Select updates in the pathology of kidney, testis, and penile cancer for 2026: Including FLCN-mutated (kidney) tumors, paratesticular mesothelial tumors, and TP53/HPV status in penile squamous cell carcinoma.

DNA Methylation Profiling Classifies and Reveals Origin of Gynecologic Central Nervous System-Like Tumors.

Abstract Background Ewing’s sarcoma primarily involving the skull is an uncommon occurrence, representing approximately 1% of all reported cases. Only a limited number of such cases have been described in the literature. The principal diagnostic challenge lies in distinguishing these tumors from other small round blue cell neoplasms of the central nervous system (CNS), such as primitive neuroectodermal tumors (PNETs). Ewing’s sarcoma typically arises in bone and is not related to intraparenchymal embryonal CNS tumors. When the CNS is affected, the disease usually extends locally from the skull or epidural space, or less commonly, through intracranial or spinal metastases. Primary intracranial lesions are exceedingly rare and have been reported predominantly as dural-based tumors. Case presentation We report the case of an 8-year-old girl diagnosed with primary intracranial Ewing’s sarcoma involving the skull. The patient presented with progressive neurological symptoms and was managed at our institution. Radiological and histopathological assessments, supported by immunohistochemical analysis and molecular confirmation of the characteristic EWSR1 gene rearrangement, established the diagnosis. The patient received multimodality therapy within a multidisciplinary treatment framework. Conclusion Primary intracranial Ewing’s sarcoma is an exceptionally rare entity that may closely resemble other dural-based pediatric tumors. Accurate diagnosis necessitates a combination of histopathological, immunohistochemical, and molecular investigations. Early recognition and the implementation of a multimodal therapeutic strategy are essential for achieving optimal clinical outcomes.

To evaluate real-time ultrasound-guided intratumoral lauromacrogol + pingyangmycin for pediatric peripheral primitive neuroectodermal tumors (pPNET) refractory to chemotherapy. Five tumor lesions in three children from our institution were treated under real-time ultrasound guidance. Color Doppler and contrast-enhanced ultrasound assessed tumor hemodynamics and size pre- and post- injection. Pre-injection, all tumors showed rich blood flow (mixed arteriovenous signals). Post-injection contrast ultrasound revealed significantly reduced arterial-phase blood supply. At 4-week follow-up, all five tumors showed statistically significant volume reduction (p < 0.05) and reduced tumor-related pain. No adverse reactions such as bleeding and pain occurred during injection. Ultrasound-guided intratumoral lauromacrogol + pingyangmycin injection effectively reduces tumor blood supply, destroys local vasculature, and shrinks tumor volume in end-stage pediatric pPNET. It is a safe and effective local palliative treatment.

18F-FDG PET/CT-guided delineation of surgical margins in adhesive primitive neuroectodermal tumor

Primitive neuroectodermal tumor of the kidney: A case report

Primary extraosseous Ewing sarcoma / primitive neuroectodermal tumor of head and neck in an adult.

Abstract Retinoblastoma is the most common intraocular malignancy in children. Heritable cases, often due to germline RB1mutations, typically present bilaterally. Trilateral retinoblastoma refers to intraocular retinoblastoma with an associated intracranial primitive neuroectodermal tumor (PNET), usually in the pineal gland, and occurs in 3–9% of heritable cases. This report describes a male infant with 13q deletion syndrome diagnosed at four months with bilateral retinoblastoma. He initially received six cycles of systemic chemotherapy (vincristine, etoposide, carboplatin) plus cyclosporine, followed by five cycles of intra-arterial melphalan and laser ablation to the left eye. A pineal lesion observed since infancy showed progression at age two. Biopsy confirmed PNET. Treatment included multiagent chemotherapy (vincristine, cyclophosphamide, cisplatin, etoposide) and autologous stem cell rescue with conditioning (carboplatin, etoposide, thiotepa). He engrafted by day +12 and remained stable for three years. At age seven, pineal tumor regrowth was treated with Gamma Knife radiosurgery. Two years later, subsequent progression led to an endoscopic third ventriculostomy and another Gamma Knife procedure. Later that same year, leptomeningeal spread developed. He began bridging chemotherapy (vincristine, cyclophosphamide), followed by proton beam craniospinal irradiation (3600 Gy with boost to pineal area), and 12 cycles of bevacizumab, irinotecan, and temozolomide. As of three years post-radiation, the patient remains without active disease. MRI shows a stable residual pineal lesion and stable post-treatment changes in both eyes. This case highlights the complex, multimodal management of trilateral retinoblastoma in a patient with 13q deletion syndrome. Prolonged disease control is possible with chemotherapy, focal therapies, stem cell transplantation, radiosurgery, and proton beam radiation. However, long-term surveillance and flexible salvage strategies remain critical for sustained outcomes.

