Classic high-grade osteosarcoma is a highly malignant spindle-cell
sarcoma of bone in which the malignant cells produce osteoid1. It is the most common primary malignant
tumor of bone, excluding myeloma, and is the third most common malignant
disease in adolescence after leukemia and lymphoma. However, it
is still a rare tumor with only 1000 new cases per year in the United States.
There appears to be no racial or ethnic influence associated with
its incidence2. However, an increased
prevalence has been noted in families affected with the Li-Fraumeni
syndrome3 and in patients who
have had retinoblastoma4 (a 40% prevalence
in those with bilateral disease), have undergone radiation therapy5, or have Paget disease6.
Classic high-grade osteosarcoma has a peak prevalence in the
second decade of life, with 75% of cases occurring between
the ages of ten and twenty-five years1.
There is a second peak in the seventh decade, which is most likely
due to its association with Paget disease of bone. The male-to-female
ratio is approximately 1.5:1. Osteosarcoma can occur in any bone
but is most common in the metaphyses of long bones, with 80% to 90% of
the tumors occurring in those locations, and it often extends into
the epiphysis. Specifically, its most frequent locations are the
distal femoral metaphysis (35%), the proximal tibial metaphysis
(20%), and the proximal humeral metaphysis (10%),
all areas of rapid skeletal growth1.
Occasionally, the tumor is found in the diaphysis of long bones
and, more rarely, in the flat bones.
Clinical Presentation
Pain is the most prevalent presenting symptom in osteosarcoma,
occurring in 85% of patients7.
It is probably due to microfractures through the involved areas
of the bone or, in severe cases, to compression or stretching of
adjacent anatomic structures. The pain usually is exacerbated by
activity, and only 21% of patients have pain at night.
Almost 50% of patients relate the onset of symptoms to an
episode of minor trauma. A palpable or visible mass is noted in
about 40% of patients. Painless masses may be obscured
when they arise in the pelvis or proximal part of the thigh. Less
common findings include a limp, weakness, a decreased range of motion
in associated joints, venous engorgement, edema, and striae. Laboratory
tests are generally not helpful in the diagnosis of osteosarcoma,
although elevated serum lactate dehydrogenase and alkaline phosphatase
levels have been associated with a poorer prognosis8,9.
Plain Radiographic Features
Classic high-grade intramedullary osteosarcoma usually appears
as a destructive lesion of the metaphysis of a long bone. It typically
exhibits a mixture of lytic and blastic areas but may be exclusively
one or the other. Its overall appearance is one of an aggressive process
characterized by destruction of both cortical and cancellous bone
and a wide (permeative) zone of transition between tumor and normal
host bone. Osteosarcoma usually has an extraosseous soft-tissue
mass with fluffy irregular densities indicative of neoplastic bone
formation. At the proximal and distal cortical margins of the tumor,
there may be triangular-shaped areas of reactive periosteal new-bone formation
known as Codman triangles. These are not specific to osteosarcoma but
rather are seen as a reaction to any aggressive bone process. The
radiographic appearances of the other types of osteosarcoma can
be quite different from that of classic osteosarcoma and are discussed
below.
Staging Studies
Staging studies are part of a process to determine the local
and distant extent of a tumor, thus helping to determine prognosis
and management strategies10. These
studies can be divided into those that determine the local extent and
those that determine the distant extent of disease. Magnetic resonance imaging
is the current standard technique for determining the local extent of
disease in the involved bone (Figs. 1-A and 1-B). The study must include the entire bone
in question. Magnetic resonance imaging is extremely accurate in
defining the marrow extent of the tumor and therefore is very helpful
in determining the appropriate resection level at surgery11. Sagittal or coronal images of the
entire bone visualize skip metastases (discontinuous foci of tumor
in the same bone outside the reactive zone)12 that
are not apparent on plain radiographs. Axial magnetic resonance images
provide an accurate depiction of the extent of any soft-tissue mass
and its relationship to nearby neurovascular structures. Adjacent
joint involvement may also be demonstrated. Planning of a biopsy
is facilitated greatly by the use of magnetic resonance imaging,
as it shows the most appropriate surgical route to the tumor without
unnecessary contamination of associated structures. Also, magnetic
resonance imaging can define areas most likely to be viable, optimizing
the chances for obtaining a diagnostic sample. Computed tomography
is complementary to magnetic resonance imaging by providing better bone
detail, and it is especially useful for visualization of pelvic
tumors, where the fat planes allow better delineation between normal
and tumor tissue.
Bone scintigraphy has an important role in staging both the local
and the distant extent of osteosarcoma. It can define areas of primary
involvement, skip metastases, and sites of synchronous metastases
to other parts of the skeleton. Chest radiographs and computed tomography
scans screen for the presence of pulmonary metastases. The lungs
are the site of most metastases. Computed tomography scans of the chest
can detect pulmonary nodules as small as 3 mm and finely pinpoint
them should resection be necessary. Lymphatic spread is so uncommon
that routine examination of lymphatics is not done.
Pathological Characteristics
Gross examination of an osteosarcoma specimen most often reveals
a soft-tissue mass originating in the medullary canal and extending
beyond the cortex. The inner part of the mass is usually more heavily
mineralized than the periphery (in contradistinction to myositis
ossificans)1. Any intra-articular
extension can be appreciated during gross examination. If present,
it usually occurs along the course of ligaments, such as the anterior
and posterior cruciate ligaments.
Histological examination reveals frankly malignant cells producing osteoid.
These cells are pleomorphic and exhibit mitotic activity. There
are often areas of spontaneous tumor necrosis. The background stroma
may also be predominantly fibrous or chondroid1.
Communication of clinical and radiographic findings to the pathologist
is essential in the diagnosis of all mesenchymal neoplasms. Without
this essential information, a pathologist may mistake the reactive
bone of fracture callus or periosteal new bone for that produced
by the malignant cells of osteosarcoma or vice versa. This could result
in a misdiagnosis and subsequent mismanagement of the patient’s
disease. The less common types of osteosarcoma, such as low-grade
central osteosarcoma and parosteal osteosarcoma, are much less cellular and
are sometimes confused with fibrous dysplasia. Periosteal osteosarcoma
is predominantly cartilaginous and must be distinguished from chondrosarcoma.
Osteosarcoma Variants
Osteosarcoma can be divided into primary and secondary types.
The primary types include high-grade central (classic), low-grade
central, juxtacortical or surface, and telangiectatic lesions. Secondary
osteosarcomas include those associated with Paget disease, post-irradiation
sarcomas, and those that "dedifferentiate" from
other benign precursors, such as fibrous dysplasia and bone infarcts.
