Skeletal Radiology

, Volume 43, Issue 9, pp 1319–1324

Diagnosis of osteosarcoma in a patient previously treated for Ewing sarcoma

Authors

    • Department of Orthopedic SurgeryOsaka City University Graduate School of Medicine
  • Makoto Ieguchi
    • Department of Orthopedic SurgeryOsaka City University Graduate School of Medicine
  • Kazumi Yamato
    • Department of PediatricsOsaka City University Graduate School of Medicine
  • Sadao Tokimasa
    • Department of PediatricsOsaka City University Graduate School of Medicine
  • Hiroaki Nakamura
    • Department of Orthopedic SurgeryOsaka City University Graduate School of Medicine
Case Report

DOI: 10.1007/s00256-014-1880-z

Cite this article as:
Hoshi, M., Ieguchi, M., Yamato, K. et al. Skeletal Radiol (2014) 43: 1319. doi:10.1007/s00256-014-1880-z
  • 248 Views

Abstract

Primary malignant bone tumors, whether Ewing sarcoma or osteosarcoma, are a rare type of tumor. The sequential occurrence of two bone sarcomas, Ewing sarcoma and high-grade osteosarcoma, in the same patient at two different locations is an exceptionally rare phenomenon. We present the case of a 13-year-old girl who presented with a high-grade osteoblastic osteosarcoma of the distal femur, 7 years after treatment for Ewing sarcoma of the left pelvis. She did not receive radiation therapy. Following the recent developing multidisciplinary therapy, long-term follow-up for monitoring latent treatment-related adverse effects may be necessary for survivors of primary malignant bone tumors.

Keywords

OsteosarcomaEwing sarcomaChemotherapyLatent adverse effect

Introduction

The prognosis of high-grade bone tumors has improved markedly and the number of long-term survivors has increased in recent years, mainly because of multidisciplinary therapy, including neoadjuvant chemotherapy, radiation therapy, and limb salvage surgery. With an increase in the number of long-term survivors, latent treatment-related adverse effects, such as secondary malignancy, have generated new problems.

Secondary osteosarcoma after treatment for Ewing sarcoma in the same patient is an extremely rare event. In this report, we report the case of a 13-year-old girl who presented with a high-grade osteoblastic osteosarcoma of the right distal femur, 7 years after treatment for Ewing sarcoma of the left pelvis.

This patient and her family were informed that the data from her case would be submitted for publication, and they provided consent.

Case report

A 6-year-old girl presented with a painful mass in the left buttock and high fever. At initial hospital presentation, chronic osteomyelitis was first suspected. After antibiotics had been administered for 3 weeks, her blood laboratory data concerning inflammatory markers of white blood cells (WBCs) and C-reactive protein (CRP) improved from 9,100/μl and 6.0 mg/dl at the initial visit, to 6,100/μl and 1.3mg/dl; however, her left leg pain continued. She visited another hospital 2 months after onset of her symptoms, and radiology identified a bone tumor of the left ilium. She was then referred to our hospital. The patient’s medical history was remarkable for bronchial asthma and atopic dermatitis. Her family history gave no indication of genetic predisposition to bone tumors.

At the first visit to our hospital, physical examination revealed a firm, non-mobile mass that was palpable in the left buttock. An initial radiograph revealed permeative-type bone destruction with focal mineralization in the left ilium (Fig. 1a). Coronal T2-weighted magnetic resonance image showed a heterogeneous, high intensity mass in the left iliac bone (Fig. 1b), and computed tomography (Fig. 1c) displayed a large mass of 16 × 6 × 4 cm, expanding the left ilium with cortical destruction. Open biopsy of the tumor confirmed uniform small round cells with round nuclei containing fine chromatin, scanty cytoplasm, and eosinophilic membranes. Areas with a pseudo-alveolar structure surrounded by tumor cells with scant osteoid production were observed. Immunohistologically, the tumor was diffusely positive for CD99, and the pathological diagnosis was consistent with Ewing sarcoma (Fig. 1d). As an alternative diagnosis, small cell osteosarcoma was considered, but ruled out because of the lack of osteoids. In reverse transcriptase polymerase chain reaction (RT-PCR) analyses, the characteristic chromosomal translocations of EWS/FLI1 and EWS/ERG were not detectable.
https://static-content.springer.com/image/art%3A10.1007%2Fs00256-014-1880-z/MediaObjects/256_2014_1880_Fig1_HTML.gif
Fig. 1

a A radiograph demonstrating an osteolytic lesion occupying the left ilium. b Coronal T2-weighted magnetic resonance image showing a heterogeneous, high-intensity mass in the left iliac bone. c Computed tomography image demonstrating the mass expanding the left ilium with cortical destruction. d Microscopically, a small round cell tumor was observed and diagnosed as Ewing sarcoma (magnification ×400)

