Updates on WHO classification for small round cell tumors: Ewing sarcoma vs. everything else.

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.

Rhabdomyosarcoma: Updates on classification and the necessity of molecular testing beyond immunohistochemistry.

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.

Evolving classification of rhabdomyosarcoma.

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.

Recent updates in the diagnosis of soft tissue tumors: Newly described tumor entities, newer immunohistochemical and genetic markers, concepts, including "inter-tumor relationships".

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".

Myxoid pleomorphic liposarcoma-a clinicopathologic, immunohistochemical, molecular genetic and epigenetic study of 12 cases, suggesting a possible relationship with conventional pleomorphic liposarcoma.

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.

DNA methylation-based profiling of bone and soft tissue tumours: a validation study of the 'DKFZ Sarcoma Classifier'.

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.

Molecular Alterations in Pediatric Fibroblastic/Myofibroblastic Tumors: An Appraisal of a Next Generation Sequencing Assay in a Retrospective Single Centre Study.

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.

Staging and Classification of Primary Musculoskeletal Bone and Soft-Tissue Tumors According to the 2020 WHO Update, From the AJR Special Series on Cancer Staging.

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.

DNA methylation patterns-based subtype distinction and identification of soft tissue sarcoma prognosis.

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.

Updates from the 2020 World Health Organization Classification of Soft Tissue and Bone Tumours.

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.

Sarcoma classification by DNA methylation profiling.

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 2020 WHO Classification: What's New in Soft Tissue Tumor Pathology?

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.

Variability in tumor margin reporting for soft tissue sarcoma and cutaneous mast cell tumors in dogs: A systematic review.

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.

The 2020 WHO Classification of Tumors of Soft Tissue: Selected Changes and New Entities.

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.

Multiparametric quantitative analysis of tumor perfusion and diffusion with 3T MRI: differentiation between benign and malignant soft tissue tumors.

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 (Ktrans, Kep, Ve, 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 µm2/s; 1132 ± 500 vs 1415 ± 374 µm2/s; p < 0.05). Ktrans, Kep, Ve, 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 Kep (0.817) had high AUCs. Subgroup analysis showed that only Ktrans, and iAUC were significantly different in myxoid tumors, while, ADC, D, Ktrans, Kep, and iAUC were significantly different in non-myxoid tumor for differentiating benign and malignant tumors. D, Kep, 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 (Ktrans), rate constant (Kep), and initial area under time-signal intensity curve (iAUC) can be used to differentiate benign malignant soft tissue tumors.2. Ktrans and iAUC enable differentiation of benign and malignant myxoid soft tissue tumors.

Hematolymphoid Neoplasms Rarely Mimic Undifferentiated Pleomorphic Sarcoma of Soft Tissue.

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.

Novel Aspects of Genetics, Molecular Biology and Clinical Oncology of Sarcomas.

The Connective Tissue Oncology Group Annual Meeting 2018 (CTOS 2018) took place in Rome from 4 to 17 November 2018, and the 39th Plenary Meeting of the Scandinavian Sarcoma Group (SSGM 2019) was held in Bergen from 8 to 10 May 2019. These two large international conferences brought together an overwhelming majority of molecular and clinical specialists in the sarcoma field, especially those working on soft tissue sarcoma. Topics discussed on the conferences included, among others, sarcoma genetics, clinical and molecular subclassification, targeted therapy, clinical prognostication, and new experimental sarcoma models. A large ongoing international study on germinal sarcoma genetics was presented, the interim results of which revealed the extremely complex nature of genetic disposition to sarcoma, and, surprisingly, a rather prominent place among predisposing genes for those coding for structural telomere constituents. Fusion oncogenes dominate somatic sarcoma genetics, especially because of their origin and impact on sarcoma clinical behaviour, and are especially relevant for karyotypically simple paediatric sarcomas. A crucial issue in karyotypically complex sarcomas are the efforts being made to obtain a subclassification of sarcoma, other than those based on pathology, using either the clinical characteristics of sarcomas (uterine leiomyosarcoma vs. soft tissue leiomyosarcoma) or specific gene expression profiles (molecular subtypes in undifferentiated pleiomorphic sarcoma), which showed that molecular characterization can open the way for subtype specific therapies. Other examples of where this type of strategy can be applied include gastrointestinal stromal tumours, infantile fibrosarcoma, and inflammatory myofibroblastic tumours, where targeted therapy could be conceived based on the actionable mutations identified. Attempts in this direction have been made also for clear cell sarcoma and dedifferentiated liposarcoma, albeit the effectiveness of molecular-targeted treatments for these sarcomas is still poor, and progress in the treatment of osteosarcoma is still rather slow. Actually, the platelet-derived growth factor signalling system holds a prominent position in searches for targeted therapies, not only against rare sarcoma types, where are activated by mutations (some gastrointestinal stromal tumours, infantile hereditary myofibromatosis, and dermatofibrosarcoma protuberans), but also against other more usual sarcoma types, where the blocking anti-PDGFRα-antibody olaratumab has been successfully integrated into combinatorial chemotherapeutic regimens. In the field of clinical prognostication, remarkable progress in sarcoma nomograms was reported. Interesting results were also presented in the area of new experimental sarcoma models. Participation on both scientifi c conferences and all the experimental work leading to the presented sarcoma models were supported by the Czech Science Foundation project No. 17-17636S. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 20. 9. 2019 Accepted: 6. 11. 2019.

Diagnostic yield of NanoString nCounter FusionPlex profiling in 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.