Ocular Lymphoma

Ocular lymphoma is a rare cancer that originates in white blood cells and can affect any part of the eye and surrounding tissues, often mimicking common eye conditions and making diagnosis challenging.

Table of contents

• What Is Ocular Lymphoma
• Types of Ocular Lymphoma
• Areas of the Eye Affected
• Risk Factors
• Symptoms
• Diagnosis
• Treatment Options

What Is Ocular Lymphoma

Ocular lymphoma is a cancer that originates in white blood cells called lymphatic cells or lymphocytes and can affect any portion of the eye and surrounding tissues^[1]. It is a very rare disease, making up less than 1 percent of total non-Hodgkin lymphoma cases^[5]. In 2020, about 3,400 adults in the United States were diagnosed with ocular cancers, including lymphoma, melanoma, and others^[5].

Ocular lymphoma is a high-grade, fast-growing cancer^[5]. Because it often mimics common eye conditions such as chronic uveitis (eye inflammation), it has become known as a “masquerade syndrome,” making it one of the most difficult types of eye cancer to diagnose and treat^[5]. On average, it takes over 1 year between symptom onset and the diagnosis of ocular lymphoma^[11].

Types of Ocular Lymphoma

There are three main types of ocular lymphoma, distinguished by the area of the eye they affect^[3][16]:

Primary vitreoretinal lymphoma is a type of primary central nervous system lymphoma. It affects the retina (the light-sensitive tissue that lines the back of the eye), vitreous (the jelly-like fluid inside the eye), and optic nerve^[1][3]. This is frequently a type of non-Hodgkin’s lymphoma called Diffuse Large B cell lymphoma^[1]. It is an extranodal non-Hodgkin, diffuse large B cell lymphoma^[2].

Primary uveal lymphoma affects the choroid layer in the eye. This type belongs to the extranodal marginal zone or mucosa-associated lymphoid tissue lymphoma^[2]. It is distinct from primary vitreoretinal lymphoma and carries a better prognosis^[2].

Secondary intraocular lymphoma is seen in patients who have systemic lymphoma elsewhere in the body. It arises outside the central nervous system or eye and later spreads to the eye^[2][3]. It usually involves the choroid, iris, and rarely the retina^[3]. The lymphoma cells here predominantly involve the uveal tissue^[2].

primary intraocular lymphoma, vitreoretinal lymphoma, primary vitreoretinal lymphoma, PIOL, PVRL

Areas of the Eye Affected

• retina
• vitreous
• optic nerve
• choroid
• iris
• ciliary body

Primary intraocular lymphoma can develop in the retina, the light-sensitive tissue that lines the back of the eye; in the vitreous, the jelly-like fluid inside the eye; or in the optic nerve at the back of the eye^[1]. About 80 percent of people who have primary intraocular lymphoma develop it in both eyes, and it may also be found in or later develop in the brain^[1]. Between 80 percent to 90 percent of people will develop intraocular lymphoma in both eyes^[5].

About 90 percent of people who have intraocular lymphoma will develop central nervous system lymphoma within approximately two years^[5]. Intraocular lymphoma can develop before, after, or at the same time as central nervous system lymphoma. The central nervous system includes the brain, spinal cord, and optic nerves^[5].

Risk Factors

The exact cause of ocular lymphoma is not known^[3]. However, several risk factors have been identified. Some risk factors to develop primary intraocular lymphoma include advanced age or having an immune system disease such as rheumatoid arthritis, AIDS (acquired immunodeficiency syndrome), or taking medications that decrease the body’s immune system, like those used for people with transplanted organs^[1][3].

Most people who have ocular lymphoma are elderly or have an immune system problem. Those with rheumatoid arthritis or who take anti-rejection drugs after a transplant are also at a higher risk for this disease^[3]. Genetics may also contribute and play a role in the development of ocular lymphoma. A person may inherit a gene from a parent that increases the chance of developing this type of cancer^[3].

Symptoms

Intraocular lymphomas have a range of symptoms, making diagnosis sometimes challenging^[1]. A common sign of intraocular lymphoma is uveitis, or eye inflammation, which occurs in 75 percent of cases^[5]. Symptoms of intraocular lymphoma may respond to uveitis treatment, which makes it a challenge for clinicians to properly diagnose intraocular lymphoma^[5].

The most common symptoms for primary intraocular lymphoma include^[1][3][5]:

• Blurry vision
• Decrease or loss of vision
• Floaters (small dots or lines in the field of vision)
• Redness or swelling in the eye
• Increased sensitivity to light
• Eye pain (although this is rare)

While lymphoma usually affects both eyes, symptoms may be more obvious in one eye than the other^[1]. Some people may also have vitreitis, an inflammation of the vitreous of the eye that requires an examination to diagnose^[5].

If intraocular lymphoma occurs with central nervous system involvement, a person may also experience behavioral and cognitive changes, seizures, or other neurological symptoms^[5].

