Author Affiliations: Departments of Ophthalmology (Mr Hwang and Drs Aaberg, Gao, and Grossniklaus) and Pathology (Dr Grossniklaus), Emory University School of Medicine, Atlanta, Georgia; and Departments of Ophthalmology (Drs Chevez-Barrios, Verner-Cole, Gombos, Paysse, and Chintagumpala) and Pathology (Drs Chevez-Barrios and Verner-Cole), Weill Cornell Medical College of Cornell University, and The Methodist Hospital, Houston, Texas.
Over the past decade, chemoreduction has become the treatment of choice for the initial management of retinoblastoma.1 Despite its established use, chemoreduction has not successfully treated diffuse infiltrating retinoblastoma, the least common subtype of retinoblastoma.1 Herein, we report 2 cases in which residual intraretinal retinoblastoma exhibiting flat and diffuse infiltration was found on pathological examination after chemoreduction failure. In both patients, chemoreduction reduced some of the tumor and unmasked the intraretinal component.
A 22-month-old boy with no family history of retinoblastoma had bilateral retinoblastoma. The right eye contained group D retinoblastoma, which was composed of a superior endophytic tumor with vitreous and subretinal seeds (Figure 1), while the left eye contained group E retinoblastoma.
Figure 1. Ultrasonographic and fundus views in case 1. A, Ultrasonographic view at presentation shows a superior endophytic tumor (arrow). B, Ultrasonographic view immediately before enucleation shows the recurrent superior endophytic tumor (arrow). C, Fundus view at presentation shows a superior endophytic tumor (arrow). D, Fundus view immediately before enucleation shows the recurrent endophytic tumor (arrow).
To salvage vision, chemoreduction with vincristine sulfate, etoposide, carboplatin, and cyclosporine was initiated in June 2005. After 3 courses of chemoreduction, the tumors persisted and grew into the vitreous. In December 2005, the child underwent external beam radiation therapy (EBRT) for persistent retinoblastoma. In October 2006, no retinoblastoma tumor was detected, and complete remission was assumed. However, despite 3 additional cycles of chemotherapy, the tumor recurred in the right eye, which was subsequently enucleated in September 2007. At the 15-month follow-up visit, the patient was well and had no tumor recurrence.
A 3-year-old girl with no family history of retinoblastoma had bilateral retinoblastoma. The right eye contained group D retinoblastoma (Figure 2), while the left eye contained group B retinoblastoma.
Figure 2. Fundus views in case 2. A, Fundus view at presentation shows superior and inferior temporal tumors (white arrows). B, Fundus view at 2 months before enucleation shows flattening of the main tumor (white arrow) and residual intraretinal tumor (black arrow). C, Fundus view immediately before enucleation shows the main tumor that has thickened (white arrow), residual intraretinal tumor (black arrow), and vitreous seeds.
To salvage vision, chemoreduction with vincristine, etoposide, and carboplatin was initiated in September 2008. After 6 courses of chemoreduction, the tumor in the right eye persisted. In May 2009, the right eye was enucleated. At the 18-month follow-up visit, the patient was well and had no tumor recurrence.
Macroscopic examination of the eye from case 1 showed a diffusely thickened retina with white elevations in the superior, inferior, and nasal areas. Numerous fine blood vessels were present on the surfaces of the iris leaflets. A diffuse multifocal tumor was present in the retina. This tumor was present throughout the entire retina and measured approximately 0.5 mm or less in thickness. The tumor was composed of small round blue cells with high nucleocytoplasmic ratios and with hyperchromatic nuclei. These cells grew in cuffs around central vascular channels. The tumor had invaded the subhyaloid space, where there were occasional vitreous seeds of tumor with central areas of necrosis. The tumor had not invaded the optic nerve, optic nerve head, or choroid. No rosettes or fluorettes were identified.
Macroscopic examination of the eye from case 2 showed a diffusely thickened retina with white elevations in the anterotemporal and posteronasal areas. Two predominant lesions were present in the retina. The first lesion in the anterotemporal retina was composed of poorly differentiated retinoblastoma replacing and expanding the retinal layers with areas of necrosis, calcification, mitosis, and apoptosis. This lesion was associated with large and small vitreous seeds. At the base of this tumor, there was a highly differentiated tumor without mitosis, apoptosis, or necrosis and mostly composed of neuronal and glial cell types, as well as a few photoreceptor-like cells. Adjacent and arising from the regressed area, there were retinoblastoma cells in the subretinal space. The second lesion was a well-differentiated tumor with neuronal, glial, and photoreceptor differentiation and was located posteronasal to the optic disc. This tumor was diffusely replacing the retina and present in the subretinal space. The tumors had not invaded the optic nerve, optic nerve head, or choroid. No rosettes or fluorettes were identified.
Diffuse infiltrating retinoblastoma is a rare subtype of retinoblastoma characterized by flat infiltration of the retina. It comprises 1% to 2% of all cases of retinoblastoma and generally manifests as unilateral sporadic tumors in older boys who have no family history of the disease.1 Although ultrasonography and computed tomography readily detect typical retinoblastoma due to calcification, they often cannot detect diffuse infiltrating retinoblastoma because of subtle or insufficient amounts of calcium.1 In addition, many of the initial symptoms of the diffuse subtype overlap with those of ocular inflammatory disease and often result in misdiagnosis.1 Because of unilaterality, its diffuse nature, and the high frequency of vitreous dissemination, the standard treatment for intraocular retinoblastoma is enucleation.2 Herein, we report 2 cases of residual intraretinal retinoblastoma that exhibited flat and diffuse infiltration of the retina on histopathological examination after chemoreduction failure.