Abstract BACKGROUND Responses to immunotherapy in pediatric brain cancers have thus far been disappointing. We, therefore, sought to understand the immunophenotype/immune environment in these tumors. METHODS The Pediatric Brain Tumor Consortium studied 100 patient samples from ependymomas, high-grade gliomas (HGGs), medulloblastomas, and historically-diagnosed supratentorial primitive neuroectodermal tumor [sPNET]). PD-1/PD-L1 expression were determined by immunohistochemistry as previously presented, and an updated study of immune-related gene expression was analyzed via a Nanostring immunologic codeset. Immune scores were calculated with a GSVA ssGSEA algorithm, and hierarchical clustering visualized by pheatmap and ComplexHeatmap. Tumor-type specific subgrouping was applied using the scores generated from Consensus Non-negative Matrix factorization (cNMF). RESULTS Approximately half of the tumors expressed PD-1 (52/100) or PD-L1 (44/100) at an intensity score of at least 1/5, with higher scores in HGG. Ependymoma and HGG demonstrated more robust immune cell signatures, while medulloblastoma and sPNET demonstrated decreased monocytic and myeloid cell signatures. Reclustering delineated three immune-related subgroups in each tumor with unique expression profiles. Ependymoma group E1 was enriched for Th17 cell differentiation, and E3 with EGFR tyrosine kinase inhibitor resistance. HGG G1 pathways related to IL-17 signaling, NOD-like receptor signaling, and cytokine signaling, while G3 was enriched for PI3K-Akt signaling and ECM-receptor interaction. Medulloblastoma M1 and M2 was enriched for pathways related to pro-inflammatory genes, and M3 enriched with PI3K-Akt signaling and NK cell mediated cytotoxicity. sPNET P1 and P2 was also enriched for pathways related to immune system genes, while P3 showed upregulated HSC lineage and antigen presentation pathways. CONCLUSION The addition of immune expression profiling in our study to PD-1/PD-L1 IHC scores enables better understanding of relevant immune-specific genes, with better characterization of noteworthy immune alterations that may aid in designing more effective immunotherapy for pediatric brain cancers.

Abstract CIC-rearranged sarcoma (CRS) is a rare disease driven by a specific fusion protein involving the CIC gene. The occurrence in the brain is 3% in all CRS patients, and these tumors frequently metastasize to the brain. The most common rearrangement is with the double homeobox 4 (DUX4) transcription factor (CIC-DUX4), and others, such as CIC-NUTM1 fusions, have been identified in a subset of pediatric primitive neuroectodermal tumors. However, the molecular mechanisms by which CIC-fusions drive CRS remain unknown. Preliminary data show that CIC-DUX4/NUTM1 fusions activate JAK and its downstream effector STAT1/3. We hypothesize that JAK/STAT1/3 signaling cooperates with CIC-fusions to drive CIC-sarcomas by inducing ETV1/4/5 expression. Patient-derived CRS cell lines showed elevated levels of JAK1/STAT1/3 activation compared to fusion-negative sarcoma lines. Inhibition of JAK1 using Ruxolitinib and Solicitinib reduced STAT1/3 phosphorylation, downregulated ETV1/4/5 expression at both mRNA and protein levels, and diminished ETV5 promoter activity, cell proliferation, and tumorigenicity. Although the mechanism by which CIC-fusions activate oncogenic targets is still under investigation, histone acetylation appears to play a central role. STAT1/3 interacts with p300/CBP to enhance transcription, and STAT1 is necessary for p300 acetyltransferase activity. Ruxolitinib significantly reduced histone acetylation at ETV1/4/5 promoters in hMSC cells expressing CIC-DUX4/NUTM1, as well as in CRS cell lines. Unlike the p300 inhibitor C646, which causes global hypoacetylation, Ruxolitinib’s effects were promoter-specific, indicating its potential as a more targeted and less toxic therapeutic option. Importantly, we found that STAT1/3 binds to ETV1/4/5 promoters only in the presence of CIC-fusions. Luciferase assays confirmed that STAT1/3 alone cannot activate ETV5 transcription without CIC-fusions, revealing a novel cooperative mechanism. In vivo, Ruxolitinib treatment of CRS xenografts led to significant reductions in tumor volume, STAT1/3 activation, and ETV1/4/5 expression. These findings support JAK1/STAT1/3 inhibition as a promising therapeutic strategy for CRS and warrant further preclinical investigation.

