Ocular and central nervous system lymphoma: clinical features and diagnosis

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Ocular Immunology and Inflammation 0927-3948/00/US$ 15.00 Ocular Immunology and Inflammation – 2000, Vol. 8, No. 4, pp. 243-250 © Swets & Zeitlinger 2000

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Accepted 15 August 2000

Ocular and central nervous system lymphoma: clinical features and diagnosis Nathalie Cassoux1 Helene Merle-Beral2 Veronique Leblond2 Bahram Bodaghi1 Dan Miléa1 Sophie Gerber3 Christine Fardeau1 Isabelle Reux1 Khe Hoang Xuan4 Chi-Chao Chan5 Phuc LeHoang1 Departments of 1Ophthalmology, 2Hematology, 3Neuroradiology, and 4Neurology, Pitié-Salpêtrière Hospital, Paris, France 5 Department of Immunology, National Institutes of Health, Bethesda, MD, USA

Abstract Purpose: To evaluate the clinical, angiographic, and cytopathologic features of ocular and central nervous system (CNS) lymphoma. Patients and methods: Retrospective study of 44 patients over a 10-year period. Results: A total of 36 women and six men, mean age 54 years (range: 36-90 years), were included. The mean time interval between onset of ocular symptoms and diagnosis was 40 months (range: 1-144 months). Ocular involvement was bilateral in 84% of the cases. Laser flare photometry readings averaged 9.6 photons/ms (2.978.3 photons/ms). Vitritis was constant. Funduscopy revealed RPE abnormalities in 60.49% of the cases and punctuate retinal infiltrates in 33.5%. The most common findings with fluorescein angiography were window defects and hypofluorescent round lesions. Patients had CNS involvement in 66% of the cases. Cytologic examination of the vitreous samples showed high-grade B lymphoma in 86% of the cases. Interleukin-10 dosage, when performed, showed elevated levels averaging 2352 pg/ml in all vitreous samples. Molecular biology based on PCR confirmed the diagnosis in 12 patients. Treatment included systemic chemotherapy alone or associated with radiotherapy in various regimens. Fourteen patients died during follow-up. Only 12 patients were in complete remission. Conclusion: The prognosis of the disease remains poor. However, the new diagnostic tools and therapeutic strategies may improve the diagnostic delay and the survival outcome. Diagnosis of ocular and cerebral lymphoma

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Correspondence and reprint requests to: Phuc LeHoang, M.D., Ph.D. Department of Ophthalmology Hôpital Pitié-Salpétrière 47-83 bd. de l’Hopital 75651 Paris cedex 13 France Tel: 33 1 42163201 Fax: 33 1 42163218 e-mail: [email protected]

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Key words Ocular lymphoma; cerebral lymphoma; diagnostic vitrectomy; PCR; chemotherapy

