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Imaging Analyses of Bone Tumors

Costantino Errani, MD Abstract
» Despite the evolution in imaging, especially the introduction of
Shinji Tsukamoto, MD
advanced imaging technologies, radiographs still are the key for the
Andreas F. Mavrogenis, MD initial assessment of a bone tumor. Important aspects to be considered
in radiographs are the location, shape and size or volume, margins,
periosteal reaction, and internal mineralization of the tumor’s matrix;
careful evaluation of these may provide for accurate diagnosis in
.80% of cases.

» Computed tomography and magnetic resonance imaging are often

diagnostic for lesions with typical findings such as the nidus of osteoid
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osteoma and bone destruction such as in Ewing sarcoma and lymphoma

that may be difficult to detect with radiographs; they may also be used
for surgical planning. Magnetic resonance imaging accurately determines
the intraosseous extent and articular and vascular involvement by the
tumor.

» This article summarizes the diagnostic accuracy of imaging analyses

in bone tumors and emphasizes the specific radiographic findings for
optimal radiographic diagnosis of the patients with these tumors.

R
adiographs are an important
imaging diagnostic modality
for bone tumors; they are easy
to get, low cost, and informa-
tive. A careful consideration of the history
of the patient and clinical and radiographic
findings may provide for the correct diag-
nosis of a bone tumor in .80% of cases
based on radiographs alone1,2. The intra-
osseous and skeletal location of the tumor,
its shape and size or volume, margins,
periosteal reaction, and mineralization of
the tumor’s matrix help to determine the
diagnosis1,2. Other imaging modalities
may also contribute. Computed tomogra-
phy (CT) optimally characterizes the
involved bone, as well as the tumor’s matrix
(internal mineralization, calcifications,
and ossifications) and the occurrence of a
pathological fracture. Magnetic resonance
imaging (MRI) accurately determines the
intraosseous and extraosseous (soft-tissue)
extent and the involvement of the adjacent
joint and vessels by the tumor3. Nuclear
medicine scintigraphy identifies areas of
increased bone turnover with a higher
sensitivity than radiographs and may
be useful to estimate the outcome and
the response to the treatment of bone
tumors 3-5 .
Radiographs
Bone tumors can be considered on the basis
of their location, shape and size or volume,
margins, periosteal reaction, and internal
mineralization of the tumor’s matrix4,6.
The patient’s age is the only clinical detail
that should be used in combination with
the findings in radiographs to establish a
correct diagnosis (Fig. 1)2,6.
Location
The intraosseous and skeletal tumor
location is important for a differential
diagnosis (Fig. 2). The majority of bone
tumors arise in the metaphyseal area in
bone; some tumors such as chondroblas-
toma, giant cell tumor of bone, and clear
cell chondrosarcoma typically arise in
the epiphyses of bone. Ewing sarcoma

COPYRIGHT © 2020 BY THE Disclosure: The authors indicated that no external funding was received for any aspect of this work.
JOURNAL OF BONE AND JOINT The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the
SURGERY, INCORPORATED article (http://links.lww.com/JBJSREV/A555).

JBJS REVIEWS 2020;8(3):e0077 · http://dx.doi.org/10.2106/JBJS.RVW.19.00077 1

 | I m a g i n g A n a l y s e s o f B o n e Tu m o r s

Fig. 1
Bone tumor distribution based on the radiographic findings and age of the patients. Y.o. 5 years old, EG 5 eosinophilic granuloma, SBC 5 simple bone cyst, NOF 5 nonossifying
fibroma, ABC 5 aneurysmal bone cyst, CMF 5 chondromyxoid fibroma, HPT 5 hyperparathyroidism, and CCC 5 clear cell chondrosarcoma.

typically arises in the diaphysis of the
long bones, the pelvis, and flat bones,
and osteofibrous dysplasia also occurs
in the diaphysis but with a specific
preference for the tibia, similarly to
adamantinoma. Periosteal osteosar-
coma also commonly arises at the
diaphysis of the long bones, but, un-
like conventional osteosarcoma, it
arises on the surface of bone. Parosteal
osteosarcoma often arises at the pos-
terior distal femoral metaphysis. Uni-
cameral cysts of bone, enchondromas,
and fibrous dysplasia almost always
are located centrally in the involved
bone, whereas aneurysmal bone cysts,
chondromyxoid fibroma, and histio-
cytic (nonossifying) fibroma are lo-
cated eccentrically in the involved
bone. Other tumors such as osteoid
osteoma and eosinophilic granuloma
do not have a specific bone and skeletal
predilection4.
Shape and Size or Volume
We consider the shape of a bone tumor
important for the diagnosis and its size or
volume helpful for the prognosis. Some
lesions such as the giant cell tumor of
bone and osteosarcoma have a tendency
for a spherical shape, and other lesions
such as enchondromas and chondrosar-
comas have a tendency to follow the
shape of the involved bone4. A chondral
tumor that is .5 cm in length more
likely represents a chondrosarcoma
rather than an enchondroma7,8. A cutoff
of 200 mL of tumor size was found to be
a useful univariate predictor of prognosis
for osteosarcoma5,9.
Radiographic Margins
We consider the bone tumor’s radio-
graphic margins important for the eval-
uation of the tumor’s growth rate and its
biological behavior (benign or malig-
nant). A radiographic classification of
bone tumor margins identifies 3 main
types10. Type-I margins (the least
aggressive) refer to tumors that are ovoid
or round in shape and geographic. These
margins have been subdivided in 3 cat-
egories. Type-IA margins (the least
aggressive) exhibit a narrow transition
zone from the tumor to the healthy
surrounding bone and a sclerotic rim;
examples include fibrous cortical de-
fects, fibrous dysplasia, and nonossifying
fibroma or fibroxanthoma. Type-IB
margins (well-defined) exhibit a narrow
transition zone without a sclerotic rim;
they indicate an indeterminate biologi-
cal potential and may be observed in the
radiographs of benign and malignant
lesions such as giant cell tumor of bone,
aneurysmal bone cyst, aggressive osteo-
blastoma, and low-grade chondrosar-
coma. Type-IC margins (poorly defined
and indistinct) exhibit a wide transition
zone and correspond to aggressive bone

