Mod. Pathol. [JOURNAL]
Sun
200 papers
Digital Spatial Profiling Demonstrates Differences Between Fibrosarcomatous Transformation of Dermatofibrosarcoma Protuberans and Its Conventional Counterparts.
Frazzette N, Maji S, Mohamed N … +5 more , Jones A, Moshiri AS, Ricciotti RW, Akilesh S, Mantilla JG
Mod Pathol · 2025 Dec · PMID 40902852 · Publisher ↗
Dermatofibrosarcoma protuberans (DFSP) is a neoplasm of the dermis with a tendency for aggressive local growth and recurrence. A minority of DFSP cases may transform into higher-grade sarcoma (fibrosarcomatous transforma...
Dermatofibrosarcoma protuberans (DFSP) is a neoplasm of the dermis with a tendency for aggressive local growth and recurrence. A minority of DFSP cases may transform into higher-grade sarcoma (fibrosarcomatous transformation [FST]) (DFSP-FST), which is associated with more aggressive behavior and risk of metastasis. The histologic diagnosis of DFSP-FST may be challenging, particularly in small biopsies. Currently, there are no specific markers to reliably support the diagnosis of DFSP-FST. We identified 33 DFSP from 32 patients, including 9 patients with FST and 1 distant metastasis. Tissue microarrays (TMAs) were created using representative areas of all cases, including DFSP-FST, conventional regions from DFSP-FST, and pure conventional DFSP. Digital spatial profiling of the entire transcriptome was performed on the TMAs using the Nanostring GeoMx platform. Expression data were queried to identify differentially expressed genes specific to the regions of transformation in DFSP. Immunohistochemistry for PReferentially expressed Antigen in MElanoma (PRAME) was subsequently performed using a clinically validated protocol. Digital spatial profiling demonstrated significant gene expression differences between DFSP-FST and conventional DFSP. Genes that were overexpressed in DFSP-FST include PRAME, CTAG1B, and MMP11. Immunohistochemical analysis for PRAME showed positive expression in 7 of 10 DFSP-FST (70%) and 1 of 23 conventional DFSP (4%) (P < .0001). Gene expression profiling shows significant upregulation of PRAME and CTAG1B in DFSP-FST compared with conventional DFSP, a finding that was validated by immunohistochemistry for PRAME. Therefore, immunohistochemistry for PRAME may be useful to support the diagnosis of FST, especially in small biopsies. Increased expression of CTAG1B (NY-ESO-1) in DFSP-FST may also offer future therapeutic potential.
Follicular Helper T-Cell Lymphomas With Epstein-Barr Virus-Positive Neoplastic Cells: A Rare Scenario With Diagnostic Implications.
Burroni B, Lamaison C, Poullot E … +17 more , Pirlog R, Robe C, Bossard C, Fabiani B, Veresezan EL, Sako N, Pelletier L, Labouyrie E, Vincent G, Lemonnier F, Willems L, Egan C, Pittaluga S, Rosenwald A, de Leval L, Jaffe ES, Gaulard P
Mod Pathol · 2025 Nov · PMID 40876773 · Publisher ↗
Follicular helper T-cell lymphomas (TFHLs) of the angioimmunoblastic type (AITL) and other TFHL variants often contain Epstein-Barr virus (EBV)-positive B blasts, but EBV infection of the neoplastic T cells has rarely be...
Follicular helper T-cell lymphomas (TFHLs) of the angioimmunoblastic type (AITL) and other TFHL variants often contain Epstein-Barr virus (EBV)-positive B blasts, but EBV infection of the neoplastic T cells has rarely been documented. Here, we report 10 cases of TFHL (9 AITLs and 1 TFHL not otherwise specified) associated with EBV infection in neoplastic T cells. The patients (5 men and 5 women), aged 56 to 81 years, presented with polyadenopathy (8/8), B symptoms (7/7), and skin lesions (4/7). EBV was confirmed in neoplastic follicular helper T-cell (TFH) by double labeling for EBV, T-cell markers (CD5 or CD3), and PD1/ICOS. In 2 patients, EBV infection in TFH was demonstrated in biopsies at relapse of an AITL (n = 2). In 3 cases, the abundance of EBV in large atypical B cells had led to a mistaken diagnosis of either classic Hodgkin lymphoma or EBV-positive large B-cell lymphoma, with the diagnosis subsequently confirmed as AITL in 2 of the 3 patients. A high viral load was observed in the 3 tested patients. Lymph node biopsies showed the typical pathological, phenotypic, and genetic features of TFHL with a CD4+ (10/10), CD10+ (5/10), PD1+ (10/10), ICOS+ (8/8), CXCL13+ (8/8), BCL6+ (5/9) TFH phenotype of the neoplastic cells, follicular dendritic cell expansion (9/10), and mutations in TET2 (10/10), RHOA (p.G17V variant in 8 cases and a previously unreported RHOA p.D120N variant in 1 case), DNMT3A (5/10), and CD28 (2/9) genes. Using PCR, type-1 EBV was detected in all 9 patients tested. All 7 patients with follow-up data available showed rapid disease progression and died 2-8 months after the diagnosis. This study shows that EBV type 1 can infect TFH cells in TFHL. Further studies are needed to understand whether the crosstalk between TFH cells and EBV-infected B cells plays a role in this phenomenon and to determine the potential clinical relevance of EBV in TFHL.
TRIM63 Overexpression in FISH-Negative MiTF Family Altered Renal Cell Carcinoma (MiTF RCC).
Mannan R, Chen YB, Wang X … +22 more , Zhang Y, Hosseini N, Sangoi AR, Acosta A, Williamson SR, Mahapatra S, Chinnaiyan AK, Hu J, Vaishampayan U, Shao L, Betz BL, Kim AS, Cao X, Su F, Wang R, Argani P, Brown N, Tickoo SK, Chinnaiyan AM, Reuter VE, Dhanasekaran SM, Mehra R
Mod Pathol · 2025 Nov · PMID 40865922 · Publisher ↗
TFE3 and TFEB break-apart fluorescent in situ hybridization (FISH) assays are the "gold standard" for diagnostic confirmation of microphthalmia-associated transcription factor (MiTF) family-altered renal cell carcinoma (...
