The diversity of soft tissue tumours with EWSR1 gene rearrangements: a review

Many soft tissue sarcomas have chromosomal translocations with resultant formation of new fusion genes. Among the genes that can be rearranged, the EWSR1 gene has been identified as a partner in a wide variety of clinically and pathologically diverse sarcomas as well as some non‐mesenchymal tumours. The former include Ewing sarcoma and similar (Ewing‐like) small round cell sarcomas, desmoplastic small round cell tumour, myxoid liposarcoma, extraskeletal myxoid chondrosarcoma, angiomatoid fibrous histiocytoma, clear cell sarcoma of soft tissue and clear cell sarcoma‐like tumours of the gastrointestinal tract, primary pulmonary myxoid sarcoma, extrasalivary myoepithelial tumours and sporadic examples of low‐grade fibromyxoid sarcoma, sclerosing epithelioid fibrosarcoma and mesothelioma. EWSR1 is a ‘promiscuous’ gene that can fuse with many different partner genes, but sometimes this results in phenotypically identical tumours. EWSR1 can, conversely, partner with the same genes in morphologically and behaviourally different neoplasms. This paper reviews the diversity of the several soft tissue tumour types that are associated with rearrangement of the EWSR1 gene.     

Immunohistochemistry of soft tissue tumours – review with emphasis on 10 markers

Immunohistochemistry is an integral component in the proper analysis of soft tissue tumours, and a simple panel of six markers is useful in practical triage: CD34, desmin, epithelial membrane antigen (EMA), keratin cocktail AE1/AE3, S100 protein and alpha smooth muscle actin (SMA). These markers frequently assist in the differential diagnosis of fibroblastic, myoid, nerve sheath and perineurial cell tumours, synovial and epithelioid sarcoma and others. However, they all are multispecific, so that one has to be cognizant of their distribution in normal and neoplastic tissues. Four additional useful markers for specific tumour types are discussed here: CD31 and ERG for vascular endothelial tumours, and KIT and DOG1/Ano‐1 for gastrointestinal stromal tumours (GISTs). However, hardly any marker is totally monospecific for any one type of tumour. Furthermore, variably lineage‐specific markers do not usually distinguish between benign and malignant proliferations, so that this distinction has to be made on histological grounds. Immunohistochemical evaluation is most useful, efficient and cost‐effective when used in the context of careful histological evaluation by an experienced pathologist, aware of all diagnostic entities and their histological spectra. Additional diagnostic steps that must be considered in difficult cases include clinicoradiological correlation and additional sampling of remaining wet tissue, if possible.     

The evolving classification of soft tissue tumours – an update based on the new 2013 WHO classification

The new World Health Organization (WHO) classification of soft tissue tumours was published in early 2013, almost 11 years after the previous edition. While the number of newly recognized entities included for the first time is fewer than that in 2002, there have instead been substantial steps forward in molecular genetic and cytogenetic characterization of this family of tumours, leading to more reproducible diagnosis, a more meaningful classification scheme and providing new insights regarding pathogenesis, which previously has been obscure in most of these lesions. This brief overview summarizes changes in the classification in each of the broad categories of soft tissue tumour (adipocytic, fibroblastic, etc.) and also provides a short summary of newer genetic data which have been incorporated in the WHO classification.     

Intratumoural lymphatics in benign and malignant soft tissue tumours

Soft tissue sarcomas do not generally metastasise via lymphatics, and the presence or absence of lymphatic vessels within sarcomas and benign soft tissue tumours is not known. In this study, we determined whether lymphatic vessels were present in a wide range of benign and malignant soft tissue lesions by examining intratumoural expression of the lymphatic endothelial cell markers, Lyve-1 and podoplanin. Intratumoural Lyve-1+/podoplanin+ lymphatics were not identified in sarcomas apart from all cases of epithelioid sarcoma (a tumour which is known to metastasise to lymph nodes) and a few cases of leiomyosarcoma, rhabdomyosarcoma and synovial sarcoma. Intratumoural lymphatics were also absent in most benign soft tissue tumours. Reparative and inflammatory soft tissue lesions contained lymphatics, as did all (pseudosarcomatous) proliferative myofibroblastic lesions including nodular, proliferative and ischaemic fasciitis, elastofibroma, nuchal fibroma and deep fibromatosis. Our results show that most soft tissue sarcomas do not contain intratumoural lymphatics, a finding which is consistent with the infrequent finding of sarcoma metastasis to lymph nodes. In contrast to fibrosarcoma and a number of other malignant spindle cell tumours, proliferative fibroblastic/myofibroblastic lesions of soft tissue contain intralesional lymphatic vessels.     