2 MARCH 2020 · VOLUME 8, ISSUE 3 · e0077


Fig. 2
Bone tumor distribution based on skeletal and bone location. EG 5 eosinophilic granuloma, Mets 5 metastases, FD 5 fibrous dysplasia, SBC 5 simple
bone cyst, ABC 5 aneurysmal bone cyst, GCT 5 giant cell tumor of bone, NOF 5 nonossifying fibroma, UPS 5 undifferentiated pleomorphic sarcoma,
and OFD 5 osteofibrous dysplasia.
tumors; most of these tumors are ma-
lignant, such as osteosarcomas and
chondrosarcomas, and aggressive be-
nign lesions such as a giant cell tumor of
the bone may also show this appearance
of radiographic margins. Type-II and
type-III margins (nongeographic) are
characterized by poorly defined areas
of bone destruction. Type-II margins
(moth-eaten) are characterized by nu-
merous areas of bone destruction (oste-
olysis) that vary in shape and size or
volume, but the cortex is relatively intact.
Type-III margins (permeative) refer to
highly aggressive tumors including small
round cell tumors such as Ewing sarcoma
and primary bone lymphoma.
Lodwick’s grading system of oste-
olytic bone lesions has been described
for the prediction of growth rate1. Re-
cently, Caracciolo et al. described the
modified Lodwick-Madewell grading
system to classify osteolytic bone tumors
based on their risk of malignancy into
low risk, moderate risk, and high risk11;
they expanded the original system and
added 2 more patterns (changing mar-
MARCH 2020 · VOLUME 8, ISSUE 3 · e0077
gination and radiographically occult), as
described by Madewell et al.10, and re-
classified into 3 grades: grade I refers to
grades IA and IB in the Lodwick system;
grade II refers to grade IC in the Lodwick
system, and grade III is subdivided into
grade IIIA (changing margination),
grade IIIB (moth-eaten and perme-
ative), and grade IIIC (radiographically
occult). In a study of the modified
Lodwick-Madewell grading system,
94% of grade-I tumors were benign and
81% of grade-III tumors were malig-
nant; benign (46%) and malignant
(54%) grade-II lesions were similarly
common. This system correlates the
grade of the tumor with its biological
activity and risk of malignancy: grade-I
tumors are usually benign (low risk),
grade-II tumors are associated with a
moderate risk of malignancy, and grade-
III tumors are associated with a high risk
of malignancy11.
Periosteal Reaction
Similar to the radiographic margins,
periosteal reaction is an important sign
I m a g i n g A n a l y s e s o f B o n e Tu m o r s |
of a tumor’s biological activity. The
types of periosteal reaction include
amorphous (thick), laminated (onion-
skin), and spiculated (sunburst); only
the amorphous type of periosteal reac-
tion indicates a relatively slow, often
benign process (Fig. 3). A fast-growing
bone tumor breaks and detaches the
cortex and destroys the newly formed
laminated bone in the periosteum;
remnants of the periosteal bone at the
site of the detachment of the periosteum
form a Codman triangle4,12. A smooth,
continuous periosteal reaction usually
indicates a slow-growing benign lesion,
and a non-continuous (interrupted)
periosteal reaction and proliferation of
periosteal bone often are seen in bone
sarcomas.
Matrix Mineralization
The evaluation of the internal mineral-
ization of a tumor’s matrix character-
izes the intracellular material (matrix)
formed by the tumor. The matrices
formed by mesenchymal cells include
osteoid, osseous, chondroid, myxoid,
3
 | I m a g i n g A n a l y s e s o f B o n e Tu m o r s
and fibrous. The matrices produced by
tumor cells may differentiate osteoblastic
from chondroblastic tumors. A typical
tumor of osteoblastic origin produces an
osteoid and osseous matrix that appears
on radiographs as dense clouds or lumps
with sharp or fuzzy margins. A chondroid
matrix appears as arcs or rings that rep-
resent enchondral ossification along
cartilaginous lobules and indicates a
chondroblastic process. Calcifications
may appear as flocculent or stippled
deposits of calcium or bone in the tumor.
In general, a chondroid matrix mineral-
izes in well-differentiated mature tumors.
Ewing sarcoma mostly does not show
any matrix mineralization4,12, and
fibrous tumors variably show a slightly
higher density on radiographs, moder-
ate ground-glass appearance, or dense
mature mineralization that can be either
homogeneous or heterogeneous13. A
gradual increase of mineralization with
4 MARCH 2020
tumor growth is called maturation and
can be seen in tumors such as fibrous
dysplasia, histiocytic fibromas (non-
ossifying fibroma, fibrous cortical
defect), osteoid osteoma, and bone
islands14.
Hematological Malignancies
Radiographic patterns of primary bone
lymphoma include osteolytic lesions
with permeative margins with multiple
small bone radiolucencies and a wide
transition zone between the involved
and healthy bone or a mixed osteolytic
and osteoblastic (sclerotic) pattern15-17.
A bone sequestrum is not a specific
radiographic finding for primary bone
lymphoma because it can also be seen in
other tumor and non-tumor entities
such as eosinophilic granuloma, fibro-
sarcoma, osteomyelitis, osseous tuber-
culosis, and osteoradionecrosis. If
present, a periosteal reaction has a per-
Fig. 3
Bone tumor types of periosteal reaction.
meative (aggressive) and usually lamellar
pattern16,18-20. Radiographic patterns of
multiple myeloma include focal or dif-
fuse osteolysis21,22. Osteolytic myeloma
lesions in the long bones show erosion of
the cortex from the side of the medullary
canal (endosteal cortical scalloping);
pathological fractures are common19,22.
A radiographic skeletal survey, MRI, or
fluorine-18 fluorodeoxyglucose (18F-
FDG) positron emission tomography
(PET) and CT (18F-FDG PET-CT) can
be used for staging multiple myeloma,
on the basis of institutional preference20.
CT and MRI
Anatomical details of the tumor, evalu-
ation of tumor matrix mineralization,
and bone marrow edema may be delin-
eated further on CT and MRI. Although
these imaging studies provide incom-
plete information on the biological
activity of the tumor23, CT and MRI are
· VOLUME 8, ISSUE 3 · e0077

