Mod. Pathol. [JOURNAL]
Sun
200 papers
DNA Methylation Profiling Classifies and Reveals Origin of Gynecologic Central Nervous System-Like Tumors.
Wang L, Vasudevaraja V, Serrano J … +18 more , Kerkhof J, Rzasa J, Kelly S, Oliva E, Young RH, Horn LC, Park KJ, Momeni-Boroujeni A, Antonescu CR, Abu-Rustum NR, Zhang Y, Wang L, Jungbluth A, Rosenblum MK, Sadikovic B, Dolgalev I, Snuderl M, Chiang S
Mod Pathol · 2026 Jan · PMID 41285250 · Full text
Gynecologic neuroectodermal tumors either exhibit central nervous system (CNS) differentiation (CNS-like) or represent Ewing sarcoma (EWS), which lacks CNS features and harbors FET-ETS gene fusions. DNA methylation profi...
Gynecologic neuroectodermal tumors either exhibit central nervous system (CNS) differentiation (CNS-like) or represent Ewing sarcoma (EWS), which lacks CNS features and harbors FET-ETS gene fusions. DNA methylation profiling reclassified CNS primitive neuroectodermal tumors into common CNS neoplasms or embryonal tumors with specific epigenetic/genetic characteristics. Its utility in classifying gynecologic neuroectodermal tumors is unknown. Whole-genome DNA methylation profiling was performed on 26 gynecologic neuroectodermal tumors (22 CNS-like tumors, 4 EWS) arising in the ovary, paratubal soft tissue, uterus, and vulva, which were classified by using sarcoma and CNS tumor DNA methylation classifiers. Sarcoma-related gene fusions were confirmed by fluorescence in situ hybridization or targeted RNA next-generation sequencing. Tumor-only whole-exome sequencing (WES) was performed in 13 cases. Copy number alterations and zygosity were inferred from DNA methylation array and WES data. Methylation abnormalities associated with imprinting were examined. The sarcoma methylation classifier identified EWS (n = 3) and high-grade endometrial stromal sarcoma (n = 1), confirmed by fluorescence in situ hybridization or next-generation sequencing detection of EWSR1 and YWHAE rearrangements, respectively. The remaining CNS-like tumors were classified by DNA methylation with positive/valid (n = 4), indeterminate (n = 9), and negative (n = 9) scores at the family level. Methylation subclasses included teratoma; embryonal tumor with multilayered rosettes, atypical; medulloblastoma, SHH-activated, subtype 3; medulloblastoma, group 3; intraocular medulloepithelioma; supratentorial ependymoma, ZFTA::RELA fused, subclass A; and diffuse pediatric-type high-grade glioma, MYCN subtype. Male biological sex was predicted in 54% of methylation-confirmed CNS-like tumors and none of the sarcomas. Among CNS-like tumors, copy number analyses identified genome-wide chromosomal gains and losses, and WES revealed genome-wide allelic imbalance suggestive of genome-wide duplications. Epigenetic imprinting analyses showed increased paternal or maternal imprinting signal across multiple chromosomes, suggesting uniparental duplication. DNA methylation profiling successfully classified gynecologic neuroectodermal tumors as known CNS tumors or sarcoma entities. Epigenetic and exomic studies indicate a male genome and increased maternal allelic contribution in CNS-like tumors, suggesting development via conception or chimerism.
Large Language Models Can Generate High-Quality Pathology Multiple-Choice Questions Comparable With Questions Written by a Human Expert.
Borowitz MJ, Blackford AL, Nagelia S … +1 more , Hruban RH
Mod Pathol · 2026 Jan · PMID 41276086 · Publisher ↗
Multiple-choice questions can be effective tools to assess student and trainee performance, but the creation of these questions can be time consuming and requires expertise. To test the quality of pathology test question...
Multiple-choice questions can be effective tools to assess student and trainee performance, but the creation of these questions can be time consuming and requires expertise. To test the quality of pathology test questions created by large language models (LLMs), 100 questions on pancreas pathology were written by a human expert, and 50 questions were generated by each of 2 LLMs (ChatGPT-4.0 and Gemini 2.5 Flash). After an initial review, 16% of the multiple-choice questions generated by the 2 LLMs had to be revised through additional interactive prompting. The final set of questions was then evaluated by 190 volunteers with a variety of backgrounds and levels of expertise. We found that ChatGPT-generated-but not Gemini-generated-questions were rated as easier than human-authored questions; there were slightly more poor/unacceptable questions compared with adequate/good/excellent questions written by the LLMs than those written by the human expert (11.7% vs 10.1%; odds ratio, 1.64; 95% CI, 1.13-2.37; P = .009), but there was no difference in the proportion of questions rated good or excellent. Qualitatively, human-authored questions were thought to be most clinically realistic but felt to be more inconsistent and sometimes thought to be testing trivial points. There was no difference in the mean point biserial between human-authored and LLM-generated questions (0.31 vs 0.29; P = .56). As LLMs improve, they will form a useful tool for the efficient generation of large numbers of high-quality pathology test questions.
ZFTA::NCOA1/2-Rearranged Epithelioid Mesenchymal Tumor-A Phenotypically Distinct Myoepithelial-Like Neoplasm Epigenetically Overlapping With Chondroid Lipoma.
Rizwan R, Venkataramani V, Haug L … +14 more , Hattery T, Chen M, Nakitandwe J, Shurtleff S, Azzato EM, Teleanu MV, Hüllein J, Fröhling S, Stoehr R, Billings SD, Michal M, Fritchie KJ, Agaimy A, Dermawan JK
Mod Pathol · 2026 Jan · PMID 41270902 · Publisher ↗
ZFTA (formerly C11orf95) gene rearrangements are recurrent in rare tumors of the central nervous system, such as ependymomas (mostly ZFTA::RELA) and soft tissue tumors, such as chondroid lipomas (ZFTA::MRTFB). To date, a...
