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}
Pub Date : 2025-12-13DOI: 10.1016/j.modpat.2025.100951
Amber Verhasselt , Geneviève Ameye , Justine Vanhevel , Thomas Tousseyn , Johanna Vets , Esther Hauben , Peter Meeus , Marlies Vanden Bempt , Koen Debackere , Robert A. Forsyth , Luuk Harbers , Jonas Demeulemeester , Lucienne Michaux , Katrina Rack , Barbara Dewaele , Jolien De Bie
Non-Hodgkin lymphoma (NHL) is a diverse and heterogeneous group of hematological malignancies. These lymphomas arise from the clonal proliferation of either B/T or natural killer lymphocytes, and their correct classification relies partly on identifying characteristic structural variants and copy number alterations. Current standard-of-care technologies for detecting these genomic features, chromosome banding analysis (CBA) and fluorescent in situ hybridization (FISH), are labor intensive and have specific limitations. CBA has low resolution and relies on viable cell culture, whereas the targeted approach of FISH does not provide the whole genome view required for comprehensive disease characterization. This highlights the need for higher–resolution nontargeted genomic methods. Previous studies have evaluated optical genome mapping (OGM) as a whole genome alternative for cytogenomic characterization in NHL diagnostics but were restricted in number and to cases with peripheral blood and/or bone marrow invasion. Here, we selected a comprehensive cohort of 110 NHL cases (79 B-NHL and 31 T-NHL/natural killer-NHL) derived from different types of tissue biopsies, all with established histopathological diagnoses. Seventy-eight samples were genomically well characterized at diagnosis by CBA and FISH. The remaining 32 cases were included because of previous CBA failure, although FISH data were available for 20 cases. OGM provided informative results in 94% of the cohort, with a high concordance rate of 97.6% compared with CBA/FISH in detecting clinically relevant aberrations. The 2 variants that were missed were both present at the detection threshold of OGM. In contrast, OGM successfully resolved 26 samples with previous CBA failure and detected 3 additional disease-defining events, resulting in diagnostic reclassification of 1 patient. Finally, OGM identified novel recurrent aberrations that warrant further investigation into their pathogenetic implications. To conclude, OGM robustly detects clinically relevant structural variants and copy number alterations and presents a promising alternative to CBA and FISH in routine diagnostic evaluation of NHL.
{"title":"Optical Genome Mapping Is a Powerful Diagnostic Tool in Non-Hodgkin Lymphoma","authors":"Amber Verhasselt , Geneviève Ameye , Justine Vanhevel , Thomas Tousseyn , Johanna Vets , Esther Hauben , Peter Meeus , Marlies Vanden Bempt , Koen Debackere , Robert A. Forsyth , Luuk Harbers , Jonas Demeulemeester , Lucienne Michaux , Katrina Rack , Barbara Dewaele , Jolien De Bie","doi":"10.1016/j.modpat.2025.100951","DOIUrl":"10.1016/j.modpat.2025.100951","url":null,"abstract":"<div><div>Non-Hodgkin lymphoma (NHL) is a diverse and heterogeneous group of hematological malignancies. These lymphomas arise from the clonal proliferation of either B/T or natural killer lymphocytes, and their correct classification relies partly on identifying characteristic structural variants and copy number alterations. Current standard-of-care technologies for detecting these genomic features, chromosome banding analysis (CBA) and fluorescent in situ hybridization (FISH), are labor intensive and have specific limitations. CBA has low resolution and relies on viable cell culture, whereas the targeted approach of FISH does not provide the whole genome view required for comprehensive disease characterization. This highlights the need for higher–resolution nontargeted genomic methods. Previous studies have evaluated optical genome mapping (OGM) as a whole genome alternative for cytogenomic characterization in NHL diagnostics but were restricted in number and to cases with peripheral blood and/or bone marrow invasion. Here, we selected a comprehensive cohort of 110 NHL cases (79 B-NHL and 31 T-NHL/natural killer-NHL) derived from different types of tissue biopsies, all with established