Open Access

Sarcomas in hereditary retinoblastoma

  • Ruth A Kleinerman1Email author,
  • Sara J Schonfeld1 and
  • Margaret A Tucker1, 2
Clinical Sarcoma Research20122:15

DOI: 10.1186/2045-3329-2-15

Received: 7 October 2011

Accepted: 23 January 2012

Published: 4 October 2012

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

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 for the development of sarcomas, both soft tissue (STS) and bone. This predisposition to sarcomas in retinoblastoma survivors has been attributed to genetic susceptibility as well as past radiation treatment for Rb.

Retinoblastoma epidemiology

Retinoblastoma is a rare pediatric cancer of the eye with an autosomal dominant inheritance pattern. It is caused by mutations in the RB1 tumor suppressor gene, located on chromosome 13q14 with very high penetrance and expressivity[1]. Approximately 80%-90% of RB1 gene carriers develop ocular tumors. This gene encodes the cell cycle regulatory retinoblastoma gene protein (pRb), controls cellular differentiation during both embryogenesis and in adult tissues, regulates apoptotic cell death, maintains cell cycle arrest and preserves chromosome stability[2].

Retinoblastoma occurs in two forms: hereditary (30-40%) and non-hereditary (60-70%). Hereditary retinoblastoma is caused by a germline mutation in one allele of the RB1 gene and an acquired somatic mutation in the other allele, whereas the non-hereditary form is caused by somatic mutations in both alleles. The hereditary form is characterized 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 diagnosed between 2–5 years of age. About 10-15% of patients with unilateral Rb, however, carry a germline mutation and are considered hereditary. This difference in diagnosis age led Knudson to develop the two-hit theory[3], in which only one additional mutation is needed for hereditary Rb and two hits or somatic mutations are needed for non-hereditary Rb[4]. The age-adjusted annual incidence rate of retinoblastoma is 3.1 per 107 with a 5-year relative survival of 97.5% in the U.S.[5]. Treatment for Rb has historically consisted primarily of radiotherapy (both external beam and radioactive plaques), enucleation, chemotherapy, focal therapies such as laser or cryotherapy, or a combination of these modalities.

Subsequent malignancies after retinoblastoma

Long-term survivors of hereditary retinoblastoma are at an increased 20-fold risk of developing and dying from a subsequent non-ocular cancer, primarily bone and soft tissue sarcomas, melanoma and brain tumors[6, 7]. Survivors of non-hereditary Rb are at much lower risk of a subsequent primary cancer, similar to the risk in the general population[810]. The risk for sarcomas in hereditary patients has been attributed to genetic susceptibility and past treatment with radiation[8, 11, 12]. In addition to radiotherapy, chemotherapy, specifically alkylating agents, has been associated with the risk of bone cancer after Rb[6, 13, 14], but less so for soft tissue sarcomas[15].

Bone sarcomas after retinoblastoma

Patterns of risk

Bone sarcomas are one of the most common second primary cancers occurring after hereditary retinoblastoma accounting for 25%-30% of all second primary cancers[68, 16, 17]. Bone sarcomas are typically diagnosed in Rb survivors between 10 and 20 years of age, similar to the incidence pattern in the general population[5]. In these studies, the majority of bone sarcomas occurred within the radiation field in the head region, but up to 40% was diagnosed outside the treatment field, primarily in the lower legs[8, 11, 17].

Table1 presents risks for bone sarcomas from epidemiologic cohort studies including at least 100 hereditary Rb survivors. The standardized incidence and mortality rates for bone sarcomas are increased several hundred-fold compared to population rates, due to the rarity of these tumors in the general population. A much lower risk for bone sarcomas was observed in the one cohort study that included non-irradiated survivors and began follow-up 25 years after Rb diagnosis[10]. It has been estimated that the cumulative incidence of bone sarcoma following retinoblastoma is 7% at 20 years[13, 18]. Osteosarcoma is the most common type of bone sarcoma reported after Rb, but both chondrosarcoma and Ewing sarcoma have been reported as well[19, 20], although risk estimates are not available for these other two types.
Table 1

