Introduction

Primary vitreoretinal lymphoma is a rare intraocular malignancy with typical clinical features that help to distinguish it from other forms of ocular lymphoma. In order to review clinical and management aspects of vitreoretinal lymphoma, it is important first to clarify the terms primary central nervous system lymphoma (PCNSL) and primary intraocular lymphoma.

PCNSL is a variant of extranodal non-Hodgkin lymphoma (NHL) that is predominantly a high-grade B-cell malignancy associated with a median survival ranging from 1–8 years depending on factors such as age and Karnofsky performance status.¹ It originates in the brain parenchyma, spinal cord, leptomeninges, and eyes.^2–4 Formerly used descriptors such as “reticulum cell sarcoma” and “microgliomatosis” are no longer preferred as both misleadingly imply that the lymphoma arises from transformed reticulum or microglial cells.^5,6

Primary intraocular lymphoma (PCNSL-O or PIOL) is a variant of PCNSL with predominantly ophthalmic involvement. In contrast to other ocular lymphomas that affect the orbit, conjunctiva, and uveal tract, PCNSL-O is characterized by vitreoretinal involvement and is therefore referred to as primary vitreoretinal lymphoma (PVRL). It is important to distinguish PVRL from other forms of primary intraocular lymphoma, particularly the primary uveal lymphomas. Primary choroidal lymphoma is generally a low-grade B-cell lymphoma that behaves similarly to extranodal marginal zone (EMZL) lymphomas found elsewhere in the body, while primary iridal lymphoma can be either of B-cell or T-cell origin.

Epidemiology

PCNSL accounts for 1–2% of all cases of lymphoma and approximately 3–5% of primary tumors of the central nervous system.^7–9 From 1973–1997, the incidence of PCNSL increased threefold, partially owing to the corresponding rise in individuals with human immunodeficiency virus (HIV) infection and possibly due to improved diagnosis and/or detection leading to more cases being ascertained.⁷ Rates have since stabilized with an age-adjusted incidence of PCNSL in the USA of 4.8 per million population reported in 2002.⁷ PCNSL is therefore a rare disease affecting fewer than 2000 individuals annually in the USA.⁴

While PVRL is frequently seen in the setting of PCNSL, the exact incidence is unknown. Between 1999 and 2002, approximately 100 new cases of PVRL were reported in the USA.¹⁰ The association between PVRL and PCNSL is variable, with CNS disease manifesting prior to, following, or occurring simultaneously with ocular presentation. Approximately 25% of patients with PCNSL will have concomitant PVRL.³ In contrast, 56–85% of individuals with PVRL will ultimately develop central nervous system involvement.^11–14 Among immunocompetent individuals, the peak incidence of PVRL occurs between ages 50 and 70 years. In the immunocompromised population, PVRL occurs in younger individuals.^15–17 There are no known racial or ethnic associations. In a large, multicenter retrospective review of 221 patients with PCNSL with intraocular involvement, a slight female predominance (57%) was observed.¹⁸

Etiology and pathogenesis

PCNSL is believed to originate from late-germinal center or post-germinal center lymphoid cells, however the neurotropic mechanism by which these cells localize to the CNS remains uncertain.¹⁹ It has been hypothesized that the trafficking of lymphoma cells from the brain to the eye and vice versa involves either invasion of the optic nerve, seeding through shared venous drainage of the brain and eye, or common integrin expression of both organs.⁴ While there are no known risk factors for the development of PCNSL in immunocompetent individuals, immunosuppression secondary to HIV, congenital immunodeficiency, and iatrogenic immunosuppression are risk factors.²⁰ PCNSL develops in as many as 6% of patients with acquired immune deficiency syndrome (AIDS).^21,22 Epstein–Barr virus infection of B-lymphocytes in the absence of T-suppressor lymphocytes results in uncontrolled lymphocytic proliferation. Rare cases of PVRL may be secondary to human T-cell lymphotropic virus type 1 (HTLV-1) infection.²³

Clinical findings

Ophthalmic findings

While individuals may be asymptomatic, more than half present with painless, decreased visual acuity or floaters.^13,24,25 Of those who are asymptomatic, many are diagnosed when ophthalmic screening examination is performed for individuals with known PCNSL. The clinical findings are bilateral in 80% of cases, but are frequently asymmetric.¹¹

