Vitreoretinal Lymphoma: from Symptoms to Diagnosis to Treatment

Kenneth Johnson knew something wasn’t right when, in May 2020, the Ann Arbor resident began experiencing a cluster of uncomfortable symptoms, including jaw pain, earache, and large black and white spots in his vision. “I’ve had floaters before, but none like these,” he says. “There was a whole solar system of spots in my left eye.”

Johnson phoned a nurse at the Veterans Administration Ann Arbor Healthcare System, who recommended he visit the emergency room. The VA team performed a battery of tests, ruling out cardiovascular disease and other issues.

To address the symptoms impacting his vision, they called upon Therese Sassalos, M.D. As a specialist in inflammatory and infectious eye conditions, Dr. Sassalos practices at the Kellogg Eye Center and leads a dedicated uveitis clinic at the Ann Arbor VA.

“Examining Mr. Johnson suggested a diagnosis of uveitis,” Dr. Sassalos recalls. “A complete systemic laboratory and radiologic evaluation ruled out an infectious cause. That left two other possible diagnostic categories: an autoimmune condition like sarcoidosis, which can impact the eyes, lungs and lymph nodes, or a malignancy such as primary vitreoretinal lymphoma.”

Earlier chest imaging had revealed a suspicious lymph node on the lung, which could have been consistent with either diagnosis. After consulting thoracic and rheumatology specialists at the Ann Arbor VA, it was determined his pulmonary node was highly calcified and therefore unlikely to produce a diagnostic sample if it were to be biopsied.

“This meant that in order to make a diagnosis, we would instead need to proceed with a biopsy of vitreous fluid from Mr. Johnson’s eye,” she continues. “Given the small size and volume of the posterior segment of the eye, it can be challenging to get a large enough sample of cells to analyze.” Dr. Sassalos turned to a colleague at Kellogg with extensive clinical and research experience in complex vitreo retinal cases. Retinal and vitreous surgeon Rajesh Rao, M.D., performed a diagnostic vitrectomy, , removing nearly all of the vitreous from the left eye. The cells tested positive for lymphoma.

"Vitreoretinal lymphoma “ is rare, and its consequences are serious,” Dr. Rao explains. “To be absolutely sure, we needed to go the extra mile.”

Much of that extra mile happened behind the scenes in the pathology lab at Kellogg and the U-M Department of Pathology. In addition to traditional analysis, which was overseen by Victor Elner, M.D., Ph.D., an ophthalmic pathologist specializing in rare ocular conditions, genetic testing was performed by a team led by Noah Brown, M.D., Medical Director of the U-M Molecular Diagnostics Laboratory.

“Genetic testing analyzes the DNA in the sample for mutations and biomarkers linked to this particular type of cancer,” explains Dr. Rao. “It is a more sensitive and specific analysis, and can be an important adjunct approach to enhance our ability to detect this hard-to-diagnose cancer.”

In order to analyze the DNA, Dr. Rao and Dr. Brown needed to harness a fundamental tool of molecular diagnostics—polymerase chain reaction (PCR) testing. PCR is used to make thousands of exact copies of DNA molecules from one small sample, creating a specimen large enough to analyze. A gold standard for testing liquid and solid tumor samples, it had not been routinely used before to detect cancer from samples with the gel-like consistency of vitreous.

“Michigan Medicine may be the only center in the U.S. routinely supplementing anatomic with molecular diagnostic testing to analyze diluted and undiluted vitreoretinal samples for lymphoma,” Dr. Rao says. “Some of the top ocular oncologists, retina surgeons, hospitals and labs across the country are now sending vitreous samples here for PCR testing.”

With a definitive diagnosis of intraocular lymphoma, Johnson’s care team expanded to plan and manage his treatment. Drs. Sassalos and Rao were joined by Hakan Demirci, M.D., Kellogg’s Director of Ocular Oncology.

This type of lymphoma can start in the retina and spread to the central nervous system, or vice versa. Initial brain and spinal cord testing found no evidence of disease. Dr. Demirci began treating Johnson’s eyes directly with chemotherapy injections, which lessens side effects elsewhere in the body.

After the diagnosis, Dr. Rao performed a vitrectomy in the right eye, which also had indications of disease.

“The tumor cells circulate in the vitreous,” Dr. Demirci explains. “The vitrectomies removed the majority of those cells, and we hope the chemotherapy will eradicate any remaining cancer.” U-M colleagues in the Neuro-oncology program will monitor Johnson’s central nervous system as treatment progresses.

“Another thing that helps set Kellogg apart is our ability to assess disease activity by sampling fluid from both anterior and posterior chambers of the eye,” he continues. “Very few centers perform this type of ‘liquid biopsy’ to diagnose and monitor treatment effectiveness.”

The journey from symptoms to diagnosis to treatment has not been easy for Kenneth Johnson, and he faces a difficult road ahead. But he is quick to credit the team from Kellogg, U-M and the VA for their persistence and professionalism. “From the start, Dr. Sassalos made it clear she wouldn’t stop until we had answers,” he recalls. “She and all of the doctors and staff who came together on my behalf made good on that commitment.”

“Complex cases like Mr. Johnson’s reinforce the value of multidisciplinary collaboration, and the importance of a patient who is willing to be part of that team,” says Dr. Sassalos. “Through it all, his attitude has been truly inspiring. He reminds all of us why we do what we do.”