High-grade central (classic) osteosarcoma is the most common
type. The typical locations are the distal aspect of the femur,
the proximal aspect of the tibia, and the proximal part of the humerus.
The clinical, radiographic, and pathological presentation is usually typical
and does not pose a difficult diagnostic challenge.
The surface or juxtacortical osteosarcomas include parosteal,
periosteal, and high-grade surface tumors. Parosteal osteosarcomas
are located predominantly in the posterior aspect of the distal
femoral metaphysis and have a lobulated radiodense "pasted
on" appearance on plain radiographs. There may be an apparent
cleavage plane between the cortex and the tumor. Some may progress
to involve the medullary canal. These tumors usually occur in a
somewhat older age-group (twenty to forty years old) and have a definite
preponderance among females. Histological examination reveals a
low-grade fibrous stroma with tumor osteoid and bone formation13. Although such tumors are most often low-grade
histologically, they may evolve into high-grade malignant lesions,
in which case they are called dedifferentiated parosteal osteosarcomas14. The treatment of histologically
low-grade tumors is wide excision without chemotherapy. Long-term
survival rates as high as 93% have been reported15.
Periosteal osteosarcoma is most commonly an intermediate-grade
tumor found in the diaphysis of long bones, especially the tibia.
Radiographically, it appears as a variably calcified mass in a saucer-shaped
defect in the cortex of a long bone. Histologically, it is composed
of intermediate-grade malignant cells producing osteoid in a predominantly
chondroid background. It most often occurs in adolescence and has
a metastatic rate between that of parosteal osteosarcoma and that
of conventional osteosarcoma. The treatment is wide excision, and
the role of chemotherapy is unclear16.
High-grade surface osteosarcoma is an extremely rare tumor that
occurs in the second and third decades of life17.
These tumors have a predilection for the diaphyseal surface of long
bones (especially the femur), although fully one-third involve only
the metaphysis. They exhibit various amounts of mineralization,
which is most pronounced at the broad base of the tumor. Most tumors
affect the underlying cortex by destruction or thickening, or both. Approximately
one-half of the tumors infiltrate the underlying bone either grossly
or histologically. Histological evaluation reveals a high-grade
malignant tumor that is essentially identical to classic osteosarcoma.
Treatment is wide surgical excision, and chemotherapy is thought
to be beneficial. The metastatic rate is similar to that of classic
high-grade osteosarcoma.
Telangiectatic osteosarcoma is a high-grade osteosarcoma that
is often seen to be purely destructive on plain radiographs. It
is hemorrhagic, and often there is little tissue present. It can
be confused with benign lesions, especially an aneurysmal bone cyst1. It is similar to classic high-grade osteosarcoma
with respect to patient demographics, treatment, and outcome.
The most common secondary osteosarcomas are associated with Paget
disease of bone or arise in a bone that has had previous irradiation.
Both types are aggressive, destructive lesions of bone with highly
anaplastic cell populations. Both have a dismal prognosis, usually with
a rapid progression to distant metastasis. The use of chemotherapy may
be beneficial, but there are limited data. In addition, the patients
with these secondary osteosarcomas are usually more than fifty years
old and do not tolerate the chemotherapy as well as younger patients
do.
Treatment of Classic High-Grade Osteosarcoma
Surgery alone was the treatment for patients with classic high-grade osteosarcoma
before 1970, and 80% of the patients died with metastatic
disease. During the next two decades, great strides were made in
the treatment of classic high-grade osteosarcoma so that, currently,
approximately 70% of patients with the disease survive
and limb-sparing surgery is possible in about 90% of patients.
Modern therapy for osteosarcoma begins with accurate clinical staging,
the final step of which is biopsy10.
The current standard of treatment is multiagent preoperative (neoadjuvant) chemotherapy
combined with wide resection or amputation followed by postoperative
(adjuvant) chemotherapy.
The history of the development of the use of chemotherapy for
osteosarcoma is an interesting one. In 1974, the New England
Journal of Medicine published reports on two chemotherapy
trials that claimed marked improvement in the survival of patients
with osteosarcoma when surgery was followed with adjuvant chemotherapy18,19. This finding seemed to set the
stage for the accepted use of adjuvant therapy in the treatment
of osteosarcoma. However, an alternate theory, attributing the apparent
increase in survival not to the chemotherapy but to a change in
the natural history of the disease, was espoused. A randomized trial
was then done to compare surgery combined with adjuvant high-dose
methotrexate therapy and surgery without chemotherapy. The study,
which was published in 1984, showed identical five-year survival
rates of 42% in the two groups, supporting the theory of
a change in the natural history of the disease20.
In response to this intriguing data, two prospective, randomized
studies were begun to answer definitively the question of the efficacy
of chemotherapy in the treatment of osteosarcoma. One was performed
at the University of California at Los Angeles, and the other was
a multi-institutional study. Both studies21,22 showed
substantial differences between the treatment groups with respect
to two-year survival rates. The patients treated with surgery and
adjuvant chemotherapy had a two-year survival rate of >60%,
whereas those treated with surgery alone had a two-year survival
rate of <20%.
In the 1970s, Rosen et al. showed a dramatic increase in survival
of patients treated with preoperative (neoadjuvant) chemotherapy23. One of the arguments for neoadjuvant chemotherapy
was that it prevented the development of resistant clones in a tumor
with a rapid doubling time. Postponing the institution of chemotherapy until
after surgery might allow spontaneous mutations to occur, resulting
in resistant clones. The second argument was that preoperative chemotherapy would
kill the microscopic metastases (that could eventually kill the
patient) already present in the majority of patients at the same
time that it was treating the primary tumor. Neoadjuvant chemotherapy
may also shrink the primary tumor and sterilize microscopic tumor
foci in the reactive zone around it, facilitating resection and increasing
the chance for limb-sparing surgery. Neoadjuvant chemotherapy also
allows time for surgical planning, the fabrication of a custom tumor
prosthesis, or the procurement of allograft tissue for implantation.
Finally, neoadjuvant chemotherapy induces necrosis in the primary
tumor, and the amount of this necrosis serves as an extremely important
prognostic indicator for long-term survival. To date, however, no large
studies have shown increased survival of patients receiving preoperative chemotherapy
compared with those receiving postoperative therapy24. Because of these theoretical advantages,
most protocols include neoadjuvant chemotherapy. The drugs that
are most commonly used in combination for the treatment of osteosarcoma
are doxorubicin, high-dose methotrexate, cisplatin, and, most recently,
ifosfamide25.
