Mod. Pathol. [JOURNAL]
Sun
200 papers
Magnetic Resonance Imaging (MRI)-Adapted Prostate Cancer Risk Tool Incorporating Cribriform and Intraductal Carcinoma.
Nguyen NJ, Liu K, Lajkosz K … +9 more , Bernardino R, Yin LB, Hollemans E, Kroon LJ, Fleshner N, van Leenders GJLH, Iczkowski KA, van der Kwast TH, Downes MR
Mod Pathol · 2025 Dec · PMID 40716754 · Publisher ↗
Current prostate cancer risk stratification tools are not adapted for magnetic resonance imaging (MRI)-targeted biopsies and do not include the presence of cribriform carcinoma/intraductal carcinoma (CC/IDC), an independ...
Current prostate cancer risk stratification tools are not adapted for magnetic resonance imaging (MRI)-targeted biopsies and do not include the presence of cribriform carcinoma/intraductal carcinoma (CC/IDC), an independent predictor of adverse clinical outcomes. We developed an MRI-adapted prostate cancer risk tool (MAPCaRT), which incorporates CC/IDC presence to the Cancer of the Prostate Risk Assessment (CAPRA) tool. We compared the prognostic power of MAPCaRT with that of CAPRA in MRI-targeted biopsies (n = 266, 2015-2023) and systematic-only biopsies (n = 1291, 2010-2018) that had matched radical prostatectomy. MAPCaRT employs the aggregate core count method for MRI-targeted lesions to calculate percent positive biopsy cores and uses the radiological stage when assessing MRI-targeted biopsies. Point attribution for CC/IDC presence and Gleason score was determined using a Cox proportional hazards model that included the CAPRA score, Gleason score, and CC/IDC status. Based on calculated MAPCaRT and CAPRA scores, patients were classified into the low-risk (0-2), intermediate-risk (3-5), or high-risk (6+) group. Model performance was assessed via the Kaplan-Meier curves, Harrell C-indices, and decision curve analysis for biochemical recurrence-free survival (BCR-FS) and event-free survival (EFS) (metastasis/cancer-specific death). CC/IDC was present in 84 of 266 (32%) MRI-targeted biopsies and 293 of 1291 systematic-only biopsies (23%). The median follow-up time was 3.4 years (IQR, 2.3-5.5 years) for the MRI-targeted biopsy cohort and 5.9 years (IQR, 3.4-8.1 years) for the systematic biopsy cohort. In the MRI-targeted biopsy cohort, MAPCaRT showed substantial improvement of the C-index compared with CAPRA (0.635 vs 0.574, P = .045) and greater net clinical benefit for 4-year BCR-FS. In the systematic biopsy cohort, MAPCaRT demonstrated improved C-index for BCR-FS (0.696 vs 0.655, P < .001) and greater net clinical benefit for 5-year BCR-FS and EFS. Other model performance metrics were marginally better with MAPCaRT. In summary, we developed MAPCaRT (prostatecancercalculator.lmp.utoronto.ca), a modified version of CAPRA incorporating CC/IDC presence, which demonstrated improved BCR-FS and EFS predictions. This may result in better clinical guidance for disease management decisions.
Spatial Evaluation and Prognostic Significance of V-Domain Immunoglobulin Suppressor of T-Cell Activation (VISTA) in Human Resectable Cervical Carcinoma: Implications for Immune Activation and Suppression.
Xie Q, Li J, Li J … +8 more , Liu C, Li Y, Zeng H, Yu J, Wu Y, Chen K, Zhang Z, Wang B
Mod Pathol · 2025 Dec · PMID 40716753 · Publisher ↗
V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a promising next-generation immune checkpoint target. This study investigated the distribution and clinical significance of VISTA expression in cervical...
V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a promising next-generation immune checkpoint target. This study investigated the distribution and clinical significance of VISTA expression in cervical carcinoma. Using a cohort of 290 patients from Sun Yat-sen Memorial Hospital, we assessed VISTA expression in tumor cells, endothelial cells, and immune cells (ICs) through immunohistochemistry, and found that it was expressed in tumor cells (18.6%), endothelial cells (38.3%), and ICs (100%). Higher infiltration of VISTA ICs was observed in the stromal region compared with that in the intratumoral region of resectable cervical carcinoma. Among the ICs, macrophages showed the highest VISTA expression compared with that by T cells and neutrophils. High intratumoral VISTA expression was an independent marker of favorable prognosis. Robust infiltration of VISTA ICs and CD8 T cells in the tumor microenvironment correlated with the best clinical outcomes. In addition, in an independent cervical carcinoma cohort (n = 48), VISTA ICs in both intratumoral and stromal regions were positively associated with CD8 T cells, CD103 T cells, and effector molecules, such as granzyme B. Elevated VISTA expression was also associated with an enriched immunosuppressive profile, including Foxp3 regulatory T cells and molecules such as TGF-β1, PD-1, LAG-3, TIM-3, and TIGIT. Moreover, multiplex staining and correlation analysis revealed a positive association between VISTA TGF-β1 ICs and FOXP3 regulatory T cells in tumor tissues. These findings establish a strong connection between intratumoral VISTA ICs and a regulatory immune contexture involving both activation and suppression signatures, with a skew toward activation dominance. Our study results suggest that VISTA can be employed as a potential prognostic biomarker for cervical carcinoma.
Histological Grade Has Clinical Validity in Neoadjuvant-Treated Breast Cancer: A Multicenter Study.
Steen S, Boissin C, Rantalainen M … +2 more , Acs B, Hartman J
Mod Pathol · 2025 Nov · PMID 40716752 · Publisher ↗
The prognostic performance of histologic grade in breast cancer is robust, but evidence for its clinical validity in the neoadjuvant setting is limited. Therefore, we evaluated grade in neoadjuvant-treated breast cancer...
