Modern Pathology最新文献

{"title":"Immune Cellular Patterns Predicting Lymph Node Status Helps Personalized Management of Stage T1 Esophageal Squamous Cell Carcinoma","authors":"Hangjia Zhu ,&nbsp;Xiangli Fan ,&nbsp;Chenghao Liu ,&nbsp;Hongbiao Yan ,&nbsp;Xueyang Luo ,&nbsp;Hu Qiu ,&nbsp;Yi Gong ,&nbsp;Caiyutian Zhang ,&nbsp;Ning Lu ,&nbsp;Jingping Yuan ,&nbsp;Ximing Xu ,&nbsp;Honglei Chen ,&nbsp;Yongshun Chen","doi":"10.1016/j.modpat.2025.100814","DOIUrl":"10.1016/j.modpat.2025.100814","url":null,"abstract":"<div><div>Endoscopic resection preserves esophageal integrity in stage T1 esophageal squamous cell carcinoma (ESCC), but its inability to address regional lymph node metastasis (LNM) necessitates novel strategies for risk stratification. This study aimed to characterize the immune microenvironmental features predictive of LNM in stage T1 ESCC and explore their implications for personalized management. We analyzed clinical data from 938 patients with stage T1 ESCC, evaluating the prognostic significance of clinicopathological factors (including LNM and lymphovascular invasion [LVI]) and immune parameters through survival analyses; multiplex immunofluorescence was performed to quantify spatial immune cell distributions within tumor nests and stromal compartments. As a result, LNM and LVI emerged as independent prognostic determinants; patients stratified by nodal status and LVI revealed distinct outcomes: LNM−/LVI− cohorts exhibited optimal progression-free survival and overall survival, whereas LNM+/LVI+ subgroups had the poorest outcomes. Notably, LNM+/LVI− patients demonstrated worse prognosis compared with LNM−/LVI+ cases (median progression-free survival, 28 vs 41 months, <em>P</em> = .003; overall survival, 35 vs 53 months, <em>P</em> &lt; .001). Multiplex immunofluorescence spatial analysis identified 2 immune signatures strongly associated with LNM: (1) elevated CD8+FOXP3+/CD8+ T-cell ratio within cancer nests (<em>P</em> = .001) and (2) reduced spatial proximity between CD8+FOXP3− T cells and FOXP3+ cells (<em>P</em> &lt; .001). The identified immune topographies (CD8+FOXP3+/CD8+ T-cell ratio within cancer nests and spatial proximity between CD8+FOXP3− T cells and FOXP3+ cells) provide novel biomarkers for preoperative LNM prediction. Integration of these immune signatures with clinical risk factors could optimize therapeutic decision-making between endoscopic resection and radical esophagectomy in stage T1 ESCC.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 10","pages":"Article 100814"},"PeriodicalIF":7.1,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144294098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proposing New Criteria for Classification of Benign Fibroepithelial Lesions Based on Clinicopathologic Evaluations of 507 Cases with Clinical Outcome","authors":"Thi Truc Anh Nguyen ,&nbsp;Jilun Zhang ,&nbsp;Jabed Iqbal ,&nbsp;Syed Salahuddin Ahmed ,&nbsp;Yi Liu ,&nbsp;Linlin Yang ,&nbsp;Gloria Zhang ,&nbsp;Bohan Ning ,&nbsp;Hua Guo ,&nbsp;Shi Wei ,&nbsp;Yanjun Hou ,&nbsp;Indu Agarwal ,&nbsp;Sayeeda Yasmeen ,&nbsp;Thaer Khoury ,&nbsp;Di Ai ,&nbsp;Huiyan Deng ,&nbsp;Yueping Liu ,&nbsp;Limin Peng ,&nbsp;Yunn-Yi Chen ,&nbsp;Kalliopi P. Siziopikou ,&nbsp;Xiaoxian Li","doi":"10.1016/j.modpat.2025.100812","DOIUrl":"10.1016/j.modpat.2025.100812","url":null,"abstract":"<div><div>Cellular fibroadenoma (cFA), benign phyllodes tumor (BePT), and borderline phyllodes tumor (BoPT) demonstrate overlapping clinicopathologic features. We evaluated 507 cases including 91 cFAs, 230 BePTs, and 186 BoPTs. The World Health Organization–recommended morphologic criteria were used to classify cFA and BePT. BoPT was diagnosed when a tumor presented at least 1 of the 5 morphologic features (permeative border, markedly increased stromal cellularity, marked stromal atypia, ≥5 mitoses/10 high-power fields, and