Preoperatively, the patient received high-dose intensive chemotherapy, according to the European Ewing Tumor Working Initiative of National Groups 1999 [1] protocol with modifications. The six preoperative cycles of chemotherapy comprised vincristine, ifosfamide, doxorubicin, and etoposide. The tumor mass extending into the soft tissue shrank and osteosclerotic changes with shell formation were visible in the left ilium. Consequently, a wide resection of the pelvic tumor was performed. Pathological findings of the resected specimen showed 100% necrosis, and a clear wide margin was obtained. Postoperatively, she received one cycle of vincristine, cyclophosphamide, and actinomycin-D, and after pre-treatment with busulfan and L-phenylalanine mustard, she also received adjuvant treatment with peripheral blood stem cell transplantation. The patient was followed up at regular intervals every 6 months, with clinical examinations, radiographs of the pelvic bone, and computed tomography scans of the lungs. She was found to be disease-free for 7 years and 4 months since the last round of chemotherapy.

Seven years and 6 months after resection of the Ewing sarcoma, she noted gradually increasing pain in her right knee joint. An outside radiograph showed an ill-defined lytic lesion with an osteoid matrix and a spiculated periosteal reaction was present in the distal right femur, suggestive of osteosarcoma or metastasis from prior Ewing sarcoma (Fig. 2a). She was referred to our hospital, where an MR scan demonstrated that coronal T1-weighted (Fig.2b) and axial T2-weighted (Fig.2c) magnetic resonance images showed a heterogeneously low to isointense (T1-weighted) and heterogeneously hyperintense (T2-weighted) mass extending from the distal femur metadiaphysis into the adjacent soft tissues. Pathological diagnosis of a biopsy specimen from the right distal femur was consistent with osteoblastic osteosarcoma, showing highly anaplastic tumor cells containing osteoids (Fig. 2d). Caffeine-assisted chemotherapy, comprising cisplatin, doxorubicin, and caffeine, was administered [2]. However, the rapid tumor growth required surgical treatment with right hip disarticulation approximately 1 month after presentation of right knee pain.
https://static-content.springer.com/image/art%3A10.1007%2Fs00256-014-1880-z/MediaObjects/256_2014_1880_Fig2_HTML.gif
Fig. 2

a Radiograph of the right distal femur demonstrating an aggressive lytic bone lesion with osteoid matrix in the distal femur metadiaphysis. b Coronal T2-weighted magnetic resonance image showing a heterogeneous, high signal intensity expansible mass. c Axial T2-weighted magnetic resonance image demonstrating high-intensity mass centered within the medullary with cortical break-through and large soft tissue component. d Microscopically, pathological examination of biopsy material confirmed osteoblastic osteosarcoma (magnification ×400)

Despite subsequent aggressive multiple regimens of chemotherapy, radiation therapies, and surgeries for metastatic lesions, the tumor progressed quickly. The patient ultimately passed away after developing disseminated metastatic disease, including worsening of lung metastases.

Discussion

The recent therapeutic results of Ewing sarcoma have improved markedly because of multidisciplinary treatment comprising surgery, radiotherapy, and chemotherapy [3, 4]. Accordingly, the number of long-term survivors after treatment for Ewing sarcoma has increased. However, long-term survivors experience latent treatment-related adverse effects of anticancer agents and radiotherapy [5].

Of all primary malignant bone tumors, osteosarcoma is the most common, accounting for 19.2% of all primary malignant bone tumors. However, its absolute incidence is low, estimated to be 5.6 cases per year per million population. The incidence of Ewing sarcoma was calculated as approximately 6–8% of primary malignant tumors, accounting for 2.1 cases per year per million [68]. The sequential occurrence of two bone sarcomas, Ewing sarcoma and high-grade osteosarcoma, in the same patient at two different locations is considered an exceptionally rare phenomenon.

