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Intraocular Lymphoma

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Primary intraocular lymphoma often poses a diagnostic dilemma with presentation like vitritis, intermediate uveitis or subretinal plaque-like lesions [1] . Diagnosis is often challenging in such cases, and this is why it is often one of the diseases referred to as a masquerade syndrome. [1] [2]

• 1.1 Etiology
• 1.3 Symptoms
• 1.4.1 Fluorescein Angiography
• 1.4.2 Optical coherence tomography
• 1.4.3 Fundus autofluorescence
• 1.4.4 Diagnostic vitrectomy
• 1.5 Systemic Evaluation
• 2.1.1 EBRT(External Beam Radiotherapy)
• 2.1.2.1 Methotrexate
• 2.1.2.2 Rituximab
• 2.1.3.1 Methotrexate
• 2.1.3.2 Rituximab
• 2.2 Prognosis
• 3 Additional Resources
• 4 References

Vitreoretinal lymphoma (as primary introacular lymphoma is now known) is the most common introacular lymphoproliferative disease. The term vitreoretinal lymphoma distinguishes it from other introcular lymphoproliferations including choroidal lymphomas (which do not have any association with central nervous system disease) and iris or ciliary body lymphomas. [3] The term intraocular lymphoma was first introduced more than 60 years ago. [4] [5] However, prior to the advent of immunohistochemistry, vitreoretinal lymphomas were known as reticulum cell sarcomas, microgliomas, perithelial sarcomas or lymphosarcomas. It is considered a variant of primary central nervous system (CNS) lymphomas and may occur only in the eye initially (thus a primary vitreoretinal lymphoma) or contemporaneously with CNS disease. Rarely, a vitreoretinal lymphoma can be classified as secondary when it arises due to metastasis from a systemic lymphoma. [2] [6]

The majority of vitreoretinal lymphomas are of a diffuse large B-cell (DLBCL) histologic subtype [3] [7] [8] , though occasionally T-cell lymphomas can occur. [9]

Vitreoretinal lymphomas represent < 1% of all intraocular tumors [10] , 4-6% of all intracranial tumors and 1-2% of all extra nodal non-Hodgkin’s lymphomas. [11] Involvement of the CNS is common, developing in 35-90% along the course of the disease. Women are more commonly affected than men [10] and patients generally present in 4th to 6th decade [11] , although a case as young as 15 years has been reported [12] [13] . Eighty to ninety percent patients will have bilateral disease, although initial presentation may be unilateral or asymmetric. [11]

On examination , anterior segment is may exhibit anterior chamber cells as well as keratic precipitates in both the primary presentation as well as in recurrences. [14] [2] Confocal microscopy of such "keratic precipitates" has demonstrated features that recapitulate atypical large lymphocytes with large nuclei and minimal cytoplasm. [15] These cells can even layer and present as a hypopyon; in these situations, the eye is generally more quiet than it would be with a hypopyon from an infectious etiology.

The manifestation of the disease can be either as vitreous inflammation, subretinal lesions, or both. Vitreous opacities may be seen extending from posterior pole to periphery which may move on movement of the eye producing an image like aurora in the sky [2] caused due to the reactive inflammatory cells in vitreous.

Subretinal lesions may begin as small, yellow to white mounds, which enlarge and expand and further coalesce to produce large yellow sub retinal masses with brown pigmentation in the center known as leopard skin pigmentation. These lesions may become atrophic and shrink with treatment and the passage of time.

The lesions may involve optic disc producing an optic nerve head swelling. Vasculitis with retinal hemorrhages can also be seen. [16] [17] Sheathing of the vessels may be seen which could be reactive or due to lymphoma cells infiltration.

The patient usually presents with the complaints of blurring of vision, floaters, or a combination of both.

Clinical diagnosis

Vitreoretinal lymphoma can be challenging to diagnose due to its uncommon occurrence and the similarities it shares with other uveitic conditions. Diseases that should be considered on the differential diagnosis include chronic endophthalmitis, syphilis, tuberculosis, Behcet disease, birdshot chorioretinopathy, secondary intraocular lymphoma, primary uveal lymphoma, and birdshot chorioretinopathy. Patients may be initially be treated with topical or systemic corticosteroids under the presumption that their presentation represents a posterior uveitis. Because lymphomatous cells are responsive to steroids, the "uveitis" may improve, only to recur with decrease in the dose of steroids or discontinuation of therapy. A diagnostic and therapeutic vitrectomy may result without a diagnosis of a lymphomatous process, particularly when a patient is still using topical or systemic corticosteroids. A study from the National Eye Institute found that patients underwent a mean of 2.1 procedures prior to a diagnosis of vitreoretinal lympoma. Furthermore, they found an average of 13.9 months from onset of symptoms to a confirmed histopathological diagnosis. [18]

Fluorescein Angiography

Hypofluorescence may be seen due to blockage of dye by the tumor cells as well as granular hyperfluorescence and late staining due to damage to the retinal pigment epithelium. The contrast between hypo- and hyperfluorescence has been noted to be reminiscent of leopard spots, but is certainly not pathognomonic for the disease. A leopard spot pattern denoted by hypofluorescent round spots has been observed in 43% of cases. [19]

Optical coherence tomography

Granular subretinal lesions (between Bruch's membrane and the retinal pigment epithelium) can be seen when subretinal lesions exist. OCT can be used to monitor progression or regression of the lymphoma. [20]

Fundus autofluorescence

Many patterns of fundus autofluorescence exist in intraocular lymphoma. A study from the National Eye Institute found that granularity on FAF was associated with active lymphoma in 61% of their cases. [19]

Diagnostic vitrectomy

For diagnosis, the gold standard is cytopathologic inspection of ocular fluid or chorioretinal biopsies. Small gauge vitrectomy may help with the yield and it is important to obtain an undiluted specimen (0.5 - 1 ml) at a low cut rate.

The sample may then be evaluated for:

• Immunohistochemistry
• Directed polymerase chain reaction (PCR) for gene rearrangements in immunoglobulin heavy chain genes or (if T-cell lymphoma is suspected) T-cell receptor genes [21]
• Directed PCR for mutation in the MYD88 gene involving codon L265P [22]
• Cytokine measurement

Even after taking the appropriate measures, this can still yield false negative results.

Cytological examination is the gold standard for diagnosis [23] which shows large atypical lymphoid cells with pleomorphic nuclei, scant basophilic cytoplasm and prominent nucleoli. However, Kimura et al showed that cytology was sufficient in only 48% of cases. [24] The reason for such low yields includes the fact that lymphomatous cells may necrose and be misinterpreted.

Directed PCR can also be performed to identify IgH gene rearrangements using FR2A, FR3A, and CDR3 primers [25] . While fine needle or laser capture microdissection is a technique that can help in procuring a relatively pure population of large, atypical lymphocytes, few ocular pathologists routinely perform such a procedure. Immunohistochemistry employing cell markers such as CD20 , CD3, CD79a, and PAX5 can help identify the cell type. Directed PCR for the MYD88 gene (codon L265P) can also be diagnostic of a DLBCL vitreoretinal lymphoma.

Cytokine evaluation assessing for interleukin (IL)-10 compared to IL-6 may also be considered as corroborating a suspicion of lymphoma. IL-10 is an immunosuppressive cytokine while IL-6 is an inflammatory cytokine; an elevated IL-10 /IL-6 ratio is suggestive of lymphoma, although there is a relatively lower diagnostic sensitivity with this test. [26] [27] [20] Aqueous levels of IL-10 are used by some to monitor for recurrence.

Systemic Evaluation

Gadolium enhanced MRI of the brain should be performed to evaluate for intracerebral disease. Care should be coordinated with a neuro-oncologist.

The treatment can be aimed as local therapy which can be radiotherapy to the eye or intracameral / intravitreal agents like (methotrexate and rituximab) or as systemic therapy which can be external beam radiotherapy or systemic chemotherapy.

Medical therapy

Ebrt(external beam radiotherapy).

In cases of bilaterality, EBRT is the most effective treatment [28] . A total dose of 30-40 Gy, divided in the fractions of 1.5 to 2 Gy is often used.The side effects associated are dermatitis, punctate keratopathy , cataract and radiation retinopathy. The 2-year overall and disease-free survival rates were reported to be 74% and 58% respectively. [29]

Local Chemotherapy

Methotrexate.

In unilateral cases, intravitreal methotrexate has been used in the dosage of 400 µg/0.1cc twice weekly for 4 weeks , followed by 1 weekly for 4 weeks, followed by 1 monthly for 12 months. It is used as a primary therapy as an alternative to radiotherapy or for cases of relapse. [30] The risks associated are conjunctival injection and keratopathy. Sometimes these can be very severe which warrants the use of alternatives. Clinical remission is achieved after mean of 6.4 +/- 3.4 injections [31]

Intravitreal rituximab which is a chimeric anti CD20 monoclonal antibody can be used in the dosage of 1mg /0.1 ml in cases which are unresponsive or cannot tolerate methotrexate. [32]

For isolated ocular lymphoma, local chemotherapy and or radiotherapy can be done. In cases of systemic involvement or CNS lymphoma, systemic chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) or rituximab-CHOP is done.

Other systemic agents that have been investigated include pomalidomide, stem cell transplantation, or ibrutinib, with or without local therapy. [33]

Systemic Chemotherapy

Intravenous high dose methotrexate is commonly used in patients with intraocular lymphoma that have CNS or systemic involvement. [34] [35]

In cases with CNS involvement, rituximab may be used in conjunction with high dose methotrexate. [35]

Currently there is no prophylactic method that completely prevents the onset of CNS lymphoma subsequent to vitreoretinal lymphoma. Patients with vitreoeretinal lymphoma must undergo careful and regular surveillance for development of CNS involvement. While the mortality rates vary widely in the literature, the 5-year overall survival rate of primary vitreoretinal lymphoma is less than 25%. In a multicenter study involving 7 different countries, the investigators found that local ocular therapy may help with the tumor control, but did not impact overall survival. In that particular study, the overall survival and median progression-free survival were reported to be 31 and 18 months, respectively. [36]

Additional Resources

• Boyd K. Eye Cancer . American Academy of Ophthalmology. EyeSmart/Eye health. https://www.aao.org/eye-health/diseases/eye-cancer-list . Accessed March 11, 2019.
• Boyd K, Vemulakonda GA. Eye Lymphoma . American Academy of Ophthalmology. EyeSmart/Eye health. https://www.aao.org/eye-health/diseases/eye-lymphoma-list . Accessed March 11, 2019.
• ↑ 1.0 1.1 Grange LK, Kouchouk A, Dalal MD, Vitale S, Nussenbla RB, Chan CC, et al. Neoplastic masquerade syndromes in patients with uveitis. Am J Ophthalmol 2014;157:526‐31.
• ↑ 2.0 2.1 2.2 2.3 Biswas J, Majumdar PD .Uveitis: An Update .Goto H.Intraocular lymphoma.2016. 93-100
• ↑ 3.0 3.1 Coupland SE, Damato B. Understanding intraocular lymphomas. Clin Experiment Ophthalmol . 2008;36:564-578.
• ↑ Cooper, E.L. & Riker, J.L. (1951) Malignant lymphoma of the uveal tract. American Journal of Ophthalmology, 34, 1153–1158.
• ↑ Qualman, S.J., Mendelsohn, G., Mann, R.B. & Green, W.R. (1983) Intraocular lymphomas. Natural history based on a clinicopathologic study of eight cases and review of the literature. Cancer, 52, 878–886.
• ↑ Salomão DR, Pulido JS, Johnston PB, Canal-Fontcuberta I, Feldman AL. Vitreoretinal presentation of secondary large B-cell lymphoma in patients with systemic lymphoma. JAMA Ophthalmo l . 2013;131(9):1151-1158
• ↑ Coupland SE, Chan CC, Smith J. Pathophysiology or retinal lymphoma. Ocul Immunol Inflamm . 2009;17:227-237
• ↑ Chan CC, Gonzales JA. Primary Intraocular Lymphoma. New Jersey, London, Singapore, Beinjing, Shanghai, Hong Kong, Taipei: Worl Publishing Co. Pte. Ltd.,2007:1-267
• ↑ Coupland SE, Anastasssiou G, Bornfeld N, Hummel M, Stein H. Primary intraocular lymphoma of T-cell type: Report of a case and review of the literature. Graefes Arch Clin Exp Ophthalmol 2005;243:189-197
• ↑ 10.0 10.1 Bardenstein DS. Intraocular lymphoma. Cancer Control. 1998;5:317–325.
• ↑ 11.0 11.1 11.2 Freeman LN, Schachat AP, Knox DL, et al. Clinical features laboratory investigations, and survival in ocular reticulum sarcoma. Ophthalmology 1987;94: 1631-1639.
• ↑ Cohen IJ, Vogel R, Matz S, et al. Successful non-neurotoxic therapy (without radiation) of a multifocal primary brain lymphoma with a methotrexate, vincristine, and BCNU protocol (DEMOB). Cancer. 1986;57:6–11.
• ↑ Wilkins CS, Goduni L, Dedania VS, Modi YS, Johnson B, Mehta N, Weng CY. Diagnostic and Therapeutic Challenge. Retina. 2021 Jul 1;41(7):1570-1576. doi: 10.1097/IAE.0000000000002820. PMID: 32332425.
• ↑ 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;17:513-521
• ↑ Zhang P, Tian J, Gao L. Intraocular lymphoma masquerading as recurent iridocyclitis: findings based on in vivo confocal microscopy. Ocul Immunol Inflamm 2018;26(3):362-364
• ↑ Akpek EK, Ahmed I, Hochberg FH, Soheilian M, Dryja TP, Jakobiec FA, Foster CS. Intraocular-central nervous system lymphoma: clinical features, diagnosis and outcomes. Ophthalmol 1999;106(9):1805-1810
• ↑ Katoch D, Bansal R, Nijhawan R, Gupta A. Primary intraocular central nervous system lymphoma masquerading as diffuse retinal vasculitis. BMJ Case Rep 2013;1-4
• ↑ Dalal M, Casady M, Moriarty E, Faia L, Nussenblatt R, Chan CC, Sen HN. Diagnostic procedures in vitreoretinal lymphoma. Ocul Immunol Inflamm. 2014 Aug;22(4):270-6.
• ↑ 19.0 19.1 Casady M, Faia L, Nazemzadeh M, Nussenblatt R, Chan CC, Sen HN. Fundus autofluorescence patterns in primary intraocular lymphoma. Retina. 2014 Feb;34(2):366-72.
• ↑ 20.0 20.1 Liu TY, Ibrahim M, Bittencourt M, et al. Retinal optical coherence tomography manifestations of intraocular lymphoma. J Ophthal Inflamm Infect 2012; 2: 215-218.
• ↑ Chan CC. Molecular pathology of primary intraocular lymphoma. Trans Am Ophthalmol Soc 2003;101:269-286
• ↑ Pulido JS, Salomão DR, Frederick LA, Viswanatha DS. MyD-88 L265P mutations are present in some cases of vitreoretinal lymphoma. Retina 2015;35(4):624-627
• ↑ Chan CC, Sen HN. Current concepts in diagnosing and managing primary vitreoretinal (intraocular) lymphoma. Discov Med 2013;15:93‐100.
• ↑ Kimura K, Usui Y, Goto H, et al. Clinical features and diagnostic significance of the intraocular fluid of 217 patients with intraocular lymphoma. Jpn J Ophthalmol 2012; 56: 383-389.
• ↑ Wang Y, Shen D, Wang VM, Sen HN, Chan CC. Molecular biomarkers for the diagnosis of primary vitreoretinal lymphoma. Int J Mol Sci 2011;12:5684‐97.
• ↑ Buggage RR, Whitcup SM, Nussenblatt RB, Chan CC. Using interleukin 10 to interleukin 6 ratio to distinguish primary intraocular lymphoma and uveitis. Invest Ophthalmol Vis Sci 1999;40:2462-2463
• ↑ Chan CC, Rubenstein JL, Coupland SE, et al. Primary vitreoretinal lympoma: A report from an international primary central nervous system lymphoma collaborative group symposium. The Oncologist. 2011;16: 1589-1599
• ↑ Berenbom A, Davila RM, Lin HS et al .Treatment outcomes for primary intra ocular lymphoma: implications for external beam radiotherapy. Eye 21: 1198-1201
• ↑ Isobe K, Ejima Y, Tokumaru S et al. Treatment of primary intraocular lymphoma with radiation therapy : a multi institutional survey in Japan . Leuk Lymphoma 47: 1800-1805
• ↑ De Smet MD, Vancs VS, Kohler D et al. Intravitreal chemotherapy for the treatment of recurrent intraocular lymphoma. Br J Ophthalmol 83: 448-451
• ↑ Frenkel S, Hendler K, Siegal T et al. Intravitreal methotrexate for treating vitreoretinal lymphoma: 10years of experience . Br J Ophthalmol 92: 383-388
• ↑ Kitzmann AS, Pulido JS, Mohney BG. Intraocular use of rituximab. Eye. 2007; 21: 1524-1527.
• ↑ Pulido, J.S., Johnston, P.B., Nowakowski, G.S.  et al.  The diagnosis and treatment of primary vitreoretinal lymphoma: a review.  Int J Retin Vitr  4, 18 (2018).
• ↑ Venkatesh R, Bavaharan B, Mahendradas P, Yadav NK. Primary vitreoretinal lymphoma: prevalence, impact, and management challenges. Clin Ophthalmol. 2019 Feb 14;13:353-364.
• ↑ 35.0 35.1 Kalogeropoulos D, Vartholomatos G, Mitra A, Elaraoud I, Ch'ng SW, Zikou A, Papoudou-Bai A, Moschos MM, Kanavaros P, Kalogeropoulos C. Primary vitreoretinal lymphoma. Saudi J Ophthalmol. 2019 Jan-Mar;33(1):66-80.
• ↑ Grimm S.A., Pulido J.S., Jahnke K. Primary intraocular lymphoma: an International Primary Central Nervous System Lymphoma Collaborative Group report. Ann Oncol. 2007;18:1851–1855.
• Oncology/Pathology
• Retina/Vitreous

Diagnosis & Treatment of Intraocular Lymphoma

A look at the distinct clinical features that help to establish the diagnosis and guide treatment of these malignancies., related articles, targeting amd with a critical carotenoid, targeting fas in retinal disease, update: treatments for diabetic retinopathy, a review of retinitis pigmentosa, may 2023 wills eye resident case series, current issue.