ZFTA (formerly C11orf95) gene rearrangements are recurrent in rare tumors of the central nervous system, such as ependymomas (mostly ZFTA::RELA) and soft tissue tumors, such as chondroid lipomas (ZFTA::MRTFB). To date, among mesenchymal tumors, the ZFTA::NCOA1 fusion has only been reported in a single case of chondroid lipoma. We describe 5 distinct soft tissue tumors harboring ZFTA::NCOA1/2 fusions. The tumors arose from 2 females and 3 males with a median age of 31 years (range, 30-72). All tumors were well circumscribed involving the deep (4 cases) or superficial (1 case) soft tissue of the proximal limbs with a median greatest dimension of 4.2 cm (range, 1.7-6.0). Histologically, they displayed lobulated architecture and were composed of monotonous epithelioid-to-plasmacytoid cells arranged in cords, chains, and nests within myxohyaline or sclerosed stroma. Focal loose myxoid reticulate areas and prominent dilated and hyalinized blood vessels were present. One tumor showed focal spindle cells, whereas another demonstrated necrosis and atypical mitotic figures. Definitive adipocytic, lipoblastic, or clear-cell features were absent, except in 1 case. Immunohistochemistry was nonspecific without any consistent lineage-defining marker expression. Targeted RNA sequencing confirmed ZFTA::NCOA1 fusions in 3 and ZFTA::NCOA2 fusion in 2 cases. DNA methylation profiling, available in 4 cases, demonstrated a shared epigenetic profile with chondroid lipoma but not other tumors with histologic or genetic overlap. Copy number variation analysis showed a flat copy number profile in 3 cases and chr9p arm-level copy number loss in the case with necrosis and mitotic activity. All patients underwent complete excision; no recurrences or metastases were observed over a limited follow-up period (available in 4 cases, range, 8-24 months; median, 10.5 months). In conclusion, ZFTA::NCOA1/2-rearranged epithelioid mesenchymal tumors represent a novel, morphologically distinct entity, genetically and epigenetically overlapping with chondroid lipoma. Expanded cohorts and long-term follow-up are necessary to clarify their precise classification and biologic behavior.
A Comprehensive Mutational and Histopathological Analysis of STK11-Mutant Non-Small Cell Lung Carcinomas.
Pineda CM, Guan Z, Kwon H … +3 more , Rangachari D, Costa DB, VanderLaan PA
Mod Pathol · 2026 Jan · PMID 41270901 · Full text
Despite recent advances in the understanding of genomic and immunopathological mechanisms of lung cancer, this disease remains the leading cause of cancer-related deaths in the United States. STK11 (LKB1) mutations are p...
Despite recent advances in the understanding of genomic and immunopathological mechanisms of lung cancer, this disease remains the leading cause of cancer-related deaths in the United States. STK11 (LKB1) mutations are present in approximately 20% of non-small cell lung cancers (NSCLCs) and drive tumor progression through disruption of cellular metabolism, polarity, and stress responses, ultimately leading to immune evasion and resistance to cancer therapy. Although these tumors are associated with poor prognoses, the clinicopathological significance of different STK11 mutation subtypes and their associations with tumor histology, cellular behavior, metastatic potential, and clinical outcomes remain incompletely understood. In this study, we retrospectively analyzed a large cohort of STK11-mutant and STK11 wild-type NSCLCs using a combination of next-generation sequencing, immunologic biomarkers, histopathological characterization, and radiographic imaging. Overall, we demonstrate that STK11-mutant tumors display diverse molecular and morphologic features and are associated with high rates of aggressive histopathological growth patterns, lymphovascular invasion, and spread through the airspaces. Among stage 4 cases, STK11 mutations had notable differences in organotropism, with the STK11-loss cohort in particular demonstrating the highest rates of brain metastases at the time of initial diagnosis. Furthermore, among stage 4 cases, whereas all STK11 mutation types resulted in decreased overall survival probability compared with the STK11 wild-type cohort, the effect appeared most pronounced among the STK11-loss/KRAS-mutant group. These findings underscore the heterogeneity of STK11-mutant NSCLCs and highlight the opportunity for further investigation into specific STK11 mutation subtypes in guiding prognosis and therapeutic decision-making for individuals with lung cancer.
Optical Genome Mapping in Pediatric Hematologic Malignancies: High Diagnostic Yield and Unique Insights Across Leukemia Subtypes.
Smith TH, Jean J, Phan S … +8 more , Kovach AE, Miller K, Han J, Ma K, Fong C, Doan A, Bhojwani D, Raca G
Mod Pathol · 2026 Jan · PMID 41242614 · Publisher ↗
Hematologic neoplasms in pediatric patients have different genomic profiles compared with the same malignancies in adults, with copy number abnormalities (CNAs) and balanced structural variants (SVs) being the most preva...
Hematologic neoplasms in pediatric patients have different genomic profiles compared with the same malignancies in adults, with copy number abnormalities (CNAs) and balanced structural variants (SVs) being the most prevalent types of oncogenic drivers. Consequently, we hypothesized that optical genome mapping (OGM), as a new method for genome-wide, high-resolution detection of CNAs and balanced SVs, could represent a powerful testing approach for pediatric leukemias. This study compared the performance of OGM in the detection of clinically significant variants with current standard-of-care (SOC) diagnostic methodologies, including karyotyping, fluorescence in situ hybridization (FISH), chromosomal microarray, and a custom pediatric next-generation sequencing panel, OncoKids. In a retrospective review of results from SOC genetic testing and OGM for 100 de novo or relapsed pediatric hematologic neoplasms, full concordance was observed in 71% of cases. A clinically significant finding (tier 1 or 2 based on the Association for Molecular Pathology/American Society of Clinical Oncology/College of American Pathologists guidelines) was missed by OGM in 7 cases, but in 22 cases, OGM identified additional tier 1 or 2 findings missed by SOC testing. The highest increase in diagnostic yield was noted in T-lymphoblastic leukemia/lymphoma (T-ALL), with nearly 40% (9/23) of T-ALL cases having additional tier 1 or 2 findings detected using OGM. The main advantage of OGM was the ability to detect cytogenetically cryptic, balanced rearrangements not targeted by routine FISH probes or OncoKids, whereas its main limitation was low resolution for identifying copy-neutral loss of heterozygosity. As a single assay, OGM detected the majority (92%) of clinically significant variants identified by the combined use of karyotyping, FISH, chromosomal microarray, and OncoKids, and revealed additional tier 1 or 2 variants missed by SOC testing in 22% of the cases. Our study shows that OGM represents a powerful assay for detection of CNAs and balanced SVs in pediatric hematologic neoplasms.
