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News Article | December 16, 2016

LUGANO-SINGAPORE, 17 December, 2016 - The first data on rare sarcomas in Asian patients is presented in three studies today at the ESMO Asia 2016 Congress in Singapore. Just half of patients with advanced angiosarcoma received chemotherapy even though it improved overall survival. CIC-rearranged sarcomas are shown to have a much worse prognosis than BCOR-rearranged sarcomas and clinical features are identified to aid accurate diagnoses. Angiosarcoma is the focus of two studies conducted by the newly formed Asian Sarcoma Consortium (ASC).1,2 This heterogeneous cancer has two distinct subtypes: elderly patients with scalp/cutaneous disease and a younger cohort with visceral disease typically in the liver, vascular systems, and breast. Treatment is challenging since the disease tends to be infiltrative, making surgery with clear margins difficult, while radiation is a poor option for tumours on the scalp and face. Chemotherapy has demonstrated activity in angiosarcoma but long term remission is rare. Both studies retrospectively included patients attending eight sites in six countries during 1990 to 2016. The first study outlines the epidemiology, real world treatment and clinical outcomes of angiosarcoma in Asia. The median age of the 423 patients was 67 years, about 60% had cutaneous angiosarcoma (they were more likely to be older, male, and have localised disease), while 40% had visceral angiosarcoma. In the localised setting, only about 60% of patients underwent surgery, but this was significantly lower in the cutaneous (55%) than visceral (75%) cohort. In those who underwent surgery, negative margins were only achieved in approximately 70% of cases. Close to half of patients who underwent surgery relapsed. Median relapse free survival was just 12.3 months with no statistical difference between the cutaneous (12.9 months) versus visceral (9.5 months) groups. Patients were more likely to relapse if they were more than 65 years old or had positive surgical margins. In the advanced setting, only about half of patients received chemotherapy. Median overall survival was 9.5 months with no significant difference between cutaneous (11.5 months) and visceral (8.3 months) groups. ECOG (Eastern Cooperative Oncology Group) performance status was an independent predictor of survival. However, after adjusting for ECOG performance status, overall survival was significantly better in patients who received chemotherapy than those who did not. "This is one of the largest studies in angiosarcoma and we found that overall prognosis was poor," said lead author Professor Richard Quek, deputy head and senior consultant, National Cancer Centre Singapore. "In patients with localised disease, negative surgical margin was prognostic for relapse free survival yet it was only achieved in 70% of patients. Neoadjuvant (pre-operative) treatment, be it chemotherapy or radiation, might enhance resectability of these tumours and thereby improve survival outcomes." Quek continued: "In patients with advanced disease we demonstrated that after adjusting for ECOG performance status, chemotherapy was associated with improved overall survival. But only half of our patients actually received chemotherapy, hence it would be important to understand the reasons behind this low treatment rate. Could these be physician-related factors? And if so, is more sarcoma-related continuing medical education needed to enhance care for our patients?" The second angiosarcoma study outlined the clinical characteristics and treatment of 277 patients with advanced metastatic or unresectable disease. The median age was 64 years. The predictors of better prognosis were younger age, female sex, and cutaneous (rather than visceral) disease. Use of chemotherapy gradually increased over the 20-year period, with a preference for paclitaxel and liposomal doxorubicin over other treatments. Progression-free survival in patients receiving at least one line of chemotherapy was 3.8 months. Overall survival was 8.3 months but was significantly higher in patients who received at least one line of palliative chemotherapy (11.5 months) than those who did not (4.4 months). "It's the first time we have data on expected survival for Asian patients with advanced metastatic or unresectable angiosarcoma," said lead author Dr Tom Chen, attending physician, National Taiwan University Hospital, Taipei, Taiwan. "This data will help us to develop clinical trials and new treatments for Asian angiosarcoma patients." The third study focused on Ewing sarcoma-like small round cell sarcomas.3 Ewing sarcoma is molecularly characterised by a EWSR1 gene alteration or FUS rearrangement. Small round cell sarcomas without these molecular characteristics are designated "Ewing sarcoma-like" disease. Recent molecular genetic studies have identified CIC-rearranged sarcoma (CIC-DUX4, CIC-DUX4L, CIC-FOXO4) and BCOR-rearranged sarcoma (BCOR-CCNB3, BCOR-MAML3, ZC3H7B-BCOR) among these Ewing sarcoma-like small round cell sarcomas. The study presented today describes the clinical characteristics and treatment outcomes of these two sarcomas. The study included 17 patients with CIC sarcoma, of whom 12 were male. Median age was 22 years, all cases were soft tissue tumours, and 59% of patients had local pain. The seven BCOR sarcoma patients were all male. Median age was 14 years and cases included bone and soft tissue tumours. The five-year overall survival rate was 28.2% for CIC sarcoma and 100% for BCOR sarcoma. Metastases were present in 71% of CIC patients at the initial visit and none of the BCOR patients. Only 29% of CIC patients responded to chemotherapy compared to 75% of BCOR patients. "CIC-rearranged sarcomas have a much worse prognosis than BCOR-rearranged sarcomas," said lead author Dr Makoto Endo, attending physician, National Cancer Centre, Tokyo, Japan. "CIC and BCOR sarcomas were previously classified as the same tumour. Our research will help us to make a precise diagnosis and should improve the management of these patients." Commenting on the studies, Professor Thomas Brodowicz, programme director, Bone and Soft Tissue-Sarcoma Unit, Medical University Vienna, Austria, said: "The two studies on angiosarcoma show that immediate progression-free survival and overall survival are low, which reflects the aggressiveness of this disease. It would be useful to have a more detailed breakdown of the patients - for example, the treatment and outcomes of primary angiosarcoma versus secondary, which forms at the site of radiation treatment for a previous cancer. It would also be helpful to know whether paclitaxel is more effective when taken every three weeks or weekly, which has an antiangiogenic effect that could be beneficial in angiosarcoma." He continued: "The study by Dr Endo provides practice-changing information. It shows that Ewing sarcoma-like small round cell sarcomas can be further categorised by their specific mutations, which have a strong prognostic impact. This should help us to tailor treatment."

