Intraocular Lymphoma

Introduction

Lymphomas include tumors of lymphocytes, and traditionally, they have been divided into Hodgkin’s disease and non-Hodgkin’s lymphomas (NHLs). NHLs constitute the largest group of lymphomas and are further subdivided into B-cell or T-cell lymphomas [1, 2].

Over the years, the classification of NHL has evolved from being based on light microscopy findings to the current World Health Organization (WHO) classification of lymphomas that correlates the clinical characteristics of each lymphoma subtype with its morphological, immunophenotypical, and genotypical features [1]. In the 1960s, Rappaport [2] classified the disease according to its presumed cellular origin: lymphocytic, histiocytic, or undifferentiated. If both lymphocytes and histiocytes were seen, the disease was classified as a mixed cell type. The term reticulum cell sarcoma is a misnomer dating to the days when it was thought that the cell of origin of PVRL was the histiocyte [2]. On routine histological examination, the histiocytes show features indistinguishable from transformed lymphocytes [3]. Immunocytochemical techniques and in vitro lymphocyte function studies have shown that the so-called ocular reticulum cell sarcoma is a large cell lymphoma arising from transformed lymphocytes and not histiocytes [3]. A study of systemic diffuse histiocytic lymphomas showed that 55% were of B-cell origin, 35% had a null cell origin, 5% were of T-cell origin, and only 5% were of true histiocytic origin [4].

In 1978, Lukes and Collins [5] recognized the need to classify the disease in terms of B and T lymphocytes. They based their system on four cell types: the smallto medium-sized cleaved cell, the medium to large noncleaved cell, the large cytoplasmic phagocyte, and the dendritic reticulum cell [5]. Transformed B lymphocytes have immunoglobulins on their cell surface unlike histiocytes [3]. B-cell lymphomas are recognized by the demonstration of monoclonal surface immunoglobulins or, if absent, by immunoglobulin gene rearrangement using specific DNA probes. Characteristic rosetting with sheep red

blood cells and T-cell-specific monoclonal antibodies identify T-cell lymphomas [6]. Most cases of primary central nervous system (CNS) lymphoma (PCNSL) and primary intraocular lymphoma (PIOL) when typed were found to be of B-cell origin [7]. Brown et al. [8] reviewed the literature and found that 57 cases of intraocular lymphoma had been reported in which cell marker studies had been done. They found that 53% were of B-cell origin, 21% of T-cell origin, 10% of null cell origin, and 16% were polyclonal or untypable.

Several other classifications were developed in an attempt to classify the lymphomas according to their clinical behavior leading to considerable confusion. In the early 1980s, the National Cancer Institute sponsored a study to resolve the differences between the different classifications. The study found that each of the classifications was useful and none was superior to the other. As a result, the International Working Formulation of NHL for Clinical Usage was born [9]. Ten major cell types were identified, and these were graded according to malignant potential: low-, intermediate-, and high-grade malignant lymphomas. In time, this became the most widely used system. Paradoxically, as treatment protocols became more effective, the prognosis of the different grades changed. Cure rates for intermediate- and high-grade malignancies improved, whereas the death rates of low-grade malignancies increased when most patients relapsed and died from their disease. In addition, a major weakness of the above classification scheme is the lack of immunological typing.

In 1994, the International Lymphoma Study Group proposed the revised European-American lymphoma (REAL) classification where lymphomas were grouped as clinical-pathological entities [1]. Each entity was recognized to have a range of morphological grades and degrees of clinical aggressiveness. Thus, B-cell lymphomas are categorized into low-, intermediate-, or highgrade lymphomas. This is the classification currently adopted by the WHO [1]. Several subtypes of B-cell lymphomas are defined according to the stage of lymphocyte development where they arise [7, 10]. These stages include the pre-germinal,

germinal, or post-germinal stages. These can be differentiated by immunophenotyping and by checking for somatic mutations in the variable region gene of the immunoglobulin. Lymphomas that arise from pre-germinal cells usually do not manifest any somatic mutations. Lymphomas derived from germinal cells are characterized by somatic mutations that are ongoing. Postgerminal derived lymphomas have somatic mutations with only few or no ongoing mutations [7].

