{"entity":{"id":"undifferentiated-pleomorphic-sarcoma","kind":"cancer","name":"Undifferentiated pleomorphic sarcoma (UPS)","aka":["UPS","Malignant fibrous histiocytoma (historic)","MFH","Pleomorphic sarcoma, not otherwise specified"],"tldr":"Undifferentiated pleomorphic sarcoma is the diagnosis for a high-grade soft tissue sarcoma whose cells show no recognisable line of differentiation. It is treated with surgery and radiotherapy, with doxorubicin-based chemotherapy for high-risk or spread disease, and it is one of the few sarcomas in which the immunotherapy drug pembrolizumab has clear activity.","summary":"Undifferentiated pleomorphic sarcoma is a diagnosis of exclusion: a genomically complex, high-grade sarcoma with no line of differentiation on histology, immunohistochemistry or molecular testing. It replaced the older label malignant fibrous histiocytoma once many such tumours were reclassified as dedifferentiated liposarcoma, myxofibrosarcoma or pleomorphic leiomyosarcoma. It arises mostly in the deep soft tissues of the limbs in people over 60, less often in the retroperitoneum, and its genome shows widespread copy number change with TP53, RB1, CDKN2A and ATRX loss rather than a driver fusion.\n\nLocalised disease is treated with wide resection and radiotherapy, given preoperatively or postoperatively, following the principles established for extremity sarcoma. In the Italian Sarcoma Group ISG-STS 1001 trial, three cycles of neoadjuvant epirubicin and ifosfamide improved relapse-free and overall survival in high-risk limb and trunk sarcomas, a benefit driven partly by the UPS group, and full-dose anthracycline-ifosfamide is offered to fit patients with large, deep, high-grade tumours. Advanced disease is treated with doxorubicin alone or with ifosfamide, gemcitabine-docetaxel, trabectedin or pazopanib.\n\nUPS stands out among sarcomas for immunotherapy: in the SARC028 phase 2 trial pembrolizumab produced objective responses in undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma but almost none in leiomyosarcoma or synovial sarcoma, and the randomised SU2C-SARC032 trial found that pembrolizumab added to preoperative radiotherapy and surgery improved disease-free survival in stage III UPS and dedifferentiated liposarcoma of the limbs. Tertiary lymphoid structures and B-cell-rich immune classes predict who benefits.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Undifferentiated_pleomorphic_sarcoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Undifferentiated_pleomorphic_sarcoma"}],"tags":["subtype-page"],"related":["extremity-soft-tissue-sarcoma","liposarcoma","myxofibrosarcoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"sarcoma","burden":"One of the commonest soft tissue sarcomas of older adults, usually a deep, fast-growing mass in the thigh or upper arm; about a third of patients with high-grade limb tumours develop lung metastases despite surgery and radiotherapy.","subtypes":["Undifferentiated pleomorphic sarcoma of the limbs (commonest)","Undifferentiated pleomorphic sarcoma of the trunk and retroperitoneum","Radiation-associated undifferentiated sarcoma","Undifferentiated round cell and spindle cell sarcomas (separate WHO categories, fusion-defined)"],"biomarkers":["FNCLCC grade, size and depth (risk)","Exclusion of specific differentiation by immunohistochemistry and molecular testing","TP53, RB1, CDKN2A and ATRX alterations","Tertiary lymphoid structures and B-cell-rich immune class (immunotherapy response)"],"standardOfCare":[{"setting":"Localised, limb or trunk","approach":"Wide resection with preoperative or postoperative radiotherapy; neoadjuvant anthracycline-ifosfamide for large, deep, high-grade tumours in fit patients (ISG-STS 