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• Cambridge Ophthalmological Symposium
• Published: 30 November 2012

Intraocular lymphoma: a clinical perspective

• J L Davis 1  

Eye volume  27 ,  pages 153–162 ( 2013 ) Cite this article

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• Cancer therapy
• Pathogenesis

Primary vitreoretinal lymphoma (PVRL) is a rare malignancy that is speculated to arise extraocularly, and preferentially invade and flourish in the ocular and CNS microenvironments. The eye is involved in about 20% of primary central nervous system lymphomas, but the brain is eventually involved in about 80% of PVRL. Most are B-cell lymphomas with small numbers of T-cell lymphomas metastatic to the vitreous and retina. Metastatic systemic B-cell lymphoma usually involves choroid. Primary choroidal lymphoma is rare. Intraocular lymphoma can usually be distinguished from uveitis clinically, although there are overlaps, which may be pronounced in eyes with a large component of reactive inflammation related to tumor surveillance and control. There are controversies in diagnosis and treatment. Diagnosis through examination of ocular fluid is technically difficult and can utilize cytology, immunohistochemistry, flow cytometry, molecular detection of gene rearrangements, and cytokine profiling. Treatment of intraocular lymphoma without detectable CNS disease could consist of a full course of systemic chemotherapy with ocular adjunctive treatment, or ocular treatment alone depending on the preference of the clinical center. In ocular only cases where the vitreous has been debulked to improve vision and there is no sight-threatening involvement of the RPE, orbital irradiation or intravitreal chemotherapy stabilizes the intraocular process but does not seem to modify the CNS component, which can present symptomatically in an advanced state. This is a highly malignant disease with a poor prognosis. Close collaboration with a pathologist and oncologist, and good communication with patients is essential.

Methodology

Online search of the Medline database through August 2012 captured information regarding the epidemiology and clinical behavior of intraocular lymphomas using keywords of intraocular lymphoma, primary vitreoretinal lymphoma, metastatic intraocular lymphoma, and choroidal lymphoma. Search for lymphoma and vitreous captured articles on animal models and diagnostic testing. Searches under lymphoma and either methotrexate or rituximab revealed studies of treatment. Recent consensus documents from the United Kingdom and United States provided current practices in treatment.

Lymphoma is a rare form of intraocular malignancy, probably accounting for <0.01% of ophthalmic diseases. 1 , 2 The majority of patients are older than 50. Most intraocular lymphoma is a primary vitreoretinal lymphoma (PVRL) that involves the retinal pigment epithelium and vitreous, rather than the uvea as do secondary lymphomas such as metastatic systemic lymphoma. 2 , 3 , 4 Metastases of systemic lymphoma to the retina is extremely rare. 5 PVRL is closely associated with primary central nervous system lymphoma (PCNSL) to the extent that most cases presenting with ocular involvement will eventually develop CNS lymphoma. 1 , 2 Primary choroidal lymphoma represents another distinct form of intraocular lymphoma. 6

Diagnosis is considered difficult. Clinically lymphoma masquerades as an intermediate and/or posterior uveitis. Acquisition and preservation of vitreous specimens is technically challenging, 7 and few cytopathologists in general hospitals will have experience with this tumor. For this reason a number of adjunctive diagnostic tests have been devised to supplement cytology: immunohistochemistry, 8 flow cytometry, 9 molecular detection of clonal gene rearrangements, 10 , 11 and cytokine profiling of intraocular fluid. 10 , 11 , 12

Treatment is controversial in the absence of concurrent CNS disease. Systemic chemotherapy with a regimen including high-dose methotrexate plus an adjuvant local ocular therapy such as radiation is advocated by some. 13 , 14 Intraocular chemotherapy with methotrexate is preferred to radiation in some centers. 15 Rituximab shows some potential as another local adjuvant that may be less toxic than methotrexate 16 or avoid the develop of methotrexate resistance with repeated exposure. 17 Combined systemic and radiotherapy treatment is proposed to lengthen the survival time from the onset of ocular symptoms in patients who present with ocular involvement only. 18 Palliative local therapy may be prescribed if prophylactic systemic treatment is not elected. 2 Local therapy alone does not seem to modify overall prognosis. 19

The role of the ophthalmologist is to suspect the diagnosis, obtain adequate material for pathological examination, and to work closely with a pathologist to confirm the diagnosis and with an hemato-oncologist to participate in a treatment plan that considers both ocular and non-ocular involvement.

Clinical correlations with the pathogenesis of PVRL

Current scientific understanding of intraocular lymphoma supports the hypothesis of an infiltration of malignant lymphocytes from the systemic circulation to the eye and the brain. 3 Cells with clonal DNA rearrangements identical to those in the brain tumor have been found in the blood and bone marrow of patients with PCNSL. 20 Permissive retinal endothelial receptors 21 and lack of a robust immune surveillance may allow preferential entry of malignant cells to the retina rather than choroid, and subsequent clonal proliferation in the eye. Migration into vitreous or RPE or both occurs, with Bruchs membrane serving as a barrier to further spread. In contrast to PVRL, the choroidal circulation is the more likely entry point in metastatic systemic lymphoma. Bruchs membrane again acts as a barrier and confines the tumor to the uveal tract. Metastatic uveal infiltration in the iris is also possible but extremely rare. 3 , 22

Other mechanisms of lymphoma entry into the eye have been proposed. Because of the strong association of PCNSL with vitreoretinal lymphoma, passage along the optic nerves would be a convenient explanation; however, clinically the optic nerve is uninvolved in concurrent disease, unlike murine models of intraocular lymphoma. 23 Cases of infectious uveitis associated with subsequent intraocular lymphoma 24 could support a hypothesis of an initial polyclonal inflammatory proliferation that becomes clonal through mutation. Endoantigens from a non-infectious uveitis hypothetically might produce the same phenomenon. There is evidence that intraocular lymphoma arises from post-germinal center cells that have already been exposed to antigen. 25 In addition, ocular inflammation might supply growth factors for tumor cells rather than killing them.

Primary choroidal lymphoma is distinct from other forms of intraocular lymphoma, usually has a benign behavior with virtually no metastatic potential, but does locally proliferate and can damage the eye. 3 Most cases of reactive lymphoid hyperplasia are felt to be low-grade B-cell lymphomas that involve the choroid. 26

Table 1 summarizes recent basic and animal research with potential applications to the clinical understanding and management of intraocular lymphoma.

Clinical features of PVRL

The distinctive feature of homogeneous, non-clumped collections of large vitreous cells correlates with the intravitreal clonal proliferation of cells. Migration to the retinal pigment epithelium leads to characteristic yellow lesions of various sizes. Solid detachments of the RPE with irregular yellow deposits are considered pathognomonic of PVRL ( Figure 1 ).

Depiction of typical growth patterns for PVRL. Left, primarily vitreous infiltration. Vitreous haze was dense enough in some areas to completely obscure the fundus; the central clear zone permitted good vision of 20/30. Vitreous stranding and clumping typical of inflammatory disease is absent. Right, large deposit under the retinal pigment epithelium in an HIV-infected patient with PCNSL. The preretinal white patch on the dome of the lesion is lymphomatous proliferation into the vitreous. Note the vascular sheathing and the small clumps of RPE over the tumor mass.

Intraocular lymphoma can be distinguished clinically from uveitis based on two principal features. The first is that the lymphoma cells increase by a proliferation in situ rather than by the amplification and recruitment of inflammatory cells that occurs in uveitis. The second feature is that in B-cell PVRL there is predominance of IL-10 cytokine, 12 presumably elaborated by the lymphoma cells. It acts as a growth factor for B lymphocytes, along with other mediators, 36 and is also anti-inflammatory. This may stifle immune defenses against the tumor cells and produce the typical ‘quiet’ eye of PVRL. In contrast the inflammatory milieu in uveitis 37 with high levels of IL-6 is associated with breakdown of vitreous structure with stranding and focal vitreous opacities.

There are exceptions to these stereotypical patterns that can complicate clinical diagnosis. Higher degrees of reactive inflammation may occur when there are more reactive T-cell lymphocytes. Iritis and keratic precipitates occurred in about 25% of the 217 patients with intraocular lymphoma reported by the Japanese collaborative group 10 vs about 75% of 53 French patients. 38 Subretinal deposits were present in about half the patients in each group. 10 , 38 The most useful signs for distinguishing lymphoma from non-lymphoma patients in the French study of diagnostic vitrectomies were better vision, less anterior chamber flare, fewer cases with posterior synechiae, and less optic disc swelling, epiretinal membrane, or retinal vasculitis. 38

Imaging is becoming increasingly useful in diagnosis of PVRL. The RPE over yellow cellular accumulations of lymphoma cells is hyperautofluorescent, presumably due to RPE dysfunction with accumulation of fluorophores. The whiter retinal deposits over the RPE are hypoautofluorescent due to blocking 39 ( Figure 2 ).

Retinal lymphoma in a patient treated for PCNSL 5 years previously. Top left, right fundus photograph shows pale, round lesions. Top right, autofluorescent imaging shows the round lesions to be mainly hypofluorescent. The clustering of the lesions along retinal arterioles is better seen in the autofluorescent image and suggests entry into the eye via the retinal circulation. The optic nerve was normal. The diffuse hyperautofluorescence likely indicates RPE level infiltration. Bottom, video and spectral domain OCT through two of the round lesions confirms their intraretinal location. The lesion on the right has eroded through retina and is resting on the RPE.

Fluorescein angiography shows early and late hypofluorescent lesions in cases with outer retinal involvement ( Figure 3 ). 38 Focal deposits are minimal on indocyanine green angiography consistent with the predilection for the retinal rather than the uveal compartment. Irregular hyper-reflective anterior protrusions from the RPE on spectral domain OCT ( Figure 4 ) probably indicate deposits of cells at this preferential site. 38

RPE involvement in PVRL. Left, grayscale rendition of a color photograph. The pale lesions are lymphomatous deposits that appear yellow clinically. The larger round lesions are growing the RPE as evidenced by the clumps of pigment on their domes. The smaller punctate and spiculated deposits are also likely sub-RPE. Notice the hazy retinal infiltrates temporally in this right eye and the obscuration of the retinal vessels in this area either from sheathing or retinal infiltration. Right, early stage fluorescein angiogram of the same eye demonstrating classic leopard spot pigmentation. The hypofluorescent lesions are the deposits of lymphoma cells.

Autofluorescence and OCT imaging in PVRL. Left, the fundus is studded with multiple punctate hyperfluorescent dots. There is one placoid lesion in the inferior macula. The dark dots may represent areas of damage to the RPE or collections of lymphoma cells that have grown above the RPE and are blocking the native autofluorescence. Right, correlation with the OCT section through the fovea where the white dots are minimal nonetheless OCT shows multiple pre-Bruchs/sub-RPE deposits that protrude anteriorally to the outer retina.

Leakage of fluorescein along the retinal veins in PVRL was detected in 7 of 53 cases (13.2%) in the largest series of imaging to date. 38 Periarteriolar staining also occurs in lymphoma. When compared with non-lymphoma patients undergoing vitreous biopsy, vascular leakage is less common. 38 This sign of reactive inflammation seems likely to be relevant for the clinical behavior of PVRL but correlations between inflammatory signs such as vasculitis and tumor control have not been made.

Table 2 summarizes the ophthalmologic features useful in the clinical diagnosis of intraocular lymphoma. Early diagnosis may identify more cases with vitreous involvement only that will develop clinically evident RPE involvement at a later stage.

Diagnosis of intraocular lymphoma

If the diagnosis is suspected, lengthy testing for CNS disease in neurologically asymptomatic patients before ocular biopsy is not necessary. Positive results from a vitreous biopsy can help justify a full oncologic work-up rather than a simple MRI of the brain with contrast to make sure there is no obvious CNS disease. Nonetheless, once the diagnosis has been suspected, most ophthalmologists will feel uncomfortable following the patient unless the MRI is normal especially if biopsy results are inconclusive.

Cassoux et al 12 have proposed using anterior chamber tap for IL-10 determination as a screening test to determine whether vitreous biopsy is indicated. A cutoff value of 50 pg/ml IL-10 in aqueous humor yielded 0.89 sensitivity and 0.93 specificity for lymphoma in a series of 51 lymphoma patients and 108 uveitis controls. 12 Sensitivity of 0.8 and specificity of 0.99 were achieved with a cutoff value of 400 pg/ml IL-10 in vitreous humor in the same series. Mochizuki and colleagues 41 replicated their work in a case–control study using the IL-10 : IL-6 ratio as a diagnostic rather than screening test in which vitreous IL-10 levels >100 pg/ml and an IL-10 : IL-6 ratio of >1 were considered positive for lymphoma. The sensitivity, specificity, positive predictive value, and negative predictive value in this study were 0.818, 1.000, 1.000, and 0.714, respectively, indicating that a negative IL-10 assay does not exclude lymphoma. 41 An IL-10 : IL-6 ratio >1 was reported in 53 of 60 lymphoma patients (88%) by Chan and colleagues. 11 A collaborative Japanese study among 25 ophthalmology departments confirmed an IL-10 : IL-6 ratio of >1 in 133 of 145 patients (91.7%) with intraocular lymphoma. 10

Oncologists generally require cytologic evidence of malignant lymphocytes on vitreous biopsy before ocular treatment. The classic description is atypical lymphoid cells with large irregular nuclei, scanty cytoplasm, and prominent nucleoli. 2 , 3 Although the appearance of the cells is straightforward, cytologic diagnosis remains challenging. For example, the large Japanese study cited above had positive cytologic diagnoses in only 73 of 164 (44.5%) patients. 10 Cells recovered often seem far fewer than predicted based on the presurgical ophthalmoscopy. Some of the intraocular cells may be dead or damaged in transit or have poor cytomorphology. Direct aspiration through 21-gauge large bore needles, 42 and vitrectomy with 20-gauge vitrectors 9 or 25-gauge vitrectors 43 produces adequate specimens for morphologic diagnosis. Rapid processing within 1 h after acquisition has been recommended. 3 If transport is required to a remote pathology unit, transport medium may help preserve cellular morphology. 3 , 44 Consultation with the pathologist in advance of sending the specimen is highly recommended.

Immunohistochemical staining of cytologic slides is useful to enhance detection of B-cell lymphomas. 2 , 3 , 8 Typically, the selected stains are CD20, a B-cell marker; and kappa and lambda light chains. The strategy fails in intraocular T-cell lymphomas (which are rare) and in B-cell lymphomas that are too poorly differentiated to express CD20 or light chains on the cell surface. 45 In addition, large numbers of reactive T cells may obscure the malignant B-cell component. 45

Flow cytometry permits the use of larger numbers of cell surface markers and a more complete profiling of the cell surface markers of the intraocular cells. 9 , 45 , 46 , 47 For example, most diffuse large B-cell intraocular lymphomas do not express CD10, which distinguishes them from extramarginal zone lymphomas (MALT lymphomas), which typically affect the ocular adnexae rather than the intraocular compartment. 47 Inclusion of more cell surface markers, especially T-cell markers and activation markers, helps differentiate uveitis from lymphoma. This is especially true for the CD4 : CD8 ratio, which is elevated in vitreous from uveitis patients. 9 , 45 Kojima et al 48 reported significantly higher CD4 : CD8 ratios in vitreous than in blood among sarcoid uveitis patients and also significantly higher CD4 : CD8 ratios compared with patients with other types of uveitis.

A typical vitreous flow cytometric panel includes a general leukocyte marker CD45; T-cell markers CD2, CD3, CD4, CD5, CD7, CD8; B-cell markers CD19, CD20, CD22; kappa and lambda light-chain markers; CD10; CD14 macrophage/monocyte lineage; and HLA-DR, CD25, CD69 activation markers. A ratio of kappa : lambda of >3 or <0.6 is useful as a marker for clonality as the usual ratio in heterogeneous inflammatory reactions is close to 1. 9 There are drawbacks to this technique. Flow cytometry displays a statistical distribution of cell types that is more accurate with larger numbers of cells than can be obtained with vitrectomy. In addition, an expert operator is required to gate the cells to produce meaningful displays. 49

Flow cytometry has enabled the observation that cells with immunologic activation markers were common in vitreous specimens from B-cell lymphoma and T-cell lymphomas, as well as uveitis. 45 Statistical differences in the percentage of activated cells among these groups could not be demonstrated. In addition, abundant T cells were present in all three types of vitreous infiltrates, although they were present in statistically higher percentages in uveitis and T-cell lymphomas. 45 Reactive T cells in B-cell lymphoma were first recognized by Kennerdell et al 32 in 1975 and seem to be a protective mechanism although no clinical correlations have been drawn between ophthalmic presentations or prognosis, and increased reactive lymphocytes. Greater use of flow cytometry might permit enough data to be collected to make such correlations.