Summary of bone sarcoma after retinoblastoma in cohort studies of 100 or more hereditary retinoblastoma survivors

Study

Study design, Years of Rb diagnosis

No. subjects with hereditary retinoblastoma

Years of follow-up: median/mean

No. bone sarcoma cases

O/E, 95% CI

O/E by treatment for retinoblastoma

Comments

1a. Incidence

Kleinerman 2005[7] US Two US medical centers

Hospital-based 1914-1984

963 1-yr survivors

Mean: 25

75

360 (283–451)

Any radiation: 406 (318–511) No radiation: 69 (8.4-250)

Radiation + chemotherapy: 539 (384–733); Radiation, no chemotherapy: 302 (205–428)

AER = 29.6

Reulen 2011[16] British Childhood Cancer Survivor Study, UK

Population-based 1940-1991

NA*, 5-yr survivors

Mean: 26

35

289 (209–402)

NA

AER = 23; * No. of Rb survivors not given but there are estimated to be 809 hereditary Rb subjects based on MacCarthy et al.[44]

Marees 2008[6] Netherlands Dutch Retinoblastoma Registry

Registry -based 1945-2005

298 survivors

Median: 22

16

314 (180–511)

Radiation only: 302 (130–596) Radiation + chemotherapy: 586 (215–1275); Surgery only: 75 (1.9-421)

AER = 23

Tucker 1987[14] US Late Effects Study Group

Hospital-based 1945-1979

319 2-yr survivors

Mean: 7

12

999 (515–1745)

 

*Hereditability not specified

1b. Mortality

    

SMR, 95%CI

SMR by treatment for retinoblastoma

 

Yu 2009[12] US Two medical centers

Hospital-based 1914-1996

1092 1-yr survivors

Median: 29

56

595 (449–773)

Radiation: 673 (506–879)

AER = 19.8; *No difference between males and females

Marees 2009[46] Netherlands Dutch Retinoblastoma Registry

Registry-based 1862 - 2005

337 (alive in 1961)

Median: 26 yr Follow-up 1961-2005

11

289 (144–517)

Radiation only: 266 (72.2-680) Radiation + chemotherapy: 659 (179–1686); Surgery only: 124 (15–449)

Majority deaths from bone cancer occur within first 30 years

Acquaviva 2006[46] Italian Retinoblastoma Registry

Registry-based 1923-2003

408

Median: 11

9

392 (204-753)

NA

 

Fletcher 2004[10] Patients from British hospitals and linkage with national registry

Hospital-based 1873-1950

144 25-yr survivors

Follow up began in 1940 Median age: 60

1

32.4 (0.82 - 180)

NA

*Radiation was not typically used to treat Rb during these years

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.

Treatment for Rb and risk of bone sarcomas

Both high-dose radiation and increasing cumulative dose of chemotherapy, mainly alkylating agents (cyclophosphamide and triethylenemelamine or TEM), have been linked to the occurrence of bone sarcomas following hereditary Rb[13, 14]. Higher risks have been noted for the combination of radiotherapy and chemotherapy compared to either treatment alone[68, 13, 14]. An earlier study of British Rb patients provided some evidence that cyclophosphamide may increase the effect of radiotherapy on the risk of bone sarcoma[8].

In a case–control study of bone and soft tissue sarcomas after hereditary Rb, risk increased with increasing dose up to 10.7-fold at doses greater than 60 Gy[11]. The mean dose to the head among cases was 32.8 Gy, whereas the lower limbs had received virtually no radiation (<0.1 Gy). In an update of that study, the location of 75 bone sarcomas was skull and face (61%), lower limbs (29%), trunk (7.6%), and unknown location (3.8%)[7].

Based on a series of 155 osteosarcomas following hereditary Rb identified from the literature and one institute, investigators reported that the mean age of onset was related to the osteosarcoma location[21]. Sarcomas occurring in the radiation field were diagnosed one year earlier compared to those diagnosed outside the field (mean age = 12.2 years [range 3–35] vs. mean age = 13.4 years [range 4–22]. This age difference suggested to the investigators that different biologic mechanisms may be associated with the development of bone sarcomas depending upon the location in the body.

