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Clinical presentation, staging, and prognostic factors of the Ewing sarcoma family
of tumors
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Treatment of the Ewing sarcoma family of tumors
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Radiation therapy for Ewing sarcoma family of tumors

Epidemiology, pathology, and molecular genetics of the Ewing sarcoma family of
tumors
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Adjuvant and neoadjuvant chemotherapy for soft tissue sarcoma of the
52
Bone sarcomas: Preoperative evaluation, histologic classification, and principles of
surgical management
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29
42
extremities
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15
62
Osteosarcoma: Epidemiology, pathogenesis, clinical presentation, diagnosis, and
histology 81
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Chemotherapy and radiation therapy in the management of osteosarcoma

Treatment protocols for soft tissue and bone sarcoma 110
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BİYOPSİ ÖZET 116
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Chondrosarcoma
93
118
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Clinical presentation, staging, and prognostic factors of the Ewing sarcoma family of
tumors
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5
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Aug 2013. | This topic last updated: Oca 14, 2013.
INTRODUCTION — Ewing sarcoma (ES) and peripheral primitive neuroectodermal tumor
(PNET, previously called peripheral neuroepithelioma) were originally described in the
early 1900s as distinct clinicopathologic entities. It became evident that these entities
are actually part of a spectrum of neoplastic diseases known as the Ewing sarcoma
family of tumors (EFT), which also includes extraosseous ES (EES), PNET, malignant
small-cell tumor of the thoracopulmonary region (Askin's tumor), and atypical ES.
Because of their similar histologic and immunohistochemical characteristics and shared
nonrandom chromosomal translocations, these tumors are considered to be derived from
a common cell of origin. Although the histogenetic origin has been debated over the
years, increasing evidence from immunohistochemical, cytogenetic, and molecular
genetic studies supports a mesenchymal progenitor cell origin for all EFT [1].
The EFT can develop in almost any bone or soft tissue, but is most common in the
pelvis, axial skeleton, and femur; patients typically present with localized pain and
8
swelling. Although overt metastatic disease is found in fewer than 25 percent at the time
of diagnosis, subclinical metastatic disease is presumed to be present in nearly all
patients because of the 80 to 90 percent relapse rate in patients undergoing local
therapy alone. As a result, systemic chemotherapy has evolved as an important
component of treatment [2].
Advances in multidisciplinary management of EFT over the past 30 years have resulted
in a marked improvement in survival and a greater likelihood of limb-sparing surgery
rather than amputation [3-6]. In data derived from the Surveillance, Epidemiology and
End Results (SEER) program of the National Cancer Institute, five year survival rates for
patients with ES rose from 36 to 56 percent during the periods 1975 to 1984 and 1985
to 1994 [3]. With modern multidisciplinary treatment, long-term survival can be
achieved in 70 to 80 percent of patients presenting with nonmetastatic disease [4,5,7].
Here we will discuss the clinical presentation, diagnosis, and staging of EFT. The
epidemiology, pathology, molecular genetics, and treatment of these tumors, principles
underlying the performance of a diagnostic bone biopsy, and central (supratentorial)
PNET are discussed elsewhere.
CLINICAL PRESENTATION
Primary sites — EFT most often arises in the long bones of the extremities
(predominantly the femur, but also the tibia, fibula and humerus), and the bones of the
pelvis. The spine, hands, and feet are affected considerably less often [8,9]. In a
compilation of data from 975 patients from the European Intergroup Cooperative Ewing
Sarcoma Studies (EI-CESS) trials, the distribution of primary sites was as follows [9]:



Axial skeleton – 54 percent (pelvis 25 percent, ribs 12 percent, spine 8 percent,
scapula 3.8 percent, skull 3.8 percent, clavicle 1.2 percent)
Appendicular skeleton – 42 percent (femur 16.4 percent, fibula 6.7 percent, tibia
7.6 percent, humerus 4.8 percent, foot 2.4 percent, radius 1.9 percent, and hand
1.2 percent)
Other bones – 0.7 percent
A minority of Ewing sarcomas arise in soft tissue. Compared to undifferentiated ES of
bone, patients with extraosseous Ewing sarcomas (EES) are more frequently older, more
likely to be female, and arise more often within the axial rather than the appendicular
skeleton [8,10-12].
Signs and symptoms — Patients with EFT typically present with localized pain or swelling
of a few weeks or months duration [13-15]. Trauma, often minor, may be the initiating
event that calls attention to the lesion. The pain may be mild at first, but intensifies
fairly rapidly; it may be aggravated by exercise and is often worse at night. A distinct
soft tissue mass can sometimes be appreciated. When present, it is usually firmly
attached to the bone and moderately to markedly tender to palpation [16,17]. Swelling
of the affected limb with erythema over the mass is not uncommon.
Patients with juxta-articular lesions may present with loss of joint motion, while lesions
involving the ribs can be associated with direct pleural extension and large extraosseous
masses [18]. When the spine or sacrum is involved, nerve root irritation or compression
can result in back pain, radiculopathy, or symptoms of spinal cord compression (eg,
weakness or loss of bowel and/or bladder control).
Constitutional symptoms or signs, such as fever, fatigue, weight loss, or anemia, are
present in about 10 to 20 percent of patients at presentation [13]. Fever is related to
cytokines produced by the tumor cells, and along with other systemic symptoms, is
associated with advanced disease.
Approximately 80 percent of patients present with clinically localized disease, although
as noted previously, subclinical metastatic disease is presumed to be present in nearly
9
all. Overt metastases may become evident within weeks to months in the absence of
effective therapy. The significance of this lies in the frequent delay between the onset of
symptoms and diagnosis, which in one report averaged over nine months [15,19].
Patients with primary pelvic tumors are significantly more likely to present with
metastatic disease compared to other sites (25 versus 16 percent) [9]. Other factors
that may be associated with clinically evident metastatic disease at presentation include
high level of lactic dehydrogenase (LDH), the presence of fever, an interval between
onset of symptoms and diagnosis less than three months, and age older than 12 years
[20]. In one series, the rate of metastatic disease at presentation in the subset of
patients with none of these risk factors was only 4 percent with two factors it was 23
percent, while it was almost double (44 percent) if three or four factors were present.
Sites of metastatic disease at diagnosis are similar to those seen with recurrent disease;
lung and bone/bone marrow metastases predominate, in roughly equal proportions. The
spine is the most frequently involved bone [21,22]. Lung metastases represent the first
site of distant spread in 70 to 80 percent of cases, and are the leading cause of death for
patients with EFT. Lymph node, liver, and brain involvement are distinctly uncommon
[14,23].
STAGING EVALUATION — The goals of the initial evaluation are to establish the
diagnosis, evaluate local disease extent, and determine the presence and sites of
metastatic spread. Clinical staging includes all of the data obtained prior to definitive
therapy, including the results of imaging, laboratory studies, physical examination, and
tissue biopsy.
Radiographic studies — The diagnostic work-up is usually initiated with a plain
radiograph of the affected area. ES involving bone typically presents as a poorly
marginated destructive lesion, most often associated with a soft tissue mass. The tumors
tend to be large, and in long bones are metaphyseal or diaphyseal in location (image 1
and figure 1).
The radiographic appearance has been described as "permeative" or "moth-eaten",
indicative of a series of finely destructive lesions that become confluent over time. The
cortex at the site of the lesion is often expanded, and the periosteum displaced by the
underlying tumor, resulting in the clinical sign of Codman's triangle. The characteristic
periosteal reaction produces layers of reactive bone, deposited in an "onion peel"
appearance (image 2). The soft tissue component of the tumor rarely shows any
calcification or ossification. Sclerosis, if present, represents a secondary bone reaction
rather than the primary bone formation that characterizes osteosarcoma. A pathologic
fracture is present at diagnosis in 10 to 15 percent of cases [13,15].
Compared to plain radiographs, a CT scan of the primary site better delineates the
extent of cortical destruction and soft tissue disease (image 3). A multi-institutional
study of 387 patients that included both children and adults concluded that CT and MRI
were equally accurate for local staging of bone and soft tissue tumors [24]. However,
MRI is preferred in most cases because of its superior definition of tumor size, local
intraosseous and extraosseous extent, and the relationship of the tumor to fascial
planes, vessels, nerves, and organs (image 4). Imaging of the entire involved bone is
necessary to exclude the presence of skip lesions (ie, medullary disease within the same
bone, but not in direct contiguity with the primary lesion).
Differential diagnosis — For EFT presenting as primary bone tumors, the differential
diagnosis includes both benign and malignant conditions. The most common
nonmalignant possibility is subacute osteomyelitis, which may present similarly
(especially the presence of fever and an elevated sedimentation rate), and be associated
with intense radiotracer uptake on bone scan and a soft tissue mass on other imaging
studies [25]. Aspiration of a tumor may yield purulent-appearing material; however, it
will be sterile on culture. (See "Hematogenous osteomyelitis in adults".)
10
"Benign" bone tumors that can present as lytic lesions include eosinophilic granuloma
and giant cell tumor of bone. Destructive eosinophilic granulomas usually occur at a
younger age and are not associated with a sizable soft tissue mass.
Malignant tumors that should be considered in the differential include other common
solid tumors of childhood, including osteosarcoma, primary lymphoma of bone,
undifferentiated high-grade pleomorphic sarcoma of bone (previously termed malignant
fibrous histiocytoma of bone or spindle cell sarcoma), acute leukemia, and metastasis
from a non-bone tumor, particularly neuroblastoma (table 1). A primarily lytic
osteosarcoma may be difficult to distinguish from Ewing sarcoma on imaging studies.
Most often, however, osteosarcoma is located in the metaphysis and usually has a rim of
bone formation, which is very uncommon in ES. Primary lymphoma of bone occurs in an
older age group, and is generally associated with less bone destruction than ES.
Chondrosarcoma is uncommon in this age group; furthermore, the soft tissue mass
usually contains calcifications.
EES and soft tissue PNETs must be distinguished from a variety of benign and malignant
soft tissue tumors.
Metastatic work-up — Guidelines for imaging studies in patients with EFT are available
from the Children’s Oncology Group Bone Tumor Committee (table 2) [26]:
The metastatic work-up should include a CT scan of the chest to evaluate the thorax for
metastatic disease. Criteria to guide the evaluation of suspected pulmonary metastases
are available from the Children’s Oncology Group that were adopted from the European
Ewing Tumor Working Group Initiative of National Groups Ewing Tumour Studies 1999
(EURO-E.W.I.N.G 99) (table 3) [27,28].
Radionuclide bone scan is recommended to evaluate the entire skeleton for the presence
of multiple lesions.
The utility of PET or integrated PET-CT for initial staging is unclear [29-34]. At least
three series note better sensitivity for PET over bone scan or other conventional imaging
modalities for detection of bone metastases [32,34,35]. However, one potential problem
is that because integrated PET-CT scanning usually scans from the neck through the
femurs, the bones are not all visualized as they would with a bone scan. PET has not yet
replaced radionuclide bone scan for initial staging at many institutions. In contrast to the
situation with bone metastases, the sensitivity of PET for detection of lung metastases
appears to be lower than that of thoracic CT [32,33], although integrated PET/CT is
superior to CT alone in this regard [36].
PET may have greater utility for monitoring the response to chemotherapy and/or
radiation therapy (particularly neoadjuvant chemotherapy), and in the postoperative
evaluation for possible recurrence [37]. Nevertheless, PET or PET/CT is increasingly used
for the initial staging of patients with Ewing sarcoma. Consensus-based guidelines from
the National Comprehensive Cancer Network recommend a PET scan and/or bone scan
for initial workup [38], and a baseline PET is recommended at presentation by the
Children’s Oncology Group, if the primary bone tumor is negative on bone scintigraphy
(table 2) [26].
Staging system — No commonly used staging systems exist for EFT as they do for other
solid tumors. Although there are tumor, node, and metastasis (TNM) staging systems for
primary tumors of both bone (table 4) [39,40] and soft tissue (table 5) [41] available
from the Musculoskeletal Tumor Society and the American Joint Committee on Cancer
(AJCC)/International Union Against Cancer (UICC), they are not in widespread use for
EFT. An obvious deficiency of these staging systems is that they do not specify the
primary site, which is one of the most important prognostic factors (see 'Prognostic
factors' below).
In addition, at least for soft tissue tumors, features of primary tumor classification in the
2002 edition (table 6) are not maintained in the 2010 version. Specifically, the inclusion
11
of both superficial and deep tumors within the same prognostic groups for tumors of the
same size eliminates a criterion that previously stratified patient risk, without supporting
data to suggest it is unnecessary.
Laboratory studies — Initial laboratory studies should include a complete blood count,
serum chemistries, and lactate dehydrogenase (LDH), which is a known prognostic factor
in patients with EFT (see 'Prognostic factors' below) [9,42,43]. For cases in which
neuroblastoma is in the differential diagnosis, urine catecholamine levels may be useful,
since they are elevated in neuroblastoma but normal in EFT.
Bone marrow aspirate and biopsy — Because of the predilection of EFT for spread to
bone marrow [44], some clinicians advocate bone marrow biopsy (at least unilateral) in
all patients to exclude widespread metastatic disease. Neither MRI nor bone scan are
sufficient to evaluate the possibility of bone marrow metastases. Although MRI is
sensitive to changes in the marrow, they are not specific. Any decrease in the marrow
fat content may alter the signal, creating difficulty in differentiating tumor from active
hematopoiesis.
Tumor biopsy — The considerations for appropriate biopsy of a soft tissue or bone mass
resemble those for other soft tissue and bone sarcomas. (See "Bone tumors: Diagnosis
and biopsy techniques".) The surgeon should be consulted before any biopsy is carried
out, and the procedure should be carefully planned to obtain adequate diagnostic tissue
without compromising a later operation, particularly the opportunity for limb salvage.
Biopsies should take place after the completion of imaging studies of the primary site,
and the surgeon, radiation oncologist, medical or pediatric oncologist, and pathologist
should review these studies in detail so that each member of the team is fully informed
of the diagnostic considerations.
Adequate amounts of tissue are necessary in order to provide sufficient diagnostic
material. The extensive pathologic evaluation that is often required to ascertain the
correct diagnosis within the group of "small round blue cell tumors" means that tissue is
usually needed for special studies, and these samples require special handling. This topic
is discussed in detail elsewhere.
The diagnosis is most often established by CT guided core-needle biopsy (image 3). If
only necrotic material is obtained on core biopsy, an open biopsy may be required. In
either case, specimens should be obtained for microbiology to rule out osteomyelitis (see
'Differential diagnosis' above). Fine needle aspiration biopsy is not acceptable as the only
diagnostic material, and should only be used to sample metastatic sites, or areas
suspicious for recurrence when the histologic diagnosis is known. These issues are
discussed in detail elsewhere.
PROGNOSTIC FACTORS — Several clinical and biologic characteristics can assist in
defining prognosis and directing the intensity of therapy [45]. These include the
presence or absence of metastases, primary tumor location and size, age, the response
to therapy, and the presence of certain chromosomal translocations.
Disease extent — The key prognostic factor in ES is the presence or absence of
metastases. Approximate five-year survival rates for patients with localized disease are
70 percent, while they average 33 percent for those who have overt metastases at
diagnosis.
The location of distant disease also impacts outcomes. In the European Intergroup
experience, the five year relapse-free survival rates for patients with localized and
metastatic disease at presentation were 55 and 21 percent, respectively [9] . Patients
with bone and lung metastases fared significantly worse than those with bone
metastases alone, who in turn, fared worse than those with isolated lung metastases.
Approximately 30 percent of patients with metastases limited to the lungs will survive
five years, as compared to only 10 percent of those with bone or bone marrow
involvement.
12
Patients with limited pulmonary metastases who are candidates for resection may have a
reasonable opportunity for cure.
Tumor site and size — For patients presenting with localized disease, those with axial
primary tumors (ie, pelvis, rib, spine, scapula, skull, clavicle, sternum) have a worse
treatment outcome than those with extremity lesions [9,46]. In one series, the five year
relapse-free survival rates were 40 versus 61 percent [9]. In addition, patients with
small primary tumors (<100 mL) fare better than those with larger tumors [9,47].
Fever, anemia, and elevated serum LDH all correlate with a greater volume of disease
and a poorer prognosis [9,20,42,43].
The poorer prognosis of large primary tumors, and those involving the pelvis and spine,
is at least partly attributable to the difficulty in achieving wide negative resection
margins, and higher rates of local failure after radiotherapy for large lesions. .)
Extraosseous as compared to osseous origin does not have an adverse influence on
survival. Origin has a significant adverse influence on outcome [11,48,49]. In fact, EFT
that arise in skin or subcutaneous sites have a generally favorable prognosis [49-51].
Response to therapy — Patients with apparently localized disease have only a 10 to 20
percent likelihood of cure if treated with surgery or radiotherapy alone; this is improved
dramatically when chemotherapy is added to treatment. (See "Treatment of the Ewing
sarcoma family of tumors".) Both the completeness of surgical resection and the
response to induction therapy are important prognostic factors. Patients who are left
with significant amounts of viable tumor in the resected specimen following neoadjuvant
chemotherapy do worse than those with minimal or no residual tumor [9,52-55]. These
topics are discussed in detail elsewhere. .)
Histology — In most but not all studies, the presence of neural differentiation (eg, as in
PNETs) does not have an adverse influence on survival [10,56-58].
Age — Older age has been linked to a poor prognosis in some reports [59-61], but not
others [62,63]. Younger children seem to have a better prognosis than older ones. As an
example, in one report, the five-year relapse-free survival was significantly better for
children younger than 10 compared to older children (86 versus 55 percent,
respectively) [60].
The situation for adults is less clear. Although many series have reported a less
favorable outcome in adults (particularly older adults [59]) as compared to children, a
greater tumor bulk in adults or use of lower doses of alkylating agents [64] may explain
some of these observations. Others have noted that adults fare as well as children,
particularly when full dose chemotherapy protocols are utilized [65].
Molecular findings — The EFT are characterized by distinct nonrandom chromosomal
translocations, which all involve the Ewing sarcoma (EWS) gene on chromosome 22.
These translocations result in the fusion of distinct genes on different chromosomes, and
these fused genes then encode hybrid proteins, which are thought to be involved in
tumorigenesis. (
At least 18 different structural possibilities for gene fusions have been reported in these
tumors. There are two sources of variability: the EWS fusion partner (eg, FLI1, ERG,
ETV1, E1A, or FEV) and the breakpoint locations within the genes. This molecular
heterogeneity may have some influence on the prognosis of EFT [66-69]. As an
example, a better outcome has been reported for patients with localized tumors
expressing the most common chimeric transcript (the so-called type I transcript in which
EWS exon 7 is fused to FLI1 exon 6, which is present in about 60 percent of cases)
compared to other fusion types [67,68]. However, more recent treatment protocols
appear to have eliminated prognostic differences based upon fusion type [70].
Studies evaluating the prognostic significance of other cytogenetic and molecular
alterations in EFT are limited. However, deletion of the short arm of chromosome 1p,
13
homozygous deletions of CDKN2A and p16/p14ARF, and p53 mutations have all been
associated with poor response to chemotherapy and a worse prognosis [66,71,72]. The
association of genetic variants of EFT with clinically significant features will require
further study.
Use of prognostic factors for treatment stratification — As noted previously, there is no
widely accepted formal staging system for EFT. One of the most important uses of a
staging system is to stratify patients for treatment purposes based upon expected
outcome. Because of the very powerful prognostic power of the presence of metastatic
disease, most studies in EFT have stratified patients by the presence or absence of
metastatic disease. Although the primary site (ie, extremity versus pelvis or spine) also
has prognostic significance, only a few studies have used site as the basis for
determining the aggressiveness of therapy.
Some investigators consider patients with localized disease, but who show features of
poor prognosis, as "advanced" or "high-risk", grouping them for the purposes of
treatment with others who have overt metastatic disease. The selection of treatment
based upon individual prognostic factors is referred to as risk-adapted therapy [52].
The data indicating prognostic differences among patients with varying fusion genes
raise the possibility that heterogeneity in the structure of chimeric transcripts may also
be used to define clinically distinct risk groups. As an example, a direct comparison
between treatment response and EWS fusion type may reveal a role of certain chimeras
in therapy resistance. However, prospective clinical studies are just beginning to be
performed to address this hypothesis. Inclusion of EWS fusion-type determination into
future clinical trials is appropriate.
SUMMARY — Ewing sarcoma (ES) and peripheral primitive neuroectodermal tumors
(PNET) comprise the same spectrum of neoplastic diseases known as the Ewing sarcoma
family of tumors (EFT), which also includes malignant small-cell tumor of the chest wall
(Askin tumor). Because of their similar histologic and immunohistochemical
characteristics and shared nonrandom chromosomal translocations, these tumors are
considered to be derived from a common cell of origin, although its histogenic origin is
debated. (See 'Introduction' above.)
EFT most often arises in the long bones of the extremities (predominantly the femur, but
also the tibia, fibula and humerus), and the bones of the pelvis. The spine, hands, and
feet are affected considerably less often. (See 'Primary sites' above.)
Patients with EFT typically present with localized pain or swelling of a few weeks or
months duration. Trauma, often minor, may be the initiating event that calls attention to
the lesion. Constitutional symptoms or signs, such as fever, fatigue, weight loss, or
anemia, are present in about 10 to 20 percent of patients at presentation. (See 'Signs
and symptoms' above.)
The goals of the initial evaluation are to establish the diagnosis, evaluate local disease
extent, and determine the presence and sites of metastatic spread. (See 'Staging
evaluation' above.)
The diagnostic work-up is usually initiated with a plain radiograph of the affected area.
EFT involving bone typically presents as a poorly marginated destructive lesion with a
permeative or “moth-eaten” appearance, most often associated with a soft tissue mass.
While CT scan better delineates the extent of cortical destruction and soft tissue disease,
definition of tumor size, local intraosseous and extraosseous extent, and the relationship
of the tumor to fascial planes, vessels, nerves, and organs is best achieved by magnetic
resonance imaging (MRI). (See 'Radiographic studies' above.)
The metastatic work-up includes a CT scan of the chest to evaluate the thorax for
metastatic disease, and a radionuclide bone scan to evaluate the entire skeleton for the
presence of multiple lesions. PET or PET/CT is increasingly used for the initial staging
14
and response assessment of EFT. Some clinicians advocate bone marrow biopsy (at least
unilateral) in all patients to exclude widespread metastatic disease.
A biopsy should be carefully planned to obtain adequate diagnostic tissue without
compromising a later operation, particularly the opportunity for limb salvage.
Several clinical and biologic characteristics can assist in defining prognosis and directing
the intensity of therapy. These include the presence or absence of metastases, primary
tumor location and size, age, the response to therapy, and the presence of certain
chromosomal translocations.
Treatment of the Ewing sarcoma family of tumors
15
16
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19
INTRODUCTION — Ewing sarcoma (ES) is a rare malignancy that most often presents as
an undifferentiated primary bone tumor; less commonly, it arises in soft tissue
(extraosseous Ewing sarcoma, EES). Both are part of a spectrum of neoplastic diseases
known as the Ewing sarcoma family of tumors (EFT), which also includes the more
differentiated peripheral primitive neuroectodermal tumor (PNET, previously called
peripheral neuroepithelioma, adult neuroblastoma, and Askin's tumor of the chest wall)
[1]. PNET can also present either in bone or soft tissue. Because these tumors share
similar histological and immunohistochemical characteristics and unique nonrandom
chromosomal translocations, they are considered to have a common origin [2-5].
In addition to their immunohistochemical and cytogenetic similarities, the EFT share
important clinical features. These include a peak incidence between the age of 10 and 20
(70 percent of affected patients are under the age of 20), a tendency towards rapid
spread to lungs, bone, and bone marrow, and responsiveness to the same treatments
that include chemotherapy and radiotherapy. As with osteosarcoma (the other major
sarcoma affecting bone), advances in multidisciplinary management over the past 30
20
years have resulted in a marked improvement in long-term survival. In data derived
from the Surveillance, Epidemiology and End Results (SEER) program of the National
Cancer Institute, five-year survival rates for patients with Ewing sarcoma rose from 36
to 56 percent during the periods 1975 to 1984 and 1985 to 1994 [6]. .)
Here we will discuss the management of the EFT. The epidemiology, pathology,
molecular genetics, clinical presentation, and diagnosis of these tumors, surgical
principles, indications for limb sparing surgery, indications for radiation therapy (RT),
and treatment of central (supratentorial) PNET tumors are discussed elsewhere. (See
appropriate topic reviews).
GENERAL TREATMENT PRINCIPLES — Despite the fact that fewer than 25 percent of
patients have overt metastases at the time of diagnosis, EFT is a systemic disease.
Because of the high relapse rate (80 to 90 percent) in patients undergoing local therapy
alone, it is surmised that the majority of patients have subclinical metastatic disease at
the time of diagnosis, even in the absence of overt metastases.
Chemotherapy can successfully eradicate these deposits, and modern treatment plans all
include chemotherapy, usually administered prior to and following local treatment. For
patients with localized disease, the addition of several months of intensive multiagent
chemotherapy to local therapy has had a dramatic impact on survival, and reported fiveand 10-year survival rates are now approximately 70 and 50 percent, respectively [716].
Even patients with advanced disease may be cured by multimodality therapy, although
the long-term survival rates are clearly lower than for localized disease [17].
Approaching a child who has metastatic EFT with noncurative intent is rarely, if ever,
appropriate, since it is not possible to predict a priori whose disease will be cured.
Because of these issues, clinicians experienced in the treatment of Ewing sarcoma must
direct the surgery and RT, and coordination with the medical oncologist is essential
[11,18,19].
Adult patients — Fewer than 5 percent of cases of EFT arise in adults over the age of 40.
There are no clinical trials that address treatment in adults; the vast majority of
published studies have specifically excluded older individuals. The available information
on treatment and prognosis is limited to six small single institution series of patients
over the age of 15 who were treated for EFT (table 1) [20-25].
It is difficult to conclude from these data whether treatment outcomes are different in
adults as compared to children. Early studies suggested worse outcomes for patients
>15 years of age as compared to those 11 to 15 or under the age of 10 at the time of
diagnosis (five-year relapse-free survival 43, 50, and 66 percent, respectively) [9].
However, only nine of the 331 individuals in this retrospective report were over the age
of 20 at the time of diagnosis.
The interpretation of studies addressing outcomes in adults is further complicated by the
fact that adults more often have pelvic or extraskeletal primaries, which are associated
with a poorer prognosis [20,22,23,25]. Despite this fact, adults who are treated with
modern adjuvant and neoadjuvant chemotherapy for localized EFT may do as well as
children [20].
Treatment of adults with EFT should be guided by the same general principles as are
used for younger individuals.
TREATMENT FOR LOCALIZED DISEASE
Chemotherapy — Most modern treatment plans utilize initial (induction or neoadjuvant)
chemotherapy followed by local treatment and additional chemotherapy. Reduction of
local tumor volume is accomplished in the majority of patients, and this can facilitate
resection. This is particularly important with regard to limb-sparing procedures for
extremity lesions. Since most treatment failures are attributable to systemic metastatic
21
disease, local therapy considerations should never compromise the administration of
effective systemic therapy.
Although patients with EES have been treated in the past on protocols for
rhabdomyosarcoma and have a similar response to multimodality therapy [13], both EES
and PNET respond to the same chemotherapy regimens as osseous ES, and these EFT
variants should be treated similarly [26-29].
Adjuvant treatment has evolved, largely due to the efforts of several cooperative
groups:



In the first Intergroup Ewing's Sarcoma Study (IESS-I), the combination of
vincristine, doxorubicin, cyclophosphamide and actinomycin D (VDCA or VACA)
was associated with a significantly better five-year relapse-free survival than
vincristine, actinomycin D, and cyclophosphamide (VAC) alone or VAC plus
adjuvant bilateral pulmonary irradiation (60 versus 24 versus 44 percent,
respectively) [9].
Increasing the doxorubicin dose intensity during the early months of therapy
further improved response, and in the second intergroup study (IESS-II), the fiveyear relapse-free survival rates using intermittent high dose four drug therapy
improved to 73 percent for non-pelvic lesions [30]. Because of concerns about
limiting the dose intensity of doxorubicin in regimens containing actinomycin D
[31], actinomycin D was omitted from most trials thereafter, with no adverse
impact on long-term outcome.
Adding alternating cycles of ifosfamide (I) and etoposide (E) to a VDC backbone
provides further benefit [14,32-34]. In the randomized IESS-III study, the
addition of I/E to VDCA was associated with significantly better five-year relapsefree survival compared to VDCA alone (69 versus 54 percent, respectively) in
patients with nonmetastatic, but not metastatic EFT or PNET [32]. A similar
outcome was shown with a slightly different IE/VDC regimen at Memorial Sloan
Kettering (four-year event-free survival 82 percent) [33] and with ifosfamide plus
VDCA by the Orthopedic Institute from Rizzoli (five-year event-free survival 79
percent) [14]. Earlier trials from the Rizzoli group had suggested no additional
benefit (five-year event-free survival rates 54 and 50 percent for VDCA plus I/E,
and for VDCA alone in two consecutive phase II trials) [35].
As a result of these data, current standard chemotherapy for EFT in the United States
includes vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and
etoposide (VDC/IE) (table 2) [32]. Typically, four to six cycles of chemotherapy are
given before local therapy. So long as there is any sign of response to preoperative
chemotherapy, additional cycles of the same treatments are given post-operatively, and
the total duration of therapy is approximately 48 weeks. Relief of pain, decrease in
tumor size, fall in LDH level, radiologic improvement, or evidence of necrosis in the
resected specimen all argue for continued chemotherapy for those who can tolerate its
sometimes considerable side effects.
Dose intense chemotherapy — The sensitivity of EFT to alkylating agents, which have a
steep dose-response curve, has prompted the evaluation of dose intense regimens in
patients with poor risk disease. The majority of patients in these studies have relapsed
or metastatic disease. The benefit of dose-intensive therapy for patients with poor risk
localized disease is unclear. Dose escalation did not improve outcomes in a COG trial
[36]. Furthermore, concerns for an increased risk of secondary malignancies in patients
receiving dose-intense therapy have tempered enthusiasm for this approach.
Another approach is “dose-dense” therapy as originally reported by Womer in 2000 [37].
A randomized trial by the Children’s Oncology Group (COG) randomized patients with
localized Ewing sarcoma family of tumors to receive VDC/IE every 21 or 14 days,
22
respectively. This trial demonstrated a significant event-free survival (EFS) benefit for
interval-compressed VDC/IE given every 14 days as compared to the same
chemotherapy given at 21-day intervals (five-year EFS 73 versus 65 percent) [38]. The
toxicity of both regimens was similar. The results of this trial suggest that interval
compressed therapy is preferred for front-line treatment of children with localized Ewing
sarcoma family of tumors.
Whether this approach is preferred in adults is unclear. In a preliminary report of this
COG randomized trial presented at the 2007 meeting of the Connective Tissue Oncology
Society, the benefit of interval compressed therapy seemed limited to patients aged 17
or younger [39]. These data have not yet been reported in a peer-reviewed publication.
Local treatment — Local control for EFT can be achieved by surgery, radiation, or both.
The choice of RT or surgery usually represents a tradeoff between functional result, and
the risk of secondary radiation-induced malignancy. Patients who lack a functionpreserving surgical option because of tumor location or extent may be recommended RT.
However, surgery is preferred for potentially resectable lesions and for those arising in
dispensable bones (eg, fibula, rib, small lesions of the hands or feet) for the following
reasons:



It avoids the risk of secondary radiation-induced sarcomas (see "Radiation therapy
for Ewing sarcoma family of tumors").
An analysis of the degree of necrosis in the excised tumor can permit refinements
in the estimate of prognosis.
In the skeletally immature child, resection may be associated with less morbidity
than RT, which can retard bone growth and cause deformity.
Although there are no randomized trials comparing surgery with RT for local control,
multiple retrospective series suggest superior local control and survival for surgery
compared to RT alone. However, selection bias may account for at least some of these
results (ie, smaller, more favorably situated peripheral tumors are more likely to be
resected while larger, axial lesions are radiated). Radiation dose and proper field
planning are also important factors in local control. The role of RT in the local
management of Ewing sarcoma is discussed separately.
The surgical principles that apply to resection of the primary tumor and reconstruction
are similar to those in patients with osteosarcoma and are discussed elsewhere.
However, there are three main differences between EFT and osteosarcoma:



EFT are radiosensitive while osteosarcoma is much less so.
EFT tend to occur in a younger population, where skeletal immaturity and concern
for radiation-induced growth inhibition must be considered.
EFT tend to arise in different areas of the long bones than osteosarcoma (the
diaphysis compared to epiphysis, (figure 1 and figure 2)) [40].
Adjuvant RT — RT is an essential component of therapy for patients undergoing
resection if the surgical margins are inadequate, although effective chemotherapy can
also reduce the risk of local failure in such patients [9,15]. RT is usually avoided in
patients without residual disease, to avoid exposing them to the risk of a radiationinduced malignancy.
TREATMENT FOR ADVANCED DISEASE — Patients with overt metastatic disease at
presentation have a significantly less favorable outcome than those with localized
disease. However, aggressive multimodality therapy can relieve pain, prolong the
progression-free interval, and cure some patients of their disease. In a review of 12
different series in which patients with metastatic EFT were predominantly treated with
chemotherapy, five year event-free and overall survival rates averaged 25 (range 9 to
23
55) and 33 (range 14 to 61) percent, respectively [7,11,41-50]. The small numbers of
patients in each series and the heterogeneity in location and extent of metastatic disease
probably accounts for these wide variations in outcome.
In particular, the site of metastatic disease is an important variable. For patients with
isolated lung and pleural metastases, cure rates up to 40 percent are reported with
multimodality therapy; for metastases involving bone or bone marrow, cure rates fall to
20 to 25 percent and for combined sites, to less than 15 percent [49]. Because it can be
difficult to predict which patients with metastatic disease will be long-term relapse-free
survivors [42], treatment should be administered with curative intent.
Several issues are pertinent to patients with metastatic EFT:





What is the optimal initial chemotherapy regimen?
Does dose escalation provide benefit in the initial treatment phase?
Is there a role for dose-intense therapy as consolidation after initial therapy?
Is RT to sites of metastatic involvement of any benefit?
How should control of the primary site be approached?
Chemotherapy — Patients with disseminated disease at diagnosis often respond well to
the same type of systemic chemotherapy as that used for localized disease. Standard
treatment options include conventional doses of doxorubicin plus cyclophosphamide,
vincristine, doxorubicin, and cyclophosphamide with or without actinomycin D (VDCA or
VDC), alternating courses of VDC and ifosfamide plus etoposide (I/E), regimens
incorporating higher doses of alkylating agents, and more intensive multiagent
combinations that generally require hematopoietic support. Unfortunately, there are few
conclusions that can be garnered from the published literature as to the superiority of
any of these regimens, because there are no randomized studies that directly compare
different regimens.
Conventional dose


Doxorubicin plus cyclophosphamide – The best results for doxorubicin and
cyclophosphamide were obtained by investigators at St. Jude using both agents
sequentially [43]. Ten of 18 patients (55 percent) receiving oral cyclophosphamide
(150 mg/m2 daily for seven days) followed by doxorubicin (35 mg/m2) who
delayed surgery and delayed lower dose limited field radiation were alive and
event-free at a median 47 months of follow-up. However, the same regimen
administered every three weeks resulted in a five year EFS of only 21 and 23
percent in two subsequent trials by the Pediatric Oncology Group (POG) and the
French Society of Pediatric Oncology [11,51].
VDCA – Results from two larger Intergroup Ewing's Sarcoma studies for patients
with metastatic disease (IESS-MD-I and II) using VDCA seem superior to these
results [50]. In the first trial (IESS-MD-I), conducted from 1975 to 1977, 53
eligible patients received VDCA with concomitant RT to areas of gross disease,
while in IESS-MD-II, conducted from 1980 to 1983, 69 eligible patients received
5-fluorouracil (5-FU) in addition to VDCA, and XRT was delayed until week 10
[50]. In both studies, the best response rate (complete and partial remissions
combined) was similar (73 and 70 percent in IESS-MD-I and II, respectively), as
was the response duration (approximately 30 percent of the patients on either
study survived five years or more), leading the authors to conclude that 5-FU was
not beneficial.
Contrasting results were noted by others, using the same VDCA regimen and RT
to the primary site with or without surgery [46]. Only 9 percent of patients with
metastatic disease were relapse-free at five years; however, RT was not
24

administered to sites of metastatic disease (pulmonary in 10 of 22 patients). (See
'Pulmonary metastases' below.)
VDC plus standard dose I/E – In contrast to data for nonmetastatic disease,
specific benefit for the addition of I/E to the VDC backbone has not been shown
for patients with metastatic disease at diagnosis [32,34,44,45,52,53].
Higher doses administered with conventional scheduling (ifosfamide 6 to 9 g/m2 and
doxorubicin 60 mg/m2), or interval compression of standard dose VDC/IE chemotherapy
using every two as compared to every three week cycling in conjunction with
hematopoietic growth factor support (as has been used for high-risk localized disease)
has resulted in possibly better results, particularly in patients with isolated pulmonary
metastases. Up to 40 percent of such patients are still alive and event-free at five years;
results are less favorable in patients with nonpulmonary metastases [37,41,45,49]. Lung
irradiation was used in the majority of patients in these trials. (See 'Dose intense
chemotherapy' above.)
High-dose chemotherapy — Because of the failure to cure the majority of patients with
metastatic disease at diagnosis and the steep dose response curve that exists for
alkylating agents, more intensive therapies incorporating high-dose chemotherapy with
hematopoietic cell support (HDT) have been studied.


