were classified by DNA methylation with positive/valid (n = 4), indeterminate (n = 9), and negative (n = 9) scores at the family level. Methylation subclasses included teratoma; embryonal tumor with multilayered rosettes, atypical; medulloblastoma, SHH-activated, subtype 3; medulloblastoma, group 3; intraocular medulloepithelioma; supratentorial ependymoma, ZFTA::RELA fused, subclass A; and diffuse pediatric-type high-grade glioma, MYCN subtype. Male biological sex was predicted in 54% of methylation-confirmed CNS-like tumors and none of the sarcomas. Among CNS-like tumors, copy number analyses identified genome-wide chromosomal gains and losses, and WES revealed genome-wide allelic imbalance suggestive of genome-wide duplications. Epigenetic imprinting analyses showed increased paternal or maternal imprinting signal across multiple chromosomes, suggesting uniparental duplication. DNA methylation profiling successfully classified gynecologic neuroectodermal tumors as known CNS tumors or sarcoma entities. Epigenetic and exomic studies indicate a male genome and increased maternal allelic contribution in CNS-like tumors, suggesting development via conception or chimerism.
{"title":"DNA Methylation Profiling Classifies and Reveals Origin of Gynecologic Central Nervous System-Like Tumors","authors":"Lucy Wang , Varshini Vasudevaraja , Jonathan Serrano , Jennifer Kerkhof , Jessica Rzasa , Stephen Kelly , Esther Oliva , Robert H. Young , Lars-Christian Horn , Kay J. Park , Amir Momeni-Boroujeni , Cristina R. Antonescu , Nadeem R. Abu-Rustum , Yanming Zhang , Lu Wang , Achim Jungbluth , Marc K. Rosenblum , Bekim Sadikovic , Igor Dolgalev , Matija Snuderl , Sarah Chiang","doi":"10.1016/j.modpat.2025.100941","DOIUrl":"10.1016/j.modpat.2025.100941","url":null,"abstract":"<div><div>Gynecologic neuroectodermal tumors either exhibit central nervous system (CNS) differentiation (CNS-like) or represent Ewing sarcoma (EWS), which lacks CNS features and harbors FET-ETS gene fusions. DNA methylation profiling reclassified CNS primitive neuroectodermal tumors into common CNS neoplasms or embryonal tumors with specific epigenetic/genetic characteristics. Its utility in classifying gynecologic neuroectodermal tumors is unknown. Whole-genome DNA methylation profiling was performed on 26 gynecologic neuroectodermal tumors (22 CNS-like tumors, 4 EWS) arising in the ovary, paratubal soft tissue, uterus, and vulva, which were classified by using sarcoma and CNS tumor DNA methylation classifiers. Sarcoma-related gene fusions were confirmed by fluorescence in situ hybridization or targeted RNA next-generation sequencing. Tumor-only whole-exome sequencing (WES) was performed in 13 cases. Copy number alterations and zygosity were inferred from DNA methylation array and WES data. Methylation abnormalities associated with imprinting were examined. The sarcoma methylation classifier identified EWS (n = 3) and high-grade endometrial stromal sarcoma (n = 1), confirmed by fluorescence in situ hybridization or next-generation sequencing detection of <em>EWSR1</em> and <em>YWHAE</em> rearrangements, respectively. The remaining CNS-like tumors were classified by DNA methylation with positive/valid (n = 4), indeterminate (n = 9), and negative (n = 9) scores at the family level. Methylation subclasses included teratoma; embryonal tumor with multilayered rosettes, atypical; medulloblastoma, SHH-activated, subtype 3; medulloblastoma, group 3; intraocular medulloepithelioma; supratentorial ependymoma, <em>ZFTA::RELA</em> fused, subclass A; and diffuse pediatric-type high-grade glioma, MYCN subtype. Male biological sex was predicted in 54% of methylation-confirmed CNS-like tumors and none of the sarcomas. Among CNS-like tumors, copy number analyses identified genome-wide chromosomal gains and losses, and WES revealed genome-wide allelic imbalance suggestive of genome-wide duplications. Epigenetic imprinting analyses showed increased paternal or maternal imprinting signal across multiple chromosomes, suggesting uniparental duplication. DNA methylation profiling successfully classified gynecologic neuroectodermal tumors as known CNS tumors or sarcoma entities. Epigenetic and exomic studies indicate a male genome and increased maternal allelic contribution in CNS-like tumors, suggesting development via conception or chimerism.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100941"},"PeriodicalIF":5.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145596797","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}
