Paediatric Retinoblastoma.eng

Introduction

Retinoblastoma is a rare eye tumor of childhood that arises in the retina and represents the most common intraocular malignancy of infancy and childhood [a]. It may occur at any age but most often it occurs in younger children, usually before the age of two years. His prognosis is good since
over 95% of children are cured in industrialized countries. Retinoblastoma is the most common intraocular tumor of the child; its incidence is stable, described around 1/15 000 to 1/20 000 births. It is unilateral in 60% of patients, with a median age at the time of diagnosis of 2 years old. It is bilateral in 40% of patients: the median age at the time of diagnosis is then about 1 year and tends to decline in industrialized countries through screening of children at risk in the neonatal period. Factors of infectious or environmental risks favoring the occurrence retinoblastoma have been reported but can not be today considered established [3,4]. The occurrence more frequent retinoblastoma in children born of pregnancies medically assisted procreation has been reported, but still unconfirmed [5].
Hereditary retinoblastoma is a form of transmissible retinoblastoma: all bilateral retinoblastomas are hereditary, but 10 to 15% of unilaterals are
also (all forms of unilateral retinoblastoma with
several identifiable retinal tumor foci are also
hereditary, but the uni- or multi-local character is often
difficult to evaluate in extended forms). From
hereditary forms of retinoblastoma, we also define
"family" forms by the existence of at least 2 patients
in the same family, most often 1 parent and 1
child. The current good prognosis for this disease is reflected in an increase in the proportion of family forms. The
hereditary forms are one of the predisposing syndromes
to cancer (retinoblastoma itself, but also sarcomas
secondary and other types of cancer).
The retinoblastoma gene, located in region 13q14, is the RB1 gene which exerts a major physiological function of cell cycle control. It is a suppressor gene of
tumor: for the malignant transformation of a cell
in the retinoblastoma cell, it is necessary that
anomaly exists at the level of each of the 2 gene alleles
RB1. In hereditary forms of retinoblastoma, there are
a constitutional anomaly of the RB1 gene and it is sufficient that a second event occurs at the level of the second allele in a retinal cell for a tumor to develop: this is
the reason why patients with hereditary form
retinoblastoma have very often bilateral tumors and
multiples in each eye (median number = 7 tumors in
each child). The transmission of the risk of developing a retinoblastoma is done in the autosomal dominant fashion with high penetrance: 90% of patient carriers
of a constitutional abnormality of the RB1 gene develop a retinoblastoma. In non-hereditary forms, the two events mutations occur successively on each of the
2 alleles of the RB1 gene at a single cell of the
retina, resulting in the development of a single tumor in
one eye.

Recent aspects of this disease include:
● the diagnosis: it is necessary to insist on the necessary
symptoms, often seemingly banal and
dine, to promote early diagnosis;
● treatments, whose morbidity has recently decreased
all thanks to the decrease in indications of irradiation
when conservative eye treatment is pos-
sible;
● genetic information to patients and their families.

2. Circumstances and methods of diagnosis
2.1. Two major signs
The 2 major telltale symptoms and still too often
unknown are leucocoria and strabismus.
Leucocoria (white pupillary reflection, "cat's eye")
responds to direct visualization of the tumor across the area
pupillary (Fig. 1). It is sufficient for parents to report such
symptom, even if it is not observed on clinical examination,
to have the child referred to an ophthalmologist without delay
to carry out an examination of the fundus after dilatation
pupillary
Strabismus, whether reported by parents or observed
by doctors, must not be neglected, even
at the young child. Do not confuse spasm
physiological accommodation with an authentic strabismus
infant. Strabismus, even intermittent, imposes a
urgent consultation of ophthalmology with examination of the merits
look. In the context of retinoblastoma, strabismus is related to
a tumor covering all or part of the resulting macula
a central visual loss of the concerned eye.
