Dedifferentiated Liposarcoma

Dedifferentiated liposarcoma is a malignant adipocytic tumour in which a well differentiated liposarcoma shows an abrupt transition to a non-lipogenic sarcoma, usually of intermediate or high grade. It carries MDM2 and CDK4 amplification, like well differentiated liposarcoma.

It makes up about 20% to 25% of liposarcomas. Over 90% occur in the retroperitoneum, with median age in the 60s. Most arise de novo, and the rest follow recurrence of a well differentiated tumour.

Pathophysiology. The dedifferentiated area is usually undifferentiated pleomorphic or spindle cell sarcoma. It can also show myofibroblastic, meningothelial like, or heterologous (rhabdomyosarcomatous, osteosarcomatous) differentiation.

Genetics. MDM2 amplification is universal, with CDK4 amplification common, plus additional genomic rearrangement. Amplified 12q13-15 sequences distinguish the tumour from other pleomorphic sarcomas.

Behaviour. Local recurrence occurs in 40% to 80%, mostly in the retroperitoneum, and is the main cause of death. Distant metastasis (lung, liver, bone) occurs in about 15% to 30%. Five year overall survival is about 40% to 50% for retroperitoneal disease and over 60% for limb disease.

Prognostic features. Grade of the dedifferentiated component, multifocality, tumour size and incomplete resection predict outcome.

• Large retroperitoneal mass with abdominal distension, early satiety, pain, weight loss, oedema, or symptoms of obstruction.
• Limb and trunk tumours present as a deep enlarging mass.
• Systemic symptoms and metastases are uncommon at presentation.

• CT abdomen and pelvis with contrast (or MRI): fatty mass with a solid non-lipomatous enhancing component, often abrupt in transition.
• Core biopsy targeted at the non-fatty component, with MDM2 FISH or MDM2 and CDK4 immunohistochemistry. Biopsy by a method and route chosen with the surgeon.
• CT chest for staging. Renal function and split function if nephrectomy is anticipated.
• Multidisciplinary review of imaging and pathology at a sarcoma centre.

Differential diagnosis.

• Leiomyosarcoma and other retroperitoneal sarcomas
• Undifferentiated pleomorphic sarcoma
• Solitary fibrous tumour
• Malignant peripheral nerve sheath tumour
• Gastrointestinal stromal tumour
• Lymphoma, germ cell tumour and adrenal or renal tumour
• Retroperitoneal fibrosis

Resectable disease. Complete en bloc surgery by a specialist centre, with resection of adjacent organs as needed.

• Preoperative radiotherapy (50.4 Gy in 28 fractions) can be considered for selected retroperitoneal tumours, since benefit appears greatest in well differentiated and low grade dedifferentiated tumours.
• The benefit of neoadjuvant chemotherapy is unproven in high grade disease and is decided case by case.

Unresectable or metastatic disease. Treatment is palliative, aimed at symptom control and tumour stability.

• 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 (for 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, 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 (after anthracycline): 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.
• 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.
• Local therapy (surgery, radiotherapy) for symptomatic bulky disease or oligometastatic disease.

Monitoring. CT every 3 months for 2 years after resection, every 6 months to year 5, then annually. Metastatic disease: imaging every 2 to 3 cycles.

Referral and escalation.

• All patients to a sarcoma multidisciplinary team before any resection.
• Urgent admission for bowel obstruction, ureteric obstruction, haemorrhage, venous thrombosis or febrile neutropenia.

Special groups.

• Older adults: reduce chemotherapy intensity. Doxorubicin alone is preferred over combination.
• Fertility: discuss sperm or oocyte preservation before ifosfamide.
• Heart disease: assess LVEF and use dexrazoxane or an alternative agent.