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Introduction Intraocular-central nervous system lymphoma (ICNSL) is a subgroup of high-grade nonHodgkin lymphoma. Primary CNS lymphoma is an uncommon cerebral tumor that accounts for approximately 0.5% of all primary brain neoplasms.1 There has, however, been a dramatic increase in the diagnosis of primary lymphoma of the brain during the past decade, prompting speculation that it may become the most frequently diagnosed tumor of the CNS by the year 2000. During the period of study, the incidence rates of brain lymphoma increased more than tenfold, from 2.5 cases per 10 million people in 1973 to 30 in 1991-1992.2 Ocular involvement is often misdiagnosed, masquerading as posterior uveitis, vitritis, and retinitis, and represents a real diagnostic challenge. The clinical presentation is now well documented.3-5 Most of the patients present with bilateral vitritis associated with perturbation of the retinal pigment epithelium and subretinal or retinal infiltrates. This chronic posterior uveitis, occurring in the elderly, is poorly responsive to corticosteroids and can be associated with neurological symptoms. The current diagnostic approach towards patients suspected of having an ocular lymphoma includes neurological examination, cerebral magnetic resonance imaging (MRI), lumbar puncture, and diagnostic vitrectomy,4,5 while the definite diagnosis of primary ocular and cerebral lymphoma is based on the cytological examination of the vitreous biopsy. Malignant cells, however, are often rare and degenerated, which makes their identification difficult. Recently, new diagnostic approaches have improved the sensitivity of the vitrectomy. Immunological and molecular biological tools can also help the clinicians. An elevated interleukin-10 (IL-10) dosage, for example, is highly suggestive of intraocular lymphoma,6,7 while polymerase chain reaction (PCR) can be useful in confirming the diagnosis of malignant lymphoma.8,9 The purpose of this retrospective study is to report the clinical features and laboratory investigations of 44 patients with proven ocular and CNS lymphoma. Materials and methods From 1989 through 1999, 44 immunocompetent patients with proven ICNSL were followed at Pitié-Salpétrière Hospital (Paris). All were retrospectively reviewed for the following information: demographic data, presenting symptoms, initial diagnosis, time from initial symptoms to ICNSL diagnosis, ophthalmologic findings, fluorescein angiography findings, neurological and neuroradiological records, and time from initial ocular to neurological involvement. The diagnosis was established with the help of diagnostic vitrectomy or lumbar puncture or cerebral biopsy. A standard 3-port pars plana vitrectomy was performed in 29 patients. An initial 1-ml specimen of undiluted vitreous was collected and immediately taken to the cytopathologist for interleukin-10 dosage (Quantikine RD Systems Europe Ltd, Oxon, UK) and cytological analysis. The rest of the vitreous with the infusion fluid was also collected. Tissue culture medium (Rosewell Park Memorial Institute, RPMI-1640, Mediatech Inc., Herdon, VA, USA) enriched with 10% fetal calf serum was added to the sample to improve cell viability 244

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as previously described and taken as quickly as possible to the laboratory for analysis.5 Standard cytological examination was performed on the vitreous sample after cytospin at 1000 rpm for 8 minutes at 4°C. The pellet was then suspended in 2 ml RPMI and cytocentrifuged in the same condition as pure vitreous at 450 rpm for 5 min; 200 µl of the cell suspension was then placed dropwise on gelatinized slides. The slides were either stained with May-Grunwald-Giemsa (MGG) or air-dried and fixed by immersion in acetone for 7 min. Immunohistochemical staining was performed using alkaline phosphatase anti-alkaline phosphatase (APAAP) for B- and T-cell markers and for kappa and lambda light chains as previously described.10 In some doubtful cases, slides were sent to the Laboratory of Immunology, National Eye Institute of Bethesda (MD, USA) for microdissection and PCR to demonstrate clonal heavy chain immunoglobulin (IgH) gene rearrangement and bcl-2 translocation.8,9 A minimum of 5 ml of cerebrospinal fluid (CSF) was cytocentrifuged and the pellet was used to prepare slides for cell counting after MGG staining. All patients underwent a complete staging evaluation including chest X-rays, thoracic and abdominal computerized tomography, lumbar puncture, cerebral MRI, bone marrow biopsy, and serum testing of human immunodeficiency virus (HIV). Patients with HIV infection were excluded from the study. Results demographic data Of the 44 patients, 36 (82%) were women and eight (18.18%) were men. All but one (Asian) of the patients were Caucasian. The mean age at the time of diagnosis of the ocular or neurological symptoms was 54 years (range: 36-90 years). The time interval between the onset of ocular or neurological symptoms and the cytological diagnosis averaged 40 months (range: 1-144 months). For the patients diagnosed before 1996, the time interval between ocular symptoms and diagnosis was 32.5 months (range: 3-144 months). This time interval was reduced for the patients diagnosed after 1997 to 7.5 months (range: 1-24 months), probably due to a better knowledge of the disease. Twenty-one (48%) patients were previously treated with corticosteroids. An optic vitrectomy was performed in three patients. ocular clinical findings Most patients were referred for uveitis of unknown etiology (35 patients, 79.5%). Other diagnoses included herpetic uveitis (1 case), Whipple’s disease (1 case), sarcoidosis (2 cases), syphilis (1 case), multiple sclerosis (1 case), toxoplasmosis (1 case), and Behçet’s disease (2 cases). Ocular involvement was bilateral in 84% of the cases. Anterior segment examination revealed no abnormalities in 34 eyes (75.30%). Tiny keratic precipitates were seen in 18 eyes (21%). Mutton fat keratic precipitates were present in two eyes. Other anterior chamber abnormalities included cellular hypopyon in one eye, posterior synechia in two eyes, and glaucoma in two eyes. Laser flare photometry was performed Diagnosis of ocular and cerebral lymphoma

