Pub Date : 2026-01-09DOI: 10.1016/j.modpat.2026.100959
Jennifer X. Ji , Amr El Maghrabi , Hezhen Carl Ren , Lawrence H. Lee , Sean Young , Stephen T. Yip , Jinesa Moodley , Chi Lai , Hemlata Shirsat , Elan Hahn , Lien N. Hoang , Johanna Mabray , Paras Patel , Gang Wang , Catherine F. Poh , Tony L. Ng , Yen Chen Kevin Ko
The diagnosis of oral epithelial dysplasia has a high degree of inter- and intraobserver variability. It is especially challenging to distinguish dysplasia from reactive squamous mucosa in the context of concurrent candidiasis. The accurate and timely diagnosis of dysplasia is imperative for patient outcomes, as progression to invasive squamous cell carcinoma will result in significant morbidity and mortality. The current management for patients with candidiasis is to treat with antifungals and rebiopsy if refractory. The treatment may be trialed for a few months, thus delaying appropriate treatment if underlying dysplasia is not identified. In this study, we collected cases of oral candidiasis with atypia and characterized them into molecularly defined groups using targeted next-generation sequencing, fluorescence in situ hybridization, and p53, p16, and MTAP immunohistochemistry. We identify a distinct molecular signature using immunohistochemical markers to capture oral dysplasia with concurrent candidiasis. We also postulate that p53 wild-type, p16 abnormal oral epithelial dysplasia cases are precursor lesions to p53 wild-type, p16 abnormal squamous cell carcinoma. In addition, we identify p53 wild-type, p16 wild-type oral epithelial dysplasia with verruciform and acanthotic features with HRAS or PIK3CA alterations as precursors to verrucous carcinoma. The proposed pattern-based p16 and p53 algorithm in our study will not only more accurately diagnose dysplasia in the context of oral candidiasis but may also provide prognostically significant information to guide clinical management of oral dysplastic lesions.
{"title":"Utility of p53, p16, and MTAP Immunohistochemistry in Oral Epithelial Dysplasia With Concurrent Candidiasis: A Novel Pattern-based Approach","authors":"Jennifer X. Ji , Amr El Maghrabi , Hezhen Carl Ren , Lawrence H. Lee , Sean Young , Stephen T. Yip , Jinesa Moodley , Chi Lai , Hemlata Shirsat , Elan Hahn , Lien N. Hoang , Johanna Mabray , Paras Patel , Gang Wang , Catherine F. Poh , Tony L. Ng , Yen Chen Kevin Ko","doi":"10.1016/j.modpat.2026.100959","DOIUrl":"10.1016/j.modpat.2026.100959","url":null,"abstract":"<div><div>The diagnosis of oral epithelial dysplasia has a high degree of inter- and intraobserver variability. It is especially challenging to distinguish dysplasia from reactive squamous mucosa in the context of concurrent candidiasis. The accurate and timely diagnosis of dysplasia is imperative for patient outcomes, as progression to invasive squamous cell carcinoma will result in significant morbidity and mortality. The current management for patients with candidiasis is to treat with antifungals and rebiopsy if refractory. The treatment may be trialed for a few months, thus delaying appropriate treatment if underlying dysplasia is not identified. In this study, we collected cases of oral candidiasis with atypia and characterized them into molecularly defined groups using targeted next-generation sequencing, fluorescence in situ hybridization, and p53, p16, and MTAP immunohistochemistry. We identify a distinct molecular signature using immunohistochemical markers to capture oral dysplasia with concurrent candidiasis. We also postulate that p53 wild-type, p16 abnormal oral epithelial dysplasia cases are precursor lesions to p53 wild-type, p16 abnormal squamous cell carcinoma. In addition, we identify p53 wild-type, p16 wild-type oral epithelial dysplasia with verruciform and acanthotic features with <em>HRAS</em> or <em>PIK3CA</em> alterations as precursors to verrucous carcinoma. The proposed pattern-based p16 and p53 algorithm in our study will not only more accurately diagnose dysplasia in the context of oral candidiasis but may also provide prognostically significant information to guide clinical management of oral dysplastic lesions.