Extra-ocular retinoblastoma: about 12 cases followed at the Mohamed VI university hospital of Marrakech

Retinoblastoma is the most frequent childhood intraocular tumor. The aim of our study is to evaluate the clinical features and management of extra-ocular retinoblastoma in the Mohamed VI university hospital of Marrakech. Retrospective case series, the patient's records were reviewed for patient and tumor features, ocular management, histopathological findings, and patient survival. Over a period of three years, 35 eyes were diagnosed with retinoblastoma; 12 children (16 eyes) (46%) had extra-ocular retinoblastoma. Mean age was 27 months, 60% were males. Six cases had unilateral tumor, five bilateral and one case of trilateral retinoblastoma. There was no positive family history, proptosis was the mean mode of presentation (41,6%) followed by staphyloma (25%) orbital cellulitis (25%) and hyphema(8,3%). The median lag period was 18 months. On imaging and histopathological analysis, there was extrascleral involvement in 41.6%, involvement of orbital part of optic nerve (75%), of orbital muscles (50%) and eyelids in 16.6%. the surgical treatment included according to the degree of extension enucleation (75%) or exenteration (25%) associated to chemotherapy in all cases and one case of external beam radiation. There were 2 cases of orbital recurrence, one death and no metastases at 30 months follow-up.Orbital retinoblastoma still stands as a tall challenge requiring multi-modal and multi-disciplinary approach. Although the survival has increased over the last few years, lack of access to medical facilities, lack of education about the need for early medical attention and cultural resistance to enucleation continue to contribute to an epidemic of extra ocular disease at diagnosis in the developing world.


Introduction
Retinoblastoma is the most frequent childhood intraocular tumor with an approximately incidence of 1/15000-20000 birth in the world [1]. In north Africa, it is the most important ocular malignancy, It is bilateral in about 25-35% of cases [2]. The recent advances for early detection and treatment like identification of genetic mutations, use of chemoreduction to minimize the size of the tumor, identification of histopathologic high risk features following enucleation and provision of adjuvant therapy to reduce the incidence of systemic metastasis, and aggressive multimodal therapy in the management of orbital retinoblastoma have contributed to improve outcomes in terms of better survival [3]. In neglected or untreated cases retinoblastoma can demonstrate extraocular spread primarily through the optic nerve and also through the sclera [4]. Orbital retinoblastoma is one of the major contributors to mortality and carries a poor prognosis for life [5,6]. Though it is a rare clinical presentation in developed countries ranging from 6.3% to 7.6% [7], it is not an unusual feature in developing and under developed world [8], mortality linked to orbital retinoblastoma in these countries is still high owing to late presentations compounded by socio-economic factors with the mortality reported as high as 50-90% [9,10]. Previous studies in morocco had reported epidemiological and clinical characteristics of retinoblastoma [2,3].
The aim of our study is to present data over three years about clinical presentation, therapeutic care and outcomes of children presenting orbital retinoblastoma treated at the Mohamed VI university hospital of Marrakech, which is a referral and tertiary care center in the south of morocco, to understand various reasons for the delayed presentation and to compare our results with those reported in the literature.

Results
During the study period a total of 35 eyes (26 patient) were diagnosed with retinoblastoma in our center, 12 patient (16eye) had an extra-ocular extension (46%). There were 60% males; none of our patients had positive family history. The disease was unilateral in 6 cases and bilateral in 5 patients, with one case of trilateral retinoblastoma. The average age of diagnosis was 27 months (range: 8months to 4years), however the age at presentation was higher in unilateral cases than bilateral. The initial mode of presentation was varied, there was proptosis (41, 6%) staphyloma (25%) orbital cellulitis (25%) ( Figure 1) and hyphema (8,3%).
However about 75% of parents had noticed leucocoria (40%) ( Figure 2) or strabismus (20%) at the time before consultation, with a lag period from detection of the first sign to consultation ranging from 2 to 18 months (median of 10 months) ( Table 1)