Ewing sarcoma was generally treated as a chemo-sensitive tumor, and multiple agent chemotherapy has made a significant improvement in the prognosis of patients with Ewing sarcoma [9]. However, these patients are at risk of secondary malignancies after treatment. This risk is thought to be related to the intensification of chemotherapeutic agents composed of adjuvant and neoadjuvant chemotherapies. Although the initial protocol consisted of a three-drug regimen (cyclophosphamide, doxorubicin, and vincristine), a five-drug regimen (cyclophosphamide, doxorubicin, vincristine, ifosfamide, and dactinomycin) has been introduced in the most recent protocol [10]. Several previous reports [5, 1118] demonstrated the incidence of secondary malignancy after treatment of Ewing sarcoma (Table 1). Fuchs et al. [11] demonstrated three secondary osteosarcomas that developed from 397 patients with Ewing sarcoma (0.76%). Navid et al. [12] reported that 12 out of 237 (0.84%) patients developed secondary osteosarcoma after treatment for Ewing sarcoma. Sultan et al. [18] demonstrated that secondary osteosarcoma was found in 4 out of 1,166 (0.34%) patients. The Italian Sarcoma Group reported that secondary osteosarcomas after Ewing sarcoma were found in 6 out of 543 patients (1.1%) [5].
Table 1

Previous papers concerning secondary malignancies in patients with Ewing sarcoma

Author

Year

Number

Regimens

Group

Cumulative doses

Secondary malignancy (number)

Interval

Reference

Fuchs et al.

2003

397

Not available

 

Not available

Hematopoietic cancers (8)

Average 9.5 (1–32.5) years

[11]

Fibrosarcoma of bone (5)

Radiation-induced osteosarcoma (3)

Malignant fibrous histiocytoma (3)

Liposarcoma (1)

Cervical cancer (3)

Breast cancer (3)

Thyroid cancer (3)

Navid et al.

2008

237

ES79

 

Doxorubicin, 210 mg/m2; cyclophosphamide, 6,300 mg/m2

 

Median 2.6 years (1.4–19.6) years

[12]

ES87

 

Doxorubicin, 480 mg/m2; vincristine, 25.5 mg/m2; dactinomycin, 15 mg/m2

[13]

Cyclophosphamide, 1,350 mg/m2; ifosfamide, 96,000 mg/m2; etoposide, 600 mg/m2

[14]

EWI92

 

Doxorubicin, 365 mg/m2; vincristine, 10.5 mg/m2; dactinomycin, 6.0 mg/m2

[15]

Cyclophosphamide, 1,650 mg/m2; ifosfamide, 58,000 mg/m2; etoposide, 4,350 mg/m2

MDS/AML(6)

[16]

POG9354

Standard group

Doxorubicin, 375 mg/m2; vincristine, 13.5 mg/m2

ALL (2)

Cyclophosphamide, 1,080 mg/m2; ifosfamide, 72,000 mg/m2; etoposide, 4,000 mg/m2

Radiation-induced osteosarcoma (2)

[17]

Intensified group

Doxorubicin, 375 mg/m2; vincristine, 13.5 mg/m2;

Cervical cancer (1)

Cyclophosphamide, 1,200 mg/m2; ifosfamide, 72,000 mg/m2; etoposide, 5,000 mg/m2

Thyroid cancer (1)

SJBCM 1998

High-risk sarcoma 1

Doxorubicin, 330 mg/m2; vincristine, 24 mg/m2;

 

Cyclophosphamide, 21,000 mg/m2; ifosfamide, 46,000 mg/m2; etoposide, 2,700 mg/m2

High-risk sarcoma 2

Doxorubicin, 270 mg/m2; vincristine, 27 mg/m2

Cyclophosphamide, 18,000 mg/m2; ifosfamide, 36,000 mg/m2; etoposide, 2,700 mg/m2

Sultan et al.

2010

1,166

Not available

 

Not available

Osteosarcoma (4)

Median 70 (0–317) months

[18]

Soft-tissue sarcoma (6)

Breast cancer (3)

Lung and bronchus (2)

Male genital system (2)

ANLL (6)

Lymphoma (3)

ALL (1)

Longhi et al.

2012

91

REN-1 1983–1987

 

Doxorubicin, 315 mg/m2; vincristine, 39 mg/m2; dactinomycin, 7.5 mg/m2; cyclophosphamide, 18,000 mg/m2;

Radiation-induced Osteosarcoma (6)

Median 84 (12—253) months

[5]

78

REN-2 1988–1991

 

Doxorubicin, 400 mg/m2; vincristine, 18 mg/m2; dactinomycin, 6.25 mg/m2

AML (2)

Cyclophosphamide, 8,400 mg/m2; ifosfamide, 54,000 mg/m2; etoposide, 1,500 mg/m2

Parotid cancer (2)

186

REN-3 1991–1999

 

Doxorubicin, 400 mg/m2; vincristine, 19.5 mg/m2; dactinomycin, 6.5 mg/m2

Thyroid cancer (2)

Ifosfamide, 54,000 mg/m2; etoposide, 1,500 mg/m2

Non-Hodgkin’s lymphoma (1)