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table 1. Retinal involvement.

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table 2. Angiographic findings.

table 3. Localization of the CNS lymphoma.

Retinal findings

Number of eyes (n=81)

%

Perturbation of the retinal pigment epithelium Punctuate retinal infiltrates Vasculitis Optic nerve swelling Subretinal mass Exudative retinal detachment No abnormalities

49

60.49%

27 7 (occlusive in 3) 3 3 2 8

33.33% 8.64% 3.70% 3.70% 2.46% 9.87

Angiographic findings

Number of patients (n=44)

%

Punctuate hyperfluorescent windows defects Round hypofluorescent lesions Vasculitis Papilledema Cystoid macular edema

24

54.5%

15 6 (occlusive in 3) 3 2

34% 13.63 3.70% 2.46%

Location of the CNS lymphoma

Number of patients (n=29)

%

Cortical Meningial lymphoma Midbrain Cerebellum Pons Central nodal nucleus Thalamus

14 5 4 3 1 1 1

48.27% 17.24% 13.79% 10.34% 3.44% 3.44% 3.44%

in 35 patients. Laser flare readings averaged 9.6 photons/ms (range: 2.978.3 photons/ms). Posterior segment examination revealed extensive vitreous cells in all of the patients. According to the Nussenblatt grading system, vitritis was noted as 1+ in 14.81%, 2+ in 35.80%, and 3+ or more in 49.38% of the eyes. Funduscopy revealed punctuate retinal infiltrates in 27 eyes (33.33%) and perturbation of the retinal pigment epithelium in 49 eyes (60.49%). Retinal involvement is summarized in Table 1. Fluorescein angiography was performed in all of the cases. The most common findings were window defects and hypofluorescent round lesions due to tumoral cell infiltrates at the level of the retinal pigment epithelium. Angiographic findings are summarized in Table 2. Retinal lesions could not be seen on funduscopy in four eyes (5%) and were only visible on fluorescein angiography. Fluorescein angiography was normal in four patients (5%). central nervous system involvement Most of the patients (66%) had CNS involvement. The diagnosis of CNS lymphoma was based on 246

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the presence of lymphoma cells in the cerebrospinal fluid or brain biopsy or on the presence of characteristic mass lesions on cerebral magnetic resonance imaging (MRI). CNS disease preceded ocular involvement in 24.10% (7 eyes). The median delay between the diagnosis of CNS lymphoma and the onset of the ocular symptoms was 54.75 months (range: 3-144). In 20.68% of the patients, ocular involvement was diagnosed at the same time as CNS lymphoma (6 patients). In 55% of the patients, ocular involvement preceded CNS localization (16 patients). The median delay between the diagnosis of ocular lymphoma and the CNS involvement was 20 months (range: 1-84). MRI disclosed only one lesion in 17 patients (58.62%), while multiple lesions were seen on MRI sequences in 12 patients (41.37%). The main CNS localizations were summarized in Table 3. Ocul Immunol Inflamm Downloaded from informahealthcare.com by NIH Pathology Lab on 08/11/13 For personal use only.

