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RETHINKING TREATMENT FOR CHONDROSARCOMA: A ROLE FOR IDH INHIBITION?
TABLE 1. Benign Cartilaginous Tumors of Bone
Benign Molecular Features Clinical Features
Enchondroma IDH1 or IDH2 mutation Ollier’s disease or Mafucci syndrome; 50% risk of syndromic transformation;
pain may herald malignant transformation
Osteochondroma EXT1 or EXT2 deletion or inactivating mutation Arise in long bones around knee or elbow; risk of fracture; 5% risk of
transformation to peripheral conventional chondrosarcoma
Chondroblastoma H3F3B Lys36Met Arise around the knee or proximal humerus; younger individuals;
more common in men; rarely metastasizes
Chondromyxoid Fibroma GRM1 gene fusion usually t(1;5)(p13;p13) Arise in metaphysis of long bones; younger individuals; very rare
malignant transformation
for survival. 14 However, as detailed below, histologic subtype
is very important in guiding therapy.
Benign Cartilaginous Tumors
Benign cartilaginous tumors commonly are found in children
and young adults. Many have a characteristic appearance
on radiology fılms and are not biopsied. Although most
tumors can be treated conservatively, enchondromas and osteochondromas
have the potential to transform into a
higher-grade chondrosarcoma, particularly in the setting of
an underlying IDH mutation as seen in Ollier’s disease and
Maffucci syndrome. 15-18 Details of genetic and molecular abnormalities
and clinical presentation can be found in Table 1.
Conventional Chondrosarcoma of the Bone
Conventional chondrosarcomas make up approximately
85% of all chondrosarcomas (Table 2). These tumors most
commonly arise in the proximal femur, bones of the pelvis,
and proximal humerus. 19,20 Clinical symptoms are nonspecifıc.
Pain is the most frequent symptom, occurring in at least
95% of patients. Pathologic fractures are found at the time of
diagnosis, affecting 3% to 17% of patients. 6 Conventional
chondrosarcomas are divided into three histologic catego-
KEY POINTS
Treatment recommendations for chondrosarcoma depend
heavily on histologic subtype, which predicts sensitivity to
chemotherapy and radiation.
RECIST response rates to anthracycline-containing
chemotherapy regimens are less than 20% for the most
common conventional and dedifferentiated subtypes.
Isocitrate dehydrogenase (IDH) enzymes normally catalyze
conversion of isocitrate into alpha-ketoglutarate during the
citric acid cycle, a function impaired in mutant enzymes.
Mutated IDH enzymes also possess a unique gain-offunction
phenotype that converts alpha-ketoglutarate to an
oncometabolite, 2-hydroxyglutarate, not present in normal
cells.
IDH mutations have been identified in numerous solid and
hematologic cancers, including chondrosarcomas, which
have led to ongoing clinical trials of novel IDH1 and IDH2
inhibitors.
ries. Central conventional chondrosarcoma (CCC) represents
approximately 75% of all chondrosarcomas. These
cancers arise within the medullary cavity from previously
normal-appearing bone. Although most are thought to arise
de novo, as many as 40% of central chondrosarcomas may
arise from a preexisting benign cartilage lesion (Table 1), or
enchondroma. 7,8,11,21,22 These secondary chondrosarcomas
often may be lower-grade with less metastatic involvement. 23
Malignant transformation has been described in patients
with Ollier’s disease (enchondromatosis) and Maffucci
syndrome (enchondromatosis associated with soft-tissue
hemangioma). 18 Most cases of chondrosarcoma in Ollier’s
disease and Maffucci syndrome are linked to IDH1 or IDH2
mutations. 24,25 Peripheral conventional chondrosarcoma
(PCC) is rarer, occurs in younger patients, and by defınition
arises in an osteochondroma. PCC also is a tumor that is resistant
to chemotherapy and relatively resistant to radiation
therapy. A third type of chondrosarcoma is periosteal chondrosarcoma
(also known as juxtacortical chondrosarcoma),
which arises from the external surface of bone. 26 This tumor
accounts for less than 1% of all chondrosarcomas. 14 Interestingly,
despite high-grade histology, this subtype has a more
favorable prognosis with adequate surgical management. 14,27
It tends to affect slightly younger adults, with slow growing
masses arising from long bones, particularly the posterior
distal femoral metaphysis or diaphysis. 6
The other 10 to 15% of all chondrosarcomas are infrequent
subtypes, such as dedifferentiated, myxoid, clear cell, and
mesenchymal chondrosarcomas. 11,28 Mesenchymal chondrosarcoma
is a high-grade malignant bone tumor that is
comprised of biphenotypic well-differentiated cartilaginous
cells and undifferentiated high-grade small round blue cells.
These occur in younger patients, arise in the axial skeleton,
and have a high propensity of metastasis at the time of diagnosis.
The small round blue cell component of this subtype of
chondrosarcoma may respond to conventional chemotherapy
regimens used for Ewing sarcoma or rhabdomyosarcoma.
Therefore, accurate diagnosis of the precise subtype is
critical for appropriate management and best outcomes.
Dedifferentiated Chondrosarcoma
Dedifferentiated chondrosarcoma is an uncommon but aggressive
subtype of chondrosarcoma that comprises approximately
10% of all chondrosarcomas. 6,11,14 The disease tends
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