Regardless of the specific mutation, the tumor grows from the nuclear layer of the retina either in an endophytic pattern seeding the vitreous or in an exophytic form into the subretinal space and to the choroid in more advanced states. Retinoblastoma usually produces a retinal detachment, and usually eyes with advanced disease show features of both exophytic and endophytic tumors. After filling the eye, retinoblastoma may disseminate to other organs. It usually does so after involving severely the eye structures, so metastatic dissemination is virtually not existent in cases with small tumors limited to the retina. Thus, extension inside the eye is usually a requisite before metastatic dissemination. The tumor can extend through the optic nerve and/or the subarachnoid space to the chiasm, the brain, and later to the meninges. Exophytic tumors may invade the choroid and later the sclera. The tumor usually remain into the eyeball for some period of time, but if left untreated, it eventually invades the orbit and beyond it to the surrounding structures. The metastatic pattern of retinoblastoma include the CNS and hematogenous metastasis involving the bone, bone marrow, or less frequently any other organ.

The diagnosis of retinoblastoma is usually made by an experienced ophthalmologist without needing pathological confirmation. However, after the eye is enucleated, it is extremely important that the eyeball is evaluated by an experienced pathologist in order to estimate with accuracy the degree and extent of tumoral dissemination in the eye structures. Retinoblastoma usually presents with small undifferentiated anaplastic cells with scanty cytoplasm and large nuclei, occasionally showing photoreceptor features. Calcification is a frequent finding. Retinoblastoma is a tumor of neuroepithelial origin and presents some similar characteristics to other neuroectodermic pediatric tumors. Thus tumor cells often express photoreceptor-differentiation antigens, neuron-specific enolase, and the ganglioside GD2. Retinoblastoma usually stains negative to CD99. However, immunohistochemistry is not vital to the diagnosis of retinoblastoma. Immunocytological evaluation is nevertheless important in cases of extraocular dissemination where tumoral cells should be readily identified by these techniques. The use of immunocytology for GD2 or for the transcription factor CRX has been reported effective for this goal [10]. The likelihood of extraocular relapse is directly correlated with microscopical invasion to critical eye structures such as the optic nerve in its orbital portion beyond the lamina cribrosa, the choroid when is massively invaded and the sclera that implies always a later stage of choroidal invasion [11].

When a child is diagnosed with retinoblastoma, it is important to assess the extent of the disease in two levels: (a) intraocular extension, which will predict eye salvage and (b) extraocular dissemination, which will predict patient survival.

Intraocular extension of retinoblastoma is assessed by the ophthalmologist using the indirect ophthalmoscope in a full examination with pupillary dilation under anesthesia. The extent of intraocular disease evaluation should consider the size of the tumors, their location especially their relationship to the macula and the presence of seeding to the vitreous or the subretinal space. On occasions, the tumor causes retinal detachment, which was previously regarded as a poor prognosis feature. Different systems were proposed to group these findings in order to predict eye salvage. The Reese-Ellsworth (R-E) grouping system was used for many years and proved to be effective in predicting eye salvage with radiotherapy treatment. More recently, an international system was proposed to predict eye salvage with modern chemotherapy treatments (Table 20.1) [12].

The evaluation of extraocular extension is usually done by the pediatric oncologist. For a proper extent of extraocular disease evaluation it is important to consider the prevalence of extraocular disease in a given patient population. Since extraocular retinoblastoma is very uncommon in developed countries, most authors recommend that no other staging procedure other than CNS imaging should be done for staging [13]. The low prevalence dissemination in the CSF or in the bone marrow makes evaluation of these sites of low yield and most authors in developed countries do not perform these evaluations routinely in their patients. However, in developing countries with high prevalence of these complications, a full extent of disease evaluation may be needed in most patients [14]. Because extraocular disease is so uncommon in developed countries, there has not been a consensus staging system for extraocular disease for years. However, in recent years, a group of international retinoblastoma experts developed a staging system by consensus that articulates with the intraocular grouping system proposed for the eye-conserving therapies with chemoreduction (Table 20.2) [15]. The TNM system has been recently updated in order to include patients with extraocular dissemination. So, each retinoblastoma program in developing countries should chose the staging system that better accommodates with their patient population, but it is important to be consistent in the use of a specific staging system over time in order to be able to compare the results.

Regardless of the disease extension and the setting, all children with retinoblastoma should undergo a head and orbital, gadolinium-enhanced MRI. MRI is preferred to CT scan because it allows for a better estimation of the invasion to the optic nerve [16]. Guidelines for the evaluation of retinoblastoma with MRI have been recently published [16], but it is important to know that in order to obtain a detailed evaluation of the optic nerve or the choroid, it is necessary to use a high-resolution MRI with orbital coils, which are seldom available in developing countries. In addition, MRI is helpful to evaluate the pineal area where it avoids the exposure to radiation in these susceptible patients. However, many centers in developing countries would have only CT scan available for staging of their retinoblastoma patients. In these cases, CT may be useful to identify obvious optic nerve or orbital involvement and CNS extension. Thus, the first step in the initial evaluations in children with retinoblastoma includes a full ophthalmological evaluation and CNS imaging. After this first step, the treating group is able to determine if an eye salvage therapy is possible, if enucleation of the affected eye is needed or if the disease has already spread outside the eye and neoadjuvant therapy is required. At this point, clinical findings are also important to take a decision since children who can only be evaluated with low resolution CT scans and present with massive buphthalmia or glaucoma but imaging studies fail to disclose extension beyond the eyeball may be better treated with preoperative chemotherapy. In these children and in those in whom extraocular disease is present, further staging evaluations are necessary before starting neoadjuvant chemotherapy. These include bilateral bone marrow aspirates and biopsies and lumbar puncture with examination of the cytospin (in those without risks related to the procedure) [14]. A full bone marrow evaluation including bilateral biopsies and aspirates may improve the yield of these procedures, but they need to be done under general anesthesia, which is not always available or recommended in children with advanced disease in developing countries. In situations where children present with obvious extraocular disease, a single bone marrow aspiration could be done, and if the results are positive, no other bone marrow study would be needed. However, a more exhaustive bone marrow evaluation should be done when a single aspiration fails to show malignant cells, especially if no other metastatic site is present. Since retinoblastoma cells may adhere to the tube, the examination of the cytocentrifugate of the CSF specimen, should be always be done regardless of the cell count in order to improve the yield of this procedure. Bone scintigraphy is only recommended in children with confirmed metastatic disease or those with bone pain. This extensive work-up is only necessary at diagnosis in children with clinically advanced disease in whom preoperative enucleation is considered. In cases where enucleation of the affected eye was decided as initial therapy, staging procedures should be done only if high risk of metastatic disease is probably based on the pathological examination. Enucleation should not be delayed because of extent of disease evaluation other than CNS imaging. Children in whom conservative therapy is undertaken do not need any other staging procedure than CNS imaging.

The treatment of retinoblastoma in developing countries poses significant and unique challenges for the treating physicians given the paucity of publications, the impact of socioeconomical factors and the influence of the availability of resources. It is important that children with retinoblastoma should be treated in centers with experience in the management of these tumors which on occasions would need the participation of eye hospitals in association with children or cancer centers in order to provide the best possible care. In order to provide tools for treating physicians in these settings, the SIOP-PODC (International Society of Pediatric Oncology-Pediatric Oncology in Developing Countries) published a consensus guideline for graduated-intensity therapy [17].