© The Author 2007. Published by Oxford University Press.
ARTICLE |
Risk of Soft Tissue Sarcomas by Individual Subtype in Survivors of Hereditary Retinoblastoma
Affiliations of authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, MD (RAK, MAT, JFF); Ophthalmic Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY (DHA); Epidemiology Service, Massachusetts Eye and Ear Infirmary, Boston, MA (JMS); International Epidemiology Institute, Rockville, MD (RET).
Correspondence to: Ruth A. Kleinerman, MPH, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, EPS 7044, 6120 Executive Blvd., Rockville, MD 20852 (e-mail: kleinerr{at}mail.nih.gov).
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ABSTRACT |
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BACKGROUND: Survivors of hereditary retinoblastoma have an increased risk for second malignancies, especially soft tissue sarcomas. However, the risks of individual histologic subtypes of soft tissue sarcomas have not been evaluated.
METHODS: We estimated the risk for six subtypes of soft tissue sarcomas (fibrosarcoma, liposarcoma, histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and others) in a cohort of 963 one-year survivors of hereditary retinoblastoma among patients diagnosed at two US institutions from 1914 through 1984. We calculated standardized incidence ratios (SIRs) for specific subtypes of soft tissue sarcomas by comparison with population data from the Connecticut Tumor Registry or from National Cancer Institute Surveillance, Epidemiology, and End Results database. We also calculated the cumulative risk for all soft tissue sarcomas combined.
RESULTS: We observed 69 soft tissue sarcomas in 68 patients with hereditary retinoblastoma. Risks were elevated for soft tissue sarcomas overall (SIR = 184, 95% confidence interval [CI] = 143 to 233) and for individual subtypes. Leiomyosarcoma was the most frequent subtype (SIR = 390, 95% CI = 247 to 585), with 78% of leiomyosarcomas diagnosed 30 or more years after the retinoblastoma diagnosis (SIR = 435, 95% CI = 258 to 687). Among patients treated with radiotherapy for retinoblastoma, we found statistically significantly increased risks of soft tissue sarcomas in the field of radiation. Irradiated patients also had increased risks of soft tissue sarcomas, especially leiomyosarcomas, outside the field of radiation, and risks of soft tissue sarcomas were increased in nonirradiated patients as well, indicating a genetic predisposition to soft tissue sarcomas independent of radiation. The cumulative risk for any soft tissue sarcoma 50 years after radiotherapy for retinoblastoma was 13.1% (95% CI = 9.7% to 17.0%).
CONCLUSION: Long-term follow-up of a cohort of survivors of hereditary retinoblastoma revealed a statistically significant excess of leiomyosarcoma and other soft tissue sarcomas that persists decades after the retinoblastoma diagnosis. Retinoblastoma survivors should undergo regular medical surveillance for sarcomas in their adult years.
Prior knowledge People who have survived hereditary retinoblastoma have a higher risk of soft tissue sarcomas overall than the general population, but risks of individual soft tissue sarcoma subtypes have not been estimated. Study design Risk of sarcomas in retinoblastoma survivors at two institutions was compared with general population rates. Contribution In this large, long-term study, risks of six different soft tissue sarcoma subtypes were evaluated. Survivors had nearly 400 times the risk of leiomyosarcomas than the general population. Risks of some subtypes remained high for several decades. Almost all of the soft tissue sarcomas were diagnosed in patients who received radiation, although some tumors developed outside the field of radiation. Implications Patients with hereditary retinoblastoma may have a genetic predisposition to soft tissue sarcomas. Long-term surveillance for sarcomas may be warranted in survivors of hereditary retinoblastoma. Limitations Conclusions for some subtypes were based on small numbers of cases. Patients came from two institutions, limiting generalizability.
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Patients with retinoblastoma have excellent survival; up to 97% will survive 5 years (1). However, survivors of hereditary retinoblastoma have substantially increased risks of developing subsequent primary malignancies, including soft tissue sarcomas (2–8). The predisposition to soft tissue sarcomas in retinoblastoma survivors has been attributed to a germline mutation in the RB1 gene (9), which encodes the cell cycle regulatory retinoblastoma protein (pRb). Alterations in the retinoblastoma pathway have also been identified in a variety of soft tissue sarcomas in patients without a history of retinoblastoma (10–14).
