Open access peer-reviewed chapter

Primary Intraocular Lymphoma: The Masquerade Syndrome

Written By

Alessandro Lupi, Barbara Iaccheri, Davide Tucci, Carlo Cagini and Tito Fiore

Submitted: 21 September 2021 Reviewed: 01 November 2021 Published: 18 December 2021

DOI: 10.5772/intechopen.101458

From the Edited Volume


Edited by Yusuf Tutar

Chapter metrics overview

218 Chapter Downloads

View Full Metrics


This chapter aims to provide a complete knowledge over the primary intraocular lymphoma (PIOL) and a correct clinical approach towards this rare condition, to avoid delays in diagnosis, which is considered the most important prognostic factor. A PIOL arises with no specific symptoms and could mimic both inflammatory and non-inflammatory ocular conditions. Also known as reticulum cell sarcoma in the past, PIOL is an ocular malignant condition, with a strong bond with primary central system lymphoma (PCNSL). This linkage is underlined by the fact that approximately 30% of the patients with PIOL have also PCNSL at presentation, while 45–90% will develop PCSNL in the following months. A correct diagnosis is currently achieved by the means of many different techniques: cytology, flow cytometry, immunohistochemistry, molecular analysis, and cytokines assay. Treatment of this condition has been completely revolutionized with the introduction of monoclonal antibodies directed against specific proteins present on the surface of lymphomatous cells.


  • primary intraocular lymphoma (PIOL)
  • primary vitreoretinal lymphoma (PVRL)
  • masquerade syndrome
  • monoclonal antibodies

1. Introduction

An intraocular lymphoma is a heterogeneous group of malignant lymphoid neoplasia, which are divided into two main categories: those arising from vitreoretinal tissue (PVRL) and those deriving from uveal tract [1]. Lymphomas of the retina and/or vitreous are considered as a primary lesion, often with a concomitant central nervous system (CNS) involvement. Conversely, uveal lymphomas can be both primary diseases or metastasis of systemic non-Hodgkin lymphoma (NHL) [1, 2].

The most common form of PIOL is the vitreoretinal lymphoma, an extra nodal, non-Hodgkin, diffuse, large, B-cell lymphoma. Rare cases of primary T-cell vitreoretinal lymphoma can occur, but they are usually secondary to human T-cell lymphotropic virus type 1 infection or metastatic T-cell lymphoma [3, 4, 5]. Among immunocompetent individuals, the average incidence of vitreoretinal lymphoma is between 50 and 60 years, while in immunocompromised populations this condition develops earlier [6, 7, 8].

The most frequent pattern of presentation of PVRL is the infiltration of the sub-retinal pigment epithelium (RPE) in the form of lymphomatous aggregates and the presence of single neoplastic cells in the vitreous cavity [9, 10]. Although less frequently than posterior segment involvement, some important findings in the anterior segment are: keratic precipitates, aqueous cells, flare, and iris nodules; however, these important elements are not specific for a correct diagnosis of intraocular lymphoma [8, 11].

Regarding the involvement of the central nervous system (CNS), the periventricular site is the most common way of presentation and would explain the tendency to spread to cerebrospinal fluid and leptomeninges.

The linkage between PVRL and PCNSL is variable, indeed CNS disease could occur before, following, or simultaneously with the ocular presentation; several previous studies show that 25% of patients with PCNSL will have the concomitant ocular disease at the time of diagnosis [12]. On the other hand 56–85% of individuals with PVRL will develop CNS involvement subsequently [13, 14, 15, 16].

Therefore, PVRL is usually fatal. Despite its rare occurrence, PVRL remains a diagnostic and therapeutic challenge and the lack of effective therapeutic tools and delay in diagnosis may lead to a poor prognosis [17].

Previously misnamed as “reactive lymphoid hyperplasia” or “uveal pseudotumor”, primary uveal lymphoma is a less common entity involving any region of the uveal tract, with a less-aggressive clinical course [18, 19]. Cockerham and associates re-evaluated pathological specimens of benign choroidal reactive lymphoid hyperplasia archived at the Armed Forces Institute of Pathology, and found out that 80% of these are low-grade, B-cell lymphomas [20] and that their subtype is of an extra-nodal, marginal zone or mucosa-associated, lymphoid tissue lymphoma [18]. Primary uveal lymphomas are typically quiescent, paucisymptomatic but with a marked propensity towards extraocular extension [18, 21].

Rarely they tend to turn into more malignant and aggressive tumors and, when treatment is necessary, they are very radiosensitive and carry a good prognosis [19, 20].

Despite the importance of the uveal form as well, we will exhaustively focus on the type of large B-cell intraocular lymphoma [1].


2. Epidemiology

Vitreoretinal lymphomas are rare tumors, with an annual incidence of 0.46 per 100,000 people, representing 4–6% of primary brain tumors and 1–2% of extra nodal lymphomas [12, 16, 22].

In the last 15 years, the incidence of this condition has tripled both in the US and in Europe. At the beginning, this increase in incidence was associated with the arise of immunocompromised persons due to AIDS condition, but since the introduction of highly active antiretroviral therapy, the development of intraocular lymphoma does not follow the decrease of patients with the acquired immune deficiency syndrome (AIDS) [23, 24, 25, 26]. Iatrogenic immunosuppression may also lead to PIOL [27]. The cause for the increased incidence in immunocompetent patients is unknown [24].


3. Aetiology

The aetiology of PIOL/PCNSL is not very clear. Two theories have been implicated in PVRL development: infectious origin and hematological spread.

3.1 Infectious origin

According to the infectious theory, neoplastic transformation occurs into two steps: in the first one, viruses such as HIV or EBV, especially in immunocompromised people, attack the lymphoid cells while, in the second one, it happens neoplastic transformation, that occurs in the CNS and/or in the eye.

This theory is supported by the frequent isolation of the EBV virus in AIDS patients with intraocular lymphoma, which also shows more aggressive characteristics [28]. In rare cases the parasite Toxoplasma gondii has also been isolated in patients with B-cell lymphoma, although the connection is much less strong than that with EBV and HIV [29].

3.2 Haematological spread

In hematological spread, neoplastic cells from nodal and extra-nodal sites spread to ocular and CNS structures [30]. According to this theory, B-cell chemokines may selectively attract lymphoma cells from the choroidal circulation to the retinal pigment epithelium (RPE) and/or retina. This theory is supported by the fact that B-cell chemokine receptors CXCR4 and CXCR5 were detected in the lymphoma cells, whereas the ligands BLC and SDF-1 were detected only in the RPE [31]. On this basis, it has been suggested that inhibition of B-cell chemo-attractants could be a future strategy for the treatment of PIOL [31].


4. Clinical presentation

4.1 Ocular features

Because its presentation can mimic a wide variety of ocular diseases, PVRL has often been addressed as a masquerade syndrome. Signs vary significantly between patients and are usually bilateral (64–83%) but often asymmetrical at presentation [1, 2]. Symptoms of hazy vision and/or floaters are the most commonly reported by patients.

