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CNS involvement in a patient with primary intraocular lymphoma. Note the enhancing mass slightly larger than 1.5 cm in the right middle frontal gyrus surrounded by modest amount of vasogenic edema.
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Diagnosis of PIOL can be challenging. It requires a high degree of clinical suspicion and differential diagnosis includes infectious and non-infectious etiologies particularly the common masquaraders sarcoidosis, tuberculosis, viral retinitis and syphilis. The definitive diagnosis depends on demonstration of malignant lymphoma cells in ocular speci...
Citations
... While a uveitis evaluation requires blood tests and various imaging studies to assess for systemic infectious and inflammatory causes, [6] physicians need to know when to suspect VRL and seek appropriate evidence for the presence of malignant lymphoma. When a diagnosis is uncertain, a biopsy is necessary to obtain a more definitive, diagnostic specimen from the aqueous, vitreous, choroid or retina; however, all biopsies may be associated with potential surgical risks and complications [7]. ...
... In addition, early detection ensures appropriate management and improves patient outcomes [14]. Unfortunately, since VRL signs and symptoms often resemble other ocular conditions, delayed diagnosis is common [7]. Therefore, the identification of characteristics strongly associated with VRL could improve the speed and accuracy of diagnosis. ...
Background
Vitreoretinal lymphoma (VRL) is a rare intraocular malignancy that poses a diagnostic challenge due to the non-specific clinical presentation that resembles uveitis. The use of spectral domain optical coherence tomography (SD-OCT) has emerged as a valuable imaging tool to characterize VRL. Therefore, we sought to determine the specific OCT features in VRL compared to the uveitides.
Methods
Retrospective chart review of patients who were seen at Mayo Clinic from January 1, 2010 through December 31, 2022.
The medical records and SD-OCT images at time of initial presentation were reviewed in patients with biopsy-proven VRL, intermediate uveitis, or biopsy-confirmed sarcoid posterior uveitis. Patients with VRL or similar uveitides including intermediate uveitis or sarcoid posterior uveitis were included.
Results
There were 95 eyes of 56 patients in the VRL group and 86 eyes of 45 patients in the uveitis group, of whom 15 (33.3%) were diagnosed with intermediate uveitis and 30 (66.7%) with sarcoid chorioretinitis. The SD-OCT features more commonly seen at initial presentation in VRL patients (vs. uveitis) included preretinal deposits (31.6% vs. 9.3%, p = 0.002), intraretinal infiltrates (34% vs. 3.5%, p < 0.001), inner retinal hyperreflective spots (15.8% vs. 0%, p < 0.001), outer retinal atrophy (22.1% vs. 2.3%, p < 0.001), subretinal focal deposits (21.1% vs. 4.7%, p = 0.001), retinal pigmented epithelium (RPE) changes (49.5% vs. 3.5%, p < 0.001), and sub-RPE deposits (34.7% vs. 0%, p < 0.001). Features more frequently seen in uveitis included epiretinal membrane (ERM) (82.6% vs. 44.2%, p < 0.001), central macular thickening (95.3% vs. 51.6%, p < 0.001), cystoid macular edema (36% vs. 11.7%, p < 0.001), subretinal fluid (16.3% vs 6.4%, p = 0.04), and subfoveal fluid (16.3% vs. 3.2%, p = 0.003). Multivariate regression analysis controlling for age and sex showed absence of ERM (OR 0.14 [0.04,0.41], p < 0.001) and absence of central macular thickening (OR 0.03 [0,0.15], p = 0.02) were associated with VRL as opposed to uveitis.
Conclusion
OCT features most predictive of VRL (vs. uveitis) included absence of ERM and central macular thickening.
... The vitreous cytology examination is a useful investigation for definite diagnosis of PVRL. Nevertheless, malignant cells are quite scarce and prone to degenerate easily (9,15). This barrier decreases the chance of vitreous cytology to diagnose PVRL. ...