the presence of stromal overgrowth) but did not meet our recently proposed refined diagnostic criteria for malignant phyllodes tumor. The median follow-up time was 79 months. Overall, 23 (4.5%) of the 507 cases developed recurrence. None had distant metastasis or recurred as malignant phyllodes tumor. The recurrence rates were 7.7%, 2.2%, and 5.9% in cFA, BePT, and BoPT, respectively. Of the 507 cases, younger age, larger tumor size, the presence of myxoid stroma, and stromal overgrowth were significantly associated with higher recurrence rate in univariate analysis (all <em>P</em> &lt; .05); in multivariate analysis, younger age (years) and larger tumor size were significantly associated with recurrence, whereas the other 2 variables were marginally associated with recurrence. Tumors &gt; 6.5 cm had a recurrence rate of 13.5% vs 3.5% in tumors ≤ 6.5 cm; tumors with stromal overgrowth had a recurrence rate of 15% vs 4.1% in tumors without stromal overgrowth. In cFA, being of Hispanic race and the presence of myxoid stroma were significantly associated with recurrence; in BePT, increased number of leaf-like structure and the presence of myxoid stroma were significantly associated with recurrence; and in BoPT, younger age (years) and large tumor size were significantly associated with recurrence. Surgical margin status (positive vs negative) was not associated with recurrence in cFAs, BePTs, or BoPTs. The recurrence rate in benign fibroepithelial lesions was low. No metastasis or recurrence as malignant phyllodes tumor was observed. Surgical margin status was not associated with recurrence rate. These results indicate that the current classification does not correlate with clinical outcomes. We propose to use tumor size of 6.5 cm and/or the presence of stromal overgrowth as the diagnostic criteria to classify these lesions as benign and borderline fibroepithelial lesions because they best correlate with clinical outcome. The significance of myxoid stroma warrants further investigation.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 10","pages":"Article 100812"},"PeriodicalIF":7.1,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144294105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Contemporary Approach to the Diagnosis and Classification of Myelodysplastic Neoplasms/Syndromes: Authors’ Response to “Concerns and Issues”","authors":"Fnu Aakash ,&nbsp;Sanam Loghavi","doi":"10.1016/j.modpat.2025.100795","DOIUrl":"10.1016/j.modpat.2025.100795","url":null,"abstract":"","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 7","pages":"Article 100795"},"PeriodicalIF":7.1,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144262185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analytical Comparison of Commonly Used Laboratory-Developed Tests for the Assessment of Ki-67 in Breast Carcinoma With a Food and Drug Administration–Approved Benchmark","authors":"Sunil Badve ,&nbsp;Jason S. White ,&nbsp;Francisco Sapunar ,&nbsp;Kelli Thoele ,&nbsp;Sameera R. Wijayawardana ,&nbsp;Xiaoxian Li ,&nbsp;Michael F. Press ,&nbsp;Souzan Sanati ,&nbsp;Kyle C. Strickland ,&nbsp;Lani Kai Clinton ,&nbsp;David Gutman ,&nbsp;Patrick Frey ,&nbsp;Tobias Lang ,&nbsp;Aaron M. Gruver","doi":"10.1016/j.modpat.2025.100813","DOIUrl":"10.1016/j.modpat.2025.100813","url":null,"abstract":"<div><div>Ki-67 immunohistochemistry (IHC), a commonly used assay for breast cancer risk prognostication, has significant interlaboratory heterogeneity. This study assessed the impact of antibody clones by comparing the Ki-67 IHC MIB-1 pharmDx assay (Dako Omnis; Agilent Technologies) with clones MIB-1 (Dako Autostainer Link 48 platform), K2 (Leica BOND-III platform), and 30-9 (Ventana BenchMark ULTRA platform) used in Ki-67 laboratory-developed IHC tests. Breast cancer tissue microarrays were processed and stained in 2 central laboratories per the