histopathological diagnoses. Seventy-eight samples were genomically well characterized at diagnosis by CBA and FISH. The remaining 32 cases were included because of previous CBA failure, although FISH data were available for 20 cases. OGM provided informative results in 94% of the cohort, with a high concordance rate of 97.6% compared with CBA/FISH in detecting clinically relevant aberrations. The 2 variants that were missed were both present at the detection threshold of OGM. In contrast, OGM successfully resolved 26 samples with previous CBA failure and detected 3 additional disease-defining events, resulting in diagnostic reclassification of 1 patient. Finally, OGM identified novel recurrent aberrations that warrant further investigation into their pathogenetic implications. To conclude, OGM robustly detects clinically relevant structural variants and copy number alterations and presents a promising alternative to CBA and FISH in routine diagnostic evaluation of NHL.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 2","pages":"Article 100951"},"PeriodicalIF":5.5,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145756904","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 : 2025-12-09DOI: 10.1016/j.modpat.2025.100947
Damiano Arciuolo , Sabina Barresi , Laura Hiemcke-Jiwa , Jennifer Black , Nicholas Willard , Roberto Carta , Michelle Roe , Andrew Bukowinski , Alessandra Stracuzzi , Lennart Kester , Marco Koudijs , Willemijn Dingemans , Giuseppe Maria Milano , Sara Patrizi , Catherine Gestrich , Ivy John , Neyaz Azfar , Robert Bubar , John Skaugen , Uta Flucke , Rita Alaggio
USP8 is one of the members of ubiquitin-specific proteases deconjugating ubiquitin from target proteins. Besides USP6, it can be involved in tumorigenesis of mesenchymal neoplasms by binding to an activating fusion partner. Until now, USP8 fusion genes have been reported in calcified chondroid mesenchymal neoplasms, an inflammatory myofibroblastic tumor, a cardiac neoplasm, and a retroperitoneal sarcoma. In this study, we describe the clinicopathologic and genetic/epigenetic features of 7 USP8-associated tumors. The cohort included 5 male patients aged between 2 and 11 years, and 2 female patients aged 38 and 52 years. Lesions arose in the tongue, finger, hallux, arm, thoracic wall, right ventricle, and leg. Five neoplasms were resected. One was a recent case; the others were without evidence of disease after 0.5 to 3 years. Two lesions were only biopsied, 1 was a recent case and the other had no signs of progression after 4 years. Histology showed nodular or infiltrative lesions comprising bland-looking myofibroblastic spindle cells arranged in mainly short fascicles. The cellularity was variable, and the background was myxoid and/or collagenous. An inflammatory reaction was variably seen. One lesion, however, had features of a chondroid calcified mesenchymal neoplasm. Using RNA-sequencing, the following fusion partners of USP8 were found: SH3KBP1, RASA1, PDGFRA, CRK, PTPN11, and FARP1. Based on RNA-expression analysis, the 2 cases analyzed had a profile of nodular fasciitis; whereas using the Heidelberg Sarcoma Classifier, all cases had a similar methylation profile apart from other soft tissue tumor entities, suggesting that they form a separate group but are closely related to USP6-associated lesions. In conclusion, we broadened the spectrum of USP8-associated mesenchymal lesions in superficial, deep soft tissues and viscera (heart). Almost all lesions in this series displayed a myofibroblastic phenotype and harbored variable USP8 fusion partners. RNA-expression profiling indicated partial clustering with nodular fasciitis, suggesting some biological similarity. However, DNA methylation analysis consistently showed that these tumors formed a distinct epigenetic group, separate from both nodular fasciitis and inflammatory myofibroblastic tumors. Taken together, these findings support the concept of a USP8-rearranged myofibroblastic neoplasm as a potentially distinct entity, but the precise relationship with nodular fasciitis and inflammatory myofibroblastic tumor remains uncertain. Further studies integrating morphology, epigenetics, and transcriptomics are needed to clarify this relationship.
