Second Malignancies After Retinoblastoma

Some secondary malignancies in patients with retinoblastoma may be long-term side effects of radiation and chemotherapy. However, rates of second cancers in people treated for hereditary retinoblastoma are higher than in people who had sporadic retinoblastoma - indicating an underlying genetic susceptibility to a variety of cancers. In a series of 1,927 retinoblastoma patients diagnosed in Britain from 1951 to 2004 MacCarthy et al (2013) reported standardised incidence rates of second malignancies of 13.7% in inherited cases compared to 1.5% in non-heritable cases. Osteosarcoma is the most frequent second malignancy following retinoblastoma, this can be associated with the RB1 gene and/or induced by radiotherapy.

Latest Publications

Chaussade A, Millot G, Wells C, et al.
Correlation between RB1germline mutations and second primary malignancies in hereditary retinoblastoma patients treated with external beam radiotherapy.
Eur J Med Genet. 2019; 62(3):217-223 [PubMed] Related Publications
Retinoblastoma (Rb) results from biallelic inactivation of the RB1 gene. Hereditary Rb patients i. e germline carriers of a RB1 mutation also have a risk of developing subsequent malignant neoplasms (SMN) such as osteosarcomas. This SMN risk is maximized by external beam radiotherapy treatments (EBRT), which is why these treatments are now avoided. Nevertheless, EBRT is still a matter of great concern, as EBRT-treated patients are in their adulthood and SMNs remain the major cause of death for patients. To decipher the relationship between RB1 genotype and SMN development in EBRT treated patients, we conducted a retrospective study in a cohort of 160 irradiated hereditary Rbs with fully resolved RB1 mutational status. Median follow-up was 22 years [1-51] and median age of patients was 27 years old [7-53]. Among these 160 Rb patients, 120 did not develop any SMN (75%) and 40 developed SMNs (25%). The age at which EBRT is given (i.e. before or after the age of 12 months) was not correlated to SMN development (p = 0.6). We didn't find any difference in RB1 mutation type between patients with or without SMN, neither could we detect any linkage between mutation type and SMN location, SMN type and age at diagnosis. Interestingly, among 13 carriers of a RB1 low penetrance mutation, 3 of them developed sarcomas, a rare tumor that cannot be attributed to the general population. Our study cannot explain why a RB1 mutation leads or not to a SMN but demonstrated that EBRT patients with a low penetrance mutation remain at risk of SMN and should be cautiously monitored.

Racher H, Soliman S, Argiropoulos B, et al.
Molecular analysis distinguishes metastatic disease from second cancers in patients with retinoblastoma.
Cancer Genet. 2016 Jul-Aug; 209(7-8):359-63 [PubMed] Free Access to Full Article Related Publications
The pediatric ocular tumor retinoblastoma readily metastasizes, but these lesions can masquerade as histologically similar pediatric small round blue cell tumors. Since 98% of retinoblastomas have RB1 mutations and a characteristic genomic copy number "signature", genetic analysis is an appealing adjunct to histopathology to distinguish retinoblastoma metastasis from second primary cancer in retinoblastoma patients. Here, we describe such an approach in two retinoblastoma cases. In patient one, allele-specific (AS)-PCR for a somatic nonsense mutation confirmed that a temple mass was metastatic retinoblastoma. In a second patient, a rib mass shared somatic copy number gains and losses with the primary tumor. For definitive diagnosis, however, an RB1 mutation was needed, but heterozygous promoter→exon 11 deletion was the only RB1 mutation detected in the primary tumor. We used a novel application of inverse PCR to identify the deletion breakpoint. Subsequently, AS-PCR designed for the breakpoint confirmed that the rib mass was metastatic retinoblastoma. These cases demonstrate that personalized molecular testing can confirm retinoblastoma metastases and rule out a second primary cancer, thereby helping to direct the clinical management.

Wong JR, Morton LM, Tucker MA, et al.
Risk of subsequent malignant neoplasms in long-term hereditary retinoblastoma survivors after chemotherapy and radiotherapy.
J Clin Oncol. 2014; 32(29):3284-90 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Hereditary retinoblastoma (Rb) survivors have increased risk of subsequent malignant neoplasms (SMNs). Previous studies reported elevated radiotherapy (RT) -related SMN risks, but less is known about chemotherapy-related risks.
PATIENTS AND METHODS: In a long-term follow-up study of 906 5-year hereditary Rb survivors diagnosed from 1914 to 1996 and observed through 2009, treatment-related SMN risks were quantified using cumulative incidence analyses and multivariable Cox proportional hazards regression models with age as the underlying time scale.
RESULTS: Nearly 90% of Rb survivors were treated with RT, and almost 40% received alkylating agent (AA) -containing chemotherapy (predominantly triethylenemelamine). Median follow-up time to first SMN diagnosis was 26.3 years. Overall SMN risk was not significantly elevated among survivors receiving AA plus RT versus RT without chemotherapy (hazard ratio [HR], 1.27; 95% CI, 0.99 to 1.63). AA-related risks were significantly increased for subsequent bone tumors (HR, 1.60; 95% CI, 1.03 to 2.49) and leiomyosarcoma (HR, 2.67; 95% CI, 1.22 to 5.85) but not for melanoma (HR, 0.74; 95% CI, 0.36 to 1.55) or epithelial tumors (HR, 0.89; 95% CI, 0.48 to 1.64). Leiomyosarcoma risk was significantly increased for survivors who received AAs at age < 1 (HR, 5.17; 95% CI, 1.76 to 15.17) but not for those receiving AAs at age ≥ 1 year (HR, 1.75; 95% CI, 0.68 to 4.51). Development of leiomyosarcoma was significantly more common after AA plus RT versus RT (5.8% v 1.6% at age 40 years; P = .01).
CONCLUSION: This comprehensive quantification of SMN risk after chemotherapy and RT among hereditary Rb survivors also demonstrates an AA-related contribution to risk. Although triethylenemelamine is no longer prescribed, our findings warrant further follow-up to investigate potential SMN risks associated with current chemotherapies used for Rb.

