Background

This article focuses on high-grade intramedullary osteosarcoma (often referred to simply as

osteosarcoma), including its classic osteoblastic form and its fibroblastic and chondroblastic
forms.
Osteosarcoma is the most common malignant bone tumor.[1, 2] This disease is thought to arise
from primitive mesenchymal bone-forming cells, and its histologic hallmark is the production of
malignant osteoid. Other cell populations may also be present, as these types of cells may also
arise from pluripotential mesenchymal cells, but any area of malignant bone in the lesion
establishes the diagnosis as osteosarcoma.
The mainstay of therapy is surgical removal of the malignant lesion. Most often, limb-sparing
(limb-preserving) procedures can be used to treat patients with this disease and, thus, preserve
function. Chemotherapy is also required to treat micrometastatic disease, which is present but
often not detectable in most patients (about 80%) at the time of diagnosis.[3]

History of the Procedure

Osteosarcoma is an ancient disease that is still incompletely understood. The term sarcoma was
introduced by the English surgeon John Abernathy in 1804 and was derived from Greek roots
meaning "fleshy excrescence."[4] In 1805, the French surgeon Alexis Boyer (personal surgeon to
Napoleon) first used the term osteosarcoma.[4, 5] Boyer realized that osteosarcoma is a distinct
entity from other bone lesions, such as osteochondromas (exostoses).
Evidence of further organized thought and purposeful investigation regarding this disease was
found by the mid 1800s. Peltier recorded that in 1847, the Baron Guillaume Dupuytren
demonstrated his intimate knowledge of the gross pathologic appearance of osteosarcoma when
he wrote the following[4] :
Osteosarcoma, which is a true cancerous degeneration of bone, manifests itself in the form of a
white or reddish mass, lardaceous and firm at an early stage of the disease; but presenting at a
later period, points of softening, cerebriform matter, extravasating blood, and white or straw
colored fluid of a viscid consistence in its interior.
Under the auspices of the American College of Surgeons, Ernest Amory Codman (along with
James Ewing and Joseph Bloodgood) created the Registry of Bone Sarcoma in 1921.[6] This was
a significant step forward in studying these rare and ominous tumors, in that individual surgeons
had only limited experience to guide them.
Another major institution that began to take shape in the early 1900s was the Rizzoli Institute in
Bologna, Italy. This institute, whose bone tumor roots were nurtured by Vittorio Putti (18801940), prospered under the later guidance of persons such as Scaglietti and Campanacci.[7] Major

contributions from this institution have included innovative treatment for unicameral bone cysts
(Scaglietti) and intense study of osteofibrous dysplasia (Campanacci tumor).
By the mid-1900s, great strides were being made in the United States in the field of bone
pathology by Henry L Jaffe (1896-1979) and his colleague Louis Lichtenstein (1906-1977). Each
of these men published textbooks devoted to bone pathology. Jaffe is also often credited with
bringing order to the chaos that was orthopedic pathology. Together, Jaffe and Lichtenstein
established virtually all of the key histologic criteria that are used to diagnose most of the
commonly encountered bone tumors.
A different Dr Jaffe, Norman Jaffe, along with other researchers, helped expand the use of a
variety of effective chemotherapeutic agents in the 1970s and early 1980s.[8] Not the least of these
agents were Adriamycin and methotrexate. These medications (and others that followed)
dramatically improved the treatment of patients with osteosarcoma through their ability to treat
the micrometastatic disease that was thought to be present in approximately 80% of patients.[9]
These drugs were found to be useful both preoperatively and postoperatively in patients with
osteosarcoma, a discovery made at the Sloan-Kettering Memorial Cancer Center somewhat
serendipitously while custom-made prostheses were being fabricated for patients awaiting
surgery.[10] Such preoperative use of chemotherapy came to be referred to as neoadjuvant
chemotherapy.
An orthopedic surgeon from Gainesville, Florida, William F Enneking, MD, introduced a
surgical staging system for musculoskeletal sarcomas.[11, 12] This staging system helped organize
the orthopedic surgical approach to both biopsy and definitive tumor resection for osteosarcoma,
as well as for other musculoskeletal sarcomas.
Dr Enneking's influence extended far beyond his staging system because of his intense
commitment to educating others regarding musculoskeletal tumors. He has educated numerous
orthopedic oncology fellows, published numerous research articles, and continued to conduct a
yearly continuing medical education course focusing on benign and malignant tumors.

