Modern Pathology最新文献

{"title":"Complex Genetics in Somatic Mosaic Disorders: Evaluating the Rate of Multiple “Hits” in Nonmalignant Lesions","authors":"Brian Nguyen ,&nbsp;Madelyn A. Gillentine ,&nbsp;Candace T. Myers ,&nbsp;Sofia Bhatia ,&nbsp;Jaya Narayanan ,&nbsp;Larissa Rogge ,&nbsp;Louisa Emery ,&nbsp;Jonathan Perkins ,&nbsp;Whitney Eng ,&nbsp;Anica Wandler ,&nbsp;Cate R. Paschal ,&nbsp;James T. Bennett ,&nbsp;Nya D. Nelson","doi":"10.1016/j.modpat.2026.100962","DOIUrl":"10.1016/j.modpat.2026.100962","url":null,"abstract":"<div><div>Vascular anomalies encompass a heterogeneous group of vascular tumors and malformations and are most often caused by singular somatic variants that arise in utero. The presence of multiple variants, including those in at least 2 different genes (multigenic variants), is rare in these mosaic disorders, and their contribution to histology and phenotype has not been well characterized. We present our molecular and histologic experience with multiple variants in a large cohort of individuals with vascular anomalies and other suspected somatic mosaic disorders. We performed a retrospective review of 1299 individuals with suspected somatic mosaic disorders who were sequenced at our institution and identified 92 (7%) individuals with at least 2 clinically reportable variants. Our cohort includes 18 individuals with multigenic variants with unknown phenotypic implications and 13 individuals with well-described multigenic variants with clear phenotypic significance. For many individuals, the multiple variants had clear clinical implications, including variants that may respond to targeted therapy (n = 73) or germline variants (n = 33) with surveillance implications for that individual and their immediate relatives. Provided clinical information and available hematoxylin and eosin–stained slides (n = 37) were reviewed, and lesions were classified according to established guidelines whenever possible. The majority of lesions had histologic features concordant with the observed genetic variants. However, 4 out of 18 lesions with multigenic variants and unknown phenotypic implications had unique or unusual histologic features that did not fit into a specific diagnostic category. Our results demonstrate that broad sequencing of vascular anomalies, even in patients with known pathogenic variants, can be useful to identify additional clinically relevant variants that may refine diagnosis, respond to targeted therapy, or reveal a germline disorder that contributes to phenotype and may require increased surveillance.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 3","pages":"Article 100962"},"PeriodicalIF":5.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145989922","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":"Predictors of Response to Neoadjuvant Therapy in Human Epidermal Growth Factor Receptor 2 (HER2)–Positive Breast Cancer and Pathological Evaluation of HER2 Heterogeneity","authors":"Jintao Hu ,&nbsp;Julia Y. Tsang ,&nbsp;Jianlan Liu ,&nbsp;Hong Hu ,&nbsp;Dajiang Guo ,&nbsp;Gary M. Tse","doi":"10.1016/j.modpat.2025.100935","DOIUrl":"10.1016/j.modpat.2025.100935","url":null,"abstract":"<div><div>Human epidermal growth factor receptor 2 (<em>HER2</em>) gene amplification and heterogeneity influence anti-HER2 therapy efficacy, but quantitative assessment of HER2 expression heterogeneity remains scarce. This study evaluates HER2 protein heterogeneity and its effect on neoadjuvant therapy (NAT) outcomes in HER2-positive breast cancer. In total, 295 patients with HER2-positive breast cancer treated with neoadjuvant anti-HER2 therapy were included. HER2 expression was quantified by the percentage of HER2-stained cells across intensities, and heterogeneity was assessed using quadratic entropy. The overall pathological complete response (pCR) rate was 51.86%. Patients with HER2 heterogeneity showed a 24.5% pCR rate, significantly &lt;62.5% in patients with HER2 homogeneity (<em>P</em> &lt; .001). HER2 heterogeneity quadratic entropy (HER2-HQE) correlated with the percentage of HER2 immunohistochemistry (IHC) 3+ tumor cells and hormone receptor (HR) status (<em>P</em> &lt; .001). Residual cancer burden (RCB) was significantly associated with HR status, tumor stage, lymph node stage, HER2 IHC 3+ cell percentage, and HQE grade (<em>P</em> ≤ .017). No correlation was found with age, histologic grade, or Ki67 index. In the HER2 IHC 3+ ≥95% subgroup, neither pCR rate nor RCB grade after NAT was associated with traditional clinicopathological parameters, even HER2-HQE and HR status (<em>P</em> ≥ .154). The American Joint Committee on Cancer anatomical stage significantly improved post-NAT for low/intermediate HER2-HQE subgroups (<em>P</em> &lt; .001) but not for high HQE cases. In summary, HER2 heterogeneity and HR status are key predictors of anti-HER2 NAT outcomes. Higher HER2-HQE is associated with increased RCB. Quantifying HER2 heterogeneity via HQE and percentage of HER2 IHC 3+ may help optimize therapeutic strategies in clinical practice.