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- 赵军阳副主任医师
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医院:
首都医科大学附属北京儿童医院
科室:
眼科
- Clinical Presentation and Group Classification of Newly Diagnosed Intraocular Retinoblastoma in China
- 作者:赵军阳|发布时间:2013-06-20|浏览量:1351次
abstract
aim to describe the clinical presentation and group classification of newly diagnosed retinoblastoma patients in china, the world’s most populous country, and to identify future priorities for improving medical care of this disease.北京同仁医院眼肿瘤科赵军阳
methods retrospective review of patients who presented with previously untreated intraocular retinoblastoma at beijing tongren hospital between august 2006 and august 2009. eligible eyes were classified according to the international intraocular retinoblastoma classification (iirc).
results 595 eyes (470 patients) with untreated intraocular retinoblastoma were encountered. most of the patients (84%) were younger than 3 years at diagnosis. the mean age at diagnosis was 23 months. bilateral disease was present in 32% of patients and was diagnosed at a younger mean age (15 months) than mean age at diagnosis in unilateral patients (27 months). leucocoria was the most common presentation (73 %). most (84%) of the 595 eyes presented with advanced (group d or e) intraocular disease.
conclusion in china most patients with intraocular retinoblastoma come to medical attention with advanced intraocular disease. a program of vigorous early detection (educating parents and physicians about early signs of retinoblastoma) widely instituted in china, could improve clinical outcome, lower treatment costs and result in fewer enucleations.
[a1]
china has the world’s largest population currently estimated over 1.3 billion people. using the published chinese births[1] and generally accepted incidence figures from developed countries, a conservative estimate is that each year more than 1100 new cases of retinoblastoma should be expected in china. this number exceeds the combined annual new patient total in north america, europe, russia, japan, australia and new zealand. there are, however, no published incidence or prevalence figures for retinoblastoma in china. this series from a single tertiary center in china does not provide such data. instead, the purpose of this study is to describe the clinical presentation and group classification of the first large intraocular retinoblastoma series from china in an effort to identify where medical resources should be targeted in the future.
the beijing tongren retinoblastoma center began using triple drug systemic chemotherapy with focal consolidation (laser and cryotherapy) for the management of intraocular retinoblastoma in 2006. because we were among the first centers in china to introduce modern treatment protocols, patients traveled to our center from all parts of china for management of their intraocular retinoblastoma. in the first 3 years of operation (2006-2009) we treated more than 600 retinoblastoma patients.
there are two group classifications of intraocular retinoblastoma in current use. the reese-ellsworth (r-e) classification published 40 years ago[2] was based on the expected response from primary external beam radiotherapy (ebrt). the international intraocular retinoblastoma classification (iirc) published in 2005[3] provides classification guidelines based on expected outcomes from initial primary chemotherapy. like most retinoblastoma centers we now use iirc as our standard classification.
methods
the beijing tongren hospital ethics board approved this retrospective chart review in 2008. the authors reviewed all patients treated for intraocular retinoblastoma between august 2006 and august 2009. the families of patients in this study traveled to beijing from all parts of china and most, especially the patients receiving chemotherapy, lived in the city during treatment. tongren hospital requires that all children treated for retinoblastoma should be hospitalized during the administration and recovery from chemotherapy. we reviewed the hospital charts and fundus retcam images (clarity medical systems, inc., dublin, california, usa) for each patient and recorded the following information: detailed history and presenting signs, hospital id, gender, age at first sign of disease noted by the family, age at medical diagnosis, family history, past medical history and the details of the diagnosis and treatment. we calculated the lag time between the first signs of the disease and the medical diagnosis of retinoblastoma.
all patients underwent regular physical examination to rule out other diseases and tumours. both eyes were examined by ocular ultrasound (b or cdi scan); we ordered a ct scan of the head and orbits in all patients and requested an mri if extra-ocular invasion or optic nerve involvement was diagnosed or suspected on ct scan. we obtained parental consent from all parents and measured the intraocular pressure (iop) by tono-pen. the treating ophthalmologist recorded retcam images of anterior chamber and fundus in all eyes. use of the sclera depressor allowed visualization of the retina to the ora serrata in both eyes of all patients. we documented the findings in each eye with colored drawings, indicating the location and size of each tumor, the presence and extent of vitreous or subretinal seeding and subretinal fluid. a pediatric oncologist performed a lumber puncture and bone marrow aspiration in most cases.
the treating ophthalmologists classified all affected eyes according to the international intraocular retinoblastoma classification (iirc) and developed a personalized treatment plan based on group assignments and protocols.
exclusion criteria included (1) suspected optic nerve invasion by any imaging modality at diagnosis, (2) positive cerebrospinal fluid at staging eua proven or suspected, (3) metastatic disease proven or suspected before treatment began (4) any treatment prior to the staging eua in unilateral patients, (5) any chemotherapy prior to staging eua in bilateral patients (prior enucleation of 1 eye only was allowed), (6) parental choice to abandon care, and (7) failure to adhere to follow up schedule.