Problem
Osteosarcoma is a deadly form of musculoskeletal cancer that most commonly causes patients to
die of pulmonary metastatic disease (see the image below).[4, 7, 13, 14, 15] Most osteosarcomas arise as
solitary lesions within the fastest growing areas of the long bones of children. The top three
affected areas are the distal femur, the proximal tibia, and the proximal humerus, but virtually
any bone can be affected.

Chest radiograph of patient with osteosarcoma who died from pulmonary metastatic disease.
Note the presence of a pneumothorax as well as radiodense (bone-forming) metastatic lesions.
Not all osteosarcomas arise in a solitary fashion. Multiple sites may become apparent within a
period of about 6 months (synchronous osteosarcoma), or multiple sites may be noted over a
period longer than 6 months (metachronous osteosarcoma).[13] Such multifocal osteosarcoma is
decidedly rare, but when it occurs, it tends to be in patients younger than 10 years.[13]

Epidemiology
Frequency
In the United States, the incidence of osteosarcoma is 400 cases per year (4.8 per million
population < 20 years).[16] The overall 5-year survival rate for patients diagnosed between 1974
and 1994 was 63% (59% for males; 70% for females).
The incidence is slightly higher in blacks than in whites. Data from the National Cancer Institute
(NCI) Surveillance, Epidemiology, and End Results (SEER) Pediatric Monograph 1975-1995 are
as follows[16] :

Blacks 5.2 cases per million per year (< 20 years)

Whites 4.6 cases per million per year

The incidence of osteosarcoma is slightly higher in males than in females. In males, it is 5.2 per
million per year; in females, it is 4.5 per million per year.
Osteosarcoma is very rare in young children (0.5 cases per million per year in children < 5
years). However, the incidence increases steadily with age, rising more dramatically in
adolescence in correspondence with the adolescent growth spurt, as follows[17] :

Age 5-9 years 2.6 (black) or 2.1 (white) cases per million per year

Age 10-14 years 8.3 (black) or 7 (white) cases per million per year

Age 15-19 years 8.9 (black) or 8.2 (white) cases per million per year

Etiology
The exact cause of osteosarcoma is unknown. However, a number of risk factors have been
identified.[4, 7, 13, 14, 15, 18, 19, 20, 21, 22, 23, 24, 25]
Rapid bone growth appears to predispose persons to osteosarcoma, as suggested by the increased
incidence during the adolescent growth spurt, the high incidence among large-breed dogs (eg,
Great Dane, St. Bernard, German shepherd), and osteosarcoma's typical location in the
metaphyseal area adjacent to the growth plate (physis) of long bones.
Genetic predisposition plays a role. Bone dysplasias, including Paget disease, fibrous dysplasia,
enchondromatosis, and hereditary multiple exostoses and retinoblastoma (germline form) are risk
factors. The combination of constitutional mutation of the RB gene (germline retinoblastoma)
and radiation therapy is linked with a particularly high risk of developing osteosarcoma, LiFraumeni syndrome (germline p53 mutation), and Rothmund-Thomson syndrome (autosomal
recessive association of congenital bone defects, hair and skin dysplasias, hypogonadism, and
cataracts).
The only known environmental risk factor is exposure to radiation. Radiation-induced
osteosarcoma is a form of secondary osteosarcoma and is not discussed further in this article.

Pathophysiology
Osteosarcoma is a bone tumor and can occur in any bone, usually in the extremities of long
bones near metaphyseal growth plates. The most common sites are as follows:

Femur (42%, 75% of which are in the distal femur)

Tibia (19%, 80% of which are in the proximal tibia)

Humerus (10%, 90% of which are in the proximal humerus)

Skull and jaw (8%)

Pelvis (8%)

A number of variants of osteosarcoma exist, including conventional types (osteoblastic,

chondroblastic, and fibroblastic), telangiectatic, multifocal, parosteal, and periosteal. This article
only addresses conventional osteosarcoma.

