Extraskeletal Ewing's Sarcoma:
Results of Combined Modality Treatment
By Timothy J. Kinsella, Timothy J. Triche, Paul S. Dickman,
Jose Costa, Joel E. Tepper, and Daniel Glaubiger
Eleven patients with extraskeletal Ewing's sarcoma
(EES) were treated with combined modality therapy
at the National Cancer Institute. The diagnosis of EES
was reserved for lesions that were identical to Ewing's
sarcoma of bone by light and electron microscopy.
Diagnostic work-up to rule out a skeletal primary included bone scan, localized views of adjacent bone,
and bone tomography. Seven patients presented with
an extremity primary and four patients had a truncal
primary. No patients had evidence of metastases at
presentation. Patients were treated with combined
modality therapy consisting of high-dose local irradiation and vincristine, actinomycin D, and cyclophos-
A
SOFT TISSUE TUMOR indistinguishable
from Ewing's sarcoma of bone by light microscopy was first described by Tefft et al in five
young children, all of whom presented with signs
and symptoms of epidural cord compression and
a paravertebral soft tissue mass.' Later, Angervall and Enzinger reported a larger series of these
soft tissue tumors in adolescents and young
adults. 2 In their retrospective series of 39 patients
whose pathology was referred to the Armed
Forces Institute of Pathology (AFIP) between
1957-1969, there also appeared to be a predilection for these tumors to arise in the paravertebral
soft tissues as well as the soft tissues of the lower
extremity. The prognosis for these patients was
poor, with approximately 75% of the patients
dying of metastatic disease to lung or bone, often
within one year of diagnosis. However, in these
series there was marked variation in the staging
and treatment and no analysis of local control.
Subsequently, several reports have confirmed
the histologic findings by light microscopy of
the so-called extraskeletal Ewing's sarcoma
(EES).Ž" More recently, electron microscopy
has shown that these round cells have no discernible cytoskeleton, intracellular collagen, nor collagenous intercellular matrix," unlike more
common soft tissue sarcomas. These findings by
electron microscopy help to distinguish EES
from primitive or undifferentiated rhabdomyosarcoma, neuroblastoma, and lymphoma.
The prognosis for EES patients appears markJournal of Clinical Oncology, Vol. 1, No. 8 (August) 1983
phamide chemotherapy following a biopsy or local
excision. No attempt was made to excise widely the
primary tumor mass. Gross tumors generally responded rapidly to the combined modality treatment. Of 11
patients, seven (64%) remain disease free, with a
follow-up of three to seven years from completion of
therapy. Long-term local control was established in
nine of 11 patients (82%). Autopsy findings on two
patients with local failure showed no tumor involvement of adjacent bone. Attempts at gross resections
by radical surgical procedures do not routinely appear
to be necessary in light of the high local control rates
with high-dose irradiation.
edly improved in the era of combined modality
therapy. In a retrospective review of 26 EES
patients treated by the multi-institutional Intergroup Rhabdomyosarcoma Study (IRS), 20 patients achieved a complete response, with 17 patients remaining disease free with a median
follow-up of two years (range, 10-110 weeks). 8
A more recent analysis by the IRS of extremity
(15 patients) and truncal (six patients) EES patients revealed local control of 76% (16 of 21)
and disease-free survival of 71% (15 of 21) with
follow-up of three to seven years. 9,10
In a five-year period from 1974-1978, 11 patients with various soft tissue tumors subsequently diagnosed as EES were treated at the National
Cancer Institute (NCI). Patients were included
for study only after careful review of light and
electron microscopic findings employing specific criteria for the identification of EES. 5 These
patients were staged and treated with combined
modality therapy according to protocol studies
designed for Ewing's sarcoma of bone." This
From the Radiation Oncology and Pediatric Oncology
Branches of the Laboratory of Pathology, Division of Cancer
Treatment, National Cancer Institute, Bethesda, Md.
Submitted December 29, 1982; accepted April 26, 1983.