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).     

Rarely metastasizing soft tissue tumours

Soft tissue tumours that rarely metastasize have been afforded their own subcategory in recent WHO classifications. This review discusses the nature of these tumours and the difficulty in constructing usefully simple classifications for heterogeneous and complex groups of tumours. We also highlight the specific rarely metastasizing soft tissue tumours that have been recently added to the WHO classification (phosphaturic mesenchymal tumour, pseudomyogenic haemangioendothelioma) and those entities where there have been recent important defining genetic discoveries (myxoinflammatory fibroblastic sarcoma, solitary fibrous tumour, myoepitheliomas).     

Molecular pathology of bone tumours: diagnostic implications

Alongside histomorphology and immunohistochemistry, molecular pathology is now established as one of the cornerstones in the tissue diagnosis of bone tumours. We describe the principal molecular pathological techniques employed, and each of the bone tumour entities where their identified characteristic molecular pathological changes can be detected to support and confirm the suspected histological diagnosis. Tumours discussed include fibrous dysplasia, classical and subtype osteosarcomas, central and surface cartilaginous tumours, Ewing's sarcoma, vascular tumours, aneurysmal bone cyst, chordoma, myoepithelioma, and angiomatoid fibrous histiocytoma. This is a rapidly evolving field with discoveries occurring every few months, and some of the newer entities (the Ewing's‐like sarcomas), which are principally identified by their molecular pathology characteristics, are discussed.     

Aquaporin-1 and -5 are involved in the invasion and proliferation of soft tissue sarcomas

Background and aim

Recent studies of several carcinomas have reported that aquaporin possesses novel oncogenic properties. The aim of this study was to clarify the involvement of aquaporin-1 and ?5 in the proliferation, invasion and metastasis of soft tissue sarcomas.

Recent developments in soft tissue tumours

This article reviews the clinicopathological features of several recently described soft tissue tumours, namely ossifying fibromyxoid tumour, angiomyofibroblastoma, epithelioid angiosarcoma, retiform haemangioendothelioma, intra-abdominal desmoplastic small cell tumour, spindle cell liposarcoma and low grade fibromyxoid sarcoma. Conceptual changes are also discussed. These include the relationship between Ewing's sarcoma and peripheral primitive neuroectodermal tumour, the proposed use of the term atypical lipoma for a subset of well differentiated liposarcomas, and the occurrence at a wide variety of sites of inflammatory myofibroblastic lesions of uncertain biological potential. In addition, advances in the study of soft tissue lesions at the molecular and cytogenetic levels are outlined, with particular emphasis on the recent identification of tumour-specific karyotypic abnormalities in a wide variety of sarcomas.     

Paraspinal mesenchymal tumors: the overlap between neuropathology and soft tissue pathology

Mesenchymal/soft tissue tumours represent a broad spectrum of lesions, ranging from benign processes to malignant sarcomas. Presenting at virtually any anatomic site, they are encountered in the surgical pathology workload of all histopathologists. The diagnosis can be substantially challenging, especially in small biopsy specimen, and require integration of morphology, clinical data, and ancillary studies. Herein, we review the most common mesenchymal/soft tissue tumours encountered in the central nervous system with particular focus on the paraspinal region, highlighting key points to help the general pathologists approaching such cases, and describing how to distinguish these lesions from potential mimics. In this article we broadly divide the discussed entities into four major categories, primarily based on their morphologic patterns: small round blue cell tumours, non-neural spindle cell tumours, vascular lesions and other (to include chordomas and chondrosarcoma).     

MicroRNA profiling of primary high-grade soft tissue sarcomas

High‐grade soft tissue sarcomas are a heterogeneous and complex group of tumors. MicroRNAs (miRNAs) are considered as attractive candidates that may improve diagnostic, prognostic, and predictive characterization of this group of malignancies. We performed a comprehensive miRNA expression analysis in a series of 76 untreated, primary high‐grade soft tissue sarcomas representing eight subtypes, and in a panel of 15 representative sarcoma cell lines using microarray technology. This screening revealed unique miRNA expression patterns for synovial sarcomas, myxoid liposarcomas, and leiomyosarcomas, and defined unique sets of miRNAs discriminating the different liposarcoma subtypes from non‐neoplastic adipose tissue. The over‐represented miRNAs included members of the miR‐200 family in synovial sarcomas, and the tumor‐associated miR‐9 and miR‐9* in myxoid liposarcomas compared to adipose tissue. Moreover, we found coexpression of 63 miRNAs clustering in a genetically imprinted chromosomal region 14q32.2 separating primary sarcoma samples and sarcoma cell lines into two molecular subgroups. Taken together, our comprehensive miRNA profiling identified a novel set of miRNAs that might contribute to sarcomagenesis and provide a starting point for experimental modulation of relevant targets for new therapeutic strategies in high‐grade sarcomas. © 2012 Wiley Periodicals, Inc.     

