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Primary bone cancers include osteosarcoma, Ewing sarcoma, and chondrosarcoma. They account for less than 1% of diagnosed cancers each year and are associated with significant morbidity and mortality. Timely diagnosis is challenging because of late patient presentation, nonspecific symptoms that mimic common musculoskeletal injuries, and low suspicion by physicians. Plain radiography is the preferred diagnostic test. Radiographic suspicion of a bone malignancy should prompt quick referral to a cancer center for multidisciplinary care. Osteosarcoma, the most common bone cancer, most often occurs in children and adolescents. It typically develops in the metaphysis of long bones, specifically the distal femur, proximal tibia, and proximal humerus. Metastasis to the lungs is common. Use of neoadjuvant and adjuvant chemotherapy, in combination with surgery, has improved survival rates to nearly 80% for patients with localized disease, and 90% to 95% of patients do not require limb amputation. Ewing sarcoma is the second most common bone cancer and is similar to osteosarcoma in terms of presenting symptoms, age at occurrence, and treatment. Prognosis for osteosarcoma and Ewing sarcoma depends on the presence of metastasis, which lowers the five-year survival rate to 20% to 30%. Chondrosarcoma is the rarest bone cancer, primarily affecting adults older than 40 years. Survival rates are higher because most of these tumors are low-grade lesions.

Pediatric sarcomas present a significant challenge in oncology. There is an urgent need for improved therapeutic strategies for high-risk patients and better management of long-term side effects for those who survive the disease. Liquid biopsy is emerging as a promising tool to optimize treatment in these patients by offering non-invasive, repeatable assessments of disease status. Circulating biomarkers can provide valuable insights into tumor genetics and treatment response, potentially facilitating early diagnosis and dynamic disease monitoring. This review examines the potential of liquid biopsies, focusing on circulating biomarkers in the most common pediatric sarcomas, i.e., osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma. We also highlight the current research efforts and the necessary advancements required before these technologies can be widely adopted in clinical practice.

Subsets of primitive round-cell sarcomas remain difficult to diagnose and classify. Among these is a rare round-cell sarcoma that harbors a CIC gene rearrangement known as CIC- rearranged undifferentiated round-cell sarcoma, which is most commonly fused to the DUX4 gene. Owing to its aggressive clinical behavior and potential therapeutic implications, accurate identification of this novel soft tissue sarcoma is necessary. Definitive diagnosis requires molecular confirmation, but only a few centers are as yet able to perform this test. Several studies have shown that PEA3 subfamily genes, notably ETV4 (belonging to the family of ETS transcription factors), are upregulated in CIC- rearranged undifferentiated round-cell sarcomas. We performed a detailed immunohistochemical analysis to investigate ETV4 expression in CIC- rearranged undifferentiated round-cell sarcomas and their potential mimics (especially Ewing sarcomas). The study cohort included 17 cases of CIC- rearranged undifferentiated round-cell sarcomas, and 110 tumors that morphologically mimic CIC- rearranged undifferentiated round-cell sarcomas: 43 Ewing sarcomas, 25 alveolar rhabdomyosarcomas, 20 poorly differentiated round-cell synovial sarcomas, 10 desmoplastic round-cell tumors, 5 BCOR-CCNB3 sarcomas, 5 lymphoblastic lymphomas, and 2 rhabdoid tumors. All CIC- rearranged undifferentiated round-cell sarcomas (on core needle biopsies and open biopsies) were ETV4-positive with a strong diffuse nuclear pattern. Among the other 110 tumors, only six cases (four Ewing sarcomas, one alveolar rhabdomyosarcoma, and one desmoplastic round-cell tumor) showed focal (<5% of tumor cells) and very weak nuclear expression of ETV4; all other tumors were completely negative for ETV4. We conclude that systematic immunohistochemical analysis of ETV4 makes it possible to diagnose undifferentiated round-cell sarcomas (with no molecular markers for sarcoma-associated translocation) such as CIC- rearranged undifferentiated round-cell sarcoma.

Introduction Liquid biopsy as a non-invasive method to investigate cancer biology and monitor residual disease has gained significance in clinical practice over the years. Whilst its applicability in carcinomas is well established, the low incidence and heterogeneity of bone and soft tissue sarcomas explains the less well-established knowledge considering liquid biopsy in these highly malignant mesenchymal neoplasms. Materials and methods A systematic literature review adhering to the PRISMA guidelines initially identified 920 studies, of whom 68 original articles could be finally included, all dealing with clinical applicability of liquid biopsy in sarcoma. Studies were discussed within two main chapters, i.e. translocation-associated and complex-karyotype sarcomas. Results Overall, data on clinical applicability of liquid biopsy in 2636 patients with > 10 different entities of bone and soft tissue sarcomas could be summarised. The five most frequent tumour entities included osteosarcoma (n = 602), Ewing sarcoma (n = 384), gastrointestinal stromal tumour (GIST; n = 203), rhabdomyosarcoma (n = 193), and leiomyosarcoma (n = 145). Of 11 liquid biopsy analytes, largest evidence was present for ctDNA and cfDNA, investigated in 26 and 18 studies, respectively. Conclusions This systematic literature review provides an extensive up-to-date overview about the current and potential future uses of different liquid biopsy modalities as diagnostic, prognostic, and disease monitoring markers in sarcoma.