The prognostic performance of histologic grade in breast cancer is robust, but evidence for its clinical validity in the neoadjuvant setting is limited. Therefore, we evaluated grade in neoadjuvant-treated breast cancer to investigate associations with overall survival (OS) in the postneoadjuvant setting. In a multicentric neoadjuvant cohort (n = 507; diagnosed 2009-2018), we examined grade in preoperative biopsies and subsequent resected specimens and compared with controls of primary operated patients (n = 297). Survival analysis for the neoadjuvant cohort related to OS was estimated, with subgroup analysis for surrogate subtypes, using the Kaplan-Meier method and log-rank test. Multivariable Cox regression models were performed to calculate hazard ratios (HR) adjusted for established clinicopathological factors. A decrease in tumor grade between preoperative biopsies and resected specimens was more frequently observed in the neoadjuvant cohort (29.8%) compared with the nontreated control group (5.7%). Patients with high-grade tumors had a considerably worse prognosis compared with low-grade tumors in both biopsies and resected specimens (P values < .001). In subgroup analysis, we found that grade had prognostic value for the ER+/HER2- subtype (P value < .001). In multivariable analysis, grade in resection specimens remained an independent prognostic marker, related to OS (HR, 2.09; 95% CI, 1.30-3.35; P = .002), whereas grade in biopsies did not (HR, 1.40; 95% CI, 0.89-2.19; P = .14). This study shows that histologic tumor grade is associated with patient outcomes after neoadjuvant treatment. Postneoadjuvant grade should be considered a prognostic factor of use in therapeutic decision-making.
Feasibility of Histological Grading System of Small-sized Pulmonary Adenocarcinoma Based on Frozen Section as a Predictor for Nodal Metastasis.
Sasahara Y, Fumimoto S, Ohtani-Kim SJ … +13 more , Tane K, Miyoshi T, Samejima J, Aokage K, Kojima M, Sakashita S, Sakamoto N, Nagamine M, Hanaoka N, Katsumata T, Tsuboi M, Ishii G, Taki T
Mod Pathol · 2025 Nov · PMID 40716751 · Publisher ↗
Accurate prediction of lymph node metastasis is the key to selecting the best surgical approach for clinical stage N0 small-sized invasive pulmonary adenocarcinoma, especially when sublobar resection is considered. This...
Accurate prediction of lymph node metastasis is the key to selecting the best surgical approach for clinical stage N0 small-sized invasive pulmonary adenocarcinoma, especially when sublobar resection is considered. This study aimed to explore the potential use of the International Association for the Study of Lung Cancer (IASLC)-graded intraoperative frozen section analysis in guiding thoracic surgeons toward optimal surgical decisions, particularly for lymph node procedures. In this retrospective study, we analyzed 190 invasive pulmonary adenocarcinomas staged clinically as N0, with tumors ≤2 cm and a consolidation-tumor ratio >0.5 on computed tomography, resected with intraoperative frozen section analysis between January 2015 and December 2022. The IASLC grade of frozen sections was evaluated by 3 independent pathologists. Interobserver agreement, concordance with corresponding permanent sections, and the association between the grade and lymph node metastasis were then assessed. Interobserver agreement of the IASLC grading on frozen sections among 3 pathologists was substantial (κ = 0.68). The overall concordance rate between the frozen and permanent sections for IASLC grade was 75.8%, with grade 3 tumors showing particularly high concordance (95.8%). While the sensitivity for detecting grade 3 tumors in frozen sections was 69.8% (60/86), as confirmed by permanent section diagnosis, the specificity was high at 97.1% (101/104), emphasizing the potential diagnostic value of frozen sections for accurately identifying grade 3 tumors. Moreover, multivariate analysis using preoperative and intraoperative characteristics identified IASLC grading of frozen sections as the only independent factor statistically associated with lymph node metastasis, characterized by an odds ratio of 4.34 (95% CI, 1.54-12.2; P = .006). Therefore, histological grading of frozen sections could serve as a predictor of lymph node metastasis and provide valuable information for thoracic surgeons when considering the surgical approach in small-sized lung adenocarcinomas (≤2 cm and consolidation-tumor ratio >0.5).
Erratum to "Beyond Hybrid Morphology: A Large Series of Fusion-Driven Benign Peripheral Nerve Sheath Tumors Including 5 Tumors With Novel Fusions" [Modern Pathology 38(2025) 100806].
Dehner CA, Platero Portillo T, Jour G … +11 more , Saoud C, Zhang Y, Buehler D, Hameed M, Michal M, Kerr D, Busam KJ, Agaimy A, Torres-Mora J, Antonescu CR, Linos K
Mod Pathol · 2025 Sep · PMID 40716357 · Publisher ↗
Abstract loading — click title to view on PubMed.
Virtual Histological Staining as a Tool for Extending Renal Segmentation Across Stains.
Denholm J, Hamidinekoo A, Burlutskiy N … +14 more , Setyo LC, Zhang I, Yousefi F, Mortimer J, Huix JP, Bagnall C, Lewis A, Hulme HE, Unwin R, Barry ST, Goodwin RJA, Gallagher FA, Söderberg M, Qaiser T
Mod Pathol · 2025 Dec · PMID 40712735 · Publisher ↗
In renal histopathology, the routine clinical use of several histological stains presents challenges for the direct application of stain-specific deep learning-based analysis tools to whole-slide images. We present an ap...
