Mini Review,  Clin Oncol Case Rep Vol: 6 Issue: 8

Ewing Sarcoma: Review of Recent Advances and Directions

Carlos A. Cardenas^*

Department of Oncology, Foundation for Research and Sciences (FORESC), USA

*Corresponding Author: Adamantia Nikolaidi,
Department of OncologyFoundation for Research and Sciences (FORESC), USA.
E-mail: Karmed@live.com

Received: August 02, 2023; Manuscript No: COCR-23-113185;
Editor Assigned: August 05, 2023; PreQC Id: COCR-23-113185 (PQ);
Reviewed: August 13, 2023; QC No: COCR-23-113185 (Q);
Revised: August 18, 2023; Manuscript No: COCR-23-113185 (R);
Published: August 28, 2023; DOI: 10.4172/cocr.6(8).310

Citation: Cardenas CA (2023) Ewing Sarcoma: Review of Recent Advances and Directions. Clin Oncol Case Rep 6:8

Abstract

Keywords: Ewing sarcoma, Sarcomas, Treatment, Targeted therapy,Immunotherapies

Keywords

Ewing sarcoma; Sarcomas; Treatment; Targeted therapy; Immunotherapies

Introduction

Ewing Sarcoma (EwS) is a rare and highly malignant cancer affecting individuals across various age groups and bodily locations. Without systemic therapy, over 90% of patients die from disseminated disease [1]. Although multimodal treatment has improved overall survival for localized disease, metastatic EwS still presents a poor prognosis, with significant rates of metastasis in the lungs (70%- 80%) and bone/bone marrow (40%-45%) [2, 3]. Moreover, recurrent disease occurs in 30%-40% of patients with primary non-metastatic disease, increasing to 60%-80% for EwS patients with metastatic disease at diagnosis. Relapse typically manifests as systemic (71%- 73%), combined (12%-18%), or local (11%-15%) relapse, with fiveyear post-relapse survival rates of 15%-25%, favoring local recurrence over systemic [4].

EwS is distinctly characterized by specific genetic fusion events, which play a crucial role in tumorigenesis. In 85%-95% of EwS cases, the fusion event involves the Ewing sarcoma breakpoint region 1 gene (EWSR1) on chromosome 22 and the friend of leukemia virus integration site 1 gene (FLI1) on chromosome 11, resulting in the t (11;22)(q24;q12) translocation [5]. The resulting EWSR1-FLI1 fusion product serves as an oncoprotein that is both necessary and presumably sufficient for tumorigenesis. Effective therapy often aims to target or inactivate the EWSR1-FLI1 fusion product, although nontargeted chemotherapy has shown efficacy in a substantial proportion of patients with localized tumors [6, 7].

Numerous facets of EwS necessitate further exploration, including its cell of origin, oncogene addiction, oncogene plasticity, and the clinical relevance of various fusion proteins. Additionally, there are related entities with morphological similarities to EwS but distinct genetic backgrounds and clinical characteristics. While consensus in clinical practice guidelines is desirable, variations exist in areas without clear evidence.

This review aims to provide an encompassing overview of the current standards and outstanding questions in the clinical management of EwS, with a special focus on translational research to enhance patient care for this challenging disease.

Diagnosis

Diagnosing Ewing Sarcoma (EwS) early poses a challenge due to the frequent occurrence of similar symptoms in benign bone lesions. Key aspects of EwS diagnosis, treatment planning, and follow-up rely heavily on imaging findings. Selecting the appropriate imaging method is crucial for both diagnosis and treatment strategy development

