Modern Pathology最新文献

{"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}

{"title":"Agreement Across 10 Artificial Intelligence Models in Assessing Human Epidermal Growth Factor Receptor 2 (HER2) Expression in Breast Cancer Whole-Slide Images","authors":"Brittany McKelvey ,&nbsp;Pedro A. Torres-Saavedra ,&nbsp;Jessica Li ,&nbsp;Glenn Broeckx ,&nbsp;Frederik Deman ,&nbsp;Siraj Ali ,&nbsp;Hillary S. Andrews ,&nbsp;Salim Arslan ,&nbsp;Meir Azulay ,&nbsp;Santhosh Balasubramanian ,&nbsp;J.C. Barrett ,&nbsp;Peter Caie ,&nbsp;Ming Chen ,&nbsp;Daniel Cohen ,&nbsp;Tathagata Dasgupta ,&nbsp;Diana Fahrer ,&nbsp;George Green ,&nbsp;Mark Gustavson ,&nbsp;Sarah Hersey ,&nbsp;Ana Hidalgo-Sastre ,&nbsp;Jeff Allen","doi":"10.1016/j.modpat.2025.100944","DOIUrl":"10.1016/j.modpat.2025.100944","url":null,"abstract":"<div><div>Historically, eligibility for receiving human epidermal growth factor receptor 2 (HER2)-targeted therapies was limited to HER2-positive tumors (immunohistochemistry 3+ or in situ hybridization amplified), but recent advances in antibody-drug conjugates have expanded these criteria to include HER2-low and HER2-ultralow expression. This evolving therapeutic landscape underscores the need for precise and reproducible HER2 assessment. Digital and computational pathology tools may help address these needs, but their measurement variability must be evaluated to inform research and clinical use. We evaluated HER2 scoring variability across 10 independently developed computational pathology artificial intelligence models applied to 1124 whole-slide images from 733 patients with breast cancer. Analyses included American Society of Clinical Oncology-College of American Pathologists categorical scores (0, 1+, 2+, and 3+), H-scores, tumor cell staining percentages, and counts of total and stained invasive carcinoma cells. Agreement among models and 3 pathologists was assessed using pairwise overall percent agreement (OPA), Cohen kappa, and hierarchical clustering. Median model pairwise OPA for categorical HER2 scores was 65.1% (kappa, 0.51). Agreement was highest for HER2 3+ vs not 3+ (OPA, 97.3%; kappa, 0.86) and lowest for HER2-low cases, reflecting existing measurement challenges. For HER2 0 (negative) vs not 0 (positive) scoring, the average negative agreement was 65.3%, compared with the average positive agreement of 91.3%, suggesting more agreement in non-HER2 0 scores. H-score and cell count analyses indicated that scoring differences were more related to staining interpretation than tumor cell detection. Pathologists showed numerically higher concordance than models, but interobserver variability persisted. In exploratory analyses, sample type, staining artifacts, and heterogeneous HER2 expression appeared to be associated with discrepancies. Artificial intelligence–based HER2 scoring demonstrated high agreement in identifying HER2 3+ cases. Variability was most pronounced in borderline HER2 categories, particularly in HER2 low, underscoring the need for continued tool refinement for handling low-intensity staining. Standardized training data sets, validation frameworks, and regulatory alignment are important to improve reproducibility. Developing reference standards and benchmarking data sets is critical to evaluate performance, support regulatory decision-making, and ensure real-world applicability.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 2","pages":"Article 100944"},"PeriodicalIF":5.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145900783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"USP8-Rearranged Mesenchymal Tumors With Myofibroblastic Phenotype: A Comprehensive Clinicopathologic, Genetic, and Epigenetic Characterization","authors":"Damiano Arciuolo ,&nbsp;Sabina Barresi ,&nbsp;Laura Hiemcke-Jiwa ,&nbsp;Jennifer Black ,&nbsp;Nicholas Willard ,&nbsp;Roberto Carta ,&nbsp;Michelle Roe ,&nbsp;Andrew Bukowinski ,&nbsp;Alessandra Stracuzzi ,&nbsp;Lennart Kester ,&nbsp;Marco Koudijs ,&nbsp;Willemijn Dingemans ,&nbsp;Giuseppe Maria Milano ,&nbsp;Sara Patrizi ,&nbsp;Catherine Gestrich ,&nbsp;Ivy John ,&nbsp;Neyaz Azfar ,&nbsp;Robert Bubar ,&nbsp;John Skaugen ,&nbsp;Uta Flucke ,&nbsp;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":"2026-02-01","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}