In a previous study of a cohort of patients with hereditary retinoblastoma (3), we reported a strong radiation dose–response relationship for soft tissue sarcomas, primarily in the head and neck region, such that patients treated for retinoblastoma with 60 Gy or more had 11 times the risk of patients treated with less than 5 Gy. Because information on radiation dose was available for only 31 of 44 patients who had developed soft tissue sarcomas, we did not calculate risks separately for individual subtypes. In a recent follow-up of this cohort, patients with hereditary retinoblastoma continued to have statistically significantly increased risks of melanoma; of cancers of the bone, nasal cavities, and brain; and of soft tissue sarcomas (4). Among survivors of hereditary retinoblastoma who had been treated with radiation, bone and soft tissue sarcomas represented 76% of all cancers diagnosed before age 25 years and 48% of all cancers diagnosed at older ages (4). Since the earlier study of cancer incidence in this cohort (3), the number of soft tissue sarcomas in retinoblastoma survivors has more than doubled. This increase enabled us to quantify the risks for individual subtypes of soft tissue sarcomas in more than 900 long-term survivors of hereditary retinoblastoma.
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Subjects and Methods |
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Study Population
The cohort analyzed in this study has been described previously (3,4,15). In brief, it consisted of 1601 one-year survivors of retinoblastoma, who had been diagnosed from 1914 to 1984 and treated at two medical centers in New York and one in Boston. The cohort was restricted to 1-year survivors because it was unlikely that new primary cancers would develop within 1 year of a retinoblastoma diagnosis. The cohort included 963 (60%) patients with hereditary retinoblastoma [two additional patients were reclassified from sporadic to hereditary retinoblastoma since an earlier report (3)] and 638 (40%) patients with nonhereditary retinoblastoma [three nonhereditary patients were excluded since an earlier report (3)]. Patients with hereditary retinoblastoma had either both eyes affected with retinoblastoma or only one eye affected with retinoblastoma and a family history of retinoblastoma; patients with nonhereditary retinoblastoma had only one eye affected with retinoblastoma and no family history of the disease. Interestingly, only approximately one-third of hereditary patients had reported a family history of retinoblastoma (4), including all 47 patients with retinoblastoma in one eye and 236 patients with retinoblastoma in both eyes. This cohort has been under study since 1984 for the occurrence of subsequent cancers and benign tumors (3,4,15–17). When the cohort was established in 1984, hospital records of study subjects were abstracted to obtain information on diagnosis and treatment of retinoblastoma (15). Reports of subsequent incident cancers in this cohort were collected from hospital records; from three follow-up telephone interviews with study subjects or their family members in 1987, 1993, and 2000; and from periodic searches of the National Death Index. When cohort members reported any tumor, we requested written permission from them to obtain pathology records from the hospital where their tumor was diagnosed. The Institutional Review Board of the National Institutes of Health approved this study.
We restricted the analysis to the 963 survivors of hereditary retinoblastoma because no soft tissue sarcomas were diagnosed in survivors of nonhereditary retinoblastoma. In a recent report of cancer incidence in this cohort, 34 of 69 invasive soft tissue sarcomas were coded by anatomic site only (4). For the present analysis, a nosologist classified invasive soft tissue sarcomas by both topography (anatomic site) and morphology (histology codes, see below) (18). The 69 soft tissue sarcomas were confirmed by pathology report (n = 48, or 70%), autopsy (n = 3, or 4%), other hospital records (n = 13, or 19%), or death certificate only (n = 5, or 7%).
Treatment for Retinoblastoma
The primary treatment for retinoblastoma in this cohort was radiotherapy, with the addition of chemotherapy beginning in the 1950s (19). Radiotherapy was used to preserve sight in at least one eye of patients with bilateral retinoblastoma; the other eye was usually surgically removed. Until 1960, the most common type of external beam radiation was orthovoltage x-ray; after 1960, it was 22- to 23-MV betatron photons. Tumor doses to the affected eye ranged from 15 to 115 Gy (average = 48 Gy), with the highest doses being delivered from orthovoltage external beam radiation. Brachytherapy involved placement of a plaque containing a radioactive isotope to the affected eye.
