Pathological high-risk factors and prognostic analysis of intraocular stage advanced retinoblastoma following enucleation_Chinese Journal of Ocular Fundus Diseases

Authors：

Bai Xueqing ^1,2 , Zhang Nan ³ , Liu Wen ¹ , Leng Fei ¹ , Zhao Junyang ¹ , Li Li ¹ ,  Zhang Chengyue ¹

1. Department of Ophthalmology, Beijing Children's Hospital, Capital Medical University National Children's Medical Centre, Beijing 100045, China;
2. Children's Hospital of Xinjiang Uygur Autonomous Region, Ophthalmology, Urumqi 831399, China;
3. Department of Pathology, Beijing Children's Hospital, Capital Medical University National Children's Medical Centre, Beijing 100045, China;

Corresponding author：

Zhang Chengyue, Email: yankeyisheng1979@126.com

Keywords：

Retinoblastoma; Intravenous chemotherapy; Intra-arterial chemotherapy; High-risk histopathological feature

DOI：

10.3760/cma.j.cn511434-20250506-00197

Video：

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Objective To observe the high-risk histopathological feature (HRF) and their correlation with prognosis in children with intraocular retinoblastoma (RB) in the intraocular stage after failed eye-preserving treatment and enucleation surgery. Methods A single-center retrospective case study. From August 2018 to January 2023, 64 children (64 eyes) with advanced intraocular RB who were diagnosed in the ophthalmology department of Beijing Children's Hospital and underwent enucleation surgery after failed eye-preserving treatment were included in the study. The median follow-up time was 51 months. The gender of the children patients, the age of visit and enucleation, International Intraocular Retinoblastoma Classification (IIRC), the initial chemotherapy regimen (hereinafter referred to as "chemotherapy"), the time of enucleation surgery, pathological results, post-enucleation treatment methods and prognosis were collected. The Mann-Whitney U test was used for comparison between groups. Survival analysis was performed using the Kaplan-Meier method, and the log-rank test was used for comparison between groups. Results Among 64 cases and 64 eyes, 370 were male and 27 were female. The age of seeking medical treatment was 20 (11-31) months. The age at which the surgery was performed was 29 (16-40) months. The number of eyes in IIRC stage D and E was 16 and 48 respectively. The initial chemotherapy regimens simply applied (hereinafter referred to as "alone") intravenous systemic chemotherapy (IVC) and ophthalmic artery infusion chemotherapy (IAC) in 40 cases and 11 cases, 13 cases of IVC+IAC. All patients with positive HRF received systemic adjuvant chemotherapy after surgery. There were 37 eyes (57.8%, 37/64) positive for HRF. There was no statistically significant difference in the positive rate of HRF between children in IIRC stage D and stage E (χ²=0.021, P=0.884). Among the 37 eyes with HRF, the numbers of eyes with extensive choroidal invasion, posterior lamina cribrosa optic nerve invasion, scleral invasion and scleral invasion were 17 (45.9%, 17/37), 16 (43.2%, 16/37), 3 (8.1%, 3/37) and 3 (8.1%, 3/37), respectively. During the follow-up period, there were 5 cases (7.8%, 5/64) of extraocular metastasis of the tumor and death, all of which were stage E and had HRF. Among them, the initial treatment plan was IAC for 4 cases, one case of IVC. The survival rates of children among the IVC, IAC or IVC+IAC regimens were 97.5% (39/40), 63.6% (7/11), and 100.0% (13/13) eyes, respectively. The comparison of survival rates among different chemotherapy regimens showed statistically significant differences (χ²=14.233, P＜0.001). The results of survival analysis showed that the cumulative survival rate of those with extensive choroidal invasion, posterior lamina cribrosa optic nerve infiltration, and those who received IAC was significantly lower than that of those without extensive choroidal invasion, posterior lamina cribrosa optic nerve infiltration, and those who received IVC+IAC and IVC (P＜0.05). Conclusions Eye-preserving treatment for children with advanced intraocular RB may increase the positive rate of HRF and the risk of extraocular metastasis. The IVC+IAC eye-protecting treatment plan can improve the survival rate of children.

