Intraocular lymphoma: a clinical perspective

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.     

原发性眼内淋巴瘤

原发性眼内淋巴瘤是一种少见的眼部恶性肿瘤，其淋巴瘤病理分类为结节外型弥漫型大细胞B细胞淋巴瘤，属于原发性中枢系统淋巴瘤（PCNSL）的一种。近年来发病率逐渐上升，在过去的20a里，美国PCNSL的发病率增长了3倍。该病临床表现无特异性，往往表现为假性葡萄膜炎，玻璃体或病变组织细胞病理学检查是诊断的金标准；但由于玻璃体活检手术，标本保存和病理诊断方法要求较高，所以诊断困难。治疗上主要应用大剂量甲氨蝶呤治疗。由于往往有神经系统受累，预后不佳，随着治疗方法的改进PIOL的平均存活率已经从1～1．5a提高到3a以上。     

原发性眼内淋巴瘤

原发性眼内淋巴瘤是一种少见的眼部恶性肿瘤,其淋巴瘤病理分类为结节外型弥漫型大细胞B细胞淋巴瘤,属于原发性中枢系统淋巴瘤(PCNSL)的一种。近年来发病率逐渐上升,在过去的20a里,美国PCNSL的发病率增长了3倍。该病临床表现无特异性,往往表现为假性葡萄膜炎,玻璃体或病变组织细胞病理学检查是诊断的金标准;但由于玻璃体活检手术,标本保存和病理诊断方法要求较高,所以诊断困难。治疗上主要应用大剂量甲氨蝶呤治疗。由于往往有神经系统受累,预后不佳,随着治疗方法的改进PIOL的平均存活率已经从1~1.5a提高到3a以上。     

Primary vitreoretinal lymphoma

Primary vitreoretinal lymphoma (PVRL) is a rare ocular lymphoid malignancy, which consists a subset of primary central system lymphoma (PCNSL) and the most common type of intraocular lymphoma. The involvement of eyes is estimated to be approximately 20% of PCNSL, but the brain involvement may be up to 80% of PVRL. Typically, PVRL is a high grade B-cell malignancy of the retina and needs to be assorted from choroidal low-grade B-cell lymphomas. Very often PVRL masquerades and can be erroneously diagnosed as chronic uveitis, white dot syndromes or other neoplasms. Establishing an accurate diagnosis may involve cytology/pathology, immunohistochemistry, flow cytometry, molecular pathology and cytokine profile analysis. There is inadequate information about PVRL’s true incidence, ethnic/geographical variation and pathogenetic mechanisms. The therapeutic approach of PVRL involves aggressive chemotherapy and radiation therapy. Although PVRL tends to have a good response to the initial treatment, the prognosis is poor and the survival restricted due to the high relapse rates and CNS involvement.     

Understanding intraocular lymphomas

The purpose of this review is to describe the clinical features, pathology and molecular biology of intraocular lymphomas, which represent a heterogenous group of malignant neoplasms; to propose an anatomical classification of these tumours according to whether they occur in the retina or uvea; and to overview laboratory investigations and highlight factors required for successful biopsy. Recent findings show that retinal lymphomas are high-grade (i.e. aggressive), B-cell malignancies and are associated with a poor prognosis, with most patients dying of central nervous system disease. Immunophenotyping and somatic mutation analyses indicate that these lymphomas are probably derived from early post-germinal centre cells. Primary choroidal lymphomas are typically low-grade (i.e. indolent), B-cell tumours with morphological, immunophenotypical and genotypic features similar to extranodal marginal zone B-cell lymphomas (EMZL) elsewhere in the body. The putative cell of origin is the post-germinal centre (memory) B cell. Primary iridal lymphomas are very rare, with an equal distribution of B- and T-cell types and with a variable clinical course, most patients succumbing to their disease as a result of systemic dissemination. Primary lymphomas limited to the ciliary body are exceptionally rare. Secondary uveal lymphomas/leukaemias occur in patients with advanced systemic lymphoma or leukaemia, respectively. In summary, the term 'primary intraocular lymphoma (PIOL)' is imprecise. It would be preferable to refer to the various forms of intraocular lymphoma according to whether they are retinal, choroidal, ciliary or iridal and whether they are primary or secondary in these locations.     

玻璃体视网膜淋巴瘤的诊断进展

玻璃体视网膜淋巴瘤(VRL)是罕见的恶性非霍奇金淋巴瘤,因无特异性临床表现,对其早期、正确地诊断仍面临很大的挑战。病理细胞学诊断是VRL诊断的金标准,但其诊断仍需要结合临床表现、影像学检查、免疫学及分子学检测等。随着诊断技术的进步,更加高效的细胞学检查及辅助诊断技术不断被探索。细胞因子及眼内淋巴瘤诊断的白介素评分(ISOLD)、髓样分化因子88(MYD88)基因突变及二代测序检测技术有良好的诊断效能而逐渐成为重要的辅助诊断手段及研究热点。     

Primary Intraocular Lymphoma: A Review

Primary intraocular lymphoma (PIOL) is a type of primary central nervous system lymphoma (PCNSL). It is the most common neoplastic masquerade syndrome involving the eye. Its protean ocular manifestations, plus in many cases the initial positive response to corticosteroid therapy for presumed uveitis, delay accurate diagnosis. A high index of suspicion is essential, followed by tissue biopsy with cytology and ancillary studies. Current treatment is based on chemotherapy featuring high-dose methotrexate and radiation therapy. Prognosis is poor due to CNS involvement, but newer therapies have had some success in prolonging survival.     

