Mod. Pathol. [JOURNAL]
Sun
200 papers
Histopathologic Insights Into Curvularia-Induced Chronic Granulomatous Fungal Sinusitis: A Guide for Surgical Pathologists.
Riegler AN, Grayson JW, Greenway JW … +4 more , Woodworth BA, McCarty TP, Pappas PG, Leal SM
Mod Pathol · 2025 Dec · PMID 41005534 · Publisher ↗
Chronic granulomatous fungal sinusitis is a rare, debilitating infection characterized by an enlarging mass affecting the orbit, nose, palate, and paranasal sinuses, with occasional intraorbital and intracranial extensio...
Chronic granulomatous fungal sinusitis is a rare, debilitating infection characterized by an enlarging mass affecting the orbit, nose, palate, and paranasal sinuses, with occasional intraorbital and intracranial extension. Most cases are reported in subtropical regions, with rare reports from the United States and Europe. Globally, Aspergillus flavus is the primary causative agent in >60% of cases, followed by other Aspergillus species and dematiaceous molds. This study highlights the histopathologic, microbiologic, and molecular diagnostic features of 6 cases with chronic granulomatous fungal sinusitis caused by the emerging pathogen Curvularia, predominantly affecting healthy African Americans in the Southeastern United States. Histopathological examination revealed multinucleated giant cells and noncaseating granulomatous inflammation. Short septate hyphae with bulbous swelling predominated, but there was significant variation in size, shape, and color, with half the cases lacking hyphal pigmentation. Lack of awareness of this emerging entity and variable morphology led to initial misidentification in 3 cases as hyaline septate hyphae (Fusarium), yeasts, and Blastomyces. All cases showed extracellular and intracellular (within multinucleated giant cells) hyphae and round forms with thick refractile cell walls lacking intracellular contents, yielding a characteristic "ghost shell" morphology, indicating fungal nonviability. Consistent with this finding, only 1 culture yielded a live isolate of Curvularia. In addition, 28S rRNA gene sequencing of formalin-fixed paraffin-embedded tissue was required for identification and identified Curvularia lunata (n = 4), Curvularia spicifera (n = 1), and Curvularia spp. (n = 1). One case with 2 hyphal morphologies also grew Aspergillus fumigatus, indicating coinfection. Chronic granulomatous fungal sinusitis, caused by the understudied and persistent pathogen Curvularia, is an emerging threat in immunocompetent hosts, characterized by pathogen persistence in critical facial and cranial structures, despite a significant host response. To accurately diagnose and guide treatment, surgical pathologists must be aware of its expanded geographic range, affected populations, and key histopathologic features, as described herein.
Loss of Ribosomal Protein L22 (RPL22) Expression Identifies a Transcriptional Subset of MLH1-Deficient Endometrial Cancers With Lower Numbers of Tumor-Associated Lymphocytes.
Osborne-Frazier ML, LaBuda SE, Parrish ML … +3 more , Atkins HM, Broaddus RR, Gladden AB
Mod Pathol · 2026 Jan · PMID 41005533 · Full text
Microsatellite instability-high defines one of the major subsets of endometrial cancer (EC), characterized by defects in DNA mismatch repair, most often by loss of MLH1 protein expression, and sensitivity to immunotherap...
Microsatellite instability-high defines one of the major subsets of endometrial cancer (EC), characterized by defects in DNA mismatch repair, most often by loss of MLH1 protein expression, and sensitivity to immunotherapies. RPL22 is selectively mutated in microsatellite instability-high cancers, resulting in loss of protein expression. The significance of this mutation is unknown. An immunohistochemistry assay was developed that reliably detected ECs with ribosomal protein L22 (RPL22) protein loss. With a cohort of ECs, we identified MLH1-deficient cancers with loss of RPL22 expression. Using digital spatial transcriptomics, a subset was identified that was characterized by no expression of RPL22, lower expression of β-2 microglobulin, lack of expression of immune activation pathways, and lower numbers of tumor-associated CD8+ lymphocytes. β-2 Microglobulin, which is necessary for antigen presentation to T lymphocytes, was decreased in EC cell lines with RPL22 knocked down. Neither RPL22 expression nor levels of tumor-associated T lymphocytes were associated with tumor mutation burden or PD-L1 expression, 2 biomarkers that are assessed in patients considered for immunotherapies. This study provides the first evidence that RPL22 deficiency is an easily measured indicator of a unique subset of MLH1-deficient ECs that can be characterized as immune low. Our study suggests that patients with RPL22-deficient tumors could represent poor candidates for CD8+ T-cell-based immunotherapies, a current frontline therapy for MLH1-deficient ECs.
A Distinctive DICER1-Related Wilms-Like Uterine Tumor: A Report of Eight Cases.
Turashvili G, Croce S, Davidson B … +10 more , Hausladen S, Solheim O, Carinelli S, Lombardi M, Lim D, Devins K, Lin LH, Dias-Santagata D, Young RH, Oliva E
Mod Pathol · 2025 Dec · PMID 40998289 · Publisher ↗
The presence of DICER1 mutations associated with overlapping morphologic features in tumors arising at different sites has been suggested to define an emerging category of DICER1-related neoplasms. We undertook a clinico...
