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Indian Journal of Orthopaedics | May 2014 | Vol. 48 | Issue 3 238
Classification, imaging, biopsy and staging of
osteosarcoma
Zile Singh Kundu
ABSTRACT
Osteosarcoma is the most common primary osseous malignancy excluding malignant neoplasms of marrow origin (myeloma, lymphoma
and leukemia) and accounts for approximately 20% of bone cancers. It predominantly affects patients younger than 20 years and mainly
occurs in the long bones of the extremities, the most common being the metaphyseal area around the knee. These are classifi ed as
primary (central or surface) and secondary osteosarcomas arising in preexisting conditions. The conventional plain radiograph is the
best for probable diagnosis as it describes features like sun burst appearance, Codman’s triangle, new bone formation in soft tissues
along with permeative pattern of destruction of the bone and other characteristics for specifi c subtypes of osteosarcomas. X-ray
chest can detect metastasis in the lungs, but computerized tomography (CT) scan of the thorax is more helpful. Magnetic resonance
imaging (MRI) of the lesion delineates its extent into the soft tissues, the medullary canal, the joint, skip lesions and the proximity of
the tumor to the neurovascular structures. Tc99 bone scan detects the osseous metastases. Positron Emission Tomography (PET)
is used for metastatic workup and/or local recurrence after resection. The role of biochemical markers like alkaline phosphatase and
lactate dehydrogenase is pertinent for prognosis and treatment response. The biopsy confi rms the diagnosis and reveals the grade of
the tumor. Enneking system for staging malignant musculoskeletal tumors and American Joint Committee on Cancer (AJCC) staging
systems are most commonly used for extremity sarcomas.
Keywords: Osteosarcoma, imaging, biopsy, Enneking staging
Symposium - Osteosarcoma
INTRODUCTION
Osteosarcoma is defined as the primary malignant
mesenchymal bone tumor where the malignant
tumor cells directly form the osteoid or bone or
both.1-12 Demonstration of osteoid directly formed by the
malignant cells in histopathology is essential for making the
diagnosis of osteosarcoma.2,3
Although the exact cause of osteosarcoma is still unknown,
defects in RB and p53 genes play an important role in
the process. Patients with germline mutations in RB have
approximately 1000-fold increased risk of osteosarcoma
and similarly patients with Li-Fraumeni syndrome
(germline p53 mutation) also have greatly elevated incidence
of this tumor. Abnormalities in INK4a, which encodes p16
(a cell cycle regulator) and p14 (which aids and abets p53
function) are also seen. It is noteworthy that osteosarcoma
occurs more commonly at sites of bone growth, presumably
because proliferation makes osteoblastic cells to acquire
mutations that could lead to transformation.1 Radiation too
has been implicated in causation.1,2 The risk of developing
postradiation osteosarcoma correlates with radiation dose
and use of electrophilic chemotherapeutic agents.13-15 An
etiological relationship has not been proven in prosthesis
and metal hardware associated osteosarcomas.16
Classifi cation
Osteosarcomas are classified as primary and secondary.
Primary are further sub-typed as intramedullry/central and
surface osteosarcomas as per World Health Organization
classification2 [Box 1].
RADIOLOGICAL INVESTIGATIONS
Common sites of involvement of osteosarcoma are the
metaphyseal areas (91%) of long bones of the extremities
with its occurrence in (descending order) lower end of femur,
upper end of tibia, upper end of humerus and upper end
of femur. It can uncommonly occur in the diaphysis (9%)
[Figure 1a]. Almost 50% of osteosarcomas occur around the
Department of Orthopaedics, Pt B D Sharma PGIMS, Rohtak, Haryana, India
Address for correspondence: Prof. Zile Singh Kundu,
1393, Sector-3, Rohtak, Haryana - 124 001, India.
