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Figueiredo, D.; Marques, I.A.; Pires, A.S.; Cavaleiro, C.F.; Costa, L.C.; Castela, G.; Murta, J.N.; Botelho, M.F.; Abrantes, A.M. Second Tumors in Retinoblastoma Survivors after Ionizing Radiation. Encyclopedia. Available online: https://encyclopedia.pub/entry/51740 (accessed on 19 May 2024).
Figueiredo D, Marques IA, Pires AS, Cavaleiro CF, Costa LC, Castela G, et al. Second Tumors in Retinoblastoma Survivors after Ionizing Radiation. Encyclopedia. Available at: https://encyclopedia.pub/entry/51740. Accessed May 19, 2024.
Figueiredo, Diana, Inês A. Marques, Ana Salomé Pires, Claudia F. Cavaleiro, Luís C. Costa, Guilherme Castela, Joaquim N. Murta, Maria Filomena Botelho, Ana Margarida Abrantes. "Second Tumors in Retinoblastoma Survivors after Ionizing Radiation" Encyclopedia, https://encyclopedia.pub/entry/51740 (accessed May 19, 2024).
Figueiredo, D., Marques, I.A., Pires, A.S., Cavaleiro, C.F., Costa, L.C., Castela, G., Murta, J.N., Botelho, M.F., & Abrantes, A.M. (2023, November 17). Second Tumors in Retinoblastoma Survivors after Ionizing Radiation. In Encyclopedia. https://encyclopedia.pub/entry/51740
Figueiredo, Diana, et al. "Second Tumors in Retinoblastoma Survivors after Ionizing Radiation." Encyclopedia. Web. 17 November, 2023.
Second Tumors in Retinoblastoma Survivors after Ionizing Radiation
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This entry is adapted from the peer-reviewed paper 10.3390/cancers15225336

Retinoblastoma (RB) is the most common ocular neoplasm in children, whose development depends on two mutational events that occur in both alleles of the retinoblastoma susceptibility gene (RB1). Regarding the nature of these mutational events, RB can be classified as hereditary if the first event is a germline mutation and the second one is a somatic mutation in retina cells or nonhereditary if both mutational events occur in somatic cells. Although the rate of survival of RB is significantly elevated, the incidence of second malignant neoplasms (SMNs) is a concern, since SMNs are the main cause of death in these patients. Furthermore, evidence confirms that hereditary RB survivors are at a higher risk for SMNs than nonhereditary RB survivors. This risk seems to increase with the use of ionizing radiation in some therapeutic approaches commonly used in the treatment of RB.

retinoblastoma RB1 gene ionizing radiation second malignant neoplasms hereditary cancer radiation biology

1. Introduction

Retinoblastoma (RB) is the most common primary intraocular tumor in children. Its worldwide estimated incidence ranges from 1 in 15,000 to 1 in 18,000 live births, showing no racial, ethnic, or gender predisposition [1][2]. Retinoblastoma’s survival rate can exceed 95% with early diagnosis and treatment. Thus, the survival rate in children diagnosed with RB in medically developed countries is significantly higher when compared to undeveloped countries due to the late diagnosis [3][4].
RB develops from the retinoblasts, precursors of retinal cells, and can be classified according to the disease’s laterality: unilateral, if only one of the eyes is affected, or bilateral (20–30% of cases) if both eyes are affected. Regarding its genetic classification, it is clinically classified as hereditary, representing about 45% of the diagnosed cases, or nonhereditary. Tumor development is associated with the retinoblastoma susceptibility gene (RB1), a recessive tumor suppressor gene involved in cell growth and development, and it is reported that it only occurs when both alleles of RB1 are lost or undergo deletion, inactivation, or mutation [3][4][5]. In 1971, Knudson et al. [6] proposed the “two-hit” hypothesis, stating that RB is caused by two complementary chromosomal mutations. Thus, nonhereditary RB is associated with two somatic mutations, whereas hereditary RB is related to a germline mutation that would be present in all body cells, followed by a mutation in somatic retina cells. The offspring of hereditary RB patients are predisposed to the disease with a penetrance of 80% [3][4][5]. All cases of nonhereditary RB are associated with a unilateral tumor, whereas the hereditary form is mainly bilateral; however, in some cases, it can be unilateral. About 85% of unilateral RB result from somatic mutational events, and only 15% are related to hereditary RB [3][5]. However, the two mutational events that affect the RB1 alleles seem to be insufficient for the formation of the malignancy, since a mutation in RB1 first leads to retinoma, a benign precursor of RB [3][7]. In 2007, Corson and Gallie [8] stated that additional mutational events were required for the formation of a malignancy, supporting a “three-hit” hypothesis [9].