TFE3 and TFEB break-apart fluorescent in situ hybridization (FISH) assays are the "gold standard" for diagnostic confirmation of microphthalmia-associated transcription factor (MiTF) family-altered renal cell carcinoma (MiTF RCC), which includes TFE3-rearranged RCC and TFEB-altered RCC. However, FISH assays, for multiple reasons, may lead to equivocal or false-negative results, especially in cryptic fusions resulting from intrachromosomal inversions involving 5' partner genes, such as non-POU domain-containing octamer-binding protein (NONO); GRIPI-associated protein 1 (GRIPAP1); RNA-binding motif protein, X chromosome (RBMX); and RNA-binding motif protein 10 (RBM10). When FISH results are negative in cases with strong morphological suspicion of the listed tumor entities, pathologists may recommend targeted RT-PCR or panel-based RNA fusion sequencing for diagnostic confirmation. Our recent RNA in situ hybridization (RNA ISH)-based study demonstrated RNA expression of the tripartite motif containing 63 (TRIM63) to be highly enriched in TFE3-rearranged RCC and TFEB-altered RCC, including 2 FISH false-negative RCC cases harboring RBM10::TFE3 fusion. Based on these observations, we hypothesized that TRIM63 positivity could aid in diagnosing cases that are negative by conventional FISH assay but remain morphologically suspicious, representing an unmet clinical need in this area. We collected 20 RCC cases with morphological suspicion (with equivocal/indeterminate immunohistochemistry panel) of MiTF RCC, which were TRIM63 positive, negative/equivocal for TFE3/TFEB gene rearrangement by FISH, and underwent next-generation sequencing (NGS). On NGS correlation, 14 of 20 (70%) FISH-negative TRIM63-positive tumors harbored an MiTF gene rearrangement. In the remaining 6 cases, we were unable to fully ascertain the MiTF rearrangement status due to the inherent limitation of the NGS panel utilized. The cases with MiTF gene rearrangement include TFE3 rearrangement in 60% (12/20) and TFEB low-level copy gains (with an additional missense mutation in 1 case) in 10% (2/20) of samples. RBM10:TFE3 fusion was seen in 67% (8/12) of TFE3-rearranged RCC in this cohort. TRIM63 RNA ISH assay could aid in identifying cases that harbor TFE3 or TFEB rearrangement associated with false-negative or equivocal TFE3/TFEB FISH results, especially those involving gene fusions with a paracentric Xp11 inversion. Overall, employment of TRIM63 RNA ISH coupled with TFE3/TFEB FISH assays and follow-up genomic interrogation enhanced diagnostic accuracy for patients with MiTF RCC.
Apolipoprotein E Immunostaining Has Diagnostic Utility in Differentiating Dense Deposit Disease and C3 Glomerulonephritis: Clone-Based Evaluation of D719N, EP1373Y, and 1B2C9.
Hurdogan O, Mirioglu S, Dirim AB … +5 more , Doksan M, Yuruk Yildirim ZN, Turkmen A, Kilicaslan I, Ozluk Y
Mod Pathol · 2025 Dec · PMID 40865921 · Publisher ↗
Electron microscopy (EM) has been essential for the diagnosis of dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). Recent research showed significantly higher accumulation of apolipoprotein E (ApoE) in DDD co...
Electron microscopy (EM) has been essential for the diagnosis of dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). Recent research showed significantly higher accumulation of apolipoprotein E (ApoE) in DDD compared with C3GN and tested the use of ApoE immunohistochemistry for DDD diagnosis. We aimed to investigate the diagnostic value of ApoE in DDD and C3GN using 3 distinct ApoE clones-D719N, EP1373Y, and 1B2C9. Kidney biopsies of 26 DDD and 18 C3GN, diagnosed based on EM findings, were subjected to immunohistochemical analyses using ApoE clones D719N, EP1373Y, and 1B2C9. Kidney biopsies of 8 immune complex-mediated membranoproliferative glomerulonephritis, 13 acute postinfectious glomerulonephritis, 13 focal segmental glomerulosclerosis, 6 minimal change disease, 13 membranous nephropathy, 11 lupus nephritis, and 9 fibrillary glomerulonephritis constituted the control group. The staining pattern, intensity, and distribution were evaluated in each renal compartment. Linear/predominantly linear staining of score 2 to 3 intensity in a diffuse/global distribution was interpreted as diagnostic for DDD. DDD and C3GN cases were reclassified using each clone individually. D719N confirmed the diagnosis of DDD in 76.9% of the cases, whereas EP1373Y and 1B2C9 in 84.6%. All 3 clones confirmed C3GN diagnosis in 94.4% of the cases. EP1373Y and 1B2C9 demonstrated superior sensitivity (85% vs 77%) and overall diagnostic accuracy compared with D719N (89% vs 85%). Clone 1B2C9 showed significantly more intense background staining compared with D719N and EP1373Y in all cases (P < .001). No cases in the control group showed false-positive staining, except for 66.7% of fibrillary glomerulonephritis. Notably, 2 among 6 D719N-negative DDDs were transplant biopsies, and 2 belonged to the same patient with Barraquer-Simons syndrome. All 3 ApoE clones, D719N, EP1373Y, and 1B2C9, can be used for routine diagnosis in the absence of EM or as an adjunct to EM to increase diagnostic accuracy in differentiating DDD and C3GN.
Flat Cell Variant of Lung Adenocarcinoma In Situ.
Oka N, Kishikawa S, Kashima J … +5 more , Watanabe H, Kusumoto M, Asakura K, Watanabe SI, Yatabe Y
Mod Pathol · 2025 Dec · PMID 40865920 · Publisher ↗
Adenocarcinoma in situ (AIS) of the lungs has been increasingly diagnosed worldwide following the establishment of its diagnostic criteria along with advances in computed tomography imaging technology. We encountered a s...
