|Year : 2016 | Volume
| Issue : 2 | Page : 79-84
Retinoblastoma in Mongolia: Clinical characteristics and survival from 1987 to 2014
Tsengelmaa Chuluunbat1, Baasankhuu Jamiyanjav2, Baylag Munkhuu1, Uranchimeg Bazarsad3, Altankhuu Molom1, Ling-Yuh Kao4, Wei-Chi Wu4
1 Department of Ophthalmology, National Center for Maternal and Child Health, Mongolia
2 Department of Ophthalmology, n National University of Medical Sciences, Ulaanbaatar, Mongolia
3 Department of Pathology, National Center of Pathology, Ulaanbaatar, Mongolia
4 Department of Ophthalmology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
|Date of Web Publication||14-May-2016|
Department of Ophthalmology, National Center for Maternal and Child Health, 16060 Khuvisglachdiin Street, Bayangol District, Ulaanbaatar
Source of Support: None, Conflict of Interest: None
Background/Purpose: This study aims to describe the clinical characteristics and treatment outcome of retinoblastoma in Mongolian children.
Methods: Data of all children diagnosed with retinoblastoma at the National Center for Maternal and Child Health of Mongolia from 1987 to January 2014 were reviewed retrospectively. The ICRB classification was used. Survival characteristics of the cohort were analyzed.
Results: Retinoblastoma was diagnosed in 79 eyes of 64 cases during the study period. Median age of diagnosis was 24.5 ± 15.8 months. There were no differences in sex ratio, and 15 cases (23%) were bilateral. Forty-three (67%) patients were from rural areas. The more frequent clinical presentations were leukocoria in 50 (78%) patients, strabismus in 24 (38%) patients, and glaucoma in 21 (33%) patients. Sixty-one (95%) patients were diagnosed with Classification D or worse when presented to us. Due to late diagnosis in the majority of cases, unilateral and bilateral enucleations were performed in 48 (61%) eyes and 24 (30%) eyes, respectively; exenteration was done in three (4%) eyes. Fifty-two (81%) patients received chemotherapy and 13 (8.3%) patients underwent external beam radiation after enucleation. At the time of last follow-up, 52 (81%) patients were alive, five (8%) patients were dead, and seven (11%) patients had lost to follow-up or unknown vital status. The mean follow-up period was 121.5 months (range, 12–360 months). In five cases with immunohistochemistry analysis in the eye specimen, neuron-specific enolase-, Ki-67 protein-, and B-cell lymphoma 2-positive cells were found in all five (100%) cases and Rb protein was detected in three (60%) cases.
Conclusion: Retinoblastoma in Mongolia is frequently diagnosed at late stages and has a poor outcome. These data show the importance of early pediatric eye examinations and better treatment of retino-blastoma in children younger than 3 years in Mongolia.
Keywords: leukocoria, retinoblastoma, Rb protein
|How to cite this article:|
Chuluunbat T, Jamiyanjav B, Munkhuu B, Bazarsad U, Molom A, Kao LY, Wu WC. Retinoblastoma in Mongolia: Clinical characteristics and survival from 1987 to 2014. Taiwan J Ophthalmol 2016;6:79-84
|How to cite this URL:|
Chuluunbat T, Jamiyanjav B, Munkhuu B, Bazarsad U, Molom A, Kao LY, Wu WC. Retinoblastoma in Mongolia: Clinical characteristics and survival from 1987 to 2014. Taiwan J Ophthalmol [serial online] 2016 [cited 2021 Jul 25];6:79-84. Available from: https://www.e-tjo.org/text.asp?2016/6/2/79/204294
| 1. Introduction|| |
Retinoblastoma (RB) is a cancer of the very young; two-thirds are diagnosed before 2 years of age and 95% before 5 years of age. For these reasons, therapeutic approaches need to consider not only the cure of the disease, but also the need to preserve vision with minimal long-term side effects. The estimated incidence of RB is one in 16,000–18,000 births per year worldwide.,
Although RB is very curable when diagnosed early and treated appropriately, the prognosis is poor when the basic elements in diagnosis and treatment are lacking. Survival rates in the developed world are very high, but the rates are much lower in developing nations due to poor medical infrastructure, low alertness of parents as well as pediatricians, and complex and deficient socioeconomic environments.