Pub Date : 2026-01-01Epub Date: 2025-11-13DOI: 10.1016/j.modpat.2025.100936
Atif Ali Hashmi, Theodore Vougiouklakis, Andrea Gazzo, Hannah Y. Wen, Dara Ross, Fresia Pareja, Edi Brogi
Lung carcinoma metastatic to the breast (bLM) or axillary lymph nodes (lnLM) may closely mimic primary triple-negative breast carcinoma (BC), leading to possible misdiagnosis. We characterized the clinical, morphologic, and molecular features of a series of lung carcinomas metastatic to breast and regional lymph nodes to identify diagnostic clues and pitfalls. The study cohort consisted of 30 patients (27 women, 3 men) with a median age of 72 years (range, 46-86); 21 patients (70%) reported a smoking history. At the time of the index biopsy, 4 patients (13.3%) had no history of lung carcinoma. Most tumors (n = 25, 83.3%) were bLM; 4 (13.3%) were lnLM, and 1 was a supraclavicular lymph node metastasis. In 7 of 23 cases (30.4%) with available paired imaging studies, the bLM was larger than the lung tumor. Of the 30 cases, 26 (86.7%) were adenocarcinomas, 2 (6.7%) were small cell carcinomas, and 2 (6.7%) were atypical carcinoids. Metastatic adenocarcinoma resembled BC with apocrine morphology in 16 of 30 cases (53.3%), 6 cases (20%) had vacuolated cytoplasm, and 6 (20%) had micropapillary features. One bLM closely mimicked ductal carcinoma in situ morphologically, and another case showed peripheral expression of CK5/14 and p63 mimicking myoepithelium around ductal carcinoma in situ. Initial diagnosis of BC had been rendered in 7 cases (6 adenocarcinomas and 1 small cell carcinoma). Molecular analysis of 18 cases showed that the most altered cancer genes were TP53 (44%), KRAS (44%), CDKN2A (33%), and MTAP (31%). Compared with a cohort of primary triple-negative BC, the bLM/lnLM exhibited a higher tumor mutation burden (P = .002), a lower rate of TP53 mutations, and more frequently harbored genetic alterations in KRAS, RBM10, CDKN2A, CDKN2B, SMARCA4, and STK11. In 10 of 18 cases, mutational signature analysis revealed a dominant smoking signature, providing evidence of lung origin. Our findings unveil diagnostic pitfalls that may warrant additional evaluation to avoid misdiagnosis of metastatic lung carcinoma as a primary BC.
{"title":"Lung Carcinoma Metastatic to the Breast: A Comprehensive Analysis of Clinical Presentation, Morphologic, and Molecular Features, With Emphasis on Diagnostic Pitfalls","authors":"Atif Ali Hashmi, Theodore Vougiouklakis, Andrea Gazzo, Hannah Y. Wen, Dara Ross, Fresia Pareja, Edi Brogi","doi":"10.1016/j.modpat.2025.100936","DOIUrl":"10.1016/j.modpat.2025.100936","url":null,"abstract":"<div><div>Lung carcinoma metastatic to the breast (bLM) or axillary lymph nodes (lnLM) may closely mimic primary triple-negative breast carcinoma (BC), leading to possible misdiagnosis. We characterized the clinical, morphologic, and molecular features of a series of lung carcinomas metastatic to breast and regional lymph nodes to identify diagnostic clues and pitfalls. The study cohort consisted of 30 patients (27 women, 3 men) with a median age of 72 years (range, 46-86); 21 patients (70%) reported a smoking history. At the time of the index biopsy, 4 patients (13.3%) had no history of lung carcinoma. Most tumors (n = 25, 83.3%) were bLM; 4 (13.3%) were lnLM, and 1 was a supraclavicular lymph node metastasis. In 7 of 23 cases (30.4%) with available paired imaging studies, the bLM was larger than the lung tumor. Of the 30 cases, 26 (86.7%) were adenocarcinomas, 2 (6.7%) were small cell carcinomas, and 2 (6.7%) were atypical carcinoids. Metastatic adenocarcinoma resembled BC with apocrine morphology in 16 of 30 cases (53.3%), 6 cases (20%) had vacuolated cytoplasm, and 6 (20%) had micropapillary features. One bLM closely mimicked ductal carcinoma in situ morphologically, and another case showed peripheral expression of CK5/14 and p63 mimicking myoepithelium around ductal carcinoma in situ. Initial diagnosis of BC had been rendered in 7 cases (6 adenocarcinomas and 1 small cell carcinoma). Molecular analysis of 18 cases showed that the most altered cancer genes were <em>TP53</em> (44%), <em>KRAS</em> (44%), <em>CDKN2A</em> (33%), and <em>MTAP</em> (31%). Compared with a cohort of primary triple-negative BC, the bLM/lnLM exhibited a higher tumor mutation burden (<em>P</em> = .002), a lower rate of <em>TP53</em> mutations, and more frequently harbored genetic alterations in <em>KRAS</em>, <em>RBM10</em>, <em>CDKN2A</em>, <em>CDKN2B</em>, <em>SMARCA4</em>, and <em>STK11</em>. In 10 of 18 cases, mutational signature analysis revealed a dominant smoking signature, providing evidence of lung origin. Our findings unveil diagnostic pitfalls that may warrant additional evaluation to avoid misdiagnosis of metastatic lung carcinoma as a primary BC.