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 3","pages":"Article 100959"},"PeriodicalIF":5.5,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145952776","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 : 2026-01-06DOI: 10.1016/j.modpat.2025.100957
Yasamin Mirzabeigi , Nikunj Shah , Kayla R. Schwartz , Jeffrey Duryea , Katiana S. Delma , Elizabeth A. Montgomery , Julio C. Poveda , Oliver G. McDonald
Poor prognosis has been reported for patients with SMAD4 deficient (dSMAD4) colorectal adenocarcinomas (CRCs). However, it remains unclear whether unique tumor morphologies or other advanced disease signatures might stratify those patients. To reappraise this possibility across a homogenous cohort of CRC patients with advanced-stage disease, we leveraged next-generation sequencing data to identify 50 dSMAD4 CRCs at our institution. An equal number of next-generation sequencing-verified SMAD4 proficient (pSMAD4) CRCs were identified in parallel, yielding a control group with similar demographics, clinicopathologic parameters, and background genetic drivers as the dSMAD4 test group. Although both groups progressed to stage IV metastatic disease at high rates (dSMAD4: 90%, pSMAD4: 86%), dSMAD4 CRC specimens were enriched with overtly high-grade (HG) mucinous and nonmucinous histomorphologies (dSMAD4, 44%; pSMAD4, 12%; P = .0007). The HG subset drove poor prognosis in dSMAD4 CRCs, as those patients developed widely metastatic disease (P = .0048) with short overall and progression-free survival (P ≤ .0001). Metastasis of unknown primary was not uncommon for HG dSMAD4 CRCs, posing diagnostic challenges in those instances. However, all dSMAD4 CRCs retained positive immunolabeling for either CDX2 or SATB2 irrespective of grade, thereby aiding diagnosis and distinguishing the HG subset from other HG CRCs that lose these biomarkers. Our reappraisal identifies an underappreciated class of HG dSMAD4 CRCs that progresses rapidly to widely metastatic disease with a dismal prognosis. Although HG morphologies may mask CRC origins, immunohistochemistry retains diagnostic utility for dSMAD4 CRCs.
{"title":"High-Grade Colorectal Adenocarcinomas With SMAD4 Deficiency","authors":"Yasamin Mirzabeigi , Nikunj Shah , Kayla R. Schwartz , Jeffrey Duryea , Katiana S. Delma , Elizabeth A. Montgomery , Julio C. Poveda , Oliver G. McDonald","doi":"10.1016/j.modpat.2025.100957","DOIUrl":"10.1016/j.modpat.2025.100957","url":null,"abstract":"<div><div>Poor prognosis has been reported for patients with SMAD4 deficient (dSMAD4) colorectal adenocarcinomas (CRCs). However, it remains unclear whether unique tumor morphologies or other advanced disease signatures might stratify those patients. To reappraise this possibility across a homogenous cohort of CRC patients with advanced-stage disease, we leveraged next-generation sequencing data to identify 50 dSMAD4 CRCs at our institution. An equal number of next-generation sequencing-verified SMAD4 proficient (pSMAD4) CRCs were identified in parallel, yielding a control group with similar demographics, clinicopathologic parameters, and background genetic drivers as the dSMAD4 test group. Although both groups progressed to stage IV metastatic disease at high rates (dSMAD4: 90%, pSMAD4: 86%), dSMAD4 CRC specimens were enriched with overtly high-grade (HG) mucinous and nonmucinous histomorphologies (dSMAD4, 44%; pSMAD4, 12%; <em>P</em> = .0007). The HG subset drove poor prognosis in dSMAD4 CRCs, as those patients developed widely metastatic