1.	Global Retinoblastoma Study Group, Fabian D, Elhassan A, et al. Global retinoblastoma presentation and analysis by national income level[J]. JAMA Oncol, 2020, 6(5): 685-695. DOI: 10.1001/jamaoncol.2019.6716.
2.	Shields CL, Mashayekhi A, Au AK, et al. The International Classification of Retinoblastoma predicts chemoreduction success[J]. Ophthalmology, 2006, 113(12): 2276-2280. DOI: 10.1016/j.ophtha.2006.06.018.
3.	Chen Q, Zhang B, Dong Y, et al. Evaluating primary intra-arterial chemotherapy versus intravenous plus intra-arterial chemotherapy for advanced intraocular retinoblastoma[J]. Cancer Chemother Pharmacol, 2020, 85(4): 723-730. DOI: 10.1007/s00280-020-04036-w.
4.	Grigorovski N, Lucena E, Mattosinho C, et al. Use of intra-arterial chemotherapy for retinoblastoma: results of a survey[J]. Int J Ophthalmol, 2014, 7(4): 726-730. DOI: 10.3980/j.issn.2222-3959.2014.04.26.
5.	Honavar SG, Singh AD, Shields CL, et al. Postenucleation adjuvant therapy in high-risk retinoblastoma[J]. Arch Ophthalmol, 2002, 120(7): 923-931. DOI: 10.1001/archopht.120.7.923.
6.	魏文斌, 周楠. 重视视网膜母细胞瘤的规范化治疗, 提升视网膜母细胞瘤的治疗水平[J]. 中华眼底病杂志, 2020, 36(6): 413-418. DOI: 10.3760/cma.j.cn511434-20200520-00209.Wei WB, Zhou N. Attach importance to standardized treatment of retinoblastoma to improve its treatment outcome[J]. Chin J Ocul Fundus Dis, 2020, 36(6): 413-418. DOI: 10.3760/cma.j.cn511434-20200520-00209.
7.	Chantada GL, Casco F, Fandiño AC, et al. Outcome of patients with retinoblastoma and postlaminar optic nerve invasion[J]. Ophthalmology, 2007, 114(11): 2083-2089. DOI: 10.1016/j.ophtha.2007.01.012.
8.	Kaliki S, Shields CL, Rojanaporn D, et al. High-risk retinoblastoma based on international classification of retinoblastoma: analysis of 519 enucleated eyes[J]. Ophthalmology, 2013, 120(5): 997-1003. DOI: 10.1016/j.ophtha.2012.10.044.
9.	Kaliki S, Srinivasan V, Gupta A, et al. Clinical features predictive of high-risk retinoblastoma in 403 Asian Indian patients: a case-control study[J]. Ophthalmology, 2015, 122(6): 1165-1172. DOI: 10.1016/j.ophtha.2015.01.018.
10.	Kaliki S, Gupta S, Ramappa G, et al. High-risk retinoblastoma based on age at primary enucleation: a study of 616 eyes[J]. Eye (Lond), 2020, 34(8): 1441-1448. DOI: 10.1038/s41433-019-0698-2.
11.	刘冬悦, 金眉, 阴捷, 等. 经眼动脉灌注化学药物治疗与经静脉全身化学药物治疗对单眼晚期视网膜母细胞瘤的临床疗效初探[J]. 中华眼底病杂志, 2022, 38(3): 187-190. DOI: 10.3760/cma.j.cn511434-20220131-00057.Liu DY, Jin M, Yin J, et al. Preliminary study on clinical efficacy of intra-arterial chemotherapy and intravenous chemotherapy for unilateral advanced retinoblastoma[J]. Chin J Ocul Fundus Dis, 2022, 38(3): 187-190. DOI: 10.3760/cma.j.cn511434-20220131-00057.
12.	中华医学会病理学分会儿科病理学组, 福棠儿童医学发展研究中心病理专业委员会. 儿童视网膜母细胞瘤规范化病理诊断共识[J]. 中华病理学杂志, 2021, 50(8): 859-864. DOI: 10.3760/cma.j.cn112151-20210127-00088.Pediatric Pathology Group, Pathology Branch of Chinese Medical Association, Pathology Professional Committee of Futang Children's Medical Development Research Center. Consensus on standardized pathological diagnosis of retinoblastoma in children[J]. Chin J Pathol, 2021, 50(8): 859-864. DOI: 10.3760/cma.j.cn112151-20210127-00088.