Studies of other pediatric malignancies have also reported an increased risk for second osteosarcomas following radiation and chemotherapy treatment for a first cancer (for a detailed review of radiation-related sarcomas, see Berrington de Gonzalez et al. in this issue).

Soft Tissue Sarcomas

Patterns of risk

Soft tissue sarcomas (STS) are also one of the most common subsequent cancers following hereditary Rb accounting for 12% up to 32% of all second cancers[6, 7, 16]. In one large cohort study, an increased risk for STS was first observed within 10 years of Rb diagnosis and continued through adult life up to 50 years after Rb, with specific subtypes occurring at similar ages as in the general population[22, 23]. Fifty years after radiation treatment for hereditary Rb, the cumulative risk of developing a STS was 13.1%, and the cumulative incidence for a STS inside the radiation field was higher than outside the field (8.9% vs. 5.1%)[22]. Table2 presents the incidence and mortality due to STS after Rb in cohort studies of at least 100 hereditary Rb survivors.
Table 2

Summary of soft tissue sarcoma after retinoblastoma in cohort studies of 100 or more hereditary retinoblastoma survivors

Study

Study Design Years of Rb diagnosis

Number of subjects with hereditary retinoblastoma

Years of follow-up: median/mean

No. of Soft tissue sarcomas

O/E, 95% CI

O/E by treatment for retinoblastoma

Comments

2a. Incidence

Kleinerman 2007[22] US Two medical centers

Hospital-based 1914-1984

963 1-yr survivors

Mean: 25

69

184 (143–233)

Any radiation: 212 (164–270); No radiation: 47 (9.4-137); Any chemotherapy: 236 (161–333); No chemotherapy: 193 (133–271)

AER = 27 *No evidence of risk modification by sex *SIRs highest within first 10 years but remained significantly elevated ≥30

Reulen 2011[16] British Childhood Cancer Survivor Study

Population-based 1940-1991

NA, 5-yr survivors

Mean: 26

16

N/A

N/A

Rates increase over time since Rb (highest >25)

Marees 2008[6] Netherlands Dutch Retinoblastoma Registry

Registry-based 1945-2005

298

Median: 22

20

243 (148–375)

Radiation only: 303 (161–517) Radiation + chemotherapy: 354 (129–770) Surgery only: 48.4 (1.23-270)

AER = 29; SIRs elevated in all time periods (3 cases ≥40)

Tucker 1987[14] US Late Effects Study Group

Hospital-based 1945-1979

319 2-yr survivors (hereditability not specified)

Mean: 7

4

235 (64–602)

 

All cases observed among females

2b. Mortality

    

SMR, 95% CI

SMR by treatment for retinoblastoma

 

Yu 2009[12] US Two medical centers

Hospital-based 1914-1996

1092 1-yr survivors

Median: 29

31

329 (223–467)

Any Radiation 395 (268–560)

AER = 10.9; SMR is higher for women vs men (not statistically significant)

Marees 2009[45] Netherlands Dutch Retinoblastoma Registry

Registry-based 1862 - 2005

337

Median: 26 Follow-up 1961-2005

13

276 (147–472)

Radiation only: 311 (101–725) Rad + chemotherapy: 940 (345–2064); Surgery only: 85.2 (10.3-308)

*Deaths observed up to ≥50 years after RB *SMR peaks at 20–29 years but SMRs significantly elevated in all time periods

Acquaviva 2006[46] Italian Retinoblastoma Registry

Registry-based 1923-2003

408

Median: 12

6

453 (203.5 - 1008)

NA

 

Fletcher 2004[10] UK Patients from British hospitals; linkage with national registry

Hospital-based 1873-1950

144 25-yr survivors

Median attained age: 60; Follow-up began in 1940

4

110 (29–281)

NA

*Treatment not available, but radiation was not typically used during these 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.

