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Sarcomas in hereditary retinoblastoma

Sarcomas in hereditary retinoblastoma Children diagnosed with the hereditary form of retinoblastoma (Rb), a rare eye cancer caused by a germline mutation in the RB1 tumor suppressor gene, have excellent survival, but face an increased risk of bone and soft tissue sarcomas. This predisposition to sarcomas has been attributed to genetic susceptibility due to inactivation of the RB1 gene as well as past radiotherapy for Rb. The majority of bone and soft tissue sarcomas among hereditary Rb survivors occur in the head, within the radiation field, but they also occur outside the radiation field. Sarcomas account for almost half of the second primary cancers in hereditary Rb survivors, but they are very rare following non-hereditary Rb. Sarcomas among hereditary Rb survivors arise at ages similar to the pattern of occurrence in the general population. There has been a trend over the past two decades to replace radiotherapy with chemotherapy and other focal therapies (laser or cryosurgery), and most recently, chemosurgery in order to reduce the incidence of sarcomas and other second cancers in Rb survivors. Given the excellent survival of most Rb patients treated in the past, it is important for survivors, their families and health care providers to be aware of the heightened risk for sarcomas in hereditary patients. Keywords: Retinoblastoma, Soft tissue sarcoma, Bone sarcoma, Radiotherapy, Epidemiology, RB1 gene, Hereditary Introduction maintains cell cycle arrest and preserves chromosome Children diagnosed with the hereditary form of retino- stability [2]. blastoma (Rb), a rare eye cancer caused by a germline Retinoblastoma occurs in two forms: hereditary (30-40%) mutation in the RB1 tumor suppressor gene, have excel- and non-hereditary (60-70%). Hereditary retinoblastoma is lent survival, but face an increased risk for the develop- caused by a germline mutation in one allele of the RB1 ment of sarcomas, both soft tissue (STS) and bone. This gene and an acquired somatic mutation in the other allele, predisposition to sarcomas in retinoblastoma survivors whereas the non-hereditary form is caused by somatic has been attributed to genetic susceptibility as well as mutations in both alleles. The hereditary form is character- past radiation treatment for Rb. ized by disease in both eyes (bilateral Rb) and is typically diagnosed before 12 months of age, whereas, the non- hereditary form affects one eye (unilateral Rb) and is diag- Retinoblastoma epidemiology nosed between 2–5 years of age. About 10-15% of patients Retinoblastoma is a rare pediatric cancer of the eye with with unilateral Rb, however, carry a germline mutation and an autosomal dominant inheritance pattern. It is caused are considered hereditary. This difference in diagnosis age by mutations in the RB1 tumor suppressor gene, located led Knudson to develop the two-hit theory [3], in which on chromosome 13q14 with very high penetrance and only one additional mutation is needed for hereditary Rb expressivity [1]. Approximately 80%-90% of RB1 gene and two hits or somatic mutations are needed for non- carriers develop ocular tumors. This gene encodes the hereditary Rb [4]. The age-adjusted annual incidence rate cell cycle regulatory retinoblastoma gene protein (pRb), of retinoblastoma is 3.1 per 10 with a 5-year relative sur- controls cellular differentiation during both embryogen- vival of 97.5% in the U.S. [5]. Treatment for Rb has historic- esis and in adult tissues, regulates apoptotic cell death, ally consisted primarily of radiotherapy (both external beam and radioactive plaques), enucleation, chemotherapy, * Correspondence: kleinerr@mail.nih.gov focal therapies such as laser or cryotherapy, or a combin- Epidemiology and Biostatistics Program Division of Cancer Epidemiology ation of these modalities. and Genetics, National Cancer Institute, National Institutes of Health, 6120 Executive Boulevard, Rockville, MD 20852, USA Full list of author information is available at the end of the article © 2012 Kleinerman et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Kleinerman et al. Clinical Sarcoma Research 2012, 2:15 Page 2 of 7 http://www.clinicalsarcomaresearch.com/content/2/1/15 Subsequent malignancies after retinoblastoma In a case–control study of bone and soft tissue sarcomas Long-term survivors of hereditary retinoblastoma are at an after hereditary Rb, risk increased with increasing dose up increased 20-fold risk of developing and dying from a sub- to 10.7-fold at doses greater than 60 Gy [11]. The mean sequent non-ocular cancer, primarily bone and soft tissue dose to the head among cases was 32.8 Gy, whereas the sarcomas, melanoma and brain tumors [6,7]. Survivors of lower limbs had received virtually no radiation (<0.1 Gy). non-hereditary Rb are at much lower risk of a subsequent In an update of that study, the location of 75 bone sarco- primary cancer, similar to the risk in the general population mas was skull and face (61%), lower limbs (29%), trunk [8-10]. The risk for sarcomas in hereditary patients has (7.6%), and unknown location (3.8%) [7]. been attributed to genetic susceptibility and past