PATHOLOGICA 2021;113:70-84; DOI: 10.32074/1591-951X-213 Review The 2020 WHO Classification of Soft Tissue Tumours: news and perspectives Marta Sbaraglia1, Elena Bellan1, Angelo P. Dei Tos1,2 1 Department of Pathology, Azienda Ospedale Università Padova, Padova, Italy; 2 Department of Medicine, University of Padua School of Medicine, Padua, Italy Summary Mesenchymal tumours represent one of the most challenging field of diagnostic pathol- ogy and refinement of classification schemes plays a key role in improving the quality of pathologic diagnosis and, as a consequence, of therapeutic options. The recent publica- tion of the new WHO classification of Soft Tissue Tumours and Bone represents a major step toward improved standardization of diagnosis. Importantly, the 2020 WHO classi- fication has been opened to expert clinicians that have further contributed to underline the key value of pathologic diagnosis as a rationale for proper treatment. Several rel- evant advances have been introduced. In the attempt to improve the prediction of clinical behaviour of solitary fibrous tumour, a risk assessment scheme has been implemented. NTRK-rearranged soft tissue tumours are now listed as an “emerging entity” also in con- sideration of the recent therapeutic developments in terms of NTRK inhibition. This deci- sion has been source of a passionate debate regarding the definition of “tumour entity” as well as the consequences of a “pathology agnostic” approach to precision oncology. In consideration of their distinct clinicopathologic features, undifferentiated round cell sarcomas are now kept separate from Ewing sarcoma and subclassified, according to the underlying gene rearrangements, into three main subgroups (CIC, BCLR and not Received: October 14, 2020 ETS fused sarcomas) Importantly, In order to avoid potential confusion, tumour entities Accepted: October 19, 2020 such as gastrointestinal stroma tumours are addressed homogenously across the dif- Published online: November 3, 2020 ferent WHO fascicles. Pathologic diagnosis represents the integration of morphologic, Correspondence immunohistochemical and molecular characteristics and is a key element of clinical deci- Angelo P. Dei Tos sion making. The WHO classification is as a key instrument to promote multidisciplinarity, Department of Medicine, University of Padua stimulating pathologists, geneticists and clinicians to join efforts aimed to translate novel School of Medicine, Padua, Italy pathologic findings into more effective treatments. E-mail: [email protected] Key words: WHO classification, soft tissue sarcoma, new entity, molecular genetics, Conflict of interest morphology The Authors declare no conflict of interest. How to cite this article: Sbaraglia M, Bellan E, Introduction Dei Tos AP. The 2020 WHO Classification of Soft Tissue Tumours: news and perspectives. Pathologica 2021;113:70-84. https://doi. The publication of the new WHO classification always generates within org/10.32074/1591-951X-213 the sarcoma community great expectations. Mesenchymal tumours are in fact regarded as one of the most challenging fields of diagnostic pathology © Copyright by Società Italiana di Anatomia Pato- and refinement of classification schemes is perceived as the cornerstone logica e Citopatologia Diagnostica, Divisione Itali- ana della International Academy of Pathology around which improving the quality of both pathologic diagnosis and ther- apeutic options 1. Published data indicate in sarcoma a rate of diagnostic OPEN ACCESS inaccuracy ranging between 20 and 30% 2-4. However, this is not at all due to pathologists’ negligence. As a matter of fact, there exist objective This is an open access journal distributed in accordance with the CC-BY-NC-ND (Creative Commons Attribution- factors that appear to impact negatively over both the accuracy and the NonCommercial-NoDerivatives 4.0 International) license: the reproducibility of pathologic diagnosis, factors the pathologist have always work can be used by mentioning the author and the license, but only for non-commercial purposes and only in the original tried to overcome through specific strategies, most of all by implementa- version. For further information: https://creativecommons. tion of diagnostic second opinion in expert centers or within collaborative org/licenses/by-nc-nd/4.0/deed.en networks 5. Four main sources of challenge can be identified. THE 2020 WHO CLASSIFICATION OF SOFT TISSUE TUMOURS 71 1 Rarity. Sarcomas as a whole are characterised ments 10-16. The WHO classification of soft tissue tu- by an incidence of approximately 5 cases/100,000 mours, since 1999 17-19. has introduced a profound thus matching the formal definition of a rare tu- change in its methodological approach aimed to mor 6. However, soft