In both cases, residual intraretinal retinoblastoma was found after chemoreduction failure. It is possible that this intraretinal tumor was initially present and did not respond to chemoreduction. Unlike typical retinoblastoma, diffuse infiltrating retinoblastoma exhibits slow growth and is of low malignant potential.1 Typical retinoblastoma promotes angiogenesis and is well vascularized,3 but the vasculature characteristics of the diffuse subtype have not yet been reported. We assessed for the presence of endoglin (CD105), which is a marker for newly formed blood vessels,4 in the residual intraretinal retinoblastoma. In both cases, this marker was not detected; however, markers for mature blood vessels (CD31 [endothelial] and smooth muscle actin [pericytes]) were detected (Figure 3 and Figure 4). Unlike neovessels, mature vessels have a basement membrane, which could impede delivery of chemotherapeutic agents to the tumor. As a result, it is plausible that the intraretinal portion of the tumor was resistant to chemotherapy, whereas systemic chemotherapy successfully treated the portion of the tumor with new leaky blood vessels. Therefore, the intraretinal tumor could have been unmasked by chemotherapy.
Figure 3. Vasculature characteristics of diffuse infiltrating retinoblastoma in case 1. A and B, The tumor diffusely infiltrates the retina and surrounds mature blood vessels (arrows) in the posterior retina (hematoxylin-eosin, ×10 and ×25, respectively). C and D, Blood vessels within the intraretinal tumor stain with CD31 (green) and smooth muscle actin antibodies (yellow), which are markers for mature vessels. Numerous mature vessels (arrows) were detected in the tumor (original magnification ×10). E, Blood vessels in the tumor failed to stain with endoglin (CD105) antibody (red), which is a marker for new blood vessels. No immature vessels were detected in the tumor (original magnification ×10). Positive control specimens were used to validate the antibody for endoglin (CD105).
Figure 4. Vasculature characteristics of diffuse infiltrating retinoblastoma in case 2. A and B, The tumor diffusely infiltrates the retina and surrounds mature blood vessels (arrows) in the posterior retina (hematoxylin-eosin, ×10 and ×25, respectively). C and D, Blood vessels within the intraretinal tumor stain with CD31 (green) and smooth muscle actin antibodies (yellow), which are markers for mature vessels. Numerous mature vessels (arrows) were detected in the tumor (original magnification ×20). E, Blood vessels in the tumor failed to stain with endoglin (CD105) antibody (red), which is a marker for new blood vessels. No immature vessels were detected in the tumor (original magnification ×20). Positive control specimens were used to validate the antibody for endoglin (CD105).
Another possibility is that the residual tumor cells of stem cell–like origin, which have been shown to exist in human retinoblastoma,5 could have evolved into the diffuse subtype as a result of chemoreduction. These cells, after being dormant for some time, are capable of forming new tumors later on. The stem cell–like tumor cells could have exhibited low proliferation rates at the time of treatment and would not have responded to chemoreduction. The non–stem cell–like tumor cells could have responded to chemoreduction and allowed the stem cell–like tumor cells to proliferate and grow as a different subtype of retinoblastoma, such as diffuse infiltrating retinoblastoma. Alternatively, diffuse infiltrating retinoblastoma, being of low malignant potential, may simply be a slower-growing subtype of retinoblastoma that is less sensitive to chemotherapeutic agents independent of vasculature.
Salvage EBRT is effective in preserving eyes in patients with bilateral retinoblastoma after failed chemoreduction.6 In the 2 cases reported herein, EBRT was administered in case 1 but failed to salvage the eye. Therefore, EBRT may not be able to eliminate residual intraretinal retinoblastoma exhibiting flat and diffuse infiltration of the retina after chemoreduction failure.
Our 2 cases of residual intraretinal retinoblastoma exhibiting flat and diffuse infiltration of the retina were not primary diffuse infiltrating retinoblastomas. They were residual intraretinal retinoblastomas that resulted after exophytic and endophytic portions of the tumor melted away with chemoreduction. Our patients had intact native intraretinal vessels without evidence of neovascularization, but the vasculature in primary diffuse infiltrating retinoblastomas may be different. Therefore, it is possible that primary diffuse infiltrating retinoblastomas respond more favorably to chemoreduction.
Ocular oncologists should be cognizant of the possibility that, although rare, intraretinal retinoblastoma exhibiting flat and diffuse infiltration of the retina can coexist with other subtypes of retinoblastoma and that this residual intraretinal retinoblastoma may not respond to systemic chemotherapy. In addition, retinoblastoma recurrences after chemoreduction may manifest in a pattern differing from that at initial presentation, and this new pattern may exhibit flat and diffuse infiltration of the retina.
Correspondence: Dr Grossniklaus, Department of Ophthalmology, Emory University School of Medicine, BT 428 Emory Eye Center, 1365 Clifton Rd, Atlanta, GA 30322 (firstname.lastname@example.org).
Author Contributions: Dr Grossniklaus had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Financial Disclosure: None reported.
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