In vitro and in ovo characterization of Ewing sarcoma cell lines: Comparison with neuroblastoma cell lines and lymphatic endothelial cells.

Askin tumour is a rare primitive neuroectodermal tumour of the chest wall belonging to Ewing family of tumours. It is diagnosed on histopathology and imaged with CT and MRI. Typical symptoms include pain, dyspnoea and weight loss. Generally has an aggressive course and is often misdiagnosed as other blue cell tumours. Standard treatment is multidisciplinary; combining chemotherapy with surgery and/or radiotherapy. Here we present a few cases of Askin tumour imaging seen on Tc-99m MDP bone scan.

Abstract BACKGROUND Embryonal tumors with multilayered rosettes (ETMR) are rare and highly aggressive pediatric brain tumors, characterized by poor prognosis and a median survival below one year. Diagnostic markers include multilayered rosettes, amplification of the C19MC microRNA cluster, and elevated LIN28A expression. To improve understanding of ETMR pathogenesis and support the development of immunotherapies, immunocompetent preclinical models are urgently needed. However, such models remain scarce. This study aims to generate and characterize a novel orthotopic ETMR mouse model in an immunocompetent setting. MATERIAL AND METHODS The murine primitive neuroectodermal tumor (PNET) cell line DF1-MYC, engineered via a MYC-overexpressing RCAS system in a C57BL/6J background, was used for tumor induction. Cells and derived allografts were implanted orthotopically into the supratentorial region of four weeks old NSG (immunodeficient) and NTV-a p53^floxed (NP53) immunocompetent mice. Tumor development and survival were monitored, with survival curves calculated using the Kaplan-Meier method. Formalin-fixed, paraffin-embedded brain tissues were analyzed by hematoxylin and eosin (H&amp;E) staining, as well as immunohistochemistry for Ki67, c-Myc and Lin28a. Transcriptomic profiling was performed by RNA sequencing (RNA-seq). RESULTS Direct implantation of DF1-MYC into NP53 mice resulted in low tumor incidence, with only one small tumor exhibiting multilayered rosettes. To improve model consistency, tumors established in NSG mice were subsequently allografted into NP53 hosts. The resulting model, termed MYC384, showed 70% tumor penetrance and a median survival of 36 days. Histopathological evaluation revealed features characteristic of human ETMR, including poorly differentiated, proliferative cells with multilayered rosettes. Further molecular refinement is underway via overexpression of LIN28A and c-Myc in the MYC384 model to enhance ETMR fidelity. CONCLUSION The MYC384 model constitutes a promising immunocompetent platform for ETMR research, reproducing key histological characteristics observed in human disease. It offers a valuable resource for studying tumor biology and evaluating novel therapeutic approaches.

