UNDIFFERENTIATED ROUND-CELL SARCOMA OF T H E
ILIUM (EWING TUMOR) CONTAINING
HEMOPOIETIC ELEMENTS
N . W. ROOME, M.D., AND P. A. D E L A N E Y , Pu.D., M.D.
(Prom the Departments of Surgerg and Pathology of the Universily oJ Chicago)
The undifferentiated round-cell sarcomata of bone grouped
together by Ewing (I) in 1922 as "diffuse endothelioma" are considered an oncological entity by most authors. Considerable doubt
exists, however, as to the origin of the Ewing sarcoma. Ewing
and his supporters believe that it is derived from an endothelial cell
of the bone marrow, possibly the perivascular lymphatic endothelium, and now apply the name "endothelial myeloma'' with that
significance. Kolodny (2), Oberling (3), and others think that
these tumors may arise from the reticulum cells or the reticuloendothelium. Certain facts suggest a relation to the myelomata:
multiple tumors frequently appear early in the disease, there is
usually regression under radiotherapy, and the structure may
"verge on myelomau( Ewing, I). Connor (4) and Kolodny (2)
mention that in a small percentage of cases some myeloid and
plasma cells are t o be found in the tumor tissue, though neither
author describes the method of identification of these cells, nor
their relation to the neoplastic cells.
I n the case to be reported, there was a large primary tumor of
the ilium, with skeletal metastases almost completely replacing
the bone marrow, and little visceral involvement. These are
unusual features for a Ewing sarcoma, but other evidence leads t o
that diagnosis. Upon the application of special staining methods,
there was found scattered among the tumor cells an admixture of
differentiated cells, apparently members of the hemopoietic series;
and a proportion of the "undifferentiated" tumor cells seemed to
resemble the myeloid stem-cell, the hemocytoblast. The possible
significance of these findings will be discussed later in this paper.
CASE REPORT
R. C., a white male, aged nineteen years, entered the University of
Chicago Clinics Aug. 9, 1928, complaining of (1) pain in the lower extremities, especially the left, (2) a swelling in the region of the left ilium,
1 This work was done under a grant from the Douglas Smith Foundation for Medical
Research.
386
UNDIFFERENTIATED ROUND CELL SARCOMA
387
(3) loss of vision in the right eye, and (4) gradual loss of weight and
strength.
Two years before admission he began to have transient sharp pains
in the left hip region and down the back and outer side of the left leg,
which were worse a t night and gradually increased in severity. For the
past ten months he had had a dull ache in his back, and fleeting pains in
the right leg, back, shoulders, and face. Four months before admission
he had suddenly lost most of the vision in the right eye, following a severe
headache; and a little later he had developed a partial anesthesia of the
right side of the face, which slowly disappeared. During the past six
months he had gradually become pale, and had lost weight and strength.
Tonsillectomy was done six months before admission because of x-ray
findings of some disease of the left ilium. Three months before admission
a mass was first palpated in that region; two exploratory operations were
performed, leading to the diagnosis of osteomyelitis, though the wounds
healed per primam, and no relief was obtained. The left leg had been
weak for several months, and because of pain and general weakness the
pat,ient had been confined to bed since the operations.
Physical examination on admission disclosed a pale, weak, emaciated
young man, suffering considerable pain. The right eye protruded
slightly, and was nearly blind; the left eye showed a contraction of the
visual field. The left pupil was the larger; both pupils reacted to light.
There was a marked primary optic atrophy of the right eye; the other
cranial nerves were objectively normal. No nodules were palpable on
the skull, and the cervical lymph nodes were not enlarged. The lung
areas were normal, as was the heart except for a soft, non-transmitted,
systolic murmur at the apex. The abdomen was normal, except for a
fulness of the left lower quadrant, where there was a firm, non-tender
mass about the left ilium, filling out the iliac fossa, and laterally resulting
in a moderate swelling of the gluteal region. On rectal examination the
lower portion of this mass was palpable, filling out the left side of the
pelvis; the prostate and seminal vesicles were normal. There were healed
scars of operative incisions along the crest of the ilium, and just above
the inguinal ligament. The left inguinal lymph nodes were moderately
enlarged, firm, and slightly tender; nowhere else in the body were enlarged nodes detected. The muscles of the left leg were paretic, and motion of the hip joint was painful and limited, but there was no sensory
disturbance. Palpation of the entire skeleton revealed no other enlargements nor areas of tenderness. The reflexes were normal except for a
diminution of the left abdominal and left cremasteric responses.
