Acta Pathol. Jpn. 35/51 : 1087-1098, 1985

EXTRASKELETAL EWING’S SARCOMA A Clinicopathologic and Electron Microscopic

Analysis of 8 Cases

Hiroshi HASHIMOTO, Masazumi TSUNEYOSHI, Yutaka DAIMARU, and Munetomo ENJOJI

Second Department of Pathology, Faculty of Medicine, Kyushu University, Fukuoka

This clinicopathologic study concerns 8 cases of extraskeletal Ewing’s sarcoma, including electron-microscopic examination of one case. In three patients, autopsy was done. The age of the patients ranged from 12 to 31 years with a median of 16 years. The tumors mainly arose in the soft tissues of the trunk (4 cases) and the lower extremity (3 cases). Histologically, they were made up of closely packed uniform, small cells, arranged in sheets separated by strands of fibrovascular stroma. The tumor cells had round to oval nuclei with finely dispersed chromatin and scanty ill-defined cytoplasm almost invariably containing a fair amount of diastase-digested PAS-positive material. Ultra- structurally, the tumor cells were composed principally of undifferentiated mesenchymal cells, and contained prominent pools of glycogen in the cyto- plasm. Aggregates of intermediate filaments were seen in a perinuclear loca- tion. These light- and electron-microscopic findings are indistinguishable from those of Ewing’s sarcoma of the bone. Differential points from other soft-tissue small round cell sarcomas such as malignant neuroepithelioma (peripheral neuroblastoma), embryonal or alveolar rhabdomyosarcoma were briefly discussed. ACTA PATHOL. JPN. 35 : 1087- 1098, 1985.

Introduction

In 1969, TEFFT et al. first described 4 paravertebral round cell tumors in children which bore a close morphologic resemblance to Ewing’s sarcoma of bone,34 and subsequently, ANGERVALL and ENZINGER thoroughly analyzed 39 cases of extra- skeletal neoplasm resembling Ewing’s sarcoma on a clinicopathologic basis.’ Since then, this tumor has been reported ~poradical ly ,~~’ 1 ~ 1 3 ~ 1 6 ~ 2 0 ~ 2 L ~ 2 4 - 2 7 ~ * g ~ 3 1 . 3 7 and SOULE et al., in a preliminary review of 26 cases of extraskeletal Ewing’s sarcoma encountered in the Intergroup Rhabdomyosarcoma Study, reported a significantly improved disease-free survival in patients managed by that Extraskeletal Ewing’s sarcoma is a relatively rare soft-tissue neoplasm and has been confused with a variety of other small

Accepted for publication November 2, 1984.

Mailing address : cine, Kyushu University 60, 3- 1-1 Maidashi, Higashi-ku, Fukuoka 812, JAPAN.

%$ R, iB& iE@, 9 h %, S%* %%I Munetomo Enjoji, MD, Second Department of Pathology, Faculty of Medi-

I OX8 EXTKASKELETAL EWINO’S SARCOMA Acta Pathol. Jpn

round cell tumors such as malignant neuroepithelioma (peripheral neuroblastoma), embryonal or alveolar rhabdomyosarcoma, trabecular (Merkel cell) carcinoma of the skin and so on.

We now report 8 cases of extraskeletal Ewing’s sarcoma clinicopathologically, including one case studied electron microscopically.

Materials and Methods

After reviewing the microscopic slides and clinical summaries of 767 cases coded as cases of soft tissue sarcomas in the files of the Second Department of Pathology, Kyushu University Faculty of Medicine during the period from 1956 to early 1982, we selected 4 cases (0.5%) of extraskeletal Ewing’s sarcoma. In addition, tissues from Kumamoto University Faculty of Medicine (2 cases), from Niigata University Faculty of Medicine ( 1 case), and from Kurume University School of Medicine ( 1 case) were available for this study.

For light microscopy, all paraffin blocks were stained with hematoxylin and eosin (H.E.). The special stains used included periodic acid-Schiff (PAS) procedure, with and without prior diastase digestion, Masson’s trichrome stain, silver impregnation for reticulin, and alcian blue stain. The mitotic rate was determined by counting the number of mitoses per 10 high power ( ~ 4 0 0 ) fields (HPF).

The fresh specimen was fixed in 3% glutaraldehyde solution (buffered pH 7.4) and postfixed in 1% phosphate-buffered osmium tetroxide. Following dehydration, the tissue blocks were embedded in Epon 812 and cut using an LKB ultrotome 111. Ultrathin sections were stained with uranyl acetate and lead citrate, and examined under a JEM 1OOC electron microscope.