The hallmark of PVRL is the presence of fine vitreous cells or clumps of cells and sub-retinal pigment epithelium (RPE) deposits comprised of aggregated lymphoma cells (Fig. 156.1).^26–28 When present, these lesions are considered pathognomonic.²⁸ Anterior segment findings including keratic precipitates, iris nodules, aqueous cells, and flare are frequently encountered but are nonspecific.^17,25 On fundus examination, focal, multifocal, or diffuse choroidal, retinal, or chorioretinal infiltrates can be seen in the presence or absence of vitreous cells (Fig. 156.2).^26,29 Other less commonly reported findings include: perivasculitis (Fig. 156.3),¹³ retinal artery occlusion,³⁰ exudative retinal detachment,³¹ multifocal “punched-out” lesions at the level of the RPE,³² and optic atrophy.³³

Fig. 156.1 A 56-year-old male presented with decreased visual acuity and floaters. On dilated fundus examination, vitreous haze and vitreous cellular condensations (A) were observed. (B) Magnetic resonance imaging of the brain showed scattered increased T2 signal intensity (arrows) in a periventricular distribution consistent with primary central nervous system lymphoma with vitreoretinal involvement. (C) Vitrectomy sample showed large atypical lymphocytes, necrotic lymphoid cells, and nuclear debris. Inset demonstrates characteristic nuclear membrane protrusions and a prominent nucleolus. (Millipore filter, H&E, original magnification ×250.) (Courtesy of RC Eagle Jr, MD, reproduced with permission from Singh AD, Lewis H, Schachat AP. Primary lymphoma of the central nervous system. Ophthalmol Clin North Am 2005; 18:199–207.) (D) Following systemic high-dose methotrexate and intravitreal methotrexate, a significant reduction in the degree of vitreous cells was observed.

Fig. 156.2 A 58-year-old female with primary central nervous system lymphoma presented with blurry vision. Fundus examination of the right eye demonstrated mild vitritis, scattered atrophic chorioretinal lesions with retinal pigment epithelium proliferation, and a white, dome-shaped subretinal infiltrates temporal to the macula.

Fig. 156.3 A 39-year-old African American female was initially presumed to have sarcoidosis based upon vitreous cellular condensations and peripheral vasculitis that were responsive to intraocular steroids. Subsequent neuroimaging and cerebrospinal fluid studies were positive for malignant cells consistent with primary central nervous system lymphoma with vitreoretinal involvement.

Diagnosis

Diagnostic evaluation should begin with a thorough history that explores questions related not only to ocular symptoms, but also to changes in cognitive functioning, neurological deficits, and risk factors for immunocompromise. A detailed ophthalmic examination of both the anterior and posterior segment is required to assess the extent of disease and to establish laterality. In the setting of existing PCNSL, the diagnosis is straightforward and biopsy of an ophthalmic site is not necessary if the clinical findings are compatible with the diagnosis.

In the absence of prior CNS disease, the diagnosis of PVRL is based upon histopathological and cytological features. Several techniques exist for biopsy to establish the diagnosis including vitreous biopsy, retinal biopsy, and subretinal biopsy. Most commonly, diagnostic 23-gauge pars plana vitrectomy is performed. Proper surgical techniques and handling are critical as aspirates are generally of low cellularity and fragile lymphoma cells are prone to lysis during sample collection. Techniques vary by center and expertise; however, it is generally recommended that an undiluted vitreous sample of approximately 1–2 mL be collected prior to the start of the saline infusion during vitrectomy.^20,36 Following collection of the first sample, the infusion fluid is started, and a second diluted vitreous specimen using gentle vitreous cutting can be collected in a separate syringe.³⁷ Some centers also submit the vitreous cassette as a third sample.³⁸ It is recommended that samples be delivered to the laboratory, without fixative, within one hour of surgery.^36,39 Repeated vitreous biopsies are commonly performed in order to establish the diagnosis. In a study of 20 patients with PVRL, three eyes required more than one vitreous biopsy before the diagnosis was confirmed.⁴⁰ More recently, there has been an interest in using 25-gauge sutureless vitrectomy for diagnostic purposes and for improved patient comfort and decreased operative times. This technique has been used with success in some centers.³⁸

When chorioretinal or subretinal lesions are present, a retinal or subretinal biopsy may be performed. A subretinal biopsy technique using a standard three-port pars plana vitrectomy approach has been described.⁴¹ An initial core vitrectomy is performed allowing access to the subretinal infiltrate. Vitreous separation is then induced and thorough vitrectomy is performed over the biopsy site. An incision in the overlying retina just large enough to allow entrance of the vitreous cutter is then made. Suction tubing is then inserted through the retinectomy incision and with gentle cutting action, several samples are obtained. Subretinal aspirates should be placed in a mild cytofixative, such as herpes-glutamic acid buffer mediated organic solvent protection effect (HOPE) fixation or CytoLyt^® (Cytyc Corporation).³⁶ In a series of 84 patients who underwent pars plana vitrectomy, additional chorioretinal biopsy with extended immunohistochemistry and polymerase chain reaction (PCR) gene rearrangement studies were performed in three patients after vitrectomy was nondiagnostic. This technique yielded a definitive diagnosis of PVRL in each case.⁴²

Although diagnostic techniques vary depending upon local expertise, cytology remains the first-line for diagnosis. Access to a pathologist or cytopathologist with experience in ophthalmic diagnosis is essential. The majority of cases of PVRL are diffuse large B-cell lymphomas. In a multicenter retrospective review of 221 individuals with histologically diagnosed PCNSL with ocular involvement, the subtype was large B-cell in 73%, T-cell in 2%, and not specified in 25%.¹⁸ The cytologic features are characteristic. PVRL cells are typically 2–4 times larger than normal lymphocytes, are pleomorphic, and have scant cytoplasm.⁴³ The nuclei may be round, oval, or indented, with conspicuous nuclear membranes, occasional fingerlike protrusions, and multiple, prominent, eccentrically located nucleoli. Mitoses are frequently observed.²⁴ With the use of electron microscopy, intranuclear inclusions, cytoplasmic crystalloids, pseudopodal extensions of the cytoplasm, cytosomes, and autophagic vacuoles can be identified.⁴⁴

As vitreous biopsy is not diagnostic in all cases, supplemental techniques can be helpful in confirming the diagnosis of PVRL. Immunohistochemistry is useful for identifying markers for leukocytes (CD45), B-cells (CD20, CD79a, PAX-5), T-cells (CD45RO), and macrophages (CD68).³⁶ Additionally, clonality can be established with the use of antibodies directed against κ and λ light chains.^14,43,45 Flow cytometry provides a means of quantitatively assessing the proportion of cells in a given sample that demonstrate these immunohistochemical markers. PCR gene rearrangement studies can detect monoclonality of the heavy chain variable (V), diversity (D), and joining (J) immunoglobulin gene segments and are therefore helpful in establishing the diagnosis, however most vitreous biopsy samples are inadequate for PCR.^46,47 Evaluation for gene rearrangement by PCR is most successful in tissue biopsy specimens in which DNA has been isolated by laser capture microdissection.^46,48 Measurement of IL-6 and IL-10 in either aqueous or vitreous fluid can also facilitate diagnosis, although an elevated IL-10/IL-6 ratio is not specific for PVRL.⁴⁹ Measurement of these cytokines has no role in the routine evaluation of suspected PVRL.

Differential diagnosis

Delay in diagnosis of PVRL is common due to the nonspecific ophthalmic manifestations that can masquerade as inflammatory, other neoplastic, and infectious conditions. In one series of 32 patients with histologically confirmed PVRL, the average interval between the onset of ocular symptoms and diagnosis was 21 months.¹⁴ The differential diagnosis includes diseases characterized by chronic anterior and posterior uveitis including sarcoidosis, syphilis, and tuberculosis, birdshot retinochoroidopathy, multifocal chorioretinitis, acute posterior multifocal placoid pigmentary epitheliopathy, serpiginous choroiditis, and punctate inner choroidopathy.⁵¹

When infiltrative subretinal or choroidal lesions are present, entities such as choroidal metastases and amelanotic melanoma should be considered. In contrast, immunosuppressed individuals with systemic lymphomas not arising from the CNS who develop retinal infiltrates are more likely to have viral or fungal retinitis, rather than PVRL. In the immunocompromised population, infectious diseases such as acute retinal necrosis, cytomegalovirus, toxoplasmosis, and Pneumocystis carinii choroiditis should be considered.

