Index terms:

Bone neoplasms
diagnosis
Radiology of Ewing’s sarcoma:
Ewing’s sarcoma
Intergroup Ewing s Sarcoma Study
(lESS)

William R. Remus, M.D.

Louis A. Gilula, M.D.

lESS Committee
z
I-.

0p4p

0fth Ae

lESS Committee

Mark Nesbit, M.D, Chairman

Fred Askin, M.D. Edmund Gehan, Ph.D. Carlos A. Perez, M.D.

Omer Burgert, Jr., M.D. John Kissane, M.D. Douglas Pritchard, M.D.
THIS EXHIBIT, A SELECTION OF THE SKEL-
grAL AND PEDIATRIC RADIOLOGY PANELS, Ayten Cangir, M.D. John T. Makley, M.D. Melvin Tefft, M.D.
WAS DISPLAYED AT THE 69TH SCIENTIFIC
Richard Evans, M.D. James B. Neff, M.D. Patrick R.M. Thomas, M.D.
ASSEMBLY AND ANNUAL MEETING OF THE
RADIOLOGICAL SOCIETY OF NORTH Mary Foulkes, Ph.D. Theresa J. Vietti, M.D.
AMERICA, NOVEMBER 13-18, 1983, CHICAGO,
ILLINOIS.

Introduction

In the Intergroup Ewing’s Sarcoma Study 7299 protocol, we evaluated patients

From the Washington University who presented with biopsy proved Ewing’s sarcoma and who, at the time of pre-
School of Medicine, Mallinckrodt In-
sentation, had no evidence of metastatic disease. Patients were added to this study
stitute of Radiology, St. Louis, Mis-
group between 1972 and 1978 and were randomly assigned to one of three treatment
souri.
regimens that have been described elsewhere (1 2, 3). We reviewed
, the radiographs
Supported by National Cancer In-
of the entire group of 373 patients who were entered into the study, evaluating the
stitute Grant CA-25474.
Address reprint requests to W. R. principal “plain film” radiographic manifestations of the lesion that were recorded
Remus, M.D., Mallinckrodt Institute of in prebiopsy or peribiopsy (within two weeks of biopsy) radiographs. In this paper,
Radiology, 510 South Kingshighway we present the results of this “plain film” radiographic evaluation and a description
Boulevard, St. Louis, MO 63110. of the diverse radiographic features of Ewing’s sarcoma.

Volume 4, Number 6 November 1984 RadioGraphics 929

Ewing’s sarcoma Remus et al.

Data Analysis

Seventeen generic types of radiographic abnormality were identified. Not all

of these abnormalities, however, were judged to be applicable to all of the radio-
graphic examinations and, in some cases, the radiographs available to the reviewer
(LAG.) were not adequate to permit him to determine whether or not a particular
abnormality was present. Accordingly, subjective judgments were made with respect
to each type of abnormality during the review of each patient’s radiographs, con-
cerning whether or not the individual abnormality might be expected to be present,
and if so, whether or not the available radiographs were adequate to demonstrate
its presence.
The incidence of each specific type of finding was then calculated on the basis
of the number of cases in which it was seen, relative to the number evaluated for
it; i.e., the number in which the finding might have been present, and in which the
radiographs were adequate to demonstrate it if it were. Patients’ radiographs for
which a particular manifestation could not be judged to be definitely present or
absent were treated as unknown and excluded from tabulation.
The radiographic abnormalities were then divided into three categories de-
pending on their frequency of occurrence: common findings, occurring in more
than 30% of the cases evaluated for their presence; uncommon findings, occurring
in 10 to 30% of such cases; and rare findings, occurring in fewer than 10% of such
cases. These data are presented in Tables I, II and III. Because of the subjective nature
of the judgments on which these incidence data are based, the incidence of each
finding is also shown as a fraction of the total number of cases in the study group.
In no case, does this alter the category (common, uncommon or rare) to which the
finding was assigned.

Table I

Common (>30%) Roentgen FindIngs-lESS

%
#/# of Evaluated % of
Evaluated Studies Total Cases

Poor margination - approximately -

96’
Soft tissue involvement 205/255 80.4 55
(72 probable/
133 definite)
Permeativecomponent 270/355 76.1 72
Laminated periosteal reaction 198/350 56.6 53
Sclerotic component 1 14/287 39.7 30

. Derived as complement of “well marginated. (Table Ill)

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Remus et al. Ewing’s sarcoma