4.1.1 Anterior segment

Anterior segment findings are usually uncommon and specific, including few anterior chamber cells, keratic precipitates [32, 33], presence of pseudo-hypopyon [34, 35], and iris and trabecular meshwork [27, 36], which could cause, respectively, heterochromia and secondary angle closure.

4.1.2 Posterior segment

Posterior segment examination reveals vitritis, ranging from mild to severe.

Lymphomatous cells present in the vitreous cavity are homogeneous and tend to be larger than the reactive cells of the immune system and they rarely aggregate each other in clusters. Ophthalmoscopically it’s possible to observe clumps, strands, sheets and membranes that cause mild-to-severe vitreous haze; these rows of cells along vitreous fibrils give it a similar appearance to the “aurora borealis”. Involvement of the retinal layer and/or RPE is manifested by creamy lesions with a characteristic yellowish appearance on examination of the fundus of the eye [14]. This can result in a characteristic “leopard skin” pigmentation overlying the mass [10]. Other retinal findings include: isolated subretinal lesions [37], exudative retinal detachment [37], RPE atrophy with subretinal fibrosis, and disciform scarring at the macula. Optic nerve infiltration may also occur [38]. Cystoid macular oedema is usually absent.

4.2 Central nervous system features

At presentation, 16–34% of PVRL cases have neurological involvement and it has been estimated that between 42% and 92% of patients can develop intracranial lymphoma within a mean interval of 30 months [14].

Neurological symptoms may occur at any time during the disease course and can be focal and/or diffuse. Most common symptoms include behavioral changes, alteration in cognitive function, focal neurological deficits (like hemiparesis or ataxia) and new-onset seizures (which is a strong indicator of neurological involvement).

Infiltration of the meninges by malignant lymphoma cells without intracerebral involvement can also be noted [12].


5. Diagnosis

5.1 Diagnostic approach

When a PIOL is suspected, it’s necessary to exclude other types of uveitis. Therefore, the patient’s examination should include chest radiography, complete blood cell count, erythrocyte sedimentation rate, routine blood chemistries, and other laboratory studies.

The definitive diagnosis of PIOL is based on the identification of atypical lymphoid cells in the eye, usually sampling the vitreous. However, it’s possible to reach a diagnosis by demonstrating the presence of lymphomatous cells in the cerebrospinal fluid (CSF), avoiding the vitreous biopsy, because PIOL is a subtype of PCNSL.

Furthermore, because PIOL is closely related to PCNSL, neuroimaging of the brain and orbits and a lumbar puncture are required, to exclude a neurological involvement [39, 40, 41].

5.2 Ocular examination

5.2.1 Optical coherence tomography (OCT)

OCT facilitates the detection of many retinal abnormalities whose presence is related to PVRL [42].

The most common alteration on OCT is the evidence of hyperreflective signals (nodules, bands, and nods) at the level of RPE, corresponding to homogenous semi-opaque greyish spots in fundus photography. Those findings are instrumental proof of invasion and proliferation of the lymphomatous cells inside the retinal tissue. Anyway, it’s important to differentiate these hyper-reflective spots from those which can be detected in other clinical entities (e.g., diabetic retinopathy, age-related macular degeneration, etc.) [43, 44, 45].

Apart from this, a wide range of other OCT findings associated with PVRL has been reported, including hyper-reflective subretinal infiltration, hyper-reflective infiltrates in inner retinal layers, RPE undulation, clumps of vitreous cells, and sub-RPE deposits [46]. Conversely, cystoid macular oedema is a rare finding [47].

5.2.2 Fundus fluorescein angiography (FFA) and indocyanine green angiography (ICGA)

The positive and negative predictive value of the combined use of FFA and ICGA is 89% and 85%, respectively [48].

The most common alteration on FFA is the presence of hypo-fluorescent spots, presenting with the so-called “leopard-spot” appearance [49].

Apart from this, a wide range of other FFA findings associated with PVRL has been reported, including punctate hyper-fluorescent window defects (55%), round hypo-fluorescent lesions (34%), and vasculitis (14%) were reported. Cystoid macular oedema did not exceed 2%. In addition, fluorescein leakage along retinal vessels and peri-arteriolar staining may also be seen in eyes with PVRL [43].

The most common alteration on ICGA is the presence of small hypo-fluorescent lesions in the early stages of PVRL, that become less obvious in later stages of the disease [49].

5.2.3 Fundus autofluorescence (FAF)

FAF may facilitate the detection of the active status of PVRL.

The most common alteration on FAF is the presence of a granular pattern of hyper-auto-fluorescent spots encircled by a hypo-auto-fluorescent ring [46]. Granular patterns were detected in several retinal areas, but this finding was not restricted to visible tumor location. Usually, these hyper-auto-fluorescents spots on FAF corresponds to the hypo-fluorescence spots on FFA (36%) and the hyperreflective spots on OCT (43%) [43].

It is noteworthy, that, after intravitreal administration of methotrexate, these hyper-auto-fluorescents spots become hypo-auto-fluorescent [42, 43].

5.2.4 B-scan ultrasound

There are no specific features for PVRL in ultrasound B-scan. However, B-scan can be very useful when visualization of the posterior segment is difficult.

Findings include elevated chorioretinal lesions, retinal detachment, vitreous debris, and enlargement of the optic nerve shadow [49].

5.3 Neurological examination

5.3.1 Imaging

Intraocular lymphoma with CNS involvement is evidenced by computed tomography (CT) and magnetic resonance (MR).

On CT it appears as an isodense or hyperdense lesion while on MR it provides a hypodense signal in both TI and T2 sequences [50]. If the diagnosis is swift, it is probable to find a single lesion up to 70% of cases; with the delay of diagnosis grows the possibility of finding multiple lesions. The most affected regions are: basal ganglia, corpus callosum, or periventricular subependymal regions [51].

5.3.2 Invasive procedure

A lumbar puncture should be performed to obtain cerebrospinal fluid (CSF), and this should be sent for routine cytologic, chemical, and cytokine analysis. Lymphomatous cells can be identified in the CSF of up to 25% of patients with known lesions on MR [50].

If lymphoma cells are found in the CSF, then a diagnosis of PCNSL can be made and no further diagnostic procedures are necessary.

In the cases with suspected CNS lesions on neuroradiological images and with negative CSF cytology, patients should undergo a stereotaxic biopsy of the brain lesion to reach a certain diagnosis [52].

In cases of both negative neuroradiological images and CSF cytology, it is necessary to acquire histological material through diagnostic vitrectomy of the eye most affected by the neoplastic process or in the one with the least visual acuity [33].