PIOL is a rather imprecise term, and Coupland and Damato [7] suggest that the various types of intraocular lymphoma be referred to according to their anatomic location and to whether or not they are primary or secondary at these sites. A distinction should be made between patients with PIOL with or without central nervous system (CNS) disease in which the intraocular involvement is usually vitreoretinal, patients with primary choroidal lymphoma, patients with primary iridal lymphoma, and patients afflicted by a systemic lymphoma with secondary uveal involvement [7]. According to the WHO classification, primary vitreoretinal lymphoma (PVRL) is usually of the diffuse large B-cell lymphoma (DLBCL) type with intermediateto high-grade malignant potential [1]. Gene expression profiling studies that include both chromosomal and immunohistochemical analyses subdivide DLBCL into three different types: activated B-cell DLBCL (ABC type), germinal center DLBCL (GCB type), and primary mediastinal (thymic large) B-cell DLBCL [7, 10]. Prognosis is dependent on this molecular subtype. Patients with the ABC subtype DLBCL have a much worse prognosis than patients with the GCB DLBCL. Immunophenotyping and somatic mutation analysis suggests that most PVRL is derived from an early post-germinal center B cell. Chromosomal translocation data identifies a subgroup of PVRL that is derived from germinal center B cells [7].

The objective of this chapter is to review the epidemiology, etiology, clinical findings, diagnosis, differential diagnosis, imaging, pathology, and management of intraocular lymphoma.

Historical Background

In 1951, Cooper and Riker [11] made the observation that an intraocular lymphoma could masquerade as an intraocular inflammatory condition. In 1955, Givner [12] reported a case of a woman who suffered from uveitis of an unknown cause and subsequently went on to develop PCNSL. Autopsy revealed intravitreal cells suggestive of PVRL. In 1968, Vogel et al. [13] reported a patient with PVRL who eventually developed neurological symptoms. The patient underwent a craniotomy, and the specimen revealed similar histopathologic findings to the enucleated eye. CNS involvement did not occur from contiguous spread from the eye through the optic nerve. In another autopsy study, the optic nerve was not involved despite involvement of both eye and CNS. However, in some cases, extension through the lamina cribrosa, and involvement of the optic nerve and orbital leptomeninges, has been demonstrated [14]. In 1968, Nevins et al. [15] reported the first isolated intraocular case confirmed by autopsy. Case 3, in the series reported by Barr et al. [16], referred to the autopsy findings in a patient with bilateral PVRL where the rest of the body was completely free of tumor. Investigators proposed that involvement of the eye and CNS was due to a multicentric origin of the tumor [13, 15, 16]. In 1972, Neault et al. [17] reviewed the Mayo Clinic experience with 17 PCNSL patients diagnosed by craniotomy. Of these 17 patients, 7 suffered from posterior uveitis. The uveitis was initially unilateral but eventually became bilateral. They noticed that uveitis was not present in any other type of intracranial tumor. None of the eyes were examined microscopically. Therefore, it was impossible to determine if the ocular findings represented neoplastic involvement, primary inflammation, or an inflammatory process secondary to or coexistent with neoplastic involvement of the uveal tract or retina. On the other hand, of 19 cases of PCNSL seen at the Massachusetts General Hospital, only one had uveitis [18]. Kennerdell et al. [19] reported a fatal case of PCNSL accompanied by uveitis. On histopathology, the

vitreous was clear of neoplastic cells. They suggested that initially the ocular involvement is a benign inflammatory process that over time evolves into a neoplastic one.

In the early days, diagnosis of PVRL or PCNSL was made by craniotomy with debulking of the mass, enucleation of a blind painful eye, or during an autopsy [11–13, 15, 16]. In the 1970s, first vitreous aspiration and then pars plana vitrectomy were employed to obtain cytological material to diagnose PVRL earlier [20, 21]. Rockwood et al. [22] suggested that pars plana vitrectomy and/or lumbar puncture should be employed prior to the consideration of craniotomy. By the late 1980s, it was well established that PVRL forms part of the spectrum of PCNSL. In patients with PCNSL, extracranial involvement, other than the eye, is rare. Both solitary PVRL and that associated with PCNSL usually involve the vitreous, retinal pigment epithelium (RPE), and retina. Very rarely, an association of uveal tract PIOL and PCNSL has been reported.

Epidemiology

NHL usually arises from lymph nodes, but up to 25% of NHLs are of extranodal origin. Approximately 1.6% of NHLs occur intraocularly and 4.5% in the CNS. However, for unknown reasons, the incidence of PCNSL in the USA has been increasing over the years [23]. Eby et al. [24] reported 2.7 cases per 10 million people in 1972–1974 compared to 7.5 cases per 10 million people in 1982–1984. The incidence of PVRL is unknown, but it has been reported that about 20% of patients with PCNSL go on to develop PVRL [23, 25]. A major risk factor for the development of PCNSL and PVRL is immunosuppression [23]. Transplant recipients, acquired immune deficiency syndrome (AIDS) patients, and children with congenital immunodeficiencies are at an increased risk of developing PCNSL. However, the increased number of immunosuppressed patients does not explain the rise in cases of PCNSL [23].

Even though PVRL has been reported in patients as young as 15 years of age, it typically

remains a disease of middle age or older people [25]. The average age of affected individuals is 58 years old, which is similar to the average age of 55 years old for PCNSL. With respect to PVRL, women appear to be slightly more commonly affected than men by a ratio of 1.5–1. In contrast, men appear to be slightly more commonly affected than women by a ratio of 1.7–1 in PCNSL. There appears to be no predilection for race [23].

Approximately 80% of cases of PVRL have bilateral involvement. At some point in their disease, 66% of patients with PVRL manifest CNS involvement. Of these, 15–20% presented with CNS disease an average of 18 months prior to the development of ocular symptoms [23, 25]. Forty-five to sixty-six percent had PVRL before the diagnosis of PCNSL. The time of onset from ocular symptoms to the development of CNS symptoms ranged from less than 1 month to 10 years with an average of 21 months. Fifteen percent were diagnosed with concurrent PCNSL and PVRL. About 25% of patients were reported to have solely ocular involvement. Uveal infiltration is the typical ocular manifestation secondary to metastasis from a systemic lymphoid malignancy. Only 5% of patients with PVRL show subsequent systemic involvement. Another 5% of patients show concurrent intraocular, systemic, and CNS involvement [13, 14, 16, 21].

Etiology

Two hypotheses have been proposed for the origin of PVRL and PCNSL [23]. The first states that an infectious or inflammatory process, probably viral, attracts into the CNS or eye a nonneoplastic, reactive population of lymphocytes. The inflammatory cell population undergoes transformation into neoplastic cells by some second event in the local site(s). A second theory proposes that B lymphocytes in a lymph node or extranodal site are activated, caused to proliferate, and transformed to become neoplastic. These neoplastic cells spread hematogenously but aggregate only in sites within the CNS or eye. In the meantime, the true primary site remains obscure and undetected.

The factors involved in cell transformations remain unclear. Low-dose immunosuppressive therapy seems to be harmful, leading to the belief that acquired immune dysfunction plays a role in the disease [21, 23]. Renal transplant patients are at an increased risk for malignancies. NHL was the most common type of tumor in these patients. It is thought that this occurs through depression of the immunological surveillance function. Cases of PVRL and PCNSL in transplant recipients maintained on immunosuppressive therapy have been reported [26]. With the appearance of the AIDS epidemic in the early 1980s, it was noticed that the incidence of NHL in these patients increased. Despite the estimate that 3% of all AIDS patients will develop PCNSL during the course of their disease, there have been only few reports of PVRL cases in AIDS patients [27, 28].

Clinical Findings and Differential

Diagnosis

PVRL is a unique disease in its protean manifestations. The clinical findings are quite nonspecific and diverse. These depend on whether the RPE, optic nerve, vitreous, or retina is most extensively involved. It can present as vitreous infiltration, intraretinal, subretinal, or subpigment epithelial masses; as a vasculitic process; or as a localized or diffuse retinal necrosis. Thus, PVRL is a paradigm for the spectrum of the manifestations of disease in the posterior pole: necrosis, vasculitis, multifocal retinochoroiditis, or mass lesions. It is not surprising then that diagnosis is often delayed with fatal consequences since early diagnosis and treatment appear to result in better disease control and survival [29].