MacCarthy A, Bayne AM, Brownbill PA, et al.
Second and subsequent tumours among 1927 retinoblastoma patients diagnosed in Britain 1951-2004.
Br J Cancer. 2013; 108(12):2455-63 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Retinoblastoma is an eye tumour of childhood that occurs in heritable and non-heritable forms. In the heritable form, there is a predisposition to the development of non-ocular subsequent primary tumours (SPTs).
METHODS: This study included 1927 retinoblastoma patients diagnosed in Britain from 1951 to 2004. Ascertainment was through the (UK) National Registry of Childhood Tumours; cases were followed-up for the occurrence of SPTs. Standardised incidence ratios (SIRs) were calculated.
RESULTS: We identified 169 SPTs in 152 patients. The SIR analysis included 145 SPTs with cancer registrations from the years 1971 to 2009. These tumours occurred in 132 patients: 112 of the 781 heritable and 20 of the 1075 (presumed) non-heritable cases under surveillance at the start of this period developed at least one registered SPT. The SIRs for all tumours combined were 13.7 (95% confidence interval 11.3-16.5) in heritable cases and 1.5 (0.9-2.3) in non-heritable cases. The main types of SPT in the heritable cases were leiomyosarcoma, (31 cases; SIR 1018.7 (692.2-1446.0)), osteosarcoma (26 cases; SIR 444.6 (290.4-651.4)), and skin melanoma (12 cases; SIR 18.6 (9.6-32.4)).
CONCLUSION: The risk of SPTs in heritable retinoblastoma is extremely high. This has important implications for the clinical follow-up and counselling of survivors and their families.

Temming P, Viehmann A, Biewald E, Lohmann DR
Sporadic unilateral retinoblastoma or first sign of bilateral disease?
Br J Ophthalmol. 2013; 97(4):475-80 [PubMed] Related Publications
BACKGROUND: A small number of children with unilateral retinoblastoma later develop retinoblastoma in the contralateral eye (metachronous bilateral retinoblastoma).
METHODS: We analysed the clinical and genetic characteristics of children with sporadic unilateral retinoblastoma to identify risk factors for the development of metachronous bilateral disease.
RESULTS: Fifteen (3.1%) of 480 children with unilateral retinoblastoma later developed metachronous bilateral retinoblastoma (latency period  >30 days). The maximum latency period was 2.3 years after initial diagnosis. Nine (22.5%) of 40 children with a RB1 mutation detectable in blood developed metachronous bilateral disease while all 155 children proved to be without a germline RB1 mutation remained unilaterally affected. Clinically, the risk of developing metachronous bilateral retinoblastoma was higher for age at diagnosis ≤0.5 years compared with >0.5 years (19.6% vs 1.2%), and for multifocal compared with unifocal unilateral retinoblastoma (17.1% vs 2.2%).
CONCLUSIONS: This study shows that an oncogenic RB1 mutation in the blood is a risk factor for metachronous bilateral retinoblastoma. Additional clinical risk factors for metachronous bilateral disease are diagnosis at young age (≤0.5 years) and multifocal unilateral retinoblastoma. Early genetic analysis may identify children at high risk of developing metachronous bilateral disease and may help to preserve vision using risk-adapted follow-up and early treatment.

de Raphélis Soissan A, Berlier P, Claude L, et al.
[Papillar thyroid cancer: a rare case of a second primary tumor in retinoblastoma].
Arch Pediatr. 2012; 19(10):1086-8 [PubMed] Related Publications
Retinoblastoma is the most common primary cancer of the eye in children. The prognosis for survival is excellent. The current therapy includes an improved survival rate and decreased iatrogenic sequelae. The relative risk of a second tumor in survivors of retinoblastoma is documented, especially in those who carry a germline RB mutation. It is strongly increased in case of radiation therapy. The most common types of second primary tumor are sarcoma of soft tissues and osteosarcoma. We present here a rare case of a retinoblastoma patient who received radiation therapy as a part of his treatment and developed a papillar thyroid cancer as a second malignancy. Papillar thyroid cancer has a good prognosis. Systematic screening for thyroid carcinoma should be undertaken in patients irradiated for congenital retinoblastoma.

