Mesenchymal Chondrosarcoma

Mesenchymal chondrosarcoma is a rare, high grade malignant tumour made of undifferentiated small round blue cells interspersed with islands of well differentiated hyaline cartilage. It accounts for under 1 to 3% of chondrosarcomas, and about one third arise in soft tissue (extraskeletal) rather than bone.

It occurs mostly in adolescents and young adults (10 to 40 years), with an equal sex distribution. In bone, the commonest sites are the jaw, craniofacial bones, ribs, spine, ilium and femur. Extraskeletal sites include the meninges, orbit and muscles of the limbs. It may be multifocal.

It is aggressive, with a tendency to early and late metastasis (lung, other bone, lymph nodes, brain), and recurrence sometimes more than 10 years after treatment. Five year survival is about 50 to 60% and 10-year survival about 20 to 30%. Complications are local recurrence, metastasis, pathological fracture, spinal cord compression, and treatment toxicity.

Pathophysiology.

A recurrent fusion gene, HEY1::NCOA2, is found in most cases and is useful for diagnosis. The small round cell component resembles Ewing sarcoma and expresses SOX9, CD99 and NKX3.1; the cartilage islands express S100. The tumour does not carry the IDH mutations of conventional chondrosarcoma. The small cell component explains the sensitivity to chemotherapy, in contrast to conventional chondrosarcoma.

Local pain and swelling that grow over weeks to months, a palpable mass, a pathological fracture, and neurological signs (cord compression in the spine; cranial nerve palsy or headache in craniofacial tumours). Systemic features are uncommon. Cough or chest pain suggests lung metastases.

Examine the mass, regional nodes, neurological state, and the chest. In craniofacial disease, check cranial nerves, vision and dentition.

• Radiographs: a lytic, destructive lesion with a permeative pattern, poorly defined margins, cortical destruction, and stippled or ring-and-arc cartilage calcification in about half, often with a soft tissue mass.
• MRI: defines the intramedullary and soft tissue extent, with heterogeneous enhancement and low T2 signal in calcified regions. MRI of the whole spine and brain when relevant.
• CT: shows calcification and bone destruction. CT chest is essential for lung metastases.
• Positron emission tomography with CT, or whole body MRI, for staging.
• Biopsy: core or open biopsy at a sarcoma centre, before treatment, in line with the planned incision; histology shows biphasic features, and testing for HEY1::NCOA2 confirms the diagnosis. Biopsy may miss the cartilage islands.
• Blood tests: full blood count, lactate dehydrogenase, alkaline phosphatase, creatinine, liver function, and tests before chemotherapy (audiometry, echocardiography).

Differential diagnosis.

• Ewing sarcoma and small round cell sarcomas.
• Conventional or dedifferentiated chondrosarcoma and osteosarcoma.
• Lymphoma and hemangiopericytoma (solitary fibrous tumour) of bone.
• Metastatic neuroblastoma and small cell carcinoma.

Treatment combines surgery with chemotherapy, in a sarcoma centre; the optimal sequence is not settled because of rarity.

Surgery. Wide en bloc resection with negative margins is the key to cure, with reconstruction by endoprosthesis, allograft or vascularised graft. Surgery after neoadjuvant chemotherapy is common in limb and pelvic lesions. Axial and craniofacial tumours need specialist surgery with radiotherapy when margins are close. Resection of isolated metastases (lung metastasectomy) is considered.

Chemotherapy (Ewing type regimen, off label). Given before and after surgery for fit patients, in 14 to 21 day cycles, alternating:

• Vincristine 2 mg (maximum) intravenously on day 1, doxorubicin 75 mg/m2 as a total dose in a cycle (over 48 hours or as a bolus split over 2 days), and cyclophosphamide 1200 mg/m2 intravenously on day 1 with mesna and hydration.
• Monitoring for this combination: check blood count, renal and liver function; the lifetime ceiling of doxorubicin is 450 mg/m2; avoid when the ejection fraction is under 50%; monitor neuropathy and haemorrhagic cystitis.
• Ifosfamide 1800 mg/m2 intravenously daily on days 1 to 5 with mesna 360 mg/m2 intravenously at 0, 4 and 8 hours (given as a divided dose), and etoposide 100 mg/m2 intravenously daily on days 1 to 5.
• Monitoring for this combination: blood count, creatinine and neurological state; ifosfamide encephalopathy and tubulopathy are risks; reduce at creatinine clearance under 60 mL/min.
• 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; ondansetron 8 mg orally or intravenously before chemotherapy and every 12 hours for 2 days (avoid with prolonged QT).
• Total duration is about 6 to 9 months, and the regimen is selected and adjusted by the sarcoma oncology team. Doxorubicin and cisplatin is an alternative.

Radiotherapy. Involved site radiotherapy (50 to 66 Gy) for unresectable disease, positive margins, or craniofacial and spinal tumours where wide resection is not possible. It is also used to treat palliative metastases.

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.

Thromboprophylaxis. Enoxaparin 40 mg subcutaneously once daily, started 6 to 12 hours after surgery and continued for 28 to 35 days after major reconstruction or when mobility is reduced (20 mg once daily at creatinine clearance under 30 mL/min).

Adjust by anti-Xa level in obesity and renal impairment, and check the platelet count on days 5 to 14 for heparin induced thrombocytopenia. Use mechanical prophylaxis until then; withhold during severe thrombocytopenia.

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 during chemotherapy with thrombocytopenia or kidney impairment.

Monitoring. Blood count, creatinine, magnesium, liver function, and neurological state before each chemotherapy cycle. Echocardiography at baseline and after every 2 to 3 cycles of doxorubicin, audiometry if cisplatin is used, and renal function for ifosfamide. Imaging of the primary site and chest CT every 3 months for 2 years, every 6 months to 5 years, then yearly for at least 10 years because late relapse occurs.

Referral and escalation. Refer every suspected case urgently to a sarcoma centre before biopsy. Emergency referral for spinal cord compression, febrile neutropenia, an impending fracture, or raised intracranial pressure.

Special groups.

• Children and adolescents: treated in paediatric or adolescent oncology units; fertility preservation before chemotherapy.
• Craniofacial and spinal disease: multidisciplinary planning, with radiotherapy.
• Pregnancy: urgent oncology and obstetric planning; avoid chemotherapy in the first trimester.
• Kidney impairment: reduce ifosfamide and cisplatin, avoid NSAIDs, reduce morphine and enoxaparin doses.