Undifferentiated Pleomorphic Sarcoma

Undifferentiated pleomorphic sarcoma (UPS) is a high grade pleomorphic soft tissue sarcoma with no identifiable line of differentiation after full histological, immunohistochemical and molecular workup. It is a diagnosis of exclusion, replacing the older label of malignant fibrous histiocytoma.

It makes up about 5% to 10% of adult soft tissue sarcomas, with the proportion falling as other lines of differentiation are identified. It affects patients over 50 (median age 60 to 70), mainly in the lower limb (about 60%), then trunk and retroperitoneum.

Risk factors are previous radiotherapy (radiation associated sarcoma, about 3% of cases), Li-Fraumeni syndrome and, rarely, chronic scars or burns.

Pathophysiology. Complex karyotype with TP53, RB1, CDKN2A, ATRX and NF1 alterations. Tumour associated immune infiltrates are present, and this is the rationale for checkpoint inhibitor therapy.

Grade. All tumours are grade 3 (high grade), with marked pleomorphism, necrosis and atypical mitoses.

Behaviour. Local recurrence is about 20% to 30% after adequate surgery and radiotherapy. Distant metastasis occurs in about 30% to 50%, mainly to lung. Five year overall survival is about 50% to 60%.

• Enlarging painless deep mass over months, often large (over 5 cm) at diagnosis, and sometimes mistaken for a haematoma after minor trauma.
• Retroperitoneal tumours produce abdominal symptoms late.
• Pulmonary metastases may cause cough, dyspnoea or pleural effusion.

• MRI of the primary site: heterogeneous mass with necrosis, haemorrhage and peritumoral oedema. CT for the retroperitoneum and chest.
• Core biopsy through a planned track, with immunohistochemistry to exclude other lines of differentiation:
  • Cytokeratins and p63 (carcinoma)
  • S100 and SOX10 (melanoma)
  • CD45 (lymphoma)
  • CD31 and ERG (angiosarcoma)
  • Desmin, caldesmon and SMA (leiomyosarcoma)
  • Myogenin and MyoD1 (rhabdomyosarcoma)
  • MDM2 FISH (dedifferentiated liposarcoma)
  • H3K27me3 (loss in MPNST)
  • INI1 (epithelioid sarcoma)
• Molecular testing for fusions in selected cases.
• Staging: CT chest, plus imaging of the primary mass. PET-CT is optional.
• Baseline echocardiography, creatinine, liver tests and pregnancy test.

Differential diagnosis.

• Pleomorphic leiomyosarcoma, rhabdomyosarcoma and liposarcoma
• Dedifferentiated liposarcoma
• Myxofibrosarcoma
• Sarcomatoid carcinoma and melanoma
• Malignant peripheral nerve sheath tumour
• Anaplastic lymphoma and radiation associated sarcoma
• Atypical fibroxanthoma

Localised disease. Wide excision with negative margins by a sarcoma surgeon, with limb preservation where possible.

• Preoperative radiotherapy 50 Gy in 25 fractions is preferred to improve resectability and reduce late fibrosis. Postoperative radiotherapy 60 Gy in 30 fractions (66 Gy for positive margins) is given when preoperative therapy was not given.
• Chemotherapy (doxorubicin with ifosfamide) is considered for large (over 5 cm), deep, high grade tumours in fit patients. Survival benefit is uncertain.

Advanced disease.