{"title":"USP8-Rearranged Mesenchymal Tumors With Myofibroblastic Phenotype: A Comprehensive Clinicopathologic, Genetic, and Epigenetic Characterization","authors":"Damiano Arciuolo , Sabina Barresi , Laura Hiemcke-Jiwa , Jennifer Black , Nicholas Willard , Roberto Carta , Michelle Roe , Andrew Bukowinski , Alessandra Stracuzzi , Lennart Kester , Marco Koudijs , Willemijn Dingemans , Giuseppe Maria Milano , Sara Patrizi , Catherine Gestrich , Ivy John , Neyaz Azfar , Robert Bubar , John Skaugen , Uta Flucke , Rita Alaggio","doi":"10.1016/j.modpat.2025.100947","DOIUrl":"10.1016/j.modpat.2025.100947","url":null,"abstract":"<div><div><em>USP8</em> is one of the members of ubiquitin-specific proteases deconjugating ubiquitin from target proteins. Besides <em>USP6</em>, it can be involved in tumorigenesis of mesenchymal neoplasms by binding to an activating fusion partner. Until now, <em>USP8</em> fusion genes have been reported in calcified chondroid mesenchymal neoplasms, an inflammatory myofibroblastic tumor, a cardiac neoplasm, and a retroperitoneal sarcoma. In this study, we describe the clinicopathologic and genetic/epigenetic features of 7 <em>USP8-</em>associated tumors. The cohort included 5 male patients aged between 2 and 11 years, and 2 female patients aged 38 and 52 years. Lesions arose in the tongue, finger, hallux, arm, thoracic wall, right ventricle, and leg. Five neoplasms were resected. One was a recent case; the others were without evidence of disease after 0.5 to 3 years. Two lesions were only biopsied, 1 was a recent case and the other had no signs of progression after 4 years. Histology showed nodular or infiltrative lesions comprising bland-looking myofibroblastic spindle cells arranged in mainly short fascicles. The cellularity was variable, and the background was myxoid and/or collagenous. An inflammatory reaction was variably seen. One lesion, however, had features of a chondroid calcified mesenchymal neoplasm. Using RNA-sequencing, the following fusion partners of <em>USP8</em> were found: <em>SH3KBP1</em>, <em>RASA1</em>, <em>PDGFRA</em>, <em>CRK</em>, <em>PTPN11</em>, and <em>FARP1.</em> Based on RNA-expression analysis, the 2 cases analyzed had a profile of nodular fasciitis; whereas using the Heidelberg Sarcoma Classifier, all cases had a similar methylation profile apart from other soft tissue tumor entities, suggesting that they form a separate group but are closely related to <em>USP6</em>-associated lesions. In conclusion, we broadened the spectrum of <em>USP8</em>-associated mesenchymal lesions in superficial, deep soft tissues and viscera (heart). Almost all lesions in this series displayed a myofibroblastic phenotype and harbored variable <em>USP8</em> fusion partners. RNA-expression profiling indicated partial clustering with nodular fasciitis, suggesting some biological similarity. However, DNA methylation analysis consistently showed that these tumors formed a distinct epigenetic group, separate from both nodular fasciitis and inflammatory myofibroblastic tumors. Taken together, these findings support the concept of a <em>USP8</em>-rearranged myofibroblastic neoplasm as a potentially distinct entity, but the precise relationship with nodular fasciitis and inflammatory myofibroblastic tumor remains uncertain. Further studies integrating morphology, epigenetics, and transcriptomics are needed to clarify this relationship.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 2","pages":"Article 100947"},"PeriodicalIF":5.5,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743388","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 : 2025-12-06DOI: 10.1016/j.modpat.2025.100946
Shruti Srikumar , Nick Evans , Melissa Yuwono Tjota , Mir Alikhan , Amandeep Kaur , Linda M. Sabatini , Nick Miller , Mike Bouma , Kruti P. Maniar , Megan Parilla
