Open research questions in Sarcoma Diagnosis and Treatment

What the literature leaves open

• PRSS PRSS 3/17(17.6%) 21/112(18.8%) 0/112(0) 0/112(0) 17.6% (6.2%-41.0%) SS18-SSX positive 13/23(56.5%) 4/17(23.5%) SS18-SSX negative with TLE1 positive and aberrant INI1 expression SS18-SSX negative with TLE1 positive and retained INI1 expression SS18-SSX negative with TLE1 negative and aberrant INI1 expression SS18-SSX negative with TLE1 negative and retained INI1 expression Note: (1) SS18-SSX and TLE1 were interpreted based on positive immunoreactivity, whereas INI1 was interpreted based on aberrant (reduced/ mosaic or absent) nuclear expression compared with internal controls SS18 molecular testing SS18 molecular testing 81.3% (73.1%-87.5%) 27.7% (20.2%-36.7%) 91.1% (84.4%-95.2%) 0 (0-18.4%) 5.9% (1.0%-27.0%) 81/112(72.3%) 10/112(8.9%) 1/17(5.9%) non-PRSS 0/17(0) (2) Combination analyses involving TLE1 were based on the 17 PRSS cases with available TLE1 immunohistochemical data 1 3Virchows Archiv in the diagnostic workup of PRSS. In recent years, IHC targeting the SS18-SSX fusion protein has emerged as a highly specific diagnostic tool and a practical surrogate for molecular testing, with previously reported sensitivities exceeding 90% and near-perfect specificity [25–27]. In contrast, SS18-SSX in our cohort demonstrated a lower sensitivity of 56.5%, while maintaining 100% specificity. Although intratumoral heterogeneity may partially contribute to this discrepancy, all positive cases in our cohort showed diffuse staining in > 50% of tumor cells, while negative cases showed no SS18-SSX immunoreactivity. This suggests that the reduced sensitivity observed in our cohort was unlikely to be primarily due to cutoff selection. In the present study, SS18-SSX immunohistochemistry was performed using two clones in two independent laboratories, thereby reducing the likelihood that the variability was attributable to technical factors. Indeed, reduced or absent SS18-SSX staining in poorly preserved or necrotic tumor areas has been reported in prior studies. Despite the reduced sensitivity observed in our cohort, the absolute specificity of SS18-SSX highlights its continued value as a confirmatory immunohistochemical marker for SS. Importantly, among the individual markers evaluated, SS18-SSX demonstrated the highest specificity and overall diagnostic accuracy in our cohort. INI1 also showed relatively strong diagnostic performance, ranking second in overall accuracy. Aberrant INI1 expression, which has been described in SS at various sites, further supports its diagnostic relevance [17, 18]. TLE1 also demonstrated favorable sensitivity in our cohort, consistent with its established role as a sensitive, though not entirely specific marker for SS in routine diagnostic practice [36–38].

  Primary renal synovial sarcoma: a clinicopathological study of 23 cases highlighting the diagnostic value of SS18-SSX, TLE1, and INI1 immunohistochemistry panel · 2026 · DOI

• Minimal criteria for malignancy have not been established; however, malignant features include a minimum mitotic rate of 1 to 4 per 10 high-power fields, nuclear atypia, and the presence of coagulative necrosis [5]. A possible association between the immunosuppressive therapy given to patients with UC and this type of malignancy has not been shown, and therefore, the type of therapy and therapeutic window have not been studied.

  Primary Colonic Leiomyosarcoma Initially Diagnosed as Kaposi Sarcoma: A Case Report · 2026 · DOI

• Background: Soft tissue sarcomas (STS) in children, adolescents, and young adults are rare and biologically heterogeneous, and prognostic factors for local recurrence, metastasis, and survival remain incompletely defined.