E-mail: zskundu2003@rediffmail.com
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DOI:
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Kundu: Investigations and biopsy of osteosarcoma
239 Indian Journal of Orthopaedics | May 2014 | Vol. 48 | Issue 3
Box 1: Classification of osteosarcoma
Primary osteosarcomas
Conventional-intramedullary/central high grade (most common)
further sub-typed as:
Osteoblastic (50%)
Chondroblastic (25%)
Fibroblastic (25%)
Small cell
Telangiectatic
Low grade central
Surface osteosarcomas:
Parosteal
Periosteal
High grade surface
Secondary osteosracomas can occur in Paget’s disease and after
radiation exposure.1,2
Unusual forms of osteosarcoma given below are viewed as subtypes
of conventional osteosarcoma because their biological behavior is
similar.2
Osteoblastic osteosarcoma-sclerosing type
Osteosarcoma resembling osteoblastoma
Chondromyxoid fi broma-like osteosarcoma
Chondroblastoma-like osteosarcoma
Clear-cell osteosarcoma
Malignant fi brous histiocytoma-like osteosarcoma
Giant cell rich osteosarcoma
Epithelioid osteosarcoma
knee. Involvement of nonlong bones like jaw (gnathic), pelvis,
scapula, spine, and skull increases with age. Involvement
beyond the wrist and ankle (acral sites) is extremely rare.2
Plain X-ray
The characteristic radiological features are sun-burst
appearance, periosteal lifting with formation of Codman’s
triangle [Figure 2], new bone formation in the soft tissues
along with permeative pattern of destruction of bone and
other features for specific types of osteosarcoma.2,8,17,18
Osteolysis and expansion in the telangiectatic variety
[Figure 3] of bone is observed while more of osteoblastic
appearance is seen in the sclerosing type of osteosarcoma
[Figure 1b]. The physis (growth plate) may, but not always,
act as a barrier to tumor growth. Surface osteosarcomas
have typical appearances [Figure 4]. After chemotherapy
the tumor becomes well defined, capsulated, and more
mineralized [Figure 5]. X-ray chest can detect metastasis
in form of cannon ball appearance or nodules in the
lungs [Figure 6a], but it is less sensitive than computerized
tomography (CT) scan of the thorax [Figure 6b] for early
detection of small sub-centimal nodules.19
Computerized tomography scan
CT scan delineates the bony anatomy/architecture like
cortical integrity more clearly and picks up pathological
fracture and is helpful in assessing ossification and
calcification (chondroid component) more accurately.20,21
However, the soft tissue component and medullary extent
is best defined by an MRI.22-24
Magnetic resonance imaging
MRI is the most accurate tool for determining the limits
of tumor within and outside the bone.7,22-24 MRI should
include the whole of the involved bone with one joint above
and below so that skip lesions are not missed in the same
bone and across the joint. MRI accurately and precisely
delineates (1) extent of the tumor into the soft tissues and
the medullary canal, (2) involvement of joint, (3) crossing of
the lesion through and/or around the growth plate, (4) any
skip lesion in the same bone and across the joint in other
bone, (5) proximity and/or encasement of the neurovascular
bundle by the tumor [Figure 7]. Recently, even the
Figure 1: (a) X-ray anteroposterior and lateral views of proximal tibia and knee joint showing diaphyseal osteosarcoma of tibia with sclerosis (arrow),
cortical destruction on posteromedial side (arrow heads) and new bone formation in the soft tissues (b) x-ray distal end of femur (anteroposterior
and lateral views) showing sclerosis/radio-opacity in sclerosing osteosarcoma
b
a
Kundu: Investigations and biopsy of osteosarcoma
Indian Journal of Orthopaedics | May 2014 | Vol. 48 | Issue 3 240
response of chemotherapy is being judged by MRI as the
neo-angiogenesis decreases with chemotherapy, necrosis
occurs, and the tumor shrinks with better capsulation. This is
done by performing a contrast enhancement and diffusion
MRI.25,26 MRI is also being coupled with Positron Emission
Tomography for detection of the systemic involvement by
the tumor, local recurrence, and metastasis after treatment.
In view of the nonspecific findings of an MRI, it should
always be correlated with the patient’s x-ray.