Liquid biopsy, which involves the detection of circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs), is revolutionizing the management of osteosarcoma, Ewing sarcoma and chondrosarcoma by enabling noninvasive diagnosis, risk stratification and real-time treatment monitoring. ctDNA analysis allows for the sensitive detection of tumor-specific alterations, whereas CTCs provide insights into metastatic potential. Baseline ctDNA burden independently predicts poor survival, while dynamic ctDNA kinetics and CTC counts guide neoadjuvant response assessment and postoperative minimal residual disease surveillance. Notably, the integration of liquid biopsy into adaptive clinical pathways can refine precision oncology for these rare, lethal bone malignancies.

Pediatric sarcomas present heterogeneous morphology, genetics and clinical behavior posing a challenge for an accurate diagnosis. DNA methylation is an epigenetic modification that coordinates chromatin structure and regulates gene expression, determining cell type and function. DNA methylation-based tumor profiling classifier for sarcomas (known as sarcoma classifier) from the German Cancer Research Center (Deutsches Krebsforschungszentrum) was applied to 122 pediatric sarcomas referred to a reference pediatric oncology hospital. The classifiers reported 88.5% of agreement between histopathological and molecular classification confirming the initial diagnosis of all osteosarcomas and Ewing sarcomas. The Ewing-like sarcomas were reclassified into sarcomas with BCOR or CIC alterations, later confirmed by orthogonal diagnostic techniques. Regarding the CNAs profile, osteosarcomas had several chromosomal gains and losses as well as chromothripsis, whereas Ewing sarcomas had few large events, such as amplifications of chromosomes 8 and 12. The molecular classification together with clinical and histopathological assessment could improve the diagnosis of pediatric sarcomas although there are limitations to deal with more rare classes. This study provides an increase in the number of sarcomas evaluated for DNA methylation profiling in the pediatric population.

BackgroundChildren and young people (CYP) with bone tumours often experience lengthy intervals prior to diagnosis that can lead to increased morbidity and mortality. Early diagnosis is key to optimising treatment options and long-term outcomes. This review aims to describe symptomatology at diagnosis, in order to develop interventions to accelerate diagnosis.MethodsA literature search of MEDLINE and EMBASE was conducted for studies published between January 2008 and May 2023, reporting signs and symptoms in CYP with bone tumours. Pooled proportions of symptoms and signs were calculated.Results16 studies (1452 patients; 492 osteosarcoma and 932 Ewing’s sarcoma) were included in the analysis. The most prevalent symptoms were pain (64%, 95% CI 52% to 75%) and swelling (22%, 95% CI 6% to 42%). Other symptoms included fever, pain and swelling, history of trauma, pathological fracture, palpable mass, functional limitation, increased volume and limp. Subanalysis identified differences in symptom clusters: osteosarcoma more frequently presented with a history of trauma, pathological fracture, pain on weight-bearing, pain worse at night, pain at rest and weight loss. Ewing’s sarcoma was associated with fever, functional limitation and a palpable mass.ConclusionsThese data highlight the differences in presentations between osteosarcoma and Ewing sarcoma, which may account for differences in survival and outcome. This will be used to inform professional and public health interventions through the Child Cancer Smart campaign to accelerate diagnosis for all. This review also highlights the need for a renewed research focus to identify patients earlier in the disease development as a strategy to improve the current static outcomes.

Background PALETTE is a phase 3 trial that demonstrated single-agent activity of pazopanib in advanced soft tissue sarcomas (aSTS). We performed retrospective subgroup analyses to explore potential relationships between patient characteristics, prior lines of therapy, dose intensity, and dose modifications on safety and efficacy of pazopanib in aSTS. Methods PALETTE compared pazopanib with placebo in patients with aSTS (age ≥ 18 years) whose disease had progressed during or following prior chemotherapy. In these subgroup analyses, median progression-free survival (mPFS) among patients receiving pazopanib was the efficacy outcome of interest. Adverse events (AEs) were also compared within subgroups. All analyses were descriptive and exploratory. Results A total of 246 patients received pazopanib in the PALETTE study. The mPFS was longer in patients who had only 1 prior line versus 2+ prior lines of therapy (24.7 vs 18.9 weeks, respectively); AE rates were similar regardless of number of prior lines of therapy. The mPFS was similar in patients aged < 65 and ≥ 65 y (20.0 and 20.1 weeks, respectively). Although AEs leading to study discontinuation were higher in older patients (≥65 y, 30%; < 65 y, 17%), rates of dose reductions, dose interruptions, and serious AEs were similar between the 2 age groups. No reduction in mPFS was noted in patients requiring dose reductions or dose interruptions to manage toxicities. Conclusions Longer mPFS was observed in patients receiving pazopanib following only 1 line of therapy. Additionally, mPFS with pazopanib was maintained regardless of patient age or dose modifications used to manage toxicity. Trial registration NCT00753688 , first posted September 16, 2008 (registered prospectively).

