Ewing sarcoma and related FET family translocation-associated round cell tumors: A century of clinical and scientific progress

Abstract

The year 2021 marked the centenary of the first publication of a cancer termed diffuse endothelioma of bone by James Ewing. Its unique features were apparent even in the first case series he described. This new diagnosis was clearly distinct from osteogenic sarcoma and myeloma, which were already well recognized at the time. We undertake this summary to better understanding Ewing sarcoma, contrasting the logarithmic evolution of the standard of care of systemic therapy for this and related diagnoses to the exponential understanding of the molecular biology of this family of tumors. We also outline in this manuscript how the finding of genomic relatives within Ewing sarcoma itself and related tumors, first noted nearly 40 years ago, helps us appreciate the need to find therapeutic plans that are specific for each small round blue cell tumor subtype. The advent of next generation sequencing regarding previously unknown small round blue cell tumor subtypes in many ways puts us back in the shoes of James Ewing in 1921, searching anew for clues leading to better treatments for increasingly rare cancer subsets.

Keywords: BCOR::CCNB3; CIC::DUX4; Ewing sarcoma; FET sarcoma; small round cell tumor; systemic therapy; translocation.

Figure 1.

Radiographs before (A) and after (B) radiation therapy for the index patient.

Figure 2.

Microscopic anatomy of the small cell portion of the primary tumor. Low (A) and high power (B) views demonstrating sheets of polyhedral cells lacking intervening stroma with small-cell rich areas of tumor.

Figure 3.

Translocations found in Ewing sarcoma, related FET-translocated cancers and other small round cell tumors. FET genes are indicated in different shades of yellow and include genes FUS, EWSR1, and TAF15. ETS (Erythroblast Transformation Specific) family genes are indicated in green. CREB (cAMP response element-binding protein) family genes are noted in lavender. Note the three class of distinct small round cell sarcomas: CIC-DUX4 family, BCOR-CCNB3, and FET-NFATC2 sarcomas. FET-CREB sarcomas are pleomorphic and include a number of histologies, including clear cell sarcoma of extremities and of the GI tract, myoepithelial tumors, primary pulmonary mesenchymal neoplasm, angiomatoid fibrous histiocytoma, and other diagnoses. Abbreviations: DSRCT: Desmoplastic small round cell tumor; Epith / Spind Rhabdo: Epithelioid and spindle cell rhabdomyosarcoma.