Small round cell sarcoma tumoroid biobank reveals CIC::DUX4 sarcoma vulnerability to MCL-1 inhibition.

Small round cell sarcomas (SRCS) are highly aggressive tumors in soft tissues and bone of mostly children and young adults. Despite being different in many aspects, including genetics, possible cell-of-origin, and pathology, patients with any of these entities all receive the same therapeutic regimen. Although several pre-clinical models of Ewing sarcoma have been established, such as cell lines and patient-derived tumor xenografts, few models exist for other SRCS.

The Role of Radiotherapy in MPNST and the Impact of NF1 Status on Outcomes: Insights From A Multicenter Cohort Study.

Background: Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are rare, aggressive sarcomas, with 40% associated with neurofibromatosis type 1 (NF1). Surgical excision is the main treatment for localized disease, however, local recurrence (LR) remains high. Radiotherapy (RTx) is increasingly used to enhance local control in STS, but its use remains controversial due to the potential for increased major wound complications and an increased risk of secondary malignancies in NF1 patients.

Cemiplimab in Locally Advanced or Metastatic Secondary Angiosarcomas (CEMangio): A Phase II Clinical Trial and Biomarker Analyses.

Purpose: Angiosarcomas (AS) are rare vascular sarcomas. Secondary AS (sAS) arise from DNA-damaging factors such as radiotherapy and UV radiation (UV-AS) or due to chronic lymphedema. The prognosis for advanced AS is poor, with limited treatment options.

Advancing sarcoma diagnostics with expanded DNA methylation-based classification.

Purpose: Sarcomas pose a severe diagnostic challenge. A wide variety of these distinct entities need to be distinguished from each other and from less aggressive types of mesenchymal tumors, to ensure correct clinical management. A machine learning based classifier for sarcomas utilizing DNA methylation data from 1077 tumors recognizing 62 sarcoma types has already been developed and termed the sarcoma classifier, which we published in 2021.

Prognostic Value of the G2 Expression Signature and MYC Overexpression in Childhood High-Grade Osteosarcoma.

Purpose: In high-grade osteosarcoma, prognostic factors at diagnosis are insufficient for stratifying patients into relevant subgroups. Recently, a transcriptomic study developed the G1/G2 gene expression signature, in which the G2 signature was associated with unfavorable survival. An orthogonal study identified amplification as an unfavorable prognostic factor using targeted next-generation sequencing.

Atypical spindle cell/pleomorphic lipomatous tumour: a clinicopathologic, immunohistochemical and molecular study of 55 cases, highlighting TP53 gene alterations as a genetic hallmark of atypical pleomorphic lipomatous tumour.

Aims: Atypical spindle cell lipomatous tumour (ASLT) and atypical pleomorphic lipomatous tumour (APLT) have been grouped together under the umbrella designation atypical spindle cell/pleomorphic lipomatous tumour (ASPLT) in the 2020 edition of the World Health Organization (WHO) Classification of Soft Tissue and Bone Tumours. They are thought to exist on a morphologic spectrum and share similar clinicopathologic and biological characteristics. The aim of this study was to further explore the genetic background of ASLTs and APLTs by employing DNA-based next-generation sequencing and immunohistochemistry, with a specific focus on the TP53 gene.

Dermatomyofibromas harbor PDGFRB mutations - another tyrosine kinase-driven neoplasm.

Platelet-derived growth factor receptor beta (PDGFRB) is one of the numerous members of the receptor tyrosine kinase protein family. When altered, it is known to be the driver mutation in different mesenchymal neoplasms, such as pericytic tumors, inflammatory myofibroblastic tumor, and sarcomas with myogenic differentiation. We investigated seven dermatomyofibromas for the presence of a PDGFRB mutation.

The Histological Spectrum of DICER1-Associated Neoplasms.

syndrome is a heterogeneous cancer predisposition syndrome, characterized by a large variety of benign and malignant tumor types, and caused by germline heterozygous pathogenic variants in the gene, which is essential in miRNA processing and RNA interference. The clinical manifestations are diverse, with pleuropulmonary blastoma, Sertoli-Leydig cell tumor, cystic nephroma, uterine cervical embryonal rhabdomyosarcoma, and thyroid follicular nodular disease being the most prevalent tumor types. Since these neoplasms are rare and particularly occur in the pediatric population, pathologists should be aware of the potential relationship of these tumors with an underlying syndrome in order to perform or suggest additional molecular pathologic analysis and refer patients and their parents for genetic counseling and testing.

Detection of PRKAR1A gene mutations in sporadic cardiac myxomas: a study of 24 cases.

The benign neoplasm cardiac myxoma represents one of the hallmarks of Carney complex (CNC), a familial multiple neoplasia syndrome. About 80% of the index cases have germline mutations in PRKAR1A encoding the RIα regulatory subunit of cAMP-dependent protein kinase A (PKA). However, the role of PRKAR1A gene mutations in the pathogenesis of non-CNC-associated sporadic cardiac myxoma is less well established.

Classification of Fibro-Osseous Tumors in the Craniofacial Bones Using DNA Methylation and Copy Number Alterations.

Fibro-osseous tumors of the craniofacial bones are a heterogeneous group of lesions comprising cemento-osseous dysplasia (COD), cemento-ossifying fibroma (COF), juvenile trabecular ossifying fibroma (JTOF), psammomatoid ossifying fibroma (PsOF), fibrous dysplasia (FD), and low-grade osteosarcoma (LGOS) with overlapping clinicopathological features. However, their clinical behavior and treatment differ significantly, underlining the need for accurate diagnosis. Molecular diagnostic markers exist for subsets of these tumors, including GNAS mutations in FD, SATB2 fusions in PsOF, mutations involving the RAS-MAPK signaling pathway in COD, and MDM2 amplification in LGOS.