The presence of DICER1 mutations associated with overlapping morphologic features in tumors arising at different sites has been suggested to define an emerging category of DICER1-related neoplasms. We undertook a clinicopathologic and molecular characterization of uterine tumors originally diagnosed as Wilms tumors to ascertain if they belong to the spectrum of DICER1-related neoplasms. Of 8 patients with a median age of 36.5 (17-69) years, 5 underwent hysterectomy, 2 endometrial curettings, and 1 polypectomy. Most tumors were centered in the endometrium, and 6 were polypoid with a median size of 8 (3.5-16) cm. All showed a variable admixture of primitive mesenchyme and epithelial-like elements set in a hypocellular, edematous to focally myxoid stroma. The epithelial-like elements were the most extensive component, showing a lobular arrangement, including variably sized and shaped primitive tubules with focal confluent/solid growth and cribriforming, as well as glomeruloid and rosette-like structures. Some primitive tubules had intraluminal projections in 3 tumors, imparting an adenosarcoma-like appearance. Scattered glands with fetal-type epithelium were seen in 7 tumors. Rhabdomyosarcomatous differentiation was present in 6 tumors, and neuroectodermal differentiation and fetal-type cartilage in 3 tumors each (including 2 with both features). DICER1 sequencing was successful in 5 of 6 tumors tested, with 4 harboring DICER1 mutations, including all 3 with neuroectodermal differentiation and adenosarcoma-like foci. Fetal-type cartilage was present in 2 of 4 DICER1-mutant tumors and 1 tumor with unknown DICER1 status. Follow-up was available for 6 patients. The patient with DICER1 wild-type tumor (associated with low-grade endometrial endometrioid carcinoma and KRAS mutation) died of disease at 9 months. Of 4 patients with DICER1-mutant tumors, 1 recurred at 7.5 months, 2 were alive without disease at 12 and 38 months, respectively, and 1 was alive with unknown disease status at 31 months. Another patient with unknown DICER1 status was alive at 196 months. Uterine tumors diagnosed as Wilms tumors belong to the spectrum of DICER1-related neoplasms at this site and are best described as a "DICER1-related Wilms-like uterine tumor." These unique tumors are likely part of the larger category of "DICER1-related primitive polyphenotypic neoplasm," warranting further studies.
Whole-Slide Imaging and Radiological Features Predict Clinical Outcomes in Patients With Neuroendocrine Tumors of the Lung.
Yolchuyeva S, Ebrahimpour L, Lemaréchal Y … +4 more , Joubert P, Bilodeau S, Després P, Manem VS
Mod Pathol · 2025 Dec · PMID 40992504 · Publisher ↗
Neuroendocrine tumors are rare and heterogeneous cancers that vary in clinical presentation, biology, and treatment response. They exhibit slow growth with varying levels of aggressiveness, highlighting the need for reli...
Neuroendocrine tumors are rare and heterogeneous cancers that vary in clinical presentation, biology, and treatment response. They exhibit slow growth with varying levels of aggressiveness, highlighting the need for reliable biomarkers to guide personalized treatment. This study aims to develop predictive models for overall survival (OS) and progression-free survival (PFS) using computed tomography scans, whole-slide images, and clinical data. This retrospective analysis included 83 patients. Predictive models were developed using radiomics features from computed tomography scans and morphologic or pathomics features from whole-slide images. The Cox model was trained using the most significant features from both radiomics and pathomics. By integrating these features with clinical data, we built predictive models combining clinical-radiomics and clinical-pathomics information. We also assessed how image harmonization across different acquisition parameters affects model performance. The radiomics model's concordance indices (C-indices) for predicting OS and PFS in the validation cohort were 0.64 ± 0.06 (95% CI, 0.55-0.73) and 0.60 ± 0.05 (95% CI, 0.52-0.67), respectively. Combining radiomics with clinical data slightly improved performance, with C-indices of 0.643 ± 0.04 (95% CI, 0.58-0.70) for OS and 0.61 ± 0.04 (95% CI, 0.54-0.68) for PFS. For the pathomics model, combining morphologic features with clinical data also showed better improvements, with C-indices for OS increasing from 0.65 ± 0.08 (95% CI, 0.53-0.76) to 0.70 ± 0.03 (95% CI, 0.57-0.82), and for PFS from 0.60 ± 0.15 (95% CI, 0.39-0.81) to 0.68 ± 0.08 (95% CI, 0.57-0.80). Harmonizing radiomics features did not significantly enhance the model's performance for predicting survival outcomes. This study developed and validated models that integrate radiomics and pathomics with clinical data, improving prognostic accuracy for OS and PFS. These multimodal approaches, supported by large data sets, offer significant potential for enhancing patient risk stratification. Further multi-institutional validation is needed, but these imaging-driven biomarkers could ultimately refine therapeutic strategies and optimize survival outcomes.
Integrated Multiomics Analysis of Microsatellite Instability-High Colorectal Cancer Identifies a Subtype With Poor Outcome.
Zhang G, Zhou B, Xu X … +6 more , Che Y, Hong W, Zheng S, Zhang S, Hu W, Yang Y
Mod Pathol · 2025 Dec · PMID 40992503 · Publisher ↗
Up to 50% of patients with metastatic microsatellite instability-high (MSI-H) colorectal cancer (CRC) are resistant to immunotherapy and experience progression or recurrence after treatment. We integrated the genomic, ep...