Endometrial carcinomas can be classified into 1 of 4 molecular subtypes, with the POLE-mutant subtype carrying the best prognosis. Pathogenic mutations in POLE are known to disrupt the proofreading function of DNA polymerase epsilon, resulting in an ultramutated genome, typically defined as ≥100 mutations per megabase. Routine next-generation sequencing was implemented on all endometrial carcinoma cases at our institution beginning in December 2023 to aid in molecular subclassification. During this routine sequencing, 6 POLE-mutated cases, with confirmed pathogenic POLE mutations, were observed to have a tumor mutational burden <100; prior to universal testing, only 1 such case had been identified. Endometrial carcinoma cases with pathogenic POLE mutations and tumor mutational burden <100 may be globally under-recognized, as universal testing is not yet a widely standard practice. These cases with pathogenic POLE mutations and a nonultramutated genome were found to have a lower frequency of classic morphologic “POLE features,” including high-grade histology, compared with classic ultramutated cases. The immunohistochemical profiles are also different from ultramutated counterparts, with a lower frequency of mismatch repair immunohistochemical abnormalities and p53 null or diffuse staining, and a higher likelihood of strong and diffuse estrogen receptor/progesterone receptor expression, aligning with fewer mutations in encoding genes. However, endometrial carcinoma with pathogenic POLE mutations, without ultramutation, appears to retain the “POLE-mutational signature” described in the literature. Additionally, clinical outcomes do not appear different; however, this phenomenon needs additional investigation.
{"title":"Pathogenic POLE-Mutated Endometrial Carcinomas With a Nonultramutated Genome","authors":"Shruti Srikumar , Nick Evans , Melissa Yuwono Tjota , Mir Alikhan , Amandeep Kaur , Linda M. Sabatini , Nick Miller , Mike Bouma , Kruti P. Maniar , Megan Parilla","doi":"10.1016/j.modpat.2025.100946","DOIUrl":"10.1016/j.modpat.2025.100946","url":null,"abstract":"<div><div>Endometrial carcinomas can be classified into 1 of 4 molecular subtypes, with the <em>POLE</em>-mutant subtype carrying the best prognosis. Pathogenic mutations in <em>POLE</em> are known to disrupt the proofreading function of DNA polymerase epsilon, resulting in an ultramutated genome, typically defined as ≥100 mutations per megabase. Routine next-generation sequencing was implemented on all endometrial carcinoma cases at our institution beginning in December 2023 to aid in molecular subclassification. During this routine sequencing, 6 <em>POLE-</em>mutated cases, with confirmed pathogenic <em>POLE</em> mutations, were observed to have a tumor mutational burden <100; prior to universal testing, only 1 such case had been identified. Endometrial carcinoma cases with pathogenic <em>POLE</em> mutations and tumor mutational burden <100 may be globally under-recognized, as universal testing is not yet a widely standard practice. These cases with pathogenic <em>POLE</em> mutations and a nonultramutated genome were found to have a lower frequency of classic morphologic “<em>POLE</em> features,” including high-grade histology, compared with classic ultramutated cases. The immunohistochemical profiles are also different from ultramutated counterparts, with a lower frequency of mismatch repair immunohistochemical abnormalities and p53 null or diffuse staining, and a higher likelihood of strong and diffuse estrogen receptor/progesterone receptor expression, aligning with fewer mutations in encoding genes. However, endometrial carcinoma with pathogenic <em>POLE</em> mutations, without ultramutation, appears to retain the “<em>POLE</em>-mutational signature” described in the literature. Additionally, clinical outcomes do not appear different; however, this phenomenon needs additional investigation.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 2","pages":"Article 100946"},"PeriodicalIF":5.5,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145701268","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 : 2025-12-04DOI: 10.1016/j.modpat.2025.100945
Steve Hrycaj , May P. Chan , Sriram Venneti , Kelly L. Harms , Paul W. Harms