In Mongolia, only three to four new cases of RB are estimated each year. However, RB is an emerging health issue with problems of late diagnosis and poor visual outcome. Although the country has good systems of registration for reflecting the burden of illness, there is no system for collating such important data. There is a need to review these situations and study survival of patients. This study aims to describe the clinical characteristics and treatment outcome of RB in Mongolian children.
| 2. Methods|| |
Data of all children diagnosed with RB from 1987 to 2014 at the National Center for Maternal and Child Health in Ulaanbaatar, Mongolia were reviewed retrospectively with approval from the Institutional Review Board of Mongolian National University of Medical Science, Ulaanbaatar, Mongolia. The National Center for Maternal and Child Health is the only referral tertiary-care level hospital with a pediatric ophthalmology department. This department is responsible for the whole country’s pediatric eye care services.
The data recorded included jurisdiction, sex, date of birth, age at diagnosis, and information on laterality of tumor, family history of RB, clinical presentations, and mode of treatment. The diagnosis of RB was based on the results of slit-lamp examination, indirect ophthalmoscopy, echography, computerized tomography, or magnetic resonance imaging, depending on the availability of the tools. The International Classification of RB was used.
Enucleation and exenteration combined with systemic chemotherapy were treatments used for these patients. No other treatment modalities such as laser, cryotherapy, selective ophthalmic arterial chemotherapy, or intravitreal chemotherapy were available at our center.
The 1-, 5-, 10-, 15-, and > 25-year survival rates of the cohort were documented and analyzed.
2.1. Histologic and immunohistochemical assessments
With hematoxylin and eosin stain, the extent of tumor in optic nerve, choroid, and anterior chamber was scored and confirmed by pathologists. The immunohistochemistry of RB was performed at Beijing Tongren Hospital, Beijing, China. The expressed protein checked in this study included RB protein, neuron-specific enolase (NSE), s-100 protein, p53, vimentin, bcl-2, ki67, and glial fibrillary acidic protein.
2.2. Statistical analysis
The data of RB patients at our center from 1987 to 2014 were collected and analyzed. The data were presented as descriptive statistics. Patient survival was calculated and analyzed using the Kaplan–Meier method. Data were expressed as mean ± standard deviation.
| 3. Results|| |
Seventy-nine eyes of 64 children were diagnosed with RB at the Department of Pediatric Ophthalmology in the National Center for Maternal and Child Health from January 1987 to January 2014. During this period, there were 2,081,930 newborns in Mongolia according to statistics of health indicators, the Ministry of Health of Mongolia. The incidence of RB was about one in 32,000–33,000 live births. Since the Pediatric Ophthalmology Department of the National Center for Maternal and Child Health treats and takes care of only RB patients in Mongolia, the estimation could represent the whole country’s estimation. The annual RB incidence between 1987 and 2013 varied from zero to 0.98 per 10,000 live births [Figure 1]. Among these 64 patients, 43 (68%) were from rural areas and 21 (32%) from the capital city Ulaanbaatar.
|Figure 1: Annual retinoblastoma incidence per 10,000 live births in Mongolia.|
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3.2. Sex and laterality
There was equal sex distribution in our study; 32 (50%) were boys and 32 (50%) were girls. In location, it was unilateral in 49 (77%) patients and bilateral in 15 (23%) patients. The disease was familial in one (2%) patient and sporadic in 63 (98%) [Table 1].
|Table 1: Characteristics of patients with retinoblastoma (1987 to January 2014, Mongolia).|
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3.3. Age at diagnosis
The age of diagnosis ranged from 1 month to 72 months. The mean age of diagnosis was 24.5 ± 15.8 months. Fifty-three (83%) patients were diagnosed before the age of 3 years. The age at diagnosis was earlier in bilateral cases (mean age, 13.1 ± 12.8 months; range, 1–42 months) than in unilateral cases (mean age, 28.1 ± 15 months; range, 1–72 months) [Table 1].
