|Year : 1994 | Volume
| Issue : 1 | Page : 19-22
New tumours in non-enucleated eyes of bilateral retinoblastoma patients
TK Roysarkar, Jyotirmay Biswas, Lingam Gopal
Medical Research Foundation, Sankara Nethralaya, Madras, India
Medical Research Foundation, 18, College Road, Madras 600 006
Source of Support: None, Conflict of Interest: None
Forty non-enucleated eyes with bilateral retinoblastoma which were treated by external beam radiation therapy (EBRT), transconjunctival cryopexy, and photocoagulation were retrospectively analysed for the age of onset and location of new intraocular tumours. Of these 40 eyes, 9 (22.5%) eyes developed 17 new tumour foci over a mean follow-up of 3 years. The risk of new tumour formation was age-related being 47% in children with age at onset of retinoblastoma less than 1 year compared to 4.4% in older children (P < 0.001). Four eyes (44%) had 2 episodes of tumour formation. All tumour foci developed within 11 months of initial treatment at an average episode interval of 4.0 months. In 89% of cases, new lesions ceased to occur by 18 months of age. Our study clearly shows that EBRT did not prevent development of new lesions. The tumour islands which developed in the peripheral retina in 88% of cases were successfully treated with transconjunctival cryopexy. In 8 cases (89%), the eye could be salvaged. All young bilateral retinoblastoma patients should undergo frequent periodic detailed examination of the retinal periphery with 360 degrees scleral depression to pick up new tumour lesion early and to treat them effectively with simple globe saving methods.
Keywords: Retinoblastoma - New tumours - Radiotherapy - Photocoagulation - Cryopexy
|How to cite this article:|
Roysarkar T K, Biswas J, Gopal L. New tumours in non-enucleated eyes of bilateral retinoblastoma patients. Indian J Ophthalmol 1994;42:19-22
Bilateral retinoblastoma is thought to be due to germinal mutation. in the retinoblastoma gene.  On the basis of mathematical modelling, Knudson postulated that two genetic events are necessary for retinoblastoma to occur,  the molecular basis for which has been confirmed by experiments on the 13th chromosome. The first mutation occurs in either a germinal cell (in potentially heritable cases) or in a retinal cell (in sporadic somatic patients). The second mutation always occurs in a retinal cell. Each of these mutations occur with a frequency of 10 -7 per year.  In germinal mutation every nucleated cell has one genetic alteration; only one additional mutation has to occur in a retinal cell for a retinoblastoma to develop. Hence, the occurrence of multiple bilateral retinoblastomas in germinal mutation.' For a tumour to occur in a somatic sporadic case, both types of mutations must occur in the same retinal cell, a statistically unlikely event, explaining the solitary nature of the tumour.
Since in bilateral retinoblastomas, all retinal cells are potentially "primed" with a genetic mutation having already taken place in all retinal cells, it is reasonable to presume that multiple tumours may develop early in life and continue to occur over a period of time in both the eyes. Generally, in bilateral tumours, the eye which leads to the detection of the tumour is far advanced and usually needs enucleation, while the fellow eye has a more favourable prognosis and is amenable to conservative treatment 4 To investigate the time course and location of new intraocular tumours that develop in such nonenucleated eyes of bilateral cases, this retrospective study was carried out.
| Materials and methods|| |
The records of all patients with bilateral retinoblastoma were reviewed from 1982 at our institute. Patients with one eye enucleated at our institute or elsewhere, having visible fundal lesions for documentation in the non-enucleated eye, and at least six months of follow-up were included in the study. Charts of all eligible cases were scrutinized and the information noted included age at presentation, duration of symptoms, age at onset of retinoblastoma, sex, laterality, family history of retinoblastoma, date of enucleation, fellow eye status, nature of treatment to fellow eye, date of treatment, worsening or new occurrence of lesions, location and size of new tumours, time interval for occurrence of new lesion, number of recurrences, treatment to new lesions, final result, and total duration of follow-up. All available data were tabulated and analysed.
