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Clinical presentation and group classification of newly diagnosed intraocular retinoblastoma in China
  1. Junyang Zhao,
  2. Songfeng Li,
  3. Jitong Shi,
  4. Ningli Wang
  1. Beijing Tongren Eye Centre, Beijing Ophthalmology & Visual Sciences Key Lab, Tongren Hospital, Capital Medical University, Beijing, PR China
  1. Correspondence to Dr Junyang Zhao, 7B Ward, No 2, Xihuan South Road, Beijing Economic-Technological Development Area, Beijing 100176, PR China; zhaojunyang{at}gmail.com

Abstract

Aim To describe the clinical presentation and group classification of newly diagnosed retinoblastoma patients in China, and to identify future priorities for improving the medical care of this disease.

Methods The retrospective review included all patients who presented with previously untreated intraocular retinoblastoma at Beijing Tongren Hospital between August 2006 and August 2009. The clinical charts were reviewed and fundus images taken for all patients were analysed. The tumours were classified according to the International Intraocular Retinoblastoma Classification.

Results The study included 595 eyes (470 patients) with untreated retinoblastoma. The mean age at diagnosis was 23 months, with 84% of the patients being younger than 3 years at the time of diagnosis. Bilateral retinoblastoma was present in 150 (32%) of the patients. Bilateral retinoblastoma as compared with unilateral retinoblastoma was diagnosed at a significantly (p<0.001) younger mean age (15 months vs 27 months). Leucocoria was the most common leading sign (73% of patients). The vast majority of eyes (501/595 or 84%) presented with an advanced stage of the tumour (Group D or E of International Intraocular Retinoblastoma Classification).

Conclusion In China, diagnosis of retinoblastoma occurs at a relatively advanced clinical stage of the disease. An intensified programme for earlier detection of retinoblastoma including educating parents and physicians may be warranted to improve clinical outcome with fewer enucleations.

  • Retinoblastoma
  • intraocular tumour
  • retinoblastoma classification
  • paediatric oncology
  • retina
  • epidemiology
  • neoplasia
  • child health (paediatrics)

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The most frequent primary intraocular cancer in children is the retinoblastoma, which is rapidly gaining in importance, in particular in Asia.1–8 The survival of the children is markedly dependent on an early diagnosis shortly after the detection of symptoms such as leucocoria or squinting. The delay in the clinical diagnosis may depend on the medical infrastructure of the country and on the alertness of the parents as well as of the paediatricians. Almost no information has been available so far on the clinical presentation and clinical signs and diagnosis of retinoblastomas of children in China, except of a recent retrospective ophthalmic histopathological investigation.9 10 China, however, is the nation with the worldwide largest population, with an estimated number of 1100 new cases of retinoblastoma each year (using the published Chinese birth rate11 and prevalence figures from Western countries).1 Until recently, retinoblastoma tumours in China were treated by enucleation without additional chemotherapy, so that the estimated survival rate was only at 30–50%, compared with about 90% in Western countries.1–7 In an attempt to increase the survival rate and to decrease the enucleation rate in China, it may be important to first know better the clinical signs at presentation of the children and the clinical staging of the tumours. We, therefore, conducted our study to analyse the clinical features and the clinical staging of retinoblastoma tumours of children treated in the Beijing Tongren Hospital in the study period from August 2006 and August 2009.

Methods

The retrospective study included all patients presenting and treated in the Beijing Tongren Hospital in the study period August 2006 and August 2009 with the newly diagnosis of retinoblastoma. The Beijing Tongren Hospital Ethics Board approved the investigation. The patients came from all provinces of China. The clinical charts of the patients were reviewed, and data were collected on a detailed history and presenting signs, gender, age at first sign of symptoms, age at medical diagnosis, family history, past medical history, and details of the diagnosis and treatment. We calculated the delay in treatment as the period between the time when the first signs of the disease were noted and the time when the medical diagnosis of retinoblastoma was made. All patients underwent a physical examination to rule out other diseases and tumours. Both eyes and orbits were examined by ultrasound. The intraocular pressure was measured, and photographs of the anterior chamber and fundus were taken for all children (RetCam camera, Clarity Medical Systems, Dublin, California). Use of a sclera depressor allowed visualisation of the retina up to the ora serrata in both eyes of all patients. In addition to the fundus photographs, we documented the ophthalmoscopic findings in each eye with drawings, indicating the location and size of the tumours, and the presence and extent of vitreous or subretinal seeding and subretinal fluid. A paediatric oncologist performed a lumbar puncture and bone marrow aspiration for most patients. A computer tomographic scan of the head and orbit was performed for all patients. Magnetic resonance imaging was carried out if an extraocular extension or an optic nerve involvement by the tumour was suspected on the computerised tomographic scans. The treating ophthalmologist classified all affected eyes according to the International Intraocular Retinoblastoma Classification (IIRC) and developed an individualised treatment plan based on Group assignments and protocols.