Kleinerman RA, Yu CL, Little MP, et al.
Variation of second cancer risk by family history of retinoblastoma among long-term survivors.
J Clin Oncol. 2012; 30(9):950-7 [PubMed] Free Access to Full Article Related Publications
PURPOSE: To evaluate the risk of second cancer (SC) in long-term survivors of retinoblastoma (Rb) according to classification of germline mutation, based on family history of Rb and laterality.
PATIENTS AND METHODS: We assembled a cohort of 1,852 1-year survivors of Rb (bilateral, n = 1,036; unilateral, n = 816). SCs were ascertained by medical records and self-reports and confirmed by pathology reports. Classification of RB1 germline mutation, inherited or de novo, was inferred by laterality of Rb and positive family history of Rb. Standardized incidence ratios and cumulative incidence for all SCs combined and for soft tissue sarcomas, bone cancers, and melanoma were calculated. The influence of host- and therapy-related risk factors for SC was assessed by Poisson regression for bilateral survivors.
RESULTS: We observed a relative risk (RR) of 1.37 (95% CI, 1.00 to 1.86) for SCs in bilateral survivors associated with a family history of Rb, adjusted for treatment, age, and length of follow-up. The risk for melanoma was significantly elevated for survivors with a family history of Rb (RR, 3.08; 95% CI, 1.23 to 7.16), but risks for bone or soft tissue sarcomas were not elevated. The cumulative incidence of SCs 50 years after diagnosis of bilateral Rb, with adjustment for competing risk of death, was significantly higher for survivors with a family history (47%; 95% CI, 35% to 59%) than survivors without a family history (38%; 95% CI, 32% to 44%; P = .004).
CONCLUSION: Rb survivors with bilateral disease and an inherited germline mutation are at slightly higher risk of an SC compared with those with a de novo germline mutation, in particular melanoma, perhaps because of shared genetic alterations.

Dommering CJ, Marees T, van der Hout AH, et al.
RB1 mutations and second primary malignancies after hereditary retinoblastoma.
Fam Cancer. 2012; 11(2):225-33 [PubMed] Free Access to Full Article Related Publications
Survivors of hereditary retinoblastoma have a high risk of second primary malignancies, but it has not been investigated whether specific RB1 germline mutations are associated with greater risk of second primary malignancies in a large cohort. We conducted a retrospective cohort study of 199 survivors of hereditary retinoblastoma with a documented RB1 germline mutation diagnosed between 1905 and 2005. In total, 44 hereditary retinoblastoma survivors developed a second primary malignancy after a median follow-up of 30.2 years (range 1.33-76.0). A significantly increased risk of second primary malignancy was observed among carriers of one of the 11 recurrent CGA>TGA nonsense RB1 mutations (hazard ratio (HR) = 3.53; [95% confidence interval (CI) = 1.82-6.84]; P = .000), and there was a significantly lower risk for subjects with a low penetrance mutation (HR = .19; [95% CI = .05-.81]; P = .025). Our findings suggest a genotype-phenotype correlation for second primary cancers of retinoblastoma survivors and may impact on long-term surveillance protocols of patients with hereditary retinoblastoma, if confirmed by future studies.

Lohmann D
Retinoblastoma.
Adv Exp Med Biol. 2010; 685:220-7 [PubMed] Related Publications
Retinoblastoma (Rb) is a malignant tumor that originates from developing retina. Diagnosis based on clinical signs and symptoms and is usually made in children under the age of five years. Mutations in both alleles of the RB1 gene are a prerequisite for this tumor to develop. In most patients with sporadic unilateral Rb, both RB1 gene mutations occur in somatic cells and are not passed over to offspring (nonhereditary Rb). Almost all patients with sporadic bilateral and virtually all patients with familial Rb are heterozygous for RB1 gene mutations that cause predisposition to Rb (hereditary Rb). In families, Rb predisposition is transmitted as an autosomal dominant trait (familial Rb). In addition to Rb, patients with hereditary disease also have an increased risk of tumors outside the eye (second cancer). This risk is enhanced in patients who have received external beam radiotherapy. Analysis of genotype-phenotype associations has shown that the mean number of tumor foci that develop in carriers of mutant RB1 alleles is variable depending on which functions of the normal allele are retained and to what extent. Moreover, phenotypic expression of hereditary retinoblastoma is subject to genetic modification. Identification of the genetic factors that underlie these effects will not only help to arrive at a more precise prognosis but may also point to mechanisms that can be used to reduce the risk of tumor development.

Marees T, van Leeuwen FE, de Boer MR, et al.
Cancer mortality in long-term survivors of retinoblastoma.
Eur J Cancer. 2009; 45(18):3245-53 [PubMed] Related Publications
This study examined long-term cause-specific mortality among 998 Dutch retinoblastoma survivors, diagnosed from 1862 to 2005, according to follow-up time, treatment and heredity. After a median follow-up of 30.8 years, only cause-specific mortality for second malignancies among hereditary retinoblastoma survivors was statistically significantly increased with 12.8-fold. Risk of death from second malignancies among non-hereditary survivors was not increased. Mortality rates of second malignancy among hereditary patients were non-significantly elevated with 1.6-fold for treated with radiotherapy, compared to those treated otherwise. Standardised mortality ratios (SMRs) for second malignancy among hereditary patients increased during the first three decades after retinoblastoma diagnosis. Whereas these risks decreased after three decades, the absolute excess risk (AER) increased significantly, up to 23.2 excess cases per 1000 patients/year after five decades of follow-up. Fifty years after retinoblastoma diagnosis the cumulative mortality from any second malignancy was 17.3% for hereditary patients. Very long-term follow-up of retinoblastoma patients revealed an emerging excess risk of mortality in hereditary retinoblastoma survivors. This implies that lifelong follow-up is needed, whereas at the same time, patients and their physicians must be alerted to the increased second malignancy risks.