Address reprint requests to Timothy J. Kinsella, MD, Radiation Oncology Branch, Division of Cancer Treatment, National Cancer Institute, Building 10, Room B3B38, NationalInstitutes of Health, Bethesda, MD 20205.
C 1983 by American Society of Clinical Oncology.
0732-183X/83/0108-0006$1.00/0
489
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KINSELLA ET AL
490
paper is an analysis of the clinical course of these
11 EES patients treated with high-dose irradiation and combination chemotherapy.
METHODS AND MATERIALS
The clinical records, diagnostic studies, and pathologic material were reviewed for all patients with the diagnosis of EES seen
at the NCI between January 1974 and December 1978. Patients
who developed cortical bone changes adjacent to the soft tissue
tumor during or shortly after therapy were excluded from
analysis.
During this five-year period, approximately 75 patients with
Ewing's sarcoma and 150 patients with soft tissue sarcoma were
referred to the NCI. The routine diagnostic work-up included a
chest roentgenogram, lung tomograms (also chest computerized
tomographic scans after 1977), bone scan, bone marrow biopsy,
and roentgenograms of any suspicious bone adjacent to the soft
tissue tumor mass. Occasionally bone tomograms also were
done to rule out an osseous primary. Fifteen patients were initially diagnosed as having EES and are the cohort group for this
retrospective review.
The pathologic diagnosis was determined from formalinfixed, paraffin-embedded tissue stained with hematoxylin and
eosin (H&E) and with the periodic acid-Schiff stain (PAS) with
and without diastase digestion. In the six more recent cases as
well as two additional cases in the cohort that were excluded
from the final study group, electron microscopy was also done.
Treatment consisted of combined modality therapy by two
protocol studies designed for Ewing's sarcoma of bone. II For
patients with a soft tissue primary of an extremity, treatment
involved local irradiation to the mass and its entire muscle group
of origin (5,000 rads at 180-200 rad fractions over five to six
weeks) followed by prophylactic lung irradiation (1,500 rads at
150-rad fractions over two weeks) and concomitant chemothera2
py. Chemotherapy consisted of vincristine, 2.0 mg/im ; actino2
mycin D, 2.0 mg/m , and cyclophosphamide, 1,200 mg/m 2;
given on day I of a 28-day cycle and repeated for four cycles
(VAC).
For a soft tissue primary of the trunk, the combined modality
therapy was more intensive, based on the poor prognosis for
3
central axis Ewing's sarcoma of bone.12-1 Induction therapy
consisted of local irradiation with a generous margin (5 cm)
about the primary to 5,000 rads at 180-200 rad fractions with a
cone down boost for an additional 500-1,000 rads. Patients also
received two to three cycles (every four weeks) of VAC chemotherapy. After a bone marrow storage procedure under general
anesthesia, patients received low-dose total-body irradiation
(150 rads at 15-rad fractions twice weekly over five weeks)
followed by an intensive three-day drug cycle (vincristine, 2.0
mg/m 2 on day 1; doxorubicin, 35 mg/m 2 on days I and 2;
2
cyclophosphamide, 1,200 mg/m on days 1 and 2; and dacarba2
zine, 250 mg/m on days 1, 2, and 3). Autologous bone marrow
was reinfused following this intensive cycle. After hematologic
recovery, maintenance therapy with vincristine, doxorubicin,
cyclophosphamide, and dacarbazine was given to truncal patients on a monthly basis for 12 cycles as tolerated.
RESULTS
Fifteen patients were initially diagnosed as
having EES after referral and work-up at the NCI
between January 1974 and December 1978. Four
patients were excluded following review of the
clinical and pathologic material; two being reclassified as having primitive soft tissue sarcomas and the other two as having Ewing's sarcoma of bone. Of the 11 remaining patients, there
were six male and five female patients. The patients' ages ranged from 11 to 31 years with a
mean age of 19 years. Seven patients presented
with a soft tissue primary in an extremity and
four patients had a soft tissue primary involving
the trunk.