superior to radiographs for surgical
planning. Additionally, in deep-seated
musculoskeletal tumors, CT guidance
increases the biopsy accuracy24-26;
intravenous contrast medium adminis-
tration is useful to guide biopsies toward
areas of contrast enhancement rather
than areas of necrosis27.
Matrix Mineralization
CT is superior to MRI for the evaluation
of a tumor’s matrix mineralization, the
involvement of the cortex, periosteal
reaction, and pathological fracture4,28. It
is particularly helpful for the evaluation of
bone tumors when radiographs are nega-
tive or non-informative because of the
nature of the lesion or of the anatomy of
the bone such as the pelvis, scapula, or
sacrum4,28. MRI also is helpful for the
evaluation of a tumor’s matrix23,29-34.
The use of variable MRI sequences facil-
itates the MRI characterization of the tis-
sue and occasionally diagnosis23,30,31.
The extent of bone marrow involvement
by the tumor is best defined on T1-
weighted sequences, with surrounding
bone marrow edema better shown on
fat-saturated T2-weighted or short tau
inversion recovery (STIR) sequences30,31.
Bone Marrow Edema
The occurrence and extent of bone
marrow edema are important for the
differential diagnosis of a bone tumor.
Benign tumors such as osteoid osteoma,
osteoblastoma, chondroblastoma, and
Langerhans cell histiocytosis are associ-
ated with more surrounding bone
marrow edema than malignancies are.
Osteoid osteoma displays imaging
findings that can be deceptive when the
nidus is small and is masked by extensive
edema of the bone marrow and the soft
tissues. Davies et al. observed a nidus in
1 slice only of the optimal sequence in 27
of 43 patients with osteoid osteoma,
reactive bone alterations in 33 of the
patients, and soft-tissue alterations in 37
of the patients35. They suggested that
reliance on MRI alone misleads the
diagnosis and concluded that inexplica-
ble areas of bone marrow edema should
be further examined with CT and a bone
MARCH 2020 · VOLUME 8, ISSUE 3 · e0077
scan to exclude an osteoid osteoma35.
Other studies have shown that gadolin-
ium contrast medium-enhanced MRI
may show osteoid osteomas more accu-
rately than non-contrast-enhanced stud-
ies and may complete thin-section CT in
this regard. Osteoid osteomas in younger
patients tend to be associated with more
extensive peritumoral edema36,37; a recent
study showed that the nidus mineraliza-
tion ratio of osteoid osteoma increased
significantly with the duration of pain and
may be a marker of tumor age38.
Minimal bone marrow edema
around a large bone tumor more likely but
not necessarily indicates a malignancy;
bone sarcomas such as osteosarcoma,
Ewing sarcoma, and chondrosarcoma
may also be associated with substantial
bone marrow edema23,31,32. Awareness of
the benign and malignant tumors that
often are associated with bone marrow
edema is important for the correct (dif-
ferential) diagnosis, ensuring that the
size or volume of the tumor is not over-
estimated and that an inappropriate
biopsy location is not selected as a result3.
The differentiation between the
tumor and its surrounding bone marrow
edema may be difficult and complicate
surgical planning and margins of resec-
tion4. Bone marrow edema presents
with a poorly defined, patchy appear-
ance of homogeneous intermediate
signal intensity on T1-weighted se-
quences and high signal intensity on
fat-suppressed T2-weighted or STIR
sequences4. Most malignant tumors also
demonstrate low to intermediate signal
intensity on T1-weighted sequences and
high signal intensity on fat-suppressed
T2-weighted sequences4. Dynamic
contrast-enhanced MRI has been rec-
ommended to improve the characteri-
zation of the nature and margins of bone
tumors39,40. Lang et al. studied dynamic
post-contrast MRI scans for the differ-
entiation of the tumor from bone mar-
row edema. They observed that an
enhancement curve with a slope of
#20% of that of the adjacent tumor was
consistent with peritumoral edema41. In
contrast, Häussler et al. reported that the
differentiation of Ewing sarcoma from
I m a g i n g A n a l y s e s o f B o n e Tu m o r s |
peritumoral bone marrow edema is
rarely possible based on MRI42.
Differential Diagnosis
from Osteomyelitis
Differential diagnosis of a bone tumor
from osteomyelitis is necessary for
appropriate management of both enti-
ties. An increased concentration of
C-reactive protein is a relatively sensitive
index for the differential diagnosis
between osteomyelitis and bone tumors
and tumor-like lesions except for bone
metastases43. Radiographic findings of
osteomyelitis including focal cancellous
osteolysis and cortical resorption, corti-
cal tunneling, periosteal reaction, and
soft-tissue swelling are often mistaken
for tumors44. In 50% of patients with
chronic osteomyelitis, additional find-
ings on radiographs include a central
zone of osteolysis and a periosteal
reaction43,45. MRI detects bone marrow
changes with a high sensitivity and gives
detailed information for the location and
extent of infection; however, MRI
findings of osteomyelitis are not specific
and vary according to bone and skeletal
location, microbial isolate, and dura-
tion. The typical MRI findings of a
Brodie abscess include a 4-layer target
appearance that consists of a hypo-
intense central abscess cavity; an inner,
relatively hyperintense ring of granula-
tion tissue; an outer hypointense ring;
and a peripheral, hypointense halo on
T1-weighted MRI scans46. The occur-
rence of a granulation tissue layer lining,
a cavity, and the penumbra sign, an
inner ring of granulation tissue on T1-
weighted MRI scans, was observed in
6 (86%) of 7 patients with subacute
osteomyelitis, in 5 (63%) of 8 patients
with chronic osteomyelitis, and in no
patients with acute osteomyelitis, com-
pared with only 2 (0.9%) of 229 pa-
tients with bone tumors and tumor-like
lesions47; therefore, the penumbra sign
is characteristic but not pathognomonic
of subacute osteomyelitis47. The
granulation tissue layer enhances
substantially, and the penumbra sign
disappears, with intravenous gado-