Table II
Uncommon (10-30% ) Roentgen Findings-lESS

of Evaluated % of
Evaluated Studies Total Cases

Spiculated periosteal reaction 87/314 27.7 23

Cortical thickening 58/274 21.2 16
Cortex violated 69/364 18.9 18
(28 probable/
41 definite)
Pure lytic component 62/333 18.6 16
Pathologic fracture 51/343 15.2 14
(18 probable/
33 definite)
Cystic component 43/357 12.0 12
Bone expansion 48/357 13.4 12
(16 probable/
32 definite)

Table Ill

Rare (<10% ) Roentgen Findings-lESS

%
#/# of Evaluated % of
Evaluated Studies Total Cases
Soft tissue calcification 30/346 8.7 8
Saucerization 15/244 6.1 4
Honeycombining 20/343 5.8 5
Well marginated 7/167 4.2 2
Vertebra plana 1/16 6.3 0.3

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Ewing’s sarcoma Remus et al.

Demographic Data

Demographic data were correlated on the patients in Table V

the lESS protocol at the Statistical Center for Pediatric In-
tergroup Studies. These data are consistent with those al- Demographics (lESS 7299)
ready published in the literature (Table IV). Our population
demonstrated a male to female ratio of 3:2 in agreement
with the male predominance of the disease reported in the
Sex: Male:Female 3:2
literature. The patients’ ages ranged from 6 months to 47
years. This range correlates well with that presented in the Age: <10 years old 30%
literature (Table IV). Caucasians accounted for 96% of the 11-15 years old 39%
affected patients, again consistent with previous reports (4, >l5yearsold 31%
5, 6). The demographic data from the lESS 7299 protocol Range: 6 months-47 years
are summarized in Table V.
Race: White: 95%
In the majority of our cases the lesions occurred in the
Black: 2%
pelvis or lower extremity (61.7%). There was a fairly even
Other: 3%
distribution of lesions among the pelvis (21%), the proximal
extremity bones (humerus and femur) taken as a group
Primary Site:
(31%), and distal extremity bones (radius, ulna, tibia, fibula
Pelvis 21%
and the bones of the hand and foot) taken as a group (27%).
Humerus/Femur 31%
Rib lesions accounted for 7% of the Ewing’s sarcomas in this
Distal Extremity 27%
series, while other locations; e.g., head and neck (scapular
Ribs 7%
and clavicular lesions) accounted for the remaining 14% of
Other 14%
cases.
The vast majority of our long bone lesions were meta- Location Within Long Bone:
diaphyseal (58.7%) or diaphyseal (35.4%). Only one epi- Epiphyseal 1
physeal lesion was identified. Eleven Ewing’s sarcomas were Metaphyseal 11
confined to the metaphysis. Metadiaphyseal 121
Diaphyseal 73

Table IV’4

Demographics (Literature)

Occurrence: 10% of all primary bone tumors

Sex: Male:Female 2:1
Age: Tumor of childhood and adolescence
Range 5 months-54 years
95% between 4 and 25 years of age
Race: Whites mainly/Blacks rarely
Genetics: Rare multiple cases in single family
Primary Site: About 70% in pelvic girdle and long tubular bones
About 50% in lower extremities
Time to Diagnosis: 6 months

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Remus et al. Ewing’s sarcoma

Common Manifestations

Figure 1 Figure 2
Typical Ewing’s sarcoma This tibial Sclerosis (diffuse increased opacity) Commonly an area
lesion exemplifies the common and of sclerosis is seen in the bone in or near the lesion. This has
well known appearance of Ewing’s been shown to be the result of reactive bone formation and
sarcoma. It is one of a metadia- osteoid deposition on foci of necrotic bone, presumably
physeal, medullary based, permea- resulting from tumor outgrowing its blood supply. Sclerosis
tive and poorly marginated lesion has also been observed following radiation therapy. ScIe-
with laminated periosteal reaction rosis differs from the less common appearance of cortical
and a soft tissue mass. Spiculated thickening with respect to the location of the osteoblastic
periosteal reaction is also evident in component. This, in the former, is not confined to the cor-
this lesion. This type of reaction oc- tex. Nevertheless, their appearances at times may be similar
curred less commonly in our patients (12).
than laminated periosteal reaction
and is discussed in Figure 4.

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Ewing’s sarcoma Remus et al.

Common Manifestations

..

