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Osteoid osteoma and osteoblastoma. a Osteoid osteoma. b Osteoblastoma show identical morphology at haematoxylin and eosin staining, with deposition of woven bone by osteoblast-like tumour cells. c Fluorescence in situ hybridization (FISH) showing FOS rearrangement in osteoblastoma. d Immunohistochemical staining for FOS in osteoblastoma showing nuclear overexpression in the tumour cells. Scale bar is 50 μm
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Bone tumours are difficult to diagnose and treat, as they are rare and over 60 different subtypes are recognised. The emergence of next-generation sequencing has partly elucidated the molecular mechanisms behind these tumours, including the group of bone forming tumours (osteoma, osteoid osteoma, osteoblastoma and osteosarcoma). Increased knowledge...
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... By CNV analysis, the SCOSs harbored an extensive aberrant genome similar to the morphologically classical COSs, in line with the literature reporting a complex aneuploid karyotype as well as random translocations and mutations in most cases [5,15]. Round cell sarcomas, on the other hand, usually have a simple karyotype and fusion gene-related translocations leading to chimeric oncoproteins with dysregulated transcription [5,20]. Affected cells of the latter might be derived from multipotent precursor cells, giving the opportunity to arise in any part of the body [21]. ...
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).
Histologically, SCOS usually possessed more pleomorphic cells in contrast to the FDRCS showing mainly monomorphic cellular features. However, osteoid was seen in the latter tumors as well, often associated with slight pleomorphism. Also, the immunohistochemical profile (CD99, SATB2, and BCOR) overlapped.
Clinically and radiologically, similarities between SCOS and FDRCS were observed, with by imaging only minimal presence or lack of (mineralized) osteoid in most of the SCOSs.
In conclusion, discrimination of SCOS, epigenetically related to COS, versus FDRCS of bone can be challenging but is important due to different biology and therefore therapeutic strategies. Methylation profiling is a reliable and robust diagnostic test especially on decalcified FFPE material. Subsequent fusion gene analysis and/or use of specific immunohistochemical surrogate markers can be used to substantiate the diagnosis.
... OS presents an aggressive clinical course with a high propensity for metastasis, especially in the lung [4,5]. Metastatic tumors are resistant to treatment, with a significant decrease in the survival rate [5,6]. These tumors most commonly develop near growth plates at the extremities of lower long bones such as the femur, but can also occur in other regions, including the jaw, humerus, pelvis, and tibia [5,7,8]. ...
... The networks also highlighted genes such as CREBBP, ITGA2/3, PRKACA, TP53, AKT1, ITGAM, ITGB2, NTRK1, RB1, CDC42, CDK4, FOS, IRF3, HIF1A, and CCND2, which act in processes including cell cycle regulation, metabolism, immune response, response to stress, differentiation, adhesion, and cell death. Several similar biological pathways have been previously found to be disrupted in OSs, such as pRb, p53, IGF, MAPK, MEK-ERK, mTOR, Notch, SHH, SMAD3, TGF-β, Wnt, and ALT [6,13,[68][69][70]. Considering the biological context of disease onset, it is not surprising that alterations in cell growth, communication, differentiation, fate, and immune factors may contribute to the oncogenic development of OS [6,13,71]. ...
... Several similar biological pathways have been previously found to be disrupted in OSs, such as pRb, p53, IGF, MAPK, MEK-ERK, mTOR, Notch, SHH, SMAD3, TGF-β, Wnt, and ALT [6,13,[68][69][70]. Considering the biological context of disease onset, it is not surprising that alterations in cell growth, communication, differentiation, fate, and immune factors may contribute to the oncogenic development of OS [6,13,71]. ...