Too often, these symptoms are reported by
parents, but not taken into consideration by doctors; they
are retrospectively found, but only
months later, when the diagnosis of retinoblastoma
is finally laid. Yet an early consideration of
these symptoms may allow a diagnosis at the moment when the
Intraocular tumor volume is lower and morbidity
treatments can be decreased

2. Another circumstance of diagnosis
Screening in at-risk subjects is now more
in more frequent, thanks to a better information of the patients
become adults and treated in childhood for retinoblastoma.
The enhanced performance of anomaly detection
RB1 gene can often be used to orient the screening. The subjects at risk are the carriers of an identical mutation.
of the RB1 gene, but also those in which, in the absence of
known family mutation, the indirect analyzes by
polymorphisms do not rule out that they are
constitutive anomaly of the RB1 gene and finally
those in whom the family genetic analyzes are not
informative despite family history. All these topics
at risk should benefit from fundus
indirect ophthalmoscopy under general anesthesia
to put an early diagnosis.
2.3. Other signs
Other diagnostic circumstances are rare (hypopion,
iris heterochromia, glaucoma, visual loss) and are not
never known because they lead quickly to a consul-
Ophthalmological examination with fundus
most often from the start the diagnosis of retinoblastoma.
2.4. Confirmation of diagnosis
The diagnosis of retinoblastoma remains clinical, based on
the fundus examination under general anesthesia thanks to the
visualization of the tumor lesion appearing in relief, white
che and hypervascularized during the ophthalmoscopic examination
indirect (Fig. 2). This examination allows the precise assessment of the lesions
intraoculars for which a new classification
is under way and provides guidance
initial therapy (Table 1) [6]. The memorization of
images of the fundus has been improved thanks to the specific camera
RETCAM® wide angle lens.
At the same time anesthesia is performed in a special environment.
An ocular ultrasound is available to measure
tumor dimensions and to confirm the diagnosis of retino
blastoma by the frequent presence of intratumour calcification
(Fig. 3).
Apart from the forms detected during the neonatal period
have no tumor lesion flush with the papilla, we realize
always at the time of the diagnosis, an assessment by orbital imaging
silent and cerebral. In case of diagnostic difficulty, the tomo-
Densitometry (CT) can be helpful if it highlights
fine intralesional calcifications (Fig. 4). imaging
Fig. 2. Fundus at the time of diagnosis of a plurifocal retinoblastoma
(photograph taken by RETCAM® camera during an ophthalmic examination
indirect copy). Three white tumors are visible: the main tumor,
hypervascularized, partially obscuring the papilla, and 2 small localizations
overlying tumors. As a scale: the diameter of the disc is
1.5 mm.
Table 1
ABC classification. International Classification of Intraocular Retinoblastoma
[6]
A: small retinal tumors at a distance from the fovea and the optical disc
Tumor <3 mm in diameter
Located more than 3 mm from the fovea and more than 1.5 mm from the optical disc
Without vitreous invasion
Without associated retinal detachment
B: all other tumors limited to the retina; serous retinal detachment
minimal
Retinal tumors limited to the retina but not included in group A
and or
Serous retinal detachment of less than 3 mm around the tumor base,
without subretinal visible fragment
C: moderate localized retinal serosal detachment; subretinal fragments or
localized intravitreal
Isolated serosal detachment (without subretinal fragment) between 3 and 6 mm around
of the tumor base
Intravitreal or subretinal tumor fragments within 3 mm of the
tumor
D: extensive retinal serosal detachment or subretinal swarming or
diffuse intravitreal
Serous detachment isolated at more than 6 mm from the tumor base
Intravitreal or subretinal tumor fragments more than 3 mm from the base
tumor
E: presence of at least one of these pejorative prognostic factors for the
eye retention
Tumor masses taking up more than 2/3 of the globe
Affecting the anterior segment
Achievement of the ciliary body
Iris neovascularization
Neovascular glaucoma
Intravitreal hemorrhage
Tumor necrosis with aseptic orbital cellulitis

magnetic resonance (MRI) is preferred for the assessment
extension, because it allows better visualization of the nerves
intraorbital disorders (Fig. 5), it contributes to the diagnosis of
in the diffuse infiltrative forms of which the
is close to that of the uveites [7] and avoids any
irradiation in subjects with a general predisposition
at risk of sarcoma.