Presentation
Symptoms may be present for weeks or months (occasionally longer) before patients are
diagnosed. The most common presenting symptom of osteosarcoma is pain, particularly pain
with activity. Patients may be concerned that their child has a sprain, arthritis, or growing pains.
Often, there is a history of trauma, but the precise role of trauma in the development of
osteosarcoma is unclear.
Pathologic fractures are not particularly common. The exception is the telangiectatic type of
osteosarcoma, which is more commonly associated with pathologic fractures. The pain in an
extremity may result in a limp. There may or may not be a history of swelling (see the image
below), depending on the size of the lesion and its location. Systemic symptoms, such as fever
and night sweats, are rare.

Clinical appearance of a teenager who presented with osteosarcoma of the proximal humerus
(same patient as in the following images). Note the impressive swelling throughout the deltoid
region, as well as the disuse atrophy of the pectoral musculature.
Tumor spread to the lungs only rarely results in respiratory symptoms and usually indicates
extensive lung involvement. Metastases to other sites are extremely rare, and therefore, other
symptoms are unusual.

Physical examination findings are usually limited to the site of the primary tumor, as follows:

Mass - A palpable mass may or may not be present; the mass may be tender and warm,
though these signs are indistinguishable from osteomyelitis; increased skin vascularity
over the mass may be discernible; pulsations or a bruit may be detectable

Decreased range of motion - Involvement of a joint should be obvious on physical

examination

Lymphadenopathy - Involvement of local or regional lymph nodes is unusual

Respiratory findings - Auscultation is usually uninformative unless the disease is

extensive

Indications
The two main procedures performed by orthopedic surgeons in patients with osteosarcoma are
biopsy and wide resection. Neither of these procedures should be undertaken unless complete
tumor staging has been completed preoperatively. Such staging would typically include (but
would not be limited to) the following (see Imaging Studies):

Plain radiography of the involved bone, including the joint above and the joint below the
affected region

Total-body bone scanning

Magnetic resonance imaging (MRI) of the primary tumor area to include the entire bone
of origin

Computed tomography (CT) of the lungs

Biopsy of malignant bone lesions is not an insignificant procedure. An improperly performed

biopsy can result in the amputation of an otherwise salvageable extremity. It has also been shown
repeatedly that oncologic outcomes are optimized when the biopsy is performed by the same
surgeon who will be responsible for the definitive tumor resection (if one is needed).[26, 27]
Incisional biopsies or core needle biopsies (Craig needle biopsy) are the most common types of
biopsies performed by orthopedic surgeons.[28] Open lines of communication between the
orthopedic surgeon and the pathologist are vital to help ensure that adequate tissue is obtained for
diagnostic purposes.
Wide resection is the goal for patients in whom primary tumor resection is contemplated. Simply
defined, wide resection means that the entire malignant tumor has been surgically excised and
that there is no remaining microscopic evidence of tumor cells at the resection margins (ie, that
the margins are negative). Over the years, many authors have suggested varying and arbitrary

amounts of the normal tissue cuff to remove along with the primary tumor to increase the
likelihood of negative margins.
There is no universally accepted definition of the appropriate thickness of the normal cuff.
Technically, a wide margin still exists even if the distance between normal tissue and tumor is 1
cell thick. Oncologically, the width achieved is less important (limb-sparing surgery vs
amputation) than the achievement of a negative margin. In other words, a limb-sparing surgery
without wide margins could do the patient less of a service than an amputation with wide
margins. This would apply in most cases where maximal preservation of life is the primary goal.

Contraindications
Because osteosarcoma is a deadly form of cancer, no absolute contraindications to treatment
exist. Relative contraindications would include situations in which the patient is so frail that the
risks of general anesthesia outweigh any potential benefits of surgery. Another relative
contraindication would be a situation in which the patient has extensive, overwhelming
metastatic disease, and the benefits of comfort or hospice care outweigh the potential benefits of
surgical intervention.

Osteosarcoma Workup

Author: Charles T Mehlman, DO, MPH; Chief Editor: Harris Gellman, MD

more...