laboratory investigations Diagnosis of ocular lymphoma was based on the results of vitreous biopsy in 29 patients (66% of the cases), anterior chamber tap in one patient, and histological examination of a retinal biopsy in one patient. Cytological examination of the vitreous samples disclosed high-grade B-cell lymphoma in 25 patients (86.20%) and T-cell lymphoma in four patients. The IL-10 dosage was performed in 16 patients. In all of the cases, the IL-10 dosage showed elevated levels averaging 2352 pg/ml (range: 70-5120 pg/ml). In four cases, vitrectomy was negative for lymphoma cells even though IL-10 dosage was elevated. In two cases, a definite diagnosis of lymphoma was made after brain biopsy. In one case, the diagnosis was made after a second vitrectomy combined with an endoretinal biopsy. In one case, the diagnosis was made by molecular biology after microdissection of suspect cells on a slide that disclosed clonal heavy chain immunoglobulin (IgH) gene rearrangement and bcl-2 gene translocation. Microdissection using the PCR technique was a helpful tool in addition to the cytological examination in 12 patients. PCR disclosed heavy chain IgH rearrangement in 12 patients and bcl-2 translocation in six. In addition, the diagnosis of CNS lymphoma was based on a brain biopsy in 11 patients. In all of the cases, histological examination revealed a large B-cell lymphoma. Lumbar puncture demonstrated lymphoma cells in five patients. Dosage of IL-10 in the CSF was positive only in seven of 29 patients with CNS lymphoma. follow-up Patients were followed for an average of 33.35 months after the diagnosis (range: 3-192 months). They were treated with various regimens of intravenous and intrathecal chemotherapy that included methylprednisolone, high-dose methotrexate, aracytine, thiotepa, cisplatin, and VP-16. Whole brain and ocular irradiation were associated in 10 patients. For refractory patients, intensive chemotherapy was followed by an autologous bone marrow transplantation as previously described.10 Fourteen patients died during follow-up. Only 12 patients were in complete remission at the end of the observation period. Discussion Intraocular lymphoma was first described in 1951.11 Later, a disease called primary reticulum cell sarcoma was described by Freeman et al.3 in a large series of patients. In 1973, Piessens et al.12 demonstrated Diagnosis of ocular and cerebral lymphoma

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the lymphocyte origin of the malignant cells. The clinical findings of ocular involvement have been well defined in the literature and more than 150 cases of ocular lymphoma have been described to date.1,4,5,13-15 ICNSL is rare, although the incidence of cerebral lymphoma has increased dramatically during the past decade, promoting the speculation that lymphoma may become the most frequent tumor of the CNS in the year 2000. The incidence rate of brain lymphoma has increased more than tenfold, from 2.5 cases per 10 million people in 1973 to 30 in 19911992. These increased incidence rates seem to be independent of age and gender.2,16 The increased incidence of people infected with HIV or treated with immunosuppressive drugs does not satisfactorily explain the recent increase in cerebral lymphoma.17,18 Primary intraocular lymphoma frequently masquerades as an idiopathic chronic vitritis or posterior uveitis, and the diagnosis remains a real challenge.5 Some clinical findings are highly suggestive of intraocular lymphoma. In our series, most of the patients were elderly women and presented with bilateral chronic vitritis associated with retinal infiltrates and/or retinal pigment epithelium abnormalities. On fluorescein angiography, the presence of perturbation of the retinal pigment epithelium, window defects, and hypofluorescent round lesions were also very suggestive of intraocular lymphoma. Neurological signs and typical lesions on cerebral MRI were associated in more than 60% of our patients. These findings are consistent with the published data.3,4,5,19 As lymphoma treatment requires intensive chemotherapy, demonstration of the malignant cells is necessary. Diagnosis of intraocular lymphoma is based on the cytological examination of the vitreous biopsy and remains problematic. Lymphoma cells are rare and fragile, and are associated with a nonspecific inflammatory reaction. Treatment with corticosteroids at the time of vitrectomy may be responsible for the paucity of lymphoma cells in the vitreous sample. Prompt processing of the vitreous cells is critical for diagnosis, as lymphoma cells start to degenerate within minutes after vitrectomy.5 New techniques improving the sensitivity and specificity have been developed over the past 10 years. Immunocytochemical staining of cellular components from the vitreous sample, for example, is currently used to identify the cells more specifically and to detect a monotypic heavy chain expression (IOL is typically of B-cell origin).20,21 Whitcup et al.6 and Chan et al.7 have shown that an elevated IL-10 dosage in the vitreous is strongly associated with intraocular lymphoma. In our series, elevated IL-10 rates were always associated with intraocular and cerebral lymphoma. In four cases in which cytological examination of the vitreous samples was unable to disclose lymphoma cells, high IL10 rates helped us decide to perform a second vitrectomy and retinal biopsy in one case. Molecular biology can also be used to detect clonal IgH rearrangement, T-cell receptor rearrangement, and bcl-2 translocation. Chan et al.8 have developed a microdissection technique to retrieve the DNA of suspicious cells on a slide. The optimal treatment of the disease remains undefined and controversial. Radiotherapy was the first treatment used in ICNSL and has long been considered the mainstay of treatment for this disease. Lymphoma cells are radiosensitive, but relapses are common. Preventive or curative whole brain irradiation fails to prevent cerebral localization or recurrences.3,22 248

