Neoplastic masquerade syndromes may account for 2%–3% of all patients evaluated in tertiary uveitis referral clinics. Primary vitreoretinal lymphoma is the most common entity.
Primary Vitreoretinal Lymphoma
Primary vitreoretinal lymphoma is a subset of primary central nervous system lymphoma (PCNSL). It is an uncommon, but potentially fatal malignancy, which may occur with or without CNS lesions. The usual age of onset is in the 50s and 60s, there is no convincing gender predilection, and immunosuppressed patients are at greater risk. Nearly all (98%) cases of PVRL are non-Hodgkin B-lymphocyte lymphomas. Approximately 2% are T-lymphocyte lymphomas. The incidence of PCNSL appears to be increasing and is projected to occur in 1 of every 100,000 immunocompetent patients.
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.
Clinical features and findings
More than two-thirds of patients with PVRL will develop CNS disease—usually within 29 months of diagnosis. About 25% of patients with intracranial lymphoma will develop intraocular disease. Sites of ocular involvement can include the vitreous, retina, subretinal pigment epithelium (sub-RPE), and any combination thereof. The most common presenting symptoms are decreased vision and floaters.
Examination reveals a variable degree of vitritis and anterior chamber cells. Posterior segment involvement can appear as creamy yellow subretinal infiltrates with overlying RPE detachments (Fig 13-1) and discrete white lesions that may mimic acute retinal necrosis, toxoplasmosis, “frosted-branch” angiitis, or retinal arteriolar obstruction with coexisting multifocal chorioretinal scars (Figs 13-2, 13-3) and retinal vasculitis. The lesions vary in thickness from approximately 1 mm to 2 mm. Because of diagnostic difficulty, often patients are already being treated with various anti-inflammatory medications that temporarily can improve the vitreous cellular infiltration, but the effect is not long-lasting. Central nervous system signs may be present and vary in nature from behavioral changes, hemiparesis, and cerebellar signs to epileptic seizures and cranial nerve palsies.
Figure 13-1 Primary central nervous system lymphoma. A, Fundus photograph of multifocal, subretinal granular infiltrates. B, These infiltrates appear as hyperautofluorescent and hypoautofluorescent granular changes on fundus autofluorescence.
(Courtesy of H. Nida Sen, MD/National Eye Institute.)
Figure 13-2 Fundus photomontage shows creamy, large, slightly elevated multifocal lesions, some of which are confluent in superotemporal retina in a patient with biopsy-proven primary vitreoretinal lymphoma. The annular atrophic lesion in the macula is less common and is likely secondary to initial corticosteroid treatment for presumed vitritis.
(Courtesy of H. Nida Sen, MD/National Eye Institute.)
Figure 13-3 Fundus photomontage of a patient with primary vitreoretinal lymphoma shows various lesions. Some are creamy yellowish and elevated; others are more atrophic. There are punctate and granular retinal pigment epithelial changes throughout the fundus.
(Courtesy of H. Nida Sen, MD/National Eye Institute.)
Ultrasonography may indicate vitreous debris, elevated subretinal lesions, and serous retinal detachment. Fluorescein angiography may show hypofluorescent areas due to blockage from a sub-RPE tumor mass or from RPE clumping. Hyperfluorescent window defects may also be caused by RPE atrophy from resolved RPE infiltration. An unusual leopard-spot pattern of alternating hyperfluorescence and hypofluorescence may also be noted. Granular autofluorescence (see Fig 13-1) and nodular elevations at the level of the RPE/sub-RPE corresponding to these areas can also be helpful in the diagnosis. Indocyanine green angiography may show ill-defined hypofluorescent lesions at the late-phase study. Optic coherence tomography (OCT) may reveal mild irregularity of the inner/outer segments of photoreceptors and the RPE/Bruch membrane complex.
All patients with suspected PVRL should be evaluated for CNS lymphoma even in the absence of neurologic symptoms. With CNS involvement, magnetic resonance imaging (MRI) studies of the brain show isointense lesions on T1-weighted images and isointense to hyperintense lesions on T2-weighted images. Computed tomography (CT) without use of contrast shows multiple diffuse periventricular lesions. If intravenous contrast is used with CT, these periventricular lesions may be enhanced. Cerebrospinal fluid analysis reveals lymphoma cells in one-third of patients.
The presence of vitreous cells in cases of uveitis that do not respond to therapy necessitates a vitreous biopsy. Ideally, at least 1 mL of undiluted vitreous sample should be obtained. A retinal biopsy, an aspirate of sub-RPE material, or both may be considered when previous vitreous biopsy results have been negative (Video 13-1). Prior to surgery, communication with an experienced pathologist for instructions on the proper and prompt handling of the specimens is necessary to avoid degeneration of the typically friable cells that may occur with delay. Examination by a pathologist is crucial, as the diagnosis may be difficult to establish because of the frequently sparse cellularity of the specimens. Portions of the specimen are typically prepared for both cytologic examination and cell surface marker determination by flow cytometry. As many as one-third of vitreous biopsies incur a false-negative result; thus, a second biopsy of the vitreous should be performed if the clinical picture warrants.
Primary vitreoretinal lymphoma.
Courtesy of Emilio M. Dodds, MD.
Access the video at www.aao.org/bcscvideo_section09.
Cytokine analysis of vitreous samples can be helpful in supporting the diagnosis of intraocular lymphoma. Interleukin-10 (IL-10) levels are elevated in the vitreous of patients with lymphoma. In contrast, high levels of IL-6 are found in the vitreous of patients with inflammatory uveitis. Thus, the ratio of IL-10 to IL-6 is often elevated in intraocular lymphoma and supports the diagnosis.
Gene rearrangement studies can provide evidence of monoclonality. Flow cytometry may reveal kappa (κ) or gamma (γ) chain restriction or large B-cell populations, both of which support the diagnosis of B-cell lymphoma. A specific mutation (proline for leucine substitution mutation at position 265) of the myeloid differentiation primary response 88 protein (MYD88) is also supportive.
If diagnosis by vitreous aspiration or subretinal aspiration cannot be established, internal or external chorioretinal biopsy techniques may be useful in the diagnosis of PCNSL.
Raparia K, Chang CC, Chévez-Barrios P. Intraocular lymphoma: diagnostic approach and immunophenotypic findings in vitrectomy specimens. Arch Pathol Lab Med. 2009;133(8):1233–1237.
Rothova A, Ooijman F, Kerkhoff F, Van der Lelij A, Lokhorst HM. Uveitis masquerade syndromes. Ophthalmology. 2001;108(2):386–399.
Sen HN, Bodaghi B, Hoang PL, Nussenblatt R. Primary intraocular lymphoma: diagnosis and differential diagnosis. Ocul Immunol Inflamm. 2009;17(3):133–141.
Cytologic specimens obtained from the vitreous or subretinal space often show pleomorphic cells with scanty cytoplasm, hyperchromatic nuclei with multiple irregular nucleoli, and an elevated nuclear-to-cytoplasm ratio (Fig 13-4). Monoclonality of cells is likely to be present in PCNSL. This can be established through immunophenotyping by immunohistochemistry or flow cytometry to demonstrate the clonality of B lymphocytes by the presence of abnormal immunoglobulin κ or γ light chain predominance, specific B-lymphocyte markers (CD19, CD20, and CD22), and/or gene or oncogene translocations or gene rearrangements. Abnormal lymphocytes may be isolated manually or by laser capture and polymerase chain reaction (PCR)–based assays performed to improve the diagnostic yield of paucicellular samples. See also BCSC Section 4, Ophthalmic Pathology and Intraocular Tumors, for discussion of intraocular lymphoma.
Zaldivar RA, Martin DF, Holden JT, Grossniklaus HE. Primary intraocular lymphoma: clinical, cytologic, and flow cytometric analysis. Ophthalmology. 2004;111(9): 1762–1767.
Figure 13-4 Cytology of a vitreous specimen from a patient with primary vitreoretinal lymphoma showing large atypical lymphoid cells (arrows). There are large irregular nuclei and scanty basophilic cytoplasm consistent with large B-cell lymphoma.
(Courtesy of Chi Chao Chan, MD, and H. Nida Sen, MD/National Eye Institute.)
The current treatment of PVRL involves intravitreal chemotherapy (methotrexate and/or rituximab) and local external beam radiation of the eye, with or without systemic chemotherapy depending on CNS involvement. In cases with concomitant PCNSL, systemic highdose chemotherapy in conjunction with intrathecal therapy, whole-brain radiotherapy, and/or autologous stem cell transplantation are considered. There are various chemotherapy regimens. Among the most commonly used is high-dose systemic methotrexate with rituximab. Some specialists use prophylactic treatment of the CNS even in cases of seemingly isolated ocular disease.
Frenkel S, Hendler K, Siegal T, et al. Intravitreal methotrexate for treating vitreoretinal lymphoma: 10 years of experience. Br J Ophthalmol. 2008;92(3):383–388.
Itty S, Pulido JS. Rituximab for intraocular lymphoma. Retina. 2009;29(2):129–132.
Primary vitreoretinal lymphoma responds well to initial treatment; however, high rates of relapse and CNS involvement usually lead to poor prognosis and limited survival. The prognosis for survival depends on whether there is CNS involvement. Despite the availability of multiple treatment modalities and regimens, the long-term prognosis for patients with PCNSL remains poor; the median survival with supportive care alone is 2–3 months, and with surgery alone, median survival is in the range of 1–5 months. The longest median survival in various reports approaches 40 months with treatment, and the 5-year overall survival is approximately 60%. Factors that negatively influence outcome include advanced age, worse neurologic functional classification level, multiple rather than single lesions present in the CNS, and deep nuclei/periventricular lesions rather than superficial cerebral and cerebellar hemispheric lesions.
Excerpted from BCSC 2020-2021 series: Section 9 - Uveitis and Ocular Inflammation. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.