  Oncological Outcomes and Prognostic Factors in Soft Tissue Sarcoma of Children, Adolescents, and Young Adults: A Retrospective Single-Center Cohort Study · 2026 · DOI

• OS is a therapeutic challenge due to its high metastatic potential, chemoresistance and high recurrence rates and although current multimodal treatment protocols combining surgery and chemotherapy have improved overall patient survival rates, outcomes for metastatic and recurrent OS remain stagnant. This review summarized recent therapeutic advances, including gene therapy, immunotherapy and other novel targeted and personalized therapies, whose clinical application is still limited by challenges regarding targeting mechanisms, toxicity control and patient strati- fication. This review also discussed the latest developments in OS modelling, highlighting a wide range of 2D and 3D in vitro systems. These include both scaffold-free and scaffold-based platforms, each contributing uniquely to mimicking the OS’s TME. Given their individual strengths and limitations, current evidence suggests that the most effective in vitro OS models are those that integrate multiple approaches and include co-cultures of various cell types to better capture OS complexity and heterogeneity.

  Next-generation osteosarcoma models for precision medicine · 2026 · DOI

• Background/Objectives: Extra-articular resection (EAR) may be considered for sarcomas involving or extending into joints, but its oncologic outcomes are not well defined.

  Oncologic Outcomes After Extra-Articular Resection of Bone and Soft Tissue Sarcomas Involving Major Joints: A Systematic Review · 2026 · DOI

• This study has several limitations. First, as a single case report, the findings may not be generalizable to all patients with dedifferentiated liposarcoma with heterologous myogenic differen- tiation. Second, the patient did not receive adjuvant chemotherapy or radiotherapy following surgical resection due to his postoperative recovery status and personal preference; therefore, the impact of systemic therapy on this rare tumor variant could not be evaluated. Third, long-term follow-up data are still being collected, and the patient’s ultimate survival outcome remains to be determined.

  A Case Report: Retroperitoneal dedifferentiated liposarcoma with heterologous myogenic differentiation and testicular metastasis · 2026 · DOI

• DDIT3 immunohistochemistry (IHC), a specific marker for MLPS, has been reported in a subset of DDLPS cases, but its frequency, staining pattern, and clinical significance remain poorly characterised.

  MDM2 and DDIT3 coexpression in dedifferentiated liposarcoma with myxoid features: a retrospective cohort study · 2026 · DOI

• It remains unclear whether this finding represents a coinci- dental epigenetic divergence or a phenomenon that could be observed in additional cases. However, one limitation is that, aside from BSNS cases, clustering analyses relied on publicly available meth- ylation datasets, which may differ in quality, platform, and data preprocessing pipelines. While the study successfully distinguished high-grade BSNS with HGRT from ARMS and ERMS in 3 of the patients, the distinct methylation profile observed in the HGRT component of patient 1 (with PAX3::FOXO1 fusion) warrants further investigation.

  A Genomic and Epigenetic Comparative Study of Low-grade Biphenotypic Sinonasal Sarcoma with Metachronous and Synchronous High-grade Rhabdomyosarcomatous Transformation · 2026 · DOI

• This review has several limitations that should be acknowl- edged. First, it primarily focuses on studies published in 2025, which may have omitted important earlier contri- butions that shaped current practice. Second, most of the cited evidence comes from single-arm phase 2 trials, single- institution retrospective series, or meta-analyses of hetero- geneous studies; large phase 3 randomized controlled trials remain scarce in many STS radiotherapy settings. Third, the review is narrative rather than systematic, and we did not perform a quantitative meta-analysis or formal risk-of-bias assessment. Fourth, long-term follow-up data (e.g., 5–10 years) are still lacking for many of the hypofractionation and ultra-hypofractionation regimens discussed. Fifth, the generalizability of findings to low- and middle-income countries, where access to advanced technologies such as proton therapy or MRI-guided adaptive RT is limited, is uncertain. Finally, despite our efforts to cover major histo- types and anatomical sites, some rare STS subtypes may be underrepresented. Readers should interpret the conclusions in light of these limitations.