{"title":"Optical Genome Mapping Is a Powerful Diagnostic Tool in Non-Hodgkin Lymphoma","authors":"Amber Verhasselt ,&nbsp;Geneviève Ameye ,&nbsp;Justine Vanhevel ,&nbsp;Thomas Tousseyn ,&nbsp;Johanna Vets ,&nbsp;Esther Hauben ,&nbsp;Peter Meeus ,&nbsp;Marlies Vanden Bempt ,&nbsp;Koen Debackere ,&nbsp;Robert A. Forsyth ,&nbsp;Luuk Harbers ,&nbsp;Jonas Demeulemeester ,&nbsp;Lucienne Michaux ,&nbsp;Katrina Rack ,&nbsp;Barbara Dewaele ,&nbsp;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":"2026-02-01","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}

{"title":"Retinoblastoma Protein Loss in p53 Abnormal Endometrial Carcinoma Is Associated With Poor Clinical Outcomes in a Canadian Cohort","authors":"Allen W. Zhang ,&nbsp;C. Blake Gilks ,&nbsp;Lien Hoang ,&nbsp;Samuel Leung ,&nbsp;Dawn Cochrane ,&nbsp;David G. Huntsman ,&nbsp;Jessica N. McAlpine ,&nbsp;Spencer D. Martin","doi":"10.1016/j.modpat.2025.100926","DOIUrl":"10.1016/j.modpat.2025.100926","url":null,"abstract":"","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100926"},"PeriodicalIF":5.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145525428","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":"Development of an Artificial Intelligence Model to Aid in Measurement of Invasion, Comprehensive Histologic Subtyping, and Grading of Pulmonary Adenocarcinoma","authors":"Jennifer M. Boland ,&nbsp;Lucas Stetzik ,&nbsp;Anja C. Roden ,&nbsp;Joseph J. Maleszewski ,&nbsp;Sarah M. Jenkins ,&nbsp;Trynda N. Kroneman ,&nbsp;Eunhee S. Yi ,&nbsp;Ying-Chun Lo ,&nbsp;Marie Christine Aubry","doi":"10.1016/j.modpat.2025.100923","DOIUrl":"10.1016/j.modpat.2025.100923","url":null,"abstract":"<div><div>The World Health Organization classification of pulmonary adenocarcinoma is complex, posing challenges for pathological reporting. Key difficulties include assessing invasive size in lepidic-predominant tumors and performing comprehensive histologic subtyping. Although these evaluations inform tumor stage, grade, and prognosis, they are time consuming and subjective, leading to interobserver variability. Artificial intelligence (AI) may help streamline these tasks and improve consistency. One representative hematoxylin and eosin slide was selected from each of 100 resected pulmonary adenocarcinomas, which were divided into training (n = 35) and validation (n = 65) sets. Slides were scanned and uploaded to Aiforia for AI model creation. Annotations were completed on the training set by 6 expert pulmonary pathologists and used to train a nested AI model, which was used to evaluate whole slide images of the training and validation sets. Manual assessment of tumor size, invasive size, and comprehensive histologic subtyping was performed by 3 pulmonary pathologists. In both the training and validation sets, the mean and median difference between manual and AI estimations of tumor size was ≤1.3 mm and invasive size was ≤3 mm. The median and mean differences in invasive percentage were ≤15.3% in both the training and validation sets for all patterns except for acinar and lepidic. However, ranges were wide, indicating examples with substantial disagreement. Predominant pattern agreement between AI and each observer ranged from 65.7% to 71.4% in the training set and 45.3% to 54.7% in the validation set. Agreement in grade ranged from 77.1% to 88.6% in the training set and 62.5% to 67.2% in the validation set. There was moderate agreement in grade between the 3 pathologists in the training set and moderate to substantial agreement between AI and each observer. In the validation set, there was substantial agreement in grade between the 3 pathologists and moderate agreement between AI and each observer. Although the AI model shows promise and warrants further refinement, manual pathologist review and potential revision of AI assessments are necessary to ensure the diagnostic accuracy needed for clinical use because disagreement clearly occurs.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100923"},"PeriodicalIF":5.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145577776","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":"POU4F3 Plus Keratin AE1/AE3 or Pan-keratin: An Optimal Sentinel Lymph Node Protocol for Merkel Cell Carcinoma","authors":"Diogo Maia-Silva ,&nbsp;Mia S. DeSimone ,&nbsp;Karen T. Shore ,&nbsp;Mai P. Hoang","doi":"10.1016/j.modpat.2025.100949","DOIUrl":"10.1016/j.modpat.2025.100949","url":null,"abstract":"<div><div>There is currently no standardized sentinel lymph node (SLN) immunohistochemistry (IHC) protocol for detecting Merkel cell carcinoma (MCC) metastases. A cost-effective, high-sensitivity panel could improve diagnostic accuracy and resource utilization. We evaluated 226 SLNs