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100936"},"PeriodicalIF":5.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145530878","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}
Pub Date : 2026-01-01Epub Date: 2025-10-22DOI: 10.1016/j.modpat.2025.100921
Igor Odintsov , Stephanie E. Siegmund , Navin R. Mahadevan , Alanna J. Church , Lynette M. Sholl , Jonathan A. Nowak
Transplant recipients are at a heightened risk of cancer, yet the full spectrum of etiologic factors is poorly understood. In this study, we analysed the mutational patterns in a clinically diverse cohort of 41,874 cancers and identified a mutational signature highly associated with a history of solid organ or allogeneic stem cell transplantation. This signature is characterized by a high tumor mutation burden and a striking predominance of C>A single base substitutions, particularly in the 5′-C[C>A]A-3′ trinucleotide context. We identified 13 transplant recipients whose tumors harbored this signature, which is distinct from previously described mutational processes, including those related to tobacco, defective DNA repair, or polymerase mutations. The discovery of this signature points to a mutagenic force in this vulnerable patient group and provides new insights into the pathogenesis of transplant-associated malignancies.
移植受者患癌症的风险较高，但其全部病因尚不清楚。在这里，我们分析了临床多样化的41874例癌症的突变模式，并确定了一个与实体器官或同种异体干细胞移植史高度相关的新的突变特征。该特征的特点是高肿瘤突变负担和C bbbba单碱基取代的显著优势，特别是在5‘-C[C> a] a -3’三核苷酸背景下。我们确定了13名移植受者，他们的肿瘤中含有这种特征，这与先前描述的突变过程不同，包括与烟草、DNA修复缺陷或聚合酶突变相关的突变过程。这一特征的发现指出了这一脆弱患者群体中以前未被认识到的诱变力，并为移植相关恶性肿瘤的发病机制提供了新的见解。
{"title":"Mutational Signature in Cancers Following Solid Organ or Allogeneic Stem Cell Transplantation","authors":"Igor Odintsov , Stephanie E. Siegmund , Navin R. Mahadevan , Alanna J. Church , Lynette M. Sholl , Jonathan A. Nowak","doi":"10.1016/j.modpat.2025.100921","DOIUrl":"10.1016/j.modpat.2025.100921","url":null,"abstract":"<div><div>Transplant recipients are at a heightened risk of cancer, yet the full spectrum of etiologic factors is poorly understood. In this study, we analysed the mutational patterns in a clinically diverse cohort of 41,874 cancers and identified a mutational signature highly associated with a history of solid organ or allogeneic stem cell transplantation. This signature is characterized by a high tumor mutation burden and a striking predominance of C>A single base substitutions, particularly in the 5′-C[C>A]A-3′ trinucleotide context. We identified 13 transplant recipients whose tumors harbored this signature, which is distinct from previously described mutational processes, including those related to tobacco, defective DNA repair, or polymerase mutations. The discovery of this signature points to a mutagenic force in this vulnerable patient group and provides new insights into the pathogenesis of transplant-associated malignancies.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100921"},"PeriodicalIF":5.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145368301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Epstein-Barr virus–positive (EBV+) diffuse large B-cell lymphoma (DLBCL) and EBV+ classic Hodgkin lymphoma (CHL) are major B-cell lymphomas with EBV infection in elderly patients. Although they are regarded as distinct clinicopathological entities, distinguishing EBV+ CHL from EBV+ DLBCL is often challenging because of their overlapping histologic and immunophenotypic features. We characterized the spectrum of EBV+ large B-cell lymphoma (LBCL) in 57 patients aged 50 years or older, including 35 EBV+ DLBCL (12 polymorphic EBV+ DLBCL [pDLBCL] and 23 monomorphic EBV+ DLBCL [mDLBCL]) and 22 EBV+ CHL. Gene expression profiling revealed interferon gamma (IFN-γ) enrichment with overexpression of indoleamine 2,3-dioxygenase 1 (IDO1), an immunosuppressive