OBJECTIVE This study aims to describe clinical characteristics and outcomes after treatment of primary vitreoretinal lymphoma (PVRL). METHODS Fifteen patients with a proven diagnosis of PVRL by histology, cytology and/or flow cytometry were analyzed. RESULTS The median age of the 15 patients was 59 years (range 41-71). Median follow-up time was 37 months (IQR 22.5-80) (range 4-106). Ophthalmic presentations of 25 eyes included vitritis (72%), chorioretinal infiltrations (60%), and retinal vasculitis (20%). Bilateral involvement was observed in 10 patients at presentation and in 4 patients during follow up. Ten patients (67%) developed brain involvement after ocular presentation with a median time of 22.5 months (range 2-84). Treatment modalities were included: 1) isolated intravitreal (IVT) methotrexate (6/15 patients; 40%) with a median number of injections of 4 (IQR 1,6) (range 1-16) 2) combined with IVT metho-trexate and/or rituximab and systemic chemotherapy and/or radiation (8/15; 53%) with a median of 6 injections (IQR 1,11) (range 1-16) and 3) systemic chemotherapy alone (1/15; 7%). Whole brain radiotherapy (WBRT) was performed in 10 of 15 patients (67%). Among the 6 patients who received isolated IVT methotrexate, 3 patients had complete remission (3/6; 50%), one died at 96 months after treatment, and one was lost to follow up after a single injection. Nine of 15 patients who received systemic chemotherapy with or without IVT chemotherapy and/or WBRT had complete remission (8/9; 89%). CONCLUSIONS Vitritis and chorioretinal infiltrations were the main ocular presentations of PVRL. Two-thirds of the patients developed brain involvement which resolved after treatment. Systemic chemotherapy tends to provide a higher rate of complete remission compared to local therapy alone.
... However, VRL remains a masquerade syndrome and is frequently misdiagnosed as chronic idiopathic uveitis due to its indistinct clinical manifestations and absence of conclusive biomarkers. 8,9 Cytology, polymerase chain reaction (PCR) analysis of the monoclonality of immunoglobulin H (IgH), and measurement of interleukin (IL)-10 and IL-6 levels are considered the gold standard diagnostic tests for VRL. In a Japanese survey, cytology demonstrated a modest detection rate of 44.5%. 4 Similarly, the detection rates of PCR analysis for IgH receptor rearrangements were also limited, with 80% in VRL cases presenting vitreous opacity and 75% in VRL cases with subretinal infiltration. ...
Purpose:
Vitreoretinal lymphoma is a high-grade malignant non-Hodgkin lymphoma with poor prognosis. The objective of this study was to elucidate the proteome profile of the vitreous in patients with vitreoretinal lymphoma (VRL), aiming to advance understanding of the pathophysiology of VRL.
Methods:
Comprehensive proteomic analyses of vitreous humor using liquid chromatography with tandem mass spectrometry were performed for 10 patients with VRL, 10 control patients with idiopathic epiretinal membrane or macular hole, and 10 patients with ocular sarcoidosis. Differentially expressed proteins (DEPs) were identified by comparing VRL with controls and sarcoidosis, and functional pathway analysis was performed. Finally, vitreous concentrations of representative DEPs that were significantly upregulated in proteomics study were measured by ELISA using a separate cohort.
Results:
In total, 1594 proteins were identified in the vitreous humor of VRL, control, and sarcoidosis samples. Also, 282 DEPs were detected in VRL, 249 upregulated and 33 downregulated, compared with controls. Enrichment pathway analysis showed alterations in proteasome-related pathways. Compared to controls and sarcoidosis, 14 DEPs in VRL showed significant upregulation. In the validation study, ELISA confirmed significantly higher vitreous concentrations of PSAT1, YWHAG, and 20S/26S proteasome complex in VRL compared with controls and sarcoidosis. Among the upregulated DEPs, vitreous PITHD1 and NCSTN concentrations correlated positively with vitreous IL-10 concentrations.
Conclusions:
This study highlights aberrations in protein expression pattern in the vitreous of patients with VRL. The DEPs identified in this study may play pivotal roles in VRL pathogenesis, providing insights to enhance understanding of VRL pathophysiology and contribute to the development of VRL biomarkers.
... The cornerstone to the differential diagnosis algorithm in VRL is better visual acuity in contrast with the severity of clinical findings, absence of posterior synechiae and cystoid macula edema, lack of disc swelling and epiretinal membrane (Davis 2004), presence of migrating retinal lesions, especially in the absence of vitritis and spontaneous resolving of large subretinal lesions due to the function of CD8+ T cells and natural killer cells (Tan et al. 2018;Rajagopal and Harbour 2011;Peterson et al. 1993;Raparia et al. 2009;Sen et al. 2009). ...
... This surgical technique optimizes sample size and removes vitreous opacities and thus improves vision in symptomatic patients (Gonzales and Chan 2007;Sagoo et al. 2014;Coupland et al. 2004). To obtain the samples, a complete standard three-port pars plana vitrectomy is used (Sen et al. 2009;Choi et al. 2006). A 3-cc syringe is incorporated into the vitrector aspiration line to draw the sample (Sen et al. 2009;Bardenstein 1998). ...