Induction phase – Initial treatment with very high doses of chemotherapy with
or without total body irradiation and autologous hematopoietic stem cell support
has been reported to improve survival in some small nonrandomized series [5459] but not others [60-65]. Variability in the definition of high risk patients and in
the regimens used makes it difficult to compare results and arrive at any firm
conclusions regarding the benefit of this approach. Allogeneic stem-cell
transplantation offers no advantage over autologous transplantation [60] and has
a higher complication rate. (See 'Secondary malignancies' below.)
Consolidation phase – Another approach is to administer HDT as consolidation
following standard dose chemotherapy and optimal local treatment. A number of
small trials which include subsets of patients with EFT suggest benefit
[45,56,58,66-69], but this is not universal. The following represents the range of
findings:
Some of the most favorable results were reported in a prospective study of 97
unselected patients with newly diagnosed metastatic EFT/PNET, who underwent
conventional chemotherapy; those with a complete or partial response (n = 75) went on
to HDT/autologous transplant [70]. The five-year event-free survival rate after HDT was
47 percent; for those with isolated pulmonary metastases it was 52 percent.
On the other hand, disappointing results were shown for patients with metastatic EFT in
a large prospective trial conducted by Children's Cancer Group, in which 32 patients with
bone or marrow metastases received induction therapy (three cycles of VDC alternated
with IE) and surgery and/or RT for local control (and RT to sites of metastatic disease),
followed by TBI over three days, high-dose melphalan and etoposide, and peripheral
blood stem cell reinfusion [71]. The two-year event-free survival rate was only 16
percent, suggesting that this approach did not represent a therapeutic advance.
Similar disappointing results (five-year survival 21 percent) were noted among patients
with metastatic EFT reported by the European Bone Marrow Transplant Solid Tumor
Registry [72].
Thus, given the mixed results seen to date in patients who present with advanced
disease, high-dose chemotherapy with autologous stem cell transplantation remains an
investigational approach and should be considered only in the context of a clinical trial.
The ongoing EURO-EWING 99 trial is comparing high-dose chemotherapy versus
25
standard approaches in a variety of clinical settings (including patients with metastatic
disease at diagnosis and those with localized tumors and a poor initial histologic
response to induction chemotherapy) [73]. It is hoped that the results will provide some
insight as to which patients benefit from this approach.
Secondary malignancies — Although the majority of EFT survivors have some late effects
of therapy [74], an additional detrimental impact of high dose chemotherapy regimens is
the risk of secondary myelodysplasia (MDS) and leukemia [60,65,75,76]. This was
illustrated in a report from the Children's Oncology Group of 578 children with EFT/PNET
who were treated with three different regimens over a six-year period [75]. Overall, 11
children developed secondary MDS/AML, and the cumulative risk was significantly higher
among children treated with a regimen incorporating higher doses of doxorubicin,
cyclophosphamide, and ifosfamide as compared to those receiving standard dose VDCA
with or without IE (11, 0.9, and 0.4 percent at five years, respectively).
Surgery and radiation therapy — Outcomes are best when chemotherapy is combined
with radiation and sometimes resection of sites of gross metastatic disease
[50,61,77,78]. This multimodality approach has been most successful for patients with
limited pulmonary metastases.
Pulmonary metastases — Patients with a limited number of lung metastases do not
share the same dismal prognosis of metastatic disease at other sites (ie, bone or bone
marrow), because of the ability to accomplish wide resections both easily and
repeatedly. In such patients, chemotherapy is a necessary component of therapy, and
between 20 and 40 percent five-year survival can be achieved [49,79,80].
For patients with more advanced pulmonary disease at diagnosis, supplemental radiation
may provide benefit, even after a complete response to chemotherapy. Most of the
available data supporting radiation in this setting are from nonrandomized series, and
patient selection factors confound interpretation of the data. Nevertheless, low dose
bilateral lung irradiation (15 to 20 Gy, in daily 1.5 to 2.0 Gy fractions) can control gross
metastatic disease in the lungs without significant pulmonary toxicity and is usually
recommended after chemotherapy, despite the paucity of data. This topic is discussed in
detail elsewhere.
Bone and soft tissue metastases — Patients with solitary or circumscribed bone or soft
tissue lesions can be irradiated at those sites, usually to doses of 45 to 56 Gy, in
addition to irradiation of the primary tumor. However, the likelihood of long-term
survival is considerably lower than for patients with isolated pulmonary metastases.
Local control — Local control can pose major issues, even for patients with metastatic
disease. The complete response rate to chemotherapy can be increased with subsequent
radiation therapy or selected excision for all sites of evident disease; however, long-term
relapse-free survival is still only achieved in the minority of patients [42].
Diffuse metastatic disease can make it difficult to justify a large resection. In selected
patients, resection may be reconsidered if chemotherapy results in significant volume
reduction, particularly if areas of small volume metastatic disease are also amenable to
surgical resection. On the other hand, radiation therapy, which is more often considered
in patients with metastatic disease, will usually provide adequate local control with
acceptable morbidity. If substantial amounts of bone marrow will need to be included in
the radiation treatment volume, then radiating the primary tumor and/or metastases
may be delayed until the end of systemic therapy to avoid interfering with
chemotherapy.
POSTTREATMENT SURVEILLANCE — For all EFT of bone or soft tissue, there are no
prospective data that address the appropriate schedule or selection of tests for
surveillance after initial treatment for localized disease. Consensus-based guidelines
from the National Comprehensive Cancer Network (NCCN) and from the Children's
Oncology Group recommend physical examination, a complete blood count, chest
26
imaging, and local imaging of the primary site every three months for two years, every
four months for year three, every six months for years 4 and 5, and annually thereafter
(table 3) [81,82]. The appropriate duration of follow-up is unknown; however, the vast
majority of recurrences are observed within 10 years.
Physicians performing posttreatment surveillance must be cognizant of concerns for
radiation exposure and the risk for secondary malignancies, particularly in younger
individuals.
RECURRENT DISEASE — The majority of relapses occur within five years, but late
relapse is not uncommon [83-85]. In a report from the Childhood Cancer Survivor
Study, the 20-year cumulative incidence of a late recurrence among five-year survivors
of Ewing sarcoma was 13 percent [85]. For this reason it is advisable that patients be
followed for the potential of late relapse indefinitely. There are no definite protocols for
this, but the authors suggest that an examination and chest radiograph be performed
every two to five years for the life of the patient. Symptoms at the primary site or
elsewhere should raise concern and be appropriately investigated.
In general, survival after an early relapse is poor, with few survivors among those who
relapse within two years of therapy. In contrast, up to 15 to 20 percent of those who
relapse later may survive long-term [86,87]. Other prognostic factors for death in
patients with recurrent Ewing sarcoma include recurrence at combined local and distant
sites, and an elevated lactate dehydrogenase (LDH) at initial diagnosis [86,87].
Evaluation — Patients with a suspected recurrence should undergo evaluation of both the
primary site and for the presence of metastatic disease before a treatment plan is
formulated. The majority of patients with a local recurrence have either gross or
microscopic metastatic disease.
The documentation of a local recurrence can be difficult. The interpretation of irradiated
areas on imaging studies can be challenging, and soft tissue masses may represent
residual fibrosis rather than recurrent tumor. The evaluation of intraosseous sites is even
more difficult, since the response to prior therapy and variability in reossification
complicates the interpretation of radiographic studies. Progressive cortical destruction or
increasing lytic areas suggest local recurrence, as do bone scans that demonstrate
increased uptake. Bone biopsies are associated with local morbidity (ie, wound
complications and bone fracture) and are subject to a high rate of sampling error.
Treatment — Although the prognosis for patients with recurrent disease is poor, some
patients can be successfully salvaged [88,89]. The sites of recurrence, prior treatment,
and relapse-free interval affect remaining treatment choices. Management of a local
recurrence usually includes surgery (and possibly an amputation if the local recurrence
involves an irradiated extremity), radiotherapy, or both. Radiation therapy to bone
lesions usually provides pain relief, while surgery can cure some cases with limited
isolated lung metastases [79].
The likelihood of response to chemotherapy retreatment increases with longer duration
of disease control. Late relapsers do better than those who progress during initial
chemotherapy (primary refractory disease). In one report, 26 of 34 patients relapsing off
treatment attained a second remission compared to none of 18 who had primary
refractory disease [90]. Twelve of the 26 responders remained in second remission for
periods up to 19 years. The role of intensive myeloablative regimens is unclear, although
a few patients may be salvaged [59].
The choice of chemotherapy regimen depends upon initial treatment and the duration of
the relapse-free interval. Patients relapsing after a disease-free interval off
chemotherapy may respond again to the same agents. Patients who have not previously
received ifosfamide and etoposide may respond to this regimen [91]. At our center, the
regimen used by the third Intergroup Ewing's Sarcoma Study is typically chosen [32],
but doses are escalated as tolerated if there is not a prompt response. Most patients
27
with relapsed disease will be treated at centers that have their own individualized
approach.
Clinical trials investigating new agents (eg, monoclonal antibodies and small molecule
inhibitors targeting the insulin-like growth factor-I (IGF 1)-receptor [92-95]) and new
combinations (eg, irinotecan plus temozolomide [96]) warrant consideration, since
completion of these trials is crucial to improving outcomes. Although most of the
available phase I or I/II studies do not specifically target advanced EFT and most phase
III studies target early rather than advanced stage or recurrent disease, opportunities
remain [97]. The National Cancer Institute clinical trials website provides information
about ongoing clinical trials
Future therapies will probably emerge from the exploitation of the molecular targets
accompanying the unique genetic alterations that are held responsible for these
malignancies [17,98].
COMPLICATIONS IN LONG-TERM SURVIVORS — Although the survival of patients with
Ewing sarcoma has improved steadily since the 1970, long-term survivors have
considerable future health risks [16,99-102]. These include second malignancy,
pathologic fractures, other radiation-associated complications (wound complications,
pulmonary fibrosis, neuropathy, limb leg discrepancy, femoral head necrosis), and
chemotherapy-related complications (renal insufficiency, bowel toxicity, neuropathy, and
cardiomyopathy) [99].
The health status of long-term (≥5 years) survivors was addressed in a cohort study of
568 individuals who were diagnosed with Ewing sarcoma before age 21 from 1970 to
1986, including a subset of 403 patients who were participating in the Childhood Cancer
Survivor study [102]. Cumulative mortality among all survivors was 25 percent at 25
years after diagnosis, and the cumulative incidence of secondary malignancy was 9
percent. Disease progression/recurrence accounted for 60 percent of all deaths, while
other causes included secondary neoplasms, cardiac disease, other medical causes, and
pulmonary disease. The cumulative mortality attributed to subsequent malignant
neoplasms and cardiopulmonary disease potentially attributed to treatment was 8.3
percent at 25 years. In addition, compared with their siblings, survivors had significantly
higher rates of severe, disabling, or chronic health conditions, significantly lower fertility
rates, and higher rates of self-reported moderate to extreme adverse health status.
It is anticipated that the adoption of tailored radiation ports in the last 15 years (as
opposed to whole bone ports used in the period 1960 to 1980) and use of lower and
risk-adopted radiation therapy doses as well as an appreciation of the rise in radiationinduced second malignancy risk with doses above 60 Gy will reduce the risk of late
effects.
Nevertheless, the relatively high complication rates seen with many of these earlier
treatment approaches, the delayed nature of many of the complications, and the
possibility that trends in chemotherapy intensification may alter the pattern of secondary
malignancies [100] underscore the need for long-term follow-up.

SUMMARY


Patients with Ewing sarcoma or another of the Ewing sarcoma family of tumors
(EFT) require referral to centers that have multidisciplinary teams of sarcoma
specialists. With rare exception, systemic combination chemotherapy and
definitive local therapy is required in all patients, and care should be coordinated
among the medical oncologist, surgeon, and radiation therapist.
In most cases, treatment will begin with chemotherapy. The primary tumor is then
most often treated with surgical resection. Radiation, or a combination of radiation
28


and surgery, is reserved for cases in which negative margins cannot be achieved
while still preserving function. The choice between surgery and RT is dictated by
the age of the patient, the location and size of the primary, and functional as well
as long-term consequences of therapy (ie, radiation-induced growth inhibition or
secondary malignancy). Following local treatment, chemotherapy is usually
continued, typically for several months. Thus, the total duration of therapy ranges
from 10 to 12 months.
Patients with clinically detectable metastatic disease at presentation, and those
who relapse after initial therapy also require multimodality therapy. All patients
with advanced disease should be approached with potentially curative treatment.
Up to 40 percent of patients with limited pulmonary metastatic disease who
undergo intensive chemotherapy and pulmonary resection with or without
radiation therapy may be long-term survivors. The prognosis for other subsets of
patients with advanced disease is less favorable.
There is no conclusive evidence that high-dose therapy with or without
hematopoietic stem cell infusion at any point during treatment is beneficial for
patients with poor-risk localized and metastatic EFT. Most patients with advanced
or recurrent disease need new approaches to improve outcomes, and participation
in clinical trials should be encouraged. Long-term follow-up is needed following
therapy because disease relapse, treatment-related complications, and second
malignancies all occur beyond five years after treatment is initiated.
Radiation therapy for Ewing sarcoma family of tumors
29
INTRODUCTION — Ewing sarcoma (ES) is a rare malignancy that most often presents as
an undifferentiated primary bone tumor; less commonly, it arises in soft tissue
(extraosseous Ewing sarcoma, EES). Both are part of a spectrum of neoplastic diseases
known as the Ewing sarcoma family of tumors (EFT), which also includes the more
differentiated peripheral primitive neuroectodermal tumor (PNET, previously called
peripheral neuroepithelioma, adult neuroblastoma, and Askin's tumor of the chest wall)
[1]. PNET can also present either in bone or soft tissue. Because these tumors share
similar histological and immunohistochemical characteristics and unique nonrandom
chromosomal translocations, they are considered to have a common origin.
EFT also share important clinical features, including a peak incidence between the age of
10 and 20, a tendency towards rapid spread to lungs, bone, and bone marrow, and
responsiveness to the same chemotherapeutic regimens and radiotherapy (RT). Because
relapse rates are high in patients undergoing local therapy alone (80 to 90 percent), it is
surmised that the majority have subclinical metastatic disease at the time of diagnosis,
even in the absence of overt metastases. The routine administration of intensive
multiagent chemotherapy, which can eradicate these deposits, has had a dramatic
impact on outcomes. Five-year survival rates for patients with Ewing sarcoma in the
United States rose from 36 to 56 percent during the periods 1975 to 1984 and 1985 to
1994 [2].
Local control at the primary tumor site can be accomplished by surgery, RT, or both. The
choice of modality usually represents a tradeoff between functional result and treatmentrelated morbidity, particularly the risk of a secondary radiation-induced malignancy.
Although modern treatment protocols emphasize surgery for optimal local control,
30
patients who lack a function-preserving surgical option because of tumor location or
extent, and those who have clearly unresectable primary tumors following induction
chemotherapy are appropriate candidates for RT.
Since more than 90 percent of patients with EFT have either detectable or subclinical
metastases at diagnosis, local therapy, if delivered correctly, is probably not the critical
event in determining survival. However, if local therapy is delivered poorly or given in
such a way that it compromises the delivery of adequate chemotherapy, survival can be
greatly compromised. Moreover, local failure is associated with a very poor survival
outcome [3].
Here we will discuss the role of radiation therapy in the local management of the EFT.
Epidemiology, pathology, molecular genetics, clinical presentation, and diagnosis of
these tumors, as well as surgical principles and the use of chemotherapy are presented
elsewhere. Central (supratentorial) PNET tumors are also discussed elsewhere.
RT FOR LOCAL CONTROL OF THE PRIMARY
General principles — The radiosensitivity of Ewing sarcoma was first noted in the original
description by James Ewing [4]. Historically, RT was preferred over surgery because of
less acute morbidity, acceptable rates of local control (50 to 77 percent), and poor longterm prognosis, largely due to distant dissemination in the absence of effective
chemotherapy [5].
The introduction of multiagent chemotherapy into the management of EFT in the 1970s
led to an increase in cure rates as well as higher local control rates after RT (72 to 90
percent) [6-11]. As more children survived their tumors, balancing long-term local
disease control with long-term functional results assumed greater importance. The
recognition of late effects of RT (eg, fracture, second malignant neoplasms) as well as
improvements in surgical techniques resulted in a shift towards the use of surgery rather
than RT.
Current protocols tailor local treatment to the individual patient with the goal of
maximizing local tumor control while minimizing treatment-related morbidity. In general,
patients are selected for local therapy in such a way that they are treated with surgery
or RT but not both, since the combined use of surgery and RT places patients at risk for
morbidity from both modalities [12]. However, there is a role for combined therapy in
some circumstances, particularly for large tumors (particularly involving the pelvis), and
for cases in which resection margins are positive or close. (See 'Adjuvant RT' below.)
RT versus surgery — Both surgery and RT represent effective local treatment for Ewing
sarcoma. There are no randomized trials which directly compare both modalities, and
their relative roles continue to be debated. Contemporary treatment guidelines
emphasize surgical resection as the local control modality of choice if it is believed that
the lesion can be resected with negative margins, without excessively morbidity, and
with the expectation of a reasonable functional result. Surgery is preferred for potentially
resectable lesions, and for those arising in dispensable bones (eg, fibula, rib, small
lesions of the hands or feet) for the following reasons:



It avoids the risk of secondary radiation-induced sarcomas.
An analysis of the degree of necrosis in the excised tumor can permit refinements
in the estimate of prognosis.
In the skeletally immature child, resection may be associated with less morbidity
than radiation, which can retard bone growth and cause deformity.
Thus, in most cases, the decision to use RT for treatment of the primary site is made
only after review of the potential surgical options for a given lesion. Patients who lack a
function-preserving surgical option because of tumor location or extent, and those who
31
have clearly unresectable primary tumors following induction chemotherapy are
appropriate candidates for RT.
Influence of tumor site — When considering the local control strategy for an individual
patient, the need to attain complete tumor eradication must be weighed against the twin
goals of maximizing function and minimizing long-term morbidity. Although treatment
decisions must be individualized according to the expected deficits from surgical
resection at any site, the following generalizations can be made regarding the influence
of tumor site on the choice of local treatment (see "Bone sarcomas: Preoperative
evaluation, histologic classification, and principles of surgical management"):




It is generally agreed that surgery is preferred for lesions arising in dispensable
bones (eg, fibula or rib).
Tumors affecting the long bones of the leg, distal humerus, or ulna can usually be
resected and reconstructed using intercalary techniques (allografts, autografts, or
metallic prostheses) or joint replacement, depending on tumor location.
On the other hand, primary tumors involving the proximal humerus and upper
scapula may be best treated with RT, since limb reconstruction is difficult and
shoulder morbidity may be substantial.
Patients with lesions of the skull, facial bones, or vertebrae are often candidates
for nonsurgical treatment because of the difficulty in achieving negative margins
without substantial functional deficit [13].
A number of series report better results with surgery over RT alone for pelvic bone
tumors [14-18], but this is a controversial area. Surgical treatment for pelvic
sarcomas, which are often bulky, is challenging. Lesions of the iliac wing, ischium,
or pubis can usually be resected after a good response to chemotherapy without
substantial functional morbidity. For tumors of the periacetabular region and those
that cross the sacroiliac joint, there is less enthusiasm for surgical resection given
the significant resulting functional deficit.
Outcomes — Because no randomized trial has directly compared both modalities, only a
relative comparison can be made from retrospective reports and the prospective trials
that have mainly tested different multiagent chemotherapy regimens.
In many retrospective series, rates of local control and survival are superior after
surgery compared to RT alone [9,10,16,19-30]. However, larger cooperative group
studies have failed to reflect this advantage, and selection bias likely accounts for at
least some of these results. Smaller, more favorably situated peripheral tumors are more
often resected while larger, axial lesions (which have a higher rate of local failure in
most series and a poorer prognosis overall [9,20,21,31]) are referred for RT.
Furthermore, RT delivery techniques may also have contributed to poorer outcomes in
early series. As an example, in the Cooperative Ewing's Sarcoma Study (CESS)-81 trial,
relapse-free survival (RFS) for patients undergoing irradiation of the primary site in the
initial phase of the trial was only 55 percent, significantly lower than for surgically
treated patients [22]. On review, the high rate of local failure after RT alone (50
percent) was attributed to geographic "miss". After a quality assurance program was
initiated, local control rates improved significantly, and RFS increased to 80 percent. In a
subsequent study, CESS-86, which included central quality assurance, the five-year RFS
rates following chemotherapy plus either RT or surgery were 67 and 65 percent,
respectively [6]. The importance of RT dose and field planning to local control is
discussed below.
Several studies support the adequacy of RT alone for local control:

One retrospective report included 39 patients who were treated between 1975 and
1991 at two Boston hospitals with multiagent chemotherapy and varying
32

combinations of surgery and RT [32]. Twenty had RT alone, 16 both surgery plus
RT, and 3 surgery alone. Despite the use of combination chemotherapy, five-year
disease-free survival (DFS) was only approximately 30 percent, emphasizing the
high-risk nature of these mainly axial lesions. However, local control rates were
similar among patients treated with RT alone or surgery (85 and 84 percent,
respectively).
Another case series included 60 patients treated for EFT at Memorial Sloan
Kettering between 1990 and 2004; 31 underwent RT as the sole modality for local
control, the remainder in conjunction with surgery [33]. The relatively poor
prognosis of this group is reflected by the fact that most were centrally located
tumors (spine, pelvis, proximal extremities), 52 percent were ≥8 cm in size, and
one-third were metastatic at diagnosis.
Nevertheless, with a median follow-up of 41 months, DFS and overall survival rates for
patients with nonmetastatic disease at presentation were 70 and 86 percent
respectively. There were only nine local recurrences, five of which developed in patients
who presented with overt metastases. The three-year actuarial local control rates for the
entire group and those undergoing definitive RT alone were 77 and 78 percent,
respectively. The presence of overt metastases emerged as the only significant adverse
prognostic factor for local control, a finding that has been confirmed by others [9,34].
Long-term treatment-related complications were minimal, and there were no secondary
malignancies. (See 'Late effects' below.)

The relationship between local control modality (surgery, RT, or both) and the
subsequent risk for local failure was examined in a subgroup of 75 patients
treated for nonmetastatic pelvic EFT in US Intergroup study 0091 (IESS III), a
randomized comparison of VACA (vincristine, doxorubicin, cyclophosphamide, and
dactinomycin) with or without alternating IE (ifosfamide plus etoposide) [35].
Choice of local control modality was left to the treating clinicians; 12 underwent
surgery, 44 received RT, and 19 received both.
The rates of five-year, event-free survival (EFS) and cumulative incidence of local failure
(as any component of first failure) in the entire group were 49 and 21 percent,
respectively. There was no significant difference in either endpoint according to tumor
size (<8 versus ≥8 cm) or choice of local control modality. However, there was a trend
toward improved local control in patients receiving VACA/IE as compared to VACA alone
(cumulative incidence of local failure 11 versus 30 percent; p = .06), which was present
regardless of the local control modality.
Although not a universal finding [6,33,36], many studies suggest that smaller rather
than larger tumors are more likely to be locally controlled after RT alone [9,15,19,3741]. As an example, in a report of 100 patients with localized Ewing sarcoma of bone,
local control rates were significantly higher after RT for the 14 lesions that were ≤100
cm3 in volume compared to larger lesions (93 versus 60 percent, respectively) [38].
Adjuvant RT — RT is usually not recommended for patients who undergo a complete
resection in order to avoid exposing them to the risk of a secondary malignancy.
Although indications for postoperative RT are not firmly established, the following are
common scenarios in which RT is recommended in conjunction with surgery for EFT
[42]:

For bulky tumors in difficult sites such as the pelvis, combined surgery and RT
might allow for a more limited surgical procedure, better functional outcome, and
enhanced local control as compared to single modality therapy [9,15,33,43]. RT
can be given either preoperatively or postoperatively, based upon institutional
protocols and experience.
33



Patients who are left with macroscopic amounts of viable tumor in the resected
specimen following neoadjuvant chemotherapy have worse survival than those
with minimal or no residual tumor [10,20,37,41,44-47]. There are no data
evaluating the effectiveness of adjuvant RT in this situation; however, it can be
considered if there is concern about the adequacy of the margins.
The role of adjuvant thoracic irradiation is unsettled. The United States Intergroup
Ewing's Sarcoma Study (IESS)-I trial showed that bilateral whole lung irradiation
was an effective adjuvant treatment for patients with localized EFT, but prolonged
follow-up favored four-drug multiagent chemotherapy [8]. Prophylactic whole lung
irradiation has not been studied in any subsequent trial, and no studies have used
it in addition to modern combination chemotherapy regimens [48], except in
patients with lung metastases at diagnosis.
On the other hand, adjuvant hemithorax irradiation improves outcomes in patients
with high-risk chest wall primary tumors (close or involved margins, initial pleural
effusion, pleural infiltration, and intraoperative contamination of the pleural space)
[49,50].
Postoperative RT is usually recommended if there is residual microscopic or gross
disease after surgery, or inadequate surgical margins. Inadequate resection
margins (ie, a marginal or intralesional resection (table 1) are associated with a
worse outcome as compared to radical or wide resection) [27,51].
The impact of surgical margins on outcome was described in a series of 244 patients
who were enrolled in CESS studies for localized EFT and underwent surgery as a
component of local therapy [27]. Ninety-four had definitive surgery alone, 131 received
postoperative RT, and 19 had preoperative RT. Surgical margins were radical, wide,
marginal, and intralesional in 29,148, 39, and 28 patients, respectively. The local and
combined (local plus systemic) relapse rate was significantly lower after a complete
resection (radical or wide) with or without RT than after an incomplete resection
(marginal or intralesional) with or without RT (5 versus 12 percent, p = 0.045).
However, the relapse rate was not significantly lower in patients who received RT after
incomplete surgery compared to those who did not (12 versus 14 percent). Ten-year
survival rates for the cohorts undergoing radical, wide, marginal, and intralesional
resection were 58, 65, 61, and 71 percent, respectively; the differences were not
statistically significant.
However, the data to support the benefit of RT in this setting are surprisingly scant, and
conflicting:
The efficacy of combined surgery and RT was evaluated in a retrospective series of 39
patients treated for localized EFT at the St Jude Hospital between 1978 and 2001 [52].
With combined local therapy, local control rates were excellent, even for patients with
positive surgical margins (eight-year local failure rates for patients with positive and
negative surgical margins were 17 and 5 percent, respectively), and the corresponding
overall survival rates were 71 and 94 percent, respectively.
On the other hand, a lack of benefit for adjuvant RT was suggested in a large singleinstitutional retrospective series, in which the addition of moderate dose adjuvant RT (45
Gy) to patients with inadequate margins did not seem to improve local control or overall
disease-free survival. The authors concluded that patients for whom inadequate margins
were anticipated at the time of preoperative evaluation might be better treated by full
dose radiotherapy alone [53].
Summary — Although most clinical protocols for EFT emphasize surgery for treatment of
the primary lesion, RT is an effective option for local control in patients who lack a
function-preserving surgical option because of tumor location or extent, and those who
have clearly unresectable primary tumors despite induction chemotherapy. If a tumor
34
appears to be categorically unresectable following induction therapy, debulking surgery
should be avoided and the patient referred for definitive RT.
Indications for adjuvant RT in patients who have undergone resection of a EFT include:




Bulky tumors in difficult sites (eg, the pelvis); in this setting, RT can be given
either preoperatively or postoperatively, based upon institutional protocols and
experience. Our own preference, when positive margins are considered likely, is to
use preoperative irradiation.
If there is residual microscopic or gross disease after surgery, or inadequate
surgical margins
Patients who are left with significant amounts of viable tumor in the resected
specimen and less than wide margins following neoadjuvant chemotherapy
Adjuvant hemithorax irradiation is indicated in patients with high-risk chest wall
primary tumors (close or involved margins, initial pleural effusion, pleural
infiltration, and intraoperative contamination of the pleural space)
RT FOR METASTATIC DISEASE — Patients with overt metastatic disease at presentation
have a significantly less favorable outcome than do those with localized disease.
However, aggressive multimodality therapy can relieve pain [54], prolong the
progression-free interval, and provide long-term relapse-free survival (and possible
cure) in some patients.
Management of the primary site — Local control can pose major issues, even for patients
with overt metastatic disease. In such cases, it may be difficult to justify a large
resection of the primary site because of the poor long-term prognosis [15,55]. However,
resection may be reconsidered in selected patients if chemotherapy results in significant
volume reduction, particularly if areas of small volume metastatic disease are also
amenable to surgical resection.
On the other hand, RT can provide adequate local control with acceptable morbidity
[6,21,22,56]. If substantial amounts of bone marrow will need to be included in the
field, RT may be delayed until the end of systemic therapy to avoid interfering with
chemotherapy.
Pulmonary metastases — Patients with a limited number of lung metastases do not
share the same dismal prognosis of metastatic disease at other sites (ie, bone or bone
marrow), because of the ability to accomplish wide resections both easily and
repeatedly. Chemotherapy is a necessary component of therapy. In highly selected
patients, between 20 and 40 percent five-year survival can be achieved [57-60].
Retrospective reports from large cooperative groups suggest that the addition of lowdose bilateral lung irradiation (15 to 20 Gy) benefits patients with EFT presenting with
pulmonary metastases, even if all lesions are resected or completely respond to
chemotherapy [8,22,48,57,59-63]. In the CESS and EICESS trials, the rate of pulmonary
relapse was reduced by 50 percent over that for patients who did not undergo lung RT,
and this was accompanied by improvements in event free survival (from 19 to 40
percent in one report [60]) as well [59,60]. However, most of the available data
supporting benefit from RT in this setting are from nonrandomized series, and patient
selection factors confound interpretation of the data. There are no randomized trials that
confirm the benefit of this approach.
Despite the lack of controlled trials, low-dose bilateral lung irradiation (15 to 20 Gy, in
daily 1.5 to 2.0 Gy fractions) with a focal boost dose to a total of 40 to 50 Gy to large
deposits is commonly recommended for patients with pulmonary metastases who have
had a good response to chemotherapy. Long-term toxicity appears to be acceptable.
This was shown in a retrospective analysis of data from the prospectively performed
European Intergroup Cooperative Ewing's Sarcoma Study, in which pulmonary function
tests were available for 37 patients who were treated with whole lung irradiation (with or
35
without a boost) [64]. At a median follow-up 25 months, none, mild, moderate or severe
pulmonary complications were seen in 43, 29, 21 and 7 percent of patients treated with
whole lung irradiation without further boost. Slightly higher complication rates were
reported in patients who had an additional radiation boost or surgery to the thorax in
addition to RT.
Bone and soft tissue metastases — Patients with solitary or circumscribed bone or soft
tissue lesions fare less well in the long run than those with isolated pulmonary
metastases. Nevertheless, with aggressive multimodality therapy, perhaps 10 percent
will be long-term survivors. For patients with solitary or limited bone metastases, RT is
delivered to metastatic lesions (doses of 40 to 50 Gy) in addition to irradiation of the
primary tumor.
Total body irradiation — Total body irradiation (TBI) or sequential hemibody irradiation
as a component of systemic treatment for patients with high-risk features or metastatic
disease at presentation has been investigated in a limited fashion at a few institutions
[36,65-67]. Unfortunately, the results of these trials have been disappointing; TBI has
not contributed significantly to the control of metastatic disease. This approach should
not be considered at present outside of the context of a clinical trial.
The use of TBI as a conditioning regimen prior to high-dose chemotherapy and
hematopoietic stem cell transplantation for patients with poor-risk disease is discussed
elsewhere.
RADIATION TREATMENT PLANNING — Because of the relative rarity of EFT, the potential
for cure, and the importance of minimizing late side effects from therapy (see below),
radiation therapy (RT) must be administered by radiation oncologists who are familiar
with the optimal treatment techniques. RT is currently planned using CT simulation to
allow for three dimensional (3-D) conformal treatment planning. Biopsy sites and
surgical scars should be marked with radioopaque markers to allow inclusion into the
target volume when deemed appropriate.
Treatment volume — Historically, Ewing sarcoma was thought to be a tumor of the bone
marrow. Consequently, RT was administered to the entire marrow cavity of the involved
bone, and the site of gross disease boosted to a higher dose. However, an analysis of
the RT fields for the Intergroup Ewing's Sarcoma Study Group (IESS) trial I suggested
that most relapses were at the site of initially bulky tumor [7,8,68]. Subsequent efforts
were geared toward reducing the irradiated field and targeting higher doses to the site of
the initial primary tumor [6,19].
In 1983, the Pediatric Oncology Group attempted a randomized trial of whole bone
versus tailored-field RT after 12 weeks of induction chemotherapy [21]. After preliminary
analysis showed that tailored field was as effective as whole-bone RT, the randomized
study was stopped and subsequent patients were treated with limited fields. At three
years, the rates of local control and event-free survival were 76 and 54 percent,
respectively.
IESS trial III, which opened in 1988, was the first cooperative group trial to include
tailored RT ports, and the first to be carried out with modern MRI imaging of the primary
site and CT-based treatment planning [69]. The main randomization was between
standard versus more intensive chemotherapy (VAC with or without IE). The addition of
IE significantly improved five-year survival (72 versus 61 percent) and event-free
survival rates (69 versus 54 percent), particularly for patients with pelvic primary
tumors. Moreover, the five-cumulative rate of local recurrence either alone or with
systemic relapse was 20 percent in the VAC group compared to only 7 percent in the
VAC/IE group. These data underscore the contribution of intensive chemotherapy to both
local control and survival for patients with nonmetastatic EFT at diagnosis.
Current recommendations for RT define an initial clinical target volume to include the
original bone and soft tissue tumor with a 2.0 cm margin. As noted above, for patients
36
with chest wall tumors and malignant effusions, the field includes the entire ipsilateral
hemithorax to a dose of 15 Gy prior to cone down to the chest wall tumor. (See
'Adjuvant RT' above.)
Attention to potential RT effects on normal tissue is critical in radiation planning to
minimize late effects, particularly in children:







Even partial treatment of uninvolved epiphyseal growth plates is avoided in order
to minimize treatment-induced limb shortening [70].
Circumferential irradiation of a limb is avoided to reduce the risk of limb edema
and fibrosis.
Gonadal avoidance or additional shielding (for the testes) is important to retain
fertility.
Excellent results can be achieved from RT of lesions of the hand or foot [71].
However, walking places repetitive stress on the soft tissues of the sole of the
feet, and dose sparing for the sole of the foot can improve the functional outcome
of treatment.
Irradiation of the Achilles tendon is usually avoided. Lesions of the calcaneus can
be treated; although some atrophy of the heel pad has been reported, the
functional impairment is usually minor [72].
Nail beds should be excluded from the radiated field when possible.
For pelvic tumors, distention of the bladder prior to each day's treatment can
reduce the amount of small bowel in the radiated field, but care must be taken to
avoid radiation to significant portions of the bladder in patients receiving
ifosfamide to reduce the risk of hemorrhagic cystitis.
It is anticipated that improvements in RT technique over the last 20 years (ie, the
adoption of tailored radiation ports as opposed to whole bone ports used in the period
1960 to 1980, three-dimensional (3D) conformal RT, intensity modulated RT (IMRT), and
proton therapy (see below) and use of lower and risk-adapted RT doses [56,73]) will
reduce the risk of late effects. Nevertheless, the relatively high complication rate seen
with earlier treatment approaches and the delayed nature of many of these
complications underscore the need for long-term posttreatment follow-up. (See
'Sequelae of treatment' below.)
Proton beam therapy — One way to reduce the volume of normal tissue irradiated is with
charged particle irradiation using protons.
The advantage of protons over conventional photons is in their dose distribution. The
physical characteristics of the proton beam result in the majority of the energy being
deposited at the end of a linear track, called a Bragg peak, with the dose falling rapidly
to zero beyond the Bragg peak. Compared to photon beam irradiation, proton beam
therapy permits the delivery of high doses of RT to the target volume while reducing the
radiation dose received by normal tissues distal to the target. Depending on the tumor
target configuration and the portal selection, this can result in up to 60 percent reduction
in the dose received by uninvolved normal tissue [74].
This approach may be particularly beneficial for Ewing sarcomas arising in the bones of
the paranasal sinus (image 1A-B), the pelvis, and the spine:


Because of the proximity of the spinal cord, the dose to vertebral body primaries
using conventional photon irradiation has been often limited to 45 Gy. Proton
beam therapy permits the delivery of higher doses while respecting spinal cord
constraints (image 2) [75].
When used for pelvic lesions, proton beam therapy is associated with better
sparing of the intestine, rectum, bladder, pelvic bone marrow, and femoral head
as compared to photon irradiation [76].
37
In addition to less acute morbidity, one would also anticipate a reduction in late, RTinduced tumors in patients treated with protons because of the lower volume of normal
tissue in the irradiated field (see below) [77]. Proton beam irradiation is approved for
use in Children's Oncology Group protocols for EFT [78].
Our group recently reported experience with proton beam irradiation in 30 children
undergoing chemoradiation with or without surgery for Ewing sarcoma [79]. At a median
follow-up of 38.4 months, the three-year actuarial rates of event-free survival, local
control, and overall survival were 60, 86, and 89 percent, respectively. RT was acutely
well tolerated, with mostly mild-to-moderate skin reactions. The only serious late effects
were four hematologic malignancies (three acute myelogenous leukemia [AML] and one
myelodysplastic syndrome [MDS]), which are known risks of topoisomerase and
anthracycline exposure. (See 'Second malignancies' below.)
Concern has been raised that neutron scatter radiation associated with passively
scattered proton beam lines may also result in secondary malignancies [80]. The
magnitude of this risk is uncertain and may be low in the beam lines in modern facilities
[81]; it is expected to be significantly reduced by the use of scanned proton beams [82].
These issues will only be addressed by careful further follow-up of patients treated with
protons.
Intensity modulated radiation therapy — Intensity modulated RT (IMRT) requires the
same careful three dimensional radiation treatment planning used for 3D-CRT. However,
IMRT utilizes variable, computer-controlled intensities within each RT beam, in contrast
to the uniform doses within each 3D-CRT beam. Compared to most other treatment
techniques, IMRT can achieve a higher degree of accuracy in conforming the radiation to
the planned target while sparing normal tissue and reducing the incidence of some late
complications. The advantages of IMRT are particularly evident when the target volumes
have complex shapes or concave regions.
Initial experience with IMRT for Ewing sarcoma has been promising [33]. However,
critics argue that the risk of a second malignancy might be higher because the multiple
portals used with IMRT to achieve conformality of the high-dose region around the target
result in delivery of low-moderate doses of radiation to a larger volume of surrounding
tissue than with 3D conformal RT techniques. In addition, for IMRT delivery, the linear
accelerator is delivering more monitor units and, therefore, a larger total-body dose
because of leakage of radiation [80]. IMRT supporters point out that since the risk of
radiation-induced tumors is dose dependent, this risk may not in fact be increased.
These questions will only be answered by careful further follow-up of patients treated
with IMRT.
Dose — RT dose is an important factor in local control, particularly for large tumors
[34,56]. For patients treated with chemotherapy and RT, recent cooperative studies in
the United States have employed 45 Gy in 25 fractions to the initial clinical target
volume as defined above, followed by a 10.8 Gy boost in six fractions to the site of
original bony disease and any residual soft tissue disease that remains following
chemotherapy. Because of the proximity of the spinal cord, the dose to vertebral body
primaries has been often limited to 45 Gy, although techniques such as protons and
IMRT can permit the safe delivery of higher doses. (
For patients undergoing adjuvant postoperative RT, doses of 45 to 50.4 Gy are
recommended for microscopic, and 55.8 Gy for gross residual disease. If preoperative RT
is given for bulky tumors, doses in the range of 45 Gy are used.
Lower doses (eg, 30 to 36 Gy) have been studied at St Jude and Sloan Kettering
[56,83]. In one early report of patients undergoing definitive RT, local control rates were
90 percent using RT doses of 35 Gy for smaller lesions (≤8 cm) with a favorable
response to chemotherapy, but they were inferior (52 percent) for larger lesions [56].
Others suggest that doses as low as 30 Gy may be sufficient in the adjuvant setting
38
[83]. However, further studies are needed before lower doses of RT can be accepted as
standard practice.
Radiation schedule — Conventional RT schedules usually consist of once daily RT doses
of 1.8 to 2.0 Gy per fraction. Accelerated fractionation RT does not seem to improve
rates of local control or survival [6,19,22,33,84]. However, data from the University of
Florida suggest that hyperfractionated RT (1.2 Gy twice daily with a six hour interfraction
interval) may be associated with less long-term toxicity [19].
The series consisted of 75 patients with localized Ewing tumor of the extremity or pelvis
(lower extremity, 30; upper extremity, 19; pelvis, 26) who were treated with definitive
RT at the University of Florida between 1970 and 2006 . RT was performed on a oncedaily (40 percent, median dose was 55.2 Gy in 1.8-Gy daily fractions) or twice-daily (60
percent, median dose 55.0 Gy in 1.2 Gy twice-daily fractions) basis. Functional outcome
was assessed using the Toronto Extremity Salvage Score [85].
Larger tumors had significantly worse cause-specific survival (81 versus 39 percent for
tumors <8 cm versus ≥8 cm), but there were no patient characteristics or treatment
variables that were predictive of local failure. No fractures occurred in patients treated
with hyperfractionation or with tumors of the distal extremities. Severe late
complications were more frequently associated with use of <8 MV photons and fields
encompassing the entire bone or hemipelvis. A significantly better Toronto Extremity
Salvage Score was associated with a late-effect biologically effective dose of <91.7 Gy
[68]. The authors concluded that limited field sizes with hyperfractionated high-energy
RT could minimize long-term complications and provide superior functional outcomes.
IORT — A benefit for intraoperative RT (IORT) has been suggested in retrospective
series involving a small number of patients [86,87]. However, peripheral nerves are
dose-limiting tissue structures for IORT, so the risk of severe neuropathy and soft tissue
necrosis must be considered if this approach is used.
SEQUELAE OF TREATMENT — Potentially curative treatment of EFT is necessarily
aggressive. The toxicity of RT given in conjunction with intensive chemotherapy can be
separated into short-term and long-term complications. The severity of both can be
limited by careful attention to technique.
Acute effects — Acute reactions are those that occur during or shortly after the
completion of RT. The most prominent affect tissues within the radiated field that contain
rapidly dividing cells, and include desquamation of the skin, myelosuppression,
mucositis, diarrhea, nausea, and cystitis. All except myelosuppression are site-specific.
Severity depends upon the amount of normal tissue in the radiated field, the radiation
fraction size, and the timing of chemotherapy in relation to the RT.
Many acute effects, particularly myelosuppression, are exacerbated or potentiated by the
use of intensive systemic chemotherapy. As examples:


Both cyclophosphamide and ifosfamide can cause hemorrhagic cystitis; the
amount of bladder in the treatment field should be limited to avoid compounding
this problem. (See "Cystitis in patients with cancer".)
Dactinomycin and doxorubicin act as radiation sensitizers and can enhance acute
radiation toxicity. If these drugs are used as a component of systemic
chemotherapy, breaks should be instituted during the RT or administration of
these agents should be delayed until acute RT reactions subside. Current practice
in the Children's Oncology Group (COG) studies is to administer RT concurrently
with the ifosfamide/etoposide cycles of chemotherapy. (See "Treatment of the
Ewing sarcoma family of tumors".)
Acute reactions are usually self-limited and subside within 10 to 14 days of RT
completion. Dry desquamation can be managed topically with emollient creams. The
39
development of wet desquamation may require a temporary break in therapy in addition
to thrice daily cleansing with warm water and mild soap, petrolatum-based ointments,
nonadherent dressings, and, if patients are neutropenic, a topical antibiotic ointment or
systemic antibiotics depending on the clinical scenario.
Mucositis and diarrhea are managed with supportive measures; if severe, a treatment
break may be required. Patients receiving proton beam irradiation for treatment of
vertebral lesions tend to have less nausea and diarrhea than those undergoing photon
beam irradiation because of the lack of an exit dose to bowel anterior to the spine.
Patients receiving whole lung irradiation are at risk for radiation pneumonitis.
Late effects — Late reactions occur months to years after completing a course of RT.
Severity is not always predicted by the severity of acute effects. Late changes in normal
tissues caused by RT are related to field size, the volume of normal tissues in the field,
and the dose received by normal tissue. Other important factors include patient age at
the time of treatment, skeletal maturity, adherence to a rehabilitation program, and
whether a pathologic fracture is present at diagnosis. As examples:




Younger, prepubertal children are at greatest risk for radiation-induced arrest of
bone growth [88]. Sparing of uninvolved epiphyseal plates minimizes limb
shortening after RT of extremity lesions.
RT doses above 60 Gy are associated with markedly increased rates of soft tissue
induration and fibrosis [89,90].
High-dose circumferential irradiation of an extremity is associated with edema,
fibrosis, and compromised limb function [91]. This can be avoided by sparing of
an adequate strip of tissue.
Weight-bearing bones are at risk for pathologic fractures [90]. The highest risk is
within the first 18 months of RT completion
Refinements in diagnostic imaging, RT planning, and techniques over time (tailored field
size, hyperfractionated treatment schedules, IMRT, proton beam irradiation) have
resulted in better limb function among long-term survivors, and more recent series
suggest that excellent functional results can be obtained in the majority of patients
following RT for EFT [19,72,89]. A posttreatment rehabilitation program, including active
range of motion of affected joints, is also important in improving and maintaining limb
function.
Second malignancies — There is an increased risk of secondary neoplasia after treatment
for EFT [73,92-95]. RT-induced osteosarcomas and therapy-related (alkylating agents,
epidophyllotoxins) leukemias predominate. Most of the radiation-related bone tumors
are osteosarcomas, although other tumors are reported. The magnitude of risk is
variable [46,73,92-94,96-98]. Early data suggested that the cumulative risk of a
secondary sarcoma after treatment for EFT was approximately 35 percent at 10 years
[97]. The Late Effects Study Group, examining the late effects of treatment for childhood
cancer, reported an estimated cumulative incidence of secondary sarcomas after
treatment of EFT that approached 22 percent at 20 years [93]. These and other
investigators identified RT dose as the major predisposing factor for development of a
radiation-induced sarcoma, particularly above 60 Gy.
Subsequent experience with protocols utilizing lower doses of RT and tailored RT fields
suggest that the magnitude of the risk is somewhat lower [46,73,94,98]. The two largest
series are described in detail:

The largest series with longest follow-up includes 266 survivors of EFT treated at
St Jude, the National Cancer Institute, and the University of Florida, and followed
for a median 9.5 years (range 3 to 30) [73]. The cumulative RT doses were none,
21 to 48, 48 to 60, and >60 Gy in 8, 23, 45, and 24 percent, respectively.
40
Overall, 16 children developed second malignancies, which included 10 sarcomas.
The estimated cumulative risk at 20 years was 9.2 percent for any malignancy,
and 6.5 percent for a secondary sarcoma. The median time to the diagnosis of the
second malignancy after completion of therapy was 7.6 years. All the secondary
sarcomas occurred near or at the primary site of the Ewing sarcoma and within
the primary irradiated field.
As has been noted by others, the cumulative incidence rate of secondary sarcoma was
radiation dose-dependent. No secondary sarcomas developed among patients who had
received less than 48 Gy, while the absolute risk of secondary sarcoma was 130 cases
per 10,000 person-years of observation among patients who had received ≥60 Gy.