In renal histopathology, the routine clinical use of several histological stains presents challenges for the direct application of stain-specific deep learning-based analysis tools to whole-slide images. We present an approach to the in silico histological staining of kidney tissue where samples stained with hematoxylin and eosin (H&E) are virtually restained with periodic acid-Schiff (PAS). Our approach is underpinned by cycle-consistent generative adversarial neural networks trained on the National Unified Renal Translational Research Enterprise data set-the first UK-wide Biobank for chronic kidney disease-which features diverse data from 16 nephrology centers. Our work is divided into the following 4 main components: (1) we developed a virtual staining model, which infers PAS staining from H&E; (2) 2 board-certified pathologists assessed the virtual staining by attempting to distinguish it from real examples; (3) we trained a glomerular segmentation model using 3 independent renal segmentation data sets (Kidney Precision Medicine Project, Human BioMolecular Atlas Program [Kidney], and data by Jayapandian et al); and (4) we demonstrated the utility of virtual staining by inferring PAS staining from previously unseen H&E test images and applying our PAS-specific glomerular segmentation model. Each pathologist was able to identify 52.5% and 75.8% of the virtually stained images, respectively, showing an overlap in the variability of the authentic and synthetic staining. We discussed the utility of virtual staining in digital pathology, the need for pathology-specific testing with respect to chronic damage, and minimal changes and steps for incorporating more stains. Furthermore, alongside this article, we included complete glomerular annotations for 20 Kidney Precision Medicine Project H&E-stained slides.
Analytical and Clinical Performance of the VENTANA CLDN18 (43-14A) RxDx Assay in Gastric and Gastroesophageal Junction Adenocarcinoma Tissue Samples in SPOTLIGHT and GLOW.
Stratton SP, Pang L, Pugh J … +7 more , Kouzova M, Baldwin D, McDonald J, Lawrence-Glaze R, Moran S, Guerrero A, Moran D
Mod Pathol · 2025 Dec · PMID 40680855 · Publisher ↗
New therapies are needed to treat patients with human epidermal growth factor receptor 2 (HER2)-negative, locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma. Zol...
New therapies are needed to treat patients with human epidermal growth factor receptor 2 (HER2)-negative, locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma. Zolbetuximab is a monoclonal antibody that targets the tight junction protein claudin 18 isoform 2 (CLDN18.2) in gastric or gastroesophageal junction (G/GEJ) adenocarcinoma cells. We describe the analytical and clinical performance of the VENTANA CLDN18 (43-14A) RxDx Assay (Roche Diagnostics Solutions) as a companion diagnostic immunohistochemistry assay for treatment with zolbetuximab. Analytical performance was assessed in commercially available G/GEJ adenocarcinoma samples. Clinical performance was assessed in the context of 2 phase 3 trials (SPOTLIGHT, NCT03504397; GLOW, NCT03653507) of first-line zolbetuximab plus chemotherapy in patients with HER2-negative, LA unresectable or mG/GEJ adenocarcinoma, whose tumors were CLDN18.2 positive (≥75% of viable tumor cells demonstrating moderate-to-strong membrane CLDN18 staining). Staining acceptability rates were assessed in patients whose tumors were tested for CLDN18.2 status using the VENTANA CLDN18 (43-14A) RxDx Assay and who met enrollment eligibility criteria not related to CLDN18.2 status. Progression-free survival and overall survival were evaluated in the enrolled patients. Analytical performance: positive and negative percent agreement compared with immunohistochemistry reference scoring was 100% for between-antibody, between-detection kit, between-instrument, between-day, and within-run precision studies. Interlaboratory reproducibility exceeded 90% average positive and negative agreement between sites and 94% average positive and negative agreement between readers across 3 sites. Clinical performance: among 3783 patient tumor samples, staining acceptability rates exceeded 94%. Patients identified for eligibility using the VENTANA CLDN18 (43-14A) RxDx Assay demonstrated statistically significant improvement in progression-free survival and overall survival with zolbetuximab plus chemotherapy in both phase 3 trials. The VENTANA CLDN18 (43-14A) RxDx Assay demonstrated robust, reproducible analytical performance and clinical utility as a companion diagnostic for first-line zolbetuximab plus chemotherapy in patients with HER2-negative, LA unresectable or mG/GEJ adenocarcinoma, whose tumors were CLDN18.2 positive.
Computational Pathology for Accurate Prediction of Breast Cancer Recurrence: Development and Validation of a Deep Learning-Based Tool.
Su Z, Guo Y, Wesolowski R … +4 more , Tozbikian G, O'Connell NS, Khan Niazi MK, Gurcan MN
Mod Pathol · 2025 Dec · PMID 40680854 · Publisher ↗
Accurate recurrence risk stratification is crucial for optimizing treatment plans for breast cancer patients. Current prognostic tools like Oncotype DX offer valuable genomic insights into hormone receptor-positive and h...
Accurate recurrence risk stratification is crucial for optimizing treatment plans for breast cancer patients. Current prognostic tools like Oncotype DX offer valuable genomic insights into hormone receptor-positive and human epidermal growth factor receptor-negative patients but are limited by cost and accessibility, particularly in underserved populations. In this study, we present Deep-Breast-Cancer-Recurrence (BCR)-Auto, a deep learning-based computational pathology approach that predicts breast cancer recurrence risk from routine hematoxylin and eosin-stained whole slide images. Our methodology was validated on 2 independent cohorts: The Cancer Genome Atlas Program breast cancer data set and an in-house data set from The Ohio State University. Deep-BCR-Auto demonstrated robust performance in stratifying patients into low- and high-recurrence risk categories. On The Cancer Genome Atlas Program breast cancer data set, the model achieved an area under the receiver operating characteristic curve of 0.827, significantly outperforming the existing weakly supervised models (P = .041). In the independent The Ohio State University data set, Deep-BCR-Auto maintained strong generalizability, achieving an area under the receiver operating characteristic curve of 0.832, along with 82.0% accuracy, 85.0% specificity, and 67.7% sensitivity. These findings highlight the potential of computational pathology as a cost-effective alternative for recurrence risk assessment, broadening access to personalized treatment strategies. This study underscores the clinical utility of integrating deep learning-based computational pathology into routine pathological assessment for breast cancer prognosis across diverse clinical settings.