disease (<em>P</em> = .0048) with short overall and progression-free survival (<em>P</em> ≤ .0001). Metastasis of unknown primary was not uncommon for HG dSMAD4 CRCs, posing diagnostic challenges in those instances. However, all dSMAD4 CRCs retained positive immunolabeling for either CDX2 or SATB2 irrespective of grade, thereby aiding diagnosis and distinguishing the HG subset from other HG CRCs that lose these biomarkers. Our reappraisal identifies an underappreciated class of HG dSMAD4 CRCs that progresses rapidly to widely metastatic disease with a dismal prognosis. Although HG morphologies may mask CRC origins, immunohistochemistry retains diagnostic utility for dSMAD4 CRCs.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 3","pages":"Article 100957"},"PeriodicalIF":5.5,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145933962","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 : 2026-01-05DOI: 10.1016/j.modpat.2025.100944
Brittany McKelvey , Pedro A. Torres-Saavedra , Jessica Li , Glenn Broeckx , Frederik Deman , Siraj Ali , Hillary S. Andrews , Salim Arslan , Meir Azulay , Santhosh Balasubramanian , J.C. Barrett , Peter Caie , Ming Chen , Daniel Cohen , Tathagata Dasgupta , Diana Fahrer , George Green , Mark Gustavson , Sarah Hersey , Ana Hidalgo-Sastre , Jeff Allen
Historically, eligibility for receiving human epidermal growth factor receptor 2 (HER2)-targeted therapies was limited to HER2-positive tumors (immunohistochemistry 3+ or in situ hybridization amplified), but recent advances in antibody-drug conjugates have expanded these criteria to include HER2-low and HER2-ultralow expression. This evolving therapeutic landscape underscores the need for precise and reproducible HER2 assessment. Digital and computational pathology tools may help address these needs, but their measurement variability must be evaluated to inform research and clinical use. We evaluated HER2 scoring variability across 10 independently developed computational pathology artificial intelligence models applied to 1124 whole-slide images from 733 patients with breast cancer. Analyses included American Society of Clinical Oncology-College of American Pathologists categorical scores (0, 1+, 2+, and 3+), H-scores, tumor cell staining percentages, and counts of total and stained invasive carcinoma cells. Agreement among models and 3 pathologists was assessed using pairwise overall percent agreement (OPA), Cohen kappa, and hierarchical clustering. Median model pairwise OPA for categorical HER2 scores was 65.1% (kappa, 0.51). Agreement was highest for HER2 3+ vs not 3+ (OPA, 97.3%; kappa, 0.86) and lowest for HER2-low cases, reflecting existing measurement challenges. For HER2 0 (negative) vs not 0 (positive) scoring, the average negative agreement was 65.3%, compared with the average positive agreement of 91.3%, suggesting more agreement in non-HER2 0 scores. H-score and cell count analyses indicated that scoring differences were more related to staining interpretation than tumor cell detection. Pathologists showed numerically higher concordance than models, but interobserver variability persisted. In exploratory analyses, sample type, staining artifacts, and heterogeneous HER2 expression appeared to be associated with discrepancies. Artificial intelligence–based HER2 scoring demonstrated high agreement in identifying HER2 3+ cases. Variability was most pronounced in borderline HER2 categories, particularly in HER2 low, underscoring the need for continued tool refinement for handling low-intensity staining. Standardized training data sets, validation frameworks, and regulatory alignment are important to improve reproducibility. Developing reference standards and benchmarking data sets is critical to evaluate performance, support regulatory decision-making, and ensure real-world applicability.