Retinoblastoma Protein Loss in p53 Abnormal Endometrial Carcinoma Is Associated With Poor Clinical Outcomes in a Canadian Cohort.
Zhang AW, Gilks CB, Hoang L … +5 more , Leung S, Cochrane D, Huntsman DG, McAlpine JN, Martin SD
Mod Pathol · 2026 Jan · PMID 41242193 · Publisher ↗
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Lung Carcinoma Metastatic to the Breast: A Comprehensive Analysis of Clinical Presentation, Morphologic, and Molecular Features, With Emphasis on Diagnostic Pitfalls.
Hashmi AA, Vougiouklakis T, Gazzo A … +4 more , Wen HY, Ross D, Pareja F, Brogi E
Mod Pathol · 2026 Jan · PMID 41241092 · Publisher ↗
Lung carcinoma metastatic to the breast (bLM) or axillary lymph nodes (lnLM) may closely mimic primary triple-negative breast carcinoma (BC), leading to possible misdiagnosis. We characterized the clinical, morphologic,...
Lung carcinoma metastatic to the breast (bLM) or axillary lymph nodes (lnLM) may closely mimic primary triple-negative breast carcinoma (BC), leading to possible misdiagnosis. We characterized the clinical, morphologic, and molecular features of a series of lung carcinomas metastatic to breast and regional lymph nodes to identify diagnostic clues and pitfalls. The study cohort consisted of 30 patients (27 women, 3 men) with a median age of 72 years (range, 46-86); 21 patients (70%) reported a smoking history. At the time of the index biopsy, 4 patients (13.3%) had no history of lung carcinoma. Most tumors (n = 25, 83.3%) were bLM; 4 (13.3%) were lnLM, and 1 was a supraclavicular lymph node metastasis. In 7 of 23 cases (30.4%) with available paired imaging studies, the bLM was larger than the lung tumor. Of the 30 cases, 26 (86.7%) were adenocarcinomas, 2 (6.7%) were small cell carcinomas, and 2 (6.7%) were atypical carcinoids. Metastatic adenocarcinoma resembled BC with apocrine morphology in 16 of 30 cases (53.3%), 6 cases (20%) had vacuolated cytoplasm, and 6 (20%) had micropapillary features. One bLM closely mimicked ductal carcinoma in situ morphologically, and another case showed peripheral expression of CK5/14 and p63 mimicking myoepithelium around ductal carcinoma in situ. Initial diagnosis of BC had been rendered in 7 cases (6 adenocarcinomas and 1 small cell carcinoma). Molecular analysis of 18 cases showed that the most altered cancer genes were TP53 (44%), KRAS (44%), CDKN2A (33%), and MTAP (31%). Compared with a cohort of primary triple-negative BC, the bLM/lnLM exhibited a higher tumor mutation burden (P = .002), a lower rate of TP53 mutations, and more frequently harbored genetic alterations in KRAS, RBM10, CDKN2A, CDKN2B, SMARCA4, and STK11. In 10 of 18 cases, mutational signature analysis revealed a dominant smoking signature, providing evidence of lung origin. Our findings unveil diagnostic pitfalls that may warrant additional evaluation to avoid misdiagnosis of metastatic lung carcinoma as a primary BC.
Clinical-Grade Interpretable Artificial Intelligence Tool for Automated Detection of Lymph Node Metastasis in Prostate Cancer.
Zabihollahy F, Shi K, Wangulu C … +7 more , Prassas I, Masoomian M, Saleeb R, Gabril MY, van der Kwast T, Fleshner NE, Yousef GM
Mod Pathol · 2026 Jan · PMID 41223994 · Publisher ↗
Lymph node metastasis (LNM) is a critical prognostic factor for prostate cancer and is associated with increased mortality and poor clinical outcomes, necessitating modifications to therapeutic strategies. Manual histopa...
Lymph node metastasis (LNM) is a critical prognostic factor for prostate cancer and is associated with increased mortality and poor clinical outcomes, necessitating modifications to therapeutic strategies. Manual histopathological evaluation of lymphatic tissue on glass slides is labor intensive, subject to interobserver variability, and prone to error. Deep learning approaches offer substantial promise in enhancing the accuracy and efficiency of LNM detection; however, their efficacy is contingent upon the availability of extensive annotated data sets. In this study, we developed a novel artificial intelligence (AI)-driven model leveraging a limited data set of annotated samples. By identifying and incorporating the most informative instances from unlabeled data into the training process, the model optimizes its learning trajectory through iterative error correction. Validation was performed on independent data sets from 3 academic medical centers, comprising 787 whole slide images and >2000 lymph node tissues. On a combined test set of 165 positive and 622 negative cases, the model achieved an area under the receiver operating characteristic curve of 0.94 (95% CI, 0.92-0.96), with slide-level sensitivity and specificity of 96% (95% CI, 92%-99%) and 92% (95% CI, 89%-94%), respectively. Importantly, the AI algorithm identified micrometastases in 17 cases that were initially missed by pathologists. Although pathologists exhibited a 9% miss rate in micrometastasis detection, the AI model demonstrated a significantly lower miss rate of 3% using the institutional data set, highlighting its potential for clinical deployment. This fully autonomous and reproducible method also significantly reduced slide examination times compared with both general and genitourinary pathologists (P < .001). The proposed method demonstrated interpretability by identifying metastasis regions on whole slide images labeled as positive. Ablation studies substantiate the robustness of the proposed methodology for LNM detection.