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 3","pages":"Article 100935"},"PeriodicalIF":5.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097285","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":"Fibrillary Light Chain Proximal Tubulopathy: A Distinct Subtype Within the Spectrum of Light Chain Proximal Tubulopathy","authors":"Xu Zhang ,&nbsp;Xiaojuan Yu ,&nbsp;Jin Xu ,&nbsp;Ying Yao ,&nbsp;Yakun Chen ,&nbsp;Yali Ren ,&nbsp;Fude Zhou ,&nbsp;Minghui Zhao ,&nbsp;Suxia Wang","doi":"10.1016/j.modpat.2026.100967","DOIUrl":"10.1016/j.modpat.2026.100967","url":null,"abstract":"<div><div>Light chain proximal tubulopathy (LCPT) is a rare kidney disorder associated with monoclonal gammopathy, traditionally defined by crystalline inclusions in proximal tubular epithelial cells. A poorly recognized variant, fibrillary LCPT, is characterized by large nonamyloid fibrillar aggregates but has remained inconsistently classified, leading to diagnostic uncertainty. We aimed to clarify its clinicopathologic features and refine its position within the LCPT spectrum. We retrospectively analyzed 41 biopsy-proven LCPT cases, reclassified by ultrastructural features into crystalline LCPT (n = 22), fibrillary LCPT (n = 11), amyloid LCPT (n = 2), and LCPT with lysosomal indigestion (n = 6). Fibrillary LCPT showed irregular cytoplasmic fibrils measuring 6 to 18 nm in diameter, arranged in intersecting, fishbone-like, or compact bundle-like patterns, confined to proximal tubular epithelial cells. These fibrils were Congo red negative and not apparent on light microscopy. Conventional immunofluorescence (IF) on frozen tissue was uniformly negative in fibrillary LCPT, and pronase–digested paraffin IF detected κ restriction in only 7 of 11 cases; immunoelectron microscopy confirmed κ light chain labeling in all paraffin IF–negative cases, yielding 100% diagnostic sensitivity. Clinically, most fibrillary LCPT cases were associated with monoclonal gammopathy of renal significance (72.7%), with the remainder linked to multiple myeloma (27.3%). This subtype was commonly associated with Fanconi syndrome and reduced estimated glomerular filtration rate, with a subset of cases developing acute kidney injury. Following clone-directed therapy, a majority of patients achieved stable renal function, and 85% showed improvement in tubular dysfunction, although proteinuria reduction was less pronounced than in crystalline LCPT. Fibrillary LCPT represents a distinct, nonamyloid entity characterized by Congo red–negative fibrils, κ light chain restriction, and frequent association with Fanconi syndrome and monoclonal gammopathy of renal significance. We propose a refined 4-tier ultrastructural classification comprising 4 LCPT subtypes (crystalline LCPT, fibrillary LCPT, amyloid LCPT, and LCPT with lysosomal indigestion) to improve diagnostic precision and guide management.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 3","pages":"Article 100967"},"PeriodicalIF":5.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146093550","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":"Deep Learning–Based Virtual Elastin Staining Improves Visceral Pleural Invasion Assessment in Lung Cancer","authors":"Cheng-Long Wang ,&nbsp;Li Zhang ,&nbsp;Ling-Feng Zou ,&nbsp;Xiao-Jing Cao ,&nbsp;Li-Juan Wang ,&nbsp;Jing-Wen Li ,&nbsp;Jian-Bo Xiong ,&nbsp;Xin Ouyang ,&nbsp;Yi-Ying Luo ,&nbsp;Lu He ,&nbsp;Yi Peng ,&nbsp;Ting Deng ,&nbsp;Ming Li ,&nbsp;Min-Na Gao ,&nbsp;Li Peng ,&nbsp;Shan-Shan Yu","doi":"10.1016/j.modpat.2026.100966","DOIUrl":"10.1016/j.modpat.2026.100966","url":null,"abstract":"<div><div>Accurate assessment of visceral pleural invasion is essential for staging and prognostication in non–small cell lung cancer, yet distinguishing elastin-rich pleural layers on routine hematoxylin and eosin (H&amp;E) sections remains a diagnostic challenge. To overcome the cost and workflow delays associated with special elastic stains, we developed a deep-learning pipeline that generates a virtual elastin stain, termed synthetic eosin-based elastin fluorescence, directly from standard brightfield H&amp;E slides. A key innovation of this study was the use of intrinsic eosin fluorescence from the same H&amp;E section to create a perfectly coregistered, high-fidelity ground truth for training a conditional generative adversarial network, eliminating