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In the 2020 5th edition of the World Health Organization classification of soft tissue and bone tumours a major reorganization of Undifferentiated Small Round Cell Sarcomas (USRCS) took place based on the underlying molecular features. The classification now recognizes Ewing sarcoma, round cell sarcoma with EWSR1-non-ETS fusions, CIC-rearranged sarcoma and sarcoma with BCOR alterations. The focus on these genetic alterations highlights the importance of molecular techniques in the diagnosis of these entities. Knowledge of these features can drastically reduce the time to diagnosis and avoid potential misdiagnosis. Molecular diagnostic capabilities should not be limited to an overall small number of centres worldwide as is reflected by the WHO's recognition of 'essential' and 'desirable' diagnostic criteria. A good knowledge of the usual histomorphology, uncommon variants and diagnostic pitfalls remains essential even in centres with access to a full molecular testing arsenal. This review aims to give an overview of the current classification of USRCS not by going over each entity, but instead going over the molecular, morphological, immunophenotypic and clinical features step by step to allow easy comparison of these features between the separate entities., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Pediatric sarcomas present heterogeneous morphology, genetics and clinical behavior posing a challenge for an accurate diagnosis. DNA methylation is an epigenetic modification that coordinates chromatin structure and regulates gene expression, determining cell type and function. DNA methylation-based tumor profiling classifier for sarcomas (known as sarcoma classifier) from the German Cancer Research Center (Deutsches Krebsforschungszentrum) was applied to 122 pediatric sarcomas referred to a reference pediatric oncology hospital. The classifiers reported 88.5% of agreement between histopathological and molecular classification confirming the initial diagnosis of all osteosarcomas and Ewing sarcomas. The Ewing-like sarcomas were reclassified into sarcomas with BCOR or CIC alterations, later confirmed by orthogonal diagnostic techniques. Regarding the CNAs profile, osteosarcomas had several chromosomal gains and losses as well as chromothripsis, whereas Ewing sarcomas had few large events, such as amplifications of chromosomes 8 and 12. The molecular classification together with clinical and histopathological assessment could improve the diagnosis of pediatric sarcomas although there are limitations to deal with more rare classes. This study provides an increase in the number of sarcomas evaluated for DNA methylation profiling in the pediatric population., Competing Interests: Declarations. Ethics approval and consent to participate: The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Ethics Committee of Boldrini Children’s Hospital (CAAE: 28386820.7.0000.5376, CAAE: 22737219.1.0000.5376, CAAE: 44219021.6.0000.5376). Informed consent was obtained from all subjects involved in the study. Consent for publication: Not Applicable. shared information does not compromise individuals' anonymity. Competing interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (© 2024. The Author(s).)

Background: A standardized reporting system for bone and soft tissue tumor cytopathology has not yet been established. The objective of this study was to explore the potential utility of a classification modified from the Milan System for Salivary Gland Cytopathology and compared it with the upcoming World Health Organization (WHO) system for fine-needle aspiration of soft tissue lesions., Methods: The authors reviewed 285 cytology cases of bone/joint (n = 173) and soft tissue (n = 112) lesions, scoring each within diagnostic categories. The results were compared with histologic diagnoses and the risk of malignancy (ROM) for each category, and diagnostic reliability was analyzed., Results: All 285 cases were successfully classified into one of the following categories: nondiagnostic (6.3%), non-neoplastic (11.9%), atypia of uncertain significance (11.9%), benign neoplasm (5.6%), bone and soft tissue neoplasm of uncertain malignant potential (25.3%), suspicious for malignancy (1.4%), and malignant (37.5%). The ROM was 44.4% (eight of /18 cases) in nondiagnostic, 0% (zero of 34 cases) in non-neoplastic, 32.4% (11 of 34 cases) in atypia of uncertain significance, 0% (zero of 16 cases) in benign neoplasm, 16.7% (12 of 72 cases) in bone and soft tissue neoplasm of uncertain malignant potential, 75.0% (three of four cases) in suspicious for malignancy, and 100% (107 of 107 cases) in malignant categories. Using the WHO system, the proportion and ROM of the benign category (non-neoplastic and benign neoplasm) was 17.5% and 0%, respectively. Among benign and malignant lesions, the diagnostic accuracy, sensitivity, and specificity for detecting malignancy were 99.4%, 100%, and 98.0%, respectively., Conclusions: The modified Milan system as well as the WHO system may be a useful cytopathologic classification tool for both bone and soft tissue lesions., (© 2024 The Author(s). Cancer Cytopathology published by Wiley Periodicals LLC on behalf of American Cancer Society.)