Up to 50% of patients with metastatic microsatellite instability-high (MSI-H) colorectal cancer (CRC) are resistant to immunotherapy and experience progression or recurrence after treatment. We integrated the genomic, epigenomic, transcriptomic, and proteomic data for 99 patients in a Chinese MSI-H CRC cohort. Proteomic profiling of primary tumors clearly classified MSI-H tumors into 2 subtypes. We found that the 2 subtypes have different mutational signatures, enriched pathways, gene fusion networks, and clinical outcomes. Notably, NCAM1 could serve as a potential biomarker for checkpoint inhibitor response in MSI-H CRC. Thus, there is an urgent need to stratify the MSI-H group into different subtypes and adopt more targeted therapies to prolong patient survival.
EWSR1::CREM Tumor of the Kidney With Florid Tubular Proliferation: Expanding the Spectrum of Biphasic Renal Tumors.
Williamson SR, Alaghehbandan R, McKenney JK … +1 more , Dermawan JK
Mod Pathol · 2025 Nov · PMID 40992179 · Publisher ↗
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An Integrated Clinical Genomic and Transcriptomic Subgrouping of Central Chondrosarcoma.
Meijer DM, Venneker S, Ameline B … +13 more , Erdem Z, Cardoso S, Ruano D, Briaire-de Bruijn IH, van den Akker BE, Wijers-Koster PM, Scholte CHJ, van Praag VM, van de Sande MAJ, Kuijjer ML, Baumhoer D, de Miranda NFCC, Bovée JVMG
Mod Pathol · 2025 Dec · PMID 40976495 · Publisher ↗
Central conventional chondrosarcoma, a malignant cartilage-producing bone tumor, is the second most common bone sarcoma. Chondrosarcomas are histologically graded, which is so far the best predictor of survival. Early mu...
Central conventional chondrosarcoma, a malignant cartilage-producing bone tumor, is the second most common bone sarcoma. Chondrosarcomas are histologically graded, which is so far the best predictor of survival. Early mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 genes are frequent, leading to the production of the oncometabolite D-2-hydroxyglutarate, which affects DNA methylation, resulting in a preferred chondrogenic differentiation over osteogenic differentiation of mesenchymal stem cells, which are currently considered the precursor cells of chondrosarcoma. DNA methylation profiling has previously revealed distinct profiles between IDH-mutant and IDH-wild-type chondrosarcomas, but the presence of further DNA methylation subgroups indicates that classification based solely on IDH status is too simplistic. In this study, we aim to identify biological subgroups in a total of 116 chondrosarcomas by integrating clinical data, IDH mutation status, gene expression, and genome-wide loss of heterozygosity (LOH). Clinical associations were observed between several factors, including sex and histological grade, as well as tumor site and IDH mutation status. RNA sequencing and genome-wide LOH confirmed the distinction between IDH-wild-type and IDH-mutant chondrosarcomas, where the number of chromosome arms affected by LOH was significantly higher in IDH-wild-type tumors than in IDH-mutant tumors. However, no clear subgroups emerged within each IDH group. Further clustering on RNA expression of differentiation markers identified subgroups characterized by chondrogenic, osteogenic, resting chondrocyte, or dedifferentiated profiles. These different subgroups showed a specific clinical presentation and suggest different precursor cells. Instead of a simple dichotomy between IDH-mutant and IDH-wild-type, our integrated approach highlights interconnected clinical, genomic, and transcriptomic patterns that offer a more nuanced view of chondrosarcoma biology and might potentially guide treatment stratification.
A Subset of Serous Tubal Intraepithelial Carcinoma (STIC)-Like Lesions and Concurrent High-Grade Endometrial Carcinoma Are Genomically Related Entities.
da Silva EM, Da Cruz Paula A, Dessources K … +5 more , Gordhandas S, Selenica P, Abu-Rustum NR, Weigelt B, Murali R
Mod Pathol · 2025 Nov · PMID 40946744 · Full text
In patients with high-grade endometrial carcinoma (HG-EC), concurrent isolated serous tubal intraepithelial carcinoma (STIC) or STIC-like lesions (STIC-LLs) in the fallopian tube(s) may be found. We sought to determine w...
In patients with high-grade endometrial carcinoma (HG-EC), concurrent isolated serous tubal intraepithelial carcinoma (STIC) or STIC-like lesions (STIC-LLs) in the fallopian tube(s) may be found. We sought to determine whether concurrently diagnosed HG-ECs and STIC-LLs are genetically related. Six HG-ECs, including serous carcinomas (n = 4) and carcinosarcomas with serous epithelial component (n = 2), with cooccurring STIC-LLs were identified and subjected to microdissection, DNA extraction, and panel sequencing targeting 468 cancer-related genes or, if DNA quantities were limited, to Sanger sequencing. WT1 and p53 protein expression was assessed by immunohistochemistry. We found that 3 HG-ECs and concurrent STIC-LLs shared pathogenic mutations, such as TP53 hotspot, NF2, FBXW7, and PIK3CA mutations. Immunohistochemical analysis revealed that the HG-EC of case 5 lacked WT1 expression and had aberrant p53 expression, although the matched STIC-LL displayed diffuse WT1 expression. Of the remaining 3 cases that did not show evidence of genetic relatedness based on the targeted sequencing panel, 1 STIC-LL harbored a clonal TP53 missense mutation, whereas the matched HG-EC had a distinct clonal TP53 hotspot mutation, a clonal FBXW7 hotspot mutation, and ERBB2 amplification. At the protein level, the p53 expression patterns of the HG-ECs and STIC-LLs were concordant in these 3 cases. Here, we demonstrate that cooccurring HG-ECs and STIC-LLs are genetically related in a subset of cases.