{"title":"Agreement Across 10 Artificial Intelligence Models in Assessing Human Epidermal Growth Factor Receptor 2 (HER2) Expression in Breast Cancer Whole-Slide Images","authors":"Brittany McKelvey , Pedro A. Torres-Saavedra , Jessica Li , Glenn Broeckx , Frederik Deman , Siraj Ali , Hillary S. Andrews , Salim Arslan , Meir Azulay , Santhosh Balasubramanian , J.C. Barrett , Peter Caie , Ming Chen , Daniel Cohen , Tathagata Dasgupta , Diana Fahrer , George Green , Mark Gustavson , Sarah Hersey , Ana Hidalgo-Sastre , Jeff Allen","doi":"10.1016/j.modpat.2025.100944","DOIUrl":"10.1016/j.modpat.2025.100944","url":null,"abstract":"<div><div>Historically, eligibility for receiving human epidermal growth factor receptor 2 (HER2)-targeted therapies was limited to HER2-positive tumors (immunohistochemistry 3+ or in situ hybridization amplified), but recent advances in antibody-drug conjugates have expanded these criteria to include HER2-low and HER2-ultralow expression. This evolving therapeutic landscape underscores the need for precise and reproducible HER2 assessment. Digital and computational pathology tools may help address these needs, but their measurement variability must be evaluated to inform research and clinical use. We evaluated HER2 scoring variability across 10 independently developed computational pathology artificial intelligence models applied to 1124 whole-slide images from 733 patients with breast cancer. Analyses included American Society of Clinical Oncology-College of American Pathologists categorical scores (0, 1+, 2+, and 3+), H-scores, tumor cell staining percentages, and counts of total and stained invasive carcinoma cells. Agreement among models and 3 pathologists was assessed using pairwise overall percent agreement (OPA), Cohen kappa, and hierarchical clustering. Median model pairwise OPA for categorical HER2 scores was 65.1% (kappa, 0.51). Agreement was highest for HER2 3+ vs not 3+ (OPA, 97.3%; kappa, 0.86) and lowest for HER2-low cases, reflecting existing measurement challenges. For HER2 0 (negative) vs not 0 (positive) scoring, the average negative agreement was 65.3%, compared with the average positive agreement of 91.3%, suggesting more agreement in non-HER2 0 scores. H-score and cell count analyses indicated that scoring differences were more related to staining interpretation than tumor cell detection. Pathologists showed numerically higher concordance than models, but interobserver variability persisted. In exploratory analyses, sample type, staining artifacts, and heterogeneous HER2 expression appeared to be associated with discrepancies. Artificial intelligence–based HER2 scoring demonstrated high agreement in identifying HER2 3+ cases. Variability was most pronounced in borderline HER2 categories, particularly in HER2 low, underscoring the need for continued tool refinement for handling low-intensity staining. Standardized training data sets, validation frameworks, and regulatory alignment are important to improve reproducibility. Developing reference standards and benchmarking data sets is critical to evaluate performance, support regulatory decision-making, and ensure real-world applicability.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 2","pages":"Article 100944"},"PeriodicalIF":5.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145900783","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 : 2026-01-01DOI: 10.1016/j.modpat.2025.100949
Diogo Maia-Silva , Mia S. DeSimone , Karen T. Shore , Mai P. Hoang
There is currently no standardized sentinel lymph node (SLN) immunohistochemistry (IHC) protocol for detecting Merkel cell carcinoma (MCC) metastases. A cost-effective, high-sensitivity panel could improve diagnostic accuracy and resource utilization. We evaluated 226 SLNs from 81 MCC patients using a panel of POU4F3, keratin 20, and keratin AE1/AE3 or pan-keratin. Metastasis was defined as positive staining for any of the tested IHC markers. Patients’ age ranged from 49 to 92 years (median, 73.5 years), with a male:female ratio of 1.8:1. Primary tumor sites were extremities (48.1%), head/neck (34.6%), and trunk (17.3%). SLN locations included cervical (29.6%), axillary (27%), femoral (20.8%), inguinal (9.7%), facial (7.1%), pelvic (3.1%), and epitrochlear (2.7%) sites. Metastases were identified in 102 of 226 SLNs (45%). Single-marker sensitivities were POU4F3 (96%, 98/102), keratin 20 (67%, 68/102), and keratin AE1/AE3 or pan-keratin (64%, 70/102). The most sensitive combinations were POU4F3 with keratin AE1/AE3 or pan-keratin (100% sensitivity) or POU4F3 with keratin 20 (98% sensitivity). Keratin 20 with keratin AE1/AE3 or pan-keratin was the least sensitive (74%). In 6 patients (7.4%), POU4F3 detected single metastatic cells in SLNs that were previously diagnosed at time of clinical diagnosis as negative by keratin 20 and keratin AE1/AE3 or pan-keratin panel. POU4F3 is the most sensitive individual IHC marker for detecting MCC SLN metastases. The optimal cost-effective panel is POU4F3 with keratin AE1/AE3 or pan-keratin, which achieves 100% sensitivity while reducing reliance on less effective stains. Adoption of this focused IHC panel may serve to standardize SLN evaluation for MCC and improve diagnostic accuracy and efficiency.