Deep Learning Predicts Survival Across Squamous Tumor Entities From Routine Pathology: Insights From Head and Neck, Esophagus, Lung, and Cervical Cancer.
Bitto V, Jiang X, Baumann M … +2 more , Kather JN, Kurth I
Mod Pathol · 2025 Dec · PMID 40680853 · Publisher ↗
Computational pathology-based models are becoming increasingly popular for extracting biomarkers from images of cancer tissue. However, their validity is often only demonstrated on a single unseen validation cohort, limi...
Computational pathology-based models are becoming increasingly popular for extracting biomarkers from images of cancer tissue. However, their validity is often only demonstrated on a single unseen validation cohort, limiting insights into their generalizability and posing challenges for explainability. In this study, we developed models to predict overall survival using hematoxylin and eosin slides from formalin-fixed paraffin-embedded samples in head and neck squamous cell carcinoma. By validating our models across diverse squamous tumor entities, including head and neck (hazard ratio [HR], 1.58; 95% CI, 1.17-2.12; P = .003), esophageal (nonsignificant), lung (HR, 1.31; 95% CI, 1.13-1.52; P < .001), and cervical (HR, 1.39; 95% CI, 1.10-1.75; P = .005) squamous cell carcinomas, we showed that the predicted risk score captures relevant information for survival beyond head and neck squamous cell carcinoma. Correlation analysis indicated that the predicted risk score is strongly associated with various clinical factors, including human papillomavirus status, tumor volume, and smoking history, although the specific factors vary across cohorts. These results emphasize the relevance of comprehensive validation and in-depth assessment of computational pathology-based models to better characterize the underlying patterns they learn during training.
GLI1-Altered Tumors of the Ovary: A Report of 4 Cases of an Underrecognized Neoplasm That May Mimic Sex Cord-Stromal Tumors.
Devins KM, Fisch AS, Young RH … +2 more , Dias-Santagata D, Oliva E
Mod Pathol · 2025 Dec · PMID 40680852 · Publisher ↗
GLI1 (glioma-associated oncogene homologue 1) altered neoplasms are an emerging group of tumors of presumed mesenchymal derivation, which occur mostly in the head and neck or soft tissues of the trunk and extremities. We...
GLI1 (glioma-associated oncogene homologue 1) altered neoplasms are an emerging group of tumors of presumed mesenchymal derivation, which occur mostly in the head and neck or soft tissues of the trunk and extremities. We have recently identified 4 ovarian neoplasms with GLI1 gene fusions; all were initially diagnosed as unusual sex cord-stromal tumors (n = 3) or endometrioid adenocarcinoma with sex cord-like morphology (n = 1). Patients' age ranged from 11 to 70 years and tumor size from 3 to 15 cm; all were confined to the ovary. Three tumors displayed dominant patterns of large irregular aggregates and smaller well-delineated nests of round cells with minimal to moderate amounts of clear to eosinophilic cytoplasm and monotonous round to ovoid nuclei divided by collagenous septae and focal myxoid areas. The final tumor showed alternating hypocellular and cellular areas composed of a loose, haphazard arrangement of spindled cells associated with myxoid stroma, imparting a "lace-like" reticular appearance, with only focal nested round cell morphology (20%). Additional minor patterns included tubules (n = 3), trabeculae (n = 2), follicle-like macrocysts (n = 2), cords (n = 1), microcysts (n = 1), and rosette-like formations (n = 1). Mitotic activity was minimal (<1 to 2/10 high-power fields). All tumors had a network of numerous capillary-sized vessels. Two tumors had some positivity for markers of sex cord-stromal differentiation, with focal, strong calretinin expression in one and diffuse, weak SF1 in another. RNA-based next-generation sequencing revealed PTCH1::GLI1 fusions in all 3 tumors with round cells and an ACTB::GLI1 fusion in the predominantly spindled tumor. Our experience with these tumors, particularly the discovery of 3 of the cases in a relatively short time frame, suggests that they are underrecognized in the ovary, where their morphologic features often mimic those of sex cord-stromal neoplasms. Awareness of their morphologic features and appropriate use of genetic testing will ensure accurate diagnosis and lead to a greater understanding of these rare neoplasms.
Comparative Analysis of Somatic and Germline Polymerase Proofreading Deficiencies in Cancer: Molecular and Clinical Implications.
Viana-Errasti J, Marín R, García-Mulero S … +6 more , Pons T, Terradas M, Capellá G, Moreno V, Mur P, Valle L
Mod Pathol · 2025 Dec · PMID 40680851 · Publisher ↗
Polymerases ε and δ maintain genome integrity through exonuclease proofreading. Germline and somatic pathogenic variants (PVs) in the exonuclease domain (ED) of POLE and POLD1 impair proofreading, causing hypermutated tu...