The white blood count was 19,000; the red blood count was 3,000,000,
and the hemoglobin 60 per cent (Tallquist). The urine was repeatedly
normal; no Bence-Jones protein was discovered. Blood Wassermann and
Kahn tests were negative.
Roentgenograms disclosed an increased thickness and density of the
greater part of the left ilium and adjacent parts of the ischium and
pubis. There was evidence of new bone formation on both surfaces of
the ilium, appearing laminated on the outer surface, and more irregular
388
N. W. ROOME AND P. A. DELANEY
and fuzzy on the inner surface (Fig. 1). No other lesions could be found
at the first x-ray examination of the remainder of the pelvis, lumbar
spine and sacrum, both femurs, chest, and skull. A tentative diagnosis
of Ewing tumor of the ilium, with metastases in the region of the optic
chiasm, was made.
A series of 31 injections of Coley's toxin was given from Aug. 13 to
Oct. 20, 1928, in doses increasing from 0.01 C.C.to 1.2 c.c., with febrile
reactions after each, of 103" to 104.4' F. X-ray therapy was begun Aug.
30, 1928, a total of 600 Roentgen units being given, half anteriorly and
half posteriorly, centered on the left ilium; a shorter course was also given
over the right and left temporal regions, centered on the optic chiasm.
Following this therapy the patient felt better. He had less pain and more
function in the legs, and the mass in the pelvis decreased slightly in size.
The x-ray findings remained almost unchanged. The eyes gradually
UNDIFFERENTIATED ROUND CELL SARCOMA
389
became more prominent, and in October the patient complained of numbness of the left buccal mucous membrane.
On Nov. 4, 1928, a n oval tumor about 1.5 X 2.0 cm. was discovered on
the right clavicle approximately 3 cm. from its sternal end; a roentgenogram showed a t the corresponding point evidence of slight periosteal
new bone formation with irregular reduction of the bone density beneath.
A biopsy was done and a soft grayish tumor was found, which had eroded
the bone and projected beyond its surface. Microscopic examination
showed it t o be made up of masses of closely packed round cells, with oval
vesicular nuclei containing scattered finely granular chromatin, and
non-staining cytoplasm; there were occasional mitotic figures (Fig. 2).
The diagnosis of undifferentiated round-cell sarcoma (Ewing tumor) was
thus confirmed.
OF
FIG. 2. TISSUEOBTAINEDBY BIOPSY
THE
RIGHTCLAVICLE,
NOV.1928. X 835
X-ray studies in November and December showed small scattered
areas of reduced density in cortex and medulla of both humeri, femora,
tibiae and fibulae, and some periosteal new bone formation in the upper
thirds of the humeri; there were no changes in the bones of the forearm
and hand. There was irregular reduction of density of the sacrum and
right and left pubic and ischial bones. The appearance of the left ilium
was little altered. The humeri, right clavicle, and right pelvis were
given short courses of x-ray therapy. The red blood count, Nov. 7, was
2,800,000.
After December the condition became progressively worse; t,he mass
in the pelvis enlarged and there were a t times increasingly severe pains
throughout the body. I n January 1929 the patient suffered minor
accidental burns of the abdomen, chest, and hands, which healed slowly.
A differential white blood count on Jan. 25 showed 74 per cent polymorphonuclear leukocytes, 3 per cent large lymphocytes, and 23 per cent
small lymphocytes; no abnormal cells were described in the smears.
390
N. W. ROOME AND P. A. DELANEY
Edema of the feet and ankles appeared in February and progressed to an
extreme degree on the left side; in March the abdomen became distended,
and free fluid and rhles were found in the chest. I n April decline was even
more rapid; on April 9 the white blood count was 8,600, the red blood
count 1,260,000, and the hemoglobin 30 per cent. Palpable metastatic
nodules appeared on the skull. The patient became incontinent and
comatose, and died April 22, 1929. Throughout the illness the mouth
temperature had fluctuated irregularly between 98" and 101" F.