Adenocarcinoma in situ (AIS) of the lungs has been increasingly diagnosed worldwide following the establishment of its diagnostic criteria along with advances in computed tomography imaging technology. We encountered a series of AISs with a peculiar flat cell morphology that were challenging to diagnose using the current diagnostic criteria. Histologically, all 5 tumors showed a lepidic pattern consisting of flat tumor cells with minimal nuclear atypia. Intra-alveolar mucin was identified in 4 cases, although cytoplasmic mucin of the tumor cells was inconspicuous. All tumors harbored genetic or immunohistochemical features of neoplasms identical to those of conventional AIS. Driver mutations were detected in 3 tumors (2 EGFR mutations and 1 ERBB2 mutation), and 4 tumors were positive for hepatocyte nuclear factor 4 alpha, although the intensity was very low. We also identified a flat cell variant of minimally invasive adenocarcinoma, suggesting a stepwise progression similar to that in conventional AIS. These findings suggest that AIS with flat cellular features is a morphologic variant of AIS and may be challenging to diagnose if pathologists are unaware of this atypical feature of lung neoplasm.
Uterine Sarcomas With Recurrent KDM2B Gene Fusions: Three Cases of a Possible Novel Subtype of High-Grade Endometrial Stromal Sarcoma.
Devins KM, Truffaux N, Azmani R … +10 more , Ancelle M, Bourdon A, Hostein I, Marion E, Blanchard L, Alame M, Soubeyran I, Le Loarer F, Oliva E, Croce S
Mod Pathol · 2025 Nov · PMID 40865919 · Publisher ↗
The advent of widespread genomic testing of uterine mesenchymal tumors has led to novel insights into the biology of these diverse tumors, and many genomically defined entities have been described in recent years. During...
The advent of widespread genomic testing of uterine mesenchymal tumors has led to novel insights into the biology of these diverse tumors, and many genomically defined entities have been described in recent years. During a larger study of endometrial stromal sarcomas and unclassified uterine sarcomas, we identified 3 tumors harboring KDM2B gene fusions. Patients were 32, 61, and 67 years old, and all initially underwent incomplete sampling via laparoscopic myomectomy (n = 1), laparoscopic biopsy (n = 1), or hysteroscopic myomectomy (n = 1). One patient's tumor was densely adherent to the pelvic sidewall; she was treated with chemotherapy and died of widely metastatic disease at 29 weeks. Another underwent a subsequent recent hysterectomy with the tumor confined to the uterus and minimal follow-up to date. The final patient refused further treatment and was alive at 28 weeks, although the status of the disease progression was unknown. On microscopic examination, 2 tumors showed infiltrative borders, whereas interface with the myometrium was not present in the third. The tumors were variably cellular with alternating hypercellular and hypocellular zones in a myxoid to loosely collagenous stroma. The hypercellular areas contained round to ovoid cells in diffuse (n = 3) and sex cord-like arrangements, including cords (n = 3), nests (n = 2), and tubules (n = 1); 2 also contained occasional spindled cells arranged in vague fascicles. These cells showed moderate atypia with open chromatin, numerous mitoses (8, 24, and 25 per 10 high-power fields), and frequent apoptosis. The hypocellular areas contained sparse, ovoid-to-spindled cells with minimal atypia. All tumors were diffusely positive for cyclin D1, whereas BCL6 corepressor was diffusely positive in 1 and negative in 2; desmin and caldesmon were negative in all 3 neoplasms. All harbored KDM2B gene fusions; partner genes included EPC1, EP400, and CITED1. MDM2 amplification was also noted in 2. Clustering analysis based on RNA expression profiling revealed tight clustering of all 3 tumors within the broad group of high-grade endometrial stromal sarcomas. Based on the overall clinicopathologic and genomic features, we suggest that these tumors may represent a novel subtype of uterine sarcoma and may be best classified as high-grade endometrial stromal sarcoma, although additional confirmatory studies are needed.
Deep Learning on Histologic Slides Accurately Predicts Consensus Molecular Subtypes and Spatial Heterogeneity in Colon Cancer.
Le Douget JE, Jacob P, Lepage C … +17 more , Gallois C, Sroussi M, De Reynies A, Cazelles A, Gonzalez D, Maussion C, Bouche O, Levache CB, Jary M, Mineur L, Jegou S, Saillard C, Morel M, Taïeb J, Bibeau F, Emile JF, Laurent-Puig P
Mod Pathol · 2025 Nov · PMID 40865918 · Publisher ↗
Colon cancer (CC) is the third most prevalent cancer type. It is highly heterogeneous, particularly in terms of molecular profiles, which have both prognostic and predictive impacts on the treatment efficacy. However, CC...
Colon cancer (CC) is the third most prevalent cancer type. It is highly heterogeneous, particularly in terms of molecular profiles, which have both prognostic and predictive impacts on the treatment efficacy. However, CC treatment in adjuvant situations is currently guided solely by T and N staging. In this context, consensus molecular subtypes (CMSs) were introduced to stratify patients with CC based on molecular profiles. Recent studies have shown that CMS can be heterogeneous in CC, leading to a worse prognosis. This study focused on predicting CMS and its heterogeneity in CC using deep learning on digitized hematoxylin and eosin ± saffron-stained whole-slide images. Data and whole-slide images of 1996 patients from the PETACC-8, The Cancer Genome Atlas-COAD, and PRODIGE-13 cohorts were used. The model is trained to predict a 4-dimensional CMS vector, reflecting intratumor heterogeneity (ITH). It comprises a self-supervised model for embedding image patches into vectors and a weakly supervised model predicting CMS calls. Ground-truth CMS scores are obtained with the CMSclassifier package. Interpretability analyses are performed at the slide and patch levels. For homogeneous tumors, the model trained on PETACC-8 achieves 93.0% (±1.4%) macroaverage area under the curve in internal cross-validation and 94.4% macroaverage area under the curve in external validation over PRODIGE-13, whereas the The Cancer Genome Atlas-COAD model reaches 85.4% (±3.0%) in cross-validation and 92.4% over PRODIGE-13. The trained models also provide spatial distributions of CMS across tumor slides and associate specific histologic features with each CMS. Finally, the models are able to predict ITH. The results show that a deep learning model trained on routine histology slides is capable of providing an efficient and robust method for predicting CMS and characterizing a patient's ITH, paving the way for the routine consideration of CMS/ITH in clinical decision making in the adjuvant setting.