Successful surgical management is predicated on attaining wide
surgical margins. This can be accomplished either by limb-sparing
resection or by amputation. There does not appear to be any significant
difference in long-term survival between patients who undergo amputation
and those who have a limb-sparing procedure provided that wide margins
are obtained26. Limb-sparing surgery
is indicated for patients in whom wide margins can be obtained without
sacrificing so much tissue that the remaining limb is nonfunctional.
Usually, the determining factor is the ability to spare major nerves.
Major vessels need to be preserved or reconstructed. There must
be adequate soft-tissue coverage either locally or in the form of
flaps to ensure survival of the reconstruction. The overall reconstruction
should function as well as or better than an appropriate prosthesis
after an amputation. The options for reconstructing the skeletal defect
include osteoarticular allograft, intercalary allograft, a metal
endoprosthesis, an allograft-prosthesis composite, arthrodesis,
rotationplasty, and free vascularized fibular transfer.
Current management protocols provide long-term survival rates
of between 60% and 80% for patients without clinically
apparent metastatic disease at presentation24,27.
Patients who have clinically apparent metastases at presentation
fare considerably worse, with five-year survival rates of between
10% and 20%28,29.
When pulmonary metastases develop after completion of therapy and
the metastases can be resected, a five-year survival rate of 20% to
40% can be expected30.
Clinical Prognostic Factors
The single most predictive factor in osteosarcoma is the presence
or absence of detectable metastatic disease at presentation. As
mentioned, the survival rate for patients who have metastases at
the time of presentation is between 10% and 20%28,29. Those who present with bone
or skip metastases fare even worse12,30.
The degree of tumor necrosis after neoadjuvant chemotherapy is also
an important prognostic factor. Patients who have tumors with a
good response to chemotherapy (>90% tumor necrosis)
have a considerably better long-term survival rate than those who
have tumors with a poor response (<90% tumor necrosis)24,27,31. Large tumor size has been
implicated as a negative prognostic indicator in several studies;
however, inconsistent methods of determining size in these studies
make it difficult to ascertain its true influence. Other poor prognostic variables
reported in the literature include elevated serum lactate dehydrogenase
and alkaline phosphatase levels8,9.
A tumor located in the pelvis, proximal part of the femur, or proximal
part of the humerus also appears to be indicative of a poor prognosis
in some studies32.
Molecular and Genetic Considerations
Cytogenetics
Ewing sarcoma and many soft-tissue sarcomas demonstrate consistent
cytogenetic abnormalities, such as reciprocal chromosomal translocations,
that are important in the diagnosis and pathogenesis of the disease.
In classic high-grade osteosarcoma, no consistent chromosomal alteration
with diagnostic, therapeutic, or prognostic importance has been
found to date. In fact, the karyotypes are often bizarre, containing
multiple aberrations that are highly inconsistent between tumors. This
finding has led to the use of molecular methods to identify events that
may be important in the pathogenesis of osteosarcoma.
Tumor Suppressor Genes
A tumor suppressor gene is any gene that by its loss of function
contributes to the pathogenesis or progression of a tumor. This
can occur at the level of the gene or at the level of the protein
for which it codes. Often, tumor suppressors function as cell-cycle
regulators. The hallmark of a putative suppressor gene is loss of
the genetic material coding for a protein that is important in the regulation
of the cell cycle or its proliferation. Studies on loss of heterozygosity
(loss of one allele on a chromosome) have shown allele loss on chromosome arms
17p, 13q, 3q, and 18q in >50% of osteosarcomas
studied33. These findings suggest
the existence of putative suppressor genes in these regions33. The known tumor-suppressor gene p53
and the retinoblastoma (Rb) gene are the most frequently mutated
in osteosarcoma (mutated in 25% to 80%) and are
localized to chromosome arm 17p and 13q, respectively33-35. Kruzelock et al. recently localized
a novel putative tumor-suppressor gene on chromosome arm 3q in osteosarcoma36.
The p53 gene product functions as a cell-cycle regulator and
has the ability to induce apoptosis (programmed cell death). It
can cause the cell to pause during the cell cycle to repair genetic damage,
or it can cause apoptosis in the cell if repair of this damage is
not possible. A defect in this gene or its protein might then allow
a mutated cell to proliferate without control, propagating DNA damage
to its progeny. Loss of p53 function in osteosarcoma has been demonstrated
to occur by several mechanisms, including point mutation, gross loss
of genetic material, and inhibition of its protein function by the
murine double-minute 2 (MDM2) gene product37,38.
Although it is one of the most commonly altered genes in osteosarcoma, little
association with disease progression or prognosis has been demonstrated.
The retinoblastoma (Rb) gene was the first characterized tumor-suppressor gene.
It acts as a negative transcriptional regulator of genes involved
in the cell-cycle progression from G1 to S phase. Loss of this function
allows cells to progress through the cell cycle unchecked. Allele
loss of the Rb gene has been reported in approximately 50% to
60% of osteosarcomas33,36.
A recent study has demonstrated that loss of heterozygosity at the
Rb locus on chromosome arm 13q is a predictor of poor outcome in
patients with osteosarcoma35.
Oncogenes
The effect of oncogenes on tumorigenesis is different from that
of tumor suppressors in that mutation of a normal proto-oncogene
to an oncogene confers a gain of function, as opposed to a loss, driving
the cell toward a malignant phenotype. C-myc is a proto-oncogene transcription
factor found to be overexpressed in many human cancers. C-fos is
another transcription factor implicated in many cell processes including cell-cycle
progression. It is also involved in osteoblast and chondrocyte differentiation.
In a recent study39, both c-myc
and c-fos were shown to be overexpressed in osteosarcoma, especially
in pulmonary metastases. Seven of thirty-eight patients showed an
overexpression of both c-fos and c-myc, and these patients had a
significantly lower rate of disease-free survival than did patients
with overexpression of only one of the two transcription factors
(p < 0.05) .
Her2/erbB-2 is a cellular proto-oncogene that encodes
the human epidermal growth-factor receptor 2 (Her2). Overexpression
of this oncogene induces malignant transformation of rodent fibroblasts
and has been implicated in decreased survival of patients with breast
carcinoma. Recently, two studies have shown overexpression in approximately
40% of the osteosarcomas and a correlation with decreased
event-free survival and histological response to neoadjuvant chemotherapy40,41. With the development of additional prospective
studies, the presence of the Her2/erbB-2 receptor eventually
may emerge as a significant prognostic indicator. It may also become
a treatment target, with use of recombinant anti-Her2 monoclonal
antibody for tumors positive for overexpression. Phase-II trials
are currently under way.