Imaging Studies
Plain radiography
Plain radiography in primary, posteroanterior (PA), and lateral chest views is helpful (see the
image below). Plain films of the suspected lesions should be obtained in two views. No single
feature on a radiograph is diagnostic. Osteosarcoma lesions can be purely osteolytic (~30% of
cases), purely osteoblastic (~45% of cases), or a mixture of both.

Radiographic appearance (plain radiograph) of a proximal humeral osteosarcoma (same patient

as previous image). Note the radiodense matrix of the intramedullary portion of the lesion, as
well as the soft-tissue extension and aggressive periosteal reaction.
Elevation of the periosteum may appear as the characteristic Codman triangle. Codman
described this entity in 1909, stating, "In many cases near the junction of the healthy bone with
the tumor, there is a reactive new bone formation beneath the periosteum. At the edge of the
tumor, this layer of new bone ends abruptly and gives a characteristic appearance in the
skiagraph [radiograph]."[4]
Extension of the tumor through the periosteum may result in a so-called sunburst appearance
(~60% of cases). An image of the entire bone and the adjacent joint should be obtained to assess
for skip lesions or joint involvement. Telangiectatic osteosarcomas are often very cystic and can
be mistaken for an aneurysmal bone cyst.

Bone scanning
Radionuclide bone scanning with technetium-99 (99m Tc)-methylene diphosphonate (MDP/MDI)
is important in evaluating for the presence of metastatic or multifocal disease (see the images
below). After the bone scan, an image of abnormal areas should be obtained with computed
tomography (CT) or magnetic resonance imaging (MRI).

Intense radionuclide uptake of the proximal humerus is noted on a bone scan (same patient as

previous 2 images).
A comparison bone scan of the involved shoulder (right image) with the uninvolved shoulder
(left image) (same patient as previous 3 images).

Computed tomography
A CT scan of the primary lesion and a CT scan of the chest (high resolution) should be obtained.
CT of the primary lesion helps delineate the location and extent of the tumor and is critical for
surgical planning.

CT of the chest is more sensitive than plain film radiography is for assessing pulmonary
metastases. Ideally, the chest CT scan of the chest should be obtained before a biopsy is
performed so as to avoid the ambiguity that can arise from postanesthesia atelectasis.

Magnetic resonance imaging

MRI of the primary lesion is the best method of assessing the extent of intramedullary disease, as
well as associated soft-tissue masses and skip lesions (see the image below). This imaging
modality is perhaps the single most important study for accurate surgical staging of the lesion
with use of the Enneking staging system.

Magnetic resonance image appearance (T1-weighted image) of osteosarcoma of the proximal

humerus (same patient as previous 4 images). Note the dramatic tumor extension into the
adjacent soft-tissue regions.

Other modalities
Echocardiography or multiple gated acquisition (MUGA) scanning may be useful. Cardiac
function should be assessed before and at various intervals after treatment with Adriamycin.

Other Tests

Audiography may be considered. Hearing loss is an adverse effect of cisplatin. It typically occurs
during treatment; once treatment is completed, obtaining audiograms is not typically a part of
long-term follow-up care.

Histologic Findings
Two elements are important to the histologic examination of the tumor. The first, tumor type, can
be assessed on the biopsy. The second, response to treatment, can be assessed on the definitive
resection following chemotherapy.
In general, the characteristic feature of osteosarcoma is the presence of osteoid in the lesion,
even at sites distant from bone (eg, lung). Although osteoid formation is usually obvious,
electron microscopy occasionally may be required to reveal this process. Stromal cells may be
spindle-shaped and atypical, with irregularly shaped nuclei.
A number of different histologic types of osteosarcoma exist, as follows:

The conventional type is the most common in childhood and adolescence and has been
subdivided according to the predominant features of the cells (osteoblastic,
chondroblastic, or fibroblastic), though the subtypes are clinically indistinguishable

The telangiectatic type contains large, blood-filled spaces and is commonly seen in
adolescence and early adulthood

The parosteal type usually arises from the bone cortex, has an intermediate prognosis,
and can be seen in childhood or adulthood; it most commonly arises on the distal
posterior aspect of the femur

The periosteal type is a low- to intermediate-grade tumor that typically arises

immediately below the periosteum in children; it most frequently involves the tibia

