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TINOCO ET AL
The Biology and Management of Cartilaginous Tumors: A Role
For Targeting Isocitrate Dehydrogenase
Gabriel Tinoco, MD, Breelyn A. Wilky, MD, Ana Paz-Mejia, MS, Andrew Rosenberg, MD,
and Jonathan C. Trent, MD, PhD
OVERVIEW
Chondrosarcomas are rare mesenchymal neoplasms defined by the production of abnormal cartilaginous matrix. Conventional chondrosarcoma
is the most common histology. The management of primary conventional chondrosarcoma generally is surgical with the
possible addition of radiation therapy. Treatment of conventional chondrosarcoma is problematic in unresectable or metastatic disease
because the tumors tend to be resistant to standard sarcoma chemotherapy regimens. Previous attempts at targeted therapy, including
inhibitors of Hedgehog signaling, the mTOR pathway, and platelet-derived growth factor receptor (PDGFR) have been largely disappointing.
However, heterozygous mutations in isocitrate dehydrogenase (IDH) enzymes recently have been identified in chondrogenic
neoplasms, with mutations reported in approximately 87% of benign enchondromas, 70% of conventional chondrosarcomas, and 54%
of dedifferentiated chondrosarcomas. The normal IDH protein continues to produce alpha-ketoglutarate (alpha-KG) whereas the mutant
IDH protein converts KG to the oncometabolite 2-hydroxyglutarate (2-HG). Clinical trials of novel IDH inhibitors are ongoing, with
evidence of early activity in IDH-mutant leukemias. IDH inhibitors show antitumor effects against IDH-mutant chondrosarcoma cell lines,
supporting the inclusion of patients with chondrosarcoma with IDH mutations on IDH inhibitor clinical trials for solid tumors. Targeting
IDH mutations may offer hope of a novel antineoplastic strategy not only for patients with chondrosarcomas, but also for other solid
tumors with aberrant IDH activity.
Chondrosarcomas constitute a diverse group of neoplasms
with varied morphologic features and different
clinical behaviors, defıned by the production of neoplastic
cartilage matrix by the tumor cells. 1 Chondrosarcomas are
the second most frequent primary sarcoma arising in bone
after osteosarcoma, 2-5 accounting for 20% to 27% of malignant
bone neoplasms. 6 They may occur at any age, but typically
they are seen more frequently in older adults. 7,8 The
clinical behavior is quite variable, with low-grade tumors displaying
slow growth and low metastatic potential, to highgrade
tumors that can be highly aggressive with the
propensity for distant metastases. Because of the avascular
matrix and low percentage of dividing cells, most chondrosarcomas
are inherently resistant to cytotoxic chemotherapy
and are relatively radiation-resistant, with the exception of
the mesenchymal subtype. 7 Thus, complete surgical resection
with wide margins remains the most critical component
of therapy, whenever possible, for patients with primary tumors.
9 Unfortunately, many patients present with inoperable
disease at the time of diagnosis or recur with metastatic disease,
and more than 10% of recurrent chondrosarcomas are
of a higher grade than the original tumor. 7 Current research
focuses on improving our understanding of chondrosarcoma
biology and identifying new therapeutic approaches, especially
for patients in whom curative surgery is not indicated.
10 Our objective in this review is to discuss classifıcation
of chondrosarcomas in the setting of standard treatments,
and to review novel pathways that may lead to novel therapies
in the future.
CLASSIFICATION
Cartilaginous tumors are categorized based on the WHO
Classifıcation of Tumours of Soft Tissue and Bone (Tables 1
and 2). 11 The importance of expert pathologist review in classifıcation
of all sarcomas cannot be overemphasized. These
tumors may have overlapping histologic features and often
require additional immunohistologic and genetic testing for
defınitive diagnosis. Various studies have suggested that histologic
grade, size, stage, and anatomic location of the lesion
are fundamental prognostic features. 12,13 In an analysis of
2,890 patients with chondrosarcoma from the Surveillance,
Epidemiology, and End Results (SEER) database, only grade
and stage were identifıed as independent prognostic factors
From the Sylvester Comprehensive Cancer Center, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL; Sylvester Comprehensive Cancer Center, Department of
Pathology, University of Miami Miller School of Medicine, Miami, FL.
Disclosures of potential conflicts of interest are found at the end of this article.
Corresponding author: Jonathan C. Trent, MD, PhD, Department of Medicine, University of Miami Miller School of Medicine, 1475 NW 12th Ave., Suite 3300, Miami FL 33136; email:
jtrent@med.miami.edu.
© 2015 by American Society of Clinical Oncology.
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