from 81 MCC patients using a panel of POU4F3, keratin 20, and keratin AE1/AE3 or pan-keratin. Metastasis was defined as positive staining for any of the tested IHC markers. Patients’ age ranged from 49 to 92 years (median, 73.5 years), with a male:female ratio of 1.8:1. Primary tumor sites were extremities (48.1%), head/neck (34.6%), and trunk (17.3%). SLN locations included cervical (29.6%), axillary (27%), femoral (20.8%), inguinal (9.7%), facial (7.1%), pelvic (3.1%), and epitrochlear (2.7%) sites. Metastases were identified in 102 of 226 SLNs (45%). Single-marker sensitivities were POU4F3 (96%, 98/102), keratin 20 (67%, 68/102), and keratin AE1/AE3 or pan-keratin (64%, 70/102). The most sensitive combinations were POU4F3 with keratin AE1/AE3 or pan-keratin (100% sensitivity) or POU4F3 with keratin 20 (98% sensitivity). Keratin 20 with keratin AE1/AE3 or pan-keratin was the least sensitive (74%). In 6 patients (7.4%), POU4F3 detected single metastatic cells in SLNs that were previously diagnosed at time of clinical diagnosis as negative by keratin 20 and keratin AE1/AE3 or pan-keratin panel. POU4F3 is the most sensitive individual IHC marker for detecting MCC SLN metastases. The optimal cost-effective panel is POU4F3 with keratin AE1/AE3 or pan-keratin, which achieves 100% sensitivity while reducing reliance on less effective stains. Adoption of this focused IHC panel may serve to standardize SLN evaluation for MCC and improve diagnostic accuracy and efficiency.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100949"},"PeriodicalIF":5.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Exploratory Application of a Central Nervous System (CNS) Tumor Methylation Classifier in Ovarian Neuroectodermal Tumors","authors":"Jie Yang ,&nbsp;Tianyu Zhang ,&nbsp;Ying Zhang ,&nbsp;Xinyue Zhang ,&nbsp;Yang Xiang ,&nbsp;Huanwen Wu ,&nbsp;Leiming Wang ,&nbsp;Xiaohua Shi ,&nbsp;Jiaxin Yang","doi":"10.1016/j.modpat.2025.100930","DOIUrl":"10.1016/j.modpat.2025.100930","url":null,"abstract":"<div><div>Ovarian neuroectodermal tumors (NETs) are rare malignancies with unclear diagnostic criteria and challenging treatment. We aimed to assess the utility of DNA methylation in the diagnostic classification and prognostic stratification of ovarian NETs. This retrospective study included 15 patients diagnosed with ovarian NETs at Peking Union Medical College Hospital between 2010 and 2024. Paraffin-embedded tumor tissues from all patients underwent clinicopathologic review, DNA methylation microarray assay, EWSR1 fluorescence in situ hybridization, and immunohistochemistry. The median age at diagnosis of ovarian NETs was 19 years (range, 9-73 years). These tumors often displayed nonspecific clinical manifestations and were frequently diagnosed at an advanced stage. Morphologic diagnosis included 3 medulloblastoma, 1 neuroblastoma, 3 embryonal tumors with multilayered rosettes (ETMRs), 3 ependymomas, 1 high-grade glioma, 1 gliosarcoma, 1 low-grade neuronal-glial tumor, and 2 tumors that cannot be specified. A teratoma background was present in 73.3% (11/15) of the cases. None of the tumors exhibited <em>EWSR1</em> gene rearrangement. Methylation classification was consistent with morphologic diagnosis in 30% of patients (5/15). A novel ETMR, non-<em>C19MC</em>-altered type ovarian tumor was identified in 3 patients. The median follow-up period of all patients was 14.9 months (range, 2.1-216.4 months), during which 60.0% of patients experienced recurrence or disease progression, and the mortality rate was 33.3%. Patients with ETMR non-<em>C19MC</em>-altered subtype and unmatched tumors exhibited extremely poor outcomes, with 80% (4/5) mortality within 12 months. DNA methylation profiling classified a subset of ovarian NETs into molecular subtypes resembling those of central nervous system (CNS) tumor counterparts, with corresponding prognostic similarities. Leveraging the CNS tumor methylation classifier to diagnose peripheral neuroectodermal tumors may offer critical clinical insights for these rare malignancies, enabling molecular subtyping, prognostication, and alignment with CNS-targeted therapeutic strategies.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100930"},"PeriodicalIF":5.