Comprehensive Molecular Profiling of Cribriform Tumors: Identification of Recurrent 6q/9q Codeletion and CD38 Expression.
Sohier P, Battistella M, Mouthon M … +15 more , Fouchardière A, Ortonne N, Vergara R, Cyrta J, Gros A, Laharanne E, Calonje E, Menguy S, Lamant L, von Deimling A, Tirode F, Pissaloux D, Cribier B, Kervarrec T, Macagno N
Mod Pathol · 2025 Nov · PMID 40946743 · Publisher ↗
Cribriform tumor is a distinctive cutaneous adnexal tumor with a cribriform growth pattern. Initially described as carcinomas, cribriform tumors exhibit an indolent clinical course. In contrast to many other adnexal skin...
Cribriform tumor is a distinctive cutaneous adnexal tumor with a cribriform growth pattern. Initially described as carcinomas, cribriform tumors exhibit an indolent clinical course. In contrast to many other adnexal skin neoplasms, the oncogenic driver of cribriform tumors is still unknown. This study aimed to provide a novel characterization of cribriform tumors, focusing on the molecular and gene expression profiles revealed by whole-transcriptome analysis using RNA sequencing and DNA methylation analysis, and describe the resulting novel genetic and protein biomarkers. The study analyzed 15 cases of cribriform tumors, including 5 female patients. The median age at diagnosis was 62 years (range, 37-86). The most common tumor locations were lower (n = 10) and upper extremities (n = 5). Histopathological analysis revealed that all tumors were dermally located, with subcutaneous extension in 11 cases. All cases exhibited a combination of trabecular, cystic, and cribriform growth patterns. Unsupervised clustering based on DNA methylation and transcriptomic profiles confirmed cribriform tumors as a strikingly homogeneous molecular entity, molecularly distinct from other adnexal neoplasms. The low-risk G2/M and Complexity INdex in SARComas (CINSARC) transcriptomic signatures detected in all tested cases further supported the indolent nature of this neoplasm. Copy number variation analysis derived from DNA methylation analysis revealed recurrent 6q/9q codeletion in 7 of 8 tested cases. This codeletion was confirmed by fluorescence in situ hybridization targeting the 6q and 9q loci in 6 cases tested. RNA sequencing data did not reveal any recurrent specific fusions or specific pathogenic variants. Gene expression analysis focusing on differentially expressed genes between cribriform tumors and other cutaneous tumors revealed overexpression of CD38 in all cribriform tumors. Consistent with these findings, immunohistochemical analysis demonstrated CD38 expression in all cribriform tumors but not in controls (n = 29). In conclusion, our findings support that cribriform tumors represent a homogeneous group of cutaneous adnexal neoplasms characterized by recurrent 6q/9q codeletions and CD38 expression.
Ovarian Sex Cord Tumor With Annular Tubules (SCTAT) Harbor Recurrent Copy Number Alterations, Including Monosomy 22.
Leader AM, Neil A, Siegmund S … +7 more , Dehghani A, Ligon A, Matulonis UA, Nucci MR, McCluggage WG, Howitt BE, Kolin DL
Mod Pathol · 2025 Dec · PMID 40946742 · Full text
Sex cord tumor with annular tubules (SCTAT) is a rare ovarian sex cord-stromal neoplasm of low or intermediate malignant potential. Although some SCTATs are associated with Peutz-Jeghers syndrome (PJS), the majority aris...
Sex cord tumor with annular tubules (SCTAT) is a rare ovarian sex cord-stromal neoplasm of low or intermediate malignant potential. Although some SCTATs are associated with Peutz-Jeghers syndrome (PJS), the majority arise in the nonsyndromic setting and typically lack STK11 mutations. As molecular alterations other than STK11 in SCTAT are largely unknown, we sought characterize the genomic landscape in these neoplasms better. SCTATs (n = 22) from 20 patients (5 with PJS, 1 with Prader-Willi syndrome, and 14 with no known syndromic status) were retrospectively identified. STK11 (LKB1) immunohistochemistry (IHC) was performed. Panel-based DNA sequencing was used to detect copy number variations and point mutations in 447 genes in 12 tumors from patients with no history of PJS, with 1 additional non-PJS tumor undergoing only targeted STK11 sequencing. Molecular profiles were compared with other ovarian sex cord-stromal tumors (n = 67). An STK11 mutation and concurrent loss of heterozygosity was in 1 of 13 sporadic tumors. STK11 IHC was intact (n = 14) or equivocal (n = 2) for STK11 wild-type tumors and lost in 1 sporadic tumor with STK11 mutation and 5 tumors from patients with known PJS. TERT promoter mutations were present in 6 of 12 tumors. Recurrent copy number alterations included monosomy 22 (8/12), as well as low-level copy number gains of FOXL2 (10/12; median, 4.3 estimated copies in FOXL2-gained tumors; range, 2.6-7.9), WT1 (9/12), and GATA4 (8/12). One tumor demonstrated biallelic inactivation of TP53 in a region of high-grade transformation characterized by significant cytologic atypia, mitotic activity, and necrosis. In conclusion, nonsyndromic SCTATs are molecularly characterized by FOXL2, WT1, and GATA4 gains, monosomy 22, and TERT promoter mutations. High-grade transformation may rarely occur, a phenomenon not previously described, and is associated with TP53 mutation. STK11 IHC appears to be a reliable surrogate for STK11 mutations and may be useful in suggesting a PJS-related tumor.