• Doxorubicin:
  • 75 mg/m2 IV every 3 weeks for up to 6 cycles.
  • Maximum cumulative working ceiling 450 mg/m2.
  • Monitoring: echocardiography at baseline and every 2 cycles, FBC before each cycle.
  • Adjustment: bilirubin 20 to 51 micromol/L reduce by 50%, 53 to 85 micromol/L reduce by 75%, over 85 micromol/L avoid. Consider reduction when eGFR is under 30 mL/min/1.73 m2.
• Doxorubicin with ifosfamide (fit patients needing a response):
  • Doxorubicin 75 mg/m2 total each cycle (25 mg/m2 daily on days 1 to 3) with ifosfamide 10 g/m2 total (2.5 g/m2 daily on days 1 to 4) IV.
  • Mesna at a total of 60% to 100% of the ifosfamide dose and pegfilgrastim 6 mg subcutaneously 24 to 72 hours after chemotherapy, every 3 weeks for up to 6 cycles.
  • Maximum doxorubicin cumulative working ceiling 450 mg/m2 and ifosfamide 10 g/m2 each cycle.
  • Monitoring: FBC, creatinine, urinalysis for haematuria, neurological status (ifosfamide encephalopathy), echocardiography.
  • Adjustment: avoid ifosfamide when eGFR is under 30 mL/min/1.73 m2 and reduce by about 25% to 50% when it is 30 to 59. Stop for grade 2 neurotoxicity. Reduce doxorubicin for hepatic impairment (bilirubin 20 to 51 micromol/L by 50%, 53 to 85 micromol/L by 75%, over 85 micromol/L avoid).
• Gemcitabine with docetaxel:
  • Gemcitabine 900 mg/m2 IV over 90 minutes on days 1 and 8 with docetaxel 75 mg/m2 IV on day 8, with pegfilgrastim 6 mg subcutaneously on day 9, every 21 days until progression.
  • Maximum gemcitabine 900 mg/m2 and docetaxel 75 mg/m2 each cycle.
  • Monitoring: FBC before each dose, liver tests, creatinine, pneumonitis, oedema.
  • Adjustment: do not give docetaxel when bilirubin exceeds the upper limit or AST or ALT exceeds 1.5 times the upper limit with alkaline phosphatase over 2.5 times. Reduce both agents by 25% for grade 3 to 4 toxicity. Caution when creatinine clearance is under 30 mL/min.
• Pazopanib (non-adipocytic sarcoma after chemotherapy):
  • 800 mg orally once daily on an empty stomach until progression; maximum 800 mg daily.
  • Monitoring: liver tests at baseline, weeks 3, 5, 7 and 9, then months 3 and 4 and as needed, blood pressure at each visit, ECG and electrolytes, thyroid function, proteinuria.
  • Adjustment: reduce in 200 mg steps for toxicity. Give 200 mg daily in moderate hepatic impairment (bilirubin over 1.5 to 3 times the upper limit). Avoid in severe impairment. Stop for ALT over 8 times the upper limit. Avoid strong CYP3A4 inhibitors.
• Pembrolizumab (unlicensed in sarcoma, activity reported in UPS):
  • 200 mg IV every 3 weeks for up to 2 years; maximum 200 mg each dose.
  • Monitoring: thyroid function, liver tests, creatinine and glucose before each dose.
  • Adjustment: no renal or hepatic dose adjustment, withhold for grade 2 immune toxicity, stop permanently for grade 3 to 4 events.
  • For grade 2 or worse pneumonitis, colitis or hepatitis give prednisolone 1 to 2 mg/kg daily tapered over at least 4 to 6 weeks.
• Resection or stereotactic radiotherapy of oligometastatic pulmonary disease.

Monitoring. Examination and MRI every 3 to 4 months for 2 years, then 6 monthly to year 5. CT chest every 3 to 4 months for 2 to 3 years, then 6 monthly to year 5.

Referral and escalation.

• Sarcoma centre referral before biopsy or excision for any deep soft tissue mass over 5 cm or enlarging.
• Urgent assessment for febrile neutropenia, pneumothorax, haemorrhage or immune related toxicity.

Special groups.

• Radiation associated sarcoma: re-irradiation is limited, so surgery is central.
• Li-Fraumeni syndrome: avoid radiotherapy where possible, with genetic counselling.
• Older adults: favour surgery and radiotherapy, with single agent doxorubicin or gemcitabine.