Presently, the primary diagnostic evaluation for bone pain, particularly in children, involves Magnetic Resonance Imaging (MRI), which demonstrates a high negative predictive value for malignant bone tumors. When MRI results are inconclusive, projection radiography or, in cases where overlapping occurs, Computed Tomography (CT) becomes necessary [8]. Projection radiography/ CT provides signs indicative of suspected malignant bone tumors like EwS. These signs include permeative osteolysis (stage III per LodwickMadewell classification), periosteal reactions featuring interrupted compact bone (onion skin phenomenon, spiculae, Codman triangle), and matrix mineralization [9]. Malignancy signs on MRI include the solid displacement of bone marrow, extraosseous tumor extension, joint infiltration, peritumoral edema, and gadolinium enhancement. MRI helps in differential diagnosis, although the selection of appropriate sequences is critical. While classic T1 and T2 contrasts are essential, proton-weighted and gradient echo sequences do not aid in tissue characterization. In MRI, EwS typically manifests as a solid bone tumor with low signal intensity in T1 and high signal intensity in T2, often displaying a sharp transition zone in the bone segment. A soft-tissue mass is frequently present. MRI lacks specific features for conclusive EwS diagnosis compared to conditions like osteomyelitis [10, 11].

Radiological differences may exist between classical EwS and related entities. For example, Small Round Cell Sarcomas (SRCS) with CIC-DUX4 fusion often appear as necrotic and hypermetabolic soft-tissue masses, while SRCS with BCOR-CCNB3 translocations are vascular bone lesions with necrosis in imaging [12].

Comprehensive imaging, encompassing both locoregional expansion assessment (T-staging) and distant metastasis evaluation (M-staging), represents a fundamental prerequisite prior to initiating chemotherapy. In instances where initial findings yield inconclusive results, further imaging or biopsy procedures are imperative to provide elucidation. It is noteworthy that the impact of chemotherapy, which encompasses alterations in bone marrow dynamics and tumor response, may introduce complexities in the interpretation of findings subsequent to the commencement of neoadjuvant chemotherapy. The radiological response to chemotherapy assumes a pivotal role in the contemplation of local therapeutic interventions. Furthermore, participation in structured follow-up care, as integrated into clinical trial protocols, confers a discernible survival advantage. The timing and modality selection for imaging are typically predicated upon trial-specific recommendations. Primary tumor evaluation is conventionally conducted via Magnetic Resonance Imaging (MRI), while the assessment of pulmonary involvement necessitates Computed Tomography (CT) examination, and a comprehensive appraisal of the entire body is undertaken using 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET)/CT/MRI. Notably, discerned suspicious findings through these imaging modalities can aptly inform clinical decision-making regarding therapeutic strategies [13].

Accurate diagnosis of Ewing Sarcoma (EwS) is essential, requiring a multidisciplinary approach. Following clinical suspicion and radiological confirmation, various methods are available to obtain biological material for histological diagnosis. Magnetic resonance imaging (MRI) aids in biopsy planning, distinguishing tumor tissue from other components like cysts, necroses, hemorrhages, and extraosseous elements. To assess the histological subtype and guide therapy effectively, a larger amount of material than fine-needle aspiration provides is necessary. Consequently, either an open biopsy or a percutaneous Core Needle Biopsy (CNB) assisted by CT/MRI is required for precise diagnosis and therapeutic planning, often with extraosseous tissue sampling negating the need for bone tissue extraction [14].

The choice between biopsy methods in EwS remains a matter of debate, as randomized controlled trials comparing CNB and open biopsy are lacking. Nevertheless, open biopsies typically yield higher accuracy rates, while experienced centers can minimize errors with CNB. Biopsy procedures must be meticulous to avoid contamination and hematoma formation. Biopsies should be performed at specialized sarcoma centers, with inadequate needle biopsy techniques occasionally necessitating more extensive resections or amputations, potentially negating limb salvage options [15].

To aid surgical identification, the biopsy site can be marked with a skin tattoo. Even open biopsies can adopt minimally invasive approaches, involving a short incision, a small bone opening, wound drainage to prevent hematoma and intracutaneous suturing techniques. Circulating EwS cells have been detected in blood during uncontaminated tumor removal, although their relationship to survival remains uncertain [16].

