Undifferentiated pleomorphic sarcoma (UPS) is a diagnosis of exclusion; given limited effective treatments and marked heterogeneity, there is a need to identify therapeutic targets, a task facilitated...

Despite the growing recognition of microRNAs (miRNAs) as critical biomarkers in cancer, current approaches to their analysis remain fragmented, disjointed, and poorly integrated with emerging computat...

Purpose of Review Sarcomas are a heterogeneous group of over 170 malignant tumours of mesenchymal origin. The poor prognosis highlights the need for novel therapeutic strategies. Preclinical modelling...

Extraskeletal myxoid chondrosarcoma (EMC) is characterised by recurrent NR4A3 gene rearrangements, most commonly EWSR1::NR4A3, and accounts for approximately 1–3% of soft-tissue sarcomas (STS). It typically arises in the deep soft tissues of the proximal lower limb, particularly the thigh. Diagnosis is best established by integrating morphology and immunophenotype with molecular confirmation; in particular, NR4A3 break-apart fluorescence in situ hybridisation (FISH) provides a practical single-assay solution. For localised disease, complete surgical excision remains the cornerstone of treatment. Radiotherapy (RT) improves local control when margins are close or tumours are large. Recurrence-free survival (RFS) varies: local recurrence (LR) rates range from 13 to 42% across studies, and distant metastases develop in around 35–45% of patients, primarily in the lungs. The median time to metastasis is approximately 28 months. Overall survival (OS) reflects the typically indolent yet metastatic course: 5-year OS 66–88%, and 10-year disease-specific survival approximately 85%. In advanced disease, anthracycline-based chemotherapy yields a low objective response rate (ORR), although occasional partial responses occur. By contrast, the anti-angiogenic tyrosine kinase inhibitor pazopanib produced an ORR of 18% and a median progression-free survival (PFS) of 19 months in a multicentre phase 2 study (NCT02066285). No clinically validated agents directly target NR4A3. This review summarises contemporary diagnostics and treatment, emphasising high-quality surgery, selective RT, and consideration of anti-angiogenic tyrosine kinase inhibitors in advanced disease. Graphical abstract Graphical summary of a review article on Extraskeletal myxoid chondrosarcoma (EMC). Diagnosis involves integrating morphology with immunohistochemistry (INSM1, S100 and synaptophysin) and NR4A3 fusion testing, particularly break-apart fluorescence in situ hybridisation (FISH). Common fusions include EWSR1::NR4A3, TAF15::NR4A3 and FUS::NR4A3. Localised management involves wide local excision with selective radiotherapy to enhance local control, and chemotherapy plays a limited role, mainly in advanced disease. The prognosis is indolent yet metastasising. 5-year overall survival (OS) is 66–88%, ten-year disease-specific survival (DSS) is approximately 85%, local recurrence (LR) is 30–50%, and the rate of distant metastasis is 30–50%, predominantly to the lungs.

Modern Pathology - Detection of sarcoma fusions by a next-generation sequencing based–ligation-dependent multiplex RT-PCR assay

Dermatofibrosarcoma protuberans (DFSP) is a rare soft tissue sarcoma with an incidence of 0.008 to 0.045 cases per 100,000 per year, accounting for less than 1% of all soft tissue sarcomas. It mainly affects adults aged 30–50 years, usually on the trunk and proximal extremities. DFSP is Locally aggressive, with metastases occurring in up to 5% of cases, typically < 1%. Diagnosis is based on histology, including CD34 antigen expression and COL1A1-PDGFB fusion detection by FISH or RT-PCR. Mohs micrographic surgery is the mainstay of treatment, ensuring clear margins to minimise recurrence. Radiotherapy is used as adjuvant or preoperative therapy to improve Local control. Imatinib, a tyrosine kinase inhibitor, is highly effective in unresectable or metastatic DFSP, especially in cases with PDGFB mutations, achieving disease control in over 70% of patients and partial responses in 36%. The 10-year overall survival rate is 90.7%, although the fibrosarcomatous variant (DFSP-FS) has worse outcomes, with a 5-year Local progression-free survival rate of 33%. Rare metastases to the lungs, lymph nodes or brain are treated surgically; chemotherapy remains ineffective. We comprehensively reviewed the clinical data regarding DFSP, highlighting subtype differences (myxoid, pigmented, myoid, granular cell, sclerosing, atrophic, and fibrosarcomatous), as well as reconstruction methods. Graphical Abstract

