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Cartilage Neoplasia

Jay S. Wunder M.D., MSc, FRCSC
Surgeon-in-Chief
Head, Division of Orthopaedic Surgery
Rubinoff-Gross Chair in Orthopaedic Oncology
Mount Sinai Hospital, and The University of Toronto
Toronto, ON

Cartilage tumours are common throughout the skeleton and present a wide biological spectrum. Patients with benign enchondromas may only require a diagnosis whereas those with chondrosarcoma require multidisciplinary management by a team including a musculoskeletal surgeon, radiologist and pathologist to ensure the best outcomes.

Cartilage Neoplasia: The Good End of the Spectrum
Most enchondromas are asymptomatic and identified incidentally on radiographs. Diagnosis should be straightforward for a well defined, calcified, intramedullary lesion with no endosteal erosion, cortical or periosteal changes or soft tissue mass. Enchondromas in the hands and feet are exceptions and may be painful with bone expansion and fracture. Enchondromas are frequently mistaken for chondrosarcomas when patients have regional pain due to other etiologies, such as rotator cuff disease. A thorough examination usually confirms that the pain is not originating from the enchondroma. A cold bone scan helps confirm a benign enchondroma; however, painless enchondromas can be hot on bone scan so this finding alone does not indicate malignancy. CT and/or MRI can help with uncertain diagnoses. Asymptomatic enchondromas should be treated nonoperatively because complications following surgery occur in up to 23% of patients1. Painless enchondromas rarely require follow-up unless associated with mild endosteal erosion in which case, observation alone usually ensures stability1. The occasional painful enchondroma can be easily managed with curettage.

In comparison, low grade intramedullary chondrosarcoma (LG-CS) commonly has pain, endosteal erosion more than two-thirds of the cortical thickness, adjacent lysis and size > 5cm 2,3. Pathologic distinction between LG-CS and enchondroma can be challenging and requires multidisciplinary assessment and expert pathological analysis. LG-CS has been managed by wide resection similar to higher grade sarcomas, but actually behaves biologically more like enchondromas with rare to no metastatic risk, and is now commonly referred to as grade chondrosarcoma, chondrosarcoma in-situ or chondrosarcoma of indeterminate malignant potential. There is a growing tendency to treat LG-CS with intralesional resection, sparing the adjacent bone and joint to improve functional outcome, except for pelvic lesions (Figure 1)4. Cryotherapy may be an effective local adjuvant but imparts additional complications5,6.

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Figure 1
Grade I intramedullary chondrosarcoma. AP (A) and lateral (B) radiographs show a lytic lesion in the humeral diaphysis with endosteal erosion but no cortical or periosteal changes (arrows). The 48-year-old patient presented with night and rest pain localized to this lesion. Coronal (C) and axial (D) fat saturated fast spin-echo T2 weighted MR images suggest chondroid matrix. Biopsy confirmed low grade chondrosarcoma which was treated by curettage and reconstruction with cement and plate stabilization (E).

Conventional Chondrosarcoma
Chondrosarcomas typically present as a painful enlarging mass which is readily identified radiographically. Staging, biopsy and wide resection employing limb sparing approaches is the standard treatment, even following most pathologic fractures. Amputation is occasionally required for very extensive or recurrent tumours, as may occur in the pelvis7,8. In a recent study 40/153 (26%) patients developed local recurrence which was correlated with inadequate resection margins and tumour size > 10cm9. Overall survival was 70% at 10 years but dropped to 38% for patients with high grade tumours. Local relapse also had a negative impact on survival, supporting the importance of adequate primary resection. Chondrosarcoma is considered radiation and chemotherapy resistant, however recent evidence supports the effectiveness of adjuvant radiation to prevent local relapse, particularly for lower grade tumours10,11.