linium contrast administration 43.
5
 | I m a g i n g A n a l y s e s o f B o n e Tu m o r s
The features of Ewing sarcoma
and osteomyelitis are similar on imag-
ing, often leading to misdiagnosis48.
McCarville et al. showed on radiographs
that, when tested individually, joint or
bone metaphysis involvement, a wide
transition zone, Codman triangle for-
mation, periosteal reaction, or a soft-
tissue mass was more likely to be
observed in patients with Ewing sar-
coma compared with patients with
osteomyelitis (p # 0.05)48. On MRI,
cortical involvement in a permeative
pattern and a soft-tissue mass were more
likely in patients with Ewing sarcoma
(p # 0.02), whereas a serpiginous tract
was more likely in patients with osteo-
myelitis (p 5 0.04). In a multiple regres-
sion analysis, a soft-tissue mass remained a
significant predictor (p # 0.01)48.
Response to Chemotherapy
Imaging findings showing the response
of bone sarcomas to chemotherapy are
important to determine the efficacy of
treatment before surgical resection.
However, there are no important imag-
ing predictors of the response to che-
motherapy. In osteosarcoma, alterations
in the tumor size or volume or bone
reaction shown in radiographs have a
moderate association with the histolog-
ical response to chemotherapy49,50. CT
or MRI is not very helpful to differen-
tiate between tumors that respond and
those that do not respond to chemo-
therapy because osteosarcomas fre-
quently do not change in size or volume
in response to chemotherapy51,52.
Moreover, MRI does not provide satis-
factory information on the viability of
the tumor, which is the variable for
determining the response of the tumors
to the treatment and prognosis of the
patients53. In Ewing sarcoma, the
response to chemotherapy is evaluated
by alterations in the tumor size or vol-
ume, most commonly with MRI54.
Recently, Aghighi et al. reported that the
3-dimensional tumor measurements
are better predictors of the response to
chemotherapy of Ewing sarcoma than
the 1-dimensional Response Evaluation
Criteria in Solid Tumors (RECIST) or
6 MARCH 2020
the 2-dimensional World Health
Organization measurements and corre-
late better with the clinical outcomes55.
In multiple myeloma, healing lesions
show a developing fatty halo within the
bone marrow around the lesion on
MRI56.
Surgical Planning
MRI is the most useful imaging modal-
ity for surgical planning4. In a study of
20 patients with osteosarcoma, Onikul
et al. found that abnormalities detected
on T1-weighted images correlated better
with the pathological findings than
did abnormalities detected on STIR
images57. On STIR images, the readers
overestimated tumor extent in 73% of
(neo-)adjuvant chemotherapy studies.
Specifically, they overestimated the size
(length) of the tumor on 29 of the 40
STIR images and on 13 of the 40 T1-
weighted images; in contrast, they un-
derestimated tumor length on 5 STIR
images and 11 T1-weighted images. The
differences between the measurements
performed at the pathological examina-
tion and those performed on the T1-
weighted images were not significant.
The measurements of tumor length on
either MRI pulse sequence did not
change significantly after chemother-
apy. The sensitivity of MRI for epiphy-
seal spread of the tumors was 100%, but
its specificity was poor. False-positive
measurements were made in 7 of 13
patients with abnormal signal intensity
that extended into the adjacent epiphy-
ses. The authors suggested that T1-
weighted longitudinal images obtained
before chemotherapy may provide for
early planning of surgical approaches to
osteosarcoma in children57. Iwasawa
et al. reported that microscopic tumor
extension was identified up to 3.5 cm
beyond the macroscopic tumor borders,
which had substantial implications on
surgical margins and management30.
Seeger et al. defined tumor
involvement of the adjacent joint by
the clear presence on imaging of an
intra-articular tumor mass, or by the
imaging finding of an intermediate-
signal-intensity tumor replacing the
hyperintensity of intrasynovial fat.
Intravenous contrast medium adminis-
tration differentiates between an intra-
articular tumor and a joint effusion31.
Schima et al. defined tumor involve-
ment of the adjacent joint as an en-
hancing tumor mass that extended into
the joint through the joint capsule, the
destroyed intra-articular cortex, or the
articular cartilage or along the cruciate
ligaments29. With respect to intra-
articular tumor invasion, the authors
reported a 100% sensitivity but a 63%
overall specificity on T1-weighted
images29. A drawback involved occur-
rence of tumor deep to the suprapatellar
pouch, which frequently was mis-
interpreted as being intra-articular29.
Although the number of patients with
joint involvement in their series was low,
the authors found tumor invasion of the
intercondylar region with extension into
the cruciate ligaments to be the most
common involvement of the knee
joint29. If the joint is invaded by the
tumor, through any route, an extra-
articular resection is required29.
Overall, the invasion of vessels by
primary bone tumors is uncommon33.
Feydy et al. showed on magnetic reso-
nance (MR) angiography that displace-
ment of the vessels without stenosis
was associated with a low risk of vessel
invasion; in contrast, the finding of ste-
nosis on MR angiography was sensitive
and specific for vascular invasion33.
Novel MRI Technologies
Novel MRI technologies have expanded
the use of MRI for tumor detection,
characterization, differential diagnosis,
and consistent assessment of response to
treatment27. Contrast-enhanced MRI is
a commonly used procedure to charac-
terize different types of lesions and to
detect all malignant lesions. Dynamic
contrast-enhanced MRI focuses on
contrast kinetics, with demands for
spatial resolution dependent on the
application. Contrast-enhanced MR
angiography allows the visualization of
vessels. Double-contrast administra-
tion (combined contrast-enhanced
MRI) uses 2 contrast agents with
· VOLUME 8, ISSUE 3 · e0077