Kleinerman RA
Radiation-sensitive genetically susceptible pediatric sub-populations.
Pediatr Radiol. 2009; 39 Suppl 1:S27-31 [PubMed] Free Access to Full Article Related Publications
Major advances in pediatric cancer treatment have resulted in substantial improvements in survival. However, concern has emerged about the late effects of cancer therapy, especially radiation-related second cancers. Studies of childhood cancer patients with inherited cancer syndromes can provide insights into the interaction between radiation and genetic susceptibility to multiple cancers. Children with retinoblastoma (Rb), neurofibromatosis type 1 (NF1), Li-Fraumeni syndrome (LFS), and nevoid basal cell carcinoma syndrome (NBCCS) are at substantial risk of developing radiation-related second and third cancers. A radiation dose-response for bone and soft-tissue sarcomas has been observed in hereditary Rb patients, with many of these cancers occurring in the radiation field. Studies of NF1 patients irradiated for optic pathway gliomas have reported increased risks of developing another cancer associated with radiotherapy. High relative risks for second and third cancers were observed for a cohort of 200 LFS family members, especially children, possibly related to radiotherapy. Children with NBCCS are very sensitive to radiation and develop multiple basal cell cancers in irradiated areas. Clinicians following these patients should be aware of their increased genetic susceptibility to multiple primary malignancies enhanced by sensitivity to ionizing radiation.

Marees T, Moll AC, Imhof SM, et al.
Risk of second malignancies in survivors of retinoblastoma: more than 40 years of follow-up.
J Natl Cancer Inst. 2008; 100(24):1771-9 [PubMed] Related Publications
BACKGROUND: Survivors of hereditary retinoblastoma have an elevated risk of developing second malignancies, but data on the risk in middle-aged retinoblastoma survivors (ie, those with more than 40 years of follow-up) are scarce.
METHODS: Data from the Dutch retinoblastoma registry were used to analyze risks of second malignancies in 668 retinoblastoma survivors, diagnosed from 1945 to 2005 (median age = 24.9 years) and classified as having had hereditary or nonhereditary disease based on the presence of family history, bilateral disease, or a germline RB1 mutation. Standardized incidence ratios (SIRs) and absolute excess risks (AERs) of subsequent cancers in patients with hereditary and nonhereditary disease were estimated by comparison with Dutch sex-, age-, and calendar year-specific rates. Multivariable Cox regression and competing risk analyses were used to determine associations of treatment with risks of second malignancies. All statistical tests were two-sided.
RESULTS: After a median follow-up of 21.9 years, the risk of second malignancies in survivors of hereditary retinoblastoma (SIR = 20.4, 95% confidence interval [CI] = 15.6 to 26.1) far exceeded the risk of survivors of nonhereditary retinoblastoma (SIR = 1.86, 95% CI = 0.96 to 3.24). Among patients with hereditary disease, treatment with radiotherapy was associated with a further increase in the risk of a subsequent cancer (hazard ratio = 2.81, 95% CI = 1.28 to 6.19). After 30 years of follow-up, elevated risks of epithelial cancers (lung, bladder, and breast) were observed among survivors of hereditary retinoblastoma. After 40 years of follow-up, the AER of a second malignancy among survivors of hereditary retinoblastoma had increased to 26.1 excess cases per 1000 person-years. The cumulative incidence of any second malignancy 40 years after retinoblastoma diagnosis was 28.0% (95% CI = 21.0% to 35.0%) for patients with hereditary disease.
CONCLUSION: Our analysis of middle-aged hereditary retinoblastoma survivors suggests that these individuals have an excess risk of epithelial cancer. Lifelong follow-up studies are needed to evaluate the full spectrum of subsequent cancer risk in hereditary retinoblastoma survivors.

de Bree R, Moll AC, Imhof SM, et al.
Subsequent tumors in retinoblastoma survivors: the role of the head and neck surgeon.
Oral Oncol. 2008; 44(10):982-5 [PubMed] Related Publications
Hereditary retinoblastoma patients are at an increased risk for subsequent primary tumors after successful treatment for their initial cancer. Two mechanisms may be responsible for this increased incidence of second malignancies: genetic susceptibility (RB1 gene alterations) and induction by radiation that is frequently used as treatment for retinoblastoma. Because of the high cure rates obtained in the treatment of retinoblastoma, the risk of subsequent primary tumors is substantial, especially in the radiation field. We present four retinoblastoma survivors who developed multiple subsequent primary tumors. Two retinoblastoma survivors developed one and the other two patients two subsequent primary tumors. Despite extensive treatments two patients died of their second primary tumor in the head and neck region. The head and neck surgeon has an increasingly important role in the diagnosis and management of subsequent primary tumors in retinoblastoma survivors.

Wilson MW, Haik BG, Billups CA, Rodriguez-Galindo C
Incidence of new tumor formation in patients with hereditary retinoblastoma treated with primary systemic chemotherapy: is there a preventive effect?
Ophthalmology. 2007; 114(11):2077-82 [PubMed] Related Publications
PURPOSE: To report the incidence of new tumor formation in hereditary retinoblastoma patients treated with primary systemic chemotherapy.
DESIGN: Noncomparative retrospective case series.
PARTICIPANTS: Fifty-eight consecutive patients with hereditary retinoblastoma treated with primary systemic chemotherapy.
METHODS: The charts of 58 consecutive patients with hereditary retinoblastoma treated between January 1996 and August 2005 were reviewed. Data extracted included gender, age at diagnosis, family history of retinoblastoma, laterality of disease, tumors per eye, Reese-Ellsworth grouping of affected eyes, starting and ending dates for chemotherapy, number of cycles of chemotherapy, chemotherapy regimen, need for external beam radiotherapy and/or enucleation, and development and location (macula, midzone, and periphery) of new tumors after the start of systemic chemotherapy.
MAIN OUTCOME MEASURE: New tumor formation after treatment with primary systemic chemotherapy.
RESULTS: Of the 58 patients, 48 had bilateral involvement at diagnosis. Median age at diagnosis was 6.6 months. Thirteen patients had a positive family history. Of the eyes with tumor (n = 106) at diagnosis, 52 (49%) were in Reese-Ellsworth groups I to III, whereas 54 (51%) were in group IV or V. Seven patients (12%) with a median age of 1.6 months at diagnosis formed 36 new tumors in 11 eyes after the start of chemotherapy. Median time from initiation of chemotherapy to detection of the first new tumor was 3 months (range, 1-15). Cumulative incidence of new tumor formation at 2 years was 10+/-3%. An age of <6 months at diagnosis, family history of retinoblastoma, and Reese-Ellsworth grouping of I to III were found to correlate significantly with an increased incidence of new tumor formation (P<0.001, P<0.001, and P = 0.021, respectively). Median follow-up for all patients was 5 years (range, 1-10.1).
CONCLUSION: New tumors continue to form in patients with hereditary retinoblastoma despite treatment with primary systemic chemotherapy. Younger patients and those with a positive family history are more likely to have new tumors formed. However, chemotherapy may impact small previously undetected lesions by slowing their growth and facilitating later focal consolidation.

