Secondary Chondrosarcoma

Review Article
Secondary Chondrosarcoma
Patrick P. Lin, MD
Charbel D. Moussallem, MD
Michael T. Deavers, MD
Abstract
Secondary chondrosarcoma is a distinctive type of tumor that
originates from a preexisting cartilaginous lesion. Most commonly,
it is associated with solitary or multiple osteochondromas. A
fraction of cases arises from other conditions, such as Maffucci
syndrome and Ollier disease. A sudden increase in the size of the
cartilaginous cap of an osteochondroma is a sign of malignant
transformation to secondary chondrosarcoma. However, there is no
strict cutoff in terms of thickness of the cartilaginous cap that can
be regarded as being pathognomonic of malignancy. Most cases of
secondary chondrosarcoma are low to intermediate grade. Distant
metastasis is uncommon, and the prognosis is good for most
patients. Overall survival at 5 years is approximately 90%. Surgical
resection with wide margins is the best treatment option, but local
recurrence remains a significant problem in approximately 10% to
20% of patients. Patients with secondary chondrosarcoma of the
pelvis are especially at risk for local recurrence.
From the Department of
Orthopaedic Oncology, University of
Texas MD Anderson Cancer Center,
Houston, TX (Dr. Lin), the Faculty of
Medical Sciences, Department of
Orthopedic Surgery, Lebanese
University, Beirut, Lebanon
(Dr. Moussallem), and the
Department of Pathology, University
of Texas MD Anderson Cancer
Center (Dr. Deavers).
Dr. Lin or an immediate family
member has received research or
institutional support from Pfizer and
the Musculoskeletal Transplant
Foundation. Neither of the following
authors nor any immediate family
member has received anything of
value from or owns stock in a
commercial company or institution
related directly or indirectly to the
subject of this article:
Dr. Moussallem and Dr. Deavers.
J Am Acad Orthop Surg 2010;18:
608-615
Copyright 2010 by the American
Academy of Orthopaedic Surgeons.
Chondrosarcomas are malignant
tumors that are distinguished
chiefly by the presence of abnormal
chondrocytes that retain the ability
to produce cartilaginous matrix.
They are the second most common
sarcoma of bone after osteosarcoma,
constituting 9.2% of cases in the
Mayo Clinic series. 1 Histologically,
secondary chondrosarcoma resembles
primary conventional chondrosarcoma,
which arises de novo in
bone without a preexisting lesion. In
both, the entire tumor is composed
of cartilaginous tissue. In secondary
chondrosarcoma, however, a preexisting
benign chondroid tumor is
present, most typically an osteochondroma.
This may reflect important
underlying genetic differences between
primary and secondary chondrosarcoma.
Clinical differences exist
in the presentation and behavior
of secondary chondrosarcoma compared
with primary chondrosarcoma.
Thus, despite histologic similarity,
the two entities should be
regarded separately.
Secondary chondrosarcoma must
be distinguished from dedifferentiated
chondrosarcoma, which also
arises from a preexisting cartilaginous
tumor but is characterized by
the presence of a high-grade sarcoma
adjacent to a low-grade cartilage tumor.
The high-grade, dedifferentiated
tumor is typically of a different
histology (eg, osteosarcoma), and it
does not resemble conventional
chondrosarcoma. Secondary chondrosarcoma,
in contrast, is composed
entirely of cartilaginous tissue, and it
is usually a low-grade malignancy.
Dedifferentiated chondrosarcoma
can arise in secondary chondrosarcomas,
but the rate of transformation
is low. In a review of 273 cases of
chondrosarcomas arising from preexisting
osteochondromas by the
Rizzoli Institute, only 15 cases
608 Journal of the American Academy of Orthopaedic Surgeons

Patrick P. Lin, MD, et al
Table 1
Major Series on Secondary Chondrosarcoma
Study
No. of
Cases
Preexisting
Lesion (No.)