Figure 3A Figure 3C

Figure 3B

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Remus et al. Ewing’s sarcoma

Uncommon Manifestations

Figure 3
Soft tissue Involvement (A) The
association of a soft tissue mass (ar-
rows) with Ewing’s sarcoma is well
known and one of the hallmarks of
the disease. It can often be detected
as a distortion of fascial planes on
plain radiographs. (B) Since the ad-
vent of computerized tomography,
direct visualization of the soft tissue
mass has been possible. Often the
mass appears larger than might have
been suspected on the basis of plain
radiographs alone. In this case, the
soft tissue involvement (arrowheads),
particularly that which is within the
pelvis at the level of the ischiorectal
fossa, would have been difficult to
image without computed tomogra-
phy. (C) Occasionally, a large soft
tissue mass can be detected by its
extrinsic effect on an adjacent bone.
In this image, the superior portion of
the fibular diaphysis (arrowheads) is
thinned by a Ewing’s sarcoma arising
from the tibia, as indicated by the
periosteal reaction along the lateral Figure 4
portion of the tibia. A similar finding Spiculated perlosteal reaction Although spiculated per-
can be seen in Figure 8A. iosteal reaction has been cited in the literature as occurring
in as many as 50% of cases ( 13), it was seen in 27.7% of our
evaluated patients either alone or, more commonly, in
combination with other types of periosteal reaction, par-
ticularly laminated periosteal reaction. In our experience,
this type of reaction typically occurs toward the center of
the tumor growing into the soft tissue mass.

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Ewing’s sarcoma Remus et al.

Uncommon Manifestations

Figure 5
Cortical thickening (A) Although Ewing’s sarcoma is
generally considered an aggressive, rapidly growing tumor,
areas of cortical thickening were observed in 21.2% of our
evaluated cases. We believe this phenomenon usually de-
velops over a prolonged period and results from maturation
of periosteal and endosteal reaction resulting in the depo-
sition of new bone along the periosteal and endosteal cor-
tical surfaces. In this case, cortical thickening is seen along
the medial femoral margin (arrowheads). (B) This is a
transverse CT section through the affected femur of the
same patient. In addition to the medial cortical thickening
(white arrow), there is also involvement of the medullary
cavity (black arrowhead).

Figure 5B

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Remus et al. Ewing’s sarcoma

Uncommon Manifestations

Figure 6
Cortical violation and pathologic fracture (A) Of our
evaluated cases, 1 5.2% demonstrated pathologic fractures
as is seen in this mid fibular lesion. (B) Actual destruction and
breakthrough of the cortex was definitely observed in 18.9%
of our evaluated cases. This number may be artifactually
low, however, because subtle areas of cortical violation may
have gone undetected on submitted films because of failure
to image the violated cortex in profile. The clavicular Ewing’s
sarcoma depicted here demonstrates gross cortical viola-
tion with expansion of the clavicle.

Figure 6A

Figure 6B

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Ewing’s sarcoma Remus et al.

Uncommon Manifestations

Figure 8A

Figure 7
Expansion 13.4% of evaluated cases in
the series
expansion.
appearance
demonstrated
In the case depicted
is consistent
new bone formation occurring
evidence
here, the
with periosteal
concurrently
of bone

j
I
with permeation and eventual destruction
of the endosteal cortical surface. With more
aggressive behavior, it can be understood
that cortical destruction instead of bone
expansion may occur.

Flgure8B

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Remus et al. Ewing’s sarcoma

Uncommon Manifestations

Figure 8C

Figure 8
Pure lytic and cystic lesions While 18.6% of our evaluated cases demonstrated
a pure lytic component, in relatively few was it the dominant finding. (A) This lytic
metatarsal lesion is also expanding the bone and a pathologic fracture involves its
midshaft (arrow). The concave margin of the second metatarsal (large arrowhead)
results from the extrinsic pressure effect of a soft tissue mass. Periosteal reaction
involves the diaphysis of the fourth metatarsal (small arrowheads). (B)This calcaneal
Ewing’s sarcoma has a lytic center with permeative borders along its posterior
margin (arrowheads) but has well defined borders anteriorly and inferiorly giving
a cystic appearance (arrows). (C) This proximal femoral lesion has a purely lytic
center with permeative borders (arrows) and some minimal periosteal reaction
(arrowheads).

Volume 4, Number 6 November 1984 RadioGraphics 939

Ewing’s sarcoma Remus et al.

Rare Manifestations

#{149}r#{149}

Flgure9A Figure9B

Figure 9
Margination (A) Anteroposterior view. (B) Lateral view. Seven patients (4.2%)
of our evaluated cases demonstrated discrete margination about their lesions in
at least one view. In these cases, the lesions tended to have an intracortical or
subperiosteal epicenter with a lytic central component. We believe that margination
implies a relatively slow rate of growth.