MSAI-Path: Predicting Microsatellite Instability From Routine Histology Slides Without Reinventing the Wheel.
Baumann E, Schäfer LEM, Meeuwsen F … +5 more , Kirsch R, Nagtegaal ID, Berger MD, Dawson H, Zlobec I
Mod Pathol · 2026 Jan · PMID 41207630 · Publisher ↗
Microsatellite instability (MSI) is an important biomarker in colorectal cancer, influencing both patient prognosis and treatment decisions. Current approaches for MSI prediction from hematoxylin and eosin--stained whole...
Microsatellite instability (MSI) is an important biomarker in colorectal cancer, influencing both patient prognosis and treatment decisions. Current approaches for MSI prediction from hematoxylin and eosin--stained whole-slide images (WSI) rely on end-to-end deep learning ("black-box") models with limited interpretability, often relying on heatmaps for visualization. However, experienced pathologists can intuitively identify MSI through specific histologic features and have developed manual classification systems such as MS-Path for Lynch syndrome screening. We present a novel hybrid approach that combines computational and pathologist expertise to create an explainable and verifiable method for MSI prediction in colorectal cancer, applicable to resection and biopsy WSI. Our proposed method uses nuclei and tissue segmentation models to automatically quantify MSI-associated histologic features outlined in the Bethesda guidelines, including intraepithelial lymphocytes, grade of differentiation, mucinous components, and tertiary lymphoid structures. After validation on annotated data sets, these features are integrated with clinical data and used in logistic regression and random forest models to predict MSI status. We validated our approach using 3256 WSI from 2267 patients across 7 cohorts from 5 centers. The method achieved an area under the curve of up to 0.88 across all resection cohorts, and 0.90 on biopsies, performing on par with published black-box deep learning models. Importantly, the learned variable importances strongly correlated with manual scoring systems and aligned with manual pathologist assessments. We observed significant intrapatient heterogeneity in predicted scores, emphasizing the importance of whole-case analysis. Our approach also shows potential as a screening tool that could exclude 41% of patients from gold-standard MSI testing while maintaining 95% sensitivity. This study demonstrates that classifiers based on clinical and validated histologic information can predict MSI status as effectively as black-box models while providing complete interpretability. Our method offers an alternative pathway for understandable, explainable, and trustworthy biomarker prediction in computational pathology.
BRAF p.Val600Glu Mutations Are Not Detected in Adenomatoid Odontogenic Tumors.
Gonçalves J, Coura BP, Bernardes VF … +5 more , De Marco LA, Martins MD, da C Perez DE, Gomez RS, Gomes CC
Mod Pathol · 2026 Jan · PMID 41207629 · Publisher ↗
The adenomatoid odontogenic tumor (AOT) is a benign, encapsulated odontogenic tumor characterized by slow growth and indolent behavior. AOT shows mitogen-activated protein kinase/ERK pathway activation, and KRAS p.Gly12V...
The adenomatoid odontogenic tumor (AOT) is a benign, encapsulated odontogenic tumor characterized by slow growth and indolent behavior. AOT shows mitogen-activated protein kinase/ERK pathway activation, and KRAS p.Gly12Val or p.Gly12Arg mutations occur in 70% of cases. The molecular events underlying the pathogenesis of the other 30% of cases remain unclear. The BRAF p.Val600Glu mutation was reported by a single study in 2 AOT cases, 1 of which also harbored KRAS p.Gly12Val. Given that BRAF p.Val600Glu has not been previously detected in AOT and that BRAF and KRAS mutations are mutually exclusive, we aimed to assess BRAF p.Val600Glu irrespective of KRAS mutational status to explore the potential involvement of BRAF mutations in AOT pathogenesis and the co-occurrence of BRAF and KRAS mutations. Whereas KRAS codon 13 and 61 hotspot mutations have not been previously detected in AOT, KRAS codon 146 hotspot mutations have been investigated in a few AOT cases to date. Therefore, we further sequenced KRAS codon 146 in KRAS codon 12 wild-type cases. A total of 29 AOT samples, including 21 KRAS codon 12 mutation-positive cases and 8 wild-type cases, were evaluated for the BRAF p.Val600Glu pathogenic mutation using allele-specific qPCR and/or Sanger sequencing. In addition, KRAS codon 146 was Sanger sequenced in 4 out of 29 samples. BRAF p.Val600Glu was not detected in any of the 29 AOT cases evaluated, either alone or as a comutation with KRAS mutations. All codon 12 wild-type cases were wild-type for KRAS codon 146 mutations. These findings reinforce that KRAS codon 12 mutant alleles predominate in the context of AOT tumorigenesis, whereas BRAF p.Val600Glu does not constitute a molecular feature of this tumor and the presence of the BRAF mutation does not support the diagnosis of AOT in challenging cases. In addition, the results further strengthen the notion that BRAF and KRAS mutations are mutually exclusive events.
Low-Grade Fibro-Osseous Lesions With Isolated Chromosome 12 Chromothripsis: A Distinct Entity Or a Low-Grade Central Osteosarcoma With a Novel Driver?
Saoud C, Zhang Y, Benhamida J … +12 more , Villafania L, Gundem G, Cimera R, Hwang S, Shukla NN, Reed D, Papaemmanouil E, Agaram NP, Linos K, Ladanyi M, Morris CD, Hameed MR
Mod Pathol · 2026 Jan · PMID 41203137 · Publisher ↗
Chromothripsis, a catastrophic genomic event causing extensive chromosomal fragmentation and rearrangement, has been identified in conventional osteosarcoma, contributing to karyotypic heterogeneity. Chromothripsis was a...