The observation that tumor infiltrating lymphocytes expanded in vitro to react with cutaneous melanoma antigens can enter the eye and produce a uveitis that resembles Vogt-Koyanagi-Harada is an example of at least one situation in which an immunologic tumor response produces a uveitis. 50 The implications is that one of the reasons that lymphoma may so often be confused with uveitis is that it is a uveitis as well in that it is a host reaction against tumor antigens inside the eye. Large numbers of reactive T cells can produce a phenotype of T-cell enriched B-cell lymphomas in the eye or brain. 33 , 51 Diagnosis is often markedly delayed in such cases because the expected B-cell phenotype is masked by inflammation. 33

Polymerase chain reaction (PCR) based assays detect a clonally expanded population of lymphocytes by demonstration of one or two identically sized PCR products after amplification and gel electrophoresis. 11 Primers target the complementarity defining regions of the variable region of the immunoglobulin heavy chain (IgH) or the T-cell receptor gamma (TCR). 52 In the case of B-cell lymphoma, the Japanese collaboration reported positive gene rearrangements in 54 of 67 patients (80.6%). 10 Only gene rearrangements in the immunoglobulin gene were performed. Chan and colleagues 11 found either IgH or TCR gene rearrangements in 100% of 114 intraocular lymphoma patients. Cells were collected by microdissection of abnormal lymphocytes from glass slides; sampling of too few cells could lead to a false-positive result. In Hochberg and colleagues 53 study of 17 patients, gene rearrangement had a higher sensitivity (0.64) for the detection of intraocular lymphoma than cytology or flow cytometry. A smaller study reported 6 of 7 samples of intraocular B-cell lymphoma with rearrangements of the kappa light chain. 45

A comprehensive review of diagnostic techniques and yields was published in 2007. 7 Yields of the various techniques in institutional series are difficult to compare because of biases introduced by clinical case selection. Multiple techniques are usually recommended. Table 3 summarizes the consensus recommendations of three panels of experts concerning diagnostic testing in intraocular and CNS lymphoma.

Randomized-controlled clinical trials have not been performed for PVRL and are unlikely. Published recommendations from the International Primary Central Nervous System Lymphoma Collaborative Group (IPCG) symposium on PVRL 2 and from the British Neuro-Oncology Society (NCAT Rare Tumor Guidelines, June 2011, http://www.bnos.org.uk ) differ in recommendations for the management of PVRL without concomitant brain lymphoma. The IPCG symposium on PVRL specifies local treatment for uniocular disease and either local treatment only or systemic chemotherapy with local treatment for bilateral ocular disease, whereas the British guidelines specify systemic chemotherapy incorporating high-dose methotrexate with whole-globe irradiation for ocular only disease. Table 3 summarizes recommendations relevant to treatment of intraocular disease from these two groups and from a third consensus group composed of 21 cancer centers in the United States ( http://www.nccn.org ).

It is unclear if treatment of ocular only disease improves outcomes. In one retrospective study, 17 patients treated for ocular only disease with chemotherapy and/or irradiation lived an average of 60 months after onset of ocular symptoms until death compared with 35 months for 14 patients who were treated only after CNS disease developed. 18 Observations of treatment outcomes in 176 patients with PCNSL with ocular dissemination were collected retrospectively by the IPCG in 2008. 19 Seventy-nine were treated with ocular irradiation and 22 with intravitreal methotrexate. Ocular treatment extended the time to progression, but not survival time, and it did not reduce the risk of ocular recurrence.

Ocular irradiation carries risks of cataract formation, radiation retinopathy, or optic neuropathy but is the preferred ocular treatment in many centers. 13 , 54 Intravitreal chemotherapy with methotrexate 400  μ g in 0.1 ml in an intensive induction-consolidation-maintenance regimen of 25 injections delivered over 1 year is used to avoid radiation complications but carries risks of keratopathy and maculopathy, as well as drug resistance. 15 , 17 Claims of therapeutic superiority of radiation over intraocular chemotherapy have not been made. Fewer intravitreal injections 55 and more widely spaced injections 56 have been advocated to increase the acceptability of intraocular chemotherapy ( Figure 5 ). The BNOS guidelines limit intravitreal methotrexate to salvage therapy after failure of radiation therapy and systemic chemotherapy ( Table 3 ). Rituximab has been proposed as an alternative to methotrexate with the idea that it may be a less toxic alternative. 16

Initial response to intravitreal methotrexate in a patient with PVRL who has not received prior treatment with corticosteroids, systemic chemotherapy, or ocular irradiation. Left, a large retinal infiltrate developed in a patient status post diagnostic vitrectomy showing B-cell predominance on flow cytometry but untreated by the hemato-oncologic consultant. Top right, spectral domain OCT through the infiltrated area on the day of injection (baseline). There are heavy deposits under the RPE and retina. The segmentation line is improperly drawn: Bruch’s membrane corresponds to the smooth white line just anterior to the choroidal vessels. Bottom right, spectral domain OCT 2-weeks after intravitreal methotrexate injection 400  μ g in 0.1 ml. There is dramatic resolution of the cellular deposits. The gray segmentation line is properly drawn along Bruch’s membrane. Overall thickness is markedly reduced.

Treatment of ocular only disease is likely complicated by presentation to vitreoretinal specialists or uveitis specialists rather than to ocular oncologists. PVRL patients are less likely to be presented to Tumor Boards and the relationship between the ophthalmologist and the oncologist is often a new one. Excellent communication and description of ocular findings and the results of tests on ocular fluid is helpful but most oncologists are reluctant to treat systemically without cytologic evidence of malignant disease. The ophthalmologist could apply intravitreal therapy or refer directly to the radiotherapist. In both cases continued observation and comanagement with the oncologist or neuro-oncologist is advised because of the high likelihood of eventual CNS disease.

Future directions

Advances in PVRL will rely on translational research to bridge gaps in diagnosis and treatment. 57 Management of intraocular lymphoma is already highly invested in molecular strategies such as PCR detection of monoclonality, characterization of cell surface markers and cytokine profiling. 11 Further extensive molecular characterization of tumor cells from individual patients may help elucidate pathogenesis and predict clinical behavior. 58 Improved chemotherapeutic regimens incorporating systemic rituximab and cytarabine may improve the prognosis of brain lymphoma. 59 Confirmation that PVRL is a manifestation of an occult, multicentric lymphoma would lead to aggressive systemic treatment for ocular only cases presenting without obvious CNS disease.

Mochizuki M, Singh AD . Epidemiology and clinical features of intraocular lymphoma. Ocul Immunol Inflamm 2009; 17 : 69–72.

Article   Google Scholar  

Chan CC, Rubenstein JL, Coupland SE, Davis JL, Harbour JW, Johnston PB et al . Primary vitreoretinal lymphoma: a report from an international primary central nervous system lymphoma collaborative group symposium. Oncologist 2011; 16 : 1589–1599.

Coupland SE, Damato B . Understanding intraocular lymphomas. Clin Experiment Ophthalmol 2008; 36 : 564–578.

Coupland SE, Foss HD, Hidayat AA, Cockerham GC, Hummel M, Stein H . Extranodal marginal zone B cell lymphomas of the uvea: an analysis of 13 cases. J Pathol 2002; 197 : 333–340.

Cao X, Shen D, Callanan DG, Mochizuki M, Chan CC . Diagnosis of systemic metastatic retinal lymphoma. Acta Ophthalmol 2011; 89 : e149–e154.

Coupland SE, Heimann H, Bechrakis NE . Primary intraocular lymphoma: a review of the clinical, histopathological and molecular biological features. Graefes Arch Clin Exp Ophthalmol 2004; 242 : 901–913.

Gonzales JA, Chan CC . Biopsy techniques and yields in diagnosing primary intraocular lymphoma. Int Ophthalmol 2007; 27 : 241–250.

Davis JL, Solomon D, Nussenblatt RB, Palestine AG, Chan CC . Immunocytochemical staining of vitreous cells. Indicat Tech Result Ophthalmol 1992; 99 : 250–256.

CAS   Google Scholar  

Davis JL, Miller DM, Ruiz P . Diagnostic testing of vitrectomy specimens. Am J Ophthalmol 2005; 140 : 822–829.

Kimura K, Usui Y, Goto H, The Japanese Intraocular Lymphoma Study Group. Clinical features and diagnostic significance of the intraocular fluid of 217 patients with intraocular lymphoma. Jpn J Ophthalmol 2012; 56 : 383–389.

Wang Y, Shen D, Wang VM, Sen HN, Chan CC . Molecular biomarkers for the diagnosis of primary vitreoretinal lymphoma. Int J Mol Sci 2011; 12 : 5684–5697.

Article   CAS   Google Scholar  

Cassoux N, Giron A, Bodaghi B, Tran TH, Baudet S, Davy F et al . IL-10 measurement in aqueous humor for screening patients with suspicion of primary intraocular lymphoma. Invest Ophthalmol Vis Sci 2007; 48 : 3253–3259.

Berenbom A, Davila RM, Lin HS, Harbour JW . Treatment outcomes for primary intraocular lymphoma: implications for external beam radiotherapy. Eye 2007; 21 : 1198–1201.

Stefanovic A, Davis J, Murray T, Markoe A, Lossos IS . Treatment of isolated primary intraocular lymphoma with high-dose methotrexate-based chemotherapy and binocular radiation therapy: a single-institution experience. Br J Haematol 2010; 151 : 103–106.

Frenkel S, Hendler K, Siegal T, Shalom E, Pe’er J . Intravitreal methotrexate for treating vitreoretinal lymphoma: 10 years of experience. Br J Ophthalmol 2008; 92 : 383–388.

Itty S, Pulido JS . Rituximab for intraocular lymphoma. Retina 2009; 29 : 129–132.

Sen HN, Chan CC, Byrnes G, Fariss RN, Nussenblatt RB, Buggage RR . Intravitreal methotrexate resistance in a patient with primary intraocular lymphoma. Ocul Immunol Inflamm 2008; 16 : 29–33.

Hormigo A, Abrey L, Heinemann MH, DeAngelis LM . Ocular presentation of primary central nervous system lymphoma: diagnosis and treatment. Br J Haematol 2004; 126 : 202–208.

Grimm SA, McCannel CA, Omuro AM, Ferreri AJ, Blay JY, Neuwelt EA et al . Primary CNS lymphoma with intraocular involvement: International PCNSL Collaborative Group report. Neurology 2008; 71 : 1355–1360.

McCann KJ, Ashton-Key M, Smith K, Stevenson FK, Ottensmeier CH . Primary central nervous system lymphoma: tumor-related clones exist in the blood and bone marrow with evidence for separate development. Blood 2009; 113 : 4677–4688.

Zamora DO, Rivere M, Choi D, Pan Y, Planck SR, Rosenbaum JR et al . Proteomic profiling of human retinal and choroidal endothelial cells reveals molecular heterogeneity related to tissue of origin. Mol Vis 2007; 13 : 2058–2065.

CAS   PubMed   Google Scholar  

Velez G, de Smet MD, Whitcup SM, Robinson M, Nussenblatt RB, Chan CC . Iris involvement in primary intraocular lymphoma: report of two cases and review of the literature. Surv Ophthalmol 2000; 44 : 518–526.

Chan CC, Fischette M, Shen D, Mahesh SP, Nussenblatt RB, Hochman J . Murine model of primary intraocular lymphoma. Invest Ophthalmol Vis Sci 2005; 46 : 415–419.

Sauer TC, Meyers SM, Shen D, Vegh S, Vygantas C, Chan CC . Primary intraocular (retinal) lymphoma following ocular toxoplasmosis. Retin Cases Brief Rep 2010; 4 : 160–163.

Malumbres R, Davis J, Ruiz P, Lossos IS . Somatically mutated immunoglobulin IGHV@ genes without intraclonal heterogeneity indicate a postgerminal centre origin of primary intraocular diffuse large B-cell lymphomas. Br J Haematol 2007; 138 : 749–755.

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; 107 : 151–158.

Mineo JF, Scheffer A, Karkoutly C, Nouvel L, Kerdraon O, Trauet J et al . Using human CD20-transfected murine lymphomatous B cells to evaluate the efficacy of intravitreal and intracerebral rituximab injections in mice. Invest Ophthalmol Vis Sci 2008; 49 : 4738–4745.

Chan CC, Shen D, 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; 110 : 421–426.

Galand C, Donnou S, Crozet L, Brunet S, Touitou V, Ouakrim H et al . Th17 cells are involved in the local control of tumor progression in primary intraocular lymphoma. PLoS One 2011; 6 : e24622.

Kitzmann AS, Pulido JS, Mohney BG, Baratz KH, Grube T, Marler RJ et al . Intraocular use of rituximab. Eye (Lond) 2007; 21 : 1524–1527.

Turaka K, Bryan JS, De Souza S, Gordon AJ, Kwong HM, Ziemianski MC et al . Vitreoretinal lymphoma: changing trends in diagnosis and local treatment modalities at a single institution. Clin Lymphoma Myeloma Leuk 2012; S2152-2650 (12): 00141–00143.

Google Scholar  

Kennerdell JS, Johnson BL, Wisotzkey HM . Vitreous cellular reaction. Association with reticulum cell sarcoma of brain. Arch Ophthalmol 1975; 93 : 1341–1345.

Cummings TJ, Stenzel TT, Klintworth G, Jaffe GJ . Primary intraocular T-cell-rich large B-cell lymphoma. Arch Pathol Lab Med 2005; 129 : 1050–1053.

PubMed   Google Scholar  

Forsyth PA, DeAngelis LM . Biology and management of AIDS-associated primary CNS lymphomas. Hematol Oncol Clin North Am 1996; 10 : 1125–1134.

Thomas JA, Crawford DH, Burke M . Clinico-pathologic implications of Epstein-Barr virus related B cell lymphoma in immunocompromised patients. J Clin Pathol 1995; 48 : 287–290.

Usui Y, Wakabayashi Y, Okunuki Y, Kimura K, Tajima K, Matsuda R et al . Immune mediators in vitreous fluids from patients with vitreoretinal B-cell lymphoma. Invest Ophthalmol Vis Sci 2012; 53 : 5395–5402.

Valentincic NV, de Groot-Mijnes JD, Kraut A, Korosec P, Hawlina M, Rothova A . Intraocular and serum cytokine profiles in patients with intermediate uveitis. Mol Vis 2011; 17 : 2003–2010.

CAS   PubMed   PubMed Central   Google Scholar  

Fardeau C, Lee CP, Merle-Béral H, Cassoux N, Bodaghi B, Davi F et al . Retinal fluorescein, indocyanine green angiography, and optic coherence tomography in non-Hodgkin primary intraocular lymphoma. Am J Ophthalmol 2009; 147 : 886–894.

Ishida T, Ohno-Matsui K, Kaneko Y, Tobita H, Shimada N, Takase H et al . Fundus autofluorescence patterns in eyes with primary intraocular lymphoma. Retina 2010; 30 : 23–32.

Jabs DA, Nussenblatt RB, Rosenbaum JT, Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol 2005; 140 : 509–516.

Sugita S, Takase H, Sugamoto Y, Arai A, Miura O, Mochizuki M . Diagnosis of intraocular lymphoma by polymerase chain reaction analysis and cytokine profiling of the vitreous fluid. Jpn J Ophthalmol 2009; 53 : 209–214.

Lobo A, Lightman S . Vitreous aspiration needle tap in the diagnosis of intraocular inflammation. Ophthalmology 2003; 110 : 595–599.

Yeh S, Weichel ED, Faia LJ, Albini TA, Wroblewski KK, Stetler-Stevenson M et al . 25-Gauge transconjunctival sutureless vitrectomy for the diagnosis of intraocular lymphoma. Br J Ophthalmol 2010; 94 : 633–638.

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). Graefes Arch Clin Exp Ophthalmol 2005; 243 : 847–852.

Davis JL, Ruiz P, Shah M, Mandelcorn E . Evaluation of the reactive t cell infiltrate in uveitis and intraocular lymphoma with flow cytometry of vitreous fluid. An AOS thesis. Trans Am Ophth Soc 2012 (in press).

Zaldivar RA, Martin DF, Holden JT, Grossniklaus HE . Primary intraocular lymphoma: clinical, cytologic, and flow cytometric analysis. Ophthalmology 2004; 111 : 1762–1767.

Raparia K, Chang CC, Chévez-Barrios P . Intraocular lymphoma: diagnostic approach and immunophenotypic findings in vitrectomy specimens. Arch Pathol Lab Med 2009; 133 : 1233–1237.

Kojima K, Maruyama K, Inaba T, Nagata K, Yasuhara T, Yoneda K et al . The CD4/CD8 Ratio in vitreous fluid is of high diagnostic value in sarcoidosis. Ophthalmology 2012; 119 (11): 2386–2392.