1001).","refs":["limb-salvage-surgery","imrt-igrt","isg-sts-1001","doxorubicin","ifosfamide","fnclcc-grade"]},{"setting":"Advanced, first line","approach":"Doxorubicin alone or doxorubicin plus ifosfamide (EORTC 62012) when response matters.","refs":["doxorubicin","ifosfamide","eortc-62012"]},{"setting":"Later lines","approach":"Gemcitabine-docetaxel, trabectedin, pazopanib; pembrolizumab in trials or off label after SARC028.","refs":["gemcitabine","docetaxel","trabectedin","pazopanib","pembrolizumab","checkpoint-inhibitor"]}],"stateOfArt":["SARC028 identified UPS as the sarcoma with the clearest response to PD-1 blockade.","SU2C-SARC032 showed pembrolizumab with preoperative radiotherapy improves disease-free survival in stage III limb UPS and dedifferentiated liposarcoma.","Immune classification by B-cell signatures is being tested to select patients for immunotherapy."],"history":[{"year":1964,"title":"O'Brien and Stout describe malignant fibrous histiocytoma","refs":[]},{"year":2002,"title":"WHO abandons malignant fibrous histiocytoma as a diagnosis in favour of undifferentiated pleomorphic sarcoma","refs":[]},{"year":2014,"title":"EORTC 62012: doxorubicin plus ifosfamide improves response and progression-free but not overall survival","refs":["eortc-62012"]},{"year":2017,"title":"ISG-STS 1001: neoadjuvant epirubicin-ifosfamide improves survival in high-risk limb sarcoma","refs":["isg-sts-1001"]},{"year":2017,"title":"SARC028: pembrolizumab responses concentrated in UPS and dedifferentiated liposarcoma","refs":["pembrolizumab"]},{"year":2024,"title":"SU2C-SARC032: pembrolizumab plus preoperative radiotherapy improves disease-free survival","refs":["pembrolizumab","imrt-igrt"]}],"pipeline":["pembrolizumab","checkpoint-inhibitor","isg-sts-1001"],"openProblems":["No molecular driver to target; the diagnosis is defined by what the tumour is not.","A third of high-grade limb tumours still metastasise to the lungs.","Which patients gain from neoadjuvant chemotherapy versus immunotherapy is not settled."],"parent":"sarcoma"},"route":"/cancers/undifferentiated-pleomorphic-sarcoma/","neighbours":{"cancer":[{"id":"liposarcoma","kind":"cancer","name":"Liposarcoma","route":"/cancers/liposarcoma/"},{"id":"myxofibrosarcoma","kind":"cancer","name":"Myxofibrosarcoma","route":"/cancers/myxofibrosarcoma/"},{"id":"sarcoma","kind":"cancer","name":"Sarcomas (soft tissue, bone, GIST)","route":"/cancers/sarcoma/"},{"id":"extremity-soft-tissue-sarcoma","kind":"cancer","name":"Soft tissue sarcoma of the extremity (localised and advanced)","route":"/cancers/extremity-soft-tissue-sarcoma/"}],"trial":[{"id":"eortc-62012","kind":"trial","name":"EORTC 62012","route":"/trials/eortc-62012/"},{"id":"isg-sts-1001","kind":"trial","name":"ISG-STS 1001","route":"/trials/isg-sts-1001/"}],"drug":[{"id":"docetaxel","kind":"drug","name":"Docetaxel","route":"/drugs/docetaxel/"},{"id":"doxorubicin","kind":"drug","name":"Doxorubicin","route":"/drugs/doxorubicin/"},{"id":"gemcitabine","kind":"drug","name":"Gemcitabine","route":"/drugs/gemcitabine/"},{"id":"ifosfamide","kind":"drug","name":"Ifosfamide","route":"/drugs/ifosfamide/"},{"id":"pazopanib","kind":"drug","name":"Pazopanib","route":"/drugs/pazopanib/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"},{"id":"trabectedin","kind":"drug","name":"Trabectedin","route":"/drugs/trabectedin/"}],"technology":[{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"},{"id":"imrt-igrt","kind":"technology","name":"IMRT / IGRT (modern external beam)","route":"/technologies/imrt-igrt/"},{"id":"limb-salvage-surgery","kind":"technology","name":"Limb-salvage surgery and endoprosthetic reconstruction","route":"/technologies/limb-salvage-surgery/"}],"term":[{"id":"fnclcc-grade","kind":"term","name":"FNCLCC grade (soft-tissue sarcoma)","route":"/terms/fnclcc-grade/"}]}}