188

ISG/SSG III

Good responders

Doxorubicin, 400 mg/m2; vincristine, 21 mg/m2; dactinomycin, 6 mg/m2;

Breast cancer (1)

Cyclophosphamide, 6,000 mg/m2; ifosfamide, 72,000 mg/m2; etoposide, 1,800 mg/m2

Melanoma (1)

Poor responders

Doxorubicin, 320 mg/m2; vincristine, 15 mg/m2; dactinomycin, 1.5 mg/m2

 

Cyclophosphamide, 6,400 mg/m2; ifosfamide, 21,000 mg/m2; etoposide, 1,700 mg/m2

ES Ewing sarcoma, REN Rizzoli Ewing neoadjuvant, POG pediatric oncology group, SJBCM St. Jude Best Clinical Management, ISG Italian study group, SSG Scandinavian study group, MDS myelodysplastic syndrome, AML acute myeloid leukemia, ALL acute lymphoblastic leukemia ANLL acute non-lymphocytic leukemia, Interval interval to the second malignancy

Recent genetic analysis using reverse transcription PCR (RT-PCR) has been applied to the diagnosis of Ewing sarcoma. The EWS-FLI1 fusion gene is detectable in 85% of patients with Ewing sarcoma, and a variant EWS-ERG fusion gene is found in 5% to 10% of cases. Neither of these two chromosomal translocations were observed in the present case. Thus, we did not examine other rare types of gene fusion, such as EWS-ETV1 and E1AF, which are detected in less than 1% of Ewing sarcomas [19]; however, our results may suggest that another diagnostic entity of round cell sarcoma, such as small cell osteosarcoma, might have been present in this case, differing from our diagnosis of Ewing sarcoma.

We initially administered caffeine-assisted chemotherapy to this patient immediately after diagnosis of osteosarcoma. Caffeine, which is a xanthine analog, has a biological modulating effect as a DNA repair inhibitor and may inhibit postreplication repair of sub-lethally damaged DNA [20]. Tsuchiya et al. [2] developed caffeine-assisted chemotherapy for osteosarcoma, and induced a high rate of complete response (> 86%). However, its efficacy was disappointing in our patient. Because of the rapid tumor growth, hip disarticulation was carried out.

At least two factors, genetic factors and acquired conditions related to treatment modalities, must be considered as the possible causes of secondary malignancy. In this patient, the familial history of the patient related to cancer showed nothing of concern and the patient did not seem to fit the clinical diagnostic criteria of Li–Fraumeni syndrome [21] or hereditary retinoblastoma [22]. Most secondary osteosarcomas after treatment for Ewing sarcoma are associated with previous radiation therapy [5, 7, 22, 23]; however, our patient had not received previous radiation therapy. Our patient was the second reported case [24] not to have received previous radiation therapy, and to have a second instance of a high-grade osteosarcoma that occurred in an anatomically unrelated site.

Some authors have suggested multi-agent chemotherapy as a possible cause of secondary malignancy in young cancer survivors [5, 10, 12, 18]. Vincristine, cyclophosphamide, ifosfamide, doxorubicin, and etoposide are commonly used in chemotherapy for Ewing sarcoma. Tucker et al. [25] concluded that the alkylating agents for childhood cancer increase the subsequent risk of secondary tumors. In this case, the alkylating agents, ifosfamide and cyclophosphamide, had been administered 7 years previously. It is impossible to clarify the link between secondary malignancy and chemotherapy, but the possibility should be considered.

In our patient, 7 years elapsed between the initial diagnosis of Ewing sarcoma and discovery of the possible secondary malignancy. Fuchs et al. [11] demonstrated that the average interval from the diagnosis of the Ewing sarcoma to the development of the secondary malignancy was 9.5 years (1–32.5 years), and additional studies have shown the median length of the interval between initial Ewing sarcoma diagnosis and secondary malignancy development to be 2.6–7.0 years [5, 12]. Thus, long-term follow-up may be necessary to reveal the development of secondary malignancy for young survivors of Ewing sarcoma in order to monitor latent treatment-related adverse effects.

In conclusion, we presented a rare case of a pelvic Ewing sarcoma and osteosarcoma of the femur 7 years after the first tumor. There is always a possibility of the occurrence of sequential malignancy, and medical professionals involved with orthopedic oncology, as well as patients, should be aware of this potential adverse latent effect. Long-term follow-up is important for young survivors, even after successful treatment.

Acknowledgements

We thank Kenichi Wakasa for the pathological examinations and interpretations.

Conflict of interest

The authors declare that they have no conflict of interest.

Copyright information

© ISS 2014