The MDM2 gene codes for a p53 binding protein and is located
on chromosome arm 12q13, a region that is often amplified in a variety
of sarcomas. It has the ability to inhibit the transcriptional activity
of p53, providing an alternative pathway of p53 inactivation. MDM2
has been found to be amplified in approximately 4% to 7% of
osteosarcomas38. It is marginally
associated with locally recurrent and metastatic disease but cannot
be used currently as a prognostic marker38.
The MDR1 (multidrug resistance) gene codes for an adenosine triphosphate-dependent
cellular efflux pump (p-glycoprotein) that actively transports doxorubicin
(among other drugs) out of the cell. It would make sense that cells overexpressing
MDR1 would be relatively resistant to doxorubicin, an important
agent in the treatment of osteosarcoma. Indeed, several large, retrospective,
immunohistochemical analyses of p-glycoprotein expression in osteosarcoma
have shown a highly significant correlation between low survival
rates and p-glycoprotein expression (p < 0.001)42,43. However, other studies have
not demonstrated this finding40.
Recently, in a large, prospective multi-institutional study of MDR1
mRNA levels in osteosarcoma, Wunder et al. demonstrated no correlation
between MDR1 gene expression and prognosis44.
Although the logic behind the theory that MDR1 confers a resistant
phenotype upon osteosarcoma cells is attractive, its true effect
remains somewhat controversial.
Angiogenesis
One of the most interesting topics in cancer therapy is that
of anti-angiogenesis. Very little work on sarcomas has been done
in this field. Anti-angiogenic agents have been shown to inhibit tumor
growth and cause tumor regression in mouse models45.
There are currently many anti-angiogenic agents being tested in
Phase-I and II clinical trials of their effects on human cancers.
Two of the targets of these trials are vascular endothelial growth
factor and its receptors. Kaya et al. recently demonstrated expression
of vascular endothelial growth factor in seventeen (63%)
of twenty-seven osteosarcomas46.
They also correlated this expression with a high prevalence of pulmonary metastasis,
suggesting that expression of vascular endothelial growth factor may
play a role in the metastatic cascade of osteosarcoma46. Given these findings, two drugs
currently in Phase-II trials, an antivascular endothelial growth-factor
antibody and a vascular endothelial growth-factor receptor inhibitor,
may well prove advantageous in the treatment of osteosarcoma.
In the near future, molecular analysis may very well help to
stratify patients with osteosarcoma into relative risk groups (molecular
staging), allowing more tailored treatment regimens. In addition,
we hope that, with further progress, highly selective targets for antisarcoma
therapy without the substantial morbidity of current cytotoxic chemotherapy
will be identified.
Great strides have been made in the diagnosis and treatment of
Ewing sarcoma over the last three decades. With the advent of modern
chemotherapy, the long-term survival rate has improved to approximately
70%47-58. Originally,
treatment consisted of surgery or irradiation of the tumor, and
the rate of survival was approximately 5% to 10%47,49-58. When adjuvant chemotherapy
was added in the 1970s, survival improved and the treatment of the
primary site became controversial. Currently, surgical resection
has become the treatment of choice in the multidisciplinary management
of Ewing sarcoma.
Ewing sarcoma is a malignant small-round-cell bone tumor47,48. It is the second most common
primary malignant bone tumor in children and accounts for approximately
10% of all primary malignant bone tumors. The peak prevalence
of Ewing sarcoma is during the second decade of life, with 80% of
tumors occurring in patients who are less than twenty years old. There
is a male preponderance. The tumor presents most frequently in the lower
extremities and the pelvic girdle but can occur in any bone.
A great deal of progress has been made in understanding the biological
mechanisms and refining the diagnosis of Ewing sarcoma. James Ewing
believed that the tumor was of vascular origin and, in 1921, he
called it "diffuse endothelioma of bone."59 More recently, cytogenetic as well
as immunohistochemical studies have supported a neural cell origin
developing into the concept of small-round-cell neuroectodermal
lesions of bone and soft tissue49,60,61.
This family of tumors includes Ewing sarcoma, primitive neuroectodermal tumor,
atypical Ewing tumor, and Askin tumor. Cytogenetic studies have shown
that these tumors share reciprocal translocations, which are identical in
Ewing sarcoma and primitive neuroectodermal tumor49,60,61.
Currently, the treatment of these tumors is very similar, with multidrug chemotherapy
for systemic treatment and surgery and/or radiation therapy
for control of the primary tumor.
Clinical and Radiographic Presentation
The most common presenting symptoms of Ewing sarcoma include
pain, swelling, or a mass. Approximately 20% of patients
present with a fever, which may lead to the mistaken diagnosis of
infection. Laboratory studies are nonspecific but may reveal anemia,
leukocytosis, or an increased erythrocyte sedimentation rate. Osteomyelitis
is more common than Ewing sarcoma, and the general orthopaedic surgeon must
consider both entities in the differential diagnosis. During an
open or needle biopsy, Ewing sarcoma often has the appearance and
consistency of pus, and it is vital to send the biopsy material
for frozen section in addition to performing cultures. Pathological
fractures occur in 10% of cases, and neurological compromise
is possible with vertebral lesions. Patients with rib lesions often present
with a malignant pleural effusion.
Any portion of any bone may be involved by Ewing sarcoma, which
typically has a mottled, permeative radiographic appearance (Fig. 2). Periosteal
reaction, with a laminated or "onion-skin" appearance,
is common in Ewing sarcoma, but it is not pathognomonic. Frequently
a large, unmineralized soft-tissue mass (best seen with magnetic
resonance imaging) is associated with the osseous lesion. The magnetic
resonance imaging scan is repeated after several cycles of chemotherapy
to assess the response of the tumor to the neoadjuvant regimen and to
help to plan definitive treatment of the primary lesion. There has
been recent interest in the use of dynamic magnetic resonance imaging
scans to assess more accurately the viability of the tumor before
definitive local control is undertaken50.
The presence and extent of metastatic disease is evaluated with
a radiograph and computed tomography scan of the chest, a bone scan,
and a bone-marrow aspirate. The bone scan is important, as 10% of
patients have involvement of multiple bones at presentation. Studies including
renal function and liver function tests and an evaluation of cardiac function
are performed routinely before chemotherapy.