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Rare Manifestations

Figure 10
Saucerization 6.1% of the evaluated lESS 7299 patients
had cortical saucerization. These patients generally also
demonstrated central spiculated periosteal reaction, and
Codman’s triangles toward the borders of the lesion, tending
to accentuate the saucerized appearance. When the cortex
underlying the saucerized area shows no destruction, Ew-
ing’s sarcoma is highly suspect because of its unique ability
to spread through haversian canals without causing mac-
roscopic destruction. This phenomenon of saucerization
differs from the extrinsic pressure effect discussed in Figure
3C. Whereas, the former results from local destruction of
the periosteal surface of the primary bone involved by the
tumor and stimulation of surrounding periosteal reaction;
in the latter circumstance, an involved bone has been re-
modeled by pressure erosion from a soft tissue mass arising
from an adjacent bone involved by tumor.

Figure 11
Honeycombing (A) Anteroposterior view. (B) Lateral view.
While the lesions of 18.6% of our evaluated patients dem-
onstrated a lytic component, 5.8% of Ewing’s sarcoma le-
sions had evidence of honeycombing. As exemplified by this
distal phalangeal Ewing’s sarcoma, these lesions show cystic
lucent areas traversed by bone creating a compartmental-
ized effect. This lesion also has accompanying soft tissue
swelling and areas of cortical destruction (arrowheads). Figure hA Figure 11B

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Ewing’s sarcoma Remus et al.

Rare Manifestations

Figure 12
Soft tissue calcification Some calcification within the soft
tissues was seen in 8.7% of evaluated cases. Possible etiol-
ogies of this phenomenon might include a dystrophic pro-
cess as observed in the sclerotic bone of Ewing’s sarcomas,
or extension of periosteal new bone foci into the soft tissues.
We have at least one case in which dystrophic calcification
on necrotic tumor was proved histologically and several
other cases have been documented.

Figure 13
Vertebra plana A single case of vertebra plana was seen
among the 16 cases affecting the spine in the 7299 lESS
protocol. More recently, a second case had been identified
in the 7896 lESS protocol. Nevertheless, this remains a form
of pathologic fracture that may occasionally present as a
radiographic manifestation of Ewing’s sarcoma. This finding
presents a major radiologic differential problem: Ewing’s
sarcoma versus eosinophilic granuloma.

942 RadioGraphics November 1984 Volume 4, Number 6

Remus et al. Ewing’s sarcoma

Rare Manifestations

Figure 14A

Figure 14
No plain radiographic findings (A) Three of our patients
had no plain radiographic evidence of bone involvement. In
two of these, the lesion was judged to be truly extraosseous,
.% and the pathologist
ing’s sarcoma
was convinced
(14). In the third patient,
of the diagnosis
depicted
of Ew-
here, the
lesion was in fact intraosseous and yet no abnormality is
seen in the radiograph. (B) In this patient, a bone scan per-
formed because of persistent pain, demonstrates a focal
area of increased uptake in the proximal tibia. On biopsy, this
proved to be Ewing’s sarcoma. Larger numbers and per-
centages of cases of extraosseous Ewing’s sarcoma are
reported in other series. However, most of these cases in
the lESS studies were treated in Intergroup Rhabydomyo-
sarcoma studies and so were not available to us for fol-
lowup.

- - ---- --

Figure 14B

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Ewing’s sarcoma Remus et al.

Differential Diagnosis

The major differential diagnoses to be considered on the basis of plain radio-

graphic findings in Ewing’s sarcoma are osteomyelitis and osteosarcoma. Less
common differential diagnoses include metastatic disease, myeloproliferative dis-
orders and simple fracture. Reports exist of Ewing’s sarcoma having been confused
with other lesions including fibrous histiocytoma, eosinophilic granuloma, fibrous
dysplasia and osteoid osteoma.

Summary

The Intergroup Ewing’s Sarcoma Study 7299 patients Ewing’s sarcoma presents with a myriad of roentgen
represent a typical population of Ewing’s sarcoma patients appearances (8, 9). Although typically the lesion is medul-
compared with those reported in the literature with regard lary cavity based, metadiaphyseal in location and poorly
to age, race, sex and distribution of lesions (7). The typical marginated, with aggressive periosteal reaction and a large
patient may be described as caucasian, in the first or second associated soft tissue mass, many patients with Ewing’s
decade of life, and more likely male than female. The pa- sarcoma will have at least one atypical; i.e., uncommon or
tient’s tumor is most likely to arise in the pelvis or the long rare component to their lesion (27.2% in our series). The
bones of the lower extremity (61.7%), and if in the long recognition of atypical Ewing’s sarcoma is important be-
bones, it is most likely to be metadiaphyseal or diaphyseal cause it may make earlier diagnosis possible and, thus, may
in location (94. 1 %). Even so, Ewing’s sarcoma may affect contribute to improved survival for patients afflicted with
any bone primarily. this frequently deadly disease (10, 11).

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