Polymerases ε and δ maintain genome integrity through exonuclease proofreading. Germline and somatic pathogenic variants (PVs) in the exonuclease domain (ED) of POLE and POLD1 impair proofreading, causing hypermutated tumors. Despite shared mutational features that make these tumors highly immunogenic, molecular and clinical distinctions between POLE and POLD1 mutations and between somatic and germline variants remain incompletely understood. We compared the molecular and clinical characteristics of POLE and POLD1 ED PVs (n = 31), assessing their location, pathogenicity, clinical phenotypes, mismatch repair (MMR) status, tumor mutational burden, and signatures. We analyzed 360 proofreading-deficient tumors (source: The Cancer Genome Atlas [TCGA] and Catalogue Of Somatic Mutations In Cancer [COSMIC]) and 70 families (249 individuals) with polymerase proofreading-associated polyposis. All germline and somatic PVs had high AlphaMissense scores (0.87-1) and clustered within or near Exo motifs. Recurrent, nonfounder germline PVs, POLE L424V and POLD1 S478N, showed low/modest REVEL scores. Somatic variants occurred mainly in endometrial cancers (75% of proofreading-deficient TCGA cancers), whereas colorectal cancer predominated in polymerase proofreading-associated polyposis (56% of carriers). Cancer risks and tumor spectra differed between POLE and POLD1 PV carriers. Aggressive hereditary phenotypes were linked to either specific POLE PVs (eg, S297F, V411L, P436R, M444K, A456P, and S461T) or the co-occurrence of germline ED PVs with germline MMR gene PVs. Distinct hypermutator profiles were confirmed for polymerase ε and polymerase δ proofreading deficiencies via unique mutational signatures (Polymerase ε: SBS10a/b, SBS28; Polymerase δ: SBS10c/d). Tumors with combined proofreading and MMR deficiencies had significantly higher tumor mutational burden and a shift in the associated mutational spectra. Unlike POLE, POLD1 ED PVs exhibited haplosufficiency, typically requiring a somatic second hit (eg, loss of heterozygosity) or MMR deficiency to drive hypermutation. In conclusion, differences between POLE and POLD1 and between somatic and germline mutations influence clinical presentation, mutagenic potential, and reliance on cooperating defects in tumorigenesis. These insights advance the understanding of proofreading-deficient cancers, with implications for diagnostics, genetic counseling, and precision oncology.
Ossifying Spindled and Epithelioid Tumor: A Novel Soft Tissue Tumor.
Gross JM, Zou YS, Michal M … +25 more , Agaimy A, Garcia RA, Hysell C, Fritchie KJ, Dermawan JK, Rubin BP, Klausner M, Morsberger L, Dudley J, Skaist A, Zhang Y, Schuebel K, Meyers J, Yegnasubramanian S, Cope L, Din NU, Alani A, Suster DI, Rooper L, Argani P, Baraban EG, Baumhoer D, Ameline B, Charville GW, Rosenberg AE
Mod Pathol · 2025 Dec · PMID 40680850 · Publisher ↗
This investigation describes the clinicoradiologic, pathologic, and molecular features of a unique soft tissue tumor characterized by a peripheral shell of bone and composed of bland myoid spindle and epithelioid cells t...
This investigation describes the clinicoradiologic, pathologic, and molecular features of a unique soft tissue tumor characterized by a peripheral shell of bone and composed of bland myoid spindle and epithelioid cells that are keratin-positive. Our study cohort consists of 6 men and 6 women, with a mean age of 32 years. The tumors arose in the extremities (n = 9) and proximal limb girdle (n = 3) and were equally distributed between deep and superficial soft tissues. Patients reported dull painless masses of several months to >10 years duration (mean: 2.9 years). Imaging demonstrated a complete or partial peripheral shell of bone that could extend centrally, and the tumor's mean size was 5.7 cm. Histologically, the tumors were composed of uniform, eosinophilic myoid spindled cells growing in sheets and intersecting fascicles, surrounded by mature lamellar and/or woven bone. Also present was an admixed component of intermediate-sized epithelioid cells with eosinophilic cytoplasm. Mitotic activity was consistently low. Immunohistochemistry showed strong multifocal staining for keratins, and 50% (5/10) showed focal staining for S100; however, all were negative for SMA, desmin, SOX10, ERG, and CD34. Genetic analysis by multiple targeted RNA sequencing panels was negative (n = 10); however, whole transcriptome sequencing (n = 8) revealed a recurrent and novel in-frame SRSF7::NFATC3 fusion in 4 tumors. Dual fluorescence in situ hybridization probes for SRSF7::NFATC3 successfully confirmed this fusion and identified a fifth case, which had not undergone whole transcriptome sequencing but was negative by a targeted RNA fusion panel. Methylation profiling (n = 8) demonstrated a shared epigenetic profile distinct from other entities. Clinical follow-up (n = 11) showed no evidence of recurrence after primary excision with a mean of 41.6 months. In summary, we describe a novel soft tissue tumor designated "ossifying spindled and epithelioid tumor" as a descriptive histologic term that also emphasizes its close radiologic mimic, ossifying fibromyxoid tumor. All cases have behaved in a benign fashion without recurrence following simple excision. Awareness of this entity is important, so that it can be distinguished from other neoplasms that have more aggressive biological potential.
A Genomic Alteration in GATA3 Affects Treatment Responses With a CDK4/6 Inhibitor Collaborating With p18 Expression in Advanced Breast Carcinoma.
Huang X, Varambally S, Anderson SA … +6 more , Bartow BB, Harada S, Wei S, Siegal GP, Khoury K, Yalniz C
Mod Pathol · 2025 Dec · PMID 40680849 · Publisher ↗
Cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6i) with endocrine therapy benefits patients with hormone receptor-positive, human epidermal growth receptor 2-negative breast carcinomas. However, most tumors develop resi...
Cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6i) with endocrine therapy benefits patients with hormone receptor-positive, human epidermal growth receptor 2-negative breast carcinomas. However, most tumors develop resistance to CDK4/6i during the course of therapy. Although preclinical studies have proposed molecular mechanisms for the resistance, predictive markers are yet to be discovered. We investigated the tumor molecular profiling in 42 patients with advanced-stage breast carcinoma who received CDK4/6i therapy. The tumors carrying a GATA-binding protein 3 (GATA3) gene mutation, mainly a frameshift variant, showed a better treatment response compared with other tumors. Furthermore, we explored the potential underlying mechanism of this association. To that end, nuclear expression of p18, one of the INK family proteins, was found to be positively associated with the GATA3 mutation, as well as a CDK4/6i treatment response. Therefore, our study suggests that a GATA3 gene mutation, collaborating with p18 protein expression in tumor nuclei, may have a predictive value for CDK4/6i therapy in breast carcinoma.
Exploring the Genetic Landscape of Primary Marginal Zone Lymphoma of the Urinary Bladder.