treatment Based on a series of 155 osteosarcomas following heredi- with radiation [8,11,12]. In addition to radiotherapy, tary Rb identified from the literature and one institute, chemotherapy, specifically alkylating agents, has been asso- investigators reported that the mean age of onset was ciated with the risk of bone cancer after Rb [6,13,14], but related to the osteosarcoma location [21]. Sarcomas occur- less so for soft tissue sarcomas [15]. ring in the radiation field were diagnosed one year earlier compared to those diagnosed outside the field (mean Bone sarcomas after retinoblastoma age = 12.2 years [range 3–35] vs. mean age = 13.4 years Patterns of risk [range 4–22]. This age difference suggested to the investi- Bone sarcomas are one of the most common second pri- gators that different biologic mechanisms may be asso- mary cancers occurring after hereditary retinoblastoma ciated with the development of bone sarcomas depending accounting for 25%-30% of all second primary cancers upon the location in the body. [6-8,16,17]. Bone sarcomas are typically diagnosed in Rb Studies of other pediatric malignancies have also survivors between 10 and 20 years of age, similar to the reported an increased risk for second osteosarcomas fol- incidence pattern in the general population [5]. In these lowing radiation and chemotherapy treatment for a first studies, the majority of bone sarcomas occurred within cancer (for a detailed review of radiation-related sarcomas, the radiation field in the head region, but up to 40% was see Berrington de Gonzalez et al. in this issue). diagnosed outside the treatment field, primarily in the lower legs [8,11,17]. Soft Tissue Sarcomas Table 1 presents risks for bone sarcomas from epi- Patterns of risk demiologic cohort studies including at least 100 her- Soft tissue sarcomas (STS) are also one of the most editary Rb survivors. The standardized incidence and common subsequent cancers following hereditary Rb mortality rates for bone sarcomas are increased sev- accounting for 12% up to 32% of all second cancers eral hundred-fold compared to population rates, due to [6,7,16]. In one large cohort study, an increased risk for the rarity of these tumors in the general population. A STS was first observed within 10 years of Rb diagnosis much lower risk for bone sarcomas was observed in the and continued through adult life up to 50 years after Rb, one cohort study that included non-irradiated survivors with specific subtypes occurring at similar ages as in the and began follow-up 25 years after Rb diagnosis [10]. It general population [22,23]. Fifty years after radiation has been estimated that the cumulative incidence of bone treatment for hereditary Rb, the cumulative risk of sarcoma following retinoblastoma is 7% at 20 years developing a STS was 13.1%, and the cumulative inci- [13,18]. Osteosarcoma is the most common type of bone dence for a STS inside the radiation field was higher sarcoma reported after Rb, but both chondrosarcoma and than outside the field (8.9% vs. 5.1%) [22]. Table 2 pre- Ewing sarcoma have been reported as well [19,20], al- sents the incidence and mortality due to STS after Rb in though risk estimates are not available for these other two cohort studies of at least 100 hereditary Rb survivors. types. Subtype heterogeneity Treatment for Rb and risk of bone sarcomas STS diagnosed in Rb patients comprise a heterogeneous Both high-dose radiation and increasing cumulative dose group of tumors of fat, cartilage and muscle; however, of chemotherapy, mainly alkylating agents (cyclophos- only one study has evaluated the risk of STS by histology phamide and triethylenemelamine or TEM), have been after hereditary Rb [22]. Leiomyosarcoma (LMS) consti- linked to the occurrence of bone sarcomas following tuted the most common type of STS after Rb, with the hereditary Rb [13,14]. Higher risks have been noted for majority diagnosed 30 and more years after Rb. This is the combination of radiotherapy and chemotherapy consistent with LMS being one of the most common compared to either treatment alone [6-8,13,14]. An earl- STS in the general population [23]. Although many LMS ier study of British Rb patients provided some evidence occurred in the head and neck region, the majority of that cyclophosphamide may increase the effect of radio- LMS in females were diagnosed in the uterus [24]. Loss therapy on the risk of bone sarcoma [8]. of heterozygosity in RB1 has been reported in uterine Kleinerman et al. Clinical Sarcoma Research 2012, 2:15 Page 3 of 7 http://www.clinicalsarcomaresearch.com/content/2/1/15 Table 1 Summary of bone sarcoma after retinoblastoma in cohort studies of 100 or more hereditary retinoblastoma survivors Study Study design, Years No. subjects with Years of follow-up: No. bone O/E, 95% CI O/E by treatment for Comments of Rb diagnosis hereditary median/mean sarcoma retinoblastoma retinoblastoma cases 1a. Incidence Kleinerman 2005 [7]US Hospital-based 963 1-yr survivors Mean: 25 75 360 (283–451) Any radiation: 406 (318–511) AER = 29.6 Two US medical centers 1914-1984 No radiation: 69 (8.4-250) Radiation + chemotherapy: 539 (384–733); Radiation, no chemotherapy: 302 (205–428) Reulen 2011 [16] British Population-based