Kleinerman RA, Tucker MA, Abramson DH, et al.
Risk of soft tissue sarcomas by individual subtype in survivors of hereditary retinoblastoma.
J Natl Cancer Inst. 2007; 99(1):24-31 [PubMed] Related Publications
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.

Acquaviva A, Ciccolallo L, Rondelli R, et al.
Mortality from second tumour among long-term survivors of retinoblastoma: a retrospective analysis of the Italian retinoblastoma registry.
Oncogene. 2006; 25(38):5350-7 [PubMed] Related Publications
Survivors of retinoblastoma (Rb) are at high risk of dying from second malignant tumour. The occurrence of second malignant neoplasm (SMN) and related mortality in a cohort of 1111 cases from the Italian Retinoblastoma Registry was analysed, considering the possible role of both genetic and iatrogenic causes. Rb patients had a greater than 10-fold excess in overall mortality compared with the general population (standardized mortality ratio (SMR) 10.73, 95% CI 9.00-12.80). Their excess risk attributable to cancers other than Rb was 14.93 95% CI 10.38-21.49). Survivors of hereditary Rb had an SMR for all causes of 16.25 (95% CI 13.20-20.00), whereas their SMR for all cancers was 25.72 (95% CI 17.38-38.07). Survivors of unilateral sporadic Rb had an SMR of 4.12 from all cancers (95% CI 1.55-10.98) and a much higher excess for overall mortality (SMR 13.34, 95% CI 10.74-16.56). As expected, survivors of hereditary Rb had higher mortality from cancers of the bone (SMR 391.90, 95% CI 203.90-753.20) and soft tissue (SMR 453.00, 95% CI 203.50-1008.40), small intestine (SMR 1375.50, 95% CI 344.00-5499.70), nasal cavity (SMR 13.71, 95% CI 1.93-97.35) and cancers of the brain and central nervous system (SMR 41.14, 95% CI 13.2-127.55).

Antoneli CB, Ribeiro Kde C, Sakamoto LH, et al.
Trilateral retinoblastoma.
Pediatr Blood Cancer. 2007; 48(3):306-10 [PubMed] Related Publications
BACKGROUND: Trilateral retinoblastoma (TRB) is a syndrome consisting of unilateral or bilateral hereditary retinoblastoma (Rb) associated with an intracranial neuroblastic tumor. Although its incidence is low, the prognosis is very poor. This article reports four cases of TRB and discusses the role of neuroimaging screening for early detection.
PROCEDURE: From January 1986 to December 2003, 470 children with Rb were admitted to the Pediatrics and Ophthalmology Departments, A C Camargo Hospital, São Paulo, Brazil.
RESULTS: There were four patients with pineoblastoma, two of whom had a positive familial history. The age at diagnosis of Rb was 4, 6, 10, and 24 months while the age of diagnosis of TRB was 10, 25, 57, and 72 months. One patient presented TRB at initial diagnosis of Rb. Three patients had bilateral disease and all of them had one eye enucleated, followed by chemotherapy and/or external beam radiation therapy (EBRT). One child with unilateral disease was only submitted to enucleation. In spite of intensive treatment, all patients died with progressive disease within 7, 8, 12, and 12 months after diagnosis of TRB.
CONCLUSIONS: Early diagnosis as well as new therapeutic approaches are needed to achieve better results.

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(7):811-4 [PubMed] Related Publications
This case describes a twin with bilateral retinoblastoma who developed leiomyosarcoma of the bladder at age 17 and again at 39. At 17-years of age she was diagnosed with a leiomyosarcoma of the bladder after presenting with recurrent urinary tract infections, hematuria, and dysuria. She was treated with partial cystectomy. After a 12-year disease-free interval, she was diagnosed with a second leiomyosarcoma of the bladder. This case supports the relationship between the genetic form of retinoblastoma and leiomyosarcoma and illustrates the necessity for extensive follow-up and well-defined treatment of secondary neoplasms.

Chantrain CF, Jijon P, De Raedt T, et al.
Therapy-related acute myeloid leukemia in a child with Noonan syndrome and clonal duplication of the germline PTPN11 mutation.
Pediatr Blood Cancer. 2007; 48(1):101-4 [PubMed] Related Publications
A 4-year-old girl with Noonan syndrome (NS) and constitutive PTPN11 mutation presented with stage 4 neuroblastoma and was treated by intensive chemotherapy. During the treatment, cytogenetic analysis revealed the development of a hyperdiploid clone with duplication of the germline PTPN11 mutation in a morphologically normal bone marrow. A few months later, the patient developed acute myelomonoblastic leukemia with an additional clonal deletion of 7q. Although, we cannot conclude whether there is an association between NS and neuroblastoma, this case suggests that duplication of germline PTPN11 mutations, potentially induced by chemotherapy, contributes to leukemogenesis in patients with NS.

