Ординатура / Офтальмология / Английские материалы / Primary Intraocular Lymphoma_Chan, Gonzales_2007
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244 Primary Intraocular Lymphoma
will increase. This will enable us to stratify our patients into prognostic categories so that we can make better judgments in treating a particular patient with PIOL.
With the sequencing of the human genome, it is now possible to identify single nucleotide polymorphisms (SNPs) that are associated with disease. Genetic variance likely plays an important role in the evolution of some diseases and their response to treatment. For example, SNPs have been associated with age-related macular degeneration (AMD)6–11 and some have reported methotrexate-toxicity due to SNPs.12 Analyses of genes important in PIOL (e.g. those associated with IL-10,13,14 chemokines and their receptors,15 and drug sensitivity or resistance proteins16,17 ) may reveal that some patients are more susceptible than others to developing PIOL.
Currently, there is no standard of care treatment for PIOL, but highdose intravenous methotrexate has proven to be the single most important therapy.18 Intrathecal and intravitreal methotrexate may also become important routes of administration depending upon the bulkiness or refractoriness of disease.19,20 We may also find intrathecal or intravitreal methotrexate becoming first-line routes of administration like systemic methotrexate. However, we must recall that most cases of PIOL will also lead to cerebral involvement, and this fact requires our consideration when determining the appropriate route of administration for our patients.21–24 The role of radiation therapy being administered after methotrexate also needs to be further defined.25,26 May we simply use methotrexate without radiation? Or do we use radiation in the face of refractory or recalcitrant disease? Other therapies, such as biologics27–29 that include immunologic agents or chemokine receptor antagonists,30,31 may become important first-line or adjunctive therapies after we have identified the optimal routes of administration and dosing schedules. Issues of toxicity associated with therapeutic agents remain,20,29,32–37 as to questions with respect to effective treatment of recurrent disease. In addition, the precise genetic nature of the PIOL, which can dictate its sensitivity to a particular therapy, will need to be identified for each patient. Some PIOLs, by virtue of drug resistance proteins, may be less susceptible to mainstay treatments. Therefore, other therapeutic strategies will need to be drawn out. This will constitute a tailored therapy for each patient so that maximal response may be obtained to prolong patients’ lives.
Animal models of PIOL that have been developed by our laboratory can help identify important factors involved in the development of PIOL as well
The Future of PIOL 245
as elucidate ways that this disease might be treated.28,38–40 We can alter various aspects of the animal, such as expression of certain proteins by ocular tissues, to determine the precise relationship between the intraocular tissues, the molecules they express, and the PIOL cells with which they interact.
We should look to the future, then, as an opportunity to not only truly understand PIOL (its unique cytological, histopathological, and immunological features, its genotypic traits, and its epidemiological features), but to also truly make a difference in the way we treat patients with this disease. Diagnosing and caring for PIOL patients requires multiple medical sub-specialists, including ophthalmologist, pathologist, neurooncologist and hematooncologist, all working closely together. Perhaps one day when we are charged with informing a patient that he or she has PIOL, we can not only say that we know why this disease has occurred in our patient, but that we also know how to effectively treat it and our patient can look forward to a bright future. Much work needs to be done to make this future a reality, and it is with this in mind that we continue our relentless pursuit of making the future brighter.
References
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2.Alizadeh A, Eisen M, Davis RE, et al. (1999) The lymphochip: a specialized cDNA microarray for the genomic-scale analysis of gene expression in normal and malignant lymphocytes. Cold Spring Harb Symp Quant Biol 64: 71–78.
3.Alizadeh AA, Eisen MB, Davis RE, et al. (2000) Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403(6769): 503–511.
4.Lossos IS, Czerwinski DK, Alizadeh AA, 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.
5.Wright G, Tan B, Rosenwald A, et al. (2003) A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma. Proc Natl Acad Sci USA 100(17): 9991–9996.
6.Hageman GS, Anderson DH, Johnson LV, et al. (2005) A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci USA 102(20): 7227–7232.
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7.Tuo J, Smith BC, Bojanowski CM, et al. (2004) The involvement of sequence variation and expression of CX3CR1 in the pathogenesis of age-related macular degeneration. Faseb J 18(11): 1297–1299.
8.Klein RJ, Zeiss C, Chew EY, et al. (2005) Complement factor H polymorphism in age-related macular degeneration. Science 308(5720): 385–389.