Subtype heterogeneity

STS diagnosed in Rb patients comprise a heterogeneous group of tumors of fat, cartilage and muscle; however, only one study has evaluated the risk of STS by histology after hereditary Rb[22]. Leiomyosarcoma (LMS) constituted the most common type of STS after Rb, with the majority diagnosed 30 and more years after Rb. This is consistent with LMS being one of the most common STS in the general population[23]. Although many LMS occurred in the head and neck region, the majority of LMS in females were diagnosed in the uterus[24]. Loss of heterozygosity in RB1 has been reported in uterine LMS[25], which may confer an increased susceptibility to this tumor in this population. LMS of other pelvic sites have also been reported after Rb[26], and there have been several case reports of LMS diagnosed in the bladder[27, 28].

Very high risks have also been observed for fibrosarcomas, rhabdomyosarcomas and pleomorphic sarcomas within the first 10 years after Rb[22, 29]. These histologic types comprised the majority of STS that were diagnosed in or near the field of radiation, in contrast to LMS, which were more likely to occur outside the radiation field (Table3). Only 10% of rhabdomyosarcomas arise in the soft tissue of the head, neck or face in the general population, whereas all of the rhabdomyosarcomas arose in the head following radiation for Rb[22].
Table 3

Location of soft tissue sarcoma after radiotherapy for retinoblastoma*

STS subtype

In-field

Out-of-field

Total

Leiomyosarcoma

8 (38.1)

13 (61.9)

21 (100.)

Fibrosarcoma

13 (100.)

0

13 (100.)

Pleomorphic sarcoma

11 (100.)

0

11 (100.)

Rhabdomyosarcoma

7 (100.)

0

7 (100.)

Liposarcoma

1 (33.3)

2 (66.7)

3 (100.)

Other STS

8 (80.0)

2 (20.0)

10 (100.)

Total

48 (72.7)

18 (27.3)

66 (100.)

*Based on data from Kleinerman et al.[22].

An increased risk for liposarcomas that began 10 years after diagnosis of hereditary Rb was observed in the study by Kleinerman et al.[22]. Lipomas, a benign tumor of fat tissue, have also been reported to be increased in that cohort, and the investigators noted a possible association between lipomas and subsequent risk of a soft tissue sarcoma[30]. Following this observation, a RB1 mutation was identified in lipomas from hereditary Rb patients[31, 32].

It has been suggested that females may be at higher risk of STS after hereditary Rb[9], but studies of Rb survivors have not consistently reported a higher risk among females. Males have a higher rate of Rb in the general population and all liposarcomas and lipomas occurred in males in the cohort in which they were evaluated[22, 30].

Treatment for Rb and risk of STS

Although both radiotherapy and chemotherapy for hereditary Rb have been associated with an increased risk for STS, the evidence is more consistent for radiotherapy. (For a detailed review of radiation-related sarcoma, see Berrington de Gonzalez et al. in this issue). Wong et al. demonstrated a radiation dose–response for STS whereby risk increased with dose up to a significant 11-fold increased risk at ≥60 Gy[11]. The risk for STS was not associated with increasing alkylating agent score in the same cohort[22], whereas in another study of STS after all types of pediatric malignancies, including Rb, the risk for STS increased significantly with cumulative dose of alkylating agents, adjusted for radiation exposure[15]. Increased risks of STS have also been noted following surgery only for hereditary Rb[6, 10].

Molecular evidence for an association of sarcomas with RB1

In additional to the epidemiologic evidence of an excess risk for both bone and STS in hereditary Rb patients, structural alterations of the RB1 gene are well documented in primary bone sarcomas[33] and soft tissue sarcomas[3436]. Most of the bone and soft tissue sarcomas diagnosed in hereditary Rb patients have complex karyotypes, including fibrosarcoma, LMS, pleomorphic sarcoma, liposarcoma and osteosarcoma that are all related to inherited defects in the RB pathway[37]. A comprehensive review by Burkhart and Sage of cellular mechanisms of tumor suppression by the retinoblastoma gene discusses the loss of RB1 function and cancer progression[2].

Conclusion

Hereditary Rb patients are at significant risk of developing a sarcoma due to past radiation treatment and genetic susceptibility. Sarcomas account for approximately 40% to 60% of second cancers in hereditary Rb survivors. There is convincing epidemiologic evidence linking past radiotherapy with sarcomas in hereditary patients. Risk of bone and STS begins within 10 years of treatment for hereditary Rb and continues throughout adulthood, most notably for STS.