Histology-Based Virtual RNA Inference Identifies Pathways Associated With Metastasis Risk in Colorectal Cancer.
Srinivasan G, Le MK, Azher Z … +9 more , Liu X, Vaickus L, Kaur H, Kolling F, Palisoul S, Perreard L, Lau KS, Yao K, Levy J
Mod Pathol · 2025 Nov · PMID 40803647 · Publisher ↗
Colorectal cancer (CRC) remains a major health concern, with >150,000 new diagnoses and >50,000 deaths annually in the United States, underscoring an urgent need for improved screening, prognostication, disease managemen...
Colorectal cancer (CRC) remains a major health concern, with >150,000 new diagnoses and >50,000 deaths annually in the United States, underscoring an urgent need for improved screening, prognostication, disease management, and therapeutic approaches. The tumor microenvironment (TME)-comprising cancerous and immune cells interacting within the tumor's spatial architecture-plays a critical role in disease progression and treatment outcomes, reinforcing its importance as a prognostic marker for metastasis and recurrence risk. However, traditional methods for TME characterization, such as bulk transcriptomics and multiplex protein assays, lack sufficient spatial resolution. Although spatial transcriptomics (ST) allows for the high-resolution mapping of whole transcriptomes at near-cellular resolution, current ST technologies (eg, Visium and Xenium) are limited by high costs, low throughput, and issues with reproducibility, preventing their widespread application in large-scale molecular epidemiology studies. In this study, we refined and implemented virtual RNA inference (VRI) to derive ST-level molecular information directly from hematoxylin and eosin (H&E)-stained tissue images. Our VRI models were trained on the largest matched CRC ST data set to date, comprising 45 patients and >300,000 Visium spots from primary tumors. Using state-of-the-art deep learning models (UNI, ResNet-50, Vision Transformer, and Vision Mamba), we achieved a median Spearman's correlation coefficient of 0.546 between predicted and measured spot-level expression. As validation, VRI-derived gene signatures linked to specific tissue regions (tumor, interface, submucosa, stroma, serosa, muscularis, and inflammation) showed strong concordance with signatures generated via direct ST, and VRI performed accurately in estimating cell-type proportions spatially from H&E slides. In an expanded CRC cohort controlling for tumor invasiveness and clinical factors, we further identified VRI-derived gene signatures significantly associated with key prognostic outcomes, including metastasis status. Although certain tumor-related pathways are not fully captured by histology alone, our findings highlight the ability of VRI to infer a wide range of "histology-associated" biological pathways at near-cellular resolution without requiring ST profiling. Future efforts will extend this framework to expand TME phenotyping from standard H&E tissue images, with the potential to accelerate translational CRC research at scale.
A Global Ring Study: Concordance Between Ventana PATHWAY Anti-HER2/neu (4B5) Companion Diagnostic Assay and Comparators in Detecting HER2-Low Breast Cancer.
Schildhaus HU, Badve S, D'Arrigo C … +14 more , Farshid G, Lebeau A, Peg V, Penault-Llorca F, Rüschoff J, Yang W, Atkey N, Lauer C, Baumann J, Beyerlein E, Newell AH, Penner A, Moh A, Viale G
Mod Pathol · 2025 Nov · PMID 40789533 · Publisher ↗
Trastuzumab deruxtecan showed improved efficacy compared with the treatment of the physician's choice in human epidermal growth factor receptor 2 (HER2)-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization-...
Trastuzumab deruxtecan showed improved efficacy compared with the treatment of the physician's choice in human epidermal growth factor receptor 2 (HER2)-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization-negative) metastatic breast cancer (BC) patients in the DESTINY-Breast04 and -06 phase 3 clinical trials. Both trials used the Ventana PATHWAY HER2/neu (4B5) IHC assay (PATHWAY 4B5) to select patients. The variety of HER2 IHC assays in clinical use complicates real-world differentiation between HER2-low and HER2 IHC 0. This study assessed concordance between PATHWAY 4B5 and comparator assays in identifying HER2-low samples. Fifty clinical BC samples from a cohort of 300 were stained using PATHWAY 4B5 and centrally scored, according to the American Society of Clinical Oncology-College of American Pathologists 2018 guidelines, as HER2 IHC 0, 1+, 2+, and 3+. Unstained samples were sent to participating laboratories in North and South America, Europe, and the Asia-Pacific regions that were actively scoring HER2 IHC for BC, had 2 independent pathologists, and did not routinely use PATHWAY 4B5 following the CDx protocol. Pathologists stained and scored the samples using their laboratory's routine protocols. Following virtual alignment on interpretation of HER2 IHC scoring guidelines (postalignment), pathologists were directed to rescore the samples. Pathologist scores were compared with centrally assessed scores; the primary endpoint was positive percentage agreement (PPA) and negative percentage agreement (NPA) for HER2-low versus HER2 IHC 0 based on postalignment scores. Overall, 129 pathologists from 68 laboratories submitted 6270 postalignment scores for analysis. PPA (agreement in identifying HER2-low) and NPA (agreement in identifying HER2 IHC 0) were 84.8% (95% CI, 83.6%-86.0%) and 69.2% (95% CI, 67.0%-71.2%), respectively. Across assay types, postalignment PPA ranged from 61.6% to 95.5% and postalignment NPA ranged from 36.9% to 81.7%. The variation in concordance rates observed between assays suggests assay choice may be important for the correct identification of patients with low levels of HER2-expression who may benefit from HER2-targeted therapies.