Necropsy Findings: Necropsy was done about two hol~rsafter death,
by Dr. H. G. Wells. The body was extremely emaciated; there was little
subcutaneous or omental fat. The mucous membranes, skin, muscles,
and viscera were very pale; the skeletal muscles were atrophic. There
was moderate edema of the lower extremities.
A small amount of clear watery fluid was found in the abdominal cavity
and there were a few fibrinous adhesions. The liver, gallbladder, stomach, esophagus, and bowel were grossly normal. I n about the middle
of the pancreas was a firm nodule 1.2 X 1.2 X 1.5 cm., creamy white,
and of brain-like texture on section. The spleen was somewhat enlarged,
weighing 200 gm.; externally it was purplish brown, with a few small
creamy white areas, the largest being 0.4 cm. in diameter and extending
0.3 cm. into the tissue. The cut surface of the spleen was reddish brown
and displayed no visible nodules. The adrenal glands were alike, and
their cortical lipoid substance appeared diminished.
The left ilium, pubis, and most of the ischium were surrounded by a
tumor mass (Fig. 3) which filled the pelvic cavity to the midline, was
1.0 to 4.0 cm. thick on the outer surface of the ilium, and extended from
the 4th lumbar vertebra above to the ischial tuberosity below. I t was
moderately firm, coarsely nodular, and covered by a pseudocapsule of
pelvic fascia on its mesial surface, and by the gluteal muscles laterally.
The iliac lymph nodes were enlarged as much as 2 X 2 X 1.5 cm. and on
section appeared markedly infiltrated by creamy-white, brain-like tissue;
the iliac vein was filled with a core of similar tissue. The head of the
femur was surrounded above by tumor and was only slightly movable;
on the anterior surface of the femur a t the level of the lesser trochanter
there was a subperiosteal tumor nodule 3 X 2 X 1 cm. Upon incision of
the mass sagittally, 6 cm, from the midline, the ilium was seen dense and
thickened, varying from 1.5 t o 3.0 cm. in thickness. The surrounding
mass was coarsely trabeculated and varied in consistency in different areas
from moderately soft t o quite firm; it nowhere contained bone or cartilage.
It, was of brain-like texture, and grayish to creamy-white in color, wit,h
small irregular areas of yellow pigment, old hemorrhage, and necrosis.
The cut surfaces of all the lower lumbar and sacral vertebrae showed a
massive infiltration with tumor similar to that to be described in the
other bones.
The lungs were small and collapsed, the right and left pleural cavities
containing 300 and 1900 C.C. respectively of clear fluid. Both pleural
surfaces were studded with many small, firm, smooth gray nodules, the
largest being 0.7 cm. in diameter and only slightly raised; these were
locnt,ed especially along the course of the pleural lymphatics and along
UNDIFFERENTIATED ROUND CELL SARCOMA
391
the lung margins, where they formed nearly continuous ridges. No
nodules could be found in the substance of the lung. The tracheobronchial lymph nodes were enlarged, in part caseous and in part firm,
and slightly calcified.
FIG. 3. ILIAC TUMOR,
A 8 REMOVED
AT NECROPBY
Note the involvement of the sacrum, and the nodule (arrow) on the surface of the
femur.
The pericardium contained 100 C.C. of clear fluid and was otherwise
normal. The heart showed a patent foramen ovale 1.0 cm. in diameter,
guarded by a fold of endocardium; and there was a moderate tricuspid
dilatat,ion. The myocardium was pale brown in color. The aorta and
great vessels were normal. The thyroid was pale but otherwise normal;
the thymus was atrophic but recognizable and weighed 5.5 gms.
3 92
N. W. ROOME AND P. A. DELANEY
The kidneys were pale and their cortex swollen. The urinary bladder
was thickened and contained small mucosal hemorrhages. The prostate
and seminal vesicles were normal, the testicles undeveloped.