Lugli E, Roederer M, Cossarizza A . Data analysis in flow cytometry: the future just started. Cytometry A 2010; 77 : 705–713.

Yeh S, Karne NK, Kerkar SP, Heller CK, Palmer DC, Johnson LA et al . Ocular and systemic autoimmunity after successful tumor-infiltrating lymphocyte immunotherapy for recurrent, metastatic melanoma. Ophthalmology 2009; 116 : 981–989.

Bashir R, Chamberlain M, Ruby E, Hochberg FH . T-cell infiltration of primary CNS lymphoma. Neurology 1996; 46 : 440–444.

Evans PA, Ch Pott, Groenen PJ, Salles G, Davi F, Berger F et al . Significantly improved PCR-based clonality testing in B-cell malignancies by use of multiple immunoglobulin gene targets. Report of the BIOMED-2 Concerted Action BHM4-CT98-3936. Leukemia 2007; 21 : 207–214.

Baehring JM, Androudi S, Longtine JJ, Betensky RA, Sklar J, Foster CS et al . Analysis of clonal immunoglobulin heavy chain rearrangements in ocular lymphoma. Cancer 2005; 104 : 591–597.

Rajagopal R, Harbour JW . Diagnostic testing and treatment choices in primary vitreoretinal lymphoma. Retina 2011; 31 : 435–440.

Velez G, Boldt HC, Whitcup SM, Nussenblatt RB, Robinson MR . Local methotrexate and dexamethasone phosphate for the treatment of recurrent primary intraocular lymphoma. Ophthalmic Surg Lasers 2002; 33 : 329–333.

Helbig H, Cerny T, de Smet MD . [Intravitreal chemotherapy for intraocular lymphoma]. Ophthalmologe 2003; 100 : 145–149.

Chan CC, Fisson S, Bodaghi B . The future of primary intraocular lymphoma (retinal lymphoma). Ocul Immunol Inflamm 2009; 17 : 375–379.

Coupland SE, Hummel M, Müller HH, Stein H . Molecular analysis of immunoglobulin genes in primary intraocular lymphoma. Invest Ophthalmol Vis Sci 2005; 46 : 3507–3514.

Wieduwilt MJ, Valles F, Issa S, Behler CM, Hwang J, McDermott M et al . Immunochemotherapy with intensive consolidation for primary CNS lymphoma: a pilot study and prognostic assessment by diffusion-weighted MRI. Clin Cancer Res 2012; 18 : 1146–1155.

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This research was supported by Len-Ari Foundation, Research to Prevent Blindness.

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Presented 14 September 2012 at the Cambridge Ophthalmological Symposium: cancer and the eye.

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Davis, J. Intraocular lymphoma: a clinical perspective. Eye 27 , 153–162 (2013). https://doi.org/10.1038/eye.2012.250

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DOI : https://doi.org/10.1038/eye.2012.250

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What Is Eye Lymphoma?

Lymphoma is a type of cancer that can affect the eye.

One type of eye cancer is called primary intraocular lymphoma (PIOL) . PIOL can develop in the retina  and in the vitreous  inside the eye. It also affects the optic nerve  at the back of the eye.

Eight out of 10 people who have PIOL get it in both eyes. Many people with PIOL also have lymphoma in a part of their brain. This is called primary central nervous system lymphoma.

PIOL is almost always a type of lymphoma called non-Hodgkin’s B cell lymphoma. Most people who have it are elderly or have immune system diseases.

Eye lymphoma causes

People whose immune systems do not work properly are at risk for getting primary intraocular lymphoma (PIOL).

Some people may have changes in their cells that increase their risk for developing eye cancer.

What are eye lymphoma symptoms?

Some patients may have no symptoms at first. But others may notice:

• blurry vision
• decrease or loss of vision
• floaters  (seeing small dots or lines in your field of vision)
• redness or swelling in the eye
• being extra sensitive to light
• eye pain (though this is rare)

Lymphoma usually affects both eyes, though the symptoms may be more obvious in one eye.

Who is at risk for eye lymphoma?

People at risk for getting eye lymphoma include those who:

• have rheumatoid arthritis or other autoimmune diseases
• have certain medical problems that affect their immune system
• have AIDS (acquired immunodeficiency syndrome)
• are taking certain medications to prevent the body from rejecting a transplanted organ

People without any of these risk factors can still develop eye lymphoma.

How is eye lymphoma diagnosed?

Your ophthalmologist  will ask about your symptoms and check your vision and eye movement. The doctor will use an ophthalmoscope—an instrument with a light and a small magnifying lens—to get a good look inside the eye.

Certain imaging tests may be done. These help the ophthalmologist look at the tumor as well as see if the cancer has spread.

A  biopsy  is usually needed. This is where a sample of tissue or cells is taken to be looked at with a microscope and tested. For a biopsy, an ophthalmologist usually does a procedure called a vitrectomy . This is where they insert tiny instruments into the eye and take samples of the jelly-like vitreous .

How is eye lymphoma treated?

Eye lymphoma usually is treated with chemotherapy and external radiation therapy (or sometimes a combination of both).

Chemotherapy is taking medication to kill cancer cells. It can be given directly in the eye, through a vein, or directly into fluid in the spine.

Radiation therapy uses beams of very high energy to shrink tumors and kill cancer cells. Radiation may be targeted only at the affected eye or at both eyes, depending upon where the cancer is.

Radiation therapy may also be targeted to the brain and spinal cord. This can help prevent cancer from spreading there or help destroy hidden cancer cells.

If you have any questions about eye lymphoma, be sure to ask. Your ophthalmologist is committed to protecting your sight.

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• What is Ocular Melanoma?
• What Is Toxoplasmosis?

Primary Intraocular Lymphoma

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• Chi-Chao Chan MD 6 ,
• Sebastian P. Haen 7 ,
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Primary intraocular lymphoma (PIOL) is a neoplasm, most frequently of B-cell and rarely T-cell origin arising from or initially presenting in the eye. PIOL of the B-cell type is a non-Hodgkin’s lymphoma of the diffuse large B-cell type that belongs within the category of primary central nervous system lymphoma (PCNSL). The lymphoma always is located in the subretinal space, retina, vitreous, and/or optic nerve. Since the retina, retinal pigment epithelium (RPE), and optic nerve are derived from the same neuroectoderm as the CNS during embryogenesis, and both the eye and CNS are immune-privileged organs, PIOL is often considered to be a subtype of PCNSL. Although a subtype of PCNSL, PIOL may arise de novo in the neuroretina rather than secondary involvement from a PCNSL.

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Chan CC, Gonzalez JA (2007) Primary intraocular lymphoma. Chennai World Scientific Publishing Co. Pte. Ltd., New Jersey

Book   Google Scholar  

Coupland SE, Anastassiou G, Bornfeld N, Hummel M, Stein H (2005) Primary intraocular lymphoma of T-cell type: report of a case and review of the literature. Graefes Arch Clin Exp Ophthalmol 243(3):189–197

Article   PubMed   Google Scholar  

Hochberg FH, Baehring JM, Hochberg EP (2007) Primary CNS lymphoma. Nat Clin Pract Neurol 3(1):24–35

Article   CAS   PubMed   Google Scholar  

Chan CC, Rubenstwin JL, Coupland SE, Davis JL, Harbour JW, Johnston PB, Cassoux N, Touitou V, Smith JR, Batchelor TT, Pulido JS (2011) Primary vitreoretinal lymphoma: a report from an international primary central nervous system lymphoma collaborative group symposium. Oncologist 16:1589–1599

Article   PubMed Central   PubMed   Google Scholar  

Chan CC (2003) Molecular pathology of primary intraocular lymphoma. Trans Am Ophthalmol Soc 101:275–292

PubMed Central   PubMed   Google Scholar  

Chan CC, Sen HN (2013) Current concepts in diagnosing and managing primary vitreoretinal (intraocular) lymphoma. Discov Med 15:93–100

Merle-Beral H, Davi F, Cassoux N, Baudet S, Colin C, Gourdet T et al (2004) Biological diagnosis of primary intraocular lymphoma. Br J Haematol 124:469–473

Coupland SE, Damato B (2006) Lymphomas involving the eye and the ocular adnexa. Curr Opin Ophthalmol 17:523–531

PubMed   Google Scholar  

Read RW, Zamir E, Rao NA (2002) Neoplastic masquerade syndromes. Surv Ophthalmol 47:81–124

Rothova A, Ooijman F, Kerkhoff F, Van Der Lelij A, Lokhorst HM (2001) Uveitis masquerade syndromes. Ophthalmology 108:386–399

Davis JL (2004) Diagnosis of intraocular lymphoma. Ocul Immunol Inflamm 12(1):7–16

Eby NL, Grufferman S, Flannelly CM, Schold SC Jr, Vogel FS, Burger PC (1988) Increasing incidence of primary brain lymphoma in the US. Cancer 62(11):2461–2465

Thomas JO (2001) Acquired immunodeficiency syndrome-associated cancers in Sub-Saharan Africa. Semin Oncol 28(2):198–206

Olson JE, Janney CA, Rao RD, Cerhan JR, Kurtin PJ, Schiff D et al (2002) The continuing increase in the incidence of primary central nervous system non-Hodgkin lymphoma: a surveillance, epidemiology, and end results analysis. Cancer 95(7):1504–1510

Chan CC, Buggage RR, Nussenblatt RB (2002) Intraocular lymphoma. Curr Opin Ophthalmol 13(6):411–418

Gupta R, Murray PI (2006) Chronic non-infectious uveitis in the elderly: epidemiology, pathophysiology and management. Drugs Aging 23(7):535–558

Kadoch C, Treseler P, Rubenstein JL (2006) Molecular pathogenesis of primary central nervous system lymphoma. Neurosurg Focus 21(5):E1

Char DH, Ljung BM, Miller T, Phillips T (1988) Primary intraocular lymphoma (ocular reticulum cell sarcoma) diagnosis and management. Ophthalmology 95:625–630

Rockwood EJ, Zakov ZN, Bay JW (1984) Combined malignant lymphoma of the eye and CNS (reticulum-cell sarcoma). J Neurosurg 61:369–374

Hormigo A, Abrey L, Heinemann MH, DeAngelis LM (2004) Ocular presentation of primary central nervous system lymphoma: diagnosis and treatment. Br J Haematol 126(2):202–208

Levy-Clarke GA, Chan CC, Nussenblatt RB (2005) Diagnosis and management of primary intraocular lymphoma. Hematol Oncol Clin North Am 19(4):739–749

Algazi AP, Kadoch C, Rubenstein JL (2009) Biology and treatment of primary central nervous system lymphoma. Am Soc Exp Neuro Ther Inc 6:587–597

CAS   Google Scholar  

Balmaceda C, Gaynor JJ, Sun M et al (1995) Leptomeningeal tumor in primary central nervous system lymphoma: recognition, significance, and implications. Ann Neurol 38:202–209

Wallace DJ, Altemare CR, Shen DF, de Smet MD, Buggage RR, Nussenblatt RB, Chan CC (2006) Primary testicular and intraocular lymphomas: two case reports and a review of the literature. Surv Ophthalmol 51:41–50

Mochizuki M, Singh AD (2009) Epidemiology and clinical features of intraocular lymphoma. Ocul Immunol Inflamm 17:69–72

Peterson K, Gordon KB, Heinemann MH et al (1993) The clinical spectrum of ocular lymphoma. Cancer 72:843–849

Cassoux N, Merle-Beral H, Leblond V et al (2000) Ocular and central nervous system lymphoma: clinical features and diagnosis. Ocul Immunol Inflamm 8:243–250

Wakefield D, Zierhut M (2009) Intraocular lymphoma: more questions than answers. Ocul Immunol Inflamm 17:6–10

Freeman LN, Schachat AP, Knox DL et al (1987) Clinical features, laboratory investigations, and survival in ocular reticulum cell sarcoma. Ophthalmology 94:1631–1639

Dean JM, Novak MA, Chan CC et al (1996) Tumor detachments of the retinal pigment epithelium in ocular/central nervous system lymphoma. Retina 16:47–56

Gass JD, Sever RJ, Grizzard WS et al (1984) Multifocal pigment epithelial detachments by reticulum cell sarcoma. A characteristic funduscopic picture. Retina 4:135–143

Gass JD, Trattler HL (1991) Retinal artery obstruction and atheromas associated with non-Hodgkin’s large cell lymphoma (reticulum cell sarcoma). Arch Ophthalmol 109:1134–1139

Michelson JB, Michelson PE, Bordin GM et al (1981) Ocular reticulum cell sarcoma. Presentation as retinal detachment with demonstration of monoclonal immunoglobulin light chains on the vitreous cells. Arch Ophthalmol 99:1409–1411

Fine HA, Mayer RJ (1993) Primary central nervous system lymphoma. Ann Intern Med 119(11):1093–1104

Barr CC, Green WR, Payne JW, Knox DL, Jensen AD, Thompson RL (1975) Intraocular reticulum-cell sarcoma: clinico-pathologic study of four cases and review of the literature. Surv Ophthalmol 19(4):224–239

CAS   PubMed   Google Scholar  

Whitcup SM, de Smet MD, Rubin BI, Palestine AG, Martin DF, Burnier MJ et al (1993) Intraocular lymphoma. Clinical and histopathologic diagnosis. Ophthalmology 100:1399–1406

Shibata S (1989) Sites of origin of primary intracerebral malignant lymphoma. Neurosurgery 25(1):14–19

Paulus W (1999) Classification, pathogenesis and molecular pathology of primary CNS lymphomas. J Neurooncol 43(3):203–208

Hochberg FH, Miller DC (1988) Primary central nervous system lymphoma. J Neurosurg 68(6):835–853

Chan CC, Shen DF, Whitcup SM, Nussenblatt RB, LeHoang P, Roberge FG et al (1999) Detection of human herpesvirus-8 and Epstein-Barr virus DNA in primary intraocular lymphoma. Blood 93(8):2749–2751

Shen DF, Herbort CP, Tuaillon N, Buggage RR, Egwuagu CE, Chan CC (2001) Detection of toxoplasma gondii DNA in primary intraocular b-cell lymphoma. Mod Pathol 14(10):995–999

Buggage RR, Chan CC, Nussenblatt RB (2001) Ocular manifestations of central nervous system lymphoma. Curr Opin Oncol 13(3):137–142

Wang SS, Cozen W, Cerhan JR, Colt JS, Morton LM, Engels EA et al (2007) Immune mechanisms in non-Hodgkin lymphoma: joint effects of the TNF G308A and IL10 T3575A polymorphisms with non-Hodgkin lymphoma risk factors. Cancer Res 67(10):5042–5054

Rothman N, Skibola CF, Wang SS, Morgan G, Lan Q, Smith MT et al (2006) Genetic variation in TNF and IL10 and risk of non-Hodgkin lymphoma: a report from the InterLymph Consortium. Lancet Oncol 7(1):27–38

Ramkumar HL, Shen DF, Tuo J, Braziel RM, Coupland SE, Smith JR, Chan CC (2012) IL-10–1082 SNP and IL-10 in primary CNS and vitreoretinal lymphoma. Graefe’s Arch Clin Exp Ophthalmol 250:1541–1548

Article   CAS   Google Scholar  

Drillenburg P, Pals ST (2000) Cell adhesion receptors in lymphoma dissemination. Blood 95(6):1900–1910

Bashir R, Coakham H, Hochberg F (1992) Expression of LFA-1/ICAM-1 in CNS lymphomas: possible mechanism for lymphoma homing into the brain. J Neurooncol 12(2):103–110

Chan CC, Shen D, Hackett JJ, Buggage RR, Tuaillon N (2003) Expression of chemokine receptors, CXCR4 and CXCR5, and chemokines, BLC and SDF-1, in the eyes of patients with primary intraocular lymphoma. Ophthalmology 110(2):421–426

Smith JR, Braziel RM, Paoletti S, Lipp M, Uguccioni M, Rosenbaum JT (2003) Expression of B-cell-attracting chemokine 1 (CXCL13) by malignant lymphocytes and vascular endothelium in primary central nervous system lymphoma. Blood 101(3):815–821

Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A et al (2000) Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403(6769):503–511

Rosenwald A, Wright G, Chan WC, Connors JM, Campo E, Fisher RI et al (2002) The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 346(25):1937–1947

Rubenstein JL, Fridlyand J, Shen A, Aldape K, Ginzinger D, Batchelor T et al (2006) Gene expression and angiotropism in primary CNS lymphoma. Blood 107(9):3716–3723

Article   PubMed Central   CAS   PubMed   Google Scholar  

Tuaillon N, Chan CC (2001) Molecular analysis of primary central nervous system and primary intraocular lymphoma. Curr Mol Med 1(2):259–272

Coupland SE, Hummel M, Muller HH, Stein H (2005) Molecular analysis of immunoglobulin genes in primary intraocular lymphoma. Invest Ophthalmol Vis Sci 46(10):3507–3514

Wallace DJ, Shen D, Reed GF, Miyanaga M, Mochizuki M, Sen HN et al (2006) Detection of the bcl-2 t(14;18) translocation and proto-oncogene expression in primary intraocular lymphoma. Invest Ophthalmol Vis Sci 47(7):2750–2756

Young LS, Murray PG (2003) Epstein-Barr virus and oncogenesis: from latent genes to tumours. Oncogene 22(33):5108–5121

