**3.1 Tumor origin**

Embryologically, retinoblastoma tumors initiate from the inner layer of the optic cup that is derived from the neuroectoderm which is a neurological tissue. At the cellular level, the retinoblastoma constituent cells appear as small, roundish blue cells. Retinal differentiation in RB is categorized as the following: differentiated, undifferentiated, or necrotic. Differentiated tumors are furtherly subdivided into (1) "fleurettes" exhibiting advanced photoreceptor differentiation, (2) the classic Flexner-Wintersteiner rosettes representing early retinal differentiation, (3) Homer Wright rosettes with primitive neuroblastic differentiation, or (4) poorly differentiated [11]. These rosettes in an ascending order of differentiation include Homer Wright, Flexner-Wintersteiner rosettes, and fleurettes providing examples of these histologic structures (**Figure 3**) [2, 10, 12–14]. The Flexner-Wintersteiner rosettes when examined by high magnification microscopy demonstrate a ring of nuclei surrounding a central clear lumen corresponding to the subretinal space (**Figure 3A**). In comparison, the Homer Wright rosettes surround a central tangle of neural filaments with no clear distinct lumen (**Figure 3A**) [10, 11]. The different types of rosettes and/ or fleurettes (**Figure 3B**) observed in RB tumors represent varying degrees of differentiation, and these are recognized based on the histologic architectural pattern.