Information on type of chemotherapy was available for most of the patients who received it. We calculated an individual alkylating agent score for the subjects for whom we had information on type of chemotherapy, as previously described (20). Each chemotherapy agent was assigned a score of 0, 1 (low), 2 (medium), or 3 or more (high), depending on the type of alkylating agent (20), and the individual scores were summed over all chemotherapy courses to determine an alkylator score for each subject. The small number of soft tissue sarcoma patients who had received specific forms of chemotherapy precluded meaningful analysis of subtype-specific risks associated with individual agents.
Statistical Methods
The expected number of soft tissue sarcomas by histologic subtype was based on age-, sex-, and calendar-year–specific incidence rates derived from the Connecticut Tumor Registry for tumors diagnosed before 1970 and from National Cancer Institute Surveillance, Epidemiology, and End Results for tumors diagnosed after 1970. Rates were created for the following histologic subtypes of soft tissue sarcomas based on International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3), morphology classification (18): soft tissue tumors and sarcomas, not otherwise specified (NOS) (M8800–8804), and other sarcomas, including mesenchymal sarcoma (8990), synovial sarcoma (9040), hemangiosarcoma (9120), and schwannoma (9560); fibrosarcoma (M8810–8814); malignant fibrous histiocytoma (M8830–8833); liposarcoma (M8850–8855); leiomyosarcoma (M8890–8891, 8894–8895); and rhabdomyosarcoma (M8900–8902, 8920). Malignant fibrous histiocytoma was not distinguished from fibrosarcomas with a separate ICD-O code until 1977.
Accrual of person-years of follow-up began 1 year after diagnosis of retinoblastoma and ended at the date last known alive, the date of death, or December 31, 2000, whichever was earliest.
The standardized incidence ratio (SIR) for soft tissue sarcoma subtypes was calculated as the ratio of any subsequent observed soft tissue sarcoma to the expected number, and exact 95% confidence intervals (CIs) were calculated based on the Poisson distribution. The excess absolute risk per year (EAR) was calculated as the observed minus the expected number of cancers divided by person-years at risk multiplied by 10 000, and exact 95% confidence intervals were calculated based on the Poisson distribution. We also calculated the cumulative incidence of developing soft tissue sarcomas for a period of 50 years with adjustment for the competing risk of death due to other causes (21). For the one patient with more than one soft tissue sarcoma, only the first sarcoma was counted in the cumulative incidence analysis.
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Results |
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The study population consisted of 963 one-year survivors of hereditary retinoblastoma. More than half of the patients (n = 545) had been diagnosed and treated for retinoblastoma when they were less than 1 year of age (Table 1). Most of the patients (n = 849, or 88.2%) were treated with radiation, which consisted of external beam radiotherapy (90% of radiation-treated patients), brachytherapy (1%), or both (9%). A total of 383 patients received chemotherapy in addition to radiation, and 16 received chemotherapy alone. The patients were followed for an average of 25.2 years (range = 1–68 years), with 791 (82.1%), 658 (68.3%), and 465 (48.3%) patients followed for 10, 20, and 30 or more years, respectively, after their retinoblastoma diagnosis.
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A total of 69 soft tissue sarcomas were diagnosed in 68 patients. Leiomyosarcoma was the most common histologic subtype (n = 23, or 33%) followed by fibrosarcoma (n = 13, or 19%), malignant fibrous histiocytoma (n = 12, or 17%), soft tissue tumors and sarcomas NOS (n = 10, or 15%), rhabdomyosarcoma (n = 8, or 12%), and liposarcoma (n = 3, or 4.3%) (Table 2). All but three of the 69 soft tissue sarcomas were diagnosed in patients who had been treated with radiation. The soft tissue sarcomas were diagnosed in the head and face (n = 49, or 71%), pelvic region (n = 11, or 16%), trunk (n = 5, or 7%), upper limbs (n = 3, or 4%), and lower limb (n = 1, or 1%). Leiomyosarcomas were diagnosed more frequently outside the radiation field than in it, whereas the other subtypes arose more often within the radiation field than outside it. Nine of the survivors who developed soft tissue sarcoma had also another cancer preceding their soft tissue sarcoma (five had an osteosarcoma and one each had an osteofibrosarcoma, an adenocarcinoma of the colon, a squamous cell cancer of the scalp, and a melanoma of the lower back).