Ewing sarcoma shows considerable histologic overlap with other round cell tumors. NKX2-2, a homeodomain transcription factor involved in neuroendocrine/glial differentiation and a downstream target of EWSR1-FLI1, has been reported as an immunohistochemical marker for Ewing sarcoma. We assessed the specificity of NKX2-2 for Ewing sarcoma compared with other round cell malignant neoplasms and other soft tissue tumors with EWSR1 translocations. We evaluated whole-tissue sections from 270 cases: 40 Ewing sarcomas (4 with atypical/large cell features), 20 CIC-DUX4 sarcomas, 5 BCOR-CCNB3 sarcomas, 9 unclassified round cell sarcomas, 10 poorly differentiated synovial sarcomas, 10 lymphoblastic lymphomas, 10 alveolar rhabdomyosarcomas, 10 embryonal rhabdomyosarcomas, 10 Merkel cell carcinomas, 10 small cell carcinomas, 20 melanomas, 5 NUT midline carcinomas, 10 Wilms tumors, 10 neuroblastomas, 10 olfactory neuroblastomas, 12 mesenchymal chondrosarcomas, 10 angiomatoid fibrous histiocytomas, 10 clear cell sarcomas, 5 gastrointestinal clear cell sarcoma-like tumors, 5 desmoplastic small round cell tumors, 10 extraskeletal myxoid chondrosarcomas, 10 soft tissue and cutaneous myoepitheliomas, and 19 myoepithelial carcinomas. NKX2-2 positivity was defined as moderate-to-strong nuclear immunoreactivity in at least 5% of cells. NKX2-2 was positive in 37/40 (93%) Ewing sarcomas, including all atypical Ewing sarcomas and cases with known EWSR1-FLI1 or EWSR1-ERG fusion; 85% of Ewing sarcomas showed diffuse (>50%) staining. NKX2-2 was positive in 9 (75%) mesenchymal chondrosarcomas, 8 (80%) olfactory neuroblastomas, 1 CIC-DUX4 sarcoma, 1 poorly differentiated synovial sarcoma, 1 neuroblastoma, 2 unclassified round cell sarcomas, and 3 small cell carcinomas; all other EWSR1 -associated tumors were negative for NKX2-2, apart from 1 desmoplastic small round cell tumor, 1 myoepithelioma, and 1 myoepithelial carcinoma. In summary, NKX2-2 is a sensitive but imperfectly specific marker for Ewing sarcoma. Nonetheless, NKX2-2 may be helpful to distinguish Ewing sarcoma from some histologic mimics including CIC-DUX4 and BCOR-CCNB3 sarcomas. Most other EWSR1 -associated soft tissue tumors are negative for NKX2-2.

Histiocytic sarcoma is a rare malignant neoplasm of presumed hematopoietic origin showing morphologic and immunophenotypic evidence of histiocytic differentiation. Somatic mutation importance in the pathogenesis or disease progression of histiocytic sarcoma was largely unknown. To identify somatic mutations in histiocytic sarcoma, we studied 5 histiocytic sarcomas [3 female and 2 male patients; mean age 54.8 (20–72), anatomic sites include lymph node, uterus, and pleura] and matched normal tissues from each patient as germ line controls. Somatic mutations in 50 “Hotspot” oncogenes and tumor suppressor genes were examined using next generation sequencing. Three (out of five) histiocytic sarcoma cases carried somatic mutations in BRAF . Among them, G464V [variant frequency (VF) of 43.6 %] and G466R (VF of 29.6 %) located at the P loop potentially interfere with the hydrophobic interaction between P and activating loops and ultimately activation of BRAF . Also detected was BRAF somatic mutation N581S (VF of 7.4 %), which was located at the catalytic loop of BRAF kinase domain: its role in modifying kinase activity was unclear. A similar mutational analysis was also performed on nine acute monocytic/monoblastic leukemia cases, which did not identify any BRAF somatic mutations. Our study detected several BRAF mutations in histiocytic sarcomas, which may be important in understanding the tumorigenesis of this rare neoplasm and providing mechanisms for potential therapeutical opportunities.