3.4. Presenting signs and stage
The most prevalent clinical conditions were as follows: leuko-coria in 50 (78%) patients, strabismus in 24 (38%) patients, secondary glaucoma in 21 (33%) patients, hyphema in seven (11%) patients, and orbital cellulitis in seven (11%) patients [Table 1]. Three (5%) patients presented with late-stage, extraocular extension of RB [Figure 2]. Sixty-one (95%) patients were diagnosed with Classification Group D or worse when presented to us. Out of all the eyes, 75 (95%) were diagnosed with Classification Groups D and E, two (2.5%) with Group B, and two (2.5%) with Group C.
|Figure 2: Presenting sign of extraocular extension of retinoblastoma in a Mongolian patient aged 4 years. This patient passed away due to late diagnosis.|
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3.5. Disease detection
Since there were no eye-screening programs in Mongolia, all (100%) patients were referred to ophthalmologists for further evaluation due to various presenting signs mentioned above. Thirty-nine (60%) patients were examined with B scan, 38 (59%) patients with computerized tomography, and 30 (46%) patients with magnetic resonance imaging.
3.6. Spread of tumor
One (2%) case had intracranial extension, three (5%) cases had extraocular extension, and one (2%) case developed orbital recurrence of RB 4 years after initial enucleation [Figure 3]. The other 59 (92%) patients had intraocular RB without any extraocular extension.
|Figure 3: Recurrence of retinoblastoma. (A) Orbital recurrence of retinoblastoma, 4 years after the initial enucleation in a 5-year-old girl. (B) The exenteration specimen was measured to be of 47 × 53 × 39 mm3. The tumor invaded the surrounding connective tissues and muscles. The superior surgical marginwas not tumor free and completely resected. Histopathological examination disclosed an undifferentiated recurrent retinoblastoma. The patient died 5 months after the exenteration.|
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3.7. Secondary tumor and metastasis
None of our cases developed a secondary malignant neoplasm before the cutoff date.
3.8. Mode of treatment
Enucleation of one eye was performed in 48 (61%) eyes, bilateral enucleation in 24 (30%) eyes, and exenteration in three (4%) eyes in the early years of this study. Additional exenteration was done in one eye due to orbital recurrence of RB after 4 years of initial enucleation. Two eyes (2.5%) received local laser treatment in Korea and China, and two (2.5%) cases received systemic intravenous chemotherapy only and the tumors were stable with partial regression [Table 2].
Histopathological examination was performed in 72/79 (91%) eyes after enucleation, and undifferentiated type was found in 34 (47%) eyes. Optic nerve infiltration was present in five (7%) eyes, rosettes (well-differentiated) in four (5.5%) eyes, calcification in four (5.5%) eyes, and necrosis and hemorrhage in one eye each. The reminder 23 (32%) was unclear due to no information on the patient’s chart.
3.10. Immunohistochemical analysis
Enucleated eyes of five children were used for histologic and immunochemical analysis study. Histologically, four tumors (80%) were classified as undifferentiated RB and one (20%) case was well-differentiated RB on the basis of the presence of areas containing Flexner–Wintersteiner rosettes and fleurettes. In five cases with an immunohistochemical analysis of the eye specimen, NSE-, Ki-67 protein-, and B-cell lymphoma 2 (Bcl-2)-pos-itive cells were found in all five (100%) cases, and Rb protein was detected in three (60%) cases. Vimentin was detected in two cases, glial fibrillary acidic protein in three cases, P-53 in two cases, and S-100 in three cases. The results are shown in [Table 3].
|Table 3: Histopathologic and Immunohistochemical results of five patients who have received enucleation.|
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Pathologically, two of five (40%) cases demonstrated nerve involvement, three (60%) cases had retinal pigment epithelium involvement, two (40%) cases had choroid involvement, and two (40%) cases had a calcification. Detailed information of the immu-nohistochemistry is given in [Table 3].
At the time of last follow-up, 52 (81%) patients were alive, five (8%) patients were dead, and seven (11%) patients had been lost to follow-up or unknown vital status. The mean follow-up period was 121.5 months (range, 12–360 months) [Figure 4]. The longest follow-up period was 27 years in a male with bilateral RB, and his son was born with inherited bilateral RB. Enucleation of father’s right eye and left eye was done at the age of 3 months and 44 months, respectively. His son also received bilateral enucle-ation in the right eye at the age of 2 months and in the left eye at the age of 61 months. Five (8%) patients died due to a delayed diagnosis of RB with the presentation of extra extension and intracranial spread.
