Ewing sarcoma represents a rare, highly malignant cancer, with most patients harboring a priori micrometastases. Since, without systemic therapy, over 90% of patients die from disseminated disease. It is most commonly diagnosed in the second decade of life; however, patients have presented as early as newborn and as late as into the eighth decade, with Tumour s in almost every bodily location. To achieve significant improvement to overcome plateaued survival rates, especially for high-risk patients, innovative clinical strategies and novel therapeutic concepts are required. EwS provides a Tumour -specific molecular target which is indispensable for Tumour development. Characteristically, EwS carry a balanced translocation.
In 85–95% of all EwS patients, this rearrangement fuses the Ewing sarcoma breakpoint region 1 gene (EWSR1) on chromosome 22 to the friend of leukemia virus integration site 1 gene (FLI1) on chromosome 11 t(11;22)(q24;q12). Still, many aspects of the disease require further study, e.g., cryptic cell of origin, phenomenon of oncogene addiction as well as oncogene plasticity, distinct molecular activities and clinical relevance of fusion proteins in EwS, CIC-rearranged sarcoma, sarcoma with BCOR genetic alterations, and round cell sarcoma with EWSR1-non-ETS fusions (all together formerly known as “Ewing-like sarcoma”.
Imaging - Diagnostic Workup—The Timeless Value of Plain Radiographs for Deciphering Bone Lesions
The early diagnosis of EwS remains challenging. Despite similar symptoms, pseudoTumour al and benign bone lesions occur more frequently. The initial staging, the biopsy, both the local and systemic therapy, as well as the follow-up care are all based on the findings of the imaging. In consequence, choosing the appropriate imaging modality for patients with EwS is decisive for both diagnostic and therapeutic assessment, while delineating the treatment strategy.
Additionally Local Tumour Assessment and Staging and Therapeutic Assessment and Follow-Up are describes in full article.
The correct diagnosis of EwS remains crucial and requires an interdisciplinary approach. Following clinical suspicion and radiologically added confirmation, a variety of options are available for retrieving the necessary biological material to achieve a histological diagnosis of a suspected bone Tumour. The MRI provides the crucial information for biopsy planning by distinguishing solid Tumour tissue, cysts, necroses, haemorrhages and extraosseous Tumour components. Different Tumour parts should be biopsied representatively with knowledge of the imaging. Additionally The Risk of Tumour Seeding along the Access Path of Biopsy and Biopsy—The Holy Tissue Grail discussed in full article.
Operative Local Therapy
Local therapy in patients with EwS is highly individualized. Patients should have the opportunity to explore local treatment options as soon after diagnosis as possible and decisions about local therapy should be made in collaboration with patients and families. The optimal approach for local control in patients with EwS is influenced by a multitude of factors, e.g., patient age, tumor site, size, and local extension, and remains a matter of discussion. Randomized studies comparing surgery and radiotherapy (RT) in general, and their timing and sequence in particular, have either been limited or not been performed.
Surgical Margins and Histopathological Response to Systemic Treatment—Implications for Additional Local Therapy
The surgical margin status is a reliable indicator of tumour left in the patient. An adequate surgical margin is one in which there is no viable tumour at the edge of the resection specimen that can be obtained by wide tumour resection, i.e., sufficient safety distance to the reactive zone of the tumour. Adequate margins significantly affect both the local recurrence rate and the overall survival. Additionally Initial Versus Chemotherapy Responsive tumour, Pathological Fracture in EwS, EwS of the Extremities and the Role of Limb Perfusion, Pelvic and Sacral EwS, Primary Thoracic EwS and Disseminated -Relapsed EwS.
Development of VACA-Based Regimens—Multi-Agent Systemic Therapy Improves Outcomes
Prior to the 1970s, EwS tumors were treated solely with surgery and/or RT with nearly all patients eventually developing either primary or distant relapse. Following the development of conventional chemotherapeutic agents in earlier decades, a number of small trials in the 1970s established a set of agents with activity against EwS.
The first of these trials evaluated two combination therapies, vincristine and cyclophosphamide, and vincristine, actinomycin-D, cyclophosphamide and doxorubicin (adriamycin) (VACA), both of which demonstrated improved survival compared to historical controls
Scientific Perspectives on Clinical Enigmas of Disseminated EwS Disease
Clonal Evolution of Metastases Seeds in Intratumor Heterogeneity and Correlates with Mutational Burden
It has been known for long that presence of clinically overt metastases at either diagnosis or at relapse constitute the strongest adverse prognostic factor in EwS, and survival of patients with primary metastatic or relapsed disease is similarly bad. Yet, primary and secondary metastatic disease are not quite the same. Primary therapy-naïve metastases arise in untreated patients from disseminated tumor cells before diagnosis. Experience from the pre-chemotherapy era taught us that resection of the primary tumor-mass alone does not prohibit disease progression, and almost every EwS patient will develop metastases during the course of disease in absence of any systemic therapy. Thus, it is assumed that micrometastatic disease is generally present at diagnosis, but chemotherapy is able to eradicate disseminated tumor cells in the approximately 70% of patients lacking evidence of metastases at diagnosis
Diagnostic, Prognostic, and Therapeutic Markers in EwS
Proteins and metabolic products in the blood, which support tumour diagnosis and allow early detection of relapse such as AFP in hepatoblastoma and germ cell tumour or catecholamine metabolites in neuroblastoma, are not yet identified in EwS. Instead, direct tumour components that are released into the blood as a liquid biopsy in EwS like circulating tumour cells, circulating tumour DNA, circulating tumour RNA, and extracellular vesicles containing tumour-specific biomaterials or signatures of the tumour microenvironment have been evaluated for their potential in clinical practice.
Despite significant efforts in both diagnostic and therapeutic strategies, many aspects of EwS remain elusive, emphasizing on the ongoing need for translational, international-coordinated and joined research. Currently, clinical decision-making balances between protocol-driven regimen, clinical facts, and interindividual concepts.