Radionuclide bone scan
Tc99 methylenediphosphonate (Tc99 MDP) bone scan
is the most commonly used investigation for detecting
osseous metastasis [Figure 6c]. It is performed by injecting
20 mCi of isotope intravenously and taking images at
different intervals, in three phases: (1) the flow phase,
(2) the immediate or equilibrium phase, and (3) the delayed
phase. The flow phase demonstrates blood flow just like
radionuclide angiogram; the equilibrium phase shows the
reactive vascular flow and the distribution in the intercellular
spaces, and the delayed phase is after 2-4 hours when the
radionuclide is excreted in the urine except in the areas of
the osteoblastic activities. This radio-isotope has special
predilection to the sites of increased osteoblastic activity and
highly vascular areas like the sites of metastasis in sarcomas.
It is most easily available and cost-effective investigation for
detecting bony metastasis in osteosarcoma.27
Positron emission tomography
Positron Emission Tomography (PET), which picks up
metabolic activity is evolving with tremendous potential
in oncology.28-34 Further combining the images of ‘form’
i.e. the anatomical structure provided by CT and MRI and
those of ‘function’ i.e. metabolic or biochemical activity,
provided by PET can be precisely aligned or correlated.
MRI combined with PET facility reduces radiation exposure
when compared to a CT.
PET is utilized in: (1) selecting the region of a tumor most
likely to yield diagnostic information for biopsy, (2) staging
known malignancies, (3) monitoring the effect of therapy,
(4) to establish the cause of suspected recurrence seen on
other imaging modalities. It differentiates between fibrosis
and recurrent tumor (5) detecting tumor recurrence,
especially in the presence of elevated levels of tumor
markers, (6) differentiating benign from malignant lesions,
(7) searching for an unknown primary tumor with metastasis
of unknown origin, (8) guiding radiation therapy planning.33
The main drawback is the difficulty and cost of producing
and transporting the radiopharmaceuticals used for PET
imaging, which are usually extremely short-lived. The
half life of radioactive fluorine18 used to trace glucose
metabolism (using fluorodeoxyglucose, FDG) is 2 hours
only. Its production requires a very expensive cyclotron as
well as a production line for the radiopharmaceuticals. It can
Figure 2: X-ray of humerus anteroposterior view showing osteosarcoma
of the proximal humerus- typical sun burst or sun ray appearance, new
bone formation in soft tissues, and Codman’s triangles (arrows)
b
a
Figure 3: Telangiectatic type of osteosarcoma of the proximal tibia: (a) X-ray anteroposterior and lateral views showing lysis and expansion
(b) MRI showing fl uid levels
Kundu: Investigations and biopsy of osteosarcoma
241 Indian Journal of Orthopaedics | May 2014 | Vol. 48 | Issue 3
b
a
Figure 5: X-ray anteroposterior and lateral views showing that after chemotherapy the tumor becomes well defi ned with better capsulation:
(a) before chemotherapy and (b) after chemotherapy
b
ac
Figure 6: (a) Plain X-ray chest of a patient of osteosarcoma showing multiple metastatic lung nodules (b) CT scan (axial section) demonstrating
multiple metastases in both lungs (c) Tc-99m bone scan of osteosarcoma in the proximal humerus with hot spot at this site and in spine, ribs
and a focus in the skull bone
give false negative and positive results and is still considered
the investigation under continuing research.33,34
Biochemical markers
The role of biochemical markers like serum alkaline
phosphatase (ALP) and lactate dehydrogenases (LDH) for
diagnosis, prognosis and response to treatment is pertinent
to mention. Levels of alkaline phosphatase are elevated in
osteosarcoma due to increased osteoblastic activity. Higher
levels are associated with heavy tumor burden and poor
prognosis. The response of therapy can be monitored with
the levels of these enzymes. High levels after treatment
may persist with residual disease or recurrence and in the
presence of metastasis.8
Biopsy
Biopsy should be performed after complete history, clinical
examination and imaging. It confirms the diagnosis,
Figure 4: X-ray of knee joint anteroposterior views showing surface
osteosarcoma: (a) parosteal (b) periosteal. See the under lying cortex is
visibly intact in ‘a’ and lifting of periosteum in ‘b’ (red arrow). However,
both are on the surface of the bone
b
a
Kundu: Investigations and biopsy of osteosarcoma
Indian Journal of Orthopaedics | May 2014 | Vol. 48 | Issue 3 242
b
ac
Figure 7: Osteosarcoma in the distal end of femur: (a) X-ray thigh with knee anteroposterior view showing big soft tissue component on the
medial side; (b) MRI-coronal section showing the medullary extent (arrow); (c) MRI-axial section showing the proximity of the popliteal vessels
reveals specific type and furnishes the grade of the tumor.