Pathological Characteristics
Grossly, Ewing sarcoma is a gray-white tumor with a variable
amount of necrosis, hemorrhage, or cyst formation. At times, the
tumor tissue may be almost liquid, mimicking purulence. Histologically,
it is composed of numerous small round cells with a diffuse homogeneous growth
pattern and sparse intercellular stroma (Fig. 3). The cells have ill-defined borders
and a finely dispersed chromatin pattern. Mitotic activity is seldom
high, and the cells are quite uniform. Atypical Ewing tumor is a
histological variant in which the cells have larger, more irregular nuclei
and more prominent nucleoli.
Previously, Ewing sarcoma was differentiated from other small-round-cell tumors
by the presence of glycogen in the cells as seen with a periodic
acid-Schiff stain51. However,
current advances in cytogenetics and immunohistochemistry allow more
precise diagnostic evaluations. Ewing sarcoma and primitive neuroectodermal
tumor cells strongly express the p30/32 MIC2 antigen, which
is a cell-surface glycoprotein encoded by the MIC2 gene49. This glycoprotein can be recognized by
commercially available monoclonal antibodies, which help to differentiate Ewing
sarcoma and primitive neuroectodermal tumor from lymphoma and embryonal
cell rhabdomyosarcoma. The MIC2 analysis has a sensitivity of up
to 95% in the diagnosis of Ewing sarcoma. There is minimal
false-positive reactivity with lymphoblastic lymphoma and other
tumors.
Cytogenetic studies have revealed that 85% of Ewing
sarcomas and primitive neuroectodermal tumors contain the t(11;22)(q24;q12)
balanced chromosomal translocation49,52,60,61.
The breakpoints on chromosomes 22, 21, and 11 are the EWS, ERG,
and FLI-1 genes, respectively. These translocations have been cloned
and are identical in Ewing sarcoma and primitive neuroectodermal
tumor. The EWS/FLI-1 or EWS/ERG fusion transcripts
can be amplified by reverse transcriptase-polymerase chain-reaction60. Scotlandi et al. compared immunohistochemical
studies with reverse transcriptase-polymerase chain-reaction and
found that fusion transcripts analyzed by reverse transcriptase-polymerase
chain-reaction were much more specific than immunostaining with
use of a monoclonal antibody61.
The definitive prognostic importance of these specific translocations
has yet to be identified.
Ewing sarcoma and primitive neuroectodermal tumor have a number
of unifying characteristics47.
The translocations are highly specific for these two tumors, both
express an MIC2 gene on the cell membrane, and they respond to similar
drugs. Primitive neuroectodermal tumor has more characteristic histological
features, with Homer-Wright rosettes in a fibrillary background,
a lobular arrangement of cells, and densely clumped nuclear chromatin.
In addition, electron microscopy demonstrates prominent organelles
and neurosecretory granules47.
Studies have shown no difference in survival between patients with
Ewing sarcoma and those with primitive neuroectodermal tumor when
histological criteria are used for diagnosis47,
but more elaborate analyses may be able to differentiate these two
lesions in terms of patient outcome.
Chemotherapy
Dramatic advances have been made in the treatment of Ewing sarcoma
in the last two decades. Development of effective chemotherapy was
a major breakthrough in the prevention and control of disseminated
disease, which increased the five-year survival rate from 5% to 10% twenty
years ago to >70% at the current time47,49-58. In 1981, the First Intergroup
Ewing Sarcoma Study demonstrated that the addition of doxorubicin
to the three-drug combination of vincristine, cyclophosphamide,
and actinomycin D increased survival57.
The Second Intergroup Sarcoma Study demonstrated that the intensity
of drug dosage was important for relapse-free survival, as intermittent
administration of high-dose vincristine, actinomycin D, cyclophosphamide,
and Adriamycin (doxorubicin) (VACA) was found to be superior to
continuous administration of a moderate dosage of the same regimen54. A combined study of the Children’s Cancer
Group and the Pediatric Oncology Group showed that a more aggressive
regimen, adding ifosfamide and etoposide to vincristine, actinomycin
D, cyclophosphamide, and Adriamycin, improved the event-free survival
rate of patients with nonmetastatic disease. The greatest effect
was seen in large pelvic tumors and in patients who were less than
nine years old55,56,58,62. Current
studies focus on intensifying the alkylating agents and administering more
intense chemotherapy over a shorter time-period.
Prognosis
A number of major prognostic factors have been identified in
Ewing sarcoma63-69. Recognition
of such factors may help to categorize this tumor according to risk
status so that future treatment protocols can be modified. Patients
with Ewing sarcoma in distal sites or a rib fare better than do
patients with central lesions, and those with a pelvic lesion have
the least favorable prognosis53,62.
An initial tumor size of >8 to 10 cm, large volume, and
metastatic disease at the time of diagnosis are negative prognostic
indicators63,65,69. Picci et al.,
in a review of the experience at the Rizzoli Institute, found significantly
improved survival when there was a good histological response to neoadjuvant
chemotherapy (p = 0.004)67,68.
Local Control
Classically, treatment for Ewing sarcoma has been chemotherapy
and radiation, with surgical resection reserved for expendable bones47,48. The newest trends, however,
suggest that surgery should always be considered when the surgeon
believes that the primary tumor can be removed completely. Radiation
therapy is still used for tumors in anatomic sites where total resection
cannot be done, when the functional deficit is unacceptable to the patient,
and when an attempted resection has unacceptable margins. Additional
site-specific analyses of the oncological results of resection and
the long-term functional results of reconstruction are necessary
before definitive recommendations can be made.
Several retrospective studies have shown that surgical excision
of the primary tumor improves survival. A study from the Mayo Clinic
showed a five-year survival rate of 74% for patients who
had surgical excision of the primary tumor compared with 34% for those
who had radiation alone for local control69.
In a study of forty-six patients with Ewing sarcoma treated at Massachusetts
General Hospital, 92% of those treated with surgical resection
were alive at five years compared with 37% of those treated
without surgical resection70.
This survival advantage is maximized in patients with a pelvic tumor.
One possible explanation for the increased survival rate is that
surgical resection of the tumor eliminates residual clones of chemotherapy-resistant
cells before they have a chance to recur locally or to metastasize.
Patients treated with surgery alone or with surgery and radiation tend
to have a lower recurrence rate than patients treated with radiation alone.
This trend becomes more important as patients are followed for longer than
five years, as it is not unusual to see late local recurrences after
radiation71. Bacci et al. reported
local recurrence in 36% of patients treated with radiation
alone, with 14% of the recurrences occurring four years
after completion of treatment53.
Overall survival was improved significantly by operative treatment
(p < 0.001). In another study, the local recurrence rate
was 3.7% for patients managed with surgery compared with 24% for
those who did not have surgical excision69.
