Treatment Of Primary Intraocular Lymphoma Research Articles

Radiotherapy for the treatment of primary intraocular lymphoma and orbital (ocular adnexa) lymphomas

AbstractPrimary intraocular lymphoma (PIOL) is a lymphomatous proliferation seen in the eye and can be subdivided into two groups: (1) those which occur in the vitreous and /or retina and (2) those which occur in the uvea [1]. The histology is usually diffuse large B‐cell lymphoma (DLBCL) and diagnosis is made by vitrectomy, vitreal biopsy, or choroidal sampling. Vitreoretinal lymphomas are lymphomas that arise primarily in the vitreous and/or the retina and are considered as a part of the primary central nervous system lymphomas (PCNSL). Primary uveal lymphomas start as a primary disease in the uveal tract. Because brain was the most common site of relapse, some old data recommended in the past to treat as for PCNSL [2]. Modern data suggest that in case of brain relapse, salvage tratements remain effective [3]. Most patients with PIOL present a high risk of bilateral involvement, even when pathologic results have been obtained from only one eye. Ocular irradiation should include both eyes. However, when there is no suspicion of disease in the contralateral eeye, it is reasonable to treat onlym the involved eye. The volume of irradiation has to include the globe of the eye (s), optic nerves (s) to the level of the chiasm. Low dose of 30‐36 Gy is recommended [4]. Primary lymphoma of the ocular adnexa (orbital lymphoma) is a very rare tumor entity and accounts less than 1% of all non‐Hodgkin lymphomas (NHL) and 8% of all extranodal NHL [5]. Most cases of extraocular orbital lymphoma are marginal zone lymphoma (MZL) and involve the conjunctiva, lacrimal gland, eyelid, or retrobulbar soft tissues. Less common are follicular lymphoma (FL) and DLBCL. Primary radiation therapy (RT) is the curative option in patients with indolent lymphoma with high response rate and acceptable toxicity [6]. RT may be indicated to consolidate systemic therapy for DLBCL. For most cases of indolent NHL, the entire bony orbit has to be included. When the disease is limited to the conjunctiva, the irradiation has to include the entire conjunctival sac and local extensions to eyelid. A standard dose of 24 to 25 Gy in 1.5 to 2 Gy per fraction is prescribed. Since indolent lymphomas are highly radiosensitive, low dose irradiation (4 Gy in 2 fractions of 2 Gy) has been used in order to minimize the toxicity. A randomized non‐inferiority trial (FORT) compared conventional radiation scheme (24 Gy) to low dose RT (4Gy) in patients with FL. Low dose RT showed inferior results in term of local progression free survival [7].REFERENCES Venkatesh R, Bavaharan B, Mahendradas P, Yadav NK. Primary vitreoretinal lymphoma: prevalence, impact, and management challenges. Clin Ophthalmol. 2019;13:353‐64. Akpek EK, Ahmed I, Hochberg FH, Soheilian M, Dryja TP, Jakobiec FA, et al. Intraocular‐central nervous system lymphoma: clinical features, diagnosis, and outcomes. Ophthalmology. 1999;106:1805‐10. Teckie S, Yahalom J. Primary intraocular lymphoma: treatment outcomes with ocular radiation therapy alone. Leuk Lymphoma. 2014;55:795‐801. Yahalom J, Illidge T, Specht L, Hoppe RT, Li YX, Tsang R, et al. Modern radiation therapy for extranodal lymphomas: field and dose guidelines from the International Lymphoma Radiation Oncology Group. Int J Radiat Oncol Biol Phys. 2015;92:11‐31. Margo CE, Mulla ZD. Malignant tumors of the orbit. Analysis of the Florida Cancer Registry. Ophthalmology. 1998;105:185‐90. Fakhrian K, Klemm S, Keller U, Bayer C, Riedl W, Molls M, et al. Radiotherapy in stage I‐III follicular non‐Hodgkin lymphoma. Retrospective analysis of a series of 50 patients. Strahlenther Onkol. 2012;188:464‐70. Hoskin PJ, Kirkwood AA, Popova B, Smith P, Robinson M, Gallop‐Evans E, et al. 4 Gy versus 24 Gy radiotherapy for patients with indolent lymphoma (FORT): a randomised phase 3 non‐inferiority trial. Lancet Oncol. 2014;15:457‐63.

