What is Primary Intraocular Lymphoma?
Primary intraocular lymphoma (PIOL) is a rare eye cancer. It’s considered as part of a group of cancers that start in the brain and nervous system but also affect the eye. This cancer type is a form of non-Hodgkin, diffuse large B cell lymphoma. It used to have other misleading names like “malignant lymphoma of the uveal tract” and “reticulum cell sarcoma,” but these are no longer used. Nowadays, it is also sometimes referred to as primary vitreoretinal lymphoma (PVRL), or primary central nervous system lymphoma-ocular or ophthalmic variant (PCNSL-O).
There’s another type of eye cancer that starts in other parts of the body and then spreads to the eye. This is known as secondary intraocular lymphoma. In this case, the cancer cells mainly affect the uveal tissue, which is the middle layer of the eye. Primary uveal lymphoma is less common and it involves B cells, a type of white blood cell, infiltrating the uveal tract. It belongs to another group of cancers, called extranodal marginal zone or mucosa-associated lymphoid tissue lymphoma. It’s distinct from PIOL that deals with diffuse large B cells, and generally has a better prognosis, which means the chances of recovery are relatively better.
What Causes Primary Intraocular Lymphoma?
The reasons behind primary intraocular lymphoma, a type of cancer that occurs in the eye, are still not fully understood.
One theory is the chemokine theory. Chemokines are a type of protein that guide cells to move in the body. There are particular chemokines in the retinal pigment epithelium (a layer at the back of the eye) which can attract lymphoma cells. Essentially, this theory suggests that these proteins might be luring cancer cells into the eye.
Another theory regards how infections can cause the lymphoma. Some infections are known to make lymphocytes, a type of white blood cell, increase in number. Over time, this increase can become uncontrolled, leading to the development of lymphoma. For instance, an Epstein-Barr virus infection can make B lymphocytes, a type of white blood cell, rapidly multiply. This is often observed in people with AIDS, where the virus is always present. That being said, this connection has not been observed in people with primary intraocular lymphoma who do not have a compromised immune system. There’s also evidence to suggest that the DNA of a parasite called Toxoplasma gondii has been found in the lymphoma cells of people with primary intraocular lymphoma.
Risk Factors and Frequency for Primary Intraocular Lymphoma
The exact details about the occurrence rate of Primary Intraocular Lymphoma (PIOL) aren’t completely known. However, the current information mainly relates to a broader category of lymphomas, specifically Primary Central Nervous System Lymphoma (PCNSL). PCNSL is a relatively rare condition, making up 1 to 2% of all lymphomas that don’t originate from lymph nodes (extranodal), and 3 to 5% of primary Central Nervous System tumors.
PCNSL is usually observed in individuals with weakened immune systems. Though, with the advent of highly active antiretroviral therapy (HAART), its occurrence among these individuals has dropped.
PIOL typically affects adults between their 30s and 80s. The average age for diagnosis falls within the 50-60 age range. Although there have been a few cases reported in very young and very old individuals. Those with weakened immune systems tend to get PIOL at a younger age. It’s also worth noting that there are no known racial or ethnic patterns for PIOL and it has been found to affect women twice as much as men.
- Primary Intraocular Lymphoma (PIOL) is a subtype of Primary Central Nervous System Lymphoma (PCNSL).
- PCNSL makes up 1-2% of all extranodal lymphomas and 3-5% of primary Central Nervous System tumors.
- It’s seen more frequently in individuals with weakened immune systems.
- The use of highly active antiretroviral therapy (HAART) has reduced its occurrence in immunocompromised individuals.
- PIOL usually affects adults aged between 30-80, with the average age of diagnosis between 50-60.
- It has been reported in individuals outside this age range, particularly in those with weakened immune systems.
- There are no identified racial or ethnic tendencies for PIOL.
- Women are twice as likely as men to develop PIOL.
Signs and Symptoms of Primary Intraocular Lymphoma
Primary intraocular lymphoma (PIOL) is a rare condition that can often be mistaken for general inflammation of the eye, known as nonspecific uveitis. It usually takes about 4 to 40 months to accurately diagnose PIOL from the time symptoms begin, which can either be related to the eye or the central nervous system (CNS). Around one-fourth of people with CNS lymphomas will have vitreoretinal lymphoma at the time of diagnosis. Conversely, between 56% to 90% of individuals with vitreoretinal lymphoma will show CNS involvement over a period of 8 to 29 months. At the first presentation of PIOL, roughly 16% to 34% of patients already have some CNS involvement.
The most common symptoms of PIOL are a painless blurring of vision or feeling like there are floating spots in your vision. This condition affects both eyes in about 80% of people and often presents asymmetrically. The most common findings on examination are cells in the anterior chamber, deposition of cells on the cornea, cell infiltration in the iris or angle, and extremely rarely, pseudohypopyon. Findings in the back of the eye could include inflammation of the choroid, inflammation of blood vessels, vitritis and frequently, “aurora borealis” or a “string of pearls” appearance in the vitreous or jelly-like substance that fills your eye. Furthermore, there could be creamy, yellowish-orange lesions found over the eye, leading to what’s described as “leopard skin pigmentation.” This may be associated with a condition where the retina detaches from the back of the eye. Over time, these conditions may resolve on their own, resulting in thinning of the RPE and formation of scar tissue beneath the retina.