NA*, 5-yr survivors Mean: 26 35 289 (209–402) NA AER = 23; * No. of Rb survivors Childhood Cancer Survivor 1940-1991 not given but there are estimated Study, UK to be 809 hereditary Rb subjects based on MacCarthy et al. [44] Marees 2008 [6] Netherlands Registry -based 298 survivors Median: 22 16 314 (180–511) Radiation only: 302 (130–596) AER = 23 Dutch Retinoblastoma 1945-2005 Radiation + chemotherapy: Registry 586 (215–1275); Surgery only: 75 (1.9-421) Tucker 1987 [14]US Hospital-based 319 2-yr survivors Mean: 7 12 999 (515–1745) *Hereditability not specified Late Effects Study Group 1945-1979 1b. Mortality SMR, 95%CI SMR by treatment for retinoblastoma Yu 2009 [12]US Hospital-based 1092 1-yr survivors Median: 29 56 595 (449–773) Radiation: 673 (506–879) AER = 19.8; *No difference between Two medical centers 1914-1996 males and females Marees 2009 [46] Netherlands Registry-based 337 (alive in 1961) Median: 26 yr 11 289 (144–517) Radiation only: 266 (72.2-680) Majority deaths from bone cancer Dutch Retinoblastoma Registry 1862 - 2005 Follow-up Radiation + chemotherapy: occur within first 30 years 1961-2005 659 (179–1686); Surgery only: 124 (15–449) Acquaviva 2006 [46] Italian Registry-based 408 Median: 11 9 392 (204-753) NA Retinoblastoma Registry 1923-2003 Fletcher 2004 [10] Patients Hospital-based 144 25-yr survivors Follow up began 1 32.4 (0.82 - 180) NA *Radiation was not typically used from British hospitals and 1873-1950 in 1940 to treat Rb during these years linkage with national registry Median age: 60 Abbreviations: O = observed number of bone sarcomas; E = expected number of bone sarcomas; CI = confidence intervals; AER = absolute excess risk per 10,000 persons, yr = year; SMR = standardized mortality ratio; NA not available. Kleinerman et al. Clinical Sarcoma Research 2012, 2:15 Page 4 of 7 http://www.clinicalsarcomaresearch.com/content/2/1/15 Table 2 Summary of soft tissue sarcoma after retinoblastoma in cohort studies of 100 or more hereditary retinoblastoma survivors Study Study Design Years Number of subjects Years of follow-up: No. of Soft O/E, 95% CI O/E by treatment for Comments of Rb diagnosis with hereditary median/mean tissue retinoblastoma retinoblastoma sarcomas 2a. Incidence Kleinerman 2007 [22]US Hospital-based 963 1-yr survivors Mean: 25 69 184 (143–233) Any radiation: 212 (164–270); AER = 27 *No evidence of risk Two medical centers 1914-1984 No radiation: 47 (9.4-137); Any modification by sex *SIRs highest chemotherapy: 236 (161–333); within first10years butremained No chemotherapy: 193 significantly elevated ≥30 (133–271) Reulen 2011 [16]British Population-based NA, 5-yr survivors Mean: 26 16 N/A N/A Rates increase over time since Rb Childhood Cancer 1940-1991 (highest >25) Survivor Study Marees 2008 [6]Netherlands Registry-based 298 Median: 22 20 243 (148–375) Radiation only: 303 (161–517) AER = 29; SIRs elevated in all time Dutch Retinoblastoma Registry 1945-2005 Radiation + chemotherapy: 354 periods (3 cases ≥40) (129–770) Surgery only: 48.4 (1.23-270) Tucker 1987 [14]US Hospital-based 319 2-yr survivors Mean: 7 4 235 (64–602) All cases observed among females Late Effects Study Group 1945-1979 (hereditability not specified) 2b. Mortality SMR, 95% CI SMR by treatment for retinoblastoma Yu 2009 [12]US Hospital-based 1092 1-yr survivors Median: 29 31 329 (223–467) Any Radiation 395 (268–560) AER = 10.9; SMR is higher for women Two medical centers 1914-1996 vs men (not statistically significant) Marees 2009 [45]Netherlands Registry-based 337 Median: 26 13 276 (147–472) Radiation only: 311 (101–725) *Deaths observed up to ≥50 years Dutch Retinoblastoma Registry 1862 - 2005 Follow-up Rad + chemotherapy: 940 afterRB*SMRpeaks at 20–29 years 1961-2005 (345–2064); Surgery only: but SMRs significantly elevated in all 85.2 (10.3-308) time periods Acquaviva 2006 [46] Italian Registry-based 408 Median: 12 6 453 (203.5 - 1008) NA Retinoblastoma Registry 1923-2003 Fletcher 2004 [10]UKPatients Hospital-based 144 25-yr survivors Median attained 4 110 (29–281) NA *Treatment not available, but radiation from British hospitals; linkage 1873-1950 age: 60; Follow-up was not typically used during these with national registry began in 1940 years of Rb diagnosis Abbreviations: O = observed number of soft tissue sarcomas; E = expected number of soft tissue sarcomas; CI = confidence intervals; AER = absolute excess risk per 10,000 persons, yr = year; SMR = standardized mortality ratio; NA not available. Kleinerman et al. Clinical Sarcoma Research 2012, 2:15 Page 5 of 7 http://www.clinicalsarcomaresearch.com/content/2/1/15 LMS [25], which may confer an increased susceptibility associated with increasing alkylating agent score in the to this tumor in this population. LMS of other pelvic same cohort [22], whereas in another study of STS after sites have also been reported after Rb [26], and there all types of pediatric malignancies, including Rb, the risk have been several case reports of LMS diagnosed in the for STS increased significantly with cumulative dose of al- bladder [27,28]. kylating agents, adjusted for radiation exposure [15]. Very high risks have also been observed for fibrosarco- Increased risks of STS have also been noted following