Clinical, Morphologic, and Molecular Findings in Neurotrophic Tyrosine Receptor Kinase 3 (NTRK3) Fusion Spitz Neoplasms.
Addo AK, Beydoun HM, Jeyakumar JE … +2 more , Olivares S, Gerami P
Mod Pathol · 2025 Nov · PMID 40945796 · Publisher ↗
Neurotrophic tyrosine receptor kinase 3 (NTRK3) fusions are a relatively common driver of Spitz neoplasms. This subset of Spitz neoplasms may have smaller cells without the typical abundant glassy eosinophilic cytoplasm...
Neurotrophic tyrosine receptor kinase 3 (NTRK3) fusions are a relatively common driver of Spitz neoplasms. This subset of Spitz neoplasms may have smaller cells without the typical abundant glassy eosinophilic cytoplasm seen in most Spitz neoplasms. This can make it difficult to recognize them as belonging to the Spitz family and potentially result in misdiagnosis as melanoma. In this study, we assessed the clinical, morphologic, and genomic features of 60 NTRK3 fusion Spitz neoplasms (13 previously reported and 47 new cases) and performed a comprehensive review of the literature. We identified 5 characteristic morphologic patterns: (1) conventional Spitz nevus (SN) or Spitz tumor (ST), (2) spindle cell nevus of Reed, (3) spindle cell tumor of Reed, (4) dysplastic SN, and (5) exclusively spindle cell variant of SN/ST. The most common fusion partners were MYO5A and ETV6. DNA copy number changes were infrequent (18% of cases), with an average of 1 copy number variant per case. Among 54 cases tested for a TERT promoter mutation, all were negative. One case had a homozygous deletion of 9p21. The majority of cases were diagnosed as SN or Reed nevi (n = 37), rather than ST or Reed tumor (n = 23), and none were diagnosed as Spitz melanoma. Among the 30 patients with outcome data, none experienced recurrence following excision (mean follow-up time was 15 months). NTRK3 fusions can produce morphologic variants of Spitz neoplasms that may be difficult to recognize as belonging to the Spitz family. Familiarity with these morphologic patterns can facilitate identification of the NTRK3 fusion, optimizing classification and distinction from melanoma.
Nonhematopoietic Malignancies in Allograft Kidneys: Where Does the Tumorigenesis Begin?
Forooshani MK, Furci F, Sharma A … +3 more , Vardouniotis A, Gattuso P, Cheng L
Mod Pathol · 2025 Nov · PMID 40945795 · Publisher ↗
Posttransplant malignancy is one of the major complications in patients who have received solid-organ transplants. Malignant cells can be donor transmitted, donor derived, or recipient derived. We undertook a retrospecti...
Posttransplant malignancy is one of the major complications in patients who have received solid-organ transplants. Malignant cells can be donor transmitted, donor derived, or recipient derived. We undertook a retrospective study on tumors arising in allograft kidneys to elucidate their clinical and histological features and to determine the origin of tumor cells. Our pathology database (2002-2022) was searched for allograft kidneys with nonhematopoietic malignancies. Clinical information and histological features were reviewed. The short tandem repeat genotypes of tumor cells were compared with those of control tissue. Eight cases of allograft kidneys with nonhematopoietic malignancies were identified, including 5 men and 3 women, with a mean age of 55 (range 37-81) years. Histologically, there were 3 clear cell renal cell carcinomas, 2 high-grade urothelial carcinomas of the renal pelvis, 2 papillary renal cell carcinomas, and 1 squamous cell carcinoma. All patients had tumors confined to the allograft kidneys. The short tandem repeat genotyping showed that the tumor cells were of donor origin in all cases. In our study, development of nonhematopoietic malignancies in allograft kidneys was very rare, with an incidence of about 0.53%. The most common histological subtype was clear cell renal cell carcinomas. All the tumors were of donor origin. Given the long interval (average 16.6 years) between kidney transplant and allograft nephrectomy, it is more likely that the tumor started de novo in the allograft kidneys after transplant (donor derived), and not from carryover donor tumor cells (donor transmitted). In addition, all patients had organ-confined disease and not widespread metastasis, which also favors de novo tumorigenesis in the allograft kidneys. Therefore, in donors without a history of malignancy, changing the current practice of donor screening to detect possible circulating tumor cells and to eliminate carryover is unlikely to be beneficial.
DNA Methylation-Based Classification of Kidney Neoplasms.
Papanicolau-Sengos A, Singh O, Park K … +15 more , Snuderl M, Tretiakova M, Merino M, Stohr B, Simko J, Deng FM, Chan E, Wu J, Barreto J, Gupta R, Park B, Turakulov R, Abdullaev Z, Solomon DA, Aldape K
Mod Pathol · 2025 Nov · PMID 40939817 · Full text
Renal neoplasms are morphologically and molecularly heterogeneous, with their diagnosis often hindered by interobserver variability and overlapping microscopic features. A subset of cases is unclassifiable despite immuno...