Hochberg FH, Miller G, Schooley RT, Hirsch MS, Feorino P, Henle W (1983) Central-nervous-system lymphoma related to Epstein-Barr virus. N Engl J Med 309(13):745–748

Bashir RM, Harris NL, Hochberg FH, Singer RM (1989) Detection of Epstein-Barr virus in CNS lymphomas by in-situ hybridization. Neurology 39(6):813–817

Sauer TC, Meyers SM, Shen D, Vegh S, Vygantas C, Chan CC (2010) Primary intraocular (retinal) lymphoma following ocular toxoplasmosis. Retin Cases Brief Rep 4:160–163

Bolin TD, Hunt RH, Korman MG, Lambert JR, Lee A, Talley NJ (1995) Helicobacter pylori and gastric neoplasia: evolving concepts. Med J Aust 163(5):253–255

Chan CC, Shen D, Mochizuki M, Gonzales JA, Yuen HK, Guex-Crosier Y et al (2006) Detection of Helicobacter pylori and Chlamydia pneumoniae genes in primary. Trans Am Ophthalmol Soc 104:62–70

Smedby KE, Baecklund E, Askling J (2006) Malignant lymphomas in autoimmunity and inflammation: a review of risks. Cancer Epidemiol Biomarkers Prev 15(11):2069–2077

Smedby KE, Hjalgrim H, Askling J, Chang ET, Gregersen H, Porwit-MacDonald A et al (2006) Autoimmune and chronic inflammatory disorders and risk of non-Hodgkin. J Natl Cancer Inst 98(1):51–60

Zintzaras E, Voulgarelis M, Moutsopoulos HM (2005) The risk of lymphoma development in autoimmune diseases: a meta-analysis. Arch Intern Med 165(20):2337–2344

Parver LM, Font RL (1979) Malignant lymphoma of the retina and brain. Initial diagnosis by cytologic examination of vitreous aspirate. Arch Ophthalmol 97(8):1505–1507

Blumenkranz MS, Ward T, Murphy S, Mieler W, Williams GA, Long J (1992) Applications and limitations of vitreoretinal biopsy techniques in intraocular large cell lymphoma. Retina 12(3):S64–S70

Davis JL, Solomon D, Nussenblatt RB, Palestine AG, Chan CC (1992) Immunocytochemical staining of vitreous cells. Indications, techniques, and results. Ophthalmology 99(2):250–256

Wolf LA, Reed GF, Buggage RR, Nussenblatt RB, Chan CC (2003) Vitreous cytokine levels. Ophthalmology 110(8):1671–1672

Whitcup SM, Stark-Vancs V, Wittes RE, Solomon D, Podgor MJ, Nussenblatt RB et al (1997) Association of interleukin-10 in the vitreous and cerebral spinal fluid and primary central nervous system lymphoma. Arch Ophthalmol 115:1157–1160

Chan CC, Whitcup SM, Solomon D, Nussenblatt RB (1995) Interleukin-10 in the vitreous of primary intraocular lymphoma. Am J Ophthalmol 120(5):671–673

Benjamin D, Park CD, Sharma V (1994) Human B cell interleukin 10. Leuk Lymphoma 12(3–4):205–210

Blay JY, Burdin N, Rousset F, Lenoir G, Biron P, Philip T et al (1993) Serum interleukin-10 in non-Hodgkin’s lymphoma: a prognostic factor. Blood 82(7):2169–2174

Chan CC, Shen DF (1999) Newer methodologies in immunohistochemistry and diagnosis. In: BenEzra D (ed) Uveitis update. Karger, Basel, pp 1–13

Chapter   Google Scholar  

Salmaggi A, Eoli M, Corsini E, Gelati M, Frigerio S, Silvani A et al (2000) Cerebrospinal fluid interleukin-10 levels in primary central nervous. Ann Neurol 47(1):137–138

Cassoux N, Giron A, Bodaghi B, Tran TH, Baudet S, Davy F et al (2007) IL-10 measurement in aqueous humor for screening patients with suspicion of primary intraocular lymphoma. Invest Ophthalmol Vis Sci 48(7):3253–3259

Chan CC, Shen D, Nussenblatt RB, Boni R, Zhuang Z (1998) Detection of molecular changes in primary intraocular lymphoma by microdissection and polymerase chain reaction [letter] [In Process Citation]. Diagn Mol Pathol 7(1):63–64

Shen DF, Zhuang Z, LeHoang P, Boni R, Zheng S, Nussenblatt RB et al (1998) Utility of microdissection and polymerase chain reaction for the detection of immunoglobulin gene rearrangement and translocation in primary intraocular lymphoma [In Process Citation]. Ophthalmology 105(9):1664–1669

Wang Y, Shen D, Wang VM, Sen HN, Chan CC (2011) Molecular biomarkers for the diagnosis of primary vitreoretinal lymphoma. Int J Mol Sci 12:5684–5697

Levy-Clarke GA, Buggage RR, Shen D, Vaughn LO, Chan CC, Davis JL (2002) Human T-cell lymphotropic virus type-1 associated T-cell leukemia/lymphoma masquerading as necrotizing retinal vasculitis. Ophthalmology 109(9):1717–1722

Levy-Clarke GA, Byrnes GA, Buggage RR, Shen DF, Filie AC, Caruso RC et al (2001) Primary intraocular lymphoma diagnosed by fine needle aspiration biopsy of a subretinal lesion. Retina 21(3):281–284

Buggage RR, Velez G, Myers-Powell B, Shen D, Whitcup SM, Chan CC (1999) Primary intraocular lymphoma with a low interleukin 10 to interleukin 6 ratio and heterogeneous IgH gene rearrangement. Arch Ophthalmol 117(9):1239–1242

Gonzales JA, Chan CC (2007) Biopsy techniques and yields in diagnosing primary intraocular lymphoma. Int Ophthalmol 27(4):241–250

Cassoux N, Charlotte F, Rao NA, Bodaghi B, Merle-Beral H, Lehoang P (2005) Endoretinal biopsy in establishing the diagnosis of uveitis: Ocul Immunol Inflamm 13(1):79–83

Sen HN, Bodaghi B, Hoang PL, Nussenblatt R (2009) Primary intraocular lymphoma: diagnosis and differential diagnosis. Ocul Immunol Inflamm 17:133–141

Wender A, Adar A, Maor E et al (1994) Primary B-cell lymphoma of the eyes and brain in a 3-year-old boy. Arch Ophthalmol 112:450–451

Ferreri AJ, Blay JY, Reni M et al (2002) Relevance of intraocular involvement in the management of primary central nervous system lymphomas. Ann Oncol 13:531–538

Hoffman PM, McKelvie P, Hall AJ et al (2003) Intraocular lymphoma: a series of 14 patients with clinicopathological features and treatment outcomes. Eye 17:513–521

Isobe K, Ejima Y, Tokumaru S et al (2006) Treatment of primary intraocular lymphoma with radiation therapy: a multi-institutional survey in Japan. Leuk Lymphoma 47:1800–1805

Berenbom A, Davila RM, Lin HS et al (2007) Treatment. Outcomes for primary intraocular lymphoma: implications for external beam radiotherapy. Eye 21:1198–1201

Jahnke K, Korfel A, Komm J, Bechrakis NE, Stein H, Thiel E et al (2006) Intraocular lymphoma 2000–2005: results of a retrospective multicentre trial. Graefes Arch Clin Exp Ophthalmol 244(6):663–669

Grimm SA, Pulido JS, Jahnke K et al (2007) Primary intraocular lymphoma: an International Primary Central Nervous System Lymphoma Collaborative Group Report. Ann Oncol 18:1851–1855, Relevance of intraocular involvement in the management of primary central nervous system lymphomas. Ann Oncol 13:531–538

Grimm SA, McCannel CA, Omuro AM (2008) Primary CNS lymphoma with intraocular involvement: International PCNSL Collaborative Group Report. Neurology 71:1355–1360

Char DH, Margolis L, Newman AB (1981) Ocular reticulum cell sarcoma. Am J Ophthalmol 91:480–483

Batchelor TT, Kolak G, Ciordia R et al (2003) High-dose methotrexate for intraocular lymphoma. Clin Can Res 9:711–715

Sandor V, Stark-Vancs V, Pearson D et al (1998) Phase II trial of chemotherapy alone for primary CNS and intraocular lymphoma. J Clin Oncol 16:3000–3006

Glantz MJ, Cole BF, Recht L et al (1998) High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer: is intrathecal chemotherapy necessary? J Clin Oncol 16:1561–1567

Cher L, Glass J, Harsh GR et al (1996) Therapy of primary CNS lymphoma with methotrexate-based chemotherapy and deferred radiotherapy: preliminary results. Neurology 46:1757–1759

Guha-Thakurta N, Damek D, Pollack C et al (1999) Intravenous methotrexate as initial treatment for primary central nervous system lymphoma: response to therapy and quality of life of patients. J Neurooncol 43:259–268

Herrlinger U, Küker W, Uhl M et al (2005) NOA-03 trial of high-dose methotrexate in primary central nervous system lymphoma: final report. Ann Neurol 57:843–847

Khan RB, Shi W, Thaler HT et al (2002) Is intrathecal methotrexate necessary in the treatment of primary CNS lymphoma? J Neurooncol 58:175–178

Taoka K, Yamamoto G, Kaburaki T, Takahashi T, Araie M, Kurokawa M (2011) Treatment of primary intraocular lymphoma with rituximab, high dose methotrexate, procarbazine, and vincristine chemotherapy, reduced whole-brain radiotherapy, and local ocular therapy. Br J Haematol 157:252–254

Article   PubMed   CAS   Google Scholar  

Reni M, Zaja F, Mason W et al (2007) Temozolomide as salvage treatment in primary brain lymphomas. Br J Cancer 96:864–867

Kurzwelly D, Glas M, Roth P, Weimann E, Lohner H, Waha A, Schabet M, Reifenberger G, Weller M, Herrlinger U (2010) Primary CNS lymphoma in the elderly: temozolomide therapy and MGMT status. J Neurooncol 97:389–392

Rubenstein JL, Hsi ED, Johnson JL, Jung SH, Nakashima MO, Grant B, Cheson BD, Kaplan LD (2013) Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (alliance 50202). J Clin Oncol 31:3061–3068

Wang Y, Liu B, Xu D, Zhao H, Zhu Y, Xu J, Tao R (2013) Phase II trial of temozolomide plus concurrent whole-brain radiation followed by TNV regimen as adjuvant therapy for patients with newly diagnosed primary CNS lymphoma. Neurol India 61:260–264

Jaglowski SM, Alinari L, Lapalombella R, Muthusamy N, Byrd JC (2010) The clinical application of monoclonal antibodies in chronic lymphocytic leukemia. Blood 116:3705–3714

Coiffier B, Lepage E, Briere J et al (2002) CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235–242

Pfreundschuh M, Trümper L, Osterborg A et al (2006) CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 7:379–391

Wolf T, Kiderlen T, Atta J et al (2014) Successful treatment of AIDS-associated, primary CNS lymphoma with rituximab- and methotrexate-based chemotherapy and autologous stem cell transplantation. Infection 42:445–447

Google Scholar  

Oki Y, Westin JR, Vega F, Chuang H et al (2013) Prospective phase II study of rituximab with alternating cycles of hyper-CVAD and high-dose methotrexate with cytarabine for young patients with high-risk diffuse large B-cell lymphoma. Br J Haematol 163:611–620

Morris PG, Correa DD, Yahalom J et al (2013) Rituximab, methotrexate, procarbazine and vincristine followed by consolidation reduced-dose whole-brain radiotherapy and cytarabine in newly diagnosed primary CNS lymphoma: final results and long-term outcome. J Clin Oncol 31:3971–3979

Pels H, Schmidt-Wolf IG, Glasmacher A et al (2003) Primary central nervous system lymphoma: results of a pilot and phase II study of systemic and intraventricular chemotherapy with deferred radiotherapy. J Clin Oncol 21:4489–4495

Smith JR, Rosenbaum JT, Wilson DJ et al (2002) Role of intravitreal methotrexate in the management of primary central nervous system lymphoma with ocular involvement. Ophthalmology 109:1709–1716

Frenkel S, Hendler K, Siegal T et al (2008) Intravitreal methotrexate for treating vitreoretinal lymphoma: ten years of experience. Br J Ophthalmol 92:383–388

Fishburne BC, Wilson DJ, Rosenbaum JT et al (1997) Intravitreal methotrexate as an adjunctive treatment of intraocular lymphoma. Arch Ophthalmol 115:1152–1156

Kitzmann AS, Pulido JS, Mohney BG et al (2007) Intraocular use of rituximab. Eye 21:1524–1527

Hashida N, Ohguro N, Nishida K (2012) Efficacy and complications of intravitreal rituximab injection for treating primary vitreoretinal lymphoma. Transl Vis Sci Technol 1:1

Ohguro N, Hashida N, Tano Y (2008) Effect of intravitreous rituximab injections in patients with recurrent ocular lesions associated with central nervous system lymphoma. Arch Ophthalmol 126:1002–1003

Pe’er J, Hochberg FH, Foster CS (2009) Clinical review: treatment of vitreoretinal lymphoma. Ocul Immunol Inflamm 17:299–306

Yeh S, Wilson DJ (2010) Combination intravitreal rituximab and methotrexate for massive subretinal lymphoma. Eye 24:1625–1627

Wong ET (2005) Salvage therapy for primary CNS lymphoma with a combination of rituximab and temozolomide. Neurology 64:934

Soussain C, Hoang-Xuan K, Taillandier L et al (2008) Intensive chemotherapy followed by hematopoietic stem-cell rescue for refractory and recurrent primary CNS and intraocular lymphoma: Société Française de Greffe de Moëlle Osseuse-Thérapie Cellulaire. J Clin Oncol 26:2512–2518

Soussain C, Choquet S, Fourme E et al (2012) 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 97:1751–1756

DeAngelis LM (1999) Primary central nervous system lymphoma. Curr Opin Neurol 12(6):687–691

Panageas KS, Elkin EB, DeAngelis LM, Ben-Porat L, Abrey LE (2005) Trends in survival from primary central nervous system lymphoma. Cancer 104(11):2466–2472

DeAngelis LM, Seiferheld W, Schold SC, Fisher B, Schultz CJ (2002) Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93-10. J Clin Oncol 20(24):4643–4648

Shibamoto Y, Tsuchida E, Seki K, Oya N, Hasegawa M, Toda Y et al (2004) Primary central nervous system lymphoma in Japan 1995–1999: changes from. J Cancer Res Clin Oncol 130(6):351–356

Kimura K, Usui Y, Goto H (2012) Clinical features and diagnostic significance of the intraocular fluid of 217 patients with intraocular lymphoma. Jpn J Ophthalmol 56(4):383–389

Abrey LE, Yahalom J, DeAngelis LM (2000) Treatment for primary CNS lymphoma: the next step. J Clin Oncol 18(17):3144–3150

Corry J, Smith JG, Wirth A, Quong G, Liew KH (1998) Primary central nervous system lymphoma: age and performance status are more important than treatment modality. Int J Radiat Oncol Biol Phys 41(3):615–620

Lossos IS, Czerwinski DK, Alizadeh AA, Wechser MA, Tibshirani R, Botstein D et al (2004) Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes. N Engl J Med 350(18):1828–1837

Dave SS, Wright G, Tan B, Rosenwald A, Gascoyne RD, Chan WC et al (2004) Prediction of survival in follicular lymphoma based on molecular features. N Engl J Med 351(21):2159–2169

Bea S, Zettl A, Wright G, Salaverria I, Jehn P, Moreno V et al (2005) Diffuse large B-cell lymphoma subgroups have distinct genetic profiles that influence tumor biology and improve gene expression-based survival prediction. Blood 106:3183–3190

Coupland SE, Chan CC, Smith J (2009) Pathophysiology of retinal lymphoma. Ocular immunology and inflammation 17:227–237

Casady M, Faia L, Nazemzadeh M et al (2014) Fundus autofluorescence patterns in primary intraocular lymphoma. Retina 34:366–372

Sagoo MS, Mehta H, Swampillai AJ et al (2014) Primary intraocular lymphoma. Survey of ophthalmology 59:503–516

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Chan, CC., Haen, S.P., Möhle, R., Zierhut, M. (2016). Primary Intraocular Lymphoma. In: Zierhut, M., Pavesio, C., Ohno, S., Orefice, F., Rao, N. (eds) Intraocular Inflammation. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-75387-2_147

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Swept-source optical coherence tomography angiography findings in a case of primary vitreoretinal lymphoma over a three-year follow-up

• Emilia Maggio 1 ,
• Francesco Bauci 1 ,
• Antonio Polito 1 ,
• Fabrizio Arena 1 &
• Grazia Pertile 1  

BMC Ophthalmology volume  24 , Article number:  194 ( 2024 ) Cite this article

Metrics details

Vitreoretinal lymphoma (VRL) still represents a diagnostic challenge for retinal specialists. Early diagnosis and treatment are critical for a better prognosis. Several diagnostic tools have proven helpful in the identification of VRL abnormalities. However, swept-source OCT angiography (SS-OCT-A) findings and their long-term follow-up are yet to be explored.