the spatial mismatches common in multislide approaches. In a multi-institutional validation, supplementing H&amp;E review with synthetic eosin-based elastin fluorescence significantly improved pathologists’ diagnostic accuracy for visceral pleural invasion compared with H&amp;E alone (<em>P</em> &lt; .0001). Notably, the preanalytical factors that optimized model performance, including thinner tissue sections (1-3 μm) and high-resolution scanning, also enhanced the perceptual contrast of elastin for pathologists, demonstrating a strong synergy between computational and conventional diagnostic optimization. This study establishes and validates a robust framework for high-fidelity virtual staining that improves diagnostic accuracy and provides a scalable pathway for integrating deep learning-based tools into routine digital pathology. The proposed approach offers a practical and cost-effective alternative to ancillary special stains in non–small cell lung cancer evaluation.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 3","pages":"Article 100966"},"PeriodicalIF":5.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146093572","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 Molecular Plasticity Underpins Lethal Morphologies in Lung Adenocarcinoma","authors":"Hannah L. Williams ,&nbsp;Nicolas Poulain ,&nbsp;Ian Powley ,&nbsp;Silvia Martinelli ,&nbsp;Robert Bielik ,&nbsp;Holly Leslie ,&nbsp;Colin Nixon ,&nbsp;Claire R. Wilson ,&nbsp;Marco Sereno ,&nbsp;Zhangyi He ,&nbsp;Leah Officer-Jones ,&nbsp;Fiona Ballantyne ,&nbsp;Rachel Pennie ,&nbsp;Colin S. Wood ,&nbsp;David Y. Lewis ,&nbsp;Nigel B. Jamieson ,&nbsp;John Le Quesne","doi":"10.1016/j.modpat.2026.100960","DOIUrl":"10.1016/j.modpat.2026.100960","url":null,"abstract":"<div><div>Adenocarcinoma of the lung (LUAD) is common and highly lethal. Clinical grading of LUAD strongly predicts recurrence and survival after surgery and is determined by morphological assessment of histological growth patterns in resected tumors. In particular, the 2 archetypally lethal morphologies, solid, and micropapillary growth patterns, are highly distinct from each other, but little is known about their defining molecular features or how their appearances are related to their biology and mechanisms of lethality. Pure epithelial growth patterns and subregions were identified within 7 distinct LUAD growth patterns across 51 resected tumors and characterized using NanoString GeoMx digital spatial profiler in 160 epithelially pure regions of interest. Results were validated in 27 cases at the protein level using Akoya PhenoImager multiplex immunofluorescence, in 432 cases at the RNA level with TempO-Seq, and in 30 cases with an independent GeoMx digital spatial profiler. Analyses of gene expression reveal fundamental divergent evolutionary trajectories leading to solid and micropapillary growth. Additionally, we identify recurrent localized intratumoral plasticity in both growth patterns. These states can explain the origins of growth patterns and their mechanisms of virulence. Our work highlights dramatic divergence in gene expression programs between highly lethal modes of LUAD tumor growth. We go on to show how microscopically localized hypoxia in the primary tumor helps to establish and maintain cellular survival strategies and tumor architecture, suggesting morphology-specific mechanisms of LUAD tumor metastasis and suggesting new therapeutic vulnerabilities.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 3","pages":"Article 100960"},"PeriodicalIF":5.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145952808","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":"Genetic Profiling of Mammary Periductal Stromal Tumors With Histologic Correlation Highlights High-Grade and Low-Grade Groups and Similarities to Phyllodes Tumors","authors":"Gregor Krings ,&nbsp;Gregory R. Bean ,&nbsp;Elizabeth M. Hosfield ,&nbsp;J Jordi Rowe ,&nbsp;Joseph Geradts ,&nbsp;Yunn-Yi Chen","doi":"10.1016/j.modpat.2026.100961","DOIUrl":"10.1016/j.modpat.2026.100961","url":null,"abstract":"<div><div>Periductal stromal tumors (PDST) of the breast are rare biphasic neoplasms with morphologic similarities to phyllodes tumors (PTs). The histologic spectrum of PDST is broad but has not been well characterized, and its genetic underpinnings remain unknown. We profiled PDST by targeted next-generation sequencing in correlation with their histomorphology, immunophenotype, and clinical characteristics (n = 15). All patients were female, including 2 with Li-Fraumeni syndrome (LFS), with a mean age of 48 years. Forty-two percent had synchronous or metachronous PT and/or fibroadenoma. Most PDST expressed CD34 (15/15), smooth