enzyme, in more than half of pDLBCL (5/8) but less in mDLBCL (3/19) and CHL (1/19). Fluorescence in situ hybridization showed a higher frequency of 9p24.1-altered cells in CHL (54%; IQR, 42%-89%) but lower frequencies in pDLBCL (18%; IQR, 12%-23%) and mDLBCL (5%; IQR, 0%-30%). Notably, immunohistochemical expression of PDL1 was higher in pDLBCL than in mDLBCL, suggesting IFN-γ–mediated upregulation. DLBCL with EBV latency type III (n = 13) exhibited lower tumor PDL1 expression and reduced IDO1-enriched microenvironment. Multivariate analysis of the total cohort revealed that both EBV latency type III and Eastern Cooperative Oncology Group performance status ≥2 were independently associated with shorter overall survival. The EBV+ LBCL spectrum was reclassified into 4 molecular groups: (1) EBV latency type III suggestive of immune senescence (n = 10, 22%), (2) high proportion of 9p24.1 alteration (n = 9, 20%), (3) high IFN-γ signature score (n = 9, 20%), and (4) low IFN-γ signature score (n = 18, 39%). Moreover, these groups were identified using the following surrogate immunohistochemical markers: EBNA2, PDL1, and IDO1. In conclusion, the molecular studies assessing the tumor-host interaction enhance the understanding of the EBV+ LBCL spectrum and benefit pathological diagnosis and clinical management.
{"title":"Redefining the Spectrum of Epstein-Barr Virus–Positive (EBV+) Diffuse Large B-cell Lymphoma and EBV+ Classic Hodgkin Lymphoma","authors":"Shunsuke Nagase , Naoya Nakamura , Yara Yukie Kikuti , Joaquim Carreras , Yuki Tanigaki , Makoto Orita , Atsushi Ito , Haruka Ikoma , Hiroshi Kawada , Yohei Masugi","doi":"10.1016/j.modpat.2025.100950","DOIUrl":"10.1016/j.modpat.2025.100950","url":null,"abstract":"<div><div>Epstein-Barr virus–positive (EBV+) diffuse large B-cell lymphoma (DLBCL) and EBV+ classic Hodgkin lymphoma (CHL) are major B-cell lymphomas with EBV infection in elderly patients. Although they are regarded as distinct clinicopathological entities, distinguishing EBV+ CHL from EBV+ DLBCL is often challenging because of their overlapping histologic and immunophenotypic features. We characterized the spectrum of EBV+ large B-cell lymphoma (LBCL) in 57 patients aged 50 years or older, including 35 EBV+ DLBCL (12 polymorphic EBV+ DLBCL [pDLBCL] and 23 monomorphic EBV+ DLBCL [mDLBCL]) and 22 EBV+ CHL. Gene expression profiling revealed interferon gamma (IFN-γ) enrichment with overexpression of indoleamine 2,3-dioxygenase 1 (IDO1), an immunosuppressive enzyme, in more than half of pDLBCL (5/8) but less in mDLBCL (3/19) and CHL (1/19). Fluorescence in situ hybridization showed a higher frequency of 9p24.1-altered cells in CHL (54%; IQR, 42%-89%) but lower frequencies in pDLBCL (18%; IQR, 12%-23%) and mDLBCL (5%; IQR, 0%-30%). Notably, immunohistochemical expression of PDL1 was higher in pDLBCL than in mDLBCL, suggesting IFN-γ–mediated upregulation. DLBCL with EBV latency type III (n = 13) exhibited lower tumor PDL1 expression and reduced IDO1-enriched microenvironment. Multivariate analysis of the total cohort revealed that both EBV latency type III and Eastern Cooperative Oncology Group performance status ≥2 were independently associated with shorter overall survival. The EBV+ LBCL spectrum was reclassified into 4 molecular groups: (1) EBV latency type III suggestive of immune senescence (n = 10, 22%), (2) high proportion of 9p24.1 alteration (n = 9, 20%), (3) high IFN-γ signature score (n = 9, 20%), and (4) low IFN-γ signature score (n = 18, 39%). Moreover, these groups were identified using the following surrogate immunohistochemical markers: EBNA2, PDL1, and IDO1. In conclusion, the molecular studies assessing the tumor-host interaction enhance the understanding of the EBV+ LBCL spectrum and benefit pathological diagnosis and clinical management.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100950"},"PeriodicalIF":5.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145724748","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}
Pub Date : 2026-01-01Epub Date: 2025-09-24DOI: 10.1016/j.modpat.2025.100899
Macy L. Osborne-Frazier , Savannah E. LaBuda , Molly L. Parrish , Hannah M. Atkins , Russell R. Broaddus , Andrew B. Gladden