Dunst et al reported on second malignancies among 674 patients enrolled in the
Cooperative Ewing's Sarcoma Study Group (CESS)-81 and 86 studies, and
followed for an average of 5.1 years [94]. Only eight developed a second
malignancy, four were treatment-related leukemias/myelodysplastic syndrome,
and there were three sarcomas. The cumulative risk of a second malignancy at 10
and 15 years was 2.9 and 4.7 percent, respectively.
Long-term follow-up guidelines after treatment of childhood malignancy have been
published by the Children's Oncology Group and are available online [99].
RT and other risk factors for secondary sarcomas after treatment of childhood cancer are
discussed further elsewhere.

SUMMARY AND RECOMMENDATIONS — Ewing sarcoma is a rare malignancy that most
often presents as an undifferentiated primary bone tumor; less commonly, it arises in
soft tissue. Both are part of a spectrum of neoplastic diseases known as the Ewing
sarcoma family of tumors (EFT), which also includes the more differentiated peripheral
primitive neuroectodermal tumor (PNET). These entities share important clinical
features, including a tendency towards rapid spread to lungs, bone, and bone marrow,
and responsiveness to the same chemotherapeutic regimens and radiotherapy (RT).
Because relapse rates are high in patients undergoing local therapy alone (80 to 90
percent), it is surmised that the majority have subclinical metastatic disease at the time
of diagnosis, even in the absence of overt metastases. Intensive multiagent
chemotherapy can eradicate these deposits, and is a critical component of therapy for
both localized and advanced disease. (See 'Introduction' above.)
Localized disease — For patients with localized EFT, local and systemic therapy are both
necessary to achieve cure.
Either surgery or RT can provide effective local control. Contemporary treatment
guidelines emphasize surgical resection as the modality of choice if it is believed that the
lesion can be resected with negative margins, without excessively morbidity, and with
the expectation of a reasonable functional result. A major advantage of surgery is the
lack of association with treatment-related sarcomas. For patients who lack a functionpreserving surgical option because of tumor location or extent, and those who have
clearly unresectable primary tumors following induction chemotherapy, we recommend
RT (Grade 1A). (See 'RT versus surgery' above.)
Although the indications for adjuvant RT are not firmly established in patients
undergoing surgery for localized EFT, we suggest adjuvant RT in the following
circumstances (Grade 2C) (see 'Adjuvant RT' above):
41




Bulky tumors in difficult sites (eg, the pelvis); in this setting, RT can be given
either preoperatively or postoperatively, based upon institutional protocols and
experience
If there is residual microscopic or gross disease after surgery, or inadequate
surgical margins (ie, a marginal or intralesional resection as compared to a wide
or radical excision)
Patients who are left with significant amounts of viable tumor in the resected
specimen following neoadjuvant chemotherapy who have less than wide surgical
margins
Adjuvant hemithorax irradiation is indicated in patients with high-risk chest wall
primary tumors (close or involved margins, initial pleural effusion, pleural
infiltration, and intraoperative contamination of the pleural space)
Advanced disease — Although prognosis is clearly worse than for localized disease, a
subset of patients who present with overt metastatic disease can be cured, particularly if
they have limited pulmonary metastases.
For patients with metastatic EFT, we suggest RT rather than surgery for treatment of the
primary site in most patients (Grade 2B). Surgery could be reconsidered in selected
patients if chemotherapy results in significant volume reduction, particularly if areas of
small volume metastatic disease are also amenable to surgical resection. (See 'RT for
metastatic disease' above.)
The role of whole lung irradiation after resection of pulmonary metastases is unclear.
Nevertheless, because of the potential for reduced pulmonary relapse and improved
event-free survival, and the low rate of pulmonary toxicity, we suggest bilateral lowdose lung irradiation (15 to 18 Gy) even if all lesions are resected or completely respond
to chemotherapy (Grade 2C). (See 'Pulmonary metastases' above.)
Epidemiology, pathology, and molecular genetics of the Ewing sarcoma family of tumors
Literature review current through: Aug 2013. | This topic last updated: May 23, 2013.
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43
44
INTRODUCTION — Ewing sarcoma (ES) and peripheral primitive neuroectodermal tumor
(PNET) were originally described as distinct clinicopathologic entities:


In 1918, Stout described a tumor of the ulnar nerve with the gross features of a
sarcoma, but composed of small round cells focally arranged as rosettes; this
entity was subsequently designated neuroepithelioma, and then PNET [1].
ES was described by James Ewing in 1921 as an undifferentiated tumor involving
the diaphysis of long bones that, in contrast to osteosarcoma, was radiationsensitive. Although most often a primary bone tumor, ES was also reported to
arise in soft tissue (extraosseous Ewing sarcoma [EES]) [2].
45
However, over the last several decades, it has become clear that these entities comprise
the same spectrum of neoplastic diseases known as the Ewing sarcoma family of tumors
(EFT), which also includes malignant small-cell tumor of the chest wall (Askin tumor)
[3], and atypical ES [4,5]. Because of their similar histologic and immunohistochemical
characteristics and shared nonrandom chromosomal translocations, these tumors are
considered to be derived from a common cell of origin, although the histogenic origin of
this cell is debated [6-13].
The EFT can develop in almost any bone or soft tissue, but the most common site is in a
flat or long bone, and patients typically present with localized pain and swelling.
Although overt metastatic disease is found in fewer than 25 percent at the time of
diagnosis, subclinical metastatic disease is assumed to be present in nearly all patients
because of the 80 to 90 percent relapse rate in patients undergoing local therapy alone.
As a result, systemic chemotherapy has evolved as an important component of
treatment.
Advances in multidisciplinary management of EFT over the past 30 years have resulted
in a marked improvement in survival and a greater likelihood of limb-sparing surgery
rather than amputation. In data derived from the Surveillance, Epidemiology and End
Results (SEER) program of the National Cancer Institute, five-year survival rates for
patients with ES rose between 1975 and 2000 in all age groups, although the
improvements were most marked in younger individuals [14]. Five-year survival rates in
those treated between 1993 and 2000 were >65 percent, whereas for those over the
age of 15, they were below 50 percent. Among young patients presenting with
nonmetastatic disease who receive modern multidisciplinary treatment, long-term
survival can be achieved in 70 to 80 percent [15,16].
Here we will discuss the epidemiology, pathology, and molecular genetics of
EFT/peripheral PNET. The clinical features, diagnosis, and treatment of these tumors,
principles underlying the performance of a diagnostic bone biopsy, and central PNET
tumors are discussed elsewhere.
EPIDEMIOLOGY AND RISK FACTORS — Primary bone tumors are responsible for 6
percent of all childhood cancers [17]. Although rare, the EFT represent the second most
common primary bone malignancy (table 1) affecting children and adolescents, after
osteosarcoma [14,18]. Despite this, EFT is responsible for only 3.5 percent of cancers in
American children 10 to 14 years old, and 2.3 percent of those arising among 15 to 19
year olds. A similar incidence (2.8 percent of all tumors in children aged 15 to 19 years
old) is described in adolescents in England [19].
In the United States, 650 to 700 children and adolescents younger than 20 years old are
diagnosed with bone tumors every year, of which only 200 are EFT and the remainder
osteosarcomas [20]. The peak incidence is between 10 to 15 years of age. However, 30
percent of cases arise in children under the age of 10, and another 30 percent are in
adults over the age of 20 [21,22]. As with many pediatric tumors, there is a slight male
predominance.
Racial and ethnic factors are of epidemiologic importance. For unclear reasons, the EFT
affect mainly Caucasians and are extremely uncommon among blacks (both in the
United States and Africa) and Asians (figure 1) [22-25]. The reason for this striking
ethnic distribution is not known. However, interethnic differences exist for certain alleles
of the Ewing sarcoma gene (the EWSR1 gene, MIM#133450), which is consistently
disrupted in these tumors [26] (see 'EWSR1 translocations in EFT' below). Furthermore,
genome-wide association studies have raised the possibility that genetic susceptibility
factors may contribute to the observed geographical/ethnic differences in Ewing sarcoma
incidence [27].
Risk factors — EFT have not been consistently associated with any familial or congenital
syndromes [28,29], although at least one series reports an excess of congenital
46
mesenchymal defects in affected patients [30], and another suggests an increase in
neuroectodermal tumors and stomach cancer in the families of patients with ES [31].
Specific environmental exposures have not been identified as risk factors [29,32]. EFT
develop rarely after treatment of a primary cancer during childhood, but most cases do
not appear to be related to radiation therapy [33,34]. An association has been suggested
between a parental occupation of farming (particularly if the mother farmed) and the
development of Ewing sarcoma [35].
Ewing sarcoma may be more common in children who have hernias [35-39]. A metaanalysis of three case-control studies (totaling 357 patients with Ewing sarcoma and 745
controls [37-39]) showed that affected children were more likely to have had a hernia in
childhood (odds ratio 3.2, 95% CI 1.9 to 5.7) [35]. The association was strongest for
umbilical hernias. The mechanism underlying a possible association between hernias and
Ewing sarcoma is unclear.
HISTOGENESIS AND HISTOLOGY — As noted above, the EFT represent a spectrum of
tumors that range from the undifferentiated ES to atypical poorly differentiated ES and
the differentiated PNET.
Histogenesis — The histogenic origin of EFTs has been debated over the years. A
neuroectodermal origin had been proposed based upon variable expression of neuronal
immunohistochemical markers, cytogenetic, and ultrastructural features, as well as the
ability of ES cell lines to differentiate along neural pathways in vitro [10-12,40,41].
Because of the resemblance of the PNET to classic neuroblastoma, the neural crest was
regarded as the most likely progenitor.
Although ES is typically described as an undifferentiated tumor whose primitive cells lack
neural differentiation, some tumors contain Homer-Wright rosettes, which are indicative
of neural differentiation. Furthermore, ES can express neural antigens (eg, gastrin
releasing peptide, a protein which is normally expressed by the brain and
neuroendocrine cells) on their surface [40], and both ES and PNET synthesize choline
acetyltransferase, a marker suggesting a common neural origin [41]. (See 'Histologic
features' below.)
Based upon these features, and the lack of precursor synthesis for the adrenergic
pathway, some investigators believe that EFT are derived from postganglionic
parasympathetic primordial cells, which are located throughout the parasympathetic
nervous system, accounting for their widespread distribution [10,12,42]. In contrast,
neuroblastomas synthesize neurotransmitters that are associated with the sympathetic
autonomic nervous system [10,42].
In contrast to this "neural crest hypothesis", an alternative theory is emerging that
suggests that EFT arise from mesenchymal progenitor or mesenchymal stem cells
(MSC). MSCs isolated from bone marrow can differentiate into osteogenic, chondrogenic,
or adipogenic lineages. Expression of the ES-specific oncoprotein EWS-FLI (see below)
blocks MSC differentiation [43], while removal of EWS-FLI from patient-derived ES cell
lines allows the cells to gain the ability to differentiate into multiple lineages and adapt a
gene expression profile that resembles that of MSCs [13]. Additional data will be
required to draw a final conclusion as to the cell of origin in ES.
Histologic features — The morphologic appearance of classic ES is that of a primitive,
undifferentiated neoplasm. On hematoxylin and eosin-stained sections, there are
monotonous sheets of small round blue cells with hyperchromatic nuclei and scant
cytoplasm that is clear because of the presence of abundant glycogen (picture 1) [44].
There is usually extensive necrosis with preservation of viable tumor around blood
vessels. Nuclear atypia, palisading, and formation of rosettes (where the tumor cells are
arranged in a circle about a central fibrillary space, indicative of neural differentiation) or
pseudorosettes are typically absent. Invasion of blood vessels can be seen, although the
47
tumors are not characteristically highly vascular. Mitotic figures are rare, and aneuploidy
is uncommon on flow cytometry studies [45].
Atypical ES are usually described as poorly differentiated rather than undifferentiated
tumors. They contain larger cells, a greater degree of cellular pleomorphism, and have a
higher mitotic rate (generally more than two mitoses per high power field). Spindle cells
may be present at the periphery, and these tumor cells invade the adjacent tissue in an
infiltrative manner. The cells can be arranged in sheets, or there may be an organoid,
lobular, or alveolar architectural pattern. As in the typical ES, evidence of neural
differentiation is usually absent.
The histopathologic features of a peripheral PNET may resemble the typical
undifferentiated ES or atypical ES; however, a neural immunophenotype or evidence of
neural differentiation on light microscopic (ie, Flexner-type rosettes or Homer-Wrighttype pseudorosettes) or ultrastructural examination is present in about one-half of
cases. However, mature neural elements (ie, ganglion cells, nerve fascicles, or a neuropil
background) are absent. The neoplastic cells are typically arranged into an organoid,
alveolar, or lobular pattern.
Differential diagnosis — Morphologically, the appearance of EFT and PNET tumors is
similar to that of other small round blue cell tumors involving bone and soft tissue,
including lymphoma, small cell osteosarcoma, mesenchymal chondrosarcoma,
medulloblastoma, dedifferentiated synovial sarcoma, desmoplastic small round cell
tumors, and rhabdomyosarcoma. As a group, these tumors often pose difficult diagnostic
problems when examined by light microscopy alone. There is little in the routine
histologic appearance of an EFT to relate it to a component of normal bone or other
tissue from which it might have arisen. Even the determination of bone versus soft
tissue origin can be challenging, because EFT involving bone often have an extensive
soft tissue component, while extraosseous tumors may invade bone secondarily.
Although ES can exhibit a variable degree of neural differentiation, this is usually subtle
and often only detected by immunohistochemical staining for markers of neural
differentiation (table 2) or by ultrastructural examination. Although no routinely used
histochemical or immunohistochemical stain can positively distinguish EFT from other
undifferentiated tumors of childhood, the vast majority of EFT express high levels of a
cell surface glycoprotein (designated CD99, MIC2 surface antigen or p30/32MIC2) that is
encoded by the CD99 (MIC2X) gene [6,46]. The finding of membrane-localized MIC2
expression is a sensitive diagnostic marker for the EFT; however, it lacks specificity since
other tumors (eg, rhabdomyosarcoma, which is often in the differential diagnosis) and
normal tissues are also immunoreactive with anti-MIC2 antibodies [47]. Another new
potential immunohistochemical marker for EFT is NKX2.2, the protein product of the
NKX2-2 gene [48].
Cytogenetic or molecular genetic studies looking for particular chromosomal
translocations and/or their fusion transcripts are usually required to secure the
diagnosis. (See 'Molecular diagnostics' below.)
MOLECULAR GENETICS — Remarkable progress has been made in defining and
classifying bone and soft tissue tumors on the basis of characteristic chromosomal
abnormalities (table 3). Because of their unique shared chromosomal translocations, the
EFT have become a model system for nonmorphologic approaches to diagnosis and
subclassification using both cytogenetic and molecular techniques. These translocations
interrupt specific genes and recombine them to create novel fusion genes, whose
products are tumor-specific and present in virtually all cases of an individual tumor
category. Thus, their characterization not only yields profound insights into tumor
biology, but also holds great promise for diagnostic and therapeutic approaches. .)
EWSR1 translocations in EFT — The unique shared pattern of nonrandom chromosomal
translocations in the EFT provides one of the most compelling arguments for a common
48
cellular origin. Virtually all cases express one of several different reciprocal
translocations, most of which involve breakpoints that are clustered within a single gene
locus designated the EWSR1 gene on chromosome 22q12 (table 3) [7,8,44,49-52].
The EWSR1 gene normally encodes a widely expressed protein, the EWS protein, whose
amino terminal domain shares some homology with eukaryotic RNA polymerase II and
whose carboxy terminus (which is replaced by tumor-specific translocations) contains an
RNA recognition motif. The EWS protein is a member of a family of highly conserved
RNA-binding proteins that are believed to mediate interaction with RNA or singlestranded DNA [53,54].
In 85 to 90 percent of cases of EFT, a recurrent chromosomal translocation,
t(11;22)(q24;q12), fuses the 5' portion of the EWSR1 gene on chromosome 22 to the 3'
portion of the FLI1 (friend leukemia integration locus-1) gene on chromosome 11
[49,50]. This can be detected using fluorescence in situ hybridization (FISH, (image 1)).
FLI1 encodes the FLI protein, a member of the ETS family of transcription factors, and is
involved in the control of cellular proliferation, development, and tumorigenesis [55].
Members of the ETS family are defined by the presence of a highly conserved 85-amino
acid domain termed the erythroblastosis virus-transforming sequence (ETS) domain,
which mediates specific binding to purine-rich DNA sequences [56]. As a result of the
t(11;22), the EWS-FLI fusion protein is expressed. EWS-FLI binds DNA via its FLIderived ETS domain, and regulates gene expression through the EWS portion of the
fusion.
In EFT that lack the EWSR1-FLI1 translocation, analogous translocations fuse the EWSR1
gene to other genes of the ETS family (ie, ERG, ETV1, ETV4, or FEV) that have structural
homology to FLI1, forming t(21;22)(q22;q12), t(7;22)(p22;q12), t(17;22)(q12;q12), or
t(2;22)(q35;q12) translocations, respectively [57-60]. The EWSR1-ERG translocation
[t(21;22) (q22;q12)] is present in 5 to 10 percent of EFT, while the others are less
common [42,60-62].
In addition to EWSR1-based translocations, rare cases of EFT are associated with
translocations involving a related gene, FUS (also called TLS) [63,64]. Tumors exhibiting
t(16;21)(p11;q24) or t(2;16)(q35;p11) translocations express FUS-ERG or FUS-FEV
fusions, respectively. Because EWS and FUS proteins are highly similar, it is believed
that FUS-based fusion proteins function similarly to EWS-based fusions. It is important
to note that tumors with these translocations can be a source of diagnostic confusion.
(See 'Molecular diagnostics' below.)
Ultimately, specific translocations are important diagnostic features of the EFT, and the
protein products of the fusion genes are believed to play an important role in tumor
development and biology. A growing body of evidence suggests that these proteins
function as transcriptional regulators, although their transcriptional targets are just
beginning to be identified. (See 'Molecular pathogenesis' below.)
EWSR1 translocations in other soft tissue tumors — Although translocations involving the
EWSR1 and ETS families of genes are specific for EFT, translocations that involve fusion
of the EWSR1 gene to other genes have been observed in many other tumors (eg, clear
cell sarcoma/malignant melanoma of soft parts, myxoid liposarcoma [65-67]). The
structure of these resultant fusion genes is analogous to that of EWSR1-FLI1 (ie, all
result in the fusion of the 5' portions of the EWSR1 gene or an EWSR1-like gene [eg, the
FUS gene] to 3' portions of genes encoding transcription factors). The resulting chimeric
proteins presumably have a similar function to the EWS-FLI fusion protein, and it is
thought that disruption of transcriptional control contributes to their transforming
potential [44]. (See 'Molecular pathogenesis' below.)
Despite these similarities, with few exceptions, a clinicopathologically distinct tumor
entity has been consistently associated with each specific translocation involving a
unique class of transcription factors. This tumor specificity is most likely related to cell49
specific influences on DNA recombination, chimeric gene expression, and intrinsic
proteins that are necessary to complement the action of the chimeric protein.
Other genetic changes in EFT — In addition to the characteristic reciprocal translocations
described above, other numerical and structural chromosomal aberrations are
occasionally found in EFT. These include a gain of chromosomes 1q, 2, 8 and 12,losses
of 9p and 16q, and the non-reciprocal translocation t(1;16)(q12;q11.2) [68-70]. In
addition, alterations in known tumor suppressor genes have been identified in some
cases. As an example, homozygous deletion of the CDKN2A gene has been described in
18 to 30 percent of cases, and TP53 mutations are detected in 5 to 20 percent [44,7173]. The biologic implications of these findings are incompletely understood.
Molecular pathogenesis — EFT-associated translocations result in the production of
chimeric proteins that contain the amino-terminal domain of the normal EWS protein
fused to the nucleic acid-binding domain of the transcription factor translocation partner.
Because of their ubiquitous presence in EFT, they are thought to be intimately connected
to the biology of these tumors.
The available data suggest two possible mechanisms by which these unique chimeric
proteins may contribute to neoplastic transformation and/or cell growth:


Chimeric proteins such as EWS-FLI may influence transcription of some of the
same genes that are normally regulated by native FLI, but because the chimeric
molecule is expressed in either a different temporal or quantitative manner, the
downstream targets are deregulated, leading to uncontrolled cellular growth.
EWS-FLI may affect target genes that are different from those regulated by the
native FLI or EWS proteins. This would explain why the chimeric gene product
(EWS-FLI) has transforming properties that are not shared by either the EWS or
the FLI wild-type counterparts [74].
Some chimeric fusion proteins can act as transcriptional activators, deregulating many
genes associated with cell signaling, proliferation, apoptosis, tissue invasion and
metastasis [44,74-80]. It is likely that this ability to regulate transcriptional activity is
associated with their oncogenic potential. EWS-FLI and other chimeric fusion proteins
are all capable of transforming cell lines equally well. As an example, expression of
either the EWS-FLI or EWS-ERG cDNAs can transform mouse NIH3T3 fibroblasts so that
they acquire tumor-like properties (eg, growth in soft agar or in immunodeficient mice)
[74,81]. Notably, EWS-FLI can only transform cells in which insulin like growth factor
signaling is intact, and thus there is a potential role for IGF1R inhibitors in the treatment
of Ewing sarcoma [82-84].
The protein products of the fused genes are also important for maintaining the growth
characteristics of EFT cell lines, and emerging data suggest the potential for molecularly
targeted therapy [85]:



Introduction of EWS-FLI RNA antisense molecules or short-interfering or short
hairpin RNAs (such as RNAi that mediate RNA-interference) into EFT cells
decreases the expression of the EWS-FLI fusion protein and results in growth
inhibition and/or loss of oncogenic potential, both in vitro and in vivo [86-90].
Likewise, inhibition of the interaction between EWS-FLI and its cellular binding
partner RNA helicase A (RHA) by a small peptide or small molecule inhibitor
reduces the growth of EFT orthotopic xenografts [91].
Truncated ETS domain-binding molecules can act as competitive inhibitors and
have a dominant negative effect on cell growth [92]. p21(WAF1/CIP1), which is
important in cell cycle regulation, might be one of the direct targets of EWS-FLI,
suggesting that this molecule could serve as a target for a molecularly based
therapy for EFT [85].
50
Because EWS-FLI and related fusions are thought to function primarily as transcriptional
regulators, a number of studies have sought to define the genes that are regulated by
the fusion proteins [88-90,93,94]. Some of the EWS-FLI regulated genes are involved in
the oncogenic phenotype of Ewing's sarcoma model systems (eg, IGFBP3, CAV1,
NKX2.2, NR0B1, GSTM4, and others) [76,88-90,95,96]. While many of the details are
still being worked out, some of these gene targets and associated pathways may prove
to be future targets for molecularly-targeted therapy.
Another mechanism whereby EWS-FLI may exert a tumorigenic effect is via deregulation
of programmed cell death (apoptosis). Cancer is believed, in part, to represent an
imbalance between cell growth and cell death. Expression of EWS-FLI1 or EWS-ERG in
NIH3T3 cells inhibits the apoptosis that would normally occur with serum deprivation or
calcium ionophore treatment [97], while antisense inhibition of EWS-FLI increases
susceptibility to chemotherapy-induced apoptosis in ES cell lines. Similarly, reduced
expression of EWS-FLI using RNAi-based approaches also resulted in increased apoptosis
[89].
EWS-ETS fusion proteins also activate human telomerase activity in Ewing tumors
through upregulation of the telomerase reverse transcriptase gene expression, probably
by acting as a transcriptional coactivator [98]. Telomerase is a ribonucleoprotein enzyme
that compensates for telomere shortening during cell division by synthesizing telomeric
DNA, thereby maintaining telomere length. In normal somatic cells, telomerase activity
is usually undetectable, with the exception of some cell types such as hematopoietic
cells, hair follicles, intestinal crypt cells, and basal cells of the epidermis. Upregulated
telomerase activity in cancer cells correlates with the stabilization of telomere length and
cellular immortalization (ie, the ability of the cells to divide indefinitely). This raises the
possibility of therapeutic approaches using telomerase inhibitors.
Molecular diagnostics — The translocations that characterize EFT are exquisitely sensitive
and specific tumor markers that have rapidly become the standard for confirming the
diagnosis, particularly for cases in which morphology is inconclusive [7]. Standard
cytogenetic analysis can reveal a wide variety of chromosomal alterations, but technical
constraints and variant translocations may complicate the interpretation, and results are
often obtained too late to influence therapy. Molecular assays are more attractive
because of the small amount of tissue required, rapid results, and higher sensitivity than
traditional cytogenetics.
Both the fusion genes and their hybrid transcripts can be identified in tumor cells using
molecular genetic approaches. Two techniques are in use, fluorescent in situ
hybridization (FISH) and reverse transcriptase polymerase chain reaction (RT-PCR), and
both are more rapid than cytogenetic analysis [99-102]. In particular, RT-PCR to detect
the presence of fusion transcripts in tumor cells has become a mainstay in molecular
diagnosis of the EFT. It is extremely sensitive and specific and allows detection of very
low levels of tumor cells even among large numbers of normal cells (eg, peripheral blood
and bone marrow), providing an extremely robust method for molecular staging and
monitoring treatment response (see below).
In addition to providing diagnostic support for challenging cases, the identification of
specific types of transcripts was at one time thought to have prognostic significance
[68,103,104]. As an example, in one report, the presence of type 1 EWS-FLI transcripts
(EWSR1 exon 7 fused with FLI1 exon 6) was associated with a threefold reduction in the
risk of developing metastatic disease as compared to non-type 1 transcripts [103].
However, more recent independent studies from both the United States and Europe do
not support the prognostic value of translocation type [105,106]. It appears that current
intensive treatment protocols may have eliminated this apparent difference in prognosis.
While molecular tests for EFT-associated translocations are important and often useful
adjuncts in the diagnostic work-up, in most cases, molecular pathology laboratories do
not test for all of the "alternate" translocations (such as those that encode EWS-ERG,
51
EWS-ETV1, EWS-ETV4, EWS-FEV, FUS-ERG, and FUS-FEV). Thus, a "negative" FISH or
RT-PCR result does not necessarily rule out the diagnosis of EFT. Physicians are strongly
advised to consult with their molecular diagnostic laboratory to understand exactly what
tests are performed, and the sensitivity and specificity of those tests for EFT. Ultimately,
the diagnosis of EFT is based upon a combination of histopathology, special stains, and
molecular diagnostics that are interpreted in the context of the patient's clinical
presentation.
Molecular staging — Disease stage as determined by standard imaging modalities
constitutes the most powerful predictor of prognosis for patients with EFT. However,
some patients considered to have localized disease have an unfavorable outcome, even
with multimodality therapy, and this may be related to the persistence of minimal
metastatic disease that is not detected by traditional methods.
Minimal disease (ie, circulating ES cells) can be detected in peripheral blood and bone
marrow using PCR-based methods in up to 30 percent of patients with apparently
localized disease and in approximately 50 percent of those with advanced or relapsed
disease [107-111]. However, the prognostic significance of this finding, particularly in
patients with localized disease, is controversial [108,110,111], and the ultimate
contribution of this finding to patient management is unclear [110,111]. Further
prospective studies using molecular methods to detect the presence of minimal residual
disease are needed in order to assess its impact on outcome.

SUMMARY — Ewing sarcoma and peripheral primitive neuroectodermal tumors (PNET)
comprise the same spectrum of neoplastic diseases known as the Ewing sarcoma family
of tumors (EFT), which also includes malignant small-cell tumor of the chest wall (Askin
tumor). Because of their similar histologic and immunohistochemical characteristics and
shared nonrandom chromosomal translocations, these tumors are considered to be
derived from a common cell of origin, although its histogenic origin is debated. (See
'Introduction' above.)
Although rare, the EFT represent the second most common primary bone malignancy
(table 1) affecting children and adolescents. EFT have not been consistently associated
with any familial or congenital syndromes, and specific environmental exposures have
not been identified as risk factors.
Morphologically, the appearance of EFT is similar to that of other small round blue cell
tumors involving bone and soft tissue, including lymphoma, small cell osteosarcoma,
mesenchymal chondrosarcoma, medulloblastoma, dedifferentiated synovial sarcoma,
desmoplastic small round cell tumors, and rhabdomyosarcoma. As a group, these tumors
often pose difficult diagnostic problems when examined by light microscopy alone.
Cytogenetic or molecular genetic studies looking for particular chromosomal
translocations and/or their fusion transcripts are usually required to secure the
diagnosis. (See 'Differential diagnosis' above and 'Molecular diagnostics' above.)
Virtually all cases express one of several different reciprocal translocations, most of
which involve breakpoints that are clustered within a single gene locus designated the
EWSR1 gene on chromosome 22q12 EFT-associated translocations result in the
production of chimeric proteins that contain the amino-terminal domain of the normal
EWS protein fused to the nucleic acid-binding domain of the transcription factor
translocation partner. Because of their ubiquitous presence in EFT, these chimeric
proteins are thought to be intimately connected to the biology of these tumors. (See
'EWSR1 translocations in EFT' above and 'Molecular pathogenesis' above.)
Adjuvant and neoadjuvant chemotherapy for soft tissue sarcoma of the extremities
52
53
Literature review current through: Aug 2013. | This topic last updated: Tem 12, 2013.
INTRODUCTION — Soft tissue sarcomas (STS) are uncommon malignant tumors that
arise from extraskeletal connective tissues, including the peripheral nervous system.
They can arise at any body site, but are most common in the extremities, particularly
the lower limbs.
In treating STS of the extremities, the major therapeutic goals are long-term survival,
avoidance of a local recurrence, maximizing function, and minimizing morbidity. Surgical
resection is the cornerstone of potentially curative treatment. For nearly all patients with
extremity sarcomas >5 cm, the addition of radiation therapy (RT) improves local control,
54
and it has also had a significant impact on limb salvage. There are advantages to
preoperative (neoadjuvant) as compared to postoperative (adjuvant) administration of
RT, and for neoadjuvant therapy utilizing combinations of RT and chemotherapy,
particularly for recurrent and large, high-grade primary tumors. These topics are
discussed in detail elsewhere.
Systemic chemotherapy is a routine component of treatment for several sarcomas that
occur predominantly in children (eg, rhabdomyosarcoma, Ewing sarcoma, and
osteogenic sarcoma). However, the value of adjuvant chemotherapy in patients
undergoing resection of the adult-type localized extremity STS (eg, leiomyosarcoma,
liposarcoma, synovial sarcoma) remains controversial due to the complexity of the group
of diagnoses involved.
This topic review will discuss the use of adjuvant and neoadjuvant chemotherapy in the
treatment of adult-type extremity STS. The role of chemotherapy in the treatment of
retroperitoneal STS, rhabdomyosarcoma and the Ewing sarcoma family of tumors, and
neoadjuvant combined modality approaches for patients with large, high-grade or
recurrent extremity STS are discussed in detail elsewhere.
ADJUVANT CHEMOTHERAPY
Pediatric-type sarcomas — The addition of systemic chemotherapy to local therapy
significantly improves outcomes for the common pediatric types of sarcoma
(rhabdomyosarcoma, osteogenic sarcoma, and the Ewing sarcoma family of tumors of
both soft tissue and bone). Most modern treatment plans utilize initial (induction or
neoadjuvant) chemotherapy followed by local treatment and additional (adjuvant)
chemotherapy.
Rhabdomyosarcoma — The vast majority of patients with rhabdomyosarcoma are
children. The routine use of multiagent chemotherapy (typically vincristine,
dactinomycin, and cyclophosphamide, VActinoC, or regimens used for Ewing sarcoma),
in addition to surgery and RT, has contributed significantly toward increasing cure rates
among those with localized disease. The rare cases of rhabdomyosarcoma that arise in
adults are managed similarly. (See "Rhabdomyosarcoma and undifferentiated sarcoma in
childhood and adolescence: Treatment".)
Ewing sarcoma — Among children, Ewing sarcoma is much more common in bone than
in soft tissue, while in adults, it more often presents in soft tissue. Regardless of whether
it arises in bone or soft tissue, the tumor is treated in the same multidisciplinary manner
in adults as in children. A combination of neoadjuvant and adjuvant chemotherapy using
vincristine, doxorubicin, and cyclophosphamide (VAC), with alternating cycles of
ifosfamide and etoposide, is a US standard of care in addition to local therapy; in Europe
a somewhat different combination of many of these agents is recommended (vincristine,
ifosfamide, doxorubicin, etoposide [VIDE]). (See "Treatment of the Ewing sarcoma
family of tumors", section on 'Treatment for localized disease'.)
Extraosseous osteogenic sarcomas — Osteosarcomas rarely arise in the soft tissue rather
than bone (image 1 and image 2). In contrast to Ewing sarcoma, when osteogenic
sarcomas arise in soft tissue rather than bone, management has to date followed the
principles established for soft-tissue tumors rather than primary bone tumors.
While adjuvant chemotherapy is a standard component of treatment for primary bone
osteosarcomas in all age groups, it has been thought to be much less effective for
tumors of extraosseous origin [1]. However, at least one study suggests that outcomes
may be better when children with extraosseous osteosarcoma are treated with the same
combination chemotherapy protocols as used for bone-primary osteogenic sarcoma [2].
Sarcomas more commonly seen in adults — The remainder of this discussion will focus
on the use of adjuvant chemotherapy for the more common adult-type STS, such as
liposarcomas, leiomyosarcomas, and synovial sarcomas.
55
Over 20 randomized trials and two meta-analyses have addressed the potential benefit
of adjuvant chemotherapy for resected extremity STS in adults. Unfortunately, these
have yielded conflicting data, and as a result, the benefit of adjuvant chemotherapy
remains uncertain.
Early randomized trials — The majority of early trials used doxorubicin alone or with
dacarbazine but did not employ ifosfamide, a compound only developed in the mid1980s. Among the first 14 published randomized trials of adjuvant doxorubicin-based
therapy versus surgery alone, two reported a significant survival advantage for
combination chemotherapy, three found higher survival in the observation arm, and the
remainder showed no difference in outcome in the treated group [3].
SMAC meta-analysis — Individual patient data from these trials, which involved 1568
adults with localized resectable STS (only some of which were localized to an extremity),
were analyzed by the Sarcoma Meta-Analysis Collaboration (SMAC) and published in
1997 [4,5]. All evaluated studies that randomly assigned patients postoperatively to
receive or not receive adjuvant doxorubicin-containing chemotherapy; fewer than 5
percent of patients received a chemotherapy regimen that included ifosfamide. The
following benefits were noted in the chemotherapy group:




Significantly longer local recurrence-free interval — hazard ratio [HR] for local
recurrence 0.73 (95% CI 0.56-0.94).
Significantly longer distant recurrence-free interval — HR 0.70 (95% CI 0.570.85).
Significantly higher overall recurrence-free survival — HR for any recurrence 0.75
(95% CI 0.64-0.87). This corresponded to an absolute 6 to 10 percent
improvement in recurrence free survival at 10 years.
There was a trend towards better overall survival that favored chemotherapy, but
it was not statistically significant (HR for death 0.89, 95% CI 0.76-1.03).
There was no consistent evidence of a difference in any endpoint according to age, sex,
stage, site, grade, histology (although there was no central pathology review), extent of
resection, tumor size, or exposure to RT. However, the strongest evidence of a beneficial
effect on survival was shown in the subset of patients with extremity and truncal
sarcomas. Among these patients who received adjuvant doxorubicin-containing
chemotherapy, there was a modest but statistically significant benefit for chemotherapy
(HR for death 0.80, p = 0.029), which translated into a 7 percent absolute benefit in
overall survival at 10 years.
The updated meta-analysis from this group, which includes many later trials, is
presented below. (See "Clinical features, evaluation, and treatment of retroperitoneal
soft tissue sarcoma", section on 'Adjuvant chemotherapy' and 'Updated meta-analyses'
below.)
Later randomized trials — Given the suggestion of a survival benefit for extremity and
truncal STS in the SMAC meta-analysis, later randomized trials largely focused on these
sites. There are few randomized trials addressing the benefit of adjuvant chemotherapy
for visceral or head and neck soft tissue sarcomas.
Four additional randomized trials explored the benefit of anthracycline and ifosfamidebased combination adjuvant chemotherapy in extremity STS [6-10], two of which
suggest a possible survival benefit for adjuvant chemotherapy [6-8]:

In an Italian trial in which 46 percent of the enrolled patients had either synovial
sarcoma or liposarcoma (two relatively chemosensitive histologies), 104 patients
with high grade large (≥5 cm) or recurrent spindle cell sarcomas involving the
extremities or girdles were randomly assigned to no postoperative therapy or to
five cycles of chemotherapy [6,7]. Chemotherapy consisted of a dose intensive
56
epirubicin/ifosfamide combination (epirubicin 60 mg/m2 on days 1 and 2 plus
ifosfamide 1.8 g/m2 on days 1 to 5) with mesna and granulocyte colonystimulating factor support. Accrual was prematurely discontinued at two years,
when a significant difference in the cumulative incidence of distant metastasis was
found (45 versus 28 percent), favoring the chemotherapy group.
Four-year overall survival was significantly greater in favor of chemotherapy (69
versus 50 percent), but the difference that favored the chemotherapy group lost
statistical significance with median follow-up of over seven years, a finding that
was attributed to the limited number of enrolled patients. Curiously, overall
relapse rates (local and distant) were similar in the two groups (44 and 45
percent).