Staging
The purpose of staging tumors is to stratify risk groups. The conventional staging used for other
solid tumors is not appropriate for skeletal tumors, because these tumors rarely involve lymph
nodes or regional spread.
Instead, the staging system introduced by Enneking in 1980 is based on histologic grade (low vs
high), anatomic location (intracompartmental vs extracompartmental), and presence or absence
of metastases. This system (also referred to as the staging system of the Musculoskeletal Tumor
Society) applies to all musculoskeletal tumors (both bone and soft tissue). It has been credited
with bringing order to the surgical treatment of a group of tumors for which treatment was
previously approached rather haphazardly.
The Enneking staging system is typically depicted as follows:

Low-grade tumor, intracompartmental IA

Low-grade tumor, extracompartmental IB

High-grade tumor, intracompartmental IIA

High-grade tumor, extracompartmental IIB

Any tumor (low- or high-grade, intra- or extracompartmental) with evidence of

metastasis III

The definition of a compartment is a central and crucial concept in this staging system. In
general, a compartment may be defined as any individual bone (ie, each bone is a compartment
unto itself), intra-articular space (ie, a purely intra-articular lesion is intracompartmental), or
clearly identified fascially enclosed space (eg, the anterior compartment of the lower leg). Many
of these compartments are the same ones that a surgeon would release in the setting of
compartment syndrome; these relate much more to soft-tissue tumors than to bone tumors.
The Enneking staging system considers some areas of the body to be extracompartmental by
definition, including the antecubital fossa, the inguinal region, the popliteal space, and
intrapelvic and paraspinal lesions. Because of the unique challenges of spinal tumors, Weinstein,
Boriani, and Biagin proposed an entirely separate staging system for these areas, commonly
referred to as the WBB staging system.
First introduced in 1996, the WBB system focuses on the general anatomic location about the
spine (conceptualizing a spinal segment as if it were the face of a clock), as well as the specific
anatomic location about the spine (eg, extraosseous soft-tissue extension into muscular areas vs
intradural extraosseous extension). Just as spinal anatomy is complex, the WBB staging system
is complex, but its use is slowly increasing.
In osteosarcoma, the foremost initial question for staging is whether the tumor has metastasized.
Other tumor features, though not technically used in staging, may impact the prognosis. These
include the following:

Lactic dehydrogenase (LDH) and alkaline phosphatase (ALP) measurements

Site of primary tumor (mostly related to ease of complete resection)

Histologic response to chemotherapy

Cause of the disease (patients with osteosarcomas arising from Paget disease have a
particularly poor prognosis)

Patients with isolated jaw lesions tend to do better and have a lower incidence of metastases.

Different primary tumor sites are associated with differing prognoses, as follows:

Distal extremity Best

Distal femur Intermediate

Axial skeleton Worst

In a retrospective study by Kim et al, the records of 331 patients with stage II osteosarcoma who
underwent surgery and chemotherapy were reviewed.[29] The authors found that the initial tumor
size appears to be associated with histologic response and is an important prognostic factor in
osteosarcoma.
Patients with tumors that have a good histologic response (the definition of which is still under
debate) to preoperative chemotherapy appear to have a better prognosis, though this still is under
investigation.

Laboratory Studies
Most of the laboratory studies that are obtained relate to the use of chemotherapy. It is important
to assess organ function before administering chemotherapy and to monitor function after
chemotherapy. Important laboratory studies include the following:

Lactic dehydrogenase (LDH)

Alkaline phosphatase (ALP)

Complete blood count (CBC), including differential

Platelet count

Liver function tests - Aspartate aminotransferase (AST), alanine aminotransferase (ALT),

bilirubin, and albumin

Electrolyte levels - Sodium, potassium, chloride, bicarbonate, calcium, magnesium,

phosphorus

Renal function tests - Blood urea nitrogen (BUN), creatinine

Urinalysis

The only blood tests with prognostic significance are LDH and ALP. Patients with an elevated
ALP at diagnosis are more likely to have pulmonary metastases. In patients without metastases,
those with an elevated LDH are less likely to do well than are those with a normal LDH.