Renal neoplasms are morphologically and molecularly heterogeneous, with their diagnosis often hindered by interobserver variability and overlapping microscopic features. A subset of cases is unclassifiable despite immunohistochemical, mutation, and cytogenetic-based diagnostic workup. Through examination of the genome-wide DNA methylation signatures of over 2000 renal neoplasms, we identified 23 coherent groups that correlate with known neoplasm types and identified novel clinically relevant subtypes of existing neoplasm types. We used machine learning models to develop and validate a classifier trained on DNA methylation profiles of 1284 samples. The classifier was tested on an external data set of 287 renal neoplasms with >90% concordance between expected neoplasm type and high-score DNA methylation-based classification. Discordance between the original histologic label and methylation class led to potential reclassification of some cases. This work demonstrates proof of principle for the feasibility of a DNA methylation classifier as a clinically useful tool to assist in the diagnosis of renal neoplasms.
Lymphovascular Space Invasion in Endometrial Cancer: Does it Matter Where and How Much to Sample? A Macroscopic Study of 208 Hysterectomies.
Ates D, Karahan S, Oruç A … +1 more , Usubutun A
Mod Pathol · 2025 Dec · PMID 40939816 · Publisher ↗
Lymphovascular space invasion (LVSI) is a key prognostic factor in endometrial cancer, guiding adjuvant treatment decisions. This retrospective study analyzed 208 hysterectomy specimens with confirmed LVSI to determine o...
Lymphovascular space invasion (LVSI) is a key prognostic factor in endometrial cancer, guiding adjuvant treatment decisions. This retrospective study analyzed 208 hysterectomy specimens with confirmed LVSI to determine optimal sampling strategies for detecting substantial LVSI. Samples/blocks from tumor infiltration fronts were reviewed microscopically, and LVSI foci were counted per slide and summed across all slides. Cutoffs of ≥5, ≥4, and ≥3 LVSI foci were evaluated. Only the ≥5 threshold significantly correlated with lymph node metastasis (P = .038) compared with <5 LVSI. Both patients with ≥5 LVSI foci either on a single slide or those reaching this threshold by summing across slides were associated with nodal metastasis (P = .023). However, significantly worse overall survival was observed only in patients with ≥5 foci on a single slide, not in those reaching the threshold by summing across multiple slides (P < .001). Focal LVSI (<5 foci) showed no significant overall survival compared with substantial LVSI. Increased sampling from the tumor infiltration front improved LVSI detection rates (P < .001), but gains in detecting substantial LVSI plateaued after 7 samples/blocks. Higher LVSI levels were associated with deep LVSI and cervical/endocervical LVSI (P < .001). Deep LVSI was linked to reduced overall survival compared with superficial LVSI (P < .001), whereas cervical/endocervical LVSI showed no significant association with overall survival (P = .273). Tumor grade, deep LVSI, and cervical involvement predicted nodal metastasis, whereas the microcystic, elongated, and fragmented pattern did not. These findings support using a threshold of ≥5 LVSI foci on at least 1 slide-as opposed to summing across slides-as a marker of worse overall survival. For optimal evaluation, at least 7 tumor infiltration front samples/blocks should be taken, including deep myometrium and cervical/endocervical canal, to ensure adequate assessment and identify patients at higher risk of nodal spread.
PolyPath: Adapting a Large Multimodal Model for Multislide Pathology Report Generation.
Ahmed F, Yang L, Jaroensri T … +11 more , Sellergren A, Matias Y, Hassidim A, Corrado GS, Webster DR, Shetty S, Prabhakara S, Liu Y, Golden D, Wulczyn E, Steiner DF
Mod Pathol · 2025 Nov · PMID 40939815 · Publisher ↗
The interpretation of histopathology cases underlies many important diagnostic and treatment decisions in medicine. Notably, this process typically requires pathologists to integrate and summarize findings across multipl...
The interpretation of histopathology cases underlies many important diagnostic and treatment decisions in medicine. Notably, this process typically requires pathologists to integrate and summarize findings across multiple slides per case. Existing vision-language capabilities in computational pathology have so far been largely limited to small regions of interest, larger regions at low magnification, or single whole-slide images (WSIs). This limits interpretation of findings that span multiple high-magnification regions across multiple WSIs. By making use of Gemini 1.5 Flash, a large multimodal model with a 1-million token context window, we demonstrate the ability to generate bottom-line diagnoses from up to 40,000 image patches of size 768 × 768 pixels from multiple WSIs at 10× magnification. This is the equivalent of up to 11 hours of video at 1 fps. Expert pathologist evaluations demonstrate that the generated report text is clinically accurate and equivalent to or preferred over the original reporting for 68% (95% CI, 60%-76%) of multislide examples with up to 5 slides. Although performance decreased for examples with ≥6 slides, this study demonstrates the promise of leveraging the long-context capabilities of modern large multimodal models for the uniquely challenging task of medical report generation where each case can contain thousands of image patches.
Deep Learning-Assisted System Improves Practical Effects in Cervical Cytopathology Diagnosis: A Comparative Study of Reading Modes.
Ye Z, Zhang P, Wei R … +5 more , Niu H, Li H, Wang M, Riggs SL, Xue P
Mod Pathol · 2025 Nov · PMID 40914500 · Publisher ↗
Deep learning (DL) has significantly improved the diagnostic accuracy and efficiency of cytopathologists. However, current DL-assisted reading modes have yet to be fully evaluated, and there is limited evidence regarding...
