Ewing’s sarcoma as second malignancy following a short latency in unilateral retinoblastoma
© The Author(s) 2011
Received: 31 December 2010
Accepted: 4 July 2011
Published: 9 August 2011
Second malignancies, mostly in the form of bone sarcomas, are known to occur in hereditary retinoblastomas, which usually present with bilateral disease. Only 2 cases of Ewing’s sarcoma have been reported in the literature following sporadic unilateral retinoblastoma. A 5-year-old boy presented to our hospital with Ewing’s sarcoma of the right humerus (proven by biopsy and immunohistochemistry) following successful treatment of retinoblastoma of the left eye with enucleation and chemotherapy 2 years previously. He was treated with 2 cycles of chemotherapy followed by radiation therapy. At 15 months follow-up, the tumor had reduced in size and the child had a good functional outcome. The cumulative risk of second malignancies in retinoblastoma survivors is 32%. Ninety-eight percent of second malignancies occur in patients with bilateral retinoblastoma. Germ line mutations have been considered in sporadic tumors occurring bilaterally and multifocal unilateral sporadic tumors. Bone and soft tissue sarcomas are the most common second malignancies. Radiation therapy increases the risk of developing a second malignancy in the irradiated field. Unilateral retinoblastomas, which comprise the majority of retinoblastomas, are not immune from the development of second malignancies. Close follow-up of all retinoblastomas—even in the early period—can improve the outcome by facilitating the early detection and aggressive treatment of second malignancies.
KeywordsEwing’s sarcoma Second malignancy Unilateral retinoblastoma Short latency
Retinoblastoma (RB) is the most common malignant ocular tumor in the pediatric age group, occurring in 1/15,000 to 1/30,000 live births , although it forms a smaller percentage of all pediatric malignancies (~5/1,00,000 children) . There are two broad subgroups—hereditary (40%) and nonhereditary (60%) . The hereditary group present at a younger age, usually have bilateral disease, and have an underlying germ line mutation of the RB1 gene. The nonhereditary group present at a later age, and have unilateral disease as well as an underlying genetic mutation arising in the somatic cells. More than 90% of these patients experience long-term survival due to successful treatment regimens . Both radiation therapy and chemotherapy with alkylating agents increase the risk of subsequent development of bone sarcomas in children who survive childhood cancers . Nonocular second malignant neoplasms have occurred almost exclusively in children with bilateral disease, who constitute only 25% of cases. The most common second malignant neoplasms in these patients are sarcomas, especially bone sarcomas, though a wide variety of second tumors have been reported, such as melanoma, chondrosarcoma, leukemia, neuroblastoma, and leiomyosarcoma . Bone and soft tissue sarcomas are the most common second malignant neoplasms; osteogenic sarcoma is the single most common second malignant neoplasm .
Previously, six cases of Ewing’s sarcoma in patients with a prior history of bilateral [1, 6, 8, 16] and two cases of unilateral [6, 12] retinoblastoma have been reported. Here, we present a case of a child with unilateral RB who developed Ewing’s sarcoma of the right humerus 2 years after enucleation of the left eye, and a review of the pertinent literature.
A whole-body bone scan showed no evidence of bony metastasis. However, contrast-enhanced computed tomography (CECT) of the chest showed two pulmonary nodules in the right lung, suggestive of metastasis. A guided biopsy of the nodules confirmed the diagnosis of metastasis.
The patient was classified as being at an advanced stage of the disease due to the presence of metastasis. Treatment was directed towards palliating symptoms at the local site by radiotherapy and aggressive chemotherapy. Since the patient was already being treated with a standard chemotherapy protocol, a modified chemotherapy regimen with ifosfamide and etoposide was undertaken. The patient underwent 2 cycles of chemotherapy with ifosfamide and etoposide followed by radiotherapy in 2 phases, initially with 44 Gy and subsequently with 20 Gy. The patient was followed up regularly for 18 months. By that time, the swelling decreased in size and was not tender. Complete elbow range of motion was regained, and the vision in the right eye was normal.
Survivors of retinoblastoma invariably carry a high risk of developing a second malignant neoplasm, with the cumulative risk being 32% . Ninety-eight percent of the secondary malignant tumors occur in patients with bilateral retinoblastoma or in 15% of patients with unilateral RB with underlying germline mutation. However, unilateral RBs comprise almost 75% of all retinoblastomas . By far the most common second malignant neoplasm has been osteosarcoma . The second most frequent second malignant neoplasms have been soft-tissue sarcomas .