With the widespread use of diverse modern molecular testing tools, the last two decades have seen significant advances in the classification of soft tissue neoplasms. Specifically, numerous molecularly defined new entities have been introduced and many established older entities have received more insightful molecular studies that have developed their classification further. The discrepant therapeutic and prognostic implications of this evolving complexity of the nosology of neoplastic diseases make the precise subtyping of soft tissue neoplasms unavoidable. However, these rapid developments of the modern diagnostic molecular pathology did not only offer efficient solutions to many complex classification issues, but they were accompanied by similarly complex and diverse emerging problems. Most importantly, these advances have not only challenged the historical dogma of some phenotypes that were once considered specific, but they also have questioned the value of diagnostic immunohistochemistry compared to emerging modern diagnostic molecular tools. Moreover, the central question of when to test, what to test, and how to test became more confusing. This review addresses the major molecular categories in soft tissue neoplasms, their characteristics, and the criteria to be used for selecting the most appropriate molecular diagnostic tool to be used in individual cases with a special focus on the value of next generation immunohistochemistry as a substitute for molecular testing., Competing Interests: Einhaltung ethischer Richtlinien. Interessenkonflikt: A. Agaimy gibt an, dass kein Interessenkonflikt besteht. Für diesen Beitrag wurden von den Autor/-innen keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien. The supplement containing this article is not sponsored by industry., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Soft tissue tumors are a very heterogeneous group of tumors. Their classification is regularly updated by the World Health Organization (WHO), most recently in 2020. The current classification of soft tissue tumors emphasizes molecular biological tumor characteristics, which enable tumor-specific treatment. In addition to Ewing's sarcoma, which occurs as bone as well as extra-skeletal soft tissue tumors as a small round cell sarcoma, three other subtypes of undifferentiated, small and round cell sarcomas have been introduced. Some names of the new sarcomas can be derived from the gene mutations. The groups of adipocytic and (myo)fibroblastic tumors have been extended by three further entities. There were further additions to vascular soft tissue tumors, smooth muscle cell tumors, peripheral nerve sheath tumors and tumors of uncertain differentiation. A distinction is made between benign, intermediate locally aggressive, intermediate rarely metastatic and malignant soft tissue tumors., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Soft tissue and bone tumors comprise a wide category of neoplasms. Their diversity frequently raises diagnostic challenges, and therapeutic options are continuously developing. The therapeutic success rate and long-term prognosis of patients have improved substantially due to new advances in immunohistochemical and molecular biology techniques. A fundamental contribution to these achievements has been the study of the tumor microenvironment and the reclassification of new entities with the updating of the molecular pathogenesis in the revised 5th edition of the Classification of Soft Tissue Tumors, edited by the World Health Organization. The proposed molecular diagnostic techniques include the well-known in situ hybridization and polymerase chain reaction methods, but new techniques such as copy-number arrays, multiplex probes, single-nucleotide polymorphism, and sequencing are also proposed. This review aims to synthesize the most recent pathogenetic and molecular classifications of soft tissue and bone tumors, considering the major impact of these diagnostic tools, which are becoming indispensable in clinicopathological practice., Competing Interests: Declaration of Competing Interest We declare that we are responsible for recognizing any conflict of interest that could bias our work in the acknowledgments, disclosing all financial support and any other personal connections. This paper contains data that have not previously published or not under consideration for publication in other journals, (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents under the age of 20. The current World Health Organization (WHO) classification for soft tissue and bone tumors recognizes 4 distinct subtypes of RMS based on clinicopathological and molecular genetic features: embryonal, alveolar, spindle cell/sclerosing and pleomorphic subtypes. However, with the increased use of molecular techniques, the classification of rhabdomyosarcoma has been evolving rapidly. New subtypes such as osseus RMS harboring TFCP2/NCOA2 fusions or RMS arising in inflammatory rhabdomyoblastic tumor have been emerging within the last decade, adding to the complexity of diagnosing skeletal muscle tumors. This review article provides an overview of classically recognized distinctive subtypes as well as new, evolving subtypes and discusses important morphologic, immunophenotypic and molecular genetic features of each subtype including recommendations for a diagnostic approach of malignant skeletal muscle neoplasms., Competing Interests: Declaration of competing interest The authors have nothing to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The WHO Classification of Soft Tissue and Bone Tumours currently recognizes four categories of undifferentiated small round cell sarcoma: Ewing sarcoma, round cell sarcoma with EWSR1-non-ETS fusions including NFATc2 and PATZ1, CIC-rearranged sarcoma, and sarcoma with BCOR genetic alterations. These neoplasms frequently pose significant diagnostic challenges due to rarity and overlapping morphologic and immunohistochemical findings. Further, molecular testing, with accompanying pitfalls, may be needed to establish a definitive diagnosis. This review summarizes the clinical, histologic, immunohistochemical, and molecular features of these neoplasms. In addition, differential diagnosis and areas of uncertainty and ongoing investigation are discussed., Competing Interests: Declaration of Competing interest The authors have no relevant conflicts of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Rhabdomyosarcomas comprise the single largest category of soft tissue sarcomas in children and adolescents in the United States, occurring in 4.5 million people aged below 20 years. Based on the clinicopathological features and genetic abnormalities identified, rhabdomyosarcomas are classified into embryonal, alveolar, spindle cell/sclerosing and pleomorphic subtypes. Each subtype shows distinctive morphology and has characteristic genetic abnormalities. This review discusses the evolution of the classification of rhabdomyosarcoma to the present day, together with a discussion of key histomorphological and genetic features of each subtype and the diagnostic approach to these tumours., (© 2021 John Wiley & Sons Ltd.)

Staging of primary musculoskeletal bone and soft-tissue tumors is most commonly performed using the AJCC and the Enneking or Musculoskeletal Tumor Society (MSTS) staging systems. Radiologic imaging is integral in achieving adequate musculoskeletal neoplastic staging by defining lesion extent and identifying regional lymph node involvement and distant metastatic disease. Additional important features in surgical planning, though not distinct components of the staging systems, include cortical involvement, joint invasion, and neurovascular encasement; these features are optimally evaluated by MRI. In 2020, the WHO updated the classification of primary musculoskeletal tumors of soft tissue and bone. The update reflects the continued explosion in identification of novel gene alterations in many bone and soft-tissue neoplasms. This growth in gene alteration identification has resulted in newly designated lesions, reclassification of lesion categories, and improved specificity of diagnosis. Although radiologists do not need to have a comprehensive knowledge of the pathologic details, a broad working understanding of the most recent update is important to aid accurate and timely diagnosis given that histologic grading is a component of all staging systems. By using a multidisciplinary approach for primary musculoskeletal neoplasms involving colleagues in pathology, orthopedic oncology, radiation oncology, and medical oncology, radiologists may promote improved diagnosis, treatment, and outcomes.

Myxoid pleomorphic liposarcoma is a recently defined subtype of liposarcoma, which preferentially involves the mediastinum of young patients and shows mixed histological features of conventional myxoid liposarcoma and pleomorphic liposarcoma. While myxoid pleomorphic liposarcoma is known to lack the EWSR1/FUS-DDIT3 fusions characteristic of the former, additional genetic data are limited. To further understand this tumor type, we extensively examined a series of myxoid pleomorphic liposarcomas by fluorescence in situ hybridization (FISH), shallow whole genome sequencing (sWGS) and genome-wide DNA methylation profiling. The 12 tumors occurred in 6 females and 6 males, ranging from 17 to 58 years of age (mean 33 years, median 35 years), and were located in the mediastinum (n = 5), back, neck, cheek and leg, including thigh. Histologically, all cases consisted of relatively, bland, abundantly myxoid areas with a prominent capillary vasculature, admixed with much more cellular and less myxoid foci containing markedly pleomorphic spindled cells, numerous pleomorphic lipoblasts and elevated mitotic activity. Using sWGS, myxoid pleomorphic liposarcomas were found to have complex chromosomal alterations, including recurrent large chromosomal gains involving chromosomes 1, 6-8, 18-21 and losses involving chromosomes 13, 16 and 17. Losses in chromosome 13, in particular loss in 13q14 (including RB1, RCTB2, DLEU1, and ITM2B genes), were observed in 4 out of 8 cases analyzed. Additional FISH analyses confirmed the presence of a monoallelic RB1 deletion in 8/12 cases. Moreover, nuclear Rb expression was deficient in all studied cases. None showed DDIT3 gene rearrangement or MDM2 gene amplification. Using genome-wide DNA methylation profiling, myxoid pleomorphic liposarcomas and conventional pleomorphic liposarcomas formed a common methylation cluster, which segregated from conventional myxoid liposarcomas. While the morphologic, genetic and epigenetic characteristics of myxoid pleomorphic liposarcoma suggest a link with conventional pleomorphic liposarcoma, its distinctive clinical features support continued separate classification for the time being., (© 2021. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Background: Pediatric fibroblastic/myofibroblastic tumors (PFMTs) can be challenging to definitively classify. Large case series or diagnostic updates have not been recently published despite identification of molecular alterations that could improve diagnostic accuracy. Our review of the literature found that over two-thirds of the more than 30 types of PFMTs harbor recurrent molecular alterations. We performed an institutional review of PFMTs to highlight limitations of a predominantly morphological classification, and evaluated the utility of a next-generation sequencing assay to aid diagnosis., Methods: PFMTs identified over a period of 12 years were reviewed, categorized per the new WHO classification, and tested using the Oncomine Childhood Cancer Research Assay., Results: Eighty-seven specimens from 58 patients were reviewed; 50 were chosen for molecular analysis, 16 (32%) lacking definitive classification. We identified alterations, some novel, in 33% of assayed cases. Expected alterations were identified for most known diagnoses and mutations were identified in 6 of 16 tumors (38%) that were initially unclassified., Conclusion: We confirmed a significant subset of PFMTs remain difficult to classify using current criteria, and that a combined DNA/RNA assay can identify alterations in many of these cases, improving diagnostic certainty and suggesting a clinical utility for challenging cases.