5.4 Ophthalmic biopsy

5.4.1 Bioptic material sampling Vitreous biopsy

Vitreous represent the preferred tissue to sample in case of chronic uveitis of unknown cause or when an intraocular malignancy/infection is suspected. Furthermore, vitrectomy can also be performed in case of suspected PCNSL, when lumbar puncture and cytologic analysis of CSF fail to reveal neoplastic cells [53]. A final diagnosis of PIOL allows clinicians to start the appropriate treatment [54, 55].

Cytologic examination of vitreous biopsy has been employed to make a diagnosis of PIOL since the mid-1970s. The technique for performing a complete pars plana vitrectomy in a suspected case of PIOL follows typical protocol:

  • a standard three-port pars plana vitrectomy is performed

  • a complete core vitrectomy is recommended because the cytological analysis is standard [56] and molecular analysis with polymerase chain reaction amplification (PCR) and cytokine-level analysis are commonly performed [41, 57]

  • the first vitreous sample is used for cytological analysis

  • the second vitreous sample is diluted to allow a subsequent analysis of cytokine levels

  • the vitreous fluid is also studied for microbiological aspects

  • aware of the easy tendency of tumor cells to deteriorate, the sample of vitreous fluid is mixed with Roswell Park Memorial Institute (RPMI) culture medium to allow better maintenance and a more complete analysis of cells.

These sample must be analyzed by expert pathologists in the shortest possible time to increase diagnostic possibilities because of the rapid deterioration of cancer cells [58]. It must be stressed out that timing is essential because lymphomatous cells rapidly begin to degenerate.

Vitreous samples may not always contain neoplastic cells and, thus, be negative for the diagnosis of PIOL. This might happen when there is minimal vitreal involvement or when cells have degenerated. In such events, it may be necessary to perform another vitrectomy and send it to a well-qualified cytological laboratory [15]. External chorioretinal biopsy

Failure to identify malignant cells in the vitreous can occur and may be due to degeneration of the cells in samples, paucity of cells into the vitreous cavity, or lack of vitreal involvement. Indeed, lymphomatous cells may be confined solely to the sub-RPE and, in this case, an external chorioretinal biopsy (pioneered by Peyman and colleagues) may lead to a definitive diagnosis of PIOL [59, 60, 61, 62].

The technique for performing an external chorioretinal biopsy in a suspected case of PIOL follows typical protocol:

  • first, if the fundus is visible, laser photocoagulation is applied 1–3 days before surgery in a zone of the area to be biopsied. When vitreous is too hazy, endo-laser is performed immediately after pars-plana-vitrectomy

  • a three-port pars plana vitrectomy is performed (in addition to an endo-laser if it was not performed before the surgery)

  • a nearly full-thickness scleral flap is made, leaving one side attached to act as a hinge; when the flap of the sclera is retracted, the surgeon can visualize the choroids

  • penetrating diathermy is located across the chorioretinal layer along the inner choroidal side

  • appropriate chorioretinal tissue is provided by two opening incisions parallel to the limbus

  • then one blade of a 0.12 nipper is inserted for the entire chorioretinal thickness

  • finally, to allow the correct removal of a block of chorioretinal tissue, two further incisions, perpendicular to the limbus, are made with Vannas scissors

  • finally, the scleral flap is locked. Internal chorioretinal biopsy

Internal chorioretinal (transvitreal retinochoroidal) biopsy is another approach by which chorioretinal tissue is acquired [63].

Biopsy should be carried out as follow:

  • a standard three-port vitrectomy is performed (sending undiluted and diluted vitrectomy to the pathology laboratory for analysis)

  • endo-diathermy is used to outline an area of the retina that is of interest

  • the intraocular scissors are taken to the vitreous chamber where they dissect the marked area of the retina

  • then the intraocular scissors carry retinal tissue out of the eye through the entry site.

5.4.2 Bioptic tissue examinations Histochemical staining

The cytological study of lymphomatous cells represents a standardized technique that has greatly been improved by different types of histochemical staining, such as Giemsa, E-E (haematoxylin-eosin) or Diff-Quick [1].

The main cytological features are: big atypical lymphoid cells with considerable, irregular nuclei and one to several prominent nucleoli, basophilic cytoplasm, rare mitoses, and increased nuclear/cytoplasmic ratio [64]. The identification of lymphomatous cells is further complicated, in addition to their fragility, by the frequent reactive inflammatory infiltrate that accompanies the tumor response. Immunophenotyping

Initial workup should always include immunophenotyping for B-cell markers (CD20, CD79a, PAX5) and T-cell markers (CD2, CD3), because atypical cells found in histochemical staining may also exist in certain reactive conditions, such as acute viral infection, leading to a misdiagnosis [65, 66].

Furthermore, immunophenotyping can detect the presence of monoclonality, which supports the diagnosis of lymphoma, because most PIOL are monoclonal B cell lymphomas that stain positively for B cell markers and show restricted expression of either kappa or lambda chain: indeed, a ratio of kappa/lambda light chains of >3 or <0.6 is considered as a reliable and useful marker for clonality expression [67].

Although most intraocular lymphomas arise from the B cell line, precursors from the T line can rarely be found.

This makes diagnosis much more difficult due to the lack of specific immunocytochemical markers.

Morphologically they can simulate a reactive inflammatory infiltrate but the immunohistochemistry for CD3 marker and the PCR for genetic rearrangements of TCR gene allow to discriminate these two different cell populations [68, 69].

In conclusion, cytology remains the diagnostic gold standard without forgetting, however, that flow cytometry guarantees important information for diagnostic purposes, indeed it can analyze several different markers simultaneously and has been used to confirm monoclonality in both B cell and T cell PIOL [1]. Cytokine’s analysis

Although it’s not diagnostic, analysis of the level of specific cytokines could give valuable information in the diagnosis of PIOL. Furthermore, it can be performed on the supernatant of the vitreous sample, sparing the main specimen for other exams.

The most useful cytokine is IL-10, which is an immune-suppressive cytokine, usually secreted by type-B lymphocytes, whose levels are elevated in both vitreous and aqueous humor (AH). Several studies have shown that interloquine 10 levels of at least 50 pg/mL in aqueous humor and 400 pg/mL in vitreous humor are strongly suspected for intraocular lymphoma.

Moreover, interloquine 10 levels into the vitreous became particularly valuable if compared to IL-6 levels (which is a pro-inflammatory cytokine commonly secreted by macrophages and T-cells): in fact, in other forms of uveitis (given the inflammatory nature of the process) IL-6 levels are lot higher than IL-10 ones, while in PIOL (due to the monoclonal proliferation of type-B lymphocytes) IL-10 levels became prominent. Therefore, also the relationship between the interloquine 10 and the interloquine 6 represents an effective method in placing the diagnostic suspicion of intraocular lymphoma; a ratio greater than 1 is very suggestive for tumor pathology.

On the other side, low interloquine 10 levels may be particularly helpful when a T-cell lymphoma is suspected [70]. PCR analysis

Molecular investigations of vitreous samples with PCR can be very useful in the research of lymphocytes’ clonality, which is essential for the validation of PIOL diagnosis [70, 71, 72, 73, 74, 75, 76].