2. Risk of Second Tumor Incidence in Survivors of Retinoblastoma Treated with Radiation Therapy

The main cause of death among hereditary RB survivors remains to be the occurrence of subsequent malignant neoplasms (SMNs). SMNs are new tumors that develop after the incidence of a primary tumor. While some authors defend that an SMN is histologically independent from the first primary tumor, others state that trilateral RB has to be reported as an SMN. As already mentioned, all cells of hereditary RB patients carry a germline mutation in one allele of RB1, a tumor suppressor gene. On the other hand, nonhereditary RB is associated with mutations that occur only in retina cells. Therefore, survivors of hereditary RB seem to present a higher risk of developing SMNs compared to the general population as well as nonhereditary RB survivors [10]. Thus, this section aims to analyze some studies (Table 1) that have been performed to compare the incidence of SMNs between hereditary and nonhereditary RB and also to evaluate the risk of developing SMNs after treatment with RT in RB patients [10].
Table 1. Studies carried out to examine the risk of SMN incidence in survivors of RB when treated with radiation therapy.
Authors Sample Size Treatment
(# Patients)		 Type of SMNs Treatment Related to SMNs
(# Patients) a		 SMNs Location (# SMNs) b
Mohney et al. (1998) [11] 180 patients:
-
82 hereditary
-
98 nonhereditary
 Hereditary:
RT (60); ChT (15); Unknown (7)
Nonhereditary:
Not disclosed		 Hereditary: 16 (6 soft tissue tumors, 4 bone tumors, 3 melanomas, 3 carcinomas—1 breast, 1 pancreas, and 1 thyroid)
Nonhereditary: 3 (1 benign soft tissue tumor and 2 carcinomas—cervical and breast)		 Hereditary: EBRT (6); EBRT + CT (4); RA (3); EBRT + BT + RA (1); ChT (1); Unknown (1)
Nonhereditary: RA (1); Unknown (2)		 Hereditary:
In-field of irradiation (4);
outside field of irradiation (10)
Nonhereditary: In-field of irradiation (1)
Kleinerman et al. (2005) [12] 1601 patients:
-
963 hereditary
-
638 nonhereditary
 Hereditary:
Surgery (94); ChT (16); RT (466); RT + ChT (383); Unknown (4)
Nonhereditary:
Surgery (480); ChT (40); RT (67); RT + ChT (47); Unknown (4)		 Hereditary: 260 (75 bone, 34 connective and soft tissue, 32 nasal cavities, 29 cutaneous melanomas, 17 eye and orbit, 10 brain, 10 female breast…)
Nonhereditary: 17 (7 female breast, 2 brain, 2 thyroid, 1 Hodgkin’s lymphoma, 1 leukemia…)		 Hereditary: RT (241); No RT (19)
Nonhereditary: Not disclosed		 Not disclosed
Marees et al. (2008) [13] 668 patients:
-
298 hereditary
-
370 nonhereditary
 Hereditary:
Surgery (70); ChT (16): RT (152); RT + ChT (58); Unknown (2)
Nonhereditary:
Surgery (322); ChT (8): RT (22); RT + ChT (8); Unknown (10)		 Hereditary: 62 (20 soft tissue, 16 bone tumors, 13 melanomas, 11 epithelial—4 bladder, 3 lung, 2 breast, and 2 non-Hodgkin lymphomas)
Nonhereditary: 12 (5 solid cancers, 3 soft tissue, 2 lung, and 2 leukemia)		 Hereditary: EBRT (38); EBRT + ChT (17); Surgery (3); Laser coagulation (3); Unknown (1)
Nonhereditary: Surgery (12)		 Hereditary: In-field of irradiation (22); outside field of irradiation (33)
Nonhereditary: In-field of irradiation (0); outside field of irradiation (0)
MacCarthy et al. (2013) [14] 1927 patients:
-
806 hereditary
-
1121 nonhereditary
 Not disclosed Hereditary: 146 (33 leiomyosarcoma, 33 osteosarcomas, 14 melanomas, 15 brain/CNS, 9 female breast, 9 meningiomas, 8 bladder…) c
Nonhereditary: 23 (3 osteosarcomas, 4 brain/CNS, 3 meningioma, 2 female breast, 2 melanomas…) c		 Not disclosed Hereditary: In-field of irradiation (45); outside field of irradiation (70)
Nonhereditary: In-field of irradiation (6); outside field of irradiation (14)
Gregersen et al. (2020) [15] 323 patients
-
133 hereditary
-
190 nonhereditary
 Hereditary:
RT (31); RT + ChT (6); RT + ChT + enucleation (13); RT + enucleation (93); ChT (2); ChT + enucleation (7); enucleation (171)
Nonhereditary:
RT (25); RT + ChT (6); RT + ChT + enucleation (11); RT + enucleation (75); ChT (2); ChT + enucleation (2); enucleation (12)		 Hereditary: 25 (14 sarcomas, 6 melanomas, 3 carcinomas—2 breast and 1 ovarian cancer—and 2 CNS)
Nonhereditary: 13 (5 carcinomas—2 lung, 1 breast, 1 cervical cancer, and 1 thyroid cancer—4 sarcomas, 3 melanomas, and 1 CNS)		 Hereditary: EBRT (13); No EBRT (12)
Nonhereditary: EBRT (0); No EBRT (13)		 Hereditary: In-field of irradiation (6); outside field of irradiation (7)
Nonhereditary: In-field of irradiation (0); outside field of irradiation (0)
Schonfeld et al. (2021) [16] 2052 patients:
-
1128 hereditary
-
924 nonhereditary
 Hereditary:
RT (550); RT + ChT (435); ChT (39); Surgery (90); Unknown (14)
Nonhereditary:
RT (101); RT + ChT (86); ChT (61); Surgery (636); Unknown (40)		 Hereditary: 265 (89 soft tissue sarcomas, 80 bone tumors, 28 melanomas, 12 breast, 11 nasal cavity, 8 pineoblastoma, 6 CNS…) d
Nonhereditary: 27 (8 breast, 3 melanomas, 3 gastrointestinal, 2 thyroid, 2 lung…) d		 Not disclosed Not disclosed
Zhao et al. (2021)
[17]		 62 patients
-
40 hereditary
-
17 nonhereditary
-
5 unknown
 RT (35); Chemotherapy (17); Surgery (16); Unknown (5) e Hereditary: 40 (37 sarcomas, 4 breast cancers, 3 adenocarcinoma, 2 meningiomas, 2 thyroid carcinoma...)
Nonhereditary: 17 (11 sarcomas, 4 carcinomas...)		 Hereditary: RT (27); No RT (10)
Nonhereditary: RT (7); No RT (10)		 Not disclosed
Sethi et al. (2013)
[18]		 86 patients Proton therapy (55)
Photon therapy (31)		 Proton therapy: 1 (osteosarcoma)
Photon therapy: 4 (3 sarcomas—orbital, maxillary, temporal bone—and 1 glioblastoma multiforme)		   Proton therapy: In-field of irradiation (0); outside field of irradiation (1)
Photon therapy: In-field of irradiation (4); outside field of irradiation (0)
Mouw et al. (2014)
[19]		 60 tumors f PRT (60) g Hereditary: 1 (osteosarcoma of the femur)
Nonhereditary: 0		   Hereditary: In-field of irradiation (0); outside field of irradiation (1)