Upon removing the calvarium, the tabula interna was found extensively infiltrated and eroded by soft, partly necrotic tumor; the tabula externa exhibited several such areas. The erosion of the inner surface
extended into the occipital bone, the right and left frontals, thence t o the
base of the skull and the sphenoid, of which the right wing was especially
involved. The lateral walls of both orbits were invaded, the right more
extensively than the left. The hypophysis and pineal gland were normal.
The dura mater was invaded by an overgrowth of tumor from the skull; it
was densely adherent to the calvarium and on removal was found covered
in about one-half of its outer surface by irregular masses of tumor tissue,
which penetrated through in places and appeared on the inner surface as
smooth, flattened nodules as large as 2.0 cm. in diameter. These were
not adherent t o the pia arachnoid, and had produced small areas of superficial brain atrophy. The falx cerebri presented none of these nodules,
and no special mass of tumor was found in the region of the optic chiasm
except as already described on the floor of the anterior fossa.
The following bones were removed from the body in addition to those
adjacent to the pelvic tumor: two and one half lumbar vertebrae, two
ribs, the right clavicle, the left femur, patella, tibia, and fibula. Of these,
all showed the same type of involvement, varying somewhat in degree;
and it may be assumed that the remainder of the skeleton would have
shown similar changes.
The femur was most involved (Fig. 4). The periosteum was roughened and thickened; under it were flat irregular nodules of soft creamy
tissue, as large as 0.3 X 2.0 X 4.0 cm., which occurred especially towards
the ends of the shaft, where they were confluent. On section, the cancellous bone and the medullary cavity were entirely filled with tumor
of soft and friable texture, extensively necrotic, and containing multiple
small areas of hemorrhage and liquefaction. The epiphyses were extensively invaded. The cortex was thinned, and irregularly eroded by soft
tissue from the medulla; the outermost layers were relatively compact,
but extensively penetrated a t the seats of the subperiosteal nodules.
The changes in the other bones were similar to those in the femur except for certain particulars. I n the tibia and fibula there was less cortical
invasion and correspondingly less subperiosteal growth, though a t the
extreme ends of the bone nearly all the surface was eroded, and there was a
large nodule a t the upper end of the tibia. The clavicle, which had received considerable irradiation, was sclerotic throughout, and the surrounding tissues fibrosed; there was only moderate medullary involvement and a few small nodules on the surface. From the ribs the tumor
had extended to the pleura, appearing on its inner surface as the small
nodules already described. There was extensive infiltration of the cancellous spaces of the vertebrae with occasional penetration of the cortex,
resulting in nodules as large as 3.0 X 2.5 X 1.5 cm. on the surface of the
bodies of the vertebrae. There was also noted a rupture of the articular
UNDIFFERENTIATED ROUND CELL SARCOMA
393
cartilage of the fourth lumbar vertebra, with expansion of the nucleus
pulposus into the body of the vertebra ("Schmorl's (5) disease") with
scanty surrounding sclerosis.
Microscopic Findings: The large iliac tumor was fixed in Kaiserling's
solution; blocks were cut from several different areas, washed, re-fixed
in formol-Zenker solution, and stained with hematoxylin-eosin, and
with Maximow's (6) hematoxylin eosin-azur 11. The microscopic appearance of the tumor varied considerably throughout its mass, most of it
showing degeneration, necrosis, and occasional hemorrhage. The tissue
contained a moderate number of blood vessels in the more viable regions
and was made up of small round and polyhedral cells, lying free in masses
and separated by non-tumorous connective-tissue septa. There was no
394
N . W. ROOME AND P. A. DELANEY
tendency towards a perithelial arrangement, nor to the formation of walls
of vascular spaces. Mitotic figures were infrequently seen. Most of the
cells were similar to the type cell of the Ewing sarcoma; they had a moderate amount of non-granular basophilic cytoplasm, a rounded vesicular
nucleus with irregularly scattered granular chromatin, and one to three
acidophilic nucleoli. There was considerable variation in cytology, and
certain cells (comprising about 10 per cent of the total number) seemed to
resemble the free basophil stem-cell of the hemopoietic series, the hemocytoblast, though few could be said to be as typical as the examples seen
in normal marrow (Fig. 5). A small proportion of cells, mostly towards
the periphery of the tumor mass, were seen t o contain in their cytoplasm
neutrophilic (and in a few cells, eosinophilic) granules, identifying them
rather positively as myelocytes and premyelocytes; these were seen in
various stages of maturation, and occurred in groups surrounded by and
apparently intimately related to the less differentiated cells (Fig. 6).