Recognition of the increased risk for sarcomas associated with past radiotherapy has influenced the current treatment of retinoblastoma with a trend towards greater use of chemotherapy, focal therapies, and most recently, chemosurgery[3840]. In addition, guidelines for imaging children for pre-treatment diagnostic evaluation of Rb without the use of ionizing radiation have been recommended to reduce the risk of second cancers in Rb patients[41]. However, the risk for bone sarcomas and STS remains, reflecting the genetic predisposition to these sarcomas due to loss of heterozygosity in the RB1 gene. Patients who were treated in 1960s and 1970s with radiotherapy are still at risk in their adult years for the development of STS. Given the excellent survival of most retinoblastoma patients, it is important for survivors, their families and health care providers to be aware of these risks, especially for hereditary patients[42]. There is on-going research to try to identify whether specific RB1 mutations or location of mutations predispose to sarcomas, which could lead to identification of those survivors at greatest risk[43]. The development of comprehensive guidelines for long-term follow-up that are specifically tailored for detection of sarcomas and other second primary cancers in retinoblastoma survivors are also needed, especially for those patients who received radiotherapy in the past.

Author contributions

RK and SS participated in the review of existing data, RK, SS and MT contributed to the interpretation of the data, and all participated in the draft of the manuscript. All authors read and approved the final manuscript.

Abbreviations

Rb: 

retinoblastoma

STS: 

soft tissue sarcoma

LMS: 

leiomyosarcoma.

Declarations

Acknowledgement

This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute.

Authors’ Affiliations

(1)
Epidemiology and Biostatistics Program Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health
(2)
Human Genetics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health