The light and electron microscopic material on
six of these 11 patients, as well as 23 other NCI
patients, has recently been reviewed.' The H&E
and PAS slides were compared in a blinded fashion with similar pathologic material from the 23
other NCI patients including patients with Ewing's sarcoma of bone, alveolar rhabdomyosarcoma, and undifferentiated soft tissue sarcoma.
In each case, the light microscopic material from
the EES patients was indistinguishable from Ewing's sarcoma of bone (Fig. lA and B). Moreover, we were able to distinguish the EES material from patients with all forms of alveolar
rhabdomyosarcoma (Fig. 1D) and undifferentiated soft tissue sarcoma (Fig. IC) by the criteria
previously mentioned. Although electron micrographs were available for only eight patients in
the cohort and six EES patients, the characteristic features of Ewing's sarcoma of bone (Fig.
2A) were noted in all six cases of EES (Fig. 2B)
in a blinded review of approximately 30 cases of
Ewing's sarcoma of bone and primitive soft tissue sarcomas similar to the light microscopic
review (Fig. 2C and D).
The clinical features of the EES patients were
presented in Table 1. The patients have been
grouped according to the location of the primary
soft tissue tumor, i.e., extremity or truncal location. The extremity group is equally divided between upper and lower extremity primaries. One
patient (no. 6) presented with a left forearm mass
associated with a large axillary nodal mass of
similar histology. There were no other cases of
nodal metastases at presentation or at relapse.
There was considerable variation in the size of
the primary tumor in both extremity and truncal
patients. In general, patients had a biopsy or local excision of the tumor mass prior to referral. A
biopsy was not performed on the adjacent bone.
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EXTRASKELETAL EWING'S SARCOMA
With large tumors, the surgical margins were
grossly positive. With the exception of a repeat
biopsy for diagnostic purposes, no further surgery to the soft tissue primary was carried out at
491
the NCI prior to initiation of combined modality
therapy as outlined.
Of the 11 patients, seven (64%) remain disease free with a follow-up of 42-79 months from
Fig. 1. Comparison of light micrographs of various sarcomas. (A) Ewing's sarcoma of bone. (B) EES. (C) Soft tissue
sarcoma. (D) Primitive rhabdomyosarcoma. The appearance of each of these tumors is remarkably similar. Nuclear
size and chromatin pattern is variable, but does not correlate with a specific tumor type. Any of these tumors may
show variation in these parameters. Very little if any matrix is discernible in any of these tumors. H&E stain. x
400.
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492
KINSELLA ET AL
Fig. 2. Electron microscopic appearance of each of the tumors in Fig. 1. The tumors are quite dissimilar, especially
compared to classic Ewing's sarcoma of bone. (A) Ewing's sarcoma of bone has no matrix, the cells usually contain
pools of cytoplasmic glycogen (g), and no cytoplasmic filaments are detectable. (B) EES likewise has no matrix or
cytoplasmic filaments, but glycogen is similar in amount and cellular disposition. (C) Unclassified soft tissue
sarcomas, like primitive rhabdomyosarcoma, display abundant collagen matrix (coil) and tumor cells are frequently elongated or "spindle cell," as here. Myofilaments of any kind are, however, absent. Glycogen is less
frequent and is not seen here. (D) Primitive rhabdomyosarcoma is superficially similar to Ewing's sarcoma of bone
and EES, with a similar or even greater amount of glycogen in some cases, but is different in several important
respects: collagenous matrix is invariably present about individual cells, the nucleus is often eccentric, and the
abundant cytoplasm contains tangled masses of fine filaments (f); these are precursors of myoblast filaments and
are biochemically related to rhabdomyosarcoma, but not Ewing's sarcoma of bone or EES.
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EXTRASKELETAL EWING'S SARCOMA
Table 1.
Group and
Patient No.