complementary mechanisms. Intrave-
nous administration of contrast agents
allows the identification of areas of hy-
pervascularity. Different contrast agents
are currently available for use in clinical
practice. The most commonly used
MRI contrast agents are the paramag-
netic contrast agents; their strongest
effect is observed on T1-weighted
sequences, by increasing T1 signal
intensity in tissues in which they have
accumulated. Paramagnetic contrast
agents contain magnetic centers that
create magnetic fields approximately
1,000 times stronger than those of water
protons; magnetic centers interact with
water protons in exactly the same way as
the neighboring protons, but with much
stronger magnetic fields, therefore ex-
hibiting a much higher impact on
relaxation rates, particularly on T1-
weighted sequences. Contrast agents are
further classified by their changes in
relaxation times after injection. Positive
contrast agents shorten the T1 relaxa-
tion time, and the enhanced parts appear
bright on T1-weighted images. Negative
contrast agents produce predominantly
spin relaxation effects that result in
shorter T1 and T2 relaxation times, and
the enhanced parts appear darker on
T2-weighted images58,59.
Conventional MRI pulse
sequences are widely used and very use-
ful, but with the evolution of chemical
shift imaging, diffusion-weighted
imaging, perfusion imaging, and MR
spectroscopy, additional quantitative
metrics are currently available to expand
the role of MRI for the detection, char-
acterization, and reliable assessment of
the treatment response27. Distinguish-
ing patterns of enhancement based on
assessing the first-pass kinetics have been
associated with benign and malignant
musculoskeletal lesions60-62. In general,
higher slopes of arterial enhancement
and early rapid enhancement have
been associated with malignant tumors,
although the specificity of this pattern
has not been substantial27. Diffusion-
weighted MRI is based on changes in the
Brownian motion of water molecules
caused by tissue microstructure63-66.
MARCH 2020 · VOLUME 8, ISSUE 3 · e0077
The apparent diffusion coefficient
quantitatively measures the Brownian
movement, and provides useful quanti-
tative information on the cellularity
of a musculoskeletal lesion using a
nonenhanced technique63. In T2-
hyperintense bone tumors (unicameral
cysts, fibrous dysplasia, and chondro-
sarcoma), Hayashida et al. found that
quantitative diffusion-weighted imag-
ing with apparent diffusion coefficient
maps did not differentiate malignant
tumors from benign tumors; however,
they observed that unicameral cysts had
higher mean apparent diffusion coeffi-
cient values than fibrous dysplasia and
chondrosarcoma64. Yakushiji et al. re-
ported that minimum apparent diffu-
sion coefficient values could be useful to
discriminate between chondroblastic
osteosarcoma and chondrosarcoma
despite the similarities in histological
features and the chondroid-type matrix
enhancement pattern65.
Quantitative perfusion parameters
are correlated with vessel permeability,
which, in turn, is associated with tumor
aggressiveness67. However, Leplat et al.
reported that the quantitative perfusion
in 3-T MRI had fair sensitivity and poor
specificity for differentiation between
benign and malignant musculoskeletal
tumors68. Proton MR spectroscopy
(1H-MRS) can detect the presence of
choline compounds (trimethylamine)
that are related primarily to tumor
mitotic rates and secondarily to tumor
aggressiveness27. In a meta-analysis
involving 122 bone and soft-tissue
tumors, qualitative 1H-MRS on 1.5-T
scanners showed an 88% sensitivity and
a 68% specificity for the differentiation
of benign from malignant tumors69.
However, with qualitative 1H-MRS on a
3-T scanner, it was not possible to dif-
ferentiate benign from malignant bone
tumors regardless of the application of
quality criteria (sensitivity was 50.0%
and specificity was 61.5%)70.
Bone Scintigraphy
Bone scintigraphy identifies areas of