References

  1. Harbour JW: Molecular basis of low-penetrance retinoblastoma. Arch Ophthalmol. 2001, 119: 1699-1704.View ArticlePubMedGoogle Scholar
  2. Burkhart DL, Sage J: Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nat Rev Cancer. 2008, 8: 671-682. 10.1038/nrc2399View ArticlePubMedGoogle Scholar
  3. Knudson AG: Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971, 68: 820-823. 10.1073/pnas.68.4.820PubMed CentralView ArticlePubMedGoogle Scholar
  4. Little MP, Kleinerman RA, Stiller CA, Li G: Kroll ME. 2011, Murphy MF: Analysis of retinoblastoma age incidence data using a fully stochastic cancer model. Int J Cancer,Google Scholar
  5. SEER: Cancer Statistics Review. 2008, [http://seer.cancer.gov/csr/1975_2008], []Google Scholar
  6. Marees T, Moll AC, Imhof SM, de Boer MR, Ringens PJ, van Leeuwen FE: Risk of second malignancies in survivors of retinoblastoma: more than 40 years of follow-up. J Natl Cancer Inst. 2008, 100: 1771-1779. 10.1093/jnci/djn394View ArticlePubMedGoogle Scholar
  7. Kleinerman RA, Tucker MA, Tarone RE, Abramson DH, Seddon JM, Stovall M, Li FP, Fraumeni JF: Risk of new cancers after radiotherapy in long-term survivors of retinoblastoma: an extended follow-up. J Clin Oncol. 2005, 23: 2272-2279. 10.1200/JCO.2005.05.054View ArticlePubMedGoogle Scholar
  8. Draper GJ, Sanders BM, Kingston JE: Second primary neoplasms in patients with retinoblastoma. Br J Cancer. 1986, 53: 661-671. 10.1038/bjc.1986.110PubMed CentralView ArticlePubMedGoogle Scholar
  9. Eng C, Li FP, Abramson DH, Ellsworth RM, Wong FL, Goldman MB, Seddon J, Tarbell N, Boice JD: Mortality from second tumors among long-term survivors of retinoblastoma. J Natl Cancer Inst. 1993, 85: 1121-1128. 10.1093/jnci/85.14.1121View ArticlePubMedGoogle Scholar
  10. Fletcher O, Easton D, Anderson K, Gilham C, Jay M, Peto J: Lifetime risks of common cancers among retinoblastoma survivors. J Natl Cancer Inst. 2004, 96: 357-363. 10.1093/jnci/djh058View ArticlePubMedGoogle Scholar
  11. Wong FL, Boice JD, Abramson DH, Tarone RE, Kleinerman RA, Stovall M, Goldman MB, Seddon JM, Tarbell N, Fraumeni JF, Li FP: Cancer incidence after retinoblastoma. Radiation dose and sarcoma risk. JAMA. 1997, 278: 1262-1267.PubMedGoogle Scholar
  12. Yu CL, Tucker MA, Abramson DH, Furukawa K, Seddon JM, Stovall M, Fraumeni JF, Kleinerman RA: Cause-specific mortality in long-term survivors of retinoblastoma. J Natl Cancer Inst. 2009, 101: 581-591. 10.1093/jnci/djp046PubMed CentralView ArticlePubMedGoogle Scholar
  13. Hawkins MM, Wilson LM, Burton HS, Potok MH, Winter DL, Marsden HB, Stovall MA: Radiotherapy, alkylating agents, and risk of bone cancer after childhood cancer. J Natl Cancer Inst. 1996, 88: 270-278. 10.1093/jnci/88.5.270View ArticlePubMedGoogle Scholar
  14. Tucker MA, D'Angio GJ, Boice JD, Strong LC, Li FP, Stovall M, Stone BJ, Green DM, Lombardi F, Newton W: Bone sarcomas linked to radiotherapy and chemotherapy in children. N Engl J Med. 1987, 317: 588-593. 10.1056/NEJM198709033171002View ArticlePubMedGoogle Scholar
  15. Jenkinson HC, Winter DL, Marsden HB, Stovall MA, Stevens MC, Stiller CA, Hawkins MM: A study of soft tissue sarcomas after childhood cancer in Britain. Br J Cancer. 2007, 97: 695-699. 10.1038/sj.bjc.6603908PubMed CentralView ArticlePubMedGoogle Scholar
  16. Reulen RC, Frobisher C, Winter DL, Kelly J, Lancashire ER, Stiller CA, Pritchard-Jones K, Jenkinson HC, Hawkins MM: Long-term risks of subsequent primary neoplasms among survivors of childhood cancer. JAMA. 2011, 305: 2311-2319. 10.1001/jama.2011.747View ArticlePubMedGoogle Scholar
  17. Woo KI, Harbour JW: Review of 676 second primary tumors in patients with retinoblastoma: association between age at onset and tumor type. Arch Ophthalmol. 2010, 128: 865-870. 10.1001/archophthalmol.2010.126View ArticlePubMedGoogle Scholar
