Clinical characteristics, treatment and prognosis of infants with retinoblastoma: a multicenter, 10-year retrospective analysis

Retinoblastoma (RB) is the most common malignant tumor in children, and its incidence ranks the third in all age groups of ocular malignancies [1]. The incidence rate of RB was at 1 in 15,000–20,000 live birth across population, corresponding to about 9000 new cases every year [2]. China is the most populous country in the world, with about 1000 new cases of RB every year, accounting for 1/8 of all cases worldwide [3, 4]. It originates from primitive retinal stem cells or cone precursors, 95% of cases occur before 5 years old, the median age of onset is 2–3 years old [5]. Infants with infantile disease may become seriously ill shortly after birth, either in one eye or in both eyes, with either endophytic or exophytic growth [6]. Leukocoria is the most common initial presenting sign of RB which is seen in 60 to 80% of newly diagnosed patients, followed by strabismus [7].

The younger the onset age of RB, the higher the incidence rate of RB in both eyes, and it is not easy to detect and diagnose early [8]. It is clear that RB has a significant genetic tendency, the clear family history of RB is about for 5% of the children with the disease in China [9]. With the improvement of early diagnosis, the treatment of RB patients has been improved. The treatment of RB depends on the age of the child, laterality, and degree of disease. There are several treatment modalities for RB, such as chemotherapy, brachytherapy, external beam radiotherapy, enucleation, and intra-arterial chemotherapy (IAC) [2]. Moreover, the treatment of infant RB is different from that of other age groups. For example, there is no clear conclusion on whether the timing of enucleation of eyeball, whether the prosthesis is installed at the same time or delayed plastic installation after enucleation of eyeball, whether it can tolerate systemic chemotherapy, and whether intraocular chemotherapy is applicable to infants within 6 months.

Patients with advanced RB usually have poor prognosis. Prognosis and survival depends on early diagnosis and appropriate treatment. Early diagnosis, care and treatment of retinoblastoma is a challengeable issue for China health system. Therefore, in order to early detection, diagnosis, treatment, improve the cure rate and preserve the eye rate, we collected the clinical data of multi-center infants with large number of RB in china and retrospectively analyzed the characteristics, family genetic tendency, treatment and prognosis of RB patients, so as to provide theoretical basis for early screening, diagnosis and treatment of RB in the future.

RB is the most common intraocular malignancy in childhood, can present in one or both eyes, which seriously endangers children’s vision and life [17]. The clinical symptoms of RB patients were leukocoria, strabismus, lachrymation, iris turn colors, pinkeye, forward antrum bleeding, orbital inflammation, glaucoma and nubecula, among which leukocoria is the most common initial presenting sign in infants [7]. It is worth mentioning that leukocoria is not only seen in RB patients, but also in pseudoretinoblastoma, including Coats' disease, persistent fetal vasculature (PFV), vitreous hemorrhage, familial exudative vitreoretinopathy (FEVR) and other eye diseases [18‐20]. Therefore, we recommend that when examining infants with possible RB consult RB specialist before planning treatment strategies. Our study may be the first and largest clinical date of RB infants (≤ 12 months) in China. In this study, 74.1% of the infants had the leukocoria as initial presenting sign, which was consistent with the literature report, followed by strabismus, decreased vision, conjunctival hyperemia and infection. A small number of children with unilateral RB later develop metachronous bilateral RB [21]. One previous study reported that the average age at the time of RB diagnosis is 23 months, the age of onset of RB in bilateral eyes was 15 months, which was smaller than the age of onset of RB in unilateral eyes at 27 months [9]. In our study, the incidence of RB in bilateral eye was higher than that in unilateral eye (56.6% vs 43.4%), and the incidence of RB in infants aged 6–12 months was slightly higher than that in children aged < 6 months (51.6% vs 48.4).

The cure of RB and the sequelae arising from RB mainly depend on an early diagnosis [22]. Tracing family history and paying attention to birth history during pregnancy are very helpful for early diagnosis of RB. By analyzing the morbidity characteristics of medical records, it suggests that not only the family history of RB should be included in the neonatal ophthalmic screening, but also the history of immediate relatives (congenital eye disease or unexplained weakness, myopia and blindness) should be included in the screening [23]. Meanwhile, it is suggested infant with low birth weight or abnormal birth should be conducted in early screening. In our study, it was worth noting that 7.2% (27/373) cases were clinically diagnosed with RB through physical examination and screening, and even higher than the proportion of strabismus (7.0%, 26/373). These findings indicated that the early screening for patients with family high-risk factors or high-risk factors in birth history was conducive to the early discovery and diagnosis of RB.