sur- mas, rhabdomyosarcomas and pleomorphic sarcomas gery only for hereditary Rb [6,10]. within the first 10 years after Rb [22,29]. These histo- logic types comprised the majority of STS that were Molecular evidence for an association of sarcomas diagnosed in or near the field of radiation, in contrast to with RB1 LMS, which were more likely to occur outside the radi- In additional to the epidemiologic evidence of an excess ation field (Table 3). Only 10% of rhabdomyosarcomas risk for both bone and STS in hereditary Rb patients, arise in the soft tissue of the head, neck or face in the structural alterations of the RB1 gene are well documen- general population, whereas all of the rhabdomyosarco- ted in primary bone sarcomas [33] and soft tissue sarco- mas arose in the head following radiation for Rb [22]. mas [34-36]. Most of the bone and soft tissue sarcomas An increased risk for liposarcomas that began 10 years diagnosed in hereditary Rb patients have complex karyo- after diagnosis of hereditary Rb was observed in the types, including fibrosarcoma, LMS, pleomorphic sarcoma, study by Kleinerman et al. [22]. Lipomas, a benign liposarcoma and osteosarcoma that are all related to inher- tumor of fat tissue, have also been reported to be ited defects in the RB pathway [37]. A comprehensive re- increased in that cohort, and the investigators noted a view by Burkhart and Sage of cellular mechanisms of possible association between lipomas and subsequent tumor suppression by the retinoblastoma gene discusses risk of a soft tissue sarcoma [30]. Following this observa- the loss of RB1 function and cancer progression [2]. tion, a RB1 mutation was identified in lipomas from her- editary Rb patients [31,32]. Conclusion It has been suggested that females may be at higher Hereditary Rb patients are at significant risk of develop- risk of STS after hereditary Rb [9], but studies of Rb ing a sarcoma due to past radiation treatment and gen- survivors have not consistently reported a higher risk etic susceptibility. Sarcomas account for approximately among females. Males have a higher rate of Rb in the 40% to 60% of second cancers in hereditary Rb survivors. general population and all liposarcomas and lipomas There is convincing epidemiologic evidence linking past occurred in males in the cohort in which they were radiotherapy with sarcomas in hereditary patients. Risk evaluated [22,30]. of bone and STS begins within 10 years of treatment for hereditary Rb and continues throughout adulthood, Treatment for Rb and risk of STS most notably for STS. Although both radiotherapy and chemotherapy for heredi- Recognition of the increased risk for sarcomas asso- tary Rb have been associated with an increased risk for ciated with past radiotherapy has influenced the current STS, the evidence is more consistent for radiotherapy. treatment of retinoblastoma with a trend towards greater (For a detailed review of radiation-related sarcoma, see use of chemotherapy, focal therapies, and most recently, Berrington de Gonzalez et al. in this issue). Wong et al. chemosurgery [38-40]. In addition, guidelines for im- demonstrated a radiation dose–response for STS whereby aging children for pre-treatment diagnostic evaluation of risk increased with dose up to a significant 11-fold Rb without the use of ionizing radiation have been increased risk at ≥60 Gy [11]. The risk for STS was not recommended to reduce the risk of second cancers in Rb patients [41]. However, the risk for bone sarcomas Table 3 Location of soft tissue sarcoma after and STS remains, reflecting the genetic predisposition to radiotherapy for retinoblastoma* these sarcomas due to loss of heterozygosity in the RB1 STS subtype In-field Out-of-field Total gene. Patients who were treated in 1960s and 1970s with Leiomyosarcoma 8 (38.1) 13 (61.9) 21 (100.) radiotherapy are still at risk in their adult years for the Fibrosarcoma 13 (100.) 0 13 (100.) development of STS. Given the excellent survival of most retinoblastoma patients, it is important for survi- Pleomorphic sarcoma 11 (100.) 0 11 (100.) vors, their families and health care providers to be aware Rhabdomyosarcoma 7 (100.) 0 7 (100.) of these risks, especially for hereditary patients [42]. Liposarcoma 1 (33.3) 2 (66.7) 3 (100.) There is on-going research to try to identify whether Other STS 8 (80.0) 2 (20.0) 10 (100.) specific RB1 mutations or location of mutations predis- Total 48 (72.7) 18 (27.3) 66 (100.) pose to sarcomas, which could lead to identification of *Based on data from Kleinerman et al. [22]. those survivors at greatest risk [43]. The development of Kleinerman et al. Clinical Sarcoma Research 2012, 2:15 Page 6 of 7 http://www.clinicalsarcomaresearch.com/content/2/1/15 comprehensive guidelines for long-term follow-up that radiotherapy and chemotherapy in children. N Engl J Med 1987, 317:588–593. are specifically tailored for detection of sarcomas and 15. 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Oncogene 2006, 25:5350–5357. doi:10.1186/2045-3329-2-15 Cite this article as: Kleinerman et al.: Sarcomas in hereditary retinoblastoma. Clinical Sarcoma Research 2012 2:15. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Sarcoma Research Springer Journals