Detection of clonal immunoglobulin (IgH) and clonal T-cell receptor (TcR) genes rearrangements can contribute to the molecular diagnosis of B-cell and T-cell lymphoma, respectively [73, 74, 75].

However, obtain a significant result of genetic analysis, an adequate number of cells should be studied and this is not always possible due to the lack and fragility of lymphoma population [75, 77]. Moreover, with the aim of avoiding misinterpretation of minor clonal expansions as evidence of lymphoma, the results should be evaluated in the context of clinical and morphological features.

5.5 Differential diagnosis

PIOL is one of the most challenging masquerade syndromes. Due to its heterogeneous clinical features, diagnosis is often belated, inducing delayed therapeutic management with poor visual prognosis and life-threatening complications [14].

Differential diagnosis must consider the age of the patient and the clinical presentation. Further investigations will be mandatory to confirm the diagnosis, when possible.

5.5.1 Infectious entities Viral retinitis

PIOL may masquerade as acute retinal necrosis (ARN), caused by a herpes virus infection, typically in immunocompetent patients. Necrosis usually starts at the peripheral retina, progresses rapidly towards the posterior pole, and is associated with vasculitis and dense vitritis. Retinal detachment may occur in 30–75% of cases during the disease.

PIOL may also masquerade as a CMV retinitis, that, conversely, typically occurs in immunocompromised patients.

In both cases, necrosis and hemorrhages can mimic a PIOL and differential diagnosis is confirmed only by AH or vitreous sampling and PCR analysis [78]. Severe ocular toxoplasmosis

The differential diagnosis with lesions caused by Toxoplasma gondii is very important; they are generally very characteristic already at the ophthalmoscopic examination in immunocompetent people but the greatest difficulties occur in immunocompromised patients because the involvement of anterior segment, vitreous cavity, and retinal scars can simulate the changes in RPE, typical of intraocular lymphoma.

It is therefore very important an appropriate analysis of the ocular fluid that allows isolating the parasite to differentiate the two conditions; nevertheless, in some cases of PIOL the parasite was isolated, suggesting a possible infectious origin of the lymphomatoid process [29]. Ocular lue

Syphilitic retinitis has very specific ophthalmoscopic and diagnostic characteristics that can allow to differentiate it from the forms of intraocular lymphoma.

It involves the peripheral retina and, more rarely, the posterior pole. It is associated with retinal vasculitis, moderate vitreous activity, and a modest spread to the anterior segment.

These lesions resolve without leaving any signs with appropriate antibiotic therapy and diagnosis is achieved thanks to serological examination. Whipple illness

Whipple condition is a rare systemic disorder caused by Tropheryma whipplei which can present rare and late ocular manifestations such as uveitis and chorioretinitis with very disabling bleeding components [79]. Various neuro-ophthalmological manifestations have also been reported, such as ophthalmoplegia, supranuclear gaze palsy, nystagmus, myoclonus, ptosis, papilledema, or optic nerve atrophy.

Persistent vitritis along with retinitis may mimic PIOL. Specific antibiotics may cure the disease without corticosteroids.

5.5.2 Non-infectious entities Granulomatous processes

The two conditions that mostly enter into differential diagnosis with intraocular lymphomas are sarcoidosis and TBC.

Both of these conditions affect older people and, specially, those with compromised immune defenses.

Although the presence of very specific elements such as posterior synechiae or cystoid macular edema enable an easy differential diagnosis with PIOL, in cases of the massive involvement of the posterior segment the clinical situation can be more difficult to define [80].

The further difficulty is given by the need to perform multiple tests to reach the correct diagnosis so that in some cases it is even necessary to analyze eye samples [81]. Bechet’s disease

Bechet’s disease occurs in young males more than females. Retinal necrosis is associated with dense vitritis, retinal vasculitis, and retinal vascular occlusion. Foci of retinitis may mimic areas of infiltration by PIOL and may resolve spontaneously.

Diagnosis is based on a set of criteria defined by the International Study Group for Bechet’s disease. Atypical Fuchs iridocyclitis

Fuchs iridocyclitis is typically unilateral disease that occurs in young adults and involves the anterior segment of the eye. Sometimes, it may also be associated with different types of intermediate uveitis as well as PIOL. Therefore, PIOL must be considered in atypical forms of FHC, especially when there is bilateral involvement. Cryptogenic inflammatory processes

The presence of idiopathic inflammatory processes, especially in elderly and immunocompromised people, represents the most common and most difficult differential diagnosis.

These processes arise with completely nonspecific inflammatory affections, concerning the posterior segment.

In these cases, it’s very important the diagnostic suspicion of lymphomatoid origin and clinicians should perform all the necessary analysis to discriminate this condition [82]. Miscellanea

Hodgkin’s lymphomas can manifest themselves in the form of non-specific inflammatory processes of the posterior segment but, unlike PIOL, the vitreous involvement is much less evident [83].

Atypical uveo-meningitis that can mimic the clinical aspects of VKH syndrome and be resistant to common attack drugs should raise the suspicion of a lymphomatoid process [84].

Uveitis associated with the HTLV-1 virus provide ophthalmological characteristics very similar to PIOL; diagnostic investigations are therefore necessary for making a correct differential diagnosis [85].


6. Treatment

Optimal management for patients with PIOL requires a team of different specialists involving an ophthalmologist, The first line of treatment is high-dose systemic chemotherapy, associated with topical intravitreal chemotherapy and/or ocular radiotherapy, even in cases where no evidence of PCNSL is detected [2, 86].

6.1 Systemic chemotherapy

According to recent guidelines, systemic intravenous therapy with methotrexate represents the gold standard for the treatment of PIOL with a CNS and/or systemic involvement. Results show a very high remission rate, with an even better outcome when combined with other treatments [11, 87]. Several studies have also shown an increase in survival compared to treatments that did not include high doses of chemotherapy [88].

Among the many chemotherapic regimens including methotrexate, several studies reported that the MATRIX regimen (methotrexate, cytarabine, thiotepa, and rituximab) offers the best clinical outcome, with a higher success rate than methotrexate alone or any other form of a combination of drugs [89].

In cases with relapse or refractory response, treatment includes high dose chemotherapy with thiotepa, busulfan, and cyclophosphamide, followed by autologous peripheral blood stem cell transplantation [88].

6.2 Ocular chemotherapy

Ocular chemotherapy means the usage of specific chemotherapic agents administered intravitreally. Two local chemotherapic agents can be used in the treatment of PIOL: methotrexate and rituximab.

6.2.1 Intravitreal methotrexate

The use of intravitreal methotrexate, combined with systemic chemotherapy, has shown good results in the local control of PIOL. Currently, the dose is 400 μg in 0.1 mL and the plan assumes two injections per week during the first month, one injection per week in the next two months, and one injection per month during the following nine months, for a total of 1 year of therapy [90]. Same regimen is recommended in the treatment of relapsed PIOL [91, 92, 93], in the ocular relapse of PCNSL [94], and intrathecal chemotherapy [95].