Thway K.,Sarcoma Unit | Hayes A.,Royal Marsden Hospital | Ieremia E.,Sarcoma Unit | Fisher C.,Sarcoma Unit
Annals of Diagnostic Pathology | Year: 2013

Dedifferentiation within solitary fibrous tumor is a rare and only recently characterized phenomenon. It differs from malignant solitary fibrous tumor in that there is abrupt transition between classical solitary fibrous tumor and the dedifferentiated component. The latter is a high-grade sarcoma, which can exhibit a number of morphologies, but heterologous differentiation is exceptionally rare. We report a case of dedifferentiated solitary fibrous tumor, with heterologous osteosarcomatous and rhabdomyosarcomatous elements, arising in the deep soft tissue of the thigh of a 59-year-old man. This comprised morphologically and immunohistochemically typical solitary fibrous tumor, juxtaposed to pleomorphic, high-grade malignant neoplasm of 2 distinct lineages. The sharp demarcation between well-differentiated and dedifferentiated components is typical of the dedifferentiation seen in other mesenchymal neoplasms. This expands the range of histopathology of this rare, newly characterized type of malignant progression in solitary fibrous tumor. © 2013 Elsevier Inc.

Cananzi F.C.M.,Royal Marsden | Judson I.,Sarcoma Unit | Lorenzi B.,Royal Marsden | Benson C.,Sarcoma Unit | Mudan S.,Royal Marsden
European Journal of Surgical Oncology | Year: 2013

The introduction of receptor tyrosine kinase inhibitors (TKIs) has revolutionized the management of gastrointestinal stromal tumour (GIST). Strong evidence supports the use of imatinib as first-line treatment in metastatic or unresectable tumours and its efficacy in the post-operative adjuvant setting has been confirmed by phase III trials. There are a number of reports concerning the administration of imatinib in the pre-operative setting, however, the heterogeneity of the terminology used and the indications for pre-operative treatment make it difficult to determine the true value of pre-operative imatinib. Larger studies, or a phase III trial could be helpful but patient accrual and standardization of care could be difficult. We propose a pre-treatment classification of GIST in order to facilitate the comparison and collection of data from different institutions, and overcome the difficulties related to accrual. Moreover, in the current era of multidisciplinary treatment of GIST, an appropriate classification is mandatory to properly design clinical trials and plan stage-adapted treatment. © 2013 Elsevier Ltd. All rights reserved.