Microsatellite instability-high defines one of the major subsets of endometrial cancer (EC), characterized by defects in DNA mismatch repair, most often by loss of MLH1 protein expression, and sensitivity to immunotherapies. RPL22 is selectively mutated in microsatellite instability-high cancers, resulting in loss of protein expression. The significance of this mutation is unknown. An immunohistochemistry assay was developed that reliably detected ECs with ribosomal protein L22 (RPL22) protein loss. With a cohort of ECs, we identified MLH1-deficient cancers with loss of RPL22 expression. Using digital spatial transcriptomics, a subset was identified that was characterized by no expression of RPL22, lower expression of β-2 microglobulin, lack of expression of immune activation pathways, and lower numbers of tumor-associated CD8+ lymphocytes. β-2 Microglobulin, which is necessary for antigen presentation to T lymphocytes, was decreased in EC cell lines with RPL22 knocked down. Neither RPL22 expression nor levels of tumor-associated T lymphocytes were associated with tumor mutation burden or PD-L1 expression, 2 biomarkers that are assessed in patients considered for immunotherapies. This study provides the first evidence that RPL22 deficiency is an easily measured indicator of a unique subset of MLH1-deficient ECs that can be characterized as immune low. Our study suggests that patients with RPL22-deficient tumors could represent poor candidates for CD8+ T-cell–based immunotherapies, a current frontline therapy for MLH1-deficient ECs.
{"title":"Loss of Ribosomal Protein L22 (RPL22) Expression Identifies a Transcriptional Subset of MLH1-Deficient Endometrial Cancers With Lower Numbers of Tumor-Associated Lymphocytes","authors":"Macy L. Osborne-Frazier , Savannah E. LaBuda , Molly L. Parrish , Hannah M. Atkins , Russell R. Broaddus , Andrew B. Gladden","doi":"10.1016/j.modpat.2025.100899","DOIUrl":"10.1016/j.modpat.2025.100899","url":null,"abstract":"<div><div>Microsatellite instability-high defines one of the major subsets of endometrial cancer (EC), characterized by defects in DNA mismatch repair, most often by loss of MLH1 protein expression, and sensitivity to immunotherapies. <em>RPL22</em> is selectively mutated in microsatellite instability-high cancers, resulting in loss of protein expression. The significance of this mutation is unknown. An immunohistochemistry assay was developed that reliably detected ECs with ribosomal protein L22 (RPL22) protein loss. With a cohort of ECs, we identified MLH1-deficient cancers with loss of RPL22 expression. Using digital spatial transcriptomics, a subset was identified that was characterized by no expression of RPL22, lower expression of β-2 microglobulin, lack of expression of immune activation pathways, and lower numbers of tumor-associated CD8+ lymphocytes. β-2 Microglobulin, which is necessary for antigen presentation to T lymphocytes, was decreased in EC cell lines with <em>RPL22</em> knocked down. Neither RPL22 expression nor levels of tumor-associated T lymphocytes were associated with tumor mutation burden or PD-L1 expression, 2 biomarkers that are assessed in patients considered for immunotherapies. This study provides the first evidence that RPL22 deficiency is an easily measured indicator of a unique subset of MLH1-deficient ECs that can be characterized as immune low. Our study suggests that patients with RPL22-deficient tumors could represent poor candidates for CD8+ T-cell–based immunotherapies, a current frontline therapy for MLH1-deficient ECs.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100899"},"PeriodicalIF":5.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145176843","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}
Pub Date : 2026-01-01Epub Date: 2025-11-26DOI: 10.1016/j.modpat.2025.100943
Xunxi Lu , Bin Luo , Yani Wei , Hong Bu , Zongchao Gou
Neoadjuvant chemoimmunotherapy (NACi) is a new standard treatment for early-stage high-risk triple-negative breast cancer (TNBC). Desmoplastic reaction (DR) is an important characteristic in the tumor-associated stroma of TNBC. Based on the presence or absence of myxoid stroma and keloid-like collagen bundles within the tumor-associated stroma, DR was classified into immature, intermediate, or mature type. The relationship between DR and NACi efficacy remains unclear. We retrospectively analyzed 209 TNBC patients who received NACi from 3 medical centers, and 75, 78, and 56 cases were categorized as mature, intermediate, and immature types of DR, respectively. The pathological