Osteosarcoma Treatment & Management

Medical Therapy
Before the use of chemotherapy (which began in the 1970s), osteosarcoma was treated primarily
with surgical resection (usually amputation).[30] Despite such good local control, more than 80%
of patients subsequently developed recurrent disease that typically presented as pulmonary
metastases. The high recurrence rate indicates that most patients have micrometastatic disease at
the time of diagnosis. Therefore, the use of adjuvant (postoperative) systemic chemotherapy is
critical for the treatment of patients with osteosarcoma.[31]
So-called neoadjuvant (preoperative) chemotherapy has been found not only to facilitate
subsequent surgical removal by causing tumor shrinkage but also to provide oncologists with an
important risk parameter. Patients in whom there has been a good histopathologic response to
neoadjuvant chemotherapy (>95% tumor cell kill or necrosis) have a better prognosis than those
whose tumors do not respond as favorably. Thus, future chemotherapy trials will incorporate
adjuvant tumor cell kill to provide risk-adapted treatment regimens.
Patients receiving methotrexate should not be given folate supplementation or Bactrim, both of
which interfere with the effects of methotrexate. Otherwise, the patient's diet is not restricted.
Xiao et al conducted a literary review intended to shed light on the clinical outcomes of various
chemotherapy regimens in the treatment of metastatic, relapsed, and refractory osteosarcoma.[32]
They concluded that a chemotherapy regimen comprising both a cell cyclespecific drug and a
cell cyclenonspecific drug could increase response rates.
Xiao et al found that for three-drug regimens, adding a cell cyclespecific drug to ifosfamideetoposide therapy may result in a better response rate than adding a cell cyclenonspecific drug
or any other two-drug regimen among those in their study.[32] For patients with metastatic,
relapsed, and refractory osteosarcoma, they recommended the use of second-line chemotherapy
that is based on the combined ifosfamide-etoposide regimen.

Consultations
As usual for any child with cancer, consultations should be made with an oncologist, as well as
with any provider with a subspecialty related to the specific clinical circumstances. Social
services, psychology, dentistry, and child life specialists are usually involved with these patients
and their families throughout their treatment course.

Activity
Restrictions on activity vary with the location of the tumor and the type of surgical procedure
required for treatment.

Surgical Therapy

The orthopedic surgeon is of paramount importance in the care of patients with osteosarcoma.
Often, patients thought to have osteosarcoma are referred to the orthopedic surgeon first to make
the diagnosis. Moreover, because osteosarcomas are not particularly responsive to radiotherapy,
surgery is the only option for definitive tumor removal (local control).[33]
In addition, an oncologic type of total joint prosthesis or complex bone reconstruction may be
required following surgical resection. Therefore, close involvement of the orthopedic surgeon
with the medical oncologist at the time of diagnosis, as well as during and after chemotherapy, is
critical.

Biopsy
Biopsy procedures include the following:

Open biopsy (preferred to avoid sampling error and to provide adequate tissue for
biologic studies)

Trephine biopsy or core-needle biopsy (preferred for vertebral bodies and many pelvic
lesions; see the images below)

Fine-needle aspiration (FNA; not recommended)

Core needle biopsy instruments commonly used for bony specimens. Craig needle set.

Close-up view of Craig needle biopsy instruments. Cutting cannula with T-handle
attached (top) and sheath through which the cutting cannula passes (bottom).

The incision for an open biopsy must be carefully planned so as to avoid tumor contamination of
the neurovascular structures and to facilitate removal of the biopsy tract en bloc during definitive
surgery (see the image below).

Resected specimen of a proximal tibia osteosarcoma. The primary lesion was such that the knee
joint was resected with the primary lesion. Note that the previous longitudinal biopsy tract was
completely excised with the specimen.
Regardless of the technique employed, a frozen section should be examined to confirm that the
tumor has been sampled accurately. If possible, extraosseous components should be sampled
rather than bone to lessen the risk of fracture. Seal bone holes with Gelfoam or a similar material
to decrease the risk of hematoma and tumor spread. Drains should be of the closed-suction
variety, and they should be placed directly in line with the skin incision (a short distance away).