During the last two decades, there have been significant strides in the diagnosis of soft tissue tumors, including identification of various tumor entities, newer immunohistochemical markers, and an increasing number of molecular signatures, defining certain tumors. Lately, there are certain emerging tumor entities, defined by their molecular features with an impact on treatment. At the same time, there is a certain degree of overlap in the expression of certain immunohistochemical antibody markers, as well as genetic markers, with certain gene rearrangements and chimeric fusions observed among completely different tumors. Moreover, a certain amount of clinicopathological, immunohistochemical, and molecular proximity has been unraveled among certain tumor types. Over the years, the World Health Organization (WHO) fascicles on tumors of soft tissue have succinctly brought out these aspects. The present review describes recent updates in the diagnosis of soft tissue tumors, including certain newly described tumor entities; emphasizing upon newer, specific immunohistochemical and molecular markers, along with concepts, regarding "intertumor relationships"., Competing Interests: None

Diagnosing bone and soft tissue neoplasms remains challenging because of the large number of subtypes, many of which lack diagnostic biomarkers. DNA methylation profiles have proven to be a reliable basis for the classification of brain tumours and, following this success, a DNA methylation-based sarcoma classification tool from the Deutsches Krebsforschungszentrum (DKFZ) in Heidelberg has been developed. In this study, we assessed the performance of their classifier on DNA methylation profiles of an independent data set of 986 bone and soft tissue tumours and controls. We found that the 'DKFZ Sarcoma Classifier' was able to produce a diagnostic prediction for 55% of the 986 samples, with 83% of these predictions concordant with the histological diagnosis. On limiting the validation to the 820 cases with histological diagnoses for which the DKFZ Classifier was trained, 61% of cases received a prediction, and the histological diagnosis was concordant with the predicted methylation class in 88% of these cases, findings comparable to those reported in the DKFZ Classifier paper. The classifier performed best when diagnosing mesenchymal chondrosarcomas (CHSs, 88% sensitivity), chordomas (85% sensitivity), and fibrous dysplasia (83% sensitivity). Amongst the subtypes least often classified correctly were clear cell CHSs (14% sensitivity), malignant peripheral nerve sheath tumours (27% sensitivity), and pleomorphic liposarcomas (29% sensitivity). The classifier predictions resulted in revision of the histological diagnosis in six of our cases. We observed that, although a higher tumour purity resulted in a greater likelihood of a prediction being made, it did not correlate with classifier accuracy. Our results show that the DKFZ Classifier represents a powerful research tool for exploring the pathogenesis of sarcoma; with refinement, it has the potential to be a valuable diagnostic tool., (© 2021 The Authors. The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland & John Wiley & Sons, Ltd.)

The fifth edition of the World Health Organization (WHO) classification of soft tissue and bone tumours was published in May 2020. This 'Blue Book', which is also available digitally for the first time, incorporates an array of new information on these tumours, amassed in the 7 years since the previous edition. Major advances in molecular characterisation have driven further refinements in classification and the development of ancillary diagnostic tests, and have improved our understanding of disease pathogenesis. Several new entities are also included. This review summarises the main changes introduced in the 2020 WHO classification for each subcategory of soft tissue and bone tumours., (© 2020 John Wiley & Sons Ltd.)

Abstract: Soft tissue sarcomas (STSs) are heterogeneous at the clinical with a variable tendency of aggressive behavior. In this study, we constructed a specific DNA methylation-based classification to identify the distinct prognosis-subtypes of STSs based on the DNA methylation spectrum from the TCGA database. Eventually, samples were clustered into 4 subgroups, and their survival curves were distinct from each other. Meanwhile, the samples in each subgroup reflected differentially in several clinical features. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was also conducted on the genes of the corresponding promoter regions of the above-described specific methylation sites, revealing that these genes were mainly concentrated in certain cancer-associated biological functions and pathways. In addition, we calculated the differences among clustered methylation sites and performed the specific methylation sites with LASSO algorithm. The selection operator algorithm was employed to derive a risk signature model, and a prognostic signature based on these methylation sites performed well for risk stratification in STSs patients. At last, a nomogram consisted of clinical features and risk score was developed for the survival prediction. This study declares that DNA methylation-based STSs subtype classification is highly relevant for future development of personalized therapy as it identifies the prediction value of patient prognosis., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To identify which classification systems have been used for tumor margin reporting and to determine whether factors (publication year, tumor type, and specialty of the contributing authors) influenced trends in margin reporting within literature describing canine soft tissue sarcoma (STS) and cutaneous mast cell tumors (MCT)., Study Design: Systematic literature review., Methods: Eligible articles were identified through electronic database searches performed for STS and MCT. Data abstracted from relevant studies included publication year, author list, specialty of contributing authors, criteria used to report the planned surgical margins, and the status of histologic margins. Categorization of papers was based on the classification systems used to report surgical and histologic tumor margins., Results: Fifty-three articles were included, 11 on STS, 37 on MCT, and five that included both tumor types. Criteria for classifying the planned surgical margins were described in only 50.9% of studies. Articles that listed a veterinary surgeon as a contributing author (P = .01) and STS articles compared to MCT papers (P = .01) were more likely to report surgical margins. Most (56.6%) studies reported the status of histologic margins dichotomously as "complete" or "incomplete." Although a previously published consensus statement recommended that quantitative criteria be used to report histologic margins, only 7.5% of articles used quantitative methods., Conclusion: Classification systems used for reporting tumor margins were highly variable among studies., Clinical Significance: The findings of this review provide evidence that a standardized classification system for reporting surgical and histologic tumor margins is required in veterinary medicine. A universal system may support more consistent reporting of neoplastic biopsy specimens and allow for more meaningful comparisons across research studies., (© 2020 American College of Veterinary Surgeons.)

Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications.

The fifth edition of the World Health Organization Classification of Tumors of Soft Tissue and Bone was published in early 2020. The revisions reflect a consensus among an international expert editorial board composed of soft tissue and bone pathologists, geneticists, a medical oncologist, surgeon, and radiologist. The changes in the soft tissue tumor chapter notably include diverse, recently described tumor types (eg, atypical spindle cell/pleomorphic lipomatous tumor, angiofibroma of soft tissue, and CIC-rearranged sarcoma), new clinically significant prognostic information for a variety of existing entities (eg, dedifferentiated liposarcoma and solitary fibrous tumor), and a plethora of novel genetic alterations, some of practical diagnostic relevance (eg, NAB2-STAT6 in solitary fibrous tumor, FOSB rearrangements in epithelioid hemangioma and pseudomyogenic hemangioendothelioma, and SUZ12 or EED mutations in malignant peripheral nerve sheath tumor, leading to loss of H3K27 trimethylation). In this review, we highlight the major changes to the soft tissue chapter in the 2020 World Health Organization Classification, as well as the new chapter on undifferentiated small round cell sarcomas, with a focus on updates in diagnostic categories, prognostication, and novel markers. Recent discoveries in molecular genetics are also discussed, particularly those of immediate utility in differential diagnosis, including protein correlates detectable using immunohistochemistry.