Results

In the study period between August 2006 and August 2009, 470 children (595 eyes) were newly diagnosed as having retinoblastoma and were eligible for our study. Of the 470 children, 263 (56%) were boys. The retinoblastoma occurred unilaterally in 319 (68%) children, and the tumour occurred bilaterally in 151 (32%) children. Twenty-six of these 151 children with bilateral retinoblastoma had previously undergone enucleation of one eye. Since some families were unable to give reliable data on a family history of retinoblastoma, this parameter was not included into the study.

Age at presentation

In the whole study population, the age at diagnosis ranged from 2 weeks to 10.2 years with a mean age of 23 months (median: 20 months). The age at diagnosis was significantly (p<0.001) higher for patients with unilateral retinoblastomas (mean: 27 month; median: 23 month) than for patients with bilateral tumours (mean: 15 months; median: 13 months) (table 1). Taking the whole study population, 84% of patients were diagnosed by the end of the third year of life.

Table 1

Age of patients at the time of diagnosis of untreated retinoblastoma at the Beijing Tongren hospital from August 2006 and August 2009, stratified by age and laterality

Presenting signs and lag time

The presenting sign most often noticed by family numbers was leucocoria in 344 (73%) patients followed by strabismus in 55 (12%) children and vision disability in 25 (5%) patients (table 2). The mean age at diagnosis and the delay in the diagnosis of the tumours did not differ significantly between the various presenting signs (table 2).

Table 2

Presenting symptoms of patients at the time of diagnosis of untreated retinoblastoma at the Beijing Tongren Hospital in the study period from August 2006 and August 2009, stratified by age at diagnosis and time elapsed since first symptoms were noticed

Group classification and laterality of intraocular retinoblastoma

All eyes included in the study were classified according to the International Intraocular Retinoblastoma Classification. Out of the 595 eyes, 330 (55%) were classified as Group E, and 171 (29%) eyes were classified as group D (table 3)

Table 3

Classification (International Intraocular Retinoblastoma Classification) of retinoblastoma treated at the Beijing Tongren Hospital in the study period from August 2006 and August 2009, stratified by laterality

Discussion

The Retinoblastoma Centre in the Beijing Tongren hospital was inaugurated in August 2006. Since then, modern triple drug chemotherapy with focal consolidation (laser and cryotherapy) for the management of intraocular retinoblastoma was performed with more than 600 children treated until August 2009. Since the Tongren hospital was among the first centres in China to introduce the modern chemotherapy of retinoblastomas, patients travelled from all provinces of China to Beijing for treatment of their retinoblastoma. The present study which summarised these patient's clinical features found that the vast majority of eyes (501/595 or 84%) presented with an advanced stage of the tumour (Group D or E of the International Intraocular Retinoblastoma Classification). Only 94 (16%) eyes presented with less advanced disease stages, in which the prognosis after chemoreduction and consolidation therapy is considerably higher than in the groups D and E.1 In our study, we did not find any eyes of Group A in patients with a unilateral retinoblastoma and only five eyes in Groups B and C. In contrast, in patients with bilateral tumours, 23 eyes were diagnosed in Group A. The tumours in these eyes were probably found at a relatively low stage of the disease, since the fellow eye showed the more advanced retinoblastoma. Interestingly, patients with unilateral tumours as compared with patients with bilateral retinoblastomas had on average a higher tumour stage. In the group of patients with unilateral tumours, 98% of the eyes belonged to Group D and E, while in the group of patients with bilateral retinoblastomas, 62% of eyes were classified as Group D or E (table 3).

Comparison of the staging results of our study with the findings of studies from Korea and Iran shows that the patients from China had the lowest percentages for combined Groups A, B and C, and the highest percentage for Groups D and E, regardless of whether the patients presented with unilateral or bilateral disease (table 4).12 13 The results of our study may suggest that children in China were often diagnosed as having retinoblastoma in a relatively advanced stage of the disease. This may be due to several reasons. Some physicians, primarily seeing the children, in particular in rural and mountainous regions, may not be familiar with the clinical features of retinoblastoma and may delay the diagnosis. Parents may not have recognised that any abnormality in the pupillary reflex could be a serious disease, and only when the symptoms deteriorated did they take their children to the hospital. Some physicians may not have examined the ocular fundus when the children presented with strabismus. And last but not least, economic reasons or infrastructural problems in the healthcare system may have contributed to the situation. These thoughts may imply that future developments in the Chinese healthcare system may focus on the education of the general public and the primary care physicians to improve the diagnosis of retinoblastoma, so that children arrive at the treating hospital at an earlier stage of the disease. These teaching efforts could closely follow the policy statement of the American Academy of Paediatrics, to improve the detection of leucocoria.14