Grade 14
(No. of Cases)
52 Solitary OC (21), HME (4),
Coley and
N/A
Higinbotham 6 enchondroma (23), Ollier
disease (4)
Garrison et al 7 75 Solitary OC (40), HME (35) 1 (64), 2 (10), 3 (1)
Hudson et al 8 15 Solitary OC (12), HME (3) 1 (11), 2 (3), 3 (1)
Sun et al 12 5 Maffucci syndrome (all) 1 (1), 2 (3), N/A (1)
Liuetal 9 12 Ollier disease (all) 1 (10), 2 (2)
Merchan et al 10 4 HME (all) 1 (4)
Wuisman
45 Solitary OC (16), HME (29) 1 (30), 2 (13), 3 (2)
et al 13
Schaison
29 Solitary OC (17), Ollier
1(9),2(18),N/A(2)
et al 11 disease (12)
Ahmed et al 4 107 Solitary OC (61), HME (46) 1 (97), 2 (10)
Altayetal 5 32 Solitary OC (14), HME (10), enchondroma
(6), Ollier disease
(1), Maffucci syndrome (1)
1(28),2(4)
HME = hereditary multiple exostosis, N/A = not available, OC = osteochondroma
Table 2
Risk Factors for Secondary
Chondrosarcoma
Clinical
Pain
Increasing size of a palpable lesion
Male predominance (2:1)
Location in the pelvis or hip
Peak age in mid 30s
Radiographic
Surface irregularity
Blurriness of the border
Osteochondroma >5 cm
Increase in size of osteochondroma
Cartilage cap >2 cm
Inhomogeneous mineralization of large
cartilage cap
Genetic
Hereditary multiple exostosis (EXT1,
EXT2, EXT3 mutations)
Ollier disease
Maffucci syndrome
(5.5%) underwent dedifferentiation. 2
Most cases of dedifferentiated chondrosarcomas
appear to originate
from central primary chondrosarcoma;
it is estimated that the fraction
of primary chondrosarcomas undergoing
dedifferentiation may be as
high as 15.4%. 3 In most cases, the
prognosis of patients with dedifferentiated
chondrosarcoma is dismal,
which is quite unlike the prognosis
of patients with secondary chondrosarcoma.
Secondary chondrosarcoma is a
well-recognized clinical diagnosis.
However, relatively little has been
published on the subject, perhaps as
a result of the rarity of the condition.
In a review of the literature, we
found only 10 studies pertaining directly
to the subject that were not
case reports (Table 1).
Clinical Presentation
The most frequent presenting complaints
with secondary chondrosarcoma
are a palpable mass and pain.
In many cases, the signs and symptoms
are subtle, and the complaints
are not severe. Large masses in the
pelvis and thigh are easily hidden
from patient and clinician alike. New
onset of pain in a preexisting osteochondroma
should alert the physician
to the possibility of enlargement
of the cartilaginous cap. Rarely,
some tumors in the pelvis may cause
urinary and bowel irregularities.
A male predilection for secondary
chondrosarcoma seems to be evident.
Based on combined data from the
published series, 63% of patients
with the disease are male and 37%
are female, resulting in a male:female
ratio of approximately 2:1. 4-13 The
mean age of persons with secondary
chondrosarcoma is 34 years, which
is notably younger than the average
age of persons with primary conventional
chondrosarcoma. 4-13 The most
common site of involvement is the
pelvis, followed by the proximal femur.
The scapula and proximal humerus
are also relatively common
sites. Clinical, radiographic, and genetic
features associated with secondary
chondrosarcomas are summarized
in Table 2.
Our review of the major published
series indicates that the great majority
of cases arise in osteochondromas
(88%), with solitary osteochondroma
being slightly more common
than multiple osteochondromas (ie,
hereditary multiple exostosis). 4-7,11,13
Secondary chondrosarcoma can also
occur in persons with Ollier disease
(ie, multiple enchondromas) and
Maffucci syndrome (ie, multiple enchondromas
associated with softtissue
hemangiomas). Other benign
cartilaginous lesions that have been
reported, although rarely to result in
secondary chondrosarcoma include
solitary enchondroma, synovial
chondromatosis, and chondromyxoid
fibroma. 6,15-20 These lesions have
been noted mostly in case reports,
and there may be some question
whether some cases were malignant
at the outset. 6,15-20
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Secondary Chondrosarcoma
Figure 1
Secondary chondrosarcoma arising from a pelvic osteochondroma. A, Preoperative AP pelvic radiograph
demonstrating a large calcified tumor arising from the iliac wing. The surfaces of the calcified areas are indistinct and
not well-delineated. B, Postoperative AP pelvic radiograph following wide excision of the tumor. C, Photograph of the
cut specimen after resection demonstrating a thick layer of white, glistening hyaline cartilage. The central area shows a
small area of ossified bone (arrow), which represents the stalk of the preexisting osteochondroma. D, T1-weighted
axial magnetic resonance image demonstrating fatty marrow in the central portion of the sessile stalk emanating from
the iliac crest, indicating the presence of an ossified central portion of the original osteochondroma. E, T2-weighted
axial magnetic resonance image demonstrating the thick layer of cartilaginous tumor surrounding the central ossified
stalk, which appears dark. F, Gadolinium-enhanced fat-saturated T1-weighted magnetic resonance image showing a
subtle speckled pattern of enhancement within the tumor.
