This cancer doesn’t want to be found

Primary vitreoretinal lymphoma presents as chronic uveitis; it remains a challenge to identify.

By Edmund Tsui, MD, Sarwar Zahid, MD, Quraish Ghadiali, MD

Our inpatient ophthalmology consult service was asked to evaluate a 71-year-old Hispanic female who reported that she had three months of decreased vision in her right eye. The patient was admitted for an asthma exacerbation and was undergoing treatment with intravenous and oral steroids. Her past medical history included steroid-dependent asthma, hypertension, hyperlipidemia and breast cancer treated with surgical excision and radiation therapy. Her initial visual acuity was hand motions in the right eye and 20/30 in the left eye. She had no afferent pupillary defect. Her IOP was 17 mmHg in both eyes. Her external examination was unremarkable. Her anterior chamber was deep and quiet in both eyes.

On dilated examination, her right fundus demonstrated a dense vitritis, preretinal hemorrhages, a swollen optic disc and a creamy white subretinal lesion along the inferior arcade (Figure 1A). Her left eye examination was unremarkable (Figure 1B). Fluorescein angiography of her right eye revealed peripapillary leakage and diffuse leakage along the subretinal lesion and inferior arcade (Figure 2A). Furthermore, there were hyperfluorescent foci inferior to the macula (Figure 2B). Spectral-domain optical coherence tomography (SD-OCT) demonstrated hyper-reflective subretinal material (Figure 3). Given the broad differential for her presentation of posterior uveitis, initial management thus consisted of empirical treatment with oral trimethoprim-sulfamethoxazole, acyclovir and voriconazole. We obtained infectious and inflammatory labs and diagnostic paracentesis of anterior chamber fluid and vitreous fluid, all of which were unrevealing.

Figure 1A. Color fundus photograph of the right eye on initial presentation demonstrating a dense vitritis, preretinal hemorrhages, a swollen optic disc and a creamy white subretinal lesion along the inferior arcade.
1B. Color fundus photograph of an unremarkable left eye.

Figure 2A. Fluorescein angiography of the right eye demonstrating peripapillary leakage as well as diffuse leakage along the subretinal lesion and inferior arcade.
2B. Hyperfluorescent foci inferior to the macula.

Figure 3. SD-OCT of the right eye demonstrates hyper-reflective subretinal material.

Her asthma improved after a few days, so her primary team discontinued steroids and discharged her. She returned to the eye clinic for follow-up two weeks later. Her right fundus demonstrated persistent vitritis, disc edema and perivascular sheathing with new satellite lesions nasally (Figure 4). She underwent chest X-ray, MRI and magnetic resonance angiography of the head and neck, all of which showed no contributory masses or lesions.

Figure 4. Color fundus photograph of the right eye two weeks after initial presentation demonstrates persistent vitritis, disc edema, as well as perivascular sheathing and satellite lesions nasally.

Then, the patient underwent pars plana vitrectomy and vitreous biopsy. Intraoperatively, a retinal detachment was noted and a subretinal biopsy also was taken. Bacterial, fungal and acid fast cultures were all negative. The vitreous biopsy showed an atypical lymphocytic cellular infiltrate; however, the sample was inadequate for flow cytometry.

We interpreted the subretinal biopsy to be consistent with non-Hodgkin B-cell lymphoma (Figure 5). Positron emission tomography–computed tomography imaging showed disease localized to the right eye, while cerebrospinal fluid cytology was unremarkable. We diagnosed the patient with primary vitreoretinal lymphoma (PVRL) and referred her to an ocular oncologist for further evaluation in conjunction with radiation oncology. She subsequently received high-dose systemic methotrexate and external beam radiation therapy to the right eye (total 30 Gy).

Figure 5. Photomicrograph of a choroidal biopsy with hematoxylin and eosin staining demonstrates atypical lymphocytic infiltrate.

PVRL discussion

As a masquerade syndrome often presenting as chronic uveitis, PVRL continues to be a challenging diagnosis.¹ On initial presentation, the differential diagnosis is usually broad and includes infectious, inflammatory or malignant etiologies. In the case presented, infectious causes were strongly considered given the history of recent high-dose systemic steroid treatment. In addition to bacterial and fungal cultures, labs should be drawn to rule out other conditions, such as syphilis, tuberculosis and viral etiologies. Another confounder was the patient’s history of breast cancer, which raised a suspicion of metastatic disease.