  18. Kleinerman R, Yu CL, Little MP, Abramson DH, Seddon JH, Tucker MA: Variation of second cancer risk by family history of retinoblastoma among long-term survivors. Journal of Clin Oncol. 2012, 30: 950-957. 10.1200/JCO.2011.37.0239. in press,View ArticleGoogle Scholar
  19. Cope JU, Tsokos M, Miller RW: Ewing sarcoma and sinonasal neuroectodermal tumors as second malignant tumors after retinoblastoma and other neoplasms. Med Pediatr Oncol. 2001, 36: 290-294. 10.1002/1096-911X(20010201)36:2<290::AID-MPO1067>3.0.CO;2-5View ArticlePubMedGoogle Scholar
  20. Moll AC, Imhof SM, Schouten-Van Meeteren AY, Kuik DJ, Hofman P, Boers M: Second primary tumors in hereditary retinoblastoma: a register-based study, 1945–1997: is there an age effect on radiation-related risk?. Ophthalmology. 2001, 108: 1109-1114. 10.1016/S0161-6420(01)00562-0View ArticlePubMedGoogle Scholar
  21. Chauveinc L, Mosseri V, Quintana E, Desjardins L, Schlienger P, Doz F, Dutrillaux B: Osteosarcoma following retinoblastoma: age at onset and latency period. Ophthalmic Genet. 2001, 22: 77-88. 10.1076/opge.22.2.77.2228View ArticlePubMedGoogle Scholar
  22. Kleinerman RA, Tucker MA, Abramson DH, Seddon JM, Tarone RE, Fraumeni JF: Risk of soft tissue sarcomas by individual subtype in survivors of hereditary retinoblastoma. J Natl Cancer Inst. 2007, 99: 24-31. 10.1093/jnci/djk002View ArticlePubMedGoogle Scholar
  23. Toro JR, Travis LB, Wu HJ, Zhu K, Fletcher CD, Devesa SS: Incidence patterns of soft tissue sarcomas, regardless of primary site, in the surveillance, epidemiology and end results program, 1978–2001: An analysis of 26, 758 cases. Int J Cancer. 2006, 119: 2922-2930. 10.1002/ijc.22239View ArticlePubMedGoogle Scholar
  24. Francis JH, Kleinerman RA: Seddon JM. 2011, Abramson DH: Increased risk of secondary uterine leiomyosarcoma in hereditary retinoblastoma. Gynecol Oncol,Google Scholar
  25. Dei Tos AP, Maestro R, Doglioni C, Piccinin S, Libera DD, Boiocchi M, Fletcher CD: Tumor suppressor genes and related molecules in leiomyosarcoma. Am J Pathol. 1996, 148: 1037-1045.PubMed CentralPubMedGoogle Scholar
  26. Venkatraman L, Goepel JR, Steele K, Dobbs SP, Lyness RW, McCluggage WG: Soft tissue, pelvic, and urinary bladder leiomyosarcoma as second neoplasm following hereditary retinoblastoma. J Clin Pathol. 2003, 56: 233-236. 10.1136/jcp.56.3.233PubMed CentralView ArticlePubMedGoogle Scholar
  27. Bleoo SL, Godbout R, Rayner D, Tamimi Y, Moore RB: Leiomyosarcoma of the bladder in a retinoblastoma patient. Urol Int. 2003, 71: 118-121. 10.1159/000071109View ArticlePubMedGoogle Scholar
  28. Brucker B, Ernst L, Meadows A, Zderic S: A second leiomyosarcoma in the urinary bladder of a child with a history of retinoblastoma 12 years following partial cystectomy. Pediatr Blood Cancer. 2006, 46: 811-814. 10.1002/pbc.20506View ArticlePubMedGoogle Scholar
  29. Cebulla CM, Kleinerman RA, Alegret A, Kulak A, Dubovy SR, Hess DJ, Murray TG: Rapid Appearance of Rhabdomyosarcoma after Radiation and Chemotherapy for Retinoblastoma: A Clinicopathologic Correlation. Retin Cases Brief Rep. 2009, 3: 343-346. 10.1097/ICB.0b013e31817377a5PubMed CentralView ArticlePubMedGoogle Scholar
  30. Li FP, Abramson DH, Tarone RE, Kleinerman RA, Fraumeni JF, Boice JD: Hereditary retinoblastoma, lipoma, and second primary cancers. J Natl Cancer Inst. 1997, 89: 83-84. 10.1093/jnci/89.1.83View ArticlePubMedGoogle Scholar
  31. Rieder H, Lohmann D, Poensgen B, Fritz B, Aslan M, Drohm D, Strombach Angersbach FJ, Rehder H: Loss of heterozygosity of the retinoblastoma (RB1) gene in lipomas from a retinoblastoma patient. J Natl Cancer Inst. 1998, 90: 324-326. 10.1093/jnci/90.4.324View ArticlePubMedGoogle Scholar
