Telangiectatic Osteosarcoma

Telangiectatic osteosarcoma is a high grade malignant bone tumour made largely of large, blood filled cystic spaces separated by thin septa that contain malignant osteoid producing cells. It accounts for 3 to 5% of osteosarcomas, and it is easily mistaken for an aneurysmal bone cyst.

It occurs between 10 and 25 years of age, with a male predominance (about 1.5 to 2 to 1). Common sites are the metaphysis of the distal femur (about 40%), proximal tibia and proximal humerus, then the fibula, pelvis and spine. It is aggressive, with rapid growth, and about 20 to 30% of patients present with a pathological fracture.

With modern chemotherapy and surgery, 5-year survival is about 65 to 80%, equal to or better than that of conventional osteosarcoma, because the tumour is very sensitive to chemotherapy. Complications are pathological fracture, local recurrence, lung metastasis (at presentation in 10 to 20%), and chemotherapy toxicity.

Pathophysiology.

The tumour has complex genomic changes typical of osteosarcoma (TP53, RB1 and others). It is grossly like a "bag of blood", and the septa contain highly atypical cells with osteoid. Rapid growth, haemorrhage and necrosis produce the cystic spaces. Few solid areas exist, and tumour mineralisation is scant, which explains the lytic radiographic pattern.

Pain for a short period (weeks to a few months), a rapidly growing, tender, warm mass, restricted joint motion, and a pathological fracture after minor trauma. Systemic features (fever, raised inflammatory markers) may mimic infection.

Examine the mass, warmth, overlying skin, joint range, neurovascular state, regional nodes and chest.

• Radiographs: a purely lytic, geographic or permeative destructive lesion in the metaphysis with cortical destruction and a soft tissue mass, with little matrix mineralisation, often with a pathological fracture. It may resemble an aneurysmal bone cyst, but is less expansile and lacks a thin intact shell.
• MRI: fluid fluid levels throughout (like an aneurysmal bone cyst), but with thick, nodular, enhancing septa (over 3 mm) and solid enhancing components, soft tissue mass and marrow replacement.
• CT: cortical destruction and fluid levels. CT chest for staging; bone scan or positron emission tomography.
• Biopsy (core or open, in line with the planned incision, from the solid septa and not the fluid) at a sarcoma centre before any treatment. Histology: cystic spaces with septa of high grade pleomorphic cells producing osteoid.
• Blood tests: full blood count, alkaline phosphatase, lactate dehydrogenase, renal and liver function, and audiometry and echocardiography before chemotherapy.

Differential diagnosis.

• Aneurysmal bone cyst (the key differential) and giant cell tumour.
• Conventional (osteoblastic) osteosarcoma and Ewing sarcoma.
• Brown tumour and osteomyelitis.
• Metastatic carcinoma.

Treatment is chemotherapy before and after surgical resection, using the regimen for conventional high grade osteosarcoma, led by a sarcoma team.

Chemotherapy (neoadjuvant and adjuvant; the regimen includes high dose methotrexate, doxorubicin and cisplatin).

• Doxorubicin 75 mg/m2 in a cycle (given as 37.5 mg/m2 intravenously daily on 2 consecutive days) and cisplatin 120 mg/m2 intravenously on day 1 (monitor blood count, creatinine clearance of 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 of at least 1 L of 0.9% sodium chloride before and after cisplatin).
• High dose methotrexate 12 g/m2 (maximum 20 g) intravenously over 4 hours, repeated in the scheduled cycles, with intensive hydration (about 3 L/m2 daily), urine alkalinisation to a pH of 7 or over, and leucovorin 15 mg/m2 intravenously or orally every 6 hours, starting 24 hours after the start of methotrexate, until the methotrexate level is under 0.1 micromol/L. Check levels at 24, 48 and 72 hours, creatinine, and liver function. Avoid with renal impairment, pleural or peritoneal effusions, and with NSAIDs, proton pump inhibitors, penicillins, co-trimoxazole and other drugs that delay clearance. Glucarpidase 50 units/kg intravenously once is used for delayed clearance with kidney injury.
• Pegfilgrastim 6 mg subcutaneously once, 24 to 72 hours after chemotherapy in each cycle (avoid within 14 days before the next cycle); ondansetron 8 mg orally or intravenously before chemotherapy and every 12 hours for 2 days (avoid with prolonged QT).
• Response is assessed by tumour necrosis at resection (over 90% necrosis is a good response), and this may change the adjuvant regimen. The schedule and doses are set by the sarcoma oncology team.

Surgery. Wide en bloc resection (limb salvage in most) after neoadjuvant chemotherapy, with reconstruction by endoprosthesis, allograft or rotationplasty. Pathological fracture: no fixation of the tumour; immobilise, give chemotherapy, then resect (amputation is needed rarely). Resection of lung metastases when feasible.

Radiotherapy. Reserved for unresectable disease, positive margins, and palliation.

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, vancomycin 15 mg/kg intravenously starting 90 to 120 minutes before incision as a single dose, with levels and creatinine checked in prolonged cases.

Tranexamic acid (major reconstruction). Tranexamic acid 15 mg/kg (maximum 1 g) intravenously over 10 minutes before incision, repeated once after 3 hours if bleeding continues (maximum 2 g); avoid with a history of thromboembolism, active intravascular clotting, or seizures; reduce the dose at creatinine clearance under 50 mL/min.

Analgesia.

• Paracetamol 1 g orally every 6 hours (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, titrated under review (start 2.5 to 5 mg with age over 75 or eGFR under 30 mL/min/1.73 m2); monitor sedation and respiration and prescribe a laxative. Children: 0.1 to 0.2 mg/kg orally every 4 hours as needed (maximum 10 mg a dose).
• Avoid NSAIDs during methotrexate and chemotherapy with thrombocytopenia or kidney impairment.

Monitoring. Blood count, creatinine, liver function and electrolytes before each cycle; methotrexate levels at 24, 48 and 72 hours after each dose; echocardiography and audiometry. Clinical review, local imaging and chest CT every 3 months for 2 years, every 6 months to year 5, then yearly to 10 years. Late effects (cardiac, hearing, fertility, second malignancy).

Referral and escalation. Refer every suspected case urgently to a sarcoma centre before biopsy or any fixation. Emergency referral for pathological fracture with neurovascular compromise, febrile neutropenia, delayed methotrexate clearance, or spinal cord compression.

Special groups.

• Children and adolescents: managed in paediatric oncology units; expandable or biological reconstruction and fertility preservation.
• Pathological fracture at presentation: chemotherapy first; limb salvage remains possible in most.
• Pregnancy: urgent oncology and obstetric planning; avoid methotrexate and chemotherapy in the first trimester.
• Kidney impairment: avoid methotrexate and cisplatin, and NSAIDs; reduce morphine and enoxaparin doses.