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      Clinical Characteristics and efficacy of chemotherapy in sclerosing epithelioid fibrosarcoma

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          Abstract

          Background

          Sclerosing epithelioid fibrosarcoma (SEF) is a very rare soft tissue sarcoma subtype. Clinically it is an aggressive tumour; however, to our knowledge there are no published reports regarding the efficacy of chemotherapy in SEF. Therefore, the aim of this study was to document the outcome of a series of patients with SEF treated at a single referral centre with reference to systemic therapy.

          Methods

          A retrospective search of a prospectively maintained database was performed to identify all patients diagnosed with SEF between 1990 and 2017. The diagnosis was confirmed in each case by a dedicated soft tissue sarcoma pathologist. We analysed those with recurrent disease and the effect of systemic chemotherapy in the metastatic setting.

          Results

          Thirteen patients were identified, median overall survival from diagnosis and metastasis were 47.3 (95% CI 25.0–131.9) and 16.3 (95% CI 5.3–20.6) months, respectively. In total, 12 (92.3%) patients developed metastatic disease of which 10 died of disease, 1 was lost to follow-up and 1 had recently commenced palliative treatment. Among the 10 patients with metastatic disease, 7 received palliative chemotherapy. Palliative chemotherapy resulted in partial response in 1 patient, stable disease in 3 patients and progressive disease in 3 patients. Median time to disease progression was 2.7 (95% CI 1.2–4.4) months. Two of 13 patients were treated with adjuvant chemotherapy, receiving 6 cycles of liposomal doxorubicin and 1 cycle of doxorubicin, respectively, with a metastasis-free survival of 28.2 and 7.1 months, respectively.

          Conclusion

          SEF is an aggressive sarcoma subtype with a poor outcome and with limited responsiveness to conventional chemotherapy. Patients with this subtype should be considered for participation in clinical trials with novel agents. Further investigation into the biology of this rare disease is required to improve outcomes.

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          Most cited references9

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          Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial.

          Effective targeted treatment is unavailable for most sarcomas and doxorubicin and ifosfamide-which have been used to treat soft-tissue sarcoma for more than 30 years-still have an important role. Whether doxorubicin alone or the combination of doxorubicin and ifosfamide should be used routinely is still controversial. We assessed whether dose intensification of doxorubicin with ifosfamide improves survival of patients with advanced soft-tissue sarcoma compared with doxorubicin alone.
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            MUC4 is a sensitive and extremely useful marker for sclerosing epithelioid fibrosarcoma: association with FUS gene rearrangement.

            Sclerosing epithelioid fibrosarcoma (SEF) is a rare aggressive fibroblastic neoplasm composed of cords of epithelioid cells embedded in a dense collagenous stroma. The reported immunophenotype of SEF is nonspecific. Some SEF cases show morphologic and molecular overlap with low-grade fibromyxoid sarcoma (LGFMS), suggesting a relationship between these tumor types. MUC4 has recently been identified as a sensitive and specific marker for LGFMS; MUC4 expression was also observed in 2 tumors with hybrid features of SEF and LGFMS. We investigated MUC4 expression in SEF and other epithelioid soft tissue tumors to determine (1) the potential diagnostic utility of MUC4 for SEF and (2) the association between MUC4 expression and FUS rearrangement in SEF. Whole sections of 180 tumors were evaluated: 41 cases of SEF (including 29 "pure" SEF and 12 hybrid LGFMS-SEF), 20 epithelioid sarcomas, 11 clear cell sarcomas, 11 metastatic melanomas, 10 perivascular epithelioid cell tumors, 10 alveolar soft part sarcomas, 10 epithelioid angiosarcomas, 10 epithelioid hemangioendotheliomas, 10 epithelioid gastrointestinal stromal tumors, 10 myoepithelial carcinomas, 17 ossifying fibromyxoid tumors, 10 leiomyosarcomas, and 10 biphasic synovial sarcomas. Immunohistochemical analysis was performed after antigen retrieval using a mouse anti-MUC4 monoclonal antibody. Fluorescence in situ hybridization (FISH) was performed on 33 SEF cases using FUS break-apart probes. A subset of cases was also evaluated for EWSR1 and CREB3L2/L1 rearrangements by FISH. Strong diffuse cytoplasmic staining for MUC4 was observed in 32 of 41 (78%) cases of SEF, including all 12 hybrid tumors. FUS rearrangement was detected in 8 of 21 (38%) MUC4-positive cases of SEF with successful FISH studies. The prevalence of FUS rearrangement was similar in hybrid LGFMS-SEF (2 of 6; 33%) and SEF without an LGFMS component (6 of 15; 40%). FUS rearrangement was not detected in any cases of MUC4-negative SEF. Two hybrid tumors had both EWSR1 and CREB3L1 rearrangements. MUC4 expression was also seen in 9 of 10 (90%) biphasic synovial sarcomas, predominantly in the glandular component. All other tumor types were negative for MUC4, apart from focal reactivity in 5 ossifying fibromyxoid tumors, 2 epithelioid gastrointestinal stromal tumors, and 1 myoepithelial carcinoma. MUC4 is a sensitive and relatively specific marker for SEF among epithelioid soft tissue tumors. MUC4 expression occurs more frequently than FUS rearrangement in SEF. The finding of EWSR1 and CREB3L1 rearrangements in 2 cases of hybrid LGFMS-SEF suggests that SEFs are genetically heterogenous. MUC4-positive SEFs with FUS rearrangement are likely closely related to LGFMS. MUC4-positive SEFs that lack FUS rearrangement may be related to LGFMS but could have alternate fusion partners, including EWSR1. SEF without MUC4 expression may represent a distinct group of tumors. MUC4 expression correlates with glandular epithelial differentiation in biphasic synovial sarcoma and is very limited in other epithelioid soft tissue tumors.
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              Sclerosing epithelioid fibrosarcoma. A variant of fibrosarcoma simulating carcinoma.