Electron microscopy was carried out on the second recurrent tumor of case 1.

Results Clinical Findings

Clinical data of the patients are summarized in Table 1. There were 5 females and 3 males and their ages a t the time of diagnosis ranged from 12 to 31 years with a mean age of 19 years (median 16 years). Of the 8 tumors, three were located in the lower extremities (lower leg 2, thigh l ) , and each one in the posterior mediastinum, chest wall, pleural cavity, shoulder, and inguinal region, respectively.

Signs and Symptoms

In five patienth3 with a tumor located in the lower extremities, shoulder or inguinal region, a rapidly growing lumpy mass or swelling was one of the chief signs. In one of the two patienh with pain associated with the masses, the pain was the first subjectjive sign. Two patients with a tumor of pleural cavity and chest wall, respec- tively, were first confirmed by a plain chest x-ray examination (cases 7 and 8). Another patient had had a progressive gait disturbance, cough and exertional dyspnea, and a plain chest x-ray examination revealed a tumor of the posterior mediastinum (case 1). The preoperative duration ranged from three to seven months, with a median of 4 months. Another patient had a large tumor on the thigh for seven months before death (case 4). In one patient in whom a urine vanillyl mandelic acid (VMA) study was done, the excretion of this compound was within normal limits (case 1).

35(5): 1985 H. HASHIMOTO el al . 1089

Table 1. Extraskeletal Ewing 's Sarcoma-Summary of 8 Cases

Case Age Sex Location :&,"f Duration Of Treatment Follon-up symptoms (cm) no.

1. 12

2. 31

3. 13

4. 24 5. 17 6. 14

7. 27

8. 14

Posterior mediastinum

Inguinal region

Lower leg

Thigh Shoulder Lower leg

Pleural cavity

Chest wall

12 x 5.5

14 x 10

9.5 x 7.5

11 x 10 5 x 3

7 x 7

Unknown

Unknown

3 mos.

7 mos.

4 mos.

7 mos. Unknown Unknown

3 mos.

Unknown

Simple excision, radiation, chemotherapy Biopsy, radiation, chemotherapy Simple excision, chemotherapy Unknown Simple excision Amputation, chemotherapy Simple excision, radiation, chemotherapy Simple excision, radiation, chemotherapy

Dead 5.6yrs.

Dead 2.8 yrs.

Dead 11 mos.

Dead 7mos. Living 14.3 yrs. Living 5.3 yrs.

Living 4.6 yrs.

Living 1.8 yrs.

Gross Appearances The size of the tumor a t the first surgical excision ranged from 5 to 14 cm with a

mean of 9.5 cm (median 9.5 cm) in the greatest diameter. Another tumor was 11 x 10 cm in size at autopsy (case 4). Of the 6 tumors occurring in the external soft tissue, all but one which was confined to the subcutis (case 6) were deeply located within the skeletal muscle and two were firmly attached to the periosteum of the adjacent bones (cases 2 and 8). One tumor of the posterior mediastinum was seated in the paraverte- bra1 region a t the level of Th 7-8th, and extended into the epidural space through an intervertebral foramen (case 1). However, there was no evidence of bone invasion by these three tumors. The tumor was relatively well circumscribed in four patients and there was an infiltrative growth in three. The consistency was stated as elastic soft or simply soft in 6 cases, and as elastic firm in one. The cubsurfaces were medullary and yellowish to grayish white or gray-tan in color, and frequently varied with other tints as necrosis and/or hemorrhage. In two cases, the necrotic areas had a cyst formation.

Microscopic Appearances

The tumors were made up of sheets of closely packed small cells with an intersper- sed fibrovascular stroma occasionally showing a lobular pattern (Figs. 1 and 5). Usually the tumor cells were strikingly uniform with round to oval nuclei containing finely dispersed chromatin with little clumping and frequently one to three minute nucleoli (Fig. 2). The mean greatest diameter of the nuclei in each case ranged from 6.3 to 8 .8pm with a mean of 7.5pm. Mitotic figures were occasionally numerous in the present study : the number of mitoses per 10 HPF ( x 400) ranged from 1 to 145

1090 EXTRASKELETAL EWING'S SARCOMA Acta Pathol. Jpn.

35(5) : 1985 H. HASHIMOTO t f a/. 1091

with a mean of 42 (median 32). The result differs from that of some other authors who pointed out that the mitotic figures were usually rare in this tumor.g The cytoplasm of the tumor cells was scanty and pale with ill-defined borders, and was occasionally vacuolated as a result of the intracellular storage of glycogen. In most cases, admixed with these predominant tumor cells were a few cells with a somewhat more elongated dark nucleus.