The prevalence of local recurrence is greatest in patients with
a pelvic lesion. An alternative explanation for these more favorable
results is a selection bias for performing surgery on smaller and
more surgically resectable tumors.
With the increase in long-term survival rates as a result of
modern chemotherapy, the problems of late local recurrence, functional
impairment secondary to radiation complications, and radiation-induced
sarcomas have been better appreciated71-74.
The local recurrence rate in patients treated with radiation alone
is 15% to 20%, and this adversely affects survival.
The complications of radiation therapy are most pronounced in skeletally
immature patients and include limb-length discrepancy, joint contracture,
muscle atrophy, and pathological fracture72.
The risk of radiation-induced malignant tumors is becoming more
apparent with longer patient survival and is particularly high in
patients who have received doses of radiation in excess of 60 Gy73,74. Tucker et al. showed that the
relative risk of secondary sarcoma formation after irradiation for
Ewing sarcoma increases with time74.
In a group of 649 children, they found that the cumulative mean
probability of secondary sarcoma formation in patients with Ewing
sarcoma was 22%, second only to that in patients with retinoblastoma.
The current philosophy of treatment is to utilize neoadjuvant
chemotherapy to decrease the size of the tumor, followed by wide
resection for lesions in expendable or surgically reconstructible
bones to avoid late chemotherapy-resistant recurrences48,65. It is not possible to identify
precisely the indications for surgical resection of Ewing sarcoma;
however, some general principles can be followed. First, the treatment
plan needs to be individualized on the basis of the location, stage, and
size of the tumor. Next, it is essential that a multidisciplinary
team consisting of a medical oncologist, radiation oncologist, and
orthopaedic oncologist formulate the treatment plan. The local therapy
should not take precedence over, nor interfere with, systemic chemotherapy.
Surgical resection should be done in all cases in which the surgeon
believes that the primary tumor can be removed completely, particularly
in expendable sites or surgically reconstructible sites. If an adequate
margin is not achievable or is found to be inadequate (<1
cm) at the time of resection, local radiation therapy should be
added. In general, a combination of surgery and radiation therapy
allows use of a dose of 45 Gy, which minimizes the side effects
of radiation. It is important to try to avoid complicated surgical
reconstructions, which may delay the initiation of postoperative
chemotherapy. When a complicated reconstruction is required, the surgeon
should consider performing a temporary, less complex reconstruction first
and delaying the more complex reconstruction until the entire chemotherapy
regimen has been administered.
Treatment principles vary depending on the location of the primary
tumor. Long-bone lesions generally can be managed by limb-sparing
resection and reconstruction (Figs. 4-A and 4-B). If radiation is used in combination with
surgery, metal prostheses provide a more reliable reconstruction.
Intercalary allografts are prone to delayed union or nonunion at
the host-graft junction, especially in patients receiving chemotherapy
or radiation, and may need to be combined with an immediate or delayed
vascularized fibular graft75.
Limb-salvage surgery is possible in most cases, but amputation is
occasionally necessary when the tumor is extremely large, a pathological
fracture is unmanageable, or the lesion is in the distal aspect
of the lower extremity in a very young child.
A pathological fracture through a Ewing sarcoma, which occurs
in 5% to 10% of patients, poses a special problem48,76. Tumor cells disseminate in the
fracture hematoma, the severity of which is related to the degree
of fracture displacement. Limb-sparing in the setting of a pathological
fracture may be difficult. Often the limb can be immobilized in
a cast or external fixator while the patient continues preoperative
chemotherapy. With a good response to chemotherapy, the fracture
often heals. Magnetic resonance imaging scans are necessary before
and after chemotherapy. Unlike a pathological fracture through an
osteosarcoma, which necessitates resection of all anatomical areas that
have been contaminated with tumor cells, it may be possible to sterilize
residual contaminated areas around a pathological fracture through
a Ewing sarcoma with external beam irradiation following a more
conservative resection.
Problem Sites
Pelvis
Ewing sarcoma in the pelvis is particularly difficult to manage
because of the large tumor volume and complex anatomy62,65,77,78 (Fig. 5). The overall
prognosis for such patients is poor. Radiation is not completely
effective for local control, but the role of surgery for pelvic
tumors remains controversial. Complete resection of the primary
tumor may improve local control, increase disease-free survival,
and eliminate the possibility of postradiation sarcoma. In a study
from Massachusetts General Hospital, the addition of surgery was
not a favorable prognostic factor, but other series have suggested
better local control following surgical resection of pelvic lesions53,62,70,78. Frassica et al. reported
that 20% of 181 patients with Ewing sarcoma evaluated over
a sixteen-year period had involvement of the pelvic ring77. Nine patients were excluded from
the study, and the remaining twenty-seven patients were categorized
into three groups according to the type of local treatment and whether
they had metastases at the time of initial presentation. The surgically
treated group had better overall survival, with a low rate of local
recurrence. These retrospective studies must be interpreted with
caution as they involve limited numbers of patients; however, there
seems to be a trend for prolonged survival and a decreased risk
of local recurrence in patients treated with surgery for local tumor
control. The functional outcome after surgery needs to be measured against
the risk of local recurrence and the development of a secondary
malignant tumor after radiation.
Proximal Part of the Femur
The appropriate treatment to achieve local control of Ewing sarcoma
of the proximal part of the femur is still a subject of debate,
and the long-term durability of proximal femoral reconstructions
is not known. Currently, the two most popular options are proximal
femoral replacement prostheses and allograft-prosthetic composite reconstructions
(Figs. 6-A, 6-B, 6-C, 6-D, and 6-E). In Ewing sarcoma,
the outcome of these reconstructions should be compared with that
of irradiation following conventional treatment, which also has limitations.
The cases of sixteen patients with Ewing sarcoma of the proximal
part of the femur who were treated in the modern chemotherapy era were
reviewed76. Local control involved
radiation alone in fourteen patients (two patients who were treated
with prophylactic internal fixation were excluded), and the most notable
orthopaedic problem was a pathological fracture, which occurred in
eleven patients. The fractures were divided nearly equally between
those occurring early and those occurring late. Possible factors
contributing to early fractures include extensive infiltration of
the bone with sarcoma cells, technical errors in the biopsy technique, and
poor compliance with protected-weight-bearing precautions. In the
late phase of treatment, the bone is weakened by infiltration of
tumor cells and the osteonecrotic effects of radiation. While structural
demands on the proximal part of the femur make it a difficult site
to reconstruct reliably following resection, the same structural
demands result in a high rate of pathological fracture when radiation
is the primary local treatment. Currently, the two treatment options
are a resection of the lesion after neoadjuvant chemotherapy or
prophylactic intramedullary fixation after completion of radiation
and chemotherapy.