Thway K.,Sarcoma Unit | Fisher C.,Sarcoma Unit
Annals of Diagnostic Pathology | Year: 2014

Malignant peripheral nerve sheath tumors are soft tissue neoplasms that show differentiation toward cells of the nerve sheath. They often arise from peripheral nerves or preexisting benign nerve sheath tumors and are generally high-grade neoplasms, which behave aggressively with high incidence of distant metastases. Malignant peripheral nerve sheath tumor can be histologically diverse and is difficult to diagnose because of its morphological overlap with a variety of other sarcomas and its lack of specific immunohistochemical markers or genetic profile. We review the pathology of malignant peripheral nerve sheath tumor, with reference to etiology, molecular genetics, and clinical factors. © 2014 Elsevier Inc.

Thway K.,Sarcoma Unit | Flora R.,Sarcoma Unit | Shah C.,Sarcoma Unit | Olmos D.,Sarcoma Unit | Fisher C.,Sarcoma Unit
American Journal of Surgical Pathology | Year: 2012

Adipocytic tumors are the most common type of soft tissue neoplasms. Distinguishing atypical lipomatous tumor-well-differentiated liposarcoma (WDL) from benign adipocytic neoplasms and dedifferentiated liposarcoma (DDL) from pleomorphic or myxoid liposarcoma (LPS) can be difficult. WDL and DDL characteristically harbor amplifications of the MDM2 and CDK4 cell cycle oncogenes with protein overexpression and can also overexpress the cell cycle regulator p16. We assessed the utility of immunohistochemistry for CDK4, MDM2, and p16 in the routine histopathologic diagnosis of WDL/DDL from other adipocytic tumors. Immunohistochemistry for the trio of markers was performed on 216 adipocytic neoplasms (31 WDLs, 57 DDLs, 11 myxoid LPS, 2 pleomorphic LPS, 91 lipomas (including intramuscular, fibro, angio, and ossifying subtypes), 18 spindle/pleomorphic lipomas, and 6 hibernomas. Sixty-eight percent of WDLs and 72% of DDLs expressed all 3 antigens, whereas 100% of WDLs and 93% of DDLs expressed at least 2 antigens. The sensitivity and specificity of the trio for detecting WDLs/DDLs were 71% and 98%, respectively. The sensitivity and specificity of CDK4 for detecting WDLs/DDLs were 86% and 89%, those of MDM2 were 86% and 74%, and those of p16 were 93% and 92%, respectively. The immunohistochemical trio of CDK4, MDM2, and p16 is a useful ancillary diagnostic tool that provides strong support in distinguishing WDLs and DDLs from other adipocytic neoplasms and is potentially more sensitive than previously assessed combinations of CDK4 and MDM2. p16 was the most sensitive and specific marker for detecting WDL/DDL, and the combination of CDK4 and p16 is of more discriminatory value than the combination of either with MDM2, the least sensitive and specific of the 3 markers. Copyright © 2012 by Lippincott Williams & Wilkins.