原发性眼内淋巴瘤

原发性眼内淋巴瘤是可以累及中枢神经系统的少见的眼部肿瘤,在眼部临床表现无特异性,主要累及玻璃体和视网膜,临床误诊率高,患者预后差.本文就原发性眼内淋巴瘤的临床特点、诊断要点及治疗等方面作一较全面综述,以引起临床医生重视.     

Primary intraocular lymphoma

Primary intraocular lymphoma (PIOL) is a rare extranodal Non-Hodgkin lymphoma (NHL), involving the retina, the subretinal space, vitreous body and/or optic nerve. The majority of PIOL are diffuse large cell B-cell lymphomas according to the new W.H.O. lymphoma classification with an immunophenotype suggesting an origin from germinal centre cells. PIOL occurs independently or together with primary central nervous system lymphoma (PCNSL), and often presents in the form of a steroid-resistant uveitis. PIOL is one of the most challenging intraocular tumours to diagnose. Cytological examination of vitreal aspirates remains the gold standard for exclusion of neoplastic disease in patients with idiopathic uveitis. Various techniques, particularly the polymerase chain reaction analysing clonal rearrangements of the immunoglobin heavy chain or the T-cell receptor genes, prove to be useful adjuncts. Chorioretinal biopsies increase the chances of diagnosing or excluding a PIOL involving the retina and choroid. Furthermore, they allow exact subtyping of the malignant lymphoma when present, enabling exclusion of an ocular manifestation of a systemic lymphoma. Currently, most PIOL/PCNSL are treated with systemic chemotherapy. Ocular recurrences are often treated with radiotherapy, and increasingly with intraocular methotrexate. Although the prognosis of patients with PCNS/PIOL remains poor, newer methods enabling earlier diagnosis establishment and treatment are gradually increasing overall survival.     

Primary intraocular lymphoma

A 65-year-old woman complained of blutrred vision in the left eye. On examination of that eye, vitreous opacity and intracameral cells were found. The patients was treated with topical and systemic corticosteroids. The vitreous opacity reduced slightly but recurred. Results of a vitreous biopsy showed B-cell malignant lymphoma. After radiotherapy, the vitreous opacities diminished. Early cytologic examination of vitreous cells should be performed in patients with steroid-resistant, idiopathic uveitis.     

原发性眼内淋巴瘤

原发性眼内淋巴瘤是一种眼部相对少见的高度恶性的非霍奇金淋巴瘤,属于原发性中枢神经系统淋巴瘤,近年来发病呈上升趋势,其临床诊断有一定难度。本文对原发性眼内淋巴瘤的流行病学、临床表现、影像学检查、细胞学和组织病理学检查,生化和分子生物学检查、鉴别诊断、治疗和预后等进行综述。     

Primary intraocular lymphoma arising during methotrexate treatment of temporal arteritis

CASE REPORT: Primary intraocular lymphoma arose over a period of 9 months in the left eye of an 81-year-old woman who was blind in both eyes from temporal arteritis. During this period, she was treated with prednisone and methotrexate. Following a sudden total hyphema, the eye was enucleated. Examination revealed that, in addition to iris neovascularisation and central retinal artery occlusion, the neurosensory retina was replaced by atypical lymphocytes. COMMENTS: Histological and immunohistochemical studies confirmed the presence of a lymphoma with features indicative of an immunosuppression-related disorder. The relationship of the lymphoma to the vascular changes within the eye is discussed.     

眼附属器淋巴瘤组织病理学及免疫表型研究

目的 探讨眼附属器淋巴瘤的临床特点，组织学分型及免疫表型。方法 收集眼附属器淋巴瘤病例33例。采用HE染色常规观察形态学特点。采用多种抗体标记B淋巴细胞，行T细胞鉴别，检测细胞增殖活性及探讨B细胞起源，进行免疫组织化学染色诊断和鉴别诊断，判定免疫表型，细胞分化及增殖状态。结果 29例（87.9%)瘤细胞B细胞标记物CD20，CD79a阳性，并出现k或λ的克隆性增生，诊断为结外边缘区B细胞淋巴瘤，黏膜相关淋巴组织型（MZL-MALT）。2例（6.1%)诊断为弥漫性大B细胞淋巴瘤。1例（3%）为组织学典型的浆细胞瘤分化，1例（3%）为此部位极为罕见的T细胞淋巴瘤，免疫表型为T细胞分化。结论 MZL-MALT型淋巴瘤是眼附属器淋巴瘤中最常见的一类，免疫组化抗体标记在诊断和鉴别诊断中起重要作用，其他类型的淋巴瘤较少见。     

