Modern Pathology最新文献

{"title":"High-Grade Colorectal Adenocarcinomas With SMAD4 Deficiency","authors":"Yasamin Mirzabeigi ,&nbsp;Nikunj Shah ,&nbsp;Kayla R. Schwartz ,&nbsp;Jeffrey Duryea ,&nbsp;Katiana S. Delma ,&nbsp;Elizabeth A. Montgomery ,&nbsp;Julio C. Poveda ,&nbsp;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":"2026-03-01","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}

{"title":"Biomarkers Informed by Single-Cell and Spatial Transcriptomics—Biomarkers for Grade 3 Follicular Lymphoma","authors":"Aarti Kanzaria ,&nbsp;Sonali Arora ,&nbsp;Anisha Naik ,&nbsp;Nisha Dhanushkodi ,&nbsp;Chia-Chen Ho ,&nbsp;Navneet Kaur ,&nbsp;Jerry Zhang ,&nbsp;Xiaobing Ren ,&nbsp;Jonathan R. Fromm ,&nbsp;Mazyar Shadman ,&nbsp;Stephen Smith ,&nbsp;Ajay Gopal ,&nbsp;Giovanna Roncador ,&nbsp;Eric Holland ,&nbsp;Kikkeri N. Naresh","doi":"10.1016/j.modpat.2026.100958","DOIUrl":"10.1016/j.modpat.2026.100958","url":null,"abstract":"<div><div>Follicular lymphoma (FL) patients have variable outcomes, underscoring the need for biomarkers for improved risk stratification. Current FL grading systems, based on subjective centroblast counts, suffer from poor reproducibility, despite evidence linking grade 3 FL to worse prognosis. We aimed to identify objective biomarkers for centroblasts and centrocytes to improve FL prognostication. We reanalyzed publicly available spatial and single-cell transcriptomic data from normal germinal centers and FL samples. Reanalysis revealed distinct gene expression profiles: <em>AICDA</em> (<em>AID</em>) and <em>CXCR4</em> were highly expressed in germinal center dark zone cells (centroblasts) and <em>CD40</em> and <em>TFRC</em> (<em>CD71</em>) in light zone cells (centrocytes). Single-cell RNA sequencing of FL samples further showed <em>AID</em> and <em>CXCR4</em> overexpression in malignant grade 3A cells and <em>CD40</em> and <em>CD71</em> in grades 1 to 2 cells. We validated these findings using immunohistochemistry (single and multiplex) on tonsils and 59 FL specimens (42 grades 1 to 2, 17 grade 3). Grade 3 FL showed significantly higher expression of AID, CD71, and Ki67 compared to grades 1 to 2, with CXCR4 approaching significance. Receiver operating characteristic curve analysis identified optimal cutoffs for AID (1.54%), CXCR4 (21.9%), Ki67 (21.6%), and CD71 (7.57%) to distinguish grade 3 from grades 1 to 2 FL, with AID showing the best discriminatory ability. Crucially, AID expression evaluation showed reproducibility across 2 different digital algorithms and 2 independent visual observers. Furthermore, we observed a trend toward shorter disease-specific survival in patients with both FL grade 3 and high AID expression. This prognostic observation held true regardless of whether AID overexpression was assessed via digital evaluation (cutoff: 1.54%) or visual estimation (cutoff: 2%). In conclusion, AID, CXCR4, CD71, and Ki67 are promising biomarkers for objectively identifying FL grade 3, potentially enhancing the reproducibility of grading and serving as independent prognostic tools. Further clinical validation in uniformly treated FL cohorts is warranted.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 3","pages":"Article 100958"},"PeriodicalIF":5.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145952748","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}

