CASE REPORT

Primary pulmonary Ewing’s sarcoma: report of a case

Yoshinobu Ichiki • Akira Nagashima •

Yasuhiro Chikaishi • Manabu Yasuda •

Ichiro Yamamoto • Satoshi Toyoshima

Received: 16 May 2011 / Accepted: 25 July 2011 / Published online: 7 April 2012

� Springer 2012

Abstract The Ewing’s sarcoma family of tumors has

been reported to originate in a variety of sites, most com-

monly in the extremities. We herein describe a rare case of

primary pulmonary Ewing’s sarcoma in a patient with a

family history of sarcoma. The patient was a 42-year-old

male, who presented with hemoptysis. Chest radiographs

revealed a pulmonary mass in the right lower lobe. Clinical

and radiological examinations (computed tomography and

positron emission tomography) revealed that the lesion was

a primary lesion. The lesion was resected by right lower

lobectomy. The tumor was located in the pulmonary

parenchyma, and there was no evidence of an extrapul-

monary involvement by the tumor. Histologically, the

tumor was composed of uniform cells with round nuclei

and scant cytoplasm which were arranged in cohesive

lobules with rare pseudorosette formation. Immunohisto-

chemically, the tumor cells were positive for CD99, and

negative for epithelial markers, neuroendocrine markers,

myogenic markers and lymphoma markers. This diagnosis

was further supported by the cytogenic and reverse trans-

criptase-polymerase chain reaction findings of EWS/FLI-1

fusion transcripts. This demonstrated the presence of a very

rare primary pulmonary Ewing’s sarcoma. The patient was

treated with chemotherapy after the operation because

Ewing’s sarcoma is an aggressive neoplasm. The patient

has had no recurrent disease for 6 months after the

operation.

Keywords Lung cancer � Ewing’s sarcoma

Abbreviations

ESFT Ewing’s sarcoma family of tumors

PNET Primitive neuroectodermal tumors

PET Positron emission tomography

CT Computed tomography,

FDG 8F-fluorodeoxyglucose

CEA Carcinoembryonic antigen,

SCC Squamous cell carcinoma related antigen

TBLB Transbronchial lung biopsy

RT-PCR Reverse transcriptase-polymerase chain reaction

SUV Standard uptake value

Introduction

The Ewing’s sarcoma family of tumors (ESFT) incorpo-

rates both the well-recognized primary bone and the

extraskeletal soft tissue sarcomas. Primitive neuroectoder-

mal tumors (PNET) and ESFT have a similar neural phe-

notype and can, therefore, be considered the same entity. A

common genetic translocation involving chromosome 22

links these tumors with the most prevalent being t(11; 22)

(q24; q12), which occurs in approximately 85 % of cases

[1]. First described in 1921 by American pathologist James

Ewing, Ewing’s sarcomas are neuroectodermal tumors

characterized by monotonous small round cells that are

arranged in sheets on histological examination. Although

Ewing’s sarcoma presenting with a lytic bone lesion is, in

itself, uncommon, it is recognized as the second most

prevalent primary bone tumor worldwide [1].

Cases of primary pulmonary ESFT have been reported

in recent years, but there are still only a few reports in the

literature. To date, only 10 cases of primary pulmonary

Y. Ichiki (&) � A. Nagashima � Y. Chikaishi � M. Yasuda �I. Yamamoto � S. Toyoshima

Department of Chest Surgery and Pathology,

Kitakyushu Municipal Medical Center,

2-1-1 Bashaku, Kokurakita-ku, Kitakyushu 802-0077, Japan

e-mail: y-ichiki@med.uoeh-u.ac.jp

123

Surg Today (2012) 42:812–815

DOI 10.1007/s00595-012-0170-4

ESFT have been reported. We herein discuss both the

clinical course and the therapeutic management of this

disease and the associated family history.

