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Nature Reviews. Cancer Oct 2020Epigenetic regulation is critical to physiological control of development, cell fate, cell proliferation, genomic integrity and, fundamentally, transcriptional... (Review)
Review
Epigenetic regulation is critical to physiological control of development, cell fate, cell proliferation, genomic integrity and, fundamentally, transcriptional regulation. This epigenetic control occurs at multiple levels including through DNA methylation, histone modification, nucleosome remodelling and modulation of the 3D chromatin structure. Alterations in genes that encode chromatin regulators are common among mesenchymal neoplasms, a collection of more than 160 tumour types including over 60 malignant variants (sarcomas) that have unique and varied genetic, biological and clinical characteristics. Herein, we review those sarcomas in which chromatin pathway alterations drive disease biology. Specifically, we emphasize examples of dysregulation of each level of epigenetic control though mechanisms that include alterations in metabolic enzymes that regulate DNA methylation and histone post-translational modifications, mutations in histone genes, subunit loss or fusions in chromatin remodelling and modifying complexes, and disruption of higher-order chromatin structure. Epigenetic mechanisms of tumorigenesis have been implicated in mesenchymal tumours ranging from chondroblastoma and giant cell tumour of bone to chondrosarcoma, malignant peripheral nerve sheath tumour, synovial sarcoma, epithelioid sarcoma and Ewing sarcoma - all diseases that present in a younger patient population than most cancers. Finally, we review current and potential future approaches for the development of sarcoma therapies based on this emerging understanding of chromatin dysregulation.
Topics: Animals; Biomarkers, Tumor; Cell Transformation, Neoplastic; Chromatin; Chromatin Assembly and Disassembly; DNA Methylation; Epigenesis, Genetic; Epigenomics; Gene Expression Regulation, Neoplastic; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Sarcoma
PubMed: 32782366
DOI: 10.1038/s41568-020-0288-4 -
Indian Journal of Otolaryngology and... Dec 2022Mass lesions of the larynx are one of the most common clinical entity which we come across in routine otorhinolaryngology and head neck practice with varied...
Mass lesions of the larynx are one of the most common clinical entity which we come across in routine otorhinolaryngology and head neck practice with varied symptomatology. Among all the mass lesions of the larynx, Epithelial neoplasms constitute up to 97%. Mesenchymal tumours of the larynx constitute only 0.3-1.0% of all the laryngeal tumors. Abundance of cartilage structures in the larynx made it a spot for mesenchymal tumors [chondromas and chandrosacrcomas]. The spectrum of mesenchymal neoplasms can vary from chondromas, chondroblastoma to chondrosarcoma. Here we want to share our experience of a mesenchymal tumour of the larynx. This case is reported for the rarity and ambiguity in diagnosis. Though these are slow-growing tumours with an early presentation, in our case, the patient had a supportive tracheostomy without definitive treatment for more than 2 years. We managed this patient by excising the mass by lateral pharyngotomy with the preservation of larynx followed by successful Decannulation in 20 days.
PubMed: 36742506
DOI: 10.1007/s12070-020-02308-8 -
Seminars in Diagnostic Pathology May 2021The SWItch Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex is a large multi-subunit protein assembly that orchestrates chromatin compaction and... (Review)
Review
The SWItch Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex is a large multi-subunit protein assembly that orchestrates chromatin compaction and accessibility for gene transcription in an ATP-dependent manner. As a key epigenetic regulator, the SWI/SNF complex coordinates gene expression, cell proliferation and differentiation, and its biologic functions, in part, antagonize the polycomb repressive complex 2. The mammalian SWI/SNF complex consists of 15 subunits encoded by 29 genes, some of which are recurrently mutated in human cancers, in the germline or sporadic setting. Most SWI/SNF-deficient tumors share common "rhabdoid" cytomorphology. SMARCB1 (INI1) is the subunit most frequently inactivated in soft tissue neoplasms. Specifically, SMARCB1 deficiency is observed as the genetic hallmark in virtually all malignant rhabdoid tumors, and most cases of epithelioid sarcoma and poorly differentiated chordoma. In addition, subsets of myoepithelial carcinoma (10-40%), extraskeletal myxoid chondrosarcoma (20%), epithelioid schwannoma (40%), and epithelioid malignant peripheral nerve sheath tumor (70%) demonstrate SMARCB1 loss. The gene encoding the SS18 subunit is involved in the SS18-SSX rearrangement, which is pathognomonic of synovial sarcoma and indirectly inactivates SMARCB1. Finally, undifferentiated SMARCA4-deficient thoracic sarcomas are defined by SMARCA4 subunit inactivation, leading to SMARCA4 and SMARCA2 loss. Rarely, inactivation of alternate but biologically equivalent key regulators can substitute for canonical subunit deficiency, such as SMARCA4 inactivation in cases of SMARCB1-retained epithelioid sarcoma. This review briefly highlights SWI/SNF complex biologic functions and its roles in human cancer and provides a detailed update on recent advances in soft tissue neoplasms with canonical SWI/SNF complex deficiency, correlating morphologic, genomic, and immunohistochemical findings.