manufacturer's instructions. Digitized images were assessed by 5 pathologists (L.K.C., X.L., M.F.P., S.S., K.C.S.) before and after training on the reference scoring algorithm. Results were compared with results obtained by an artificial intelligence software for biomarker assessment (Mindpeak Breast Ki-67). Positive percent agreement (sensitivity), negative percent agreement (specificity), and overall percent agreement were calculated against the reference assay for the 20% cutoff, with exploratory analysis conducted for 5%, 10%, and 30% cutoffs. At the 20% cutoff, none of the laboratory-developed IHC tests achieved high overall agreement with the reference assay (predetermined as ≥85%). Both clones MIB-1 on Dako Autostainer Link 48 (sensitivity = 24.8% [95% CI, 20.2-29.9]; specificity = 99.5% [95% CI, 98.6-99.8]) and K2 on Leica BOND-III (sensitivity = 25.1% [95% CI, 20.5-30.3]; specificity = 100% [95% CI, 99.4-100]) had specificity comparable to that of the reference test, whereas clone 30-9 (Ventana BenchMark ULTRA) differed substantively in specificity from the reference assay in these measures (sensitivity = 99.3% [95% CI, 97.6-99.8]; specificity = 53.6% [95% CI, 49.6-57.5]). Intraclass correlation coefficient (ICC) for each pathologist ranged from 0.6 to 0.8, indicating good consistency across pathologists with little variability (variance component = 7.1 [95% CI, 2.1-29.7]). Training did not substantively alter within-assay or within-pathologist agreement. Ki-67 artificial intelligence analysis (ICC, 0.7; 95% CI, 0.4-0.9) was comparable to pathologists’ assessment (ICC, 0.6-0.8). Commonly used IHC assays for Ki-67 assessment in breast cancer can significantly vary. Pathologists should be aware of variables that may impact Ki-67 interpretation and look to standardize biomarker assessments for early breast cancer patient care.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 10","pages":"Article 100813"},"PeriodicalIF":7.1,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144294095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinicopathologic Features of Untreated Colorectal Cancer with Acellular Mucin–Only Lymph Nodes","authors":"Wenyi Luo ,&nbsp;Shaomin Hu ,&nbsp;Irene Rana Riahi ,&nbsp;Hanlin L. Wang ,&nbsp;Nuha Shaker ,&nbsp;Ibrahim Abukhiran ,&nbsp;Tiffany Wang ,&nbsp;Alexandros D. Polydorides ,&nbsp;Adeyinka Akinsanya ,&nbsp;Iván A. González ,&nbsp;Catherine Hagen ,&nbsp;Rondell P. Graham ,&nbsp;Mikhail Lisovsky ,&nbsp;Teri A. Longacre ,&nbsp;Bindu Challa ,&nbsp;Wei Chen ,&nbsp;Daniel Harter ,&nbsp;Cameron Beech ,&nbsp;Mehran Najibi ,&nbsp;Wenqing Cao ,&nbsp;Xuchen Zhang","doi":"10.1016/j.modpat.2025.100811","DOIUrl":"10.1016/j.modpat.2025.100811","url":null,"abstract":"<div><div>Lymph nodes (LNs) containing only acellular mucin are considered negative for metastasis in treated colorectal cancers (CRCs). However, no data exist on how to stage these LNs in untreated CRCs. We collected 63 untreated CRC cases with LNs containing only acellular mucin from 27 US institutions and 23 additional cases from the Dutch Nationwide Pathology Databank. The practice patterns of pathologists in handling such cases, as well as the clinicopathological features of these cases, were analyzed. The survival of the study group was compared with 2 control groups: 102 pN0 and 76 pN1 untreated CRC cases. US and Dutch pathologists demonstrated similar practice patterns in assigning the pN stage and in the use of additional studies. Tumors in the study group were more likely to be located in the right colon, exhibit mucinous features, and be mismatch repair deficient compared with tumors in the pN0 and pN1 control groups. Compared with the pN1 control group, the study group showed significantly lower frequencies of lymphovascular invasion, local recurrence, and distant metastasis. No patient in the study group died of CRC, similar to the pN0 group. In contrast, the pN1 group had a significantly higher risk of CRC-related death. These findings suggest that LNs containing only acellular mucin in untreated CRCs should be interpreted as negative and staged as pN0, in line with current practice in neoadjuvant-treated CRCs.