Balestri I, Ivanova VS, Gašljević G … +7 more , von Gunten M, Volavšek M, Hamelin B, Dirnhofer S, Mertz K, Menter T, Tzankov A
Mod Pathol · 2025 Nov · PMID 40645588 · Publisher ↗
Extranodal marginal zone B-cell lymphoma (MZL) of mucosa-associated lymphoid tissue is the most frequent primary lymphoma of the urinary bladder. Although MZLs from various anatomical sites are often associated with auto...
Extranodal marginal zone B-cell lymphoma (MZL) of mucosa-associated lymphoid tissue is the most frequent primary lymphoma of the urinary bladder. Although MZLs from various anatomical sites are often associated with autoimmune disorders, infections, and site-characteristic genetic alterations, the molecular foundations and potential infectious triggers of urinary bladder MZL remain poorly understood. To elucidate the disease etiology and correlation with MZLs arising in other locations, we examined a cohort of 17 cases (11 women and 6 men) diagnosed with primary bladder MZL between 2005 and 2025. Immunohistochemical analysis confirmed the literature, with all samples testing positive for the pan B-cell markers CD20 and CD79a and negative for CD5 (except 1), cyclin D1, and SOX11. Thirteen samples exhibited secretory differentiation and displayed immunoglobulin light chain restriction (9 κ and 4 λ). No gene rearrangements in BCL2, BCL6, BCL10, IRF4, MALT1, and MYC were detected. High-throughput sequencing identified 31 pathogenic/likely pathogenic somatic mutations across 18 genes, with TBL1XR1 (n = 8), MAP2K1 (n = 4), and TNFAIP3 (n = 2) being the most frequently mutated ones. Additionally, all cases included variants of unknown significance. The sample of 1 patient tested positive for Chlamydia trachomatis, human betaherpesvirus 6B, and Epstein-Barr virus. Escherichia coli was detected in 5 samples. We provide compelling evidence that urinary bladder MZL is a point mutation-driven disease rather than gene fusion-driven disease and that E coli is present in approximately one-third of tumor biopsies. These tumors frequently harbor pathogenic mutations in genes encoding components regulating plasma cell differentiation and the pleiotropic MAPK/ERK signaling pathway. TBL1XR1, which was unexpectedly frequently mutated, is generally linked to more aggressive variants of MZL and diffuse large B-cell lymphoma; however, its prognostic significance in urinary bladder MZL remains to be determined. Comparative analysis highlighted partial overlap of urinary bladder MZL mutational profiles with those found in salivary gland MZL.
Hyalinizing Clear Cell Carcinoma of the Head and Neck: A Multicenter Retrospective Study of 87 Cases Focusing on Prognostic Pathologic Features and Grading Scheme.
Xu B, Viswanathan K, Barbesier M … +16 more , Ladenheim A, Antonescu CR, Ghossein R, Lubin D, Magliocca K, Matar S, Mikula MW, Resta IT, Roy D, Sohn SY, Verma A, Prasad ML, Rooper L, Brandwein-Weber M, Baloch Z, Katabi N
Mod Pathol · 2025 Nov · PMID 40617532 · Full text
Hyalinizing clear cell carcinoma (HCCC) is a salivary gland carcinoma characterized by the presence of clear and eosinophilic cells within a hyalinized stroma and the EWSR1 rearrangement. Aiming to identify prognostic fa...
Hyalinizing clear cell carcinoma (HCCC) is a salivary gland carcinoma characterized by the presence of clear and eosinophilic cells within a hyalinized stroma and the EWSR1 rearrangement. Aiming to identify prognostic factors and establish a grading system, we herein conducted a detailed clinicopathology review of a large retrospective cohort of 87 HCCCs from 7 tertiary centers. Most HCCCs (91%) originated from minor salivary glands, although major salivary glands were affected in 8%. The most common sites were base of tongue, palate, nasopharynx, and maxilla. Eosinophilic cells were more prevalent than clear cells. Histologic features included intraosseous component (19%), perineural invasion (48%), lymphovascular invasion (LVI, 16%), nuclear pleomorphism (14%), tumor necrosis (26%), and a mitotic index (MI) ≥ 5/2 mm (9%). Factors associated with increased risk of nodal metastasis at presentation included LVI, high MI, and tumor necrosis. The 10-year disease-specific survival (DSS), disease-free survival (DFS), and distant metastasis-free survival (DMFS) rates were 80%, 51%, and 87%, respectively. Significant prognostic factors identified on univariate survival analysis included MI ≥ 5/2 mm, tumor necrosis, atypical mitosis, and nuclear pleomorphism for DSS; LVI, MI ≥ 5/2 mm, and percentage of clear cells for DFS; and nodal metastasis, LVI, MI ≥ 5/2 mm, tumor necrosis, and atypical mitosis for DMFS. The only independent prognostic factor for DFS identified on multivariate survival analysis was MI ≥ 5/2 mm. High-grade HCCCs, defined as tumors with MI ≥ 5/2 mm and/or tumor necrosis, were associated with an increased risk of nodal metastasis at presentation and shortened DSS and DMFS. Among 67 HCCCs examined for EWSR1 rearrangement, 65 (97%) harbored EWSR1 translocation. In conclusion, we identified multiple prognostic factors in HCCC, including MI, necrosis, atypical mitosis, nuclear pleomorphism, LVI, and percentage of clear cells. We herein proposed a prognostically relevant 2-tiered grading system, classifying HCCC with a MI ≥ 5/10 2 mm and/or tumor necrosis as high grade.
Pitfalls in the Histological Diagnosis of Morphologic Variants of Invasive Lobular Carcinoma of the Breast.