Topics: Chromosomal Proteins, Non-Histone; DNA Helicases; Humans; Immunohistochemistry; Nuclear Proteins; Rhabdoid Tumor; Soft Tissue Neoplasms; Sucrose; Transcription Factors
PubMed: 32646614
DOI: 10.1053/j.semdp.2020.05.005 -
Cancers Sep 2023Mesenchymal chondrosarcoma (MCS) is a rare subtype of chondrosarcoma with a poor prognosis. Although these tumors are sensitive to radiotherapy/chemotherapy, the... (Review)
Review
Mesenchymal chondrosarcoma (MCS) is a rare subtype of chondrosarcoma with a poor prognosis. Although these tumors are sensitive to radiotherapy/chemotherapy, the standard treatment for localized MCS is only surgical resection, and there are no established treatment guidelines for patients with advanced and metastatic MCS. Due to the low incidence of MCS, the pathology of these tumors is still unknown, and other therapeutic options are lacking. Some studies show the potential role of the PDGF/PPI3K/AKT, PKC/RAF/MEK/ERK, and pRB pathways, and BCL2 overexpression in the pathogenesis of MCS. These findings provide an opportunity to use protein kinases and BCL2 inhibitors as potential therapy in MCS. In this review, we summarize the current knowledge about MCS diagnosis and treatment options. We show the immunological and molecular biomarkers used in the diagnosis of MCS. In addition, we discuss the known prognostic and predictive factors in MCS. Finally, we present the novel trends, including targeted therapies and ongoing clinical trials using protein kinase inhibitors and the death receptor 5 (DR5) agonist, which may be the focus of future MCS treatment studies.
PubMed: 37760551
DOI: 10.3390/cancers15184581 -
Skeletal Radiology Feb 2021To describe imaging and clinical features of primary mesenchymal chondrosarcoma (MCS) and evaluate for presence of a distinct biphasic pattern on imaging.
OBJECTIVE
To describe imaging and clinical features of primary mesenchymal chondrosarcoma (MCS) and evaluate for presence of a distinct biphasic pattern on imaging.
MATERIAL AND METHODS
Patients with a pathologic diagnosis of MCS were identified along with imaging of their primary tumor. Size, location, appearance (lytic, sclerotic, or mixed), presence, extent and distribution of calcifications, cortical destruction, soft tissue extension, periosteal reaction, contrast enhancement, and radiotracer uptake were recorded. The presence of T2-hyperintense tumor lobules on MRI and a biphasic morphology (distinct calcified and non-calcified components) on CT were assessed. Presence and location of metastases were documented.
RESULTS
Twenty-three patients (mean age 28.0 ± 13.8 years) were reviewed (13 skeletal, 10 extraskeletal). Overall mean tumor size was 10.2 ± 7.2 cm, 7.1 ± 7.3 cm in non-metastatic and 13.2 ± 5.9 cm (p = 0.004) in metastatic cases. Locations were extremities (n = 11), head/neck (n = 4), chest wall (n = 4), pelvis (n = 3), and retroperitoneum (n = 1). Skeletal MCS were aggressive mixed lytic and sclerotic (n = 8), purely lytic (n = 4), or juxtacortical (n = 1) lesions with cortical destruction and soft tissue extension. Chondroid calcifications were common (80%). On MRI, the presence of T2-hyperintense lobules was seen in 35%. A biphasic morphology on imaging was seen in 30%. Metastases were common (52%) with the most common site being the lungs (75%). All tumors were hypermetabolic with a mean SUVmax of 14.3 (5.6-34) on PET/CT.
CONCLUSION
Skeletal MCS commonly present as aggressive lytic bone lesions with chondroid calcifications. A biphasic morphology was seen in one-third of cases. Metastases were common at initial presentation and more commonly seen with larger tumors.
Topics: Adolescent; Adult; Bone Neoplasms; Chondrosarcoma; Chondrosarcoma, Mesenchymal; Humans; Magnetic Resonance Imaging; Positron Emission Tomography Computed Tomography; Retrospective Studies; Young Adult
PubMed: 32734374
DOI: 10.1007/s00256-020-03558-x -
Diagnostics (Basel, Switzerland) Mar 2022Mesenchymal chondrosarcoma is an uncommon malignant mesenchymal tumor with an aggressive behavior. Diagnoses of mesenchymal chondrosarcoma are established based on...
Mesenchymal chondrosarcoma is an uncommon malignant mesenchymal tumor with an aggressive behavior. Diagnoses of mesenchymal chondrosarcoma are established based on histomorphological, immunohistochemical, and molecular findings. Only one case of extraskeletal mesenchymal chondrosarcoma (EMC) of the uterus has been reported. This article presents the second case of primary uterine EMC, occurring in a 33-year-old woman. We describe the histological and immunophenotypical features of EMC. Our observations will help pathologists and clinicians perform accurate histological diagnoses of uterine EMC and plan appropriate treatment strategies for this rare tumor.
PubMed: 35328196
DOI: 10.3390/diagnostics12030643 -
Cancers May 2022Bone sarcomas are rare primary malignant mesenchymal bone tumors. The three main entities are osteosarcoma, chondrosarcoma, and Ewing sarcoma. While prognosis has... (Review)
Review
Bone sarcomas are rare primary malignant mesenchymal bone tumors. The three main entities are osteosarcoma, chondrosarcoma, and Ewing sarcoma. While prognosis has improved for affected patients over the past decades, bone sarcomas are still critical conditions that require an interdisciplinary diagnostic and therapeutic approach. While radiotherapy plays a role especially in Ewing sarcoma and chemotherapy in Ewing sarcoma and osteosarcoma, surgery remains the main pillar of treatment in all three entities. After complete tumor resection, the created bone defects need to be reconstructed. Possible strategies are implantation of allografts or autografts including vascularized bone grafts (e.g., of the fibula). Around the knee joint, rotationplasty can be performed or, as an alternative, the implantation of (expandable) megaprostheses can be performed. Challenges still associated with the implantation of foreign materials are aseptic loosening and infection. Future improvements may come with advances in 3D printing of individualized resection blades/implants, thus also securing safe tumor resection margins while at the same time shortening the required surgical time. Faster osseointegration and lower infection rates may possibly be achieved through more elaborate implant surface structures.
PubMed: 35681674
DOI: 10.3390/cancers14112694