Statistical analysis was done by chi-square test, Student's t-test and paired t-test.
| Results|| |
A total of 152 retinoblastoma patients were seen at our institute from 1982 to 1992, of which 71 (49%) were found to be bilateral. Forty patients satisfied the inclusion criteria and formed the basis of this study.
The mean age of onset of retinoblastoma in these 40 patients was 16.87 months, of which 14 'patients had onset of retinoblastoma at or after 2 years of age. Twenty nine (72.5% ) patients were male and 11 (27.5%) were female. In 23 (57.5%) patients, the right eye was enucleated while 17 (42.5%) patients had the left eye enucleated. Two (5%) patients gave positive family history of retinoblastoma. The conservative treatment given to these 40 eyes at or soon after enucleation of the fellow eye is shown in [Table - 1].
A temporal approach was used for external beam radiation therapy with a total dose of 4500 rads given in fractions. Photocoagulation was applied by xenon photocoagulator and argon laser. In addition to the slit-lamp delivery system, indirect laser delivery using the binocular indirect ophthalmoscope was also used. Transconjunctival cryopexy using the triple freeze thaw technique was utilized wherever applicable.
Of the 40 patients who received conservative therapy, cure could be achieved in 24 patients (60%) as seen over a mean follow-up of three years. In 16 patients, however, the progression of disease could not be controlled; 9 (22.5%) developed new sites of intraocular tumour formation, 4 (10%) showed lack of response to initial therapy, and 3 (7.5%) developed vitreous seedlings despite therapy. Fifteen of the 16 patients (94%) who showed no response to initial therapy were males as compared to 29 of the 40 patients (73%) in the study. This difference was found to be significant (p<0.05). Of the 9 patients who showed new sites of retinoblastoma formation, 8 were males. This ratio of 89% was not found to be significantly different from the study population.
In the nine patients who showed new sites of tumour formation, the mean age at onset of retinoblastoma was 7.05 months. Barring one patient whose age at onset of retinoblastoma was 3 years, the rest had an average of 3.62 months. The difference between the mean ages at onset of retinoblastoma in the group showing occurrence of new lesions (7.05 months) and the study population (16.87 months) was found to be significant (p<0.05). Fortyseven percent of children less than one year of age developed new lesions as compared to 4.4% of children older than one year (P<0.001).
At the time of enucleation, 8 of the 9 patients who subsequently developed new tumour foci, had a total of 13 tumour islands in their non-enucleated eyes, while one patient did not have any tumour mass. Among those 8 eyes, 3 eyes (33%) received external beam radiation, 2 eyes (22%) received transconjunctival cryopexy, and 3 (33%) received photocoagulation, at or soon after enucleation of the fellow eye. Thus, 3 of the 14 eyes (21 %) which received EBRT developed new tumours and 5 of the 25 eyes (20%) which received local therapy in the form of photocoagulation, cryopexy, or both, developed new tumours.
Four patients had 2 recurrent episodes of tumour formation, while 5 patients had new tumour formation only once, giving rise to 13 episodes of tumour formation. A total of 17 new tumours were documented in these episodes, with an average of 2 new lesions per eye, increasing the total number of tumour foci to 30 in 9 patients (3.3 lesions per eye).
The temporal characteristics of the new lesions are depicted in [Table - 2]. The time interval between the initial detection of tumour (which was at the time of enucleation of the fellow eye) and the subsequent occurrence of new lesions was considered as episode interval (1) and the time span between the first and second episode of new lesion formation was taken to be episode interval(2). The average episode interval(1) was 4.4 months and average episode interval for both (1) and (2) was 4 months. The mean time span between enucleation and the last documented tumour formation for the nine patients was 5.9 months. No patient developed any tumour masses 11 months after enucleation. The average age at which the new lesions developed in these patients was 12.36 months. In 8 of the 9 patients new lesions ceased to occur after 17 months of age.