Radiologic Features
Conventional radiography may offer
important clues regarding the diagnosis
of secondary chondrosarcoma.
Osteochondromas have well-defined
bony edges, including the subchondral
bone of the cartilaginous cap. In
contrast, secondary chondrosarcomas
demonstrate irregularity or blurriness
of the surface of the osteochondroma
(Figure 1). A soft-tissue
mass outside the osseous portion of
the osteochondroma may be subtly
appreciable, and this mass may exhibit
scattered foci of calcification. 4,5
CT and MRI are important in
demonstrating the malignant features
of the tumor. Most critically,
they reveal an abnormally large cartilaginous
cap on the osteochondroma
(Figure 1, D through F). The
portion of the osteochondroma that
becomes malignant is the cartilaginous
tissue that forms the cap of the
lesion. The osseous tissue that makes
up the base or stalk is not thought to
610 Journal of the American Academy of Orthopaedic Surgeons

Patrick P. Lin, MD, et al
undergo malignant transformation.
Plain radiography may not demonstrate
the cartilage cap as well as either
CT or MRI do, which may lead
the unwary clinician to underestimate
the true size of the cap.
Osteochondromas may have the
appearance of an enlarged cartilage
cap on T2-weighted magnetic resonance
images when there is a large
bursa around the cap. The fluid
within the bursa appears similar to
that of cartilage tissue because both
entities have high water content.
Gadolinium contrast is used to distinguish
bursal structures from true
cartilage tissue. The bursas have only
rim enhancement of the bursal tissue
without contrast enhancement of the
fluid inside the bursa.
Many clinicians believe that a cartilage
cap with a thickness of 2 cm seems to be
strong evidence for the presence of
secondary chondrosarcoma.
Some authors have stressed the importance
of the character of the cartilage
cap in addition to its absolute
size. Ahmed et al 4 stated that “a
qualitative assessment of the cartilaginous
cap was more helpful than a
precise measurement of cap thickness.”
Irregularity of the surface of
the cartilage cap correlated with the
fuzzy appearance of the lesions on
radiographs; this irregularity may reflect
an increased invasive nature of
the lesion.
Pathology
The diagnosis of secondary chondrosarcoma
is confirmed by histologic
examination of biopsy samples. Like
conventional chondrosarcoma, secondary
chondrosarcoma is not always
easy to diagnose, and the histologic
features alone may not be
sufficient to determine that a lesion
has become malignant. Most secondary
chondrosarcomas are low grade.
The overlap in appearance between
benign lesions and low-grade cartilage
tumors has led to a high rate of
inter- and intraobserver variability in
diagnosis. 24 Critical information
from the clinical history and imaging
studies must be correlated with the
pathologic data to render the correct
diagnosis.
On the pathology slides, sarcomatous
transformation is usually identified
by the presence of malignant
chondroid tissue. Hallmarks include
hypercellularity, binucleate cells,
multiple cells in lacunae, atypical nuclei,
and myxoid changes in the hyaline
cartilage matrix (Figure 2).
Thickening of the cartilage cap can
be observed grossly. 23
A few abnormal features may
make it difficult to distinguish the
cartilage of osteochondromas from
low-grade chondrosarcomas on the
basis of histologic findings alone,
even for experienced pathologists. 25,26
There may be mild nuclear atypia,
slight hypercellularity, and occasional
binucleate cells. In these cases,
the radiographic and clinical findings
are important. 27 A lesion with a thin
cartilage cap that has not grown or
changed for years is unlikely to have
transformed into a malignant tumor.