- Blurred, painless vision
- Seeing ‘floaters’
- Findings in anterior eye segment
- Findings in posterior eye segment
- Possible creamy lesions or ‘leopard skin pigmentation’
If involvement with the central nervous system occurs, seizures could be experienced as an initial symptom. The symptoms can either be localized or spread throughout the body, with common localized symptoms being one-sided weakness (51%) and a lack of coordination (23%). Impairment in the frontal lobe could lead to behavioral changes and cognitive impairment.
- New onset seizures
- Possible one-sided weakness
- Possible lack of coordination
- Possible behavioural changes and cognitive impairment
It’s important to note that orbital involvement in PIOL is highly unusual and helps distinguish it from other conditions. In contrast to other comparable inflammatory conditions of the eye, swelling in the macula of the eye (cystoid macular edema) is often not present, and vision is relatively maintained.
Testing for Primary Intraocular Lymphoma
If you are suspected of having a condition called primary intraocular lymphoma (PIOL), your doctor may use a variety of methods to diagnose this. These methods can be broadly classified into imaging, biopsy and analysis, and blood tests.
Imaging involves using different technologies to create pictures of the inside of your eyes and brain. Some of the common methods used are optical coherence tomography (OCT), fundus fluorescein angiography (FFA), indocyanine green angiography (ICGA), fundus autofluorescence (FAF), ultrasonography (USG), and neuroimaging like computed tomography (CT) and magnetic resonance imaging (MRI). These methods all work in slightly different ways, but the ultimate aim is to locate and examine any unusual growths or lesions in your eyes and brain.
During OCT, for instance, a special light is used to capture detailed 3D images of the inside of your eyes, which can reveal much about the health of your eyes. FAF is another helpful technique where your eyes are exposed to a blue light and the reflections from this light are used to create an image. These images can be hard to get if the eyes are clouded due to inflammation.
Imaging the brain through CT or MRI scans can also show many details not visible otherwise. These methods can unveil harmful growths or lesions.
Biopsy is another diagnostic approach where a small sample is taken from your eyes (like vitreous, the jelly-like substance filling your eyeballs) or the fluid surrounding your brain (cerebrospinal fluid). The sample is then tested in the lab to look for abnormal cells that could indicate PIOL.
This process could take various methods to be fruitful; for example, steroids should be stopped two weeks before the biopsy, and the sample should be processed in the lab as fast as possible to prevent degradation of cells. More than one biopsy may be required for a definitive diagnosis.
Analysis of these samples could involve checking for the structure and appearance of cells (histopathology), checking for specific proteins on the cell surface (immunohistochemistry), looking at the DNA of the cells (polymerase chain reaction), and measuring chemicals in the fluid (cytokine analysis).
In addition to these methods, doctors may recommend getting blood tests done, to rule out other types of illness (like infections or inflammation) that can mimic the symptoms of PIOL. These tests also help prepare for the side effects of further treatment.
Treatment Options for Primary Intraocular Lymphoma
The primary goal in treating CNS disorders like PCNSL and PIOL is controlling the underlying illness and keeping it from spreading. There are several treatments available for this, including injections into the eye (intravitreal injections), chemotherapy (medication that destroys cancer cells), and radiation therapy, which uses high doses of radiation to kill cancer cells.
Depending on the specific case, doctors might use a combination of these treatments or just one. Although chemotherapy in general is the first line of defense for PCNSL, not all treatments that work for regular lymphomas are successful for PCNSL and PIOL.
Localized Therapy involves treatments such as intravitreal injections of chemotherapy drugs, radiation therapy, and a surgical procedure called vitrectomy.
Intravitreal Methotrexate (MTX) is a chemotherapy drug that’s injected directly into the eye to treat PIOL. It might also be used alongside systemic chemotherapy for PVRL when there is CNS involvement, for relapsed PIOL, or in the case of ocular relapse of PCNSL. The therapeutic dose of intravitreal MTX is usually applied twice a week for four weeks, followed by weekly for eight weeks, and then monthly for another nine months. The most common complications with this treatment include cataracts, optic atrophy, and sterile endophthalmitis, a serious eye infection.
Intravitreal Rituximab, another chemotherapy drug, can also be injected directly into the eye in the form of an anti-CD20 monoclonal antibody. The exact schedule varies, from a single injection to multiple injections at varying intervals, usually given at four-week intervals. The primary response is good, but later relapses might require intravitreal methotrexate and radiation.
Radiation Therapy might be given to patients with PIOL without CNS involvement. The exact dose will be determined by the doctor based on individual’s case and patient’s health condition.
Vitrectomy is a surgical procedure that might be considered if there is significant cellular load. In these cases, Vitrectomy is combined with intravitreal chemotherapy.