9.Edwards AO, Ritter R, 3rd, Abel KJ, et al. (2005) Complement factor H polymorphism and age-related macular degeneration. Science 308(5720): 421–424.
10.Haines JL, Hauser MA, Schmidt S, et al. (2005) Complement factor H variant increases the risk of age-related macular degeneration. Science 308(5720): 419–421.
11.Zareparsi S, Branham KE, Li M, et al. (2005) Strong association of the Y402H variant in complement factor H at 1q32 with susceptibility to agerelated macular degeneration. Am J Hum Genet 77(1): 149–153.
12.Linnebank M, Pels H, Kleczar N, et al. (2005) MTX-induced white matter changes are associated with polymorphisms of methionine metabolism. Neurology 64(5): 912–913.
13.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.
14.Merle-Beral H, Davi F, Cassoux N, et al. (2004) Biological diagnosis of primary intraocular lymphoma. Br J Haematol 124(4): 469–473.
15.Chan CC, Shen D, Hackett JJ, et al. (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.
16.Ferreri AJ, Dell’Oro S, Capello D, et al. (2004) Aberrant methylation in the promoter region of the reduced folate carrier gene is a potential mechanism of resistance to methotrexate in primary central nervous system lymphomas. Br J Haematol 126(5): 657–664.
17.Hooijberg JH, Broxterman HJ, Kool M, et al. (1999) Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2. Cancer Res 59(11): 2532–2535.
18.Levy-Clarke GA, Chan CC, Nussenblatt RB. (2005) Diagnosis and management of primary intraocular lymphoma. Hematol Oncol Clin North Am 19(4): 739–749.
19.de Smet MD. (2001) Management of non Hodgkin’s intraocular lymphoma with intravitreal methotrexate. Bull Soc Belge Ophtalmol 279: 91–95.
20.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(9): 1709–1716.
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21.Char DH, Ljung BM, Miller T, Phillips T. (1988) Primary intraocular lymphoma (ocular reticulum cell sarcoma) diagnosis and management.
Ophthalmology 95: 625–630.
22.Char DH, Margolis L, Newman AB. (1981) Ocular reticulum cell sarcoma.
Am J Ophthalmol 91(4): 480–483.
23.Rockwood EJ, Zakov ZN, Bay JW. (1984) Combined malignant lymphoma of the eye and CNS (reticulum-cell sarcoma). J Neurosurg 61: 369–374.
24.Chan CC, Buggage RR, Nussenblatt RB. (2002) Intraocular lymphoma. Curr Opin Ophthalmol 13(6): 411–418.
25.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(4): 531–538.
26.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.
27.Schaedel O, Reiter Y. (2006) Antibodies and their fragments as anti-cancer agents. Curr Pharm Des 12(3): 363–378.
28.Kim H, Csaky KG, Chan CC, et al. (2006) The pharmacokinetics of rituximab following an intravitreal injection. Exp Eye Res 82(5): 760–766.
29.Pels H, Schulz H, Manzke O, et al. (2002) Intraventricular and intravenous treatment of a patient with refractory primary CNS lymphoma using rituximab. J Neurooncol 59(3): 213–216.
30.Hendrix CW, Flexner C, MacFarland RT, et al. (2000) Pharmacokinetics and safety of AMD-3100, a novel antagonist of the CXCR-4 chemokine receptor, in human volunteers. Antimicrob Agents Chemother 44(6): 1667–1673.
31.Wu L, LaRosa G, Kassam N, et al. (1997) Interaction of chemokine receptor CCR5 with its ligands: multiple domains for HIV-1 gp120 binding and a single domain for chemokine binding. J Exp Med 186(8): 1373–1381.
32.Dietlein M, Pels H, Schulz H, et al. (2005) Imaging of central nervous system lymphomas with iodine-123 labeled rituximab. Eur J Haematol 74(4): 348–352.
33.Nelson DF, Martz KL, Bonner H, et al. (1992) Non-Hodgkin’s lymphoma of the brain: can high dose, large volume radiation therapy improve survival? Report on a prospective trial by the Radiation Therapy Oncology Group (RTOG): RTOG 8315. Int J Radiat Oncol Biol Phys 23(1): 9–17.
34.Pels H, Schulz H, Schlegel U, Engert A. (2003) Treatment of CNS lymphoma with the anti-CD20 antibody rituximab: experience with two cases and review of the literature. Onkologie 26(4): 351–354.