Diagnosis

Ophthalmologists diagnose intraocular lymphoma by assessing patients’ symptoms, checking vision and eye movement, examining the inside of the eye using an ophthalmoscope (an instrument with a light and a small magnifying lens), and by removing a sample of cells from the vitreous for examination^[1].

The diagnosis of primary vitreoretinal lymphoma has been very difficult through the years, and treatment has often been delayed^[11]. The delay has caused some patients to develop central nervous system involvement, resulting in the need for systemic treatment^[11]. In many cases, patients have had multiple eye examinations and have been considered to have uveitis (ocular inflammation) before the correct diagnosis was made^[11].

A procedure called vitrectomy biopsy involves removing a sample of cells from the vitreous for examination^[1]. Ocular oncologists can differentiate between the types of lymphomas around and in the eye and arrange the proper testing and treatment^[1]. The ophthalmologist will work with other specialists to coordinate care.

Recent developments in the diagnosis of primary intraocular lymphoma include immunohistochemistry, flow cytometry, cytokine evaluation, and molecular analysis^[9]. However, definitive diagnosis still requires harvesting of tissue for histopathology^[9]. The MYD88 L265P mutation is seen in about 80% of cases; therefore, a polymerase chain reaction for this mutation helps in making the diagnosis^[11].

Treatment Options

Treatment depends on whether or not the cancer is in other parts of the body^[3]. Ocular lymphoma is treated with a team of doctors including medical, neuro (brain), and radiation oncologists (cancer doctors)^[3]. Management of intraocular lymphoma is best coordinated in association with neuro-oncology clinicians due to the tendency for intracranial involvement^[8].

Treatment options include^[3][7][18]:

Chemotherapy involves the use of particular drugs to kill cancer cells both inside the eye and that may have spread outside the eye. It may be injected directly into the eye, into a vein, or into the spinal fluid. Several different ways exist to give chemotherapy, including through a needle into a vein (intravenous) or as a pill taken by mouth. These drugs travel through the blood to reach and destroy cancer cells all over the body, including cells that may have broken away from the primary tumor.

Other chemotherapy drugs may be given by a needle into the eye’s vitreous humour (called intravitreal) or the cerebrospinal fluid around the eye (called intrathecal)^[7]. Chemotherapy drugs that may be used include methotrexate, cytarabine, thiotepa, chlorambucil, vincristine, cyclophosphamide, etoposide, lenalidomide, and temozolomide^[7]. Sometimes chemotherapy for lymphoma of the conjunctiva may be given as eye drops (a form of topical chemotherapy), such as mitomycin C or fluorouracil^[7].

Local therapy using intravitreal methotrexate and rituximab has been very helpful in the treatment of local disease^[11]. Systemic high-dose intravenous methotrexate is helpful in treating bilateral disease in conjunction with intravitreal therapy^[11]. Initial therapeutic regimens should include methotrexate-based chemotherapy^[9].

External Radiation Therapy may be directed to the brain, spinal cord, or eye. It will help prevent the cancer from spreading or kill any cancer cells that may be there^[3]. Radiation therapy uses high-energy rays or particles to destroy cancer cells. It is the standard treatment for lymphoma of the eye^[7]. External radiation therapy is delivered using a machine outside of the body. The technique used for lymphoma of the eye is called stereotactic radiosurgery^[7]. Radiation is usually given to both eyes and to the central nervous system to help destroy cancer cells that may have spread^[7].

Initial therapeutic regimens should include radiotherapy to the brain and eye^[9]. Because of the risks of redevelopment of disease, local radiation should be given if other options are not possible^[11].

Radioimmunotherapy combines radiation therapy with a monoclonal antibody, which specifically targets cancer cells. A type called yttrium-90 (Y-90) ibritumomab tiuxetan (Zevalin) may be offered for lymphoma in the uvea or adnexal structures^[7]. Very few people will have radioimmunotherapy for lymphoma of the eye^[7].

Immunotherapy helps to strengthen or restore the immune system’s ability to fight cancer. The drug interferon alfa-2b may be offered for lymphoma of the conjunctiva, usually given as eye drops directly to the eye^[7].

Targeted therapy uses drugs to target specific molecules on cancer cells. In very rare cases, targeted therapy is offered for lymphoma of the eye. The targeted therapy drug rituximab may be used^[7].

If there is development of central nervous system lymphoma or recurrent ocular disease, alternatives to high-dose methotrexate under investigation include pomalidomide, stem cell transplantation, or ibrutinib, with or without local therapy^[11]. Promising results have been seen with intravitreal methotrexate and autologous stem cell transplantation for recurrent and refractory disease^[9]. Vitrectomy alone might be helpful as a debulking procedure^[11].

Optimal treatment for primary intraocular lymphoma remains unclear^[9]. Future studies are required to determine the role of radiotherapy and optimal local and systemic chemotherapeutic regimens^[9].