13.	张诚玥, 金眉, 阴捷, 等. 经眼动脉与经静脉化学疗法治疗单眼D期视网膜母细胞瘤的临床研究[J]. 中华眼科医学杂志(电子版), 2021, 11(2): 70-75. DOI: 10.3877/cma.j.issn.2095-2007.2021.02.002.Zhang CY, Jin M, Yin J, et al. The effect of intravenous chemotherapy and intra-arterial chemotherapy for unilateral group D retinoblastoma[J]. Chin J Ophthalmol Med (Electronic Edition), 2021, 11(2): 70-75. DOI: 10.3877/cma.j.issn.2095-2007.2021.02.002.
14.	Kopelman JE, McLean IW, Rosenberg SH. Multivariate analysis of risk factors for metastasis in retinoblastoma treated by enucleation[J]. Ophthalmology, 1987, 94(4): 371-377. DOI: 10.1016/s0161-6420(87)33436-0.
15.	Kaliki S, Shields CL, Cassoux N, et al. Defining high-risk retinoblastoma: a multicenter global survey[J]. JAMA Ophthalmol, 2022, 140(1): 30-36. DOI: 10.1001/jamaophthalmol.2021.4732.
16.	Mallipatna A, Gallie BL, Chvez-Barrios P, et al. Retinoblastoma[M]//Amin MB, Edge SB, Greene FL. AJCC Cancer Staging Manual. 8th ed. New York: Springer, 2017: 819-831.
17.	Kaliki S, Shields CL, Eagle RC Jr, et al. High-risk intraocular retinoblastoma: comparison between Asian Indians and Americans from two major referral centers[J]. Retina, 2018, 38(10): 2023-2029. DOI: 10.1097/IAE.0000000000001816.
18.	Wang J, Zhang C, Zhang L, et al. Comparative study on genomic and epigenomic profiles of retinoblastoma or tuberous sclerosis complex via nanopore sequencing and a joint screening framework[J]. Cancer Gene Ther, 2024, 31(3): 439-453. DOI: 10.1038/s41417-023-00714-y.
19.	Mohammad M, Shehada R, Al-Nawaiseh I, et al. A comparison of high risk pathological features between primary and secondary enucleation for retinoblastoma[J]. Eur J Ophthalmol, 2023, 33(5): 2014-2023. DOI: 10.1177/11206721231155671.
20.	Wilson MW, Qaddoumi I, Billups C, et al. A clinicopathological correlation of 67 eyes primarily enucleated for advanced intraocular retinoblastoma[J]. Br J Ophthalmol, 2011, 95(4): 553-558. DOI: 10.1136/bjo.2009.177444.
21.	顼晓琳, 李彬, 高飞, 等. 以眼球摘除术作为首次治疗的482例视网膜母细胞瘤患者的高危病理因素分析[J]. 中华眼科杂志, 2018, 54(10): 782-786. DOI: 10.3760/cma.j.issn.0412-4081.2018.10.012.Xu XL, Li B, Gao F, et al. Analysis of high-risk histopathologic features of 482 primarily enucleated retinoblastomas[J]. Chin J Ophthalmol, 2018, 54(10): 782-786. DOI: 10.3760/cma.j.issn.0412-4081.2018.10.012.
22.	Zhao J, Dimaras H, Massey C, et al. Pre-enucleation chemotherapy for eyes severely affected by retinoblastoma masks risk of tumor extension and increases death from metastasis[J]. J Clin Oncol, 2011, 29(7): 845-851. DOI: 10.1200/JCO.2010.32.5332.
23.	范先群. 重视视网膜母细胞瘤的国际分期应用和综合序列治疗[J]. 中华眼科杂志, 2017, 53(8): 561-565. DOI: 10.3760/cma.j.issn.0412-4081.2017.08.001.Fan XQ. Pay attention to the application of the international intraocular retinoblastoma classification and sequential multiple modality treatment[J]. Chin J Ophthalmol, 2017, 53(8): 561-565. DOI: 10.3760/cma.j.issn.0412-4081.2017.08.001.