It is difficult to interpret these results, since the main expected benefit of adjuvant
systemic chemotherapy is to reduce the rate of distant relapse. However, this may
have reflected a preponderance of patients with local recurrence later amenable to
local surgical salvage approaches.
A follow-up Italian trial randomly assigned 88 patients with high-risk extremity
sarcoma to surgery with or without RT (n = 43) or to surgery plus chemotherapy
(n = 45, 26 with epirubicin alone, and 19 to epirubicin plus ifosfamide) with or
without RT [8]. The five-year survival rate of patients treated with chemotherapy
was significantly higher than that of patients who did not receive chemotherapy
(72 versus 47 percent). However, the large number of treatment variables and
the small number of studied patients makes interpretation of this result difficult.
In contrast to these results, a survival benefit from adjuvant doxorubicin and ifosfamidecontaining chemotherapy could not be shown in two other trials [9,10]:


The EORTC randomly assigned 351 patients with completely resected STS (67
percent extremity tumors, 60 percent high-grade, 40 percent ≥10 cm) to
observation versus five cycles of adjuvant chemotherapy (doxorubicin 75 mg/m2
and ifosfamide 5 g/m2 per cycle) [10]. The estimated five-year relapse-free
survival was similar in both arms as was overall survival (67 versus 68 percent,
HR 0.94, 95% CI 0.68-1.31). Interpretation of these results is limited by the
inclusion of patients with nonextremity, small, and low/intermediate-grade
primaries, as well as the relatively low ifosfamide dose.
An Austrian trial of 59 patients assigned to perioperative chemotherapy or surgery
alone was also negative, but the small number of patients makes it likely that the
study was underpowered to detect a small difference between the arms, if one
were present [9].
Updated meta-analyses — An updated 2008 meta-analysis was conducted on published
data from 18 randomized trials of 1953 patients with localized and potentially resectable
soft tissue sarcoma that were reported between 1973 and 2002, including the Austrian
and both Italian trials discussed above, but not the most recent large EORTC trial [11].
Five of the trials used doxorubicin plus ifosfamide, while the others used doxorubicin
alone or in combination with other agents.
The odds ratio (OR) for local recurrence was 0.73 (95% CI 0.56 to 0.94) in favor of
chemotherapy; the corresponding value for distant and overall recurrence was 0.67
(95% CI 0.56 to 0.82), again favoring chemotherapy. These values are nearly identical
to those found in the earlier meta-analysis (see 'SMAC meta-analysis' above).
However, in contrast to the earlier analysis, the use of doxorubicin with ifosfamide was
associated with a statistically significant overall survival benefit (OR for death 0.56, 95%
CI 0.36 to 0.85). The absolute risk reduction for doxorubicin in combination with
57
ifosfamide was 11 percent (30 versus 41 percent risk of death). Benefit could not be
shown for doxorubicin alone (OR 0.84, 95% CI 0.68 to 1.03), implying the fundamental
importance of ifosfamide in the adjuvant treatment of sarcomas overall.
Pooled analysis of the EORTC trials — In contrast to this result, a pooled analysis of
individual patient data from the two largest adjuvant trials of doxorubicin and
ifosfamide-based chemotherapy (both performed by the EORTC [10,12] and totaling 819
patients) presented at the 2008 ASCO meeting was negative [13]. Compared to surgery
alone, the use of postoperative adjuvant chemotherapy was not associated with a
significant survival benefit, except in the subset of patients undergoing incomplete (R1)
resection. In multivariate analysis, tumor size, histologic subtype, and grade were not
associated with any progression-free or overall survival benefit from adjuvant
chemotherapy.
Impact of histology — Adjuvant clinical trials in adult sarcomas have, out of necessity,
included patients with multiple histologies, in contrast to pediatric studies, which focus
on one specific sarcoma subtype. It is well recognized that myxoid/round cell
liposarcomas and synovial sarcomas are relatively chemosensitive subtypes of STS, at
least in the setting of metastatic disease. (See "Systemic treatment of metastatic soft
tissue sarcoma", section on 'Histologic subtype and response to chemotherapy'.)
Although it has been proposed that the benefit of adjuvant chemotherapy may be
preferentially seen when patients are selected based upon tumor histology, grade [14]
or tumor size, this hypothesis has never been validated in a prospective clinical trial in
adult sarcoma patients, nor in any of the pooled analyses of randomized trial data
[11,13].
Furthermore, the results from retrospective reports evaluating adjuvant chemotherapy in
patients with the more chemotherapy-sensitive histologic subtypes are conflicting [1519]. While three contemporary retrospective series suggest a potential survival benefit
for adjuvant chemotherapy in patients with the liposarcoma and synovial sarcoma
subtypes of extremity STS [15,16,18], two others do not [17,19]. As examples:


Benefit for adjuvant chemotherapy was suggested in a single-center Italian report
of 251 patients (aged 5 to 87 years) with a localized synovial sarcoma [16].
Adjuvant chemotherapy was administered to 61 of 215 patients who had a
macroscopically complete resection (28 percent), while the remainder received no
adjuvant systemic therapy. Five-year metastasis-free survival was greater for
those treated with chemotherapy (60 versus 48 percent), and benefit appeared to
be greatest for patients aged 17 or older who had tumors measuring >5 cm (fiveyear metastasis-free survival 47 versus 27 percent, respectively).
On the other hand, a lack of long-term benefit from adjuvant chemotherapy was
suggested in a report of the combined experience of two major cancer cancers
(MSKCC and M. D. Anderson) that included 674 consecutive adults undergoing
resection of a high-grade, ≥5 cm extremity STS between 1984 and 1999 [17].
Adjuvant doxorubicin-based chemotherapy was administered to 336 (50 percent),
while the remainder received local therapy only.
Although not a randomized trial, there were no statistically significant differences
between the chemotherapy and local therapy alone groups with respect to tumor
size, anatomic site, histopathologic subtype, or resection margin status. With a
median follow-up of 6.1 years, the effect of chemotherapy appeared to vary over
time. During the first year, the HR for disease-specific survival for chemotherapy
versus no chemotherapy was 0.37 (95% CI 0.20-0.69); thereafter, the HR was
1.36 (95% CI 1.02-1.81) and did not vary according to histology or tumor size.
58
Interpretation of retrospective data such as these is hampered because several
biases are operative that favor the control arm:


Chemotherapy was likely recommended for those patients whose tumors were
thought to have the highest risk of recurrence, while those thought to have more
favorable outcomes were not offered chemotherapy.
Although none of the differences were statistically significant, there were
differences in tumor histology and size between the two groups. In the combined
report from MSKCC and M. D. Anderson, 50 percent of the patients who did not
receive chemotherapy had 5 to 10 cm primary tumors, while only 42 percent of
those receiving chemotherapy had this relatively favorable tumor size. It is well
recognized that the risk of metastasis increases for every centimeter increase in
the size of a primary sarcoma. In addition, 21 percent of the control patients had
liposarcoma histology compared to 14 percent in the treatment group.
These data can be interpreted positively or negatively; the negative view is that overall
survival was not improved with the use of chemotherapy. The positive view is that
patients with inferior prognosis had their survival improved to that of lower risk patients
with the use of systemic chemotherapy in the adjuvant setting.
Summary — The role of chemotherapy for patients with a resected extremity STS
remains uncertain and controversial [20,21]. The updated meta-analysis from the
Sarcoma Meta-Analysis Collaboration [11] suggests that use of an optimal, adequately
dosed anthracycline/ifosfamide-containing regimen significantly prolongs survival in
patients with resected extremity STS [11] with the ifosfamide component as the more
important of the two drugs. However, the analysis did not include data from the single
largest negative trial, which so far has been reported only in abstract form [12]. A
preliminary report of a pooled analysis of this trial and another European large trial, both
of which tested the value of an anthracycline and ifosfamide-containing regimen,
indicated no benefit from adjuvant anthracycline-ifosfamide chemotherapy [13].
Taken together, despite the most recent positive meta-analysis, it is difficult to
recommend adjuvant chemotherapy as a standard practice for all patients with extremity
STS. If there is a survival benefit for doxorubicin-based adjuvant chemotherapy, it
appears to be small, no more than 5 percent absolute increase in survival at 5 to 10
years [11]. Conversely, the positive meta-analysis from 2008 is arguably the strongest
evidence in support of the use of adjuvant chemotherapy. The challenge wrought by
treating many different sarcoma subtypes with one particular therapeutic plan has not
worked in other cancers, and should be not be expected to apply to what are 50 or more
sarcoma subtypes.
In keeping with the consensus-based guidelines of the National Comprehensive Cancer
Network (NCCN) and the European Society of Medical Oncology [22], which encompass
adjuvant chemotherapy as an option for high-risk patients, our present approach is to
individualize therapy, taking into consideration the patient's performance status,
comorbid factors (including age), site of disease, and histologic subtype (eg, younger
patients with synovial sarcoma or the round cell version of myxoid liposarcoma). The
potential for benefit from adjuvant chemotherapy must be discussed in the context of
expected treatment-related toxicities, including potential sterility in younger people,
cardiomyopathy, renal damage, second cancers, and overall impairment of quality of life.
Even for those patients in whom the decision has been made to administer adjuvant
chemotherapy, the optimal regimen is undefined. We prefer five to six cycles of
doxorubicin (usually 75 mg/m2 per cycle in split bolus doses or continuous infusion over
three days), ifosfamide (9 to 10 g/m2 in split doses over three hours per day for three to
four days), with mesna [AIM (table 1 and table 2)] rather than MAID (mesna,
doxorubicin, ifosfamide, and dacarbazine [23]) since this permits the administration of
59
maximal doses of the two most active drugs for sarcoma (doxorubicin and ifosfamide),
rather than adding myelotoxicity with dacarbazine. Three cycles of chemotherapy may
suffice, although the data supporting this statement are limited to a single trial of three
versus five cycles of chemotherapy in 328 patients with high-risk (deeply seated, high
grade, or large [≥5 cm] primary, or locally recurrent) extremity sarcomas [24]. Given
the limitations of the available data, we still consider that five or six cycles of
chemotherapy represents the preferred approach. (See "Treatment protocols for soft
tissue and bone sarcoma".)
Given that the benefit of chemotherapy appears to be dependent upon the use of
ifosfamide, at least from the most recent meta-analysis, and the known age-dependent
toxicities of ifosfamide, it makes a decision to use adjuvant chemotherapy in older
patients even more difficult. In view of the uncertainty of long-term benefit for patients
with most sarcoma subtypes, extreme caution is indicated in treating elderly patients
with adjuvant chemotherapy.
NEOADJUVANT CHEMOTHERAPY — Theoretical advantages to neoadjuvant approaches to
therapy include tumor cytoreduction, immediate treatment of micrometastases, and an
early indication as to the effectiveness of chemotherapy/radiotherapy. Cytoreduction
may allow less radical surgical resection to be performed, and this approach is often
considered in patients with large extremity sarcomas, particularly if the patient is a
borderline candidate for limb salvage surgery.
Most often, when induction therapy is considered for a patient with a large or recurrent
extremity sarcoma, particularly if limb salvage is an issue, radiotherapy is chosen with or
without chemotherapy. Adjuvant radiotherapy with and without chemotherapy is
discussed in detail elsewhere.
The benefit of induction chemotherapy alone in this setting is uncertain. Adequately
powered, randomized phase III trials are not available, and the results of uncontrolled
studies are conflicting [25,26]. A randomized phase II EORTC study in which 150
patients were randomly assigned to three cycles of neoadjuvant doxorubicin (50 mg/m2
per cycle) plus ifosfamide (5 g/m2 per cycle) versus surgery alone failed to show better
survival in the chemotherapy arm, and the trial was stopped before expansion into a
phase III study [27]. The low chemotherapy intensity used in this study may have
contributed to the negative result.
At least some data supports the use of neoadjuvant trabectedin, where available, in
patients with locally advanced myxoid liposarcoma. In an uncontrolled study of 23
patients, seven had an objective partial response, and at surgery, three had a pathologic
complete response after three to six cycles of trabectedin (1.5 mg/m2 over 24 hours,
once every 21 days) [28]. Trabectedin is available in Europe and in some other
countries, but not in the US. (See "Systemic treatment of metastatic soft tissue
sarcoma", section on 'Trabectedin'.) Given the lack of data regarding the impact of
adjuvant or neoadjuvant trabectedin on long-term outcomes, its use in these settings is
still considered experimental.
Chemotherapy with regional hyperthermia — A European randomized trial reported
benefit from the addition of regional hyperthermia to neoadjuvant chemotherapy
compared to neoadjuvant chemotherapy alone among patients with large high grade
tumors, or initially unresectable disease. This approach, which is not widely used outside
of Europe, is discussed in detail elsewhere. (See "Treatment of locally recurrent and
unresectable, locally advanced soft tissue sarcoma of the extremities", section on
'Chemotherapy with regional hyperthermia'.)
Summary — The role of neoadjuvant chemotherapy in the management of STS remains
undefined. Nevertheless, NCCN guidelines suggest that preoperative chemotherapy
(followed by postoperative RT) is an acceptable alternative to preoperative RT or
preoperative chemoradiotherapy for patients with large (>10 cm) potentially resectable
60
STS or if there is concern for adverse functional outcomes from initial surgery. For most
of these patients, we prefer radiation therapy with or without chemotherapy rather than
chemotherapy alone.
These patients should be managed in a center with multidisciplinary expertise in the
management of STS, and ideally, treatment should be administered in the context of a
clinical trial. If such a trial is not available or if patients are ineligible, we suggest
sequential rather than concurrent chemotherapy and RT. We administer chemotherapy
first (typically AIM rather than MAID) followed by RT and then surgery. Others utilize
concomitant chemoradiotherapy using low radiosensitizing doses of chemotherapy
during RT. The specific approach used remains a function of an institution's experience
and expertise. However, it should be emphasized that there are no data that
simultaneous administration of chemotherapy and RT improves local control over
sequential use; it is well recognized from larger randomized studies that adjuvant
chemotherapy improves local relapse-free survival rates. (See "Local treatment for
primary soft tissue sarcoma of the extremities and chest wall", section on 'Initial
chemoradiotherapy for large high-grade STS'.)

SUMMARY AND RECOMMENDATIONS


Surgical resection is the cornerstone of treatment for virtually all patients with an
extremity soft tissue sarcoma. The combination of surgery and radiation therapy
(RT) achieves better outcomes than either treatment alone for nearly all soft
tissue sarcomas more than 5 cm in greatest dimension. (See 'Introduction'
above.)
Systemic chemotherapy is a routine component of treatment for several soft
tissue sarcomas that occur predominantly in children (ie, rhabdomyosarcoma,
Ewing sarcoma). (See 'Pediatric-type sarcomas' above.)
However, despite many randomized trials, the role of adjuvant chemotherapy for
the more common adult subtypes of soft tissue sarcoma (such as liposarcoma,
synovial sarcoma, and leiomyosarcoma) remains uncertain:



The most recent analysis from the Sarcoma Meta-Analysis Collaboration (SMAC)
suggests a significant 11 percent improvement in survival for doxorubicin and
ifosfamide-based adjuvant chemotherapy compared to resection alone [11].
However, a pooled analysis of individual patient data from the two largest
adjuvant trials of doxorubicin and ifosfamide-based chemotherapy (both
performed by the EORTC [10,12], only one of which was included in the SMAC
meta-analysis) presented at the 2008 ASCO meeting was completely negative
[13]. (See 'Pooled analysis of the EORTC trials' above.)
There is no evidence that adjuvant chemotherapy is relatively more beneficial for
the chemotherapy-sensitive subtypes of STS. (See 'Impact of histology' above.)
Thus, in our view, this approach cannot be adopted as a standard treatment for all
extremity soft tissue sarcomas, regardless of histology.

In keeping with the guidelines of the National Comprehensive Cancer Network
(NCCN) and the European Society for Medical Oncology [22], we suggest that the
appropriateness of adjuvant chemotherapy be addressed on a case by case basis,
taking into consideration the patient's performance status, comorbid factors
(including age), disease location, tumor size, and histologic subtype. The potential
for benefit must be discussed in the context of expected treatment-related
61
toxicities including sterility in younger individuals, cardiomyopathy, renal damage,
second cancers, and overall impairment of quality of life.

For patients who decide to undergo adjuvant chemotherapy despite the
uncertainty of benefit and the potential for treatment-related toxicity, we
recommend using a regimen that contains both ifosfamide and doxorubicin (Grade
1A). We prefer doxorubicin plus ifosfamide and mesna [AIM (table 2 and table 1)]
rather than the MAID regimen. (See 'Summary' above and "Treatment protocols
for soft tissue and bone sarcoma".)
Neoadjuvant therapy is most often considered in the setting of a large or
recurrent high-grade tumor, particularly if limb salvage is an issue. In these
situations, RT is most commonly selected with or without chemotherapy. The
optimal neoadjuvant regimen, and how best to integrate radiation therapy,
chemotherapy, and surgery are unknown.
The benefit of induction chemotherapy alone in this setting is uncertain. However, NCCN
guidelines indicate that preoperative RT alone, preoperative chemotherapy (with
postoperative RT), or preoperative chemoradiotherapy are all acceptable options. Where
available, another option is neoadjuvant chemotherapy combined with regional
hyperthermia.
There are no data to support one approach over the other, and the specific neoadjuvant
approach chosen typically depends upon institutional expertise and experience. If
possible, we prefer that these patients be treated in the context of a clinical trial.
Bone sarcomas: Preoperative evaluation, histologic classification, and principles of
surgical management
62
63
64
65
INTRODUCTION — Osteosarcoma is the most common primary malignant tumor of bone.
Osteosarcomas are characterized by the production of osteoid tissue or immature bone
by the malignant cells [1-3]. Osteosarcomas are uncommon tumors compared to
carcinomas, with approximately 900 cases diagnosed each year in the United States,
mainly in children and adolescents [4]. Among 15 to 29 year olds, bone tumors account
for 3 percent of all tumors, and osteosarcoma accounts for about one-half of these cases
[5]. Most osteosarcomas present as high-grade tumors and most are located around the
anatomic regions of high growth rate.
The survival of patients with malignant bone sarcomas has improved dramatically over
the past 30 years, largely as a result of chemotherapeutic advances. Before the era of
66
effective chemotherapy, 80 to 90 percent of patients with osteosarcoma developed
metastatic disease despite achieving local control from surgery and died of their disease.
It was surmised (and subsequently demonstrated [6]) that the majority of these patients
had subclinical metastatic disease that was present at the time of diagnosis, even in the
absence of overt metastases.
In osteosarcoma, chemotherapy can successfully eradicate microscopic deposits in the
majority of cases if initiated at a time when disease burden is low (ie, following resection
of the primary tumor). As a result, all patients with intermediate- or high-grade
osteosarcoma receive chemotherapy, although the optimal timing (ie, preoperative or
postoperative) is controversial (see 'Adjuvant therapy' below) [7]. Low-grade
osteosarcomas, such as parosteal osteosarcomas, are not treated routinely with
chemotherapy because the risk of metastatic spread is low.
With modern therapy, approximately two-thirds of patients with non-metastatic
extremity osteosarcoma will be long-term survivors, up to 50 percent of those with
limited pulmonary metastases may be cured of their disease, and long-term relapse-free
survival can be expected in about 25 percent of those who present with metastatic
disease overall [8-12].
Surgical management has evolved in parallel with the emergence of effective
chemotherapy. Although complete extirpation of the tumor remains the primary
objective, the nature and scope of the approach taken to accomplish this goal has
changed, with an emphasis on more conservative surgery in order to maintain function.
Functional outcome depends not only on the extent of resection and the amount of
muscle that is removed, but also the quality of the reconstruction and its associated
complications. Limb-sparing surgery rather than amputation is now possible in the
majority of patients, particularly when preoperative (neoadjuvant) chemotherapy is
used.
Here we will discuss the principles of surgical management for primary bone sarcomas.
Although the focus of this topic review will be on osteosarcoma, most of the same
surgical principles apply to other bone sarcomas as well. Intermediate or high-grade
fibrosarcoma of bone (previously referred to as malignant fibrous histiocytoma) is
treated in a similar manner as osteosarcoma. Other bone sarcomas, such as
leiomyosarcoma and chondrosarcoma, may be managed with a slightly different
approach because of differences in their responsiveness to chemotherapy and radiation
therapy. As an example, neoadjuvant chemotherapy is usually not considered routine for
chondrosarcomas, because they are relatively chemoresistant. Leiomyosarcoma of bone
has typically been treated in a similar manner to that of the leiomyosarcoma in soft
tissues. In contrast, Ewing sarcoma is usually approached initially with systemic
chemotherapy due to its chemosensitivity. Radiation and/or surgery may be used to aid
in local control for Ewing sarcoma.
Surgery can be a component of management of metastatic disease both at initial
presentation, and at the time of recurrence, is addressed elsewhere.
PREOPERATIVE EVALUATION — The goal of the preoperative evaluation is to establish
the tissue diagnosis, evaluate disease extent, and assess the feasibility of a limb-sparing
approach. Clinical staging includes all of the data obtained prior to definitive therapy,
including the results of imaging, physical examination, laboratory studies, and tissue
biopsy.
A thorough history and physical examination that evaluates all systems is necessary
prior to definitive treatment. However, physical examination should focus particularly on
the involved bone or joint. The regional lymph nodes (although they are a rare site for
metastases), other bones (sometimes synchronous but may be site for distant disease),
and lungs (the most common metastatic site) are sites for disease dissemination.
67
Radiographic imaging — Plain radiographs are nearly always a good way to begin to
evaluate a bone lesion, as they provide data that often cannot be replicated even with
MRI or CT. Nonetheless, although plain radiographs can often predict the probable
histology of a potentially malignant bone lesion, the definition of tumor size and local
intraosseous and extraosseous extent is most accurately achieved by magnetic
resonance imaging (MRI). The entire involved bone should be imaged to avoid missing
skip metastases (ie, medullary disease within the same bone, but not in direct contiguity
with the primary lesion) (image 1).
CT scans are best suited to evaluate the thorax for metastatic disease, which is essential
because approximately 80 percent of metastatic lesions in osteosarcoma occur in the
lungs [13,14]. The most common metastatic site for all bone sarcomas is pulmonary.
Thin-section imaging of the chest using high-resolution helical CT is the preferred
modality, detecting approximately 20 to 25 percent more nodules than conventional CT,
and the reliable detection of nodules as small as 2 to 3 mm.
Radionuclide bone scanning with technetium is the preferred method for evaluating the
entire skeleton for the presence of multiple lesions and help in identifying skip
metastases [15]. Although positron emission tomography (PET) scans may have greater
utility for assessing the response of the primary tumor to neoadjuvant chemotherapy, at
least one study suggests it is inferior to radionuclide bone scanning for the detection of
osseous metastases from osteosarcoma [16] and to spiral (helical) CT for detecting
pulmonary metastases [17]. Nevertheless, guidelines from the National Comprehensive
Cancer Network (NCCN) suggest a PET scan and/or bone scan in the workup of a
suspected osteosarcoma, and imaging guidelines from the Children’s Oncology Group
Bone Tumor Committee for both osteosarcoma and Ewing sarcoma recommend
radionuclide bone scan and/or PET scan for whole body staging. This subject is
addressed in detail elsewhere.
Tissue biopsy — Biopsy of the tumor completes the staging process. As with soft tissue
sarcomas, the biopsy must be carefully planned to ensure that adequate tissue is
obtained for diagnosis without compromising the opportunity for limb salvage. Biopsies
should take place after the completion of the staging studies, and the surgeon,
radiologist, and pathologist should review these studies in detail so that each member of
the team is fully appraised of the diagnostic considerations.
Either a core needle or open biopsy may be performed as long as adequate tissue is
obtained. For CT-guided core biopsies, multiple cores of tissue should be obtained for
frozen section (to ensure that adequate tissue has been obtained), permanent
hematoxylin and eosin (H&E) stained sections, microbial culture (in case the diagnosis
should turn out to be osteomyelitis), and one core is reserved for special stains or
cytogenetic studies.
Although fine needle aspiration biopsy under radiologic guidance may obviate the need
for open biopsy, the risk of a nondiagnostic or nonrepresentative sample must be
considered [18]. In one report of 359 patients with musculoskeletal lesions, the accuracy
rates of CT-guided biopsies and fine needle aspirates were 74 and 63 percent,
respectively [19].
If an open biopsy is performed, the incision should be placed in accordance with the
planned surgical resection; the primary tumor and the entire biopsy tract should be
resected en bloc. Meticulous hemostasis and the judicious use of a drain are important to
avoid the spread of hematoma-containing tumor cells. If a soft tissue mass is not
present, or material is nondiagnostic, a bone defect may be required to obtain tissue. If
so, it should be a small, oval defect, and a polymethylmethacrylate plug may be used to
close the hole in order to minimize hematoma.
Tumor staging — The staging system used primarily for bone sarcomas was developed
by Enneking et al at the University of Florida and based upon a retrospective review of
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cases of primary malignant tumors of bone treated by primary surgical resection (table
1) [20,21]. This system characterizes nonmetastatic malignant bone tumors by grade
(low grade [stage I] versus high grade [stage II]), and further subdivides these stages
according to the local anatomic extent. The compartmental status is determined by
whether the tumor extends through the cortex of the involved bone. Patients with
distant metastases are categorized as stage III.
The American Joint Committee on Cancer (AJCC) adopted a similar staging system in its
1997 fifth edition [3], but this was modified in 2002, with additional minor refinements
in the latest 2010 edition (table 2) [22]. The TNM classification is not widely used for
primary bone tumors, particularly for Ewing sarcoma, since it does not take into account
several important clinicopathologic features such as primary tumor site, patient age, and
histology. The staging classification used for Ewing sarcoma is complex and discussed in
detail elsewhere.
HISTOLOGIC CLASSIFICATION — Primary bone sarcomas are classified according to
their cytologic features and cellular products (eg, osteoid) (table 3). The different types
of osteosarcomas are briefly described here. For other sarcomas of bone (eg,
chondrosarcoma), subtypes exist as well, based upon the histology. .) The histologic
appearance of the Ewing sarcoma family of tumors is described elsewhere.
The diagnosis of a primary bone malignancy should be rendered only in the setting of
radiologic studies, including plain films and MRI or CT of the primary lesion. While
radiologic or histologic findings may not be specific by themselves, a histologic diagnosis
in the context of consistent radiographic findings secures the diagnosis with much
greater certainty.
The histologic diagnosis of an osteosarcoma depends upon the presence of a malignant
sarcomatous stroma associated with the production of tumor osteoid or tumor bone.
Osteosarcomas are thought to arise from a mesenchymal stem cell that is capable of
differentiating towards fibrous tissue, cartilage, or bone. As a result, they share many
features with chondrosarcomas and fibrosarcomas of bone. However, chondrosarcomas
and fibrosarcomas of bone are distinguished by their lack of osteoid substance, which is
required for the diagnosis of osteosarcoma (table 4). Of note, the degree of osteoid
production in osteosarcomas may be limited; because of this and variability in tumor
morphology, electron microscopy may be required for histologic confirmation.
The largest group of osteosarcomas are conventional (intramedullary high grade)
osteosarcomas, which account for approximately 90 percent of all osteosarcomas [23].
These tumors usually involve the metaphysis of long bones in adolescents and young
adults (figure 1).
Conventional osteosarcomas can be classified as osteoblastic, chondroblastic, or
fibroblastic, depending upon the predominant cellular component (table 3); all are
managed similarly if they are of the same grade:



Osteoblastic osteosarcoma, which accounts for 50 percent of cases, is
characterized by abundant osteoid production, which forms a fine or coarse
lacelike pattern around the tumor cells; massive amounts may result in distortion
of the malignant stromal cells. Some tumors contain thick trabeculae of osteoid
that form an irregular anastomosing network. The amount of mineralization is
variable.
Fibroblastic osteosarcomas are predominantly composed of a high-grade spindle
cell stroma that contains only focal osteoid production. More pleomorphic tumors
may resemble malignant fibrous histiocytoma, but the distinction can be made by
the identification of osteoid.
In chondroblastic osteosarcomas, cartilaginous matrix production may be evident
throughout most of the tumor or only in certain locations, underscoring the
heterogeneity of these tumors. While some chondroblastic osteosarcomas tend to
69
be lower grade, the chondroid areas may contain cytologically atypical cells that
are characteristic of higher grade tumors. These chondroblastic foci are admixed
with malignant spindle cells that produce osteoid trabecula.
In addition to the three categories of conventional osteosarcoma, there are several
variants (ie, telangiectatic, small cell, multifocal, and the malignant fibrous histiocytoma
[fibrosarcoma] subtypes) that were originally thought to carry a worse prognosis.
However, with modern aggressive therapy, they behave in general like conventional
osteosarcomas and are treated similarly:



Small cell osteosarcoma is noteworthy for the confusion that may arise in
distinguishing it from other "small round blue cell tumors" such as Ewing sarcoma
by conventional light microscopy of H&E stained sections [24].
Immunohistochemical staining, cytogenetics, and molecular genetic studies may
be required to establish the diagnosis.
Telangiectatic osteosarcoma has a purely lytic appearance on plain radiographs,
and there is a high rate of pathologic fracture [25]. Grossly, these tumors appear
like a "multicystic bag of blood"; a solid mass of tumor is usually absent [23].
Telangiectatic osteosarcomas have overlapping features with aneurysmal bone
cysts and giant cell tumors. However, the cells are highly pleomorphic, unlike the
benign appearance of the aneurysmal bone cyst. Because they often contain
minimal osteoid and numerous multinucleated giant cells, they may be mistaken
for a giant cell tumor. Although once thought to carry a poorer prognosis that
conventional osteosarcomas, more recent series indicate similar survival with
multimodality therapy [25,26].
Fibrosarcoma of bone (previously referred to as malignant fibrous histiocytoma of
bone) has an appearance similar to osteosarcoma, but without osteoid production.
Although these tumors tend to have a lower rate of tumor necrosis following
induction chemotherapy, long-term survival rates for intermediate and high-grade
fibrosarcomas of bone are similar to conventional osteosarcomas [27], with the
possible exception of spine primaries [28].
With very careful examination, occasionally osteoid will be found in rare sections
of tumor, suggesting that this subtype of primary bone tumor may represent an
undifferentiated version of a more classic osteosarcoma.
In contrast to these variants, surface or juxtacortical osteosarcomas differ as a group
with respect to prognosis and therapy. These osteosarcomas include [29-31]:



Parosteal osteosarcoma is a low-grade osteosarcoma
Periosteal osteosarcomas are usually chondroblastic intermediate grade tumors
(image 2)
There are rare high-grade surface osteosarcomas
Among the surface osteosarcomas, surgery alone may be curative, particularly for
tumors that are low-grade and do not enter the marrow cavity [32,33]. However, at
least some data support the benefit of adjuvant chemotherapy in periosteal and highgrade surface osteosarcomas [31]. Given the rarity of this diagnosis, it is worthwhile
obtaining a second opinion regarding the pathology and radiology for such tumors at
expert centers.
Because of the rarity of osteosarcoma in adults, other cancers should be considered in
the differential diagnosis, such as primary lymphoma of bone and metastatic carcinoma,
in addition to the primary bone tumors discussed above. (See "Primary lymphoma of
bone".)
70
Besides osteosarcomas, fibrosarcomas, and chondrosarcomas, other less common
primary bone tumors include primitive neuroectodermal tumor/Ewing sarcoma,
chordomas, angiosarcomas (a subtype with a particularly high rate of metastatic disease
at presentation [34]), and a variety of other rare tumor types (table 3). Histologic
characteristics of the Ewing sarcoma family of tumors are discussed elsewhere.
SURGICAL MANAGEMENT OF THE PRIMARY TUMOR — Despite the favorable response of
osteosarcomas to chemotherapy (see 'Neoadjuvant chemotherapy' below), surgery is a
necessary component of curative therapy [35]. The specific surgical procedure is
dictated by the location and extent of the primary tumor [36]. Axial tumors tend to do
worse probably because they are larger when discovered and more difficult to resect.
Although all patients with extremity sarcomas are candidates for amputation, emphasis
on functional outcome has focused efforts on limb-sparing procedures. However, not all
patients are candidates for more conservative surgery (see 'Patient selection' below). In
order to avoid sacrificing oncologic outcome, tumor control must be the primary
therapeutic concern, and functional outcome a secondary goal. One of the most
important tasks of the preoperative evaluation is to assess the feasibility of performing a
limb-salvage procedure based upon the clinical presentation and disease extent (see
'Preoperative evaluation' above).
Types of resections — Bone resections fall into one of three categories, depending upon
the anatomic site and the extent of the involved bone that needs to be excised. Because
most bone sarcomas arise in the metaphysis of the long bones near a joint (figure 2),
the majority of resections, for tumors in the lower extremity, include both the segment
of tumor-bearing bone and the adjacent joint (osteoarticular resection). Most often, the
incision is performed through the joint (intraarticular resection); however, when the
tumor extends along the joint capsule or ligamentous structures or invades the joint, the
entire joint can be resected (extraarticular resection) to avoid cutting through tumor.
Less frequently, tumor arises within the diaphysis or shaft region of a long bone, and the
bone alone is resected (an intercalary resection). Uncommonly, extensive involvement
along the length of the bone precludes adequate resection and reconstruction without
sacrificing the entire bone, and a whole bone resection, including both proximal and
distal joints, is required.
Resection margins — An important consideration in selecting the type of operation is the
ability to attain a negative margin of resection with the planned surgical procedure. The
quality of the tissue forming the margin is as important as the distance between tumor
and uninvolved tissue. The Musculoskeletal Tumor Society recognizes a wide local
excision either by amputation or a limb-sparing procedure as the recommended surgical
approach to bone sarcomas [37]. The wide local excision removes the primary tumor en
bloc along with its reactive zone and a cuff of normal tissue in all planes. However, in
many cases, particularly for tumors involving the spine, wide local excision cannot be
accomplished easily. An "intralesional" surgical resection margin is more frequently
obtained during a procedure that removes the tumor in a piecemeal fashion or by
curettage, while a "marginal" resection margin refers to a situation where the
pseudocapsule and reactive zone surrounding the tumor form the surgical margin. These
operations may result in residual tumor cells being left behind.
Extremity lesions: limb-sparing procedures — For lesions involving either the upper or
lower extremity, limb salvage can improve functional outcome without sacrificing local
disease control as long as complete tumor resection is anatomically possible and
adjuvant chemotherapy is used [12,38,39]. Although the functional results are generally
better, the available data do not support the position that quality of life or long-term
psychosocial outcome is substantially superior after limb salvage than after amputation
[40-44]. There is, however, a higher complication rate in patients who undergo limb
salvage as compared to amputation [40,45].
71
Despite the increasing numbers of limb salvage procedures, there are no randomized
prospective studies that prove its oncologic safety compared to amputation. However,
retrospective series with long-term follow-up of patients with osteosarcoma who undergo
amputation or limb salvage do not show a difference in overall or disease-free survival
[46]. Nevertheless, appropriate patient selection is critical (see below). If there is any
doubt that a wide local excision can be accomplished, amputation, the oncologic "gold
standard", is the indicated procedure in order to avoid local recurrence, which is
invariably followed by metastatic tumor spread and diminished survival [47-50].
Compared to amputation, limb salvage procedures are usually associated with narrower
surgical margins, which can increase the likelihood of a local failure [48,51]. The degree
of chemotherapy-induced tumor necrosis and surgical margin status are the important
prognostic factors for local control [49,52]. For patients undergoing neoadjuvant
chemotherapy in order to increase the feasibility of a limb sparing procedure, it is
unclear whether the reduction in surgical margins afforded by a favorable antitumor
response increases the likelihood of a local recurrence. The available data are
contradictory. Several multicenter series suggest an increased risk of local recurrence,
even in patients with a good response to chemotherapy [49,51,53], while other single
institution studies indicate similar local recurrence rates for limb-sparing and amputation
procedures [48,52].
Patient selection — Tumor location and extent are the most important determinants of
the feasibility of limb-sparing surgery. Among the contraindications for limb-sparing
surgery are nerve and/or vessel encasement by tumor, the presence of a large biopsyrelated hematoma, and possibly the presence of a pathologic fracture.
A pathologic fracture is present at diagnosis or occurs during the course of treatment in
5 to 10 percent of patients with osteosarcoma (image 3). Historically a pathologic
fracture was considered an indication for immediate amputation because of the
theoretical presence of tumor cells within the hematoma, and a greater risk of both local
recurrence and shorter survival with limb-sparing procedures [54-58]. However, more
recent studies have suggested that limb salvage is possible with an acceptable rate of
local control:


A multi-institutional series from the Musculoskeletal Tumor Society compared
outcomes for 52 patients with osteosarcoma and a pathologic fracture versus
those in 55 concurrently treated patients, matched for age and tumor location,
who had an osteosarcoma without a pathologic fracture [54]. Overall, both fiveyear overall (55 versus 77 percent) and local recurrence-free survival rates (75
versus 96 percent) were significantly poorer for those presenting with a pathologic
fracture. However, there were no significant differences in outcome when limb
salvage was compared to amputation in patients with a pathologic fracture: 11 of
30 patients managed with limb salvage (37 percent) versus 10 of 22 who
underwent amputation (45 percent, p = 0.05) died of their disease.
A single-institution retrospective review compared outcomes of 31 patients with
high-grade osteosarcoma who presented with a pathologic fracture versus 201
patients without a pathologic fracture [59]. In the pathologic fracture group, 19
patients had limb salvage surgery (61 percent), while 12 underwent an
amputation; limb salvage surgery was performed in 86 percent of the non-fracture
group. Five-year overall survival was significantly worse for patients presenting
with a pathologic fracture (41 versus 60 percent), but there was no difference in
local recurrence rate after limb-sparing surgery in the pathologic fracture versus
no-fracture group (10 versus 8 percent).
Other reports indicate that healing of pathological fractures during neoadjuvant
chemotherapy may permit limb-salvage surgery to be undertaken safely, as long as wide
surgical margins can be achieved. In many of these series, the majority of patients were
72
treated with limb-sparing approaches, and the presence of a pathologic fracture did not
constitute a negative prognostic factor for either local recurrence or survival [55,60].
Despite these data, many investigators still consider a pathologic fracture to be a
relative rather than an absolute contraindication to limb-sparing procedures.
Indications for amputation — In certain circumstances, amputation or rotationplasty (see
below) may be preferred over limb-sparing surgery for extremity sarcomas. Prosthetic
improvements have enhanced the amputee's functional results. Furthermore, some
types of amputation do not require the patient to wear a prosthesis, and they are
associated with lesser cosmetic and functional deformity as compared with those
individuals who have undergone an amputation and need a prosthesis to return to the
normal activities of daily living.
Although amputation does not preclude a local recurrence, the risk is less than 5
percent. Stump recurrence has been attributed to extensive intramedullary tumor spread
and the existence of skip lesions. It is important to assess the joint that is adjacent to
the primary extremity sarcoma to determine whether an intraarticular or extraarticular
resection will be necessary and to exclude the presence of skip metastases within the
involved bone (image 1). Among the factors that lessen the likelihood of local recurrence
are a wide surgical margin and a good histologic response to neoadjuvant therapy (see
below) [49].
Rotationplasty and the skeletally immature patient — Growth considerations following
resection and reconstruction are not a major concern for patients with lower extremity
lesions who are at or near skeletal maturity or for lesions involving the upper extremity.
However, for skeletally immature children with lower extremity lesions, vigorous
functional demands, and limb length inequality following a limb-sparing procedure is a
major problem. In this setting, surgical options include rotationplasty, amputation, or
reconstruction with an expandable metal endoprosthesis. (See 'Allografts and
endoprostheses' below.)
The Van Ness rotationplasty is a surgical technique for lesions involving the femur that
was originally described in 1930. It involves resection of the tumor and surrounding
tissues as an intercalary amputation, saving only the sciatic nerve, while either twisting
and curling the femoral vessels or segmentally resecting a portion of the vessels with a
subsequent vascular anastomosis [61-63]. Typically, the distal femur and its adjacent
musculature are excised, and the tibia and foot preserved by maintaining an intact
neurovascular bundle. The tibia is then fixed with plates and screws to the proximal
femur, and the distal extremity rotated 180º, permitting the foot and ankle to function
like a knee (picture 1). The vessels adjacent to the tumor can be resected and
reanastomosed if necessary. The retained foot acts as the amputation stump for a
transtibial amputation, and this prosthetic arrangement requires less energy expenditure
than that required for a transfemoral amputation.
Although the appearance of the reconstructed limb is cosmetically displeasing, the major
advantage of rotationplasty in the skeletally immature patient is the ability to tailor the
limb length at maturity. Functional results are excellent, with patients able to achieve
recreational, sporting, and career goals [64].
A series of 25 children treated with rotationplasty focused on risk factors for failure and
postoperative complications [65]. The majority of cases (22 of 25) produced excellent
functional outcome. The few failures were a result of vascular impairment by the tumor,
necessitating amputation. Patients with larger tumors, unresponsiveness to
chemotherapy, or a preoperative pathologic fracture appeared to be at higher risk of
failure.
In view of these favorable functional results, rotationplasty is often the reconstructive
procedure of choice for children under the age of eight who have proximal lower
extremity sarcomas. However, some patients and their families refuse rotationplasty and
73
amputation, and allografts are frequently used to reconstruct the defect in the skeletally
immature patient, with standard limb equalizing procedures carried out at a later date.
An alternative to allografts is the use of expandable or modular metal prostheses which
can be lengthened as the child grows. All of these approaches have limitations, and their
advantages and disadvantages in very young patients are discussed below (see
'Reconstruction techniques' below).
Upper extermity lesions involving the shoulder — Tumors of the scapula present an
unusual challenge. Although subtotal or complete scapulectomy can be considered for
some lesions [66,67], limb reconstruction is difficult and shoulder morbidity may be
substantial. For massive tumors of the shoulder girdle (including the proximal humerus),
the Tikhoff-Linberg (interscapulothoracic) resection is an alternative to forequarter
amputation as long as resection of the brachial plexus is not necessary [68]. The
proximal humerus and scapula are resected without the need for bony replacement, and
the function of distal arm, elbow, and hand is preserved. Because the resulting shoulder
region is unstable, with telescoping of the intervening structures when stresses are
applied to the hand or forearm, stabilization is necessary using dacron tape. This is
usually sufficient to prevent telescoping and stress to the remaining neurovascular
structures. When the scapula can be preserved, an arthrodesis with or without allograft
can be attempted even if the surrounding deltoid and rotator cuff musculature requires
resection.
Non-extremity lesions — The principles derived from extremity sarcoma resections have
now been applied to the axial structures. Osteosarcomas involving the axial skeleton
have a worse prognosis than those involving the extremities, in part due to the difficulty
in achieving complete surgical resection in these difficult locations [69-71]. In particular,
primary malignant non-extremity tumors are more difficult to resect secondary to their
large size, surrounding neurologic and vascular structures, reconstructive challenges,
and frequent comorbidities.
Pelvic and spine tumors are associated with unique challenges. In the spine, en bloc
resections may be intralesional, marginal, or wide. Radical resections or removing the
entire epidural space is not feasible. The dura and epidural space offer a unique region
for tumor management.
Pelvic tumors — Pelvic tumors represent a unique challenge. A tumor arising in the
pelvis can involve a segment of nonarticular bone, the acetabulum, or both. En bloc
excision of the hemipelvis with preservation of the extremity (internal hemipelvectomy)
produces equivalent oncologic results when compared to external formal
hemipelvectomy (hindquarter amputation) and better functional outcome [72,73]. It is
preferred over external hemipelvectomy, usually because of patient preference.
External hemipelvectomy may be necessary in up to one-third of patients, and despite
this, local recurrence rates are high because of difficulty obtaining adequate margins
[74-77]. In a large series of 67 patients with pelvic osteosarcoma, 50 underwent surgical
excision, 12 of whom required external hemipelvectomy; the remainder had limb-sparing
procedures [76]. The incidence of local recurrence overall was 70 percent, and it was 62
percent for those undergoing definitive surgery. Despite the use of multiagent systemic
chemotherapy, the five-year overall and progression-free survival rates were only 27
and 19 percent, respectively. Postoperative radiation therapy improved the outcome for
patients with an intralesional or no surgical excision.
Hemipelvectomy has been combined with intraoperative radiation therapy (IORT) in an
attempt to improve local control [78]. Initial results are promising, but further clinical
experience is needed. (See "Radiation therapy for Ewing sarcoma family of tumors",
section on 'Radiation schedule'.)
The extent of resection determines the functional deficit and influences the decision
regarding the type of reconstruction, if any, to optimize function. An internal
74
hemipelvectomy may not require allograft or a metallic endoprosthesis reconstruction.
Resection without reconstruction is a reasonable option, particularly in view of the high
complication rate with reconstruction of pelvic defects using allografts (approximately 50
percent) [79]. The femur and remaining pelvis can be left flail and the gap is bridged by
scar tissue, or postoperative traction can be applied to initiate the development of scar
tissue. Although this allows for stable weight bearing, it also results in a significant limb
length inequality, and most patients require crutches for ambulation.
Metallic endoprosthesis reconstruction (saddle prosthesis) has occasionally been
successful, but fixation is extremely difficult and prosthesis loosening can be a problem
long-term [73,80,81]. Another method of obtaining structural integrity is to fuse the
proximal femur to the ilium or sacrum [82]. The choice of procedure is dependent on the
clinical situation and the surgeon and patient preference, but they in general offer
reasonable alternatives to external hemipelvectomy, with superior functional and
psychological results.
Spine tumors — The spine presents a particularly difficult problem with regard to surgical
margins. Local recurrence rates are closely tied to surgical margin status [69]. In one
report of 30 patients with primary sarcomas of the mobile spine, the resection was
classified as wide, marginal or intralesional in 23, 10, and 67 percent respectively [83].
Resection margins were histologically positive in 60 percent and associated with a
fivefold increased risk of a local recurrence. At least one series suggests an advantage
for either wide or marginal surgery compared to intralesional or no surgery for
osteosarcomas of the spine [69]. They recommended that these patients be treated with
a combination of chemotherapy and at least marginal surgery.
En bloc resection (vertebrectomy) followed by stabilization and fusion is possible with
wide margins in some cases as long as dural invasion is absent. If the tumor abuts or
invades the dura (image 4), a segment can be excised. However, this procedure may be
accompanied by seeding of tumor cells into the cerebrospinal fluid. Postoperative
(adjuvant) radiation therapy can be employed to manage a microscopically positive dural
margin. Largely because of the potential for dural involvement, local recurrence rates
are higher for tumors located in the vertebral body and posterior elements (particularly
those with extra-osseous extension into the canal and paraspinal region) as compared to
the anterior vertebral column.
Patients with sacral tumors do especially poorly. In one report that included 22 patients
with primary high-grade osteosarcoma of the spine or sacrum, all of whom received
neoadjuvant chemotherapy, only two of the 12 who underwent surgery had wide
excision to negative margins [69]. Although total sacrectomy may improve local control,
neurologic and sexual dysfunction is inevitable [84]. Local recurrence may still develop
despite maximal surgical resection and intraoperative or postoperative radiation therapy
[70,78].
Postoperative radiotherapy may be beneficial [69]. Newer methods of adjuvant radiation
therapy, including combined proton beam and photon irradiation using three dimensional
conformal techniques, may permit a higher dose of radiation to be administered while
sparing adjacent normal tissues [85].
Allograft reconstruction is an effective means of filling the massive osseous defects
following spine resection. Combined anterior and posterior instrumentation provides the
best stability following tumor vertebral body resection. In the anterior spine, femoral and
humeral shafts used to substitute for resected vertebral bodies have provided excellent
stability. Metal cages provide an alternative to allografts in the anterior spine, and they
do not require biologic healing of the graft to the host bone [86]. New posterior
instrumentation, bone graft products, and pedicle screws provide improved fixation and
better rates of fusion. In setting where radiation therapy has been used to improve local
control, complications such as fractures and non-unions may occur more frequently. The
75
bridging of a large osseous defect may also be augmented with vascularized grafts. (See
'Vascularized grafts' below.)
RECONSTRUCTION TECHNIQUES — The majority of patients with osteosarcoma will
require reconstructive procedures in order to restore structural integrity. However, some
locations and circumstances do not always require reconstruction to deal with the
surgical defect. As an example, pelvic tumors may not require postresection
reconstruction following an internal hemipelvectomy (see 'Non-extremity lesions' above).
Expendable bones that do not require replacement include the ulna, patella, fibula,
scapula, and ribs. Resection techniques for tumors in these locations are well described,
and the resultant functional disability without bony reconstruction is frequently minimal
with the exception of complete scapulectomy, which may result in significant morbidity,
especially if muscle loss is great.
For patients who do require reconstruction, available methods include metal
endoprostheses/hardware, allografts, arthrodeses, vascularized fibular transfers,
rotationplasty, and various unusual methods that are specific for certain anatomic
locations. The choice of reconstructive method should be individualized. The following
factors influence the selection of a reconstructive method [87]:







Anatomic location and integrity of the surrounding structures
The stage of disease and extent of resection
The tissue diagnosis
Preference of the surgeon
The likelihood and nature of complications related to a particular type of
reconstruction
The patient's age, expectations, and anticipated functional demands
The availability of the materials for the reconstructive procedure
Because the majority of patients receive preoperative (neoadjuvant) chemotherapy,
planning of the surgical procedure is essential in order to coordinate chemotherapy
schedules and anticipated bone marrow recovery with the time needed to manufacture a
prosthesis or procure the necessary reconstructive materials.
An understanding of the capabilities and limitations of available reconstructive
techniques is necessary so that the appropriate method is chosen for the surgical
reconstruction. A brief description of some of these techniques follows. Rotationplasty is
discussed above. (See 'Rotationplasty and the skeletally immature patient' above.)
Allografts and endoprostheses — Allografts and metal endoprostheses are common
means of reconstructing bone defects that result from sarcoma surgery. Other methods
listed below may be preferred to fill the osseous defect depending on the clinical
situation and the availability of the product.
Allografts — While autologous bone grafting is of limited use in patients undergoing
resection of bone tumors because of the large size of the defect, allografts have been
successfully used for many years. Allografts provide the potential for long-lasting
reconstruction of large bony defects by providing a structural lattice for the ingrowth of
the patient's own bone elements (image 5) [88-94]. The host normal tissue slowly
invades the allograft by creeping substitution of normal bone and vascular elements at
the osteosynthesis site and periosteum. Large segments of allografted bone probably do
not completely fill with autogenous bone, and this may lead to allograft fracture over
time (this occurs in about 18 percent of the cases). The articular cartilage is slowly
replaced by an inflammatory pannus-like tissue, and some patients may ultimately
require joint resurfacing.
Allografts are available from tissue banks and need to be matched to the size of the
resected bone. Although bone is a relative nonantigenic structure, matching for the class
II major histocompatibility antigens results in better clinical outcomes [95,96]. Freezing
76
further decreases the likelihood of immune rejection, and the addition of glycerol or
dimethyl sulfoxide during freezing preserves the articular cartilage somewhat. Soft
tissues are left attached to the allograft to increase function by providing a site of
attachment for host soft tissues. This is particularly important for reconstructions around
the knee.
The major advantages of allografts over endoprosthetic reconstruction are restoration of
bone stock, sparing of the uninvolved portion of adjacent joints, and providing a site of
attachment for host soft tissues. Intercalary allograft reconstructions tend to perform
better than osteoarticular grafts, and clearly better than allograft arthrodeses, which
have the highest rate of complications [97].
There are some disadvantages to allografts. Compared to metal endoprostheses,
allografts must be fixed to the host bone and allowed to heal. Thus, they must be
protected from weight bearing for prolonged periods. Early complication rates (15 to 20
percent) are higher than those seen in patients undergoing placement of metal
prostheses. While implant loosening does not occur as it does for metal prostheses,
nonunion and fractures may result in allograft failure [98]. As with endoprosthetic
reconstructions, infection in the reconstructed site is devastating and may necessitate
amputation of the extremity. Late complications include degenerative arthritis and joint
instability. Despite these limitations, satisfactory functional results are achieved in 70
percent of patients undergoing allografting [89,93,99,100].
Metal endoprostheses — Initially, the metallic implants that were used to reconstruct
bone defects following tumor resection were custom made and manufactured for specific
patient requirements. More recently, modular metal prostheses have become available
that permit reconstruction without having to resort to a custom implant. The
components are readily available and can be assembled at the time of surgery to match
the extent of the defect (image 6). Modular metal prosthetic reconstructions are
performed most frequently about the shoulder, hip, and knee [101,102]. Total femoral
reconstructions have been performed in certain circumstances.
Most bone tumors are located adjacent to joints, and metal endoprostheses are well
suited to joint replacement. The implants used for reconstruction after sarcoma surgery
are similar to those that are used in patients with arthritis. (See "Total joint replacement
for severe rheumatoid arthritis".) As compared to allografts, endoprostheses allow for
immediate joint stability and early weight bearing. However, they are not free of
complications, which include fatigue fracture, loosening, and infection. The fatigue
fracture potential of the metal is a design and stress problem that can be potentially
improved by manufacturing changes.
Loosening at the bone-cement interface is a function of repetitive stresses during
activities of daily living [87,103]. Loosening can be minimized by using a meticulous
cementing technique and stress-reducing total joint mechanics such as a rotating-hinge
knee design. Nevertheless, most, if not all, implants will need to be replaced at some
point in the long-term survivor's lifetime. The survivorship of the prosthetic arthroplasty
reconstruction varies, and ranges from 60 to 90 percent estimated survival at five years
to 40 to 80 percent at ten years [102,104-106]. These data have generated the impetus
for development of cementless or press-fit implants. Implants placed without cement
may have a better long term survival, but this is a controversial area.
Because the prostheses act as a large foreign body, infections, which occur in 2 to 5
percent of cases, are difficult to treat [87,102,104,105,107]. Deep infections usually
require removal of the implant and sometimes an amputation.
Expandable prostheses — Expandable prostheses have been developed for
reconstruction in skeletally immature children with malignant bone tumors [108-110].
Different types of prostheses are available; one type has a telescoping unit that can be
expanded using a gear device [110,111], and another employs the principle of a loaded
77
spring which is gradually released via external exposure to an electromagnetic field
[112]. Because these devices permit an expansion of the overall length of the
prosthesis, they can be implanted in skeletally immature patients, increasing the
numbers of those eligible for limb-salvage surgery.
Estimation of growth potential in the younger child is important in determining whether
this means of reconstruction is appropriate for the situation. The Lewis Expandable
Adjustable Prosthesis (LEAP) was initially successful in young patients (five to eight
years). However, newer expandable prostheses that can be lengthened without invasive
surgery are popular in this age group. One of these, the Phoenix, uses a magnetic field
to provide the energy to lengthen the prosthesis.
The modular prostheses are better for large preadolescent and adolescent children. Most
children require several lengthenings in those prostheses, and it is frequently necessary
to excise the pseudocapsule around the implant to gain length; as a result, the
lengthening procedures are not small operations.
Expandable prostheses frequently require replacement after they have been fully
extended because they lose some structural strength. Difficulties in using this prosthesis
occur primarily in the rehabilitation phase, but loosening, fatigue failure of the implant,
and inability to gain equal limb lengths can also occur. Close follow-up is crucial to
optimize the functional outcome and properly time periodic lengthenings.
Allograft-prosthetic composites — For extremity reconstructions, allografts can be
combined with metal prostheses (the prosthesis is cemented to the allograft) to form
what is called an allograft-prosthetic composite, or alloprosthesis (image 7). This has
certain advantages over allografts or metal prostheses alone. Since the articular surface
is formed by the metal portion of the construct, it does not fracture or collapse as may
happen with osteoarticular allografts. The allograft portion of the composite restores
bone stock and provides soft tissue attachment points for insertion of muscle tendons.
Even though a great deal of research has been done to improve attachments of muscle
units to prostheses, this is still an unsolved problem with this type of reconstruction.
Alloprosthetic reconstructions usually result in good or excellent functional results, but
the operation is more complex and time consuming than either osteoarticular allografts
or prostheses alone [113].
Arthrodesis — Arthrodesis (joint fusion) is important for tumors involving the spine;
otherwise, the hardware fails as a result of nonunion, and pain may be a persistent
complaint. In the spine almost all fusions require implantation of bone graft material.
Transplantation of structured or morcelized autologous corticocancellous bone obtained
from the iliac crest is the most frequently used technique.
Arthrodesis may also be considered for selected patients with extremity lesions.
Although a nonmobile joint is less desirable than a mobile one to the majority of
patients, it may provide the best mode of reconstruction in certain cases and is one
method by which durable function can be achieved. Arthrodesis of various joints
following extraarticular resection of malignant bone tumors may be the best
reconstructive option if resection includes most of the surrounding joint soft tissues and
joint arthroplasty cannot be accomplished [114,115].
The most common joints that are considered for arthrodeses following resection of bone
sarcomas resection are the hip, knee, and shoulder. Hip and shoulder arthrodeses do not
produce as much functional disability as knee fusions because of the capacity for
excellent compensatory motion at other joints in the affected extremity. Despite
functional limitations, knee arthrodesis can be achieved in the majority of patients, even
when a long segment of bone has been excised. However, this procedure is complicated
by a high incidence of nonunion, fatigue fracture, and infection. Although the operation
successfully achieves tumor-free margins, the revascularization and rehabilitation
78
processes are prolonged and complicated. Patients must adjust their lifestyles to
accommodate the arthrodesis.
Vascularized grafts — Vascularized bone grafts are also used to reconstruct osseous
defects and augment other reconstructive techniques, such as intercalary allograft
segments [116,117]. They are of particular benefit in the treatment of allograft
nonunions and fractures and in surgical beds which have poor vascularity and perfusion
following radiation. If the vascular graft remains viable, healing occurs more rapidly than
with nonvascularized grafts and is a more durable construct.
The surgical procedure for implantation of a vascularized graft is lengthy and the
vascular anastomosis is technically demanding. One of the most commonly used grafts
for this purpose is the fibula; fortunately, donor site complications are rare. Vascularized
fibular grafts have also been used to augment healing of intercalary grafts following
intraepiphyseal resections of the distal femur and proximal tibia, where only a short
segment of epiphyseal bone remains for fixation.
ADJUVANT THERAPY — As previously noted, more than 80 percent of patients with
osteosarcoma or Ewing sarcoma treated with surgery alone develop metastatic disease,
despite having adequate local tumor control. It is surmised that subclinical metastatic
disease is present at diagnosis, even in the absence of overt metastases. Chemotherapy
can eradicate these deposits if initiated at a time when disease burden is low. As a
result, adjuvant chemotherapy is considered a standard component of management for
these primary bone tumors.
For osteosarcoma, postoperative chemotherapy was used initially, and five year overall
survival rates rose from less than 20 percent to between 40 and 60 percent in the 1970s
[118]. Two subsequent randomized studies conducted in the 1980s demonstrated a
significant relapse-free and overall survival benefit for adjuvant chemotherapy, although
the trials were limited in size, and the survival benefits were modest. (See
"Chemotherapy and radiation therapy in the management of osteosarcoma".)
Neoadjuvant chemotherapy — For patients with osteosarcoma, presurgical or
neoadjuvant chemotherapy was originally considered because of the time needed for
fabrication of custom metallic implants; chemotherapy was given while awaiting
definitive surgery. Due to its success in shrinking tumors, neoadjuvant chemotherapy
evolved to a method of increasing the proportion of patients who were suitable
candidates for limb-salvage surgery and to facilitate limb-sparing procedures by
diminishing tumor burden. A major concern in this regard is the possibility that
inexperienced surgeons may expand selection criteria to accommodate inappropriate
candidates who might be better served by amputation. Adjuvant chemotherapy is never
a substitute for sound surgical principles.
One of the most compelling rationales for neoadjuvant chemotherapy is its ability to
function as an in vivo drug trial to determine the drug sensitivity of an individual tumor
and to customize postoperative therapy. A grading system for assessing the effect of
preoperative chemotherapy in osteosarcoma was developed at Memorial Sloan Kettering
and is in widespread use (table 5) [118].
The response to neoadjuvant chemotherapy is a major prognostic factor. Patients with a
near-complete absence of viable tumor cells in the resection specimen after neoadjuvant
therapy do well when the same therapy is continued after surgery. In contrast, if the
tumor contains 10 percent or more residual viable cells after neoadjuvant chemotherapy,
a change in the chemotherapeutic regimen might be beneficial, although this is a
controversial area. This topic is discussed in detail elsewhere.
The majority of limb-sparing surgical procedures for osteosarcoma are performed at
institutions using presurgical chemotherapy. On the other hand, immediate resection is
an acceptable option in situations where the surgical procedure would not be changed by
79
a good response to neoadjuvant chemotherapy. In such cases, adjuvant chemotherapy
should be administered postoperatively.
Issues surrounding the use of neoadjuvant and adjuvant chemotherapy for Ewing
sarcoma are also discussed elsewhere.
Radiation therapy — Unlike Ewing sarcoma, conventional osteosarcoma is relatively
resistant to radiation therapy. Because of this, primary radiation therapy is not usually
adequate to achieve local disease control, particularly for bulky tumors. Issues
surrounding the use of radiation therapy for Ewing sarcoma are discussed elsewhere.
(See "Radiation therapy for Ewing sarcoma family of tumors".)
There has been renewed interest in a potential role for radiation therapy for patients
with osteosarcoma whose tumors respond to chemotherapy and in whom surgery would
be debilitating. A recent report described a five-year local control rate of 56 percent
among 31 patients with nonmetastatic extremity osteosarcoma who refused surgery and
were instead treated with radiotherapy (median dose 60 Gy) [119]. No local failures
developed in 11 patients who responded well to chemotherapy with both a radiographic
and biochemical response (normalization of alkaline phosphatase), and the five-year
metastasis-free survival rate was 91 percent. Among patients who achieved local
control, 86 percent had "excellent" limb function.
Although local adjuvant radiation therapy and prophylactic whole lung radiation have
been used in an attempt to improve outcomes following surgery, neither is effective in
the absence of systemic chemotherapy [13,120,121]. Furthermore, in patients treated
with effective surgery and chemotherapy, adjuvant radiation does not improve survival
and increases the risk for secondary tumors [122]. Adjuvant radiation should be
considered only in the setting of an unresectable or incompletely resected primary tumor
or in patients with the small cell variant of osteosarcoma, which may be more
radiosensitive [123].
The role of adjuvant radiation therapy in patients with Ewing sarcoma is discussed
elsewhere. (See "Radiation therapy for Ewing sarcoma family of tumors", section on
'Adjuvant RT'.)

SUMMARY



Osteosarcoma is the most common primary malignant tumor of bone; other less
common types of bone sarcoma include peripheral primitive neuroectodermal
tumor (PNET)/Ewing sarcoma, malignant fibrous histiocytoma, fibrosarcoma,
chondrosarcoma, and chordoma. (See 'Histologic classification' above.)
The goal of the preoperative evaluation for a primary bone sarcoma is to establish
the tissue diagnosis, evaluate disease extent, and assess the feasibility of a limbsparing approach. Clinical staging includes all of the data obtained prior to
definitive therapy, including the results of imaging, physical examination,
laboratory studies, and tissue biopsy. The biopsy must be carefully planned to
ensure that adequate tissue is obtained for diagnosis without compromising the
opportunity for limb salvage. Biopsies should take place after the completion of
the staging studies. (See 'Preoperative evaluation' above.)
Surgery and systemic chemotherapy are the mainstays of treatment for patients
with osteosarcomas and other primary bone tumors such as fibrosarcoma of bone.
Chondrosarcoma and chordoma have not been routinely or historically treated
with chemotherapy or radiation and therefore surgery is the mainstay of
management. (See "Chondrosarcoma" and "Chordoma and chondrosarcoma of the
skull base" and "Spinal cord tumors", section on 'Chordomas'.)
80



Although there is no specific survival benefit to preoperative as compared to
postoperative chemotherapy in osteosarcoma patients, the neoadjuvant approach
may permit a greater number of patients to undergo limb-sparing procedures.
However, chemotherapy is no substitute for sound surgical judgment when
assessing the need for amputation versus limb-sparing surgery. The optimal
chemotherapy regimen has not been established. In general, patients with a
nearly complete response to neoadjuvant chemotherapy do better than those with
a lesser response. Even if the patient has a chemosensitive tumor, it may be
reasonable to proceed to immediate surgery followed by adjuvant chemotherapy if
the nature of the resection would not necessarily be influenced by a good
response to chemotherapy. (See "Chemotherapy and radiation therapy in the
management of osteosarcoma", section on 'Neoadjuvant chemotherapy' and
'Neoadjuvant chemotherapy' above.)
Reconstructive options vary depending upon the factors listed above. In addition,
there is surgeon preference and no absolute consensus in many circumstances as
to the optimal reconstructive method. In some circumstances, if the tumor is
located in an expendable bone, reconstruction is not even necessary. (See
'Reconstruction techniques' above.)
There is no role for adjuvant radiation therapy except in patients with
unresectable or incompletely resected sarcomas and possibly in the rare patient
with a small cell osteosarcoma. Radiation therapy for local control can be used in
patients who decline surgery or for whom there is no effective surgical option.
(See 'Radiation therapy' above.)
In contrast to osteosarcoma and other primary bone sarcomas, Ewing sarcoma is
more radiosensitive, and radiation may be considered an effective option for local
control. Although modern treatment protocols emphasize surgery for optimal local
control, patients who lack a function-preserving surgical option because of tumor
location or extent, and those who have clearly unresectable primary tumors
following induction chemotherapy are appropriate candidates for radiation
therapy. Furthermore, adjuvant radiation may be considered for bulky tumors in
difficult sites (eg, the pelvis), if there is residual microscopic or gross disease after
surgery, and for patients with high-risk chest wall primary tumors (close or
involved margins, initial pleural effusion, pleural infiltration, and intraoperative
contamination of the pleural space). (See "Radiation therapy for Ewing sarcoma
family of tumors", section on 'Adjuvant RT'.)
Osteosarcoma: Epidemiology, pathogenesis, clinical presentation, diagnosis, and
histology
Literature review current through: Aug 2013. | This topic last updated: May 30, 2013.
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INTRODUCTION — Osteosarcomas are primary malignant tumors of bone that are
characterized by the production of osteoid or immature bone by the malignant cells [13]. Osteosarcomas are uncommon tumors. Approximately 750 to 900 new cases are
diagnosed each year in the United States, of which 400 arise in children and adolescents
younger than 20 years of age [4,5]. Despite their rarity, osteosarcomas are the most
common primary malignancy of bone in children and adolescents (figure 1), and the fifth
most common malignancy among adolescents and young adults aged 15 to 19 [6,7].
The survival of patients with malignant bone sarcomas has improved dramatically with
effective chemotherapy. Prior to the use of chemotherapy, 80 to 90 percent of patients
with osteosarcoma developed metastatic disease despite achieving local tumor control
and died of their disease. It was surmised (and subsequently demonstrated) that the
majority of patients had subclinical metastatic disease that was present at the time of
diagnosis, even in the absence of overt clinical metastases [8,9].
Chemotherapy can successfully eradicate these deposits if initiated at a time when
disease burden is low. As a result, all patients with osteosarcoma are treated with
84
adjuvant chemotherapy, and most receive this treatment modality in the preoperative
period. With multimodality therapy, at least two-thirds of patients with non-metastatic
extremity osteosarcomas will be long-term survivors, up to 50 percent of those with
limited pulmonary metastases may be cured of their disease, and long-term relapse-free
survival can be expected in about 25 percent of all patients who present with more
extensive metastatic disease.
This topic review will provide an overview of the epidemiology, clinical presentation,
diagnosis, staging, and histopathology of patients with osteosarcoma. Diagnostic
evaluation and biopsy techniques for primary bone tumors, an overview of treatment
and outcomes, principles guiding surgical management of bone sarcomas, and
chemotherapy in the treatment of osteosarcoma are discussed in detail elsewhere. (See
"Bone tumors: Diagnosis and biopsy techniques" and "Bone sarcomas: Preoperative
evaluation, histologic classification, and principles of surgical management" and
"Chemotherapy and radiation therapy in the management of osteosarcoma".)
EPIDEMIOLOGY — As noted previously, osteosarcoma is an uncommon tumor; it
accounts for only 1 percent of all cancers diagnosed annually in the US. In contrast to
Ewing sarcoma, which is extremely rare in older adults, there is a bimodal age
distribution of osteosarcoma incidence, with peaks in early adolescence and in adults
over the age of 65 [10]. There are differences in tumor site and survival according to
age at presentation.
Children — Bone sarcomas account for about 6 percent of all childhood cancers, and
osteosarcomas account for approximately 3 percent of childhood cancers overall [11].
However, osteosarcoma is the most common primary bone tumor affecting children and
young adults. Osteosarcomas comprise 56 percent of all bone cancers in individuals
under the age of 20, while Ewing sarcoma accounts for 34 to 36 percent, and
chondrosarcomas are responsible for less than 10 percent [10]. (See "Epidemiology,
pathology, and molecular genetics of the Ewing sarcoma family of tumors".)
In children, the peak incidence is between 13 and 16 years of age (figure 1), a time that
appears to coincide with the adolescent growth spurt. For unclear reasons,
osteosarcomas are more common in boys than in girls, and in blacks and other races as
compared to Caucasians [4,10,12].
The most common sites of osteosarcoma in children are the metaphyses of long bones,
especially the distal femur (75 percent of cases in one large population-based series
[10]), proximal tibia, and proximal humerus [13,14].
Adults — Osteosarcomas in adults are often considered secondary neoplasms, attributed
to sarcomatous transformation of Paget disease of bone or some other benign bone
lesion [10]. In the US, over one-half of all osteosarcomas arising in patients over the
age of 60 arise are secondary [15]. In contrast, in Asia, Paget's disease is less frequent,
and a higher percentage of osteosarcomas in patients over the age of 60 arise primarily
[16]. Osteosarcomas arising in the setting of Paget's disease (Pagetic sarcomas) have a
worse prognosis overall. (See 'Risk factors' below.)
Compared to cases diagnosed in children, osteosarcomas arising in adults more
commonly occur in axial locations (although as in children, the lower leg bones are the
single most common site [10]), and in areas that have been previously irradiated or that
have underlying bone abnormalities.
As is seen in children, among older adults, males are affected more often than females
[10]. However, in contrast to children, osteosarcoma is more common in whites than in
blacks or individuals of other races [10].
RISK FACTORS AND PATHOGENESIS — In children, the majority of osteosarcomas are
sporadic, while inherited predisposition accounts for a minority of cases. In older adults,
about one-third of cases arise in the setting of Paget disease of bone or as a second or
later cancer [10].
85
Risk factors — Several predisposing factors have been identified [17].
Prior irradiation or chemotherapy — Osteosarcoma is the most frequent second primary
cancer occurring during the first 20 years following radiation therapy for a solid cancer in
childhood. Early estimates suggested that approximately 3 percent of osteosarcomas
could be attributed to prior irradiation. However, a higher incidence is likely to be
revealed, as more patients survive long enough after primary irradiation to develop this
complication. The interval between irradiation and the appearance of a secondary
osteosarcoma averages 12 to 16 years; it is shorter in childhood cancer survivors. (See
"Radiation-associated sarcomas", section on 'Epidemiology and histologic distribution'
and "Radiation-associated sarcomas", section on 'Radiation dose and age of exposure'.)
Prior exposure to chemotherapy, particularly alkylating agents, is also associated with
secondary osteosarcomas in childhood cancer survivors and may potentiate the effect of
previous radiation. (See "Radiation-associated sarcomas", section on 'Chemotherapy
agents'.)
Paget disease and other benign bone lesions — Cases of osteosarcoma in patients older
than 40 years of age are frequently associated with Paget disease, a focal skeletal
disorder characterized by an accelerated rate of bone turnover [18]. Although the
incidence of bone tumors is markedly increased in patients with Paget disease, they only
occur in 0.7 to 1 percent of cases [19]. Sarcomatous transformation is most often seen
in long-standing Paget disease, but is not necessarily related to the extent of skeletal
involvement. Although histologically indistinguishable from other osteosarcomas,
multiple bone involvement is common, and the prognosis is poor overall. (See "Clinical
manifestations and diagnosis of Paget disease of bone".)
The etiology of Paget disease is unclear, but genetic factors are thought to play a
pathogenetic role. Both Paget disease and pagetic osteosarcomas are associated with
loss of heterozygosity of chromosome 18, possibly involving the same site of a
postulated tumor suppressor gene [20-22]. Somatic mutations in the SQSTM1 gene on
chromosome 5q35 have been identified in both sporadic Paget disease of bone as well as
pagetic osteosarcomas [23].
In addition to Paget disease, other benign bone lesions are associated with an increased
risk of malignant degeneration to a primary bone tumor. These include chronic
osteomyelitis, multiple hereditary exostoses, fibrous dysplasia, sites of bone infarcts,
and sites of metallic implants for benign conditions [24,25].
Inherited conditions — Genetic conditions with a known predisposition to osteosarcoma
include hereditary retinoblastoma, Li-Fraumeni syndrome, Rothmund-Thomson
syndrome, and the related Bloom and Werner syndromes. Because of the association of
these genetic conditions with osteosarcomas, particularly in the setting of multiple
primary malignancies [26], careful detailing of family history is important for patients
with newly diagnosed osteosarcoma.
The genetic abnormality associated with heritable forms of retinoblastoma (ie, germline
mutations of the retinoblastoma gene) are associated with an increased risk of
developing second primary tumors, 60 percent of which are soft tissue sarcomas and
osteosarcomas [27-29]. The risk for later development of osteogenic sarcoma is not only
within irradiated fields, but also in long bones distant from radiation ports. Patients with
the sporadic type of retinoblastoma are at a much lower risk. As an example, in one
study of 1604 patients with retinoblastoma, the cumulative incidence of a second cancer
at 50 years after diagnosis was 51 percent for hereditary cases, compared to only 5
percent for nonhereditary (sporadic) disease [27]. (See "Overview of retinoblastoma",
section on 'Epidemiology' and "Radiation-associated sarcomas", section on 'Genetic
predisposition'.)
Li-Fraumeni syndrome is a familial cancer syndrome in which affected family members
display a spectrum of cancers, including breast, soft tissue, adrenocortical, and brain
86
tumors, leukemias, and osteosarcomas [30]. Many of these patients carry germline
inactivating mutations in the p53 tumor suppressor gene, which is involved in cell cycle
regulation and maintaining the integrity of the genome [31,32]. (See "Li-Fraumeni
syndrome".)
Despite this important association, the number of osteosarcomas that are attributable to
Li-Fraumeni syndrome is small [33,34]. In one series of 235 unselected children with
osteosarcoma, only 3 percent carried constitutional germline mutations in p53 [33].
Rothmund-Thomson syndrome (RTS, also called poikiloderma congenitale) is an
autosomal recessive condition characterized by distinctive skin findings (atrophy,
telangiectasias, pigmentation), sparse hair, cataracts, small stature, skeletal anomalies,
and a significantly increased risk for osteosarcoma [35,36]. In one cohort of 41 patients
with RTS, 13 (32 percent) developed osteosarcoma [35]. Clinically, these tumors tend to
develop at a younger age than seen in the general population.
A specific loss of function mutation in the RECQL4 gene has been identified in
approximately two-thirds of patients with RTS and is closely associated with the risk for
osteosarcoma. In one series of 33 patients with RTS, none of the 10 patients without a
truncating mutation in this gene developed osteosarcoma, while among the 23 patients
with truncating mutation, the incidence of osteosarcoma was five cases per year with
230 person-years of observation [37]. Other members of the RecQ gene family are
mutated in Bloom syndrome and Werner syndrome, two diseases with overlapping
clinical features, including a predisposition to develop osteosarcoma [37].
Molecular pathogenesis — Although the etiology of osteosarcoma is unclear, a
relationship between rapid bone growth and the development of osteosarcoma is
suggested by the following:



The peak incidence of osteosarcoma occurs during the adolescent growth spurt.
The tumor appears most frequently at sites where the greatest increase in bone
length and size occurs (the metaphyseal portions of the distal femur, proximal
tibia, and proximal humerus) (figure 2).
Osteosarcomas occur at an earlier age in girls, corresponding to their more
advanced skeletal age and earlier adolescent growth spurt.
These data have led to speculation that bone tumors arise from an aberration of the
normal process of bone growth and remodeling at a time when rapidly proliferating cells
are particularly susceptible to oncogenic agents, mitotic errors, or other events leading
to neoplastic transformation [38]. However, studies examining the relationship between
factors related to growth and development and the risk of bone sarcomas have revealed
no consistent pattern [39,40].
The specific nature of this aberration or aberrations that leads to tumorigenesis remains
elusive and is the subject of intense investigation [17,41,42]. In contrast to other
sarcomas, there are no characteristic translocations or other molecular genetic
abnormalities in osteosarcomas. (See "Pathogenetic factors in soft tissue and bone
sarcomas", section on 'Genetics and molecular pathogenesis'.)
Most osteosarcomas have a complex unbalanced karyotype. The highest frequency of
loss of heterozygosity (which implies the loss of a putative tumor suppressor gene) in
osteosarcomas is reported for chromosomes 3q, 13q (the location of the retinoblastoma
gene), 17p (the location of the p53 gene), and 18q, the chromosomal region that has
been linked to osteosarcomas arising in the setting of Paget disease (see 'Paget disease
and other benign bone lesions' above) [20,21,43-45].
Combined inactivation of the retinoblastoma and p53 tumor suppressor pathways is
common in osteosarcomas [17,46,47]. The potential contribution of p53 pathway
abnormalities to tumorigenesis is particularly intriguing, given the increased incidence of
87
osteosarcoma in families with the Li-Fraumeni syndrome, an inherited condition in which
p53 is mutationally inactivated. (See 'Inherited conditions' above.)
Normal or "wild type" p53 appears to play a role in the normal development and
physiology of bone [48], since p53-null mice display failure of skull growth and delayed
longitudinal bone growth in utero [49]. Furthermore, bone cell lysates from p53-null
mice also fail to activate normal apoptotic pathways [46]. The contribution of p53 and
other molecular pathways, such as the Wnt, Notch, IGF and mTOR signaling pathways,
to the pathogenesis of osteosarcoma is beyond the scope of this discussion; excellent
reviews are available [41,50].
As will be discussed below, the majority of patients are presumed to have metastatic
disease at presentation, with the majority being subclinical. Gene expression profiling
through the use of DNA microarray analysis as well as whole genome sequencing efforts
are beginning to uncover the molecular events that dictate metastatic potential, findings
that may pave the way for future molecularly targeted therapies [41].
CLINICAL PRESENTATION — The majority of patients with osteosarcoma present with
localized pain, typically of several months' duration. Pain frequently begins after an
injury, and may wax and wane over time. Systemic symptoms such as fever, weight
loss, and malaise are generally absent. The most important finding on physical
examination is a soft tissue mass, which is frequently large and tender to palpation.
Osteosarcomas have a predilection for the metaphyseal region of the long bones (figure
3). The most common sites of involvement, in descending order, are: distal femur,
proximal tibia, proximal humerus, middle and proximal femur, and other bones [51].
Laboratory evaluation is usually normal, except for elevations in alkaline phosphatase (in
approximately 40 percent) [52], lactate dehydrogenase (LDH, in approximately 30
percent) [53], and erythrocyte sedimentation rate. Laboratory abnormalities do not
correlate with disease extent, although a very high LDH level is associated with a poor
clinical outcome [54].
At the time of presentation, between 10 and 20 percent of patients have demonstrable
macrometastatic disease and are classified as stage III according to the staging system
used by the Musculoskeletal Tumor Society (see 'Staging system' below). Distant
metastases most commonly involve the lungs, but can also involve bone [55].
Occult micrometastases are presumed to be present in the majority of those who appear
to have clinically localized disease, since before the era of adjuvant chemotherapy, over
80 percent of patients with osteosarcoma developed metastatic disease despite
achieving local tumor control. It was postulated that these patients had subclinical
metastases that were present at the time of diagnosis [56]. With routine use of systemic
adjuvant chemotherapy, at least two-thirds of children and adolescents with
nonmetastatic osteosarcoma will be long-term survivors, implying the success of
chemotherapy in eradication of micrometastases. Prognosis is worse in adults with
osteosarcoma, particularly those over the age of 65 [57].
DIAGNOSIS AND STAGING EVALUATION — The first diagnostic test to arouse suspicion
for a primary bone tumor is generally a plain radiograph of the affected area [58].
Characteristic features of conventional osteosarcomas (which account for the majority of
cases, see below) include destruction of the normal trabecular bone pattern, indistinct
margins, and no endosteal bone response. The affected bone is characterized by a
mixture of radiodense and radiolucent areas, with periosteal new bone formation, lifting
of the cortex, and formation of Codman's triangle (image 1). The associated soft tissue
mass is variably ossified in a radial or "sunburst" pattern. (See "Bone tumors: Diagnosis
and biopsy techniques".)
Differential diagnosis — The correct histologic diagnosis of osteosarcoma may be
predicted in up to two-thirds of patients who have a characteristic radiographic
appearance, clinical features, and tumor location [59]. However, no radiographic finding
88
is pathognomonic, and biopsy is required for definitive diagnosis. The differential
diagnosis includes other malignant bone tumors (ie, Ewing sarcoma, lymphoma, and
metastases), benign bone tumors (eg, chondroblastoma, osteoblastoma), and
nonneoplastic conditions, such as osteomyelitis, eosinophilic granuloma, and aneurysmal
bone cysts.
Occasionally, no abnormalities will be evident on plain radiographs. In such cases,
magnetic resonance imaging (MRI) should be obtained if clinical suspicion for a bone
tumor is high. Even for patients with characteristic plain radiographic findings, MRI is
indicated for surgical planning (see 'Staging system' below).
Staging work-up — Patients with overt metastatic disease at presentation have a
significantly worse outcome than those with localized disease. Because a significant
proportion of patients with metastases (including up to one-half of those with limited
pulmonary involvement) may be amenable to cure, a thorough staging workup is
imperative to facilitate surgical planning.
Imaging studies — The staging work-up should include the following (table 1) [60]:


MRI of the entire length of the involved long bone. A multi-institutional study of
387 patients that included both children and adults concluded that CT and MRI
were equally accurate for local staging of bone and soft tissue tumors [61].
However, MRI is preferred in most cases because of its superior definition of soft
tissue extension, particularly to the neurovascular bundle, joint and marrow
involvement, and the presence of skip lesions (ie, medullary disease within the
same bone, but not in direct contiguity with the primary lesion) (image 2) [62].
CT scans are best suited to evaluate the thorax for metastatic disease, which is
essential because approximately 80 percent of osteosarcoma metastases involve
the lungs [56,63]. Because of the possibility of false-positive results, histologic
confirmation is indicated for suspected sites of metastatic disease, particularly if a
given lesion was not detected on plain films.
However, CT may underestimate the extent of pulmonary involvement by
metastatic tumor [64,65]. In one study, metastases would have been missed in
more than one-third of cases by any method other than manual palpation of the
lung during open thoracotomy [64]. These data raise doubt as to the advisability
of minimal access procedures (eg, thoracoscopic metastasectomy) when the goal
is resection of all pulmonary metastases [66-68]. (See "Surgical resection of
pulmonary metastases: Benefits; indications; preoperative evaluation and
techniques".)

Distinguishing metastatic lesions from benign nodules can be difficult, particularly
in adults who have a high prevalence of granulomatous disease and in children
living in areas with endemic fungal disease, especially histoplasmosis.
While calcification can be a sign of benign disease, it may also be seen in
metastases from osteosarcoma [69]. Criteria to guide the evaluation of suspected
pulmonary metastases are available from the European and American
Osteosarcoma Study Group, as are being used in the EURAMOS 1 (AOST0331)
trial (table 2) [70].
Radionuclide bone scanning with technetium is the preferred method for
evaluating the entire skeleton for the presence of multiple lesions. Although a
positron emission tomography (PET) scan may have greater utility for assessing
the response to preoperative chemotherapy, at least one study suggests it is
inferior to radionuclide bone scanning for the detection of osseous metastases
from osteosarcoma [71] and to spiral CT for detecting pulmonary metastases
[72].
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The role of PET and integrated PET/CT imaging in patients with osteosarcoma is
incompletely characterized, and there is no consensus on their use [72,73].
Guidelines from the National Comprehensive Cancer Network (NCCN) suggest a
PET scan and/or bone scan in the workup of a suspected osteosarcoma [74].
Imaging guidelines from the Children’s Oncology Group Bone Tumor Committee
recommend radionuclide bone scan and/or PET scan for whole body staging (table
1) [60]. Regardless of which is chosen, the same imaging modality should be used
throughout treatment and during posttreatment surveillance.
Biopsy — Once the diagnosis of a primary bone tumor is suspected, referral should be
made to a facility with expertise in pediatric oncology for further management, including
a diagnostic biopsy. The biopsy should be carried out by an orthopedic surgeon who is
experienced in the management of osteosarcoma and ideally by the same surgeon who
will perform the definitive surgery. If a core needle biopsy is planned by an
interventional radiologist, the orthopaedic surgeon and radiologist should communicate
about the placement of the biopsy tract. Proper planning of the biopsy with careful
consideration of the future definitive surgery is important so as not to jeopardize the
subsequent treatment, particularly a limb salvage procedure [75]. This topic is discussed
in detail elsewhere. (See "Bone tumors: Diagnosis and biopsy techniques".)
Staging system — The Musculoskeletal Tumor Society (MSTS) staging system is most
often used for bone sarcomas and was developed by Enneking at the University of
Florida [76,77]. This is a surgical staging system and is not used to decide medical
(chemotherapy) treatment for patients with osteosarcoma.
The MSTS staging system characterizes nonmetastatic malignant bone tumors by grade
(low-grade [stage I] versus high-grade [stage II]) and further subdivides these stages
according to the local anatomic extent (intracompartmental [A] versus
extracompartmental [B]). For bone tumors, the compartmental status is determined by
whether the tumor extends through the cortex of the involved bone; the majority of high
grade osteosarcoma are extracompartmental. Patients with distant metastases are
categorized as stage III.
HISTOLOGIC CLASSIFICATION — The histologic diagnosis of an osteosarcoma is based
on the presence of a malignant sarcomatous stroma, associated with the production of
tumor osteoid and bone. Osteosarcomas are thought to arise from a mesenchymal stem
cell that is capable of differentiating towards fibrous tissue, cartilage, or bone. As a
result, they share many features with chondrosarcomas and fibrosarcomas, tumors of
the same family of bone sarcomas (table 3), with which osteosarcoma can be easily
confused. However, chondrosarcomas and fibrosarcomas are distinguished by their lack
of woven bone matrix, which is required for the diagnosis of osteosarcoma.
Because some osteosarcomas have a limited degree of osteoid production and variable
histomorphology, immunohistochemistry may be required for confirmation of the
diagnosis. In contrast to Ewing sarcoma and many soft tissue sarcomas, osteosarcomas
are not associated with any characteristic chromosomal translocations [78].
Conventional osteosarcomas — The largest group are the conventional (intramedullary
high-grade) osteosarcomas, which account for approximately 90 percent of all
osteosarcomas [79]. These tumors typically involve the metaphysis of long bones (figure
2) and are most common in adolescents and young adults.
Depending upon the predominant cellular component, conventional osteosarcomas are
subclassified as osteoblastic (accounting for 50 percent of conventional osteosarcomas),
chondroblastic (25 percent), or fibroblastic (25 percent) (table 3) [58]. Despite histologic
differences, their clinical behavior and management are similar.

Osteoblastic osteosarcoma is characterized by abundant osteoid production that
forms a fine or coarse lacelike pattern around the tumor cells; massive amounts
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

may result in distortion of the malignant stromal cells (picture 1). Some tumors
contain thick trabeculae of osteoid that form an irregular anastomosing network.
The degree of mineralization is variable.
Fibroblastic osteosarcomas are predominantly composed of high-grade spindle cell
stroma that contains only focal osteoid production (picture 2). More pleomorphic
tumors may resemble malignant fibrous histiocytoma, but the distinction can be
made by the identification of osteoid.
In chondroblastic osteosarcomas, cartilaginous matrix production is evident
throughout most of the tumor. While the majority of the tumor tends to be of
lower grade, the chondroid areas may contain cytologically atypical cells that are
characteristic of higher-grade tumors. These chondroblastic foci are admixed with
malignant spindle cells that produce osteoid trabecula (picture 3).
Histologic variants — In addition to the three subcategories of conventional
osteosarcoma, there are several variants:




Small cell
Telangiectatic
Multifocal
Malignant fibrous histiocytoma [MFH] subtype
These variants were originally thought to carry a worse prognosis. However, with
modern aggressive therapy, they appear to behave similarly. Other subtypes (the
juxtacortical parosteal and periosteal osteosarcomas) are associated with a more
indolent biologic behavior. Parosteal osteosarcomas are more common in older patients
and periosteal osteosarcoma has a similar age distribution to classic osteosarcoma.
Small cell osteosarcoma — Small cell osteosarcoma is noteworthy for the confusion that
may arise in its distinction from other "small round blue cell tumors" such as Ewing
sarcoma by conventional light microscopy of hematoxylin and eosin (H&E) stained
sections [80]. Immunohistochemical staining, cytogenetics, and molecular genetic
studies may be required to establish the diagnosis [81,82]. (See "Treatment of the
Ewing sarcoma family of tumors".)
Telangiectatic osteosarcomas — Telangiectatic osteosarcomas are high-grade, vascular
tumors which contain little osteoid. Because of their purely lytic appearance on plain
radiographs, they can be confused with aneurysmal bone cysts or giant cell tumors of
bone (GCTB). Grossly they appear as a "multicystic bag of blood", and a solid mass of
tumor is usually absent [79]. As a result, it may be difficult to obtain diagnostic tissue on
biopsy. Histologically, the minimal osteoid formation and numerous multinucleated giant
cells (picture 4) are reminiscent of a benign GCTB. However, the cells are highly
pleomorphic. (See "Giant cell tumor of bone".)
The age distribution and treatment are identical to classic high-grade osteosarcoma. The
response to chemotherapy and survival are similar to conventional osteosarcomas [83].
Multifocal osteosarcoma — Rarely, patients present with multiple synchronous sites at
diagnosis, all resembling the primary tumor. It is difficult to determine whether these
represent synchronous multiple primary lesions or considered metastases. Regardless of
their designation, the prognosis is usually dismal. Multicentric osteosarcoma may also be
metachronous in that other bony lesions occur years after treatment of the first.
Malignant fibrous histiocytoma — MFH of bone appears similar to osteosarcoma, but
without osteoid production. Although they tend to have a lower rate of tumor necrosis
following induction chemotherapy, long-term survival rates are similar to conventional
osteosarcomas [84].
Surface (juxtacortical) osteosarcomas — In contrast to these intramedullary variants,
the surface osteosarcomas differ with respect to prognosis and therapy. These
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osteosarcomas include the parosteal low-grade type, the intermediate-grade periosteal
type, and the high-grade surface osteosarcomas [84,85]. Surgery alone may be curative
for the low-grade and intermediate-grade varieties, as long as they do not enter the
marrow cavity or have a de-differentiated component [86,87].



Parosteal osteosarcoma — The most common of these entities, typical parosteal
osteosarcoma, is a surface lesion composed of low-grade fibroblastic cells that
produce woven or lamellar bone. It occurs in an older age group than conventional
intramedullary osteosarcoma, usually between the ages of 20 and 40 years. The
posterior aspect of the distal femur is the most commonly involved site, but other
long bones may be affected. The tumor arises from the cortex as a broadly based
lesion. With time, however, this lesion may invade the cortex and enter the
endosteal cavity. Treatment for conventional parosteal osteosarcomas is surgical
resection alone with expected survival rates of approximately 90 percent [88,89];
however, de-differentiated parosteal osteosarcomas may require adjuvant
chemotherapy.
Periosteal osteosarcoma — Periosteal osteosarcoma is a moderate-grade,
chondroblastic surface osteosarcoma frequently located in the proximal tibia,
which has the same age distribution as conventional intramedullary osteosarcoma
(image 2). The likelihood of metastases is greater than that for the low-grade
parosteal tumors, but lower than the classic intramedullary osteosarcoma.
The role of adjuvant chemotherapy for periosteal osteosarcomas is controversial.
Adjuvant chemotherapy is recommended in many centers because of the
estimated 20 percent metastatic rate. However, retrospective reports indicate
more favorable outcomes than seen with classic osteosarcomas (84 percent tenyear survival rate in one study [90]), a lack of benefit when patients who received
adjuvant chemotherapy were compared to those treated by surgery alone
[90,91], and a concerning number of second malignant neoplasms in patients
treated with adjuvant chemotherapy [90]. Randomized trials have not been
conducted, which limits the conclusions that can be drawn from the available
literature.
High-grade surface osteosarcoma — Conventional high-grade osteosarcomas may
also develop on the surface of the bone, where they may be confused with
parosteal or periosteal osteosarcoma. They are treated similar to conventional
intramedullary osteosarcomas.
Osteosarcoma of the jaw — Another distinct variant is osteosarcoma of the jaw, which
tends to occur in older patients, has an indolent course, and is more often associated
with local recurrences than with distant metastases.
Extraosseous osteosarcoma — Extraosseous osteosarcoma is a malignant tumor arising
in the soft tissue, without involving the bone or periosteum, that produces osteoid, bone,
or chondroid material (image 3 and image 4) [92-97]. Most arise in the setting of prior
radiation exposure.
In contrast to osseous osteosarcomas, extraskeletal osteosarcomas present in older age
groups, they have a different anatomic predilection (the most common site is in the
thigh) and show relative chemoresistance to doxorubicin-based chemotherapy [93-95].
They are generally treated as a soft tissue sarcoma with aggressive behavior.
SUMMARY

Osteosarcomas are uncommon primary malignant tumors of bone that are
characterized by the production of osteoid or immature bone by the malignant
cells. (See 'Introduction' above.)
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





The age distribution of osteosarcoma incidence is bimodal, with peaks in early
adolescence and in adults over the age of 65. Osteosarcoma is the most common
primary bone tumor affecting children and young adults; the peak age is between
13 and 16. (See 'Children' above.)
In children, the majority of osteosarcomas are sporadic. A minority of cases are
associated with inherited predisposition syndromes such as hereditary
retinoblastoma, Li-Fraumeni syndrome, Rothmund-Thomson syndrome, and the
related Bloom and Werner syndromes. (See 'Risk factors' above.)
Osteosarcomas in adults are often considered secondary neoplasms, attributed to
sarcomatous transformation of Paget disease of bone or some other benign bone
lesion. In the US, over one-half of all osteosarcomas arising in patients over the
age of 60 are secondary, while in, Asia, Paget disease is less frequent and a
higher percentage arise primarily. (See 'Adults' above and 'Paget disease and
other benign bone lesions' above.)
The majority of patients with osteosarcoma present with localized pain, typically of
several months' duration. The most important finding on physical examination is a
soft tissue mass, which is frequently large and tender to palpation. At
presentation, between 10 and 20 percent have demonstrable metastatic disease,
most often involving the lung. (See 'Clinical presentation' above.)
Biopsy is required for definitive diagnosis. Proper planning of the biopsy with
careful consideration of future definitive surgery is important so as not to
jeopardize subsequent treatment, particularly the opportunity for limb salvage.
(See 'Biopsy' above.)
The histologic diagnosis of an osteosarcoma is based on the presence of a
malignant sarcomatous stroma, associated with the production of tumor osteoid
and bone. Conventional (intramedullary high-grade) osteosarcomas account for
approximately 90 percent of all osteosarcomas. Other less common histologic
variants are small cell, telangiectatic, multifocal, surface (juxtacortical), and
extraosseous osteosarcomas, malignant fibrous histiocytoma, and osteosarcoma
of the jaw. Jaw osteosarcoma is more common in older patients. (See 'Histologic
classification' above.)
Once the diagnosis of an osteosarcoma is established, the staging evaluation
should include MRI of the entire length of the involved bone, CT of the thorax,
radionuclide bone scanning with technetium, and/or a PET scan. (See 'Staging
work-up' above.)
Chemotherapy and radiation therapy in the management of osteosarcoma
Literature review current through: Aug 2013. | This topic last updated: Tem 8, 2013.
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94
95
INTRODUCTION — Osteosarcomas are primary malignant tumors of bone that are
characterized by the production of osteoid or immature bone by the malignant cells.
Osteosarcomas are uncommon; only about 750 to 900 cases are diagnosed each year in
the US, of which 400 are in children and adolescents under the age of 20 [1,2].
This topic review will cover the use of adjuvant and neoadjuvant chemotherapy and
radiation therapy (RT) in the management of osteosarcoma. The same principles apply
to other primary bone tumors such as fibrosarcoma and undifferentiated high-grade
pleomorphic sarcoma (previously referred to as malignant fibrous histiocytoma of bone),
and they are treated similarly [3,4]. On the other hand, primary bone angiosarcomas do
96
not behave clinically like other primary bone tumors, and these patients are treated
according to the principles of soft tissue sarcoma rather than osteosarcoma.
The surgical management of patients with primary bone tumors, the clinical features,
epidemiology, diagnosis, pathology and pathogenesis of osteosarcoma, management of
osteosarcomas arising in the head and neck, management of chondrosarcomas and of
chordomas and chondrosarcomas arising in the skull base, and the treatment of Ewing
sarcoma are addressed separately.
Rarely osteosarcomas can occur in soft tissue. There are conflicting data on their
management as soft tissue sarcomas or osteosarcoma of bone [5,6]. These tumors are
treated as soft tissue sarcomas at some institutions with surgery and radiation alone, or
surgery, radiation, and soft tissue-based chemotherapy. At other institutions, they are
treated as osteogenic sarcomas, with surgery, radiation and doxorubicin plus cisplatin
with or without methotrexate. The choice of chemotherapy is best determined by the
availability of clinical trials, and otherwise is decided on a patient-by-patient basis,
balancing the risks and benefits of chemotherapy for this very high risk diagnosis.
PROGNOSIS AND EVOLUTION OF TREATMENT — The survival of patients with malignant
bone sarcomas has improved dramatically over the past 30 years, largely as a result of
the use of effective chemotherapy. Previously 80 to 90 percent of patients with bone
sarcomas developed metastases despite achieving local tumor control, and died of their
disease. It was surmised (and subsequently demonstrated [7]) that subclinical
metastatic disease was present at the time of diagnosis in the majority of patients and
that chemotherapy can successfully eradicate these deposits if initiated at a time when
disease burden is low. The benefits of chemotherapy are best illustrated by a systematic
review of the literature, which showed that long-term survival after local tumor control
without chemotherapy was only 16 percent (95% CI 9 to 23 percent) [8]. In contrast,
the addition of systemic chemotherapy with three or more drugs provided a five-year
overall survival rate of 70 percent.
Chemotherapy is now considered a standard component of osteosarcoma treatment,
both in children and in adults. The choice of regimen and optimal timing (ie,
preoperative versus postoperative) are controversial; however, many centers
preferentially utilize preoperative chemotherapy, particularly if a limb-sparing procedure
is being contemplated for an extremity osteosarcoma.
With modern therapy, at least two-thirds of children, adolescents, and adults under the
age of 40 with nonmetastatic extremity osteosarcomas will be long-term survivors and
presumably cured of their disease. In addition, up to 35 to 40 percent of those with
limited pulmonary metastases may be cured with multimodality therapy. In contrast,
long-term survival can be expected in less than 20 percent of all other patients who
present with or develop overt metastatic disease. In most (but not all [9]) series,
prognosis is worse for adults than for children [10-13].
PRIMARY MANAGEMENT
Adjuvant chemotherapy — More than 80 percent of patients with osteosarcoma treated
with surgery alone develop metastatic disease, despite achieving local control. It is
presumed that subclinical metastases are present at diagnosis in the majority of
patients. Chemotherapy can eradicate these deposits if initiated at a time when disease
burden is low.
Initially, postoperative chemotherapy was used, and five-year survival rates rose from
less than 20 percent to between 40 and 60 percent in the 1970s [14]. Two subsequent
randomized studies conducted in the 1980s demonstrated a significant relapse-free and
overall survival benefit for adjuvant chemotherapy that persisted over time [15-18],
although the trials were limited in size and the survival benefits modest. The
chemotherapy regimens used in these studies included high-dose methotrexate
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(HDMTX) plus doxorubicin, bleomycin, cyclophosphamide and dactinomycin and either
vincristine [15], or cisplatin [16,17].
Neoadjuvant chemotherapy — The concept of induction or neoadjuvant chemotherapy
arose in concert with the evolving use of limb-sparing surgery. Because of the time
needed for fabrication of custom metallic endoprostheses, chemotherapy was often given
while awaiting definitive surgery [19]. Accumulating experience with this approach led to
the suggestion that induction chemotherapy might also be improving survival.
Neoadjuvant versus adjuvant chemotherapy — These observations ultimately led to a
randomized clinical study conducted between 1986 and 1993 by the Pediatric Oncology
Group (POG trial 8651) that compared immediate surgery and postoperative
chemotherapy versus 10 weeks of the same chemotherapy regimen followed by surgery
in 100 patients under the age of 30 with nonmetastatic high-grade osteosarcoma [20].
Chemotherapy consisted of alternating courses of HDMTX with leucovorin rescue,
cisplatin plus doxorubicin, and bleomycin, cyclophosphamide, and dactinomycin (BCD).
The five-year relapse-free survival rates were similar between the two groups (65 versus
61 percent for adjuvant and neoadjuvant therapy, respectively) as was the limb salvage
rate (55 and 50 percent for immediate and delayed surgery, respectively).
The study was criticized for the relatively low rate of limb-sparing surgery in both groups
(by modern standards) and the inclusion of BCD as a component of the regimen. The
contribution of BCD to the therapeutic efficacy of this regimen is unclear, while it can
clearly contribute to long-term bleomycin-related pulmonary toxicity. (See "Bleomycininduced lung injury".)
Nevertheless, this trial established that survival was similarly improved by either
presurgical or postsurgical chemotherapy and established a benchmark outcome for
future studies (five-year event-free survival 65 percent).
Due to its success in killing cancer cells (although actual tumor shrinkage during
treatment is not common, particularly with chondroblastic osteosarcomas), neoadjuvant
chemotherapy has evolved to a method of increasing the proportion of patients who are
suitable candidates for limb-salvage surgery. The majority of limb-sparing surgical
procedures for extremity osteosarcomas are now performed at institutions using
presurgical chemotherapy.
While it is clear that the number of patients with osteosarcoma who are deemed suitable
candidates for limb-sparing surgery has increased in parallel with the increasing use of
presurgical chemotherapy, this finding may reflect improvements in reconstructive
techniques and the increased experience and confidence of tumor surgeons rather than a
benefit attributable to the use of induction chemotherapy. A major concern in this regard
is the possibility that inexperienced surgeons may expand selection criteria to
accommodate inappropriate candidates who might be better served by amputation.
Neoadjuvant chemotherapy is never a substitute for sound surgical principles.
Histology and response to chemotherapy — Response to neoadjuvant chemotherapy is
histology dependent (table 1) [21,22]. In the larger series, in which 1058 patients
received presurgical chemotherapy for osteosarcoma over a 20-year period, the
likelihood of a "good" response (>90 percent necrosis) was significantly higher for
fibroblastic and telangiectatic osteosarcomas (83 and 80 percent, respectively)
compared to chondroblastic (43 percent) or osteoblastic osteosarcomas (58 percent)
[21]. Five-year survival rates paralleled the quality of the response to induction
chemotherapy (83, 75, 62, and 60 percent for fibroblastic, telangiectatic, osteoblastic,
and chondroblastic osteosarcomas, respectively).
For the two principal subtypes (osteoblastic and chondroblastic), the difference in “good”
response rate has not translated into any survival difference. Thus, the lack of a “good”
response to induction chemotherapy does not necessarily predict a poor outcome.
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Tailored postoperative chemotherapy based upon initial response — One of the most
compelling rationales for neoadjuvant chemotherapy is its ability to function as an in
vivo drug trial to determine the drug sensitivity of an individual tumor and to customize
postoperative therapy. A grading system for assessing the effect of preoperative
chemotherapy on the tumor was developed at Memorial Sloan Kettering and is in
widespread use (table 2) [14].
Responsiveness of an osteosarcoma to neoadjuvant chemotherapy is a major
determinant of clinical outcome [21-28]. Five-year survival rates for patients with an
extremity sarcoma and a "good" response to chemotherapy (as defined by 90 percent or
more necrosis in the surgical specimen) are significantly higher than for those with a
lesser response (71 to 80 versus 45 to 60 percent, respectively) [21,22,27,29].
Response to chemotherapy is usually defined by histologic appearance in the resected
specimen (picture 1). However, at least some data suggests that three-phase thallium
scintigraphy is a useful method for noninvasively evaluating tumor response to
neoadjuvant chemotherapy [30-32]. This approach may be most useful in a patient with
an equivocal clinical response for whom alternative chemotherapy might be attempted
prior to resection.
Patients with a near-complete absence of viable tumor cells in the resection specimen
after neoadjuvant therapy tend to do well when the same therapy is continued after
surgery [14,23-25,33]. However, when the tumor contains 10 percent or more residual
viable cells after neoadjuvant chemotherapy, a change in the chemotherapeutic regimen
might be beneficial. This strategy of altering the postoperative chemotherapy regimen
based upon the response to the neoadjuvant regimen was pioneered in the T10 protocol
at the Memorial Sloan-Kettering Cancer Center (MSKCC) [14,33] and confirmed by at
least one other group [34,35].
However, this strategy came under scrutiny for the following reasons:


With more mature follow-up, the initial beneficial results from the T10 protocol
have not been sustained at MSKCC [36].
Major cooperative groups (eg, Children's Cancer Group, German Society for
Pediatric Oncology, Scandinavian Sarcoma Group) have been unable to confirm
that altering the postoperative chemotherapy regimen in patients with a less than
complete response to presurgical chemotherapy improves their overall outcome
[37-41].
As noted above, POG trial 8651 failed to show a survival benefit for neoadjuvant as
compared to adjuvant chemotherapy [20]. It seems reasonable to conclude from these
data that the administration of presurgical chemotherapy (with or without treatment
individualization based upon initial tumor response) does not appear to have improved
cure rates.
On the other hand, experience with ifosfamide plus etoposide (I/E) has once again
brought the issue of modifying postsurgical treatment based upon response to induction
therapy to the forefront [34,35,42,43]. The high level of antitumor activity of I/E in
patients with measurable metastatic osteosarcoma (66 percent in one trial [42]) has
prompted investigators to consider the use of I/E in patients with resectable disease who
have a poor initial histologic response to standard chemotherapy.
Because of the potential for additional toxicity (gonadal and renal) from the addition of
these agents to standard chemotherapy, the Children's Oncology Group (COG)
performed a pilot trial that demonstrated that the addition of I/E to doxorubicin, cisplatin
and HDMTX was feasible and safe [43]. Subsequently, an international multigroup trial
(COG AOST 0331, the EURAMOS1 trial [44]) was developed to test prospectively the
benefit of altering postoperative chemotherapy based upon the response to initial
chemotherapy. In this trial, patients who had a poor histological response to standard
99
induction chemotherapy were randomly assigned to HDMTX, cisplatin, and doxorubicin
with or without I/E after resection, while those with a good histologic response after
induction chemotherapy were randomly assigned to continued HDMTX, cisplatin, and
doxorubicin with or without the addition of pegylated interferon alpha 2b for two years.
The only result that is available is an analysis of the 715 patients with a confirmed “good
response” who were randomized to maintenance IFN or no IFN, a preliminary report of
which was presented at the 2013 annual meeting of the American Society of Clinical
Oncology [45]. At a median follow-up of 3.1 years, EFS for MAP plus interferon is not
statistically superior to MAP alone (77 versus 74 percent, HR 0.82, 95% CI 0.61-1.11).
The ability to detect a benefit from maintenance IFN may have been limited by the fact
that one-fourth of patients did not even start IFN, and of those that did, 45 percent
terminated treatment prematurely.
Nevertheless, maintenance IFN cannot be considered a standard approach for patients
with a good histologic response to upfront MAP. Until results of the “poor histologic
response” arm from this trial are available, in the absence of data to indicate that a
change in therapy improves cure rate, we suggest not pursuing a change in the
chemotherapeutic regimen after surgery in patients who have less than a complete
response to neoadjuvant chemotherapy. While the results with chemotherapy as
initiated are not as good in a patient with a poor response to chemotherapy than with a
good response to chemotherapy, outcomes are overall better with chemotherapy than
without it, arguing for completion of the regimen that had been started. Better methods
are needed to prospectively identify chemoresistant tumors at diagnosis are
needed. Regardless of the regimen chosen, based on available evidence, in patients
with localized disease of an extremity, we suggest resuming chemotherapy within 21
days after definitive surgery, when feasible [46].
Choice of regimen — There is no worldwide consensus on a standard chemotherapy
approach for osteosarcoma. The development of adjuvant chemotherapy has been
largely empiric, with the majority of regimens incorporating doxorubicin and cisplatin,
with or without high-dose methotrexate (HDMTX, 6 to 12 g/m2 with leucovorin rescue)
(table 3) [16,17,35,39,47-50]. (See "Therapeutic use and toxicity of high-dose
methotrexate".)
Role of methotrexate — The role of HDMTX has been questioned, particularly in adults:




Nearly all of the trials purporting to show benefit for chemotherapy regimens that
include HDMTX are phase II trials that have been conducted predominantly in
children, although many have enrolled patients up to age 40 [8].
Neither of the two randomized studies comparing HDMTX plus doxorubicin and
cisplatin versus doxorubicin/cisplatin alone have shown an advantage to threedrug therapy [40,49]. However, one of these studies was criticized because the
outcome in the group receiving HDMTX, cisplatin, and doxorubicin was particularly
poor by modern standards (41 percent five-year disease-free survival compared
to 57 percent with doxorubicin/cisplatin alone) [40].
A single randomized trial comparing higher as compared to intermediate doses of
methotrexate did not show a survival advantage for high-dose therapy [51].
However, a benefit for HDMTX is supported by at least one phase II trial
demonstrates a superior outcome with high-dose as compared to intermediatedose methotrexate in the context of a multiagent chemotherapy regimen [26].
Furthermore, many studies have shown a correlation between peak serum levels
of methotrexate, tumor response, and outcome [38,52-54]. Thus, it is possible
that determining a benefit for HDMTX has been compromised by the use of
insufficient doses [55] or administration schedules.
Additional information comes from a literature-based systematic review of
chemotherapy trials for localized high-grade osteosarcoma [8]. In an analysis of
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
18 trials, almost all conducted in patients under the age of 40, treatment with
three or more drugs (including methotrexate, doxorubicin, and cisplatin) was
associated with a significant improvement in both event-free survival (hazard ratio
[HR] 0.701, 95% CI 0.615-0.799) and overall survival (HR 0.792, 95% CI 0.6770.926) compared to a two-drug regimen. However, only two of the trials included
in this analysis were randomized trials comparing a three-drug regimen containing
methotrexate doxorubicin and cisplatin versus a two-drug regimen.
Investigators at St. Jude’s Hospital have demonstrated good outcomes (five-year
event free and overall survival rates 66 and 75 percent) with a non-methotrexatecontaining chemotherapy regimen consisting of carboplatin plus ifosfamide and
doxorubicin [56].
The role of HDMTX in chemotherapy for osteosarcoma requires further study [57]. Until
further information is available, we and others consider that a methotrexate-containing
regimen represents a standard approach for children and adults age 40 or younger.
The optimal methotrexate-containing regimen is not established. The most recent study
from COG, AOST 0331, has completed accrual [44]. We consider the control arm of the
protocol (MAP: high dose methotrexate plus doxorubicin and cisplatin) (table 4) to
represent a reasonable and appropriate standard treatment [44]. At least some data
suggest that substitution of carboplatin for cisplatin is associated with inferior long-term
outcomes, at least in patients with metastatic disease at diagnosis [58].
Older adults are more commonly offered the combination of doxorubicin and cisplatin,
although control arm of the AOST 0331 protocol (MAP chemotherapy) (table 4) is also a
reasonable standard of care in this population. (See 'Chemotherapy for adults' below.)
Practical tips on administration of HDMTX, including the rationale for leucovorin rescue
and prevention and management of prolonged high plasma MTX levels, is discussed in
detail elsewhere.
Benefit of adding a fourth drug — The upfront addition of ifosfamide with or without
etoposide to HDMTX, doxorubicin, and cisplatin improves initial tumor response rates,
but it also increases toxicity, and the influence on overall and event-free survival is
unclear [59-63]. A meta-analysis of 14 trials in localized osteosarcoma (the majority
studying the addition of ifosfamide to methotrexate plus doxorubicin and cisplatin)
concluded that treatment effect was not significantly better with four as compared to
three drugs (HR for event-free survival 0.956, 95% CI 0.779-1.177, HR for overall
survival 1.043, 95% CI 0.851-1.280) [8]. Thus, the routine addition of ifosfamide (with
or without etoposide) to adjuvant chemotherapy for osteosarcoma is difficult to
recommend outside of a clinical trial. It is not known if adding or changing to ifosfamide
for poor responders will help increase overall survival.
Benefit of mifamurtide — The benefit of ifosfamide in conjunction with the liposomal
formulation of the immune stimulant muramyl tripeptide phosphatidylethanolamine
(MTP-PE, mifamurtide, Junovan®) was evaluated in a single large phase III study
involving 677 patients (age up to 30 years) with nonmetastatic osteosarcoma [59]. All
patients received doxorubicin, cisplatin, and methotrexate, and were randomized in a 2 x
2 scheme to receive or not receive ifosfamide, and then to receive or not receive
liposome encapsulated mifamurtide (see 'Newer and investigational approaches' below).
The addition of mifamurtide significantly improved the overall survival rate (78 versus 70
percent at six years), a finding which led to European regulatory approval of this agent
for patients with osteosarcoma [64]. However, the results of this trial are complex for
several reasons. Importantly, the data were initially analyzed, then reanalyzed when
more complete survival data could be assembled, leading to two separate publications of
the same data set with somewhat different results. The initial published report stated
that there was an interaction between ifosfamide and mifamurtide that prevented the
results from being analyzed as originally intended [65]. In addition, the improvement in
101
event free survival (67 versus 61 percent) with mifamurtide did not reach statistical
significance, which is very unusual in an oncology study in which the intervention leads
to a statistically significant improvement in overall survival. Such paradoxical results
have been observed in other diseases treated with immunotherapy (eg, sipuleucel-T and
prostate cancer).
As a result of these data, there is interest in further studying the efficacy of this agent in
osteosarcoma prior to including mifamurtide as a standard component of chemotherapy
for osteosarcoma [59,66,67]. Although the drug has received regulatory approval in
Europe and some other countries, further development of this agent (and drug approval
in the United States) may prove difficult given a "not approvable" letter for use of
mifamurtide in the adjuvant setting from the US Food and Drug Administration (FDA),
resulting from the presentation of the initial data, not the follow-up dataset, to the FDA.
Chemotherapy for adults — Intensive treatment with chemotherapy and resection is
warranted in adults, since osteosarcoma is a potentially curable tumor [11,60]. Similar
to children, the lack of a near-complete response to neoadjuvant chemotherapy predicts
a poor prognosis [60].
In many (but not all [68]) series, adults, especially older adults, have a worse prognosis
than do children with osteosarcoma. This was shown in a population-based series from
the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer
Institute [12]. Of the 3482 cases of osteosarcoma reported between 1973 and 2004,
there were 1855 cases in the 0 to 24 age group, 974 cases in adults 25 to 59 years of
age, and 653 in adults 60 to ≥85 years of age. Five-year survival rates in the three age
groups were 62, 59, and 24 percent, respectively. When broken down by decade of age,
five-year survival rates for adults in their 50s, middle to late 60s, and 80 to 84 years
were 50, 17, and 11 percent, respectively.
The optimal chemotherapy regimen for adults (at least those over the age of 40) is not
established; almost all of the trials included in the systematic review discussed above
were limited to individuals age 40 or younger [8]. Only one trial enrolled older adults up
to the age of 65 (range 14 to 62; median 42 years) and failed to show a benefit for the
addition of HDMTX to cisplatin and doxorubicin [49].
Older adults are most often offered doxorubicin plus cisplatin (AP, doxorubicin 25 mg/m2
per day days 1 to 3, cisplatin 100 mg/m2 day 1, every three weeks for six cycles)
[3,40,49]. However, the dose and tolerability of high-dose cisplatin and the role of
HDMTX remain unanswered questions. A methotrexate-containing regimen is a
reasonable standard of care in this population, if patients can tolerate it. Options include
a five-week cycle of cisplatin (100 mg/m2 day 1) and doxorubicin (25 mg/m2 days 1 to
3), followed by two weekly doses of HDMTX (6 to 12 g/m2 with leucovorin rescue), with
three cycles administered preoperatively and three postoperatively [59], or the control
arm of the AOST 0331 protocol (MAP chemotherapy) (table 4) [44], recognizing that
dose reductions may be necessary in older adults. Monitoring renal function before and
during treatment is paramount in such patients to minimize the risk of irreversible renal
failure.
Radiation therapy — In contrast to Ewing sarcoma, conventional osteosarcoma is
believed to be relatively resistant to radiation therapy (RT), although the small cell
variant may be more radiosensitive [69]. Primary RT is usually inadequate to achieve
local control, particularly for bulky tumors; surgery is preferred if possible.
Prophylactic whole lung radiation has been used in an attempt to improve outcomes
following surgery for nonmetastatic localized disease; however, it is not effective in the
absence of systemic chemotherapy [70-72]. Furthermore, in patients treated with
effective surgery and chemotherapy, adjuvant radiation does not improve survival and
increases the risk for secondary tumors; it should be considered only in the setting of an
unresectable or incompletely resected primary tumor [73].
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With the improvements in RT techniques over time, there has been renewed interest in
the use of RT for patients whose tumors respond to chemotherapy and in whom surgery
would be debilitating. One report described a five-year local control rate of 56 percent
among 31 patients with nonmetastatic extremity osteosarcoma who refused surgery and
were instead treated with radiotherapy (median dose 60 Gy) [74]. The five-year
metastasis-free survival rate was 91 percent, and there were no local failures among the
11 patients who responded well to chemotherapy (ie, had both a radiographic and
biochemical response with normalization of serum alkaline phosphatase). Among
patients who achieved local control, 86 percent had "excellent" limb function. However,
this single study does not represent sufficient data to recommend the use of RT as a
replacement for surgery in patients with resectable tumors. RT should not be considered
a substitute for inadequate surgery.
The benefit of RT for local control may need to be readdressed in view of the availability
of newer radiation techniques such as intensity modulated RT (IMRT), proton beam
irradiation [75], and carbon ion radiotherapy [76].
Summary — Surgery and systemic chemotherapy are the mainstays of treatment for
patients with nonmetastatic osteosarcomas. Preoperative as compared to postoperative
administration may permit a greater number of patients with extremity tumors to
undergo limb-sparing procedures. However, chemotherapy is not a substitute for sound
surgical judgment when assessing the need for amputation. It is reasonable to proceed
to immediate surgery followed by adjuvant chemotherapy if the nature of the resection
would not necessarily be influenced by a good response to chemotherapy.
Response to neoadjuvant chemotherapy is a major prognostic factor. It is unclear
whether outcomes can be improved in poor responders by changes in the postoperative
chemotherapy regimen.
The optimal regimen has not been established; however, the available evidence supports
the benefit of a three-drug as compared to a two-drug regimen in particular for children
and younger adults [8].
For children and adolescents, we recommend the MAP regimen as was used in the
control arm of the AOST 0331 protocol (table 4) [44]. If preoperative therapy is chosen,
we administer 10 weeks of chemotherapy prior to surgery and continue postoperative
chemotherapy for 29 weeks, beginning three weeks postoperatively. Where available,
mifamurtide (MTP-PE) can be used in addition to chemotherapy.
For adult patients under the age of 40, we use the same regimen as in children and
adolescents. For older patients, in whom the biology of the tumor may be somewhat
different, we generally employ doxorubicin and cisplatin only, although a methotrexatecontaining regimen is also a reasonable approach.
There is no role for adjuvant RT except in patients with incompletely resected
osteosarcomas and possibly in the rare patient with a small cell osteosarcoma. RT for
local control can be used in patients who decline surgery or for whom there is no
effective surgical option.
TREATMENT OF PATIENTS WITH METASTATIC DISEASE AT DIAGNOSIS — Patients who
present with overtly metastatic osteosarcoma have a poor prognosis; long-term survival
rates with standard chemotherapy and surgery range from 10 to 50 percent
[9,28,61,77,78]. This is in contrast to patients with apparently localized disease at
presentation, two-thirds of whom will achieve long-term survival with appropriate
therapy.
Analogous to the situation with primary osteosarcomas, the ability to control all foci of
macroscopic disease is an essential element for successful treatment [27,79,80]. The
minority of patients with overt metastatic disease who achieve long-term survival and
are presumably cured have usually been treated with a combination of surgery,
chemotherapy, and sometimes RT [9,78,81-83].
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The location of the metastases is of prognostic importance. Patients with only pulmonary
disease appear to have a chance of long-term event-free survival on the order of 20 to
30 percent [82,84]. In contrast, most series report a dismal prognosis for patients with
bone metastases [58,85,86], with the exception of a single study that added etoposide
and high-dose ifosfamide to standard chemotherapy (see 'Choice of chemotherapy'
below) [42].
Although it might be argued that pulmonary lesions are more susceptible to
chemotherapy than are bone metastases, there is also a tendency to surgically pursue
pulmonary lesions more aggressively. In some studies, long-term survival correlates
with the number of pulmonary nodules at diagnosis and the ability to successfully resect
those that persist after chemotherapy [9,42,82,83,87-89].
As noted previously, patients with bone metastases do less well. There are some longterm survivors among patients in whom bone disease has been treated aggressively
(usually with chemotherapy in addition to complete resection, sometimes with
irradiation) [42,77,86,90].
Choice of chemotherapy — Optimal management for patients who present with
metastatic osteosarcoma has not been defined by randomized clinical trials, and thus,
there is no single standard approach. The most active drugs in patients with measurable
disease (HDMTX, doxorubicin, cisplatin, ifosfamide) have single-agent response rates
between 20 and 40 percent [58,85,87,91-93]. Response rates are higher with
multiagent regimens but a lower proportion of patients treated for metastatic disease
show a good histological response to neoadjuvant chemotherapy as compared to those
with apparently localized disease [52,81,94]. This suggests an underlying difference in
the biological behavior.
In an effort to improve outcomes, the Children’s Oncology Group (COG) and others have
utilized a strategy of applying novel agents to patients with newly diagnosed metastatic
disease prior to standard therapy (termed the "therapeutic window" approach)
[42,58,83,87].
Using this approach, the Pediatric Oncology Group (one of the predecessors of COG)
identified the combination of ifosfamide/etoposide as effective induction therapy,
particularly for those with metastatic bone disease. In one report, 43 patients under the
age of 30 with measurable metastatic osteosarcoma at diagnosis (28 lung only, 12 with
metastatic bone involvement, with or without lung metastases), received two threeweek courses of etoposide and high-dose ifosfamide (17.5 g/m2 per cycle) with
hematopoietic growth factor support, followed by surgery and an additional 34 weeks of
"continuation therapy" [42]. Postoperative therapy consisted of ten courses of HDMTX
with leucovorin rescue, four courses of doxorubicin/cisplatin, one course of doxorubicin
alone, and three additional courses of etoposide plus lower-dose ifosfamide [42].
Treatment-related toxicity was prominent, and included 83 percent grade 4 neutropenia,
24 percent sepsis, 29 percent grade 4 thrombocytopenia, and five patients with
Fanconi's syndrome.
However, the overall response rate was 59 percent, and it was 80 percent for patients
with synchronous bone metastases. The projected two-year progression-free survival
rates were 34 and 58 percent for patients with lung-only and bone involvement,
respectively. These results are superior to any other reports of patients with metastatic
disease at diagnosis, particularly bone metastases.
Nevertheless, few patients with metastatic osteosarcoma are cured, and new therapeutic
approaches are needed.
Dose-intensive chemotherapy with peripheral blood stem cell support is ineffective in
metastatic osteosarcoma [95-97]. For patients who present with overt metastatic
disease, participation in experimental trials should be encouraged. Such a trial,
AOST06P1, tested the feasibility of adding zoledronic acid to multiagent chemotherapy
104
(MAP chemotherapy plus ifosfamide and etoposide); results from this study are pending
[98]. (See 'Bisphosphonates' below.)
POSTTREATMENT SURVEILLANCE — For all bone sarcomas, there are no prospective
data that address the appropriate schedule or selection of tests for surveillance after
initial treatment for localized disease. As with other cancers, there are no data indicating
that a particular follow-up schedule improves survival. Consensus-based guidelines from
the National Comprehensive Cancer Network (NCCN) and from the Children's Oncology
Group recommend physical examination, a complete blood count, chest imaging, and
local imaging of the primary site every three months for two years, every four months
for year three, every six months for years 4 and 5, and annually thereafter (table 5)
[99]. The appropriate duration of follow-up is unknown; however, the vast majority of
recurrences are observed within 10 years.
At diagnosis, an initial technetium bone scan or PET scan is performed to explore for
bone metastases. There are no comparative data of bone scan versus PET scan in this
context. COG guidelines suggest either as appropriate (table 5).
A restaging bone scan (or PET, depending on which study was originally done, and
whether or not the disease was FDG-avid on the baseline PET) may be performed in
some institutions at the completion of therapy (and is included in imaging guidelines
from the bone tumor committee of the Children’s Oncology Group (table 5) [99]), but it
is rarely positive. At most institutions, bone scans and PET scans are utilized primarily
for evaluation of new symptoms following therapy. In the uncommon subset of patients
with unresectable tumors (eg, in the proximal sacrum), PET scan may be preferable to
bone scan for following the patient after radiation therapy since bone scans can show
persistent activity reflective of ongoing bone remodeling in this setting.
Following primary therapy, long term follow-up of patients should continue indefinitely,
because of treatment-related toxicity (including secondary malignancy) and the
possibility of a late relapse, which may occur as late as 20 years after therapy [100].
Recommendations for long-term follow-up are available from the Children’s Oncology
Group Survivorship Guidelines. For individuals treated with anthracycline-containing
chemotherapy, the recommendation includes an echocardiogram or equilibrium
multigated blood pool imaging (MUGA scan) at the first long-term follow-up visit, then
periodically reassessment of cardiac function, with the frequency of testing dependent on
age at initial treatment, the total anthracycline dose, and whether chest irradiation was
also administered.
TREATMENT OF RECURRENT DISEASE — Patients with a disease recurrence after
resection alone can often be salvaged with additional surgery and chemotherapy,
although their long-term survival is inferior to that of patients who received conventional
multiagent chemotherapy in conjunction with surgery upfront [101,102].
Treatment of relapse in patients who have already received adjuvant and/or neoadjuvant
chemotherapy is a more difficult situation. Such patients usually have received most of
the effective drugs, and presumably their tumors are more chemotherapy-resistant than
those that have never been exposed to antineoplastic agents [103].
Nevertheless, salvage is still possible and is more likely in patients with a longer relapsefree interval. In a large database of 565 osteosarcoma patients who relapsed after being
treated on one of three different neoadjuvant chemotherapy protocols within the
European Osteosarcoma Intergroup, five year survival post-relapse in those whose
disease recurred after two years versus within two years of randomization was 35 versus
14 percent, respectively [104]. Other favorable prognostic factors in recurrent
osteosarcoma include no more than one or two pulmonary nodules, the presence of
unilateral pulmonary involvement, lack of pleural disruption, and achieving a second
surgical remission [29,101,105-108].
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The predominant site of disease relapse is in the lung, but the increasing use of
adjuvant/neoadjuvant chemotherapy for localized osteosarcoma may have changed the
pattern of relapse. Patients whose disease recurs following adjuvant chemotherapy tend
to relapse later and with fewer pulmonary lesions than those treated with surgery alone;
they also have a higher chance of relapsing at distant bony sites [103,109-111].
However, others have observed no change in relapse pattern with the increasing use of
upfront intensive chemotherapy [112]. Although rare, the possibility of metachronous,
sometimes multiple osteosarcomas must be considered in a patient who has what
appears to be isolated bone relapse without pulmonary involvement [113].
Therapeutic approach — The therapeutic approach to recurrent disease and the
likelihood of prolonged survival are related to the location, extent, and timing of relapse
[101,106,114]. Attempted resection is probably the most appropriate initial treatment
for patients who relapse late (ie, beyond one year after initial therapy) with a small
number of pulmonary nodules that do not invade the pleura and that can be completely
resected [80,115-122].
Surgery — Complete resection of all metastatic sites is a prerequisite for long-term
survival. The importance of resection can be illustrated by a series of 249 consecutive
patients who developed a second or subsequent recurrence after modern combined
modality treatment of osteosarcoma [114]. While only one of 205 patients with
recurrence survived past five years without surgical remission, the five-year survival and
event-free survival rates were 32 and 18 percent for 119 second, 26 and 0 percent for
45 third, 28 and 13 percent for 20 fourth, and 53 and 0 percent for five fifth recurrences,
respectively, in which a surgical remission was achieved.
Some patients with isolated pulmonary metastases that develop more than one year
after original treatment will be long-term survivors with just surgical removal of their
lung nodules [80,115]. Multiple procedures may be necessary, although the odds of
long-term survival decrease with each subsequent relapse. Many investigators advocate
the use of postthoracotomy chemotherapy (and even lung irradiation) to destroy
presumed residual microscopic deposits after surgical treatment of overt metastatic
disease [123]. The contribution of such therapy to long-term outcomes has not been
examined in a controlled study and remains to be defined. However, it is probably
reasonable to administer such treatment to patients who undergo resection of more than
three lesions appearing within six months to one year of surgery.
Patients who relapse early (ie, within six months of surgery) seem to fare poorly even if
their disease is amenable to complete resection [80,105,116,124]. This is most likely
because of drug resistance that develops during chemotherapy. Although aggressive use
of surgery, chemotherapy, and at times RT aimed at eradicating all sites of disease can
lead to prolonged survival in some of these patients [103,105,117,123,125-127], it is
difficult to be overly optimistic about the chances of cure after early relapse, especially
relapse involving nonpulmonary sites or unresectable pulmonary disease
[23,105,116,118].
Unresectable disease — Patients who relapse with unresectable metastatic disease are
most often incurable and should be considered for palliative therapy (eg, RT) [128].
For selected patients with a limited volume of unresectable disease, particularly those
who have no prior exposure to systemic chemotherapy, consideration should be given to
administering chemotherapy before resection. While chemotherapy rarely produces a
complete response at metastatic sites, some patients with inoperable metastases
(including the rare patient with bone metastases [129]) may respond sufficiently to
permit complete resection at a later date. While it has not been shown that
chemotherapy given before or after resection of metastatic lung disease improves
patient survival in comparison to patients who have resection of metastases alone [88],
there are no randomized trials that directly address this issue.
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Choice of chemotherapy regimen — Most of these patients will already have received
standard chemotherapy with HDMTX, doxorubicin, and cisplatin. Combinations of
etoposide and ifosfamide are more active than either agent alone [83,130] and
commonly used, without or with carboplatin (ICE) [131-133]. In general, response rates
are lower than in the setting of newly diagnosed disease. However, although ifosfamide
clearly shows a higher response rate in newly diagnosed patients, objective responses
have been reported in patients whose disease relapses after they have received
ifosfamide-containing adjuvant therapy [83,131,134]. Combinations of
cyclophosphamide with etoposide are also active [135].
In an early report 14 of 42 children with recurrent osteosarcoma (33 percent) responded
to etoposide (100 mg/m2 daily for three days) and lower dose ifosfamide (2 g/m2 daily
for three days) [134]. With the expectation that adding G-CSF would permit dose
intensification, a phase I trial of etoposide and escalating doses of ifosfamide in patients
with recurrent osteosarcoma was completed; in a preliminary report, six of 13 patients
exhibited a partial response [136].
Other options include cyclophosphamide plus etoposide [135,137,138] or gemcitabine
plus docetaxel [139]. Clinical trials, when available, are appropriate as well.
Samarium — Samarium-153 lexidronam is a bone-seeking radiopharmaceutical that may
provide pain palliation for patients with an unresectable local recurrence or skeletal
metastases [140,141]. However, as a radioactive agent that is taken up by bone,
Samarium-153 can be toxic to bone marrow and can leave patients transfusion
dependent. Thus, marrow reserve should be considered before its use. (See "Radiation
therapy for the management of painful bone metastases", section on
'Radiopharmaceuticals'.)
NEWER AND INVESTIGATIONAL APPROACHES — A study of the mTOR inhibitor
ridaforolimus in patients with metastatic sarcoma suggested potential activity for this
class of compounds in patients with osteosarcoma [142], raising the possibility of using
agents of this drug class in patients with metastatic disease; since the RECIST response
rate in this study was very low, mTOR inhibitors remain investigational; perhaps it will
become possible to identify patients who do benefit from these agents.
Among other interesting agents that may have clinical utility are inhibitors of insulin-like
growth factor I receptor (IGF IR), since IGF signaling is critical for bone formation during
development. Early studies with a variety of monoclonal antibodies and small molecule
inhibitors of the IGF IR have been completed, with largely disappointing results even for
the combination of an mTOR inhibitor and an IGF IR inhibitor [143].
A study evaluating the feasibility of adding trastuzumab to standard chemotherapy for
patients with HER2-positive osteosarcoma was just completed by the Children's
Oncology Group (COG) [144]. The results of this study are not yet available.
Bisphosphonates — Numerous in vitro and xenograft studies support the concept that
bisphosphonates have activity against osteosarcoma alone or in combination with
chemotherapy (reviewed in [145]); the safety of combining pamidronate with
chemotherapy in patients with newly diagnosed osteosarcoma has been shown in a small
phase II trial [145]. However, until further data are available, this approach should not
be considered outside of the context of a clinical trial. The COG is evaluating the
feasibility of adding zoledronic acid to standard chemotherapy for patients with
metastatic osteosarcoma.
Immunotherapy — Immune responses may influence the survival of patients with
osteosarcoma. Cytotoxic lymphocytes are present in such patients [146,147], and in at
least one study, the degree of lymphocytic infiltration correlated with survival [147].
These findings have prompted investigators to explore a variety of immunotherapeutic
approaches for patients with advanced osteosarcoma.
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The addition of Bacille Calmette-Guerin (BCG) and interferon did not improve survival
when added to multiagent chemotherapy [148,149]. However, as noted above,
liposomal muramyl tripeptide-phosphatidyl-ethanolamine (mifamurtide), an agent
derived from BCG that activates macrophages and increases circulating cytokine levels
[150,151], was studied in a randomized study, described above, in which patients were
assigned, using a 2 x 2 factorial design, to standard chemotherapy with or without
ifosfamide and then to receive or not receive mifamurtide [59]. The addition of
mifamurtide to standard chemotherapy significantly improved overall survival but there
was only a trend toward improved event-free survival. (See 'Benefit of mifamurtide'
above.).
However, when the analysis was restricted to the 91 patients with metastatic disease at
diagnosis, there was only a nonstatistically significant trend toward improved five-year
event free survival (42 versus 26 percent) and overall survival (53 versus 40 percent)
that favored mifamurtide [152]. Thus, the role of mifamurtide in patients with metastatic
osteosarcoma remains uncertain and a further randomized trial seems warranted.
Another immunotherapeutic approach that is being pursued for pulmonary metastatic
disease is inhalation of aerosolized granulocyte macrophage colony-stimulating factor
(GM-CSF). GM-CSF stimulates the proliferation and differentiation of hematopoietic
progenitor cells and augments the functional activity of neutrophils, monocytes,
macrophages, and dendritic cells. Early data using aerosolized GM-CSF in a variety of
cancers with pulmonary metastases suggested potential efficacy [153,154]. However,
benefit could not be shown in a trial of inhaled GM-CSF in 43 patients with pulmonary
relapse from osteosarcoma in the American Osteosarcoma Study Group [AOST] protocol
0221 [155]. There was no detectable immunostimulatory effect on the pulmonary
metastases or suggestion of improved outcomes post relapse. Aerosolized GM-CSF is not
a standard approach and should only be considered in the context of a clinical trial.
SUMMARY AND RECOMMENDATIONS
Localized disease

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
The survival of patients with malignant bone sarcomas has improved dramatically
over the past 30 years, largely owing to chemotherapeutic advances. Adjuvant
chemotherapy significantly improves survival compared to surgery alone and is
considered a standard component of therapy for both children and adults. (See
'Prognosis and evolution of treatment' above.)
The optimal timing of chemotherapy (ie, preoperative versus postoperative) has
not been established. There is no survival benefit for neoadjuvant as compared to
adjuvant chemotherapy, but many centers preferentially utilize preoperative
chemotherapy, particularly if a limb-sparing procedure is being contemplated for
an extremity osteosarcoma.
For children, adolescents, and young adults up to age 40, we suggest a
methotrexate-containing chemotherapy regimen over a two-drug nonmethotrexate containing regimen (Grade 2B). (See 'Role of methotrexate' above.)
The optimal methotrexate-containing regimen has not been established. For
children, adolescents, and young adults up to age 40 with localized osteosarcoma,
the control arm of the recently closed protocol AOST0331 (MAP chemotherapy,
HDMTX plus doxorubicin and cisplatin, (table 4)) is a reasonable and appropriate
choice for standard therapy. If preoperative therapy is chosen, we administer 10
weeks of chemotherapy prior to surgery and continue postoperative chemotherapy
for 29 weeks, starting one week postoperatively.
For most patients, we suggest against a four-drug as compared to a three-drug
regimen (Grade 2B). However, in countries where mifamurtide is available,
mifamurtide in conjunction with ifosfamide, methotrexate, doxorubicin, and
cisplatin chemotherapy may be used. (See 'Benefit of mifamurtide' above.)
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For older adults, the benefit of HDMTX is unproven, and we suggest cisplatin and
doxorubicin alone (Grade 2B). However, a HDMTX-containing regimen is a
reasonable alternative in patients with adequate renal function. (See
'Chemotherapy for adults' above.)
Practical tips on administration of HDMTX, including therapeutic drug monitoring,
the rationale for leucovorin rescue and prevention and management of prolonged
high plasma MTX levels, are discussed in detail elsewhere.
For patients who demonstrate intolerance of HDMTX and for institutions that
cannot provide pharmacokinetic monitoring for HDMTX, the combination of
carboplatin, ifosfamide, and doxorubicin appears to be a reasonable alternative.
However, the increased doses of alkylating agents may possibly increase the risk
of second malignancies (leukemia). (See 'Role of methotrexate' above.)
For patients treated off protocol, we suggest not pursuing a change in the
chemotherapeutic regimen after surgery in patients who have less than a
complete response to the initial neoadjuvant chemotherapy (Grade 2B). (See
'Tailored postoperative chemotherapy based upon initial response' above.)
There is no role for adjuvant RT in patients with completely resected
osteosarcoma, and for most patients, we recommend not pursuing this approach
because of the risk for late toxicity (Grade 1B). We restrict the use of adjuvant RT
to those patients with incompletely resected sarcomas and for the rare patient
with a small cell osteosarcoma. RT should be considered as the primary modality
for local control only for patients who decline surgery or for whom there is no
effective surgical option. (See 'Radiation therapy' above.)
Metastatic disease at diagnosis


Patients who present with overtly metastatic osteosarcoma have a poor prognosis,
although long-term survival is possible in up to 50 percent of those with isolated
pulmonary metastases who are treated with combined systemic and surgical
therapy.
For children and adolescents with metastatic osteosarcoma at the time of
diagnosis who do not have a surgical option, there is no single standard approach
to treatment, and these patients should be encouraged to enroll on clinical trials
testing new therapies. If protocol enrollment is not available or if patients are
ineligible, treatment with the control arm of the AOST0331 protocol (MAP
chemotherapy alone, (table 4)) or as per AOST06P1 without zoledronic acid (MAP
plus ifosfamide and etoposide) are reasonable and appropriate choices for
standard therapy.
Posttreatment surveillance — We follow guidelines for posttreatment surveillance from
the Children’s Oncology Group, which are outlined in the table (table 5). (See
'Posttreatment surveillance' above.)
Recurrent disease


The predominant site of disease relapse following initially successful treatment is
lung. Attempted resection is probably the most appropriate initial treatment for
patients who relapse beyond one year after initial therapy with a small number of
pulmonary nodules that do not invade the pleura and that can be completely
resected. Although some of these patients may be cured with resection alone,
most receive a combination of surgery plus chemotherapy.
Patients who relapse with unresectable metastatic disease are incurable and
should be considered for palliative therapy (eg, RT, chemotherapy). However, in
selected patients with a limited volume of unresectable disease, particularly those
who have no prior exposure to systemic chemotherapy, consideration should be
109
given to administering chemotherapy before resection. While chemotherapy rarely
produces a complete response at metastatic sites, some patients with inoperable
metastases may respond sufficiently to permit complete resection at a later date.
(See 'Therapeutic approach' above.)
The choice of chemotherapy depends upon prior treatment. Most patients will have
already received HDMTX, doxorubicin, and cisplatin. For these patients, we suggest
treatment on a research study, when feasible. Off study, we typically use etoposide
plus ifosfamide, without or with carboplatin (ICE). If chemotherapy has not been
previously administered, we suggest the same regimens as are used for primary
management. (See 'Choice of chemotherapy regimen' above.)
Treatment protocols for soft tissue and bone sarcoma
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BİYOPSİ SUMMARY
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Primary malignant bone tumors are uncommon malignancies, but they are an
important cause of cancer morbidity and mortality, especially among teenagers
and young adults. (See 'Introduction' above.)
Primary malignant bone tumors are classified according to their cytologic features
and cellular products (table 1).
The goals of the preoperative evaluation are to establish the tissue diagnosis,
evaluate disease extent, and assess the feasibility of a limb-sparing approach.
Although plain radiographs can often predict the probable histology of a
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potentially malignant bone lesion, the definition of tumor size and local
intraosseous and extraosseous extent is most accurately achieved by magnetic
resonance imaging (MRI). CT is the best method to evaluate the thorax for
metastatic disease. PET scans are increasingly being used in place of radionuclide
bone scans to evaluate the rest of the skeleton as well as other distant metastatic
sites. (See 'Diagnostic and staging work-up' above.)
The radiographic differential diagnosis depends upon recognition of the tissue type
and the degree of aggressiveness (as determined by lesion size and relationship
with the surrounding tissues [invasiveness]). Recognition of fat within a tumor is
generally a sign that it is benign. (See 'Differential diagnosis' above.)
Bone biopsy is indicated in the following circumstances (see 'Indication for biopsy'
above):
Whenever there is significant doubt as to the diagnosis of a benign or malignant
lesion
When the histologic distinction among possible diagnoses could alter the planned
course of treatment
When definitive confirmation of the diagnosis is required before undertaking a
hazardous, costly, or potentially disfiguring treatment

The biopsy of a suspected primary bone tumor must be carefully planned to avoid
compromising the oncologic outcome. Although a fine needle aspiration biopsy
may be adequate for the diagnosis of a metastatic or recurrent bone lesion, core
needle biopsy, or an open biopsy is usually required for most primary bone
tumors. Open biopsies are being done less frequently since most core needle
biopsies can deliver sufficient tissue on multiple passes for all diagnostic studies.
Given the heterogeneity of most sarcomas, the ability to guide the core needle to
regions of more aggressive tumor is very important to accurately diagnosis and
grade the sarcoma. (See 'Biopsy techniques' above.)

The extensive pathologic evaluation that is often required to ascertain the correct
diagnosis may require special handling for all or part of the specimen. This
process can last one to two weeks depending on the number of tests necessary.
Among patients undergoing an open biopsy, frozen section analysis is important in
determining whether sufficient tissue has been acquired.
Chondrosarcoma
Literature review current through: Aug 2013. | This topic last updated: Tem 26, 2013.
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INTRODUCTION — Chondrosarcomas are a heterogeneous group of malignant bone
tumors that share in common the production of chondroid (cartilaginous) matrix [1].
Chondrosarcomas are the third most common primary malignancy of bone after
myeloma and osteosarcoma [2]. They account for 20 to 27 percent of primary malignant
osseous neoplasms [3].
Clinical behavior is variable. Ninety percent are conventional chondrosarcomas, 90
percent of which are low- to intermediate-grade tumors [4]. These tumors are slow
growing with a low metastatic potential. They are considered relatively refractory to
chemotherapy and radiation therapy.
In contrast, high-grade chondrosarcomas, which include 5 to 10 percent of conventional
chondrosarcomas as well as some rare variants, have a high metastatic potential and a
poor prognosis following resection alone [4]. Some of the rare subtypes are more
responsive to chemotherapy and radiation.
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This topic review will provide an overview of the classification, clinical characteristics,
and therapeutic options for chondrosarcoma. The rare chondrosarcomas involving the
head and neck and skull base, as well as diagnosis and biopsy techniques for bone
sarcomas in general, are discussed elsewhere.
HISTOLOGIC GRADING AND PROGNOSIS — Histologic grade is one of the most
important indicators of clinical behavior and prognosis [5-8]. Chondrosarcomas are
graded on a scale from 1 to 3, based upon nuclear size, staining pattern
(hyperchromasia), mitotic activity, and degree of cellularity (picture 1).


Grade 1 chondrosarcomas were reclassified in the updated World Health
Organization (WHO) 2013 classification system as "atypical cartilaginous tumours"
(ACT/CS1) [1]. They are moderately cellular, with an abundant hyaline cartilage
matrix. The chondrocytes have small, round nuclei and are occasionally
binucleate. Mitoses are absent. ACT/CS1 almost never metastasize (1 percent risk
in one series of patients [4]) and are therefore now considered a locally
aggressive neoplasm rather than a malignant sarcoma. Ten-year survival is 83 to
95 percent [4,5,9].
Grade 2 chondrosarcomas are more cellular with less chondroid matrix than
ACT/CS1 tumors. Mitoses are present, but widely scattered. The chondrocyte
nuclei are enlarged and can be either vesicular or hyperchromatic. The metastatic
potential is intermediate between low-grade and high-grade chondrosarcomas
(approximately 10 to 15 percent). Ten-year survival is approximately 64 to 86
percent [4,5,9].
The vast majority of conventional (primary and secondary) chondrosarcomas are
ACT/CS1 or chondrosarcoma grade 2 [4,9,10].

Grade 3 chondrosarcomas are highly cellular, with nuclear pleomorphism and
easily detected mitoses. Chondroid matrix is sparse or absent. High-grade
chondrosarcomas have a high metastatic potential (approximately 32 to 70
percent) and a poor prognosis with surgical resection alone [4,5]. The 10-year
survival rate is about 29 to 55 percent [4,9].
In most cases, the histologic grade of differentiation of a recurrent chondrosarcoma is
the same as the primary lesion; however, up to 13 percent of recurrences exhibit a
higher grade of malignancy when compared with the original neoplasm [5,9,11]. This
suggests that chondrosarcomas can progress biologically.
Histologic grading is subject to interobserver variability [12,13], which can be
problematic since surgical therapy for ACT/CS1 and grade 2 chondrosarcomas is often
different. Because of this, there is an urgent need for molecular markers that can be
used to predict clinical behavior, guide therapeutic decision making, and provide novel
targets for molecularly targeted therapy [14].
CLASSIFICATION, HISTOLOGY, AND CLINICAL FEATURES
Precursor lesions — Two benign cartilaginous lesions that can precede chondrosarcoma
are described:
Osteochondroma — An osteochondroma (osteocartilaginous exostosis) is a cartilagecapped bony projection arising on the external surface of a bone (picture 2 and image
1); it contains a marrow cavity that is continuous with that of the underlying bone. The
majority are located in the long bones, predominantly around the knee.
The inherited condition multiple osteochondromas (hereditary multiple exostoses) is
characterized by the development of two or more osteochondromas in the appendicular
and axial skeleton. This syndrome is inherited in an autosomal dominant fashion. The
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prevalence in the general population is 1:50,000, and males are affected slightly more
often than females.
Almost 90 percent of cases of multiple osteochondromas are caused by inheritance of a
germline mutation in one of the tumor suppressor genes EXT1 or EXT2.
Although most are asymptomatic, osteochondromas can cause pain, functional
problems, and deformity; they also carry a risk for fracture. Malignant transformation is
estimated to occur in 5 percent of patients with a solitary or multiple osteochondromas
[15-20]. In one series, the average time between initial diagnosis and malignant
transformation was 9.8 years [19]. All chondrosarcomas arising in the setting of an
osteochondroma are secondary peripheral tumors.
A change in the size of an osteochondroma or new onset of symptoms warrants
investigation, as each may herald malignant transformation [21,22]. Osteochondromas
located at the pelvis, hips and shoulder girdle are reported to be particularly prone to
malignant transformation [21,22]. Among patients with multiple osteochondromas,
malignant transformation appears to be unrelated to the presence or absence of an EXT
mutation, sex, severity of disease, or the number of lesions [20].
Enchondroma — Enchondromas are common benign cartilaginous tumors that develop in
the medulla (marrow cavity) of bone (image 2). When multiple enchondromas are
present, the condition is called enchondromatosis (image 3), of which the most common
form is Ollier disease (estimated prevalence 1 in 100,000) [23]. When multiple
enchondromas are associated with soft tissue hemangiomas, the designation is Maffucci
syndrome (image 4). Both are congenital but not inherited.
Although the vast majority are asymptomatic, clinical problems caused by
enchondromas include skeletal deformity, limb-length discrepancy, and a risk for
malignant transformation. Malignant transformation in a solitary enchondroma is
presumed to be extremely rare (<1 percent) but it has been described (image 5) [19].
The risk of chondrosarcoma in patients with Ollier disease or Maffucci syndrome is as
high as 50 percent [23-28]. The risk is highest with enchondromas located in the pelvis
[27]. Malignant transformation usually presents after skeletal maturity and may be
heralded by the development of pain [19].
The histologic and radiographic distinction between an enchondroma and a low-grade
chondrosarcoma may be difficult, even in experienced hands (see 'Histologic appearance'
below).
Conventional chondrosarcomas
Central chondrosarcoma — Central chondrosarcomas of bone arise within the medullary
cavity and constitute approximately 75 percent of all chondrosarcomas (table 1). The
majority are thought to arise primarily (ie, without a benign precursor lesion). However,
the finding of remnants of a preexisting enchondroma in 40 percent of central
chondrosarcomas and the fact that most enchondromas remain asymptomatic and
clinically silent have led some to hypothesize that as many as 40 percent of central
chondrosarcomas could be secondary to a preexisting enchondroma [29].
The majority of patients are over the age of 50. There is a slight male predominance.
The most commonly involved skeletal sites are the proximal femur, bones of the pelvis
(particularly the ilium), and proximal humerus (together accounting for about 75 percent
of cases), followed by distal femur, ribs, tibia, and metacarpal and metatarsal bones
[3,4,30,31]. Other less frequently involved sites include the spine, the skull base, and
the craniofacial bones. (See "Chordoma and chondrosarcoma of the skull base" and
"Head and neck sarcomas".)
Local swelling and pain are the most common presenting symptoms. Pain is typically
insidious, progressive, worse at night, and often present for months to years before
presentation. A pathologic fracture is present at diagnosis in 3 to 17 percent of patients
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[3]. Primary spinal chondrosarcomas are rare but can cause compression of the spinal
cord.
Peripheral chondrosarcoma — By definition, all peripheral chondrosarcomas arise within
the cartilage cap of a preexisting osteochondroma (table 1). Patients with a peripheral
chondrosarcoma are generally younger than those with a central chondrosarcoma (table
1) [21]. The clinical presentation is similar to that of central chondrosarcoma, usually
pain and local swelling. The most commonly involved bones are the pelvis and bones of
the shoulder girdle, although in some series, the long bones predominate [19]. The
distinction between osteochondroma and secondary peripheral atypical cartilaginous
tumour/chondrosarcoma grade I arising in osteochondroma can be difficult and should
be made in a multidisciplinary team. The size of the cartilaginous cap is the most
important parameter [32].
Periosteal chondrosarcoma — Fewer than one percent of conventional chondrosarcomas
arise on the surface of a bone and are designated periosteal (previously termed
juxtacortical) chondrosarcomas. They most frequently affect adults in their 20s and 30s,
and have a slight male predilection. The metaphyses of long bones are most frequently
involved, especially of the distal femur (figure 1). Patients typically present with a
palpable, painless, slowly growing mass [3].
Periosteal chondrosarcomas usually have a good prognosis after adequate local surgery
despite histologic features of a high-grade lesion [7,33-36]. Histological grading is
therefore not used at this location.
Histologic appearance — Despite their different origin and location, primary and
secondary chondrosarcomas appear histologically similar (picture 1). At low
magnification, there is abundant cartilage matrix production, and the irregularly shaped
lobules of cartilage, often separated by fibrous bands, may permeate the bony
trabeculae [1]. Necrosis or mitoses may be seen in high-grade lesions. The histology of
periosteal chondrosarcomas is similar except that the appearance is often more
worrisome with increased cellularity and nuclear atypia.
The histologic (and radiographic) distinction between a benign cartilage lesion and an
atypical cartilaginous tumour/chondrosarcoma grade 1 (ACT/CS1) can be extremely
difficult [12,37,38]. ACT/CS1 is hypercellular when compared to benign cartilage lesions.
The chondrocytes appear mildly to moderately atypical and contain enlarged
hyperchromatic nucleoli. Permeation of preexisting host bone and mucomyxoid matrix
changes are important characteristics that can be used to separate ACT/CS1 from an
enchondroma [13]. Periosteal chondrosarcoma is distinguished from periosteal
chondroma based upon size (≥5 cm) and the presence of cortical invasion. For
phalangeal enchondromas, more worrisome histologic features are tolerated, and the
diagnosis of chondrosarcoma at this site is based upon the presence of cortical
destruction, soft tissue invasion, and mitoses [39].
Fortunately, the distinction between enchondroma and ACT/CS1 is not always essential
for clinical decision making, since treatment (curettage and adjuvant phenol application
or cryosurgery) is often similar for enchondromas as well as central ACT/CS1 (see
'Surgical treatment' below).
Rare chondrosarcoma subtypes — In addition to conventional central, peripheral, and
periosteal chondrosarcomas, several rare subtypes are described, together constituting
less than 10 percent of all chondrosarcomas.
Dedifferentiated chondrosarcoma — Dedifferentiated chondrosarcomas contain two
juxtaposed components: a well-differentiated cartilage tumor (which can be either an
enchondroma or a low-grade chondrosarcoma), and a high-grade non-cartilaginous
sarcoma which most frequently is an osteosarcoma, fibrosarcoma, or an undifferentiated
high-grade pleomorphic sarcoma (previously termed malignant fibrous histiocytoma)
(picture 3) [40].
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Both components appear to share some genetic aberrations [41,42] with additional
genetic changes in the high-grade component [41-44]. This suggests a common
precursor cell with early divergence of the two components.
The average age at presentation is older (between 50 and 60 years) than other
chondrosarcoma subtypes (table 1). The majority occur centrally in medullary bone; the
most common sites of involvement are the pelvis, femur, and humerus. The typical
presentation is with pain, although swelling, paresthesias, and pathologic fractures are
also common [45]. The majority of patients have an associated soft tissue mass [46].
Dedifferentiated chondrosarcomas are biologically aggressive and they have a poor
prognosis [11,46,47]. In a multicenter review of 337 patients, 71 (21 percent) had
metastases at the time of diagnosis; they had a 10 percent chance of survival at two
years [11]. Even for patients without metastases at diagnosis, survival was only 28
percent at 10 years. Poor prognostic factors include pathologic fracture, pelvic location,
and older age.
Mesenchymal chondrosarcoma — Mesenchymal chondrosarcomas are highly malignant
tumors that are characterized by differentiated cartilage admixed with solid highly
cellular areas that are composed of undifferentiated small round cells (picture 3) [48].
The average age is 25, younger than that of other types of chondrosarcoma (table 1).
There is a high proportion of extraskeletal primary tumors, which is not seen with other
chondrosarcoma subtypes [49]. Of the approximately one-third of cases that affect the
extraskeletal soft tissues, the meninges are one of the most common sites [50]. Also in
contrast to conventional chondrosarcomas, mesenchymal tumors most commonly
involve the axial skeleton, including the craniofacial bones (especially the jaw) [51], ribs,
ilium, and vertebra, and there may be involvement of multiple bones. About 20 percent
have metastatic disease at diagnosis [52].
The main symptoms are pain and swelling, and it is not uncommon for symptoms to
have been present for many months.
Mesenchymal chondrosarcomas have a tendency toward both local and distant
recurrences, which may arise as long as 20 years following the initial diagnosis [53]. The
prognosis is markedly worse than for conventional primary chondrosarcomas. Reported
10-year survival rates are 10 to 20 percent [49,52-54].
Clear cell chondrosarcoma — Clear cell chondrosarcoma is a rare low-grade variant of
chondrosarcoma which is characterized by the presence of lobulated groups of blandappearing tumor cells with large, centrally-located nuclei and clear, empty cytoplasm in
addition to hyaline cartilage (picture 3). Mitotic figures are rare. Many tumors contain
zones of conventional chondrosarcoma with hyaline cartilage and minimally atypical
nuclei.
Although these tumors can arise at any age, most patients are between the ages of 25
and 50 (table 1). Men are three times more likely as women to develop this particular
subtype [55]. Approximately two-thirds of tumors arise in the epiphyseal ends of the
humerus or femur (figure 1). Pain, which may have been present for longer than one
year, is the most common complaint.
Serum alkaline phosphatase levels are often elevated at diagnosis and may provide a
useful tumor marker [56].
Despite their low-grade nature, marginal excision or curettage is associated with a 70
percent or higher recurrence rate and should be avoided [56,57]. In incompletely
excised cases, metastases may develop, usually to the lungs and other skeletal sites,
and the overall mortality rate is up to 15 percent [55]. In contrast, en bloc wide local
excision is usually curative.
Disease recurrence may occur up to 24 years after initial diagnosis [56,57]. Long-term
follow-up is mandatory.
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Myxoid chondrosarcoma — It is debated whether myxoid chondrosarcoma of bone is a
true separate entity or if it represents a high-grade conventional chondrosarcoma with
prominent myxoid change. The light microscopic features of myxoid chondrosarcoma of
bone are similar to those of the more commonly described extraskeletal myxoid
chondrosarcoma (EMC), a soft tissue sarcoma which most commonly arises in the lower
extremities [58,59]. However, these two entities are unrelated [60], and the term
"chondrosarcoma" to describe EMC is a misnomer. Well-formed hyaline cartilage is found
only in a minority of EMCs [61,62], while S100 expression (which is present in all or
most chondrosarcomas) is often very focal or absent. Expression of collagen II and
aggrecan (two other markers of cartilaginous differentiation) are absent in 86 percent of
EMCs [62].
Furthermore, the translocation t(9:22) that is specific for EMC is generally absent in socalled myxoid chondrosarcoma of bone, and its ultrastructure is different [61,63]. The
reported cases of myxoid chondrosarcoma of bone that contain a proven translocation of
t(9:22) have a large soft tissue component which makes distinction from EMC with
secondary bone destruction extremely difficult [64], although some convincing cases
have been reported [65].
Thus, EMC and so-called myxoid chondrosarcoma of bone appear to represent two
different entities. The 2013 WHO classification classifies the entity EMC in the "tumors of
uncertain differentiation" category [1]. Myxoid chondrosarcomas of bone are not
designated as a unique entity, and these tumors should be regarded as a myxoid variant
of intermediate- or high-grade conventional chondrosarcoma.
Molecular pathogenesis — Cartilaginous tumors are nearly always found in bones that
arise from enchondral ossification. Research has uncovered some parallels between
chondrocyte growth and differentiation in the normal growth plate and both benign and
malignant cartilaginous tumors [66].
Within the normal growth plate, resting zone chondrocytes proliferate and differentiate,
becoming hypertrophic. These cells undergo apoptosis, allowing the invasion of vessels
and osteoblasts that start to form bone and lead to longitudinal bone growth. This
physiologic process is tightly regulated by components of the Indian hedgehog
(IHH)/parathyroid hormone related (PTHRP) protein signaling pathway.
Patients with multiple osteochondromas (previously called hereditary multiple exostoses)
have germline mutations in the exostosin (EXT1 or EXT2) genes [67-69], with loss of the
remaining wild type allele in the cartilage cap of the osteochondroma [70]. The end
result is decreased EXT expression. Loss of expression of the EXT genes through
homozygous deletion of EXT1 is also seen in solitary osteochondromas that are
unassociated with the hereditary syndrome [71,72]. The EXT gene products are involved
in the biosynthesis of heparan sulfate proteoglycans (HSPGs), which are essential for cell
signaling through IHH/PTHLH and other pathways [73].
In osteochondromas where EXT is inactivated, the HSPGs seem to accumulate in the
cytoplasm and Golgi apparatus instead of being transported to the cell surface [72]. This
hampers multiple growth signaling pathways (including the Indian hedgehog
(IHH)/parathyroid hormone related (PTHRP) protein pathways), which, as noted above,
are important for normal chondrocyte proliferation and differentiation within the normal
human growth plate.
In secondary peripheral chondrosarcomas arising in osteochondromas EXT is usually wild
type, suggesting that the wild type cells in osteochondroma are prone to malignant
transformation through EXT independent mechanisms [74]. The specific trigger
underlying malignant transformation of osteochondromas is unknown. A role for IHH
signaling has been suggested, although the data are not entirely consistent [75-79]:
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