Clinicopathologic and Genomic Characterization of SMARCA4-Deficient Carcinoma of the Gallbladder.
Jia Q, Chen Y, Pan Y … +11 more , Gao S, Wei X, Fan Y, Li P, Yang Z, Pu J, Nan P, Chang H, Zheng J, Zhang G, Liu X
Mod Pathol · 2025 Nov · PMID 40789532 · Publisher ↗
As a key subunit of the SWItch/sucrose nonfermentable chromatin-remodeling complex, SMARCA4 plays a critical role as a tumor suppressor in various tumors. However, the clinicopathological and molecular features of SMARCA...
As a key subunit of the SWItch/sucrose nonfermentable chromatin-remodeling complex, SMARCA4 plays a critical role as a tumor suppressor in various tumors. However, the clinicopathological and molecular features of SMARCA4-deficient carcinoma of the gallbladder (SMARCA4-dGBC) have not been well explored. In this study, a retrospective cohort of 926 nonsquamous cell gallbladder carcinomas (GBCs) was analyzed on tissue microarrays using immunohistochemistry for SMARCA4, comprising 813 adenocarcinomas, 53 adenosquamous carcinomas, 43 undifferentiated carcinomas, 7 sarcomatoid carcinomas, 6 small cell neuroendocrine carcinomas, and 4 large cell neuroendocrine carcinomas. Twenty-six (2.8%) SMARCA4-dGBCs were identified and further analyzed using immunohistochemistry, whole-exome sequencing, and clinicopathological data. SMARCA4-dGBCs are frequently identified in advanced stages and exhibit diverse patterns of differentiation. The majority were identified as monotonous diffuse sheets, nests, and cords, whereas a subset exhibited gland-forming and rhabdoid morphologies (11.5%). Tumors retained mismatch repair proficiency (100%) but showed variable HER2 expression (11.5% scored as 2+/3+) and limited PD-L1 positivity. Genomic profiling revealed SMARCA4 alterations in 88.5% (23/26) of patients, predominantly deletions (91.3%) and truncating mutations-p.K892∗ and p.R979∗-that disrupt the critical ATPase/helicase domains. Co-occurring TP53 mutations (56.5%) highlighted the presence of synergistic chromatin-remodeling defects. Enrichment of oncogenic signaling pathways, including the RTK-RAS (78.3%), TP53 (60.9%), NOTCH (47.8%), and HIPPO (39.1%) pathways, was observed. Patients with SMARCA4-dGBC exhibited significantly shorter progression-free survival (median, 6 vs 14 months) and overall survival (median, 11 vs 16 months) than those with SMARCA4-retained tumors. Overall, these findings revealed that SMARCA4-dGBC is a rare, distinct entity characterized by the destabilization of the SWItch/sucrose nonfermentable complex, genomic instability, and resistance to conventional therapies. The prevalence of targetable pathways, such as RTK-RAS and cell cycle dysregulation, highlights opportunities for precise therapeutic strategies involving EZH2, CDK4/6, or ATR inhibitors. SMARCA4 immunohistochemistry and molecular profiling are essential for accurate diagnosis, prognostic stratification, and therapeutic innovation of this GBC subtype.
Recurrent BEND2 Fusion Genes Identified by Whole Transcriptome Sequencing of Nonfunctional Pancreatic Neuroendocrine Tumors Correlate With Poor Patient Prognosis.
Wood-Trageser MA, Nichols CT, Hutchings DA … +53 more , Bell D, Wald AI, Smith K, Hong SM, Luchini C, Brosens LAA, Verschuur AVD, Bevere M, Lawlor RT, Scarpa A, Keating S, Tucker J, O'Sullivan RJ, Liu TC, McGrath K, Fasanella K, Brand RE, Lennon AM, Das R, Singh H, Slivka A, Mahmood S, Hosmer AE, Khalid A, Romutis SL, Zureikat AH, Zeh HJ, Hogg ME, Lee KK, Paniccia A, Nunns G, Ongchin M, Park WG, Polanco PM, He J, Simeone DM, Ferrone CR, Hsu D, Zhang J, Gorantla V, Rhee J, Hruban RH, Singhi AH, Singhi SA, Wang CK, Shaker N, Bubar R, Grupillo M, Lai YT, Nikiforova MN, Heaphy CM, Waters KM, Singhi AD
Mod Pathol · 2025 Oct · PMID 40784487 · Publisher ↗
Pancreatic neuroendocrine tumors (PanNETs) exhibit heterogeneous clinical behavior, and a growing number of nonfunctional PanNETs (NF-PanNETs) have been discovered incidentally. Although chromatin remodeling and telomere...
Pancreatic neuroendocrine tumors (PanNETs) exhibit heterogeneous clinical behavior, and a growing number of nonfunctional PanNETs (NF-PanNETs) have been discovered incidentally. Although chromatin remodeling and telomere maintenance gene alterations, such as ATRX and DAXX mutations, are well established in the metastatic progression of PanNETs, many tumors lack known driver mutations. To identify additional prognostic biomarkers and alternative oncogenic mechanisms in primary NF-PanNETs, we employed whole transcriptome sequencing on 73 nonsyndromic NF-PanNETs with extended clinical follow-up (>4 years). Findings were validated via immunohistochemistry in an independent multi-institutional cohort of 539 PanNETs. Clinicopathologic correlation and survival analyses assessed the prognostic significance of identified biomarkers. Transcriptomic profiling identified 6 distinct clusters, with cluster 6 (C6) demonstrating aggressive features, including high World Health Organization grade and distant metastases. Gene ontology pathway analysis of C6 tumors revealed upregulation of protein homeostasis, immune regulation, insulin metabolic activity, and telomere maintenance via telomerase activation. Recurrent fusion genes involving the chromatin remodeling gene, BEND2 (CHD7::BEND2 and EWSR1::BEND2), were detected in 7% (5/73) of NF-PanNETs, exclusively in C6 and independent of ATRX/DAXX status. Orthogonal validation showed BEND2 expression in 3% (16/539) of PanNETs, all harboring BEND2 fusion genes by whole transcriptome sequencing. Patients with BEND2-positive tumors had significantly shorter disease-free survival (P < .001) and disease-specific survival (P < .001). Furthermore, multivariate analysis confirmed BEND2 as an independent negative prognostic factor for disease-free survival (P < .001) and disease-specific survival (P = .001). Overall, ATRX, DAXX, and BEND2 alterations were present in 62% of metastatic NF-PanNETs. This study identifies recurrent BEND2 fusion genes as a novel oncogenic mechanism in aggressive NF-PanNETs and establishes BEND2 expression as an independent prognostic biomarker, emphasizing the importance of chromatin remodeling and telomere maintenance in the metastatic progression of NF-PanNETs.