Floris G, Djerroudi L, Zels G … +12 more , De Schepper M, Richard F, Brahimaj R, Derksen PWB, Christgen M, Lakhani SR, Van Diest PJ, Brogi E, Desmedt C, Schnitt SJ, Vincent-Salomon A, European Lobular Breast Cancer Consortium
Mod Pathol · 2025 Sep · PMID 40617531 · Full text
Invasive lobular carcinoma (ILC) is the second most frequent histological type of breast cancer and the most frequent special type. Disruption of cell-to-cell adhesion, caused most often by E-cadherin loss of function, r...
Invasive lobular carcinoma (ILC) is the second most frequent histological type of breast cancer and the most frequent special type. Disruption of cell-to-cell adhesion, caused most often by E-cadherin loss of function, results in the distinctive histomorphology of ILC, which is characterized by single threads of monotonous, dyscohesive neoplastic epithelial cells infiltrating the breast parenchyma with little or no stromal reaction, referred to as classic ILC. In the past 4 decades, ILC variants that differ from classic ILC with regard to architectural, cytological, and/or nuclear features have been described. The recognition and correct characterization of ILC, including its variant forms, is essential to avoid misdiagnosis and its possible treatment implications. Some ILC variants may be associated with more aggressive clinical behavior compared with classic ILC, independent of standard predictive and prognostic parameters. Additionally, the distinctive biological and clinical features of ILC are increasingly being investigated as therapeutic targets in ILC-tailored clinical trials. In this manuscript, we have undertaken an in-depth review of the current state of knowledge about ILC variants. Evidence gained from molecular analysis of ILC and its microenvironment suggests that ILC variants are biologically distinct from classic ILC. However, this conclusion is undermined by the imprecise histopathological identification of ILC variants. In the absence of standardized and simplified criteria for the diagnosis of ILC, underrecognition of ILC variants may translate into missed opportunities for tailored treatment of ILC patients. Therefore, we propose steps toward the development of a roadmap that will ultimately lead to a more reproducible classification of ILC variants and improve our knowledge of these challenging tumors.
Distinct Patterns of GLUT1 Expression in Human Papillomavirus Associated and Human Papillomavirus Independent Vulvar Intraepithelial Neoplasia and Squamous Cell Carcinoma.
Zhang G, Yang B
Mod Pathol · 2025 Nov · PMID 40614899 · Publisher ↗
The expression of GLUT1 in vulvar squamous cell carcinoma (SCC) and its precursors remains largely unknown. We systematically investigated GLUT1 expression in human papillomavirus (HPV)-associated and HPV-independent vul...
The expression of GLUT1 in vulvar squamous cell carcinoma (SCC) and its precursors remains largely unknown. We systematically investigated GLUT1 expression in human papillomavirus (HPV)-associated and HPV-independent vulvar intraepithelial neoplasia (VIN) and SCC. Our study had a total of 240 cases, including 40 cases of non-neoplastic vulva, 45 HPV-associated high-grade squamous intraepithelial lesions (HSILs), 65 HPV-independent VINs, and 90 invasive SCCs. Immunohistochemical analysis revealed that GLUT1 was expressed noncontinuously at the basal layer near stromal papillae in most non-neoplastic vulvar squamous epithelium. Overexpression of GLUT1 was observed in 82.2% and 88.9% of HPV-associated HSIL and SCC, respectively, compared with 96.9% and 100% of HPV-independent VIN and SCC. Two distinct patterns of the GLUT1 expression were observed in HPV-associated and HPV-independent VIN and SCC. In HPV-associated HSIL, overexpression of GLUT1 was mainly noted in the upper intermediate layers, accompanied by negative or weak immunostaining in the basal and parabasal layers. Similar patterns were also found in HPV-associated SCC, characterized by increased GLUT1 staining intensity in the centers of tumor sheets or nests with spared basal peripheral layers. Conversely, intense membranous GLUT1 staining was mainly observed in the basal and suprabasal layers in HPV-independent VIN, regardless of p53 status. Similar intense basal and parabasal GLUT1 staining patterns and no or weak staining intensity in central areas were seen in HPV-independent SCCs. In conclusion, overexpression of GLUT1 was found in most vulvar SCCs and their precursors. We identified 2 distinct GLUT1 patterns between HPV-associated and HPV-independent VINs and SCCs. Given its high sensitivity, immunohistochemistry for GLUT1 can be a valuable tool for facilitating accurate diagnosis of VIN, especially the HPV-independent type.
Revisiting Hepatic Small Vessel Neoplasms and Anastomosing Hemangiomas as a Unique Capillary Liver Neoplasm: A 25-Case Series With Pathomolecular Correlations.
Beaufrère A, Laurent-Bellue A, Lemoine A … +8 more , Bourillon A, Sturm N, Gosset P, Cahn V, Vilgrain V, Lewin M, Paradis V, Guettier C
Mod Pathol · 2025 Oct · PMID 40614898 · Publisher ↗
Hepatic small vessel neoplasm (HSVN) and anastomosing hemangioma (AH) are 2 capillary liver neoplasms that are challenging to differentiate in clinical practice. This study aimed to refine their classification through in...