3. Therapeutic aspects
3.1. Unilateral retinoblastoma extended
This is the most common form of retinoblastoma: 80%
patients with unilateral retinoblastoma
still today be treated by enucleation first because
the intraocular extension does not allow to consider
conservative.
It is essential that the quality criteria of the enuclea-
are optimal because they are life-threatening and
aesthetic: enucleation must be performed by a surgeon
having sufficient experience of this intervention to
guarantee these quality criteria. Indeed, any break-in
must be avoided, as this would expose
risk of tumor invasion orbital section of the nerve
optics must be sufficiently posterior to increase the
chances of moving to a healthy zone, and an intra-oral implant, the
more often hydroxyapatite type, must be put in place and
sutured to the oculomotor muscles, to improve the results
postoperative aesthetics. Histopathological examination should
be standardized, examining the entire eyeball and the
path of the optic nerve. It is essential to carry out
tumors for molecular studies that may
contribute to the genetic information of
patients and their families, but these samples must be
performed under standardized conditions so as not to
interfere with the interpretation of histological risk factors.
The histological examination of the enucleation room must therefore
be performed by an experienced pathologist as it conditions
postoperative therapeutic indications.
In the absence of invasion of the optic nerve or enven-
eyelids, no adjuvant treatment is indicated;
the case today of the majority of patients in the countries
industrialized.
When the excision is microscopically incomplete (envi-
transscleral hoisting or invasion of the slice of sec-
of the optic nerve), postoperative chemotherapy and
Orbital irradiation must be performed: these cases have become
rare in the industrialized countries and the development of
orbital brachytherapy can now reduce
sequelae of irradiation [8]. In the particular and rare case
of an extensive retinoblastoma with involvement of the optic nerve
intraorbital detectable on the initial imaging, we realize
currently rather a first chemotherapy followed by a
enucleation with double neurosurgical and ophthalmic team
allowing the section of the optic nerve in a healthy zone,
enucleation with preservation of oculomotor muscles and
the placement of an orbital implant; the treatment is
followed by postoperative chemotherapy [9].
Therapeutic indications are more debated in case
microscopic invasion of the optic nerve not reaching
not the section slice, in case of choroidal invasion
or intra-scleral that does not cross the sclera, or in case of
hollowing of the anterior segment of the eye [10]. A chemotherapy
without orbital irradiation is nevertheless often recommended.
under these circumstances [11].
Tumor genetic studies make it possible to better understand
retinoblastoma oncogenesis and associated abnormalities
inactivation of the RB1 gene [12]. However, no
biological risk is not yet identified in
complement the histological risk factors to help
the postoperative therapeutic decision.
bilateral. They are also tempted more and more often
in unilateral forms in case of small tumors scattered
the macula (thus letting hope for a visual preservation
of the affected eye), or occurring in a very young child,
in the context of screening, and therefore in a context of
risk of developing metachronous bilateral retinoblastoma,
that is, shifted in time. Conservative treatments
Today, about 20% of patients with
unilateral retinoblastoma.
The basic principles of conservative treatments are the
following:
● Minimize the use of external irradiation as much as possible
because of its risks: repercussions on the orbital growth
tofacial, cataract (even if operable), retinopathy
radiation, a rare risk of irradiation of the hypo-
thalamohypophyseal and endocrine resonance, and
especially the increased risk of second cancer in the
irradiated area;
● preserve vision as much as possible.