Nonhereditary: In-field of irradiation (0); outside field of irradiation (0)
a Treatment approaches in patients who developed SMNs; b Location of SMNs in the irradiated group of patients. This classification between in-field and outside the field of radiation is based on the region where the SMNs develop (within the head and neck region is considered in-field of irradiation); c Among the hereditary group of patients, 146 SMNs were detected in 112 patients, whereas in the nonhereditary group of patients, 23 SMNs were detected in 20 patients; d Among the hereditary group of patients, 265 SMNs were detected in 239 patients, whereas in the nonhereditary group of patients, 27 SMNs were detected in 25 patients; e Data not disclosed regarding therapeutic approaches by hereditary/nonhereditary group; f Data show 60 tumors in 49 RB patients; g Among this group of patients treated with PRT, 25 patients had also received chemotherapy, and 43 tumors were treated with cryotherapy/laser; #: number; RT: radiation therapy (not specified); EBRT: external beam radiation therapy; BT: brachytherapy; RA: radium implants; ChT: chemotherapy; PRT: proton radiation therapy.

3. Conclusion

This research has allowed for the confirmation of a higher predisposition for SMNs in hereditary RB patients compared to nonhereditary RB patients. Even though the increase of SMNs in irradiated patients is clear, especially when that exposure is associated with photon therapy, there is no significant association between exposure to IR and the incidence of SMNs in survivors of RB. Thus, these conclusions seem to justify why radiation therapy tends to be avoided as the primary treatment approach to RB. However, knowing in advance that RBs tumors are highly responsive to radiation therapy and that, in some cases, especially when extraocular involvement occurs, EBRT is utilized, it is extremely important to carry out more studies on this matter. Future studies should expand the sample size, increase the follow-up time, and be complemented with radiobiological studies.