Sarcomas in hereditary retinoblastoma

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Abstract

Children diagnosed with the hereditary form of retinoblastoma (Rb), a rare eye cancer caused by a germline mutation in the RB1 tumor suppressor gene, have excellent survival, but face an increased risk of bone and soft tissue sarcomas. This predisposition to sarcomas has been attributed to genetic susceptibility due to inactivation of the RB1 gene as well as past radiotherapy for Rb. The majority of bone and soft tissue sarcomas among hereditary Rb survivors occur in the head, within the radiation field, but they also occur outside the radiation field. Sarcomas account for almost half of the second primary cancers in hereditary Rb survivors, but they are very rare following non-hereditary Rb. Sarcomas among hereditary Rb survivors arise at ages similar to the pattern of occurrence in the general population. There has been a trend over the past two decades to replace radiotherapy with chemotherapy and other focal therapies (laser or cryosurgery), and most recently, chemosurgery in order to reduce the incidence of sarcomas and other second cancers in Rb survivors. Given the excellent survival of most Rb patients treated in the past, it is important for survivors, their families and health care providers to be aware of the heightened risk for sarcomas in hereditary patients. Keywords: Retinoblastoma, Soft tissue sarcoma, Bone sarcoma, Radiotherapy, Epidemiology, RB1 gene, Hereditary Introduction maintains cell cycle arrest and preserves chromosome Children diagnosed with the hereditary form of retino- stability [2]. blastoma (Rb), a rare eye cancer caused by a germline Retinoblastoma occurs in two forms: hereditary (30-40%) mutation in the RB1 tumor suppressor gene, have excel- and non-hereditary (60-70%). Hereditary retinoblastoma is lent survival, but face an increased risk for the develop- caused by a germline mutation in one allele of the RB1 ment of sarcomas, both soft tissue (STS) and bone. This gene and an acquired somatic mutation in the other allele, predisposition to sarcomas in retinoblastoma survivors whereas the non-hereditary form is caused by somatic has been attributed to genetic susceptibility as well as mutations in both alleles. The hereditary form is character- past radiation treatment for Rb. ized by disease in both eyes (bilateral Rb) and is typically diagnosed before 12 months of age, whereas, the non- hereditary form affects one eye (unilateral Rb) and is diag- Retinoblastoma epidemiology nosed between 2–5 years of age. About 10-15% of patients Retinoblastoma is a rare pediatric cancer of the eye with with unilateral Rb, however, carry a germline mutation and an autosomal dominant inheritance pattern. It is caused are considered hereditary. This difference in diagnosis age by mutations in the RB1 tumor suppressor gene, located led Knudson to develop the two-hit theory [3], in which on chromosome 13q14 with very high penetrance and only one additional mutation is needed for hereditary Rb expressivity [1]. Approximately 80%-90% of RB1 gene and two hits or somatic mutations are needed for non- carriers develop ocular tumors. This gene encodes the hereditary Rb [4]. The age-adjusted annual incidence rate cell cycle regulatory retinoblastoma gene protein (pRb), of retinoblastoma is 3.1 per 10 with a 5-year relative sur- controls cellular differentiation during both embryogen- vival of 97.5% in the U.S. [5]. Treatment for Rb has historic- esis and in adult tissues, regulates apoptotic cell death, ally consisted primarily of radiotherapy (both external beam and radioactive plaques), enucleation, chemotherapy, * Correspondence: kleinerr@mail.nih.gov focal therapies such as laser or cryotherapy, or a combin- Epidemiology and Biostatistics Program Division of Cancer Epidemiology ation of these modalities. and Genetics, National Cancer Institute, National Institutes of Health, 6120 Executive Boulevard, Rockville, MD 20852, USA Full list of author information is available at the end of the article © 2012 Kleinerman et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Kleinerman et al. Clinical Sarcoma Research 2012, 2:15 Page 2 of 7 http://www.clinicalsarcomaresearch.com/content/2/1/15 Subsequent malignancies after retinoblastoma In a case–control study of bone and soft tissue sarcomas Long-term survivors of hereditary retinoblastoma are at an after hereditary Rb, risk increased with increasing dose up increased 20-fold risk of developing and dying from a sub- to 10.7-fold at doses greater than 60 Gy [11]. The mean sequent non-ocular cancer, primarily bone and soft tissue dose to the head among cases was 32.8 Gy, whereas the sarcomas, melanoma and brain tumors [6,7]. Survivors of lower limbs had received virtually no radiation (<0.1 Gy). non-hereditary Rb are at much lower risk of a subsequent In an update of that study, the location of 75 bone sarco- primary cancer, similar to the risk in the general population mas was skull and face (61%), lower limbs (29%), trunk [8-10]. The risk for sarcomas in hereditary patients has (7.6%), and unknown location (3.8%) [7]. been attributed to genetic susceptibility and past treatment Based on a series