Case report

The patient was a 42-year-old male who was admitted to

our hospital because of hemoptysis. His past history was

noncontributory, but his family history was notable. His

brother had undergone amputation of the right wrist

because of synovial sarcoma. Chest radiographs of the

patient revealed a right lower lobe mass. Computed

tomography (CT) disclosed a well-circumscribed and

homogeneous mass measuring 3.9 9 2.6 cm with slight

lobulation in segment 9 of the right lower lobe of the lung

(Fig. 1). A positron emission tomography (PET) with 18F-

fluorodeoxyglucose (FDG) scan showed increased FDG

uptake (maximal standard uptake value 3.2) without any

other abnormal uptake. As a result, the lesion seemed to be

a primary malignant tumor of the lung. None of the serum

tumor markers, including carcinoembryonic antigen

(CEA), squamous cell carcinoma related antigen (SCC),

Cyfra, NSE and proGRP, was elevated.

The patient underwent the bronchoscopy, then a trans-

bronchial lung biopsy (TBLB) and washing cytology were

performed. However, no malignant cells were detected.

The lesion was resected by a right lower lobectomy. The

tumor was 3.6 9 3.0 9 2.5 cm in size. The tumor was

located in the pulmonary parenchyma, and there was no

evidence of an extrapulmonary involvement by the tumor

(Fig. 2). The cut surface was well-demarcated, and showed

a lobulated configuration with a yellowish area remaining

in the periphery of the tumor. Histologically, the tumor was

composed of uniform cells with round nuclei and scant

cytoplasm which were arranged in cohesive lobules with

rare pseudorosette formation (Fig. 3a). Immunohistoche-

mially, the tumor was positive for CD99 (Fig. 3b), but

negative for epithelial markers (cytokeratin AE1/AE2,

EMA), neuroendocrine markers (chromogranin A, synap-

tophysin), myogenic markers (desmin, a-SMA) and lym-

phoma markers (LCA, CD3, CD20, CD79a, CD30). This

diagnosis was further supported by the cytogenic and

reverse transcriptase-polymerase chain reaction (RT-PCR)

to detect ESFT-associated chimeric mRNA (data not

shown). After the operation, the patient was treated with

adjuvant chemotherapy including doxorubicin, vincristine,

ifosfamide, etoposide and cyclophosphamide. The courses

of adjuvant chemotherapy have been and will be admin-

istered every 3 weeks for a total of 17 courses. The planned

duration of adjuvant chemotherapy is 49 weeks. The

patient has demonstrated no recurrent disease for 6 months

after the operation.

Comment

A ESFT is an uncommon malignant neoplasm. The tumors

in this family share a common histological feature of clo-

sely packed small primitive round cells. ESFT most fre-

quently arises in the bones, followed by the soft tissue, but

they have also rarely been reported at other sites [2, 3]. The

pathological diagnosis of ESFT used to require standard

light and electron microscopy, looking for small, round,

blue cells with abundant glycogen and absent cytoplasmic

filaments [4]. Because of the lack of any specific mor-

phological features, the misdiagnosis rate was high due to

the lack of a diagnostic histopathology. Now, with the

advent of specific staining and genomic techniques, we are

able to confidently identify ESFT that displays the

same immunohistochemical and molecular features. CD99

Fig. 1 A chest computed tomography scan of the patient revealed a

solitary intrapulmonary mass in the right lower lobe

Fig. 2 The cut surface of the lobectomy specimen revealed a

medullary tumor with necrotic or hemorrhagic foci confined to the

pulmonary parenchyma

Surg Today (2012) 42:812–815 813

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staining reveals the MIC2 gene product, which presents a

cell-surface glycoprotein p30/32mic2, and has recently been

used in the evaluation of the EWS family, although it is not

entirely specific for this family [5–7].