CNB offers a safe, minimally invasive, cost-effective option with shorter hospitalization periods and presumed lower complication rates. The potential for peri-interventional tumor seeding along the CNB tract is not fully understood, prompting some authors to recommend resecting the CNB tract. However, evidence supporting either the increased risk of tumor seeding along the CNB tract or local recurrence in the absence of resection remains insufficient [17].

Until robust data conclusively rule out an increased risk of tumor seeding following CNB in EwS, biopsy needle placement should prioritize maximal yield while minimizing contamination of normal tissues. The recommendation for open biopsy also underscores the necessity for research-oriented tissue procurement, as only open biopsies provide sufficient material for both histological diagnosis and translational research on tumor tissue before systemic treatment. Therapy-naïve tumor specimens are vital for preclinical drug testing and molecular investigations aimed at ultimately enhancing EwS patient survival. In cases of the first EwS relapse, re-biopsy is often recommended for definitive diagnosis and to provide tissue for genetic testing. However, re-biopsy may affect clinical trial eligibility and response assessment. Further investigation is needed to determine the clinical benefit of molecular analysis in EwS relapse [18].

The definitive diagnosis of Ewing Sarcoma (EwS) should be conducted or reviewed at a sarcoma reference center through biopsy, ensuring the procurement of sufficient material for conventional histology, immunohistochemistry, molecular pathology, and biobanking [19].

Upon gross examination, untreated EwS typically presents a grey-white, soft appearance with frequent areas of hemorrhage and necrosis. Histologically, EwS displays a solid growth pattern consisting of monomorphic small cells with round nuclei. These cells exhibit finely stippled chromatin, and nucleoli are typically not conspicuous. Approximately half of EwS tumors contain extensive glycogen deposits in the cytoplasm, resulting in positive Periodic Acid-Schiff (PAS) staining. An 'atypical' variant of EwS, known as the 'large cell' variant, has been reported, characterized by larger nuclei with irregular contours, prominent nucleoli, and usually negative PAS staining [20].

Immunohistochemistry often employs CD99, a cell surface glycoprotein, as a sensitive but nonspecific diagnostic marker for EwS, with approximately 95% of EwS cases exhibiting strong, diffuse membranous CD99 expression [21]. However, CD99 expression is also found in various normal tissues and a wide range of tumor types, including other Small Round Cell Sarcomas (SRCSs), lymphoblastic lymphoma, and leukemia. Therefore, several more specific or supplementary immunohistochemical markers have been proposed. For instance, the detection of FLI1 is relatively specific for EwS, although its specificity is limited due to its expression in lymphoblastic leukemias, lymphomas, several soft-tissue sarcomas, and because approximately 15% of EwS cases involve variant translocations not linked to FLI1 [22]. Other markers like Caveolin-1, NK2 homeobox 2 (Nkx-2.2), or combinations of immunohistochemical markers like B-cell CLL/lymphoma 11B (BCL11B) and Golgi glycoprotein 1 (GLG1) have been suggested to support EwS diagnosis, especially in CD99-negative cases, but require validation in prospective studies [23, 24].

Currently, the definitive diagnosis of EwS can only be confirmed through molecular pathology, which is particularly crucial in cases with unusual clinical and pathological characteristics. Fluorescence in situ hybridization (FISH) to detect EWSR1 rearrangements and/ or Reverse Transcription-Polymerase Chain Reaction (RT-PCR) to detect FET-ETS gene fusions specific to EwS have served as diagnostic tools for the past 25 years [25]. Commercially available assays using EWSR1 break-apart probes primarily detect EWSR1 rearrangements, which is significant for distinguishing EwS from other sarcoma subtypes that involve EWSR1 fusions with non-ETS genes. However, FISH for EWSR1 break-apart can sometimes yield misleading results in Malignant Rhabdoid Tumors (MRTs) due to deletions in the genetic region encompassing SMARCB1, which may also involve the EWSR1 gene. In such cases, an immunohistochemical stain for INI1 (encoded by SMARCB1) is recommended, especially in young patients or cases with congenital small-round cell tumors, and when FISH suggests an EWSR1 break-apart [26]. Loss of INI1 expression should prompt further confirmation of the diagnosis of MRT.