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The expected number of soft tissue sarcomas in survivors of hereditary retinoblastoma was 0.37, yielding a highly increased risk (SIR = 184, 95% CI = 143 to 233) (Table 3). The risks were greatest for leiomyosarcoma (SIR = 390, 95% CI = 247 to 585) and fibrosarcoma (SIR = 398), followed by rhabdomyosarcoma (SIR = 279), histiocytoma (SIR = 100), liposarcoma (SIR = 99), and other subtypes of soft tissue tumors and sarcomas NOS (SIR = 96). The excess absolute risk for all soft tissue sarcoma subtypes combined per 10 000 persons was 27, with the excess being most pronounced for leiomyosarcomas (EAR = 9.1).
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Almost all the soft tissue sarcomas developed in patients who had been treated with radiation (observed = 66; SIR = 212, 95% CI = 164 to 270), although 18 of these arose outside the radiation field (SIR = 58, 95% CI = 34 to 91) and three (one histiocytoma, one leiomyosarcoma, and one rhabdomyosarcoma) arose in nonirradiated patients (SIR = 47, 95% CI = 9.4 to 137). The excess absolute risk for all soft tissue sarcomas was greater in irradiated patients (30.3, 95% CI = 23.4 to 38.6) than in nonirradiated patients (8.2, 95% CI = –0.03 to 22.6). Fifty years after radiotherapy for hereditary retinoblastoma, the cumulative risk of developing any soft tissue sarcoma was 13.1% (95% CI = 9.7% to 17.0%), of developing a soft tissue sarcoma in the radiation field was 8.9% (95% CI = 6.1% to 12.2%), and of developing a soft tissue sarcoma outside the radiation field was 5.1% (95% CI = 2.8% to 8.4%).
Comparing the risks for soft tissue sarcomas by radiotherapy with and without chemotherapy (Table 4) showed that there was little difference in excess absolute risks when all soft tissue sarcomas were considered together. Only the standardized incidence ratios for leiomyosarcomas were statistically significantly different, with a higher risk among those treated with radiation and chemotherapy (SIR = 859, 95% CI = 490 to 1395) than those treated with radiation alone (SIR = 223, 95% CI = 82 to 486). No soft tissue sarcomas occurred following chemotherapy alone, but only 16 patients were treated exclusively with chemotherapy, which limited our ability to detect an increased risk.
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Of the 389 subjects with some information on chemotherapy, 310 (79.7%) had one course, 61 (15.9%) had two courses, and 18 (4.4%) had three or more courses. The most frequently used chemotherapy agent was the alkylating agent triethylene melamine (TEM; alkylator score = 1), which was used in 262 (67.3%) patients, followed by cytoxan alone or in combination with other drugs (n = 73, or 18.8%) and vincristine alone or in combination with other drugs (n = 54, or 13.9%). Among the patients later diagnosed with soft tissue sarcomas, 31 (47%) had been treated with alkylating agents, mainly with TEM. Risks for all soft tissue sarcomas did not increase with increasing alkylator score (SIR = 155 [95% CI = 108 to 216], 250 [95% CI = 165 to 364], and 129 [95% CI = 35 to 330] for no chemotherapy, alkylator score 1, and alkylator score 2 or higher, respectively). All 16 patients with leiomyosarcomas who received both chemotherapy and radiation had been treated with TEM.
Although the relative risk for all soft tissue sarcomas was highest within 10 years of the retinoblastoma diagnosis (SIR = 335, 95% CI = 183 to 562), only 20% of the soft tissue sarcomas were diagnosed within this time interval (Table 5). In contrast, 45% of all soft tissue sarcomas were diagnosed 30 or more years after the retinoblastoma diagnosis (SIR = 193, 95% CI = 131 to 274). The excess absolute risk for all soft tissue sarcomas was 67.4 for survivors 30 or more years after retinoblastoma, compared with 18.3 for survivors 1–9 years after diagnosis, 21.6 for survivors 10–19 years after diagnosis, and 13.9 for survivors 20–29 years after diagnosis. We noted that fibrosarcomas and rhabdomyosarcomas occurred predominantly in the first 20 years after retinoblastoma, soft tissue tumors and sarcomas NOS, as well as malignant fibrous histiocytomas appeared across all time intervals, whereas 18 of the 23 leiomyosarcomas (78%) were diagnosed 30 or more years after retinoblastoma (SIR = 435, 95% CI = 257 to 687; EAR = 39).