Deep learning (DL) has significantly improved the diagnostic accuracy and efficiency of cytopathologists. However, current DL-assisted reading modes have yet to be fully evaluated, and there is limited evidence regarding cytopathologists' preferences and experiences. This study employs a randomized, controlled, 4-way crossover design to assess the effectiveness of 4 distinct cytopatholog reading modes. This study included retrospectively collected 1620 cervical slides between 2021 and 2022. These slides were read by 108 certified cytopathologists with varying expertise using the 4 reading modes: unassisted, concurrent, second, and triage mode. A questionnaire survey was conducted to gather the cytopathologists' adoption of each mode, including mode score and their confidence and preferences. Compared with unassisted, all DL-assisted modes improved the cytopathologists' diagnostic performance. The unassisted mode had a sensitivity of 66.2% and a specificity of 72.5%. The second, concurrent, and triage modes all improved on these metrics: sensitivity increased by 20.2%, 17.3%, and 16.7%, respectively, whereas specificity increased by 13.2%, 10.8%, and 22.3%, respectively. The median reading time per slide was prolonged in second mode from 200 to 235 seconds but substantially reduced to 130 seconds in triage mode, and 53 seconds in concurrent mode (P < .0001 for all). Moreover, the questionnaire survey showed that >90% of cytopathologists agreed that the DL-assisted mode was useful in improving diagnostic confidence, and they preferred the concurrent mode, whereas the triage mode achieved the highest performance in the mode score. The second mode stands out for its heightened sensitivity, the triage mode boasts superior specificity, and the concurrent mode leads in efficiency when assisting cytopathologists. These findings provide useful information for choosing appropriate DL-assisted modes in cytopathological practice.
Methylation Signatures Identify Two Distinct Clusters of Uterine Leiomyosarcoma With Unique Histologic and Clinical Behaviors.
Felicelli C, Duckett D, Coty-Fattal Z … +6 more , Feng Y, Obeidin F, Alexiev BA, Santana Dos Santos L, Jennings L, Wei JJ
Mod Pathol · 2025 Nov · PMID 40914499 · Publisher ↗
Uterine leiomyosarcoma (uLMS) is a rare and deadly gynecologic malignancy. uLMS is histologically heterogeneous and presents with a wide spectrum of tumor differentiation, with a broad range of genomic DNA instability, w...
Uterine leiomyosarcoma (uLMS) is a rare and deadly gynecologic malignancy. uLMS is histologically heterogeneous and presents with a wide spectrum of tumor differentiation, with a broad range of genomic DNA instability, which can make the diagnosis and prognosis of uLMS challenging. Methylation has emerged as a useful molecular tool in tumor classification and diagnosis in certain neoplasms. We initiated this study to investigate the role of global methylation in the differential diagnosis of uLMS from its mimics in correlation with pathologic characteristics and clinical outcomes. In this study, we performed array-based global methylation profiling analysis in a total of 71 uLMS and compared the methylation signatures of uLMS with several other uterine mesenchymal tumors and soft tissue leiomyosarcoma. We found that uLMS demonstrated distinct methylation patterns differing from all other tumor types. Notably, methylation profiling defines 2 distinct subgroups of uLMS with differing copy number alterations, resulting in unique histologic and clinical behaviors, further emphasized by differences in methylation pathway analysis. This study is the first to report methylation profiling as a useful diagnostic tool in differentiating uLMS from mimics and defines 2 subtypes of uLMS based on methylation signatures.
Epstein-Barr Virus-Associated Gastric Cancer: A Histopathologic Study With Comprehensive Molecular Profiling.
Angerilli V, Gasparello J, Collesei A … +13 more , Ceccon C, Bergamo F, Sabbadin M, Parente P, Vanoli A, Niero M, Luchini C, Gafà R, Dei Tos AP, Grillo F, Mastracci L, Lonardi S, Fassan M
Mod Pathol · 2025 Nov · PMID 40912408 · Publisher ↗
A subset of gastric cancers (GCs) is linked to Epstein-Barr virus (EBV) infection. This study aims to characterize the histopathological and molecular features of EBV-associated GCs (EBVaGCs), focusing on predictive biom...
A subset of gastric cancers (GCs) is linked to Epstein-Barr virus (EBV) infection. This study aims to characterize the histopathological and molecular features of EBV-associated GCs (EBVaGCs), focusing on predictive biomarkers and genomic and transcriptomic analysis. A total of 35 primary EBVaGCs were considered. The presence of EBV was confirmed with in situ hybridization. Immunohistochemical analyses for HER2, PD-L1, claudin 18.2, and mismatch repair proteins were performed. Genomic and transcriptomic profiles were assessed using AmoyDx Master Panel, which can identify single-nucleotide variants, InDels, and copy number variations on 571 hot genes, as well as microsatellite status, tumor molecular burden, and homologous recombination deficiency at the DNA level; however, at the RNA level, it identifies rearrangements/fusions in 45 genes and also quantifies the expression of 2396 cancer-related transcripts. The following histotypes were identified: carcinoma with lymphoid stroma (CLS; 69%), tubular (20%), and mixed (11%). Most cases were associated with atrophic gastritis (71%), and only 11% with dysplasia. The vast majority (94%) of EBVaGCs expressed EBV-encoded RNA in all tumor cells. Mismatch repair deficiency and HER2 overexpression were each observed in 6% of cases, whereas all tumors had a PD-L1-combined positive score ≥10. Sixty-six percent of cases showed moderate/strong claudin 18.2 expression in ≥75% of cancer cells. The most frequently altered genes were PIK3CA (41%) and ARID1A (17%). Transcriptomic analysis revealed substantial differential gene expression between EBVaGCs and EBV-negative controls, with upregulation of genes involved in antigen presentation, natural killer cell-mediated cytotoxicity, and cytokine-cytokine receptor interaction in EBVaGCs. Within EBVaGC, CLS showed higher expression of immune-related transcripts and higher PD-L1 expression than other histotypes. This study establishes EBVaGC as a distinct molecular class, with a distinctive profile of genomic alterations and expression of predictive biomarkers, and also with a unique immune microenvironment with enhanced cytotoxic activity. The findings highlight EBV's role in early tumor development and EBVaG-CLS as a distinct subgroup within EBVaGC, characterized by unique morphologic features and a pronounced immune activation profile.