Soft tissue tumors are a relatively rare and diagnostically challenging group of neoplasms that can have varying lines of differentiation. Accurate diagnosis is important for appropriate treatment and prognostication. In the 8 years since the publication of the 4th Edition of World Health Organization (WHO) classification of soft tissue tumors, significant advances have been made in our understanding of soft tissue tumor molecular biology and diagnostic criteria. The 5th Edition of the 2020 WHO classification of tumors of soft tissue and bone incorporated these changes. Classification of tumors, in general, but particularly in soft tissue tumors, is increasingly based on the molecular characteristics of tumor types. Understanding tumor molecular genetics improves diagnostic accuracy for tumors that have been difficult to classify on the basis of morphology alone, or that have overlapping morphologic features. In many large hospitals in the United States and Europe, molecular tests on soft tissue tumors are a routine part of diagnosis. Therefore, surgical pathologists should be familiar with newly emerging molecular genetic techniques in clinical settings. In the near future, molecular tests, particularly in soft tissue tumor diagnosis, will become as routine during diagnosis as immunohistochemistry is currently. This new edition provides an updated classification scheme and essential diagnostic criteria for soft tissue tumors. Newly recognized entities and subtypes of existing tumor types, several reclassified tumors, and newly defined molecular and genetic data have been incorporated. Herein, we summarize the updates in the WHO 5th Edition, focusing on major changes in each category of soft tissue tumor, and the newly described tumor entities and subtypes.

Context.—: Undifferentiated pleomorphic sarcoma (UPS) of soft tissue is defined as a sarcoma with no recognizable line of differentiation. During the past few decades, advances in ancillary studies and review of prior UPS diagnoses have narrowed the category of UPS by excluding more-specific malignancies. However, few of those studies have specifically targeted pleomorphic hematolymphoid neoplasms., Objective.—: To determine what fraction of UPS cases are misclassified pleomorphic hematolymphoid neoplasms, such as anaplastic large cell lymphoma, diffuse large B-cell lymphoma, histiocytic sarcoma (HS), myeloid sarcoma, and follicular dendritic cell sarcoma., Design.—: Sixty-one UPS cases were screened by tissue microarray and an immunostain panel with subsequent analysis on whole block sections for suspicious cases., Results.—: Five of 61 tumors (8%) were suggestive of HS based on the screening panel and were further evaluated with additional immunostains (PU.1, CD45, CD163) using whole sections. The 5 candidate HS cases were only focally positive for at most one stain with most staining in smaller, less-pleomorphic cells. Ultimately, no UPS met criteria for anaplastic large cell lymphoma, diffuse large B-cell lymphoma, myeloid sarcoma, follicular dendritic cell sarcoma, or HS., Conclusions.—: Our results suggest that a UPS of somatic soft tissue is unlikely to represent a misclassified hematopoietic malignancy. Exclusion of HS is most challenging, but immunostaining for PU.1, a nuclear transcription factor, may be easier to interpret in this context., (© 2020 College of American Pathologists.)

Objective: To evaluate multiparametric MRI for differentiating benign and malignant soft tissue tumors., Methods: This retrospective study included 67 patients (mean age, 55 years; 18-82 years) with 35 benign and 32 malignant soft tissue tumors. Intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI)-derived parameters ( D , D* , f ), apparent diffusion coefficient (ADC), and dynamic contrast-enhanced (DCE)-MRI parameters ( K trans , K ep , V e , iAUC) were calculated. Myxoid and non-myxoid soft tissue tumors were divided for subgroup analysis. The parameters were compared between benign and malignant tumors., Results: ADC and D were significantly lower in malignant than benign soft tissue tumors (1170 ± 488 vs 1472 ± 349 µm 2 /s; 1132 ± 500 vs 1415 ± 374 µm 2 /s; p < 0.05). K trans , K ep , V e , and iAUC were significantly different between malignant and benign soft tissue tumors (0.209 ± 0.160 vs 0.092 ± 0.067 min -1 ; 0.737 ± 0.488 vs 0.311 ± 0.230 min -1 ; 0.32 ± 0.17 vs 0.44 ± 0.28; 0.23 ± 0.14 vs 0.12 ± 0.09, p < 0.05, respectively). ADC (0.752), D (0.742), and K ep (0.817) had high AUCs. Subgroup analysis showed that only K trans , and iAUC were significantly different in myxoid tumors, while, ADC, D , K trans , K ep , and iAUC were significantly different in non-myxoid tumor for differentiating benign and malignant tumors. D , K ep , and iAUC were the most significant parameters predicting malignant soft tissue tumors., Conclusion: Multiparametric MRI can be useful to differentiate benign and malignant soft tissue tumors using IVIM-DWI and DCE-MRI., Advances in Knowledge: 1. Pure tissue diffusion (D), transfer constant (K trans ), rate constant (K ep ), and initial area under time-signal intensity curve (iAUC) can be used to differentiate benign malignant soft tissue tumors.2. K trans and iAUC enable differentiation of benign and malignant myxoid soft tissue tumors.

Diagnostic histopathology of soft tissue tumors can be troublesome as many entities are quite rare and have overlapping morphologic features. Many soft tissue tumors harbor tumor-defining gene translocations, which may provide an important ancillary tool for tumor diagnosis. The NanoString nCounter platform enables multiplex detection of pre-defined gene fusion transcripts in formalin-fixed and paraffin-embedded tissue. A cohort of 104 soft tissue tumors representing 20 different histological types was analyzed for the expression of 174 unique gene fusion transcripts. A tumor-defining gene fusion transcript was detected in 60 cases (58%). Sensitivity and specificity of the NanoString assay calculated against the result of an alternative molecular method were 85% and 100%, respectively. Highest diagnostic coverage was obtained for Ewing sarcoma, synovial sarcoma, myxoid liposarcoma, alveolar rhabdomyosarcoma, and desmoplastic small round cell tumor. For these tumor types, the NanoString assay is a rapid, cost-effective, sensitive, and specific ancillary screening tool for molecular diagnosis. For other sarcomas, additional molecular testing may be required when a translocation transcript is not identified with the current 174 gene fusion panel., (© 2020 The Authors. Genes, Chromosomes & Cancer published by Wiley Periodicals, Inc.)

Tissue diagnosis of a soft tissue neoplasm is of paramount importance for the development of an appropriate treatment plan. Biopsy technique including approach and biopsy method is important to the success of diagnosis and subsequent treatment. Histologic and cytologic diagnoses are difficult and complicated by the large number of soft tissue lesions described, distinctly different biopotential for morphologically similar lesions, often small biopsy specimen size, and the generally limited experience many pathologists have in the diagnosis of soft tissue neoplasms. While utilized less frequently than core-needle biopsies, fine-needle aspiration is a valuable initial approach for the classification of soft tissue neoplasms. The combination of pattern based morphologic analysis, immunohistochemistry, and molecular diagnostics represents a utilitarian and generally successful approach for the diagnosis of soft tissue lesions., (© 2019 Wiley Periodicals, Inc.)

