Extraskeletal Osteosarcoma

Extraskeletal osteosarcoma is a high grade malignant soft tissue tumour that produces osteoid and bone, with no attachment to bone or periosteum. It is a diagnosis made after exclusion of a primary bone osteosarcoma and of other sarcomas with osseous differentiation.

It forms about 1% of soft tissue sarcomas and about 4% of osteosarcomas. Median age is in the 50s to 60s, in contrast to osteosarcoma of bone, and there is a male preponderance. Common sites are the thigh, buttock, upper limb and retroperitoneum.

About 5% to 10% follow radiotherapy after a latency of years. Prior trauma is reported, and myositis ossificans is not a recognised precursor.

Pathophysiology. The cells are malignant with TP53 and RB1 alterations. Subtypes are osteoblastic, chondroblastic, fibroblastic, telangiectatic, small cell and mixed types.

Behaviour. Local recurrence is 45% to 70%. Metastasis occurs in about 60% to 80%, mainly to lung. Five year survival is about 25% to 40%.

Prognostic features. Tumour size over 5 cm, retroperitoneal site, high proliferation and incomplete resection predict worse outcome.

• Painless, enlarging deep mass, firm, often calcified, occasionally painful or tender.
• Retroperitoneal tumours produce abdominal symptoms late.
• Metastatic symptoms: cough, dyspnoea, chest pain, bone pain.

• Radiograph and CT: soft tissue mass with irregular mineralisation (central or peripheral), separate from the adjacent bone. MRI defines extent.
• Core biopsy through a planned track: malignant spindle or pleomorphic cells with directly formed osteoid. Special AT-rich sequence binding protein 2 (SATB2) staining supports osteoblastic differentiation.
• Exclude a primary bone osteosarcoma with a bone scan or whole body imaging, and exclude other sarcomas (dedifferentiated liposarcoma, malignant peripheral nerve sheath tumour) with osseous metaplasia using MDM2 and H3K27me3 stains.
• Staging with CT chest, and imaging of the abdomen and pelvis for deep tumours. FDG-PET is helpful.
• Baseline echocardiography, creatinine, liver tests, alkaline phosphatase and lactate dehydrogenase.

Differential diagnosis.

• Myositis ossificans and heterotopic ossification
• Dedifferentiated liposarcoma and malignant peripheral nerve sheath tumour with osseous differentiation
• Osteosarcoma of bone with soft tissue extension
• Synovial sarcoma and extraskeletal chondrosarcoma with calcification
• Carcinosarcoma and sarcomatoid carcinoma
• Tumoral calcinosis and soft tissue giant cell tumour

Localised disease. Wide excision with negative margins by a sarcoma surgeon, with limb preservation where possible.

• Radiotherapy: preoperative 50 Gy in 25 fractions, or postoperative 60 Gy in 30 fractions (66 Gy for positive margins), for large, deep or close margin tumours.
• Perioperative chemotherapy: younger fit patients are considered for an osteosarcoma type multi-agent regimen in a sarcoma centre. Older adults are considered for doxorubicin based therapy. The benefit is not proven.

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).
• Resection of pulmonary metastases in selected patients with limited disease.

Monitoring. Examination and MRI of the primary site every 3 to 4 months for 2 years, then 6 monthly to year 5. CT chest at the same intervals.

Referral and escalation.

• Sarcoma centre referral before biopsy or excision.
• Thoracic surgery review for resectable lung metastases.
• Urgent assessment for pneumothorax, haemoptysis or febrile neutropenia.

Special groups.

• Radiation associated tumours: re-irradiation is limited, so surgery is central.
• Older adults: surgery and radiotherapy are preferred, and single agent doxorubicin when systemic therapy is needed.
• Li-Fraumeni syndrome: avoid radiotherapy where possible, with genetic counselling.