Chromothripsis, a catastrophic genomic event causing extensive chromosomal fragmentation and rearrangement, has been identified in conventional osteosarcoma, contributing to karyotypic heterogeneity. Chromothripsis was also detected in a subset of parosteal osteosarcomas, primarily involving chromosome 12, but not well documented in low-grade central osteosarcoma (LGCOS). Here, we report 2 cases of low-grade fibro-osseous lesions with isolated chromosome 12 chromothripsis, aiming to characterize them by comparing their genomic and epigenetic profiles to those of other bone neoplasms. Case 1 was a 12-year-old male with a destructive lesion involving the proximal left tibia, and case 2 was a 13-year-old female with an expansile lucent bone lesion involving the distal tibia with cortical breakthrough. Both cases consisted of hypocellular bland fibroblastic proliferation. Areas of thin trabeculae of woven bone surrounded by osteoblasts were present. In addition, case 1 showed areas of atypical cartilaginous islands and areas reminiscent of LGCOS. By single-nucleotide polymorphism array, both cases showed extremely complex and numerous genomic alterations involving chromosome 12. Whole-genome sequencing and optical genome sequencing confirmed the chromothriptic event involving chromosome 12. Using the Heidelberg Epignostix sarcoma methylation classifier (v12.3), both cases matched to fibrous dysplasia methylation class. Dimensionality reduction using Uniform Manifold Approximation and Projection demonstrated that the 2 index cases clustered primarily with low-grade osteosarcomas lacking MDM2 amplification and with fibrous dysplasia, whereas remaining separate from parosteal osteosarcomas and MDM2-amplified low-grade osteosarcomas. Our findings suggest that chromothripsis of chromosome 12 may represent an early and/or an alternate mechanism in fibro-osseous lesions progressing to LGCOS instead of or before the development of the well-recognized CDK4/MDM2 amplification. Larger cohorts with long-term follow-ups and integrative molecular studies are needed to clarify the biological significance and clinical implications, including recurrence, dedifferentiation, and survival.
An Exploratory Application of a Central Nervous System (CNS) Tumor Methylation Classifier in Ovarian Neuroectodermal Tumors.
Yang J, Zhang T, Zhang Y … +6 more , Zhang X, Xiang Y, Wu H, Wang L, Shi X, Yang J
Mod Pathol · 2026 Jan · PMID 41203136 · Publisher ↗
Ovarian neuroectodermal tumors (NETs) are rare malignancies with unclear diagnostic criteria and challenging treatment. We aimed to assess the utility of DNA methylation in the diagnostic classification and prognostic st...
Ovarian neuroectodermal tumors (NETs) are rare malignancies with unclear diagnostic criteria and challenging treatment. We aimed to assess the utility of DNA methylation in the diagnostic classification and prognostic stratification of ovarian NETs. This retrospective study included 15 patients diagnosed with ovarian NETs at Peking Union Medical College Hospital between 2010 and 2024. Paraffin-embedded tumor tissues from all patients underwent clinicopathologic review, DNA methylation microarray assay, EWSR1 fluorescence in situ hybridization, and immunohistochemistry. The median age at diagnosis of ovarian NETs was 19 years (range, 9-73 years). These tumors often displayed nonspecific clinical manifestations and were frequently diagnosed at an advanced stage. Morphologic diagnosis included 3 medulloblastoma, 1 neuroblastoma, 3 embryonal tumors with multilayered rosettes (ETMRs), 3 ependymomas, 1 high-grade glioma, 1 gliosarcoma, 1 low-grade neuronal-glial tumor, and 2 tumors that cannot be specified. A teratoma background was present in 73.3% (11/15) of the cases. None of the tumors exhibited EWSR1 gene rearrangement. Methylation classification was consistent with morphologic diagnosis in 30% of patients (5/15). A novel ETMR, non-C19MC-altered type ovarian tumor was identified in 3 patients. The median follow-up period of all patients was 14.9 months (range, 2.1-216.4 months), during which 60.0% of patients experienced recurrence or disease progression, and the mortality rate was 33.3%. Patients with ETMR non-C19MC-altered subtype and unmatched tumors exhibited extremely poor outcomes, with 80% (4/5) mortality within 12 months. DNA methylation profiling classified a subset of ovarian NETs into molecular subtypes resembling those of central nervous system (CNS) tumor counterparts, with corresponding prognostic similarities. Leveraging the CNS tumor methylation classifier to diagnose peripheral neuroectodermal tumors may offer critical clinical insights for these rare malignancies, enabling molecular subtyping, prognostication, and alignment with CNS-targeted therapeutic strategies.
Updates in Peripheral Nerve Sheath and Adipocytic Tumors.
Dry S
Mod Pathol · 2026 Jan · PMID 41183597 · Publisher ↗
Certain areas in peripheral nerve sheath and adipocytic neoplasm diagnosis historically were characterized by a lack of clarity and consensus regarding terminology, diagnostic criteria, and prognosis. Recent work has led...
Certain areas in peripheral nerve sheath and adipocytic neoplasm diagnosis historically were characterized by a lack of clarity and consensus regarding terminology, diagnostic criteria, and prognosis. Recent work has led to important clarifications in diagnostic criteria and/or outcome data for neurofibromas with atypia and MDM2 amplification-negative adipocytic tumors. However, these clarifications remain incompletely recognized by many pathologists, in part due to the paucity of these neoplasms. This paper reviews the history and recent advances in diagnostic criteria, terminology, and understanding of prognosis for neurofibromas with atypia, malignant peripheral nerve sheath tumor (MPNST), malignant melanotic nerve sheath tumor, and atypical spindle cell/pleomorphic lipomatous tumor. Melanoma may be histologically identical to MPNST, and this paper also provides an overview of helpful clinical and molecular features that allow accurate identification of melanoma, including undifferentiated, dedifferentiated, and transdifferentiated melanoma, and their distinction from MPNST.