35.Flombaum CD, Meyers PA. (1999) High-dose leucovorin as sole therapy for methotrexate toxicity. J Clin Oncol 17(5): 1589–1594.
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36.Hoffman PM, McKelvie P, Hall AJ, et al. (2003) Intraocular lymphoma: a series of 14 patients with clinicopathological features and treatment outcomes. Eye 17(4): 513–521.
37.Abrey LE, DeAngelis LM, Yahalom J. (1998) Long-term survival in primary CNS lymphoma. J Clin Oncol 16(3): 859–863.
38.Chan CC, Fischette M, Shen D, et al. (2005) Murine model of primary intraocular lymphoma. Invest Ophthalmol Vis Sci 46(2): 415–419.
39.Gonzales JA, Shen D, Zhou M, et al. (2006) Chemokine and chemokine receptor expression in two models of primary intraocular lymphoma. ARVO Poster: #2831.
40.Li Z, Mahesh SP, Shen D, et al. (2006) Eradication of tumor colonization and invasion by a B cell specific immunotoxin in a murine model for human primary intraocular lymphom (PIOL)(in preparation).
Chapter 16
Case Illustrations
Case 1
A 75-year-old woman presented with bilateral cataracts, an afferent pupillary defect and questionable disc elevation in the left eye that was worrisome for an anterior ischemic optic neuropathy. A fluorescein angiogram was performed and showed mottling (Fig. 16.1). A borderline elevated erythrocyte sedimentation rate (ESR) was found, and the patient was treated with oral corticosteroids. Visual acuity, however, declined. A temporal artery biopsy was performed and was negative. The patient went on to develop bilateral vitritis, and after cataract extraction in the left eye, ophthalmoscopic exam showed that there was diffuse retinal pigment epithelium (RPE) depigmentation with an edematous optic nerve. Intraocular lymphoma was suspected, and a vitreous biopsy was performed. Microscopic examination of the Giemsa-stained slide showed many large lymphoid cells with large nuclei having irregular borders and scant cytoplasm (Fig. 16.2). These cells were highly suspicious for PIOL, but their lack of preservation precluded a definitive diagnosis by cytology. Assay for IL-10 and IL-6 in the vitreous fluid was 184 pg/ml and 26 pg/ml, respectively, further confirming suspicion for PIOL. Microdissection along with PCR revealed monoclonal rearrangement of the IgH gene in the FR3A site (Fig. 16.3). Magnetic resonance imaging (MRI) was subsequently performed, which showed an enhancing mass in the left basal ganglia. The diagnosis of PIOL was confirmed.
Commentary. This case has the classical presentation of PIOL: a bilateral vitritis of unknown etiology with a supposed chorioretinitis appearing in an older patient. Clinical examination can often be non-specific, and even if PIOL is suspected (e.g. as shown by the existence of creamy
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Fig. 16.1 Case 1. Fluorescein angiogram showing multiple hypofluorescent areas in the posterior pole of the left eye. Most of them are small, round lesions with some confluence.
Fig. 16.2 Case 1. Photomicrograph showing cytology of the vitreous sample. Large, atypical lymphocytes with basophilic cytoplasm and large nuclei exhibiting open chromatin are seen (Giemsa, original magnification × 640).
Fig. 16.3 Cases 1–5. Polymerase chain reaction (PCR) amplification products demonstrating monoclonal rearrangement of the immunoglobulin heavy chain (IgH) gene from the microdissected PIOL cells (lanes 1–5), negative control (lane 6), and positive control (lane 7).
Case Illustrations 251
yellow sub-RPE subretinal infiltrates) one needs cytopathologic proof that a malignancy is at play. Often, treatment with corticosteroids is initiated for a presumed idiopathic uveitis. It is not until the “uveitis” is unresponsive to treatment or (in this patient’s case) visual acuity shows marked deterioration that a more invasive test, such as a lumbar puncture, diagnostic vitrectomy, or a retinochoroidal biopsy, is pursued. It is also rather common for an MRI to be performed after PIOL has been diagnosed (as in this case). Currently, if PIOL is suspected it is important to perform an MRI and a lumbar puncture with CSF cytology to check for CNS lesions and malignant lymphoma cells.1 Elevated IL-10 level with a high ratio of IL-10 to IL-6 in the vitreous and the finding of IgH gene rearrangement in the vitreal infiltrating cells support the presence of PIOL cells in the vitreous.2,3 This patient did go on to develop brain lesions, and the fact that she is over 60 years of age and had involvement of deep brain structures were poor prognostic factors for PCNSL.4
Case 2
A 67-year-old woman reported blurred vision in the left eye for three weeks and developed bilateral vitritis and chorioretinitis of unknown etiology (Fig. 16.4).5 Upon review of systems, it was revealed that she had been worked up for seizures two months prior to presentation. During her work up for the seizures, CSF studies and a computed tomographic (CT)
Fig. 16.4 Case 2. Ophthalmoscopic photographs showing subretinal lesion inferior to the optic nerve head (left) with progression to a peripapillary 360° infiltrates, edema and multiple hemorrhages (right).