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Risks for all types of soft tissue sarcomas did not differ statistically significantly by sex (P = .251). However, the location of leiomyosarcoma, a malignant tumor of smooth muscle, did differ by sex. For example, in males, leiomyosarcomas were located mainly in the head and face (7 of 11, or 64%), whereas many of the leiomyosarcomas in females (7 of 12, or 58%) were in the pelvic area. Five female survivors developed a leiomyosarcoma of the corpus uteri, one survivor developed a leiomyosarcoma in the pelvis, and one developed a leiomyosarcoma in the retroperitoneum. The expected number of leiomyosarcomas in the entire cohort at any organ site was 0.06, so the five uterine leiomyosarcomas represent a substantial excess risk.
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Discussion |
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This study is the first, to our knowledge, with sufficient long-term follow-up to quantify the risk for individual subtypes of soft tissue sarcoma in 1-year survivors of hereditary retinoblastoma. Although very high risks were found for fibrosarcomas, rhabdomyosarcomas, and malignant fibrous histiocytomas within the first 10 years after the diagnosis of retinoblastoma, there was a pronounced risk for leiomyosarcomas 20 years after diagnosis. Because the majority of patients with hereditary retinoblastoma are diagnosed before they are 1 year old, the temporal pattern of risk for soft tissue sarcoma diagnoses that we observed is approximately equivalent to the expected age distribution for individual subtypes in the general population, e.g., with rhabdomyosarcoma appearing before age 20 years and leiomyosarcomas arising later (1,22,23).
Leiomyosarcomas constituted the largest group of soft tissue sarcomas in the cohort. The anatomic distribution differed by sex. Although most of the leiomyosarcomas occurred in the head and face, a portion arose in the uterus in females, which is consistent with the location of this tumor in the general female population (24).
Our findings of leiomyosarcomas are consistent with several case reports of leiomyosarcomas diagnosed in patients with hereditary retinoblastoma 12–50 years after radiation treatment (25–27). These tumors were reported in the head and neck region, including the orbit and oral cavity, occurred in males, and were aggressive in nature. There is a case report of pelvic leiomyosarcoma in a patient with hereditary retinoblastoma (28), but we are unaware of any series of hereditary retinoblastoma patients who have reported uterine leiomyosarcomas. Uterine sarcoma has been reported in women exposed to high-dose radiotherapy for cervical cancer (29) but not to the lower radiation doses received by atomic bomb survivors (30). Average radiation doses to the uterus in our cohort were low, ranging from 0.08 to 0.20 Gy (4); therefore, it seems unlikely that the radiation exposure caused the uterine leiomyosarcomas in our cohort. Loss of heterozygosity in RB1 has been reported in uterine leiomyosarcoma (31). Therefore, it is possible that radiation-induced loss of the single normal RB1 copy in survivors of hereditary retinoblastoma could result in uterine leiomyosarcomas. This loss may reflect radiation-induced chromosome instability rather than inactivation by radiation (10,32). Because the uterus is outside the radiation field during treatment for retinoblastoma, the excess risk we observed for uterine leiomyosarcomas indicates that a mutation in the RB1 gene confers susceptibility to uterine leiomyosarcomas without radiation or at very low doses.
We also observed three other leiomyosarcomas of the pelvic area, two of which were diagnosed in the colon and one in the scrotum. Several cases of leiomyosarcoma of the urinary bladder have been reported in survivors of hereditary retinoblastoma (28,33), but none were observed in our cohort.
In addition to the increase in leiomyosarcoma, we observed an increase in liposarcoma starting 10 years after the diagnosis of hereditary retinoblastoma. Males have a higher rate of liposarcomas than females in the general population (23), and all three liposarcomas in our cohort were diagnosed in males. In an earlier report from this cohort, we noted an excess of lipomas, a benign tumor of adipose tissue, also predominantly in males (16). Alteration of the RB1 gene has been demonstrated in both liposarcomas (34) and lipomas (35), suggesting a possible connection between these malignant and benign tumors of adipose tissue. We hypothesized previously (16) that lipomas in retinoblastoma survivors may be a marker for sarcomas because in our earlier study of lipomas in this cohort (16), three of the 20 retinoblastoma patients with lipomas also reported sarcomas (malignant fibrous histiocytoma, leiomyosarcoma, or fibrosarcoma). However, none of the patients with liposarcoma in the current study were reported to have a previous lipoma.