Most positively identified were several megakaryocytes, huge cells of
irregular outline, with characteristic irregular lobulated nucleus; these also
presented various stages of maturation (Fig. 5). Certain cells were seen
with a relatively smaller and more compact nucleus, and non-granular
acidophilic cytoplasm; these may possibly represent normoblastic types,
but are difficult to differentiate from pyknotic degeneration of other cells
(because of the fixative used). Sections of the bony portions showed
dense trabeculae, with cancellous spaces filled with degenerated tumor
cells; no normal bone marrow was found.
The adjacent iliac lymph nodes were densely filled with tumor cells,
nearly obliterating their norm81 structure. The occluded iliac vein was
UNDIFFERENTIATED ROUND CELL SARCOMA
395
found filled with an organizing thrombus which contained a small island
of tumor cells near its center.
In the other bones the marrow was almost completely replaced by
metastases composed of cells similar to those of the iliac tumor but with
less pleomorphism. The Haversian systems were irregularly invaded
and expanded, with slight erosion of the bone produced by the tumor
cells without the aid of giant cells. Small scattered areas of fatty, normal,
and fibrous marrow were seen at various points. There were occasional
areas of reactive new bone formation, and in certain locations a considerable sheet of subperiosteal new bone, but no evidence of actual tumor
bone or cartilage.
The tumor tissue in the pancreas was irregularly lobulated, separated
by strands of white fibrous connective tissue. It was densely cellular
and contained in certain areas small groups of pancreatic acini. Most
of the tumor cells resembled the predominating cells of the iliac tumor;
there were a few small islands of cells resembling erythroblasts and normoblasts. The spleen contained a multitude of minute clumps of tumor
cells in its sinuses, occurring mostly near the periphery of the organ, and
with little tendency to invade the pulp. A few myelocytes and normoblasts were identifiable in these tumor clumps; there was nothing to
indicate whether these developed from the tumor cells or merely developed
near them from non-neoplastic immature blood cells. The splenic pulp
was increased, contained much brown pigment, and showed evidence of
considerable myelopoiesis; there were several small peripheral anemic
infarcts. The liver showed slight or no evidence of hemopoiesis, and
there was no tumor seen in the organ. The kidneys contained a few
very minute clumps of tumor cells in capillary blood vessels.
Several sections of lung parenchyma showed no tumor growth, and no
396
N. W. ROOME AND P. A. DELANEY
tumor cells in the blood channels; there was marked atelectasis, but no
inflammatory changes, and much brown pigment in fixed and free "heartfailure" cells. The pleura was thickened and irregularly infiltrated by
groups of tumor cells which occasionally extended very slightly into the
lung tissue. Small clumps of tumor cells were found in the pleural fluid,
which may explain the method of spread t o the visceral pleura. The
peribronchial lymph nodes were found moderately infiltrated with tumor.
The dura mater showed a dense irregular infiltration by tumor, much of
which was contained in blood vessels; there were a few myeloid cells seen
scattered among the mass of undifferentiated cells.
The other visceral tissues showed no tumor invasion. The gall-bladder, stomach, esophagus, bowel, prostate, testicles, adrenals, and thyroid
gland were essentially normal. The heart showed evidences of myocardial degeneration. The skeletal muscles were extremely atrophic,
with hyalinization of the remaining fibers. The eyes, serially sectioned,
showed no tumor invasion, but a toxic endothelial proliferation as described by Salzmann (7), springing from the arachnoid sheath of the right
optic nerve.
COMMENT
The tumor reported is best considered an unusual type of
Ewing sarcoma. The onset, the clinical course, and the x-ray
appearance of the primary tumor are characteristic; the exceptionally large iliac tumor and the great extent and distribution of the
metastases are very unusual features. Microscopically, by the
routine staining methods, the findings are entirely compatible with
this diagnosis.