References

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  2. Sengupta, S.; Pan, U.; Khetan, V. Adult Onset Retinoblastoma. Indian J. Ophthalmol. 2016, 64, 485–491.
  3. AlAli, A.; Kletke, S.; Gallie, B.; Lam, W.-C. Retinoblastoma for Pediatric Ophthalmologists. Asia Pac. J. Ophthalmol. 2018, 7, 160–168.
  4. Shields, C.L.; Shields, J.A. Diagnosis and Management of Retinoblastoma. Cancer Control 2004, 11, 317–327.
  5. Chintagumpala, M.; Chevez-Barrios, P.; Paysse, E.A.; Plon, S.E.; Hurwitz, R. Retinoblastoma: Review of Current Management. Oncologist 2007, 12, 1237–1246.
  6. Knudson, A.G. Mutation and Cancer: Statistical Study of Retinoblastoma. Proc. Natl. Acad. Sci. USA 1971, 68, 820–823.
  7. DiCiommo, D.; Gallie, B.L.; Bremner, R. Retinoblastoma: The Disease, Gene and Protein Provide Critical Leads to Understand Cancer. Semin. Cancer Biol. 2000, 10, 255–269.
  8. Corson, T.W.; Gallie, B.L. One Hit, Two Hits, Three Hits, More? Genomic Changes in the Development of Retinoblastoma. Genes Chromosomes Cancer 2007, 46, 617–634.
  9. Di Fiore, R.; D’Anneo, A.; Tesoriere, G.; Vento, R. RB1 in Cancer: Different Mechanisms of RB1 Inactivation and Alterations of PRb Pathway in Tumorigenesis. J. Cell. Physiol. 2013, 228, 1676–1687.
  10. Fabius, A.W.M.; van Hoefen Wijsard, M.; van Leeuwen, F.E.; Moll, A.C. Subsequent Malignant Neoplasms in Retinoblastoma Survivors. Cancers 2021, 13, 1200.
  11. Mohney, B.G.; Robertson, D.M.; Schomberg, P.J.; Hodge, D.O. Second Nonocular Tumors in Survivors of Heritable Retinoblastoma and Prior Radiation Therapy. Am. J. Ophthalmol. 1998, 126, 269–277.
  12. Kleinerman, R.A.; Tucker, M.A.; Tarone, R.E.; Abramson, D.H.; Seddon, J.M.; Stovall, M.; Li, F.P.; Fraumeni, J.F. Risk of New Cancers after Radiotherapy in Long-Term Survivors of Retinoblastoma: An Extended Follow-Up. J. Clin. Oncol. 2005, 23, 2272–2279.
  13. Marees, T.; Moll, A.C.; Imhof, S.M.; De Boer, M.R.; Ringens, P.J.; Van Leeuwen, F.E. Risk of Second Malignancies in Survivors of Retinoblastoma: More than 40 Years of Follow-Up. J. Natl. Cancer Inst. 2008, 100, 1771–1779.
  14. MacCarthy, A.; Bayne, A.M.; Brownbill, P.A.; Bunch, K.J.; Diggens, N.L.; Draper, G.J.; Hawkins, M.M.; Jenkinson, H.C.; Kingston, J.E.; Stiller, C.A.; et al. Second and Subsequent Tumours among 1927 Retinoblastoma Patients Diagnosed in Britain 1951–2004. Br. J. Cancer 2013, 108, 2455–2463.
  15. Gregersen, P.A.; Gregersen, P.A.; Olsen, M.H.; Urbak, S.F.; Funding, M.; Dalton, S.O.; Overgaard, J.; Alsner, J. Incidence and Mortality of Second Primary Cancers in Danish Patients with Retinoblastoma, 1943–2013. JAMA Netw. Open 2020, 3, e2022126.
  16. Schonfeld, S.J.; Kleinerman, R.A.; Abramson, D.H.; Seddon, J.M.; Tucker, M.A.; Morton, L.M. Long-Term Risk of Subsequent Cancer Incidence among Hereditary and Nonhereditary Retinoblastoma Survivors. Br. J. Cancer 2021, 124, 1312–1319.
  17. Zhao, N.O.; Daewoo, P.; El-Hadad, C.; Debnam, J.M.; Ning, J.; Esmaeli, B. Characteristics and Survival Outcomes of Second Primary Cancers in Long-Term Retinoblastoma Survivors. Asia Pac. J. Ophthalmol. 2021, 10, 366–372.
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Subjects: Ophthalmology; Oncology; Genetics & Heredity
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Diana Figueiredo
,
Inês A. Marques
,
Ana Salomé Pires
,
Claudia F. Cavaleiro
,
Luís C. Costa
,
Guilherme Castela
,
Joaquim N. Murta
,
Maria Filomena Botelho
,
Ana Margarida Abrantes
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Revisions: 3 times (View History)
Update Date: 20 Nov 2023
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