In the 2018 World Health Organization Classification of Skin Tumors, a wide range of predominantly benign mesenchymal neoplasms are included in the fibroblastic, myofibroblastic, and "fibrohistiocytic" categories. By far the most common of these tumors is dermatofibroma (fibrous histiocytoma). There are many histologic variants of dermatofibroma, some of which (cellular, aneurysmal, and atypical) are associated with a higher risk of local recurrence; these variants may be mistaken for more aggressive tumor types, including sarcomas. Furthermore, distinguishing among the fibrous and "fibrohistiocytic" tumors can be a diagnostic challenge, given their sometimes-similar histologic appearances and confusing nomenclature. Immunohistochemistry and molecular genetic assays play a relatively limited role in the diagnosis of these tumor types, with notable exceptions (i.e., epithelioid fibrous histiocytoma and dermatofibrosarcoma protuberans). Proper recognition of dermatofibrosarcoma protuberans is critical, since this tumor type is associated with locally aggressive behavior; transformation to the fibrosarcomatous variant brings metastatic potential. In recent years, understanding of the molecular pathogenetic basis for cutaneous mesenchymal neoplasms has increased dramatically, with the discovery of gene rearrangements in some of these tumor types. In this review, the histologic features of the most common fibrous and "fibrohistiocytic" cutaneous mesenchymal neoplasms will be discussed, as well as recently identified molecular genetic alterations.

Cutaneous soft tissue tumors with epithelioid features present a diagnostic challenge given that many entities in this category are rare, and they show morphologic overlap with significantly more common cutaneous epithelial and melanocytic neoplasms. The challenge is compounded by overlapping expression of epithelial or melanocytic markers in some of these entities. A broad spectrum of primary cutaneous epithelioid soft tissue tumors exists, including benign and malignant counterparts of tumors with various differentiation including melanocytic, peripheral nerve sheath, angiomatous, fibrohistiocytic, and myoid or myoepithelial, in addition to translocation-associated tumors lacking a derivative tissue type. Given this spectrum, an initial targeted immunohistochemical panel for epithelioid dermal and subcutaneous neoplasms is recommended, covering a broad spectrum of differentiation. In diagnostically challenging cases, select molecular studies can be employed to make critical distinctions between entities sharing morphologic and immunohistochemical properties. Due to sometimes marked differences in prognosis and treatment, knowledge and familiarity with epithelioid soft tissue tumors is key for any surgical pathologist who evaluates skin and subcutaneous biopsies and excision specimens. This concise review provides brief descriptions, key diagnostic features, and important modern ancillary studies for the diagnosis of non-epithelial, non-melanocytic cutaneous tumors that can exhibit a prominent degree of epithelioid morphology.

Molecular diagnostics of sarcoma subtypes commonly involve the identification of characteristic oncogenic fusions. EWSR1-PATZ1 is a rare fusion partnering in sarcoma, with few cases reported in the literature. In the current study, a series of 11 cases of EWSR1-PATZ1 fusion positive malignancies are described. EWSR1-PATZ1-related sarcomas occur across a wide age range and have a strong predilection for chest wall primary site. Secondary driver mutations in cell-cycle genes, and in particular CDKN2A (71%), are common in EWSR1-PATZ1 sarcomas in this series. In a subset of cases, an extended clinical and histopathological review was performed, as was confirmation and characterization of the fusion breakpoint revealing a novel intronic pseudoexon sequence insertion. Unified by a shared gene fusion, EWSR1-PATZ1 sarcomas otherwise appear to exhibit divergent morphology, a polyphenotypic immunoprofile, and variable clinical behavior posing challenges for precise classification.

Background: Although eribulin is used to treat soft tissue sarcomas (STSs), treatment data for rare subtypes are limited. We conducted a post-marketing surveillance study to assess safety and efficacy of eribulin in STS patients stratified by subtype., Methods: Japanese patients (n = 256) with advanced or metastatic STS receiving eribulin treatment were monitored for treatment status, adverse events, diagnostic imaging, and clinical outcomes at 3 months and 1 year. Interim analysis was performed. Patients will be monitored up to 2 years., Results: Interim analysis included 3-month (n = 255), imaging (n = 226), and 1-year (n = 105) data. STS subtype distribution was normal. Median number of eribulin cycles was 3.0 (range: 1-17 cycles). Among patients with imaging data, best overall tumor response (12 weeks) was partial response, 7.5% (n = 17); stable disease, 34.5% (n = 78); and stable disease ≥11 weeks, 10.2% (n = 23). Overall response rate (ORR), disease control rate (DCR), and clinical benefit rate (CBR) for all patients were 7.5%, 42.0% and 17.7%, respectively. ORR, DCR, and CBR were 10.3%, 32.0% and 16.5%, respectively, for patients with STS subtypes other than liposarcoma and leiomyosarcoma and included responses from patients with rare STS subtypes. Adverse drug reactions (ADRs) occurred in 211 (82.7%) patients (42 [16.5%] patients had serious ADRs), and none led to death. ADRs leading to drug withdrawal and dose reduction occurred in 27 (10.6%) and 55 (21.6%) patients, respectively., Conclusion: Eribulin was generally well tolerated and showed antitumor activity against STSs, including rare subtypes that currently have few treatment options., Clinical Trial Number: NCT03058406 (ClinicalTrials.gov)., (© The Author(s) 2019. Published by Oxford University Press.)

Purpose: To determine whether the new American Joint Committee on Cancer (AJCC) 8 grouping of soft tissue sarcoma (STS) with nodal disease (N1M0) and metastatic disease (M1) as stage IV correctly represents the prognosis of these previously separate patient groups, using the National Cancer Database., Methods and Materials: Adults with STS identified in the 2004 to 2014 National Cancer Database, classified by the World Health Organization 2013 system into 10 histologic subgroups, were grouped according to AJCC 8 staging and analyzed according to demographic characteristics, histology, primary site, disease extent, and adjuvant treatment. Primary retroperitoneal sites, "other/unusual" histologic subgroups, and those with delays in therapy (>180 days from diagnosis) were excluded. We used χ 2 tests, Cox proportional hazard models, and propensity-score matched analyses., Results: Of 82,987 patients identified, 55,417 met inclusion criteria; 29,855 (53.9%) were male, and 25,262 (46.1%) were female. Median age was 60 years (range, 18-90 years). Overall survival (OS) of STS of all sites was significantly different between N1M0 and N0-1M1 patients at 5 years (34.4%; [95% confidence interval {CI}, 30.1%-38.8%] vs 10.1% [95% CI, 9%-11%], respectively) and 10 years (27.3% [95% CI, 22.5%- 32.2%] vs 5.4% [95% CI, 4.5%-6.5%], respectively; log-rank test, P < .001). For STS of trunk and extremities in N1M0 and N0-1M1 patients, the N1M0 cohort was associated with significantly greater OS on multivariate Cox proportional hazards models (hazard ratio, 0.48; 95% CI, 0.41-0.58; P < .001), and this OS difference remained significant for propensity-matched cohorts of all primary sites (HR, 0.53; 95% CI, 0.44-0.64; P < .001)., Conclusions: In adult STS, including those of the trunk and extremity, OS is superior with N1M0 compared with N0-1M1 disease. These results suggest that the AJCC 8th edition grouping of N1 and M1 patients into stage IV may obscure the more favorable prognosis of patients with N1M0 disease., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A major breakthrough in the classification of soft tissue tumors has been the recent identification of NTRK-fusion related neoplasms which are amenable to highly effective targeted therapies. Despite these therapeutic opportunities, diagnostic challenges have emerged in recognizing tumors characterized by protein kinase fusions, as they are associated with a wide morphologic spectrum, variable risk of malignancy and a rather nonspecific immunoprofile. As such, NTRK-related fusions may occur in infantile fibrosarcoma, lipofibromatosis-like neural tumors (LPF-NTs), tumors resembling malignant peripheral nerve sheath tumors, etc. Triggered by an index case resembling LPF-NT but harboring RET gene rearrangement, we investigated our files for cases showing RET gene abnormalities to establish their clinicopathologic features. Tumors were tested with a combination of targeted RNA sequencing and fluorescence in situ hybridization methods. Six cases with RET gene rearrangements were identified, all except 1 occurred in children, including 4 infants. Their morphologic spectrum was quite diverse, but closely reproduced the phenotype of NTRK-fusion-positive tumors, including LPF-NTs (n=3), infantile fibrosarcoma-like tumor (n=2) and malignant peripheral nerve sheath tumor-like (n=1). Three cases showed coexpression of S100 and CD34, whereas the remaining 3 had a nonspecific immunoprofile. The tumors ranged morphologically and clinically from benign to highly malignant. None of the LPF-NT cases recurred, whereas 2 patients with malignant histology had a highly aggressive course with distant metastases to lung and other viscera. By targeted RNA sequencing these tumors harbored RET fusions with an identical break in exon 12, which retains the tyrosine kinase domain in the fusion oncoprotein and involving various gene partners (CLIP2, CCDC6, SPECC1L, MYH10, and NCOA4). Our results suggest that RET fusion-positive neoplasms share a similar phenotypic spectrum with the NTRK-positive tumors, displaying either fibroblastic or neural-like differentiation, and spanning a wide spectrum of clinical behavior. These findings open new avenues for targeted therapy with RET inhibitors currently available in clinical trials.