The 1-, 5-, and 10-year survival rates of the RB cases were 95.3% (61/64), 82.8% (53/64), and 81.1% (52/64), respectively.
| 4. Discussion|| |
Our study shows that the mean age of RB patients at presentation was 24.5 months. The age of diagnosis was earlier in bilateral cases (13.1 months) than in unilateral cases (28.1 months). The common clinical presentations were leukocoria (78%), strabismus (38%), and glaucoma (33%). Sixty-one (95%) patients were diagnosed with Classification D or worse when they were presented to us. Chemotherapy has achieved an important role in the management of intraocular RB. We have been using the standard intravenous chemotherapy (etopside, carboplatin, and vincristine) for intraocular RB since 2012 in Mongolia. Prior to 2012, a different guideline was used for the RB treatment in Mongolia, which included chemotherapy and external beam radiation therapy. There is a need to compare the clinical outcomes between patients diagnosed before 2012 and those diagnosed after 2012. Enucleation is still frequently used in advanced cases, including large tumors, neovascular glaucoma, pars plana tumor seeding, anterior chamber involvement or choroid, optic nerve, or orbital tumor extension with no expectation of useful vision.
Late diagnosis is fairly common in our cases series; destructive procedures such as unilateral and bilateral enucleations and exenteration were performed in 75 (95%) eyes. Globe salvage and preservation of vision were only 5%, much lower than the data reported from developed countries.,,,,, Our data have shown that RB in Mongolia is frequently diagnosed at late stages and the outcomes are poor. These data show that there are room for improvement regarding the awareness of RB and its early treatment in Mongolia.
In studies conducted worldwide, there are no gender differences in RB, the average age at diagnosis is 18 months, and the vast majority become clinically apparent before the age of 3 years.,,,,,In most of the developed countries, patients with bilateral tumors present earlier than those with unilateral involvement., The age at initial diagnosis is: 23 months in China and 84% of them were diagnosed younger than 3 years, 25 months in Brazil, 25 months in Turkey, 23.9 months in India, 28.5 months in Iran, and 18 months in America.,,,,, In our case series, the median age of diagnosis was 24.5 months in Mongolia, similar to prior reports from other countries.
Leukocoria is the most common presenting sign of RB, followed by strabismus, across the world [Table 4]. The figures vary from country to country, and from time to time in the same country. This could probably be due to geographical variation of the disease awareness of the disease among public, availability of medical facilities in that country, and the number of patients examined. The pattern of presentations in our study is consistent with many studies from different parts of the world. In addition to the above Abramson et al reported many uncommon/rare presenting signs such as inflammatory signs, proptosis, orbital cellulitis, hyphema, anisocoria, heterochromia iridis, vitreous hemorrhage, and micro-phthalmos RB. However, proptosis as the presenting sign at the time of diagnosis was reported in high frequency from some of the developing countries such as Nigeria (84.6%), Korea (80%),Pakistan (52.8%), Nepal (44.2%), Thailand (26.7%), and India (25.3%). In our studies, presenting signs of leukocoria, strabismus and secondary glaucoma are more common and were seen in 78% 38%, and 33% of our patients, respectively. Proptosis was a rare presenting sign, seen in only 5% of our patients. Bilateral RB was seen in 23.4% of patients in our case series, which was lower than the figures reported from China (32%), Korea (31.4%), USA (41.5%), Australia (41%), India (37.2%), and Thailand (36.7%).
|Table 4: Comparative frequency of common presenting signs of retinoblastoma in different parts of the world.|
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Saving patients’ life is the primary goal of treatment in RB Enucleation and exenteration are effective methods to achieve that goal. However, now with the introduction of local treatments, such as laser and cryotherapy, intravitreal chemotherapy, chemo-reduction, and selective ophthalmic artery infusion, ocular preservation rates have become much higher. Some patients even enjoy good vision after treatment. Saving eyes and vision requires disease recognition before leukocoria, as demonstrated by better ocular salvage rates among patients who had a positive family history and received clinical surveillance via early and routine dilated fundu-scopic examinations by an ophthalmologist.