The biological role of the MIC2 gene product is

unknown so far, and the structural analysis of the MIC2

gene and protein has not yet provided any clues as to its

molecular function. However, it seems dangerous to rely

solely on immunopositivity for MIC2, and a complete

absence of positive staining for both epithelial and neuro-

endocrine makers made the diagnosis of EWS likely, since

tumors positive for MIC2 are usually negative for those

markers. A characteristic reciprocal cytogenetic transloca-

tion t(11; 22)(q24;q12) is also shared with members of the

ESFT. This translocation results in a hybrid gene product

between the EWS gene located on the long arm of

chromosome 22 and the FL-1 gene on the long arm of

chromosome 11, which can be detected by RT-PCR.

The first case of primary ESFT of the lung was reported

in 1989 by Hammer and colleagues and was described by

Takahashi et al. [8]. Eleven cases, including this case, have

been reported in total since then. A review of the literature

revealed a male preponderance with a mean subject age of

30.4 (ranging from 8 to 67) [8, 9]. Combinations of ther-

apy, including surgery with chemotherapy, with or without

radiotherapy, have been performed. Out of the patients

with available data, five patients survived without recurrent

disease for eight to twenty-four months after the surgery.

All five patients had undergone surgery and chemotherapy.

Four patients died, all within 2 years after the surgery, and

two of these had undergone surgery alone [10].

Extraskeletal Ewing’s sarcoma is potentially curable.

The disease-free survival rates have been increased sig-

nificantly by management with aggressive surgical resec-

tion in combination with multi-agent chemotherapy, with

or without radiotherapy [9]. The treatment of choice is an

early surgical removal, with intensive chemotherapy and

radiation therapy to ablate any residual microscopic dis-

ease. The 5-year disease-free survival rate is estimated to

be 60–70 % for localized disease managed with multi-

agent chemotherapy and surgical resection [10]. Unfortu-

nately, the outcomes have not yet improved for patients

with metastasis or recurrent disease; the 5-year survival

rates remain less than 25 % [11].

We have herein presented a rare example of primary

pulmonary Ewing’s sarcoma, which was suggested by a

combination of microscopic and immunohistochemical

studies, and was confirmed by a genetic analysis, disclosing

the existence of EWS/FLI-1 fusion transcripts. In 85 % of

cases, the gene fusion is a result of a translocation between

EWS and FLI1 (11q24), and in 5–10 % of cases it is a

result of a translocation between EWS and ERG (21q22)

[12]. We, therefore, used primers for EWS–FLI1 and

EWS-ERG. EWS–FLI1 was detected by RT-PCR, but

EWS-ERG was not. It is important to note that extraskel-

etal Ewing’s sarcoma is recognized as a potential cause of a

pulmonary mass. The optimal treatment of primary pul-

monary ESFT has not yet been clearly established. How-

ever, adjuvant and/or neoadjuvant chemotherapy may thus

be able to improve the treatment outcome.

In this case, the maximal standard uptake value (SUV)

of FDG PET was 3.2. The value of the delayed phase of

SUV was not measured. This value might indicate the

possibility that it was due to inflammatory changes, but

malignancy was nevertheless suspected. Therefore, a sur-

gical resection was performed. The value is compatible

with that of a previous study of Ewing’s sarcoma (SUV of

4.5 ± 2.79). In the diagnosis of Ewing’s sarcoma, a FDG

PET scan is not diagnostic, but the sensitivity and speci-

ficity of the examination are quite high, with values of 96

and 78 %, respectively [13].

Fig. 3 a The histopathological findings of hematoxylin–eosin stained

sections revealed small round neoplastic cells with rare pseudorosette

formation. b Immunostaining for CD99 revealed tumor cells q

strongly linear surface staining

814 Surg Today (2012) 42:812–815

123

Interestingly, the brother of this patient had a synovial

sarcoma of the right wrist. A detailed family history of

malignant disease for patients with sarcoma including

ESFT is particularly important because an array of many

types of malignant diseases may be present. Hereditary

syndromes associated with ESFT were reported and a large

number of different transcriptions were identified [14].

Although germline mutations have been identified as cau-

sal for the expression of malignant disease in only a limited

number of these disorders, when such a mutation is present,

it provides the essential requirement for integrating the

sarcoma into a hereditary cancer syndrome of concern.