Thway K.,Sarcoma Unit | Wang J.,Sarcoma Unit | Mubako T.,Sarcoma Unit | Fisher C.,Sarcoma Unit
Sarcoma | Year: 2014

Introduction. Soft tissue tumour pathology is a highly specialised area of surgical pathology, but soft tissue neoplasms can occur at virtually all sites and are therefore encountered by a wide population of surgical pathologists. Potential sarcomas require referral to specialist centres for review by pathologists who see a large number of soft tissue lesions and where appropriate ancillary investigations can be performed. We have previously assessed the types of diagnostic discrepancies between referring and final diagnosis for soft tissue lesions referred to our tertiary centre. We now reaudit this 6 years later, assessing changes in discrepancy patterns, particularly in relation to the now widespread use of ancillary molecular diagnostic techniques which were not prevalent in our original study. Materials and Methods. We compared the sarcoma unit's histopathology reports with referring reports on 348 specimens from 286 patients with suspected or proven soft tissue tumours in a one-year period. Results. Diagnostic agreement was seen in 250 cases (71.8%), with 57 (16.4%) major and 41 (11.8%) minor discrepancies. There were 23 cases of benign/malignant discrepancies (23.5% of all discrepancies). 50 ancillary molecular tests were performed, 33 for aiding diagnosis and 17 mutational analyses for gastrointestinal stromal tumour to guide therapy. Findings from ancillary techniques contributed to 3 major and 4 minor discrepancies. While the results were broadly similar to those of the previous study, there was an increase in frequency of major discrepancies. Conclusion. Six years following our previous study and notably now in an era of widespread ancillary molecular diagnosis, the overall discrepancy rate between referral and tertiary centre diagnosis remains similar, but there is an increase in frequency of major discrepancies likely to alter patient management. A possible reason for the increase in major discrepancies is the increasing lack of exposure to soft tissue cases in nonspecialist centres in a time of subspecialisation. The findings support the national guidelines in which all suspected soft tissue tumour pathology specimens should be referred to a specialist sarcoma unit. © 2014 Khin Thway et al.

Noujaim J.,Sarcoma Unit
American Journal of Clinical Oncology: Cancer Clinical Trials | Year: 2015

OBJECTIVES:: Treatment options for metastatic soft-tissue sarcomas are limited. The aim of this study was to investigate the clinical activity of ifosfamide rechallenge in synovial sarcoma (SS), liposarcoma (LPS), leiomyosarcoma (LMS), and high-grade sarcomas not otherwise specified. METHODS:: A retrospective search of the Royal Marsden Sarcoma Unit Database was performed to identify patients initially treated with ifosfamide (as single agent or in combination) and who were subsequently rechallenged with single-agent ifosfamide. Baseline demographics and response assessment were retrospectively obtained. RESULTS:: Sixty-seven patients were identified and the median age at diagnosis was 41 years (range, 18 to 71 y). There were 29 cases of SS, 17 of LPS, 12 of LMS, and 9 of sarcomas not otherwise specified. First-line ifosfamide-containing therapy was given to 14 patients as adjuvant therapy (adjuvant group) and 53 patients as palliative therapy (palliative group). Clinical activity (partial response or stable disease) with single-agent ifosfamide rechallenge was documented in 50.0% of patients in the adjuvant group (7 in the second line) and 34.0% of patients in the palliative group (15 in the second line, 1 in third line, and 2 in the fourth line). The median progression-free survival in patients with documented clinical activity was 11.5 months (95% CI, 8.8-12.3) and 6.9 months (95% CI, 5.1-9.0), respectively, in the adjuvant and palliative group. Ifosfamide rechallenge was mostly active in SS patients (49.3%, 14 out of 29 patients with partial remission or stable disease). CONCLUSIONS:: Ifosfamide rechallenge has clinical activity in soft-tissue sarcoma and can be considered a viable option in treating metastatic disease. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Background:Soft tissue sarcomas are a group of neoplasms with differentiation towards mesenchymal tissue, many of which are aggressive and chemotherapy resistant. Histology and immunoprofiles often overlap with neoplasms of other lineages, and establishing an accurate histopathological diagnosis is crucial for correct management, and therapeutic stratification. The endosialin cell surface glycoprotein is predominantly expressed by stromal fibroblasts and pericytes in epithelial neoplasms; however, tumour cell expression has been reported in small series of sarcomas.Methods:We assessed endosialin expression by immunohistochemistry in a large set of 514 human soft tissue sarcomas.Results:Tumour cell endosialin expression was seen in 89% of undifferentiated pleomorphic sarcomas (104/117), 77% adult fibrosarcomas/spindle cell sarcomas (20/26), 62% synovial sarcomas (37/60), 51% leiomyosarcomas (94/185) and 31% rhabdomyosarcomas (39/126).Conclusions:Endosialin immunohistochemistry has potential to distinguish undifferentiated and poorly differentiated sarcomas from other poorly differentiated, non-mesenchymal neoplasms. A Phase II trial randomising patients with advanced sarcomas to receive chemotherapy with/without an endosialin therapeutic antibody has recently completed enrolment. Endosialin expression could be used to select patients for such clinical trials. Based on our results, patients with undifferentiated pleomorphic sarcoma may be particularly suitable for such a therapeutic approach.British Journal of Cancer advance online publication, 19 July 2016; doi:10.1038/bjc.2016.214 © 2016 Cancer Research UK

