Periosteal Osteosarcoma

Periosteal osteosarcoma is an intermediate grade (grade 2), chondroblastic osteosarcoma that arises on the surface of the cortex of a long bone, with a periosteal reaction, and spares the medullary canal in most cases. It accounts for about 1 to 2% of osteosarcomas, and is the second commonest surface osteosarcoma after parosteal osteosarcoma.

It occurs between 10 and 30 years of age (the mean is about 20), with a female predominance in some series. The commonest site is the diaphysis or metadiaphysis of the tibia (about 50%), then the femur and the humerus. Lesions are small compared with conventional osteosarcoma (often 3 to 10 cm).

The tumour has a better prognosis than conventional osteosarcoma, with 5-year survival of about 80 to 90%, but 15 to 25% develop lung or other metastases, and local recurrence follows incomplete excision. Complications are local recurrence, metastasis, medullary invasion and treatment toxicity.

Pathophysiology.

The tumour grows from the inner layer of the periosteum, builds cartilage (lobules of malignant chondroblastic tissue with lace like osteoid), and lifts the periosteum to produce spicules at right angles to the cortex. The cortex shows saucerisation, with the medulla invaded in a minority. The genetic changes are less well defined than in parosteal osteosarcoma and MDM2 amplification is not typical.

A painful or tender swelling of a long bone shaft, usually for weeks to months, sometimes with a palpable fixed mass. Pain is often mild. General symptoms are uncommon. There may be a limp or reduced use of the limb.

Examine the mass (size, tenderness, fixation), joint range, neurovascular state and the regional lymph nodes, and the chest.

• Radiographs: a fusiform soft tissue mass on the surface of the diaphysis with saucerised cortical erosion, cortical thickening, and radiating, perpendicular periosteal spicules (a "sunburst" pattern at right angles to the cortex); the medulla is usually intact. The matrix is often poorly mineralised, with a Codman triangle at the margins.
• MRI: shows the surface mass, high T2 signal (cartilage matrix), marrow oedema, medullary extension (in about 25%), and soft tissue spread.
• CT: shows the cortical changes and matrix; CT chest for lung metastases.
• Bone scan or positron emission tomography for staging.
• Biopsy (core or open, in line with the planned incision) at a sarcoma centre. Histology: lobules of chondroblastic osteosarcoma with spindle cell stroma and osteoid.
• Blood tests: full blood count, alkaline phosphatase, lactate dehydrogenase, renal and liver function.

Differential diagnosis.

• Parosteal and high grade surface osteosarcoma.
• Periosteal chondroma and juxtacortical chondrosarcoma.
• Ewing sarcoma and osteomyelitis (subperiosteal abscess).
• Stress fracture and myositis ossificans.

Wide resection is the key to local control. The role of chemotherapy is less certain than in conventional osteosarcoma.

Surgery. Wide en bloc resection with a cuff of normal tissue and reconstruction (intercalary or osteoarticular allograft, endoprosthesis, vascularised fibular graft). Limb salvage is possible in most. Amputation is used for extensive disease.

Chemotherapy. Often given because of the risk of metastasis, before and after surgery, using the osteosarcoma regimen, in specialist centres. The benefit is unproven, and the decision is made by the sarcoma team.

• The usual regimen is doxorubicin 25 mg/m2 intravenously daily on days 1 to 3 (total 75 mg/m2 in a cycle) and cisplatin 100 mg/m2 intravenously on day 1, every 3 weeks, for 3 cycles before and 3 cycles after surgery.
• Monitor blood count, creatinine clearance (cisplatin needs at least 60 mL/min), magnesium, potassium, audiometry and echocardiography. The lifetime ceiling of doxorubicin is 450 mg/m2.
• Avoid with an ejection fraction under 50%, hearing loss and significant neuropathy.
• Give hydration (at least 1 L of 0.9% sodium chloride before and after cisplatin).
• Antiemetics: ondansetron 8 mg orally or intravenously before chemotherapy and every 12 hours for 2 days; dexamethasone 8 mg once on day 1 of each cycle.
• Pegfilgrastim 6 mg subcutaneously once, 24 to 72 hours after chemotherapy in each cycle (avoid within 14 days before the next cycle), reduces neutropenia.

Radiotherapy. Reserved for unresectable tumours or positive margins that cannot be re-excised.

Operative antibiotic prophylaxis. Cefazolin 2 g intravenously (3 g when weight is 120 kg or over; 30 mg/kg to a maximum of 2 g in children) within 60 minutes before incision as a single dose (repeat after 4 hours or blood loss over 1500 mL). With severe penicillin allergy, give vancomycin 15 mg/kg intravenously starting 90 to 120 minutes before incision as a single dose, with levels and creatinine checked in prolonged cases.

Thromboprophylaxis. Enoxaparin 40 mg subcutaneously once daily in adolescents and adults, started 6 to 12 hours after surgery and continued for 28 to 35 days after major limb reconstruction. Use 20 mg once daily at creatinine clearance under 30 mL/min. Adjust by anti-Xa level in obesity and renal impairment. Check the platelet count on days 5 to 14 for heparin induced thrombocytopenia. Use mechanical prophylaxis in younger children.

Analgesia.

• Paracetamol 1 g orally every 6 hours as needed for up to 5 to 7 days (maximum 4 g daily; 3 g daily when weight is under 50 kg, with chronic alcohol use or hepatic impairment). Children: 15 mg/kg orally every 4 to 6 hours (maximum 75 mg/kg daily and not exceeding 4 g daily).
• Oral morphine 5 to 10 mg every 4 hours as needed for severe pain for up to 3 days. Start 2.5 to 5 mg with age over 75 or eGFR under 30 mL/min/1.73 m2. Avoid exceeding 60 mg in 24 hours without senior review.
• Monitor sedation and respiration and prescribe a laxative. Children: morphine 0.1 to 0.2 mg/kg orally every 4 hours as needed (maximum 10 mg a dose).
• Avoid NSAIDs during chemotherapy with thrombocytopenia, and while bone healing is awaited.

Monitoring. Clinical review, local imaging and chest CT every 3 months for 2 years, every 6 months to year 5, then yearly for at least 10 years. Chemotherapy safety tests before each cycle, and growth and limb length in children.

Referral and escalation. Refer every suspected periosteal osteosarcoma to a sarcoma centre before biopsy. Urgent referral for a growing mass, pathological fracture, neurological or vascular compromise, or suspected metastasis.

Special groups.

• Children and adolescents: managed in paediatric or adolescent oncology units, with expandable or biological reconstruction options.
• Women of reproductive age: fertility preservation before chemotherapy.
• Recurrent disease: re-resection; imaging for medullary involvement.
• Kidney impairment: avoid cisplatin and NSAIDs, reduce morphine doses, and adjust enoxaparin.