The indication of the conservative treatments must imperatively
be placed in an onco-ophthalmological
because of their complexity. An initial phase of chemotherapy
neoadjuvant may be useful when the initial tumor volume
does not allow direct accessibility to different techniques
conservative local treatments or in case of detachment
retinal to promote retinal reapplication and better
their vision [13-17]. Indications of the different techniques
conservative treatments are applied according to the evaluation
evaluation of each tumor: diameter, thickness and situation by
compared to the papilla and the macula (this topography conditions
the visual prognosis and the type of treatment that can be used to
not to compromise the vision). We also take into account
the existence of a vitreous invasion (located opposite
tumor or diffuse throughout the vitreous cavity), as well as
the existence of pre-lethal invasion and decolonization
retinal, partial or total.
In front of the equator of the eye, tumors can be
treated with cryotherapy or interstitial brachytherapy (eg
radioactive iodine or ruthenium disc) - this technique
being indicated in case of larger tumor or with
vitreous invasion localized [18,19]. Back from the equator
of the eye, a laser treatment technique alone or in combination with
The combination with carboplatin chemotherapy was introduced
more than 10 years ago by Murphree and allowed a change in
radical treatment in the management of retinoblastoma
making ocular preservation possible without irradiation
in the very frequent cases of tumor of the posterior pole.
laughter [20,21]. Where there is a widespread infringement of
retina or vitreous, the only conservative treatment possible is
external irradiation [22], but progress in the achievement
of this technique (conformational technique, use of
beams of protons) also allow to hope
to minimize side effects by minimizing radiation
orbital, as well as the risk of second cancer in the territory
irradiated.
Currently the majority of patients with retinoblast
bilateral volume still needs to undergo unilateral enucleation and
contralateral conservative treatment: only one third of
patients can benefit from bilateral conservative treatment
[23].
In the months and first years following the end of the
treatment, ophthalmological monitoring continues under
general anesthesia at the monthly rate and then gradually
spaced, but maintained at least quarterly. The goal
this monitoring is to detect as early as possible the
intraocular recurrence or new tumors, in order to increase
to improve the chances of ocular and visual preservation. The
risk of recurrence decreases over time, but recurrences
or new tumors may occur even late;
improving child collaboration, ophthalmic
mological continues in consultation, but does not fall apart
beyond the quarterly pace. This monitoring also
for the purpose of identifying ocular lesions induced by
treatment and accurately assess the vision [24]. Finally, the evaluation
evaluation of functional impact and orientation towards
specialized structures of visual impairment, when this is
necessary, is also an essential part of the monitoring, as soon as
early childhood and even when the disability is relatively
moderate: early and appropriate care is the guarantor of
the optimization of long-term results.
Multidisciplinary follow-up involving pediatric oncologists
also continues beyond initial care.
tial. The oncological risk of extraocular recurrence of retino-
Blastoma has become extremely rare in the industrialized countries. A
new classification has recently been published allowing
stratify the severity of the different extraocular lesions [25]
(Table 2). The prognosis of forms with
orbital and pre-cervical or cervical lymph nodes
is significantly improved by the use of chemotherapy
conventional and radiotherapy [26]. Metastatic lesions
ticks, mainly bone and bone marrow, but
the central nervous system, have become more often
accessible to treatment through the use of chemothera-
Intensive maggots with haematopoietic stem cell support
[27]. In contrast, metastatic
central nervous system remains a poor prognosis despite
preliminary encouraging results of some
chemotherapy [28].
Table 2
New international classification system for retinoblastoma [25]
Stage 0. Eye accessible to conservative treatment.
Stage I. Enucleated eye with microscopically complete resection.
Stage II. Enucleated eye with microscopically incomplete resection
Stage III. Regional extension
at. Orbital involvement
b. Pregaginal or cervical lymph node involvement
Stage IV. Metastatic extension
at. Hematogenous metastases (without invasion of the central nervous system)
b. Achievement of the central nervous system
In case of bilateral involvement, the highest stage is retained.