Discussion
In developed countries, retinoblastoma is usually diagnosed in its early intraocular stages leading to high chances for preservation of vision, globe and disease free survival of the patient. However, in developing countries, retinoblastoma is often diagnosed at a later stage with extraocular dissemination, thus leading to much lower rates of ocular salvage and patient survival [11][12][13]. We prospectively studied 12 consecutive children (16 eyes [13], 52.3% in Senegal [15]. Orbital retinoblastoma was reported in very low frequency from some of the developed countries like USA (5%) [16].
Retinoblastoma has no sex predilection; there was not much difference in the occurrence of retinoblastoma in boys (60%) and girls (40%). The average age at diagnosis is 18 months and vast majority become clinically apparent before the age of 3 years, The age at diagnosis of retinoblastoma in developing countries varies from 24 months to 3 years [13,15]. In this study, the age of our patients ranged from 8 months to 4 years and averaged 27 months which is slightly higher. Patients with bilateral tumors present earlier than those with unilateral involvement [15]. In our series, Bilateral retinoblastoma was seen in 41,6% of patients which is similar to the figures reported from USA (41.5% ) [16], India (37.2% ) [13].
However, it was observed in very less percentage in countries like Nepal (9.3%) [9]. The mean lag period in our patients was 10 months, with no statistically significant difference as per laterality and age. Other studies from the developing world have also described a long lag period and have analyzed various reasons for the same [13,15]. Erwenne and Franco [12] concluded that delayed presentation with extra-ocular invasion is strongly associated with age at diagnosis and lateness of referral. Antoneli Another study concluded that it is not only longer lag time but also denial of management by parents that are responsible for the delayed diagnosis [13]. It is likely that parents with a poorer educational background have limited information regarding signs and symptoms of retinoblastoma. Parents often stated that even though they noted an abnormality in the eye, often leukocoria, they did not relate this to the possibility of having cancer. The various Page number not for citation purposes 4 reasons reported by parents for the consultation delay in our study are limited access to ophthalmologist, lack of finances and health insurance and denial of enucleation. Another explanation rises as been reported from the use of self treatments or traditional healers' treatments before reaching a hospital [13].
Leucocoria is the most common presenting sign of retinoblastoma followed by strabismus all over the world ( Table 3). The frequency of common modes of presentation of retinoblastoma in our study is consistent with many studies from different parts of the world.
Leucocoria as presenting sign was seen in 22.6% [13] to 97.9% [16] of patients of retinoblastoma, while strabismus was noted in 5.6% [13] to 26% [15] of these patients at the time of diagnosis. In addition to the above, Abramson [16] reported many uncommon/rare presenting signs like anisocoria, heterochromia iridis, inflammatory signs, nystagmus, microphthalmia/buphthalmos, proptosis, orbital cellulitis, hyphema, ptosis, aniridia, phthisis, vitreous haemorrhage in their study of 1265 patients of retinoblastoma. However, proptosis was present in 41.6% of cases in our study; it was reported in high frequency from some of the developing countries like India (25.3%) [13]. Proptosis as presenting sign was reported in very low frequency from some of the developed countries like USA (0.5%) [16]. Orbital extension of the tumor results in proptosis, orbital cellulitis, lid swelling and echymosis; and the disease is considered to be in moderately advanced stage [9]. In our series, three children presented with signs of orbital cellulitis. Two children had unilateral retinoblastoma while the third child had bilateral retinoblastoma. The diagnosis was confirmed by CT scan of orbits and brain which showed tumor mass in the globe with areas of calcification in the affected eyes. Although extremely rare, orbital cellulitis as presenting sign in patients of retinoblastoma has been well documented in the literature [18]. It is suggested that necrotic changes occurring in the ciliary body and iris root trigger an inflammatory response in adjacent orbital soft tissue.
Another possible route for necrotic tumor to reach out of the eye is through trabecular mesh work [18]. Histological optic nerve infiltration was noted in 75% of patients in our study which is higher than the study reported from India (32.3%) [13]. In our study we describe one case of trilateral retinoblastoma with orbital invasion and a pineal tumor, which died of intracranial complications three months after the diagnosis. Patients with germline mutations in RB1 have a risk of about 5% of developing intracranial midline primitive neuroectodermal tumors. Such a tumor in a child who typically has unilateral or bilateral familial or sporadic hereditary intraocular retinoblastoma is known as trilateral retinoblastoma [19]. With rare exceptions, trilateral retinoblastoma is located in the pineal gland or the suprasellar and parasellar region, and histopathologically, they resemble retinoblastoma. A meta-analysis [20] published in 1999, showed that 88% of children with trilateral retinoblastoma did not survive for longer than 5 years. Survival of patients with pineal and non-pineal trilateral retinoblastoma has increased. Early detection of smaller tumors predicted better survival for patients with pineal trilateral retinoblastoma. In most cases, retinoblastoma is a clinical diagnosis and is based on clinical examination and use of ancillary tests, The diagnosis of high-risk retinoblastoma is a clinical diagnosis only in cases with anterior chamber pseudohypopyon, clinically apparent iris infiltration, and choroidal or optic nerve invasion detected by imaging modalities. However, in most cases, high-risk retinoblastoma is a histopathology diagnosis that can be detected on examination of enucleated specimens [18]. There are very few human malignancies where definitive treatment is started without any confirmed histopathological diagnosis and imaging plays an important role in diagnosis and staging of the disease. Imaging (preferably magnetic resonance imaging) is required to confirm the diagnosis, access for local spread into the orbit through the sclera or into the optic nerve, metastasis into the central nervous system and for trilateral retinoblastoma [18]. Enucleation is a definitive treatment for retinoblastoma and is associated with a low

Competing interests
The authors declare no competing interest.  Tables and figures   Table 1: lag period between first symptom and diagnosis of intra orbital retinoblastoma (months)  Table 3: comparative frequency of common presenting signs of retinoblastoma in different parts of world