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Fig. 16.5A & B Case 2. (A) Ophthalmoscopic photograph showing a peripheral, creamy yellowish subretinal lesion, which was subsequently biopsied. At the superonasal area of the lesion there is a “leopard spot pattern,” a typical feature of PIOL caused by small foci of tumor infiltration. (B) Photomicrograph of frozen section from endoretinal biopsy showing many lymphoid cells in the disorganized retina (hematoxylin and eosin, original magnification × 100).
scan with contrast of the brain were normal. Clinical examination failed to identify any cause for the ocular findings, and as the patient’s vision in the left eye significantly worsened and her retinal lesion was progressing without responding to antiviral therapy (Fig. 16.5A), a vitrectomy with internal chorioretinal biopsy was performed in addition to a lumbar puncture. Both the vitrectomy and the CSF specimens failed to reveal any malignant lymphocytes by cytology. Despite this, the IL-10 level in the vitreous and CSF samples were elevated, being 5456 pg/ml and 25 pg/ml, respectively. IL-6 levels in the vitreous and CSF were found to be 193 pg/ml and undetectable, respectively. Thus, for the vitreous sample, the IL-10 to IL-6 ratio was greater than 1.0, suggesting that PIOL could potentially be the culprit involved in this patient’s declining visual status. Interestingly, the retinal biopsy showed infiltrating lymphoid cells, although definite malignant cells could not be identified (Fig. 16.5B). However, immunohistochemistry revealed that the overwhelming majority of infiltrating lymphocytes were of B-cell origin (positive for CD19, CD20, and CD22) and that they were monoclonal, staining positive for kappa (κ), but not lambda (λ) light chains (Fig. 16.6). Monoclonality of the B-cell proliferation was further confirmed by the polymerase chain reaction (PCR) showing the same IgH gene rearrangement (Fig. 16.3). In light of these findings, a diagnosis of
Case Illustrations 253
Fig. 16.6 Case 2. Photomicrographs of frozen sections from endoretinal biopsy showing positive kappa (κ) light chain (left) and negative lambda (λ) light chain (right) (avidinbiotin complex immunoperoxidase, original magnification × 100).
PIOL was attained, and an MRI with gadolinium was performed to check for cerebral involvement. Indeed, a 1 × 1 cm contrast-enhancing mass was discovered in the right frontal lobe. A biopsy of this mass was performed via craniotomy and this confirmed the diagnosis of PCNSL. The patient received radiation, but the left eye developed a retinal detachment. The right eye responded to the radiation therapy, and the visual acuity improved in this eye from hand motion to 20/40 over six weeks. The patient refused systemic chemotherapy, and she died six months later.
Commentary. This case has a presentation like that of a viral retinitis. Therefore, while PIOL can often present as an idiopathic uveitis, findings in the retina produce their own diagnostic challenges. Others have similarly noted that retinal involvement in PIOL can produce a clinical picture comparable to that of a viral retinitis.6–8 In such instances treatment with anti-viral medication has occurred prior to making the diagnosis of PIOL, much like PIOL mistaken for uveitis is frequently treated first with corticosteroids. The non-diagnostic CSF and vitreous examinations are not unusual in PIOL, and the elevated vitreal IL-10 level with the IL-10 to IL-6 ratio greater than 1 shows how this adjunctive test can be important in prodding us to be persistent in seeking out PIOL in the absence of malignant cells in biopsied tissues. The retinochoroidal biopsy revealed definite monoclonal B-cell infiltration in the retina, and PCR analysis further confirmed this with IgH gene rearrangment. It is important, then, that when tissue biopsy is considered there be an experienced pathologist or ocular