Definitive resection
The primary aim of definitive resection is patient survival. Accordingly, margins on all sides of
the tumor must contain normal tissue (wide margin). The thickness of the margin is important
only for the marrow, where an adequate margin is thought to be 5-7 cm from the edge of an
abnormality depicted on magnetic resonance imaging (MRI) or bone scanning.
Radical margins, defined as removal of the entire involved compartment (bone, joint to joint;
muscle, origin to insertion), are usually not required for cure. A less-than-wide margin (marginal
or intralesional margin) may be functionally helpful as a debulking therapy, but intrinsically, it
will not be locally curative. Amputation may be the treatment of choice in some circumstances.
If possible, a number of options exist for limb-salvage reconstruction, which must be chosen on
the basis of individual considerations, as follows:

Autologous bone graft

Allograft

Prosthesis

Rotationplasty

Autologous bone grafts may be vascularized or nonvascularized. Rejection does not occur with
these grafts, and the rate of infection is low. The growth plates of patients who are skeletally
immature may limit options for stable bone fixation (osteosynthesis).
With allografts, graft healing and infection can be problematic, particularly during
chemotherapy. Immunologic rejection can also occur. Allograft-prosthesis composites are also an
option.
Prosthetic joint reconstruction can be solitary or expandable, though it is usually expensive. The
longevity of such implants is a major concern in young children.
Rotationplasty (see the images below) is particularly suitable for patients with distal femur and
proximal tibia tumors, particularly large tumors in which a high amputation is the only
alternative. Lesions located in other areas of the femur or tibia may also be amenable to this
treatment approach. Patients who are very young or athletic may benefit greatly from this
procedure from a functional standpoint, and this procedure may also serve to minimize the
number of future surgeries needed.

Intraoperative photograph of a Van Ness rotationplasty procedure. Osteosynthesis of the tibia to

the residual femur is being performed. Courtesy of Alvin H. Crawford MD, FACS.

Clinical photograph taken at the conclusion of a Van Ness rotationplasty procedure (same patient
as previous image). Note that the new "knee" of the operative side (left side) is purposely
reconstructed distal to the normal right knee. This is in anticipation of the future growth potential
of the unoperated limb. Courtesy of Alvin H. Crawford MD, FACS.
After tumor resection, vessels are usually repaired in an end-to-end fashion to optimize patency.
The distal portion of the leg is rotated 180 and reattached to the thigh at the proximal edge of the
resection. Other variations are also possible.[1, 29] The rotation allows the ankle to become a
functional knee joint, so the length of the leg should be adjusted to match the contralateral knee.
Ideally, before rotationplasty is embarked on, patients and families should either meet or review
a video recording of a patient who has had the procedure.
Metastatic lung nodules can be cured by means of complete surgical resection (most often wedge
resection). Lobar resection or pneumonectomy may occasionally be required for clear margins.
This procedure should be performed at the time of the primary tumor resection. Although
bilateral nodules can be resected via a median sternotomy, surgical exposure is superior with a
lateral thoracotomy. Therefore, bilateral thoracotomies are recommended for bilateral disease
(each side separated by a few weeks).
For an osteosarcoma that recurs as one or more lung lesions only more than 1 year after the
patient is off therapy, surgical resection alone can be curative; the likelihood of metastases to
other sites is low. Chemotherapy is warranted if recurrence occurs earlier; in such cases, the risk
of other micrometastatic disease is high.

Follow-up
Inpatient care

Further cycles of chemotherapy generally necessitate inpatient admission for administration and
monitoring. Active drugs include methotrexate, cisplatin, doxorubicin, and ifosfamide. Patients
treated with high-dose alkylating agents are at higher risk for myelodysplasia and leukemia.
Therefore, a complete blood count (CBC) should be performed periodically.
Patients with fever and neutropenia should be admitted for intravenous (IV) antibiotic therapy
and monitoring.
Admission is required perioperatively for local control (surgical resection, amputation), usually
around week 10 of therapy. Resection of metastatic disease (eg, lung nodules) is also performed
at this time.
Patients may require admission for a multitude of other medical problems during their
chemotherapy treatment phase, including, but not limited to, varicella infection (for IV acyclovir
and monitoring), mucositis (for narcotics), dehydration, meningitis, constipation, fungal
pneumonia, and cystitis.