Early diagnosis and prompt treatment are important factors in achieving high survival rates. In developing countries, late referral has been implicated as an important factor related to prognosis of RB patients. In our analysis of 79 eyes with RB, globe salvage and preservation of vision was observed in four (5%) eyes, much lower than that for developed countries. As for survival, 53 (83%) patients lived, seven (11%) patients had unknown vital status, and four (6%) patients died. In developing countries, poor education, lower socioeconomic conditions, and inefficient health care systems result in delayed diagnosis and suboptimal care. Furthermore, it is seldom possible to achieve the complexity of multidisciplinary care required. While ocular salvage is a priority in the Western world, death from RB is still a major problem in developing countries.
Worldwide, the incidence of RB is recorded to be about 11 cases per million children younger than 5 years. A more commonly used estimate is one case of RB per 18,000–30,000 live births, depending on the nation. An estimated 250–500 new cases of RB occur in the United States yearly. The average incidence of RB varies by race or geographic location, but the average incidence is approximately one in 15,000 newborns.,,, In our studies, the estimated incidence of RB was about one in 32,000–33,000 live births in Mongolia, which is slightly lower than the internationally reported incidence. This retrospective review may provide limited information on some patients who might have obtained medical help in other countries with no registration in the National Center for Maternal Health, leading to an underestimation of the incidence. However, all pediatric patients who sought medical help in other countries usually first visited the center and were registered here because of reimbursement mechanisms of some medical fees by insurance. Therefore, the chance of being unregistered or not visiting the center is rare.
The incidence of RB is not distributed equally around the world. Whether these geographical variations are due to ethnic or socioeconomic factors is not well known. However, the fact that even in industrialized countries an increased incidence of RB is associated with poverty and low levels of maternal education suggests a role of the environment. In our study, 68% of RB cases were diagnosed from rural areas where the socioeconomic status is lower than the urban areas in Mongolia.
The Rb protein is a tumor suppressor protein, which when inactivated results in the development of RB cancer. In our series, three of five cases (60%) were detected to express Rb protein on immunohistochemical analysis. Sun et al found that NSE is a substance that has been detected in patients with certain tumors, and stained strongly positive in undifferentiated tumor cells and weakly positive in rosettes and fleurettes in most of the cases (21/ 27). In our study, NSE-positive cells were found in all five RB cases, and four of five (80%) cases were classified to have undifferentiated RB cells.
Karim et al revealed that S-100 protein, glial fibrillary acidic protein, vimentin, NSE were positive only for glial elements, and NSE and bcl-2 for almost all tumor cells. These means that the majority of RBs are sporadic and composed of neuron-committed cells. In our study, NSE- and Bcl-2-positive cells were found in all five RB (100%) cases.
In the current study, undifferentiated tumor cells were the most common type of histopathological findings and were positive in 47% of advanced enucleated cases. Kashyap et al identified poorly differentiated RB in 80.3% and well-differentiated RB in 19.7% of 609 eyes enucleated for advanced intraocular RB. Well-differentiated tumors were found to present earlier (median, 1.2 years) than poorly differentiated tumors (median, 2.5 years) and had better prognosis than the undifferentiated ones.
This study has several limitations. The retrospective nature of the study, incomplete clinical data of some patients, and the immunohistochemical analysis data were available only for five patients, which could compromise the study outcome. Computed tomography scanning and magnetic resonance imaging were not introduced until 2001 in Mongolia. Cryotherapy, laser, or trans-pupillary thermal therapy was not available in the whole country. Selective ophthalmic arterial infusion has not yet been introduced at our center. Furthermore, RB is a paramount example of multi-disciplinary care in a pediatric cancer, which is difficult to achieve in a developing country like Mongolia.
In conclusion, patients with RB from rural areas are more frequently diagnosed at late stages in Mongolia. This shows the importance of regular screening programs for early detection of tumors among children aged younger than 3 years. In addition, most Mongolian children with RB usually present with leukocoria noted by parents, rather than being detected by routine pediatric screening via the red reflex test performed by an ophthalmologist. Further efforts are needed to detect early stages of RB and render better treatments to increase survival, ocular preservation, and even functional vision of the patients in Mongolia.
Conflicts of interest: No conflicting relationship exists for any author.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]