The risk of second cancer unfortunately still exists
in patients with inherited form of retinoblastoma
[29]. The earliest of these is the retinoblastoma
lateral "which is a primary neuroectodermal tumor
of the pineal (pinealoblastoma) or suprasellar region:
this is a rare cause of second cancer after retinoblastoma,
occurring most often around the age of 4-5, but sometimes
earlier, or even concomitant with the diagnosis of retinoblast-
tome; its prognosis is dark [30]. The most frequent
Secondary cancers are sarcomas, the majority of which are
develops in the irradiation field of retinoblastoma,
osteogenic sarcomas can also occur
come, often on long bones, outside any irradiation
[31]. Many other secondary cancers are possible
in these patients, often in adulthood (glial tumors, mel-
nomes, carcinomas). It is important to inform families and
the patients themselves on the attention to be paid to the symptoms
my possible these second tumors and suggest them
to avoid risk-increasing behaviors such as smoking
or excessive sun exposure. Monitoring includes
also the follow-up of the visual handicap and its assumption of responsibility,
as well as the detection of an exceptional auditory reverberation
carboplatin chemotherapy. The essential objective of
these follow-up consultations is the graduated information from these
patients on the risk of disease transmission and risk
second cancer, leading to an informa-
in adolescence or young adulthood.
4. Consultation of genetic information
The questions asked during this consultation concern:
the risk of having an affected child when treated in
childhood for retinoblastoma, the risk of having a second
child reaches, the risk of second cancer.
The tools available for this consultation are:
● diagnosis and clinical examination: the existence of antecedent
family, uni- or bilaterality of retinoblastoma, uni-
or plurifocality in case of unilateral tumor, the existence
of a dysmorphic syndrome in the event of a deletion
over a wider region of the chromosome
13q than the single RB1 gene [32].
● the direct detection of constitutional mutation of the gene
RB1. This is a complex gene, comprising 27 exons,
and for which there is no preferred site identified
occurrence of mutation;
● indirect studies on constitutional material and, where appropriate
appropriate, on the tumor material (studies of loss of alleles,
losses of heterozygosity).
Major progress has been made in recent years
in the detection of constitutional abnormalities of the RB1 gene,
to identify a genetic anomaly in more than one
80% of cases of bilateral form of retinoblastoma [33]; the
Negative cases mostly discuss non intronic mutations
detected or germ mosaics. Even in the absence of
detection of a constitutional abnormality of the RB1 gene, all
patients with bilateral retinoblastoma are at risk of
to transmit the disease to their descendants. A general anomaly
The constitutional syndrome of the RB1 gene is found only in
10 to 15% of cases of unilateral retinoblastoma. Negative cases
most of them correspond to forms of retinoblasts-
unilocal unilateral tome where the 2 mutations of the RB1 gene are
of somatic origin, occurring at the level of a cell
nien; however, the absence of anomaly detection
of the RB1 gene should not lead to the conclusion that
predisposition and risk of transmission in the uni-
side. The proposed modalities of ophthalmic surveillance
risk-based logic are shown in Fig. 6: he
these are surveillance recommendations before any study
genetic.
The proposed genetic analyzes are summarized on the
Fig. 7: when informative, they often allow
avoid ophthalmological surveillance
have identified the absence of risk or, on the contrary,
in case of mutation. They also allow
to suggest an antenatal or postnatal diagnosis. The diagnosis
pre-implantation may also be proposed in this
die [34].
Recent progress on finding anomalies
of the RB1 gene make the information essential.
complete treatment of former patients, including those treated
for unilateral retinoblastoma. So far we have not been able
demonstrate a relationship between the type of constitutional anomaly
of the RB1 gene and the risk of second cancer.
5. Conclusion
It is essential to improve the earliness of the diagnosis of
retinoblastoma. The recent reissue of the new notebook
health attention draws even more attention than previously
essential symptoms are leucocoria and strabismus.