Osteosarcoma (OS) is the most prevalent type of bone tumor, but slow progress has been achieved in disentangling the full set of genomic events involved in its initiation and progression. We assessed by NGS the mutational spectrum of 28 primary OSs from Brazilian patients, and identified 445 potentially deleterious SNVs/indels and 1176 copy number alterations (CNAs). TP53 was the most recurrently mutated gene, with an overall rate of ~60%, considering SNVs/indels and CNAs. The most frequent CNAs (~60%) were gains at 1q21.2q21.3, 6p21.1, and 8q13.3q24.22, and losses at 10q26 and 13q14.3q21.1. Seven cases presented CNA patterns reminiscent of complex events (chromothripsis and chromoanasynthesis). Putative RB1 and TP53 germline variants were found in five samples associated with metastasis at diagnosis along with complex genomic patterns of CNAs. PTPRQ, KNL1, ZFHX4, and DMD alterations were prevalent in metastatic or deceased patients, being potentially indicative of poor prognosis. TNFRSF11B, involved in skeletal system development and maintenance, emerged as a candidate for osteosarcomagenesis due to its biological function and a high frequency of copy number gains. A protein–protein network enrichment highlighted biological pathways involved in immunity and bone development. Our findings reinforced the high genomic OS instability and heterogeneity, and led to the identification of novel disrupted genes deserving further evaluation as biomarkers due to their association with poor outcomes.
... OS has a complex karyotype, and the molecular mechanisms related to carcinogenesis, progression and resistance to therapy are still largely unknown. The cause of the high genomic instability has been hypothesized to be chromothripsis, i.e., 'the shattering of one or a few chromosomes into small fragments that are stitched together in a random order and orientation', which occurs in about 30% of OSs [8]. Chromothripsis may be caused by physical chromosomal damage (e.g., ionizing radiation) or by the progressive shortening after many cell divisions of telomeres, which are responsible for maintaining the genomic integrity in normal cells. ...
Conventional high-grade osteosarcoma (OS) is the most common primary cancer of bone and it typically affects the extremities of adolescents. OS has a complex karyotype, and molecular mechanisms related to carcinogenesis, progression and resistance to therapy are still largely unknown. For this reason, the current standard of care is associated with considerable adverse effects. In this study, our aim was to identify gene alterations in OS patients using whole exome sequencing (WES) to find new potential prognostic biomarkers and therapeutic targets. We performed WES on formalin-fixed paraffin-embedded (FFPE) biopsy materials collected from 19 patients affected by conventional high-grade OS. The clinical and genetic data were analyzed according to response to therapy, presence of metastasis and disease status. By comparing good and poor responders to neoadjuvant therapy, we detected a clear prevalence of mutations in the ARID1A, CREBBP, BRCA2 and RAD50 genes in poor responders that negatively influence the progression-free survival time. Moreover, higher tumor mutational burden values correlated with worse prognosis. The identification of mutations in ARID1A, CREBBP, BRCA2 and RAD50 may support the use of a more specific therapy for tumors harboring these alterations. In particular, BRCA2 and RAD50 are involved in homologous recombination repair, and could thus be used as specific therapy targets of inhibitors of the enzyme Poly ADP Ribose Polymerase (PARP). Finally, tumor mutational burden is found to be a potential prognostic marker for OS.
... In agreement with the fact that OS arises more commonly during puberty, several genes and signaling pathways involved with bone growth and remodeling have been associated with the disease. Recurrent somatic point mutations include ATRX, BRCA1/2, PTEN, RB1, and TP53, although most osteosarcomas are characterized by a high genomic instability that is likely to play a significant role in their pathogenesis (Rickel et al. 2017;Franceschini et al. 2020). In addition, these tumors present a highly heterogeneous pattern of somatic copynumber alterations (CNA), including 1p, 1q, 5p, 6p, 8q, 17p, and 18p gains, MYC, CCNE1, COPS3, CDK4, MDM2, AKT, and RECQL4 amplifications, and 3, 5q, 6q, 8p, 9, 10, 13, 16, 17, 18q, and 19 losses, including TP53, RB1, DLG2, PTEN, ATRX, and CDKN2A deletions (Franceschini et al. 2020;Tirtei et al. 2020). ...