Systemic Therapy includes chemotherapy, which is usually used alongside radiation therapy or as a primary therapy itself. Methotrexate and Cytosine arabinoside are the common drugs used since they can penetrate the blood-ocular barrier and access the eye.
Methotrexate is able to penetrate the blood-brain barrier, with a significant response rate, and is usually included in all chemotherapeutic regimens. Intrathecal methotrexate, which is administered within the spinal canal or brain ventricles, plays a role in cases with PIOL with CNS involvement.
Cytosine Arabinoside also used as a chemotherapy drug, can penetrate the ocular blood barrier. This drug can cause ocular irritation, conjunctivitis, and keratitis.
Systemic Rituximab often used along with Methotrexate in cases of relapse or recurrences of PVRL.
Combination Chemotherapy includes combinations of several chemotherapeutic agents such as Methotrexate, Cytosine Arabinoside, and Rituximab. Autologous stem cell transplantation is another procedure done in cases of refractory or recurrent PCNSL and PIOL.
Drugs currently under ongoing trials include Pomalidomide, Ibrutinib, and Lenalidomide plus Rituximab.
Chemoradiation, which combines chemotherapy with radiation, can be used as primary therapy or as salvage therapy (used after an initial treatment hasn’t worked) in PIOL. Intra-thecal chemotherapy can also be combined with radiation, and this multimodal therapy has shown better disease control with delayed cognitive neurotoxicity.
What else can Primary Intraocular Lymphoma be?
Diagnosing Primary Intraocular Lymphoma (PIOL) can be a real challenge as there are numerous other diseases, both infectious and non-infectious, that can appear very similar clinically. These include:
- Inflammatory Diseases
- Posterior uveitis/panuveitis
- Intermediate uveitis
- Sarcoidosis
- Vogt Koyanagi Harada disease
- Behçet disease
- Multifocal choroiditis
- Multiple evanescent white dot syndrome
- Acute posterior multifocal placoid pigment epitheliopathy
- Birdshot choroidopathy
- Serpiginous chorioretinopathy
- Frosted branch angiitis
- Infectious Diseases
- Tubercular uveitis
- Endophthalmitis
- Syphilis
- Toxoplasmosis
- Acute retinal necrosis
- Herpetic uveitis
- Neoplasms
- Amelanotic melanoma
- Metastatic cancers
In one study, the most telltale signs that distinguished lymphoma from these other conditions included factors like better vision, less inflammation inside the front part of the eye (anterior chamber flare), less adhesion of the iris to the lens or cornea (posterior synechiae), and less swelling of the optic disc or involvement of the blood vessels in the retina (retinal vasculitis).
What to expect with Primary Intraocular Lymphoma
In cases of PIOL (Primary Intraocular Lymphoma) that have spread to the central nervous system (CNS), the outlook for eye health isn’t great because of very aggressive nature of the disease. Within 12 to 35 months after diagnosis, 9-81% of PIOL patients may no longer be living. If diagnosed before it spreads to the CNS, patients were found to live an average of 60 months. If found after spreading to the CNS, patients were found to live an average of 35 months.
The IELSG score is a method used to predict the outcome of patients with PCNSL (Primary Central Nervous System Lymphoma), but only if it originated in the eyes and has since spread to the CNS. PCNSL doesn’t typically have a good five-year survival rate, which is at around 30% of patients. If these patients are treated with only radiation therapy or a combination of radiation and chemical therapy, they could live an average of 10-16 months. When certain chemotherapy drugs, like methotrexate-based chemotherapy, ifosfamide or trofosfamide, are used, this time can extend to an average of 30 months.
According to a study by Grimm and his team, patients who were given a mix of therapies survived for about 31 months and didn’t see the cancer progressing for about 18 months. The treatments for the eyes didn’t increase their survival rates.
Possible Complications When Diagnosed with Primary Intraocular Lymphoma
Unlike other conditions that affect the back part of the eye (a condition known as posterior uveitis), if PIOL (a specific type of eye disease) is not detected and treated early, it can develop into a serious condition that affects the brain and nervous system. This condition can be fatal if not managed properly.
Treatment typically involves chemotherapeutic drugs, but these can lead to their own set of problems. Possible complications include a reduction in all types of blood cells (pancytopenia), liver problems, dry eye, cataract, and damage to the retina caused by radiation exposure.
Common Side Effects:
- Developing a serious brain and nervous system related condition if not detected and treated early
- Can become fatal
- Possibility of systemic complications like reduction in all types of blood cells
- Liver problems due to chemotherapeutic drugs
- Local complications such as dry eye and cataracts
- Damage to the retina caused by radiation exposure
Preventing Primary Intraocular Lymphoma
If you have been diagnosed with a type of eye cancer known as primary intraocular lymphoma, it’s important you understand that there is a chance it could spread to your central nervous system. The central nervous system is a crucial part of your body, including your brain and spinal cord. If the lymphoma spreads there, it could create noticeable changes in your behavior, cause you to have seizures, weaken one side of your body (hemiparesis), or affect your balance and coordination (ataxia).