Changes of fundus autofluorescence and spectral-domain optical coherence tomographic findings after treatment of primary intraocular lymphoma

BackgroundWe report the fundus autofluorescence (FAF), spectral-domain optical coherence tomographic (SD-OCT), microperimetric, and multifocal electroretinographic (mfERG) findings before, during, and after successful treatment of a primary intraocular lymphoma (PIOL).FindingsA 57-year-old man had biopsy-proven PIOL in his left eye, and he was treated with intravitreal methotrexate injections for 8 months. Before treatment, fundus examination disclosed many small, yellow lesions with distinct boundaries in the posterior fundus which became atrophic 9 months after the initial treatment. FAF showed a pattern of granular hypoautofluorescence and hyperautofluorescence before the treatments and patchy hypoautofluorescence corresponding to retinal pigment epithelial (RPE) atrophy after the treatments. SD-OCT showed increased nodularity at the level of and above the RPE, a separation of Bruch membrane from the RPE, partial damage of the RPE, disruption of the photoreceptor inner segment/outer segment (IS/OS) junction, multiple hyperreflective signals in the inner retina, foveal thinning, and parafoveal thickening. After treatment, the hyperreflective infiltrations in the inner retina were markedly decreased, and the RPE and IS/OS junction were restored. The foveal thinning and parafoveal thickening resolved, and the central choroidal thickness decreased. During the follow-up, the mfERGs remained decreased. In contrast, microperimetry showed a partial improvement of the retinal sensitivity.ConclusionFAF and SD-OCT are useful noninvasive methods to evaluate the retinal and choroidal changes before and after treatment of PIOL. Our results suggest that visual recovery after successful treatment may be limited once macula is infiltrated.

The use of intravitreal rituximab in conjunction with systemic temozolomide and intravenous rituximab for the treatment of primary intraocular lymphoma

Introduction Primary intraocular lymphoma (PIOL) is a rare malignancy that affects the ocular system [1,2]. This disease is directly related to primary central nervous system lymphoma (PCNSL). The eyes are involved in approximately 15-25 % of PCNSL while 80% of PIOL eventually develop PCNSL [3,4]. PIOL has been reported to be

The evaluation and treatment of primary intraocular lymphoma

Primary intraocular lymphoma (PIOL) is a relatively rare form of Non-Hodgkin's Lymphoma arising in the lymphoid tissues of the eye. It is highly correlated with primary CNS lymphoma (PCNSL) and it is estimated that up to 80% of patients presenting with PIOL will eventually manifest intracranial malignancy, which is the largest contributor to mortality. Most patients present with nonspecific visual symptoms, including floaters and blurry vision, and are often initially diagnosed with uveitis or retinitis. Definitive diagnosis requires biopsy of malignant tissues with demonstration of malignant lymphoid cells. Optimal therapy is to this point undefined, and the available literature is limited to case reports and retrospective series. Currently employed therapies include the use of localized external beam radiation therapy (EBRT), whole brain radiation therapy (WBRT), systemic chemotherapy, intrathecal chemotherapy, and, most recently, direct intravitreal (IVT) chemotherapy. While radiation therapy and chemotherapy can produce a high response rate, they have not been shown to effectively prevent relapse or the incidence of CNS spread. Methotrexate has been the most popular therapy used for the treatment of intraocular lymphoma. It has been administered systemically, intrathecally or intravitreally. However due to multiple mechanisms of resistance developed by lymphoma cells against methotrexate, this drug has been unable to prevent disease recurrence. The newest, and perhaps most promising, reported therapy includes the use of rituximab anti-CD20 monoclonal antibody either alone or in combination chemotherapy via intrathecal or IVT administration. Most cases in the literature employ combinations of available therapies, and there are no comparative studies of significant power to date. Multicenter collaboration will be required to determine the true relative efficacy and adversity of the therapeutic options available.