Table 4

Comparison of classification (International Intraocular Retinoblastoma Classification) of eyes with retinoblastoma in Iran, Korea and China

In our study, 56% of the patients were boys. This is the expected gender ratio in Chinese population in the age group of 0–4 years.15 These data are consistent with previous publications showing no significant difference between males and females in retinoblastoma.16–18 One-third of our patients (32%) initially presented with bilateral tumours. This percentage is similar to that for bilateral retinoblastomas reported from the UK (36%) and Korea (31%),12 16 and it is higher than the figure of 9% from developing countries such as Nepal,13 where unilateral tumours dominated. It has been suggested that the higher incidence of unilateral disease in those populations may reflect a maternal diet deficient in fruits and vegetables.19

The mean age at diagnosis of retinoblastoma in our study was 23 months, which was similar to the figure of 24 months from India,20 28 months from Iran,21 21 months from Korea12 and 26 months in Taiwan.2 In our study, 84% of the patients were diagnosed at an age of 3 years or less, while 4% of the children were older than 5 years at the time of diagnosis. The latter figure is less than the figure of 5% to 10% as reported in previous studies.2 22 In our series, the mean age at diagnosis was 27 months for patients with unilateral tumours and 15 months for patients with bilateral tumours. These data are similar to those from India (29 and 19 months),20 Taiwan (30 and 14 months),2 and the USA (23 and 13 months).23 In contrast, in a previous report from Australia,24 patients were diagnosed at an earlier age (21 months for unilateral and 5 months for bilateral disease). This may be attributed to the presence of a smaller population with better access to medical care in Australia or, in the case of the strikingly low age at diagnosis for bilateral disease, to greater family awareness of the disease risk in the case of a positive family history of retinoblastoma.

It is of interest to note that almost half (51%) of our patients diagnosed below 1 year of age had unilateral tumours. For these patients (figure 1), tight follow-up examinations for the fellow eye may be necessary and important, since tumours may still develop in the fellow during the follow-up. The low age at the diagnosis of these patients with unilateral retinoblastoma may not lead to assumption of an RB1 status and should not be used for genetic counselling purposes (Zhao J, Shi J, Murphree LA, et al. Older age at diagnosis in unilateral sporadic retinoblastoma patients does not eliminate individual risk for new germ line mutations. 2009 AAO Poster: PO507). It is equally important not to assume that an age at diagnosis of 4 or 5 years means that the child has non-heritable unilateral disease. Mosaicism can be found in older unilaterally affected patients.

Figure 1

Histogram showing the distribution of unilateral versus bilateral retinoblastoma, treated at the beijing tongren hospital in the study period from August 2006 to August 2009, stratified by age at diagnosis

These data are consistent with many reports in that leucocoria was the most common presenting sign of retinoblastoma.12 20 23 Since leucocoria as a presenting sign leads to diagnosis at an earlier mean age than other signs, the significance of its presence should be taught to parents and physicians in a comprehensive early detection programme in China. The delay in the diagnosis of retinoblastoma with leucocoria as the presenting sign was 9 weeks and for strabismus 11 weeks (table 2). The finding that strabismus was associated with a relatively late age at the time of diagnosis may indicate that physicians relatively often diagnose strabismus in that age group and may not routinely perform a fundus examination in these children. This may imply the recommendation that all children with strabismus should have a careful ophthalmoscopic examination.

Potential limitations of our study should be mentioned. First, it was a retrospective hospital-based study with the possibility of a major bias by the referral of patients. The Beijing Tongren hospital, is, however, well known throughout all China, and parents of a child with a rare and life-threatening disease will not avoid major obstacles to find the best possible treatment for the child. Correspondingly, the patients in our study came from almost all provinces of China and may thus partially represent the situation in the country. Second, due to the profound and fast economic development of China, also the medical system has started to undergo major changes. The figures in our study on patients treated in the period from 2006 to 2009 may, therefore, no longer be valid in the near future.

In summary, the diagnosis of retinoblastoma occurs at a relatively advanced clinical stage of the disease in China. An intensified programme for earlier detection of retinoblastoma including educating parents and physicians may be warranted to improve clinical outcome with fewer enucleations.

Acknowledgments

L Murphree and J Jonas revised this paper.

References

Footnotes

  • Competing interests None.

  • Ethics approval Ethics approval was provided by the Beijing Tongren Hospital Ethics Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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