Although no Homer Wright-type rosettes were recognized, there were occasional perivascular pseudo-rosettes in two of the 8 cases. Tumor necrosis was evident in most cases, but varied considerably in extent. In some tumors, necrosis was limited to small foci, but in others, a wide trabecular necrosis followed by dystrophic calcification was present. Focal areas of hemorrhage were often seen, and the hemorrhagic, microcyst-like spaces produced an angiomatoid appearance (Fig. 3).

Diagnostically, one of the most significant findings was the presence of intracyto- plasmic glycogen. In all tumors of our series stained with PAS, a fairly large amount of diastase-digested PAS-positive material, presumably glycogen, was present in many tumor cells (Fig. 4). Silver impregnation for reticulin revealed an intervening fibrovascular stroma, but there was no evidence of the presence of a reticulin meshwork between the tumor cells (Fig. 5 ) .

In two of the three autopsied patients, both surgical and autopsy specimens were histologically examined, and the degree of nuclear atypism of tumor cells and mitotic rate was higher than those in the surgical specimens (cases 1 and 2). I t is noteworthy that, in one patient with an extraskeletal Ewing’s sarcoma showing a typical histologic pattern a t operation, pleomorphic tumor cells with bizarre nuclei were prominent a t autopsy even in the metastatic sites; this feature may be misinterpreted as rhab- domyosarcoma (case 2) (Fig. 6).

Electron Microscopic Findings ( 1 case)

The tumor cells were compactly arranged, and posed a moderately high nuclear/ cytoplasmic ratio. Cellular outlines exhibited a spectrum of shapes from round, spheroid to elongate. The principal cells were composed of undifferentiated cells of a round or polygonal shape, in close contact. Tight junction complexes were rarely encountered. The tumor cells had a bright electron lucent cytoplasm and a round or oval single nucleus which was slightly indented and occasionally convoluted. The chromatin was finely dispersed and the nucleolus was prominent. The cytoplasm was scarce in organelles and appeared poorly differentiated. A few mitochondria were irregularly distributed. Abundant free ribosomes in occasional association to profiles of rough endoplasmic reticulum were evident and Golgi complexes were scattered.

Fig. 1. Case 1. Densely cellular tumor with an interspersed fibrovascular stroma. H.E., x 144. Fig. 2. The considerably uniform tumor cells have round to oval nuclei with finely

Fig. 3. Case 1. Hemorrhagic microcyst-like spaces showing an angiomatoid appearance. H.

Case 1. dispersed chromatin and scanty, poorly defined cytoplasms.

E., x 101.

H.E., x 468.

EXTRASKELETAL EWING'S SARCOMA Acta PathoE. Jpn.

35(5) : 1985 H. HASHIMOTO ct a l . 1093

Characteristic was that the majority of the tumor cells contained pools of glycogen, mainly in the periphery of the cytoplasm (Fig. 7). An additional finding was the presence of aggregated filaments which were often in a perinuclear location and the diameters were between 7-11 nm. These filaments were structurally identical with intermediate filaments (Fig. 8).

In addition to these principal cells, fewer numbers of the tumor cell type were found and such were not as regular in structure and size as the principal ones. These cells displayed some increase of cytoplasmic densities, and the cell organelles were more numerous and prominent. In the scanty intercellular space, there was an amorphous material together with a few small collagen fibers.

Treatment and Prognosis

All but one patient who refused surgery (case 4) were treated by various modes of surgery ; biopsy only ( 1 case), local excision (5 cases), and amputation after excisional biopsy (1 case). Adjuvant chemotherapy was prescribed for six patients, and four received both radiation and chemotherapy. The type of chemotherapy varied with the patient.

Four patients were alive and well 1.8, 4.6, 5.3, and 14.3 years after treatment, respectively, while three patients died of a tumor 11 months, 2.8 years, and 5.6 years after the initial treatment, respectively. Another patient had a large tumor on the thigh for seven months before death (case 4). Autopsy was done in three of the four patients (case 1, 2, and 4), and metastases to the lung and pleura were evident in all patients. Other metastatic sites were regional lymph nodes (2 cases), bones, including vertebrae and ribs (2 cases), liver (1 case), and adrenal gland (1 case). There were, however, no tumors in the bones which could be identified as the primary site.