complete response rate was the highest in the mature group (77.3%), followed by the intermediate (30.8%) and immature (17.9%) groups. Multivariate logistic regression analysis indicated that in addition to histological type, Ki-67, T stage, N stage, and stromal tumor–infiltrating lymphocytes, DR was also an independent predictor of pathological complete response. Cases with intermediate and immature stroma exhibited fewer stromal tumor–infiltrating lymphocytes, an immunosuppressive tumor microenvironment, and upregulation of genes related to extracellular matrix and epithelial-mesenchymal transition. These findings demonstrate the predictive value of DR for NACi efficacy in TNBC and highlight its potential as a histopathological biomarker. The association between DR and molecular hallmarks provides important insights into the biological basis of DR in TNBC.
{"title":"Histological Categorization of Desmoplastic Reaction in Triple-Negative Breast Cancer: Its Relevance to Neoadjuvant Chemoimmunotherapy Response and Tumor Biology","authors":"Xunxi Lu , Bin Luo , Yani Wei , Hong Bu , Zongchao Gou","doi":"10.1016/j.modpat.2025.100943","DOIUrl":"10.1016/j.modpat.2025.100943","url":null,"abstract":"<div><div>Neoadjuvant chemoimmunotherapy (NACi) is a new standard treatment for early-stage high-risk triple-negative breast cancer (TNBC). Desmoplastic reaction (DR) is an important characteristic in the tumor-associated stroma of TNBC. Based on the presence or absence of myxoid stroma and keloid-like collagen bundles within the tumor-associated stroma, DR was classified into immature, intermediate, or mature type. The relationship between DR and NACi efficacy remains unclear. We retrospectively analyzed 209 TNBC patients who received NACi from 3 medical centers, and 75, 78, and 56 cases were categorized as mature, intermediate, and immature types of DR, respectively. The pathological complete response rate was the highest in the mature group (77.3%), followed by the intermediate (30.8%) and immature (17.9%) groups. Multivariate logistic regression analysis indicated that in addition to histological type, Ki-67, T stage, N stage, and stromal tumor–infiltrating lymphocytes, DR was also an independent predictor of pathological complete response. Cases with intermediate and immature stroma exhibited fewer stromal tumor–infiltrating lymphocytes, an immunosuppressive tumor microenvironment, and upregulation of genes related to extracellular matrix and epithelial-mesenchymal transition. These findings demonstrate the predictive value of DR for NACi efficacy in TNBC and highlight its potential as a histopathological biomarker. The association between DR and molecular hallmarks provides important insights into the biological basis of DR in TNBC.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100943"},"PeriodicalIF":5.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145636130","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}
Pub Date : 2026-01-01Epub Date: 2025-10-28DOI: 10.1016/j.modpat.2025.100925
Emad A. Rakha , Puay Hoon Tan , Mieke R. Van Bockstal , Kimberly H. Allison , Edi Brogi , Grace Callagy , Gábor Cserni , Shabnam Jaffer , Maria Pia Foschini , Helenice Gobbi , Janina Kulka , Xiaoxian Li , Elena Provenzano , Abeer M. Shaaban , Gary M. Tse , Zsuzsanna Varga , Anne Vincent-Salomon , Rin Yamaguchi , Wentao Yang , Soha ElSheikh , Cecily Quinn
The concept of “HER2-negative” breast cancer is evolving, with the recognition of HER2-low and HER2-ultralow subsets. These subsets are clinically relevant regarding treatment with the antibody-drug conjugate trastuzumab deruxtecan (T-DXd), which has shown survival benefit in patients with metastatic carcinoma with minimal HER2 protein expression that lack HER2 gene amplification by in situ hybridization. In clinical trials using T-DXd, HER2-low was defined as an immunohistochemistry (IHC) score 1+ or an IHC score 2+ without HER2 gene amplification. HER2-ultralow was defined as faint or barely perceptible, incomplete membrane staining in >0% to ≤10% of tumor cells (IHC score 0+/with membrane staining) and HER2-null as the complete absence of staining (IHC score 0/absent membrane staining). These results now necessitate more detailed evaluation and reporting of traditional “HER2-negative” results to identify patients with metastatic breast cancer who may benefit from T-DXd therapy. Both