Histopathological Diagnostic Discrepancies in Soft Tissue Tumours Referred to a Specialist Centre

Aims. A study was performed to determine areas of diagnostic discrepancy in the reporting of cases of soft tissue tumours referred to a specialist sarcoma unit. This was to pinpoint common discrepancies and to determine their causes. Methods and Results. We compared the sarcoma unit's histopathology reports with referring reports on 349 specimens from 277 patients with suspected or proven soft tissue tumours in a one-year period. Conclusions. Diagnostic agreement was found in 256 of 349 cases (73.4%), with minor diagnostic discrepancy in 55 cases (15.7%) and major discrepancy in 38 cases (10.9%). Benign/malignant discordances accounted for only 5% of all discrepancies (5 cases). The most common discrepancies occurred in tumour classification, including diagnosis of gastrointestinal stromal tumour and leiomyosarcoma and the subtyping of spindle cell sarcomas, as well as in tumour grading that could conceivably lead to changes in clinical management. Major diagnostic discrepancies leading to management change occurred in a relatively select range of tumour groups, and almost all discrepancies occurred due to differences in tumour interpretation between general or nonsoft tissue pathologists, and pathologists at the specialist unit. The findings support guidelines by the National Institute for Health and Clinical Excellence that diagnostic review of soft tissue tumours should be performed by specialist soft tissue pathologists

Impact of fusion gene status versus histology on riskâ stratification for rhabdomyosarcoma: Retrospective analyses of patients on UK trials

BackgroundLongâ term toxicities from current treatments are a major issue in paediatric cancer. Previous studies, including our own, have shown prognostic value for the presence of PAX3/7â FOXO1 fusion genes in rhabdomyosarcoma (RMS). It is proposed to introduce PAX3/7â FOXO1 positivity as a component of risk stratification, rather than alveolar histology, in future clinical trials.ProcedureTo assess the potential impact of this reclassification, we have determined the changes to risk category assignment of 210 histologically reviewed patients treated in the UK from previous malignant mesenchymal tumour clinical trials for nonâ metastatic RMS based on identification of PAX3/7â FOXO1 by fluorescence in situ hybridisation and/or reverse transcription PCR.ResultsUsing fusion gene positivity in the current risk stratification would reassign 7% of patients to different European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) risk groups. The next European trial would have 80% power to detect differences in eventâ free survival of 15% over 10 years and 20% over 5 years in reassigned patients. This would decrease treatment for over a quarter of patients with alveolar histology tumours that lack PAX3/7â FOXO1.ConclusionsFusion gene status used in stratification may result in significant numbers of patients benefitting from lower treatmentâ associated toxicity. Prospective testing to show this reassignment maintains current survival rates is now required and is shown to be feasible based on estimated recruitment to a future EpSSG trial. Together with developing novel therapeutic strategies for patients identified as higher risk, this may ultimately improve the outcome and quality of life for patients with RMS.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137481/1/pbc26386_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137481/2/pbc26386.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137481/3/pbc26386-sup-0002-FigureS2.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137481/4/pbc26386-sup-0001-FigureS1.pd

Pharmacotherapeutic strategies for epithelioid sarcoma: are we any closer to a non-surgical cure?

Introduction: Epithelioid sarcoma (ES) is a rare soft tissue sarcoma subtype, predominantly occurring in children and young adults. Despite optimal management of localized disease, approximately 50% of patients develop advanced disease. The management of advanced ES remains challenging due to limited response to conventional chemotherapy and despite novel oral EZH2 inhibitors that have better tolerability but similar efficacy to chemotherapy. Areas covered: We performed a literature review using the PubMed (MEDLINE) and Web of Science databases. We have focused on the role of chemotherapy, targeted agents such as EZH2 inhibitors, potential new targets and immune checkpoint inhibitors and combinations of therapies currently undergoing clinical investigation. Expert opinion: ES is a soft tissue sarcoma with a heterogeneous pathological, clinical, and molecular presentation. In the current era of precision medicine, more trials with targeted therapies and a combination of chemotherapy or immunotherapy with targeted therapies are required to establish optimal treatment for ES

Chemotherapy responsiveness in a patient with multiply relapsed ameloblastic fibro-odontosarcoma of the maxilla

Ameloblastic fibro-odontosarcoma (AFOS) is an extremely rare malignant odontogenic tumor. Complete surgical excision is the treatment of choice. Deaths due to disease recurrence and/or progression are documented. Here, we report the case of a 15-year-old female with multiple recurrent AFOS. She responded to chemotherapy with ifosfamide and doxorubicin consolidated by stereotactic reirradiation using cyberknife and remained in complete remission 14 months from the end of reirradiation therapy. Chemotherapy with ifosfamide and doxorubicin should be considered in advanced cases of AFOS. (C) 2015 The Authors. Pediatric Blood & Cancer Published by Wiley Periodicals, Inc

Utility of Multi-Parametric Quantitative Magnetic Resonance Imaging for Characterization and Radiotherapy Response Assessment in Soft-Tissue Sarcomas and Correlation With Histopathology