Objectives: Misnaming low-grade lipomatous tumors poses a clinical and medicolegal challenge, potentially subjecting patients to expensive and unnecessary surgeries. The terms atypical lipomatous tumor (ALT) and "well-differentiated" liposarcoma (WDL) have been used interchangeably in pathology reports, scholarly works and consensus recommendations, creating vagaries between low-virulence extremity tumors and retroperitoneal disease with metastatic potential., Methods: A systematic review was performed on all studies that reported on the local recurrence rate and metastasis of ALTs and WDLs in living human subjects. Local recurrence and metastases were compared using Fisher's Exact Test., Results: In total, 20 studies evaluated ALTs (n=936), whereas 13 studied WDLs (n=626). Mean follow-up was 6.6±2.0 years (median, 7.0 y). No metastatic disease was observed among ALTs, whereas 15 patients with WDLs (2.7%, P<0.0001) had metastases. The local recurrence rate of ALTs was significantly lower than WDLs after both marginal (15.1%, 141/936 vs. 46.0%, 288/626, P<0.0001) and wide excisions (3.3%, 2/59 in ALT vs. 17.4%, 19/109, P=0.007)., Conclusions: ALT should be reserved for extremity lesions meeting appropriate histopathologic criteria that represent nonmetastatic disease, reducing over-diagnosis, over-treatment, and patient risk.

Objective: The aim of this study was to retrospectively evaluate the patients who were operated in our orthopedics and traumatology clinic with the suspection of bone and soft tissue tumors., Methods: A total of 3133 patients (1146 (46.5%) female and 1318 (53.5%) male) who presented to our tertiary clinic from different regions of Turkey between January 2002 and July 2013 with the presumed diagnosis of bone and soft tissue tumors were analyzed according to age, gender, bone/soft tissue localization, tumoral localization, histopathological diagnosis, tumor size and incidence., Results: Of all operated patients, 2464 (78%) were diagnosed with tumor, while non-tumoral causes were found in 669 (22%) patients. Of the cases diagnosed with tumor, 1139 were bone localized, 1004 soft tissue localized, and 321 metastasis. The most common benign bone tumors were osteochondroma (130, 20%), enchondroma (96, 15%), and simple bone cysts (90, 14%), while the most common malignant bone tumors were osteosarcoma (241, 44%), ewing's sarcoma (89, 16%), and chondrosarcoma (77, 14%); respectively. The most common benign soft tissue tumors were lipoma (141, 22%), giant cell tumors (108, 16%) and ganglion (107, 16%), while the most common malignant soft tissue tumors were liposarcoma (55, 16%), synovial sarcoma (53, 16%) and malignant mesenchymal tumors (45, 13%); respectively., Conclusion: Musculoskeletal tumors are rare, but descriptive data in any region are important in order to reduce mortality and improve treatment. No significant difference was found between the data of our hospital regarding epidemiology of the musculoskeletal system tumors and those from the other regions around the world., Level of Evidence: Level IV, Therapeutic study., (Copyright © 2019 Turkish Association of Orthopaedics and Traumatology. Production and hosting by Elsevier B.V. All rights reserved.)

Objective:  MRI is the most important and sensitive imaging modality in the differentiation of unclear soft tissue tumors. A systematic approach helps to narrow down the large number of possible differential diagnoses., Method:  Our review systematically compares MRI characteristics of the major soft-tissue masses and aims to gain access to these often difficult tumor entities., Results and Conclusion:  MRI, as the most important modality in the imaging of soft tissue tumors, allows a more detailed classification of the tumor entity and in many cases a differentiation between benign and malignant masses., Key Points:   · MRI is the method of choice for classifying unclear soft tissue tumors.. · A systematic approach may differentiate benign from unclear lesions.. · In cases of doubt, a biopsy should be performed to rule out malignancy.., Citation Format: · Lisson CS, Lisson CG, Beer M et al. Radiological Diagnosis of Soft Tissue Tumors in Adults: MRI Imaging of Selected Entities Delineating Benign and Malignant Tumors. Fortschr Röntgenstr 2019; 191: 323 - 332., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (© Georg Thieme Verlag KG Stuttgart · New York.)

Gene fusion transcripts containing PRDM10 were recently identified in low-grade undifferentiated pleomorphic sarcomas (UPS). Here, we describe the morphologic and clinical features of 9 such tumors from 5 men and 4 women (age: 20 to 61 y). Three cases had previously been diagnosed as UPS, 3 as superficial CD34-positive fibroblastic tumor (SCD34FT), 2 as pleomorphic liposarcoma, and 1 as pleomorphic hyalinizing angiectatic tumor. The tumors were located in the superficial and deep soft tissues of the thigh/knee region (4 cases), shoulder (2 cases), foot, trunk, and perineum (1 case each) ranging in size from 1 to 6 cm. All showed poorly defined cellular fascicles of pleomorphic cells within a fibrous stroma with frequent myxoid change and a prominent inflammatory infiltrate. All displayed highly pleomorphic nuclear features, but a low mitotic count. Most tumors were well circumscribed. One of 9 tumors recurred locally, but none metastasized. Immunohistochemically, all were CD34 and showed nuclear positivity for PRDM10; focal positivity for cytokeratins was seen in 5/6 cases. PRDM10 immunoreactivity was evaluated in 50 soft tissue tumors that could mimic PRDM10-rearranged tumors, including 4 cases exhibiting histologic features within the spectrum of SCD34FT. Except for 2/6 pleomorphic liposarcomas and 1/4 myxofibrosarcomas, other tumors did not show nuclear positivity but displayed weak to moderate cytoplasmic immunoreactivity. In conclusion, PRDM10-rearranged soft tissue tumor is characterized by pleomorphic morphology and a low mitotic count. Its morphologic spectrum overlaps with SCD34FT. Clinical features of this small series suggest an indolent behavior, justifying its distinction from UPS and other sarcomas.