Hongeng S, Parapakpenjun S, Pakakasama S, et al.
Secondary Burkitt lymphoma in a retinoblastoma patient with 13q deletion syndrome.
Pediatr Blood Cancer. 2006; 46(4):524-6 [PubMed] Related Publications
We report a boy with constitutional deletion 13q chromosome associated with dysmorphic features and bilateral retinoblastoma. The patient developed secondary Burkitt lymphoma 5 years after the diagnosis of retinoblastoma at the age of 8 months. He has completed treatment for both malignancies. At present, he is 7 years old and still in remission.

Sedghizadeh PP, Angiero F, Allen CM, et al.
Post-irradiation leiomyosarcoma of the maxilla: report of a case in a patient with prior radiation treatment for retinoblastoma.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2004; 97(6):726-31 [PubMed] Related Publications
Post-irradiation sarcoma is a well-defined complication of radiation therapy, yet few reports document such lesions in the head and neck. A 30-year-old man presented for evaluation of an expansile lesion of the left posterior maxilla. His medical history was significant for a childhood ocular malignancy - unilateral retinoblastoma - which was treated with a combination of surgical enucleation of the eye and external beam radiation therapy. Biopsy of his maxillary lesion revealed a spindle cell malignancy that was morphologically and immunohistochemically consistent with a diagnosis of leiomyosarcoma. Further investigation into the case revealed that the patient had three children, every one of whom developed unilateral retinoblastoma in infancy. Compared to the more frequent presentation of bilateral tumors in hereditary cases of retinoblastoma, such cases of heritable unilateral retinoblastoma are exceptional. Importantly, heritable forms of retinoblastoma confer a significant risk for development of second primary cancers, necessitating long-term clinical follow-up in these patients.

Hon C, Chan GC, Ha SY, et al.
Bone marrow transplantation for therapy-related acute myeloid leukemia in congenital retinoblastoma associated with 13q deletion syndrome.
Ann Hematol. 2004; 83(7):481-3 [PubMed] Related Publications
Children with constitutional deletion of the long arm of chromosome 13 are at risk for retinoblastoma (RB) due to loss of the RB tumor suppressor gene. The prognosis is poor since the tumors are often bilateral, aggressive, and recurrent and the patients often harbor other congenital abnormalities. One further complication is that of therapy-related malignancies later in life. We report a case of allogeneic stem cell transplantation for therapy-related acute myeloid leukemia in an 8-year-old girl after multimodality treatment for refractory bilateral relapsing RB, with excellent outcome in both the ophthalmic and marrow disease.

Fletcher O, Easton D, Anderson K, et al.
Lifetime risks of common cancers among retinoblastoma survivors.
J Natl Cancer Inst. 2004; 96(5):357-63 [PubMed] Related Publications
BACKGROUND: Compared with the general population, carriers of germline mutations in RB1 who survive retinoblastoma (i.e., hereditary retinoblastoma survivors) are at increased risk of early-onset second cancers, particularly sarcomas, brain tumors, and melanoma. However, their risks for the epithelial cancers that commonly occur after age 50 years are not known.
METHODS: We used hospital records to identify British retinoblastoma survivors born between 1873 and 1950, a period when few British retinoblastoma patients received high-dose radiotherapy. Cancers and deaths were identified by linkage with national registration records. All statistical tests were two-sided.
RESULTS: We could trace the cancer histories of 144 survivors of hereditary retinoblastoma. From age 25 to age 84, there were 58 subsequent cancers, for a cumulative cancer incidence of 68.8% (95% confidence interval [CI] = 48.0% to 87.4%) and a cumulative cancer mortality of 56.3% (95% CI = 40.5% to 73.3%). Only eight of the 58 cancers were of bone or soft tissue, in marked contrast to findings from contemporary studies of American patients treated with external beam radiotherapy, among whom most second tumors are sarcomas. Compared with the general population, hereditary retinoblastoma survivors had higher mortality from lung cancer (standardized mortality ratio [SMR] = 7.01, 95% CI = 3.83 to 11.76), bladder cancer (SMR = 26.31, 95% CI = 8.54 to 61.41), and all other epithelial cancers combined (SMR = 3.29, 95% CI = 1.64 to 5.89). The overall standardized mortality ratio for epithelial cancer was inversely proportional to the approximate square of age (exponent of age = -2.1, 95% CI = -3.6 to -0.7), declining from 11.32 (95% CI = 4.15 to 24.64) at age 25-44 to 2.83 (95% CI = 1.04 to 6.16) at age 65-84.
CONCLUSIONS: Survivors of hereditary retinoblastoma who are not exposed to high-dose radiotherapy have a high lifetime risk of developing a late-onset epithelial cancer. Most of the excess cancer risks in hereditary retinoblastoma survivors might be preventable by limiting exposures to DNA damaging agents (radiotherapy, tobacco, and UV light).