  Advances in Radiotherapy for Soft Tissue Sarcomas in 2025: A Review · 2026 · DOI

• ● Integration of Biomarkers for Personalized RT: The future lies in moving beyond a one-size-fits-all ap- proach. The integration of histotype-specific response patterns [2], molecular profiles (e.g., CINSARC [42], PARP expression [25]), and real-time response data from mpMRI [23] or circulating tumor DNA will enable truly personalized RT prescriptions. Future trials must stratify patients using these biomarkers to test adaptive dose escalation, de-escalation, or specific combinatorial strategies. ● Next-Generation Systemic-RT Combinations and Sequencing: Building on early successes with PARPi and ICIs, research must optimize the sequencing, tim- ing, and dosing of these combinations. Furthermore, exploring novel agents (e.g., next-generation anti-an- giogenics, bispecific antibodies) and cellular therapies (CAR-T/NK cells) in combination with RT, guided by predictive biomarkers of synergy, represents a fertile frontier [12, 29]. ● AI-Enhanced Adaptive Radiotherapy and Quanti- tative Response Assessment: The fusion of artificial intelligence (AI) with adaptive RT platforms will be transformative. AI algorithms can automate the analy- sis of mpMRI and other imaging data to predict early response, enabling fully dynamic treatment adaptation [22]. Similarly, AI can aid in validating and standardiz- ing novel surrogate endpoints like hyalinization [28] or radiomic signatures, accelerating trial conduct. ● Validation of Surrogate Markers: Surrogate markers such as hyalinization [28], monocyte infiltration [41], and mpMRI parameters [23] need validation in large- scale prospective, multi-institutional trials to potentially replace traditional endpoints (e.g., OS, PFS) in clinical trials. This would accelerate the development of novel RT strategies by reducing trial duration and sample size requirements. ● Standardized QoL Measurement and Value-Based Care: Implementation of standardized QoL tools such as STS-QoL [43] in clinical practice and trials will enable Page 11 of 15 50 consistent monitoring of patient-reported outcomes. Fu- ture research should focus on identifying interventions to mitigate QoL declines during RT (e.g., supportive care, rehabilitation) and correlating QoL with long- term functional outcomes. Integrating patient-reported outcomes into clinical decision-making is essential for value-based oncology care. ● Global Access to Advanced RT Technologies: Ad- dressing disparities in access to hypofractionation, par- ticle therapy, and adaptive RT is critical. Foppele et al. [5] showed that hypofractionation can be implemented in resource-limited settings during the pandemic, and future efforts should focus on expanding access to cost- effective advanced RT technologies worldwide. This includes technology transfer, training, and the develop- ment of simplified yet effective hypofractionated proto- cols suitable for diverse healthcare environments.

  Advances in Radiotherapy for Soft Tissue Sarcomas in 2025: A Review · 2026 · DOI

• MDM2 expression levels (TPM) vary widely in confirmed DDLPS cases (ranging from 103.44 to 1564.01), yet the biological and prognostic significance of this variation, and whether the 100 TPM threshold optimally discriminates MDM2-amplified DDLPS from non-amplified sarcomas, are not systematically evaluated.

  RNA-based next-generation sequencing strategy for screening MDM2-amplified sarcomas · 2026 · DOI

• The paper identifies that Cases 13, 14, and 15 contain ≥3 fusion events in 12q13-15 but are not DDLPS; the specific genomic and transcriptomic features (fusion type, breakpoint location, expression ratios) that distinguish these false-positive cases from true DDLPS are not systematically analyzed, limiting the clinical applicability of the fusion count threshold.

  RNA-based next-generation sequencing strategy for screening MDM2-amplified sarcomas · 2026 · DOI

• Cases 14-20 in Table 1 represent non-DDLPS sarcomas (metastatic melanoma, Ewing sarcoma, CCS-ST) with MDM2 expression and/or amplification; the diagnostic criteria and RNA fusion signatures that reliably differentiate these mimics from true MDM2-amplified DDLPS using the RNA panel strategy require further specification and prospective validation.