Genomic and Transcriptomic Landscape of Epstein-Barr Virus-Positive Inflammatory Follicular Dendritic Cell Sarcoma: A Multicenter Study.
Li Y, Weng ZL, Fei HX … +17 more , Li HF, Liu YN, Zhang LL, Zhang Q, Weng X, Wang YY, Huang WY, Cao ZX, Yang KY, Chen XL, Gao J, Yang WS, Liu F, Yong JJ, Yun JP, Zhang H, Huang YH
Mod Pathol · 2025 Oct · PMID 40784486 · Publisher ↗
Epstein-Barr virus (EBV)-positive inflammatory follicular dendritic cell sarcoma (EBV+ IFDCS) is a rare indolent malignant neoplasm, which occurs almost exclusively in the liver or spleen and may arise from a common EBV-...
Epstein-Barr virus (EBV)-positive inflammatory follicular dendritic cell sarcoma (EBV+ IFDCS) is a rare indolent malignant neoplasm, which occurs almost exclusively in the liver or spleen and may arise from a common EBV-infected mesenchymal cell that differentiates along the follicular or fibroblastic dendritic cell pathway. Despite its rarity, it presents a pressing need for an improved understanding of its genetic underpinnings and potential treatment strategies for recurrent or disseminated cases. To address this, we conducted comprehensive whole-exome sequencing and transcriptome sequencing (mRNA-seq) analyses on 31 and 6 cases of EBV+ IFDCS, respectively, collected from multiple centers in China. We also compared the genetic features of EBV+ IFDCS with those of other EBV-associated malignancies. Our analyses revealed a relatively high somatic mutation rate and widespread copy number variations affecting the major histocompatibility complex-I/II in EBV+ IFDCS. Integrated mutational profiling identified key signaling pathways involved in epigenetic regulation, NF-κB signaling, RTK/RAS/PI(3)K, and the Hippo pathway. Furthermore, we identified several frequently altered genes that could serve as potential therapeutic targets in EBV+ IFDCS. Transcriptomic analysis unveiled significant upregulation of pathways related to virus infection, immune responses, and multiple immune checkpoint genes in EBV+ IFDCS. Comparative analysis demonstrated clear genetic distinctions between EBV+ IFDCS and other EBV-associated tumors. In conclusion, our study provides comprehensive insights into the unique genomic and transcriptomic landscape of EBV+ IFDCS. We have identified multiple genetic alterations that likely contribute to the development and progression of this malignancy. Our results suggest that targeted therapy and immune checkpoint inhibitors may hold promise as potential therapeutic approaches for patients with recurrent or disseminated EBV+ IFDCS.
Prognostic Significance of Desmoplastic Reaction Classification and Its Association With Stromal Biomarkers in Pancreatic Ductal Adenocarcinoma.
Noguchi S, Yamamoto T, Nakanishi Y … +8 more , Matsumoto T, Shimada Y, Shindo K, Nakata K, Fujita N, Ishigami K, Nakamura M, Oda Y
Mod Pathol · 2025 Oct · PMID 40784485 · Publisher ↗
Pancreatic ductal adenocarcinoma (PDAC), an aggressive malignancy with poor prognosis, is characterized by a dense desmoplastic stroma. Although preoperative treatments are increasingly utilized, the histological assessm...
Pancreatic ductal adenocarcinoma (PDAC), an aggressive malignancy with poor prognosis, is characterized by a dense desmoplastic stroma. Although preoperative treatments are increasingly utilized, the histological assessment of posttreatment tissues remains challenging because of the overlapping features of the fibrous stroma from both cancer progression and tumor regression. Thus, simple and reliable histological prognostic markers are urgently needed. The desmoplastic reaction (DR) classification, a prognostic marker in colorectal cancer, has been proposed as a potential indicator of PDAC; however, its relationship with cancer-associated fibroblasts remains unclear. This study evaluated the prognostic utility of the DR classification and its association with stromal characteristics in PDAC. In total, 292 PDAC cases treated at the Kyushu University Hospital between 2015 and 2022 were analyzed, including 145 upfront surgery and 147 neoadjuvant chemotherapy (NAC) cases. The immature DR type was identified as a significant independent prognostic factor associated with poor survival outcomes, irrespective of NAC. Cases with immature stroma demonstrated higher early recurrence and PDAC-related mortality rates. The immature stroma at the invasive front exhibited high expression levels of tumor-promoting cancer-associated fibroblast markers, such as fibroblast activation protein and periostin (POSTN). Furthermore, the DR classification correlated with treatment response because low POSTN expression was noted in cases achieving partial response per the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. In this study, the DR classification is an independent prognostic factor for PDAC, irrespective of NAC. Immature stroma, characterized by high fibroblast activation protein and POSTN expression levels, is associated with poor outcomes. POSTN expression at the invasive front may be a potential biomarker for treatment response and chemoresistance.
Optical Genome Mapping in Myelodysplastic Syndromes: Clinical Value and Limitations Derived From a Cohort of 236 Patients.