... In addition, these tumors present a highly heterogeneous pattern of somatic copynumber alterations (CNA), including 1p, 1q, 5p, 6p, 8q, 17p, and 18p gains, MYC, CCNE1, COPS3, CDK4, MDM2, AKT, and RECQL4 amplifications, and 3, 5q, 6q, 8p, 9, 10, 13, 16, 17, 18q, and 19 losses, including TP53, RB1, DLG2, PTEN, ATRX, and CDKN2A deletions (Franceschini et al. 2020;Tirtei et al. 2020). Nevertheless, some tumors exhibit complex chromosomal phenomena, such as kataegis and chromothripsis (Perry et al. 2014;Franceschini et al. 2020). ...
... It is possible that at least part of the DMRs' hypomethylation was induced by the unbalance between copy-number gains and the reestablishment of original DNA methylation patterns. Both mutational processes are associated with high genomic instability (Pfeifer 2018;de Azevedo et al. 2020;Franceschini et al. 2020). Furthermore, several genes related to DNA damage response and repair, such as BAP1, BRCA1, BRCA2, PALB2, PARP1, PTEN, RB1, SETD2, and TP53, presented copy-number losses or loss-of-function mutations (but no differential methylation), although these pathways were not enriched in our analyses. ...
DNA methylation may be involved in the development of osteosarcomas. Osteosarcomas commonly arise during the bone growth and remodeling in puberty, making it plausible to infer the involvement of epigenetic alterations in their development. As a highly studied epigenetic mechanism, we investigated DNA methylation and related genetic variants in 28 primary osteosarcomas aiming to identify deregulated driver alterations. Methylation and genomic data were obtained using the Illumina HM450K beadchips and the TruSight One sequencing panel, respectively. Aberrant DNA methylation was spread throughout the osteosarcomas genomes. We identified 3146 differentially methylated CpGs comparing osteosarcomas and bone tissue samples, with high methylation heterogeneity, global hypomethylation and focal hypermethylation at CpG islands. Differentially methylated regions (DMR) were detected in 585 loci (319 hypomethylated and 266 hypermethylated), mapped to the promoter regions of 350 genes. These DMR genes were enriched for biological processes related to skeletal system morphogenesis, proliferation, inflammatory response, and signal transduction. Both methylation and expression data were validated in independent groups of cases. Six tumor suppressor genes harbored deletions or promoter hypermethylation (DLEC1, GJB2, HIC1, MIR149, PAX6, and WNT5A), and four oncogenes presented gains or hypomethylation (ASPSCR1, NOTCH4, PRDM16, and RUNX3). Our analysis also revealed hypomethylation at 6p22, a region that contains several histone genes. Copy-number changes in DNMT3B (gain) and TET1 (loss), as well as overexpression of DNMT3B in osteosarcomas provide a possible explanation for the observed phenotype of CpG island hypermethylation. While the detected open-sea hypomethylation likely contributes to the well-known osteosarcoma genomic instability, enriched CpG island hypermethylation suggests an underlying mechanism possibly driven by overexpression of DNMT3B likely resulting in silencing of tumor suppressors and DNA repair genes.
... Histopathologically, OO is characterized by a high proportion of non-mineralized bone matrix (osteoid), fibrous stroma, and no signs of necrosis or cellular atypia (Figure 4). When comparing the histological presentation of OO with Osteoblastoma, they are histologically indistinguishable [38]. However, the two bone-forming tumors are characterized by the size of their nidus, which in Osteoblastoma is defined as more than 2 cm in diameter [2]. ...
... This tumor with extremely high mortality appears as a lytic, sclerotic, or mixed lytic and sclerotic lesion, often combined with a reaction of the surrounding soft tissue and destruction of the cortical bone. Histologically, several subtypes can be distinguished [38]. However, recent studies have shown that in case of uncertain differentiation between benign OO or Osteoblastoma and Osteosarcoma, the diagnosis can benefit from using fluorescence in situ hybridization (FISH) analysis for FOS gene arrangement [39]. ...
... However, recent studies have shown that in case of uncertain differentiation between benign OO or Osteoblastoma and Osteosarcoma, the diagnosis can benefit from using fluorescence in situ hybridization (FISH) analysis for FOS gene arrangement [39]. FOS, and at a lower frequency, FOSB rearrangements were found in the majority of OO and Osteoblastomas, whereas they have only been detected less frequently in osteosarcomas [38][39][40]. This provides an additional tool in the histopathological examination for differentiation of the tumor after surgical resection. ...