It is performed by either an open (incisional) or a closed
method. Closed biopsy is performed as fine needle aspiration
cytology (FNAC) and core needle biopsy.7 Open or incisional
biopsy is performed through a small incision [Figure 8] and
has the major advantage of obtaining adequate amount of
sample for histopathology as well as for ancillary studies
like immunohistocytochemistry (IHC) and genetic studies.
But it takes more time and requires operation theatre set-up
with instruments. There are more chances of contamination
of normal soft tissue by tumor cells through an impending
hematoma and also other complications like infection and
wound problems posing greater morbidity. Further, there is
more cost to the patient as it may require short stay in the
hospital. However, if performed meticulously and properly, the
complications can be reduced markedly almost comparable
to those of a core needle biopsy.7 Percutaneous core needle
biopsy has now evolved as a better, safe and accurate method
for diagnosing of bone tumors. It is performed through a
small stab using the Jamshidi needle and taking multiple
cores from the representative part of the tumor [Figure 9]. It is
less extensive and less time consuming outpatient procedure
performed safely and quickly under local anesthesia and is
cost effective. There is minimal soft tissue trauma with less
contamination of normal tissue by the tumor cells around
the tract of the needle which is easily excisable during the
limb salvage surgery. It is very suitable for deep and difficult
areas like the pelvis and spine.5,6 The efficacy and accuracy
can be further increased by performing this under image
guidance i.e. under CT scan, MRI or ultrasonography. The
recent literature advocates core needle biopsy as it provides
adequate amount of sample for the diagnosis and the ancillary
studies, and has less number of complications.35-48
FNAC does not have much role in majority of bone and soft
tissue sarcomas as only few cells are inadequate for making
a specific diagnosis and conducting ancillary studies. Ideally
one should not start oncological treatment on the basis of
a cytological diagnosis.7
Whether performed open or close, there are set principles
for biopsy of musculoskeletal tumors which holds true for
osteosarcoma too. Where, who, and how the biopsy should
be performed are important issues. The biopsy is such an
instrumental step that if not performed properly, the end
result of definitive treatment can be affected significantly. We
have noticed poorly performed biopsies in patients referred
from periphery by nonspecialized general orthopedic
surgeons and by un-experienced junior surgeons even at
our institute. The incisions for biopsy were wrongly placed
[Figure 10], patients had infection at the biopsy site due to
big hematoma, and there were nondiagnostic samples due
to inadequate material taken from nonrepresentative areas
of the tumor. Due to these improper biopsies, the optimal
treatment plan required alteration. The importance of biopsy
has been well emphasized in literature by Mankin et al. who
observed that because of wrong biopsies unnecessary
amputations were performed in 4.5% of patients and
the prognosis and outcome was altered in 8.5% of their
patients. They found 18.2% major errors in diagnosis and
10.3% of biopsies being nonrepresentative. It has been
emphasized that ideally the biopsy should be performed
at the center where the definitive treatment of the tumor
is to be performed under the guidance of a welltrained
oncologist, taking all precautions, and following the basic
principles.46-50 If the principles are followed properly the final
Figure 8: Open biopsies taken through small two cm incisions without
making different planes. The incisions were placed such that these can
be well resected with defi nitive resection of the tumor
Kundu: Investigations and biopsy of osteosarcoma
243 Indian Journal of Orthopaedics | May 2014 | Vol. 48 | Issue 3
Figure 9: Core needle biopsy: (a) Jamshidi needle with trochar and
stylet. (b) Biopsy being taken through stab incision. (c) Five good
cores taken
b
ac
outcome will obviously be better with lesser complications.
This will prevent the repetition of biopsy and the treatment
delay with reduction of overall cost42 [Box 2].