Indeed, it is certain that the rapid recognition of symp-
and diagnosis at a stage where intraocular invasion
is limited to reduce the morbidity of
while increasing the chances of survival [35] and
also allow better chances of eye preservation
and visual. We can also hope to reduce the risk
second cancer by reducing the use of irrational
and reducing the cumulative doses of cholesterol
miotherapy; however, this risk can never be abolished
in hereditary forms. Other treatments are in
development course, such as dynamic phototherapy
where the drugs used in combination with the laser are no
mutagens [36,37]. New experimental models
consider valid in vivo validations before
the early therapeutic trials planned in the forms
refractories [38]. In economically disadvantaged countries,
It must be remembered that retinoblastoma remains an unfortunate
often deadly. Promoting a pre-diagnosis
and the acceptance of enucleation would allow
today to improve the vital prognosis of retinoblastoma

in these countries ; a partnership in the field of training
and medical facilities should be put in place to improve
to improve the tumor control of this theoretically easy disease.
curable.
The management of retinoblastoma is particularly
complex, imperatively requiring a multidisciplinary team
specialist. In France, specialized cancer centers
pediatrics are grouped together in the Retinoblas-
tome of the French Cancer Treatment Society and
children's and adolescents' leukemias (SFCE) and have developed
rules concerning the management of cases of retinoblast-
extended unilateral volumes, including standard procedures
surgery and histological examination, as well as a
prospective study in progress concerning indications and modalities
postoperative treatment. The Institut Curie is the center of
reference in France for the diagnosis and treatment of
noblastoma, especially for all patients who may benefit
enjoy a conservative treatment, in order to carry out studies
prospects for adapting the intensity of treatment to the
severity of intraocular involvement [14,21,23]. The laboratory of
oncological genetics of the Institut Curie is also the
national reference for the search for constitutional anomalies
of the RB1 gene [33]. The RETINOSTOP association
which brings together parents of children with retinoblastoma
and adults treated in childhood for this affection deploys
all its energy to promote early diagnosis, information
sea, help and support the families concerned and support the
research on this orphan cancer. This partnership is illustrated by
active participation in the development of research protocols
clinic and the preparation of information forms and
consent, support for biological research activities
(in the field of constitutional genetics and
tumor, experimental therapy and biology
the development of an information booklet (also
available on the website of the French Pediatric Society:
www.sfpediatrie.com), the distribution of a DVD intended for
general practitioners and pediatricians to promote the diagnosis
early diagnosis of this disease as well as through
a website (www.retinostop.org).
The announcement of the diagnosis, made at the very moment when
heavy treatments, is made particularly
very delicate in the parents of these very young children
since the serious information accumulates within a
very short: malignant nature of the affection, risk of enucleation,
risk of visual impairment, dimension of general predisposition
certain or possible tick, risk of second possible cancer-
favored by certain treatments that are necessary today,
risk of transmission of this disease to future descendants.
In this context, the therapeutic alliance is of course
between each affected child, his or her parents and the
involved; this alliance is well supported by
active participation of many affected families in
promoting information on retinoblastoma and its
early diagnosis.
Thanks
I would like to pay tribute to Professor Jean-Michel Zucker, Chief
of the Honorary Department of Pediatric Oncology of the Institute
Curie, an internationally recognized specialist in retinoblast
tome, for all he taught me and the confidence he has
granted, and to Dr. Laurence Desjardins, head of the oph-
talmology of the Institut Curie for its professional competence
his enthusiasm and openness to the exercise
multidisciplinary. I also thank Dr. Jean Michon,
Head of the Department of Pediatric Oncology, and Dr. Domi-
Stoppa-Lyonnet, Head of the Department of Genetic Oncology
at the Institut Curie, whose laboratory has become a Reference Center
national office for the study of the constitutional anomalies of the

a)
Abramson DH, Schefler AC: Update on retinoblastoma. Retina. 2004, 24: 828-848. 10.1097/00006982-200412000-00002.