increased bone turnover with a higher
sensitivity than radiographs because
I m a g i n g A n a l y s e s o f B o n e Tu m o r s |
approximately 50% of bone must be
gone for an osteolytic lesion to become
visible on radiographs. It is typically
performed with technetium-99m
(99mTc) methylene diphosphonate
(MDP). Bone scintigraphy is not indi-
cated at the initial workup of a patient
with a known primary osseous tumor; it
is best performed to assess for the pres-
ence and extent of metastatic bone dis-
ease in patients with a known primary
tumor71,72. In general, multiple mye-
loma does not have osteoblastic activity;
therefore, it is typically negative on a
99m
Tc bone scan21.
Traditionally, a thallium-201 bone
scan has been used to evaluate myocar-
dial perfusion; subsequently, it was used
for the differential diagnosis of benign
and malignant bone tumors because of
its active uptake mechanism by sodium-
potassium adenosine triphosphatase
(Na1/K1-ATPase)73. The radiographic
differential diagnosis of giant cell tumor
of bone is challenging because of the risk
of misdiagnosis of giant cell tumors of
bone as malignant lesions such as atyp-
ically presenting osteosarcomas74. Keller
et al. reported that the early-phase
tumor-to-background contrast was
increased in giant cell tumor of bone
compared with atypical osteosarcoma
(p 5 0.070)74. The delayed-phase
tumor-to-background was increased in
giant cell tumor of bone compared with
atypical osteosarcoma (p 5 0.020). The
median washout rate in giant cell tumor
of bone was not significantly decreased.
The cutoff value for the early-phase
tumor-to-background contrast showed
an 80% sensitivity and a 47.8% speci-
ficity, and the cutoff value for the
delayed-phase tumor-to-background
contrast showed an 80% sensitivity and
a 52.2% specificity. The authors sug-
gested that the intense thallium-201
uptake of giant cell tumor of bone can
facilitate the differential diagnosis of
giant cell tumor of bone and atypically
presenting osteosarcoma74.
18
F-FDG PET-CT
FDG uptake alone is not appropriate
to characterize primary bone tumors75.
7
 | I m a g i n g A n a l y s e s o f B o n e Tu m o r s
Despite their generally benign nature,
high FDG avidity is observed in chon-
droblastoma, osteoblastoma, osteoid
osteoma, Langerhans cell histiocytosis,
chondromyxoid fibroma, brown tumor,
fibrous dysplasia, histiocytic fibroma
(fibroxanthoma, nonossifying fibroma),
desmoplastic fibroma, and aneurysmal
bone cyst75,76. Most highly avid benign
bone tumors contain substantial num-
bers of histiocytic or giant cells77. Some
malignant bone tumors may show a
confusing paucity of FDG uptake. In a
study, low-grade osteosarcoma and
Ewing sarcoma had a low FDG avidity
that was confused with benign tumors78
such as osteochondroma, enchon-
droma, hemangioma, and intraosseous
lipoma75-77. The comparison between
tumors of similar histological origin such
as cartilaginous tumors is interesting.
Lee et al. reported that the mean maxi-
mal cumulative standardized uptake
values (SUV) (and standard deviation)
were 1.147 6 0.751 for benign carti-
laginous tumors, 0.898 6 0.908 for
grade-I chondrosarcomas, and 6.903 6
5.581 for grade-II and III chondrosar-
comas79. The values were not signifi-
cantly different between the benign
cartilaginous tumors and the grade-I
chondrosarcomas (p . 0.05). However,
the values were significantly different
between the low-grade chondrosar-
comas (benign and grade-I) and the
grade-II and III chondrosarcomas
(p 5 0.009)79. Another study suggested
that whole-body FDG PET-CT is an
important imaging addition to conven-
tional imaging studies to evaluate
possible malignant degeneration of
osteochondromas80.
The default window setting on
PET-CT workstations is soft-tissue
windows, which may overemphasize
tumor margins and may spuriously
make cortical or trabecular bone appear
intact. Costelloe et al. compared bone
with soft-tissue windows in a study of
64 malignant tumors and 34 benign