M&M: an RNA-seq based pan-cancer classifier for paediatric tumours.

Background: With many rare tumour types, acquiring the correct diagnosis is a challenging but crucial process in paediatric oncology. Historically, this is done based on histology and morphology of the disease. However, advances in genome wide profiling techniques such as RNA sequencing now allow the development of molecular classification tools.

Survival after resection of malignant peripheral nerve sheath tumors: Introducing and validating a novel type-specific prognostic model.

Background: This study aimed to assess the performance of currently available risk calculators in a cohort of patients with malignant peripheral nerve sheath tumors (MPNST) and to create an MPNST-specific prognostic model including type-specific predictors for overall survival (OS).

Methods: This is a retrospective multicenter cohort study of patients with MPNST from 11 secondary or tertiary centers in The Netherlands, Italy and the United States of America. All patients diagnosed with primary MPNST who underwent macroscopically complete surgical resection from 2000 to 2019 were included in this study.

Spindle Cell Lesions with Oncogenic EGFR Kinase Domain Aberrations: Expanding the Spectrum of Protein Kinase-Related Mesenchymal Tumors.

EGFR aberrations are reported in a subset of myofibroblastic lesions with kinase domain duplication (EGFR-KDD) and exon 20 mutations being assigned to infantile fibrosarcomas (IFS), mesoblastic nephroma, and fibrous hamartoma of infancy (FHI), respectively. In this retrospective study, we correlated molecular findings with the histomorphology of 14 myofibroblastic lesions harboring such genetic changes identified by NGS. We additionally performed DNA methylation profiling (DNAmp) and immunohistochemistry.

Small cell osteosarcoma versus fusion-driven round cell sarcomas of bone: retrospective clinical, radiological, pathological, and (epi)genetic comparison with clinical implications.

Small cell osteosarcoma (SCOS), a variant of conventional high-grade osteosarcoma (COS), may mimic fusion-driven round cell sarcomas (FDRCS) by overlapping clinico-radiological and histomorphological/immunohistochemical characteristics, hampering accurate diagnosis and consequently proper therapy. We retrospectively analyzed decalcified formalin-fixed paraffin-embedded (FFPE) samples of 18 bone tumors primarily diagnosed as SCOS by methylation profiling, fusion gene analysis, and immunohistochemistry.In eight cases, the diagnosis of SCOS was maintained, and in 10 cases it was changed into FDRCS, including three Ewing sarcomas (EWSR1::FLI1 in two cases and no identified fusion gene in the third case), two sarcomas with BCOR alterations (KMT2D::BCOR, CCNB3::BCOR, respectively), three mesenchymal chondrosarcomas (HEY1::NCOA2 in two cases and one case with insufficient RNA quality), and two sclerosing epithelioid fibrosarcomas (FUS::CREBL3 and EWSR1 rearrangement, respectively).

Prognostic Factors in Epithelioid Hemangioendothelioma: Analysis of a Nationwide Molecularly/Immunohistochemically Confirmed Cohort of 57 Cases.

Epithelioid hemangioendothelioma (EHE) is an extremely rare vascular sarcoma with variable aggressive clinical behavior. In this retrospective study, we aimed to investigate prognostic factors based on clinicopathologic findings in a molecularly/immunohistochemically confirmed nationwide multicenter cohort of 57 EHE cases. Patients had unifocal disease ( = 29), multifocal disease ( = 5), lymph node metastasis ( = 8) and/or distant metastasis ( = 15) at the time of diagnosis.

The Prognostic Relevance of MRI Characteristics in Myxofibrosarcoma Patients Treated with Neoadjuvant Radiotherapy.

To improve local control, neoadjuvant radiotherapy (nRT) followed by surgery is the standard of care in myxofibrosarcoma (MFS) because of its infiltrative growth pattern. Nevertheless, local recurrence rates are high. Data on prognostic factors for poor clinical outcomes are lacking.

Insertion of the CXXC domain of KMT2A into YAP1: An unusual mechanism behind the formation of a chimeric oncogenic protein.

Most neoplasia-associated gene fusions are formed through the fusion of the 5'-part of one gene with the 3'-part of another. We here describe a unique mechanism, by which a part of the KMT2A gene through an insertion replaces part of the YAP1 gene. The resulting YAP1::KMT2A::YAP1 (YKY) fusion was verified by RT-PCR in three cases of sarcoma morphologically resembling sclerosing epithelioid fibrosarcoma (SEF-like sarcoma).

Clinical differences in sirolimus treatment with low target levels between children and adults with vascular malformations - A nationwide trial.

The clinical presentation of patients with slow-flow vascular malformations is very heterogeneous. High clinical burden and subsequent reduced health-related quality of life is something they have in common. There is an unmet medical need for these patients for whom regular treatments like surgery and embolization are either insufficient or technically impossible.

Establishment and characterization of the first patient-derived radiation-induced angiosarcoma xenograft model (RT-AS5).

Angiosarcomas are a heterogeneous group of rare endothelial malignancies with a complex, not completely unravelled biology. They encompass primary (sporadically occurring) angiosarcomas of several origins and secondary angiosarcomas, which often arise due to DNA damaging factors including radiotherapy or ultraviolet light exposure. The optimal treatment of metastatic angiosarcomas is unclear and the prognosis is poor.