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© The Author 2007. Published by Oxford University Press.
EDITORIAL |
Retinoblastoma Survivors: Sarcomas and Surveillance
Correspondence to: Anna T. Meadows, MD, Division of Pediatric Oncology, Children's Hospital of Philadelphia, 3400 Civic Center Blvd., Philadelphia, PA 19104 (e-mail: meadows{at}email.chop.edu).
Modern therapy for childhood cancer began in 1970, and when, in the 1980s, cure rates increased and survivors were sufficiently numerous, reports of second cancers began to emerge. Despite its rarity among children with cancer (3%), retinoblastoma was the most frequent first neoplasm in a large cohort of survivors with second cancers (1,2). During that same period, our knowledge of the genetics of retinoblastoma increased, and the RB-1 gene, cloned from a secondary sarcoma, was found to be a critical regulator of cell proliferation in all cells (3,4). This raised a question: why did mutations in this gene predispose carriers to retinoblastoma specifically? We now know that the gene was not specific for this cancer and, in fact, other cancers were also part of the predisposition.
As early as 1969, secondary sarcomas following external beam radiation for retinoblastoma were reported (5). When these same secondary tumors were noted to also arise outside the radiation field and only in children with bilateral disease (i.e., children who had the genetic form of retinoblastoma), it was suggested that the gene predisposed to second cancers, with radiation shortening the latent period and increasing the risk (6).
The report by Kleinerman et al. (7) in this issue of the Journal contains new information that is important for clinicians who follow retinoblastoma survivors. It concerns secondary soft tissue sarcomas in 963 survivors of the genetic form of retinoblastoma, who carry a germline mutation in RB-1. These subjects are a subset of a cohort of 1601 one-year survivors who were followed by these same investigators for an average of 25 years, almost half of them for more than 30 years (8). The authors began a medical record review in 1984 and, in 2000, held additional telephone interviews with survivors. Analysis of the entire cohort (8) clearly demonstrated differences in second cancer frequency at 50 years based on whether the patients had the genetic form of retinoblastoma (i.e., bilateral disease or unilateral disease with a positive family history) or the nongenetic form (36% versus 6%) and whether the second tumor was associated with radiation therapy or not (38% versus 21%). None of the 638 survivors of nongenetic retinoblastoma in that larger cohort reported secondary soft tissue sarcomas. Unlike earlier reports (9,10), in which the estimate of second cancer incidence was considerably greater, ascertainment of unaffected individuals in this cohort was virtually complete. And, because of the large size of this cohort and the long follow-up period, with 35 additional soft tissue sarcomas reported since 1993, the analysis in this issue provides further details regarding a variety of specific histologic subtypes of sarcomas in survivors of the genetic form of retinoblastoma.
During the period from 1914 to 1984, when these patients were diagnosed, treatment consisted of removal of the eye, external beam radiation therapy, and, rarely, chemotherapy with triethylene melamine (TEM), an alkylating agent that has not been used since the 1960s. Most children with unilateral disease were curable with retention of vision when the affected eye was removed. However, for children with bilateral disease, who are generally younger than 1 year at diagnosis, concern for subsequent development required treatment options that would enable them to eradicate the tumors and, therefore, retain vision in at least one eye. Radiation therapy offered an ideal solution, especially when higher energy radiation became available and lower doses could be used successfully. Cosmetic deformity due to radiation-associated failure of orbital bone growth at such young ages (85% of this cohort were <2 years of age at diagnosis) was recognized early on (11), but only during the latter years of the era during which these children were treated was there concern regarding second cancers; the hope was that vision could be preserved in spite of the risks.
Although 66 of the 69 sarcomas identified in the 963 survivors of hereditary retinoblastoma analyzed by Kleinerman et al occurred in children who received radiation to the orbits (see Table 2), 18 did not arise in the irradiated field, a fact that reinforces the singular importance of genetic predisposition in carriers of the germline RB-1 mutation. Genetic predisposition may be especially important in the etiology of leiomyosarcoma, the most frequent of the soft tissue sarcomas reported here, because 14 of the 22 leiomyosarcomas did not occur in the field of radiation. Loss of heterozygosity for RB-1 has been found in uterine leiomyosarcomas in noncarriers of RB-1 mutations, and second mutations in RB-1 can be associated with radiation but not through "chromosomal instability." The usual mechanism for the second event in retinoblastoma carriers is recombination, although point mutations and deletion are also known to occur. Moreover, one might question whether radiation to the orbit could have had any effect on the development of tumor in the pelvis.
Radiation with chemotherapy (primarily TEM) was associated with a greater risk for leiomyosarcoma than radiation alone. However, because patients in the older cohort (the ages at which the majority of leiomyosarcomas occurred; see Table 5) were the only ones treated with TEM, this apparent "increased risk" might be spurious. Unlike many other second cancers, such as carcinomas of the breast and gastrointestinal tract, that occur at earlier than expected ages in survivors of childhood cancer who had radiation therapy (12–14), leiomyosarcomas occurred at the same ages as individuals in the general population. Eighteen of the 23 cases were diagnosed more than 30 years after the diagnosis of retinoblastoma, and four were diagnosed 20–29 years after the retinoblastoma diagnosis. Therefore, the older individuals with leiomyosarcomas would have been more likely to receive TEM since they were diagnosed and treated for retinoblastoma in the early years of this cohort.
Rhabdomyosarcoma, the only embryonal sarcoma in the group, seems to be associated primarily with radiation. Not unexpectedly, therefore, all but one of eight were diagnosed in the first two decades after treatment, during a normal growth period. Fibrosarcomas, fibrous histiocytomas, and miscellaneous other soft tissue sarcomas also appeared to be more frequent in the field of radiation, but only longer follow-up will determine whether they too will emerge in more recently treated patients who were spared radiation but in whom an RB-1 mutation is exerting an influence.
Of the 963 patients in this cohort, only 283 reported a positive family history, 236 with bilateral disease and 47 with a tumor in only one eye. (The other 680 were not truly "hereditary" in that they did not inherit the mutation from a parent, but they were known to carry a germline mutation.) If the family history in the 47 unilateral patients had been negative, they would have been indistinguishable from those with the nongenetic form of retinoblastoma, and their increased risk for second cancers would not have been appreciated. It is now possible to determine whether children with unilateral disease carry a germline RB-1 mutation, especially if tumor tissue is available (15,16). Increased surveillance for second cancer in survivors of retinoblastoma should include all those with bilateral disease, as well as those with unilateral disease who were less than 2 years at diagnosis, regardless of their family history, unless the screening for germline mutations is unequivocally negative.
Radiation for bilateral disease was still the therapy of choice until the last decade. When chemotherapeutic agents were found to be useful in treating brain tumors, they began to be used in children with retinoblastoma whose eyes might otherwise have been enucleated or exposed to radiation. Clinicians used two, three, or four drugs to reduce the size of intraretinal lesions, rendering them amenable to focal laser or cryotherapy (17–20). In this way, as many as 70% of eyes could be saved, and few required radiation therapy (21).
Improved treatment can be expected to reduce the incidence of soft tissue (and bone) sarcomas associated with radiation. The importance of this report lies in its emphasis on leiomyosarcoma, a tumor that occurs in RB-1 gene carriers whether or not they were treated with radiation and that can be expected to continue to occur in older survivors, who will require more careful follow-up.
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J Natl Cancer Inst 2007 99: 24-31.
J Natl Cancer Inst 2007 99: 1.
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