{"title":"POU4F3 Plus Keratin AE1/AE3 or Pan-keratin: An Optimal Sentinel Lymph Node Protocol for Merkel Cell Carcinoma","authors":"Diogo Maia-Silva , Mia S. DeSimone , Karen T. Shore , Mai P. Hoang","doi":"10.1016/j.modpat.2025.100949","DOIUrl":"10.1016/j.modpat.2025.100949","url":null,"abstract":"<div><div>There is currently no standardized sentinel lymph node (SLN) immunohistochemistry (IHC) protocol for detecting Merkel cell carcinoma (MCC) metastases. A cost-effective, high-sensitivity panel could improve diagnostic accuracy and resource utilization. We evaluated 226 SLNs from 81 MCC patients using a panel of POU4F3, keratin 20, and keratin AE1/AE3 or pan-keratin. Metastasis was defined as positive staining for any of the tested IHC markers. Patients’ age ranged from 49 to 92 years (median, 73.5 years), with a male:female ratio of 1.8:1. Primary tumor sites were extremities (48.1%), head/neck (34.6%), and trunk (17.3%). SLN locations included cervical (29.6%), axillary (27%), femoral (20.8%), inguinal (9.7%), facial (7.1%), pelvic (3.1%), and epitrochlear (2.7%) sites. Metastases were identified in 102 of 226 SLNs (45%). Single-marker sensitivities were POU4F3 (96%, 98/102), keratin 20 (67%, 68/102), and keratin AE1/AE3 or pan-keratin (64%, 70/102). The most sensitive combinations were POU4F3 with keratin AE1/AE3 or pan-keratin (100% sensitivity) or POU4F3 with keratin 20 (98% sensitivity). Keratin 20 with keratin AE1/AE3 or pan-keratin was the least sensitive (74%). In 6 patients (7.4%), POU4F3 detected single metastatic cells in SLNs that were previously diagnosed at time of clinical diagnosis as negative by keratin 20 and keratin AE1/AE3 or pan-keratin panel. POU4F3 is the most sensitive individual IHC marker for detecting MCC SLN metastases. The optimal cost-effective panel is POU4F3 with keratin AE1/AE3 or pan-keratin, which achieves 100% sensitivity while reducing reliance on less effective stains. Adoption of this focused IHC panel may serve to standardize SLN evaluation for MCC and improve diagnostic accuracy and efficiency.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100949"},"PeriodicalIF":5.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743390","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 : 2026-01-01DOI: 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}
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 : 2026-01-01DOI: 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 : 2025-12-30DOI: 10.1016/j.modpat.2025.100955
Johann W. Schneider , Anthony B. Eason , Meredith Chambers , Huanjuan Su , Kyle Shifflett , Shuyan Guo , Micheline Sanderson , Cassandra Bruce-Brand , Henriette Burger , Dirk P. Dittmer
The lineage of the Kaposi sarcoma (KS) tumor cell remains elusive, limiting opportunities for targeted therapy. We performed concurrent spatial imaging of 5 bona fide lymphatic endothelial cell markers together with the KS herpesvirus viral protein latency-associated nuclear antigen (LANA) in 30 well-characterized HIV-positive KS biopsies (n = 1,740,744 cells). Nodular KS lesions showed significantly more circular nuclei than plaque KS, indicating distinct cellular morphologies. Both forms contained dense areas of LANA-positive cells—termed “LANA nests.” Among the endothelial cell markers, vascular endothelial growth factor receptor 3 was most abundantly expressed, although many vascular endothelial growth factor receptor 3–positive cells were LANA negative. Podoplanin and LYVE-1 consistently colocalized with each other, whereas CD31 and VE-Cadherin were variably expressed within and across lesions. Together, these observations reveal that KS lesions are composed of multiple microenvironments: LANA-dense nests, LANA-sparse fascicles, and mature lymphatic or blood vessels, some of which also harbored LANA-positive lining cells. At present, targeted therapies do not account for this variability; generally, responses are not based on pathology. Spatial changes in the tumor microenvironment that may provide insights into drug action and resistance mechanisms are missed.