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 10","pages":"Article 100811"},"PeriodicalIF":7.1,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144294096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deciphering Pseudoendocrine Sarcoma: A Clinicopathological, Molecular, and Epigenetic Study Suggesting Biological Links With Solid Pseudopapillary Neoplasm of the Pancreas","authors":"Juan Fernández-Pérez ,&nbsp;Isabelle Pommepuy ,&nbsp;Michael Michal ,&nbsp;Michal Michal ,&nbsp;Arjen H.G. Cleven ,&nbsp;Corinne Bouvier ,&nbsp;Anne Gomez-Brouchet ,&nbsp;Noelle Weingertner ,&nbsp;David J. Papke ,&nbsp;Vickie Y. Jo ,&nbsp;Jeremy Garcia ,&nbsp;Abbas Agaimy ,&nbsp;Rihab Azmani ,&nbsp;Aurelien Bourdon ,&nbsp;Isabelle Hostein ,&nbsp;Isabelle Soubeyran ,&nbsp;Melissa Alame ,&nbsp;Valérie Velasco ,&nbsp;Jean-Michel Coindre ,&nbsp;François Le Loarer ,&nbsp;Raul Ezequiel Perret","doi":"10.1016/j.modpat.2025.100810","DOIUrl":"10.1016/j.modpat.2025.100810","url":null,"abstract":"<div><div>Pseudoendocrine sarcoma (PS) is a recently described neoplasm of uncertain differentiation, characterized by recurrent <em>CTNNB1</em> mutations, frequent paravertebral location, and a neuroendocrine-like histomorphology. In this study, we report the clinicopathologic, immunohistochemical, transcriptomic, and epigenetic findings of 12 PS cases. The tumors affected 7 men and 5 women with a median age of 66 years and were located in the paraspinal/paravertebral region (n = 11) and the thigh (n = 1). Median tumor size was 82 mm (range, 32-170 mm). Histologically, the tumors comprised sheets and nests of epithelioid-to-ovoid cells with uniform nuclei and speckled chromatin, frequently associated with extracellular hyaline globules and fibrovascular cords/septa. Uncommon findings included microcalcifications, myxoid stroma, pseudopapillary, pseudoglandular, microcystic or corded architecture, and lumen and rosette-like structures. Necrosis was absent, and mitotic activity was low. On immunohistochemistry, the tumors showed aberrant nuclear staining for beta-catenin (8/8) and expression of CD56 (7/7), S100 (8/8), desmin (2/6), and androgen receptor (1/4). Pankeratin (AE1/AE3), progesterone receptor, synaptophysin, chromogranin, and INSM1 were negative. All tested cases harbored <em>CTNNB1</em> mutations. Using a customized cohort, methylation profiling revealed that PS formed a common cluster with solid pseudopapillary neoplasm of the pancreas (SPNP), distinct from all methylation classes from the Heidelberg sarcoma classifier and a subset of paragangliomas. Transcriptomic analysis showed that PS formed an independent cluster from a control group of tumors (including SPNP). Differential gene expression analysis showed enrichment in genes of the Wnt signaling pathway (HALLMARK gene sets) and biological processes related to sensory perception, among others (gene ontology - biological process [GO-BP]). Additionally, upregulated genes were related to various fetal cell types from the cell type signature data set (MSigDB), particularly of neuronal and epithelial lineage. Immunohistochemical assessment of potential markers identified through gene expression analysis revealed focal-to-diffuse expression of GLUT1 (6/6) and focal/multifocal expression of Brachyury (4/9) and HuD (3/7). Follow-up information, available for 10 cases (median duration of 18 months; range, 7-69 months), showed local recurrences and metastatic spread in 2 patients each. Evidence of response to radiotherapy was documented in one tumor. Altogether, this study expands knowledge on PS and suggests biological links with SPNP, including a potential shared cell of origin.