Background: Uterine primitive neuroectodermal tumors (PNETs) are a rare group of embryonal tumors, with less than 100 cases reported, mostly in postmenopausal women. Their rarity poses diagnostic and management challenges, contributing to high mortality. Case presentation: A 13-year-old presented with a 2-month history of abdominal pain, swelling, and heavy menstruation. Physical examination revealed a firm, fixed, nontender pelvic mass. She underwent a panhysterectomy and nodal resection. Histopathology confirmed PNET. The tumor recurred within a month, and intraoperative spillage occurred during repeat surgery. She developed obstructive uropathy and succumbed approximately 11 months after initial presentation. Conclusion: Uterine PNETs are aggressive tumors that rapidly infiltrate and obstruct pelvic structures. Owing to their rarity, diagnosis and management remain challenging, with high mortality. Keywords: embryonal tumors, obstructive uropathy, primitive neuroectodermal tumor, uterus

Embryonic-type neuroectodermal tumor (ENT; previously referred to as primitive neuroectodermal tumor, PNET) of the testis and gynecologic tract share morphologic features with small round blue cell tumors, including Ewing sarcoma (ES), yet are biologically, therapeutically, and prognostically distinct. The diagnosis of ENT can be challenging, and it is unclear if there are reliable biomarkers that can be used to confirm this diagnosis. This study characterized 50 ENTs arising from the testis (n=38) and gynecologic tract (n=12; 7 ovary/5 uterus) with 27 biomarkers (AE1/AE3, ATRX, CD99, chromogranin-A, Cyclin D1, Fli-1, GFAP, GLUT-1, IDH1/2, INSM1, MTAP, NANOG, Nestin, neurofilament, NKX2.2, NSE, OCT3/4, OLIG2, p16, PAX6, PHOX2B, S100, SALL4, SOX2, SOX10, SOX17, synaptophysin). Expression was evaluated for extent (0, negative; 1, ≤10% positive; 2, 11% to 50% positive; 3, >50% positive) and intensity (1, weak; 2, moderate; 3, strong) of staining to obtain a combined score (CS) of 0-9; a CS ≥4 was considered "significant staining." SOX2 was the most sensitive biomarker for ENT, as 85% of the tumors demonstrated CS=9. GLUT-1, Fli-1, SALL4, and Cyclin D1 also showed CS ≥4 in more than half of the ENTs; however, only a minority demonstrated CS=9. All other biomarkers showed CS ≥4 in fewer than half of the ENTs, including synaptophysin (38%), GFAP (15%), S100 (15%), and chromogranin-A (14%). NKX2.2, CD99, and SOX17 showed CS ≥4 in 7%, 0%, and 3% of tumors, respectively. Overall, we found that in the appropriate clinicopathologic context, utilizing a panel of SOX2, OCT3/4 (to exclude embryonal carcinoma), AE1/AE3, NKX2.2, CD99, and SOX17 could be helpful in the diagnosis of ENT; many other traditional diagnostic biomarkers show limited utility.

BackgroundThe 2021 WHO Classification of Tumors of the Central Nervous System, 5th edition (WHO CNS5), introduced revised diagnostic criteria for pediatric brain tumors (BTs), redefining pediatric-type diffuse high-grade gliomas (pHGGs) into 4 subtypes: diffuse midline glioma, H3 K27-altered (DMG-H3K27), diffuse hemispheric glioma, H3 G34-mutant (DHG-H3G34), diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype (DpHGG-H3wt/IDHwt), and infant-type hemispheric glioma (IHG). This study revisits prior diagnoses of HGGs and primitive neuroectodermal tumors (PNETs) in children and incorporates next-generation sequencing (NGS) to classify tumors according to the revised criteria and analyze their clinicogenomic characteristics and outcomes.MethodsA retrospective review of pediatric patients diagnosed with glioblastoma (GBM), anaplastic astrocytoma, anaplastic oligoastrocytoma (AOA), gliomatosis cerebri, or PNET between 1997 and 2023 was conducted. Cases underwent pathology review, immunohistochemistry (IHC), and BT-targeted NGS for reclassification per WHO CNS5. An additional 20 patients diagnosed with pHGG via genetics-integrated diagnosis since 2020 were included. Clinical characteristics, genomic alterations, and outcomes were analyzed.ResultsAmong the 78 reviewed cases, 41 were reclassified as pHGGs. TP53 mutations were the most prevalent, particularly in DpHGG-H3wt/IDHwt, which showed associations with cancer predisposition syndrome (CPS). Two patients with Li-Fraumeni syndrome (LFS) developed DpHGG-H3wt/IDHwt adjacent to prior radiation fields. The 2-year overall survival (OS) rates were lowest in DpHGG-H3wt/IDHwt (23.2%) and highest in IHG (92.3%). Long-term survival was observed in IHG patients, with a 5-year OS rate of 73.8%, indicating the need for different adjuvant treatment strategies compared to other pHGGs.ConclusionsBT-targeted NGS facilitates the reclassification of pHGGs, revealing associations with CPS. Routine germline sequencing is warranted, and accurate molecular diagnosis enables a shift in treatment strategies tailored to specific pHGG subtypes.