Outpatient care
For patients on granulocyte colony-stimulating factor (G-CSF) therapy, a CBC should be
performed twice weekly so that G-CSF can be discontinued when the absolute neutrophil count
has reached a predetermined level (usually 1000 or 5000/L) (see the Absolute Neutrophil Count
calculator).
It is important to monitor the blood chemistries and liver function test results for patients on
parenteral nutrition or who have a history of toxicity (especially if nephrotoxic or hepatotoxic
antibiotics or other drugs are continued).
To monitor for recurrence, patients should continue to have blood work and radiographic scans
on an outpatient basis, with the frequency decreasing over time. Generally, these visits occur
every 3 months for the first year; every 6 months for the second and, perhaps, third year; and
yearly thereafter.
When patients have been without therapy for 5 or more years, they are considered long-term
survivors. These individuals should be seen annually in a late-effects clinic and monitored with
appropriate studies depending on their therapy and side effects. Visits may include hormonal,
psychosocial, cardiology, and neurologic evaluations.

Complications
Hearing loss is an adverse effect of cisplatin. Fever and neutropenia may occur, and if they do,
patient admission is required for IV antibiotics and monitoring. Patients may require admission
for a multitude of other medical problems during their chemotherapy treatment phase, including,
but not limited to, varicella infection (for IV acyclovir and monitoring), mucositis (for narcotics),
dehydration, meningitis, constipation, fungal pneumonia, and cystitis.

Outcome and Prognosis

The present understanding of outcome and prognosis for osteosarcoma is driven by certain serum
markers, clinical staging, and histologic response to chemotherapeutic agents.[34]
The overall 5-year survival rate for patients diagnosed between 1974 and 1994 was 63% (59%
for males, 70% for females). Patients with an elevated ALP at diagnosis are more likely to have
pulmonary metastases. In patients without metastases, those with an elevated LDH are less likely
to do well than are those with a normal LDH.
Bu et al conducted a meta-analysis of eight published studies to determine whether p16(INK4a)
is a prognostic factor for patients with osteosarcoma.[35] The meta-analysis showed that a high
level of expression of p16(INK4a) was significantly associated with favorable overall survival.
The investigators concluded that p16(INK4a) is an effective biomarker of survival for patients
with osteosarcoma.
Ma et al conducted a study to determine the diagnostic and prognostic value of circulating miR148a in the peripheral blood of patients with osteosarcoma.[36] Expression of miR-148a was
significantly associated with tumor size and distant metastasis. High expression of miR-148a was
associated with poor overall survival and poor disease-specific survival. The investigators
concluded that detection of circulating miR-148a expression in the peripheral blood is useful in
identifying patients with osteosarcoma who have a poor prognosis.
Clinical staging as it relates to prognosis is discussed elsewhere (see Staging).
In a retrospective study by Kim et al, the records of 331 patients with stage II osteosarcoma who
had undergone surgery and chemotherapy were reviewed.[37] The authors found that initial tumor
size appears to be associated with histologic response and is an important prognostic factor in
osteosarcoma. Other studies have shown that patients in whom a good histopathologic response
to neoadjuvant chemotherapy has been achieved (>95% tumor cell kill or necrosis) have a better
prognosis than those whose tumors do not respond as favorably.

Future and Controversies

The genetic roots of cancer are irrefutable, and gene-focused basic science research holds
tremendous promise for risk stratification, as well as for effective and innovative treatments.
Multidrug-resistant varieties of osteosarcoma are a case in point. These cell lines have been
shown to be genetically encoded with a certain membrane-bound glycoprotein that helps render
these cancer cells "immune" to many chemotherapeutic agents. Early identification of such
patients (perhaps at initial biopsy) would allow a tailored approach to neoadjuvant
chemotherapy.
Metastatic or locally recurrent osteosarcoma presents an especially tough treatment challenge
that remains incompletely answered. Patients in such cases find themselves in a particularly poor

survival bracket. Future efforts must be aimed at improving chemotherapeutic and surgical
treatments that can be offered to these patients.
One potential example of this is the bone-seeking radioisotope samarium (153-samarium
ethylene diamine tetramethylene phosphonate), which has the potential to selectively deliver
high doses of radiation to osteosarcoma cells. The safety and efficacy of this agent are being
studied in patients with metastatic and locally recurrent osteosarcoma.

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