From the ashes of “Ewing-like” sarcoma: A contemporary update of the classification, immunohistochemistry, and molecular genetics of round cell sarcomas

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Abstract

Round cell sarcomas include a diverse group of bone and soft tissue tumors, which comprise well-defined entities as well as several nascent categories presented in the 2020 World Health Organization classification. The morphologic overlap yet disparate nosology, prognostic implications, and management strategies places a high value on ancillary testing, including a strategic immunohistochemical approach and directed confirmation by cytogenetic and molecular genetic methods. We review the diagnostic categories that have emerged from the former wastebasket “undifferentiated round cell sarcoma” (“Ewing-like” sarcomas), with an emphasis on algorithmic exclusion of nonsarcomatous entities, diagnostic stratification of well-defined entities (Ewing sarcoma, rhabdomyosarcomas, poorly differentiated synovial sarcoma), and a discussion of the new categories with novel genetic alterations (CIC-rearranged sarcomas, sarcomas with BCOR genetic alterations, and round cell sarcomas with EWSR1-non-ETS fusions).

Introduction

The category of round cell sarcomas describes a diverse group of tumors of bone and soft tissue, including well-known entities that demonstrate overlapping morphologic features, as well as a growing family of “undifferentiated” sarcomas that lack EWSR1 (or FUS) rearrangements (formerly designated “Ewing-like” sarcomas). Long established entities with round cell morphology include Ewing sarcoma, rhabdomyosarcomas (the alveolar and embryonal subtypes), desmoplastic small round cell tumor (DSRCT), and several other sarcomas that can sometimes display round cell morphology (high grade myxoid (formerly “round cell”) liposarcoma, poorly differentiated synovial sarcoma, mesenchymal chondrosarcoma, small cell variant of osteosarcoma). The differential diagnostic considerations may also include nonsarcomatous tumors, which should be carefully excluded (depending upon clinical context), but will not be discussed in-depth in this review; these include leukemias and lymphomas (particularly diffuse large B-cell lymphoma, Burkitt lymphoma, and lymphoblastic leukemia/lymphoma), neuroblastoma, melanoma, and carcinomas including small cell / neuroendocrine carcinoma. In addition, recent genetic discoveries and clinicopathologic studies have allowed subclassification of tumors within the former wastebasket of undifferentiated round cell sarcomas into new distinct entities in the 2020 World Health Organization (WHO) classification: round cell sarcomas with EWSR1-non-ETS fusions, CIC-rearranged sarcomas, and sarcomas with BCOR genetic alterations.1 The Ewing sarcoma section is now included with the other undifferentiated small round cell sarcomas of bone and soft tissue, to reflect a more accurate biologic understanding of the complex genomic landscape and clinical implications of this updated category.
Of note, a recent consensus statement from the HUGO gene nomenclature committee has introduced a new recommended symbol for gene fusion events, namely, the use of a double colon between the involved genes – e.g., BCR::ABL1 (or the non-italicized version for the corresponding fusion protein product).2 The updated nomenclature will be used in this review.
Because these tumors share overlapping morphologic features as well as a similar predilection for pediatric and adolescent patients, ancillary techniques are becoming increasingly important for diagnosis, which ultimately direct therapy and dictate prognosis. Nonetheless, morphologic evaluation by H&E and awareness of epidemiology retain central diagnostic importance, particularly when combined with a strategic immunohistochemical approach, as discussed below. This review will provide an update on the immunohistochemical and molecular features of the discrete tumor categories of round cell sarcomas, with a focus on an algorithmic approach to diagnosis, and a discussion of novel and emerging entities. Due to their rarity and complexity, these tumors are best diagnosed with multidisciplinary collaboration between pathologists, musculoskeletal radiologists, medical oncologists, orthopedic and surgical oncologists, and radiation oncologists, preferably within a regularly convening interdisciplinary sarcoma tumor board.

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Section snippets

Role of immunohistochemistry and molecular genetics

A key first task in evaluation of a round cell tumor is exclusion of nonsarcomatous entities, such as carcinomas, melanoma, leukemias, and lymphomas (Fig. 1). Vimentin is expressed not only in sarcomas, but also in some carcinomas and lymphomas, and is therefore not diagnostically useful. Broad-spectrum keratin antibodies are critical for exclusion of carcinoma; applying more than one keratin antibody is advisable. A reasonable panel might include the keratin cocktail AE1/AE3 or the clones

Undifferentiated small round cell sarcomas of bone and soft tissue

The 2020 WHO Classification has reorganized this section to include Ewing sarcoma, as well as three new entities (formerly referred to as “Ewing-like” sarcomas): round cell sarcoma with EWSR1-non-ETS fusions, CIC-rearranged sarcoma, and sarcomas with BCOR genetic alterations. These tumor types will be discussed below, with a focus on a directed immunohistochemical approach to diagnosis, although confirmation by molecular genetic techniques is often needed. Finally, there remains a small subset

Ewing sarcoma

Ewing sarcoma is a small round cell sarcoma with a gene fusion involving a member of the FET gene family (usually EWSR1; much less commonly FUS) and a member of the ETS (Erythroblast Transformation Specific) transcription factor family. Ewing sarcoma is the second most common malignant bone tumor in children and young adults (after osteosarcoma) ,19 with a slight male predominance; nearly 80% of patients are under 20 years.1 Osseous tumors arise in the diaphysis and metaphysis of long bones,

Round cell sarcomas with EWSR1-non-ETS fusions

A new category in the WHO includes round or spindle cell sarcomas with EWSR1 or FUS rearrangements partnered with non-ETS family members; emerging categories are the EWSR1::PATZ1 and EWSR1::NFATC2 sarcomas. EWSR1::PATZ1 sarcomas have a broad age range and equal gender distribution and a predilection for the deep soft tissue of the chest wall and abdomen, with extremity and head and neck involvement also described.60, 61, 62 This fusion has also been detected in CNS glioneuronal tumors63, 64, 65

Conclusions

The category of undifferentiated round cell sarcomas encompasses diverse tumor types with somewhat overlapping morphologic features, including well-established entities such as Ewing sarcoma, and more recently described, novel entities including CIC-rearranged, BCOR family, and round cell sarcomas with EWSR1-non-ETS fusions. The clinicopathologic overlap between these groups of tumors (but disparate prognoses and yet-to-be determined optimal therapies) mandates a rational immunohistochemical

Declaration of Competing Interest

Michael E. Kallen has no disclosures to report. Jason L. Hornick is a consultant to Aadi Biosciences and TRACON Pharmaceuticals.

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