Radiotherapy was associated with an increase in risk of each soft tissue sarcoma subtype in survivors of hereditary retinoblastoma, consistent with our previous finding of a radiation dose–response for all soft tissue sarcomas combined (3). Soft tissue sarcomas are an established sequelae of radiation for hereditary retinoblastoma, with and without chemotherapy (2–8,36), as well as other similarly treated pediatric malignancies (37–41). In most studies, soft tissue sarcomas have appeared within 20 years of radiation treatment for the initial primary cancer. It should be noted that our cohort has been followed longer than most other cohorts of childhood cancer survivors, and this increased follow-up would account for more retinoblastoma survivors being at risk for soft tissue sarcomas that are typically seen in adults, such as leiomyosarcomas. Fibrosarcoma and malignant fibrous histiocytoma, which are more typical of adolescents, have been the most common subtypes following radiotherapy (42), with leiomyosarcomas reported less often. As observed in earlier studies (42), we found that fibrosarcoma, malignant fibrous histiocytoma, and rhabdomyosarcoma comprised the majority of soft tissue sarcomas that were diagnosed in or near the field of radiation in this cohort, whereas leiomyosarcomas were diagnosed most often outside the radiation field. In the general population, only 10% of rhabdomyosarcomas arise in the soft tissue of the head, neck, or face (24), whereas in this cohort, all rhabdomyosarcomas occurred in these locations, likely as a result of radiation exposure.
Radiation combined with chemotherapy was associated with a heightened risk for leiomyosarcoma in our study compared with that associated with radiation alone. The majority of retinoblastoma patients who had been treated with chemotherapy received the alkylating agent TEM, which is no longer used. Only one other study (36) has evaluated the risk of second cancers in retinoblastoma patients treated with TEM in combination with radiotherapy; that study found possible associations between TEM treatment and cancers of the brain, parotid gland, and femur but not soft tissue sarcomas.
In addition to being at an increased risk for soft tissue sarcomas, patients with hereditary retinoblastoma are prone to cutaneous melanoma (3–7). In this context, it is noteworthy that one of the patients with a uterine leiomyosarcoma in our study had been diagnosed with a cutaneous melanoma of the lower back 20 years earlier. Reports of melanoma and soft tissue sarcomas as multiple primary cancers in individuals without retinoblastoma have suggested an underlying genetic susceptibility to both tumors (40,43,44).
Our study has several limitations. One is the possible misclassification of malignant histiocytic fibrosarcomas because these tumors were coded as fibrosarcomas before 1977. However, further review of available histology and pathology reports determined that the six fibrosarcomas that were diagnosed before 1977 were likely to have been correctly classified. Our analyses of liposarcomas and rhabdomyosarcomas were based on only three and eight cases, respectively. The World Health Organization initiated a new coding scheme for soft tissue sarcomas in 2002, but the patients in our study were diagnosed only through 2000, so we were unable to apply this system to our data. A strength of our study was the high rates of follow-up; only 2.9% of the patients with hereditary retinoblastoma were lost to follow-up, and the study includes a large number of long-term survivors (
30 years after the diagnosis of retinoblastoma).
The major contribution of this study is the estimation of risk by histologic type of soft tissue sarcomas by time since diagnosis of hereditary retinoblastoma in a large cohort of long-term survivors. Soft tissue sarcomas began occurring within 10 years of the diagnosis of retinoblastoma and continued throughout adult life, with specific subtypes occurring at similar ages as in the general population. Most striking was the dramatically increased risk for soft tissue sarcomas, particularly leiomyosarcomas, diagnosed 30 years and later after treatment for hereditary retinoblastoma. Given the excellent survival of retinoblastoma patients, it is important that survivors continue to undergo regular medical surveillance for sarcomas in their adult years.
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This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. The authors take full responsibility for the study design, data collection, analysis and interpretation of the data, the decision to submit the manuscript for publication, and the writing of the manuscript.
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Manuscript received May 11, 2006; revised October 19, 2006; accepted November 8, 2006.
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