Ewing sarcoma is a relatively rare aggressive tumor of bones and soft tissues characterized by specific chromosomal translocations involving genes and transcription factors of the FET and ETS families. A number of studies have demonstrated the presence of molecular genetic events preceding these specific rearrangements.The article presents a clinical observation of the treatment of a 24-year-old patient with Ewing sarcoma of the X rib and CHEK2-associated cancer predisposition syndrome with an oncologically burdened family history, including Ewing sarcoma in a first-degree relative. Specific translocation of the EWSR1 gene (22q12) was identified, characteristic of tumors of the Ewing sarcoma/PNET (primitive neuroectodermal tumors) family, as well as 59 variants of different functional significance in suppressor genes and driver genes was identified in the course of a comprehensive molecular genetic study using fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) with a targeted custom panel including 415 genes involved in carcinogenesis. The patient underwent combined treatment in the volume of neoadjuvant polychemotherapy, surgical stage (extirpation of the X rib with plastic surgery) and subsequent adjuvant polychemotherapy. During dynamic observation for the period 2022–2025, there were no signs of progression and metastatic process. Molecular genetic profiling in Ewing sarcoma has identified markers that may act as risk modifiers for disease development and progression, determine sensitivity/resistance to standard treatment methods, and serve as potential targets for personalized treatment.

ABSTRACTLarge circumferential tumors encasing the heart are exceedingly rare, and the differential diagnosis include primary pericardial sarcomas, non‐Hodgkin lymphoma, pericardial primitive neuroectodermal tumor, primary pericardial mesothelioma, and exceptionally mature benign lipoma. Lipomas are rare primary heart tumors. Most are epicardial in origin, although they may arise in the myocardium. They are usually soft masses of mature fat tissue encapsulated by a thin layer of fibrous tissue. Signs and symptoms depend on the tumor's location and size, however in several case they are found incidentally at cardiac imaging. In this 48‐year‐old woman referred to the emergency department for severe intestinal bleeding, echocardiography showed a large circumferential hypoechogenic space, and CT confirmed a large mediastinal fat mass encasing the heart. Multimodal imaging allowed differential diagnosis confirmed by histologic examination performed at surgery.

Case report and review of the literature regarding management of primary uterine primitive neuroectodermal tumors (PNET).

Abstract Ewing's sarcoma is an uncommon and highly metastatic form of sarcoma affecting children and young adults, occurring in approximately 1 in 1.5 million individuals, with a predominance in males. We present an exceptionally unique case highlighting Ewing's sarcoma metastasis to the peritoneum and omentum, identified through an 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) scan and its unforeseen treatment response. In contrast to previously published literature concerning primary peritoneal primitive neuroectodermal tumors, this exceedingly notable instance illuminates the occurrence of metastatic Ewing's sarcoma within the peritoneum, as opposed to originating as a primary tumor within the peritoneum, revealing diagnostic intricacies. This case accentuates several pivotal learning points that enhance our understanding of Ewing's sarcoma. Also, the noteworthy high sensitivity and specificity of 18F-FDG PET/CT allow for early detection of recurrence and treatment response, substantially improving prognosis in Ewing's sarcoma patients, aiding in timely therapeutic interventions and optimizing patient outcomes.