tissue malignancies are fur- support a more rational therapeutic approach. Major ther subclassified in approximately 70 subtypes, changes can be summarised as follows: each characterized by a distinct morphology, that 1 Integration of morphology with immunohisto- often translates into a specific clinical behaviour as chemistry and molecular genetics. The mar- well as into specific therapeutic approaches. More- riage between morphology and genetics by direct over, many histotypes are exceedingly rare (in the involvement of cytogeneticists has certainly repre- range of 0.1 cases/100,000), to the extent that a sented a major step forward. pathologist not working in a high-volume centre 2 Involvement of a broad number of sarcoma ex- may not encounter them for years. In this scenario, pert pathologists. This approach has minimised achieving specific expertise represents undoubt- the risk of generation of “opinion-leader” bias and edly a challenge. has led to a broader diffusion of the classification 2 Intrinsic complexity. Mesenchymal tumours are among pathologists. characterised by specific diagnostic peculiarities. 3 Precise definition of clinicopathological cate- First of all, the mere application of morphologic cri- gories. It is now broadly accepted that in between teria of malignancy used for epithelial cancer are benign and malignant categories there exists an ”in- not always applicable. The best example is repre- termediate” category of lesions that can be either lo- sented by nodular fasciitis, a benign condition most cally aggressive (i.e. desmoid fibromatosis) or rarely often occurring in the forearm of a young adults, metastasizing (i.e. plexiform fibrohistiocytic tumour). who exhibits clinicopathologic features (rapid 4 Involvement of clinicians. For the first time the growth, hypercellularity and high mitotic activity) 2020 WHO classification of soft tissue and bone that in the context of an epithelial cancer would be tumours, representatives of clinical disciplines highly supportive of a diagnosis of malignancy. The such as medical, surgical and radiation oncology relatively frequent violation of diagnostic criteria of have been directly involved. This close interaction malignancy appears to represent a unique feature has strongly enhanced the clinical value of patho- of mesenchymal tumours and represents one of logical diagnosis. the major reasons for diagnostic inaccuracy. The aim of this paper is to review the main advances 3 Technological complexity. The diagnostic pro- contained in the current classification and also dis- cess of mesenchymal tumours relies upon a com- cuss new perspectives that most likely will generate plex combination of conventional microscopic mor- some debate in the years to come. In consideration of phology, immunohistochemistry, and molecular the complexity of the new classification and despite genetics 7. This requires state of the art molecular the fact that some soft sarcomas can rarely arise pri- technology that more and more includes Next Gen- marily in bone 20, with the exception of undifferentiated eration Sequencing approaches 8. In contrast with round cell sarcoma that can occur both in soft tissue popular belief molecular genetics requires high and bone, we will focus on tumours of the soft tissue. professional expertise coupled with even higher quality control standards (as compared for exam- ple to immunohistochemistry). In this perspective, Advances in classification it is quite intuitive that centralisation of molecular diagnostics in high volume centres is mandatory ADIPOCYTIC TUMOURS on order to maintain high analytic quality 9. The entities characterised by adipocytic differentiation 4 Lower impact of educational efforts. Even if ed- are listed in Table I. Newcomers are represented by ucation still plays a fundamental role in increasing atypical spindle cell/pleomorphic lipomatous tumour diagnostic expertise, it has to be admitted that in and myxoid pleomorphic liposarcoma. Importantly, the field of rare cancers its efficacy is somewhat both lesions are now regarded as benign and there- hampered. Unless a pathologist is continuously fore treated with simple surgical excision. exposed to soft tissue tumours diagnostics, the ex- The label atypical spindle cell lipomatous tumour rep- pertise developed through educational efforts is at resents a new name for the entity formerly known as risk of being gradually lost. spindle cell liposarcoma 21,22 and at the time of first de- The field of sarcoma oncology is rapidly evolving scription regarded as a variant of well differentiated li- through the development of an even close correla- posarcoma. The entity is now defined as an ill-circum- tion between pathologic diagnosis and tailored treat- scribed, moderately