HNF1A-inactived Hepatocellular Adenomas in Fibropolycystic Kidney and Liver Disease Are Associated With Germline HNF1B Variant.
Hagen CE, Karamchandani DM, Ricaurte L … +7 more , Nagaraj N, Sarangi V, Hartley CP, Patel C, Salomao M, Pai R, Graham RP
Mod Pathol · 2025 Nov · PMID 40902854 · Publisher ↗
HNF1A-inactivated hepatocellular adenomas are rarely described in patients with hepatorenal fibrocystic disease, and their genetic relationship remains unexplored. This study reports a series of HNF1A-inactivated hepatoc...
HNF1A-inactivated hepatocellular adenomas are rarely described in patients with hepatorenal fibrocystic disease, and their genetic relationship remains unexplored. This study reports a series of HNF1A-inactivated hepatocellular adenomas with molecular sequencing analysis in patients with fibrocystic kidney and/or liver disease. Cases were retrospectively identified from the pathology archives of 3 institutions. Clinical history was collected from chart review, and hematoxylin-and-eosin-stained slides along with relevant immunohistochemistry were reviewed for liver specimens. Next-generation sequencing was performed on paired lesional hepatocellular adenoma and nonneoplastic tissue. The study group comprised 8 patients (median age, 25 years; male:female, 1:7). Six patients had evidence of congenital hepatic fibrosis, 1 had polycystic liver disease with multiple cysts and bile duct hamartomas, and 1 had an uninvolved background liver but with polycystic kidney disease. Histologic examination revealed that all hepatocellular adenomas showed circumscribed, well-differentiated hepatocellular proliferation with unpaired arterioles and loss of liver fatty acid-binding protein staining via immunohistochemistry. Three patients were found to have novel HNF1B germline variants (c.1430A>C). Our data reveal a new syndromic association for HNF1A-inactivated hepatocellular adenomas. We hypothesize that aberrant interactions between HNF1A and HNF1B may contribute to the pathogenesis of hepatocellular adenomas in these patients. Further studies are necessary to discover additional germline variants that may result in a similar phenotype.
Cross-Platform Methylation-Based Site of Origin Classification for Squamous Cell Carcinomas.
Zhang AW, Akbari V, Galbraith A … +29 more , Kore Z, Li Y, Leung S, Ji JX, Dever K, MacIsaac J, Brewis H, Pan D, Kürten C, Ajisebutu A, Contreras-Sanz A, Moeen A, Zuccato JA, Patil V, Black PC, Lam W, Pleasance E, O'Neill K, Jones S, Marra M, Laskin J, Zadeh G, Mansouri S, Kobor M, Prisman E, McGuire A, Huntsman DG, Yip S, Naso JR
Mod Pathol · 2025 Nov · PMID 40902853 · Publisher ↗
Squamous cell carcinomas (SCCs) are one of the most common cancer types and can arise at nearly any anatomic site. Because SCCs are one of the most common metastases, do not have reliable site-specific morphologic or gen...
Squamous cell carcinomas (SCCs) are one of the most common cancer types and can arise at nearly any anatomic site. Because SCCs are one of the most common metastases, do not have reliable site-specific morphologic or genomic features, and have considerable morphologic and immunohistochemical overlap with urothelial carcinomas, distinguishing between primary and metastatic squamous-appearing tumors can be challenging. This distinction can be critical to clinical management. We present Squamous cell carcinoma Methylation for Origin Site (SquaMOS), a methylation-based classifier to predict site of origin of squamous-appearing carcinomas. Trained on publicly available array-based methylation data from 1062 primary SCCs (from lung, head and neck, cervix, and esophagus) and urothelial carcinomas, SquaMOS predicted site of origin in primary tumors with 96.1% accuracy in an internal test set (n = 458) and 97.4% accuracy in an external test set from 3 institutions (n = 78). On metastatic tumors (n = 51), SquaMOS predictions were 96.1% accurate. SquaMOS was directly applicable to shallow Nanopore sequencing data (CpG probe site coverage, 0.25-2.88×) with an accuracy of 91.7% (n = 36; 100% accurate for high-confidence predictions). When tested on SCCs outside the training set types (n = 15, including 3 metastases to lung), no cases were misclassified as of lung origin, supporting accuracy of lung vs nonlung origin classification for diverse SCC types. Overall, we demonstrate highly accurate performance of the SquaMOS classifier on primary and metastatic tumors from multiple data sources, robust to suboptimal tumor purity. We illustrate transferability of our array-based classifier to low-depth Nanopore sequencing data, a potentially rapid means of site of origin determination in a clinical setting.
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