Clinical studies show that for early stage patients, conservative treatment can be optional with follow-up of retinal tumor morphologic changes [24]. One study has indicated that, the treatment method could be selected according to the degree of progress of the tumor for D stage patients, in order to maximize patients’ life quality. The proposal to E stage patients was enucleation to prevent recurrence and metastasis [25]. In our study, 584 eyes were affected. According to the IIRC stage, the stages of tumor space occupying in the left and right eyes were mainly D and E stages, which were 71.9% (41.6% + 31.3%) and 68.7% (46.4% + 26.3%) respectively. Survival analysis showed that the prognosis of stage E infants was worse than that of other stages. There was no consistent conclusion at home and abroad whether it indicated that the condition of RB infant was serious. In this study, infants with intraocular phase E, especially those within 6 months, often chose to delay enucleation after chemotherapy and volume reduction because they were unable to install artificial eyes immediately after enucleation. Statistical analysis that preoperative chemotherapy followed by eyeball enucleation did not affect the prognosis of stage E and extraocular children. Furthermore, it is worth noting that the prognosis of children with vitrectomy is worse than that of children without vitrectomy, so the indications should be more cautious.

The diagnosis level, average age of onset and prognosis of RB patients vary slightly in different countries and regions. The mortality rate of RB in most developed countries such as Europe is lower than that in developing countries [26]. The treatment principle of RB is to preserve life first, and then to use a variety of diagnosis and treatment methods to preserve eye organs and functions as much as possible on the premise of preserving life [2]. In the United States, 75% of children with advanced or refractory RB, who cannot be treated with focal therapy alone, may undergo systemic chemotherapy, external beam radiotherapy, or enucleation [27]. In this study, intrathecal therapy was added for RB infants with definite retrobulbar optic nerve invasion and extraocular phase. Moreover, due to the young age of onset and the high dispersion of local drugs, IAC also brought a high risk of local side effects, thus systemic chemotherapy was as the main treatment method, instead of IAC. A number of studies at home and abroad have reported that intra-arterial chemotherapy and/or intravitreal chemotherapy are the main diagnosis and treatment scheme for RB, and stem cell transplantation index is also recommended for distant tissue metastasis. According to the those reports, children under 2 years of age have also achieved a good rate of eyeball preservation, with the enucleation rate of about 43%, and the recurrence rate of less than 25% [15, 28, 29]. In this study, the rate of eyeball extraction was basically the same as reported or slightly lower than that reported in the literature, and the recurrence rate was only 7.8% (29/373). During follow-up, 9 cases died, 20 cases fell out, 345 case survived, and the OS was high as 97.7% (345/353), which was similar to the report of Tamaki et al. (OS rate, 94.9%) [8]. The OS rate of patients with unilateral or bilateral eye affected was 99.4% (161/162) and 96.2% (203/211), respectively, indicating that the prognosis of OS in infants with unilateral RB was higher than that with bilateral RB.

It is clear that RB is a prototypical genetic cancer, which is related to the mutation of RB1 gene located in the long arm of chromosome 13 (13q14) [30]. The occurrence of RB has a clear tendency, mainly including germline inheritance and non-germline inheritance. RB is heritable in 40% of the cases and, in such cases, tumors are bilateral in 80%, unilateral in 15%, and trilateral in 5% of the cases [31]. In this study, familial RB germline genetic pattern accounts for 4.6% (17/373), and the occurrence of RB in other children may be related to secondary mutation [32]. Moreover, 82.4% (14/17) of the 17 cases of familial RB infant have binocular disease, which was consistent with previous report. Rare deaths in our study might be related to the probable germline defect of RB1 gene, although most patients received no genetic study. To pursue a better quality of life, neonatal screening is being more actively promoted for high-risk families in China under collaboration between ophthalmologists and pediatricians. Moreover, in familial RB, the only death case was intracranial spread death caused by recurrence and progression after interventional therapy, indicating that intraocular surgery and interventional chemotherapy should pay attention to the prevention and treatment of the indication and postoperative prognosis of tumor spread caused by arteriovenous.

In general, the onset of RB in infants was early, and the onset can occur as early as a few days after birth. Recurrence is an independent factor for prognosis of RB infants, which still needs attention after treatment. Although some of the infants had a clear family history, the prognosis was high after comprehensive diagnosis and treatment, reaching 97.7%. Therefore, early diagnosis/screening and comprehensive treatments should be adhered to in order to achieve long-term survival of RB infants.