Discussion DAHLIN (1962) briefly described the soft-tissue counterpart of Ewing’s sarcoma in

his t e ~ t b o o k , ~ and in 1969, TEFFT et al. first reported four cases of paravertebral round cell tumor in children which bore a close morphologic resemblance to Ewing’s sarcoma of bone.34 Subsequently, ANGERVALL and ENZINGER (1975) thoroughly analyzed the clinicopathologic features of 39 cases of a malignant tumor of soft-tissue origin that bore a close resemblance to Ewing’s sarcoma of bone.’ Although, in 10 of the 39 cases examined by ANGERVALL and ENZINGER and in 3 of our series, periosteal changes in the underlying bones were present, there was no evidence of a primary bony localiza-

Fig. 4. Case 7. Abundant intracellular glycogen. PAS preparation, x 382. Fig. 5. Case 1.

pattern. impregnation, x 210.

E., x390. (b) The metastatic lesion of paratracheal lymph node at autopsy. tumor giant cells are evident.

Reticulin fibers in the intervening fibrovascular stroma revealing a lobular Note the absence of a reticulin meshwork between the tumor cells. Silver

Fig. 6. Case 2. (a) The initial tumor showing a typical extraskeletal Ewing’s sarcoma. H. Bizarre

H.E., x 226.

EXTRASKELETAL EWING’S SARCOMA Acta Pathol. Jpn.

~ ~ ~~

Fig. 7. Case 1. organelles. High magnificat.ion of pools of glycogen. x 32,000.

mately from 7 to 11 nm in diameter. x 32,000.

Electron micrograph of undifferentiated cells showing scanty intracytoplasmic Characteristic pools of glycogen are found in the cytoplasm. x 6,400. Inset :

Electron micrograph showing aggregates of intracytoplasmic filaments ranging approxi- Fig. 8.

35(5) : 1985 H. HASHIMOTO Pf a l . 1095

tion of the tumor, even in two autopsy cases in our series.6 Extraskeletal Ewing’s sarcoma commonly affects adolescents and young adults

between 10 and 30 years of age and mainly occurs in the soft tissues of the paraverte- bra1 region or in the epidural ~pace,”*~4-~9 the chest wall, and the lower extremities.’ On light and electron microscopy, this tumor bears striking similarities to typical Ewing’s sarcoma of bone.13,‘6,20’21.27.31,37 However, the present study revealed an additional ultrastructural finding, that is the presence of intermediate filaments with the diameter of 7-11 nm in the perinuclear area of the cells. These filaments have not been described in any English literature, although thinner intracytoplasmic microfilaments of 5-7 nm in diameter were reported by other a u t h o ~ s . ’ ~ , ~ ’ . ~ ~ Recently, MIETTINEN et al. immunohistologically confirmed that the tumor cells of Ewing’s sarcomas contained vimentin-type intermediate filament proteins but not keratin, desmin or neurofilament.22 Darker cells other than principal bright tumor cells were first noted in the bony counterpart by FRIEDMAN and GOLD,'^ and were also found in the extraskeletal form of Ewing’s sarcoma,20*21*27*31 Some workers consider that these are merely cells undergoing degeneration,20 but the state of preservation of the cytoplasmic organelles and nucleus never suggested that these cells are either pyknotic or degenera t i~e .~’*~~

This tumor completely lacks cellular differentiation a t both light microscopic and ultrastructural levels as in Ewing’s sarcoma of the bone, although origins from particular cell types, such as hemangiogenic cells,4Jo.28*32 myeloid cells,15 reticulum and osteogenic cells,3 were proposed in some literatures. More reasonably, these soft-tissue tumors represent primitive mesenchymal cells as well as the bony counterpart of the same des igna t i~n .~*‘~ . ‘~ There is to date, however, no evidence to determine the cell origin of these tumors.

Whereas histologic features of extraskeletal Ewing’s sarcoma are distinctive and may be readily recognized by persons familiar with this tumor, such may be occasion- ally mistaken for those of other small, round cell malignancies, particularly for malignant neuroepithelioma (peripheral neuroblastoma), embryonal or alveolar rhab- domyosarcoma, and malignant lymphoma. The differential diagnosis from these tumors is particularly important, because specific therapy exists and biological behav- ior is better understood for some of these tumors.