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 10","pages":"Article 100810"},"PeriodicalIF":7.1,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144294097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognostic Value of an Integrated Human Papillomavirus and Immunoscore Model to Predict Survival in Vulva Squamous Cell Carcinoma","authors":"Rammah Elnour ,&nbsp;Ingjerd Helstrup Hindenes ,&nbsp;Malene Færevaag ,&nbsp;Ingrid Benedicte Moss Kolseth ,&nbsp;Liv Cecilie Vestrheim Thomsen ,&nbsp;Anne Christine Johannessen ,&nbsp;Daniela Elena Costea ,&nbsp;Line Bjørge ,&nbsp;Harsh Nitin Dongre","doi":"10.1016/j.modpat.2025.100809","DOIUrl":"10.1016/j.modpat.2025.100809","url":null,"abstract":"<div><div>Although the prognostic value of immune-related biomarkers is well characterized in many solid tumors, their significance in vulva squamous cell carcinoma (VSCC) remains unclear. In this study, we report a comprehensive analysis of programmed death ligand protein 1 (PD-L1) and immune cell infiltration in VSCC and establish immunoscore models for classification of the disease. Tissue microarrays, immunohistochemistry, and digital quantification were used to investigate the number of CD4+, CD8+, CD68+, CD14+, FoxP3+, and PD-L1+ cells in epithelial and stromal compartments of VSCC (<em>n</em> = 117). Immunoscores were developed using these parameters and applying the least absolute shrinkage and selection operator to identify predictors of survival. Immunoscores were then integrated with human papillomavirus (HPV) status, as determined using messenger RNA in situ hybridization, to construct internally validated nomograms. The prognostic models were subsequently applied in whole tissue sections (<em>n</em> = 25) to investigate agreement. Advanced VSCC (International Federation of Gynecology and Obstetrics stage III/IV) was characterized by high densities of CD68+ macrophages and PD-L1+ cells (Spearman correlation, ρ = 0.80) in the epithelium. PD-L1 status independently predicted poor progression-free survival (PFS) (hazard ratio = 1.828; 95% CI, 1.039-3.215; <em>P</em> = .036). Immunoscore^PFS and immunoscore^DSS were developed and found to be independent prognosticators of PFS (<em>P</em> = .003) and disease-specific survival (DSS) (<em>P</em> = .007), respectively. Integrating immunoscores with HPV status (IS-HPV index) improved model performance. The concordance index of IS-HPV index^PFS was 0.750 for prediction of PFS compared with 0.666 for HPV status and 0.667 for immunoscore^PFS. The concordance index of IS-HPV index^DSS was 0.752 for predicting DSS compared with 0.631 for HPV status and 0.715 for immunoscore^DSS. Strong agreement (phi coefficient [ϕ] = 0.76-0.8) was observed when the IS-HPV index models developed using tissue microarrays were applied to whole tissue sections. In summary, an index based on HPV status and an immunoscore built on PD-L1 expression and immune cell infiltrates could potentially serve as prognostic tools to refine risk stratification in VSCC. Further validation is warranted to demonstrate clinical use.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 10","pages":"Article 100809"},"PeriodicalIF":7.1,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144285501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond Hybrid Morphology: A Large Series of Fusion-Driven Benign Peripheral Nerve Sheath Tumors Including 5 Tumors With Novel Fusions","authors":"Carina A. Dehner ,&nbsp;Tania Platero-Portillo ,&nbsp;George Jour ,&nbsp;Carla Saoud ,&nbsp;Yanming Zhang ,&nbsp;Darya Buehler ,&nbsp;Meera Hameed ,&nbsp;Michael Michal ,&nbsp;Darcy Kerr ,&nbsp;Klaus J. Busam ,&nbsp;Abbas Agaimy ,&nbsp;Jorge Torres-Mora ,&nbsp;Cristina R. Antonescu ,&nbsp;Konstantinos