Clear Cell Chondrosarcoma

Clear cell chondrosarcoma is a rare, low grade malignant cartilage tumour that arises in the epiphysis of a long bone and is made of cells with abundant clear cytoplasm. It accounts for under 2% of chondrosarcomas.

It occurs between 20 and 50 years of age (and rarely in adolescents), with a male to female ratio of about 3 to 1. The commonest sites are the proximal femur (femoral head and neck, about 50%) and the proximal humerus, then the distal femur and proximal tibia. It grows slowly and is often present for years before diagnosis, and it is often confused with chondroblastoma, particularly in patients under 25 years.

Complications are pathological fracture, joint destruction and secondary osteoarthritis, local recurrence (up to 70 to 80% after curettage, and under 10% after wide resection), and late metastases (in about 15%, to the lungs and bone, sometimes many years later). Five year survival is about 80 to 90% when treated properly, and dedifferentiation occurs in a few cases.

Pathophysiology.

The tumour cells are chondrocyte like with clear cytoplasm (glycogen), an eccentric nucleus, and a matrix of hyaline cartilage and woven bone, with giant cells and fine calcification. Immunohistochemistry is positive for S100, SOX9 and type II collagen, and negative for the H3K36M and IDH1 and IDH2 mutations found in chondroblastoma and conventional chondrosarcoma, which helps in diagnosis. It is relatively slow growing, and it is not sensitive to chemotherapy or conventional radiotherapy.

Dull, progressive pain near a joint for months or years, joint stiffness, a limp, and, in the hip, groin or knee pain. A sudden worsening of pain suggests a pathological fracture. A mass is unusual, since epiphyseal lesions are deep. General symptoms are absent.

Examine the joint line, range of motion, gait, muscle bulk, limb length, and neurovascular state. Check for pulmonary symptoms.

• Radiographs: an epiphyseal, well defined lytic lesion with a sclerotic margin (3 to 6 cm), often extending into the metaphysis, with stippled calcification in about 30%, and mild cortical expansion or destruction. Radiographs may look like chondroblastoma in a young patient.
• MRI: lobulated lesion with heterogeneous signal, bone marrow oedema (less than in chondroblastoma), and cartilage like high signal on T2; defines extent, joint involvement and soft tissue spread.
• CT: shows matrix and cortical breakthrough. CT chest for staging.
• Positron emission tomography or bone scan for staging.
• Biopsy (CT-directed, along the line of the surgical approach) in a sarcoma centre before treatment. Histology: sheets of clear cells with distinct borders, hyaline matrix and osteoclast like giant cells; the diagnosis requires an experienced pathologist.
• Blood tests: full blood count, alkaline phosphatase, calcium, and renal and liver function before surgery.

Differential diagnosis.

• Chondroblastoma and giant cell tumour of bone.
• Conventional chondrosarcoma and osteosarcoma (chondroblastic or clear cell).
• Metastatic renal cell carcinoma and aneurysmal bone cyst.
• Osteomyelitis and avascular necrosis.

Surgery by wide resection is the treatment. Chemotherapy and radiotherapy are not effective, and local control is the aim.

Surgery.

• Wide en bloc resection of the lesion with a cuff of normal bone, with reconstruction: endoprosthesis (proximal femur, humerus, knee), osteoarticular allograft, or intercalary reconstruction when the joint can be saved. This gives local control in over 90%.
• Intralesional curettage with adjuvants (phenol, cryotherapy, cement) is used only for a small, well contained lesion in a patient with a strong reason to avoid resection, with a very high recurrence (up to 70 to 80%), so it is not preferred.
• Recurrence: re-resection with wide margins. Isolated lung metastases: surgical resection (metastasectomy), which may give long survival.
• Radiotherapy is used for inoperable lesions or positive margins that cannot be re-excised (conventional doses of 50 to 60 Gy have limited benefit). Chemotherapy has no proven value. Targeted therapy is not established.

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 proximal femoral or major joint reconstruction (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 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).
• 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.
• Avoid NSAIDs while bone healing or osteointegration is awaited.

Monitoring. Clinical review, local imaging (radiograph with MRI for suspicion) and chest CT every 3 to 6 months for 2 years, every 6 months to year 5, and then yearly for at least 10 years, since late recurrence and metastasis occur. Function of the reconstruction and complications (loosening, infection, fracture).

Referral and escalation. Refer every suspected clear cell chondrosarcoma to a sarcoma centre before biopsy. Urgent referral for pathological fracture, rapid growth, soft tissue extension, or suspected lung metastases.

Special groups.

• Young patients: the risk of overdiagnosis as chondroblastoma is high; expert review of the pathology.
• Hip and proximal femur: endoprosthetic reconstruction gives good function; plan for revision surgery.
• Pulmonary metastases: resect when possible.
• Kidney impairment: avoid NSAIDs, reduce morphine doses, and adjust enoxaparin and tranexamic acid.