Defining NECTIN4 Amplification and Protein Expression in Urothelial Carcinoma and Histologic Subtypes.
Cheville JC, Orme JJ, Gupta S … +20 more , Lucien-Matteoni F, Karnes RJ, Thapa P, Khanna A, Naik S, Sharma V, Frank I, Pagliaro L, Quevedo F, Tekin B, Knudson R, Greipp P, Brandt C, Koepplin J, Costello B, Heath E, Vasmatzis G, Florio A, Boorjian SA, Shah PH
Mod Pathol · 2026 Jan · PMID 41173324 · Publisher ↗
Chromosome 1q23.3 is commonly amplified in metastatic urothelial carcinoma (UC). This region contains NECTIN4 that encodes for a membrane protein, and amplification may result in increased NECTIN4 expression. Enfortumab...
Chromosome 1q23.3 is commonly amplified in metastatic urothelial carcinoma (UC). This region contains NECTIN4 that encodes for a membrane protein, and amplification may result in increased NECTIN4 expression. Enfortumab vedotin, an antibody-drug conjugate, targets NECTIN4. The objective of this study was to determine the frequency of NECTIN4 amplification by fluorescence in situ hybridization and protein expression by immunohistochemistry in primary UC and subtypes. Tissue microarrays (TMA) were constructed from 841 patients who underwent cystectomy between 2000 and 2020. In 218 patients, TMA were constructed from a concurrent pelvic lymph node metastasis. NECTIN4 amplification varied by subtype and was present in 18% of UCs, 13% of UCs with squamous differentiation, 25% of micropapillary carcinoma, 19% of plasmacytoid carcinoma, 17% of high-grade neuroendocrine carcinoma, 8% of pure squamous cell carcinoma, 6% of nested carcinoma, and 6% of sarcomatoid carcinoma. Tumors with NECTIN4 amplification had significantly higher H scores compared with nonamplified tumors (P < .0001), and H scores increased with increasing copy number in amplified tumors. NECTIN4 amplification was identified in 17% of lymph node metastases, and 70% of amplified primary tumors had an amplified metastasis, which increased to >90% when whole section fluorescence in situ hybridization was performed in discordant TMA cases. There was a moderate agreement between immunohistochemical staining of primary and lymph node metastases (kappa = 0.41). NECTIN4 amplifications vary in frequency among UC and subtypes, and amplifications result in higher protein expression. Bladder cancer with NECTIN4 amplification may have limited protein expression, whereas nonamplified tumors may show high expression. There was concordance of NECTIN4 amplification and protein expression between primary and lymph node metastases, but there were a small number of cases with amplified primary tumors and unamplified metastases, primary tumors with high protein expression, and metastasis with low expression.
International Expert Consensus Recommendations for HER2 Reporting in Breast Cancer: Focus on HER2-Low and Ultralow Categories.
Rakha EA, Tan PH, Van Bockstal MR … +32 more , Allison KH, Brogi E, Callagy G, Cserni G, Jaffer S, Foschini MP, Gobbi H, Kulka J, Li X, Provenzano E, Shaaban AM, Tse GM, Varga Z, Vincent-Salomon A, Yamaguchi R, Yang W, ElSheikh S, Bhargava R, De Brot M, Canas-Marques R, Marchiò C, Warren MV, van Deurzen CHM, Mir Y, Deb R, Wen H, Ellis IO, Schnitt SJ, Pinder SE, Raymond W, Quinn C, UK National Coordinating Committee of Breast Pathology, the Association of Breast Pathology, the European Working Group for Breast Screening Pathology and the International Society of Breast Pathology
Mod Pathol · 2026 Jan · PMID 41167529 · Publisher ↗
The concept of "HER2-negative" breast cancer is evolving, with the recognition of HER2-low and HER2-ultralow subsets. These subsets are clinically relevant regarding treatment with the antibody-drug conjugate trastuzumab...
The concept of "HER2-negative" breast cancer is evolving, with the recognition of HER2-low and HER2-ultralow subsets. These subsets are clinically relevant regarding treatment with the antibody-drug conjugate trastuzumab deruxtecan (T-DXd), which has shown survival benefit in patients with metastatic carcinoma with minimal HER2 protein expression that lack HER2 gene amplification by in situ hybridization. In clinical trials using T-DXd, HER2-low was defined as an immunohistochemistry (IHC) score 1+ or an IHC score 2+ without HER2 gene amplification. HER2-ultralow was defined as faint or barely perceptible, incomplete membrane staining in >0% to ≤10% of tumor cells (IHC score 0+/with membrane staining) and HER2-null as the complete absence of staining (IHC score 0/absent membrane staining). These results now necessitate more detailed evaluation and reporting of traditional "HER2-negative" results to identify patients with metastatic breast cancer who may benefit from T-DXd therapy. Both the US Food and Drug Administration and the European Medicines Agency have extended the regulatory approval of T-DXd to patients with metastatic breast cancer showing HER2-low or HER2-ultralow expressions. Updated clinical management guidelines now, therefore, incorporate the spectrum of HER2 results into treatment selection algorithms in the metastatic setting. To align histopathologic practice with these developments, the College of American Pathologists has issued a new biomarker-reporting template that recommends explicit distinction between IHC 0/absent membrane staining and IHC 0+/with membrane staining. Key concerns among pathologists include assay variability, scoring reproducibility, and quality assurance standards for accurately detecting such low levels of HER2 expression. This manuscript provides expert consensus, evidence-based practical recommendations for identifying and reporting tumors with HER2-low and HER2-ultralow expression. We emphasize standardized testing protocols, validated assays, robust internal and external controls, and focused training for pathologists. A universal structured pathology report is proposed to highlight the accurate distinction between IHC 0 (null), IHC 0+ (ultralow), and HER2-low expressions.