Treatment of primary intraocular lymphoma with rituximab, high dose methotrexate, procarbazine, and vincristine chemotherapy, reduced whole‐brain radiotherapy, and local ocular therapy

Treatment of primary intraocular lymphoma with rituximab, high dose methotrexate, procarbazine, and vincristine chemotherapy, reduced whole‐brain radiotherapy, and local ocular therapy

Combined therapy associating systemic platinum-based chemotherapy and local radiotherapy into the treatment of primary intraocular lymphoma

Combined therapy associating systemic platinum-based chemotherapy and local radiotherapy into the treatment of primary intraocular lymphoma

Correspondence

Correspondence

Using Human CD20-Transfected Murine Lymphomatous B Cells to Evaluate the Efficacy of Intravitreal and Intracerebral Rituximab Injections in Mice

The treatment of primary central nervous system lymphoma (PCNSL) and its subset, primary intraocular lymphoma (PIOL), remains of limited efficiency, and salvage therapies are often used without prior testing in adequate animal models. Most PNCSL/PIOL are aggressive B-cell malignancies. Two animal models that closely mimic the human situation were established to evaluate the efficiency of intravitreal and intracerebral anti-CD20 monoclonal antibody (rituximab) injections. Human CD20-transfected murine B-lymphoma cells (38C13 CD20(+)) were inoculated in the vitreous through the pars plana or in the caudate nucleus with the use of a stereotaxic frame in immunocompetent syngeneic mice. Animals were monitored clinically and by funduscopic and histologic examination. Rituximab was injected intravitreally or intracerebrally. Occurrences of exophthalmia, neurologic disturbance, and weight loss were monitored over 2 months. Inoculation of 38C13 CD20(+) cells in the eye or the brain resulted in tumor occurrence after a median of 15 days or 22 days, respectively, with histologic characteristics closely resembling those of PIOL and PCNSL. Local rituximab injections eradicated tumor colonization in more than half the graft recipients and inhibited tumor progression significantly in the others compared with progression in mice that underwent grafting with the control 38C13 cell line (no human CD20 expression) and in mice that underwent grafting with 38C13 CD20(+) cells that received local injections of an irrelevant antibody (trastuzumab). Inoculation of native or human CD20-transfected murine 38C13 cells in the vitreous or the brain of immunocompetent mice provides useful novel models for evaluating the biology and treatment of PIOL and PCNSL. Intravitreal and intracerebral rituximab injections reduced tumor occurrence and growth in each model.

Treatment of primary intraocular lymphoma with intravitreal methotrexate

To report the efficacy of intravitreal chemotherapy for primary intraocular lymphoma (PIOL). Retrospective, noncomparative interventional case reports are presented for six patients (ten eyes; mean age, 58.8 years) with pathologically confirmed PIOL who participated in this study and were treated at our hospital with intravitreal injections of methotrexate (MTX) between January 2004 and February 2007. Intravitreal injections of MTX (400 microg MTX/50 microl Opeguard-MA) were administered once or twice weekly for 1 month followed by ten monthly injections. Interleukin-10 (IL-10) and IL-6 were measured in the vitreous before and after injections to determine tumor activity. All eyes were clinically cleared of malignant cells. One eye lost vision. After intravitreal chemotherapy, the vitreous IL-10 concentration reached barely detectable levels. Intravitreal chemotherapy achieves clinical remission and preserves vision in patients with PIOL.

Ocular manifestations and treatment of central nervous system lymphomas

Intraocular primary central nervous system lymphoma (PCNSL), also called primary intraocular lymphoma (PIOL), is a subset of PCNSL in which lymphoma cells invade the subretinal pigment epithelial space and vitreous cavity with or without central nervous system involvement at the time of ocular diagnosis. The frequency of this rare condition has increased over the past years in immunosuppressed as well as immunocompetent patients. The authors review the current status of PIOL and elaborate on their group's experience with its diagnosis and treatment. The incidence of PIOL is increasing. There is evidence that chronic antigenic stimulation may result in the development of PIOL. Recent advancements in the diagnosis of PIOL include better handling of vitreous specimens for cytological studies, immunocytological investigation for lymphoid cells, flow cytometry, cytokine evaluation, and molecular analysis. Because PIOL has a nonspecific presentation, the differential diagnosis should include infectious and noninfectious causes presenting with vitreitis and/or subepithelial infiltration as well as paraneoplastic syndromes including CRMP-5 optic neuropathies. Given that therapy is long-term and has significant systemic and ocular complications, tissue diagnosis is important. Treatment of PIOL may include systemic chemotherapy in which high-dose methotrexate-based regimens are used as well as intraocular injections of methotrexate and rituximab (anti-CD20 antibody). Cranial and ocular external-beam radiotherapy is being used less often today. Further studies are needed to prevent the tumor formation in terms of eliminating antigenic load and inhibiting Bcell chemokines as well as to determine the optimal local and systemic chemotherapy and immunotherapy options in the management of PIOL.