{"title":"Alternative Lengthening of Telomeres in Malignant Perivascular Epithelioid Cell Neoplasms: Correlation With Molecular Features Including ATRX Gene Mutation Status","authors":"Ruihe Lin ,&nbsp;John M. Gross ,&nbsp;Deyin Xing ,&nbsp;Pedram Argani ,&nbsp;Tamara Lotan ,&nbsp;Alan K. Meeker ,&nbsp;Ezra G. Baraban","doi":"10.1016/j.modpat.2026.100964","DOIUrl":"10.1016/j.modpat.2026.100964","url":null,"abstract":"<div><div>A subset of perivascular epithelioid cell neoplasms (PEComas) is histologically malignant and at high risk for metastasis, and there is limited literature available on the genetic features of these lesions. In addition to driver alterations in the tuberous sclerosis complex/mammalian target of rapamycin pathway or <em>TFE3</em> fusions, recurrent <em>ATRX</em> mutations have been identified in malignant PEComas. <em>ATRX</em> mutations have been tightly associated with the alternative lengthening of telomeres (ALT) phenotype in a variety of other tumor types. Whether malignant PEComas—regardless of <em>ATRX</em> mutational status—harbor the ALT phenotype has not been characterized. We conducted immunohistochemistry (IHC), next-generation sequencing (NGS), and telomere-specific fluorescence in situ hybridization (FISH) on a cohort of 32 malignant PEComas to evaluate for the ALT phenotype and to correlate with underlying genomic features. <em>TSC1/2/mTOR/RICTOR</em> mutations or <em>TFE3</em> translocations were detected in 16 of 31 (52%) cases by NGS. Recurrent <em>ATRX</em> alterations were identified in 10 (32%) cases. Sixteen cases underwent ALT FISH, 8 of which harbored <em>ATRX</em> alterations by NGS and/or ATRX loss based on IHC, and 8 cases without detectable <em>ATRX</em> alterations by NGS or loss based on IHC. Twelve (75%) of these 16 cases demonstrated the ALT phenotype by FISH. All 8 (100%) cases with <em>ATRX</em> mutations were ALT positive by FISH. In 8 (50%) cases without <em>ATRX</em> alterations based on NGS, 4 cases demonstrated ALT by FISH. Of these 4 ALT-positive cases lacking <em>ATRX</em> genomic alterations, IHC revealed ATRX protein loss in 1 case. Overall, <em>ATRX</em> alterations were identified in 75% of ALT-positive tumors. Our study provides the first correlation between ALT and genomic features of malignant PEComas, demonstrating that <em>ATRX</em> alterations invariably predict ALT, but that a subset of tumors without mutations in known ALT suppressor genes also activate ALT. These findings confirm that the association between <em>ATRX</em> alterations and ALT observed in other tumor types applies to PEComas and indicates that in a subset of cases, ALT may be activated by <em>ATRX</em>-independent mechanisms.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 3","pages":"Article 100964"},"PeriodicalIF":5.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146041105","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}

{"title":"Utility of p53, p16, and MTAP Immunohistochemistry in Oral Epithelial Dysplasia With Concurrent Candidiasis: A Novel Pattern-based Approach","authors":"Jennifer X. Ji ,&nbsp;Amr El Maghrabi ,&nbsp;Hezhen Carl Ren ,&nbsp;Lawrence H. Lee ,&nbsp;Sean Young ,&nbsp;Stephen T. Yip ,&nbsp;Jinesa Moodley ,&nbsp;Chi Lai ,&nbsp;Hemlata Shirsat ,&nbsp;Elan Hahn ,&nbsp;Lien N. Hoang ,&nbsp;Johanna Mabray ,&nbsp;Paras Patel ,&nbsp;Gang Wang ,&nbsp;Catherine F. Poh ,&nbsp;Tony L. Ng ,&nbsp;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":"2026-03-01","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}

{"title":"ALKATI Drives Nuclear Anaplastic Lymphoma Kinase (ALK) Expression in Histiocytic Neoplasms Without ALK Fusions","authors":"Zofia Hélias-Rodzewicz ,&nbsp;Irena Antonia Ungureanu ,&nbsp;Paul Geraeds Kemps ,&nbsp;Jean Donadieu ,&nbsp;Sébastien Héritier ,&nbsp;Mohamed-Aziz Barkaoui ,&nbsp;Nathalie Terrones ,&nbsp;Rim Ben Jannet ,&nbsp;Mariama Bakari ,&nbsp;Thamila Satour ,&nbsp;Maxime Battistella ,&nbsp;Philippe Drabent ,&nbsp;Pierre Sohier ,&nbsp;Pierre Reimbold ,&nbsp;Marie-Laure Jullié ,&nbsp;Ahmed Idbaih ,&nbsp;Fleur Cohen-Aubart ,&nbsp;Abdellatif Tazi ,&nbsp;Frédéric Charlotte ,&nbsp;Sylvie Fraitag ,&nbsp;Jean-François Emile","doi":"10.1016/j.modpat.2025.100956","DOIUrl":"10.1016/j.modpat.2025.100956","url":null,"abstract":"<div><div>Anaplastic lymphoma kinase (ALK)–positive histiocytosis is a rare histiocytic neoplasm defined by oncogenic <em>ALK</em> fusions. The disease frequently involves the nervous system and is responsive to ALK inhibition. A distinct subset of histiocytoses expresses ALK in the absence of detectable <em>ALK</em> fusions. We aimed to determine the frequency and molecular characteristics of these ALK protein–positive, fusion–negative neoplasms. RNA was extracted from histiocytosis-affected tissue samples of 398 patients with diverse histiocytoses, converted to cDNA, and subjected to targeted sequencing using a custom gene panel. <em>ALK</em> fusions and gene expression levels were assessed; the presence of <em>ALK</em> isoforms was investigated using targeted digital PCR. In a subset of cases, ALK protein expression was evaluated using immunohistochemistry (clone 1A4). Of 398 cases, 303 (76%) passed quality control and were included in the analysis. Among these, 64 (21.5%) had substantial <em>ALK</em> gene expression, while not harboring <em>ALK</em> fusions. Immunohistochemistry revealed consistent nuclear and cytoplasmic ALK expression in these cases, whereas ALK expression in fusion-positive cases was restricted to the cytoplasm. Analysis of <em>ALK</em> intron 19 expression by targeted PCR revealed the presence of a novel <em>ALK</em> isoform (<em>ALK</em>^<em>ATI</em>), which was linked to nuclear ALK expression. No specific clinical or molecular features distinguished histiocytic neoplasms with <em>ALK</em>^<em>ATI</em> from those without. In conclusion, many histiocytic neoplasms express ALK but are not ALK-positive histiocytosis. Most cases can be identified by nuclear ALK expression, which is linked to alternative transcription initiation—a known mechanism of ALK activation independent of genetic aberrations. Future studies should elucidate whether these neoplasms respond to ALK inhibition.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 2","pages":"Article 100956"},"PeriodicalIF":5.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889006","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}

