Pleomorphic Liposarcoma

Pleomorphic liposarcoma is a rare, high grade pleomorphic sarcoma containing pleomorphic lipoblasts in a background of undifferentiated pleomorphic sarcoma. It does not show MDM2 amplification, which separates it from dedifferentiated liposarcoma.

It accounts for about 5% of liposarcomas and under 1% of soft tissue sarcomas. Patients are older adults (median age 55 to 65), and the limbs are the commonest site (about 60%), followed by trunk and retroperitoneum.

Pathophysiology. Complex karyotypes with TP53 and RB1 loss and widespread chromosomal rearrangement are typical. Amplification of 12q13-15 is absent.

Grading. All tumours are high grade, with marked pleomorphism, mitoses and necrosis. Epithelioid variants lose some staining for other lineages.

Behaviour. Distant metastasis occurs in about 30% to 50%, mainly to lung. Local recurrence is about 30% to 40%. Five year overall survival is about 50% to 60%.

• Enlarging deep painless mass in the limb, often over several months.
• Pain, rapid growth, or haemorrhage into the tumour in some patients.
• Metastatic symptoms: cough, dyspnoea, chest pain, bone pain.

• MRI of the primary mass: heterogeneous mass with necrosis, with little fat. CT of the retroperitoneum or trunk.
• Core biopsy with immunohistochemistry: pleomorphic lipoblasts on histology and negative MDM2 FISH, with S100 sometimes focally positive. Exclusion of other pleomorphic tumours needs a broad panel.
• Staging with CT chest and imaging of the primary site. FDG-PET for equivocal findings.
• Baseline echocardiography, renal function, liver tests and pregnancy test before chemotherapy.

Differential diagnosis.

• Undifferentiated pleomorphic sarcoma
• Dedifferentiated liposarcoma (MDM2 amplified)
• Pleomorphic leiomyosarcoma and pleomorphic rhabdomyosarcoma
• Myxofibrosarcoma
• Pleomorphic or spindle cell lipoma (benign, CD34 positive with RB1 loss)
• Metastatic carcinoma or melanoma
• Atypical fibroxanthoma

Localised disease. Wide excision with negative margins, preferably with preoperative radiotherapy 50 Gy in 25 fractions, or postoperative 60 Gy (66 Gy for positive margins). Limb preservation is the aim.

Adjuvant and neoadjuvant chemotherapy. Considered for deep tumours over 5 cm, high grade. The benefit for survival is uncertain, and doxorubicin with ifosfamide is used in fit patients.

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: 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, with 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 (second line): 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.
• Eribulin (after anthracycline): 1.4 mg/m2 IV over 2 to 5 minutes on days 1 and 8 of each 21-day cycle until progression; maximum 1.4 mg/m2 each dose; monitoring: FBC before each dose, ECG when there is heart failure, bradyarrhythmia or QT-prolonging medicines, neuropathy, liver tests; adjustment: 1.1 mg/m2 in mild hepatic impairment or when creatinine clearance is 30 to 50 mL/min, 0.7 mg/m2 in moderate hepatic impairment.
• Pazopanib is not effective in adipocytic sarcoma and is not used.
• Resection or stereotactic radiotherapy of limited lung metastases in selected patients.

Monitoring. Examination and MRI of the primary site 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.

• Referral to a sarcoma centre before any surgery or biopsy.
• Urgent assessment for febrile neutropenia, cord compression, pneumothorax or major haemorrhage.

Special groups.

• Older adults: radiotherapy and surgery over multi-agent chemotherapy when frail.
• Prior chest or limb irradiation: ensure histology is not radiation associated pleomorphic sarcoma, since options for re-irradiation are limited.