However, a major problem is that sarcomas are exceed-

ingly rare, and this problem is coupled with the fact that the

compilation of a sufficiently detailed family history of

malignant disease has often been ignored. Consequently, it

is exceedingly difficult to discern which patients/families

may be candidates for germline testing.

Acknowledgments We would like to thank Professor Hiroshi

Hashimoto and his colleagues in the Department of Pathology, School

of Medicine, University of Occupational and Environmental Health

for their detailed genetic analysis.

Conflict of interest Yoshinobu Ichiki and co-authors have no

conflict of interest to report.

References

1. Bernstein M, Kovar H, Paulussen M, Randall RL, Schuck A, Teot

LA, et al. Ewing’s sarcoma family of tumors: current manage-

ment. Oncologist. 2006;11:503–11.

2. Tsuji S, Hisaoka M, Morimitsu Y, Hashimoto H, Jimi A,

Watanabe J, et al. Peripheral primitive neuroectodermal tumour

of the lung: report of two cases. Histopathology. 1998;33:369–74.

3. Rud NP, Reiman HM, Pritchard DJ, Frassica FJ, Smithson WA.

Extraosseous Ewing’s sarcoma. A study of 42 cases. Cancer. 1989;

64:1548–53.

4. Triche TJ, Askin FB. Neuroblastoma and the differential diagnosis

of small-round-, blue-cell tumors. Hum Pathol. 1983;14:569–95.

5. Dei Tos AP, Wadden C, Calonje E, Sciot R, Pauwels P, Knight

JC, et al. Immunohistochemical demonstration of glycoprotein

p30/32 MIC (CD99) in synovial sarcoma. A potential cause of

diagnostic confusion. Appl. Immunohistochem. 1995;3:168–73.

6. Fellinger EJ, Garin-Chesa P, Triche TJ, Huvos AG, Retting WJ.

Immunohistochemical analysis of Ewing’s sarcoma cell surface

antigen p30/32 MIC2. Am J Pathol. 1991;139:317–25.

7. Lumadue JA, Askin FB, Perlman EJ. MIC2 analysis of small cell

carcinoma. Am J Clin Pathol. 1994;102:692–4.

8. Takahashi D, Nagayama J, Nagatoshi Y, Inagaki J, Nishiyama K,

Yokoyama R, et al. Primary Ewing’s sarcoma family tumors of

the lung—a case report and review of the literature. Jpn J Clin

Oncol. 2007;37:874–7.

9. Hancom K, Sharma A, Shackcloth M. Case report-thoracic on-

cologic Primary extraskeletal Ewing’s sarcoma of the lung.

Interact Cardiovasc Thorac Surg. 2010;10:803–4.

10. Raney RB, Asmar L, Newton WA Jr, Bagwell C, Breneman JC,

Crist W, et al. Ewing’s sarcoma of soft tissues in childhood: a

report from the Intergroup Rhabdomyosarcoma Study, 1972 to

1991. J Clin Oncol. 1997;15:574–82.

11. Cotterill SJ, Ahrens S, Paulussen M, Jurgens HF, Voute PA, Gadner

H, et al. Prognostic factors in Ewing’s tumor of bone: analysis of

975 patients from the European Intergroup Cooperative Ewing’s

Sarcoma Study Group. J Clin Oncol. 2000;18:3108–14.

12. Zucman J, Melot T, Desmaze C, Ghysdael J, Plougastel B, Peter

M, et al. Combinatorial generation of variable fusion protein in

the Ewing family of tumours. EMBOJ. 1993;12:4481–7.

13. Gyorke T, Zajic T, Lange A, Schafer O, Moser E, Mako E, et al.

Impact of FDG PET for staging of Ewing sarcoma and primitive

neuroectodermal tumours. Nucl Med Commun. 2006;27:17–24.

14. Arvand A, Denny CT. Biology of EWS/ETS fusions in Ewing’s

family tumors. Oncogene. 2001;20:5747–54.

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