Staging
The common staging systems for malignant bone
tumors are: Enneking system for staging malignant
musculoskeletal tumors and the American Joint Committee
on Cancer (AJCC) System for staging bone sarcomas.6
The former is based on the histological grade of the
tumor, its local extent and the presence or absence of
metastasis [Table 1]. Low grade lesions are stage-I, are
well differentiated, have few mitoses and exhibit only
moderate cytological atypia with low risk of metastasis (less
than 25%). High grade lesions are stage-II are poorly
differentiated, have high mitotic rate, and high cell to matrix
ratio. On the basis of the involvement of the anatomical
compartment (as determined by the natural anatomical
barriers to tumor growth like cortical bone, articular
cartilage, fascial septa, or joint capsules) these are further
sub-divided as A and B. Stage–IA and IIA are contained
in well defined compartment (intracompartmental) and
stage–IB and IIB lesions extend beyond the compartment
of origin (extracompartmental). Stage –III are lesions with
metastasis (lymph node or distant) regardless of the size
and grade.2,7
The AJCC system for bone sarcomas is based on tumor
grade, size, presence, and location of metastases [Table 2].
Stage-I tumors are low grade and stage-II are high grade,
which are subdivided based on tumor size. Stages I-A and
II-A are 8 cm or less in their greatest linear measurement;
stage I-B and II-B are larger than 8 cm. Stage III tumors
have “skip metastases”, which are defined as discontinuous
lesions within the same bone. Stage IV-A involves pulmonary
metastases, whereas Stage IV-B involves nonpulmonary
metastases. The stage IV is subdivided because patients with
nonpulmonary metastases from osteosarcoma have worse
prognosis than those with only pulmonary metastases.7,51-53
CONCLUSION
The plain radiograph provides the best clue to the
diagnosis and MRI the local extent. Thorax CT scan and
Tc99 bone scan are used for the detection of lung and bony
Table 1: Enneking system for staging malignant
musculoskeletal tumors
Stage Grade Site Metastasis
IA Low Intracompartmental None
IB Low Extracompartmental None
IA High Intracompartmental None
IIB High Extracompartmental None
III Any Any Regional or distant metastasis
Table 2: American joint committee on cancer system for
staging bone sarcomas
Stage Grade Size Metastasis
I-A Low <8 cm None
I-B Low >8 cm None
II-A High <8 cm None
II-B High >8 cm None
III Any Any Skip metastasis
IV-A Any Any Pulmonary metastasis
IV-B Any Any Nonpulmonary metastasis
Figure 10: Poorly performed biopsies: (a) Avoid transverse incision in the extremity because this is diffi cult to excise with defi nitive resection.
(b) Never biopsy through buttock as this is the fl ap for the coverage in the hind quarter amputation if required. (c) Never biopsy through rectus
femoris; very important for knee extension (d) Poor biopsy: Long incision and widely placed sutures marks will require excision of wide area of
skin and under lying tissues if salvage surgery is contemplated and the wound closure may be compromised
b
ad
c
Kundu: Investigations and biopsy of osteosarcoma
Indian Journal of Orthopaedics | May 2014 | Vol. 48 | Issue 3 244
metastasis respectively. The biopsy confirms the diagnosis
and reveals the grade of the lesion. The basic principles
of biopsy should be followed precisely and meticulously.
After clinical, radiological and the histopathological
examinations the tumor can be staged adequately [Box 3].
It is pertinent to mention that the patient should be
immediately referred to the treating specialist centre
for early diagnosis and treatment as this can make limb
salvage possible in large number of patients. The urgent
need of the MDT (multidisciplinay team) for the better
out come in all musculoskeletal sarcomas can not be
over-emphasised. However, the biological behavior of
osteosarcoma is yet to be fully understood.
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Box 2: Principles of biopsy
Perform all the relevant imaging investigations before biopsy.
Biopsy should be performed at the treating center by the member of
the treating team or at least under his/her guidance. Refer the patient
before biopsy if treatment is not feasible at the peripheral center.
If tourniquet is used, elevate the limb but do not exsanguinate with
compression.
No transverse incision in the extremities. Avoid major neurovascular
structures.