Venkatraman L, Goepel JR, Steele K, et al.
Soft tissue, pelvic, and urinary bladder leiomyosarcoma as second neoplasm following hereditary retinoblastoma.
J Clin Pathol. 2003; 56(3):233-6 [PubMed] Free Access to Full Article Related Publications
This report describes two patients who developed leiomyosarcomas, one involving the subcutaneous tissue of the thigh and the pelvic soft tissues and the other the urinary bladder, following hereditary retinoblastoma 36 and 38 years earlier, respectively. There is an increased risk of the development of sarcoma, most commonly osteosarcoma, as a second malignancy following hereditary retinoblastoma. Leiomyosarcoma developing as a second malignancy has rarely been reported and most have occurred in the field of previous radiotherapy. The literature on leiomyosarcoma occurring as a second neoplasm following retinoblastoma is reviewed.

Liang SX, Lakshmanan Y, Woda BA, Jiang Z
A high-grade primary leiomyosarcoma of the bladder in a survivor of retinoblastoma.
Arch Pathol Lab Med. 2001; 125(9):1231-4 [PubMed] Related Publications
Second nonocular malignancies develop with increased incidence in patients with hereditary retinoblastoma. Osteosarcoma is by far the most common type with an incidence of up to 50%, followed by soft tissue sarcomas. Visceral leiomyosarcoma is extremely rare and only 2 cases have been reported in the past 2 decades, one in the liver and another one in the urinary bladder, both of which developed after cyclophosphamide therapy. Here we report a case of vesical leiomyosarcoma that was diagnosed in a 49-year-old woman 47 years after the diagnosis of a hereditary retinoblastoma. The patient's retinoblastoma was treated with unilateral enucleation without adjuvant radiation or chemotherapy. We believe that this is the first report of vesical leiomyosarcoma occurring in a patient with retinoblastoma without a prior history of radiation or chemotherapy. This report is significant not only because of the rarity of vesical leiomyosarcoma as a second nonocular tumor in retinoblastoma patients, but also because of the infrequency of vesical leiomyosarcoma in general. We also investigated the potential molecular pathogenesis of the leiomyosarcoma.

Moppett J, Oakhill A, Duncan AW
Second malignancies in children: the usual suspects?
Eur J Radiol. 2001; 38(3):235-48 [PubMed] Related Publications
The aim of this article is to provide an up to date review of second malignant neoplasms (SMN's) following treatment for childhood cancer, referring to their incidence, the role of genetic factors, and how the primary malignancy and treatment received influence the type, site and prognosis of SMN's. The role of genetic factors will be discussed as far as they impact upon a predisposition to later development of SMN's. The primary malignancies that have important associations with SMN's will then be discussed, in particular Hodgkin's disease, retinoblastoma and acute lymphoblastic leukaemia. The important second malignancies will be highlighted, including tumours of the CNS and thyroid, osteosarcoma, secondary acute myeloid leukaemia and melanoma. Emphasis will be put upon identifying which patients are most likely to suffer from these tumours. An important part of the article are case histories. These are provided in combination with illustrations as a useful adjunct to the text, with a particular emphasis on radiological features, diagnosis and screening. Finally, the important but different roles of causal agents, in particular chemotherapy and radiotherapy are highlighted.

Moll AC, Imhof SM, Schouten-Van Meeteren AY, et al.
Second primary tumors in hereditary retinoblastoma: a register-based study, 1945-1997: is there an age effect on radiation-related risk?
Ophthalmology. 2001; 108(6):1109-14 [PubMed] Related Publications
OBJECTIVE: The aim of this study is to evaluate the influence of age at external beam irradiation (EBRT) on the occurrence of second primary tumors (SPTs) inside and outside the irradiation field in hereditary retinoblastoma patients.
DESIGN: Cross-sectional study.
PARTICIPANTS: The study included 263 hereditary retinoblastoma patients born in The Netherlands between 1945 and 1997.
METHODS: A national register-based follow-up cohort study was performed on hereditary retinoblastoma patients. Information on therapy, age at irradiation, and location of SPT was obtained from the register. The Kaplan-Meier method calculated cumulative incidences of SPT in three subgroups: irradiation before (early EBRT) and after 12 months of age (late EBRT), and no irradiation. The Mantel-Cox method determined the statistical significance of differences between the cumulative incidence curves.
MAIN OUTCOME MEASURES: Development of SPT inside and outside a precisely defined irradiation field in relation to age at irradiation. Our definition excluded pineoblastoma as SPT, because they constitute part of a trilateral retinoblastoma; in addition, they lie outside the field of irradiation.
RESULTS: The cumulative incidence of SPT at the age of 25 years was 22% (95% confidence intervals 13%-34%) in the early EBRT group, 3% (0%-14%) in the late EBRT group, and 5% (1%-16%) in the nonirradiated group (Mantel-Cox overall: P = 0.001; between early and late EBRT, P = 0.04). However, in early irradiated patients, the incidence of SPTs inside and outside the irradiation field was similar (11%), and the difference between early and late EBRT in incidence of SPT inside the field of irradiation was less prominent than overall (11% vs. 3%: P = 0.37). Sensitivity analysis showed the results depended on the way SPT, irradiation field, and, especially, pineoblastomas are defined.
CONCLUSIONS: Hereditary retinoblastoma confers an increased risk for the development of SPT, especially in patients treated with EBRT before the age of 12 months. However, the presence of similar numbers of SPTs inside and outside the irradiation field suggests that irradiation is not the cause. In other words, this study does not show an age effect on radiation-related risk. Rather, early EBRT is probably a marker for other risk factors of SPT.