Hepatic small vessel neoplasm (HSVN) and anastomosing hemangioma (AH) are 2 capillary liver neoplasms that are challenging to differentiate in clinical practice. This study aimed to refine their classification through integrated histopathologic and molecular analyses. We conducted a bicentric retrospective study of 25 cases (15 resections and 10 biopsies). Four liver pathologists (A.B., A.L.B., V.P., C.G.) independently reviewed histologic and immunohistochemical features. Targeted DNA next-generation sequencing and RNA sequencing were performed on 21 and 15 cases, respectively. Seven lesions (28%) were diagnosed as AH, presenting as well-demarcated tumors with fibrotic stroma, often associated with cirrhosis (5/7, 71%). The remaining 18 lesions (72%) were identified as HSVN, typically infiltrative and occurring predominantly in noncirrhotic livers (78%). Microscopically, HSVN displayed 2 distinct patterns: (1) a classic pattern (8/18, 44%) composed of small, thin-walled vessels and (2) a hepatocellular-reactive pattern (7/18, 39%) with small vessels interwoven with regenerative hepatocellular trabeculae. A mixed pattern appeared in 3 of 18 cases (17%). No cytologic atypia or mitoses were observed. Tumor cells consistently expressed ERG, CD31, and CD34, with Ki67 indices <10% in all cases. Mutations in GNA genes were found in 20 of 21 cases (95%), distributed between GNA14 (81% overall: 4 AH and 13 HSVN, P = .544) and GNAQ (19% overall: 2 AH and 2 HSVN, P = .544). Transcriptomic analysis revealed no differentially expressed genes between AH and HSVN. After a median follow-up of 18 months, no recurrence was observed in resected tumors. Tumor growth was noted in 3 nonresected or partially resected cases (2 AH and 1 HSVN). In conclusion, despite subtle pathological differences, HSVN and AH exhibit overlapping clinical and molecular features, supporting their reclassification as a single benign entity, namely AH. Notably, some lesions exhibit a hepatocellular-reactive pattern that closely mimics hepatocellular adenoma, posing a significant diagnostic challenge, particularly in biopsy specimens.
Cyclin D1 Overexpression Predicts Poor Disease-Specific Survival in Human Papillomavirus-Independent Vulvar Squamous Cell Carcinoma.
Carreras-Dieguez N, Ordi O, Peñuelas N … +11 more , Del Pino M, Diez-Ahijado L, Sisuashvili L, Darecka K, Marimon L, Vega N, Torné A, Saco A, Albero R, Gaba L, Rakislova N
Mod Pathol · 2025 Nov · PMID 40614897 · Publisher ↗
The amplification of CCND1 is associated with the development and progression of various cancers. In a recent study, we showed that almost all adverse outcomes in vulvar squamous cell carcinomas (VSCC) occurred in patien...
The amplification of CCND1 is associated with the development and progression of various cancers. In a recent study, we showed that almost all adverse outcomes in vulvar squamous cell carcinomas (VSCC) occurred in patients with human papillomavirus (HPV)-independent, TP53-mutated tumors harboring CCND1 gains. In this study, we analyzed the association between CCND1 gain, cyclin D1 immunohistochemistry (IHC), and disease-specific survival (DSS) in a series of patients with HPV-independent VSCC. All patients who underwent primary surgery for VSCC at the Hospital Clínic of Barcelona, Spain, from 1975 to 2023 were recruited ("overall" cohort, n = 139). IHC for p53 and cyclin D1 was performed in all cases. In a subset of patients, we performed DNA sequencing to evaluate CCND1 copy number variations ("sequencing" cohort, n = 54). Cyclin D1 IHC overexpression (≥50% of tumor cells) had 94% sensitivity and 67% specificity as a surrogate marker of CCND1 gain. In the "sequencing" cohort, only CCND1 gains were significantly associated with impaired DSS in the multivariate analysis (hazard ratio [HR], 4.15; 95% CI, 1.08-5.40; P = .032), whereas stage or mutant TP53 status did not reach statistical significance. In the "overall" cohort, advanced stage (HR, 2.41; 95% CI, 1.08-5.39; P = .032) and cyclin D1 IHC overexpression (HR, 4.89; 95% CI, 1.77-18.5; P = .001) were associated with worse DSS in the multivariate analysis, whereas abnormal p53 IHC was not (HR, 5.06; 95% CI, 0.68-647; P = .138). In conclusion, cyclin D1 overexpression is an acceptable surrogate for CCND1 gain and has a much stronger adverse prognostic impact than altered p53 IHC in patients with HPV-independent VSCC.
Whole Slide Image vs Microscope Glass Slide Performance for the Evaluation of Programmed Death-Ligand 1 (PD-L1) Expression in 14 Tumor Types Using PD-L1 IHC 22C3 pharmDx.
Adams M, Moquin D, Tabuena-Frolli S … +5 more , Ruvalcaba-Rodarte J, Morones A, Marczak R, Simmons E, Hund S
Mod Pathol · 2025 Nov · PMID 40609861 · Publisher ↗
Agilent Technologies Inc investigated the concordance of programmed death-ligand 1 (PD-L1) expression level results (binary: positive/negative) recorded by qualified study readers using microscope glass slide (MGS) and A...
Agilent Technologies Inc investigated the concordance of programmed death-ligand 1 (PD-L1) expression level results (binary: positive/negative) recorded by qualified study readers using microscope glass slide (MGS) and Aperio AT2 scanner-generated whole slide image (WSI) scoring for 14 tumor types and cutoffs. All study readers were qualified by completing Agilent training and certification testing specific to the tumor types and cutoffs they scored for the study. Formalin-fixed, paraffin-embedded specimens were stained using the qualitative immunohistochemical assay, PD-L1 immunohistochemical 22C3 pharmDx, on Autostainer Link 48 and scored using the Tumor Proportion Score or Combined Positive Score algorithm at predefined cutoffs. The objective was to demonstrate comparable performance of scoring for MGS and WSI. Three study readers determined the numerical score and the corresponding PD-L1 expression level for specimens of each tumor type using (1) MGS and (2) WSI viewed with Aperio ImageScope with a ≥14-day washout period between MGS and WSI reads. Agreement between MGS (reference condition) and WSI was evaluated for each individual tumor type and cutoff. Concordance correlation coefficient analysis was also performed on individual tumor type MGS and WSI numerical score data. MGS and WSI percent agreement results for all individual tumor types and cutoffs were ≥89%. Concordance correlation coefficient value results for all tumor types and cutoffs were ≥0.80. The high concordance and the low variability and bias between scoring modalities demonstrate comparable performance between MGS and WSI scoring for PD-L1 expression evaluation across multiple tumor types and cutoffs.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe