PRIMARY VITREORETINAL LYMPHOMA
H. Nida Sen
Primary vitreoretinal lymphoma (PVRL), previously known as primary intraocular lymphoma (PIOL) or reticulum cell sarcoma, is a subset of primary central nervous system lymphoma (PCNSL) that involves the retina, vitreous, and optic nerve head with or without simultaneous CNS involvement. Most PVRLs are extranodal, non-Hodgkin, diffuse, large B-cell lymphomas.
Epidemiology and Etiology
• More commonly seen in immunocompromised individuals
• Incidence in the United States is estimated at 0.46 per 100,000 person-years.
This contribution to the work was done as part of the authors’ official duties as NIH employees and is a work of the U.S. government.
• It typically affects an older population, usually in the fifth to sixth decades of life.
• Slight male preponderance
• Bilateral in approximately 80%, but can be very asymmetric at presentation
• Immunosuppression (secondary to AIDS or transplantation) is a risk factor. Infectious agents (Epstein-Barr virus, human herpes virus 8, Toxoplasma) have been associated with PVRL.
• Vitreous cells (occurring in sheets) and haze (Fig. 13-1
• AC cells, keratic precipitates (KP) (Fig. 13-5
• Visual acuity is far better than expected based on the amount of inflammation.
• Macular edema is usually absent despite the amount of vitreous inflammation.
• Viral retinitis (cytomegalovirus, varicella zoster virus, herpes simplex virus), acute retinal necrosis
• Metastatic cancer
• The diagnosis is difficult and requires malignant cells or tissue for diagnosis.
• Fluorescein angiography demonstrates diffuse retinal pigment epithelium (RPE) perturbation and late staining at the RPE level with a granular or “mottled” pattern, early blockage with late staining of retinal/subretinal lesions, optic nerve staining or leakage, and pigment epithelial detachments. Lack of cystoid macular edema (CME) and retinal vascular leakage is an interesting feature of PVRL.
• Indocyanine green angiography shows small, round hypofluorescent areas that disappear in the late phase.
• Optical coherence tomography (OCT) demonstrates nodular hyperreflective lesions in the RPE
• Fundus autofluorescence (FAF) shows granular hypo- and hyper autofluorescent spots
• Tissue diagnosis: cytology (large atypical lymphoma cells) (Fig. 13-6
), flow cytometry, cytokine analysis (IL-10 and IL-6), and molecular analyses from ocular fluids (aqueous or vitreous)
• Brain/spinal MRI and lumbar puncture (LP; for flow cytometry and cytology) to identify CNS involvement
• Prognosis is poor.
• Median progression-free survival is less than 3 years, and overall survival is approximately 5 years with systemic chemotherapy.
• Resolution of ocular tumor (either by systemic or local therapy) can help maintain visual acuity and improve quality of life (even though it may not have an effect on overall survival). • Systemic spread outside of the CNS is extremely rare (<10% in autopsy specimens).
• Ocular complications can include glaucoma, cataract (both due to inflammation or radiotherapy), retinal and/or optic nerve atrophy, vitreous hemorrhage, and retinal detachment.
Chan CC, Gonzalez JA. Primary Intraocular Lymphoma. Hackensack, NJ: World Scientific Publishing Co Pte Ltd; 2007.
Chan CC, Rubenstein JL, Coupland SE, et al. Primary vitreoretinal lymphoma: a report from an International Primary Central Nervous System Lymphoma Collaborative Group symposium. Oncologist. 2011;16(11):1589-1599.
Coupland SE, Damato B. Understanding intraocular lymphoma. Clin Exp Ophthalmol. 2008;36(6):564-578.
Fardeau C, Lee CP, Merle-Béral H, et al. Retinal fluorescein, indocyanine green angiography, and optic coherence tomography in non-Hodgkin primary intraocular lymphoma. Am J Ophthalmol. 2009;147(5):886-894.
Grimm SA, McCannel CA, Omuro AM, et al. Primary CNS lymphoma with intraocular involvement: International PCNSL Collaborative Group Report. Neurology. 2008;71:1355-1360.
Sen HN, Bodaghi B, Hoang PL, Nussenblatt R. Primary intraocular lymphoma: diagnosis and differential diagnosis. Ocul Immunol Inflamm. 2009;17(3):133-141.
FIGURE 13-1. Primary vitreoretinal lymphoma. Vitreous cytology shows large lymphoma cells with scant cytoplasm and large convoluted nuclei.
FIGURE 13-2. Vitreous cells. A 65-year-old white man developed PVRL and PCNSL. Vitreous cells in sheets are seen (inset).
FIGURE 13-3. A. A 67-year-old Asian man with PCNSL and PVRL had large subretinal masses in the right eye and diffuse subretinal infiltrates in the left eye with significant vitreous haze. B. The same patient following treatment has resolution of tumor infiltration.
FIGURE 13-4. Subretinal infiltrates. A, B. There is a large white-yellowish subretinal infiltrate temporal to the macula. The fluorescein angiogram shows granular (punctate) RPE perturbance throughout (C) and early blockage (D). E. There is late staining of the large temporal infiltrate.
FIGURE 13-4. (continued) Primary CNS lymphoma. F. MRI shows a solidly enhancing, apparently hypercellular mass in the left temporal lobe with surrounding edema. A brain biopsy was consistent with PCNSL.
FIGURE 13-5. Keratic precipitates (KPs). A. Diffuse, small- to medium-sized KPs in a patient with PIOL. B. There are large granulomatous-appearing pigmented KPs intermixed with stellate KPs more centrally.
FIGURE 13-6. Primary vitreoretinal lymphoma and primary CNS lymphoma. Left eye of a PVRL and PCNSL patient with small subtle subretinal infiltrates hardly visible on color photographs (A) that appear as granular hyper- and hypo autofluorescent spots in a striking pattern on FAF (B). Note that hyper autofluorescent spots on FAF correspond to hypofluorescent spots on FA (C).
RETINOBLASTOMA SIMULATING UVEITIS
Carol L. Shields
Support provided by the Eye Tumor Research Foundation, Philadelphia, PA.
Retinoblastoma classically manifests as a solitary or multifocal, well-circumscribed retinal mass with dilated feeding arteries and veins. Initially, this tumor appears as a translucent subtle intraretinal mass. As the tumor enlarges, it assumes an exophytic, endophytic, or combined growth pattern. Exophytic retinoblastoma appears as a solid retinal tumor with bullous subretinal fluid, whereas endophytic tumor appears as a mass with overlying seeding into the vitreous cavity. A rare growth pattern is diffuse infiltrating retinoblastoma where the tumor assumes a relatively flat, ill-defined horizontal growth along the retinal tissue, simulating uveitis or vitritis. Diffuse retinoblastoma can seed into the anterior segment with neoplastic pseudo-hypopyon and can cause intraocular hemorrhage, further confusing the findings. Often diffuse retinoblastoma is mistaken for uveitis. The least common form of retinoblastoma is diffuse anterior retinoblastoma in which the tumor arises in the anterior segment without retinal involvement and simulates endogenous endophthalmitis or chronic uveitis.
Etiology and Epidemiology
• Retinoblastoma is the most common cancer of the eye in children. It is estimated that there are over 7000 cases per year worldwide with approximately 1800 in Africa, 4000 in Asia, 400 in Europe, 300 in the United States, and 600 in South America.
• The mortality rate from retinoblastoma varies depending on the continent with 70% mortality in Africa, 40% in Asia, 20% in South America, and <5% in Europe and the United States.
• Diffuse retinoblastoma represents <3% of all cases. In a large report on this condition in 34 patients, there were no cases of metastatic disease, as the eye was treated promptly.
• Anterior segment
• White tumor seeds on the corneal endothelium
• Posterior segment
Vitreous tumor seeding appearing as round, fluffy infiltrates with minimal fibrosis
Underlying tumor infiltrating the retina with dilated, tortuous retinal vessels
Vitreous hemorrhage occasionally
Calcification (often subtle) on clinical examination, ultrasonography, or computed tomography
• Vitreous hemorrhage
• Coats disease
• Pars planitis
• Juvenile rheumatoid arthritis
Lesions Simulating Retinoblastoma
• There are several conditions that simulate retinoblastoma, called pseudoretinoblastomas (Table 13-1
• The most common pseudoretinoblastomas include Coats disease, persistent fetal vasculature, and vitreous hemorrhage, depending on the patient’s age.
• B-scan ultrasonography: demonstrates retinal mass with intralesional dystrophic calcification. Must look closely for the calcification as it might just be a single fleck of calcium.
TABLE 13-1. Top 10 Leading Simulators of Retinoblastoma
Percentage Per Age Group (n = 604 patients)
0-1 y n = 283 (%)
>1-2 y n = 57 (%)
>2-5 y n = 89 (%)
>5 y n = 175 (%)
All ages n = 604 (%)
Persistent fetal vasculature PFV
Familial exudative vitreoretinopathy FEVR
Rhegmatogenous retinal detachment
Adapted from Shields CL, Schoenberg E, Kocher K, Shukla SY, Kaliki S, Shields JA. Lesions simulating retinoblastoma (pseudoretinoblastoma) in 604 cases. Ophthalmology. 2013;120:311-316.
• Fluorescein angiography: demonstrates dilated feeding artery and draining vein leading to a retinal mass. The mass might be minimally thickened and subtle.
• Computed tomography (CT): demonstrates a thickened intraocular mass, occasionally with intralesional calcification.
• Magnetic resonance imaging (MRI): demonstrates the intraocular mass but will not show the calcification.
• Fine-needle aspiration biopsy (FNAB): should be reserved for cases that are diagnostically challenging. If retinoblastoma is present, tumor seeding into the orbit with risk for metastasis could occur following FNAB. This test should only be used if retinoblastoma is not high in the differential diagnosis. Usually, FNAB is performed via the pars plana into the mass, but not in cases of possible retinoblastoma. In these cases, FNAB should be performed in the anterior chamber to sample
cells if present. Care should be taken to not seed the tumor and cryotherapy to the entry site should be performed at completion of the procedure. For entry into the vitreous in these cases, the pars plana route should be avoided. A preferred approach would be through the peripheral cornea into aqueous, through the peripheral iris, through the zonules (avoiding the lens), and then into vitreous in an anteroposterior direction. At the conclusion of the procedure, place cryotherapy at the entry site. This is a difficult procedure. Immediate cytologic preparation with preservative is important.
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