Mohney BG, Robertson DM, Schomberg PJ, Hodge DO
Second nonocular tumors in survivors of heritable retinoblastoma and prior radiation therapy.
Am J Ophthalmol. 1998; 126(2):269-77 [PubMed] Related Publications
PURPOSE: The principal objectives of this study were to estimate the incidence of second tumors among children treated for heritable retinoblastoma during a 50-year period and to investigate the relationship between these tumors and previous radiation therapy.
METHODS: The records of all retinoblastoma patients examined at the Mayo Clinic from 1941 through 1990 were retrospectively reviewed. The therapeutic modality used to manage the tumor, the occurrence of any second malignancy, and current follow-up on all patients were evaluated.
RESULTS: Eighty-two (46%) of 180 children with retinoblastoma had bilateral tumors (76 patients) or unilateral disease and a positive family history (six patients) and were followed for an average of 21.8 years (range, 1 month to 53 years). The Kaplan-Meier estimates of second nonocular tumors among the 82 patients with heritable retinoblastoma were 12% at 10 years, 16% at 25 years, and 30% at 40 years. Although 14 of the 15 patients who developed second malignancies had received radiation therapy, only four of the malignancies occurred within the field of irradiation.
CONCLUSIONS: The relatively low incidence of second tumors among long-term survivors of heritable retinoblastoma in this series of patients occurred predominantly outside the field of irradiation. The variable incidence of second nonocular malignancies in previous reports may reflect variations in radiation technique and dosage.

Bayar E, Robinson MG, Kurczynski TW
Unilateral retinoblastoma with acquired monosomy 7 and secondary acute myelomonocytic leukemia.
Cancer Genet Cytogenet. 1998; 105(1):79-82 [PubMed] Related Publications
Patients with a nongenetic form of retinoblastoma are not particularly at high risk of developing second malignant neoplasms. We report here a case of treatment-related leukemia (secondary leukemia) with acquired monosomy 7, in a child with unilateral retinoblastoma.

Wong FL, Boice JD, Abramson DH, et al.
Cancer incidence after retinoblastoma. Radiation dose and sarcoma risk.
JAMA. 1997; 278(15):1262-7 [PubMed] Related Publications
CONTEXT: There is a substantial risk of a second cancer for persons with hereditary retinoblastoma, which is enhanced by radiotherapy.
OBJECTIVE: To examine long-term risk of new primary cancers in survivors of childhood retinoblastoma and quantify the role of radiotherapy in sarcoma development.
DESIGN: Cohort incidence study of patients with retinoblastoma followed for a median of 20 years, and nested case-control study of a radiation dose-response relationship for bone and soft tissue sarcomas.
SETTING/PARTICIPANTS: A total of 1604 patients with retinoblastoma who survived at least 1 year after diagnosis, identified from hospital records in Massachusetts and New York during 1914 to 1984.
RESULTS: Incidence of subsequent cancers was statistically significantly elevated only in the 961 patients with hereditary retinoblastoma, in whom 190 cancers were diagnosed, vs 6.3 expected in the general population (relative risk [RR], 30 [95% confidence interval, 26-47]). Cumulative incidence (+/-SE) of a second cancer at 50 years after diagnosis was 51.0% (+/-6.2%) for hereditary retinoblastoma, and 5.0% (+/-3.0%) for nonhereditary retinoblastoma. All 114 sarcomas of diverse histologic types occurred in patients with hereditary retinoblastoma. For soft tissue sarcomas, the RRs showed a stepwise increase at all dose categories, and were statistically significant at 10 to 29.9 Gy and 30 to 59.9 Gy. A radiation risk for all sarcomas combined was evident at doses above 5 Gy, rising to 10.7-fold at doses of 60 Gy or greater (P<.05).
CONCLUSIONS: Genetic predisposition has a substantial impact on risk of subsequent cancers in retinoblastoma patients, which is further increased by radiation treatment. A radiation dose-response relationship is demonstrated for all sarcomas and, for the first time in humans, for soft tissue sarcomas. Retinoblastoma patients should be examined for new cancers and followed into later life to determine whether their extraordinary cancer risk extends to common cancers of adulthood.

Draper GJ, Sanders BM, Kingston JE
Second primary neoplasms in patients with retinoblastoma.
Br J Cancer. 1986; 53(5):661-71 [PubMed] Free Access to Full Article Related Publications
In a series of 882 retinoblastoma patients, 384 known to have the genetic form of the disease and 498 others, 30 patients developed second primary neoplasms. The spectrum of these second neoplasms is discussed in relation to the forms of treatment used for the retinoblastoma. Cumulative incidence rates of second tumours in the whole series are 2.0% at 12 years after diagnosis and 4.2% after 18 years. For patients with the genetic form of retinoblastoma the cumulative incidence rate after 18 years is 8.4% for all second neoplasms and 6.0% for osteosarcomas alone. The inherent risk among survivors from genetic retinoblastoma of developing an osteosarcoma, excluding all possible effects of treatment, is estimated to be 2.2% after 18 years. Within the field of radiation treatment the cumulative incidence rate for all second neoplasms after 18 years is 6.6% and for osteosarcomas alone 3.7%. There is some evidence that patients with genetic retinoblastoma are particularly sensitive to the carcinogenic effects of radiation. The results also suggest that the use of cyclophosphamide may increase the risk of second primary neoplasms in patients with genetic retinoblastoma. The incidence rates of second primary neoplasms in retinoblastoma survivors reported here are lower than those quoted for previously published series. Evidence from this and other papers strongly suggests an association between retinoblastoma and malignant melanoma.

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Cite this page: Cotterill SJ. Second Malignancies After Retinoblastoma, Cancer Genetics Web: http://www.cancer-genetics.org/Retinoblastoma_2nd_Cancers Accessed:

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