While break-apart FISH assays can reliably detect rearrangements of EWSR1 and FUS, which are most common in classical EwS, RNAbased approaches may be necessary for cases involving specific gene fusions (e.g., EWSR1-ERG) that are challenging to detect using routine FISH. The same applies to rearrangements involving CIC and BCOR, where FISH and RNA-based analyses may complement each other. In the current landscape, molecular genetic testing is essential for the diagnostic accuracy of sarcoma and proper clinical management, even when histological diagnosis is established by expert pathologists in the field. Next-Generation Sequencing (NGS) is advisable for SRCSs where FISH and/or RT-PCR cannot definitively confirm the EwS diagnosis [27].

Treatment

Local treatment strategies for Ewing Sarcoma (EwS) are highly individualized, involving collaboration between patients, families, and expert interdisciplinary tumor boards. The choice of the optimal approach for local control in EwS patients is influenced by various factors, including patient age, tumor characteristics, and extension. However, there is a scarcity of randomized studies directly comparing surgery and Radiotherapy (RT), as well as their timing and sequence [28].

While some studies suggest the potential superiority of surgical resection over definitive RT for local control, conducting future randomized trials in this context presents practical challenges. Consequently, many clinicians advise consultations with both surgical oncologists and radiation oncologists to provide comprehensive insights into the pros and cons of different local control approaches for patients and their families [15]. Multidisciplinary tumor boards also play a pivotal role in guiding decisions related to local control.

Balancing the risk of local recurrence with potential late effects is paramount. Surgical resection typically follows an initial phase of neoadjuvant chemotherapy, with exceptions made for emergency surgical interventions, such as those necessitated by spinal cord compression. Patients should be referred to experienced centers for surgical procedures, with the timing contingent on the duration of neoadjuvant chemotherapy, logistical considerations, and technical factors [29].

Principles of surgical resection adhere to Enneking's guidelines, emphasizing wide resections. Intralesional resection or debulking surgery offers no improvement in prognosis, underscoring the importance of comprehensive pretreatment imaging. Reconstructive surgical methods are employed as needed, with options including vascularized fibula grafts, allografts, and irradiated autografts. Tumor endoprostheses are commonly used for bone reconstruction, particularly in cases requiring joint replacement. Growth prostheses see less use in very young children due to concerns regarding softtissue coverage and future revisions [30].

Regardless of the chosen surgical method, achieving long-term functional outcomes necessitates lifelong physical and psychosocial rehabilitation. The surgical margin status, indicating the presence of tumor tissue at the resection edge, significantly impacts local recurrence rates and overall survival. Striking the right balance between adequate margins for the oncological control [31] and functional preservation is crucial. While various criteria exist, an adequate response to chemotherapy generally involves >90% necrosis [15].

Additional RT is recommended for positive margins, with European protocols also suggesting RT for narrow margins and/or poor histological response (≥10% feasible tumor cells in the sample) [19]. Combined local therapeutic approaches may be considered for large primary tumors with extensive soft-tissue involvement. Recent studies have shown improved overall survival with combined surgical resection and RT, particularly in non-sacral tumors, even when a wide resection and good histologic response to neoadjuvant chemotherapy are achieved. Nevertheless, the need for additional RT in extremity EwS remains a subject of debate due to low rates of local recurrence and associated toxicity [27,32].

Local treatment strategies for Ewing Sarcoma (EwS) should be tailored to each patient, complementing systemic therapies. Comprehensive local treatment involving both the primary tumor and extrapulmonary metastases yields better outcomes than treating them separately [33].

For disseminated EwS, surgery for both primary and metastatic sites or definitive radiotherapy (RT) offers similar survival rates, but combining these modalities enhances survival. Solitary bone metastases can be treated with surgery, RT, or both if morbidity is acceptable [33]. Patients with lung metastases should receive similar local treatments as those without them.