              We report 25 cases of a peculiar sclerosing epithelioid variant of fibrosarcoma (SEF) simulating an infiltrating carcinoma. The tumors occurred primarily in the deep musculature and were frequently associated with the adjacent fascia or periosteum. The patients' ages were 14 to 87 years (median, 45). Fourteen were male and 11 female. The tumors were located in the lower extremities and limb girdles (12 cases), trunk (9), upper limb girdles (2), and neck (2). They measured 2 to 14.5 cm in greatest dimension (median size, 7 cm) and were gray to white and firm. Histologically, the lesions were characterized by a proliferation of rather uniform, small, slightly angulated, round to ovoid epithelioid cells with sparse, often clear cytoplasm arranged in distinct nests and cords. In all cases there was prominent hyaline sclerosis, sometimes reminiscent of osteoid or cartilage and foci of conventional fibrosarcoma. Occasional myxoid zones with cyst formation and foci of hyaline cartilage, calcification, and metaplastic bone were also seen. Mitotic figures were generally scarce. Vimentin was detected in 13 of 14 cases, epithelial membrane antigen in seven, S100 protein in four, and neuron-specific enolase in two. Cytokeratins were detected with AE1/AE3 and CAM 5.2 in two cases. Leukocyte common antigen, CD68 antigen, HMB45, desmin, and alpha-smooth muscle actin were negative in all cases. In 13 of 14 cases, 75% or more of the cells stained for proliferating cell nuclear antigen (PCNA). Ki67 immunostaining with MIB 1 showed low proliferative activity in all cases, averaging 5% of tumor cells or less. In all cases, p53 was detected by immunohistochemical methods; bcl-2, an antiapoptosis marker, was detected in more than 90% of the cells in 11 of 12 cases. Ultrastructurally, both the epithelioid and spindled tumor cells had features of fibroblasts. Follow-up in 16 cases ranging from 13 months to 17 years 3 months (median, 11 years 4 months) revealed persistent disease or local recurrences in 53% of patients and metastases in 43%. The metastases were to the lungs (4 cases), skeleton (3), chest wall/pleura (3), pericardium (1), and brain (1). Four patients died of disease, four were alive with disease, two were known to be alive but disease status unknown, and six had no evidence of further disease at last follow-up. The data suggest that SEF is a relatively low-grade fibrosarcoma; yet it is fully malignant despite the presence of histologically benign-appearing foci. The proliferation markers PCNA and Ki67 did not correlate with prognosis.(ABSTRACT TRUNCATED AT 400 WORDS)
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                Author and article information

                Contributors
                +44 207 808 2590 , robin.jones4@nhs.net
                Journal
                Med Oncol
                Med. Oncol
                Medical Oncology (Northwood, London, England)
                Springer US (New York )
                1357-0560
                1559-131X
                5 September 2018
                5 September 2018
                2018
                : 35
                : 11
                : 138
                Affiliations
                [1 ]ISNI 0000 0004 0417 0461, GRID grid.424926.f, Sarcoma Unit, , Royal Marsden Hospital, ; Fulham Road, London, SW3 6JJ UK
                [2 ]ISNI 0000 0001 1271 4623, GRID grid.18886.3f, Division of Molecular Pathology, , Institute of Cancer Research, ; London, UK
                [3 ]ISNI 0000 0001 1271 4623, GRID grid.18886.3f, Division of Radiotherapy and Imaging, , Institute of Cancer Research, ; London, UK
                [4 ]ISNI 0000 0001 1271 4623, GRID grid.18886.3f, Division of Clinical Studies, , Institute of Cancer Research, ; London, UK
                Article
                1192
                10.1007/s12032-018-1192-6
                6132781
                30187231
                3652f892-33ee-4721-a312-47aab2bc7818
                © The Author(s) 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 11 June 2018
                : 10 August 2018
                Categories
                Short Communication
                Custom metadata
                © Springer Science+Business Media, LLC, part of Springer Nature 2018

                Oncology & Radiotherapy
                sclerosing epithelioid fibrosarcoma,treatment,prognosis,chemotherapy
                Oncology & Radiotherapy
                sclerosing epithelioid fibrosarcoma, treatment, prognosis, chemotherapy

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