Results show very high remission rates, while ocular complications are unlikely to happen and are essentially represented by transient changes in intraocular pressure and corneal epitheliopathy [96].

6.2.2 Intravitreal rituximab

The use of intravitreal Rituximab (an anti-CD20 monoclonal antibody) has recently been proposed for the treatment of CD20-positive PVRL [88]. The most studied treatment plan assumes one injection per week in four weeks.

Results show a high rate of the initial response to treatment, but there is still a high rate of tumor recurrence. In these cases, treatment can be with a new course of rituximab which has less toxicity than other chemotherapy drugs or by initiating therapy with methotrexate [97].

6.3 Radiation therapy

The use of radiation therapy for PIOL can vary according to various factors.

In forms of PIOL with exclusive ocular localization, local radiation exposure with external radiotherapy represents the current therapeutic standard, with an optimal dosage of 30–35 Gy administered in approximately 15 fractions [2, 98].

In cases, with concomitant involvement of both eyes and/or CNS and in cases in which systemic chemotherapy treatment has failed, panencephalic and ocular irradiation treatment can be added, but this could lead to complications both at the cerebral and ocular level, such as cognitive deterioration, ataxia, and, rarely, even death [98].

6.4 Rising treatments

In consideration of the continuous emerging of new resistance mechanisms put in place by cancerous cells against current therapies, there is a rising interest in developing new therapeutical approaches with engineered techniques.

One of the most studied strategies involves the use of FasL vesicles membranes, to stimulate the immune system to invade the eye (interrupting its situation as a privileged immune site) [99].

Another very promising strategy (tested only in animals) is the use of intraocular injection with recombinant immunotoxin HA22, which shows a very satisfactory response rate [100].

Other monoclonal antibodies (such as daclizumab, efalizumab, and alemtuzumab) have been tested and showed positive results in animal models [101].

Some authors described autologous stem cell transplantation as a possible therapeutic strategy in case of refractory and/or recurrent intraocular lymphomas, but, the lack of data does not allow to define of universal therapeutic standards as well as the correct chemotherapy regimen for transplant preparation [88, 102].


7. Prognosis

The diagnosis of PVRL is often delayed, due to late referral to an ophthalmologist: indeed, most patients present with unalarming symptoms, like persistent floaters but relatively preserved visual acuity.

The mortality rates between the various studies differ enormously.

This is partly due to the rarity of the disease which makes it impossible to identify a standardized and universally used therapeutic regimen, partly due to the clinical differences of the patients under examination.

Despite this, literature states that the rate fluctuates between 9 and 81%, guaranteeing an average survival of about 2 years from diagnosis [1, 98].


8. Conclusion

Management of PIOL is very challenging for the ophthalmologist because diagnosis is usually made difficult by the great capacity of this condition to masquerade other common ocular affections and treatment strategies that have poor clinical evidence (due to lack of cases). Anyway, in recent years the improvement of diagnostic techniques allowed a more rapid diagnosis and the development of new therapeutical strategies. The hope is that increasing in diagnostic efficiency and therapeutic perspectives could lead to the definition of univocal guidelines thanks to an increasing number of intraocular lymphomas to be subjected to various trials.

In conclusion, it’s essential to create a multidisciplinary network of specialists involving an oncologist, onco-hematologist, and ophthalmologist to define the best diagnostic and therapeutic process.