{"title":"Spatial Profiling Shows That Lymphatic Endothelial Cells Form the Core of Kaposi Sarcoma (KS)","authors":"Johann W. Schneider , Anthony B. Eason , Meredith Chambers , Huanjuan Su , Kyle Shifflett , Shuyan Guo , Micheline Sanderson , Cassandra Bruce-Brand , Henriette Burger , Dirk P. Dittmer","doi":"10.1016/j.modpat.2025.100955","DOIUrl":"10.1016/j.modpat.2025.100955","url":null,"abstract":"<div><div>The lineage of the Kaposi sarcoma (KS) tumor cell remains elusive, limiting opportunities for targeted therapy. We performed concurrent spatial imaging of 5 bona fide lymphatic endothelial cell markers together with the KS herpesvirus viral protein latency-associated nuclear antigen (LANA) in 30 well-characterized HIV-positive KS biopsies (n = 1,740,744 cells). Nodular KS lesions showed significantly more circular nuclei than plaque KS, indicating distinct cellular morphologies. Both forms contained dense areas of LANA-positive cells—termed “LANA nests.” Among the endothelial cell markers, vascular endothelial growth factor receptor 3 was most abundantly expressed, although many vascular endothelial growth factor receptor 3–positive cells were LANA negative. Podoplanin and LYVE-1 consistently colocalized with each other, whereas CD31 and VE-Cadherin were variably expressed within and across lesions. Together, these observations reveal that KS lesions are composed of multiple microenvironments: LANA-dense nests, LANA-sparse fascicles, and mature lymphatic or blood vessels, some of which also harbored LANA-positive lining cells. At present, targeted therapies do not account for this variability; generally, responses are not based on pathology. Spatial changes in the tumor microenvironment that may provide insights into drug action and resistance mechanisms are missed.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 2","pages":"Article 100955"},"PeriodicalIF":5.5,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889389","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 : 2025-12-26DOI: 10.1016/j.modpat.2025.100954
Wen Shuai , Zhihong Hu , C. Cameron Yin , Lei Chen , Wei Wang , Guilin Tang , Dawen Sui , Shaoying Li , Jie Xu , Nourhan Ibrahim , Zenggang Pan , M. James You , Keyur P. Patel , Francisco Vega , L. Jeffrey Medeiros , Pei Lin
In 2021, the International Myeloma Working Group lowered the threshold to establish the diagnosis of primary plasma cell leukemia (pPCL) from ≥20% to ≥5% circulating plasma cells (CPCs) as assessed by morphologic evaluation (ME). However, the threshold for defining secondary PCL (sPCL) remains unclear. We retrospectively studied the clinicopathological features of 52 PCL patients, 30 pPCL and 22 sPCL, with ≥5% CPCs determined by either ME or flow cytometry immunophenotyping (FCI). FCI often revealed a higher percentage of CPCs than ME, likely due to difficulties in identifying morphologically abnormal plasma cells with certainty, and this discordance was statistically significant in sPCL patients. pPCL and sPCL both exhibited leukocytosis, thrombocytopenia, infrequent CD56 expression, high bone marrow tumor burden, and complex karyotypes. MYC rearrangement was observed only in sPCL cases. Paired cytogenetic data before and after leukemic transformation were available in a small subset of sPCL patients (8/22). Compared with the prior myeloma, sPCL more frequently harbored a complex karyotype, hypodiploidy, and additional cytogenetic abnormalities, most commonly gain of chromosome 1q. Using 5% CPCs as the diagnostic threshold, patients with sPCL had significantly poorer outcomes than patients with pPCL (P < .0001). Furthermore, the outcomes of sPCL patients with 5% to 19% CPCs were similarly poor as those patients with ≥20% CPCs (P = .4781), highlighting the need to recognize patients with ≥5% CPCs promptly. FCI appears to be a more sensitive method for this purpose in most cases. Using FCI, further studies are needed to determine whether a diagnostic threshold of 5% or lower may be used to establish the diagnosis of sPCL.