tumors75. The specificity of CT in bone
windows was significantly higher com-
pared with PET-CT only (90% com-
pared with 75%; p 5 0.0005), but the
8 MARCH 2020
specificity of CT in soft-tissue windows
was not (96% compared with 90%;
p 5 0.0759). Bone windows may show
the osteolysis that is obscured by the soft-
tissue window setting and provide their
higher specificity to distinguish between
benign and malignant primary bone
tumors; therefore, bone windows are sug-
gested when viewing FDG PET-CT75.
The cumulative SUV-volume
histogram (CSH) is a novel modality to
characterize heterogeneity in intra-
tumoral tracer uptake. The heteroge-
neity index (area under the curve-CSH)
has a higher diagnostic accuracy than
SUV analysis to differentiate between
primary benign and malignant mus-
culoskeletal tumors, although it
does not obviate histological analysis
importantly81.
Directing Biopsy
Kasalak et al. reported that PET-CT
may replace non-guided bone marrow
biopsy of the posterior iliac crest in
Ewing sarcoma, it may be used to screen
for metastases in the bone marrow, and,
if positive, subsequent CT-guided bone
biopsy may be performed for histologi-
cal confirmation82. Cesari et al. reported
on 504 patients with Ewing sarcoma;
27% had metastases at diagnosis, and
the rest had localized disease83; 2.4%
had a positive bone marrow biopsy, and
only 1 patient with Ewing sarcoma of
the foot had bone marrow involvement
without any imaging findings. They
suggested reconsidering the role of bone
marrow biopsy in the initial staging of
patients with Ewing sarcoma without
any evidence of metastases on imag-
ing83. In metastatic bone disease, the
assessment of the bone marrow is useful
to identify patients at very high risk who
could benefit from different treatment
strategies83.
Response to Chemotherapy
A major advantage of PET-CT is early
identification of poor responders to
chemotherapy. This may allow neo-
adjuvant chemotherapy to be modified
or extended and to shorten the delay
associated with a surgical procedure and
the histopathological analysis of the
tumor specimen. Bone tumors usually
metabolize glucose at an increased rate;
therefore, changes in FDG-PET imag-
ing can be used to grade and charac-
terize the biological aggressiveness of
the tumors and to predict the histo-
logical response after neoadjuvant
chemotherapy84-86.
The maximum tumor SUV widely
describes tumor activity before and after
chemotherapy51; a cutoff point of 2.5 for
an SUV after chemotherapy has been
reported between good and poor FDG-
PET bone sarcoma responders87,88.
However, studies have shown a different
relationship of FDG-PET uptake with
prognosis between osteosarcoma and
Ewing sarcoma. Denecke et al. reported
a significant relationship between FDG-
PET uptake and tumor necrosis in
osteosarcoma but not in Ewing sar-
coma89. Gaston et al. observed a maxi-
mum SUV of ,2.5 after treatment to be
predictive of tumor necrosis in osteo-
sarcoma but not in Ewing sarcoma90.
They also found that a 50% decrease in
metabolic tumor volume was predictive
of tumor necrosis in osteosarcoma,
whereas a 90% reduction in metabolic
tumor volume was necessary for signifi-
cance in Ewing sarcoma90.
The use of FDG PET-CT for
evaluation of the chemotherapy re-
sponse in 18F-FDG-avid subtypes of
lymphoma is encouraged; however, its
use as a routine surveillance study after
remission is not recommended20,91.
FDG PET-CT has high sensitivity and
specificity for multiple myeloma lesions
and are especially good for demonstrat-
ing extramedullary disease92. FDG
PET-CT can be used to monitor for
response to treatment of these patients
because the 18F-FDG uptake of bone
lesions is expected to decrease with suc-
cessful treatment93.
Evaluation of Outcome
PET-CT was compared with conven-
tional imaging (CT, MRI, ultrasonog-
raphy, and bone scintigraphy) in a study
of 86 scans (314 tumors) in children
with metastatic osteosarcoma and
· VOLUME 8, ISSUE 3 · e0077

