Clinical evaluation

Primary intraocular lymphoma (PIOL), more accurately termed primary vitreoretinal lymphoma (PVRL) to differentiate it from primary uveal lymphoma, is considered the most aggressive of the ocular lymphomas. It is a non-Hodgkin diffuse large B-cell lymphoma (DLBCL). Ocular signs and symptoms may occur before, concurrently with, or subsequent to CNS disease. When the eye is involved first, the disease may be mistaken for a nonspecific posterior uveitis. PIOL is considered a masquerade syndrome because it simulates many diagnoses, most commonly posterior uveitis. In patients older than 50 years with onset of bilateral posterior uveitis, PIOL should be considered in the differential diagnosis. Although 30% of patients present with unilateral involvement, delayed involvement of the second eye occurs in approximately 85% of patients. Approximately 25% of patients with PCNSL will have PIOL at some point, and at least 60% of patients who present with PIOL will develop CNS disease.

Figure 20-10 Fundus photograph from a patient with primary intraocular (vitreoretinal) lymphoma (PIOL). Note the vitreous haze, optic nerve head involvement, and subretinal infiltrate (arrowheads).

(Courtesy of Jacob Pe’er, MD.)

Patients with PIOL often report decreased vision and floaters. They present with diffuse vitreous cells and haze, which may be associated with deep subretinal and/or sub-RPE yellow-white infiltrates (Fig 20-10). Often, fine details of the retina are obscured by the density of the vitritis. Retinal vasculitis and/or vascular occlusion may be noted. The RPE may reveal characteristic clumping overlying the sub-RPE infiltrates (see Chapter 10, Fig 10-14). Anterior chamber reaction may be absent or minimal. See the discussion of cytologic findings of PIOL in Chapter 10.

Imaging

In patients with PIOL, fluorescein angiographic findings can be variable; however, most often hypofluorescent spots are persistent from early to late frames of the angiogram. This is thought to be secondary to tumor cell aggregates between Bruch membrane and the RPE, which do not absorb fluorescein owing to an intact overlying cell membrane. Hypofluorescent window defects can also be present because of damaged RPE. Indocyanine green (ICG) angiography is rarely indicated for PIOL but may show hypocyanescent spots. Ultrasonographic examination may reveal discrete nodular or placoid infiltration of the subretinal space, associated retinal detachment, and vitreous syneresis with increased reflectivity. Although ocular coherence tomography (OCT) findings are not diagnostic, amorphous nodular lesions at the level of the RPE may be seen. If the diagnosis is suspected, consultation with a neurologist and/or an oncologist should be considered, coupled with CNS imaging studies and lumbar puncture. Diagnostic vitrectomy is often performed to confirm PIOL even when the CNS imaging and/or cerebrospinal fluid analysis reveals lymphoma.

Pathologic studies

Diagnostic confirmation of ocular involvement requires sampling of the vitreous and, when appropriate, the subretinal space. Coordinated presurgical planning with the ophthalmic pathologist regarding sample handling is critical to clarify all the steps needed for obtaining the vitreous specimen and transporting it to the laboratory. The pathology laboratory to which the vitreous sample is submitted must be skilled in the processing of small-volume cytologic specimens and experienced in the cytologic evaluation of vitreous samples. If the laboratory lacks the skills to process these samples, the opportunity to diagnose PIOL may be missed and a second biopsy, after cells have re-accumulated in the vitreous, may be required. Even in cases where the biopsy and laboratory evaluation are executed as planned, the diagnosis may be elusive. After consultation with the pathologist, diagnostic pars plana vitrectomy can be performed to obtain the vitreous specimen. When a subretinal nodule is accessible in a region of the retina that is unlikely to compromise visual function, subretinal aspiration of the lesion can be done. Expedited transport of the vitreous to the pathology laboratory is important to ensure cell viability.

The methodology for evaluation of the vitreous and subretinal specimens varies depending on the laboratory. Cytopathology (see Chapter 10, Fig 10-16), including immunohistochemical studies for subclassification of the cells, flow cytometry, and polymerase chain reaction or fluorescence in situ hybridization analysis for gene rearrangements and mutations, and the ratio of interleukin-10 to interleukin-6 are all possible methods of pathologic analysis for lymphoma; see Chapter 3 for a discussion of some of these methods. Specimens with atypical, large lymphocytic cells (Fig 20-11) and characteristic cell surface markers establish the diagnosis of large B-cell lymphoma.

Figure 20-11 Large cell lymphoma, histology. Note the nuclear atypia with irregular nuclear contours and prominent nucleoli (arrows) of these neoplastic lymphoid cells, which were obtained by fine-needle aspiration biopsy.

Treatment

In general, high-dose intravenous methotrexate is given for PCNSL and may also be effective for PIOL. When there is only ocular involvement, intravitreal injections of methotrexate or rituximab or external beam radiotherapy is usually employed. Because the blood–ocular barriers may limit penetration of chemotherapeutic agents into the eye, these modalities may be used in addition to high-dose intravenous methotrexate when there is minimal response of the ocular disease after systemic therapy for the CNS disease. There is no consensus as to whether irradiation of the affected eye using fractionated external beam radiation is more efficacious for the treatment of intraocular lymphoma than intravitreal injection of methotrexate or rituximab. However, although radiotherapy may induce ocular remission, the tumor can recur, and further irradiation places the patient at risk for vision loss due to radiation retinopathy. Radiotherapy to the eye is also associated with substantial ocular surface discomfort. Intravitreal injection of methotrexate or rituximab tends to produce very good local tumor response and low ocular recurrence rates; however, retinal toxicity may occur. CNS or systemic lymphoma is treated in parallel with the intraocular disease by a medical oncologist.

Prognosis

Although the prognosis for patients with PIOL is poor, particularly with CNS involvement, advances in early diagnosis have produced a cohort of long-term survivors. Serial follow-up with the ophthalmologist and an experienced medical oncologist is critical in the management of this disease. Patients with PCNSL without ocular involvement should be observed longitudinally by an experienced ophthalmologist for possible ocular involvement, even after remission of the CNS disease.

• Coupland SE, Bechrakis NE, Anastassiou G, et al. Evaluation of vitrectomy specimens and chorioretinal biopsies in the diagnosis of primary intraocular lymphoma in patients with Masquerade syndrome. Graefes Arch Clin Exp Ophthalmol. 2003;241(10):860–870.

• Kim MM, Dabaja BS, Medeiros J, et al. Survival outcomes of primary intraocular lymphoma: a single-institution experience. Am J Clin Oncol. 2016;39(2):109–113.

• Sagoo MS, Mehta H, Swampillai AJ, et al. Primary intraocular lymphoma. Surv Ophthalmol. 2014;59(5):503–516.

Excerpted from BCSC 2020-2021 series: Section 4 - Ophthalmic Pathology and Intraocular Tumors. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.