The exophytic tumor grows towards the choroid into the subretinal space, detaching the retina and forming subretinal tumor seeds, which are prone to choroidal invasion (Fig. 16.1b).

The mixed growth pattern is the most common and displays both endophytic and exophytic patterns (Fig. 16.1c).

Another growth pattern of clinical importance is the diffuse infiltrative type, which typically presents in older children. Diffuse tumors infiltrate the retina without forming an obvious retinal mass, and often invade the anterior segment forming a pseudohypopyon of tumor cells. This pattern has prognostic importance because it can be mistaken clinically for an inflammatory process [2].

Often the diagnosis is made by cytologic assessment of the anterior chamber material or a vitrectomy specimen [1–3].

Finally, an extensively necrotic retinoblastoma can present clinically as an inflammatory process that mimics orbital cellulitis with chemosis and proptosis [1, 5, 6]. Histopathologically, such cases show total tumor necrosis associated with intraocular tissue necrosis. This type carries an increased incidence of poor prognostic factors for metastasis (see below).

The characteristic histopathologic findings in retinoblastoma include a tumor that replaces the retina with medium-sized cells that have a high nuclear/cytoplasmic ratio, marked apoptotic and mitotic activity, and foci of necrosis with calcification (Fig. 16.2a, b). The areas of necrosis typically surround vessels that are cuffed by a layer of viable cells measuring 90–100 μm in radius (Fig. 16.2c). The active turnover of the tumor often releases DNA from the cells, which forms basophilic deposits around vessels and on basement membranes. Most of the tumor grows as sheets or large foci of undifferentiated cells (Fig. 16.3a) [1–4]; however, sometimes there are areas of tumor differentiation evident as rosettes and fleurettes. The most differentiated tumors exhibit actual photoreceptor differentiation that is evident as bouquet-like aggregates of cells called fleurettes, which lack mitoses or necrosis (Fig. 16.3b). A tumor composed solely of fleurettes is designated a retinocytoma or retinoma – the benign counterpart of retinoblastoma (Chap.​ 7) [1–3]. Rosettes represent varying degrees of retinal differentiation. Flexner–Wintersteiner rosettes comprise a ring of nuclei surrounding an empty lumen analogous to the subretinal space. The cells are joined by intercellular attachments similar to those found between photoreceptors (Fig. 16.3c). Primitive Homer Wright rosettes are formed by a rim of nuclei with a center filled by tangles of cytoplasmic filaments (Fig. 16.3d). These rosettes also occur in neuroblastomas and other tumors. Both types may contain mitotic figures.

If left untreated, retinoblastoma usually fills the eye and completely destroys the internal architecture of the globe. The tumor tends to spread locally by invading the optic nerve and choroid, then hematogenously, and by lymphatics once it reaches the extraocular structures such as the conjunctiva and eyelids.

Metastatic disease is still associated with a poor prognosis [11–19]. Most clinical findings are not useful in predicting the occurrence of metastasis in children with retinoblastoma, although histopathologic data provide a fair estimate of its risk. Multivariate statistical analysis has suggested the correlation of certain histopathologic findings with metastastic disease (Table 16.1) [17, 19, 20]. The most important prognostic indicators for the development of metastasis are the presence of tumor in the optic nerve posterior to the lamina cribrosa, tumor at the site of surgical transection, and extrascleral extension of tumor into the orbit (Fig. 16.4) [7–12, 20]. Other factors associated with probable risk for metastatic behavior, especially in conjunction with the major factors cited above, are massive choroidal invasion, tumor invasion into the anterior chamber (Fig. 16.6b), large tumor size with vitreous seeding, neovascularization of the iris, and glaucoma (Table 16.2) [12–21].