Round cell sarcomas morphologically similar to Ewing sarcoma, but lacking the classic immunohistochemical features, EWSR-ETS family fusions, and other signs of differentiation, are classified as Ewing-like sarcomas. Recent molecular advances led to the discovery and characterization of two recurrent oncogenic fusion rearrangements, CIC-DUX4 and BCOR-CCNB3, in a significant subset of Ewing-like sarcomas. Uncovered alternate fusion partners broadened the proposed classification of these tumors to CIC-rearranged sarcomas and BCOR-rearranged sarcomas. This article summarizes the clinicopathologic and molecular features of these entities, with particular attention paid to those features that overlap with and distinguish these sarcomas from other round cell sarcomas., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Myogenic sarcomas include soft tissue sarcomas that show skeletal muscle differentiation (rhabdomyosarcoma) and those with smooth muscle differentiation (leiomyosarcoma). Rhabdomyosarcomas are more common in the pediatric age group and leiomyosarcomas occur more often in the adult population. Based on the clinico-pathologic features and genetic abnormalities identified, the rhabdomyosarcomas are classified into embryonal, alveolar, spindle cell/sclerosing, and pleomorphic subtypes. Each subtype shows distinctive morphology and has characteristic genetic abnormalities. In this update on myogenic sarcomas, each entity is discussed with special emphasis on recent updates in genetic findings and the diagnostic approach to these tumors., (Copyright © 2018 Elsevier Inc. All rights reserved.)

This article focuses on pleomorphic sarcomas, which are malignant mesenchymal tumors with complex genetic background at the root of their morphologic pleomorphism. They are poorly differentiated tumors that may retain different lines of differentiation, sometimes correlating with clinicopathological or prognostic features. Accurate diagnosis in this group of tumors relies on adequate sampling due to their heterogeneity and assessment with both microscopy and large panels of immunohistochemistry. Molecular analyses have a limited role in their diagnosis as opposed to translocation-related sarcomas but may provide theranostic and important prognostic information in the future., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Vascular malformations and tumors, also known as "vascular anomalies", comprise an extensive variety of lesions involving all parts of the body. Due to a lack of a complete understanding of the origin and histopathology of such lesions, this field has been traditionally obscured by the use of an unclear nomenclature. Knowledge of the classification and clinical and imaging characteristics of this group of lesions is paramount when managing these patients. The objective of this series of two articles is to review the current classification of vascular anomalies, to describe the role of imaging in their diagnosis, to summarize their distinctive histopathologic, clinical and imaging features, and to discuss the treatment options. High-flow lesions were discussed in the first article of this series. In this second article, we will focus on low-flow lesions, including complex syndromes with associated low-flow malformations., (Copyright © 2018 SERAM. Publicado por Elsevier España, S.L.U. All rights reserved.)

Among the various genes that can be rearranged in soft tissue neoplasms associated with nonrandom chromosomal translocations, EWSR1 is the most frequent one to partner with other genes to generate recurrent fusion genes. This leads to a spectrum of clinically and pathologically diverse mesenchymal and nonmesenchymal neoplasms, variably manifesting as small round cell, spindle cell, clear cell or adipocytic tumors, or tumors with distinctive myxoid stroma. This review summarizes the growing list of mesenchymal neoplasms that are associated with EWSR1 gene rearrangements., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Pediatric soft tissue tumors are relatively rare and show significant overlap in morphology and immunoprofile, often posing diagnostic and management challenges. Thus, their classification remains often subjective or lumped under "unclassified categories," as a number of lesions lack objective and reproducible criteria in diagnosis. Although in a subset of cases immunohistochemistry has been proved useful to identify a specific line of differentiation, most tumors lack a readily defined histogenesis, being characterized by a rather non-specific immunoprofile. Furthermore, tumors with an ambiguous diagnosis are difficult to grade and their risk of malignancy or clinical management remains uncertain. Advances in molecular genetics, including the more wide application of next generation sequencing in routine clinical practice, have improved diagnosis and refined classification based on objective molecular markers. Importantly, some soft tissue tumors in children are characterized by recurrent gene fusions involving either growth factors (eg, PDGFB) or protein kinases (eg, ALK, ROS, NTRK, BRAF), which have paved the way for new targeted treatments that block the respective upregulated downstream pathways. However, the majority of gene fusions or mutations detected in soft tissue tumors result in an abnormal function of transcription factors or chromatin remodeling. The present review focuses on the latest genetic discoveries in the spectrum of both benign and malignant pediatric soft tissue neoplasia. These genetic abnormalities promise to provide relevant insight for their proper classification, prognosis, and treatment. The entities discussed herein are grouped either based on their shared genetic mechanism or based on their presumed line of differentiation., (© 2018 Wiley Periodicals, Inc.)

Vascular malformations and tumors, also known as "vascular anomalies", comprise an extensive variety of lesions involving all parts of the body. Knowledge of their classification and imaging characteristics is paramount. Whereas hemangiomas are benign vascular tumors, characterized by cellular proliferation and hyperplasia; vascular malformations are not real tumors and characteristically exhibit normal endothelial turnover. Vascular malformations are classified according to the predominant vascular channel as arterial, capillary, venous, lymphatic, or mixed. Ultrasound and MRI are the main imaging modalities used in the diagnosis and classification of the vascular anomalies. In this series of two articles we review the classification of vascular anomalies, describe the role of imaging, summarize their distinctive histopathogenic, clinical and imaging features, and discuss the treatment options. On the first article we discuss the high-flow lesions, whereas the slow-flow lesions will be reviewed on the second. Complex syndromes with associated vascular tumors and malformations will be also presented., (Copyright © 2018 SERAM. Publicado por Elsevier España, S.L.U. All rights reserved.)

Tumors characterized by co-expression of S100 and CD34, in the absence of SOX10, remain difficult to classify. Triggered by a few index cases with monomorphic cytomorphology and distinctive stromal and perivascular hyalinization, immunopositivity for S100 and CD34, and RAF1 and NTRK1 fusions, the authors undertook a systematic review of tumors with similar features. Most of the cases selected were previously diagnosed as low-grade malignant peripheral nerve sheath tumors, while others were deemed unclassified. The tumors were studied with targeted RNA sequencing and/or FISH. A total of 25 cases (15 adults and 10 children) with kinase fusions were identified, including 8 cases involving RAF1, 2 BRAF, 14 NTRK1, and 1 NTRK2 gene rearrangements. Most tumors showed a monomorphic spindle cell proliferation with stromal and perivascular keloidal collagen, in a patternless architecture, with only occasional scattered pleomorphic or multinucleated cells. Most cases showed low cellularity, a low mitotic count, and absence of necrosis. Although a subset showed overlap with lipofibromatosis-like neural tumors, the study group showed distinctive hyalinization and overt malignant features, such as highly cellular fascicular growth and primitive appearance. All tumors showed co-expression of S100 and CD34, ranging from focal to diffuse. SOX10 was negative in all cases. NTRK1 immunohistochemistry showed high levels of expression in all tumors with NTRK1 gene rearrangements. H3K27me3 expression performed in a subset of cases was retained. These findings together with the recurrent gene fusions in RAF1, BRAF, and NTRK1/2 kinases suggest a distinct molecular tumor subtype with consistent S100 and CD34 immunoreactivity., (© 2018 Wiley Periodicals, Inc.)