Linos","doi":"10.1016/j.modpat.2025.100806","DOIUrl":"10.1016/j.modpat.2025.100806","url":null,"abstract":"<div><div>Benign peripheral nerve sheath tumors (PNSTs) represent a heterogeneous group of neoplasms with varying histologic and molecular characteristics. Although traditional classifications categorize these tumors based on predominant cell types, recent advances in molecular pathology have revealed the presence of hybrid tumors featuring elements from at least 2 nerve sheath tumors (hybrid peripheral nerve sheath tumor [hPNST]). We herein studied 20 cases of hPNST involving 15 female and 5 male patients (median age, 29.5 years; range, 3 weeks-71 years). Tumors occurred on the upper extremity (6), scalp (3), trunk (3), face (3), lower extremity (2), right lateral neck (1), nasal sinus (1), and retroperitoneum (1). Follow-up information was available in 9 of 20 cases (45%; median, 10 months; range, 2 weeks-144 months) and documented local recurrence in 2 of 9 patients (22%) at 10 and 144 months after incomplete excision. Next-generation sequencing demonstrated vestigial-like family member 3 (<em>VGLL3</em>) fusions in 14 cases, fused with <em>CHD7</em> (10 tumors), <em>CHD9</em> (3 tumors), and <em>MAMLD1</em> (1 tumor), an alternative <em>TEAD1::NCOA2</em> (1 tumor) fusion and several novel fusions including <em>TOX::TEAD1</em> (2 tumors), <em>RREB1::LPP</em> (1 tumor), <em>SRF::MYOCD</em> (1 tumor), and <em>KANK1::CDK5RAP2</em> (1 tumor). Most tumors with <em>VGLL3</em> fusions showed morphologically and immunophenotypically classic features of hybrid schwannoma-perineurioma, whereas rare cases showed unusual microscopic features, such as prominent myxoid stroma, pseudolipoblasts, prominent Schwannian nodules, or solely schwannomatous morphology. The <em>RREB1::LPP</em>-driven tumor showed features of hybrid schwannoma-neurofibroma. Lastly, 1 tumor with a novel <em>SRF::MYOCD</em> fusion displayed morphologic features reminiscent of desmoplastic melanoma although exhibiting a combined neural and smooth muscle phenotype. Our data expand on the morphologic and molecular spectrum of fusion-driven hPNSTs, including 5 previously undescribed fusions, and further expand on noncentral nervous system schwannomas with <em>VGLL3</em> fusions.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 10","pages":"Article 100806"},"PeriodicalIF":7.1,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Spectrum of Placental Findings of First-Trimester Cytomegalovirus Infection Related to the Presence of Symptoms in the Newborns and Stillbirths","authors":"Eva Manuela Pena-Burgos ,&nbsp;Rita María Regojo-Zapata ,&nbsp;Ángela Caballero-Ferrero ,&nbsp;Cristina Martínez-Payo ,&nbsp;María del Carmen Viñuela-Benéitez ,&nbsp;Dolores Montero ,&nbsp;María De La Calle","doi":"10.1016/j.modpat.2025.100808","DOIUrl":"10.1016/j.modpat.2025.100808","url":null,"abstract":"<div><div>Cytomegalovirus (CMV) is one of the most common congenital infections worldwide and a leading cause of prenatal neurological disorders, sensorineural hearing loss, and stillbirth. The placental factors involved in CMV transmission from mother to fetus remain poorly understood. We aimed to evaluate the histopathological placental findings associated with first-trimester CMV infection in relation to stillbirth and symptomatic presentation in newborns. This retrospective case-control study analyzed pregnancies with confirmed first-trimester CMV infection followed at 2 tertiary referral hospitals between 2012 and 2024. Symptomatic newborns were compared with asymptomatic newborns and stillbirths. Univariate statistical analyses were performed. A total of 40 placentas were included: 23 from asymptomatic newborns, 11 from symptomatic newborns, and 6 from stillbirths. Compared with asymptomatic cases, placentas from symptomatic newborns were smaller and showed increased chronic plasma