In children previously irradiated for retinoblastoma, 70% of second malignant neoplasms have occurred in the field and 30% outside the field of radiation . Abramson et al.  reviewed 2,302 survivors of childhood retinoblastomas. 71.3% of neoplasms occurred within the radiation therapy field after an average latent period of 11.4 years, and 18.8% occurred outside the radiation field after an average latent period of 11.1 years. Osteosarcoma was the most common second malignant neoplasm, irrespective of the relation between radiation therapy field and location of the tumor. Roarty et al.  evaluated 215 patients for the cumulative incidence of second neoplasms in patients with bilateral retinoblastoma using life table methods. Second tumors developed in 4.4% of the patients during the first 10 years of follow-up, 18.3% after 20 years, and 26.1% after 30 years. In their group of patients, the 30-year cumulative incidence was 35.1% for the 137 patients who received radiation therapy, compared with 5.8% of 78 patients who did not receive radiation therapy. There was a 30-year incidence rate of 29.3% for second tumors within the field of irradiation, and 8.1% outside the field. These findings suggested that carriers of the retinoblastoma gene have an increased incidence of second tumors and that the incidence rate is further increased in patients who received radiation therapy.
Heritable retinoblastoma and osteosarcoma were found to be associated in some cases with the deletion of the 13q14 locus of the RB-1 gene . A variety of second malignant neoplasms have been reported in the literature, including osteosarcoma, fibrosarcoma, skin carcinomas, malignant melanomas, rhabdomyosarcomas, acute lymphoblastic leukemia, and sinonasal carcinoma, but few reports indicate the frequency of development of Ewing’s sarcoma after retinoblastoma . Clinically, it is difficult to differentiate a unilateral retinoblastoma of heritable type from nonheritable but generally sporadic tumors occurring bilaterally, and multifocal unilateral sporadic tumors are considered germ cell mutations . Patients with unilateral, unifocal retinoblastoma and negative family histories have not been considered to be at increased risk for second malignant neoplasms. Although, to the best of our knowledge, the current report is the third (after Helton et al.  and Mittal et al. ) on Ewing’s sarcoma in unilaterally affected patients with retinoblastoma, it is not possible to exclude the presence of a germinal mutation in any of these cases.
Skeletal scintigrams are not economically feasible to use for screening purposes to detect second malignant neoplasms, despite their capacity for earlier detection . MRI is a very sensitive method of displaying bone lesions but, in the absence of localizing symptoms, it is not yet a practical method of routine skeletal imaging.
Children of affected parents have a 50% risk of having retinoblastoma . The risk of second malignant neoplasms in retinoblastoma has been variably estimated to be between 1.5 and 90% [11, 16]. This increased incidence is believed to be secondary to the loss of normal tumor suppression activity of the retinoblastoma gene on chromosome 13. Radiation or chemotherapy or both put these patients at further risk, though second malignant neoplasms are also common in patients who have not received these adjuvant treatments. Patients with the genetic form of retinoblastoma are also at higher risk.
Ewing’s sarcoma as a second malignant neoplasm after retinoblastoma:literature review
Year of publication
Age of presentation
Schifter et al. 
Abrahamson et al. 
Abrahamson et al. 
Helton et al. 
Helton et al. 
Death due to metastasis
Mittal et al. 
Chemotheray + surgery + autologous stem cell transplantation
The present case highlights the fact that patients with retinoblastoma are at an increased risk of developing a second malignant neoplasm, the latency of which is highly variable. It is also worth noting that unilateral retinoblastoma, which represents the majority of cases, is not immune from the development of second malignant neoplasms, considering that a germline mutation can never be ruled out. Ewing’s sarcoma, a tumor which responds excellently to chemoradiotherapy, should not be missed in the primary diagnosis of bone sarcomas presenting as second malignant neoplasms. Close follow-up, early detection and aggressive treatment of second malignant neoplasms can improve the outcome.
Written consent was obtained from the parents of the child before submission of this case report and of any accompanying images.
We are thankful to Mr. Martin Richardson for his review and useful comments on the content of this article.
Conflict of interest
This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution and reproduction in any medium, provided the original author(s) and source are credited.
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