Variations in the Presentation of Primary Intraocular Lymphoma: Case Reports and a Review

Primary intraocular lymphoma is a distinct subset of primary non-Hodgkin's lymphoma of the central nervous system (CNS). Diagnosis can be difficult and is often delayed, as the clinical presentation can mimic a number of other ocular conditions. This report describes four different presentations of intraocular lymphoma and focuses on its modes of clinical presentation. Primary intraocular lymphoma can present with a wide variety of manifestations frequently mimicking diffuse uveitis that is refractory to corticosteroids. Subretinal pigment epithelium tumors may be seen. However, other presentations may include multiple deep white dots in the retina secondary to tumor infiltration; retinal infiltration, causing a necrotizing retinitis; or infiltration of the retinal vasculature, causing arterial or venous obstruction. Finally, optic nerve invasion may be seen. CNS lymphoma develops in the majority of patients before, in conjunction with, or after the development of eye disease. Intraocular lymphoma often has a fatal outcome, but recognition of its modes of presentation facilitates early diagnosis and treatment that may improve prognosis.     

Diagnosis of intraocular lymphoma

Purpose: To review current techniques for the diagnosis of intraocular lymphoma. Methods: Literature review. Results: There are a limited number of small case series and case reports reporting the diagnosis of intraocular lymphoma. Limitations in the ability to diagnose lymphoma through cytologic examination of the vitreous has led to investigations into immunohistochemistry either manually or by automated cytofluorography, intraocular cytokine determinations, and polymerase chain reaction of the vitreous or tissue lymphoid cells to detect gene rearrangements in the IgH, bcl-2, or T-cell receptor gamma gene. Data regarding diagnostic efficiency of the various testing strategies is limited by small patient numbers. Careful handling of the vitreous specimen and adequate laboratory and pathological support is critical. Conclusions: Despite a proliferation of new techniques for the diagnosis of intraocular lymphoma, none is clearly superior. Use of multiple testing strategies may improve diagnostic yield.     

Primary vitreoretinal natural killer/T-cell lymphoma with breast involvement: A case report and review of the literature

A 50-year-old woman developed recurrent vitreous opacities in her left eye. The first diagnostic vitrectomy revealed no significant abnormality. Optical coherence tomography showed multiple high-density reflective nodules. The ratio of interleukin-6 to interleukin-10 was over 1 in her aqueous humor, and Epstein-Barr virus was present. A conventional immunohistochemistry examination of vitrectomy specimens was diffusely positive for CD2, CD3, and Ki-67. Highly metabolic nodules were found in her right breast on positron emission tomography-computed tomography scan. Immunohistochemistry of the breast biopsy was suggestive of natural killer/T-cell lymphoma. Considering the homology between the two lesions, combined with ancillary cytokine, cytology, and flow cytometry findings, the final diagnosis was primary vitreoretinal natural killer/T-cell lymphoma with involvement of the breast. The lymphoma resolved with chemotherapy, intravitreal injection of methotrexate, and ocular radiotherapy. This case shows that primary vitreoretinal natural killer/T-cell lymphoma can present with concomitant systemic involvement. We reviewed relevant published literature and summarized some new approaches that make the diagnosis easier and faster; however, the cytopathologic analysis of intraocular fluid is irreplaceable. An effective treatment strategy is still a matter of speculation.     

Ocular adnexal lymphoma: Five case reports and a literature review

This article reports the clinical course and treatment of ocular adnexal lymphoma based on a retrospective review of five cases with a histologically approved ocular adnexal lymphoma at Kaohsiung Veterans General Hospital over 10 years. Extranodal B-cell lymphoma in the orbit, lacrimal gland, eyelid, or conjunctiva was found in these patients. Four of them were female, and they were aged 45–64 years. All patients were also consulted with hematologists for possible systemic involvement and therapeutic plan. The patient with retrobulbar and orbital apex involvement received systemic chemotherapy. The patient with lacrimal gland involvement experienced tumor recurrence after local excision, and therefore received adjuvant radiotherapy. The remaining three patients had localized lymphoma on the eyelid or bulbar conjunctiva, and they all showed no recurrence after surgical excision. The incidence of ocular adnexal lymphoma has risen worldwide over the last few decades. Although most cases are confined to ocular adnexal, some may also be associated with disseminated lymphoma. Accurate diagnosis and staging is mandatory for appropriate treatment. Generally speaking, localized and low-grade ocular adnexal lymphoma involved eyelid or conjunctiva seem to have good outcome after surgical excision only. Systemic chemotherapy should be considered in patients with advanced disease or systemic manifestations, and radiotherapy also offers a good choice for lacrimal gland lymphoma.