Demographic characterization of the Portuguese population
During the 5 years of study period, 28 children were diagnosed with retinoblastoma at our center. Fifteen children were included in the hereditary retinoblastoma group, from which 12 presented with bilateral retinoblastoma and 3 were unilateral but had a positive genetic test for a RB1 pathogenic variant (2 of these had known family history of retinoblastoma).
The overall mean age at diagnosis was 13.6 ± 11.1 months. Hereditary retinoblastomas were diagnosed slightly precociously at 9.6 ± 6.3 months, compared to non-hereditary retinoblastomas in which the mean age at diagnosis was 18.3 ± 13.6 months (p=0.065). A familial history of retinoblastoma was found in only 4 (14.3%) of the cases. Full demographic characteristics of the included children can be found in table 1.
Table 1 Demographic and clinical characterization of the Portuguese population diagnosed with Rb
|
Non-Hereditary Rb
n=13
|
Hereditary Rb
n=15
|
p-value
|
Total
N=28
|
Males (%)
|
6 (46.2)
|
8 (53.3)
|
0.7051
|
14 (50)
|
Age at diagnosis, mean (sd)
|
18.31 (13.63)
|
9.60 (6.32)
|
0.0652
|
13.64 (11.08)
|
Family History
|
-
|
4 (26.7)
|
-
|
4 (14.3)
|
Bilateral (%)
|
-
|
12 (80.0)
|
-
|
12 (42.9)
|
Pineal (%)
|
-
|
0 (0)
|
-
|
0 (0)
|
Presenting symptom (%)
|
|
|
|
|
Leukocoria
|
11 (84.6)
|
9 (60.0)
|
0.1501
|
20 (71.4)
|
Strabismus
|
6 (46.2)
|
6 (40.0)
|
0.7431
|
12 (42.9)
|
Buphthalmus
|
0 (0)
|
2 (13.3)
|
0.1721
|
2 (7.1)
|
Cellulitis
|
0 (0)
|
2 (13.3)
|
0.1721
|
2 (7.1)
|
No symptoms
|
0 (0)
|
2 (13.3)
|
0.1721
|
2 (7.1)
|
Geographic distribution
|
|
|
0.0611
|
|
North
|
0
|
5
|
-
|
5
|
Center
|
1
|
3
|
-
|
4
|
South
|
11
|
6
|
-
|
17
|
Islands
|
1
|
1
|
-
|
2
|
A pathogenic mutation in the RB1 gene was found in 13 (46.4%) of the children. The mutations found in our cohort are represented in table 2. In two children with bilateral disease, both with a negative familial history, a mutation for the RB1 gene could not be found in the standard genetic testing and further testing is being performed using the pathology specimen.
Table 2 Mutations found in genetic testing
RB1 mutations
|
c.1467C>A p.(Cys489Ter)
c.1072C>T p.(Arg358Ter)
c.1654C>T p.(Arg552Ter)
c.297G>A p.(Trp99Ter)
c.751C>T p.(Arg251Ter)
c.1450_1451del p.(Met484Valfs*8)
c.1128-2A>G p.?
c.(?_-1)_(1969+1_1961-1)
c.106del p.(Asp36Thrfs*29)
c.1947del p.(Tyr651Ilefs*7)
c.1023_1024del p.(Lys341Asnfs*5)
del RB1
|
Considering the geographic distribution of the included cases, 5 children were born in the north of the country, 4 in the center, 17 in the south and 2 in the Portuguese islands, but the age at diagnosis was not significantly different between the regions (11.9 months in the north, 16.5 months in the center, 14.76 in the south and 14.75 in the islands, p=0.859).
Clinical characterization at Presentation and ocular and global survival analysis
At the time of the first observation at our center, we found that 71.4% of the cases had been referred due to leukocoria, the most common initial presentation symptom in our population, followed by strabismus that was present in 42.9% of the included participants (table 1). Four children, all included in the hereditary retinoblastoma group, presented with advanced intraocular retinoblastoma manifesting with cellulitis (n=2) and buphthalmus (n=2). During the study inclusion period, no cases of extra-ocular retinoblastoma or pineal involvement were referred to our center. Two children with a previously known positive family history of retinoblastoma and a prenatal diagnosis of retinoblastoma were referred during their first months of life while still asymptomatic.
Considering the Classification of the tumours according to the ICRB (table 3), non-hereditable hereditary retinoblastomas were referred to our center 2 (15.4%) in an early stage (group C) and the remaining in advanced intraocular stages (8 [61.5%] group D and 3 [23.1%] group E). Considering the hereditable retinoblastomas (table 3), 13 (86.7%) presented with one of the eyes with advanced intraocular retinoblastoma (group D or E), from which 2 (13.3%) presented group D or E lesions in both eyes. In this group, 3 patients presented with unilateral retinoblastoma, staged as follows: 1 group A and 2 group D.
During the study period, 14 children had one eye enucleated due to retinoblastoma. In the non-hereditable retinoblastoma group 6 (46.2%) of the affected eyes were preserved. In the hereditary retinoblastoma group, 8 (53.3%) children had both eyes preserved and 7 (46.7%) children had one eye preserved. No deaths were registered during the study period.
Table 3 Classification of non-hereditable and hereditable retinoblastoma according to ICRB
|
Non-hereditable Rb
n=13
|
Hereditable Rb
n=15
|
|
|
A
|
C
|
D
|
E
|
Total
|
No Rb
|
-
|
1 (6.7)
|
-
|
2 (13.3)
|
-
|
3 (20)
|
A
|
-
|
-
|
1 (6.7)
|
1 (6.7)
|
-
|
2 (13.3)
|
B
|
-
|
-
|
-
|
2 (13.3)
|
2 (13.3)
|
4 (26.7)
|
C
|
2 (15.4)
|
-
|
-
|
2 (13.3)
|
2 (13.3)
|
4 (26.7)
|
D
|
8 (61.5)
|
-
|
-
|
1 (6.7)
|
1 (6.7)
|
2 (13.3)
|
E
|
3 (23.1)
|
-
|
-
|
-
|
-
|
-
|
Total
|
13 (100)
|
1 (6.7)
|
1 (6.7)
|
8 (53.3)
|
5 (33.3)
|
15 (100)
|
Retinoblastoma incidence in the Portuguese population
Considering the standard incidence analysis, we registered a retinoblastoma annual incidence rate of 1.05 per 100.000 children under the age of 5 years (IC 95% -0.00 – 2.09) and of 5.36 per 100.000 living births (IC 95% 0.11 – 10.62). Year-of-birth controlled analysis registered an annual incidence of 4.04 per 100.000 living births (IC 95% 1.59 – 6.49).