Most patients present with a painless loss of vision, floaters, or both [7, 25, 30]. Less common presentations of the disease include a red eye, photophobia, and pain [13, 16, 21].

Pseudohypopyon has been seen in a handful of cases [16]. In one case, it mimicked late postoperative endophthalmitis. In addition, certain cases of secondary glaucoma have been due to PVRL. Rubeosis iridis with neovascular angle

closure, accumulation of cellular debris, and synechial closure secondary to inflammation account for the mechanisms of the glaucoma [7].

Vitritis has virtually been reported in every case of PVRL and may vary from infiltration of the vitreous with scattered cells to large aggregates. A posterior vitreous detachment is often present with collections of tumor cells on the detached posterior face [7]. Traditionally, it has been emphasized that PVRL is a common masquerader in the elderly [7, 11, 13, 16, 25, 30]. The typical patient is an older individual with vitritis that is resistant to corticosteroid treatment. However, in a series of newly diagnosed uveitis in 58 patients older than 60 years, 19 patients were suspicious for PVRL. They underwent diagnostic vitrectomy, and only 1 case of PVRL was found (3.4% prevalence). [31]

Initial infiltrations of the lymphoma cells in the sub-RPE space produce small yellow-white placoid lesions that resemble lesions of the multiple evanescent white dot syndrome or punctate inner choroidopathy [7, 32]. As the lesions grow and become elevated, they may resemble multifocal choroiditis, birdshot choroidopathy, or acute multifocal placoid pigment epitheliopathy. Further expansion and solid volume gain leads to multiple, large sub-RPE tumors with sharply circumscribed, yellow-white, dome-shaped masses covered by fine mottled and attenuated pigment epithelium (Fig. 13.1a, b) [32]. Gass et al. [32] consider this clinical picture pathognomonic for PVRL. Nevertheless, these nodular lesions can be mistaken as sarcoidosis, tuberculosis, brucellosis, metastatic lesions, or the Vogt-Koyanagi- Haradadisease[6].Thelesionsmayspontaneously undergo complete necrosis and resolution, leading to atrophic or disciform scars simulating the ocular histoplasmosis syndrome [6, 32].

The lymphomatous process may then infiltrate the overlying retina producing white or grayish-green intraretinal lesions with fluffy outlines that rapidly become confluent obscuring the underlying RPE deposits (see Fig. 13.1) [6, 7, 32]. The retinal capillaries may be disrupted causing focal intraretinal hemorrhages. Arterial and venous sheathing have figured prominently in some cases of PVRL (Fig. 13.2).

Fig. 13.1 Subretinal pigment epithelium (RPE) elevations with sharply circumscribed, yellowwhite, dome-shaped masses covered by fine, mottled, and attenuated pigment epithelium.

(a) Note two lesions in the right eye, nasal to the optic disc and temporal to the fovea. (b) One yellowish lesion temporal to the fovea in the left eye (Courtesy of Raul Vianna, M.D.)

Fig. 13.2 Lymphomatous process infiltrating the overlying retina producing white intraretinal lesions with fluffy outlines that rapidly become confluent and obscure the underlying retinal pigment epithelium. Arterial and venous sheathing have figured prominently in some cases of intraocular lymphoma

The resulting clinical picture of a necrotizing retinitis may be confused with toxoplasmosis, acute retinal necrosis secondary to herpetic

infection, CMV retinitis, syphilitic retinitis, Whipple’s disease, Candida endophthalmitis, sarcoidosis, frosted branch angiitis, Eales disease, Behcet’s disease, systemic lupus erythematosus, HTLV-1-associated uveitis, and multiple sclerosis [6, 7]. Extension of the hemorrhage through the internal limiting membrane can lead to vitreous hemorrhage. Plaques of neoplastic cells in a retinal artery wall leading to retinal artery occlusion have been reported [32]. In other cases, the retina is edematous, and if the macula is involved, cystoid macular edema (CME) results [16, 20]. Exudative retinal detachment has also been reported [33].

A difficult situation occurs in AIDS patients with retinal lesions that are being treated with protease inhibitors. As their CD4+ count rises, a syndrome known as immune recovery uveitis may occur. Vitreous inflammation in conjunction with the aforementioned retinal lesions may lead one to the erroneous diagnosis of PVRL [27].