Conversely, sudden growth in a cap
with marked enlargement of the cap
strongly suggests the presence of
chondrosarcoma, even when the histologic
findings show minimal abnormalities
that would be compatible
only with a diagnosis of grade 1
chondrosarcoma (low grade).
An important feature consistent
with malignancy is permeative infiltration
of soft tissues and the presence
of discrete nodules of cartilage
in the soft tissues separated from the
main tumor mass. In one study, 57%
of all cases of secondary chondrosarcoma
showed histologic evidence of
such permeative changes on the pathology
slides. 4 Medullary extension
of cartilaginous tumor into bone also
demonstrates invasive and malignant
behavior. This may be found in up to
one third of cases, and it tends to be
more common in broad-based osteochondromas.
13
The grading of secondary chondrosarcomas
is similar to that of primary
chondrosarcomas and includes
grade 1, low; grade 2, intermediate;
and grade 3, high. 14,28 In general, increasing
grade is associated with
greater cellularity, number of binucleate
cells, and mitoses.
Most secondary chondrosarcomas
are grade 1 or 2 lesions. In the pub-
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Secondary Chondrosarcoma
lished data of the large series that we
reviewed, more than three fourths of
the cases were grade 1 tumors, and
nearly all of the remaining lesions
were grade 2. 4,5,7,11,13 Only 1% of
cases were reported to be grade 3.
Figure 2
Genetics and Mutations
Histologic comparison of osteochondroma and secondary chondrosarcoma.
A, Cartilaginous tissue of an osteochondroma demonstrating features that
recapitulate the hyaline cartilage of articular surfaces. Note the gradual
enlargement of cells as they near the subchondral bone and become
hypertrophic. Most cells reside in solitary lacunae, with occasional lacunae
having two cells (arrowhead). The cells are relatively sparse in the abundant
extracellular matrix (hematoxylin-eosin, original magnification ×40). B, Grade
2 secondary chondrosarcoma demonstrating greater cellularity and less
discernible organization of the chondrocytes. Lacunae with multiple cells are
more common. Because cells retract from the walls of the lacunae during the
fixation process, pleomorphism of cells is not easy to identify (hematoxylineosin,
original magnification ×20). C, Osteochondroma under high-power
magnification demonstrating cells that are fairly well-spaced in their lacunae.
Slight atypia may be visible, making the distinction between benign lesions
and low-grade chondrosarcoma difficult on the basis of histology alone.
Certain lacunae contain two cells (hematoxylin-eosin, original magnification
×400). D, Grade 1 secondary chondrosarcoma under high-power
magnification demonstrating atypical features, such as the binucleate cell in
the center of the field. No significant nuclear pleomorphism is present
(hematoxylin-eosin, original magnification ×400).
Hereditary multiple exostosis
(HME), also referred to as multiple
hereditary exostosis and hereditary
multiple osteochondromatosis, is a
rare familial disease characterized by
multiple osteochondromas throughout
the skeleton. The disease is inherited
as an autosomal dominant condition
with high penetrance. Three
related genes have been implicated in
the disorder, EXT1, EXT2, and
EXT3, which are located on 8q24,
11p13, and 19p, respectively. 29-31
EXT1 and EXT2 mutations are
more common and make up most
cases. 32 Patients with EXT1 mutation
tend to have more severe phenotypes
than do patients with EXT2
mutation. 32 It is not clear how the
EXT genes are related to the pathophysiology
of osteochondromas.
Mutation of the genes usually results
in truncated forms of the proteins,
which are needed for the synthesis of
heparan sulfate. This may secondarily
impair diffusion of cellsignaling
molecules. 33
A genetic model for cartilaginous
tumorigenesis in the setting of HME
has been proposed. 34 First, inactivation
of both copies of the EXT1 gene
in cartilage cells is essential for the
formation of osteochondroma. This
typically occurs via loss of heterozygosity
in sporadic cells. Cells that
maintain one normal copy of the
gene are apparently normal. Of note,
it appears that solitary osteochondromas
also develop as a result of
mutation of both copies of an EXT
gene, the difference being that this
occurs in isolated cells and no germline
mutation is inherited. Without
further mutations in other genes, the
lesion remains benign; most osteochondromas
remain in this state and
do not progress further. One or more
additional mutations in other genes
612 Journal of the American Academy of Orthopaedic Surgeons

is required for secondary chondrosarcomas
to arise within the benign
cartilaginous origin. This process is
sometimes accompanied by chromosomal
instability and aneuploidy, the
severity of which may depend on the
particular genes that are mutated.