Clinically, the malignant neuroepithelioma also affects principally young adults, and is composed histologically of closely packed, small round or ovoid tumor cells of considerable uniformity, such as in the case of extraskeletal Ewing’s ~ a r c o m a . ’ ~ * ’ ~ Cytoplasmic glycogen is found on rare occasions in malignant neuroepithelioma as well as glycogen-containing neurobla~toma,~~ but i t tends to be much less prominent than in Ewing’s sarcoma. The most characteristic and significant finding in malignant neuroepithelioma is the presence of Homer Wright-type rosettes that can be distin- guished from occasional perivascular pseudo-rosettes in Ewing’s sarcoma. Further- more, in malignant neuroepithelioma, the nuclei of the tumor cells contain more

Either way, their differentiation and function remain obscure. Histogenesis of Ewing’s sarcoma has long been a subject of debate.

1096 EXTRASKELETAL EWING'S SARCOMA Acta Pathol. Jpn.

clumping chromatin. Distinction from a metastatic tumor of classical neuroblastoma also causes

difficulties in diagnosis. The average patient with Ewing's sarcoma was much older than the average patient with classical neuroblastoma, and in one patient with Ewing's sarcoma of our series, the tumors had originated in the adrenal gland or the symphath- etic ganglionic chains. Moreover, neuroblastic tumors can be distinguished ultras- tructurally by the presence of scattered neurosecretory granules and cytoplasmic processes containing neurofilaments and micro tubule^.^^

Embryonal or alveolar rhabdomyosarcoma may display a similar closely packed cellular area and is a primary consideration in the diagnosis. The tumor, however, tends in general to be composed of less uniform cells and more or less nearly always contains cells with an irregularly outlined, hyperchromatic nucleus and a well-defined, eosinophilic cytoplasm more characteristic of rhabdomyoblasts. In the alveolar type, areas showing a distinct alveolar pattern and occasional multinucleated giant cells are characteristic. A t autopsy, however, Ewing's sarcomas may show some pleomorphism, probably induced through both intensive radiation and ~ h e m o t h e r a p y , ' ~ * ~ ~ as we observed in one patient of our series.

It may prove difficult to differentiate between malignant lymphoma and extra- skeletal Ewing's sarcoma. However, this possibility can be excluded by the difference in cell characteristics, the presence of intracellular glycogen, and the lack of reticulin fibers within the tumor lobules in extraskeletal Ewing's sarcoma. The absence of lymph node involvment a t the time of initial surgical procedure is also helpful in the differential diagnosis.

Anaplastic small cell carcinoma, particularly of pulmonary origin, has to be considered in patients over 30, but this possibility was excluded by a thorough clinical history and by the absence of demonstrable neoplastic disease originating in the lung or any other visceral organ a t the time of excision. Furtheromore, ultrastructural features of epithelial origin may be indicated in the undifferentiated carcinoma. Other small or round cell tumors, such as primary trabecular (Merkel cell) carcinoma of the skin, extraskeletal mesenchymal chondrosarcoma, monophasic synovial sarcoma, malignant hemangiopericytoma, and leukemia (granulocytic sarcoma), must excep- tionally be included in the differential diagnosis.

Tumors recently reported by ASKIN et al. (1979) as malignant small cell tumors of the thoracopulmonary region closely resemble extraskeletal Ewing's sarcomas in clinical and histologic appearances.2 These tumors may be related to malignant neuroepithelioma rather than to extraskeletal Ewing's sarcoma, because half had cellular profiles arranged about a central acidophilic focus suggestive of Homer Wright-type rosettes, and electron microscopy of three cases suggested a neuroepith- elial derivation.

According to the preliminary review of 26 cases documented in the Intergroup Rhabdomyosarcoma Study, the prognosis is not always ominou~.~" In the review, 17 of the 26 patients managed by that protocol were alive and well. ENZINGER and

35(5) : 1985 n. HASHIMOTO I097

WEISS stated that treatment similar to that employed in Ewing’s sarcoma of bone, i. e. wide local excision, radiotherapy, and intensive sequential chemotherapy, was advisable, although appraisal of the most effective mode of therapy was hampered by the various therapeutic procedures employed in their series and ours.g

Acknowledgements : We thank M. OHARA for critical reading of the manuscript, Dr. H. MIYAYAMA, Kumamoto University Faculty of Medicine ; Dr. T. MORITA, Niigata University Faculty of Medicine ; and Dr. S. KOMIYA, Kurume University School of Medicine for making available the materials used in this study.

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