1. Global Retinoblastoma Study Group, Fabian D, Elhassan A, et al. Global retinoblastoma presentation and analysis by national income level[J]. JAMA Oncol, 2020, 6(5): 685-695. DOI: 10.1001/jamaoncol.2019.6716.
2. Shields CL, Mashayekhi A, Au AK, et al. The International Classification of Retinoblastoma predicts chemoreduction success[J]. Ophthalmology, 2006, 113(12): 2276-2280. DOI: 10.1016/j.ophtha.2006.06.018.
3. Chen Q, Zhang B, Dong Y, et al. Evaluating primary intra-arterial chemotherapy versus intravenous plus intra-arterial chemotherapy for advanced intraocular retinoblastoma[J]. Cancer Chemother Pharmacol, 2020, 85(4): 723-730. DOI: 10.1007/s00280-020-04036-w.
4. Grigorovski N, Lucena E, Mattosinho C, et al. Use of intra-arterial chemotherapy for retinoblastoma: results of a survey[J]. Int J Ophthalmol, 2014, 7(4): 726-730. DOI: 10.3980/j.issn.2222-3959.2014.04.26.
5. Honavar SG, Singh AD, Shields CL, et al. Postenucleation adjuvant therapy in high-risk retinoblastoma[J]. Arch Ophthalmol, 2002, 120(7): 923-931. DOI: 10.1001/archopht.120.7.923.
6. 魏文斌, 周楠. 重视视网膜母细胞瘤的规范化治疗, 提升视网膜母细胞瘤的治疗水平[J]. 中华眼底病杂志, 2020, 36(6): 413-418. DOI: 10.3760/cma.j.cn511434-20200520-00209.Wei WB, Zhou N. Attach importance to standardized treatment of retinoblastoma to improve its treatment outcome[J]. Chin J Ocul Fundus Dis, 2020, 36(6): 413-418. DOI: 10.3760/cma.j.cn511434-20200520-00209.
7. Chantada GL, Casco F, Fandiño AC, et al. Outcome of patients with retinoblastoma and postlaminar optic nerve invasion[J]. Ophthalmology, 2007, 114(11): 2083-2089. DOI: 10.1016/j.ophtha.2007.01.012.
8. Kaliki S, Shields CL, Rojanaporn D, et al. High-risk retinoblastoma based on international classification of retinoblastoma: analysis of 519 enucleated eyes[J]. Ophthalmology, 2013, 120(5): 997-1003. DOI: 10.1016/j.ophtha.2012.10.044.
9. Kaliki S, Srinivasan V, Gupta A, et al. Clinical features predictive of high-risk retinoblastoma in 403 Asian Indian patients: a case-control study[J]. Ophthalmology, 2015, 122(6): 1165-1172. DOI: 10.1016/j.ophtha.2015.01.018.
10. Kaliki S, Gupta S, Ramappa G, et al. High-risk retinoblastoma based on age at primary enucleation: a study of 616 eyes[J]. Eye (Lond), 2020, 34(8): 1441-1448. DOI: 10.1038/s41433-019-0698-2.
11. 刘冬悦, 金眉, 阴捷, 等. 经眼动脉灌注化学药物治疗与经静脉全身化学药物治疗对单眼晚期视网膜母细胞瘤的临床疗效初探[J]. 中华眼底病杂志, 2022, 38(3): 187-190. DOI: 10.3760/cma.j.cn511434-20220131-00057.Liu DY, Jin M, Yin J, et al. Preliminary study on clinical efficacy of intra-arterial chemotherapy and intravenous chemotherapy for unilateral advanced retinoblastoma[J]. Chin J Ocul Fundus Dis, 2022, 38(3): 187-190. DOI: 10.3760/cma.j.cn511434-20220131-00057.
12. 中华医学会病理学分会儿科病理学组, 福棠儿童医学发展研究中心病理专业委员会. 儿童视网膜母细胞瘤规范化病理诊断共识[J]. 中华病理学杂志, 2021, 50(8): 859-864. DOI: 10.3760/cma.j.cn112151-20210127-00088.Pediatric Pathology Group, Pathology Branch of Chinese Medical Association, Pathology Professional Committee of Futang Children's Medical Development Research Center. Consensus on standardized pathological diagnosis of retinoblastoma in children[J]. Chin J Pathol, 2021, 50(8): 859-864. DOI: 10.3760/cma.j.cn112151-20210127-00088.