{"title":"Lowering the Diagnostic Threshold in Secondary Plasma Cell Leukemia? Comparison With Primary Cases and Implications for Flow Cytometry Immunophenotyping","authors":"Wen Shuai , Zhihong Hu , C. Cameron Yin , Lei Chen , Wei Wang , Guilin Tang , Dawen Sui , Shaoying Li , Jie Xu , Nourhan Ibrahim , Zenggang Pan , M. James You , Keyur P. Patel , Francisco Vega , L. Jeffrey Medeiros , Pei Lin","doi":"10.1016/j.modpat.2025.100954","DOIUrl":"10.1016/j.modpat.2025.100954","url":null,"abstract":"<div><div>In 2021, the International Myeloma Working Group lowered the threshold to establish the diagnosis of primary plasma cell leukemia (pPCL) from ≥20% to ≥5% circulating plasma cells (CPCs) as assessed by morphologic evaluation (ME). However, the threshold for defining secondary PCL (sPCL) remains unclear. We retrospectively studied the clinicopathological features of 52 PCL patients, 30 pPCL and 22 sPCL, with ≥5% CPCs determined by either ME or flow cytometry immunophenotyping (FCI). FCI often revealed a higher percentage of CPCs than ME, likely due to difficulties in identifying morphologically abnormal plasma cells with certainty, and this discordance was statistically significant in sPCL patients. pPCL and sPCL both exhibited leukocytosis, thrombocytopenia, infrequent CD56 expression, high bone marrow tumor burden, and complex karyotypes. <em>MYC</em> rearrangement was observed only in sPCL cases. Paired cytogenetic data before and after leukemic transformation were available in a small subset of sPCL patients (8/22). Compared with the prior myeloma, sPCL more frequently harbored a complex karyotype, hypodiploidy, and additional cytogenetic abnormalities, most commonly gain of chromosome 1q. Using 5% CPCs as the diagnostic threshold, patients with sPCL had significantly poorer outcomes than patients with pPCL (<em>P</em> < .0001). Furthermore, the outcomes of sPCL patients with 5% to 19% CPCs were similarly poor as those patients with ≥20% CPCs (<em>P</em> = .4781), highlighting the need to recognize patients with ≥5% CPCs promptly. FCI appears to be a more sensitive method for this purpose in most cases. Using FCI, further studies are needed to determine whether a diagnostic threshold of 5% or lower may be used to establish the diagnosis of sPCL.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 2","pages":"Article 100954"},"PeriodicalIF":5.5,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145850431","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}
Long-standing diabetes mellitus (long-DM) (≧3 years) is associated with worse clinical outcomes in patients with pancreatic ductal adenocarcinoma (PDAC). Emerging evidence suggests that epigenetic alterations may contribute to this association; however, the underlying mechanisms remain largely unclear. This study aimed to elucidate the role of the tumor-suppressive long noncoding RNA maternally expressed gene 3 (MEG3) and related molecules in the development of PDAC with long-DM. A total of 117 patients who underwent surgical resection for PDAC at Hirosaki University Hospital were retrospectively analyzed. Histopathological assessment followed World Health Organization criteria and the Union for International Cancer Control tumor-node-metastasis classification. Promoter methylation of MEG3 was assessed via methylation-specific PCR using formalin-fixed paraffin-embedded tissue. MEG3 expression levels were assessed by real-time quantitative PCR. Additionally, proteomic profiling was performed using liquid chromatography-tandem mass spectrometry on formalin-fixed paraffin-embedded tissue samples. Among the 117 cases with PDAC, patients with long-DM exhibited significantly poorer tumor differentiation and reduced cancer-specific survival. MEG3 promoter methylation was more prevalent in patients with long-DM. MEG3 methylation was correlated with reduced MEG3 expression, increased venous invasion, higher recurrence rates, and worse prognosis. Proteomic analysis and protein structure prediction tool revealed F11 receptor (F11R) as a potential downstream effector of MEG3. F11R protein expression levels were evaluated using semiquantitative immunohistochemistry. Higher F11R expression was observed in patients with long-DM, correlating with poor histologic differentiation and unfavorable outcomes. Patients with PDAC showing simultaneous MEG3 methylation and F11R high expression were more likely to have long-DM, with additive effects of these changes and tumor recurrence. Our results demonstrated that MEG3 and its potential downstream regulator, F11R, could be involved in PDAC progression, particularly in patients with long-DM. The findings underscore the clinical significance of epigenetic regulation in DM-related PDAC, suggesting novel targets, such as MEG3 and F11R, for potential therapeutic intervention.