Clinical Characteristics of 11 Patients With Extraskeletal Ewing's Sarcoma
Age
(yr)
Sex
Extremity
1
2
3
4
5
6
16
25
15
18
20
20
M
M
F
M
M
M
7
32
M
14
F
Epidural mass
at L4-5
9
16
F
10
21
F
11
11
F
Retroperitoneum and pelvis
R lateral
chest wall
Posterior neck
mass overlying
C6
Truncal
8
493
Primary
Location*
R forearm
L calf
L thigh
L axilla
L thigh
L forearm with
axillary mass
R calf
Size (cm)
4
4
8
4
10
2
9
8
X
x
x
x
x
x
x
x
4
6
6
3
15
3 &
8
10
3 x 2
Surgery
Local excision
Incisional biopsy
Local excision
Local excision
Incisional biopsy
Local excision
& biopsy
Incisional biopsy
3 x 3
Excision of mass
with dura left
intact
Laparotomy with
biopsy
Local excision
3 x 4
Local excision
20 x 15
Pattern of Failure (mo)
Local Bone
Lung
Statust
(mo)
-
-
+ (16)
-
NED
DOD
NED
NED
NED
NED
-
-
+ (24)
DOD (28)
-
-
(72)
(39)
(66)
(42)
(79)
(74)
NED (48)
+
+
+ (0)
DOD (16)
+
+
+ (10)
DOD (14)
-
-
-
NED (46)
*L, left; R, right.
tNED, no evidence of disease; DOD, dead of disease.
the initiation of treatment (Table 1). Of seven
patients with an extremity primary, two failed in
the lung at 16 and 24 months and later died of
progressive disease. Of the four patients with a
truncal primary, one patient (no. 9) showed evidence of distant metastases in lung and bone during induction therapy and later failed locally.
One other patient failed locally and distantly in a
synchronous fashion while receiving maintenance therapy.
Clinical local control was established in nine
of 11 patients (82%). In retrospect, the radiation
portals were inadequate in one patient with local
failure (no. 9). An autopsy on another patient
(no. 2) who died with widely metastatic disease
without clinical evidence of local failure,
showed a few tumor cells surrounded by extensive fibrosis at the primary site in the area of
high-dose irradiation. There was no evidence of
adjacent bone involvement in this patient nor in
two other patients who had clinical evidence of
local failure prior to autopsy.
DISCUSSION
EES is an uncommon yet distinct clinicopathologic entity that should be considered in the
differential diagnosis of a soft tissue tumor occurring in adolescents and young adults. The
major differential diagnoses include Ewing's sarcoma of bone with extensive soft tissue extension and an inapparent intraosseous component,
undifferentiated or primitive soft tissue sarcoma (including rhabdomyosarcoma), metastatic neuroblastoma, and, rarely, other tumors,
such as peripheral neuroepithelioma, mesenchymal chondrosarcoma of soft tissue, hemangiopericytoma, synoviosarcoma, and metastatic oat
cell (small cell) carcinoma of the lung.
The frequency of EES is difficult to determine. In a five-year period during which our
series of 11 patients was generated, approximately 75 patients with Ewing's sarcoma of bone
were referred to the NCI. Of 314 soft tissue tumors entered on the IRS protocols from 1972 to
1976, 26 patients were diagnosed with EES (i.e.,
special types I and 2).8 As in our series, the
typical patient is an adolescent or young adult
with a soft tissue tumor, most commonly involving an extremity. In the less common truncal
primary, there appears to be a predilection for
involvement of the paravertebral soft tissues.
The histologic diagnosis of EES should be re-
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494
served for soft tissue tumors that are identical to
Ewing's sarcoma of bone by both light and electron microscopy. Typically, the light microscopy
reveals sheets of small round cells with a high
nuclear/cytoplasmic ratio. A PAS stain is usually
strongly positive with diastase sensitivity, indicating the presence of cytoplasmic glycogen. Extracellular collagen is sparse. The ultrastructural
description of EES has been less clearly defined.
