Histopathologic Features and Prognostic Factors

Retinoblastoma is a tumor that arises from the neuroblastic cells that comprise the nuclear layers of the retina. Grossly, the tumor is classified by its pattern of growth into endophytic, exophytic, mixed, diffuse infiltrative, and necrotic variants. 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. If left untreated, retinoblastoma usually fills the eye and 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. Multivariate statistical analysis has suggested the correlation of histopathologic findings such as 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 with risk of metastasis. Other factors associated with probable risk for metastatic behavior, especially in conjunction with the major factors cited above, are massive (>3 mm) choroidal invasion, tumor invasion into the anterior chamber, large tumor size with vitreous seeding, neovascularization of the iris, and glaucoma. It is important to analyze the eye appropriately to evaluate the possible high-risk features. Guidelines for handling the eye have been published as a result of a consensus from the International Retinoblastoma Staging Working Group that also includes criteria used in the prospective clinical trial from the Children's Oncology Group (ARET0332 A Study of Unilateral Retinoblastoma With and Without Histopathologic High-Risk Features and the Role of Adjuvant Chemotherapy: A Groupwide Phase III Study). The later study recognized a higher histopathologic risk feature for central nervous system recurrence and death of disease that includes more than 3 mm of peripapillary choroidal invasion concomitant with post-laminar optic nerve invasion of more than 1.5 mm. Genetic alterations also provide specific tumor changes and prognosis to the patients. Animal models and histopathological and collaborative clinical trials will certainly facilitate the understanding of these factors and ultimately allow the use of targeted therapies to prevent metastasis and death from retinoblastoma.