Pleomorphic sarcomas are a heterogeneous group of mesenchymal neoplasms with widely varied clinical behavior but overlapping histologic appearances. The following guidelines are helpful when approaching the diagnosis of a pleomorphic sarcoma. (1) Be aware of the relative incidence of the various sarcoma types: several pleomorphic sarcomas are relatively common (e.g., dedifferentiated liposarcoma and undifferentiated pleomorphic sarcoma), whereas others are exceptionally rare. (2) Pay attention to anatomic location: some pleomorphic sarcomas have a predilection for somatic soft tissues, especially the thigh (e.g., undifferentiated pleomorphic sarcoma, pleomorphic liposarcoma, pleomorphic rhabdomyosarcoma), whereas other pleomorphic sarcomas most often arise in the retroperitoneum (e.g., dedifferentiated liposarcoma). (3) Carefully sample the resection specimen, paying particular attention to areas with differences in gross appearances (e.g., fleshy, fibrous, mucoid, or gritty). (4) Search for histologic clues (i.e., myxoid stroma, lipoblasts, and osteoid matrix, in order to diagnose myxofibrosarcoma, pleomorphic liposarcoma, and extraskeletal osteosarcoma, respectively); these critical diagnostic features may be limited in extent. (5) Apply immunohistochemistry judiciously, after generating a differential diagnosis; always exclude metastatic sarcomatoid carcinoma and melanoma before diagnosing a pleomorphic sarcoma. This review will present an approach to the diagnosis of pleomorphic sarcomas, emphasizing differential diagnosis and the application of ancillary studies (immunohistochemistry and FISH), when relevant., (Copyright © 2018 Elsevier Inc. All rights reserved.)

ACTB-GLI1 fusions have been reported as the pathognomonic genetic abnormality defining an unusual subset of actin-positive, perivascular myoid tumors, known as "pericytoma with the t(7;12) translocation." In addition, GLI1 oncogenic activation through a related MALAT1-GLI1 gene fusion has been recently reported in 2 unrelated gastric tumors, namely plexiform fibromyxoma and gastroblastoma. Triggered by unexpected targeted RNA-sequencing results detecting GLI1-related fusions in a group of malignant neoplasms with round to epithelioid morphology, and frequently strong S100 protein immunoreactivity, we investigated their clinicopathologic features in relation to other known pathologic entities sharing similar genetics. On the basis of a combined approach of targeted RNA sequencing and fluorescence in situ hybridization screening, we identified 6 cases with GLI1 gene fusions, including 4 fused to ACTB, 1 with MALAT1 and 1 with PTCH1 gene. Patients had a mean age of 36 years at diagnosis (range, 16 to 79 y) and slight female predilection all except 1 tumor originated in the soft tissue. Microscopically, the tumors had a monomorphic epithelioid phenotype arranged in a distinctive nested or cord-like architecture, separated by thin septae and delicate capillary network. All except 2 cases were strongly positive for S100 protein, whereas being negative for SOX10, SMA, and EMA. Only 1 tumor showed focal cytokeratin positivity in rare cells. Although the tumors showed some resemblance to pericytic/glomus tumors or myoepithelial tumors, the immunoprofile was not supportive of either lineage. Moreover, in contrast to the benign course of so-called pericytoma with t(7;12), 3 patients in this series developed metastatic disease to either lymph nodes or lung. In fact the only patient with lung metastases showed a novel PTCH1-GLI1 gene fusion. It remains to be determined whether these tumors represent a clinically and immunohistologically distinct subset of pericytoma, or an altogether novel soft tissue sarcoma. Our findings open new opportunities for targeted therapy, as tumors with GLI1 oncogenic activation, and subsequent PTCH1 overexpression, might be sensitive to sonic hedgehog pathway inhibitors.

Background: Soft-tissue sarcomas (STSs) are a group of rare, heterogeneous, and aggressive tumors, with high metastatic risk and relatively few efficient systemic therapies. We hypothesized that the Genomic Grade Index (GGI), a 108-gene signature previously developed in early-stage breast cancer, might improve the prognostic assessment of patients with early-stage STS., Patients and Methods: We collected gene expression and clinicopathological data of 678 operated STS, and searched for correlations between the GGI-based classification and clinicopathological variables, including the metastasis-free survival (MFS)., Results: Based on GGI, 275 samples (41%) were classified as 'GGI-low' and 403 (59%) as 'GGI-high'. The 'GGI-high' class was more associated with poor-prognosis features than the 'GGI-low' class: pathological grade 3 (P = 9.50E-11), undifferentiated sarcomas and leiomyosarcomas (P < 1.00E-06), location in extremities (P < 1.00E-06), and complex genetic profile (P = 2.1E-20). The 5-year MFS was 53% (95%CI 47-59) in the 'GGI-high' class versus 78% (95%CI 72-85) in the 'GGI-low' class (P = 3.02E-11), with a corresponding hazard ratio for metastatic relapse equal to 2.92 (95%CI 2.10-4.07; P = 2.23E-10). In multivariate analysis, the GGI-based classification remained significant, whereas the pathological grade did not. In fact, the GGI-based classification stratified the patients with pathological grades 1 and 2 and those with pathological grade 3 in two classes with different 5-year MFS. Comparison of the GGI and CINSARC multigene signatures revealed similar correlations with clinicopathological variables, which were, however, stronger with GGI than with CINSARC, a strong concordance (71%) in terms of low-risk or high-risk classifications, and independent prognostic value for MFS in multivariate analysis, suggesting complementary prognostic information., Conclusion: GGI refines the prediction of MFS in operated STS and might improve the tailoring of adjuvant chemotherapy. Further clinical validation is warranted in larger retrospective, then prospective series, as well as the functional validation of relevant genes that could provide new therapeutic targets., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Soft tissue tumours are relatively rare, but are diagnostically challenging as they comprise a large spectrum of diagnostic entities. Substantial advances have been made in recent years in identifying the underlying recurrent chromosomal and genomic alterations in a significant subset of soft tissue tumours, and this continues to enrich our understanding of the biological mechanisms of tumour development and progression. Ongoing validation and integration of these findings into existing pathological-diagnostic algorithms has led to re- or subclassification of diagnostic categories and will continue to shape a more nuanced (and hopefully clinically relevant) tumour classification system in the future. This review provides a selective overview of recent diagnostic or conceptual advances in the categories of peripheral nerve sheath tumours, vascular and adipocytic tumours, round cell and myogenic sarcomas, and gastrointestinal stromal tumours, as well as their underlying molecular mechanisms, some of which have been translated successfully into useful immunohistochemical stains. A thorough and critical validation of newly identified diagnostic markers-acknowledging the fact that some genetic alterations may not necessarily be tumour-specific-and ongoing correlation with clinical and prognostic implications will be necessary in this regard., (Copyright © 2017 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)