Ewing family tumours: a paediatric perspective

Sarcomas are malignant tumours of the connective tissues and are proportionately much more common in children than in adults. The Ewing family of tumours (EFT) is a group of sarcomas sharing rearrangement of the EWSR1 gene on 22q12, and include Ewing sarcoma/primitive neuroectodermal tumour, desmoplastic small round cell tumour, angiomatoid fibrous histiocytoma and clear cell sarcoma. Other tumours harbouring EWSR1 rearrangements include myoepithelial tumours, myxoid liposarcoma and extraskeletal chondrosarcoma. In addition, a group of Ewing-like primitive round cell sarcomas have been recently described in a paediatric population, further expanding the list of EFT. This review will focus on the histopathological, immunohistochemical and molecular genetic features of EFT, with an emphasis on those predominantly occurring in the paediatric population.     

A renal cell carcinoma with EWSR1‐TFE3 fusion gene

Both EWSR1 and TFE3 are well‐known oncogenes. EWSR1 encodes an RNA‐binding protein involved in multiple soft tissue tumors, including Ewing's sarcoma/peripheral neuroectodermal tumor, desmoplastic small round cell tumor, soft tissue clear cell sarcoma (malignant melanoma of soft parts), extraskeletal myxoid chondrosarcoma, and myxoid liposarcomas. TFE3 regulates both Golgi and lysosomal homeostasis and is rearranged in renal cell carcinoma (RCC), alveolar soft part sarcoma, epithelioid hemangioendothelioma, and perivascular epitheloid cell tumors (PEComas). In this report, we found a rare case of RCC with a fusion between 5′ EWSR1 and 3′ TFE3. The fusion product retained most functional motifs of TFE3. The oncogenic mechanism likely involves TFE3 overexpression through its juxtaposition with the regulatory elements of EWSR1 and its translocation to the nucleus, resulting in the deregulation of Golgi and lysosomal homeostasis. This is a second case of RCC containing EWSR1‐TFE3 fusion.     

‘I Can’t Keep Up!’: an update on advances in soft tissue pathology occurring after the publication of the 2020 World Health Organization classification of soft tissue and bone tumours

Progress in our understanding of the pathogenesis and diagnosis of soft tissue neoplasia is exceptionally rapid. Although the most recent World Health Organization classification of soft tissue tumours contains many new entities and refinements of older ones, even this comprehensive document is by now incomplete or in need of modification. This review will attempt to summarise the developments in soft tissue pathology that have occurred since 2020, emphasising lesions for which morphology and genetics intersect in a complementary fashion. Novel entities discussed include KMT2A-rearranged sarcoma, PRRX::NCOAx fibroblastic tumours, EWSR1::PATZ1 sarcomas, BRAF-altered infantile fibrosarcoma-like lesions, NUTM1-rearranged colorectal sarcomas, and a variety of interesting giant cell-rich and matrix-producing lesions. In addition, recently described mimics of atypical lipomatous tumour/well-differentiated liposarcoma are covered, as is a wholly new, morphologically defined and genetically confirmed entity, pseudoendocrine sarcoma. Finally, exciting new developments in the use of immunohistochemistry as a surrogate for molecular genetic techniques are discussed.     

Round cell sarcomas beyond Ewing: emerging entities

Primitive small blue round cell tumours (SBRCT) of childhood and young adults have been problematic to diagnose and classify. Diagnosis is also complicated in cases with atypical morphology, aberrant immunoprofiles and unusual clinical presentations. Even with the increased use of ancillary techniques in archival material, such as immunohistochemistry and molecular/genetic methods, a proportion of these tumours cannot be subclassified into specific histological types. A subset of tumours resembling microscopically the Ewing sarcoma family of tumours (EFT), being composed of primitive small round cells and occurring in paediatric or young adult age groups, remain unclassified, being negative for EWSR1, SS18(SYT), DDIT3(CHOP) and FOXO1(FKHR) gene rearrangements by FISH/RT–PCR. A small number of cases sharing the undifferentiated EFT appearance have been characterized recently carrying BCOR–CCNB3 or CIC–DUX4 fusions. However, based on the somewhat limited number of cases, it remains unclear if these newly defined genetic entities belong to any of the pre‐existing clinicopathological disorders or represent altogether novel conditions. This review presents the latest molecular findings related to these SBRCTs, beyond the common EWSR1–ETS fusions. Specific attention has been paid to morphological features not associated typically with classic EFT, and the value of ancillary tests that can be applied when dealing with EWSR1‐negative SBRCTs is discussed.     

Undifferentiated sarcoma of bone with a round to epithelioid cell phenotype harboring a novel EWSR1-SSX2 fusion identified by RNA-based next-generation sequencing

Due to the increased application of RNA-based next-generation sequencing techniques on bone and soft tissue round cell sarcomas new fusions are frequently found, thereby expanding the molecular landscape of these tumors. In this report, we describe and discuss the finding of an undifferentiated sarcoma of the bone with a round to epithelioid cell phenotype harboring a novel EWSR1-SSX2 fusion. Treatment of this new bone tumor entity according to the Euro Ewing 2012 protocol led to complete pathologic response.     

Adamantinoma‐like Ewing sarcoma of the parotid gland: Cytopathologic findings and differential diagnosis

Adamantinoma‐like Ewing sarcoma (AES) is a rare variant of Ewing sarcoma family of tumors (EFTs), primarily affecting bone and soft tissue. AES has mixed features of Ewing sarcoma (ES)/primitive neuroectodermal tumor (PNET) and adamantinoma with a complex immunoprofile and EWSR1 gene rearrangements. Herein, we report a 72‐year‐old male who presented with left parotid mass, right neck mass and thyroid nodules. Fine needle aspiration of the left parotid mass displayed nests of monotonous epithelioid cells with basaloid features in a background of small round blue cells and lymphocytes. AES can involve head and neck region and is characterized by groups of primitive small round blue cells admixed with groups of epithelioid cells with amphophilic cytoplasm and focal squamous differentiation. The proportion of these components can be variable, creating diagnostic challenges, particularly in unusual anatomic sites such as the parotid gland. However, when additional material is available, CD99 and/or FLI1 immunostains need to be included for diagnostic confirmation.     

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

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).