Case presentation

a 42-year-old man presented with blurred vision in his left eye for 2 weeks. He denied any systemic symptoms. A multimodal imaging examination was performed, raising the clinical suspicion of VRL and guiding the ensuing diagnostic procedures. The patient underwent treatment and at the last FU visit three years later, no disease signs were present on fundus examination, nor on oncologic evaluation. Some novel SS-OCT-A features were identified, and uncommonly reported findings were examined over a long-term follow-up. At baseline multiple hyperreflective alterations were detected on the enface outer retina slabs and choriocapillary analysis revealed low reflectance areas in the foveal and parafoveal areas. One month after the first presentation, multiple hyperreflective retinal lesions in a vertical shape were detected on OCT which appeared on midretinal slabs of enface SS-OCT-A as hyperreflective spots mainly located near second-order retinal vessels. These alterations remarkably reduced after treatment.

SS-OCT-A may be a useful imaging technique in the detection of VRL, providing ophthalmologists additional findings that assist the diagnosis and follow-up of this disease. This may prove useful for a more timely and precise diagnosis, prompt therapy, and treatment response monitoring. The original aspects found in this case may provide grounds for future studies, ultimately fostering a better understanding of the disease.

Peer Review reports

Vitreoretinal lymphoma (VRL) is a rare intraocular neoplasm, representing < 1% of all intraocular tumors. Nevertheless, it is the most common intraocular lymphoproliferative pathology [ 1 , 2 ]. It is considered a subset of primary central nervous system lymphoma (PCNSL) with ocular involvement on presentation [ 1 , 2 , 3 ]. Central nervous system (CNS) localization is very common, ranging from 35 to 90% of all cases throughout its course, as well as a typically asymmetric bilateral presentation. Women are more prone to develop this pathology, with presentation usually between the 4th and 6th decade of life [ 1 , 2 , 3 , 4 ].

VRL is often referred to as a masquerade syndrome for its uveitis-mimicking clinical features. Patients generally refer to an ophthalmologist complaining of blurred vision, floaters, or both. Presentation can be very similar to ocular inflammation with signs of iritis, vitritis, and retinitis. Due to this ambiguous appearance, VRLs may be misinterpreted and treated as uveitis, usually showing clinical improvement after steroid-based therapy. Recrudescence can be common with steroid tapering or discontinuation, and patients may undergo further steroid therapy cycles. This behavior can hamper physician judgement and lead to a significant delay in the diagnosis. The average time between symptom onset and histopathological diagnosis is reported to be 13.9 months [ 5 ]. However, early diagnosis and prompt treatment are critical for a better prognosis.

Several diagnostic tools have proven helpful to identify VRL abnormalities and thus assist diagnosis. However, OCT angiography (OCT-A) findings need further exploration, since little has been described to date [ 6 – 7 ], and long-term follow-up is still lacking. Enhancing knowledge in this field would facilitate early diagnosis and therapy response monitoring.

Herein, we report a case of VRL with the identification of novel swept-source OCT angiography (SS-OCT-A) features and the long-term analysis of uncommonly reported OCT-A findings.

A 42-year-old white male presented with blurred vision in his left eye (LE) for 2 weeks and without systemic symptoms. On examination, best-corrected visual acuity (BCVA) was 20/20 in both eyes. Intraocular pressure was 17 mmHg OU. Clinical examination of the right eye (RE) was unremarkable. Slit lamp examination of the LE did not show any anterior segment abnormalities. Dilated fundoscopy of the LE showed a clear vitreous with multiple retinal yellowish white deposits at the posterior pole and mid-periphery (Fig.  1 A). Optical coherence tomography (OCT) (Spectralis Heidelberg Engineering, Heidelberg, Germany) examination showed multiple hyper-reflective deposits under the retinal pigment epitelium (RPE) and a slight subfoveal neuroretinal detachment (SND) (Fig.  1 D, E). On autofluorescence (AF) and fluorescein angiography (FA), the multifocal sub-RPE deposits appeared hyperautofluorescent and hypofluorescent, respectively, with no leakage on the late-phase angiograms (Fig.  1 B, C). Indocyanine green angiography (ICGA) late angiograms revealed circumscribed hypofluorescent areas, corresponding to the sites with the most OCT alterations (Fig.  2 A, B). Through swept-source OCT angiography, after projection removal, (SS-OCT-A, PLEX Elite 9000, Carl Zeiss Meditech Inc, Dublin, CA), multiple hyperreflective alterations were detected on the enface outer retina slabs (Fig.  1 F), corresponding to the alterations identified through fundoscopy, OCT, AF, and FA. Upon SS-OCT-A analysis, the superficial and deep plexuses reconstructions showed no alterations of the retinal vascular network. On the contrary, choriocapillary analysis revealed circumscribed low reflectance areas in the foveal and parafoveal areas (Figs.  2 C and 5 A), which colocalized with the hypofluorescent areas seen in the late-phase ICGA angiograms (Fig.  2 A).

Multimodal imaging at first presentation. Baseline color fundus photo ( A ) showing multiple yellowish white deposits at the posterior pole and mid-periphery, appearing hyperautofluorescent on autofluorescence ( B ), and hypofluorescent on fluorescein angiography ( C ). ( D , E ) Baseline OCT scans showing multiple subretinal hyper-reflective infiltrates and a slight subfoveal neuroretinal detachment. ( F ) Sub-RPE deposits appearing hyperreflective on enface SS-OCT-A outer retina slabs, with a leopard spot pattern

( A ) Baseline late-phase ICGA angiograms revealing circumscribed hypofluorescent areas at the posterior pole, corresponding to sites with the most OCT alterations. ( B ) Magnification of above image highlighting hypofluorescent areas (yellow and red arrowheads) and corresponding OCT alteration ( C ). ( D ) SS-OCT-A choriocapillary analysis showing circumscribed low reflectance areas in foveal and parafoveal areas, corresponding to the hypofluorescent areas seen on ICGA

(A) Midretinal slab of enface SS-OCT-A, showing hyperreflective spots mainly located near second-order retinal vessels, corresponding to hyperreflective vertical retinal lesions. (B) OCT scans crossing the hyperreflective vertical retinal lesions

An extensive workup to rule out infectious posterior uveitis and systemic diseases was performed, including serologies for syphilis, toxoplasmosis, and tuberculosis, as well as screening for liver and renal function, glycemia, homocysteine levels, and inflammatory indexes. The results of all these examinations were negative. Cerebral magnetic resonance imaging (MRI) was performed and showed no abnormalities.

Based on the clinical presentation and multimodal imaging, a diagnosis of vitreretinal lymphoma was suspected. For confirmation, a diagnostic 27-gauge pars plana vitrectomy (PPV) was performed to obtain a vitreous sample for cytopathology. However, the results of this analysis were also negative.

Interleukin 10/Interleukin 6 (IL-10:IL6) ratio analysis on a vitreous sample was considered but was not available in our laboratory nor in neighboring hospitals. An MYD88 gene sequencing analysis of the aqueous humor, vitreous samples, and vitrectomy cassette fluid was performed, again with negative results. Consequently, a chorioretinal biopsy was planned.

Meanwhile, the patient complained of worsening LE visual acuity. Multimodal imaging showed a progression of the lesions in the LE and new involvement of the RE. One month after the first presentation, multiple new hyperreflective retinal lesions in a vertical shape were detected on OCT in the LE (Fig. 3 B). On midretinal slabs of enface SS-OCT-A, these appeared as hyperreflective spots mainly located near second-order retinal vessels (Fig. 3 A). These lesions were not detectable on baseline examinations and appeared like those previously referred to as perivascular flower-bud-like-lesions (PFBLs) [ 6 ].

OCT scans in the superotemporal quadrant showing a large flat PED, along with an increase in the thickness and reflectivity of the overlying retina ( A - C ). Red arrows highlight vertical shaped retinal lesions, which appeared in continuity with the thick and hyperreflective overlying retina ( C ). ( D ) After chemotherapy and autologous stem cell transplant, the superior temporal flat PED regressed, along with a thickening of the overlying retina

Three weeks later, an increase in sub-RPE deposits in the LE was detected on OCT, and the presence of a large flat pigment epithelial detachment (PED) in the superotemporal quadrant was observed, along with an increase in the thickness and reflectivity of overlying retina (Fig. 4 A, B,C). In this area, the PFBLs were more numerous and appeared in continuity with the thick and hyperreflective overlying retina (Fig. 4 C). On SS-OCT-A, a choriocapillary analysis showed an extension of the low reflectance areas, which affected the central posterior pole and superotemporal quadrant (Fig. 5 B, C). In the RE, yellowish white lesions in the upper part of the posterior pole were detected upon fundus examination, which appeared as sub-RPE hyper-reflective deposits on OCT, and which were hyperautofluorescent on AF.

( A ) SS-OCT-A choriocapillary analysis at baseline, revealing circumscribed low reflectance areas in foveal and parafoveal areas. ( B , C ) SS-OCT-A choriocapillary analysis performed seven weeks after the presentation, showing an extension of the low reflectance areas in the central posterior pole and superior temporal quadrant. ( D ) SS-OCT-A choriocapillary analysis after chemotherapy and autologous stem cell transplant, showing a remarkable reduction of the large central and superior temporal low reflectance areas, with the persistence of some hyporeflective central spots. Similar changes were detected on ICGA examination ( E )

A chorioretinal biopsy was performed, collecting a specimen from the thickened tissue in the superior temporal quadrant of the posterior pole. The specimen was put in formaldehyde and sent to a National Referral Center for histological analysis. A dense, large lymphoid population was found, which was immunoreactive for CD20, bcl-2, and MUM-1, partly so for bcl-6, and negative for CD3m and CD10.The immunocytochemical determination of Ki67 (clone 30 − 9) performed on a histological section in paraffin demonstrated about 80–90%. A diagnosis of a large B-cell lymphoma with non-germinal centre B cell-like phenotype was formulated. The patient underwent cancer staging, including a bone marrow biopsy and a Positron Emission Tomography, which showed no other disease foci.

In the meantime, LE visual acuity had decreased to 20/100, while still 20/20 in the RE. Multimodal imaging showed spreading in the mid-periphery of the sub-RPE lesions in the RE, in the same fashion previously seen in the LE.

For the treatment, the patient was referred to a national reference center for Oncological Hematology. He underwent three chemotherapy cycles, followed by autologous bone marrow stem cell sampling, two additional chemotherapy cycles, and a final stem cell reimplantation. Eight months after the chorioretinal biopsy and 2 months after completing chemotherapy and the autologous stem cell transplant, LE visual acuity increased to 20/20.

The patient was then followed-up in our department for three years. Multimodal imaging examination performed during follow up visits showed changing retinal lesions. On OCT examination, sub-RPE deposits had reduced remarkably, SND had disappeared (Fig.  6 C, D), and the superior temporal flat PED had regressed along with the thickening of the overlying retina (Fig. 4 D). On SS-OCT-A, a reduction in the multiple hyperreflective alterations corresponding to the sub-RPE deposits was detected on enface outer retina slabs (Fig.  6 E). The PFBLs had regressed, and in their sites dystrophic/atrophic RPE alterations were detected on OCT (Fig.  7 shows evolution of the PFBLs over 3 years). SS-OCT-A examination showed regression of the hyperreflective spots on the enface midretinal slabs that had corresponded to the PFBLs (Fig.  7 G).

Multimodal imaging after chemotherapy and autologous stem cell transplant. ( A ) Color fundus photo showing sharp scar margins at the chorioretinal specimen collection site. ( B ) Autofluorescence showing a reduction in hyperautofluorescen lesions. ( C , D ) OCT scans performed 10 months after the first presentation (corresponding to eight months after chorioretinal biopsy, and 2 months after completing chemotherapy and autologous stem cell transplant) showing remarkable reduction of sub-RPE deposits and SND disappearance. ( E ) SS-OCT-A enface outer retina slabs showing reduction of the multiple hyperreflective alterations, corresponding to the sub-RPE deposits

Evolution of the PFBLs over 3 years. ( A , B ) One month after the first presentation. OCT scans showing PFBLs as hyperreflective vertical-shaped retinal lesions. ( C , D ) After 1 year. OCT scans showing PFBLs regression, alongside dystrophic/atrophic RPE alteration onset their sites. ( E , F ) After 2 years. Dystrophic/atrophic RPE alterations detectable on OCT at the PFBL location. ( G ) SS-OCT-A at 1 year after presentation. Regression of the hyperreflective spots on enface midretinal slabs, which corresponded with the PFBLs

On SS-OCT-A analysis, choriocapillary reconstruction showed a remarkable reduction of the large low reflectance areas, with the persistence of some hyporeflective central spots (Fig. 5 D). Similar changes were detected on ICGA examination (Fig. 5 E).

At the chorioretinal specimen collection site, the scar margins were sharp, and no signs of proliferative vitreoretinopathy (PVR) were present on fundus examination. At the last FU visit, a posterior polar cataract was found in the LE. Follow-up PET and MRI were negative.

Discussion and conclusions

VRL diagnosis can be challenging due to the wide range of clinical presentations, including similarities with chronic uveitis. Moreover, when a VRL diagnosis is clinically suspected, reaching confirmation can be problematic as well [ 8 ]. In our case, a young man with no relevant medical or ocular history was diagnosed with VRL after a challenging assessment path, where many procedures turned out to be negative, making the diagnostic confirmation even more difficult. Multimodal imaging improved the diagnostic suspicion, guided the ensuing diagnostic procedures, and showed treatment response. When compared with previous literature, novel features were identified on SS-OCT-A and uncommonly described findings were confirmed.

Diagnostic vitrectomy was performed as the first procedure to confirm VRL. The cytological analysis of vitreous biopsies obtained during PPV remains a hallmark procedure in diagnosing the disease. However, its sensitivity varies widely from 31 to 87.5% [ 9 , 10 ]. Many factors can affect the result, including the cellularity of the sample and the expertise of the pathology labs [ 9 , 10 ]. Lymphoma cells may undergo morphological degradation within 60 min in absence of appropriate preservatives and when samples are not gently handled. Moreover, the cellularity may be reduced by corticosteroid treatments. In our case, the negative result could also be explained by the absence of any vitreous involvement. International consensus recommendations suggest that diagnostic vitrectomy is preferred in cases with vitreous involvement [ 9 ].

IL-10:IL-6 ratio analysis on a vitreous sample was also considered in our case. IL-10 levels tend to be elevated in the presence of malignant B-lymphocytes, whereas IL-6 is elevated in inflammatory states. Therefore, an IL-10:IL-6 ratio of > 1 is considered in favor of a B-cell lymphoma. However, the use of the IL-10:IL-6 ratio is controversial. In fact, elevation may occur in eyes with non-neoplastic uveitis. In one report, the IL-10:IL-6 ratio was elevated in 8 out of 14 vitreous samples with non-neoplastic vitritis. An IL-10:IL-6 ratio < 1 has been found in known cases of VRL [ 10 ]. Moreover, it has also been reported that in the presence of extensive and severe sub-RPE or retinal infiltration, as we found in our case, the IL-10:IL-6 ratio may not be typical and should thus be interpreted carefully [ 9 ]. The IL10:IL6 ratio was not performed in our case because it was not available. Nevertheless, for the reasons mentioned, it would not have been enough to achieve a definitive conclusion.

In a similar vein, MYD88 mutation analysis may be considered a valuable additional tool in VRL diagnosis [ 9 ], but a negative result may not definitively rule out the diagnosis since MYD88 mutations have been found in only up to 70% of all VRL [ 11 ].

Given the negative result of the above procedures, a chorioretinal biopsy was performed for our case, which confirmed the clinically suspected diagnosis. This approach has been helpful in other cases where previous diagnostic procedures proved inconclusive [ 12 , 13 ].

Considering the invasive nature of the procedures for a VRL diagnosis, better knowledge of multimodal imaging features of the disease would be desirable to increase pre-test probability. Previous studies described several VRL features [ 5 , 14 , 15 ]. However, few studies have reported SS-OCT-A findings, and their long-term follow-up remains unexplored. In this report, we describe various retinal findings in a case of VRL over a three-year FU, focusing on SS-OCT-A features. Our analysis led to the detection of novel SS-OCT-A features and confirmed uncommonly described findings that were analyzed throughout the three-year FU.

Outer-retinal abnormalities in VRL patients have been described in several previous studies. They are thought to be due to the infiltration of malignant lymphoma cells into the retina. Sub-RPE deposits, also found in our case, have mainly been examined with OCT [ 5 , 8 , 14 ] and AF [ 15 ] Pierro et al. [ 7 ] firstly described their appearance on SS-OCT-A as multiple hyperreflective spots on enface outer retina slabs and SS-OCT-A analysis, thus interpretable as a movement signal provided by white cell infiltration. Similarly, in our case, sub-RPE deposits appeared hyperreflective on enface SS-OCT-A outer retina slabs (Fig.  1 F). We also analyzed this feature during the FU, finding a remarkable reduction of the hyperreflective lesions previously detected on SS-OCT-A (Fig.  6 E) alongside the reduction of sub-RPE deposits on OCT.