... To obtain the samples, a complete standard three-port pars plana vitrectomy is used (Sen et al. 2009;Choi et al. 2006). A 3-cc syringe is incorporated into the vitrector aspiration line to draw the sample (Sen et al. 2009;Bardenstein 1998). First, 1-2 cc of undiluted vitreous is aspirated with aspiration-only mode to prevent mechanical tissue disruption from the vitrector (Sen et al. 2009). ...
Intraocular lymphomas are rare, non-Hodgkin, large B-cell lymphomas affecting the vitreous, the retina, the retinal pigment epithelium (RPE) or the uvea tract. Vitreoretinal lymphomas (VRLs) are the most common subtype and are associated with central nervous system (CNS) involvement. Both the eye and the brain share mutual characteristics and are targeted by the spreading lymphoma cells.Intraocular lymphoma is a rare invasion of intraocular malignancy. More common form is VRL involving the vitreous and the retinal pigment epithelium. The uvea tract is affected in metastatic lymphomas. VRL is firmly correlated with CNS involvement. Diagnosis of VRL is challenging as its initial appearance is like intermediate or posterior uveitis. Treatment strategies are debated when concurrent CNS involvement is not confirmed.Intraocular lymphoma is a great mimic of chronic uveitis and taking into consideration the malignant nature of lymphoma disease, every ophthalmologist should be aware of it and a multidisciplinary approach is vital for the patient.KeywordsChemotherapyIntraocular lymphomaMethotrexateMYD88PCNSL uveitisPrimary central nervous lymphomaVitreoretinal lymphomaVitritisVRL
... The differential diagnosis includes infectious etiologies such as viral retinitis, Bartonella, tick-borne infections, tuberculosis, and syphilis, and non-infectious etiologies such as sarcoidosis, acute posterior multifocal placoid pigment epitheliopathy (APMPPE), and Behcet's disease. High index of clinical suspicion for vitreoretinal lymphoma, with careful consideration of the patient's immune status and the characteristics of intraocular inflammation, requires prompt biopsy for quick and accurate diagnosis to prevent rapid intraocular progression and further CNS involvement [1,2]. We herein report a case of large B-cell vitreoretinal lymphoma that initially presented with unilateral involvement and within one month had undergone rapid progression in the affected eye. ...
A 56-year-old male who presented with unilateral localized sub-retinal lesions suspicious for primary vitreoretinal lymphoma (PVRL) developed florid bilateral ocular involvement and was found to have lesions on MRI of the brain in a five-week period despite the absence of vitreous involvement during the entire course of his disease. His ocular lesions were monitored while on systemic treatment and an excellent clinical response was achieved. His central nervous system (CNS) lesions, however, continued to progress despite chemotherapy and whole-brain radiation. He died 12 months from his time of ocular diagnosis. To our knowledge, this case represents the most rapid progression of PVRL reported in the literature - from unilateral, localized lesions in the sub-retinal space to bilateral ocular involvement and identification of CNS involvement in a five-week period. This case highlights the potential for rapid ocular progression of PVRL stressing the need for early diagnosis. Therefore, we recommend prompt vitreous and, if necessary, sub-retinal biopsy in cases of suspected vitreoretinal lymphoma in addition to neuro imaging. We emphasize the importance of coordination between pathologists, ophthalmologists, and oncologists for prompt, accurate diagnosis. Delay in diagnosis and treatment can result in rapid intraocular progression and central nervous system spread.
... The immunophenotype of monoclonality supports the cytological diagnosis of IOL and can be established using immunohistochemistry (IHC) or flow cytometry [41] (Table 1). IHC utilizes antibodies to stain specific protein markers of B-cells or T-cells on cytologic preparations, providing a semi-quantitative diagnostic adjunct to cytology. ...
The diagnosis of primary vitreoretinal lymphoma and central nervous system lymphoma is challenging. In cases with intraocular involvement, vitreous biopsy plays a pivotal role. Several diagnostic tests are employed to confirm a diagnosis and include cytologic evaluation, immunohistochemistry, flow cytometry, and cytokine analysis. The limitations of these conventional diagnostic tests stem from the often paucicellular nature of vitreous biopsy specimens and the fragility of malignant cells ex vivo. Several emerging molecular techniques show promise in improving the diagnostic yield of intraocular biopsy, possibly enabling more accurate and timely diagnoses. This article will review existing diagnostic modalities for intraocular lymphoma, with an emphasis on currently available molecular tests.