It is obviously impossible to think of the tumor as an undifferentiated osteogenic sarcoma; and it is unlike myeloma in several
features, vix: (1) tendency to new bone formation in the original
tumor (before radiotherapy); (2) the absence of sharply defined
bone destruction in the metastases, giving an x-ray appearance in
the extremity bones altogether unlike the punched-out areas of
myeloma; (3) the absence of any tendency t o skeletal collapse
(pathological fracture); (4) the formation of a large isolated primary tumor long before metastasis occurred; (5) the age of the
patient, myelomata being quite rare under the age of thirty (Coley,
8)
It is interesting to consider the character and significance of the
differentiated cells found in the tumor.2 The granular cells are
certainly myelocytes, and there seems no reasonable doubt concerning the megakaryocytes. The identification of the normo2 Our opinion as to the character of the differentiated cells in this tumor was confirmed by Dr. Wm. Bloom of the Department of Anatomy, University of Chicago.
UNDIFFERENTIATED ROUND CELL SARCOMA
397
blastic types is somewhat obscured by the fixation of the large
mass of tissue in Kaiserling's solution and two hours post-mortem.
It is difficult to say, therefore, whether the differentiated cells
represent a reaction to the tumor, or are hemopoietic; and if the
latter, whether they are differentiated from the tumor cells or from
cells carried out from the original marrow. There is, however,
considerable evidence in favor of the opinion that they represent
hemopoiesis, and since it is unusual to find myeloid tissue so far
removed from bone as at the periphery of this large tumor, it is
thought that the tumor may possibly be a myeloid stem-cell tumor,
a hemocytoblastoma.
Ewing (1) seems to believe that the "endothelial myeloma" is
of endothelial origin, and has potentialities of development towards
either angio-endothelium or hemopoietic tissue. The tumor reported in this paper may represent a borderline tumor, considerably differentiated towards the myelomata. We are not, however,
convinced of the endothelial origin of the Ewing sarcoma, and believe that further study of such tumors with Romanowsky-type
stains may shed interesting light on the problem of their origin.
We have applied Maximow's technic to a group of tumors diagnosed Ewing's sarcoma by a majority of observers (obtained
through the courtesy of the Bone Sarcoma Registry of the American College of Surgeons) ; none of these seemed exactly similar to
the present case, there being a considerable variation in their cytology, and in none were any hemopoietic elements found. Case
385 most nearly approaches the picture of extreme skeletal involvement seen in the case reported here, and also presents a somewhat similar histology, but no tissue was obtained for special
staining. (Photographs of material from this case are included in
Kolodny's report, 2 .)
SUMMARY
A case of round-cell sarcoma of the ilium, with extensive
skeletal and few visceral metastases is described. I t is classified
as an atypical Ewing sarcoma. Special stains show the presence
of hemopoietic elements in the tumor. The possibility that the
tumor is a borderline Ewing sarcoma, merging into a myeloid
stem-cell tumor (hemocytoblastoma), is discussed.
398
N. W. ROOME AND P. A. DELANEY
1. EWING,J.: Review and classification of bone sarcomas, Arch. Surg. 4:
485-533, 1922.
2. KOLODNY,
A.: Bone sarcomas, Surg. Gynec. & Obst., 1st suppl., 126154, 1927.
3. OBERLING,
C. : Les rkticulosarcomes et les rkticuloendothkliosarcomes
de la moelle osseuse (sarcomes d7Ewing), Bull. de 1'Assoc. frang.
l'ktude du cancer 17: 259-296, 1928.
4. CONNOR,
C. L.: Endothelial myeloma, Ewing, Arch. Surg. 12: 789-829,
1926.
5. SCHMORL,
G., Die pathologische Anatomie der Wirbelsaule, Verhandl.
d. deutsch. orthop. Gesellsch. 21: 3, 1927.
6. MAXIMOW,
A,: Uber zweckmassige Methoden fiir cytologische und
histogenetische Untersuchungen, Ztschr. f. wiss. Mikr. 26: 177-190,
1909.
7. SALZMANN,
M. : Anatomy and Histology of the Human Eyeball, English translation by E. V. L. Brown, Chicago, 1912, p. 101.
8. COLEY,W. B. : Multiple myeloma, Ann. Surg. 93: 77-89, 1931.