  1. 1. Coupland SE, Damato B. Understanding intraocular lymphomas. Clinical and Experimental Ophthalmology. 2008. DOI: 10.1111/j.1442-9071.2008.01843.x
  2. 2. Chan C et al. Primary vitreoretinal lymphoma: A report from an international primary central nervous system lymphoma collaborative group symposium. The Oncologist. 2011. DOI: 10.1634/theoncologist.2011-0210
  3. 3. Abrey LE et al. Primary central nervous system lymphoma: The memorial sloan-kettering cancer center prognostic model. Journal of Clinical Oncology. 2006. DOI: 10.1200/JCO.2006.08.2941
  4. 4. Marshall AG et al. HTLV-I associated primary CNS T-cell lymphoma. Journal of the Neurological Sciences. 1998. DOI: 10.1016/S0022-510X(98)00111-7
  5. 5. Coupland SE et al. T-cell and T/natural killer-cell lymphomas involving ocular and ocular adnexal tissues: A clinicopathologic, immunohistochemical, and molecular study of seven cases. Ophthalmology. 1999. DOI: 10.1016/S0161-6420(99)90492-X
  6. 6. Babu K, Murthy KR, Krishnakumar S. Two successive ocular malignancies in the same eye of a HIV-positive patient: A case report. Ocular Immunology and Inflammation. 2010. DOI: 10.3109/09273940903374237
  7. 7. Mathai A, Lall A, Jain R, Pathengay A. Systemic non-Hodgkin’s lymphoma masquerading as Vogt-Koyanagi-Harada disease in an HIV-positive patient. Clinical & Experimental Ophthalmology. 2006. DOI: 10.1111/j.1442-9071.2006.01205.x
  8. 8. Rajagopal R, Harbour JW. Diagnostic testing and treatment choices in primary vitreoretinal lymphoma. Retina. 2011. DOI: 10.1097/IAE.0b013e31820a6743
  9. 9. Dean JM, Novak MA, Chan CC, Green WR. Tumor detachments of the retinal pigment epithelium in ocular/central nervous system lymphoma. Retina. 1996. DOI: 10.1097/00006982-199616010-00009
  10. 10. Gass JDM et al. Multifocal pigment epithelial detachments by reticulum cell sarcoma: A characteristic funduscopic picture. Retina. 1984. DOI: 10.1097/00006982-198400430-00001
  11. 11. Akpek EK et al. Intraocular-central nervous system lymphoma: Clinical features, diagnosis, and outcomes. Ophthalmology. 1999. DOI: 10.1016/S0161-6420(99)90341-X
  12. 12. Hochberg FH, Miller DC. Primary central nervous system lymphoma. Journal of Neurosurgery. 1988. DOI: 10.3171/jns.1988.68.6.0835
  13. 13. Peterson K, Gordon KB, Heinemann MH, De Angelis LM. The clinical spectrum of ocular lymphoma. Cancer. 1993. DOI: 10.1002/1097-0142(19930801)72:3<843::AID-CNCR2820720333>3.0.CO;2-#
  14. 14. Cassoux N et al. Ocular end central nervous system lymphoma: Clinical features and diagnosis. Ocular Immunology and Inflammation. 2000. DOI: 10.1076/ocii.
  15. 15. Char DH, Ljung BM, Miller T, Phillips T. Primary intraocular lymphoma (ocular reticulum cell sarcoma) diagnosis and management. Ophthalmology. 1988. DOI: 10.1016/S0161-6420(88)33145-3
  16. 16. Freeman LN, Schachat AP, Knox DL, Michels RG, Green WR. Clinical features, laboratory investigations, and survival in ocular reticulum cell sarcoma. Ophthalmology. 1987. DOI: 10.1016/S0161-6420(87)33256-7
  17. 17. Fend F, Ferreri AJM, Coupland SE. How we diagnose and treat vitreoretinal lymphoma. British Journal of Haematology. 2016. DOI: 10.1111/bjh.14025
  18. 18. Coupland SE et al. Extranodal marginal zone B cell lymphomas of the uvea: An analysis of 13 cases. The Journal of Pathology. 2002. DOI: 10.1002/path.1130
  19. 19. Coupland SE, Joussen A, Anastassiou G, Stein H. Diagnosis of a primary uveal extranodal marginal zone B-cell lymphoma by chorioretinal biopsy: Case report. Graefe's Archive for Clinical and Experimental Ophthalmology. 2005. DOI: 10.1007/s00417-004-1050-4
  20. 20. Cockerham GC, Hidayat AA, Bijwaard KE, Sheng ZM. Re-evaluation of ‘reactive lymphoid hyperplasia of the uvea’: An immunohistochemical and molecular analysis of 10 cases. Ophthalmology. 2000. DOI: 10.1016/S0161-6420(99)00025-1
  21. 21. Neudorfer M, Kessler A, Anteby I, Goldenberg D, Barak A. Co-existence of intraocular and orbital lymphoma. Acta Ophthalmologica Scandinavica. 2004. DOI: 10.1111/j.1600-0420.2004.00354.x
  22. 22. Aziz HA, Peereboom DM, Singh AD. Primary central nervous system lymphoma. International Ophthalmology Clinics. 2015. DOI: 10.1097/IIO.0000000000000055
  23. 23. Goldberg DE, Smithen LM, Angelilli A, Freeman WR. HIV-associated retinopathy in the HAART era. Retina. 2005. DOI: 10.1097/00006982-200507000-00015
  24. 24. Nasir S, DeAngelis LM. Update on the management of primary GNS lymphoma. Oncology. 2000
  25. 25. Rivero ME et al. Acquired immunodeficiency syndrome-related intraocular B-cell lymphoma. Archives of Ophthalmology. 1999. DOI: 10.1001/archopht.117.5.616
  26. 26. Sen HN et al. Intravitreal methotrexate resistance in a patient with primary intraocular lymphoma. Ocular Immunology and Inflammation. 2008. DOI: 10.1080/09273940801899764
  27. 27. Chan SM, Hutnik CML, Heathcote JG, Orton RB, Banerjee D. Iris lymphoma in a pediatric cardiac transplant recipient: Clinicopathologic findings. Ophthalmology. 2000. DOI: 10.1016/S0161-6420(00)00172-X
  28. 28. Margolis L, Fraser R, Lichter A, Char DH. The role of radiation therapy in the management of ocular reticulum cell sarcoma. Cancer. 1980. DOI: 10.1002/1097-0142(19800215)45:4<688::AID-CNCR2820450412>3.0.CO;2-F
  29. 29. Shen DF et al. Detection of Toxoplasma gondii DNA in primary intraocular B-cell lymphoma. Modern Pathology. 2001. DOI: 10.1038/modpathol.3880424
  30. 30. Buettner H, Bolling JP. Intravitreal Large-Cell Lymphoma. Mayo Clinic Proceedings. 1993. DOI: 10.1016/S0025-6196(12)62276-9
  31. 31. Chan CC, Shen DF, Hackett JJ, Buggage RR, Tuaillon N. Expression of chemokine receptors, CXCR4 and CXCR5, and chemokines, BLC and SDF-1, in the eyes of patients with primary intraocular lymphoma. Ophthalmology. 2003. DOI: 10.1016/S0161-6420(02)01737-2
  32. 32. Coupland SE, Heimann H, Bechrakis NE. Primary intraocular lymphoma: A review of the clinical, histopathological and molecular biological features. Graefe's Archive for Clinical and Experimental Ophthalmology. 2004. DOI: 10.1007/s00417-004-0973-0
  33. 33. Buggage RR, Chan CC, Nussenblatt RB. Ocular manifestations of central nervous system lymphoma. Current Opinion in Oncology. 2001. DOI: 10.1097/00001622-200105000-00001
  34. 34. Corriveau C, Easterbrook M, Payne D. Lymphoma simulating uveitis (masquerade syndrome). Canadian Journal of Ophthalmology. 1986
  35. 35. Lobo A, Larkin G, Clark BJ, Towler HMA, Lightman S. Pseudo-hypopyon as the presenting feature in B-cell and T-cell intraocular lymphoma. Clinical & Experimental Ophthalmology. 2003. DOI: 10.1046/j.1442-9071.2003.00624.x
  36. 36. Velez G et al. Iris involvement in primary intraocular lymphoma: Report of two cases and review of the literature. Survey of Ophthalmology. 2000. DOI: 10.1016/S0039-6257(00)00118-1