... [1] Majority of the patients with lymphoma are elderly individuals over 50 years of age. [2] The disease when untreated is obviously lethal, and hence, rapid and accurate diagnosis is crucial to increase the survival, especially if one is able to diagnose the disease before CNS involvement. [1,3] PIOL can have various presentations; most commonly, it masquerades as an intermediate and/or posterior uveitis. ...
... Thus, the diagnosis of PIOL can be best established by cytologic examination of the vitreous specimen obtained through vitreous biopsy. [2] However as seen in our series, vitreous biopsy may be negative due to the fact that the lymphoma cells are fragile and easily degenerate in the vitreous. While observing lymphoma cells in cytological examination directly are still the gold standard with the highest specificity, the sensitivity is only around 80%. [8] Hence, multiple biopsies from different sites may be needed. ...
Primary intraocular lymphoma can have various presentations; most commonly, it masquerades as an intermediate and/or posterior uveitis.
It usually originates from vitreoretina, known as primary vitreoretinal lymphoma (PVRL) or from uveal tissue and the optic nerve.
This gives the ophthalmologist an avenue to use the eye as a window to the brain or the body and suspect/diagnose disease before its spread.
... [1] The majority of the patients are elderly individuals, usually aged over 50 years. [2] Because of the potential lethality of this condition, rapid and accurate diagnosis is crucial and may increase the survival, especially if diagnosed before central nervous system (CNS) involvement. [1,3] PIOL can have a plethora of presentations; most commonly, it masquerades as an intermediate and/or posterior uveitis. ...
To report a case of non-Hodgkin lymphoma (NHL) that was diagnosed 35-month of initial ocular manifestation. Retrospective chart review. A 53-year-old male presented with painless diminution of vision in both eyes. He subsequently underwent extensive laboratory investigations including multiple vitreous biopsies with a suspicion of intraocular lymphoma. Cytology from the vitreous aspirate failed to diagnose any relevant pathology. After 35-month from the onset of his ocular symptom, a brain biopsy revealed a round cell tumor suggestive of NHL. Even with high index of suspicion, consultation with ocular oncologist, imaging, and diagnostic vitrectomy, the diagnosis of lymphoma remains challenging
... An early biopsy may lead to early diagnosis and treatment. If it is possible, it should be done prior to non-specific conservative anti-inflammatory treatment [5]. GO is an ophthalmological manifestation of Graves' disease, which is an autoimmunological disorder of the thyroid. ...
Proptosis is a characteristic sign that might suggest the diagnosis of different diseases. Proptosis is characterised by the anterior displacement of the eye and its protrusion. The most commonly associated symptoms of proptosis are deteriorated vision, elevated intraocular pressure and inflammation of periocular tissues. The presented study describes two cases of patients with proptosis and periocular pain. In each case, the primary cause of proptosis was initially incorrectly diagnosed and required in-depth diagnostics.
In Patient A extrabulbar optic neuritis caused by Lyme disease was suspected and treated with steroids and antibiotics. Subsequently, Graves’ disease was diagnosed and treated with anti-thymocyte globulin. Complete loss of vision was observed after one month of treatment. Radiotherapy and steroid therapy were introduced. Afterwards, the patient’s vision was restored.
Patient B, who was treated for hypothyroidism, was admitted to the hospital with elevated intraocular pressure, double vision, a restricted visual field and proptosis. The primary diagnosis was Graves’ ophthalmopathy (GO). However, after in-depth imaging and pathomorphological studies of a specimen taken from the orbit, B-cell lymphoma was diagnosed. After the introduction of correct treatment, significant improvement was noted.
Presented work indicates that in-depth diagnostics are crucial when it comes to the differential diagnosis of GO and a tumor of the orbital cavity.
... PIOL is a condition which may be closely mimicked by the common masqueraders such as sarcoidosis, tuberculosis, viral retinitis, and syphilis. [8] The diagnosis requires a high degree of clinical suspicion and ruling out all infectious and noninfectious causes. For the demonstration of malignant lymphoma cells in aqueous fluid, vitreous aspirate, transvitreal retinal, subretinal, or chorioretinal biopsy-a complete diagnostic vitrectomy is the preferred method. ...
A 70-year-old lady presented with left eye subretinal mass, diagnosed as posterior uveitis previously. Fine-needle aspiration biopsy via transvitreal route proved to be a minimally invasive and effective diagnostic modality for sample collection with minimal complications and of high diagnostic potential.
