Myxofibrosarcoma

Myxofibrosarcoma is a fibroblastic soft tissue sarcoma with a myxoid stroma, curvilinear thin walled vessels and pleomorphic spindle cells, with a spectrum from low to high grade. It is among the commonest sarcomas of older adults and has a very high local recurrence rate.

It accounts for about 5% to 10% of soft tissue sarcomas in adults. Patients are mostly aged 60 to 80, with lower limb (subcutaneous or dermal) tumours the most frequent, followed by upper limb and trunk.

No inherited predisposition is established. Previous radiotherapy is a rare association.

Pathophysiology. Complex karyotypes with CDKN2A, TP53, RB1 and NF1 loss. Tumours progress to higher grade at recurrence.

Grade. Low grade tumours have low cellularity and low pleomorphism, with mostly myxoid stroma. High grade tumours have hypercellular solid areas with pleomorphism, mitoses and necrosis, with myxoid stroma of at least 10% by usual practice.

Infiltrative growth. Tumour cells infiltrate along fascial planes and subcutaneous fat, which forms an extension (the tail) on MRI beyond the visible mass. This explains positive margins and recurrence.

Behaviour. Local recurrence is 30% to 60% even after complete resection. Metastasis is under 5% for low grade tumours and about 20% to 35% for high grade tumours (mainly lung, then bone, lymph nodes and liver). Five year survival is 60% to 70% overall.

• Slowly enlarging painless mass in the subcutaneous tissue or deep fascia, often present for many months, sometimes with overlying skin changes.
• Large, multinodular lesions in the lower limb, with satellite nodules after recurrence.
• Local recurrence is often multifocal.

• MRI: lobulated T2-bright mass with enhancing septa and a linear tail extending along fascia. The tail defines the extent of resection. CT for the trunk and retroperitoneum.
• Core biopsy through a planned track. Immunohistochemistry is non-specific (CD34 variable, SMA focal), and the purpose is to exclude other tumours.
• Staging: CT chest. Retroperitoneal or high grade deep tumours also need abdominal imaging.
• Baseline echocardiography and renal function if chemotherapy is likely.

Differential diagnosis.

• Myxoid liposarcoma
• Low grade fibromyxoid sarcoma and extraskeletal myxoid chondrosarcoma
• Intramuscular myxoma and nodular fasciitis
• Undifferentiated pleomorphic sarcoma
• Myxoid leiomyosarcoma and myxoid MPNST
• Sclerosing epithelioid fibrosarcoma
• Ganglion and benign myxoid neural tumours

Surgery. Wide excision, with margins of 2 to 3 cm including the MRI tail, and fascial and overlying skin resection where needed. Margin status is the main determinant of recurrence. Incomplete resection needs re-excision.

Radiotherapy. Preoperative 50 Gy in 25 fractions for tumours over 5 cm, deep, or high grade, and to widen the margin of resectability. Postoperative 60 Gy in 30 fractions (66 Gy for positive margins) is used when preoperative treatment was not given. Radiotherapy lowers local recurrence but not survival.

Chemotherapy. Not routine in localised disease. Doxorubicin with ifosfamide is considered for large, deep, high grade tumours in fit patients, though evidence is limited.

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.
• 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 (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, 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.
• Isolated limb perfusion and electrochemotherapy for recurrent limb disease in specialist centres.

Monitoring. Clinical and MRI review every 3 to 4 months for 2 years, then 6 monthly to year 5, and annually after that. CT chest at the same intervals for high grade tumours.

Referral and escalation.

• Sarcoma centre referral before excision of any enlarging subcutaneous or deep mass, since unplanned excision is common.
• Urgent review for rapidly recurring or ulcerating lesions.

Special groups.

• Older adults: surgery with preoperative radiotherapy, with attention to wound complications (up to 30% in the lower limb).
• Anticoagulated or vasculopathic patients: plan wound closure and reconstruction in advance.