Osteoid osteoma (OO) is a benign bone tumor that rarely occurs in the bones of the hand. Due to the comparatively non-specific symptoms when occurring in the hand, OO is often misdiagnosed at first presentation, posing a diagnostic challenge. In the present case study, six cases of phalangeal and carpal OO, treated surgically at our department between 2006 and 2020, were retrospectively reviewed. We compared all cases regarding demographic data, clinical presentation, imaging findings, time to diagnosis, surgical treatment, and clinical outcome in follow-up examinations. When OO occurs in the bones of the hand, it can lead to swelling and deformities, such as enlargement of the affected bone and nail hypertrophy. Initial misdiagnoses such as primary bone tumors other than OO, tendinitis, osteomyelitis, or arthritis are common. Most of the presented cases showed a prolonged time until diagnosis, whereby the primarily performed imaging modality was often not sensitive. CT proved to be the most sensitive sectional imaging modality for diagnosing OO. With adequate surgical treatment, complications and recurrence are rare.
... In parosteal osteosarcoma as well as ALT/WDLPS and DDLPS two cell cycle oncogenes localized on the chromosomes 12q14-15, murine double minute type 2 (MDM2) and cyclin-dependent kinase 4 (CDK4), are amplified and overexpressed [3,4], whereas this is not the case in high grade osteosarcoma and pleomorphic liposarcoma [1]. MDM2 and CDK4 can be analyzed immunohistochemically, the detection of an amplification can be further improved by fluorescence in situ hybridization (FISH) analysis which is more sensitive than immunohistochemistry [5]. ...
Osteosarcomas are the most common primary malignant bone tumors and are classified by the WHO into several intramedullary and surface subtypes. One of these is the rare parosteal osteosarcoma. Liposarcomas are the second most common soft tissue sarcoma and are classified into several types ranging from intermediate to high grade tumors. In one of our recent patients we found an unusual combination of a parosteal osteosarcoma and a large fatty component, which fluorescence-in-situ-hybridization revealed as liposarcoma. Radiologists, pathologists, and surgeons should consider the possibility of bone and soft tissue malignancies consisting of different components, as this may be of paramount importance for oncologically complete resection.
... The central area of the nidus can be mineralized. The nidus in osteoid osteoma is, by definition, less than 2 cm in size, but often measures up to 1 cm in largest dimension [1,10]. ...
... Intra-articular osteoid osteomas can present with joint effusion and decreased range of motion. Osteoid osteomas in the spine may present with painful spinal scoliosis with the nidus typically on the concave side of the curvature secondary to muscle spasm [10,11]. ...
... In a study including 32 cases of osteoblastoma, 90% of cases harbored FOS or FOSB rearrangements [16]. Given that they share the same genetic alterations and histology, osteoblastomas and osteoid osteomas are thought to represent the same disease [1,10]. ...
There are numerous bone tumors in the pediatric population, with imaging playing an essential role in diagnosis and management. Our understanding of certain bone tumors has rapidly evolved over the past decade with advancements in next-generation genetic sequencing techniques. This increased level of understanding has altered the nomenclature, management approach, and prognosis of certain lesions. We provide a detailed update of bone tumors that occur in the pediatric population with emphasis on the recently released nomenclature provided in the 5th edition of the World Health Organization Classification of Soft Tissue and Bone Tumours.
... Chemotherapeutic drugs could induce caspase-3-mediated GSDME cleavage with high GSDME expression and form N-GSDME termini, which caused pyroptosis of tumor cells. In the granzyme-mediated pathway, CAR-T cells activate caspase-3 in target cells and release GzmB, causing GSDME-mediated pyroptosis, while GzmA secreted from CD8 + T cells and NK cells induces GSDMB-mediated pyroptosis the combination of surgical resection and neoadjuvant chemotherapy, osteosarcoma is among the most curable malignant tumors of high-grade sarcomas and achieves a long-term survival rate about 70% in patients with localized disease [105,106]. However, patients still suffer from unsatisfactory clinical outcomes including physical disability, drug resistance and other serious adverse effects [107,108], especially in patients with pulmonary metastasis or local relapse. ...