Place the incision such that it can be easily excised with the
defi nitive resection and should not jeopardize the future plan of
surgery and function of the limb. The needle biopsy tract should be
tattooed in order to excise it easily. The surgeon should be familiar
with incisions of limb salvage and those for the standard and
nonstandard amputation fl aps.
Make no different planes during open biopsy rather reach the tumor
with a single deep stab/incision until the depth of the tumor to avoid
seepage of tumor cells under these planes. Do not reach the lesion
in between the muscle planes rather go through a single muscle
plane to avoid contamination of more muscle groups.
Sample the soft tissue component in the bone sarcomas. Material
should be taken from the viable peripheral area of the tumor and not
from the central necrotic area and the Codman’s triangle having just
reactive bone. Do not squeeze the tumor during biopsy.
If required, make circular/oval window in the bone to decrease the
chances of pathological fracture; avoid quadrangular widow. Protect the
limb if the chances of fractures are likely which alters the prognosis.
Achieve complete hemostasis to avoid contamination of the tissues
with seepage of blood under tissue planes. In the bone, the hole can
be plugged with small amount of bone cement. The wound should
be sutured tightly and avoid widely placed suture. If required, the
drain should be in the line of incision, not on the side.
If frozen section facility exists the diagnostic tissue can be confi rmed
intraoperatively. Take adequate material and do not divide the tissue
for different pathologists rather furnish them the slides/block if the
review is required.
Tissue should be adequately immersed in formalin/preservation fl uid
in a ratio of 1:20 (tissue: fl uid) and do not allow it to dry on the table.
The sample could be sent immediately as a fresh specimen for
potential frozen section and immunohistocytochemistry studies.
Fill up the biopsy form properly with all relevant clinical, radiological,
and the previous FNAC/biopsy details if available. Assist the
pathologist in making diagnosis rather than testing or confusing them.
There should be always a multidisciplinary team (MDT) to discuss
oncological cases. The MDT should include the surgeon, radiologist,
pathologist, chemotherapist, and the radiation oncologist.
“Always culture a biopsy and biopsy a culture” as we are in the endemic
area of infections (including tuberculosis) which can mimic tumors.
MDT: Multidisciplinary team, FNAC: Fine needle aspiration cytology
Box 3: Algorithm for staging osteosarcoma in distal femur
Clinical examination: Painful, ill-defi ned diffuse mass lesion in the
metaphyseal area of the distal femur- suspect osteosarcoma
Plain X-ray of the lower thigh with knee (for probable diagnosis) and
X-ray chest (may detect lung nodules i.e. metastasis)
MRI of the distal thigh with inclusion of hip and knee joint
(for tumor size, local extent and skip lesion, if any)
CT scan thorax (for lung metastasis),
Tc-99 bone scan (for osseous metastasis)
Biopsy (for confi rmation of diagnosis and grade of the lesion)
Stage the lesion as per local extent including the size, grade and
metastasis in view of the above mentioned investigations
Example-if MRI shows the lesion extending all around the femur into the soft tissues
with no metastasis on CT scan thorax and bone scan; and is high grade on biopsy it
is stage-II-B lesion (Enneking staging) as are the majority of the osteosarcomas at
presentation, MRI: Magnetic resonance imaging, CT: Computerized tomography
Kundu: Investigations and biopsy of osteosarcoma
245 Indian Journal of Orthopaedics | May 2014 | Vol. 48 | Issue 3
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Kundu: Investigations and biopsy of osteosarcoma
Indian Journal of Orthopaedics | May 2014 | Vol. 48 | Issue 3 246
How to cite this article: Kundu ZS. Classifi cation, imaging, biopsy
and staging of osteosarcoma. Indian J Orthop 2014;48:238-46.
Source of Support: Nil, Confl ict of Interest: None.
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Retraction Notice
The following article is being retracted due to authorship dispute:
Kambali M, Anand HSV, Priyamargavi H, Varma RB. Traumatic posterior atlantoaxial dislocation without related fractures of C1-C2. Indian
J Orthop 2013;47:624-29.
Editor, Indian J Orthop
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