results
there were 470 children newly diagnosed with retinoblastoma between august 2006 and august 2009 and eligible for this study. of the 470 children, 56% (263) were males and 44% (207) were females; 68% (319) had unilateral and 32% (151) had bilateral disease. there were a total of 595 evaluable eyes in the 470 patients in this series (26 of the 151 bilateral patients had prior enucleation of one eye but were enrolled to evaluate the second untreated eye). since some families refused to acknowledge a family history of retinoblastoma, these data were not considered reliable and were not included.
age at diagnosis
age at diagnosis ranged from 2 weeks to 10.2 years (122 months). the total number of patients with unilateral and bilateral disease as well as the mean and median age at diagnosis is given in table i below.
table i patient laterality vs. mean and median age at diagnosis
| no. of patients | % | mean age at dx in mo. | median age at dx in mo.
|
unilateral | 319 | 68 | 27 | 23 |
bilateral | 151 | 32 | 15 | 13 |
total | 470 | 100 | 23 | 20 |
[a2]
the laterality of patients diagnosed in each year of life if compared in table ii. percentages are rounded to the nearest whole number and may not sum to 100. in this series 84% of patients are diagnosed by the end of the 3rd year of life.
table ii patient age at diagnosis by year and laterality
age at diagnosis in years | total no. | % total | unilateral no, | bilateral no, | % bilateral
|
0-1 | 138 | 29 | 67 | 71 | 51 |
1-2 | 165 | 35 | 112 | 53 | 32 |
2-3 | 91 | 19 | 71 | 20 | 22 |
3-4 | 43 | 9 | 38 | 5 | 12 |
4-5 | 13 | 3 | 11 | 2 | 15 |
5- | 20 | 4 | 20 | 0 | 0 |
total | 470 | 100 | 319 | 151 |
|
presenting signs and lag time
initial presenting signs noticed by family numbers are detailed in table iii. after the four most common signs, all others (tearing, glaucoma, exophthalmus etc.) were lumped together as “other”. the mean age at diagnosis and lag-time (time from first detection of the sign to diagnosis of retinoblastoma by a physician) for each of the initial presenting signs were included.
table iii patient presenting signs by age at diagnosis and lag time
initial sign | no. | (%) | mean age at diagnosis (months) | lag time (weeks) |
leucocoria | 344 | 73 | 21 | 9 |
strabismus | 55 | 12 | 26 | 11 |
poor vision | 25 | 5 | 39 | 9 |
red eye | 23 | 5 | 28 | 8 |
others | 23 | 5 | na | na |
total | 470 | 100 |
|
|
group classification and laterality of intraocular retinoblastoma
of the 151 bilateral retinoblastoma patients, 26 included patients who had one eye removed but no treatment for the remaining eye before they came to our hospital; we did not include those previously enucleated eyes in our data. therefore the numbers of bilaterally affected eyes are 276 rather than 302. all evaluable eyes (595) were classified according to iirc at staging eua. the data are presented in table iv.
table iv group classification of each eye vs. laterality
iirc group | unilateral | bilateral | total | |||
no. | % | no. | % | no. | % | |
a | 0 | 0 | 23 | 8 | 23 | 4 |
b | 2 | 1 | 45 | 16 | 47 | 8 |
c | 3 | 1 | 21 | 8 | 24 | 4 |
d | 90 | 28 | 81 | 29 | 171 | 29 |
e | 224 | 70 | 106 | 38 | 330 | 55 |
|
|
|
|
|
|
|
total | 319 |
| 276 |
| 595 |
|
discussion
in our study 56% of affected patients were males and 44% females. this is the expected gender ratio in china’s 0-4 year-old population[4]. these data are consistent with previous publications showing no significant difference between males and females in retinoblastoma[5-7]
one third of our chinese patients (32%) presented initially with bilateral disease. this percentage is similar to that for bilateral disease reported from great britain (36%)[5] and korea (31%)[8] but different from the lower incidence of bilateral disease reported from developing countries (91%)[9] where unilateral disease predominates. it has been suggested that the higher incidence of unilateral disease in those populations may reflect a maternal diet deficient in fruits and vegetables[10]
mean age at diagnosis of retinoblastoma in our beijing-treated patients is 23 months compared to 24 months in india[11], 28 months in iran[12], 21 months in korea[8] and 26 months in taiwan[13]. among our patients 84% were diagnosed at age 3 years of younger; 4% were older than 5 years. in reports from others 5%[14]-10%[13] of patients were older than 5 years at initial diagnosis.