{"title":"MEG3 Promoter Methylation and F11 Receptor (F11R) Overexpression Define a High-Risk Subtype of Diabetic Pancreatic Cancer","authors":"Keisuke Yamazaki , Hiroki Mizukami , Takahiro Yamada , Yutaro Hara , Hiroaki Tamba , Yota Tatara , Zhenchao Wang , Akiko Itaya , Hanae Kushibiki , Masaki Ryuzaki , Takanori Sasaki , Hidefumi Ruike , Saori Ogasawara , Yi Tu , Keinosuke Ishido , Ken Itoh , Kenichi Hakamada","doi":"10.1016/j.modpat.2025.100953","DOIUrl":"10.1016/j.modpat.2025.100953","url":null,"abstract":"<div><div>Long-standing diabetes mellitus (long-DM) (≧3 years) is associated with worse clinical outcomes in patients with pancreatic ductal adenocarcinoma (PDAC). Emerging evidence suggests that epigenetic alterations may contribute to this association; however, the underlying mechanisms remain largely unclear. This study aimed to elucidate the role of the tumor-suppressive long noncoding RNA maternally expressed gene 3 (<em>MEG3</em>) and related molecules in the development of PDAC with long-DM. A total of 117 patients who underwent surgical resection for PDAC at Hirosaki University Hospital were retrospectively analyzed. Histopathological assessment followed World Health Organization criteria and the Union for International Cancer Control tumor-node-metastasis classification. Promoter methylation of <em>MEG3</em> was assessed via methylation-specific PCR using formalin-fixed paraffin-embedded tissue. <em>MEG3</em> expression levels were assessed by real-time quantitative PCR. Additionally, proteomic profiling was performed using liquid chromatography-tandem mass spectrometry on formalin-fixed paraffin-embedded tissue samples. Among the 117 cases with PDAC, patients with long-DM exhibited significantly poorer tumor differentiation and reduced cancer-specific survival. <em>MEG3</em> promoter methylation was more prevalent in patients with long-DM. <em>MEG3</em> methylation was correlated with reduced <em>MEG3</em> expression, increased venous invasion, higher recurrence rates, and worse prognosis. Proteomic analysis and protein structure prediction tool revealed F11 receptor (F11R) as a potential downstream effector of <em>MEG3</em>. F11R protein expression levels were evaluated using semiquantitative immunohistochemistry. Higher F11R expression was observed in patients with long-DM, correlating with poor histologic differentiation and unfavorable outcomes. Patients with PDAC showing simultaneous <em>MEG3</em> methylation and F11R high expression were more likely to have long-DM, with additive effects of these changes and tumor recurrence. Our results demonstrated that <em>MEG3</em> and its potential downstream regulator, F11R, could be involved in PDAC progression, particularly in patients with long-DM. The findings underscore the clinical significance of epigenetic regulation in DM-related PDAC, suggesting novel targets, such as <em>MEG3</em> and F11R, for potential therapeutic intervention.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 2","pages":"Article 100953"},"PeriodicalIF":5.5,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145781564","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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