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Radiotherapy fails to cure the majority of the patients and causes severe side effects.23,24 Systemic chemotherapy has been developed over the past 10 years. Loeffler and coworkers, among others, have reported a prolongation of medial survival using various chemotherapy regimens.25-28 De Angelis et al.24 have demonstrated that intravenous and intrathecal chemotherapy together with radiotherapy improved patient survival compared to patients treated with radiotherapy alone. The combination of systemic chemotherapy and radiotherapy does, however, cause neurotoxicity and 50% of the treated patients develop severe dementia. Efforts are now directed not only at increasing survival, but also at minimizing leukoencephalopathy. Protocols are currently directed towards using chemotherapy alone. Intravenous and intrathecal high-dose methotrexate and cytosine arabinoside have been shown to be temporarily effective in the treatment of cerebral lymphoma,28 while promising results have been obtained with highdose chemotherapy followed by autologous bone marrow transplantation.10 Intravitreal methotrexate or thiotepa injections are a new therapeutic option that has been tried in a few patients.29,30 In conclusion, ICNSL should de suspected in cases of chronic, steroidresistant vitritis associated with retinal pigment epithelium abnormalities in elderly patients, especially women. Cerebral MRI is required to rule out CNS involvement. The prognosis of patients with CNS involvement remains poor. However, the new diagnostic and therapeutic strategies may improve the delay of diagnosis and the survival outcome. References 1 Freeman CR, Shustik C, Brisson ML, Meagher-Villemure K, Dylewski I. Primary malignant lymphoma of the central nervous system. Cancer 1986; 58:1106-1111. 2 Corn BW, Marcus SM, Topham A, Hauck W, Curran WJ Jr. Will primary central nervous system lymphoma be the most frequent brain tumor diagnosed in the year 2000? Cancer 1997;79:2409-2413. 3 Freeman LN, Schachat AP, Knox DL, Michels RG, Green WR. Clinical features, laboratory investigations, and survival in ocular reticulum cell sarcoma. Ophthalmology 1987;94: 1631-1639. 4 Peterson K, Gordon KB, Heinemann MH, DeAngelis LM. The clinical spectrum of ocular lymphoma. Cancer 1993;72:843-849. 5 Whitcup SM, De Smet MD, Rubin BI, Palestine AG, Martin DF, Burnier M Jr, et al. Intraocular lymphoma. Clinical and histopathologic diagnosis. Ophthalmology 1993;100:1399-1406. 6 Whitcup SM, Stark-Vancs V, Wittes

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Diagnosis of ocular and cerebral lymphoma

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