  32. Genuardi M, Klutz M, Devriendt K, Caruso D, Stirpe M, Lohmann DR: Multiple lipomas linked to an RB1 gene mutation in a large pedigree with low penetrance retinoblastoma. Eur J Hum Genet. 2001, 9: 690-694. 10.1038/sj.ejhg.5200694View ArticlePubMedGoogle Scholar
  33. Friend SH, Bernards R, Rogelj S, Weinberg RA, Rapaport JM, Albert DM, Dryja TP: A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature. 1986, 323: 643-646. 10.1038/323643a0View ArticlePubMedGoogle Scholar
  34. Stratton MR, Williams S, Fisher C, Ball A, Westbury G, Gusterson BA, Fletcher CD, Knight JC, Fung YK, Reeves BR: Structural alterations of the RB1 gene in human soft tissue tumours. Br J Cancer. 1989, 60: 202-205. 10.1038/bjc.1989.251PubMed CentralView ArticlePubMedGoogle Scholar
  35. Friend SH, Horowitz JM, Gerber MR, Wang XF, Bogenmann E, Li FP, Weinberg RA: Deletions of a DNA sequence in retinoblastomas and mesenchymal tumors: organization of the sequence and its encoded protein. Proc Natl Acad Sci U S A. 1987, 84: 9059-9063. 10.1073/pnas.84.24.9059PubMed CentralView ArticlePubMedGoogle Scholar
  36. Bookstein R, Lee WH: Molecular genetics of the retinoblastoma suppressor gene. Crit Rev Oncog. 1991, 2: 211-227.PubMedGoogle Scholar
  37. Helman LJ, Meltzer P: Mechanisms of sarcoma development. Nat Rev Cancer. 2003, 3: 685-694. 10.1038/nrc1168View ArticlePubMedGoogle Scholar
  38. Gobin YP, Dunkel IJ, Marr BP, Brodie SE, Abramson DH: Intra-arterial chemotherapy for the management of retinoblastoma: four-year experience. Arch Ophthalmol. 2011, 129: 732-737. 10.1001/archophthalmol.2011.5View ArticlePubMedGoogle Scholar
  39. Turaka K, Shields CL, Meadows AT, Leahey A: Second malignant neoplasms following chemoreduction with carboplatin, etoposide, and vincristine in 245 patients with intraocular retinoblastoma. Pediatr Blood Cancer. 2012, 59: 121-125. 10.1002/pbc.23278View ArticlePubMedGoogle Scholar
  40. Abramson DH: Chemosurgery for retinoblastoma: what we know after 5 years. Arch Ophthalmol. 2011, 129: 1492-1494. 10.1001/archophthalmol.2011.354View ArticlePubMedGoogle Scholar
  41. de Graaf P, Goricke S, Rodjan F, Galluzzi P, Maeder P, Castelijns JA, Brisse HJ: Guidelines for imaging retinoblastoma: imaging principles and MRI standardization. Pediatr Radiol. 2012, 42: 2-14. 10.1007/s00247-011-2201-5PubMed CentralView ArticlePubMedGoogle Scholar
  42. Meadows AT: Retinoblastoma survivors: sarcomas and surveillance. J Natl Cancer Inst. 2007, 99: 3-5. 10.1093/jnci/djk014View ArticlePubMedGoogle Scholar
  43. Dommering CJ, Marees T, van der Hout AH, Imhof SM, Meijers-Heijboer H, Ringens PJ, van Leeuwen FE, Moll AC: RB1 mutations and second primary malignancies after hereditary retinoblastoma. Fam Cancer. 2011, 11: 225-233.PubMed CentralView ArticleGoogle Scholar
  44. MacCarthy A, Bayne AM, Draper GJ, Eatock EM, Kroll ME, Stiller CA, Vincent TJ, Hawkins MM, Jenkinson HC, Kingston JE: Non-ocular tumours following retinoblastoma in Great Britain 1951 to 2004. Br J Ophthalmol. 2009, 93: 1159-1162. 10.1136/bjo.2008.146035View ArticlePubMedGoogle Scholar
  45. Marees T, van Leeuwen FE, de Boer MR, Imhof SM, Ringens PJ, Moll AC: Cancer mortality in long-term survivors of retinoblastoma. Eur J Cancer. 2009, 45: 3245-3253. 10.1016/j.ejca.2009.05.011View ArticlePubMedGoogle Scholar
  46. Acquaviva A, Ciccolallo L, Rondelli R, Balistreri A, Ancarola R, Cozza R, Hadjistilianou D, Francesco SD, Toti P, Pastore G: Mortality from second tumour among long-term survivors of retinoblastoma: a retrospective analysis of the Italian retinoblastoma registry. Oncogene. 2006, 25: 5350-5357. 10.1038/sj.onc.1209786View ArticlePubMedGoogle Scholar

Copyright

© Kleinerman et al.; licensee BioMed Central Ltd. 2012

This article is published under license to 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.

Advertisement