These have not been well characterized.
Most secondary chondrosarcomas
arise in osteochondromas; thus, it
seems as though the model of tumorigenesis
starting with mutation of
EXT genes would apply to most of
the tumors. However, this may not
account for all secondary chondrosarcomas,
and the genetic pathway
may well be distinct in chondrosarcomas
that arise in enchondromas.
Ollier disease and Maffucci syndrome
are characterized by multiple
enchondromas dispersed through the
skeleton. Maffucci syndrome is distinguished
from Ollier disease by the
presence of multiple soft-tissue hemangiomas,
and it is less common
than Ollier disease. Both diseases are
known to give rise to secondary
chondrosarcoma, but because of the
rarity of the conditions, the rate at
which malignant transformation occurs
is not well-documented. Estimates
range from 10% to 40% in
patients with Ollier disease at longterm
follow-up. 9,11,35 Some authors
believe that patients with Maffucci
syndrome may be at greater risk of
developing malignancy; in one series,
4 of 7 patients with Maffucci syndrome
developed chondrosarcoma. 35
However, reviews of published case
reports have indicated estimates approximately
15% to 20%. 12,36
The genetics of Ollier disease and
Maffucci syndrome differ from those
of HME. Both diseases seem to arise
sporadically without an obvious genetic
inheritance pattern. It is believed
that a combination of multiple
genes may be involved, but those
have not been identified. One report
identified two cases of a mutation
(one somatic, one germline) in the
gene encoding the PTH/PTHrP type I
receptor. 37 It was hypothesized that
the mutation could delay the differentiation
of proliferating chondrocytes
by constitutively activating
hedgehog signaling. However, this
mutation was not found consistently
in other tumors upon further study. 38
Prevention, Treatment,
and Outcome
The risk of malignant transformation
of benign cartilage tumors has not been
well established, and estimates vary
widely. For solitary osteochondromas,
the risk is most likely 5-year
follow-up. 5,7,13 Patients with solitary
osteochondromas tend to have a better
overall prognosis, with a 5-year
mortality rate of 6.5%, compared
with 19.6% for patients with HME. 7
Metastasis may be more apt to occur
in the rare high-grade secondary
chondrosarcoma. 7
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Secondary Chondrosarcoma
Local recurrence is a significant
problem for patients with secondary
chondrosarcoma, and this may affect
10% to 20% of patients. 4,5,13 Local
control of disease is particularly important
for patients with pelvic and
centrally located disease. In one series,
more deaths occurred from local
recurrence than from distant metastasis.
4 The ramifications of local recurrence
on the patient’s chances for
survival should not be underestimated.
Local recurrence of conventional,
primary low-grade chondrosarcoma
has been associated with
decreased survival, increased metastasis,
and increased grade of tumor.
44,45 Thus, an oncologically
sound operation for the primary tumor
with wide surgical margins is of
critical importance to maximize the
chances for long-term patient survival.
Summary
Secondary chondrosarcoma is an uncommon
tumor that arises from a
benign cartilaginous lesion. The tumor
frequently develops in the context
of a syndrome that produces
multiple cartilaginous tumors, including
HME, Ollier disease, and
Maffucci syndrome. It appears most
commonly in the pelvis and proximal
femur. Several signs may alert the clinician
to the possibility of malignant
transformation, such as new onset of
pain, sudden growth of a lesion, and
radiographic changes.
The size of the cartilage cap of an
osteochondroma is important. MRI
with gadolinium contrast may help
define the thickness of the cap. Although
no demarcation in size of the
cap can be considered diagnostic of
malignant transformation, a cap
thickness of >1 cm is worrisome,
particularly when there is documented
growth of the cap.
The overall prognosis for patients
is good. Most tumors are low grade,
and distant metastasis is uncommon.
Secondary chondrosarcomas must be
distinguished from dedifferentiated
chondrosarcomas, which are very
aggressive, high-grade tumors with a
poor prognosis. The management of
secondary chondrosarcoma relies
chiefly on wide surgical excision. Inadequate
surgical resection can lead
to uncontrollable local recurrence,
which is perhaps as likely a cause of
demise as distant metastasis.
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