13. 张诚玥, 金眉, 阴捷, 等. 经眼动脉与经静脉化学疗法治疗单眼D期视网膜母细胞瘤的临床研究[J]. 中华眼科医学杂志(电子版), 2021, 11(2): 70-75. DOI: 10.3877/cma.j.issn.2095-2007.2021.02.002.Zhang CY, Jin M, Yin J, et al. The effect of intravenous chemotherapy and intra-arterial chemotherapy for unilateral group D retinoblastoma[J]. Chin J Ophthalmol Med (Electronic Edition), 2021, 11(2): 70-75. DOI: 10.3877/cma.j.issn.2095-2007.2021.02.002.
14. Kopelman JE, McLean IW, Rosenberg SH. Multivariate analysis of risk factors for metastasis in retinoblastoma treated by enucleation[J]. Ophthalmology, 1987, 94(4): 371-377. DOI: 10.1016/s0161-6420(87)33436-0.
15. Kaliki S, Shields CL, Cassoux N, et al. Defining high-risk retinoblastoma: a multicenter global survey[J]. JAMA Ophthalmol, 2022, 140(1): 30-36. DOI: 10.1001/jamaophthalmol.2021.4732.
16. Mallipatna A, Gallie BL, Chvez-Barrios P, et al. Retinoblastoma[M]//Amin MB, Edge SB, Greene FL. AJCC Cancer Staging Manual. 8th ed. New York: Springer, 2017: 819-831.
17. Kaliki S, Shields CL, Eagle RC Jr, et al. High-risk intraocular retinoblastoma: comparison between Asian Indians and Americans from two major referral centers[J]. Retina, 2018, 38(10): 2023-2029. DOI: 10.1097/IAE.0000000000001816.
18. Wang J, Zhang C, Zhang L, et al. Comparative study on genomic and epigenomic profiles of retinoblastoma or tuberous sclerosis complex via nanopore sequencing and a joint screening framework[J]. Cancer Gene Ther, 2024, 31(3): 439-453. DOI: 10.1038/s41417-023-00714-y.
19. Mohammad M, Shehada R, Al-Nawaiseh I, et al. A comparison of high risk pathological features between primary and secondary enucleation for retinoblastoma[J]. Eur J Ophthalmol, 2023, 33(5): 2014-2023. DOI: 10.1177/11206721231155671.
20. Wilson MW, Qaddoumi I, Billups C, et al. A clinicopathological correlation of 67 eyes primarily enucleated for advanced intraocular retinoblastoma[J]. Br J Ophthalmol, 2011, 95(4): 553-558. DOI: 10.1136/bjo.2009.177444.
21. 顼晓琳, 李彬, 高飞, 等. 以眼球摘除术作为首次治疗的482例视网膜母细胞瘤患者的高危病理因素分析[J]. 中华眼科杂志, 2018, 54(10): 782-786. DOI: 10.3760/cma.j.issn.0412-4081.2018.10.012.Xu XL, Li B, Gao F, et al. Analysis of high-risk histopathologic features of 482 primarily enucleated retinoblastomas[J]. Chin J Ophthalmol, 2018, 54(10): 782-786. DOI: 10.3760/cma.j.issn.0412-4081.2018.10.012.
22. Zhao J, Dimaras H, Massey C, et al. Pre-enucleation chemotherapy for eyes severely affected by retinoblastoma masks risk of tumor extension and increases death from metastasis[J]. J Clin Oncol, 2011, 29(7): 845-851. DOI: 10.1200/JCO.2010.32.5332.
23. 范先群. 重视视网膜母细胞瘤的国际分期应用和综合序列治疗[J]. 中华眼科杂志, 2017, 53(8): 561-565. DOI: 10.3760/cma.j.issn.0412-4081.2017.08.001.Fan XQ. Pay attention to the application of the international intraocular retinoblastoma classification and sequential multiple modality treatment[J]. Chin J Ophthalmol, 2017, 53(8): 561-565. DOI: 10.3760/cma.j.issn.0412-4081.2017.08.001.

Chinese Journal of Ocular Fundus Diseases

Latest ArticlesPathological high-risk factors and prognostic analysis of intraocular stage advanced retinoblastoma following enucleation

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