of 155 osteosarcomas following heredi- with radiation [8,11,12]. In addition to radiotherapy, tary Rb identified from the literature and one institute, chemotherapy, specifically alkylating agents, has been asso- investigators reported that the mean age of onset was ciated with the risk of bone cancer after Rb [6,13,14], but related to the osteosarcoma location [21]. Sarcomas occur- less so for soft tissue sarcomas [15]. ring in the radiation field were diagnosed one year earlier compared to those diagnosed outside the field (mean Bone sarcomas after retinoblastoma age = 12.2 years [range 3–35] vs. mean age = 13.4 years Patterns of risk [range 4–22]. This age difference suggested to the investi- Bone sarcomas are one of the most common second pri- gators that different biologic mechanisms may be asso- mary cancers occurring after hereditary retinoblastoma ciated with the development of bone sarcomas depending accounting for 25%-30% of all second primary cancers upon the location in the body. [6-8,16,17]. Bone sarcomas are typically diagnosed in Rb Studies of other pediatric malignancies have also survivors between 10 and 20 years of age, similar to the reported an increased risk for second osteosarcomas fol- incidence pattern in the general population [5]. In these lowing radiation and chemotherapy treatment for a first studies, the majority of bone sarcomas occurred within cancer (for a detailed review of radiation-related sarcomas, the radiation field in the head region, but up to 40% was see Berrington de Gonzalez et al. in this issue). diagnosed outside the treatment field, primarily in the lower legs [8,11,17]. Soft Tissue Sarcomas Table 1 presents risks for bone sarcomas from epi- Patterns of risk demiologic cohort studies including at least 100 her- Soft tissue sarcomas (STS) are also one of the most editary Rb survivors. The standardized incidence and common subsequent cancers following hereditary Rb mortality rates for bone sarcomas are increased sev- accounting for 12% up to 32% of all second cancers eral hundred-fold compared to population rates, due to [6,7,16]. In one large cohort study, an increased risk for the rarity of these tumors in the general population. A STS was first observed within 10 years of Rb diagnosis much lower risk for bone sarcomas was observed in the and continued through adult life up to 50 years after Rb, one cohort study that included non-irradiated survivors with specific subtypes occurring at similar ages as in the and began follow-up 25 years after Rb diagnosis [10]. It general population [22,23]. Fifty years after radiation has been estimated that the cumulative incidence of bone treatment for hereditary Rb, the cumulative risk of sarcoma following retinoblastoma is 7% at 20 years developing a STS was 13.1%, and the cumulative inci- [13,18]. Osteosarcoma is the most common type of bone dence for a STS inside the radiation field was higher sarcoma reported after Rb, but both chondrosarcoma and than outside the field (8.9% vs. 5.1%) [22]. Table 2 pre- Ewing sarcoma have been reported as well [19,20], al- sents the incidence and mortality due to STS after Rb in though risk estimates are not available for these other two cohort studies of at least 100 hereditary Rb survivors. types. Subtype heterogeneity Treatment for Rb and risk of bone sarcomas STS diagnosed in Rb patients comprise a heterogeneous Both high-dose radiation and increasing cumulative dose group of tumors of fat, cartilage and muscle; however, of chemotherapy, mainly alkylating agents (cyclophos- only one study has evaluated the risk of STS by histology phamide and triethylenemelamine or TEM), have been after hereditary Rb [22]. Leiomyosarcoma (LMS) consti- linked to the occurrence of bone sarcomas following tuted the most common type of STS after Rb, with the hereditary Rb [13,14]. Higher risks have been noted for majority diagnosed 30 and more years after Rb. This is the combination of radiotherapy and chemotherapy consistent with LMS being one of the most common compared to either treatment alone [6-8,13,14]. An earl- STS in the general population [23]. Although many LMS ier study of British Rb patients provided some evidence occurred in the head and neck region, the majority of that cyclophosphamide may increase the effect of radio- LMS in females were diagnosed in the uterus [24]. Loss therapy on the risk of bone sarcoma [8]. of heterozygosity in RB1 has been reported in uterine Kleinerman et al. Clinical Sarcoma Research 2012, 2:15 Page 3 of 7 http://www.clinicalsarcomaresearch.com/content/2/1/15 Table 1 Summary of bone sarcoma after retinoblastoma in cohort studies of 100 or more hereditary retinoblastoma survivors Study Study design, Years No. subjects with Years of follow-up: No. bone O/E, 95% CI O/E by treatment for Comments of Rb diagnosis hereditary median/mean sarcoma retinoblastoma retinoblastoma cases 1a. Incidence Kleinerman 2005 [7]US Hospital-based 963 1-yr survivors Mean: 25 75 360 (283–451) Any radiation: 406 (318–511) AER = 29.6 Two US medical centers 1914-1984 No radiation: 69 (8.4-250) Radiation + chemotherapy: 539 (384–733); Radiation, no chemotherapy: 302 (205–428) Reulen 2011 [16] British Population-based NA*, 5-yr survivors