muscle actin (12/14), and at least focal nuclear HMGA2 (8/12) and/or beta-catenin (6/12). High-grade PDST (HGPDST, n = 8) were defined by marked nuclear pleomorphism (8/8), and most had high (≥10 mitoses/10 high-power field) and/or atypical mitotic activity (7/8) and pleomorphic multinucleated tumor cells (7/8). All HGPDST had p53 (88%, 7/8) and/or Rb/<em>CDKN2A</em> (75%, 6/8) alterations by next-generation sequencing or immunohistochemistry. p53 Aberrations correlated with the presence of pleomorphic multinucleated tumor cells. Both patients with LFS had HGPDST with loss of heterozygosity of the germline <em>TP53</em> variant. Other altered genes in HGPDST included <em>EGFR</em> (25%, 2/8), <em>NF1</em> (25%, 2/8), <em>TERT</em> promoter, <em>PIK3CA</em>, <em>CDKN2A/B</em>, <em>LZTR1</em>, <em>KMT2B</em>, and <em>ARID2</em> (1 case each). Low-grade PDST, which lacked marked pleomorphism, high mitotic activity, or atypical mitoses (n = 7), had simpler genomes than HGPDST and lacked bona fide cancer gene alterations, with <em>TERT</em> promoter mutation in 1 case. Copy number alterations in PDST overlapped with those reported in PT, including 13q loss in all HGPDST. Copy number profiling revealed shared clonality of synchronous low-grade PDST and PT in 1 patient. In summary, we describe herein the genetic landscape of PDST, demonstrate correlation of genetic features with high-grade vs low-grade histology, and identify <em>TP53</em> among key oncogenic drivers of HGPDST, including in LFS. The genetics of HGPDST overlap with borderline or malignant PT, consistent with their classification as PT variants that arise through a <em>MED12</em>-independent pathway.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 3","pages":"Article 100961"},"PeriodicalIF":5.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145985007","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":"A Worldwide Survey on Pathological Measurement of Residual Breast Cancer After Neoadjuvant Therapy: Different Interpretations of the ypTNM Classification","authors":"Koen Kwakkenbos ,&nbsp;Mieke R. Van Bockstal ,&nbsp;Abeer M. Shaaban ,&nbsp;Edi Brogi ,&nbsp;Gabor Cserni ,&nbsp;Ian O. Ellis ,&nbsp;Maria Pia Foschini ,&nbsp;Stephen B. Fox ,&nbsp;Zsuzsanna Bago-Horvath ,&nbsp;Shabnam Jaffer ,&nbsp;Agnes Jager ,&nbsp;Sarah E. Pinder ,&nbsp;Elena Provenzano ,&nbsp;Cecily M. Quinn ,&nbsp;Emad A. Rakha ,&nbsp;Wendy A. Raymond ,&nbsp;Puay Hoon Tan ,&nbsp;Gary M. Tse ,&nbsp;Zsuzsanna Varga ,&nbsp;Hannah Y. Wen ,&nbsp;Carolien H.M. van Deurzen","doi":"10.1016/j.modpat.2026.100963","DOIUrl":"10.1016/j.modpat.2026.100963","url":null,"abstract":"<div><div>The extent of residual disease after neoadjuvant chemotherapy (NAC) in patients with breast cancer (BC) holds prognostic value. However, current practices for reporting post-NAC BC specimens according to the ypTNM classification vary. This study aimed to map these practices and provide recommendations for standardization. A survey was developed and globally circulated to pathologists with a special interest in BC through personal networks and working group mailing lists. The survey included general questions about tumor diameter assessment, as well as graphical scenarios presenting different distributions of tumor cells. We did not provide definitions mentioned in reporting guidelines to capture unbiased current real-world practices. A total of 208 pathologists from 35 countries completed the survey. Almost all responding pathologists (97.1%) reported the ypTNM in daily practice. Despite self-reported strict adherence to the eighth edition of the international ypTNM classification, we found substantial variation in practice concerning the application of this staging system, particularly in cases with an uneven distribution of scattered residual disease. Notably, 57.2% of respondents reported measuring the largest “continuous cluster of tumor cells,” but the interpretation of this definition varied widely. This international survey identifies the challenges and practice heterogeneity in the current application of the ypTNM staging system, which hampers the value of ypTNM reporting in daily practice. To enhance reproducibility and to provide more reliable post-NAC risk stratification, we recommend adopting standardized reporting with clearer pattern-based definitions of the ypTNM guidelines, supplemented with the elements of the residual cancer burden system.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 3","pages":"Article 100963"},"PeriodicalIF":5.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044270","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":"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}