Mumbai: Dr Arsheed Hussain Hakeem, Senior Consultant – Surgical Oncology, Apollo Cancer Centre, Hyderabad speaking to Prabhat Prakash of ETHealthworld discussed the rarity of mesenchymal chondrosarcomas, how it is differentiated from other bone tumours microscopically and the management and treatment protocols that should be followed in such cases. Edited excerpts.
What is the typical clinical presentation of mesenchymal chondrosarcoma? What are the characteristic radiologic findings of mesenchymal chondrosarcoma?
Mesenchymal chondrosarcomas are rare high-grade tumours affecting younger patients with a peak incidence during their third decade. The most common presentation is swelling which is initially painless with varying duration from a week to a year. Pain is a late complaint due to the extensive osteolysis and peri-osteal involvement. On physical examination, the swelling is firm to hard mass destroying the bone of origin. If neglected, they may also present with disseminated metastasis to the lungs and other organs.
Radiographic correlation is important for evaluation of the mesenchymal chondrosarcoma. Radiology plays an important role in differential diagnosis, provides guidance in biopsy planning, and is essential for staging. An orthopantomogram may show osteolytic bone lesions. On computerised tomography scans, the majority of these tumours present as mixed lytic/sclerotic or purely lytic features, with few also presenting as juxtacortical mass. Most of the cases will show calcifications predominant pattern being chondroid-type rings-and-arcs either in the periphery or in the centre or both. Most of the cases will show cortical destruction and soft tissue extension with aggressive osteolysis but little periosteal reaction. On MRI, the masses are heterogeneously hyperintense and classic ‘chondroid’ T2-hyperintense lobules are only seen in 35 per cent of cases.How can mesenchymal chondrosarcoma be differentiated from other bone tumours microscopically?
Microscopically, mesenchymal chondrosarcoma is a definite pathological entity showing a characteristic biphasic pattern made of solid areas of small round malignant cells, which are known as Ewing-like or spindle malignant cells around blood vessels, which are also known as hemangiopericytoma like interspersed with islands of well-differentiated cartilage. The morphology of this tumour imitates that of Ewing’s sarcoma and pathologists need to be careful while diagnosing this rare entity. A novel fusion transcript called HEY1-NCOA2 is a helpful diagnostic tool for mesenchymal chondrosarcoma that helps in differentiating this entity from other chondrosarcomas in equivocal cases. This HEY1-NCOA2 fusion gene can be analysed using the fluorescence in situ hybridization (FISH) technique.
Immuno-histochemistry may help in differentiating it from other sarcomas. Negative staining for TLE-1, STAT-6 and CD34 may also help in the differential diagnosis. MIB-1 index should also be done to predict aggressiveness.
What factors influence the prognosis of mesenchymal chondrosarcoma patients? How frequently should patients with mesenchymal chondrosarcoma follow up after initial treatment?
Overall younger age, small tumour size, absence of metastasis and complete radical resection of the tumour are the good prognostic factors. Metastases are more common at initial presentation, especially with larger tumours (>10 cm). The prognosis for mesenchymal chondrosarcoma of the jaw bones is better than for other sites as the 5–year and 10–year survival rates are 82 per cent and 56 per cent, respectively as compared to other skeletal areas and soft tissues. These patients need to be treated with radical local surgery. There is insufficient information regarding the benefit of chemotherapy and radiation therapy in the control of local or systemic disease in mesenchymal chondrosarcoma of the jaw bones.
Due to the rarity of the disease these, cases should be followed up regularly and lifelong. It is not like other common tumours of the bone as it appears that a 5–year survival does not translate into a cure for this disease. Many of these cases may develop recurrent disease even after surviving for five years. Even 10–year survival does not guarantee a cure as some cases have died after surviving for 13 and 24 years after initial treatment.
What is the potential for local recurrence and distant metastasis in mesenchymal chondrosarcoma?
Mesenchymal chondrosarcoma is a rare high-grade variant of chondrosarcoma that affects young patients, with a high propensity to metastasise to lungs and bone but also uncommon locations These tumours need to be treated with radical surgery if operable. If not treated adequately, chances of local recurrence are high. The disease may be detected 1–10 years after the initial treatment. This tumour may also develop distant metastasis even after 22 years after initial treatment. Half of the patients developed metastatic disease with a mortality of 30 per cent. The most common site of metastases are the lungs in 75 per cent of cases followed by bones, soft tissues, liver, pancreas, adrenals and lymph nodes.
Are there any ongoing research or clinical trials investigating novel treatment approaches for this tumour?
During the last decade, research has been focused on elucidating the molecular events underlying the pathogenesis of chondrosarcomas and it has led to the identification of several new potential therapeutic targets. Most of these targets demonstrated meaningful antitumor activity in preclinical studies, although the results in early-phase clinical studies have been inconsistent. Future studies should further explore the utility of these candidates for molecularly targeted therapies in the different sub-groups of chondrosarcoma patients.
Approximately 50 per cent of dedifferentiated chondrosarcomas have been reported to express PD-L1 (programmed death ligand 1), which has given cause for investigation of anti-PD-1 (programmed death) and/or PD-L1 antibodies in this patient population. Despite the emerging preclinical evidence, clinical evidence remains limited, with a number of clinical trials currently ongoing. Nivolumab, an anti-PD1 monoclonal antibody, in patients with metastatic sarcoma, has been used. A partial response after six cycles of nivolumab alone in a patient with dedifferentiated chondrosarcoma has been seen, while stable disease was observed in a patient with mesenchymal chondrosarcoma after four cycles of nivolumab. The SARC028 trial, a multicenter phase II trial investigating the activity of pembrolizumab in patients with advanced soft-tissue and bone sarcoma, reported a partial objective response in only one of five patients with chondrosarcoma. There is also an ongoing phase II trial investigating the efficacy of nivolumab plus ipilimumab in non-resectable sarcoma. Another ongoing phase I/II study is investigating combined nivolumab and the mTOR inhibitor ABI-009 in patients with chondrosarcoma and other advanced malignancies. There are currently three ongoing clinical trials investigating IDH (Isocitrate dehydrogenase) inhibition in chondrosarcoma patients.
What is the recommended management approach for mesenchymal chondrosarcoma? Are there any specific challenges or considerations in the treatment of this tumour?
As of now wide surgical excision with adequate margins is the standard of care to achieve long-term disease-free survival. Reconstruction in cases where the primary tumour is of mandibular origin should be done at the same time. Although these tumours are resistant to chemotherapy and radiotherapy, they can be used in cases where tumours cannot be completely resected because of location, inoperability or other contraindications.
Diagnosing mesenchymal chondrosarcoma on limited biopsy tissue is a challenge. To avoid the wrong diagnosis at the initial biopsy, I am in favour of obtaining an adequate and representative pathology specimen to exactly diagnose this rare form of chondrosarcoma. Even a second opinion from an experienced pathologist is of value to arrive at a correct diagnosis so that standard treatment can be instituted as early as possible to achieve favourable treatment outcomes. The morphology of this tumour imitates that of Ewing’s sarcoma and pathologists need to be careful while diagnosing this rare entity. To overcome such a challenge, a potential diagnostic tool, a unique fusion transcript called HEY1-NCOA2 was identified for mesenchymal chondrosarcomas to help differentiate it from other variants.
The second challenge is the complete resection of the tumour, which can be achieved by having a skilled surgical team consisting of experienced surgeons and microvascular surgeons to minimise functional and cosmetic morbidity.