In relapsed EwS, local control strategies like surgery or RT can improve outcomes for localized relapses but are less feasible for widespread metastases. Aggressive surgery may be considered for locally recurrent disease without metastases. The role of pulmonary metastasectomy remains debated. For disseminated relapsed EwS, surgery and radiation are mainly palliative [33].

RT is a crucial component of EwS treatment, whether as definitive therapy or in conjunction with surgery. The timing of RT depends on tumor characteristics. Modern RT techniques, like intensitymodulated RT (IMRT) and Proton Beam Therapy (PBT), minimize side effects. Fractionation regimens, such as hyperfractionation, reduce long-term toxicity, especially for extremity or pelvic EwS [34, 35].

Dose prescription varies based on factors like tumor extent and patient age. Postoperative RT enhances local control but may not always be necessary for extremity EwS. Target volume delineation aims to encompass all tumor areas [36].

In disseminated EwS, RT addresses both primary and extrapulmonary sites. Whole-Lung Irradiation (WLI) is indicated for exclusive pulmonary metastases. Radiation toxicity should be considered, especially when combined with chemotherapy [37].

In palliative care, RT can provide medium-term local control, especially for cases of previous local failure. It is effective for symptom relief, addressing issues like pain, fractures, or compression through hypofractionated RT [38].

Markers

In the context of Ewing sarcoma (EwS), the identification of diagnostic, prognostic, and therapeutic markers within the bloodstream remains a challenge. Unlike some other cancer types, EwS lacks specific proteins or metabolic products that can be used for diagnostic purposes or early relapse detection. Instead, researchers have turned their attention to liquid biopsy components, such as Circulating Tumor Cells (CTCs), circulating tumor DNA (ctDNA), circulating tumor RNA, and extracellular vesicles like exosomes. These components may carry tumor-specific materials or reflect the tumor microenvironment, offering potential clinical utility [39].

Prognostic markers in EwS, intended to predict the risk of disease progression or recurrence and associated outcomes, primarily revolve around histomorphological features and genetic markers. These markers encompass genomic, transcriptomic, and epigenetic alterations. However, these markers have not yet been incorporated into established clinical standards. Currently, disease status remains the most reliable clinical prognostic marker, but it lacks the ability to distinguish between individuals with varying responses to therapy within the group of metastasized and/or recurrent patients [39].

The use of 18F-FDG-PET/CT as a prognostic tool in EwS is a subject of conflicting research findings. Therapy response is primarily assessed using imaging techniques based on morphological criteria, such as tumor volume and morphological regression (e.g., necrosis). 18F-FDG-PET provides additional quantitative parameters like Metabolic Tumor Volume (MTV) and Total Lesion Glycolysis (TLG) [40]. However, the effectiveness of treatment following induction chemotherapy can only be objectively evaluated through intratumoral histopathological examination, which is not applicable when definitive radiotherapy is the chosen treatment approach. Biomarkers capable of indicating the toxicity of systemic and local treatments in EwS are still not well understood.

Conclusion

In conclusion, Ewing Sarcoma (EwS), a challenging malignancy primarily affecting adolescents and young adults, demands a multifaceted approach for optimal management. Accurate diagnosis, relying on biopsies, molecular markers, and advanced imaging techniques, lays the foundation for tailored treatment. The current therapeutic paradigm involves neoadjuvant chemotherapy followed by surgery or radiation, with modern radiation techniques such as IMRT and PBT showing promise. Local therapy decisions are contingent on individual factors, with combined approaches often proving advantageous for disseminated and relapsed EwS cases. Maintenance therapy trials with agents like oral cyclophosphamide, celecoxib, and zoledronic acid are ongoing, although conclusive evidence remains elusive. Biomarkers for diagnosis and prognosis continue to evolve, with liquid biopsy components exhibiting potential. Imaging, particularly 18F-FDG-PET/CT, plays a crucial role in assessing treatment response. As research in EwS advances, the ongoing quest for refined management strategies offers hope for improved outcomes in combating this disease.

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