Recently, Chen et al. [ 6 ] described PFBLs as novel characteristics of VRL on OCT-A, highlighting their possible role in facilitating early diagnosis and appearing as vertical intraretinal lesions. These features were also found in our case (Fig. 3 ). They were absent upon initial presentation, only appearing one month later during the diagnostic confirmation process and thus interpretable as a sign of disease progression. Moreover, we found that three weeks later, the PFBLs had become more numerous alongside an increase in sub-REP infiltration, and in some areas, they were in continuity with alterations in the overlying retina which appeared thick and hyperreflective. This may be interpretable as further disease progression with more extensive infiltration of malignant lymphoma cells into the retina. In the ensuing FU, we found a regression of VRL both on enface SS-OCT-A and on OCT scans in which they were replaced by dystrophic/atrophic RPE alteration. In parallel, a regression of the other sign of infiltration was detected.

Unlike Pierro et al. and Chen et al., we also found alterations in SS-OCT-A choriocapillary analysis. It firstly revealed circumscribed low reflectance areas in foveal and parafoveal areas that subsequently evolved into larger hyporeflective areas, which affected the central posterior pole and superior temporal quadrant (Fig. 5 ). Notably, these areas were also those most affected by retinal thickening and hyperreflectivity on OCT. They reduced considerably after treatment. We could not find any description of these SS-OCT-A findings in any previous study, since the choriocapillary plexus reconstruction has always been described as revealing no alteration. The clinical meaning of such alterations is yet to be understood. They could be interpretable as areas of flow signal impairment. However, they are more likely due to a shadowing artifact from the overlying infiltrated retinal tissues.

In conclusion, greater knowledge of VRL features would be helpful for timely diagnosis and therapy. In our case, we report multimodal imaging findings and long-term FU in a case of VRL, focusing on SS-OCT-A features. We describe novel SS-OCT-A findings and the evolution of uncommonly reported features, adding to current knowledge on the clinical presentation of VRL. Moreover, these aspects could provide avenues for future study on the characteristic presentation of the disease and improve disease understanding.

Data availability

All data and material are included in the manuscript and the figures.

Abbreviations

vitreoretinal lymphoma

primary central nervous system lymphoma

central nervous system

optical coherence tomography

autofluorescence

fluorescein angiography

indocyanine green angiography

swept-source OCT angiography

best-corrected visual acuity

subfoveal neuroretinal detachment

retinal pigment epithelium

pigment epithelial detachment

pars plana vitrectomy

interleukin 10

interleukin 6

proliferative vitreoretinopathy

Venkatesh R, Bavaharan B, Mahendradas P, Yadav NK. Primary vitreoretinal lymphoma: prevalence, impact, and management challenges. Clin Ophthalmol. 2019;13:353–64. https://doi.org/10.2147/OPTH.S159014 .

Article   CAS   PubMed   PubMed Central   Google Scholar  

Aziz HA, Peereboom DM, Singh AD. Primary central nervous system lymphoma. Int Ophthalmol Clin. 2015 Winter;55(1):111–21.

Kalogeropoulos D, Vartholomatos G, Mitra A, Elaraoud I, Ch’ng SW, Zikou A, Papoudou-Bai A, Moschos MM, Kanavaros P, Kalogeropoulos C. Primary vitreoretinal lymphoma. Saudi J Ophthalmol. 2019 Jan-Mar;33(1):66–80.

Chan CC, Rubenstein JL, Coupland SE et al. Primary vitreoretinal lymphoma: a report from an International Primary Central Nervous System Lymphoma Collaborative Group symposium. Oncologist. 2011;16:1589–1599.

Dalal M, Casady M, Moriarty E, Faia L, Nussenblatt R, Chan CC, Sen HN. Diagnostic procedures in vitreoretinal lymphoma. Ocul Immunol Inflamm. 2014;22(4):270–6. https://doi.org/10.3109/09273948.2013.848905 .

Article   PubMed   Google Scholar  

Chen W, Gu J, Liu S, Zhao Z, Jiang T, Xu G, Chang Q. PERIVASCULAR FLOWER-BUD-LIKE LESIONS ON ENFACE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY IN PATIENTS WITH VITREORETINAL LYMPHOMA. Retina. 2022;42(11):2169–75.

Pierro L, Arrigo A, Casalino G, Miserocchi E, Aragona E, Bandello F. Enface Optical Coherence Tomography Angiography of primary Vitreoretinal Lymphoma. Ophthalmic Surg Lasers Imaging Retina. 2018;49(10):e173–4.

Sehgal A, Pulido JS, Mashayekhi A, Milman T, Deák GG. Diagnosing Vitreoretinal Lymphomas-An analysis of the sensitivity of existing tools. Cancers (Basel). 2022;14(3):598. https://doi.org/10.3390/cancers14030598 .

Article   CAS   PubMed   Google Scholar  

Carbonell D, Mahajan S, Chee SP, Sobolewska B, Agrawal R, Bülow T, Gupta V, Jones NP, Accorinti M, Agarwal M, Batchelor T, Biswas J, Cimino L, tenDam-van Loon NH, de-la-Torre A, Frenkel S, Pe’er J, Kramer M, Miserocchi E, Mochizuki M, Ness T, Rosenbaum JT, Sen HN, Simion M (VRL patient), Sitter H, Vasconcelos-Santos DV, Habot-Wilner Z, Coupland SE, Pulido JS, Smith J, Thorne JE, Zierhut M. Study Group for Vitreoretinal Lymphoma Diagnostics. Consensus Recommendations for the Diagnosis of Vitreoretinal Lymphoma. Ocul Immunol Inflamm. 2021;29(3):507–520. https://doi.org/10.1080/09273948.2021.1878233 .

Sagoo MS, Mehta H, Swampillai AJ, Cohen VM, Amin SZ, Plowman PN, Lightman S. Primary intraocular lymphoma. Surv Ophthalmol. 2014 Sep-Oct;59(5):503–16. https://doi.org/10.1016/j.survophthal.2013.12.001 .

Bonzheim I, Giese S, Deuter C, Süsskind D, Zierhut M, Waizel M, Szurman P, Federmann B, Schmidt J, Quintanilla-Martinez L, Coupland SE, Bartz-Schmidt KU, Fend F. High frequency of MYD88 mutations in vitreoretinal B-cell lymphoma: a valuable tool to improve diagnostic yield of vitreous aspirates. Blood. 2015;126(1):76–9. https://doi.org/10.1182/blood-2015-01-620518 .

Mastropasqua R, Thaung C, Pavesio C, Lightman S, Westcott M, Okhravi N, Aylward W, Charteris D, da Cruz L. The role of Chorioretinal Biopsy in the diagnosis of intraocular lymphoma. Am J Ophthalmol. 2015;160(6):1127–e11321. https://doi.org/10.1016/j.ajo.2015.08.033 .

Johnston RL, Tufail A, Lightman S, Luthert PJ, Pavesio CE, Cooling RJ, Charteris D. Retinal and choroidal biopsies are helpful in unclear uveitis of suspected infectious or malignant origin. Ophthalmology. 2004;111(3):522–8. https://doi.org/10.1016/j.ophtha.2002 .

Makita J, Yoshikawa Y, Kanno J, Igawa Y, Kumagai T, Takano S, Katsumoto T, Shoji T, Shibuya M, Shinoda K. Electroretinographic and optical coherence tomographic evaluations of eyes with Vitreoretinal Lymphoma. J Clin Med. 2023;12(12):3957.

Casady M, Faia L, Nazemzadeh M, Nussenblatt R, Chan CC, Sen HN. Fundus autofluorescence patterns in primary intraocular lymphoma. Retina. 2014;34(2):366–72.

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EM designed the study, participated in the acquisition, analysis and interpretation of data and wrote the manuscript. FB conceived the study, participated in the acquisition, analysis and interpretation of data and critically revised the manuscript. AP participated in the interpretation of data and critically revised the manuscript. FA participated in the acquisition of data and critically revised the manuscript. GP participated in the design and coordination of the study, gave contribution in the analysis and interpretation of data and critically revised the manuscript. All authors read and approved the final manuscript.

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Maggio, E., Bauci, F., Polito, A. et al. Swept-source optical coherence tomography angiography findings in a case of primary vitreoretinal lymphoma over a three-year follow-up. BMC Ophthalmol 24 , 194 (2024). https://doi.org/10.1186/s12886-024-03438-1

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• Primary intraocular lymphoma
• Vitreoretinal lymphoma
• OCT-angiography
• Chorioretinal biopsy
• Ocular oncology

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Primary small lymphocytic lymphoma of the breast: a rare presentation of non-Hodgkin’s lymphoma

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Matthew Passeggiata, Geovanna Badaro, Hui Un Kim, Landry Umbu, Penelope Mashburn, Manju Nath, Primary small lymphocytic lymphoma of the breast: a rare presentation of non-Hodgkin’s lymphoma, Oxford Medical Case Reports , Volume 2024, Issue 4, April 2024, omae028, https://doi.org/10.1093/omcr/omae028

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Primary Small Lymphocytic Lymphoma of the breast is a rare presentation of Non-Hodgkin’s lymphoma. In this report, we present the case of primary small lymphocytic lymphoma of the breast in a 65-year-old female who presented with an abnormal breast ultrasound significant for a nodule of the right breast consistent with BI-RADS 4, indicating follow-up with ultrasound-guided biopsy for further diagnostic evaluation. The patient had no prior history of extramammary lymphoma or widespread disease. A sample of the breast mass was obtained via ultrasound-guided core needle biopsy and the pathology report revealed low-grade B-cell Lymphoma. After discussion with medical oncology and the explanation of risks, benefits and alternatives to surgery, a lumpectomy was performed, and the final pathology report of the mass revealed primary low-grade B-cell lymphocytic lymphoma of the breast. On follow up, the PET scan was unremarkable and showed no evidence of abnormal glucose metabolism or adenopathy.

Breast lymphomas are classified into primary breast lymphoma (PBL) and secondary breast lymphoma (SBL) [ 1–3 ]. The incidence of PBL from 1975 to 2017 was 1.35/1 000 000 [ 4 ]. PBL is most commonly due to Non-Hodgkin’s Lymphoma (NHL) without previous diagnosis of extramammary lymphoma, whereas SBL is due to metastasis also most commonly from NHL that developed from extrammamary tissue. PBL and SBL are clinically similar, and both may exhibit B-symptoms such as fever, night sweats and weight loss [ 3 ]. NHL is a solid tumor of the lymphatic system, representing 90% of lymphomas [ 1 ]. NHL can be indolent or aggressive, Indolent NHL typically manifests with waxing and waning lymphadenopathy. Of the indolent types, the most common are follicular lymphoma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and splenic marginal zone lymphoma [ 5 ].

An asymptomatic 65-year-old postmenopausal female with a past medical history of hypertension, diabetes mellitus, hyperlipidemia, and hysterectomy was referred to the surgery clinic after a non-diagnostic mammogram (BI-RADS Category 1) and ultrasound (US) significant for a nodule at the 7 o’clock position of the right breast measuring 4.6 × 3.5 × 3.6 centimeters (cm) ( Fig. 1 ), consistent with BI-RADS 4, indicating the need for an US-guided biopsy for further diagnostic evaluation.

Imaging of the right breast mass at the 7 o’clock position measuring 4.6 × 3.5 × 3.6 cm.

Her prior routine mammograms had been unremarkable for the past 6 years. Family history was significant for breast cancer in her sister who succumbed to aggressive metastatic breast cancer with unknown hormonal or HER2 status. The patient denied breast pain, nipple discharge, fever, night sweats, fatigue, chest pain, or palpitations. On exam there were no dimpling, retraction, or secretions of bilateral breasts. On palpation there was a palpable mass at the 7 o’clock position. There was no cervical, supraclavicular, or axillary lymphadenopathy.

The US-guided core needle biopsy revealed low-grade mature small B-cell lymphoma. The peripheral blood smear was within normal limits and complete blood count was normal outside of rare target cells, slight poikilocytosis, and rare schistocytes. There were no immature white blood cells and platelet count was normal with rare giant forms. The results were discussed with oncology, lumpectomy was recommended with follow up positron emission tomography (PET) scan imaging. After the explanation of risks, benefits, and alternative treatment options to lumpectomy the patient agreed to lumpectomy.

A lumpectomy was performed with no complications and the pathology report of the mass revealed atypical lymphoid cell population infiltrating the breast duct ( Fig. 2 ) and lymphoid tissue infiltration fat ( Fig. 3 ). Immunohistochemical staining confirmed low-grade NHL with positive B-cell markers for CD3, CD5, and CD20 ( Fig. 4 ) and negative CD10, cyclin D1, BCL6, and CD23 markers. The final diagnosis of primary small lymphocytic lymphoma was made. On follow up, the PET scan was unremarkable with no evidence of abnormal glucose metabolism or adenopathy. The planned surveillance for this patient consisted of follow up mammogram imaging every 6 months for 1 to 2 years with yearly mammograms subsequently. A 6-month follow-up mammogram revealed no evidence of malignancy or significant changes.

Atypical lymphoid cell population infiltrating the breast duct.

Lymphoid tissue infiltrating fat.

Immunohistochemical staining positive for B-cell marker CD20.

NHL is a heterogeneous group of lymphoproliferative malignancies originating from B and T-cell precursors, as well as mature B and T-cells [ 5 ]. 25% of NHL cases disseminate to extranodal areas, most commonly the stomach, Waldeyer’s ring, central nervous system, lung, bone, and skin [ 1 ]. Breast lymphoma is rare with a prevalence of 0.04%–0.7% [ 2 , 6 ], which can be attributed to the scarcity of lymphoid tissue in the breast [ 4 ]. Breast lymphomas are classified into primary breast lymphoma (PBL) and secondary breast lymphoma (SBL) [ 1–3 ]. The current diagnostic criteria for PBL was initially proposed by Wiseman and Laio in 1972 [ 7 ]. The criteria consists of mammary tissue and lymphoma infiltrates in close proximity to each other, no evidence of concurrent widespread disease, and no prior diagnosis of extramammary lymphoma.

SLL consists of monomorphic small round B lymphocytes involving the lymph nodes, peripheral blood, and bone marrow [ 8 ]. In this patient, the histopathologic report of the mass showed two small foci of lymphoid infiltration predominantly composed of small lymphocytes positive for CD20, CD3, and CD5 markers. The peripheral blood smear showed a normal CBC without the presence of small lymphocytes. The presence of the neoplastic lymphocytes primarily in the lymphatic tissue rather than circulating in peripheral blood is more consistent with SLL rather than CLL [ 8 ].

PBL management consists of surgery, chemotherapy such as cyclophosphamide, hydroxy daunomycin, and vincristine sulfate, prednisone, radiotherapy, and immunotherapy, which can be done alone or in different combinations [ 9 ]. The classic treatment for PBL is chemotherapy, radical surgical excision has been shown to have no influence on survival or risk of recurrence therefore it is not recommended as a therapeutic measure [ 9 , 10 ]. Despite this it is important to note that due to the scarcity of PBL, definite therapeutic guidelines have not been established. Therefore, surgical excision may be indicated when the core needle biopsy sample is insufficient for classification or due to individualized treatment plans and patient preference [ 10 ]. In this case, we have performed surgical excision for therapeutic purposes with follow-up PET scan dictating required additional treatment. If the PET scan detected metastasis of the PBL, then an assessment for further treatment would be followed.

Primary breast lymphoma is a rare malignancy of the breast which shares many radiological and clinical presentations with breast carcinoma and other breast malignancies. Despite this, it is vital to have primary breast lymphoma as a differential diagnosis and to obtain an adequate sample for flow cytometry, allowing for an accurate diagnosis and appropriate treatment options. Although there are no definite therapeutic guidelines as there are for breast carcinoma, treatment options should be individualized to each patient’s case, taking stage, symptoms, overall health, patient preference and lymphoma subtype into consideration when deriving a treatment plan. Here we discussed the case of PBL successfully treated with surgical excision thereby avoiding the side effects and associated risks of chemotherapy and radiation.

There are no conflicts of interests to disclose.

Written informed consent was obtained for both the procedure and manuscript publication, including photographs and images.

Singh   R , Shaik   S , Negi   BS , Rajguru   JP , Patil   PB , Parihar   AS . et al.    Non-Hodgkin's lymphoma: a review . J Family Med Prim Care   2020 ; 9 : 1834 – 40   PMID: 32670927; PMCID: PMC7346945 .

Google Scholar

Duncan   VE , Reddy   VVB , Jhala   NC , Chhieng   DC , Jhala   DN . Non-Hodgkin’s lymphoma of the breast: a review of 18 primary and secondary cases . Ann Diagn Pathol   2006 ; 10 : 144 – 8 .

Raj   SD , Shurafa   M , Shah   Z , Raj   KM , Fishman   MDC , Dialani   VM . Primary and secondary breast lymphoma: clinical, pathologic, and multimodality imaging review . Radiographics   2019 ; 39 : 610 – 25 .

Peng   F , Li   J , Mu   S , Cai   L , Fan   F , Qin   Y . et al.    Epidemiological features of primary breast lymphoma patients and development of a nomogram to predict survival . Breast   2021 ; 57 : 49 – 61   Epub 2021 Mar 17. PMID: 33774459; PMCID: PMC8027901 .

Sapkota   S , Shaikh   H . Non-Hodgkin Lymphoma. [Updated 2022 Dec 2] . In: Shumway S, (ed) StatPearls [Internet] . Treasure Island (FL) : StatPearls Publishing , 2022 . Available from:   https://www.ncbi.nlm.nih.gov/books/NBK559328/ .

Google Preview

Shim   E , Song   SE , Seo   BK , Kim   YS , Son   GS . Lymphoma affecting the breast: a pictorial review of multimodal imaging findings . J Breast Cancer   2013 ; 16 : 254 – 65 .