in our series the mean age at diagnosis was 27 months for unilateral patients and 15 months for bilateral patients. these data are similar to those from india[11] (29 and 19 months), from taiwan[13] (30 and 14 months) and from the us[15] (23 and 13 months). however, in a report from australia[16] 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 disease. the age at diagnosis in unilateral retinoblastoma does not predict rb1 status and should not be used for genetic counseling purposes[17]. it is equally important not to assume that an age at diagnosis of 4 or 5 years means the child has non-heritable unilateral disease. mosaicism is commonly found in older unilaterally affected patients.
our data are consistent with many reports[8,11,15] that leukocoria is the most common presenting sign of this disease. since leukocoria as a presenting sign leads to diagnosis at an earlier mean age than other signs, the significance of its presence should be stressed to parents and physicians in a comprehensive early detection program in china. the fact that strabismus is associated with a relatively late age of diagnosis like means that physicians see strabismus in this age group commonly and are not routinely doing fundus examinations on these children.
the value of group classification of intraocular retinoblastoma is clear when we examine our data. the striking observation is that 501 of 595 (84%) eyes in our study presented with advanced intraocular group d (171 eyes) or group e (330 eyes) disease. only 94 eyes (16%) presented with less advanced group a-c disease. it is the latter 3 groups that are most likely to be cured with chemoreduction and consolidation therapy. we found no group a eyes in unilateral patients and only 5 eyes in groups b and c, most likely, because there is no genetic testing for retinoblastoma parents in china. by contrast, in bilateral patients, 23 eyes were diagnosed in group a; they were found because of the fellow eye contained more advanced retinoblastoma. unilateral patients had worse stage eyes than bilateral patients; among unilateral patients group d and e eyes were diagnosed 98% of the time; for bilateral patients 62% of eyes were grouped as d or e disease.
we compared the iirc group classification of the eyes in our series of chinese patients with reports from korea[8] and iran[12].
table v comparison of group classification of eyes in iran, korea and china
| iran | korea | current series | |||
iirc group | uni no. (%) | bil no. (%) | uni no. (%) | bil no. (%) | uni no. (%) | bil. no. (%) |
a | 0 | 12 (12) | 0 | 6 (14) | 0 | 23 (8) |
b | 4 (7) | 32 (31) | 6 (13) | 13 (30) | 2 (1) | 45 (16) |
c | 5 (9) | 12 (12) | 4 (8) | 2 (5) | 3 (1) | 21 (8) |
d | 23 (43) | 20 (20) | 17 (35) | 13 (30) | 90 (28) | 81 (29) |
e | 22 (41) | 26 (26) | 15 (31) | 6 (14) | 224 (70) | 106 (38) |
u |
|
| 6(13) | 4 (9) |
|
|
total | 54 (100) | 102(100) | 48(100) | 44 (100) | 319 (100) | 276 (100) |
no unilateral group a eye was found in any of the three countries; china had the lowest percentages for combined groups a,b,c and the highest percentage of group d and e eyes, regardless of whether the patients presented with unilateral or bilateral disease. these data provide evidence that patients in china were often in late stage of intraocular disease at diagnosis; enucleation is still the most common choice of treatment for these patients.
if future priorities of the health care system in china focus on education of both the general public and primary care physicians to improve earlier diagnosis of retinoblastoma, treatment outcomes could be improved and the need for enucleation decreased. teaching material could closely follow the policy statement of the american academy of pediatrics[18] to improve the detection of leukocoria. finally these data also support the early referral to ophthalmology when strabismus is present in the early years of life.
references
1 http://www.cpirc.org.cn/en-cpdrc/en-file/endata/en-data-10.html (date accessed june 17, 2010)
2 reese ab, ellsworth rm. the evaluation and current concept of retinoblastoma therapy. trans am acad ophthalmol otolaryngol 1963;67:164-72.
3 al murphree. intraocular retinoblastoma: the case for a new group classification. ophthalmol clin north am 2005;18(1):41-53.
4 http://www.cpirc.org.cn/tjsj/tjsj_cy_detail.asp?id=1199 (date accessed june 17, 2010)
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10 manuela a. orjuela, lina titievsky, xinhua liu, et al. fruit and vegetable intake during pregnancy and risk for development of sporadic retinoblastoma. cancer epidemiol biomarkers prev 2005;14(6):1433-40.
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13 chia-yau chang, tzeon-jye chiou,betau hwang, et al. retinoblastoma in taiwan: survival rate and prognostic factors. jpn j ophthalmol 2006;50:242?9.
14 zeynel a, karcioglu, emad b. et al. retinoblastoma in older children. j of aapos 2002;6(10):26-32.
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16 edwina l berman, craig e donaldson, michael giblin. outcomes in retinoblastoma, 1974?2005: the children’s hospital, westmead. clin and expe ophthalmol 2007;35: 5?12.
17 junyang zhao, jitong shi, la murphree, 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.
18 american academy of pediatrics et al. policy statement. red reflex examination in neonates, infants and children. pediatr 2008;6:1401-04