Ewing Sarcoma-Diagnosis, Treatment, Clinical Challenges and Future Perspectives

Abstract

Ewing sarcoma, a highly aggressive bone and soft-tissue cancer, is considered a prime example of the paradigms of a translocation-positive sarcoma: a genetically rather simple disease with a specific and neomorphic-potential therapeutic target, whose oncogenic role was irrefutably defined decades ago. This is a disease that by definition has micrometastatic disease at diagnosis and a dismal prognosis for patients with macrometastatic or recurrent disease. International collaborations have defined the current standard of care in prospective studies, delivering multiple cycles of systemic therapy combined with local treatment; both are associated with significant morbidity that may result in strong psychological and physical burden for survivors. Nevertheless, the combination of non-directed chemotherapeutics and ever-evolving local modalities nowadays achieve a realistic chance of cure for the majority of patients with Ewing sarcoma. In this review, we focus on the current standard of diagnosis and treatment while attempting to answer some of the most pressing questions in clinical practice. In addition, this review provides scientific answers to clinical phenomena and occasionally defines the resulting translational studies needed to overcome the hurdle of treatment-associated morbidities and, most importantly, non-survival.

Keywords: EWSR1-FLI1; chromosomal translocation; ewing sarcoma; fusion protein; limb salvage; metastasis; small round cell sarcoma; splicing; transcription.

Figure 1

Radiological modalities and time points. The different stages of diagnosis and therapy are juxtaposed to the time points of radiological work-up with indicated modalities. CTX, chemotherapy; CT, computed tomography; MRI, magnetic resonance imaging; CM, contrast medium; SE, conventional spin echo; TSE, turbo spin echo; STIR, short tau inversion recovery sequence.

Figure 2

Schematic diagnostic workflow of EwS and related entities.

Figure 3

Schematic pathological workflow of EwS and related entities.

Figure 4

The broad spectrum of Ewing sarcoma (EwS) and related entities in historical evolution. Historical evolution of the concept of EwS and related entities. Several representative milestones are shown: 1980, introduction of the concept of atypical (large-cell) EwS and extraskeletal EwS [69]; 2008, introduction of mass sequencing [85]; 2013, fourth edition of the WHO classification of bone and soft-tissue tumors [86]; 2020, fifth edition of the WHO classification of bone and soft-tissue tumors [16]. The names in the circles indicate the genes most commonly involved in gene fusions of each sarcoma entity. ELS, Ewing-like sarcoma; ITD, internal tandem duplication; (p)PNET, (peripheral) primitive neuroectodermal tumors.

Figure 5

The broad spectrum of EwS and related entities in diagnostical work-up. Representative images of small round cell sarcomas showing classic EwS with uniform small round cells, strong expression of CD99, and aberrant patterns of EWSR1 break-apart FISH, pointing to a genomic rearrangement (upper panel left). EWSR1-NFATc2 translocated sarcoma with a more epithelioid cytology, positivity for CD99, and amplified isolated red signals in EWSR1 break-apart FISH, suggesting rearrangement of the EWSR1 gene associated with additional chromosomal aberrations (upper panel right). BCOR-CCNB3 translocated sarcoma with primitive round to spindle cells arranged in sheets, heterogeneous CD99 expression, and positivity for BCOR by immunohistochemistry (lower panel left). CIC-rearranged sarcoma with a higher degree of cytological variability compared to classic EwS, inconsistent patchy CD99 positivity, and a classic break-apart in a CIC FISH assay (lower panel right).

Figure 6

Schematic workflow for local therapy decision in primary localized sacral/pelvic Ewing sarcoma (EwS) and related entities based on EURO Ewing 2012 and COG AEWS1031 guidelines. The EURO Ewing 2012 recommends adjuvant radiotherapy for most sacral/pelvic tumors (dotted line). * 45 Gy if organs at risk (e.g., joints, myelon) are near the tumor. CTX, chemotherapy; CR, complete response; MRI, magnetic resonance imaging; R, resection status; RT, radiotherapy; TB, tumor board.

Figure 7

Schematic workflow for local therapy decision in thoracic/mediastinal Ewing sarcoma (EwS) and related entities based on EURO Ewing 2012 and COG AEWS1031 guidelines. Preoperative RT concepts are not included. * in case of local pleural infiltration, pleurectomy may be indicated. CTX, chemotherapy; CR, complete response; ITB, international tumor board; PR, partial response; R, resection status; RT, radiotherapy.