Immunohistochemistry in the diagnosis of soft tissue tumours

Immunohistochemistry is particularly important in the field of soft tissue tumours because of their variety and the frequent difficulty of diagnosis. The first part of this paper discusses useful or new antibodies, together with others that are no longer of use. The second part is devoted to the role of immunohistochemistry in the diagnosis of soft tissue tumours: identification of some rare or atypical benign lesions, identification of non-mesenchymal malignant tumours, and classification of sarcomas. The respective roles of immunohistochemistry and molecular biology are underlined.     

Soft tissue tumours in childhood

The spectrum of soft tissue tumours in youg adults is very similar to that in more mature individuals, while those in childhood form a distinct group rarely seen outside the first decade. The majority of these are benign vascular or fibroblastic proliferations; in young children they may be highly cellular and mitotically active, but malignancy should be diagnosed with caution. Congenital soft tissue tumours constitute a special group in which the clinical outcome may be particularly difficult to predict from the histological appearances. This review focuses on those malignant soft tumours which are either peculiar to childhood or which manifest special features in childhood. Some recently recognized benign soft tissue tumours which occur mainly in childhood are also described. The fibromatoses are not discussed. As a guide to the appropriate treatment regime, the main histological distinctions to be drawn are between: 1 tumours of neuroectodermal origin (Ewing's sarcoma and primitive neuroectodermal tumour); 2 other sarcomas; and 3 the fibromatoses and other benign and potentially locally aggressive lesions requiring local excision. Immunohistochemical staining may be of considerable help in achieving the correct diagnosis, but it is vital that a panel of antibodies be applied and the results critically assessed. Cytogenetic analysis is also of growing importance, characteristic karyotypic abnormalities having been demonstrated in Ewing's sarcoma/primitive neuroectodermal tumour, alveolar rhabdomyosarcoma and synovial sarcoma.     

Paediatric and adult soft tissue sarcomas with NTRK1 gene fusions: a subset of spindle cell sarcomas unified by a prominent myopericytic/haemangiopericytic pattern

Neoplasms with a myopericytomatous pattern represent a morphological spectrum of lesions encompassing myopericytoma of the skin and soft tissue, angioleiomyoma, myofibromatosis/infantile haemangiopericytoma and putative neoplasms reported as malignant myopericytoma. Lack of reproducible phenotypic and genetic features of malignant myopericytic neoplasms have prevented the establishment of myopericytic sarcoma as an acceptable diagnostic category. Following detection of a LMNA–NTRK1 gene fusion in an index case of paediatric haemangiopericytoma‐like sarcoma by combined whole‐genome and RNA sequencing, we identified three additional sarcomas harbouring NTRK1 gene fusions, termed 'spindle cell sarcoma, NOS with myo/haemangiopericytic growth pattern'. The patients were two children aged 11 months and 2 years and two adults aged 51 and 80 years. While the tumours of the adults were strikingly myopericytoma‐like, but with clear‐cut atypical features, the paediatric cases were more akin to infantile myofibromatosis/haemangiopericytoma. All cases contained numerous thick‐walled dysplastic‐like vessels with segmental or diffuse nodular myxohyaline myo‐intimal proliferations of smooth muscle actin‐positive cells, occasionally associated with thrombosis. Immunohistochemistry showed variable expression of smooth muscle actin and CD34, but other mesenchymal markers, including STAT6, were negative. This study showed a novel variant of myo/haemangiopericytic sarcoma with recurrent NTRK1 gene fusions. Given the recent introduction of a novel therapeutic approach targeting NTRK fusion‐positive neoplasms, recognition of this rare but likely under‐reported sarcoma variant is strongly encouraged. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Mis-splicing in breast cancer: identification of pathogenic BRCA2 variants by systematic minigene assays

This commentary addresses the issue of the classification of sarcomas in the article written by Watson and colleagues published recently in this journal. The article delves into the molecular characterization and distinct phenotypes of some recently described entities (e.g. BCOR-rearranged sarcomas, CIC-fused sarcomas) and describes new groups with common characteristics. This commentary focuses on several questions raised in the article, such as what makes a group of sarcomas become a clinical entity, which should be the main driver of sarcoma classification, how the classification of small round cell sarcomas is expected to evolve and how high-throughput techniques could be applied to sarcoma diagnosis in the short term. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

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.