PTHRP signaling, which is downstream of IHH and is involved in chondrocyte
proliferation, is absent in osteochondromas, but upregulated with malignant
transformation towards secondary peripheral chondrosarcoma, especially in highgrade lesions [76,77,80-83].
There is decreased expression of downstream targets in the IHH signaling cascade
during tumor progression in peripheral chondrosarcomas, while they are still
active in central chondrosarcomas [84].
Data from in vitro and in vivo models show that treatment of central
chondrosarcoma cells with recombinant Hedgehog increases proliferation, whereas
treatment with Hedgehog signaling inhibitors inhibits tumor proliferation and
growth in a small subset of tumors and chondrosarcoma cell cultures [79,84,85].
A multistep genetic model for the development of secondary (peripheral)
chondrosarcomas has been proposed (figure 2) [14].
Until recently, less was known about the molecular genetics of enchondromas and the
far more common primary (central) chondrosarcomas. However, recently, point
mutations in isocitrate dehydrogenase-1 and isocitrate dehydrogenase 2 genes IDH1 and
IDH2 have been identified in 40 to 56 percent of enchondromas and chondrosarcomas
and seem to be an early event [86,87]. Also, Ollier disease and Maffucci syndrome are
caused by somatic mosaic mutations in IDH1 and IDH2 [86,88]. The identification of
IDH1 and IDH2 mutations in four chondrosarcoma cell lines provides an in vitro model to
study the role of these mutations in tumorigenesis [86].
In addition, although EXT is not involved, involvement of the IHH/PTHLH signaling
pathway is suggested by the observations that parathyroid hormone-related protein
(PTHRP) signaling is active in enchondromas [80,83], and hedgehog signaling is active in
central chondrosarcomas [84]. Moreover, a mutation in the gene encoding the receptor
for PTHRP (PTH-1 receptor or PTH1R) has been identified in enchondromatosis that is
claimed to lead to constitutive activation of IHH signaling [78,89]. Three new
heterozygous missense mutations have been described in the PTH1R gene in patients
with Ollier disease, which result in reduced receptor function [90]. Mutations in PTH1R
have not been found in sporadic chondrosarcomas, nor in Maffucci syndrome [86,88,91];
this gene may contribute to pathogenesis in only a very small subset (<5 percent) of
patients with Ollier disease. Moreover, using whole exome sequencing, mutations were
found in different genes involved in hedgehog signaling [92].




While enchondromas and low-grade chondrosarcomas are near-diploid and carry
few karyotypic abnormalities, high grade chondrosarcomas are aneuploid and
have complex karyotypes [39,93]. Some of the few consistent genetic aberrations
include 12q13-15 and 9p21 rearrangements [39,93-96].
Chondrosarcoma progression has been linked to the CDKN2A (p16) tumor
suppressor gene, located at 9p21 [97,98] and by alterations in p53 [99].
Mutations in COL2A1 are found in a subset of chondrosarcomas, the meaning of
which is as yet unknown [92].
Activation and/or overexpression of platelet-derived growth factor receptor-alpha
(PDGFRA) and beta (PDGFRB) has been described in conventional primary
chondrosarcomas, although activating mutations have not been found [100,101].
The therapeutic implications of this finding are discussed below. (See 'Novel
therapies' below.):
A multistep genetic model for development of primary chondrosarcomas has been
proposed (figure 3) [14].
Dedifferentiated chondrosarcomas also contain IDH1 or IDH2 mutations in approximately
50 percent of the cases [86,87,102].
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The majority of mesenchymal chondrosarcomas was shown to harbor a specific HEY1NCOA2 fusion product caused by an intrachromosomal rearrangement of chromosome
arm 8q [103]. Alternatively, a IRF2BP2-CDX1 fusion gene brought about by translocation
t(1;5)(q42;q32) was described [104].
For clear cell chondrosarcoma, no specific recurrent alterations have been found so far
[102].
DIAGNOSTIC AND STAGING WORK-UP — The goals of the preoperative evaluation are to
establish the tissue diagnosis and evaluate disease extent, in order to select the
appropriate therapeutic approach. One fundamental principle applying to diagnosis of
both tumors of bone and cartilage is that both the histology and radiography of bone
tumors are not specific. Integration of the clinical history, radiography, and pathology is
necessary to render a specific diagnosis.
Radiographic imaging — The initial imaging study in a patient with a painful
musculoskeletal swelling is often a plain radiograph. The location and radiographic
appearance of the different chondrosarcoma subtypes are often characteristic [1].
However, although plain radiographs can provide a clue as to the probable histology of a
potentially malignant bone lesion, evaluation of tumor size and local extent is most
accurately achieved by magnetic resonance imaging (MRI) and/or CT [105].


CT is optimal to detect matrix mineralization, particularly when it is subtle or the
lesions are located in an anatomically complex area. Because of their high water
content, most chondrosarcomas are of low attenuation on CT.
MRI is better for delineating the extent of marrow and soft tissue involvement.
The high water content of chondrosarcomas is manifest as very high signal
intensity on T2-weighted images [3].
In the long bones, central chondrosarcomas produce a fusiform expansion in the
metaphysis or diaphysis (figure 4). The tumor has a mixed radiolucent and sclerotic
appearance with the mineralized chondroid matrix appearing as a punctate or ring-andarc pattern of calcifications that may coalesce to form a more radiopaque flocculent
pattern of calcification (the so-called chondroid type of calcification (image 6)). Higher
grade chondrosarcomas often contain relatively less extensive areas of mineralization
(image 7).
The cortex is often thickened but a periosteal reaction is scant or absent. There may be
features of endosteal scalloping and soft tissue extension. Evidence of a large, soft tissue
mass, particularly if unmineralized, that is associated with a lesion whose radiologic
features otherwise suggest a chondrosarcoma should raise the level of suspicion for a
high-grade tumor (image 7 and image 8).
Conventional radiographs are not reliable to distinguish between an enchondroma and
central ACT/CS1 [12,37,106,107], although localization in the axial as opposed to the
appendicular skeleton and size greater than 5 cm favor chondrosarcoma [37,108]. The
presence of a soft tissue mass excludes the diagnosis of an enchondroma. The thickness
and staining characteristics of the cartilaginous cap on dynamic contrast-enhanced MRI
provides a fairly reliable assessment of the likelihood of malignancy in an
osteochondroma [109,110]. However, an absolute distinction between benign and
malignant cannot be made on radiologic grounds alone [37,111,112].
Osteochondromas appear as a sessile or broadly-based smoothly calcified lesion at the
surface of bone, with the cortex of the bone typically extending into the stalk of the
osteochondroma and normal trabeculation centrally. The cartilaginous cap is best
assessed on T2-weighted MRI and should not exceed 1.5 to 2 cm. The thickness and
appearance of the cap on dynamic contrast-enhanced MRI provide a fairly reliable
assessment of the likelihood of malignancy. A thickened cap and irregular distribution of
vague calcifications suggest the development of a secondary chondrosarcoma.
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Periosteal chondrosarcomas appear as a round to oval soft tissue mass on the surface of
bone, containing typical chondroid matrix mineralization. They cause variable amounts of
cortical bone erosion and appear to be covered by an elevated periosteum (Codman
triangles). The medullary canal is typically not involved. The radiographic differentiation
between a periosteal chondrosarcoma, periosteal osteosarcoma, and parosteal
osteosarcoma can be difficult.
Clear cell chondrosarcomas have a predilection for the epiphyseal ends of the femur and
humerus (figure 1). Radiographs reveal a well-defined, predominantly lytic lesion,
sometimes with a sclerotic rim. Matrix mineralization is not as frequently apparent as
with conventional chondrosarcoma.
As noted above, aggressive chondrosarcomas, such as the mesenchymal and
dedifferentiated subtypes, often contain areas of matrix mineralization that suggest a
low-grade chondroid neoplasm; however these areas are relatively less extensive
compared to conventional chondrosarcoma and usually ill-defined. On CT and MRI
imaging, dedifferentiated chondrosarcomas may be seen to contain two distinct areas
with differing radiographic characteristics: the low-grade conventional
chondrosarcomatous component has low attenuation on CT and high signal intensity on
T2-weighted MRI images, while the high-grade noncartilaginous component may have
soft tissue attenuation on CT (isointense to muscle) and variable signal intensity on MRI
T2-weighted images. There may be intraosseous lytic areas and an aggressive pattern of
bone destruction with a moth-eaten or permeative pattern. These aggressive tumors are
often associated with perforation of the cortex and a large soft tissue mass.
Imaging features of extraskeletal mesenchymal chondrosarcomas are nonspecific, with
chondroid-type calcification and foci of lost signal intensity within enhancing lobules
[113].
Role of PET — The imaging methods described above provide limited information as to
the biologic activity of a suspected chondrosarcoma. PET scanning with
fluorodeoxyglucose (FDG) has been proposed as a noninvasive method to assess tumor
grade, to distinguish benign from malignant chondroid lesions, to identify otherwise
occult metastatic disease, and differentiate recurrent tumor from postoperative change
[114-117]. However, the overall place of PET in the diagnostic and staging evaluation
remains uncertain:


Although grade 2 and 3 chondrosarcomas have a higher glucose metabolism (and
therefore, a higher standardized uptake value [SUV]), PET cannot differentiate
between benign cartilage tumors and ACT/CS1 [117].
The value of PET scanning to screen for metastatic or recurrent disease is also
uncertain.
Biopsy — For suspicious lesions, a diagnostic biopsy is frequently undertaken to establish
the diagnosis and plan the surgical approach. The initial percutaneous biopsy may not
accurately reflect the true histologic grade of the lesion because of lesion heterogeneity
and the possibility of sampling error [118]. If it is undertaken, biopsy should always be
directed at the more aggressive-appearing areas as seen on the radiographic studies (ie,
the soft tissue components, or the more diffusely enhancing regions with limited or no
matrix mineralization).
Specific issues surrounding the diagnostic biopsy for suspected primary bone tumors are
discussed elsewhere.
Staging system — The staging system used for bone sarcomas was developed by
Enneking et al at the University of Florida and based upon a retrospective review of
cases of primary malignant tumors of bone treated by primary surgical resection (table
2) [119,120]. This system characterizes nonmetastatic malignant bone tumors by grade
(low grade [stage I] versus high grade [stage II]), and further subdivides these stages
131
according to the local anatomic extent. The compartmental status is determined by
whether the tumor extends through the cortex of the involved bone. Patients with
distant metastases are categorized as stage III.
The American Joint Committee on Cancer (AJCC) had a similar staging system in its
1997 fifth edition [121], but this was modified in 2002, with additional minor
refinements in the latest 2010 edition (table 3) [122]. The TNM classification is not
widely used for primary bone tumors.
Completing the staging workup — As with other sarcomas, the lungs are the main site of
metastatic disease; much less commonly, the regional nodes and liver are involved.
Given the low rate of metastases in patients with ACT/CS1 (less than 10 percent),
imaging of the lungs is generally not necessary. However, patients with intermediate and
high-grade chondrosarcomas have a higher rate of metastatic disease (10 to 50 percent
for grade 2 lesions and 50 to 70 percent for grade 3 lesions) [3,5]. In these patients, the
staging evaluation should at least include a thoracic CT to rule out the presence of
pulmonary metastases.
As noted above, the place of PET scanning (which in other oncologic settings is generally
more sensitive but less specific than CT for detection of metastatic disease) is uncertain.
Although the use of PET can reveal sites of metastatic disease among patients with
grade 2 or 3 chondrosarcomas, it is clear that sensitivity is lower than that of
conventional CT for small lung metastases [117]. The utility of integrated PET/CT has
not been addressed.
SURGICAL TREATMENT — For all grades and subtypes of nonmetastatic
chondrosarcoma, surgical treatment offers the only chance for cure. The optimal type of
surgical management depends upon histologic grade, location, and tumor extent.
Intermediate and high-grade tumors — Wide en bloc local excision is the preferred
surgical treatment for all nonmetastatic intermediate- and high-grade chondrosarcomas
[8]. Depending on the location of the primary, wide excision can lead to considerable
morbidity and may require a demanding reconstruction.
Low-grade central tumors — The goal of minimizing functional disability provides the
rationale for pursuing less extensive surgery for ACT/CS1 that are confined to the bone.
In appropriately selected cases, extensive intralesional curettage, followed by local
adjuvant chemical treatment (phenolization) or cryotherapy, and cementation or bone
grafting of the cavity produces satisfactory long-term local control while minimizing the
need for extensive reconstruction [123-128].
The best outcomes are with small extremity conventional ACT/CS1. For patients with
large tumor size, intraarticular or soft tissue involvement, and the periosteal, clear cell,
mesenchymal and dedifferentiated subtypes [36], intralesional excision represents an
inadequate form of local treatment, with high rates of local recurrence [3,129]. Wide
local resection is preferred [129].
For large tumors, curettage can be technically difficult, and sampling error may result in
a focus of higher-grade disease being missed. The tumor size cutoff beyond which a wide
resection is preferred has not been studied and is highly dependent on location.
Most authors also consider wide local excision to be the preferred treatment for a lowgrade chondrosarcoma involving the axial skeleton and pelvis. Several (but not all
[8,56,130]) reports note higher local recurrence rates with curettage or marginal
excision of tumors at these sites, with a higher tendency to metastasize [129-133].
The decision to perform a curettage rather than wide local excision on the basis of a
diagnostic biopsy is complicated by tumor heterogeneity and variation in histopathologic
interpretation. A failure to recognize higher-grade areas of differentiation in a
predominantly low-grade chondrosarcoma is possible when a needle or limited open
biopsy has been performed. Thus, a presumed ACT/CS1 treated by curettage and local
132
adjuvant treatment that is found to contain foci of intermediate- or high-grade
differentiation on the final histologic sections might require additional surgery. In order
to minimize this risk, the diagnostic biopsy should always be directed at the more
aggressive-appearing areas on the radiographic studies (ie, the soft tissue components
or the more diffusely enhancing regions with limited or no matrix mineralization).
Peripheral chondrosarcomas — For patients with a preexisting osteochondroma,
complete surgical removal of the cartilage cap with the pseudocapsule provides excellent
long-term clinical and local results. In one series of 107 patients with a tumor arising in
solitary or multiple osteochondromas, five- and 10-year local recurrence rates after
surgery were 16 and 18 percent, and the 10-year mortality rate was only 5 percent [21].
Of the 63 patients who had their primary treatment at the author's institution, 26 had
wide excision (none of whom recurred), 36 had a marginal excision (ten of whom
recurred locally), and the one patient who had an intralesional excision also developed a
local recurrence. Of the 45 patients who received treatment for a local recurrence, 15
died of their disease.
When these tumors arise in the pelvis, the large cartilage cap can be difficult to excise,
but outcomes are better if the excision is complete [129,134]. As an example, in a series
of 61 patients with ACT/CS1 or grade 2 secondary peripheral chondrosarcoma of the
pelvis, local recurrence rates after wide local or incomplete excision were 3 versus 23
percent, respectively [134].
Management of recurrent disease — Local recurrence of a ACT/CS1 in the long bones
compromises survival, and aggressive management is warranted [135]. If the local
recurrence is solitary, without progression in grade and located in the long bones, repeat
intralesional resection with local adjuvant therapy is reasonable. Local recurrence of an
intermediate- or high-grade chondrosarcoma located in the long bones or recurrence of
any grade histology in the flat bones is an indication for a wide excision [130], although
it is often challenging to reach adequate wide resection margins in these patients.
RADIOTHERAPY — As most chondrosarcomas are slow growing, with a relatively low
fraction of dividing cells and radiation-related cytotoxicity is dependent upon cell
division, chondrogenic tumors are considered relatively (but not absolutely [136,137])
radioresistant. Nevertheless, radiation therapy (RT) may be of benefit in two situations:
after an incomplete resection of a high-grade conventional, dedifferentiated, or
mesenchymal chondrosarcoma to maximize the likelihood of local control (potentially
curative intent) and in situations where resection is not feasible or would cause
unacceptable morbidity (palliative intent).
When RT is given with curative intent, doses in excess of 60 Gy are required to achieve
local control. However, application of this dose with conventional high energy photons is
often impossible in the vicinity of critical structures, especially in chondrosarcomas
arising in the skull base and axial skeleton. Unfortunately, it is in this exact situation that
postoperative RT is often indicated, as these tumors are less accessible for radical
resection as compared to lesions in the appendicular skeleton.
The benefits of RT can be illustrated by a series of 21 patients with primary
chondrosarcoma of the spine who underwent 28 surgical procedures that included seven
complete and 21 subtotal resections [138]. The median survival for the entire group was
six years, and the addition of RT to resection prolonged the median disease-free interval
from 16 to 44 months. Others have shown a high rate of local control (90 percent) with
the addition of neoadjuvant or adjuvant RT to surgical resection in a group of 60 patients
with high-risk extracranial chondrosarcoma, of whom 50 percent had either an R1
(microscopically positive) or R2 (grossly positive margins) resection [139].
Palliative RT is also a reasonable option for local treatment of a primary or locally
recurrent chondrosarcoma if resection is not feasible or would cause unacceptable
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morbidity. This is particularly true for mesenchymal chondrosarcomas, which, in our
experience, are more radiosensitive than are other subtypes.
The benefit of RT in this setting can be illustrated by a retrospective review of 15
patients with mesenchymal chondrosarcoma (all but one nonmetastatic, most
extraosseous) treated in several protocols of the German Society of Pediatric Oncology
and Hematology [49]. All patients had surgical resection, which was complete in eight;
13 received chemotherapy and six were irradiated. At a median follow-up of 9.6 years,
four of seven incompletely resected patients were still alive, three of whom had been
irradiated.
Conventional RT can sometimes provide local control and symptom relief for other
histologies, as long as sufficient doses are administered [140,141]. In an early report
from M. D. Anderson of 20 patients with chondrosarcoma who were treated for cure, 5 of
11 patients who received RT as monotherapy achieved local control with doses from 40
to 70 Gy [140].
Charged particle irradiation — Given the limitations of conventional photon irradiation,
alternative radiation modalities have been tested. Unlike photons, which lack mass and
charge, particle beams interact more densely with tissue, causing greater levels of
ionization per unit length, and therefore, an increased radiobiologic effect (RBE). The
most data are available for protons, but there is limited experience with carbon ions as
well.


Proton beam irradiation — The theoretical advantage of charged particle
irradiation using protons is in its dose distribution. The physical characteristics of
the proton beam result in the majority of the energy being deposited at the end of
a linear track, in what is called a Bragg peak. The radiation dose falls rapidly to
zero beyond the Bragg peak. Proton beam therapy permits the delivery of high
doses of RT to the target volume while limiting the "scatter" dose received by
surrounding tissues.
Proton beam RT has been studied most for incompletely resected chondrogenic
tumors of the skull base and axial skeleton. Local control rates of 78 to 100
percent with mixed photon-proton or proton only protocols (doses up to 79
centigray-equivalents [CGE]) are reported by several authors [142-146], with
limited severe late effects (<10 percent RTOG grade 3 toxicity). (See "Chordoma
and chondrosarcoma of the skull base".)
Carbon ions — Carbon ions represent another attractive radiation modality, which
combines the physical advantages of protons with a higher radiobiological activity.
The available data are in patients treated for skull based chondrosarcomas, which
are discussed elsewhere.
Although promising, these techniques are not widely available, in contrast to photon
irradiation. Particle beam irradiation requires adaptation of particle accelerators designed
for other purposes or specialized dedicated equipment.
SYSTEMIC TREATMENT — Chemotherapy is generally considered ineffective in
chondrosarcomas, especially for the most frequently observed conventional type and the
rare (low grade) clear cell variant (table 1). Chemoresistance in these tumors may be
attributable to several factors:


Most chondrosarcomas are slow-growing, with a relatively low fraction of dividing
cells; most conventional chemotherapeutic agents act on actively dividing cells.
Expression of the multidrug-resistance-1 gene, P-glycoprotein, by
chondrosarcoma cells may also play a role [147,148].
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

Access of anticancer agents to the tumor may be hampered because of the large
amount of extracellular matrix and the poor vascularity.
High activity of anti-apoptotic and pro-survival pathways (eg, high expression of
Bcl-2 family members) [149].
The benefit of chemotherapy for higher-grade (grade 2 or 3) chondrosarcomas is difficult
to assess. Due to the rarity of chondrosarcomas in general and especially of intermediate
and high-grade tumors, there are few prospective studies, and no randomized trials. The
reported series are few in number, retrospective, and consist mainly of a small number
of patients. There is an urgent need for inclusion of these patients in prospective trials.
Adjuvant chemotherapy — While there is no role for adjuvant chemotherapy in patients
who undergo surgical treatment for a ACT/CS1, its benefit for dedifferentiated and
mesenchymal chondrosarcomas is unclear.
Dedifferentiated chondrosarcoma — At least two studies (both retrospective) suggest
that patients with dedifferentiated chondrosarcoma who are managed with surgery and
chemotherapy may have a better outcome than those managed with surgery alone
[150,151]. However, benefit from chemotherapy in patients with nonmetastatic disease
is not a universal observation [11,46,47,152].
We suggest that eligible patients consider enrolling in clinical trials testing the value of
adjuvant chemotherapy. As an example, patients with dedifferentiated chondrosarcomas
are allowed in the EUROBOSS adjuvant chemotherapy trial of the Scandinavian Sarcoma
Group [153].
Mesenchymal chondrosarcoma — Limited experience with adjuvant (or neoadjuvant)
chemotherapy in patients with mesenchymal chondrosarcoma suggests a potential
benefit for chemotherapy:



An early study suggested chemotherapy responsiveness in patients with a
prominent small round cell content [54]. In a retrospective series of nine patients
with mesenchymal chondrosarcoma treated with preoperative chemotherapy, six
received a multiagent doxorubicin-containing Rosen T-10 or T-11 osteosarcoma
protocol, and there were three complete and three partial responses.
The potential benefit of neoadjuvant chemotherapy in high-grade spindle cell
sarcomas of bone (other than osteosarcoma or malignant fibrous histiocytoma)
was addressed in a prospective study conducted by the European Osteosarcoma
Intergroup [152]. Of the 21 patients with potentially resectable localized tumors
who underwent attempted resection after three cycles of doxorubicin and
cisplatin-based chemotherapy, one of two patients with a mesenchymal
chondrosarcoma had a good pathological response in the primary tumor [152].
Experience with 15 cases of mesenchymal chondrosarcoma (all but one
nonmetastatic, most extraosseous) was reported from the soft tissue and
osteosarcoma study groups of the German Society of Pediatric Oncology and
Hematology [49]. All patients had surgical resection, which was complete in eight;
13 received chemotherapy and six were irradiated. The treatment regimens
consisted of a variety of chemotherapy drugs given in various combinations in
several trials.
Response to induction chemotherapy could be assessed in seven patients, four of
whom had a 50 percent reduction in tumor volume or ≥50 percent "histologic
devitalization". At a median follow-up of 9.6 years, characteristic late recurrences
were not observed, and the actuarial event-free and overall survival rates at 10
years were 53 and 67 percent. The authors concluded that these outcomes were
better than expected, and attributed the improved outcomes to combined
modality treatment.
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
A retrospective series of 26 patients with mesenchymal chondrosarcoma treated
at the Rizzoli Institute included 24 surgically treated patients, 12 of whom
received chemotherapy [52]. After a median follow-up of 48 months, 10 remained
alive. The 10-year rates of disease-free survival were markedly higher among
those who received chemotherapy (31 versus 19 percent) as was overall survival
(76 versus 17 percent).
Questions will remain as to the worth of adjuvant chemotherapy until randomized trials
are carried out. However, even in the absence of prospective trials, there is evidence
that mesenchymal chondrosarcomas are sensitive to doxorubicin-based combination
chemotherapy as used in other bone tumors. The poor prognosis seen with surgery
alone provides a strong argument to consider the use of adjuvant chemotherapy in
patients who are medically fit and able to tolerate the therapy. Initial induction
chemotherapy is a reasonable option if the disease is locally advanced, and a response
to therapy might increase the likelihood of function-preserving surgery.
The best regimen is unknown, but it seems reasonable to use a doxorubicin/cisplatinbased chemotherapy regimen [152], as is used for osteosarcoma.
Advanced disease — Although the majority of patients with recurrent or metastatic
sarcoma do not respond to the usual chemotherapy regimens for advanced sarcoma,
there have been isolated reports of successful treatment with ifosfamide alone or with
doxorubicin, or single agent methotrexate [49,54,154-156].
High-grade chondrosarcomas seem to preferentially benefit, but this is unpredictable. In
the small prospective European trial in high-grade spindle cell sarcomas of bone
described above, two of six patients treated for an advanced dedifferentiated
chondrosarcoma had a complete response to doxorubicin plus cisplatin, while the best
response among five patients with metastatic mesenchymal chondrosarcoma was stable
disease in two [152].
Novel therapies — The relative lack of efficacy of conventional chemotherapy and the
discovery of novel signaling pathways in several histologic subtypes of chondrosarcoma
has prompted interest in molecularly-targeted therapies, particularly for chemotherapy
refractory nonoperable or metastatic chondrosarcomas [66]. As examples:

Receptor tyrosine kinases are commonly activated in chondrosarcomas, the most
active of which are Akt1/GSK3beta, the src pathway and PDGFR [157]. Activation
and/or overexpression of platelet-derived growth factor receptor-alpha (PDGFRA)
and PDGFR-beta (PDGFRB) has been described in conventional chondrosarcomas,
although activating mutations have not been found [100,101]. Investigators have
shown that SU6668, an inhibitor of several tyrosine kinase receptors, including
PDGFRB, represses the growth of chondrosarcoma xenografts [158]. Although the
role of these receptors in molecular pathogenesis or malignant transformation
remains uncertain, these data suggest a therapeutic potential for inhibitors of
these receptor tyrosine kinases. Unfortunately clinical trials have been
disappointing to date:

A phase II trial of imatinib, a PDGFR/C-KIT tyrosine kinase inhibitor, failed to
demonstrate meaningful clinical activity in 26 patients with metastatic
nonresectable chondrosarcoma [159].
The tyrosine kinase inhibitor dasatinib was explored in a SARC trial which included
a cohort of 32 patients with chondrosarcoma within a larger group of indolent
sarcoma subtypes [160]. The chondrosarcoma cohort did not meet its primary
endpoint (>50 percent six month PFS) and the drug was considered inactive in
this group.

136

Estrogen is important in the regulation of longitudinal skeletal growth. Estrogen
receptors and aromatase activity have been identified in chondrosarcomas [161163]. Interference with estrogen signaling may have therapeutic value in this
disease. However, in one study, dose-response assays showed no effect of any of
the aromatase inhibitors on proliferation of conventional chondrosarcoma in vitro,
and the median progression-free survival of patients treated with aromatase
inhibitors did not significantly deviate from untreated patients [163].

There are other promising areas of investigation. Antitumor effects of histone
deacetylase (HDAC) and angiogenesis inhibitors have been described in
chondrosarcoma cell lines and in vivo models [158,164].
Several phase I studies report incidental responses of chondrosarcomas to newer
targeted agents, such as vascular endothelial growth factor antisense molecules [165],
recombinant human Apo2L/TRAIL [166], and a fully human IgG1 monoclonal antibody
that triggers the extrinsic apoptosis pathway through death receptor 5 [167].
In the absence of effective systemic therapy, eligible patients should be encouraged to
enroll in phase I or multi tumor-type trials testing novel strategies
(www.clinicaltrials.gov).
POSTTREATMENT SURVEILLANCE — As with other bone sarcomas, there are no
prospective data that address the appropriate schedule or selection of tests for
surveillance after initial treatment for localized disease. Consensus-based guidelines
from the National Comprehensive Cancer Network (NCCN) recommend physical
examination, complete blood count, and chest as well as local imaging every three
months for the first two years, every four months during year three, every six months
for years four and five, then annually [168]. Routine posttreatment surveillance should
be extended to ten years, as late recurrences can occur [7].
Our practice is to perform MRI of the lesion one, two, and five years after initial surgery.
SUMMARY AND RECOMMENDATIONS — Chondrosarcomas are a very heterogeneous
group of malignant bone tumors that share in common the production of chondroid
(cartilaginous) matrix. Clinical behavior is variable and predicted by the histologic grade.
Ninety percent are conventional chondrosarcomas, the majority of which are low-grade
tumors which are slow growing with a low metastatic potential. High-grade
chondrosarcomas, which include 5 to 10 percent of conventional chondrosarcomas as
well as the dedifferentiated and mesenchymal subtypes, have a high metastatic potential
and a poor prognosis following resection alone. (See 'Introduction' above.)
Experienced assessment of radiographic imaging studies (conventional X-ray, MRI, and
CT) and histopathologic grade as assessed on a diagnostic biopsy are used to guide
treatment decisions. (See 'Diagnostic and staging work-up' above.)
Surgical resection — For all grades and subtypes of nonmetastatic chondrosarcoma,
surgical treatment offers the only chance for cure. The optimal type of surgical
management depends upon histologic grade, location, and tumor extent. The goal of
surgery is complete excision while minimizing functional disability. (See 'Surgical
treatment' above.)


For small, central ACT/CS1 involving an extremity that are confined to the bone,
we suggest intralesional curettage with local adjuvant therapy (phenol application
or cryosurgery followed by cementation or bone graft of the cavity) rather than
wide local excision (Grade 2C).
For all other patients with intermediate or high-grade histology (including the
mesenchymal and dedifferentiated subtypes), large tumor size, intraarticular or
soft tissue involvement, periosteal or clear cell subtypes, a low-grade central
137

chondrosarcoma in the pelvis or axial skeleton, or a peripheral chondrosarcoma,
we recommend wide local resection (Grade 1B).
Locally recurrent chondrosarcomas should be managed aggressively, as they may
be of higher histological grade than the original tumor, increasing the risk of
metastases and fatal outcome. For nonmetastatic recurrence of a ACT/CS1, we
suggest repeat intralesional resection with local adjuvant therapy if the local
recurrence is solitary, without progression in grade and located in the long bones
(Grade 2C). Otherwise, wide local excision is preferred. (See 'Management of
recurrent disease' above.)
Role of radiotherapy — While most low-grade chondrosarcomas are considered relatively
radioresistant, radiation therapy (RT) may be of benefit in two situations (see
'Radiotherapy' above):


We generally suggest adjuvant radiotherapy for incompletely excised high-grade
conventional, dedifferentiated, or mesenchymal chondrosarcomas (Grade 2C).
Doses of more than 60 Gy are needed for maximal local control after incomplete
resection, and depending on the tumor site, this may not be feasible with
conventional photon beam irradiation. In such cases, referral for treatment using
newer techniques, such as proton beam irradiation, is appropriate, where
available.
Palliative RT is a reasonable option for local treatment of patients with a primary
or locally recurrent chondrosarcoma if resection is not feasible or would cause
unacceptable morbidity, as well as for those with symptomatic metastatic disease.
Chemotherapy — Conventional low-grade and clear cell chondrosarcomas are
chemotherapy-resistant. Chemotherapy is possibly effective in the mesenchymal
subtype, particularly those that contain a high percentage of round cells, and is of
uncertain value in dedifferentiated chondrosarcoma; both subtypes are rare and bear a
poor prognosis. (See 'Systemic treatment' above.)
Adjuvant chemotherapy — There is no role for adjuvant chemotherapy after complete
resection of a conventional low-grade chondrosarcoma, and we recommend not pursuing
this approach (Grade 1C).
The role of chemotherapy after complete resection of a dedifferentiated chondrosarcoma
is unknown. Retrospective studies suggest that patients who are managed with surgery
and chemotherapy have a better outcome than those managed with surgery alone. We
recommend that eligible patients be enrolled on clinical trials testing adjuvant
chemotherapy, such as the Euroboss I trial [153]. If the protocol is not available or if
patients are unable or unwilling to participate, we manage these patients on a case by
case basis. If the high-grade component is an osteosarcoma, we treat the patient as per
osteosarcoma protocols. (See 'Adjuvant chemotherapy' above.)
For patients with a completely resected mesenchymal chondrosarcoma, retrospective
studies suggest that those with a substantial round cell component are sensitive to
doxorubicin-based combination chemotherapy. The poor prognosis seen with surgery
alone provides a strong argument to discuss the risks and potential benefits of adjuvant
doxorubicin-based chemotherapy with these patients as long as they are medically fit and able to
tolerate the therapy. Initial induction chemotherapy is a reasonable option if the disease is locally
advanced, and a response to therapy might increase the likelihood of complete resection or
function-preserving surgery. (See 'Adjuvant chemotherapy' above.)
Advanced disease — The benefit of conventional chemotherapy is limited in advanced disease,
with the exception of mesenchymal osteosarcomas. We suggest that patients be enrolled in
clinical trials testing new strategies. If trial enrollment is not available or not feasible, we use a
doxorubicin plus cisplatin combination as is used for other bone sarcomas.
138