Treatment of primary intraocular lymphoma with radiation therapy: A multi-institutional survey in Japan

This study evaluated the clinical features and treatment outcome of 15 patients with primary intraocular lymphoma. There were nine females, with a median age of 68 years. Thirteen patients presented with bilateral lesions and median time from the onset of symptoms to diagnosis was 12 months. All but one showed the B-cell phenotype. All patients received radiation therapy (RT) with a median of 41 Gy and 10 were administered chemotherapy as well. Three patients were treated with high-dose methotrexate and nine received prophylactic cranial irradiation (PCI) with a median of 30.6 Gy. Thirteen patients obtained a complete remission. The 2-year overall and disease free survival were 74% and 58%, respectively. Although only one patient experienced local recurrence, PCI did not prevent intracranial recurrence. One patient developed a grade 3 cognitive disturbance. It was concluded that ocular RT was effective to control primary lesions. However, some modifications are indispensable to improve outcomes.

Intraocular lymphoma: update on diagnosis and management.

Primary intraocular lymphoma (PIOL) is a subset of primary central nervous system lymphoma (PCNSL) in which lymphoma cells initially invade the retina, vitreous, or optic nerve head, with or without concomitant CNS involvement. The incidence of this previously rare condition has increased dramatically. Given its nonspecific presentation and aggressive course, PIOL provides a diagnostic and therapeutic challenge. We review the current strategies for diagnosis and treatment of PIOL and present our own experience with PIOL. Recent developments in the diagnosis of PIOL include immunohistochemistry, flow cytometry, cytokine evaluation, and molecular analysis. However, definitive diagnosis still requires harvesting of tissue for histopathology. Optimal treatment for PIOL remains unclear. Initial therapeutic regimens should include methotrexate-based chemotherapy and radiotherapy to the brain and eye. In addition, promising results have been seen with intravitreal methotrexate and autologous stem cell transplantation for recurrent and refractory disease. Efforts to further determine the immunophenotype and molecular characteristics of PIOL will continue to assist in the diagnosis of PIOL. Future studies are required to determine the role of radiotherapy and optimal local and systemic chemotherapeutic regimens.

Pharmacokinetics and toxicity of intravitreal chemotherapy for primary intraocular lymphoma.

To investigate the pharmacokinetics and toxicity of intravitreal chemotherapeutic agents in the rabbit eye for the potential treatment of primary intraocular lymphoma and other intraocular malignancies. The ocular pharmacokinetics of intravitreal methotrexate sodium (400 microg) was studied in 10 New Zealand white rabbits, and a single-compartment, first-order elimination model was used to calculate the drug half-life. With the use of these data, a treatment schedule using serial injections of intravitreal methotrexate and single injections of fluorouracil and dexamethasone sodium phosphate was developed. This schedule was studied in 4 New Zealand white rabbits to explore the combined toxicity of these agents. Methotrexate vitreous levels, following a 400-microg intravitreal injection, remained therapeutic (>0.5 microM) in the rabbit eye for 48 to 72 hours. Intravitreal methotrexate, combined with fluorouracil and dexamethasone, showed no evidence of drug toxicity as determined by electroretinography and histopathologic examination. A treatment schedule for primary intraocular lymphoma consisting of methotrexate intravitreal injections every 48 to 72 hours provides therapeutic drug concentrations in the vitreous and, in combination with fluorouracil and dexamethasone, appears to be safe in the rabbit eye. Although responsive to conventional chemotherapy or radiotherapy, recurrence of ocular involvement with primary central nervous system lymphoma occurs in more than 50% of treated cases. Anecdotal reports of the use of intravitreal chemotherapy for primary intraocular lymphoma have been encouraging. However, animal data on the pharmacokinetics and toxicity of combined intravitreal agents for the treatment of this disease are lacking.