Mean: 26 35 289 (209–402) NA AER = 23; * No. of Rb survivors Childhood Cancer Survivor 1940-1991 not given but there are estimated Study, UK to be 809 hereditary Rb subjects based on MacCarthy et al. [44] Marees 2008 [6] Netherlands Registry -based 298 survivors Median: 22 16 314 (180–511) Radiation only: 302 (130–596) AER = 23 Dutch Retinoblastoma 1945-2005 Radiation + chemotherapy: Registry 586 (215–1275); Surgery only: 75 (1.9-421) Tucker 1987 [14]US Hospital-based 319 2-yr survivors Mean: 7 12 999 (515–1745) *Hereditability not specified Late Effects Study Group 1945-1979 1b. Mortality SMR, 95%CI SMR by treatment for retinoblastoma Yu 2009 [12]US Hospital-based 1092 1-yr survivors Median: 29 56 595 (449–773) Radiation: 673 (506–879) AER = 19.8; *No difference between Two medical centers 1914-1996 males and females Marees 2009 [46] Netherlands Registry-based 337 (alive in 1961) Median: 26 yr 11 289 (144–517) Radiation only: 266 (72.2-680) Majority deaths from bone cancer Dutch Retinoblastoma Registry 1862 - 2005 Follow-up Radiation + chemotherapy: occur within first 30 years 1961-2005 659 (179–1686); Surgery only: 124 (15–449) Acquaviva 2006 [46] Italian Registry-based 408 Median: 11 9 392 (204-753) NA Retinoblastoma Registry 1923-2003 Fletcher 2004 [10] Patients Hospital-based 144 25-yr survivors Follow up began 1 32.4 (0.82 - 180) NA *Radiation was not typically used from British hospitals and 1873-1950 in 1940 to treat Rb during these years linkage with national registry Median age: 60 Abbreviations: O = observed number of bone sarcomas; E = expected number of bone sarcomas; CI = confidence intervals; AER = absolute excess risk per 10,000 persons, yr = year; SMR = standardized mortality ratio; NA not available. Kleinerman et al. Clinical Sarcoma Research 2012, 2:15 Page 4 of 7 http://www.clinicalsarcomaresearch.com/content/2/1/15 Table 2 Summary of soft tissue sarcoma after retinoblastoma in cohort studies of 100 or more hereditary retinoblastoma survivors Study Study Design Years Number of subjects Years of follow-up: No. of Soft O/E, 95% CI O/E by treatment for Comments of Rb diagnosis with hereditary median/mean tissue retinoblastoma retinoblastoma sarcomas 2a. Incidence Kleinerman 2007 [22]US Hospital-based 963 1-yr survivors Mean: 25 69 184 (143–233) Any radiation: 212 (164–270); AER = 27 *No evidence of risk Two medical centers 1914-1984 No radiation: 47 (9.4-137); Any modification by sex *SIRs highest chemotherapy: 236 (161–333); within first10years butremained No chemotherapy: 193 significantly elevated ≥30 (133–271) Reulen 2011 [16]British Population-based NA, 5-yr survivors Mean: 26 16 N/A N/A Rates increase over time since Rb Childhood Cancer 1940-1991 (highest >25) Survivor Study Marees 2008 [6]Netherlands Registry-based 298 Median: 22 20 243 (148–375) Radiation only: 303 (161–517) AER = 29; SIRs elevated in all time Dutch Retinoblastoma Registry 1945-2005 Radiation + chemotherapy: 354 periods (3 cases ≥40) (129–770) Surgery only: 48.4 (1.23-270) Tucker 1987 [14]US Hospital-based 319 2-yr survivors Mean: 7 4 235 (64–602) All cases observed among females Late Effects Study Group 1945-1979 (hereditability not specified) 2b. Mortality SMR, 95% CI SMR by treatment for retinoblastoma Yu 2009 [12]US Hospital-based 1092 1-yr survivors Median: 29 31 329 (223–467) Any Radiation 395 (268–560) AER = 10.9; SMR is higher for women Two medical centers 1914-1996 vs men (not statistically significant) Marees 2009 [45]Netherlands Registry-based 337 Median: 26 13 276 (147–472) Radiation only: 311 (101–725) *Deaths observed up to ≥50 years Dutch Retinoblastoma Registry 1862 - 2005 Follow-up Rad + chemotherapy: 940 afterRB*SMRpeaks at 20–29 years 1961-2005 (345–2064); Surgery only: but SMRs significantly elevated in all 85.2 (10.3-308) time periods Acquaviva 2006 [46] Italian Registry-based 408 Median: 12 6 453 (203.5 - 1008) NA Retinoblastoma Registry 1923-2003 Fletcher 2004 [10]UKPatients Hospital-based 144 25-yr survivors Median attained 4 110 (29–281) NA *Treatment not available, but radiation from British hospitals; linkage 1873-1950 age: 60; Follow-up was not typically used during these with national registry began in 1940 years of Rb diagnosis Abbreviations: O = observed number of soft tissue sarcomas; E = expected number of soft tissue sarcomas; CI = confidence intervals; AER = absolute excess risk per 10,000 persons, yr = year; SMR = standardized mortality ratio; NA not available. Kleinerman et al. Clinical Sarcoma Research 2012, 2:15 Page 5 of 7 http://www.clinicalsarcomaresearch.com/content/2/1/15 LMS [25], which may confer an increased susceptibility associated with increasing alkylating agent score in the to this tumor in this population. LMS of other pelvic same cohort [22], whereas in another study of STS after sites have also been reported after Rb [26], and there all types of pediatric malignancies, including Rb, the risk have been several case reports of LMS diagnosed in the for STS increased significantly with cumulative dose of al- bladder [27,28]. kylating agents, adjusted for radiation exposure [15]. Very high risks have also been observed for fibrosarco- Increased risks of STS have also been noted following sur- mas, rhabdomyosarcomas