PVRL is the most common intraocular lymphoma and is defined as a subtype of primary central nervous system lymphoma (PCNSL). PVRL is most commonly of the B-cell type and less frequently of the T-cell type. In patients with PVRL, studies report the incidence of CNS involvement ranging from 56% to 85%. Approximately 15% of patients with PCNSL may subsequently develop intraocular lymphoma.²

Each year, approximately 380 cases of PVRL are diagnosed in the United States.³ Patients who are immunosuppressed (such as our patient who received steroids) have an increased incidence of PVRL, a more aggressive clinical course and a worse prognosis.⁴

Primary vitreoretinal lymphoma generally presents in older patients with a median age of about 60 years with bilateral involvement commonly noted. Patients generally complain of a gradual albeit painless decline in vision or the presence of floaters. Anterior segment inflammation is uncommon, therefore patients may not complain of pain, redness or photophobia.

Dilated fundoscopic examination may demonstrate vitreous cells, retinal or subretinal lesions that appear as white, creamy infiltrates and retinal vascular sheathing. Optic nerve involvement may be indicated by disc hyperemia or edema.4 SD-OCT may demonstrate nodular hyper-reflective lesions at the level of the retinal pigment epithelium. Fluorescein angiography may demonstrate granularity, blockage caused by infiltrates and late staining.⁵

As with the diagnosis of other masquerading syndromes, the diagnosis of lymphoma may be delayed by several months;⁶ therefore, it is crucial to obtain prompt diagnostic testing. Definitive diagnosis of PVRL requires cytologic evaluation through vitreous biopsy or chorioretinal biopsy. Additionally, studies of cytokine analysis demonstrate that increased levels of IL-10 and an increased IL-10:IL-6 ratio in aqueous and vitreous humor could be suggestive of lymphoma.⁷ Flow cytometry can help detect monoclonal populations, characterize and identify subtypes of lymphocytes present and differentiate between B-cell and T-cell lymphomas. Microdissection to obtain cells of interest can permit molecular analysis to evaluate for specific gene rearrangements.

Additionally, the association between primary central nervous system lymphoma and the vitreoretinal type necessitates MRI imaging of the central nervous system.^1,7

Along with its diagnostic complexity, PVRL is also a therapeutic challenge. An exceedingly rare disease, it has not been studied in randomized controlled clinical trials, so there are no defined standards of treatment.⁸ However, multiple approaches to PVRL have been centered around localized vs. systemic therapy.⁸ For disease localized to the eye, treatment may include intravitreal chemotherapy (such as methotrexate) or localized radiotherapy (ranging from 30 Gy to 50 Gy) with systemic high-dose methotrexate.

However, external beam radiation therapy complications include dry eye syndrome, radiation retinopathy, cataracts and optic atrophy. Other therapeutics, such as rituximab, a monoclonal antibody directed against the CD20 antigen, have been reported to be efficacious in certain B-cell lymphomas.⁷

In summary, it is important to maintain a high index of suspicion in patients who present with chronic uveitis and to obtain prompt diagnostic testing. After diagnosing PVRL, a physician should coordinate a multidisciplinary approach between the ophthalmology, oncology and radiation oncology teams. Systemic or localized chemotherapy and radiotherapy have been used to treat PVRL, although no current standard of care exists given the rarity of the disease.

Patient outcome

Following systemic chemotherapy and local radiotherapy, the patient experienced disease remission until 22 months after initial presentation, where follow-up brain MRI showed lesions consistent with CNS lymphoma.

She received more systemic chemotherapy (methotrexate and rituximab) with almost complete resolution of her CNS disease. Thirty months after initial presentation, the patient has no light perception secondary to optic atrophy. OM

REFERENCES

About the Authors
	Edmund Tsui, MD, is an ophthalmology resident (PGY-3) at New York University School of Medicine. He aspires to be an academic uveitis specialist and can be reached at Edmund.Tsui@nyumc.org
	Sarwar Zahid, MD, is an ophthalmology resident (PGY-4) at New York University. His long-term career goal is to become an academic vitreoretinal surgeon.
	Quraish Ghadiali, MD, is a vitreoretinal surgery fellow at Manhattan (N.Y.) Eye Ear & Throat Hospital, Vitreous Retina Macula Consultants of New York and Bellevue Hospital, New York, N.Y.
	Acknowledgements: Thanks to Norman Charles, MD, for his expertise in ocular pathology.