Spine
Fortunately, only 3.5% of patients with Ewing sarcoma
have spinal involvement, and this rate decreases to 1% if the
sacrum is excluded48,79. Although
primary lesions of the spine are rare, metastasis of Ewing sarcoma to
the spine is common in the terminal stages. In a retrospective study
of thirty-six patients with Ewing sarcoma of the spine, twenty-one
(58%) presented with neurological deficits79. The most common location was the lumbar
or lumbosacral spine. All patients were treated with radiation and chemotherapy.
Of the patients with neurological deficits, the majority had improvement
after decompressive laminectomy. The five-year survival rate was
33%, and there was no difference in the disease-free survival
rate between patients with a primary lesion of the sacrum and those
with a tumor in the mobile spine, although other studies have found
that sacral lesions portend a worse prognosis80.
Local recurrence occurred in approximately one-half of the patients.
Anterior spinal procedures have gained widespread popularity in
the last decade and have a growing role in the treatment of Ewing
sarcoma, particularly with the high prevalence of late kyphosis
following conventional radiation therapy. Because complex surgical procedures
for Ewing sarcoma of the spine frequently are performed in a staged
fashion, it may be prudent to complete chemotherapy and radiation preoperatively
so that the postoperative recovery and possible complications of vertebral
resection and reconstruction do not interfere with systemic treatment.
In summary, considerable strides have been made in the treatment
of Ewing sarcoma as currently about 70% of patients are
long-term survivors47,49-58. A
multidisciplinary team approach is necessary to combine chemotherapy, surgery,
and/or radiation in the care of the patient. New developments
in molecular biology and cytogenetics have allowed a more accurate
diagnosis to be made and may have prognostic implications in the
future. Modern multidrug chemotherapy is the mainstay of current
treatment. Historically, local control of the tumor was achieved
with radiation, but an important role for surgery is evolving with
improved limb-salvage techniques. Surgical resection of the tumor
in reconstructible bones is often a reasonable option, decreasing the
risk of local recurrence and the development of radiation-induced
sarcoma. The treatment plan must be individualized on the basis
of the location, stage, and size of the tumor. Future studies will
focus on the treatment of patients with metastatic disease, as their overall
survival remains poor.
Chondrosarcoma of bone is the third most common primary malignant
bone tumor following osteosarcoma and Ewing sarcoma. Chondrosarcoma
can arise de novo (primary) or secondary to a preexisting benign
cartilaginous lesion (for example, exostosis, enchondroma, or, rarely, synovial
chondromatosis). Chondrosarcomas can be classified according to the
relationship to the underlying bone (peripheral compared with central),
as primary or secondary, or by histological type.
Pathological Characteristics
The histological classification of cartilaginous tumors poses
a great diagnostic challenge to the musculoskeletal pathologist81-87. The difficulty lies in differentiation between
benign active and low-grade malignant cartilaginous lesions. These tumors
look similar histologically, and there are no markers that clearly
allow distinction. The most difficult distinction is between enchondromas
and low-grade central chondrosarcomas. Because of the similarity,
clinical and radiographic criteria must be used to separate a benign
enchondroma from a low-grade malignant cartilaginous neoplasm. The
identification and classification of high-grade, dedifferentiated, clear-cell,
and mesenchymal chondrosarcoma require extensive knowledge and yet
are less controversial.
Cartilaginous tumors usually can be classified as benign, borderline
(grade 1/2), low-grade malignant, or high-grade malignant.
Low-grade chondrosarcomas can be distinguished from enchondromas
histologically on the basis of cortical destruction or permeation
of cancellous bone or the development of a soft-tissue mass. High-grade chondrosarcomas
typically show severe cytologic atypia and a high mitotic rate.
Radiographic Characteristics
Cartilaginous neoplasms, which are difficult to classify on the
basis of histological findings, can frequently be identified by
their radiographic appearance (Table I). Enchondromas typically are metaphyseal
in location and do not have an extraosseous soft-tissue mass, cortical destruction,
or periosteal reaction. In contrast, low-grade central chondrosarcomas
cause a periosteal reaction, may destroy the cortex, and often have
an extraosseous soft-tissue mass (Figs. 7-A, 7-B, 7-C, 7-D, and 7-E); these lesions are usually seen
in patients who are older than thirty years of age. The development
of a thickened cartilaginous cap (>2 cm) is a sign of malignant
transformation from an osteocartilaginous exostosis to a secondary
chondrosarcoma. Mesenchymal chondrosarcomas and dedifferentiated
chondrosarcomas usually have a more aggressive radiographic appearance.
Clear-cell chondrosarcomas frequently present as a destructive lesion
in the epiphyseal portion of a long bone.
Chondrosarcoma Secondary to Exostosis
Chondrosarcomas arise from <1% of osteocartilaginous
exostoses. Exostoses stem from an outgrowth of the physis due to
a defect in the perichondral node of Ranvier that surrounds it. They
can occur singly or multiply in the genetic syndrome of multiple
hereditary exostoses. The classic radiographic feature of an exostosis
is that of an osseous stalk arising from the metaphysis of a bone
covered with a cartilaginous cap. The cartilaginous cap is analogous
to the physeal plate. The histological organization of the cap,
with columns of chondrocytes, resembles that of the physis, albeit
in a disorganized fashion. During growth, the cartilaginous cap
proliferates, enchondral ossification takes place, causing the stalk
to grow, and the exostosis enlarges. At the time of skeletal maturity
or shortly thereafter, the cartilaginous cap becomes quiescent and
the exostosis stops growing. Histologically, the cap becomes less
active and thin (usually <1 cm). When a secondary chondrosarcoma
develops, the cartilaginous cap begins to grow uncontrollably and
the cap thickens (>2 cm). These secondary sarcomas are
almost always histologically low-grade and slow-growing, and patients
are at a low risk for metastases. Metastatic disease occurs in approximately
1% to 10% of patients with multiple hereditary
exostoses and rarely in patients with solitary exostoses. If not
treated surgically, the lesions can attain enormous size and cause
local morbidity or even death. Rarely, they dedifferentiate into
a highly malignant dedifferentiated chondrosarcoma. Treatment consists
of surgical resection, with wide surgical margins. Education of
patients with multiple hereditary exostoses and their families is
important to facilitate early recognition and diagnosis.