and pleomorphic sarcomas gery only for hereditary Rb [6,10]. within the first 10 years after Rb [22,29]. These histo- logic types comprised the majority of STS that were Molecular evidence for an association of sarcomas diagnosed in or near the field of radiation, in contrast to with RB1 LMS, which were more likely to occur outside the radi- In additional to the epidemiologic evidence of an excess ation field (Table 3). Only 10% of rhabdomyosarcomas risk for both bone and STS in hereditary Rb patients, arise in the soft tissue of the head, neck or face in the structural alterations of the RB1 gene are well documen- general population, whereas all of the rhabdomyosarco- ted in primary bone sarcomas [33] and soft tissue sarco- mas arose in the head following radiation for Rb [22]. mas [34-36]. Most of the bone and soft tissue sarcomas An increased risk for liposarcomas that began 10 years diagnosed in hereditary Rb patients have complex karyo- after diagnosis of hereditary Rb was observed in the types, including fibrosarcoma, LMS, pleomorphic sarcoma, study by Kleinerman et al. [22]. Lipomas, a benign liposarcoma and osteosarcoma that are all related to inher- tumor of fat tissue, have also been reported to be ited defects in the RB pathway [37]. A comprehensive re- increased in that cohort, and the investigators noted a view by Burkhart and Sage of cellular mechanisms of possible association between lipomas and subsequent tumor suppression by the retinoblastoma gene discusses risk of a soft tissue sarcoma [30]. Following this observa- the loss of RB1 function and cancer progression [2]. tion, a RB1 mutation was identified in lipomas from her- editary Rb patients [31,32]. Conclusion It has been suggested that females may be at higher Hereditary Rb patients are at significant risk of develop- risk of STS after hereditary Rb [9], but studies of Rb ing a sarcoma due to past radiation treatment and gen- survivors have not consistently reported a higher risk etic susceptibility. Sarcomas account for approximately among females. Males have a higher rate of Rb in the 40% to 60% of second cancers in hereditary Rb survivors. general population and all liposarcomas and lipomas There is convincing epidemiologic evidence linking past occurred in males in the cohort in which they were radiotherapy with sarcomas in hereditary patients. Risk evaluated [22,30]. of bone and STS begins within 10 years of treatment for hereditary Rb and continues throughout adulthood, Treatment for Rb and risk of STS most notably for STS. Although both radiotherapy and chemotherapy for heredi- Recognition of the increased risk for sarcomas asso- tary Rb have been associated with an increased risk for ciated with past radiotherapy has influenced the current STS, the evidence is more consistent for radiotherapy. treatment of retinoblastoma with a trend towards greater (For a detailed review of radiation-related sarcoma, see use of chemotherapy, focal therapies, and most recently, Berrington de Gonzalez et al. in this issue). Wong et al. chemosurgery [38-40]. In addition, guidelines for im- demonstrated a radiation dose–response for STS whereby aging children for pre-treatment diagnostic evaluation of risk increased with dose up to a significant 11-fold Rb without the use of ionizing radiation have been increased risk at ≥60 Gy [11]. The risk for STS was not recommended to reduce the risk of second cancers in Rb patients [41]. However, the risk for bone sarcomas Table 3 Location of soft tissue sarcoma after and STS remains, reflecting the genetic predisposition to radiotherapy for retinoblastoma* these sarcomas due to loss of heterozygosity in the RB1 STS subtype In-field Out-of-field Total gene. Patients who were treated in 1960s and 1970s with Leiomyosarcoma 8 (38.1) 13 (61.9) 21 (100.) radiotherapy are still at risk in their adult years for the Fibrosarcoma 13 (100.) 0 13 (100.) development of STS. Given the excellent survival of most retinoblastoma patients, it is important for survi- Pleomorphic sarcoma 11 (100.) 0 11 (100.) vors, their families and health care providers to be aware Rhabdomyosarcoma 7 (100.) 0 7 (100.) of these risks, especially for hereditary patients [42]. Liposarcoma 1 (33.3) 2 (66.7) 3 (100.) There is on-going research to try to identify whether Other STS 8 (80.0) 2 (20.0) 10 (100.) specific RB1 mutations or location of mutations predis- Total 48 (72.7) 18 (27.3) 66 (100.) pose to sarcomas, which could lead to identification of *Based on data from Kleinerman et al. [22]. those survivors at greatest risk [43]. The development of Kleinerman et al. Clinical Sarcoma Research 2012, 2:15 Page 6 of 7 http://www.clinicalsarcomaresearch.com/content/2/1/15 comprehensive guidelines for long-term follow-up that radiotherapy and chemotherapy in children. N Engl J Med 1987, 317:588–593. are specifically tailored for detection of sarcomas and 15. 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Oncogene 2006, 25:5350–5357. doi:10.1186/2045-3329-2-15 Cite this article as: Kleinerman et al.: Sarcomas in hereditary retinoblastoma. Clinical Sarcoma Research 2012 2:15. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit

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