Section 3 -

Retinal Tumors Alexandre Nakao Odashiro Lac – Pathology Laboratory Campo Grande , MS , Brazil Universidade para o Desenvolvimento do Estado e Região do Pantanal – UNIDERP Campo Grande, MS, Brazil

Retina The retina has two functions. The first, performed by the rod and cone photoreceptors, is to transduce information from an optical image into electrical signals. The second, performed by the neural circuits of the retina, is to process certain features of the visual world from the photoreceptor signals and relay this information to the brain via the optic nerve (Rodieck, 1973). The sensory retina is composed of layers: 1.layer of the photoreceptors of the rods and cones. 2.external limiting membrane. 3.outer nuclear layer. 4.outer plexiform layer. 5.inner nuclear layer. 6.inner plexiform layer. 7.ganglion cell layer. 8.never fiber layer. 9.internal limiting membrane. It is beyond the scope of this handout to describe the functional role of the retina. The retinal pigment epithelium (RPE) is a monolayer of cells extending from the optic disc to the ora serrata, where it is continuous with the pigmented epithelium of the ciliary body. The RPE cells are essential for photoreceptor health and have several other functions, including vitamin A metabolism, phagocytosis,, light absorption, heat exchange, and active transport of materials between the choriocapillare and the subretinal space (Duane, 1994). Neoplasia Retinoblastoma (RB) RB is the most common intraocular malignancy of childhood, and the incidence is about 1:15.000 to 1:30.000 live births. There are no differences in incidence by sex, race, or right versus left eye. The mean age of diagnosis is 18 months. RB in adults is extremely rare (Odashiro et al., 2005) . Genetics : Knudson (Knudson, 1971) proposed the two hit model after noting the differences in tumor development in patients with unilateral versus bilateral disease. RB requires 2 complementary tumor inducing genetic events. The first event for a genetic-induced RB is a germinal or inherited mutation, therefore, genetic-induced RB requires only one more tumor-inducing event. It represents 1/3 of the cases, is transmitted as an autosomal dominant trait, and the tumor is frequently bilateral. Non genetic-induced (sporadic) RB, however, requires 2 tumor-inducing events, represents 2/3 of the cases, is caused by somatic mutations and is not transmissible. Hereditary Non-Hereditary Diagnosed earlier Diagnosed later Bilateral or Unilateral Unilateral Chromosomal abnormality from germinal mutation or inherited Chromosomal abnormality from somatic mutation Offspring affected Offspring normal Risk of other malignancies No increased risk of other malignancies Retinoblastoma gene : the well-known RB gene is a tumor suppressor gene, located on the region q14 of the chromosome 13. The gene also encodes the Esterase D, an enzyme responsible for radiation repair. Clinical features : initially RB presents as a small and transparent mass that gradually becomes more opaque. More advanced tumors present as an elevated dome-shaped white retinal mass. Leukocoria (white eye) can occur early or late, and is a clinical characteristic of the tumor. Growth patterns: the endophytic growth pattern can simulate endophthalmitis; the exophytic growth pattern can simulate Coat's disease, and there is the diffuse-infiltrating pattern. Some cases of spontaneous regression have been documented, and it is believed that it occurs more frequently in RB than in other malignant neoplasm. Ultrasound is very helpful for diagnosis and characteristically shows calcifications. Histopathological findings: small, round, blue, neuroblastic cells compose the tumor. Rosettes are characteristic features: the Flexner-Wintersteiner rosettes, observed in well- differentiated tumors, are lined by tall cuboidal cells that circumscribe an apical lumen. In the Homer-Wright rosettes, that are less specific for RB, cells are not arranged around a lumen but instead send out cytoplasmatic process that form a tangle within the center of the rosette. Fleurettes are photoreceptor differentiation observed in well-differentiated tumors. Areas of necrosis and calcifications are commonlly observed. Vascular cuffs are spheroid aggregates of viable tumor cells around vessels, with peripheral necrosis (Burnier et al., 1990). Demirci et al studied enucleated eyes previously treated with chemotherapy (Demirci et al., 2003). Histopathologic examination of 10 enucleatedeyes following chemoreduction alone revealed that the main retinoblastomaregressed in all eyes. Calcified glialscar and an apical calcified glial scar with a basalresidual well-differentiated component with retinomalike and/orretinocytomalike features were the main findings. Fociof mitotically active, viable-appearing malignant retinoblastoma cells can be present and should be reported. Despite the lack of viable-appearing retinoblastomawithin the main tumor, enucleation was performed for viable subretinal and/or vitreous seeds in 7 cases and confirmed histopathologically. Prognostic factors : tumor extension through the optic nerve is the most important histopathological prognostic factor, when enucleation is performed. The optic nerve is the main route for retinoblastoma to produce extraocular extension and metastasize. Massive choroidal extension is also a prognostic factor. The presence of tumor beyond the lamina cribrosa is a risk factorfor metastatic disease, and although the choroidal invasionhas been considered an important risk factor for metastaticdisease because it allows for access to sclera and emissaryvessels, it is not clear whether choroidal invasion alone necessitatesthe use of systemic chemotherapy (Finger et al., 2002). Lungs, bones and brain are the main sites of metastases. Metastases usually occur 1-2 years after the treatment. Later metastases are so rare that should raise the possibility of a new independent primary tumor. Trilateral retinoblastoma (TRb) is represented by a bilateral retinoblastoma plus pinealoblastoma or parasellar tumor. It occurs in the first 3 years of life, and is often a fatal tumor. Marcus et al (Marcus et al., 1998) evaluated the histopathologic findings, clinical features, treatment modalities, and survival rates from 80 cases of RB with intracranial tumors. Histopathologic findings from intracranial malignancies demonstrated primitive neuroectodermal tumors in 61.5% of cases. Various degrees of neuronal or photoreceptor differentiation were seen in the other 38.5% of cases. The findings suggest that more likely arises from a germinal layer of predisposed primitive subependymal neuroblasts that are not necessarily destined for pineal or photoreceptor differentiation. TRb is usually fatal, with an average survival time of 11.2 months. Therapies include radiation, systemic chemotherapy, intrathecal chemotherapy, and surgical resection/craniotomy in combination with radiation and/or chemotherapy. Survival may be prolonged with combination chemotherapy (24.6 months) and if neuroradiologic screening identifies TRb before symptoms are present (23.5 months). Recent success with platinum-based chemoreduction of intraocular retinoblastoma may indicate a similar role for platinum-based chemotherapy in the treatment of TRb. Routine central nervous system imaging should be considered in the management of TRb. Treatment: treatment for retinoblastoma has changed in the past few years. Enucleation is reserved for selected cases and conservative forms of treatment have gained popularity. Such measures include external beam irradiation, episcleral plaque brachytherapy, cryotherapy, laser photocoagulation, and chemotherapy. In an attempt to preserve vision and avoid enucleation and thecomplications associated with external beam radiation therapy, new drug regimens were developed,and chemotherapy is currently considered to be an importantmodality for the treatment of Rb. Chemotherapeutic drugsinduce tumor regression and therefore allow for focal treatmentssuch as photocoagulation, thermotherapy, and cryotherapy. However, intraocular or local Rb recurrence continues to bea major problem, even with the use of multidrug regimens. Local tumor recurrence in such cases could suggest a lack ofresponse to chemotherapy also known as tumor resistance (Filho et al., 2005). A recent publication described the histopathological featuresof Rb treated with chemotherapy and observed that several tumorsshowed residual areas of well-differentiated cells (Demirci et al., 2003). RB recurrence after chemotherapy continues to be a major problem, even with the use of multidrug regimens. Tumor recurrence in such cases suggests inherent insensivity of RB to chemotherapy (Souza Filho et al., 2005) . Overall, the 3-year follow-up survival in the USA is about 90% (Filho et al., 2005). Genetic counseling for families of retinoblastoma patients is complex and challenging. Secondary tumors can develop in patients with genetically induced RB, due to the esterase D defect. The most common are osteogenic sarcomas of the skull and long bones, soft tissue sarcomas, pinealoblastomas, cutaneous melanomas, brain tumors, Hodgkin's disease, lung and breast cancer. Differential diagnosis : the clinical differential diagnosis includes other causes of leukocoria such as toxocariasis, coats disease, persistent hyperplastic primary vitreous, and retinopathy of prematurity. The most important histopathological differential diagnosis is Medulloepithelioma (see below). Important feature to the diagnosis is the highly malignant small blue cells with irregular chromatin and several mitotic figures. Tumors of the Ciliary Epithelium Primary tumors of the pigmented or non-pigmented ciliary epithelium arerare. Zimmerman proposed dividing these tumours into two classes — congenital (embryonic)and acquired (non-embryonic). Congenital tumours arise in the embryonic or earlypostnatal period, and include medulloepithelioma and glioneuromas.The acquired tumours are seen in adulthood and include Fuch'sadenoma, adenoma, and adenocarcinoma (McLean et al., 1994). Medulloepithelioma Intraocular medulloepithelioma is a rare embryonal neoplasmthat occurs predominantly in children and arises from the primitivemedullary epithelium of the optic cup. Medulloepitheliomas thatcontain heterotopic elements or tissues such as brain, cartilage,or rhabdomyoblasts are classified as teratoid, and tumors lackingthese elements are classified as nonteratoid medulloepitheliomas.Both nonteratoid and teratoid medulloepitheliomas may be benignor malignant. Clinically and histopathologically the tumor shows cystic areas intermixed with solid areas in the ciliary body area. The histopathological criteriafor malignancy includes the presence of poorly differentiatedneuroblastic cells, numerous mitoses, pronounced pleomorphism, sarcomatous areas, or invasion of other ocular structures withor without extraocular extension (Font & Rishi, 2005). Different from RB, the neuroblastic cells of the medulloepitheliomas are elongated with a fusiform nuclei. Adenoma and Carcinoma of the Ciliary Epithelium These are rare tumors. As Medulloepitheliomas, they are also tumors of the ciliary epithelium and can be benign (adenoma) or malignant (adenocarcinoma). However, they are acquiredlesions that occur after embryonic development, in adult patients. Primary Retinal Lymphoma (PRL) PRL is a non-Hodgkin large B cell lymphoma (high grade) also called non-Hodgkin's lymphoma of the central nervous system (Whitcup et al., 1993). It represents 1% of all lymphomas and may involve the retina, vitreous, optic nerve and central nervous system. It occurs in elderly patients that may have a misdiagnosis of chronic uveitis for a long period. Immunocompromised patients, especially AIDS patients, have a high-risk predisposition for this tumor. Vitreous aspiration biopsy and cytological examination can establish the diagnosis (Lopez et al., 1991). Prognosis is generally poor. Other Retinal Tumors Other retinal tumors include astrocytic tumors like astrocytomas and vascular tumors. Vascular tumors: the retinal capillary hemangioma can be present in the von Hippel-Lindau syndrome; the cavernous hemangioma is a rare congenital malformation. 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