Alveolar Soft Part Sarcoma

Alveolar soft part sarcoma is a rare, slowly growing, highly vascular sarcoma with an ASPSCR1::TFE3 fusion from der(17)t(X;17). Cells form alveolar nests with eosinophilic granular cytoplasm, and PAS-positive, diastase resistant crystals.

It makes up under 1% of soft tissue sarcomas. Peak age is 15 to 35, with a female predominance in young patients. Sites are the thigh and other limb muscles in adults, and the tongue and orbit in children.

No predisposing syndrome is known.

Pathophysiology. The fusion protein overactivates TFE3 targets, including MET and genes that promote angiogenesis (VEGF signalling), which explains the hypervascularity and response to anti-angiogenic and immune checkpoint therapy.

Histology. Large epithelioid cells in alveolar nests separated by thin sinusoidal vessels, with strong nuclear TFE3 staining. Desmin and S100 staining is variable.

Behaviour. The primary tumour grows slowly, but metastases (lung, brain, bone) occur early, often before diagnosis (20% to 65%), and may remain silent for years. Survival is long even with metastases (median 3 to 5 years or more), and late relapse after 10 years is described. Chemotherapy has low activity.

• Painless, slowly growing, deep mass with prominent vascularity, sometimes with a bruit.
• Paediatric head and neck presentation: tongue mass, proptosis.
• Metastatic presentation: cough, haemoptysis, headache, seizure, focal deficit, bone pain.

• MRI: mass with high signal on T1 and T2 and prominent flow voids, with avid enhancement. Angiography shows hypervascularity.
• Core biopsy (with attention to bleeding) and nuclear TFE3 immunohistochemistry. Confirm ASPSCR1::TFE3 by FISH or RT-PCR.
• Staging: CT chest and abdomen, MRI brain (mandatory at diagnosis), and bone scan or FDG-PET.
• Exclude metastasis from a TFE3-rearranged renal carcinoma with renal imaging.

Differential diagnosis.

• TFE3-rearranged renal cell carcinoma (metastatic)
• Paraganglioma and granular cell tumour
• Alveolar rhabdomyosarcoma and rhabdomyoma
• Melanoma and perivascular epithelioid cell tumour
• Metastatic hepatocellular or adrenocortical carcinoma
• Vascular malformation and haemangioma

Localised disease. Wide excision with negative margins. Preoperative embolisation can reduce bleeding. Radiotherapy 50 Gy in 25 fractions preoperatively, or 60 Gy in 30 fractions postoperatively (66 Gy for positive margins), for close or positive margins.

Metastatic disease.

• Atezolizumab: 1200 mg IV every 3 weeks until progression or unacceptable toxicity; maximum 1200 mg each dose; monitoring: thyroid function, liver tests, creatinine, glucose and morning cortisol before each dose, infusion reactions; adjustment: no dose reduction (withhold for grade 2 immune toxicity and stop permanently for grade 3 to 4 events), no renal or hepatic adjustment in mild to moderate impairment; 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. Response rate is about one third, with durable responses.
• Pazopanib (alternative or later line): 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.
• Stereotactic radiosurgery or surgery for brain metastases, and resection or ablation of limited lung metastases.
• Cytotoxic chemotherapy has little activity and is a late option.

Monitoring. MRI of the primary site and CT chest every 3 to 4 months for 2 years, then 6 monthly to year 5. MRI brain every 6 months for 2 years, and lifelong surveillance because of late relapse.

Referral and escalation.

• Sarcoma centre referral before biopsy or excision of a vascular deep mass.
• Neurosurgery for brain metastases and neuro oncology review before starting immunotherapy.

Special groups.

• Children: tongue and orbital tumours need specialist head and neck surgery. Atezolizumab is used in patients aged 2 years or over, at 15 mg/kg (maximum 1200 mg) every 3 weeks.
• Pregnancy: tumours can grow and bleed. Surgery is possible, and systemic therapy is deferred.
• Autoimmune disease or organ transplant: caution with checkpoint inhibitors.