Polyostotic Conditions
Chondrosarcoma developing from a solitary osteochondroma or enchondroma is uncommon. The risk of malignant degeneration in multiple osteochondromatosis may be much lower than previously thought, possibly only 1-2%, and is related to EXT tumour suppressor gene mutations (Figure 2)12. Most chondrosarcomas arising from an osteochondroma are low grade and following resection, the ten-year survival approaches 95%13. Although patients with multiple enchondromatosis syndromes are at higher risk for secondary tumours, their chondrosarcomas are also lower grade with a good prognosis. Chondrosarcoma risk in Ollier's disease (enchondromas alone) was estimated at 25-30% but is likely lower14-16. In comparison, the incidence of malignancy in Maffucci syndrome (enchondromas and hemangiomas) ranges from 23-100% and includes both chondrosarcomas and non-skeletal cancers which have a more guarded prognosis15,17.

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Figure 2
Multiple osteochondromatosis and secondary chondrosarcoma. AP pelvis radiograph (A) shows typical femoral and pelvic changes consistent with multiple osteochondromatosis. The large left iliac osteochondroma exhibits extensive soft tissue calcification suggestive of malignant degeneration. The 40-year-old patient presented with a painful enlarging buttock mass. Axial fat saturated fast spin-echo T2 weighted MR image (B) and CT scan (C) show the soft tissue extent of a secondary chondrosarcoma with a large cartilaginous cap and invasion into the posterior ilium (arrows). Postoperative AP pelvis radiograph following iliosacral resection.

Cartilage Neoplasia: The Bad End of the Spectrum
Dedifferentiated chondrosarcoma is the most aggressive form of this disease and commonly presents with severe pain, large destructive lytic lesions and pathologic fracture (Figure 3). Because the histology shows low grade chondrosarcoma and high grade spindle cell sarcoma (e.g. fibrosarcoma), patients have been treated with adjuvant chemotherapy and surgery18. However recent studies reported no benefit from chemotherapy and dismal outcomes including median survival of eight months, five-year survival less than 10%, and local recurrence as high as 20-50% 19-21.

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Figure 3
Dedifferentiated chondrosarcoma. AP hip radiograph (A) shows a subtrochanteric pathologic fracture through a large permeative lytic lesion with cortical destruction, periosteal new bone formation and soft tissue calcification. The 55-year-old patient had three months of increasing thigh pain and limp before suffering this fracture while getting out of a chair. CT scan (B) through the proximal fracture fragment shows intramedullary calcification and endosteal erosion suggestive of low grade chondrosarcoma. Axial fat saturated fast spin-echo T2 weighted MR image (C) through the distal fracture fragment shows marrow replacement by tumour, a large soft tissue mass almost encircling the bone, and soft tissue edema related to the fracture. Postoperative AP radiograph of the femur (D) following proximal femur resection including most of the soft tissues of the proximal thigh and hip and reconstruction with a cemented proximal femur tumour prosthesis.

Hedgehog Signaling Blockade: A Future Treatment Strategy for Chondrosarcoma
Targeting genetic events in chondrosarcoma may provide the best opportunity for curative treatment. Indian hedgehog and parathyroid hormone related protein (PTHrP) normally act in a feedback loop regulating proliferation and differentiation of growth plate chondrocytes. Hopyan et al. identified a mutation in the human PTHrP receptor (PTHR1) which causes overactive hedgehog signaling and enchondromatosis typical of Ollier's disease22. Transgenic mice expressing the mutant human PTHR1 gene in the growth plate developed tumours similar to human enchondromatosis (Figure 4)22. The hedgehog pathway is constitutively re-activated in both benign and malignant cartilage tumours23. Human chondrosarcoma xenografts in immunodeficient mice treated with hedgehog inhibiting agents demonstrated reduced cell proliferation and tumour size23. We are currently examining new hedgehog targeting agents in preclinical studies for treatment of patients with poor prognosis or inoperable chondrosarcoma.

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Figure 4
Enchondromas in PTHR1 transgenic mice. Mouse enchondromas (arrows) are evident in histologic sections of the proximal humerus of PTHR1 mutant mice (B) but not wild type mice (A) at 8.5 weeks of age. Paraffin-embedded sections were stained with safranin-O to highlight cartilage and revealed multiple cartilage islands in the metaphysis adjacent to the growth plate.

References

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