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145471480","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":"Expression of Programmed Death-Ligand 1 and Programmed Cell Death-1 Across the Anal Neoplasia Disease Continuum and Association With Survival in Anal Cancer","authors":"Sona Chowdhury ,&nbsp;Cynthia Gasper ,&nbsp;Ann A. Lazar ,&nbsp;Kathryn Allaire ,&nbsp;Teresa M. Darragh ,&nbsp;Lawrence Fong ,&nbsp;Joel M. Palefsky","doi":"10.1016/j.modpat.2025.100918","DOIUrl":"10.1016/j.modpat.2025.100918","url":null,"abstract":"<div><div>High-risk human papillomavirus (HPV) is associated with anal high-grade intraepithelial lesion (aHSIL) and anal squamous cell carcinoma (aSCC). The prognostic significance of programmed death-ligand 1 (PD-L1)- expression in aSCC and its impact on overall survival is controversial. ASCC can evade immune surveillance by coopting the PD-L1/programmed cell death-1 (PD-1) immune checkpoint pathway, enhancing tumorigenesis. To assess the potential role of the PD-L1/PD-1 axis on tumor progression, we assessed PD-L1 and PD-1 expression on epithelial cells and immune cells by immunohistochemistry in nonlesional anal tissue (n = 22), aHSIL (n = 22), and aSCC (n = 52) from HIV-negative participants and people living with HIV. PD-L1 expression on epithelial cells was restricted to tumor cells with no expression in nonlesional and HSIL tissues, whereas PD-L1-positive immune cells were present across all 3 diagnostic stages. PD-1 expression was absent on epithelial cells, whereas PD-1-positive immune cells increased along the disease continuum from nonlesional to aSCC. The overall PD-L1 expression on epithelial cells and immune cells measured by the combined positive score (CPS) in aSCC and the aggregate PD-L1 score in nonlesional and HSIL showed a substantial increase from nonlesional to aHSIL to aSCC. In aSCC, PD-L1 expression on immune cells was more prominent than in tumor cells and correlated with increased immune cell infiltration and interferon gamma secretion. Ninety-two percent of aSCC exhibited an adaptive PD-L1 expression pattern characterized by PD-L1 expression on tumor cells, immune cells, or both. HIV status did not affect PD-L1/PD-1 expression in nonlesional, aHSIL, or aSCC. PD-L1 expression in treatment-naive aSCC was associated with improved overall survival. Those with CPS of 0 had a higher risk of death (hazard ratio, 15.2 [95% CI, 3.3-69; <em>P</em> = .0004; log-rank <em>P</em> &lt; .0001]) compared with those with CPS &gt;0. CPS may indicate the presence of immune activation and serve as a potential prognostic marker.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100918"},"PeriodicalIF":5.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145313249","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":"Tumor Deposits in Colorectal Cancer: Definitions for Ninth Edition of the Tumor Node Metastasis Staging System","authors":"Iris D. Nagtegaal ,&nbsp;Kay Washington ,&nbsp;James D. Brierley ,&nbsp;George J. Chang ,&nbsp;Richard M. Goldberg ,&nbsp;Qian Shi ,&nbsp;Sanjay Kakar ,&nbsp;Heidi Kaur","doi":"10.1016/j.modpat.2025.100924","DOIUrl":"10.1016/j.modpat.2025.100924","url":null,"abstract":"<div><div>Tumor deposits (TDs) have been a contentious element of the tumor node metastasis staging system for colorectal cancer since their introduction in 1997. Classified within the nodal category, their definition has changed repeatedly due to unclear distinctions from lymph node metastases, extramural vascular invasion, and perineural invasion. Despite updates in the tumor node metastasis system eight edition, ambiguity remains, with current criteria relying heavily on pathologist discretion. The fact that TDs are among the most powerful prognostic indicators warrants standardization, based on scientific evidence. A Delphi consensus among expert pathologists confirmed the lack of specificity and reproducibility in the current definition. In response, a new definition was developed, identifying TDs as discrete tumor nodules in pericolic or perirectal fat, distinct from lymph nodes, extramural vascular invasion, or perineural invasion but possibly originating from them. This definition emphasizes the need to report TDs separately when there is unequivocal tumor extension in relation to vessels or nerves. Size and distance from the primary tumor are debated as potential criteria, although they are not part of the proposed definition. The new definition is a first step to incorporate a more robust, biologically relevant definition of TDs into cancer staging.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 1","pages":"Article 100924"},"PeriodicalIF":5.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145527443","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}