Ewing sarcoma; PET-CT showed a
higher sensitivity (98%) and specificity
(97%) compared with conventional
imaging (sensitivity of 83% and speci-
ficity of 78%) for the detection of distant
metastases but not for the detection of
pulmonary nodules94. In contrast, PET-
CT showed a higher specificity (96%
compared with 87%) but lower sensi-
tivity (80% compared with 93%) com-
pared with conventional imaging for the
detection of pulmonary nodules94.
For the detection of bone metas-
tases in patients with Ewing sarcoma,
PET-CT had a sensitivity of 100%, a
specificity of 96%, and a diagnostic
accuracy of 97%, and bone scintigraphy
had a sensitivity of 68%, a specificity of
87%, and a diagnostic accuracy of 82%.
None of the bone metastases from
osteosarcoma were detected by PET-
CT, but all of them were detected by
bone scintigraphy. Therefore, the sen-
sitivity, specificity, and accuracy of
PET-CT are superior to those of bone
scintigraphy for the detection of bone
metastases from Ewing sarcoma but not
from osteosarcoma95. Therefore, it is
recommended to perform PET-CT
imaging prior to biopsy and whole-body
imaging from the skull to the toes96.
Angelini et al. reported that PET-
CT has a sensitivity of 96% and a spec-
ificity of 100% for osteosarcoma local
recurrence and a sensitivity of 80% and a
specificity of 100% for lung recurrence
detection97. Intermittent imaging
follow-up for 10 years is necessary for
patients with primary and metastatic
bone disease96.
Novel PET Imaging Technologies
PET-MRI is in its infancy, without
current specific clinical applications. It is
expected that PET-MRI could be more
valuable than PET-CT for situations in
which MRI is superior to CT imaging,
such as for brain and soft-tissue lesions.
Whole-body PET-MRI with concur-
rent diagnostic MRI may allow for
Tumor, Node, Metastasis (TNM)
staging in a single session; patients’
convenience and financial savings; and
decreased radiation exposure98. Addi-
MARCH 2020 · VOLUME 8, ISSUE 3 · e0077
tionally, the PET component can direct
biopsies; therefore, it can provide for
complete staging and grading, with
subsequent impact on treatment selec-
tion and outcome for the patients98.
Conclusions
Radiographs should be considered the
mainstay in the diagnostic approach for
bone tumors because they provide the
most useful details about the location,
shape and size or volume, and mor-
phology of the tumors, including
periosteal reaction and matrix minerali-
zation. Knowledge and appropriate
interpretation of the specific bone tumor
radiographic findings may provide for
the correct diagnosis in .80% of cases.
Advanced imaging modalities are very
useful for surgical planning. CT is
superior to radiographs and MRI for the
detection and characterization of matrix
mineralization, cortical involvement,
periosteal reaction, and pathological
fracture and for directing biopsy. MRI
accurately determines the tumor’s
intraosseous extent, joint involvement,
and vessel invasion. MRI and FDG-
PET-CT can be used to evaluate the
response to chemotherapy for osteosar-
coma, Ewing sarcoma, and hematolog-
ical malignancies.
Costantino Errani, MD1,
Shinji Tsukamoto, MD2,
Andreas F. Mavrogenis, MD3
1Department of Orthopaedic Oncology,
IRCCS Istituto Ortopedico Rizzoli,
Bologna, Italy
2Department of Orthopaedic Surgery,
Nara Medical University, Nara, Japan
3First Department of Orthopaedics,
National and Kapodistrian University of
Athens, School of Medicine, Athens,
Greece
Email address for A.F. Mavrogenis:
afm@otenet.gr
ORCID iD for C. Errani:
0000-0002-4504-2867
ORCID iD for S. Tsukamoto:
0000-0002-8419-2008
ORCID iD for A.F. Mavrogenis:
0000-0003-0807-0719
I m a g i n g A n a l y s e s o f B o n e Tu m o r s |
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