Reid A.,Sarcoma Unit | Martin-Liberal J.,Sarcoma Unit | Benson C.,Sarcoma Unit
Therapeutics and Clinical Risk Management | Year: 2014

Patients with locally advanced or metastatic soft tissue sarcoma have a poor outlook with median survival in the order of 1 year. There is therefore an urgent need for novel agents to impact this disease. Trabectedin is one such novel agent that has demonstrated activity for patients with advanced soft tissue sarcoma and it was licensed in Europe in 2007 for patients in the second-line setting or frst-line in those patients deemed unsuitable to receive cytotoxics. In order to best serve patients with novel agents, it is imperative to understand the mechanism or mechanisms of action and the best ways of assessing response in order to optimize antitumor activity. Frequently, the mechanism of action and the optimal means of assessing response will be different from those of traditional cytotoxics. Trial design should refect these factors to ensure that active drugs are not wrongly marked as futile. This review discusses a number of factors that may infuence the optimization of trabectedin use. These factors include the administration schedule, the optimal timing of trabectedin administration in the disease process, the histopathological and molecular subtypes that may be most sensitive to trabectedin, the challenge of assessing response, particularly using radiology, and, fnally, the safety considerations with this agent. © 2014 Reid et al.

Thway K.,Sarcoma Unit | Fisher C.,Sarcoma Unit
Annals of Diagnostic Pathology | Year: 2015

Perivascular epithelioid cell tumors, or PEComas, are mesenchymal neoplasms composed of histologically and immunohistochemically distinctive epithelioid or spindle cells, which are immunoreactive for both smooth muscle and melanocytic markers. The cells in PEComas are typically arranged around blood vessels and appear to form the vessel wall, often infiltrating the smooth muscle of small- to medium-sized vessels. Periluminal cells are usually epithelioid and the more peripheral cells are spindle shaped. The cells have small, round to oval nuclei, sometimes with focal nuclear atypia, and clear to eosinophilic cytoplasm, and no counterpart normal cell has been identified. The PEComa "family" now includes angiomyolipoma, pulmonary clear cell "sugar" tumor and lymphangioleiomyomatosis, primary extrapulmonary sugar tumor, clear cell myomelanocytic tumor of the falciform ligament/ligamentum teres, abdominopelvic sarcoma of perivascular epithelioid cells, and other tumors with similar features at various sites that are simply termed PEComa. Some PEComas occur in patients with tuberous sclerosis complex and share the genetic abnormalities. There is a behavioral spectrum from benign to frankly malignant, and histologic criteria have been proposed for assessing malignant potential. The differential diagnosis can include carcinomas, smooth muscle tumors, other clear cell neoplasms, and adipocytic tumors. PEComas constitute a genetically diverse group that includes neoplasms harboring TFE3 gene rearrangements and those with TSC2 mutations, indicating alternative tumorigenic pathways. Recent advances in therapy of malignant PEComas relate to increased knowledge of specific genetic changes and their effects on metabolic pathways that are susceptible to specific interventions. We review PEComas, emphasizing the diagnostic spectrum and recent immunohistochemical and genetic findings. © 2015 Elsevier Inc. All rights reserved.

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