Of 17 foci of new tumour formation, 15 (88%) were in the periphery and 2 (12%) just posterior to equator. All the five locally treated eyes developed multiple peripheral tumours. Of the three eyes treated with EBRT, two eyes had peripheral lesions and the remaining eye developed a solitary posterior tumour. The second posterior lesion occurred in a normal untreated eye which was kept on observation. It was also single in nature. All new lesions were located away from the previous foci. No patients developed new lesions in the posterior pole or macula. The peripheral lesions averaged 1 DD in size with minimal elevation. Both the post-equatorial lesions were slightly larger in size with an average diameter of 2.5 DD.
All (100%) peripheral lesions were successfully treated with cryo therapy and had no recurrence on follow-up. Of the two post-equatorial lesions, one which developed in an otherwise untreated normal fundus required external beam radiation therapy and did well on follow-up. The second patient was advised enucleation since the new lesion developed posteriorly and the two original foci did not regress despite radiotherapy. Sixteen of 17 new lesions were successfully treated and there were no recurrences when seen over an average follow-up of 3 years. Totally, 27 of 30 lesions (89%) in the non-enucleated eyes of patients showing new islands of tumour formation could be treated by conservative methods of transconjunctival cryopexy, photocoagulation and EBRT.
| Discussion|| |
Retinoblastoma can occur in two forms - unilateral or bilateral. The incidence of bilateral tumours has been reported to be 25-30%.  Our incidence of 50% bilateral tumour reflects the high percentage of referrals. Unilateral retinoblastomas are due to sporadic mutations, whereas all bilateral retinoblastomas are due to germinal mutations. The bilateral form of the disease is hereditary. With an initial germinal mutation, all retinal cells are at risk and so it is natural for the neoplasm to be multicentric and expressed bilaterally in early life.
The average age at diagnosis for bilateral retinoblastoma is 12 months. In our series, we found the mean age in bilateral retinoblastomas to be slightly higher at 16.87 months, similar to other reported Indian studies 6 We found that those patients who developed new retinoblastoma (RB) lesions following conservative treatment had a much younger mean age of onset of RB of 7.05 months, significantly different from the rest of the RB population. Excluding one case with a delayed onset of 3 years of age, the mean age of onset of retinoblastoma in rest of the patients was 3.6 months with a range from 0.5 to 8.5 months. This is similar to an earlier reported series .  We found that children whose age at onset of retinoblastoma was less than 1 year, had 14 times more risk of developing new intraocular tumours as compared to older children.
Though no clear sex predilection has been documented for RB cases, we found a significant male predominance in patients who had worsening of the disease despite therapy. However, this predominance was not statistically significant when only cases with new foci of tumours were considered.
A mean number of 3.3 tumours in single nonenucleated eyes after the formation of new islands of tumour lesions was found. Occurrence of new tumours indicate previously undetected independent areas of tumour. We found 22.5% of patients to develop new intraocular sites of tumour formation, similar to the reported frequency. 
Twenty-one percent of patients who received EBRT and 20% of patients who received local treatment in the form of photocoagulation, cryopexy, or both, developed new tumours in our series. This is similar to the Essen study where the risk of new tumour development was found to be 27% with EBRT and 20% with local methods of treatment. 
Eighty-three percent of lesions developed in the periphery and 17% developed posterior to equator. No new tumours appeared in the macula or in the posterior pole. It has been reported that tumour sites at the periphery result from migration of tumour cells in the subretinal space to the ora serrata where they grow.  However, the more plausible explanation for retinoblastoma occurrence in the far periphery is given by the fact that peripheral retina differentiates last and hence, new tumours are expected to arise here during the initial years of life before complete differentiation of the retina has taken place.  A third factor that comes into play is the development of new lesions in the shadow zone of the anterior retina after treatment with EBRT. With almost all techniques including the temporal approach, an underdosage results in a higher incidence of new tumours anterior to the equator.
There were 13 episodes of new tumour formation in 9 cases. The average time interval between the initiation of treatment and development of subsequent new tumour was found to be 4.4 months, with a range from 1.5 to 9 months. This is similar to the report of the Essen series where the median latency between the start of treatment and the appearance of a new tumour was 4 months with local treatment- and 9 months with EBRT (P=0.02).  The average age at which the lesions were first noted in our series was 12.36 months. In eight out of nine patients no lesions developed after the age of 17 months as compared to 25 months being the cessation age, as reported by Stallard. 