Central Chondrosarcoma
Central chondrosarcoma can arise secondary to an enchondroma
or de novo within a bone. Chondrosarcomas are almost
always associated with pain, while enchondromas rarely are. Because
pain is often associated with other musculoskeletal conditions (for example,
rotator cuff arthropathy), the difficult clinical problem is ascertaining whether
the pain reported by the patient is due to the apparent bone lesion
or to some other problem. When the lesion has no radiographic signs
of chondrosarcoma but seems to be the cause of pain, classification
as a painful enchondroma, a borderline chondrosarcoma, or "chondrosarcoma in
situ" can be difficult. Treatment of these lesions
varies, with expectant observation, intralesional curettage, and
resection all being acceptable options. There is a low risk of local
recurrence or metastasis of these controversial lesions. On the
other hand, central chondrosarcomas that have all or some of the
classic radiographic and clinical characteristics of a frank sarcoma—namely,
cortical destruction, periosteal reaction, and a soft-tissue mass—will behave
more like a true malignant tumor. These true central chondrosarcomas
are typically low to medium-grade histologically, with a prevalence
of metastatic disease of approximately 30%. Treatment is
surgical resection. Chemotherapy or radiation therapy is indicated
infrequently. For the more rare high-grade central chondrosarcomas,
aggressive surgery with radical surgical margins or amputation is sometimes
necessary for local control.
Clear-Cell Chondrosarcoma
Clear-cell chondrosarcoma, described by Unni et al. in 1976,
is a rare variant of chondrosarcoma with a characteristic histological
appearance and a specific anatomic predilection88,89.
The histological appearance of clear-cell chondrosarcoma is a combination of
immature chondroid matrix surrounding chondrocytes with a characteristic
clear cytoplasm. Clear-cell chondrosarcoma arises primarily in the epiphyses
of the long bones after skeletal maturity. Because of the similar
anatomic distribution of clear-cell chondrosarcoma and chondroblastoma, careful
histological distinction is necessary. Histologically, the differential diagnosis
primarily includes other tumors that contain a clear cytoplasm, such
as renal cell carcinoma, clear-cell sarcoma, mucinous adenocarcinoma, and
the physaliferous cells of a chordoma. Immunohistochemical stains
can help to distinguish between clear-cell chondrosarcoma and the
other diagnoses. The prognosis for patients with clear-cell chondrosarcoma
is intermediate, between those associated with low-grade and high-grade
chondrosarcomas. Metastases occur most often in the lung but can
occur in bone and may appear years later. Treatment is wide local
excision. Chemotherapy and radiotherapy are indicated.
Dedifferentiated Chondrosarcoma
Dedifferentiated chondrosarcomas, first described by Dahlin and
Beabout in 1971, occur when a benign or low-grade malignant lesion
transforms into a highly malignant variety of sarcoma90,91. The diagnosis is made histologically when
a high-grade sarcoma is found in conjunction with either an underlying benign
or a lower-grade malignant cartilaginous bone tumor. The most common
type of high-grade sarcoma is an osteosarcoma followed by malignant fibrous
histiocytoma. These tumors tend to be radiographically, histologically,
and clinically aggressive. The prognosis is quite poor, with few
survivors two years after diagnosis and a five-year survival rate
of only 10% to 15%. Treatment usually consists
of either palliation with radiotherapy or radical ablative surgery.
The role of chemotherapy has not been established.
Mesenchymal Chondrosarcoma
Mesenchymal chondrosarcoma is a rare variety of chondrosarcoma.
Approximately 70% arise in bone, and 30% develop
in soft tissue. The tumor consists of an immature cartilaginous matrix
and aggregates of primitive mesenchymal cells. Since the mesenchymal component
often predominates, the lesions are sometimes confused with Ewing
sarcoma, lymphoma, or hemangiopericytoma. The most common anatomic
areas of occurrence are the maxilla, mandible, vertebrae, and ribs. The
radiographic features are usually a destructive lesion in bone with
stippled calcification. Treatment is primarily surgical excision.
Irradiation is indicated when the tumor cannot be completely excised.
Adjuvant chemotherapy may improve overall survival.
Molecular and Genetic Considerations
Like osteosarcoma, chondrosarcoma has few consistent cytogenetic
findings, with the exception of the t(9;22) (q22;q12) translocation,
which is found in approximately 25% of extraskeletal myxoid
chondrosarcomas. The translocation forms a fusion gene EWS/TEC that
in turn codes for a protein that is a member of the orphan nuclear
receptor family. It is thought that this receptor helps to control
cellular proliferation and differentiation by modulating the response
to specific growth factors or by interfering with the signaling
pathway of retinoic acid92. Cytogenetic
changes seen in high-grade bone chondrosarcomas are of a numerical,
as opposed to a structural, type. Losses of chromosomes 10, 6, and 13
are often seen, and gains of chromosomes 7 and 20 are occasionally
noted.
Collagenase activity is responsible, in part, for the ability
of tumor cells to degrade and migrate through surrounding tissue.
Recent in vitro studies93 have
shown that increased collagenase activity and matrix metalloproteinase-1 gene
expression, relative to its inhibitor, correlate directly with invasive
potential and inversely with the level of differentiation in human
chondrosarcoma cell lines. Collagenase activity may increase the
ability of tumor cells to migrate in vivo, resulting
in a poorer prognosis for patients with chondrosarcoma. Other proteases
have been implicated in the progression of chondrosarcoma as well. Hackel
et al. showed that overexpression of cathepsin B correlated significantly
with increased rates of local recurrence in a study of 114 patients with
chondrosarcoma (p = 0.006)94.
Treatment and Prognosis
The treatment of chondrosarcoma is primarily surgical since the
response to chemotherapy and radiotherapy is relatively low95. Radiation therapy may be of benefit for
the local control of chondrosarcoma or for palliation. Chemotherapy
has been reported to be effective in the treatment of mesenchymal
chondrosarcoma. The role of chemotherapy in the treatment of dedifferentiated
or high-grade chondrosarcoma is unclear. The risk of local recurrence
is related to the surgical margin obtained at the time of resection.
Low-grade tumors have a high rate of local recurrence with intralesional
margins. Wide or radical surgical margins are often necessary to gain
local control of high-grade chondrosarcomas. The prognosis is related
to the histological grade, the surgical stage, the subtype of chondrosarcoma, and,
as found recently, to molecular markers. Future advances in the
diagnosis and treatment of cartilaginous tumors are likely to result
from their molecular characterization, allowing better prediction
of clinical behavior. This should lead to better treatment and hopefully
will solve the problem of differentiating between benign and low-grade
cartilaginous neoplasms.