Diagnosis of osteosarcoma in a patient previously treated for Ewing sarcoma
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- Hoshi, M., Ieguchi, M., Yamato, K. et al. Skeletal Radiol (2014) 43: 1319. doi:10.1007/s00256-014-1880-z
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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.
KeywordsOsteosarcomaEwing sarcomaChemotherapyLatent adverse effect
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.
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.
Preoperatively, the patient received high-dose intensive chemotherapy, according to the European Ewing Tumor Working Initiative of National Groups 1999  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.
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.
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 .
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 [6–8]. 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.
Previous papers concerning secondary malignancies in patients with Ewing sarcoma
Secondary malignancy (number)
Fuchs et al.
Hematopoietic cancers (8)
Average 9.5 (1–32.5) years
Fibrosarcoma of bone (5)
Radiation-induced osteosarcoma (3)
Malignant fibrous histiocytoma (3)
Cervical cancer (3)
Breast cancer (3)
Thyroid cancer (3)
Navid et al.
Doxorubicin, 210 mg/m2; cyclophosphamide, 6,300 mg/m2
Median 2.6 years (1.4–19.6) years
Doxorubicin, 480 mg/m2; vincristine, 25.5 mg/m2; dactinomycin, 15 mg/m2
Cyclophosphamide, 1,350 mg/m2; ifosfamide, 96,000 mg/m2; etoposide, 600 mg/m2
Doxorubicin, 365 mg/m2; vincristine, 10.5 mg/m2; dactinomycin, 6.0 mg/m2
Cyclophosphamide, 1,650 mg/m2; ifosfamide, 58,000 mg/m2; etoposide, 4,350 mg/m2
Doxorubicin, 375 mg/m2; vincristine, 13.5 mg/m2
Cyclophosphamide, 1,080 mg/m2; ifosfamide, 72,000 mg/m2; etoposide, 4,000 mg/m2
Radiation-induced osteosarcoma (2)
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)
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.
Median 70 (0–317) months
Soft-tissue sarcoma (6)
Breast cancer (3)
Lung and bronchus (2)
Male genital system (2)
Longhi et al.
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
Doxorubicin, 400 mg/m2; vincristine, 18 mg/m2; dactinomycin, 6.25 mg/m2
Cyclophosphamide, 8,400 mg/m2; ifosfamide, 54,000 mg/m2; etoposide, 1,500 mg/m2
Parotid cancer (2)
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)
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
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
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 ; 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 . Tsuchiya et al.  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  or hereditary retinoblastoma . 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  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.  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.  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.
We thank Kenichi Wakasa for the pathological examinations and interpretations.
Conflict of interest
The authors declare that they have no conflict of interest.