Wei Q, Wang SA, Garcia-Manero G … +7 more , Kanagal-Shamanna R, Toruner GA, Hu S, Loghavi S, Ok CY, Medeiros LJ, Tang G
Mod Pathol · 2025 Oct · PMID 40780682 · Publisher ↗
Identification of cytogenetic abnormalities is critical for the classification and risk stratification of myelodysplastic syndromes (MDS). Optical genome mapping (OGM) is an emerging cytogenomic platform that enables hig...
Identification of cytogenetic abnormalities is critical for the classification and risk stratification of myelodysplastic syndromes (MDS). Optical genome mapping (OGM) is an emerging cytogenomic platform that enables high-resolution genome-wide cytogenetic analysis. We analyzed bone marrow specimens of 236 MDS patients, 149 newly diagnosed and 87 with relapsed/refractory disease, using OGM, conventional karyotyping, and next-generation sequencing analysis. OGM and karyotyping showed concordant results in 68% of cases, including 34% with normal findings by both assays. OGM provided additional information in 27% of patients. Common abnormalities detected exclusively by OGM included chromoanagenesis (n = 33), KMT2A partial tandem duplication (n = 7), and MECOM rearrangement (n = 4). These OGM findings led to disease reclassification and/or changes in risk stratification in 14 patients (9.4%) with newly diagnosed MDS. In contrast, OGM failed to detect small clones or subclones in 5% of patients, resulting in risk group changes in 2% of newly diagnosed MDS patients. We conclude that OGM enhances the cytogenetic assessment of MDS in approximately 25% of patients and leads to a change in disease classification and/or risk stratification in approximately 10% of patients. However, low sensitivity for detecting small clones or subclones remains a limitation of OGM.
Human Papillomavirus-Associated Penile Squamous Cell Carcinoma With Acquired p16 Null Immunophenotype.
Luu BE, Siegmund SE
Mod Pathol · 2025 Sep · PMID 40774062 · Publisher ↗
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Erratum to "Prediction of Response to Anti-HER2 Therapy Using A Multigene Assay" [Modern Pathology 38 (2025) 100713].
Atallah N, Makhlouf S, Li X … +3 more , Zhang Y, Mongan NP, Rakha E
Mod Pathol · 2025 Sep · PMID 40768798 · Publisher ↗
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Clinical and Prognostic Correlates of the Reticulin-Collagen-Osteosclerosis Score in Primary Myelofibrosis.
Santi R, Coltro G, Di Stefano G … +9 more , Atanasio A, Cicogna P, Loscocco GG, Capecchi G, Boldrini V, Pescia C, Guglielmelli P, Vannucchi AM, Gianelli U
Mod Pathol · 2025 Oct · PMID 40738326 · Publisher ↗
Primary myelofibrosis (PMF) is hallmarked by stromal bone marrow changes, whose accurate evaluation holds diagnostic and prognostic implications. The reticulin fibrosis (MF), collagen (Co), osteosclerosis (Ost) score (RC...
Primary myelofibrosis (PMF) is hallmarked by stromal bone marrow changes, whose accurate evaluation holds diagnostic and prognostic implications. The reticulin fibrosis (MF), collagen (Co), osteosclerosis (Ost) score (RCO-S) was developed in 2017 and proved to be accurate and prognostically informative. In this retrospective, single-center study, we validated the RCO-S and explored its clinical, genetic, and prognostic correlates in a large cohort of patients with PMF, including 121 prefibrotic (pre-PMF) and 101 overt PMF (oPMF). Overall, stromal changes evolved harmonically in the 2 PMF subtypes, with pre-PMF showing milder alterations. A higher RCO-S was associated with distinct high-risk clinical and molecular features and shortened overall survival, particularly in oPMF. Receiver operator characteristic analysis confirmed 5 as the most accurate RCO-S cutoff value (RCO-S) to differentiate low-grade (<5) and high-grade (≥5) PMF. High-grade disease was associated with adverse clinical and molecular profiles, worse overall survival, and higher cumulative incidence of leukemic transformation. Notably, integrating RCO-S into the mutation-enhanced international prognostic score system prognostic model improved risk stratification and accuracy compared with the standard scoring system. Despite study limitations, our findings showed that (1) the RCO-S provides a comprehensive assessment of PMF stromal changes; (2) it holds clinical, genetic, and prognostic relevance; and (3) its integration into existing prognostic models has the potential to improve prognostic stratification.
Human Papillomavirus Infection Is a Favorable Prognostic Factor for Patients With Stages I to IVA Esophageal Squamous Cell Carcinoma but not Adenocarcinoma.
Reynders C, Bruyere D, Roncarati P … +26 more , Geuzaine R, Koopmansch B, Gofflot S, Monnien F, Craciun L, Piazzon N, Hendrick E, Poulain F, Lerho T, Miceli S, Pilard C, Ancion M, Luyckx M, Renard M, Lambert F, Gheit T, Molimard C, Bibeau F, Larsimont D, Fasquelle F, de Leval L, Delvenne P, Kervarrec T, Hubert P, Peulen O, Herfs M
Mod Pathol · 2025 Dec · PMID 40738325 · Publisher ↗
With its 2 distinct histological subtypes (squamous cell carcinoma [SCC] and adenocarcinoma [ADC]), its increasing incidence in both high- and low-income countries and its elevated 5-year mortality rate, esophageal cance...