the US Food and Drug Administration and the European Medicines Agency have extended the regulatory approval of T-DXd to patients with metastatic breast cancer showing HER2-low or HER2-ultralow expressions. Updated clinical management guidelines now, therefore, incorporate the spectrum of HER2 results into treatment selection algorithms in the metastatic setting. To align histopathologic practice with these developments, the College of American Pathologists has issued a new biomarker-reporting template that recommends explicit distinction between IHC 0/absent membrane staining and IHC 0+/with membrane staining. Key concerns among pathologists include assay variability, scoring reproducibility, and quality assurance standards for accurately detecting such low levels of HER2 expression. This manuscript provides expert consensus, evidence-based practical recommendations for identifying and reporting tumors with HER2-low and HER2-ultralow expression. We emphasize standardized testing protocols, validated assays, robust internal and external controls, and focused training for pathologists. A universal structured pathology report is proposed to highlight the accurate distinction between IHC 0 (null), IHC 0+ (ultralow), and HER2-low expressions.
{"title":"International Expert Consensus Recommendations for HER2 Reporting in Breast Cancer: Focus on HER2-Low and Ultralow Categories","authors":"Emad A. Rakha , Puay Hoon Tan , Mieke R. Van Bockstal , Kimberly H. Allison , Edi Brogi , Grace Callagy , Gábor Cserni , Shabnam Jaffer , Maria Pia Foschini , Helenice Gobbi , Janina Kulka , Xiaoxian Li , Elena Provenzano , Abeer M. Shaaban , Gary M. Tse , Zsuzsanna Varga , Anne Vincent-Salomon , Rin Yamaguchi , Wentao Yang , Soha ElSheikh , Cecily Quinn","doi":"10.1016/j.modpat.2025.100925","DOIUrl":"10.1016/j.modpat.2025.100925","url":null,"abstract":"<div><div>The concept of “HER2-negative” breast cancer is evolving, with the recognition of HER2-low and HER2-ultralow subsets. These subsets are clinically relevant regarding treatment with the antibody-drug conjugate trastuzumab deruxtecan (T-DXd), which has shown survival benefit in patients with metastatic carcinoma with minimal HER2 protein expression that lack <em>HER2</em> gene amplification by in situ hybridization. In clinical trials using T-DXd, HER2-low was defined as an immunohistochemistry (IHC) score 1+ or an IHC score 2+ without <em>HER2</em> gene amplification. HER2-ultralow was defined as faint or barely perceptible, incomplete membrane staining in >0% to ≤10% of tumor cells (IHC score 0+/with membrane staining) and HER2-null as the complete absence of staining (IHC score 0/absent membrane staining). These results now necessitate more detailed evaluation and reporting of traditional “HER2-negative” results to identify patients with metastatic breast cancer who may benefit from T-DXd therapy. Both the US Food and Drug Administration and the European Medicines Agency have extended the regulatory approval of T-DXd to patients with metastatic breast cancer showing HER2-low or HER2-ultralow expressions. Updated clinical management guidelines now, therefore, incorporate the spectrum of HER2 results into treatment selection algorithms in the metastatic setting. To align histopathologic practice with these developments, the College of American Pathologists has issued a new biomarker-reporting template that recommends explicit distinction between IHC 0/absent membrane staining and IHC 0+/with membrane staining. Key concerns among pathologists include assay variability, scoring reproducibility, and quality assurance standards for accurately detecting such low levels of HER2 expression. This manuscript provides expert consensus, evidence-based practical recommendations for identifying and reporting tumors with HER2-low and HER2-ultralow expression. We emphasize standardized testing protocols, validated assays, robust internal and external controls, and focused training for pathologists. A universal structured pathology report is proposed to highlight the accurate distinction between IHC 0 (null), IHC 0+ (ultralow), and HER2-low expressions.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100925"},"PeriodicalIF":5.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145408978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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