Dedifferentiated Chondrosarcoma

Dedifferentiated chondrosarcoma is a high grade, aggressive malignant bone tumour in which a low grade cartilage tumour (enchondroma like or atypical cartilaginous tumour, or grade 1 to 2 chondrosarcoma) abruptly transitions to a high grade non-cartilaginous sarcoma such as osteosarcoma, undifferentiated pleomorphic sarcoma or fibrosarcoma. It accounts for about 10% of chondrosarcomas.

It occurs mainly between 50 and 70 years of age, with equal sex distribution. The commonest sites are the femur (about 40%), pelvis, humerus and the ribs. It often arises in a long standing cartilage lesion, and it can be a late complication of Ollier disease or Maffucci syndrome.

The prognosis is poor: 5-year survival is only 10 to 25%, and most patients die of lung metastases within 2 years. Presentation is often with a pathological fracture (in about 20 to 30%) or rapid worsening of pain in a known cartilage lesion. Complications are local recurrence, pulmonary and bone metastasis, fracture, and surgical morbidity.

Pathophysiology.

Both components share IDH1 or IDH2 mutations (in about 50%), so the high grade part evolves from the low grade cartilage tumour through additional genetic events (TP53, CDKN2A, and others) with loss of cartilage differentiation. The high grade component grows fast, destroys bone, and causes the early metastases. The cartilage component is resistant to chemotherapy and radiotherapy, and the high grade component is partly sensitive.

Pain of recent onset or sudden worsening in a lesion that was painless until recently (often a patient aged over 50), a rapidly growing mass, pathological fracture, and limited function. Systemic features (weight loss, fatigue) occur in advanced disease. Cough, dyspnoea and chest pain suggest lung metastases.

Examine the mass, joint range, neurovascular state, nodes, and chest. Ask for a history of enchondroma, Ollier disease or Maffucci syndrome.

• Radiographs: a biphasic appearance: a mineralised cartilage tumour (stippled, ring-and-arc calcification) with an adjacent lytic, destructive area, with a sharp transition, cortical breakthrough and a soft tissue mass.
• MRI: shows the two components: a lobulated, T2 bright cartilage area and a solid enhancing, non-cartilage area (low T2, restricted diffusion); extent, soft tissue mass and relation to nerves and vessels. Sampling should target the solid area.
• CT chest, abdomen and pelvis; positron emission tomography or whole body MRI for staging; bone scan.
• Biopsy by core needle from the lytic, solid, non-mineralised region identified on MRI, in a sarcoma centre and in line with the surgical incision. Sampling only the cartilage may miss the dedifferentiated area and lead to under treatment. Histology: abrupt change from low grade cartilage to high grade sarcoma.
• Blood tests: full blood count, alkaline phosphatase, lactate dehydrogenase, calcium, creatinine, liver function, and pre-chemotherapy tests.

Differential diagnosis.

• Conventional (grade 2 or 3) chondrosarcoma and chondroblastic osteosarcoma.
• Atypical cartilaginous tumour with fracture and metastatic carcinoma.
• Mesenchymal chondrosarcoma and malignant fibrous histiocytoma of bone.
• Infarct with malignant transformation and osteomyelitis.

Wide surgical resection is the cornerstone. The role of chemotherapy is uncertain and it is considered mainly in younger, fit patients.

Surgery. Wide en bloc resection with negative margins, and reconstruction with an endoprosthesis or allograft; amputation is used for extensive disease or when limb salvage cannot give clear margins. Pathological fractures are managed by resection and not by fixation, which spreads the tumour. Resect isolated lung metastases when feasible.

Chemotherapy (selected patients, usually aged under 65, with a good performance status; off label).

• Doxorubicin 25 mg/m2 intravenously daily on days 1 to 3 (total 75 mg/m2 a cycle) and cisplatin 100 mg/m2 intravenously on day 1, every 3 weeks, for 3 cycles before and 3 cycles after surgery, as used in osteosarcoma. 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) and 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) to prevent neutropenia.
• The evidence for benefit is limited, with some series showing better survival with osteosarcoma type regimens and others showing none; the decision is made by a sarcoma team after discussion with the patient.

Radiotherapy. For positive margins, unresectable disease or palliation of pain and bleeding; the cartilage component is radioresistant and the effect is modest. Conventional doses are 60 to 70 Gy for local control when surgery is impossible, and 20 to 30 Gy for palliation.

Operative antibiotic prophylaxis. Cefazolin 2 g intravenously (3 g when weight is 120 kg or over) 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.

Thromboprophylaxis. Enoxaparin 40 mg subcutaneously once daily, started 6 to 12 hours after surgery and continued for 28 to 35 days after major reconstruction (cancer and reduced mobility raise the risk) (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 until then.

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).
• 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. Convert to a modified release preparation when the daily need is stable.
• Neuropathic pain: gabapentin 300 mg orally at night, increased by 300 mg every 1 to 3 days to 300 to 600 mg three times daily (maximum 1800 mg daily; reduce at creatinine clearance under 60 mL/min); monitor sedation and dizziness.
• Avoid NSAIDs during chemotherapy and with thrombocytopenia or kidney impairment.

Monitoring. Clinical review, local imaging and chest CT every 3 months for 2 years, every 6 months for years 3 to 5, then yearly. Blood count and kidney function during chemotherapy; echocardiography and audiometry during chemotherapy. Palliative care early for symptom control.

Referral and escalation. Refer every suspected dedifferentiated chondrosarcoma to a sarcoma centre before biopsy or surgery. Urgent referral for a rapidly growing lesion, new pain in a cartilage tumour, pathological fracture, or suspected metastases. Emergency referral for spinal cord compression or febrile neutropenia.

Special groups.

• Older adults: radical surgery and chemotherapy may be unsuitable; discuss goals and offer palliative radiotherapy and early supportive care.
• Ollier disease and Maffucci syndrome: lifelong surveillance, with prompt biopsy of any lesion that changes.
• Pathological fracture: do not fix before biopsy and staging.
• Kidney impairment: avoid cisplatin and NSAIDs, reduce morphine doses, and adjust enoxaparin.