With its 2 distinct histological subtypes (squamous cell carcinoma [SCC] and adenocarcinoma [ADC]), its increasing incidence in both high- and low-income countries and its elevated 5-year mortality rate, esophageal cancer still represents a significant global health challenge. Although the implication of high-risk human papillomaviruses (HPV) in both anogenital and head and neck carcinogenesis is well-established, the association between these mucosotropic viruses and esophageal cancers has been a subject of debate for nearly 2 decades. In an effort to resolve this unclear situation and advance precision medicine, data from a large cohort of 378 patients diagnosed with locally advanced esophageal carcinoma (SCC [n = 226] and ADC [n = 152]) over a 20-year period were collected and thoroughly characterized (at clinical, histopathological, immunological, and virological levels). In total, about one-third (48/152, 31.58%) of ADC were positive for high-risk HPV DNA, but a transcriptionally active infection was only detected in 17.76% of the samples. Surprisingly, only a minority of malignant cells (typically <20%) showed viral transcripts, and HPV positivity had no prognostic significance for patients with esophageal ADC. Regarding SCC, 12.39% (28/226) of tissue specimens were HPV-positive, with viral/transcriptional activity observed in virtually 100% of neoplastic cells. These HPV-positive neoplasms more frequently exhibited basaloid differentiation and nonaberrant p53 expression and were significantly less associated with tobacco/alcohol use than their virus-negative counterparts. Importantly, uni-multivariate analyses indicated that HPV positivity was a reliable predictor of improved progression-free survival in patients with esophageal SCC. Taken together, our findings indicate that unlike in ADC, where testing for HPV is unnecessary, a dual classification system for esophageal SCC based on HPV status could/should be considered, with potential implications for personalized and optimized treatment strategies.
Clinicopathologic and Molecular Analysis of Colorectal Carcinomas With Spectrum of Neuroendocrine Carcinoma Components.
Albayrak NE, Liu BL, Mehrotra M … +3 more , Houldsworth J, Polydorides AD, Ward SC
Mod Pathol · 2025 Dec · PMID 40738324 · Publisher ↗
The genetics of colorectal carcinoma (CRC) with neuroendocrine differentiation remain poorly understood; recent studies focusing on pure neuroendocrine carcinomas (NECs) demonstrated mutation profiles closely resembling...
The genetics of colorectal carcinoma (CRC) with neuroendocrine differentiation remain poorly understood; recent studies focusing on pure neuroendocrine carcinomas (NECs) demonstrated mutation profiles closely resembling colorectal adenocarcinomas (ACAs) with more frequent BRAF mutations and Rb/p16 pathway dysregulation. However, pathogenesis of mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) and ACAs with minor NEC component (AMiNECs) remains controversial. We aimed to define the behavior and molecular underpinnings of these tumors in comparison with conventional ACAs. In total, 20 NECs, 10 MiNENs, and 8 AMiNECs were compared with 100 controls with ACAs. Well-differentiated neuroendocrine tumors of any grade were excluded. CRCs with NEC components presented at a slightly earlier age (mean, 59 vs 65 years; P = .24) in a similar sex distribution (male:female, 1:1.11 vs 1.04:1; P = .97). The majority of cases arose either from a precursor adenoma (42%) or in the setting of inflammatory bowel disease (18%), whereas 5 of 10 cases (50%) originating from the rectum were human papillomavirus driven. Despite similarity in tumor size and depth of invasion among all groups, CRCs with NEC components showed more frequent lymph node and distant metastases (P < .001 each), leading to more advanced disease stage (stage III/IV; P < .001) and worse 5-year survival outcomes (35.4% for NECs, 30% for MiNENs, and 41.6% for AMiNECs vs 85.1% for ACAs; P < .001), compared with ACAs. Next-generation sequencing revealed more frequent BRAF (40% vs 3%; P < .001) and BRCA1 alterations (15% vs 1%; P = .001) in NECs compared with ACAs. Genomic alterations in RB1 were exclusively found in NECs (10%) and MiNENs (20%). In conclusion, the presence of any NEC component (from AMiNEC to pure NEC) in CRC carries a dismal prognosis. Yet, these tumors are more likely to harbor potentially targetable mutations such as BRAF p.V600E and alterations in BRCA1/2, which are of therapeutic value.
Analysis of Oncogene Mutations in Odontogenic Myxoma.
Pankam J, Kitkumthorn N, Khovidhunkit SP … +2 more , Bumalee D, Lapthanasupkul P
Mod Pathol · 2025 Dec · PMID 40738323 · Publisher ↗
Odontogenic myxoma (OM) is a rare, benign mesenchymal odontogenic tumor. Presently, the molecular mechanisms underlying OM remain unclear, and no diagnostic markers have been identified. This study aimed to investigate g...
Odontogenic myxoma (OM) is a rare, benign mesenchymal odontogenic tumor. Presently, the molecular mechanisms underlying OM remain unclear, and no diagnostic markers have been identified. This study aimed to investigate gene mutations related to the MAPK/ERK, PI3K/mTOR, and β-catenin/Wnt pathways in OM, including KRAS, PIK3CA, and CTNNB1, and their associated proteins. Additionally, the association between gene mutations and their associated protein expression was also investigated. DNA was extracted from 11 formalin-fixed, paraffin-embedded OM tissues for PCR. PCR-positive samples using KRAS, PIK3CA, and CTNNB1 primers were sent for DNA sequencing to investigate mutations in KRAS exon 2 codons 12 and 13, PIK3CA exon 9 codons 542 to 549, and CTNNB1 exon 3 codons 32 to 45. Proteins associated with these pathways, including p-ERK1/2, p-mTOR, and β-catenin, were examined using immunohistochemistry. We found that 2 of 11 cases (18.18%) had KRAS mutation (G12V), with almost all cases (90.91%) expressing p-ERK1/2 in the spindle-shaped tumor cells. Only 1 of 9 cases (11.11%) possessed PIK3CA mutation (Q546E), although all cases variably expressed p-mTOR in the tumor cells. None of the case showed CTNNB1 mutation and β-catenin expression. Statistical analysis indicated no significant association between gene mutations and their associated proteins in OM (P > .05). In conclusion, the presence of KRAS and PIK3CA mutations, along with p-ERK1/2 and p-mTOR expression in a subset of OM, suggests that the pathogenesis of this tumor may involve the MAPK/ERK and PI3K/mTOR signaling pathways. In contrast, the absence of CTNNB1 mutations and β-catenin expression indicates no association between OM pathogenesis and the β-catenin/Wnt signaling pathway. However, further studies with larger sample sizes are needed to confirm these findings.
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