Purpose: To evaluate repeatability of quantitative multi-parametric MRI in retroperitoneal sarcomas, assess parameter changes with radiotherapy, and correlate pre-operative values with histopathological findings in the surgical specimens.Materials and Methods: Thirty patients with retroperitoneal sarcoma were imaged at baseline, of whom 27 also underwent a second baseline examination for repeatability assessment. 14/30 patients were treated with pre-operative radiotherapy and were imaged again after completing radiotherapy (50.4 Gy in 28 daily fractions, over 5.5 weeks). The following parameter estimates were assessed in the whole tumor volume at baseline and following radiotherapy: apparent diffusion coefficient (ADC), parameters of the intra-voxel incoherent motion model of diffusion-weighted MRI (D, f, D*), transverse relaxation rate, fat fraction, and enhancing fraction after gadolinium-based contrast injection. Correlation was evaluated between pre-operative quantitative parameters and histopathological assessments of cellularity and fat fraction in post-surgical specimens (ClinicalTrials.gov, registration number NCT01902667).Results: Upper and lower 95% limits of agreement were 7.1 and −6.6%, respectively for median ADC at baseline. Median ADC increased significantly post-radiotherapy. Pre-operative ADC and D were negatively correlated with cellularity (r = −0.42, p = 0.01, 95% confidence interval (CI) −0.22 to −0.59 for ADC; r = −0.45, p = 0.005, 95% CI −0.25 to −0.62 for D), and fat fraction from Dixon MRI showed strong correlation with histopathological assessment of fat fraction (r = 0.79, p = 10−7, 95% CI 0.69–0.86).Conclusion: Fat fraction on MRI corresponded to fat content on histology and therefore contributes to lesion characterization. Measurement repeatability was excellent for ADC; this parameter increased significantly post-radiotherapy even in disease categorized as stable by size criteria, and corresponded to cellularity on histology. ADC can be utilized for characterizing and assessing response in heterogeneous retroperitoneal sarcomas

Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma

The undruggable nature of oncogenic Myc transcription factors poses a therapeutic challenge in neuroblastoma, a pediatric cancer in which MYCN amplification is strongly associated with unfavorable outcome. Here, we show that CYC065 (fadraciclib), a clinical inhibitor of CDK9 and CDK2, selectively targeted MYCN-amplified neuroblastoma via multiple mechanisms. CDK9 — a component of the transcription elongation complex P-TEFb — bound to the MYCN-amplicon superenhancer, and its inhibition resulted in selective loss of nascent MYCN transcription. MYCN loss led to growth arrest, sensitizing cells for apoptosis following CDK2 inhibition. In MYCN-amplified neuroblastoma, MYCN invaded active enhancers, driving a transcriptionally encoded adrenergic gene expression program that was selectively reversed by CYC065. MYCN overexpression in mesenchymal neuroblastoma was sufficient to induce adrenergic identity and sensitize cells to CYC065. CYC065, used together with temozolomide, a reference therapy for relapsed neuroblastoma, caused long-term suppression of neuroblastoma growth in vivo, highlighting the clinical potential of CDK9/2 inhibition in the treatment of MYCN-amplified neuroblastoma

Undifferentiated and dedifferentiated soft tissue neoplasms: Immunohistochemical surrogates for differential diagnosis.

Undifferentiated soft tissue sarcomas (USTS) are described in the current World Health Organization Classification of Soft Tissue and Bone Tumours as those showing no identifiable line of differentiation when analyzed by presently available technologies. This is a markedly heterogeneous group, and the diagnosis of USTS remains one of exclusion. USTS can be divided into four morphologic subgroups: pleomorphic, spindle cell, round cell and epithelioid undifferentiated sarcomas, with this combined group accounting for up to 20% of all soft tissue sarcomas. As molecular advances enable the stratification of emerging genetic subsets within USTS, particularly within undifferentiated round cell sarcomas, other groups, particularly the category of undifferentiated pleomorphic sarcomas (UPS), still remain difficult to substratify and represent heterogeneous collections of neoplasms often representing the common morphologic endpoints of a variety of malignant tumors of various (mesenchymal and non-mesenchymal) lineages. However, recent molecular developments have also enabled the identification and correct classification of many tumors from various lines of differentiation that would previously have been bracketed under 'UPS'. This includes pleomorphic neoplasms and dedifferentiated neoplasms (the latter typically manifesting with an undifferentiated pleomorphic morphology) of mesenchymal (e.g. solitary fibrous tumor and gastrointestinal stromal tumor) and non-mesenchymal (e.g. melanoma and carcinoma) origin. The precise categorization of 'pleomorphic' or 'undifferentiated' neoplasms is critical for prognostication, as, for example, dedifferentiated liposarcoma typically behaves less aggressively than other pleomorphic sarcomas, and for management, including the potential for targeted therapies based on underlying recurrent molecular features. In this review we focus on undifferentiated and dedifferentiated pleomorphic and spindle cell neoplasms, summarizing their key genetic, morphologic and immunophenotypic features in the routine diagnostic setting, and the use of immunohistochemistry in their principal differential diagnosis, and highlight new developments and entities in the group of undifferentiated and dedifferentiated soft tissue sarcomas