  37. 37. Levy-Clarke G, Byrnes GG, Buggage RR, Chan C-C. Primary intraocular lymphoma diagnosed by fine needle aspiration biopsy of a subretinal lesion. Retina. 2002. DOI: 10.1097/00006982-200208000-00026
  38. 38. Hedayatfar A, Chee SP. Presumptive primary intraocular lymphoma presented as an intraocular mass involving the optic nerve head. Journal of Ophthalmic Inflammation and Infection. 2012. DOI: 10.1007/s12348-011-0045-7
  39. 39. Hormigo A, DeAngelis LM. Primary ocular lymphoma: Clinical features, diagnosis, and treatment. Clinical Lymphoma. 2003. DOI: 10.3816/CLM.2003.n.010
  40. 40. Bataille B et al. Primary intracerebral malignant lymphoma: Report of 248 cases. Journal of Neurosurgery. 2000. DOI: 10.3171/jns.2000.92.2.0261
  41. 41. Tuaillon N, Chan C. Molecular analysis of primary central nervous system and primary intraocular lymphomas. Current Molecular Medicine. 2005. DOI: 10.2174/1566524013363915
  42. 42. Egawa M, Mitamura Y, Hayashi Y, Naito T. Spectral-domain optical coherence tomographic and fundus autofluorescence findings in eyes with primary intraocular lymphoma. Clinical Ophthalmology. 2014. DOI: 10.2147/OPTH.S58114
  43. 43. Folgar FA et al. Spatial correlation between hyperpigmentary changes on color fundus photography and hyperreflective foci on SDOCT in intermediate AMD. Investigative Ophthalmology and Visual Science. 2012. DOI: 10.1167/iovs.12-9813
  44. 44. Ota M et al. Optical coherence tomographic evaluation of foveal hard exudates in patients with diabetic maculopathy accompanying macular detachment. Ophthalmology. 2010. DOI: 10.1016/j.ophtha.2010.06.019
  45. 45. Barry RJ et al. Characteristic optical coherence tomography findings in patients with primary vitreoretinal lymphoma: A novel aid to early diagnosis. The British Journal of Ophthalmology. 2018. DOI: 10.1136/bjophthalmol-2017-311612
  46. 46. Casady M et al. Fundus autofluorescence patterns in primary intraocular lymphoma. Retina. 2014. DOI: 10.1097/IAE.0b013e31829977fa
  47. 47. Jiang T, Zhao Z, Chang Q. Evaluation of cytologic specimens obtained during experimental vitreous biopsy using B-cell lymphoma line. European Journal of Ophthalmology. 2014. DOI: 10.5301/ejo.5000488
  48. 48. Fardeau C et al. Retinal fluorescein, indocyanine green angiography, and optic coherence tomography in non-hodgkin primary intraocular lymphoma. American Journal of Ophthalmology. 2009. DOI: 10.1016/j.ajo.2008.12.025
  49. 49. Sagoo MS et al. Primary intraocular lymphoma. Survey of Ophthalmology. 2014. DOI: 10.1016/j.survophthal.2013.12.001
  50. 50. DeAngelis LM. Primary central nervous system lymphoma. Current Opinion in Neurology. 1999. DOI: 10.1097/00019052-199912000-00005
  51. 51. Basso U, Brandes AA. Diagnostic advances and new trends for the treatment of primary central nervous system lymphoma. European Journal of Cancer. 2002. DOI: 10.1016/S0959-8049(02)00031-X
  52. 52. Blumenkranz MS et al. Applications and limitations of vitreoretinal biopsy techniques in intraocular large cell lymphoma. Retina. 1992. DOI: 10.1097/00006982-199212031-00014
  53. 53. Parver LM, Font RL. Malignant lymphoma of the retina and brain: Initial diagnosis by cytologic examination of vitreous aspirate. Archives of Ophthalmology. 1979. DOI: 10.1001/archopht.1979.01020020167016
  54. 54. Klingele TG, Hogan MJ. Ocular reticulum cell sarcoma. American Journal of Ophthalmology. 1975. DOI: 10.1016/0002-9394(75)90453-5
  55. 55. Michels RG, Knox DL, Erozan YS, Green WR. Intraocular reticulum cell sarcoma: Diagnosis by pars plana vitrectomy. Archives of Ophthalmology. 1975. DOI: 10.1001/archopht.1975.01010020961005
  56. 56. Whitcup SM et al. Intraocular lymphoma: Clinical and histopathologic diagnosis. Ophthalmology. 1993. DOI: 10.1016/S0161-6420(93)31469-7
  57. 57. Wolf LA, Reed GF, Buggage RR, Nussenblatt RB, Chan CC. Vitreous cytokine levels. Ophthalmology. 2003. DOI: 10.1016/S0161-6420(03)00811-X
  58. 58. Whitcup SM et al. Improving the diagnostic yield of vitrectomy for intraocular lymphoma. Archives of Ophthalmology. 2000
  59. 59. Peyman GA, May DR, Ericson ES, Goldberg MF. Full-thickness eye wall resection: An experimental approach for treatment of choroidal melanoma. II. Homo- and heterograft. Investigative Ophthalmology. 1972
  60. 60. Peyman GA, Meisels HI, Batko KA, Vlchek JK. Full thickness eye wall biopsy. I. An experimental approach to the tissue diagnosis and study of choroidal and retinal lesions. Investigative Ophthalmology. 1975
  61. 61. Peyman GA, Homer P, Kasbeer R, Vlchek J. Full thickness eye wall biopsy. II. In primates. Investigative Ophthalmology. 1975
  62. 62. Peyman GA, Juarez CP, Raichand M. Full-thickness eye-wall biopsy: Long-term results in 9 patients. The British Journal of Ophthalmology. 1981. DOI: 10.1136/bjo.65.10.723
  63. 63. Nussenblatt RB, Davis JL, Palestine AG. Chorioretinal biopsy for diagnostic purposes in cases of intraocular inflammatory disease. Developments in Ophthalmology. 1992. DOI: 10.1159/000429641
  64. 64. Araujo I, Coupland SE. Primary vitreoretinal lymphoma-A review. Asia-Pacific Journal of Ophthalmology. 2017. DOI: 10.22608/APO.2017150
  65. 65. Coupland SE, Chan CC, Smith J. Pathophysiology of retinal lymphoma. Ocular Immunology and Inflammation. 2009. DOI: 10.1080/09273940903168696
  66. 66. Kimura K et al. Clinical features and diagnostic significance of the intraocular fluid of 217 patients with intraocular lymphoma. Japanese Journal of Ophthalmology. 2012. DOI: 10.1007/s10384-012-0150-7
  67. 67. Davis JL, Ruiz P, Shah M, Mandelcorn ED. Evaluation of the reactive T-cell infiltrate in uveitis and intraocular lymphoma with flow cytometry of vitreous fluid (an American ophthalmological society thesis). Transactions of the American Ophthalmological Society. 2012
  68. 68. White VA, Gascoyne RD, Paton KE. Use of the polymerase chain reaction to detect B- and T-cell gene rearrangements in vitreous specimens from patients with intraocular lymphoma. Archives of Ophthalmology. 1999. DOI: 10.1001/archopht.117.6.761
  69. 69. Hoffman PM, McKelvie P, Hall AJ, Stawell RJ, Santamaria JD. Intraocular lymphoma: A series of 14 patients with clinicopathological features and treatment outcomes. Eye. 2003. DOI: 10.1038/sj.eye.6700378
  70. 70. Merle-Béral H et al. Biological diagnosis of primary intraocular lymphoma. British Journal of Haematology. 2004. DOI: 10.1046/j.1365-2141.2003.04800.x
  71. 71. Langerak AW et al. EuroClonality/BIOMED-2 guidelines for interpretation and reporting of Ig/TCR clonality testing in suspected lymphoproliferations. Leukemia. 2012. DOI: 10.1038/leu.2012.246