The electron microscopic criteria used by some
authors fail to distinguish EES from the other
major differential diagnoses. 4 ,7,14 In a study of the
ultrastructural features of Ewing's sarcoma at the
NCI, it was found that these cells do not contain a
cytoskeleton, intracellular collagen, or collagenous intercellular matrix.5 ,6 These electron microscopic criteria should distinguish EES from
its major differential, primitive soft tissue sarcoma and solid areas of alveolar rhabdomyosarcoma. Other tumors, such as neuroblastoma and
lymphoma can be excluded by virtue of the absence of dense core granules (neuroblastoma) or
the presence of primitive cell-cell attachments
(lymphoma).
The combination of local high-dose radiation
therapy and VAC chemotherapy is effective in
the curative treatment of EES. In an attempt to
improve the systemic treatment in Ewing's sarcoma,15-17 prophylactic lung irradiation and lowdose total-body irradiation were added to the
treatment protocols for extremity and truncal patients, respectively. These systemic adjuvants
were added since the typical pattern of failure is
metastatic (usually lung), and it was argued that
micrometastatic disease may respond to relatively low doses of radiation.' 8 However, recent
analysis of these trials in patients with Ewing's
sarcoma of bone do not show any clear benefit to
these adjuvants over local irradiation and VAC
chemotherapy. 12.13.18.19
Overall, our results are quite similar to the IRS
reports" '• in that 65%-70% of the patients remain disease free with follow-up of three to seven years. Although the number of patients in
these two series is small, the prognosis of EES is
as good as or better than Ewing's sarcoma of
bone.'17 It should be noted, however, that the
histogenesis of EES is as unclear as that of
Ewing's sarcoma of bone; 20 a common cellular
origin is thus not established. In fact, EES may
be histogenetically more closely related to alveo-
KINSELLA ET AL
lar rhabdomyosarcoma, as suggested by Riopelle
and Theriault, who first described alveolar rhabdomyosarcoma,21 and more recently by one of
us.6 Despite this, the morphology, clinical
evolution, response to treatment, and ultimate
prognosis of EES more closely resembles Ewing's sarcoma of bone"• "5- than alveolar rhabdomyosarcoma. 9 10 The location of the primary
soft tissue tumor appears to be of major prognostic significance: patients with extremity lesions
fare much better than those with truncal lesions,
similar to Ewing's sarcoma of bone. 2 "13The
exact opposite is found in alveolar rhabdomyosarcoma, where extremity lesions indicate an especially poor prognosis.9'0
Although the chemotherapy for EES is quite
0
similar in our patients and those from the IRS,-•
the management of the primary tumor is substantially different. In our series, local control was
established in nine of 11 patients (82%), with one
local failure being attributed to inadequate radiation fields. Typically, patients had only a local
excision or an incisional biopsy prior to referral
and no further definitive surgery at the NCI. This
is in contrast to the surgical approach recommended by the IRS, where the basic surgical
strategy is an attempt at a wide local excision
followed by local irradiation only if the margins
are positive for tumor, if the local lymph nodes
are positive, or if gross residual tumor remains.
Only one of the 21 EES patients undergoing surgery in the IRS reports had an adequate wide
local excision not requiring postoperative irradiation. 8s-l In comparing the local control and
disease-free survival data from the two series,
wide local excision does not routinely appear to
be necessary and may compromise the functional
results when combined with high-dose local irradiation. Thus, the nonsurgical treatment employed at the NCI appears to be as effective in
terms of local control and ultimate survival as the
surgical intervention combined with radiation
and chemotherapy employed by the IRS.
In summary, EES appears to be a distinct clinicopathologic entity that can be distinguished
from the other common round cell tumors arising
in soft tissues of young adults. The light and
electron microscopic features appear to be identical to the more common Ewing's sarcoma of
bone. The natural history of EES also appears to
be similar to Ewing's sarcoma of bone. With
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EXTRASKELETAL EWING'S SARCOMA
combined modality therapy including high-dose
irradiation and combination chemotherapy, the
majority of patients are potentially curable.
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