Myxoid Liposarcoma

Myxoid liposarcoma is a malignant adipocytic tumour of uniform round to ovoid cells with a myxoid stroma, a plexiform capillary network and scattered lipoblasts. It carries a FUS::DDIT3 fusion (t(12;16)) in about 90% and an EWSR1::DDIT3 fusion in about 5%.

It makes up about 20% to 30% of liposarcomas. It occurs in younger patients (median age 35 to 50) than other liposarcomas, with a deep thigh location in about 75% of cases and a notable incidence in the second to fourth decades.

No hereditary predisposition is known.

Pathophysiology. The fusion transcription factor blocks adipocyte differentiation. Additional mutations (TERT promoter, PIK3CA) are present in a subset and predict worse outcomes.

Grade. Low grade tumours have under 5% hypercellular (round cell) component. A round cell component of 5% or more defines high grade disease, with a markedly worse prognosis. Tumours with over 80% round cells are the most aggressive.

Behaviour. The tumour is both radiosensitive and chemosensitive. Metastasis occurs in about 30% to 40%, with a characteristic pattern: soft tissue (retroperitoneum, contralateral limb, axilla, chest wall) and bone (spine) metastases before lung metastases. Five year survival is over 90% for low grade tumours and about 60% for high grade tumours.

• Painless, slowly enlarging deep mass in the thigh, popliteal fossa, or other limb site.
• Bone pain, neurological deficit or abdominal masses suggest unusual metastatic sites.

• MRI of the limb: lobulated mass with high T2 signal (cystic appearance due to myxoid matrix), feathery enhancement and thin septa, with fat in a minority.
• Core biopsy. Confirm the fusion by DDIT3 break apart FISH or RT-PCR (FUS::DDIT3, EWSR1::DDIT3). Quantify the round cell component, since it determines grade and risk.
• Staging: CT chest, abdomen and pelvis, and MRI of the spine or whole body MRI at diagnosis because of the unusual metastatic pattern.
• Baseline echocardiography and renal function before chemotherapy.

Differential diagnosis.

• Intramuscular myxoma
• Myxofibrosarcoma
• Extraskeletal myxoid chondrosarcoma
• Low grade fibromyxoid sarcoma
• Dedifferentiated liposarcoma
• Other myxoid soft tissue tumours and metastatic myxoid tumours

Localised disease. Wide excision with negative margins by a sarcoma surgeon, combined with radiotherapy.

• Preoperative radiotherapy 50 Gy in 25 fractions is used for most tumours, with excellent responses. A reduced dose (36 Gy in 18 fractions) has been used in selected cases to limit toxicity, though experience is limited.
• Postoperative radiotherapy 60 Gy in 30 fractions (66 Gy for positive margins) when preoperative therapy was not given.
• Adjuvant or neoadjuvant chemotherapy with doxorubicin and ifosfamide is considered for high grade tumours (round cell component of 5% or more), large tumours (over 5 cm, deep) or those in younger fit patients. The benefit is not proven.

Advanced disease. Chemosensitivity makes systemic therapy effective.

• 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).
• Trabectedin: 1.5 mg/m2 IV over 24 hours through a central line every 3 weeks until progression or intolerance; maximum 1.5 mg/m2 each cycle; monitoring: ALT, AST, bilirubin, alkaline phosphatase and creatine kinase before each cycle, FBC, LVEF at baseline and every 2 to 3 months; premedication with dexamethasone 20 mg IV 30 minutes before; adjustment: do not give when bilirubin exceeds the upper limit, hold for ALT or AST over 2.5 times the upper limit or creatine kinase over 5 times, reduce to 0.9 mg/m2 in moderate hepatic impairment, not studied when creatinine clearance is under 30 mL/min. Response rates are high in this subtype.
• Radiotherapy or surgery for painful or threatening metastases (spine, soft tissue).

Monitoring. MRI of the primary site every 3 to 4 months for 2 years, then 6 monthly to year 5. CT chest and abdomen and spine or whole body MRI at similar intervals, since extrapulmonary relapse comes first.

Referral and escalation.

• Sarcoma centre review before any excision or biopsy.
• Urgent review for back pain with neurological symptoms (spinal metastasis, cord compression).

Special groups.

• Adolescents and young adults: discuss fertility preservation before ifosfamide and doxorubicin, and long term cardiac surveillance.
• Pregnancy: surgery is possible in any trimester. Defer radiotherapy and systemic therapy.