Expanding the Clinicopathologic Spectrum of EWSR1::SSX-Rearranged Sarcomas: Series of 11 Cases Including Osteosarcomas and a Novel EWSR1::SSX4 Fusion.
Gross JM, Suster DI, Zou Y … +16 more , Mata DA, Amary F, De Noon S, Flanagan AM, Wakeman KM, Wangsiricharoen S, Dong F, Lam SW, Bovée JVMG, Baltres A, Pissaloux D, Pasmant E, Larousserie F, Miettinen M, Hameed M, Charville GW
Mod Pathol · 2026 Jan · PMID 41139024 · Full text
Gene rearrangements involving EWSR1 or SSX genes are known to play a role in sarcomagenesis; however, sarcomas harboring EWSR1::SSX fusions are rare. To better understand tumors associated with this distinctive genetic e...
Gene rearrangements involving EWSR1 or SSX genes are known to play a role in sarcomagenesis; however, sarcomas harboring EWSR1::SSX fusions are rare. To better understand tumors associated with this distinctive genetic event, we studied 11 additional EWSR1::SSX sarcomas, affecting 10 women and 1 man with an average age of 46 years (range, 22-72 years). Eight tumors arose in the bone (rib, femur, pelvis, or vertebra with multifocal bone involvement at presentation in 3 cases); 2 tumors arose in soft tissue (deep thigh or groin); and 1 patient presented with a visceral (lung) mass. The tumors were bulky, averaging 12.1 cm (range, 4-20 cm). Histologically, in keeping with a translocation-driven sarcoma, all tumors were cytologically monotonous. Seven tumors were osteosarcomas, 6 of which were classified as sclerosing osteosarcomas with extensive bone matrix production. Three tumors were composed of uniform fascicles of spindle cells, punctuated in 2 cases by a biphasic glandular or nested epithelioid component, reminiscent of synovial sarcoma. One tumor was an undifferentiated sarcoma with round to spindle cell cytomorphology and focal osteogenic differentiation. By immunohistochemistry, 5 of 5 cases tested were positive for SSX C-terminus; 1 of 5 showed patchy weak staining with SS18::SSX fusion-specific antibody. All tested tumors were positive for CD99 (4/4) and TLE1 (3/3). Next-generation sequencing identified EWSR1::SSX fusions in all cases, involving SSX1 (n = 7), SSX2 (n = 2), and SSX3 (n = 1), along with a novel EWSR1::SSX4 fusion. Follow-up was available for 9 patients; 5 patients died of disease 1.5 to 14 years (average, 6 years) after diagnosis, 2 patients were alive with metastatic disease, 1 patient was alive without disease at 25 months, and 1 patient presented recently. Sarcomas with EWSR1::SSX fusions are rare and clinically aggressive; the histologic patterns in this series and in prior reports are heterogeneous, consisting of essentially 3 phenotypes: (1) primitive round or epithelioid cells, (2) osteoblasts that produce bone, or (3) uniform small spindle cells arranged in tight fascicles, sometimes with a biphasic epithelioid component, as seen in synovial sarcoma. By studying 11 additional examples of these rare sarcomas, we provide an expanded view of their clinicopathologic and molecular genetic spectrum.
Mutational Signature in Cancers Following Solid Organ or Allogeneic Stem Cell Transplantation.
Odintsov I, Siegmund SE, Mahadevan NR … +3 more , Church AJ, Sholl LM, Nowak JA
Mod Pathol · 2026 Jan · PMID 41135769 · Full text
Transplant recipients are at a heightened risk of cancer, yet the full spectrum of etiologic factors is poorly understood. In this study, we analysed the mutational patterns in a clinically diverse cohort of 41,874 cance...
Transplant recipients are at a heightened risk of cancer, yet the full spectrum of etiologic factors is poorly understood. In this study, we analysed the mutational patterns in a clinically diverse cohort of 41,874 cancers and identified a mutational signature highly associated with a history of solid organ or allogeneic stem cell transplantation. This signature is characterized by a high tumor mutation burden and a striking predominance of C>A single base substitutions, particularly in the 5'-C[C>A]A-3' trinucleotide context. We identified 13 transplant recipients whose tumors harbored this signature, which is distinct from previously described mutational processes, including those related to tobacco, defective DNA repair, or polymerase mutations. The discovery of this signature points to a mutagenic force in this vulnerable patient group and provides new insights into the pathogenesis of transplant-associated malignancies.
Expanding the Molecular Characterization of Adenoid Ameloblastoma by Assessing a Panel of Oncogenes and Tumor Suppressor Genes.
Fonseca YG, Bastos VC, Moreira RG … +8 more , Fonseca FP, Vargas PA, Wright JM, Aguiar RS, Odell EW, Gomez RS, Guimarães LM, Gomes CC
Mod Pathol · 2026 Jan · PMID 41109353 · Publisher ↗
Adenoid ameloblastoma (AA) is a rare epithelial odontogenic tumor microscopically characterized by ameloblastoma-like epithelium, duct-like structures, epithelial whorls, cribriform architecture, and dentinoid matrix. Wn...