  RNA-based next-generation sequencing strategy for screening MDM2-amplified sarcomas · 2026 · DOI

• The RNA NGS panel successfully identified MDM2-amplified cases, but the paper does not provide data on the analytical performance (sensitivity, specificity, limit of detection) of the RNA-based approach compared directly to DNA NGS and FISH across the same sample set, particularly for borderline MDM2 expression levels near the 100 TPM threshold.

  RNA-based next-generation sequencing strategy for screening MDM2-amplified sarcomas · 2026 · DOI

• The paper demonstrates differential fusion event patterns between DDLPS and non-DDLPS sarcomas with ≥3 fusions in 12q13-15, but does not characterize the specific molecular mechanisms by which these fusion events (e.g., CTDSP2::DNM3OS) contribute to DDLPS tumorigenesis or distinguish DDLPS from other 12q13-15-amplified malignancies.

  RNA-based next-generation sequencing strategy for screening MDM2-amplified sarcomas · 2026 · DOI

• The RNA-based NGS strategy for MDM2-amplified sarcoma screening was validated on a limited cohort of 20 cases; the generalizability of the genomic complexity threshold (≥3 fusion events in 12q13-15) and diagnostic accuracy of this RNA panel approach needs validation across larger and more geographically diverse sarcoma populations.

  RNA-based next-generation sequencing strategy for screening MDM2-amplified sarcomas · 2026 · DOI

• An algorithm to distinguish between DSRCT (where WART is standard) and other sarcoma subtypes for individualized WART consideration is proposed but not fully validated.

  Whole Abdominal Radiotherapy in Bone and Soft Tissue Sarcomas: Indications, Techniques, Clinical Outcomes, and Future Directions · 2026 · DOI

• WART use in sarcoma subtypes other than DSRCT (rhabdomyosarcoma, Ewing sarcoma, myxoid liposarcoma) should be individualized based on peritoneal involvement and prior treatment response, but evidence remains emerging rather than definitive.

  Whole Abdominal Radiotherapy in Bone and Soft Tissue Sarcomas: Indications, Techniques, Clinical Outcomes, and Future Directions · 2026 · DOI

• However, DI is frequently reduced in routine practice, particularly in adults, and its prognostic relevance in real-world settings remains unclear.

  Dose intensity and clinical outcomes across age groups in high-grade osteosarcoma treated with methotrexate, adriamycin, and cisplatin therapy · 2026 · DOI

• In this case report, EES of the prostate was initially diagnosed and treated as SCNC given the limited information available.

  The case of mistaken identity: Extraskeletal Ewing sarcoma of the prostate masquerading as small cell neuroendocrine carcinoma · 2026 · DOI

• This case contributes to the limited literature on colonic leiomyosarcomas and emphasizes the importance of distinguishing these tumors from other gastrointestinal neoplasms to optimize patient outcomes.

  Primary Colonic Leiomyosarcoma Initially Diagnosed as Kaposi Sarcoma: A Case Report · 2026 · DOI

• BACKGROUND/PURPOSE: Sarculator is a prognostic nomogram for extremity soft-tissue sarcoma (eSTS), but its performance in East Asian populations has not been validated.

  Prognostic performance of the sarculator model in an Asian cohort of patients with extremity soft tissue sarcomas · 2026 · DOI

• Precise definition of the tumor type based on cellular morphology is insufficient in these cases and requires the application of advanced molecular techniques.

  Metachronous spindle cell sarcoma of the lung with spinal cord infiltration in a patient following oncological treatment: A case report · 2026 · DOI

• Owing to its rarity, an optimal treatment strategy has not been fully established, and management has historically followed treatment protocols for Ewing sarcoma.