The treatment of new tumours is essentially by cryotherapy. In our series, we found 88% of new tumours to be peripheral and accessible to cryotherapy. All (100%) lesions were cured at one sitting of cryotherapy.
Since the tumour is in transparent media and usually is entirely visible with the indirect ophthalmoscope, in most instances, 6 months is adequate to ascertain its growth.  Though 5 years has been generally considered the minimum period for a cancer 'cure', it is felt that chances of resumed growth is extremely remote after 3 years in retinoblastoma patients. Recurrence of a treated retinoblastoma or development of new tumours usually happens within 6 months of the initial therapy.  Development of a new tumour more than one year after primary treatment is extremely rare. [13 ] We followed up our patients for an average period of 3 years following enucleation. No patient developed any fresh lesions, 9 months after initial therapy.
Serial ocular examination with fully dilated pupils by using binocular indirect ophthalmoscope and scleral depression of the retinal periphery, following diagnosis and treatment of retinoblastoma is mandatory. A specific follow-up schedule of examination under anaesthesia at three 4 weekly intervals after initial treatment [14 ] followed by every 3 months for the first year, every 4 months for the next year and then every 6 months for the following 2 years has been recommended. Early follow-up schedules are especially important in cases where photocoagulation and cryotherapy have been used exclusively as a primary local treatment modality, as new tumours tend to occur earlier in these cases .  The examination schedule must be strictly followed not only in all cases of bilateral retinoblastomas but also in unilateral cases as 19 % of all unilateral cases are known to develop retinoblastoma in the second eye.  One patient in our series who developed a tumour focus in the normal fellow eye one month after enucleation is exemplary of this fact.
| References|| |
Shields JA, Shields CL. Intraocular Tumours. A Text and Atlas. WB Saunders, Philadelphia. 1992; pp.306.
Knudson AG. Mutation and Cancer. A statistical study of retinoblastoma. Proc Natl Acad Sci USA. 68:820823, 1971.
Shields JA, Shields CL. Intraocular Tumours. A Text and Atlas. WB Saunders, Philadelphia. 1992; pp.334.
Duane TD. Clinical Ophthalmology. Harper & Row, Maryland. 1983; Vol.3, pp.13.
Rubenfield M, Abraham DH, Ellsworth RH, and Kitchin FD. Unilateral vs bilateral retinoblastoma - Correlations between age at diagnosis and stage of ocular disease. Ophthalmology. 93:1016-1019, 1986.
Dhir SP, Jain IS, Das GR, Gupta HD. Survival of retinoblastoma cases in North India. Ind J Ophthalmol. 28:97-100, 1980.
Stallard HB. Multiple islands of retinoblastoma - Incidence rate and time span of appearance. Br J Ophthalmol. 39:241; 1955.
Bedford MA, Bedotto C, MacFaul PA. Retinoblastoma - A Study of 139 cases. Br J Ophthalmol. 55, 1971.
Messmer EP, Sanermein W, Heinrich T. New and recurrent tumour foci following local treatment as well as external beam radiation in eyes of patients with hereditary retinoblastoma. Graefes Arch Clin Exp Ophthalmol. 228: 426-431, 1990.
Reese AB. Tumours of the eye. 3rd ed. Harper and Row, Maryland. 1976; pp.105.
Duane TD. Clinical Ophthalmology. Harper and Row, Maryland. 1983; Vol.3, pp.4.
Reese AB. Tumours of the eye.
3rd ed. Harper and Row, Maryland. 1976; pp.120.
Char DH. Clinical Ocular Oncology. Churchill Livingstone, New York. 1989; pp.219.
Messmer EP. In Coagulation Treatment and Surgery in Retinoblastoma. Radiotherapy of Intraocular and Orbital Tumours. ed. Alberti WE, Sagerman RH. SpringerVerlag, Berlin, 1993.
Harley RD. Paediatric Ophthalmology. WB Saunders, Philadelphia. 2nd Ed. 1983; pp.1227.
[Table - 1], [Table - 2]