{"title":"Pathogenic POLE-Mutated Endometrial Carcinomas With a Nonultramutated Genome","authors":"Shruti Srikumar ,&nbsp;Nick Evans ,&nbsp;Melissa Yuwono Tjota ,&nbsp;Mir Alikhan ,&nbsp;Amandeep Kaur ,&nbsp;Linda M. Sabatini ,&nbsp;Nick Miller ,&nbsp;Mike Bouma ,&nbsp;Kruti P. Maniar ,&nbsp;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 &lt;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 &lt;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":"2026-02-01","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}

{"title":"Spatial Profiling Shows That Lymphatic Endothelial Cells Form the Core of Kaposi Sarcoma (KS)","authors":"Johann W. Schneider ,&nbsp;Anthony B. Eason ,&nbsp;Meredith Chambers ,&nbsp;Huanjuan Su ,&nbsp;Kyle Shifflett ,&nbsp;Shuyan Guo ,&nbsp;Micheline Sanderson ,&nbsp;Cassandra Bruce-Brand ,&nbsp;Henriette Burger ,&nbsp;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":"2026-02-01","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}

{"title":"Corrigendum to “Aleukemic Chronic Myeloid Leukemia Without Neutrophilia and Thrombocytosis: A Report From the BCR::ABL1 Pathology Group” [Modern Pathology. 2024;37(2):100406]","authors":"Daniel Rivera ,&nbsp;Wei Cui ,&nbsp;Juehua Gao ,&nbsp;Deniz Peker ,&nbsp;Qian-Yun Zhang ,&nbsp;Rajan Dewar ,&nbsp;Lianqun Qiu ,&nbsp;Sergej Konoplev ,&nbsp;Zhihong Hu ,&nbsp;Koji Sasaki ,&nbsp;Aileen Y. Hu ,&nbsp;E. Shuyu ,&nbsp;Meng Liu ,&nbsp;Hong Fang ,&nbsp;Wei Wang ,&nbsp;Guilin Tang ,&nbsp;Jane F. Apperley ,&nbsp;Andreas Hochhaus ,&nbsp;Jorge E. Cortes ,&nbsp;Joseph D. Khoury ,&nbsp;Shimin Hu","doi":"10.1016/j.modpat.2025.100952","DOIUrl":"10.1016/j.modpat.2025.100952","url":null,"abstract":"","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 2","pages":"Article 100952"},"PeriodicalIF":5.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941157","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}

{"title":"MEG3 Promoter Methylation and F11 Receptor (F11R) Overexpression Define a High-Risk Subtype of Diabetic Pancreatic Cancer","authors":"Keisuke Yamazaki ,&nbsp;Hiroki Mizukami ,&nbsp;Takahiro Yamada ,&nbsp;Yutaro Hara ,&nbsp;Hiroaki Tamba ,&nbsp;Yota Tatara ,&nbsp;Zhenchao Wang ,&nbsp;Akiko Itaya ,&nbsp;Hanae Kushibiki ,&nbsp;Masaki Ryuzaki ,&nbsp;Takanori Sasaki ,&nbsp;Hidefumi Ruike ,&nbsp;Saori Ogasawara ,&nbsp;Yi Tu ,&nbsp;Keinosuke Ishido ,&nbsp;Ken Itoh ,&nbsp;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":"2026-02-01","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}

{"title":"Lowering the Diagnostic Threshold in Secondary Plasma Cell Leukemia? Comparison With Primary Cases and Implications for Flow Cytometry Immunophenotyping","authors":"Wen Shuai ,&nbsp;Zhihong Hu ,&nbsp;C. Cameron Yin ,&nbsp;Lei Chen ,&nbsp;Wei Wang ,&nbsp;Guilin Tang ,&nbsp;Dawen Sui ,&nbsp;Shaoying Li ,&nbsp;Jie Xu ,&nbsp;Nourhan Ibrahim ,&nbsp;Zenggang Pan ,&nbsp;M. James You ,&nbsp;Keyur P. Patel ,&nbsp;Francisco Vega ,&nbsp;L. Jeffrey Medeiros ,&nbsp;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> &lt; .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":"2026-02-01","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}