Merkel cell carcinoma (MCC) is an aggressive cutaneous tumor that must be distinguished from other cutaneous tumors and metastatic small cell carcinoma (SmCC). Additional diagnostic markers are limited for MCC with immunophenotypic aberrancy. MCC can display immunohistochemical loss of the epigenetic marker histone H3 lysine 27 trimethylation (H3K27me3), but to our knowledge, the diagnostic utility of this observation has not been evaluated. In this study, we investigate H3K27me3 labeling in MCC (n = 195), cutaneous epithelial tumors (n = 48), noncutaneous SmCCs (n = 56), and olfactory neuroblastoma (n = 11), comparing with diagnostic markers, cytokeratin-20, neurofilament, SATB2, and POU4F3. H3K27me3 patterns in MCC included global loss, variable/mosaic labeling, and diffuse labeling. Global loss significantly associated with polyomavirus negativity, squamous atypia, and sarcomatoid change. Tumors with global loss displayed EZHIP expression (9 cases) and SUZ12 mutation (1 case). Low but retained H3K27me3 labeling was associated with longer overall and MCC-specific survival. Diagnostically, H3K27me3 labeling in MCC was significantly lower than potential mimics, and global loss of H3K27me3 was highly specific for MCC; stronger H3K27me3 labeling was not informative. Considering reduced/absent H3K27me3 as favoring MCC, diagnostic performance was similar to SATB2. However, H3K27me3 displayed consistent performance in MCC with challenging immunophenotypes, unlike SATB2. In summary, we expand upon descriptions of H3K27me3 labeling in MCC and characterize patterns of H3K27me3 in other tumor types including SmCCs and olfactory neuroblastoma. Our findings support diagnostic utility for the widely available marker H3K27me3 in MCC, with weaker labeling favoring MCC over mimics in challenging cases.
{"title":"Diagnostic Utility and Clinicopathologic Associations of Histone H3 Lysine 27 Trimethylation (H3K27me3) Immunohistochemistry for Merkel Cell Carcinoma","authors":"Steve Hrycaj , May P. Chan , Sriram Venneti , Kelly L. Harms , Paul W. Harms","doi":"10.1016/j.modpat.2025.100945","DOIUrl":"10.1016/j.modpat.2025.100945","url":null,"abstract":"<div><div>Merkel cell carcinoma (MCC) is an aggressive cutaneous tumor that must be distinguished from other cutaneous tumors and metastatic small cell carcinoma (SmCC). Additional diagnostic markers are limited for MCC with immunophenotypic aberrancy. MCC can display immunohistochemical loss of the epigenetic marker histone H3 lysine 27 trimethylation (H3K27me3), but to our knowledge, the diagnostic utility of this observation has not been evaluated. In this study, we investigate H3K27me3 labeling in MCC (n = 195), cutaneous epithelial tumors (n = 48), noncutaneous SmCCs (n = 56), and olfactory neuroblastoma (n = 11), comparing with diagnostic markers, cytokeratin-20, neurofilament, SATB2, and POU4F3. H3K27me3 patterns in MCC included global loss, variable/mosaic labeling, and diffuse labeling. Global loss significantly associated with polyomavirus negativity, squamous atypia, and sarcomatoid change. Tumors with global loss displayed EZHIP expression (9 cases) and <em>SUZ12</em> mutation (1 case). Low but retained H3K27me3 labeling was associated with longer overall and MCC-specific survival. Diagnostically, H3K27me3 labeling in MCC was significantly lower than potential mimics, and global loss of H3K27me3 was highly specific for MCC; stronger H3K27me3 labeling was not informative. Considering reduced/absent H3K27me3 as favoring MCC, diagnostic performance was similar to SATB2. However, H3K27me3 displayed consistent performance in MCC with challenging immunophenotypes, unlike SATB2. In summary, we expand upon descriptions of H3K27me3 labeling in MCC and characterize patterns of H3K27me3 in other tumor types including SmCCs and olfactory neuroblastoma. Our findings support diagnostic utility for the widely available marker H3K27me3 in MCC, with weaker labeling favoring MCC over mimics in challenging cases.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100945"},"PeriodicalIF":5.5,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145695738","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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