  BCOR-CCNB3 fusion–positive sarcoma treated with chemotherapy and carbon-ion radiotherapy: a case report of long-term disease control of a cervical spine case with a 12-year follow-up · 2026 · DOI

• Although congenital anomalies are among the strongest known risk factors for childhood cancer, the risk of specific sarcoma subtypes among affected individuals has not yet been thoroughly evaluated.

  Increased Risk of Sarcomas in Children With Congenital Anomalies: Findings From the Genetic Overlap Between Anomalies and Cancer in Kids (GOBACK) Registry Linkage Study · 2026 · DOI

Most-cited papers in Sarcoma Diagnosis and Treatment

• Afamitresgene autoleucel for advanced synovial sarcoma and myxoid round cell liposarcoma (SPEARHEAD-1): an international, open-label, phase 2 trial · The Lancet · 2024 · 263 citations
• Doxorubicin–Trabectedin with Trabectedin Maintenance in Leiomyosarcoma · New England Journal of Medicine · 2024 · 79 citations
• Safety and efficacy of pembrolizumab, radiation therapy, and surgery versus radiation therapy and surgery for stage III soft tissue sarcoma of the extremity (SU2C-SARC032): an open-label, randomised clinical trial · The Lancet · 2024 · 76 citations
• The landscape of drug sensitivity and resistance in sarcoma · Cell stem cell · 2024 · 61 citations
• The diagnosis and treatment of osteosarcoma and Ewing’s sarcoma in children and adolescents · Deutsches Ärzteblatt international · 2023 · 19 citations
• Ultrasound-guided biopsy of musculoskeletal soft-tissue tumors: basic principles, usefulness and limitations · Journal of Ultrasonography · 2022 · 9 citations
• Ewing's sarcoma of the mandible with multilocular radiolucency · Journal of Oral and Maxillofacial Pathology · 2022 · 8 citations
• Head and neck sarcomas: treatment outcomes in a tertiary referral center in Argentina · Oral and Maxillofacial Surgery · 2021 · 7 citations
• The Role of Adjuvant Radiotherapy in the Treatment of Papillary Tumors of the Pineal Region: Some General Considerations and a Case Report · Klinicka onkologie · 2017 · 6 citations
• Outcomes and computed tomography radiomic features extraction in soft tissue sarcomas treated with neoadjuvant radiation therapy · Reports of Practical Oncology & Radiotherapy · 2021 · 6 citations

Most recent work

• Automated detection of primary soft tissue sarcomas of the extremities using artificial intelligence and ChatGPT · Frontiers in Oncology · 2026
• Whole Abdominal Radiotherapy in Bone and Soft Tissue Sarcomas: Indications, Techniques, Clinical Outcomes, and Future Directions · Current Treatment Options in Oncology · 2026
• Development of a web-based machine learning model for early prediction of delayed high-dose methotrexate clearance in pediatric osteosarcoma · Frontiers in Pediatrics · 2026
• The combination of EWSR1-FLI1 and loss of one EWSR1 allele leads to the induction of trisomy 8 · bioRxiv · 2026
• Stereotactic Body Radiation Therapy Augmented Checkpoint Inhibitor Immunotherapy Response in Heavily Pretreated Metastatic Osteosarcoma · International Journal of Radiation Oncology*Biology*Physics · 2026
• POSSIBILITIES AND RESULTS OF SURGICAL TREATMENT OF PATIENTS WITH RETROPERITONEAL NONORGAN LIPOSARCOMAS WITH INVASION OF THE MAIN VESSELS · Science and Innovations in Medicine · 2026
• Letter to the editor “Leiomyosarcoma of the inferior vena cava: case report” · Annals of Medicine & Surgery · 2026
• RNA-based next-generation sequencing strategy for screening MDM2-amplified sarcomas · Scientific Reports · 2026
• Synovial Sarcoma: Molecular Biology, Pathology, and Therapeutic Strategies · International Journal of Molecular Sciences · 2026
• Primary osteogenic sarcoma of the sternum with intravascular invasion and rapid progression: a rare case report · Annals of Medicine & Surgery · 2026

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