Adenoid ameloblastoma (AA) is a rare epithelial odontogenic tumor microscopically characterized by ameloblastoma-like epithelium, duct-like structures, epithelial whorls, cribriform architecture, and dentinoid matrix. Wnt/β-catenin activation, usually by CTNNB1 mutations, is thought to characterize AA, which are BRAF and KRAS wild type. The present study aimed to expand the genetic characterization of AA by interrogating variants at several sites known to be linked to solid tumor pathogenesis. Six AA samples were sequenced at an unprecedented sequencing depth using a 22-gene panel including oncogenes and tumor suppressor genes commonly mutated in solid human tumors, namely AKT1, ALK, BRAF, CTNNB1, EGFR, ERBB2, ERBB3, ESR1, FOXL2, GNA11, GNAQ, IDH1, IDH2, KRAS, KIT, MET, NRAS, PDGFRA, PIK3CA, RAF1, RET, and TP53. Reinforcing the distinct molecular identity of AA, absence of BRAF p.Val600Glu and KRAS p.Gly12Val/Arg mutations was observed. CTNNB1 mutations were identified in 4 of 6 cases (67%), including previously reported variants (p.Ser33Cys and p.Gly34Arg) as well as novel ones (p.Leu31Leu and p.Gln68∗), supporting the involvement of the Wnt/β-catenin signaling pathway in AA pathogenesis. In 2 cases, CTNNB1 variants co-occurred with either TP53 or ERBB2 and PIK3CA variants, suggesting potential secondary oncogenic events. Notably, in 2 cases, no variants were detected. Our findings provide further evidence for AA classification as a separate tumor entity. The identification of previously reported CTNNB1 and novel genetic variants contributes to better characterization of the molecular profile of AA. Future studies are required to interrogate variants in other genes in wild-type cases.
CD180 as a Robust Immunophenotypic Marker for Differentiating Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia From Marginal Zone Lymphoma.
Guo Z, Su J, Liu L … +8 more , Zhang N, Chen X, Zhong Q, Qiao C, Jin H, Li J, Fan L, Wu Y
Mod Pathol · 2025 Dec · PMID 41106478 · Publisher ↗
Precise differential diagnosis between lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) and marginal zone lymphoma (MZL) remains a challenging issue because of overlapping clinicopathological and immunop...
Precise differential diagnosis between lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) and marginal zone lymphoma (MZL) remains a challenging issue because of overlapping clinicopathological and immunophenotypic features. In the present study, the differential diagnostic potential of CD180 was assessed by determining its expression patterns in patients with MZL and LPL/WM through flow cytometry. The results indicated that LPL/WM cases exhibited a complete absence of CD180 expression on malignant B cells, whereas MZL cases showed robust CD180 expression (P < .001). Receiver operating characteristic analysis demonstrated that CD180 expression percentage showed optimal diagnostic accuracy in LPL/WM and MZL cases (area under the curve = 0.998, sensitivity = 100%, and specificity = 98.0%), with a further improvement in differentiation potential by the CD180 mean fluorescence intensity ratio (lymphocytes/monocytes) of ≤ 0.47 (area under the curve = 0.937). Moreover, although the MYD88/CXCR4 mutation was not detected by next-generation sequencing in 2 LPL/WM cases, these cases still showed the absence of CD180 expression. Subsequently, droplet digital PCR revealed low-frequency MYD88 mutations (0.95% and 1.6% variant allele frequency) in these CD180-negative cases, which confirmed the superior sensitivity of CD180 in identifying LPL/WM with low tumor burden. Overall, our findings establish CD180 as a novel, rapid, and precise flow cytometry-based biomarker with robust ability for the differential diagnosis of LPL/WM and MZL, particularly relevant in resolving diagnostically challenging cases and providing prompt tumor diagnosis in time-constrained situations.
Perianal Intestinal-Type Paget Disease With and Without Invasion, Unassociated With Internal Malignancy: A Distinct Form of Primary Perianal Adenocarcinoma.
Bahceci D, Saoud C, Isidro RA … +9 more , Caires D, Moher CJ, Urganci N, Pulitzer M, Garcia-Aguilar J, Weiser MR, Vakiani E, Srivastava A, Shia J
Mod Pathol · 2026 Jan · PMID 41106477 · Full text
Primary perianal adenocarcinoma of intestinal type (PPAI) has been described in recent literature and proposed as a subtype of extramucosal anal adenocarcinoma. Whether this represents a unique entity remains to be eluci...
Primary perianal adenocarcinoma of intestinal type (PPAI) has been described in recent literature and proposed as a subtype of extramucosal anal adenocarcinoma. Whether this represents a unique entity remains to be elucidated. Herein, we analyzed the clinicopathologic and genomic features of 14 cases of PPAI. Fourteen patients, predominantly older adults with a median age of 73 years (range, 50-85), with a slight woman predilection (5 men and 9 women) were identified. All cases presented with pagetoid intraepithelial growth, and 9 were eventually found to have underlying invasive carcinoma at the site of the Paget disease. Clinical and radiographic evaluation failed to detect another primary site, either in the anorectal region or elsewhere, in all patients. By immunohistochemistry, all but 1 case showed an intestinal phenotype with cytokeratin 20 and caudal-related homeobox transcription factor 2 (CDX2) positivity and variable cytokeratin 7. Metastasis developed in 4 of 14 patients, including regional lymph node and distant bone metastasis. Patient survival for localized disease ranged from 29 to 176 months (median, 62 months), whereas for metastatic disease, it ranged from 13 to 75 months (mean, 31 months). Genomic profiling revealed a high frequency of TP53 mutations (86%, 12/14), ERBB2 alterations (57%, 8/14), and MYC amplification (36%, 5/14), with absence of genetic alterations typically seen in rectal adenocarcinomas, such as APC, KRAS, and BRAF. In contrast, a control group of primary extramammary Paget disease cases displayed distinct genomic features, including recurrent PIKC3A and KMT2C mutations. Treatment included surgical excision, radiation therapy, and systemic chemotherapy in metastatic cases, with radiation proving effective in preventing local recurrence among those with localized disease. In metastatic cases, chemotherapeutic regimens including capecitabine/oxaliplatin and folinic acid, fluorouracil, and oxaliplatin were employed. The absence of anorectal or other visceral adenocarcinomas along with distinct genomic findings supports the classification of PPAI as a distinct clinicopathologic entity.
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