Purpose of Review The review compares the effectiveness of neoadjuvant(pre-operative, NAC) and adjuvant(post-operative, AC) in Soft Tissue Sarcomas as this topic is controvesial and multiple new studies have been over the years. Recent Findings Sarculator and other nomograms assess patients with a predicted 10-year OS below 60% who will benefit from perioperative chemotherapy. Further research supports perioperative chemotherapy’s role. European guidelines do not recommend anthracycline and ifosfamide (AI) perioperative chemotherapy as a standard treatment for STS of the extremities and trunk. However, some studies show that AI chemotherapy can improve recurrence-free survival (RFS). The EORTC 62,771 trial found that the CYVADIC regimen (doxorubicin, dacarbazine, cyclophosphamide, vincristine) reduced RFS without affecting OS. Meanwhile, the EORTC 62,931 trial showed no effect of AI chemotherapy on RFS or OS, but a pooled analysis suggested an OS benefit for patients with R1 (microscopically positive) resections. The AI regimen shows further support from Sarculator-based data, with EORTC 62,931 analysis indicating an improvement in disease-free survival and OS in patients with low expected OS. Similar outcomes were seen in the ISG-STS 1001 study. Recently, PERSARC analysis revealed that AI chemotherapy significantly improves OS in high-grade STS patients with a low 5-year OS prediction (< 33%). Summary NAC improves the chances of complete tumour removal, especially in large, high-grade tumours. It often reduces the need for more aggressive surgeries by shrinking tumours before surgery, leading to higher rates of successful resections with clear margins (R0). Sarculator and other nomograms assess patients with a predicted 10-year OS below 60% who will benefit from perioperative chemotherapy. Further research supports perioperative chemotherapy’s role.

Selinexor is a new compound studied for the treatment of liposarcoma, particularly dedifferentiated liposarcoma (DDLPS), where treatment options remain limited. As a first-in-class oral exportin-1 (XPO1) inhibitor, selinexor has shown anti-tumour activity in preclinical models, particularly in MDM2- and CDK4-amplified DDLPS, where it induces apoptosis, inhibits tumour growth and promotes nuclear retention of p53. Preclinical studies have also suggested potential synergy with doxorubicin and eribulin, although these findings have yet to be validated in randomised clinical trials. The phase II/III SEAL trial (NCT02606461) evaluated selinexor versus placebo in patients with advanced, previously treated DDLPS. While the study demonstrated a statistically significant, albeit modest, improvement in median progression-free survival (PFS) from 2.1 to 2.8 months, no overall survival benefit was observed. In addition, selinexor was associated with significant toxicity, including fatigue, nausea and weight loss. Similarly, a phase Ib/II study (NCT03042819) evaluating selinexor in combination with doxorubicin reported a 21% response rate and a median PFS of 5.5 months, although this regimen was also associated with high rates of neutropenia and fatigue. Despite these results, selinexor is not currently approved for the treatment of liposarcoma and its clinical utility remains under investigation. Ongoing studies, such as the SeliSarc trial (NCT04595994) evaluating selinexor in combination with gemcitabine and the NRSTS2021 trial (NCT06239272) evaluating selinexor in paediatric soft tissue sarcoma, aim to further define its role. The results of these studies will be critical in determining whether selinexor can be incorporated into standard sarcoma treatment.

Dermatofibrosarcoma protuberans (DFSP) is a rare, low-grade mesenchymal neoplasm that arises in the dermis and subcutaneous tissue. Clinically, DFSP presents as a slow-growing cutaneous plaque or nodular mass that is often initially mistaken for a benign dermatological condition, such as a keloid, a dermatofibroma or morphea. Due to its local aggressiveness and proclivity for subclinical spread and recurrence, accurate diagnosis and complete surgical excision are critical. Although DFSP rarely metastasises, its morbidity primarily stems from locally invasive growth and potential disfigurement due to extensive resections. The pathognomonic COL1A1-PDGFB fusion, which can be detected using fluorescence in situ hybridisation (FISH) or reverse transcription polymerase chain reaction (RT-PCR), sustains autocrine PDGFRβ activation and can be used as a diagnostic marker and a target for the drug imatinib. Emerging genomic studies have revealed additional fusions, such as COL1A2-PDGFB and FBN1-CSAD, as well as mutations, such as CDKN2A/B deletions, that correlate with more aggressive, fibrosarcomatous (FS) variant. We reviewed the diagnostics of DFSP, including histopathology, immunohistochemistry (e.g. CD34, factor XIIIa, S100 and PRAME) as well as clinical presentation and recommended imaging modalities (e.g. ultrasound, MRI and PET/CT). To provide a better understanding of DFSP we discussed the molecular basis of DFSP, including the main genetic drivers and downstream signalling pathways, such as Ras-MAPK, PI3K-Akt and FGFR. Moreover, as there is no definitive staging system for DFSP, we proposed a novel one, integrating the presence of FS differentiation.