  72. 72. Coupland SE, Hummel M, Müller HH, Stein H. Molecular analysis of immunoglobulin genes in primary intraocular lymphoma. Investigative Ophthalmology and Visual Science. 2005. DOI: 10.1167/iovs.05-0401
  73. 73. Baehring JM et al. Analysis of clonal immunoglobulin heavy chain rearrangements in ocular lymphoma. Cancer. 2005. DOI: 10.1002/cncr.21191
  74. 74. Wang Y, Shen D, Wang VM, Sen HN, Chan CC. Molecular biomarkers for the diagnosis of primary vitreoretinal lymphoma. International Journal of Molecular Sciences. 2011. DOI: 10.3390/ijms12095684
  75. 75. Sugita S et al. Diagnosis of intraocular lymphoma by polymerase chain reaction analysis and cytokine profiling of the vitreous fluid. Japanese Journal of Ophthalmology. 2009. DOI: 10.1007/s10384-009-0662-y
  76. 76. Coupland SE, Perez-Canto A, Hummel M, Stein H, Heimann H. Assessment of HOPE fixation in vitrectomy specimens in patients with chronic bilateral uveitis (masquerade syndrome). Graefe's Archive for Clinical and Experimental Ophthalmology. 2005. DOI: 10.1007/s00417-005-1166-1
  77. 77. Montesinos-Rongen M et al. Interphase cytogenetic analysis of lymphoma-associated chromosomal breakpoints in primary diffuse large B-cell lymphomas of the central nervous system. Journal of Neuropathology and Experimental Neurology. 2002. DOI: 10.1093/jnen/61.10.926
  78. 78. Balansard B et al. Necrotising retinopathies simulating acute retinal necrosis syndrome. The British Journal of Ophthalmology. 2005. DOI: 10.1136/bjo.2004.042226
  79. 79. Drancourt M et al. Culture of tropheryma whippelii from the vitreous fluid of a patient presenting with unilateral uveitis. Annals of Internal Medicine. 2003. DOI: 10.7326/0003-4819-139-12-200312160-00025
  80. 80. Evans M, Sharma O, LaBree L, Smith RE, Rao NA. Differences in clinical findings between caucasians and african americans with biopsy-proven sarcoidosis. Ophthalmology. 2007. DOI: 10.1016/j.ophtha.2006.05.074
  81. 81. Lisa JF, Chan CC. Primary intraocular lymphoma. Archives of Pathology and Laboratory Medicine. 2009. DOI: 10.5858/133.8.1228
  82. 82. Gupta R, Murray PI. Chronic non-infectious uveitis in the elderly: Epidemiology, pathophysiology and management. Drugs and Aging. 2006. DOI: 10.2165/00002512-200623070-00001
  83. 83. Towler H, De La Fuente M, Lightman S. Posterior uveitis in Hodgkin’s disease. Australian and New Zealand Journal of Ophthalmology. 1999. DOI: 10.1046/j.1440-1606.1999.00224.x
  84. 84. Pahk PJ et al. Intravascular lymphoma masquerading as Vogt-Koyanagi-Harada syndrome. Ocular Immunology and Inflammation. 2008. DOI: 10.1080/09273940802023810
  85. 85. Buggage RR. Ocular manifestations of human T-cell lymphotropic virus type 1 infection. Current Opinion in Ophthalmology. 2003. DOI: 10.1097/00055735-200312000-00016
  86. 86. Hoang-Xuan K et al. Diagnosis and treatment of primary CNS lymphoma in immunocompetent patients: Guidelines from the European Association for Neuro-Oncology. The Lancet Oncology. 2015. DOI: 10.1016/S1470-2045(15)00076-5
  87. 87. Abdel-Reheim FA, Edwards E, Arber DA. Utility of a rapid polymerase chain reaction panel for the detection of molecular changes in B-cell lymphoma. Archives of Pathology & Laboratory Medicine. 1996
  88. 88. Soussain C et al. Intensive chemotherapy with thiotepa, busulfan and cyclophosphamide and hematopoietic stem cell rescue in relapsed or refractory primary central nervous system lymphoma and intraocular lymphoma: A retrospective study of 79 cases. Haematologica. 2012. DOI: 10.3324/haematol.2011.060434
  89. 89. Ferreri AJM et al. Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: Results of the first randomisation of the International Extranodal Lymphoma Study Group-32 (IELSG32) phase 2 trial. The Lancet Haematology. 2016. DOI: 10.1016/S2352-3026(16)00036-3
  90. 90. Fishbume BC, Wilson DJ, Rosenbaum JT, Neuwdt EA. Intravitreal methotrexate as an adjunctive treatment of intraocular lymphoma. Archives of Ophthalmology. 1997. DOI: 10.1001/archopht.1997.01100160322009
  91. 91. De Smet MD et al. Intraocular levels of methotrexate after intravenous administration. American Journal of Ophthalmology. 1996. DOI: 10.1016/S0002-9394(14)70444-1
  92. 92. De Smet MD, Vancs VS, Kohler D, Solomon D, Chan CC. Intravitreal chemotherapy for the treatment of recurrent intraocular lymphoma. The British Journal of Ophthalmology. 1999. DOI: 10.1136/bjo.83.4.448
  93. 93. Wang JK et al. An Asian patient with intraocular lymphoma treated by intravitreal methotrexate. Japanese Journal of Ophthalmology. 2006. DOI: 10.1007/s10384-005-0327-4
  94. 94. Kim E, Kim C, Lee J, Cho Y. A case of primary intraocular lymphoma treated by intravitreal methotrexate. Korean Journal of Ophthalmology. 2009. DOI: 10.3341/kjo.2009.23.3.210
  95. 95. Sou R, Ohguro N, Maeda T, Saishin Y, Tano Y. Treatment of primary intraocular lymphoma with intravitreal methotrexate. Japanese Journal of Ophthalmology. 2008. DOI: 10.1007/s10384-008-0519-9
  96. 96. Chan CC, Sen HN. Current concepts in diagnosing and managing primary vitreoretinal (intraocular) lymphoma. Discovery Medicine. 2013
  97. 97. Hashida N, Nakai K, Saitoh N, Nishida K. Association between ocular findings and preventive therapy with onset of central nervous system involvement in patients with primary vitreoretinal lymphoma. Graefe's Archive for Clinical and Experimental Ophthalmology. 2014. DOI: 10.1007/s00417-014-2584-8
  98. 98. Berenbom A, Davila RM, Lin HS, Harbour JW. Treatment outcomes for primary intraocular lymphoma: Implications for external beam radiotherapy. Eye. 2007. DOI: 10.1038/sj.eye.6702437
  99. 99. Gregory MS et al. A novel treatment for ocular tumors using membrane fasl vesicles to activate innate immunity and terminate immune privilege. Investigative Ophthalmology and Visual Science. 2005. DOI: 10.1167/iovs.05-0048
  100. 100. Li Z et al. Eradication of tumor colonization and invasion by a B cell-specific immunotoxin in a murine model for human primary intraocular lymphoma. Cancer Research. 2006. DOI: 10.1158/0008-5472.CAN-06-1981
  101. 101. Rodrigues EB et al. Therapeutic monoclonal antibodies in ophthalmology. Progress in Retinal and Eye Research. 2009. DOI: 10.1016/j.preteyeres.2008.11.005
  102. 102. Soussain C et al. A single-center study of 11 patients with intraocular lymphoma treated with conventional chemotherapy followed by high-dose chemotherapy and autologous bone marrow transplantation in 5 cases. Leukemia & Lymphoma. 1996. DOI: 10.3109/10428199609054837

Written By

Alessandro Lupi, Barbara Iaccheri, Davide Tucci, Carlo Cagini and Tito Fiore

Submitted: 21 September 2021 Reviewed: 01 November 2021 Published: 18 December 2021