cell deciduitis, chronic villitis (without avascular villi, breakdown villi, necrosis, or hemosiderin deposits), more CMV inclusions in fibroblasts, and higher rates of positive CMV immunostaining. Stillbirth placentas exhibited more severe chronic villitis (with avascular villi, breakdown villi, necrosis, and hemosiderin deposits), more extensive intervillous fibrin deposition, CMV inclusions in endothelial and trophoblastic cells, and higher frequencies of maternal and fetal vascular malperfusion compared with placentas from symptomatic newborns. Ultrasound screening did not appear to be a reliable predictor of placental involvement in first-trimester CMV infection. Greater involvement of the villous and vascular barriers—both direct and indirect—was associated with more severe fetal outcomes, likely facilitating viral transmission to the fetus. Adjunctive treatments aimed at reducing villous and vascular damage may help prevent symptomatic infection and stillbirth in first-trimester CMV cases.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 9","pages":"Article 100808"},"PeriodicalIF":7.1,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phenotypic and Molecular Features of Somatically Derived “Yolk Sac Tumors”: Similarities and Differences With Counterparts of Germ Cell Origin","authors":"João Lobo ,&nbsp;Nuno Tiago Tavares ,&nbsp;Fernanda Fernandes-Pontes ,&nbsp;Diana Fonseca ,&nbsp;Carmen Jerónimo ,&nbsp;Rui Henrique ,&nbsp;Costantino Ricci ,&nbsp;Antonio de Leo ,&nbsp;Katrina Collins ,&nbsp;Muhammad T. Idrees ,&nbsp;Thomas M. Ulbright ,&nbsp;Sounak Gupta ,&nbsp;Andres M. Acosta","doi":"10.1016/j.modpat.2025.100807","DOIUrl":"10.1016/j.modpat.2025.100807","url":null,"abstract":"<div><div>A subset of somatic carcinomas shows morphologic and immunophenotypic similarities to yolk sac tumor (YST) of germ cell origin, including fetal adenocarcinomas of the lung and somatic carcinomas with “YST”/enteroblastic differentiation. At least some of these tumors may result from reprogramming somatic cancer cells, leading to the acquisition of a “pluripotent” phenotype. Although these somatic tumors express markers such as SALL4, glypican 3, and alpha-fetoprotein, which are positive in germ cell-derived YST, it is currently uncertain to what degree their molecular features overlap with those of germ cell tumors (GCTs). We assessed i(12p) (fluorescence in situ hybridization) and levels of micro-RNA-371-373 (real-time PCR), hallmarks of germ cell neoplasia in situ (GCNIS)-derived GCTs, in a cohort of 11 somatically derived neoplasms with YST/enteroblastic phenotype (designated as “YST-like” tumors hereafter). In addition, we used immunohistochemistry to assess expression of FOXA2, a critical regulator of induction and maintenance of YST phenotype in GCTs. All YST-like tumors showed expression of FOXA2 and were negative for i(12p). Expression of miR-371a-3p (the most specific member of the miR-371-373 cluster) was detectable in 6 of 10 (60%) of YST-like tumors. Four samples showed levels in the gray zone of detection (ie, expression of uncertain clinical significance), and 2 samples (separate tumors from a single patient) showed positive levels similar to those found in nonteratoma GCNIS-derived GCTs. The remaining members of the micro-RNA cluster (miRs 372 and 373) followed the same patterns. Our results show that the overlap of somatically derived YST-like tumors and YSTs of germ cell origin goes beyond morphology, including expression of one of the master regulators of the YST phenotype and, in some cases, miR-371a-3p. However, these neoplasms lack a hallmark finding of GCNIS-derived GCTs (i[12p]) and show significant biologic and clinical differences with GCTs.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 9","pages":"Article 100807"},"PeriodicalIF":7.1,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}