Wiseman   C , Liao   KT . Primary lymphoma of the breast . Cancer   1972 ; 29 : 1705 – 12 .

Wierda   WG , Brown   J , Abramson   JS , Awan   F , Bilgrami   SF , Bociek   G . et al.    NCCN guidelines® insights: chronic lymphocytic leukemia/small lymphocytic lymphoma, version 3.2022 . J Natl Compr Cancer Netw   2022 ; 20 : 622 – 34 .

Moura   C , Leite   MI , Parreira   R , Medeiros   A . Primary breast lymphoma . J Surg Case Rep   2020 ; 2020 : rjz405 .

Alyass   F , Ray   LA . Surgical excision versus medical Management of Primary Breast Lymphoma: a case report . Cureus   2022 ; 14 : e32802 .

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• Int J Ophthalmol
• v.10(8); 2017

Intraocular lymphoma

Li-juan tang.

1 Department of Ocular Pathology, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, Guangdong Province, China

Chang-Lin Gu

2 Department of Traditional Chinese Medicine, the Second Health Service Center of Tangxia, Tianhe District, Guangzhou 510665, Guangdong Province, China

Intraocular lymphoma (IOL) is a rare lymphocytic malignancy which contains two main distinct forms. Primary intraocular lymphoma (PIOL) is mainly a sub-type of primary central nervous system lymphoma (PCNSL). Alternatively, IOL can originate from outside the central nervous system (CNS) by metastasizing to the eye. These tumors are known as secondary intraocular lymphoma (SIOL). The IOL can arise in the retina, uvea, vitreous, Bruch's membrane and optic nerve. There are predominantly of B-cell origin; however there are also rare T-cell variants. Diagnosis remains challenging for ophthalmologists and pathologists, due to its ability to masquerade as noninfectious or infectious uveitis, white dot syndromes, or occasionally as other metastatic cancers. Laboratory tests include flow cytometry, immunocytochemistry, interleukin detection (IL-10: IL-6, ratio >1), and polymerase chain reaction (PCR) amplification. Methotrexate-based systemic chemotherapy with external beam radiotherapy and intravitreal chemotherapy with methotrexate are useful for controlling the disease, but the prognosis remains poor. Therefore, it is important to make an early diagnose and treatment. This review is focused on the clinical manifestations, diagnosis, treatment and prognosis of the IOL.

The designation of intraocular lymphoma (IOL) includes primary intraocular lymphoma (PIOL), mainly arising from the central nervous system (CNS) and secondary intraocular lymphoma (SIOL, from outside the CNS as metastasis from a non-ocular neoplasm) [1] – [2] . IOL incidence is very low. Most cases are of B-cell origin and associated with primary CNS non-Hodgkin's lymphoma. Fewer cases are of T-cell origin. Intraocular T-cell lymphomas are uncommon, some are secondary to metastatic systemic T-cell lymphomas including primary cutaneous peripheral T-cell lymphoma (PCPTCL), the NK-T cell lymphoma, and rarely adult T-cell leukemia/lymphoma (ATL) [3] – [7] , and the disease is usually confined to the iris and ciliary body and peripheral choroid. The most common PIOL by far is primary vitreoretinal lymphoma (PVRL). SIOL has different clinical features and prognosis [8] , and the most common subtype is systemic diffuse large B cell lymphoma (DLBCL) [9] . Although still rare, the incidence of IOL has increased in the recent years, and prognosis remains poor. Here, we summarize mainly the current literature on IOL.

EPIDEMIOLOGY

The incidence of IOL has been increasing in recent years, due to the increase in the patients of immunodeficiency and immunosuppression, the increase in life expectancy, and the improvements in diagnostic tools [8] , [10] . The overall incidence of IOL has been estimated to represent 1.86% of ocular malignant tumors [11] . The median age of this disease is 50-60y [12] – [13] , with a range between 15-85 years of age [14] . These are estimated to represent 4%-6% of primary brain tumors and 1%-2% of extranodal lymphomas [15] – [16] . Among IOL patients, the percentage of cases that involve the CNS is 60%-80% [17] . While 15%-25% of primary central nervous system lymphoma (PCNSL) patients develop ophthalmic manifestations of lymphoma, 56%-90% of PIOL patients have or will develop CNS manifestations of lymphoma [18] . In terms of gender, some reported that women were more commonly affected than men by 2:1 [19] – [21] . But some reported that even greater cases occurred in men [22] . There appears to be no racial predilection for the disease [22] – [23] .

The etiology of IOL remains unclear. Multiple hypotheses of lymphomagenesis are involved. Immunocompromise, Epstein-Barr virus, and Toxoplasma gondii infection may be the related factors [24] – [26] . Moreover, an infectious antigen driven B-cell expansion may be the primary trigger, which then becomes cloned [8] . Thus, genetic, immunologic, and microenvironmental factors are probably necessary in order to induce malignant B-cell phenotype [27] . Proofs of causation are still lacking, and the lymphomagenesis requires further investigation.

CLINICAL FEATURES

PIOL is a masquerade syndrome that mimics uveitis, even responds to steroid therapy, which makes the diagnosis difficult. Ocular disease is bilateral in 64%-83% of cases [28] . Blurred vision, reduced vision, and floaters are the common initial subjective symptoms [17] . More than 50% of patients have significant vitreous haze and cells that can be seen insheets or clumps with vision impairment [29] . Posterior vitreous detachment and hemorrhage may occur occasionally [30] . Posterior uveitis is the most common presenting symptoms, and anterior segment inflammatory findings are frequently absent [18] . Another characteristic from optical coherence tomography (OCT) is the development of creamy lesions with orange-yellow infiltrates to the retina or retinal pigment epithelium (RPE) [1] , [31] – [32] . They can give rise to a characteristic “leopard skin” pigmentation overlying the mass which may be seen in fluorescein angiography (FA) [32] – [35] . There may beisolated subretinal lesionsor associated exudative retinal detachment [23] , [33] . A single vitreous lesion is rare, sometimes simple vitreous inflammatory response or optic nerve infiltration may occur [36] . At presentation of PIOL, 56%-90% patients have or will develop CNS manifestations of lymphoma [14] . Sometimes IOL may masquerade as bilateral granulomatous panuveitis [37] . When there is infiltration to the brain, behavioral changes and alteration in cognitive function may occur [38] .

Intraocular T-cell lymphomas are uncommon, some of them are secondary to metastatic systemic T-cell lymphomas. SIOL should be considered when there is a bilateral sudden and severe inflammatory reaction of the anterior segment that does not respond to treatment or recurs. Anterior reaction and keratic precipitates may be presented especially in SIOL [39] . The most common ocular manifestation of this disease is non-granulomatous anterior uveitis and vitritis. Other rare ocular symptoms include inflammatory glaucoma, neurotrophic keratopathy, fully dilated pupil, and choroidal detachment [40] . Previous systemic primary site reported indicated that the skin was the most common site. Concurrent CNS involvement was reported in 31.0% cases [41] .

DIAGNOSTIC TESTS

The delay between a positive diagnosis and the onset of ocular or neurological symptoms usually ranges from 4-40mo [23] , [28] , [42] , although more rapid progression may occur [43] .The diagnosis of IOL requires a multidisciplinary approach, involving morphological assessment in conjunction with traditional immunocytochemistry and molecular analysis [such as flow cytometry and polymerase chain reaction (PCR) analysis]. Histologic identification remains one of the essential procedures in diagnosing IOL [44] – [45] . Morphologically and immunohistochemically, the typical lymphoma cells are usually with scanty cytoplasm, an elevated nucleus: cytoplasm ratio, round, oval, bean, or irregular shaped nuclei with a coarse chromatin and prominent or multiple nucleoli [46] – [47] ( Figure 1A ). In B cell lymphoma the predominance of lymphoma cells were identified as CD20, CD79α positive and CD3 negative ( Figure 1B , ​ ,1C). 1C ). And in T cell lymphoma, medium to large sized lymphoid cells with atypical nuclei are visualized with HE staining ( Figure 2A ). While the tumor cells are identified as CD3 positive and CD20 negative ( Figure 2B , ​ ,2C). 2C ). Both the two types of IOL are with high Ki-67 positive rate (average >80%) indicates extensive proliferation ( Figures 1D , ​ ,2D). 2D ). Specimens can be obtained by fine needle vitreous aspiration or pars plana vitrectomy. And multiple biopsies may be required to reach a definite pathological diagnosis. Removed ocular fluids ( via aqueous tap, vitreous tap, or diagnostic vitrectomy) need to be delivered quickly for laboratory analysis, to prevent cell degeneration that can make diagnosis difficult [47] . Furthermore, a negative vitrectomysample is common, sparse number of cells is also the main reason for misdiagnosis. In addition, vitreous specimens contain many reactive T-lymphocytes, necrotic cells, debris, and fibrin that can also confound the identification of malignant cells [46] . Then, retinal or chorioretinal biopsies may be required. Microscopically, the typical lymphoma cells are large B-cell lymphoid cells with scanty cytoplasm, an elevated (nucleus:cytoplasm) ratio, heteromorphic deeply stained nuclei with a coarse chromatin pattern and prominent nucleoli can be seen ( Figure 3 ). Pars plana vitrectomy has several advantages, including improved vision by clearance of vitreous debris and maximizing the sample size [44] , [48] – [49] , although the lymphoma may extend to the epibulbar space through the sclerotomy port following vitrectomy [50] .

The atypical cells have pleomorphic nuclei with conspicuous nucleoli and scanty cytoplasm (A, HE staining, 200×). It is positive for CD20 (B, 200×) and negative for CD3 (C, 200×); the high Ki-67 positive rate (average >80%) indicates extensive proliferation (D, 200×).

Medium-to-large-sized lymphoid cells with atypical nuclei are visualized with HE staining (A, 200×) and identified as CD3 positive (B, 200×), CD20 negative (C, 200×); the high Ki-67 positive rate (average >80%) indicates extensive proliferation (D, 200×).

Molecular analysis detecting immunoglobulin gene rearrangements in the lymphoma cells and ocular cytokine analysis of vitreous fluid show elevated interleukin (IL-10) with an IL-10:IL-6 ratio >1.0 are helpful for the diagnosis, while inflammatory conditions typically show elevated IL-6 [17] , [51] – [53] . In addition, if the eyes have no function or conservative treatment is impossible, a diagnostic enucleation may become necessary [54] . Flow cytometry can examine cell surface markers and demonstrate monoclonal B-cell populations. IOL is typically comprised of amonoclonal B-cell population with restricted κ or λ chains. A κ:λ ratio of 3 or 0.6 is a highly sensitive marker for lymphoma [55] . PCR has been used to amplify the immunoglobulin heavy chain DNA. In B-cell lymphomas, molecular analysis can detect IgH gene rearrangements, while in T-cell lymphomas, T-cell receptor gene rearrangements can be detected [56] . Detection of the bcl-2 t (14;18) translocation is also an effective method to diagnose IOL. Wallace et al [57] reported that 40 of 72 (55%) PIOL patients expressed the bcl-2 t (14;18) translocation at the major breakpoint region. A PCR analysis of EB virus with aqueous humor might be useful for supporting the diagnosis of intraocular NK-cell lymphoma [58] . Microdissection with a minimum of 15 atypical lymphoid cells has been shown to have a diagnostic efficiency of 99.5% by using PCR [59] .

Besides, ophthalmological examinations frequently demonstrate the presence of vitritis, usually in association with infiltrates of the retina and the retinal pigment epithelium. Hyperfluorescense on fundus autofluorescence imaging can demonstrate active sub-retinal pigment epithelium deposits, while hypofluorescent spots can correspond to areas where tumor cells were suspected to have once been [60] . Fluorescein angiography (FA) may show mottling, granularity, and late staining patterns with a characteristic “leopard spotappearance” [23] , [32] , [34] – [35] , [61] . OCT demonstrates hyper reflective lesions at the level of the RPE in PVRL. The valuable diagnostic tools include fundoscopy, FA, OCT, fundus autofluorescence, and fluorescein and indocyanine green angiography. There has been reported that ophthalmological examinations finding had a positive predictive value of 88.9% and a negative predictive value of 85% [32] . In addition, once cerebral lymphoma is suspected, contrast-enhanced cranial magnetic resonance imaging (MRI) is the best imaging modality. Lesions are often isointense to hypointense on T2-weighted MRI, with variable surrounding edema and a homogeneous and strong pattern of enhancement [62] – [63] .

Due to the rarity of IOL, standard and optimal therapy is not defined. Treatment modalities for IOL include intravitreal chemotherapy, systemic chemotherapy, and radiotherapy, which is used alone or in an appropriate combination. The therapies vary according to the disease degree, the presence or absence of CNS involvement, and performance status of the patients [64] . The current recommendation for the treatment of IOL without CNS or systemic involvement should be limited to local treatment, including intraocular methotrexate and/or ocular radiation in order to minimize systemic toxicities [38] . Ocular irradiation with prophylactic CNS treatment is used to control IOL, maintain vision, and prevent CNS involvement [24] . The average external beam radiation dose is close to 40 Gy, but can range from 30 to 50 Gy [29] . The complications of radiotherapy include radiation retinopathy, vitreous hemorrhage, dry eye syndrome, conjunctivitis, neovascular glaucoma, optic atrophy, punctate epithelial erosions or cataract [29] . While the treatment of the patients with CNS involvement includes a combination of radiotherapy and chemotherapy [63] , [65] . As with systemic chemotherapy, the mainstay of intravitreal chemotherapy is methotrexate [66] . Rituximab is an anti-CD20 monoclonal antibody. And intravitreal rituximab is often used to decrease the frequency of methotrexate injections or for methotrexate-resistant IOL [67] – [69] . Initial response was good with clearance of PIOL, but subsequent relapse required intravitreal methotrexateand radiation [67] . Methotrexate can also use alone or in combination with other medications, such as thiotepa and dexamethasone [34] , [70] – [72] . High dose methotrexate is the most active drug, producing a response rate of up to 72% when used alone and up to 94%-100% in combinations [73] – [74] . Combined intravitreal methotrexate and systemic high-dosemethotrexate treatment is effective in patients with PIOL [75] . However, polychemotherapy is also associated with higher drug toxicity [29] . In addition, intravitreal chemotherapy with 0.4 mg methotrexate in 0.1 mL achieved local tumor control in relapsed IOL [76] – [77] . Also the intravitreal chemotherapy is a primary treatment in combination with systemic chemotherapy [70] . Drug resistance may occur with repeated injections [78] . For relapsed or refractory PIOL with PCNSL has been treated with intrathecal methotrexate and cytarabine [79] . These treatment decisions are often complex and require personalized treatment for different patients.

IOL is a rare lymphocytic malignancy, the reported mortality rate range between 9% and 81% in follow-up periods, and the survival time is 12-35mo [19] , [80] – [82] . However, the reported mortality rate of IOL is very inconsistent because of the rare patient populations, variation in treatment modalities, and the delayed diagnosis. Tumor recurrence is common, and sometimes the existing treatment cannot effectively prevent the local recurrence and the CNS involvement. The prognosis depends on the following aspects: 1) whether the CNS is involved. A trend toward better survival was seen among patients with isolated ocular presentation [83] – [84] . Moreover, the IOL patients with CNS involvement are almost died in the short term. Neuroimaging is important for the patients after treatment since the IOL patients carry a risk for recurrence or CNS involvement [85] ; 2) histopathologic type is another important factors. Generally T cell type has poorer prognosis than B cell type; 3) treatment opportunity, early treatment after onset of symptoms may improve the prognosis for a better visual outcome [86] . In PCNSL, median survival of patients treated with radiotherapy alone or chemotherapy plus radiotherapy ranges from 10 to 16mo [38] ; 4) the vision and survival rates are both poor in recurrent patients. Due to the rarity of the disease, there is often misdiagnosis, delay in diagnosis, and mismanagement of IOL.

In conclusion, IOL often masquerades as intraocular inflammation resulting in misdiagnosis or delayed diagnosis, with subsequent inappropriate management and high mortality rates. Patients with suspected IOL should undergo cytopathologic examination of vitreal fluid or vitrectomy before therapy. On the ocular cytokine levels, mainly IL-10:IL-6 ratio and molecular analysis can provide useful supplementary data for the diagnosis. Once IOL is diagnosed, all patients are required to be examined the subtle neurological symptoms and signs with the oncologist. Meanwhile, neuroimaging is performed to detect any evidence of CNS involvement. Optimal therapy for IOL is considered a great challenge to the clinical. Intravitreal chemotherapy with more than one agent may be proved to be useful in controlling the ocular disease. When the CNS involved, methotrexate-based systemic chemotherapy with external beam radiotherapy should be undertaken. Because of the rarity of this disease, multicenter studies are needed to obtain optimized treatment methods in order to get better vision and prognosis.

METHOD OF LITERATURE SEARCH

PubMed (1970 to end of 2016) database was searched using the search terms IOL, PIOL and SIOL. Removing duplicate articles, excluding articles that clearly related to extraocular lymphoma, and removing foreign language papers provided a total of 86 unique articles in English.

Acknowledgments

Foundation: Supported by the National Natural Science Foundation of China (No.30371515).

Conflicts of Interest: Tang LJ, None; Gu CL, None; Zhang P, None.

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