CORR Insights®: What Factors Are Associated with Treatment Outcomes of Japanese Patients with Clear Cell Chondrosarcoma?

Where Are We Now?

Clear cell chondrosarcoma is a rare subtype of chondrosarcoma that comprises only 1% to 2% of all chondrosarcomas; since chondrosarcomas are themselves rare, very little is known about clear cell chondrosarcoma. Only few case series have evaluated patients with this disease [1, 4, 6].

In this month’s Clinical Orthopaedics and Related Research®, Nakayama et al. [8] performed a retrospective, multicenter study on clear cell chondrosarcoma through the Japanese Musculoskeletal Oncology Group (JMOG), focusing on the patient and tumor characteristics, details of the diagnostic process, oncological outcomes, and related risk factors. In their study, the authors found that nearly one-third of the patients diagnosed with clear cell chondrosarcoma were initially misdiagnosed (29%; 10 of 35), and that core needle biopsy was especially susceptible to diagnostic error in patients with clear cell chondrosarcoma. The incorrect initial diagnoses in patients with clear cell chondrosarcoma were conventional chondrosarcoma, chondroblastic osteosarcoma, and benign chondroblastoma. The authors suggested wide resection in patients with initial inadequate surgery in order to minimize the likelihood of local recurrence, a finding that echoes suggestions from other work [5].

Where Do We Need To Go?

Practical strategies for preventing misdiagnosis need to be further developed. Core needle biopsy resulted in pathological misdiagnosis of clear cell chondrosarcoma in this study [8], but considering its predominant site (proximal femur) and the difficulty in accessing it using incisional biopsy techniques, core needle biopsy will remain appealing to some. I agree with Nakayama et al. [8] that identifying specific markers useful for differentiating among clear cell chondrosarcoma, chondroblastoma, and other cartilaginous tumors is strongly needed.

This study [8] and others [4, 6] have called for long-term follow-up of patients with clear cell chondrosarcoma, but because of the rarity of this tumor, a number of practical follow-up principles, as well as the appropriate modalities to use for radiological evaluation still need to be developed. Risk stratification to determine which patients would benefit from long-term follow-up may be helpful both to patients and physicians.

More data is also needed to improve treatment outcomes of patients with high-grade clear cell chondrosarcoma. The clinical benefits of adjuvant and neoadjuvant chemotherapy in such patients are unknown and should be further studied. Management strategies for patients involving relapse need to be established. In the present series, patients with multiple lung metastases died of the disease. Metastasectomy was performed only in one instance with solitary lung metastasis, resulting in temporary disease control [8]. The clinical benefits of metastasectomy for lung or bone lesions and of systemic chemotherapy and bone-modifying agents need to be confirmed.

Finally, although we have some case series describing the clinical behavior of clear cell chondrosarcoma, we know far less about its biological properties. Genetic and molecular knowledge on the development, progression, and metastasis of clear cell chondrosarcoma, as well as on the difference between this cancer and other cartilaginous tumors like conventional chondrosarcoma, may be helpful for the management of patients with this rare tumor.

How Do We Get There?

Several practical options are available, such as developing a retrospective analysis on the nationwide tumor registry, meta-analysis, and retrospective multicenter studies. Based on the clinical questions clarified through the past chart analysis on a particular nation or area, the chart analysis should be extended to an international population. A recent study conducted by Heng et al. [3] on extraskeletal osteosarcoma, an extremely rare condition, through international collaborations including that with the JMOG, is a good example of this model approach.

Educating general practitioners on recognizing rare entities seems impractical. Perhaps developing a caution system for rare entities, supported by artificial intelligence technology for radiological diagnosis, could be a practical solution not only for clear cell chondrosarcoma but also other rare diseases.

The accumulation of biological and genetic data is urgent especially for establishing management strategies for patients with advanced or high-grade tumors. For such a rare tumor, a randomized clinical trial is not feasible; rather, genetic and molecular-based approaches are more-practical options. The treatment of infantile fibrosarcoma harboring the ETV6-NTRK3 fusion gene using tropomyosin receptor kinase inhibitors is a good example [2]. Researchers gathered data on targetable driver genetic alterations across different types of tumors, and then applied certain drugs to several different cancers harboring common genetic alterations. This is a good alternative to expensive and, for these purposes, impractical randomized control studies. Thus, routine preservation of biopsy or operation specimens with genetic data of each case is encouraged.

Finally, developing a common platform for the integration of clinical, radiological, pathological, and genomic information on bone and soft tissue tumors based on concepts such as “radiomics” should be considered [7]. One real-world example of this is a project from NF1 Research Initiative, an international study group for malignant peripheral nerve sheath tumors (www.nfresearch-childrens.org). On such a platform, genomic data from samples will be tagged with clinical, radiological, and pathological data and any relationship between these factors and oncological outcomes will be analyzed. Feedback from such an integrated database, when brought to bedside medicine, can provide solutions to the issues highlighted in the present study.