Treatment

Ophthalmic treatment

Consensus guidelines for treatment selection for PVRL have not been firmly established and therefore depend upon patient factors as well as local expertise. When disease is unilateral and limited to the eye, local delivery of intravitreal chemotherapy with either methotrexate or rituximab has been shown to be effective and well tolerated.^52–55 Methotrexate as single agent intravitreal chemotherapy for PVRL was first reported in seven eyes of four patients in 1997. All patients achieved complete remission without serious ocular side-effects.⁵² In a larger series of 26 eyes in 16 patients with PVRL at two centers, methotrexate (400 µg/0.1 mL saline) was injected intravitreally twice weekly as an induction phase, then weekly for 1 month in one center and weekly for 2 months in the other center as consolidation therapy, followed by once monthly for 1 year as maintenance therapy. All eyes achieved remission following a maximum of 12 injections. During a median follow-up of 18.5 months, a total of three patients from the first center developed relapsed PVRL and were treated again following the same protocol with complete remission.⁵⁵ The largest series reported to date included 44 eyes in 26 patients treated with the same induction–consolidation–maintenance regimen. Clinical remission was achieved following an average of 6.4 injections and 95% of eyes required 13 injections or less to be free of clinically detectable disease.⁵⁶ None of the patients in this series developed relapse after a follow-up period ranging from 41 to 107 months.⁵⁶ The most commonly reported ocular side effects associated with intravitreal injection of methotrexate include cataract, conjunctival hyperemia, and transient keratopathy ranging from mild punctuate epithelial erosions to severe epitheliopathy.^55,56 Symptoms typically resolved when intravitreal injections were no more than once monthly.^55,56 Early evidence suggests that rituximab may have fewer side-effects and require fewer injections to achieve remission, however further investigation is required.^53,57 Larger, collaborative studies are required to firmly establish guidelines regarding dose, frequency of administration, and duration of treatment.

Prior to acceptance of intravitreal chemotherapy for PVRL, bilateral external beam radiotherapy (EBRT) was widely employed. EBRT remains an important therapy, particularly in patients with bilateral involvement, for those who may not tolerate intravitreal chemotherapy, and in individuals who find it difficult to return for multiple injections (Fig. 156.4). EBRT to both eyes is more commonly performed due to the high incidence of bilateral involvement, however in patients with unilateral disease, EBRT limited to the affected eye is preferred.

Fig. 156.4 A 69-year-old male with known large B-cell lymphoma of the left frontal lobe presented with blurry vision. Dilated fundus examination revealed vitreous cells bilaterally. (A) A yellow, subretinal infiltrate was noted temporal to the macula in the right eye. (B) At 1 month following bilateral external beam radiotherapy there was significant improvement in the subretinal infiltrate.

Radiation doses have varied between centers and have ranged from 30 Gy to 50 Gy with an average dose of approximately 40 Gy given in fractions of 1.5–2.0 Gy.^13,58–63 Response to radiation and relapse rates are difficult to assess due to differences in standard practices and because patients are frequently treated with combinations of therapy. In one series of 19 eyes treated by radiation, nine achieved clinical remission although relapse eventually occurred in two eyes.⁵⁸ In a second series of 13 patients treated by radiotherapy with or without chemotherapy, three had only a partial response and two developed recurrent disease.⁶¹ In another series of 21 eyes in 12 patients, initial treatment included EBRT and systemic chemotherapy (six patients), systemic chemotherapy alone (four patients), EBRT alone (one patient), and no treatment (one patient). No ocular recurrence was observed in those receiving EBRT. Two patients who did not receive EBRT suffered ocular relapse.⁶³ Radiation-related side-effects include optic neuropathy, retinopathy, conjunctivitis, dry eyes, cataracts, and glaucoma.⁶⁴ In most cases, EBRT is reserved for individuals under age 65 years due to the high incidence of neurotoxicity.

Although EBRT is quite effective, one concern relates to the possible need for whole-brain radiotherapy (WBRT) at the time of parenchymal relapse. Matching the field of radiation for WBRT with that of prior EBRT to the eyes can be quite difficult; overlap of fields can result in a region of radiation overdose while significant gaps between adjacent fields leaves a strip of underdosed tissue with the increased risk of progressive disease in that strip. While treatment of a single field that includes both the brain and the eyes would circumvent this problem, the administration of WBRT in the absence of known parenchymal disease is not justified due to the associated neurocognitive toxicity.

Systemic chemotherapy can be used effectively with the advantage that occult disease in the rest of the CNS is addressed at the same time that overt ocular disease is treated. High-dose IV methotrexate penetrates the vitreous in cytotoxic concentrations. Small series of patients have documented efficacy of this approach to PVRL.

Prognosis

Unfortunately, the majority of patients (56–85%) with PVRL subsequently develop CNS disease.^11,12,14,67 In a large, multicenter, retrospective study of 221 immunocompetent patients with CNS lymphoma with ocular involvement, the median progression-free survival and overall survival in patients was reported to be 18 and 31 months, respectively.¹⁸ Age less than 60 years at the time of diagnosis and high initial performance status are recognized as favorable prognostic factors in PCNSL.^68,69 Conversely, involvement of the brainstem and leptomeninges portends a poor prognosis.⁶⁹ The presence or absence of retinal involvement in the setting of existing CNS disease does not appear to be an influential factor.⁶⁹ While large retrospective studies have shown that ocular treatment appears to improve disease control, no overall survival benefit of ocular therapy has been proven.¹⁸