Pediatric cancers are the driving cause of death for children and adolescents. Due to safety requirements and considerations, treatment strategies and drugs for pediatric cancers have been so far scarcely studied. It is well known that tumor cells tend to progressively evade cell death pathways, which is known as apoptosis resistance, one of the hallmarks of cancer, dominating tumor drug resistance. Recently, treatments targeting nonapoptotic cell death have drawn great attention. Pyroptosis, a newly specialized form of cell death, acts as a critical physiological regulator in inflammatory reaction, cell development, tissue homeostasis and stress response. The action in different forms of pyroptosis is of great significance in the therapy of pediatric cancers. Pyroptosis could be induced and consequently modulate tumorigenesis, progression, and metastasis if treated with local or systemic therapies. However, excessive or uncontrolled cell death might lead to tissue damage, acute inflammation, or even cytokine release syndrome, which facilitates tumor progression or recurrence. Herein, we aimed to describe the molecular mechanisms of pyroptosis, to highlight and discuss the challenges and opportunities for activating pyroptosis pathways through various oncologic therapies in multiple pediatric neoplasms, including osteosarcoma, neuroblastoma, leukemia, lymphoma, and brain tumors.
... 152 At the molecular level, osteoid osteomas exhibit FOS or FOSB rearrangements. 154 The product of those genes FOS and FOSB are members of the activated protein-1 family of transcription factors. These alterations are identical to those found in vascular tumors, where they lead to the expression of a truncated protein more resistant to degradation, c-Fos. ...
Benign tumors that grow in the spinal canal are heterogeneous neoplasms with low incidence; from these, meningiomas and nerve sheath tumors (neurofibromas and schwannomas) account for 60% to 70% of all primary spinal tumors. Benign spinal canal tumors provoke nonspecific clinical manifestations, mostly related to the affected level of the spinal cord. These tumors present a challenge for the patient and healthcare professionals for they are often difficult to diagnose, and the high frequency of posttreatment complications.
In this review we describe the epidemiology, risk factors, clinical features, diagnosis, histopathology, molecular biology, and treatment of extramedullary benign meningiomas, osteoid osteomas, osteoblastomas, aneurysmal bone cysts, osteochondromas, neurofibromas, giant cell tumors of the bone, eosinophilic granulomas, hemangiomas, lipomas, and schwannomas located in the spine, as well as possible future targets that could lead to an improvement in their management.
... A classification of tumors, useful to paleopathologists, has been provided by Ragsdale et al. (2018:27): They "can be malignant or benign, primary or secondary (metastases), slow or fast growing, (and manifest) … as lytic, blastic or mixed lesions, originating in, on, or beside bone." Bone tumors are quite heterogeneous in origin, with over 60 subtypes recognized histologically (Franceschini et al. 2020). Further, eight different types of benign bone tumors can be distinguished: osteochondroma, osteoma, osteoid osteoma, osteoblastoma, giant cell tumor, aneurysmal bone cyst, fibrous dysplasia and enchondroma (Hakim et al. 2015). ...
Burial 280 is a 31-to 40-year-old male Native American individual who lived in a 10th to 16th century coastal foraging society in California. His remains display a large ectocranial elevation on the occipital, measuring 23.3 mm anteroposteriorly, 25.3 mm mediolaterally, and is elevated to 20.1 mm. It is located along the superior nuchal line on the left side of the occipital and represents an extremely rare occipital localization of a particular type of trauma-related osteoma. In our prior study of Burial 280, trauma etiology was not considered; herein, we present evidence for such a cause. Such trauma-related neoplasms are sometimes called ballooned (or giant, depending on size) osteomas. The presence of this tumor appears to have resulted in asymmetrical cranial muscle use and consequent skeletal changes. This case study illustrates that cranial trauma may sometimes induce benign tumor elevations, rather than a depression or pronounced fracture.
